AOGD Bulletin December 2020.Indd

Vol.20, No.8; December, 2020 AAOGDOGD

BBULLETINVolumeU 20 LI DecemberL 2020E I T MonthlyI IssueN 8 Price `30 Only

CARING FOR WOMEN’S HEALTH : EVIDENCE, ATTITUDE & PRACTICE

Dedicated Issue: High Risk Pregnancy

AOGD SECRETARIAT Institute of Obstetrics & Gynaecology, Sir Ganga Ram Hospital Sarhadi Gandhi Marg, Old Rajinder Nagar, New Delhi-110060 Tel.: 011-42251768, 1789 E-mail: [email protected]

Website: www.aogd.org 1 AOGD Bulletin

AOGD Offi ce-Bearers 2020-21

Dr Mala Srivastava Dr Kanika Jain President Vice President

Dr Mamta Dagar Dr Neeti Tiwari Dr Sunita Kumar Dr Shweta Mittal Gupta Dr Tarun Das Hon. Secretary Joint Secretary Treasurer Co-Treasurer

Dr Debasis Dutta Dr Geeta Mediratta Dr Chandra Mansukhani Dr Punita Bhardwaj Scientifi c Advisors

Editorial Board

Dr Geeta Mediratta Dr Chandra Mansukhani Dr Ruma Satwik Dr Sharmistha Garg Dr Sakshi Nayar Dr Ila Sharma Editors Co-Editors

Dr Debasis Dutta Dr Gaurav Majumdar Dr Ankta Srivastava Web Editors

2 Vol.20, No.8; December, 2020 AOGD Bulletin Volume 20 • Monthly Issue 8 • December 2020

AOGD Executive Committee 2020-21 Contents President Patrons Dr Mala Srivastava Dr B G Kotwani Dr I Ganguli • From the President’s Pen 4 Vice President Dr Kamal Buckshee Dr Kanika Jain Dr M Kochhar • From the Vice President’s Pen 5 Hony. Secretary Dr Neera Agarwal Dr Mamta Dagar Dr P Chadha • From the Secretary’s Desk 6 Dr S K Bhandari Scientifi c Advisors Dr S N Mukherjee • From the Editor’s Desk 7 Dr Debasis Dutta Dr Sheila Mehra Dr Geeta Mediratta Dr Suneeta Mittal Dr Chandra Mansukhani Dr Swaraj Batra • Recurrent Pregnancy Loss 8 Dr Punita Bhardwaj Dr Urmil Sharma Mala Arora Dr V L Bhargava Joint Secretaries • GDM Screening: What’s New? 15 Dr Neeti Tiwari Advisors Dr Sunita Kumar Dr A Majumdar Pikee Saxena Dr Alka Kriplani Treasurer Dr Amita Suneja • Screening For Pre Eclampsia- An update 20 Dr Shweta Mittal Gupta Dr Chitra Raghunandan Sakshi Nayar, Kanwal Gujral Co-Treasurer Dr H Khullar Dr Tarun Das Dr K Gujral • Op mising Perinatal Outcome in Fetal Growth Restric on 25 Dr Pratima Mittal Chanchal Singh Editors Dr S B Khanna Dr Geeta Mediratta Dr Sharda Jain • Newer Diagnos c Criteria for Placenta Accreta Syndrome (PAS) 30 Dr Chandra Mansukhani Dr Shubha Sagar Trivedi Divya Pandey, Sugandha Bansal Dr Sudha Prasad Web Editor Dr Sudha Salhan Dr Debasis Dutta • Antepartum S ll Birth-Predic on & Preven on 35 Dr Gaurav Majumdar Ex Offi cio Sangeeta Gupta, Aprajita Dr Ankita Srivastava Executive Past Presidents Dr P Chadha (1990-94) • Ra onal use of Antenatal Cor costeroids 42 Co-Editors Dr Neera Agarwal (1994-97) Dr Ruma Satwik Pankaj Garg, Kumari Gunjan, Manjusha Goel Dr Maya Sood (1997-99) Dr Sharmistha Garg Dr D Takkar (1999-2001) Dr Sakshi Nayyar • Antenatal Magnesium Sulphate for Fetal Neuroprotec on: 49 Dr Sudha Salhan (2001-03) Dr Ila Sharma Dr Swaraj Batra (2003-05) The Controversies Finance Committee Dr N B Vaid (2005-06) Nikhil Teneƫ , Anup Thakur Dr Abha Singh Dr S S Trivedi (2006-07) Dr Manju Puri Dr Suneeta Mittal (2007-08) • Proceedings of AOGD Monthly Clinical Mee ng on 27.11.20 54 Dr N B Vaid Dr I Ganguli (2008-09) Mr Pankaj Jain (CA) Dr Shashi Prateek (2009-10) • Journal Scan 56 Dr Pratima Mittal Dr U Manaktala (2010-11) Ruma Satwik Dr Reva Tripathi Dr Neerja Goel (2011-12) Dr Shalini Rajaram Dr C Raghunandan (2012-13) • Cross Word 57 Dr Sudha Prasad Dr Alka Kriplani (2013-14) Ruma Satwik Dr Sunesh Kumar Dr U P Jha (2014-15) Dr U P Jha Dr Pratima Mittal (2015-16) • Pictorial Quiz 57 Dr Sudha Prasad (2016-17) Sharmistha Garg Executive Members Dr Shalini Rajaram (2017-18) Dr Abha Sharma Dr Abha Singh (2018-19) Dr Achla Batra Dr A G Radhika Immediate Past President (2019-2020) Dr Anita Sabharwal Dr Sunesh Kumar Dr Ashok Kumar Immediate Past Vice-President (2019-2020) Dr Asmita Rathore Dr Ashok Kumar Surg. Cdr. Anupam Kapoor Dr Bela Makhija Immediate Past Secretary (2019-2020) Dr Dinesh Kansal Dr Vatsla Dadhwal Dr Gauri Gandhi Dr Indu Chawla President Elect AOGD (2021-2022) Disclaimer Dr Kiran Guleria Dr Achla Batra The advertisements in this bulletin are not a warranty, endorsement or approval of the products Dr Malvika Sabharwal Vice President Elect (2021-2022) or services. The statements and opinions contained in the articles of the AOGD Bulletin are solely Dr Manash Biswas Dr Jyotsna Suri Dr Manju Khemani those of the individual authors and contributors, and do not necessarily refl ect the opinions or Dr Manju Puri Chairpersons recommendations of the publisher. The publisher disclaims responsibility of any injury to persons Dr Neerja Bhatla AOGD Sub-Committees or property resulting from any ideas or products referred to in the articles or advertisements. Dr Ranjana Sharma Dr Manju Khemani Dr Renu Mishra Dr Manju Puri Plagiarism Disclaimer Dr Reva Tripathi Dr Amita Suneja Any plagiarism in the articles will be the sole responsibility of the authors, the editorial board or Dr Rupali Dewan Dr Achla Batra publisher will not be responsible for this. Dr Sangeeta Gupta Dr Kiran Aggarwal Dr Sanjeevni Khanna Dr Anita Rajorhia Publisher/Printer/Editor Dr Shalini Rajaram Dr Jyotsna Suri Dr Geeta Mediratta and Dr Chandra Mansukhani on behalf of Association of Obstetricians & Gynecologists Dr S N Basu Dr Manisha Kumar of Delhi. Dr Suman Lata Dr Reema Bhatt Dr Surveen Ghumman Dr Richa Sharma Printed at Dr Susheela Gupta Dr Sushma Sinha Process & Spot C-112/3, Naraina Industrial Area, Phase-1, New Delhi 110 028 Dr Usha Gupta Dr Kavita Aggarwal Dr Seema Prakash Published from Dr Shashi Lata Kabra Maheshwari Institute of Obstetrics & Gynaecology AOGD Secretariat Sir Ganga Ram Hospital, Sarhadi Gandhi Marg, Old Rajinder Nagar, New Delhi-110 060 Institute of Obstetrics and Gynecology, Sir Ganga Ram Hospital Editors Sarhadi Gandhi Marg, Old Rajinder Nagar, New Delhi-110060 Dr Geeta Mediratta Tel.: 011-42251768, 1789 Dr Chandra Mansukhani E-mail: [email protected] | www.aogd.org Ph. No. 011-42251768, 1789; Email: [email protected]

3 AOGD Bulletin

From the President’s Pen

Gree ngs from AOGD Secretariat. The corona crisis con nues with greater waves touching our city. I thank each and every AOGD member for the great success of the annual conference. It was the hard work of the team and the co-opera on of the AOGD members that was responsible for the success of the fi rst virtual conference of AOGD 2020. The e-elec on for the post of President of AOGD 2021-2022 also held. It was another challenge for our AOGD team to make the data base, co-ordinate with virtual pla orm consultants and get the proceedings going to the sa sfac on of the members of AOGD. We are happy that e-elec ons went on smoothly. We thank our returning offi cers Dr. Kiran Guleria, Dr. K. Gujral and Dr. Surveen Ghuman under the overall leadership of Dr. Reva Tripathi for such an excellent and successful e-elec ons. We were happy that most of our AOGD members did exercise their votes. I thank to all of them. I also congratulate Dr. Achla Batra and Dr. Jyostna Suri for being the President elect and the Vice- President elect of AOGD for the year 2021-2022. Hopefully they will be able to take over the Secretariat physically. The posi on for the chairpersons of sub-commi ees of AOGD are falling vacant from 01/04/2021. We are invi ng applica ons for the posts ll 31/01/2021. We are also proposing an Execu ve mee ng and General Body Mee ng in the month of February 2021. Hope we are able to streamline these important ac vi es and do live up to the expecta ons of all our members. At every step we solicit co-opera on and assistance from all our members. This edi on of bulle n is on high risk pregnancy. The topics touched are recurrent pregnancy loss, newer screening aspects for GDM and Pre-Eclampsia, IUGR and perinatal outcome together with criteria for PAS and predic on of s ll birth. We have been lucky to have inputs from our neonatologists and they have penned down ra onal use of antenatal cor costeroids and antenatal Magnesium Sulphate for fetal neuroprotec on. Hope these corona mes goes away and we have the luxury of mee ng everyone physically. Long Live AOGD.

Dr Mala Srivastava President, AOGD

4 Vol.20, No.8; December, 2020

From the Vice President’s Pen

GreeƟ ngs to all members of the associaƟ on ! As we are into the last month of this much even ul and challenging year 2020, we are seeing a tremendous upsurge in the number of CORONA posi ve cases in our city. But all this has not deterred our medical fraternity, rescue and relief agencies to perform their du es. I hope we, at the AOGD Secretariat have been able to live up-to the expecta ons of all AOGDians. We’ve tried to put our best eff orts possible in the current challenging Scenario to con nue our journey of Learning. As the challenges posed in front of us were new and unexplored, we used Technology based innova ve ideas to fulfi l our objec ves of con nuing medical educa on in the fi eld of Obstetrics and Gynaecology. Our expert Editorial team has brought out this December’s E-Bulle n dedicated to ‘High Risk Pregnancy’. I’m sure this exclusive Bulle n with expert write-ups from senior Obstetricians and Neonatologists would be of great interest to the readers. ‘The strength of our Associa on is Unity’. It was decided unanimously in the Execu ve Commi ee mee ng to hold E-Elec ons for the post of President AOGD 2021-22 for the fi rst me since the incep on of the Associa on. They were very successfully and graciously conducted by Electronic Vo ng on a Virtual pla orm from 5th to 10th December under the supervision of Dr Reva Tripathi, jointly by the Returning Offi cers Dr Kiran Guleria, Dr K. Gujral, Dr Surveen Ghumman and AOGD secretariat. We congratulate Dr Achla Batra and Dr Jyotsna Suri on being chosen to be the President and Vice President Elect AOGD 2021-22 respec vely. Here I would like to quote: ‘Individually we are a drop, but together we are an Ocean’ – Ryunosuke Satoro I wish all our members a “Merry Christmas and A very Happy New Year” Regards,

Dr Kanika Jain Vice President, AOGD

5 AOGD Bulletin

From the Secretary’s Desk

Gree ngs to all ! Hope you all are keeping safe and healthy. As we are now towards the end of year 2020, we wish the coming year helps the global eff orts to vanquish the CORONA virus. AOGD E-elec ons for the post of President AOGD were successfully conducted from 5 to 10 December 2020. Hear est Congratula on to Dr. Achla Batra and Dr. Jyotsna Suri from Safdarjung Hospital for being elect President and Vice President AOGD for the year 2021-22. The academic ac vi es in the month of November-December con nued on the virtual pla orm as webinars and e-CMEs post 42nd AOGD Annual Conference. Our editorial team has brought the AOGD E-bulle n December version dedicated to High Risk Pregnancy, which should be of great interest and immense use to our readers. Looking forward to your con nued support. IN ORDER TO CARRY A POSITIVE ACTION, WE MUST DEVELOP HERE A POSITIVE VISION- Dalai Lama Warm Regards

Dr Mamta Dagar Hon. Secretary

Monthly Clinical Meeting AOGD Monthly Virtual Clinical Meet will be organised by Sir Ganga Ram Hospital, New Delhi on 18th December, 2020 from 04:00pm to 05:00pm.

6 Vol.20, No.8; December, 2020

From the Guest Editor’s Desk

Dear Friends, Gree ngs from AOGD Secretariat!!! We end the even ul year 2020 with a bulle n on High Risk Pregnancy. As you are aware that pregnancies with risk factors are increasing day by day mainly because of advanced maternal age, obesity, hypertension, diabetes mellitus, other

Dr Kanwal Gujral medical disorders and placental problems, all leading to abor ons, preterm births, Guest Editor growth restric on and s llbirths. We have selected some common risk situa ons star ng with recurrent pregnancy losses. Dr. Mala Arora has given a detailed account of its e ology and a very prac cal management approach. India is the Diabe c Capital of the world. Screening for Gesta onal Diabetes Mellitus lacks consensus. Dr. Pikee Saxena has dealt with various screening strategies, their effi cacy and what best suits to Indian scenario. Pre-eclampsia is one of the top three causes of maternal mortality besides being a major contributor to perinatal mortality and morbidity. While the western world has Dr Geeta Mediratta accepted universal screening at the end of fi rst trimester and Asprin prophylaxis for Chief Editor screen posi ve women, we are s ll far from it. Dr. Sakshi Nayar has given an in-depth review of screening strategies through each trimester. Fetal growth restric on complicates 10% of pregnancies. Dr. Chanchal in her ar cle has detailed diagnosis, surveillance methods and ming of delivery to op mize the perinatal outcome. Accurate pre-opera ve diagnosis and mul disciplinary management approach is the key to successful outcome in pregnancies with Placenta Accreta Spectrum. Standardiza on of ultrasound terminology and various scoring systems addi onally Dr Chandra Mansukhani help to diagnose and plan the management. Dr. Divya Pandey has beau fully Co-Editor summarized all this in her ar cle. India with its 1.32 billion popula on has been ranked fi rst in absolute numbers in s llbirths. Dr. Sangeeta Gupta has given an excellent account of not only how to predict, but also how to prevent s llbirths. Antenatal cor costeroids for decreasing respiratory distress syndrome and related morbidi es and Magnesium Sulphate for fetal neuroprotec on in women who are likely to deliver preterm have been extensively studied in the last three decades. However, there are some recent controversies regarding their fetal safety. Dr. Pankaj Garg & Dr. Nikhil Tene have run through the evidence brilliantly in their ar cles. We sincerely hope you enjoy reading this bulle n on High Risk Pregnancy. Wishing all the AOGDIANS a Happy, Healthy, Prosperous and Corona Free 2021.

Dr Kanwal Gujral HOD & Chairperson Ins tute of Obstetrics & Gynaecology Sir Ganga Ram Hospital New Delhi

7 AOGD Bulletin

Recurrent Pregnancy Loss Mala Arora Senior Consultant For s Le Femme Greater Kailash 2, New Delhi Director, Noble Hospital Sector 14 Market, Faridabad 121007

Recurrent Pregnancy Loss (RPL) was earlier defi ned • Parental balanced transloca ons, inversions, as three or more consecu ve pregnancy losses at dele ons, duplica ons 20 weeks or less or with fetal weight of less than • Skewed inac va on of X chromosome, 500 grams1,2. The American College changed it to Fragile X syndrome two or more spontaneous miscarriages for clinical • Single gene defects e.g Alpha thalassemia 3 purposes . American Society of Reproduc ve major, Re s syndrome etc Medicine (ASRM) defi nes recurrent pregnancy 4. Hormonal loss as two or more failed clinical pregnancies, which should be documented by either ultrasound • Polycys c ovarian syndrome or histo-pathological examina on. None of the • Progesterone receptor gene polymorphism defi ni ons include biochemical pregnancies, ectopic & Luteal phase defects pregnancies or pregnancy of uncertain loca on. • Hyperandrogenism The causes of Recurrent miscarriages are listed below:- • Hypothyroidism/hyperthyroidism 1. Immunological – Auto immune • Hyperprolac naemia • Primary an phospholipid syndrome (PAPS) • Low AMH / Poor Ovarian Reserve • Secondary an phospholipid syndrome • Adrenal hyperplasia/Addison’s disease (SAPS)– SLE, Autoimmune condi ons • Defeciency of Vitamin D • Any systemic autoimmune disorder e.g • Uncontrolled diabetes mellitus Rheumatoid arthri s, may lead to abnormal 5. Anatomical immunological response to pregnancy. • Müllerian abnormali es, septate uterus 2. Immunological – Alloimmune (Currently • Myomas– submucous, intramural classifi ed as Unexplained) • Uterine synechiae & polyps • Normally the maternal immune system • T-shaped uterus tolerates the fetal allogra which is foriegn. • Cervical incompetence Lack of this immunotolerance leads to 6. Inherited thrombophilia miscarriage. This may be manifest in the endometrium as:- • An thrombin III defi ciency • Abnormali es of cytokine produc on- lack of • Defi ciency of protein C and protein S shi of Th1 to Th 2 response • Ac vated Protein C resistance • Lack of alpha V beta 3 integrin • Factor V Leiden muta on • Increased levels of tumour necrosis factor • Methyl tetrahydrofolate gene homozygosity& alpha (TNF) in the endometrium Hyperhomocysteinaemia • Increased Uterine Natural Killer cells • Prothrombin gene muta on • Low concentra on of Macrophage Inhibitory • Plaminogen Ac vator Inhibitor Cytokines (MIC) 7. Semen Factors • Asynchronous ming of Ovula on and • High Sperm DNA fragmenta on index Implanta on window as seen in PCOD also • Male urogenital infec ons leads to poor implanta on and miscarriage 8. Infec ons 3. Gene c • Genital bacterial vaginosis, chlamydia, latent • Fetal Aneuploidy- trisomy/ monosomy & tuberculosis polyploidies • Subclinical chronic Endometri s diagnosed by

8 Vol.20, No.8; December, 2020

increased plasma cells in the endometrium. should be strongly discouraged. Exposure to • Abnormal Uterine microbiome –Non environmental toxins like pes cides, anaesthe c lactobacilli dominated microbiome. gases, dry cleaning chemicals and endocrine • Systemic syphilis, Lyme’s disease, disruptors released from plas c should be avoided. toxoplasmosis, brucellosis 9. Systemic condi ons Systemic Condi ons • Hypertension Maternal Co morbidi es like chronic kidney, liver, cardiac or respiratory illness can result in pregnancy • Chronic renal disease loss. Such mothers need to be counseled regarding • Chronic pulmonary disease surrogacy to safe guard their health and fulfi ll their • Heart disease reproduc ve desires. Women with true rhesus • Severe rhesus sensi sa on sensi za on are managed with intrauterine blood • Other diseases associated with RPL are Sickle transfusions and early delivery. cell anemia, Myotonic dystrophy, Marfan’s syndrome, Homocys nuria, factor VIII Infec ons defi ciency, dysfi brinogenemia and Ehler’s Genital tract infec ons o en result in Infer lity. Danlos syndrome. However milder forms may result in recurrent 10. Life Style factors pregnancy loss e.g bacterial vaginosis,6 latent • Maternal Age > 35 years genital tuberculosis7 and non specifi c bacterial • Maternal Obesity BMI > 30 endometri s post intrauterine procedures like • Paternal Age dilata on & cure age. There is growing evidence that altera on of the microbiome of the vagina and 11. Environmental endometrial cavity will lead to implanta on failure • Endocrine disrupters and miscarriages.8 Although microbiome tes ng is • Smoking, alcohol, drugs s ll a research tool and not available in the clinical • Exposure to irradia on se ng, probio cs like lactobacilli may play a role in • Exposure to environmental toxins, pes cides, correc ng the uterine microbiome. DDT, Drycleaning chemicals Certain systemic infec ons like brucellosis, Lymes • Exposure to anaesthe c gases disease and toxoplasmosis are also associated with 9 Chemicals which have been associated with sporadic miscarriages. These are rare and may be RPL include nitrous oxide, arsenic, aniline dyes, diagnosed by posi ve serology if suspected. benzene, ethylene oxide, lead, pes cides, mercury and cadmium. Semen Factors Although an exhaus ve list of causes exists, we s ll An unhealthy paternal life style, exposure to have 40-50% pa ents that fall in the unexplained alcohol and smoking are associated with increased category. In many pa ents more than one sperm DNA fragmenta on, which in turn, can lead factor may lead to miscarriage and in some each to poor embryo quality and recurrent pregnancy 10 miscarriage may have a diff erent e ology. This loss. These pa ents need life style modifi ca on poses a diagnos c diffi culty to the physician. and long-term (i.e. 3 months or longer) treatment with an oxidants to reverse the damage Life Style & Environmental Factors Male accessory gland infec ons (MAGI) e.g. seminal Maternal age has a very posi ve corela on with vesiculi s and prosta s will coat the sperm with recurrent pregnancy loss.4 Over the age of 40 years bacteria prior to ejacula on. This in turn may cause majority of pregnancies are lost with autologous chronic endometri s and recurrent pregnancy loss. oocytes. Hence reproduc on should be encouraged before the age of 35 years. Inherited Thrombophilia Parental obesity should be addressed posi vely5 These are most commonly associated with second and parental smoking, alcohol & drug exposure & third trimester pregnancy loss. However some

9 AOGD Bulletin

disorders like prothrombin gene and factor V procoagulant state with increased coronary heart leiden muta on may be associated with recurrent disease, could also poten ally cause recurrent pregnancy loss.11 pregnancy loss Abnormal maternal thyroid funcƟ ons have been Anatomical implicated as a cause of recurrent miscarriage.16 An es mated 15% of couples (one in six) However, mild or subclinical thyroid dysfunc on with recurrent miscarriage have an anatomic is not associated with recurrent miscarriage, as it abnormality of the uterus as the primary cause.12 more o en leads to infer lity, but increased levels These abnormali es include the following. of thyroid peroxidase and/or microsomal an bodies • Defects of Müllerian fusion, which include septate have been associated with recurrent miscarriage.17 uterus, unicornuate uterus and bicornuate uterus In Autoimmune thyroid disease (AITD), the risk of with unequal uterine horns. miscarriage was the same whether the status was • Acquired anatomical defects, such as, submucous hypothyroid or euthyroid, indica ng that AITD or intramural myomas, endometrial polyps and nega vely aff ects fetal implanta on. Hence all uterine synechae. women with posi ve thyroid an bodies should be treated with a low dose of thyroxine replacement • Small tubular uterine cavity: this may be to suppress thyroid autoimmunity and achieve a congenital, secondary to diethyl s lboestrol favourable maternal and perinatal outcome.17 exposure in utero or genital tuberculosis. • Cervical incompetence, which is diagnosed by HyperprolacƟ naemia usually causes infer lity due visualizing the cervix with an empty bladder on to luteolysis; however, in par ally treated cases, transvaginal ultrasound scan and assessing the the picture may change to early pregnancy loss due width at the internal os as well as the cervical to corpus luteum defeciency. length from internal to external os.13 It maybe a Although rare, the pa ent with an untreated late congenital weakness or secondary to repeated onset congenital adrenal hyperplasia may have cervical dilata on. It is also associated with an increased chance of recurrent miscarriage unicornuate or bicornuate uteri. owing to hyperandrogenism. On the other hand, incipient Addison’s disease will also cause recurrent Hormonal miscarriages; the pa ent o en has low blood A mul tude of endocrinal disorders can cause pressure and hyperpigmenta on. recurrent miscarriage. Poor Ovarian reserve, diagnosed by low levels of An PolycysƟ c ovarian syndrome is one of the mullerian hormone (AMH) and a poor antral follicle commonest endocrinal abnormality aff ec ng count, remains an important factor responsible for female reproduc ve performance. Besides recurrent miscarriage, owing to increased rate of infer lity, it presents higher risks of fi rst and aneuploidy in oocytes. Women with AMH levels second-trimester miscarriages.14 below 1ng/ml not only experience diffi culty in conceiving but also have a higher rate of pregnancy Factors associated with a high miscarriage rate loss due to a higher rate of aneuploidy in the are hyperandrogenism, hyperinsulinemia and/or embryo.18 Therapy with Dehydroepianrostenedione ovulatory dysfuncƟ on that accompanies high levels of sulphate (DHEAS) andCo enzyme Q 10 (CoQ 10) luteinising hormone and low levels of progesterone. has been tried but there is no robust evidence to Women with poorly controlled type 1 (insulin- support it. dependent) diabetes mellitus with glycosylated (HbA1C) haemoglobin levels greater than four Gene c standard devia ons above the mean had a higher pregnancy loss rate. Well-controlled diabetes Gene c Abnormali es had pregnancy loss rates similar to those of non- in Karyotypically Normal Parents diabe cs. Apart from frank diabetes, syndrome X,15 Various studies demonstrate that at least 50 percent which comprises of impaired glucose tolerance test of clinically recognised pregnancy loss results from 19 (GTT), hypertension, hypertriglyceridaemia and a a cytogene c abnormality, of which 51% show

