©Filodiritto Editore – Proceedings

PROCEEDINGS OF THE

8th Congress of the Romanian Society of Ultrasound in Obstetrics and Gynaecology

SRUOG

(Romania, 30 September-2 October 2020)

Editors Prof. Dr. Radu Vlădăreanu, Prof. Dr. Claudiu Mărginean

FILODIRITTO INTERNATIONAL PROCEEDINGS

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INDEX

Foreword 7

The Role of Ultrasound in the Diagnosis of Rare Forms of Ectopic Pregnancy after Assisted Reproduction Techniques (ART) 8 ALBU Dragoș, ALBU Alice

The Association of Congenital Cardiac Malformations with in Vitro Fertilization 13 ALBU Dragoș, ALBU Alice

Diagnostic Value of Ultrasound Imaging in Pelvic Floor Prolapse 17 BADIU Diana, TICA I. Vlad

The Implication of Ultrasound Accuracy in the Early Diagnosis of 24 BADIU Diana, TICA I. Vlad

Gestational Trophoblastic Disease – The Border Between Benign and Malignant 30 BĂLAN Andreea, CASAP Stela, DIMIENESCU Oana Gabriela, MOGA Marius Alexandru, BAGAN Gabriela

Ovarian Rupture During Pregnancy – A Rare Complication? Case Presentation and Review of the Literature 38 BĂLAN Andreea, MOGA Marius Alexandru, BÎGIU Nicușor Florin, PODAȘCĂ Cezar, ALDEA Florina, MANEA Rosana Mihaela

The Role of Neonatal Cranial Ultrasound in the Early Diagnosis of Intracranial Haemorrhage in Preterm Infants Compared to Term New-borns 45 BOIA Marioara, BOIA Eugen S, CIOBOATA Daniela, NAVOLAN Dan, VLADAREANU Simona, VLADAREANU Radu, ZAHARIA Gabriela, MANEA Aniko

The Role of Ultrasonography in the Early Diagnosis of Localized Neural Tube Brain Malformations 51 BOIA Marioara, BOIA Eugen S., CIOBOATA Daniela, NAVOLAN Dan, VLADAREANU Simona, VLADAREANU Radu, ZAHARIE Gabriela, MANEA Aniko, BRANDIBUR Timea

Fetal Congenital Heart Block Risk in Anti-Ro/SSA Antibodies Positive Pregnancy – How to Prevent 57 BOIANGIU Andreea Grațiana, BĂLĂNESCU Andra, FILIPESCU George Alexandru, TĂTĂRUȘ Cristina Alina, VLĂDĂREANU Radu, VLĂDĂREANU Simona

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Current Status of Ultrasound in Cervical Pregnancy 63 CHICEA Radu, CHICEA Anca, NIȚĂ Paula

Is Pelvic MRI Required as a Complementary Examination to Ultrasound? 72 DICULESCU Doru, MIHU Dan, NICULA Renata, MOCAN-HOGNOGI Radu, MĂLUȚAN Andrei, IUHAS Cristian, OANCEA Mihaela, BUCURI Carmen, PORUMB Ciprian, POP Daria

Posterior Urethral Valves and Associated Pop-Off Mechanisms in a New-born – Case Report 78 FILIPESCU Alexandru-George, MARIN Alina-Gabriela, MUNTEANU Alexandra, VLĂDĂREANU Radu, VLĂDĂREANU Simona

Hip Ultrasound and Periarticular Alterations in Third Trimester Pregnancy 85 FILIPESCU Iulia, BARBU Madalina-Gabriela, POPESCU Marius Nicolae, BEIU Cristina, VLADAREANU Radu

Normalisation of Placenta Thickness After Amnio-drainage: Case Report 90 GORUN Florin, GORUN Oana, OLARU Flavius, GADEA Ramona, POPA Andreea, COSTESCU Sergiu, FORGA Marius, MOTOI Sorin

Reversal of Altered Cerebro-Placental Ratio After Amnio-drainage 93 GORUN Florin, GORUN Oana, COJOCARU Ioana, GADEA Ramona, POPA Andreea, FORGA Marius, OLARU Flavius, MOTOI Sorin

Cytomegalovirus Seroprevalence in Pregnant Women by Age and Environment 96 GORUN Oana, GORUN Florin, COSTESCU Sergiu, CIOHAT Ioana, GADEA Ramona, POPA Andreea, OLARU Flavius, MOTOI Sorin, FORGA Marius

Ultrasonographic Evaluation of Abnormal Uterine Bleeding 100 MĂLUȚAN Andrei Mihai, DICULESCU Doru, CIORTEA Răzvan, MOCAN-HOGNOGI Radu Florin, IUHAS Cristian, BUCURI Carmen Elena, DUDEA Marina, SUCIU Viorela Elena, MIHU Dan

Management in a Case with Leiomyoma of the Uterine 110 MITRACHE Danuta, CRAINA Marius, MOZA Andreea, MARINCAS Sebastian, BERNAD Brenda, BERNAD Elena

Congenital High Airway Obstruction – See it Once and Never Forget it Case Report 115 MUNTEANU Alexandra Elena, CONSTANTIN Mona Elena, ZAMFIRESCU Vlad, VLĂDĂREANU Radu, VLĂDĂREANU Simona, FILIPESCU George Alexandru

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Active Management of Gynaecological Malignancies During Pregnancy – Fetal Risk Versus Oncological Safety 121 PÂRVULEȚU-ALI Saphia, VLĂDĂREANU Radu, SOLOMON Oana Alina, VLĂDĂREANU Simona, BOIANGIU Andreea Grațiana, FILIPESCU George Alexandru

Managing Invasive Cervical Cancer During Pregnancy 127 PÂRVULETU ALI Saphia, VLĂDĂREANU Simona, BOLOCAN Georgiana, SOLOMON Oana-ALINA, DUMITRASCU Mihai Cristian, BOIANGIU Andreea Gratiana, VLĂDĂREANU Radu

Challenges in Prenatal Diagnosis of Craniosynostosis 134 PLEȘ Liana, POENARU Mircea-Octavian, STĂNESCU Anca-Daniela, OLARU Octavian-Gabriel, SIMA Romina-Marina

Early Diagnosis of Hypoplastic Left Heart Syndrome 141 POENARU Mircea Octavian, TALPALARU Alina, SIMA Romina, PLEȘ Liana

Is 3D Ultrasound Becoming Mandatory in Future Pregnancy Surveillance? 148 POP Daria Maria, NICULA Renata, PORUMB Ciprian, MĂLUȚAN Andrei, MOCAN HOGNOGI Radu Florin, BLAGA Ligia, IUHAS Cristian Ioan, MIHU Dan, DICULESCU Doru

Dilated Fetal Coronary Synus. Case Series and Literature Review 152 PUIU Serghei, TAMBALA Carolina

The Role of Ultrasound in the Preoperative Evaluation of Pelvic Inflammatory Disease Sequelae 159 SIMA Romina-Marina, RĂDUCANU Georgiana, POENARU Mircea-Octavian, OLARU Octavian-Gabriel, BADIU Dumitru-Cristinel, PLEȘ Liana

To Screen or Not to Screen for CMV in 1st Trimester Pregnancy? 164 SOCOLOV Demetra, ROSIN Oana, FLOREA Gabriela, MURĂRAȘU Mara, PANCU Doina, PĂDURARU Luminița, DAVID Cristina, SOCOLOV Razvan, MIHĂLCEANU Elena

Giant Uterine Fibroid and Postoperative Outcome 170 STERIU Liliana, IZVORANU Silvia, NOUR Corina, PENCIU Roxana, BALTĂȚESCU Gabriela, TICA Vlad

Low Molecular Weight Heparin Therapy in Placental Insufficiency 174 TICA Vlad, COCOS Adelina, STERIU Liliana, BADIU Diana, IZVORANU Silvia, BANARIU Gheorghe, NOUR Corina, PENCIU Roxana

IOTA Criteria for Diagnosis of Ovarian Masses – Cases Analysis 177 TÎRNOVANU Mihaela Camelia, TOMA Bogdan, MUCILENIŢA Cerasela, CORDUNEANU Roxana, IOV Alexandra, TÎRNOVANU Vlad Gabriel

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The Role of Ultrasonography for Operability Evaluation of Cervical Cancer 184 TÎRNOVANU Mihaela Camelia, IOV Alexandra, TÎRNOVANU Vlad Gabriel, HIMINIUC Loredana, TOMA Bogdan

Onco-fertility Outcomes After Fertility-Sparing Treatment and Factors that Predict Recurrence in Young Patients with Serous Borderline Ovarian Tumour 191 VLĂDĂREANU Radu, BOIANGIU Andreea Grațiana, DUMITRASCU Mihai Cristian, APOSTEANU Antonia, TRĂISTARU Andrei Vlad, VLĂDĂREANU Simona

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FOREWORD

The Romanian Ultrasound Society in Obstetrics and Gynaecology is a young and dynamic society and adapted to the world situation caused by the pandemic. The annual congress was organized exclusively online and reached a large number of participants that had access to a variety of topics and lectures from international and national specialist in their fields. Expanding on three days, the meetings reunited around 700 participants and over 100 invited speakers and was followed by a very interesting ISUOG Basic Training presented by top speakers from Europe. This event has been dedicated to the study of all aspects of perinatal biology, physiology, screening, diagnosis, management and ethics, with the goal of continuous quality improvement in the care of maternal, fetal and neonatal patients. All the presentations were available in the platform for later viewing for 7 days after the event, giving the registered participants the opportunity to review the subject that interested them the most and that we are sure will help them in their future practice. The representative papers of this congress were proposed for publishing in this volume. We selected a number of 32 papers that we are sure the reader will find to be significant and to bring important scientific information, consistent in all topics related to ultrasound in obstetrics and gynaecology and in the field of perinatal medicine.

Editors

Prof. Radu Vlădăreanu Prof. Claudiu Mărginean

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The Role of Ultrasound in the Diagnosis of Rare Forms of Ectopic Pregnancy after Assisted Reproduction Techniques (ART)

ALBU Dragoș1, ALBU Alice2

1 UMF Carol Davila Bucuresti, Facultatea de Medicină Dentară, (ROMANIA) 2 UMF Carol Davila, Facultatea de Medicină Generală, Spitalul Clinic Elias (ROMANIA) Emails: [email protected], [email protected]

Abstract

The incidence of extrauterine pregnancies after in vitro fertilisation (IVF) compared to those obtained naturally is 2.5 to 5 times higher. Among these, difficult diagnostic problems include ovarian pregnancy, cervical pregnancy, heterotopic pregnancy, interstitial pregnancy, abdominal pregnancy, tubal stump pregnancy and uterine scar pregnancy, with transvaginal ultrasound playing a decisive role. The objective of the study was to present the role of ultrasound in the diagnostic algorithm. We conducted a retrospective study, on 2180 patients, who performed ART, in the period 2014-2018, in a private centre. The rate of biochemical pregnancy was 52.9%. In that period, there were eight extrauterine pregnancies, challenging to locate, representing 40% of the total ectopic. Of these, we note four heterotopic pregnancies, one cervical pregnancy, one ovarian pregnancy, one abdominal pregnancy and one tubal stump pregnancy. The ovarian pregnancy was diagnosed ultrasound by the presence of a hyperechogenic ring in the ovary, surrounded by its cortex, separated by the yellow body, in the context of the absence of the intrauterine gestational sac. In the cervical pregnancy, the gestational sac, under the internal cervical ostium was visualized, the uterine cavity being empty. The four heterotopic pregnancies were ultrasound diagnosed, but three under conditions of hemodynamic instability. In the first case, the gestational sac with the embryo with cardiac activity was present latero-uterine, in the second case a suggestive image was seen: , accompanied by a liquid in Douglas. In the other two cases, it was visible a heterogeneous, inhomogeneous mass, latero-uterine, separated by the yellow body. Abdominal pregnancy could only be diagnosed intraoperatively, in hemodynamic instability. Ultrasound plays an essential role in the diagnosis of rare localizations of extrauterine pregnancies after in vitro fertilization. Early diagnosis, before hemodynamic instability, allows the avoidance of surgical treatment and permit the rescue of concomitant intrauterine pregnancies.

Keywords: ectopic pregnancy, in vitro fertilisation, heterotopic pregnancy

Introduction

Extrauterine pregnancy (EP) represents approximately 1.3-2% of the pregnancies obtained by assisted reproduction techniques (ART). The percentage of heterotopic pregnancies after ART is under 1%; most are detected when the patient becomes symptomatic. The incidence of ectopic pregnancies after in vitro fertilization (IVF) compared to those obtained naturally is 2.5 to 5 times higher. The diagnosis could be difficult due to unusual locations of the pregnancy, and this represents a danger for women health.

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The risk factors for extrauterine pregnancy are smoking, tubal disease, pelvic inflammatory disease, previous ectopic pregnancy (EP) intrauterine device. Regarding in vitro fertilisation the factors that could determine an EP are the number of embryos transferred, changes in endometrial receptivity, deep fundal transfer, higher volume at transfer, the day of transfer [1]. Heterotopic pregnancy (HP) is defined by the coexistence of an intrauterine and an extrauterine pregnancy determined by two different implantation sites. This is very rare in spontaneous pregnancy 1/30000 cases, but it is increased after ART 1/100 cases [2]. The diagnosis of heterotopic pregnancy is often delayed, which endangers both lives of the affected mother and embryos.

Methodology

Our aim was to study the percentage of ectopic pregnancies of the total pregnancies obtained from ART procedures and evaluate their diagnosis and management. We conducted a retrospective study on 2180 patients who underwent ART, in the period 2014-2018, in a private centre. IVF or intracytoplasmic sperm injection (ICSI) were performed in the day of egg collection according to standard laboratory procedures. Only patients from fresh cycles were analysed and from intrauterine insemination. We used controlled ovarian stimulation with a GnRH agonist or GnRH antagonist protocol. The number of embryos transferred was according to ASRM guideline. For intrauterine insemination, we used sperm washing techniques, one procedure after 36 hours of β-Hcg trigger.

Results

The biochemical pregnancy rate was 52.9%. During that period, there were eight ectopic pregnancies difficult to locate, representing 40% of the total ectopic pregnancies. Of these, we had observed four heterotopic pregnancies, a cervical pregnancy, an ovarian pregnancy, an abdominal pregnancy and tubal stump pregnancy. Tubal pregnancies have been treated by laparoscopic or classic unilateral salpingectomy or methotrexate. The pregnancy on the tubal stump was treated by excising the stump. As far as it concerns the heterotopic pregnancies, two pregnancies were ultrasonographically diagnosed, when patients became symptomatic after hemodynamic instability. In both laparotomy situations, the patient also lost the intrauterine pregnancy. Another heterotopic pregnancy was diagnosed when the patient presented hemodynamic instability, 7 days after curettage for spontaneous abortion. There was one case of heterotopic pregnancy when we managed to put the diagnosis by ultrasound, before the patient became symptomatic. Unilateral salpingectomy was performed, and the other intrauterine pregnancy was evolving to term. Cervical pregnancy was treated with methotrexate and embolization of the uterine arteries (Fig. 1).

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Fig. 1. Cervical pregnancy

Ovarian pregnancy is very rare extrauterine pregnancy, with approximately 100 cases being reported and less than 15% of them are intrafollicular. We present a 34 years old woman referred to our department for secondary . Histerosonography showed a delay permeability of the right tube and the constriction of the left tube. Spermogram was normal, and ovulation was present. Beta-hCG was measured after two weeks from intrauterine insemination (IUI), and the result was 2.91 mUI/l. The patient reported menstruation two days after beta-hCG analysis. Three weeks after the determination of beta-hCG, the patient presented with abdominal pain, hypotension, tachycardia and dizziness. Ultrasound exam revealed free blood in the abdominal cavity, no intrauterine pregnancy and a heterogeneous mass of 3/2.5 cm in the right ovary, with a small gestational sac with yolk sac inside, suggesting intraovarian pregnancy. Separated from the gestational sac, another heterogeneous mass in the right ovary was present, with peripherical circulation, suggesting a corpus luteum. Beta-hCG at that moment was 2200 mUI/l. At the surgical intervention, we found 1000 ml of blood in the abdominal cavity and a heterogenous mass in the right ovary. We performed surgical resection of the bleeding mass with the conservation of the ovary. The histopathologically exam result confirmed intraovarian pregnancy with corpus luteum in the wall of the excised ovarian mass. We presented this very rare case of intrafollicular ovarian pregnancy because of the atypical clinical presentation and very suggestive ultrasound images. The abdominal pregnancy was obtained by IUI and was treated by laparoscopy.

