Case Discussions in

OBSTETRICS AND GYNECOLOGY

Case Discussions in AND GYNECOLOGY

Editors

YM Mala MD DNB Professor

Madhavi M Gupta MS Associate Professor

Swaraj Batra MBBS MD FICOG Director-Professor and Head Department of Obstetrics and Gynecology Maulana Azad Medical College and Lok Nayak Hospital, New Delhi, India

®

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD New Delhi • St Louis (USA) • Panama City (Panama) • London (UK) • Ahmedabad Bengaluru • Chennai • Hyderabad • Kochi • Kolkata • Lucknow • Mumbai • Nagpur Published by Jitendar P Vij Jaypee Brothers Medical Publishers (P) Ltd

Corporate Office 4838/24 Ansari Road, Daryaganj, New Delhi - 110002, India, Phone: +91-11-43574357, Fax: +91-11-43574314

Registered Office B-3 EMCA House, 23/23B Ansari Road, Daryaganj, New Delhi - 110 002, India Phones: +91-11-23272143, +91-11-23272703, +91-11-23282021 +91-11-23245672, Rel: +91-11-32558559, Fax: +91-11-23276490, +91-11-23245683 e-mail: [email protected], Website: www.jaypeebrothers.com

Offices in India • Ahmedabad, Phone: Rel: +91-79-32988717, e-mail: [email protected] • Bengaluru, Phone: Rel: +91-80-32714073, e-mail: [email protected] • Chennai, Phone: Rel: +91-44-32972089, e-mail: [email protected] • Hyderabad, Phone: Rel:+91-40-32940929, e-mail: [email protected] • Kochi, Phone: +91-484-2395740, e-mail: [email protected] • Kolkata, Phone: +91-33-22276415, e-mail: [email protected] • Lucknow, Phone: +91-522-3040554, e-mail: [email protected] • Mumbai, Phone: Rel: +91-22-32926896, e-mail: [email protected] • Nagpur, Phone: Rel: +91-712-3245220, e-mail: [email protected]

Overseas Offices • North America Office, USA, Ph: 001-636-6279734, e-mail: [email protected], [email protected] • Central America Office, Panama City, Panama, Ph: 001-507-317-0160, e-mail: [email protected] Website: www.jphmedical.com • Europe Office, UK, Ph: +44 (0) 2031708910, e-mail: [email protected]

Case Discussions in Obstetrics and Gynecology

© 2011, Jaypee Brothers Medical Publishers

All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editors and the publisher.

This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure accuracy of material, but the publisher, printer and editors will not be held responsible for any inadvertent error (s). In case of any dispute, all legal matters are to be settled under Delhi jurisdiction only.

First Edition: 2011

ISBN: 978-93-5025-129-4 Typeset at JPBMP typesetting unit

Printed at Dedicated to all our patients who have taught us the art of case discussion and will continue to do so

Contributors

Anjali Tempe Avantika Gupta Professor Resident Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and Lok Nayak Hospital Lok Nayak Hospital New Delhi, India New Delhi, India

Anvika Binni Makkar Senior Resident Senior Resident Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and Lok Nayak Hospital Lok Nayak Hospital New Delhi, India New Delhi, India

Arima Nigam Chanchal Gupta Assistant Professor Senior Resident Department of Cardiology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and G B Pant Hospital Lok Nayak Hospital New Delhi, India New Delhi, India Ashok Kumar Chandan Dubey Professor Assistant Professor Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and Lok Nayak Hospital Lok Nayak Hospital New Delhi, India New Delhi, India Asmita Muthal Rathore Deepti Goswami Professor Professor Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and Lok Nayak Hospital Lok Nayak Hospital New Delhi, India New Delhi, India viii Case Discussions in Obstetrics and Gynecology

Devender Kumar Maulana Azad Medical College and Assistant Professor Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Meenakshi Garg New Delhi, India Senior Resident Department of Obstetrics and Gynecology Gauri Gandhi Maulana Azad Medical College and Professor Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Minu New Delhi, India Resident Department of Obstetrics and Gynecology Jyoti J Banavaliker Maulana Azad Medical College and Resident Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Mumtaz Khan New Delhi, India Senior Specialist Department of Obstetrics and Gynecology Krishna Agarwal Maulana Azad Medical College and Associate Professor Lok Nayak Hospital, New Delhi Department of Obstetrics and Gynecology Maulana Azad Medical College and Nancy Singh Lok Nayak Hospital Resident New Delhi, India Department of Obstetrics and Gynecology Maulana Azad Medical College and Latika Sahu Lok Nayak Hospital Associate Professor New Delhi, India Department of Obstetrics and Gynecology Maulana Azad Medical College and Neha Gupta Lok Nayak Hospital Senior Resident New Delhi, India Department of Obstetrics and Gynecology Leena Wadhwa Maulana Azad Medical College and Assistant Professor Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Neha Singh Resident New Delhi, India Department of Obstetrics and Gynecology Madhavi M Gupta Maulana Azad Medical College and Associate Professor Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Contributors ix

Nilanchali Singh Maulana Azad Medical College and Senior Resident Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Reva Tripathi New Delhi, India Director Professor Department of Obstetrics and Gynecology Pooja Pundhir Maulana Azad Medical College and Senior Resident Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Ronita Devi New Delhi, India Senior Resident Department of Obstetrics and Gynecology Poonam Sachdeva Maulana Azad Medical College and Junior Specialist Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Rupali Goyal New Delhi, India Senior Resident Department of Obstetrics and Gynecology Puneet K Kochhar Maulana Azad Medical College and Senior Resident Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Sangeeta Bhasin New Delhi, India Chief Medial Officer (NFSG) Department of Obstetrics and Gynecology Rachna Sharma Maulana Azad Medical College and Junior Specialist Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Sangeeta Gupta New Delhi, India Professor Department of Obstetrics and Gynecology Raksha Arora Maulana Azad Medical College and Professor Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Saritha Shamsunder New Delhi, India Junior Specialist Department of Obstetrics and Gynecology Renu Tanwar Maulana Azad Medical College and Assistant Professor Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India x Case Discussions in Obstetrics and Gynecology

Saumya Sudha Prasad Trainee Professor Vardhmaan Mahaveer Medical College and Department of Obstetrics and Gynecology Safdarjung Hospital Maulana Azad Medical College and New Delhi, India Lok Nayak Hospital Savita Sigchi New Delhi, India Resident Department of Obstetrics and Gynecology Sushmita Behera Maulana Azad Medical College and Senior Resident Lok Nayak Hospital Department of Obstetrics and Gynecology New Delhi, India Maulana Azad Medical College and Lok Nayak Hospital Shakun Tyagi New Delhi, India Assistant Professor Department of Obstetrics and Gynecology Swaraj Batra Maulana Azad Medical College and Lok Nayak Hospital Director-Professor New Delhi, India Department of Obstetrics and Gynecology Maulana Azad Medical College and Shalini Khanna Lok Nayak Hospital Senior Resident New Delhi, India Department of Obstetrics and Gynecology Maulana Azad Medical College and Usha Manaktala Lok Nayak Hospital Director-Professor New Delhi, India Department of Obstetrics and Gynecology Sharda B Ghosh Maulana Azad Medical College and Assistant Professor Lok Nayak Hospital Department of Obstetrics and Gynaecology New Delhi, India Lady Hardinge Medical College New Delhi, India Vijay Zutshi Shikha Sharma Senior Specialist Chief Medical Officer Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and Lok Nayak Hospital Lok Nayak Hospital New Delhi, India New Delhi, India Sonali Gupta YM Mala Resident Professor Department of Obstetrics and Gynecology Department of Obstetrics and Gynecology Maulana Azad Medical College and Maulana Azad Medical College and Lok Nayak Hospital Lok Nayak Hospital New Delhi, India New Delhi, India Foreword

Obstetrics and gynecology is a very challenging specialty which requires combination of both good clinical as well as surgical skills. This book, entitled Case Discussions in Obstetrics and Gynecology is a complete book covering all the common problems in a comprehensive manner easily understood by the students. The case discussions in question and answer pattern will be helpful to students in viva as well as theory examinations. Each discussion is followed by the ideal management and recent advances in that area along with adequate references. The authors’ endeavor to review the various cases in an elaborate manner is commendable. I recommend this book since it will be helpful to students for learning a particular topic as well as for the final revision before the examination. I wish this book and its readers all the success.

AK Agarwal Dean Maulana Azad Medical College New Delhi

Preface

Case discussions are an integral part of teaching in medicine. Since time immemorial, all practitioners of medicine have been learning on patients. Medicine has been evolving at a fast pace with many advances in science and technology and new discoveries every other day. With advent of modern methods of teaching, there have been drastic changes in all aspects. But case discussions continue to hold the same importance may be, more because with the availability of a multitude of investigations and diagnostic aids we might be missing on to something when we rely more on these. Trainees and young practitioners need to realize the significance of a good history and a thorough clinical examination before ordering only the most required investigations to arrive at the right diagnosis. Also, case discussions are part of all examinations and this book tries to present the near ideal case discussion of the commonly encountered problems in obstetrics and gynecology on a daily basis. Case Discussions in Obstetrics and Gynecology is an ideal combination of evidence-based knowledge and years of clinical experience of faculty in patient management and conducting both undergraduate and postgraduate exams. It includes recent advances in this field which might not be included in the textbooks. The approach in this book is problem based and tells how a list of differential diagnosis can be eliminated step-wise before clinching the diagnosis. In standard textbooks the approach is retrospective that is, what symptoms and signs can be found or expected in a particular pathology. The book is in the form of question and answers to make it more problem based and telling the art of postgraduate and undergraduate exams and reaching a clinical diagnosis. This book, prepared and produced by the Department of Obstetrics and Gynecology at the Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi contains the long teaching experience of the faculty. They are teachers who have been training postgraduate students for a number of years and are very well aware where even a well read, hard working student is likely to falter in the exam. Learning to diagnose a patient via a systematic approach is the key and basis of proper management. Many of the students after clearing the exam will go out in the society and practice what they have learnt during the course of their postgraduate training. Having a scientific basis made easier will help them to diagnose and treat patients correctly to their fullest capability. We invite you to join us on a roadmap to preserve and pass on the art of case discussions to the coming generations for the larger good of our patients.

YM Mala Madhavi M Gupta Swaraj Batra

Contents

SECTION 1: OBSTETRICS

1. with Previous Congenital Disorders...... 1 Sangeeta Gupta, Sonali Gupta 2. Recurrent Pregnancy Loss ...... 17 Madhavi M Gupta 3. Thrombophilia in Pregnancy...... 29 Shakun Tyagi 4. Anemia in Pregnancy...... 37 Usha Manaktala, Avantika Gupta 5. Diabetes in Pregnancy ...... 53 Ashok Kumar, Minu 6. Hypertension in Pregnancy ...... 63 Anjali Tempe, Nancy Singh, Ronita Devi 7. Heart Disease in Pregnancy ...... 75 Leena Wadhwa, Arima Nigam, Savita Sigchi 8. Fetal Growth Restriction ...... 87 Chandan Dubey 9. Rh Alloimmunization...... 98 Sangeeta Bhasin, Rupali Goyal, Anvika 10. Multiple Gestation ...... 117 Devender Kumar 11. Pregnancy with Previous Cesarean Section ...... 133 Renu Tanwar 12. Pregnancy with Previous Intrauterine Death of Fetus ...... 142 Krishna Agarwal xvi Case Discussions in Obstetrics and Gynecology

13. Preterm Labor ...... 148 Poonam Sachdeva, Chanchal Gupta, Jyoti J Banavaliker 14. Antepartum Hemorrhage ...... 159 Mumtaz Khan 15. HIV Positive Pregnancy ...... 182 Shikha Sharma 16. Septic Abortion: A Clinical Review ...... 198 Rachna Sharma, Susmita Behera

SECTION 2: GYNECOLOGY

17. ...... 207 Deepti Goswami 18. Approaches to Improve the Diagnosis and Management of ...... 219 Sudha Prasad, Shalini Khanna, Saumya 19. Fibroid ...... 231 YM Mala, Pooja Pundhir, Sharda B Ghosh 20. Prolapse Uterus ...... 245 Asmita Muthal Rathore 21. Vesicovaginal ...... 259 Latika Sahu 22. Abnormal Uterine ...... 285 Saritha Shamsunder, Meenakshi Garg 23. Approach to a Case of in a Young Patient ...... 302 Vijay Zutshi, Binni Makkar 24. Lump in Abdomen ...... 311 Reva Tripathi, Nilanchali Singh 25. Management of Abnormal Pap Smear and Cervical Cancer ...... 327 Raksha Arora, Neha Gupta 26. Postmenopausal Bleeding ...... 339 Swaraj Batra, Puneet K Kochhar 27. Carcinoma Vulva...... 355 Gauri Gandhi, Neha Singh Index ...... 365 SECTION 1: OBSTETRICS

Sangeeta Gupta, Sonali Gupta

1 Pregnancy with Previous Congenital Disorders

Fetal congenital disorders are an important cause weeks pregnancy and had level 2 ultrasound at of prenatal loss and perinatal morbidity and 19 weeks of gestation. She was diagnosed as mortality. Congenital disorders can be broadly occipitomeningomyelocele and opted to terminate classified into structural anomalies, aneuploides and the pregnancy. On neonatal review the diagnosis genetic disorders. Prenatal diagnosis is the science of occipitomeningomyelocele was confirmed and of identifying structural and functional no other gross congenital anomalies were detected. 1 abnormalities birth defects in the fetus. Prenatal The parents did not consent for postmortem diagnosis helps couples to make reproductive autopsy or chromosomal study. choices and the clinicians to provide appropriate counseling and optimize treatment. In the following Relevant History section, a case based approach to common Present Pregnancy congenital defects from each catogery will be discussed. • • History of exposure to drugs particularly which NEURAL TUBE DEFECTS interfere with folic acid metabolism CASE 1 • Any history of hyperthermia and hyperglycemia • Intake of folic acid in periconceptional period Mrs X 30 years old G3+1+0+1+0 with history of • History of consanguinity. both affected by neural tube defects (NTD) presented at 8 weeks and 3 days period of History of Previous Pregnancies gestation. In the first pregnancy patient had conceived spontaneously after one year of • Any history of folic acid intake in periconcep- marriage and did not seek any antenatal care. tional period. Patient delivered at a hospital and anencephaly • History of hyperthermia or hyperglycemia in was detected at birth. However, no comment was periconceptional period. made on presence or absence of other anomalies. • History of antifolate drug intake in periconcep- In the second pregnancy she booked at fifteen tional period. 2 Case Discussions in Obstetrics and Gynecology

• Mode of diagnosis of NTDs (prenatal ultrasound, If the woman is on antiepileptic therapy postnatal diagnosis) particularly valproate or multidrug therapy, it is • Associated malformations and dysmorphisms advisable to switch her to monotherapy in the to delineate genetic disorders preconceptional period and valproate should be • Fetal autopsy done or not replaced by lesser teratogenic drugs like phenytoin. • Fetal karyotype done or not Time to change the medication is before conception • Family history of neural tube defects. as organogenesis is almost complete in the first trimester. Examination Q.3. What are the high risk factors which In the first half of pregnancy, there may not be predispose to neural tube defect in fetus? anything remarkable in the examination. However, with advanced gestational age, polyhydramnios Ans: Neural tube defects are example of multi- may cause increased fundal height and presence of factorial inheritance. The following factors fluid thrill. The presentation of the fetus may be influence the development of neural tube defects: breech or face. 1. Environmental agents like diabetes, obesity, hyperthermia. 2. Antifolate medications: The antifolate Q.1. How will you counsel this woman? medications implicated in causation of NTD are Ans: The woman would be counseled on the issues valproate,2 carbamazepine, coumadin and regarding the risk of recurrence in this pregnancy. aminopterin. The risk of having a baby with neural tube defect Neural tube defects associated with type 1 in this pregnancy is about 10%. diabetes are more likely to be cervical and cervico- Anencephaly can be detected as early as thoracic; with valproic exposure lumbosacral 10 weeks of pregnancy and hence she would be defects and with hyperthermia anencephaly.3-5 advised an early . However, for the 3. Genetic Causes defects in the spinal cord patient would be taken • Family history up for level II sonography between 18 to 20 weeks • Autosomal recessive condition—Meckel- of pregnancy. Gruber syndrome • MTHFR gene polymorphism such as Q.2. If this woman comes in the preconceptional C677T and A1298C mutations are period what counseling should be done? associated with hyperhomocystinemia and Ans: She is advised to take high dose of folic acid folate insufficiency is thought to play a role supplementation (4 mg) starting 3 months prior to in the phenotypic expression of MTHFR conception. mutations.6 She will be counseled regarding the risk of • Recurrent NTD have been reported to be recurrence of NTD in this pregnancy and early associated with partial trisomy 2p22 and detection of NTDs by ultrasonography is advised. 20p, resulting from a maternally derived trans- If the woman is hyperglycemic, then she is location.7,8 referred to a physician for adequate control of her 4. Geographical Distribution glycemic status before she conceives. If her Certain populations in particular geographic glycemic status is not known then she would be areas have increased incidence of NTDs. United evaluated with blood sugar fasting and postprandial. Kingdom has the highest frequency of NTD that Pregnancy with Previous Congenital Disorders 3

is 1%1. In India, the incidence is 0.5-11 per 1000 70% reduction in recurrence rate.15,16 Similar doses births.9 are used in patients who are diabetic or on antifolate medication but data is limited about their benefit. Q.4. What is the significance of parental consanguinity in a case of pregnancies with Q.7. Disruption of folic acid metabolism recurrent neural tube defects? predisposes to which congenital abnormalities? Ans: There is evidence of major gene involvement Ans: Several congenital abnormalities like neural in familial neural tube defects with parental tube defects, cardiac defects, cleft lip and palate, consanguinity and is likely to be recessive in and even Down syndrome are known to arise, at inheritance. A single gene cause of recurrent NTD least in part from disturbance of folic acid metabolic is the Meckel-Gruber syndrome. It is a rare pathways. autosomal recessive disorder and carries a 25% risk of recurrence. Other features of this syndrome triad Q.8. Besides NTD folic acid intake prevents include polycystic kidneys and polydactyl.10,11 which other congenital malformations? Ans: Congenital heart diseases and cleft lip and Q.5. What is the recurrence risk for NTDs? palate are also prevented to certain extent by folic 17 Ans: Recurrence risk with one affected child is 3- acid intake. 4% and after two affected children it is 10%. Q.9. What is the screening strategy for neural The recurrence risk is 4-5% if one parent is defects? affected. The recurrence risk is 25% when NTD is part Ans: Universal screening of NTDs in antenatal of Meckel-Gruber syndrome. period is recommended as 95% of the cases are seen in the low risk populations. Recurrence risk for first degree relatives of The screening for open neural tube defects is affected children in 1 in 30 and second degree done by estimation of maternal serum alfa-feto- relatives is 1 in 220.12 protein (MSAFP) between 15-20 weeks of pregnancy. The levels are raised in open neural tube Q.6. What is the role of folic acid supplemen- defects. Cut-offs between 2 and 2.5 MOMs as upper tation in prevention of neural tube defects? limits yield detection rates of 100% for anencephaly Ans: There are two aspects in the administration and 85-94% for open spina bifida. For efficient of folic acid supplementation for prevention of MSAFP screening determination of accurate NTD- the timing and the dose.2 Pre-conceptional gestational age by first trimester scan is important. intake of folic acid, beginning 3 months prior to Other factors which influence MSAFP are maternal conception in the dose of 400 microgram daily has weight and ethnicity. been recommended for prevention of first occurrence of NTDs and should be continued Q.10. How are patients with elevated MSAFP through the first trimester of pregnancy13,14 evaluated? However, higher doses of folic acid supplementation Ans: For patients with elevated MSAFP, further (4 mg) are recommended for women at higher risk testing with targeted ultrasound or amniocentesis of NTDs. These include women with prior affected is required. Presently, the best approach to evaluate children or if the women or the partner has NTD. elevated MSAFP is ultrasound. Ultrasound In women with previous affected offspring there is evaluation is done to confirm the gestational age, 4 Case Discussions in Obstetrics and Gynecology rule out twin pregnancy, fetal demise and identify Ultrasound diagnosis of meningomylocele is structural defects that cause elevated MSAFP. frequently based on a cystic mass protruding from Targeted sonographic evaluation for spina bifida the dorsal vertebral bodies without skin covering. in high risk cases has sensitivity of about 97% and This is ideally seen in the transverse plane as a wide specificity of 100%. Amniocentesis for the separation of the lateral processes of lamina measurement of amniotic fluid AFP and the (Fig. 1.1). detection of acetylcholinesterase (AChE) has been Indirect sonographic signs of meningomylocele replaced by ultrasonography. have been found to be as important as visualization When no fetal abnormality is detected, MSAFP of the spinal lesion and are somewhat easier to elevation may be associated with adverse pregnancy image. These include ventriculomegaly, microcephaly, outcomes like fetal growth restriction, frontal bone scalloping (lemon sign) (Fig. 1.2), and oligohydramnios, placental abruption, preterm obliteration of the cisterna magna with either an membrane rupture, and even fetal absent cerebellum or abnormal anterior curvature death.18 However, optimal management is unclear of the cerebellar hemispheres (banana sign)20 and prenatal care for these women is not altered (Fig. 1.3). Banana and lemon sign are produced by unless specific complication arises. caudal displacement of cerebellar vermis, fourth ventricle and medulla constituting the Arnold- Q.11. What are the causes of raised MSAFP? Chiari II malformation. These findings are seen in Ans: In 50% of cases, incorrect dating will be over 95% of cases of neural tube defects in the identified and adjustment of initial value resolves middle of the second trimester. The banana sign the issue. and the lemon sign may not be present after 22 to Fetal demise is also associated with raised 24 weeks’ gestation. MSAFP. The presence of neural tissue in the meningeal The various structural defects associated with sac and level and length of the lesion should be raised MSAFP are open neural tube defects, fetal abdominal defects such as omphalocele and gastroschisis, sacrococcygeal teratoma, fetal urinary tract obstructions and urinal atresia.

Q.12. What are the causes of low MSAFP? Ans: Obesity, diabetes, chromosomal trisomies, gestational trophoblastic disease, fetal death, overestimated gestational age.

Q.13. What are the sonographic features in various neural tube defects? Ans: The antennal diagnosis of anencephaly is based on absence of fetal calvaria. Anencephaly can be identified by ultrasound as early as 10 weeks of gestation but should be reconfirmed by a scan at around 13 weeks because ossification of the skull in some cases may not be completed until that time.19 Fig. 1.1: Axial view of spina bifida Pregnancy with Previous Congenital Disorders 5

approximately 24 and 26 days after conception, respectively.

Q.15. How will you counsel and manage the couple if anencephaly is detected? Ans: Anencephaly is lethal and can be diagnosed accurately by antenatal ultrasound. In our country termination of pregnancy can be offered till 20 weeks of gestation as per the PNDT act. Fetal autopsy should be offered for all fetuses with anencephaly to detect other anomalies as it may form a part of genetic syndrome and helps in predicting the recurrence risk. In recurrent NTDs fetal and parental karyotyping Fig. 1.2: Lemon sign could be useful in the future management since partial trisomies are the implicated cause.22 However, couples who refuse termination are followed up with routine antenatal care. The woman is more likely to have complications like polyhydramnios, malpresentation (face, breech) and postmaturity. Polyhydramnios, may result from diminished fetal swallowing, secretion of cerebrospinal fluid directly into the amniotic cavity and excessive micturition. Postmaturity is a consequence of absent or hypoplastic pituitary gland. During labor, shoulder dystocia and obstructed labor should be anticipated.

Q.16. How will you counsel the patient if meningomyelocele is detected? Fig. 1.3: Banana sign Ans: Patient should be counseled regarding the ascertained on sonography to predict the extend and prognosis which depends on the presence of neural severity of the neurological deficits. tissue in the meningeal sac and spinal level and Besides the detailed evaluation of the cranium length of the lesion. The spinal cord below the and spine, comprehensive ultrasound examination lesion is dysplastic and lower limb paralysis and should be performed to exclude genetic syndromes. incontinence of bowel and bladder is common. Intelligence may be affected from either the lesion Q.14. When does neural tube close in the embryo? itself or the impact of treatment (shunt placement). Ans: Neural tube closure occurs in the 3rd to 4th Early closure of the defect and ventriculoperitoneal week after fertilization.21 Closure in the region of shunting of any associated hydrocephalus should the developing head and sacrum is completed be performed.23,24 6 Case Discussions in Obstetrics and Gynecology

The option of pregnancy termination should be Q.17. What recurrence risk would you attribute included in counseling if the gestational age is less to this lady? than 20 weeks. Ans: Down’s syndrome cases result from If patient plans to continue the pregnancy, a nondisjunction, translocation or mosaic. multidisciplinary team consisting of a pediatric With a pregnancy complicated by trisomy 21 neurologist, neurosurgeon, obstetrician, and from nondisjunction, the woman has 1% risk of neonatologist should manage the patient to optimize having a pregnancy with trisomy in subsequent the neonatal outcome and plan surgical management. pregnancy. This risk pertains unless her age related In utero surgical repair of NTDs is still in risk exceeds it. experimental phase and currently there is Because of this risk, she would be offered insufficient data to judge the benefits and risk of invasive prenatal diagnosis. 25 this approach. Parental karyotype is not indicated in this couple. DOWN’S SYNDROME CASE 2 Q.18. What is the incidence of Down syndrome in general population? Mrs B, 24 years old had a previous baby with Ans: Down’s syndrome occurs in 1 in 800 to 1 in Down syndrome one year old. 1000 newborns.26 History Q.19. What are the different cytogenetic • Age of the mother at delivery mechanisms associated with Down syndrome? • Period of gestation at which the pregnancy was Ans: Chromosomal abnormalities in Down registered syndrome.27 • First trimester scan for nuchal translucency • Whether first or second trimester screening was Abnormality Frequency (%) done Trisomy 95 • Second trimester anomaly scan Translocation 4 • Pregnancy outcome: , stillborn or Mosaic 1 live born • Obstetrical history: P1+0+0+1 Ninety-five percent of Down syndrome cases Her first pregnancy was a spontaneous have primary trisomy of chromosome 21(47 instead conception. She sought antenatal care at 20 weeks of normal 46). These cases show the well-known of pregnancy. She had a term delivery at a hospital relationship to maternal age. Ninety-five percent of a small for gestational age baby. The baby had of trisomy children inherit their additional mongoloid facies and a ventricular septal defect chromosome as a result of nondisjunction of was diagnosed. The baby had delayed milestones maternal gametes while only 5% are paternally derived.28 and on investigations the baby was diagnosed with Four percent of Down syndrome cases have Trisomy 21. Robertsonian or unbalanced translocation. By Case: The woman is desirous of further child- contrast, translocations show no definite bearing but is apprehensive about similar problem relationship to parental age and may be either in the next baby and has come for preconceptional sporadic (two third) or familial (one third).28 The counseling. The karyotype of the effected child familial translocations carry greater risk of showed Trisomy 21 (47,XY). recurrence for future offspring. Pregnancy with Previous Congenital Disorders 7

Children with mosaicism are often less severely sterile. The risk of a chromosomally normal fetus affected than in the full syndrome. having a or mentally handicapped could be as high as 30%.31 Q.20. What recurrence risk is attributed for Down syndrome with unbalanced or Q.23. What is the fetal death rate with trisomy Robertsonian translocation? 21? Ans: If a child has down syndrome as a result of Ans: With trisomy 21, the fetal death rate is about de novo translocation, that is neither parent will 30% between 12 and 40 weeks, and about 20% have a balanced translocation, the likelihood of between 16 and 40 weeks.32 Down syndrome offspring’s recurring in such a couple is 0.5 to 1%. Q.24. What is the significance of parental aging However, if either of the parents harbors in Down syndrome? balanced translocation, the risk of recurrence exists. Ans: There is well documented association between For female carriers of Robertsonian 14;21 advancing maternal age and nondisjunction trisomy translocation, the risk of having a liveborn infant 21. The most favored explanation is an aging effect with Down syndrome is approximately 10%. The on the primary oocyte which can remain in a state 29,30 risk is approximately 1% for a male carrier. of suspended inactivity. Paternal age has no When parental translocations involve homologous association with Down’s syndrome though in chromosomes, that is 21, 21 possibility of a normal nondisjunction, in 5% children the extra liveborn infant is precluded. For such couples, chromosome is paternally derived. The parental age donor gametes should be considered. has no bearing in the Down syndrome due to translocations.33 Q.21. What is the indication of parental karyotype in cases of Down syndrome? Maternal age at Risk of Down delivery (in years) syndrome Ans: When a fetus or child is found to have a 20 1 in 1500 translocation trisomy, chromosomal studies of both 25 1 in 1350 parents should be performed. If neither parent is a 30 1 in 900 carrier and the translocation occurred 35 1 in 400 spontaneously, the recurrence risk is extremely 37 1 in 250 low.26 In one third cases one parent will be a carrier. 40 1 in 100 45 1 in 30 Other relatives can also be carriers and efforts should be made to identify all adult translocation Case: The woman in the above scenario reports carriers in a family so that they can be alerted to to you at 8 weeks pregnancy. possible risks to future offspring. This is sometimes referred to as translocation tracing or chasing.28 Q. 25 What is your plan of management in the current pregnancy? Q.22. What is the risk of Down syndrome in Ans: Since the recurrence in this pregnancy is about offspring of parents with Down syndrome? 1%, the women will be directly offered invasive Ans: Females with Down syndrome are fertile and testing with chorionic villous sampling to ascertain a third of their offspring will have Down syndrome. the chromosomal configuration of the fetus. In such Males with Down syndrome have markedly patients there is no role of serum screening or decreased spermatogenesis and are almost always combined screening. If she reports later than 14 8 Case Discussions in Obstetrics and Gynecology weeks she is offered prenatal diagnosis with through a history of repeated miscarriage, amniocentesis. the risk for an abnormal liveborn is much lower (1-5%).34 Q.26. What are the indications of invasive prenatal testing? Case 3: A 28 years old primigravida comes to your antenatal clinic at 10 weeks pregnancy for routine Ans: antenatal care. The woman is offered prenatal 1. Maternal age > 35 years 2. Previous offspring with aneuploidy. screening for aneuploides. 3. Multiple or major congenital malformations on Q.27. What options are available for the ultrasonography 4. Positive screening test. woman? 5. Parental aneuploidy. Ans: The options available for the woman along 6. Intracytoplasmic sperm injection: there is with their detection rates are as per Table 1.1.35 increased risk of (1%) sex chromosomal It is very important to remember that whichever abnormalities in pregnancies established by method is chosen for screening, determination of ICSI. correct gestational age by ultrasonography is 7. Recurrent spontaneous . mandatory for correct risk assessment. 8. Family history of single gene defects. The maternal age is another important 9. Structural chromosomal rearrangements. determinant of risk estimate as discussed earlier a. Either parent with Robertsonian trans- that increasing maternal age predisposes to a higher locations risk for aneuploides. Thus, it forms an integral part b. Parental reciprocal translocations: mode of of any screening test. Patient’s weight, diabetic ascertainment is very important. If a status, ethinicity and smoking should be taken into balanced reciprocal translocation is account as they have bearing on serum markers level. ascertained through an unbalanced child or another liveborn relative, the likelihood of Case: A 28-year-old primigravida on Ist trimester unbalanced liveborns is approximately 20%. combined screening is found to have a high risk of If balanced translocation is ascertained trisomy 21 (1:80).

Table 1.1: Options available for prenatal screening for aneuploides along with their detection rates Methods of screening Detection False rate (%) positive Maternal age 30% 5% Maternal age and triple test at 15-18 weeks (alpha fetoprotein, free beta-hCG, uE3) 50-70 5% Maternal age and quad test at 15-18 weeks (alpha fetoprotein, free beta-hCG, uE3, inhibin-A)36,37 80% 5% Maternal age and nuchal translucency (NT) at 11-13 weeks 70-80% 5% Maternal age and fetal NT and maternal serum free beta-hCG and PAPP-A at 11-13 weeks 85-90% 5% Maternal age and fetal NT and nasal bone and maternal serum free beta-hCG and PAPP-a at 11-13 weeks 95% 5% Serum integrated- PAPP-A in first trimester and Quad test in second trimester38 85% 5% Fully integrated- PAPP-A and NT in first trimester and Quad in second trimester) 85-90% 1-2% Pregnancy with Previous Congenital Disorders 9

Flow chart 1.1: Management of the woman with normal karyotype and NT > 3 mm

Q.28. What will be the future course of Q.29. How will you manage this woman if on management including patient counseling? chorionic villous biopsy the karyotype is normal Ans: A cut off of more than or equal to 1 in 250 is but the NT is 4 mm? classified into high risk group. Hence, all patients Ans: In this woman, since the nuchal translucency with risk more than 1 in 250 should be offered (NT) was more than 3 mm and the karyotype is invasive testing. Definitive diagnosis is established normal, the protocol is followed as per Flow chart by invasive testing only. 1.1. The invasive tests available are chorionic villous sampling between 11 to 14 weeks and amnio- Q.30. What are the inferences drawn from NT centeses between 15 to 20 weeks. The advantages, evaluation? Do you think cystic hygroma confers disadvantages and complications of each test should a different risk estimate? be discussed with the couple. Ans: The prevelance of fetal abnormalities and If the result of the karyotype is abnormal, the adverse pregnancy outcome increases exponentially couple has the option to terminate or continue the with NT thickness. However, the parents can be pregnancy. The methods of termination of reassured that the chances of delivering a baby with pregnancy available at various gestational ages and no major abnormalities is more than 90% if the fetal their complications should also be discussed. NT is between the 95th and 99th centiles, about 10 Case Discussions in Obstetrics and Gynecology

70% for NT of 3.5-4.4 mm, 50% for NT 4.5-5.4 diaphragmatic hernia, omphalocele, it is advisable mm, 30% for NT of 5.5-6.4 mm and 15% for NT to offer fetal karyotyping, even if these of 6.5 mm or more.39 abnormalities are apparently isolated, as chances Increased fetal NT thickness at 11-13 weeks is of associated aneuploidy are high.42 a common phenotypic expression of chromosomal If the abnormalities are either lethal or they are defects and a wide range of fetal malformations associated with severe handicap, such as and genetic syndromes. holoprosencephaly, fetal karyotyping constitutes Increased NT is associated with40 one of a series of investigations to determine the 1. Aneuploidy possible cause and thus the risk of recurrence. 2. Major cardiac defects Genetic sonography refers to systematic use of 3. Diaphragmatic hernia composite of diverse mid trimester markers to 4. Omphalocele estimate the risk of Down syndrome. This screening 5. Body stalk anomaly was developed and has been found to be of value 6. Skeletal defects in high risk population. The highest yield is 7. Fetal akinesia deformation sequence achieved with the combination of serum and 8. Noonan syndrome ultrasound screening in the general population. 9. Smith-Lemli-Opitz syndrome Various studies have revealed low diagnostic sensitivity for mid trimester ultrasound screening 10. Spinal muscular atrophy in low risk population.the composite rather than First trimester cystic hygroma has the strongest isolated sonographic markers are the current prenatal association with aneuploidy with paradigm for sonography based down syndrome significantly worse outcome compared with simple risk estimation. increased nuchal translucency.41 • Genetic sonogram should be an option for In about 75% of fetuses with cystic hygroma, women with advanced maternal age even if their there is a chromosomal abnormality and in majority serum screen results are normal, as few of cases, the abnormality is Turner syndrome. additional fetuses with Down syndrome could be identified. For those patients who have a Q.31. What is pathophysiology associated with normal genetic sonogram and a normal maternal increased NT? serum screening results, the risk of trisomy 21 Ans: The following mechanisms are implicated in is very low and probably does not warrant 39 the pathophysiology of increased NT: invasive testing.43 Seuter and coworker 1. Cardiac dysfunction demonstrated that serum screening and the 2. Venous congestion in the head and neck genetic sonogram were largely independent of 3. Altered composition of the extracellular matrix each other and therefore, could be used as 4. Failure of lymphatic drainage independent modifiers of the risk of Down 5. Fetal anemia syndrome.44 6. Fetal hypoproteinemia • Minor fetal abnormalities or soft markers like 7. Fetal nuchal thickness, middle phalanx, sandal gap, echogenic bowel, echogenic cardiac focus, Q.32. What is the role of second trimester short femur, short humerus are common and sonography in risk estimation of aneuploidy? they are not usually associated with any Ans: If the second trimester scan demonstrates handicap, unless there is an underlying major abnormalities like congenital heart disease, chromosomal defect. Pregnancy with Previous Congenital Disorders 11

Q.33. What are the new advances in noninvasive or no anemia. Peripheral smear shows hyperchromia diagnosis of Down syndrome? and microcytosis with basophilic stippling. Ans: With the use of chromosome- specific DNA HbA2 and HbF levels are increased. probes and fluorescent in situ hybridization (FISH) Unlike iron deficiency anemia, it is cha- it is possible to suspect fetal trisomy by the presence racterized by normal to increased proliferation of of three-signal nuclei in some of the cells of the RBCs. maternal blood enriched for fetal cells. There is evidence that increased level of cell free fetal DNA βββ Thalassemia Major is present in trisomy 21 pregnancies. However, this Results from homozygous or double heterozygous method is more likely to find an application as a mutations in the β globin gene. method for assessment of risk, rather than the non- In β 0 thalassemia, the most severe form, no invasive prenatal diagnosis of chromosomal β globin chains are synthesized. Only HbA and 45,46 2 defects. HbF are found on electrophoresis. When small amount of β globin chains are Beta Thalassemia synthesized, the condition is called β+ thalassemia. Beta thalassemia is the most common single gene HbA2, HbF and HbA are found on electrophoresis. disorder in our country. Carrier frequency varies It is milder than β0 thalassemia. from 3-17% in different populations. The most effective approach to reduce the burden of the βββ Thalassemia Intermedia society and reduce the disease incidence is These patients carry two β thalassemia mutations implementation of a carrier screening program, but present with symptoms later in life and have offering genetic counseling, prenatal diagnosis and milder anemia than patients who have β thalassemia selective termination of affected fetuses. major. They are not transfusion dependent but may require transfusions periodically. Despite the low βββ Q.34. What are various variants of thalassemia? transfusion rate, iron overload occurs in these Ans:β thalassemia is characterized by diminished patients as a result of increased intestinal absorption production of β globin chains which causes of iron that is caused by ineffective erythropoiesis. unmatched α globin chains to accumulate and The complications of iron overload present later aggregate. The deficiency of β globin synthesis may but may be as severe as those seen in patients who be compensated partially by an increase in δ and γ have β thalassemia major. chain synthesis. This leads to increased levels of α δ β γ HbA2 ( 2, 2) and HbF ( 2, 2) on hemoglobin Q.35. How will you screen for thalassemia in electrophoresis. β thalassemia has three major pregnancy? β clinically important syndromes. thalassemia Ans: Screening is offered to the women if she is β β minor, thalassemia major and thalassemia identified as belonging to an ethic population whose intermedia. members are at higher risk of being carriers. Ideally screening should be done preconceptionally or as βββ Thalassemia Minor early as possible in the pregnancy. Patients who have β thalassemia minor are 1. The preliminary screening method for all forms heterozygous for β globin mutation. They have mild of thalassemia relies on hematologic index 12 Case Discussions in Obstetrics and Gynecology

cutoffs, which involves an accurate blood count Combination of NESTROF and red cell indices using an electronic cell counter. Individuals with increases the sensitivity and negative predictive mean corpuscular volume (MCV) < 80fl and value to almost 100%. mean corpuscular hemoglobin (MCH) < 27pg The finding of any abnormality ( low MCV, low should be further examined to confirm or MCH, abnormal hemoglobin electrophoresis ) exclude the diagnosis of β thalassemia. This, requires screening of the partner. however, requires an expensive electronic blood cell counting apparatus and cannot be applied Q.36. How will you proceed if screening tests in rural areas where laboratory facilities and are positive? 47 economic resources are limited. Ans:Raised HbA2 level is the gold standard for the 2. A cheaper, rapid, simple and cost effective diagnosis of thalassemic trait. The definitive test alternative for screening is NESTROF (naked for β thalassemia status is HbA2 of >3.5%. eye single tube red cell osmotic fragility test). Next step is hemoglobin electrophoresis or HPLC (High performance liquid chromatography) Principle: It is based on the limit of hypotonicity for the quantification of HbA2 and HbF. which the red blood cells can withstand. Hemoglobin Typing Method: 2 ml of 0.36% buffered saline solution is taken, 0.02 ml of patient’s blood is added to it and HbA (96-99%) + HbA2 (2-3.5%), Normal MCV normal allowed to stand for 20 minutes. β HbA (92-96%) + HbA2 (>3.5%), -thal trait After 20 minutes reading is taken on a MCV < 80fl

NESTROF stand on which thin black line is HbA (96-99%) + HbA2 (<3.5%), Iron deficiency marked. MCV < 80 fL anemia HbA (0-0.4%/2.1-10.6%), Thalassemia major β0 β+ Interpretation: If the line is visible through the HbA2 (4-10%), HbF (>90%) ( / ). solution the test is taken as negative and if the line is not visible, the test is positive. Case: Mrs Y 24 yr old G2P1L0 presented at 8 In β thalassemia trait cases, black line is not weeks of gestation clearly visible since microcytic hypochromic red O/H: She had mild anemia during the pregnancy. cells of thalassemia trait are more resistant to lysis Previous child had history of repeated blood than normal normocytic normochromic red cells. transfusions with delayed milestones and died at 5 Limitations: other conditions which give year of age because of heart failure. positive result are: Past history: No history of blood transfusions in • Iron deficiency anemia the woman. • Hb E thalassemia • Hb D thalassemia Q.37. What is your provisional diagnosis? NESTROF has sensitivity ranging from Ans:Couple may be a thalassemia carrier 94-99%. NESTROF has been recommended for the mass Q.38. How will you confirm the diagnosis? screening due to its low cost, simplicity and high Ans:The carrier status of the couple is confirmed negative predictive value. by performing HPLC on both the partners. Pregnancy with Previous Congenital Disorders 13

Mr. X, 29 years identifies the mutation in more than 90% of the Clinical Pathology LNH cases. If the mutation is not identified, screening B-THAL Short Program for the broader range of mutations is performed. REPORT 23-3-10 Studies conducted in India have identified about ANALYTE ID ...... % 28 mutations in Indian population. Generally, when F ...... 5.5 both the partners are carriers, their DNA is studied P ...... 4.0 2 for 5 common and 12 rare mutations. Prenatal P3 ...... 3.6 diagnosis is offered if mutations are identified.48 A0 ...... 79.9 A ...... 5.6 2 Case: The couple was desirous of prenatal Mrs. X, 25 years diagnosis and the mutations in both the partners ANALYTE ID ...... % were identified F ...... 0.0 P2 ...... 4.7 Q.40. How will you carry out prenatal diagnosis P3 ...... 3.6 in this couple? A0 ...... 85.7 Ans: Once the carrier status of the couple is A2 ...... 6.3 Unknown I ...... 0.3 confirmed and the DNA mutations of the couple In this case, the HbA2 of both the partners was have been identified, the next step is to offer more than 3.5% and hence diagnosed as β- prenatal diagnosis and selective abortion of fetuses thalassemia traits. affected with thalassemia. In this couple, prenatal diagnosis can be accomplished by chorionic villi Q.39. What is the risk of transmission to the fetus sampling between 11-14 weeks of pregnancy. CVS in this couple ? is preferred as the results of prenatal diagnosis are available early in pregnancy. Usual reporting time Ans:Since both the partners are found to be carriers, is about one week. they should be referred for genetic counseling. It is single gene disorder and has autosomal Q.41. What are the various methods of prenatal recessive pattern of inheritance. Since both parents diagnosis? are carrier there are 25% chances for thalassemia major, 50% chances for thalassemia trait and 25% Ans: Prenatal diagnosis of hemoglobinopathies is chances that baby will be normal.47 best accomplished by DNA analysis of cultured To offer the prenatal diagnosis to the couple it amniocytes or chorionic villi by amniocentesis or is essential to characterize the DNA mutations of chorionic villous sampling (CVS). the parent.48 The β thalassemias are extremely Early and specific diagnosis by molecular heterozygous at the gene level, more than 200 methods has almost completely replaced mutations have been described from different parts cordocentesis. Cordocentesis is only performed for of the world. The mutations are distributed the following indications: geographically so that for a given high risk • pregnant patients who report late, population, there are only 4 to 10 dominant • CVS is unconclusive,49 mutations. Therefore, the general approach to the • DNA diagnostic facilities are not available molecular diagnosis of β thalassemia is to identify • One or both mutations are unidentified or and test for the region specific mutations based on molecular markers for linkage are unin- the patient’s ethnic background. This approach formative.50 14 Case Discussions in Obstetrics and Gynecology

If the test shows that the baby is affected, the • Fetal growth and well being should be followed. couple is counseled regarding the natural history Women with β thalassemia minor are found to of the disorder, prospects for treatment and cure have significantly higher rate of intrauterine and their risk. Termination of pregnancy can be growth restriction and oligohydramnios than offered upto 20 weeks of gestation. non-thalassemic females.51 The role of the genetic counselor and the obstetrician in these cases is extremely important. Q.43. How will you manage pregnant woman Even at this stage decision may be taken by the with βββ thalassemia major or thalassemia couple to continue the pregnancy accepting the life intermedia? long treatment of the affected child. Ans: Until recently, pregnancy in females with β For some couples preimplantation genetic thalassemia major was extremely rare. However, diagnosis in combination with in vitro fertilization with the introduction of hypertransfusion and iron may be a desirable option to avoid termination of chelation therapy several reports have been an affected pregnancy.51 documented with favorable pregnancy outcome in β Case: On prenatal diagnosis the fetus is diagnosed female with thalassemia major. Pregnancy should to be βββ thalassemia carrier. be managed by interdisciplinary team who is familiar with high-risk pregnancy and care of Q.42. The couple continues the pregnancy, how patients with thalassemia. will you manage the pregnancy? • Periconceptional folic acid supplementation should be given. Ans: β thalassemia minor is well tolerated • Baseline cardiac, hepatic and endocrine pregnancy. Pregnancy outcome and obstetric evaluation is recommended at initial visit and complications do not differ from general should be repeated at second and third trimester. population. • S. ferritin levels and blood counts should be • Periconceptional folic acid supplementation followed regularly. should be given as the risk of fetal neural tube • Hemoglobin levels should be maintained at or defects may be increased in pregnant woman near 10 gm/dl with transfusions. who are thalassemia carriers, possibly because • Fetal growth and well being should be followed of relative folic acid deficiency secondary to closely because of increased risk of intrauterine increased erythropoiesis. The optimum dosage growth restrictions. of folate has not been determined, however, • Mode of delivery should be individualized with high dose supplementation of at least 4 mg daily cesarean section reserved for obstetrics should be considered based on benefits in other indications. populations who are at higher risk for neural tube defects.52 REFERENCES • Iron supplementation should be given and concomitant iron deficiency anemia should be 1. Cunningham FG, Leveno K, Bloom SL, et al. Prenatal diagnosed (S. Ferritin levels, S iron, total iron diagnosis and fetal therapy. In Twickler DM, Wendel 50 GD (Eds). Williams Obstetrics 2010;23:287-311. binding capacity) and treated. In absence of 2. Fisher B, Rose NC, Carey JC. Principles and Practise documented iron deficiency anemia, replace- of teratology for the obstetrician. Clin Obs and Gynae ment beyond prophylactic doses of iron is not 2008;51:106-18. indicated.51 Parental iron therapy is contra- 3. Becerra JE, Khoury MJ, Cordero JF, et al. Diabetes indicated as it causes iron overload. mellitus during pregnancy and the risk for specific Pregnancy with Previous Congenital Disorders 15

birth defects: A population- based case control study. 18. Katz VL, Chescheir NC, Cefalo RC: Unnexplained Paediatrics 1990;85:1. elevation of maternal serum alpha fetoprotein. Obstet 4. Hunter AGW. Neural tube defects in eastern Ontario Gynaecol Surv 1990;45:719. and western Quebec: Demography and family data. 19. Jenkins TM, Wapner RJ. Prenatal diagnosis of Am J Med Genet 1984;19:45. congenital disorders. In Creasy RK, Resnik R (Eds): 5. Lindhout D, Omtzigt JGC, Cornel MC: spectrum of Maternal-Fetal Medicine, Elsevier, Pennsylvania neural tube defects in 34 infants prenatally exposed 2004;5:235-80. to antiepileptic drugs. Neurology 1992;42(suppl 5): 20. Nicolaides KH, Campbell S, Gabbe D, et al. Screening 111. for spina bifida: Cranial and cerebellar signs. Lancet 6. Isotalo PA, Wells GA, Donnelly JG. Neonatal and fetal 12:72,1986. methylhydrofolate reductase genetic polymorphism: 21. Sadler TW. Third to eighth weeks: The embryonic an examination of C677T and A1298C mutations. Am period. In Sadler TW (Ed).Langman’s medical J hum Genet 2000;67:986-90. embryology, Lippincott Williams and Wilkins, 7. Doray B, Favre R, Gasser B, et al. Recurrent neural Philadelphia 2006;1:67-88. tube defects associated with partial trisomy 2p22-pter: 22. Gohsl, Tan JVK, Kwek KYC, Yeo GSH. Recurrent a report of two siblings and review of the literature. neural tube defects. Singapore Med J 2006;47(8): Genet Cous 2003;14:165-72. 728-9. 8. Zumel RM, Darnaude MT, Delicado A, et al. Trisomy 23. Peralta CF, Bunduki V, Plese JP, et al. Association 20p from maternal translocation and anencephaly. between prenatal sonographic findings and postnatal Case report and genetic review. Am Genet outcomes in 30 cases of isolated spina bifida aperta. 1989;32:247-9. Prenat Diag 2003;23:311-14. 9. Godbole K, Deshmukh U, Yajnik C. Nutri-genetic 24. Jobe AH: Fetal for myelomeningocele. N Engl determinants of neural tube defects in India. Indian J Med 2002;347:230-31. Pediatrics 2009;46:467-75. 25. Walsh DS, Adzick NS, Sutton LN, et al. The rationale 10. Shaffer LG, Marazita ML, Bodrtha J, Newlin A, Nance for in utero repair of myelomeningocele. Fetal Diagn WE. Evidence for a major gene in familial Ther 2001;16:312. anencephaly. Am J Med Genet 1990;36:97-101. 26. Cunningham FG, Leveno K, Bloom SL, et al. Genetics. 11. Tanriverdi HA, Hendrik HJ, Ertan K, Schmidt W. In Twickler DM, Wendel GD (Eds). Williams Meckel Gruber syndrome: a first trimester diagnosis Obstetrics, McGraw Hill, United States of America of a recurrent case. Euro J Ultrasound 2002;5:69-72. 2010;23:266-86. 12. Toriello HV, Higgins JV. Occurrence of neural tube 27. Mueller RF, Young ID. Chromosome disorders. In defects among first, second, and third degree relatives Mueller RF, Young ID (Eds). Emery’s elements of of probands: results of a United States study. Am J medical genetics. Elsevier, Philadelphia 2002;11:249- Med Genet 1983;15:601-06. 66. 13. Centers of Disease Control and Prevention. Alcohol 28. Mueller RF, Young ID. Chromosomes and cell use among women of childbearing age- United division. In Mueller RF, Young ID (Eds). Emery’s States,1991-1999.MMWR 51:273,2002a. elements of medical genetics. Elsevier, Philadelphia 14. Centers of Disease Control and Prevention. Spina 2002;11:29-54. bifida and anencephaly before and after folic acid 29. Boue J, Gallano PA. A collaboration of the segregation mandate—United States,1995-1996 and 1999- of inherited chromosome structural rearrangements in 2000.MMWR53:362,2004. 1356 prenatal diagnosis. Prenat diagn 1984;4:45. 15. Group MRCVSR: Prevention of neural tube defects: 30. Farndon PA, Kilby MD. Genetics, Risks, and genetic results of the Medical Research Council Vitamin counseling. In James DK, Weiner CP, Steer PJ, Gonik Study. MRC Vitamin Study Research group. Lancet B (Eds): High risk pregnancy, Elsevier, Pennsylvania 1991;338:131-7. 2006;3:43-66. 16. Blencowe H, Cousens S, Bernadett M, Lawn J. Folic 31. Rani As, Jyoti A, Reddy PP, Reddy OS: Reproduction acid to reduce neonatal mortality from neural tube in Down’s syndrome. Int J Gynaecol Obstet disorders. Int J Epid 2010;39:110-21. 1990;31:81-86. 17. Criezel AE, Dudas I.Prevention of the first occurrence 32. Snijders RJM, Sundberg K, Holzgreve W, et al: of neural tube defects by periconceptional vitamin Maternal age and gestation specific risk for trisomy supplements. N Engl J Med 1992;327:1832. 21. Ultrasound Obstet Gynecol 1999;13:167. 16 Case Discussions in Obstetrics and Gynecology

33. Cuckle HS, Wald NJ, Thompson SG. Estimating 42. Heath V, Nicolaides KH. Sonographic features of women’s risk of having a pregnancy associated with chromosomal defects. In Nicolaides KH(Ed): The 11- Down’s syndrome using her age and serum alpha- 13+6 weeks scan, Fetal Medicine Fondation, London fetoprotein level. Br J Obstet Gynaecol 1987;94:387- 2004: 45-70. 402. 43. DeVore GR, Romero R. Genetic sonography: An 34. Daniel A, Hook EB, Wulf G. Risks of unbalanced option for women of advanced maternal age with progeny at amniocentesis to carrier of chromosome negative triple marker maternal serum screening rearrangements: Data from United States and Canadian results. J Ultrasound Med 2003;22:1191-99. laboratories. Am J Med Genet 1989;33:14. 44. Souter VL, Nyberg DA, Benn PA, et al. Correlation 35. Saller DN, Canick JA. Current methods of prenatal of second trimester sonographic and biochemical screening for Down syndrome and other fetal markers. J Ultrasound Med 2004;23:505-11. abnormalities. Clin Obs and Gynae 2008;51(1):24-36. 36. Wald NJ, Rodeck C, Hackshaw AK, et al. First and 45. Sebre N, Nicolaides KH. Multiple pregnancy. In +6 second trimester antenatal screening for Down’s Nicolaides KH(Ed). The 11-13 weeks scan, Fetal syndrome: the results of the serum, and Medicine Fondation, London 2004:95-110. ultrasound screening study (SURUSS). J Med Screen 46. Lee T, Leshane ES, Messerlian GM, et al. Down 2003;10:56-104. syndrome and cell free fetal DNA in archived maternal 37. Malone FD, Canick JA, Ball RH, et al. First and serum. Am J Obstet Gynecol 2002;187:1217-21. second trimester evaluation for fetal aneuploidy 47. Sanchaisuriya K, Fucharoen S, Fucharoen G, et al. A (FASTER): Principle results of the NICHD reliable screening protocol for thalassemia and multicentric Down syndrome screening study. N Engl hemoglobinopathies in pregnancy. Am J Clin Pathol J med 2005;353:2001-11. 2005;123:113-18. 38. Said S, Malone FD. The use of nuchal translucency 48. Maheshwari M, Arora S, Kabra M, et al. Carrier in comtemporary obstetric practice. Clin Obs and screening and prenatal diagnosis of β-thalassemia. Gynae 2008;51(1):37-47. Indian Pediatrics 1999;36:1119-25. 39. Souka A, Kaisenbverg CV, Nicolaides KH. Increased 49. Panirahi I, Ahmed RPH, Kannan M, et al. Cord blood nuchal translucency with normal karyotype. In analysis for prenatal diagnosis of thalassemia major Nicolaides KH(Ed). The 11-13+6 weeks scan, Fetal and hemophilia A. Indian Pediatrics 2005;42:577-81. Medicine Fondation, London 2004:71-94. 50. Hedge UM, Khunda S, Marsh GW, et al. Thalassemia, 40. Hyett J,Perdu M, Sherland G, et al. Using fetal nuchal Iron, and pregnancy. Br Med J 1975;3(5982):509-11. translucency to screen for major congenital heart defects at 10-14 weeks of gestation: population based 51. ACOG practice Bulletin No. 78: Hemoglobinopathies cohort study.BMJ 1999;318:81-5. in Pregnancy. Obs and Gynaecol 2007;109(1):229- 41. Malone F, Ball R, Nyberg D, et al. First trimester 38. septated cystic hygroma: prevalence, natural history, 52. Rappaport VJ, Velazquez M, Williams K. and pediatric outcome. Obstet Gynaecol 2005;106: Hemoglobinopathies in pregnancy. Obstet Gynaecol 288-94. Clin N Am 2004;31:287-317. Madhavi M Gupta 2 Recurrent Pregnancy Loss

Miscarriage in the general reproductive population CASE 1 is a frequent occurrence with nearly 30% to 50% A 36-year-old P0+1+3+1 presents with a history of all conceptions and 15% of all clinically of one preterm birth of a healthy unaffected recognized pregnancies resulting in pregnancy female infant at 33 weeks period of gestation failure.1-3 followed by three consecutive miscarriages at 8- Recurrent pregnancy loss (RPL), also referred 10 weeks period of gestation (POG) in the past 4 to as or habitual abortion, is years. She has unremarkable medical, surgical, historically defined as 3 consecutive pregnancy and gynecological histories. All three miscarriages losses prior to 20 weeks from the last menstrual required curettage. The products of conception period; however, newer guidelines from the of her last loss were karyotyped and revealed a American Society of Reproductive Medicine normal karyotype, 46 XY. have defined RPL as the loss of two or more pregnancies.4 Important points in history Epidemiologic studies have revealed that 1% • Age of the patient and her partner. The risk of to 2% of women experience recurrent pregnancy miscarriage is highest when the woman is 35 loss.5 Because the incidence of recurrent years or older and the man is 40 years or older.9 miscarriage is higher than that expected by chance • A detailed history of her prior pregnancies. alone (0.34%),6,7 a proportion of couples with – Antepartum period in the first pregnancy recurrent miscarriage have a persistent underlying – Any history of high blood pressure record. cause for their pregnancy losses. If so, at what gestation and whether required The risk of miscarriage in subsequent preg- any treatment. Associated complications. nancies is 30% after 2 losses, compared with 33% – Any special investigations ordered and was after 3 losses among patients without a history of a treatment instituted based on the results. live birth.8 Hence, there is a role for evaluation after – Fetal growth restriction. If so,when was it just 2 losses in patients with no prior live birth. An diagnosed and how was the pregnancy earlier evaluation is recommended if fetal cardiac monitored after that. activity was documented prior to a loss, the age of – Reason for preterm birth, spontaneous or the female partner is more than 35 years, or there induced. If induced, reason for induction. is a history of infertility. If cesarean birth, indication for the same. It 18 Case Discussions in Obstetrics and Gynecology

is advisable to ask for the previous discharge confounded by alternative or additional environ- ticket. mental exposures.8,14 – Postpartum period—any specific treatment • History of any surgical procedure on the or complication which can lead to pregnancy losses (mostly mid- • A descriptive sequence of all previous preg- trimester) like conisation, forcible dilatation nancies including the estimated gestational age which can cause cervical tear and also weak- of each miscarriage, on the basis of ultrasound, ness in future pregnancies. embryopathology and serum hCG results. Examination Gestational age may not be as informative as General physical examination fetal death occurs several weeks before symp- A complete examination is a must so as to identify toms appear. any previously undiagnosed underlying systemic • Previous cytogenetic results to determine any disorder. A review of systems should include numeric chromosome abnormality. assessing for features of rheumatic disease. Menstrual History • General built and nutritional status (Body • Length and regularity of the menstrual cycle habitus). may indicate oligo-ovulation, PCOS, and dys- • Height and weight 2 synchronous fertilization. Polycystic ovary • BMI (kg/M ) may be abnormal in diabetics and in thyroid dysfunction. Poorly controlled dia- syndrome with insulin resistance has higher rate 15 of miscarriage. betics have an increased risk of miscarriage. • Thyroid swelling • History suggestive of thyroid dysfunction like • Evidence of galactorrhea as hyperprolactinemia lassitude, weakness, extreme changes in weight, may be associated with recurrent pregnancy loss diet, hyperactivity. Untreated hypothyroidism through the hypothalamic-pituitary-ovarian axis may increase the risk of miscarriage. but the supporting evidence is insufficient.16 • How long the couple has been attempting con- • Skin texture ception as difficulty in achieving conception • Clinical features of hyperandrogenemia may in some instances indicate subclinical • Pedal edema (preimplantation) pregnancy loss.10 Pelvic examination • Family History • A per speculum and a bimanual pelvic – History of thrombosis would indicate examination will identify local infection, uterine inherited thrombophilias size and shape and any gross uterine anomaly. – Recurrent pregnancy loss • A per speculum will also identify a torn cervix, – Stillbirths or a grossly short cervix. – Birth defects • History of exposure to smoking, alcohol, and Q.1. What investigations will you offer this caffeine.11-13 The risk of caffeine, alcohol, and patient? nicotine intake with RPL is even weaker than Ans: their association with sporadic loss. • Parental karyotype • History of occupational and environmental • Pelvic ultrasound for intrauterine cavitary exposures to organic solvents, medications, assessment ionizing radiation, and toxins as they could • Luteal phase endometrial biopsy possibly have a role in RPL but may be • Screening for antiphospholipid antibodies. Recurrent Pregnancy Loss 19

Q.2. What are the different etiological factors Ans: Routine screening for occult diabetes and contributing to RPL? thyroid disease with oral glucose tolerance test and Ans: thyroid function tests in asymptomatic women • Genetic 2%-5% presenting with recurrent miscarriage is uninfor- • Anatomic 10%-15% mative.18 Also, routine screening for thyroid • Autoimmune 20% antibodies in women with recurrent miscarriage is • 0.5%-5% not recommended.18 • Endocrine 17%-20% Women with diabetes who have high hemo- • Unexplained 40%-50% globin A1c levels in the first trimester are at risk of (including non-APS thrombophilias) miscarriage and fetal malformation. However, it is not so in cases of well controlled diabetes mellitus Q.3. What are the different tests available for and, treated thyroid disorder.15 diagnostic evaluation based on the causative The prevalence of diabetes mellitus and thyroid factors and what percent of each will have an abnormal result? dysfunction in women who suffer recurrent mis- carriage is similar to that expected in the general Ans: Shown in Table 2.1. population.19 Q.4. Is glucose tolerance test and thyroid The above patient underwent immunologic function tests done in all patients of recurrent tests, parental karyotype, a pelvic ultrasound and pregnancy loss? an endometrial biopsy. The anticardiolipin IgG was

Table 2.1: Standard evaluation of recurrent early pregnancy loss17 Factor Diagnostic evaluation Abnormal result Immunologic Lupus Anticoagulant 15% to 20% Anticardiolipin IgG/IgM β 2-glycoprotein-1 IgG/IgM Phosphatidylserine IgG/IgM Embryotoxic assay Immunophenotyping Parental structural Cytogenetic analysis of both partners 2.5% to 8% chromosome rearrangement Endocrinologic Endometrial biopsy or midluteal progesterone 8% to 12% Thyroid-stimulating hormone, Prolactin Fasting insulin and glucose Anatomic Hysteroscopy, hysterosalpingogram or sonohysterography, 15% to 20% 2D or 3D ultrasound, Magnetic Resonance Imaging Thrombophilic Factor V Leiden Prothrombin gene 8% to 12% Fasting homocysteine Antithrombin activity? Protein C activity? Protein S activity? Microbiologic Endometrial biopsy 8% to 10% Cervical/vaginal cultures? Psychologic Mental status evaluation Iatrogenic Review tobacco, alcohol and caffeine use 5% Review exposure to toxins, chemicals 20 Case Discussions in Obstetrics and Gynecology

50GPL and IgM was 45GPL. Rest all of the test embryonic miscarriage inhibition of cytotro- results were normal. phoblast fusion, invasion, and differentiation has been noted.22-24 Q.5. What is the patient suffering from and how will you manage her further? Q.8. What are the diagnostic criteria for APS? Ans: The patient is most probably a case of primary Ans: The antiphospholipid syndrome is strictly Antiphospholipid Antibody Syndrome (APS) but defined, on the basis of both clinical and laboratory the anticardiolipin antibody titers should be positive criteria. in medium or high titers repeated 12 weeks apart. Diagnosis of the Antiphospholipids Syndrome25 The antibody titers need to be estimated in the Clinical Criteria non-pregnant state for a definite diagnosis. • One or more episodes of arterial, venous, or APS in patients with chronic inflammatory small vessel thrombosis. diseases, such as systemic lupus erythematosus is • One or more unexplained pregnancy loss of referred to as “secondary APS”. In contrast, a morphologically normal fetus of atleast “primary APS” affects patients with no identifiable 10 weeks of gestation. underlying systemic connective tissue disease. • One or more premature births of a morpho- The patient will require low-dose aspirin from logically normal newborn at or before the 34th conception till 36 weeks and, heparin since week of gestation because of severe pregnancy conception till delivery. induced hypertension or severe placental A recent meta-analysis concluded that the insufficiency. combination of unfractionated heparin and • Three or more unexplained consecutive aspirin confers a significant benefit in live births miscarriages before 10 weeks of gestation, with in APS. However, the efficacy of low molecular anatomic, hormonal, and parental structural 20 weight heparin plus aspirin remains unproven. genetic factors excluded. Laboratory Criteria: The same antibody must be Q.6. What are antiphospholipid antibodies? positive twice when drawn at least 12 weeks apart. Ans: Antiphospholipid antibodies are a family of • Anticardiolipin IgG and/or IgM, present in heterogenous antibodies that react with epitopes on medium or high titers (>40 GPL or MPL). proteins that are complexed with negatively charged β • Anti 2-glycoprotein-1 IgG and/or IgM, present phospholipids. in titer >99th percentile. • Lupus anticoagulant, detected according to the Q.7. What is the mechanism of pregnancy loss guidelines of the International Society on in patients with APS? Thrombosis and Hemostasis. Ans: Placental damage resulting from thrombosis Patients should have at least one clinical and is thought to be the end result of autoimmunity to one laboratory criteria. phospholipids. Originally, antiphospholipid antibodies were Q.9. How should this patient be managed in reported in patients with slow, progressive throm- future pregnancy as she is very keen on further bosis and infarction in the placenta;21 however this child bearing? finding is not seen on the histopathology of the first Ans: Once the diagnosis is confirmed, whenever trimester deciduae. In recurrent preembryonic or the patient conceives she can be started on Recurrent Pregnancy Loss 21 low-dose aspirin (LDA, 81-100 mg/day) plus However, in a few studies the role of Intra- prophylactic heparin as she is an otherwise healthy venous Immunoglobulin has been documented and woman (i.e. absence of a systemic autoimmune found to be useful in secondary miscarriage in disease such as systemic lupus erythematosus, or a women with recurrent early pregnancy losses history of thrombosis). following one previously successful birth.30 But till LDA should be started before conception or date no definite guidelines exist about the beneficial with a positive pregnancy test. role and use of IVIG in recurrent pregnancy loss. Heparin should be started with a positive Steroids are associated with a lower live birth 26 pregnancy test. Heparin is a large complex of rate but significantly increase maternal and fetal molecules that do not cross the placenta and, as complications.31,32 Also, they should not be used such, is regarded safe during pregnancy. concomitantly with heparin, because of the In case the patient presents after conceiving, potentiation of osteoporosis with these agents but, she should be immediately started on LDA the risk appears lower with low-molecular weight 81mg/day and heparin. heparin.

Q.10. Is treatment with LDA and heparin Q.13. Apart from APS does this patient have mandatory in APS? any other risk factor for RPL? Ans: Yes. Ans: The patient is 36 years of age. Combination therapy with aspirin and heparin Maternal age is a well known risk factor for may reduce pregnancy loss in women with sporadic miscarriage and is a likely risk factor for antiphospholipid antibodies by 54%.27 RPL as well. Women over the age of 35 years In untreated pregnancies with APS the live birth (“advanced maternal age” AMA) have an increased rate may be as low as 10%.28 rate of meiotic errors in oocyte development leading The American College of Obstetricians and to increased embryonic aneuploidy. Gynecologists (2005a) recommends low-dose The reported miscarriage rate among women aspirin—81mg orally per day, alongwith under 35 years of age is 14% compared with 40% unfractionated heparin-5000 units subcutaneously, for women over 40 years old.33 twice daily. Hence, this patient should be counseled for Q.11. In what other conditions is antithrombotic and offered invasive testing for aneuploidies. therapy effective? Q.14. The above patient had no significant Ans: Apart from APS antithrombotic therapy is recommended in inherited thrombophilias. medical history and general examination was (discussed in detail in a separate case discussion) unremarkable. Should antinuclear antibody levels be ascertained? Q.12. Is there any role of Intravenous Immuno- Ans: Routine testing for an antinuclear antibody globulin (IVIG) and steroids in the treatment (ANA), in the absence of rhematic autoimmune of APS? disease, is not indicated. Steroid therapy in recurrent Ans: Heparin is more effective than intravenous pregnancy loss with an elevated ANA without immunoglobulin as the first line treatment of clinical criteria, increases maternal and fetal antiphospholipid syndrome.29 complications without improving the live birth rate. 22 Case Discussions in Obstetrics and Gynecology

Q.15. How should a patient with secondary APS, Progestogen supplementation is recommended (with SLE) be counseled with respect to preg- only in either unexplained losses or where luteal nancy outcome and impact of pregnancy on phase deficiency exists. their disease? Q.18. How is luteal phase deficiency (LPD) Ans: The prevalence of antiphospholipid antibodies defined and diagnosed? in patients with SLE is ~37% and are the most sensitive indicator of poor obstetrical outcomes.34,35 Ans: Luteal phase deficiency has been historically Such women have a higher rate of pregnancy losses defined as a lag of more than 2 days in the histologic development of the vis a vis the day in all three trimesters. of the cycle. Underlying renal disease and prepregnancy Midluteal progesterone of <10 ng/ml is also lupus flares are associated with poor pregnancy 36,37 taken to be diagnostic. Also, a sum of three random outcomes. serum progesterone measurements less than 30 ng/ ml measured during the luteal phase is suggestive Q.16. What are the other obstetric risks asso- of luteal phase deficiency. ciated in the antenatal period with APS? Ans: Q.19. Is ascertaining progesterone levels nece- • Preterm labor ssary in determining luteal phase insufficiency? • Prematurely ruptured membranes Ans: No, as there is considerable overlap between • Fetal growth restriction due to placental progesterone levels and endometrial biopsy insufficiency specimens. Biopsy specimens can be normal despite • Preeclampsia, Eclampsia low levels of progesterone in peripheral blood. • Placental abruption Considerable overlap also exists between normal Inspite of treatment with aspirin and heparin and abnormal levels in women having successful these pregnancies are at high risk for complications pregnancies. necessitating careful antenatal surveillance. Q.20. Had this patient had the results of all the Q.17. Will progesterone supplementation in tests normal, would treatment with aspirin, or aspirin plus heparin be of any help presuming early pregnancy help support the pregnancy in the losses to be unexplained? this patient? Ans: No, Neither aspirin combined with LMWH Ans: No, the definitive treatment in APS is LDA (nadroparin) nor aspirin alone improved the live- plus heparin. birth rate, as compared with placebo, among There is insufficient evidence to evaluate the women with unexplained recurrent miscarriage.39 effect of progesterone supplementation in In another study there was no reduction in pregnancy to prevent miscarriage in early to mid- pregnancy loss rate with antithrombotic inter- pregnancy. However, there might be some benefit vention in pregnant women with 2 or more in women with recurrent miscarriage. consecutive previous pregnancy losses with no Treatment for these women may be warranted identifiable cause.40 given the reduced rates of miscarriage in the treatment group and the finding of no statistically Q.21. What if this patient has a parental balan- significant difference between treatment and ced structural chromosome rearrangement and control groups in rates of adverse effects suffered all the other investigations are normal? How by either mother or baby in the available evidence.38 should she be counseled? Recurrent Pregnancy Loss 23

Ans: Of the two partners, women are more likely partner she fails to produce the blocking factors. then men to carry most types of chromosomal The role of endometrial immunity in recurrent early rearrangements.41 The ratio of female-to-male pregnancy loss is currently under investigation. abnormalities was approximately 2:1. Previously, sharing of HLA between partners The most common types of parental chromo- was thought to be associated with recurrent somal abnormalities are balanced translocations pregnancy loss. A large RCT, however, did not either reciprocal (50%), or Robertsonian (24%). confirm this association.43 Other abnormalities are: X chromosome Immunotherapy, including paternal cell mosaicism such as 47, XXY—Klinefelter syn- immunization, third-party donor leucocytes, drome (12%); and inversions.42 trophoblast membranes and intravenous immuno- Although carriers of a balanced translocation globulin (IVIG), in women with previous unex- are phenotypically normal, their pregnancies are at plained recurrent miscarriage does not improve the an increased risk of miscarriages or birth of a baby live birth rate. with multiple congenital malformations and mental Immunotherapy is expensive and has serious handicaps due to unbalanced chromosomal adverse effects including transfusion reaction, rearrangements. anaphylactic shock and infections. This warrants genetic counseling offering Hence, it should not be offered to women with prognosis for future pregnancies, prenatal unexplained recurrent miscarriage and routine tests diagnostic options, and the opportunity to perform for HLA type and anti-paternal cytotoxic antibody familial chromosomal studies. should be abandoned.18

Q.22. What are the various reproductive options CASE 2 in such a patient? A 28-year-old G4P0+1+2+0 presents at 10 weeks Ans: pregnancy with history of one preterm birth at • Proceed to a further natural pregnancy with or 28 weeks period of gestation followed by two without, prenatal diagnostic tests, chorionic consecutive losses at 18-20 weeks gestation. She villous sampling, or amniocentesis. has unremarkable medical, surgical, and • Gamete donation gynecological histories. • Adoption • Preimplantation genetic diagnosis in trans- Q.24. • What is the most likely cause of these location carriers and in unexplained RPL. losses? There is a 40% to 50% chance of a healthy live • What history will point to the likely cause? birth in future untreated pregnancies after natural • How should she be managed in this preg- conception. nancy? Ans: Q.23. What is the role of alloimmune factors in • The most likely cause is . RPL? • There is no history of bleeding, pain or clear Ans: Normal pregnancy requires formation of signs of labor preceeding the miscarriage. The blocking factors preventing paternally derived late miscarriage is preceded by spontaneous foreign fetal antigens. If the female shares the rupture of membranes or painless cervical Human Leukocyte Antigens (HLA) with the male dilatation. 24 Case Discussions in Obstetrics and Gynecology

• The losses occur at progressively earlier The use of a cervical stitch should not be offered gestations. to women at low or medium risk of mid trimester • A transvaginal ultrasound assessment of the loss.44 cervical length and shape is called for. Transabdominal or laparoscopic cerclage seems • The three ultrasound signs that suggest to be a promising alternative where transvaginal cervical incompetence are shortening of the cerclage has failed in the previous pregnancy.44 endocervical canal, funneling of the internal os, and sacculation or prolapse of the membranes Q.26. Apart from cervical incompetence what into the cervix, either spontaneously or on are the other anatomic factors implicated in RPL applying fundal pressure. and prognosis? A short cervix (< 25 mm) is the best independent Ans: Acquired predictor of spontaneous birth before 34 Intrauterine synechiae—Asherman syndrome, weeks’gestation. leiomyomas (intramural of >5 cm and submucosal • The cervical length on the second-trimester fibroids of any size), short cervix because of ultrasound was 20 mm hence, a cervical conisation, amputation, cervical weakness owing cerclage is offered at ~16 weeks, after a fetal to forcible dilatation of the internal os during some anomaly scan. The stitch can be put either procedure. vaginally or abdominally. This is therapeutic cerclage, applied when the ultrasound reveals Developmental defects a short cervix. Septate, unicornuate and as well • Preoperatively, a long-acting progesterone as uterine didelphys. generally, 17 Hydroxy Progesterone Caproate Anatomic abnormalities are believed to cause preparation is given for uterine quiescence and miscarriage by interrupting the vasculature of the can be repeated. There are, however, limited endometrium, prompting abnormal and inadequate data supporting the utilization of supplemental placentation. progesterone after cerclage. Near normal pregnancy outcomes with term • The stitch should be removed at 37-38 weeks delivery rates of ~75% and live birth rates of ~85% are seen after successful hysteroscopic septum pregnancy or whenever the patient goes into 45 labor. resection. • A prophylactic cerclage is applied before the Myomectomy is to be considered in case of cervix is dilated and emergency, when the intramural fibroids of > 5 cm and submucosal fibroids of any size improving live birth rates from cervix has started to shorten and dilate with 46 fetal membranes bulging at times. 57 to 93%.

Q.25. Who are the candidates for cervical CASE 3 cerclage? A 32-year-old P0+0+4+0 with all the four mid Ans: The current literature suggests that women trimester losses at ~20 weeks of gestation is being with a history of at least three second-trimester or evaluated. On bimanual pelvic examination the at least three preterm births or those with a history fundus of the uterus appeared broad, although of prematurity who have < 25 mm cervical length the per speculum examination was unremarkable. on ultrasound will benefit from cerclage by All other investigations for recurrent pregnancy preventing preterm delivery.44 loss were normal, except that the pelvic ultrasound Recurrent Pregnancy Loss 25 had a suspicion of two endometrial cavities. Out- These patients should be encouraged to line the plan of management. continue attempts at pregnancy, because prospective studies show that these women, even • Hysteroscopic evaluation of the endometrial with advanced maternal age, have a high rate of cavity revealed a uterine septum. 49 • Hysteroscopic septal resection in the post- live births with their subsequent pregnancies. menstrual phase. The most effective therapy for patients with • Post resection, start on combined oral contra- unexplained RPL is most simple: Antenatal ceptive pills for 6-months which in addition to counseling and psychological support. These contraception, will help in tissue healing. measures have been shown to have subsequent • Patient can attempt conception after 6-months pregnancy success rates of 86% as compared to 50 with ~85% live birth rates. 33% when no additional antenatal care was given. • Monitor the pregnancy closely. General advice about quitting smoking, • Cervical studies. avoiding excess alcohol, and caffeine intake and • No indication for cerclage. Although she has weight loss in obese women, and dietary balance had four second-trimester miscarriages the is important. Folic acid (400 μg/day) for atleast causative factor has been corrected. The patient 2 months prior to attempting conception is indicated should undergo a transvaginal scan for the to prevent neural tube defects. length of the cervix ~15-16 weeks and if found to be < 25 mm (associated factor) a stitch can Q.29. How should the patients of recurrent be applied ~18 weeks after an anomaly scan. pregnancy loss be monitored in the postcon- ception period? Q.27. Are any infections responsible for RPL? Ans: Ans: Those particular infections speculated to play First Trimester a role in RPL include Ureaplasma, Chlamydia • Close monitoring, psychological support and trachomatis, L monocytogenes, and Herpes simplex reassurance in the first trimester to allay anxiety. 47 virus. • Confirm intrauterine pregnancy. Recurrent The most pertinent risk for RPL secondary to pregnancy loss appears to be a risk factor for infection is chronic infection in an immuno- both ectopic pregnancy and complete molar compromised patient. gestation.51 Evaluation and therapy should be indivi- dualized. Usually investigations for chronic • Continue folic acid. infections is warranted only in immuno- • Start progesterone (Unexplained RPL). compromised patient with RPL and with a history • Treatment with antithrombotics depending on of sexually transmitted infections. the etiology of RPL. Routine TORCH screening should be • Assessment of fetal karyotype for all women abandoned.47,48 as they are more likely to have aneuploid pregnancies.52 Q.28. Inspite of extensive investigations if no • Glucose Challenge Test (GCT) with 50 Gm causative factor is found in a patient with RPL glucose or Glucose Tolerance Test (GTT) as how is the patient counseled and managed Indians belong to the high risk group for further? developing diabetes. May be helpful for women Ans: The patient is labeled as “UNEXPLAINED” with PCOS because of the increased risk of accounting for nearly 40%-50% of cases of RPL. gestational diabetes. 26 Case Discussions in Obstetrics and Gynecology

• Ultrasound examination is recommended every Delivery and Puerperium two weeks and continued till that time in • If no associated obstetric complication no gestation when the woman had lost her indication for increased intervention before 40 pegnancies.53 weeks but the pregnancy should not be allowed to go beyond the expected date of delivery. Second Trimester Labor can be induced at term electively. • When cervical incompetence is suspected • Mode of delivery to be decided in consultation Transvaginal assessment of the cervix is done. with the patient. Recurrent pregnancy loss per It is an objective means of assessing the cervical se is not an indication for cesarean delivery. length and shape for predicting preterm birth Cesarean section to be done for any associated in high-risk population.54 obstetric or medical complication. Patients may • Prophylactic may be applied request for elective cesarean delivery. at 13 to 16 weeks in women at increased risk • Aspirin to be stopped at 36 weeks. for second trimester miscarriage including those • Anesthesia to be planned accordingly in patients with three or more second-trimester on heparin (LMWH/UFH) keeping in mind the miscarriages or spontaneous preterm births half-life of the preparation used. without bleeding or clear signs of labor • Postpartum thromboprophylaxis may be preceeding the miscarriage. An ultrasound scan indicated in women with certain types of inheri- to assess fetal viability and exclude apparent ted thrombophilias. fetal anomalies should be offered to the woman. • In women with APS and no additional throm- The stitch can be removed at 37 to 38 weeks or botic risk factors, postnatal thromboprophylaxis earlier if the patient goes into labor. is not recommended. • The stitch can also be applied in a high-risk REFERENCES patient with a singleton pregnancy who has a short cervix in the second-trimester. 1. Edmonds DK, Lindsay KS, Miller JF, et al. Early • A second trimester anomaly scan at 18-20 weeks embryonic mortality in women. Fertil Steril 1982;38:447-53. gestation. 2. Wilcox AJ, Weinberg CR, O’Connor JF, et al. • Repeat (GCT) with 50 Gm glucose or Glucose Incidence of early loss of pregnancy. N Engl J Med Tolerance Test (GTT) at 24-28 weeks if pre- 1988;319:189-94. vious test results were normal. 3. Jacobs PA, Hassod T. Chromosome abnormalities: • Uterine artery Doppler ultrasonography at origin and etiology in abortions and live births. In: Vogel F, Sperling K, eds. Human Genetics. Berlin: 22 to 24 weeks may be useful in predicting Springer-Verlag; 1987:233-44. preeclampsia and intrauterine growth restric- 4. The Practice Committee of the American Society for tion in women with APS.55 Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss. Fertil Steril 2008; 89:1603. Third Trimester 5. Stephenson M. Frequency of factors associated with Due to the high risk for intrauterine growth habitual abortion in 197 couples. Fertil Steril 1996; restriction in patients with RPL especially those 66:24-29. 6. Alberman E: The epidemiology of repeated abortion. with APS and thrombophilias: In Beard RW, Sharp F, eds: Early pregnancy loss: • Serial growth scans Mechanism and Treatment. London, RCOG press, • Umbilical artery Doppler. 1988;9-17. Recurrent Pregnancy Loss 27

7. Stirrat GM: Recurrent miscarriage: II. Clinical 20. Ziakas PD, Pavlou M, Voulgarelis M. Heparin associations, causes, and management. Lancet 1990; treatment in antiphospholipid syndrome with recurrent 336:728-33. pregnancy loss: a systematic review and meta-analysis 8. The American College of Obstetricians and Gyneco- Obstet Gynecol 2010;115(6):1256-62. logists. Management of Recurrent Early Pregnancy 21. De Wolf F, Carreras LO, Moerman P, et al. Decidual Loss. Washington, DC: The American College of vasculopathy and extensive placental infarction in a Obstetricians and Gynecologists; 2001. ACOG patient with repeated thromboembolic accidents, Practice Bulletin No. 24. recurrent fetal loss, and a lupus anticoagulant. Am J 9. De la Rochebrochard E, Thonneau P. Paternal age and Obstet Gynecol 1982;142:829-34. maternal age are risk factors for miscarriage: Results 22. Adler RR, Ng AK, Rote NS. Monoclonal anti- of a multicentre European study. Hum Reprod phosphatidylserine antibody inhibits intercellular 2002;17:1649-56. fusion of the choriocarcinoma line, JAR. Biol Reprod 10. Joseph AH. Recurrent Pregnancy Loss. In Creasy RK, 1995;53:905-10. Resnik R (Ed): Maternal-Fetal Medicine, Elsevier, 23. Katsuragawa H, Kanazaki H, Inoue T, et al. Pennsylvania 2004;5:587. Monoclonal antibody against phosphatidylserine 11. Rasch V. Cigarette, alcohol, and caffeine consumption: inhibits in vitro human trophoblastic hormone risk factors for spontaneous abortion. Acta Obstet production and invasion. Biol Reprod 1997;56:50-58. Gynecol Scand 2003;82:182-88. 24. Quenby S, Mountfield S, Cartwright JE, et al. 12. Kline J, Levin B, Kinney A, et al. Cigarette smoking Antiphospholipid antibodies prevent extravillous and spontaneous abortion of known karyotype: precise trophoblast differentiation. Fertil Steril 2005;83: data but uncertain inferences. Am J Epidemiol 691-98. 1995;141:417-27. 25. Miyakis S, Lockshin MD, Atsumi T, et al. International 13. Mills JL, Holmes LB, Aarons JH. Moderate caffeine consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). use and risk of spontaneous abortion and intrauterine J Thromb Haemost 2006;4:295-306. growth retardation. JAMA 1993;269:593-7. 26. Derksen RHWM, Groot PhG. The obstetric anti- 14. Fox-Lee L, Schust DJ. Recurrent pregnancy loss. In: phospholipid syndrome. J Reprod Immunol 2008; Berek JS, ed. Berek and Novak’s Gynecology. Phila- 77:41-50. delphia: Lippincott Williams and Wilkins 2007:1277- 27. Empson M, Lassere M, Craig JC, et al. Prevention of 1322. recurrent miscarriage for women with antiphospho- 15. Hanson U, Persson B, Thunell S. Relationship lipid antibody or lupus anticoagulant. Cochrane between hemoglobin A1c in early type I diabetic Database Syst Rev 2005;18(2):CD002859. pregnancy and the occurrence of spontaneous abortion 28. Rai RS, Clifford K, Cohen H, Regan L. High pros- and fetal malformation in Sweden. Diabetologia pective fetal loss rate in untreated pregnancies of 1990;33:100-4. women with recurrent miscarriage and antiphos- 16. Hirahara F, Andoh N, Sawai K, et al. Hyperpro- pholipid antibodies. Hum Reprod 1995;10:3301-4. lactinemic recurrent miscarriage and results of 29. Triolo G, Ferrante A, Ciccia F, et al. Randomized study randomized bromocriptine trials. Fertil Steril of subcutaneous low molecular weight heparin plus 1998;70:246-52. aspirin versus intravenous immunoglobulin in the 17. Stephenson M, Kutteh W. Evaluation and treatment of recurrent fetal loss associated with Management of Recurrent Early Pregnancy Loss. Clin antiphospholipid antibodies. Arthritis Rheum 2003; Obstet Gynecol 2007;50(1)132-45. 48:728-31. 18. Royal College of Obstetricians and Gynaecologists. 30. Hutton B, Sharma R, Fergusson D, et al. Use of The investigation and treatment of couples with Intravenous Immunoglobulin for treatment of recurrent miscarriage. RCOG Green Top Guideline recurrent miscarriage: a systematic review. BJOG No.17, 2003www.rcog.org.uk/files/rcogcorp/up- 2007;114:34. loadedsfiles/GT17RecurrentMiscarriage2003. 31. Cowchock FS, Reece EA, Balaban D, et al. Repeated 19. Li TC, Spuijbroek MD, Tuckerman E, Anstie B, fetal losses associated with antiphospholipid Loxley M, Laird S. Endocrinological and endometrial antibodies: a collaborative randomized trial comparing factors in recurrent miscarriage. BJOG 2000;107: prednisone with low-dose heparin treatment. Am J 1471-9. Obstet Gynecol 1992;166:1318-23. 28 Case Discussions in Obstetrics and Gynecology

32. Laskin CA, Bombardier C, Hannah ME, et al. 44. Daskalakis GJ. Prematurity prevention: the role of Prednisone and aspirin in women with autoantibodies cerclage. Curr Opin Obstet Gynecol 2009;21(2):148- and unexplained recurrent fetal loss. N Engl J Med 52. 1997;337:148-53. 45. Grimbizis GF, Camus M, Tarlatzis BC, et al. Clinical 33. The Practice Committee of the American Society for implications of uterine malformations and hystero- Reproductive Medicine. Aging and infertility in scopic treatment results. Hum Reprod Update women. Fertil steril 2006;86:S248-52. 2001;7:161-74. 34. Kutteh WH. Antiphospholipid antibodies and repro- 46. Bajekal N, Li TC. Fibroids, infertility and pregnancy duction. J Reprod Immunol 1997;35:151-71. wastage. Hum Reprod Update 2000;6:614-20. 35. Lockshin MD, Druzin M, Goei S, et al. Antibody to 47. Summers PR. Microbiology relevant to recurrent cardiolipin as a predictor of fetal distress or death in miscarriage. Clin Obstet Gynecol 1994;37:722-9. pregnant patients with systemic lupus erythematosus. 48. Regan L, Jivraj S. Infection and pregnancy loss. In: N Engl J Med 1985;313:152-56. Infection and Pregnancy. London: RCOG Press; 36. Bobrie G, Liote F, Houillier P, et al. Pregnancy in lupus 2001;291-304. nephritis and related disorders. Am J Kidney Dis 49. Brigham SA, Conlon C, Farquharson RG, A 1987;9:339-43. longitudinal study of pregnancy outcome following 37. Hayslett JP, Lynn RI. Effect of pregnancy in patients idiopathic recurrent miscarriage. Hum Reprod 1997; with lupus nephropathy. Kidney Int 1980;18:207-20. 12:387-9. 38. Haas DM, Ramsey PS. Cochrane Database Syst Rev 50. Stray-Pedersen B, Stray-Pedersen S. Etiologic factors 2008;16(2). and subsequent reproductive performance in 195 39. Kaandorp SP, Goddijn M, van der Post JA, et al. couples with a history of prior habitual abortion. Am Aspirin plus Heparin or Aspirin Alone in Women with J obstet Gynecol 1984;148:140-46. Recurrent Miscarriage. N Engl J Med 2010 Mar 24. 40. Clark P, Walker ID, Langhorne P, et al. SPIN (Scottish 51. Joseph AH. Recurent Pregnancy Loss. In Creasy RK, Pregnancy Intervention) Study: A Multicenter, Resnik R (Ed): Maternal-Fetal Medicine, Elsevier, Randomized Controlled Trial of Low-Molecular- Pennsylvania 2004;5:590. Weight Heparin and Low-Dose Aspirin in Women 52. Drugan A, Koppitch FC III, William JC III, et al. With Recurrent Miscarriage, on behalf of the Scottish Prenatal genetic diagnosis following recurrent early Pregnancy Intervention Study (SPIN) collaborators. pregnancy loss. Obstet Gynecol 1990;75:381. Blood 2010;115(21):4162-67. © 2010 American 53. Joseph AH. Recurent Pregnancy Loss. In Creasy RK, Society of Hematology. Resnik R (Ed): Maternal-Fetal Medicine, Elsevier, 41. de Braekeleer M, Dao TN: Cytogenetic studies in Pennsylvania 2004;5:591. couples experiencing repeated pregnancy losses. Hum 54. Owen J, Yost N, Berghella V, et al. National Institute Reprod 1990;5:519-28. of Child Health and Human Development, Maternal- 42. Tharapel AT, Tharapel SA, Bannerman RM. Recurrent Fetal Medicine Units Network: Midtrimester endo- pregnancy losses and parental chromosome abnor- vaginal sonography in women at high risk for malities: a review. Br J Obstet Gynecol 1985; 92:899. spontaneous preterm birth. JAMA2001;19:1340-48. 43. Ober C, Karrison T, Odem RR, et al. Mononuclear- 55. Venkat-Raman N, Backos M, Teoh TG, et al. Uterine cell immunization in prevention of recurrent mis- artery Doppler in predicting pregnancy outcome in carriages: a randomized trial. Lancet 1999;354: 365- women with antiphospholipid syndrome. Obstet 69. Gynecol 2001;98:235-242. Shakun Tyagi

3 Thrombophilia in Pregnancy

Thrombophilias are inherited or acquired with past history of thromboembolic episode conditions which predispose an individual to have underlying thrombophilia. thromboembolism. Severe pregnancy compli- • Detailed obstetric history is required to elicit cations such as severe pre-eclampsia, intrauterine the history which is suggestive of thrombo- growth retardation, abruption placentae and philia. All previous available clinical records, stillbirth have been shown to be associated with i.e. OPD records, discharge slips, USG scans, thrombophilia. Recurrent miscarriage has also been histopathological examination of products of associated with thrombophilia. conception, karyotyping reports and autopsy records if available should be evaluated. Ques- CASE tions should be asked to specifically know the period of gestation of onset of adverse fetal and A 26-year-old lady, Mrs T, G4P1A2L0 presents to maternal outcomes such as intrauterine growth antenatal clinic when 5 days overdue for restriction, fetal demise or early onset pre- confirmation of pregnancy. On detailed history, eclampsia. Mode of delivery in previous it was revealed that patient had previous pregnancy should be asked. In case of induction 2 intrauterine fetal demise at 10 weeks and of labor or LSCS the indication for same should 12 weeks detected at around 14 weeks period of be clarified. gestation followed by dilatation and evacuation. • Family history of thromboembolic episode In the third pregnancy, patient had severe should be taken to rule out inherited placental abruption at 31 weeks, 1.4 kg male baby thrombophilias. was delivered by cesarean section. The baby had • History should also try to exclude other systemic early neonatal death due to complications of complications related to Antiphospholipid prematurity and hypoxia. Anti-cardiolipin Syndrome (APS) like endocarditis, associated antibody test, which was performed one year back SLE. during interpregnancy period, was found to be positive. Q.2. What are the specific signs to look on examination? Q.1. What further history needs to be taken? Ans: The specific signs will depend on previous Ans: history of complications related to antiphos- • Past history suggestive of thromboembolic pholipid Syndrome, i.e. venous, arterial and episode in the self will point towards microvascular thrombosis; livedo reticularis and thrombophilia in the patient. 50% of patients associated disorders like SLE or other autoimmune 30 Case Discussions in Obstetrics and Gynecology disorders which might be present along with Laboratory criteria APS. • Anticardiolipin antibodies IgG and/or IgM in blood present in medium or high titre, on two Q.3. How the diagnosis of APS will be or more occasions, at least 6 weeks apart. confirmed? β • Anti- 2-glycoprotein I antibodies IgG and/or Ans: IgM in blood present in medium or high titre, • Definite Antiphosphoplipid Syndrome may be on two or more occasions, at least 6 weeks diagnosed if at least one of the clinical criteria apart. and at least one of the laboratory criteria are • Lupus Anticoagulant (LA) Antibodies- LA met. present in plasma, on two or more occasions, Clinical criteria at least 6 weeks apart, detected according to Vascular thrombosis- following guidelines: • Arterial – Prolonged phospholipid dependent coagu- • Venous lation demonstrated on a screening test, for • Superficial/small vein thrombosis. example, activated partial thromboplastin Pregnancy related morbidity time, Kaolin clotting time, dilute Russel’s • One or more unexplained death of a morpho- viper venom time. logically normal fetus at or beyond 10 weeks – Failure to correct the prolonged coagulation of gestation, normal fetal morphology docu- time on the screening test by mixing with mented by ultrasound or by direct examination normal platelet poor plasma. of the fetus. – Shortening or correction of the prolonged • One or more premature birth of a morpho- coagulation time on screening test by the logically normal neonate before the 34th week addition of excess phospholipid. of gestation because of eclampsia or severe – Exclusion of other coagulopathies, for pre-eclampsia or recognized features of example, factor VIIIc deficiency. placental insufficiency such as: In this patient antiphospholipid antibody test i. Abnormal or non-reassuring fetal sur- was previously performed once only and that also veillance tests, e.g. a nonreactive non- one year back therefore it needs to be repeated stress test. before making the diagnosis. ii. Abnormal Doppler flow velocimetry waveform analysis suggestive of fetal Q.4. What other investigations should hypoxemia, e.g. absent end diastolic be performed in the above described patient, flow. Mrs T? iii. Oligohydramnios—AFI< 5 iv. Post natal weight < than 10th percentile Ans: for the age of gestation. • Confirmation of the pregnancy: Following • Three or more consecutive spontaneous abor- pervaginal examination pregnancy should be tions before tenth week of gestation with confirmed by a urine pregnancy test. A Trans- maternal anatomic or hormonal abnormalities vaginal Sonography should be performed to and paternal and maternal chromosomal causes confirm an intrauterine pregnancy, also whether excluded. the sac diameter corresponds to the period of Thrombophilia in Pregnancy 31

gestation and if fetal node is present, whether • Family history of thrombosis. cardiac activity is there. • Family history of thrombophilia (especially • Routine antenatal investigations: BG and AT-III deficiency). Rh factor, Hb, PCV, STS, HIV after pretest counseling, HBsAg and urine routine and Q.7. What are the physiologic changes during microscopy examination. pregnancy that predispose to thromboembo- • Other investigations for recurrent pregnancy lism? loss like Glucose Tolerance Test and Thyroid Ans: The physiologic changes in the clotting system Stimulating Hormone should be done if the during pregnancy are geared up towards reducing clinical findings are suggestive of Diabetes or hemorrhage postabortal and in postpartum period Hypothyroidism. but in turn lead to a hypercoagulable state. • Platelet count – thrombocytopenia may be Changes in clotting and fibrinolytic proteins as present along with APS. follows: • Two to three fold increase in concentration of Q.5. What is the possible differential diagnosis? fibrinogen. Ans: If tests for APLS come out to be negative • 20 to100% increased factors VII, VIII, IX, X when repeated, this patient needs to be investigated and XII. for inherited thrombophilias. It will include • Upto 55% decline in protein S and C leading to • Polymerase chain reaction to detect pro- increase in resistance to protein C. This decline thrombin 20210A and MTHFR mutations. has been found to be exacerbated by cesarean • Activity assays for antithrombin, protein C, and delivery and infection. Protein S (with consideration of the normally • 3 to 4 fold increase in type I Plasminogen reduced protein S level in pregnancy). Activator Inhibitor (PAI) as well as type II PAI. • Fasting homocystein levels Mechanical factors • Thrombocythemia • Venous stasis in lower extremities due to Ideally the lab investigations for these disorders compression of inferior vena cava and pelvic are best performed in the nonpregnant state when veins by the enlarging uterus and hormone – not on hormonal or anticoagulation therapy and mediated increase in deep vein capacitance more than six months of any acute thromboembolic secondary to increased circulating levels of episode. estrogens and local production of nitric oxide. • Vascular damage – tissue trauma during vaginal Q.6. What are the indications of performing delivery and cesarean section. thrombophilia profile during pregnancy? Ans: Thrombophilia testing is recommended if Q.8. What is the prevalence of thrombophilias there is: in patients with adverse pregnancy outcome in • Personal history of thrombosis. India? • Prior early onset severe pre-eclampsia (<34 Ans: In Indian studies, thrombophilia is an weeks gestation). important contributing factor for both early and late • Prior severe fetal growth restriction, severe pregnancy losses which is in line with other western placental insufficiency (oligohydramnios, studies.1 Approximately two-third of all the cases abnormal Doppler velocimetry, abnormal fetal of unexplained fetal losses could be explained by testing, abnormal placental histology). acquired or heritable thrombophilia or both. A clear 32 Case Discussions in Obstetrics and Gynecology association has been established between fetal loss Q.11. This patient did not report before planning and antiphospholipid antibody syndromes and the pregnancy. Had this patient come at pre- antithrombin deficiency, and combined defects. pregnancy, what counseling should be done in However, reports on the prevalence of inherited such patients? prothrombotic defects such as factor V Leiden Ans: At the time of pre-pregnancy counseling mutation and methylene tetrahydrofolate reductase • The levels of anticardiolipin antibodies should C677T polymorphism in fetal loss are contra- have been repeated. dictory.2 Larger, well planned studies are lacking • The various maternal and fetal complications in this regard. should have been discussed with her. Q.9. What are the prevalence rates of thrombo- • She should have been assessed for various long philias in patients with VTE? term complications of APLS by performing kidney function tests, platelet counts and Ans: The prevalence rates of thrombophilias in Hemogram. patients with VTE is given in Table 3.1. • The requirement for anticoagulation throughout Table 3.1: Prevalence of inherited thrombophilias3 pregnancy should be discussed along with the Thrombophilia General Patients with side effects of long term heparin therapy, i.e. population VTE heparin induced osteoporosis and heparin Antithrombin, Protein C, 1% 7% induced thrombocytopenia. Protein S deficiency Factor V Leiden Caucasians 21% Q.12. What will be the antepartum management 4-7% in this patient, Mrs T with APLS? Non- Caucasians 6% 0-1% Ans: Prothrombin 20210A Caucasian 6% • Anticoagulation: 2-3% – For women with these pregnancy compli- Non- Caucasians cations who test positive for APLAs and 0-1% have no history of venous or arterial Elevated FVIII;c levels 11% 25% Mild hyperhomocysteinemia 5% 10% thrombosis, antepartum administration of prophylactic UFH or prophylactic LMWH Q.10.What is the risk of thromboembolism combined with aspirin is recommended during pregnancy with thrombophilia? (Grade 1B). – Prophylactic LMWH: Deltaparin, 5000 Ans: The risk of thromboembolism during pregnancy with thrombophilia is given in Table 3.2 units/day SC, Enoxaparin, 40 mg/d SC – Prophylactic UFH: SC 5000-10,000U Table 3.2: Risk for venous thromboembolism during 12 hrly, SC pregnancy in women who have thrombophilia4 – Low dose aspirin (75mg OD) should be Thrombophilic defect Odds ratio for started as soon as pregnancy test is positive. thromboembolism – Heparin (Low molecular weight heparin or Factor V Leiden heterozygous 9.32 Unfractionated Heparin) should be started Factor V Leiden homozygous 34.40 as soon as cardiac activity is found to be Protein C deficiency 4.76 positive on sonography. Protein S deficiency 3.19 – During first few weeks of starting Unfrac- Prothrombin 20210A heterozygous 6.80 tionated Heparin careful watch must be kept Thrombophilia in Pregnancy 33

on Platelet count of the patient due to risk Ans: Recommended regimen in women with of immune mediated severe thrombo- history of thromboembolic episode will be: cytopenia due to unfractionated heparin. • Unfractionated heparin: 8-12 hrly adjusted dose The risk of immune mediated thrombo- SC according to aPTT, to keep the mid-interval cytopenia is much less with low molecular (between two doses) aPTT 1.5 times the control weight heparin as compared to unfrac- mean. tionated heparin. • LMWH: Weight –adjusted (Enoxaaparin 1/mg/ • Monitoring of anticoagulation: No moni- kg 12 hrly or Deltaparin 200 U/kg 12 hrly SC. toring is required when low dose aspirin alone is given to the patient. When unfractionated Q.14. What are the various obstetric and non- heparin is prescribed, APTT should be obstetric complications of APLS and other monitored biweekly when starting the dose and thrombophilias? it can be made weekly later on. Low molecular weight Heparin may need to be monitored with Ans: Obstetric Complications Anti-Xa activity at extremes of maternal weight • Gestational Hypertension/Pre-eclampsia: (Anti-Xa level should be .6 to 1.0U/ml 4 to 6 30-50% of all patients with APLS suffer from hours after injection). Gestational Hypertension/Pre-eclampsia which • Calcium supplementation and weight bearing might be early in onset. exercises should be encouraged. • Intra Uterine Growth Restriction (IUGR) and • All women with previous VTE or a thrombo- preterm Birth: The rate of IUGR is almost philia should be encouraged to wear graduated 30% in patients with APLS. The preterm compression stockings throughout their delivery rate ranges from 32-65% partly due to pregnancy and for 6–12 weeks after delivery. high rate of Pre-eclampsia and IUGR. Good hydration and mobilization along with • 10 to 20% of all women with recurrent preg- Compression Stockings reduce the chances of nancy loss have circulating antiphospholipid VTE during pregnancy. antibodies. • Antenatal care: Regular antenatal care and Thrombotic complications of APS in pregnancy close maternal and fetal monitoring is required • Venous thrombotic events constitute 70% of all for detection of fetal growth restriction, thrombotic events in patients with APLS. The hypertensive disorders of pregnancy and rate of thromboses and stroke during pregnancy placental insufficiency. Umbilical Artery has been reported to be 5-12%. Doppler velocimetry is recommended at the age of viability. The NICU should be informed Q.15. What are the side-effects of long-term about severe growth restriction if it is present. LMWH? Early transfer to a higher facility should be considered in case of nonavailability of good Ans: NICU facilities for the neonate. The mode of • The side-effects of LMWH are much less than delivery should be decided according to unfractionated heparin. The incidence of obstetric considerations. osteoporotic fractures with LMWH is reported to be 0.04% (95% CI 0.01–0.2), and of allergic Q.13. What will be anticoagulation regimen in skin reactions as 1.8% (95% CI 1.34–2.37). The women with APLA and history of thrombotic risk of significant bleeding is likely to be less event? than 2% with prophylactic doses.5 34 Case Discussions in Obstetrics and Gynecology

Q.16. What intrapartum care will be provided Q.18. What are the principles of postpartum in this patient? management of patient with APLS? Ans: Ans: • For women receiving heparin, the dose of • Good hydration, mobilization and compression heparin should be withheld 24 hours prior if stockings should be continued during post- the woman is planned for induction of labor or partum period also. elective cesarean section. • In postpartum period the risk for thrombosis • If the patient goes into spontaneous labor further should be re-evaluated and decision should be dose of heparin need to be omitted and coagu- made regarding anticoagulation during post- lation profile needs to be performed. If patient partum period. The duration of anticoagulation is receiving unfractionated heparin its action can be 7 days only if there is no history of prior may be neutralized using protamine sulfate at thromboembolic episode. In case of history of the doses of 1mg Protamine sulphate/100 IU any thromboembolic episode, anticoagulation of Unfractionated Heparin to be neutralized. As is recommended for 12 weeks postpartum. Both only sixty percent of activity of LMWH is heparin and warfarins are safe during breast- reversed by Protamine sulphate, Fresh frozen feeding. plasma may be used if the patient who has • Contraceptive advice will depend on the recently received low molecular weight heparin obstetric outcome and whether the couple have goes into labor. completed the family. Combined hormonal • Good hydration and mobilization must be contraceptives are contraindicated in the maintained during first stage of labor. patients with thrombophilias. Barrier method • Continuous electronic fetal heart rate moni- and intrauterine contraceptive devices may be toring is recommended during labour. LSCS used. should be performed for obstetric indications. Q.19. Is there any randomized controlled trial Q.17. How can the chances of epidural hema- of efficacy of LMWH in preventing pregnancy toma in a patient on LMWH be reduced? complications in women with thrombophilias? Ans: To minimize or avoid the risk of epidural Ans: hematoma: • The Thrombophilia in Pregnancy Prophy- • Regional techniques should not be used until laxis Study (TIPPS)6 is under way to determine at least 12 hours after the previous prophylactic the safety and efficacy of Low Molecular dose of LMWH. Weight Heparin (LMWH) in preventing preg- • When a woman presents while on a therapeutic nancy complications (venous thromboembolic regimen of LMWH, regional techniques should events (VTE), pre-eclampsia, intrauterine not be employed for at least 24 hours after the growth restriction (IUGR), abruptio placentae, last dose of LMWH.5 miscarriage and stillbirth) in thrombophilic • LMWH should not be given for 4 hours after women. It is a multicentre, multi-national open- use of spinal anesthesia or after the epidural label randomized controlled clinical trial. Three catheter has been removed; the cannula should hundred and eighty-five (385) thrombophilic not be removed within 10–12 hours of the most women at risk for VTE or placenta mediated recent injection.5 pregnancy complications are being recruited. Thrombophilia in Pregnancy 35

Patients who require anticoagulant prophylaxis history of VTE but antithrombin deficiency6 during this pregnancy (as judged by the local is recommended (Grade 2C). investigator) or have participated in TIPPS 4. For pregnant patients with a single prior before will not be eligible for the trial. Inclusion episode of VTE associated with a transient critera are–Thrombophilic women < 16 weeks risk factor that is no longer present and no gestation with: (1) a history of previous pre- thrombophilia, clinical surveillance eclampsia, IUGR, abruptio placentae, mis- antepartum and anticoagulant prophylaxis carriage or stillbirth; or (2) a symptomatic first postpartum is recommended (Grade 1C). degree relative with thrombophilia would be 5. Pregnant women with a history of a single randomized to subcutaneous injections of prior episode of VTE associated with deltaparin or saline placebo throughout preg- pregnancy or exogenous estrogen use who nancy. Main Outcome Measures would be: are not receiving long-term anticoagulant (1) VTE, (2) Pre-eclampsia, (3) IUGR, therapy, antepartum prophylactic LMWH/ (4) Abruptio placentae, (5) Miscarriage, UFH or intermediate-dose LMWH/UFH or (6) Stillbirth, (7) Pre-term delivery, and clinical surveillance throughout pregnancy (8) Safety outcomes (bleeding, heparin induced plus postpartum anticoagulants is recom- thrombocytopenia, reductions in bone mineral mended (Grade 1C). density and fractures). The results of this ten 6. For patients with a history of a single prior year study are expected by year 2011. episode of VTE with a high risk throm- Q.20. What are the latest guidelines of American bophilia or with prior multiple episodes College of Chest Physicians Guidelines for the of VTE not receiving long term antico- antenatal and peripartum management of agulation, antepartum prophylactic or thrombophilia? intermediate-dose LMWH or prophylactic Ans: or intermediate-dose UFH and postpartum • Summary of 2008 Guidelines of American warfarin for 6 weeks is recommended College of Chest Physicians for the antenatal (Grade 2C). and peripartum management of thrombophilia 7. For those pregnant women with prior VTE (2008)7 are as follows: who are receiving long-term anticoagulants, 1. For women with recurrent early pregnancy LMWH or UFH is recommended through- loss or unexplained late pregnancy loss, out pregnancy (either adjusted-dose LMWH screening for antiphospholipid antibodies or UFH, or intermediate-dose LMWH) (APLA) is recommended [Grade 1A]. followed by resumption of long-term antico- 2. For women with these pregnancy compli- agulants postpartum (Grade 1C). cations who test positive for APLA and have 8. For pregnant women with acute VTE, it is no history of venous or arterial thrombosis, recommended that subcutaneous LMWH or antepartum administration of prophylactic UFH should be continued throughout preg- or intermediate-dose UFH or prophylactic nancy (Grade 1B) and it is suggested that LMWH combined with aspirin is recom- anticoagulants should be continued for at mended (Grade 1B). least 6 weeks postpartum (for a total 3. Both antepartum and postpartum pro- minimum duration of therapy of 6 months) phylaxis for pregnant women with no prior (Grade 2C). 36 Case Discussions in Obstetrics and Gynecology

9. For all other pregnant women with throm- 3. Michiel Coppers, MD Stef P Kaandorp, Middeldorp bophilia but no prior VTE, antepartum Saskia. Inherited. Thrombophilias in Obstet Gynecol Clin N Am. Edited by Blickstein Isaac, Rayburn clinical surveillance or prophylactic LMWH William. F. 2006;33:357-74. or UFH, plus postpartum anticoagulants, 4. L Robertson, O Wu, P Langhorne, S Twaddle, et al. rather than routine care (Grade 2C) is Thrombophilia in pregnancy: a systematic review. suggested. British Journal of Haematology 2006;132:171-96 5. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of REFERENCES venous thromboembolism in pregnancy: a systematic 1. Vora S, Shetty S, Ghosh K.Thrombophilic dimension review of safety and efficacy. Blood 2005;106:401-7. of recurrent fetal loss in Indian patients.Blood Coagul 6. Horlocker TT, Wedel DJ, Benzon H, Brown DL, Enneking FK, Heit JA, et al. Regional anesthesia in Fibrinolysis. 2008;19(6):581-4. the anticoagulated patient: defining the risks (the 2. Biswas A, Choudhry P, Mittal A, Meena A, Ranjan R, second ASRA Consensus Conference on Neuraxial Choudhry VP, Saxena R. Recurrent abortions in Asian Anesthesia and Anticoagulation). Reg Anesth Pain Indians: no role of factor V Leiden Hong Kong/ Med 2003;28:172-97. Cambridge mutation and MTHFR polymorphism. Clin 7. American College of chest Physicians Guidelines for Appl Thromb Hemost. 2008;14(1):102-4. Epub 2007 the Antenatal and Peripartum Management of Dec 26. Thrombophilia (2008). Usha Manaktala, Avantika Gupta 4 Anemia in Pregnancy

DEFINITION 1. Nutritional: Iron deficiency, folate and World Health Organization (WHO) has defined vitamin B12 deficiency. anemia during pregnancy as hemoglobin concen- 2. Anemia of chronic disease: For example, tration of less than 11 gm% and a hematocrit of chronic malaria, TB. less than 33%.1 CDC (Center for Drug Control) 3. Bone marrow insufficiency: Due to drugs, proposes a cut off point of 11 gm% in 1st and 3rd radiation. trimester and 10.5 gm% during 2nd trimester. 4. Chronic blood loss from any site, e.g. bleeding piles, hookworm infestation. Magnitude of Problem • Hereditary: Thalassemias, sickle cell hemoglo- Anemia is the most common medical disorder binopathies, hereditary hemolytic anemia. during pregnancy, resulting in increased maternal Only nutritional anemias which are common in morbidity and mortality. According to National pregnancy are discussed in details in this chapter. Family Health Survey-3 (2005-2006), prevalence of anemia in pregnancy is 57.9%.2 FOGSI-WHO CASE 1 study on maternal mortality revealed that 64.4% of women who died had hemoglobin of less than Patient Mrs X wife of Mr Y, resident of UP, 8 gm% and 21.6% had hemoglobin less than belonging to lower socioeconomic class, is 30 5 gm%.3 years old fourth gravida, para 3 with 3 living issues, with 30 weeks period of gestation presented Severity of Anemia for the first time in ANC OPD with complaint of: According to ICMR, severity of anemia is graded 1. Amenorrhea since 7 months. as: 2. Weakness and easy fatiguability since last Mild degree 10-10.9 gm% 3 months. Moderate degree 7-10 gm% 3. Breathlessness on exertion since last 15 days. Severe degree Less than 7 gm% Patient complains of easy fatiguability and Very severe degree Less than 4 gm% weakness since last 3 months which has gradually increased over last 15 days to an extent that she Etiology gets tired on doing household activities. Patient also • Physiological complaints of breathlessness on exertion since last • Acquired 15 days. Patient gets breathless on climbing 2 flight 38 Case Discussions in Obstetrics and Gynecology of stairs. It is not associated with palpitations or Obstetric History any chest pain. There is no history of pedal edema, She is gravida 4, para 3, with 3 living issues. All sudden onset breathlessness, cough or decreased children were full-term normal vaginal delivery at urine output. There is no history of asthma or home. All issues are alive and healthy and immu- chronic cough. There is no history of chronic fever with chills or rigors. There is no history of passage nized. There is no history of postpartum hemorr- of worms in stool nor blood loss from any site. hage in any pregnancy. There is no history of easy bruisability or petechiae. Past History There is no history of yellow discoloration of urine, skin or eyes. She did not take iron folate prophylaxis • There is no history of blood transfusion in the in this pregnancy. past. There is no history of jaundice, any chronic illness or recurrent urinary tract infection. Trimester History • There is no past history of tuberculosis. She is First Trimester not a known case of asthma. No history of fever, joint pain or recurrent sore throat in the past. • Spontaneous conception • No history of radiation or any teratogen Personal History exposure • No history of fever with rash, burning mictu- • My patient is a housewife. She does not have ration, discharge or bleeding per vaginum any kind of addiction. • No history of any drug intake • She belongs to endemic area for malaria. • No history of hyperemesis. Family History Second Trimester There is no history of repeated blood transfusions • She perceived quickening at 3rd month or thalassemia in any of the family member. • Only single ANC visit • Patient did not take any IFA prophylaxis Socioeconomic History • She has received one dose of tetanus She belongs to lower middle class according to immunization from local dispensary modified Kuppuswamy scale. • No history of high BP records, pedal edema, headache, epigastric pain, blurring of vision Dietary History • No history of polyuria, polydipsia, polyphagia • No history of pain abdomen, leaking or bleeding Total calorie intake is 1500 Kcal and protein intake per vaginum. is 17 gm per day which is grossly inadequate. Iron intake is around 15 mg/day. Menstrual History On Examination Her LMP is _____ EDD is _____ My patient is conscious and well oriented to time, Her menstrual cycles were regular with normal place and person. She is thin built. Her height is blood flow. 5 feet and weight is 50 kg. Her gait is normal. Anemia in Pregnancy 39

Vitals • Abdominal girth is around 29 inches • Fundal grip – Broad irregular mass suggestive • Her pulse rate is 80/min regular, good in of breech volume, bilateral synchronous without any • Lateral grip – Back felt on right side and limbs radiofemoral delay. felt on left side • Her BP is 120/80 mm Hg • Pelvic grip – Smooth hard ballotable mass • Her JVP is not raised. She is afebrile suggestive of head felt • Her Respiratory rate is 20/min • Liquor appears to be adequate. General Physical Examination Auscultation: Fetal heart rate is 140/min regular.