10 Vol.20, No.8; December, 2020

autosomal trisomies, 22% show polyploidy, 19% func on, abnormal placenta on, and placental show monosomy, 4% show transloca ons, and the thrombosis / infarc on. This may lead to rest are unclassifi ed gene c defects. The autosomal pregnancy-induced hypertension, intrauterine trisomies commonly encountered are those of growth retarda on (IUGR), intrauterine fetal chromosomes 3, 4, 9, 13–16, 19, 21 and 22.12 death and recurrent miscarriage. Both early fi rst- Products of concep on (POC) should be rou nely trimester losses and late third-trimester losses can submi ed for gene c tes ng preferably with Array occur. There is usually an ultrasound confi rma on CGH and couples with abnormal gene c tes ng of a viable pregnancy prior to the pregnancy loss in should have parental karyotyping.20 If POC results most fi rst trimester losses. show an aneuploidy, and parental karyotype is The diagnosis of APS is made by the presence of normal, the couple should be counseled regarding one clinical criterion and one-laboratory criterion, an op mis c outcome in future pregnancies. which must be posiƟ ve on two occasions 3months (12 weeks) apart. Gene c Abnormali es in Karyotypically Abnormal Parents Clinical Criteria Include The Following21,22 Women may have structural chromosomal - one or more unexplained deaths of a abnormality in the following forms. morphologically normal fetus of more than 10 • Dele ons and duplica ons produce large weeks’ gesta on documented by ultrasonography chromosomal defects, which may cause severe or direct examina on; phenotypic anomalies, thus individuals with - one or more preterm births at or before 34 these anomalies rarely reproduce. weeks’gesta on due to severe pre-eclampsia or • Dicentric and ring chromosomes are mito cally placental insuffi ciency with evidence of IUGR; unstable, so the chances of off spring acquiring - three or more consecu ve miscarriages before these anomalies are very small. 10 weeks’ gesta on with no maternal hormonal, • In balanced transloca ons in men, the anatomic abnormali es, normal fetal gene c reproduc ve fi tness is only slightly diminished. tes ng and other causes of recurrent losses being In spite of their good reproduc ve performance, ruled out. these individuals show a signifi cant decrease Laboratory criteria include detec on of any of the in live births, and a signifi cant increase in both following fetal death and interval infer lity; hence they will 1. Lupus an coagulant by DRVVT, APTT or PTT present with recurrent miscarriage. 2. An cardiolipin an bodies • In unbalanced transloca ons in men, not only is 3. An phospholipid an bodies there produc ve fi tness greatly decreased but 4. An beta 2 glycoprotein an bodies the riskof abnormal off spring is also increased. 5. An phospha dylserine an bodies • In single gene defects, diagnosis can only be made by a detailed family history coupled with Array Autoimmune disorders, such as systemic complete genomic hybridiza on (CGH) tes ng. lupus erythematosus, systemic sclerosis, and Alterna vely if the gene locus is well iden fi ed autoimmune thrombocytopenia are associated PCR tes ng or SNP will help in diagnosis. with recurrent miscarriage, and are o en classifi ed as secondary an phospholipid syndrome (or SAPS). Immunological Causes The mechanism of loss and the treatment are the same as those for primary APS. An phospholipid an body syndrome (APS) is the commonest immunological cause of recurrent Treatment with steroids is not recommended miscarriage. It is the most rewarding as far as the based on current evidence. A combina on of low treatment is concerned. An bodies are directed dose aspirin and unfrac onated /low molecular against nega vely charged phospholipids, which weight heparin currently gives the best pregnancy are the major cons tuents of trophoblast. These outcome. Heparin is not only an an coagulant, it an bodies can cause impaired trophoblas c has a potent complement inhibitory ac on which

11 AOGD Bulletin

is benefi cial in preven ng complement mediated these tests the unexplained group shrinks to much damage in APS syndrome. Aspirin should be less than half. With future research we believe we started pre-conceptually and heparin a er a will be able to fi nd an explana on for all causes posi ve pregnancy test and con nued un l the of recurrent pregnancy loss, thereby reducing the me of delivery. Post partum thromboprophylaxis percentage of unexplained miscarriages to almost is recommended for 2 weeks to prevent deep vein ex nc on. thrombosis. In cases of SAPS due to systemic Lupus Summary erythematosis, hydroxychloroquine (HCQ) has been All women presen ng with two or more used with good success rates during pregnancy. It is miscarriages need to be worked up to iden fy the started in the preconcep on period and con nued cause of miscarriages. All women should have the throughout pregnancy in a dose of 400 mg once or following twice daily a er meals. It is a pregnancy category C ◊ Uterine cavity evalua on by 3D ulltrasound scan/ drug and it controls both disease ac vity and fl ares sonohysterogram for cavity lesions like polyps/ during pregnancy. It also prevents heart block in myoma. Alterna vely a Hysterosalpingogram the fetus.23 may be done and in posi ve cases hysteroscopy Intravenous Immunoglobulins (IVIG) therapy is is both a confi rmatory and therapeu c op on. indicated in women with secondary recurrent ◊ Hormonal profi le –Thyroid func on test and an - miscarriages, very high tres of an bodies where thyroid an bodies. HbA1C and in women with treatment with aspirin and low molecular weight galactorrhea serum prolac n levels. In women heparin fails to prevent a pregnancy loss.24 over 35 years serum AMH ◊ Autoimmune Screening for APLA syndrome. Autoimmunity An nuclear an bodies (ANA) tes ng could be Women with any autoimmune disorder are prone considered .28 to miscarriage due to altera on of the T regulator ◊ Infec on Screening – for bacterial vaginosis, cells and Natural killer cells in the endometrium. cervici s and endometri s Hence the autoimmune condi ons need to be well ◊ Semen Analysis and Culture and Sperm DNA controlled prior to planning a pregnancy. fragmenta on index if indicated. A recent meta-analysis by Chen25 et al shows that If all above inves ga ons are normal, a diagnosis of women with posi ve ANA tres (>1 in 160) have a Unexplained RPL should be made. Any subsequent higher incidence of miscarriage. As a corollary there pregnancy losses should have gene c screening of are a higher number of ANA posi ve individuals in products of concep on by Array CGH for gene c the ANA posi ve group as compared to controls.26 abnormali es. In women with recurrent aneuploidy Hence it may be prudent to include ANA tes ng as miscarriages, IVF with PGD or Oocyte dona on part of the RPL work up. have been suggested. Treatment of specifi c causes has been discussed in Unexplained each sec on, however treatment in unexplained Almost 50% of recurrent miscarriages remained RPL is largely empirical. Evidence for use of unexplained by standard work up, which was empirical therapy with the following is lacking :- very frustra ng for both the pa ent and the ◊ heparin or low dose aspirin Obstetrician. However, if we analyze all POC ◊ Vaginal progesterone supplementa on29 with CGH microarray, we will fi nd a reason for ◊ IVIg 27 miscarriage in >90% of pa ents. Then again ◊ Glucocor coids sperm DNA fragmenta on index and semen ◊ Intralipid therapy culture will iden fy paternal factors. Tes ng for beta 2 glycoprotein 1, an thyroid and an nuclear Vitamin D3 defi ciency should be corrected and they an bodies helps to iden fy autoimmune causes to should receive a maintenance dose of 60,000 units a greater extent. With the rou ne performance of of vitamin D3 weekly during pregnancy.

12 Vol.20, No.8; December, 2020

ProbioƟ cs are helpful in subclinical endometri s The machine learning is based on ESHRE guidelines28 as they correct the uterine micobiome and make it and provides an evidence based management plan lactobacilli dominant, that favors implanta on. for pa ents with RPL. Diet A vegan diet helps control autoimmune There is an 80% chance that these women will disorders. Elimina ng an genic foods like gluten, achieve a live birth, however they may have an eggs, dairy, soya and meat helps to tone down the increased incidence of pregnancy complica ons autoimmune process. like gesta onal diabetes, preterm deliveries and 32 Progesterone therapy is widely prescribed, although hepa c cholestasis. there is evidence that use of vaginal progesterone The following algorhithms summarize clinicians does not improve pregnancy rates.29 Immune approach to a pa ent with RPL. modula on with dydrogesterone may show some For a full workup all the possible causes have to be benefi t. looked into.33 Tender loving care with reassurance scans in early ANA Tes ng may soon be a part of the work up of pregnancy is eff ec ve in reducing stress levels. In RPL. a study Brigham et al reported that seeing a heart beat at 6 weeks of pregnancy resulted in 78% of References the pregnancy to con nue and then again seeing 1. Royal College of Obstetricians and Gynecologists. The a heart beat at 8 weeks resulted in 98% of the inves ga on and treatment of couples with recurrent 30 pregnancies to con nue. This favors the right fi rst-trimester and second-trimester miscarriage.Green- cytokine balance in the endometrium and prevents top Guideline No.17;April 2011.www.rcog.org.uk a miscarriage. 2. Bha acharya S Recurrent miscarriage: should the defi ni on be revised ? In World Clinics Obstetrics & Gynecology vol 1 Complimentary therapies Acupuncture, refl exology no 1 Jun 2011 Jaypee ed Mala Arora and other stress relieving therapies can also be 3. Prac ce Commi ee of the American Society for tried. Reproduc ve Medicine. Defi ni ons of infer lity and Since the diagnos c workup is extensive and the recurrent pregnancy loss. Fer l Steril 2008;89:1603. treatment op ons varied, stra fi ca on of RPL 4. Prac ce Commi ee of the American Society for Reproduc ve Medicine. Aging and infer lity in women. pa ents with Machine learning has also been Fer l Steril 2006; 86(5 Suppl) :S248-52 31 a empted. 5. Pandey S & Bha acharya S Obesity and miscarriage in

Euploid POC After > 2 Pregnancy Losses OR At Least 2 Consecutive Miscarriages with No POC Diagnosis OR At Least 3 Nonconsecutive Miscarriages With No POC Diagnosis

Anatomic Endocrinologic Autoimmune Evaluation of Genetics Evaluation Evaluation Factors PAPS Lifestyle/Environment Karyotype of (eg : HSG, SHG) (Ex : TSH, /SAPS (eg : caffeine, Tobacco, Parents if no Prolactin, APL ,LAC Alcohol, Environmental POC Karyotype Hyperglycemia ß 2GP 1 Exposures Obesity) Obtained

Targeted Targeted Starts ASA,SQ, Preimplanta on Appropriate Surgical Medical or Heparin / LMWH +- Gene c Tes ng Altera ons to Correction Surgical HCQ Preconceptually if Appropriate & Lifestyle Nutri on, Correction & continue until Desired : PGS/PGD or Environment delivery

13 AOGD Bulletin

World Clinic Obstetrics & gynecology vol1 no1 2011 Jaypee 21. Rai RS. An phospholipid syndrome and recurrent ed Mala Arora miscarriages J Post grad Med 2002;48:3-4 6. Kuppusamy R, Visvanathan D, Hollingworth T Pregnancy 22. Ernest JM, Marshburn PB, Ku eh WH. Obstetric loss and bacterial vaginosis in World Clincs in Obstetrics & an phospholipid an body syndrome- an update on gynecology vol1 no1 2011 Jaypee ed Mala Arora pathophysiology and management. Semin reprod Med 7. JaiswarSP, Gautam S Latent genital infec ons & subclinical 2011;29522-39 endometri s. In Recurrent Pregnancy Loss third edi on 23. Autoimmune disorders Pal N Arora S In Recurrent 2019 Jaypee ed Arora & Mukhopadhaya Pregnancy Loss third edi on 2019 Jaypee ed Arora & 8. Moreno I Codoner FM,Vilella F et al Evidence that the Mukhopadhaya endometrial microbiota has an eff ect on implanta on 24. Chris ansen OB, Larsen EC, Egerup P et al Intravenous success or failure Am J Obstet Gynecol 2016 Dec 215(6) Immunoglobulin treatment for secondary recurrent 684-703 miscarriage : a randomized double blind placebo controlled 9. Pal N Thyroid and medical disorders In Recurrent Pregnancy trial BJOG 2015; 122:500-8 Loss second edi on 2007 Jaypee ed Arora & Konje 25. Chen S et al An nuclear an bodies posi vity is a risk factor 10. Sperm DNA fragmenta on Index Opuwari CS, Henkel RR, of recurrent pregnancy loss :a meta analysis. Seminars in Agarwal A in Recurrent Pregnancy Loss third edi on 2019 Arthri s & rheuma sm 2020 Aug;50(4):534-43 Jaypee ed Arora & Mukhopadhaya 26. Cavalcante MB, de Melo Bezerra CT An nuclear an bodies 11. Mishra S Inherited Thrombophilia In Recurrent Pregnancy and recurrent miscarriage: Systema c review and meta- Loss third edi on 2019 Jaypee ed Arora & Mukhopadhaya analysis. Am J Reprod Immunol 2019 Dec; 83(3):e13215 12. Basiri A, Kabessa M, Gvenetadze A et al Anatomical factors 27. Popescu F, Jaslow CR, Ku eh WH. Recurrent pregnancy In Recurrent Pregnancy Loss third edi on 2019 Jaypee ed loss evalua on combined with 24 chromosome microarray Arora & Mukhopadhaya of miscarriage ssue provides a probable or defi nite 13. John O’Brien Cervical causes of Preterm labor In World cause of pregnancy loss in over 90% of pa ents. Human Clinics Obstetrics & Gynecology Jun 2012 vol 2 no 1 Jaypee reproduc on 2018 April.vol 33(4):579-87 ed Mala Arora 28. ESHRE guidelines for recurrent pregnancy Human 14. Venkataraman M & Thanawala U Pregnancy complica on Reproduc on Open, Volume 2018, Issue 2, 2018 in Polycys c ovaries In World Clinics in Obstetrics & 29. Coomarasamy A, Helen Williams, Ewa Truchanowicz, Paul Gynecology 2017 vol 6 no 1 Jaypee ed Mala Arora T. Seed, Rachel Small, Siobhan Quenby, Pra ma Gupta 15. Zaveroni I, Bonini L, Fantuzzi M, et al. Hyperinsulinemia, et al A randomized trial of progesterone in women with obesity and AQ Syndrome X. J Intern Med 1994;235: 51–6 Recurrent miscarriages. Promise study N Engl J Med 2015; 373:2141-2148 DOI: 10.1056/NEJMoa1504927 16. Alexander EK et al American Thyroid associa on guidelines for thyroid disease in pregnancy 2017 Thyroid vol 27(3) 30. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent 17. Lata K, Du a P, Sridhar S et al Thyroid autoimmunity and miscarriage. Hum Reprod 1999;14(11):2868-71 obstetric outcomes in women with recurrent miscarriage: a case control study. Endocrine connect 2013Jun 1;2(2):118- 31. Bruno V, D’Orazio M, Ticconi C et al Machine learning (ML) 124 based method applied in recurrent pregnancy loss (RPL) pa ents diagnos c work up: a poten al innova on in 18. Atasever M, Soyman Z, Demirel E et al Diminished common clinical prac ce. Sci Rep 10,7970 (2020) ;64512-4 ovarian reserve : is it a neglected cause in the assessment of recurrent miscarriage ? a cohort study Fer l Steril 32. Cozzolino M, Rizzello F, Riviello C, Romanelli C, Coccia 2016;105(5):1236-40 Elisabe a M. Ongoing pregnancies in pa ents with unexplained recurrent pregnancy loss: adverse obstetric 19. Boui J, Boui A, Lazar P. Retrospec ve and prospec ve outcomes. Hum FerƟ l (Camb). 2019;22(3):219-225. doi:1 epidemiological studies of 1500 karyotyped spontaneous 0.1080/14647273.2018.1475754 human abor ons. Teratology 1975; 12: 11. 33. Brezina PR, Ke RW, Ku eh WH Preimplanta on gene c 20. Kasak L, Rull K, Laan M Overview of Gene c Causes In screening: a prac cal guide. Clinical Medicine insights in Recurrent Pregnancy Loss third edi on 2019 Jaypee ed Reproduc ve health. Jan 2013 p 197-208 Arora & Mukhopadhaya

14 Vol.20, No.8; December, 2020

GDM Screening: What’s new? Pikee Saxena Professor Department of Obstetrics & Gynaecology, Lady Hardinge Medical College & SSK Hospitals, New Delhi

Introduc on Diabetes Gesta onal Prevalence of GDM varies in India from 4.5% to in Pregnancy Diabetes Mellitus 18.9% depending on the screening test used, urban Pregnancy in Hyperglycemia or rural popula on screened, gene c, ethnic and previously known during pregnancy socioeconomic varia ons. It has been observed diabetes that is not diabetes that prevalence of GDM is directly propor onal to the women with impaired glucose tolerance and OR Type 2 diabetes in non-pregnant women. Hyperglycemia diagnosed for Terminologies for Hyperglycemia the fi rst me Hyperglycemia in Pregnancy during pregnancy diagnosed for the that meets WHO fi rst me during Tradi onally, gesta onal diabetes mellitus is criterion for pregnancy defi ned as onset or fi rst recogni on of abnormal diabetes mellitus in glucose tolerance during pregnancy. In 2015, the non−pregnant Interna onal Federa on of Gynecology and state Obstetrics (FIGO) has given the following 1 terminologies (Figure 1): May occur any me May occur any me Hyperglycemia in pregnancy during pregnancy during pregnancy including the fi rst but most likely a er trimester 24 weeks

Diabetes in Gesta onal Figure 2: Diff erence between diabetes in pregnancy and gesta onal diabetes mellitus. pregnancy diabetes mellitus Perpetual Controversy − Diagnosed before Diagnosed for the Screening and diagnosis of GDM the start of fi rst me during Mul ple guidelines have been given regarding pregnancy pregnancy screening of GDM by reputed authori es a er taking into considera on their local popula on, risks prevalence and cost implica ons. These appear apt Type 1 Type 2 Type 1 Type 2 for their own set up, but they vary widely and do Figure 1: Types of hyperglycemia in pregnancy not provide uniform consensus regarding the best approach. Diabetes in pregnancy is also known as “overt diabetes” or “prediabetes”. It may be Type1 DM / It appears that the screening strategy should be IDDM or Type 2 DM /NIDDM. It may be diagnosed locally developed; taking in stock the prevalence of before pregnancy or during pregnancy if fas ng GDM in their popula on, available infrastructure, plasma glucose level is > 126mg/dl or if random, exper se for conduc ng the test, economic post glucose load or post prandial plasma glucose considera on, prac cal ease of tes ng and validity level any me is > 200 mg/dl or if HbA1c >6.5%. of the test ll an ideal screening test is discovered. Diff erence between diabetes in pregnancy and gesta onal diabetes mellitus is depicted 1below in What is the Signifi cance of Screening? Fig 2. Diabetes in pregnancy is associated with several

15 AOGD Bulletin

adverse outcomes for the mother and the fetus. and hyperbilirubinemia also showed signifi cant Approximately 2/3rd will develop GDM in subsequent posi ve associa ons with maternal glycaemia. pregnancy and 50% develop type 2 DM within 20-28 years of delivery. GDM off ers a unique opportunity Whom to Screen? for ini a on of strategies for preven on of not High risk or selec ve screening: Should be only immediate pregnancy complica ons but also conducted in low risk popula ons; Na onal diabetes preven on later in life. Hence there is a Ins tute for Health and Care Excellence (NICE, need for screening and early diagnosis. 2015)3 recommends assessment of risk factors In the landmark HAPO study3, 25,505 pregnant during the fi rst visit and selec ve screening. women at 15 centers in 9 countries underwent 75-g oral glucose-tolerance tes ng at 24-32week Risk Factors 2 gesta on. Primary outcomes parameters were • Body mass index (BMI)> 30kg/m birthweight > 90th percen le, primary cesarean • Previous macrosomic baby weighing >4.5 kg sec on, clinically diagnosed hypoglycemia and • Previous s ll birth or anomalous baby cord-blood C-pep de > 90th percen le (fetal • Previous history of gesta onal diabetes hyperinsulinemia). It was observed that with • Family history of diabetes (fi rst degree rela ve) increasing maternal glucose levels, the frequency • High risk ethnic popula on for DM- African, of each primary outcome increased. Secondary Asians and Non-Caucasians outcomes of preeclampsia, shoulder dystocia or birth injury, premature delivery, NICU admission • History of polycys c ovarian syndrome (PCOS) Table 1: Maternal and fetal adverse eff ects of gesta onal diabetes mellitus. Maternal morbidity Fetal/neonatal/child morbidity Early pregnancy S llbirth Spontaneous abor ons Neonatal death Pregnancy Nonchromosomal congenital malforma ons Pre-eclampsia Prematurity Gesta onal hypertension Fetal growth restric on Excessive fetal growth (macrosomia, large for gesta onal age) Macrosomia Hydramnios Birth Injury Urinary tract infec ons Shoulder dystocia Delivery Neonatal Preterm labor Neonatal hypoglycemia Trauma c labor Respiratory distress syndrome Instrumental delivery Neonatal polycythemia Cesarean delivery Neonatal hyperbilirubinemia Postopera ve/postpartum infec on Neonatal hypocalcemia Postopera ve/postpartum hemorrhage Neonatal hypothermia Thromboembolism Hyperviscosity Syndrome Maternal morbidity and mortality Neonatal hypomagnesemia Hemorrhage Childhood Puerperium Obesity Failure to ini ate and/or maintain breas eeding Impaired glucose tolerance Infec on Adulthood Long-term postpartum Hypertension Weight reten on Diabetes GDM in subsequent pregnancy Coronary Artery Disease Future overt diabetes Metabolic Syndrome Future cardiovascular disease CVA

16 Vol.20, No.8; December, 2020

Universal screening: Implies screening of the • 50gram oral glucose load irrespec ve of last en re popula on or sub group irrespec ve of the meal. risk factors. ACOG4, American Diabetes Associa on • If a er one hour, venous plasma glucose >140mg/ (ADA)5, Interna onal Associa on of Diabetes and dl, proceed to second step. 6 Pregnancy Study Group (IADPSG) and Diabetes • If one-hour venous plasma glucose is ≥ 200mg/ 7 In Pregnancy Study group India (DIPSI) support dl, then a diagnosis of pregesta onal diabetes is universal screening. It has been suggested that made. selec ve screening would miss 20% of GDM nd cases as compared to universal screening. In India, Step 2: Glucose Tolerance Test (GTT) -2 visit universal screening is essen al, as Indian women • A er an overnight fast of 8-10 hours and three have 11 fold increased risk of developing glucose days of unrestricted diet, measure fas ng plasma intolerance in pregnancy as compared to Caucasian glucose. women. • Give 100 gram of glucose load • Blood is then drawn at hourly intervals (3 samples) When to Screen? Time Carpenter & Coustan NDDG It is now known that several adulthood diseases FASTING 95mg/dl 105mg/dl like diabetes, hypertension, coronary artery ONE HOUR 180mg/dl 190mg/dl disease, obesity, metabolic syndrome originate in TWO HOUR 155mg/dl 165mg/dl fetal life. Adverse intrauterine events permanently THREE HOUR 140mg/dl 145mg/dl “program” the fetus through a process known as early metabolic imprin ng.8 Hence, screening in If any two or more of the above men oned values the fi rst trimester helps us to iden fy those women are deranged, woman is diagnosed to be having who already have pre-exis ng diabetes and helps to gesta onal diabetes mellitus. ACOG criteria is control the sugar levels to avoid the complica ons based on the risk of development of overt diabetes in the off spring by modifying the treatment at an mellitus and not on the fetal and maternal outcome. early gesta on. Both Carpenter and Coustan and Na onal Diabetes Data Group (NDDG) criteria are considered in • NICE3: 24 – 28 weeks in high risk popula on ACOG. Advantage of 2 step screening is that not 4 • ACOG : 24 – 28 weeks, except, women with high all women have to undergo intensive 3 hour OGTT, risk factors who are screened at fi rst visit. where 5 blood samples are drawn. • ADA and IADPSG6: First ANC visit and then at 24 Disadvantage of this test is that pa ent has to come – 32 weeks in previously undiagnosed GDM for a second visit in a fas ng state and therefore 7 • DIPSI : First visit, if normal then at 24-28 weeks may be lost to follow up especially in developing and repeat at 30-32 weeks countries, where 50-60% women receive antenatal • Na onal Guidelines of India8: First visit, if normal care and about one third are lost to follow up. It then repeat at 24-28 weeks is costly, inconvenient and me consuming as fi ve samples are required. How to Screen and Diagnose? A universal guideline for the ideal screening and NICE3 diagnosis method is lacking. A number of methods A woman is diagnosed as having gesta onal have been suggested on the basis of popula on diabetes mellitus if she has either: risks, cost eff ec veness and lack of large na onal • Fas ng plasma glucose ≥ 5.6mmol/l or 100mg/dl. screening programmes. • 2-hour plasma glucose ≥ 7.8mmol/l or 140mg/dl a er 75g of glucose intake. ACOG 20174 Although it is a one-step screening test, Con nues to recommend two step procedure: disadvantage is that the pa ent has to come for a Step 1: Glucose Challenge Test (GCT)/ Glucose second visit in a fas ng state and may be lost to Loading Test (GLT) follow up.