Discussion

The greatest predictors of EP were the number of embryos transferred. An average increase of 31% on the odds of EP is seen with each additional embryo transferred. The risk factors for EP are the number of oocytes retrieved, demographic characteristics, previous history of a fresh IVF cycle, infertility diagnosis and ovarian stimulation protocol. The measures we took for reducing EP after ART are: reducing the number of embryos transferred, extending the time for embryo transfer (day 5), decreasing the incidence of tubal disease [1]. Regarding heterotopic pregnancies, early ultrasound and β-HCG are not very helpful in diagnosis. The extrauterine pregnancy in these cases was tubal located. When tubal pregnancy ruptured, the lives of the mother and of the intrauterine pregnancy were affected [2]. Tubal

10 ©Filodiritto Editore – Proceedings inflammation seems to be a risk factor for HP [3]. Pelvic infection and pelvic surgery were identified as a risk factor for HP by Yu [4]. Serum oestradiol (E2) level before triggering was also correlated with the incidence of HP after ART [5]. Generally, the level of serum β-Hcg and serum progesterone (P) in day fourteenth after embryo transfer (14th IVF-ET) is lower in HP than in twin intrauterine pregnancy after ART, but higher than in single intrauterine pregnancy [6]. If we had a serum β-Hcg level >300mUI/l in (14th IVF-ET), we should take into consideration the possibility of multiple pregnancies [2]. The careful ultrasound examination of the adnexa and the presence of the fluid in pelvis could help you in the diagnosis of HP. The best treatment in this situation is laparoscopic removal of the EP, permitting to the intrauterine pregnancy to evolute till term [7]. Tubal stump pregnancy could occur after ipsilateral salpingectomy [8]. If complete resection of the tube is realized during initial salpingectomy, these situations will be extremely rare. One possible explanation is the migration of a pregnancy from the contralateral tube by intrauterine fluids [9]. These pregnancies are located in the tubal interstitium at the uterotubal junction where the muscular layer is thicker with a rich blood supply, so it is an increased risk of bleeding during surgery. The proper treatment is a laparoscopically complete removal of the stump [10]. The mechanism of ovarian pregnancy after ART is not very well understood. It could be related to blastocyst transfer [11]. Abdominal pregnancy (AP) represents 1% of EP but has eight times higher maternal mortality rate in comparison with tubal pregnancy [12]. The mechanism of AP could be uterine perforation during embryo transfer or micro fistulous tract after salpingectomy [12]. False diagnosis in extrauterine pregnancy, is determined by heterophilic antibodies (HABs), which could be present in patients with infertility. A low persistent level of β-Hcg represents a challenge in the diagnosis of a pregnancy of unknown location, possibly ectopic. HABs influence the ELISA sandwich test, resulting in false-positive β-Hcg. It should be tested in hemodynamically stable patients. There is also persistent Hcg of pituitary origin. A small amount of Hcg is produced by the pituitary gland in conjunction with LH, FSH, TSH, in quantities of 13-20 mUI/l, especially in postmenopausal women. It can be identified by contraceptives.

Conclusions

Extrauterine pregnancy (EP) is a possible complication of the ART. Due to bleeding risk, early diagnosis is important to avoid maternal morbidity.

REFERENCES

[1] Lin S, Yang R, Chi H, Lian Y, Wang J, Huang S, Lu C, Liu P, Qiao J. Increased incidence of ectopic pregnancy after in vitro fertilization in women with decreased ovarian reserve. Oncotarget. 2017 Feb 28; 8(9): pp. 14570-14575. doi:10.18632/oncotarget.14679. PMID: 28099907; PMCID: PMC5362426. [2] Liu M, Zhang X, Geng L, Xia M, Zhai J, Zhang W, Zhang Y, Sun Y, Zhang J, Zhu D, Zhao H, Chen ZJ. Risk Factors and Early Predictors for Heterotopic Pregnancy after In Vitro Fertilization. PLoS One. 2015 Oct 28; 10(10): e0139146. doi: 10.1371/journal.pone.0139146. PMID: 26510008; PMCID: PMC4624796. [3] Casikar I, Reid S, Condous G. Ectopic pregnancy: Ultrasound diagnosis in modern management. Clin Obstet Gynecol 2012; 55 (2): pp. 402-09.doi: 10.1097/GRF.0b013e31825109bd PMID: 22510621. [4] Yu Y, Xu W, Xie Z, Huang Q, Li S. Management and outcome of 25 heterotopic pregnancies in Zhejiang, China. Eur J Obstet Gynecol Reprod Biol 2014; 180(9): pp. 157-61. [5] Verhulst G, Camus M, Bollen N, Van Steirteghem A, Devroey P. Pregnancy: Analysis of the risk factors with regard to the occurrence of ectopic pregnancy after medically assisted procreation. Human Reproduction 1993; 8(8): pp. 1284-87. PMID: 8408528

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[6] Zhang Xiuqing, Xia Mingdi, Geng Ling. Risk Factors and Early Predictors for Fallopian Pregnancy after In Vitro Fertilization (in Chinese). Chin J Mod Nurs 2013, 7(2): pp. 3511-14. [7] Pezzuto A, Pomini P, Steinkasserer M, Nardelli GB, Minelli L. Successful laparoscopic management of spontaneous hemoperitoneum at 15 weeks of pregnancy: case report and review of literature. Journal of Minimally Invasive Gynaecology 2009; 16(6): p. 7924. doi: 10.1016/j.jmig.2009.08.007 PMID: 19896614. [8] Xi Q, Yu Y, Zhang X, Zhang H, Jiang Y, Liu R, Zhang H. Two cases of intrauterine pregnancy with tubal stump pregnancy after in vitro fertilization and embryo transfer following ipsilateral salpingectomy: A case report. Medicine (Baltimore). 2019 Dec; 98(49): e18183. doi: 10.1097/MD.0000000000018183. PMID: 31804336; PMCID: PMC6919399. [9] Keeping D, Harrison K, Sherrin D. Ectopic pregnancy contralateral to unilateral GIFT. Aust N Z J Obstet. Gynaecol. 1976; 33: pp. 95-6. [10] Bernardini L, Valenzano M, Foglia G. Spontaneous interstitial pregnancy on a tubal stump after unilateral adnexectomy followed by transvaginal colour Doppler ultrasound. Hum Reprod 1998; 13: pp. 1723-6. [11] Atabekoglu CS, Berker B, Dunder I. Ovarian ectopic pregnancy after intracytoplasmic sperm injection. Eur J Obstet. Gynecol. Reprod Biol 2004; 112: pp. 104-6. [12] Yoder N, Tal R, Martin JR. Abdominal ectopic pregnancy after in vitro fertilization and single embryo transfer: a case report and systematic review. Reprod Biol Endocrinol. 2016 Oct 19; 14(1): p. 69. doi: 10.1186/s12958-016-0201-x. PMID: 27760569; PMCID: PMC5070159.

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The Association of Congenital Cardiac Malformations with in Vitro Fertilization

ALBU Dragoș1, ALBU Alice2

1 UMF Carol Davila Bucuresti, Facultatea de Medicină Dentară, (ROMANIA) 2 UMF Carol Davila, Facultatea de Medicină Generală, Spitalul Clinic Elias (ROMANIA) Email: [email protected]

Abstract

The incidence of in vitro fertilization (IVF) pregnancies increases from year to year, reaching in some developed states, approximately 4% of the total births. The American Cardiology Association considers fetal echocardiography mandatory in these situations. In our retrospective evaluation, from 2011 to 2017, 2471 women who performed IVF in a private center were included. The number of clinical pregnancies in this group was 989 (40%). All analysed pregnancies were obtained by the transfer of fresh embryos. The purpose of the study was to see the incidence and type of congenital cardiac abnormalities in them. Of the total number of pregnancies, 75.8% were single, 22.9% twin, 1.3% triple. The incidence of congenital cardiovascular abnormalities in the studied group was 0.8%. Of the eight cardiac abnormalities, three occurred in the context of chromosomal changes: A Down syndrome with atrioventricular septal defect, a Down syndrome with Fallot tetralogy, and one Edwards’s syndrome with ventricular septal defect (DSV). The other cardiac abnormalities, without chromosomal changes, were two severe and three minors. Severe cardiac abnormalities were a case of tricuspid valve atresia with DSV and pulmonary artery hypoplasia (PA), at a diamniotic, dichorionic pregnancy and a case of transposition of large vessels. Minor congenital heart defects were DSV. In the twin pregnancy the affected fetus was stopped selectively, the evolution of the second one being normal, in the transposition of large vessels, the fetus died at birth, despite the postnatal surgery. The fetus diagnosed with DSV evolved favourably. Pregnancies with concomitant cardiac and chromosomal abnormalities were discontinued parental consent in the second trimester of pregnancy. The probability of congenital heart malformations is an increase in the foetuses obtained by IVF, which is why fetal echocardiography should be performed at these routine tasks.

Keywords: congenital cardiac malformations, in vitro fertilisation, fetal echocardiography

Introduction

The incidence of in vitro fertilization (IVF) pregnancies increases from year to year, reaching in some developed states, approximately 4% of the total births. IVF conception may carry a risk for congenital malformations. The American Cardiology Association considers fetal echocardiography mandatory in these situations. Congenital heart defect (CHD) is the most common congenital malformation and a significant cause of perinatal morbidity. It would represent 0,71% of total live births and 0,61% if we excluded underlying genetic disease [1]. 15% of all CHD are represented by chromosomal abnormalities (Down, Edwards, Turner, Patau, Di George syndromes) and genetic mutations. The increase rate of congenital malformations is due

13 ©Filodiritto Editore – Proceedings to relatively advanced paternal age in infertile couples and of the increase rate of fertilization by abnormal sperm. Point mutations in IVF are also determined by chemical and physical teratogens [2].

Methodology

In our retrospective evaluation, from 2011 to 2017, 2471 women who performed IVF in a private centre entered. The number of clinical pregnancies in this group was 989 (40%). All analysed pregnancies were obtained by the transfer of fresh embryos. The purpose of the study was to see the incidence and type of congenital cardiac abnormalities in them. We used a long agonist GnRH (gonadotropin-releasing hormone) mixt protocols: highly purified human menopausal gonadotropin (HP-hMG) in association with recFollitropinum alpha or beta, or a mixt antagonist protocol. Transvaginal egg collections were performed 36 hours after human chorionic gonadotropin (hCG) administration and embryo transfer were realized on day three or day five. The number of embryos transferred was according to ASRM guidelines.

Results

Of the total number of pregnancies, 75.8% were single, 22.9% twin, 1.3% triple. The incidence of congenital cardiovascular abnormalities in the studied group was 0.8%. of the eight cardiac abnormalities, three occurred in the context of chromosomal changes: A Down syndrome with atrioventricular septal defect, a Down syndrome with Fallot tetralogy, an Edwards syndrome with ventricular septal defect (DSV). The other cardiac abnormalities, without chromosomal changes, were two severe and three minors. Severe cardiac abnormalities were a case of tricuspid valve atresia with DSV and pulmonary artery hypoplasia (PA), at a diamniotic, dichorionic pregnancy (Fig. 1) and a case of transposition of large vessels (Fig. 2).

Fig. 1. Tricuspid valve atresia with DSV and pulmonary artery hypoplasia (PA)

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Fig. 2. Transposition of great vessels

Minor congenital heart defects were DSV. In the twin pregnancy, the affected fetus was stopped selectively, the evolution of the second one being normal, in the transposition of large vessels, the fetus died at birth, despite the postnatal surgery. The foetuses diagnosed with DSV evolved favourably. Pregnancies with concomitant cardiac and chromosomal abnormalities were discontinued with parental consent in the second trimester of pregnancy.

Discussion

There is a 50% increase in CHD after IVF/ICSI. The rate of termination of pregnancy (TOP) in these situations is 20-30%. Maternal age is a risk factor for major chromosomal defects and CHD, but also in non-chromosomal CHD. IVF could determine early placental dysfunction. Placental dysfunction may determine significantly lower PAPP-A in these pregnancies. The increased risk for congenital malformation in IVF is seen for fresh transfer but not in freezing transfer [4]. The heart in twin pregnancies after IVF in comparison with spontaneous pregnancy is bigger, the atria are more globular, and the right ventricle is thicker and more globular. In a recent meta-analysis minor CHD as VSD and ASD were more frequently associated with IVF than with spontaneous conception, but this is not met for major CHD [1]. In Shofield study, there was a non-significant increase in CHD for children after ART but the odds ratio was reduced after adjustment for gestation, parity and maternal age. The specific CHD associated with IVF were atresia or stenosis of the pulmonary valve in Heisey study [6].

Conclusion

The probability of congenital heart malformations is increased in the foetuses obtained by IVF, which is why fetal echocardiography should be performed at these routine tasks.

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REFERENCES

[1] Giorgione V, Parazzini F, Fesslova V, Cipriani S, Candiani M, Inversetti A, Sigismondi C, Tiberio F, Cavoretto P. Congenital heart defects in IVF/ICSI pregnancy: systematic review and meta-analysis. Ultrasound Obstet. Gynecol. 2018 Jan; 51(1): pp. 33-42. doi: 10.1002/uog.18932. PMID: 29164811. [2] Anthony S, Buitendijk SE, Dorrepaal CA, Lindner K, Braat DD, den Ouden AL. Congenital malformations in 4224 children conceived after IVF. Hum Reprod. 2002 Aug; 17(8): pp. 2089-95. doi:10.1093/humrep/17.8.2089. PMID: 12151442. [3] Udholm S, Udholm L, Nyboe C, Kesmodel US, Hjortdal VE. Pregnancy outcome in women with atrial septal defect: associated with in vitro fertilisation and preeclampsia. Open Heart. 2019 Nov 2; 6(2): e001148. doi: 10.1136/openhrt-2019-001148. PMID: 31798916; PMCID: PMC6861110. [4] Davies MJ, Moore VM, Willson KJ, Van Essen P, Priest K, Scott H, Haan EA, Chan A. Reproductive technologies and the risk of birth defects. N Engl J Med. 2012 May 10; 366(19): pp. 1803-13. doi: 10.1056/NEJMoa1008095. Epub 2012 May 5. PMID: 22559061. [5] Schofield SJ, Doughty VL, van Stiphout N, Franklin RCG, Johnson MR, Daubeney PEF, Cullinan P. Assisted conception and the risk of CHD: a case-control study. Cardiol. Young 2017; 27: pp. 473-479. [6] Heisey AS, Bell EM, Herdt-Losavio ML, Druschel C. Surveillance of congenital malformations in infants conceived through assisted reproductive technology or other fertility treatments. Birth Defects Res A Clin Mol Teratol 2015; 103: pp. 119-126.

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Diagnostic Value of Ultrasound Imaging in Pelvic Floor Prolapse

BADIU Diana1*, TICA I. Vlad1

1 Department of Obstetrics & Gynaecology, Institute of Doctoral Studies, Faculty of Medicine, “Ovidius” University of Constanta, “Sf. Apostol Andrei” Emergency Clinic County Hospital, Constanta, (ROMANIA) * Email: [email protected]

Abstract

For decades, childbirth-related trauma played a major role in the structural integrity of the female (POP). For this reason, modern imaging – as ultrasound (US) – has recently allowed us to better achieve information in real-time, like Valsalva manoeuvres and muscle contraction. Considering the cost, access and performance of the US, its implication in POP diagnosis represents an important benefit. It offers multiple advantages, like replacing defecation proctographic for posterior compartment and diagnosing postoperative complications, such as urinary retention. The present review outlines current clinical utility for both patients and clinicians, providing an overview of the imaging utility in investigating of anterior, central and posterior POP compartments. Therefore, the present study supports the idea of up-to-date resources in real-time teaching and ultrasound training in the next generation of urogynaecology practitioners.