• Hair shows signs of malnutrition: Final Diagnosis • Pallor is seen in the conjunctiva and skin • There is no icterus Thirty years old G4P3L3 with 30 weeks period of • There is no angular stomatitis, glossitis or gestation with single live fetus in cephalic pre- cheilosis sentation with anemia not in failure. • Nails show platonychia • She is suspected to be anemic and her blood • There is no pedal edema sample was ordered for examination which showed. Breast Examination • Hb 7.4 gm % (12-14 gm%) • Hct 22 % ( 36-44%) Breasts show normal changes of pregnancy. • MCV 72 fL (80-97 fL) • MCH 25 pg (27-33 pg) Systemic Examination • MCHC 30 % (32-36%) Cardiovascular: Apex beat is present in 5th • Peripheral smear shows microcytic hypo- intercostals space and is hyperdynamic S1S2 chromic RBCs with anisopoikilocytosis normal. • Naked eye single tube red cell osmotic fragility Ejection systolic murmur grade II/VI is heard test (NESTROFT) is negative. best over pulmonary area not radiating to any site. Q.1. What investigations will you order in a case Respiratory: Air entry equal on both the sides. of anemia? No added sounds or crepts heard. Ans: Investigations which should be done in a case CNS: No abnormality detected of anemia are: Abdominal Examination Investigations which are recommended in all antenatal patients are: Inspection • Blood group • Abdomen uniformly distended. • HIV antigen 1 and 2 • Linea nigra and stria gravidarum present • Australia antigen • No scar mark • VDRL • All hernia sites are free • Glucose challenge test at 24-28 weeks • No hepatosplenomegaly • Urine routine and microscopy Palpation • Hemoglobin to be done at 1st visit, 28, 32 and • Fundal height is around 28 weeks 36 weeks • Symphysiofundal height is 28.5 cm • Obstetric ultrasound at 20 weeks. 40 Case Discussions in Obstetrics and Gynecology

Apart from the above investigations, following Q.3. What should the approach to the manage- investigations are required for the work-up of ment of anemia in pregnancy? anemia. Ans: 1. Routine tests for anemia, i.e. if Hb < 11 gm% 1. Confirm the diagnosis of anemia by hemoglobin are as follows: and hematocrit estimation, i.e. Hb < 11gm% or • Complete blood count which includes he- hematocrit < 33%. moglobin, MCV, MCH, MCHC, reticulo- 2. Grade the severity of anemia according to cyte count, total leukocyte count and platelet hemoglobin levels, i.e count. • Hb < 7 gm% severe anemia • Peripheral smear should be made to see the: • 7-10 gm% moderate anemia – Morphology of RBC’s for type of • 10-10.9 gm% mild anemia anemia 3. Find out the type of anemia which is determined – Hypersegmentation of neutrophils (5% by the RBC indices, i.e. MCV, MCH, MCHC neutrophils showing 5 lobes or more or and the peripheral smear. even a single neutrophil with 6 or more 4. Investigate for the cause of anemia and treat lobes) the cause. – Hemoparasite – Evidence of hemolysis Q.4. Describe the physiology of iron metabolism. – Platelet count Ans: Iron is a trace element which is required for 2. Screening for thalassemia should be done in all erythropoeisis. Dietary iron is found in two forms: patients attending antenatal clinic as the 1. Heme: Found in meat and meat products incidence of thalassemia is high in North India (5-10% of dietary iron). It is the most around 3-5%. The screening test done is known bioavailable source of iron. as NESTROFT test. 2. Non heme: Found in cereals, pulses, vegetables 3. Iron studies are done to confirm the diagnosis (90-95% of dietary iron). of iron deficiency anemia in case the woman Figure 4.2 depicts the process of iron does not respond to the treatment. It includes: metabolism. – Serum ferritin Iron is absorbed in duodenum and upper 2+ – Serum iron concentration jejunum. Fe present in diet is oxidized to ferric 3+ – Transferrin saturation state (Fe ) in presence of gastric acidic pH so that – Total iron binding capacity it is maintained in the solution form and is taken to Figure 4.1 gives the protocol for diagnosis of the duodenum. At the brush border of the absorptive 3+ 2+ anemia. cell, Fe is reduced to ferrous form (Fe ) by ferrireductase. Transport across membrane is accomplished by bivalent metal transporter Q. 2. What is the aim of the management of 2+ anemia? (DMT-1). Once inside the gut cell, Fe is oxidized again to Fe3+ form so that it can bind to Ans: The aim of the treatment of anemia is to apotransferrin to form transferrin which is the achieve a safe level of hemoglobin at the time of transport protein.4 delivery which is associated with minimum Iron circulates in plasma bound to transferrin complications. The desired hemoglobin level at the and binds to transferrin receptors on the surface of time of delivery is around 8 gm%. marrow erythroid cells. Once the iron-transferrin Anemia in Pregnancy 41

Fig. 4.1: Diagnosis of anemia complex binds with its receptor, the complex is Ans: Factors enhancing absorption: The heme form internalized via clathrin coated pits. The iron is then of iron has the better bioavailability and is absorbed made available for heme synthesis while the in the ferrous form. transferrin receptor complex is recycled back into • Ascorbic acid circulation. The iron is incorporated into heme • Fermented food items and alcohol • Gastric acidity containing enzymes for hematopoeisis and the • Low iron stores excess iron binds to the storage protein, apoferritin, • Increased erythropoeitic activity forming ferritin which gets stored mainly in bone Factors inhibiting absorption: marrow and liver. • Phytates • Calcium Q.5. What are the factors affecting iron • Tea and coffee absorption? • High iron stores 42 Case Discussions in Obstetrics and Gynecology

Fig. 4.2: Iron metabolism

Q.6. What are the stages of iron deficiency Q.7. What is iron folic acid prophylaxis? anemia? Ans: In National Anemia Control Program under Ans: Iron depletion is the earliest stage of iron Ministry of Health and Family Welfare, all pregnant deficiency, in which storage iron is decreased or women who are not anemic are given folifer tablet absent but serum iron concentration, transferring containing 100 mg elemental iron along with 500 saturation and blood hemoglobin levels are normal. μg folic acid for at least 100 days. This prophylaxis Iron deficiency without anemia is a somewhat more against anemia needs to be continued till lactation.5 advanced stage of iron deficiency, characterized by decreased or absent storage iron, usually low serum Q.8. Why is iron folic acid prophylaxis required iron concentration and transferring saturation, but for every antenatal woman? without frank anemia. Iron deficiency anemia is Ans: This increased requirement during pregnancy the most advanced stage of iron deficiency. It is is not fulfilled by normal vegetarian diet. In India, characterized by decreased or absent iron stores, where deprived women consume only 1400 to 1800 low serum iron concentration, low transferring Kcal per day, inadequate food intake is the most saturation and low blood hemoglobin common reason for iron deficiency. Further, iron concentration.4 has a very poor bioavailability (1.5-5%), in the Anemia in Pregnancy 43

Normal Negative iron Iron deficient Iron deficiency balance erythropoiesis anemia\ Marrow iron stores 1-3 + 0-1+ 0 0 Serum ferritin (μg/L) 50-200 < 20 < 15 < 15 TIBC (μg/L) 300-360 > 360 > 380 > 400 Serum iron (mg/dL) 50-150 50-150 < 50 < 30 Transferrin saturation (%) 30-50 30-50 < 20 < 10 RBC morphology Normocytic Normocytic Normocytic Microcytic Normochromic Normochromic Normochromic hypochromic From Harrison’s Principles of Internal Medicine, 17th edition. TIBC - Total iron binding capacity, RBC - red blood cell traditional Indian diet that chiefly comprises cereals mg for fetus + 150 mg for placenta. Maternal and pulses. In endemic areas women suffer from blood loss at delivery = 250 mg. Total loss is chronic blood loss due to hookworm and malarial about 1200 mg. The total amount of iron that is infestation further enhancing the incidence and conserved due to amenorrhea amounts to severity of anemia. Hence, iron and folate 400 mg. Thus, net iron expenditure is prophylaxis is essential for every pregnant woman approximately 800 mg.5 to meet the increased demands. This increased demand is not met by the daily Indian diet and thus routine iron supple- Q.9. What is physiological anemia of pregnancy? mentation is required for every woman. Ans: The increase in plasma volume (30-40%) is 2. Dietary deficiency: It is the most common cause much more than the increase in red cell mass of iron deficiency in India, more so in socio- (10-15%) leading to apparent decrease in economically weaker section. It is amplified by hemoglobin level. wrong foods and food fads. · Starts at 7th-8th weeks 3. Impaired absorption: Due to various malab- · Maximum by 32 weeks sorption syndromes, chronic diarrhea, etc. · Does not go below 11 gm% in 1st trimester, 10 gm% in 2nd and 3rd trimester. The rise in RBC 4. Increased blood loss: Usually 5 mg of iron is volume begins at 20 weeks continues till term. lost for loss of about 10 ml of blood. Some of Therefore, in 3rd trimester there is slight rise in the common causes are: hemoglobin concentration. a. Hookworm infestation: Prevalent in areas In severs to reduce maternal blood viscosity, where people defecate in open fields. The thereby enhancing placental perfusion and larva of hookworm enters the body by facilitating nutrient and oxygen delivery to the fetus. penetrating the sole. The blood loss caused is about 0.2 ml/worm/day. Q.10. What are the causes of iron deficiency b. Multiple pregnancies in Indian patients anemia in pregnancy? result in IDA since in each pregnancy there Ans: Common causes of iron deficiency anemia is loss of 650 mg iron equivalent to about are: 1300 ml blood. 1. Increased demand, 280, mg iron is required for c. In lactation, loss of iron is to the tune of basal iron + 570 mg for RBC expansion + 350 0.5 to 1 mg/day. 44 Case Discussions in Obstetrics and Gynecology

Q.11. What are the complications of severe Ans: anemia during pregnancy? Iron deficiency Thalassemia Ans: The complications of severe anemia during anemia pregnancy are as follows: RBC count < 5.5 million >5.5 million Anisopoikilocytosis Marked Mild Maternal Red cell distri- Increased Normal bution width A. During pregnancy Serum ferritin Decreased Normal or slightly reduced 1. Poor weight gain Serum iron Decreased Normal 2. Decreased immune response TIBC Increased Normal 3. Preterm labor Transferrin saturation < 15 % 30-40 % 4. CHF at 30-32 weeks of pregnancy HbA2 level Normal or Increased reduced (<3.5%) (3.6 – 8.0%) 5. Decreased work capacity TIBC - Total iron binding capacity, RBC - Red blood cell B. During labor HbA2 - Hemoglobin-A2 1. Dysfunctional labor 2. CHF Q.14. How is NESTROFT test done? How it is 3. Inability to stand even slight blood loss interpreted? 4. Anesthesia risk Ans: NESTROFT test is ‘naked eye single tube C. Puerperium red cell osmotic fragility test’. In this test 2 ml of 1. Puerperal sepsis 0.36% buffered saline solution is taken in one tube 2. Subinvolution and 2 ml of distilled water in another tube. A drop 3. Pulmonary embolism of blood is added to each test tube and both the 4. Lactation failure tubes are left undisturbed for 20 minutes. Both the tubes are then shaken and held against a white paper Fetal on which a black line is drawn. Normally, the line is clearly visible through the contents of tube 1. IUGR containing distilled water. If the line is clearly 2. Low iron stores at birth if mother has severe visible similarly through the contents of tube with anemia buffered saline, the test is negative. If the line is 3. Poor Apgar score. not clearly visible the test is considered positive. The principle is that normocytic normochromic Q.12. What is the differential diagnosis of cells when put in hypotonic solution will undergo microcytic hypochromic anemia? lysis wheras in thalassemia trait, the cells are Ans: The differential diagnosis of mirocytic microcytic and hypochromic which are resistant to hypochromic anemia are : hemolysis due to decreased fragility. It has 91% 1. Iron deficiency anemia sensitivity and 95% specificity and the negative 7 2. Thalassemia predictive value is 99%. NESTROFT test is only 3. Sideroblastic anemia a screening test for thalassemia. The definite test is the estimation of HbA2 levels by high liquid Q.13. How do we differentiate iron deficiency performance chromatography. In thalassemia HbA2 anemia from thalassemia? levels are > 3.5%. Anemia in Pregnancy 45

Q.15. What is the treatment for anemia in this 3. Improvement in other symptoms. patient? Laboratory parameters:6 Ans: Since the period of gestation is 30 weeks and 5-7 days: Increase in reticulocyte count to up to the patient has iron deficiency anemia of moderate 5% (Normal 0.2 -2 %) type, we can give both the the options to the patient 2-3 weeks: Increase in hemoblobin level @ 0.8- – oral as well as parenteral iron. 1.0 gm/dL/week We can start oral iron therapy for this patient as Improvement in RBC indices – MCV, we have enough time to monitor the response of MCH, MCHC the treatment before she reaches term pregnancy. 6-8 weeks: Hemoglobin level comes to normal Secondly, oral iron is safe, easy to administer and level cheap. Peripheral smear shows normocytic Deworming is done with mebendazole (100 mg normochromic RBC’s twice daily for 3 days) as the prevalence of iron Increase in serum ferritin level. deficiency anemia due to hookworm infestation is high in our country. Q.19. What are the causes of non-improvement Iron is given as 180-200 mg in elemental form of anemia after 3 weeks of iron treatment? in two to three divided doses in between the meals along with vitamin C to enhance its absorption. The Ans: The causes of non-improvement of anemia patient is also given high protein diet which is also after 3 weeks are: required for hemoglobin synthesis. 1. Inaccurate diagnosis – Thalassemia, pyridoxine deficiency Q.16. What is the duration of oral iron therapy? 2. Non-compliance Ans: Hemoglobin levels start rising in 2-3 weeks 3. Continuous blood loss, e.g. hookworm infes- and reaches normal value after 6 weeks of therapy. tation, bleeding hemorrhoids To build-up the stores, treatment should be 4. Co-existing infection continued for next 3 months. Iron folic acid 5. Faulty absorption prophylaxis should be continued even after the 6. Concomitant folate deficiency. treatment till lactation.5 Q.20. How will you check for the compliance of Q.17. What should be done if this patient does the oral iron treatment? not tolerate oral iron? Ans: Compliance to oral iron is checked by: Ans: 1. Repeated questioning about the intake 1. Take oral iron in between the meals 2. Color of the stool which should be black 2. Change the iron salt preparation 3. Associated symptoms like constipation, gastritis 3. Switch over to parenteral route. 4. Return of the empty blister packs if she is following regularly. Q.18. How do we assess the response of treat- ment of iron deficiency anemia? Q.21. What are the management options for Ans: Clinical improvement assessed as: treatment of iron deficiency anemia? 1. Increased sense of well-being Ans: Oral iron: 180-200 mg elemental iron given 2. Increase in work capacity daily in divided doses in between meals. 46 Case Discussions in Obstetrics and Gynecology

The various iron salts available are ferrous Q.22. What are the indications of parenteral sulfate, ferrous fumarate, ferrous ascorbate, etc. iron? Other salts are ferrous gluconate, carbonyl Ans: The rise in hemoglobin after parenteral iron. therapy is 0.7- 1.0 gm% per week which is same as 1. Ferrous sulfate has high amount of elemental seen with oral iron therapy. The main advantage of iron and has good bioavailability but is parenteral therapy is the certainity of its adminis- associated with gastrointestinal side effects and tration. The indications of parenteral iron are: staining of teeth. 1. Intolerance to oral iron 2. Ferrous fumarate has a similar efficacy and GI 2. Impaired iron absorption tolerance to ferrous sulphate. 3. Chronic blood loss 3. Of all the preparations, ferrous ascorbate is 4. Gastrointestinal disorders which gets aggra- preferred because: vated by oral iron-peptic ulcer disease, – It contains high proportion of elemental iron ulcerative colitis – Converts ferric to ferrous form 5. After 32 weeks period of gestation, parenteral – Inhibits the formation of insoluble iron iron is preferred as the compliance is 100%. complexes – Inhibits the conversion of ferritin to hemo- Q.23. What are the disadvantages of intra- siderin preventing iron overload. muscular over intravenous iron administration? 4. Iron polymaltose complex is a combination of Ans. Intramuscular iron has some disadvantages ferric iron with maltol. It has less absorption over intravascular iron administration: than ferrous salts. It may be tried as an 1. It causes staining of the skin. alternative for those patients who cannot tolerate 2. It is more painful. ferrous form as compliance is of significant 3. It can cause abscess. concern during pregnancy. 4. Multiple injections are required as maximum Parenteral iron: It can be given by either intra- 2 ml containing 100 mg iron can be given at a muscular or intravenous route. time. Therefore, it causes more discomfort to Dose of parenteral iron is calculated as:5 the patient. Body weight in kg × (Desired Hb – patient’s Hb) 5. Its absorption is irregular. × 2.21 + 1000 mg 1000 mg is taken for complete restoration of Q.24. What are the various parenteral iron the stores in patients with continuing blood loss preparations available? otherwise 500 mg is adequate for patients whose Ans. Intramuscular preparation:6 blood loss has been arrested. 1. Iron sorbitol citrate complex is a low molecular OR weight complex, and therefore, it gets easily Give 250 mg elemental iron for each gm of Hb absorbed. The recommended single dose for deficit and add another 50% for replenishment of injection is 1.5 mg/kg body weight after giving stores. an intramuscular test dose. The single daily Intramuscular iron preparations available are injection of more than 2 ml containing 100 mg iron dextran, iron sorbitol citrate complex. of iron is not recommended. Hence, multiple Intravenous iron preparations available are iron injections are required to administer the com- dextran, iron sucrose, ferrous gluconate. plete dose. It is given by Z technique to avoid Anemia in Pregnancy 47

staining of the skin. It can cause local Q.25. What are the advantages and disadvan- discomfort, pain, flushing, metallic taste. tages of oral and parenteral iron? Severe systemic reaction can occur in case Ans: of overdose. Advantages Disadvantages 2. Iron dextran: It also requires a test dose and a maximum of 2 ml is given at a time. It is Oral 1. No anaphylaxis 1. Gastrointestinal associated more systemic complications and has 2. Easy to take disturbances, e.g. 3. Cheap constipation, an erratic absorption. Therefore, it is not diarrhea, gastritis preferred nowadays. 2. Metallic taste in Intravenous preparation:8 mouth 1. Iron sucrose has certain advantages over other 3. Non-compliance preparation as: Parenteral 1. 100% compliance 1. Invasive a. No test dose is recommended 2. Preferred in gas- 2. Painful adminis- trointestinal tration b. It has minimum side effects malabsorption 3. Staining and abs- c. It is usually not associated with anaphylactic syndromes, e.g. cess formation at reaction Ulcerative colitis, the site of intra- d. Most preferred in patients undergoing Crohn’s disease, muscular injection hemodialysis as it has low molecular weight. Tropical sprue administration It can be given as iv push undiluted @ 1 ml/ 3. Preferred in 4. Anaphylaxis reac- min maximum dose being 100 mg, i.e. over patients who are tion 5 minutes as 5 ml contains 100 mg iron. The unable to tolerate 5. Thromboplebhitis oral iron, e.g. Peptic in intravascular other way is to dilute 5 ml vial in 100 ml normal ulcer disease administration saline (1 mg/mL) and administer it over at least 4. Certainity of 6. Expensive 20 minutes. No test dose is required. Only the restoration of initial 20-25 ml in given slowly to see for any stores in shorter signs of reaction. A maximum of 200 dose can time span be given at a time not more than thrice a week. 5. Correction of 2. Sodium ferric gluconate: It is administered as anemia near term direct iv push @ 12.5 mg/min as 5 ml contains 62.5 mg of iron or 125 mg, i.e. 10 ml can be Q.26. What are the indications of blood diluted in 100 ml saline and infused over 60 transfusion in anemia in pregnancy? minutes. No test dose is required. Ans: Blood transfusion in an anemic patient does 3. Iron dextran: It is associated with anaphylactic not treat the cause of anemia nor corrects the reaction, so a test dose is required.The total dose nonhematological effects of iron deficiency. can be given as one large dose or divided in According to WHO guidelines, the indications many smaller doses. It is either given in iv drip of blood transfusion are:9 by diluting 100 mg in 250 ml saline and infused 1. Less than 36 weeks over 30-60 minutes. 100 mg dose can be given a. Hb 5 gm% or below undiluted as iv push maximum @ 20 mg/min. b. Hb 5-7 gm% with established or incipient However, it is associated with systemic cardiac failure or clinical evidence of reactions like hypotension, urticaria, dizziness, hypoxia, pneumonia or any other bacterial arthralgia, lymphadenopathy, fever, etc. infection and malaria 48 Case Discussions in Obstetrics and Gynecology

2. 36 weeks or more 3rd stage: a. Hb 6 gm% or below with established or • Active management of 3rd stage except in very incipient cardiac failure or clinical evidence severe anemia for fear of congestive heart of hypoxia, pneumonia or any other failure bacterial infection and malaria • Slow delivery of baby in 2-3 months 3. Elective LSCS: When elective LSCS is planned • Controlled cord traction and there is a history of antepartum hemorrhage, • Avoid postpartum hemorrhage as even a small postpartum hemorrhage or previous section. amount of blood loss can cause decompensation a. Less than 8 gm% - 2 units of blood should • Look for any genital trauma and control be cross matched bleeding. b. 8-10 gm% - 1 unit of blood should be cross Peurperium: matched. • Watch meticulously till 6 hours postpartum for any signs of failure Q.27. A woman presents at 37 weeks in active • Prophylactic antibiotic to prevent sepsis labor with hemoglobin 6 gm% not in failure. • Continue iron and folic acid for at least 3 months How will you manage this patient? IFA prophylaxis to be continued till lactation Ans: The hemoglobin levels at the time of delivery • Adequate rest should be at least 7 gm% and it is known that one • Contraceptive advice unit of blood increases hemoglobin levels by 0.8-1 – Postpartum sterilization if family is gm%. So this patient requires at least 1 unit packed completed. cell volume, each should be transfused slowly over – She should not conceive for at least 2 years 4-6 hours. giving time for iron stores to recover. 1st stage: – Barrier contraception is safe. • Patient should be propped up • Oxygen should be given if required Q.28. What is the role of erythropoietin in • Intermittent chest auscultation anemia? • Sedation and analgesic Ans: Erythropoietin can be given along with • Minimum number of per vaginum examinations parenteral iron in a dose of 50-150 U/kg given • Strict asepsis to be maintained subcutaneously twice/thrice weekly. It has certain • Partograph to be maintained advantages like : • Fluid restriction 1. Rapid correction of severe anemia in less than • Start antibiotic prophylaxis 2 weeks. 2nd stage: 2. Anemia not responding to intravenous iron • Prophylactic ventouse or outlet forceps to cut alone. short 2nd stage 3. Treatment of moderate to severe iron deficiency • Strict asepsis to be maintained anemia as an alternate to blood transfusion. • 0.2 mg intravenous methergin at delivery of anterior shoulder Megaloblastic Anemia • Restrict intravenous fluids • Oxytocin if required should be given in Megaloblastic anemias are characterized by concentrated form macrocytic blood picture and megaloblastic bone Anemia in Pregnancy 49 marrow. There is impaired DNA synthesis due to 3 weeks and investigations were repeated as there lack of vitamin B12 and/or folic acid. was no improvement with the therapy. Hb came to Both folic acid as well as vitamin B12 are be 6.5 gm% , Hct 21%, MCV 105 fL, MCHC 33%, required for DNA synthesis. MCH 24 pg/L. Her platelet count is 80,000/cc. Mechanism resulting in anemia are: Peripheral smear showed macrocytic RBC’s along 1. Unbalanced cell growth: The nuclear with nucleated RBC’s. Hypersegmented maturation lags behind the cytoplasmic neutrophils seen 7 per HPF. Diagnosis of maturation because there is retarded DNA macrocytic anemia was made. synthesis while RNA synthesis is normal. 2. Ineffective erythropoeisis: The destruction of Q.29. What are hematological findings in a case intermediate and late normoblasts in bone of megaloblastic anemia? marrow leads to formation of only few red cells Ans: The hematological findings in a case of although there is hyperplastic erythropoiesis. megaloblastic anemia are: 3. Hemolysis: Because the late normoblasts die 1. Complete blood count: prematurely in the bone marrow there is a mild • Hemoglobin < 10 gm% hemolytic component • Hematocrit < 33% The causes of folic acid deficiency are: • Macrocytosis MCV > 100 fL 1. Insufficient intake of green leafy vegetables • MCHC will be normal 2. Malabsorption syndrome and gastrointestinal • Reticulocyte count is normal or mildly diseases, e.g. Gluten induced enteropathy increased to 2-3% 3. Abnormally high demands are needed in 2. Peripheral blood smear shows: multiple pregnancies • Macrocytes 4. Drugs, e.g. phenytoin, pyrimethamine, OCPs. • Moderate to marked anisopoikilocytosis The causes of vitamin B12 deficiency are: • Macro-ovalocytes are diagnostic of • Dietary deficiency and in pure vegetarians megaloblastic anemia • Malabsorption syndromes • Nucleated RBC’s • Ileal disease, Crohn’s disease • Basophilic stippling, Cabot ring, Howel • Small bowel bacterial overgrowth Jolly bodies There is megaloblastic erythropoiesis in bone • Hypersegmented neutrophils: Five percent marrow showing an asynchrony of nuclear and of neutrophils with 5 or more lobes or even cytoplasmic maturation because of impaired DNA a single neutrophil with 6 or more lobe. This synthesis. is the first manifestation of megaloblastic anemia. CASE 2 • 10-20% cases show pancytopenia. Twenty-five years old multigravida presented at 28 3. As there is ineffective erythropoiesis, there is a weeks period of gestation with chief complaints of component of accompanying hemolysis due to easy fatiguability, weakness and breathlessness on which serum unconjugated bilirubin and serum exertion since 2 months. On examination she has LDH rises. tachycardia, pale conjunctiva, nail beds and palmer creases. She has also got glossitis, cheilosis and Q.30. How will you confirm the diagnosis ? angular stomatitis. Her Hb was 6.8 gm% and she Ans: After confirming the type of anemia with the was prescribed oral iron. She took treatment for help of complete blood count and peripheral smear, 50 Case Discussions in Obstetrics and Gynecology empirical treatment with folate and vitamin B12 is Q.31. What is the treatment of megaloblastic started as the diagnostic tests to confirm folate and anemia? vitamin B12 deficiency are not available easily and Ans: Megaloblastic anemia in pregnancy is nearly are very costly. always secondary to folate deficiency. Pregnancy

Wherever available, Serum B12 levels and does not greatly affect meternal vitamins B12 levels. serum folate levels can be measured. In establilshed folated deficiency anemia, 5 mg Fasting folate and RBC folate levels are more folate is given orally daily during pregnancy which specific for the diagnosis of folate deficiency as is continued till 3 months postpartum. Vitamin B12 deficiency is always caused due to malabsorption, there is no interference by the food. therefore it is usually given in parental form. One Serum B12 level < 100 pg/ml suggests B12 mg vitamins B12 is given intramuscular on alternate deficiency. days for 2 weeks followed by 1 mg IM once a month Serum folate levels < 2 ng/ml suggests folate for 6 months.10 6 deficiency anemia. Iron preparation is given along as there is Fasting serum folate level < 6 μg/L and RBC increased requirement during erythropoiesis. Folate < 165 μg/L are diagnostic of folate defi- Figure 4.3 depicts the protocol for treatment of ciency.6 megaloblastic anemia.

Fig. 4.3: Treatment of anemia in pregnancy Anemia in Pregnancy 51

Q.32. How will you monitor the response of the Q.35. What is the requirement of iron, vitamin treatment? B12 and folate during pregnancy? Ans: Clinical improvement assessed as: Ans: Current recommendations avise folic acid 1. Increased sense of well-being intake of 400 μg daily with 60 mg of iron for 2. Increase in work capacity 6 months during pregnancy and continuing for

3. Improvement in other symptoms 3 months postpartum, 30 μg of vitamin B12 is 4. Improvement of glossitis required daily during pregnncy.11 Laboratory parameters: 3-4 days: Decrease in LDH levels. Q.36. What is the cause of the macrocytosis? 5-7 days: Increase in reticulocyte count and gets Ans: As the DNA synthesis is impaired and established by day 15. cytoplasmic maturation is normal, the hemo- 2-3 weeks: Increase in hemoblobin level @ 0.8- globinization of cytoplasm continues for a longer 1.0 gm/dL/week. time between 2 cell divisions and therefore the red Improvement in RBC indices – MCV, MCH, cells become enlarged. MCHC. 6-8 weeks: Hemoglobin level comes to normal Q.37. What are the causes of macrocytic anemia level. with normoblastic bone marrow? Peripheral smear shows normocytic normo- Ans: chromic RBC’s. 1. Hepatic disease 2. Hypothyroidism Q.33. This patient was treated with folate and 3. Myelodysplastic syndromes vitamin B for 1 month after which Investi- 12 4. Aplastic anemia gations were repeated which showed iron deficiency picture. How do you explain this? RECENT ADVANCES Ans: RBC synthesis is inhibited during the vitamin deficiency, available iron is underused. As soon as 1. Two injections of iron dextran 250 mg each therapy with folate or B12 is initiated, red cell given intramuscularly at 4 weeks interval along synthesis starts again, use of iron is maximal and with tetanus toxoid injection have been iron deficiency becomes apparent. recommended for prophylaxis of iron deficiency anemia as it has better compliance and better Q.34. Which deficiency is more common– results. vitamin B12 or folate deficiency? Also state the 2. Newer oral iron preparations are ferrous reason. oxalate, microencapsulated ferrous sulphate and Ans: Folate deficiency is more common than microencapsulated ferrous fumarate. These vitamin B12 deficiency because: microencapsulated preparations have equal 1. Folate stores last only for 2-4 months whereas bioavailability as the other salts but have fewer stores of vitamin B12 are sufficient for 2-3 years. gastrointestinal side effects. 2. Folate gets destroyed by prolonged cooking. 3. Intravenous iron sucrose is a new drug which 3. Dietary deficiency of vitamin B12 occurs only is given intravenously without any test dose and in pure vegetarians. is associated with minimum complications. 4. Pernicious anemia is associated with infertility. Total dose calculated is given in divided doses 52 Case Discussions in Obstetrics and Gynecology

on alternate days not more than 200 mg at a 4. Adamson JW. Harrison’s Principles of Internal time. If given slowly over 1 hour it is well Medicine; 16th edition Mc Graw Hill:586-92. tolerated and very safe. 5. Sharma JB. Nutritional anemia during pregnancy in 4. Other intravenous iron preparations are ferrous non-industrialized countries. In: Studd J, ed. Progress in Obstetrics and Gynaecology. New Delhi: Churchill gluconate, ferrous carboxymaltose Livinstone; 2003:103-22. 5. Erythropoetin 50-150 U/kg given sub- 6. Trivedi SS, Puri M. Anemia in pregnancy, 1st Edn. cutaneously twice/thrice weekly till course of New Delhi: Jaypee Brothers Medical Publishers (P) parenteral iron is over has additional Ltd. 2007. advantages:12 7. Maheshwari M, Arora S, Kabra M, menon PSN. 1. Rapid correction of severe anemia in less Carrier screening and prenatal diagnosis of β than 2 weeks. thalassemia J Indian Paediatric 1996;36:1119-25. 2. Anemia not responding to intravenous iron 8. Danielson BG. Structure, Chemistry and alone. Pharmacokinetics of intravenous iron agents. J Am Soc. Nephrol 2004;15:593-8. 3. Treatment of moderate to severe iron 9. The Clinical use of Blood Handbook: WHO Blood deficiency anemia as an alternate to blood Transfusion Safety, 2001. transfusion. 10. Bertram G Katzung. Basic and Clinical Pharmacology; 9th edn, Mc Graw Hill: 531-5. REFERENCES 11. Arias F, Daftary NS, Bhide G. Practical Guide to High- risk Pregnancy and Delivery 3rd edn. Elsevier; 2008; 1. World Health Organization: Report of a WHO group of experts on nutritional anemias. Technical report 465-70. series no. 503, Geneva WHO, 1992. 12. Breyman C, Visca E, Huch R, Huch A. Efficacy safety 2. Ministry of Health and Family Welfare, Govt of India. of intravenously administered iron sucrose with and NFHS-III, 2005-06: India Vol I. New Delhi: MOFHW, without adjuvant recombinant human erthyropeitin for 2007. the treatment of resistant iron-deficiency anemia 3. Bhatt RV. Maternal Mortality in India- WHO FOGSI during poregnancy. Am J Obstet Gynaecol 2001; 184: Study. J Obstet Gynaecol India 1997;47:205. 662-7. Ashok Kumar, Minu 5 Diabetes in Pregnancy

Abnormal maternal glucose regulation occurs in Q.1. What is the significant history to be asked 3-10% of pregnancies. Gestational diabetes mellitus in present pregnancy of this patient? (GDM) is defined as glucose intolerance of variable Ans: degree with onset or first recognition during a. History of polyuria, polydipsia, polyphagia. pregnancy. Gestational diabetes mellitus accounts b. Curdy discharge per vaginum (diabetic for 90% of cases of diabetes mellitus in pregnancy. patients are prone to vaginal candidiasis). Type II diabetes mellitus accounts for 7-8% of cases c. Presence of skin infections Boils, furuncles. of diabetes mellitus in pregnancy, and given its d. Recurrent urinary tract infections. increasing incidence, pre-existing diabetes mellitus e. History of excessive nausea and vomiting (due now affects 1-2% of pregnancies. to diabetic gastropathy). The risk of fetal morbidity is directly f. History of headache, epigastric pain, bilateral proportional to the degree of maternal pedal edema, blurring of vision. hyperglycemia. Women with gestational diabetes GDM patients have 10 to 25% risk of deve- are at increased risk of developing type 2 diabetes loping pre-eclampsia. mellitus after pregnancy, while their offsprings are • Obstetric history1 prone to developing childhood obesity, with type 2 a. History of previous first trimester abortions diabetes later in life. Most patients are treated only Patients with persistent preprandial blood with diet modification and moderate exercise but glucose >120 mg/dl in first trimester are at high- some take antidiabetic drugs, including insulin. risk of first trimester abortions.2 b. History of previous stillbirths CASE 1 Diabetic patients have hyperglycemia mediated chronic aberrations in transport of oxygen and A 29 years old weighing 70 kg, G4P1+0+2+0 fetal metabolites leading to sudden fetal presented with single live fetus of 27 weeks demise.3 estimated gestational age. On her antenatal c. History of malformations in previous evaluation, her glucose tolerance test was found pregnancies to be deranged (Fasting 106 mg%, 1 hour Diabetic patients are at increased risk (6-10%) 224 mg%, 2 hours 209 mg%, 3 hours 128 mg% of fetal congenital malformations—hydro- by carpenter and coustan). cephalus, anencephaly, spina bifida (1.95%), 54 Case Discussions in Obstetrics and Gynecology

cardiovascular abnormalities (5 fold increased • Abdominal examination risk), renal abnormalities, situs inversus and Abdominal girth and symphysio fundal height (to caudal regression syndrome (0.2-0.5%). GDM monitor fetal growth). per se not associated with congenital ano- Polyhydroamnios: Fetal hyperglycemia is malies). associated with polyuria leading to polyhydramnios d. Weight of previous babies, any instrumental (26.4-28%). deliveries, difficult delivery Macrosomia: Maternal hyperglycemia prompts Gestational diabetes is associated with 17 to fetal hyperinsulinemia during second half of 29% increased risk of macrosomia—baby gestation leading to excessive deposition of fat on 4 weight > 4.5 kg (ACOG). shoulder and trunk which predisposes to shoulder e. History of early neonatal deaths dystocia and cesarean section. Early neonatal deaths are common due to Intrauterine growth restriction (IUGR): hypoglycemia (blood sugar < 35 mg/dl in term (associated with vasculopathy (21% especially with infants (ACOG), hypomagnesemia, hypo- nephropathy). calcemia in baby.4 • Speculum examination f. History of diabetes in previous pregnancy Fourty percent recurrence rate in subsequent At first visit to look for vaginal infections. pregnancies. • Per vaginal examination • Past history It is done at term to rule out cephalopelvic History of diabetes mellitus prior to pregnancy disproportion as these patients are prone to have controlled on diabetic diet, oral hypoglycemics or macrosomia. insulin therapy.2 • Family history Q.3. Apart from the routine antenatal Family history of diabetes in first degree relatives investigations what are the special investigations of the patient. would you like to order for this patient? • Dietary history Ans: Caloric intake. Percentage break up of carbo- • Blood glucose monitoring by capillary blood hydrate, fat and protein. glucose levels is done in patients with deranged GTT (Table 5.1). Q.2. What are the essential aspects of examination in this patient? Table 5.1: Self-monitored capillary blood glucose levels by ACOG 2005 Ans: • General physical examination Specimen Level (mg/dl) Body mass index (BMI) calculated according to Fasting ≤ 95 mg/dl prepregnancy weight. Premeal ≤ 100 mg/dl Presence of skin infections e.g. boils are 1 hour postprandial ≤ 140 mg/dl specifically noted. 2 hours postprandial ≤ 120 mg/dl Blood pressure measurement 2-6 am ≥ 60 mg/dl • Cardiovascular system, respiratory system and neurological examination and fundus • Urine albumin, sugar, ketones examination These are to be assessed. Renal glucosuria This is performed to rule out neuropathy, during pregnancy occurs at blood sugar levels retinopathy or vascular disease. of 70 to 100 mg/dl. It is not benign as these Diabetes in Pregnancy 55

women are at high risk for preterm delivery and • Twenty-four hours urinary protein. macrosomia. Patients may lose 100 gm/day of • Urine routine microscopy and culture. glucose in urine. Such large losses of glucose decreases amount of glucose available for Q.4. What are the various modalities of fetal caloric needs and thus lipolysis is activated to assessment in the above case? maximum leading to production of ketones and Ans: ketoacidosis. • Level II ultrasound: At 18 to 22 weeks of 2 • Glycosylated hemoglobin levels (HbA1c) gestation to detect gross congenital Basal and every 6 to 8 weekly must be malformations. performed in first trimester. It is a product of • Fetal echocardiography: At 22 to 24 weeks nonenzymatic glycosylation of hemoglobin. It of gestation in all diabetic patients as reflects average blood sugar in preceding 6 to cardiovascular anomalies are common in fetuses 8 weeks. HbA1c should be < 6 gm% during of diabetic patients. Cardiac anomalies pregnancy for good glycemic control. High associated with GDM are atrial septal defects, HbA1c during the first trimester is associated ventricular septal defects and transposition of with increased risk of gross congenital great arteries. One proposed mechanism for malformations and during second trimester is cardiac defects is hyperglycemia induced associated with macrosomia (HbA1c oxidative stress that inhibits expression of < 8.5 gm% risk of malformation is 3.4%, HbA1c cardiac neural crest migration. > 9.5 gm% risk of malformation is 22%). • Ultrasound for fetal growth: It starts at 28 HbAlc should not be used routinely for weeks of gestation and is done every 4 weekly. assessing glycemic control in the second and It is done to detect macrosomia/IUGR. third trimesters of pregnancy. Physiological • Doppler velocimetry: It is helpful in patients changes that occur in all pregnant women lead with IUGR. to reduced HbA1c in women without diabetes, • Nonstress test/Biophysical profile: It is meaning that any apparent reduction in HbA1c advisable to do it twice weekly 32 weeks in women with diabetes during the second and onwards, especially in patients with IUGR with third trimesters of pregnancy does not abnormal umbilical artery Doppler, vasculo- necessarily indicate improved glycemic pathy, or with high BP, suboptimal control of control.6 diabetes. – Liver function test – Renal function test Q.5. How will you manage this patient? – Fundoscopy2 Nonproliferative diabetic retinopathy: Capillary Ans: closure and dilatation, microaneurysm, AV Antenatal care shunt, dilated veins, hemorrhages (dots and Once diagnosed, patient has to be counseled blots), cotton wool spots/soft exudates, hard regarding the need for checking periodic capillary exudates. glucose herself. Proliferative diabetic retinopathy: Neo- • Importance of euglycemia to prevent maternal vascularization, vitreous hemorrhage, retinal and fetal complications . detachment.4 • Treatment of complications if they arise. 56 Case Discussions in Obstetrics and Gynecology

Aim of the treatment is to maintain fasting regulation. Persistent elevation of fasting capillary glucose level < 95 mg% and 2 hour capillary glucose indicate increased hepatic postprandial < 120 mg% to prevent compli- gluconeogenesis and require treatment with oral cations. hypoglycemic agents or insulin therapy a. Diet: c. Oral hypoglycemic agents: Medical nutrition therapy (MNT): It is the Easy to use, non-invasive, have minimal side cornerstone of treatment of diabetes in effects and are better accepted by patients. pregnancy. Caloric requirement is 25-35 kcal/ kg body weight/ day according to body mass Q.6. What are the different oral hypoglycemic index (Table 5.2). It is advisable to take 3 major agents available to be used in pregnancy visa and 3 minor meals so that there is no intermittent vis insulin therapy? hypoglycemia and still ideal blood sugars are Ans: maintained. Dietary care of diabetic patient Sulphonylureas: Glibenclamide (glyburide)6 is includes determining the carbohydrate ingested the most commonly used agent. It reaches peak in meals and snacks, so called carbohydrate plasma level in 4 hours, its half life is 10 hours and counting. Carbohydrate counting estimates steady state level is reached in 50 hours. It is carbohydrate amount in each meal by metabolized in liver and is excreted in the bile. They determining carbohydrate serving. Each 15 gm act by increased insulin secretion, induce better of carbohydrate is equivalent to one insulin sensitivity and suppress production of carbohydrate serving. 1 gram of carbohydrate hepatic glucose. Starting dose is 2.5 mg in the produces 4 kcal of energy. morning. Dose is changed every 3-5 days according to blood sugar profile till blood sugar is stabilized. Table 5.2: Caloric requirement Dose is increased by 2.5 mg/ week until 10 mg/ Body mass index(BMI) kg/m2 Calories intake day, and then switch to twice daily dosing until 18.5-24.9 (Normal) 30 kcal/kg/day maximum of 20 mg/day is reached. Glucose levels, 16.5-18.4 (Underweight) 35 kcal/kg/day fasting <100 mg/dl, 1 hour < 155 mg/dl, 2 hour 25-30 (Overweight) 25 kcal/kg/day < 130 mg/dl. Its side effects are hypoglycemia (11- > 40 (Morbid obesity) 12 kcal/kg/day 38% in non-pregnant females, with much lower incidence in pregnant females), sudden intrauterine Diet composition should be 50-60% of deaths near term. carbohydrates, 20% proteins and 25-30% fats. Biguanides: Metformin7 is most commonly used. b. Exercise: It mainly acts on peripheral insulin sensitivity, Planned physical activity for 30 minutes/ day counteracting insulin resistance. It decreases is recommended for all individuals capable of hepatic glucose output by decreasing glyco- participating. Advising patients to walk briskly genolysis and increases glucose output by skeletal or do arm exercises while seated in chair for at muscle. It is mainly excreted by kidney. Dosage is least 10 minutes after each meal accomplishes 500-850 mg in the beginning with maximum of the goal. Exercise in conjunction with diet 2000 mg/day in divided doses. control improves blood glucose control and may Thiazolidenediones: They are category C drugs reduce the need for insulin. and should be prescribed with potential risks Patients with newly diagnosed diabetes should explained. have their blood sugar levels within normal Alpha glucosidase inhibitors: Few data exist limits within 2 weeks of institution of the diet regarding use of Acarbose in pregnancy. It reduces Diabetes in Pregnancy 57 postprandial glucose excursions in GDM patients. 2 hour postprandial < 120 mg/dl. Dosage is 25 mg orally three times daily to Nocturnal 60-120 mg/dl. maximum of 100 mg three times a day. A small Insulin aspart, lispro are expensive, short acting amount of drug may be absorbed systemically and and actually ideal in pregnancy as they effectively safety and potential transplacental passage has not control hyperglycemia between meals compared to been fully evaluated. regular insulin that takes longer time (3-6 hours). Generally 2/3rd and 1/3rd distribution of Q.7. What are the different types of insulin intermediate acting drugs with two doses, one each available and dosage recommended? at breakfast and dinner and also the same division for NPH and regular at a given time are prescribed Ans: covering at least breakfast and dinner or three doses a. Insulin therapy7: Pregnant women with type at breakfast, lunch and dinner are given. With 2 diabetes mellitus and persistent hyperglycemia insulin pump1 U/hour is given continuously, there despite adequate nutritional intake and therapy is decrease in dose requirement by 50 to 60% and with glyburide require insulin therapy. Normally it can be adjusted with boluses per meal. 3 to 4 divided doses of insulin are preferred 1 unit of insulin takes care of 30 mg rise in blood before each meal and 1 or 2 long or intermediate sugar levels in gm%. Hypoglycemia is to be avoided acting insulin dosages per day. by glucose drink. Glucagon injection is to be kept In type 1 diabetes generally the requirement is ready. The relatives are informed about this 0.9U/kg in first trimester, 1 U/kg in second possibility and bracelet with name and dose of trimester and 1.2 U/kg in third trimester. In type insulin for patient to wear is advisable.8 2 diabetes 0.9, 1.2 and 1.6 U/kg respectively The above patient was started on tablet indicating greater insulin resistance.5 Different glyburide 5mg once daily from 30 weeks onwards. types of insulin are given in Table 5.3. How will you monitor her and when will you decide Target plasma glucose levels with insulin to deliver her? Would it have been different had therapy are: she developed IUGR? Preeclampsia? Fasting 60-90 mg/dl. Patient on glyburide should be delivered at 37 1 hour postprandial < 140 mg/dl. completed weeks or earlier in case of IUGR or

Table 5.3: Types of insulin Type Source Onset (hours) Peak (hours) Duration of action Short acting Humulin R Human 0.5 2-4 5-7 Lispro Analog 0.25 0.5-1.5 6-8 Aspart Analog 0.25 1-3 4-5 Glulisine Analog 0.25 1 4 Intermediate acting Human lente Human 1-3 6-12 18-24 Human NPH (Isophane) Human 1-2 6-12 18-24 Long acting Humulin ultralente Human 4-6 8-20 >36 Glargine Analog 1 5 24 Determir Analog 1-2 5 24 Combined Mixtard Human (30% soluble: 70% isophane) 58 Case Discussions in Obstetrics and Gynecology pre-eclampsia or any other adverse obstetrical Sliding scale: 140-180 mg% - 4 units complication. 181-250 mg% - 8 units. 251-400 mg% - 12 units. Q.8. When will we consider termination of > 400 mg% - 16 units. pregnancy in GDM patients controlled on diet If blood sugar < 80 mg/dl, infuse 5% dextrose at rate of 100 ml/hour. or on insulin? Frequent fetal heart monitoring for high risk pregnancy. Ans: The timing of termination of pregnancy of diabetic patients3 is given in Table 5.4 Q.11. How will you induce and monitor labor in GDM patients on insulin therapy? Table 5.4: Timing of termination of pregnancy Ans: See Table 5.6 GDM on Diet Await spontaneous delivery till Table 5.6: For induction and monitoring of labor of Uncomplicated 40 weeks with fetomaternal surveillance patients with GDM on insulin therapy GDM on insulin Elective induction at 38 weeks (elective Good control induction reduces risk of shoulder Nil per mouth after midnight. Fetal surveillance dystocia from 10% to 1-4%) Bedtime dose of insulin to be given. normal Unfavorable cervix: Vaginal prostaglandin to be used.(short acting insulin+ light snacks till labor commences) Q.9. What are the indications of termination of Blood sugar monitoring1-2 hourly. pregnancy in GDM patients before 38 weeks? CTG monitoring preferred in active labor. Ans: Blood sugar monitoring 2 hourly • Maternal indications: Severe PIH, vascular Serum electrolytes 12 hourly Urine sugar, ketones 4 hourly disease, uncontrolled diabetes. 5 unit insulin in 500 ml of 5% dextrose at rate of 100 ml/ • Fetal indication: IUGR, fetal compromise. hour If blood sugar> 140 mg/dl-plain insulin to be given Q.10. How do we monitor GDM patients during subcutaneously according to sliding scale spontaneous labor? If blood sugar <80 mg/dl, infuse 5% dextrose at rate of 100 ml/hour. Ans: See Table 5.5

Table 5.5: During spontaneous labor Q.12. What are the indications of Elective LSCS in GDM patients ? GDM patients controlled on diet Blood glucose is maintained between 80-110 mg/dl.Blood Ans: Indications of elective LSCS in GDM patients sugar monitoring 2 hourly, serum electrolytes 12 hourly, is given in Table 5.7 urine sugar, ketones 4 hourly Table 5.7: Indications of elective LSCS GDM patients controlled on insulin Nil per orally Macrosomia > 4 kg (for predicting macrosomia, shoulder Blood glucose is maintained between 80-110 mg/dl width > 14 cm, EFW > 4 kg on ultrasound) Blood sugar monitoring 2 hourly Demonstrable fetal compromise (Severe IUGR) Serum electrolytes 12 hourly Bad obstetric history Urine sugar, ketones 4 hourly Other obstetric indications 5 unit insulin in 500 ml of 5% dextrose at rate of 100 ml/ hour Q.13. How should we prepare a GDM patient If blood sugar> 140 mg/dl-plain insulin to be given on insulin for elective LSCS and and how to subcutaneously according to sliding scale monitor this patient in postpartum period? Diabetes in Pregnancy 59

Ans: See Tabel 5.8 safe method of contraception, particularly suitable in diabetic women as it is as effective as sterilization Table 5.8: For elective LSCS of patients with GDM and produces low circulating hormone levels.12 on insulin therapy Omit morning dose of insulin. Problem Oriented Management Fasting blood sugar and serum electrolytes to be done. Case: A 35-year old G3 P2 L2 female, known Regional anesthesia (epidural) preferred. diabetic for 5 years on tab metformin 1 OD came Postoperative blood sugar 2 hourly for 12 hours, 4 hourly to antenatal clinic with 16 weeks of pregnancy. after that. Diabetic patients taking metformin for control Insulin according to sliding scale. of diabetes may either continue with oral Urine albumin, sugar, ketone charting to be done. hypoglycemic throughout the pregnancy or can switch over to insulin after titrating the dose of Q.14. How should patients with GDM be insulin. The side effects of metformin are assessed in postpartum period? polydactyly, lactic acidosis, neonatal hypoglycemia, Ans: GDM patients normally do not need insulin but they are rarely seen in newborns so patient can or oral hypoglycemic agents in postpartum period. continue oral hypoglycemic drugs.4 Metabolic assessments recommended after pregnancy with gestational diabetes are given in Q.16. What are the complications associated Table 5.9. with diabetes during pregnancy? Ans: Maternal complications associated with Q.15. What contraception will you advise diabetes.5 diabetic patient? Antepartum Ans: Contraception should be discussed on 1. Medical problems:Emotional stress, individual basis with all women of childbearing age hypoglycemia, infections, starvation ketosis, with diabetes. diabetic ketoacidosis, hyperosmolar Combined estrogen progesterone pill should be hyperglycemic nonketotic syndrome, avoided in women with complications or risk retinopathy, nephropathy, cardiovascular factors for vascular disease. problems, neuropathy. Progesterone only pill may be suitable in these 2. Obstetric complications: Chronic hypertension, women, but there is increased failure rate.10,11 pre-eclampsia, preterm labor, premature rupture Mirena (Levonorgesterol containing IUCD) is a of membranes, hydramnios.

Table 5.9: Fifth international Workshop conference: Metabolic assessments recommended after pregnancy with Gestational diabetes9 Time Test Purpose Post delivery (1-3 days) Fasting or random plasma glucose Detect persistent, overt diabetes. Early post partum (6-12 weeks) 75 gm 2 hour GTT Postpartum classification of glucose metabolism. 1 year postpartum Annually 75 gm 2 hour GTT Assess glucose metabolism. Tri-annually Fasting plasma glucose Assess glucose metabolism. Pre-pregnancy 75 gm 2 hour GTT Classify glucose metabolism. 75 gm 2 hour GTT 60 Case Discussions in Obstetrics and Gynecology

Intrapartum: Prolonged labor, uterine inertia, at fifth international workshop of gestational instrumental deliveries, perineal , diabetes, 2005.9 postpartum hemorrhage, LSCS. Postpartum: Puerperal sepsis, wound infection. Table 5.11: Etiological classification of Fetal complications associated with diabetes: diabetes(NDDG) 1. Spontaneous abortions. 1. Type 1: β cell destruction, usually absolute insulin 2. Congenital malformations. deficiency 3. IUGR (Intrauterine growth restriction). a. Immune mediated 4. Unexplained stillbirth. b. Idiopathic 2. Type 2: Ranges from predominantly insulin resistance 5. Macrosomia. to predominantly insulin secretory defect with insulin Neonatal complications: Hypoglycemia, resistance. hyperbilirubinemia, hypocalcemia, hypothermia, 3. Other types: polycythemia, neonatal jaundice, respiratory a. genetic defects in insulin action. distress syndrome, renal vein thrombosis, growth b. genetic syndromes: Down, Klinefelter, Turner. c. Diseases of exocrine pancreas: pancreatitis, cystic restriction, . fibrosis. d. Endocrinopathies: Cushing syndrome, Q.17. How do we classify diabetes in pregnancy? Pheochromocytoma. Ans: There are three classifications of diabetes e. Drug or chemical induced: glucocorticoids, thiazides, β (Tables 5.10 to 5.12). adrenergic agents f. Infections: congenital rubella, cox sackie virus, cytomegalovirus Q.18. What are the changes in carbohydrate 4. Gestational diabetes (GDM) metabolism during pregnancy?

Ans: Pregnancy exacerbates the diabetic tendency Table 5.12: Classification of American Diabetes of asymptomatic woman (Table 5.13). Association13 Normal Impaired fasting Diabetes Q. 19. What are the methods of screening of glucose or impaired mellitus GDM? glucose tolerance Ans: Patients to be screened for GDM are divided Fasting < 110 mg/dl 110-125 mg/dl ≥ 126 mg/dl into three groups according to recommendations 2hr < 140 mg/dl 2hr ≥ 140-199 mg/dl 2 hr≥200 mg/dl

Table 5.10: Modified White’s classification Class Onset Fasting plasma Two hour postprandial Therapy glucose glucose A1 Gestational < 105 mg/dl < 120 mg/dl Diet A2 Gestational > 105 mg/dl > 120 mg/dl Insulin/Oral hypoglycemic agents Class Age of onset Duration Vascular disease Therapy B > 20 < 10 None Insulin/OHA C 10-19 10-19 None Insulin D < 10 > 20 Benign retinopathy Insulin F Any Any Nephropathy Insulin R Any Any Proliferative retinopathy Insulin H Any Any Atherosclerosis, heart disease Insulin Diabetes in Pregnancy 61

Table 5.13: Diabetogenic effects of pregnancy14 > 3 spontaneous abortions. Recurrent • Insulin resistance monoliasis, age > 30 years. impaired glucose 1. Production of human placental lactogen. metabolism, glucosuria. (Perform glucose 2. Increased production of cortisol, estriol and testing as soon as feasible, using one step or progesterone. two step technique and repeated at 24 to 28 3. increased insulin destruction by kidney and placenta. weeks.) • Increased lipolysis Two step technique: 50 gm glucose challenge test • The mother utilizes fat for her caloric needs and saves (GCT) followed by diagnostic 100 gm glucose glucose for fetal needs. tolerance test for those meeting the threshold value • Changes in gluconeogenesis in GCT. • The fetus preferentially uses alanine and other amino One step technique: Diagnostic 100 gm glucose acids, depriving mother of a major neoglucogenic tolerance test performed on all subjects. source. How to perform GCT: Measure venous plasma glucose 1 hour after 1. Low-risk group: Members of ethnic group with administering 50 gm glucose. Cut off value ≥ 130 low prevalence of GDM, no known diabetes in (90% sensitivity) and ≥140 mg/ dl or 7.8 mmol/l first degree relatives, age < 25 years, weight (80% sensitivity). It is not necessary to follow any normal before pregnancy, weight normal at special diet before the test and it is not necessary birth, no history of abnormal glucose to be in the fasting state. metabolism, no history of poor obstetrical How to perform GTT15 outcome.(blood glucose testing not routinely The test should be performed in the morning after required) overnight fast of at least 8 hours but not more than 2. Average risk: Members of ethnic group with 14 hours and after at least 3 days of unrestricted high prevalence of GDM, diabetes in first diet (≥ 150 gm carbohydrate/day) and physical degree relatives, age > 25 years, overweight activity. The subject should remain seated and before pregnancy, weight high at birth (Perform should not smoke during test. The blood sugar blood glucose testing at 24-28 weeks using two values during GTT are given in Table 5.14. step or one step procedure). Approximately 5% of women doing 3 hour 3. High risk: Marked obesity, strong family history GTT experience hypoglycemia during test. This of type 2 DM, previous history of GDM, history reactive hypoglycemia is as a result of release of of stillbirth, History of delivery of large baby large amount of insulin by the pancreatic beta cells (> 4 kg), glycosuria, h/o unexplained neonatal in response to glucose load. Two or more of venous death, h/o congenital malformation, plasma glucose concentrations indicated above polyhydramnios, h/o traumatic delivey with must be met or exceeded for a positive diagnosis. associated neurological disorder in infant, h/o (Table 5.14). Table 5.14: Oral glucose tolerance test Recommendation by Glucose load Criteria Venous plasma glucose Fasting 1st hour 2nd hour 3rd hour ADA 100 gm Carpenter and Coustan ≥95 ≥180 ≥155 ≥140 75 gm Carpenter and Coustan ≥95 ≥180 ≥155 ACOG 100 gm NDDG and Carpentar ≥105 ≥190 ≥165 ≥145 WHO 75 gm WHO ≥126 ≥140 62 Case Discussions in Obstetrics and Gynecology

A fasting plasma glucose level >126 mg% or 4. Cunningham, Leveno, Bloom, Hauth, Rouse, Spong. random plasma glucose level >200 mg% meets the Williams obstetrics.23rd edition. New York. McGraw- Hill.2009. threshold for diagnosis of diabetes and precludes 5. Diabetes in pregnancy. National Institute for Health the need of any glucose challenge test. and Clinical Excellence (NICE) 2008. Intravenous glucose tolerance test is done in 6. Jacobson GF, Ramos GA, Ching JY, Kirby RS, Ferrara patients with gastrointestinal diseases or intolerance A, Field DR. Comparison of glyburide and insulin for the management of gestational diabetes in a large to glucose or polymer solutions. managed care organization. Am J Obstet Gynecol Method: Measure the rate of disappearance of 2005;193(1):118-24. glucose (k value). 7. Homko CJ, Reece EA. Insulins and oral hypoglycemic Equation: Logc Y= LogcA-kt agents in pregnancy. J Matern Fetal Neonatal Med (Y=Blood glucose concentration in mg/dl, A=y 2006;19(11):679-86. 8. Crowther CA, Hiller FE, Moss JR, McPhee AJ, Jeffries intercept, t= time elapsed.) WS, Robinson FS, For the Australian Carbohydrate K value from 10 minutes to 60 min glucose level intolerance study in pregnant women (ACHOIS) Trial after infusion of 25 gram glucose in 50% solution group: Effect of treatment of gestational diabetes over 2 minutes.(lower limit of normal k= i.37(1st mellitus on pregnancy outcomes. N Engl J Med 2005;352:2477-86. trimester), 1.18(2nd trimester, 1.13(3rd trimester). 9. Metzger BE, Buchanan TA, Coustan DR, de Leiva A, HbA1c and serum fructosamine have lower Dunger DB. Summary and Recommendations of the sensitivity and are poor screening technique. Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007;30:S251-S260. Q.20. What is the future risk in GDM patients? 10. Petersen KR, Skouby SO< Jespersen J. Contraception Ans: In GDM patients, risk of developing GDM guidance in women with preexisting disturbances in in next pregnancy is more than 50%. There is about carbohydrate metabolism. European journal of Contraception and reproductive health care 1996;1:53- 70% risk of developing frank diabetes over 10-20 9. years. Normally diabetes affects 5 to 7% of 11. Gupta S. Clinical guidelines on contraception and pregnancies. diabetes. European journal of contraception and reproductive health care 1997;2:167-71. 12. Luukkainen T, Toivonen J. Levonorgestrol releasing REFERENCES IUCD as a method of contraception with therapeutic 1. Cousins L. Pregnancy complications among diabetic properties. Contraception 1995;52:269-76. 13. American Diabetes Association. Expert committee on women: Review 1965-1985. Obstet Gynecol Surv. the Diagnosis and Classification of Diabetes Mellitus: 1987;42(3):140-9. Roport of the Expert Committee on the Diagnosis and 2. Rosenn BM, Miosdovnik M, Comnbs CA, et al. Classification of Diabetes Mellitus. Diabetes Care. Glycemic thresholds for spontaneous abortion and 2002;25(Suppl 1):S5-20 congenital malformation in insulin dependent diabetes 14. Lain KY, Catalano P. metabolic changes in pregnancy. mellitus. Obstes Gynecol 1995;85:417. Clin Obstet Gynecol 2007;50(4):938-48. 3. Galerneau F, Inzucchi SE. Diabetes mellitus in 15. Carpenter MW, Coustan DR. Criteria for screening pregnancy. Obstet Gynecol Clin North Am tests for gestational diabetes. Am J Obstet Gynecol. 2004;31(4):907-33. 1982;144(7):768-73. Anjali Tempe, Nancy Singh, Ronita Devi

6 Hypertension in Pregnancy

INTRODUCTION occurs in 5-8% of all pregnancies. Eclampsia is defined as the occurrence of seizures in The hypertensive disorder of pregnancy women with preeclampsia that cannot be complicates 5 to 10% of pregnancies and is one of attributed to other causes. the leading causes of perinatal morbidity and 1 • Chronic hypertension, defined as blood mortality. It also causes maternal morbidity and pressure of > 140/90 mm of Hg, either predating mortality, more so in developing countries. The pregnancy or developing before 20 weeks classification of hypertensive disorders compli- gestation, complicates ~ 3% of pregnancies. It cating pregnancy by the Working group of the is more frequent in women who are of advanced National High Blood Pressure Education maternal age or who are obese. Although at Program (NHBPEP) 2000 is as follows: (i) increased risk for superimposed preeclampsia, Gestational Hypertension (ii) Pre-eclampsia and many will experience a physiological lowering eclampsia syndrome (iii) Pre-eclampsia super- of blood pressure during pregnancy and a imposed on chronic hypertension (iv) Chronic reduction in the requirement for antihyper- hypertension tensive medication particularly in the second • Gestational hypertension occurs in 6% of trimester. pregnancies and is the hypertension developing • Superimposed preeclampsia complicates 25% in the latter half of pregnancy not associated of pregnancies in women with chronic with proteinuria.2 Final diagnosis is often made hypertension. 12 weeks postpartum when the blood pressure returns to normal level. Almost half of the PATHOPHYSIOLOGY OF PREECLAMPSIA women with gestational hypertension One of the earliest abnormalities noted in women subsequently develop pre-eclampsia syndrome, in whom preeclampsia develops, is as under: which includes signs such as proteinuria and • Failure of second wave of trophoblastic thrombocytopenia or symptoms such as invasion into the spiral arteries of the uterus headache or epigastric pain. leading to narrowing of their lumen and • Preeclampsia-eclampsia is a syndrome that impairment of placental blood flow. manifests clinically as a new onset hypertension • Diminished perfusion and a hypoxic in the latter half of pregnancy (usually after 20 environment eventually lead to release of weeks), with associated proteinuria of >300 mg placental factors that incite a systemic per 24 hours of urine collection. This syndrome inflammatory response. 64 Case Discussions in Obstetrics and Gynecology

• Worsening hypoxia at the uteroplacental including platelets and fibrinogens, are interface leads to production of excessive deposited subendothelially. With diminished amounts of antiangiogenic factors like soluble blood flow, because of maldistribution, fms-like tyrosine kinase 1 and soluble ischemia of the surrounding tissues would lead endoglin. These antiangiogenic factors and to necrosis, hemorrhage and other end other inflammatory mediators like TNF α and disturbances characteristics of the syndrome. As interleukins provoke endothelial cell . a result of this defect in placentation, there is a • They also contribute to the oxidative stress failure of cardiovascular adaptations (increased associated with preeclampsia. This is plasma volume and reduced systemic vascular characterized by reactive oxygen species and resistance) that are characteristics of normal free radicals that lead to formation of self pregnancy. Unless delivery supervenes, these propagating lipid peroxide. These in turn changes ultimately result in multiorgan generate highly toxic radicals that injure involvement with a clinical spectrum ranging endothelial cells, modify their nitric oxide from barely noticeable to one of cataclysmic production, and interfere with prostaglandin pathophysiological deterioration that can be life balance. threatening for both mother and fetus. • Other consequences of oxidative stess include • Preeclampsia, as of now, is not preventable as production of lipid laden macrophages (foam it is considered to be also a multifactorial cells) seen in atherosis; activation of polygenic disorder. microvascular coagulation manifested by Half of the women with gestational hyper- thrombocytopenia; and increased capillary tension later on develop preeclampsia. Gestational permeability manifested by edema and hypertension – preeclampsia appears to be a proteinuria. continuum of same worsening disease.3 • Immunological maladaptive tolerance Figure 6.1 shows the pathogenesis of hyper- between maternal, paternal and fetal tissues has tension and preeclampsia in pregnancy. also been implicated in the etiology of preeclampsia. There is dysregulation or loss of CASE 1 maternal immune tolerance to paternally Q.1. A 25-year old 2nd gravida with a pregnancy derived placental and fetal antigens. The histological changes at the maternal-placental of 28 weeks of gestation comes for antenatal visit interface are suggestive of acute graft rejection. and on routine check up, she is found to be Tolerance dysregulation might also explain an having blood pressure of 150/100 mm of Hg. increased risk when the paternal antigenic load What is the diagnosis? is increased, that is, with two sets of paternal Ans: Repeat blood pressure measurement should chromosome—a “double dose”. For example, be performed after 6 hours for the diagnosis of women with molar pregnancies have a higher hypertension in pregnancy.4 Urine should be incidence of early onset preeclampsia. checked for presence or absence of proteinuria, • Preeclampsia is characterized by vasospasm diagnosis of the patient will depend on the presence which causes increased vascular resistance and or absence of the proteinuria. subsequent hypertension. At the same time If blood pressure is found to be same or > 140/ endothelial cell damage causes interstitial 90 mm of Hg on two occasions, 6 hours apart leakage through which blood constituents, without proteinuria, it is gestational hypertension. Hypertension in Pregnancy 65

Fig. 6.1: Pathogenesis of hypertension in pregnancy

However, the diagnosis of gestational hypertension If blood pressure comes to normal 6 hours later can be confirmed only 12 weeks after delivery when by rest, patient should be observed carefully as there the blood pressure returns to normal. is high possibility of developing gestational If proteinuria (defined as the urinary excretion hypertension later on in pregnancy. Also, if she of 300 mg/L or more of protein in a 24 hour urine gives history of hypertension in earlier pregnancy, collection or > 30 mg/dl or 1+ by qualitative she is likely to develop hypertension in this assessment using reagent strips) is present, it is pregnancy suggestive of susceptibility of chronic preeclampsia, therefore proteinuria should be ruled hypertension later on in life. out by testing for urine albumin. If patient gives history of pre-pregnancy high It is a mild variety as blood pressure of > 140/ blood pressure, or has history of high blood pressure 90 mm of Hg to <160/110 mm of Hg is considered before 20 weeks of gestation during this pregnancy, as mild or non-severe. If it is more than 160/110 the diagnosis is chronic hypertension. mm of Hg persistently, it is severe hypertension. 66 Case Discussions in Obstetrics and Gynecology

Q.2. Elaborate the points in the history of with BMI<20 kg/m2 to 13.3% in those with hypertensive patients in pregnancy which would BMI>35 kg/m2.3 help in the diagnosis and management • Thyroid swelling: Any obvious fullness is to Ans: be noted and investigated. 1. Age and parity: Preeclampsia often affects • Cardiovascular system: signs of congestive young and nulliparous women; whereas older cardiac failure like basal crepitations, raised women >35 years of age are at greater risk for JVP, dyspnea and tachypnea have to be ruled chronic hypertension with superimposed out. preeclampsia. • Obstetric examination: Fundal height should 2. History of hypertension in family, in earlier correspond to the period of gestation. Fundal pregnancy or prepregnancy high blood pressure: height more than period of gestation suggests If there is history of gestational hypertension twins, hydramnios, molar pregnancy and these in earlier pregnancy, there are more chances of conditions are more commonly associated with developing hypertension in this pregnancy, the hypertension in pregnancy. Fundal height less incidence being 70%.5 The risk of developing than period of gestation is suggestive of fetal preeclampsia is 20-40% for daughters of growth retardation and also may be associated preeclamptic mothers; 11-37% for sisters of with hypertension or antihypertensive therapy, preeclamptic women; and 22-47% in twin particularly atenolol. sisters. 3. Race and ethinicity: Africans are more Q.4. How will you manage the above patient? susceptible than caucasians Ans: First we will like to confirm the diagnosis of 4. History of diabetes, thyroid disorder, anemia: gestational hypertension . To rule out severe These are related disorders. Both hypo- hypertension hospitalization is advisable at least thyroidism and hyperthyroidism are associated initially for 48 hours. During this period 4 hourly with hypertension. In India, hypothyroidism is blood pressure measurements with other more common than hyperthyroidism. investigations are performed. They are as follows: 5. History of twins, hydramnios, H.mole: would • Complete blood count including platelet count cause earlier hypertension in this pregnancy. • Urine albumin 4 hourly by dipstix method or 6. Smoking reduces the risk of preeclampsia. 24 hour urinary protein • Liver function test including enzymes aspartate Q.3. What are the important points in transaminases (AST) and alanine transaminases examination? (ALT) levels. Ans: Besides vital parameters like pulse, blood • Kidney function tests including serum pressure, respiratory rate, temperature, urine output, creatinine and uric acid levels. Protein/ pallor, pedal edema, other important points in creatinine ratio and creatinine clearance in examination are: severe cases is also advisable. • Height, weight and BMI of the patient: obesity • Lactate dehydrogenase (LDH) for the diagnosis is more commonly associated with of HELLP syndrome preeclampsia. The relationship between • PT and PTTK-Only if platelet count is abnormal maternal weight and the risk of preeclampsia is • Fundus examination to rule out severity of the progressive. It increases from 4.3% for women disease. Hypertension in Pregnancy 67

Urine albumin should be done daily by dipstick maternal and fetal status. From the maternal side method. If the patient is confirmed to be mild the review includes the levels of blood pressure at hypertensive after investigation without any organ home, the presence or absence of symptoms dysfunction, she may be allowed to go home. suggestive of end organ damage (blurred vision, However, those who don’t understand the epigastric pain) and the presence of proteinuria. implications of the disease and have no help at Fetal monitoring includes daily charting of fetal home or no access to nearby hospital would remain movements by the patient and antenatal growth hospitalized. charting ( weight gain of the patient, fundal height, All investigations are repeated once a week or abdominal girth measurement). Other investi- fortnightly depending on the severity except urine gations for fetal monitoring have already been albumin and blood pressure measurement which mentioned. should be done daily. Proteinuria (>2 +) in random urine sample is In addition to maternal investigations, fetal diagnostic of preeclampsia, when proteinuria is monitoring is also required. Fetal assessment trace or 1+ it is necessary to send the random sample includes daily fetal movement count by the patient to the lab for the determination of the protein/ which should be more than 10 in 24 hours or more creatinine ratio. A protein/creatinine ratio of >0.30 than 3 in one hour three times a day, non-stress test is indicative of preeclampsia and a value less than (NST), biophysical profile, umbilical artery and 0.20 rules out significant proteinuria. Normally in cerebral artery Doppler. These investigations are our hospital, 24 hour urinary protein is estimated performed between 28-30 weeks of gestation even though it is cumbersome to collect 24 hour initially and the biophysical profile/NST is repeated urine. at least once a week till patient delivers. The The development of proteinuria, elevation of frequency may increase if hypertension becomes the blood pressure above 150/100 mm of Hg of a severe variety or Doppler shows changes threshhold, decreased fetal movements, abnormal suggestive of fetal growth restriction. fundal growth or development of maternal symptoms suggestive of end organ damage require Q.5. How to follow up the patient once she is admission to the hospital for further evaluation and diagnosed to have mild hypertension and perhaps for the termination of pregnancy. discharged after investigations? Patients with negative findings for abnormality Ans: Patient will be discharged if all the above in their weekly assessment may continue with the parameters are found to be normal and blood pregnancy until they reach 38 weeks of gestation. pressure is below 150/100 mm of Hg. These At this time labor induction is performed with the patients can be managed on outpatient basis, if they help of cervical ripening agents like dinoprostone/ understand the seriousness of disease and oxytocin/artificial rupture of membrane or cesarean implications. They should also have the facility of section offered to the patient depending on obstetric daily blood pressure measurement at home and if indication. necessary should be able to come to the hospital or Pregnancy complicated by gestational nearby center in one hour time. Patient is followed hypertension is managed according to severity, every weekly in ANC OPD with blood pressure gestational age and presence of preeclampsia. The record of one week, and urine albumin. The weekly management of severe variety of hypertension in assessment of patients with gestational pregnancy with or without proteinuria is on the hypertension must include a systematic review of same line and is discussed later. 68 Case Discussions in Obstetrics and Gynecology

Termination of pregnancy is the only cure for Ans: Most obstetricians would like to start preeclampsia. Headache, visual disturbances, or antihypertensive drugs after blood pressure reaches epigastric pain is indicative that convulsions may 150/100 mm of Hg thinking that these will prevent be imminent, and oliguria is another ominous sign. the progression of mild disease into severe disease Severe preeclampsia demands anticonvulsants and and also prevent the complication like severe usually antihypertensive therapy followed by hypertension, abruptio placentae, IUD, cardiac delivery. The prime objectives are to prevent failure, pulmonary edema, cerebral hemorrhage. convulsions and serious end organ damage and also However, there are studies showing that the use of to deliver a healthy infant. When the fetus is antihypertensive drugs like labetalol in pregnancy preterm, the tendency is to temporize in the hope is associated with intrauterine growth retardation that a few more weeks in utero will reduce the risk of the fetus 6. The initial dose of labetalol is 100 of neonatal death or serious morbidity from mg twice a day. This dose may be increased prematurity. Assessment of fetal well being and according to patient’s response and the maintenance placental function are performed using NST and dose is usually 200-400 mg twice daily. biophysical profile, especially when the fetus is Calcium channel blocker like nifedipine is also immature. With moderate or severe preeclampsia being used. The usual dose is 10-30 mg orally every that does not improve after hospitalization, delivery 6-8 hourly(20-80 mg in divided doses). It has no is usually advisable for the welfare of both mother deleterious effect on utero placental blood flow. The and fetus. Labor induction is carried out, using most common side effects of nifedipine are facial usually preinduction cervical ripening with a flushing and headache. prostaglandin. Whenever it appears that induction Methyldopa (aldomet) has been the most widely almost certainly will not succeed, or attempts have used antihypertensive drug during pregnancy and failed, cesarean delivery is indicated for more longest followed up. It is found to be safe from the severe cases. point of view of development of children later on in life, whose mothers were administered this drug Q.6. What is the role of elective cesarean during pregnancy. It has been submitted to many delivery? controlled trials during pregnancy and has been Ans: Patients with mild disease are generally shown to have beneficial effects.7 The usual starting allowed vaginal delivery unless there are obstetric dose is 250 mg of methyldopa three times a day. indications for cesarean sections. Once severe This amount may be increased up to a total of preeclampsia is diagnosed, labor induction and 2 gm /day according to the patient’s response. vaginal delivery have been considered ideal. Higher dose of more than 2 grams indicates severity Temporization with an immature fetus is considered of hypertension, though up to 4 grams of subsequently. Several concerns, including an methyldopa can be used. The common side effects unfavorable cervix, a perceived sense of urgency are postural hypotension, excessive sedation and because of severity of preeclampsia, and the need depression. Positive Coombs’ test and abnormal to coordinate neonatal intensive care, have led some liver test are also reported. obstetricians to advocate cesarean delivery. CASE 2 Q.7. What is the role of antihypertensive drugs Q.8. A 32-years old multiparous woman with 32 in mild hypertension in pregnancy? weeks of period of gestation has come to the Hypertension in Pregnancy 69 casualty with blood pressure of 160/110 mm of exudates or extensive arteriolar changes suggest Hg and complains of headache and urine chronic hypertension. (3) Papilledema is not a albumin on dip stix is 2 +. What is the diagnosis? common finding in preeclampsia. it suggests Ans: The diagnosis of this patient is more likely of the possibility of a brain tumor, causing increase severe preeclampsia with impending eclampsia. in intracranial pressure and secondary The diagnosis may also be that of severe pre- hypertension. Rarely, papilledema is found eclampsia superimposed on chronic hypertension suggestive of fulminating nature of disease with if the patient gives history of chronic hypertension raised intracranial tension where termination of in the interval between pregnancy or before 20 pregnancy is required. weeks of the pregnancy. Q.10. What are the main objectives of the Q.9. What are the additional points in the history management? and examination to be looked for? Ans: The basic management objectives for any Ans: Important points to be noted in the history pregnancy complicated by preeclampsia are: are: 1. Termination of pregnancy with the least 1. history of excessive weight gain possible trauma to mother and fetus. As of now 2. history of headache/visual disturbances like only cure for preeclampsia is the termination blurring of vision, scotoma, bright or black of pregnancy. At best, it may be controlled only spots: suggestive of impending eclampsia when it is of mild variety. It is dangerous to 3. history of epigastric pain/ right upper quadrant continue pregnancy in severe preeclampsia for pain more than 1-2 weeks. 4. history of decreased urinary output 2. Birth of an infant who subsequently thrives 5. any history of convulsion 3. Complete restoration of health to the mother 6. any history of intake of antihypertensive drugs 7. any history of breathlessness/chest pain/ Q.11. What are the points of severity of the ghabrahat etc: suggestive of impending cardiac disease? failure/pulmonary edema Ans: Table 6.1 describes the differences in 8. any history of renal disease ‘nonsevere’ and ‘severe’ variety of hypertension in In addition to examination points discussed in pregnancy. the case1 of mild hypertension mentioned earlier, following points to be noted: Q.12. What is the immediate management of this 1. Reflexes: Brisk deep tendon reflexes are also patient? common and result from central nervous system irritability. In some cases clonus and twitching Ans: Our aims for the immediate management of of digits may also occur. It is unusual for this patient are: preeclamptic patients to have seizures without • To bring down the blood pressure to safe levels first showing signs of nervous system (from severe variety to moderate variety) irritability. • Assess general condition for presence of 2. Fundus examination: Most common findings on immediate risk factors for convulsions fundus in severe preeclampsia are: (1) increase (headache, altered sensorium, drowsiness, in a vein to artery ratio and segmental agitation, patients having premonitory vasospasm (2) The presence of hemorrhage, symptoms). 70 Case Discussions in Obstetrics and Gynecology

Table 6.1: Characteristcs of ‘nonsevere’ and ‘severe’ variety of hypertension in pregnancy Abnormality Non-severe Severe Diastolic blood pressure <110 mm Hg >110 mm Hg Systolic blood pressure <160 mm Hg > 160 mm Hg Proteinuria <2+ >3+ Headache Absent Present Visual disturbances Absent Present Oliguria Absent Present Upper abdominal pain Absent Present Convulsions Absent Present Serum creatinine Normal Elevated Thrombocytopenia Absent Present Serum transaminase elevation Minimal Marked Fetal growth restriction Absent Obvious Pulmonary edema Absent Present Papilledema Absent Present Hyper-reflexia Absent Present Signs of CCF Absent Present Signs of multi organ dysfunction Absent Present

• With the help of investigations and monitoring 250 mg thrice a day (maximum up to 2000 of urine output we will like to assess the patient mg/day) or nifedipine 10 mg twice to thrice for presence or absence of multiorgan a day (maximum up to 80 mg) may be involvement and HELLP syndrome. started. The dose of oral drug can be titrated • Assessment of the fetal wellbeing and according to the blood pressure levels. reasonable maturity (which is more than 32 2. Use of magnesium sulphate: It is the most weeks ≥ 1 kg of weight, as in our hospital where commonly used drug for the prevention and baby can survive better). It may depend on the treatment of eclampsia. Magpie trial (2002) individual nursery and neonatology facility. proved that magnesium sulphate has a Therefore, one must do the following: definite role in the treatment of severe 1. Use of antihypertensive drugs, importantly preeclampsia. In this trial, the incidence of intravenous labetalol or oral nifedipine. eclampsia was (2.7%) in the placebo group Intravenous labetalol is used in the doses of versus 1.1% in the magnesium sulphate 20 mg→40 mg→80 mg→80 mg repeated group. Magnesium sulphate is used as 4 gm every 10-20 minutes till a maximum dose (20% solution) of loading dose intra- of 220 mg. Oral nifedipine in the doses of venously followed by 5 gm of 50% solution 10 mg→20 mg→20 mg→20 mg→20 mg intramuscularly in each buttock. may also be used upto a maximum dose of Maintenance dose is 5 gm in alternate 90 mg,with blood pressure monitoring every buttock 4 hourly till 24 hours after delivery. 10-20 minutes.8 Once the blood pressure 3. Send investigations as discussed earlier with control is achieved ( blood pressure < 160/ immediate urine albumin examination 110 mm of Hg) maintenance dose in the 4. Monitoring: blood pressure should be form of oral labetalol 100 mg twice a day measured every 15 minutes till it comes (maximum up to 1200 mg) or methyldopa down from severe to moderate variety and Hypertension in Pregnancy 71

then every one hourly. Urine albumin Q.14. How do we manage a patient with charting should be done every 4 hourly. eclampsia? Urine output monitoring preferably by Ans: Management includes following: catheterization should be done. 1. Check vitals 5. USG and Doppler examination to asses the 2. Place patient in lateral decubitus position to maturity of the fetus if not done earlier to prevent aspiration. The bed rails should be be done after patient settles down. elevated to prevent maternal injury. Padded 6. Decision regarding termination of tongue blade should be inserted between teeth pregnancy, if the fetus has achieved viable to avoid injury to the tongue. maturity has to be taken after counseling the 3. Quick history and examination. relatives. 4. Keep airway clean and patent by frequent oral suctioning. Q.13. What is the expectant management in the 5. Give oxygen by mask at 8-10 litres/minute, if case of severe preeclampsia? convulsion occurs or pulse oximetry shows Ans: Most obstetricians would like to terminate hypoxia the pregnancy if reasonable maturity of fetus is 6. Prevent convulsions further by keeping silence, present ( >32 weeks or >1 kg). Patient has to be dim lights, and minimal noise treated only in a tertiary care center where facility 7. Give loading dose of magnesium sulphate, 4 gm of expert neonatologists, anaesthesiologists, senior of 20% solution intravenously slowly over 5 obstetricians, O.T facility,and blood bank facility minutes and 5 gm of 50% solution intra- are available. In a rare case, when period of muscularly in each buttock followed by a gestation is less than 28 weeks, to gain 1 or 2 weeks maintenance dose of 5 gms IM in alternate more, patient would be observed by extremely close buttocks every 4 hourly till 24 hours after monitoring that is done every 2 hourly blood delivery. pressure, urine output, general conditions 8. Intravenous labetalol or oral nifedipine to bring (tachypnea, dyspnea, crepts in chest) monitoring down the blood pressure to moderate level. and if necessary, everyday monitoring by 9. Pulse oximetry: There is possibility of help from investigations like hemogram with platelet count, anesthetists if patient is not maintaining oxygen Liver function test, kidney function test, PT and saturation on pulse oximeter or is having PTTK. The dangers are: frequent convulsions. 1. Patients throwing convulsions 10. After the patient is stabilized, do per vaginum 2. HELLP syndrome ( 40% mortality) examination and decide termination, preferably 3. Unannounced abruption and IUD vaginal delivery by instilling dinoprostone gel 4. DIC if cervix is too unfavorable or oxytocin 5. Cardiac complications like pulmonary edema augmentation in higher concentration to prevent 6. Fetal complications like intrauterine growth fluid overload (for primi patients 5 units in 500 retardation, absent or reversed umbilical artery ml of Ringer lactate @ 5 miliunits/minute and Doppler, intrauterine death, neonatal death. to be titrated according to the contractions.) However, neonatal death may occur even after 11. It should be noted that cesarean section in termination of the pregnancy. eclampsia has higher morbidity and mortality 72 Case Discussions in Obstetrics and Gynecology

than vaginal delivery. However, indications of • Renal changes: The distinctive renal lesion in cesarean in eclampsia sometimes can be, though preeclampsia is “glomerular endotheliosis”. It rarely (1) obstetric indication like transverse lie, consists of swelling, vacuolization, and deposits malpresentation, placenta previa, cephalo pelvic of osmophilic material resulting in the disproportion (2) uncontrolled fits not obliteration of the capillary lumen. Rarely, responding to the anticonvulsants treatment and preeclampsia alone causes acute tubular for termination of pregnancy if there is no necrosis and thus acute renal failure. Although immediate prospect of vaginal delivery inspite mild degrees are encountered in neglected of induction of labor. cases, clinically apparent renal failure is invariably induced by coexistent hemorrhagic Q.15. What are the causes of death in eclampsia? hypotension. Ans: Death in eclampsia may result due to • Liver involvement: The characteristic lesions following conditions: commonly found were regions of periportal • Intracranial hemorrhage, cerebrovascular hemorrhage in the liver periphery. Hepatic accidents hemorrhage from areas of infarction may extend • Pulmonary edema to form a hepatic hematoma. These in turn may • Status eclampticus extend to form subcapsular hematoma which • Congestive cardiac failure may rupture. There may also be moderate to • Acute renal failure/hepatic failure severe pain in right upper quadrant or epigastric • Hypertensive encephalopathy region. • Acute tubular necrosis or cortical necrosis • Cerebrovascular changes: Important neuro- • Disseminated intravascular coagulation (DIC) anatomical lesions in the brain are intracerebral • Hyperpyrexia due to pontine hemorrhage hemorrhage, cortical and subcortical petechial • ARDS hemorrhage, subcortical edema, multiple non- • Aspiration pneumonitis hemorrhagic areas of “softening” throughout • All above conditions either singly or in the brain and hemorrhagic area in the brain. combination. Q.17. What is the prognosis of the disease? Q.16. What are the other organ systems Ans: The seizure characteristics of eclampsia are involved? acute and transient and long-term neurologic Ans: Organ systems involved are: deficits are rare in patients adequately treated. • Cardiovascular changes: Women with However, 35% of patients who develop eclampsia preeclampsia initially have increased cardiac will have preeclampsia in a subsequent pregnancy. output (CO) and normal peripheral vascular However, recurrence of eclampsia is 1.4%. resistance (PVR). However, with worsening of • In women with preeclampsia in first pregnancy, the disease there is a hemodynamic crossover the probability of recurrence in second to low CO and elevated PVR. The most serious pregnancy is about 30% and is in inverse hematological complication is the HELLP relation to the gestational age at which the syndrome that is a form of severe preeclampsia patient developed the disease. with hemolytic anemia with thrombocytopenia • The incidence of chronic hypertension was with elevated liver enzymes. significantly increased 5.2 fold in those who Hypertension in Pregnancy 73

had gestational hypertension, 3.5 fold after mild • Placental abruption preeclampsia and 6.4 fold after severe Fetal complications are: preeclampsia. • Fetal growth restriction • The risk of developing preeclampsia is 20-40% • Preterm delivery and perinatal mortality for daughters of preeclamptic mothers; 11-37% • Prone to developmental anomalies due to for sisters of preeclamptic women; and 22-47% exposure to fetotoxic drugs like ACE inhibitors in twin sisters. in early pregnancy. Modified treatment includes searching for CASE 3 confounding medical diseases like obesity, diabetes Q.18. A 35-year old lady with first trimester mellitus, and hypothyroidism. These associated pregnancy with history of hypertension being medical conditions must be controlled. One must treated with combination of drugs like atenolol also look for structural defects in fetus if mother and enalapril (ace inhibitor), comes to ANC has been exposed to fetotoxic drugs early in OPD. How will you manage? pregnancy. USG at 14-16 weeks and then repeat at 18-20 weeks must be done to rule out gross Ans: congenital anomalies. 1. First of all, enalapril being fetotoxic should be Aspirin and antioxidants like vitamin C and stopped. Enalapril belongs to angiotensin vitamin E have also been used for the prevention converting enzyme inhibitors group and is of superimposed preeclampsia. However, the known to cause abnormal renal development benefits of these drugs have not been established in the fetus. They also cause growth restriction, yet. limb shortening and maldevelopment of the calvaria. Atenolol should also be stopped as it Q.20.What are the complications in neonates of is associated with intrauterine growth retar- mother with hypertension in pregnancy? dation. Ans: The complications are: 2. Patient should be admitted for initial work up • Intrauterine growth restriction and blood pressure monitoring. Since there is • Prematurity and perinatal morbidity spontaneous reduction in blood pressure in early • Low birth weight second trimester, this patient may not require • Hypoglycemia any antihypertensive drugs. However if the • Gross congenital anomalies if mother exposed blood pressure is still high, this patient can be to fetotoxic drugs in early pregnancy switched over to other antihypertensive agents • Long-term sequel: Risk of development of which are safe in pregnancy like methyldopa hypertension in later life or labetalol.

Q.19. What are the complications expected in REFERENCES this patient and what modified management 1. Borghi C, Esposti DD, Cassani AJ, Immordini V, besides those discussed earlier is needed? Bovicelli L, Ambroisioni E. The treatment of Ans: Maternal complications are: hypertension in pregnancy. Journal of Hypertension 2002;20(suppl2):S52-S56. • Super imposed preeclampsia (incidence being 2. Podymow T, August P. Update on the use of 25%) antihypertensive drugs in pregnancy. Hypertension • Development of severe hypertension. 2008;51;960-69. 74 Case Discussions in Obstetrics and Gynecology

3. Cunningham FG, Leveno KJ, Hauth JC, Bloom SL, hospitalisation done in the management of pre- Rouse DJ, Spong CY. Pregnancy hypertension.L . eclampsia remote from term. Obstet Gynaecol Williams Obstetrics.23rd edition. New York: Mc Graw 1987;70:323-7. Hill Medical Publishing Division; 2010;705-56. 7. Cockburn J, Moar V.A, Ounsted M, Redman CWG. 4. Arias F, Daftary SN, Bhide AG. Hypertensive disorders Final report of study on hypertension during in pregnancy. Practical guide to high risk pregnancy pregnancy: The effects of specific treatment on the and delivery. 3rd edition. Elsevier publication; growth and development of children.Lancet 2008;397-439. 1982;1:647-9. 5. Hjartardottir S, Leifsson BG, Geirsson RT, et al. 8. Vermillion ST, Scardo JA, Newman RB, Chauhan SP. Reccurence of hypertensive disorder in second A randomized, double blind trial of nifedipine and pregnancy. Am J Obstet Gynecol 2006;194:916. intravenous labetalol in hypertensive emergencies 6. Sibai BM, Gonazalec AR, Mabie WC, Moretti M. A of pregnancy. Am J Obstet Gynecol 1999;181:858- comparison of labetalol plus hospitalisation versus 61. Leena Wadhwa, Arima Nigam, Savita Sigchi

7 Heart Disease in Pregnancy

CASE 1 Past history: History of tuberculosis, diabetes Mrs X, 32-yr-old female, married for 10 years, mellitus, hypertension, hypercholestrolemia, G2P1+0+0+1, last child birth 7 years ago, full pulmonary embolus or deep vein thrombosis, blood term normal vaginal delivery, known case of transfusion, allergy to any drug, any history of Rheumatic heart diseases with mitral stenosis for previous cardiac surgery or cardiac event. last 8 years was admitted in labor room at 30 Family history: History of tuberculosis, diabetes weeks with chief complaints of dyspnea, mellitus, hypertension, thromboembolic disease, productive cough and palpitations for last genetic problems, congenital anomalies, any history 2-3 days. of congenital heart disease. Personal history: History of cigarette smoking, Q.1. How will you elaborate the history in the alcohol and illicit drug use and domestic violence. above mentioned case? Bowel and bladder habits, history of contraceptive Ans: practice prior to pregnancy. Cardiac history Dietary history: Total caloric intake with reference • Age at diagnosis of cardiac problem, any history to carbohydrates, protein and fat intake. Dietary of previous surgery/intervention. advice is given for adequate protein intake (80-90 • Results of previous investigations for gm/day) and to restrict sodium intake. comparison as ECG, ECHO Treatment history: Details of taking cardiac drugs • History of previous cardiac events (arrythmias, as digoxin, diuretics, beta-blocker, injection ischemic events, etc.) penicillin/3 week, syrup potassium chloride, etc. • Medication(previous/current) Socioeconomic and occupational history: • Exercise tolerance (and pre-pregnancy Occupation of the patient should be noted to comparison), with reference to NYHA classi- interpret symptoms due to fatigue or occupational fication • History of palpitations, dyspnea, orthopnea, hazards and occupation of the husband to know paroxysmal nocturnal dyspnea and easy about socioeconomic condition of the patient and fatigability, syncope, chest pain, hemoptysis per capita income. This helps to anticipate and treat • History of recurrent chest infection, cough, complications associated with low socioeconomic fever, urinary infection, periodontal infection status like anemia, preeclampsia, prematurity etc. Obstetric history: Any significant history related Also enquire about the educational status of the to cardiac problem in previous pregnancy and in patient to judge her understanding of the disease postpartum period, any obstetric complications. and explain her about the treatment. 76 Case Discussions in Obstetrics and Gynecology

Q.2. How will you examine this case? Comment on liquor and fetal growth, uterine Ans: activity, fetal heart rate General physical examination In the above patient on cardiac examination Built pulse rate was 130/min irregularly irregular, Nutrition JVP raised, mid-diastolic murmur heard at Height: in cms apex, S loud, opening snap following S at apex. Weight: in kg 1 2 Chest auscultation revealed fine crepts at bases. Body mass index (BMI = wt.in kg/Ht2 [m]) Gait Q.3. How will you investigate this case? Pallor: note in lower palpebral conjunctiva, dorsum of tongue and nail beds Ans: Cyanosis/clubbing Base line investigations Jaundice Hemogram, liver function test, kidney function test, Tongue, teeth, gums and tonsils: look for stomatitis, serum electrolytes, coagulation profile is to be done glossitis or any evidence of infection in mouth if patient is on anticoagulants. PT/INR is an Neck: JVP, thyroid gland and lymph nodes important marker if patient is on warfarin, aPTT if Pedal edema patient is on unfractionated heparin, ECG and Pulse: rate, mention if regular or irregular, volume, ECHO. note if radiofemoral delay (to rule out coarctation In the above mentioned patient: of aorta) ECG (12 long lead): Rate 130/minute, no Blood pressure - mm Hg in right arm supine discernible P wave, variable RR interval, findings position suggestive of atrial fibrillation. Temperature Echo – RHD/Severe MS (0.7 cm2)/severe TR/Mild Respiratory rate AR/trivial MR/Left ventricular ejection fraction Systemic examination 60%, right ventricular systolic pressure = 50 mm Cardiovascular Hg [secondary pulmonary artery hypertension]. Inspection—JVP raised or not, any visible cardiac impulse Q.4. What is the diagnosis and how will you Palpation—Apex beat, heave, thrill, manage atrial fibrillation (AF) in this case? Auscultion—mention type and grade of murmur, Ans: The diagnosis is Rheumatic heart disease, specify area where murmur is best heard over the severe mitral stenosis (MS), moderate pulmonary chest (Benign soft ejection systolic murmurs are arterial hypertension (PAH), atrial fibrillation with present in about 80% of pregnant women and those fast ventricular rate, CHF, NYHA class IV, without of low grade are unlikely of clinical significance, infective endocarditis. however diastolic murmurs are considered abnormal). Atrial fibrillation with fast ventricular rate is a Chest examination medical emergency in a patient of severe MS as • Air entry there is risk of embolism and hemodynamic • Breath sound, any adventitious sounds deterioration. A patient of MS cannot tolerate • Basal crepts indicating left ventricular failure increased heart rate associated with atrial Per abdomen fibrillation well because of further compromise in Hepatomegaly/splenomegaly diastolic filling. In rheumatic MS patients atrial Fundal height/lie and presentation, whether fibrillation is usually chronic and is associated with corresponding to period of gestation chronically enlarged left atria, cardioversion by Heart Disease in Pregnancy 77 electrical or pharmacotherapeutic means may not ↓ lead to sustained sinus rhythm so heart rate control Oxygen desaturation becomes a priority. Ventricular rate should be ↓ controlled with beta blockers, calcium channel Retention of CO2. It leads to generalized tissue blockers or digoxin in that order of preference. hypoxia, acidosis and death. Target heart rate should be 60-70 beats/minute. Apart from cardiac diseases, fluid overload, Antithrombotic therapy is recomemended for all preeclampsia, eclampsia, CHF, chorioamniotic AF patients to prevent embolic complications infection, use of beta agonist can lead to pulmonary including pregnant women. edema. Apart from diuretics, pharmacological Q.5a. How will you manage heart failure in this management of pulmonary edema is dependent case? on the underlying cardiac condition. In case of Ans: This patient needs immediate admission and critical mitral stenosis where the left ventricular management of CHF which consists of the ejection fraction is usually normal the treatment of following. choice is rate control by beta blockers, calcium 1. Multidisciplinary team of senior obstetrician, channel blockers or digoxin in that order of anesthetic, cardiologist. preference. 2. Bed rest to reduce the cardiac work In case of regurgitant lesions like MR, AR 3. Decreasing the preload with diuretics afterload reduction is needed to increase the cardiac • Propped up position output. Nitroglycerine and sodium nitroprusside are • Oxygen by mask, vital charting the chief afterload reducing agents. • Diuretics—furosemide 20-40 mg I/V 8 In patients with dilated cardiomyopathy with hourly low ejection fraction, avoid fluid overload, give • In any patient of critical MS heart rate diuretics (preferably IV), morphine, dobutamine to control is must. Beta blockers, calcium increase contractility of heart and decrease the after channel blockers or digoxin can be used IV load resistance by nitroglycerine. in that order of preference to achieve target heart rate of 60-70 beats/minute. Q.6a. How will you treat mitral stenosis in this Note: There is maximum chance of cardiac failure case? during pregnancy around 30 weeks, during labor Ans: This is the most common lesion during and soon following delivery. pregnancy. It may lead to pulmonary edema, atrial fibrillation, thromboembolic complications and Q.5b. If any pregnant patient has acute severe PAH. The normal mitral valve area is 4-6 pulmonary edema, how will you manage her? cm2. Stenosis is graded as mild, moderate and Ans: This is a life threatening condition that occurs severe according to MVA of >1.5 cm2, 1 -1.5 cm2 frequently during pregnancy. It should be managed and <1 cm2 respectively. in intensive care unit. It can occur any time during In this case mitral valve area is 0.7 cm2 that is pregnancy. critical mitral stenosis and this needs to be corrected The basic pathology of pulmonary edema is by balloon mitral valvotomy (BMV).1 BMV should Fluid accumulation in alveolar space be done in the second trimester (20-24 weeks) with ↓ adequate shielding of abdomen to avoid radiation Impaired gas exchange risk to the fetus. 78 Case Discussions in Obstetrics and Gynecology

Open heart surgery and valve replacement is • Nifedipine is contraindicated in conduction indicated when valvotomy fails or valve is not defect, left ventricular failure due to side effects suitable for valvotomy. Heavily calcified valves, as tachycardia, hypotension, etc. severe associated regurgitation and left atrial thrombus are not suitable candidates for BMV. Q.9a. What are the ECG and ECHO findings in a normal pregnant female? Q.6b. How will you manage a patient of mild- Ans: moderate mitral stenosis? ECG: Ans: Patient with mild to moderate MS (valve area Sinus tachycardia 2 >1 cm and mean gradient less than 10 mm Hg) Decrease PR, QRS and QT intervals who is asymptomatic or mildly symptomatic can Left axis deviation almost always be managed with judicious use of Small Q wave and negative P wave in lead III diuretics and beta blockers. Diuretics are given to T wave flattening and small ST depression relieve pulmonary and systemic venous congestion. Atrial and ventricular premature contractions Beta blockers (cardioselective as atenolol or Echocardiography metoprolol) are given to attenuate the increase in Mild left atrial and left ventricular enlargement heart rate (maintain rate between 60-70 beats per Trivial pulmonic and tricuspid valvular regur- minute) and optimize diastolic filling. gitation Physiological MR. Q.7. How will you monitor this patient in ward after stabilization and post-BMV? Q.9b. What are Hemodynamic changes in Ans: Enquire about symptoms such as breathless- normal pregnancy and labor and their effect on ness, palpitations and chest pain. Examine pulse, a cardiac patient? blood pressure, heart sounds and chest examination. Carefully monitor for any signs of pregnancy Ans: The hemodynamic changes during pregnancy 3 induced hypertension and/or pre-eclampsia. are: Anemia and hyperthyroidism need to be recognized • The plasma volume by second trimester and treated promptly. Infections like chest, urinary, approaches 50% above normal. dental etc, needs to be recognized and treated • The heart rate increases to about 20% above promptly. baseline. • There is fall in peripheral vascular resistance. Q.8. What is the role of tocolytics in pregnancy • The venous pressure in lower extremity rises. with heart disease? • In normal pregnant females there is rise in Ans: cardiac output. It increases by 30-50% above • Most of them are contraindicated in pregnancy baseline. • Safest tocolytic is atosiban (oxytocin anta- So volume load compromises a patient who has gonist) impaired ventricular function (e.g. Patient of dilated • Beta agonist is contraindicated in cardiac cardiomyopathy). arrthymias, valvular disease and cardiac Stenotic lesions like AS and MS are less well ischemia because of their sympathomimetic side tolerated during pregnancy as compared to effects such as tachycardia, palpitation and regurgitant valvular lesions like AR or MR. hypotension.2 Decrease in peripheral vascular resistance during Heart Disease in Pregnancy 79 pregnancy increases the gradient and severity of Q.11. What are the predictors of cardiac events AS. Since regurgitant lesions regurgitate less in the during pregnancy? presence of decreased afterload they are better Ans: Potential for an adverse cardiac event in a tolerated. pregnant female as pulmonary edema, sustained Mitral stenosis patients cannot tolerate rapid arrhythmia, stroke, cardiac arrest or cardiac death ventricular rate because when heart rate increases can be estimated by following parameters.6 it is the diastolic time which is decreased so left N New York Heart Association (NYHA) class >2 ventricle cannot fill and thus eject properly. O Obstructive lesions of the left heart (Mitral valve Ventricular rate control is must in an MS patient. or aortic valve area <1 cm2). During labor and delivery the hemodynamic P Prior cardiac event before pregnancy—Heart changes are abrupt. There is increase in cardiac failure, arrhythmia, transient ischemic attack, stroke output and blood-pressure. The cardiac output E ejection fraction <40% during 2nd stage of labor is often 50% above The risk of cardiac complications is 3%, 30% normal. So conditions like Marfan’ syndrome with and 60% when none, one or more than one of these dilated aorta is not tolerated well and there may be complications are present. acute aortic dissection or rupture.To avoid abrupt NYHA classification7 (revised 1979) increase in blood pressure (during second stage of Class I: No limitation of physical activity labor) cesarean section is indicated in a Class II: Slight limitation of physical activity compromised Marfan’s patient. Class III: Marked limitation of physical activity Class IV: Dyspnea at rest. Q.10. What is the effect of cardiac disease on pregnancy? Q.12a.What is the risk of cardiac events during Ans: Maternal mortality is maximum in patient pregnancy in women with heart disease? of severe pulmonary arterial hypertension of any Ans: The risk of cardiac events during pregnancy cause (specially Eisenmenger’s syndrome). are:8 Maternal complications of heart disease include Low risk: congestive heart failure, pulmonary edema, arrythmias and sudden cardiac arrest. • Small left to right shunts such as ASD, VSD In fetus: There is risk of and PDA • IUGR • Repaired lesions with normal cardiac functions • Prematurity • Mild to moderate pulmonic or tricuspid lesions • Abortion • Marfan’s syndrome with normal aortic roots • Inheriting congenital heart lesion. • Homograft or bioprosthetic valves There is high risk of inheriting a congenital • Bicuspid aortic valve without stenosis heart disease in the child of a mother with Intermediate risk: congenital heart disease (3% in TOF and 10% in • Uncorrected cyanotic heart disease ASD, coarctation of aorta and aortic stenosis). • Large left to right shunts Since Marfan syndrome is an autosomal dominant • Uncorrected, uncomplicated aortic stenosis condition, it has a 50% recurrence rate in offspring. • Mechanical valve prosthesis A fetal echo is indicated if the mother has congenital • Severe pulmonic stenosis heart disease.4, 5 • Moderate to severe left ventricular dysfunction 80 Case Discussions in Obstetrics and Gynecology

• Previous left ventricular dysfunction now • Prosthetic cardiac valve resolved (such as peripartum cardiomyopathy) • Previous IE • Previous myocardial infarction • Unrepaired congenital heart disease (including High risk: palliative shunts and conduits) • Pulmonary hypertension • Completely repaired congenital heart defect • Marfan’s syndrome with aortic valve involve- with prosthetic material or device, during the ment first 6 months after the procedure. • Cardiomypathy • Repaired congenital heart disease with residual • Complicated aortic coarctation. defects at the site or adjacent to the site of a prosthetic patch or device. Q.12b. What are the indications for admitting a • Cardiac transplantation recipients who develop patient with heart disease in pregnancy? cardiac valvulopathy. Ans: Patients with NYHA class I and II need Q.14. What antibiotic regimen for IE pro- regular frequent follow up in OPD whereas patients phylaxis is recommended? with NYHA III and IV need hospitalization. Heart Ans: Only a few regimens are recommended by disease patient require emergency admission the American College of Obstetricians and whenever there is deterioration of functional Gynecologists (2008)10 for prophylaxis which is grading, appearance of sign/symptoms of failure given preferably 30-60 minutes before the or any pregnancy complications as anemia, toxemia procedure. Either ampicillin, 2 gm, or cefazolin or etc. ceftriaxone, 1 gm, is given intravenously. For penicillin sensitive patients, one of the later regimen Q.13. What are the recommendation of is given, or if there is history of anaphylaxis, then American College of Cardiology/American clindamycin, 600 mg is given intravenously.The Heart Association for endocarditis prophylaxis recommended oral regimen is 2 gm of amoxicillin. regimens (AHA 2007)? If Enterococcus infection is of concern, Ans: The American Heart Association recently vancomycin is also given. updated its guidelines regarding which patients should take a precautionary antibiotic to prevent Q.15. How will you plan delivery in above case? infective endocarditis (IE).9 Ans: The plan will be to await spontaneous labor Prophylactic antibiotics are no longer if maternal condition is stable and there is no recommended for gastrointestinal or genito- evidence of fetal compromise. With careful urinary tract procedures. This recommendation monitoring vaginal delivery poses fewer risks. follows from the observation that most cases of IE result from bacteremia caused by routine activities Q.16. What is the role of induction in labor? such as chewing food, brushing teeth, and flossing. Ans: This has little role in management of heart Moreover, no published data clearly indicate that disease. It may lead to prolong time between prophylaxis prevents IE from invasive procedures. induction and delivery interval which results in It is recommended that IE prophylaxis may infection, failure and increase in cesarean section be given during labor in the following subgroups rates. of patients who carry substantially high mortality However if there is obstetric indication there is no from IE contraindication for induction. Heart Disease in Pregnancy 81

The method of induction which is preferable is precipitate heart failure. Severe heart failure concentrated syntocinon. During syntocinon symptoms may necessitate early delivery. Cesarean infusion precaution should be taken to avoid fluid is considered in severe AS in view of abrupt overload. The concentration of syntocinon infused hemodynamic changes. should be doubled compared with the standard • Abrupt fall in afterload when the baby is dilution and infusion rate should be halved.2 delivered vaginally may lead to maternal Prostaglandin can be used but with caution as it collapse. may lead to pulmonary edema if it is associated • AS patients are critically dependent on preload with preeclampsia. volume for maintenance of cardiac output as increase in preload will cause pulmonary edema Q.17. What are the indications of elective and decrease in preload due to blood loss at the cesarean section in heart disease? time of parturitation can also lead to maternal Ans: In pregnancy with heart disease usually collapse. Epidural anesthesia is not preferred cesarean section is indicated for obstetrical in these patient’s due to same reasons. reasons only. Asymptomatic patients should be managed by Exceptions to this rule are: bed rest and beta blockers. Diuretics and potent 1. Coarctation of aorta with valvular involvement. vasodilators should be avoided as these patients are 2. Marfan’s syndrome with aortic involvement. dependant on preload. In case of severe AS 3. If there is abrupt hemodynamic deterioration. percutaneous aortic balloon valvuloplasty may be 4. Some authors recommend cesarean section in done especially if the valve morphology is suitable. women with severe pulmonary hypertension or severe aortic stenosis.11 Q.19. What will be the management of 1st stage 5. A patient who is fully anticoagulated with of labor? warfarin at the time of labor needs to be Ans: counseled for cesarean section because the baby • Patient should be in lateral decubitus position is also anticoagulated and vaginal delivery • Vital charting (pulse and respiratory rate every carries increase risk to the fetus of intracranial 15-30 minutes and BP monitoring 2 hourly) hemorrhage. • Intermittent chest auscultation • Adequate pain relief Q.18. How will the management differ if the • Restrict IV fluid to 75 ml/hr, avoid bolus valvular lesion is aortic stenosis (AS) in this oxytocin patient? • Antibiotic prophylaxis Ans: AS during pregnancy mostly has congenital • Strict input output charting etiology (bicuspid aortic valve). Rheumatic AS is • Intermittent/continous electronic FHR less common and occurs in association with mitral monitoring valve disease. Most patients with mild to moderate • Per vaginum examination under strict aseptic AS have a favorable outcome. However those with precautions and only when indicated severe AS (valve area < 1cm2 or mean gradient > • Avoid or delay artificial rupture of membranes 50 mm Hg) should be counseled not to have • Pulse oximetry especially in NYHA III and IV pregnancy as the maternal mortality is as high as • With highly compromised patient Swan-Ganz 17%.11 The decrease in peripheral resistance during catheter facilitates maintenance of optimal pregnancy will exaggerate the gradient and may hemodynamics. 82 Case Discussions in Obstetrics and Gynecology

Q.20. How will you manage 2nd stage of labor? The normal pregnant patient has a faster resting Ans: heart rate, bounding pulse, widened pulse pressure, • Lateral decubitus position low blood pressure and warm extremities. • Oxygen by mask a. Features suggestive of severe anemia: • Pulse oximeter History: Enquire about socioeconomic strata, • Intermittent chest auscultation dietary history in detail and history of regular • Pain control (I/M tramadol, IV morphine 2-4 antenatal iron intake mg ) Look for other factors as: • Anesthesia of choice (Epidural block, or Multigravida, multiple pregnancy, chronic epidural narcotics) illness as UTI, worm infestation, bleeding piles, • IV fluid 75 ml/hour dysentery, lethargy, palpitations, breathlessness on • Vaginal delivery is the better option exertion, history of menorrhagia, blood transfusions • Cut short the second stage ( Either vacuum or Examination: forceps may be used for operative vaginal • Pallor ++, edema feet +, chelosis, koilonychia delivery if required) • Pulse regular good volume • Maintained BP Q.21. How will you manage 3rd stage of labor? • Soft systolic murmur Ans: • JVP not raised (unless in failure) • Injection methergin should be avoided • Hepatosplenomegaly • Injection frusemide 20-40 mg IV to be given to b. Features suggestive of respiratory disease: avoid postpartum pulmonary edema History: Fever with chills and rigors, cough with • Sedation sputum, pleuritic chest pain, hemoptysis • Intermittent chest auscultation. Examination: Tachycardia, temperature, con- Q.22. What will you monitor in the immediate ducted sounds on chest examination postpartum period? c. Features suggestive of heart disease Symptoms: Ans: In the immediate postpartum period (initial • Progressive dyspnea 24-72 hours) there is abrupt increase in venous • Orthopnea return not only because of autotransfusion from • Nocturnal cough uterus but also due to removal of vena caval compression post-delivery. So women is vulnerable • Hemoptysis for pulmonary edema. • Syncope • W/F signs and symptoms of CHF • Chest pain • W/F bleeding per vaginum • Palpitation on ordinary activities • Input output charting • Easy fatigability • Vital charting Signs: • Intermittent chest auscultation. • Irregularly irregular pulse • JVP raised Q.23. What will be the differential diagnosis in • Diastolic murmur/systolic murmur gr>III this case? • Cadiomegaly Ans: Normal pregnancy changes, anemia and • Persistent arrhythmia respiratory problems need to be differentiated from • Persistent split S2 cardiovascular disease in pregnancy. • Pulmonary hypertension Heart Disease in Pregnancy 83

CASE 2 osteoporosis, lower risk of bleeding and need for lab monitoring. LMWH should be used only if Mrs Y, 30 years old female, married for 5 years, facility of monitoring anti Xa level is available. Primigravida, known case of Rheumatic heart disease undergone double valve replacement prior Q.25. What are the recommendations of to pregnancy has presented in OPD at 6 weeks of American College of Chest Physicians for pregnancy. Anticoagulation of Pregnant Women12 with mechanical prosthetic valves? Q.24. How will you manage this patient with prosthetic valve in situ? Ans: For pregnant women with mechanical heart valves, any one of the following is recommended: Ans: It is important to enquire whether patient has • Adjusted-dose LMWH twice daily throughout mechanical or bioprosthetic valves in situ. Women pregnancy. The doses should be adjusted to keep who have undergone valve replacement or had a manufacture’s peak anti-Xa level 4 hours after congenital lesion surgically corrected prior to subcutaneous injection. pregnancy, should be considered for anticoagulants • Adjusted dose UFH administered every 12 if they have mechanical valve. Bioprosthetic valve hours throughout pregnancy. The doses should or homograft valve do not require any treatment be adjusted to keep the midinterval aPTT at least but these valve have shorter half-life of six to eight twice control or attain an anti-Xa heparin level years which is further shortened by hemodynamics 0.35 to 0.70 U/ml. changes of pregnancy. • LMWH or UFH until 13 weeks gestation with Management of patient with mechanical valve warfarin substitution until close to delivery in situ is: when LMWH or UFH is resumed. The patient should be admitted at 6 weeks to In women judged to be at very high-risk of switch over from warfarin to heparin. Up to 12th thromboembolism and in whom concerns exist week-heparin to be given ( Unfractionated heparin about the efficacy and safety of LMWH or UFH as UFH or subcutaneous low molecular weight dosed above—some examples include older- heparin LMWH ) UFH should be given in dose generation prosthesis in the mitral position or which maintains aPTT twice as high as control. history of thromboembolism. In these patients 12th to 36 week—warfarin (Dose should maintain Warfarin is suggested throughout pregnancy with an INR between 2.5-3.5). replacement by UFH or LMWH (as above) close 36 weeks onwards—omit warfarin, restart heparin. to delivery. In addition, low-dose aspirin-75 to 100 Stop heparin when patient goes in labor and should mg daily should be orally administered. be started 6 hours after delivery and 24 hours after cesarean section. This heparin may be omitted after Q.26. How will you manage if a fully anti- overlapping with warfarin therapy once the target coagulated patient on warfarin goes into labor? INR is achieved. Ans: If the patient is still on warfarin and goes into Low molecular weight heparin may be used in place labor, injection vitamin K should be given and fresh of conventional unfractionated heparin (Enoxa- frozen plasma should be arranged. In a patient who parin, Therapeutic dose 2 mg/kg body weight).The is on heparin and goes into labor or there is advantages of LMWH includes less excessive bleeding, protamine sulphate should be thrombocytopenia, longer half life which permits arranged (dose is 1 mg/100 units heparin if once or twice daily doses, less incidence of required). 84 Case Discussions in Obstetrics and Gynecology

Q.27. What are the cardiac conditions in which to venous thrombosis which may lead to the maternal risk is very high and even paradoxical embolism. termination of pregnancy is indicated? • Mechanical prosthetic valves: Already Ans: Conditions in which risk to mother and fetus described. is exceptionally high are: Termination of pregnancy is indicated in • Pulmonary artery hypertension (PAH)13: following conditions Pulmonary hypertension (PA systoic • Eisenmenger’s syndrome: Patients with this > 50 mm Hg or 2/3 systemic) regardless of the syndrome have pulmonary hypertension with cause, carries a high mortality when associated shunt (R to L) through an open ductus, an ASD with pregnancy. Causes include thrombo- or VSD. Maternal mortality is about 50%. embolic disease, anorexic drugs, valvular heart Termination of pregnancy should be seriously disease and idiopathic primary pulmonary considered. Heparin should be used through out hypertension. Pregnancy is poorly tolerated, the pregnancy as there is risk of systemic and with a risk of worsening cyanosis and hypoxia, pulmonary thromboembolism. Epidural arrythmias, heart failure and death.. Maternal anesthesia is contraindicated. Inhaled nitric mortality rate is as high as 50% in PAH. oxide or IV prostacycline is used as a pulmonary • Dilated cardiomyopathy with ejection fraction vasodilator. < 40% due to volume overload of pregnancy • Primary pulmonary hypertension. • Symptomatic obstructive lesions as AS, MS, • Marfan’s syndrome with aortic involvement Coarctation of aorta. • Uncorrected coarctation of aorta especially • Marfan’s syndrome with aortic root > 40 when associated with other anomalies as mm, as patient is vulnerable to progressive aneurysm of circle of willis. aortic dilatation, dissection and rupture. This occurs because of increased stroke volume in CASE 3 pregnancy and due to hormonal changes in P2L2 patient, 3rd postoperative day of cesarean pregnancy which adversely affect aortic develops sudden cardiac failure. changes. Estrogens interfere with collagen deposition within media of large and medium Symptoms: Weakness, shortness of breath, muscular arteries. Circulating elastase breaks palpitation, nocturnal dyspnea and cough. the elastic lamellae and relaxin decreases Sign: Tachycardia, arrhythmia, peripheral edema, collagen synthesis and predisposes to aortic pulmonary rales. S3 present and no murmur dissection. Beta blocker should be used. She had been a booked patient with regular Hypertension should be avoided to prevent antenatal check-ups and with no prior heart problem aortic dissection. and uneventful prior obstetric history. • Cyanotic lesions: As peripheral vascular resistance falls in pregnancy, right to left shunt Q.28. What is the probable diagnosis and how increases and hence maternal hypoxia increases will you confirm it? and affects fetal growth and survival. Only 12% Ans: The diagnosis of peripartum cardiomyopathy of such pregnancies result in live born fetus if should be kept in mind. oxygen saturation is < 88%. Apart from this The criteria for diagnosis are14 erythrocytosis of cyanotic lesions and 1. Cardiac failure within last month of pregnancy hypercoagulable state of pregnancy may lead or within 5 month postpartum. Heart Disease in Pregnancy 85

2. No determinable cause for failure (may be Q.30. What are the cardiovascular drugs used immunological or nutritional). during pregnancy and their side effects? 3. No previous heart disease. Ans: 4. Left ventricular dysfunction (Echocardio- Amiodarone: Goiter, hypothyroidism and hyper- graphy) as evidenced by ejection fraction < 45% thyroidism, IUGR. 5. Left ventricular end-diastolic dimension > 2.7 Angiotensin-converting enzyme inhibitor 2 cm/m . (contraindicated): IUGR, oligohydramnios, renal Predisposing factors failure, abnormal bone ossification; • Multiparous Beta blocker (relatively safe): IUGR, neonatal • Young 20-35 years bradycardia, hypoglycemia. • Twins pregnancy Calcium channel blocker (relatively safe): • Chronic hypertension pre-eclampsia Digoxin (safe); no adverse effects. • Prolonged tocolytic therapy. Lasix (safe): Caution regarding maternal hypo- Investigation volemia and reduced placental blood flow. Chest X-ray: Enlarged heart and pulmonary Warfarin: Fetal embryopathy, placental and fetal vascular redistribution. Echo: Enlargement of all chambers of the heart hemorrhage, central nervous system abnormalities. (predominantly left heart). Q.31. What is the role of preconceptional Left ventricular global hypokinesia with decreased counseling in case of heart disease? ejection fraction. Treatment: Ans: Pre-pregnancy counseling has a major • Salt restriction preventive role in ensuring an optimal pregnancy • Bedrest outcome. The assessement is best performed by the • ACE inhibitors obstetrician and the cardiologist. The topics for • Beta blockers discussion are15: • Diuretics • Characteristics of the heart condition, functional • Digitalis and risk classifications. Risk of recurrence is high in women in whom • Effects of cardiac conditions on pregnancy. there is persistent left ventricular dysfunction. • Effects of pregnancy on cardiac conditions. • Fetal and neonatal complications associated Q.29. What will be the contraceptive advice to with specific heart condition. women with heart disease? • Need for multi disciplinary care. Ans: Steroidal contraception is contraindicated as • Frequency of prenatal visits and need for it may precipitate thromboembolic phenomenon. maternal and fetal testing. Intrautetrine device is avoided for fear of infection. • Need for anticoagulation, hemodynamic Barrier method of contraceptive (condom) is safely monitoring. recommended. Sterilization should be considered • Timing of birth, type of hospital facility required with completion of the family at the end of first for . week in the puerperium preferably through • Pain control and type of anesthesia required abdominal route by minilap technique. If the during labor and delivery. husband is willing vasectomy should be advised. • Potential need for cesarean delivery. 86 Case Discussions in Obstetrics and Gynecology

• All potential source of infection should be 8. Arafeb JM, Baird SM. Cardiac disease in pregnancy. looked for and eliminated by clinical Crit Care Nurse Q 2006;29:35-52. examination and laboratory investigation. 9. Walter Wilson, Kathryn A. Taubert, Michael Gewitz, • Women who are receiving warfarin should be Peter B. Lockhart, Larry M. Baddour, Matthew Levison, Ann Bolger, et al. AHA guidelines: considered for switch over to heparin therapy. Prevention of Infective Endocarditis Circulation. • Genetic testing if the patient is suffering from 2007;116:1736-54. heritable congenital heart disease. 10. ACOG Committee Opinion No. 421, November 2008: antibiotic prophylaxis for infective endocarditis. REFERENCES Obstet Gynecol. 2008;112(5):1193-4. 1. Gupta A, Lokhandwala YY, Satoskar PR, et al. Ballon 11. Silversides CK, Colman JM, Sermer M, et al. Early mitral valvotomy in pregnancy: maternal and fetal and intermediate-term outcomes of pregnancy with outcomes. J Am Coll surg 1998;187:409-15. congenital aortic stenosis.Am J Cardiol 2003;91(11): 2. Deans Charlotte L, Uebing A, Steer J. Cardiac disease 1386-89. in pregnancy: John studd, volume 17, Progress in 12. Bates SM, Greer IA, Pabinger I, et al. Venous obstetrics and Gynaecology 2006;164-82. thromboembolism, thrombophilia, antithrombotic 3. Cunningham FG, Lenovo KJ, Bloom SL, Hauth JC, therapy, and pregnancy:American College of Chest Rouse DJ, Spong CY. Williams Obstetrics, 23rd edn, Physicians Evidence-based Clinical Practice Cardiovascular disease, 2010. Guidelines (8th edn) Chest 2008;133:844. 4. Thorne SA. Head CEG, Congenital heart disease in 13. James DK, Steer PJ, Weiner. High Risk Pregnancy. pregnancy. Postgrad Med J 2005;81(955):292-8. Management Options. 3rd edn. Saunders. Phila- 5. Uebing A, Steer PJ, Yentis SM, Gatzoulis MA. Pregnancy and congenital heart disease. BMJ.2006; delphia. CP 2006. 332(7538):401-6. 14. Hibbard JU, Lindheimer M, Lang RM. A modified 6. Siu and Colman. Heart disease and pregnancy. Heart definition of peripartum cardiomyopathy and 2001;85:710-5. prognosis-based on echocardiography. Obstet Gynecol 7. Criteria Committee of the New York Heart Association 1999;94(2):311-16. Nomenclature and Criteria for diagnosis of Disease 15. Arias F, Daftary SN, Bhide A. Practical Guide to High of Heart and Great vessles, 6th edn. Boston, Little, Risk Pregnancy and Delivery, 3rd edn. Elsevier Brown 1964. publication. Chandan Dubey 8 Fetal Growth Restriction

A fetus that has been unable to achieve a specific CASE 1 biometric or estimated weight threshold by a Mrs R, a primigravida with 31 weeks pregnancy specific gestational age is called a small-for is suspected to have fetal growth restriction gestational-age [SGA] fetus. The most commonly because her fundal height corresponds to 26 used threshold is the tenth centile for abdominal weeks only. circumference and estimated fetal weight.1 This is an arbitrary selection. A more rigorous criterion like Important points in history the third or fifth centile would be more specific but • Determining the period of gestation with less sensitive thus resulting in many at risk fetuses accuracy is crucial for diagnosing FGR. being missed from crucial surveillance. • Date of last menstrual period, sure of dates with SGA fetuses comprise: regular cycles or any history of prolonged • Fetuses with growth restriction. cycles. • Constitutionally small and healthy fetuses. • History of using hormonal pills like oral (50-70% of SGA fetuses.)2 contraceptives just prior to conception. Classification of fetal growth restriction [FGR]: • An ultrasound done in the first trimester with Clinical relevance of earlier classification as pregnancy dated by CRL between 8-14 weeks symmetric or asymmetric based on concordance of would help to date the gestation most accurately. growth of head and abdomen as measured on First trimester ultrasound is now controversial as studies have • History of fever with or without rash to rule shown significant overlap.3,4 Early onset growth out infections like rubella, herpes, chickenpox, restriction is defined as growth compromise malaria which can lead to FGR if transmitted clinically recognizable before 28 weeks of to the fetus in utero. gestation.5 • History of exposure to drugs or radiation. Fetuses with FGR are at increased risk of stillbirth, asphyxia, prematurity, neonatal Second and third trimester complications, impaired neurodevelopment and • History of poor weight gain, or excessive weight possibly type 2 diabetes and hypertension in later gain as in preeclampsia with swelling of feet life. and tightening of rings suggesting edema. 88 Case Discussions in Obstetrics and Gynecology

• History of pain abdomen, bleeding or leaking Blood pressure. per vaginum to rule out chronic abruption and Respiratory rate preterm premature rupture of membranes. Pallor, cyanosis or icterus. • History of perceiving fetal movements. Thyroid swelling Obstetric history Cervical lymphadenopathy • In a multiparous patient details of previous Jugular venous pulsations outcomes regarding birth weights, mode of Pedal edema deliveries. Systemic Examination • Any complications like preeclampsia, abrup- Detailed CVS and Respiratory system examination. tion, miscarriages, growth retricted babies, Abdominal examination: intrauterine deaths or stillbirths may suggest Inspection- Distended uterine ovoid, any visible APLA syndrome. scars, hernial sites. Past history Palpation-Liver and spleen may be enlarged in • History of hypertension, renal disease, diabetes chronic malaria. mellitus, heart disease, asthma, autoimmune Renal angle tenderness. Renal angle tenderness diseases like SLE. may be present in recurrent upper urinary tract • History of clots in blood vessels suggestive of infections and chronic pyelonephritis which may thrombophilias. be the causes of FGR. Fundal height in weeks and symphysiofundal Personal history height [SFH] in cms. • Smoking, alcoholism and drug abuse especially Fetal lie, presentation, amount of liquor. cocaine as all these can cause FGR. Decreased liquor may be clinically apparent and is Dietary history often associated with FGR. • Diet adequate in calories and proteins with iron Auscultation- Fetal heart rate. and calcium supplementation or not. Q.1. How do you measure SFH? Socioeconomic history • Poor socioeconomic status and maternal Ans: Patient should be empty bladder and lying malnutrition may be contributory to FGR. supine with legs straight. Start the measurement by first identifying the variable point the fundus Family history and then measuring to the fixed point the symphysis • Family history of genetic disorders or pubis, with the centimeter values hidden from the syndromes. examiner to avoid observer bias.6 • History of thalassemias or thrombophilias. Examination Q.2. What is the accuracy of SFH measurement General Physical Examination in detecting SGA fetuses? General build and nutritional status. Ans: SFH has limited diagnostic accuracy in Height and weight – A constitutionally small mother predicting SGA fetuses, with a sensitivity of only may have a healthy small-for-gestational-age fetus. 27% and specificity of 88%.7 Pulse: Rate, rhythm, volume, peripheral pulses and Serial measurements and use of customized any radiofemoral delay SFH charts may improve sensitivity and specificity.8 Fetal Growth Restriction 89

Q.3. What are the causes of FGR? HIV Ans: Maternal factors: HBsAg • Preeclampsia, chronic or essential hypertension, HPLC (High Performance Liquid Chromato- secondary hypertension. graphy) for HbA2 estimation Fetal Hemoglo- • Renal disease binopathy may cause FGR. • Diabetes with vasculopathy Urine routine, microscopy, culture and sensitivity. • Autoimmune syndromes-APLA, SLE. Others: • Thrombophilia TORCH test. (Toxoplasma Rubellla CMV, herpes • Severe or cyanotic heart disease and others). • Asthma Screen for Anti-phospholipid Antibodies (LAC, • Hemoglobinopathy ACL both IgG and IgM) • Smoking, alcoholism and substance abuse like Thrombophilia screen. cocaine • Therapeutic agents like anti-cancer drugs KFT(Kidney Function Test) • Malnutrition LFT(Liver Function) Fetal Factors: Thyroid function tests (Thyroid disorders may be • Aneuploidies- Trisomy 13, 18, 21 or triploidy a part of autoimmune diseases.) • Genomic imprinting and uniparental disomy A detailed level II ultrasound for: • Malformations-heart disease, diaphragmatic • Fetal anatomic survey to rule out congenital hernia, gastroschisis, omphalocele anomalies as anomalies may be a cause of FGR • Multiple gestation • Fetal biometry to confirm FGR, repeated every • Fetal infections-malaria, cytomegalovirus, two weeks, to assess for fetal growth herpes, toxoplasmosis • Abdominal circumference (AC) and estimated Placental factors: fetal weight (EFW) specifically. • Confined placental mosaicism • Fetal echocardiography to rule out congenital • Placenta previa heart disease. • Abruptio placenta • Doppler flow studies of the umbilical artery, • Infarction repeated weekly if normal or twice a week if • Placenta accreta compromised blood flow. • Hemangioma • MCA and venous Doppler only if umbilical • Circumvallate placenta. artery Doppler is showing compromise. Amniocentesis is indicated and may be offered Investigations in cases where: Q.4. What investigation would you like to do for 1. Fetat karyotype is needed to rule out aneu- this patient, Mrs R ? ploidies as in early onset FGR. Chromosomal Ans: anomalies may be found in 19% of fetuses with Routine AC and estimated fetal weight (EFW) less than 9 Hemogram fifth centile. This risk increases with the Blood group and Rh type presence of anomalies and normal AFI and VDRL Doppler parameters on ultrasound.9 Glucose challenge test 2. Gene probes for specific genetic disorders. 90 Case Discussions in Obstetrics and Gynecology

3. PCR for fetal viral infections in early onset Third trimester fundal 28 to 36 days FGR, with normal AFI and Doppler studies, height maternal TORCH positive, calcifications in Investigations Crown rump length 5 to 7 days fetal brain and liver on ultrasound. {CRL) first trimester Screening for anomalies and aneuploidies is Gestational sac diameter 7 days important because presence of severe anomalies first trimester BPD (<28 weeks) 5 to 7 days with poor prognosis for fetus or aneuploidies will BPD (third trimester) 14 to 28 days indicate avoidance of fetal surveillance for growth and well being and unnecessary interventions like Crown rump length (CRL) is the most accurate LSCS for fetal indication. method of dating a pregnancy in the first trimester15 Biophysical tests of fetal well being: follwed by BPD in the second trimester. Biophysical Profile [BPP] Non-stress test [NST] Q.7. What is the reliability of various biometric Amniotic fluid assessment by amniotic fluid Index parameters in the diagnosis of FGR? (AFI) or single deepest pocket Ans: Cardiotocography [CTG] Fetal AC HC/AC AC/FL Doppler These will be performed weekly or more weight UA frequently as the severity of the case demands. Sensitivity(%) 65.8 62.2 49.1 28.9 66.7 Specificity(%) 88.9 90.7 83.7 47.8 68.5 Q.5. Are there any newer investigations that you Positive 63.6 67.3 47.1 47.8 38.4 know of ? predictive Ans: Transverse cerebellar diameter has been value (%) shown to correlate well with gestational age in Negative 89.8 89.8 84.8 81.3 87.5 FGR.10 It’s advantage over bony parameters is predictive controversial.11 value (%) 3-D ultrasound12,13 and MRI14 are being False positive 8.6 7.2 12.6 7.2 24.4 (%) evaluated for diagnosis and management of FGR. False negative 7.8 8.0 11.6 16.2 7.8 (%) Q.6. Dating a pregnancy is crucial to arrive at a diagnosis of FGR. What is the reliability of AC-Abdominal circumference, HC- Head circumference, FL- Femur length, UA- umbilical artery various parameters for the same? Ans: • Abdominal circumference (AC) and estimated fetal weight (EFW) show the best specificity, Parameter Error[95%] positive and negative predictive value and the History LMP(excellent history) 14 to 17 days lowest false positive and negative values. They LMP(poor history) >28 days are the most accurate in predicting SGA IVF 1 day fetuses.1 Ovulation induction 3 days • Combining AC or EFW with umbilical artery Physical First trimester PV 14 days (UA) Doppler studies improves the accuracy examination of diagnosing FGR.16 Second trimester fundal 28 days • An individual test alone may not be predictive height of FGR, but a combination of abnormal findings Fetal Growth Restriction 91

such as a small fetus for dates on ultrasound with reduced liquor and/or abnormal umbilical artery Doppler, may indicate pathology. • A threshold of tenth centile for AC and EFW is better for diagnosing SGA than other centiles.1 • Customized EFW charts adjusted for physiological variables like maternal weight, height, ethnic group and parity have better sensitivities for identifying SGA fetuses. • Serial scans every two weeks to measure AC and EFW are superior to single estimate of AC or EFW in the prediction of FGR and poor perinatal outcome.17, 18 Fig. 8.1: Doppler of umbilical artery showing normal and absent end diastolic flow Q.8. What is the role of Doppler in diagnosis and followup of pregnancies with FGR? (Fig. 8.1). The PI has the advantage of smaller error Ans: Use of umbilical artery Doppler in managing and can be numerically analyzed even with absent 21 pregnancies with FGR decreases the risk of end diastolic velocity. perinatal mortality by 38%.19 Q.9. Why and how do these changes in Doppler The identification of abnormal UA flow pattern occurring as a result of fetal adaptation to impaired indices occur? utero-placental blood flow, is a very useful Ans: diagnostic and surveillance tool for FGR fetuses.20 • In the normal fetus Doppler of umbilical artery It helps to distinguish constitutionally small shows presence of diastolic flow by 15 weeks fetuses from growth restricted ones. gestation. As the placental resistance decreases Doppler indices used for estimation are: with advancing gestation due to trophoblastic Systolic-to-diastolic ratio (S/D ratio) invasion, diastolic flow increases. This is Systolic peak velocity manifested as decrease in S/D ratio or PI. Thus Diastolic peak velocity the UA shows a waveform with continuous flow during systole and diastole. Pulsatility index (PI) • In a growth restricted fetus with decreased Systolic – end diastolic peak velocity placental perfusion and increasing resistance to Time averaged maximum velocity flow due to atherosclerotic like process with Resistance index (RI) local ischemia and necrosis, the UA Doppler shows an increasing S/D ratio, RI and PI as the Systolic – end diastolic peak velocity diastolic flow decreases. Gradually the diastolic Systolic peak velocity flow ends (AEDV-absent end diastolic velocity) A relative decrease in end-diastolic velocities and then reverses (REDV- reversed end elevates each of the indices and usually reflects diastolic velocity) (Fig. 8.2).22 increased downstream resistance. With absent end • AEDV and REDV are associated with increased diastolic velocity (AEDV), the S/D ratio approaches perinatal morbidity and mortality 23 and if infinity and the resistance index becomes 1 identified, urgent intervention with steroid 92 Case Discussions in Obstetrics and Gynecology

Doppler assessment of UV, IVC and DV may be used as back up tests in fetuses with umbilical artery Doppler showing AEDV 26 at less than 34 weeks. Presence of such pre-terminal changes may indicate urgent delivery.