17 AOGD Bulletin

Interna onal Associa on of Diabetes • HAPO study was not done on South East Asian and Pregnancy Study Group (IADPSG)6 popula on The IADPSG criteria has been adopted by ADA in 2010 • The Asians have higher insulin resistance in and by WHO in 2013. It is the only criteria based on pregnancy and hence increased blood glucose adverse pregnancy outcomes. In the hyperglycemia levels, unlike Caucasians on whom HAPO study and adverse pregnancy outcome (HAPO) study, cut was conducted off levels for diagnosis of GDM were lowered to give • Mostly, pregnant women do not come fas ng to an odd’s ra o of 1.75 mes the likelihood of adverse the hospital and if asked to come back in a fas ng outcomes at mean glucose levels of HAPO study. It state, the dropout rate is very high, especially in was observed in this study that adverse pregnancy developing countries. outcomes were noted even below the threshold of • HbA1c is an expensive test and is not possible in diagnos c criteria of GDM (<95mg/dl). low resource se ng. IADPSG recommend screening at fi rst visit and one step, diagnos c two hours 75-gram oral glucose Diabetes in Pregnancy Study Group, tolerance test at 24- 28 weeks. India (DIPSI)7 First antenatal visit (universal /selec ve Diabetes in pregnancy study group, India have screening depending on the prevalence of DM in suggested a universal, one step screening and local popula on) diagnos c procedure keeping in mind the high prevalence of diabetes in India. Plasma glucose Fas ng plasma glucose is es mated 2 hours a er 75gm of oral glucose or Random plasma load given to the pregnant woman at the fi rst ANC glucose or HbA1c visit, irrespec ve of the last meal. This single step Fas ng Fas ng 92- Fas ng ≥126mg/dl procedure is convenient, economical and evidence <92mg/dl 125mg/dl HbA1c ≥6.5% based 9,10. Pa ent need not be fas ng and there is Random plasma no issue of loss to follow up as pa ent is screened glucose ≥200mg/ at the fi rst visit. This method has been approved dl (confi rmed with and recommended by the Na onal Guideline of fas ng glucose or India for diagnosis of GDM and also accepted by HbA1c) FIGO for resource constraint countries. Interpreta on of DIPSI No GDM GDM Overt DM Plasma Glucose Diagnosis in Diagnosis Outside level (mg/dl) Pregnancy Pregnancy At 24-28 Weeks ≥140-200 Gesta onal Impaired Glucose At 24 to 28week gesta on, plasma glucose is Diabetes Mellitus Tolerance es mated in the fas ng state and again at 1 and 2 ≥ 200 Pre- exis ng Diabetes Mellitus Diabetes hours a er glucose load of 75 gm. Time Plasma Glucose (mg/dl) WHO 1999 FASTING ≥92 1 HOUR ≥180 Hyperglycaemia fi rst detected at any me during 2 HOUR ≥153 pregnancy should be classifi ed as either as diabetes mellitus in pregnancy or gesta onal diabetes If any one or more value is deranged, then GDM is mellitus. diagnosed. • Fas ng plasma glucose ≥ 7.0 mmol/l (126 mg/ dl) ACOG stated that lowering the thresholds of • 2-hour plasma glucose ≥ 11.1 mmol/l (200 mg/dl) diagnosis of GDM would result in increasing the following a 75g oral glucose load prevalence and hence, the cost of care.2 • Random plasma glucose ≥ 11.1 mmol/l (200 mg/ 7 Seshiah et al opined that IADPSG had the following dl) in the presence of diabetes symptoms. shortcomings:

18 Vol.20, No.8; December, 2020

Summary Organiza on Year Screening Approach Glucose Diagnos c Remarks mode load criteria(mg/dl) F 1hr 2hr 3hr ACOG 2017 Universal Two step 100gm 95 180 155 140 Carpenter & Coustan; ≥ 2 value abnormal 105 190 165 145 NDDG; ≥ 2 value abnormal NICE 2015 Selec ve One step 75gm 100 - 140 - ≥ 1 value abnormal WHO 2013 Universal One step 75gm 92 180 153 - ≥ 1 value abnormal ADA & IADPSG 2010 Universal One step 75gm 92 180 153 - ≥ 1 value abnormal DIPSI 2006 Universal One step 75gm - - 140 - 1 value MOHFW 2018 Universal One step 75gm - - 140 - 1 value Na onal Guidelines

• 2-hour plasma glucose ≥ 7.8 mmol/l (140 mg/dl) References following a 75g oral glucose load- diagnosis of 1. Hod M,Kapur A, Sacks DA et al. The Interna onal GDM is made Federa on of Gynecology and Obstetrics (FIGO) Ini a ve on gesta onal diabetes mellitus: A pragma c guide for WHO has recently adopted the IADPSG Criteria for diagnosis, management and care. Int J Gynaecol Obstet diagnosing diabetes in pregnancy in 2013. 2015; 131 Suppl 3:S173 2. Metzger BE, Lowe LP, Dyer AR, et al. Hyperglycemia Challenges in GDM Screening and adverse pregnancy outcomes. N Eng J Med 2008; 358:1991-2002 in Low Resource Se ngs 3. NICE clinical guideline, February 2015. Diabetes in Health System Barriers- Lack of healthcare pregnancy: management from preconcep on to the professionals/ sampling & diagnos c facili es postnatal period. Pa ent related barrier- Coming back for a 2nd visit 4. ACOG Prac ce Bulle n No. 180: Gesta onal Diabetes in fas ng state, economic, social & accessibility Mellitus .Obstet Gynecol. 2017 Jul;130(1):e17-e37. doi: 10.1097/AOG.0000000000002159.PMID:2864433 barriers. 5. Classifi ca on and Diagnosis of Diabetes, American Diabetes Associa on, Diabetes Care 2017 Jan; 40(Supplement Conclusion 1): S11-S24. h ps://doi.org/10.2337/dc17-S005 • There is insuffi cient evidence to suggest which 6. Metzger BE, Gabbe SG, Perrson B et al. Interna onal associa on of diabetes and pregnancy study group strategy is best for diagnosing GDM. Indian recommenda ons on the diagnosis and classifi ca on of popula on is diverse and variable, hence judging hyperglycemia in pregnancy. Diabetes Care. 2010;33:676- interna onal criteria on Indian popula on may 682 not be conclusive. 7. Seshiah V, BK, Das AK et al. Diagnosis and Management • Clinician should understand the evidence but of Gesta onal Diabetes mellitus: Indian guidelines. Diabetology.2013;44(5):201-204. individualize decision making to the specifi c 8. Waterland Robert A, Garza Cutberto. Poten al mechanisms pa ent or set up. of metabolic imprin ng that lead to chronic disease 1,2,3. • For low and middle income countries like India, Am J Clin Nutr, February 1999, vol.69 no.2 179-197 with high diabe c burden, universal, early 9. Saxena, P., Verma, P. & Goswami, B. J Obstet Gynecol India screening with single step, DIPSI criteria appears (2017) 67: 337. h ps://doi.org/10.1007/s13224-017- to be convenient, prac cal and evidence based. 0962-y 10. Pikee Saxena, Aruna Nigam. Screening and diagnosis of • DIPSI test is cost eff ec ve- even if repeated in hyperglycemia in pregnancy. Challenges and controversies. each trimester- 66% lesser than IADPSG In: Pikee Saxena, Alka Pandey, Anupam Prakash (Eds). • For India, DIPSI criteria is most appropriate (2018). Clinical guidelines for management of diabetes and has also been advocated by the Na onal in pregnancy.1st Edi on. New Delhi: FOGSI Publica on, Jaypee Publishers; 2018. p.32-41 Guidelines and accepted by FIGO.

19 AOGD Bulletin

Screening for Pre Eclampsia- An update Sakshi Nayar1, Kanwal Gujral2 1Associate Consultant, 2Chairperson & Head, Ins tute of Obstetrics & Gynaecology, Sir Ganga Ram Hospital, New Delhi

Pre-eclampsia (PE) is a leading cause of maternal Table 1: and perinatal morbidity and mortality aff ec ng NICE ACOG 2-5% of pregnancies worldwide.1,2 It is defi ned as High Risk Factors: • Previous pregnancy PE early onset pre-eclampsia (EOPE) when it leads to • Hypertensive disease in • Chronic Hypertension delivery < 34 weeks and late onset pre-eclampsia previous pregnancy • Chronic renal disease • CH, CKD, DM, Autoimmune • Diabetes mellitus (LOPE) when delivery happens a er 34 weeks. disease • SLE or thrombophilia It is also sub-classifi ed as preterm PE or term PE Moderate Risk Factors: • Nulliparity depending upon whether the onset occurs <37 • Age> 40 years • Nulliparity 2 weeks or >37 weeks respec vely. • Age≥ 40 years • BMI≥ 30Kg/m 2 • Family history of PE EOPE is because of a defec ve placenta on i.e. • BMI≥ 35Kg/m • Family history of PE • Concep on by In-vitro failure of trophoblasts to migrate, invade the • Interpregnancy interval >10 yrs fer liza on spiral arterioles and convert them into wide CH-Chronic Hypertension, CKD-Chronic Kidney Disease, fl accid channels from narrow contrac le ones. DM-Diabetes Mellitus, SLE-Systemic Lupus Erythematoasis When this remodelling is incomplete, there is an increase in resistance to the blood fl ow within Risk factors based screening has moderate uterine arteries as refl ected by measurement performance for PE predic on and inclusion of uterine artery doppler. Because of reduced of factors like nulliparity, obesity etc. increases utero-placental perfusion and resultant sensi vity, but lowers specifi city. ischemia, there is release of various analytes, A. Uterine Artery Doppler- Harrington in 1997, angiogenic and an -angiogenic factors, which fi rst published a prospec ve study correla ng can be measured in maternal serum. These abnormal uterine artery Doppler with PE. This was resul ng ischemic products subsequently cause followed by many studies through years each using mul organ dysfunc on. Also it is a known fact diff erent criteria and cut-off values. (Table-2)6 that certain women are at risk of development of Inference from these studies is that screening PE as indicated by NICE and ACOG.3,4 Therefore, has greater accuracy for EOPE and accuracy a combina on of maternal factors, uterine artery increases with inclusion of maternal risk factors. doppler and serum biomarkers form the basis of A recent large meta-analysis on 55974 women fi rst trimester screening of PE. has further validated the use of uterine artery LOPE is because of aging of normal placenta and / Doppler for PE screening (sensi vity 47.8%, or increased maternal predisposi on. specifi city 92.1% for early PE, 26.4% and 93.4% 12 Screening for PE in early pregnancy is fully jus fi ed for any PE respec vely). as ASPRE Study has fi rmly established that 150mg B. Maternal Serum Analytes: Many biomarkers of Asprin from 14 – 36 weeks of pregnancy in have been associated with risk of developing women at high risk for developing preterm PE PE. Detec on rate (DR) of 7 biomarkers at a led to 62% reduc on in PE < 34 weeks, 78% < 32 fi xed false posi ve rate (FPR) of 10% is depicted 13 weeks.5 below. - Not very promising. Angiogenic & An -Angiogenic Markers First Trimester Screening of PE Angiogenic marker PIGF is decreased and an - angiogenic markers sFLT and sENG are increased Risk factors based screening – Iden fi ca on of in women who are des ned to develop PE. Also, women at risk of developing PE at fi rst antenatal there is plausible hypothesis that an imbalance visit allows focused and mely prophylaxis (Risk between the two i.e. an altered ra o can predict factors as indicated by NICE & ACOG are as below) PE with greater accuracy. Following tables depict their performance (Table 4 & 5).

20 Vol.20, No.8; December, 2020

Table 2: 1st Trimester Uterine Artery Doppler Velocimetry & the Predic on of PE Author/ year Prevalence of PE Doppler Criteria Sen. Spec. PPV NPV Mar n (2001)7 Mean PI>2.35 27 95.4 11 98.4 63/3045 (2.1%) Mar n (2001)7 14/3045 (0.46%) Mean PI>2.35 50 95.1 4.5 99.8 Early PE Gomez (2005)8 22/999 (2.2%) Mean PI>95th percen le 24 95.1 11.3 97.9 Melchiorre (2008)9 90/3058 (2.9%) Mean UtA-RI>90th cen le 48.5 91.8 6.2 99.4 Plasencia (2008)10 22/3107 (0.71%) Mean PI>95th percen le + history 90.9 90 6 99.9 Early PE Plasencia (2008)10 71/3107 (2.3%) Mean PI>95th percen le + history 40.8 90 8.7 98.4 Late PE Poon (2009)11 37/8366 (0.44%) Lowest UtA-PI MOM+ history 81.1 90 3.1 99.9 Early PE Poon (2009)11 128/8366 (1.5%) Lowest UtA-PI MOM + history 45.3 90 10.1 99 Late PE

Table 3: Detec on rate (DR) of 7 biomarkers Marker No. of Studies Detec on Rates PP13 5 36 – 80% for early PE PAPP A 8 22 – 43% for early PE PIGF 4 41 – 59% for early PE, 33% for late PE ADAM 12 5 37% unspecifi ed PE Inhibin A 2 35% unspecifi ed PE Ac vin 1 20% unspecifi ed PE HCG 1 22% unspecifi ed PE

Table 4: Systema c Rev 22 case control and 12 cohort studies PIGF (27), VEGF (3), sFLT 114 PIGF Diag OR 9.0 (95% CI 5.6-14.5) FPR 5% Sens 32% sFLT 1 Diag OR 6.6 (95% CI 3.1-13.7) FPR 5% Sens 26% sENG Diag OR 4.2 (95% CI 2.4-7.2) FPR 5% Sens 18%

Table 5: sFlt-1/PIGF ra o – Screening for PE15 Study Number of pa ents with PE (control) Pa ents Sensi vity (%) Specifi city (%) Before onset of PE Stepan et al. (2007) 12 (38) All pa ents 62 51 9 (38) Early-onset PE 67 51 Kim et al. (2007) 46 (100) All pa ents 80.4 78 Crispi et al. (2008) 38 (76) Early-onset PE 84.2 90 Diab et al. (2008) 33 (108) All PEs 100 85 8 (108) Early-onset PE 90 90 De Vivo A. et al. (2008) 52 (52) All pa ents 88.5 88.5 Kusanovic et al. (2009) 62 (1560) All pa ents 40.3 78.5 9 (1613) Early-onset PE 100 89.1 Two studies have highlighted that concentra on C. Ophthalmic Artery Doppler: Meta-analysis of of these biomarkers alone or their ra o was 3 studies have shown changes in ophthalmic predic ve of PE but levels do not change artery for EOPE predic on at a Sensi vity 61.0% signifi cantly un l second half of pregnancy & Specifi city 73.2 %. More work needs to be specially sFLT/PIGF ra o – a me rather late for done before it can be incorporated in clinical aspirin prophylaxis.16,17 prac ce.18

21 AOGD Bulletin

PE Screening Models Going a step ahead, Poon et al have reported that Maternal risk factors are used by NICE & ACOG3,4 for women who were screen posi ve for preterm PE by PE predic on whereas Fetal Medicine Founda on ACOG or NICE but nega ve by FMF algorithm, the (FMF) algorithm uses a combina on of maternal risk of preterm PE was reduced to within or below 21 factors, mean arterial pressure (MAP), uterine background levels. artery PI, PAPP-A and PIGF19. A cut-off of 1 in 100 To summarise, a combina on of maternal factors, is taken as screen posi ve. Screen performance of uterine artery doppler, PIGF is op mal for fi rst NICE vs FMF is depicted in the following tables 6 & trimester screening for all pregnant women. Other 7 (THE SPREE STUDY)20. screening methods are inferior to FMF algorithm. In the non-availability of PIGF, PAPP-A can be Table 6: PE: Screen Performance: NICE vs Combina on of Maternal factors & biomarkers considered for inclusion. Method of screening Detec on rate %, (95% CI) nd rd All pre-eclampsia (n=473) Screening of PE in 2 and 3 Trimester NICE guidelines 30.4%, (26.3-34.6) sFLT/PIGF ra o is extensively being evaluated Maternal factors + 42.5 %, (38.0-46.9) for PE predic on in second and third trimester. MAP+PAPP-A PROGNOSIS study has reported a nega ve Preterm pre-eclampsia (n=142) predic ve value of 99.8% at a level of ≤38 for ruling NICE guidelines 40.8%, (32.8-48.9) out PE within one week in women with signs and symptoms sugges ve of PE. The PPV value of sFLT/ Maternal factors + 53.5 %, (45.3-61.7) MAP+PAPP-A PIGF ra o >38 for ruling in the occurrence of PE Maternal factors + 69.0 %, (61.4-76.6) within 4 weeks, was 36.7% and for HELLP syndrome 22 MAP+PIGF it was 65.6%. A post hoc analysis from PROGNOSIS Maternal factors + 82.4 %, (76.1-88.7) study highlighted that a ra o of sFLT/PIGF at ≤ 38 MAP+PIGF+ UtA-PI can rule out PE within 4 weeks at a NPV of 94.3%.23

Table 7: PE Screening: Detec on rate, at screen posi ve rate Based on available literature, it is recommended of 10%, by various combina ons of maternal factors (MF) with that, a er a fi rst trimester screen, a repeat risk biomarkers using Bayes’ theorem-based method stra fi ca on for evolving PE in 2nd and 3rd trimester Method of screening Detec on rate {(%, 95% CI)} should be carried out. Following model is proposed PE<34 weeks (n=60) by Poon et al which is prac cal and doable.24 MF 48.3 %, (35.2-61.6) MF+MAP 65.0 %, (51.6-76.9) Key Points MF+UtA-PI 73.3 %, (60.3-83.9) 1. PE, especially early onset PE is a disease of high MF+PAPP-A 55.0 %, (41.6-67.9) maternal, perinatal mortality & morbidity MF+PIGF 66.7%, (53.3-78.3) 2. Aspirin 150mg/day started before 14 weeks of MF+ MAP+ UtA-PI 88.3%, (77.4-95.2) pregnancy signifi cantly reduces incidence of PE, MF+ MAP+ PAPP-A 65.0%, (51.6-76.9) more so preterm PE MF+ MAP+ PIGF 73.3%, (60.3-83.9) 3. At the moment, best screen performance is by a MF+ UtA-PI + PAPP-A 73.3%, (60.3-83.9) combina on of maternal factors, MAP, Uterine MF+ UtA-PI+ PIGF 75.0%, (62.1-85.3) artery Doppler and serum PIGF (FMF Algorithm). MF+PAPP-A+PIGF 68.3%, (55.0-79.7) 4. PAPP-A can be considered for inclusion in FMF MF+ MAP+ UtA-PI + PAPP-A 86.7%, (75.4-94.1) Algorithm in the event of non-availability of PIGF MF+ MAP+ UtA-PI + PIGF 90.0%,(79.5-96.2) 5. Screening based on maternal factors only as MF+ MAP + PAPP-A+ PIGF 76.7%, (64.0-86.6) recommended by ACOG & NICE are inferior MF+UtA-PI+PAPP-A+PIGF 78.3 %, (65.8-87.9) to FMF Algorithm regarding detec on, false MF+MAP+UtA-PI+- 90.0%, (79.5-96.2) PAPP-A+PIGF posi ve and false nega ve rates MAP, mean arterial pressure; PAPP-A, pregnancy-associated plasma 6. A er a fi rst trimester screen, repeat risk protein-A; PIGF, placental growth factor; UtA-PI, uterine artery stra fi ca on for evolving PE in 2nd and 3rd pulsa lity index. trimester is recommended.

22 Vol.20, No.8; December, 2020

Figure 1: FMF combined algorithm for screening u lizes combina on of maternal factors, uterine artery pulsa lity index, mean arterial pressure and angiogenic biomarkers. BP, blood pressure; FMF, Fetal Medicine Founda on; PAPP-A, pregnancy-associated plasma protein-A; PI, pulsa lity index; PIGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1.

References at 11-14 weeks of gesta on to screen for hypertensive disorders and associated complica ons in an unselected 1. Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, popula on. Ultrasound Obstet Gynecol. 2005;26:490-494. Vogel JP, Souza JP. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: a secondary analysis 9. Melchiorre K, Wormald B, Leslie K. First trimester of the World Health Organiza on Mul country Survey on uterine artery Doppler indicates in term and preterm pre Maternal and Newborn Health. BJOG 2014; 121 (Suppl 1): eclampsia. Ultrasound Obstet Gynecol. 2008;32:133-137. 14 – 24. 10. Plasencia W, Maiz N, Poon L. Uterine artery Doppler 2. Duley L. The global impact of pre-eclampsia and eclampsia. at 11+0 to 13+6 weeks and 21+0 to 24+6 weeks in the Semin Perinatol 2009; 33: 130–137. predic on of pre eclampsia. Ultrasound Obstet Gynecol. 2008;32:138-146. 3. Na onal Collabora ng Centre for Women’s and Children’s Health (UK). Hypertension in Pregnancy: The management 11. Poon LC, Karagiannis G, Leal A. Hypertensive disorders in of Hypertensive Disorders during pregnancy. London: pregnancy: screening by uterine artery Doppler imaging RCOG Press 2010. and blood pressure at 11-13 weeks. Ultrasound Obstet Gynecol. 2009;34:497-502. 4. ACOG Commi ee Opinion No. 638: First-trimester risk assessment for early-onset preeclampsia. Obstet 12. Velauthar L, Plana MN, Kalidindi M, Zamora J, Thilaganathan Gynecol 2015; 126: e25– e27. B, Illanes SE, Khan KS, Aquilina J, Thangara nam S. First- trimester uterine artery Doppler and adverse pregnancy 5. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki outcome: a meta-analysis involving 55,974 women. A, de Paco Matallana C et al. Aspirin versus placebo in Ultrasound Obstet Gynecol. 2014;43(5):500-507. pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377: 613– 622. 13. Kuc S, Esther JW, Bas BV, Arie F, Gerard HA, Peter CJ. Evalua on of 7 serum biomarkers and uterine artery 6. Harrington K, Goldfrad C, Carpenter RG, Campbell Doppler ultrasound for fi rst trimester predic on of pre- S. Transvaginal uterine and umbilical artery Doppler eclampsia: a systema c review. Obstet Gynecol Survey. examina on of 12–16 weeks and the subsequent 2011;66(4):225–39. development of pre-eclampsia and intrauterine growth retarda on. Ultrasound Obstet Gynecol. 1997;9:94–100. 14. Kleinrouweler CE, Wiegerinck MM, Ris-Stalpers C, Bossuyt PM, van der Post JA, von Dadelszen P, Mol BW, Pajkrt E. 7. Mar n AM, Bindra R, Curcio P. Screening for pre- eclampsia Accuracy of circula ng placental growth factor, vascular and fetal growth restric on by uterine artery Doppler at endothelial growth factor, soluble fms-like tyrosine 11-14 weeks of gesta on. Ultrasound Obstet Gynecol. kinase 1 and soluble endoglin in the predic on of pre- 2001;18:583-586. eclampsia: a systema c review and meta-analysis. BJOG. 8. Gomez O, Mar nez JM, Figueras F. Uterine artery Doppler 2012;119(7):778–87.