Keywords: ultrasound, pelvic organ prolapsed, real-time, investigation, clinical utility

1. Introduction

Although radiological techniques have been first described in the bladder investigation and its descent [1, 2], the first imaging on pelvic floor dysfunction appeared in the 1920s. With the incoming of the B-mode real time ultrasound (US), ultrasonography became a popular technique, either through the trans-perineal [3-5] or the vaginal way [6]. As an alternative, magnetic resonance imagining (MRI) has been introduced; although, considering its cost and accessibility, its general utility has been hindered. Clinical examination was shown to be less satisfactory in assessing the pelvic floor compartments and their related anatomy, even if the practitioner uses the prolapse quantification system of the International Continence Society – ICS Pelvic Organ Prolapse (POP) Quantification system (POP-Q). Besides clinical examination [7], US imaging [8] can, nowadays, differentiate among asymptomatic nulliparous with first- or even second-degree POP. The relevance of the disease is important [9], causing significant economic and social losses [10], increasing the number of hospitalizations [11] and biochemical testing for patients, in early stages [12]. A fertility problem [13], even with POP in younger women, is not a concern – so, neither fertility treatments [14] nor their possible side effects [15-18]. It is known that, generally, both nulliparous and parous women (related to age and environmental area), show, at some moment, symptoms of POP, but most of them are asymptomatic, without feeling any vaginal bulge [19-21]. In symptomatic patients, many practitioners consider that urinary or bowel symptoms are symptoms related to prolapse, without

17 ©Filodiritto Editore – Proceedings taking into account the symptoms like dragging sensation, vaginal laxity, [22, 23], [24, 25], tissue trauma or vaginal injury, some involved or similar to other diseases, like adenomyosis, [26-28] or endometriosis-associated ovarian neoplasm [29]. Some authors managed to have a better definite diagnosis for , by using radiology – even since the 1960s [30]. The cystocele has been also assessed by trans-labial US [31]. However, the posterior compartment was difficult to visualize, considering the different anatomical entities included [32]. Although many imaging techniques have been developed to date, our examination skills on POP are still scarce. Moreover, nowadays, depending on the device used, a special attention should be carried out regarding multiple exposures; especially at different high US level [33]. Therefore, the medical interest was oriented more on surgical procedures for POP, and less on the pathophysiology and on the comprising anatomical parts of the pelvic floor. However, many surgical methods still have recurrence rates, partly due to insufficient diagnosis techniques – which can be reached by using the newly US imaging. The present review outlines current clinical utility of US for both patients and clinicians, providing an overview of the probable future utility of imaging in the investigation of the anterior, central and posterior POP compartments.

2. Diagnosis by Imaging

For a better assessment of the pelvic floor dysfunction, US imaging has promising results, reconsidering even what we have called ‘prolapse’. When the anterior vaginal wall descent is involved, the practitioners use the word ‘cystocele’, and for the posterior vaginal wall it is called ‘’. The anterior wall descent varies and can be due to different causes like cystocele, urethral diverticulum, Gartner duct cyst, or anterior [34]. In such cases, US can make a difference for an early diagnosis. For example, urethral structure is particularly better visualized in a multiaxial view, with accent on the axial plane, offering a much easier differential diagnosis with a Gartner duct cyst [35]. Concerning the central compartment, when voiding symptoms are present, the US can visualize an anteriorized cervix with an enlarged, retroverted . Sometimes, the patients can present the compression of “plugging” of anorectum, which can be seen in acute anteverted uterus, explaining the symptoms of ‘recto-colpocele’ on defecation proctographic [36]. Moreover, the US can be very useful in the posterior vaginal wall prolapse, including obstructed defecation. In such cases, the collaboration between different techniques from surgery, gastroenterology and gynaecology can help in achieving not only the diagnosis, but also promising results [37]. Although in defecatory symptoms defecation proctographic has been the gold standard technique, US proved to be better, replacing radiological methods [38, 39]. Three-dimensional (3D) and four-dimensional (4D) US can better distinguish the levator ani muscle, enabling diagnosis of avulsion and hiatal ballooning [40]. Therefore, by using US, it has become possible to define any recurrence after conventional reconstructive surgery, especially for surgical planning [41]. In the end, a final US report should contain information about organ descent (i.e., cystocele), levator integrity (i.e., complete levator avulsion) and distensibility (i.e., moderate ballooning). Also, in the same report, the presence of the implants should be mentioned (i.e., tension free vaginal tape) [42].

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3. Clinical Uses

3.1 Anterior Compartment Prolapse For the anterior compartment, usually called ‘cystocele’, the use of US imaging can bring more benefits than clinical examination. With the help of US, the two types of cystocele can be viewed, in which each has different functions [43]. A voiding dysfunction maybe due to a major trauma of the levator ani – during difficult labor [44], large or malformed foetuses [45, 46] is generated by cystocele with intact retro-vesical angle (described as Green type III), while urodynamic stress incontinence usually is generated by cystourethrocele (Green type II) [47]. These two types of cystocele are very difficult to differentiate at clinical examination, being grouped together, resulting in the same prolapse position [48], and only occasionally a cystocele will turn out to be due to a urethral diverticulum, a Gartner duct cyst or an anterior enterocele. Important to note, the exclusion of a urethral diverticulum is not made only by using US, but also by using MRI technique [49]. In contrast with this, synthetic meshes used in prolapse surgery are better seen on US than X-ray, CT or MRI. When superior mesh aspects need to be visualized, transvaginal US technique is a better option. In many cases, the signs and symptoms of different prolapse types often superimpose with signs and symptoms of urethral diverticula and ectopic ureters. Therefore, endovaginally US can differentiate ectopic from and dystopic ureters [50]. Moreover, US imaging can also differentiate a diverticulum from other periurethral cystic lesions, such as ectopic ureters, calcifications, or injected materials [51]. Endovaginally US is also useful in the diagnosis and monitoring of urethral tumours [52], in which US will show homogenous mass, with increased vascularity [53]. Finally, endovaginally US of the bladder can bring sufficient information regarding foreign bodies or bladder diverticula. The thickness of the bladder wall can also be measured, being positively correlated with the detrusor instability [54].

3.2 Central Compartment In the central compartment, the uterus seems more difficult to be visualized than other entities, like bladder or rectal ampulla. That’s why is more prominent on US than on clinical examination. This can be in respect to the functional anatomy of the levator hiatus, which has a major impact on the uterine descent [55]. However, in the co-activation of levator ani condition, false-negative findings can result in the normal uterine support. In the same context, the anteriorized cervix can be easily shown, especially in the case of , explaining at the same time, symptoms like voiding dysfunction. When the anorectum is compressed, it can result in mild descent of an anteverted uterus, showing symptoms manifestation like obstructed defecation [56].

3.3 Posterior Compartment Endovaginally US provides important key points regarding posterior compartment, by showing the integrity of the rectovaginal septum, and the anorectal angle. With the help of the Valsalva method, other important aspects can be visualized – like enterocele, rectocele, or [57] and the movement of the puborectalis angle or inter-susception [58]. On the other hand, endoanal US can visualize the anal canal [59, 60], along with a defecation dysfunction [61]. For any posterior vaginal wall prolapse, the practitioners use the word ‘rectocele’. However, ‘true rectocele’ represents the herniation of the anterior rectal wall into vagina [62], which can be

19 ©Filodiritto Editore – Proceedings visualized on US. In such conditions, a trans-perineal US can be better used instead of endoluminal US, which can, by compression, prevent the prolapse from occurring. When a downward movement of the abdominal content into vagina is visualized, there may be an enterocele. When hyperechoic stool movement from the surrounding tissue is seen, a sigmoidocele can be suspected. Moreover, the differentiation of a sigmoidocele from an enterocele is very useful concerning the planning of the surgical procedure [62]. When the rectal wall telescopes into rectal lumen, an intussussception can be suspected. The lack of normal relaxation of the puborectalis muscle during defecation is interpreted like a pelvic floor dyssynergy. At this point, clinical examination is of no importance. This can be visualized by US during a Valsalva method, considering the fact that anorectal angle becomes narrower and the puborectalis muscle thickens [61].

4. Primary Prevention

In general, many affected women are not disturbed by their prolapse, except the cases when urinary incontinence, prolapsed uterus, obstructed defecation or other symptoms are bothersome [63]. In the primary prevention, caretakers should involve lifestyle changing (i.e., weight loss), perineal massage, epidural analgesia, avoidance of forceps or vaginal delivery, bowel management or pelvic floor muscle training [64]. The later may increase resting tone of the levator ani muscle and reduce, this way, the symptoms [65]. Therefore, for a patient with mild or moderate prolapse symptoms, a pelvic floor physiotherapist should be recommended, at the beginning. The next step might be the application of a vaginal pessary, especially ring pessaries, without causing many complications. Usually, the menopausal women are treated with local oestrogen or ovula (i.e., per vaginam) and pessary change every 3-4 months, when any possible erosion can be viewed. In the case of vaginal erosion, the re-insertion should be delayed. Surgical intervention is useful in case of failure of the previously described measures [66]. Different types of anaesthesia have been described [67]. Today, there is a tendency to begin the primary prevention in the early stages of prolapse.

5. Conclusions

Starting from the 1980s, it was quite evident that US imaging can make a difference in the pelvic floor assessment and reconstruction. Considering the higher prevalence of intravaginal mesh implants which are not quite visible on X-ray, CT or MRI, US is becoming more and more useful. Moreover, the clinical assessment in the urogynaecology field, ideally should involve US imaging, especially in the recurrence cases. Therefore, we support the idea that the provision of up-to-date resources in teaching and training of US in the next generation of urogynaecology practitioners will prove to be of paramount importance.

6. REFERENCES

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The Implication of Ultrasound Accuracy in the Early Diagnosis of Adenomyosis

BADIU Diana1*, TICA I. Vlad1

1 Department of Obstetrics & Gynaecology, Institute of Doctoral Studies, Faculty of Medicine, “Ovidius” University of Constanta, “Sf. Apostol Andrei” Emergency Clinic County Hospital Constanta, (ROMANIA) * Email: [email protected]

Abstract

Adenomyosis, a frequent cause of pelvic pain, represents the most common benign uterine condition. Nowadays, transvaginal ultrasonography (TVUS) has gained an important role in the diagnosis of adenomyosis. Besides other US techniques useful in detecting adenomyosis, like cine clips or coronal images, which can help detecting endometrial-myometrial border and diffuse focal junctional zone, TVUS has proved to have a bigger impact, along with three-dimensional US and volume contrast imaging. The present article reviews the pathophysiology of adenomyosis and correlates it with US findings, which are able to accurately offer an early diagnosis, before treatment has to be instituted.

Keywords: adenomyosis, , pathophysiology, ultrasonography, junctional zone

1. Introduction

Adenomyosis, considered in the past a type of endometriosis, represents a common uterine condition of ectopic endometrial tissue in the myometrium [1], in which imaging like transvaginal (TV) ultrasonography (US) may reveal characteristic findings. This abnormal endometrial proliferation is not well understood – and even particular receptors’ expression can be involved [2, 3]. Considering a benign disease, most of the multiparous women of reproductive age are asymptomatic [4]. However, some may express pain [5-7], condition that has to be differentiated from other causes [8], including endometriosis-related ovarian malignancy [9]. Furthermore, these findings are more based on pathologic studies which resulted from hysterectomy specimens. Interestingly, patients with higher oestrogen exposure, such as a history of contraceptives, are considered to be at higher risk of adenomyosis. Hypofertility may be observed [10] and the various infertility treatment could imply multiple side effects [11-14]. The normal myometrial signalling [15, 16], calcium transport [17, 18] and contraction [19, 20] may be altered. Labor in these women might necessitate alternative assessment methods [21]. Medical and surgical treatments may be necessary, by laparotomy, hysteroscopy or/and laparoscopy – alongside with various anaesthesia methods [22]. Although some studies have shown that TVUS is highly observer-dependent, it can clearly contribute to an early diagnosis in suspected cases. Further, this diagnosis can be used in unselected premenopausal women with myomas. Therefore, a good workout of a trainer should be involved in TVUS for adenomyomas diagnosis [23].

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The objective of this review is to relate the image findings of TVUS to structural changes of adenomyosis pathophysiology, in order to summarize the present clinical diagnostic approach in early diagnosis of adenomyosis.

2. Pathophysiology of Adenomyosis

The basic expression of adenomyosis consists in smooth uterine enlargement, which was not well assessed, using TVUS, until 1980 [24], the diagnosis being made on quantifiable magnetic resonance imaging (MRI). The MRI findings consists of region of low myometrial signal intensity, with indistinct margins and diffuse focal junctional zone greater than 12 mm, together with punctuate hyperintense foci [25, 26]. Nowadays, the TVUS imaging techniques have shown a significant improvement and the accuracy of adenomyosis has increased, more than the MRI’s had. Usually, the characteristics involve two thirds of the myometrium, with a slight decrease in the echogenicity [27]. Some anechoic lesions of 1 to 3 mm diameter can be observed, more frequently in the posterior wall. This kind of lesions represents a limit for US imaging, being detected only in 53% to 85% of the patients [27]. Furthermore, histological studies have more clearly explained that these lesions are ectopic endometrial glands, which become sonographically clear when focal haemorrhage is present [28, 29]. In the same context, biochemical tests for revealing organ damages are non-invasive, easily accessible, cheap, and effective in establishing standard parameters, guiding other supplementary investigations [30, 31], which could depend also on demographic, seasonality [32] or time of hospitalization [33, 34]. The fluid nature of these lesions produces increased posterior acoustic enhancement rather than the degree of attenuation that is normally seen, posteriorly to the uterus. US detection is often complicated by the presence of coexisting leiomyomas, vascular calcifications, artefactual echoes [35] or neovascularization like in endometriosis [36]. Usually, it is better to evaluate the contour and border of uteri, by using colour Doppler – which can differentiate between feeding arteries of myoma from adenomyosis, which rarely shows feeding arteries [37]. One study supports the idea that MRI is as accurate as TVUS in adenomyosis diagnosis [25]. The same study, based on hysterectomy specimens, found no statistical difference in sensitivity or specificity between MRI and TVUS [38]. Considering the three histologic parts of adenomyosis like “adeno,” or ectopic endometrial glands, “myosis,” or muscular hyperplasia, and increased vascularity, additional US techniques – like cine clips, two-dimensional (2D) and three-dimensional (3D) coronal reconstructions – can help improving the diagnostic confidence [39, 40]. Therefore, taking into account the safety, widespread and lower cost, US should be considered the primary tool in adenomyosis diagnosis.

3. The Improving Adenomyosis Diagnostic by Ultrasonography

In general, both transverse and sagittal cine sweeps can be used by US. The imaging of the coronal plane of uterus follows, in order, to adjunct the two measures. Important to be mentioned, the coronal plane on either 2D or 3D reconstructed images allows for complete fundal endometrial-myometrial visualization [41, 42]. However, there is still a debate regarding the number of (many) exposures, at high US level, depending also on the devices used [43]. Therefore, the 2D sonographic reconstruction of adenomyosis characteristics is caused by alterations of the outer myometrium. The basic 2D TVUS characteristics for adenomyosis are

25 ©Filodiritto Editore – Proceedings constituted by a globally enlarged uterus, round cystic area within the myometrium, asymmetrical, inhomogeneous uterus, and myometrial area with decreased echogenicity [44, 45] (Fig. 1).