Q.12. What is the importance of amniotic fluid assessment in pregnancies with fetal growth restriction? Ans: • Decreased amniotic fluid may signify placental insufficiency or fetal anomalies like renal agenesis or dysplasia, urethral obstruction, Fig. 8.2: Doppler of umbilical artery showing reversed end bilateral polycystic/multicystic kidneys. Oligo- diastolic flow hydramnios may also be a feature of congenital administration for fetal lung maturity and viral infections. delivery is required even in a preterm fetus. • Both amniotic fluid index (AFI) and single deepest pocket measurement are equally good Q.10. What is the role of middle cerebral artery for liquor assessment according to current (MCA) Doppler in follow-up of a pregnancy evidence when used as a part of biophysical with FGR? profile.27 ≤ Ans: In the normal fetus MCA is characterized by • Antepartum AFI 5 is associated with increased higher impedance to flow as compared to umbilical risk of cesarean section for fetal distress and an 28 artery and hence it exhibits a low amplitude of Apgar score of < 7 at 5 minutes. diastolic flow in the normal circumstances. The • A low or marginal AFI should be followed by ≤ flow increases in a hypoxic fetus due to cerebral more frequent surveillance. AFI 5 should 29 vasodilation which occurs as an adaptive prompt consideration for delivery. mechanism, resulting in a decreased PI value. This Q.13. What is the role of biophysical profile is usually a later change in a hypoxic fetus and (BPP) in evaluating growth restricted fetuses? occurs after the UA shows AEDV. Ans: Q.11. What is the role of venous Doppler in • BPP has a high false positive rate of 40 to 50% monitoring a fetus with growth restriction? and a low false negative of 8 per 1000. • BPP is a standard practice in management Ans: Venous Doppler changes usually occur late protocols of FGR pregnancies. in fetuses with growth restriction when there is fetal • It is rarely abnormal when Doppler of UA is acidosis with cardiac function compromise. normal.30 Increased preload manifests as: • It may be more useful when UA Doppler is • Pulsations in umbilical vein (UV). abnormal as it has a high negative predictive • Increased reversed flow during atrial value in high-risk cases.31 contraction in the inferior vena cava (IVC). • Fetal death is rare in women with a normal BPP. • Absence or reversal of flow during atrial Usually done once a week, and increased to contraction in the ductus venosus (DV).24,25 twice weekly or daily in severe cases. Fetal Growth Restriction 93

• Progessive fetal hypoxemia is associated with • Low dose aspirin initiated this late in pregnancy decline in AFV, fetal breathing, gross body does not improve placental function.37 movements, fetal tone and NST.32,33 Fetal • First trimester is being explored in high risk breathing is affected first followed by AFV, and patients with hypertension, thrombophilia, or a then fetal heart rate variability decreases. history of pre-eclampsia and FGR. Those with • Fetal movements and tone are lost with fetal bilateral uterine artery notching at 12 to 14 acidemia,34 and are late events weeks may benefit by low dose aspirin • Although originally all parameters were given therapy.38 equal importance, it has been shown that oligohydramnios has an independent risk and Treatment its presence requires reassessment of manage- Q.16. Is there a role of therapeutic measures in ment plan. management of pregnancies with FGR? Ans: Depending on the cause various therapies Q.14. What is the role of NST in managing FGR have been tried, but most etiologic factors are not pregnancies? amenable to therapy and do not benefit fetal growth. Ans: • Antihypertensives used in hypertensive • NST is a frequently used test of fetal well being disorders of pregnancy do not help fetal growth. with a false positive rate of 80% and a false • Lifestyle modifications like smoking cessation, negative rate of 2-3/1000. A reactive NST or cessation of alcohol intake or illicit drug use signifies that fetal compromise is remote and is may be helpful. reassuring, but a nonreactive NST may be • Diagnosis of fetal viral and parasitic infections associated with adverse perinatal outcome and is important for prognosis and neonatal fetal sleep cycle. management. Maternal therapy in toxo- • NST may be used weekly in FGR pregnancies plasmosis and malaria may prevent the spread or increased to twice weekly or daily in severe of infection to fetus in utero. A thorough history, cases. maternal blood antibody titres and amnio- • A modified BPP profile with just NST and AFI centesis or cordocentesis may help in detecting as it’s components may be used to follow up the infectious agent. FGR fetuses. • There is no concrete evidence to evaluate benefits and risks of hospitalisation and bed rest, Q.15. Is there a role of uterine artery Doppler oxygen therapy to mother, nutrient therapy, in management of FGR pregnancies? betamimetics, calcium channel blockers, hor- Ans: monal therapy and plasma volume expanders • Uterine artery Doppler has a role in the for treatment of FGR.8 prediction of FGR. • Combined aspirin and heparin therapy may • Deficient placentation is highly associated with benefit fetal outcome in women with APLA. gestational hypertensive disorders, FGR and fetal demise. Uterine artery Doppler resistance Q.17. How will you follow up the patient, Mrs profile that is high, persistently notched, or both, R, further and when will you plan delivery? identifies women who are at risk for pre- Ans: Assume that there are no maternal compli- eclampsia and FGR. It has a sensitivity of 85% cations, dates are excellent, diagnosis of FGR is when done between 22 to 23 weeks.35,36 confirmed by AC and EFW < fifth centile, there 94 Case Discussions in Obstetrics and Gynecology are no anomalies on scan and UA Doppler and BPP Q.19. What are your concerns for labor and are normal. delivery and how will you prevent compli- • Patient may be followed up on outpatient basis cations? with weekly antenatal visit. Ans: • Explained to keep a daily fetal movement record • Consent for labor induction is taken from the at home and report earlier in case of diminished patient explaining the increased likelihood of movements. emergency cesarean for fetal distress. Presence • Check blood pressure, urine albumen, maternal of oligohydramnios increases the risk of cord weight gain and SFH on each visit. compression and variable decelerations. Late • Fortnightly biometric scans to detect severity deceleration may occur due to fetal asphyxia. of growth lag. • Delivery should be conducted in a facility with • Weekly Doppler of UA is recommended as the optimal anesthesia and neonatology services. primary modality for fetal well being. (Level • Antenatal steroids 48 hours prior to induction 1 evidence). should be given if gestation is less than 34 • BPP or NST and AFI may be done weekly as a weeks to reduce the incidence of respiratory primary testing though they may be used as back distress syndrome.39 up tests when UA Doppler starts showing • Intrapartum fetal monitoring with continuous abnormal changes. CTG is recommended.8 • Admission will be needed if Doppler shows • If CTG is not available intermittent auscultation abnormal ratios. every 15 minutes in first stage and every 5 If the UA Doppler shows present end diastolic minutes or after every contraction in second flow delivery may be delayed till 37 weeks provided stage is done. other surveillance findings are normal.8 • Secondary tests like fetal scalp blood sampling or scalp stimulation should be performed when Q.18. How will you plan the mode of delivery indicated and if available. and what factors will you take into account? • ST segment analysis of the fetal electro- Ans: cardiogram has been shown by 2 randomized • The mode of delivery will be dictated by trials as an effective tool for fetal monitoring in 40,41 gestational age, Bishop’s score, fetal presen- labor. tation, fetal tolerance of labor depending on • In case of any signs of fetal compromise Doppler parameters and BPP and maternal decision for cesarean section should be prompt complications. as the fetus with growth restriction has poor • An elective cesarean delivery may be consi- capacity to tolerate labor. dered in the presence of pretem gestation with • A skilled pediatrician should be present at unfavorable cervix or serious fetal compromise delivery and a neonatologist should be present like AEDV or REDV, BPP ≤ 4, ominous venous when gestation is extremely preterm or growth 8 Doppler changes or any maternal medical or restriction is severe. obstetric complications. If no such compli- cations are present, a vaginal delivery is planned CASE 2 and patient is induced at 37 weeks if delivery is Mrs X, a primigravida with proven FGR :AC < not indicated earlier. 5th centile and low AC growth rate at 32 weeks Fetal Growth Restriction 95 pregnancy with Doppler of UA showing abnor- • REDV is a preterminal event and needs mally increased S/D ratio. How will you manage admission, steroid cover and immediate her? delivery,which is most likely by LSCS8 after careful counseling of parents and considering • Needs admission, daily fetal movement record, their wishes. Unfortunately, this may not ensure weekly SFH, weekly weight check a favorable perinatal outcome. • Weekly Doppler of UA • Patient has to be explained the high-risk of • Twice weekly BPP prematurity, with severe FGR and fetal compro- • Steroid cover for fetal lung maturity mise and high risk of perinatal morbidity and • Delivery is planned at 37 weeks if diastolic flow mortality despite LSCS. Neonatologist should is present on UA Doppler and fetal well being also be involved in counseling. tests do not show compromise unless indicated • The option of no LSCS for fetal indication may earlier for obstetric or maternal factors. be given to the patient in cases where there is CASE 3 very high risk of adverse perinatal outcome. Mrs Y, G2P1L1 with 32 weeks pregnancy with REFERENCES proven FGR with no other complications shows 1. Chang TC, Robson SC, Boys RJ, Spencer JA. AEDV on UA Doppler. Outline management plan. Prediction of the small for gestational age infant: • Admit. which ultrasonic measurement is best? Obstet Gynecol 1992;80:1030-8. • Give steroid cover. 2. Ott WJ. The diagnosis of altered fetal growth. Obstet • Doppler of UA, MCA, venous Doppler daily Gynecol Clin North Am 1988;15:237-63. • BPP daily. 3. Vik T, Markestad T Ahlsten C, et al. Body proportions • Deliver at 34 weeks or earlier if REDV occurs, and early neonatal morbidity in small-for-gestation- BPP shows compromise, CTG shows age infants of successive births. Acta Obstet Gynecol decelerations or reduced variability, or there is Scand suppl. 1997;165:76-81. reversed flow in ductus venosus during atrial 4. Dashe JS, McIntire DD, Lucas MJ, et al. Effects of contraction or umbilical vein pulsations. symmetric and asymmetric fetal growth on pregnancy outcomes. Obstet Gynecol 2000;96:321-7. • Mode of delivery is likely to be by cesarean 5. Maulik D. Fetal Growth Compromise: definitions, section in these scenarios. standards and classification. Clinical Obstetrics and • Risk of prematurity and a compromised growth Gynecology 2006;49(2):214-8. restricted fetus may result in an adverse 6. Gardosi JO, Mongelli JM, Mul T. Intrauterine growth perinatal outcome despite delivery and patient retardation. Baillieres Clin Obstet Gynecol 1995; has to be counseled about the prognosis 9:445-63. accordingly. Neonatologist should be involved 7. Persson B, Stangenberg M, Lunell NO, Brodin U, in the decision making. Holmberg NG, Vaclvincova V. Prediction of size of infants at birth by measurement of symphysis-fundal height. Br J Obstet Gynaecol 1986;93:206-11. CASE 4 8. Royal College of Obstetricians and Gynaecologists. Mrs Z with 30 weeks gestation, with severe proven The investigation and management of the small-for- growth restriction of fetus with a normal fetal gestation age fetus. RCOG Green Top Guideline No.31, 2002. www.rcog.org.uk/resources/Public/ karyotype, no anomalies on scan and no maternal Small_Gest_Age_Fetus_No31.pdf. complications shows REDV on UA Doppler. How 9. Sniders RJ, Sherrod C, Gosden CM, Nicolaides KH. will you manage her? Fetal growth retardation: associated malformations 96 Case Discussions in Obstetrics and Gynecology

and chromosomal abnormalities. Am J Obstet Gynecol 23. Bashat AA, Gembruch U, Reiss I, et al. Relationship 1993;168:547-55. between arterial and venous Doppler and perinatal 10. Smith PA, Johansson D, Tzannatos C, Campbell S. outcome in fetal growth restriction. Ultrasound Obstet Prenatal measurement of the fetal cerebellum and Gynecol 2000;16:407-13. cisterna cerbellomedullaris by ultrasound. Prenat 24. Chiba C, Kanzaki T, Weiner Z. Doppler investigation Diagn 1986;6:133. of the fetal inferior vena cava. In: Maulik D. ed. 11. Hill LM, Guzick D, Rivello D, et al. The transverse Doppler Ultrasound in Obstetrics and Gynecology. 2nd cerebellar diameter cannot be used to assess gestational ed. Heidelberg: Springer; 2005. age in the small for gestation age fetus. Obstet Gynecol 25. Ferrazi E, Rigano S. Doppler investigation of the 1990;75:329. umbilical venous flow. In: Maulik D. ed. Doppler 12. Lee W, Deter RL, Ebersole JD, et al. Birth weight Ultrasound in Obstetrics and Gynecology. 2nd ed. predictions by three-dimensional ultrasonography. J Heidelberg: Springer;2005. Ultrasound Med 2001;20:1283-92. 26. Baschat AA, Guclu S, Kush ML, et al. Venous Doppler 13. Boito S, Struijk PC, Ursem NTC, et al. Fetal brain in the prediction of acid-base status of growth- liver volume ratio and umbilical volume flow restricted fetuses with elevated placental blood flow parameters relative to normal and abnormal human resistance. Am J Obstet Gynecol 2004;191:277-84. development. Ultrasond Obstet Gynecol 2003;21:256- 27. Chauhan SP, Doherty DD, Magann EF, et al. Amniotic 61. fluid index Vs single deepest pocket technique during 14. Zaretsky MV, Reichel TF, McIntire DD, et al. modified biophysical profile: a randomized clinical Comparison of magnetic resonance imaging to trial. Am J Obstet Gynecol 2004;191:661-7. ultrasound in the estimation of birth weight at term. 28. Chauhan SP, Sanderson M, Hendrix NW, et al. Am J Obstet Gynecol 2003;189:1017-20. Perinatal outcome and amniotic fluid index in the 15. Robinson HP, Fleming JEE. A critical evaluation of antepartum and intrapartum periods: a meta-analysis. sonar “ crown-rump length “ measurement. Br J Obstet Am J Obstet Gynecol 1999;18:1473-8. Gynaecoln 1975;82:702-12. 29. Moulik D. Management of Fetal Growth Restriction: 16. Dashe JS, McIntire DD, Lucas MJ, et al. Effects of An Evidence-Based Approach. Clincal Obstetrics and symmetric and asymmetric fetal growth on pregnancy Gynecology 2006;49(2):320-33. outcomes. Obstet gynecol 2000;96:321-7. 30. Tyrrell SN, Lilford RJ, Macdonald HN, Nelson EJ, 17. Chang TC, Robson SC, Spencer JA, Gallivan S. Porter J, Gupta JK. Randomized comparison of routine Prediction of perinatal morbidity at term in small vs highly selective use of Doppler ultrasound and fetuses: comparison of fetal growth and Doppler biophysical scoring to investigate high-risk ultrasound. Br J Obstet Gynecol 1994;101:422-7. pregnancies. Br J Obstet Gynaecol 1990;97:909-16. 18. De Jong CL, Francis A, Van Geijn HP, Gardosi J. Fetal growth rate and adverse perinatal events. Ultrasound 31. Dayal AK, Manning FA, Berck DJ, Mussalli GM, Obstet Gynecol 1999;13:86-9. Avila C, Harman CR, et al. Fetal death after normal 19. Alfirevic Z, Neilson JP. Doppler ultrasonography in biophysical profile score: An eighteen-year experience. high risk pregnancies: Systematic review with meta- Am J Obstet Gynecol 1999;181:1231-6. analysis. Am J Obstet Gynecol 1995;172:1379-87. 32. Ribbert LS, Snijders RJ, Nicolaides KH, et al. Relation 20. Fleisher AC, Romero R, Manning FA, Jeanty P, James of fetal blood gases and data from computer-assisted AE. The principles and practice of Ultrasonography analysis of fetal heart rate patterns in small for in Obstetrics and Gynaecology, 5th edn. Prentice Hall, gestation fetuses. Br J Obstet Gynaecol 1991;98: 1996. 820-3. 21. Thompson RS, Trudinger BJ, Cook CM. Dopple 33. Smith JH, Anand KJ, Cotes PM, et al. antenatal fetal ultrasound waveform indices: A/B ratio, pulsatility heart rate variation in relation to the respiratory and index and Pourcelot ratio. Br J Obstet Gynaecol metabolic status of the compromised human fetus. Br 1988;95:581-8. J Obstet Gynaecol 1988;95:980-9. 22. Callen PW. Ultrasonography in obstetrics and 34. Ribbert LS, Visser GH, Mulder EJ, et al. Changes with gynecology, 4th edn. Philadelphia, PA: WB Saunders, time in fetal heart rate variation, movement incidences 2000. and haemodynamics in intrauterine growth retarded Fetal Growth Restriction 97

fetuses: A longitudinal approach to the assessment of 38. Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa fetal well being. Early Hum Dev 1993;31:195-208. J. Low dose acetylsalicylic acid in prevention of 35. Coleman MA, McCowan LM, North RA. Mid- pregnancy-induced hypertension and intrauterine termester uterine artery Doppler screening as a growth retardation in women with bilateral uterine predictor of adverse pregnancy outcome in high-risk artery notches. Br J Obstet Gynaecol 2002;109: women. Ultrasound Obstet Gynecol 2000;15:7-12. 161-7. 39. Cochrane database syst rev. DOI:0.1002/14651858. 36. Aquilina J, Barnett A, Thompson O, Harrington K. CD000262.pub3(2007). Comprehensive analysis of uterine artery flow velocity 40. Amer-Wahlin C, Hellsten C, Noren H, et al. Cardio- waveforms for the prediction of pre-eclampsia. tocography only versus cardiotocography plus ST Ultrsound Obstet Gynecol 2000;16:163-70. analysis of fetal electrocardiogram for intrapartum fetal 37. Yu CK, Papageorghious AT, Parra M, et al. Medicine monitoring: A Swedish randomized controlled trial. Foundation Second Trimester Screening Group: Lancet 2001;358:534-8. Randomized controlled trial using low-dose aspirin 41. Westgate J, Harris M, Curnow JS, et al. Randomized in the prevention of pre-eclampsia in women with trial of cardiotocography alone or with ST waveform abnormal uterine artery Doppler at 23 week’s ges- analysis for intrapartum monitoring. Lancet 1992; tation. Ultrasound Obstet Gynecol 2003;22:233-9. 340:194-8. Sangeeta Bhasin, Rupali Goyal, Anvika 9 Rh Alloimmunization

The introduction of Anti-D immunoglobulin in heterozygous Rh positive, the chances of the 1969 has led to a steep fall in the incidence of offspring being positive is 50%. Rhesus red cell alloimmunization from 5% to There are at least 40 Rhesus antigens other than 1.7 %. Consequently, there has been an increase in D,C and E but the Rh D antigen is the most alloimmunizations attributable to non-D Rhesus red immunogenic followed by Rh c, E, e and C. A cell antigens like C and E and non Rhesus red cell common antigenic variant is the Du antigen also antigens like Kell, Duffy and Kidd. However, known as weak D wherein the patient is Rh positive Rhesus alloimmunization remains the most but the D expression is weak. These women are prevalent cause of Hemolytic disease of the fetus not at risk of developing Rh alloimmunization. and newborn (HDFN) even today. The e, E antigens as well as Kell, Duffy and Kidd The Rhesus Blood group system consists of 5 antigens usually cause immunization through blood antigens C, D, c, E and e. There is no d antigen transfusion rather than through fetomaternal bleeds. and Rh negative or D negative implies the absence The incidence of Rh negative individuals varies of the D antigen. These antigens are codified by 2 with race and ethnicity, being as low as 1% in genes, the RhD gene which encodes for the RhD Asians, 15% in whites and as high as 100% in antigen and the RhCE gene which encodes for the Basques. A Rh negative woman has a 60% chance other 4 antigens (E, e, C, c). Both are located on of bearing an Rh positive fetus.1 the short arm of chromosome 1. The rhesus genotype is inherited according to Mendelian CASE 1 principles and the individual is either homozygous or heterozygous for each antigen represented in the A young primigravida at 24 weeks period of genotype. The parental genotype may therefore be gestation attends the antenatal OPD. Her represented as, for e.g. CDe/cde, one set being pregnancy till now has been smooth and inherited from each parent. Rh negative persons uneventful. Routine investigations show her blood are homozygous for a complete absence of the Rh group to be B negative. D gene. Rh positive persons may be homozygous (2 copies of D antigen) or heterozygous (1 copy of Q.1. What is the importance of the Rh factor D antigen). This has practical importance. When a during pregnancy? homozygous Rh positive male mates with a Rh Ans: negative woman, the offspring will be Rh positive • The Rh factor is an antigen (protein) present in 100% of the cases whereas if the man is on the red cell membrane which has the ability Rh Alloimmunization 99

to stimulate an immune antibody response when of fetal blood entering the maternal circulation may presented to an individual who does not possess vary from less than 0.1ml to >30 ml.3 Both the one. This is the phenomenon of development frequency and magnitude of the bleed increases as of alloimmunization and therein lies the pregnancy advances. In majority of the cases (15- importance of an Rh negative pregnancy. 50%) fetomaternal hemorrhage (FMH) sufficient • About 75% of pregnant woman have fetal RBCs to cause alloimmunization occurs at the time of circulating in their blood sometime during delivery. pregnancy and delivery. If these fetal RBCs are However, inspite of this, an immune response Rh positive, they stimulate a maternal immune is mounted by only 10-15% of Rh negative women response against the non self Rh antigen. A during delivery and by less than1% during primary exposure leads to the production of pregnancy. antigen specific IgM antibodies after 6 weeks There could be varying reasons for this. to 12 months. These IgM antibodies are high 1. Maternal inborn responsiveness- 30% of Rh molecular weight heavy antibodies which do negative woman are immunogenic non- not cross the placenta and therefore do not harm responders who do not become sensitized to the the fetus (Primary sensitizing pregnancy). Rh positive antigen, a characteristic which is • A subsequent exposure of the mother to the genetically controlled.2 antigen, as in her second pregnancy, produces 2. Strength of the antigenic stimulus- Rh D is the an amnestic response and rapid production of most potent Rh antigen. large amounts of Ig G antibodies which actively 3. The volume of the fetomaternal hemorrhage, cross the placenta and bind to the Rh antigens i.e. size of the inoculum- Greater the number on the fetal red cells causing their sequestration of fetal cells entering the maternal circulation, and destruction leading to a spectrum of greater is the possibility of maternal sensitization, hemolytic disease in the fetus and neonate (First though some mothers may become sensitized sensitized pregnancy). with as little as 0.25 ml of fetal red cells. • The first sensitizing pregnancy is therefore usually unaffected and only 1% of RhD negative 4. Co-existence of ABO incompatibility between mothers will have detectable RhD antibodies mother and fetus reduces the risk of before delivery of their first RhD positive baby.2 sensitization by 50-70% because of rapid • After birth of the first Rh positive baby, clearance of ABO incompatible fetal cells from antibodies can be detected in 8% of at risk the maternal circulation or damage to the fetal mothers 6 months after delivery.2 Rh antigen rendering it non-immunogenic. This • By the end of the second Rh D positive effect is especially seen when the mother is O pregnancy, in the absence of AntiD prophylaxis, and father is A, B or AB. Risk of Rh isoimmuni- 17% of Rh D negative mothers will have zation is 2-3% in ABO incompatible pregnancy detectable antibodies.2 as compared to 13-15% in ABO compatible pregnancy. Q.2. On what factors does the development of 5. Bowman observed that longer the interval alloimmunization depend? between primary and secondary sensitizations, Ans: Fetal red cells may gain access to the maternal greater is the quantity of antibodies produced circulation any time during pregnancy, delivery or and the avidity with which it binds to the red in the immediate postpartum period. The amount cells. 100 Case Discussions in Obstetrics and Gynecology

Q.3. Are there any specific investigations to be serum decreases this intercellular distance and done? facilitates agglutination of red cells). Ans: The specific investigations required are the • The concentration of Anti D antibody is father’s blood group and Rh and the maternal Rh determined by a titration procedure. The titre antibody titre for the detection of maternal Rh values are reported as the tube with the greatest alloimmunization. dilution with a positive agglutination reaction. If the husband is Rh negative, nothing further In most first sensitized pregnancies the needs to be done. concentration of antibody is very low and can All Rh negative pregnant women with Rh be detected only in undiluted serum or after positive husbands should be screened for the enzyme pretreatment (papain activated by presence of Rh antibodies on their first visit cysteine hydrochloride is the most popular enzyme used). A titre value of 1:4 indicates including those who have received Anti D in their alloimmunization. Titer values vary between first pregnancy (as postpartum administration of laboratories, as also the critical titer level Anti D does not guarantee prevention of Rh associated with significant risk for fetal alloimmunization) as well as those who have a hydrops; so the same laboratory should be used history of blood transfusion, unexplained fetal when repeat titers are done. For most labs the losses or infants with unexplained jaundice. critical titer varies between 8 and 32, usually 1:16.4 Q.4. How can you detect maternal allo- immunization? A direct relationship does not exist between Ans: The presence of Anti D antibodies in the antibody titre and severity of HDFN. maternal serum is diagnostic of maternal allo- immunization. Quantitation of Rh antibody: In the UK, quanti- Determination of Rh titer: Previously used agglu- fication of Anti D is done through the autoanalyser. tination methods using saline or albumin are no Levels of < 4 IU/ml are rarely associated with longer used as they detect IgM which is of no HDFN. Between 4 and 15 IU/ml there is moderate clinical significance in Rh alloimmunization. fetal hemolysis warranting close monitoring by repeated levels every 3 weeks. Levels >15 IU/ml The Human Antiglobulin Titer are associated with severe hemolysis requiring 5 (Indirect Coombs’ Test) intervention. Anti D Concentration can also be estimated by radioimmunoassay using I labeled • It is the most sensitive and reliable method used AHG and enzyme-linked immunosorbent assay to determine the degree of isoimmunization. (ELISA). Here, maternal plasma is incubated with Rh Since measurement of maternal Anti D is a poor positive erythrocytes. Agglutination of red cells predictor of HDFN, in vitro bioassays have been on the addition of serum rich in antihuman developed which predict fetal disease by mimicking globulin (AHG) antibody (Coombs’ serum) red cell destruction that occurs in the fetus. The indicates the presence of IgG Rh antibody in commonly used ones are: the mother’s serum. (the IgG antibodies have a • The antibody dependent cell mediated small molecular weight and are incapable of cytotoxicity assay (ADCC) bridging the red cells which are repelled by their • Monocyte monolayer assay negative surface charge. Addition of Coombs’ • The monocyte chemiluminescence test. Rh Alloimmunization 101

These tests are not used widely though some often only reaches the subcutaneous tissue and countries like Belgium routinely use ADCC. They absorption is delayed. are based on the premise that adherence of A verbal/written consent should always be taken sensitized erythrocytes (target cells) to Fc receptor before administering RhIg as it is a blood product. on monocytes or macrophages (effector cells) is Anti D does not protect against the development the initial event which leads to erythrophagocytosis of immunization by other antigens capable of and the lytic potential of anti D can be assayed using causing HDFN. lymphocytes, monocytes or cultured macrophages as effector cells. Q.7. What are the standard recommendations for the prevention of Rh alloimmunization? Q.5. What is the objective of management of a Ans: The current major recommendations for the Rh negative nonimmunized mother ? prevention of Rh alloimmunization include: Ans: The main objective in the management of a • A systematic program of routine antenatal anti nonsensitized Rh negative pregnant woman is D prophylaxis (RAADP) at 28 weeks along prevention of alloimmmunization through the with postpartum prophylaxis within 72 hours passive administration of Rh immunoglobulin of delivery.6 (termed antibody mediated immune suppression). • Apart from this, it is recommended that anti D should be given after potentially sensitizing Q.6. What is Rh Immunoglobulin ? events before delivery and after abortion.6 Ans: Rh immunoglobulin (RhIg) is an antibody • For every 3 units of Rh positive platelets preparation used for the prevention of Rh transfused 50 µg of Anti D should be given.7 alloimmunization. It could be polyclonal or • In the event of inadvertent transfusion of Rh monoclonal. positive blood, the dose of Anti D should be • Polyclonal RhIg is a sterile, concentrated calculated on the basis that 500 IU of Anti D solution of gammaglobulin that contains a neutralizes 4 ml Rh positive blood.7 measured amount of Rh antibody obtained from carefully screened, pooled and fractionated Q.8. What is Routine Antenatal Anti D plasma of sensitized Rh negative donors. Prophylaxis (RAADP)? Screening for HIV, Hepatitis B and C is done All pregnant Rh negative woman should be but the potential risk of infection still exists. screened for Rh antibodies at the first antenatal visit. Polyclonal antibody is the standard • If negative, the screening should be repeated at recommended prophylaxis to prevent Rh 4 weekly intervals. alloimmunization. • As the incidence of Rh alloimmunization in the • Monoclonal antibody is a synthetic antibody antenatal period is small (< 1%), antibody still undergoing clinical trials. screening every 4 weeks is not universally The exact mechanism by which RhIg prevents accepted and a repeat test may be done at 28 alloimmunization is not known. It could be partly weeks. However, testing every 4 weeks will due to masking of the Rh D antigenic sites and detect those rare patients who do become partly through a Fc dependent mechanism which sensitized before delivery.4 causes down regulation of B lymphocytes.4 • It is recommended that RAADP should be given It should be given deep intramuscular in the to all nonsensitized women at 28 weeks in a deltoid muscle as injection in the gluteus muscle dose of 300 µg (1500 IU) which is sufficient to 102 Case Discussions in Obstetrics and Gynecology

neutralize a fetomaternal bleed of 15 ml of fetal Q.9. What is Postnatal immunoprophylaxis? 6 red cells or 30 ml of fetal blood. In some Ans: countries like the UK, 2 doses of Anti D, of • The dose used for postnatal prophylaxis varies 500 IU each, are given at 28 weeks and 34 in different countries. A standard postnatal dose 7 weeks. of 1500 IU or 300 µg is used in USA, India and • The rationale behind the use of RAADP is the some European countries (except UK, France, prevention of antepartum sensitization by Ireland) within 72 hours of delivery if the baby administering Rh antiglobulin before is Rh positive and Direct Coombs Test on alloimmunization has begun. Once sensitization umbilical cord blood is negative (which detects has occurred, drug therapy to suppress it has the presence of irregular antibodies in the fetal limited value.Thus, RAADP takes care of the circulation), with no requirement for a routine silent bleeds that occur in the antepartum period. Kleihauer test.6 • RAADP is not recommended before 28 weeks • This prevents alloimmunization in more than since the risk of sensitization is less than 0.1%. 99% cases but does not take care of the those The cost-effectiveness of RAADP has also been 0.3%, who may have a fetomaternal bleed of questioned but is still recommended as it has more than 15 ml fetal red cells which will not been shown to reduce the incidence of antenatal be neutralized by 1500 IU of Anti D. Ideally, alloimmunization from 2 to 0.1%.5 therefore, fetomaternal hemorrhage should be • After RAADP, the antibody screen may show quantified and postnatal prophylaxis must anti D antibodies in the patients serum but the include a quantitative screening test for FMH titre values do not go beyond 1:4. A titer >1:4 when the possibility of a larger bleed exists.6,7 probably results from alloimmunization rather • The standard policy in the UK and some other than anti-D immunoglobulin administration. European countries is to administer 500 IU or • The option for an informed choice for RAADP 100 µg of Anti D (which is sufficient for the 4 should also be given when RAADP is neither ml bleed seen in 99% of postpartum women) considered necessary nor cost effective like in and obtain an anticoagulated blood sample the woman who has opted for sterilization after within 2 hours after delivery to undertake the delivery or is certain that she will not have Kleihauer Betke screening test to identify another child.8 women who need additional Anti D.7 • The administration of RAADP should not be • The MRC dosage trial has shown that 500 IU affected by whether she has received Anti D is as effective as 1500 IU.2 prophylaxis for a potentially sensitizing event • Women with weak D should not receive anti D early in pregnancy. as they are genetically Rh positive and are at • Since the half life of Anti D is 26 days, this low risk of producing Anti D and at very low dose will provide protection for 12 weeks. A risk of having an affected fetus. repeat dose of 300 µg may be administered if • Though the maximal protective effect occurs if the woman does not deliver by 40 weeks but Anti D is given within 72 hours, it may be given there is insufficient evidence to make a any time upto 4 weeks after delivery and recommendation. If delivery occurs within 3 treatment should not be withheld if > 72 hours weeks of a full dose of Anti D and if FMH is have passed postpartum.4,6 not in excess of 15 ml of red cells, then Postnatal prophylaxis reduces the incidence of administration after delivery can be omitted.6,9 Rh sensitization from 15 to 1-2%. Rh Alloimmunization 103

Q.10. What are the risk factors for excessive Anti D should preferably be given within 72 postpartum FMH? hours of the sensitizing event but may be given 2,6,7 Ans: These include:2 upto 10 days. • cesarean delivery • manual removal of placenta Q.12. How can fetomaternal hemorrhage be • intrauterine manipulations detected? • multiple gestation Ans: Fetomaternal hemmorrhage can be detected • antepartum hemmorrhage through tests which either detect cells with fetal • abdominal trauma in third trimester hemoglobin or RhD antigen. • still births and intrauterine death • The test most commonly used to detect HbF is • unexplained hydrops. the Kleihauer Betke test. It is sensitive and • However, the majority of cases of excessive cost-effective but difficult to standardize and FMH occur after uncomplicated, vaginal false positives can occur. It is an acid elution delivery. test. The maternal RBCs are rendered colorless or ghost like on the addition of an acid solution Q.11. What are the other antepartum events (citric acid phosphate buffer) because the adult requiring Anti D? What are the doses used? hemoglobin is more soluble and gets eluted out Ans: In 1-2% of women, antepartum events may leaving only the red cell membrane. Fetal cause alloimmunization without disruption of the hemoglobin is more resistant to elution and so choriodecidual junction.2 fetal RBCs retain their color. The maternal • First trimester spontaneous/induced abortion- blood is then examined on a counting chamber 50 µg. after fixation with 80% ethanol and A first trimester spontaneous complete hematoxylin-eosin staining. The number of fetal abortion without any surgical evacuation does cells per 1000 ghost cells are counted under the not need Anti D. light microscope. Anti D is not considered necessary in women Amount of fetal bleed is calculated by the with first trimester threatened abortion with a following formula: viable fetus and cessation of bleeding. It may No. of fetal cells be required when bleeding is continuous or 5000 × = ml of bleed 1000 adult cells repeated.6,7 • Ectopic pregnancy/partial molar pregnancy- False-positives can occur –HbF also elutes if 50 µg. left too long in the eluting solution. A complete mole does not need Anti D.6 – some women may have high HbF levels • Chorionic villus biopsy-50 µg – genetic hemoglobinopathies • Second trimester spontaneous/induced/ • The other quantitative test used for FMH threatened abortion-300 µg detection is Flow cytometry. The results of A threatened abortion with persistent bleeding flow cytometry are more accurate and may require Anti D at 6 weeks intervals. reproducible and since it detects Rh D positive • Amniocentesis/fetal blood sampling-300 µg cells, it is helpful in patients with high Hb F • External cephalic version/abdominal trauma- levels. 300 µg • Rosetting test is another simple serological • Antepartum hemorrhage-300 µg qualitative test where Rh positive fetal cells 104 Case Discussions in Obstetrics and Gynecology

coated with anti D form rosettes with Rh • baby being born with jaundice/developing positive indicator cells. jaundice after birth • severity of jaundice/h/o phototherapy/exchange CASE 2 transfusion G2P1L1 with 28 weeks pregnancy comes to you • receiving antepartum or postpartum Anti D for antenatal care. Her previous pregnancy was Q.14. Is the fetus at risk of developing anemia? uneventful. Her Blood group is B negative and ICT positive in titre 1:8. She has not received Anti This is the first sensitized pregnancy of the woman D in her previous pregnancy. and the risk of development of fetal anemia can be determined by performing serial anti Rh antibody Q.13. What specific history would you like to titres. As long as the titre remains below the critical know from her? level of 1:16 or antibody concentration on The important points to be noted in history are: immunoassay remains < 2.5 IU/ml., the risk of anemia in the fetus is low. Severe erythroblastosis Present pregnancy or perinatal death does not occur if antibody levels remain below 1:16. h/o any bleeding p/v, when, how much, how long h/o associated pain abdomen Q.15. What is the goal of management in this h/o undergoing any procedure like CVS, amniocentesis patient? h/o abdominal trauma In Rh negative pregnant women who are already h/o receiving Anti D after any such event sensitized, the objective of management is early detection and adequate treatment of fetal anemia. Previous Obstetric History Once maternal antibody quantification has been This plays an important role. In the first sensitized done the next step would be to find out paternal pregnancy, the risk of fetal anemia is low. After an and fetal blood group phenotype and genotype. affected pregnancy, risk to the subsequent fetus increases and anemia occurs at an earlier gestation. Q.16. What is the importance of paternal If hydrops has occurred in a previous pregnancy, genotyping? it is likely to occur at an earlier gestation. Ans: If the father is Rh negative, the fetus will also History of: be Rh negative and hence no further tests are • any abortion/ectopic in the past required. • any sensitizing event in the previous antenatal If the father is Rh positive, his genotype is period determined indirectly by serological testing for the • any intrauterine blood transfusion being antigens produced by the RhD and RhCE genes required and comparing the results with genotype frequency • development of polyhydramnios/pre-eclampsia tables. If the father is homozygous, the fetus will • gestation at delivery/presentation at delivery be Rh positive and further testing for fetal Rh is • mode of delivery-induced or spontaneous/ unnecessary. If the father is heterozygous, then vaginal or cesarean testing for fetal Rh becomes necessary to avoid • intrauterine manipulation/manual removal of unnecessary testing in the 50% fetuses that are Rh placenta negative. Rh Alloimmunization 105

Q. 17. Why is determination of fetal blood group labor by then and if no other indication for early important? termination exists. Ans: • The pediatrician should be notified in advance 1. When the father is heterozygously Rh positive, so that evaluation and treatment of the newborn half of the fetuses may be D negative and no can be started without delay. further testing is required. • The cord blood should be collected for Rh 2. The presence of maternal Rh antibodies does typing, direct Coombs test, hemoglobin, not necessarily mean that the fetus is Rh positive reticulocyte count, red cell morphology and and affected. This could occur because of: serum bilirubin. • A previously sensitized women may produce high levels of antibodies in a subsequent Q.20. How does ultrasound help in the pregnancy even with a D negative fetus management of such a patient? through an “amnestic response”. Ans: Ultrasound plays a key role in the management • Many women sensitized to non D red cell of the alloimmunized patient. antigens become immunized after a blood • Accurate dating of pregnancy is important for transfusion and the antigen may not be the interpretation of gestation dependent fetal present on paternal erythrocytes. assessments. • 1-3 weekly assessment for fetal growth and Q.18. How is fetal blood group determined? surveillance. Ans: Chorionic villus sampling and fetal blood • Detection of fetal anemia (defined as fetal Hb sampling to determine fetal genotype have been < 5 gm%) by10 replaced by amniocentesis which has a lower risk – Measurement of liver length and spleen of miscarriage and fetomaternal hemorrhage and circumference. Both are sites of extra- can be easily performed under ultrasound guidance. medullary erythropoiesis and an increase in The amniocytes obtained are cultured to obtain an size indicates fetal compensation for adequate amount of DNA which is then amplified developing anemia. by PCR to identify the Rhesus gene locus on The liver length is measured from chromosome 1. diaphragm to the tip of the right lobe in the Free fetal DNA or DNA extracted from fetal parasagittal plane. A length > 95th percentile red cells in maternal plasma is now being used as a is predictive of fetal anemia. noninvasive method for the detection of fetal RhD The spleen circumference (L + B × 1.57) is gene sequence by using highly sensitized measured at the level of the fetal stomach fluorescence based PCR. in a transverse view. A perimeter more than 2 SD is predictive of severe fetal anemia. Q.19. If the antibody titre remains below the – Measurement of placental thickness and critical level, what will your management be? intraperitoneal volume. Placenta may • If the antibody titre remains below the critical increase 3-4 times in size. There is an overall level on 4 weekly repeated titre testing, the increase in echogenicity with a patient can be followed up with serial ultrasound characteristic ground glass appearance. scans till term – Changes in liquor volume—The common • Labor can then be electively induced at presentation is polyhydramnios which may 40 weeks, if she does not go into spontaneous occur because of increased renal blood flow 106 Case Discussions in Obstetrics and Gynecology

due to hyperdynamic circulation or the hepatic dysfunction. Normal hepatic protein release of Atrial Natriuretic factor from an synthesis is impaired and the portal venous enlarged right atrium which suppresses pressure is increased leading to formation of ADH and increases diuresis. Sometimes fetal ascites.11 liquor may be normal or reduced. • Umbilical venous hypertension develops with Oligohydramnios in a sensitized pregnancy the placenta showing hydropic changes and is a sign of grave prognosis. consequent enlargement. This impairs normal • Identification of fetal hydrops—High placental diffusion of aminoacids and this in resolution ultrasound allows a clear combination with decreased protein synthesis visualization of fetal structures and early results in fetal hypoproteinemia. Combination diagnosis of fetal hydrops. However, USG of decreased colloid oncotic pressure and detected hydrops should not be used as the main increased capillary permeability with criterion for the evaluation of fetal anemia since consequent increase in volume load and fetal hydrops develops when severe hemolysis accumulation of fluid in the extravascular has already set in and fetal hematocrit has gone spaces predisposes to cardiac failure. These below 20%. Besides, the onset of fetal hydrops changes usually set in when fetal hemoglobin in many patients is sudden. falls below 4 gm%. Weiver and coworkers • Doppler ultrasound correlates blood velocity evaluated umbilical venous pressure during in different fetal vessels to the level of antenatal transfusions in isoimmunized hemoglobin. It is best measured as peak systolic pregnancies and found that elevated pressure velocity in the middle cerebral artery (MCA normalized within 24 hours of transfusion PSV) and umbilical vein maximal velocity (UV suggesting that elevated pressure was a result Vmax). Increased flow in the portal vein is of hypoxic myocardial dysfunction which was reflected in the ductus venosus which appears reversed by transfusions. prominent. The intrahepatic portal venous • The hydropic fetus may die in utero from severe waveform may show a saw-toothed appearance anemia, cardiac and circulatory failure. A sign which indicates a need for intervention. This of severe anemia and impending death is a appearance disappears after transfusion. sinusoidal fetal heart-rate pattern on CTG. Q.21. What is Hydrops fetalis? What is the pathophysiology behind it? Q.22. How can hydrops be diagnosed on ultrasound? Ans: Hydrops fetalis is a condition characterized 10 by abnormal collection of fluid in the fetal Ans: Ultrasound features of hydrops are: extravascular compartments and serous body • Hepatosplenomegaly demonstrated by increase cavities. Rh alloimmunization is one of the major in measurement of abdominal circumference. causes of immune hydrops. • Increased blood flow through umbilical vein • Severe and prolonged hemolysis occurs as a causing an increased diameter of umbilical vein result of sequestration of fetal RBCs after the and intrahepatic portal vein to > 5 mm. transplacental passage of maternal IgG • Presence of fluid in serous cavities indicates antibodies. Severe fetal anemia sets in. There severe anemia. The first site of fluid collection is marked erythroid hyperplasia as well as is the pericardial space and abnormal pericardial extramedullary hematopoiesis in the liver and effusion should be diagnosed when the spleen leading to hepatosplenomegaly and thickness of the fluid is >2 mm. Rh Alloimmunization 107

• The earliest sign of fetal ascites is a clear delineation of the small bowel due to fluid in between the loops. Ascites could be minimal and seen as a rim of fluid around the abdominal circumference. This has to be differentiated from pseudoascites. True ascites covers the portal vein and outlines the bowel loops whereas pseudoascites is seen only in the periphery of the abdomen in between the abdominal wall and liver (Fig. 9.1). • Pleural effusion and diaphragmatic elevation from ascites and hepatosplenomegaly may compress the lungs with consequent hypoplasia. • Skin edema may be localized to the scalp and Fig. 9.1: USG picture showing gross fetal ascites face or may extend to the entire body. Diagnosis is made when skin thickness is > 5 mm. The ideal site of measurement is the forehead. • Right atrium of the heart is the first chamber to enlarge followed by Right ventricular enlargement. A dilated nonpulsatile IVC with exaggerated flow reversal is seen on Doppler. Finally the left heart enlarges. Cardiomegaly is diagnosed when the cardiac circumference to thoracic circumference ratio is > 50%.

Q.23. How does management change if the antibody titer rises above the critical level? Ans: If at any point of time, the antibody titre exceeds the critical level or there is a significant rise in titre (two tube dilution) between two Fig. 9.2: Doppler velocimetry of the middle cerebral artery consecutive samples, further evaluation is done by Doppler velocimetry of the middle cerebral artery at risk of anemia is 100% with a false positive rate (MCA PSV) as antibody titres are no longer helpful. of 12% (Fig. 9.2).5 The physiology behind this is: Fetal anemia is Q.24. What role does Doppler ultrasound play associated with decreased oxygen carrying capacity, in the management of such patients? low hemoglobin and albumin levels resulting in Ans: Middle cerebral artery Doppler has decreased blood viscosity. The compensatory revolutionized the management of the Rh sensitized hemodynamic changes that ensue lead to increased woman by minimizing the need for invasive testing cardiac output and increased blood flow velocity. by 70%. The sensitivity of MCA PSV for the Though these changes are generalized and seen prediction of moderate to severe anemia in the fetus through out the entire fetal circulatory system, the 108 Case Discussions in Obstetrics and Gynecology middle cerebral artery depicts these changes very Table 9.1: Values of middle cerebral artery peak accurately because of its sensitivity to hypoxemia. systolic veloctiy (cm/s) based on multiples of the median between the 23rd and 35th gestational weeks. Technique of measuring MCA PSV Multiples of the median for MCAPSV To view the MCA, a transverse view of the fetal Gestational age 1.0 1.29 1.50 1.55 brain,which is adequate for the measurement of the (weeks) BPD is used. The vascular structures are identified with color Doppler. The MCA of the cerebral 23 35.44 45.72 53.16 54.93 24 35.48 45.77 53.22 55.00 hemisphere closer to the US transducer is identified 25 35.81 46.20 53.72 55.51 at its origin from the internal carotid artery and the 26 36.45 47.03 54.68 56.50 US probe placed over it such that the angle of 27 37.43 50.01 56.15 60.09 insonation is as close to 0-degree as possible. The 28 38.77 50.01 58.15 62.75 fetus should be resting as activity will falsely elevate 29 40.49 52.23 60.73 62.75 the PSV. 30 42.61 54.97 63.91 66.04 The distal part of the MCA should not be used 31 45.16 58.26 67.74 70.00 32 48.17 62.13 72.25 74.66 as it leads to a false depression of the real PSV. If it 33 51.65 66.62 77.47 80.05 is difficult to identify the proximal part, then the 34 55.63 71.76 83.44 86.22 MCA of the other cerebral hemisphere should be 35 60.13 77.56 90.19 93.20 used. MCAPSV, middle cerebral artery peak systolic velocity. Once the typical waveform is obtained, the highest point on this waveform is measured. At least 3 consistent waveforms are measured and averaged.

Interpretation of MCA-PCV 5,12 In the initial report by Mari and coworkers, nomograms for MCA PSV values for different gestational ages was established and a value equal or greater than 1.5 multiples of median (MOM) for that gestational age was used as threshold value for the diagnosis of moderate to severe fetal anemia (Table 9.1). Fig. 9.3: Behavior of the middle cerebral artery peak systolic Deti and coworkers (2002) studied the trend of velocity (median, 2.5th and 97.5th percentiles) as related to the gestational age. [X: gestational age (weeks); Y: MCA- MCA PSV and proposed the following protocol PSV]. for use of MCA Doppler in detecting fetal anemia. • Three consecutive weekly MCA PSV Doppler • If the MCA PSV is less than 1.5 MOM and the values are determined and a slope of the slope is 1.95, studies are repeated at weekly regression line is calculated (the slope can be intervals. determined using the SLOPE function in • If the MCA PSV is equal to or more than 1.5 Microsoft excel) (Fig. 9.3). MOM, further evaluation is required. • If the MCA PSV is less then 1.5 MOM and the • MCA PSV should not be used after 35 weeks slope is less than 1.95, studies are repeated at 2 gestation as the number of false-positives is very week intervals. high. Rh Alloimmunization 109

Q.25. If the MCA PSV in this patient, who is 28 • Assesment of ammiotic fluid for fetal hemolysis weeks pregnant, exceeds 1.5 MOM what will you is based on the fact that spectrophotometric do? analysis of amniotic fluid bilirubin correlates Ans: If the MCA PSV is 1.5 MOM or more, and if well with the severity of fetal anemia. there are other ultrasound features consistent with • Grossly, a yellow colored amniotic fluid fetal anemia, amniocentesis for bilirubin levels suggests the presence of bilirubin. should be done. • Bilirubin is a byproduct of fetal red cell If there are no ultrasound features of fetal hemolysis and is excreted in the AF through anemia, the MCA Doppler should be repeated pulmonary and tracheal secretions and by within 24 hours to confirm the elevation and if diffusion across the fetal membranes and found to be persistent, amniocentesis should be umbilical cord. Since the amount of bilirubin performed. in AF is low, spectrophotometry is used and is Fetal blood sampling and Intrauterine demonstrated as a change in absorbance at Transfusion will then be limited to fetuses showing 450 nm –this difference is referred to as Δ OD abnormally elevated MCA PSV plus elevated AF 450. The curve of optical density of normal bilirubin. amniotic fluid when plotted on a semilogarithmic graph is approximately linear Q.26. If this patient was more than 34 weeks, between wavelengths 375 nm and 525 nm. what would you have done? Bilirubin causes a shift in the optical density Ans: If lung maturity has been achieved, the with a peak at a wavelength of 450 nm. The pregnancy can be terminated. Otherwise, amount of shift from linearity at 450 nm (Δ OD glucocorticoids can be given to achieve lung 450) is used to estimate the degree of fetal red maturity. Glucocorticoids decrease OD450 values, cell hemolysis (Fig. 9.4). so it is necessary to avoid a false sense of security and deliver the fetus 24 hours after the last dose of steroid.

Q.27. What help is amniocentesis in the management of the Rh alloimmunized patient? Ans: In the Rh alloimmunized patient amniotic fluid assessment can help in the Detection of lung maturity Detection of fetal genotype Detection of fetal anemia

Q.28. How does amniocentesis detect fetal anemia? Ans: 50 years ago, amniocentesis was the traditional method to indirectly estimate the severity of fetal anemia. Today, it is used in conjunction Fig. 9.4: Curve of optical density of amniotic fluid at with MCA PSV.4 different wavelengths 110 Case Discussions in Obstetrics and Gynecology

Q.29. How is amniotic fluid optical density Q.30. How is the procedure performed? interpreted in terms of fetal anemia and Ans: A 3.5-7 inches long 22 G disposable needle neonatal outcome? is inserted under aseptic precautions under Ans: ultrasound guidance to the desired depth so that Δ •William Liley correlated OD 450 values with the tip of the needle is in the center of the fluid neonatal outcome. For this, he plotted a graph pocket. 5 -10 ml is aspirated, kept in a brown bottle of gestational age from 27-40 weeks versus to protect it from sunlight, centrifuged at 4000 rpm ΔOD 450 and divided it into 3 zones. for 20 minutes and analysed by spectrophotometry. • Unaffected fetuses and those with mild anemia had ΔOD 450 values in zone 1, (lowest zone). Q.31. What are the complications that can Severely affected fetuses (Hb below 8 gm%) with the possibility of developing hydrops occur? within 7 days, had ΔOD 450 values in zone 3 Ans: (highest zone). Zone 2 indicates that moderate Preterm labor pains anemia is present. In lower zone 2, the Amnionitis anticipated Hb is 11-14 gm%, whereas in upper Bloody tap- there is gross visible contamination zone 2, Hb ranges form 8-11 gm%. with maternal or fetal blood and the procedure • The boundaries of the zones slope downward should be postponed for 1 week (A small button of as gestational age increases because AF red cells may even be found after centrifugation of bilirubin decreases with gestational age a clear tap. This is not termed bloody). (Fig. 9.5).

Fig. 9.5: Liley graph Rh Alloimmunization 111

Q.32. What are the limitations of the Lileys zones? Ans: Since the Lileys graph begins at 27 weeks gestation and extrapolation of the graph backwards is inaccurate, OD450 levels in the second trimester are less reliable predictors of true fetal anemia. The Liley graph was modified by Queenan et al who developed a curve from 14-40 weeks (Fig. 9.6). OD450 values above 0.15 indicate severe immunization and need for cordocentesis and transfusion. Values below 0.09 indicate mild Fig. 9.6: Queenan curve for Δ0D450 values disease. Values between 0.09 and 0.15 require repeat amniocentesis in 1 week. Because of the maturity has not been attained.The patient naturally high bilirubin levels in amniotic fluid at should be induced if she is beyond 34 weeks or midpregnancy, a large indeterminate zone is created if lung maturity has been achieved. where bilirubin levels do not accurately predict fetal • If the repeat value shows a decreasing trend, Hb.4 Therefore, when severe fetal anemia or the test may be repeated in 2-4 weeks. hydrops develops before 25 weeks, cordocentesis • If the repeat value has gone up to a higher level is a better method of fetal assessment than in zone 2 or to zone 3 or if the original OD450 amniocentesis. value was in zone 3, cordocentesis with evaluation of fetal hematocrit is indicated.4,11 Q.33. What will the management be if AF OD450 lies in zone 1? Q.35. What are the principal disadvantages of Ans: Management depends upon serial amnio- amniocentesis? centesis to determine the trend of ΔOD450 values Ans: over time. • It is an invasive test and serial tests have to be If OD450 value is in zone 1, amniocentesis carried out. should be repeated in 4 weeks. If it remains in zone • It is only an indirect predictor of fetal anemia. 1 throughout in amniocentesis repeated 4 weekly, 9% of predictions based on a zone 2 ΔD450 the fetus will be mildly affected or unaffected and may be erroreous. In a series of 11 fetuses with can be induced at 38 weeks in the absence of any OD450 in zone 3, who Liley followed for alarming ultrasound features. several weeks, 30% had a clinically acceptable hematocrit at birth. Hence, the experience and Q.34. How will you manage the patient if OD450 judgement of the individual assessing the AF value lies in zone 2 or 3? findings is important. Ans: • It is not accurate for second trimester • If OD450 values are in zone 2, amniocentesis assessments because of the naturally high should be repeated in 1 week. bilirubin content of AF. The trend of several • If the repeat value shows a horizontal trend, the amniocentesis findings or finding of a very high test is again repeated in 1 week and if the OD450 value is more predictive. horizontal trend continues, cordocentesis with • Presence of meconium causes a rise in bilirubin evaluation of fetal hematocrit is indicated if lung values 112 Case Discussions in Obstetrics and Gynecology

• It is a poor predictor of Kell alloimmunization. Bleeding from puncture site is usually transient but Anti Kell antibodies cause severe fetal anemia may be severe enough to cause fetal death. and HDFN by erythroid suppression rather than Thrombosis of umbilical vessels. direct fetal red cell hemolysis. Amniotic fluid Amnionitis. bilirubin concentration, therefore, correlates Fetomaternal bleeding with worsening hemolysis poorly with fetal hematocrit, being much lower Fetal loss rates vary from 1.5 % after 24 weeks to for the degree of anemia present.3 5% before 24 weeks.

Q.36. What is the role of cordocentesis/fetal Q.38. When is intrauterine transfusion blood sampling? performed? Ans: Ultrasound guided fetal blood sampling has Ans: The goal of intrauterine transfusion is to an established role in the management of Rh correct anemia and reduce extramedullary alloimmunization as it allows precise measurement hematopoiesis leading to a fall in portal venous of fetal Hb and hematocrit and the need for pressure with improved hepatic function. The main intrauterine blood transfusion. It requires expertise indication for intrauterine transfusion is a and is technically difficult before 20 weeks. hematocrit below 25% before 26 weeks gestation The main indications of FBS are: and below 30% after 26 weeks gestation as • MCA PSV >1.5 MOM and DOD450 in upper indicated by fetal blood sampling IUT can be started zone 2 or zone 3. earliest at around 20 weeks.. • Rising trend of AF DOD450 and ultrasound features of fetal anemia. Q.39. How is the procedure performed? • Picture of hydrops fetalis on ultrasound. Ans: The routes of approach could be: • It may be the preferred choice when there is • Intravascular (IVT) (Fig. 9.7) severe polyhydramnious with diluted bilirubin • Intraperitoneal (IPT) concentration or early onset hydrops. • Combined intravascular and intraperitoneal • Intracardiac Site for Sampling Fresh O negative, CMV negative blood which The umbilical vein at the site of placental insertion has been cross matched against the mother and of umbilical cord is the commonly used site though leucocyte depleted, irradiated and double packed 8 the preferred site is the intrahepatic portion of the to a hematocrit of 70-80% is used. umbilical vein as it provides a pure fetal venous sample, avoids injury to the umbilical arteries and Q.40. What are the steps of an intravascular is associated with a reduced rate of fetal transfusion? bradycardia.5 Ans: A 20 G spinal needle is inserted under • An informed consent is mandatory. The parents ultrasound guidance and adequate blood withdrawn should be informed about the fetal status, the for Hb, Hematocrit, blood grouping and typing, justification of the transfusion and the possible Direct Coombs test and Reticulocyte count. risks involved. • The procedure is performed in a sterile room Q.37. What are the complications that can or O.T under asepsis, tocolysis and antibiotic occur? cover. Fetal lie and attitude should be confirmed Ans: Umbilical artery spasm and fetal bradycardia by real time ultrasound before starting the Cord tamponade. procedure. Rh Alloimmunization 113

Fig. 9.7: Site of intrauterine transfusion

• A threeway stop cock with an extender tube Q.41. At what level should hematocrit be along with a transfusion set is assembled. A 20/ maintained? 22 G needle is introduced into the amniotic Ans: cavity and fetal paralysis is achieved with • At the first IVT aim is to raise hematocrit a little pancuronium (0.25 mg/kg) or vencuronium above the physiological range of 35-40% before bromide, injected into the fetal thigh, deltoid 24 weeks, 45-50% after 24 weeks and 50-55% or gluteal region.FBS is performed and after 28 weeks. hematocrit obtained. During the procedure fetal • Hematocrit falls at the rate of 1% per day after heart is checked intermittently. the first IVT.The second IVT is therefore • The threeway stop cock is connected to the performed after 1-2 weeks thereafter, rate of fall needle and packed cells transfused at the rate decreases and subsequent IVTs are performed of 1-2 ml/min. Volume of blood needed for at 3-4 week intervals depending on post IVT transfusion is calculated according to the hematocrit. The aim is to maintain a hematocrit Nicolaides chart or Macgehan guideline at 40-45% with adult Rh negative red cells at a where,10 physiological level and suppress fetal Rh positive red cell production. Volume of blood needed is • The fetus can tolerate large transfusion volumes (Desired hematocrit-actual hematocrit) × because of the capacity of the placental estimated fetoplacental blood volume × vasculature to dilate However, a stepwise estimated fetal weight in kg correction should be done in severe anemia < 24 Donor hematocrit. weeks as the fetus is less able to adapt to the 114 Case Discussions in Obstetrics and Gynecology

acute correction of IVT. Therefore, in the Indications severely anemic fetus, post transfusion Fetus is smaller than 18 weeks and umbilical vein hematocrit should not be more than 25% or is too thin. more than 4 times the pretransfusion value after Fetus lies with spine anterior and umbilical vein the first IVT. The 2nd IVT is done after 48 is inaccessible hours, then after 7-10 days. Thereafter, repeat Abnormal cord insertionm e.g. velamentous transfusions are based on hematocrit and KB insertion. stain.5 Failed IVT with cord hematoma/thrombosis. • Non invasive MCA PSV can be used to monitor It is used as a supplement to IVT to prolong and predict anemia after transfusions. However, intervals between IVTs. there are currently no data on the accuracy of IPT is not helpful in hydropic fetuses as blood fetal MCA PSV for the prediction of fetal is not well-absorbed from the abdominal cavity. anemia after the 2nd IVT. Combined IVT and IPT • In severely hydropic fetuses with cardiac This approach achieves a more stable hematocrit, decompensation, an exchange transfusion is with a decline in hematocrit of only 1.01% per day. another option to reduce the load on the fetal It also achieves a larger interval between heart. transfusions. • Prior to every IVT a fetal platelet count should Intracardiac transfusion be done as it may decrease since only packed It is used only when urgent transfusion is required cells are being transfused. and no other route is available. The needle is placed in the right ventricle. Q.42. What is the response rate of IVT? CASE 3 Ans: Survival after IVT varies with the experience of the performer and the the presence of hydrops. A Rh negative G4 P3 with 24 weeks pregnancy Overall survival is 84% in nonhydropic fetuses and comes with an obstetric history which includes a first live born healthy child followed by the birth 70% in hydropic fetuses. Mild hydrops is reversed of a jaundiced baby who died within 24 hours in 88% fetuses and severe hydrops is reversed in followed by an intrauterine death at 8 months 39% fetuses.5 gestation. She did not receive Anti D at any time. Her Anti D titre is positive 1:32 Q.43. What are the complications of IVT? Ans: Same as FBS Q.45. Outline your management. Ans: Q.44. If umbilical vein access is not possible, is • The woman is severely sensitized to Rh antigen. there any other alternative? Since the incidence of still birth before 37 weeks Ans: Intraperitoneal transfusion in a sensitized woman with high titres and a A 20 G needle is introduced into the flank of the previously affected baby is 32%, investigations fetus and donor blood transfused into the peritoneal should be started straight away. cavity at the rate of 5-10 ml/min from where it is • She should also be assessed for the absorbed via the subdiaphragmatic lymphatics over developmentof pre-eclampsia placentomegaly 7-10 days. of hydrops may cause pre eclampsia. The pre- Rh Alloimmunization 115

eclamptic mother may also develop severe • Careful intrapartum monitoring is required as edema mimicking that of the fetus, referred to these babies are prone to intrapartum hypoxia as the mirror syndrome).11 and acidosis. Early involvement of the Investigations should include: neonatologist is essential. • Complete hemogram, renal and liver function • The preterm baby may be safely delivered by tests cesarean. • Serial ultrasound for evidence of hydrops, fetal viability, fetal growth Q.46. How can a neonate with Rh • MCA PSV every 2 weeks. The general rule is incompatibility present? to start MCA PSV 10 weeks before the gestation Ans: There is a wide spectrum of clinical of intervention or bad outcome in the previous manifestations8 affected pregnancy. As the fetal reticulo- • Normal baby who develops mild jaundice and endothelial system is too immature to filter and responds to conservative treatment. hemolyse antibody coated erythrocytes, hydrops • Normal baby who develops rapid jaundice and does not develop before 18 weeks. So requires exchange transfusions. monitoring of at risk fetuses is not started before • Baby with hydrops fetalis, anemia with 18 weeks. hepatosplenomegaly, generalized edema, • If MCA PSV remains below 1.5 MOM, 2 ascitis, pleural effusion. The severely affected weekly estimations are continued till 35 weeks, infant may suffer perinatal asphyxia, acidosis, steroids administered for lung maturity and hypothermia, may develop disseminated patient delivered by 36-37 weeks. intravascular coagulation with leucopenia and • Amniocentesis for OD 450 should be done as thrombocytopenia. Hypoglycemia in the first 24 soon as MCA PSV ≥ 1.5 MOM. In women with hours is due to hyperplasia of islet cells. high titres and a h/o hydropic or stillborn fetus, • In extreme cases there may be a still born baby the first amniocentesis may be done at 16-20 or early neonatal death due to difficulty in weeks. establishing ventilation and perfusion. • A rising trend of ΔOD450 or a picture of hydrops on ultrasound is an indication for FBS Q.47. How should the baby be monitored? and intravascular transfusion if hematocrit is Ans: < 25%. • Cord blood should be sent for hematocrit, blood • The primary objective is to allow pregnancy to grouping and typing, direct Coombs test, complete 34-35 weeks, which is the time that bilirubin level and reticulocyte count. the last transfusion should be scheduled around, • Cord stump should be maintained such that so that delivery can be aimed at by 36-37 weeks. catherization is possible. The risk of continued invasive sampling and • In severely affected babies, S. Bilirubin should transfusions should be weighed against the be done every 6-12 hours depending on rise of neonatal morbidity and mortality associated bilirubin. The serum bilirubin is plotted on with prematurity.5. charts based on gestational age and need for • Labor should be induced at 36-37 weeks with phototherapy/exchange transfusion decided appropriate blood in hand. accordingly. If required, Double volume 116 Case Discussions in Obstetrics and Gynecology

exchange transfusion with 170 ml/kg of fresh plasmapheresis. An IV infusion of 400-500 mg/kg O negative blood is recommended. maternal weight is used to reduce the severity of • Tests done for suspected kernicterus are: hemolysis. Serum albumin Chemotherapeutic agents like promethazine Serum bilirubin to albumin ratio interfere with the ability of human fetal Carboxyhemoglobin levels macrophages to phagocytize red cells coated with Bilirubin saturation index Anti D cells. Bilirubin reserve binding capacity • Early indications for exchange transfusion in REFERENCES such babies are; 1. Immunologic disorders in pregnancy, Porter, Peltier, Cord Hb < 10 gm% Branch; Danforths obstetrics and gyne, Scott, Gibbs, Cord bilirubin > 5mg% Haney; 313-26. Unconjugated bilirubin of 10 gm% within 24 2. Alloimmunization in pregnancy;Rhesus and other red hours or 15 mg% within 48 hours or rate of rise cell antigens; Charles HR odeck, Anna P. Cockell; > 0.5 mg% Turnbulls Obstetrics (3rd edn); Geoffrey Chamberlain, Philip Steer, 247-61. 3. Fetal hemolytic disease, Carl Weiner. High Risk Q.48. What complications can the new born Pregnancy Management options; James, Steer; 291- have? 310. Ans: The new born is at risk of prematurity, anemia, 4. Rh alloimmunization; Practical guide to High risk jaundice (as bilirubin is no longer cleared across pregnancy and delivery (3rd edn); Fernando Arias, the placenta into the mothers circulation), Daftary, Bhide. 358-71. 5. Hemolytic disease of fetus and newborn, Kenneth J disseminated intravascular coagulation, severe Moise; Maternal Fetal Medicine- Principles and thrombocytopenia, necrotizing enterocolitis, Practice (5th edn); Robert Creasy, Robert Resnik. bronchopulmonary dysplasia and kernicterus if 537-61. unconjugated bilirubin exceeds 310 µmol/l. 6. Prevention of Rh alloimmunization.SOGC Clinical Practice Guidelines No. 133, Sept 2003. Q.49. What are the other treatment modalities 7. Royal College of Obstetricians and Gynecologists, in a severely immunized Rh negative patient? green top guidelines 22. Anti D immunoglobulins for Rh prophylaxis. London. RCOG 2002. Ans: Several methods have been used to suppress 8. Rh negative pregnancy. Fogsi focus, July 06 the maternal antibody concentration or its effect 9. Hartwell E. Use of Rh Immunoglobulin. ASCP on the fetus. Of them, only few appear to have Practice Parameter. Am. J Clin Pathol 1998;110 ;281- limited potential. 302. Plasmapheresis is indicated only when there 10. The Rhesus factor. Current Concepts; Duru Shah, is h/o hydrops before 20-22 weeks. The exchange Vinita Salvi. 11. Diseases of fetus and newborn;Williams obstetrics transfusion is begun at 12 weeks, removing about (23rd edn). 618-27. 2 liters of blood per week. This reduces antibody 12. Mari G, Deter RL, Carpenter RL, et al. Noninvasive concentration by 80% although transiently. diagnosis by Doppler ultrasonography of fetal anemia Immunoglobulins; intravenous immuno- due to red cell alloimmunization. New Eng. J Med globulin therapy may be used as an adjunct to 2000;342:9-14. Devender Kumar 10 Multiple Gestation

Multiple gestation refers to a pregnancy in which Q.2. What is the incidence of multiple gestation? two or more fetuses are present in the womb. The Ans: response to their conception till birth has ranged • Twin pregnancy occurs in the proportion of from awe to fear. It can occur when two or more about 1 in 80 to 1 in 90 births. An accepted ovas are released from the ovary and fertilized in formula of incidence is (Hellin’s law) twins 1 the same cycle or single zygote divides at an early in 80, triplets 1 in 802, quadruplets 1 in 803, stage of development. It is important to diagnose a and so on.3 multiple gestation to ensure proper care of the • Uniovular is fission of single fertilized ovum. mother and fetuses. • Uniovular twins are always of the same sex and are identical in appearance, resembling each Q.1. Why should we worry about multiple other both physically and mentally, and even at gestation? times showing the same pathological tendencies. Ans: • Binovular is fertilization of two ova. Binovular • Although multifetal births account for only 3% may occur from the fertilization of two distinct of all live births, they are responsible for a follicles which rupture at the same time of disproportionate share of perinatal morbidity ovulation. 1-3 and mortality. • Binovular twins are more frequent than • The fraction of multiple pregnancies due to ART uniovular (3:1). They may be of the same sex 3 has increased from 28% in 1986 to almost 60%. or opposite sexes and show a degree of • There is a higher risk of low birth weight babies resemblance no greater than that of brothers and and preterm labor. Multiple pregnancies are sisters from different births. For this reason they commonly associated with moderate to severe can be referred to as “fraternal twins”. anemia, gestational hypertension mal- presentation, polyhydramnios, cord prolapse, Q.3. What are the complications unique to abruption or placenta previa.3-7 multiple gestation? • It’s also associated with abnormalities like Ans: The incidence of malformations is increased discordance, twin reversed arterial perfusion in twin and higher order compared to singleton. (TRAP) or conjoint twins.8 Congenital abnormalities reported in multiple 118 Case Discussions in Obstetrics and Gynecology gestations vary from 6.86% to 17.4%.4,5 Monozygotic d. Higher maternal age is also associated with twins are at greater risk due to following reasons8 congenital malformations like trisomies. 2. The Last Menstrual Period (LMP) and Expected 1. Defects due to division of zygote. Date of Delivery (EDD) should be noted. Try 2. Defects resulting from vascular interchange to ascertain the reliability. The following criteria between monochorionic twins. are for excellent dates 3. Defects that occur as the result of crowding. a. Patient had regular cycles and is sure of dates. CASE b. Gestational age by LMP and clinical examination should correspond. 35 years age Primi gravida came to ANC opd with c. The first and/or second trimester USG 16 weeks amenorrhea. She had moderate pallor gestation age estimation corresponds to and 18 to 20 weeks size uterus. How will you dates by LMP and clinical examination. manage the case? 3. Hyperemesis is quite common in theses cases. In this case period of amenorrhea is not 4. History of bleeding or blood stained discharge corresponding to clinical examination of uterus. So should be asked. It may be due to fetal loss or we have to consider the clinical conditions where improper implantation. uterus is larger than amenorrhea. 5. Edema is quite common in these cases. It may 1. Wrong dates be associated with hypoproteinemia or anemia. 2. Multiple gestation Breathlessness and easy fatiguability is common 3. Large for gestation in these cases due to anemia and hydramnios. 4. Trophoblastic diseases In fact unexplained anemia is often associated 5. Anomalies of the fetus or hydramnios multiple gestation. 6. Associated fibroid uterus or adnexal mass 6. Hypertensive disorders are quite common in So history and examination must include or multiple gestation. It is significant to know how exclude the above mentioned causes or their much weight she gained during this pregnancy complications, diligently. and blood pressure records during regular antenatal care. History related to complications Q.4. What should be elaborated in the history of hypertensive disorder should be asked. and examination? 7. Increased carbohydrate intolerance is seen in these cases. History of diabetes or glucose Ans: challenge or tolerance test should be asked. Present obstetric history 8. History of abdominal discomfort/labor pains/ 1. Age of the Patient: discharge or bleeding per . a. Increasing maternal age and parity have been shown to increase the incidence of Menstrual history twinning independently in all populations • The history of previous menstrual cycles is studied. significant. History of may b. There is growing proportion of older women indicate underlying Polycystic Ovarian undergoing fertility treatment. Syndrome (PCOS). PCOS is associated with c. The ovarian stimulation increases with age. which is commonly treated with The rise in serum FSH is observed ovarian hyperstimulation in women who desire consistently with reproductive aging. pregnancy. This can lead to multiple gestation. Multiple Gestation 119

• Use of oral contraceptive pills (as contraception Per abdomen examination or management of Dysfunctional Uterine • Over-distended abdomen may or may not be Bleeding) can be a cause of multiple gestation. associated with stretched shiny skin depending Past obstetric history upon the amount of liquor. • These cases are associated with similar • Fundal height (in weeks) and symphysio-fundal condition (multiple pregnancy) in the previous height (in cms) should be recorded. pregnancies. • The feel of more than two fetal poles can clinch • Multiparous women have higher chance of the diagnosis. Palpation of three poles is multiple gestation.9 diagnostic. • The presence of more than one fetal heart Past history sounds with difference of at least 10 beats per • History of anovulatory cycles or subfertility minute and at a distance of 10 cm (auscultated period prior to this conception can hint on the by two persons simultaneously) will confirm the dependability of dates. clinical diagnosis. • Knowledge of ovulation or ART provides a • Abdominal girth should be recorded to monitor strong clue. the growth of pregnancy. Family history • Hydramnios is not rare in these cases. • Racial variation is observed in multiple Sometimes it’s difficult to make out the fetal gestation and is associated with increase in FSH parts which may feel smaller, multiple fetal levels. poles and excess amount of liquor raises the • Family history of mother is more important than clinical suspicion of multiple gestation. father. It is explained that these cases have Per speculum examination tendency to release multiple ova, in same cycle. • Autosomal dominant genes are reported in • It should be performed on first visit and cervix dizygotic twinning.3 and vagina should be examined. • Subsequent examination depends on the General examination complaints like labor pains or discharge per • The built and nutrition status should be recorded vagina. and BMI should be calculated with weight and • Multiple gestation is associated with abortion, height. PCOS is common in obese cases. fetal losses or preterm labor. • The pallor, icterus, and edema should be • Vaginal infection can be treated if present. recorded. • Thyroid disorders are associated with Per vaginum examination anovulation. Thyroid dysfunction should be • It should be done to notice the cervical length checked. Note any swelling in thyroid gland. and os. • Pulse rate and blood pressure should be recorded. • In the first trimester its mandatory to assess • Observe the hair distribution over face and body uterus size otherwise there may be delay in the hyperadrogenism (Hirsuitism). This is diagnosis. associated with hyperandrogenism which is commonly observed in PCOD. Q.5. How do we measure fundal height? • Examine the cardiac and respiratory system to Ans: Explain the procedure to the patient and take rule out any associated disorder complicating informed consent. Ask the patient to void the present pregnancy. completely and lie down supine. Flex the hip and 120 Case Discussions in Obstetrics and Gynecology knee joint about 45 degrees to lax the abdominal Q.8. How do we confirm our suspicion? wall. The abdomen is exposed from anterior Ans: An early USG should be performed in all superior iliac spines to xiphisternum but cover the suspected cases. Trans-vaginal sonography is lower extremities. Correct the dextro (or levo)- preferred technique. Routine 16 to 24 weeks USG rotation (with right hand) to bring the uterus in examination detects 99% of the cases whereas just midline and just feel the max height of the uterus 62% if done for a specific indication. Currently, by sliding the other hand (left) over the uterus or there is no better method than USG. The 3D/4D starting from the xiphisternum and where the first may provide better fetal sacs orientation.10 resistance is encountered without indenting or There are pitfalls in USG like sac appearing altering the position of the uterus. Express the later or due to fetal demise. Prediction is more position in weeks. accurate from 6 weeks to 10 weeks. Less than 6 weeks, it may undercount in 15% of cases.11 Q.6. How do we express the fundal height? Ans: Fundal height is expressed in weeks. The Q.9. What are the clinical problems in number is determined by the position. examination of these cases? When the fundus of uterus is just palpable above Ans: Sometimes it may be difficult to identify twins symphisis pubis, it corresponds to 12 weeks by abdominal palpation, especially if one twin gestational age by LMP. overlies the other, obese mother or hydramnios. At the lower border of umbilicus, the gestational age is 20 weeks. Q.10. What are the investigations routinely done At the upper border of umbilicus, the gestational in multiple gestation? age is 24 weeks. Close to xiphisternum, it is 36 weeks. Ans: Hb, PCV, Urine examination, Blood group Above umbilicus, the part of abdomen is and type (ICT if Rh incompatible), VDRL, HIV, divided into three equal parts, 24 to 28, 28 to 32, HBsAg, GCT, and USG. In third trimester NST is and 32 to 36 weeks. The 32 weeks gestation lies at integral part of investigation for fetal well being. the level of subcostal margin. Other investigations like LFT, doppler and Amniocentesis/PUBS, etc. depends on associated Q.7. When do we suspect multiple gestation? complications. Ans: Whenever the fundal height is more than expected for that gestational age we should suspect Q.11. What is the role of doppler in multiple multiple gestation. If three or more fetal poles are gestation? palpable it means multiple gestation. The pole Ans: Doppler study provides a measure of fetal means either head or breech. The localization of well being and helps in the management of IUGR two or more fetal heart rates is also diagnostic of fetuses. Doppler values are same and used in similar multiple gestation. Many of these cases are manner as in singletons. It was reported that associated with hypertension, anemia and/or velocimetry alone was not consistently useful in significant edema. This condition is more common identifying twin discordancy but absent end in ART cases so all the cases should undergo diastolic flow in the umbilical artery was associated assessment once they are pregnant. with low birth weight and perinatal mortality.14,15,21 Multiple Gestation 121

Q.12. What is zygocity? Q.14. How do we determine the chorionicity in Ans: It means whether the pregnancy developed pregnancy beyond first trimester? from single or multiple ova fertilization. Zygocity Ans: Sonographically, criteria shifts to “twin peak determines the chorionicity and amnionicity of the sign”, fetal gender, number of placentas, and multiple gestation. Monochorionic twin means thickness of inter-fetal membrane to assess uniovular pregnancy. As chorion develops before chorionicity. “Twin peak sign” is seen in the amnion so it helps in determination of dichorionicity, and has 94% sensitivity and 88% amnionicity. The counting of gestation sacs before specificity. In dichorionic gestation, the membrane 10 weeks, accurately predicts chorionicity. The rate is composed of two layers of chorion and two layers of monozygotic twins is 1 in 250 births and is of amnions. Triangular portion of placenta apparently constant through out the world.9, 10 extending into the intertwin membranes can be seen where the membranes attach to placenta (Fig. 10.1). Q.13. How do we determine the chorionicity and In monochorionic diamniotic twin, the layer is amnionicity? composed of two layers of amnions only and there Ans: In early gestation, amnion is closely applied is no extension of placental tissue in between the to embryo, so fluid filled gestational sac is membranes.16 predominantly chorionic fluid and represents chorionic cavity. As the pregnancy progresses, the Q.15. What is the role of membrane thickness amniotic cavity enlarges until it obliterates the in prediction of chorionicity? chorionic cavity by 10th gestational week, approxi- Ans: Prediction of chorionicity based on mately. membrane thickness is more reliable before 26 The amnion develops after the chorion, so weeks pregnancy as thinning of the membrane dichorionicity implies diamnionicity. Identification occurs with the progress of pregnancy. A of two gestational sacs with a single embryo or membrane is considered thick if it is well defined, embryonic heartbeat in each sac confirms hyperechoic and has a finite measurable thickness dichorionic and diamniotic. Single gestational sac greater than 1 mm. A thick membrane 2 mm or with two embryos can be either monoamniotic or more (dichorionic diamniotic) was identified in diamniotic which require repeat USG assessment 100% of cases before 12 weeks, 89% in 13th to after 10 weeks of pregnancy to confirm the 26th weeks and 36% in pregnancy of more than amnionicity.10-13 27 weeks.17, 18

Fig. 10.1: Triangular portion of placenta 122 Case Discussions in Obstetrics and Gynecology

Q.16. How do we diagnose monoamniotic twins? AC 20 mm or more are most sensitive parameters Ans: Monoamniotic twin pregnancy is rare (1 in of significant discordance. The growth monitoring 12500 births). This is associated with late division with USG should be performed once in 3 to 4 weeks of the fertilized ovum. Sonography can directly after 26 weeks of pregnancy and more frequently 21-24 confirm the monoamnionicity when entanglement if there is discordance or IUGR. of cords, conjoined twins, non-visualization of intertwine membrane or single umbilical cord Q.20. What are the criteria to diagnose containing more than three vessels is visualized.19,20 discordance postnatally? Ans: Postnatal, the common criteria for discordance Q.17. Why do we worry about monoamniotic are birth weight discrepancy of >20% of the weight twin pregnancy? of heavier twin23 and hemoglobin difference of Ans: The perinatal mortality is 50% and associated >5 gm%. with Twin to Twin Transfusion Syndrome (TTTS), congenital malformations like acardiac, conjoint Q.21. What are the causes of discordance? twins, or preterm deliveries.19 Ans: The causes are diverse: • Twin to Twin Transfusion Syndrome (TTTS) Q.18. What are the antenatal advices to women • Abnormal karyotype with multiple pregnancy? • IUGR Ans: ANC should be in referral center and should be once in two weeks in second trimester and Q.22. What is TTTS? weekly in third trimester. Dietary improvements Ans: The AV malformation in placenta leads to should be advised as early as possible. She has to TTTS. It is always seen in monochorionic placenta. consume additional 300 kcal per day. Daily iron It’s rare in dichorionic. In 35% of monochorionic (100mg) and folic acid (1mg) requirement also pregnancies, one of the twins may have more increases. Early USG to confirm the zygocity and amniotic fluid whereas the other will have less or serial USG examinations are performed for growth nil liquor. and to rule out anomalies. In monoamniotic twins • In twin pregnancies, the combined presence of fetal surveillance should be done once in 2 weeks. same sex twins, a single placenta with thin Frequent fetal surveillance before 36 weeks is not separating membrane, weight discordance and mandatory in dichorionic diamniotic twins with major difference in fluid volume between concordant growth. amniotic sacs with severe oligohydramnios in one sac has been termed as Twin Oligo- Q.19. How will you monitor the growth of the hydramnios/Polyhydramnios Sequence pregnancy? (TOPS).28 Ans: Dizygotic twins have different genes so may • In most of TOPS (Fig. 10.2) there is unbalanced vary in growth. Monozygotic twins have same shunting in the deep arteriovenous anastomoses genes, theoretically they should have identical within the placenta. In this true type of TTTS, parameters. The highest accuracy for growth there is gradual antepartum transfusion from the prediction is obtained by estimated fetal weight and restricted or stuck twin into the vascular system abdominal circumference. Significant discordancy of the other, the communication being from the means that one twin is average and the other is umbilical arterial system of the “donor” twin to small. The difference in expected weight of 20%, the umbilical vein of the “recipient”. Multiple Gestation 123

• The donor twin is growth restricted, is removed for every 10 cms rise above normal. hypovolemic, and anemic. The recipient is This procedure takes care of polyhydramnios larger, hypervolemic, and plethoric. and fetuses are born later in gestation and weigh • The earlier the TOPS appears, worse will be more than untreated cases with TOPS.28-30 the prognosis. • Amniotic septostomy can create artificial • TTTS is more common in female fetuses. opening between the gestational sacs to produce • By injecting O negative leukocyte poor washed in effect a monoamniotic pregnancy. TTTS is RBC into the smaller (donor) twin and seldom seen in monoamniotic gestations. There immediately removing the blood from the co- is speculation that the donor twin has access to twin and testing it with Kleihauer-Betke stain, amniotic fluid via the opening so it can correct twin to twin transfusion can be confirmed. In a the oligohydramnios by oral rehydration.29 study they found 4 out of 6 cases with TOPS • The vessels on the placental surface can be by this method while the Hb difference of >5% ablated by neodymium:yttrium-aluminum- was present only in 1 of those 4 cases. garnet laser (Fig. 10.3).28 • Arterial supply from the donor twin drains into • Some advocate ablation of all the vessels the venous system of recipient. Doppler can crossing the interwining septum, others pick up the vessels from one twin’s umbilical recommend identifying the causative cord and then finding a continuing vessel with arteriovenous communications and ablation of venous flow coursing towards the co-twin’s those vessels. umbilical cord. • Severe twin–twin transfusion syndrome presenting before 26 weeks of gestation should Q.23. How do we manage TOPS? be treated by laser ablation rather than by Ans: The TOPS can cause TTTS, Preterm delivery, amnioreduction or septostomy. Polyhydramnios, IUGR or fetal demise. • Finally, selective fetoreduction (SFR) can treat • Amnioreduction has shown improvement in TTTS but this method is reserved for refractory fetal survival in 65% of cases. When the cases to other forms of therapy or when in utero amniotic fluid exceeds 40 cm, one liter of fluid death of one of the twins is imminent.

Fig. 10.2: Twin oligohydramnios/polyhydramnios Fig. 10.3: The placenta was symmetrically shared by the sequence: An unbalanced shunting twins. The laser surgery was performed at 20 weeks, with the 4 lb. 5 oz. and 3 lb. 14 oz. Twin boys born 12 weeks later 124 Case Discussions in Obstetrics and Gynecology

Q.24. How is the Twin-Twin Transfusion • In the ductus venosus, the diastolic flow is either Syndrome (TTTS) classified? absent or reversed. This pattern is usually seen Ans: Dr. Rubén Quintero is the director of the Fetal in the recipient twin due to early heart failure. Therapy Center at the University of Miami Miller • The recipient twin can also exhibit leakage School of Medicine. He developed the field of across the main valve on the right side of the operative fetoscopy to treat birth defects in utero heart – this is known as tricuspid regurgitation. via a minimally-invasive approach by designing Stage IV: surgical instruments and techniques. He pioneered • One or both babies shows signs of hydrops. This the selective laser surgery technique to treat Twin- means there is excess fluid in parts of the baby such as swelling of the skin around the head to-Twin Transfusion Syndrome (TTTS) and has (scalp edema), fluid in the abdomen (ascites), proposed 5 stages of TTTS based on ultrasound fluid around the lungs (pleural effusions) or findings:32 fluid around the heart (pericardial effusion). Stage I: • These findings are evidence of heart failure and • This is the initial way TTTS is seen on are typically seen in the recipient twin. ultrasound. Stage V: • There is oligohydramnios in the donor’s sac • One or both babies are dead. with a Max Vertical Pocket (MVP) of 2 • The survival of the twins is poorer when there centimeters or less (3/4 inch) and is progression to a higher stage over time. polyhydramnios in the recipient’s sac with a • It has been estimated that half of the patients maximum vertical pocket of fluid of 8 will progress to a higher stage, 30% will remain centimeters or more (just over 3 inches). at the same stage and 20% will improve to a • The bladder of the donor baby is still seen. lower stage II or III Stage II: • As defined above, there is polyhydramnios and Q.25. How do we manage multiple gestation if oligohydramnios but the bladder is no longer one fetus dies? seen in the donor twin during the ultrasound Ans: evaluation. • The first trimester estimation of multiple Stage III: gestation is higher than incidence of births. One • Blood flow in the fetus can be measured with twin was lost (vanished) in as many as 20% of doppler. In addition to the findings of Stages I twin gestation diagnosed in first trimester.12 and II, careful study of the blood flow in the • The early loss is reported to have negligible umbilical cord and fetal ductus venosus (the effect on the pregnancy. large blood vessel in the fetus that returns blood • Second and third trimester loss is associated to the heart from the placenta) reveals with significant morbidity and mortality in the abnormal patterns in Stage III. survivor. There is 20% probability of • These patterns can occur in either or both neurological damage which is difficult to fetuses. predict. The surviving twin should be evaluated • In the umbilical cord, the diastolic flow is either with USG and/or MRI. If no lesions are absent or reversed. This pattern is usually seen observed, the patient may be councelled and in the donor twin. expectant management should be adopted.33,34 Multiple Gestation 125

• The outcome is worse in monochorionic than very small amount of devitalized fetal tissue, dichorionic pregnancies. The lesions are spontaneous reduction (vanishing) occurs infarction, necrosis in the brain (multicystic before this period and remaining fetuses are encephalomalacia), liver, and kidney (renal large enough to be evaluated by USG. cortical necrosis) causing major neurological • The needle is introduced into the heart of the 34,35 or renal impairment. fetus and potassium chloride (0.4 to 1 ml) • The reversal of blood flow from live to dead injected under USG guidance. fetus, release of thromboplastin in circulation • The fetus most conveniently punctured is and/or necrotic emboli may pass from the dead selected for reduction. to the live fetus are the main postulates for • There was no statistically significant difference complications (hypotension, DIC, anemia in gestational age at delivery between control necrosis or infarction). twins and twins obtained by reduction.39 • Delivery of the live fetus as soon as the survivor • In cases of triplet gestations, however, this can be expected to live without undue adverse option remains controversial. consequences of prematurity is recommended. Corticosteroid for lungs maturity can be given Q.29. What are the complications associated and fetus should be delivered by 34 weeks. with SFR? Q.26. What is selective fetal reduction? Ans: Ans: From 8% to 20% of multiple pregnancies • After fetal reduction, there is a 2-10% chance reduce spontaneously by the end of the first that the woman will lose the entire pregnancy trimester. When the phenomenon of the “vanishing prior to 20 weeks’ gestation. twin” occurs prior to 14 weeks’ gestation, it has no • The risk may be slightly higher if the presenting adverse effect on the remaining fetus. If the higher- fetus is terminated. order gestation does not reduce spontaneously, • The original number of fetuses, the route of the selective multifetal reduction (SFR) or multifetal needle as well as the number terminated may pregnancy reduction (MFPR) can be offered as an influence the likelihood and the rate of pregnancy option. This is an abortion procedure where one or loss. more babies are aborted in order to improve • In monochorionic placenta the vascular 36-38 perinatal outcome for the remaining fetuses. anastomosis can cause death of both fetuses, Q.27. What are the principles of SFR? so reduction of monochorionic gestation should be avoided. Ans: Fetal reduction in multiple gestation has two • Periodic clotting studies should be done after principles. selective reduction. • It should be done in higher order pregnancy (more than 3). Q.30. What is the main advantage of SFR? • Elimination of fetus with known serious ano- malies to improve the outcome of the normal Ans: co-twin. • Every additional viable fetus present in the first trimester shortens the duration of gestation by Q.28. When should we perform SFR? about 3.6 weeks. 37-39 Ans: • Each fetus reduced, either spontaneously or • Multifetal reduction is usually carried out in the medically, can potentially prolong gestation by first trimester. In 10 to 14 weeks, the fetus has about 3 weeks. 126 Case Discussions in Obstetrics and Gynecology

Q.31. Is it ethically justified to do SFR? • Guidelines for corticosteroid therapy are not Ans: different for multiple gestation. • Ethical justification was articulated by • Prophylactic cerclage does not improve the Chevernak and colleagues40 in terms of three outcome. goals: – Achieving a pregnancy that results in a live Q.33. What are the malformations unique to birth of one or more infants with minimal multiple gestation? neonatal morbidity and mortality. Ans: – Achieving a pregnancy that results in the Conjoint twin birth of one or more infants without Fetal acardia antenatally detected anomalies. – Achieving a pregnancy that results in a Q.34. What are conjoint twins? singleton live birth. Ans: • Too often MFPR is assumed by the medical and • Conjoint twins are a rare anomaly (1 in 50000 research community to be what the parents want to 100000). It affects 1 of every 200 mono- without obtaining true informed consent or zygotic twin pregnancies.41-43 giving them a choice about the number of • Most of them have preterm delivery and 40% fetuses to be kept alive. are still born. • More research needs to be done into the effects • They develop from single zygote and result of MFPR on couples and on their future family from incomplete division of the embryonic disc life with the surviving babies. This research 13 days after fertilization. should be carried out by investigators not • 70% of them are female fetuses. Risk of already involved in performing and advocating recurrence is negligible. this procedure. • They are grouped under following types • Parents’ reactions to the loss of some of the 1. Craniopagus – head to head fusion fetuses conceived are similar to those 2. Thoracopagus – chest to chest fusion experienced after abortion for genetic reasons 3. Omphalopagus – abdomen to abdomen viz: sadness, guilt, and depression. fusion 4. Pyopagus – joined at buttocks Q.32. Is there any role of routine hospitalization, 5. Ischiopagus – joined at ischium tocolysis or corticosteroid? Ans: Q.35. How do we diagnose conjoint twins? • Routine hospitalization is not necessary to prolong multifetal pregnancy. Ans: • Limited physical activity, early work leave, • It should be suspected in monoamniotic twins, more frequent health care visits and USG inseparable fetal bodies, no change in the examinations and structured maternal education relative position of the fetuses, or single on the risks of preterm delivery have been umbilical cord with more than three vessels. advocated to reduce preterm births. • Most of them are fused ventrally. The following • There is no role of prophylactic tocolysis. USG findings increase the probability of • In fact tocolytics are associated with cardio- conjoint twins vascular and pulmonary complications more in – The fetal heads at same level and plane. multiple gestation than singleton. – Both fetal heads hyperextended. Multiple Gestation 127

– There is no change in the relative position • The flow pattern leading to acardia has been of the fetuses with movement. described as twin reversed arterial perfusion • If the sonogram and fetogram are suggestive of (TRAP) sequence. conjoint twins, the diagnosis may be confirmed by injecting 40ml of radiopaque material into Q.38. Why caudal portion is mostly well the amniotic cavity. This is called Amniography developed in acardiac twin? and helps in location of fusion between the Ans: 20, 42 fetuses. • Caudal aspect of the perfused fetus receives • Prenatal diagnosis of conjoint twins is now well- blood with relatively more nutrients and oxygen reported from the mid first-trimester, using B- than the upper torso, resulting in better mode ultrasound, Doppler, color Doppler and development of the and lower extremities three-dimensional imaging techniques, with in the acardiac fetus (Fig. 10.4). detailed assessment of cardiovascular anatomy • Fully desaturated blood then flows in a important for determining prognosis and retrograde fashion to the upper body and head, planning management. leading to mal-development of the heart, head, and upper torso, which are either completely Q.36. What should be the mode of delivery in absent or severely deficient. Therefore, on USG conjoint twins? it appears as a heterogeneous mass, simulating Ans: a teratoma or intrauterine fetal demise. • MTP should be counseled if diagnosed before 20 weeks. Q.39. What are types of acardiac twins? • Vaginal deliveries of conjoint twins have been Ans: reported in prenatally undiagnosed cases but • This condition mainly have the following most of them are associated with risk of dystocia presentations and uterine rupture. – Acardius anceps – when head is poorly • If diagnosed late (in third trimester) then they formed should be delivered by elective cesarean section.43

Q.37. What is acardiac twin? Ans: • It is a rare anomaly that occurs in approximately 1 in 30000 of monozygotic twin pregnancies. • Typically, the acardiac twin has a poorly developed upper body with a small or absent head and often absent or underdeveloped upper extremities. • All cases are associated with placental arterial to arterial and venous to venous anastomoses. The blood flows from “normal” fetus referred as pump twin through vascular anastomoses to the acardiac twin via a single placenta.44 Fig. 10.4: Well-developed caudal portion in an acardiac twin 128 Case Discussions in Obstetrics and Gynecology

– Acardius acephalus – if the head is absent – Acardius acormus – presence of head only – Acardius amorphous – unrecognizable amorphous mass

Q.40. What are the other complications asso- ciated with acardiac twins? Ans: • Chromosomal anomalies may be present in up to 50% of cases of acardiac fetus. • The acardiac twin usually has a dorsal cystic hygroma. If the head is formed, holo- prosencephaly or other severe brain mal- formations may occur. The other structures may be absent, hypoplastic or severely malformed. Fig. 10.5: Acardiac-acephalic twin Q.41. How do we diagnose acardiac twin – The relative size of the ‘acardiac’ twin to antenatally? the pump twin Ans: It’s not simple and most commonly confused – The presence of any cardiovascular with anencephaly or fetal demise of one of the impairment in the ‘pump’ twin. twins. It is easy to erroneously diagnose fetal death • Careful monitoring and ultrasound surveillance in these cases because of the absence of cardiac is required. Mortality of the normal twin is motion in one of the twins approximately 50%. • The pump twin is at great risk for high output congestive cardiac heart failure, poly- Q.43. How do we manage a case of 36 weeks hydramnios, and hydrops fetalis. multiple gestation? • The condition should be suspected when a Ans: severely malformed fetus is observed in a • Fetal biophysical profile should be done twice monochorionic twin gestation. a week at least. • In contrast to TTTS, upper extremities are not • Wait for the spontaneous onset of labor. Twins formed and diffuse edema and cystic hygroma are usually allowed vaginal delivery if there is are common. no obstetric indication for LSCS like fetal distress, major degree placenta previa, Q.42. How do we manage acardiac twin contacted pelvis, malpresentation of the first pregnancy? fetus, or cord prolapse etc. Ans: • Indication for Induction is similar to singleton • The acardiac twin should be terminated with pregnancy if planned for vaginal delivery. intracardiac potassium chloride or radio- • Higher order pregnancy (triplet or more) are frequency ablation (Fig. 10.5) or umbilical delivered by LSCS if not extreme preterm or 45,47 artery occlusion. Not all pregnancies with survival of fetus is doubtful. TRAP sequence require invasive treatment and • Monoamniotic twins should be delivered by this appears to be dependent on: elective LSCS at 34 weeks. Multiple Gestation 129

Q.44. How do we manage the Twin pregnancy rate, presenting part, expected weight and its in labor? relationship to birth canal carefully and quickly. Ans: Multiple gestation should be delivered in a USG is very useful at this stage. If the presentation referral institution or a place where following is transverse and there is no CPD or fetal heart facilities are available. abnormality then ECV may be attempted.45,46 Once • An obstetrician, pediatrician and anesthetist the lie is longitudinal (cephalic or breech), the labor • Blood transfusion facility is allowed to resume. The safest interval is cited as • Operation Theater less than 30 minutes. If CTG is available then • Ultrasonography interval can be longer but vigilance is • CTG and Pulse-oxymeter mandatory.50,51 – Epidural analgesia is very effective in these cases. Q.46. What are the neonatal outcomes with – The labor is monitored with partograph. different mode of deliveries? – Augmentation of the labor of first of the twin Ans: should be done judiciously. Labor is allowed to • Neonatal outcomes were same in the vaginal progress spontaneously most of the time. and LSCS delivery of 23 sets of triplets in a – Electronic fetal heart (CTG) monitoring is ideal. study.52, 53 Malposition, premature separation USG may be required in the management of of placenta causing hemorrhage, and mani- second of the twin delivery. pulations required to deliver the babies – After first baby delivery, wait for progress of (requiring skilled obstetrician) are more likely labor with spontaneous contractions and fetal to complicate vaginal delivery so LSCS is heart rate monitoring. If contractions are not preferred. effective even after 10 minutes, augmentation • The safety of neonates depends on obstetrician’s may be done. skills. – Once the presenting part of the second of the • Monoamniotic twins or conjoint twins are direct twin is engaged, membrane may be ruptured. indication for LSCS. The delivery depends on the fetal heart rate, dilatation of cervix and station of fetal • The phenomenon of locked twin is rare, but if presenting part like any other case. suspected, LSCS is the mode of delivery. – Prophylactic methergin is always withheld • Elective LSCS does not improve the neonatal 54 after delivery of the first baby. Episiotomy can outcome when both twins are cephalic. be made during first baby delivery if required. • Internal podalic version can be performed for – The placenta should be examined thoroughly second twin in second stage. after delivery. Indications for instrumental • Breech extraction was considered superior to delivery are similar to singleton pregnancy. external cephalic version for second of twin – PPH should be prevented with continuous according to a study.55 oxytocic infusion. Q.47. What is internal podalic version? Q.45. What is the ideal interval between the Ans: It is used only for the delivery of a second deliveries of twins? twin. It consists of the insertion of hand into the Ans: Soon after the delivery of the first baby, the uterine cavity to turn the fetus manually by holding second of the twin should be assessed for fetal heart the feet. This procedure is performed under 130 Case Discussions in Obstetrics and Gynecology adequate analgesia and aseptic conditions REFERENCES preferably in the OT. The obstetrician seizes one 1. Mac Gillivray I. Epidemiology of twin pregnancy. or both feet of the baby and draws them through Semin Perinatol 1986;10(1):4. the fully dilated cervix while using the other hand 2. Luke B. The changing pattern of multiple births in to transabdominally push the upper portion of the the United States: Maternal and infant characteristics, fetal body in the opposite direction. This is followed 1973 and 1990. Obstet Gynecol 1994;84(1):101. 3. Wenstrom KD, Gall SA. Incidence, morbidity and by breech extraction of the baby. mortality and diagnosis of twin gestations. Clin Perinatol 1988;15(1):1. Q.48. When should we admit the patient in 4. Guttmacher AF, Kohl S. The fetus of multiple hospital? gestations. Obstet Gynecol 1958;12:528-41. 5. Naeye RL, Tafari N, Judge D et al. Twins; Causes of Ans: The duration of gestational age, type of perinatal death in 12 United States cities and one multiple gestation and associated complication African city. Am J Obstet Gynecol 1978;131:267-72. determine the time of admission in the hospital. 6. Ghai V, Vidyasagar D. Morbidity and mortality factors • Any case that is associated with complications in twins. An epidemiologic approach. Clin Perinatol like moderate to severe anemia, hypertension, 1988;15(1):123. 7. Hendricks CH. Twinning in relation to birth weight, hydramnios causing respiratory distress, mortality and congenital anomalies. Obstet Gynecol diabetes, bleeding per vaginum or labor pains 1966;27:47-53. should be admitted immediately. 8. Schinzel AA, Smith DW, Miller JR. Monozygotic • The patients are admitted for the procedures like twinning and structural defects. J Pediatr 1979; fetal reduction, amnioreduction or surgical 95(6):21. 9. Azubuike JC. Multiple births in Igbo women. Br J procedure like laser ablation. Obstet Gynecol 1982;89:77. • The patients with single fetal demise are 10. Kurtz AB, Wapner RJ, Mata J et al. Twin pregnancies: admitted for investigation and psychological Accuracy of first trimester abdominal USG in support. predicting chorionicity and amnionicity. Radiology • The suggested time of admission for twin 1992;185(3):759. 11. Doubilet PM, Benson CB. "Appearing twin": pregnancy is 36 weeks or more, for triplet is 30 Undercounting of multiple gestations on early first to 32 weeks and for higher multiple gestation it trimester sonograms. J Ultrasound Med 1998;17(4): can be as early as 26 to 30 weeks. This is due to 199. following reasons 12. Landy HJ, Weiner S, Corson SL, et al. The "vanishing – Preterm delivery chances are higher in twin": Ultrasonographic assessment of fetal disappearance in the first trimester. Am J Obstet higher multiple gestation, so to prevent Gynecol 1986;155(1):14. preterm birth and improve the perinatal 13. Sepulveda W. Chorionicity determination in twin outcome patient should get adequate bed pregnancies: double trouble. Ultrasound Obstet rest. Gynecol 1997;10(2):79. – Steroid has to be given for early fetal lung 14. Gaziano EP, Knox GE, Bendel RP, et al. Is doppler velocimetry useful in the management of multiple maturity. gestation pregnancies? Am J Obstet Gynecol 1991; – The monoamniotic twins should be admitted 164:1426-33. at 30 to 32 weeks. 15. Hastie SJ, Danskin F, Neilson JP, et al. Prediction of • The routine hospitalization is not required if the small for gestational age twin fetuses by Doppler patient compliance is good. umbilical artery waveform analysis. Obstet Gynecol 1989;74:730-33. Multiple Gestation 131

16. Finberg HJ. The "twin peak" sign: Reliable evidence 30. Denbow ML, Sepulveda W, Ridout D et al. of dichorionic twinning. J Ultrasound Med 1992; Relationship between change in amniotic fluid index 11(11):571. and volume of fluid removed at amnioreduction. 17. Townsend RR, Simpson GF, Filly RA. Membrane Obstet Gynecol 1997;90(4):529. thickness in ultrasound prediction of chorionicity of 31. De Lia JE, Kuhlmann RS, Harstad TW et al. twin gestations. J Ultrasound Med 1988;7(6):327. Fetoscopic laser ablation of placental vessels in severe 18. Stagiannis KD, Sepuiveda W Southwell D et al. preciable twin - twin transfusión syndrome. Am J Ultrasonographic measurement of the dividing Obstet Gynecol 1995;172(4):1202-8. membrane in twin pregnancy during the second and 32. Quintero R, Morales W, Allen M, Bornick P, Johnson third trimesters: A reproducibility study. Am J Obstet P, Krueger M. Staging of twin-twin transfusion Gynecol 1995;173(5):1546. syndrome. J Perinatol 1999;19:550-55. 19. Tessen JA, Zlatnik FJ. Monoamniotic twins: A 33. Enbom JA. Twin pregnancy with intrauterine death retrospective controlled study. Obstet Gynecol 1991; of one twin. Am J Obstet Gynecol 1985;152:424-29. 77:832-34. 34. Fusi L, Gordon H. Twin pregnancy complicated by 20. Finberg HJ, Clewell WH. Definitive prenatal diagnosis single intrauterine death. Problems and outcome with of monoamniotic twins. Swallowed amniotic contrast conservative management. Br J Obstet Gynecol 1990; agent detected in both twins on sonographically selected 97(6):511. CT images. J Ultrasound Med 1991;10(9): 513. 35. Yoshioka H, Kadomoto Y, Minto M et al. Multicystic 21. Divon MY, Girz BA, Sklar A, et al. Discordant twins encephalomalacia in liveborn twin with a stillborn - A prospective study of the diagnostic value of real - macerated co-twin. J Pediatr 1979;95:798-800. time ultrasonography combined with umbilical artery 36. Berkowitz RL, Lynch L, Chitkara U et al. Selective velocimetry. Am J Obstet Gynecol 1989;161:757-60. reduction of Multifetal pregnancies in the first 22. Erkkola R, Ala-Mello S, Piiroinen O, et al. Growth trimester. N Engl J Med 1988;318:1043-47. discordancy in twin pregnancies: A risk factor not 37. Berkowitz RL, Stone JL, Eddleman KA. One hundred detected by measurement of biparietal diameter. Obstet consecutive cases of selective termination of an Gynecol 1985;66:203-6. abnormal fetus in a multifetal gestation. Obstet 23. O'Brien WF, Knuppel RA, Scerbo JC et al. Birth Gynecol 1997;90(4):606. weight in twins: An analysis of discordancy and 38. Evans MI, Fletcher JC, Zador IE, et al. Selective first growth retardation. Obstet Gynecol 1986;67(4):483. trimester termination in octuplet and quadruplet 24. Storlazzi E, Vintzileous AM, Campbell WA et al. pregnancies: Clinical and ethical issues. Obstet Ultrasonic diagnosis of discordant fetal growth in twin Gynecol 1988;71:289-96. gestations. Obstet Gynecol 1987;69(3):363. 39. Torok O, Lapinski R, Salafia CM, et al. Multifetal 25. Blickstein I. The twin to twin transfusion syndrome. pregnancy reduction is not associated with an Obstet Gynecol 1990;76(4):714. increased risk of intrauterine growth restriction, except 26. Bruner JP, Anderson TL, Rosemond RL. Placental for very - high - order multiples. Am J Obstet Gynecol pathophysiology of the twin oligohydramnios - 1998;179(1):221. polyhydramnios sequence and twin to twin 40. Chervenak FA, McCullough LB, Wapner R. Three transfusion. Placenta 1998;19(1):81. ethically justified indications for selective termination 27. Suresh S, Krishnamurthy R, Anand B et al. Twin in multifetal pregnancy: a practical and comprehensive reversal arterial perfusion (TRAP) sequence: management strategy. J Assist Reprod Genet 1995; Diagnosis and management options based on 12:531-6. sonography. Radiology 1998;209(suppl):17. 41. Maggio M, Callen NA, Hamod KA et al. The first 28. Bruner JP, Rosemond RL. Twin to twin transfusion trimester ultrasonographic diagnosis of conjoint twins. syndrome: A subset of the twin oligohydramnios - Am J Obstet Gynecol 1985;152(7):833. polyhydramnios sequence. Am J Obstet Gynecol 1993; 42. Gore RM, Filly RA, Parer JT. Sonographic antepartum 169(4):925. diagnosis of conjoint twins. Its impact on obstetrics 29. Dennis LG, Winkler CL. Twin to twin transfusion management. JAMA 1982;247(24):3351. syndrome: Aggressive therapeutic amniocentesis. Am 43. Sakala EP. Obstetric management of conjoint twins. J Obstet Gynecol 1997;177(2):342-47. Obstet gynecol 1986;67(3, Suppl):21S. 132 Case Discussions in Obstetrics and Gynecology

44. Suresh S, Krishnamurthy R, Anand B et al. Twin 50. Rayburn WF, Lavin JP Jr, Miodovnik M et al. Multiple reversal arterial perfusion (TRAP) sequence: gestation: Time interval between delivery of the first Diagnosis and management options based on and second twins. Obstet Gynecol 1984;63:502. sonography. Radiology 1998;209(suppl):17. 51. American College of Obstetricians and Gynecologists. 45. Carr SR, Aronson MP, Coustan DR. Survival rates of Special problems of multiple gestation. Education monoamniotic twins do not decrease after 30 bulletin No 253, November 1998. weeks’ gestation. Am J Obstet Gynecol 1990;163:719- 52. Alamia V Jr, Royek AB, Jaekle RK, et al. Preliminary 22. experience with a prospective protocol for planned 46. Porreco RP, Barton SM, Haverkamp AD. Occlusion vaginal delivery of triplet gestations. Am J Obstet of umbilical artery in acardiac acephalic twin. Lancet Gynecol 1998;179:1133. 1991;337:326-27. 53. Grobman WA, Peaceman AM, Haney EI et al. 47. Robie GF, Payne GG, Morgan MA. Selective delivery Neonatal outcomes in triplet gestations after a trial of of an acardiac acephalic twin. N Engl J Med 1989; labor. Am J Obstet Gynecol 1998;179:942. 320:512-13. 54. Hogle KL, Hutton EK, Mc Brien KA et al. Cesarean 48. Chervanak FA, Johnson RE, Berkowitz RL et al. delivery for twins: A systematic review and meta- Intrapartum external version of the second twin. Obstet analysis. Am J Obstet Gynecol 2003;188:220. Gynecol 1983;62:163. 55. Chauhan SP, Roberts WE, McLaren RA et al. Delivery 49. Chervanak FA, Johnson RE, Youcha S et al. of the non-vertex twin: Breech extraction versus Intrapartum management of twin gestation. Obstet external cephalic version. Am J Obstet Gynecol 1995; Gynecol 1985;65:119. 173:1015. Renu Tanwar

11 Pregnancy with Previous Cesarean Section

INTRODUCTION • Stage of labor Rising incidence of cesarean section worldwide has • Type of CS from history or pervious record/ become a matter of concern to the obstetrician, the notes if available. patient and the health care providers. This problem • History of puerpueral infection/wound can be tackled by infection 1. The indication for primary cesarean section • History of resuturing should be stringent and highly selective. • Any blood transfusion. 2. More trial of labor for nonrecurring conditions would result in fewer number of repeat Physical Examination: cesarean section. The dictum once a cesarean, General built and nutritional status always a cesarean is no longer tenable. Height and weight Pulse: rate, rhythm, volume, peripheral pulses and CASE 1 any radiofemoral delay Blood pressure. Mrs X, 28-year-old G2P1L1 at 34 weeks preg- Respiratory rate nancy with previous cesarean section came to ANC OPD for her routine check-up. Pallor, cyanosis or icterus. Jugular venous pulsations Q.1. What history and examination would be Pedal edema required in this case? Systemic examination: Ans: For this the routine detailed history and Detailed CVS and respiratory system examination. examination is a must but more importance should be given to the following points. Abdominal examination: Inspection Previous obstetric history • Distended uterine ovoid, a. Number of vaginal deliveries • Details of scar (type, length and healing of the b. History of vaginal birth after CS c. History of interdelivery interval. scars) d. Number of CS • hernial sites • Indication of CS, and at what period of Palpation gestation Fundal height in weeks and symphysiofundal height • Elective/Emergency CS [SFH] in cm. 134 Case Discussions in Obstetrics and Gynecology

Fetal lie, presentation, amount of liquor, estimated and benefits of planned VBAC and ERCS fetal weight. (elective repeat cesarean section). Scar tenderness: Palpate the lower part of the • Chances of successful planned VBAC are uterus between the suprapubic region and the 72–76%.1 symphysis pubis and try to engage the patient in some conversation and look whether the patient Q.4. Which patients would fit for VBAC? winces in pain on palpation. This suggest scar Ans: Only women who meet specific criteria and tenderness. If the patient is in labor, then it should who can deliver in appropriate facilities should be be elicited in between the contraction, when the offered VBAC. uterus relaxes. (Recommendations of ACOG useful for selection 2 Auscultation: Fetal heart rate. of candidates for VBAC) Per speculum examination: Look for vaginal 1. Patient consent discharge/leaking. 2. No more than one prior low transverse cesarean delivery Per vaginal examination: Under aseptic pre- 3. Clinically adequate pelvis caution (hand washing and sterile gloves) 4. No other uterine scars or previous rupture Done at 36 completed weeks 5. Physician immediately available throughout • Cervical dilatation and effacement active labor who is capable of monitoring labor • Confirm the presentation, station of presenting and performing emergency cesarean delivery part, position and degree of flexion 6. Availability of anesthesia and personnel for • Status of membrane emergency cesarean delivery • Pelvic adequacy and rule out CPD Q.5. What are absolute contraindications to Q.2. What investigations are required? VBAC?3 Ans: Ans: • Apart from the routine blood and urine 1. Prior classic, T-shaped incision or other trans- investigations mural uterine surgery • USG to rule out GCA (level II ) at 16-18 weeks 2. Contracted pelvis of gestation 3. Medical or obstetric complication that preclude • Placental localization, rule out placenta accreta vaginal delivery and thickness of scar in the third trimester 4. Patient refusal 5. Inability to immediately perform cesarean Q.3. How should women be counselled in section because of unavailable surgeon or antenatal period? anesthesia personnel, inadequate staff or facility Ans: Antenatal counselling should be documented 6. Previous rupture or scar dehiscence in notes 7. Non reassuring fetal status • Plans for future pregnancy. 8. Previous two LSCS • Final decision for mode of birth should be agreed between the woman and the obstetrician Q.6. What are the factors influencing VBAC? (by 36 weeks of gestation ) before the expected/ Ans: The following are the factors for consideration planned delivery date. when determining labor and delivery management • Counsel about the maternal and perinatal risk of a patient with a prior cesarean. Pregnancy with Previous Cesarean Section 135 a. Prior vaginal delivery Q.7. What is the role of induction of labor in a Those women who have given birth vaginally patient with a previous CS? atleast once are 9 to 28 times more likely to Ans: have a successful VBAC and the success rate INDUCTION OF LABOR is 83-95%4 Spontaneous labor is preferable to labor induction b. Prior VBAC and augmentation of labor after previous cesarean It is the single best predictor for successful delivery. Induction of labor may be either indicated VBAC and is associated with an approximately 87-90% planned VBAC success rate.5 or elective. c. Large for gestational age/Macrosomia An indicated induction of labor implies that Successful VBAC with suspected large for the maternal or fetal benefits of delivery will be gestational age infants > 4000 gm often have a greater than the benefits of continuing the vaginal delivery rate of only 50-60%.3 Elkousy pregnancy. et al (1) found a statistically significant increase An elective induction of labor is in the absence in the rate of uterine rupture among women of the medical or obstetrical indication. without a prior vaginal delivery when delivering an infant > 4000 gms. Absolute risk of 3.6% Advantages for uterine rupture. Discourage VBAC attempts The elective timing of delivery allows for planning in those gestations with estimated fetal weight and organization of the remaining member of their of 4250 gm or greater. family. It ensures an adequate core of labor and d. Indication for prior cesarean delivery delivery staff as well as advances in the option of The success rate for a trial of labor depends to cervical ripening have led to increased rate of some extent on the indication of the prior induction of labor. cesarean delivery, i.e. Breech, fetal distress and in relation to cervical dilatation achieved before Disadvantages the original cesarean delivery. Success rate was • Iatrogenic prematurity less for dystocia, failure to progress and in the • No randomized control trials available completely dilated group. The likelihood of The Bishop score has been useful in predicting vaginal delivery in the completely dilated group the success of labor induction at term. is as low as 13% and patient should be informed When the Bishop score exceeds 8, the her low chance of a successful VBAC.6 likelihood of vaginal delivery after induction is e. Maternal obesity similar to the rate associated with spontaneous As the maternal weight increases (body mass labor.8 Await spontaneous labor beyond 40 weeeks index >30), the rate of VBAC success gestation in VBAC candidates. However, at 41 decreases.7 f. Other factors1 weeks in well dated patients, consider induction if • At or after 41 weeks of gestation there is favorable cervix (Bishop score > 8), • Previous preterm cesarean birth adequate clinical pelvimetry and an estimated • Advance maternal age fetal weight of < 4000 gm. If these criteria Are associated with a decreased likelihood of cannot be met, a repeat cesarean section is reco- planned VBAC success. mmended.3 136 Case Discussions in Obstetrics and Gynecology