23 AOGD Bulletin

15. Verlohren S, Stepan H, Dechend R. Angiogenic growth 21. Poon LC, Rolnik DL, Tan MY, Delgado JL, Tsokaki T, Akolekar factors in the diagnosis and predic on of pre-eclampsia. R, Singh M, Andrade W, Efeturk T, Jani JC, Plasencia Clin Sci (Lond). 2012;122(2):43–52. W, Papaioannou G, Blazquez AR, Carbone IF, Wright 16. Agrawal S, Cerderia AS, Redman C, Va sh M. Meta-Analysis D, Nicolaides KH. ASPRE trial: incidence of preterm pre- and Systema c Review to Assess the Role of Soluble FMS- eclampsia in pa ents fulfi lling ACOG and NICE criteria Like Tyrosine Kinase-1 and Placenta Growth Factor Ra o according to risk by FMF algorithm. Ultrasound Obstet in Predic on of Preeclampsia: The SaPPPhirE Study. Gynecol 2018; 51: 738– 742. Hypertension: 2018 Feb;71(2):306-316. 22. Zeisler H, Llurba E, Chantraine F, Va sh M, Staff 17. Kleinrouweler C, Wiegerinck M, Ris-Stalpers C, Bossuyt P, AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan van der Post J, von Dadelszen P, Mol B, Pajkrt E, for the H, Allegranza D, Dilba P, Schoedl M, Hund M, Verlohren EBM CONNECT Collabora on. Accuracy of circula ng S. Predic ve value of the sFlt-1:PIGF ra o in women with placental growth factor, vascular endothelial growth factor, suspected preeclampsia. N Engl J Med 2016; 374: 13– 22. soluble fms-like tyrosine kinase 1 and soluble endoglin in 23. Zeisler H, Llurba E, Chantraine FJ, Va sh M, Staff the predic on of pre-eclampsia: a systema c review and AC, Sennstrom M, Olovsson M, Brennecke SP, Stepan meta-analysis. BJOG 2012;119:778–787. H, Allegranza D, Schoedl M, Grill S, Hund M, Verlohren 18. Kalafat E, Laore A, Khalil A, Costa FDS, Thilaganathan S. Soluble fms-like tyrosine kinase-1 to placental B. Ophthalmic artery Doppler for predic on of pre- growth factor ratio: ruling out pre-eclampsia for up eclampsia: systema c review and meta-analysis. to 4 weeks and value of retesting. Ultrasound Obstet Ultrasound Obstet Gynecol 2018 Jun;51(6):731-737. Gynecol 2019; 53: 367– 375. 19. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides KH. 24. Poon, L.C., Galindo, A., Surbek, D., Chantraine, F., Stepan, First-trimester predic on of hypertensive disorders of H., Hye , J., et al. From fi rst-trimester screening to risk pregnancy. Hypertension 2009; 53:812-818. stra fi ca on of evolving pre-eclampsia in second and 20. Tan MY, Wright D, Syngelaki A, Akolekar R, Cicero S, Janga D third trimesters of pregnancy: comprehensive approach. et al. Comparison of diagnos c accuracy of early screening Ultrasound Obstet Gynecol, 55: 5-12. doi:10.1002/ for pre-eclampsia by NICE guidelines and a method uog.21869 combining maternal factors and biomarkers: results of SPREE. Ultrasound Obstet Gynecol 2018; 51: 743–750.

Calendar of Virtual Monthly Clinical Mee ngs 2020-21 29thMay, 2020 B L Kapoor Hospital 26thJune, 2020 VMMC & Safdarjung Hospital 31stJuly, 2020 AIIMS 14thAugust,2020 Lady Hardinge Medical College 28thAugust, 2020 Army Hospital- Research & Referral 11thSeptember,2020 Apollo Hospital 25thSeptember, 2020 DDU Hospital 23rdOctober to 6thNovember, 2020 AOGD Annual Conference Ac vi es 27thNovember, 2020 MAMC & LNJP Hospital 18thDecember, 2020 Sir Ganga Ram Hospital 1stJanuary, 2020 ESI Hospital 29thJanuary, 2021 Dr RML Hospital 26thFebruary, 2021 UCMS & GTB Hospital 26thMarch, 2021 Lady Hardinge Medical College 23rdApril, 2021 Apollo Hospital

24 Vol.20, No.8; December, 2020

Op mising Perinatal Outcome in Fetal Growth Restric on Chanchal Singh1, Gazala Shahnaz2 1MD, MRCOG, FICOG, Lead Consultant, Fetal Medicine, 2DNB, FNB (MFM), Associate Consultant, Fetal Medicine, BirthRight by Rainbow Children’s Hospital, New Delhi

Introduc on Very small fetuses, i.e., those with an es mated rd Fetal growth restric on (FGR) has been defi ned fetal weight (EFW) of less than 3 cen le would as ‘a fetus unable to reach its growth poten al’.1 be considered growth restricted even if Dopplers rd th However, since it is diffi cult to determine the are normal. Fetuses with EFW between 3 to 10 op mal ‘growth poten al’ of any given fetus, cen le should have a Doppler abnormality before ultrasound criteria including es mated fetal weight being considered pathologically small. (EFW), ‘plateauing’ in fetal growth accompanied All growth restricted fetuses may not have EFW by Doppler abnormali es have been suggested below the 10th cen le. Use of growth chart helps to diff eren ate small for gesta onal age (SGA) in iden fying a ‘plateauing’ growth or falling of fetuses from those small fetuses that are at risk of weight cen le which is usually accompanied with adverse perinatal outcomes and thus truly ‘growth cerebral redistribu on. restricted’.2 FGR has also been recategorized as Table 1: Diagnos c criteria for Early and Late Fetal growth ‘early’ and ‘late’ fetal growth restric on when restric on (in a structurally normal fetus) diagnosed before or a er 32 weeks of gesta on. It is Early FGR (diagnosed before Late FGR (diagnosed a er important to note at the outset that a ‘discrepancy 32 weeks) 32 weeks in weeks’ in fetal head circumference (HC) and AC*/EFW < 3rd cen le AC/EFW < 3rd cen le abdominal circumference (AC) on ultrasound OR OR is no longer considered a criteria for defi ning Umbilical artery – A/REDF# growth restric on. Also iden fi ca on of Doppler OR abnormali es should be based on the Pulsa lity AC/EFW < 10th cen le AND Any 2 of the following 3 index (PI) of the target vessel rather than the Uterine artery PI > 95th criteria: th tradi onal ‘SD ra o’. Es mated fetal weight should cen le AND/OR AC/EFW < 10 cen le OR Umbilical artery PI > 95th AC/EFW crossing cen les >2 be plo ed on a ‘growth chart’. Use of growth charts cen le quar les on growth chart (irrespec ve of which chart is used) is essen al for AND no ng the degree of smallness (‘cen le’) as well as CPR< 5th cen le OR weight gain over a period of me, typically over 2-3 Umbilical artery PI > 95th weeks. cen le *AC: Abdominal circumference, #A/REDF: Absent or reversed end diastolic fl ow Diagnosis Early Fetal Growth Restric on If a fetus is iden fi ed to be small on ultrasound, the Early FGR, diagnosed before 32 weeks, accounts fi rst step is to rule out wrong dates. Thus da ng for 1/3rd of antenatally diagnosed FGR and is should be confi rmed, preferably from the early usually associated with hypertensive disorders fi rst trimester crown to rump length (CRL). The of pregnancy. It is easily iden fi ed on ultrasound next step is to diff eren ate small for gesta onal and follows a predictable deteriora on in fetal age (SGA) fetuses from ‘growth restricted’ fetuses, Dopplers: increase in umbilical artery Pulsa lity ie those small fetuses that are at risk of adverse index (PI) followed by decrease in middle cerebral perinatal outcomes. Thus, newer diagnos c criteria artery (MCA) PI followed by venous Doppler that include both fetal as well as maternal Dopplers abnormali es. The deteriora on in umbilical artery have been proposed by a Delphi consensus in 2016 Doppler follows a typical and predictable pa ern in 3 and should be used for diagnosing FGR (table 1). early FGR (fi gure 1). The mean uterine artery PI is usually above the 95th cen le in these pregnancies.

25 AOGD Bulletin

Figure 1: Typical deteriora on in umbilical artery Doppler in early FGR (clockwise): normal waveform, increased PI, absent end diastolic fl ow (AEDF) followed by reversal in end diastolic fl ow (REDF).

Figure 2: A fall in EFW by 2 quar les or more than 50 percen le along with a cerebroplacental ra o (CPR) below 5th cen le due to cerebral redistribu on is typically seen in late FGR.

26 Vol.20, No.8; December, 2020

Early onset FGR especially those presen ng before Early FGR 22-24 weeks warrant detailed evalua on to rule Once a diagnosis of early FGR is made, the pa ent out fetal structural abnormali es, fetal infec ons should be managed in a ter ary care centre with and chromosomal and non-chromosomal gene c maternal-fetal medicine specialists and NICU abnormali es. Amniocentesis for fetal microarray facili es. The Trial of Randomized Umbilical and should be considered in FGR presen ng in the Fetal Flow in Europe (TRUFFLE) trial randomised second trimester. 503 women with early FGR defi ned as EFW < 10th th Although easier to diagnose, early FGR diffi cult to cen le and umbilical artery PI above 95 cen le manage as the only treatment at present is fetal at 26 to 32 weeks’ gesta on to three arms that surveillance and op mal ming of delivery. The would trigger delivery: early DV changes (PI above th perinatal mortality remains high for this subgroup 95 cen le), late DV changes (absent or reversed a of FGR. Since the underlying pathophysiology wave in DV) and reduced fetal heart rate short term 7 seems to involve poor placental implanta on and variability (STV) on computerised CTG (cCTG). 82% spiral artery abnormali es, this is the type that of children had a normal neurodevelopmental is amenable to antenatal predic on in the fi rst outcome at 2 years – the primary outcome of the 8 trimester using the Fetal Medicine Founda on (FMF) trial – which was be er than previously reported. algorithm. The importance of picking up women at risk is the possibility of primary preven on of early Surveillance preeclampsia (requiring delivery prior to 34 weeks) The usual modali es for fetal surveillance of a by giving 150 mg of aspirin to screen posi ve growth restricted fetus include daily kick count, women – this strategy is proven to prevent 80% of biophysical profi le that includes nonstress test early preeclampsia as well as preterm SGA.4,5 (NST) and assessment of Dopplers. There is no consensus on whether one or all modali es should Late Fetal Growth Restric on be used nor how frequently the monitoring should Late FGR accounts for 2/3rd of growth restricted be done. Both would be guided by the gesta on fetuses and may be missed as all fetuses may at which the diagnosis is made, severity of the not necessarily be small. In fact the main vessel condi on and presence of maternal preeclampsia. which is abnormal in early FGR, ie, the umbilical Since cCTG may not be available universally, artery waveform may be normal in majority of conven onal CTG can be used; however the these fetuses. The main Doppler abnormality in expected higher baseline fetal heart rate and late FGR is cerebral redistribu on refl ected by a lower variability of preterm fetuses must be taken cerebroplacental ra o (CPR) of less than the 5th into account while interpre ng the CTG. 60% of cen le for gesta on. Hypertensive disorders are recruited women in TRUFFLE had preeclampsia at not frequent in this subtype. study entry; this fi gure rose to 70% by delivery.7 Thus, maternal surveillance by BP monitoring, Management urine protein:crea nine ra o and baseline liver and There is no known treatment for fetal growth renal func on test is recommended. Fetuses with restric on at present. The results of the recent high PI in umbilical artery with EDF present should STRIDER trial did not show any benefi t of Sildenafi l be reviewed twice weekly. Fetuses with absent/ 6 either. Thus, current management of fetal growth reversed EDF should be reviewed daily. restric on remains op mizing the surveillance of these high-risk pregnancies and planning delivery Timing of Delivery at a gesta on that provides the best trade-off The TRUFFLE trial provided the best evidence between iatrogenic prematurity and intrauterine to guide ming of delivery in early FGR. Fetuses fetal demise. A proposed protocol for evalua on, with absent end diastolic fl ow (AEDF) in umbilical frequency of surveillance and ming of delivery artery should be delivered by 32-34 weeks. Fetuses 1,2 of ‘small’ fetuses is given in fi gure 1. Since early with reversed end diastolic fl ow (REDF) should be and late FGR are two dis nct clinical en es, delivered by 30-32 weeks. Delivery prior to 30 weeks management is discussed separately for each. (and a er viability) should be based on late ductus venosus (DV) changes. Conven onal CTG may be

27 AOGD Bulletin

used in place of cCTG as a safety net – however a poor role in predic ng s llbirth in late FGR and only persistent, repe ve decelera ons on NST hence should not guide frequency of monitoring. should be considered an indica on for delivery. In one study, the median interval between low MCA PI and/or cerebroplacental ra o (CPR) should MCA PI and s llbirth as less than 5 days and almost not be used to me iatrogenic preterm delivery in 90% of s llbirths occurred within one week of early FGR. normal BPP.12 Thus weekly to twice weekly Doppler Delivery can be done any me for maternal surveillance a er 34 weeks has been proposed. indica on. Antenatal Steroids and Magnesium Sulphate for Neuroprotec on Antenatal Steroids There is lack of consensus amongst various All available guidelines recommend a single guidelines for giving steroids between 34-36 weeks’ course of cor costeroid prophylaxis to prevent gesta on though the ROG recommends steroid neonatal respiratory distress syndrome if birth is prophylaxis upto 35 weeks and 6 days. There is no an cipated prior to 34 weeks. The Royal College role of magnesium sulphate for neuroprotec on of Obstetricians and Gynecologists’ (RCOG) a er 32 weeks. recommends antenatal steroids can be considered upto 35 weeks and 6 days.1 Since steroids are most Timing of Delivery eff ec ve when delivery occurs within a week a er There is lack of consensus amongst guidelines as being given, the single course should be med to when to off er delivery in late FGR. The RCOG judiciously to maximise neonatal benefi t. As per recommends that delivery should be ‘off ered’ a er Indian guidelines, 4 doses of Dexamethasone 37 weeks in late FGR.1 The recent ISUOG guidelines 6 mg, 6 hourly is the regime and drug of choice. propose that women with late FGR and cerebral Administra on of steroids may cause a transient redistribu on should be delivered at around 38 improvement in fetal blood fl ows but it should not weeks and not later than 38 weeks and 6 days.2 If in aff ect management as the underlying pathology addi on, umbilical artery is above the 95th cen le, remains unchanged. delivery can be considered a er 36 weeks and no later than 37 weeks and 6 days. Fetuses with birth Neuroprotec on weight below the 3rd cen le have the highest risk Magnesium sulphate for fetal neuroprotec on of s llbirth, hence these pregnancies should not be should be given when preterm delivery is allowed to con nue beyond 37 weeks and 6 days 9,10 an cipated prior to 32 weeks’ gesta on. irrespec ve of fetal Dopplers. Mode of Delivery Mode of Delivery Fetal indica ons for elec ve Cesarean delivery Induc on of labour can be done depending on usual in early FGR include abnormal venous Dopplers, obstetric parameters. Con nuous intrapartum absent or reversed EDF in umbilical artery, deranged CTG monitoring is recommended. These fetuses biophysical profi le and persistently abnormal are at higher risk of requiring emergency LSCS for 1,2 CTG. nonreassuring fetal heart rate trace.2 Late FGR As men oned earlier, the main Doppler abnormality Conclusion in late FGR is cerebral redistribu on. Umbilical Fetal growth restric on should be strictly iden fi ed artery and ductus venosus are usually normal in and categorised into early and late on the basis these fetuses. Since these abnormali es may be of the revised Delphi consensus. Considering the subtle and fetuses near tern have a lower tolerance dis nct pathophysiology and clinical phenotypes, to hypoxemia, late FGR remains an important cause management should be tailored to each type of unexpected s llbirth in late gesta on. as outlined. Since there is no consensus on the modali es and frequency of surveillance, local Surveillance protocols should be made. The op mal frequency of ultrasound surveillance in late FGR is not known. Biophysical profi le has

28 Vol.20, No.8; December, 2020

Small for gesta onal age (EFW < 10th cen le)

Assess umbilical artery, MCA, Ductus Venosus and uterine artery Dopplers, AFI Maternal assessment for preeclampsia

Dopplers, AFI UA PI > 95th cen le but end Absent or reversed EDF normal diastolic fl ow (EDF) present (AREDF) in umbilical artery

Repeat USG a er 2 weeks Dopplers biweekly Daily Dopplers (MCA Dopplers a er 32 weeks) Weekly Biometry Weekly EFW May be SGA or Early FGR Late FGR Delivery Delivery AEDF: Deliver at 32-34 weeks If MCA PI and/or Delivery REDF: Delivery at 30-32 weeks CPR < 5th cen le, off er delivery Delivery by 37 weeks Abnormal DV: Delivery a er at 37 weeks >34 weeks: If no weight gain viability >34 weeks: If no weight gain over 3 weeks ‘Safety net’: Persistent, over 3 weeks repeƟ Ɵ ve deceleraƟ ons on NST Figure 3: Suggested monitoring and ming of delivery in small fetuses (adapted from RCOG and ISUOG guidelines).

References the trial of randomized umbilical and fetal fl ow in Europe (TRUFFLE). Ultrasound Obstet Gynecol 2013; 42: 400 – 1. Royal College of Obstetricians and Gynaecologists. Small- 408. for-Gesta onal-Age Fetus, Inves ga on and Management (Green-top Guideline No. 31). 2013. h ps:// www.rcog. 8. Bilardo CM, Hecher K, Visser GHA, Papageorghiou AT, org.uk/globalassets/documents/guidelines/gtg_31.pdf Marlow N, Thilaganathan B, et al; TRUFFLE Group. Severe fetal growth restric on at 26-32weeks: key messages from 2. Lees CC, Stampalija T, Baschat A, et al. ISUOG Prac ce the TRUFFLE study. Ultrasound Obstet Gynecol 2017; 50: Guidelines: diagnosis and management of small-for- 285–290. gesta onal-age fetus and fetal growth restric on. Ultrasound Obstet Gynecol. 2020 Aug;56(2):298-312. 9. Ting JY, Kingdom JC, Shah PS. Antenatal glucocor coids, magnesium sulfate, and mode of birth in preterm fetal 3. Gordijn SJ, Beune IM, Thilaganathan B, Papageorghiou A, small for gesta onal age. Am J Obstet Gynecol 2018; 218: Baschat AA, Baker PN, Silver RM, Wynia K, Ganzevoort W. S818–828. Consensus defi ni on of fetal growth restric on: a Delphi procedure. Ultrasound Obstet Gynecol 2016; 48: 333–339. 10. Raju TNK, Mercer BM, Burchfi eld DJ, Joseph GF Jr. Periviable birth: execu ve summary of a joint workshop 4. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus Placebo by the Eunice Kennedy Shriver Na onal Ins tute of Child in Pregnancies at High Risk for Preterm Preeclampsia. N Health and Human Development, Society for Maternal- Engl J Med. 2017 Aug 17;377(7):613-622. Fetal Medicine, American Academy of Pediatrics, and 5. Tan MY, Poon LC, Rolnik DL, et al. Predic on and preven on American College of Obstetricians and Gynecologists. of small-for-gesta onal-age neonates: evidence from Obstet Gynecol 2014; 123: 1083–1096. SPREE and ASPRE. Ultrasound Obstet Gynecol. 2018 11. Torrance HL, Bloemen MC, Mulder EJ, Nikkels PG, Derks JB, Jul;52(1):52-59. de Vries LS, Visser GH. Predictors of outcome at 2 years of 6. Pels A, Derks J, Elvan-Taspinar A, van Drongelen J, de Boer age a er early intrauterine growth restric on. Ultrasound M, Duvekot H, et al. Maternal Sildenafi l vs Placebo in Obstet Gynecol 2010; 36: 171–177. Pregnant Women With Severe Early-Onset Fetal Growth 12. Crimmins S, Desai A, Block-Abraham D, Berg C, Gembruch Restric on: A Randomized Clinical Trial. JAMA Netw Open. U, Baschat AA. A comparison of Doppler and biophysical 2020 Jun 1;3(6):e205323. fi ndings between liveborn and s llborn growth-restricted 7. Lees C, Marlow N, Arabin B, Bilardo CM, Brezinka C, Derks fetuses. Am J Obstet Gynecol 2014; 211: 669.e1–10. JB, et al; TRUFFLE Group. Perinatal morbidity and mortality in early-onset fetal growth restric on: cohort outcomes of

29 AOGD Bulletin

Newer Diagnos c Criteria for Placenta Accreta Syndrome (PAS) Divya Pandey1, Sugandha Bansal2 1Associate Professor, 2Post Graduate Resident, Department of Obstetrics and Gynecology Vardhman Mahavir Medical College and Safdarjung Hospital, Delhi-110029

Introduc on manual removal of placenta, Ashermann syndrome Placenta Accreta Syndrome (PAS) disorders formerly and In-Vitro-Fer lisa on pregnancy, other uterine known as morbidly adherent placenta refers to pathologies like bicornuate uterus, adenomyosis, 1 spectrum of abnormal pathology of placenta on submucous fi broids. ranging from accreta, increta to percreta. Maternal mortality and morbidity remains high due to severe How to Diagnose? life-threatening hemorrhage requiring massive Before availability of high resolu on USG, the blood transfusion and even hysterectomy. PAS diagnosis was made usually at the me of delivery. disorders remain undiagnosed before delivery in But with the advent of gray scale and color Doppler half to two-thirds of cases. Maternal mortality USG, prenatal diagnosis has been possible thereby and morbidity are reduced when women with improving the overall outcome. Since then, there PAS disorders, par cularly the invasive forms— have been many studies on diff erent diagnos c placenta increta or percreta—deliver at a ter ary criteria for PAS. The real challenges are precise centre equipped with a mul disciplinary team detec on of PAS in the fi rst trimester and predic on which can eff ec vely tackle the surgical challenges of its degree and the extent of invasion of placental and periopera ve risks. “Levels of maternal care” villi i.e. the severity of PAS. have been designated for these disorders. ACOG Ultrasonography (USG) with grayscale and color and Society of Materno-fetal-medicine recommend Doppler imaging is the recommended fi rst- level III or IV maternal care with mul disciplinary line modality for diagnosing morbidly adherent facility for these women before onset of labor or placenta. Other more promising imaging tools hemorrhage for most op mum outcome. Timely to defi ne the placental topography, such as transfer to these ter ary centres is required for 3-dimensional Doppler and volume contrast females with PAS disorders. This defi nitely depends ultrasound are there, yet generalized applicability largely on both the recogni on of the “at risk of technique and valida on studies are lacking. women” as well as on accurate prenatal diagnosis.1 Features of accreta may be seen by ultrasonography Iden fi ca on of “at Risk Women” as early as the fi rst trimester; however, most women are diagnosed in the second and third The most common risk factor is previous cesarean trimesters. Ideally, women with risk factors for sec on (CS) delivery with the rise of incidence PAS, such as placenta previa and previous cesarean with the number of prior cesarean deliveries. In a delivery, should be evaluated by Obstetricians with systema c review, incidence of PAS rose from 0.3% in experience and exper se in its diagnosis by USG. one previous CS to 6.74% in women with fi ve or more Perhaps the most important ultrasonographic previous CS. Another major risk factor is placenta associa on of PAS in the second and third previa (PP) where PAS disorders are seen in 3% cases trimesters is the presence of placenta previa, which of PP without prior CS. In presence of two risk factors is present in more than 80% of accretas. Other i.e. Prior CS as well as PP the risk of PAS increases gray-scale abnormali es that are associated with drama cally. For women with PP, the risk of PAS is 3%, PAS include mul ple vascular lacunae within the 11%,40%, 61%, 67%for the fi rst, second, third, fourth placenta (fi gure 1), loss of the normal hypoechoic and fi h or more CS respec vely. Other risk factors zone between the placenta and myometrium, are advance maternal age (35 years or more) without decreased retroplacental myometrial thickness previous CS, prior uterine surgeries of cure age, (less than 1 mm), abnormali es of the uterine post-partum endometri s, h/o myomectomy,

30 Vol.20, No.8; December, 2020

serosa-bladder interface, and extension of placenta risk of PAS approaches 100% if pregnancy is allowed into myometrium, serosa, or bladder. The use ll term. Other fi rst trimester USG feature of PAS of color fl ow Doppler imaging may facilitate the is presence of gesta onal sac in lower uterine diagnosis. Turbulent lacunar blood fl ow (fi gure 2) segment along with presence of mul ple irregular is the most common fi nding of PAS on color fl ow vascular spaces within the placental bed. These Doppler imaging. Other Doppler fi ndings of PAS features can help in mely detec on, counselling, include increased sub-placental vascularity, gaps successful management and safe referral. in myometrial blood fl ow, and vessels bridging the placenta to the uterine margin.