Fig. 1. US image of adenomyosis

The 2D TVUS imaging of the junctional zone seems to need higher-frequency (5-10 MHz) examination, and sonographic differentiation of the outer-myometrium is not always indicated. It was shown that 3D TVUS coronal sections can help us in distinguishing the junctional zone more clearly, with some post-processing arrangements [46, 47]. The role of power Doppler is to show the difference between myometrial cysts and blood vessels. Moreover, it can show the characteristics of leiomyoma – with a circular flow along the myoma capsule – different from those of the focal adenomyosis – with diffuse spread vessels inside the lesions [48]. The 3D TV sonography of adenomyosis involves specific features, obtained from assessing the junctional zone on a set volume in a coronal image. The junctional image appears hypoechoic around the [49]. In order to better see a multiplanar images, volume contrast imaging (VCI) with 2-4 mm slices can be used, including the anterior and posterior junctional zones. The important image which can be seen is the infiltration of hypoechoic junctional zones by hyperechoic endometrial tissues. Usually, the objective parameters of the junctional zone thickness can be seen as an anormal image [50]. The 3D scan may be used, therefore, to measure the thickness, by using VCI – in which the higher (maximal junctional zone thickness ¼ JZ max), and the lowest (minimal thickness of the junctional zone ¼ JZ min) diameters of the junctional zone can be measured [50]. When the junctional zone thickness is altered, an infiltration of the hypoechoic inner myometrium by hyperechoic endometrial tissue can be seen. Some studies have shown that both sensitivity and specificity of 2D TV scan are comparable with those of MRI, ranging 75%-88% and 67%-93%, respectively [51-53]. In general, MRI shows features of the junctional zone measurements, and 2D US helps finding the alterations of outer myometrium, such as hypertrophy or cystic zones. The 2D TVUS assessment of the junctional zone seems to have an insignificant impact on the adenomyosis diagnosis [45]. The same study showed that the 2D TVUS junctional zone assessment had a low sensitivity (46%) but a high specificity (82%) [45].

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Therefore, the non-invasive imaging, like TVUS in the diagnosis of women with pelvic endometriosis and adenomyosis, showed to be of real help. Moreover, 3D TVUS seems to be more precisely than 2D TVUS in order to detect the junctional zone, especially in earlier stages and for further counselling and treatment [54]. Therefore, the newer improved US techniques, including 3D and VCI, can help us to obtain an earlier diagnosis [55, 56].

4. Conclusions

For a better understanding of the adenomyosis features, TVUS represent the first line in achieving an earlier diagnosis. In the majority of cases, the technique can offer a precise diagnosis, especially when 3D coronal images and volume contrast imaging are obtained. Therefore, the correlation of the pathophysiology and US findings may be an important task in achieving the diagnosis of adenomyosis, before an early treatment may be instituted.

REFERENCES

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[37] Popp, LW, Schwiedessen, JP, Gaetje, R. (1993). Myometrial biopsy in the diagnosis of adenomyosis uteri. Am J Obstet Gynecol 169, pp. 546-549. [38] Ascher, SM, Arnold, LL, Patt, RH, et al., (1994). Adenomyosis: prospective comparison of MR imaging and transvaginal sonography. Radiography 190, pp. 803-806. [39] Seidman, JD, Kjerulff, KH. (1996). Pathological findings from the Maryland Women’s Health Study- practice patterns in the diagnosis of adenomyosis. Int J Gynecol. Pathol 15, pp. 217-221. [40] Penciu, RC, Steriu, L, Izvoranu, S, Postolache, I, Tica, AA, Mocanu, D, Tica, OS, Sarbu, V, Deacu, M, Baltatescu, G, Tica, I, Petcu, L, Tica, VI. (2019). CD10, CD34 and Ki67 immunohistochemical markers expression in endometriosis and adenomyosis. REV CHIM 70(4), pp. 1323-1327. [41] Reinhold, C, Atri, M, Mehio, A, Zakarian, R, Aldis, AE, Bret, PM. (1995). Diffuse uterine adenomyosis: morphologic criteria and diagnostic accuracy of endovaginal sonography. Radiology 197(3), pp. 609-614. [42] Wong, L, White, N, Ramkrishna, J, Araujo Júnior, E, Meagher, S, Costa, FS. (2015). Three-dimensional imaging of the uterus: the value of the coronal plane. World J Radiol 7(12), pp. 484-493. [43] Nemescu, D, Berescu, A, Onofriescu, M, Navolan, DB, Rotariu, C. (2015). Safety indices during fetal echocardiography at the time of first-trimester scan are machine dependent. PLoS ONE 10(5), pp. e0127570. doi: 10.1371/journal.pone.0127570. [44] Vandermeulen, L, Cornelis, A, Kjaergaard Rasmussen, C, Timmerman, D, Van den Bosch, T. (2017). Guiding histological assessment of uterine lesions using 3D in vitro ultrasonography and stereotaxis. Facts Views Vis Obgyn 9, pp. 77e84. [45] Kepkep, K, Tuncay, YA, Goynumer, G, et al., (2007). Transvaginal sonography in the diagnosis of adenomyosis: which findings are most accurate? Ultrasound Gynecol. Obstet. 30, pp. 341-345. [46] Exacoustos, C, Luciano, D, Corbett, B, et al., (2013). The uterine junctional zone: a 3-dimensional ultrasound study of patients with endometriosis. Am J Obstet. Gynecol. 209, pp. 248-255. [47] Naftalin, J, Jurkovic, D. (2009). The endometrial-myometrial junction: a fresh look at a busy crossing. Ultrasound Obstet. Gynecol. 34, pp. 1-11. [48] Chiang, CH, Chang, MY, Hsu, JJ, et al., (1999). Tumour vascular pattern and blood flow impedance in the differential diagnosis of leiomyoma and adenomyosis by colour Doppler sonography. J Assisted Reprod Genet 16, pp. 268-275. [49] Exacoustos, C, Brienza, L, Di Giovanni, A, et al., (2011). Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet. Gynecol. 37(4), pp. 471- 479. [50] Exacoustos, C, Brienza, L, Di Giovanni, A, et al., (2011). Adenomyosis: three-dimensional sonographic findings of the junctional zone and correlation with histology. Ultrasound Obstet. Gynecol. 37, pp. 471-479. [51] Dueholm, M, Lundorf, E. (2007). Transvaginal ultrasound or MRI for diagnosis of adenomyosis. Curr Opin Obset. Gynecol. 19, pp. 505-512. [52] Bazot, M, Cortez, A, Darai, E, et al., (2001). Ultrasonography compared with magnetic resonance imaging for the diagnosis of adenomyosis: correlation with histopathology. Hum Reprod 16, pp. 2427-2433. [53] Dueholm, M, Lundorf, E, Hansen, ES, et al., (2001). Magnetic resonance imaging and transvaginal ultrasonography for diagnosis of adenomyosis. Fertil Steril 76, pp. 588-594. [54] Lazzeri, L, Di Giovanni, A, Exacoustos, C, Tosti, C, Pinzauti, S, Malzoni, M, et al., (2014). Preoperative and Postoperative clinical and transvaginal ultrasound findings of adenomyosis in patients with deep infiltrating endometriosis. Reprod Sci 21, pp. 1027e33. [55] Gordts, S, Brosens, JJ, Fusi, L, Benagiano, G, Brosens, I. (2008). Uterine adenomyosis: a need for uniform terminology and consensus classification. Reprod Biomed Online 17, pp. 244e8. [56] Votino, A, Van den Bosch, T, Install_e, AJ, Van Schoubroeck, D, Kaijser, J, Kacem, Y, et al., (2015). Optimizing the ultrasound visualization of the endometrial-myometrial junction (EMJ). Facts Views Vis Obgyn 7, pp. 60e3.

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Gestational Trophoblastic Disease – The Border Between Benign and Malignant

BĂLAN Andreea1, CASAP Stela1, DIMIENESCU Oana Gabriela1, MOGA Marius Alexandru1, BAGAN Gabriela2

1 Department of Medical and Surgical Specialities, Faculty of Medicine, Transylvania University of Brasov (ROMANIA) 2 Clinical Hospital of Obstetrics and Gynaecology “Dr. I.A. Sbarcea”, Brașov (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Introduction Gestational trophoblastic disease (GTD) includes a broad spectrum of pathologies that originate from the trophoblastic cells. The most representative subtypes of GTD are hydatiform mole and choriocarcinoma. Although this trophoblastic condition might count as a rare pathology, the global incidence varies from 23 to 1300 at 100.000 cases, depending on the geographic area. The purpose of this paper was to assess the incidence and the management of the disease.

Methodology We are presenting a retrospective study of the last five years (January 2014-December 2018), which includes all the cases diagnosed in the Clinical Hospital of Obstetrics and Gynaecology “Dr I.A. Sbarcea” Brasov. The study evaluates the incidence of the pathology and the associated features of the cases, such as age, personal and familial records, rural versus urban environment, and the subtype of the GTD.

Results We recorded a total of 34 patients, with hydatidifrom mole and choriocarcinoma, with ages between 13 and 69. Within the study group, there was found a higher incidence of hydatidiform mole in patients under 40 years old and a higher incidence of choriocarcinoma in patients above 40 years old. A higher incidence of the disease was found in women with obstetrical antecedents, such as recurrent abortion or ectopic pregnancy. When it comes to the therapeutic strategies, the most used method was uterine curettage, total hysterectomy being practiced by assessing many factors, including the desire of the woman to preserve their reproductive function.

Conclusions GTD is a very complex pathology sharing both malignant and benign features, as the diagnosis and management become challenging. Extreme ages and low incomes tend to be contributory factors to those subtypes of the disease, and the treatment needs to be led by a multidisciplinary team, including the gynaecologist, oncologist, and pathologist.

Keywords: Trophoblastic gestational disease, hydatiform mole, choriocarcinoma, obstetrical antecedents, molar pregnancy

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Introduction

A woman life stages are based on her reproductive cycle [1]. Gestational trophoblastic disease (GTD) represents a group of pathologies, originated from the trophoblastic cells, which can affect women of all ages. Few days after conception, a zygote develops into a blastocyst. The outer layer of the blastocyst consists of trophoblastic cells which will invade the endometrium and the uterine blood vessels [2]. When the proliferation and invasion mechanisms are poorly controlled, the trophoblastic cells can determine a rare complication of pregnancy, known as hydatidiform mole (partial or complete) [3], [4]. Histologically, there is a dynamic proliferative process that involves the fetal chorion, which evolves to invasive mole and choriocarcinoma. Therefore, a benign hydatidiform mole can persist or develop into a malignant form. The hydatidiform mole precedes the invasive mole and 50% of the choriocarcinomas [2]. The hydatidiform mole is represented by the proliferation of the trophoblast and the hydropic thickening of chorionic villi, with no detectable myometrium or blood vessels invasion. On the other hand, the invasive mole (chorioadenoma destruens) invades the myometrium, although is rarely metastatic [3]. Complete mole is associated with particular elevated beta HCG levels (>100.000 UI/L), which suggest the diagnosis. The partial mole presents with beta HCG levels that are accepted as normal in a pregnancy [5]. Harma et al., [6] reported that complete hydatiforme mole is characterized by increased reactive oxygen species, being similar with ovarian carcinoma [7] or other malignant conditions. Choriocarcinoma is a malignant tumour of the trophoblastic tissue. The myometrium and the blood vessels are invaded by haemorrhagic and necrotic areas [8]. Trophoblastic cells are invading healthy tissue and spread into the lungs, brain, liver, pelvis, vagina, spleen, bowel a kidney [3]. Sun et al., [9] reported a rare case of choriocarcinoma sellar region metastasis. Clinical symptoms included the loss of binocular eyesight acuity, bilateral temporal hemianopsia, and laboratory data revealed increased values of prolactin and β-human chorionic gonadotropin, severe hyponatremia (serum sodium <135 mmol/L) [10]. The hydatidiform mole has an incidence of 1/1000-2000 pregnancies in the USA, leading to a malignant transformation in 6% to 19% of cases. A complete mole occurs in 1 out of 40 molar pregnancies, 1 in 15.000 abortions and 1 in 150.000 normal pregnancies. Choriocarcinoma is associated with a history of mole (50% of cases), abortion (25%), term delivery (20%) and ectopic pregnancy (5%) [11], [12]. Early diagnosis is crucial in order to improve the mortality and morbidity of the patients, being comparable to the role of the prenatal diagnosis of fetal anomalies [13]. The aim of this paper is to evaluate of the incidence, symptomatology and the therapeutic strategies of GTD. Secondary objectives are to highlight the evolution assessment of the hydatidiform mole and its transformation potential into choriocarcinoma, in patients with relevant obstetrical history, such as abortion, ectopic or molar pregnancies.

Methodology

We are presenting a retrospective study on a period of five years (January 2014-December 2018), which includes all the cases of GTD diagnosed and treated in the Clinical Hospital of Obstetrics and Gynaecology “Dr I.A. Sbarcea” Brasov. The study includes 34 patients aged between 13 and 69 years. In order to establish the diagnosis, we used transvaginal ultrasound, which is currently accepted as the most accurate diagnosis tool in many gynaecological disorders [14]. The absence of the fetal heart activity at 6-7 weeks of gestation suggests a pathological

31 ©Filodiritto Editore – Proceedings pregnancy and the diagnosis is established when the hydropic degeneration of chorionic villi determine “cluster of grapes” or “snow-storm” images. The parameters that we analysed in our study were: patient age, body mass index, living environment, gynaecological and obstetrical antecedents (recurrent abortion, preterm deliveries, total number of deliveries, ectopic pregnancy). The results have been analysed and interpreted using Microsoft Office Excel 2010.

Results

From 2014 to 2019, 34 cases of GTD have been identified, including hydatiform mole and choriocarcinoma. There was a total number of 26 patients (76.47%) with hydatidiform mole and 8 patients (23.53%) with choriocarcinoma. The majority of patients were under 18 years old, which represents 42.31% of the subjects diagnosed with hydatiform mole, corresponding to 11 patients. This group is followed by the group of patients aged between 25 and 35 years old, which include 6 patients (23.08% of cases). The 18 to 25 years old group included 5 patients (19.23% of cases) and the group with ages above 30 years old included 4 patients, representing a percentage of 15.38%. The minimal age was 13 years old and the maximum age was 47.

15,38% 42,31% 23,08% <18 years old 18-25 years old 25-35 years old 19,23% >35 years old

Fig. 1. The distribution of the cases with hydatidiform mole by age

More than a half of patients with choriocarcinoma were above 50 years old (62.50%). The minimum age was 19 and the maximum was 69 years old. There has been noticed the predominance of benign pathology in patients under 18 years old, with no patient with choriocarcinoma. The high incidence has been found in women above 40 years old.

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37.50% 62.50% >50 years old 62.50% <50 years old 37.50%

Fig. 2. The distribution of the cases with choriocarcinoma by age

Other criteria that we analysed in our study was represented by demographic areas of the subjects. From the total number of patients, 21 cases were originating from rural areas and 13 patients were originating from urban areas.

Table 1. The distribution of the cases with hydatidiform mole and choriocarcinoma by the demographic area Rural Urban Hydatidiform mole 16 patients (61.4%) 10 patients (38.46%) Choriocarcinoma 5 patients (51.61%) 3 patients (48.39%)

The distribution by weight was made by assessing the Body Mass Index (BMI) values. The majority of the patients (23 cases, representing 68%) were within the range on a normal BMI (20- 20,9). Nine of the patients (26%) were overweight (BMI=25-29.9) and 2 cases were obese (BMI>30). Almost a half of the study cases did not present significant pathological antecedents (46.15%). Four patients (15.38%) presented recurrent miscarriages, suggesting a potential connection. Another group of 4 patients had a caesarean section in the past. A group of 3 patients presented endocrinological disorders and 2 patients had ectopic pregnancies. A small group of 3.85% were represented by the women with uterine leiomyomas.

7,69% 11,54% No antecedents 3,85% 46,15% Uterine scar Repeated miscarriage 15,38% Uterine leiomyomas Autoimmune tiroiditis Ectopic pregnancy 15,38%

Fig. 3. The distribution of the patients with hydatiform mole by pathological history

Out of the patients with choriocarcinoma, 5 (62.50%) presented no antecedents, while 2 patients (25%) had recurrent spontaneous abortions. The last group is represented by one patient (12.5%) with recurrent spontaneous abortions and a hydatidiform mole history at the age of 12.