Q.8. What are the different methods of labor safe alternative in women with previous uterine scar induction and the risk associated with it? will likely be investigated in the near future.15 Ans: OXYTOCIN Q.9. What are the other mechanical labor • Can be used for induction or augmentation of induction methods? labor if cervix is favorable with close Ans: Membrane stripping results in a significant monitoring in women with a prior cesarean increase in phospholipase A2 actitvity and PGF2- delivery undergoing a trial of labor. alpha levels and hence greater frequency of • Use of standard regimens of oxytocin is spontaneous labor and fewer postdated inductions. considered safe and efficacious and may in fact It is done at 38 weeks and repeated at the following enhance the overall VBAC success rate.9 appointment, if the patient remains undelivered. The cervix should be at least 1 cm dilated.16 DOSE OF OXYTOCIN • If cervix is favorable (BS > 8), consider • Start with 0.4 mu/ml and increase every 30 amniotomy and oxytocin augmentation. minutes till the patient has adequate • If cervix is unfavorable and one is unable to contractions (3 contractions in 10 minutes and await labor onset, then Foley’s bulb cervical each lasting for at least 45 minutes) until a dilatation 17 and amniotomy when possible and maximum dose of 22.8 mu/ml of syntocinon is then oxytocin for induction/augmentation. reached.10 • Rate of uterine rupture in patient undergoing a Q.10. How is the labor to be monitored in a trial of labor.11 patient with a previous cesarean section? – Spontaneous 0.4% Ans: The following points have to be kept in mind. – Augmented 1% • Establish IV line – Induced 2.3% • Blood for cross-matching to be sent. PROSTAGLANDINS-E2 (DINOPROSTONE) • Clear fluids are to be allowed. Fluid replace- Can be used for ripening (only one dose).12 There ment same as normal labor. should be a clear and compelling clinical indication. • Maternal monitoring – pulse rate every half The potential increased risk of uterine rupture with hourly, BP- 2 hourly till she progresses to prostaglandin use should be discussed with the established labor. patient and documented (ACOG 2003, 2004). • Oxytocin can be used for induction/aug- The rate of uterine rupture is 1.3%.13 mentation after amniotomy. Titration of dose has to be done with careful fetal and maternal MISOPROSTOL monitoring. ACOG has recommended a moratorium on • Record electronic FHR continuously and in misoprostol use in women undergoing a trial of absence of this facility, intermittent auscultation labor. It is contraindicated because of an extremely of fetal heart rate half hourly in early labor, high rate of disruption of the previous uterine scar. every 15 minutes in first stage of labor and after The incidence of scar rupture is 5.6%.14 each pain during the second stage of labor. MIFEPRISTONE • Record progress of labor on a partogram. It is being studied as an agent for labor induction • Labor Analgesia – Epidural analgesia can be in France but data are sparse. Its potential use as a used and the fear that it would mask the signs Pregnancy with Previous Cesarean Section 137

and symptoms of uterine rupture have not been 8. Sudden cessation of uterine contractions or substantiated.18 there is receeding of presenting part on PV Injection Pethedine (50 mg) + Injection examination Phenargan (25 mg) IM. 9. Fetal parts palpable superficial on Per abdomen Injection Tramadol (10 mg) IM 8 hourly. No examination sedation after 6 cm dilation. 10. Hematuria • Watch for signs of scar dehiscence. Q.12. What are the risk factor for uterine • During second stage of labor careful watch to rupture during trial of labor after cesarean be maintained. delivery?18 • No mid cavity forceps to be applied. If second stage > one hour, outlet forceps/vaccum can be Ans: 1. Types of prior uterine incision applied provided all criteria are fulfilled, as shortening the second stage reduces the strain Prior uterine incision Estimated rupture (%) on the cesarean scar. Classical 4-9 • No routine digital exploration of scar. T-shaped 4-9 • Patient to be kept under observation for 4 hours Low vertical 1-7 in the labor room after delivery. Low transverse 0.2-1.5 • If condition is not stable (rising pulse rate, falling BP/pallor) prepare the patient for In about 1/3rd of the women, the classical scar exploration in OT. Inform the senior consultant will rupture before the onset of labor. on call. 2. Interdelivery interval 19 Emergency ceserean section is required in 30 Shipp et al hypothesized that, short interval to 40% of cases. between a cesarean section and subsequent trial of labor might increase the risk of uterine rupture because of inadequate time of healing. Q.11. What are the signs of scar dehiscence? In inter delivery of interval of 18 months or less Ans: rupture rate was 2.3% compared with a rupture 1. Unexplained maternal tachycardia – if present/ rate of 1% for women with longer interdelivery rising, check temperature/hydration. interval. 2. Pain at incision site 3. Postpartum fever after cesarean 3. Deceleration of FHR on CTG – prolonged • Predisposed to poor wound healing. deceleration or variable decelerations that are • Tend to have wider scars though clinical persistent and severe is the most specific sign significance of this finding has not been assessed. of uterine rupture. Deceleration of fetal heart • It is associated with threefold increase in rate to 60 to 70 beats per minute or less that the risk of uterine rupture during a sub- lasts for more than a few minutes that does not sequent trial of labor. return to baseline requires rapid intervention. 4. Uterine anomalies 4. Meconium stained liquor Includes bicornuate, unicornuate, didelphic and 5. Scar tenderness septate uterus. The rate of rupture in this group 6. Fresh bleeding PV was 8% as compared with the rate of 0.6% for 7. Bladder tenesmus women without these anomalies.20 138 Case Discussions in Obstetrics and Gynecology

5. Closure of prior incision Flamm et al23 in his series suggested that this A review of studies published to date implies procedure is not likely to be associated with an that the single layer uterine closure is not prone extremely high rate of uterine rupture. But more to uterine rupture than the traditional double studies are required. layer closure.21 6. Current pregnancy characteristics Q.14. Can vaginal delivery be offered in twin a. Macrosomia – a small increase in risk is pregnancy with previous one cesarean scar? possible when fetus weighed 4 kg or more. Ans: Role of VBAC in twins1 b. Thickness of the lower uterine segment in The safety of VBAC in women with twin gestation late pregnancy (36-38 weeks).22 It may be has been examined in small case series and found useful for screening high-risk population. that the rates of successful VBAC and uterine Thickness Risk of rupture rupture do not differ significantly between study >4.5 mm 0% subjects and women with singleton gestations who 3.6-4.5 mm 0.6% were attempting VBAC. 2.6-3.5 mm 6.6% 1 < or = 2.5 mm 9.8% Role of VBAC with preterm birth It was found that planned preterm VBAC has c. Induction and augmentation of labor (as similar success rate to planned term VBAC but with previously discussed): Additional large a lower risk of uterine rupture. studies that distinguish between prostag- landins and oxytocin use are needed. Q.15. What are the complications in pregnancy Women with uterine rupture had a somewhat with previous cesarean sections? higher mean oxytocin dose and duration of oxytocin exposure but they were not Ans: statistically significant. 1. UTERINE RUPTURE Classification Emergency response time for vaginal birth a. Complete rupture – When all layers of the after cesarean patients in labor.13 uterine wall are separated. It includes Emergent cesarean delivery is required in extrusion of intrauterine contents into the approximately 2% of labors regardless of whether the uterus is scarred. ACOG abdominal cavity. guidelines do not mention specific time b. Incomplete or partial rupture or uterine interval. dehiscence Practice crash ceasarean fire drills with the Uterine muscle is separated but visceral goal of moving the patient to the operating peritoneum is intact. This includes extrusion room and having her ready for surgery in of intra uterine contents into the broad the shortest possible time interval. ligament. Make a crash cesarean operative tray that includes only those instruments that are SYMPTOMS needed to deliver the baby. • Pain in lower abdomen/incision site Ranging from mild to severe and sometimes as Q.13. Can external cephalic version be attemp- a tearing sensation ted in a previously scarred uterus? • Shoulder pain Ans: Role of VBAC with external cephalic • often diminish in intensity version and frequency Pregnancy with Previous Cesarean Section 139

• Dizziness and weakness a specificity of 96.8%. The positive and negative • Gross hematuria predictive values are 87.5 and 95.3% respectively.24 MRI may be helpful in assessing deep myometrial, SIGNS • As mentioned above (in the signs of scar dehis- parametrial or bladder involvement but sensitivity cence) is low. Hence, color flow Doppler is the • If it is scar rupture investigation of choice until further experience or – Tenderness over the whole abdomen refinements occur with MRI. Patient should be – Distension of the abdomen consented for possible cesarean in – Uterine contour not well made out these cases . Blood products should be immediately – Fetal parts more superficially palpated available and preferably should be done electively – Fetal heart sound absent in day time with senior obstetrician and – Bleeding per vaginum may or may not be anesthesiologist. The maternal mortality rate is as present high as 10%. – Hematuria may or may not be present – Receeding of the presenting part on per Q.17. How would you counsel the patient with vaginum the history of prior uterine rupture? MANAGEMENT Ans: The rate of repeat rupture or dehiscence in Exploratory Laparotomy followed by repair or labor is 6% if the site of ruptured scar is confined hysterectomy to the lower segment. If the upper segment is • Repair the uterine defect–If it is technically involved the rate of repeat rupture is 32%.2 Hence, feasible these patients with prior uterine rupture are best – Hemostasis can be achieved delivered by repeat cesarean as soon as fetus is – If the patient wants to retain fertility mature or at 36 to 37 weeks of gestation. These The wound should be reapproximated patients should not be allowed to go in labor. followed by closure similar to that used for 2. PERINATAL MORTALITY AND cesarean delivery. • Cesarean hysterectomy is required MORBIDITY – If extension into broad ligament vessels Planned VBAC carries a 2-3/10,000 additional risk – Uncontrollable uterine hemorrhage of birth related perinatal death when compared with – The presence of placenta accreta. elective repeat cesarean section (ERCS). It is comparable to the risk for women having their first Q.16. Discuss role of both MRI and Doppler in birth.VBAC is estimated with 10/10,000 risk of the diagnosis of morbidly adherent placenta antepartum still birth beyond 39 weeks of gestation accreta? and 4/10,000 risk of delivery related perinatal death. Ans: The risk of placenta previa accreta in a patient Incidence of intrapartum HIE is significantly with previous cesarean is as high as 30%.12 greater in planned VBAC (7.8/10,000) compared Antenatal imaging can help to establish a diagnosis with ERCS (zero rate).1 in such cases and techniques used include VBAC reduces the risk that the baby will have ultrasound imaging, power amplitude ultrasonic respiratory problems like transient tachypnea of the angiography, MRI and color flow Doppler. Doppler new born and respiratory distress syndrome (TTN/ ultrasonography gives a sensitivity of 82.4% and RDS). After birth, the rates are 2-3% with planned 140 Case Discussions in Obstetrics and Gynecology

VBAC and 3-4% with ERCS. It can be reduced if 5. Elkousy MA, Sameul M, Steven E et al.The effect of ERCS is done at 39 weeks of gestation.25 weight on vaginal birth after cesarean delivery success rate . Am J Obstet Gynecol 2003;188:824-30. 3. MATERNAL MORTALITY AND 6. Hoskin IA, Gomez JL, Correlation between maximum MORBIDITY cervical dilatation at Cesarean delivery. Obstet The vast majority of maternal deaths in women with Gynecol 1997;89:591-93. prior cesarean section arise due to medical disorders 7. Hibbard JH, Gilbert S, Landon MB, Levero KJ, Spong CY, et al. Increased success of trail of labor after such as thromboembolism, amniotic fluid previous vaginal birth after cesarean. Obstet Gynecol embolism, pre-eclampsia, surgical complications 2006;108:125-33. and uterine rupture. No statistically significant 8. American College of Obstetricians and Gynecologist. difference between planned VBAC (17/100,000) Induction of labor ACOG Technical Bulletin No 217, and ERCS (44/100,000).1 1995. Maternal morbidity is higher in women with 9. Grubb DK, Kjos SL, Paul RH. Latent labor with an unsuccessful VBAC. unknown uterine scar.Obstet gynecol 1996;88:351- 55. PENDING RELEVANT TRIALS 10. Goelze L, Shipp TD, Zelop CM, Liberman Repke and • BAC (Birth after cesarean)—Planned vaginal Ellice. Oxytocin dose and risk of uterine rupture in birth or planned cesarean section for women at trail of labor after cesarean section. Obstet Gynecol, 2001;97:381-84. term with a single previous cesarean birth, 11. Zelop CM, Shipp TD, Repke JJ, et al. Uterine rupture ISRCTN 53974531, Professor C Crowther, during or augmented labor in gravid women with one University of Adelaide, Australia. cesarean delivery. Am J Obstet Gynecol 1999;18: • The twin study multicenter randomized 882-6. controlled trials, Canada. 12. Benjamin.P, VBAC:Contemporary issues, Lippincott • DIAMOND. (Decison Aids for Mode of Next Co. Clin Obstet Gynecol 2001;44(3):553-629. Delivery) UK. 13. Flamm BL, Anton D, Goings JR, et al. Prostaglandin E2 for cervical ripening: a multicenter study of patients • CAESAR (Ceserean Section Surgical with previous Cesarean delivery. Am J Perinatol. Techniques) UK. 1997;14:157-60. 14. Plaut MM, Schwartz ML, Lubarsky SL. Uterine REFERENCES rupture associated with the use of misoprostol in the gravid patient with a previous cesarean section. Am J 1. Royal College of Obstetricians and Gynecologists: Obstet Gynecol 1999;180;1535-42. Clinical green top guidelines No.45 Feb 2007. Birth 15. Lelaidier C, Baton C, Benifla JL, et al. Mifepristone after previous cesarean birth. for labor induction after previous csarean section. 2. American College of Obstetricians and Gynaecologist. Br J Obstet Gynecol 1994;101:501-3. Vaginal birth after previous Cesarean delivery ACOG 16. Magann EF, Chauhan SP, Nevils BG, Beyond forty- Practice Bulletin No 54. Obstet Gynecol 2004; one weeks gestation with an unfavorable. AM J Obstet 104:203-12. Gynecol 1998;178:1279-87. 3. Jill G Maudin, Roger B Newman. Prior cesarean: A 17. Bujold E, Blackwell SC, Gaudier F, Kaunitz AM. Cervical Ripening with transcervical Foley catheter contraindication to Labor Indication? Lippincott Co. and the risk of uterine rupture. Obstet Gynecol Clin Obstet Gynecol 2006;49(3):684-97. 2004;103:18-23. 4. Caughey AB, Shipp TD, Repke JJ, et al. Trial of labor 18. American College of Obstetricians and Gynecologist. after cesarean delivery, the effect of previous vaginal Vaginal birth after cesarean delivery.Washington DC, delivery. Am J Obstet Gynecol 1998;179:938-41. ACOG Practice Bulletin No 5; July 1999;1017-23. Pregnancy with Previous Cesarean Section 141

19. Shipp T, Zelop CM, Repke JT, et al. Inter delivery segment to assess risk of defects of scarred uterus. interval and risk of symptomatic uterine rupture. Lancet 1996;347:281-84. Obstet Gynecol 2001;97(2):175-7. 23. Flamm BL, Fried MW, Lonky NM, et al. External 20. Ravasia DJ, Brain PH, Pollard JK. Incidence of uterine cephalic version after previous cesarean section, Am rupture among women with Mullerian duct anomalies J Obstet Gynecol 1991;165:370-72. who attempt vaginal birth after cesarean delivery. Am 24. Chou MM, Ho ES, Lee YH. Prenatal diagnosis of J Obstet Gynecol 1999;181:877-81. placenta praevia accret by transabdominal color 21. Durmold C, Nercer B. Uterine rupture, perioperative Doppler Ultrasound.Ultrasound Obstet. Gynecol and perinatal morbidity after single layer closure at 2000;15:28-35. cesarean delivery. Am J Obstet Gynecol 2003; 25. Dalziel SR, Walker NK, et al. Cardiovascular risk 189:925-29. factors after antenatal exposure to betamethasone: 22. Rozenberg P, Goffinet F, Phillippe HJ, et al. 30 year follow-up of a randomized controlled trail. Ultrasonographic measurement of lower uterine Lancet 2005;365:1856-62. Krishna Agarwal

12 Pregnancy with Previous Intrauterine Death of Fetus

Intrauterine death of the fetus is a difficult situation • Any medical problem like hypertension, for both the couple as well as the treating diabetes mellitus, asthma, thyroid disorders, obstetrician. Intrauterine death of the fetus ( IUFD) jaundice or any other medical disorder is defined as the death of a fetus at any time after • Any history suggestive of abruption placentae the 20th week of pregnancy. • When was IUFD diagnosed? • How the deliveries took place? CASE 1 • What was the weight and sex of the baby? Mrs A, 25-year old, G4P3LO, presented with 5 • Any congenital anomaly and whether autopsy months amenorrhea and previous three was performed. intrauterine deaths. How would you manage this Personal history patient? • H/O smoking, alcoholism Pregnancy with previous recurrent IUDs is an Past history important situation where we need to establish the • History suggestive of any thrombotic disorder cause for previous IUDs. History taking, in past like deep vein thrombosis or stroke examination and investigations are important in Family history establishing the cause of previous IUFD and in • H/o any such occurrence in family management of this pregnancy. • H/o birth of any congenitally malformed baby History in the family In this particular case, since it is a case of recurrent The situation is very different in our setup, IUFD, history of previous pregnancies in detail is generally the couple does not remember any of the very important to establish the cause. events and either the earlier pregnancies were Obstetric history: Following history is asked for unsupervised or they have lost all the papers. each pregnancy: So we have to mainly depend on the examination • Was it a spontaneous conception? and investigations. • Any history of rash or fever. • History of pregnancy induced hypertension, Q.1. What is the etiology of IUFD? preeclampsia or eclampsia, gestational Ans: IUFD may occur during pregnancy or during diabetes labor. Generally, the cause of IUFD is different in Pregnancy with Previous Intrauterine Death of Fetus 143 antepartum period from that of intrapartum period. IUFD. The first infection results in subsequent Antepartum IUFD may occur in following protection against maternal and fetal infections. situations:1 Maternal syphilis is another important cause for 1. Genetic abnormalities IUFD. 2. Infections-viruses, bacteria, protozoa or spirochetes On history, the patient says the IUFDs were at 3. Placental abruption around eight month period of gestation with 4. Medical conditions-preeclampsia, diabetes spontaneous onset of labor. All were singleton mellitus, thyroid disorders, SLE, intrahepatic pregnancies with macerated stillbirth and the cholestasis of pregnancy and chronic liver weight of the babies is not available and there were disease. no congenital malformations in any of the fetuses. 5. Multifetal pregnancies There is no history suggestive of any medical 6. Antiphospholipid antibody syndrome (acquired disorder in the mother. thrombophilia) Detailed examination is performed. 7. Inherited thrombophilia Thorough general physical examination and Q.2. What are the genetic abnormalities systemic examination is done. Important points to responsible for IUFD? be kept in mind are: • BMI is important. The malnourishment and Ans: Chromosomal anomalies are responsible for obesity both have been associated with adverse around 6-12% of IUFD.2 The most common among pregnancy outcomes. these are aneuploidies and the most common • Look for anemia, jaundice, cyanosis, clubbing aneuploidies are trisomies (trisomy 21, 18 and 13). • Thyroid swelling A genetic abnormality which is confined to placenta • Look for hepatosplenomegaly with normal fetal karyotype (known as confined Detailed obstetric examination is performed for placental mosaicism, CPM) is responsible for fetal growth. severe IUGR and IUFD. On examination, the patient is average built and Q.3. Which infections can cause IUFD? height, with mild IUGR. Ans: 10-25% of IUFD occur because of the maternal infections.3 The most important causes for recurrent IUFD are Cardiovascular sequelae of some infections like diabetes, thyroid disorder, antiphospholipid maternal influenza, dengue, chicken pox, and polio antibody syndrome, SLE, thrombophilias and lead to IUFD. syphilis. Therefore, patient would be investigated However, infection with malaria leads to for these conditions. infection of placenta and placental insufficiency The investigations are: resulting in IUFD. Routine investigations- Parvovirus infects the fetus through membranes 1. ABO grouping and cross-matching and results in fetal organ damage, nonimmune 2. Hemogram peripheral smear, platelet count hydrops fetalis and IUFD. Exposure of a nonimmune 3. Serum VDRL mother results in maternal infection in 25% of cases. 4. HIV Out of these, 30% will pass the infection to fetus, 5. HbsAg only 10% will develop hydrops and 1% will have 6. Urine R/M and culture 144 Case Discussions in Obstetrics and Gynecology

Special investigations • Through antibodies directed against the 1. Glucose tolerance test (GTT) - undiagnosed substrates of activated protein C thus preventing diabetes is an important cause of unexplained them from inactivation. third trimester IUFD. The reason for fetal demise is hyperglycemia, ketoacidosis, Q.7. What is thrombophilia workup? congenital anomalies and infections. Ans: For detection of maternal inherited 2. Thyroid profile - hypothyroidism has been thrombophilia (1) following investigations are done:1 implicated to increase pregnancy complications including stillbirths. Even subclinical Detection method hypothyroidism has been found to increase the Factor V Leiden (FVL) PCR risk of abruption and preterm birth. mutation 3. Antiphospholipid antibodies Prothrombin 20210A PCR mutation 4. Thrombophilia work up Hyperhomocysteinemia ELISA The last two investigations are performed if Antithrombin deficiency Functional assay with a cut off GTT and thyroid profile are normal. of <60% Protein S deficiency Measure total free antigen Q.4. What are the antiphospholipid antibodies? with a cut off of <45% during Ans: These are anticardiolipin antibodies (ACA) pregnancy and lupus anticoagulant (LA). These are immuno- Protein C deficiency Functional assay with a cutoff globulins directed against proteins bound to of <50% negatively charged phospholipids. Protein Z antigen ELISA

Q.5. What is antiphospholipid antibody Q.8. What is the role of inherited thrombophilia syndrome? in causing IUFD? Ans: Clinically, it is defined as presence of venous Ans: Combined thrombophilic defects exert a or arterial thrombosis, intrauterine fetal death in greater influence on fetus as compared to isolated second or third trimester, or thrombocytopenia, thrombophilia.4 Association is most strong with combined with laboratory evidence of presence of FVL resulting from point mutation in factor V gene. anticardiolipin antibodies or lupus anticoagulant in The European Prospective Cohort on maternal serum.1 Thrombophilia Study showed two times increase in risk of IUFD in subjects with combined Q.6. How antiphospholipid antibody syndrome thrombophilic defects and antithrombin deficiency. causes IUD? Ans: Antiphospholipid antibodies cause placental Q.9. Which subjects would you like to screen thrombosis and IUFD by various mechanisms: for thrombophilia? • Interference with prostacyclin and thromboxane Ans: balance • History of unexplained IUFD in second or third • Interference with activation of protein C trimester • Inhibition of activity of protein C directly or • History of recurrent severe preeclampsia or through its cofactor protein S HELLP Pregnancy with Previous Intrauterine Death of Fetus 145

• H/O unexplained abruption In this case, the history suggested the pregnancy • Personal/family h/o thrombosis was post-dated with intrapartum birth asphyxia. From the history, it is revealed that the labor On investigations, this patient has found protein S was prolonged therefore it is important to know deficiency how will you proceed? the cause for prolonged labor. We have to rule out Studies have revealed that treatment with low cephalopelvic disproportion and uterine molecular weight heparin and low dose aspirin incoordinate activity. reduces the recurrence risk of fetal loss.1 Treatment Q.12. How are you going to manage the case? is started early in pregnancy and continued throughout pregnancy. Ans: The patient is monitored strictly by DFMC, NST and biophysical profile. If everything is Q.10. How would you monitor the patient? normal patient can be induced after 39 completed Ans: In patients with previous IUFD increased weeks. She is not allowed to go postdate. fetal surveillance increases the chance of fetal Cephalopelvic disproportion should be ruled out. survival. When to start monitoring would depend During labor, patient is considered as a high-risk upon the maternal age and the gestation at patient and strict monitoring of FHR and progress previous IUFDs. Usually, it is started at 32 weeks of labor should be done. but started earlier in patients with IUGR. Partogram is maintained in active labor. Surveillance includes: CASE 3 • Daily fetal kick count-started at 28 weeks • USG scan for fetal growth- every 2 weeks Mrs C G3P2L1 presented with 9 months ameno- • NST- twice weekly rrhea with history of previous IUD. • Biophysical profile- twice weekly History is taken to know about the cause of previous IUD. Q.11. When would you terminate the Previous pregnancy was an unbooked pregnancy? pregnancy and patient presented at term in Ans: Pregnancy is terminated at 39 weeks or at spontaneous early labor. During labor, she had a 37-38 weeks after confirmation of fetal lung gush of leaking and the cord prolapsed. She maturity. delivered after 2 hours an average-sized fresh still born baby. CASE 2 From the history, it is revealed there was cord Mrs B G2P1LO presented with 9 months prolapse during labor which resulted in fresh amenorrhea with history of previous IUD. stillbirth. The reason for prolapse of cord is usually contracted pelvis, hydramnios or cephalopelvic History is taken to know about the cause of disproportion leading to non-engagement of fetal previous IUD. head, malpresentations and malpositions. This was an intrapartum death when patient During labor, the uterine contraction-force is was in spontaneous labor. She had labor for 40 directed to the loose fetal membranes overlying hours, there was thick meconium stained liquor cervix. It results in early rupture of membranes and and baby was fresh stillborn. cord prolapse. 146 Case Discussions in Obstetrics and Gynecology

Q.13. How are you going to manage the case? as the importance of blood sugar level control. She Ans: Since patient is in labor, complete general is advised diabetic diet with total calorie intake of physical, systemic and obstetric examination 30 kcal/ kg of body weight and total calorie performed to rule out contracted pelvis and requirement is divided into 3 major and 3 minor cephalopelvic disproportion. Obstetric exami- meals covering the whole day. 5 nation is performed to know the size of the fetus, Patient advised following investigations: lie and engagement of fetal head. Pelvic • Glycosylated Hb–Done in the first trimester. examination is carried out for adequacy of pelvis, • Glucose profile-performed every week. 7 values dilatation and effacement of cervix and station of including fasting, 1 hour post-breakfast, fetal head. If cephalopelvic disproportion ruled prelunch, 1 hour post-lunch, predinner, bed time out, patient is allowed for spontaneous labor, and at 2 am. maintaining partogram. Patient kept in lateral The target levels of patient monitored capillary position and under continuous CTG monitoring blood glucose levels are: if available. Fasting:-60-90 mg/dl Premeal:-60-105 mg/dl CASE 4 Postprandial 1 hour:-140 mgm% 2 am-6 am:-60-120 mg/dl Mrs D G3P2LO presented with 2 months • First trimester and second trimester ultrasound amenorrhea with history of previous IUD. screening for congenital anomalies. Detailed history is taken to know about the cause • Maternal serum alpha-fetoprotein at 16 weeks of previous IUDs. • Fetal echo at 20-24 weeks The first pregnancy was an unbooked • Maternal fundus examination for retinopathy pregnancy, in the 9th month of pregnancy she • Fetal surveillance in addition to above had loss of fetal movements for 2 days and investigations delivered stillborn baby at home. The baby was – Daily fetal movement count started at of good size and there were no congenital 28 weeks anomalies according to patient. Second – Biweekly nonstress test and weekly pregnancy was again an unbooked pregnancy. At biophysical test started at 28 weeks in 9 month of pregnancy, she was diagnosed to have patients on insulin or at 36 weeks in patients IUFD and delivered a macerated baby after on diet control. 4 days. • At 36 weeks fetal weight estimated by ultrasound. Q.14. How are you going to manage the case? The 7-value glucose profile performed after 7 Ans: This patient should be investigated with days and if blood glucose is not controlled, patient routine investigations and 100 g oral GTT and should be switched over to insulin therapy. thyroid profile. Patients of GDM on diet can carry pregnancy On GTT, the 1 and 2 hour plasma glucose up to 40 weeks but in this case since she had an values were 200 mg/dl and 160 mg/dl respectively. IUD at 9 months amenorrhea, the obstetrician The patient explained about effects of high would feel safer to deliver her once fetal maturity blood sugar levels on herself and the fetus as well is certain. Pregnancy with Previous Intrauterine Death of Fetus 147

REFERENCES 4. Rey EKahn SR, David M, Sherier I: Thrombophilic 1. Michael J, Paidas, Nazli Hossain. Embryonic and Fetal disorders and fetal loss: A meta-analysis. Lancet Demise. In Creasy and Resnik’s Maternal-Fetal 2003;361:901-8. Medicine. 6th edn. 2009;619-34. 5. Diabetes. In Williams Obstetrics. F Gary Cunningham, 2. Wapner RJ, Lewis D: Genetics and metabolic causes Kenneth J Leveno, Steven L Bloom, John C Hauth, of stillbirth. Semin Perinatol 2002;26:70-4. Larry C Gilstrap, Katherine D Wenstrom. 22nd edn. 3. Fretts RC:Etiology and prevention of stillbirth. Am J Obstet Gynecol 2005;193:1923-35. 2005;1169. Poonam Sachdeva, Chanchal Gupta, Jyoti J Banavaliker 13 Preterm Labor

DEFINITION • Any history of trauma, blow over abdomen. Preterm labor is defined as presence of uterine • Any history of coitus recently (Sometimes contraction of sufficient frequency and intensity to coitus can initiate uterine contractions). cause progressive effacement and dilatation of • Confirmation of dates and maturity is important cervix before 37 weeks of gestation. If uterine to rule out any wrong dates. contractions are perceived in the absence of cervical • Any history of dragging sensation or heaviness changes, the condition is called threatened preterm in lower abdomen or menstrual like cramps. labor. • Any history of labor pains prior to that or any The incidence of preterm birth ranges from 10- drug intake for the same complaints. 15% of all deliveries. Preterm birth leads to Obstetric history perinatal morbidity and mortality. Neonatal • In multipara history of previous recurrent mortality rate varies from 5/1000 babies in USA to abortions especially second trimester (spon- 40-150/1000 birth in India.1 taneous or induced) or previous history of CASE preterm labor. Mrs X 32 years old G3P+0+1+0+1 with 32weeks • Short intervals between two pregnancies(less pregnancy presented to the Gynecological than 12 months) are more prone to preterm casualty as unbooked patient with complaints of labor. pain in lower abdomen for last 4 hours, pain is Menstrual history: Any history of prolonged or dull in nature, coming at half hourly interval, also short cycles for ascertaining maturity of the fetus. associated with tightening of the abdomen; there Past medical history: History of hypertension, are no relieving or aggravating factors. diabetes, renal disease, heart disease, asthma, Points to be noted in history thyroid disease or severe periodontal disease or any • History of perception of normal fetal move- other chronic illness can predispose to preterm ments. labor. • Any history of bleeding, leaking or foul smell- Past Surgical history: Any history of cervical ing discharge per vaginum. conization or in multipara history of cervical • Any history of fever. encerclage is to be elicited. • Any history suggestive of urinary or bowel Personal history: History of any alcohol or drug complaints. abuse or smoking is associated with higher Preterm Labor 149 incidence of preterm labor. Any history of domestic On Per vaginum examination: Cervix is 2 cm violence especially injury due to physical abuse is dilated, 80% effaced, soft, central, appears associated with preterm birth. membranes present, head at -3 station, Pelvis Occupational history: Long hours of standing, gynecoid and adequate for vaginal delivery. physical fatigue during work and high stress jobs Diagnosis- Early Preterm labor are strong predictors of labor. Dietary history: Patient with poor nutritional status • Early preterm labor is when on digital exami-nation is more prone to preterm labor. cervix is more than 1 cm but less than 3 cm dilated Socioeconomic history: Patient with low and more than 80% effaced in a patient with socioeconomic status is more prone to preterm preterm labor pains. labor. • Advanced preterm labor is when cervix is 3 or more cm dilated in a patient with preterm labor pains. • Threatened preterm labor is when digital exami- Q.1. What are the important points to be noted nation reveals cervix < 1 cm dilated and < 80% on examination? effaced and cervical length on ultrasound is < 2.5 Ans: cm. • Built and nutrition (Thin built and poor nutrition • False labor pains are when cervix is < 1 cm dilated and < 80% effaced on digital examination and are more prone to preterm labor). cervical length on ultrasound is > 2.5 cm. • Height, weight and BMI –(BMI<19.8 is associated with more risk of preterm labor). Q.2. What would be the management of this • Pulse, BP, Temperature (infections can lead to case? preterm labor). • Pallor, pedal edema, icterus, thyromegaly and Ans: lymphadenopathy. A. This patient should be admitted to labor ward: • Chest and CVS examination. • Adequate rest should be advised. Per abdomen examination of the above patient • Reassurance and counseling regarding risk Mrs X revealed following findings: of preterm delivery. On Inspection: Abdomen is uniformly distended, • Prognosis of preterm baby to be explained umbilicus is inverted, striae gravidarum and linea in writing. nigra are present. No scar marks, no obvious • Pulse and temperature charting should be pulsations and peristalsis. Hernial sites are free. done. On Palpation: Fundal height is corresponding to • Frequency and intensity of uterine contrac- 32 weeks pregnancy. tions is to be monitored. Symphysio fundal height is 32 cm. B. Investigations: By all grips fetus is in longitudinal lie and • Hb, TLC, DLC cephalic presentation. • ABO Rh Uterine contractions are present, coming at an • Routine antenatal investigations –CGI, STS, interval of 20 min and each contraction lasting for HIV, HBsAg, urine for routine and micro- 15 seconds, there is no uterine tenderness. scopy On Ascultation: Fetal heart rate is 144/min regular • C Reactive Protein (CRP)—(>3-4 mg/dl auscultated in left spino umbilical line. indicate infection) On per speculum examination: No leaking or • Urine for culture and sensitivity bleeding is observed, Cervix is patulous and central • High vaginal swab for microscopy and in position. culture sensitivity 150 Case Discussions in Obstetrics and Gynecology

• Vaginal fluid for pH 1. Steroids: Steroid administration reduces the • CTG tracing for fetal heart rate pattern incidence and severity of respiratory distress • Ultrasonography: For fetal growth, syndrome and hence reduces neonatal morbidity morphology, estimated fetal weight, amount and mortality. of liquor, location and grade of placenta (any Dose: Inj. Betamethasone 12 mg 2 doses decreased liquor or prematurely calcified 24 hours apart or Inj. Dexamethasone 6 mg 4 placenta may be suggestive of placental doses 12 hours apart. insufficiency as cause of preterm labor). Delivery should be delayed by tocolysis for C. Management: After detailed history and examination one minimum 12 hours for maximum effect of should look for any indication of termination steroid, although optimal benefit begins 24 of pregnancy given in the Box 13.1. hours after therapy and lasts for seven days. Benefit of repeated courses of glucocorticoids Box 13.1: Iindications of termination of pregnancy is doubtful and not currently recommended.6,7 in patient with early preterm labor 2. Tocolytic agents: Maintenance tocolysis is not 1. Features of choriamnionitis – occurs in 0.5-1.0% recommended in routine practice. Various of all pregnancies. Patient would present with: tocolytic agents are described. • Tachycardia (p >100/min) Before starting tocolytic agent one should rule • Fever (>100°F) out any contraindication to tocolytic therapy • Fetal tachycardia (>160 bpm) given in Box 13.2. • Uterine tenderness • Foul smelling discharge Box 13.2: Contraindications of tocolytic therapy • TLC>15000 cell/mm3 • CRP >3-4 mg/dl 1. Advanced labor (cervix >4 cm dilated) • Increased IL-6 in amniotic fluid3 2. Features of chorioamnionitis. 2. Adequate lung maturity by L:S ratio or POG 3. Severe preeclampsia and eclampsia. >34 weeks 4. Abruptio/placenta praevia with hemodynamic 3. Nonreactive nonstress test or repeated severe instabilities. variable decelerations 5. Acute fetal distress 4. USG suggestive of congenital anomalies, severe 6. Fetal demise (singleton)/congenital IUGR or oligohydroamnios or severe placental malformations. insufficiency. 7. Fetal maturity (>34 weeks) 5. Associated complicating factors like-Abruption, 8. Hyperthyroidism uncontrolled DM 9. Severe anemia

If there are any indications of termination of Nifedepine: It is a calcium channel blocker and pregnancy, one should allow the labor to continue safe and effective tocolytic. It is considered the best as preterm labor is protective mechanism for fetus first line tocolytic agent and is recommended by threatened by problems like infection, placental RCOG as the first line treatment in preference to β insufficiency or abruption. Steroids to be started to accelerate pulmonary maturity. mimetics. If there are no indications of termination of Dose is 20-30 mg orally stat followed by same pregnancy the patient should be managed dose after 30 min if contractions persists and conservatively till fetal lung maturity or 34 weeks maintain at 10-20 mg 6 hourly for 48-72 hours. POG on following: Maximum dose is 160 mg in 24 hours. Preterm Labor 151

Main side effect is maternal hypotension, tachy- Patient on oral β adrenergic therapy should be cardia, headache, dizziness and facial flushing. monitored with pulse rate and the next dose should The patient is monitored with pulse rate prior be postponed till the pulse rate is less than 100 to each dose of medications and new dose is beats/min. When the pulse rate is more than 120 postponed if the pulse rate is more than 100 beats/ beats/min, 90% of the β adrenergic receptors are min. saturated hence an additional dose will not be Contraindications of nifedepine are maternal beneficial for the patient, rather the possibility of cardiac disease, maternal hypotension (<90/50 mm serious side effects is increased (Boxes 13.3 and Hg). It should be used cautiously in renal 13.4). compromise. Its concomitant use with Magnesium Box 13.3: Recommended guidelines for monitoring sulphate should be avoided. IV β agonists Maternal tachycardia > 120 bpm, BP < 100/60 mm Hg, pulse oxymetry <95% or fever are reasons Monitoring: to discontinue the treatment. • Maternal Pulse and BP every 15 min • Chest auscultation every 4 hours Other tocolytics which can be prescribed are • Strict intake and output chart for fluid balance 2 Betamimetic agents: available drugs are • Urea, electrolytes, and hematocrit every 24 hours terbutaline, ritodrine and isoxsuprine. • Maternal blood glucose every 4 hr i. Terbutaline can be given as 0.25 mg S/C every 20 min to 3 hours, dose is to be omitted Box 13.4: Contraindications to the use of IV if pulse rate is >120 beats/min. Beta adrenergic agents Side effects of terbutaline are cardiac • Symptomatic heart disease especially outflow arrhythmias, pulmonary edema, myocardial obstruction ischemia, hypotension, tachycardia, shortness • Symptomatic cardiac rhythm and conduction of breath, hyperglycemia, hyperinsulinemia, disturbances antidiuresis, altered thyroid function, hyper- • Sickle cell disease kalemia, hypokalemia, tremor, nervousness • Hyperthyroidism and nausea or vomiting,. • Uncontrolled insulin dependent diabetes Fetal side effects are fetal tachycardia, hyper- • Patients on monoamine oxidase inhibitors for insulinemia and fetal hyperglycemia. psychiatric treatment ii. Ritodrine: 2 ampules (100 mg) in 500 ml of • Relatively contraindicated in asthmatics 5% Dextrose @5 drops/min (0.05 mg) and Magnesium sulphate: 4-6 gm IV over 20 min. increasing by 5 drops/min every 15 min. up followed by 2-3 g/hr as continuous infusion. to 15 drops/min. Magnesium sulphate being highly toxic is Effective dose is 0.05-0.15 mg/min and maxi- monitored with urine output charting (25-30 ml/ mum up to 0.30 mg/min. hr), respiratory rate and deep tendon reflexes. Side effect of ritodrine is maternal halluci- nations. Nitroglycerine: Is the tocolysis of choice in case iii. Isoxsuprine: 4 ampules (40 mg) in 500 ml of an emergency, used as IV 100 μg bolus followed of 5% Dextrose by IV infusion @1 μg/kg/min. It can also be used 0.2-0.5 mg/min IV over 10 hours followed as transdermal patch 50 μg patch for 24 hours. by 0.1-0.3 mg/min IV over 12 hours. Maintain Side effects of nitroglycerine are headache and at 10-20 mg IM 6-8 hrly. maternal and fetal hypotension. 152 Case Discussions in Obstetrics and Gynecology

Diazoxide: It is structurally related to thiazide 6 mg/hr for up to 45 hours. Total duration of diuretic and acts by inhibiting contractility of treatment should not exceed 48 hours and the total arterial and venous smooth muscles. Dose- 5 mg/ dose not be more than 330 mg of atosiban. kg slow IV over 15-30 min. Side effects of atosiban can be chest pain, Side effects are tachycardia, hypotension and palpitations, tachycardia, hypotension, dyspnea, decreased uteroplacental blood flow. nausea, vomiting and headache (Evidence level Ia). Trials of the drug were carried out in UK and NSAIDs: Indomethacin, ketorolac and sulindac are the drug is licenced for usage in Europe and is the NSAIDs which can be used as tocolytics. currently not available in India. Indomethacin is preferably used in preterm 3. Antibiotics: Antibiotics in case of preterm labor labor associated with polyhydramnios. Dose is are recommended for – 100mg per rectal followed by 50mg orally every Prevention of group B streptococcus infection 6-8 hrly. in fetus, Prophylaxis for genital tract infections Potential fetal adverse effects include premature mainly . closure of the ductus arteriosus, necrotizing Antibiotics of choice in this case is Inj. enterocolitis, respiratory distress syndrome and Penicillin 5 million U IV followed by 2.5 mU bronchopulmonary dysplasia and potential every 4 hours after sensitivity testing till increased risk of development of periventricular delivery. Due to highly allergic reaction to leukomalacia. penicillin group of drugs, combination of Inj Ketorolac: Dose is 60 mg IM then 30 mg IM Clinda-mycin 900 mg IV 8 hrly and 6 hrly. It is contraindicated in active peptic ulcer Erythromycin 500 mg every 6 hrly is preferred. disease. Due to increased number of reports of resistance Sulindac: Dose is 200 mg orally every 12 hrly. of GBS to both erythromycin and clindamycin, It is contraindicated in coagulation disorders or Inj. cefazolin is the best choice.3,4 The dose is thrombocytopenias or any sensitivity to NSAIDs. 2 gm IV followed by 1 gm IV 8 hourly. Side effects of NSAIDs are nausea, heartburn 4. Treatment of associated infections – 5-10% gastritis, proctitis with hemalochezia, impairment of patients in preterm labor may have infection of renal function, increased postpartum hemorr- outside uterus, mostly in the urinary tract and hage, heartburn, headache, dizziness and depres- they should be treated by appropriate anti- sion. biotics. In fetus they may cause constriction of ductus 5. Intrapartum management – If inspite of arteriousus, pulmonary hypertension, reversible tocolytic therapy, labor progresses, then labor decrease in renal function with oligohydramnios, should be allowed. Aim of management is to intraventricular hemorrhage, hyperbilirubinemia, prevent asphyxia and birth trauma. Patient and necrotizing enterocolitis. should be delivered in place where adequate Oxytocin antagonist: Atosiban is an oxytocin facility for premature neonate is present. antagonist. It is recommended by RCOG as a first First stage line agent in the management of preterm labor • Bed rest to prevent premature rupture of though its cost may be a factor to preclude its use membrane. in developing countries. • Delivery by LSCS not preferred as there is no Dose: 6.75 mg IV stat over one minute followed difference in frequency of periventricular- by an infusion of 18 mg/hr for 3 hours and then intraventricular hemorrhage. Preterm Labor 153

• Strong sedatives and oxytocics are avoided. • Cervical incompetence, . • Intensive clinical monitoring with CTG is ideal. • Multiple pregnancies. • Repeat digital examination is to be avoided to • Medical problems (pre-eclampsia, DM, asthma, increase risk of infection. thyroid disease, cardiac diseases). • Epidural analgesia can be given • Chorioamnionitis. • Extrauterine infections (5-10%). Second stage • Drugs and alcohol in pregnancy. • Delivery should be attended by Obstetrics and Pediatrics registrar. Methods to identify women at risk of preterm • Episiotomy is recommended especially in birth are primigravida to minimize head compression. 1. Questionnaire evaluation of above mentioned • Prophylactic forceps should not be used. risk factors • Immediate cord clamping should be done to 2. Home uterine activity monitoring (HUAM): prevent hypervolemia to baby. It has been tried in women with risk markers • Role of Inj. Vit K is controversial for prevention for preterm labor. This system provides of IVH. recording and transmission of uterine activity by a device called tocodynamometry and giving Q.3. How would you manage a patient in feedback to the health practitioner on daily advanced preterm labor? basis. Though it has been described in European Ans: Patients in advanced preterm labor are to be literature, the method is not yet available in assessed for any indication of termination of India. A large trial on 2422 patients showed no pregnancy as given in Box 13.1. In those conditions, benefit in predicting preterm labor. Hence this labor should be allowed. If there are no contra- method cannot be recommended in routine indications to conservative management patient can clinical practice.9 be put on tocolytics, steroid and antibiotics. If labor 3. Cervicovaginal fibronectin levels (fFN):5 It pains subside, patient can be put on expec-tant is a basement membrane protein which is management. normally secreted by chorionic tissues and acts as glue between chorioamnion and deciduas. It Q.4. What are the risk factors for preterm labor is present in cervicovaginal secretions up to and what are the methods to identify women at 16-22 weeks, then disappears and reappears risk of preterm birth? after 37 weeks till labor. Presence of fFN in Ans: Risk factors of preterm labor include: cervical secretions after 24 weeks of pregnancy • Lower socioeconomic status may indicate disruption between decidua and • Extremes of maternal age < 17 yrs and > 35 chorioamnion. The test is performed by taking yrs. swab from ectocervix or posterior vaginal wall, • Stressful maternal conditions. ELISA done to detect fetal fibronectin. It has • Low pre-pregnancy weight. got a negative predictive value of 99.7% and a • Low BMI. positive predictive value of 14.7%. This test has • Poor nutritional status. a value in excluding risk of preterm delivery • Previous history of preterm birth, multiple within 2-3 weeks. Its presence between 24-37 induced 2nd trimester abortion (2 fold increase weeks is an important marker of preterm labor. in risk). A negative fFN test rules out an imminent 154 Case Discussions in Obstetrics and Gynecology

preterm delivery whereas implication of a Attempts have been made to screen for bacteria positive test is uncertain. in the vagina so that antibiotic treatment can be 4. Salivary estriol levels: Premature activation of given to prevent infection and hence preterm fetal hypothalamo-pituitary-adrenal axis may labor. Most commonly involved organisms are result in increase in production of estriol from group B streptococcus, Chlamydia trachomatis, placenta and hence increase in serum and Ureaplasma urealyticum, Mycoplasma hominis salivary levels of estriol can predict preterm and Fusobacterium species. labor. Maternal estriol has diurnal variation and is suppressed by betamethasone given to affect Q.5. What are the warning symptoms and signs surfactant production, therefore has got low of preterm labor? positive predictive value. However, this test also Ans: In most of the patients who develop preterm has poor sensitivity and specificity and high labor, some of the patients may develop warning false positive rate. symptoms several days or weeks before the regular 5. Cervical length measurement by endo- contractions, though these warning symptoms are vaginal USG: Short cervical length < 25 mm nonspecific and should not be disregarded as a is taken as a cut off for short cervix predicting minor complaint or may be attributed to round preterm labor; It has positive predictive value ligament pain or gastrointestinal flu. Warning of 14% and high negative predictive value of symptoms and signs can be: 97%. There is no evidence to support routine 1. Menstrual like cramps—off and on or cervical assessment using ultrasound between constant. 24-28 weeks for predicting preterm labor, 2. Dull low backache—off and on or constant. however combination of ultrasound with fFN 3. Pressure sensation as if baby is pushing down. may help in predicting preterm delivery in high 4. Abdominal cramping with/without diarrhea. risk women. 5. Increase or change in the which may be watery, thick or bloody. Table 13.1: Combination of cervical length assess- 6. Leaking per vaginum. ment and fFN in predicting recurrent risk of preterm delivery9 7. Uterine contractions. 8. Short cervix. Cervical length Recurrent risk of 9. Lower uterine segment thinned (developed). preterm delivery 10. Presenting part deep in the pelvis. Cervical length fFN positive fFN negative <25mm 65% 25% 26-35mm 45% 14% Q.6. What are the various tests for assessing fetal >25mm 25% 7% lung maturity? Ans: The various tests are done on amniotic fluid 6. Search for vaginal infections: Bacterial collected on amniocentesis. These tests may be vaginosis (BV) refers to alteration of normal required to be done when maturity of the fetus is in bacterial flora of the vagina where lactobacilli doubt and termination of pregnancy is required to are replaced by anaerobic infection. BV may be done. be present in 10-25% of pregnant women and a. L:S Ratio, i.e. lecithin to sphingomyelin ratio half of these women are asymptomatic. An in amniotic fluid. A ratio of 1.8 or more is an association has been found between BV and indicator of fetal lung maturity in 95% of fetuses preterm labor, it increases the risk by two fold. for absence of HMD (hyaline membrane Preterm Labor 155

disease). However, false positive results can be to achieve alcohol concentration ranging from there in 5% of cases. L:S ratio is not informative 44-50%. The chances of developing RDS is if amniotic fluid is contaminated with blood or 0.35% if the bubbles are produced when the meconium. ethanol concentration is 47%. b. Phosphatidylglycerol (PG): The 5% false h. Tap test: One ml of amniotic fluid is added to positive result of L:S ratio can be decreased by one drop of 6N HCl and 1.5 ml of diethyl ether. simultaneously determining the presence of PG Bubbles are created after briskly tapping the in the amniotic fluid. Presence of PG in the test tube. In mature fetus the bubbles will rise amniotic fluid is a marker of final biochemical to the surface and break down. If the fetus is maturation of the fetal lungs. immature the bubbles are stable or break down c. Dipalmitoylphosphatidyl Choline(DPPC): It slowly. The test has an excellent positive is the main component of pulmonary surfactant predictive value up to 100% but a negative test and is not present in the blood or meconium or is not a good predictor of fetal lung immaturity. in vaginal secretions so when the amniotic fluid is contaminated with blood or meconium, Q.7. What is the role of steroids in management quantitative measure of DPPC should be used of preterm labor? instead of L/S ratio to assess fetal pulmonary Ans: Glucocorticoid administration is reco- maturity. DPPC > 500 μgm/dl is predictive of mmended for gestation age between 24-34 weeks. fetal lung maturity. It was introduced in 1972 for enhancing fetal lung d. Fluorescent polarization: This test measures maturity and preventing respiratory distress the micro viscosity of the amniotic fluid syndrome and neonatal mortality.6 It stimulates phospholipids in fluorescence polarization differentiation of epithelial cells into type II units, although the test is unreliable if the pneumocytes and synthesis and release of surfactant amniotic fluid is contaminated with blood or from type II pneumocytes into alveolar spaces. meconium. Besides lung maturity steroid causes decrease in e. Amniotic fluid optical density at 650 nm will water loss from skin, decrease in chances of accurately predict mature L/S ratio in 92% of necrotizing enterocolitis and intraventricular the cases. Values between 0.1-0.2 should be hemorrhage. Delivery should be delayed for evaluated with additional fetal lung maturity minimum 12 hours for maximum effect of steroid, tests. although optimal benefit begins 24 hours after f. Shake test: It estimates qualitatively the therapy and lasts for seven days. Benefit of repeated stability of the bubbles that are formed after courses of glucocorticoids is doubtful and not shaking a mixture of amniotic fluid with currently recommended.6,7 ethanol. The test is easy to perform and the accuracy is close to 100%, but a negative test is Q.8. What is the role of infection in onset of not a good predictor of pulmonary immaturity. preterm labor? A negative test is to be confirmed by further Ans: There is strong evidence that infection plays testing. a role in pathogenesis of preterm labor. Three lines g. Foam stability index (FSI): The test is a of evidence that support the role of infection in semiquantative measurement of the surfactant onset of preterm labor are:10 present in the amniotic fluid. Amniotic fluid is • Abortion or labor is induced by administration mixed with ethanol in the necessary amounts of bacteria or bacterial products in animals. 156 Case Discussions in Obstetrics and Gynecology

• Systemic infections in the patient like pyelo- another third is associated with preterm premature nephritis, pneumonia, malaria and typhoid fever rupture of the membranes and the remaining third are associated with the onset of preterm labor. results from delivery of the preterm baby due to • Intrauterine infections are associated with onset maternal or fetal indications (preeclampsia, of preterm labor and delivery. eclampsia, IUGR). Microorganisms may gain access to the The prevalence of is also higher amniotic cavity and the fetus via any of the in women delivering preterm as compared to term. following pathways. The prevalence of neonatal sepsis is 4.3 per 1000 • Ascending from the vagina and the cervix. livebirths as compared to 0.8 per 1000 livebirths in (most common route). term fetus. The overall mortality rate of neonates • Transplacental with congenital neonatal sepsis ranges between • Retrograde from the peritoneal cavity through 25-90%. the fallopian tubes. • Iatrogenic introduction at the time of procedures Q.9. What are the neonatal complications of a like amniocentesis, chorionic villus sampling, preterm baby? percutaneous fetal blood sampling. Ans: The definitive test for the diagnosis of an intra- 1. HMD: See below uterine infection is a positive microbiological 2. Hypoxia-ischemia in the preterm is characte- culture for microorganisms that can be either intra- rized by necrosis of periventricular white matter. amniotic or extra-amniotic. Amniotic fluid sample Preterm infants are more severely affected by can be obtained from the amniotic cavity but it is hypoxia and acidosis than the fetus at term. not easy to obtain material from decidua (extra- 3. Hypothermia Preterm infant is more prone to amniotic). Therefore practically, most studies in hypothermia. patients with preterm labor have focused on 4. Intraventricular hemorrhage (IVH): The most amniotic fluid culture obtained by transabdominal common site is subependymal germinal matrix. amniocentesis. The severity of IVH is estimated by USG and The term ‘clinical chorioamnionitis’ is des- CT scan of the fetal head and depends on the cribed as a clinical syndrome associated with characteristics of the bleeding. microbial invasion of the amniotic cavity. Studies Grade I-bleeding is confined to the germinal have shown that only 12.5% of women with preterm matrix. labor and intact membrane with positive amniotic Grade II-bleeding is extending to the lateral 10 fluid culture have clinical chorioamniotic as ventricles. compared to 32.4% positive amniotic fluid cultures Grade III is IVH with ventricular enlargement. in women in preterm PROM. Grade IV is bleeding in the cerebral paren- The most common microorganisms isolated chyma. from amniotic cavity of women with preterm labor The incidence of IVH and grade I to grade III and intact membranes are: Ureaplasma urealyticum, or IV is related to active phase of labor rather fusobacterium species, Mycoplasma hominis. In than the route of delivery. Mild-to-moderate 50% of the patients, more than one microorganisms degree of IVH is associated with good prognosis are isolated from amniotic cavity. and recovery without neurological sequel. Of all the preterm deliveries one third is asso- Severe bleeding is usually fatal and survivors ciated with preterm labor with intact membranes, frequently develop hydrocephaly. Preterm Labor 157

5 Sepsis: The common types of infections features appear abruptly few (4-6) hours after birth. in preterm infant are bronchopneumonia, Clinical features include hyperventilation, respi- meningitis and gastroenteritis. ratory rate>60/min, nasal flaring, rib retraction, 6. Jaundice: Because of immature liver function, expiratory grunt, cyanosis. the bilirubin produced by hemolysis cannot be X-ray shows a ground glass appearance due to conjugated adequately leading to rise in severe atelectasis. unconjugated bilirubin which results in Meconium aspiration syndrome, pneumo- exaggerated physiological jaundice. The level thorax, diaphragmatic hernias, congenital heart however may rarely be raised to toxic level disease, are the other causes of respiratory distress requiring treatment. syndrome in a newborn which is a differential 7. Retinopathy of prematurity diagnosis of HMD. Q.10. What is hyaline membrane disease of Treatment aims at: newborn and describe its management? 1. Prevention of hypoxia and acidosis Ans: Hyaline membrane disease is the most 2. Maintain fluid balance common cause of neonatal respiratory distress 3. Prevent atelectasis and pulmonary edema syndrome. It is more commonly seen in preterm 4. Avoid lung Injury and infection babies, babies of diabetic mothers, infant’s Management: delivered by caesarean section. • Baby should be placed in a neonatal ICU and It is due to the inadequate production of should be kept in an incubator with high pulmonary surfactant by alveolar cells type II. The humidity with ventilatory support. Continuous surfactant spreads in the lung tissue, preventing the positive pressure ventilation prevents the alveolar collapse during expiration and allows the collapse of the alveoli. High frequency osci- alveoli to open up during next inspiration. llatory ventilation can also be used; it reduces Surfactant deficiency increases the alveolar surface barotrauma; in this a low constant pressure is tension, thus the alveoli collapse during expiration maintained and small variations to promote and require considerable effort to open up during alveolar patency. Air passages should be cleared inspiration. There is poor lung compliance, periodically through endotracheal suctioning. reduction in ventilation-perfusion and progressive atelectasis. Pneumocyte nutrition is compromised • Hypoxemia is indicative of need of oxygen. by hypoxia and systemic hypotension leading to Warm, humidified oxygen therapy should be ischemic necrosis of alveolar cells. Protein filled used with maintenance of PO2 not more than fluid leaks into the alveolar ducts, and the cells 50 mm Hg. Higher concentration may cause lining the ducts slough off. Thus, the hyaline lung injury and retinopathy of prematurity. membrane forms which is composed of fibrin rich • Monitoring of PO2, PCO2, and pH to diagnose protein and cellular debris lining the alveoli and respiratory and metabolic acidosis. Any terminal bronchioles. The underlying epithelium abnormality must be rectified. becomes necrotic. • Correction of anemia, electrolyte imbalance, The clinical features may range from a mild hypovolemia, if any. distress to rapidly progressive fatal disease. The • Surfactant therapy. 158 Case Discussions in Obstetrics and Gynecology

• Intragastric feeding is the preferred method. If REFERENCES there is risk of vomiting and aspiration, IV fluids 1. Michael G Ross. Preterm labor emedicine obstetrics are preferred. and gynaecology 2010;1-9. 2. Anotayanoth S, Subhedar NV, Garner P, et al. Q.11. What is surfactant and how is replace- Betamimetics for inhibiting preterm labor. Cochrane ment therapy given? Database Syst Rev 2004; issue 3: CD004352. 3. Fernando Aries. Preterm labor: Practical guide to high Ans: Surfactant is a complex mixture of phos- risk pregnancy and delivery. 3rd edn; 217-23. pholipids and proteins. The most important phos- 4. Fernando Aries. Premature rupture of membranes. pholipids are DPPC and PG. The most important Practical guide to high risk pregnancy and delivery, proteins are surfactant associated proteins A, B and 3rd edn; 240-61. C. Both natural and artificial surfactant can be used 5. Faron G, Boulvain M, Irion O, et al. Prediction of for the treatment of neonatal HMD. Natural preterm delivery by fetal fibronectin: a meta analysis. surfactant can be obtained from the human amniotic Obstet Gynecol 1998;92:153-8. 6. Crowley Patricia. Antenatal corticosteroids prior to fluid and cow, calf and pork lungs. The artificial preterm delivery: Recent Advances in Obstetrics and surfactants are made up of mixtures of DPPC and Gynecology; Churchill Livingstone; 20:81-96. PG with or without emulsifiers. Surfactant can be 7. Elimian A, Verma U, Camnterino J, et al. Effectiveness used as soon as a preterm baby is delivered and of antenatal steroids in obstetrics subgroups. Obstet before the development of symptoms and signs of Gynecol 1999;93:174-9. HMD. It can also be used after the development of 8. http://www.rcog.org.ulc/guidelines/tocolytic.htlm. symptoms. It is administered via an endotracheal 9. Edwin C, Arulkumaran S. Recent advances in manage- ment of preterm labor. Journal of Obstet Gynecol India tube. It is given in single or multiple doses accor- 2005;2(55):118-24. ding to different protocols. The response to the 10. Romero R, Gomez R, et al. The role of infection in surfactant is immediate, resulting in decrease of preterm labor and delivery: Paediatric and Perinatal oxygen requirement and ventilation pressure. epidemiology 2001;15(Suppl 2):41-56. Mumtaz Khan 14 Antepartum Hemorrhage

Antepartum hemorrhage (APH) is defined as DISCUSSION bleeding from or into the genital tract from 20/22 weeks of pregnancy (period of viability) till the birth CASE 1 of the baby. It complicates 2-5% of all pregnancies A 32-year-old G3 P2+0+0+2 with 32 weeks and is a leading cause of maternal and perinatal pregnancy reported to gynae casualty with history morbidity and mortality the world over. of bleeding per vaginum for 2 hours. On The bleeding may be from the placental site or examination, a cesarean scar is present and the extraplacental in origin. uterus is relaxed. How will you manage this The main causes of placental site bleeding are: patient? a. from an abnormally situated low lying placenta (placenta previa) Q.1. What are the important causes of APH and b. or due to separation of a normally situated their incidence? placenta (abruptio placentae or accidental Ans: It is important to keep the various causes of hemorrhage). APH in mind while evaluating a patient so that a Together these two conditions account for more probable diagnosis is reached soon after history and than 50% of causes of APH. examination. Antepartum hemorrhage is a potentially serious Causes Incidence complication of pregnancy where both mother and 1. Placenta previa 31.0% fetus are at risk. The patient’s condition can 2. Abruptio placentae 22.0% deteriorate suddenly at any time. The aim of management is to institute: 3. Unclassified 47.0% a. General measures to prevent deterioration Marginal 60.0% b. Specific measures are taken to reach a Show 20.0% diagnosis and plan further management. 8.0% Management of such patients should be in a Trauma 5.0% hospital with facilities for blood transfusion, Vulvovaginal varicosity 2.0% operative delivery, neonatal resuscitation and Genital tumor 0.5% intensive care. Genital infection 0.5% Any patient with significant bleeding should be Hematuria 0.5% transferred by ambulance (after immediate Vasa previa 0.5% resuscitation) to above recommended facility. Others 0.5% 160 Case Discussions in Obstetrics and Gynecology

Q.2. What are the important points to be elicited • Is the pain intermittent and colicky, or is it in the history? constant, continuous and of great intensity? Ans: • Has the pain subsided since then? Bleeding per vaginum • Is the pain associated with rupture of • Ascertain the amount of bleeding (soaked how membranes? If the liquor is blood stained it is many garments, spoonful, glassful, presence of suggestive of revealed abruption placenta clots, etc.) to decide the need for transfusion. • Intermittent colicky pain could be the onset of • Painless or is associated with pain abdomen labor, and the presence of blood mixed with • What initiated the bleeding—history of mucos could be show (at times the bleeding intercourse, trauma, fall, etc. may be more than normal and will require • Recurrent bleeding, whether the patient has careful evaluation). had similar episodes earlier in this pregnancy. In concealed abruptio placentae the pain may • Color and character of the bleeding. Is it bright be continuous and severe as the retroplacental red or dark altered blood? collection of blood stretches the uterus to produce • Whether the bleeding has stopped on its own pain. or is still continuing? Pain is less common in posterior placed • Unprovoked, painless, causeless, recurrent placentae. bleeding is characteristic of placenta previa. 10% of women with placenta previa can have Sometimes it can be initiated by an act of coitus. coexisting abruption and can present with pain Bleeding is inevitable in placenta previa and abdomen. Also onset of labor pains following the color of blood is bright red. bleeding in placenta previa can cause confusion in The first episode of bleeding in placenta previa diagnosis. usually occurs: Pain which was severe and subsides • Before 30 weeks in 1/3rd of cases dramatically could be diagnostic of rupture uterus. • Between 30 to 35 weeks in 1/3rd of cases • After 36 or more weeks in 1/3rd of patients Gestational age and parity (Crenshaw et al 1973). Ascertain the gestational age by last menstrual The initial episode is small and stops period (LMP), or if the patient has an early (first completely on its own. It is a warning hemorrhage trimester) ultrasound. which should not be ignored. Management will depend on the diagnosis, The second major cause of bleeding is abruptio condition of the patient and gestational age and placentae, where the bleeding is from the parity. Increased parity is a risk factor for both separation of a normally situated placenta which placenta previa and placental abruption. depends on the site and amount of placental Placental localization separation. It is usually associated with uterine If there is an early 18-20 week ultrasound contractions. The bleeding may be concealed or • Try to localize the placenta, and rule out revealed and by the time it trickles down it is dark placenta previa. and altered blood. • Rule out multiple pregnancy (which is a risk In ruptured uterus, the bleeding is fresh and factor for both placenta previa and abruption) red in color. • And congenital malformation in the fetus, Pain abdomen which will affect the management of the case. • Is pain abdomen associated with bleeding? If (There is a high association of congenital so it is malformations with placenta previa). Antepartum Hemorrhage 161

Fetal movements- • Previous cesarean section is also a risk factor • Is the patient perceiving fetal movements and for ruptured uterus. how frequently? History of APH in earlier pregnancy and its • Is there a history of loss of fetal movements? cause- In case of concealed and severe revealed • Risk of recurrence of both placenta previa and hemorrhage in abruption, the fetus may already be placental abruption is there. dead. • The recurrence risk for placenta previa is In placenta previa despite heavy bleeding the increased 12 times. fetus is usually alive, except in severe shock. • The risk of a placenta previa is also increased In ruptured uterus, the fetus may be dead or if the previous pregnancy was complicated by severely distressed. abruption. Symptoms of pre-eclampsia/impending • For placental abruption risk of recurrence is 6- eclampsia– 16.7% after one episode and 25% after second • Are there any past BP records in this pregnancy episode. and whether they were high readings? History of an overdistended uterus (multiple • Is she having headache, blurring of vision, pregnancy, hydramnios) with sudden rupture of pain right hypochondrium, edema of legs, puffiness of face or sudden gain in weight, membranes tightening of finger rings, etc? • Sudden decompression of an over-distended • History of any episode of convulsion? uterus, can lead to placental abruption. 15-30% of women with abruption have • History of preterm premature rupture of symptoms of pre-eclampsia. membranes is also a causal factor for placental abruption. History of previous abortions (spontaneous or induced) History of any manipulation performed on the • The greater the number of surgical abortions, uterus prior to onset of bleeding greater the risk of placenta previa and morbid • External cephalic version which may lead to adherence of the placenta. placental abruption. • A previous surgical abortion increases the risk • It may also cause rupture uterus, more common by a factor of 1.8. in scarred uterus History of previous cesarean section Past history • The risk of placenta previa increases with the • History of hypertension, diabetes mellitus, heart number of cesarean sections performed on the disease, tuberculosis. patient. • History of any bleeding diathesis or After 1 CS risk is 0.65% thrombophilia (Any history of venous After 2 CS risk is 1.5% thrombosis) After 3 CS risk is 2.2% • The common thrombophilias are: factor V After 4 CS risk is 10% Leiden mutation, the prothrombin gene • Chances of placenta accreta and the need for (G20210A) mutation, the antiphospholipid cesarean hysterectomy are also greater in syndrome, antithrombin III (ATIII) deficiency, patients with placenta previa with prior methylene tetrahydrofolate reductase poly- cesarean section than in patients of placenta morphisms, hyperhomocysteinemia, protein C previa with an unscarred uterus. deficiency and protein S deficiency. 162 Case Discussions in Obstetrics and Gynecology

• Any history suggestive of fibroid uterus From her history she is probably a case of (menorrhagia, , previous history placenta previa. of abortions) is a risk factor for abruption. Examination: Proceed for examination as follows:- Family history General physical examination- Hypertension, diabetes mellitus and any bleeding • Assess the general condition of the patient diathesis or thrombophilias running in the family. whether it is good or poor? Personal history • Whether patient is conscious, oriented to time • Smoking and drug abuse (cocaine) are and place or is confused or in shock. important factors in the etiology of both • Assess quickly the amount of blood loss. placenta previa and abruptio placentae • Look for pallor, jaundice, cyanosis and • In placental abruption there is a 90% increase peripheral edema. in risk with smoking, also there is a positive • Check the pulse, blood pressure, respiratory correlation between the risk and the amount rate and temperature of the patient. smoked. Pallor, tachycardia and hypotension are directly proportional to the blood loss. Menstrual history Shock out of proportion to the visible blood Document the date of last menstrual period and loss is a feature of abruptio placentae, especially calculate the expected date of delivery to ascertain the concealed variety. the gestation period. Regularity of cycles is Edema and hypertension could also be important to determine gestation age. associated with abruption, and hypertension could Obstetric history mask true hypovolemia. • History of first or second trimester abortions, • Assess the patient for the need for blood spontaneous or induced, whether followed by transfusion D and E or not? • Start I/V infusion with a wide bore cannula (14- • Find out about the mode of previous deliveries 16 G) (whether vaginal or cesarean section). • Draw blood samples for blood grouping and Placenta previa with previous LSCS can be cross matching and for other investigations as complicated by morbidly adherent placenta. will be discussed later. • Indication for previous LSCS. Systemic examination • Enquire about any antepartum, intrapartum The cardiovascular system and the chest are and postpartum complications. evaluated for any evidence of associated heart or • History of APH in prior pregnancies. respiratory disease. Abdominal examination is performed to check In this case, she is G3P2002, first a normal 1. Height of uterus vaginal delivery at term 5 years ago, second a • In placenta previa, the height of uterus cesarean section for transverse lie at 36 weeks in corresponds to the period of gestation labor, 3 years ago. Both children are alive and • In abruption the fundal height is more than healthy. period of gestation because of retroplacental There is history of spotting 2 weeks ago and accumulation of blood. now she has soaked her under garment and 2-3 2. Uterus contour and consistency and presence pads. There is no history of pain abdomen. of tenderness Antepartum Hemorrhage 163

• The contour of the uterus is maintained in Vaginal examination both placenta previa and abruption, • As mentioned earlier vaginal examination is • In ruptured uterus, the contour may be contraindicated at this stage unless placenta distorted, fetal parts may be felt easily, previa is ruled out. abdomen will be tense and tender with • Every case of bleeding P/V in late pregnancy evidence of free fluid. is presumed to be placenta previa unless • In placenta previa, the uterus is relaxed and proved otherwise. (Even when the vaginal fetal parts are easily palpable and presenting examination is done very gently and cautiously, part can be felt easily. 1 out of every 16 examinations produces a major • In a case of abruptio placentae, the uterus is hemorrhage and 1 out of every 25 examinations tense, tender and rigid (depending on the results in hypovolemic shock).1 severity of abruption) and the fetal parts are • Such digital cervical examination is never felt with difficulty. permissible unless the woman is in an 3. Presentation operating room with all the preparations for • Malpresentations like breech, transverse, immediate cesarean delivery- even the oblique lie or a free floating head are gentlest digital examination can cause common in placenta previa and are torrential hemorrhage. Furthermore, this type attributed to the presence of the placenta in of examination should not be performed unless the lower segment which prevents delivery is planned. stabilization of the head. • An examination of the vulva can be done to • In abruption the lie is usually vertical and ascertain whether bleeding is still continuing the head is often engaged. or has stopped and also to note the amount of 4. Fetal heart sounds bleeding. • Are usually present in case of placenta • A gentle speculum examination may be previa unless the patient is in shock. performed after 5-7 days to rule out other local • In case of abruption, the fetal heart sounds causes such as cervicitis, trauma, cervical are absent in concealed type or severe polyps or cervical malignancy. Speculum revealed type, but are present in less severe examination is not associated with increased degrees. risk of hemorrhage. The presence of any of these • In ruptured uterus, the fetal heart sounds still does not rule out placenta previa. may be absent or there may be fetal distress. • In severe bleeding, speculum examination need 5. Multiple pregnancy not be done. • The number of fetuses and their lie and This patient is conscious, oriented, vitals are presentation to be noted. maintained, and pallor is mild. The uterus is • Multiple pregnancy is a risk factor for both relaxed, 32 weeks in size, cephalic free floating, placenta previa and abruption. fetal movements are present and fetal heart 6. Uterine contractions sounds heard. No active bleeding seen at present. • The presence of uterine contractions is to be noted as further management will depend Q.3. What is your provisional diagnosis? on it. Ans: In this case under discussion she is most likely • This may indicate onset of labor. a case of placenta previa as: 164 Case Discussions in Obstetrics and Gynecology

1. The bleeding was painless, fresh, red in color PTT, Serum Fibrinogen, Fibrinogen 2. There is history of previous cesarean section degradation products (FDP) and D-Dimer to 3. The uterus is relaxed, not tense or tender be done depending on facilities available. (For 4. Height of uterus corresponds to period of emergency management of patient these are not gestation essentially required if BT, CT and CRT are 5. Head free floating normal). 6. No scar tenderness • Blood urea, serum creatinine, serum 7. Fetal movements perceived and fetal heart electrolytes and blood sugar are done as base sounds heard. line investigations and also for anesthesia purposes if surgery is to be performed. Q.4. What are the differential diagnoses? • Urinalysis must be done for presence of Ans: proteins and sugar. • Placenta previa • An Apt test can be performed on vaginal blood • Abruptio placentae if Vasa previa is suspected and the blood is • Marginal bleed suspected to be fetal in origin. • Ruptured uterus Ultrasonography: • Bloody show • Ultrasonography is essential for localizing the • Cervicitis placenta. • Trauma • The ultrasound could be a transabdominal or an endovaginal ultrasound. • Vulvovaginal varicosities • The accuracy of transabdominal USG is • Genital tumors excellent with false positive and false negative • Genital infections rates of 7 and 8% respectively. • Hematuria • The accuracy is further improved with • Vasa previa endovaginal method (positive predictive value of 93.3% and negative predictive value of Q.5. What investigations are to be done in a case 97.6%)—Farine et al, 1988.2 of APH? • Endovaginal technique is not only safe but also Ans: The following investigations are reco- superior to transabdominal method, as the mmended:- internal cervical os was visualized in all cases • Investigations are done after initial resuscitation with endovaginal USG, but only in 70% cases and stabilization of patient. by transabdominal method. • Blood sample is taken for blood grouping and • Transperineal USG also allowed visualization cross-matching and arranging blood as per the of the internal os in all the cases studied and need. (In case of severe bleeding, 4 units of has a positive predictive value of 90% and blood must be cross matched and made readily negative predictive value of 100%—Hertzberg available). and associates (1992). • Complete hemogram with hematocrit and • False-positive results on transabdominal scans platelet counts is to be sent. are usually due to bladder distension. Hence • BT, CT and CRT is done in all cases of APH. in apparently positive cases the scan should be • Coagulation profile is to be done keeping in repeated after emptying the bladder. mind abruptio placentae and associated • Another cause of wrong reporting is the finding disseminated intravascular coagulation. PT, of abundant placental tissue implanted in the Antepartum Hemorrhage 165

fundus of the uterus, and presuming it to be in cesarean section (18% versus 4.5%).This upper segment, but failing to appreciate a large abnormally firm attachment of the placenta may placenta extending all the way down to the be due to poor decidualization of the lower internal os. segment of the uterus and may present as If the placenta is found located in the lower placenta accreta or in more advanced forms segment of the uterus the diagnosis of placenta as placenta increta or percreta. previa is clinched. • Other findings to be noted on USG are gestational age of the fetus/birth weight, fetal Q.6. What are the different types of placenta heart, presentation, amount of liquor, previa? multiple pregnancy and to rule out congenital Ans: With use of endovaginal ultrasound one can malformations. identify the type of placenta previa. Depending on the distance of the lower edge Q.8. Is there any role of color Doppler in of the placenta from the internal cervical os:- diagnosis? a. Low lying—When the placental border is more Ans: Transvaginal sonography and color Doppler than 2.0 cm from the internal os. imaging improve the diagnostic accuracy in the b. Partial previa—When the placenta does not prediction of placenta accreta in patients with cover the internal os but its lower border is persistent placenta previa. A pattern of turbulent within 2.0 cm of the internal os. blood flow extending from the placenta into the c. Total previa—When the placenta completely surrounding tissues should alert the physician to covers the os and extends over both lips. the possibility of placenta accreta. The latter two are major degrees of placenta Twickler and colleagues (2000) reported that two previa and it has been seen that the cesarean rate factors were highly predictive of myometrial is 90% when placenta is within 2.0 cm of the invasion: (1) A distance less than 1 mm between the os and 37% when it is over 2.0 cm (Bhide et al, uterine serosal- bladder interface and the 2003).3 retroplacental vessels, and (2) Identifications of large intraplacental lakes. These had a sensitivity of 100 Q.7. What else to look for in USG after placental percent and positive predictive value of 78 percent. localization? Q.9. Is there any role of MRI in diagnosis? Ans: • Look for retroplacental clots (also important Ans: Magnetic resonance imaging (MRI) has been in cases of placenta previa because of its used successfully in identifying morbidly adherent association with abruption). placentation, but its high cost and nonavailability • The diagnosis of placental abruption is mainly in most centers has limited its use. In times to come clinical but rarely one can see signs of placental it may prove useful. separation such as membrane elevation. From above history, examination, investi- • It is important to note that negative findings on gations and USG (if available) a diagnosis as to USG do not exclude placental abruption. It can the cause of APH is reached and in this case it is diagnose 15-25% of this condition. a case of placenta previa as the USG reveals • Always keep in mind the morbid adherence anterior placenta 1.6 cm from cervical os and of the placenta in cases of placenta previa, there is no evidence of morbid adherence on color especially those associated with previous Doppler. 166 Case Discussions in Obstetrics and Gynecology

Q.10. What is the management of placenta a. Pregnancy reaches 36-37 weeks. previa with reference to this case in particular? b. There is severe hemorrhage at any time Ans: Management can be in the form of expectant endangering the life of the mother. or active management depending on c. The fetus is dead or is malformed. • The severity of blood loss and whether it has d. At onset of labor or rupture of membranes. stopped or is continuing e. When frank accidental hemorrhage is suspected • The condition of the mother and fetus as cause of APH. • Gestational age • The onset of labor. Q.13. What protocol is to be followed in The aim of management of pregnancies expectant management? complicated by placenta previa is Ans: Following protocol is followed for expectant • To allow them to progress to as close to term as management:4 possible and then terminate them by cesarean 1. Admit the patient in labor room, give sedation section. and keep her nil orally. • Only in case of minor degrees of previa (Type I 2. Start an IV drip and draw blood for grouping and Type II anterior) vaginal delivery can be and cross-matching and send all relevant allowed (provided there is no obstetrical investigations as discussed earlier. contraindication). 3. Monitor the vitals of the patient- pulse, BP, As in this patient the gestational age is 32 every 15 minutes till there is active bleeding weeks and bleeding has stopped since admission, and then ½ hourly. Record output one hourly it is advisable to continue with conservative/ and maintain an I/O chart. expectant management to allow for fetal lung 4. Assess the blood loss and transfuse if bleeding maturity, provided the mothers’ condition remains is moderately severe or patient is already stable. Steroids to be given and a cesarean section anemic. Aim is to maintain a Hb level of 10 should be performed around 36-37 weeks. gm/dl or hematocrit of 30% for fetal oxygenation. Q.11. What is expectant management? 5. Maintain an abdominal girth and fundal height chart ½ hourly to rule out abruption and Ans: • It is conservative management concealed hemorrhage. • The aim is to delay delivery as much as possible 6. Monitor fetal heart sound by auscultation or to allow for fetal lung maturity and at the same electronic fetal monitoring. time not jeopardizing the condition of the 7. Steroids must be given for lung maturity. mother. Betamethasone 12 mg IM 24 hourly for 2 doses. • Only hemodynamically stable patients remote 8. In selected cases, tocolysis should be given to from term should be managed conservatively. prolong the gestation, once bleeding has • The objective is to reduce perinatal mortality stopped. and morbidity due to prematurity. • Nifedipine 10 to 20 mg orally is the drug of choice and should continue till patient Q.12. When should the expectant management delivers. be interfered with? • Terbutaline and Ritodrine cause maternal Ans: This expectant line of management must be tachycardia and make the assessment of the abandoned when patients pulse rate unreliable. Antepartum Hemorrhage 167

• Indocin is also not preferred as it prolongs oxytocin drip. This helps in effectively the bleeding time. controlling hemorrhage from further placental However, the evidence suggesting that adminis- separation. tration of tocolytic agents results in better • At any time if bleeding is excessive cesarean pregnancy outcomes is not conclusive. section should be done. 9. Rhesus negative women require a Kliehauer In this particular case, the mode of delivery test every time there is fresh bleeding and should be by cesarean section as it is a case of appropriate anti-D immunoglobulin prophy- previous cesarean section with major degree of laxis. placenta previa. 10. Once the bleeding has stopped patient can be shifted to the ward after 24 hours. Q.16. Supposing the USG facility is not available, • She should continue with bedrest how would you manage the patient? • Give iron supplementation. Ans:If and when ultrasound findings are • Stool softener is advisable to prevent inconclusive for placenta previa, or if USG facility straining at stools not available, the patient can be taken for • Intercourse, vaginal douching and suppo- examination in operation theater (also known as sitories are contra indicated double set-up examination) as this provides the • Limited bathroom facilities are permitted most accurate assessment of the relationship once bleeding has stopped for 6-7 days between the lower edge of the placenta and the 11. A per speculum examination is done, 5-7 days cervical os. after bleeding has stopped, to exclude any local pathology. Q.17. What is double set-up examination? 12. USG if not done earlier can be done now. Ans: Double set-up examination is p/v examination Q.14. Can anything more be done to delay in operation theater to assess the relationship of delivery in a case of placenta previa? the lower edge of the placenta with the cervical os. • It is done only when delivery is to be Ans: Elective cervical cerclage is one intervention undertaken. that may be considered. • A second obstetrician is scrubbed and ready for • Its benefits are still doubtful as two studies are performing cesarean if required, along with a in favor with respect to prolongation of nurse who is also scrubbed and the surgery and pregnancy, increase in birth weight and anesthesia trolleys kept ready. reduction in number of bleeding episodes, while the third study does not show any such benefit. • Anesthetist and pediatrician must be present. • Further studies need to be done to prove its • Cross matched blood should be available. benefits. • The examination can be performed with or without anesthesia with everything ready to Q.15. What is the mode of delivery in placenta quickly induce the patient if cesarean is to be previa? performed. Ans: Termination of pregnancy is done by • The patient is put in lithotomy position and • Cesarean section in major degree of placenta cleaned (only the vulva, not the vagina) and previa. draped, bladder is emptied. • In minor degree of placenta previa artificial • A per speculum examination is done to look rupture of membranes is followed by for any local cause of bleeding. 168 Case Discussions in Obstetrics and Gynecology

• Two fingers are then introduced carefully into • A few patients can be managed on an outpatient the vagina and directed towards the fornices. basis if the following criteria are fulfilled:- Each fornix is then palpated to feel the presence 1. No bleeding for 72 hours while being of placenta between the presenting part and the observed as inpatient. vaginal fornix. There is a feeling of bogginess 2. Stable, serial hematocrit of 35% or more. if placenta is present. 3. Reactive nonstress test at time of discharge. • If the fornices are empty then the index finger 4. Compliance with bed rest at home. is gently introduced in the os and the 5. Availability of transport 24×7 between surrounding is felt for the placental edge. home and hospital. • If no placental edge is felt within 3 cm of the 6. Communication facility to be available. os, or if it is felt only anteriorly but does not 7. Patient and family members must be reach the os and no bleeding is provoked the counseled and made aware of potential membranes should be ruptured in preparation complications. for vaginal delivery. 8. Follow-up every week in ANC till delivery • An organized blood clot can at times be or readmission. mistaken for the placenta, but the former is friable unlike the placenta which is firm and Q.20. Supposing this patient was bleeding nonfriable. profusely and signs of shock were present, what • If the os is closed or there is bright red persistent would be the management then? bleeding after membrane rupture, or there is Ans: After initial resuscitation with crystalloids and brisk during the procedure, it blood transfusion, patient to be taken up for should be abandoned and cesarean performed emergency cesarean section after ruling out/ immediately. correction of DIC and arranging adequate blood and blood products. This would be in maternal Q.18. What are the contraindications for the interest. above procedure? Ans: Q.21. What is active management of a case of 1. Profuse hemorrhage where immediate delivery antepartum hemorrhage? is to be undertaken. Ans: Active management is 2. Clear cut sonographic evidence of major degree • The decision to terminate the pregnancy of placenta previa. immediately after resuscitating the mother and 3. Malpresentation, malposition or other stabilizing her condition. conditions where vaginal delivery cannot be • Coagulation profile should be corrected before undertaken. any operative intervention. 4. Fetal distress Active management is to be considered in following circumstances: Q.19. Do patients with placenta previa need to 1. When the fetus is mature. be in hospital all the time? 2. The fetus is dead or has an anomaly not Ans: compatible with life, such as anencephaly. • Continued hospitalization is the best 3. There is risk to the life of the mother because management option for patients of placenta of excessive and/or continuing blood loss. previa. 4. Patient is in labor. Antepartum Hemorrhage 169

5. When accidental hemorrhage is suspected 8. If no facility for USG is available or if the USG clinically and ultrasound confirms the placenta report is inconclusive a p/v examination is done is located in the upper segment. In such cases: in OT under double set up arrangement in cases • P/V examination is done in labor room after of mild to moderate APH admitting the patient In minor degree-type I and type IIa, the • Depending on the cervical status an artificial membranes can be ruptured and oxytocin drip rupture of membranes is done, followed by is started and patient may be kept for vaginal oxytocin drip. delivery. In type IIb, III and IV placenta previa, • If the fetus is salvageable patient may be immediate cesarean section is performed. taken for cesarean section in the interest of 9. When no placenta is felt on digital examination the fetus. (as in cases of abruptio placentae) then also the • Only mild cases of abruption can be left on membranes are ruptured and oxytocin drip is conservative management under careful started and patient allowed to deliver vaginally. monitoring. If the cervix is not favorable and the fetus is salvageable a cesarean section may be Q.22. What protocol is followed for active ma- performed in fetal interest. nagement? 10. If the patient continues to bleed following Ans: Following protocol is to be followed for active artificial rupture of membranes, decision for management:- cesarean section is to be taken in maternal 1. Resuscitate the patient by giving I/V fluids, interest. blood transfusion 2. Correct coagulation profile by giving fresh Q.23. Is the method of performing cesarean frozen plasma or other blood components section any different in case of placenta previa? depending on the laboratory reports. Ans: Technique of cesarean section in cases of 3. Arrange operation theater and shift patient to placenta previa. OT. • All major degree of placenta previa require 4. Counsel the relatives about the high risk cesarean delivery either emergency or elective. condition of the mother and fetus. 5. Take informed consent for the need for cesarean • It is better to plan an elective cesarean as there section and maybe hysterectomy. is increased perinatal morbidity and mortality 6. Keep adequate blood and blood components irrespective of gestational age following an ready for surgery. emergency section 7. Cesarean section is to be performed directly in • A senior obstetrician should perform the section cases of as there are great chances of complications in • Major degree of placenta previa confirmed the hands of inexperienced obstetricians. on ultrasound • The uterus is usually opened by a transverse • If there is profuse bleeding incision in the lower segment. In case of any • There are other obstetric conditions in which difficulty this incision may be extended to an vaginal delivery is contraindicated, e.g. inverted T, J or U shape. malpresentation and previous cesarean • At times the lower segment may be nonexistent section etc. or it may be very vascular or when the placenta 170 Case Discussions in Obstetrics and Gynecology

is anterior, going through the placenta may common because of the increased incidence of cause fetal bleeding. In such circumstances cesarean births. some people have advocated a vertical incision. • Arterial embolization in selected cases is Such an incision is rarely justified because of another method of controlling intraoperative its long-term consequences. and postpartum hemorrhage. If antenatal • After the transverse incision in the uterus one ultrasound suggests morbid adherence of the may either go through the placenta to deliver placenta one should discuss preoperative the baby or go by the side of the placenta and arterial balloon embolization of the uterine/ rupture the membranes to extract the fetus. internal iliac arteries with the interventional • Early cord clamping should be done. radiologist as a method of controlling • If there is suspicion or prenatal diagnosis of hemorrhage. The catheters are placed before a morbidly adherent anteriorly sited starting the cesarean and soon after the baby is placenta previa then an upper segment delivered, the arteries are embolized. cesarean section is preferable with the placenta left intact and may even be left in Q.25. What type of anesthesia is preferable for situ. LSCS in a case of placenta previa? Ans: Earlier the dictum was that for a cesarean for Q.24. How to control the bleeding from the lower placenta previa only general anesthesia should be segment following cesarean? given, and regional anesthesia was considered a Ans: Intraoperative hemorrhage is quite common contraindication because of the ensuing as the lower segment is less muscular and hemorrhage and associated hypotension. contraction and retraction do not occlude the • Epidural anesthesia by lowering blood pressure placental bed sinuses adequately. This bleeding can may critically reduce uterine and placental be controlled by:- perfusion endangering the life of the fetus. • Applying mattress sutures intermittently on the • Now there is sufficient data to establish the placental bed with 0 chromic sutures. safety of regional anesthesia in the hands of • Cho and colleagues (1991) have described the experienced anesthetists and also the amount placement of square interrupted 0 chromic of blood loss is less, compared to general sutures around the lower segment above and anesthesia. below the transverse incision to control the • When the patient condition is stable and there hemorrhage. is no active bleeding, epidural or spinal • Uterine artery ligation and unilateral or anesthesia is no longer contraindicated in bilateral internal iliac artery ligation can be experienced hands. considered. • When these conservative approaches fail total Q.26. What are the maternal risks associated hysterectomy is performed in maternal interest. with placenta previa? • Hysterectomy is particularly indicated in cases Ans: where there is morbid adherence of the placenta • Hypovolemic shock due to hemorrhage (accrete, increta or percreta). This situation is (antepartum and intrapartum/intraoperative). commonly seen in cases of previous uterine scar • Postpartum hemorrhage due to inadequate including cesarean with the placenta anterior occlusion of sinuses in the lower segment and encroaching on to the scar and is becoming following delivery. Antepartum Hemorrhage 171

• Anesthetic and surgical risks especially during • One also has to take into account the clinical emergency cesarean section. condition of the patient before bleeding started. • Puerperal sepsis due to ascending infection. An anemic patient may not withstand a loss of • Air embolism is a rare possibility when the one unit of blood and will have hypovolemia sinuses get torn. whereas a normal patient may not manifest any • Disseminated intravascular coagulation may changes in vitals following a similar loss. occur with massive hemorrhge, although it is • For purposes of uniformity, severity of bleeding less common with placenta previa. may be classified into four groups:5- • Placenta accreta leading to increased maternal 1. In the first group, the bleeding is said to be mortality and morbidity because of increased mild with blood loss <750 ml (only 15% of chances of postcesarean hysterectomy and the intravascular volume).There is no intraoperative bleeding. change in the vitals, urinary output or CNS. • Recurrence risk of placenta previa in future 2. In group II or those with moderate pregnancies. bleeding, blood loss is between 750 to 1500 ml. These patients have base line Q.27. What are the risks to the fetus? tachycardia (change of 10 to 20 beats per minute) and a fall in BP (drop of 10 mm or Ans: more in diastolic BP), urine output is • Increased perinatal morbidity and mortality due between 20 -30 ml per hour and patient may to preterm birth. be anxious and agitated. • Intrauterine growth restriction (more common 3. In group III and IV, those with severe with repeated episodes of bleeding). bleeding the blood loss is1500 ml to more • Congenital malformations usually of the CNS, than 2500 ml and 30% to more than 40% CVS, respiratory and GI systems. blood volume is depleted. Patient is in shock • Fetal anemia following accidental vasa previa with decreased or unrecordable BP, oliguria rupture. or anuria and patient may be confused or • Sudden intrauterine death when there is severe lethargic. The fetus may be severely maternal hypovolemic shock. distressed or dead. • Risks associated with malpresentations, cord prolapse, etc. Q.29. How to manage patients with severe bleeding? Q.28. How to assess the severity of blood loss in Ans: cases of antepartum hemorrhage?. • Assessment of blood loss is important for initial Ans: management of the patient. • It is difficult to gauge the severity of bleeding • This particular classification can be useful in and the amount of blood loss as blood pressure guiding volume replacement. and pulse may remain normal despite significant • Patients with severe bleeding require life blood loss in a pregnant patient because of support measures and immediate operative hypervolemia. intervention to save the mother. • The hemoglobin and hematocrit may be normal • Besides intensive monitoring, intravenous for some time in a bleeding patient not receiving fluid replacement and transfusion therapy is fluids. required. 172 Case Discussions in Obstetrics and Gynecology

• Crystalloids such as Ringer lactate is given fast, bleeding and shock. A Foleys’ catheter must be till blood is made available for transfusion. One inserted and the output should be aimed to be liter of crystalloid solution expands the maintained at 30 ml/hour to protect the kidneys intravascular volume by approximately from damage from acute tubular or cortical 250 ml. necrosis leading to anuria or oliguria. • The patients’ response to I/V fluids is a rough • Following expansion of intravascular guide to assess severity of bleeding. If with less compartment by adequate fluid and blood than 3 liters of fluid the blood pressure becomes replacement, Frusemide 20-40 mg may be given normal and pulse rate decreases then the blood I/V to reestablish urinary output. volume loss is probably less than 50%. • Remember that blood loss is grossly • Packed red cells and specific blood underestimated. components should be used for combating shock and replacement of blood and clotting Q.30. Is postpartum hemorrhage common in a factors where required. case of APH and why? • In extreme emergency situations if type specific Ans: Yes, in all cases of APH one should anticipate blood is not readily available patient should be PPH. In placenta previa, PPH is caused because transfused O negative or even O positive blood. of: • With massive transfusions (more than 10 units a. Failure of the lower segment to retract properly. in 24 hours) the clotting factors get depleted b. Large surface area of the placenta with atonic and an assessment should be done for the same, uterus. especially platelet counts. c. Morbidly adherent placenta. • Platelet transfusion should be given when In abruptio placentae PPH is due to: 3 counts are less than 50,000/mm . It is preferable a. Atonic uterus. to give platelets from a single donor to reduce b. Coagulation failure. antigenic exposure. c. Couvelaire uterus. • One unit of single donor platelets increase the count by 50,000 approximately, while Q.31. How to prevent or control PPH in a case pooled platelets from multiple donors will of APH? accomplish the same with 5-6 units and Ans: antigenic exposure will be much more. • Active management of the third stage is • If there are alterations in PT or PTT then fresh important for controlling PPH. frozen plasma should be given. For every 4 • Intravenous methergine, oxytocin infusion units of packed cells I unit of fresh frozen (10-40 units), intramuscular PG F2α 250 μg and plasma should be transfused. misoprostol 800 μg per rectum may be used to • In patients in critical condition it may not be control PPH. possible to monitor the intravascular status with • Replace blood adequately and correct pulse and BP monitoring alone, hence there is coagulopathy. need for a central venous pressure line to • If these measures fail internal iliac ligation/ monitor fluid replacement. If coagulopathy is arterial embolization to be attempted. suspected a more peripheral CVP line is • Hysterectomy is the last resort. preferred. • In a case of placenta previa at cesarean section • Urine output measurement is an important hemostatic sutures to be applied on the placental aspect in management of patients with severe bed. Antepartum Hemorrhage 173

• Systematic devascularization of the uterus to • Hematoma of the rectus abdominis muscle. be done. • Acute hydramnios. • B-Lynch suture can be tried. • Retroperitoneal hematoma. • Internal iliac ligation and hysterectomy as a last resort. Q.33. What is the provisional diagnosis and • Hysterectomy for placenta previa should be a why? total hysterectomy. Ans: • In this patient, the bleeding is associated with CASE 2 pain abdomen. • Features of pre-eclampsia are present A 30-year-old primigravida with 36 weeks pregnancy presented to gynae casualty with • Uterus is tense and tender bleeding P/V and pain abdomen for 1 hour. On • The fetus is dead. examination her BP is 144/90 mm of Hg, pulse These findings are in favor of abruptio placentae rather than placenta previa (see history 120/minute, severe pallor+, uterus is tense and tender, FHS is absent. Urine albumin is ++. What and examination for differential diagnosis). The is your diagnosis and how will you manage this abruption is also of severe variety (more of case? concealed) as the fetus is already dead. Patient must As already discussed in the previous case have been hypertensive as the BP after the episode scenario immediate aim is is 130/90 mm of Hg. • To resuscitate the patient, • Ascertain the amount of bleeding Q.34. Why it could not be a case of ruptured • Take a quick history followed by examination uterus? in order to reach a provisional diagnosis as to Ans: It could not be a case of ruptured uterus the cause of bleeding. because: • Further management will depend on the • Patient is a primigravida maternal and fetal condition. In this case the • There is no history of previous scarring of uterus fetus is already dead. • No history of any abortion or MTP • Patient has not been in labor for long Q.32. What are the differential diagnosis? • Pain abdomen is still present (not subsided as Ans: it should dramatically stop after ruptured uterus) • Placenta previa • The uterine contour is maintained • Abruptio placentae • In ruptured uterus, the fetal parts are felt • Unclassified bleeding (marginal sinus rupture) superficially and the uterus contour is not • Vasa previa maintained and it may be felt as a mass in the • Ruptured uterus abdomen-which is not the case in this patient. • Labor pains • Bloody show Q.35. What investigations are required for • Other local cervical and vaginal pathology. diagnosis and management of this case? In concealed type of accidental hemorrhage Ans: following conditions to be kept in mind as • The diagnosis of placental abruption is based differential diagnosis:6 on history and clinical findings. • Nonobstetric acute abdominal conditions such • All investigations as listed in the previous case as acute appendicitis. are to be done. 174 Case Discussions in Obstetrics and Gynecology

• The DIC profile is important in this case to the baby, resulting in bleeding into the decidua confirm and manage DIC. basalis. • An ultrasound examination is important to rule • Its incidence is 1% approximately. out placenta previa and to see any features of • On histological examination of the placenta it abruption (as detailed earlier). is noted that many cases go undetected. Histological examination incidence is 4.5%. Q.36. What are the values of various • The incidence of abruption increases with components in the DIC profile? gestational age and more than 90% fetuses Ans: weigh 1500 gm and above at birth. • Fibrinogen—150-600 mg/dl. • Abruptio placentae presents as vaginal • Prothrombin time (PT)—11-16 seconds. bleeding, present in 78% of the cases— • Partial thromboplastin time (APTT)—22-37 revealed type or the concealed type where seconds. there is no overt bleeding (around one third of 3 • Platelet count—120,000-350,000/mm. all cases). • D-dimer—<0.5 mg/L. • Uterine tenderness and back pain in 66% of • Fibrin degradation products FDP—less than 10 patients. μg/dl. • Uterine hypertonicity and contractions in 17% of the patients. Woody consistency of Q. 37. What is the role of ultrasonography in uterus. diagnosis of placental abruption? • Size of the uterus more than period of gestation. Ans: • Shock may be out of proportion to the apparent • As stated earlier placenta previa should be blood loss. excluded by USG in all cases of antepartum • Fetal death may occur in 25-35% of cases hemorrhage. before admission. • The sensitivity of USG for presence of an • It is rare to find all of these features together, abruption is poor (24%), although it is often performed in cases where immediate delivery but at least one is present. Sometimes none may is not indicated. be present. • When the retroplacental clot is large USG • The concealed type where there is no vaginal identifies it as hyperechogenic or isoechogenic bleeding is the more severe form of the disease compared to the placenta, and may be (25-35%). It is usually associated with DIC misinterpreted as a thick placenta. (disseminated intravascular coagulopathy) • A resolving clot becomes sonolucent within and the abruption is severe enough to cause fetal 2 weeks. demise. • In concealed hemorrhage, the placenta appears thick and globular, almost 6 cm in diameter. Q.39. What are the risk factors for developing • Ultrasound is also useful in assessing fetal abruption placentae? presentation, fetal weight and well-being. a. Cigarette smoking has an increase in risk upto 90%, with a direct correlation with the amount Q.38. What is placental abruption and how does smoked. it manifest? b. Pre-existing hypertension and hypertensive Ans: Abruptio placentae is the premature separation disorders of pregnancy. Together with smoking of a normally situated placenta before the birth of the risk increases further. Antepartum Hemorrhage 175 c. Abdominal trauma sustained in a fall, road In all symptomatic grades, the hemorrhage may traffic accident or physical abuse. be concealed or revealed. d. Sudden decompression of an overdistended uterus such as membrane rupture in Q.41. What is the management in this case? polyhydramnios, multiple pregnancy. Ans: As discussed earlier the immediate e. External cephalic version. management is: f. Preterm premature rupture of membranes, • General management specially in cases where bleeding precedes 1. Resuscitate the patient by expanding the rupture of membranes. intravascular volume with crystalloids g. Acquired and inherited thrombophilias-factor 2. Replace blood by transfusing packed red V Leiden mutation, the prothrombin gene cells mutation, antiphospholipid syndrome, 3. Stabilize the vitals and maintain adequate antithrombin III (ATIII) deficiency, methylene urinary output. tetrahydrofolate reductase polymorphisms, 4. It is then followed by specific management hyperhomocysteinemia, protein C deficiency pertaining to the diagnosis. and protein S deficiency. • Management of abruptio placentae is guided by h. Increased maternal age, parity, diabetes mellitus. • The grade at presentation i. Unexplained elevation in maternal serum • Gestational age alphaproteins (after excluding neural tube • Presence of complications. defects, multiple pregnancy and intrauterine The objective of management of severe hemorrhage). abruption causing fetal demise as in this case is to j. Cocaine abuse. decrease maternal morbidity and mortality and this can be achieved by delivery of the fetus. k. Uterine leiomyomata especially if they are When the fetus is dead located behind the placental implantation. • The placental separation is more than 50% l. Uterine malformations. • Coagulopathy is present in 30% of the cases • Renal failure in about 10%. Q.40. What is the grading of placental ab- A careful assessment of the maternal condition ruption? should be undertaken and blood clotting factors to Ans: Clinical classification of Abruptio placentae: be replaced. • Grade 0: The patient is asymptomatic and it is • As the blood loss in cases of abruption severe incidentally diagnosed on seeing retroplacental enough to kill the fetus is estimated to be around clots after delivery of placenta. 2500 ml. All patients must be transfused 2 units • Grade I: Hemorrhage with pain and irritable of PRC (packed red cells) irrespective of their uterus but no fetal or maternal compromise. initial vital parameters and hemoglobin/ • Grade II: No maternal compromise but fetal hematocrit, to prevent further impairment in distress is evident. organ perfusion. • Grade III: There is uterine tetany, maternal • If the patient was hypertensive then the initial compromise and fetal demise. DIC and renal BP may be normal, the pulse may also rise when shut down are important complications. Average the vascular compartment expands. retroplacental blood loss is said to be more than • In concealed hemorrhage, the blood loss is 2500 ml. grossly underestimated and by the time the vitals 176 Case Discussions in Obstetrics and Gynecology

deteriorate there is profound hypovolemia and • The coagulopathy resolves early in the it is difficult to reverse the shock. postpartum period but the high levels of FDP • While waiting for PRC, the intravascular (fibrinogen degradation products) interfere with volume should be expanded with Lactated myometrial contractility and cause postpartum Ringer solution at a rapid rate. hemorrhage. Hence, all steps outlined earlier • The aim should be to maintain a hematocrit of for prevention and control of PPH must be 30% and an output of 30 ml/hour. followed. • A CVP line should be inserted to monitor fluid replacement. Q. 44. In what dose is cryoprecipitate given and when? Q.42. What is the pathophysiology of DIC in Ans: Patients having a fibrinogen level of less than abruption placentae? 100 mg/dl should be administered cryoprecipitate Ans: DIC in cases of abruption develops due to in a dose of 10-20 units immediately before and massive release of thromboplastin into the during cesarean section. circulation which in turn leads to: • Intravascular formation of fibrin Q.45. Is there any role of heparin in manage- • Consumption of coagulation factors ment of coagulopathy? • Subsequent activation of the fibrinolytic system. Ans: • Heparin should not be used for management of Q.43. How to diagnose and manage coagulo- DIC in a case of abruption as it increases the pathy? blood loss and there is need for further Ans: transfusion. • For evaluation of coagulopathy a DIC profile • As DIC in abruption is due to a premature is done. separation of the placenta, treatment is to deliver • There is a drop in fibrinogen level to 100 mg/dl the fetus and placenta at the earliest. or less. • PT and PTT are prolonged Q.46. What should be the mode of delivery when • Platelets are reduced fetus is dead as in this case? • D-dimer values are raised. Ans: When fetus is dead • Abnormal values do not warrant therapy unless • Vaginal delivery should be aimed for, unless excessive bleeding is seen to be present. • Vaginal delivery can be effected in the presence • There is a malpresentation warranting a of depleted coagulation factors, but to avoid cesarean section, excessive bleeding at time of delivery and • Or the hemorrhage is brisk endangering the subsequently, it is prudent to correct the mothers’ life. coagulopathy. • The presentation should be confirmed by • Correction of coagulopathy is by transfusing ultrasound as it is difficult to find out clinically platelets, fresh frozen plasma and cryo- with a rigid uterus. precipitate. • External version should not be attempted in • No surgical intervention should be undertaken cases of abruption with a rigid uterus. before correcting the coagulopathy as severe • Amniotomy should be performed early bleeding may ensue. • Oxytocin infusion to be started. Antepartum Hemorrhage 177

• Parity and maternal age are no contraindication With the fetus alive and the uterus soft for oxytocin infusion, unless labor has already 1. The grading is of a less severe degree and it is started. presumed that abruption is no more than 25%. • With a dead fetus and an unripe cervix either 2. The chances of coagulopathy are also very low. misoprostol 50 μg every 4 hourly 5 doses 3. Such patients should have induction of labor intravaginally or high doses of oxytocin will and a vaginal delivery. be required. 4. Cesarean section may be done if there is fetal • Uterine contractions may not be appreciated distress at any time. clinically because of the rigid uterus and already raised baseline intrauterine pressure. Q.48. Is there any role of conservative/expectant • Cervical dilatation is the best index for progress management in abruption placentae? of labor. Ans: Expectant management has a role • With a dead fetus there is no time limit for • In cases of mild placental abruption with obtaining a vaginal delivery, unlike in earlier pregnancy less than 34 weeks,with stable times when it was 6-8 hours. It can now be maternal and fetal condition and normal safely extended to 24 hours. laboratory values. This management should be • Maternal outcome depends on the adequate on an inpatient basis. expansion of intravascular compartment with • The aim is to prolong pregnancy to allow for fluid and replacement of blood, rather than on fetal lung maturity. the interval to delivery. • These patients have mild bleeding and pain and are hemodynamically stable. Q.47. If the fetus was alive in this case would • There should be regular assessment of maternal the management change? condition (maternal hematologic parameters and coagulation profile). Ans: Yes, the management would be more complex • The fetus should be monitored closely in this as period with nonstress test and biophysical • Both mother and fetus are at risk of death. profile. • Two groups are identified, one where the uterus • Betamethasone to be administered. is rigid and another where the uterus is soft. • Tocolysis in select cases. When the fetus is alive and the uterus is rigid • Anti-D where needed. 1. It is presumed that the abruption is large but • Pregnancy should be terminated when there is probably less than 50%. recurrent bleeding, or any feature of fetal 2. Allowing such patients to go into labor means compromise such as fetal growth restriction, that chances of fetal distress will be as high as oligamnios, abnormal CTG or BPS. 90%. • With no maternal or fetal compromise still 3. Hence these patients should be prepared for induction of labor at term is advocated. emergency cesarean section except when the fetus is previable or the maternal condition is Q.49. What tests are performed to assess fetal serious and will deteriorate with surgery. lung maturity? 4. The rest of the management (replacement of Ans: The Lecithin to Sphingomyelin L/S ratio is blood, expansion of intravascular volume with the test used for assessing fetal lung maturity. fluids and work up for DIC) should continue • If the ratio is greater than 2, the patient should simultaneously. be delivered. 178 Case Discussions in Obstetrics and Gynecology

• There are 2 other rapid tests—fetal lung e. Postpartum hemorrhage of the atonic type, may maturity (FLM) and Phosphatidyl glycerol and be due to coagulopathy or development of in majority of patients under 36 weeks they Couvelaire uterus. show fetal lung immaturity. f. Amniotic fluid embolization. • Delivery should not be delayed because of these g. Puerperal sepsis. once L/S ratio is more than 2 as the chances of h. Fetomaternal hemorrhages can be large in developing RDS would be less than 5% and it abruption and risk of alloimmunization is would be of a mild variety. increased. There is need to give larger doses of anti-D. All patients to undergo a Kleihauer Q.50. Is tocolysis advocated in abruptio pla- Betke test to quantify the fetomaternal centae? hemorrhage and adjustment of anti-D dosage. Ans: i. Pulmonary edema, cesarean section and post- • Mild cases of abruption complicated by labor partum anemia are other major maternal may be given a trial of tocolytics to prolong the morbidities. pregnancy in order to achieve fetal lung j. Risk of recurrence in future pregnancies. maturity. • Many people say that tocolytics are Q.52. What is Couvelaire uterus and what are contraindicated as they worsen abruption. its implications? • Scientific evidence supports tocolytic therapy Ans: Couvelaire uterus is: in an environment where close maternal and • The condition in which severe bleeding occurs fetal monitoring is feasible and facilities for emergency cesarean section exist.1 into the subsequent to placental abruption. Q.51. What are the risks to the mother with • This impairs the ability of the myometrium to placental abruption? contract and is one of the reasons for postpartum hemorrhage in a case of abruption. Ans: a. Chances of maternal mortality around 1% and • Diagnosis of Couvelaire uterus is confirmed at higher morbidity. The maternal mortality is on cesarean section/laparotomy where the uterus account of severe hemorrhage and also due to shows bluish discoloration (because of blood disseminated intravascular coagulation seeping under the serosa) and the uterus is large which again causes further bleeding and renal and flaccid. failure. • Effusion of blood can also be seen under the b. Hypovolemic shock, especially in concealed tubal serosa, in the connective tissue of the hemorrhage where blood loss is underestimated. broad ligaments, in the substance of the ovaries c. Disseminated intravascular coagulation. and also free in the peritoneal cavity. Coagulopathy present in 10% cases of • It is not an indication to perform cesarean abruption. Fulminant DIC ensues within 1-2 section or hysterectomy per se. hours of complete abruption and is present in • Uterotonics are used to make the uterus contract 40% of cases with fetal demise. and control postpartum hemorrhage. d. Acute renal failure attributed to hypovolemia • The bleeding is not severe enough to warrant a as well as to DIC. hysterectomy. Antepartum Hemorrhage 179

Q.53. What is the recurrence rate of placental j. Of the surviving infants there are adverse abruption and what is the prognosis for future sequelae in the form of neurological deficit pregnancies? within 1 year of life and cerebral palsy, etc. Ans: • The recurrence rate is 6-17% after one episode Q.55. If placenta previa and abruptio placentae and increases to 25% after second episode. are ruled out, what could be the cause of APH? • Severe abruption causing fetal demise has the Ans: In about 47% cases the cause of bleeding is same outcome in next pregnancy in not known or it may become evident later on.The approximately 7% of cases.14% of future causes identified are: pregnancies end in abortions and almost 30% a. Marginal sinus rupture 60%. do not produce a living child. b. Show 20%. • Incidence of recurrence may be reduced by c. Cervicitis 18%. correction of causative factors such as poor d. Trauma 5%. nutrition, smoking, low folate intake and poor e. Vulvovaricosities 2%. weight gain. f. Genital tumors, hematuria, genital infection and • Induction of labor before term has no proven vasa previa 0.5% each. benefit for preventing recurrence. These are grouped under “unclassified bleeding” and marginal sinus rupture is the most Q.54. What are the fetal risks associated with important cause. Minor cases of placenta previa and placental abruption? abruption also get included in this group. Ans: a. High incidence of perinatal mortality and Q.56. What is marginal sinus rupture and why morbidity which is directly proportionate to the is it important? gestational age, 50% of these are still births. Ans: Incidence varies from 4.4% to 68% depending • This is a diagnosis of exclusion and can be on the newborn care available. Besides confirmed or ruled out after delivery. prematurity, other causes contributing to fetal • The speculum examination is negative. mortality are fetal growth restriction, con- • There is peripheral placental separation which genital malformations and associated manifests as a clot at the junction of the maternal hypertension. membranes and the placental border on b. Fetal growth restriction in approximately 80%. examination of the placenta after delivery. c. Congenital malformations (4.4%) and are • It can rarely be diagnosed by ultrasonography. mostly involving the central nervous system. • Its importance is because of its association with d. Fetal anemia as a result of fetal bleeding and preterm labor and premature rupture of deranged hematology. membranes e. Respiratory distress syndrome. • Patients with chronic bleeding may also develop f. Hyperbilirubinemia. chorioamnionitis. g. Fetal hypoxia. h. Hypovolemic shock of the newborn, although Q.57. What is the management? rare, it can be associated with any kind of APH. Ans: i. A fetal and neonatal coagulopathy associated • As the bleeding is usually not severe and it stops with abruption, but it is very uncommon. spontaneously, the management is expectant. 180 Case Discussions in Obstetrics and Gynecology

• Maternal and fetal monitoring is carried on at Q.60. Are there any conditions where vasa regular intervals previa should be suspected antenatally? • Pregnancy is allowed to progress to term. Ans: • Some people advocate induction of labor at 38 • Vasa previa is associated with placentas that are weeks citing placental dysfunction as a cause, low-lying, and have succenturiate or multilobed and risk to the fetus. composition. • Opinion is in favor of intervention when fetus • It is also seen with velamentous insertion of cord is in distress. • Tocolytics can also be used safely to prevent which in turn is found more commonly with preterm labor. artificial reproductive techniques such as in- vitro fertilization (due to disturbed orientation Q.58. What is vasa previa? of the blastocyst on implantation). It is also more Ans: common in multiple pregnancies. • Vasa previa is a rare condition (1 in 2000-3000 • Antenatal diagnosis is possible in these deliveries) wherein the fetoplacental blood conditions by color Doppler visualization of vessels rather than the placenta are overlying the these vessels by endocavitary ultrasound. internal cervical os, traversing the membranes • Sometimes the diagnosis is made antenatally and lying ahead of the presenting part. during a p/v examination before or during labor, • In this position they are likely to get lacerated or at the time of amniotomy when these vessels at the time of membrane rupture and may cause are felt. severe fetal bleeding. • During labor they may get compressed by the Q.61. How is Apt test performed? presenting part and cause fetal hypoxia. • It is associated with a very high fetal mortality Ans: (75-100%). • This is a simple test to differentiate fetal from • As the bleeding is mainly fetal in origin the risk maternal blood. to the mother is not much increased. • 5 ml of tap water is taken in two test tubes and six drops of 10% KOH is added to each. To Q.59. How to diagnose Vasa previa? one test tube add 3 drops of vaginal blood and Ans: to the other add 3 drops of maternal blood. • Diagnosis of vasa previa is usually made when • After 2 minutes the maternal blood in test tube there is bleeding following amniotomy or after will turn green yellowish brown. spontaneous rupture of membrane. • If there are fetal red cells in the other test tube • There is fetal bradycardia accompanying,or containing vaginal blood the KOH will remain tochographic evidence of fetal compromise is pink (Loendersloot,1979). present. • A bedside test is done to find out if the bleeding Q.62. How to manage vasa previa? is of fetal origin by testing the fetal hemo- globins’ ability to withstand alkali denaturation. Ans: As the fetal mortality and morbidity is very It can sometimes be diagnosed on antenatal or high, emergency cesarean section must be done intranatal p/v examination when vessels are felt, once diagnosis is confirmed by presence of fetal or before doing an amniotomy. red cells in the vaginal blood. Antepartum Hemorrhage 181

Q.63. What are the recent advances in the allowing one to plan the management timely diagnosis and management of APH? and reducing the risks. Ans: Human recombinant factor VIIa Safety of regional anesthesia for cesarean section • Is a new, potent drug for control of obstetric in cases of APH: hemorrhage specially severe bleeding • Cesarean section in a case of placenta previa associated with abnormalities of hemostasis. has commonly been performed under general • This medication complexes with tissue factor anesthesia rather than regional anesthesia and promotes the activation of factors IX and because of fear of hemorrhage and hypotension. X and synthesis of thrombin. • Recent data suggest that the hemorrhage may • It is given as a bolus injection of 60-100 μg/kg. increase under general anesthesia and that and the effect is seen after 10 minutes. regional anesthetic techniques-both epidural Cervical cerclage and spinal anesthesia are quite safe for both • In cases of placenta previa with prematurity in elective and emergency cesareans in cases of order to prolong pregnancy. placenta previa. • A recent Cochrane systematic review looked at the information available (Neilson 2003) and REFERENCES found that cervical cerclage may reduce the risk 1. Arias F, Daftary SN, Bhide AG. Bleeding during of delivery before 34 weeks (RR 0.45, CI 0. pregnancy. Practical guide to high risk pregnancy and 23-0.87) and that of the birth of a baby less than delivery 2008;(3):323-55. 2 kg. (RR 0.34, CI 0.14-0.83) or having a low 2. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC et al. Obstetrical Hemorrhage. Williams Obstetrics 5 minute Apgar score (RR 0.19, CI 0.04-1.00). 2010;(22):809-54. • Conclusion is to encourage further work on this 3. Studd J, Tan SL, Chervenak FA. Antepartum subject. hemorrhage. Progress in Obstetrics and Gynaecology Role of MRI to study the placenta. 2006;(17);203-16. • Compared to ultrasound imaging it allows for 4. Zutshi V, Kumar A, Batra S. Problem based Approach better visualization of soft tissues, clearer in Obstetrics and Gynaecology: 2002;(1):135-41. definition of cervix and reduced margin of error 5. David K James, Carl P Weiner, Philip J Steer, Bernard Gonik. Bleeding in Late Pregnancy. High Risk from overfilling of bladder. Pregnancy Management Options 2006;(3):1259-75. • MRI has made possible the antenatal diagnoss 6. Renu Mishra. Antepartum hemorrhage. IAN Donald’s of placenta accreta, increta and percreta Practical Obstetric Problems 2006;(6):310-32. Shikha Sharma 15 HIV Positive Pregnancy

The human immunodeficiency virus (HIV) is a at reducing the vertical transmission of HIV small RNA retrovirus that causes the clinical infection. disease termed as the acquired immunodeficiency All women should be counseled to undertake syndrome (AIDS) was first described in 1981.1,2 HIV testing prepregnancy or early pregnancy or Roughly one-third of infected patients develop whenever they come in contact with the health care clinical AIDS within the first five years after system. Therefore, the concerned women would be inoculation and 75 percent by the end of ten years.3 counseled to undertake HIV Test. Before The virus may be transmitted through: undertaking the test, pretest counseling is • Unprotected anal or vaginal intercourse performed which includes: especially in the presence of genital ulceration, • Information regarding HIV and modes of • Sharing of contaminated needles, acquiring infection • Unscreened blood products, • Effect of HIV on pregnancy • Vertical transmission either antepartum, • Parent to child transmission and its prevention intrapartum or postpartum (breast milk). • Safe sex practices. Early HIV infection is characterised by a high As antibodies to HIV are far easier to detect viral load. The main target of HIV is to the CD4 than the virus itself, it is the basis for the most lymphocyte population and which are gradually lost widely used screening test of HIV infection. To during the latent phase. Loss of CD4 lymphocytes confirm an initial positive a repeated Enzyme reduces both cell-mediated immunity and humoral Linked Immunoassays (ELISA)/Rapid tests or immunity, leading to the development of infections electrophoresis test for a multiple of specific viral and allowing more rapid replication of HIV. proteins, usually the Western blot4 [specific antibody to viral core protein (p24) and envelop CASE 1 glycoprotein (gp41)] is done. This protocol has a specificity of 99.4% and a false positive rate of less Mrs A, a primigravida, at 20 weeks gestation has than 0.001%, when used with the modern ELISA/ come to ANC Clinic for the first time. Will you Rapid tests and Western blot methods.5 In the counsel the women to take HIV test? If yes, how PPTCT centre (or asymptomatic individuals) 3 HIV is HIV Testing done? kits based on three different principles and/or HIV testing is the first step towards PPTCT different antigens are used. The Strategy/Algorithm (Prevention of parent to child transmission) aimed followed is:6 HIV Positive Pregnancy 183

1. If first test kit shows positive result (A1+), Ans: The pregnant woman with HIV infection proceed to the second and third kit. should be provided with appropriate counseling 2. If second and third kit also shows positive result about her disease, its implications for herself and

(A1+ A2+A3+), test is labelled as positive. her baby, and the importance of medical care in 3. If both second and third kit show negative result the post-test counseling.

(A1+A2-A3-), test result is reported as negative. After taking detailed history, performing clinical (Here the reasoning being that 1st screening test examination and investigations, we assess the stage is as sensitive as possible while 2nd and 3rd of disease and identify risk factors, to see whether test should have highest specificity). patient requires immediate antenatal (anti-retroviral 4. If either of the second or the third kit shows therapy or treatment for accompanying infections) negative result, test is labelled as indeterminate. treatment or not. 5. “Indeterminate” (discordant) test result should be repeated on second blood sample after 4-6 Q.3. What is important to be elicited in history weeks or Western blot test performed. Western and clinical examination? blot assay also gives indeterminate results in Ans: History and clinical examination should be some cases. able to clinically stage the disease and be able to Following the availability of results post-test aid in diagnosing the specific opportunistic counseling is performed. infection if present. Therefore the following points should be kept Q.1. How is counseling different if the test is in mind while taking history: negative or positive? a. Detail and duration of presenting complaints if Ans: If Test is HIV negative: any • Client is advised regarding safe sex practices • Prolonged history (>1 month ) and if she falls in high risk category she is – fever (intermittent or continuous) explained about window period and the – cough requirement of repeat test after three months. – diarrhea If HIV test is positive: – weight loss(>10% body weight) • Results are disclosed on one to one basis • Associated symptoms - acquiring infections maintaining utmost confidentiality. early. • Partner testing and disclosure is important. b. Obstetric history • Course of infection and transmission to the fetus • Parity is important- if multiparous women and infant and the effect of pregnancy on present in first trimester, MTP can be offered infection so as to make an informed choice • Record of earlier HIV testing (previous regarding continuation of pregnancy or MTP. pregnancy) • Information is provided regarding measures to • HIV status of previous issue decrease mother to child transmission. c. Past history • Importance of delivering in a multidisciplinary • Any prolonged illness setting is emphasized with involvement of other • Blood transfusion relevant health professionals. d. Family/Sexual/Personal History • Husband’s HIV status if known Q.2. Mrs A, was tested positive for HIV during • Sexual contact –self/partner routine screening. How will you proceed? • Drug abuse/alcohol intake/smoking 184 Case Discussions in Obstetrics and Gynecology e. Vaccination History the virus, most HIV-infected people have no • BCG symptoms for the first five years or so. • Hepatitis A vaccine HIV antibodies usually take between 2 to 12 • Hepatitis B vaccine weeks to appear in the blood-stream. The period Clinical Examination before antibodies are produced is the “window Should include a detailed general physical period” during which, although the person is examination followed by systemic and local particularly infectious because of the high examination as we follow with other patients but concentration of virus in the blood, he or she will with emphasis on the following. test negative on the standard antibody blood test. General Physical Examination Asymptomatic carrier state • General build and nutritional status (including Infected people have antibodies (i.e. test positive weight and height). on routine screen for HIV) but no overt signs of • Generalized lymphadenopathy disease except persistent generalized • Fundus examination (CMV retinitis ) lymphadenopathy. • Skin examination for lesions or abnormal AIDS-related complex (ARC) patches (opportunistic infections) A person with ARC has illnesses caused by damage • Mouth - inspection for candidiasis to the immune system, but without the opportunistic Systemic Examination – should include detailed infections (Fig. 15.1) and cancers associated with • Neurological examination AIDS, but they exhibit one or more of the following – Visual fields and signs of neuropathy – Focal neurologic deficit clinical signs; unexplained diarrhea lasting longer • Respiratory examination than a month, fatigue, malaise, loss of more than – Opportunistic infections 10 per cent body weight, fever, night sweats, or • Abdomen other milder opportunistic infections such as oral – Hepatosplenomegaly, masses thrush, generalized lymphadenopathy or enlarged Local examination should include spleen. Per speculum and Per vaginum examination – to Patients from high-risk groups who have two rule out or more of these manifestations (typically including • Other STD’s generalized lymphadenopathy), and who have a • Look for bacterial vaginosis, candidiasis decreased number of T helper lymphocytes are • Cervical cancer considered to have AIDS-related complex. AIDS Q.4. What are the various stages of disease in AIDS is the end-stage of HIV infection. A number HIV infection? of opportunist infections commonly occur at this Ans: The clinical features of HIV infection have stage (Fig. 15.1). been classified into four broad categories.7 Initial infection Q.5. How do the various opportunistic infections Except for a generally mild illness (fever, sore throat present in HIV-infected individuals? Is there a and rash) which about 70 per cent of people relationship between these infections and CD4 experience a few weeks after initial infection with count of these individuals? HIV Positive Pregnancy 185

Fig. 15.1: Relationship of CD4 count to development of opportunistic infection (Source: See Reference 9)

Ans: To diagnose various opportunistic infections Oropharyngeal Candidiasis we should know about their clinical features (sign Caused by a common yeast fungus, oral thrush and symptoms). presents with soreness and redness, with white plaques on the tongue, and in the mouth and throat; Tuberculosis and sometimes a white fibrous layer covering the When the immune system breaks down, as in HIV tonsils and back of the mouth. Infection of the infection, tuberculosis becomes active and the esophagus presents with pain behind the person becomes contagious to others. HIV– breastbone. positive individuals are 30-50 times more likely to develop active tuberculosis than HIV negative Cytomegalovirus Retinitis people.8 of the eye (retina) which may lead to blindness. Persistent Generalized Lymphadenopathy Lymph nodes are larger than one centimeter in Pneumocystis Carinii Pneumonia diameter, in two or more sites other than the groin Symptoms can include a dry, non-productive cough; area for a period of at least three months. inability to take a full breath and occasional pain on breathing; and weight loss and fever. Kaposi’s Sarcoma A tumor featuring reddish brown or purplish Toxoplasma Encephalitis plaques or nodules on the skin and mucous Protozoal infection in the central nervous system, membranes. It is characterized by lesions in the presenting with focal neurological signs such as mouth or gut; or lesions are generalized (in two or mild hemiplegia or stroke, resulting from damage more places) or rapidly progressive or invasive. to part of the brain, seizures or altered mental status. 186 Case Discussions in Obstetrics and Gynecology

Hairy • Toxoplasma gondii IgM and IgG White patches on the sides of the tongue, in vertical • Chest X-ray with abdominal shield if clinically folds resembling corrugations. indicated due to suspicion of PCP or tuberculosis Cryptoccocal Meningitis A fungal infection in the central nervous system HIV Specific (Table 15.1) which usually presents with fever, headache, vomiting and neck stiffness. Table 15.1: Laboratory finding with HIV infection Herpes Zoster or Shingles Test Significance Viral inflammation of the central nervous system, HIV-enzyme- Screening test for HIV infection. presenting with localized pain and burning linked sensations, followed by vesicle eruption (skin immunosorbent blistering) and ulceration. assay (ELISA) Western blot Confirmatory test for HIV. Severe Prurigo or Pruritic Dermatitis Specificity when combined with Chronic skin inflammation in the form of a very ELISA >99.99%. Indeterminate itchy rash of small flat spot developing into blisters. results with early HIV infection, Severe or Recurrent Skin Infections HIV-2 infection, autoimmune disease, pregnancy and recent tetanus Warts; dermatophytosis or ring-worm; and toxoid administration. folliculitis (inflammation of hair follicles). The Figure 15.1 shows a relationship between CBC Anemia, neutropenia, and thrombo- cytopenia common with advanced various opportunistic infections and CD4 count of HIV infection. a HIV-infected individual. Absolute CD4 Most widely used predictor of HIV lymphocyte count progression. Risk of progression to Q.6. What investigations would you like to do an AIDS opportunistic infection or for this patient? malignancy is high with CD4 < 200 Ans: Routine cell/ml.