Figure 3: Gray scale USG showing Caesarean scar pregnancy The classical USG signs of PAS are loss of the clear Figure 1: Gray scale USG showing placenta lacunae space, placental lacunae, bladder wall interrup on, and uterovesical hypervascularity (fi gure 4). These signs can be looked as early as early 11-14 weeks and also at a mid-trimester morphology scan. Being a progressive condi on, PAS can also be picked up at serial follow-up scans, star ng from 28 weeks of gesta on.1

Figure 2: Color doppler USG showing mul ple vascular lacunae

Timing of Ultrasound Scan in Women with The Risk of PAS Though there is no fi xed consensus or protocol for USG ming for PAS detec on in high risk women. ACOG has suggested a reasonable protocol Figure 4: Color doppler USG showing uterovesical involving a fi rst trimester scan followed by scan hypervascularity at 18-20 weeks, 28-30 weeks and 32-34 weeks in This screening can accurately predict the degree asymptoma c pa ents. This permits assessment and extent of the invasion, stra fy the prognosis of previa resolu on, placental loca on to plan the and plan the best surgical treatment. ming of delivery and to rule out possibility of bladder invasion.1 FIGO Clinical Grading First trimester- In women with prior CS.USG done The Interna onal Federa on of Gynecology and in the early fi rst trimester has been recommended Obstetrics (FIGO) introduced a clinical grading to look for features of Caesarean scar pregnancy system for PAS which uses per opera ve fi ndings (CSP) (fi gure 3),which is a precursor of PAS in its for stra fi ca on of PAS disorders. Although it natural history.2 Low implanta on of the gesta onal diff eren ates focal and complete placenta accreta sac within or in close vicinity to a Caesarean scar in from placenta percreta but it cannot diff eren ate the fi rst trimester is associated with an increased placenta accreta from placenta increta.3 Also, the incidence of placenta accrete in the third trimester clinical grading is performed at delivery so it cannot This sign has high diagnos c accuracy with a be used for prenatal counselling and planning case sensi vity of 93.0% and a specifi city of 98.9%. The management.

31 AOGD Bulletin

Prenatal Diagnosis the USG fi ndings which were very subjec ve For precise prenatal diagnosis, there was need with lot of inter-observer variability. There of standardised USG system and predic ve was no agreed terminology for these fi ndings. models which can help in me culous case based European working group on abnormal invasive management. placenta on (EW-AIP) iden fi ed and analyzed terms commonly used in the literature and 1. Standardised USG Terminologies proposed standardized unambiguous defi ni ons Accurate antenatal diagnosis, which is the basis of these AIP descriptors and accompanied them of risk assessment and planning, depended on

Table 1: European working group on abnormal invasive placenta on (EW-AIP) standard USG terminologies. USG fi nding EW-AIP suggested standardized defi nition 2D gray scale (6 descriptors) 1. Loss, or irregularity, of hypoechoic plane in myometrium underneath placental bed 1. Loss of ‘clear zone’ (‘clear zone’) 2. Abnormal placental lacunae 2. Presence of numerous lacunae including some that are large and irregular (Grade 3. Bladder wall interruption 3), often containing turbulent fl ow visible on grayscale imaging 4. Myometrial thinning 3. Loss or interruption of bright bladder wall (hyperechoic band or ‘line’ between 5. Placental bulge uterine serosa and bladder lumen) 6. Focal exophytic mass 4. Thinning of myometrium overlying placenta to <1mm or undetectable 5. Deviation of uterine serosa away from expected plane, caused by abnormal bulge of placental tissue into neighbouring organ, typically bladder; uterine serosa appears intact but outline shape is distorted 6. Placental tissue seen breaking through uterine serosa and extending beyond it; most often seen inside fi lled urinary bladder 2D color Doppler (4 descriptors) 1. Striking amount of color Doppler signal seen between myometrium and posterior 1. Uterovesical hypervascularity wall of bladder; this sign probably indicates numerous, closely packed, tortuous 2. Subplacental hypervascularity vessels in that region (demonstrating multidirectional fl ow and aliasing artifact) 3. Bridging vessels 2. Striking amount of color Doppler signal seen in placental bed; this sign probably 4. Placental lacunae feeder vessels indicates numerous, closely packed, tortuous vessels in that region (demonstrating multidirectional fl ow and aliasing artifact) 3. Vessels appearing to extend from placenta, across myometrium and beyond serosa into bladder or other organs; often running perpendicular to myometrium 4. Vessels with high-velocity blood fl ow leading from myometrium into placental lacunae, causing turbulence upon entry 3D ultrasound ± power Doppler Complex, irregular arrangement of numerous placental vessels, exhibiting tortuous (1 descriptor) courses and varying calibres (as in 2D) 1. Intraplacental hypervascularity 2. Placental bulge (Focal exophytic mass) 3. Utero-vesical hypervascularity 4. Bridging vessels (fi gure 5) Adapted from European Working Group on Abnormal Invasive Placentation (EW-AIP)4

Figure 5: Color doppler showing bridging vessels

32 Vol.20, No.8; December, 2020

with characteris c ultrasound images. Following Table 2: Placenta Accreta Index Score and score related this EW-AIP mee ng in November 2014 the probability of invasion various terminologies were unifi ed into a set of Parameters Score 11 descriptors, six for 2D grayscale ultrasound, >2 cesarean deliveries 3 four for 2D color Doppler and one for 3D power Lacunae Doppler (Table 1).4 Grade 3 3.5 Grade 2 1 2. Predic ve models for precise planning of SagiƩ al smallest myometrial management of PAS disorders thickness The predic ve models in the form of Scoring ≤1mm 1 or Staging systems have been suggested which >1-≤3mm 0.5 can help in standardizing evalua on of women >3-≤5mm 0.25 at risk for PAS. This may help in individual risk Anterior placenta previa 1 stra fi ca on, planning of a mul disciplinary Bridging vessels 0.5 management approach and decision about PAI SCORE RELATED PROBABILITY OF INVASION delivery ming. Predic on models involving USG PAI Score Probability of invasion, %(95% CI) signs with or without pregnancy characteris cs have been shown to predict PAS. Two such >0 5 (1-15) models suggested recently are Placenta Accreta >1 10 (4-22) Index and Ultrasound staging system.5,6 >2 19 (10-32) >3 33 (22-47) A. Placenta Accreta Index (PAI) >4 51 (36-66) It was found that a score derived from the >5 69 (50-83) ultrasound parameters (smallest myometrial >6 83 (63-93) thickness, lacunar spaces, and presence >7 91 (73-97) of bridging vessels) alongwith the number of prior cesarean deliveries and placental >8 96 (81-99) loca on, was highly predic ve of placental Adapted from Rac et al(5) invasion among pregnancies at increased B. Ultrasound staging system risk. The applica on of the PAI can be helpful An ultrasound staging system of PAS disorders in stra fying individual risk of invasion. It can was proposed, based on the presence of help in counselling, preopera ve planning ultrasound signs of PAS in women presen ng and mely referral to a ter ary center. Also, with placenta previa. The last ultrasound instead of using each ultrasound variable examina on prior to surgery was used to individually, PAI is a scoring system for assess the presence and distribu on of a standardized ultrasound evalua on of ultrasound signs of PAS and to build the all pa ents at risk for morbidly adherent staging system.5 This is as follows. placenta that can be universally adopted. PAS 0: Placenta previa with no ultrasound Assigning the PAI in clinical prac ce may signs of invasion or placenta previa with be helpful in interpre ng these various placental lacunae but no evidence of sonographic variables in light of the pa ent’s abnormal uterus–bladder interface (i.e. no history. (table 2)5 Limita on of PAI: this loss of the clear zone and/or bladder wall model was developed for pregnancies in the interrup on); third trimester with prior cesarean delivery and placenta previa. Other factors like PAS 1: Presence of at least two of placental maternal age, parity, and history of other lacunae, loss of the clear zone and bladder uterine surgical procedures that have been wall interrup on; associated with morbidly adherent placenta, PAS 2: PAS1 plus utero-vesical such as dila on and cure age, myomectomy, hypervascularity; and endometrial abla on were not included. PAS 3: PAS1 or PAS2 plus evidence of increased vascularity in the inferior part of

33 AOGD Bulletin

the lower uterine segment extending into the Role of Biomarkers parametrial region. Some biomarkers have been found to be raised in This prenatal ultrasound staging of PAS condi on of PAS. These are Maternal Serum Alfa fetal disorders was feasible and found that fetoprotein(MSAFP) PAPP-A(Pregnancy-Associated increased USG stage of PAS disorders was plasma protein A), pro-B type natriure c pep de, associated with signifi cant increase in Troponin, Free b-HCG(mRNA) and Human Placental expected blood loss, units of blood products Lactogen (cell-free mRNA) and total placental cell transfused during surgery, opera on free mRNA. Though found to be raised in PAS but me, length of hospital stay and surgical are nonspecifi c to be recommended for clinical use complica ons. When considering the depth of at present. invasion, all women with PAS1 had placenta accreta or increta, while those with PAS 2 Conclusion or PAS 3 had exclusively placenta percreta. Iden fi ca on of at risk women and mely antenatal Though presen ng with the same depth of diagnosis of PAS permits proper planning of placental invasion, women with PAS 3 were management and a mul disciplinary facility thereby at signifi cantly higher risk of hemorrhage and op mizing outcomes. During early fi rst trimester scan, need for transfusion compared with those presence of CSP is a sensi ve sonographic marker. with PAS 2. USG with color Doppler examina on can be done Moreover, this ultrasound staging system in the second or third trimester. Prenatal predic on of PAS disorders showed good correla on of the extent of placental invasion and topography with the clinical grading system suggested are the major determinants of maternal morbidity. by FIGO.PAS0 and PSA1 correlated with FIGO Clinical grading can’t be used for prenatal counselling grade 1-2 and 3 respec vely, while PAS2 and and management. Use of subjec ve USG (Grayscale PAS3 correlated with FIGO grade 4-5 and 6 and Doppler) descriptors and predic on models can respec vely. help in precise diagnosis and thus proper prenatal counselling and planned mely management. Magne c Resonance Imaging (MRI) MRI is the other major tool used for the antenatal References diagnosis of PAS. Magne c resonance imaging 1. Placenta Accreta Spectrum.Obstetric Care Consensus No. features associated with PAS include dark intra- 7.American College of Obstetricians and Gynecologists. placental bands on T2-weighted imaging, abnormal Obstet Gynecol 2018;132:e259-75 bulging of the placenta or uterus, disrup on of the 2. Timor-Tritsch IE, D’Antonio F, Calí G, Palacios-Jaraquemada zone between the uterus and the placenta, and J, Meyer J, Monteagudo A. Early fi rst-trimester transvaginal abnormal or disorganized placental blood vessels. ultrasound is indicated in pregnancy a er previous Cesarean delivery: should it be mandatory? Ultrasound The accuracy of MRI for the predic on of PAS is Obstet Gynecol 2019; 54:156-63. reasonably good, with sensi vi es of 94.4% (95% 3. Jauniaux E, Chantraine F, Silver RM,Langhoff -Roos J; FIGO CI, 86.0-97.9) and the specifi city was 84.0% (95% Placenta Accreta Diagnosis and Management Expert CI, 76.0-89.8), which is comparable to USG. But Consensus Panel. FIGO consensus guidelines on PAS disorders: MRI are even more prone to selec on bias than Epidemiology. Int J Gynaecol Obstet 2018;140: 265–273. USG because it is used generally for pa ents with 4. Collins SL, Ashcro A, Braun T, et al. Proposal for standardized ultrasound descriptors of abnormally an indeterminate USG or at very high risk of PAS. invasive placenta (AIP). Ultrasound Obstet Gynecol. MRI is specifi cally useful for diagnosis of diffi cult 2016;47(3):271-275. doi:10.1002/uog.14952 cases, like posterior placenta previa, and to assess 5. Rac MW, Dashe JS, Wells CE, Moschos E, McIn re depth of invasion in suspected percreta. Compared DD, Twickler DM. Ultrasound predictors of placental to USG,MRI is more expensive, less widely available invasion: the Placenta Accreta Index. Am J Obstet and needs exper se for interpreta on. Thus, it is Gynecol. 2015;212(3):343.e1-343.e3437. doi:10.1016/j. ajog.2014.10.022 not the preferred recommended modality for the 6. Cali G, Forlani F, Lees C, et al. Prenatal ultrasound staging ini al evalua on of possible PAS. system for PAS disorders. Ultrasound Obstet Gynecol. 2019;53(6):752-760. doi:10.1002/uog.20246

34 Vol.20, No.8; December, 2020

Antepartum S ll Birth - Predic on & Preven on Sangeeta Gupta1, Aprajita2 1MD, MRCOG, Director Professor, 2MS, Senior Resident, Obstetrics & Gynecology, Maulana Azad Medical College, New Delhi

S llbirth is one of the most common devasta ng Causes of S llbirth complica ons of pregnancy. Currently, the most S llbirth has diverse ae ology (Table 1) which includes recognized defi ni on of s llbirth is a fetal death that maternal epidemiological risk factors, medical occurs at or greater than 20 weeks gesta on or at disorders, and obstetrical complica ons; placental 1 a birth weight greater than or equal to 350 grams. diseases and fetal condi ons. Late-onset prenatal An es mated 98% of global s llbirths occur in low care and prior home delivery are independent risk 2 and middle-income countries. S llbirth aff ects at factors for subsequent adverse perinatal outcomes.5 least 2.6 million families worldwide every year and Cause of s llbirth may remain elusive in a signifi cant it is a poten al trigger for major economical and number of cases despite extensive workup or due to psychological consequences in women, families, failure of appropriate workup at the right me. healthcare providers, and communi es.3 Maternal Factors: S llbirths can also occur as Globally, India has been ranked fi rst in the absolute an intrapartum complica on and is of par cular number of s llbirths. Wide range of varia on in concern in neglected and mismanaged labor. Hence, s llbirth rate (12.5 to 26.48) has been reported ins tu onal delivery is recommended for all. across the states of India. Recently, Government of India has set a target for bringing down the s llbirth Fetal: Monochorionic twins have higher incidence rate to single digit by 20254. of s llbirth is due to the unique complica ons secondary to placental sharing. Monoamnio c twins have a higher risk of s llbirth due to the risk of Table 1: Ae ology of S llbirth Maternal Fetal Placental Risk Factors Fetal Growth Restric on (FGR) Placental insuffi ciency; FGR Nulliparity Mul ple Gesta on par cularly Placental abrup on Age Monochorionic twins including twin to Cord prolapse Obesity twin transfusion syndrome Ruptured vasa praevia Excessive weight gain in pregnancy Feto-Maternal Haemmorhage Anatomical disorders Cigare e smoking Fetal Anemia e.g. Rh isoimmunisa on Substance abuse Placental chorio-angioma Major Birth Defects Alcohol consump on Nuchal cord Gene c Previous s ll birth Autosomal Recessive Metabolic Medical Diseases disorders e.g. galactosialidosis, sialic Diabetes acid storage disease, neiman pick, GMI Hypertension gangliosidosis type I, gaucher’s disease Chronic renal disease Hemoglobinopathies e.g. thalassemia An phospholipid syndrome Amino acid disorders e.g. Lupus erythematosus glutaricaciduria type II Maternal InfecƟ ons Peroxisomal disorders e.g. zellweger Viral hepa s E syndrome Malaria Amnio c Fluid Abnormali es e.g. Syphilis oligohydramnios, polyhydramnios Obstetric ComplicaƟ ons Cholestasis of pregnancy Chorio-amnioni s

35 AOGD Bulletin

cord entanglement. Fetal growth restric on (FGR) Biochemical Markers: The placenta is a powerful owing to placental insuffi ciency is iden fi ed in about source of hormones and other placenta-derived 40–60% of s llbirths, also in otherwise unexplained proteins, which can be measured in the maternal s llbirths.6 Many unexplained s llbirths are fetuses circula on. Abnormal placental func on measured who fall in average for gesta onal age category either by aberra on of the placental blood fl ow when classifi ed as per their weights but are resistance or produc on of placenta-derived actually growth restricted as there is signifi cant proteins, is associated with fetal growth restric on. lag in growth velocity. Post –term pregnancy is Thus, this supports the role of placental hormones an independent risk factor for s llbirth. This may as a proxy for abnormal placental func on and as a be due to progressive uteroplacental insuffi ciency predictor of s llbirth. In the FASTER trial, elevated when the pregnancy progresses past term. Alfa-feto-pro ens, human chorionic gonadotropin (hCG), and inhibin A at or above 2.0 MoMs, each Predic ve Markers of S llbirths showed a signifi cant associa on with fetal death The S llbirth Collabora ve Research Network study at more than 24 weeks of gesta on. However, found s llbirth risk factors known at the start of the presence of two or more abnormal markers, pregnancy accounted for only a small frac on of although associated with fetal death at more than s llbirth risk.7 Understanding the circumstances of the 24 weeks, was a poor predictor and does not support previous s llbirth is important for counseling about the use of these markers for screening for s llbirth 9 s llbirth recurrence risk and planning care for current in a general popula on. The incorpora on of pregnancy. The associa on of the risk factors and the these markers to more comprehensive algorithms es mated rate of s llbirth8 is shown in table 2. may be the key to a be er predic ve performance regarding SGA and term s llbirth. Table 2: Maternal factors and es mated Rate of S llbirth Condi ons Es mated Rate Odds Monitoring Fetal Growth of S llbirth Ra o (per 1000 births) Clinical monitoring: The measurement of fundal All pregnancies 6.4 1.0 height in weeks is subjec ve. The plo ng of Low risk pregnancies 4.0-5.5 0.86 symphysio-fundal height serially on growth charts 10 Chronic hypertension 6-25 1.5-2.7 (fi gure 1) has be er accuracy for detec ng FGR. Pregnancy induced 9-51 1.2-4 The sensi vity for the detec on of SGA has hypertension: MILD increased from 29% to 48% with the use of growth Pregnancy induced 12-29 1.8-4.4 charts. hypertension: SEVERE Diabetes: DIET ALONE 6.0-10 1.2-2.2 Diabetes: INSULIN+DIET 6.0-35 1.7-7 SLE 40-150 6-20 Renal disease 15-200 2.2-30 Thyroid disease 12-20 2.2-3.0 Thrombophilia 18-40 2.8-5.0 Cholestasis of pregnancy 12-30 1.8-4.4 Smoking of >10 cigare es 10-15 1.7-3.0 Obesity: BMI 25-29.9 12-15 1.9-2.7 Obesity: BMI >30 13-18 2.1-2.8 Prior FGR (<10%) 12-30 2.0-4.6 Prior s llbirth 9-20 1.4-3.2 Figure 1: Interna onal Standards for Symphysio-Fundal Height Mul fetal gesta on: TWIN 12 1.0-2.8 Ultrasound growth charts: Although in pregnancy Mul fetal gesta on: TRIPLET 34 2.8-3.7 ultrasound has several benefi ts, the current Maternal age: 35-39 YRS 11-14 1.8-2.2 prac ce of ante-natal ultrasound in pregnancy Maternal age: >/=40 YRS 11-21 1.8-3.3 (a er 24 weeks gesta on) has not demonstrated

36 Vol.20, No.8; December, 2020

benefi t in reducing s llbirths.11 The main limita on a growing evidence for the use of uterine, umbilical, of an ultrasound-based program for the detec on and middle cerebral artery Doppler indices - even of SGA at term is eff ec vely diff eren a ng in fetuses with abdominal circumference/EFW physiologically small babies from SGA babies above the 10th cen le as markers of FGR. FGR in compromised by placental dysfunc on (reducing current pregnancy is a very important risk factor for false-posi ves) and iden fying the burden of s llbirth. These Doppler parameters have u lity in disease in placental dysfunc on where fetuses the detec on of placental hypoperfusion (uterine are s ll normal-sized (reducing false-nega ves). Doppler) and fetal redistribu on (umbilical and S llbirth is strongly associated with fetal growth middle cerebral artery Doppler), as func onal restric on. The risk factors and poten al causes parameters with superior performance to isolated of s llbirth and fetal growth restric on largely fetal biometric measurements.16 There is emerging overlap. The main purpose of the management evidence of role of materno-fetal vessel dopplers in of fetal growth restric on is the preven on of predic ng adverse fetal outcomes par cularly FGR s llbirths. The risk of s llbirth is rela ve to the both in AGA and SGA categories. degree of growth restric on, with the highest risk An phospholipid An bodies (APS): APS in addi on of s llbirth for those delivering the most growth- to thrombo c events, has been linked to s llbirths. restricted fetuses. Fetuses weighing under the 10th An increased risk for pregnancy morbidity in women cen le are found approximately 2–3 mes more with APS is seen with a history of systemic lupus 12 frequently among s llbirths than live births. The erythematosus (SLE), thrombosis, previous adverse accuracy of the diagnosis of fetal growth restric on pregnancy outcomes, and low complement levels can be increased by serial ultrasound es mates of in the fi rst trimester. Pa ents with SLE have a 15% fetal weight. This is because serial es mates allow to 25% risk of s llbirth.17 assessment of the rate of growth or the trend of declining growth. Decreased Fetal Movements: Fetus at risk may stop movement to conserve energy in the Confounding the rela onship between birthweight presence of placental dysfunc on. Decreased fetal and s llbirth is the fi nding that intrauterine s llbirths movement at or near the end of the pregnancy progressively lose 20%–25% of body weight in utero places the pregnancy at substan al increased through macera on in the me interval between risk of poor pregnancy outcome. However, there demise and delivery due to shrinkage in fetal mass is no evidence that fetal kick count monitoring is 13 by dehydra on. Accoun ng for the post-demise useful in all pregnancies or that it helps to prevent fetal weight loss, the true prevalence of SGA births s llbirths. Despite this, fetal movement coun ng is in s llbirth at term is near 20%–25%, meaning that recommended for all pregnancies. the majority of adverse pregnancy outcomes occur in fetuses with average gesta onal weight but Antepartum Fetal Testsing: Tests for fetal well- probably faltered growth velocity.14 being: Although evidence to support the ability of the BPP and the MBPP to reduce s llbirth is lacking, Large for Gesta onal Age confers a signifi cantly the American College of Obstetrics and Gynecology increased risk of s llbirth for pregnancies reaching supports star ng tes ng no earlier than 32 weeks 36 weeks’ gesta on, independent of maternal of gesta on for high-risk pregnancies and sooner diabetes status. LGA fetus may benefi t from only if delivery is considered to impact perinatal antenatal tes ng star ng at 36 weeks. In the se ng benefi t.18 Vibroacous c s mula on has also not of reassuring fetal tes ng, a reasonable delivery been shown to reduce s llbirth rates. target would be 39 weeks in order to balance the risk of s llbirth with the risks associated with early Predic on Models: Mul parameter models and term births.15 predic ve algorithms using maternal risk factors, and biochemical and Doppler parameters have Umbilical and Uterine Artery Doppler: The fetal been developed, but need to be prospec vely monitoring method that has been associated validated to demonstrate their eff ec veness. Some with a decrease in perinatal mortality is umbilical authors have proposed a mul parameter validated artery Doppler velocimetry in high-risk pregnancies algorithm with the objec ve of iden fying fetuses including those with fetal growth restric on. There is

37 AOGD Bulletin at high risk for fetal demise: the Individual • Management of any ante-natal complica ons as Risk assessment (IRIS) predic on model. The warranted combina on of three antenatal factors (gesta onal • Ins tu onal delivery age, parity, and cerebroplacental ra o) and three • Appropriate postnatal and neonatal care intrapartum factors (use of epidural, induc on of labor, and use of oxytocin) can be used to assess Because nearly half of all s llbirths are associated the risk for intrapartum compromise requiring with fetal growth restric on, serial monitoring of opera ve delivery. The IRIS algorithm demonstrated growth using growth charts should be performed. moderate to good discrimina on and no sign of Primary triage in low risk pregnancies is clinical serial poor fi t, and is available as a smartphone app to plo ng of SFH, whereas in high risk pregnancies or aid clinical decision making regarding the mode if there is clinical suspicion of growth restric on, of delivery for SGA fetuses (h ps://mail13240. serial sonographic biometric assessment should be wixsite.com/website). Whether such management resorted to. protocols or algorithms can improve pregnancy Exis ng evidence strongly supports infec on outcome can only be evaluated in adequately control measures including syphilis screening and powered, blinded trials.19 treatment and malaria prophylaxis in endemic areas, for preven ng antepartum s llbirths. Strategies for Preven on of S llbirths These interven ons should be incorporated into S llbirth can be prevented by addressing and trea ng antenatal care programs based on a ributable risks 20 infec ons, malnutri on, non-communicable and burden of disease. diseases, lifestyle factors, preterm labor and post- Approach for Women with Prior S llbirths term birth. Addressing birth control in adolescents, Evalua on of the index pregnancy when the fetal pregnancy spacing and poverty will also benefi t. We demise had occurred is of paramount importance must strive to provide access healthcare resources, in guiding care for the next pregnancy. which will help women to prepare for pregnancy. Determining the cause and iden fying the me This includes providing eff ec ve antenatal care of prior s llbirth are integral elements to plan the and support, folic acid supplementa on, family strategy of s llbirth preven on in next pregnancy. planning services, intermi ent treatment of The most important opportunity to explore the sexually transmi ed infec ons (syphilis), smoking cause of the index s llbirth is at the me of the cessa on counseling, screening and management event. At the me of s llbirth, tests should be of maternal illnesses, and the detec on and conducted in accordance with the clinical picture. All management of fetal growth restric on and other parents should be off ered an autopsy or equivalent, fetal disorders. placental pathology, gene c tes ng from fetal Perinatal audits may help to reduce the s llbirth source, and tes ng for feto-maternal hemorrhage. rate. This is impacted by the accuracy and reliability At the ini al booking visit, if the previous s llbirth of recording and retrieving s llbirth informa on was not adequately inves gated, it should be noted from delivery or birth records. that no universal tests are recommended. Clinical Women and families with a s llbirth in current history and workup at the me of s llbirth should 21 or previous pregnancy need emo onal and be used to guide tes ng on a case-by-case basis. psychological support Verbal autopsy is a benefi cial tool to evaluate SB in limited resource se ngs. But many a mes, the Approach for Women with No Prior S llbirth death was assigned to ‘unexplained’ category due Intensive surveillance of development of pregnancy to non-inves ga on or under-inves ga on, in such complica ons in the early part of gesta on itself by cases treatment for placental causes may improve employing inverted pyramid of pre-natal care. outcomes. • Rou ne ante-natal care like early booking and An outline of approach for care for these women is high risk triage as follows: • Screening for diabetes, pre-eclampsia and aneuploidy