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12.50% No antecedents 25% 62.50% Recurrent abortion

Antecedents of hydatidiform mole

Fig. 4. The distribution of the patients with choriocarcinoma by pathological history

Regarding the symptomatology of GTD, the most common causes of presentation to the doctor was pelvic pain, elevated beta-HCG levels, and minimal to abundant metrorrhagia. In women with choriocarcinoma, the most common cause of showing up to the doctor was abundant metrorrhagia after menopause (5 patients-65.50%), pelvic pain and heavy bleeding (2 patients or 25%) and an abnormal ultrasound exam (1 patient-12.50%). Considering the parity, we observed that nulliparous had a higher incidence of hydatidiform mole in comparison with multiparous (15 patients-62.50%). Following this, the rest of the cases had at least one vaginal delivery or caesarean section. In case of the choriocarcinoma, the incidence was higher in multiparous than nulliparous, with 7 patients that had at least on delivery. From a total of 26 patients with hydatidiform mole, in 17 (65.38% of cases) of them an evacuatory and haemostatic uterine curettage was performed. From them, 3 patients (11.54%) needed antibiotic therapy, and 4 of the cases (15.38%) needed a secondary curettage. Only 2 patients (3.85%) had more complicated evolutions. First patient was diagnosed with uterine polyfibromatosis and needed repeated myomectomies and evacuatory hysterotomies. The second patient had ineffective haemostasis, and because it was an elderly woman, total hysterectomy with bilateral salpingo-oophorectomy (THSO) was performed, although a hysterectomy is rarely practiced for a benign mole. Most patients with choriocarcinoma (5 patients or 62.50%) underwent THSO. The decision was made based on the complications and the desire to not maintain the reproductive function, the majority of women with choriocarcinoma being postmenopausal. Three groups including one subject had different approaches. The first patient had a uterine curettage followed by chemotherapy. The second women were a young patient, who wanted to conserve its reproductive function, and chemotherapy represented the therapeutic tool in its case. The third patient had a total hysterectomy with ovarian conservation.

Discussions

Different studies have reported a wide geographical variation in the incidence of the trophoblastic disease, throughout the world [8]. The incidence was reported as being greatest in underdeveloped areas of the world, in parts of Africa, Asia and Latin America, and significantly lower in Europe, North America and Australia [15], [16]. Smith et. al confirmed a higher incidence among Hispanic migrants in New Mexico, mostly of them having a precarious life style [17], [18]. Some authors associated this pathology with a poor protein diet, folic acid deficiency and a potential role of vitamin A deficiency was also mentioned [19]. Our study showed a higher

34 ©Filodiritto Editore – Proceedings incidence of the GTD in rural settlements of Brasov County. Rural areas of Romania registered alarming values of At-risk-poverty rate, with up to 15.7% differences, in comparison with the countries with the highest standards of living from European Union [20]. The relation between the parity and the risk of GTD development was evaluated in other studies, with comparable results. In a study which included 1228 women with GTD, 19.5% were multiparous, 28.4% were primiparous and 52.1% were nulliparous [21]. Goldstein et al., conducted a study to determine the risk factors for GTD. The investigators pointed out that 18.4% of the women with spontaneous abortion in antecedents, 3.4% of the women with therapeutic abortion and 0.8% of the women with an ectopic pregnancy in the past developed GTD [22]. The risk factors for GTD highlighted by Donald et al., were comparable with our results, with a higher incidence of the abortion and a lower incidence of the ectopic pregnancies. Regarding the treatment strategy, in our study the majority of patients undergone uterine curettage (65.38%) and most of the women with choriocarcinoma had THSO (62.50%). Other studies support THSO in women that no longer desire a future pregnancy [23]. Osborne and collab. Reported a similar therapeutic approach as in our study, their study results showing that a second curettage was found to cure 40% of 60 women without significant morbidity [24]. The current study was an attempt towards understanding the incidence, demographic distribution, clinical presentation, treatment strategies and their clinical correlation with GTD in the Clinical Hospital of Obstetrics and Gynaecology “Dr I.A. Sbarcea” Brasov. More studies are needed on larger number of patients in order to better understand the risk factors and the best management strategies for improving the quality of life of the patients with GTD.

Conclusions

GTD is a very complex pathology sharing both malignant and benign characteristics. The diagnosis and the management are often challenging. Extreme ages and low incomes tend to be contributory factors of the disease development. The hydatidiform mole had a higher incidence in patients under 15 years old (42.31%) and choriocarcinoma had a higher incidence (62.50%) in older women. The women with obstetrical antecedents seem to have a higher incidence of benign mole, 15.38% of the patients having at least an abortion. In women with choriocarcinoma, there was a rate of 25% of recurrent miscarriages in antecedents. More data are needed in order to establish a connection between uterine leiomyomas and the incidence of GTD. The BMI did not seem to have a relevance in ethiology of the disease. When it comes to the numbers of deliveries, nulliparous had a higher incidence of GTD than multiparous (62.50% versus 37.50%). Regarding the therapeutic strategies, the majority of patients with benign mole had a single uterine curettage (65.38%), while 15.38% had more than one curettage for uneffective haemostasis. In the cases of the patients with choriocarcinomas, THSO was practiced in 5 cases (62.50%). The women at reproductive age who wanted a future pregnancy, had uterine curettage followed by chemotherapy and a careful monitoring. The diagnosis and the treatment of GTD needs to be led by a multidisciplinary team, including the gynaecologist, oncologist, and pathologist. We consider that larger cohorts and longer periods of study are necessary in order to establish the influence of different factors on the incidence and evolution of this pathology.

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REFERENCES

[1] Balan, A., Moga, M.A., Dima, L., Toma, S., Neculau, A.E., Anastasiu, C.V. (2020). Royal Jelly-A Traditional and Natural Remedy for Postmenopausal Symptoms and Aging-Related Pathologies. Molecules. 25 (14), p. 3291. [2] Hoffman, B. L., Schorge J. O., (2015). Williams Gynaecology, pp. 898-912. [3] Munteanu, I. (2000). Tratat de obstetrică Editura Academia Română, pp. 983-1000. [4] Stanescu, A. D., Banica, R., et al., (2018): Low dose aspirin for preventing fetal growth restriction: a randomised trial. J Perinat Med, 46(7), pp. 776-779. [5] Petignat, P., Billieux, M. H., Blouin, J.L, Dahoun, S., Vassilakos, P. (2003). Is genetic analysis useful in the routine management of hydatidiform mole. Hum Reprod, 18(2), pp. 243-9. [6] Harma, M., Harma, M., Erel, O. (2003). Increased oxidative stress in patients with hydatiform mole. Swiss Med Week. 133, p. 4142. [7] Trifanescu, O., Gruia, M.I., Gales, L., Trifanescu, R., Pascu, A.M., Poroch, V., Toma, S., Poiana, C., Anghel, R. (2019). Malondialdehyde as a Prognostic Marker in Patients with Ovarian Adenocarcinoma. Rev Chim. 70 (7), pp. 2561-2565 [8] Savage, J., Adams, E., Veras, E., Murphy, K.M., Ronnett, B.M. (2017): Choriocarcinoma in Women. Am J Surg Pathol, 41(12), pp. 1593-1606. [9] Sun, J., Huang, Y. (2015). One case of choriocarcinoma seller region metastasis and literature review. Chinese Neurosurg J, p. 16. [10] Trifanescu, R.A., Soare, D., Cirstoiu, C., Popescu, G., Pascu, A.M., Poroch, V., Toma, S., Poiana, C. (2018). Mild Chronic Hyponatremia and Osteoporctic Fractures Risk in Elderly. Rev Chim. 69 (12), pp. 3520-3523. [11] Lurain, J. R. (2010): Gestational trophoblastic disease: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet. and Gynecol., 203(6), pp. 531-39. [12] Eysbouts, Y. K., Bulten, J., Ottevanger, P.B., Thomas, C.M.G., Ten Kate-Booij, M.J., van Herwaarden, Siebers, A.G., Sweep, F.C.G.J., Massuger, L.F.A.G. (2006): Trends in incidence for gestational trophoblastic disease over the last 20 years in a population-based study. Gynecol. Oncol, 140(1), pp. 70-75. [13] Ples, L., Sima, R. M., Stanescu, A. D., Olaru, O. G., (2017). The Importance of a National Congenital Anomalies Registry – the Role of the Prenatal Diagnosis, pp. 505-510. [14] Pleş, L., Sima, R. M., Burnei, A., Albu, D. F., Bujor, M.A., Conci, S., Teodorescu, V., Edu, A. (2018): The experience of our Clinic in laparoscopy for adnexal masses and the correlation between ultrasound findings and pathological results. Rom J Morphol Embryol, 57(4), pp. 1337-1341. [15] Berkowitz, R. S., Goldstein, D. P. (2002): Gestational trophoblastic neoplasm. Berck JS, pp. 1353-74. [16] Aziz, M. F., Kampono, N., Moigni, E. M. (1984): Epidemiology of gestational trophoblastic neoplasia at the Dr. Cipto Mangukusmo Hospital Jakarta, Indonesia. Adv Exp Med Biol, 176, pp. 165-75. [17] Flam, F., Lundstrom-Lindstedt, V., Rutqvist, L. E. (1992): Incidence of gestational trophoblastic disease in Stockholm County, 1975-1988. Eur. J. Epidemiol, 8(2), pp.173-177. [18] Smith, H. O., Hilgers, R. D., Bedrick, E. J., Qualls, C.R., Wiggings, C.L., Rayburn, W.F., Waxman, A.G., Stephens, N.D., Cole, L.W., Swanson, M., Key, C.R. (2003): Ethnic differences at risk for gestational trophoblastic disease in New Mexico: a 25-year population-based study. Am. J. Obstet. Gynecol. 188(2), pp. 357-366. [19] Kokanali, M. K., Öztürkkan, D., Unsal, N., Moroy, P., Gungor, T., Mollamahmutoglu, L. (2008). Plasma homocysteine, vitamin B12 and folate levels in hydatidiform moles and histopathological subtypes. Arch Gynecol Obstet. 278(6), pp. 531-534. [20] Ulman, S. R., Dobay, K. M. (2020): Ptential Solutions for rural poverty in Romania through educational and entrepreneurial improvements. J. Publ. Adm. Finance Law, 17. [21] Braga, A., Biscaro, A., Melgarejo do Amal Giordani, J., Viggiano, M., Elias, K.M., Berkowitz, R.S., Seckl, M.J. (2018): Does a human chorionic gonadotropin level of over 20,000 IU/L four weeks after uterine evacuation for complete hydatidiform mole constitute an indication for chemotherapy for gestational trophoblastic neoplasia? Eur. J. Obstet. Gynecol. Reprod. Biol. 223, pp. 50-55. [22] Horowitz, N. S., Goldstein, D. P., Berkowitz, R.S. (2017): Placental site trophoblastic tumours and epithelioid trophoblastic tumours: Biology, natural history, and treatment modalities. Gynecol. Oncol. 144(1), pp. 208-214. [23] Elias, K. M., Goldstein, D. P., Berkowitz, R. S. (2010): Complete hydatidiform mole in women older than age 50. J Reprod Med. 55, pp. 208-212.

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[24] Osborne, R. J., Filiaci, V. L., Schink, J.C., Mannel, R.S., Behbakht, K., Hoffman, J.S., Spirtos, N.M., Chan, J.K., Tidy, J.A., Miller, D.S. (2016): Second curettage for low-risk nonmetastatic gestational trophoblastic neoplasia. Obstet. Gynecol. 128, p. 535.

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Ovarian Endometrioma Rupture During Pregnancy – A Rare Complication? Case Presentation and Review of the Literature

BĂLAN Andreea1, MOGA Marius Alexandru1, BÎGIU Nicușor Florin1, PODAȘCĂ Cezar1, ALDEA Florina2, MANEA Rosana Mihaela1

1 Department of Medical and Surgical Specialities, Faculty of Medicine, Transylvania University of Brasov (ROMANIA) 2 Clinical Hospital of Obstetrics and Gynaecology “Dr. I.A. Sbarcea”, Brașov (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Introduction Ovarian are benign tumours that modify their morphology and evolve differently during pregnancy, making from these cases a real subject of interest. The present study will present a case of ovarian endometrioma diagnosed in the first trimester of pregnancy, focusing on the complications and the management of the patient. We compared our results to those from the literature, following a thorough revision of the past studies.

Materials and methods We identified a rare case of ovarian endometrioma developed by a pregnant woman. Serial ultrasound examinations were performed and correlated with serum concentrations of Carbohydrate Antigen 125 (CA-125) and Human Epididymis protein 4 (HE4). This study also included 20 other studies from the literature regarding the natural history, diagnosis, and management of ovarian endometriomas in pregnancy.

Results The pregnant woman, aged 33, primigesta, was diagnosed in the first trimester of pregnancy with an of 5 cm. The ultrasound examination suggested an ovarian endometrioma, but no other symptoms were recorded. During the first trimester of pregnancy, the tumour increased its dimensions. Serum concentrations of CA-125 and HE4 were initially constant, but the levels increased proportionally with the cysts’ dimensions. At 15 weeks of gestation, transvaginal ultrasound examination revealed a 7 cm ovarian tumour and free intraperitoneal fluid. The patient was admitted to the hospital for acute surgical abdomen. The patient underwent surgery, and a ruptured ovarian endometrioma was identified. A cystectomy was performed. The clinical and paraclinical evolution was favourable, and the pregnancy reached the term. The histopathological exam confirmed the diagnosis and decidual transformation was also observed.

Conclusion The progesterone during pregnancy usually shrinks the ovarian endometriomas. In the reported case, the increase of the endometrioma size might be due to serum levels of CA-125 and, especially of HE4 – which ensures the differential diagnosis with malignant tumours. The rupture of endometriomas during pregnancy is an infrequent complication. Their growth, which is an atypical phenomenon, predisposes to other acute complications.

Keywords: endometrioma, CA-125, HE4, pregnancy

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Introduction

Endometriosis is a gynaecological pathology characterized by the presence of ectopic endometrial stroma and glands. This pathology affects approximately 10% of the fertile females worldwide [1-4]. This condition is characterized by local inflammation, which leads to infertility and chronic pelvic pain, and lowers the quality of life of the patients. Multiple mechanisms are involved in the pathogenesis of endometriosis, including endocrine imbalance, immunologic mechanisms consisting of a chronic inflammatory response and molecular mechanisms. The latest consist of the abnormal implantation of endometriotic tissue. The neuro-somatic mechanism is considered to be responsible for the chronic and often refractory pain. The changes in the hormonal profile and the molecular aberrations cause significant changes in the normal endometrial tissue. All these changes are leading to defective decidualization and abnormal placentation, in case of pregnancy [5-7]. Ovarian endometriomas account for approximately 40% of the cases with endometriosis [8, 9]. Endometriomas can be easily diagnosed via ultrasound examination as adnexal masses with characteristic appearance [10, 11]. During pregnancy the endometrium becomes hypertrophic, due to the high-progesterone status, and this process is known as decidualization. Similar to the eutopic endometrium, the endometriotic foci suffer the decidualization process, and these foci are characterized by increased vascularisation and neoangiogenesis. Neoformation vessels appear as vascular nodules placed inside the endometrial implants [12]. An interesting and controversial subject is represented by the evolution of the ovarian endometriomas during pregnancy [13]. One of the reasons is that a remission of endometriosis is expected once with gestation due to the hormonal shift to progesterone dominance. On the other hand, pregnancy may lead to a modified ultrasound appearance, making the diagnosis a great challenge for the physicians [14]. The image of a decidualized endometrioma may mimic an ovarian malignancy [15-24]. The appearance of the solid nodules inside the , may suggest an ovarian cancer, which is nowadays the second cause of gynaecological cancer-associated death and the third cause of gynaecological cancer [25]. About 2.8% of the ovarian tumours diagnosed during pregnancy are malignant [26], and endometriosis itself represents a risk factor for ovarian neoplasia. For this reason, complementary imaging tools should be used. In most cases, the positive diagnosis of ovarian endometriomas is anatomopathological, secondary to surgical removal. Complex tumoral masses of the adnexa, which develop during pregnancy, represent a big challenge for the physicians regarding the proper management. Nuclear magnetic resonance (MRI) gives a broad perspective and helps in choosing the most suitable treatment for each patient. Routine ultrasound has increased the detection rate of the adnexal masses during the first trimester of pregnancy when the ovaries and the fallopian tubes can still be examined [25]. Ovarian endometriotic cysts count for approximately 11% of the adnexal tumours [14]. Despite it is an unusual event, the progression of endometriosis to ovarian cancer is sometimes possible. The symptomatology is unspecific and may consist of bloating, abdominal pain, gaining or wasting weight, swelling of the legs, or pain in the legs. Because ovarian malignancy is usually a pathology of the elderly population, the symptoms of endometriosis-related ovarian cancer may be confounded with other conditions characteristic for this period, such as neuropathic pain, hyponatremia, osteoporosis, dyslipidaemia, etc. [28].