• Blood group and Rh factor CD4 lymphocyte Percentage may be more reliable than • Complete blood count (CBC) percentage the CD4 count. Risk of progression • Urine examination to an AIDS opportunistic infection • Glucose challenge test (GCT) or malignancy is high with • VDRL/TPHA (syphilis screening) for both percentage < 20% partners HIV viral load tests These tests measure the amount of • Ultrasound – To confirm gestational age, screen actively replicating HIV virus. for anomalies, placental localization at about Correlates with disease progression and response to antiretroviral 18 weeks. drugs.(available only in specialized HIV Related center) • Hepatitis A, B, and C serologies and LFTs p24 antigen Indicates active HIV replication. • Pap smear in all HIV positive women Tends to be positive prior to • Test for Chlamydia trachomatis and Neisseria seroconversion and with advanced gonorrhoeae in order to identify high-risk disease. behavior and the need for STD therapy (Source: See References 9 and 10) HIV Positive Pregnancy 187

Q.7. How would you manage Mrs A and when – Measles vaccine is contra-indicated during would you add prophylaxis for any oppor- pregnancy. tunistic infections in such a patient? • Counseling regarding breastfeed or replacement Ans: HIV positive pregnant women should be feed should be done during antenatal period so jointly followed by an HIV specialist, an that decision regarding the same is made prior obstetrician with expertise in managing HIV to delivery. pregnancy, and a pediatrician. Q.8. What are the criteria for starting antiretro- • Nutritional assessment, correct diet and weight viral (ARV) therapy in a HIV positive patient monitoring and counseling for the same. who has been diagnosed for the first time during • Regular ANC check-up routine screening in pregnancy? • Treat any associated RTI and STI (Respiratory tract and sexually transmitted infections) Ans: All HIV positive women should be referred to • Treat bacterial vaginosis, candidiasis the ART center for registration into care and • Care of opportunistic infections, if any, and if screened for medical eligibility for ART once they absent have been diagnosed in the PPTCT program. In the case of pregnant HIV – positive women, – Pneumocystis carinii prophylaxis is the CD4 count should be assessed as per the required if CD4 < 200. Co-trimoxazole national guidelines. These women should be jointly (Trimethoprim/sulphamethoxazole) DS managed by the ART center for the HIV/ART (160/800 mg) 1 tablet a day is the drug of aspects and the antenatal team for obstetric choice. concerns. – Toxoplasmosis if Antitoxoplasma IgG is The criteria for initiating ART in pregnant positive and CD4 < 100. Trimethoprim/ women are the same as for other adults (Table 15.2). sulphamethoxazole DS 1 tablet is given • WHO clinical stage 3 or 4 disease once a day. • WHO clinical stage 1 or 2 disease and CD4 – Mycobacterium Avium intracellulare < 200 cell/mm3 Complex (MAC) prophylaxis is added when • WHO stage 3 disease and CD4 < 350 cell/mm3 CD4 < 50 in the form of Azithromycin 1200 mg/week. However, routine prophylaxis for MAC is presently not recommended in Table 15.2 : When to start ART in pregnant women India.11 WHO stage CD4 testing not CD4 testing – Pneumococcus, Hepatitis A and B, available Influenza Vaccination should be performed (or results pending) available if available and not provided in 1 Do not treat prepregnancy period. 2 Do not treat – Postexposure Prophylaxis should be given 3 Treat Treat if CD4 for Hepatitis A, Hepatitis B and Varicella < 350 cells/mm3 Zoster exposure in the form of 4 Treat Treat irrespective immunoglobulins in all patients before the of CD4 CD4 count falls to < 200/cumm,11 after Note: Consider initiation of ART in asymptomatic HIV- consultation with an expert in HIV and viral infected pregnant women with CD4 < 250 cells/mm3 and hepatitis infection and screening for initiate before CD4 count drops below 200 cells/mm3 complete viral serology. (Source: See Reference 12) 188 Case Discussions in Obstetrics and Gynecology

The initiation of ART helps prevent Table 15.3: Managing OIs before starting ART transmission of HIV to the newborn and also Clinical picture Action benefits the mother’s own health. Once initiated, it should be continued postpartum. Any undiagnosed Diagnose and treat first; start ART The total lymphocyte count (TLC) is no longer active infection when stable used in the national ART program as global with fever evidence has shown that TLC is a poor parameter TB Treat TB first; start ART as recommended by HIV specialist for deciding on the initiation of ART, especially in asymptomatic persons, and monitoring the response PCP Treat PCP first; start ART when PCP treatment is completed to ART. 1. Women who need antiretro-viral therapy for Invasive fungal Treat esophageal candidiasis first; diseases: esophageal start ART as soon as the patient can their own health should continue with treatment candidiasis, swallow comfortably during pregnancy and afterwards. cryptococcal Treat cryptococcal meningitis, 2. HIV positive pregnant women who do not have meningitis, penicilliosis, histoplasmosis first; indication for antiretro-viral therapy should penicillosis, start ART when patient is stabilized have ART prophylaxis to prevent mother to Histoplasmosis or OI treatment is completed child transmission Bacterial pneumonia Treat pneumonia first; start ART when treatment is completed Q.9. Should ART be started in the presence of Malaria Treat malaria first; start ART when active Opportunistic Infections (OIs)? If not, treatment is completed then, when should it be started? Drug reaction Do not start ART during an acute Ans: Do not start ART in the presence of an active reaction OI. In general, OIs should be treated or stabilized Acute diarrhea Diagnose and treat first; start ART which may reduce when diarrhea is stabilized or before commencing ART. Mycobacterium Avium absorption of ART controlled Complex (MAC) and progressive multifocal Non-severe anemia Start ART if no other causes for leukoencephalopathy (PML) are exceptions, in (Hb< 8 g/liter) anemia are found (HIV is often the which commencing ART may be preferred cause of anemia); avoid AZT treatment, especially when specific MAC therapy Cytomegalovirus Treat if drugs available; if not, start is not available. infection ART • Some conditions which may regress following Toxoplasmosis Treat; start ART after 6 weeks of the commencement of ART include candidiasis, treatment and when patient is cryptosporidiosis and microsporidiosis and skin stabilized conditions such as seborrheic dermatitis, HIV- (Source: See Reference 12) related exfoliative dermatitis. • The OIs and HIV-related illnesses need Q.11. If the patient, Mrs A, has CD4 count treatment or stabilization before commencing < 200 cells/mm3, how would you start ARV ART (Table 15.3). therapy? Ans: Two different types of combination regimes Q.10. What are the group of drugs available and have demonstrated maximum virologic and their doses under ARV therapy? immunlogic efficacy: Ans: Different groups of drugs available for ARV A. Non-nucleoside Reverse Transcriptase Inhibitor therapy along with their side effects and ways to – based (1 NNRTI + 2 NRTIs): Preferred monitor them are listed in Table 15.4. NNRTI is Nevirapine and preferred NRTI are HIV Positive Pregnancy 189

Table 15.4: Anti-retroviral therapy

Drug Dose Common side effects Monitoring Nucleoside analogs (NRTIs) Zidovudine (AZT) 500-600 mg orally Anemia, neutropenia, Complete blood count and differential daily in two or three nausea, malaise, headache, (every 3 months once stable) divided doses insomnia, myopathy Didanosine (ddI) 300 mg orally once Peripheral neuropathy, CBC and differential, aminotransferases daily (for pill pancreatitis, dry mouth, K+, amylase, triglycerides, bimonthly formulation) hepatitis neurologic questionnaire for neuropathy Zalcitabine (ddC) 0.375-0.75 mg Peripheral neuropathy, Monthly neurologic questionnaire for orally three times aphthous ulcers, hepatitis neuropathy, aminotransferases a day Stavudine (d4T) 30 mg orally twice Peripheral neuropathy, Monthly neurologic questionnaire for daily hepatitis , pancreatitis neuropathy, aminotransferases, amylase Lamivudine (3TC) 150 mg orally twice Rash, Peripheral neuropathy No additional monitoring daily Abacavir (ABC) 300 mg orally twice Rash, fever-if occur, No specific monitoring daily rechallenge may be fatal Nucleotide analog (NRTIs) Tenofovir (TDF) 300 mg orally once Gastrointestinal distress Renal function daily Protease inhibitors Saquinavir (SQV) 600 mg orally three Gastrointestinal distress, No additional monitoring times daily headache Ritonavir (RTV) 600 mg orally twice Gastrointestinal distress, Bimonthly aminotransferases, uric acid, daily or 400 mg orally peripheral paresthesias triglycerides twice daily in combination with other protease inhibitors Indinavir (IDV) 800 mg orally three Kidney stones Bimonthly aminotransferases, bilirubin times daily level Nelfinavir (NLF) 750 mg orally Diarrhea No additional monitoring Three times daily Amprenavir 1200 mg orally Gastrointestinal, rash Cholesterol, triglycerides twice daily Lopinavir/ritonavir 400 mg/100 mg orally Diarrhea Cholesterol, triglycerides, every other (LPV-r) twice daily month aminotransferases Non-nucleoside reverse transcriptase inhibitors (NNRTIs) Nevirapine (NVP) 200 mg orally daily for Rash No additional monitoring 2 weeks, then 200 mg orally twice daily Delavirdine 400 mg orally three Rash No additional monitoring times daily Efavirenz (EFV) 600 mg orally daily Neurologic disturbances No additional monitoring (Source: See Reference 10) 190 Case Discussions in Obstetrics and Gynecology

Table 15.5: Recommended first-line antiretroviral regimens

Recommendation Regimen Comments Preferred first-line AZT+3TC+NVP AZT may cause anemia, which requires Hb monitoring, but is preferred regimen over d4T toxicity (lipoatrophy, lactic acidosis, peripheral neuropathy) Patients who develop severe anaemia while on an AZT-based regimen should not be re-challenged with AZT. In such cases, the patient should receive either d4T or TDF in place of AZT. For women with CD4> 250 cells/mm3, monitor for hepatotoxicity closely if started on the NVP-based regimen Alternative first- AZT+3TC+EFV EFV is substituted for NVP in cases of intolerance to the latter or if patients line regimens are receiving rifampicin-containing anti-TB treatment. EFV should not be used in patients with grade 4 or higher elevations of ALT or first trimester of pregnancy D4T+ 3TC + If the patients have anemia, a d4T-based regimen should be prescribed (NVP or EFV) Other Options TDF + 3TC + TDF substituted for AZT or d4T when there is toxicity or (NVP+EFV) or contraindications AZT + 3TC +TDF For individuals unable to tolerate NVP+EFV

Zidovudine (AZT), Lamivudine (3TC) or dosed twice daily, should be used irrespective of Stavudine (d4T). the patient’s body weight in adults and adolescents. Recommended choices of first-line regimens by This recommendation is now the preferred dose NACO (Table 15.5) when d4T is used as part of an ARV therapeutic Principles for selecting the first-line regimen: regimen. 1. Choose 3TC (Lamivudine) in all regimens 2. Choose one NRTI to combine with 3TC (AZT Q.13. What is fixed-dose combinations (FDCs)? or d4T) Ans: Currently, the National programme (under 3. Choose one NNRTI (NVP or EFV) NACO guidelines) provides the following B. Protease inhibitor based (1PI with or without combinations for first-line regimens.12 ritonavir boosting + 2NRTI): PI based regimens Stavudine (30 mg) + Lamivudine (150 mg). are costlier and associated with hyperglycemia, Zidovudine (300 mg) + Lamivudine (150 mg) new onset diabetes mellitus and require a close Stavudine (30 mg) + Lamivudine (150 mg) + monitoring in pregnancy and are second line Nevirapine (200 mg) drugs in ARV therapy. Zidovudine (300 mg) + Lamivudine (150 mg) + Nevirapine (200 mg) Q.12. What is the latest recommendation on Efavirenz (600 mg) stavudine (d4T) dosing? Nevirapine (200 mg) Ans: Previously, the preferred d4T dosing was Fixed-dose combinations (FDCs) are weight-based. Dosing for patients > 60 kg was preferred because they are easy to use, have recommended at 40 mg twice daily; dosing for distribution advantages (procurement and stock patients < 60 kg was recommended at 30 mg twice management), improve adherence to treatment and daily. thus reduce the chances of development of drug Based on review of available evidence, WHO resistance. The current national experience shows recommends that 30 mg formulation of stavudine, that bid (twice a day) regimens of FDCs are well- HIV Positive Pregnancy 191 tolerated and complied with. At present, second- • In cases with clinical or laboratory evidence of line drug regimens are not available under the hepatic dysfunction, e.g. due to hepatitis B/C national program. co-infection or other causes. • In patients with significant NVP side-effects/ Q.14. How will you start as NVP-based regimen? toxicity and in whom NVP re-challenge cannot Or What is lead-in period for NVP dosing? be done. Ans: The lead-in period for NVP dosing at 200 mg Patients on an NVP regimen who have been once daily for the first two weeks produces adequate switched over to EFV because of rifampicin- NVP levels. Due to enzyme auto-induction, NVP containing anti-TB treatment should be shifted back levels decline over two weeks and an increase in to NVP after completion of the TB treatment (unless the dosage to 200 bid is required to maintain other contraindications to NVP exist). adequate levels. Starting with the full NVP dosage • The change from EFV to NVP should be made without a lead-in period results in a very high serum two weeks after completing the anti-TB concentration of the drug and increases the risk of treatment. hepatotoxicity and rash. If NVP is restarted after • In this particular scenario, the lead-in dose/ more than 14 days of treatment interruption (due period is not necessary while shifting from EFV to NVP (i.e. should start immediately on bid to whatever reason, e.g. elevated liver enzymes), NVP dosage). the lead-in dosing is again necessary (Table 15.6). • Patient should be monitored closely for NVP Pls are not recommended in first-line regimen toxicity (hepatotoxicity), particularly if the CD4 because their use in an initial treatment regimen count is >250 cells/mm3, especially in women. essentially rules out second-line regimen options. EFV is contraindicated in pregnancy HIV- Table 15.6: Starting an NVP-based regimen infected women during the first trimester of pregnancy because of concerns of teratogenicity Starting nevirapine-based regimen Morning Evening Q.16. Is there any relationship between NVP and Lead-in NVP FDC (AZT or FDC (AZT or CD4 count? dose for the d4T + 3TC) d4T + 3TC) one pill Ans: NVP in women with CD4 count of 200-350 first 2 weeks one pill + NVP No NVP cells/mm3: There are data to show that women with one pill a CD4 count of > 250 cells/mm3 face a higher risk Escalate to full FDC (AZT or FDC (AZT or of severe hepatotoxicity when they are started on NVP dose after d4T + NVP) d4T + TC + NVP) an NVP based regimen. This happens most often 2 weeks one pill one pill in the first 6-12 weeks of therapy. It is recommended (Source: Reference 12) that such women should undergo the following. • Close observation over the first 12 weeks of Q.15. What are the indications and contra- therapy (every 2 weeks). indications of Efavirenz (EFV)? • Baseline and regular monitoring of liver Ans: Efavirenz (EFV) should be given to the enzymes (at baseline and at 2, 4, 8 and 12 weeks, following groups of persons: followed by symptom-directed evaluation). • In patients receiving concurrent rifampicin- • Patient education to encourage them to return containing anti-TB regimen (ATT) for the if there are problems such as rash, abdominal duration of the anti-TB treatment. pain, jaundice and fever. 192 Case Discussions in Obstetrics and Gynecology

If the liver enzymes increase to grade 3 or higher are receiving EFV and are in the second or third (ALT and/or AST > 5.1 times the upper normal trimester of pregnancy can continue the current limit) without an alternative explanation, NVP regimen. Alternatively, a triple Nucloside Reverse should be permanently discontinued. If symptoms Transcriptase Inhibitor (NRTI) or Protease Inhibitor suggesting hepatic toxicity, including rash, develop (PI) based regimen could be used. in pregnant women, NVP should be discontinued immediately. Q.18. How is a pregnant woman, who has For those with anemia during pregnancy, the already been diagnosed HIV +ve (whether in problem should be managed by conservative present pregnancy or earlier) and has CD4 methods, such as giving ferrous folate, other oral count 475 cells/mm3, managed? preparations and blood transfusion (if required). Ans: The maternal ARV prophylaxis for prevention of HIV transmission in HIV-infected pregnant Q.17. How will you monitor response to ART? women who do not need treatment for their own Ans: Response to ART is monitored by: health, two equally efficacious options 1. CD4 T-cell estimation recommended13 are:- 2. Viral load assays 1. Option A consists of a. RT-PCR (reverse transcriptase polymerase • Antepartum daily AZT chain reaction) • sd-NVP (Single dose NVP) at onset of labor b. b-DNA assay • AZT + 3TC during labor and delivery c. Nucleic acid based amplification (NASDA) • AZT + 3TC for 7 days postpartum Monitoring is done sd-NVP and AZT + 3TC intra and postpartum • 2-3 weeks—after initiating ART can be omitted if mother receives more than 4 weeks • Every 3-4 months—during ART of AZT during pregnancy. In breastfeeding infants, maternal ARV CASE 2 prophylaxis should be coupled with daily A primigravida, 8 weeks of gestation already on administration of NVP to the infant for birth until ART reports to ANC Clinic and has no problem one week after all exposure to breast milk has otherwise. What is the recommended treatment? ended. In non-breastfeeding infants, maternal ARV Women who have been receiving antiretroviral prophylaxis should be coupled with daily treatment for their HIV-1 infection should continue administration of AZT or NVP from birth until 6 same treatment during pregnancy, intrapartum and weeks of age. postpartum period except for Efavirenz (EFV). 2. Option B consists of: Although exposure to EFV during pregnancy is not For all HIV-infected pregnant women who are not an indication for abortion for women who become eligible for ART, ARV prophylaxis option B pregnant while receiving an EFV-containing consists of triple ARV drugs provided to pregnant regimen and are in the first trimester of pregnancy, women starting from as early as 14 weeks of NVP should be substituted for EFV. Close gestation until one week after all exposure to breast monitoring of those women who have CD4 cell milk has ended (Table 15.7). The recommended counts more than 250 cells/mm3 is required while regimens include: starting NVP as hepatotoxicity along with skin rash • AZT + 3TC + LPV/r has been observed in these women. Women who • AZT + 3TC + ABC HIV Positive Pregnancy 193

Table 15.7: ARV-prophylaxis options recommended for HIV-infected pregnant women who do not need treatment for their own health

Option A: Maternal AZT Option B: Maternal triple ARV prophylaxis Mother Mother • Antepartum AZT (from as early as 14 weeks Triple ARV from 14 weeks until one week after all gestation) exposure to breast milk has ended • sd-NVP at onset of labor* • AZT + 3TC + LPV/r • AZT + 3TC during labor and delivery* • AZT + 3TC + ABC • AZT + 3TC for 7 days postpartum* • AZT + 3TC + EFV • TDF + XTC + EFV *sd-NVP and AZT+3TC can be omitted if mother receives > 4 weeks of AZT antepartum Infant Infant Breastfeeding infant Breastfeeding infant Daily NVP from birth until one week after all exposure to Daily NVP from birth to 6 weeks breast milk has ended Non-breastfeeding infant Non-breastfeeding infant AZT or NVP for 6 weeks AZT or NVP for 6 weeks

• AZT + 3TC + EFV is associated with development of resistance to • TDF + XTC + EFV Nevirapine (NVP) therefore compromising the In breastfeeding infants, the maternal triple treatment option of the women and the child in ARV prophylaxis should be coupled with the daily future. If the patient has to undergo elective administration NVP to the infant from birth until 6 cesarean section Tablet Nevirapine should be weeks of age. given four to six hours prior to starting the In non-breastfeeding infants, the maternal triple surgery. ARV prophylaxis should be coupled with the daily 2. Antenatal Tab. Zidovudine (AZT) 300 mg BD after 28 weeks. Dosage of Lamivudine (3TC) administration of AZT or NVP to the infant from is 150 mg BD. Both are given intrapartum and birth until 6 weeks of age. 7 days postpartum. Q.19. What are the doses of the drugs used in Q.20. Should a HIV-positive patient be offered option A? LSCS or normal vaginal delivery? Ans: Ans: Mode of delivery should be decided upon after 1. Nevirapine – single dose tab. Nevirapine 200 taking into various factors which determine the viral mg to the pregnant women in labor 4-6 hrs transmission, the disease stage and the availability before expected time of delivery and Syrup of resources. Nevirapine 2 mg/kg body weight to the baby Patient having viral load of less than 50 within 72 hours of birth reduces the HIV copies/ml at 36 weeks can be offered vaginal transmission rate. It is cheap and can be given delivery if no obstetric contraindication. orally and therefore ideal for low resource Developed countries are recommending Highly settings. However, as it is a highly lipophilic Active Anti-Retroviral Therapy (HAART) which drug and stays in circulation in low reduces the HIV RNA load to undetectable levels concentration for almost one week, this regimen and thus reducing the HIV transmission. 194 Case Discussions in Obstetrics and Gynecology

• If cesarean section is done before onset of labor • ARV prophylaxis or rupture of membranes, it reduces perinatal • Partogram HIV-1 transmission by 50-87% even if no • Augment labor to expedite chemoprophylaxis is given by reducing the time • Avoid multiple per vaginal examinations the fetus is in contact with virus containing • Avoid early ARM. Preserve membrane as long maternal blood and cervicovaginal secretions. as possible However, it is associated with increased • Avoid fetal invasive procedure maternal morbidity, especially with advanced – (Like Fetal Blood Sampling. Fetal scalp disease. electrode, etc.). • Note should be made of any concurrent • Prophylactic antibiotics to be given untreated genital infections as viral load is 2nd Stage of Labor higher in vaginal secretions as compared to • Avoid episiotomy plasma in women with bacterial vaginosis or • If given, stitch without delay genital infections. • Avoid instrumental and traumatic delivery • If Bishop’s score is poor or prolonged and 3rd Stage of Labor difficult labor or Instrumental delivery is • Active management of third stage of labor anticipated, the women should be counseled • Given oxytocin immediately after birth • Safe disposal of placenta, blood and body fluids accordingly regarding the chances of HIV • Avoid operative procedure on baby before bath transmission during vaginal delivery. • Minimize risk of postpartum hemorrhage Therefore, HIV infected women should be • Repair genital tract lacerations counseled regarding the increased risks and • Carefully remove all products of conception potential benefits associated with cesarean delivery • Do not milk umbilical cord at the time of tying based on their HIV-1 RNA levels, CD4 count, the umbilical cord. current antiretro-viral therapy and presence of any • Management of neonate – 2 mg/kg single dose obstetric indication for cesarean section. Decision NVP within 72 hrs or Zidovudine (AZT) regarding mode of delivery should be taken 2 mg/kg 6 hrly for 6 weeks postpartum in accordingly. patients who were on ARV during antenatal period. Q.21. How would you manage labor in a HIV • DNA PCR is done to diagnose infection in the positive women? neonate at 6-8 weeks. A positive PCR result Ans: Intrapartum management is aimed at during window period must be confirmed by minimizing the exposure of the baby to infected demonstration of seroconversion for which cervicovaginal secretions. If the mode of delivery ELISA is done at 18 months. decided upon is cesarean section, standard pre- cautions should be taken before starting the cesa- Q.22. What are the recommendations for breast- rean section. Antiretro-viral prophylaxis should be feeding for a HIV-positive patient? given as discussed above. Ans: Decision regarding the type of feed, i.e. breast- Following precautions should be taken in case feed for replacement feed, should be made during of vaginal delivery. antenatal period itself depending upon whether 1st Stage of Labor replacement feed is Acceptable, Feasible, • Nutrition Affordable, Sustainable and Safe (AFASS). As • Psychosocial support to boost up morale mixed feed is associated with increased rate of HIV HIV Positive Pregnancy 195 transmission as compared to breastfeed alone, it is The consistent use of condoms is recommended suggested the weaning must be complete and abrupt for all HIV-infected women who are on ART. This after six months of breastfeed or earlier if is for the prevention of secondary transmission of replacement feed is AFASS. Dopamine agonist Tab. HIV from/to the partner, as well as the prevention Cabergoline 0.5 mg is indicated for milk of unplanned pregnancy.14 suppression along with tight breast support if decision is taken for replacement feed. Q.25. What pre-pregnancy counseling is given to a HIV positive woman? Q.23. What advice regarding contraception is Ans: HIV-infected women should have given to such a woman? preconceptional counseling to optimize their status Ans: Both permanent as well as temporary methods before pregnancy. of contraception may be offered to the couple • They should be educated and counseled about depending on whether they have completed their risk factors for perinatal HIV transmission, family. If they have not completed their family strategies to reduce those risks, and potential combined oral contraceptive pills along with the effects of HIV or treatment on pregnancy course use of Barrier contraception provides good and outcomes. contraceptive coverage along with protection from • They should be counseled on safe sexual STD’s. DMPA should be avoided as it adversely practices that prevent HIV transmission to affects the HIV related immune system. Intra- sexual partners and protect women from uterine Contraceptive Devices are also not acquiring sexually transmitted diseases and the contraindicated unless the female suffers from potential to acquire more virulent or resistant advanced disease or in the presence of high risk HIV strains. behavior in which case there is increased risk of • HIV positive women should be evaluated for PID. The couple is counseled regarding safe sex appropriate prophylaxis for opportunistic practices and maintaining relations with single infections and administration of medical partner. immunizations (e.g. influenza, pneumococcal, or hepatitis B vaccines) as indicated. Q.24. What is the interaction between ART and • Before taking the decision for pregnancy, the hormonal contraception? What is recommen- woman‘s nutritional status, her clinical stage ded? of disease and CD4 cell count be obtained and Ans: NVP, Ritonavir (RTV), Nelfinavir (NLF), if need be, change in ARV drugs to be done. Lopinavir/ritonavir (LPV/r) and Saquinavir/ ritonavir (SQV/r) result in reduced ethinyl estradiol Q.26. What is a discordant couple? Who is more levels. Estrogens are slightly increased by likely to be infected during sexual contact in case Atazanavir (ATV), Indinavir (IDV) and Efavirenz of a discordant couple? What is the advice (EFV). Thus, women on ART should not use given? hormonal contraception or should use it with Ans: A discordant couple is a couple where only caution and appropriate dose adjustment. They one partner is HIV positive. Women are more likely should consult a gynecologist for expert opinion. to be infected through sexual contact than men in Intrauterine contraceptive devices may be used such a case. with caution in HIV-infected women with close For HIV discordant couples where the woman monitoring because of the risk of intrauterine is HIV positive, the couple may be advised about infection. artificial insemination at the time of ovulation. 196 Case Discussions in Obstetrics and Gynecology

Where a woman who is HIV negative has a HIV- with daily administration of NVP to the infant positive partner, the risk of transmission to the from birth until one week after all exposure to woman, estimated as approximately 1:500 per breast milk has ended. In non-breastfeeding sexual act, can be reduced by limiting sexual infants daily administration of AZT or NVP is intercourse to around the time of ovulation. ‘Sperm recommended from birth until 6 weeks of age. washing’, whereby spermatozoa are separated from Stopping breastfeeding abruptly is not advisable surrounding HIV-infected seminal plasma by a anymore. Rather, it is recommended that it sperm swim-up technique can also be tried. should be done over a period of one month as rapid and abrupt cessation breastfeeding was Q.27. What are the salient points of WHO’s reported to be associated with adverse latest Nov 2009 guidelines which were revised consequences for the infant such as growth from previous (2006) guidelines? failure and increased prevalence of diarrhea. Ans: They are as follows13 • Mothers known to be HIV-infected (and whose • Initiation of ART for her own health is infants are HIV uninfected or of unknown HIV recommended for all HIV infected pregnant status) should exclusively breastfeed their women with CD4 cell count < 350 cells/mm3, infants for the first 6 months of life, introducing irrespective of WHO clinical staging; and for appropriate complementary foods thereafter, all HIV infected pregnant women in WHO and continue breastfeeding for the first 12 clinical stage 3 or 4 irrespective of CD4 cells months of life. Breastfeeding should then only count (earlier it was < 200 cells/mm3). stop once a nutritionally adequate and safe diet • For infants of mothers with HIV who are taking without breast milk can be provided. therapeutic ART for their own health, the • Mothers known to be HIV-infected may duration of prophylactic ART has been consider expressing and heat-treating breast increased irrespective of whether the infant is milk as an interim feeding strategy:15 breastfeeding or not. For breastfeeding infants, – In special circumstances such as when the it is recommended that daily NVP is instituted infant is born with low birth weight or is from birth until 6 weeks of age. For non- otherwise ill in the neonatal period and breastfeeding infants: daily AZT or NVP from unable to breastfeed; or birth until 6 weeks of age is recommended. – When the mother is unwell and temporarily • It is recommended that antepartum ARV unable to breastfeed or has a temporary prophylaxis should be started in all women from breast health problem such as mastitis: or as early as 14 weeks gestation (second trimester) – To assist mothers to stop breastfeeding: or or as soon as possible when women present late – If antiretroviral drugs are temporarily not in pregnancy, in labor or at deliver (earlier it available was 28 weeks). • If infants and young children are known to be • For all HIV-infected pregnant women who are HIV infected, the mothers are strongly not in need of ART for their own health, ARV encouraged to exclusively breastfeed for the prophylaxis option A or B as outlined in Table first 6 months of life and continue breastfeeding 15.7. In the women who receive Prophylactic as per the recommendations for the general Triple, a continued regimen of triple therapy is population, i.e. up to 2 years or beyond.15 recommended through the end of the (Mortality of HIV - infected infants was breastfeeding period. In breastfeeding infants, higher among those who stopped breastfeeding maternal ARV prophylaxis should be coupled early). HIV Positive Pregnancy 197

REFERENCES 8. WHO. AIDS, images of the epidemics, 1994. 9. Current Medical Diagnosis and Treatment Edited by 1. Gottlieb MS, Schroff R, Schanker HM, et al. Lawrence M Tierncy Jr, Stephen J, McPhee and Pneumocystis carinii pneumonia and mucosal Maxine A Papadakis, 8th edn. 1999. candidiasis in previously healthy homosexual men. 10. Current Medical Diagnosis and Treatment Edited by New England Journal of Medicine 1981;305:1425- Lawrence M Tierncy Jr, Stephen J, McPhee and 31. Maxine A Papadakis, 43rd edn. 2004. 2. Masur H, Michelis MA, Greene JB, et al. Outbreak of 11. Guidelines for Prevention and Management of community-accquired Pneumocystis carinii Common Opportunistic Infections/Malignancies pneumonia. New England Journal of Medicine among HIV-infected Adult and Adolescent, May 2007. 1981;305:1431-8. National AIDS Control Organisation (NACO), 3. PN Sahgal. Health for the millions. 1991 P-1, 8, 26. Ministry of Health and Family Welfare, Government 4. Food and Drug Administration (1989) Guidelines for of India. the Prevention of Human Immunodeficiency Virus 12. Antiretroviral therapy Guidelines for HIV-Infected (HIV) Transmission by Blood Products. Rockville, Adults and Adolescent Including Post-exposure MD: Food and Drug Administration. Prophylaxis, May 2007. NACO, Ministry of Health 5. Centres for Disease Control. Update: serologic testing and Family Welfare, Government of India:A4 Section, for antibody to human immunodeficiency virus. ART in Adults and Adolescents. Morbidity and Mortality Weekly Report 1988;36:833- 13. World Health Organisation, RAPID ADVICE, Use of 45. antiretroviral drugs for treating pregnant women and 6. Manual on Quality Standards for HIV Testing preventing HIV infection in infants, November 2009. Laboratories March 2007, Ministry of Health and 14. Antiretroviral therapy Guidelines for HIV-Infected Family Welfare, National AIDS Control Organisation Adults and Adolescent Including Post-exposure ( NACO) HIV Testing at counseling and testing sites Prophylaxis, May 2007. NACO, Ministry of Health (ICTCs/VCTCs and PPTCTCs),etc. Pg 16-20: and Family Welfare, Government of India: A6 Section, Laboratory Diagnosis of HIV/AIDS and National HIV ART in Pregnant Women, PPTCT and Previous Testing strategies Pg 6-15. Exposure to NVP. 7. Population Reports (1986). AIDS: A Public Health 15. HIV and infant feeding, Revised Principles and Crisis, Sr. L, No.6, July-Aug 1986. John Hopkins Recommendation, RAPID ADVICE November 2009, University, Baltimore, Maryland, USA. WHO. Rachna Sharma, Susmita Behera

16 Septic Abortion: A Clinical Review

INTRODUCTION pain, spasmodic cramping pain) association with diarrhea, constipation, burning mictu- Septic abortion was once the leading cause of maternal death around the world and the condition ration. remains still same in developing countries. In India 3. Fever—duration, pattern (continuous low 12% of maternal mortality is because of septic grade, spiking with chills rigor, progressively abortion. Mortality rate after voluntary termination rising. of pregnancy is 0.6/100000. It is unfortunate that 4. Other eliciting questions should be asked even after 40 years of legalization of abortion only regarding drug intake, foreign body insertion. 10% are registered.1 This patient had gone to a local doctor where she had evacuation done for excess bleeding DISCUSSION and all her problems started since then. A 32 years old P6L5 A1 presented to gynecology Usually illegal terminations are by unauthorized emergency with chief complain of bleeding per persons, in below standard set-ups with lack of vaginum on and off for 15 days, fever and pain proper antisepsis, so actual history is concealed and abdomen with vomiting for 3 days following an efforts should be made to elicit the facts. evacuation at private clinic. Menstrual History Detailed History of Present Illness • Whether she had previous normal cycles 1. Bleeding Per vaginum (BPV)—duration/ • Her cycle pattern if prolonged amount/onset acute or chronic. How it started • Date of last menstrual period and whether it was (whether continuous with last cycle/following overdue amenorrhea/intermenstrual). This patient had • Amount of flow in her last cycle, whether amenorrhea of 2 months for which she took normal or spotting only. medicines after which she had bleeding per Obstetrics History vaginum. In patients of septic abortion there is history of amenorrhea followed by interference • Parity of patient and desire to have children in followed by bleeding per vaginum. future. 2. Pain abdomen—duration, type (dull aching • Number of previous spontaneous abortions/ generalized, distension pain, suprapubic MTPs (method, person, place, eventful or not) Septic Abortion: A Clinical Review 199

Past Medical/Surgical History 7. Failed abortion (continued intrauterine or ectopic pregnancy)—failure to terminate History of previous hospital stay, surgical interventions, blood transfusions. pregnancy is relatively common with very early abortion < 6 weeks GA. Such patient presents Personal History with symptoms of continuing pregnancy such as hyperemesis, increased abdominal girth and • Contraception used (type of contraception used, breast engorgement. In addition an unrecognized regular or irregular use and any failure of ectopic pregnancy in postabortion period can contraception) • History of sexual abuse, promiscuity, STDs present as acute abdomen. Socioeconomic Status Q.2. What is septic abortion? Poor socioeconomic status unable to avail medical Ans: The term septic abortion refers to spontaneous services on time. miscarriage or therapeutic/artificial abortion Illiteracy—lack of awareness of contraceptive complicated by pelvic infection.2 options. Q.3. What are the causes of sepsis in abortion? Q.1. What are other clinical presentations? Ans: The uterus of pregnant women is normally Ans: Presentation depends upon type of protected by plug of mucus in cervix, and 2 complication patient develops. membrane surrounding the fetus.3 1. Patient usually presents with pain, bleeding and A septic abortion may be caused by any one or low grade fever caused by retained products of more of the following factors: conception (RPOC) known as postabortion 1. The membranes surrounding the fetus have triad. ruptured, sometimes without being detected. 2. Hemorrhage—excessive bleeding during or 2. The woman has sexually transmitted disease, after abortion signify uterine atony, cervical such as Chlamydia. laceration, uterine perforation, cervical 3. An intrauterine device (IUD) was left inside the pregnancy, a more advanced gestational age than anticipated or coagulopathy. uterus after a miscarriage or abortion. 3. Postabortion syndrome—patient presents with 4. Attempts were made to end the pregnancy, often lower abdominal pain, absent or decreased illegally, by inserting tools, chemicals, or soaps vaginal bleeding and at times hemodynamically into the uterus. compromised patients may have The infection can spread through fetal tissue to or retained product of conception (RPOC). endometrium and further to myometrium and 4. Patient presenting with abdominal pain, . can progress to peri- distension, fever, blood in stool, nausea and tonitis. Such patient may develop bacteremia and vomiting, failure to pass flatus are suggestive sepsis at any stage and progress to multiorgan of bowel injury. failure. 5. Patient presenting with suprapubic pain, hematuria, retention of urine, distension, Q.4. What are the examination findings in a case 2,3 features of peritonitis. Patient may have bladder of septic abortion? injury. Ans: General examination: Patient may have 6. Symptoms of sepsis—fever with chills, pain • Toxic look abdomen, foul smelling vaginal discharge and • Pallor according to amount of blood loss, persistent vaginal bleeding. hemolysis. 200 Case Discussions in Obstetrics and Gynecology

• Icterus due to hemolysis. • A large tender uterus may be a sign of • Peripheral edema due to hypoproteinemia, acute hematometra. renal failure • Adnexal tenderness or a mass may suggest • Ecchymosis due to coagulopathy, septicemia. pelvic inflammatory disease (PID), ectopic • Dry coated tongue dehydration, ketosis. pregnancy, , or broad ligament • Altered sensorium due to electrolyte imbalance. hematoma. Vital Signs Rectal Examination • Temperature—high to low grade fever. • A rectal examination must be performed if • Increase in trend may be the sign of progressive bowel injury is suspected. uncontrolled infection. • The presence of rectal tenderness and blood (or • Hypothermia could be the ominous sign of guaiac positive stool) makes the diagnosis of endotoxic shock. bowel injury almost certain. • Pulse and BP—tachycardia and hypotension Case examination revealed a moderately ill patient may be sign of hemodynamic septic shock. Temperature—102ºF • Respiratory rate—increase respiration rate Pulse—108/min because of acidosis, and accessory muscles of Respiratory rate—28/min respiration working due to pain and guarding BP—110/80 mm Hg Per abdomen of abdomen. • Mild distention, tenderness in lower abdomen, Abdominal Examination guarding and rigidity present • Suprapubic tenderness is common in the post- • Bowel sound present abortion period. Severe tenderness is unusual • No free fluid and may be a sign of hematometra, bladder Local examination—mild offensive discharge perforation or bowel injury present • Tenderness in other areas of abdomen (e.g. Per vaginum—Uterus was multiparous size, tender rebound tenderness, guarding) strongly and no adnexal mass —Cervical motion tenderness indicates instrumental injury complications (e.g. present, internal os admitting tip of finger. Patient perforation, bowel injury, bladder injury) was admitted and diagnosed the case of septic • A tender mass in suprapubic area suggests abortion. hematometra. Causative pathogens2 • Diminished or absent bowel sounds are sign of They are mixed and derived from normal vaginal developing peritonitis. flora, exogenous and sexually transmitted bacteria. • Escherichia coli and other aerobic, enteric, Vaginal Examination gram-negative rods. • Assess the quantity and rate of hemorrhage. • Group B (beta hemolytic) streptococci. • Look for possible vaginal and cervical • Staphylococcal organisms. laceration. • Bacteroides species. • Identify the source of bleeding (e.g. uterine, • Neisseria gonorrhea. cervical, vulva and vagina). • Chlamydia trachomatis. • Cervical motion tenderness on bimanual • Clostridium perfringens. examination may be suggestive of pelvic • Mycoplasma hominis. infection or ectopic pregnancy. • Haemophilus influenza. Septic Abortion: A Clinical Review 201

Q.5. How to make the diagnosis of septic Special Investigations abortion? • Urine and serum Beta-hCG if features Ans: A septic abortion is diagnosed when a woman suggestive of ectopic and choriocarcinoma. has temperature of at least 100.4°F for 24 hours or • X-ray chest for pulmonary tuberculosis. more, offensive and purulent vaginal discharge and • CECT abdomen and pelvis (optional). other evidence of pelvic infection such as lower • Histopathology and culture of retained POCs abdominal pain and tenderness.4 evacuated. Treatment and monitoring2,3 Q.6. What are the clinical grading of septic Prehospital care abortion? • Monitor vital signs, stabilize with intravenous Ans: The grading of septic abortion is1 fluid.

1. Grade I: Infection localized to uterus and its •O2 inhalation. Input/output charting then contents. transfer to tertiary center. 2. Grade II: Infection spreads beyond the uterus Management at Tertiary Care Center. to parametrium, tubes and ovary or pelvic Consultation with Gynecologists, Surgeons and peritoneum. Urologists. 3. Grade III: Generalized peritonitis and/or endotoxic shock, jaundice, or acute renal Anesthetist for ICU cares if required. failure. Definite management: • Tetanus toxoid/tetanus immunoglobulin Q.7. How to manage a septic abortion? • Antigas gangrene serum in established cases of Clostridium perfrigens on blood cultures. Ans: Investigations2,3 • Adequate blood, fresh frozen plasma and platelet Routine: to correct shock and deranged coagulation profile • Complete blood count if deranged. • Blood grouping and Rh typing. • Proper antibiotic therapy (broad spectrum • Kidney function test antibiotics) covering both gram-positive, gram- • Liver function test negative and anaerobic organisms. • Serum electrolytes • Screen all patients for Rh factor and administer • Blood culture and sensitivity anti-D if patient is Rh incompatible and ICT • Coagulation profile negative. • Random blood sugar • Serology for STD, HIV, Hbs Ag, syphilis Antibiotics • High vaginal swab, Culture and sensitivity • Cefoxitin: For gram-positive cocci and gram- • Urine routine/microscopic, culture and negative bacilli. sensitivity Doses: 2 gm IV 6 hourly and doxycyclin 100 mg • X-ray abdomen supine and erect to look for IV q 12 hour at least 48 hours after improvement free gas under diaphragm and multiple air fluid followed by tab doxycycline 100 mg BD for level 10-14 days. • Ultrasound abdomen and pelvis for retained • Gentamycin: For gram-negative coverage. POCs, adnexal mass, free fluid in abdomen and Doses: Serious infection with normal KFT: 3 pelvis. mg/kg/day q8h. 202 Case Discussions in Obstetrics and Gynecology

• Life-threatening infection: 5 mg/kg/day 6 - 8 • Unresponsive peritonitis or pelvic abscess. hourly with Monitoring of kidney function test • Septic shock or oliguria not responding to • Maintenance: 1 - 2. 5 mg/kg/day q8h. conservative treatment. • Ticarcillin and clavunate potassium (Timentin) • Presumptive therapy prior to identification of Surgical Options organism. Type of surgery needed depends on extent and type Doses: < 60 kg : 200 - 300 mg/kg/day IV q 4- 6 of pathology and they are: hour >60 kg: 3.1 g IV q 4-6 hour or 200-300 • Evacuation and curettage. mg/kg/day divided doses q 4-6 hourly not to • Posterior colpotomy exceed 18-24 gm/day • Laparotomy—to drain pelvic abscess, to repair • Ampicillin and sulbactam sodium: uterine perforation, gut injury with or without Doses: 1.5 (1 g ampicillin + 0.5 g sulbactam) performing colostomy to 3 g (2 g ampicillin + 1 g sulbactam) IV/IM • Hysterectomy q6-8h; not to exceed 4 g/d sulbactam Evacuation and Curettage • Imipenem and cilastatin sodium Dose: 250-500 mg IV divided q6h; not to • Give antibiotic coverage before 24 hours of the exceed 3-4 g/d, based on severity of infection procedure Alternatively, administer 500-750 mg IM or • If there is heavy bleeding, one may not wait for intra-abdominally q12h completion of 24 hours of antibiotics • Piperacillin and tazobactam sodium • Inj. Prostodin 1 hr before the procedure Dose: 12 g piperacillin + 1.5 g tazobactam IV • Procedure has to be carried out by senior in equally divided doses of 3 g q6h for 7- 10 d surgeon-gentle but complete evacuation has to • Clindamycin be done Useful as treatment against aerobic streptococci • Avoid perforation: It is likely as tissues are very and most staphylococci. Serious infections due friable to aerobic and anaerobic organisms: 600-1200 • Send the obtained tissue for histopathology and mg/d IV divided q6-8h culture • Cefotaxime • Complications: Perforation, bleeding Moderate-to-severe infections: 1-2 g IV/IM q6- Posterior Colpotomy 8h Indication: Pelvic abscess drainage- diagnosed by Life-threatening infections: 1-2 g IV/IM q4h constant throbbing , tenesmus, high rise • Vancomycin HCl of temperature, digital rectal examination showing 500 mg/d to 2 g/d IV tid/qid for 7-10 d bulging on anterior rectal wall and conformed on • Ceftriaxone pelvic USG. 1-2 g IV qid or divided bid depending on type Pre-requisite for colpotomy drainage are that and severity of the infection, to exceed 4 gram/ abscess must be day. • In midline • Adherent to cul-de-sac peritoneum Surgical Management 6 • Cystic or fluctuant Indication of surgical intervention: Complications • Retained products of conception. • False passage • Visceral injuries. • Intraperitoneal rupture of abscess • Presence of foreign body. • Bleeding Septic Abortion: A Clinical Review 203

Method of Posterior Colpotomy Laparotomy in case of Tubo-ovarian Abscess • Anesthesia, lithotomy position, catheterization • Midline vertical or paramedian incision • Examination under anesthesia to confirm area • Pus drained and sent for culture of maximum fluctuation • Omentum and small bowel separated from tubo- • Posterior lip of cervix grasped and pulled ovarian mass by gentle blunt dissection with upwards and forwards. fingers • Colpopuncture with wide bore needle on near • Separate ovary and tubes from uterus, sigmoid midline keeping direction of needle in axis of colon, and broad ligament pelvis • Apply clamps • Pus withdrawn and sent for culture – Clamp-1 Infundibulopelvic ligament • A transverse incision of 2 cm at the level of – Clamp-2 Broad ligament below ovary colpopuncture – Clamp-3 and ovarian tube • Blunt Kelly’s forceps introduced in pouch of and ovary removed, wash given, drain kept Douglas and opened to allow pus to drain. • Abdomen closed in layers • Septations in abscess cavity are broken with Hysterectomy gloved index finger • Drain kept and sutured with vaginal vault Indication • Drain should be removed after 48 hours to • Irreparable injury to uterus and bilateral tubo- prevent pressure necrosis of anterial rectal wall ovarian abscess • Avoid extension of incision to laterally to • Spreading gas gangrene infection in uterus. prevent injury to or uterine artery.

Laparotomy Method Indications • Maylard or midline incision • Pus drained out • Injury to uterus, or gut • Separate T-O masses from bowel, back of • Presence of foreign body in abdomen uterus, POD and broad ligament by upward and • Unresponsive peritonitis or pelvic abscess lateral maneuvering • First round ligament identified and ligated Method • Anterior fold of peritoneum opened • Transverse Maylard incision is ideal • Infundibulopelvic ligament ligated • Pelvic released and bowel packed off • Due precaution for ureter • pus drained out and sent for culture • Subtotal hysterectomy may have to be done • Foreign body removed • Vaginal vault kept open for drainage • Uterus, adenexa and intestines are explored for • Abdomen closed in layers. injury or bleeding • Uterine perforation repaired in single layer Q.8. What are the possible complications in • Intestinal perforation repaired in 2 layers Septic abortion? • Peritoneal lavage with warm saline Ans: Immediate:2,3 • Drain kept 1. Complications of anesthesia during surgical • Abdomen closed in layers MTP. 204 Case Discussions in Obstetrics and Gynecology

General anesthesia: Atony leading to severe color loaded with pus cells, strongly +ve for hemorrhage. albumin. Urine bilirubin, not present. Local anesthesia: Paracervical block causing Coagulation profile was within normal limit. accidental intravascular injection of anesthetic • Cervical smear showed gram-negative rods agents leading seizure, cardiopulmonary arrest, suggestive of E.coli. and death. • Ultrasonography showed minimal fluid 2. Neurogenic shock: Vasovagal syncope produced collection in uterine cavity with retained by stimulation of the during products dilatation • X-Ray showed dilated loops intestine 3. Hemorrhage: Due to uterine atony, cervical suggestive of paralytic ileus, no evidence of free laceration, uterine perforation, undiagnosed gas or foreign body cervical pregnancy, more advanced gestational • After correcting electrolyte imbalance, under age than anticipated, coagulopathy. antibiotic cover, evacuation was done. Patient 4. Perforation and peritonitis: Uterine, bladder improved after 48 hours, staying afebrile for and bowel perforation. Perforation with suction 24 hours with relief of symptoms. She was cannula is more dangerous than a solid metallic discharged on 7th day with advice for dilator. sterilization after 6 weeks. 5. Disseminated intravascular coagulation- Deterrence and Prevention2,3 especially in mid trimester abortions and rate 1. Educate patient about contraceptive methods is even higher for saline instillation techniques and deter them from using abortion as means due to electrolyte imbalance flaring of previous of birth control. tubercular infection. 2. Safe and legal abortion Sequelae 3. Easy access to prenatal care .and women to be Septicemia and its associated multi organ tested and treated for common STDs in first involvement—Acute renal failure, hepatic failure, trimester. paralytic ileus, DIC and death. 4. If a women thinks she might be miscarrying or has miscarried should call for health care Remote provider right away. 1. Infection and surgical intervention can cause 5. Prompt diagnosis and timely antibiotics and scar tissue leading to chronic pelvic pain prompt evacuation of retained POCs. (chronic PID) Medicolegal Pitfalls2,3 2. Intestinal obstruction • Underestimating amount and rate of bleeding. 3. Secondary infertility • Failure to diagnose uterine perforation and gut 4. Depression injuries. Diagnosis and Management in this Case • Failure to diagnose ectopic pregnancy. In the case stated patient was admitted and all • Failure to administer broad-spectrum antibiotic investigations sent. Patient was monitored for vitals, therapy and to treat shock. abdominal girth, input output, bleeding PV. Patient • Failure to obtain adequate history about recent was kept nil orally with maintenance fluids and termination of pregnancy. started on IV antibiotics (Tazobactam, piperacillin) • Failure to immediate evacuation of uterus of its • Lab findings showed Hb 10.5 gm%, TLC contents. 19000, Deranged LFT, urine—port-wine in • Failure of timely laparotomy. Septic Abortion: A Clinical Review 205

Special Case Reports 6. A rare case of intra-abdominal hemorrhage 1. A 37-year-old G4 P3 presented with fever and following in expert injection into abdominal right hip pain on POD11 from a second wall of calcium-heparin concentrate in a case trimester abortion. She was initially found to of septic abortion was reported.12 have septic arthritis involving right Sacroiliac Under research trial joint and Group B Streptococcal bacteremia Procalcitonin (PCT) as a monocytic marker for with right-sided Endocarditis. She further early diagnosis for septic abortion.13 developed septic pulmonary emboli and PCT was recently promoted as a sensitive and successfully treated with anticoagulation specific marker of systemic infection. Daily PCT therapy and parenteral antibiotics.7 values in a patient of septic abortion were compared 2. A woman developed necrotizing fascitis, with established markers of systemic inflammation. myonecrosis and TSS, after elective MTP. She Cultivated monocytes were analyzed by means of had confirmed Group A Streptococcus on blood IIF .additionally PCT release into culture medium culture and underwent surgical debridement. was examined. PCT was found superior to other She survived after aggressive surgical treatment inflammatory markers with regards to early and below knee amputation and antibiotics therapy.8 progression diagnosis. 3. An unusual case of uterocutaneous fistula that developed in a multiparous woman was reported REFERENCES after surgical evacuation of an incomplete 1st trimester septic abortion. Fistulous tract was 1. Das V, Agarwal A, et al. Septic Abortion. J Obstet detected on CT scan and to verify methylene Gynaecol India 2006:(56)3:236-39. blue was injected transcervically and dye flow 2. Slava V Gaufberg. Overview: abortion, complications: was seen through external opening of fistula. eMedicine Emergency medicine (http://emedicine. medscape.com/article/795001-overview). At laparotomy fistulous tract was excised with 3. Eva Martin. Infected abortion, septic abortion health 9 enclosing omentum. topic information http://www.healthopedia.com/ 4. A multigravida at 18 weeks became septic after septic-abortion/. laminaria tent placement and rupture of 4. Cunningham G, Leveno J, et al. Abortion.William’s membrane. She developed ovarian vein and Obstretics 23rd edn. McGraw Hill, USA 2005. IVC thrombosis and was treated successfully 5. Kander M, Anderson V. Septic abortion with with retrievable IVC filter, anticoagulation and Heamoglobinuria and renal insufficiency with special antibiotics. The filter was removed after ref to C. welchii infection. J Obstretics and Gynaecol Vol. 21, No 1. 9th day.10 6. Grimes A. Management of abortion. Te Linde’s So ovarian vein and IVC thrombosis are rare Operative Gynaecology, 9th edn; Lipincott Williams but life-threatening complication of severe and Wilkins, Philadelphia: 2003. obstetrics infection and IVC filters has been 7. McKenna T, O’Brien K. Group B streptococcal used to reduce the risk of pulmonary embolism bacteremia and sacroiliitis after mid-trimester dilation in patients who has risk of recurrent thrombotic and evacuation. J Perinatol 2009;29(9):643-45. or embolic events or underlying risk factors. 8. Dait JL, Levie M, et al. Group A Streptococcus causing 5. A women at 10 weeks gestation developed necrotizing fasciitis and toxic shock syndrome after MTP. Obstet Gynecol. 2009;113:504-06. abdominal pain, fever, leukositosis, peritoneal 9. SA Inmezer M, et al. Uterocutaneous fistula after signs, closed cervix and a viable pregnancy. surgical treatment of an incomplete abortion: Progression from acute to septic Methylene blue test to verify the diagnosis. Arch abortion was documented.11 Gynecol Obstet 2009;279(2):225-27. 206 Case Discussions in Obstetrics and Gynecology

10. Rochelson B, et al. Use of a temporary vena cava filter 12. Susemihl D, et al.Intraabdominal bleeding following in a women with septic abortion and inferior vena cava subcutaneous heparin application in septic abortion. thrombosis. A case report. J Reprod Med 2003;48(7): Geburtshilte Frauenheilkd 1976;36(2):126-27. 557-9. 13. Russwurm S, Wiederhold M, Oberhoffer M, 11. Lara-Torre E, Pinkerton JS. Viable intrauterine Stonans I, Peiker G, Reinhart K. Procalcitonin pregnancy with acute salpingitis progressing to septic (PCT) as a monocitic marker for early diagnosis abortion. A case report. J Reprod Med 2002;47(11): for septic abortion. Geburtshilte Neonatal. 959-61. 2000;204(1):34-38. SECTION 2: GYNECOLOGY

Deepti Goswami 17 Amenorrhea

Primary amenorrhea is diagnosed when there is • Physiologic delay of puberty — 20% absence of menses by age 14 years with the absence • Müllerian agenesis (Mayer Rokitansky Kuster of development of secondary sexual characteristics Hauser syndrome) — 15% or when there is absence of menses by age 16 years • Transverse vaginal septum or imperforate with normal development of secondary sexual hymen — 5% characteristics. • Absent hypothalamic production of GnRH — Secondary amenorrhea is diagnosed when 5% there is cessation of menstruation for at least 6 • Anorexia nervosa — 2% months or for at least 3 of the previous 3 cycle • Hypopituitarism — 2% intervals in a woman who was previously Q.2. What should be the approach to diagnosis menstruating. in this case? CASE 1 Ans: The evaluation of amenorrhea begins by establishing the presence or absence of the vagina. A 17-year old girl presents with primary ameno- The other important point is to note the presence rrhea. or absence of secondary sexual characteristics. The history and physical findings help in selecting tests Q.1. What are the likely causes of amenorrhea? to investigate primary amenorrhea.1-3 Ans: Primary amenorrhea is usually the result of a genetic or anatomic abnormality. In about 60% of Q.3. What is important to elicit in history? cases the underlying cause is abnormalities in the Ans: development of the ovaries, genital tract, or external • Childhood growth and development. genitalia. However, all causes of secondary • If she has short stature compared to family amenorrhea can also present as primary members. amenorrhea. • Ascertaining the age at menarche of the patient’s The usual causes are: mother and sisters because the age at menarche • Chromosomal abnormalities (most common in family members can occur within a year of being Turner syndrome) — 45% the age in others. 208 Case Discussions in Obstetrics and Gynecology

• History of cyclical abdominal pain which may b. General and neurological findings: be progressively worsening. Patient may • Fundi, visual field, sense of smell complain of difficulty in emptying the bladder • Stigmata of Turner syndrome—short or acute retention of urine. These features are stature, a webbed neck, low hairline, low- classical of mullerian tract obstruction in the set ears, a broad chest (“shield” chest) with form of imperforate hymen or transverse vaginal widely spaced nipples, epicanthal folds, septum. micrognathia, and an increased carrying • History of in a sexually active angle of the arms. woman would suggest shortness of vaginal • Palpation of inguinal areas for masses- length. which may be testis in case of androgen • Information regarding, exercise, diet, recent insensitivity syndrome. weight change, home and school situations, and c. Breast findings and Tanner staging: psychosocial issues. • Turner syndrome - Undeveloped breasts, • Symptoms of headache, hearing loss, visual shield chest, and widely spaced nipples. changes, fatigue, polyuria or polydipsia, • Delayed puberty is associated with under- galactorrhea, virilizing changes. developed breasts and sparse pubic hair. • Sense of smell-anosmia is present in Kallman • Mullerian agenesis, obstruction in mullerian syndrome. tract and complete androgen insensitivity • Any history of poor nutrition and chronic illness syndrome are associated with normal breast (anorexia nervosa, malabsorption, regional development. ileitis, renal disease), trauma, surgery, irradia- • Hyperprolactinemia may cause galactorr- tion chemotherapy and other medications. hea. • History of surgery for inguinal hernia in child- d. Pubic hair and external genitalia findings and hood should raise the suspicion for androgen Tanner staging: insensitivity syndrome. • Turner syndrome—normal growth of pubic • A sexual history should be obtained in a hair. confidential manner. • Delayed puberty is associated with sparse • Illegal drug use (especially marijuana). pubic hair. • Mullerian agenesis, obstruction in mulle- Q.4. What are the important points in her rian tract –normal pubic hair. examination? • Complete androgen insensitivity syndrome Ans: —Absent or sparse axillary and pubic hair. a. Vital signs, height and weight: e. Signs of androgen excess: Acanthosis nigricans, • Short stature is a feature of Turner syn- hirsutism, acne, striae, clitromegaly. These may drome. be seen in: • Tall stature may be seen in androgen • Androgen secreting tumors of the ovary. insensitivity syndrome and hypogonado- • Congenital adrenal hyperplasia. tropic hypogonadism. • Partial androgen insensitivity syndrome. • Cachexia, bradycardia, hypotension, hypo- • Cushing’s syndrome. thermia, yellow skin (carotenemia), body • Acanthosis nigricans and polycystic ovarian mass index (BMI) of less than 18 are disease usually present with secondary suggestive of anorexia nervosa. amenorrhea. Amenorrhea 209 f. Pelvic examination: • In patients with mullerian agenesis it is impor- Check for the presence of patent vagina, cervix tant to screen for (a) anomalies of the kidneys and uterus by per vaginum or per rectal (ranging from ectopic kidney to congenital examination. This will help detect imperforate absence) by USG and/or intravenous pyelo- hymen, vaginal septum, or congenital absence graphy (IVP) and (b) skeletal abnormalities by of the vagina. Rarely one may detect an ovarian X-ray of dorsolumbar spine. mass on examination. • If no uterus is found and patient lacks pubic If normal vagina or uterus are not obviously hair there is suspicion of androgen insensitivity present a pelvic ultrasonography (USG) helps syndrome. Women with complete androgen confirm the presence or absence of uterus, and insensitivity syndrome have no functional cervix. Ovaries can also be visualized on USG. androgen receptors and therefore do not have • Imperforate hymen – Bluish bulge seen at normal androgen-induced development of pubic and axillary hair. Further evaluation should introitus. This may be associated with lower include a karyotype (which would be 46 XY) abdominal swelling—The distended bla- and measurement of serum testosterone (which dder or a large cystic swelling anterior to would be in normal male range). rectum (). • Mullerian agenesis – Absent or shortened Q.6. How will you investigate a case of primary (if patient is sexually active) vagina with a amenorrhea with normal reproductive tract? rudimentary or absent uterus. Ans: • Androgen insensitivity syndrome – Shor- • If the presence of a normal genital tract is tened vagina without uterus. Gonads, which confirmed, the next step is to investigate the are the testes, may be palpable in the ingui- patient’s estrogen status. If the breasts have nal region in hernial sac. developed, then she has been exposed to estro- • Uterine findings—If the uterus is enlarged, gen, at least in the past. If no breast development hematometra is an important cause of has occurred, then the patient has never been uterine enlargement in patient presenting exposed to estrogen, the explanation is likely with primary amenorrhea. Pregnancy must to be failure of ovarian development or failure be excluded in girls with history of sexual of gonadotropin production by the pituitary. contact. • An endocrine evaluation should be performed. Serum follicular stimulating hormone (FSH), Q.5. How will you investigate a case of primary luteinizing hormone (LH), thyroid stimulating amenorrhea who lacks a normal vagina but has hormone (TSH), and prolactin should be well developed breasts? checked. Low or absent gonadal estrogen Ans: production (hypogonadism) is due to (a) abnor- • In the patient who appears to lack a normal mal ovaries or to (b) abnormal hormonal stimu- vagina, the first step is to distinguish true lation of otherwise normal ovaries. vaginal absence from an imperforate hymen or • Elevated FSH and LH levels in patients with complete transverse vaginal septum; ultrasono- primary amenorrhea are caused by gonadal graphy and at times magnetic resonance dysgenesis or premature ovarian failure. Turner imaging (MRI) may provide useful information. syndrome (45, XO karyotype) is the most 210 Case Discussions in Obstetrics and Gynecology

common form of female gonadal dysgenesis. A Q.7. How should a case of constitutional delay patient with primary amenorrhea, sexual of puberty be diagnosed and managed? infantilism (no normal breast development or Ans: This condition is characterized by lack of secondary sexual characteristics), an elevated physical development caused by delayed activation FSH value, and a 46, XY karyotype is typically of the gonadotropin releasing hormone (GnRH) diagnosed with Swyer syndrome. With absent pulse generator. The patient will be short for her or nonfunctioning ovaries, pituitary FSH pro- chronologic age and normal for her bone age. She duction continues to rise (hypergonadotropic will have underdeveloped breasts and sparse pubic hypogonadism). A normal karyotype is treated hair. Normally plasma levels of sex hormones and as premature ovarian failure. • Low FSH and LH levels (hypogonadotropic gonadotropin correlate with bone age, not with hypogonadism) may be a result of delay in chronological age. If gonadotropin levels are progression of normal maturation or an inability prepubertal in a patient who is otherwise healthy to secrete adequate amounts of gonadotropins. and has a bone age of >11 years it is unlikely to be The most common cause is constitutional delay constitutional delay and is due to gonadotropin 4 of growth and puberty. A detailed family history deficiency. may help detect this etiology, because it is often Cases with constitutional delay of puberty may familial. The condition may be clinically have short stature but history reveals consistent indistinguishable from that associated with growth rate and a family history of delayed puberty. hypothalamic or pituitary failure but following There is no abnormality on assessment of smell, features help in making the differential optic disks, and visual fields. diagnosis. These patients achieve pubertal development a. Kallmann syndrome, which can cause on their own when bone age has advanced to 13 hypogonadotropic hypogonadism is asso- years. Watchful waiting is therefore appropriate. A ciated with anosmia. rise in LH level is the sign of pubertal onset and b. MRI of the brain may detect abnormalities eventually there is a normal pubertal development like tumor or empty sella syndrome where and establishment of normal menstrual cycles. A pituitary is significantly affected causing girl who has bone age >11 years for several years decreased gonadotropin secretion. and continues to show low gonadotropic levels is c. Bone age radiograph: It helps distinguish likely to have permanent hypogonadism due to the cases of constitutional delay of puberty pituitary or hypothalamic cause. from those with permanent hypogonado- tropic hypogonadism. Q.8. How will you manage a case of hypo- • If signs or symptoms of hyperandrogenism are gonadotropic hypogonadism? present, serum testosterone, dehydroepiandro- sterone sulphate (DHEAS) and 17-hydro- Ans: xyprogesterone should be measured to assess • Low serum gonadotropins result from distur- for an androgen-secreting tumor of the ovary bances in pituitary or hypothalamus. Hypo- or adrenal gland and for adrenal hyperplasia. gonadism and delayed puberty in presence of • Presence of galactorrhea or obvious thyroid low serum gonadotropins warrant brain enlargement should be investigated with serum evaluation by MRI to look for anatomic defects prolactin and TSH levels. like tumor and empty sells syndrome. Amenorrhea 211

• The anatomic defect will not reverse sponta- • Estrogen therapy should be coordinated with neously (e.g., Kallmann syndrome; hypopitui- the use of growth hormone therapy. This should tarism; central nervous system tumors, trauma, be individualized for each patient so as to infection, or irradiation). By contrast consti- optimize both growth and pubertal develop- tutional delay, anorexia, hypothyroidism are ment. reversible causes which may respond to medical • These patients have a high rate of cardio- or surgical intervention or, in some cases, may vascular and renal anomalies and are resolve spontaneously. predisposed to Hashimoto’s thyroiditis. The • Management involves removal of any organic cardiovascular anomalies can be detected by lesion which may be detected on MRI. In cases echocardiography. Cardiac imaging should be where pituitary is affected levels of other repeated at 5- to 10-yr intervals and hyper- pituitary hormones should also be checked. tension should be aggressively treated. • Cases with absent sexual development require • Fertility is possible through donated oocytes. pubertal induction with low incremental doses Their pregnancy is a high risk one due to of estrogen.5 This is followed by cyclical associated cardiovascular problems and require estrogen-progesterone therapy or combined oral close monitoring contraceptive pills to correct hypoestrogenism and provide regular withdrawal bleed. Q.10. How will you manage a case of premature • When fertility is required ovulation induction ovarian failure? may be achieved by administration of exo- Ans: genous gonadotropins or, more physiologically, • Premature ovarian failure is diagnosed on the by pulsatile gonadotropin releasing hormone basis of amenorrhea and raised serum FSH treatment. levels (>40 IU/L).8,9 It may present with primary or secondary amenorrhea. Most of the cases are Q.9. How will you manage a case of Turner idiopathic. Karyotypic abnormalities in form of syndrome? 45XO (Turner syndrome), 47XXX and struc- Ans: tural abnormalities of X chromosomes need to • Turner syndrome (45XO karyotype) occurs due be excluded.10 Autoimmune disorders parti- to ovarian dysgenesis and functionally presents cularly of thyroid may coexist.11 with ovarian failure. The major health problems • Management of POF involves explanation of in Turner syndrome are: growth failure, the condition to the patient and counseling. The cardiovascular disease, gonadal failure, and two major medical issues are—hormone learning disabilities.6,7 replacement therapy and infertility. Young • From gynecologic perspective hormonal women with POF experience pathologically low replacement therapy should begin timely to serum estradiol levels which put them at risk of facilitate pubertal induction and should be osteoporosis. Pubertal induction with low doses continued until the age of 50 years. For pubertal of estrogen may be needed in those who have induction the dosing and timing of estrogen not developed secondary sexual characters. therapy should be aimed at mimicking normal Estrogen and progesterone replacement is pubertal development. Current recommen- required until the age of normal menopause. dations advocate use of microdose estradiol to Ovarian biopsy is not required as it does not initiate puberty. alter the management. 212 Case Discussions in Obstetrics and Gynecology

• These women may have associated pathology – Gonadectomy should be delayed until after like thyroid dysfunction which needs evaluation puberty in patients with complete androgen and management. Long term follow-up is insensitivity syndrome to ensure proper essential to monitor hormone replacement breast development which occurs due to therapy and for health surveillance. peripheral aromatization of testosterone • Adoption and oocyte donation are among the (secreted by the testis) to estrogen. available options for infertility treatment. • Androgen secreting tumor of ovary or adrenal • Embryo cryopreservation, ovarian tissue or will require surgical removal. oocyte cryopreservation and in vitro maturation • Rarely one may encounter patients with partial of oocytes hold promise in cases where ovarian androgen insensitivity syndrome, congenital failure is foreseeable as in women undergoing adrenal hyperplasia or rare enzymatic disorders cancer treatments. who present with virlilization at puberty and clitromegaly which requires surgical correction. Q.11. Which patients with primary amenorrhea require surgical intervention? CASE 2 Ans: • Surgery is required in patients with either A 30-year old lady presents with secondary congenital anatomic lesions or Y chromosome amenorrhea of 6 months duration. material. • Anatomic obstruction in mullerian tract may Q.12. What are the likely causes of amenorrhea? require drainage of hematocolpos, excision of Ans: First and foremost pregnancy should be vaginal septum and vaginoplasty. excluded. a. An imperforate membrane obstructing the The causes of secondary amenorrhea are: lower vagina requires a simple incision to • — 40% relieve the retained blood. All aseptic pre- • Hypothalamic dysfunction — 35% cautions should be taken and no instrument • Pituitary disease — 19% should be inserted inside the genital tract to • Uterine disease — 5% avoid contamination of the blood collection. • Other — 1% b. Vaginal absence requires the construction of an artificial vagina by one of a variety of Q.13. What is important to elicit in history? methods. The most common technique • Duration of amenorrhea, menstrual history being the Mc Indoe’s vaginoplasty. Newer techniques including the laparoscopic ones • Pregnancy to be ruled out are also described. • Contraceptive history—Recent initiation or • In patients with Y chromosome, gonadectomy discontinuation of oral contraceptive pills or should be performed to prevent the development depot medroxyprogesterone acetate. Amenorr- of gonadal neoplasia (usually gonadoblastoma). hea occurring after discontinuation of oral – In Swyer syndrome gonads are neither contraceptives (“post-pill” amenorrhea) is not ovaries nor testes but, rather, an undifferen- caused by pill use but is attributable to other tiated streak. They are at a significant risk causes. of developing gonadal cancer; hence the • Symptoms suggestive of hyperandrogenism- gonads must be removed.12 acne, hirsutism, voice deepening. Amenorrhea 213

• Exercise levels, weight loss or gain, eating • Breast- galactorrhea. habits, and recent stressful events or illness. • Abdomen- masses, tenderness. • Symptoms of other hypothalamic-pituitary • Evaluate genital tissue for signs of estrogen disease, including headaches, visual field deficiency. defects, fatigue, or polyuria and polydipsia. • Symptoms of estrogen deficiency, including Q.15. How will you investigate a case of secon- hot flashes, vaginal dryness, poor sleep, or dary amenorrhea? decreased libido. Ans: • Inquiry about galactorrhea and hirutism (and • The most common cause of secondary other signs of hyperandrogenism). amenorrhea is pregnancy. After pregnancy is • A thorough drug history should be taken, as ruled out, the initial work-up should be based several drugs can cause menstrual irregularity on patient history and physical examination or amenorrhea, such as danazol/androgenic findings. Menstrual periods may cease as a drugs, high-dose progestins, metoclopramide, result of faults in the hypothalamus, the pitui- the antipsychotic phenothiazines or previous tary, the ovary or other systems. treatment with cytotoxic agents. • The first tests to perform after pregnancy is • History of obstetrical catastrophe, severe bleed- ruled out are: ing (which may lead to Sheehan’s syndrome). – Progesterone withdrawal test • History of endometrial curettage (particularly – TSH multiple or after infection that might have – Prolactin level caused scarring of the endometrial lining), • After pregnancy, thyroid disease and hyper- endometritis (possible Asherman’s syndrome). prolactinemia are eliminated as potential • History of tuberculosis particularly with genital diagnoses. The risk of amenorrhea is lower with tract involvement. subclinical hypothyroidism than with overt • Past history of surgery, chronic diseases. disease. The treatment of hypothyroidism is simple with thyroid hormone replacement and Q.14. What are the important points in her leads to prompt return of ovulatory menstrual examination? cycles. Hyperprolactinemia is discussed under • Height and weight, body mass index (BMI) question 6. 2 – BMI > 30 kg/m seen in 50% of women with • The remaining causes of secondary amenorrhea polycystic ovarian syndrome (PCOS). are classified as normogonadotropic amenorr- – BMI < 18.5 kg/m2 may have functional hea, hypogonadotropic hypogonadism, and hypothalamic amenorrhea. hypergonadotropic hypogonadism; each is • Signs of systemic illness/cachexia associated with specific etiologies. • Neurological examination for visual field defects • Progestogen challenge test helps evaluate for • Skin exam, evaluating for a patent outflow tract and detect endogenous – Stigmata of PCOS: Hirsutism, acne, estrogen that is affecting the endometrium. acanthosis nigricans. Medroxyprogesterone acetate-10 mg is given – Stigmata of thyroid disorders: thyromegaly, for 5-10 days. A withdrawal bleed usually thin/dry skin, skin thickening. occurs two to seven days after the challenge • Stigmata of Cushing’s disease: striae, easy test. If she bleeds consider anovulation to be bruising. the cause of amenorrhea as is the case in PCOS. 214 Case Discussions in Obstetrics and Gynecology

• A negative progestogen challenge test signifies subsequently present with secondary amenorr- an outflow tract abnormality or inadequate hea due to ovarian failure. These women are estrogenization. An estrogen/ progestogen also at risk for cardiac problems and should be challenge test can differentiate the two investigated for cardiovascular anomalies. diagnoses. The test involves administration of estrogen and progesterone in a sequential Q.16. What are the principles of management manner, e.g., conjugated equine estrogen 0.625 in a case of secondary amenorrhea? mg per day from day 1 to 21 and medroxy- Ans: Management of patients with amenorrhea progesterone acetate 10 mg given in the last involves correcting any underlying disorder-for 7-10 days. example, weight loss, hypothyroidism or • A negative estrogen/progestogen challenge test hyperprolactinemia, treatment for anovulation typically indicates an outflow tract obstruction. associated with PCOS and replacement of cyclical A positive test indicates an abnormality within estrogen progesterone in women with estrogen hypothalamic-pituitary axis or the ovaries. deficiency (hypergonadotropic or hypogonado- • The gonadotropin levels can further help tropic) till the normal age of menopause. determine the source of the abnormality. • Normal or low FSH or LH levels suggest a Q.17. How will you manage a case of hyper- pituitary or hypothalamic abnormality prolactinemia? (hypogonadotropic hypogonadism). MRI of the Ans: Rule out use of medications (e.g. antipsy- sella turcica can rule out a pituitary tumor or an chotics, antidepressants, antihypertensives, empty sella. Normal MRI indicates a hypo- histamine H2 blockers, opiates) which may cause thalamic cause of amenorrhea. hyperprolactinemia. Medications usually raise • Elevated FSH and LH levels suggest an ovarian prolactin levels to less than 100 ng per mL. abnormality (hypergonadotropic hypogona- A prolactin level more than 100 ng per mL dism). suggests a prolactinoma, and MRI should be • Patients younger than age 40 with secondary performed. amenorrhea, and elevated FSH level (>40 IU/ Microadenomas (smaller than 10 mm) are slow L) are considered to have premature ovarian growing and rarely malignant. Treatment of failure. Patients with premature ovarian failure microadenomas should focus on management of should undergo investigation of the other infertility, galactorrhea, and breast discomfort. A endocrine organs (particularly thyroid) that have dopamine agonist helps in relieving symptoms and been known to fail along with the ovaries as restores fertility. Bromocriptine is effective, but part of a larger endocrinopathy. A karyotype cabergoline has been shown to be superior in should be considered in women with secondary effectiveness and tolerability. Bromocriptine is amenorrhea at age 30 years or younger to rule started in a dose of 2.5mg at bed time to minimize out complete or partial deletion of the X side effects (orthostatic hypotension, nausea, chromosome, or presence of any Y chromosome headache, fainting). The dose is slowly increased. material. Ovarian biopsy and antiovarian Some patients may require a dose of 7.5 to 10 mg antibody testing have not been shown to have per day. Cabergoline is started in a dose of clinical benefit. 0.25 mg per day once a week and then increased • Turner mosaic patients have a normal up to 3 mg weekly as required. The dose can be appearance and a history of childbearing but divided into twice weekly if necessary. Amenorrhea 215

Macroadenomas may be treated with dopamine • Elevated levels of 17-hydroxyprogesterone are agonists or removed with transsphenoidal resection diagnostic of adult-onset congenital adrenal or craniotomy, if necessary. hyperplasia. • Cushing’s syndrome is rare; therefore, patients Q.18. What are the causes of normogonado- should only be screened when characteristic tropic amenorrhea? signs and symptoms (e.g., striae, buffalo hump, significant central obesity, easy bruising, Ans: Two common causes of normogonadotropic hypertension, and proximal muscle weakness) amenorrhea are outflow tract obstruction and are present. The test used to detect Cushing chronic anovulation as is seen in PCOS. syndrome is the dexamethasone suppression The most common cause of outflow obstruction test. in secondary amenorrhea is Asherman’s syndrome (intrauterine synechiae and scarring, usually from Q.19. What are the important aspects of curettage or infection). Other causes of outflow tract manage-ment of PCOS? obstruction include cervical stenosis and obstruc- Ans: tive fibroids or polyps. • Treatment depends on the presenting com- Polycystic ovary syndrome (PCOS) is the most plaints of the patient. common cause of chronic anovulation. The primary • In patient with secondary amenorrhea or etiology of PCOS is unknown, but resistance to oligomenorrhea endometrial protection against hyperplasia is provided via hormonal therapy insulin is thought to be a fundamental component. i.e. cyclical progesterones (10- to 14-days per PCOS is a diagnosis of exclusion. Important month) or oral contraceptive pills which cause distinguishing features are its peripubertal onset and cyclical endometrial shedding. worsening with weight gain. Thin women are not • Prevention of obesity and metabolic defects: excluded from having this disorder. The primary treatment for PCOS is weight loss • To diagnose PCOS, any 2 of the following through diet and exercise. Modest weight loss 3 criteria should be present:13 (as low as 5%) can lower androgen levels, – Oligomenorrhea/amenorrhea improve hirsutism, normalize menses, and – Signs of androgen excess decrease insulin resistance.14 – Presence of polycystic ovaries on ultrasound • Insulin sensitizing agents such as metformin can (≥ 12 follicles-2-9 mm in size, increased reduce insulin resistance and improve ovulatory ovarian volume ≥ 10 mL) function. The usual dose of metformin is 500 mg twice a day or 850 mg twice a day. Most The diagnosis of PCOS is primarily clinical, common side effects are gastrointestinal. although laboratory studies may be needed to rule • Patients with associated hirsutism require out other causes of hyperandrogenism. Other management with antiandrogens- most common diagnoses should be particularly considered in being spironolactone and cyproterone acetate. scenario of sudden onset and rapid progression of • Infertility due to PCOS is managed with ovu- hyperandrogenic symptoms. In these cases levels lation induction with clomiphene. In resistant of testosterone and other androgens should be cases laparoscopic ovarian drilling or gonado- ascertained. tropins are needed to induce ovulation. • Significantly elevated testosterone levels • The insulin resistance associated with PCOS indicate a possible androgen-secreting tumor increases a patient’s risk of diabetes mellitus; (ovarian or adrenal). Raised DHEAS level is therefore, testing for glucose intolerance should suggestive of adrenal cause. be considered. 216 Case Discussions in Obstetrics and Gynecology

Q.20. What are the causes of Asherman’s including miscarriage, premature labor, spon- syndrome? taneous uterine rupture, placenta accreta,

Ans: Asherman’s syndrome describes the intrauterine growth retardation, and postpartum occurrence of intrauterine adhesions. Asherman’s hemorrhage. syndrome mostly affects women who have had dilatation and curettage, especially those who have Q.22. How will you manage a case of secondary undergone this procedure postpartum. The amenorrhea with hypogonadotropic hypogona- endometrium is highly susceptible to adhesions, dism (low serum FSH and LH)? between week 2 and week 4 postpartum due to Ans: The cause could be hypothalamic amenorrhea injury to the pars basalis of the endometrium. or pituitary disorder as in Sheehan syndrome. Other causes of Asherman’s syndrome include a. Hypothalamic amenorrhea is associated with • Surgical trauma to the non-gravid uterus (for abnormalities in GnRH secretion and disruption example, via dilatation and curettage or of the hypothalamic-pituitary ovarian axis. The endometrial ablation) and condition often is caused by excessive weight • Uterine infection, including genital tuberculosis loss, exercise, or stress. and schistosomiasis. • Treatment of hypothalamic amenorrhea depends on the etiology. Women with Q.21. How will you diagnose and manage a case excessive weight loss should be screened of Asherman’s syndrome? for eating disorders and treated if anorexia Ans: nervosa or bulimia nervosa is diagnosed. • In presence of above mentioned history, Menses usually will return after a healthy diagnosis is suggested by absence of normal body weight is achieved. endometrial stripe on pelvic ultrasound and • Young athletes may develop a combination absence of withdrawal bleeding after adminis- of health conditions called the female athlete tration of estrogen- progesterone. triad that includes an eating disorder, • , hysteroscopy, or sono- amenorrhea, and osteoporosis. Menses may hysterography can help confirm the diagnosis. return after a modest increase in caloric • The lysis of intrauterine adhesions under intake or a decrease in athletic training. hysteroscopic guidance is required. Adhesions • In patients with amenorrhea caused by can be divided with scissors, electrosurgery, or eating disorders or excessive exercise, the laser energy. If the uterine cavity is obliterated use of oral contraceptive pills or combined completely, hysteroscopy is done under laparo- estrogen-progesterone therapy may decrease scopic guidance. The main risks of hysteroscopy bone turnover and partially reverse bone include uterine perforation and hemorrhage loss; however, neither therapy has been from uterine vascular damage. shown to significantly increase bone mass. • Long-term treatment with estrogen and pro- • Bisphosphonates, traditionally used to treat gestogen may stimulate regrowth of the postmenopausal osteoporosis, are possible endometrium. Prognosis depends on the degree teratogens and have not been studied as a of adhesions present. therapy in women of reproductive age. • Women who become pregnant after treatment • Adequate calcium and vitamin D intake are are at high risk of obstetric complications, recommended for these patients. Amenorrhea 217 b. Sheehan’s syndrome occurs due to pituitary The condition can be associated with auto- necrosis following massive obstetric hemorr- immune endocrine disorders such as hypothyroi- hage. dism, Addison’s disease, and diabetes mellitus. • The diagnosis is based on characteristic Even if initial laboratory tests are normal, periodic history of massive postpartum hemorrhage screening is required. and often failed lactation and loss of pubic Fertility is possible through donor oocyte and and axillary hair. in vitro fertilization. • Patient will have decreased levels of estradiol, FSH and LH. Serum levels of REFERENCES other anterior pituitary hormones should 1. Amenorrhea. In Speroff L, Fritz MA (Eds). Clinical also be checked. Gynecological Endocrinology and Infertility, 7th • Hormone replacement with estrogen- Edition, Philadelphia: Lippincott Williams & Wilkins progesterone helps correct hypoestro- 2004;401-63. 2. Edmonds DK. Primary amenorrhea. In Studd J (Ed) genemia and restores menstrual function. Progress in Obstetrics and Gynaecology, Volume 10. • Other anterior pituitary hormones (parti- Churchill Livingstone 1993; p. 281-96. cularly TSH and ACTH) may also be 3. Master-Hunter T, Heiman DL. Amenorrhea: evalua- deficient and require replacement with tion and treatment. Am Fam Physician 2006; 73: thyroid hormone and corticosteroid. 1374-82. 4. Houk CP, Lee PA. Early, precocious and delayed • Pregnancy can be achieved with ovulation female pubertal development. In Lavin N (Ed) Manual induction with exogenous gonadotropins.15 of Endocrinology and Metabolism, 4th edition. New Delhi, Lippincott Williams & Wilkins, Philadelphia Q.23. Discuss the management of secondary 2009; p. 144-263. amenorrhea due to premature ovarian failure. 5. Styne DM, Grumbach MM. Puberty: Ontogeny, neuroendocrinology, physiology, and disorders in Ans: Premature ovarian failure is characterized by Kronenberg HM, Melmed S, Polonsky KS, Larsen amenorrhea, hypoestrogenism, and increased PR (Eds) Williams Textbook of Endocrinology, 11th gonadotropin levels (FSH > 40 IU/L) occurring edition, Philadelphia, Saunders Elsevier 2008; p. 969- 1166. before 40 years of age. 6. Saenger P, Wikland KA, Conway GS, et al. Fifth A karyotype should be considered in most International Symposium on Turner Syndrome. women of secondary amenorrhea age 30 years or Recommendations for the diagnosis and management younger to rule out complete or partial deletion of of Turner syndrome. J Clin Endocrinol Metab 2001; the X chromosome, or presence of any Y chromo- 86:3061-9. 7. Davenport ML. Approach to the patient with Turner some material which would require removal of syndrome. J Clin Endocrinol Metab 2010;95:1487- gonadal tissue. 95. Women with premature ovarian failure have 8. Goswami D, Conway GS. Premature ovarian failure. an increased risk of osteoporosis due to hypoestro- Horm Res 2007;68:196-202. genism. Therefore estrogen- progesterone replace- 9. Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update 2005;11:391-410. ment is required to correct hypoestrogenism and 10. Goswami R, Goswami D, Kabra M, Gupta N, Dubey restore menstrual function. The treatment needs to S, Dadhwal V. Prevalence of the triple X syndrome in be continued till the normal age of menopause. phenotypically normal women with premature ovarian 218 Case Discussions in Obstetrics and Gynecology

failure and its association with autoimmune thyroid on diagnostic criteria and long-term health risks disorders. Fertil Steril 2003;80:1052-4. related to polycystic ovary syndrome. Fertil Steril 11. Goswami R, Marwaha RK, Goswami D, Gupta N, Ray 2004;81:19-25. D, Tomar N, Singh S. Prevalence of thyroid auto- immunity in sporadic idiopathic hypoparathyroidism 14. RCOG Green top guideline. Polycystic Ovary Syn- in comparison to type 1 diabetes and premature ovarian drome, Long-term Consequences (Green-top 33), failure. J Clin Endocrinol Metab 2006;91:4256-9. 2007. www.rcog.org.uk 12. Michala L, Goswami D, Creighton SM, Conway GS. 15. Kriplani A, Goswami D, Agarwal N, Bhatla N, Swyer syndrome: presentation and outcomes. BJOG Ammini AC. Twin pregnancy following gonado- 2008;115:737-41. 13. Rotterdam ESHRE/ASRM-Sponsored PCOS trophin therapy in a patient with Sheehan’s syndrome. Consensus Workshop Group. Revised 2003 consensus Int J Gynaecol Obstet 2000;71:59-63. Sudha Prasad, Shalini Khanna, Saumya Approaches to Improve 18 the Diagnosis and Management of Infertility

Infertility can be defined as the failure to achieve a Both Partners pregnancy within 1 year of regular unprotected • Age intercourse in the absence of known reproductive • Occupation, occupational hazards 1 pathology. This condition may be further classified • Family history, e.g. hereditary diseases, cancer, as primary infertility, in which no previous thrombosis, personal health problems pregnancies have occurred and secondary infertility, • Current/past regular medications or any history in which a prior pregnancy, although not necessarily related with tuberculosis, substance abuse a live birth, has occurred. Fecundability is the probability of achieving (smoking, alcohol, caffeine) pregnancy within a single menstrual cycle and • Allergy fecundity is the probability of achieving a live birth • Previous surgery, previous genital surgery, within a single cycle. The fecundability of a normal pregnancies woman has been estimated to be 20 to 25%. Female Partners On the basis of this estimate, about 90% of • Age at menarche couples should conceive after 12 months of unprotected intercourse.2 Infertility affects about • Menstrual cycle details 10% to 15% of reproductive-age couples. • Duration of infertility • Sexual activity and problems, e.g. dyspareunia, CASE 1 coital frequency. • Hirsutism, acne, galactorrhea, enlarged thyroid A young couple, who was not able to conceive after five years of marriage, consult you for infertility gland. treatment. Elaborate the essential components in The physical examination of the female should the infertility history and what are the specific be thorough with particular attention to height, body important investigations in relation to infertility weight, body habitus, hair distribution, thyroid management? gland and detailed pelvic examination. Evaluation begins with a detailed docu- Male should be thoroughly evaluated by a mentation of the history and physical examination reproductive medicine specialist, clinical of both the partners. Adequate counseling is an andrologist or uroandrologist for the identification integral part of the management. of underlying unrecognized male factors as 220 Case Discussions in Obstetrics and Gynecology prevalence of significant pathology among male helps to guide individual management decisions partner is as high as 40%. and maximize infertility/ART treatment outcomes.

Q.1. What are the causes of infertility? CASE 2 Ans: The main causes of infertility are listed below A 30 years old patient consults you with a normal in the Table 18.1. semen report and patent fallopian tubes and normal uterine cavity on hysterosalpingogram for Table 18.1: Causes of infertility3 further treatment, how will you proceed? Infertility % Utmost important point is to find out whether Female factors (single) 40-55 this patient is ovulating or not. • Tubal factor 30-40 Preovulatory follicles produce high levels • 6 (200 pg/ml) of estrogen. This sustained level for • Ovulatory dysfunction 30-40 more than 48 hours causes positive feedback and • Diminished ovarian reserve 8 LH surge. Due to mid cycle LH surge local • Uterine factor 1 concentration of prostaglandins and proteolytic Male factor (single) 19 enzymes are increased. This event progressively Other causes 7 weakens the follicular wall till perforation and Unexplained causes 12 extrusion of the oocyte occurs (Fig. 18.1). Multiple factors (female only) 12 Multiple factors (female + male) 18

Therefore, clinical evaluation of the infertile couple may be grouped into five categories: semen analysis, the postcoital test (PCT), assessment of ovulation, uterine and tubal evaluation, and laparoscopy.4

Q.2. In certain group of patients do you think early investigation for infertility is required? Ans: Few set of patients may not have a long duration of infertility but can be investigated and treated early when • Age > 35 years Fig. 18.1: Release of egg through the follicle • H/o oligomenorrhea/amenorrhea • Known or suspected uterine/tubal disease, There are various methods to diagnose ovulation. endometriosis or diminished ovarian reserve Indirect: • Suspected or infertile partner • Menstrual history: regular cycle • Expected chemotherapy/ of • Evaluation of peripheral or end organ changes either partner for the underlying disorders – BBT The detailed history, examinations and accurate – Cervical mucus study detection of underlying reproductive abnormalities – Vaginal cytology Approaches to Improve the Diagnosis and Management of Infertility 221

Hormone estimation Patient records her oral or rectal temperature a. Serum progesterone each morning before the patient arises; eats or b. Serum LH drinks. There is increase of 0.58°F over the Endometrial biopsy baseline temperature of 97 degree to 98.8 Sonography degree in the follicular phase. The nadir in BBT Direct: coincides with LH surge (Fig. 18.3). Laparoscopy 3. Cervical mucus study: Ovulatory cervical Conclusive: mucus is thin, profuse, elastic and withstands Pregnancy stretching up to 10 cm (Spinnbarkeit). This can Often more than one cause is identified in a couple. be also assessed by the patients itself which is called Billings’ Test. Q. 3. How can you document ovulation? 4. Fern Test: Cervical mucus and saliva are strongly influenced by progesterone and Ans: estrogen. Fern test can be done by both. Sodium 1. Menstrual history: Regular cycles, mid cycle chloride levels in the mucus secreted under the pain or spotting ( syndrome), influence of estrogen are high around the time primary dysmenorrhea are strong evidences of of ovulation. These causes crystallization when ovulation. Five days before and the day of it dries up on a glass slide (Fig. 18.4). ovulation is called as “Fertile Window” of 6 - Disappearance of fern pattern and elasticity days. This period remains for six days in women which was present in the mid-cycle is suggestive with regular cycles (Fig. 18.2). of ovulation. 5. Postcoital test: The PCT provides an assessment of the quantity and quality of cervical mucus, number of motile sperms per high power field, sperm-mucus interactions and the presence of antisperm antibodies. It can be performed after 2 days of abstinence and 2 to 12 hours of intercourse. There is poor correlation between PCT result and pregnancy outcome as its results can be reflected due to poor cervical mucus or abnormal semen parameters. Hence, it is not the standard investigation of infertility now.5 6. Hormones estimation: a. Progesterone: Above 3ng/ml (10 nmol/L) on day 21 to 23 of an ideal 28 day cycle Fig. 18.2: Six-day fertile window confirms ovulation. However, lower values are not necessarily diagnostic of 2. Basal body temperature (BBT): Ovulatory anovulation.6 cycles produce a characteristic biphasic pattern b. Luteinizing hormone monitoring: There of BBT. Secretion of progesterone occurs after is an increase in LH level over 2 to 3 times ovulation as corpus luteum secretes progesterone. in preovulatory phase. Ovulation occur 34- Due to thermogenic effect of progesterone there 36 hours after the onset of the LH surge and is rise of temperature in post ovulatory phase. 10-12 hours after LH peak. 222 Case Discussions in Obstetrics and Gynecology

Fig. 18.3: Basal body temperature

histological dating to diagnose corpus luteum defect (LPD). 8. Ultrasound monitoring: Irregular and decrease in the size of a monitored ovarian follicle and appearance of fluid in cul-de-sac characterizes ovulation.

Q.4. How do you define tubal, paratubal, and peritoneal factors for infertility and what are the diagnostic tests? Ans: Tubal disease is responsible for 25%-35% of Fig. 18.4: Fern test: Cervical mucus/salivary changes . Pathology may involve the proximal, distal or entire tube due to previous PID, 7. Endometrial biopsy: Endometrium is biopsied genital tuberculosis, sexually transmitted disease on day 21 to 23 day by endometrial biopsy like gonorrhea or chlamydial infection, curette or Karman’s canula no 4. endometriotic or previous pelvic or tubal surgery. Histopathological report of secretory The diagnostic tests for tubal infertility are: endometrium in the second half of the cycle is • Detection of infection: Cervical culture, serum diagnostic of ovulation. Endometrial sample antibodies (IgG) for chlamydia trachomatis or should be subjected to AFB stain and culture to endometrial tissue culture for tuberculous rule out tuberculosis and calendar and mycobacterium. Approaches to Improve the Diagnosis and Management of Infertility 223

• Hysterosalpingography (HSG): HSG has a Recent Advances sensitivity of 85% -100% in delineating uterine Virtual hysterosalpingography:7 With the anatomy and assessing tubal patency. It is demand for more accurate imaging methods for usually performed between 6 to 11 days of cycle identifying the specific cause of female infertility by water based soluble contrast medium; and other gynecologic disorders, Virtual Meglumine diatrizoate (Renografin- 60) is hysterosalpingography is an emerging modality in rapidly absorbed with no risk of lipid embolism which aspects of the established technique of or granuloma formation. However, the hysterosalpingography are combined with the resolution of tubal architecture is better with cutting-edge technology of multidetector computed oil based dyes (Ethiodol). It can pick up tomography (CT). It is capable of depicting both abnormalities in endometrium like submucosal the external and internal surfaces of the uterus, fibroids, , uterine septa and fallopian tubes, and other pelvic organs, providing synechiae. HSG can cause pain and pelvic high-resolution data for two- and three-dimensional infection (1%-3%), and rarely uterine reconstructions and virtual endoscopic views. perforation, hemorrhage, collapse and allergic reaction. Q.5. What are the methodologies available to • Laparoscopy: It directly visualizes all pelvic assess intrauterine pathology and what is its organs especially assesses the external impact? architecture of the tubes including fimbria. Simultaneously it also detects and treat Ans: intramural and subserous uterine fibroids, Hysteroscopy: Office hysteroscopy is only peritubal and periovarian adhesions and recommended by the WHO when clinical or endometriosis. complementary tests (ultrasound, HSG) suggest 8 • Sonosalpingography: It can detect tubal intrauterine abnormality or after in vitro 9 patency under ultrasound scanning. With a slow fertilization (IVF) failure. and deliberate injection of about 200 ml of Ultrasound: Late follicular phase TVS has proved physiological saline mixed with air into the to be a useful tool for the detection of intrauterine uterine cavity through a Foleys catheter. The abnormalities such as polyps, synechiae, fibroids saline flow is observed as shower through the and Müllerian anomalies.10 fimbrial end and the presence of free fluid in Saline infusion sonography: This offers enhanced the pouch of Douglas. Saline flow can also be visualization of the endometrium and better observed through Doppler. detection of intrauterine pathology than does Other diagnostic modalities are: standard TVS, and may be as effective as • Transcervical fallopscopy: Transcervical hysteroscopy in detecting intracavitary fallopscopy allows direct visualization of tubal abnormalities.11,12 ostia and intratubal architecture, abnormal tubal There is some evidence from basic science mucosal pattern and even intraluminal debris studies to suggest a detrimental effect of polyps on causing tubal obstruction. fertility. Polyps diagnosed prior to commencement • Selective salpingography: Small guide wires of controlled ovarian hyperstimulation (COH) for are used to permit selective tubal canalization in vitro fertilization (IVF) should therefore be and radiographic visualization under removed. The management of polyps seen during fluoroscopy. the course of COH for IVF should be individualized.13 224 Case Discussions in Obstetrics and Gynecology

MRI: MRI may be used for patients with suspected Table 18.2: Associated factors with unexplained complex Müllerian anomalies.14 infertility 1. Ovulatory dysfunction CASE 3 2. Subclinical infection leading to tubal dysfunction A young couple was investigated for infertility 3. Minimal to mild endometriosis abnormality. If on basic work up there is no male 4. Sperm dysfunction factor abnormality, and assessment of ovulation 5. Immunological factors 6. Subclinical pregnancy loss and tubes on laparoscopy were found normal. 7. Psychological factors How will you treat this patient further for infertility? If both these approaches fail to result in Most probably we are dealing with a case of pregnancy or fertilization failure, then IVF with or unexplained infertility. Unexplained infertility is without ICSI may be considered. defined as when couple has failed to establish a All patients should be assessed for ovarian pregnancy despite no abnormality detected on reserve before enrolling for assisted reproduction. completion of the basic work up. This includes “Ovarian reserve” simply means the number of history and examination, assessment of ovulation eggs the ovary has in reserve. The greater the and HSG or laparoscopy for tubal status and the ovarian reserve, the more time is left on individual’s tests for the male partner. Evaluation of a male biological clock. partner usually includes history, examination and The parameters of assessment for ovarian semen analysis. reserve during infertility evaluation are: Various studies have reported that 0 to 26% of i. Age infertile couples have unexplained infertility. ii. D2 FSH Unexplained infertility is associated with few iii. D2 estradiol 15 following factors: iv. Anti Mullerian hormone v. Antral follicle count Management of unexplained infertility vi. Inhibin B These patients require further assessment like vii. Clomiphene citrate challenge test estimation of serum prolactin, serum TSH, cervical viii. GnRH agonist stimulation test (GAST) cultures for Chlamydia and Ureaplasma ix. Exogenous FSH ovarian reserve test urealyticum. The role of diagnostic laparoscopy if (EFFORT) not done early is debatable. It may uncover sub x. Ovarian biopsy serous and pedunculated fibroids, peritubal adhesions and endometriosis. The diagnostic CASE 4 laparoscopy should be performed in women with unexplained infertility even with normal HSG as it An infertile couple presents to you for evaluation. may identify and treat endometriosis (Table 18.2). A semen analysis is ordered on the same day. The sample of 1 cc contains 8 million sperm counts Treatment of unexplained infertility per milliliter, 30% are motile and 5% are of The therapy “superovulation and IUI”; aims at normal morphology. What advice you should give increasing the available numbers and proximity of to this couple? healthy gametes. Superovulation by clomiphene citrate or letrozole with IUI for 3 cycles is followed The evaluation of infertile man begins with by COH using gonadotropins and IUI for another proper counseling. The confidentiality is 3 cycles. maintained and a thorough history and examination Approaches to Improve the Diagnosis and Management of Infertility 225 is to be taken. Male factor is solely responsible for Teratozoospermia: Increased proportion of 19% of subfertile couples and contributes in another abnormal forms of spermatozoa 18% of cases.16 Oligoaesthenoteratozoospermia: All sperm Semen collection is the foremost simple and parameters are abnormal diagnostic investigation for male infertility. Azoospermia: No sperm in the ejaculate There are few significant points in giving Aspermia/anejaculation: Ejaculate/ejaculation semen samples. failure a. Abstinence for 2 to 3 days b. Delivery to laboratory within 1 hour of Q.6. What are the important points while collection investigating the male partner? c. Keep sample at body temperature (37oC) Ans: d. Masturbation preferred History e. Avoid normal condoms or lubricants • Medical (illnesses requiring radiotherapy or The normal semen value with sperm morphology chemotherapy) is important for a conceptual cycle. Normal • Surgical (childhood hernia, undescended testes, spermatogenesis depends on adequate gonadotropic varicocele) stimulation of the testis, proper testicular function • Sexually transmitted infection (Chlamydia, and patent and normally functioning seminal ducts Gonococcus, Tuberculosis) (Table 18.3 and 18.4). • Trauma • Exposure to drugs or toxins Table 18.3: Normal values for a semen analysis17 • Family history Volume > 2.0 ml • Coital history: Erectile dysfunction/Ejaculatory Sperm concentration > 20 million/ml failure Motility > 50% Morphology > 30% normal forms Examinations General examination (i.e. height, weight, BP etc) Table 18.4: Strict Tygerberg classification18 Secondary sexual characteristics Genital examination Normal sperm Prognosis morphology • Testes (volume and consistency) • Epididymis (volume and consistency) > 14% Normal fertilization in IVF cycles • Vasa deferens (presence or absence) 4-14 % Good prognosis < 4% Poor prognosis • Assess for any abnormalities (e.g. lumps/ varicocele) Accepted definition of semen quality Investigations Normozoospermia: All norma semen parameter • Repeat second sample of semen analysis, three defined by WHO. months apart. Oligozoospermia: • Post-ejaculate urine (if retrograde ejaculation • Mild 10 to 20 million spermatozoa/ml suspected). • Moderate 5 to 10 million spermatozoa/ml • Sperm pelleting (Specimen is centrifuged at • Severe < 5 million spermatozoa/ml 2000 rpm and the resulting pellet) examined • Extreme < 1 million spermatozoa/ml for sperms before confirming azoospermia. Aesthenozoospermia: Reduced total sperm Endocrine profile: FSH, testosterone, prolactin motility or reduced sperm progression (Flow chart 18.1) 226 Case Discussions in Obstetrics and Gynecology

Flow chart 18.1: Endocrinal assessment of male partner

Genetic tests: • Drugs: hCG 2000 IU, twice weekly for 6 – Peripheral karyotype months/HMG – 150 IU thrice weekly – Y micro-deletions • For testicular and post-testicular azoospermia, – Cystic fibrosis mutations IVF/ICSI either by ejaculation or surgically Ultrasound scan (if indicated, i.e. abnormal retrieved sperms. examination) • Testicular biopsy should not be done for the confirmation of diagnosis. Management • Discontinue adverse medication Q.7a. What is retrograde ejaculation? In which • Stop smoking. Abstain from alcohol. conditions it can occur? • Avoid scrotal heating When bladder neck coaptation is not complete, • Antioxidant therapy – Vitamin E and selenium the seminal fluid may travel retrograde into the to improve mortality bladder during periurethral muscular contraction. α • For retrograde ejaculation – -sympatho- Patient may present with low semen volume, low mimetic drugs (phenylpropanolamine, imi- motility and sperm concentration. pramine). Retrograde ejaculation is commonly seen in • Donor insemination: for azoospermia, severe following conditions: oligospermia • Patients with diabetes. • For mild/moderate oligospermia: • After transurethral surgery iatrogenic surgical Intrauterine insemination offers good results damage to the bladder neck innervation. where 0.3 ml of washed, processed and concen- • Retroperitoneal lymph nodes dissection. trated sperms is placed into intrauterine cavity. • Spinal cord injuries. • Varicocele repair involves interruption of the • Alpha adrenergic blockers used as hypertensive internal spermatic vein, despite its widespread disorder. use, the therapeutic benefits remain contro- Urinalysis performed immediately after versial. ejaculation and examined for sperm under the microscope. If sperms are present, specimen is For Hypogonadotropic Hypogonadism processed further to evaluate concentration, motility • Rule out hyperprolactinemia and morphology. Sperms can be retrieved from the • CT/MRI or pituitary fossa urine may be used for assisted reproduction. Approaches to Improve the Diagnosis and Management of Infertility 227

Q.7b. What is split ejaculate? Assisted Reproductive Technology (ART) Ans: The ejaculate is split in two or more and All treatment or procedures which, include the in collected in different jars. First fraction contains vitro handling of human oocytes and sperm or majority of the spermatozoa suspended in prostatic embryos for the purpose of establishing a fluid. Later fraction of the ejaculate consists of pregnancy. This includes IVF and transcervical seminal vesicle secretion. embryo transfer, gamete intra-fallopian transfer, zygote intra-fallopian transfer, tubal embryo CASE 5 transfer, gamete and embryo cryopreservation, oocyte and embryo donation and gestational A 26-years-old lady had a past history of vaginal surrogacy. ART does not include assisted discharge and lower abdominal pain for which insemination (artificial insemination) using sperm she took treatment. She couldn’t conceive after from either a woman’s partner or sperm donor.1 two years of married life. On per vaginal examination she had bilateral tubo-ovarian mass Q.8. What are the other indications of assisted and laparoscopy confirm bilateral TO masses with reproductive technologies? . During infertility evaluation all 20 other significant investigations were normal. How Ans: The indications of ART are: will you treat this patient? • Abnormal fallopian tubes- blocked/impaired tubal function or absent tubes following surgery There is an adverse effect of hydrosalpinx on • Endometriosis affecting tubo-ovarian ovum fertility. This may cause following effects: pick-up function • Hydrosalpinx fluid includes microorganisms, • Idiopathic or unexplained infertility of >3 years endotoxins, cytokines, oxidative stress and lack or earlier if women >36 years of nutrients which are embryotoxic. • No conception after 3 or 4 IUI cycles • The endometrial receptivity may be reduced as • Male infertility an effect of disturbed expression of the cytokine – TMC > 1 m-10 m – IVF cascade, which is essential for implantation. – THC > 10 million in unexplained infertility. • The presence of excessive fluid in the uterine • Cervical or immunologic infertility cavity may also be a mechanical hindrance to • Failure of donor semen insemination implantation. • Failure of ovulation Cochrane review has shown a significant increase in clinical pregnancy rate with surgical treatment of hydrosalpinx (Peto OR 4.66, 95% CI CASE 6 2.47 to 10.01). Meta-analysis has shown that Few patients cannot conceive by IVF as they patients with visible hydrosalpinx on ultrasound require intracytoplasmic sperm injection? should be encouraged to undergo prophylactic salpingectomy prior to IVF. The meta-analysis from Semen parameters play an important role in the three clinical studies demonstrated superior management of infertility. Depending upon the pregnancy [odds ratio (OR) 1.75, 95% confidence count, motility and morphology of the semen interval (CI) 1.07–2.86] and live birth rates (OR following are the different methods helpful for 2.13, 95% CI 1.24–3.65) following salpingectomy conception, provided there is no female factor compared with no surgical intervention.19 infertility (Table 18.5). 228 Case Discussions in Obstetrics and Gynecology

Table 18.5: Sperm count in relation with different methods for conception Method Concentration Motility Morphology Natural conception 20 million/ml or more 50% or more with forward progression 30% or > normal forms IUI 5-15 millions/inseminate 30-50% with forward progression 15% or > normal IVF 1-5 millions/inseminate 25-30% with forward progressions 5-15% or > normal ICSI <2 millions/inseminate progressive motility <5% > 95% abnormal sperm

Indications of ICSI CASE 7 1. Total motile sperm count < 1 million 2. Normal morphology < 4% with TMC < 5 An anovulatory infertile woman was induced million ovulation by gonadotropins. What is an ovarian 3. No or poor fertilization in previous IVF cycle hyperstimulation syndrome? with TMC <10 million OHSS is an iatrogenic complication of so called 4. No or poor fertilization in previous two IVF controlled ovarian hyperstimulation. It is directly cycle with TMC >10 million related with increasing number of stimulated 5. Epididymal or testicular spermatozoa Oocytes retrieval is the procedure which follicles and is hCG dependent. Vasoactive requires excellent degree of relaxation. Normally mediators are released from ovaries – PG, cytokines, it takes maximum of 10 minutes. VEGF, renin, angiotensin, endothelin which causes IVF/ICSI procedures are done under anesthesia. endothelial injury and vasodilatation leading to 3rd There should be minimum exposure of oocytes to space fluid collection with circulatory dysfunction. the anesthetic agents which accumulates rapidly in There is variable degree of ovarian enlargement follicular fluid during procedure. and/or ascites, pleural effusion, oliguria, hemo- Anesthetic drugs used for oocytes retrieval: concentration, thromboembolism, and electrolyte 1. Fentanyl: 1 to 2 g/kg intravenous disturbances which may be life threatening. 2. Midazolam: 0.05 to 0.1 mg/kg intravenous 3. If required: Propofol 1 to 2 mg/kg may be added Classification (Table 18.6)

Table 18.6: Classification of OHSS

Grade Ovarian size Clinical presentation Lab tests Mild 5 to 10 cc Abdomen distension, GI upset HCV < 45, TLC < 15,000/cc Normal renal function Moderate 10 to 12 cc Moderate ascites Normal renal function Severe > 12 cc Marked ascites HCV > 45 Dyspnea TLC > 15.999/cc Hypovolemia Impaired renal function Mild thromboembolism Critical Marked enlargement Tense ascites, hydrothorax HCV (55%), TLC > 25000/mm3, (Life threatening) Thromboembolism serum creatinine >1.6 mg%^, Adult respiratory distress creatinine clearance < 50 ml/min. syndrome Approaches to Improve the Diagnosis and Management of Infertility 229

Causes of OHSS REFERENCES Cause is unknown. But, women at risk of 1. Fernando Zegers-Hochschild, KG Nygren, G David developing OHSS include: Adamson, Jacques de Mouzon, Paul Lancaster, Ragaa • Over response to ovulatory drugs. Mansour, Elizabeth Sullivan; The ICMART glossary • Women with polycystic ovaries. on ART terminology. Hum Reprod 2006 21:1968- • High estrogen hormone levels and a large 1970;doi:10.1093/humrep/del171. 2. Mylene WM Yao and Danial J. Schust. Chapter number of follicles or eggs. Infertility page 973, Novak’s Gynecology edited by • Administration of GnRh agonist. Jonathan S Berek, ed 13th 2002 published by • The use of hCG for luteal phase support. Lippincott Williams and Wilkins. 3. Adapted from the Centres for Disease Control and Management Prevention. 2004 Assisted Reproductive Technology A. Mild cases: Spontaneous recovery occurs Success Rates, December 2006. within 2-3 weeks (conservative measures and 4. Balasch J. Investigation of the infertile couple: follow-up). investigation of the infertile couple in the era of assisted reproductive technology: a time for B. Moderate and severe cases: Assessment is reappraisal. Hum Reprod 2000;15:2251-7. made after thorough history, examination, and 5. Guid Oei, Frans M Helmerhorst, Kitty WM investigations and if patient is stable, outpatient Bloemenkamp, Frederieke AM Hollants, Debbie E M care can be given which involves daily follow- Meerpoel, and Marc JNC Keirse, Effectiveness of the postcoital test: randomised controlled trial; BMJ up with restricted activity and daily weight 1998;317:502-5. monitoring. Intake (1 liter/day) and output 6. Mylene WM Yao and Danial J. Schust. Chapter should be monitored. Infertility page 995, Novak’s Gynecology edited by Jonathan S Berek, ed 13th 2002 published by The patient needs to be hospitalized in case of Lippincott Williams and Wilkins. If weight gain > 2 lb/day, hemodynamic instability, 7. Carrascosa PM, Capuñay C, Vallejos J, Martín López respiratory comprise, tense ascites, hemo- EB, Baronio M, Carrascosa JM. Virtual hysterosalpingography: a new multidetector CT concentration, renal failure, or decreased oxygen technique for evaluating the female reproductive concentration. system. Radiographics. 2010 May-Jun; 30(3):643-61. 8. AC de Sa Rosa e de Silva, JC Rosa e Silva, FJ Candido Supportive care dos Reis, AA Nogueira, and RA Ferriani, “Routine The intravascular volume and renal perfusion office hysteroscopy in the investigation of infertile should be maintained preferrably by intravenous couples before assisted reproduction,” Journal of colloids even crystalloids in the form of normal Reproductive Medicine for the Obstetrician and Gynecologist 2005;50:501-6. saline with/without glucose can be given total 9. JP Balmaceda and I Ciuffardi, “Hysteroscopy and volume replacement may require 1.5-3L of fluids assisted reproductive technology,” Obstetrics and and even albumin infusion is helpful (20%). Gynecology Clinics of North America 1995,22:3:507- 18. Symptomatic treatment 10. Van Voorhis BJ. Ultrasound assessment of the uterus • Peripheral dopamine inhibitor: cabergoline and fallopian tube in infertile women. Semin Reprod • Analgesia: paracetamol and opiods. Med 2008;26:232-40. • Antiemetics: metoclopramide 11. Ragni G, Diaferia D, Vegetti W, Colombo M, Arnoldi M, Crosignani PG. Effectiveness of sonohysterography • Prevention of thromboembolism by anti- in infertile patient work-up: a comparison with coagulant therapy if there is clinical or transvaginal ultrasonography and hysteroscopy. laboratory evidence Gynecol Obstet Invest 2005;59:184-8. 230 Case Discussions in Obstetrics and Gynecology

12. Valenzano MM, Mistrangelo E, Lijoi D, Fortunato T, 16. Irvine DS. Epidemiology and aetiology of male Lantieri PB, Risso D, Costantini S, Ragni N. infertility; Hum Reprod 1998;13(Suppl.1):33-44. Transvaginal sonohysterographic evaluation of uterine 17. WHO laboratory manual for the examination of human malformations. Eur J Obstet Gynecol Reprod Biol. semen and sperm-cervical mucus interaction. 2006;124:246-9. Cambridge University Press, 3rd edition, 1992. 13. Khaled Afifi, Sujatha Anand, Soumendra Nallapeta 18. Menkveld R, and Kruger TF. Advantages of strict and Tarek Ahmed Gelbaya. Management of (Tygerberg) criteria for evaluation of sperm endometrial polyps in subfertile women: a systematic morphology. Int J Androl 1995;18 Suppl 2:36-42. review. European journal of Obstetrics and 19. Johnson NP, Mak W, Sowter MC. Surgical treatment Gynecology and Reproductive Biology, Available for tubal disease in women due to undergo in vitro online 28 April 2010 doi:10.1016/j.ejogrb. fertilization. Cochrane Database Syst Rev (2004) 2010.04.005. CD002125. 14. Deutch TD, Abuhamad AZ. The role of 3-dimensional 20. Nicholas S. Macklon, Bart CJM Fauser. Chap ultrasonography and magnetic resonance imaging in the diagnosis of müllerian duct anomalies: a Indication of IVF treatment: from diagnosis to review of the literature. J Ultrasound Med 2008; prognosis: Text book of Assisted Reproductive 27:413-23. Techniques, Laboratory and clinical perspectives, 15. Evers JL. Female substerility. Lancet 2002 jul13; 360 second addition, edited by David K. Gardener; (9327):151-9. 2004;498. YM Mala, Pooja Pundhir, Sharda B Ghosh 19 Fibroid Uterus

Fibroids (leiomyomas, myomas) are the most 1. Age: seen in women of reproductive age group, common benign tumours of the uterus arising from mostly between 35 and 45 years. They do not uterine smooth muscles. There are a number of long occur de novo before menarche and after ongoing researches investigating the underlying menopause. pathogenesis of these highly prevalent benign 2. Parity: more commonly seen in nulliparous or tumours linking the latter to high levels of intrinsic those having one child infertility. Multiparity aromatase activity, estrogen and progesterone confers a risk reduction. receptors, and genetic predisposition (aberrations Presenting Complaints: in chromosome 3, 6, 7, 10, 12). They are symp- 1. Menstrual complaints (Menorrhagia): tomatic in only 50% of cases, manifesting with a Specifically ask about menorrhagia, multitude of symptoms and complications. Recent metrorrhagia. Though not a classical symptom, developments in the management of fibroids polymenorrhea can be occasionally found due include the advent of minimally/non-invasive to altered ovarian blood supply on account of procedures (embolotherapy, focused ultrasonic associated pelvic congestion. therapy) and modifications of laparoscopic Menorrhagia is the most common complaint in myomectomies. symptomatic patients with fibroids. The cause of menorrhagia is: CASE 1 a. increased endometrial surface area (normal 15 cm2) A 45-year-old lady, Mrs P presented with meno- b. presence of fibroid restricts normal uterine rrhagia of 6 months duration. On examination contractility uterus was enlarged equivalent in size to 20 weeks c. pelvic congestion pregnancy. Ultrasound revealed multiple fibroids d. obstruction by the tumor resulting in dila- in the uterus. tation of subadjacent endometrial venous plexus Q.1. What are the important points in the e. due to hyper- history? estrogenism Ans: A patient of fibroid uterus can present with In case of heavy menstrual flow enquire the following complaints. The following history regarding use of any hemostatic agent and should be taken in detail. degree of relief. 232 Case Discussions in Obstetrics and Gynecology

2. Dysmenorrhea: Menstrual History: a. congestive due to pelvic congestion or To be taken in detail associated endometriosis or Pelvic • LMP: rule out pregnancy inflammatory disease (PID). • Bleeding duration (days), regularity b. Spasmodic when associated with a sub- • Number of pads used per day mucous polyp during attempts of the uterus • History of passage of clots to expel the submucous fibroid. • Association with dysmenorrhea Take any history of relief in symptoms and if • Young adolescents–menarche and the so with what drugs–antispasmodics/simple characteristics of previously normal menstrual analgesic cycles. 3. Pain/heaviness in abdomen: Pain is an Obstetric history uncommon feature of fibroids and if present is • If previous cesarean delivery any mention of due to complications of the tumor (e.g. fibroid seedling in the operation notes. degeneration, torsion of a pedunculated • Any complication during pregnancy (red subserous fibroid, extrusion of the polyp, degeneration)/during or following delivery sarcomatous change, or adhesion with other (PPH etc.) organs) or associated pathologies (endometriosis, • In history of RPL – sub clinical abortion/early PID). abortion/may be associated with submucous 4. Lump in lower abdomen: The duration of the fibroid lump and rate of increase in size of the lump. • History of use of OCPs Obese patients might not be able to appreciate any lump. Past history 5. Pressure symptoms: posterior wall fibroids • Any chronic medical/surgical illness which may compress the rectum causing constipation, preclude surgical management while cervical and broad ligament fibroids cause • Any treatment sought for the above complaint retention of urine due to ureteric compression. and any relief with that Ureteric compression can lead to hydro- • History of prior medication (including hor- nephrosis and pyelitis. Anterior wall fibroids mones) or any procedure if she underwent in produce urinary symptoms due to direct the past pressure effect. • History of long-term intake of anticoagulants 6. Infertility (warfarin, aspirin) or tamoxifen which can lead 7. Recurrent pregnancy loss (RPL) to menorrhagia 8. Something coming out per vaginum: Fibroid Personal history polyp with long pedicle may present as some • Smoking: associated with a lower risk of mass coming out of vagina especially on straining. fibroids 9. History suggestive of anemia: Easy fatigability, tiredness, lassitude, palpitations, etc. Q.2. What are the important points on 10. History of any bleeding disorder: Bleeding from examination? other mucosal sites 11. History suggestive of malignancy and distant Ans: General Physical Examination spread: Significant weight loss, anorexia, • General Condition jaundice, bone pains, headache, chest pain, • Built and nutrition: fibroids are more often hemoptysis. found in obese women Fibroid Uterus 233