38 Vol.20, No.8; December, 2020

Preconcep on or Ini al Prenatal Visit restric on, star ng at 28 weeks and to be • Detailed medical history (diabetes, hypertension, considered earlier (24-26 weeks) in women autoimmune condi ons, infec ons), examina on where loss was at earlier gesta on and prenatal op miza on of medical condi on if o Antepartum fetal surveillance star ng at any 32 weeks or 1–2 weeks earlier prior to • Obstetric history: Evalua on/workup/review gesta onal age of previous s llbirth as clinically of previous s llbirth- Universal preconcep on appropriate. Antepartum fetal tes ng, such as and antenatal tests are not recommended, twice weekly nonstress tests and amnio c fl uid but specifi c tests based on the clinical scenario index or biophysical profi les, may be ini ated at might help guide management in the subsequent 32 weeks or 1–2 weeks before the gesta onal pregnancy. age of the previous s llbirth as clinically • An phospholipid an bodies / Thrombophilia appropriate. Cau on must be used when workup depending on previous pregnancy interpre ng the antepartum fetal surveillance circumstances of a fetus at less than 32 weeks of gesta on. At • Determina on of recurrence risk: Stra fi ed on 28 weeks of gesta on, only approximately 60% basis of cause of previous s ll birth and other of normal fetuses will have reac ve nonstress 18 known maternal risk factors tes ng. This is not a result of uteroplacental insuffi ciency but refl ects the immature fetal • Modifi able risk factors for s llbirths like alcohol, autonomic nervous system. smoking, substance abuse, obesity, undernutri on should be appropriately addressed. • Individual care plans are required for women during a pregnancy following s llbirth. • Gene c counseling if family gene c condi on exists or evidence/suspicion of gene c disorder • When the cause of the previous s llbirth is in index fetus known, appropriate treatment of the underlying cause may reduce the risk of recurrence. Families have increased psychosocial needs • Unexplained or unexplored s llbirths, as well as in pregnancies a er s llbirth. Respec ul and those related to fetal growth restric on and early suppor ve care is essen al, including bereavement or severe pre-eclampsia, may be a ributed to care a er a s llbirth. placental insuffi ciency. In these cases, the use of During Pregnancy: Management plan depends on low-dose aspirin (LDA) may be benefi cial.21 cause of previous s llbirth. • In women with an phospholipid an body • Early booking from fi rst trimester onwards syndrome or known thrombophilias, low- o Da ng ultrasonography by crown-rump length molecular-weight heparin therapy is ini ated o First-trimester aneuploidy and PE screen: but there is no role in cases of previous s llbirths Pregnancy associated Plasma protein-A where these diseases are not present. (PAPP-A), hCG, and nuchal translucency, • Cases where the index s llbirth is known to be Placental growth factor (PlGF), Uterine Artery obviously of a nonplacental, nonrecurrent cause, Pulsality Index, Mean arterial pressure, etc such as cord accident or infec ons (TORCH, malaria, o Diabetes screen hepa s E), may not require addi onal treatment or o Appropriate prenatal tes ng if indicated increased frequency of monitoring and ultrasound, (gene c cause) though women need reassurance in current pregnancy and care may be tailored accordingly. • Close surveillance in current pregnancy is warranted with intensifi ed maternal and fetal • Evidence does not support the use of third- monitoring at least two weeks prior to the party leukocyte immuniza on, intravenous IgG gesta onal age of previous demise. Some women and progestogen therapies for preven on of 3 may require admission elec vely or opt for it and recurrent s llbirth. such cases need to be individualized. • Delivery plan to be formulated in advance-of o Serial sonograms with biometry plo ng the third trimester: Decisions around ming on growth charts to rule out fetal growth of birth should incorporate the circumstances

39 AOGD Bulletin

surrounding the previous s llbirth, the clinical 2. Lawn JE, Blencowe H, Pa nson R, Cousens S, Kumar picture of the current pregnancy and the wishes R, Ibiebele I et al. Lancet’s S llbirths Series steering commi ee. S llbirths: Where? When? Why? How to make of the couple. In select cases, there may be a role the data count? Lancet. 2011 Apr 23;377(9775):1448-63. of early term (37−39weeks) birth. There is no [PubMed: 21496911] evidence for delivery before 37 weeks based on 3. Wojcieszek AM, Shepherd E, Middleton P, Lassi ZS, Wilson the risk factors of s llbirth alone.21 T, Murphy MM et al. Care prior to and during subsequent • Intrapartum care- High quality obstetric and pregnancies following s llbirth for improving outcomes. Cochrane Database of Systema c Reviews 2018, Issue 12. midwifery care should be universally available. Art. No.: CD012203. DOI: 10.1002/14651858.CD012203. Childbirth must be provided with skilled pub2 a endants who can perform assisted vaginal 4. Newtonraj A, Kaur M, Gupta M, Kumar R. Level, causes, deliveries and cesarean sec ons for fetal and and risk factors of s llbirth: a popula on-based case maternal indica ons. Of all s llbirths, half occur control study from Chandigarh, India. BMC Pregnancy and during birth. Seventy-fi ve percent of these Childbirth 2017: 17, 371 DOI 10.1186/s12884-017-1557-4 are preventable with access to quality care. 5. Bililign YN, Tenaw Z, Solomon K, Mulatu T. Inadequate Prenatal Visit and Home Delivery as Determinants of The ability to provide induc on of labor for Perinatal Outcomes: Does Parity Ma er? J Pregnancy. premature rupture of membranes and post-term 2019; 1-9. Doi:10,1155/2019/9024258 pregnancy needs to be addressed. Con nuous 6. Flenady V, Koopmans L, Middleton P, Frøen JF, Smith GC, cardiotocography, when compared to no or Gibbons K et al: Major risk factors for s llbirth in high- intermi ent cardiotocography, was associated income countries: a systema c review and meta-analysis. Lancet 2011, 377, 1331–1340. with higher cesarean rates but less neonatal 22 7. S llbirth Collabora ve Research Network Wri ng Group. seizures and improvement in s llbirth. Causes of death among s llbirths. JAMA. 2011 Dec 14;306(22):2459-68. [PMC free ar cle: PMC4562291] Conclusion [PubMed: 22166605 The challenges to be overcome in preven ng 8. Cunningham SG,Leveno KJ, Bloom SL, Dashe JS, Hoff man s llbirths are: VL, Casey BM et al. Es mated maternal risk factors and risk of s llbirths. Williams Obstet 25;35:644-50. Incomplete workup of index case: Few reasons are 9. Dugoff L, Hobbins JC, Malone FD, Porter TF, Luthy D, the unwillingness of parents for fetal autopsy due Comstock CH, et al. First-trimester maternal serum PAPP-A to ethical and religious reasons, non-availability of and free-beta subunit human chorionic gonadotropin resources, poor follow-up of pa ents for further concentra ons and nuchal translucency are associated screening for medical causes and psychological with obstetric complica ons: a popula on-based screening study (the FASTER Trial). Am J Obstet Gynecol trauma due to s llbirth experience. 2004;191:1446–51 The dilemma of unexplained s llbirth seems far 10. Papageorghiou AT, Ohuma EO, Grave MG, Hirst J, from resolu on. daSilveira MF, Lambert A et al.Inetrna onal standards for symphysio-fundal height based on serial measurements Furthermore it is probable that there is from fetal growth longitudinal study of the INTERGROWTH- heterogeneity of many of the antecedent causes 21st project:prospec ve cohort study in eight countries. However, for improvement in predic on and BMJ 2016;355:i5662. preven on of s llbirth, modifi able risk factors 11. Bricker L, Medley N, Pra JJ. Rou ne ultrasound in late should be targeted. To date there are no eff ec ve pregnancy (a er 24 weeks’ gesta on). Cochrane Database Syst Rev. 2015 Jun 29;(6):CD001451. [PMC free ar cle: methods of s llbirth preven on. Eff ec ve risk PMC7086401] [PubMed: 26121659] assessment algorithms using combina ons of 12. Getahun D, Ananth CV, Kinzler WL. Risk factors for antepartum maternal, ultrasonic, and biochemical measures and intrapartum s llbirth: a popula on-based study. Am. J. need to be developed similar to aneuploidy or Obstet. Gynecol. 2007 Jun;196(6):499-507. [PubMed: 17 preclampsia screening. 13. Man J, Hutchinson JC, Ashworth M, Heazell AE, Levine S, Sebire NJ. Eff ects of intrauterine reten on and postmortem interval on body weight following intrauterine death: References implica ons for assessment of fetal growth restric on at 1. Maslovich MM, Burke LM. Intrauterine Fetal Demise. autopsy. Ultrasound Obstet Gynecol. 2016;48(5):574–8. NCBI Shelf. A service of the Na onal Library of Medicine, 14. Cou nho CM, Melchiorre K, Thilaganathan B. S llbirth Na onal Ins tutes of Health. 2020 Jan. Last Update: May at term: Does size really ma er? Intern J of Obstet and 23, 2020. Gynecol. h ps://doi.org/10.1002/ijgo.13229

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15. Ebony B, Carter EB, Stockburger J, Tuuli MG, Macones fetal compromise in small-for-gesta onal-age fetuses at GA, Odibo AO, Trudell AS. Large for gesta onal age and term: external valida on of the IRIS algorithm. J Matern s llbirth: Is there a role for antenatal tes ng? Ultra in Neonatal Med [Internet]. 2019;0(0):1–10. Available from: Obstet and Gynecol.2018 Doi: 10.1002/uog.20162 h ps://doi.org/10.1080/14767058.2018.1560412 16. Khalil A, Morales-rosello J, Townsend R, Morlando M, 20. Menezes EV, Yakoob MY, Soomro T, Haws RA, Darmstadt Papageorghiou A, Bhide A et al:Value of third-trimester GL, Bhu a ZA. Reducing s llbirths: preven on and cerebroplacental ra o and uterine artery Doppler indices management of medical disorders and infec ons during as predictors of s llbirth and perinatal loss.Ultrasound pregnancy. BMC Pregnancy and Childbirth 2009, 9(Suppl Obstet Gynecol 2016;47:74-80. 1):S4- 2009. doi: 10.1186/1471-2393-9-S1-S4 17. Fredi M, Andreoli L, Aggogeri E, Be ga E, Lazzaroni MG, 21. Ladhani NNN, Fockler ME, Stephens L, Barre JFR, Heazell Le Guern V. Risk Factors for Adverse Maternal and Fetal AEP. No. 369-Management of Pregnancy Subsequent to Outcomes in Women With Confi rmed aPL Posi vity: S llbirth. J Obstet Gynaecol Can 2018;40(12):1669−1683. Results From a Mul center Study of 283 Pregnancies. Front Doi: 10.1016/j.jogc.2018.07.002 Immunol. 2018;9:864. [PMC free ar cle: PMC5949611] 22. Devane D, Lalor JG, Daly S, McGuire W, Smith V. [PubMed: 29867924] Cardiotocography versus intermi ent ausculta on of 18. Reddy UM. Predic on and Preven on of Recurrent fetal heart on admission to labour ward for assessment S llbirth. Obstet gynecol. 2007; 110, 1151-1164 of fetal wellbeing. Cochrane Database Syst Rev. 2012 Feb 19. Kalafat E, Morales-Rosello J, Scarinci E, Thilaganathan 15;(2):CD005122. [PubMed: 22336808] B, Khalil A. Risk of opera ve delivery for intrapartum

AOGD Events Held On 17th February 2020, Web CME on “Op mizing Menopausal Health” was held under the aegis of IMS Delhi Chapter & QI Commi ee of AOGD. On 25th November 2020, E-CME on “Urogynaecology Master Class” was held under the aegis of Urogynaecology commi ee of AOGD. On 26th November, “FOGSI-JOGI-E-PICSEP 2020 Webinar” was held under the aegis of AOGD. On 27th November, “AOGD Monthly Mee ng” was organized by MAMC & LNJP Hospital, New Delhi. On 28th November, “Virtual CME on Diabetes in Pregnancy: Providing Op mum Care” was held under the aegis of Quality Improvement and Safe Motherhood Commi ee of AOGD & Delhi Diabe c Forum to celebrate World Diabetes Day. On 29th November, “Sankalp travelling workshop for FP, Updates in contracep on: Part-1” was conducted by Department of Obstetrics & Gynaecology UCMS & GTB Hospital, Delhi. On 10th December 2020, “FAQ on Ovarian Cyst” was conducted under the aegis of AOGD.

Forthcoming Events On 18th December 2020, “AOGD Monthly Mee ng” will be organized by Sir Ganga Ram Hospital, New Delhi. On 20th December 2020, “Panel on IUGR” will be conducted under the aegis of AOGD

41 AOGD Bulletin

Ra onal Use of Antenatal Cor costeroids Pankaj Garg1, Kumari Gunjan2, Manjusha Goel3 1Senior Consultant, Department of Neonatology, Sir Ganga Ram Hospital, New Delhi 2DNB Neonatology Fellow, Department of Neonatology, Sir Ganga Ram Hospital, New Delhi 3Senior Consultant, Department of Obstetrics, For s Hospital, Shalimar Bagh, New Delhi

The survival of preterm neonates has improved a treatment dose consists of two 12-mg doses of lot in last thirty years and the be er respiratory betamethasone given intramuscularly 24 hours management of these neonates is one of the apart or four 6-mg doses of dexamethasone extremely important reasons for that. Along administered intramuscularly every 12 hours. with be er ven la on strategies, early and more Best eff ect is expected 24 hours a er the last widespread use of CPAP & surfactant, antenatal dose. cor costeroids (ACS) have made the respiratory Despite having similar biological ac vity, there care much be er in current neonatal units. It all are no clear evidence confi rming superior started in 1969 when Liggins observed that lambs clinical effi cacy of one steroid over another who received ACS and then delivered prematurely and also there are only few direct comparisons had rela vely par ally expanded lungs.1 This led to between them. In 2013 Cochrane review which a human RCT involving 282 mothers who were at included 12 RCTs to assess the superiority of risk for preterm delivery, to assess the eff ect of ACS 1 cor costeroid over the other found that on neonatal morbidity which showed reduc on in dexamethasone was associated with a reduced respiratory distress syndrome (RDS). This fi nding risk of IVH compared with betamethasone (RR, was reconfi rmed in mul ple subsequent trials 0.44; 95% CI, 0.21–0.92). In addi on, in one trial followed by fi rst Cochrane review in 1996 which signifi cantly shorter stay in NICU was noted in has been recently updated. The recent Cochrane those exposed to dexamethasone. In contrast review (2017) consolida ng results of mul ple RCTs Lee and colleagues found decreased likelihood confi rmed the results that ACS not only reduces of impaired neurodevelopmental status and the risk of RDS but also has signifi cant impact in reduced risk of hearing impairment among preven ng other morbidi es such as necro zing those who were exposed to betamethasone as enterocoli s (NEC), intraventricular hemorrhage compared with dexamethasone in antenatal (IVH), need for mechanical ven la on as well as period. Results of STEROID trial which mortality.2 For these reasons ACS for pregnancies at randomized 1500 women at risk of preterm risk of preterm delivery between 24 and 34 weeks birth comparing the two steroids with primary is a standard of care as recommended by WHO and outcome of death or any neurosensory disability obstetric socie es worldwide. in children at two years of age is awaited. Due However, there are s ll many ques ons regarding to present insuffi cient evidence suppor ng the the use of ACS which are unanswered and needs recommenda on of one cor costeroid regimen further research. This ar cle aims to address over the other, choice of ACS use is based on various controversial aspects of steroid use during provider preference, ease of administra on, antenatal period so as to use ACS ra onally in our cost, and availability. day to day prac ce. The route of ACS has been preferably intravenous 1. Choice of ACS (IV) only and the trial of oral dexamethasone as compared to IV dexamethasone has shown to be Betamethasone and dexamethasone have associated with increased risk of sepsis (15.9 vs both been acceptable op ons diff ering by 1.6%, P=0.009) and IVH (15.9 vs 3.3%, P=0.03).3 only 1 methyl group and are noted to cross placenta without ge ng metabolized by There is a very India specifi c issue related to ACS placental enzyme. They both have high affi nity which needs to be discussed before making a towards the glucocor coid receptor with fi nal decision regarding the choice of ACS. Most minimal mineralocor coid ac vity. Standard of trials globally have been done on Celestone

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(MSD) which is a combina on of betamethasone impairment at 18 to 22 months for neonates acetate and betamethasone sodium phosphate. who had been exposed to ACS and born at 23 Unfortunately in India the only betamethasone weeks’ gesta on (83.4% with steroids vs 90.5% prepara on available (Betnesol; GSK) contains without steroids; adjusted odd ra o [AOR], 0.58; only betamethasone sodium phosphate and 95% CI, 0.42–0.80).5 There was no signifi cant hence the use of this prepara on is not expected diff erence in these outcomes but was associated to show similar results to that of celestone. There with signifi cant less death or NEC (73.5% with are no trials with this prepara on to support its steroids vs 84.5% without steroids; AOR, 0.54; use. Keeping this fact in mind along with the cost 95% CI, 0.30–0.97) at 22 weeks of gesta on. and easy availability of dexamethasone, Govt of This led to considera on of steroids for pregnant India, Ministry of health and welfare have issued women star ng at 23+0 weeks of gesta on” at guidelines on the use of dexamethasone for all risk of preterm delivery within seven days by expected preterm deliveries between 24-34 ACOG in its most recent Commi ee Opinion weeks of gesta on. update. This is amenable to change in future with further improvement in neonatal care. 3. ACS in late preterm Despite the fact that late preterms comprise 70% of total preterm birth, use of ACS in this group is s ll controversial. In the original NIH recommenda on (1995), there was no considera on of extended use of steroids beyond 34 weeks because of lack of studies showing benefi t and misbelief that late preterms have almost similar outcomes as that of term.6 Antenatal Late Preterm Steroids (ALPS) trial, double-blinded, placebo-controlled, randomized, controlled trial assessed 2831 women with a singleton gesta on, who were at high risk for preterm birth between 34 0/7 and 36 6/7 weeks’ gesta on between 2010 and 2015.7randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gesta on who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days In this trial need for respiratory support within the fi rst 72 hours of life (14.4% vs 11.6%; RR, 0.80; 95% CI, 0.66–0.97) along with signifi cant decreases in the rates of severe respiratory morbidity, bronchopulmonary 2. Use of ACS in previables dysplasia, transient tachypnea of the newborn, With advancement of neonatal care and the need for resuscita on at birth, and the need documented increased survival rates of for postnatal surfactant was demonstrated approximately 25-35% for infants born at 22 (Table 1). Neonates treated with betamethasone weeks’ gesta on, limits of viability is ever did have an increased risk of hypoglycemia (24% 4 changing and tends to be pushed further lower. vs 14.9%; RR, 1.61; 95% CI, 1.38–1.88). Also Observa onal data from NICHD Neonatal pa ents treated with ACS as compared to placebo Research Network demonstrated a signifi cant had increased risk of clinical chorioamnioni s, reduc on in death or neurodevelopmental endometri s, or cesarean delivery.

43 AOGD Bulletin

Table 1: Results of ALPS trial Outcome Placebo Betamethasone RR(95%CI) P val NNT/NNH (n=1400) (n=1427) n (%) n (%) Primary outcome 202(14.4) 165(11.6) 0.80(0.66-0.97) 0.023 35.7 Severe respiratory morbidity 169(12.1) 115(8.1) 0.67(0.53-0.84) <0.001 25 RDS 89(6.4) 79(5.5) 0.87(0.65-1.17) 0.356 TTN 138(9.9) 95(6.7) 0.67(0.53-0.87) 0.002 31.25 Surfactant use 43(3.1) 26(1.8) 0.59(0.37-0.96) 0.031 76.9 Chorioamnioni s 32(2.3) 20(1.4) 0.61(0.35-1.07) 0.080 Proven neonatal sepsis 11(0.8) 9(0.6) 0.80(0.33-1.93) 0.623 Neonatal hypoglycemia(<40mg/dl) 210(15.0) 343(24.0) 1.60(1.37-1.87) <0.001 11.1 Gesta on at delivery 36.1+8.2 36.1+7.5 0.517 Time from ini al dose to delivery 30.6(14.6-111) 33(15.2-111.6) 0.565 (hours; median(Q3,Q1) NNT=number needed to treat; NNH= number needed to harm; RDS= respiratory distress syndrome; TTN= transient tachypnea of neonate

In ALPS study benefi t was shown despite the World Health Organiza on’s (WHO) guidelines fact that only 60% of enrolled women received on interven ons to improve preterm birth the full course of two doses of betamethasone outcomes last updated in 2015 and RCOG before delivery and tocolysis was not rou nely Green-top Guideline on ACS published in administered. Notably ACS have not adequately 2010 both before the ALPS study does not been studied for all women with threatened late recommend the use of ACS in late preterms. But preterm birth as women with pre-gesta onal current ACOG guidelines say “a single course of diabetes, mul ple gesta ons, or who had received betamethasone is recommended for pregnant previous ACS were excluded from the study. It is women between 34+0 weeks and 36+6 weeks of important to draw per nent conclusions from gesta on at risk of preterm birth within 7 days, ALPS; numbers needed to treat for primary and who have not received a previous course of outcome (respiratory morbidity) is 35.7 while ACS.”9 It’s also worth men oning here that these numbers needed to harm for hypoglycemia is recommenda ons are s ll with betamethasone 11.1. It means in simple terms that if ANS is given acetate and betamethasome sodium phosphate to 35.7 late preterm neonates, one preterm combina on and not with betamethasone would be saved from respiratory distress but 3.2 sodium phosphate and defi nitely not with neonates would have hypoglycemia. The risk of dexamethasone as there are no trials with hypoglycemia becomes much more relevant as dexamethasone in late preterms. most of these neonates are cared with mother 4. ACS in Early term in most situa ons without rou ne blood sugar Infants born at 37 0/7 weeks to 37 6/7 weeks monitoring. are at 1.7 mes increased risk for respiratory A recent meta-analysis of three trials, including complica ons than those born between 38 0/7 ALPS, had similar conclusions to the ALPS trial. and 38 6/7 weeks’ gesta on; and these neonates (Table 2).8 are at 2.4 mes increased risk than those born Table 2: Results of outcome of RCTs included in meta- between 39 0/7 and 39 6/7 weeks’ gesta on. analysis by Saccone et al for eff ect of ACS for fetal maturity These risks are even higher for infants born via at term or near term gesta on planned cesarean sec on, prior to the onset of STUDY Hypoglycemia % labor,10. Balci, et al (2010) Not reported The Antenatal Steroids for Term Caesarean Porto et al (2011) 11 vs 7 Sec on (ASTECS) randomized trial tested (NS) whether ACS reduce respiratory distress in Ramadan et al (2016) 20.3 vs 10.9 (p<0.04) neonates born by elec ve cesarean sec on at term and found signifi cantly decreased