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CASE REPORT

A 33-years-old primigravida, diagnosed with endometriosis, attended a routine transvaginal ultrasound examination during the first trimester of pregnancy. An ovarian cyst of 47x51 mm was discovered. The echographic appearance has raised the suspicion for an ovarian endometrioma, despite clinical symptomatology was missing. By the end of the first trimester of gestation, the ovarian tumour increased in size. Serial ultrasound examinations reported a healthy fetus with normal development. In the context of the presence of an adnexal mass, the serum concentration of Carbohydrate Antigen 125 (CA-125) and Human Epididymis protein 4 (HE4) were measured. The values of CA-125 and HE4 recorded a continuous rise, proportionally with the ovarian cysts’ dimensions. At 15 weeks of gestation, the patient addressed the hospital accusing acute abdominal pain with sudden onset and lipothymic state. Its blood pressure was 75/56 mmHg, and she had pale skin and sweats. The transvaginal ultrasound revealed a 68x72 mm ovarian tumour, free intraperitoneal fluid and the level of CA-125 was 84 U/ml. The appearance of the mass was resembling a cyst with irregular contour, fluid-filled with a “ground glass” pattern. After the clinical and paraclinical examination, the pregnant underwent emergency surgery for a ruptured ovarian cyst. Intraoperative it was discovered a ruptured ovarian endometrioma, and approximately 400 mL of blood and cystic content. The management consisted of the removal of the ovarian cyst and peritoneal cavity lavage. The evolution of both patient and fetus was favourable, followed by an uneventful pregnancy. The patient underwent a caesarean section at 37 weeks and 4 days of gestation. A healthy female of 3120 g was extracted, with an Apgar score of 10. Both mother and new-born were discharged on day 3. The histopathological exam (haematoxylin-eosin stain) revealed a decidualised haemorrhagic cyst, lined with endometrial stroma and large regions of inflammation and hemosiderin-laden macrophages. The peritoneal cytology was negative for malignant cells.

Fig. 1. Ultrasound aspect of the ovarian cyst Fig. 2. Ruptured endometriotic ovarian cyst

Discussions and Literature Review

In order to have a clearer image of the prevalence and the management strategies of the ovarian endometriosis during pregnancy, we performed a systematic research of the literature. The research was performed using Google Academic and PubMed databases. All the studies on this topic from the last 10 years were included. After the first research, 20 articles that fitted our inclusion criteria were found. We used the key words endometrioma, CA-125, HE4, pregnancy.

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All the studies on this topic conducted in the last 10 years have shown an increased incidence of pregnant women with decidualized endometriomas. Furthermore, it has been reported a higher endometriosis prevalence in the last decades. The cases were classified either by their ultrasound appearance, by the serum levels of CA-125 and HE4, therapeutic management, natural history of the adnexal masses during pregnancy and by the pregnancy outcomes and foetal impact. The studies that we included in our review were reported cases from Asia, Europe and United States (U.S.), reflecting the global spread of this pathology and its association with pregnancy. Rozalli et al., [29] presented a case of a 22-year-old gravida diagnosed with an ovarian mass at 12 weeks of gestation. Although ultrasound examination is able to indicate the benign character of the ovarian tumours diagnosed during pregnancy, many of the echographic findings remain nonspecific. Because nonspecific ultrasonographic characteristics could not be considered for positive diagnosis, a secondary imagistic tool is required. MRI is considered a safe investigation during pregnancy, with no impact on the foetal wellbeing and development. In these conditions, it is the following step to establish the nature of the ovarian tumour. Both decidualized endometrium and decidualized endometrioma share the same aspects regarding the texture and appearance [20]. The need for complementary exanimations was to exclude the malignant nature of the ovarian cyst. The malignant tumours appear to have an intermediate signal intensity on T2 weighted imaging. The outcome of the patient whose case was reported by Rozalli et al., was similar with the evolution of our patient. At 15 weeks of gestation, the woman undergone an emergency surgery for the rupture of the endometrioma, suggested by acute abdomen symptoms. In addition, left salpingo-oophorectomy was performed due to the massive bleeding, in order to provide a proper haemostasis. Taylor et al., [30] reported 27 cases of women with decidualized endometriomas. They established that asymptomatic endometriomas in pregnancy require surgical management only if malignancy is suspected or the endometriotic cysts appear to be either ruptured or infected. Most of the endometriomas decrease in size after delivery due to the progesterone dominance, which falls down. However, if the surgical management is mandatory, the recommended time span in which surgery is safe for the foetus is the second trimester of pregnancy, between 12 and 16 weeks of gestation, in order to minimize the risks of miscarriage or foetal malformations [31, 32]. For the evaluation was use the “risk of malignancy index” that gathers the ultrasonographic characteristics, the levels of CA-125 and the fertile status of the patient [33]. Other studies reported extra-ovarian decidualized endometriomas located on the skin, on the caesarean scar or episiotomy incision, on breasts, lungs, diaphragm, bowel, peritoneum, abdominal wall, bladder or rectum. During pregnancy, the lesions become hypertrophic due to the high levels of progesterone, and undergo decidualization [34, 35]. A more recent study conducted by Adhikari and Shen reported peritoneal endometriosis resembling carcinomatosis [36]. Leone Roberti Maggiore et al., explained in his study the mechanisms through which endometriosis can complicate the pregnancy. The first complication is represented by post- inflammatory adhesions, which create a tension between the intraperitoneal organs, leading to abdominal pain, bowel obstruction, bladder malfunction and even intestinal perforation. All of these events can be secondary to an inflammatory status with fibrin deposition, coagulation cascade activation and a massive release of cytokines and pro-inflammatory cells, such as macrophages, growth factors and pro-angiogenic factors [37]. The rupture or perforation of various organs follows the invasion of decidualized endometriotic lesions into the vascular wall, overlaid on the chronic inflammation state that weakens the tissues. Regarding the serum levels of ovarian cancer markers, CA-125 was reported to rise during the first trimester of pregnancy, but it has a lower specificity in early gestation [38]. A recent marker

41 ©Filodiritto Editore – Proceedings for ovarian cancer diagnosis is HE4, which promises to differentiate ovarian tumours with higher sensitivity and specificity than CA-125. Although ROMA score provides the best diagnosis score for epithelial ovarian cancer, it is not feasible for gestational state due to wider fluctuation. In a study from 2017, Lu and collab. have designed an ideal algorithm for ovarian masses, diagnosed or ingrowing during the pregnancy [39]. Nowadays, the research in this field is continuous, and more non-invasive markers are discovered and tested to differentiate endometriosis, a benign pathology, from malignant lesions. In a recent study from 2019, circulating micro-RNA (miRNA) is proposed as a novel non-invasive biomarker for endometriosis diagnosis [40]. One of the well-known causes of infertility in young women, endometriosis, may benefit from various treatment approaches, both pharmaceutical and surgical. The novelty in the management of endometriosis is represented by the use of complementary and alternative medicine, which promotes biomolecules such as phenols and antioxidants [41]. In the literature there are also studies regarding the pregnancy outcome in patients with endometriosis, which obtained a pregnancy following In Vitro Fertilization (IVF). The course of the pregnancies obtained via IVF in women with endometriosis does not seem to be affected by the maternal pathology, especially since recent studies indicated low-dose aspirin administration for the prevention of foetal growth restriction [42], because the pregnancy and the foetus are considered “precious”.

Conclusions

Endometriosis is a gynaecological pathology, characteristic for young women, at reproductive age, with an increasing incidence. The quality of life of the patients is affected in most of the cases by the pelvic pain, with different characteristics, varying from acute pain episodes, to chronic pelvic pain, often resistant to analgesics. The opportunity of conceiving is another important aspect in context of endometriosis, and in some cases, it may complicate the normal course of the pregnancy. The literature presents several cases of ovarian endometriosis and cyst decidualization during pregnancy. During the gestational period, the fluid-filled tumours usually increase in size due to high progesterone level, which promotes a decidual transformation inside of the tumoral ovary. Sometimes, the decidualized endometriomas can mimic ovarian malignancies, and the serum levels of the ovarian markers (CA-125, HE4) also create confusions. These markers are not applicable during pregnancy and in fertile women in general. As the pregnancy continues, some complications may appear, such as the rupture of the endometriomas. This event is the most severe, and it is characterized by acute abdomen symptoms that require surgical management. Concerning the foetal development and outcomes, no the literature nor the present study reported any complications.

REFERENCES

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[5] Brosens, I.A., Fusi, L., Brosens, J.J. (2009) Endometriosis is a risk factor for spontaneous hemoperitoneum during pregnancy. Fertil Steril, 92, pp. 1243-1245. [6] Petraglia, F., Arcuri, F., de Ziegler, D., Chapron, C. (2012) Inflammation: a link between endometriosis and preterm birth. Fertil Steril, 98, pp. 36-40. [7] Viganò, P., Somigliana, E., Panina, P., Rabellotti, E., Vercellini, P., Candiani, M. (2012) Principles of phenomics in endometriosis. Hum Reprod Update, 18, pp. 248-259. [8] Redwine, D.B. (1999) Ovarian endometriosis: a marker for more extensive pelvic and intestinal disease. Fertil Steril, 72, pp. 310-315. [9] Vercellini, P., Fedele, L., Aimi, G., De Giorgi, O., Consonni, D., Crosignani, P.G. (2006) Reproductive performance, pain recurrence and disease relapse after conservative surgical treatment for endometriosis: the predictive value of the current classification system. Hum Reprod, 21, pp. 2679-2685. [10] Moore, J., Copley, S., Morris, J., Lindsell, D., Golding, S., Kennedy, S. (2002) A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet. Gynecol., 20, pp. 630-634. [11] Pleş, L., Sima, R.M., Burnei, A., Albu, D.F., Bujor, M.A., Conci, S., Teodorescu, V., Edu, A. (2016) The experience of our Clinic in laparoscopy for adnexal masses and the correlation between ultrasound findings and pathological results. Romanian J Morphol Embryol, 57(4), pp. 1337-1341. [12] Zaytsev, P., Taxy, J.B. (1987) Pregnancy-associated ectopic decidua. Am J Surg Pathol, 11, pp. 526-530. [13] Asch, E., Levine, D. (2007) Variations in appearance of endometriomas. J Ultrasound Med, 26, pp. 993- 1002. [14] Bromley, B., Benacerraf, B. (1997) Adnexal masses during pregnancy: accuracy of sonographic diagnosis and outcome. J Ultrasound Med, 16, pp. 447-452. [15] Fruscella, E., Testa, A.C., Ferrandina, G., Manfredi, R., Zannoni, G.F., Ludovisi, M., Malaggese, M., Scambia, G. (2004) Sonographic features of decidualized ovarian endometriosis suspicious for malignancy. Ultrasound Obstet. Gynecol., 24, pp. 578-580. [16] Iwamoto, H., Suzuki, M., Watanabe, N., Minai, M., Hirata, S., Hoshi, K. (2006) Case study of a pregnant woman with decidualized ovarian endometriosis whose preoperative findings suggested malignant transformation. Eur J Gynaecol. Oncol, 27, pp. 301-303. [17] Guerriero, S., Ajossa, S., Piras, S., Parodo, G., Melis, G.B. (2005) Serial ultrasonographic evaluation of a decidualized endometrioma in pregnancy. Ultrasound Obstet. Gynecol., 26, pp. 304-306. [18] Machida, S., Matsubara, S., Ohwada, M., Ogoyama, M., Kuwata, T., Watanabe, T., Izumi, A., Suzuki, M. (2008) Decidualization of ovarian endometriosis during pregnancy mimicking malignancy: report of three cases with a literature review. Gynecol. Obstet. Investig, 66, pp. 241-247. [19] Miyakoshi, K., Tanaka, M., Gabionza, D., Takamatsu, K., Miyazaki, T., Yuasa, Y., Mukai, M., Yoshimura, Y. (1998) Decidualized ovarian endometriosis mimicking malignancy. Am J Roentgenol, 171, pp. 1625- 1626. [20] Poder, L., Coakley, F.V., Rabban, J.T., Goldstein, R.B., Aziz, S., Chen, L.M. (2008) Decidualized endometrioma during pregnancy: recognizing an imaging mimic of ovarian malignancy. J Computer Assist Tomograph, 32, pp. 555-558. [21] Takeuchi, M., Matsuzaki, K., Nishitani, H. (2008) Magnetic resonance manifestations of decidualized endometriomas during pregnancy. J Computer Assist Tomograph, 32, pp. 353-355. [22] Tanaka, Y.O., Shigemitsu, S., Nagata, M., Shindo, M., Okamoto, Y., Yoshikawa, H., Itai, Y. (2002) A decidualized endometrial cyst in a pregnant woman: a case observed with a steady-state free precession imaging sequence. Magnetic Resonance Imaging, 20, pp. 301-304. [23] Sammour, R.N., Leibovitz, Z., Shapiro, I., Degani, S., Levitan, Z., Aharoni, A., Tal, J., Lurie, M., Ohel, G. (2005) Decidualization of ovarian endometriosis during pregnancy mimicking malignancy. J Ultrasound Med, 24, pp. 1289-1294. [24] Yoshida, S., Onogi, A., Shigetomi, H., Tsuji, Y., Haruta, S., Naruse, K., Kanayama, S., Noguchi, T., Sakata, M., Furukawa, N. et al., (2008) Two cases of pregnant women with ovarian endometrioma mimicking a malignant ovarian tumour. J Clin Ultrasound, 36, pp. 512-516. [25] Trifanescu, O., Gruia, M.I., Gales, L., Trifanescu, R., Pascu, A.M., Poroch, V., Toma, S., Poiana, C., Anghel, R. (2019). Malondialdehyde as a Prognostic Marker in Patients with Ovarian Adenocarcinoma. Rev Chim. 70 (7), pp. 2561-2565. [26] Whitecar, M.P., Turner, S., Higby, M.K. (1999) Adnexal masses in pregnancy: a review of 130 cases undergoing surgical management. Am J Obstet. Gynecol., 181, pp. 19-24. [27] Balci, O., Gezginc, K., Karatayli, R. et al., (2008) Management and outcomes of adnexal masses during pregnancy: a 6-year experience. J Obstet. Gynaecol. Res, 34, pp. 524-528.