• Pallor and severity • Any polyp protruding through or arising from • Vitals: Pulse rate, blood pressure, respiratory cervix rate–evaluate the degree of anemia and need for immediate transfusion of blood products. Mrs P’s per-vaginal examination (p/v) findings • Lymphadenopathy were as follows: • Thyroid Cervix was firm and regular, pointing downwards, • B/L breasts uterus anteverted size corresponding and Systemic examination: This is important for equivalent to 20 weeks pregnant uterus, irregular, anaesthesia fitness prior to planning surgery. firm, mobility present from side to side, non- If the patient has other co-morbid medical tender. Cervical movements transmitted to the problems, the patient can be planned for non mass surgical modalities for treatment of fibroid. In any case of lump abdomen, it is important to Per abdominal Examination differentiate a uterine mass from an adnexal mass 1. Inspection: Contour of the abdomen, uniform/ by the following points:3 unequal distension, any scar marks • Uterus will not be felt separate from the uterine 2. Palpation: mass • Description of the mass if present: size • Movements of the mass felt per abdomen are (corresponding to weeks of a gravid uterus), transmitted to the cervix and vice versa in case condition of overlying skin (tender, warm, of a uterine mass fixity to mass), mobility–sideways and • No groove will be felt between the mass and vertical, confirm pelvic origin (inability to the uterus in contrast to an adnexal mass where reach the lower limit of the mass), a groove is found between the adnexal mass consistency, margins of the mass (well and uterus defined/vague), surface regularity (smooth/ (The above 3 points may not hold true for a irregular). subserosal pedunculated fibroid) • Any other associated organomegaly • Hingorani’s sign: examination of the patient • Presence of free fluid in Trendelenburg position results in upward • B/L renal angles for any mass/tenderness displacement of the adnexal mass and one can (large fibroids can compress ureter and can lucidly elicit the groove between the uterus and cause hydronephrosis an adnexal mass. 3. Percussion: The swelling will be dull on percussion. Q.3. What are the causes of uterine Local Examination enlargement? What is the differential diagnosis? • External genitalia whether healthy or not Ans: • If currently bleeding, the severity of menorrhagia 1. Pregnancy: It must be ruled out in patients with Per-speculum examination history of amenorrhea/overdue periods prior to • Look for cervix and vagina for any associated investigating other gynecological causes. pathology 2. Uterine fibroid • Presence of clots in the vagina, bleeding seen 3. : through the cervical os a. Patients are often multiparous with com- • Any descent of cervix, , plaints of menorrhagia and dysmenorrhea. 234 Case Discussions in Obstetrics and Gynecology

b. It usually does not exceed 14 weeks in size. a. uterine contour irregularity and enlargement c. The uterus on P/V may be slightly soft and are the most common findings tender. Diagnosis can be confirmed on USG b. hypoechoic heterogeneous well-defined which shows localized or diffuse loss of lesions within the myometrium causing endomyometrial junction with presence of distortion of uterine outline, any protrusion subendometrial cysts. In the latter case, it is into the endometrial cavity. important to rule out endometrial cancer and c. degenerative changes can take on different it is here where an MRI has a crucial role. echogenic patterns such as irregular central Treatment is hysterectomy after which the anechoic areas seen in cystic degeneration diagnosis is confirmed on histology. or bright highly echogenic areas with distal 4. Myohyperplasia: Clinical presentation shadowing seen in calcific degeneration. simulates that of fibroid uterus and diagnosis is d. hydroureter or hydronephrosis in cases of confirmed on histology. large/broad ligament fibroids 5. , hematometra: History and 3. Pap smear examination will be suggestive of causes 4. Endometrial aspiration and Endocervical conducive to cervical stenosis, e.g. Cervical curettage (ECC): Mandatory in patients with cancer, tubercular endometritis, previous history of irregular bleeding PV to rule out cervical amputation. Diagnosis is confirmed on associated endometrial pathology. sonography. Management consists of drainage 5. IVP: Recommended in cases of large subserosal of the intrauterine collection along with a fibroids, cervical and lower uterine segment cervical/endometrial biopsy followed by fibroids, and broad ligament fibroids to see for appropriate treatment of the underlying cause. relation of ureter and any signs of compression 6. Malignancy of uterus: as cervical and broad ligament fibroids may a. Uterine sarcoma displace the ureter. b. Sarcomatous degeneration of a pre-existing 6. Investigations for PAC work-up prior to neglected fibroid surgery: Complete blood count, blood sugar, c. Endometrial cancer: As it usually presents kidney function tests, chest X-ray, ECG, urine in its early stages, such marked enlargement routine and microscopy. of the uterus is rarely seen. Q. 5. Classify the different types of fibroids. Q.4. What investigations should be ordered in Ans: the above patient? Fibroids are classified according to their anatomical Ans: location1-3 1. Hemoglobin, 1. Body of uterus Complete blood count (CBC) with peripheral a. intramural/interstitial (75%) smear (especially in menorrhagia/anemia and b. subserous (15%) also as a part of pre-operative work up if i. true subserous planned for surgery) ii. broad ligament fibroid (pseudo) 2. USG pelvis: For mapping, number and size of iii. wandering/parasitic fibroids. Trans-abdominal sonography (TAS) c. submucous (5%) may not identify fibroids less than 2 cm in size. i. sessile Findings on USG include4 ii. pedunculated/polyp Fibroid Uterus 235

2. cervical d. Calcific degeneration a. anterior e. Red degeneration – in mid-pregnancy and b. posterior puerperium (explained later) c. central – produces “Lantern on Dome of St. 2. Vascular changes – telangiectasis and lymphan- Paul’s appearance” due to uterus sitting on giectasis inside the myoma top of the expanded cervix. 3. Necrosis and infection – seen in submucous d. Lateral fibroid polyps 3. Intravenous leiomyomatosis–polypoid intra- 4. Sarcomatous change – Leiomyosarcoma vascular projections into the veins of the follows less than 0.1% of fibroids. It is sus- parametrium and broad ligament. pected when there is sudden enlargement of a 4. Leiomyomatosis peritonealis disseminata – fibroid, fibroid along with postmenopausal benign nodules replace peritoneal deciduas on bleeding, or recurrence of a fibroid polyp after subperitoneal surface of the uterus and other its removal. pelvic and abdominal viscera due to a reparative 5. Torsion of subserous pedunculated fibroid process. 6. Hemorrhage – It can be intracapsular or intraperitoneal due to rupture of surface veins Q.6. How can one distinguish between true and of a subserous fibroid. false broad ligament fibroids? 7. Rare paraneoplastic complications – Ans: polycythemia, thromboembolism, hypo- True False glycemia, hypokalemia. Origin Arise from the Arise from the muscle fibers in lateral wall of the In the above patient Mrs P, ultrasonography parametrium uterine body/ revealed multiple fibroids in the uterus. How will cervix and bulge you manage her? between layers of As the above patient is 45 years and has the broad ligament completed her family, the best treatment would be Uterine artery Lies beneath and Uterine artery is on the inner side displaced hysterectomy, which can be performed either by (medial) of the outwards and laparotomy or laparoscopy. tumor upwards Ureter Displaced inwards- Displaced Q.8. What are the indications of treatment of lies medial to the outwards towards fibroids? tumor the pelvic wall- lies lateral to the Ans: Asymptomatic fibroids less than 12 weeks tumor don’t require treatment but must be followed up regulary at 6 monthly intervals. Q.7. What complications can be anticipated in Indications for treatment: a patient with fibroid uterus? 1. asymptomatic fibroid > 12 weeks in size Ans: 2. abnormal uterine bleeding 1. Degenerations 3. pain and pressure symptoms a. Hyaline degeneration (most common) 4. urinary tract symptoms or obstruction b. Atrophic degeneration 5. infertility after excluding other causes c. Fatty degeneration 6. recurrent pregnancy loss 236 Case Discussions in Obstetrics and Gynecology

7. rapid growth (defined as a gain of 6 weeks or Magnetic resonance imaging guided focused more in gestational size within a year or less) ultrasound surgery (MRgFUS)6,7: 8. growth after menopause It is a non-invasive procedure which destroys myoma tissue using ultrasonic energy but still in Q.9. What are the various treatment modalities? the research phase. Ans: Treatment needs to be individualized Selection criteria includes: depending on presentation age, parity etc. 1. fibroids between 4 and 10 cm size 1. Medical management 2. completed family 2. Non invasive procedure: Magnetic resonance 3. perimenopausal age group imaging guided focused ultrasound surgery 4. maximum depth of subcutaneous tissue to (MRgFUS) fibroid < 12 cm 3. Minimally invasive techniques 5. fibroids clearly visible on MRI a. Uterine artery embolization Procedure: It is a non-invasive outpatient procedure b. Myolysis that uses high intensity focused ultrasound waves 4. Surgery to ablate the fibroid tissue. This method of tissue a. polypectomy destruction is thermal ablation. During the b. hysteroscopic resection procedure, an interventional radiologist uses c. myomectomy – open/laparoscopic magnetic resonance imaging (MRI) to provide a d. Hysterectomy- Total abdominal hysterectomy/ three-dimensional view of the targeted tissue, Non descent vaginal hysterectomy/ allowing for precise focusing and delivery of the laparoscopic assisted vaginal hysterectomy/ ultrasound energy. MRI also enables the physician Total laparoscopic hysterectomy to monitor tissue temperature in real-time to ensure adequate but safe heating of the target. The Q.10. What is the role of medical management procedure is FDA approved for treating uterine in a patient with fibroid uterus? fibroids. Immediate imaging of the treated area Ans: Medical therapy can be used for either one of following MRgFU helps the physician determine the following two purposes (Refer Table 19.1): if the treatment was successful. Symptoms abate within 3 months of the procedure. Temporary palliation As an alternative Complications: Minor skin burns, worsening to surgery menorrhagia, and non target sonification of uterine a. To improve menorrhagia a. Perimenopausal women serosa. b. Correct anemia before b. Women medically unfit surgery for surgery Q.11. What is the role and indications of uterine c. To minimize size and c. Women unwilling to artery embolization in the treatment of fibroid vascularity and reduce undergo surgery blood loss during uterus? surgery Ans: d. To facilitate laparoscopic Indications: Symptomatic uterine fibroids in women surgery/allow use of who have completed child bearing but are unfit for a transverse incision surgery (morbid obesity, diabetes mellitus, multiple e. Temporary postponement medical problems) or not willing to undergo of surgery surgery. Fibroid Uterus 237

Table 19.1: Various drugs available for treatment of fibroids5 Drug Dosage Advantages Disadvantages Antifibrinolytics Tranexamic acid: • Significant reduction • No effect on the size of the 1-4 gm/day during days in the amount of blood fibroid of heavy flow loss • Improvement of anemia GnRH agonist Goserelin (Zoladex): • 40-60% reduction in • Hypoestrogenic side effects 3.6 mg every 28 days size of fibroids limits its use to no more than for 3-6 months, • Reduction of intraoperative 6 months subcutaneous blood loss • Rebound increase in size after discontinuation of therapy • Loss of surgical planes during surgery • Small seedling fibroids may be missed during surgery and reappear later • Expensive GnRH antagonist Cetrorelix, Ganirelix • Quicker response to therapy • Needs further evaluation (2-4 weeks) • No flare up effects Antiandrogens Danazol: 200-400 mg • Decreases fibroid volume • Androgenic side effects: acne, PO/day for 6-12 months and bleeding hirsutism, hoarse voice, Gestrinone • No hypoestrogenic S/E altered libido, decreased • Fibroids do not regrow breast size, headaches after discontinuation of therapy Progesterone antagonist Mifepristone: • 25-75% reduction in size • Endometrial hyperplasias 25-30 mg/day for of fibroid develop on long-term use 3-6 months • Amenorrhea and improves • S/E: hot flushes, joint pains, Hb levels deranged LFTs • No bone loss Selective progesterone Asoprisnil • Suppresses menstruation • Further evaluation required Receptor modulator • Improves Hb level • Inhibits growth of the fibroid • No effect on ovulation or endometrial proliferation Aromatase inhibitors Fadrazole • Under trial • Under trial Progesterone IUDs Mirena • Reduces blood loss • Expensive • Reduction of size of the • Not suited for uterus uterus > 12 weeks size • Improves Hb level due to • Can’t be used where the suppression of menstruation uterine cavity is distorted • Also provides effective contraception • Effective for 5 years 238 Case Discussions in Obstetrics and Gynecology

Procedure: It is performed by an interventional 4. Immunocompromised patient radiologist under deep sedation or local anesthesia. 5. Malignancy Percutaneous single femoral artery catheterization 6. Undiagnosed pelvic mass is done through which bilateral uterine arteries are 7. Pedunculated subserosal fibroid- can cause catheterized and occluded with polyvinyl alcohol peritonitis and bowel adhesions particles (PVA, 500-710 um diameter) to produce 8. Adenomyosis – poor response to UAE ischemic necrosis of the fibroid. The procedure is 9. Pregnancy followed by parenteral antibiotics. 10. Arteriovenous malformations Advantages: 1. least invasive procedure which avoids surgery Q.12. What is myolysis? 2. shorter hospital stay and recovery Ans: Laparoscopic procedure which destroys the 3. success rate between 85 and 95% myoma employing either laser, cryotherapy, or 4. 50% reduction in uterine size after 6 months electrosurgical energy. High recurrence rates and 5. fewer incidence of major complications extensive adhesion formation limits its use. Disadvantages: Ideal candidates are perimenopausal women 1. Not suitable for women desirous of preserving having symptomatic fibroids between 3 and 10 cm their fertility but conclusive data is still lacking or uterine size less than 14 weeks. regarding its safety. 2. Can only be performed in a setting with an ACOG criteria for hysterectomy for leiomyomata interventional radiologist. Confirmation of Indication: Complications: They are seen in 1-5% of 1. Asymptomatic leiomyomata of such size that they procedures. are palpable abdominally (12 weeks) and are a 1. Abdominal cramps concern to the patient 2. Post-embolization syndrome: Results from 2. Excessive uterine bleeding evidenced by either necrosis of the fibroid and release of of the following: inflammatory mediators. Patients complain of a. Profuse bleeding with flooding or clots or repetitive periods lasting more than 8 days fever, nausea, vomiting, anorexia and malaise. b. Anemia due to acute or chronic blood loss 3. Chronic vaginal discharge 3. Pelvic discomfort caused by myomata (a/b/c) 4. Target organ embolization: uterine infection, a. Acute and severe. sloughing of the fibroid, b. Chronic lower abdominal or low back 5. Non target organ embolization of ovary: pressurec. menopausal symptoms, amenorrhea c. Bladder pressure with urinary frequency not 6. Chances of emergency hysterectomy in 1% in due to urinary tract infection. case of infected fibroids, severe post- Actions Prior to Procedure: embolization syndrome, procedural failure 1. Confirm the absence of cervical malignancy 7. Complications in subsequent pregnancy: 2. Eliminate anovulation and other causes of spontaneous abortions, placental insufficiency, abnormal bleeding preterm delivery, PPH and uterine rupture 3. When abnormal bleeding is present, confirm the absence of endometrial malignancy Contraindications: 4. Assess surgical risk from anemia and need for 1. Acute pelvic infection treatment 2. Uncontrolled coagulopathy 5. Consider patient’s medical and psychologic risks 3. Contrast allergy concerning hysterectomy Fibroid Uterus 239

Contraindication: 6. In coordinate uterine contractions leading to 1. Desire to maintain fertility, in which case dysfunctional labour and greater incidence of myomectomy should be considered Cesarean section. 2. Asymptomatic leiomyomata of size less than 12 7. Abnormal uterine action – may lead to weeks’ gestation size determined by physical a. retained placenta examination or ultrasound examination b. PPH c. delayed involution Q.13. What are the indications of emergency 8. Obstructed labor – seen with cervical and broad hysterectomy for uterine fibroid? ligament fibroids Ans: 9. Fetal anomalies 1. uncontrolled bleeding from the fibroid a. Limb reduction 2. intraperitoneal hemorrhage b. Congenital torticollis 3. torsion in older patients. c. Head deformities

Q.14. What precautions must one take during Q.16. What changes can occur in a fibroid hysterectomy of cervical fibroids? during pregnancy? Ans: There are greater chances of inadvertent injury Ans: to the ureter, bladder and uterine vessels in this case. 1. increase in size and vascularity of fibroids The principle to be followed is enucleation 2. torsion of subserous fibroids followed by hysterectomy to minimize injury to the 3. infection in puerperium ureter. Alternatively, one can also give preoperative 4. red/carneous degeneration: It is common in mid- GnRH analogues 3 months prior to facilitate pregnancy due to rapid growth of the fibroid surgery. leading to ischemic necrosis and release of inflammatory mediators. Patients present with Q.15. How do fibroids affect the course of fever, nausea, vomiting and acute abdominal pregnancy? pain. Examination reveals localized tenderness Ans: over the fibroid. Management is conservative 1. Abortions/recurrent pregnancy loss due to: consisting of bed rest and analgesics. There is a. interference with enlargement of the uterus no role of surgery. b. initiation of abnormal uterine contractions c. inefficient placentation Q.17. What is to be done for fibroids 2. Placental abruption encountered during cesarean section? 3. Preterm labor Ans: Fibroids encountered during surgery should 4. IUGR- due to be left untouched (but mentioned in detail in the a. defective implantation of the placenta peroperative notes and discharge ticket) due to risk b. poorly developed endometrium of excessive blood loss. Surgery, if required, can c. reduced space for the growing fetus and be taken up 3 months after delivery. Conditions placenta where emergency myomectomy may be required 5. Malposition and malpresentations: contributing during pregnancy or cesarean section are: factors are- 1. Intractable pain a. distortion of shape of the uterine cavity 2. Removal of a pedunculated subserosal fibroid b. prevention of head engagement at the time of CS 240 Case Discussions in Obstetrics and Gynecology

3. Large fibroid hindering uterine repair List the important investigations to be 4. Fibroid interfering with delivery of the fetus performed in the above patient. from the uterus 1. Husband semen analysis – to evaluate the male 5. Incarcerated fibroid partner for infertility 6. Rapidly enlarging fibroid having compressive 2. Hysterosalpingography – rule out tubal block symptoms and to see if the fibroid is distorting the endometrial cavity CASE 2 (All other investigations which have been described A 24 years old lady, Mrs R married for three years, previously will remain the same). seeking treatment for primary infertility presents Q.20. How will you manage the above patient with a lump lower abdomen equivalent to 16 Mrs R? weeks of pregnant uterus. Ans: After excluding other causes of infertility Q.18. What are the causes of infertility in a myomectomy should be planned either by patient with fibroid uterus? laparoscopically or by laparotomy. Ans: Q.21. What are the various types of myo- 1. Uterine factors: mectomy? a. Difficult sperm transport: Due to distortion and elongation of the uterine cavity and Ans: Myomectomy procedures: hinderance with rhythmic uterine 1. Laparotomy (Abdominal myomectomy) contractions 2. Hysteroscopic myomectomy: suited for b. Defective nidation: Due to congested and submucous fibroids/polyps dilated endometrial venous plexus. Atrophy 3. Laparoscopic myomectomy: particularly for and ulceration over a submucous fibroid removing pedunculated subserosal fibroids and interfere with nidation. small subserosal fibroids not growing too 2. Tubal factors: deeply into the uterus. The fibroids are a. Cornual block due to position of the fibroid morcellated and suctioned out through the b. Elongation of the tube over a large laparoscope. subserosal fibroid Newer modifications of laparoscopic myo- c. Associated salpingitis mectomy:9-11 3. Ovarian: Anovulation a. Laparoscopy assisted myomectomy: Combines 4. Peritoneal: Endometriosis laparoscopy with 2-4 cm abdominal incision 5. Idiopathic. done for myoma more than 8 cm or in deep myoma requiring extensive morcellation and Q.19. What are other gynecological diseases uterine repair in layers. The advantage is associated with fibroid uterus? reduced operating time and reduced need for Ans: extensive laparoscopic experience. 1. Anovulation and multiple follicular ovarian cysts b. Laparoscopy assisted transvaginal myo- 2. Endometrial hyperplasia mectomy: Done for extensive and deeply 3. Endometrial carcinoma (3%) infiltrating fundal and posterior wall fibroid. 4. Endometriosis/adenomyosis (30%) Laparoscopy is done to confirm the size, 5. Salpingo- (15%) location and number of myoma. Intra- Fibroid Uterus 241

myometrial vasopressin is injected. Posterior ACOG criteria for myomectomy in infertility colpotomy is done to deliver the myoma and patients uterus. After myoma removal, uterine Leiomyomata in infertility patients, as a probable reconstruction is performed by conventional factor in failure to conceive or in recurrent pregnancy suturing transvaginally. Uterus is replaced back loss into its anatomical position and colpotomy In the presence of failure to conceive or recurrent repaired. Final laparoscopic survey done and pregnancy loss: peritoneal lavage given. 1. Presence of leiomyomata of sufficient size or c. Robot assisted laparoscopic myomectomy with specific location to be a probable factor 2. No more likely explanation exists for failure to the Da Vinci surgical system: Use of robot conceive or recurrent pregnancy loss assisted technology overcomes the challenges Actions Prior to Procedure: encountered with uterine incision, enucleation, 1. Evaluate other causes of male and female repair and extraction that are seen with infertility or recurrent pregnancy loss conventional laparoscopic myomectomy. This 2. Evaluate the endometrial cavity and fallopian provides surgeons with improved dexterity and tubes, e.g. hysterosalpingogram precision coupled with advanced imaging and 3. Document discussion that complexity of disease allows endoscopic approach to be more process may require hysterectomy. accurately modeled after open surgical technique. Q.23. How will you proceed for a myomectomy d. Laparoscopic myoma coagulation [myolysis] (laparotomy)? and cryosurgery: Blood supply of the fibroid Ans: is coagulated using ND-YAG laser or with long • Surgery is planned in the postmenstrual phase bipolar needle electrode. The main advantage • Optimal Hb status and adequate arrangement is no regrowth of the myoma. However, risk of of blood prior to surgery (at least 10 gm%) uterine rupture in future pregnancy has been should be ensured. reported. In cryomyolysis, myoma is frozen with The patient is counseled regarding the following liquid nitrogen delivered with a special probe. points: The efficacy of this technique need to be 1. The patient may require hysterectomy in case determined by further trials. of excessive haemorrhage. 2. Chances of pregnancy after myomectomy: 40- Q.22. What are the ACOG criteria for 60% myomectomy in infertility patients? 3. Chances of recurrence/persistence of fibroid Ans: after myomectomy: 30-50% 1. Patients in the reproductive age group and 4. Risk of re-laparotomy after myomectomy: 20- desirous of future fertility 25% 2. Unexplained infertility with distorted uterine 5. Chances of persistence of menorrhagia after cavity due to fibroid myomectomy: 1-5% 3. Unexplained RPL Steps of myomectomy: 4. Fibroid in lower part of the uterus and likely to 1. Induction of the patient, appropriate position, complicate delivery clean and drape 242 Case Discussions in Obstetrics and Gynecology

2. After the abdomen is entered, uterine anatomy myoma screw. A cut section is done and the is identified (is often distorted) by noting specimen is sent for histopathology position of the round ligaments. The adnexa are c. Myometrial dead space is closed in layers. also noted and are identified It is important to maintain hemostasis and a. Prevention of intraoperative hemorrhage: at the same time ensure patency of the i. Occlusion of uterine artery (through a endometrial cavity if the cavity has been transparent area in the broad ligament opened. The latter can be done either by around the cervix at the level of lower inserting a dilator through the cervix in the uterine isthmus) and ovarian artery uterine cavity or staining the endometrium (around the infundibulopelvic ligament using methylene blue prior to surgery. through the same hole in broad ligament)- d. Abdomen is closed in layers. either tourniquet or Bonney’s myomec- Q.24. What is Bonney’s hood operation? tomy clamp can be used. It is important to release the tourniquet every 30 min as Ans: It is done to remove a large fundal fibroid. A prolonged occlusion of blood supply low transverse incision is made on the myoma over leads to ischemic necrosis of tissues and the anterior uterine surface. After removal of the release of histamines which can result in fibroid, the capsule is trimmed and is sewn over the anterior uterine wall. This procedure minimizes shock. adhesion formation. ii. Vasopressin injection over the fibroid: 20 U of vasopressin diluted in 20 ml of NS Q.25. How is myomectomy performed for a iii. Controlled hypotensive anesthesia (less central cervical fibroid? popular): Sodium nitroprusside or NTG Ans: After incising the peritoneum of the is used to maintain mean BP 60 mm Hg uterovesical pouch and dissecting the bladder and the patient is placed in Trendelenburg down, hemisection of the uterus is done from above position. downwards to reach the fibroid which is then b. A longitudinal incision is given over the enucleated. The dead space is obliterated without most prominent part of the fibroid and closing the cervical canal followed by repair of the deepened till the plane between the capsule bisected uterus. and fibroid is reached. All myomas should be removed through a single incision. Q.26. What are the advantages and disadvan- Posterior wall fibroids are also removed tages of laparoscopic myomectomy? through an anterior incision by transcavitary Ans: approach. Incision is not given on the Advantages: posterior surface to avoid adhesions which 1. Shorter hospital stay may impede future fertility. Another 2. Lower morbidity advantage of an anterior incision is easy 3. cosmetically better accessibility to clinical suspicion of Disadvantages: imminent scar dehiscence during pregnancy 1. Requires expertise by eliciting scar tenderness. The fibroid is 2. laparoscopic myomectomy is limited to patients separated from the capsule by sharp and with fibroid size less than 8 cm or less than 4 blunt dissection. The fibroid is removed by fibroids . Fibroid Uterus 243

3. high recurrence rates (35%) 2. USG: It confirms the presence of uterine polyps. 4. greater adhesion formation Mucous polyps can be differentiated from 5. Greater chances of rupture in pregnancy fibroid polyps by the fact that the former are hyperechoic whereas the latter appear Q.27. What postoperative advice will you give hypoechoic on USG. to a patient after myomectomy? 3. Saline infusion sonohysterography: confirms Ans: Because fibroids can grow back, it is best to the presence of uterine polyps in case of doubt. try to conceive as soon after a myomectomy as is 4. HSG: shows a filling defect safely possible. It is recommended that patients 5. Hysteroscopy: It carries the advantage of being should wait 4 to 6 months after surgery to allow a combined diagnostic and therapeutic the uterus to heal before pregnancy. It should also procedure. be mentioned in the discharge slip regarding entry European Soceity of Hysteroscopy Classification into the endometrial cavity which mandates an of Submucous Fibroids (depending on the degree elective cesarean section in the subsequent of myometrial extension of the fibroid) pregnancy at 37 completed weeks of pregnancy. Type 0 Submucous polyps lying entirely in the endometrial cavity CASE 3 Type 1 < 50% extension into the myometrium A 38 years old multiparous lady attends the Gynae Type 2 > 50% extension into the myometrium OPD with and severe dysmenorrhea for last three months and mild Q.29. How should a fibroid polyp be managed? pallor. On examination there was a polyp seen Ans: The management depends on the following through cervical os about 3 centimeters diameter factors: 1. Age of the patient Q.28. How can you explain metrorrhagia in this 2. Desire for future fertility patient? 3. Associated uterine pathology Ans: 4. Location of the polyp 1. Ulceration of submucous fibroid polyp 1. Polyp confined to the cavity 2. Bleeding from the torn vessels of the sloughing a. Hysteroscopic resection of the polyp base of the polyp with endometrial sampling (expertise 3. Associated endometrial cancer. needed). b. Hysterectomy with the polyp in situ Differential diagnosis: 2. Polyp lying in the cervical canal • Polyp a. Thin pedicle: Polypectomy with 1. Benign – Mucous polyp, Fibroid polyp endometrial sampling 2. Malignant – De novo or secondary change b. Thick/inaccessible pedicle: Vaginal • Chronic inversion of the uterus myomectomy/hysterectomy Diagnosis: c. Uterine preservation not desired: 1. Sound test: It is used to differentiate a fibroid Hysterectomy with the polyp in situ polyp from chronic inversion. If a uterine sound Pre-operative criteria for vaginal myomectomy: is passed all around between the pedicle and 1. Uterine size less than or equal to 16 the cervical os, it is a polyp. It cannot be passed weeks in case of chronic inversion. 2. Good uterine mobility 244 Case Discussions in Obstetrics and Gynecology

3. Adequate vaginal access 4. Gynaecologic ultrasound: a primer for clinicians. In 4. Intramural/subserosal myomas John Studd, Seang Lin Tan, Frank A. Chervenak 5. Absence of adnexal pathology (Eds) Progress in Obstetrics and Gynaecology, 2008;18:316. 3. Big fibroids lying in the vagina: The polyp 5. Schindler AE. The value of gonadotropin-releasing is removed by morcellation followed by a hormone-agonists together with other drugs for transfixation suture on the pedicle and medical treatment and prevention. Gynecol removal of redundant pedicle distal to the Endocrinol. 2009;25(12):765-7. ligature. 6. Wallach E, Vlahos NF. Uterine myomas: An overview of development, clinical features, and management. Q.30. What are the contraindications of Obstetrics and Gynecology, 2004;104(2):393-406. 7. Jolesz FA. MRI-guided focused ultrasound surgery. hysteroscopic resection of submucous fibroid?12 Annu Rev Med. 2009;60:417-30. Ans: 8. Fibroid Emblisation. In John Studd, Seang Lin Tan, 1. Endometrial cancer Frank A. Chervenak (Eds) Progress in Obstetrics and 2. Local infection Gynaecology, Volume 17, 2006;333-42. 3. Extensive intramural component 9. Nazli Hameed, Asghar Ali. Recent trends in Laparoscopic Myomectomy.J Ayub Med Coll 4. Severe/persistent menorrhagia leading to severe Abottabad 2004;16(1):58-63. anemia 10. Sangeeta Senapati, Arnold P. Advincula. Surgical techniques: Robot-assisted laparoscopic myomectomy REFERENCES with the da Vinci® surgical system. J Robotic Surg 1. Benign Lesions of the Uterus. In D. C. Dutta (Ed) 2007;1:69-74. Textbook of Gynaecology, 5th Edition, 2007;262-78. 11. Agdi M, Tulandi T. Minimally invasive approach for 2. Benign Diseases of the female reproductive tract. In myomectomy. Semin Reprod Med. 2010;28(3):228- Jonathan S. Berek (Ed) Novak’s Gynaecolgy, 14th 34. Epub 2010 Apr 22. edition, 2007;479-81. 12. Camanni M, Bonino L, Delpiano EM, Ferrero B, 3. Leiomyomata Uteri and Myomectomy. In John A. Migliaretti G, Deltetto F. Hysteroscopic management Rock, Howard W. Jones III (Eds) TeLinde’s Operative of large symptomatic submucous uterine myomas. J Gynaecology, 10th edition, 2009;687-725. Minim Invasive Gynecol. 2010;17(1):59-65. Asmita Muthal Rathore 20 Prolapse Uterus

With increased lifespan of women, the problems especially the treatable factors and also helps us in of pelvic floor dysfunction are increasing and making management decisions. becoming major health issue. Though, generally • History of presenting complaints – should not life-threatening, they significantly impair include duration of prolapse, rate of increase in physical functioning, emotional well-being and the severity, any bladder and bowel complaints. quality of life. The lifetime risk of undergoing Irreducibility of prolapse indicates long- surgery for prolapse or urinary incontinence for a standing nature of the problem and is due to woman is 11%.1 congestion, edema and hypertrophy of the This chapter will discuss the clinical evaluation tissues. and management of few cases of pelvic organ • History of precipitating factor–like chronic prolapse. The traditional goal of treatment to restore cough, constipation, any abdominal swelling normal pelvic anatomy does not necessarily return should be elicited. They need to taken care of to normal function of pelvic organs and therefore before surgical treatment is instituted so as to evaluation of women should also focus on specific reduce risk of recurrence. symptoms and the degree to which they affect • Obstetric history—the most common quality of life. The definitive treatment of prolapse aggravating factors are birth injury and is nearly always some sort of surgery but should be postmenopausal tissue atrophy. A detailed performed only if the condition is causing obstetric history should elicit factors like symptoms. If the prolapse is incidental or it is not pregnancies at short intervals, prolonged labor, certain that the patients symptoms are attributable big babies, and lack of perineal exercises. Parity to it, the operation is best deferred.2 of the patient, desire to preserve fertility should be noted as it will affect the choice of treatment CASE 1 option. • Menstrual history—postmenopausal state A 42-year-old Mrs X, Para 3 presents to should be noted as deficiency of estrogen gynecology outpatient department with complaint around menopause results in weakening of of mass descending per vaginum for one year and connective tissue and aggravation of prolapse. difficulty in initiating micturition. Any associated menstrual abnormality may need further evaluation and may modify choice Q.1. What details will you ask in history? of treatment. Ans: The history taken in detail can give us useful • Other symptoms—the presence of white information regarding etiology of prolapse, discharge, metrorrhagia or 246 Case Discussions in Obstetrics and Gynecology

may be due to decubitus ulcer but should be • The pelvic examination is most important to appropriately evaluated. It is vital to assess the assess severity of prolapse and plan surgical urinary tract, defecatory or sexual dysfunction. procedure. The goal is to objectively assess the History of any other associated problems should anatomy of pelvic floor and organs and to be asked to get overall picture of womans health attempt to correlate symptoms with anatomic status. findings. Local examination should be • Treatment History—any treatment in past performed in dorsal lithotomy position. especially in form of pessary or surgery and its – Inspection of external genitalia for any results should be noted. lesions, rashes, etc. should be done. The perineum should also be inspected for any Q.2. What are the common urinary symptoms evidence of old healed perineal tears, in prolapse and their mechanism? integrity of perineal body. Ans: The woman with prolapse may present with – Eliciting stress incontinence—the bladder variety of urinary symptoms. should be full if there is history of stress • Difficulty in initiating micturition is common incontinence and any leakage of urine on problem in women with large cystocele. It is coughing should be noted. If present, then Bonneys test should be performed by difficult to empty the bladder and the difficulty elevating bladder neck with index and increases with straining as bladder base and middle fingers on either side which should trigone descend below the level of . She stop leakage of urine on stress. can empty the bladder only after reducing the – Examination of prolapse—the degree of mass digitally. prolapse should be assessed after maximum • Frequency and dysuria—symptoms suggestive straining. of cystitis can be seen as incomplete emptying - Look for evidence of hypertrophy of of bladder leads to increased risk of cystitis. cervix, congestion, edema, decubitus • Stress urinary incontinence may be present if ulcer, keratinization, infection or vaginal prolapse is associated with descent of atrophy. urethrovesical junction. - Note the degree of descent of cervix, • Rarely retention of urine can also be seen. anterior and posterior vaginal wall and quantify the degree of support using Q.3 What important points will you note in POPQ system. examination of this woman? - Identify the specific anatomic defects— Ans: that can be addressed with surgical • The general examination—should note general intervention. The dominant prolapse is condition of patient and assess mental status, considered to be first hernia to descend body mass index, nutritional status. Since many or the most dependent part of prolapse women will most likely need surgical and provides key clue about where most intervention, presence of anemia, any lympha- significant fascial damage is located.3 denopathy should be looked for. – Bimanual pelvic examination is done to note • The abdominal examination—should focus on direction of uterus, size and mobility of hernial sites, any abdominal mass or free fluid uterus and any adnexal mass and tenderness. in abdomen. The levator tone should be assessed. Prolapse Uterus 247

Q.4. How do you look for tone of levator ani • First degree-descent of uterus below ischial muscle? spine but cervix remains within the introitus. Ans: The levator tone is assessed by palpating • Second degree–descent of cervix up to introitus vaginal wall at 5 and 7o’ clock position about 2-4 • Third degree–descent of cervix outside introitus. cm above hymen. The woman is asked to squeeze • Fourth degree–entire uterus prolapses outside her vaginal muscles as though she is holding gas the vulva. or stopping urine flow. The strength is graded from POPQ system–It is approved by International 0 to 5 using modified oxford scale 4 as follows: Continence Society in 1995 and more accurately • Grade 0 –no discernible pelvic floor contraction quantifies pelvic support findings. It allows accurate • Grade 1 –a flicker under finger. quantification for scientific comparisons and is thus • Grade 2 – a weak contraction or increase in reproducible. In this system the positions of 9 sites tension without any discernible lift or squeeze are measured in cm in relation to hymen (negative • Grade 3 – a moderate contraction with partial number for proximal and positive number for distal) lifting of postvaginal wall and squeezing of and recorded in grid form (Fig. 20.1). These 9 sites finger, contraction > grade 3 is visible. are as follows: • Grade 4–good pelvic contraction causing 1. Aa–point 3 cm proximal to urethral meatus on elevation of postvaginal wall against resistance anterior vaginal wall and indrawing of perineum. 2. Ba–the most distal portion of upper anterior • Grade 5 – strong contraction of pelvic floor vaginal wall against strong resistance. 3. C–cervix or vaginal cuff Levator muscles should also be palpated for 4. D–posterior vaginal fornix tenderness or spasm. The integrity of the pudendal 5. Ap–point 3 cm proximal to hymen on post nerve is tested by eliciting anal and bulbo- vaginal wall cavernosus reflexes. The anal reflex is elicited by 6. Bp–most distal position on posterior vaginal gently stroking perianal skin which results in wall contraction of external anal sphincter and in bulbocavernosus reflex, the bulbocavernosus and ischiocavernosus muscles contract in response to tapping the .

Q.5. What are the different classifications of prolapse and their advantages? Ans: Though there are many classifications, the one traditionally used is Shaw’s classification and now widely recommended worldwide is the the Quantification system [POPQ] 5 which objectively quantifies the prolapse. Shaw’s classification – This is the simplest and most widely used in the past. It classifies prolapse in four stages and uses ischial spine as reference point. Fig. 20.1: POPQ staging 248 Case Discussions in Obstetrics and Gynecology

7. Gh–the diameter of genital hiatus (measured Mrs X Age 42 years Hospital from middle of external urinary meatus to record no posterior midline of hymen). 8. Pb–the width of perineal body (measured from posterior midline of hymen to the midanal opening). 9. Tvl–total vaginal length (greatest depth of vagina in cm after reducing the prolapse). It should also be recorded if the measurements were taken in lithotomy or standing position and whether straining or traction was applied. Based on measurements at above 9 sites the prolapse is staged from 0-4 according to most distal position of prolapse - • Stage 0–no prolapse is demonstrated. • Stage I–the criteria for stage 0 are not met but Fig. 20.2: POPQ staging of Mrs X the prolapse is >1cm above the hymen. • Stage II–within 1 cm of hymen (i.e., the Q.7. What is differential diagnosis of prolapse quantification value is > -1 but < +1) • Stage III–more than stage II but 2 cm less than uterus? total vaginal length [i.e., quantification value > Ans: The common differential diagnosis of +1 but < + (TVL-2)]. prolapse uterus are: • Stage IV–complete eversion of genital tract [ie, • Gartner cyst or anterior vaginal wall cyst may quantification value > + (TVL-2)]. look similar to cystocele but is not reducible. • Congenital elongation of cervix—though Q.6. How will you perform POPQ staging and congenital, elongation may many time present what is the stage of prolapse in your patient? for the first time after childbirth. It is identified Ans: Women is placed in lithotomy position. Ayres by deep fornices and long infravaginal portion spatula is used for measurements and grid with 3 of cervix. columns and rows is drawn and labeled with • Fibroid polyp coming out of vagina may look patients name. like prolapse but can be diagnosed by rim of • First measurement of genital hiatus and perineal cervix felt all around the tumor and associated body is completed and entered in grid. menstrual complaints. • Then speculum is inserted and Tvl is measured • Chronic inversion can also mimic prolapse. with spatula. • Points C and D are next measured during Q.8. How will you investigate your patient? maximal Valsalva’s maneuver. • Lastly points Aa, Ba, Ap and Bp are measured. Ans: The woman should have– The severity of prolapse in my patient is Stage • Baseline assessment - of her general condition 4 with leading point C, [lithotomy position with by having complete hemogram, routine urine straining] with decubitus ulcer. analysis. The quantification in my patient is as follows • Urine culture and sensitivity—It is mandatory (Fig. 20.2) to rule out urinary tract infection (UTI). Prolapse Uterus 249

• Other investigations—should be directed by Ans: presence of associated factors like X-ray chest • The aim of surgery is to restore the normal in women with chronic cough. anatomy, to maintain or restore visceral and • Complete preoperative assessment for sexual function. anesthesia—should be done in women planned • The reconstruction of normal supports and for surgical treatment which will include blood normal vaginal length with its axis directed sugar estimation, renal function tests, ECG and towards S3-S4 is important. chest X-ray or any other investigation as advised • Correct identification of deficiency whether by anesthesiologists. central or lateral and strength of supporting • Special investigations—in woman with urinary, ligaments will rationalize the choice of surgical defecatory or sexual dysfunction further treatment. evaluation by appropriate consultation and • Woman’s wish for preserving sexual, menstrual investigations like urodynamic studies should and childbearing function will also influence be done. choice of operation.

Q.9. What is decubitus ulcer and how will you Q.12. What is DeLancey’s classification of manage it? supports of uterus? Ans: The decubitus ulcer is benign and is present Ans: De Lancey6 has classified supports of uterus on dependant part. It is usually an ischemic process in three levels: due to venous stasis resulting in tissue anoxia. The Level I – apical support by uterosacral ligaments, decubitus ulcer is treated by keeping the prolapse Mackenrodt’s ligament and paracolpium reduced, which will restore circulation and help in Level II – midvaginal support due to lateral healing. Prolapse can be kept in reduced position attachment to levator fascia by packing. Packing with glycerin-acriflavin may Level III – lower vaginal supports by perineal body help if tissues are hypertrophied and edematous. or fusion of distal urethra to pubic bone. In an atrophic vagina, application of estrogen cream CEE 0.625 mg/day for 2-3 weeks will help Q.13. What are different surgical options in your in tissue vascularisation and improve healing power patient? of tissues, but should be stopped at least 2 weeks Ans: In my patient which can be prior to surgery. performed are: If hospitalization is not possible for regular Vaginal hysterectomy with site specific repair packing, option of insertion of pessary for short of anterior and posterior vaginal wall defects: duration can be considered. The removal of uterus will permit better reconstruction of supports and thus reduce risk of Q.10. How will you treat your patient? recurrence. The uterus which may be site of Ans: Since my patient is 42 years of age, completed unsuspected disease will be removed. Site specific her family and symptomatic with prolapse repair will reconstruct the pelvic supports. interfering with her normal life, I will offer her Manchester operation: It has advantage of surgical treatment. preserving menstrual and childbearing potential. The sexual function may also be better after Q.11. What are the objectives of surgical Manchester operation than after vaginal treatment of prolapse? hysterectomy. The possibility of future surgery for 250 Case Discussions in Obstetrics and Gynecology recurrence or other uterine pathology should be Q.15. How do you diagnose site specific defects? explained to the woman. Ans: The site specific defects can be diagnosed by Hysteropexy: Uterine preservation in cases of clinical assessment and extesive dissection during uterovaginal prolapse was previously only surgery. considered if future fertility was a particular Clinically these can be identified by examining concern. However, today some women are inclined a woman in lithotomy position during straining and to retain uterus or cervix in an attempt to prevent with help of ring forceps, Sims speculum and change in postoperative sexual function. Bivalve Cusco’s speculum. Look for rugosities of Sacrospinous ligament fixation with uterine vagina which should correlate with with pattern of conservation can be done vaginally and sacral fascial breaks found during surgery.3 hysteropexy which uses the same principles as • Anterior vaginal wall defects can be midline, sacral colpopexy and graft placement, can be paravaginal or transverse apical. To assess them, performed by laparotomy or laparoscopy. posterior vaginal wall is retracted by Sims single bladed speculum and anterior vaginal wall Q.14. What is site specific repair? What are the inspected. common sites of specific defects? Midline defect is suspected if midline Ans: The specific defects in connective tissue bulge is noted when the lateral sulci and apex network of pelvis are identified and the anatomic of vagina are supported with ring forceps. corrections of specific defects are performed in The paravaginal defects appear as blunting individual woman instead of midline placations in or descent of lateral sulcus on either side with all women. The common sites for defects are: straining. Bilateral paravaginal defects are Anterior vaginal wall: The main support to assessed by opening the blades of ring forceps anterior vaginal wall is due to pubocervical septum and supporting both lateral sulci. Unilateral which is attached superiorly to pericervical ring and paravaginal defects are assessed by supporting cardinal ligaments, to arcus tendinous fascia of each sulcus to the sidewalls separately with pelvis (ATFP) laterally and pubic tubercle on each closed ring forceps. The transverse defects are side inferiorly. The common defects identified in seen as distinct bulging out of anterior fornix this support are- central defect in pubocervical which is smooth and without rugosities. septum, paravaginal defect on one or both sides • Apical defects are seen in patients with uterine due to detachment of pubocervical septum from prolapse and are due to detachment of ATFP or transverse apical defect due to detachment pericervical ring. The can be evaluated by using of pubocervical septum from pericervical ring. an open bivalve speculum that is withdrawn Posterior vaginal wall: The postvaginal wall is slowly while patient is straining when posterior supported by rectovaginal septum which is attached and lateral walls seen bulging with downward superiorly to pericervical ring and uterosacral mobility of cervix. ligaments, laterally to levator fascia and inferiorly • Posterior vaginal wall defects are evaluated to perineal body. The common sites of injury to while supporting anterior vaginal wall and apex this septum are-transverse apical defect due to with Sims speculum and gradually withdrawing detachment from pericervical ring or uterosacral the single bladed speculum over posterior wall. ligaments, midvaginal defects may be central or Upper posterior wall prolapse appears as lateral due to injury or attenuation of levator fascia bulging down of posterior wall of vagina and and inferior defect due to detachment from perineal cul-de-sac and are associated with apical and body or there may be disruption of perineal body. posterior entroceles. They are best evaluated by Prolapse Uterus 251

doing rectovaginal examination and palpating 1. The traditional anterior colporrhaphy for breaks and thickness of rectovaginal septum. involves polication of vesicovaginal fascia The clinical value of determining the location in the midline after dissection of vagina from of defects is limited as most women have mixture bladder using absorbable or delayed of defects and the correlation between clinical and absorbable suture material. There is only one intraoperative findings is also not reliable.7,8 The midline repair. It does not expose or identify reproducibility of clinical examination is poor the white line and thus if the woman has a within the same examiner and in between different paravaginal defect, this midline plication examiners.9 may aggravate it resulting in recurrence. The The specific defects become evident only during site specific repair involves extensive the intraoperative dissection. Thus irrespective of dissection of vaginal wall and complete clinical findings, the extensive dissection should exposure of pubocervical fascia/septum be performed during surgery to identify the defects. from ATFP. The specific defects are After complete dissection inspection is started for identified and accordingly repair is fascial defects keeping in mind the normal anatomy. performed using nonabsorbable suture The fascia is whitish, fibrous and in different plane material. The repair sites may be multiple from underlying visceral fascia. Irrigation with depending on defects. saline may make the color difference obvious. 2. In posterior colporrhaphy, the epithelium of Careful inspection reveals the torn edges. The postvaginal wall is dissected and underlying ability to recognize fascial defects is acquired endopelvic fascia of rectovaginal septum is during careful dissection and observation. plicated in the midline using chromic catgut, sometimes from vaginal apex to perineal Q.17. How does traditional pelvic floor repair body and levator muscles. Though this (anterior colporrhaphy and posterior colpo- corrected midline bulge, it did not correct perineorrhaphy) differ from site specific repair? incomplete emptying and caused dyspareunia Ans: in many cases. In site specific the recto- • The traditional prolapse surgery did not vaginal septum is exposed and various emphasize on entire connective tissue network defects are identified. There might be but incorrectly thought as organ specific multiple suture line in rectovaginal septum prolapse, e.g. cystocele, rectocele, etc. and after repair and they may be transverse, operations focused on reinforcing attenuated vertical in midline or laterally. The defects tissues surrounding these organs. The support are repaired using nonabsorbable suture for pelvis is not from ligaments and fascia but material. from the network of connective tissue that interwines as it surrounds organs. Q.18. How do you identify and repair entero- • In surgical correction of prolapse by site specific cele during surgery? repair, the portions of this entire network are Ans: The is identified by per speculum used to restore the continuity and support the examination done under anesthesia just before uterus, bladder, rectum, vagina. The prolapse surgery. The posterior lip of cervix is held by allis is considered as hernia and the defects are forceps and speculum is inserted in posterior fornix. repaired using nonabsorbable material and use The speculum is gradually withdrawn, when a bulge of meshes if the defects are large. in upper third represents enterocele in which cough 252 Case Discussions in Obstetrics and Gynecology impulse may be present. During surgery it is – Halbans Technique—The closure of cul-de- diagnosed after extensive dissection of posterior sac is done by sewing posterior vaginal wall vaginal wall and identified by peritoneal sac and to the rectum back to front from its most preperitoneal fat. Unidentified enterocele is caudal to most cephalad position in parallel common cause of recurrence and efforts should be rows. taken to identify and repair it at the time of primary – Moschcowitz technique—The cul-de-sac surgery. is closed with sequential concentric purse • Repair during vaginal surgery- string sutures placed from caudal post cul- – Uterosacral ligament suspension—At the de-sac to the level of uterosacral ligaments time of vaginal hysterectomy, enterocele incorporating peritoneum over the should be dissected free, a high ligature of sacrum. the peritoneum done by a purse string suture incorporating uterosacral ligaments drawing Q.19. What are the common intraoperative the cul-de-sac and uterosacral ligaments complications of prolapse surgery and how can together and redundant peritoneum excised. they be prevented? The vaginal cuff is attached to cardinal Ans: The common intraoperative complications uterosacral ligament complex to avoid include hemorrhage and injury to bladder and descent of vaginal apex. rectum. – Mc call culdoplasty—It is a technique for • Hemorrhage can be reduced by identifying enterocele repair useful when uterosacral correct tissue planes and morbidity due to ligaments are strong. It consists of rows of hemorrhage can be reduced by raising internal and external sutures. The internal preoperative hemoglobin of the woman and suture is applied using nonabsorbable suture arranging adequate blood during surgery. material and passes through one uterosacral • The injury to bladder and rectum can be reduced ligament, then peritoneum of cul-de-sac as by correct technique. Bladder sound may be high as possible to obliterate enterocele sac used if there is difficulty in identifying bladder and then passing through other side margins. Intraoperative per rectal examination uterosacral ligament. The external suture will help to avoid rectal injury. uses delayed absorbable suture material and passes through vaginal wall on one side, Q.20. What is the postoperative care for your ipsilateral uterosacral ligament, peritoneum patient? of cul-de-sac and then uterosacral ligament Ans: Postoperative care of woman includes of other side, finally coming out through postoperative fluid management, adequate other side vaginal wall. These sutures are analgesia and monitoring for vital signs and tied in the end of surgery after all repairs bleeding. The prophylactic antibiotics should are completed. It can be used as prophylaxis include broad spectrum antibiotics covering as well treatment of enterocele at the time anaerobic organisms also. The most commonly of vaginal hysterectomy and also for vault used regimen is amoxicillin + clavulanic acid 1.2 prolapse. gm and metronidazole 500 mg perioperatively in • Repair during abdominal surgery—The prophylactic doses. The duration of postoperative enterocele can be repaired abdominally by catheterization should be minimum depending on Halbans technique or Moschcowitz operation. extent of bladder dissection and type of surgery Prolapse Uterus 253 performed. Woman should be ambulated after effect defects is recently introduced. These large mesh of anesthesia wears off. The perineal hygiene grafts can be used in any of the vaginal should be taken care of. compartments and are tunneled to the site where they are to be used via a transobturator, transgluteal, Q.21. Is hysterectomy necessary for treatment suprapubic, or combined approaches. Though early of prolapse? reports appear favorable, long-term reports are not Ans: No, but generally forms a part of prolapse yet available. surgery in older women who have completed Despite their increasing use, great controversy family, as retention of uterus with significant degree exists over their use of synthetic mesh grafts of prolapse compromises the long-term operative especially when packaged delivery-system kits results as cervix limits access to structures of produced by medical devise manufacturers and paracolpium that are necessary to achieve proper FDA has issued public notification regarding proximal suspension of vaginal vault. However, complications that can be associated with many women are now opting for uterine transvaginal placement of surgical mesh in repair conservation to maintain normal sexual function of pelvic organ prolapse and stress incontinence.10 after surgery. Continued research on graft use in pelvic reconstructive surgery is needed and patient need Q.22. What is role of meshes and grafts in to be informed about the unique risks associated prolapse surgery? with graft use. Ans: Although various grafts, bolsters and synthetic meshes can be valuable tools in prolapse surgery Q.23. What are common causes for failed they should be used cautiously and selectively. prolapse surgery? They are rarely required in primary surgery and Ans: The common reasons for failure or recurrence not always in repeat surgery. Even in advanced of prolapse surgery can be any of the following: prolapse, fascia (which does not atrophy like • Wrong choice of surgical procedure muscles) is present in most cases. It may be scarred • Poor surgical technique or retracted but can be identified by meticulous • Omission to recognise and treat enterocele dissection by proper technique. They should not • Shortening of anterior vaginal wall be used as substitute for extensive dissection and • Inherent weakness of supports meticulous technique. Although the use of grafts • Pregnancy and delivery following operation. has the potential to improve the quality of life, the overzealous use of grafts and meshes may produce Q.24. What is role of laparoscopic surgery in side effects due to exposure and erosion. Cost is a treatment of POP? limiting factor. Ans: The techniques used abdominally for pelvic The use of grafts and meshes for supporting organ prolapse can also be performed laparo- large defects in site specific repairs especially in scopically with advantage of minimally invasive repeat procedures for failed prolapse surgey is likely techniques. Most transabdominal procedures to become standard of care. The use of suspend vaginal apex but do not deal effectively commercially available kits for nonsite specific with distal half of vagina or perineum. With transvaginal mesh-graft repairs where very large laparoscopy, surgeons are repairing not only apical pieces of mesh are placed to provide support supports but all compartments of pelvic floor using without site specific approximation of anatomic synthetic mesh grafts. Laparoscopic sacral 254 Case Discussions in Obstetrics and Gynecology colpopexy is the most commonly performed procedure. Other procedures which are performed laparoscopically include sacral hysteropexy/ cervicopexy, uterosacral colpopexy/hysteropexy, anterior and posterior vaginal wall support procedures using mesh. The laparoscopic approach is associated with similar surgical outcomes in expert hand and have advantage of less blood loss, less postoperative hospitalization. The disadvantages include longer operating time, higher costs and deep learning curve. Robotic assisted laparoscopic surgery is devised to shorten learning curve associated with traditional laparoscopic surgery for prolapse. Current literature Fig. 20.3: POPQ staging of Mrs Y on this approach is limited and there is need for more data to substantiate the results. progression from early stages or prevent recurrence after surgery. They are useful only in milder degree Q.25. What is the role of conservative manage- of prolapse and need to be continued for prolonged ment in prolapse? time. Ans: Definitive management of prolapse is surgery. However, some women may not be willing for CASE 2 surgery and some may be very high risk for 27-year Mrs Y, Para 2 presents with third degree anesthesia though advances in anesthesiology is uterovaginal prolapse. How will you proceed? making it a rare situation. Insertion of pessary is one option for such History: The detailed history should be taken with women. Pessary is a palliative treatment providing special emphasis on poor nutrition, poor only symptomatic relief. The pessaries of many intrapartum care, early return to activity after shapes are available but ring pessary is the most delivery, any other factors suggestive of congenital commonly used. It is important to fit correct size weakness of tissues like hernia, prolapse rectum, of pessary as too small ring may be expelled and etc. as prolapse at such a young age is not very too large a ring may cause discomfort and difficulty common. Any urinary or bowel symptoms should in passing urine. The size of pessary is assessed by be asked to help in planning treatment. doing pervaginal examination and measuring the General examination should specifically look distance of subpubic angle from apex of posterior for spina bifida and other neurological problems fornix by an examining finger. Postmenopausal which may contribute to prolapse in young woman. women may require application of local estrogen Local examination should assess degree of cervical to prevent erosion by pessary. The pessary should descent, elongation of cervix and whether it is supra be changed every 3-6 months to allow inspection or infravaginal, sites of anterior and posterior of vaginal mucosa and reducing risk of infection. vaginal wall defects, tone of pelvic floor muscles. Pelvic floor exercises–Kegels exercises aim at POPQ staging of my patient is –Stage III Ba, increasing the tone of pelvic floor muscles. They lithotomy with straining are unlikely to reduce prolapse but may reduce The quantification is as follows (Fig. 20.3). Prolapse Uterus 255

Q.26. How will you treat your patient? after giving circular incision on cervix, vaginal flaps Ans: Taking into consideration young age and are dissected. After bladder dissection, the pouch parity of the woman the preservation of future of Douglas is opened, uterosacral ligaments are fertility is important. Unless the problem is severe, dissected, detached from its cervical attachment, the women should be advised to complete the brought anteriorly and crossed in front of cervix. childbearing so that definitive treatment can be Enterocele is then repaired by excising and closing offered. Ring pessary provides temporary relief, peritoneum and obliterating the space by permits intercourse and can be offered till she approximation of uterosacral ligaments. The completes childbearing after thorough counseling. anterior colporrhaphy and postcolpoperineorrhaphy The definitive treatment in this case is surgical. is then performed. The advantage of this operation Various operations which can be considered are- over Manchester is that amputation of cervix with Manchester operation: It is appropriate in young its effect on childbearing is avoided and opening woman with any degree of prolapse. Though uterus of cul-de-sac allows better repair of enterocele. It is conserved, there may be some effect on future may not be suitable for women with elongation of childbearing in form of increased incidence of cervix. infertility, midtrimester abortions, preterm delivery Sling operations: In young or nulliparous woman and cervical dystocia and this should be discussed with prolapse there is congenital weakness of with the woman. supporting tissues and these abdominal operations aim at supporting weak ligaments by various natural Q.27. What are the main components of or synthetic slings. The point of attachment of slings Manchester operation? and material used as sling varies with technique. The enterocele if present should be repaired by Ans: The main components of Manchester Moschowitz or Halban technique. They do not operation are: affect future fertility. They should be avoided when • Dilatation and curettage done first to rule out there is procidentia, infected hypertrophied cervix, any associated endometrial pathology. marked elongation of cervix. • Anterior colporrhaphy Vaious types of sling operations are as follows- • Amputation of cervix – Khannas operation: The sling is made of • Anterior plication of Mackenrodts ligament and mersilene tape and is attached posteriorly to other paracervical tissues in front of cervix cervix, passes retroperitoneally to be attached • Sturmdoffs suture to cover amputated cervix to anterior superior iliac spine. Vaginal delivery • Repair of enterocele and posterior colpoperi- is allowed. neorrhaphy if necessary. – Shirodkars sling operation: The sling is The intraoperative complications include prepared from fascia lata or mersilene tape. It bleeding and injury to surrounding structures. The is attached to cervix posteriorly at one end and postoperative complications include bleeding, follows the course of uterosacral ligaments infection on short term and recurrence of prolapse retroperitoneally to be attached to the on long-term. intervertebral disc between L5 and S1. It is difficult technically. The woman can have Q.28. What are the other operations which can vaginal delivery. be performed in this woman? – Purandares sling operation: The sling is Ans: Shirodkars modification of Manchester fashioned from two strips of anterior rectus operation: In this vaginally performed operation, sheath which remain attached at one end and 256 Case Discussions in Obstetrics and Gynecology

other end goes along course of round ligaments through internal inguinal ring to get attached to anterior lip of cervix. The woman can deliver vaginally but there can be a problem if she need LSCS and incision should be made above the level of attachment of strip. The disadvantage is that it relies on intrinsic strength of rectus sheath which may not be good in woman developing prolapse at young age. Sacrospinous fixation with uterine preservation: A unilateral sacrspinous fixation with uterus in place may be beneficial and does not prohibit subsequent childbirth. Sacral hysteropexy: It can be performed by open Fig. 20.4: POPQ staging of Mrs Z laparotomy or laparoscopy and uses mesh, which Q.29. How will you investigate and manage her? is attached to sacrum at one end and posterior or Ans: Since this woman has developed incisional both anteroposterior suface of uterine isthmus on hernia along with vault prolapse the connective other. Burch operation may be performed tissue disorders should be ruled out in addition to concomitantly. routine work up for prolapse. Treatment: This woman needs treatment for CASE 3 incisional hernia as well as vault prolapse both of 35-year Mrs Z, Para 3 comes with abdominal which is surgical and can be combined in single swelling during coughing and mass descending sitting by coordinating with surgeons. per vaginum since 2 years. She has undergone The first choice of surgery in this woman would abdominal hysterectomy for fibroid uterus 3 years be. back and has developed above symptoms one year Abdominal sacrocolpopexy with hernia repair: after previous surgery. How will you proceed? Taking into account need for incisional hernia repair, young age of woman and possibility of History: The details of previous surgery like inherent weakness, abdominal sacrocolpopexy with indication, technique especially method of vault hernia repair will be choice of surgery in this suspension should be found out. Any pathology like woman. chronic cough, constipation that may predispose Technique: After opening the abdomen, the two to recurrence should be ruled out. Any associated limbs of a Y-shaped mesh are attached to anterior urinary symptoms if present should be asked for. and posterior vaginal walls after dissection of Examination: General examination should note bladder and rectum. The peritoneum is dissected general health of woman, any evidence of in front of sacrum and the other end of the mesh is connective tissue disorder like hyperelasticity of attached to the anterior longitudinal ligament of first joint, etc. This woman has midline subumbilical sacral vertebra. The mesh is peritonealized to avoid incision with incisional hernia and vault prolapse. bowel entrapment. A culdoplasty by Halbans or On local examination - Moschowitz technique is done as essential part of POPQ stage was Stage IV C, lithotomy with operation. Repair of incisional hernia is done using straining, with quantification as follows (Fig. 20.4). appropriate technique. Prolapse Uterus 257

Intraoperative complications: are unusual and nerves can occur. It is durable and strong include injury to bowel, bladder, ureter, nerves and surgical correction of vaginal vault prolapse. It hemorrhage. Hemorrhage from presacral vessels is safer and require less operative time. may be life threatening and should be controlled • High uterosacral ligament suspension–It was with pressure, sutures, clips, bone wax and sterile introduced by Richardson and based on main thumbtracks as last resort. Postoperative concept that endopelvic fascia surrounding complications like infections can occur as with all vagina does not attenuate but breaks at specific abdominal operations. Commonest long-term points. This procedure identifies fascial defects, complication is erosion of mesh which may need reduces enterocele sac, closes defects and removal by abdominal or vaginal route. resuspends vagina at original level I support of The advantage of this operation is that it uterosacral ligaments. Though primarily used provides surest and strongest correction for vaginally, it can also be performed abdominally prolapse in young women with more strenuous or laparoscopically. The main risk during this activity. It provides good vaginal length. The procedure is of ureteric injury and cystoscopy disadvantage is longer operative time and longer should be performed after the vaginal recovery time. procedure. The success rate of abdominal sacral colpopexy • Laparoscopic colposuspension–The techniques is higher than sacrospinous fixation The reoperation used abdominally can also be performed rates were 33% in vaginal group and 16% in laparoscopically with advantage of minimally abdominal group.11 invasive techniques and have similar results in expert hands. Q.30. What are the other surgical options for • Obliterative procedures–In very old women treatment of vault prolapse? who are poor risk for surgery and no longer Ans: The other surgeries that can be performed for sexually active, obliterative procedures like treatment of vault prolapse are partial colpocleisis is an option but is rarely used Vaginal: Generally vaginal route is preferred for with increasing safety of anesthesia techniques. primary repair as it has advantage of less operating In this operation vaginal mucosa on anterior and time, less morbidity and permits better visualization posterior wall are removed and cut edges of and repair of anterior and posterior vaginal wall denuded vaginal walls are stitched together with defects. interrupted delayed absorbable sutures after • Sacrospinous vaginal fixation–After extensive turning inward uterus and cervix. Since there dissection and site specific repair of anterior is no support aggressive perineorrhaphy is done. and postvaginal wall defects the vaginal apex Complete breakdown and recurrence can occur. is attached to sacrospinous ligament on one or Postoperative stress incontinence is reported in both sides. The sacrospinous ligament is about 30% cases. Early postoperative identified by its attachment to ischial spine and complication are hematoma and infection. In exposed by dissecting pararectal pillars. The cases of vault prolapse, colpectomy with nonabsorbable suture material is used and the colpocleisis can be done. vault is attached to ligament about 2 cm away from ischial spine to avoid injury to pudendal REFERENCES vessels and nerve. In unilateral fixation, the 1. Oslen A, Smith V, Bergstrom J et al. ‘Epidemiology of vagina is pulled to one side but rarely cause surgically managed pelvic organ prolapse and urinary dyspareunia. Injury to pudendal vessels and incontinence’. Obstet Gynecol 1997;89(4): 501-6. 258 Case Discussions in Obstetrics and Gynecology

2. Kumar P, Malhotra N (Eds). ‘Pelvic Organ Prolapse’ 7. Barber M, Cundiff G, Weidner A, et al. Accuracy of from Jeffcoates Principles of Gynecology, 7th edition, clinical assessment of paravaginal defects in women New Delhi, Jaypee Medical Publishers. p275-92. with anterior vaginal wall prolapse’. Am J Obstet 3. Zimmerman C. ‘Pelvic Organ Prolapse: Basic Gynecol 1999;181 91 0:87-90. Principles’ In Te Linde Operative Gynecology, Rock 8. Burrows L, Sewell C, Leffler K, et al. ‘The accuracy JA, Jones HW Eds 10th edition, New Delhi, Lippincott of clinical evaluation of posterior vaginal wall defects.’ and Williams and Wilkins, 2008;854-73. Int Urogynecol J Pelvic Floor Dysfunct 2003;14: 4. Laycock J, Whelan M, Dumoulin C. ‘Patient 160-3. 9. Whiteside J, Barber M, Paraiso M, et al. Clinical Assessment’ Chapter 7 in Haslam J, Laycock J Editor. evaluation of anterior vaginal wall defects; Therapeutic management of incontinence and pelvic interexaminer and intraexaminer reliability.’ Am J Pain, 2nd edition London;Springer-Verlag; 2008;62. Obstet Gynecol 2004;191:100-4. 5. Bump R, Mattiason A, Bo K, et al. ‘The 10. Murphy M. ‘Use of mesh and materials in pelvic floor standardization of terminology of female pelvic organ surgery’ Obstet Gynecol Clin N Am 2009;36,615-35. prolapse and pelvic floor dysfunction.’ Am J Obstet 11. Benson JT, Lucente V, Mc Clellan G, vaginal vs Gynecol 1996;175:10-7. abdominal reconstructive surgery for treatment of 6. DeLancey JO. ‘Anatomic aspects of vaginal eversion pelvic support defects;a prospective randomized study after hysterectomy.’ Am J Obstet Gynecol with long term evaluation . Am J Obstet Gynecol 1996; 1992;166:1717. 175:1418. Latika Sahu

21

Every minute, a woman dies in pregnancy or B. Duration of labor—Prolonged labor especially childbirth, and for every woman who dies, 20-30 in 2nd stage can lead to VVF and urine leak others will survive but with morbidity, one of which per vaginum. is .1 Vesicovaginal fistula is seen in women Vesicovaginal fistula (VVF) is a subtype of following obstructed labor. So, history female (UGF). VVF is an suggestive of obstructed labor to be extracted abnormal fistulous tract extending between the from the patient. bladder and the vagina that allows the continuous C. Any other complication intrapartum and involuntary discharge of urine into the vaginal vault. postpartum—postpartum hemorrhage and sepsis are associated with poor tissue healing CASE 1 and make the patient prone for developing VVF. Mrs X, 19-year-old woman delivered her 1st dead D. Voiding urine per urethra apart from the born child 1 month back at home conducted by leakage—Depends on the site and size of an untrained dai, come to the Gynecology OPD fistula. Patients with small may void with complains of urine leak per vaginum since normal amounts of urine and notice only slight 8th postpartum day. position-dependent drainage. Alternatively, they may have leakage only at maximal bladder Q.1. What is important to elicit in history? capacity. Those with larger fistulas may not void A. Age and socioeconomic status of the woman– transurethrally and may have total incontinence. In poor young woman there is increased E. Amount of leakage—The size and site of fistula incidence of cephalopelvic disproportion and determines the amount of leakage. VVF due to: F. Other common comorbitities associated with • Pelvic bone immaturity. obstetric fistula-like • Reduced birth canal size before age 18. Gynecologic—Amenorrhea, PID. • Reduced inlet, midplane, outlet dimensions. Musculoskeletal—Lower limb contracture 2o • Late onset of puberty. to nerve damage. • Malnutrition. Neurological—Footdrop from sacral and • Net “Low” gynecological age. (Chronological perineal nerve compression, Neurogenic bladder age – age at menarche). dysfunction • Younger age at marriage and teen age Dermatologic—Ammmonical dermatitis,Vulvar pregnancy.2 excoriation. 260 Case Discussions in Obstetrics and Gynecology

Examination If this test fails to locate the fistula, do tampon General examination test of Moir (described later) Height Per vaginal examination: Digital examination will Weight give better idea of fistula than speculum BMI examination. Assessment of tissue mobility; Pallor accessibility of the fistula to vaginal repair; Features of malnutrition determination of the degree of tissue inflammation, Per abdomen examination edema, and infection, scarring; can be better Any organomegaly assessed by digital examination. Palpable mass On Examination of Mrs X: Short statured, Surgical scar malnourished, anemic, anxious looking. Per speculum examination: Any pooling of fluid Per abdomen: Nothing significant. in the vagina that is noted should be sent for Per Speculum examination: Vaginal rugosities analysis if the diagnosis is unclear. Next, perform present , urine seen leaking from anterior vaginal a careful speculum exam that allows visualization wall. Single fistulous opening of 2 cm size over of the entire anterior vaginal wall to identify the middle portion of anterior vaginal wall .Tissue fistula tract. In many cases, the fistula is grossly around opening shows puckering. visible. Per vaginal examination Determine the location of the fistula in relation Uterus well involuted, bilateral fornices free, the fistula to the vaginal apex and bladder trigone and assess margin feels indurated, inflamed, a ~2 × 2 cm the quality of surrounding tissue (e.g. presence of opening felt over midanterior vaginal wall, no inflammation, edema, or infection), tissue mobility; induration/fixity to underlying bone, no mass/ accessibility of the fistula to vaginal repair; and tenderness around the opening. association of a . Fistulas near Per rectal examination – the vaginal apex may require a more complicated Nothing significant. abdominal approach, and those close to the trigone Since the fistula is seen clearly diagnosis of may be associated with increased risk of ureteral VVF is made. injury during repair. If the fistula is particularly small, no tract may Q.2. How will you manage this patient? be apparent. In such cases, bimanual exam with Ans: The principles of management of obstetric careful palpation of the anterior wall may help VVF in this case are: locate the fistula (e.g. when there is a surrounding A. Catheterization—Foley’s for 6 -12 weeks. zone of induration). Advantages—Viable treatment during first 90 If no fistula is noted despite highly suspicious days +/-. signs and symptoms and careful examination, a Avoid urine flowing through fistula. simple office test can be performed. Using a Promotes spontaneous closure of fistula. catheter, fill the bladder with a dyed solution such B. Surgery—After 12 weeks. as normal saline with indigo carmine and repeat C. Rehabilitation—Stretching and mobilizing the pelvic exam with a half-speculum to visualize limbs. the anterior wall. Ask the patient to cough and bear Physiotherapy of lower limbs, foot. down, and identify the fistula by visualizing urine Psychological and emotional counseling. leakage. Employment skill building. Vesicovaginal Fistula 261

Q. 3. What is the preferable method of surgical continuous postoperative bladder drainage were repair in this patient? factors considered crucial to success. Success rates Ans: Flap-splitting technique is the preferable ranged from 90-100%. method for repair of this patient with an obstetric VVF. Q.4. What is the ideal time for repair of obstetric Important points to remember in this repair VVF? • In case of fibrosis, the edges have to be Ans: The obstetric VVF requires 3 months time freshened for recovery of local tissue before surgical • Her fistula is in her midvagina, it is usually intervention. The traumatic fistula should be easier to suture the first layer transversely. repaired immediately and repair can be attempted • Avoid diathermy if bleeding, especially near the if recognized within 48 hours. walls of her vagina and bladder, because it destroys tissue, and reduces the blood supply. Q.5. What is the size of VVF can be best repaired • If it is low (juxtaurethral) near vesicourethral with flap-splitting technique? junction, suture it longitudinally • Check the patency of the repair done by Ans: Most small (<4 cm) VVFs can be repaired instilling colored fluid into bladder. If it leaks, with a flap-splitting technique. large (>4 cm) VVFs insert more sutures, or take them out and start are complicated by increased rates of vaginal again. stenosis and atresia when repaired in this manner. • For the first two layers use ‘0’ delayed absorbable Full-thickness Martius grafts to preserve vaginal sutures. depth may be considered as an adjunct to • Close the intermediate layer (if you have been transvaginal flap-splitting surgery for the repair of able to define it) with interrupted sutures, and large vaginal fistulas. eliminate all dead space. • Close the vaginal wall with interrupted sutures. Q.6. What postoperative care you will give to • If possible, place the line of sutures transversely. the patient after obstetric VVF repair? Otherwise place it whichever way the edges lie Ans: Catheters left in place. Urinary 2 weeks. easiest. • Clamped for short periods to accustom the • Try to arrange the sutures on the three layers so bladder to distention. that they don’t immediately overlie one another. • Confined to bed rest for 2 weeks. Check again that the repair does not leak. Good nursing care to avoid bedsores Numerous surgeons have found this procedure • Abstain from intercourse for >3 months. as efficacious as the Latzko technique. It has better • Contraceptive counseling. applicability for large VVFs while not foreshortening • Advise future deliveries to be cesarean.3 the vaginal vault. An asymmetric J incision in the anterior vaginal Q.7. What is the surgical management of wall can be given whereby the lower curve of the J urinary incontinence after obstetric fistula loops around the fistula site. This modification enables the surgeon to advance one flap over the repair? fistula repair and prevent overlapping suture lines. Ans: Urinary incontinence after obstetric fistula Martius grafts require in cases where fistula repair: closure is tenuous. Tension-free closure of viable • >25% of women still incontinent after fistula tissue, avoidance of overlapping suture lines, and repair. 262 Case Discussions in Obstetrics and Gynecology

• Most common in women who had a bladder Ensure a high fluid intake so as to reduce the neck/juxtaurethral fistula, urethral-vaginal risk of infection. fistula. Mobilize her early, always keeping the bag • Second operation can be done to repair using a below her bladder. combination of urethralization (urethral After 7–10 days put her into the Sims’ position lengthening), plus fibromuscular sling of rectus and examine her anterior vaginal wall with a Sims’ fascia.3 speculum. • Postfistula stress incontinence has been If her bladder is still bruised or necrotic, controlled by modified needle suspension leave the catheter in and only remove it when later procedure. examinations show it is healthy. If you use a latex catheter, change it every 7 days. Q.8. What are the medical consequences of If she develops a VVF, continue catheter fistula? drainage for 3 weeks, unless the fistula is so big Ans: Left untreated, fistula can lead to frequent that the balloon falls into her vagina. If it is very ulcerations and infections, kidney disease and even small, drain her bladder for 6 weeks. If you can death. Some women drink as little as possible to keep her bladder empty, it may close spontaneously. avoid leakage and become dehydrated. If a large area of sloughing tissue causes a persistent foul discharge, debride the dead tissue Q.9. How does fistula occur in a case of under general anesthesia. obstructed labor? If her pubic bone is exposed, it will be infected Ans: By reduced blood supply due to tissue (osteitis), so give her a broad spectrum antibiotic necrosis caused by prolonged labor during and rectal metronidazole 1 g twice daily. Touch her childbirth. with weak clorhexidine. Unattended obstructed labor can last for up to As soon as her VVF develops and her vulva is six or seven days, although the fetus usually dies exposed to urine, wash her vulva and perianal area after two or three days. During the prolonged labor, twice daily with soap and water. Twice daily zinc the soft tissues of the pelvis are compressed and castor oil ointment will keep her vulva healthy between the descending baby’s head and the and reduce smell. mother’s pelvic bone. The lack of blood flow causes Q.11. What is the epidemiology of obstetric tissue necrosis and create a vesicovaginal fistula. VVF? Q.10. What is the ideal way of managing a case Ans: There are certain countries in South Asia, of obstructed labor to prevent VVF? specifically Bangladesh, and in sub-Saharan Africa, such as the Sudan, Ethiopia, Chad, Ghana, and Ans: In a case of obstructed labor a FISTULA is Nigeria, where fistula prevalence is reported to be going to form: high.4 In 2002, the UNFPA conducted a 6-month 1. When labor is long enough to kill the baby. needs assessment in 9 African countries, and 2. After craniotomy. estimated that there could be up to 1 million women 3. When there is gross intrauterine infection . living with fistulas in Nigeria alone, and that If you suspect a fistula is goint to form: incidence rates could be as high as 2 to 3 per 1000 Insert an indwelling silastic catheter and start women in countries with high maternal mortality continuous closed drainage. rates.4 Vesicovaginal Fistula 263

In developing countries, mostly in African A fistula may also arise from avascular necrosis countries:5 secondary to crush injury or erosion of a vaginal • Estimates of 2-7 million women affected. cuff suture into the bladder.7 • Estimates of >75,000 new cases each year. A fistula may also follow an uncomplicated • Estimates of 3-5 cases per 1000 pregnancies. operation as the result of a pelvic hematoma that • Limited indigenous surgical repair capability. ruptures into the bladder postoperatively. • Cultural and religious worldviews serve to Devascularizing the bladder or vaginal cuff perpetuate the status quo: could lead to fistula formation and can be – “whatever will be, will be” minimized with mobilization of tissue planes. – “the will of God (Allah)” Placement of transobturator midurethral • Women currently have neither the education, slings are touted as being less likely to cause bladder resources, nor rights to change the underlying injury. However, recent reports have documented causes of fistula. VVF following trauma to the bladder with trocar placement and with the presence of a foreign body Q.12. What are the etiologies of VVF? in the bladder; the latter may be caused by directly Ans: Frequencies and the causes of VVF reflect placing the tape through the bladder or erosion of 8 the culture and geography. Kelly showed that in the material into the bladder wall. England, 95% of the VVFs occurred with non- obstetric causes.6 Predisposing Factors for Bladder Injury Direct causes: • Coexisting pelvic pathology, • Obstetric: In Nigeria, 98% of the VVFs were • Distortion of normal anatomy, secondary to obstructed labor.6 Obstructed labor • Previous pelvic surgery, adhesions can occur in an android pelvis, malnutrition, Radical pelvic surgery for extensive disease. orthopedic disorders including rickets, and Indeed, the incidence of bladder injury during hydrocephalus contribute to dystocia. Fistulas radical hysterectomy is three times higher than with may be caused by forceps, destructive simple hysterectomy. instruments used to deliver stillborn infants, or surgical abortion. Other Risk Factors • Surgery: The most common cause of fistula in • History of pelvic irradiation developed countries is trauma associated with • Cesarean section pelvic operation, and the operation most often • Endometriosis involved is total abdominal hysterectomy and • Prior pelvic inflammatory disease the most common indication is benign • Diabetes mellitus leiomyoma. The overall incidence of urinary • Concurrent infection tract injuries during pelvic surgery is estimated • Vasculopathies to be 0.33%. Cystotomy and VVF account for • Tobacco abuse. more than three-fourths of the injuries. The • Malignant disease of the pelvic organs is the etiology of VVF at the time of hysterectomy is 2nd most common cause in developed the result of an unrecognized bladder laceration countries. Carcinoma cervix is the common at the time of dissecting the bladder off the malignancy associated with VVF. cervix. Even cystotomies that are repaired have • Radiation-induced fistulas are commonly a risk of fistula formation.7 associated with treatment for carcinoma of the 264 Case Discussions in Obstetrics and Gynecology

cervix or other pelvic malignancies. Fistulas • Culture/tradition—early marriage and conception, may appear during the course of radiotherapy female circumcision, health seeking practice (usually from necrosis of the tumor itself) or • Limited access to medical services. after treatment is completed. Late fistulas arise secondary to endarteritis obliterans within the Q.13. When do women typically present after first 2 years. It is essential to rule out recurrent various antecedent events? malignancy with biopsies. Ans: Women typically present within specific • Trauma (Road traffic accidents, Sharp object intervals after the various antecedent events (pelvic injury), surgery, childbirth, radiation therapy) with a • Infections such as tuberculosis, schisto- primary complaint of constant, painless urinary somiasis, syphilis, and lymphogranuloma incontinence. venereum, HIV. • If the fistula is related to traumatic childbirth, • Congenital VVF is usually associated with most patients experience urine leakage within other genitourinary anomalies. the first 24 to 48 hours. • Foreign body- There are case reports of VVFs • Following pelvic surgery, symptoms usually caused by vaginal foreign bodies, direct trauma occur within the first 30 days. from masturbation or automobile accidents, • In contrast, radiation-induced fistulae develop bladder calculi, forgotten vaginal pessaries. over a much longer interval secondary to • Female Genital Mutilation Vesicovaginal progressive devascularization necrosis, and may fistula occurs when there is introital stenosis present 30 days to 30 years after the antecedent secondary to female circumcision, Symphy- event. siotomy, the use of postpartum vaginal caustic agents, and self-inflicted “Gishiri cuts” also Q.14. What are the preventive measures for have a role. obstetrics fistula? • Sexual trauma through coerced vaginal penetration and even consensual sexual Ans: intercourse have been reported to have led to Primordial prevention—Girls’ education. VVF. • Women’s empowerment. • Urethrovaginal fistulas may occur postpartum • Increase the marriage age. and are associated with operative vaginal • Nutritious diet since childhood. delivery, after surgery for urethral diverticulum, Primary prevention anterior vaginal wall prolapse, or urinary Making family planning available to all who want incontinence, and after radiation therapy. to use it. It would reduce maternal disability and Pressure necrosis resulting in an urethrovaginal death by at least 20 percent. fistula can occur with a prolonged indwelling Follow strategy to make motherhood safer. transurethral catheter. Urethrovaginal fistulas Skilled attendants at all births and emergency may also be congenital. obstetric care for those women who develop • In rare instances, spontaneous vesicouterine complications during delivery would make fistula fistulae were reported following uncomplicated rare. vaginal birth after cesarean section. Secondary prevention Indirect causes—Low status of women in society • Early recognition of cephalopelvic dispro- • Poverty and gender discrimination—mal- portion and prevention of obstructed labor. nutrition, contracted pelvis, • LSCS in indicated cases. Vesicovaginal Fistula 265

• Avoidance of difficult forceps and destructive A. Intraoperative findings operations. An unrecognized injury to the bladder resulting in • Catheter drainage for 14 days in prolonged or urinary extravasation. obstructed labor. Theoretically, with early recognition, it may be possible to avert the formation of a VVF. Q.15. What are the various ongoing projects B. Postoperative period available worldwide for prevention of obstetric Excessive postoperative abdominal pain, distention fistula? What is the Campaign to End Fistula? or paralytic ileus, or both. Hematuria and symptoms of irritability of the Ans: Two projects available worldwide. bladder, and prolonged postoperative fever and • Women’s dignity project (WDP) work on increased white blood cell count are common obstetric fistula in eastern Africa has two main findings in a posthysterectomy fistula. The patient themes: may experience recurrent cystitis or pyelonephritis – Poverty, which precludes access to care, and with costovertebral angle tenderness; Flank, – Power of society to reject, banish and isolate vaginal, or suprapubic pain; Abnormal urinary In 2003, UNFPA9 and its partners launched the stream. first-ever global campaign to end fistula. This The most common presenting feature of VVF includes interventions to: is continuous leakage of urine from the vagina. • Prevent fistula from occurring. Urinary leakage may make the patient a social • Treat women who are affected. recluse, disrupt sexual relations, and lead to • Renew the hopes and dreams of those who depression, low self-esteem, and insomnia. The leakage of urine may cause irritation of the suffer from the condition. This includes vulva and vagina mucosa, perineum and usually bringing it to the attention of policy-makers and produces a foul ammoniacal odour. Phosphate communities, thereby reducing the stigma encrustations may be noted in more neglected cases. associated with it, and helping women who have These crystals serve to further irritate what can be undergone treatment return to full and productive already compromised tissue. lives. C. Voiding urine perurethal apart from the leakage The Campaign currently covers more than 40 and the amount of leakage. countries in sub-Saharan Africa, Asia and the Arab D. Some patients report exacerbation during region. physical activities, which can sometimes lead to erroneous diagnosis of uncomplicated stress CASE 2 incontinence. If the fistula is small, intermittent Mrs Y, 48-year-old multiparous woman presented leakage with increased bladder distention or physical activity may be noted. to you with H/o one previous cesarean section, E. Other patients may complain of vaginal H/o undergoing total abdominal hysterectomy for discharge or hematuria (vesicouterine fistula). cervical fibroid uterus, 15 days back in a private F. If there is concurrent ureteric involvement, the hospital, H/o urine leak for 3 days. patient may experience constitutional symptoms (such as fever, chills, and flank pain) or even Q.16. What is important to elicit in history? gastrointestinal symptoms. Ans: Enquire from the patient operative details as Obstetric history: Parity, mode of deliveries, last per her records and postoperative period. delivery, sterilized or not. 266 Case Discussions in Obstetrics and Gynecology

Menstrual history: Regular cycles or not. H/o Per speculum examination dysmenorrhea. Showed sodden vulva and a single fistula of 4-5 mm Past history: H/o Surgeries (other than cesarean) size in the anterior vaginal wall near the apex. in past, history suggestive of endometriosis, history Tissue around opening showed puckering. suggestive of PID, H/o radiotherapy in past, H/o As her fistula size is small she should be any malignancies, H/o any medical disorders. investigated further to confirm diagnosis of VVF. Mrs X had intraoperative history of cervical fibroid enucleated to facilitate hysterectomy. Q.17. How will you diagnose bladder or ureteral Bladder was pulled up due to adhesions of previous injury during surgery? cesarean section. Continuous bladder catheteri- Ans: Intraoperative assessment for bladder or zation for 2 days, discharged after 8 days. She noted ureteral injury may be performed by: urine leakage from vagina after 12 days of surgery. • Administering indigo carmine intravenously C/o persistent urine leaking from vagina, using pads and closely observing for any subsequent daily and not able to pass urine normally, no H/o extravasation of dye into the pelvis. Fever, chills and rigor but C/o itching and soreness • Cystourethroscopy to assure bilateral ureteral over vulva. patency and absence of suture placement in the Per Abdomen examination bladder or urethra. Inspection—condition of scar of hysterectomy, any • Alternatively, intraoperative back-filling of the other scars/dilated veins bladder with methylene blue or sterile milk Palpation—Organomegaly, before completing abdominal or vaginal surgery Renal angles free or not mass over the scar, Free also may help detect a bladder laceration. fluid. • Retrograde filling of the bladder also can be Local examination –The aim of local examination used during surgery to better define the bladder is to know regarding VVF: base in more difficult dissections. • The precise anatomical situation. • The number and size of the fistula. Q.18. What are the guidelines to follow intra- • Tissue condition, tissue loss, scarring and operatively during pelvic surgery to minimize infection. VVF formation? • Vaginal accessibility. Ans: A summary of these guidelines follows.10 • Mobility or fixity to bone. • Adequate exposure of the operative field. • Local ulceration/excoriation over vulva, • Minimize bleeding and hematoma formation. perineum needing prior treatment. The closure of dead space at the anterior vaginal Per speculum –look for urine leaking through wall upon completion of an anterior vagina. Patient smelling of urine, size and site of colporrhaphy will prevent hematoma formation. fistula, condition of tissue around fistula. This technique employs intermittently Per vaginal examination— feel induration/fixity incorporating pubocervicovaginal fascia with to underlying bone—Any mass/tenderness around the vaginal mucosal layer as the vaginal wall is the opening. sutured. Per rectal examination—Any associated recto- • Widely mobilize the bladder from the vagina vaginal fistula. during hysterectomy to diminish the risk of On examination of Mrs Y—nothing significant in suture placement into the bladder wall. A general examination. minimum of a 1 to 2 cm margin of dissection of Vesicovaginal Fistula 267

the bladder from the vaginal cuff should be considered in repair of a cystotomy involving developed prior to cuff closure. or encroaching on ureteric orifices. • Dissect the pubocervicovaginal endopelvic • Consider performing cystourethroscopy when fascia between the vagina and the bladder in performing pelvic surgery. Cystourethroscopy the appropriate plane. Dissection may be easier to assure bilateral ureteral patency and the with a sharp technique compared to a blunt absence of suture placement in the bladder or technique; the key is to prevent trauma and the urethra has been advocated by some authors separation of bladder wall fibers as the bladder as a standard for all pelvic surgery. is mobilized off the anterior vaginal wall. • If scarring is present at the pubocervicovaginal Q.19. What is the ideal position for examination fascia and dissection is difficult, consider (EUA) and also for VVF repair? performing an intentional anterior extra- Ans: peritoneal cystotomy. This technique enables Lawson position: This position is ideal for proximal the surgeon to assess the anatomic boundaries urethral and bladder neck fistulas. The patient is of the bladder wall with digital palpation. placed in a prone position with the knees spread • If scarring is present at the pubocervicovaginal and ankles raised in the air and supported by fascia and dissection is difficult, consider stirrups. Combining it with reverse Trendelenburg employing an intrafascial technique of positioning enhances visualization with this hysterectomy to best dissect the endopelvic technique. fascial plane. Jack knife position: This is ideal for proximal • Intraoperative retrograde filling and emptying urethral and bladder neck fistulas. The patient is of the bladder or mild traction on a temporarily placed in a prone position with the hips abducted placed small Foley catheter inserted into the and flexed and the table jackknifed. fistula itself are helpful to optimally identify Dorsal lithotomy position: Dorsal lithotomy anatomical planes and reveal intraoperative position with standard Trendelenburg positioning bladder lacerations. provides excellent access for repair of a high VVF. • Consider supracervical abdominal hysterectomy Knee chest position: To visualize retropubic fistulas. instead of total abdominal hysterectomy (TAH) Sim’s position : The patient on the left side and chest, in difficult cases. The incidence of UGF the right knee and thigh drawn up, the left arm along (urogenital fistula) formation is lower for the back. supracervical versus total hysterectomy. • If an intraoperative bladder injury does occur, Q.20. Classify VVF. widely mobilize the bladder from the underlying Ans: Classification according to site- structures (fascia and vagina, cervix, or uterus). A. High fistula In doing so, the surgeon can effect a VVF a. Juxtacervical closure under no tension. b. Vault (indirect, vesicouterine) • For repairing a cystotomy at the trigonal area, a B. mid vaginal fistula transverse closure is preferable over a vertical C. Low fistula- one. Vertical closure would be more likely to a. juxtacervical. produce ureteral obstruction because the b. bladder neck–urethra intact, ureteral orifices would be drawn inward toward • urethral involvement-segmental (partial each other. Ureteral catheters should be bladder neck loss) 268 Case Discussions in Obstetrics and Gynecology

• Circumferential vesicourethral fistula Contd... (complete bladder neck loss). Classification Description D. –a small fistula below the • Vaginal length is shortened bladder neck is also incompetent. • Fistula is greater than 3 cm in size E. Massive vaginal fistula encompasses all three • Fistula is distant from cuff or has levels and often includes one or both ureters in trigonal involvement addition. • Associated with scarring. Posthysterectomy fistulas are usually supra- • Involving the urethra, vesical neck or trigonal, medial to both ureteral orifices, and lie ureter. within the vaginal vault at the vaginal cuff. • Associated with intestinal fistulas. Fistulas from obstetric causes may be located • Previous unsuccessful attempts at repair. more distally, typically are larger, and are more commonly associated with a urethral injury. Q.21. How will you differentiate VVF from Classification according to size: ? What are the tests • Small <2 cm performed to differentiate? • Medium 2-3 cm, Ans: To differentiate variety of fistula—single or • Large 4-5 cm, multiple vesicovaginal, urethrovaginal, or • Extensive >6 cm ureterovaginal fistulas and fistula formation Obstetric vesicovaginal fistulae usually are between the urinary tract and the cervix, uterus, categorized according to their cause, complexity, and vagina or vaginal cuff. The following tests can be site of obstruction. In contrast, gynecologic fistulae done: are generally classified as simple or complicated. • Tampon test of Moir/Three swab test- These levels may have important implications Bladder is filled with sterile milk/methylene for the surgical approach and prognosis. For blue (100-250 ml) in retrograde fashion using example, simple vesicovaginal fistulae are usually a small transurethral catheter. uncomplicated surgical cases with good prognosis. • Placement of three swabs/tampons in tandem Complicated vesicovaginal fistulae, on the other in the vaginal vault and observation for staining hand, can challenge even highly practiced and of the tampons by methylene blue may help to skilled gynecologic surgeons and are associated identify and locate fistulas. with a high rate of recurrence. • The patient is asked to do exertional maneuvers, including stair climbing, jumping in place, walk, Table 21.1: Classification of vesicovaginal fistulae cough, do deep knee bends for twenty minutes. Classification Description After that tampons are removed and examined. Simple • Fistula is less than 2 to 3 cm in size • Staining of the apical tampon would implicate and near the cuff (supratrigonal) the vaginal apex or cervix/uterus; staining of a • Patient has no history of radiation or distal tampon raises suspicion of a urethral malignancy fistula. • Vaginal length is normal • If the tampons are wet but not stained, oral Complicated • Patient has had previous radiation phenazopyridine (Pyridium) or intravenous therapy • Pelvic malignancy is present indigo carmine then can be used to rule out a ureterovaginal, ureterouterine, or uretero- Contd... cervical fistula. Vesicovaginal Fistula 269

• Evidence of staining or wetting of a tampon • Renal ultrasound shows calyceal dilatation and should then prompt the physician to proceed ureteric duplication. with additional diagnostic testing prior to • Transvaginal ultrasound—can help in diagnosis proceeding with definitive management. of urethral fistula associated with diverticulum. • Indigo carmine dye can be given intravenously • MRI and CT scan can display renal anatomy and if the dye appears in the vagina, a fistula is and in the pelvis may delineate extravasation confirmed. and associated abscess formation. Double-dye test: Give the patient oral phenazo- • Cystography pyridine (Pyridium), fill the bladder with the blue- • hysterography can demonstrate vesicouterine tinted solution, and insert a tampon. The presence fistula. of blue staining suggests vesicovaginal or urethrovaginal fistula, while red staining (Pyridium) Q.23. What are the diagnostic procedures for suggests ureterovaginal fistula. VVF? Ans: Diagnostic procedures are: Q.22. What are the relevant investigations you • Cystoscopic examination with a small scope like to do for this patient? (e.g. 19F) may be used to identify VVF in the Ans: Laboratory Studies bladder or urethra, to determine the number and • vaginal vault fluid collection—tested for urea, location and proximity to ureteric orifices, and creatinine, or potassium concentration to to identify and remove abnormal entities such determine the likelihood of a diagnosis of VVF as calculi or sutures in the bladder. as opposed to a possible diagnosis of . • Water cystoscopy may be inadequate in the face • Once the diagnosis of urine discharge is made, of large or multiple fistulas. identify its source. • A cystoscopic examination using carbon • Cystourethroscopy may be performed, and the dioxide gas may be used with the patient in the fistula(s) may be identified. genupectoral position. With the vagina filled • Urine C/S- if positive results should be treated with water or isotonic sodium chloride solution, prior to surgery. the infusion of gas through the urethra with a • Biopsy of the fistula tract/urine microscopy if cystoscope produces air bubbles in the vaginal suspicious of malignancy. fluid at the site(s) of a UGF (flat tire sign). Imaging Studies- Radiologic studies are • Combined vaginoscopy—cystoscopy: Andreoni recommended prior to surgical repair of a et al describe their technique of simultaneously vesicovaginal fistula to fully assess the defect and viewing 2 images on the monitor screen (both exclude the presence of multiple fistulae. cystoscopic and vaginal examinations).11 They • IVU/IVP - Necessary to exclude ureteral injury used a laparoscope and clear speculum in the or fistula because 10% of VVFs have associated vagina and a regular cystoscope in the bladder ureteral fistulas. If suspicion is high for a to enhance visualization and identification of ureteral injury or fistula and the IVU findings VVFs. Transillumination of the bladder or are negative, then retrograde uretero- vagina by turning off the vaginal or bladder light pyelography should be performed at the time source allows for easier identification of the of cystoscopy and examination under anesthesia. fistula in the more difficult cases. • A Tratner catheter can be used to assist in • Color Doppler ultrasonography with contrast evaluation of an urethrovaginal fistula. media of the may be considered 270 Case Discussions in Obstetrics and Gynecology

in cases where cystoscopic evaluation is Foley’s catheter, examine the patient every 2 weeks suboptimal, such as in those patients with severe and plan for surgery after 6-12 weeks once the tissue bladder wall changes like bullous edema or condition is optimal for surgery. diverticula. Color Doppler ultrasonography demonstrated a VVF in 92% of the patients Q.27. What is conservative management? studied by Volkmer and colleagues using diluted Ans: Conservative therapy should be reserved for contrast media and observing jet phenomenon simple fistulae that are less than 1 cm in size, through the bladder wall toward the vagina. 12 diagnosed within 7 days of the index surgery, • Fistulograms: A targeted fistulogram may be lacking associated carcinoma or radiation, and indicated if conservative therapy is planned, subject to at least 4 weeks of constant bladder including expectant management, continuous drainage. bladder drainage, fulguration, or fibrin occlusion. Persistent, large, or complex fistulae are best • In patients with a history of urogenital treated surgically. malignancy, biopsy of the fistula tract and urine If VVF is diagnosed within the first few days cytology is warranted. of surgery, a transurethral or suprapubic catheter should be placed and maintained for up to 30 days. Q.24. What is the role of cystoscopy in the Small fistulas (<1 cm) may resolve or decrease diagnosis of VVF? during this period if caution is used to ensure proper Ans: Relatively insensitive in the diagnosis of continuous drainage of the catheter. VVF, cystoscopy should be performed to visualize In 1985, Zimmern concluded that if the fistula the fistulous tract, assess its location in relation to is small and the patient’s vaginal leakage of urine the ureters and trigone, assure bilateral ureteral is cured with Foley placement, the fistula has a high patency, and exclude the presence of a foreign body spontaneous cure rate with a 3-week trial of Foley or suture in the bladder. drainage. He also noted that in general, if at the Best combined with vaginal examination under end of 30 days of catheter placement the fistula anesthesia, with or without retrograde bladder has diminished in size, a trial of continued catheter filling. In case of larger fistula, distention of the drainage for an additional 2-3 weeks may be bladder with fluid for viewing is possible only when beneficial. Finally, Zimmern concluded that if no the fistula is occluded with finger or vaginal improvement is observed after 30 days, a VVF is tampon.13 not likely to resolve spontaneously. Under these circumstances, prolonged catheterization only Q.25. What are the various management increases the risks of infection and offers no options? increased benefit to fistula cure.14 Ans: • Conservative management Q.28. What are the medical management • Medical Therapy, options? • Surgical therapy. Ans: Medications • Non-surgical interventions. • Estrogen replacement therapy–in the postmenopausal patient may assist with Q.26. How will you manage this patient Mrs Y? optimizing tissue vascularization and healing. Ans: After confirmation of diagnosis, conservative Oral hormone replacement therapy/estrogen management by putting the patient on an indwelling replacement therapy (HRT/ERT) alone has been Vesicovaginal Fistula 271

found to suboptimally estrogenize urogenital components of a double fistula should only be tissue in 40% of patients. repaired simultaneously if it can be done without • Treatment with estrogen vaginal cream is tension. The genital malignancy should get biopsy recommended for patients with VVFs who are first to prove the absence of disease locally. hypoestrogenic. A 4-6 week treatment regimen prior to surgery is commonly recommended. It Q.30. What are the preoperative care required? may be used alone or in combination with oral Ans: Perineal care. HRT/ERT. Dosages range from 2-4 g placed • Frequent pad changes to minimise inflammation, vaginally at bedtime once per week. edema and vulval irritation. Alternatively, the patient may place 1 g • Zinc oxide ointment or vaseline application vaginally at bedtime 3 times per week. locally is helpful in the treatment of perineal • Corticosteroid and nonsteroidal anti- and vulval dermatitis. inflammatory therapy is theorized to minimize • Three sterile urine cultures must be present, early inflammatory changes at the fistula site. obtained on a sterile Sim’s speculum However, its efficacy has not been proven. • Catheter drainage. Because it also carries potential risks for impairment of wound healing, when early repair Q.31. What preoperative local assessment will is planned, cortisone is not recommended for you perform before fistula repair? the treatment of VVF. Ans: This is best done 1 to 3 days before the repair, • Acidification of urine to diminish risks of so that you know what to expect and are not obliged cystitis, mucus production, and formation of to repair a patient immediately after you have bladder calculi may be a consideration, particularly in the interval between the diagnosis assessed her. and surgical repair of VVF. Vitamin C at 500 mg • How big is the fistula? orally 3 times per day may be used to acidify • How far it is from her urethral orifice? urine. Alternatively, methenamine mandelate at • What is the state of the surrounding tissues? 550 mg plus sodium acid phosphate at 500 mg Are they soft and friable, or soft and healthy? 1-4 times per day also can be administered to Mildly, or severely fibrosed? achieve urine acidification. • Is her urethra stenosed or obstructed? • Urised is effective for control of postoperative • Is her vagina narrowed, or almost obliterated bladder spasms. It is a combination of antiseptics by scar tissue? (methenamine, methylene blue, phenyl • Does she seem to have ‘lost her urethra’? salicylate, benzoic acid) and parasympatholytics It is easy to repair if a fistula is: (1) Less than (atropine sulfate, hyoscyamine sulfate). 1 cm in diameter. (2) More than 2.5 cm from her • Sitz baths and barrier ointments, such as zinc urethral meatus. (3) Not significantly fibrosed. oxide preparations, can provide needed relief from local ammoniacal dermatitis. Q.32. How will you decide the route of approach to surgery? Q.29. How will you plan surgical therapy? Ans: Ans: The associated ureteric fistula is usually dealt • In low fistula (urethral and juxtaurethral)- at the same sitting while the intestinal fistula may vaginal approach (face down or jack knife require some operation for fecal diversion. Both position) 272 Case Discussions in Obstetrics and Gynecology

• Circumferential loss of bladder neck-combined a. external diversion like ileal conduit abdominovaginal approach. Lithotomy b. internal diversion like ureterosigmoidostomy, Trendelenburg position. colpocleisis. • Midvaginal fistula –transvaginal approach. • High vaginal fistula (post hysterectomy fistula Q.36. What is the ideal time to repair a VVF of or in a juxtacervical position)—abdominal or gynecological cause? vaginal approach. Ans: The timing of repair should be dictated by the overall medical condition of the patient and the Q.33. What should be the position of patient tissue quality surrounding the fistula. While the during surgery? emotional status of the patient should not be Ans: This is critical and depends on the skill of the underestimated, it also should not play a dominant anesthetist, and surgeon’s personal preference. role in the decision process of when to repair a VVF. 1. If anesthetist is skilled, patient can lie on her Traditionally, an interval of 3 months was front, her thighs abducted as far as possible, recommended between the index surgery and fistula and her legs supported in double lithotomy repair, with a delay of up to 1 year when the fistula stirrups. Bandage her legs to the poles, have was radiation-induced. A one-year interval for her buttocks clear of the table, and an overtable radiation-induced fistulas is recommended to just below her. Tilt her 5° head- down, and raise ensure full resolution of tissue necrosis. However, the table to a convenient height to let you see little data support these recommendations. into her vagina. 2. If anesthetist is less skilled, patient can lie on Today most experts recommend an individua- her back in the exaggerated lithotomy position, lized approach, delaying the surgery until with a steep (30°) head-down tilt, her buttocks inflammation and infection of the surrounding well over the edge of the table, and her tissue have resolved. The use of estrogen, shoulders supported by shoulder rests. antibiotics, or steroids to facilitate healing during this period also has been recommended. Q.34. What anesthesia should be used? Comparable success rates have been reported for Ans: If patient is lying prone, use general early and late repair of surgery-induced fistulae anesthesia, intubate her, use relaxants, and control based on these principles. her ventilation. Put a pillow under her chest, and Margolis and Mercer simply recommend another smaller one under her pubis; make sure that delaying surgery until inflamed and infected tissue her abdomen is free. Don’t rely on spontaneous has been treated and the infection and inflammation ventilation, because she will not ventilate have resolved.15 adequately. CAUTION! No patient should lie prone under Q.37. What is the role of Antibiotic prophylaxis general anesthesia, and be expected to breathe in VVF repair? spontaneously. Hypoxia, cardiac arrest, brain Ans: Patients given prophylactic antibiotic therapy damage, and death may follow. will have fewer urinary infections and will require less antibiotic therapy postoperatively. Q.35. What are the surgical options? Ans: Q.38. What is the debate on the fistula tract 1. Surgical closure should be the first option. excision—To excise or not to excise? 2. Urinary diversion is required when primary Ans: Debate continues about whether resection of surgical closure of fistula is not possible. the fistulous tract is necessary. Some experts believe Vesicovaginal Fistula 273 that wide resection increases the size of the fistula caution that this procedure is efficacious only in and, therefore, the risk of recurrence. They also the smallest of VVFs. maintain that the fibrous tissue surrounding the Other methods used to de-epithelialize the fistula helps to reinforce the surgical repair. fistula tract include electrocoagulation and sharp Proponents of fistulectomy counter that resection knife dissection. of the fistula and exposure of healthy tissue optimizes wound healing and improves surgical Q.40. What is Saucerization? success rates. Comparable success has been Ans: The original Marion Sam’s technique may be reported for both techniques. used for very small fistula, particularly for residual In their experiences, Vasavada, and Margolis fistula after previous surgery. A bevelled cut and Mercer15 note that routine excision of the fistula through the vagina to the small visceral aperture tract is not mandatory. They emphasize the risks of should clear scar tissue to allow healthy tissues for increasing the size of the fistula tract with attempts apposition.13 to resect it. Additionally, these surgeons contend that the fibrous ring of the fistula may add to the Q.41. What are the available techniques of strength of the repair and prevent postoperative repair? bladder spasms. Ans: The best chance for a surgeon to achieve Elkins and Thompson state that a small fistula successful repair is by using the type of surgery may be resected, but large tracts should only be with which he or she is most familiar. freshened. They warn of the risk of overexcising Techniques of repair include: fistula edges, thereby causing an increase in the 1. The vaginal approach size of the fistula. They point out further risks of 2. The abdominal approach intracystic bleeding and blood clot formation from 3. Electrocautery the mucosal edge of the bladder with fistula 4. Fibrin glue resection. Subsequent blockage of the catheter 5. Endoscopic closure using fibrin glue with or postoperatively would then increase the risk of without adding bovine collagen 16 failure of the VVF repair. 6. The laparoscopic approach, and It is preferable to have an individualized 7. Using interposition flaps or grafts. approach, with minimal resection of the fistulous tract to simplify the procedure and minimize Q.42. What are the determinants of successful associated complications, including recurrence. repair? Ans: The literature documents excellent success Q.39. What are the methods of de-epithe- rates for both the vaginal and abdominal approaches lialization? if the following general surgical principles are Ans: De-epithelialization of the fistula tract can followed: be accomplished by various techniques. Screw 1. Complete preoperative diagnosis curette is one method. In 1977, Aycinena described 2. Exposure the use of a common type of screw to strip away or 3. Hemostasis and closure of dead space curet the epithelial lining of small VVFs. He then 4. Mobilization of tissue simply allowed spontaneous healing to occur. Seven 5. Tissue closure under no tension patients were reported in this series, all of whom 6. Watertight closure of bladder with any were treated successfully. Experts in the field cystotomy repair 274 Case Discussions in Obstetrics and Gynecology

7. Timing to avoid infection and inflammation of • Multiple in number, tissue • When there is concurrent uterine or bowel 8. Adequate blood supply at area of repair, and involvement continuous catheter drainage postoperatively. • Multiple operated fistula with significant 9. Preservation of vaginal vault caliber and scarring. pliability. • Radiation-induced fistula. • Relative position of ureters to the fistula is seen Q.43. What are the advantages of vaginal as problematic. approach? • When omental flap is to be used. Ans: Advantages of vaginal approach are: • When a very large fistula or high and • Minimal blood loss inaccessible or a contracted bladder may require • Low postoperative morbidity bladder patching or augmentation with sigmoid • Shorter operative time, and shorter post- colon, caecum or ileum. operative recovery time. Q.45. In which type of fistula abdomino-vaginal • Additionally, the vaginal approach obviates approach is required? bowel manipulation, reducing operative Ans: In circumferential fistula (circumferential loss morbidity, particularly in patients with with the anterior bladder wall completely adherent radiation-associated fistulas. to the body of the pubis). • Angioli et al emphasize that the absolute • In Massive fistula . contraindications for vaginal repair of VVF are the concomitant presence of fistulas with other Q.46. What are the essential steps in the abdominopelvic organs, such as ureters and management of radiation-induced fistulas? 10 small and large bowel, and multiple VVFs. Ans: The essential steps in the management of radiation-induced fistulas are: Q.44. What are the indications of abdominal • Exclusion of the diagnosis of recurrent approach? malignancy. Ans: Absolute indications for abdominal approach • Avoidance of surgery during acute necrosis include: • Diversion of fecal stream in case of concomitant • the need for concomitant abdominal surgery, rectovaginal fistula. such as augmentation cystoplasty and ureteral • Increasing the blood supply with the use of reimplantation; grafts/flaps. • the inability to adequately expose the fistula • Proper closure of fistula. vaginally; • a complex presentation of VVF involving the Q.47. What is Bonney’s principle for repairing ureters, bowel, or other intraabdominal any fistula? structures; and Ans: Bonney described 6 general principles which • involvement of the VVF with ureteric orifices. should be adhered to when repairing any fistula.17 Abdominal approach is preferred in following 1. The tissue to be repaired must be healthy. In conditions: case of urinary fistula the urine should be • When ureteroneocystostomy is needed or a need rendered sterile and the area free of infection. for ureteral reimplantation. Slough due to irradiation, trauma or infection • Complex fistula. must be separated to leave clean healthy surface. Vesicovaginal Fistula 275

2. There must be adequate exposure of the affected going through the levator ani and the coccygeus area and the tissue surfaces surrounding the muscle, to ultimately gain access into the defect. ischiorectal fossa. Hemorrhage is an expected 3. There must be no tension on the suture lines complication encountered using this technique. when the fistula is closed. • Catheterization of the fistula tract: Exposure and 4. Meticulous hemostasis is essential throughout access to a VVF can be facilitated by catheteri- the operation to avoid hematoma formation and zation of the fistula with a bulb catheter, such as to facilitate healing. a Fogarty catheter. An uninflated catheter may 5. Infection must be guarded against or it will thread the fistula where the bulb is inflated, and jeopardize healing. then traction is placed on the catheter to draw 6. The urinary incontinence may be difficult when the VVF into the field. A small VVF may be a bladder fistula affects the region of bladder probed first with a lacrimal duct probe and dilated urethral junction. This is a vulnerable area in with cervical dilators to permit placement of a relation to urinary control and for this reason it pediatric catheter/ureteral bulb catheter. is not only important to close the fistula but also to reinforce the area with adjacent fascia and Q.49. How will you perform low tension closure? muscle including the anterior fibers of Ans: Low-tension closure—The critical issue of pubococcygeous muscle when necessary, thus closure of suture lines without any tension is a tenet reducing the risk of postoperative stress of surgical repair of VVF. The methods are: incontinence. • Extensive vaginal wall dissection and mobilization from the underlying vesicovaginal Q.48. How will you improve exposure during endopelvic fascia. surgery in vaginal approach? • Lateral radial or circumferential relaxing Ans: Exposure can be improved by: incisions. The relaxing incisions are the full • Suturing of the labial folds to the ipsilateral thickness of the vaginal wall without extension thigh provides improved visibility of the vaginal into the endopelvic fascia. The margins are not vault. reapproximated; instead, they may be sutured • Episiotomy incision afford greater exposure in in running fashion for desired hemostasis. A the vaginal repair of fistulas that were located significant danger to performing lateral relaxing high in the vaginal vault. incisions is further devascularization of the • Duhrssen incision is a deep vaginoperineal vaginal tissue. incision or extended episiotomy initially • An alternative approach that avoids this proposed for usage in other types of vaginal potential complication is to employ vascularized surgery. Its application to fistula surgery was flaps or grafts at the site of fistula repair, such recommended by Mackenrodt in 1894. as a Martius bulbocavernosus fibromuscular • In 1893, Schuchardt introduced a parasacral pedicle with or without an intact skin patch. incision as an extension of a Duhrssen incision, whereby a deep vaginoperineal incision is Q.50. What is the standard surgical procedure carried cephalad to the vault apex and then for posthysterectomy VVF as in Mrs Y? posteriorly toward the tip of the coccyx. Ans: Latzko (1942) partial colpocleises procedure • Schuchardt’s paravaginal incision is performed is the standard for repair of simple post by incising the posterior vaginal wall in a hysterectomy VVFs. Alternately fistulectomy with direction angled toward the ischial tuberosity, flap-splitting closure can be done.== 276 Case Discussions in Obstetrics and Gynecology

• Latzko partial colpocleisis: This technique, on suture lines. In addition, create a fascial flap first reported in 1942, remains a common to prevent apposition of the incision planes and procedure, with success rates of 90 to 100%. reduce the risk of recurrence. • The colpocleisis technique applied a transverse Vaginal cuff excision closure of the vagina beneath the fistula defect. • Technique: The vaginal mucosa is denuded • Disadvantage: Formation of a symptomatic circumferentially for a radius of 3-5 mm from diverticulum between the bladder and cervix if the vaginal cuff, including the fistula. This fistula occurs following subtotal hysterectomy. incision is then extended obliquely to the • Two prerequisite conditions: First, adequate bladder wall so as to resect the fistula tract and preoperative vaginal vault length must be vaginal cuff scar in a funnel-shaped specimen. present because the vagina is shortened by The defect is closed in 4 layers. 1.5 cm. Second, the fistula must be located at • Intravenous indigo carmine and cystoscopy is the vaginal apex “so that the posterior margin used to ensure bladder and ureteral integrity. of the fistula and the scar of the vaginal vault Abdominal approach—The abdominal approach coincide.” may be facilitated by cystoscopically-guided • Advantages of the Latzko procedure include placement of a catheter through the fistulous tract simplicity of technique, high success rate, low to assist in subsequent identification and dissection. morbidity, no impairment in bladder capacity, To begin, make a vertical skin incision to short operative time, low intraoperative and optimize visualization and allow mobilization of postoperative morbidity, and low risk of ureteral an omental flap, if necessary. Expose the bladder injury, even with fistulas lying close to the and perform a high extra peritoneal cystotomy to ureteral orifices. visualize the fistulous tract. Place ureteral stents if • Latzko technique: Make a circumferential the fistula is in close proximity to the ureteral incision in the vagina approximately 2 cm from orifice. the fistulous tract. Mobilize the vagina and close Extend the bladder incision to the fistulous tract it over the fistulous tract, with delayed and completely excise it following mobilization of absorbable suture in a double layer, without the vagina. Then close the vagina and bladder with disturbing the bladder mucosa. The vaginal interrupted, delayed absorbable suture in a double mucosa is then closed, completing the repair. layer. Transpose an omental flap between the The vaginal wall in contact with the bladder vaginal and bladder incisions. • Exposure: As with the transvaginal approach, becomes the posterior vesical wall and exposure with the transabdominal approach can eventually is reepithelialized with transitional be augmented with the use of traction sutures epithelium. and with catheterization of the fistula with a Other Procedures Fogarty catheter. • The classic positioning of the patient for • Fistulectomy technique—Fistulectomy with a abdominal procedures is supine, with flap-splitting closure, begin by resecting the Trendelenburg orientation. However, modifying fistulous tract to expose healthy tissue at the this by flexing the patient’s hips and abducting wound margins. Then close the defect in a and supporting her legs in stirrups is wise. multilayer fashion, beginning with the bladder Simultaneous access and examination of the mucosa, bladder serosa, pubocervical fascia, vaginal vault may assist with laparotomy and vaginal mucosa. Be careful to avoid tension procedures. Vesicovaginal Fistula 277

• The choice of incision may include suprapubic, the ability to add an interposition graft with this Pfannenstiel, or midline vertical. procedure. • Transvesical extraperitoneal technique: In 1885, Technique: The posterior wall of the bladder is Trendelenburg introduced this method of dissected free as much as possible. The bladder then vesicovaginal repair. With the patient placed in is bivalved at the dome. This incision is extended a steep Trendelenburg position, a transvesical posteriorly to the level of the fistula. The fistula incision is performed to visualize the fistula. tract and scarred and necrotic tissue are resected. The bladder mucosa adjacent to the fistula is Dissection of the posterior wall of the bladder from circumscribed and removed. The bladder is the underlying endopelvic fascia and vagina is dissected off the vagina and the bladder, and completed. The bladder and vagina are closed in vaginal defects are closed separately. separate layers. Commonly, peritoneal or • Transperitoneal technique: It was developed by interposition grafts are added. von Dittel in 1803 for the repair of VVFs. • Vesical autoplasty • Transvesical transperitoneal suprapubic • Gil-Vernet and colleagues presented a bladder method: In 1913, Legueu combined both the wall flap procedure in 1989 as an alternative Trendelenburg and the von Dittel techniques, technique for the repair of complicated VVF. whereby the peritoneal cavity is accessed by The approach may be transvesical, laparotomy and a sagittal incision is made in extraperitoneal, or transperitoneovesical. the bladder. This cystotomy incision is extended Advantages are the capability of repairing large VVFs without compromising bladder capacity, a to the fistula. The bladder is mobilized off the low-tension closure, direct and easy identification, vagina, and the bladder and vaginal defects are and preservation of the submucosal ureteral portion. closed separately. Technique: The fistula tract is completely excised. • Extravehicular transperitoneal procedure: The bladder wall is carefully mobilized off the Margolis and Mercer15 and O’Conor and Sokol endopelvic fascia and vaginal wall. The vaginal find this method of great benefit when the defect is closed with a single-layer closure. A bladder is densely adhered to the endopelvic bladder flap is constructed to close the bladder fascia and underlying structures (e.g. lower defect. The anterior margin of the flap is drawn uterine segment, cervix, anterior vaginal wall). down over the bladder defect to meet the caudal • O’Conor and Sokol technique (1951): margin of the bladder defect. It is sutured in place Intraperitoneal or transperitoneal technique for with 3-0 catgut through the submucosal and the suprapubic repair of trigonal and supra- muscular layers in interrupted fashion with sutures trigonal VVFs. Success rates 85%. not less than 10 mm apart. • Bladder mucosal autologous grafts Q.51. What are the procedures for complex • The use of autologous bladder mucosa grafts fistula repair? was first introduced in 1947 as a technique Ans: Among the complex fistula are radiation- designed for urethral reconstruction. associated cases and difficult repairs. Simplicity of technique, high success rates, lack • The transperitoneal approach is preferred of the need for interposition grafts, and decreased because it allows for the addition of patient morbidity were notable advantages to this interposition grafts. Advantages of this procedure. Re-epithelialization of the denuded technique are high success rate, optimum mucosa donor site is believed to occur surgical access to the fistula and ureters, and spontaneously over the following 4-6 weeks. 278 Case Discussions in Obstetrics and Gynecology