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rates of RDS requiring admission to the NICU either administered one addi onal course or (RR, 0.46; 95% CI, 0.23–0.93) in the treatment placebo.17 A decreased risk of RDS, ven lator group.11 Similarly, Cochrane review, updated in support and surfactant use with repeat ACS 2018---comparing ACS (either betamethasone with no documented diff erence in birth or dexamethasone) to placebo or control prior to weight, intrauterine growth restric on or head planned cesarean delivery at term (3956 women circumference in either group was found by and four trials) concluded that ACS decrease the author in the group of women who received an risk of RDS by approximately 50% and TTN by addi onal dose of steroids. Long term outcome approximately 60% and NICU admission rates from mul ple Courses of ACS trial (at 5 years) for respiratory complica ons by 55%.12However, and the Australasian Collabora ve Trial of Repeat the quality of evidence for all of these outcomes Doses of Cor costeroids for the Preven on of was rated as low. Neonatal Respiratory Disease (at 6-8 years-old) Only long term outcome reported by ASTECS2 were reassuring without any increased risk of at 8-15 years found overall no adverse neurodevelopmental disability, cardiometabolic consequences from a single ACS course at problems, or other serious outcome in those term.13 Though, lower propor on of children that received more than one course of ACS.18,19 in the ACS group were perceived to be in the Also, body size and composi on were similar in top quar le of achievement (p=0.03) by their groups receiving mul ple ACS courses compared teachers, no signifi cant diff erences were found to single courses. Currently ACOG recommends in any other outcomes between the groups, considera ons of a single repeat course of ACS in including objec ve assessments of achievement women <34 0/7 weeks’ gesta on [<33 6/7 wks] and test scores. Larger randomized trials with who is at imminent risk of delivery within the longer follow up are needed to resolve the next 7 days and in whom prior course of ACS was confl ict in recommenda on in this group by administered >14 days ago [as earlier as 7 days- varying na onal obstetrical socie es. -WHO]. However maternal chorioamnioni s 5. Rescue dosing versus repeated dosing remains a contraindica on of second course of antenatal steroids. RCOG guidelines are very There are some studies which shows that conserva ve regarding the second course of benefi cial eff ect of antenatal steroids diminishes antenatal steroids and recommend it only for beyond seven days of administra on.14 It is mothers who have received fi rst course before seen that less than 10% of women that present 26 weeks of gesta on. in preterm labor deliver within seven days.15 24-35 This led to weekly administra on of 6. Steroids in mul ple gesta on steroids ll delivery to ensure steroid coverage Preterm delivery is six mes more likely to occur within one week of delivery. A meta-analysis in women with mul ple gesta on as compared in 2015 of ten randomized controlled trials to them with singleton gesta on.20 Moreover, involving 4700 women and 5700 babies neonates from mul ple pregnancies are also at compared those that received a single course of an increased risk cerebral morbidity, including IVH ACS to those with mul ple courses.16 The results and periventricular leukomalacia.21Only a small showed a decreased risk of RDS and severe number of mul ple gesta ons were included lung disease with concomitant increased risk of in the antenatal cor costeroid trials in recently reduced birth weight. It is thus a diffi cult clinical updated systema c review.2 This lack of robust challenge for providers to balance the risk of data precluded a defi nite conclusion about the imminent preterm birth and avoiding addi onal eff ec veness of the therapy or the op mum dose. doses of ACS. Rescue course regimen of steroid RDS in mul ple gesta ons exposed to antenatal was evaluated in a mul centric RCT in 2009 steroids has rela ve risk of 0.90, 95% CI 0.67-1.22; where women<33+0 weeks who had received 4 trials, 320 infants. Current recommenda on of a a course of ACS at least 14 days previously course of ACS to women with mul ple gesta ons and were judged to have a recurring threat of at risk of preterm delivery within seven days at preterm labor within the next seven days were less than 34+0 weeks’ gesta on by ACOG is based

45 AOGD Bulletin

on undeniable benefi ts of steroids in singleton recommends against use of second course of pregnancy.22 Theore cally higher doses of antenatal steroids. ACS may be required in mul ple gesta on but in a 8. ACS in Low and middle income countries (LMIC) randomized trial similar levels of betamethasone Though evidence for benefi ts of antenatal was found in maternal and cord blood in singleton steroids are undeniable, there are several 23 and mul ple gesta ons. Outcome data from a limita ons in generalizing the results of recent French cohort for ACS for twins between 24 and evidence from Cochrane review to lower and 31 weeks of gesta on were comparable in those middle income countries. All 30 trials included who received repeated courses versus a single in this evidence were done in high resource 24 course. and further document the infl uence of se ng, in high-income (20 trials) and upper the ACS-to-delivery interval. Design: EPIPAGE-2 middle-income (nine trials) countries, except is a na onwide observa onal mul centre one trial that was conducted in Tunisia (a lower prospec ve cohort study of neonates born middle-income country). In 2015, fi ndings of between 22 and 34 completed weeks of gesta on. antenatal cor costeroid trial (ACT) which was a Se ng: All French maternity units, except in a community-based, cluster-randomised trial was single administra ve region, between March published.25 This mul centric trial conducted in and December 2011. Popula on: A total of 750 six LMIC -Argen na, Guatemala, India, Kenya, twin neonates born between 24 and 31 weeks Pakistan and Zambia capturing nearly 100000 live of gesta on. Methods: Exposure to ACSs was births was aimed to evaluate eff ec veness and examined in four groups: single complete course, feasibility of mul ple interven ons designed to with an ACS administra on-to-delivery interval increase the use of ACS at all level of health care. of ≤7 days; single complete course, with an ACS- While use of ACS was shown to be increased by to-delivery interval of >7 days; repeated courses; fourfold there were few concerning fi ndings or no ACS treatment. Main outcome measures: which need reconfi rma on before generalizing Neonatal outcomes analysed were severe his prac ce in LMIC. (Table 3) These alarming bronchopulmonary dysplasia, periventricular fi ndings included lack of benefi t in the less-than- leukomalacia or intraventricular haemorrhage fi h-percen le newborns, evidence of increased grade III/IV, in-hospital mortality, and a composite perinatal mortality in larger newborns and the indicator of severe outcomes. Results: Compared increase in suspected maternal infec on. with no ACSs, in mul variable analysis, a single course of ACSs with an administra on-to- Table 3: Results of antenatal cor costeroid trial delivery interval of ≤7 days was signifi cantly 21 studies 21 studies (7000+ Maternal (7000+ Infants) Infants) – ACS infec on associated with a reduced rate of periventricular – ACS led led to Neonatal (Puerperal leukomalacia or intraventricular haemorrhage to Neonatal deaths>36weeks sepsis-3 studies) grade III/IV (aOR 0.2; CI 95% 0.1–0.5 As per death<34weeks ACOG guidelines single rescue course of steroid 30% lower 3.25 mes 1.35 mes high is considered for mul ple gesta on. high(CI-0.99-10.66) (CI:0.93-1.95) 7. ACS in PPROM WHO recommends ACS for women at risk Reduc on in the risk of RDS, IVH, NEC, and of preterm birth from 24 weeks to 34 weeks neonatal death without any increase in risk gesta on in se ngs where certain criteria are of maternal and neonatal infec on has been met with: demonstrated with the administra on of a single • Gesta onal age assessment can be accurately course of ACS to women with a history of preterm undertaken rupture of membrane at gesta on <34 weeks of • Preterm birth is considered imminent gesta on.2 Also, single rescue course of steroids • There is no clinical evidence of maternal infec on in PPROM has been found to be associated with short term benefi ts with no adverse long • Adequate childbirth care is available (including term eff ects in children followed at 6-8 years of the capacity to recognize and safely manage age.19But in maternal chorioamnioni s ACOG preterm labor and birth)

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• The preterm newborn can receive adequate care betamethasone acetate and betamethasone if needed (including resuscita on, thermal care, sodium phosphate combina on (12mg 24 hrly feeding support, infec on treatment and safe two doses) or dexamethasone between 24- oxygen use) 33 weeks of gesta on. Use of ANS in 29-34 9. Safety concerns with ANS: short term/ weeks has reduced the incidence of RDS and long-term: impaired growth, hypoglycemia, mortality while use in 24-28 weeks has not hypertension, Poor glucose tolerance) reduced the incidence of RDS but has reduced severity, mortality and risk of intraventricular Long term studies by Dalziel SR, 2005 in 24-33 hemorrhage. weeks gesta on over 30 years have shown no side eff ects except mild insulin resistance. But 2. Second course of ANS (only one more) is similar long-term harmful eff ects of usage of recommended by ACOG a er 7-14 days of fi rst ANS in late preterm and term pregnancies is course with gesta on ll 33 weeks except in not known. ASTEC trial in term pregnancies maternal chorioamnioni s. RCOG recommends has shown some serious concerns related to second course only if fi rst course given at developmental outcome. ASTECS trial compared gesta on less than 26 weeks. administra on of betamethasone 48 hours 3. Use of ANS in late preterm has respiratory before planned cesarean delivery at ≥37 weeks benefi ts but has increased risk of hypoglycemia. to usual care. When follow-up was performed at 4. Use of steroids in term pregnancies has reduced 8 to 15 years of age, schools were more likely transient tachypnea of newborn but long term to perceive steroid-exposed children to be in follow up studies raise concerns. the lowest achievement group compared with the control group. However, objec ve tes ng of Bibliography academic ability was not performed as part of 1. Liggins GC. Premature delivery of foetal lambs infused the trial and results from na onal standardized with glucocor coids. J Endocrinol. 1969;45:515–23. assessments did not show sta s cal diff erences 2. Roberts D, Brown J, Medley N, Dalziel SR. ACS for accelera ng between the scores for each group. fetal lung matura on for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;CD004454. There is a biological mechanism suggested for 3. Egerman RS, Mercer BM, Doss JL, Sibai BM. A randomized, harmful eff ects of ANS in late preterm and term controlled trial of oral and intramuscular dexamethasone in pregnancies. A surge in endogenous cor sol the preven on of neonatal respiratory distress syndrome. occurs near term when the fetus is in a cri cal Am J Obstet Gynecol. 1998;179:1120–3. period of brain development in prepara on for 4. Ishii N, Kono Y, Yonemoto N, Kusuda S, Fujimura M. parturi on and transi on to life ex utero. High Outcomes of infants born at 22 and 23 weeks’ gesta on. levels of 11β-hydroxysteroiddehydrogenase-2 in Pediatrics. 2013;132:62–71. 5. Carlo WA, McDonald SA, Fanaroff AA, Vohr BR, Stoll BJ, the fetal brain help to protect it from the eff ects of Ehrenkranz RA, et al. Associa on of ACS with mortality and the physiological rise in endogenous cor sol, but neurodevelopmental outcomes among infants born at 22 to do not protect it from maternally administered 25 weeks’ gesta on. Obstet Gynecol Surv. 2012;67:215–7. betamethasone or dexamethasone due to the 6. Wright LL. Eff ect of cor costeroids for fetal matura on on resistance of these drugs to metabolism by perinatal outcomes: Introduc on. Am J Obstet Gynecol. 11β-HSD-2. Thus, these steroids may cause 1995;173:253. unphysiological ac va on of glucocor coid 7. Gyamfi -Bannerman C, Thom EA, Blackwell SC, Tita ATN, Reddy UM, Saade GR, et al. Antenatal betamethasone receptors in the fetal brain near term leading to for women at risk for late preterm delivery. N Engl J Med. poten al of brain damage. 2016;374:1311–20. 8. Saccone G, Berghella V. ACS for maturity of term or near Key Messages term fetuses: Systema c review and meta-analysis of 1. Single course of dexamethasone (6 mg 12 hrly randomized controlled trials. BMJ. 2016;355:1–10. four doses) is recommended by GOI MoFW 9. Antenatal cor costeroids therapy for fetal matura on. Commi ee opinionNo.713. American College of for all threatened preterm births between 24- Obstetricians & Gynecologists. Obstet Gynecol 2017; 130:e 34 weeks of gesta on (24 weeks to 33 weeks 102-9. 6 days at start of therapy). ACOG recommend

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10. Jain L, Eaton DC. Physiology of fetal lung fl uid clearance study outcomes in children at 5 years of age (MACS-5). and the eff ect of labor. Semin Perinatol. 2006;30:34–43. JAMA Pediatr. 2013;167:1102–10. 11. Stutchfi eld P, Whitaker R, Russell I. Antenatal 19. Crowther CA, Anderson PJ, Mckinlay CJD. Mid-Childhood betamethasone and incidence of neonatal respiratory Outcomes of Repeat ACS: A Randomized Controlled Trial. distress a er elec ve caesarean sec on: Pragma c 2016;138:e20160947. randomised trial. Br Med J. 2005;331:662–4. 20. Mar n JA, Hamilton BE, Osterman MJK, Driscoll AK, 12. So riadis A, Makrydimas G, Papatheodorou S, Ioannidis Drake P. Births: Final data for 2016. Vol. 67, Na onal Vital JPA, Mcgoldrick E. Cor costeroids for preven ng neonatal Sta s cs Reports. 2018. respiratory morbidity a er elec ve caesarean sec on at 21. Re witz-Volk W, Tran TM, Veldman A. Cerebral morbidity term. Cochrane Database Syst Rev. 2018:CD006614. in preterm twins. J Matern Neonatal Med. 2003;13:218– 13. Stutchfi eld PR, Whitaker R, Gliddon AE, Hobson L, Kotecha 23. S, Doull IJM. Behavioural, educa onal and respiratory 22. Borders AEB, Gyamfi -bannerman C. Antenatal outcomes of antenatal betamethasone for term caesarean Cor costeroid Therapy for Fetal Matura on. Pediatrics. sec on (ASTECS trial). Arch Dis Child Fetal Neonatal Ed. 2017;140:102–9. 2013;98:195–200. 23. Gyamfi C, Mele L, Wapner RJ, Spong CY, Peaceman A, 14. McLaughlin KJ, Crowther CA, Walker N, Harding JE. Eff ects Sorokin Y, et al. The eff ect of plurality and obesity on of a single course of cor costeroids given more than 7 days betamethasone concentra ons in women at risk for before birth: A systema c review. Aust New Zeal J Obstet preterm delivery. Am J Obstet Gynecol. 2010;203:219. Gynaecol. 2003;43:101–6. e1–219.e5. 15. Fuchs IB, Henrich W, Osthues K, Dudenhausen JW. 24. Palas D, Ehlinger V, Alberge C, Truff ert P, Kayem G, Sonographic cervical length in singleton pregnancies with Goffi net F, et al. Effi cacy of ACS in preterm twins: the intact membranes presen ng with threatened preterm EPIPAGE-2 cohort study. BJOG An Int J Obstet Gynaecol. labor. Ultrasound Obstet Gynecol. 2004;24:554–7. 2018;125:1164–70. 16. Crowther CA, Mckinlay CJD, Middleton P, Harding JE. 25. Althabe F, Belizán JM, McClure EM, Hemingway- Repeat doses of prenatal cor costeroids for women at risk Foday J, Berrueta M, Mazzoni A, et al. A popula on- of preterm birth for improving neonatal health outcomes. based, mul faceted strategy to implement antenatal Cochrane Database Syst Rev. 2015;CD003935. cor costeroid treatment versus standard care for the 17. Garite TJ, Kurtzman J, Maurel K, Clark R. Impact of a reduc on of neonatal mortality due to preterm birth “rescue course” of ACS: a mul center randomized placebo- in low-income and middle-income countries: The ACT controlled trial. Am J Obstet Gynecol. 2009;200:248.e1-9. cluster-randomised trial. Lancet. 2015;385:629–39. 18. Asztalos E V., Murphy KE, Willan AR, Ma hews SG, Ohlsson A, Saigal S, et al. Mul ple courses of ACS for preterm Birth

Answer: December 2020 Issue Crossword Across 3. Eleven 4. Pappa 5. Six 7. Thirty Two 8. CPR 9. Magnet

Down 1. Dexamethasone 2. DIPSI 6. Torch 10. NMDA

Pictorial Quiz Answers Ans. 1: Three dis nct lines are seen at the level of the fetal nose: a. The top line represents the skin. b. The bo om one, which is thicker and more echogenic than the overlying skin, represents the nasal bone. c. A third line in front of the bone and at a higher level than the skin represents the p of the nose. Ans. 2: The nasal bone is considered to the present if it is more echogenic than the overlying skin and absent if it is either not visible or its echogenicity is the same or less than that of the skin.

48 Vol.20, No.8; December, 2020

Antenatal Magnesium Sulphate for Fetal Neuroprotec on: The controversies Nikhil Tene 1, Anup Thakur2 1MD (Pediatrics), DNB Final Year (Neonatology), Department of Neonatology, Sir Ganga Ram Hospital, New Delhi 2MD (Pediatrics), DNB (Neonatology), Quality Improvement Graduate (IHI, Massachussets), CEURF, Cri cal and Lung Ultrasound, Hospital Ambroise Pare (Paris), Consultant Neonatologist, Department of Neonatology, Sir Ganga Ram Hospital, New Delhi

Introduc on channel blocking eff ect, along with the modula on Improving neurological outcomes in preterm of the Na-K ATPase ac vity plays an important role births remains the most important objec ve of in cardiac func on, nerve impulse conduc on and neonatologists and obstetricians alike. It also muscle ac vity. con nues to be the unresolved issue in the care of preterm neonates. The causes of injury to Mechanisms Involved preterm brain are numerous and include cerebral in Neuroprotec on white ma er injury, periventricular leukomalacia The an -infl ammatory and an -excitotoxic and intraparenchymal hemorrhage. Data from proper es of MgSO4 through various mechanisms the Na onal Ins tute of Child Health and Human confer it with neuroprotec ve eff ects. Mul ple Development (NICHD), Neonatal Research studies in animal models emula ng various forms 1 Network and EPICure studies show the prevalence of brain injury explored the eff ects of magnesium of moderate to severe disability to be ranging sulfate. Magnesium sulfate has been found to between 20-30% in preterm infants born at 26 have dose dependent neuroprotec ve eff ect on weeks gesta onal age, with disability increasing postnatal rats who were administered N-methyl further with decreasing gesta onal age. Abnormal d-aspartate (NMDA), known to cause excitotoxicity- neurological outcomes were seen in 25% of induced neuronal death3. Similar neuroprotec ve extremely low birth weight infants followed up ll 2 eff ects have also been seen following intracerebral 2 years in Indian se ngs . Mul ple neuroprotec ve injec on of ibotenate4. The an -excitotoxic eff ect of interven ons have been a empted to reduce MgSO4 is thought to be due to the non-compe ve the morbidity in preterm neonates. Antenatal inhibi on of NMDA receptor. It reduces excitotoxic administra on of Magnesium Sulfate (MgSO4) in injury due to glutamate release by decreasing the mothers with threatened preterm labour to reduce infl ux of calcium. Decreased calcium infl ux further neurological morbidity has been widely studied. In reduces induced apoptosis of neurons. Magnesium this ar cle, we a empt to briefl y review the role sulfate in addi on also causes reduc on in of antenatal MgSO4 in fetal neuroprotec on and expression of glutamate in ischemic regions of controversies related to its long term eff ects. brain. An -infl ammatory eff ect of MgSO4 has been Mechanism of Ac on also demonstrated in eclampsia rat models, Biological Perspec ves where it a enuated seizure severity, neuronal Magnesium is fourth most prevalent ion in the hippocampal loss, cerebrospinal fl uid levels of human body. Skeletal system accounts for 60% neuro-infl ammatory markers like ferri n, S-100 of total body magnesium, while the rest 40% is and cerebral edema. Magnesium sulfate has been stored between the muscles and so ssues. also found to ameliorate microglial and astrocyte It plays a major role in mul ple physiological ac va on and promote neuronal survival in CA3 processes including oxida ve phosphoryla on, region in eclampsia rat models5. Pretreatment of glycolysis, cell membrane integrity and aggrega on rats in hypoxia-ischemia model with MgSO4 have of DNA, protein synthesis, nerve conduc on and also resulted in reduced neuronal apoptosis and neuromuscular excitability. It also func ons as a loss in the hippocampal regions of the brain6. cofactor in various enzyma c processes. Its calcium

49 AOGD Bulletin

Role of Magnesium Sulfate in Obstetrics meta-analysis of observa onal studies showed Magnesium sulfate has been for long, used in that antenatal MgSO4 in mothers with preterm preven on or treatment of seizures in women with birth reduced the risk for mortality (RR 0.73; 95% pre-eclampsia/eclampsia. Systema c review on CI 0.61–0.89) and cerebral palsy (OR, 0.64; 95% 9 role of MgSO4 in preclapmisa/eclampsia reported CI 0.47–0.89) . Suggested benefi ts in reduc on of that administra on of MgSO4 compared with mortality and cerebral palsy, albeit retrospec ve, placebo resulted in reduced risk of eclampsia (RR has led to mul ple large scale randomized trials 0.41; 95% CI, 0.29– 0.58) and placental abrup on assessing the benefi t of antenatal administra on of (RR 0.64; 95% CI, 0.50–0.83)7. Role of MgSO4 as magnesium sulfate. tocolysis is less clear and evidence is not sugges ve that it is eff ec ve in delaying preterm birth. Randomized Trials Assessing Neuroprotec ve Eff ects Early Clinical Observa onal of Magnesium Sulfate Studies on Fetal Neuroprotec on Five large RCTs were conducted between 1990 and Following data on neuroprotec ve eff ects of MgSO4 2010, while two RCTs are s ll con nuing longer in animal model, mul ple observa onal studies follow up. The MAGnet trial, ACTOMgSO4 trial, assessing its role in neuroprotec on of preterm BEAM trial and PREMAG trial10-13 were done to assess infants were published. Nelson and Grether the role of antenatal MgSO4 for neuroprotec on in observed that very low birth (VLBW) infants born preterm infants while the Magpie trial was done to mothers exposed antenatally to MgSO4 had to assess the role of MgSO4 for neuroprotec on lower incidence of cerebral palsy with an odds in neonates born to mothers with pre-eclampsia/ ra o of 0.14 (95% CI 0.05-0.51)8. Although results eclampsia14. Apart from the MAGnet trial, all other across observa onal studies were not consistent, RCTs were mul centric. These RCTs and their outcomes are summarized in table 1 and 2. Table 1: Characteris cs of major RCTs Study Period Inclusion criteria Groups Number of par cipants MitMi endorf et al10 MagNET GA > 24wk and < 34 weeks with MgSO4 – 4 g bolus followed MgSO4 – 55 1995-97 or without PPROM by infusion of 2-3 g/hr. Other tocoly cs – 51 Cervical dila on < 4cm Other tocoly cs –ritodrine, indomethacin, nifedipine Mi endorf et al10 MAGnet GA > 24wk and < 34 weeks with MgSO4 – 4 g bolus and no MgSO4 – 30 1995-97 or without PPROM maintenance. Placebo – Placebo – 29 Cervical dila on > 4cm Saline Marret et al13 PREMAG Women in preterm delivery MgSO4 – 4 g bolus IV and MgSO4 – 362 1997-2003 with GA < 33 wk and delivery no maintenance. Placebo – 336 expected with 24 hr Placebo – Saline Crowther et al11 ACTO MgSO4 Women in preterm delivery MgSO4 – 4 g bolus IV and MgSO4 – 629 1996-2000 with GA < 30 wk and delivery maintenance with 1 g/h IV Placebo – 626 expected with 24 hr un l delivery or upto 24 h. Placebo – Saline Rouse et al12 BEAM Women of GA 24-31 wk with MgSO4 loading 6 g over MgSO4 – 1188 1997-2004 PPROM or in ac ve preterm 30 mins IV followed by Placebo – 1256 labour with cervical dila on of maintenance of 2 g/h for 4 – 8 cm with intact membranes 12 h. or indicated preterm delivery Placebo not reported an cipated in 2 – 24 h Altman et al14 Magpie Trial Women of GA < 37 wk with pre- MgSO4 loading dose 4 g IV MgSO4 – 5055 1998-2001 eclampsia who had not given followed by maintenance of Placebo – 5055 birth or were < 24 h postpartum 1 g/h for upto 24 h and at risk of eclampsia Placebo - Saline GA: gesta onal age; PPROM: preterm premature rupture of membranes.