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[28] Trifanescu, R.A., Soare, D., Cirstoiu, C., Popescu, G., Pascu, A.M., Poroch, V., Toma, S., Poiana, C. (2018). Mild Chronic Hyponatremia and Osteoporctic Fractures Risk in Elderly. Rev Chim. 69 (12), pp. 3520-3523. [29] Izza Rozalli, F., Rahmat, K., Fadzli, F., Boylan, C., Deb, P. (2015). Decidualized Ovarian Endometrioma in a Pregnant Woman Mimicking Ovarian Malignancy: Magnetic Resonance Imaging and Ultrasonographic Findings. Iran J Radiol, 12. [30] Taylor, L.H., Madhuri, T.K., Walker, W., Morton, K, Tailor, A., Butler-Manuel, S. (2015) Decidualisation of ovarian endometriomas in pregnancy: a management dilemma. A case report and review of the literature. Arch Gynecol. Obstet., 291, pp. 961-8. [31] Akira, S., Yamanaka, A., Ishihara, T. et al., (1999) Gasless laparoscopic ovarian cystectomy during pregnancy: comparison with laparotomy. Am J Obstet. Gynecol., 180, pp. 554-557. [32] Ples, L., Sima, R.M., Stanescu, A.D., Olaru O.G. (2017) The Importance of a National Congenital Anomalies Registry – the Role of the Prenatal Diagnosis. Proceeding paper for the 5th Romanian Congress of The Romanian Society of Ultrasound in Obstetrics and Gynaecology, pp. 505-510. [33] Moolthiya, W., Yuenyao, P. (2009) The risk of malignancy index (RMI) in diagnosis of ovarian malignancy. Asian Pacific J Cancer Prev., 10, pp. 865-868. [34] Bergqvist, A. (1993) Different types of extragenital endometriosis: a review. Gynecol. Endocrinol, 7, pp. 207-221. [35] Nogales, F.F., Martin, F., Linares, J., Naranjo, R., Concha, A. (1993) Myxoid change in decidualized scar endometriosis mimicking malignancy. J Cutaneous Pathol., 20, pp. 87-91. [36] Adhikari, L.J., Shen, R. (2013) Florid diffuse peritoneal deciduosis mimicking carcinomatosis in a primigravida patient: a case report and review of the literature. Int J Clin Experiment Pathol, 6, pp. 2615- 2619. [37] Anastasiu, C.V., Moga, M.A., Neculau, E., Bălan, A., Scârneciu, I., Dragomir, R.M., Dull, A.M., Chicea, L.-M. (2020) Biomarkers for the Noninvasive Diagnosis of Endometriosis: State of the Art and Future Perspectives. Int J Mol Sci, 21, p. 1750. [38] Bottoni, P., Scatena, R. (2015) The role of CA 125 as tumour marker: biochemical and clinical aspects. Adv Experiment Med Biol., 867, pp. 229‐244. [39] Moore, R.G., Miller, M.C., Eklund, E.E., Lu, K.H., Bast, R.C., Lambert-Messerlian, G. (2012) Serum levels of the ovarian cancer biomarker HE4 are decreased in pregnancy and increase with age. Am J Obstet. Gynecol., 206, pp. 341-347. [40] Moga, M.A., Bălan, A., Dimienescu, O.G., Burtea, V., Dragomir, R.M., Anastasiu, C.V. (2019) Circulating miRNAs as Biomarkers for Endometriosis and Endometriosis-Related Ovarian Cancer – An Overview. J Clin Med, 8, p. 735. [41] Dull, A.M., Moga, M.A., Dimienescu, O.G., Sechel, G., Burtea, V., Anastasiu, C.V. (2019) Therapeutic Approaches of Resveratrol on Endometriosis via Anti-Inflammatory and Anti-Angiogenic Pathways. Molecules, 24, p. 667. [42] Stanescu, A.D., Banica, R., Sima, R.M., Ples, L. (2018) Low dose aspirin for preventing fetal growth restriction: a randomised trial. J Perinat Med, 46(7), pp. 776-779.

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The Role of Neonatal Cranial Ultrasound in the Early Diagnosis of Intracranial Haemorrhage in Preterm Infants Compared to Term New-borns

BOIA Marioara1, BOIA Eugen S6, CIOBOATA Daniela2, NAVOLAN Dan3, VLADAREANU Simona4, VLADAREANU Radu4, ZAHARIA Gabriela5, MANEA Aniko1

1 University of Medicine and Pharmacy “Victor Babes” Timisoara, Department of Puericulture and Neonatology, (ROMANIA) 2 Emergency Clinical Hospital for Children “Louis Turcanu”, Timisoara, (ROMANIA) 3 University of Medicine and Pharmacy “Victor Babes” Timisoara, Department of Obstetrics and Gynaecology, (ROMANIA) 4 University of Medicine and Pharmacy “Carol Davila”, Bucuresti, Department of Obstetrics and Gynaecology, (ROMANIA) 5 University of Medicine and Pharmacy “Iuliu Hateganu”, Cluj-Napoca, Department of Neonatology, (ROMANIA) 6 University of Medicine and Pharmacy “Victor Babes” Timisoara, Department of Pediatric Surgery (ROMANIA) Emails: [email protected], [email protected], [email protected]

Abstract

Introduction Neonatal cranial ultrasound is effective in evaluating the term new-born and premature new- born with brain lesions. It allows the early diagnosis of brain lesions and their dynamic follow-up as long as the size of anterior fontanelle allows. The ultrasound signs are in close correlation with the clinical and neuropathological data.

Aims The authors propose a comparative study of the forms of intracranial haemorrhage in the new- born at term and in the premature new-born, the opportunity of the ultrasound evaluation according to the gestational age, chronological age and type of lesion.

Material and methods The forms of intracerebral haemorrhage analysed by groups of gestational age were: epidural haemorrhage, subdural haemorrhage, subarachnoid haemorrhage, periventricular/intraventricular haemorrhage predominates increasing with weight loss. The neonatal cranial ultrasound, performed with the sectorial probe of 5 MHz for the deep areas, or 7-10 MHz for the superficial areas was the basis of the differentiated study.

Results Intracranial haemorrhages are rarely present at birth: 50% occur on the first day after birth, 80- 90% occur by the third day after birth and 20-40% progress during the first week of life. Epidural bleeding is rare at new-born, 2% of all bleeding, difficult to diagnose, with symptoms which appear late. Subdural haemorrhage is more common in term new-borns, in fetal pelvic disproportions, severe evolution, diagnosis must be established quickly. Subarachnoid haemorrhage is more frequent in premature new-borns than in term new-borns, 29% in premature new-borns whit birth weight bellow 2000g. Peri/intraventricular haemorrhage is more common in premature new-borns, 50% with gestational age below 30 weeks and birth weight 1500g,

45 ©Filodiritto Editore – Proceedings occasionally occurring also at term new-borns, with severe neurological sequelae. Intraventricular grade IV haemorrhage is the most severe form characterized by massive bleeding within the left ventricle of the brain, which is associated with adjacent brain tissue haemorrhage. Intracerebellar haemorrhage is a serious form of haemorrhage, 15-25% occurs in prematurity with the gestational age <32 weeks and the birth weight <1500g, in close association with severe intraventricular brain haemorrhage.

Conclusions Grade IV of peri/intraventricular haemorrhage and cerebral haemorrhage are the most severe forms of the disease in premature new-borns, with severe evolution. Cerebral ultrasonography is useful in the early diagnosis of these lesions.

Keywords: cerebral haemorrhage, ultrasonography, new-born

Introduction

Intracranial haemorrhage (ICH) can have major impact on the mortality, morbidity and long- term neurodevelopment of new-borns [1]. The ethiology of ICH differs according to the gestational age of the infant and the site of haemorrhage. In the preterm new-borns, the major lesions are germinal matrix haemorrhage (GMH)/intraventricular haemorrhage (IVH) and it occur prior to labor or usually as a result of hemodynamic instability [2]. The incidence of IVH increases with decreasing gestational age. In full-term new-borns intracranial haemorrhage often occur during labor as the results of mechanical factors: prolonged, precipitous vaginal breech, instrumental – forceps or ventouse delivery and extreme fetal weight [3]. Subarachnoid haemorrhage is the most common type of haemorrhage among the symptomatic term new-borns while subdural haemorrhage is the most frequent type among the asymptomatic new-borns [4]. Cranial sonography is an important part of neonatal care in general, and high-risk and unstable premature infants, in particular. It provides important diagnostic information and it is effective in evaluating both term and premature new-born with brain lesions. It allows the early diagnosis of brain lesions and their dynamic follow-up as long as the size of anterior fontanelle allows. The ultrasound findings are in close correlation with the clinical and neuropathological data. Cranial sonography is less expensive, free from radiation, does not require sedation and allows bedside evaluation of critical ill patients.

Aims

The authors propose a comparative study of the forms of intracranial haemorrhage in the new- born at term and in the premature new-born, the opportunity of the ultrasound evaluation according to the gestational age, chronological age and type of lesion.

Material and methods

We performed a retrospective study over a period of 24 months, from January 2018 to December 2019 in the Neonatology and Premature Clinic, Emergency Hospital for Children “Louis Ţurcanu” Timisoara, on a group of 98 new-borns admitted during the specified period of time with clinical suspicion of intracranial haemorrhage. Clinical data were retrieved from their

46 ©Filodiritto Editore – Proceedings medical records and informed consent was obtained from the parents of the patients included in the study. The study included 75 preterm and 23 term infants. There were 56 males and 42 females. According to the World Health Organization preterm infants are infants born before 37 weeks. Low birth weight (LBW) are new-born babies with birth weight (BW) less than 2500g, very low birth weight (VLBW) is those with BW less than 1500g and extremely low birth weight (ELBW) are those with BW less than 1000g. New-born at term and normal weight baby is defined as new-born baby with gestational age (GA) of 38-42 weeks and BW of 2500-4000g [5]. The exclusion criteria – new-borns with congenital Central Nervous System (CNS) malformations and with meningitis. The variables included for the analysis were gestational age (Ballard’s), birth weight, Apgar scores at 1 and 5 minutes, mode of delivery, history of hypoxic insult or birth trauma, and developmental outcomes, when available. The new-borns were examined by ultrasound, and standard images in sagittal and coronal planes were obtained through the anterior fontanelle. Cranial sonography was performed with a Philips PureWave CX50 Ultrasound machine. The sectorial probe of 5 MHz used for the deep areas, and those of 7-10 MHz for the superficial areas was the basis of the differentiated study. Imaging was performed in the first day of life, the 3rd, the 7th day and 1 month after birth. The forms of intracerebral haemorrhage analysed by groups of gestational age were: epidural haemorrhage, subdural haemorrhage, subarachnoid haemorrhage, and peri/intraventricular haemorrhage, Fig. 1, Fig. 2.

Fig. 1. Transfontanellar ultrasonography, II/III- Fig. 2. Transfontanelar ultrasonography, IV- degree IVH (coronal section) degree IVH (posterior coronal section)

Results

The study group included 98 new-borns of whom 75 were preterm new-borns with GA 28-36 weeks, and 23 were term infants. There was no significant difference in gender ratio, 56 (57.14%) males and 42 (42.86%) females. In the study group, the APGAR score was better at both 1 and 5 minutes in preterm infants compared to full-term infants. The most common mode of birth was in both age groups by caesarean section and the use of instruments (forceps) was rare, only in 2 full-term infants. The hypoxic insult was the most common cause of intracranial haemorrhage in both term and preterm infants. The variables included for analysis are summarized in Table 1.

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Table 1. Characteristics of the study group (n-98 patients) Variables Total (n=98) Premature new-borns n=75 Term new-borns n=23 (23.5%) (76.5%) Gestational age in weeks, 31.5 (28-36) 39.1 (38-41) (average/min-max) Birth weight in grams, 1450.6 (750-2390) 3256.7 (2950-4150) (average/min-max) Apgar scores at 1 minute, 7.3±2 5.3±1.2 Apgar scores at 5 minutes, 8.6±2 6.3±2.2 Mode of delivery, Caesarean section 43 (43.9%) 13 (13.3%) Spontaneous vaginal delivery 32 (32.7%) 8 (8.16%) Instrumental delivery 0 (0.0%) 2 (2.04%) History of hypoxic insult, 63 (64.3%) 18 (18.4%) Birth trauma, 12(12.24%) 5 (5.1%)

Cranial ultrasound was performed in the first day of life, the 3rd, the 7th day and 1 month after birth. Intracranial haemorrhages are rarely present at birth; 50% occur on the first day after birth, 80-90% occur by the third day after birth and 20-40% progress during the first week of life. At one month of age we followed-up the evolution of intracranial haemorrhage and possible complications, especially post – haemorrhagic hydrocephalus. Distribution of term and preterm new-borns depending on cranial ultrasound findings at different days of examination are summarized in table 2.

Table 2. Distribution of new-borns at different days of examination Days Preterm new-borns (n) Term new-borns (n) 1 21 6 3 45 13 4-7 9 4 30-Post-hemorrhagic hydrocephalus 15 2

Epidural bleeding is rare at new-born. In our study group 2 term new-borns developed this type of haemorrhage representing 2% of all bleeding, difficult to diagnose, with symptoms which appear late. Subdural haemorrhage is more common in term new-borns, in fetal pelvic disproportions, severe evolution, diagnosis must be established quickly. 8 (34.8%) of term new- borns and only 3(4%) of preterm infants had this kind of haemorrhage. Subarachnoid haemorrhage is more frequent in premature new-borns than in term new-borns. 22 of preterm infants representing 29% of premature new-borns with birth weight bellow 2000g have been diagnosed with subarachnoid haemorrhage. Peri/intraventricular haemorrhage is more common in premature new-borns, 38 (50%) with gestational age below 30 weeks and birth weight 1500g. Peri/intraventricular haemorrhage occasionally occurring also at term new-borns, with severe neurological sequelae. In our group cranial ultrasound helped to diagnosed 5 term new-borns with intraventricular haemorrhage and 2 of them developed post-haemorrhagic hydrocephalus. Intraventricular grade IV haemorrhage is the most severe form characterized by massive bleeding within the left ventricle of the brain, which is associated with adjacent brain tissue haemorrhage. The development outcome was severe with neurological sequelae and post – haemorrhagic hydrocephalus in 17 (17.34%) patients from our study.

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Intracerebellar haemorrhage is a serious form of haemorrhage, 15-25% occurs in prematurity with the gestational age <32 weeks and the birth weight <1500g, in close association with severe intraventricular brain haemorrhage.

Discussions

Current brain-imaging techniques are limited, especially for critically ill neonates. Cranial ultrasonography provides important diagnostic information in neonates. The clinical indications for routine scanning in new-born infants are well established. Routine scanning is suggested in all premature infants as well as term infants with Apgar scores at 1 and 5 minute less than 7 and with history of hypoxic insult and birth trauma [6]. Any change in the normal clinical behaviour of the new-born is an indication for cranial ultrasound. Concerning the variables included for analysis: birth weight gestational age and APGAR score there was a significant correlation between them and the presence of intracranial haemorrhage. [7] In our study the average APGAR score at 5 minutes of life was 8,6 in preterm neonates and 6,3 in term new-borns. In a study published by H.S. Hong and Lee, a low Apgar score at 5 min (P = 0.014) and a history of perinatal asphyxia (P = 0.027) were associated with poor clinical outcomes (n = 12/27) [3]. In the current study, preterm neonates with lower BW were found to be at a higher risk of intracranial haemorrhage especially IVH. 38 (50%) preterm neonates with gestational age below 30 weeks and birth weight 1500g were diagnosed after ultrasonographic examination with IVH. According to literature IVH could be detected in approximately 60-70% of VLBW neonates. Moreover, the incidence of IVH is reported to be inversely associated with the gestational age (GA) and birth weight (BW) [8, 9]. IVH is very rarely reported in full-term neonates and may occur in these children with a variety of clinical conditions, mostly due to perinatal trauma and asphyxia [10]. In our study 5 term infants developed IVH and all of them had history of birth trauma. Post-haemorrhagic hydrocephalus occurs in approximately 17.34% of infants with IVH. In a review Bouz P et al., reported an incidence of 25% of infants with IVH [11]. In our study the incidence of subdural and subarachnoid haemorrhage was lower 34.8% respectively 29 %, compared with the literature. H.S. Hong and Lee reported an incidence of subdural haemorrhage in term new-borns of 95.2% [3]. Regarding the ultrasound examination on different days, ultrasound has proven to be a useful tool in establishing the diagnosis of intraventricular haemorrhage, especially in the first three days of life and in the critical ill new-borns.

Conclusions

Grade IV of peri/intraventricular haemorrhage and cerebral haemorrhage are the most severe forms of the disease in premature new-borns, with severe evolution. Cerebral ultrasonography is still the first line neuroimaging modality in the early diagnosis of these lesions. It is less expensive and burdensome than magnetic resonance imaging (MRI) and Computer tomograph, which requires patient transport and sedation.

REFERENCES

[1] Intrapiromkul J, Northington F, Huisman TA, Izbudak I, Meoded A, Tekes A. Accuracy of head ultrasound for the detection of intracranial haemorrhage in preterm neonates: comparison with brain MRI and susceptibility-weighted imaging. J Neuroradiol. 2013; 40(2): pp. 81-88.