Technique: Bladder mucosa is denuded setting, reduced operating time, and reduced circumferentially at the fistula site at a distance of morbidity.20 Essential to the technique are 1 cm. The fistula tract and vaginal wall are left suprapubic visualization with a shorter scope undisturbed. A free bladder mucosal graft is sharply such as an arthroscope, large-caliber sheaths dissected from its underlying muscularis layer at used transurethrally to allow passage of the edge of the anterior cystotomy margin. This relatively large curved needles, self-righting graft of mucosa is then secured over the fistulous needle driver, and adequate fulguration of the tract with interrupted 4-0 chromic catgut sutures fistula tract and the surrounding bladder that are placed into the superficial muscularis at a mucosa. distance of 2-3 cm. Q.54. Which type VVF get benefit from inter- Q.52. How will you suture bladder opening? position graft/flap placement? Ans: The bladder is closed with a 2-0 chromic/ Ans: Multiple operated fistulas, post-irradiation vicryl suture in continuous running fashion fistulas, post-surgical fistulas more than 4 cm in beginning at the apex and extending through the diameter or large tissue loss fistulas (large obstetric full muscle layers and imbricated with a second fistulas) often are complicated with marked tissue layer with interrupted 1-0 chromic/vicryl sutures. devascularization, necrosis, and cicatrization and will get benefit from flap placement. Q.53. What are the newer techniques of VVF In cases with a high risk of recurrence, such as repair? complex or large fistulae, a Martius fat-pad graft Ans: The newer techniques are: should be interposed between the closure layers to • Laparoscopic approach: Laparoscopic repair promote vascularization and reduce the risk of has been reported with comparable results, but recurrence. requires advanced skills with endoscopic suturing and knot tying. Q.55. What are the various interposition grafts • This technique involves cystoscopy, or flaps available for vaginal approach? catheterization of the fistula tract, dissection of Ans: the bladder from the vagina, laparoscopic 1. Martius flap: Martius first described his cystotomy, excision of the tract, adequate procedure in 1928 as a technique used in VVF dissection of the bladder from the vaginal wall, repair. He isolated the bulbocavernosus muscle cystotomy, and colpotomy closure with and its overlying fibroadipose tissue as a interposition of a flap of healthy tissue.18 pedicled graft for VVF repair. The fibroadipose • Melamud and colleagues reported their tissue possessed sufficient blood supply and successful attempt in the repair of a VVF in a strength for success. Its application today 44-year-old woman. Their approach was a extends to numerous types of vaginoplasties minimally invasive laparoscopic approach using performed for urethral, vaginal, and rectal the DaVinci robotic system. In their technique disorders that include VVF, vaginal scarring and they added fibrin glue between the bladder and atresia, urethrovaginal fistulas, and rectovaginal vagina to separate the suture lines.19 fistulas. The dual blood supply to this tissue • Transurethral suture cystorrhaphy (TUSC): and the bulbocavernosus muscle (dorsally via This technique offered multiple advantages internal pudendal artery and ventrally via including minimal intervention, outpatient external pudendal artery) enables the surgeon Vesicovaginal Fistula 279

the choice of using a flap with a superior or Q.56. What are the interposition grafts or flaps inferior base. Various modifications of Martius’ used in abdominal approach VVF repairs? original procedure have been published. Ans: Abdominal approach interposition grafts or Success rates range from 85-100%. flaps are: Complications of classic Martius graft 1. Omental J flap: Omentum, with its rich technique: There is risk of hemorrhage because lymphatic and vascular supply, is ideal as an it requires a deep plane of dissection to isolate interposition graft. The omentum may be the bulbocavernosus muscle. Mild dyspareunia mobilized off the transverse colon, and ligation over the graft site is a potential complication. and division of the short gastric branches may The graft is obtained through a vertical be required. The omentum can be mobilized on incision over the labium majus. It is separated the right gastroepiploic artery from the from the underlying vestibular bulb and transverse colon. Absorbable sutures must be bulbocavernosus muscle and then tunnelled used at the distal omentum in order to avoid beneath the labium minora and through the contact of permanent suture at the bladder. paracolpium to finally reach and overlay the A number of surgeons have performed 2-layer bladder closure. It is secured at its distal VVF repair with an omental J flap under end with 4-corner stay sutures. The vaginal wall laparoscopic technique and have found it to be is closed using interrupted chromic or Vicryl a good alternative to the traditional abdominal sutures, and then the labial incision is closed. A approach. Penrose drain is placed at the bed of the graft 2. Peritoneal flap: As with transvaginal approach, and brought out at a lateral site if any persistent peritoneal flaps may be used during a bleeding is noted. This drain is then removed transabdominal approach to provide an on the third to fifth postoperative day. Perform additional layer between the bladder and vaginal cystoscopy prior to and following the procedure cuff at the time of repair of a VVF. to exclude ureteral compromise. In an effort to decrease the likelihood of 2. Gracilis muscle flap: The predominant VVF formation, it has been suggested as a application for this flap is in total vaginal technique to be used at the time of repair of reconstruction following pelvic exenteration. both incidental and intentional cystotomies that The gracilis muscle reaches to cover the medial occur during simple and complicated pelvic portion of the groin, the vulva, the perineum, surgeries. and the lower abdomen. Its major blood supply 3. Rectus abdominis muscle flap: Kanavel first is a branch of the profunda femoris entering described using a flap isolated from the rectus the upper one-third of the muscle. This abdominis muscle for repair of a space of dominant vascular pedicle is the point of Retzius defect in 1921. rotation for the flap and supports the entire In 1965, Banerji published his experience with muscle and overlying skin island. rectus abdominis musculofascial pedicle grafts 3. Peritoneal flap: Peritoneum is mobilized in the treatment of 7 patients with VVFs. All of carefully from the posterior bladder wall and the fistulas resulted from obstetric trauma. Of brought down to reach beyond the fistula site 7 patients, 4 were cured. and be secured over the fistula repair suture line 4. Autologous bladder mucosa interposition graft: with 2-0 polyglycolic sutures. Closure integrity A site is selected at the bladder dome for is assessed with indigo carmine. Vaginal harvesting of the donor mucosal graft. The graft packing is used. is dissected from the muscularis and interposed 280 Case Discussions in Obstetrics and Gynecology

between the bladder and vaginal walls so that Q.58. What postoperative care to be given after the mucosal surface faces the vagina. The VVF repair? bladder wall is then closed over the graft using Ans: 5-0 continuous catgut. The anterior cystotomy 1. Bladder drainage: Urethral drainage is done is closed in 2 layers with 3-0 interrupted via 16-18 Foley’s catheter. One hourly urinary chromic sutures. output charting should be maintained. It is Vyas and colleagues report of a 91% success usually 70-100 ml/hr with good hydration. rate using mucosal autografts for repair of VVF. Continuous bladder drainage postoperatively is A transabdominal approach was used for vital for successful UGF repair. A large-caliber fistulae above the trigone and a combined catheter minimizes the potential for catheter abdominal and vaginal approach for fistulae blockage by blood clots, mucus, and calcaneus involving the trigone. deposits. 5. Free supporting graft: Moharram and El-Raouf Type and duration of catheter drainage: For report their 100% success rate in the repair of fistulas involving the lower portion of the urogenital fistulas in 26 women using a bladder trigone, bladder neck, or urethra, retropubic transvesical approach with transurethral bladder catheters should not be placement of a support graft from the anterior used. A large suprapubic catheter for an average 21 abdominal wall fat. of 3 weeks (upto 60 days in certain cases) 6. Human dura mater interposition graft: In a preferable to minimize excess tension on the prospective study of 11 patients with VVF, suture line and to ensure nonobstructed Alagol and colleagues used solvent dehydrated, continuous drainage. gamma-radiated human dura mater. They In post hysterectomy VVF repairs, both reported a 100% success rate. Surgical tech- transurethral and suprapubic catheters may be nique included a transvesical extraperitoneal placed. The urethral catheter may be 22 approach. discontinued by fourteenth day (7-14 days). 7. Broad ligament flaps: Plastic reconstruction If vesical integrity is noted 2 weeks later on a technique for the repair of mega vesicovaginal cystogram, the suprapubic catheter may be fistulae resulting from obstetric compli- removed. Surgeries to repair pelvic 23 cations. radiotherapy-associated VVFs require longer 8. Placement of a cadaveric biomaterial graft also periods of drainage. has been reported, reducing the need for The suprapubic drainage is done when: complicated flap procedures. • Abdominal approach is used. • Large vesicovaginal fistula is repaired via Q.57. How do interposition flaps/grafts increase vaginal approach. the success rate of VVF repair? • Urethal reconstruction is done. Ans: Interposition flaps or grafts/Rotated The basic aim is to ensure a continuous vascularized pedicle flaps increase success by drainage so that bladder does not become enhancing granulation tissue formation, increasing overdistended. neovascularity to the area, and obliterating dead Urethal catheter is removed in 2 weeks and space. They also provide a barrier layer between suprapubic catheter should be clamped for every the bladder suture line and the vaginal suture line. one hour and residual urine should be checked Vesicovaginal Fistula 281

after voiding, if it is less than 30cc suprapubic • Electrocautery catheter can be removed. – Reported a 73% cure rate with electro- 2. Alternate day urine sample should be sent for coagulation. The fistulas that can be culture and sensitivity. successfully managed with electrocautery as 3. Perineal care to keep the area clean. the sole treatment modality should be small 4. Acidification of urine to diminish risks of in size (either pinhole openings or bladder cystitis, mucus production, and formation of mucosal dimples). bladder calculi is a consideration for patients – Details of the technique include both vaginal with an indwelling catheter. and cystoscopic routes and fulguration with 5. Estrogen replacement therapy in the a Bugbee electrode and placement of a large postmenopausal patient may assist with Foley catheter for a minimum of 2-3 weeks. optimizing tissue vascularization and healing. – Care should be taken to use low-current 6. Control of postoperative bladder spasms: settings in order to minimize the potential Urised is effective for control of postoperative of thermal damage and enlargement of the bladder spasms. fistula. 7. Antibiotic therapy: The use of antibiotic therapy • Fibrin glue postoperatively is controversial. Many physi- – Occlusion therapy using fibrin glue is cians administer oral antibiotic prophylaxis to considered useful and safe for intractable patients with VVF postoperatively until the fistulas. Fibrin glue facilitates healing by Foley catheter is discontinued. recruiting macrophages and providing a Others check closely for the development semisolid support structure rich in growth of a urinary tract infection and administer and angiogenic factors. This system antibiotic therapy when urine cultures are continues to support the fibroblast to positive for bacterial growth. Close follow-up connective tissue transition. and prompt evaluation for any urinary tract – Fibrin occlusion of a VVF was first infections and antibiotic therapy, when developed by Pettersson and associates in indicated, are mandatory. 1979. The VVF was incurred following Antibiotics are administered for 14 days starting surgery and radiotherapy and was cured with preoperatively on the day of surgery. the first attempt. 8. Minimizing valsalva maneuvers: Stool softeners • Electrocautery and endoscopic closure using and a high-fiber diet postoperatively minimize fibrin glue and bovine collagen valsalva maneuvers in the patient. – Morita and Tokue published a case report 9. Examinations: Avoid pelvic and speculum of successful closure of a radiation-induced vaginal examinations during the first 4-6 weeks and markedly fibrosed VVF measuring postoperatively because the tissue is delicate. 5 mm. They buttressed the fibrin glue in the 10. Pelvic rest: Prohibit coitus and tampon use for fistula tract between collagen cushions at a minimum of 4-6 weeks. Some advocate strict the proximal and distal sites of the fistula to pelvic rest for 3 months. prevent its mechanical disruption by the efflux of urine from the bladder.24 Q.59. What are the available methods of non- – Technique: After performing electro- surgical interventions in VVF? coagulation of the fistula, a cystoscope was Ans: The available methods of non-surgical introduced transurethrally into the bladder, interventions are: and 1 mm of bovine collagen was injected 282 Case Discussions in Obstetrics and Gynecology

submucosally under direct visualization Blocked Catheter around the fistula opening. Fibrin glue was Infection, anuria, hemorrhage, thromboembolism injected transvaginally into the fistula tract. new-onset incontinence after anatomical closure of A second application of 1 mm of bovine fistula collagen was then injected transvaginally Death- Very rare. The documented fatality rate for into the vaginal mucosal layer around the fistula surgery ranges from 0.5 to 1 percent in sub- fistula tract. A transurethral Foley was used Saharan Africa. for 3 weeks. – Laser welding: Dogra and Nabi reported their Preoperatively, patients should be informed of success in the repair of a 3-mm VVF in the the possibilities of sexual dysfunction or supratrigonal area of the bladder. They used a dissatisfaction, and the progression of preexisting Nd-YAG laser to fulgurate the fistula opening urge and/or stress incontinence symptoms. and the full tract. A transurethral catheter was Abdominal approach procedures carry used for 3 weeks. The authors emphasize that additional risks of abdominal and pelvic adhesions. the Nd-YAG laser has the advantage over Vaginal approach procedures carry increased risks electrocoagulation of precise and accurate of dyspareunia, tenderness at the site of the donor destruction of the areas involved.25 Martius graft, and diminished vaginal length and caliber. Q.60. What is the palliative treatment available Careful screening and management before if surgical repair is not possible? surgery is vital, as women with fistula tend to be Ans: Use in the vagina of a sponge tampon tucked malnourished and may be more susceptible to into a length of Paul’s tubing draining into a bag disease. Postoperative care and close long-term may provide socially acceptable temporary follow-up to manage both the surgical and medical continence. Every movement squeezes a small problems that may occur is also essential. amount of urine out of the bottom of the sponge, within the lumen of the Paul’s tubing.13 Q.63. What are the causes of dribbling of urine in the postoperative period? Q.61. If VVf is associated with RVF (recto-vaginal fistula) which one should be repaired first? Ans: If patient complains of dribbling in the postoperative period, the reason can be: Ans: A bladder fistula heals better if not bathed in • Breakdown of repair feces during recovery. Preliminary loop ileostomy • Leakage by the side of catheter due to or transeverse colostomy should be performed and incompetent internal sphincter. then it is better to treat the urinary fistula first as avoidance of suture line tension is essential.13 • Overflow incontinence following blockage of catheter. Q.62. What are the complications of fistula surgery? Q.64. How will you manage postoperative Ans: Intraoperative complications: Creation of intravesical hemorrhage? another fistula Ans: Intravesical hemorrhage threatens the integrity Ligation of/injury to the ureter of the repair by obstruction of the catheter and Failure to achieve complete closure of fistula. overdistention of the bladder; gentle attempts to • Postoperative complication: Most important evacuate the clots can be made by transurethral complication is breakdown of the repair. This bladder irrigations. If these are not successful, then usually occurs about 7-10 days after operation. immediate suprapubic cystotomy has to be Vesicovaginal Fistula 283 performed to remove the clots and suture the REFERENCES bleeding points in the bladder mucosa. 1. WHO. In: Lewis G, de Bernis L (Eds): Obstetric Exclusion of the urothelium from the actual Fistula: Guiding Principles for Clinical Management suture line diminishes the risk of hematuria, but in and Program Development. Geneva: WHO Press; some cases this is unavoidable. In such cases 2005. combination of suprapubic and urethral drainage 2. Wall LL, Karshima JA, Kirshner C, Arrowsmith SD. The Obstetric vesicovaginal fistula characteristics of is preferred. Urethral catheter preferably a Jaques 899 patients from Jos, Nigeria. Am J Obstet Gynecol or McCarthy “whistletip”catheter which will 2004;190:1011-19. facilitate the evacuation of any clot that may form. 3. Browning A. A new technique for the surgical Gentle irrigation should be continued until the management of urinary incontinence after obstetric efflux is clear. Early diuresis, if necessary with fistula repair. BJOG 2006;113:475-8. 4. United Nations Population Fund and Engender Health. frusemide or similar agent is desirable. Obstetric fistula needs assessment report: Findings from nine African countries. New York (NY): United Q.65. How will you manage postoperative Nations Population Fund and Engender Health, 2003. ureteral obstruction? 5. Wall LL. Obstetric vesicovaginal fistula as an international public-health problem. Lancet 2006;368: Ans: If patient exhibits signs of ureteral obstruction 1201-09. (persistent fever, abdominal distention, pain and 6. Kelly J. Vesicovaginal and rectovaginal fistulae. J Roy tenderness), an excretory urogram should be Soc Med 1992;85:257. performed immediately. If complete ureteral 7. Bai SW, Huh EH, Jung da J, et al. Urinary tract injuries during pelvic surgery: incidence rates and predisposing obstruction is diagnosed, either the repair can be factors. Int Urogynecol J Pelvic Floor Dysfunct broken down or T tube can be placed in the ureter 2006;17(4):360-4. for drainage or ureteroneocystostomy can be 8. Starkman JS, Meints L, Scarpero HM, Dmochowski performed or percutaneous nephrostomy can be RR. Vesicovaginal fistula following a transobturator done. midurethral sling procedure. Int Urogynecol J Pelvic Floor Dysfunct 2007;18(1):113-5. 9. Donnay F, Ramsey K. Eliminating obstetric fistula: Q.66. What is the prognosis of VVF? Progress in partnerships. Int J Gynecol Obstet 2006; Ans: Recent advances have improved the success 94:254-61. of VVF repair—a challenge that can test even the 10. Angioli R, Penalver M, Muzii L, Mendez L, Mirhashemi R, Bellati F. Guidelines of how to manage most experienced gynecologic surgeon. For vesicovaginal fistula. Crit Rev Oncol Hematol example, it now is apparent that some small 2003;48(3):295-304. uncomplicated fistulae respond to conservative 11. Andreoni C, Bruschini H, Truzzi JC, Simonetti R, treatment. Further, in selected cases, laparoscopic Srougi M. Combined vaginoscopy-cystoscopy: a repair can eliminate the need for complicated novel simultaneous approach improving vesicovaginal fistula evaluation. J Urol 2003;170(6 Pt 1):2330-2. laparotomy. 12. Volkmer BG, Kuefer R, Nesslauer T, Loeffler M, Vesicovaginal fistula presentation and Gottfried HW. Colour Doppler ultrasound in prognosis vary, depending on location and size of vesicovaginal fistulas. Ultrasound Med Biol 2000; the defect, as well as coexisting factors such as 26(5):771-5. tissue devascularization and previous radiation. 13. John H, Christopher NH. Genital Fistula. Shaws text book of operative gynecology. 6th edition, chap18; However, surgical repair is associated with a high 238,241,246. cure rate if it is performed by an experienced 14. Zimmern PE, Hadley HR, Staskin D. Genitourinary surgeon. fistulas: vaginal approach for repair of 284 Case Discussions in Obstetrics and Gynecology

vesicovaginal fistulas. Clin Obstet Gynaecol. Jun 21. el-Lateef Moharram AA, el-Raouf MA. Retropubic 1985;12(2):403-13. repair of genitourinary fistula using a free supporting 15. Margolis T, Mercer LJ. Vesicovaginal fistula. Obstet graft. BJU Int. 2004;93(4):581-3. Gynecol Surv. 1994;49(12):840-7. 22. Alagöl B, Gözen AS, Kaya E, Inci O. The use of human 16. Elkins T, Thompson J. Lower urinary tract fistulas. dura mater as an interposition graft in the treatment In: Walters M, Karram M (Eds): Urogynecology and Reconstructive Pelvic Surgery. St Louis, Mo: Mosby; of vesicovaginal fistula. Int Urol Nephrol. 2004; 1999:355-66. 36(1):35-40. 17. Bonney, Operations for the correction of urinary fistula. 23. Singh RB, Pavithran NM, Nanda S. Plastic Bonney’s Gynecological surgery. Chap 15;162-3. reconstruction of a mega vesicovaginal fistula using 18. Sotelo R, Mariano MB, García-Segui A, Dubois R, broad ligament flaps—a new technique. Int Spaliviero M, Keklikian W. Laparoscopic repair of Urogynecol J Pelvic Floor Dysfunct. vesicovaginal fistula. J Urol 2005;173(5):1615-8. 2003;14(1):62-3. 19. Melamud O, Eichel L, Turbow B, Shanberg A. 24. Morita T, Tokue A. Successful endoscopic closure of Laparoscopic vesicovaginal fistula repair with robotic radiation-induced vesicovaginal fistula with fibrin glue reconstruction. Urology 2005;65(1):163-6. 20. McKay HA. Transurethral suture cystorrhaphy for and bovine collagen. J Urol 1999;162(5):1689. repair of vesicovaginal fistulas: evolution of a 25. Dogra PN, Nabi G. Laser welding of vesicovaginal technique. Int Urogynecol J Pelvic Floor Dysfunct. fistula. Int Urogynecol J Pelvic Floor Dysfunct. 2001; 2001;12(4):282-7. 12(1):69-70. Saritha Shamsunder, Meenakshi Garg

22 Abnormal Uterine Bleeding

Normal menstrual cycle is defined as occurring CASE 1 at an interval of 28 days (±7 days) with an average History duration of 4 to 7 days and mean menstrual blood A young unmarried nulliparous 15-year-old girl loss of 35 ml (range 31-80 ml). Abnormal uterine gives history of irregular cycles since menarche bleeding (AUB) is defined as any change in the with weakness and fatigue. frequency of menstruation, duration of flow or amount of blood loss. AUB is defined as dysfunc- Examination findings tional uterine bleeding (DUB) when palpable • Pallor ++ pelvic pathology or underlying medical causes have • Tachycardia ++ BP 100/60, been excluded. AUB is responsible for 20-30% of • No lymph nodes the visits to Gynecology Out Patient Department • No petechiae palpation amongst women in the reproductive age group and • Per abdomen – soft, liver and spleen not 69% in a peri or postmenopausal age group.1 palpable • Local examination – bleeding per vaginum Types of Abnormal Uterine Bleeding (AUB) present ++ • Menorrhagia – excessive or prolonged bleeding • Per rectal examination – uterus was normal at regular intervals. size, no adnexa mass. • Polymenorrhea –bleeding at intervals of less than 21 days. Q.1. What are the important points in history • Oligomenorrhea – bleeding at intervals of 35 and examination in a patient of puberty menorr- days or more with scanty flow. hagia? • Metrorrhagia – irregular acyclical bleeding. Ans: • Menometrorrhagia – prolonged and excessive A. History bleeding at irregular intervals. 1. Age at menarche. • Postmenopausal bleeding – bleeding per 2. Duration and amount of bleeding to know the vaginum at least 12 months after the cessation severity of problem. of regular menses, or unscheduled bleeding 3. Cycle length and regularity, to ascertain whether after use of hormone replacement therapy cycles are ovulatory or anovulatory. (HRT) for 12 months or more.2 4. History of preceding amenorrhea indicates Five different problem cases of AUB are anovulatory cycle or incidental pregnancy in a discussed in this chapter. sexually active female. 286 Case Discussions in Obstetrics and Gynecology

5. History of sexual activity should be taken Per rectal examination should be carried out to discretely in the absence of parent/guardian. assess: 6. Dysmenorrhea – spasmodic dysmenorrhea • Uterine size, position, consistency mobility, (pain during menstruation) without an organic tenderness. cause is seen in 5-10% of young girls and is • Adnexal masses. associated with ovulatory cycles. Congestive Per rectal examination is essential to rule out dysmenorrhea (premenstrual pain relieved by less common causes like associated pregnancy, flow) due to endometriosis or PID although rare, fibroid, uterine or ovarian tumor. but could occur in this age group. Anovulatory cycles are painless. Q.2. How will you investigate a patient of 7. History of easy bruisability/prolonged bleeding puberty menorrhagia? from wounds, heavy bleeding after any surgery/ Ans: Essential investigations dental procedure, h/o of nosebleed which lasted 1. Urine pregnancy test – pregnancy should be for more than 10 min or required medical ruled out in every case of uterine bleeding attention to stop is suggestive of coagulation which is irregular in the reproductive age disorder. group. 8. History of fever/cough/night sweats/chest pain 2. Complete hemogram and peripheral smear. is suggestive of tuberculosis. 3. Bleeding time, clotting time. 9. History of weight gain/acne/excessive hair 4. Prothrombin time and partial thromboplastin growth or unwanted hair is suggestive of time. PCOD. 5. Erythrocyte sedimentation rate, Mantoux test, 10. History of weight gain/cold intolerance/fatigue/ chest X-ray to rule out tuberculosis. lethargy/constipation is suggestive of hypo- 6. Thyroid function test – if symptoms are thyroidism. suggestive of hypothyroidism. 7. USG pelvis to note the endometrial thickness, B. Examination look for fibroid and any adnexal mass. General physical examination – important findings to be noted: Special investigations • Pallor to know severity of bleeding. 1. Menstrual blood for PCR tuberculosis – can be • Lymphadenopathy is suggestive of tuberculosis sent if there is strong suspicion of tuberculosis. or hematological causes like leukemia or 2. Endometrial assessment by endometrial lymphomas. aspiration should ONLY be considered in obese • Thyromegaly–as hypothyroidism could be a girls with persistent anovulatory cycles for 2-3 cause of menorrhagia. years despite treatment to rule out chances of • Petechiae/ecchymosis/gum bleeding are endometrial cancer (risk in women aged under suggestive of a coagulation disorder. 30 years the estimate is less than 0.01% or 1 Per abdominal examination: per 10,000 consultations for heavy menstrual • Splenomegaly is present in a patient of ITP, bleeding in primary care, risk increases in the hepatosplenomegaly in a patient of leukemia. presence of risk factors like obesity and chronic • Abdomino-pelvic mass – could be due to fibroid, anovulation.3 estrogen secreting ovarian tumor (although 3. Special hematological investigations when rare). indicated are: Abnormal Uterine Bleeding 287

• Bone marrow aspiration in the ratio of endometrial vasoconstrictor • vWD antigen assay (PGF2α) to endometrial vasodilator (PGE2) • vWD ristocetin cofactor activity and increase in total endometrial • FVIII coagulant activity prostaglandins have been seen in patients • Factor assay (VIII and IX) with ovulatory DUB.1 • Platelet function study 2. Tuberculosis Menorrhagia is seen in 19% of patients with Q.3. What is your provisional diagnosis in this genital tuberculosis. Symptoms of fever/cough/ patient? night sweat/chest pain and family history of Ans: Anovulatory dysfunctional uterine bleeding, tuberculosis are suggestive. as the urine pregnancy test is negative, uterus is 3. Coagulation abnormalities Coagulation abnormalities are responsible for normal sized, investigations for coagulation 1 disorders, tuberculosis and thyroid function are 30% of cases of puberty menorrhagia. The commonest disorder is vWD in 5 to 15% of normal. cases, other disorders which can present in this age group are ITP, platelet function disorder, Q.4. What are the important causes of puberty factor XI deficiency and hemophilia.5 menorrhagia? Coagulation abnormalities are suspected when Ans: The important causes are: there is a family history of bleeding diatheses, 1. Dysfunctional Uterine Bleeding – could be when the patient gives a history of frequent ovulatory or anovulatory DUB. epistaxis, bleeding from the mucous membranes • Anovulatory DUB is the most common (e.g. with the toothbrush), and excessive cause due to immaturity of the hypothala- bleeding following minor surgery like tooth mo-pituitary-ovarian axis. Unopposed extraction. estrogen causes endometrial proliferation 4. Hypothyroidism and hyperplasia to abnormal heights when Hypothyroidism should be suspected in patients it becomes fragile. Without the growth presenting with associated symptoms like limiting and organizing effects of proges- fatigue, weakness, pedal edema, weight gain, terone, the endometrium lacks the stromal constipation, excessive sleepiness, mental support structure to maintain stability. Focal slowing. areas breakdown and bleed, as these areas 5. Systemic illness leukemia, anticoagulant later heal under the influence of continued therapy and injudicious use of hormones could estrogen stimulation, others break down and be a cause. bleed, resulting in irregular shedding of the endometrium leading to heavy, prolonged Q.5. How will you treat a patient of pubertal and continuous bleeding.4 It is also part of DUB? the syndrome of polycystic ovarian disease. Ans: The following treatment is to be initiated only • Ovulatory DUB is cyclic with a predictable if all other causes are ruled out. pattern. The cause is not well defined, A Patient can be divided into three categories however, some theories suggest a change on the basis of severity of anemia.6 in endometrial hemostasis, and alterations 1. Mild anemia (Hb 9-10.5 gm) in the synthesis and release of prostag- • Reassurance. landins as key etiological factors. A change • Menstrual charting. 288 Case Discussions in Obstetrics and Gynecology

• Perimenstrual nonsteroidal anti-inflam- Maintenance therapy matory drugs. • Hormones: Cyclic progesterones; usually • Iron and vitamin supplementation. medroxyprogesterone (lesser side effects and • Cyclical oral contraceptive pill for 3-6 more effective in reverting hyperplasia) in a months if symptoms persist. dose of 10 mg/day in a divided doses, typically, 2. Moderate anemia (7-9 gm) for 10-14 days each month starting from day • Oral or parenteral iron with other hematinics 15 to day 26 of menstrual cycle for 3-4 cycles. • Non-hormonal – NSAIDS like mefenamic • Oral contraceptive can also be prescribed in a acid 500 mg bd to tds. dose of 1 tablet/day for 21 days for 3-4 cycles. • Tranexamic acid 1 to 3 gm daily during • Oral hematinics to correct anemia. menstruation. • Exercise and dietary advise to reduce weight if • Hormonal treatment – cyclical progesterone obese. treatment (medroxy progesterone acetate • Menstrual charting. 10 mg/day for 14 days every 3 months). • Follow-up after every cycle to see improvement, • Oral contraceptives (continuous or cyclical). check compliance. 3. Severe anemia (< 7 gm) • Treatment can be stopped after 3-4 months or • Hospitalization. can be continued longer if patient desires. On • If in hypovolemic shock – resuscitate with stopping treatment patient should be evaluated IV fuids (crystalloid) and blood transfusion. to ascertain if cycles are regular with normal • Blood products will be required if coagu- flow. lation profile is deranged, such patient The treatment of systemic diseases causing should be managed in liaison with hemato- menorrhagia is outside the scope of this chapter. logist. • Hormonal therapy CASE 2 – IV conjugated equine estrogen (25 mg History every 4 hours) as indicated till bleeding A 30-year primiparous women presented to the stops or diminishes significantly gyne OPD with complaints of heavy bleeding followed by oral progesterone or oral during periods for the last six months. contraceptive pills. – Oral progestin norethisterone acetate can Examination findings be given in a dose 10-20 mg 8 hourly • No pallor till bleeding stops followed by gradual • Abdomen soft tapering. • Speculum exam – cervix and vagina healthy – Oral combined contraceptive 3-4 tablets • Vaginal examination – uterus normal sized, per day till bleeding stops followed by firm, smooth, nontender, no adnexal mass. tapering to 1 tablet/day over 3-4 weeks. What are the relevant points to be included • If bleeding is does not repond to above in the history of this patient? measures than surgical intervention with D History and C or balloon tamponade may be 1. Menstrual history like amount, duration of necessary. bleeding and cycle length. Abnormal Uterine Bleeding 289

2. History of postcoital bleeding suggest cervical Q.7. What are the important differential pathology like polyps, fibroid, ectropian and diagnosis in this patient? cancer of the cervix. Ans: 3. History of could be due 1. Dysfunctional uterine bleeding to endometrial polyp or submucous fibroid. 2. Pelvic inflammatory disease 4. History of pain abdomen and discharge per 3. Adenomyosis vaginum suggests pelvic inflammatory disease. 4. Hypothyroidism. 5. History of weight gain/lethargy/sleepiness/ constipation suggests hypothyroidism. Q.8. List examination finding for and against 6. History of dysmenorrheal/dyspareunia/dys- the differential diagnosis of dysfunctional chezia/dysuria/infertility is suggestive of uterine bleeding in this patient? endometriosis. Ans: Table 22.1 would help in the differential 7. History of usage of intrauterine contraceptive diagnosis: device. Q.9. What is your provisional diagnosis in this 8. History of hormonal drug intake or herbal patient ? Will you order imaging for this patient? remedies which may contain estrogen. 9. History suggestive of bleeding disorder (as Ans: The above patient is case of ovulatory DUB, described in problem A). as on history there are no sign and symptom suggestive of any systemic disease, the cycles are Q.6. List the causes of menorrhagia in the regular and on examination uterus is normal in size reproductive age group. and nontender. In this patient imaging is not indicated as it is Ans: Menorrhagia – is cyclical bleeding at regular required only if: intervals which is excessive in amount (> 80 mL) 1. The uterus is palpable per abdomen or duration (longer than 7 days) or both. It is 2. Vaginal examination has revealed mass of generally caused by conditions affecting the uterus uncertain origin and its vascular apparatus. 3. Pharmacological treatment has failed. Causes of menorrhagia could be: Transvaginal ultrasound (TVS) should be the 1. Anatomical first line modality to assess the pelvis for structural a. Submucous fibroid abnormality. TVS is done to assess the endometrial b. Adenomyosis lining, its thickness, detect any endometrial polyp, c. Endometriosis fibroid and adenomyosis, adnexal pathologies such d. Pelvic inflammatory disease as tubo-ovarian masses, , etc. The e. Tubercular endometritis (early) detection of focal pathology within the uterine f. Intrauterine contraceptive device cavity (e.g. polyp and fibroid) can be enhanced by g. Functioning ovarian tumors performing the scan immediately postmenstrual or h. Uterine A-V malformation. with the use of saline as a contrast agent (sono- 2. Hormonal salpingography). a. Hypothyroidism Q.10. How will you manage this patient? b. Dysfunctional uterine bleeding. Ans: This patient will be managed medically 3. Systemic – thrombocytopenia, leukemia. • Menstrual charting 4. Drug related – anticoagulant like warfarin, • Tab Tranexamic acid (500 mg) 8 hourly during heparin, antiplatelet like aspirin, some herbal periods. remedies rich in estrogen. • Follow-up after 3 months for response. 290 Case Discussions in Obstetrics and Gynecology

Table 22.1: Differential diagnosis of dysfunctional uterine bleeding Symptoms and DUB PID Adenomyosis Hypothyroidism signs Menorrhagia + + + + Discharge foul – + – – smelling P/V Dysmenorrhea +/– + ++ – Dyspareunia – + ++ – Dyschezia – – ++ –

On Examination Perspeculum DUB PID Adenomyosis Hypothyroid Vagina Normal Discharge Red, blue, brown deposits of endometriosis may be present Normal Cervix Normal Discharge seen do Normal Pervaginum Cervix Normal Tender + Tender + Normal Uterus- Normal Normal Normal Normal Size, shape Mobility Mobile Restricted mobility Restricted if associated Normal if chronic PID with endometriosis Tenderness Nontender Tenderness + Tenderness + Normal Fornix Free One or both fornices Adnexal tenderness and Normal may be thickened, thickening is seen if associated tender or tender adnexal with endometriosis masses may be present

Q.11. What is definition of dysfunctional uterine metrium even on day 5-6 of menstruation. bleeding? What are the different types of Treatment is NSAIDs up to 6 months. It is a endometrial histology obtained in patients of self-limiting process. DUB? b. Irregular ripening: In this condition, the endo- Ans: Dysfunctional uterine bleeding is defined as metrium receives inadequate support of abnormal uterine bleeding that occurs in the progesterone due to deficient corpus luteal absence of systemic or organic pathology of the function and so breakthrough bleeding occurs genital tract. DUB is classified into Anovulatory before the actual menstruation in the form of and ovulatory bleeding. spotting or brownish discharge. The endo- Ovulatory DUB: The endometrial histology metrium reveals incomplete secretory changes. reveals various types of secretory endometrium. Treatment is to administer progesterone in the a. Irregular shedding of endometrium (Halban’s premenstrual phase. disease): It is due persistent corpus luteum. The Anovulatory DUB: The endometrial histology menstruation comes on time, but is prolonged could be of the following types, the percentage of and not heavy. Histopathology reveals mixed patients with abnormal histology in DUB is as picture of secretory and proliferative endo- shown in Table 22.2 Abnormal Uterine Bleeding 291 a. Proliferative endometrium b. Simple hyperplasia without atypia c. Complex hyperplasia without atypia d. Simple hyperplasia with atypia e. Complex hyperplasia with atypia.

Table 22.2: Endometrial histology in DUB7 Type of endometrial histology Percentage (%) 1 Normal endometrium 50% 2 Endometrial hyperplasia 31.7% 3 Irregular shedding 6.9% 4 Irregular ripening 3.6% 5 Atrophic endometrium 3.6% 6 Chronic endometritis 1.4%

• Simple hyperplasias have endometrial glands with predominately simple (tubular or cystic) shapes, lack gland crowding, and have a low gland-to-stroma ratio.8 • Complex hyperplasias show gland crowding Fig. 22.1: Assessment of menstrual blood loss using a pictorial chart, British Journal of Obstetrics and Gynaecology, with an increased ratio of glands relative to the 97, 734-39. Source-Higham et al, (1990). stroma. Complex glands have irregular shapes with branching and infoldings.8 Table 22.3: Nonlaboratory menstrual blood assessment methods • Cytologic atypia is defined when epithelial cells or nuclei lose their normally polarized Methods Points Degree of staining columnar shape (i.e. loss of polarity), and when Towels 1 Lightly stained nuclear enlargement or variation in size and 5 Moderately soiled towel shape are present or abnormal nuclear staining 20 Completely saturated with blood quality with chromatin clumping or clearing.8 Tampon 1 Lightly stained 5 Moderately soiled towel Q.12. What is a pictorial blood assessment 20 Completely saturated with blood Clots 1 Small clot chart? List other method of evaluation of 5 Large clot amount of blood loss? Ans: Pictorial blood assessment chart (PBAC) scored. Although the validity of this chart has been (Fig. 22.1 and Table 22.3) is a simple nonlaboratory debated as it is very subjective, it is simple to use method for semiobjective diagnosis of menorrhagia, and is at present the best practical tool available using scores recorded by women themselves. It was for the assessment of menstrual blood loss. The first described by Higham et al. The scoring was method has been reported to have a sensitivity of based on the number of sanitary towels and tampons 86% and a specificity of 89%.9 used each day and their degree of soiling. A score The alkaline hematin method is highly precise of 100 was used to define menorrhagia in its method of measuring blood loss. However, it is originally described form. The number and size of cumbersome and an impractical method in routine any clots passed were also taken into account and practice. 292 Case Discussions in Obstetrics and Gynecology

Other tests used to quantify menorrhagia are Endometrial biopsy should also be done if on hemoglobin, serum iron and serum ferritin. ultrasonography endometrial morphology is Measuring menstrual blood loss either directly abnormal or increased endometrial thickness on (alkaline hematin) or indirectly (‘pictorial blood ultrasound (ET > 12 mm)11 in premenopausal loss assessment chart’) is not routinely recom- women. mended for HMB. Whether menstrual blood loss is a problem, it should be determined not by Q.15. List different methods of endometrial measuring blood loss but by the woman herself.9 sampling? Ans: Q.13. What are the causes of menorrhagia in 1. Dilatation and curettage was used earlier for patients using intrauterine copper T device as a evaluation of endometrium, the disadvantages contraceptive? are that it requires dilatation and secondly, that Ans: The exact cause of increased blood loss is it is a blind procedure which may miss focal not known; the postulated mechanisms are:10 lesion. In a study by Leather et al 60% of • Increased production of plasminogen activating patients were found to have less than half of enzymes leading to lysis of fibrin of blood clot. uterine cavity curetted and less than quarter in another in 16%.12 In another study, D and C • Increased vascularity of the endometrium. failed to detect 62.5% of intrauterine disorders • Hormonal asynchronization, because menstrua- subsequently found at hysterectomy.13 tion is advanced by about 2 days before the end 2. Office endometrial aspiration biopsy is also of the luteal phase when the level of proges- a blind sampling technique like D and C. But it terone still remains relatively high. The bleeding is less painful as it does not require dilatation is more related to surface contact and as such is and chances of perforation are also very less. greater with the lippes loop than copper T. Endometrial aspiration showed a sensitivity of 89.6% and specificity of 100% in diagnosis of Q.14. What are the indications of endometrial abnormal uterine bleeding.14 Endometrial sampling in AUB? sampling can be done by Karman cannula, Ans: The recommendations for endometrial biopsy Pipelle device and Vabra aspirator. are: 3. Hysteroscopic directed biopsy is the gold 1. All women with AUB > 45 years of age as standard for evaluation of endometrial patho- incidence of endometrial cancer increases with logy because it allows for direct visualization age (Table 22.4). of endometrium and taking targeted biopsies. 2. Women who do not respond to medical therapy. Hysteroscopy has shown to have a high 3. Persistent intermenstrual bleeding. sensitivity of 90-97% and specificity of 4. Those who have other risk factors for endo- 62-97%.15 Office hysteroscopy is not used as metrial cancer. routine screening method for evaluation of 5. Even in adolescents after 2 to 3 years of menorrhagia because it is invasive, expensive, anovulatory bleeding, particularly in obese girls. requires specialized training to perform and

Table 22.4: Likely rates of endometrial cancer per 10,000 consultations for HMB in primary care9

Age range (years) 30 35 40 45 50 55 60 65 70 % risk of endometrial cancer 0.01 0.03 0.06 0.13 0.25 0.45 0.76 1.14 1.52 Abnormal Uterine Bleeding 293

interpret. Its main role has been to verify the 2. Tranexamic acid reduces menstrual loss by intrauterine status visually and take a directed inhibiting the action of plasminogen activators, biopsy when less invasive measures such as which activate lysis of blood clots. If given in a endometrial blind biopsy, sonography are in dose of 1 gm three to four times per day during conclusive. menstruation it reduces blood loss by 50%. Hormonal therapy Q.16. List the investigations done under special 1. Progesterone – progestins halt endometrium circumstances? growth and allow for an organized sloughing Ans: Laboratory tests (NICE guideline)9 of the endometrium. They increase the PGF-2/ =• Testing for coagulation disorders (for example, PGE ratio stimulating arachidonic acid von Willebrand disease) should be considered formation in the endometrium.1 in women who have had HMB since menarche • Cyclic progesterone therapy – are typically and have personal or family history suggestive efficacious for anovulatory bleeding in of a coagulation disorder. pubertal and perimenopausal women as the • Thyroid testing should only be carried out when goal of treatment for is to restore the natural other signs and symptoms of thyroid disease cycle of orderly endometrial growth and are present. shedding. Medroxyprogesterone acetate 5 to10 mg daily for 2 weeks every month for Q.17. What is the role of dilatation and curettage 3-4 cycles is sufficient for anovulatory 11 in management of patient of menorrhagia? cycle. Cyclic progesterone for 21 days starting from day 5 to 26 every month for Ans: Dilatation and curettage was traditionally used 3-6 cycles is advocated for endometrial earlier for both diagnosis and as a therapeutics hyperplasia. procedure. It has been replaced by less traumatic, • Continuous progesterone can also be given less painful and equally efficacious, outpatient in those patients who cannot tolerate heavy procedure of endometrial aspiration biopsy in withdrawal bleeding and are anemic.18 which dilatation is not required as the cannula is Ovulatory DUB does not respond to luteal only of 4 mm hence less painful. The therapeutic phase progesterone, hence treatment with effect of dilatation and curettage is limited to the progesterone (norethisterone or medroxy- current menstrual cycle, therefore, its use is justified progesterone) for 21 days is effective.1 only in patient with heavy bleeding not responding • Intrauterine progesterone – the levonor- to medical management, or patients presenting with gestrel IUD (Mirena) contains 52 mg of shock due to heavy bleeding.16 levonorgestrel, which is released at daily dose of 20 μg over 5 years. The daily dose Q.18. What is the medical management of DUB? of progesterone causes decidualization of Ans: The medical management consists of: the endometrium stroma and atrophy of the Nonhormonal methods are the first line drugs: endometrium glands. The LNG-IUS is 1. NSAIDs reduce menstrual blood loss by effective in both ovulatory and anovulatory 20-50% as they inhibit cyclo-oxygenase thus bleeding. It has been demonstrated to reduce reducing prostaglandin levels (increased levels menstrual blood loss by 94% after 3 months found in patients with menorrhagia). and is well tolerated by majority of women. Mefenamic acid is prescribed in a dose of • Depot medroxyprogesterone(depoprovera) 500 mg three times per day during the menstrual 150 mg every 3 month is also given in cycle.17 anovulatory DUB. The progestin causes 294 Case Discussions in Obstetrics and Gynecology

endometrial thinning to atrophic levels, the estrogen stimulated endometrial which causes amenorrhea with intermittent growth.11 spotting hence is not a very popular therapy. 4. Gonadotropin Releasing Hormones Agonist 2. Combined estrogen and progesterone: Oral (GnRHa): Gonadotropin releasing hormones contraceptives are among the best treatment agonist-like goserein acetate, leuprolide acetate options in women who present with episodes can achieve short-term relief of bleeding and of heavy bleeding. They are also effective in are often used prior to surgical treatment such ovulatory DUB. To stop or slow a heavy period, as ablation, myomectomy, and hysterectomy. a “ taper” can be performed with any of the When administered continuously, GnRH ago- low-dose monophasic pill. The treatment begins nists reversibly suppress pituitary secretion of with 3-4 tablets per day till bleeding stops, and gonadotropins and create a hypoestrogenic then gradual tapering to 2 tablets per day for state.1 The amenorrhea thus achieved by use of the next three days, and then one pill per day GnRHa provides relief of bleeding, which allow until pack is finished and withdrawal bleeding the hemoglobin to rise and decrease the risk of begins. The patient can be started on one tablet transfusion in subsequent surgery. The role of per day of OCP for next 3-4 cycles or can be GnRHa in DUB is limited because of the high started on cyclic progestin therapy if estrogens cost, effect on bone density, and other side are contraindicated.11 effects from the estrogen deficiency (e.g. hot 3. Estrogen: High dose estrogen therapy is useful flushes and night sweat), as long-term use (more in controlling acute bleeding episodes as than 6 months) is generally not recommended. because it promotes rapid endometrial growth to cover denuded endometrial surfaces. Q.19. What are the surgical management Estrogen is usually used in the intravenous or options in of DUB? oral form for acute heavy bleeding. It is very Ans: The options are endometrial ablation, effective method but not used commonly at endometrial resection and hysterectomy. present but could be given if one method fails to control acute heavy bleeding. Endometrial ablation • Intravenous estrogen (25 mg conjugated Endometrial ablation is an option in women in equine estrogens every 4 hours for 24 hours whom medical management has failed, who not or until bleeding diminishes significantly) desirious of future fertility, who wish to avoid a is the usual regimen and has been shown to hysterectomy and who are not candidates for major be successful in most of the cases. surgery. Endometrial resection involves destruction • Oral estrogen – when bleeding is heavy and of the entire endometrial thickness with superficial does not require inpatient treatment, high myometrium while leaving the rest of uterus intact. doses oral estrogen can be used as an Exclusion criteria1 alternative (1.25 mg conjugated estrogen or • Uterine size >12 weeks 2.0 mg micronized estradiol every 4-6 hours • Premalignant or malignant lesion of the cervix for 24 hours), the dose is then taperd down and endometrium to one dose per day for 7 to 10 days after • Acute pelvic inflammatory lesion the bleeding is controlled. • Bleeding disorder All of these initial estrogen treatments • Submucous and intramural fibroids should be followed by progestin treatment • Septate uterus or combi-nation contraceptives to stabilize • Previous failed endometrial ablation procedure Abnormal Uterine Bleeding 295

• Incidental pregnancy Table 22.5: Endometrial ablation techniques • Desire for future fertility First generation Second generation techniques • History of gynecological malignancy within the techniques (Global endometrial ablation) last 5 years. • Hysteroscopic laser • Fluid balloon: cavaterm, Pretreatment with an agent such as GnRHa, ablation (HLA) thermachoice, menotreat medroxyprogesterone acetate, or danazol is • Transcervical resec- • Microwave: MEA essential to make the endometrium thin for better tion of endometrium results. (TCRE) Endometrial Ablation Techniques (Table 22.5) • Rollerball • Cryotherapy: Cryogen, Her- The first generation procedures (endometrial endometrial ablation choice resection and roller ball or laser ablation) are • Electrode-Mesh: Vesta performed through a hysteroscope after uterine Balloon: Novasure infusion of a distention media to improve visuali- • Interstitial laser: ELITT zation. They are more time consuming, require • Photodynamic therapy regional or general anesthesia, and are technically • Hydrothermal ablation more difficult than the second gene-ration methods. The second generation methods are performed Major risks “blind” (without hysteroscope), usually in the • Injury to the bladder and/or the ureter (seven outpatient setting under local anesthesia, require women in every 1000) and/or long-term less operative time and minimum cervical disturbance to the bladder function (un- dilatation. These methods include cryoablation, common). thermal balloon ablation, radiofrequency ablation, • Injury to the bowel: Four women in every microwave, and diode laser thermotherapy. 10,000 (rare). However there is no difference in patient outcome, • Hemorrhage requiring blood transfusion, 23 rate of amenorrhea and patient satisfaction rate with women in every 1,000 (common). any method. • Return to theater because of bleeding/wound dehiscence, and so on – seven women in every Q.20. When should hysterectomy be done in 1,000 (uncommon). patient of DUB.? • Pelvic abscess/infection: Two women in every Ans: Hysterectomy should not be used as a first- 1,000 (uncommon). line treatment solely for HMB. Hysterectomy • Venous thrombosis or pulmonary embolism, should be considered only when:9 four women in every 1,000 (uncommon). • Other treatment options have failed, are • Risk of death within 6 weeks, 32 women in contraindicated or are declined by the woman every 100,000 (rare). The main causes of death • The woman no longer wishes to retain her uterus are pulmonary embolism and cardiac disease. and fertility. Frequent risks • Wound infection, pain, bruising, delayed wound Q.21. How would you counsel a woman wanting healing or keloid formation. a hysterectomy? • Numbness, tingling or burning sensation around Ans: Counseling will include explaining the major, the scar (the woman should be reassured that minor risks and extra procedures that might be this is usually self-limiting but warned that it required during surgery.19 could take weeks or months to resolve). 296 Case Discussions in Obstetrics and Gynecology

• Frequency of micturition and urinary tract • Mobility and descent of the uterus infection. • Laxity of the vagina • Ovarian failure. • Previous surgery Any extra procedures which may become nece- • Expertise of the operating surgeon. ssary during the procedure • Blood transfusion. CASE 3 • Repair to bladder, bowel or major blood vessel. History • Oophorectomy for unsuspected disease. A 42 year-old P3L3 presented to the gyne OPD Oophorectomy for unexpected disease found at with complaints of the menorrhagia with severe hysterectomy should not be performed without dysmenorrhea, dyspareunia with increased consent. All women undergoing hysterectomy should be informed that unexpected disease may frequency of urine for 2 years. There is no family be found in one or both ovaries and their wishes or personal history of any cancer. (to remove this or leave alone) should be Examination documented. • Obesity + • Pallor + Q.22. What are types of hysterectomy done in • No Lymph nodes, thyroid and breast normal patients of DUB refractory to medical manage- • Per abdomen – uterus is just palpable ment? • Per speculum examination – cervix and vagina Ans: Three types of are performed healthy. based on the route of removal of the uterus9 • Per vaginum examination – uterus is 12 weeks, 1. Abdominal hysterectomy (AH) midposition, firm, restricted mobility, both 2. Vaginal hysterectomy (VH) fornices free and nontender. 3. Laparoscopic hysterectomy (LH) LH has three subdivisions: Q.23. What is the differential diagnosis in this a. Laparoscopically assisted vaginal hyste- patient? rectomy (LAVH), where a vaginal hysterec- Ans: tomy is assisted by laparoscopic procedures 1. Uterine fibroid (discussed in a separate chapter) that do not include uterine artery ligation. 2. Adenomyosis b. Laparoscopic hysterectomy [LH(a)], where 3. Uterine malignancy (endometrial cancer, the laparoscopic procedures include uterine sarcomas) (see chapter on post-menopausal artery ligation. bleeding). c. Total laparoscopic hysterectomy (TLH), where there is no vaginal component and Q.24. What is adenomyosis? the vaginal vault is sutured laparoscopically. Individual assessment is essential when Ans: Adenomyosis is a condition whereby endo- deciding the route of hysterectomy. The following metrial glands and stroma deep in the myometrium factors need to be taken into account: are associated with surrounding myometrial • Presence of other gynecological conditions or hypertrophy. It is thought to affect 1% of women. disease The average age of symptomatic women is usually • Uterine size older than 40 years, but it can be present in younger • Presence and size of uterine fibroids women.20 Abnormal Uterine Bleeding 297

Q.25. How does it present? However, there are no pathognomonic sono- Ans: Adenomyosis is often asymptomatic. graphic characteristics that correlate completely The common symptoms associated with with the histology, hence tissue diagnosis is essential. adenomyosis are:20 • Menorrhagia (23-82%) Q.27. What is the role of conservative manage- • Dysmenorrhea (up to 50%) ment in adenomyosis? • Dyspareunia and chronic, erratic or constant Ans: The definitive treatment is hysterectomy. pelvic pain (less commonly reported) However, there are some reports suggesting that • Pressure symptoms on bladder and bowel from conservative options may be effective. Like bulky uterus (uncommon). endometriosis and uterine myomas, adenomyosis Signs presents the typical characteristics of estrogen- • The uterus is diffusely enlarged (usually less dependent diseases. The medical treatment of than 14 weeks size), and it is soft and tender, adenomyosis is based on the hormonal dependency particularly at the time of menses.21 of the disease and its similarities with endo- • Mobility of uterus is not restricted, if there is metriosis. that targets the ectopic endometrium no associated adnexal pathology. However, it directly. Gonadotropin-releasing hormone agonists, commonly coexists with a number of other danazol and intrauterine levonorgestrel, or danazol- pelvic pathologies like endometriosis and releasing devices have been used in the treatment of adenomyosis. There are reports suggesting that fibroid which can cause restricted mobility. medicated intrauterine device, uterine artery artery embolization and MRI guided focused ultrasound Q.26. What are the ultrasound feature of adeno- urgery may be effective.23,24 Despite the evidence myosis? What is the sensitivity and specificity of benefit with hormonal treatment, few studies of ultrasound for diagnosing adenomyosis? have been performed on medical therapy for Ans: Ultrasound features of adenomyosis include:22 adenomyosis. • Rainy pattern of acoustic shadowing, normal vessels, enlarged uterus. CASE 4 • Myometrial cysts characterized by cystic spaces History ranging from 2-7 mm in diameter located within A 48-year-old multiparous lady with history of the myometrium (52% of uteri). Presence of irre-gular and heavy bleeding: 12 months. myometrial cysts for diagnosing adenomyosis Examination has a sensitivity of 45%, a specificity of 100%, • Per speculum – cervix and vagina healthy a positive predictive value of 100%, and a • Per vaginum – uterus 8 weeks, firm, smooth, negative predictive value of 82%. mobile, nontender. • Some other diagnostic features are diffuse heterogeneous echo-texture of myometrium, Q.28. What are possible differential diagnosis asymmetric thickening of either the anterior in this patient? or posterior wall of the uterus, subendo- Ans: The possible differential diagnosis are: metrial myometrial cysts which cause the 1. Perimenopausal DUB endometrial - myometrial junction to be poorly 2. Fibroid polyp defined. 3. Endometrial carcinoma 298 Case Discussions in Obstetrics and Gynecology

The above conditions have been discussed in • History of bowel or bladder complaints. various sections. • History of hormonal drug intake. • History of onset of symptom following D & C CASE 5 (retained POCs or endometritis can cause History irregular bleeding). • A 36 year-old P2 • Personal and family history of any cancers. • Irregular uterine bleeding not associated with period of amenorrhea. Q.30. What is the differential diagnosis? How will you differentiate between two? Examination • Abdominal examination – normal. Ans: • Per speculam – 4 × 4 cm polyp coming out of A. Uterine fibroid polyp. cervix, surface inflamed but smooth, vagina B. Chronic uterine inversion (Table 22.6) healthy. • Per-vaginum- cervical rim felt all around the Q.31. How will you do a polypectomy in this polyp, seems to be originating from the uterine case? cavity, firm in consistency with a smooth Ans: Vaginal polypectomy will be planned with a surface. Uterus 8 weeks in size, mobile, ante- consent for hysterectomy in case of uncontrolled verted, firm, nontender, no adnexal mass. vaginal bleeding. Under anesthesia traction is given on the pedicle of the polyp to locate its origin. Q.29. What are the salient points to be taken in Clamps are then applied on the pedicle as high as the history? possible, the pedicle is cut distal to the clamp and Ans: transfixed. • Age – as the age advances, risk of endometrial If the pedicle is broad and cannot be reached, cancer increases. the myoma is initially removed by incising the • Parity – high parity is a risk factor for cervical psuedocapsule (enucleatation as done in an cancer and low parity is a risk factor for abdominal myomectomy) followed by transfixation endometrial cancer. suture on the pedicle and removal of the redundant • Menstrual complain like amount, duration, pedicle distal to the ligature. cycle length, period of amenorrhea prior to A polyp can harbor malignancy both in the heavy bleeding. • History of postcoital bleeding indicates cervical pedicle and in core of the tumor and should be sent pathology like polyps, fibroid, ectropian and for histopathology. cancer. • History of intermenstrual bleeding can be due Q.32. What are the different types of polyp and to endometrial polyp or submucous fibroid. management for each type? • History of pain abdomen, discharge per vagi- Ans: Polyps can be of different types: num, backache to rule out pelvic inflammatory 1. Endometrial polyp – these are single or disease. multiple and pedunculated, they are usually • History of intrauterine contraceptive device larger than 1 cm, arise from the endometrium insertion. and are soft in consistency. Abnormal Uterine Bleeding 299

Table 22.6: Differential diagnosis of fibroid polyp and chronic uterine inversion

Fibroid polyp Chronic uterine inversion History No relation to vaginal delivery Onset of symptom following vaginal delivery usually Per speculum Cervical rim is seen all around polyp Cervical rim is high up in incomplete uterine Surface is smooth version but not seen in complete uterine inversion Surface has shaggy appearance Per vaginum Uterus is in normal position Uterus is not felt or cup shaped depression is felt at fundus Per rectal examination – is more informative to note fundal depression or displacement of the uterus. Uterine sound test Uterine sound can be passed into Uterine sound can be passed only for short distance the uterine cavity in incomplete uterine inversion and cannot be passed at all in complete uterine inversion USG pelvis Associated fibroid can be diagnosed Absence of endometrial cavity is diagnostic

2. Fibroid polyp – is almost always due to 3. Polypectomy – vaginal approach for removing extrusion of a submucous fibroid into the uterine polyp lying in the vagina is discussed above. If cavity, the overlying surface is lined by the pedicle of polyp is thin which can be endometrium. The uterus contracts to expel the removed by simply twisting it after holding it polyp out through the cervix. There is usually with sponge holder. necrosis, infection and hemorrhage at the 4. Hysterectomy can be done under following surface. The pedicle is broad. There could be circumstances associated uterine fibroids. • If woman does not desire to preserve the 3. Placental polyp – a placental polyp is an uterus intrauterine, polypoid or pedunculated mass of • Coexistent uterine or adnexal pathology placental tissue retained after an incomplete • Recurrent symptomatic polyp abortion or term pregnancy. A retained bit of • High suspicion of malignancy. placental tissue when adherent to the uterine Q.33. What are the other potential structural wall gets organized with the surrounding blood cause of irregular uterine bleeding? clots. Ans: Management options for polyps • Endometrial hyperplasia 1. Dilatation and curettage – endometrial polyps • Endometrial carcinoma can be curetted out, however, the chances of • Uterine cancers recurrence are higher due to incomplete removal • Infections – endometritis, PID, tuberculosis as it is a blind procedure and can miss 60% of • Foreign objects (intrauterine device) due to focal lesions in the uterine cavity. chronic inflammatory response 2. Operative hysteroscopy – hysteroscopic • Vascular (arteriovenous malformations). removal of endometrial polyp, fibroid polyp (intrauterine) and placental polyp has a higher Q.34. What is the treatment for chronic endo- success rate, as it is visually directed procedure. metritis causing irregular uterine bleeding? 300 Case Discussions in Obstetrics and Gynecology

Flow Chart 22.1: Management of a woman > 20 years with AUB

Ans: Endometritis may be caused by several REFERENCES processes, including infections, intrauterine foreign 1. H Hatasaka. The evaluation of abnormal uterine bodies or growths, and radiation therapy; however, bleeding. Clin obstet Gynecol 2005;48(2). a significant number of patients have no obvious 2. Albers JR, Hull SK, Wesley RM. Abnormal uterine cause. Inflammatory cells in this condition produce bleeding. Am Fam Physician 2004;69(8):1915-26. proteolytic enzymes that delay normal healing and 3. Management of anovulatory bleeding. 2007 Com- damage the endometrium, which makes it fragile pendium of Selected Publication, Volume II Practice and prone to erosions. The inflammatory cells also Bulletins. ACOG Practice Bulletin #14, March 2000. can release prostaglandins and platelet-activating 4. Speroff L, Glass R, Kase N. Dysfunctional uterine bleeding. Clinical gynecologic endocrinology and factors, which are potent vasodilators. Chronic infertility, 7th edn. Lippincott Williams and Wilkins, endometritis may be one of the causes of abnormal 2004; 549-71. bleeding in women with leiomyomas or polyps. The 5. American College of Obstetricians and Gynecologists. treatment consists of antibiotics, such as doxy- Von Willebrand Disease in women. Practise bulletin cycline, 100 mg, twice a day for 10-14 days. # 451, December 2009. Abnormal Uterine Bleeding 301

6. Frishman GN. Evaluation and Treatment of Menorr- 15. Farquahar L, Ekeroma A, Furness S, Arroll B. A hagia in an Adolescent population. J minimally systemic review of transvaginal ultrasonography, invasive gynecol 2008;15:682-88. sonohysterography and hysteroscopy for the investi- 7. P Heera. Common Menstrual Disorders. Postgraduate gation of abnormal uterine bleeding in premenopausal. Obstetrics and Gynaecology. 4th edn, Menon, Devi Acta Obstet Gynecol Scand 2003;82:493-503. and Bhasker Rao (Eds) 1989;310-31. 16. Goldrath MH. Office hysteroscopy and suction 8. Espindola D, Kennedy KA, Fischer EG. Management curettage: Can we eliminate the hospital diagnostic of Abnormal Uterine Bleeding and the Pathology of dilatation and curettage? Am J Obstet Gynecol Endometrial Hyperplasia. Obstet Gynecol Clin N Am 1985;150:220-29. 2007;34:717-37. 17. Lethaby A, Augood C, Duckitt K, et al. Nonsteroidal 9. National Institute for Clinical Excellence. Heavy anti-inflammatory drugs for . menstrual bleeding: Investigation and treatment. Cochrane Database Syst Rev 2008;1:CD000400. Clinical guideline CG44. London: NICE, 2007. 18. Kumar P, Malhotra N. Abnormal and excessive uterine 10. Chaudhuri SK. Practice of fertility control. 7th edn, bleeding. Jeffcoate’s Principles of Gynecology, 7th Elsevier 2008 pg. 94. edn, Jaypee Brothers medical Publishers 2008;598-616. 11. Casablanca Y. Management of Dysfunctional Uterine 19. Royal College of Obstetricians and Gynaecologists Bleeding. Obstet Gynecol Clin N Am 2008;35:219- Consent Advice No. 4 May 2009. 34. 20. Peric H, Fraser IS. The symptomatology of adeno- 12. Leather AT, Savvas M, Studd WW. Endometrial myosis. Best practice and Research Clin Obst and histology and bleeding patterns after 8 years of gynecol 2006;20(4):547-55. continuous combined estrogen and progesterone 21. Berek JS. Pelvic pain and dysmenorrhea, Novak’s therapy in postmenopausal women. Obstet Gynecol gynecology, 13th edn, 520. 1991;78:1008-10. 22. Zalud I, Busse R. Gynecological ultrasound: A primer 13. Bettocchi S, Ceci O, Vicino M, Marello F, Impedova for clinicians. In Progress in Obstetrics and Gyne- L, Selvaggi L. Diagnostic inadequacy of dilatation and cological 2008;18:313-28. curettage. Fertil Steril 2001;75:803-05. 23. Bratby MJ, Walker WJ. Uterine artery embolisation 14. Tansathit T, Chichareon S, Tocharoenvanich S, for symptomatic adenomyosis—mid-term results. Eur Dechsukhum C. Diagnostic evaluation of Karman J Radiol 2009;70(1):128-32. endometrial aspiration in patients with abnormal 24. AI Hilli MM, Stewart EA. Magnetic resonance guided uterine bleeding. J Obstet Gynecol Res 2005; 31(5): focused ultrasound surgery. Semin Reprod Med 480-85. 2010;28(3):242-49. Vijay Zutshi, Binni Makkar Approach to a Case of 23 Adnexal Mass in a Young Patient

INTRODUCTION Y chromosome have a 25% chance of deve- loping a malignant neoplasm. Endometriosis is Adnexal masses present a diagnostic dilemma; the uncommon in adolescent women but may be differential diagnosis is extensive, with most masses present in as many as 50% of those who present representing benign processes. However, without with a painful mass.1 In sexually active histopathologic tissue diagnosis, a definitive adolescents, one must always consider a tubo- diagnosis is generally precluded. Physicians must ovarian abscess as the cause of an adnexal mass. evaluate the likelihood of a pathologic process • In women of reproductive age who have had using clinical and radiologic information and adnexal masses removed surgically, most are balance the risk of surgical intervention for a benign benign cysts or masses. Ten percent of masses versus malignant process. are malignant, many tumors in patients younger The term adnexa is derived from the pleural than 30 years are of low malignant potential. form of the Latin word meaning “appendage.” The Thirty-three percent are adult cystic teratomas, adnexa of the uterus include the ovaries, fallopian and 25% are endometriomas.2 The rest are tubes, and structures of the broad ligament. Most serous or mucinous cystadenomas or functional frequently, adnexal masses refer to ovarian masses cysts. or cysts; however, paratubal cysts, hydrosalpinx, and other non-ovarian masses are also included CASE 1 within the broader definition of adnexal masses. A 25-year-old lady, Mrs A presented with pain Frequency lower abdomen since 2 months. On examination a 5 × 5 cm firm to cystic mass, slightly tender Determining the true frequency of adnexal masses with restricted side to side mobility is felt in the is impossible because most adnexal cysts develop left adnexa. and resolve without clinical detection. When assessing the clinical significance of an adnexal To arrive at a diagnosis, following history should mass, considering several age groups is important. be taken • In girls younger than 9 years, 80% of ovarian 1. Amenorrhea masses are malignant and are generally 2. Chronic pelvic pain germ cell tumors. During adolescence, 50% 3. Infertility of adnexal neoplasms are adult cystic terato- 4. Dyspareunia mas. Women with gonads that contain a 5. Backache Approach to a Case of Adnexal Mass in a Young Patient 303

6. Discharge per vaginum by direct pressure on nodules and endometriosis 7. Urinary complaints embedded in fibrous tissue. 8. Bowel complaints 5. Dysmenorrhea 1. Amenorrhea Congestive dysmenorrhea seen in cases of PID, Important in cases of ectopic pregnancy and may endometriosis. In endometriosis, dysmenorrhea is be present in later stages of genital kochs usually progressive and is not relieved by NSAIDs/ oral contraceptive pills. 2. Chronic pelvic pain May be seen in cases of chronic pelvic inflam- 6. Urinary complaints matory disease (PID) due to hydrosalpinx. The pain • Dysuria may be seen in cases of PID due to can also be related to adhesions surrounding the associated urethritis. ovary and fallopian tube. • Urinary complaints like flank pain, urgency, Also seen in endometriosis due to secretion of frequency and hematuria may be seen in cases inflammatory substances such as prostaglandins, of involvement of by endo- metriotic implants. cytokines and growth factors that initiate the • Urinary difficulty may be seen in large ovarian sequences of events resulting in development of tumors due to compression. pain. The extravasated debris and blood from endometriotic implants may stimulate an 7. Bowel complaints inflammatory reaction in peritoneal Cavity with • Constipation is seen in cases of ovarian tumors production of the above mentioned substances.3 due to compression and or gut involvement. • Also, complaints like diarrhea, hematochezia, 3. Infertility dyschezia, tenesmus, etc. may be seen in cases • In chronic PID, it occurs due to peritubular and of bowel involvement by endometriotic im- periovarian adhesions which may interfere with plants.3 ovum pick up or due to complete obstruction of tube and disturbance of tubo-ovarian 8. Backache relationship. Seen in endometriosis due to involvement of • In endometriosis, possible mechanisms for rectovaginal septum or uterosacral region as there infertility include pelvic adhesions, chronic is premenstrual swelling of ectopic implants. salpingitis, altered tubal mobility, distorsion of 9. Mentrual irregularities tubo-ovarian relation and impaired oocyte pick • Menorrhagia may be seen in initial stages of up. Other mechanisms proposed include, altered genital tuberculosis.4 immune system response, implantation failure • Irregular uterine bleeding/spotting preceded by etc.3 amenorrhea in ectopic pregnancy. • It is also commonly seen in genital tuberculosis. • Metrorrhagia/menometrorrhagia in cases of Possible mechanisms include destruction of granulosa cell tumors. endometrium, tubal obstruction, peritubal 10. History of low grade fever with evening rise of adhesions, etc. temperature, night sweats, anorexia, weight loss, cough with sputum, hemoptysis to rule out 4. Dyspareunia tuberculosis. Seen in endometriosis due to stimulation of pain 11. History of prior medication/any procedure if she fibers by stretching of scarred, inelastic tissue or underwent in the past. 304 Case Discussions in Obstetrics and Gynecology

Menstrual history – An infected mass such as a tubo-ovarian • Bleeding duration, regularity, amount of blood abscess results in an increased WBC count loss (Clots+/-) with an associated left shift.5 • Associated dysmenorrhea – Adnexal masses rarely cause anemia, but • If present –(spasmodic/congestive) because they often require surgical removal, • History of relief in symptoms and if so, with this information should be known. which drug. • Chest X-ray, Mantoux test – these are done to • Any irregularity in menses rule out tuberculosis • Urine or serum beta human chorionic Obstetric history H/o surgical MTPs, if repeated gonadotropin (β-hCG) should be obtained in predisposes to PID women of reproductive age to rule out preg- Past history nancy and pregnancy-related etiologies of Any chronic medical/surgical illness adnexal masses. On examination • CA-125 is a marker that is elevated in approxi- General examination: mately 80% of women with epithelial ovarian • General condition cancer with sensitivities of 50% in women with • Vitals stage I disease and 90% in patients with • Pallor advanced disease.6 However, it can be elevated • Cervical/axillary lymphadenopathy in many other conditions, including gynecologic Per abdomen: etiologies such as endometriosis, uterine fib- • Description of mass if present, e.g. mass arising roids, pregnancy, and nongynecologic conditions from the lower abdomen, its consistency, such as gastroenteritis, pancreatitis, cirrhosis, surface, any vascularity over the surface, side and congestive heart failure. As such, the to side mobility, whether lower limit could be specificity of CA-125 is limited and is not reached or not, tenderness present/absent. recommended for routine screening purposes • Associated free fluid. in the general population. • Any other associated organomegaly • Other serum markers such as AFP and LDH Per speculum examination: can be helpful when a germ cell tumor is • Condition of cervix and vagina. Any associated suspected. discharge. • Urine analysis (U/A) results are generally Per vaginal examination (P/V): normal in the presence of an adnexal mass. • Size of uterus –Anteverted (A/V) retroverted – Bladder pathology may present with (R/V). If any mass felt –description of the mass, symptoms of an adnexal mass and may be its consistency, side to side mobility, tender/non discovered based on U/A results. tender, relationship with uterus, mobility – Appendicitis can present similar to an associated with cervical motion. adnexal mass but is often associated with Per rectal examination (P/R): WBCs in the U/A findings. • For confirmation of P/V findings • Results from testing stool for blood should be • To feel for any nodularity on uterosacrals. negative for adnexal masses but may be positive Laboratory studies in those women with colonic pathology. • A complete blood count (CBC) helps evaluate • Serum electrolytes should not be altered by an for presence of inflammation and anemia. adnexal mass; however, symptoms associated Approach to a Case of Adnexal Mass in a Young Patient 305

with masses, such as nausea and vomiting, can As with ultrasonography, CT scan can help cause alterations that must be known before identify the size, location, and relationship to anesthesia and surgery is considered. other organs. CT scan is less effective than • Measuring other hormone levels is generally of ultrasonography for determining the internal limited value in the evaluation of adnexal architecture of these masses. masses. Obtaining estrogen and progesterone • MRI scans can help characterize adnexal mass levels may be helpful in women suggested to characteristics in select cases when have functional tumors, such as germ cell ultrasonographic findings are limited. tumors, or if a girl younger than 12 years is being evaluated. In the above case of Mrs A, following differential Imaging studies diagnosis should be considered: • The most commonly performed test to evaluate 1. Ectopic pregnancy an adnexal mass is transabdominal or 2. Ovarian tumour (benign/malignant) transvaginal ultrasonography. 3. – This test helps to demonstrate the presence 4. Genital tuberculosis of the mass and organ of orign (e.g., ovarian, 5. Pelvic inflammatory disease (Tubo-ovarian uterine, bowel). It also provides the mass mass) size, consistency, and internal architecture. 6. Broad ligament/pedunculated fibroid Scoring systems, such as that suggested by 7. 7 DePriest and associates, can then be used 8. Folicular cysts to determine the likelihood of a malignant 9. Corpus luteum component. 10. Follicular cysts – Hysterosonography (ultrasonography with 11. Hydrosalpinx the presence of fluid in the uterine cavity) 12. Non-gynecological causes like appendicitis, may be used to help distinguish a uterine diverticular disease. mass. However, active tuberculosis is a contra indication. Management – Color Doppler ultrasonography can be used If the final diagnosis is ectopic pregnancy, the to evaluate the resistive index of the mass various options available are: vessels, which, when low, has been indi- 1. Expectant management, which may not be cative of a malignancy because of rapid possible in this patient in view of big tender 7 vascularization. mass. • Pelvic radiographs are generally not helpful in 2. Conservative (medical management) the evaluation of adnexal masses. A dermoid cyst generally contains areas of calcification that Q.1. What are the criteria for medical manage- may be picked up on a plain radiograph. ment? • CT scans are most useful for assessing the remainder of the abdomen and pelvis when Ans: metastatic disease is suspected. Incidental a. gestational sac <3.5 cm adnexal masses are sometimes found when CT b. βHCG <15000 mIU/ml is performed for evaluation of other conditions. c. hemodynamically stable8,9 306 Case Discussions in Obstetrics and Gynecology

This patient has mass 5 × 5 cm and beta hCG because salpingostomy may cause scarring and was 20,000 mIU/ml, so she was not a fit patient for subsequent narrowing of small isthmic lumen. medical management. Q.7. What are the risk factors for persistent Q.2. What are the criteria for the expectant ectopic pregnancy? management in ectopic pregnancy? Ans: Ans: 1. Small pregnancies viz. less than 2 cm a. Gestational sac <2 cm 2. Early therapy viz. before 42 days β b. βHCG < 1000 U/ml 3. -hCG levels>3000 u/ml c. Hemodynamically stable patient 4. Implantation medial to the salpingostomy site

Q.3. What are the various options in medical CASE 2 management of ectopic pregnancy? A 32-year-old Mrs B, P3 with history of pain in Ans: lower abdomen. On examination mass about 4 × a. Single dose methotrexate in the dose of 50 mg/ 4 cm felt in left fornix, nodularity on uterosacrals. sq.m IM, measure β-hCG on day 4 and 7 βββ-hCG negative,USG (right ovary normal, left If difference >15 percent, repeat weekly until ovary 4.3 × 3.8 cm cystic lesion with internal undetectable echoes). CA-125 78 mIU/ml. Provisional diagnosis If difference <15 percent repeat methotrexate of ovarian endometrioma. and begin as new day 1 b. Variable dose regime: Methotrexate 1 mg/kg Q.8. What are the various options in medical IM days 1,3,5,7 therapy? Leukovorin 0.1 mg/kg IM days 2,4,6,810-12 Ans: Measure weekly β-hCG till undetectable. 1. High dose estrogen/progesterone combination: act by causing decidualization followed by Q.4. What are the common side effects of involution and necrosis. However, this regime methotrexate therapy? has side effects like mastalgia, weight gain, Ans: Liver involvement (12%), stomatitis (6%) and nausea, headache, irregular bleeding. 2. Progesterogen only regimens: Because of the gastroenteritis (1%).13 Rarely bone marrow side effect of the above mentioned regimen depression may be seen. these have become more popular. These act by inhibiting LH release and thereby suppressing Q.5. What are the various surgical management ovarian steroidogenesis and promoting deci- procedures? dualization of the endometrium. Ans: Options—salpingectomy (laproscopic or on 3. GnRH analoges: Act by down regulation of laprotomy) pituitary ovarian axis leading to fall in the • Salpingotomy estrogen levels. • Salpingostomy 4. Danazol: It is a 17 α-ethinyl testosterone. It acts by inhibiting GnRH secretion, thereby inhibi- Q.6. In which cases segmental resection and ting ovarian steroidogenesis. Also, it displaces anastamosis is done? the androgens from sex binding globulin and Ans: Resection of tubal mass and reanastomosis is increases the clearance of estradiol. Dose: 400- sometimes used for unruptured isthmic pregnancy 800 mg/day for 6 months. Approach to a Case of Adnexal Mass in a Young Patient 307

Q.9. What is add back therapy? Q.13. What is the role of assisted reproductive Ans: Estrogen replacement “add back therapy” is techniques in patients with associated infertility? given to reduce unwanted side effects of hypo- Ans: It is indicated when spontaneous conception estrogenism in cases of long-term GnRH agonist is not achieved within 3 years of surgical resection regimens, without reducing the efficacy of or within one year of repair of tubal obstruction treatment. The rationale for this approach is associated with endometriosis or when there is 15 “estrogen threshold hypothesis” which states that associated male factor infertility. certain threshold level of estrogen is low enough CASE 3 to suppress endometriosis but is enough to relieve symptoms and minimize bone loss. The various A 24 years P 1, with secondary infertility and back combination “add back therapy” used are – ache. On examination 6 × 6 cm mass variegated conjugated equine estrogens 0.3 mg, 0.625 mg + feel in right fornix.Ultrasonography showed 7 cm medroxy progesterone acetate 2.5 mg daily. complex mass in right adnexa. CA-125 was Estradiol patches 25 pgm/day and 50 pgm/ 50 mIU/ml, ESR raised, tuberculin test positive, X-ray chest negative. Endometrial biopsy showed day.Norethisterone acetate 5-10 mg/day also has few granulomas, but no acid-fast bacilli. some beneficial effect on menopausal therapy. With all this background diagnosis of genital Q.10. What are the side effects of danazol tuberculosis was made. therapy? Q. 14. How do you manage genital tuberculosis? Ans: These include acne, hirsutism, dyslipidemia, The mainstay of treatment is medical though vasomotor symptoms, weight gain, muscle cramps, surgery may be required in some cases Treatment etc. is given under category I under DOTS strategy. The principle is to give four drugs (H, R, Z, E) for initial Q.11. What are the other options in the manage- 2 months followed by 2 drugs for remaining 4 ment of endometriosis?13 months (H,R) in the continuation phase.16 DOTS is the strategy to ensure cure by providing the most Ans: Conservative surgery may be done which effective medicine and confirming that it is taken. include a. Incision and drainage of the cyst contents Recommended adult dosages of anti-tubercular followed by fulguration of the cyst lining in case drugs: of small cysts (< 3 cm). Drug Daily dosages b. Cyst excision (laparoscopic/laparotomy): if cyst Isoniazid 5-10 mg/kg size > 3 cm. Rifampicin 10 mg/kg Pyrizinamide 20-40 mg/kg Q.12. What is the role of postoperative medical Ethambutol 15-25 mg/kg Streptomycin 15 mg/kg treatment? Ans: Initiation of this therapy may inhibit the Q.15. What are the various side effects of anti- activity of any residual disease, suppress ovulation tubercular drugs? and decrease the activity of adverse effects of Ans: peritoneal spillage during resection. However, it is 1. Isoniazid—Hepatitis, rash, peripheral neuro- to be avoided in patients who are trying to conceive pathy, neurological disturbances. as best chance for postsurgical conception is during 2. Rifampicin—Gastrointestinal side effects, rash, the initial 6 months.14 hepatotoxicity, thrombocytopenia. 308 Case Discussions in Obstetrics and Gynecology

3. Pyrizinamide—Hepatitis, rash, hyperuricemia, Q.19. What are the various oral regimens arthralgia, gout available? 4. Ethambutol—Retrobulbar neuritis Ans: Regimen A 16 5. Streptomycin—Ototoxicity, nephrotoxicity Ofloxacin 400 mg orally once a day daily for 14 days Q.16. Treatment options in cases of tuberculosis Or resistant to first line therapy? Levofloxacin 500 mg orally once daily for 14 days Ans: These patients are treated with second line With or without drugs including kanamycin, amikacin, capreo- Metronidazole 500 mg orally twice a day for 14 mycin, ethionamide, cycloserine, paraaminosali- days.18 cylic acid, ofloxacin, clofazimine, thiocetazone. These have lower efficacy and higher toxicity. Regimen B Ceftriaxone 250 mg I/M in a single dose or cefoxitin Q.17. What is the role of surgical treatment in 2 gm IM in a single dose and probenecid, 1g orally. such cases? Plus Ans: Indications of surgery are as follows:17 Doxycycline 100 mg twice a day for 14 days 1. Progression or persistence of active disease in With or without spite of adequate medical therapy. Metronidazole 500 mg orally twice a day for 14 2. Presence of large inflammatory masses, pyo- days18 salpinx, ovarian abscess. 3. Recurrence after 6 months of chemotherapy. Q.20. What are the indications of hospitalization in PID? Contraindications Ans: 1. Active disease elsewhere in the body. 1. Severe illness, high grade fever with nausea, 2. Presence of dense adhesions around pelvic vomiting organs. 2. Tubo-ovarian abscess CASE 4 3. Lack of response to oral therapy 4. Adolescents A 28-year-P 2 with severe pelvic pain for two days. 5. Intolerance to oral therapy On examination 8 × 8 cm tender cystic mass felt 6. Diagnosis is unclear and surgical emergency in right fornix. TLC 20,000, temperature 101 cannot be excluded. degree F, hCG negative, CA-125, 67 mIu/ml, USG: 8 cm complex mass with free fluid. Q.21. Indications for parenteral therapy Provisional diagnosis of PID with tubo-ovarian Ans: It is indicated in patients who are intolerant abscess made. or non responsive to oral therapy or in severe cases Various options are as follows: Q. 18. How do you manage pelvic inflammatory Parenteral regimen A disease? Cefototan 2gm IV 12 hourly Treatment options Or 1. Oral antibiotics Cefoxitin 2 gm IV 6 hourly 2. Parental antibiotics Plus 3. Surgical treatment Doxycycline 100 mg orally or IV 12 hourly Approach to a Case of Adnexal Mass in a Young Patient 309

Parenteral regimen B Ans: Expectant management if Clindamycin 900 mg IV 8 hourly • Mass is cystic Plus • Size is less than 6 cm Gentamycin loading dose IV or IM(2 mg/kg) • There is no doubt of malignancy on clinical followed by a maintenance dose (1.5 mg/kg) 8 findings and investigations. hourly. • Ultrasound is to be repeated in such cases after Patient is switched over to oral therapy after 24 6 weeks/suppression with birth control pills can hours of clinical improvement.18 be done • If mass >6 cm or is a complex/solid mass, Q.22. What is the role of surgical intervention? surgical removal is preferred. Ans: It is required in severe cases or in cases of pelvic abscess or tubo-ovarian abscess. Dramatic Q.25. Which is the most common tumor in the improvement is seen in patient’s condition after the reproductive age group women? drainage of pus. It is also indicated in patients who Ans: Dermoid cysts. It constitutes 25% of all are not responding to treatment. ovarian neoplasms. Mostly these are aymptomatic (i.e. in about 50% of the cases). About 15% of CASE 5 dermoid cysts are bilateral. Malignant change is A 35-year-old female P 2 with mild menorrhagia, seen in 1-2% of such cases. Treatment of choice is off and on pain lower abdomen was detected to ovarian cystectomy or oophorectomy. have left adnexal mass 6 × 6 cm on examination. hCG negative, CA-125: 25 mIU/ml, USG: bulky Q.26. What are the complications of benign uterus with subserous fibroid 8 × 8 cm. cystic teratoma? Provisional diagnosis of pedunculated fibroid was Ans: These include rupture, torsion, infection, made. hemorrhage, malignant transformation, thyrotoxi- Planned for myomectomy. cosis.

Management of broad ligament fibroid and Q.27. What are the non-gynecological causes of pedunculated fibroid: adnexal mass? Small and aymptomatic fibroid do not require any Ans: treatment. Surgical removal is done in case of large 1. Appendicitis – Managed by surgical removal. and symptomatic fibroid. 2. Diverticular disease – Managed by antibiotics Q.23. What complications can occur while for acute attacks, dietary changes. Surgery is operating on broad ligament fibroid? done if needed. Ans: As in such cases, anatomy of ureter gets Q.28. Describe management of hemorrhagic distorted, ureteric injuries can occur. To avoid that cyst? one should remain within the capsule of fibroid. In case this patient was diagnosed to have Ans: These are usually managed with narcotic ovarian cyst analgesics as these are usually self limiting. Occasionally surgical intervention is required. Q.24. How do you manage benign ovarian Suppression with birth control pills is also accep- tumors/ovarian cysts? table. 310 Case Discussions in Obstetrics and Gynecology

REFERENCES 10. Buster J, Pisarka M. Medical management of ectopic pregnancy. Clin Obstet Gynecol 1999;l42:23. 1. Cliby W. The Adnexal Mass.Clin of Obstet Gynecol sep 2006:433-37. 11. Lipscomb G, Puckett K. Management of separation 2. Berek S. Ovarian and fallopian tube cancer. Berek and pain after single dose methotrexate therapy for ectopic Novak Gynecology 2006;14:1490-1525. pregnancy.Obstet Gynecol 1999b;93:590. 3. Rock J, Jones H. Endometriosis.Te Linde’s Operative 12. Pisarka M, Karson S. Ectopic pregnancy. Lancet Gynecology 2007;10:595-630. 1998;351:1115. 4. Bobneate K, Kadar G, Khan A. Female Genital 13. Kooi S, Kock C. A review of literature on non surgical tuberculosis. A pathological appraisal. J Obstet treatement of tubal pregnancy. Obset Gynecol Surv. Gynecol India 1986;36:676-80. 1992;47:739. 5. Hall M, Leach L, Beck E. Clinical inquiries. Which 14. Andrews W, Larsen G. Endometriosis: Treatment with blood tests are most useful in evaluating pelvic inflammatory disease? J Fam Pract 2004;53:326-30. hormonal pseudopregnancy and/or operation. Am J 6. Zurawari R, Knapp C. An initial analysis of pre- Obstet Gynecol 1974;118:643. operative serum CA 125 levels in patients with early 15. Wardel G , Hostel J. Endometriosis and IVF. Lancet stage ovarian carcinoma.Gynecol Oncol 1988;30: 1986;1:256. 7-14. 16. Govt of India RNTCP at a glance, Revised national 7. Kawai M, Kano K, Kikawa F. Transvaginal Doppler TB control programme, central TB divison, Ministry ultrasound with color flow imaging in the diagnosis of health and family welfare, New Delhi. of ovarian cancer. Obstet Gynecol 1992;79:163-67. 17. Schaefer G. Female genital tuberculosis. Current 8. Lipscomb G, McCord M, Stoval G. Predictors of therapy in obstetrics and gynecology 1994:51-55. success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999a;341:1974. 18. Centre for disease control and prevention. Pelvic 9. Stoval G. Medical management should be routinely inflammatory disease. Sexually transmitted diseases used as primary therapy for ectopic pregnancy. Clin treatment guidelines. MMWR Recomm Rep 2002; Obstet Gynecol 1995;38:346. 51:48-52. Reva Tripathi, Nilanchali Singh 24 Lump in Abdomen

An abdominopelvic lump in a female is a clinical in old age. More than 80% epithelial ovarian finding which may have varied causes which could cancers are found in postmenopausal women. be either gynecological or non-gynecological. The peak incidence of invasive epithelial Causes of lump in the lower abdomen will also ovarian cancer is 56 to 60 years. About 30% of differ depending on the age at presentation. ovarian neoplasms in postmenopausal woman Detailed history and physical examination along are malignant, whereas only 7% of ovarian with various ancillary aids will be required to arrive epithelial tumors in premenopausal women are at the diagnosis. frankly malignant. For Breast Related Cancer Antigen (BRCA)-associated ovarian cancer, the CASE average age at diagnosis is about 50 years, and A 60-year-old postmenopausal woman presented for HNPCC (Hereditary Non-Polyposis to gynae OPD with complaints of progressive Colorectal Cancer), it is 40 years. distension of the abdomen for three months, loss • Symptoms of the patient give a clue to the origin of appetite and weight. A 24 weeks size ill defined, of pathology. Vague symptoms, non-specific firm, non-tender mass was found arising from the lower abdominal pain and discomfort, pelvis. How is this case to be managed? distension and pressure can be present in lump of any origin but are frequently present in case After taking history and doing clinical of ovarian malignancy. examination, work up of the patient should be done • Gastrointestinal problems like flatulence, to identify the cause. On the basis of her eructations and bloating after meals, symptomatology, age group and clinical finding, constipation, diarrhea or bleeding per rectum ovarian malignancy appears to be a likely may point towards gastrointestinal pathology possibility. like inflammatory bowel disease, diverticular disease or colonic or rectal tumors. Q.1. What are the points to be especially sought • Predominance of urinary complaints may point for in history? towards urinary tract disorders. Ans: • Loss of appetite and weight loss are non-specific • Age of the patient is very important. The causes symptoms which may indicate malignancy at of abdominopelvic lump vary with the age of any site. Patients with ovarian malignancy may the patient. Ovarian malignancies are common present with respiratory distress due to 312 Case Discussions in Obstetrics and Gynecology

associated ascites and pleural effusion. Apart • Family history: It is important in some cases from the lump the presence of ascites will of ovarian cancer. Any family history of ovarian, further contribute to the distension. breast, colorectal, pancreatic, stomach, small • Acute symptoms like pain which may be bowel, urinary tract, and biliary tract cancer secondary to rupture or torsion of ovarian tumor needs to be enquired for. Familial or hereditary are unusual. ovarian cancers account for 5 to 10% of ovarian • History of any discharge per vaginum or post- malignancies. Most hereditary ovarian cancers coital bleeding should also be enquired as they are associated with BRCA I (Chromosome 17), may be due to carcinoma cervix which could BRCA II (Chromosome 13) and Lynch II lead to pyometra presenting as lump in (Hereditary non-polyposis colorectal cancer abdomen. syndrome). The risk of familial ovarian cancer • Menstrual history: Menstrual history is likely decreases with age. The proportion of ovarian to be of little relevance in these patients. cancers in the general population attributable However, early menarche and late menopause to BRCA I gene is estimated to be 5.9% for may increase the risk of ovarian cancer and women in the third decade or younger, and postmenopausal bleeding may be present in steadily declines with increasing age, dropping granulosa cell tumor. Irregular menses may be to 1.8% in the seventh decade.5,6 This cause is present in few cases of ovarian tumor in to be sought for in case of malignancy perimenopausal woman. presenting at a younger age and must not be • Obstetric history: Obstetric history is also confused with coincidental occurrence of important. Ovarian malignancy has been malignancy in family members. associated with low parity and infertility. Having at least one child is protective of the Q.2. How should such a patient be examined? disease with a risk reduction of 0.3 to 0.4.1 The Ans: risk gets even lower with each pregnancy. • General examination: As in any other case Breast-feeding may lower the risk even further. general examination is important for this However, most patients we see in India are patient. A patient of ovarian malignancy may multiparous who have lactated their children. reveal cachexia and pallor of varying degrees, • Contraceptive history: History of oral jaundice, left supraclavicular lymph node contraceptive usage during the reproductive (Virchow’s), edema of leg and vulva and years needs to be taken. Oral contraceptive pills varicose veins. Women who are obese (Body are the only documented method of mass index 30) do have a higher risk of chemoprevention for ovarian cancer.2,3 developing ovarian cancer. Systemic • Past history: History of any previous examination including heart and lung gynecological surgery is also relevant. Tubal examination to exclude co-existing medical ligation may reduce the chance of developing disorders or distant metastasis must also be ovarian cancer by up to 67%.4 A hysterectomy performed. (without oophorectomy) also seems to reduce • Per abdominal examination is the next the risk of getting ovarian cancer by about one- important step. Any organomegaly needs to be third.4 It also rules out any uterine cause of the detected if present. The presence of lump. hepatomegaly, indicated by the presence of an Lump in Abdomen 313

enlarged, firm, and nodular liver may be fornix. It is not unusual to detect another small indicative of hepatic metastasis. A mass may pelvic mass on the contralateral side of the be felt in the hypogastrium arising from the abdominal mass. This would then make the pelvis. The features of the mass are to be noted patient a case of bilateral ovarian tumor which with special reference to the following: is more likely to be malignant. – Consistency needs to be noted whether it • P/V/R: Examination is incomplete without this is soft, firm, cystic or hard. In ovarian procedure. It is done to confirm findings of malignancy it may be of solid or vaginal examination and check for presence of heterogeneous consistency. mass or nodularity in the pouch of Douglas, – Mobility is also important as restricted parametrial thickening and whether rectal mobility points towards malignancy or may mucosa is free or not. In ovarian malignancy, be an indirect evidence of local spread P/V/R may reveal nodularity in the pouch of though it is difficult to comment in presence Douglas and involvement of the rectal mucosa of large tumors. in advanced stages. In some cases where the – Tenderness may or may not be present. uterus is not identifiable on vaginal examination – Surface may be smooth or irregular. it may be felt as a small structure during per Irregular surface points towards malignancy. rectal examination. – Margins may or may not be well-defined. The lower pole is usually not reached in Q.3. How should such a patient be investigated? pelvic lump. Ans: Investigations in these patients aim at: – Abdominal examination is incomplete • Confirming site of origin of tumor and presence without testing for percussion note. On of malignancy. percussion, there is usually dullness over the • Identifying extent of lesion tumor though there may be resonance due • Identifying primary if any. to overlying intestinal adhesions. Shifting Investigations for preoperative evaluation like dullness may be present in case of ascites. hematocrit, complete blood count, kidney and • Local examination: Any growth, ulceration, liver function tests, urinalysis and ECG are abnormal pigmentation should be noted on routinely done in all patients. Two important vulva, perineum, urethra, suburethral region and investigations which are done for all the patients anus. in whom ovarian malignancy is suspected are • Per speculum: Cervix and vagina should be ultrasonography and estimation of CA-125. inspected. Any discharge, ulcer, growth, white • Ultrasonography: It may identify the site of patches, warts, varicosities, atrophic changes origin or other associated pathologies. It may should be looked for as in any gyne case. also aid in differentiating malignant from benign • Per vaginum: Check uterine size and mobility, ovarian tumors. The sonographic findings feel for presence of an adnexal mass and for suggestive of malignancy are multilocularity, nodularity in pouch of Douglas. The most bilaterality, presence of solid areas, metastasis important sign of ovarian malignancy is and ascitis. Increased neoangiogenesis as shown presence of solid or solid/cystic, irregular and in Doppler study increases the risk of fixed mass felt per vaginum. Uterus may or may malignancy. Thin wall, smooth inner wall not be separated from the mass felt per structure and anechogenicity or low abdomen. There may be nodularity in posterior echogenicity of the lesions are important 314 Case Discussions in Obstetrics and Gynecology

features of benign tumors. Complex mass These factors should be taken into account without demonstrable wall, indistinct inner wall when interpreting CA-125 test results. structure and highly echogenic lesion with solid Others tumor markers are Macrophage Colony component are predictors of malignancy. Stimulating Factor (M-CSF), OVXI, HER-2/ Ovarian tumor may be cystic or solid and can neu and inhibin but are rarely done except when be benign or malignant.7 Cystic ovarian masses specifically indicated or in research settings. have a smooth wall, no internal echoes, and • Abdominal and pelvic CT scan and MRI: demonstrate enhanced through transmission. Either CT scan or MRI can be done to identify But cystic masses often contain low-level the extent of disease and detect presence of echoes representing blood, pus, or cellular enlarged lymph nodes. Although MRI is not debris.8 Solid tumors are highly, but irregularly, widely used in the staging and subsequent echogenic masses. Solid ovarian tumors are follow-up of ovarian cancer patients, this relatively uncommon, forming 7.8% of all the technology may have a role in the diagnosis of ovarian tumors, but tend to be more often recurrent disease. It is currently not considered malignant (51.7%). They could present with superior to CT scan, although no comparative varied pictures of solid-cystic areas, complex studies have been performed. masses or truly solid tumors. If more than 80% • Cytologic examination: Malignant cells can of the tumor mass has solid areas, they will be be detected from the fluid collected by classified as solid and carry a risk of malignancy abdominal paracentesis or culdocentesis. Fine which can be 40% or more.9,10 needle aspiration cytology can be done from Tumor markers: CA-125 is a glycoprotein the ovarian mass to detect malignant cells. used for screening and diagnosis of epithelial Ovarian masses are easily accessible for cancers of ovary. Value more than 35 U/ml is cytological evaluation by fine needle aspiration significant. It is also used for monitoring of during laparoscopy or sonography. Aspiration patients on chemotherapy and for follow-up. It cytology can provide particularly useful may be raised in several other malignancies like information in young women with functional carcinoma breast, lung, colon and endometrium ovarian cysts, preventing unnecessary and also in some benign conditions viz. operations. Acellular cystic fluids should not endometriosis, pelvic inflammatory disease, be considered non-diagnostic because they peritonitis and in 1% of normal women. represent benign cysts in the majority of cases. However, a number of factors are known to • Chest X-ray: This is done to exclude pleural influence serum CA-125 levels in healthy effusion and chest metastasis. women like age (pre-menopausal women have Once ovarian malignancy has been diagnosed, higher serum CA-125 levels than few investigations which aid in differentiating postmenopausal women); menstrual cycle between primary and secondary malignancy (some women have fluctuating serum CA-125 may be done, as mentioned below: levels throughout the menstrual cycle); • Barium enema/colonoscopy: These investi- pregnancy (CA-125 levels increase during gations help to rule out large bowel malignancy. pregnancy) and race (significantly higher CA- • Upper GI series/gastroscopy: This is done if 125 levels are found in healthy Caucasian there are any signs and symptoms of upper women compared to Asian or African women). involvement. Lump in Abdomen 315

• Intravenous Pyelography: This is helpful in as a score of 0, 1 or 3) and the menopausal status detecting ureteral obstruction and deviation (1 if premenopausal and 3 if postmenopausal). • Other possible modalities of evaluation are Using an RMI cut-off level of 200, the sensitivity Positron Emission tomography (PET), was 85% and the specificity was 97%. Patients with cystoscopy, laparoscopy and mammography. an RMI score of greater than 200 had, on average, 42 times the background risk of cancer and those Q.4. What is the differential diagnosis of lump with a lower value 0.15 times the background risk arising from pelvis in a postmenopausal woman? as shown in a study. The risk of cancer is 75% when Ans: The causes of an abdominopelvic lump can the RMI value is >250. be divided into gynecologic and non-gynecologic causes. Q.6. How should such a patient be managed? Gynecological causes: Ans: Surgery is the mainstay of treatment. These • Benign neoplasm of ovary patients require staging laparotomy and debulking • Malignant ovarian tumor followed by chemotherapy in most cases. • Pyometra • Sarcoma uterus Q.7. How is the surgical staging done for these • Tubo-ovarian abscess patients? • Uterine leiomyoma (Pedunculated/non- Ans: The staging laparotomy is done as follows: pedunculated) • Liberal vertical incision should be given as it Non-gynecological causes: minimizes chances of tumor rupture and • Inflammatory bowel disease facilitates better exploration of peritoneal cavity. • Colonic neoplasms • The character of ascitic fluid is noted and • Pelvic kidney collected for cytology. If fluid is absent or not • Diverticular mass sufficient then a sample of peritoneal washing • Mesenteric cyst is taken from the paracolic gutters, the pouch • Retroperitoneal tumors of Douglas and the under surface of diaphragm • Enlarged lymph nodes by instilling 10-20 ml of normal saline or distilled water. Q.5. What is risk of malignancy index (RMI)? • A systematic visual and manual inspection is Ans: This index is used to differentiate between done- palpation of liver, GIT, subdiphragmatic malignant and benign ovarian lesion. The risk of area, omentum and para-aortic lymph nodes. malignancy index11 is calculated as follows: The palpation of gastrointestinal tract is done RMI = U × M × CA-125 in clockwise manner starting from cecum. U = Ultrasound score (one point each for: • Pelvic exploration is done and gross physical multilocular cyst; solid areas; metastasis; ascitis; characteristic of tumor should be noted along bilateral lesion) with extent of adhesions, condition of the M =3 (postmenopausal women) contralateral ovary, uterus and tubes. Palpation CA-125 in U/ml of the pelvic lymph nodes and rectovaginal area The above mentioned values could be combined is also done. in a risk of malignancy index (RMI) which is simply • Any suspicious metastatic deposit on the calculated using the product of the serum CA-125 peritoneal surface and the under surface of level (U/ml), the ultrasound scan result (expressed diaphragm should be biopsied. 316 Case Discussions in Obstetrics and Gynecology

• Pelvic and para-aortic lymph node sampling surface, or cancer cells in the ascites or should be done. peritoneal lavage. • Multiple peritoneal biopsies should be taken Stage2: Tumor involves one or both ovaries with even in absence of any obvious metastatic spread into the pelvis. disease. 2a:Tumor has spread and/or attaches to the uterus • The type of surgery depends upon the stage of and/or fallopian tubes. There are no cancer cells tumor. The surgeon may perform unilateral in ascites or peritoneal lavage. oophorectomy or bilateral oophorectomy along 2b:Tumor has spread to other pelvic tissues. There with salpingectomy and hysterectomy. For early are no cancer cells in ascites or peritoneal tumors (stage 1, low grade or low-risk disease), lavage. only unilateral salpingo-oophorectomy can be 2c: Tumor has spread to pelvic tissues, with cancer done, especially in young females who wish to cells in ascites or peritoneal lavage. preserve their fertility. In advanced malignancy, Stage3: Tumor involves one or both ovaries, with where complete resection is not feasible, as microscopically confirmed peritoneal metastasis much tumor as possible is removed (debulking outside the pelvis and/or metastasis to regional surgery). In cases where this type of surgery is (nearby) lymph node(s). successful (i.e. < 1 cm in diameter of tumor is 3a:Microscopic peritoneal metastasis beyond the left behind known as optimal debulking), the pelvis. prognosis is improved compared to patients 3b:Macroscopic (visible to the naked eye) where large tumor masses (> 1 cm in diameter) peritoneal metastasis beyond the pelvis, 2 cm are left behind. or less in greatest dimension. 3c:Peritoneal metastasis beyond the pelvis, more Q.8. How are ovarian malignancies staged? than 2 cm in greatest dimension. Ans: Ovarian cancer staging usually is described Stage4: Distant metastases are present. Pleural in terms of the FIGO system (staging scheme effusion if present is included in stage IV if developed by the International Federation of malignant cells are present. Parenchymal liver Gynecology and Obstetrics). In general, the lower disease is also included in stage IV. the stage, the more favorable is the prognosis. Stage1: Tumor is limited to one or both ovaries. Q.9. What are the risk factors for epithelial 1a:Tumor is limited to one ovary. The capsule, or ovarian cancer? outer wall of the tumor, is intact, there is no Ans: tumor on the external ovarian surface, and there • Age: The risk of developing ovarian cancer gets are no cancer cells in ascites (abdominal fluid higher with age. Ovarian cancer is rare in build-up) or peritoneal lavage (“washings” from women younger than 40. Most ovarian cancers the abdominal cavity). develop after menopause. Half of all ovarian 1b:Tumor is limited to both ovaries. The capsule cancers are found in women over the age of 65. is intact, there is no tumor on the ovarian • Obesity: Various studies have looked at the surface, and there are no cancer cells in ascites relationship of obesity and ovarian cancer. or peritoneal lavage. Overall, it does seem that obese women (those 1c: Tumor is limited to one or both ovaries with with a body mass index of at least 30) do have any of the following: ruptured capsule (burst a higher risk of developing ovarian cancer. A outer wall of the tumor), tumor on ovarian study from the American Cancer Society also Lump in Abdomen 317

found a higher rate of death from ovarian cancer inherited gene mutations that can be identified in obese women.12 by genetic testing. • Reproductive history: A woman who has had • Personal history of breast cancer: The risk children has a lower risk of ovarian cancer than of ovarian cancer after breast cancer is highest women who have no children. The risk gets in those women with a family history of breast even lower with each pregnancy. Breastfeeding cancer. A strong family history of breast cancer may lower the risk even further. Using oral may be caused by an inherited mutation in the contraceptives also lowers the risk of ovarian BRCA1 or BRCA2 genes. These mutations can cancer. also cause ovarian cancer. • Gynecologic surgery: Tubal ligation may • Others: Many other causes or protective agents reduce the chance of developing ovarian cancer have been mentioned in literature. Some of the by up to 67%.4 Hysterectomy (removal of the common ones are enumerated below. Talcum uterus without removing the ovaries) also seems powder applied directly to the genital area or to reduce the risk of getting ovarian cancer by on sanitary napkins may be carcinogenic about one-third.4 (cancer-causing) to the ovaries. Some, studies • Fertility drugs: In some studies, researchers suggest a very slight increase in risk of ovarian have found that using clomiphene citrate for cancer in women who used talc on the genital longer than one year may increase the risk for area.13 Some studies have shown a reduced rate developing ovarian tumors. The risk seemed to of ovarian cancer in women who ate a diet high be highest in women who did not get pregnant in vegetables, but other studies disagree. In while on this drug. However, women who are some studies, both aspirin and acetaminophen infertile may be at higher risk than fertile have been shown to reduce the risk of ovarian women even if they do not use fertility cancer. However, the information is not enhancing drugs so the extent of the consistent. Smoking and alcohol use do not contribution of the drugs to the development of increase the risk for most ovarian cancers, but malignancy is difficult to quantify. some studies have found they increase the risk • Androgens: Women who took androgens were for the mucinous type. found to have a higher risk of ovarian cancer. Further studies of the role of androgens in Q.10. What are familial ovarian cancers? ovarian cancer are required. Ans: While approximately 90% of ovarian cancers • Estrogen therapy: Some recent studies suggest occur sporadically, 10% of women with ovarian women using estrogens for hormone cancer have inherited genetic changes that replacement therapy have an increased risk of predisposed them to ovarian cancer.14 There are developing ovarian cancer. The risk seems to three hereditary syndromes that predispose to be higher in women taking estrogen alone ovarian cancer: (without progesterone) for many years (at least • Hereditary breast-ovarian cancer syndrome due 5 or 10). The increased risk is less certain for to mutations in the tumor suppressor genes women taking both estrogen and progesterone. BRCA1 and BRCA2 • Family history of ovarian cancer, breast • Hereditary non-polyposis colorectal cancer cancer, or colorectal cancer: Many cases of (Lynch syndrome) familial epithelial ovarian cancer are caused by • Hereditary site-specific ovarian cancer. 318 Case Discussions in Obstetrics and Gynecology

Hereditary Breast Ovarian Cancer Syndrome BRCA2: The BRCA2 tumor suppressor gene is Approximately 10% of women with ovarian cancer also associated with high rates of breast and ovarian are carriers of a breast/ovarian cancer susceptibility cancer. The lifetime risk of breast cancer has been gene. The proportion of cases of ovarian cancer reported to be similar to that of BRCA1 (55-85%), due to such a gene decreases with age and is while the lifetime risk of ovarian cancer is estimated estimated to be 14% for women diagnosed in the to be 10-20%. BRCA2 is also associated with a 5- fourth decade, dropping to 7% for women 6% risk of male breast cancer, as well as increased diagnosed in the sixth decade.15,16 Gene carriers risk of pancreatic cancer and melanoma.18 BRCA2 have a greater than fifteen-fold risk of ovarian features are similar to those outlined for BRCA1, cancer compared to non-carriers. The lifetime risk but also include a family history of pancreas cancer for ovarian cancer in the general population is 1.3%, in addition to breast and/or ovarian cancer.19 while estimates for gene carriers range from 10 to Hereditary non-polyposis colorectal cancer 17 60%. BRCA1 and BRCA2 together have been (Lynch syndrome II) estimated to account for 85% of breast ovarian Hereditary non-polyposis colorectal cancer cancer families. Both BRCA1 and BRCA2 are (HNPCC), also known as Lynch syndrome II, is a transmitted in an autosomal dominant fashion. hereditary syndrome most commonly characterized Certain ethnic groups, such as Ashkenazi Jews, by an increased risk for colorectal cancer. The have high rates of specific mutations of these genes. lifetime risk of colorectal cancer is 80%, and is The large number of mutations described makes typically diagnosed in the individual’s mid-40s.20 genetic testing and patient counseling complex, and The risk of endometrial (uterine) cancer associated illustrates the need for genetic counseling by a with HNPCC is approximately 40%, while the risk qualified health care provider. of ovarian cancer is 10%.21 Other associated BRCA1: BRCA1 is a gene associated with cancers include stomach, small bowel, urinary tract, increased risk for breast and ovarian cancer. The and biliary tract. lifetime risk of breast cancer is estimated to be 55- Germ line mutations of mismatch repair (MMR) 85%, while the lifetime risk of ovarian cancer is genes have been demonstrated in individuals with 20-40%, with some studies suggesting as high at HNPCC causing widespread genomic instability, 60%. The proportion of ovarian cancers in the or a hypermutable state, which provides the general population attributable to this gene is background for an accelerated accumulation of estimated to be 5.9% for women in the third decade mutations. Genetic testing is available for HNPCC, or younger, and steadily declines with increasing but is complex because five causative genes have age, dropping to 1.8% in the seventh decade. been identified, thus far. Again, genetic counseling Features suggestive of a BRCA1 mutation include is advised. Features strongly suggestive of HNPCC a family history of: include (The Amsterdam II Criteria) 22,23 • Two or more cases of ovarian cancer 1. At least three members of family must have • Breast and ovarian cancer in the same woman been diagnosed with a cancer associated with • One or more cases of premenopausal breast HNPCC—cancer of the colon, endometrium, cancer with or without a case of ovarian cancer small bowel, ureter, or renal pelvis. diagnosed at any age (Note: Not all relatives must have the same kind • Two or more cases of postmenopausal breast of cancers.) cancer and one or more cases of ovarian cancer 2. One of the three family members must be a first- diagnosed at any age degree relative (parent, offspring, or sibling) of • Male breast cancer. the other two. Lump in Abdomen 319

3. At least two successive generations of family of ascitis and postoperative factors like the extent should be affected. of the residual disease after surgery are independent 4. At least one of these relatives must have been prognostic variables. diagnosed with cancer before age 50. Pathological factors: The morphologic and 5. Familial adenomatous polyposis (or FAP, the histologic pattern, including the architecture and other hereditary colon cancer syndrome) as the grade of the lesion, are important prognostic cause of colon cancer should be ruled out. variables. Clear cell carcinoma are associated with Although not as strongly suggestive, HNPCC prognosis worse than other histologic types. should be considered in a family with one case of Biological factors: Diploid tumors have longer early-onset colorectal cancer and one case of survival rate than those with aneuploid tumors. ovarian cancer diagnosed at any age. HER-2/neu expression has been associated with poorer prognosis. The tumor suppressor genes Site-specific ovarian cancer evaluated in ovarian malignancy are p53, PTEN Limited data are available on the site-specific and ras. ovarian cancer syndrome. This is the least common of the three hereditary cancer syndromes, and is Q.13. What are the histopathological types of characterized by an increased risk of ovarian cancer. epithelial ovarian tumors? Findings from one group of investigators suggested that most families with this syndrome are linked to Ans: mutations in the BRCA1 gene. Histologic type Cellular type Percent (%) Serous Endosalpingeal 75% Q.11. How does an ovarian cancer metastasize? Mucinous Endocervical 20% Ans: Endometrioid Endometrial 2% • Direct: The spread occurs to adjacent organs Clear cell Mullerian <1% like uterus and fallopian tubes. Brenner Transitional <1% • Transcoelomic: Metastasis occurs to intra- Mixed epithelial Mixed <1% peritoneal organs and omentum. Undifferentiated Anaplastic <1% • Lymphatic- Lymphatic dissemination to pelvic Unclassified Mesothelioma, etc. - and para-aortic lymph nodes is common especially in advanced stages. According to a Q.14. What are borderline ovarian tumors? series,1 the rate of dissemination to para-aortic Ans: They are tumors of low malignant potential. nodes is 18% in stage I, 20% in stage II, 42% They tend to remain confined to the ovary for long in stage III and 67% in stage IV. periods. The criteria for diagnosis of borderline • Hematogenous spread is less common. Spread tumors are as follows: to vital organ like lungs and liver occurs in 2% • Epithelial hyperplasia to 3% patients. • Nuclear atypia and increased mitotic activity • Detached cell clusters Q.12. What are the prognostic factors of ovarian • Absence of destructive stromal invasion malignancy? Ans: Q.15. What is the management of borderline Clinical factors: Preoperative clinical factors like ovarian tumors? age of patient and performance status, intra- Ans: The principal treatment of borderline tumor operative factors like stage of disease, the volume is surgical resection of primary tumor. After a frozen 320 Case Discussions in Obstetrics and Gynecology section has determined that the histology is omentectomy and resection of any metastatic borderline, premenopausal patients who desire lesions from the peritoneal surfaces or from the preservation of ovarian function may undergo a intestines. Patients whose disease has been conservative surgery, which is usually a unilateral completely resected to no macroscopic residual oophorectomy. This needs to be confirmed by disease (only microscopic disease) have the best detailed histopathology and such patients must be overall survival. 60% will be free of disease at the kept under close surveillance as distant metastasis end of 5 years. This should be performed by a are known to occur even with borderline tumors. gynecologic oncologist at the time of initial laparotomy. The volume of residual disease at the Q.16. What is palpable ovary syndrome? completion of surgery represents one of the most Ans: In patients who are 1 year past menopause, powerful prognostic factors. Patients with advanced the ovaries should have become atrophic and not ovarian cancer are classified in three groups as palpable. It has been proposed that any pelvic mass follows, based on the postoperative residual tumor: in these patients should be considered potentially • Good risk: Microscopic disease outside the malignant, a situation that has been referred to as pelvis (stage IIIa). the postmenopausal palpable ovary syndrome. • Intermediate risk: Macroscopic disease less This concept has been challenged because only than 2 cm outside the pelvis only after surgery 3% of palpable masses measuring < 5 cm have been • Poor risk: Macroscopic disease more than 2 cm reported to be malignant. after surgery or disease outside the peritoneal cavity. Q.17. What are the guidelines for management of an enlarged ovary? Q.19. What is interval debulking? Ans: The guidelines for management of ovarian Ans: Interval debulking is performed in patients enlargement are as follows: in whom adequate debulking is not able to be • Any ovarian enlargement of > 8 cm during performed at the time of initial surgery. Such child-bearing period needs careful follow-up. patients receive 3 cycles of chemotherapy after • In postmenopausal women any ovarian initial surgery and approximately 60% of patients enlargement should be assessed by serum CA- are subsequently able to undergo optimal resection. 125 and TVS. Cysts that are simple, unilocular This interval debulking is followed by 3 more cycles and < 8 cm in diameter with normal serum CA- of chemotherapy. Interval debulking surgery may 125 can be managed conservatively. 4 monthly also be considered in those patients in whom an follow-up should be done in these patients. initial debulking surgery was not attempted and chemotherapy was given without any staging Q.18. What is debulking or cytoreductive laparatomy. CA-125 levels are also a good indicator surgery? of the volume of residual disease. Ans: A patient with advanced ovarian malignancy who is medically stable should undergo a Q.20. Which patients of ovarian malignancy cytoreductive surgery to remove as much of the require chemotherapy? tumor and its metastasis as possible. The surgery Postoperative chemotherapy is indicated in all typically involves the performance of a total patients with ovarian cancer except those who have abdominal hysterectomy and bilateral salpingo- surgical-pathologic stage I disease with low-risk oophorectomy, along with an infracolic characteristics. Literature suggests that post- Lump in Abdomen 321 operative platinum-based chemotherapy prolongs The combination of paclitaxel and carboplatin both progression-free survival and overall survival is customarily given every 3 weeks (day 1 of a 21- in the majority of patients with early stage ovarian day cycle). cancer. In patients with early stage disease (Stage I Intraperitoneal chemotherapy: Results from and II) the risk of recurrence may be classified as randomized clinical trials suggest that in patients follows: with optimally debulked disease, intraperitoneal Low risk for recurrence is indicated by the administration of chemotherapy (cisplatin) is following: superior to intravenous administration. Recent • Grade 1 or 2 disease meta-analyses confirm that intraperitoneal • No tumor on external surface of the ovary administration of chemotherapy is associated with • Negative peritoneal cytology an improvement in survival. However, this • No ascites approach is also associated with more toxicity. The • Tumor growth confined to the ovaries national cancer institute supports the use of High risk for recurrence is indicated by the intraperitoneal chemotherapy in optimally debulked following: ovarian cancer. • Grade 3 disease Neoadjuvant chemotherapy: Patients with • Preoperative rupture of the capsule advanced ovarian cancer who are not candidates • Tumor on the external surface of the ovary for surgical cytoreduction may be treated initially • Positive peritoneal cytology with 2-3 cycles of conventional chemotherapy and • Ascites can then be re-evaluated for surgical cytoreduction. • Tumor growth outside of the ovary However, initial optimal cytoreduction remains the • Clear cell tumors standard of care for most patients. • Surgical stage II and beyond Maintenance chemotherapy: Most patients with Q.21. What are the chemotherapeutic regimens ovarian cancer achieve a complete clinical response used in ovarian malignancy? after debulking surgery and platinum-based chemotherapy. However, 50% experience relapse Ans: Standard postoperative chemotherapy is and ultimately die of the disease. Therefore, combination therapy with platinum based and strategies to decrease the risk of recurrence have paclitaxel. Cisplatin and paclitaxel or carboplatin been investigated. A phase III randomized trial and paclitaxel are commonly used. Randomized studies have proven that both regimens result in exploring the impact of 12 monthly cycles of equivalent survival rates. However, because of an paclitaxel as maintenance chemotherapy was improved toxicity profile, the combination of discontinued by the Data Safety and Monitoring carboplatin and paclitaxel is preferred. If patients Committee when a prospectively defined interim are treated with cisplatin, paclitaxel should be analysis revealed a highly statistically significant administered as a 24 hours infusion to decrease the improvement in progression-free survival; an risk of neurotoxicity. Another alternative is to ongoing phase III trial is addressing the question combine carboplatin with docetaxel. Cisplatin, of whether this maintenance strategy has a carboplatin, and paclitaxel are chemotherapy agents significant effect on overall survival. approved for the initial treatment of ovarian cancer. Second-line chemotherapy: Recurrent ovarian Results from randomized studies have shown that cancer is classified into 2 categories, depending on platinum-containing regimens are superior to those the length of time the patient remained disease-free that do not contain platinum. after completing chemotherapy: 322 Case Discussions in Obstetrics and Gynecology

1. Relapse that occurs more than 6 months after and stage III patients having no residual disease or initial chemotherapy is considered platinum- less than 2 cm of residual disease. Currently, sensitive; chemotherapy is the standard of care after surgery 2. Relapse that occurs before 6 months is due to the lack of large prospective randomized considered platinum-resistant. Patients with trials involving postoperative radiotherapy. platinum-sensitive disease may exhibit a good Radiation may be utilized as salvage therapy in response if retreated with a platinum-based patients who have failed surgery followed by regimen. The probability of response increases chemotherapy. Optimal results have been found in with the duration of the disease-free interval. patients who have microscopic residual disease or Results from clinical trials suggest that disease confined to the pelvis. Radiotherapy can combination chemotherapy offers an also be considered as consolidative therapy improvement in response rate, progression-free following optimal cytoreductive surgery and survival, and overall survival. Several platinum based chemotherapy for select individuals chemotherapy agents elicit a response in with intermediate or high risk of relapse. For patients whose disease is resistant to platinum- patients with advanced disease that is unresectable based therapies. These include liposomal and chemoresistent, radiotherapy has been shown doxorubicin, topotecan, oral etoposide, to have an important palliative role in reducing gemcitabine, docetaxel, and vinorelbine. Other symptoms, such as controlling vaginal or rectal agents that may be used are ifosfamide, 5- bleeding, pulmonary metastasis, and pain control. fluorouracil with leucovorin, and altretamine (Hexalen). Tamoxifen, an oral antiestrogen, Q.23. What is the role of immunotherapy? exhibits modest activity but has a favorable Ans: Immunotherapy (sometimes called biological toxicity profile. therapy, biotherapy, or biological response modifier therapy) is one of the innovative ovarian cancer Q.22. What is the role of radiotherapy in ovarian treatment options. Biotherapy utilizes immune malignancies? system either directly or indirectly against cancer Ans: Evidence that radiation therapy is an effective cells. Ovarian cancer may develop when the adjuvant therapy in certain stages of ovarian cancer immune system breaks down or is not functioning has been proven in several trials. For early and adequately. Biotherapy is designed to enhance the intermediate stage disease, trials have shown that natural immune responses. Aside from fighting radiotherapy to the whole abdomen following ovarian cancer, biotherapy may help strengthen the surgery to be more effective than certain body against side effects caused by conventional chemotherapy and pelvic radiation. Although there ovarian cancer treatments. Biotherapy can be used have been no randomized trials comparing platinum as a stand-alone ovarian cancer treatment, or it may based chemotherapy to whole abdominal therapy, be used in conjunction with other modalities such platinum based chemotherapy has largely as surgery, radiation therapy and chemotherapy. supplanted the use of radiotherapy in the United Cytokines have been used extensively in second States. However, radiotherapy does have a role in line therapy and the activity of interferon-α, both cure and symptom control in patients with interferon-γ, and interleukin-2 has been ovarian cancer. demonstrated. Biotherapy/immunotherapy may be Surgery followed by whole abdominal used to: radiotherapy has shown favorable results in patients • Halt or interfere with the growth process of with high risk stage I patients, as well as stage II ovarian cancer cells Lump in Abdomen 323

• Make ovarian cancer cells more recognizable, Q.25. How is the follow-up done in ovarian and therefore more susceptible, to destruction cancer patients? by immune system Ans: Regular follow-up is essential for all ovarian • Boost the killing power of immune system cells, cancer patients. This includes patients whose including T-cells, NK-cells and macrophages disease is in remission after treatment. Although • Alter ovarian cancer cells’ growth patterns to most women who develop a recurrence do so within normal the first 2 years after treatment, ovarian cancer can • Block or reverse the process that changes a reappear up to 20 years later. Patients should be normal cell or a pre-cancerous cell into a examined every 3 months for the first 2 years. cancerous cell Thereafter, follow-up visits may be scheduled every • Enhance ability to repair or replace normal cells 4 to 6 months. During each visit, serum CA-125 damaged or destroyed by other forms of ovarian level should be checked. If the CA-125 level is cancer treatment (e.g. chemotherapy, radiation) increased, tests such as CT scan, biopsy and • Prevent ovarian cancer cells from spreading to peritoneal lavage may be performed to locate the other parts of body. new cancer site. The observation that the presence of certain immune cells in tumors is associated with improved Q.26. What is the role of second look operation? survival, suggests that stimulation of anti-tumor Ans: Second-look surgery is performed after a immune responses, i.e. immunotherapy, might be procedure or course of treatment to determine if a useful approach to improve prognosis of ovarian the patient is free of disease. If disease is found, cancer. In this review, the feasibility of antigen- additional procedures may or may not be performed specific active immunotherapy is evaluated. at the time of second-look surgery. Antigen-specific active immunotherapy aims at the A second-look procedure is sometimes induction of tumor-directed immune responses performed to determine if a cancer patient has through the administration of a tumor-antigen, a responded successfully to a particular treatment. molecule that is preferentially expressed by tumor Examples of cancers that are assessed during cells and can induce immune responses. second-look surgery are ovarian cancer and colorectal cancer. In many cases, before a round of Q.24. What is the role of hormone therapy? chemotherapy and/or radiation therapy is started, a Ans: There is no evidence that hormone therapy patient will undergo a surgical procedure called alone is appropriate primary therapy for advanced cytoreduction to reduce the size of a tumor. This ovarian cancer. The use of progestational agents in debulking increases the sensitivity of the tumor and the treatment of recurrent well-differentiated decreases the number of necessary treatment cycles. endometrioid carcinoma is supported by current Following cytoreduction and chemotherapy, a data. A trial of tamoxifen in combination with second-look procedure may be necessary to multiagent chemotherapy is being conducted. determine if the area is cancer-free. Leuprolide acetate and aromatase inhibitors are also An advantage of second-look surgery following being studied. The study, published in Clinical cancer treatment is that if cancer is found, it may Cancer Research, has proved for the first time that be removed during the procedure in some patients. the targeted use of an antiestrogen drug could In other cases, if a tumor cannot be entirely prolong the life of some patients by up to three removed, the surgeon can debulk the tumor and years, and delay the use of chemotherapy in others. improve the patient’s chances of responding to 324 Case Discussions in Obstetrics and Gynecology another cycle of chemotherapy. However, second- The treatment of a patient with germ cell look surgery cannot definitively prove that a patient malignancy will depend upon the stage of the is free of cancer as some microscopic cancer cells disease and her desire to preserve fertility. In can persist and begin to grow in other areas of the advanced stages, management is the same as in body. Even if no cancer is found during second- epithelial malignancies, i.e. staging laparotomy look surgery, the rate of cancer relapse is with panhysterectomy followed by chemotherapy. approximately 25%. But in early stages, fertility preserving surgeries should be offered. Treatment also depends on Q.27. What is the survival rate in these patients? whether the tumor is dysgerminoma or another type Ans: The 5 years survival rates of patients with of germ cell tumor. ovarian malignancy depend on the stage of the • In young patients surgery should ideally be disease. The stage-wise 5 years survival rates are conservative in order to preserve fertility if the as follows: stage of the disease allows. Consequently a. Stage I-73% unilateral salpingo-oophorectomy is performed b. Stage II-45% for all stages of GCT. Even if extraovarian c. Stage III-21% disease is present, the contralateral ovary and d. Stage IV-Less than 5% uterus should not be removed as these tumors are curable with chemotherapy. However, if Q.28. How would you have modified your fertility is not of concern, total abdominal management if your patient was 26-year-old? hysterectomy and bilateral salpingo-oopho- Ans: Germ cell tumors (GCT) are the more rectomy, together with removal of as much common ovarian malignancies present in the tumor tissue as possible, is recommended for younger age group. GCT predominantly affect stage II, III and IV of GCT. young women, but they sometimes occur in infants • Chemotherapy is preferable, despite these and older women. GCT account for over 60% of tumors being highly radiosensitive (except ovarian neoplasms in children and adolescents, one- endodermal sinus tumor (EST) and embryonal third of which are malignant. Hence, apart from carcinoma), in order to preserve ovarian the investigations already mentioned, tumor function. All patients irrespective of tumor markers specific for germ cell tumors need to be histology, except those with immature teratomas done. These tumor markers are as follows: (stage IA, grade1), receive postoperative chemotherapy, for adjuvant or curative Tumor Tumor marker purposes. Adjuvant chemotherapy is given to Dysgerminoma 10% have elevated hCG patients with completely resected stages I, II or (Human chorionic gonado- III ESTs, mixed cell tumors, embryonal tropin), serum lactate dehydro- carcinomas, choriocarcinomas and immature genase teratomas due to high recurrence rates. All GCT Embryonal carcinoma Pure tumors do not secrete hCG receive the same chemotherapy regimes based or AFP (Alpha feto-protein) on a combination cisplatin therapy. Combi- Endodermal sinus tumor AFP, alpha-1 anti-trypsin nation therapies include vinblastine, bleomycin, Choriocarcinoma hCG and cisplatin (VBP); bleomycin, etoposide and Teratoma hCG or AFP cisplatin (BEP) and also etoposide and cisplatin Mixed Depends on elements present (EP). Combination chemotherapy is given to Lump in Abdomen 325

patients with bulky residual disease, extra- • The survival rates for stage I and II ESTs are abdominal metastases, or those who failed reported to be 60-100%, whereas for those with primary treatment with a curative intent. stage III or IV disease the prognosis is less Survival rates for ovarian germ cell favorable (50-75%). malignancies have increased dramatically with • Survival rates for embryonal carcinoma are the use of platinum-based combination slightly higher than those for ESTs. chemotherapy. Approximately 15-25% of • The prognosis of immature teratomas is dysgerminomas recur, but these are usually governed by grade and stage. Grade 1, stage 1 treated with a curative outcome by newer have 100% survival rate, whereas stage III, chemotherapy regimes. grade 1 has only a 50% chance of survival. Meanwhile, most patients with mature Q.29. How does a patient of germ cell tumor teratomas show long survival times. present? • The prognosis is better for gestational Ans: Most GCT are benign and unilateral, with choriocarcinoma than non-gestational the exception of dysgerminomas. Patients usually carcinoma. present at stage I. Abdominal pain or adnexal • The prognosis for mixed GCT is dictated by torsion is the commonest presenting symptom of the proportion of the more malignant component and the stage. GCT, however they may be asymptomatic. The mass may cause acute pain due to torsion, rupture, REFERENCES or hemorrhage. Patients may also have abdominal distension, vaginal bleeding or fever. Teratomas are 1. Kvåle G, Keuch I, Nilssen S, et al. Reproductive usually diagnosed in premenopausal women factors and risk of ovarian cancer: A prospective study. Int J Cancer 1988;42:246-51. without presenting symptoms. Complications of 2. WHO Collaborative Study of Neoplasia and Steroid mature cystic teratoma (dermoid cyst) include Contraceptives. Epithelial ovarian cancer and torsion, rupture, infection and hemolytic anemia. combined oral contraceptives. Int J Epidemiol Approximately 50% of prepubertal girls with 1989;18:538-45. 3. Kaunitz AM. Oral contraceptive health benefits: nongestational choriocarcinoma are isosexually Perception versus reality. Contraception 1999; precocious. Only 1-2% of dermoid cysts become 59(suppl 1):29S-33S. malignant, usually in postmenopausal women. 4. Green A, Purdie D, Bain C, et al. Tubal sterilisation, Patients with ESTs frequently present following hysterectomy and decreased risk of ovarian cancer. spontaneous rupture and hemorrhage. Int J Cancer 1997;71:948-51. 5. Narod SA, Madlensky L, Bradley L, et al. Hereditary and familial ovarian cancer in Southern Ontario. Q.30. What is the prognosis of ovarian germ cell Cancer 1994;74:2341-6. tumor? 6. Boyd J, Rubin SC. Hereditary ovarian cancer: Ans: Malignant ovarian germ cell tumors are very Molecular genetics and clinical implications. Gynecol Oncol 1997;64:196-206. aggressive, but the prognosis is still good provided 7. Chervanak FA, Issacson GC, Campbell S. it is treated without delay with combination Gynaecological Malignancy. In: Morley P, Hollman chemotherapy. AS (eds.) Ultrasound in Obstetrics and Gynaecology. • The survival rates for dysgerminomas 1st Ed. 1993;1746-59. 8. Sanders RC, Jammes AE. The principles and practice presenting at early and advanced stages are 95% of ultrasonography in obstetrics and gynaecology. 3rd and >80% respectively. Ed. Appleton- Century Crofts, 1985 ;473-16. 326 Case Discussions in Obstetrics and Gynecology

9. Rumack CM, Wilson SR, Charboneay JW. The uterus 17. Burke W, Daly M, Garber J, Botkin J, Kahn MJ, Lynch and abdomen. In: Salem S (ed). Diagnostic P, McTiernan A, Offit K, Perlman J, Petersen G, Ultrasound. 2nd Ed. Mosby Year Book, Inc., 1998; Thomson E, Varricchio C. Recommendations for 544-6. follow-up care of individuals with an inherited 10. Mc Gahan JP, Goldberg BB. Female Pelvis. In: Levine predisposition to cancer. II. BRCA1 and BRCA2. D (ed). Diagnostic Ultrasound . A Logical Approach. Cancer Genetics Studies Consortium. JAMA. 1997; 4th Ed. Lippincott-Raven, Philadelphia, 1998;955-62. 277:997-1003. [PubMed]. 11. Tingulstad S, Hagen B, Skjeldestad FE, Onscud M, 18. Cannistra SA. BRCA1 mutations and survival in Kiserud T, Halvorsen T, Nustad K. Evaluation of a women with ovarian cancer. N Engl J Med risk of malignancy index based on serum CA124, 1997;17:1254. [PubMed]. ultrasound findings and menopausal status in the pre- 19. Casey MJ, Synder C, Bewtra C, Narod SA, Watson P, operative diagnosis of pelvic mass. Br J Obstet Lynch HT. Intra-abdominal carcinomatosis after Gynecol 1996;103:826-31. prophylactic oophorectomy in women of hereditary 12. Michael F Leitzmann, Corinna Koebnick, Kim N breast ovarian cancer syndrome kindreds associated Danforth, Louise A Brinton, Steven C Moore, Albert with BRCA1 and BRCA2 mutations. Gynecologic Oncology. 2005;97:457-67. [PubMed]. R Hollenbeck, Arthur Schatzkin, James V Lacey, Jr. 20. Lynch H.. Hereditary nonpolyposis colorectal cancer Body mass index and risk of ovarian cancer. Cancer, (Lynch Syndrome): An updated review. Cancer Online: January 05, 2009; Print: February 15, 2009 1996;78:1149-67. DOI: 10.1002/cncr.24086. 21. Rodriguez-Bigas M, et al. A National Cancer Institute 13. Cook LS, Kamb ML, Weiss NS. Perineal powder workshop on hereditary non-polyposis colorectal exposure and the risk of ovarian cancer. Am J cancer syndrome: Meeting highlights and Bethesda Epidemiol 1997;145:459-65. guidelines. Journal of the National Cancer Institute 14. American Society of Clinical Oncology; 1997;89(23):1758-62. Recommended breast cancer surveillance guidelines. 22. Syngal S. Hereditary nonpolyposis colorectal cancer: J Clin Oncol 1997;15:2149-56. [PubMed]. A call for attention. J Clin Oncology 2000;18(11): 15. American Society of Clinical Oncology Policy 2189-91. statement update (pdf): Genetic testing for cancer 23. Vasen H, et al.. New clinical criteria for hereditary susceptibility, 2003. non-polyposis colorectal cancer (HNPCC, Lynch 16. Brunet JS, Narod SA, Tonin P, Foulkes WD. BRCA1 syndrome) proposed by the International Collaborative mutations and survival in women with ovarian cancer. Group on HNPCC. Gastroenterology 1999;116: N Engl J Med 1997;336:1256 [PubMed]. 1453-6. Raksha Arora, Neha Gupta Management of 25 Abnormal Pap Smear and Cervical Cancer

Screening is a public health intervention based on • False-negative rate is low because the specimen a population at risk or target population. Screening obtained is more representative of the areas is not undertaken to diagnose a disease, but to sampled. identify individuals with a high probability of • Fewer unsatisfactory smears. having or of developing a disease. Women targeted • Increased efficiency and cost effectiveness due for screening of cervical cancer may actually feel to a shorter interpretation time. perfectly healthy and may see no reason to visit a • The material collected can also be tested for health facility. HPV DNA (reflex HPV testing) Pap smear (cytology) is a time tested method of screening and has reduced incidence and Q.3. Sometimes we get the reports of Pap smear mortality of cervical cancer in developed countries. as CIN, Carcinoma in situ or dysplasia, LSIL and HSIL? What is the difference between all Q.1. What are the other screening tests which these terminologies? may be more practicable for our country? Ans: All these terminologies point towards pre- Ans: invasive lesions of the cervix. The concept of I. Visual inspection after acetic acid (VIA) precursors was brought out way back in 1888 when II. Visual inspection after Lugol’s Iodine ( VILI) certain areas of non invasive atypical changes were III. HPV DNA test recognized in tissue specimens adjacent to invasive cancers. The term carcinoma in situ (CIS) was Q.2. What is liquid based cytology (LBC)? introduced in 1932 for those lesions in which Ans: It is a refinement of conventional cytology in undifferentiated malignant cells involved the full which the specimen from the cytobrush/spatula is thickness of the epithelium without disruption of transferred to a preservative solution instead of basement membrane (Borders). Subsequently, smearing of the scraped cervical cells from the association between carcinoma in situ and invasive transformation zone on a slide. The specimen is cancer was reported. sent to a laboratory where the slide is prepared. It The term ‘dysplasia’ was introduced in the late is more expensive and laboratory staff needs special 1950s to designate the cervical epithelial atypia that training, however: it has few advantages over the is intermediate between normal epithelium and CIS conventional Pap smear: (Regan, 1953). Dysplasia was further categorized 328 Case Discussions in Obstetrics and Gynecology into mild, moderate and severe, depending on the Q.4. How will you manage such a case? degree of involvement of the epithelial thickness Ans: The algorithm of management of ASC-US is by the malignant cells. provided by the American Society of Colposcopy Later on, a direct correlation of progression and and Cervical pathology (ASCCP), 2007.1 Accor- histological grade was observed on the basis of ding to ASCCP, reflex HPV DNA testing should follow-up studies. This led to the concept of a single be advised for a combined triage provided that it is continuous disease process by which normal affordable. In circumstances in which it is not epithelium evolves into preinvasive and then to available, two repeat Pap smear at 6 months interval invasive cancer. On this basis, the term cervical is advised, as the negative predictive value of two intraepithelial neoplasia (CIN) was introduced to consecutive negative Pap smear after an ASC-US denote the whole range of cellular atypia confined is quite high. After this, she can return to routine to the epithelium. CIN 1 corresponds to mild, CIN screening. However, if one of the Pap report is again 2 to moderate and CIN 3 to both severe dysplasia same or higher, colposcopy is indicated. Third and carcinoma in situ. The Bethesda System (TBS) opinion is that if patient can not come back for a was introduced in 1991 and 2001 in which the term six monthly follow-up, colposcopy should be done. CIN was replaced by squamous intraepithelial If colposcopy does not show any abnormal findings, lesion (SIL). The correlation between all these she can be followed up with Pap smear after one systems is elaborated in Table 25.1. year. Routine use of diagnostic excisional pro- cedure is unacceptable. CASE 1 Mrs Laxmi (name changed), 30 years old P 4+2 Q.5. Is the management same if Mrs Laxmi’s had a normal vaginal delivery one year back. She age was less than 20 or if she was pregnant? came to gynecology OPD with complaint of vaginal Ans: No. For a woman who is in the adolescent discharge. Per speculum examination showed age group ( 20 or below), management of ASC-US cervical erosion (ectopy) and moderate amount of and LSIL is conservative; colposcopy or HPV DNA mucoid vaginal discharge. She also brought a Pap testing need not be done because high-risk HPV smear report of ASC-US. DNA is likely to be positive in this age group and

Table 25.1: Correlation between original CIN, modified CIN and Bethesda system Dysplasia terminology Original CIN Modified CIN Bethesda system terminology terminology Normal Normal Normal Within normal limits Benign Cellular changes (infection or repair) ASC-US, AG-US Atypia Koilocytic atypia Low grade CIN LSIL Flat condyloma without epithelial changes Mild dysplasia or dyskeratosis CIN 1 Low grade CIN LSIL Moderate dysplasia or dyskeratosis CIN 2 High grade CIN HSIL Severe dysplasia or dyskeratosis CIN 3 High grade CIN HSIL Carcinoma in situ CIN 3 High grade CIN HSIL Invasive carcinoma Invasive carcinoma Invasive carcinoma Invasive carcinoma Management of Abnormal Pap Smear and Cervical Cancer 329 is of no clinical use. She should be called for repeat Q.8. How will you manage? Pap smear after every 6 months for a year. If she Ans: As given in the algorithm of ASCCP,1 was pregnant, options would be to allow for deferral colposcopy is indicated for this patient. If of colposcopy until 6 weeks after delivery because colposcopy shows no identifiable lesion or it is an the risk for invasive cancer following ASC-US, unsatisfactory colposcopy, endocervical sampling 1 LSIL and CIN I is very low. should also be done to rule out pathology in the endocervix. If colposcopy shows an abnormal area, CASE 2 targeted biopsy should be taken along with 35 years old, Mrs Ratna (name changed), P 2+0, endocervical sampling. If no CIN 2 or 3 is found comes to OPD with a Pap smear report of ASC-H. after colposcopy, either call her for high-risk HPV She had no symptoms of vaginal discharge or inter DNA after one year or repeat cytology after 6 and menstrual bleeding. 12 months. If HPV DNA test is negative or two consecutive Pap smears are negative, she can be Q.6. How will you manage her? kept for routine screening. Colposcopy is again to be done if follow-up HPV test comes positive. Ans: Since the prevalence of CIN 2 and 3 is higher Previously, if CIN 1 was detected in a woman in such situation, colposcopy is indicated straight with unsatisfactory colposcopy, then a diagnostic away. If that is normal (i.e. no CIN 2 or 3), she can excisional procedure was recommended but in be followed up with HPV DNA testing at 12 months 2006, this recommendation was removed. or Pap smear at 6 months interval for a year. If HPV Diagnostic excisional or ablative procedures are is positive at the follow-up visit at one year or again unacceptable in the initial management of LSIL has ASC-US or greater on cytology, again colpo- according to ASCCP guidelines. scopy should be done. If HPV is negative or 2 repeat cytology reports are normal, this patient can return 1 Q.9. What will you do if colposcopy directed to routine cytologic screening. biopsy report shows CIN 2? Q.7. Why HPV DNA testing is not considered Ans: If the histopathology report is CIN 2 or 3 i.e. as one of the options in the initial management high grade lesion, there is 1.44% chance of cervical of ASC-H as in the case of ASC-US? cancer in the two year time. So she must receive treatment in the form of ablative or excisional Ans: Recent studies have shown high rates (37- procedure. 100%) of positive high-risk HPV DNA among women with ASC-H. Since the prevalence of CIN Q.10. What are the different ablative and 2or 3 is very high in such women and there is high excisional procedures? How to decide which rate of HPV positivity, testing of HPV DNA will procedure to choose? not be of any clinical value in the initial manage- Ans: Different ablative procedures are cryotherapy, ment in this case.2 laser electrofulguration or cold coagulation. Excisional procedures include loop electrosurgical CASE 3 excisional procedure, cold knife conisation, laser Mrs Anju (name changed), 40 years old woman, conisation. Ablative therapies are not appropriate complaining of persistent vaginal discharge comes if colposcopy is unsatisfactory, if the entire to OPD with a Pap smear report of LSIL or mild squamocolumner junction or entire lesion is not dysplasia. seen, if the lesion is large (covers three or more 330 Case Discussions in Obstetrics and Gynecology quadrants of cervix) or if innasive cancer is Q.13. How will you manage? suspected. In such situations excisional procedure Ans: As per ASCCP guidelines,1 colposcopy is is preferred. The biggest advantage of excisional indicated in this patient. Endocervical curettage at procedure is that tissue sample is obtained for the time of colposcopy and directed biopsy from histopathology. any abnormal lesion is also done. Since this patient has come from a distant place and may not be able Q.11. What are the advantages and disadvan- to come, immediate treatment with a loop tages of ablative procedures? electrosurgical excisional procedure may be a better Ans. Advantages are: alternative. a. Easy to perform b. Equipment needed is inexpensive Q.14. Would the management be the same if she c. No risk of acute bleeding was pregnant? d. Useful in low resource setting Ans: No. Colposcopy is done and biopsy should Disadvantages: be taken only if CIN 2 or worse is suspected. a. No tissue is obtained for histopathology Cervical dysplasia should not be treated during b. Cryotherapy can cause profuse watery discharge pregnancy because pregnancy does not hasten the for 2-4 weeks and many patients may course of disease and moreover, regression rate for experience cramping or vasonagal symptoms CIN after pregnancy is high. Route of delivery also during the procedure. does not affect the process of regression. Endo- cervical curettage is never done during pregnancy. Q.12. Is the management different in post- menopausal with a LSIL report? Q.15. What would be the management for a Ans: Yes. She should be managed in the similar HSIL report in a younger patient (20 years or manner as premenopausal woman who has ASC- less)? US report, i.e. triage with HPV testing, immediate Ans: According to ASCCP guidelines,1 colposcopy colposcopy or serial cytology. Repeat cytology after is recommended but see and treat policy by surgical course of intravaginal estrogen is no more recom- excisional procedure is not accepted. If colposcopy 2 mended according to 2006 guidelines. If HPV does not show CIN 2 or 3, she is simply followed DNA is negative or colposcopy is normal, repeat up by repeat colposcopy and cytology every cytology is done after 12 months. If HPV is positive 6 months for two years. If colposcopy is not satis- or if repeat cytology reveals ASC-US or greater, factory or endocervical sampling is positive for then colposcopy is recommended. If two conse- dysplasia, only then diagnostic excisional proce- cutive repeat cytology smears are negative, she can dure is done. The rationale behind the conservative be followed up by routine screening. management is that although HPV infection is common in young adolescent woman, cervical CASE 4 cancer is uncommon and most of dysplasia would A 35 years old Mrs Aman (name changed) brings regress spontaneously. with her a report of HSIL with the presenting symptom of white discharge per vaginum. She Q.16. What would be the management if belongs to a poor socioeconomic status and has colposcopy directed biopsy of Mrs Aman does come from outside Delhi. not show CIN 2 or 3? Management of Abnormal Pap Smear and Cervical Cancer 331

Ans: In that situation, according to the guidelines. abnormality is found on colposcopy and endo- A diagnostic excisional procedure may be cervical/ endometrial sampling and HPV DNA test performed as the risk for having CIN 2 or 3 is very is negative, she will be called for follow-up for high. Even the Pap smear slide and histopathology repeat cytology and HPV DNA test in 12 months. report can be reviewed by the pathologist and If only HPV test is positive in the initial evaluation, managed accordingly. If this can not be done, repeat cytology and HPV DNA testing should be patient can be followed up with Pap tests and done after 6 months. colposcopy every 6 months for a year. If any of the tests is positive, diagnostic excisional procedure Q.18. What will be the management if the same must be done. If the Pap test results and woman’s report is AGC (favors neoplasia)? colposcopies are negative both times, the patient Ans: Since these are atypical endometrial cells, can be returned to routine Pap smear screening. endometrial biopsy and endocervical sampling is Any patient who is 20 years or older with a Pap first done. If it is negative, complete cervical smear report of HSIL and unsatisfactory evaluation is done by colposcopy and HPV DNA colposcopy, straightaway diagnostic excisional testing. procedure is done. In a postmenopausal woman, evaluation of endometrial thickness by ultrasound may be a CASE 5 logical alternative before doing endometrial biopsy Forty years Mrs Tina (name changed) brings the because thickness of less than 5 mm has a high Pap report showing atypical glandular cells (AGC). negative predictive value. If ultrasound or endo- She is obese multiparous and complains of menorr- metrial biopsy does not reveal neoplasia, D and C hagia. and hysteroscopy may be necessary.