50 Vol.20, No.8; December, 2020

Table 2: Results of major RCTs10-14 Outcomes PREMAG BEAM Magpie MAGnet ACTOMgSO4 Pediatric mortality 0.87 1.18 1.27 9.41 0.81 (0.61–1.07) (0.89–1.55) (0.96–1.68) (1.23–71.9) (0.61–1.07) Intraventricular hemorrhage 0.83 0.91 - 1.11 1.11 (0.62–1.09) (0.78–1.08) (0.53–2.34) (0.92–1.34) Periventricular leukomalacia 0.92 0.82 - 2.83 1.04 (0.55–1.53) (0.47–1.45) (0.12–68.37) (0.58–1.88) Cerebral palsy at 2 yrs 0.70 0.59 0.40 0.94 0.85 (0.41–1.19) (0.40–0.85) (0.08–2.05) (0.20–4.53) (0.55–1.31) Death or cerebral palsy 0.80 0.90 1.09 4.83 0.82 (0.58–1.10) (0.73–1.10) (0.92–1.29) (0.60–38.90) (0.66–1.02) Values reported as Rela ve risk (Confi dence interval)

Meta-analyses Assessing Long Term Follow Up Data of PREMAG Neuroprotec ve Eff ects and ACTOMgSO4 Cohorts of Magnesium Sulfate Long term follow up data on neurodevelopmental Till date, fi ve meta-analyses have been published outcomes of PREMAG and ACTOMgSO4 preterm and these have included data from major RCTs cohorts have been published recently21,22. Children evalua ng neuroprotec ve eff ect of antenatal in the ACTOMgSO4 and PREMAG cohort were MgSO4 in preterm infants15-19. Pediatric mortality, assessed at the age of 6-11 yrs and at 7-14 yrs of age cerebral palsy (CP) and composite of two were respec vely. Lost to follow up rate was 27% in the assessed in all studies. The outcomes of meta- PREMAG cohort and 23% in the ACTOMgSO4 cohort. analyses were consistent with reduc on in risk of CP Follow up data from both these cohorts showed no at 18-24 months in children with in -utero exposure signifi cant diff erence in the motor, cogni ve and to MgSO4. The rela ve risk (RR) varied from 0.61 behavioral aspects in children with in utero exposure to 0.7 and the number needed to treat (NNT) to to magnesium sulfate. The limited power of the studies prevent one case of CP was 56 to 74 for infants might be a ributed to the number of par cipants lost born before 34 weeks gesta on and 29 for infants to follow up from the original cohorts. born before 28 weeks gesta on. No signifi cant diff erence was seen in mortality or composite of Recommenda ons According CP and mortality in the standard meta-analyses. to Various Interna onal Socie es An individual pa ent data meta-analysis was Benefi ts of antenatal MgSO4 administra on has performed by the AMICABLE (Antenatal Magnesium been accepted by various interna onal socie es. sulfate Individual par cipant data interna onal Guidelines, however are not uniform regarding the Collabora on: Assessing the benefi ts for babies dose of MgSO4, dura on of therapy and gesta onal 20 using the Best Level of Evidence) group . Individual age below which it should be administered. ACOG23 pa ent data meta-analyses are considered to be recommends antenatal MgSO4 to be administered superior to standard meta-analyses because of the for fetal neuroprotec on below gesta onal age be er availability of pa ent data and hence can of 32 weeks, although the dose and dura on of overcome the limita ons posed by standard meta- therapy has not been men oned. Similarly, NICE analyses. The combined outcome of death and CP guidelines24 recommend off ering antenatal MgSO4 at 2 years was seen to be signifi cantly lower with between gesta onal age of 24-29+6 weeks and a RR of 0.86 (95% CI of 0.75-0.99). No major side considering the same for gesta onal age of 30-33+6 eff ects were seen in the mothers receiving MgSO4 weeks at a dose of 4 g IV loading followed by an and minor side eff ects included fl ushing, swea ng, infusion of 1 g/hour ll birth or 24 hours whichever nausea or vomi ng and injec on site pain. These is earlier. WHO recommends administra on of reports are consistent with robust compelling antenatal MgSO4 to mother below 32 weeks evidence suppor ng the role of antenatal MgSO4 gesta on with risk of preterm birth in the next as a neuroprotec ve agent.

51 AOGD Bulletin

24 hours25. Therefore, most guidelines in general of 56-74 for infants born before 34 weeks and 29 recommend administra on of antenatal MgSO4 in for infants born before 28 weeks. threatened preterm delivery, although uniformity Interna onal organisa ons like WHO, ACOG is lacking and further clarity in desirable. and NICE have adopted the administra on of magnesium sulfate in preterm birth for fetal Contraindica ons and Toxicity neuroprotec on. The only absolute contraindica on for administra on The recommended loading dose of MgSO4 is 4 of MgSO4 is a pa ent with myasthenia gravis. gm intravenous followed by a maintenance of 1 Rela ve contraindica ons include pa ents with gm/hr for 12-24 hours. chronic kidney disease, heart block or myocardial damage. Injec on site discomfort, pain, fl ushing References and swea ng can be seen with administra on 1. Costeloe KL, Hennessy EM, Haider S, Stacey F, Marlow N, of magnesium sulfate. Monitoring of serum Draper ES. Short term outcomes a er extreme preterm magnesium levels and pa ents general condi on birth in England: comparison of two birth cohorts in 1995 is necessary. Clinical indica ons of safe dosage and 2006 (the EPICure studies). BMJ. 2012;345:e7976. regimen include presence of deep tendon 2. Mukhopadhyay K, Mahajan R, Malhi P, Kumar A. Neurodevelopmental Outcome of Extremely Low Birth refl exes (knee jerk) and absence of respiratory Weight Children at Corrected Age of Two Years. Indian depression (>16 breaths/minute). Cau on must Pediatr. 2016;53:391-3. be exercised while being used concomitantly with 3. McDonald JW, Silverstein FS, Johnston MV. Magnesium neuromuscular blocking agents, cardiac glycosides reduces N-methyl-D-aspartate (NMDA)-mediated brain and central nervous system depressants. injury in perinatal rats. NeurosciLe 1990; 109: 234–8. 4. Marret S, Gressens P, Gadisseux JF, Evrard P. Preven on by magnesium of excitotoxic neuronal death in the Conclusion developing brain: an animal model for clinical interven on Magnesium sulfate is a safe interven on with role studies. Dev Med Child Neurol 1995; 37: 473–84 in fetal neuroprotec on in threatened preterm 5. Li X, Han X, Yang J et al. Magnesium Sulfate Provides delivery. Although long term benefi ts in motor, Neuroprotec on in Eclampsia-Like Seizure Model by Ameliora ng Neuroinfl amma on and Brain Edema. cogni ve and behavioral aspects are lacking at MolNeurobiol. 2017;54:7938-48. school age, its benefi t in reducing CP at 2 years 6. Koning, G, Lyngfelt, E, Svedin, P, Leverin, A.L, Jinnai, age, the possible benefi t in composite outcome M, Gressens, P et al. Magnesium sulphate induces of death and CP and the cost eff ec veness have precondi oning in preterm rodent models of cerebral been established26. Further studies are required hypoxia ischemia. Interna onal Journal of Developmental to address issues regarding dura on of therapy, Neuroscience (2008), 70: 56-66. 7. Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou the best dosing regimen and long term eff ects of D. Magnesium sulphate and other an convulsants for antenatal MgSO4 at school age. women with pre-eclampsia. Cochrane Database Syst Rev. 2010;2010 (11):CD000025. Key points 8. Nelson KB, Grether JK. Can magnesium sulfate reduce the risk of cerebral palsy in very low birthweight infants? Magnesium sulfate has an -infl ammatory, an - Pediatrics (1995) 95:263–69. apopto c and an -glutaminergic proper es 9. Wolf HT, Hegaard HK, Greisen G, Huusom L, HedegaardM. through which it is thought to exert its Treatment with magnesium sulphate in preterm birth: a neuroprotec ve eff ect. systema c review and meta-analysis of observa onal Mul ple RCTs have been conducted to study the studies. J ObstetGynaecol 2012; 32: 135–40. eff ect of antenatal magnesium sulfate in fetal 10. Mi endorf R, Covert R, Boman J, Khoshnood B, Lee KS, Siegler M. Is tocoly c magnesium sulphate associated with neuroprotec on, largest among which are the increased total paediatric mortality? Lancet 1997; 350: PREMAG trial, BEAM trial, ACTOMgSO4 trial and 1517–18. MAGnet trial. 11. Crowther CA, Hiller JE, Doyle LW, Haslam RR, Australasian Meta-analyses have shown the effi cacy of Collabora ve Trial of Magnesium Sulphate (ACTOMg SO4) antenatal magnesium sulfate in reducing Collabora ve Group. Eff ect of magnesium sulfate given for neuroprotec on before preterm birth: a randomized incidence of cerebral palsy at 2 years with a NNT controlled trial. JAMA 2003; 290: 2669–76.

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12. Rouse DJ, Hirtz DG, Thom E et al. A randomized controlled 20. Crowther CA, Middleton PF, Voysey M, Askie L, Duley L, trial of magnesium sulfate for the preven on of cerebral Pryde PG, et al. Assessing the neuroprotec ve benefi ts palsy. N Engl J Med 2008; 359: 895–905. for babies of antenatal magnesium sulphate: an individual 13. Marret S, Marpeau L, Zupan-Simunek V et al. Magnesium par cipant data meta-analysis. PLoS Med (2017) 14. sulphate given before very-preterm birth to protect infant 21. Chollat C, Enser M, Houivet E, Provost D, Bénichou J, brain: the randomised controlled PREMAG trial. BJOG Marpeau L, et al. School- age outcomes following a 2007; 114: 310–18. randomized controlled trial of magnesium sulfate for 14. Altman D, Carroli G, Duley L et al. Do women with pre- neuroprotec on of preterm infants. J Pediatr(2014) eclampsia, and their babies, benefi t from magnesium 165:398–400. sulphate? The Magpie Trial: a randomised placebo- 22. Doyle LW, Anderson PJ, Haslam R, Lee KJ, Crowther C; controlled trial. Lancet 2002; 359: 1877–90. Australasian Collabora ve Trial of Magnesium Sulphate 15. Doyle LW, Crowther CA, Middleton P, Marret S. (ACTOMgSO4) Study Group. School-age outcomes of very Magnesium sulphate for women at risk of preterm birth preterm infants a er antenatal treatment with magnesium for neuroprotec on of the fetus. Cochrane Database Syst sulfate vs placebo. JAMA (2014) 312:1105–13. Rev (2007):CD004661. 23. American College of Obstetricians and Gynecologists 16. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Commi ee on Obstetric Prac ce; Society for Maternal- Magnesium sulphate for women at risk of preterm birth Fetal Medicine. Commi ee Opinion No. 455: for neuroprotec on of the fetus. Cochrane Database Syst Magnesium sulfate before an cipated preterm birth for Rev (2009):CD004661. neuroprotec on. Obstet Gynecol. 2010;115:669-671. 17. Conde-Agudelo A, Romero R. Antenatal magnesium sulfate 24. h ps://www.nice.org.uk/guidance/ng25 accessed on 15 for the preven on of cerebral palsy in preterm infants August 2020. less than 34 weeks’ gesta on: a systema c review and 25. WHO recommenda on on the use of magnesium sulfate metaanalysis. Am J ObstetGynecol(2009) 200:595–609. for fetal protec on from neurological complica ons 18. Costan ne MM, Weiner SJ; Eunice Kennedy Shriver (November 2015). The WHO Reproduc ve Health Library; Na onal Ins tute of Child Health and Human Geneva: World Health Organiza on. h ps://extranet.who. Development Maternal-Fetal Medicine Units Network. int/rhl/topics/newborn-health/who-recommendation- Eff ects of antenatal exposure to magnesium sulfate on use-magnesium-sulfate-fetal-protection-neurological- neuroprotec on and mortality in preterm infants: a meta- complica ons accessed on 15 August 2020. analysis. ObstetGynecol (2009) 114:354–64 26. Shih STF, Tonmukayakul U, Imms C et al. Economic 19. Zeng X, Xue Y, Tian Q, Sun R, An R. Eff ects and safety of evalua on and cost of interven ons for cerebral palsy: a magnesium sulfate on neuroprotec on: a meta-analysis systema c review. Dev Med Child Neurol 2018; 60: 543– based on PRISMA guidelines. Medicine (BalƟ more) (2016) 58. 95:e2451.

Dr Achla Batra President Elect AOGD (2021-2022)

Dr Jyotsna Suri Vice President Elect (2021-2022)

53 AOGD Bulletin

Proceedings of AOGD Monthly Clinical Mee ng held at Maulana Azad Medical College & Lok Nayak Hospital Hospital, New Delhi on 27th November, 2020

A Rare Case of COVID 19 Desatura on in 2020: with Hypopituitarism Is it always COVID ??? Poonam Kashyap, Reena Rani Chetna Arvind Sethi, Pushpa Mishra Shikha Sharma, Deep Goswami Madhavi Gupta, Sangeeta Bhasin Maulana Azad Medical College, New Delhi Maulana Azad Medical College, New Delhi

Pa ent is Mrs K w/o Mr Y 25 yr, resident of Delhi, Cogni ve error is universal in medicine can lead G3P1L1A1 with 35 weeks, Gesta onal hypertension to errors. It is hard not to focus on the diagnosis and moderate anaemia, with complaints of cough of covid-19 while evalua ng a pa ent in 2020, and breathlessness referred in view of COVID + ve. specially the one with desatura on. In the 2 cases, Pa ent delivered vaginally and had trauma c post fi nal diagnosis was helped by a nega ve RTPCR partum haemorrhage with blood loss of 1.5 litre. report and clinical response of pa ents. Pa ent was given general anaesthesia for s tching but she could not be extubated and transferred to Case 1 ICU. Her vitals were stable and extubated on 5th Referred as a COVID suspect, G3P2L2 at 40 + weeks post natal day and put on O2 at 8 litres/min through with severe pre-eclampsia with SOB & desatura on non rebreathing mask. Pa ent started having in second stage of labour, had a NEWS 2 score of 10 polyuria and hyponatremia. On postnatal day 6th (RR-3 + Spo2-3 + Supp Oxygen-2 + Temp-0 + SBP-0 pa ent had seizures for which she was started on + PR-2, Alert +0) an convulsant. She also complained of polydipsia Suppor ve management was given and delivery and polyuria with 8 litres of input and 9 litres of was conducted. Pa ent was admi ed in ICU on output and there was failure of lacta on. On oxygen by NRBM. Rapid an gen test was nega ve th postnatal day 7 , pa ent had developed aggressive but CXR showed mul ple ground glass opaci es, behaviour and agita on. She was started on Tab basal and peripheral in loca on s/o typical COVID Haloperidol. Medicine opinion was taken and pa ern. RTPCR for SARS CO V 2 was nega ve. She and was advised to get all hormone levels a er improved on diure cs, rate control with beta blocker, keeping the possibility of Sheehan’s Syndrome or an bio cs, an coagulants and steroids. A repeat COVID 19 associated hypopituitarism. Her seum CXR a er 48 hours was normal. Final diagnosis was FSH,LH,Prolac n, was low and TSH was mildly severe pre-eclampsia, type 1 respiratory failure raised.Her MRI showed normal pituitary gland and with pulmonary edema. Pa ent was transferred hypothalamus. Pa ent was symptoma c for 21 back to non - COVID facility in stable condi on on days and she failed to lactate her baby. She could post-natal day 3. be discharged a er one month. Her inves ga ons were repeated on day 21 which showed the low Case 2 levels of FSH, LH, Prolac n which got normalized on Renu Tanwar, Niharika Dhiman Day 40. Normal MRI and involvement of anterior Reena Rani, Deep Goswami and posterior pituitary excluded the diagnosis of A COVID suspect, Primigravida at 29+ weeks with Sheehan’s syndrome and pa ent was diagnosed as hypothyroidism, high grade fever, severe headache, a case of COVID 19 associated hypopituitarism. vomi ng and malaise was referred from non- COVID facility. At 2 hours of admission she developed dizziness, hallucina ons and altered sensorium

54 Vol.20, No.8; December, 2020

along with desatura on, SPO2 was 91% on room air referred from district hospital in Delhi. . Injec on ( started on NRBM at 8l/min). With a NEWS 2 score Mgso4 was given for neuro protec on and Injec on of 9 (2+0+3+0+0+ 1+3+0= 9) she was shi ed to ICU. dexamethasone was given for lung maturity in She had neck rigidity. Diff eren al diagnosis was a the same district hospital .Pa ent was diagnosed COVID suspect with neurological symptoms with with severe anemia (Hb-5.1) pancytopenia ( TLC- ?Encephalo-meningi s ?Cerebral malaria ?Hepa c 2900 ,platelets -10000 ) and severe preeclampsia encephalopathy. She was empirically started on (BP-160/90 , urine albumin-2+) with par al HELLP IV Ce riaxone, Inj Artesunate, Rifaxamine and syndrome .Pa ent was worked up and stabilized lactulose for encephalopathy protec on. Her on an hypertensives.She was asymtoma c for RTPCR ( 22.8.20 ) was nega ve for SARS CO V 2, CXR covid infec on .On 3rd day of admission pa ent was normal, NCCT head was also reported normal. had complain of headache,vomi ng and had all Pa ent was stabilised and was shi ed back to non- features of HELLP SYNDROME . Induc on of labour COVID facility for further management. Follow up was done in view of uncontrolled BP and HELLP CSF and MRI were s/o Tubercular meningi s. Final syndrome followed by preterm vaginal breech diagnosis was a Primigravida at 29+5 weeks with delivery . .Inj MgSO4 and Injec on nitroglycerine tubercular meningi s drip was started during intrapartum period and trated.. Prophylac c balloon tamponade was Discussion: How we approach medical decision put and removed a er 24 hours .No PPH. Total making during the COVID-19 pandemic? Eventually 5 units of packed RBC and 14 units of platelets not diagnosed with COVID-19 but with Pulmonary in the antepartum and intra partum period was edema and Tubercular meningi s which should transfused .She went into hypertensive crisis just have been considered as the primary alterna ve a er delivery and was managed by NTG drip and diagnosis. Desatura on in 2020 does not imply an hypertensives. Both mother and twin babies only COVID, there are other pulmonary and non- were discharged a er 18 and 45 days of admission pulmonary causes too. respec vely with a nega ve covid report. COVID Non-specifi c overlapping symptoms and signs 19 is an emerging epidemic showing signifi cant with ambiguous laboratory inves ga ons make impact on mother and fetus . Systema c reviews diagnosis diffi cult. Chest radiographs though and meta-analyses conclude that pregnant women may show typical bilateral air-space ground glass experiencing coronavirus infec on are at increased opaci es are non-specifi c, chest computerized risk of miscarriage, preeclampsia, cesarean birth tomography fi ndings are also non-specifi c though and perinatal death.Laboratory parameters of sensi vity is reportedly 97% and has limited pre-eclampsia and covid infec on mimic each availability and high cost. other and are confusing . Pregnant women with It is important that we avoid the biases that aff ect severe COVID-19 can develop a PE-like syndrome our medical decision making in the situa on that might be dis nguished from actual PE by of a pandemic and follow the evidence based sFlt-1/PlGF, LDH and Uterine artery pulsa lity clinical approach to avoid mul ple drug therapy, Index( UtAPI) assessment. UtAPI and sFlt-1/PlGF repeated transfer entailing risk of further infec on, ra o have a high nega ve predic ve value to deteriora on and transit complica ons and predict the short-term absence of PE, but are not provided be er and safer medical care. diagnos c criteria of Pre-eclampsia .More studies are required to confi rm or refute this associa on. A Case of Obstetric Emergency Early diagnosis and mely interven on of rare in Covid Times en es in pregnancy like pancytopenia and HELLP Renu Tanwar, Niharika Dhiman, Reena Rani syndrome can arrest further complica ons and Maulana Azad Medical College, New Delhi bring favourable maternal and fetal outcome.

27 years old G3P1L1A1 with 30 weeks of gesta on with DADC twins with severe anemia with pancytopenia with preeclampsia with covid 19 was admi ed in LNJP Hospital on 28/8/20 a er being

55 AOGD Bulletin

Journal Scan Ruma Satwik Consultant, Centre of IVF and Human Reproduc on, Sir Gangaram Hospital, New Delhi

Ultrasound Obstet Gynecol 2020 May;55(5):676-682. Natural History of Pregnancy-related Enhanced Myometrial Vascularity following Miscarriage K Grewal1, M Al-Memar1, H Fourie1, C Stalder2, D Timmerman3, T Bourne1,2,3 Abstract Objec ves: Our primary aim was to report the incidence of enhanced myometrial vascularity (EMV) in consecu ve women a ending our early pregnancy assessment unit, following fi rst-trimester miscarriage. We aimed further to evaluate the clinical presenta on and complica ons associated with expectant and surgical management of EMV in these women. Methods: This was a prospec ve cohort study conducted in a London teaching hospital between June 2015 and June 2018, including consecu ve pa ents with an observa on of EMV on transvaginal ultrasonography following fi rst-trimester miscarriage. The diagnosis was made following the subjec ve iden fi ca on of EMV using color Doppler ultrasonography and a peak systolic velocity (PSV) ≥ 20 cm/s within the collec on of vessels. Women were followed up with repeat scans every 14 days. Management was expectant unless interven on was indicated because of excessive or prolonged bleeding, persistent presence of retained ssue in the endometrial cavity or pa ent choice. The fi nal clinical outcome was recorded. Time to resolu on of EMV was defi ned as the interval from detec on of EMV un l resolu on. Results: During the study period, there were 2627 fi rst-trimester fetal losses in the department and, of these, 40 pa ents were diagnosed with EMV, hence the incidence of EMV following miscarriage was 1.52%. All cases were associated with ultrasound evidence of retained products of concep on (RPOC) at presenta on (mean dimensions, 22 × 20 × 20 mm). Thirty-one pa ents opted ini ally for expectant management, of which 18 had successful resolu on without interven on, fi ve were lost to follow-up and eight subsequently had surgical evacua on due to pa ent choice. No expectantly managed case required emergency interven on. Nine pa ents chose surgical evacua on as primary treatment. No signifi cant correla on was seen between PSV within the EMV at presenta on and blood loss at surgery. Median PSV was 47 (range, 20-148) cm/s. The es mated blood loss in all cases managed surgically ranged from 20-300 mL. Presence of RPOC was confi rmed in all specimens that were sent for analysis following surgery. For cases successfully managed expectantly, the mean me to resolu on was 48 (range, 21-84) days. In the nine cases managed surgically from the beginning, the mean me to resolu on of EMV was 10.6 (range, 3-29) days. Conclusions: This study suggests that EMV is an uncommon fi nding following miscarriage and is associated with the presence of RPOC. Expectant management was a safe op on in our cohort, with minimal bleeding, although it was associated with protracted me to resolu on. In pa ents who opted for surgery, the maximum blood loss was 300 mL and no pa ent required blood transfusion or emboliza on.

56 Vol.20, No.8; December, 2020

Cross Word Puzzle Ruma Satwik Consultant, Centre of IVF and Human Reproduc on, Sir Gangaram Hospital, New Delhi

CROSSWORD Test your knowledge of Reproduc ve Anatomy and Physiology

1 Across

23 3. In women with Anterior placenta praevia and one cesarean sec on, the risk of Placenta accrete syndrome is ------% (6) 4 4. In pre-eclampsia screening in fi rst trimester, measurement of Placental

5 growth factor could be subs tuted with ----- (5) 6 5. European working group on abnormal 7 invasive placenta on (EW-AIP) defi nes how many descriptors on 2-D ultrasound

8 grey-scal 7. The gesta onal age in weeks before and a er which “Early’ and “Late” fetal growth restric on is diagnosed is (9) 910 8. In late FGR the Doppler parameter to watch out for is… (3) 9. Trial done to assess the role of antenatal MgSO4 for neuroprotec on in preterm infants. (6) Down 1. Antenatal steroid most preferred for fetal lung maturity (13) 2. This study group supports universal screening for diabetes amongst pregnant women. (5) 6. A non-recurrent, infec ous cause of S ll birth, that does not require special monitoring in the next pregnancy (5) 10. The an -excitotoxic eff ect of MgSO4 is thought to be due to the non-compe ve inhibi on of ------receptor (4)

PICTORIAL QUIZ Sharmistha Garg

Ques 1. What is “equal to ‘’ sign in the assessment of the fetal nasal bone? Ques 2. What is the criteria of for absent nasal bone?

Answer to November Crossword and Pictorial Quiz given on Page No. 47

57 AOGD Bulletin

AOGD Sub Commi ee Nomina on (2021-23) Nomina ons are invited for the post of chairperson of the following sub-commi ees for the year 2021-23 1. Urogynecology commi ee 2. Endoscopy Commi ee 3. Adolescent Commi ee 4. Safe Motherhood Commi ee 5. Fetal Medicine and Gene cs commi ee 6. Oncology Commi ee 7. Reproduc ve Endocrinology Commi ee 8. Endometriosis commi ee 9. QI Obst & Gynae Prac ce commi ee

Eligibility Criteria 1. Person should be a member of AOGD and have at least 10 years standing in the profession with at least 5 years dura on of holding senior posi on in the respec ve ins tu ons. 2. Chairperson of a subcommi ee has to be a member of any subcommi ee earlier for at least 1 year. 3. No repeat nomina on will be considered a er one term of two years. 4. In case of two people applying for the same post, the decision of the execu ve commi ee will be fi nal. 5. In case of any devia on, the decision would be taken by execu ve commi ee. 6. Two posts cannot be held by any member at one par cular me. Please send the nomina ons by email on [email protected] Or By post, the nomina ons on plain paper should reach: Gynae Offi ce, Ins tute of Obstetrics and Gynecology, Sir Ganga Ram Hospital, Sarhadi Gandhi Marg, Old Rajinder Nagar, New Delhi-110060 by 31st January, 2021 along with bio-data sta ng the eligibility.

Dr Monika Gupta Safdarjung Hospital Received FOGSI DC DUTTA Award for Best Textbook Publica on

58 Vol.20, No.8; December, 2020

Centre of IVF and Human Reproduction SIR GANGA RAM HOSPITAL Your Safety is Our Priority Restar ng Essen al Fer lity and IVF Services Con nuing Obstetrics Services

Restarting IVF treatment at Sir Ganga Ram Hospital  Your work and travel commitments are less at this time  SGRH is a COVID free hospital For  Less waiting time as fewer patients in the hospital appointment call us at +91-11-42254000  All treatment by tele-medicine  Multiple safety precautions setup by hospital  Backup team of clinicians and embryologist for every patient For Dr Abha Majumdar Dr M Kochhar IVF appointments or Dr Shweta Mittal Dr Neeti Tiwari queries call us at +91-11-42251777 Dr Gaurav Majumdar Dr Ruma Satwik

Tele-consulta ons available to visit www.sgrh.com or download my follow-up app

59 AOGD Bulletin

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