Q.17. What is AGC and what is the difference Q.19. What will be the management in between AGC and AGUS and how will you postmenopausal woman if the Pap smear results manage such a case? show AGC (favor neoplasia or adenocarcinoma in situ (AIS)? Ans: In the revised Bethesda system (2001), AGUS terminology has been replaced by AGC. The Ans: The management of cytology smear showing glandular abnormalities are expressed as AGC AGC (favors neoplasia) or AIS is same, i.e. (specify endocervical, endometrial, not otherwise endocervical curettage. The initial evaluation is specified) and AGC (favors neoplasia). The done the same way as in AGC. If no lesion is found underlying significant neoplasia rate changes from or only CIN 1 is found, it is necessary to perform 9 to 50%. According to the current management excisional biopsy because the chances of under- for AGC, coloposcopy and directed biopsies, lying cancer rate are high. If a significant lesion is endocervical curettage and HPV DNA testing is found, treatment should be directed by histo- recommended. This multimodality testing is pathology report. necessary to detect the lesions which are in gland crypts and may escape detection by sampling CASE 6 devices and visual methodology. This patient will A 38 years old, Mrs Nagma (name changed) brings also require endometrial sampling since she is the Pap smear report of benign appearing endo- above 35 years and has menorrhagia. If no metrial cells. She has no complaints. 332 Case Discussions in Obstetrics and Gynecology

Q.20. What is its significance and how to features. Markedly atypical keratinization can be manage? seen in invasive tumors but can also overly a Ans: Benign appearing endometrial cells, endo- keratininzing dysplasia. Invasive squamous cell metrial stromal cells or histiocytes in an asympto- carcinoma can demonstrate the presence of matic patient are not associated with significant prominent nucleoli; however, that feature can also neoplasia. So this patient does not require any be seen in CIN 3. further evaluation. The action plan for such a patient has just to be If the same woman was postmenopausal, same as for HSIL, i.e. colposcopy with endocervical endometrial evaluation should be done even if she curettage even if the colposcopy is satisfactory. is asymptomatic because underlying rate of Loop excisional procedure is done only if colpo- hyperplasia or malignancy may be found in 7% of scopic features are not suggestive of invasive these cases. A recent review (ref) has shown the carcinoma. In that case, punch biopsy can be taken incidence of hyperplasia as 20%, atypical from the most abnormal area or even four quadrant hyperplasia 8% and that of cervical carcinoma as biopsy can be taken if no abnormal lesion is seen 3 high as 15%. on colposcopy.

Q.21. What would you advise if the cytology Q.23. This patient comes back with the histo- report shows adenocarcinoma? pathology report of CIN 3. Discuss the further Ans: Initial evaluation by HPV DNA, colposcopy, management. endocervical and endometrial sampling by Ans: In this patient cone biopsy will be a preferred excisional biopsy and D and C/ hysteroscopy is approach since there is discrepancy between the done. If all are negative, USG imaging of pelvis is Pap smear report and histopathology report. Pap recommended. Even CT scan, Ca 125 may be smear has reported malignant cells, so taking a necessary if clinical suspicion of underlying malignancy is confirmed by second review.1 bigger biopsy is essential to rule out the involvement of stroma beyond the epithelium. CASE 7 Q.24. What is the recommended management A 40 years old woman complaining of persistent of a woman with CIN 1? white discharge per vaginum for the last two years, on per speculum examination shows a hyper- Ans: CIN 1 preceded by ASC-US, ASC-H or LSIL trophied cervix with ectropion. Pap smear was done can be followed with HPV DNA every 12 months which shows malignant cells. or cytology every six months. Colposcopy should be done if HPV is positive or cytology report is Q.22. How do we interpret such a report? What ASC-US or greater. If CIN 1 persists for two years, is the action plan for such a patient? ablative procure (if colposcopy is satisfactory) and Ans: The morphology of sqaumous cell carcinoma excisional procedure (if colposcopy is unsatis- can vary in the degree of differentiation and factory), should be done. However, if CIN 1 is presence or absence of keratinization. Some appear preceded by HSIL or AGC-NOS, diagnostic identical to HSIL on Pap test. False positive pap excisional procedure should be done.2 diagnosis of squamous cell carcinoma is possible Adolescent and pregnant women with CIN 1 because of some overlap in key morphologic should be followed up with repeat cytology. Management of Abnormal Pap Smear and Cervical Cancer 333

Q.25. What is the recommendation for per vaginum examination, hard growth is felt on managing CIN 2 or 3? anterior cervical lip, uterus is bulky, bilateral Ans: A diagnostic excisional procedure is recom- fornices are free. mended for women with a histological diagnosis of CIN 2/3. Hysterectomy as primary therapy is Q.27. What is the differential diagnosis of a unacceptable.2 granulomatous growth on cervix? Follow-up should be with HPV DNA at 6-12 Ans: months or combination cytology and colposcopy • Carcinoma cervix at 6 month interval. Further management depends • Tuberculosis upon reports. • Schistosomiasis • Coccidoidomycosis Q.26. What are the situations in which cone • Crohn’s disease biopsy is indicated? • Brucellosis Ans: The indications of cone biopsy are as follows: • Actinomycosis • The lesion extends into the endocervical canal • Sarcoidosis and it is not possible to confirm the exact extent. • Syphilis (ulcerative/ excavating growth) • The lesion extends into the canal and the farthest extent exceeds the excisional capability of the Q.28. From where should biopsy be taken in LEEP cone technique (maximum deapth of such a case? 1.5 cm). Ans: Biopsy should be taken from the margin of • The lesion extends into the canal and the farthest the growth, not from the center because of less extent exceeds the excisional capability of the blood supply to that area, making it necrotic. colposcopist. • The cytology is repeatedly abnormal, suggests CASE 9 neoplasia, but there is no corresponding colpo- 45 years old, Kamla (name changed), P5L5, scopic abnormality of the cervix or vagina on married at the age of 16 years, comes to the gyne- which to perform biopsy. cology OPD with complaint of postcoital bleeding • Cytology suggests a much more serious lesion and foul smelling discharge per vaginum. On than that which is seen and biopsy confirmed. examination, she is thin built and pale. On per • Cytology shows atypical glandular cells that speculum examination, there is a fungating growth suggest the possibility of glandular dysplasia seen on the anterior lip of the cervix. On per or adenocarcinoma. vaginum examination, same growth is felt, uterus • Colposcopy suggests the possibility of glandular is retroverted, normal size and bilateral fornices are dysplasia or adenocarcinoma. free. Punch biopsy taken from the growth shows • Endocervical curettage reveals abnormal moderately differentiated sqaumous cell carcinoma. histology. Q.29. What are the symptoms with which, CASE 8 patient can present in early cervical cancer? A 40 years P5L5, comes to the OPD with complaint Ans: In early stage of invasive cervical cancer, of blood stained discharge per vaginum. On per presenting symptoms can be excessive vaginal speculum examination, there is a growth on the discharge which may sometimes be foul smelling, anterior lip of the cervix and it bleeds on touch. On irregular bleeding (intermenstrual), postcoital 334 Case Discussions in Obstetrics and Gynecology bleeding, postmenopausal bleeding. Unfortunately, Stage II Cervical carcinoma invades beyond the women in our country do not seek medical help in uterus, but not to the pelvic wall or to the lower the early stage. Eighty percent of them come in late third of the vagina. stage. When they present with blood stained vaginal IIA without parametrial invasion. discharge which may be very foul smelling, IIA1 clinically visible lesion ≤ 4.0 cm in greatest backache or lower abdominal pain, urinary dimension. frequency and urgency or even decreased urinary IIA2 clinically visible lesion > 4 cm in greatest output, urinary or fecal incontinence, swelling of dimension. lower limbs or even breathlessness.4 IIB with obvious parametrial invasion. Stage III The tumor extends to the pelvic wall Q.30. How will you manage further? and/or involves lower third of the vagina and/or Ans: Once a histological diagnosis of cervical causes hydronephrosis or non-functioning cancer has been made; next step is to stage the kidney.** disease to formulate the most effective therapy. IIIA tumor involves lower third of the vagina, Cervical cancer is clinically staged, supplemented with no extension to the pelvic wall. by a limited number of investigations. IIIB extension to the pelvic wall and/or hydro- nephrosis or non-functioning kidney. FIGO Staging of Cervical Cancer, 2009 Stage IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the Stage I The carcinoma is strictly confined to the mucosa of the bladder or rectum. A bullous edema, cervix (extension to the corpus would be dis- as such, does not permit a case to be allotted to regarded). Stage IV. IA invasive carcinoma which can be diagnosed IVA spread of the growth to adjacent organs. only by microscopy, with deepest invasion ≤ 5 mm IVB spread to distant organs. and largest extension ≥ 7 mm. IA1 measured stromal invasion of ≤ 3.0 mm in Q.31. How will you evaluate the case further depth and extension of ≤ 7.0 mm. before formulating a management plan? IA2 measured stromal invasion of > 3.0 mm 4 and not > 5.0 mm with an extension of not > 7.0 Ans: Pretreatment evaluation will include mm. • Complete blood count IB clinically visible lesions limited to the cervix • Urine for albumin, sugar, microscopy, culture uteri or preclinical cancers greater than stage IA*. and sensitivity. IB1 clinically visible lesion ≤ 4.0 cm in greatest • Chest X ray dimension. • IVP/ ultrasound to rule out renal involvement. IB2 Clinically visible lesion > 4.0 cm in greatest Cystoscopy/ barium enema/ sigmoidoscopy if dimension. bladder or rectal involvement is suspected.

*All macroscopically visible lesions—even with superficial invasion—are allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of not > 7.00 mm. Depth of invasion should not be > 5.00 mm taken from the base of the epithelium of the original tissue—superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with “early (minimal) stromal invasion” (~1 mm). The involvement of vascular/lymphatic spaces should not change the stage allotment. **On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or non-functioning kidney are included, unless they are known to be due to another cause. Management of Abnormal Pap Smear and Cervical Cancer 335

CT scan or MRI should be done, if available, If the invasion is more than 3mm and up to to determine disease status with regards to its extent. 5 mm and < 7 mm in horizontal spread (stage IA2), This might change the proposed treatment then, type II radical hysterectomy (modified radical) modalities; however, it does not change the clinical with pelvic lymph node dissection should be done stage of the disease. since the incidence of lymph node involvement is up to 5% or more. Same treatment would also be Q.32. How will you counsel the patient? advisable if on discussion with the pathologist, Ans: We will tell the patient about the different depth of invasion is not certain. treatment modalities: • Surgery (total hysterectomy with bilateral Q.35. How will the management differ if the salpingo-oophorectomy with lymph node dis- patient was 35 years old and multiparous? section). Ans: In this patient, total hysterectomy (abdominal • Radiotherapy (radical or palliative). or vaginal) will be the ideal management. Lymph node dissection is not required as the incidence of Q.33. What are the indications of surgery? involvement is very low (< 1% in stage IA 1). Ans: Ovaries should be conserved and preferably trans- • Associated PID posed above the pelvic brim. • Associated fibroid, ovarian tumor, prolapse uterus, endocervical carcinoma CASE 11 • Stump carcinoma Forty-five years old, Mrs Rani (name changed) • Radioresistant adenocarcinoma of cervix came with history of inter menstrual bleeding. On • Young patient examination there was a small growth on the • Recurrence after radiation therapy. anterior lip of the cervix, vagina and parametrium CASE 10 were free. Biopsy taken from the growth showed a histopathology report of moderately differentiated Mrs A had come from outside with Pap smear report large cell keratinizing sqaumous cell carcinoma. of severe dysplasia and colposcopic directed biopsy report showed CIN 2. Cone biopsy was done and Q.36. What is the management? histopathology report showed microinvasive carcinoma. Ans: As this patient is stage IB 1, different treat- ment options which can be offered to her are: Q.34. How will you manage? • Type III radical hysterectomy with bilateral Ans: Management of patient will depend upon age pelvic lymph node dissection and parity. If the patient wants fertility preservation, • Radiation therapy we need to discuss the histopathology report with • Concurrent chemoradiation. the pathologist, for a comment on the margins of the specimen and involvement of lymphovasular Q.37. What are the treatment options for stage space and depth of invasion. If the margins are clear IB 2 and IIA? and there is no involvement of the lymphovascular Ans: The treatment options are: space and depth of invasion is up to 3 mm, patient • Type III radical hysterectomy with bilateral can be kept on follow-up. pelvic lymph node dissection 336 Case Discussions in Obstetrics and Gynecology

• Radiation therapy (external + intracavitary) teletherapy, radiation is given from a distance with • Radiation combined with chemotherapy the help of a radioactive source such as cobalt 60 (chemoradiation) or linear accelerator targeting the primary disease • Neoadjuvant chemotherapy followed by surgery as well as the probable draining nodes. or radiation. In brachytherapy, the tumor and surrounding areas are treated by direct contact of high energy Q.38. What are the criteria which decide the small wire like or pellet like sources which move choice of treatment modality? into the hollow tubes placed in the vagina and in Ans: the uterine cavity or in the substance of the cervix. • Age of the patient The dose is calculated according to the amount of • Associated gynecological problem (fibroid, radiation received at two arbitrary points. ovarian tumor, prolapse) Point A: It is 2 cm above external os and 2 cm lateral • Associated co-morbid condition to cervical canal. It is point of crossing over of ureter • Facilities and expertise available by uterine artery. • Patient’s choice. Point B: It is 3 cm lateral to point A. This point is on the lateral pelvic wall at the obturator gland. Q.39. What are the advantages of surgery over Intracavitary radiotherapy gives 7,000 rads at radiotherapy? point A (over a period of three weeks) 2,000 rads Ans: The advantages are: at point B. Supplementation is done by external • Preservation of ovarian function beam radiation. Telegamma therapy gives 4,000 • Assessment of extent and spread of disease rads at point B (over next three 200 rads/ day). Thus, • No risk of secondary uterine cancer point B receives 6,000 rads in six weeks which is • Complications that occur after surgical treat- cancericidal for parametrium and pelvic lymph ment are more readily correctable than that of nodes. radiotherapy. Q.42. How will you follow-up after treatment? Q.40. In this patient, radical surgery has been done. What criteria in the histopathological Ans: Women who have been treated with surgery report of the specimen, will indicate the need alone should have three monthly follow-up consultations for a period of first 2 years and then for adjuvant therapy? annually for the rest of the life. With careful Ans: The criteria are: Positive lymph nodes and recording of symptoms, particularly bleeding, positive surgical margins, parametrial extension discharge or pelvic pain. During the consultations, (high-risk category) the following examinations should be performed: Deep invasion of cervical stroma, lyphmo- • Speculum examination and visualization of the vasular space invasion, tumor size more than 4 cm vaginal vault at the last two of the above criteria must be present • Cytological smear of the vault and of any for requiring adjuvant therapy (intermediate risk). abnormality noted on examination In patients not having any of the above criteria, • Bimanual vaginal and rectal examination to adjuvant therapy is not recommended (low risk). palpate for recurrence of disease • Chest X-ray should be done every year. Q.41. Explain about the radiotherapy options • Other investigations depending on the clinical available. findings and resources available. Recurrent Ans: Radical radiotherapy in cervical cancer disease in these women can be treated with comprises of teletherapy and brachytherapy. In radiation. Management of Abnormal Pap Smear and Cervical Cancer 337

Q.43. How will the management differ if the • In adolescent (< 20 years) girls who have patient was pregnant? abnormal Pap smear report and histology, Ans: Management of carcinoma cervix in observation by yearly cytology is favored pregnancy will depend upon stage of the disease according to recent guidelines. as in a non-pregnant patient. • In adolescent girls triage with HPV DNA for In stage IA1, pregnancy can be followed till cytology report of ASC-US is not recommended term and vaginal delivery can be allowed. Vaginal as recurrent HPV infection is common in this hysterectomy can be done, 6 weeks later, if age group. pregnancy is not desired. • Screening guidelines are similar in pregnant In stage IA2, continue pregnancy till fetal patients. Colposcopic examination may be maturity followed by cesarean section and modified deferred until postpartum period unless there radical hysterectomy with pelvic lymph node is suspicion of invasive cancer. dissection. • Therapeutic conization is contraindicated in For stage IB1, do not delay treatment for more pregnancy. Indications of diagnostic conization than 4 weeks to attain fetal maturity. Do classical are: Microinvasion/AIS on punch biopsy, strong cesarean section and radical hysterectomy with suspicion of invasive cancer on colposcopy or lymph node dissection. cytology. In stage II to IV, if the fetus is viable deliver by • ECC is contraindicated in pregnancy. classical cesarean section and follow-up with • Recommended management of AGC is colpo- radiotherapy immediately. scopy and directed biopsy, ECC and endo- In the first trimester and stage II-IV disease start metrial evaluation. external beam radiotherapy, wait till fetal maturity, • If cytology report is AGC- favors neoplasia or if second trimester. AIS then ecxisional biopsy is preferred. • Symptoms of early cervical cancer are inter- Key Points and Good Clinical Practice menstrual bleeding, postcoital or postmeno- • According to revised ASCCP guidelines (2007), pausal bleeding and persistent excessive vaginal there are three options for women with cytology discharge. All sexually active women must be report of ASC-US; repeat cytology, HPV DNA asked about these symptoms to detect cervical testing or colposcopy. HPV DNA testing is ideal cancer at an early stage. but management depends upon resources • Histological confirmation of cervical cancer available and patient affordability. Follow-up must be done before planning the treatment. is done with repeat HPV at 12 months or • There are few changes in clinical [FIGO] cytology every six months until two consecutive staging of cervical cancer in 2009, i.e. deletion reports are negative after which patient can of stage O and stage II A to be divided into into return to routine screening. II A1 and II A 2. • For all Pap smear reports showing ASC-H or • Pretreatment evaluation includes IVP or above, colposcopy should be done. abdominal ultrasound, cystoscopy, chest X-ray • HPV DNA testing is useful for ASC-US and and ECG in addition to the routine blood and not ASC-H as there is high prevalence of urine investigations. CT scan MRI and PET oncogenic HPV and high grade cervical intra- scan may be done if affordable to tailor the epithelial neoplasia in the latter. management. 338 Case Discussions in Obstetrics and Gynecology

• Surgery, radiotherapy, and concurrent chemo- REFERENCES radiation are the main modalities of treatment, 1. Apgar BS, Kittendorf AL, Bettcher CM, et al. Update the choice of which depends upon different on ASCCP consensus guidelines for abnormal cervical criteria, e.g. age of the patient, stage of the screenibg tests and cervical histology. Am Fam disease, associated gynecological problem, Physician 2009;80(2):147-55. 2. Obstetrics and Gynecology Clinics of North Obstetrics comoirbidities, facilities available and patient and Gynecology America; Colposcopy, Cervical preference. Screening & HPV. December 2008;35(4). • Follow-up after treatment is same after both 3. Greespan DL, Cardill M, Davey DD, et al. Endometrial surgery and radiotherapy, i.e. vault smear, cells in cervical cytology: review of cytologic features bimanual vaginal and rectal examination and and clinical assessment. J Low Genit Tract Dis 2006; 10(2):111-22. other investigations depending upon the clinical 4. WHO. Comprehensive cervical cancer control, a guide findings. to essential practice 2006. Swaraj Batra, Puneet K Kochhar

26 Postmenopausal Bleeding

Bleeding from genital tract occurring after 12 women increases the risk of endometrial months of amenorrhea in a woman of post- cancer 4-8 times), topical oestrogen, menopausal age (other than cyclical bleeding that Tamoxifen (four fold increase in endometrial occurs in women taking sequential hormone cancer after 5 years of use), and any drugs replacement therapy) is known as postmenopausal especially for hypertension, hypothyroidism, bleeding. For most women, menopause is in late diabetes should also be elicited. Risk is 40’s or early 50’s. increased in diabetes due to increased oestrogen levels, hyperinsulinemia or CASE 1 insulin like growth factor. Mrs X, a 60 years old postmenopausal lady d. It is important to note whether the patient complains of bleeding per vaginum off and on was having regular screening with Pap for one month. How will you manage this case? smear or not, as another important cause of postmenopausal bleeding can be cervical After taking history and doing clinical cancer. examination, work up of the patient to exclude e. Associated symptoms like pain, fever, genital cancers will be done. changes in bladder and bowel function (to exclude pyometra). Q.1. What is important to elicit in history and f. Urinary frequency, burning micturition, examination? hematuria and h/o piles or bleeding per Ans: rectum or pain during defecation (fissure in A. ano) should also be elicited to find out a. Age of the patient is noted. As the age whether bleeding is not vaginal. advances, risk of endometrial cancer B. Menstrual history: Age of menarche and increases. It is 1% at 50 years and 25% at menopause should also be noted. In late 80 years of age. menopause the risk is increased 2-3 times. It is b. Details of duration and severity of bleeding important to note whether the patient had any are noted, in addition to whether it is related treatment for polycystic ovarian disease, to trauma, intercourse, recent genital tract anovulation or endometrial hyperplasia or surgery, etc. oestrogen use for gonadal dysgenesis or c. History of radiation, HRT (oestrogen use treatment for granulose theca cell tumors, as without progestins in postmenopausal cancer is more common in conditions with high 340 Case Discussions in Obstetrics and Gynecology

oestrogens (see risk factors). 25% to 43% cases varicosities, atrophic changes in vagina (like of atypical hyperplasia have associated loss of rugae, dry vagina, inflammation and endometrial cancer. petechiae) and atrophic changes on cervix, C. Obstetrical history: Parity should be noted. whether flushed with vagina, bleeding through Endometrial cancer is more common in cervical os, whether stenotic and approach to nulliparous (2-3 times ↑ risk) and infertile, while cervix should be noted. multiparous women are at risk for cervical J. Per vaginum: Check uterine size, mobility, cancer. adnexal mass and feel for nodularity in pouch D. Past history: History of treatment of any other of Douglas and thickening or induration in cancer like breast or cervical cancer. parametrium. E. Family history of bleeding disorders; breast, K. P/V/R: Confirm P/V findings and check for colorectal or endometrial cancer or others mass, nodularity in the pouch of Douglas, associated with hereditary nonpolyposis parametrial thickening and whether rectal colorectal cancer should be elicited. Women mucosa is free or not. with hereditary nonpolyposis colorectal cancer syndrome (HNPCC) with germline mutations This patient, Mrs X had menopause at 50 years, in mismatch repair genes MLH1, MSH2 and is obese, hypertensive Para1+0 and has no other MSH6 have 40-60% life-time risk of positive history or findings on general endometrial as well as colon cancer. examination. F. General examination: Note BMI. In obesity, On P/S, cervix is healthy, flushed with vagina, there is 3-fold increase in risk of endometrial os stenotic, upper vagina narrow with difficulty cancer because androstenedione, (85% in exposing cervix. produced from adrenals and 15% from the On P/V, bleeding through os is present, and ovary), is converted into oestrone in peripheral on P/V/R, uterus is anteverted, normal size, fat and there is lesser binding of steroids due to mobile, adnexae free, parametrium and POD free. decreased levels of sex hormone binding What would be your most probable diagnosis? globulin. Features of hypothyroidism should Since this patient has no local lesion on also be noted. Assess pallor, blood pressure, examination, and bleeding is seen through the os, note lymphadenopathy, pedal edema, thyroid it is likely to be uterine bleeding. Endometrial and breast abnormalities. Do systemic cancer should be suspected as she has low parity, examination including heart and lung is obese and hypertensive (which are risk factors examination to exclude co-existing medical for carcinoma endometrium), uterine bleeding is disorders or distant metastasis as the patient may present and no other positive findings are present require surgery. on examination. G. Per abdomen examination: Any organomegaly or lump/ascites should be noted. Q.2. What investigations should be done? H. Local examination: Any growth, ulceration, Ans: Complete blood count, blood sugar (fasting abnormality should be noted on vulva, and postprandial), blood urea, Pap smear, X-ray perineum, urethra, suburethral region and anus. chest, ECG, and urine microscopy should be done. I. Per speculum: Cervix, vagina should be Transvaginal sonography should be done to exclude inspected for discharge, ulcer, or growth and any pelvic pathology and note the endometrial any abnormalities like white patches, warts, thickness. Postmenopausal Bleeding 341

It is traditional to do differential curettage under cystoscopy and sigmoidoscopy after adjusting GA to obtain tissue for histopathology. antihypertensive drugs. No abnormality was found Alternatively, endometrial biopsy from all walls, and the patient was instructed to take her aspiration biopsy from endometrium with antihypertensives regularly and is fine for last one endocervical curettings or office hysteroscopy and year. biopsy can be done in OPD setup. Pipelle sampling Alternatively, we could consider the patient for has a failure rate of 3% and there is insufficient hormonal therapy in the form of medroxypro- sampling in 5%. If reports are negative for cancer gesterone for 2 weeks every cycle for 3 months as on endometrial biopsy, then detailed D and C or her endometrium was showing proliferative hysteroscopic directed biopsy should be done. changes. As her bleeding stopped after D and C, These are indicated when USG is nondiagnostic, nothing more than antihypertensives were given i.e., after the first episode. Progestins (10-30 mg/day a. Endometrium cannot be visualised in totality medroxyprogesterone acetate) can be given in b. Endometrial thickness is >5 mm simple hyperplasia without atypia but hysterectomy c. Focal endometrial abnormality is recommended when there is associated atypia. d. Margins of endometrium are indistinct Endometrial cancer is present in 10% cases Q.5. What will you do in case she comes with while polyps, hyperplasia and fibroids are present recurrence again? in 40% cases. SIS (saline infusion sonography) or Ans: It is safer to do laparotomy and hysterectomy hysteroscopy can better delineate endometrial as none of the investigations can exclude pathology cavity, but tissue biopsy is mandatory for planning with 100% certainty (Table 26.1). any definitive treatment. Q.6. What are the Type I and Type II endo- Q.3. Is TVS required in all cases? metrial cancer? Ans: It is an optional complementary modality but Ans: tissue biopsy is mandatory. Type I – Endometrial cancers that are typically of endometroid pathology, low grade and associated Q.4. What is the correlation between with exposure to unopposed estrogens. These are endometrial thickness and endometrial cancer? diagnosed at an early stage and have an excellent Ans: Endometrial cancer is seen in 0.8% cases prognosis. They account for 90% of endometrial 1 when thickness is < 4 mm. At 5 mm thickness cancers. sensitivity of TVS for endometrial disease is 92% Type II – Endometrial cancers that are typically high and endometrial cancer is 96%. TVS is as sensitive grade, estrogen independent and often of papillary as endometrial biopsy and can complement when serous or clear cell pathology. They tend to be EB is not possible or nondiagnostic. diagnosed at a later stage, but have a poor prognosis 1 Differential curettage revealed proliferative even if diagnosed at an early stage. endometrium and endocervical curettings were scanty and inadequate for reporting. TVS showed Q.7. What are the high-risk factors for endometrial thickness of 4 mm. Patient was put developing endometrial malignancies? under observation and reported recurrent bleeding Ans: Most high-risk factors are related to presence after 6 months. Her BP was 170/100 mm Hg and of prolonged, unopposed estrogen stimulation of she was investigated further by TVS, hysteroscopy, endometrium.2,3 342 Case Discussions in Obstetrics and Gynecology

Table 26.1: Important causes of postmenopausal bleeding HRT Exclude endometrial malignancy and, if fine, continue with medroxyprogesterone 10 mg for 12 days along with conjugated oestrogen 0.625 mg daily Atrophy or senile vaginitis/endometritis HRT DUB – Hyperplasia without atypia Medroxyprogesterone acetate - Hyperplasia with atypia Hysterectomy Inflammation Treat infection, HRT Pyometra Drain and do endometrial and endocervical curettage after one week Foreign body Remove foreign body and treat infection Trauma vagina Treat infection and stitch in fresh case, or packing in old case Decubitus ulcer Vaginal packing, pessary or surgical treatment of prolapse after the healing of ulcer Polyp Polypectomy and D and C, and histopathological examination Cervical cancer Stage and treat by chemoradiation or surgery Endometrial cancer Staging laparotomy/panhysterectomy, lymphadenectomy – pelvic and para- aortic, omentectomy if indicated. Radiotherapy postoperatively (see text) Ovarian cancer Staging laparotomy and panhysterectomy + lymphadenectomy + omentectomy, or debulking depending on stage Fallopian tube cancer Staging laparotomy and panhysterectomy + lymphadenectomy + omentectomy Diseases of adjoining organs like piles, Surgical consultation and referral for appropriate treatment fissure in ano, etc.

Factor Relative Risk Endometrial hyperplasia may precede or occur 1. Atypical endometrial 8-29% simultaneously with endometrial cancer. The risk hyperplasia of progression to cancer in hyperplasia is as follows: 2. Nulliparous women 2-3 times • Simple cystic hyperplasia without atypia 1% 3. Infertility 8 times the risk • Complex adenomatous hyperplasia 3% 4. Irregular cycles/anovulatory 2-3 times without atypia cycles/PCOS • Simple cystic hyperplasia with atypia 8% 5. Late menopause (>52yrs) 2-4 times • Complex adenomatous hyperplasia 29% 6. Obesity with atypia 21-50 pounds overweight 3 times 25-43% of patients with atypical hyperplasia >50 pounds overweight 10 times detected in an endometrial biopsy or curettage 7. Exogenous HRT 4-8 times specimen will have an associated, usually well- (estrogens without progestins) differentiated endometrial cancer detected during 8. Tamoxifen for breast cancer 2-4 times hysterectomy. 9. Diabetes/Hypertension 1.3-2.8 times Certain factors which have been associated with 10. Functioning ovarian tumors 3.5-27 times decreased risk of endometrial cancer include 11. Genetic predisposition 20% multiparity, smoking, consumption of isoflavnes (Lynch II Syndrome) and lignans, diet rich in fruits, vegetables and fibers, 12. Higher socio-economic class, Increased risk physical activity and oral contraceptive use (50% white women 13. Endometrial hyperplasia Increased risk reduction in endometrial cancer perhaps secondary (as below) to net progestational effect due to use of the pill). Postmenopausal Bleeding 343

Table 26.2: Various methods available for cancer evaluation Method Advantages Disadvantages Sensitivity Specificity Pap smear Easy, available, Non-sensitive, no patient discomfort not-specific, pick up rate only 30-50% Office endometrial Cost-effective, disposable, Small risk of perforation, 83-94% 98-99% aspiration biopsy no anaesthesia needed patient discomfort Differential curettage Cost-effective Small risk of perforation, patient discomfort, can miss the lesion in 10% cases TVS Non-invasive, NPV 99%, Not cost-effective, PPV 9%, Asymptomatic 48% detects co-existent disease histopathological examination patients: 90% is still required for treatment Patients with 80% bleeding: 82% CT, MRI Not cost-effective Tumor markers not suitable CA-125, CA 19-9 Hysteroscopy Allows direct visualization Not feasible, invasive, 86.4% 99.2% of endometrial cavity, requires anesthesia useful in focal lesions and recurrent PMB Saline infusion Allows identification of Cannot diagnose malignancy, sonography (SIS) polyps/fibroids distorting histopathological examination endometrial cavity is still required for diagnosis and treatment

In the endometrium, progesterone stimulates bleeding at an early stage. Thus, screening for low- estradiol 17-β dehydrogenase enzyme, which risk population is not recommended. converts oestradiol to less potent estrone. The Screening for endometrial cancer or its relative risk is 0.2 after 10 years use of oral precursors may be justified in certain high-risk contraceptives, and reduced risk lasts for 20 or more women such as:2 years after discontinuation. i. Women receiving postmenopausal estrogen therapy without progestins Q.8. What is the role of universal screening in ii. Members of families with Hereditary non- endometrial cancer? What are the possible polyposis colon cancer (HNPCC) methods of screening? (No benefit has been demonstrated from routine Ans: Universal screening for endometrial cancer screening with transvaginal ultrasound or should not be undertaken because of lack of an endometrial biopsy in women taking tamoxifen). appropriate, cost-effective test and acceptable test that reduces mortality. Although many risk factors Q.9. How can the diagnosis of carcinoma for endometrial cancer have been described, endometrium be confirmed? screening the high-risk cases could at best detect Ans: The diagnosis of carcinoma endometrium can only half of all cases. It is also not warranted as be confirmed on histopathologic examination of more than 95% of patients are symptomatic and endometrial tissue. Various endometrial sampling present with abnormal peri- or post-menopausal procedures are: 344 Case Discussions in Obstetrics and Gynecology

Endometrial aspiration biopsy with endo- Contd... cervical curettage is the accepted first step in Squamous carcinoma Rare, poor prognosis, 36% evaluation of a patient with abnormal peri- or post- survival rate in stage I menopausal bleeding. It is done using a No.4 Undifferentiated carcinoma Karman’s cannula with a 20 or 50 ml syringe. Other Mixed carcinoma instruments which can be used are vabra aspirator, Pipelle, Novak curette, Z sampler. The diagnostic Q.11. What is the incidence of synchronous accuracy of an office EB is 90-98%, and if it is endometrial and ovarian cancer? negative, the patient should have differential Ans.: 1.4 to 3.8%. Mostly both endometrial and curettage. ovarian cancers are well-differentiated adeno- In-patient techniques include fractional carcinoma of low stage with excellent curettage, differential curettage, and hysteroscopic prognosis. directed endometrial biopsy. These should be reserved for cases where cervical stenosis or patient Q.12. What is the role of imaging modalities in tolerance does not permit adequate evaluation by diagnosis? aspiration biopsy, in cases with negative Ans: Various imaging modalities used in diagnosis endometrial biopsy or the specimen obtained on of endometrial cancer are: biopsy is inadequate, or EB and TVS reports don’t Ultrasound, especially transvaginal ultrasound tally. Hysteroscopy is more accurate in identifying is a simple non-invasive method. The findings polyps and submucous myomas than EB or D and C (see Table 26.2). suspicious of carcinoma endometrium are: 1. Endometrial thickness more than 4-5 mm in a Q. 10. Discuss the various histological types of postmenopausal lady. TVS has a sensitivity of endometrial cancer. 100% and specificity of 96% for identifying Ans: The histological classification of endometrial endometrial abnormalities. carcinoma is as follows2 (Table 26.3): 2. Polypoidal endometrial mass. 3. Collection of fluid in the uterus. Table 26.3: Histological classification Saline infusion sonography increases the Endometroid adenocarcinoma Accounts for 80% of sensivity to detect endometrial polyps from 35% endometrial cancer to 75%. Myometrial invasion can be detected in Variants: Villoglandular or Accounts for 2% 75% cases on USG. papillary Secretory 1% MRI: The accuracy of MRI to diagnose endometrial With squamous 15-25% cancer and depth of myometrial invasion varies differentiation from 70-97%. Mucinous carcinoma 5%, good prognosis CT scan has 84-88% accuracy in picking up Papillary serous carcinoma 3-4%, high grade, enlarged lymph nodes, though not as sensitive as associated with deep MRI for picking myometrial invasion. myometrial and lymphvascular space Q.13. What is the role of tumor markers in invasion, poor prognosis carcinoma endometrium? Clear cell carcinoma <5%, very aggressive, overall survival 33-64% Ans: Various tumor markers include CA-125, CA Contd... 19-9, CA 15-3. Postmenopausal Bleeding 345

• Little role in screening – not cost effective. depth of invasion and cervical involvement. • CA-125 useful in prognosticating, predicting – Barium enema, cystoscopy/IVP – not myometrial invasion and extrauterine spread indicated unless dictated by patient and in follow-up of patients with advanced and symptoms or clinical findings. recurrent cancer. It is specially useful in follow- (Barium enema, colonoscopy and procto- up if initial values are high. sigmoidoscopy should be done in cases with suspected HNPCC.) CASE 2 Q.15. How do you stage endometrial carcinoma? Mrs Y,a 60-year old obese patient comes with recurrent postmenopausal bleeding of 6 months Ans: Patients with endometrial cancer should duration. Endometrial biopsy shows moderately undergo surgical staging based on 2008 FIGO differentiated endometroid adenocarcinoma. system:

Q.14. How will you work up this patient pre- 2008 FIGO surgical staging for endometrial cancer4 operatively? Stage I * Tumor confined to corpus uteri Ans: After the diagnosis is confirmed by IA* No or less than half myometrial invasion histopathology, thorough pre-surgical evaluation is IB * Invasion equal to or more than half of performed to assess operability and the best the myometrium approach to management by taking into Stage II * Tumor invades cervical stroma, but does consideration history, clinical examination and not extend beyond the uterus** following investigations.3 Stage III* Local and/or regional spread of the Routine investigations: tumor • Blood tests: Blood grouping and cross- III A Tumor invades the serosa of the corpus uteri and/or adnexae# matching, Hemogram, LFT, KFT, serum III B Vaginal and/or parametrial involvement electrolytes, blood sugar, optional CA-125 III C Metastasis to pelvic and/or para-aortic • Urine analysis and culture lymph nodes • ECG III C 1 Positive pelvic lymph nodes • Pap smear III C 2 Postive para-aortic lymph nodes with • Endocervical and endometrial sampling is or without positive pelvic lymph nodes already done Stage IV* Tumor invades bladder and/or bowel • Imaging studies: mucosa, and/or distant metastasis – Chest X-ray IV A Tumor invasion of bladder and/or bowel – Contrast enhanced MRI abdomen/pelvis mucosa can be used to assess myometrial invasion IV B Distant metastasis, including intra- and cervical involvement pre-operatively abdominal metastasis and/or inguinal and plan the procedure with regard to need lymph nodes for lymph node sampling. Sensitivity for * - Either G1, G2 or G3 myometrial invasion is 80-100% and ** - Endocervical glandular involvement only should be specificity 70-100%. It can also assess considered as stage I and no longer stage II # depth of invasion in parametrium, and - Positive cytology has to be reported separately without ureteral, vascular and nerve entrapment. It changing the stage G1 - 5% or less of tumor shows a non-squamous or non- is specially useful in management of young morular (solid) growth pattern patients with low grade cancer, who desire G2 – 6-50% of the tumor shows a non-squamous or non- conservative therapy to preserve the uterus. morular (solid) growth pattern – CT abdomen/pelvis – not indicated as it is G3 – More than 50% of the tumor shows a non-squamous expensive, poor predictor of nodal disease, or non-morular (solid) growth pattern 346 Case Discussions in Obstetrics and Gynecology

At minimum, the surgical staging procedure FIGO clinical staging of endometrial should include: carcinoma (1971) i. Sampling of peritoneal fluid for cytological Stage I Confined to corpus, including isthmus evaluation Ia Length of uterine cavity <8 cm Ib Length of uterine cavity >8 cm ii. Systematic exploration of abdomen and Stage II Involves corpus and cervix, but has not pelvis with biopsy or excision of any extra- extended outside the uterus uterine lesions suggestive of metastatic Stage III Extends outside the uterus, but not cancer outside the true pelvis iii. Extrafascial hysterectomy and bilateral Stage IV Extends outside the true pelvis or involvement of mucosa of bladder/ salpingo-oophorectomy rectum iv. The uterine specimen should be opened and IVa Spread to adjacent organs tumor size, depth of myometrial invasion and IVb Spread to distant organs cervical extension assessed. v. Any suspicious pelvic and para-aortic lymph Q.17. What are the prognostic factors in endo- metrial carcinoma? nodes should be removed for pathologic examination. In addition, clinically negative Ans: retroperitoneal lymph nodes should be • Age: Younger women with endometrial cancer sampled in the cases with any of the following have a better prognosis than older women. risk factors: There is a higher incidence of grade 3 tumors • Serous/clear cell or high grade histology or unfavorable histological subtypes in older • Myometrial invasion > 50% women. • Histological type: Nonendometroid histo- • Tumor size >2 cm logical subtypes account for 10% of endo- • Cervical or isthmus involvement metroid cancers and carry an increased risk for • Adnexal or pelvic extension of disease recurrence and distant spread. In contrast to the • Enlarged lymph nodes 92% survival rate among patients with endometroid tumors, the overall survival rate Q.16. Is there any role of clinical staging in this for patients with these more aggressive patient? subtypes, is only 33%. Anss: If the medical conditions (diabetes and • Histological grade: Increasing tumor anaplasia hypertension) in this patient are well-controlled, is associated with a worse prognosis. surgical staging is preferred for management as • Tumor size: It is a significant prognostic factor clinical staging may not be as accurate. According for lymph node metastasis and survival in to 1971 FIGO staging system, clinical staging patients with endometrial cancer. Lymph node should be performed in patients unsuitable for metastasis has been reported in 4% cases with surgery because of poor medical condition or spread tumor < 2 cm, 15% cases with tumor > 2 cm, of disease (gross cervical involvement, parametrial and in 35% with tumor involving the entire spread, invasion of bladder or rectum, or distant uterine cavity. Reported 5-year survival is 98%, metastasis). 84% and 64%, respectively. Postmenopausal Bleeding 347

• Myometrial invasion: Increasing depth of • Genetic, molecular tumor markers: The invasion is associated with increased risk of presence of mutations of K-ras is an extrauterine spread and recurrence. The unfavorable prognostic factor. Alteration of distance from tumor-myometrial junction to the tumor suppressor gene p53 is also associated uterine serosa is a sensitive indicator of survival. with advanced stage, papillary serous subtype Risk of recurrence and death is much higher and poor prognosis. Expression of MIB-I (Ki- when the distance is < 5 mm. 67), a proliferative marker, is associated with • Lymph-vascular space invasion: 83% 5-year extrauterine disease spread and decreased survival rate has been reported for patients survival. On the other hand, microsatellite without LVSI, compared with 64.5% in those instability, PTEN mutation and absence of p53 with LVSI. overexpression predict a favorable outcome. • Isthmus-cervical extension: This is associated with increased risk of extrauterine disease and Q.18. Describe the steps of surgery in this lymph node metastasis, and thus is a poor patient. prognostic factor. Ans: This patient should undergo staging • Adnexal involvement: Most of these patients laparotomy as follows: have other poor prognostic factors. Abdominal route: • Lymph node metastasis: It is the most 1. Abdomen should be opened by low midline important prognostic factor in clinically early incision. stage endometrial cancer. Patients with lymph 2. Peritoneal washings should be taken with 50- node metastasis have a 6-fold higher risk of 100 ml saline and collected in heparinised sterile developing recurrent cancer. 5-year survival rate container. in patients with lymph node metastasis is 3. Paracolic gutters, ascending colon, hepatic reported as 54%, compared to 90% for patients flexure, liver, hemi-diaphragm, transverse without lymph node metastasis. colon, splenic flexure and spleen, descending • Intraperitoneal tumor: Extrauterine spread of colon, omentum, and kidneys should be the disease is associated with poor prognosis inspected and palpated. and decreased 5-year disease free survival. 4. Retroperitoneum and para-aortic area should be • Peritoneal cytology: Positive peritoneal inspected and palpated. cytology has an adverse effect on survival only 5. Any suspicious adhesions or implants should if endometrial cancer has spread to adnexa, be biopsied. peritoneum or lymph nodes; not if the disease 6. Uterus, tubes and ovaries should be thoroughly is confined to the uterus (5-yr survival 90%). explored. • Hormone receptor status: Patients whose 7. Extrafascial total abdominal hysterectomy along tumors are positive for estrogen and/or with removal of vaginal cuff, and bilateral progesterone receptors have longer survival salpingo-oophorectomy should be done. rates than patients whose carcinomas lack these 8. Partial omentectomy should be considered in receptors. uterine papillary serous and Mixed mullerian • DNA ploidy status/proliferative index: tumors which have a high-risk of intra-abdominal Aneuploid tumors tend to be poorly spread and upper abdominal recurrence. differentiated, metastatic and associated with 9. Any suspicious pelvic and para-aortic lymph decreased survival. nodes should be removed for pathologic 348 Case Discussions in Obstetrics and Gynecology

examination. Clinically negative retroperitoneal Q.20. What information is required from the lymph nodes should be sampled in cases with histopathologic examination of the specimen? any of the high-risk factors mentioned earlier. Ans: Complete excision of lymph nodes located i. Histologic subtype and grade around the iliac vessels and above obturator nerve ii. Ploidy status allows identification of 90% of node positive iii. Estrogen and progesterone receptor status patients. Isolated involvement of para-aortin nodes iv. Myometrial invasion is rare. If pelvic nodes are positive on frozen v. Isthmus/cervical extension section, then para-aortic lymph nodes up to the vi. Parametrial spread inferior mesenteric artery should be removed. vii. Adnexal involvement The decision on whether to undertake viii. Lymph node involvement lymphadenectomy should not be based on palpation of nodal area because less than 10% of patients Q.21. This patient, Mrs Y is found to have well- with nodal metastasis have grossly enlarged lymph differentiated endometroid adenocarcinoma nodes. involving >50% of myometrium, with normal adnexa, negative lymph nodes and peritoneal Q.19. Is there any role of vaginal hysterectomy cytology. How will you further manage the case? or laparoscopic surgery in this case? Ans: The histopathology suggests Stage Ib G1 Ans: Role of vaginal hysterectomy in cases of disease. This patient should receive pelvic endometrial cancer: radiotherapy and vaginal boost following surgery. Vaginal hysterectomy with BSO may be done in Post-operative therapy should be based on extremely obese patients or those with uterine prognostic factors determined by surgical and prolapse, who are at low risk for extra-uterine pathological staging. Patients can be classified into spread (clinical stage I, well-differentiated tumor). three treatment categories as follows: For those where extensive dissection is required, it may add to the morbidity as approach to upper Post-surgical treatment of endometrial cancer abdomen and para-aortic lymph nodes is based on surgical-pathological findings and stage compromised. Pertitoneal washings are taken when Surgical-pathological Post-operative the posterior pouch is opened. These patients are findings treatment usually given post-operative radiotherapy because Stage I, G1/2, no myometrial None (Observe and follow appropriate surgical staging is not done. invasion up) Role of laparoscopic surgical staging: G3, no myometrial invasion Vaginal cuff radiation Laparoscopic assisted vaginal hysterectomy Stage I G1/2, <50% myometrial invasion (LAVH) with BSO and laparoscopic retroperitoneal Stage I, >50% myometrial Pelvic irradiation plus lymph node sampling/removal for staging and invasion vaginal cuff boost treatment of patients of endometrial cancer can be Grade 3, any myometrial used in selected group of patients. It has been shown invasion Isthmus, cervical to result in shorter hospital stay, lower complication and pelvic extension rates and no difference in recurrence rates when Lymph node metastasis compared to laparotomy. Manipulation of the tumor Positive para-aortic/common Pelvic irradiation + vaginal (including macroscopically involved lymph nodes) iliac lymph nodes cuff boost + Extended field radiation should be avoided to prevent the rare occurrence of port-site metastasis. Contd... Postmenopausal Bleeding 349

Contd... Q.25. What cases require post-operative vaginal Positive peritoneal cytology Progestins vault therapy and how is it given? Adnexal/parametrial Whole abdominal radiation spread Intraperitoneal disease Ans: Post-operative vaginal irradiation reduces the completely resected or chemotherapy incidence of vaginal recurrence in patients with Bladder/rectal invasion Pelvic and vaginal tumors confined to the uterus from 15% to 1-2%. irradiation Procedure: Earlier this was administered using low dose radium or caesium sources via colpostats to Q.22. How would your treatment differ if there deliver a surface dose of 6000 to 7000 cGy to upper was no or minimal myometrial invasion? vagina. Recently, afterloading outpatient techniques Ans: This correlates with stage Ia disease, which using high dose rate iridium sources have been has excellent prognosis. Only observation and employed. regular follow up is recommended after surgery. Side-effects: It is associated with low morbidity. 100% disease free 5 yr survival has been reported and dysparunia may be a problem after appropriate surgery. No recurrences have been for postmenopausal patients in the absence of reported so far. regular vaginal dilatation. Q.23. What is the role of hormone receptor Q.26. What cases will need external pelvic status? radiation? Ans: Estrogen and progesterone receptor levels Ans: have shown to be prognostic indicators, • Stage Ib, grade 3 (Stage I, grade 1/2 with deep independent of grade. myometrial invasion) Patients whose tumors are positive for one or • Cervical involvement both receptors have longer survival times than those lacking the receptors. Even metastatic tumors which • Adnexal or parametrial involvement are receptor positive have improved prognosis. • Pelvic lymph node metastasis Progesterone receptor levels appear to be better • Large tumors >2 cm with high grade predictors of survival than estrogen receptor levels. • Any grade of tumor with lymph vascular space The higher the absolute level of receptors, better invasion the prognosis. Benefits: Reduces locoregional recurrence, improves disease free survival Q.24. What is the significance of knowing the In a recent GOG trial (2004), including cases histological grade? of intermediate risk endometrial cancer, disease Ans: Histological grade is strongly associated with recurrence was reduced by 58% with the use of prognosis. In a study of patients with stage I disease: post-operative pelvic irradiation. Grade Recurrence 5 years survival Technique of post-operative whole pelvic external Grade I 7.7% 92% beam radiation: 4500 to 5040 cGy in 180 cGy Grade II 10.5% 86% fractions over 5 to 6 weeks, to a field encompassing Grade III 36.1% 64% upper-half of vagina inferiorly, lower border of L4 Increasing tumor anaplasia is associated with superiorly and 1cm lateral to margin of bony pelvis. deep myometrial invasion, cervical extension, Vaginal apex usually boosted to 6000 to 7000 cGy. lymph node metastasis and local and distant Side-effects: Most frequent side-effects are gastro- metastasis. intestinal, usually abdominal cramps and diarrhea. 350 Case Discussions in Obstetrics and Gynecology

More serious complications such as bleeding, rates. Ultrasound or MRI may suggest cervical proctitis, bowel obstruction and fistula formation invasion. Thus, histological proof of cancer can occur, and may require surgical correction. infiltration of cervical stroma or presence of Hematuria, cystitis or vesico-vaginal fistulae may obvious tumor on the cervix is the only reliable also occur. Overall complication rate ranges from means of diagnosing cervical involvement. 25 to 40%. The rate of serious complications In patients with stage II cancer endometrium, requiring surgical intervention is 1.5 to 3%. the incidence of pelvic lymph node metastasis is 30-40%. Thus, treatment should include Q.27. When is extended field radiation given? management of pelvic lymph nodes. Ans: Extended field radiation is given in patients Two approaches may be used for management with histologically proven para-aortic nodes in this case: metastasis, who have no other evidence of disease a. Initial surgical staging laparotomy followed by outside the pelvis. The entire pelvis, common iliac RT: The best approach is initial surgical staging lymph nodes, and para-aortic lymph nodes are followed by irradiation. This confirms the included within the radiation field. Para-aortic correct stage of the disease, which is important radiation dose is limited to 4500-5000 cGy. as there are discrepancies in clinical and surgical staging in up to 50%. Q.28. What is the role of whole abdomen The surgical staging includes exploratory radiation? laparotomy, peritoneal washings for cytology, modified radical hysterectomy with bilateral Ans: Whole abdominal radiation is given in: salpingo-oophorectomy, resection of iliac and • Patients with stage III/IV disease (adnexal or lower para-aortic lymph nodes. This is followed upper abdominal disease such as in the postoperatively by pelvic or extended field omentum, that has been completely excised) radiation depending on surgico-pathological • Papillary serous/mixed Mullerian tumor with stage. The reported 5-yr survival following this propensity for upper abdomen recurrence. management is 70%. Some surgeons do only It should not be used in patients with gross extrafascial hysterectomy, as post-operative RT residual intraperitoneal disease. is required. Dose: 3000 cGy in 20 daily fractions of 150 cGy. b. Initial RT followed by surgery: In patients who Renal shielding is done at 1500-2000 cGy. are unsuitable for extensive surgery (obese, Additional 1500 cGy is delivered to para-aortic elderly, medical problems, ballooned up cervix), nodes and 2000 cGy to pelvis. the preferred approach is initial external and Side-effects: Gastrointestinal side-effects, e.g. intracavitary radiotherapy followed within 6 nausea, vomiting and diarrhea are common. weeks by less extensive surgery (TAH with Hematological toxicity may occur and is usually BSO). Reported 5-yr survival rates are 60-65%. mild. Late complications (mainly chronic diarrhea c. Radiation alone: In patients unsuitable for and small bowel obstruction) occur in 5-10% cases. surgery, radiotherapy alone may be used but 5- yr survival rates are reduced to 50%. Q.29. How would you manage a case of stage II disease? Q.30. How would you manage this patient if she Ans: Pre-operative assessment of cervical was found to have stage III endometrial cancer? involvement is difficult. Endocervical curettage has Ans: Stage III cancer accounts for 7-10% of all high false positive (50-80%) and false negative cases of endometrial cancer. Treatment needs to be Postmenopausal Bleeding 351 individualised. Surgery should be performed with Ans: There is no single accepted strategy for the aim of determining extent of the disease and to follow up of patients with endometrial cancer. remove the bulk of the disease if possible. Preferred Routine follow-up visits at 3-6 months with treatment is extrafascial hysterectomy with BSO vaginal cytology at each visit and annual chest X- and partial omentectomy, peritoneal washings, ray is neither clinically productive, nor cost- peritoneal biopsy from suspicious areas and effective.1 60-75% patients will be symptomatic selective pelvic and para-aortic lymphadenectomy at the time of recurrence, and most patients with and partial omentectomy. curable recurrence had vaginal bleeding from a Post-operative radiotherapy is tailored vaginal lesion. Despite this, a periodic according to the extent of the disease. Patients examination provides psychological reassurance treated with surgery and radiotherapy both, fare to the patient. better than those treated with radiation alone. Thus, routine post-treatment surveillance for patients with endometrial cancer should include:1 Q.31. How will you manage stage IV endo- • Education of the patients regarding symptoms metrial cancer? of recurrence (vaginal bleeding, abdo- Ans: Stage IV tumor is found in 3% of all cases. minopelvic or back pain, leg swelling, Management needs to be individualized. The abdominal bloating, cough or shortness of primary aim is control of symptoms and local breath). Symptomatic patients should be control of tumor to provide palliative relief of instructed to report promptly for evaluation and bleeding, discharge and complications involving treatment. bladder and rectum. It usually involves a • ACOG recommends follow-up of patients every combination of surgery, radiotherapy and systemic 3-4 months for 2-3 years, then every 6 months. hormonal or chemotherapy. Several reports have After 5 years, patients can return to routine noted a positive impact of cytoreductive surgery annual follow-up. on survival, median survival being 3 times greater • At each visit, history and clinical examination with optimal cytoreduction (18-34 months versus (including general physical, systemic, 8-11 months, respectively). abdominal and pelvic examination, with careful If pulmonary metastasis is present, further inspection and palpation of whole length of imaging of abdomen and pelvis by CT or MRI is vagina, parametrium and rectovaginal needed. If no other site of disease is found, examination) should be done. treatment includes TAH with BSO, progestogens, • Routine Pap smear and chest X-ray cannot and adjuvant RT if pelvic and para-aortic lymph currently be recommended. nodes are involved. The management of metastatic • CT scan, USG, MRI, IVP is done only if disease is variable depending on factors such as clinically indicated. co-morbidities, tumor grade, performance status, • CA-125: Elevated levels are seen in advanced and prior treatment. Hormonal therapy and and recurrent disease, and correlate with clinical cytotoxic chemotherapy have traditionally been course. CA-125 is helpful in monitoring patients used. Surgical resection of lung metastasis has also with uterine papillary serous carcinoma, or been found to improve survival rates. those with high-risk of recurrence/previously elevated levels. Q.32. How will you follow up this patient after • Patients treated with radiation and/or treatment is completed? chemotherapy need more intensive follow-up 352 Case Discussions in Obstetrics and Gynecology

to monitor them for long-term complications endometrial cancer was grade 1, with younger age of therapy. at recurrence, recurrent tumor < 2 cm, time from initial treatment to recurrence more than 1 year, Q.33. What are the overall 5-yr survival rates? and in cases that have received brachytherapy Ans: The overall 5-yr survival rate in endometrial vaginal boost. cancer is approximately 75%. Role of surgery in recurrent disease: 1. Surgical resection of a metastatic vaginal nodule Stage 5 years survival rates >2 cm prior to radiation may improve local I 82% (in well-differentiated) control. II 65% 2. Few patients with intraperitoneal recurrence III 44% may need surgery to relieve intestinal IV 15% obstruction. 3. Tumor reductive surgery may be performed Q.34. She comes back after 1 year with vaginal before administration of whole abdomen bleeding and examination and investigations radiation therapy or systemic hormonal or reveal recurrent . How would you chemotherapy. manage? What are the common sites of 4. In patients with isolated central pelvic recurrence? recurrence after irradiation, exploratory Ans: About one-fourth of the patients treated for laparotomy and pelvic exenteration may be done cancer endometrium develop recurrent disease. if there is no evidence of disease outside the 50% recurrences develop in 2 yrs and three-fourths pelvis and no lymph node metastasis. occur within 3 years of initial treatment. In patients Site of recurrence Treatment available treated with surgery alone, most recurrences tend Vaginal vault After primary surgery, to be vaginal/pelvic. While patients treated with recurrence treated with radiation combined surgery and radiotherapy tend to have (EBRT + ICRT – 6000 distant metastasis (70%) involving lung, abdomen, cGy). Surgical resection lymph nodes (aortic, supraclavicular, inguinal), of a metastatic vaginal liver, brain and bone. Vaginal bleeding is the most nodule >2 cm prior to common symptom associated with local recurrence, radiation may improve and pelvic pain is most often present with pelvic local control. recurrence. Lymph nodes Radiation therapy Patients with initial well-differentiated tumors Long-term progestin and recurrence occurring 3 yrs after primary therapy therapy if progesterone have better prognosis. receptor positive Management: Pelvic or vaginal recurrence in Lung metastasis Long-term progestin patients who have not received prior pelvic therapy irradiation is best treated with external irradiation followed by brachytherapy boost to deliver a total Q.35. What is the role of hormonal therapy in tumor dose of at least 6000 cGy. Reported survival endometrial cancer? What agents are used? rates in patients with isolated vaginal recurrence Ans: Indications: treated with irradiation range from 24 to 45%. i. Advanced/Recurrent endometrial cancer Survival rates are better in cases where the initial ii. Metastatic disease Postmenopausal Bleeding 353

Agents: Q. 37. What is the prognosis if histopathology i. Oral medroxy-progesterone acetate 50-100 shows papillary serous and clear cell carcinoma? mg TDS Ans: These account for only 10% cases, but are ii. Megestral acetate 160-320 mg/day associated with 50% relapse. 5-yr survival for iii. MPA (depo provera) 500-1000 mg im weekly papillary serous carcinoma is 30% and for clear iv. Tamoxifen, 20-40 mg/day cell carcinoma 40%. These are not estrogen Progestins are currently recommended as initial dependent. Recommended treatment is extensive treatment for all patients with recurrent endometrial surgical staging including pelvic and para-aortic tumors which are hormone receptor positive. lymphadenectomy, and partial omentectomy. Response depends on estrogen and progesterone For patients with stage Ia, no further treatment receptor status. Response is better if tumor is is needed. For patients beyond stage Ia, give pelvic progesterone receptor positive. If a response is RT and CAP regimen. Only pelvic radiation is not obtained, the progestin should be continued for as enough. long as the disease is static or in remission. In cases with relative contra-indication to high-dose Q.38. What is the role of estrogen replacement therapy after treatment of endometrial cancer? progestin therapy (e.g. prior or current thromboembolic disease, severe heart disease, or Ans: Post-surgery, many women may suffer from inability to tolerate progestins), tamoxifen 20 mg menopausal symptoms. There has been concern BD is recommended. Failure to respond to regarding use of estrogen replacement in treated hormonal therapy is an indication for initiating cases of endometrial cancer because occult disease chemotherapy. may be activated by estrogen. ACOG states that for women with history of Q.36. What is the role of chemotherapy in endometrial cancer, hormone replacement therapy management of adenocarcinoma endometrium? could be used, but selection of appropriate candidates should be based on prognostic indicators What chemotherapeutic agents are available? and the risk she is willing to assume. Most Ans: Chemotherapy has a palliative role in authorities do not prescribe estrogens for 1 year advanced/metastatic disease. Most active after surgery since recurrences appear within 1-3 chemotherapeutic agents are doxorubicin (50- years. If all disease has been removed by surgery 2 2 60mg/m every 3 weeks), cisplatin (60-75mg/m or destroyed by RT, then HRT may be given after every 3 weeks), carboplatin (350-400 mg/m2 every explaining the risk of occult disease. 4 weeks) and paclitaxel (250 mg/m2 as a 24-hr Alternatively, topical estrogen alone can be used infusion or 175 mg/m2 as a 3-hr infusion every 3 to treat vaginal symptoms. Symptomatic relief of weeks). Response rates reported with paclitaxel hot flushes patients can be achieved by giving only alone are 36%, while those with mono-agent progestins like: chemotherapy using other mentioned agents are i. MPA 20 mg OD 21-29%. Combination chemotherapy (with cyclo- ii. MPA 150 mg IM every 3 months phosphamide, doxorubicin, and cisplatin or iii. Non-hormonal agents like clonidine, cispatin/carboplatin + paclitaxel) results in response venlafaxine. rates ranging from 38-76%. Despite this, the median iv. SERMS like raloxifene and weight bearing survival time has been less than 12 months. exercises can reduce bone loss. 354 Case Discussions in Obstetrics and Gynecology

REFERENCES Pg. 1343-1401. Lippincott Williams and Wilkins ©2007. 1. Crispens MA. Chapter “Endometrial Cancer” in book: 3. Rose P.G. Endometrial Cancer. NEJM 1996;335(9): Te Linde’s Operative Gynecology- 10th ed. Rock JA, 640-9. Jones III HW. Lippincott Williams and Wilkins 4. Revised FIGO staging for carcinoma of the vulva, ©2008;1291-1304. cervix, and endometrium. FIGO Committee on 2. Lurain JR. Chapter “Uterine cancer” in book: Gynecologic Oncology. International Journal of Berek and Novaks Gynecology- 14th ed. Berek JS. Gynecology and Obstetrics 2009;105:103-4. Gauri Gandhi, Neha Singh 27 Carcinoma Vulva

Carcinoma vulva is an uncommon malignancy Q.1. What are the important points in history? accounting for 2-5% of the malignancies of the Ans: genital tract. Although this cancer appears most • History of discharge or bleeding from vulva frequently in women aged 65-75 years (usually • History of discharge or bleeding per vaginum associated with lichen sclerosis and squamous as vulvar malignancies can be associated with hyperplasia), it can appear in patients younger than malignancies of vagina and cervix due to ‘field 40 years. These young patients tend to have early phenomenon’. microcarcinomas, which may be associated with • History of sexually transmitted diseases. diffuse intraepithelial neoplasia of the vulva and Vulvar cancer is occasionally associated with human papillomavirus. syphilis, Lymphogranuloma venerum and The most common presentation is a pruritic granuloma inguinale. These patients develop the lesion of the vulva or a mass detected by the disease at an earlier age and have more poorly patient herself. However, early vulvar cancer may differentiated lesion. be asymptomatic and recognized only with careful HPV infection is associated with VIN and inspection of the vulva. A biopsy should be basaloid or warty type of vulvar cancer. DNA of performed on all visible lesions on the vulva. A HPV is found in 89% of VIN3 and up to 86% of basaloid or warty type of carcinoma vulva, although delay in diagnosis appears to occur mainly because it is present in <10% of keratinizing type. the patient does not seek medical attention for • History of treatment received for cervical many months or because the lesion is treated precancer or cancer and VIN medically for months, without biopsy for • History of any mass in the groin definitive diagnosis. Hence, there is need for • History of HIV/ AIDS or immunosuppressant awareness regarding early diagnosis and proper therapy as this is a risk factor for carcinoma vulva. management of carcinoma vulva in both patients • History of diabetes and hypertension should be and the physicians. elicited as these diseases are more common in this age. CASE 1 Mrs X, a 64-year old postmenopausal lady Q.2. How would you proceed to examine the case? presented with complaints of itching in the vulvar Ans: area. • A general physical examination is done. 356 Case Discussions in Obstetrics and Gynecology

• A systemic examination should be done Q.4. What is the incidence of carcinoma vulva? including examination of thyroid and breasts, Ans: Vulvar cancer is not so common and CVS, CNS, respiratory system. represents 2-5% of the malignancies of the female • A per abdominal examination is done to rule genital tract. The estimated incidence is out any abnormality. The inguinofemoral region 1-2/100,000 women. should be examined for any lymphadenopathy. • Local examination: Examine the vulva for any Q.5. How will you confirm the diagnosis? leukoplakia, raised areas, growth or ulcerative lesion. Vulvar cancer may present as an Ans: The diagnosis should be confirmed by taking exophytic growth, an ulcerative lesion or a a wedge biopsy under local or regional anesthesia. raised flat area. It may be pigmented, fleshy, The biopsy should be taken from an area where and may sometimes be tender. The lesion may there is transition from normal to malignant tissue. be merging in the surrounding area of vulvar The biopsy should include sufficient underlying dystrophy. In keratinizing carcinoma, associated dermis to assess the depth of invasion. lichen sclerosis or squamous hyperplasia is If the lesion is less than 1 cm, then an excisional found in 80% cases, although their causative biopsy with a 1 cm margin all around is preferable. role remains controversial. A careful assessment of location and size of Q.6. What are the histological types of vulvar lesion should be done and also assess whether it is cancer? unifocal or multifocal. Ans: Squamous cell carcinoma is the most common • Extension of the tumor to adjacent mucosal histological type of carcinoma vulva occurring in structures like vagina, urethra, bladder base or 85-90% patients. It can be of the following two anus should be noted. • Vulvar cancer is often associated with other types: squamous intraepithelial and invasive lesions a. Basaloid or warty type: They tend to be of lower genital tract, therefore do careful multifocal, occur in younger age, and are speculum examination of cervix and vagina. associated with HPV, VIN and cigarette • It may be sometimes necessary to examine smoking. under anesthesia if palpation of tumor is very b. Keratinizing type: They tend to be unifocal, painful. occur in older age, and are associated with On local examination of Mrs X, an exophytic lichen sclerosis and squamous metaplasia. growth of about 3 × 3 cm was present, tender, not Other histological types of carcinoma vulva are- fixed to underlying bone. There were no palpable – Melanomas 2-4% lymph nodes. P/S – NAD. P/V- NAD. – Basal cell carcinoma 2-3% – Bartholin gland carcinoma 1% Q.3. What is the diagnosis? (adenocarcinoma) Ans. The first clinical diagnosis is carcinoma vulva. – Sarcoma < 1% The differential diagnosis includes: – Verrucous carcinoma < 1% • Tuberculosis of vulva – Metastatic carcinoma < 1% • Condyloma accuminata If the lesion is ulcerative, the differential The biopsy has come out to be keratinizing diagnosis would include syphilitic ulcer, chancroid. squamous cell carcinoma, invading >1 mm. Carcinoma Vulva 357

Q.7. How will you stage the lesion? IIIC With positive nodes with extracapsular Ans: In 1988, FIGO approved a surgico-patho- spread logical system for staging carcinoma vulva. • Stage IV Tumor invades other regional (2/3 This staging has been revised by FIGO in 2008 upper urethra, 2/3 upper vagina), or distant and published in 2009. Although the previous stage structures IA remains unchanged because this is the only IVA Tumor invades any of the following: group of patients with a negligible risk of lymph (i) Upper urethral and/or vaginal mucosa, node metastasis, the previous stages I and II have bladder mucosa, rectal mucosa, or fixed been combined because many studies have to pelvic bone, or demonstrated that the size of the lesion (with (ii) Fixed or ulcerated inguinofemoral lymph negative lymph nodes) is no longer a prognostic nodes factor in previous stages I and II. Moreover, the number and morphology (size and extracapsular IVB Any distant metastasis including pelvic spread) of positive lymph nodes have been taken lymph nodes into account because they have been shown to be Since the growth of the patient is >2 cm but does important prognostic factors, whereas the not involve adjacent perineal structures and no bilaterality of positive nodes have been discounted palpable nodes are present, it appears to be Stage due to controversy from previous studies. IB according to the new staging (and earlier The revised FIGO staging for carcinoma vulva would have been Stage II) is: • Stage I Tumor confined to the vulva Q.8. What other investigations should be done? IA Lesions < 2 cm in size, confined to the vulva or perineum and with stromal invasion <1.0 Ans: mm*, and no nodal metastasis 1. The following investigations should be done to IB Lesions >2 cm in size or with stromal rule out surrounding vulvar dystrophies and invasion >1.0 mm*, confined to the vulva other genital malignancies or perineum, with negative nodes. • Pap smear • Stage II Tumor of any size with extension to • Colposcopy of cervix and vagina adjacent perineal structures (1/3 lower urethra, • Vulvoscopy for lesions at other sites on 1/3 lower vagina, anus) with negative nodes vulva • Stage III Tumor of any size with or without 2. Pre-operative investigations, which include– extension to adjacent perineal structures (1/3 • Complete blood count lower urethra, 1/3 lower vagina, anus) with • LFT, KFT positive inguinofemoral lymph nodes. IIIA (i) With 1 lymph node metastasis >5 mm, • Blood sugar or • Serum electrolytes (ii) 1-2 lymph node metastasis <5 mm • Chest X-ray, ECG IIIB (i) With 2 or more lymph node metastases • Urine-albumin, sugar, microscopy and >5 mm culture (ii) 3 or more lymph node metastases <5 mm • Special investigations for co-morbid diameter. conditions in elderly

* The depth of invasion is defined as the measurement of the tumor from the epithelialstromal junction of the adjacent most superficial dermal papilla to the deepest point of invasion. 358 Case Discussions in Obstetrics and Gynecology

3. Imaging: external iliac group. The overall incidence of • Ultrasound pelvis to rule out other pelvic inguino-femoral lymph node metastases is about pathology 30%. Metastases to pelvic nodes occur in about • CT/MRI scan of groin, pelvis and abdomen 12% cases. Pelvic nodal metastases is rare may be done to see the extent and (0.6%) in the absence of groin node involvement. resectability of the tumor and involvement 3. Hematogenous spread to ditant sites, including of lymph nodes the lungs, liver and bone. Hematogenous spread If the lesion is large and locally advanced, the usually occurs late and is rare in the absence of following investigations may be required: lymph node metastasis. • Cystourethroscopy – if bladder or urethra seems involved Q.10. What is the treatment for this patient? • Intravenous pyelography – if bladder base Ans: Surgery is the mainstay of treatment. is involved Earlier radical vulvectomy with bilateral • Proctosigmoidoscopy – if anus or rectum inguinofemoral lymphadenectomy by en bloc seems involved dissection was the standard therapy for Stage IB. However, the disadvantages of en bloc dissection Q.9. What are the routes of spread of vulvar are: cancer? • Large loss of vulvar tissue with psychosexual Ans: Vulvar cancer spreads by the following routes: sequelae 1. Direct extension, to involve adjacent structures • A 50% wound breakdown rate such as vagina, urethra and anus • A high incidence of lower extremity 2. Lymphatic spread: Lymphatic metastases may lymphedema occur early in the disease. Initially, spread is The en bloc dissection has now been replaced usually to the inguinal lymph nodes, which are by the triple incision technique. Separate incisions located between Camper’s fascia and fascia lata. are given for vulvectomy and lymphadenectomy. From these superficial groin nodes, the disease This results in significant reduction in wound will spread to the deep femoral nodes, which morbidity. are located medially along the femoral vessels. Cloquet’s or Rosenmuller’s node, situated Radical Vulvectomy beneath the inguinal ligament, is the most caphalad of the femoral node group. Metastases This is done by two elliptical incisions on the vulva. to the femoral nodes without involvement of The outer one is placed on the labiocrural folds the inguinal nodes have been reported and the and anteriorly brought across the mons pubis and lymphatics of the vulva from either side form a posteriorly across the perineal body. The inner rich network of anastomoses along the midline. incision circumscribes the vaginal introitus and Lymphatic drainage from the clitoris, anterior vulvar vestibule. The dissection is carried down to labia minora and perineum is bilateral. For the deep perineal fascia. The aim should be to have lateral tumors, metastases to contralateral lymph 2cm tumor free margin. Once dissection is nodes in the absence of ipsilateral nodal complete, the levator ani muscles should be involvement is rare. approximated to prevent rectocele formation. After From the inguinofemoral nodes, the cancer achieving hemostasis, the skin is sutured to vaginal spreads to the pelvic nodes, particularly the mucosa by interrupted sutures. Carcinoma Vulva 359

Lymphadenectomy negligible. The negative predictive value of this method is 97%. Bilateral inguinofemoral lymphadenectomy is done – If positive, pelvic lymphadenectomy or by separate longitudinal incisions centered midway pelvic LN radiation can be done. between the femoral artery and pubic tubercle, – The advantage of this method is that extending from one inch above to two inch below extensive lymphadenectomy is avoided in the inguinal ligament. The skin and subcutaneous cases where sentinel node is negative. tissue is incised. The superficial inguinal lymph – Sentinel node mapping is still under trial. nodes lie above the cribriform fascia and associated with saphenous vein and its tributaries (superficial Q.12. What is the role of unilateral groin circumflex, superficial external pudendal and dissection? superficial epigastric). These tributaries of saphenous vein are first identified and ligated and Ans. This has been done in well lateralized early superficial inguinal lymph nodes are removed. The tumors that are well differentiated, with no saphenous vein is identified and ligated at its entry capillary or lymphatic space involvement and to the femoral vein. A segment of the saphenous negative ipsilateral inguinal lymph nodes. Stehman vein along with the longitudinal group of lymph et al (1992), in a GOG study reported 3 out of 121 nodes is removed. All lymph nodes around the patients undergoing unilateral lymphadenectomy saphenofemoral junction should be removed and had a recurrence in contralateral lymph nodes but any prominent deeper lymph node (Cloquet node) all these tumors were poorly differentiated. medial to the femoral vein should also be removed. This can be used as the sentinel node and sent for Q.13. When can groin dissection be omitted? frozen section. If positive, extraperitoneal pelvic Ans: This can only be done in non midline tumors lymphadenectomy may be done. The alternative <2 cm, with no capillary or lymph space treatment for positive inguinofemoral nodes is involvement which are well differentiated and have postoperative radiotherapy to the pelvis and groin. stromal invasion less than or equal to 1 mm (Stage IA). Q.11. What is the role of sentinel node mapping? Ans: The sentinel node is the initial site of Q.14. What is the treatment according to the metastatic disease and the histology of the sentinel stage? node reflects the histology of the rest of the lymph Ans: The management of carcinoma vulva nodes in that basin. according to the stage is: • The inguinal femoral lymph nodes are the Stage IA (tumor < 2 cm with stromal invasion < 1 sentinel nodes for carcinoma vulva mm, no nodal metastasis) – Sentinal node can be identified by lymphatic • Wide local excision with 1-2 cm normal tissue mapping using the isosulfan blue dye or margin is usually sufficient technetium-99m-labelled nanocolloid. • Lymph node dissection may be omitted except Lymphoscintigraphy is done preoperatively when the following high-risk factors are and intra-operatively to identify nodes with present: metastases. a. poorly differentiated tumor – When negative by frozen section, the risk b. capillary or lymphatic space involvement of metastasis to pelvic lymph nodes is c. multifocal lesions 360 Case Discussions in Obstetrics and Gynecology

• Proper follow up is necessary as there is risk of Advanced vulvar cancer can be managed by recurrence a. Ultra-radical surgery Stage IB (tumor > 2 cm or stromal invasion > 1 mm b. Radiotherapy with no nodal metastasis): c. Combined modality using chemotherapy and Various factors have to be considered to decide the radiotherapy surgical approach. These include the patient’s age, a. Ultra-radical vulvectomy with bilateral size of tumor and site of lesion. inguinofemoral lymphadenectomy by a. Radical local excision with inguinofemoral triple incision technique. lymphadenectomy: When tumor involves the distal urethra, • It is suitable for younger patients with a vagina or anus, but is still resectable by well-localized small unifocal lesions. partial resection of these structures may be • Recommendation is to resect the primary done. If >1 cm of urethra is excised then tumor with a 2 cm margin of normal tissue risk of urinary incontinence is there. Partial and to carry the dissection up to the deep resection of the external anal sphinter in perineal fascia of the urogenital diaphragm. combination with radical local resection of • In tumors < 2 cm size, radical local excision perianal tissue is associated with a results in 90% survival rate. significant rate of subsequent fecal • In well-lateralized early tumor that is well incontinence. Careful sphincter reapproxi- differentiated, with no capillary or lymphatic mation and levator muscle placation are space involvement ipsilateral inguinofemoral done in an effort to minimize incontinence. lymphadenectomy is done. These are sent for This surgery should be done in highly frozen section. If positive, then contralateral selected cases which are clearly respectable and pelvic lymph node dissection is done. If with none or 1 or 2 lymph nodes positive. negative, no further dissection or b. Radiotherapy postoperative radiotherapy is needed. This may be the only option in medically • Bilateral lymph node dissection should be unfit patients or unresectable disease. The done in tumors involving midline structures current high energy radiotherapy techniques (clitoris or labia minora or perineal body) have relative skin sparing effect. Teletherapy or within 2 cm of midline. at a dose of 45-55 Gy to the whole pelvis, b. Radical vulvectomy with bilateral inguino- including vulva and groins, is given. This femoral lymphadenectomy: can be combined with 65-70 Gy to the tumor • Radical vulvectomy with bilateral bed by a single direct electron beam or inguinofemoral lymphadenectomy by triple interstitial needles, but this local treatment incision technique which has been described is highly morbid. A more effective method earlier. is to combine preoperative chemoradiation followed by a more limited resection. Treatment of Advanced Vulvar Cancer Megavoltage radiotherapy causes regression of advanced cancer to a point where limited Stage II Tumor involving adjacent perineal resection can be done, with sparing of organ structures, i.e. lower 1/3 urethra, lower 1/3 vagina, function and better quality of life. Surgery anus). is performed 2-6 weeks after completion of Stage III (stage I or II with positive inguinofemoral external beam radiotherapy, delivering 50 lymph nodes). Gy to whole pelvis. Carcinoma Vulva 361

Stage IV Tumor invades other regional (2/3 upper Ans: There has been a paradigm shift towards a urethra, 2/3 upper vagina), or distant structures more conservative surgical approach without The options available are: compromised survival and with markedly decreased a. Ultra-radical surgery - pelvic exenteration physical and psychosexual morbidity. The changes b. Radiotherapy (Teletherapy of pelvis including include: the vulva and groin has been done at a dose of 1. Individualization of treatment for all patients 45 to 55 Gy), followed by limited resection if with invasive disease. possible 2. The use of separate incisions for groin c. Combination modality using chemoradiation dissection to improve wound healing and surgery 5-flurouracil, cisplatinum, 3. Modified radical vulvectomy/wide radical mitomycin and bleomycin have been used for resection : This refers to the removal of the chemotherapy. portion of vulva containing the tumor ensuring that 2 cm tumor free skin margin is removed. Q.15. What is the role of radiation in the The types of modified radical vulvectomy treatment of cancer vulva? include anterior or posterior hemivulvectomy Ans: Radiotherapy for cancer vulva is indicated or lateral hemivulvectomy with clitoral sparing. in: Sparing of as much normal tissue as possible is a. Preoperatively in patients with advanced disease likely to reduce sexual dysfunction and who would otherwise require pelvic disfigurement of the vulva as compared to exenteration, as described earlier. radical vulvectomy. b. Postoperatively to treat the pelvic and groin 4. Omission of groin dissection for patients with lymph node of patients with positive groin Stage IA and no risk factors. nodes. 5. Omission of contralateral groin dissection in c. To prevent local recurrence in patients with patients with lateral lesions < 2 cm and negative close surgical margins (<5 mm). ipsilateral nodes d. As primary therapy for young patients with 6. Elimination of routine pelvic lymphadenectomy small primary tumor involving clitoral and if inguinofemoral nodes are negative. periclitoral lesions. 7. The use of postoperative radiation therapy to decrease the incidence of groin recurrence in Q.16. What is the role of neoadjuvant patients with multiple positive groin nodes. chemotherapy? Ans: Neoadjuvant chemotherapy for vulvar cancer Q.18. How will you manage the patient after may be considered for tumors that manifest with radical vulvectomy and what are the post- bowel or bladder involvement that would require operative complications? extensive or exenterative surgery. Ans: Surgery is usually well-tolerated by these Except in the neoadjuvant setting, chemo- patients despite their old age and associated medical therapy for vulvar cancer is palliative or when conditions. The patients are advised to have: combined with radiotherapy. Bleomycin, cisplatin • Bed rest for 3-5 days and 5-flurouracil have been used for chemotherapy. • A low residue diet can be started from the second day Q.17. What are the recent modifications in the • Perineal hygiene to be maintained surgical management? • Frequent dry dressing of the local wound 362 Case Discussions in Obstetrics and Gynecology

• Self-retaining foley catheter till the patient is f. Inguinofemoral hernia after lymphadenectomy ambulatory or longer if the lower portion of can be prevented by proper closure of femoral urethra is removed. canal with suture from inguinal ligament to • Pneumatic calf compression or subcutaneous Cooper’s ligament. heparin can be used to prevent deep vein g. Pubic osteomyelitis and rectovaginal fistula are thrombosis. rare complications. The postoperative complications may be early or late: Q.19. What is the prognosis of carcinoma vulva? Early complications Ans: The overall 5-year survival rate in operable a. Wound breakdown: Groin wound infection, cases is 70-80% necrosis and breakdown is seen in about 50% Prognosis of the disease depends on: patients having ‘en bloc excision’ and is reduced a. Stage of the disease: The 5-year survival rates to about 20% with the ‘triple incision of vulvar cancer according to the stage of the technique’. disease are: b. Lymphocyst formation may occur in the femoral Stage I - 95-98% triangle in 10-20% cases. Periodic sterile Stage II - 80-85% aspirations may be required. Stage III - 40-50% c. Femoral nerve injury is a rare but debilitating Stage IV - 20-40% complication of inguinofemoral lympha- b. Lymph node status: The number of positive denectomy. It can be prevented by avoiding groin nodes is the most important prognostic dissection lateral to the femoral artery. factor. Patients with one microscopically d. UTI: It responds to antibiotics. positive lymph node have a prognosis similar e. Thromboembolic complications: Deep vein to those with negative nodes, whereas patients thrombosis and pulmonary embolism may occur with more than 3 positive nodes have poor due to immobilization. Prophylactic low prognosis with a two-year survival rate of 20%. molecular weight heparin is given in high-risk The survival rate also varies with the nodal patients to avoid this compication. group involved. With negative groin nodes, the f. Osteitis pubis is rare. Treatment includes bed 5-year survival for invasive carcinoma is about rest and nonsteroidal anti-inflammatory drugs. 90%, which falls to about 50% for patients with Late complications: positive groin nodes. With positive pelvic a. Lower limb edema is seen in 7-10% patients. nodes, the survival falls further to about 11%. b. Recurrent lumphadenitis or cellulitis of leg c. Tumor ploidy is the second most important occurs in 10% patients. It usually responds to prognostic factor after lymph node status. antibiotics. Aneuploid tumors have 23% and diploid tumors c. Dyspareunia can occur due to stenosis of the have 62% five-year survival. introitus. It can be minimized by limiting tissue d. Depth of stromal invasion and lymph vascular resection. space involvement. d. Stress incontinence or misdirection of urinary e. Histologic grade of the tumor. stream can occur in 10% cases due to poor alignment of urethra. Urethra should be suspended if distal urethra is to be excised. Q.20. How will you follow up? e. Posterior vaginal wall prolapse if levators are Ans: After completion of treatment for vulvar not approximated. cancer, a long-term follow up is needed. It is Carcinoma Vulva 363 reasonable to examine these women at least every – Therapy: depends on the location and extent 6 months for the first 5 years and annually of recurrence thereafter. - Localized to vulva- wide local excision • Follow up is directed at early detection of local or combination of external beam and recurrence or later, a new primary vulvar tumor interstitial radiotherapy. and recurrence in the groin nodes, and any - Groin – radical groin dissection and/or distant metastasis. radiotherapy • Look for any treatment related complications - Advanced beyond vulva – pelvic listed earlier. irradiation/chemotherapy/palliative • Surveillance for associated malignancies of surgery vagina and cervix by Pap smear and Distant recurrences are difficult to manage colposcopy. and have poor prognosis.

Q.21. What is the rate of recurrence and its REFERENCES management? 1. Kim HS, Song YS. International Federation of Ans: Incidence: 15-35%. Gynecology and Obstetrics (FIGO) staging system revised: what should be considered critically for • Majority are seen within 2 years of initial gynecologic cancer? J Gynecol Oncol 2009; 20(3): surgery. 135-6. • The sites are: 2. Hacker NF. Revised FIGO staging for carcinoma of vulva (70%)- commonest site of recurrence the vulva. Int J Gynaecol Obstet 2009;105:105-6. 3. Pecorelli S. Revised FIGO staging for carcinoma of groin (24%) the vulva, cervix, and endometrium. Int J Gynecol pelvis (15%) Obstet 2009;105:103-4. distant organs (18%) 4. Berek JS. Vulvar cancer. Berek and Novak’s – Status of surgical margins is the most Gynaecology 14th ed. Lippincott Williams & Wilkins 2007:1549-80. powerful predictor of recurrence, with 5. Rock JA, Jones HW. Malignancies of the vulva. Te almost 50% recurrence risk with margins Linde’s Operative Gynaecology, 10th edition; closer than 0.8 cm. Lippincott Williams & Wilkins 2008:1151-207.

Index

A Alkaline hematin method 291 Aplastic anemia 51 Abdominal Alloimmune factors in RPL 23 Approach to case of adnexal mass in a and pelvic CT scan and MRI 314 Alpha glucosidase inhibitors 56 young patient 302 examination 39, 54 Altered composition of extracellular Approaches to improve diagnosis and hysterectomy 296 matrix 10 management 219 Arnold-Chiari II malformation 4 sacrocolpopexy with hernia repair Amenorrhea 207, 303 256 American Society of Reproductive Arterial embolization 170 trauma in third trimester 103 Medicine 17 Artificial rupture of membranes 167 Abnormal Amiodarone 85 Ascorbic acid 41 karyotype 122 Amniocentesis 105 Asherman’s syndrome 24, 216 uterine bleeding 285 Amnionicity 121 Aspartate transaminases 66 Aspermia 225 Abruptio placentae 159, 160, 162, Amniotic fluid 173, 174, 178 index 92 Aspiration pneumonitis 72 Acarbose 56 optical density 155 Aspirin 317 Acardiac twin 127 Androgen insensitivity syndrome 209 Assisted reproductive technology 227 Acardius Androgens 317 Auscultation 134 acephalus 128 Anemia in pregnancy 37, 40 Australia antigen 39 acormus 128 Anemia of Autologous bladder mucosa amorphous 128 chronic disease 37 interposition graft 280 anceps 128 pregnancy 43 Azoospermia 225 Accepted definition of semen quality Aneuploidy 10 B 225 Angiotensin-converting enzyme Acetaminophen 317 inhibitor 85 Back pain 174 ACOG criteria for hysterectomy for Anovulatory DUB 287, 290 Backache 303 leiomyomata 238 Antenatal Barium enema 314 Acquired immunodeficiency syndrome care 33, 55 Basal body temperature 221 182 period 22 Base line investigations 76 Actinomycosis 333 Antepartum hemorrhage 103, 159, Beta Acute 168, 171 blocker 85 renal failure 72 Anterior vaginal wall 250 thalassemia 11 tubular necrosis 72 Antibiotic therapy 281 Betamimetic agents 151 Adenocarcinoma 332 Antibiotics 152 Biguanides 56 Adenomyosis 296 Antibody dependent cell mediated Bishop score 135 Adequate rest 48 cytotoxicity assay 100 Bladder Adnexal involvement 347 Antifolate medications 2 distension 164 Advanced preterm labor 153 Antiphospholipid antibodies 20, 144 drainage 280 Aesthenozoospermia 225 Aortic Bleeding AIDS-related complex 184 root 84 diathesis 161 Alanine transaminases 66 stenosis 81 per vaginum 160 366 Case Discussions in Obstetrics and Gynecology

Blood Cervical Continue folic acid 25 grouping 164 cancer 334 Continuous progesterone 293 loss 162 cerclage 24 Contraceptive advice 48 pressure 76, 133, 162 length measurement 154 Control of postoperative bladder measurement 54 mucus study 221 spasms 281 sugar 164 Cervicovaginal fibronectin levels 153 Cortical necrosis 72 transfusion 159 Cesarean Crohn’s disease 333 in anemia in pregnancy 47 delivery 68, 103 Cryptoccocal meningitis 186 urea 164 hysterectomy 139, 161 Crystalloids 172 Blurring of vision 161 section 81, 167 Cushing’s Body stalk anomaly 10 section in heart disease 81 disease 213 Bone marrow insufficiency: 37 Chemotherapeutic agents 116 syndrome 208 Bonney’s Chemotherapy 324 Cyanotic lesions 84 hood operation 242 Chest X-ray 314 Cyclic progesterone therapy 293 principle 274 Chlamydia trachomatis 25, 186, 200 Cytologic Borderline ovarian tumors 319 Chorioamnionitis 179 atypia 291 Bowel complaints 303 Chorionic villous examination 314 BP records 161 biopsy 9 Cytomegalovirus retinitis 185 Breast sampling 105 Cytoreductive surgery 320 cancer 317 Chorionicity 121 examination 39 Chronic D Broad ligament flaps 280 blood loss 37, 46 Danazol therapy 307 Brucellosis 333 hypertension 63 Delancey’s classification 249 Built 76 inversion of uterus 243 Delivery 26 pelvic pain 303 Depot medroxyprogesterone 293 C Classification of fetal growth Detection of Caloric requirement 56 restriction 87 fetal anemia 105 Carcinoma Clear cell carcinoma 344 infection 222 cervix 333 Clostridium perfringens 200 Determination of Rh titer 100 endometrium 344 Coagulation Diabetes in vulva 355 abnormalities 287 pregnancy 53 Cardiac dysfunction 10 profile 164 previous pregnancy 54 Cardiomypathy 80 Cocaine 162 Diagnosis of antiphospholipids Cardiovascular Coccidoidomycosis 333 syndrome 20 changes 72 Colonoscopy 314 Diaphragmatic hernia 10 system 54 Combined estrogen and progesterone Diazoxide 152 Causes of 294 Dietary deficiency 43 amenorrhea 207, 212 Complete Dilated cardiomyopathy 74, 84 Asherman’s syndrome 216 blood count 49, 86, 34 Diminished perfusion 63 infertility 220 rupture 138 Dipalmitoylphosphatidyl choline 155 iron deficiency anemia in pregnancy Complex hyperplasias 291 Disadvantages of amniocentesis 111 43 Complicated aortic coarctation. 80 Disseminated intravascular macrocytic anemia 51 Complications of severe anemia during coagulation 72, 178 macrocytosis 51 pregnancy 44 coagulopathy 174 normogonadotropic amenorrhea Confirmation of pregnancy 30 DNA ploidy status 347 215 Congenital Doppler OHSS 229 abnormalities 3 in multiple gestation 120 Cefoxitin 201 malformations 3, 60, 79 ultrasound 106, 107 Central cervical fibroid 242 Congestive cardiac failure 72 velocimetry 55 Cerebrovascular changes 72 Conjoint twins 126 Dorsal lithotomy position 267 Index 367

Dose of oxytocin 136 blood Glucose challenge test 25, 39, 144, Down’s syndrome 6, 7, 11 group 105 186 Duration of catheter drainage: 280 sampling 105, 112 Glycosylated hemoglobin levels 55 Dysfunctional uterine bleeding 285, complications 60 Gonadotropin 287 congenital disorders 1 levels 214 Dysmenorrhea 303 death 174 releasing hormones agonist 294 Dyspareunia 303 DNA 105 Gracilis muscle flap 279 echocardiography 55 Grading of placental abruption 175 E growth 105 Growth of pregnancy 122 Gynecologic surgery 317 Early restriction 22, 73, 87, 179 preterm labor 149 heart sounds 163 H ultrasound 160 hypoproteinemia 10 Echocardiography 78 indication 58 Haemophilus influenza 200 Edema of legs 161 infection 10 Hairy leukoplakia 186 Efavirenz 191 lung maturity 154, 177 Halban’s disease 290 Eisenmenger’s syndrome 84 movements 161 Headache 53, 161 Elective cervical cerclage 167 Fetomaternal hemorrhage 103 Heart disease 78 Electronic fetal heart 129 Fibrinogen degradation products 164 in pregnancy 75 Emergency cesarean 180 Fibroid Height of uterus 162 Endometrial polyp 299 HELLP syndrome 66, 71 ablation 294 uterus 162, 231 Hematogenous 319 techniques 295 FIGO staging of cervical cancer 334 Hematologic index cutoffs 12 Hemoglobin 39 biopsy 222 Fire drills 138 typing 12 cancer 351 First or second trimester abortions 162 Hemolysis 49 polyp 298 Fixed-dose combinations 190 Hemorrhage 204 Endovaginal USG 154 Flow cytometry 103 cyst 309 Environmental agents 2 Fluorescent Hepatic Enzyme linked immunoassays 182 in situ hybridization 11 disease 51 Epigastric pain 53 polarization 155 failure 72 Escherichia coli 200 Foam stability index 155 Hereditary breast ovarian cancer Estrogen 294 Free supporting graft 280 syndrome 318 replacement therapy 281 Fresh frozen plasma 176 Herpes therapy 317 Fundal simplex virus 25 Etiology of IUFD 142 grip 39 zoster 186 height 119, 120 Expected date of delivery 118 High iron stores 42 Fundoscopy 55 External Higher morbidity 178 cephalic version 161 G Hingorani’s sign 233 pelvic radiation 349 History of Gastric acidity 41 polyuria 53 F Gastrointestinal disorders 46 previous Failure of lymphatic drainage 10 GDM on insulin 58 first trimester abortions 53 False-positive results 164 General anesthesia 204 pregnancies 1 Favors neoplasia 331 Genital tuberculosis 307 stillbirths 53 Female genital mutilation 264 Gentamycin 201 HIV positive pregnancy 182 Fermented food items and alcohol 41 Geographical distribution 2 Hormonal therapy 293 Fern test 221 Gestational Hormone receptor status 347 Fertility drugs 317 age 1, 165 Hormones estimation 221 Fetal diabetes mellitus 53 Human akinesia deformation sequence 10 hypertension 63 antiglobulin titer 100 anemia 10, 110 Glibenclamide 56 dura mater interposition graft 280 368 Case Discussions in Obstetrics and Gynecology

immunodeficiency virus 182 Intraperitoneal Laparoscopy 223 leukocyte antigens 23 chemotherapy 321 Laparoscopy assisted Hydrops fetalis 106 transfusion 114 myomectomy 240 Hyperprolactinemia 214 tumor 347 transvaginal myomectomy 240 Hyperpyrexia due to pontine Intrauterine Laparotomy 203 hemorrhage 72 death of fetus 142 Laser welding 282 Hypertension in pregnancy 63, 68 device 199 Last menstrual period 118, 160 Hypertensive encephalopathy 72 growth restriction 54, 60 Lateral grip 39 Hypoglycemia 73 manipulations 103 Latzko partial colpocleisis 276 Hypo-gonadotropic hypogonadism 210 progesterone 293 Lawson position 267 Hypothyroidism 51, 287 synechiae 24 Leiomyomas 24 Hypoxic environment 63 Intravenous Level II ultrasound 55 Hysterectomy 170, 203, 299 estrogen 294 Life support measures 171 Hysteropexy 250 immunoglobulin 21, 23 Lileys zones 111 Hysterosalpingography 223 iron administration 46 Liver Hysteroscopic directed biopsy 292 pyelography 315 function test 55 Hysteroscopy 223 Iron involvement 72 absorption 41 Local anesthesia 204 I deficiency anemia 42, 44, 45 Low Identification of fetal hydrops 106 dextran 47 birth weight 73 Immunoglobulins 116 folic acid prophylaxis 42 iron stores 41 metabolism 40 Immunological maladaptive tolerance lying 165 Irregular 64 Lump in abdomen 311 ripening 290 Impaired Lupus anticoagulant 30 shedding of endometrium 290 absorption 43 Luteal phase deficiency 22 Isoxsuprine 151 iron absorption 46 Luteinizing hormone monitoring 221 Isthmus-cervical extension 347 Imperforate hymen 209 Lymph node metastasis 347 Incidence of carcinoma vulva 356 J Increased status 362 blood loss 43 Jack knife position 267 Lymphadenectomy 359 capillary permeability 64 Jaundice 76, 162 Lymph-vascular space invasion 347 erythropoeitic activity 41 Jugular venous pulsations 133 Lynch syndrome II 318 Indications of ICSI 228 K M Indirect Coombs’ test 100 Induction of labor 135 Kaposi’s sarcoma 185 Macrosomia 54, 60 Ineffective erythropoeisis 49 Khannas operation 255 Magnesium sulphate 151 Infertility 303 Kidney function test 89 Magnetic resonance imaging 165 Inguinofemoral lymphadenectomy 360 Kleihauer Magnitude of problem 37 Insulin therapy 57 Betke test 103 Maintenance chemotherapy 321 Intensive care 159 test 167 Major cardiac defects 10 Intercourse 160 Knee chest position 267 Malpresentations 163 Interim feeding strategy 196 Management of Internal L abnormal Pap smear and cervical iliac artery ligation 170 L monocytogenes 25 cancer 327 podalic version 130 Lactate dehydrogenase 66 anemia 40 Interpretation of MCA-PCV 108 Laparoscopic unexplained infertility 224 Intra uterine growth restriction 33 colposuspension 257 Manchester operation 249, 255 Intracardiac transfusion 114 hysterectomy 296 Manual removal of placenta 103 Intramuscular preparation 46 myoma coagulation 241 Marfan’s syndrome 79, 80, 81, 84 Intrapartum management 152 myomectomy 242 Marginal sinus rupture 179 Index 369

Martius grafts 261 Neisseria gonorrhea 200 Oropharyngeal candidiasis 185 Maternal Neoadjuvant chemotherapy 321 Orthopnea 82 hypertension 179 Neonatal Ovarian cancer 317, 344 mortality 178 complications 60 Ovulatory DUB 287 obesity 135 deaths 54 Oxidative stress 64 serum alfa-feto-protein 3 resuscitation 159 Oxytocin 136 Mechanical prosthetic valves 84 Nestroft test 44 antagonist 152 Medical nutrition therapy 56 Neural tube drip 167 Megaloblastic anemia 49 close in embryo 5 Membrane elevation 165 defects 1, 3 P Neurogenic shock 204 Meningomyelocele 5 Packed red cells 172 Menometrorrhagia 285 Newer modifications of laparoscopic Pain Menorrhagia 285 myomectomy 240 abdomen 160 Mentrual irregularities 303 Nifedepine 150 control 82 Metformin 56 Nitric oxide production 64 right hypochondrium 161 Method of posterior colpotomy 203 Nitroglycerine 151 Palpable ovary syndrome 320 Metrorrhagia 285 Nonhormonal methods 293 Pap smear 331 Microcytic hypochromic anemia 44 Nonproliferative diabetic retinopathy Parental Middle cerebral artery 107 55 aneuploidy 8 Mifepristone 136 Nonstress test 55, 90 karyotype 7, 18 Mild anemia 287 Noonan syndrome 10 Normal Parenteral iron 46 Minimizing valsalva maneuvers 281 menstrual cycle 285 Partial previa 165 Misoprostol 136 reproductive tract 209 Pathophysiology of preeclampsia 63 Mixed carcinoma 344 vaginal delivery 193 Pedal edema 76, 133 Mniocentesis detect fetal anemia 109 Normoblastic bone marrow 51 Moderate Pelvic Normozoospermia 225 anemia 288 grip 39 NSAIDs 152 bleeding 171 inflammatory disease 200, 308 Nucloside reverse transcriptase Molecular tumor markers 347 rest 281 inhibitor 192 Monitor fetal heart 166 Perinatal mortality 139, 179 Nutrition 76 Monitoring of anticoagulation 33 Period of gestation 17 NYHA classification 79 Monoamniotic twin pregnancy 122 Peripheral edema 162 Peritoneal Morbid adherence 161, 165 O Mucinous carcinoma 344 cytology 347 Obesity 316 Mullerian agenesis 209 flap 279, 280 Obliterative procedures 257 Multifactorial polygenic disorder 64 Perperium 26 Obstetric history 38 Multiorgan involvement 64 Persistent generalized Office endometrial aspiration biopsy Multiple lymphadenopathy 185 292 gestation 103, 117, 120 Personal history of breast cancer 317 Oligoaesthenoteratozoospermia 225 pregnancy 160, 163 Phosphatidylglycerol 155 Oligohydramnios 30 Multiples of median 108 Pictorial blood assessment chart 291 Oligomenorrhea 285 Musculoskeletal 259 Placenta Oligozoospermia 225 Mycoplasma hominis 200 accreta 171 Omphalocele 10 Myelodysplastic syndromes 51 increta 165 Operative Myolysis 238 previa 159, 160, 161, 169, 170 delivery 159 Myometrial invasion 347 Placental hysteroscopy 299 intervention 171 abruption 22, 73, 174 N Oral localization 160 National High Blood Pressure estrogen 294 polyp 299 Education Program 63 iron therapy 45 Plasmapheresis 116 370 Case Discussions in Obstetrics and Gynecology

Platelet Puberty menorrhagia 285 VBAC with count 31 Puffiness of face 161 external cephalic version 138 transfusion 172 Pulmonary preterm birth 138 Pneumocystis carinii pneumonia 185 artery hypertension 84 Rosetting test 103 Polycystic ovary syndrome 215 edema 72 Routine Polydipsia 53 Pulse oximeter 82 antenatal investigations 31 Polyhydroamnios 54 Purandares sling operation 255 tests for anemia 40 Polymenorrhea 285 Rovera 293 Polymerase chain reaction 31 Q Rupture Polypectomy 299 Quantitation of Rh antibody 100 of membranes 160 Polyphagia 53 uterus 160 Positive screening test 8 R Russel’s viper venom 30 Postcoital test 221 Radical vulvectomy 358 Posterior S Radiotherapy 360 placed placentae 160 Reactive oxygen species 64 Sacral hysteropexy 256 vaginal wall 250 Rectus abdominis muscle flap 280 Sacrospinous fixation with uterine Postmenopausal bleeding 285, 339 Recurrent preservation 256 Postnatal immunoprophylaxis 102 bleeding 160 Saline infusion sonography 223 Postoperative ureteral obstruction 283 pregnancy loss 17, 232 Salivary estriol levels 154 Preconceptional period 2 skin infections 186 Sarcoidosis 333 Pregnancy 78 Scar tenderness 134 Pregnancy with previous spontaneous miscarriages 8 Scarred uterus 138 cesarean section 133 urinary tract infections. 53 Schistosomiasis 333 congenital disorders 1 Relatively safe 85 Screen for thrombophilia 144 intrauterine death of fetus 142 Remote 204 Search for vaginal infections 154 Premature Renal Second trimester 26, 38 ovarian failure 211 changes 72 Secondary amenorrhea 207, 214 rupture of membranes 179 function test 55 Selective salpingography 223 Prematurely ruptured membranes 22 Repair uterine defect 139 Sepsis in abortion 199 Presence of skin infections 53 Requirement of iron 51 Septic abortion 198, 199 Preterm Respiratory Sequelae 204 labor 22, 148, 179 rate 76, 133, 162 Serial growth scans 26 premature rupture of membranes system 54 Serum 161 Retained product of conception 199 creatinine 164 Previous Retroplacental clots 165 electrolytes 164 cesarean section 161 Rh alloimmunization 98 ferritin 40 pregnancy 54 Rh immunoglobulin 101 fibrinogen 164 Primary amenorrhea 207, 209 Rheumatic heart disease 83 iron concentration 40 Primordial prevention 264 Ritodrine 151 Severe Problem oriented management 59 Robertsonian translocation 7 anemia 288 Procalcitonin 205 Robot assisted laparoscopic bleeding 171 Progesterone 221, 293 myomectomy 241 hemorrhage 178 only pill 59 Role of Severity of anemia 37 Progestogen challenge test 213, 214 cordocentesis 112 Sexual trauma 264 Prognosis of carcinoma vulva 362 erythropoietin in anemia 48 Prolapse uterus 245 laparoscopic surgical staging: 348 Shake test 155 Proliferative MRI 181 Shirodkars diabetic retinopathy 55 vaginal hysterectomy in cases of modification of Manchester index 347 endometriosis 348 operation 255 Prophylactic cerclage 24 VBAC in twins 138 sling operation 255 Index 371

Shock out of proportion 162 Thromboembolism during pregnancy U Sideroblastic anemia 44 32 Ultra-radical vulvectomy 360 Signs of scar dehiscence 137 Thrombophilia 31, 32, 144, 161 Ultrasonography 164, 313 Sim’s position 267 in pregnancy 29 Ultrasound 223 Simple hyperplasias 291 screen 89 for fetal growth 55 Skeletal defects 10 Thrombotic complications of APS in monitoring 222 Sling operations 255 pregnancy 33 Umbilical artery Doppler. 26 Smith-Lemli-Opitz syndrome 10 Thyroid disease 213 Unbalanced cell growth 49 Smoking and drug abuse 162 Tightening of finger rings 161 Unclassified bleeding 179 Sodium ferric gluconate 47 Timing of termination of pregnancy 58 Unexplained Sonosalpingography 223 Tocolytic agents 150 hydrops. 103 Specific blood components 172 Tolerate oral iron 45 stillbirth 60 Spinal muscular atrophy 10 Tone of levator ani muscle 247 Spontaneous Tongue 76 Upper GI series/gastroscopy 314 abortions 60 Total Ureaplasma 25 conception 38 hysterectomy 173 Urethrovaginal fistulas 264 Squamous carcinoma 344 iron binding capacity 40 Urinary complaints 303 Stage endometrial carcinoma 345 previa 165 Urine Start progesterone 25 Toxoplasma encephalitis 185 albumin, sugar, ketones 54 Status eclampticus 72 Tranexamic acid 293 output 172 Steroids 150 Transcervical fallopscopy 223 routine Still births and intrauterine death 103 Transferrin saturation 40 and microscopy 39 Structural chromosomal Transperineal USG 164 microscopy and culture 55 rearrangements 8 Transurethral suture cystorrhaphy 278 Uterine Sudden gain in weight 161 Transvaginal ultrasound 289 artery ligation 170 Sulphonylureas 56 Trauma 160 contractions 163 Superimposed preeclampsia 63 Treatment for anemia 45 findings 209 Symphysiofundal height 133 Treatment of hypertonicity 174 Symptomatic obstructive lesions 84 advanced vulvar cancer 360 rupture 138 Synchronous endometrial 344 associated infections 152 tenderness 174 Systemic endometrial cancer 353 illness 287 megaloblastic anemia 50 V inflammatory response 63 unexplained infertility 224 Vaginal 257 Triple incision technique 358 bleeding 174 T Trophoblastic diseases 118 examination 163 Talcum powder 317 True hypovolemia 162 hysterectomy 296 Tampon test of Moir 260, 268 Tuberculosis 185, 287, 333 Vasa previa 180 Tap test 155 Tumor Venous congestion in head and neck 10 Target plasma glucose levels 57 markers 314 Vesicovaginal fistula 259 Teratozoospermia 225 ploidy 362 Virtual hysterosalpingography 223 Terbutaline 151 size 346 Termination of pregnancy 150 Turner syndrome 211 W Twenty-four hours urinary protein. 55 Thalassemia 44 Warning hemorrhage 160 Twin to twin transfusion syndrome 122 Thalassemia intermedia 11, 14 Women’s dignity project 265 Two step technique 61 Therapeutic cerclage 24 World Health Organization 37 Types of Thiazolidenediones 56 Worsening hypoxia 64 Three abnormal uterine bleeding 285 swab test 268 fibroids 234 Z ultrasound signs 24 myomectomy 240 Zygocity 121 Thrombocythemia 31 vulvar cancer 356