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[2] Khan IA, Wahab S, Khan RA, Ullah E, Ali M. Neonatal Intracranial Ischemia and Haemorrhage: Role of Cranial Sonography and CT Scanning. J Korean Neurosurg Soc. 2010; 47(2): pp. 89-94. [3] Hong HS, Lee JY. Intracranial haemorrhage in term neonates. Childs Nerv Syst. 2018; 34(6): pp. 1135-1143. [4] Shahina Bano, Vikas Chaudhary, Umesh Chandra Garga, Sachchidanand Yadav and Sachin Kumar Singh (September 10th 2014). Intracranial Haemorrhage in the New-born, Intracerebral Haemorrhage, Vikas Chaudhary, IntechOpen, DOI: 10.5772/58476. Available from: https://www.intechopen.com/books/intracerebral-hemorrhage/intracranial-hemorrhage-in-the-newborn [5] M. Boia. Postnatal growth and development. Ed. Victor Babes, 2010, Timisoara: pp. 39-41. [6] Franco A, Lewis KN. Neonatal cranial ultrasound: current perspectives. Reports in Medical Imaging. 2013; 6: pp. 93-103. [7] Fouladinejad M, Khorsand Zak H, Shirvani S, Besharat M, Alaee E. Cerebral Intraventricular Haemorrhage and Interleukin-6 in Preterm Neonates. Iranian Journal of Neonatology. 2020 Jun: 11(2). [8] Navolan, Dan; Vladareanu, Simona; Ciohat, Ioana; Carabineanu, Adrian; Craina, Marius; Nemescu, Dragos; Birsasteanu, Bogdan; Onofriescu, Alina; Boia, Marioara; Tepetzikiotis, Efstathios; Craciunescu, Mihaela; Birsasteanu, Florin Distribution of Biochemical and Ultrasound Markers Values in the First Trimester Screening Program in Timisoara REVISTA DE CHIMIE, Volume: 68, Issue: 7, Pages: 1636-1639, Published: JUL 2017. [9] Kurjak, Asim; Antsaklis, Panos; Stanojevic, Milan; Vladareanu, Radu; Vladareanu, Simona; Neto, Raul Moreira; Barisic, Lara Spalldi; Porovic, Selma; Delic, Taib Multicentric studies of the fetal neurobehavior by KANET test JOURNAL OF PERINATAL MEDICINE, Volume: 45, Issue: 6, Pages: 717-727, Special Issue: SI DOI: 10.1515/jpm-2016-0409, Published: AUG 2017. [10] Szpecht D, Frydryszak D, Miszczyk N, Szymankiewicz M, Gadzinowski J. The incidence of severe intraventricular haemorrhage based on retrospective analysis of 35939 full-term new-borns-report of two cases and review of literature. Childs Nerv Syst. 2016; 32(12): pp. 2447-2451. [11] Bouz P, Zouros A, Taha A, Sadanand V. Neonatal intracerebral haemorrhage: mechanisms, managements, and the outcomes. Transl Stroke Res. 2012 Jul; 3(Suppl. 1): pp. 6-9.

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The Role of Ultrasonography in the Early Diagnosis of Localized Neural Tube Brain Malformations

BOIA Marioara1, BOIA Eugen S.6, CIOBOATA Daniela2, NAVOLAN Dan3, VLADAREANU Simona4, VLADAREANU Radu4, ZAHARIE Gabriela5, MANEA Aniko1, BRANDIBUR Timea1

1 University of Medicine and Pharmacy “Victor Babes” Timisoara, Department of Peiculture and Neonatology (ROMANIA) 2 Emergency Clinical Hospital for Children “Louis Turcanu” Timisoara (ROMANIA) 3 University of Medicine and Pharmacy “Victor Babes” Timisoara, Department of Obstetrics and Gynaecology (ROMANIA) 4 University of Medicine and Pharmacy “Carol Davila” Bucuresti, Department of Obstetrics and Gynaecology (ROMANIA) 5 University of Medicine and Pharmacy “Iuliu Hateganu” Cluj-Napoca, Department of Neonatology (ROMANIA) 6 University of Medicine and Pharmacy “Victor Babes” Timisoara, Department of Pediatric Surgery (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected]

Abstract

Introduction Cerebral malformations represent the major cause of morbidity and mortality both in the neonatal period, but also in the infant and small child stage. Immediate and remote complications depend on the type of malformation, its severity and the degree of cerebral maturity. (1.) Neural tube defects appear relatively early, after the caudal neuropore has been closed (26 days). (2.) In medical practice, several types are described, depending on the location and the gestational age at which the injury occurs: anencephaly, encephalocele, myelomeningocele. (3.)

Objectives The authors propose a review of the most common neural tube malformations. To establish a correlation between clinical, anamnestic and imaging data in order to anticipate the short-term and remote prognosis.

Material and method Clinical-ultrasound analysis of new-borns with lesions consisting of herniation of sac-shaped intracranial tissues, by frontal or occipital cranial bone defects, or at the level of the spine. The clinical evaluation criteria were: convulsions, paresis, hypotonia, presence of the sucking reflex, incontinence. Prenatal or postnatal ultrasound evaluation was completed with CT or cerebral and/or spinal MRI.

Results The most common types of neural tube malformations encountered were: occipital encephaloceles, anterior encephaloceles, myelomeningocele with or without Arnold Chiari Malformation. (4) Myelomeningocele is frequently associated with hydrocephalus and Chiari II Malformation; The vertebral defect is most commonly located in the lumbar-sacral region, in 80% of cases this being the last part of the neural tube that closes. Arnold Chiari Malformation, the most severe form of this type of malformation, is characterized by hypotrophy of the cerebellum, herniation of cerebellar vermis in the foramen magnum with posterior displacement of the

51 ©Filodiritto Editore – Proceedings cerebellum with varying degrees of cerebellar dysplasia. Postnatal ultrasound diagnosis is easy in the presence of these signs, the dilation of the ventricular brain system representing the reference of therapeutic-surgical intervention. (5)

Conclusions Positive diagnosis is relatively easy from the antenatal period with the help of ultrasonography, but the certainty of diagnosis is established by cerebral MRI. Cranial cerebral dyspraxia although it presents an immediate good prognosis following rapid therapeutic intervention, the long-term prognosis of distance sequelae is high, especially in those associated with Chiari II Malformation. (6.)

Keywords: malformation, ultrasonography, neural tube

Introduction

The ultrasound is the most widely used diagnostic tool in obstetrics nowadays, in particular in the detection of developmental disorders. (1) However, it is important to know which are those disorders that can be detected prenatally with great certainty, and which ones can be detected only partially or not at all prior to giving birth. Cerebral malformations are commonly detected during prenatal screening. (2.) The diagnostic accuracy of prenatal cerebral imaging is not 100%, disagreement between pre- and postnatal imaging with a prognostic impact being observed in about 9% of cases. Depending on geographic location, approximately 1 to 10:1000 infants are born with neural tube defects. Of the NTDs detectable during pregnancy, 40% are anencephaly, 50% myelomeningocele, 3% craniorachischises, and 7% encephalocele. (3) Faced with more complex diagnoses, magnetic resonance imaging (MRI) has become widely used as an important complement to prenatal ultrasonography (US). Due to its higher contrast resolution than US, fetal MRI allows normal versus abnormal tissue to be better differentiated, providing detailed imaging information on fetal structures, particularly the brain. (4) As the indications for fetal brain MRI are mainly based on abnormal US findings, fetal MRI is usually performed during the second half of gestation, from 18 to 20 weeks onward. After that point, the utility of prenatal US is limited due to decreased amniotic fluid volume, fetal positioning, and acoustic shadowing from the ossifying calvaria. (5.)

Aims

The authors propose a review of the most common neural tube malformations. To establish a correlation between clinical, anamnestic and imaging data in order to anticipate the short-term and remote prognosis.

Material and method

This is a retrospective study, conducted over a 5-year period from January 2015 to December 2019, on all new-borns with neural tube defects (NTDs) admitted in the Neonatology and Preterm Department, Emergency Hospital for Children “Louis Ţurcanu” Timisoara. The clinical evaluation criteria were: convulsions, paresis, hypotonia, presence of the sucking reflex, incontinence.

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Prenatal ultrasound examination is initially performed transabdominally with 3.5‐ or 5.0‐MHz curvilinear transducers, but when a fetal defect is suspected, a transvaginal scan is also offered to the patient to further assess the fetal anatomy. Information on prenatal sonographic findings, fetal karyotype if available, antenatal medical history, and perinatal outcome, including congenital malformations detected prenatally or postnatally, was obtained by reviewing the ultrasound report, medical records, and neonatal discharge summary. Fetal MRI is routinely performed using 1.5-T or 3.0-T MRI scanners. Conventional T1- and T2-weighted images are obtained in the sagittal, coronal, and axial planes relative to the fetal head. T2-weighted sequences are useful for evaluating the anatomy and the sulcation pattern of the central nervous system (CNS), while T1-weighted sequences are valuable for assessing the presence of bleeding and myelination. Even with rapid image acquisition, fetal motion can still affect the quality of the results, as high spatial and temporal resolution is required. Ethical approval was granted from the Ethics Committee of our University Hospital.

Results

Of the 11 patients hospitalized in a 5-year period, 6 were female and 5 were male. The median birth weight was 3080 g and the median delivery week was 38 weeks. Seven new-borns came from dispensary pregnancy (63,6%), and all cases of neural tube brain malformations were diagnosed on prenatal ultrasonography (100%). Eight of the patients (72,7%) had meningomyelocele, 2 patients (18,2%) had encephalocele, and one patient (9%) had meningocele. Seven of the patients (63.6%) had Arnold-Chiari type 2 malformation and five was associated with hydrocephalus, Fig. 1, Fig. 2. Cranial ultrasound was performed in the first day of life, the 3rd, the 7th day and 2 weeks after birth. The ultrasonography findings of Chiari II include a small posterior fossa, hypoplastic cerebellar hemispheres, and ventricular dilatation. Dysgenesis of the corpus callosum, polymicrogyria, and hydrocephalus are present in 90% of cases, and spina bifida is found in 100% of cases, Fig. 3. The median time of making a diagnosis of NTD by prenatal ultrasonography was 20 (16-24) weeks. Six of the patients (54.5%) had other organ disorders, some with multiple systemic disorders. The clinical evaluation criteria showed that eight new-borns presented seizures during the hospitalization (72,7%), ten maintained hypotonic until the day of discharge (90,9%), three presented paresis (27,2%), nine had sucking reflexes (81,8%) and five had incontinence (45,5%). In our study, the first clinical signs in myelomeningocele appeared in the 20th week after birth. In those who had hydrocephalus, the clinical signs appeared in the 6th week. Data collected by neonatal records and follow-up charts were related to familiar and/or maternal risk factors (maternal pre-existing and/or gestational diseases, exposure to teratogen/infectious agents, lack of preconception folic acid supplement), demographic (ethnicity/origin, residence), clinical features (prenatal diagnosis, gestational age, fetal presentation, type of delivery, birth weight, preoperative imaging, comorbidities, complications), and neurodevelopmental outcomes. Leakage of cerebrospinal fluid (CSF) can cause intracranial hypotension and result in a Chiari malformation Type II. (6.) The hindbrain herniation seen in this malformation is caused by a downward displacement of the cerebellum below the level of the foramen magnum, and may result in a compressed brainstem, small posterior fossa and obstructed fourth ventricle. This obstruction may prevent the movement of CSF and result in hydrocephalus. A common treatment for hydrocephalus is the placement of a ventriculoperitoneal shunt. In all cases of hydrocephalus, a cerebral MRI was requested by the neurosurgery team to establish a certainty diagnosis. In our

53 ©Filodiritto Editore – Proceedings study, all new-borns with hydrocephalus required surgery, and 80% of cases required a shunt revision.

Fig. 1. Median coronal scan. Mild hydrocephalus in association with a type II Chiari

Fig. 2. Median coronal scan. Severe hydrocephalus in association with a type II Chiari.

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Fig. 3. Posterior coronal scan. The corpus callosum agenesia. Hypertrofia of cavum septum pellucidi.

Discussions

Concerning prenatal diagnosis of all NTDs, an 100% detection rate was identified by routine ultrasound. While the prenatal detection rate has ranged from 79 to 100% during the last 20 years in studies performed in high-risk populations of Europe, our 100% detection rate was one of the highest observed in the general population. (6) Recent evolution in ultrasound equipment enables a more refined diagnoses of most congenital malformations of the brain. Only through a structured analysis of the fetal CNS anatomy, even rare conditions may be detected more often. Although some brain anomalies are only visible late in gestation there is a strong tendency towards a more detailed neurosonogram in the second or even first trimester of pregnancy. (7)

Conclusion

Prenatal US represents at this point the gold standard for the detection of spina bifida aperta in early gestation and employed to offer supplementary information in the determination of the level and the size of the spinal injury. The standard prenatal evaluation of the fetus is by second trimester ultrasound. (8, 9) Cranial ultrasonography provides important diagnostic information in neonates. If a CNS abnormality is suspected, then the patient may go on to fetal MRI. In cases where the diagnosis is made in time, it is observed that families decide to continue pregnancy because of sociocultural factors. The postnatal diagnosis may differ depending on the modality with which the infant with CNS abnormality is imaged after birth. MRI of the fetal brain is an accurate imaging method that allows better characterization of lesions and of the remaining brain parenchyma, especially when US has limitations. (9, 10, 11)

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REFERENCES

[1] Aydın E, Tanacan A, Büyükeren M, Uçkan H, Yurdakök M, Beksaç MS. Congenital central nervous system anomalies: Ten-year single center experience on a challenging issue in perinatal medicine. J Turk Ger Gynecol Assoc. 2019; 20(3): pp. 170-177. doi: 10.4274/jtgga.galenos.2018.2018.0079 [2] Werner H, Gasparetto TD, Daltro P, Leandro Gasparetto E, Araujo Júnior E. Typical lesions in the fetal nervous system: correlations between fetal magnetic resonance imaging and obstetric ultrasonography findings. Ultrasonography. 2018; 37(3): pp. 261-274. doi:10.14366/usg.17040 [3] Werner H, Gasparetto TD, Daltro P, Leandro Gasparetto E, Araujo Júnior E. Typical lesions in the fetal nervous system: correlations between fetal magnetic resonance imaging and obstetric ultrasonography findings. Ultrasonography. 2018; 37(3): pp. 261-274. [4] Kaur A, Kaur A. Transvaginal ultrasonography in first trimester of pregnancy and its comparison with transabdominal ultrasonography. J Pharm Bioallied Sci. 2011; 3(3): pp. 329-338. doi:10.4103/0975- 7406.84432 [5] Piro E, Serra G, Schierz IAM, Giuffrè M, Corsello G. Neonatal ten-year retrospective study on neural tube defects in a second level University Hospital. Ital J Pediatr. 2020; 46(1): p. 72. Published 2020 May 24. doi:10.1186/s13052-020-00836-1 [6] Hidalgo JA, Tork CA, Varacallo M. Arnold Chiari Malformation. [Updated 2020 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK431076/ [7] Altman NR, Altman DH (1987) MR imaging of spinal dysraphism. Am J Neuroradiol 8: pp. 533-538 [8] K. Aaron Geno, Mark A. Cervinski, Robert D. Nerenz, Pregnancy and the fetus, Handbook of Diagnostic Endocrinology, 10.1016/B978-0-12-818277-2.00015-7, (pp. 543-579), (2021). [9] Navolan, Dan; Vladareanu, Simona; Ciohat, Ioana; Carabineanu, Adrian; Craina, Marius; Nemescu, Dragos; Birsasteanu, Bogdan; Onofriescu, Alina; Boia, Marioara; Tepetzikiotis, Efstathios; Craciunescu, Mihaela; Birsasteanu Distribution of Biochemical and Ultrasound Markers Values in the First Trimester Screening Program in Timisoara REVISTA DE CHIMIE, Volume: 68, Issue: 7, Pages: 1636-1639, Published: JUL 2017 [10] Arthur M. Mandel, Diagnosis and management of congenital neurologic disease during pregnancy, Neurology and Pregnancy – Pathophysiology and Patient Care, 10.1016/B978-0-444-64239-4.00015-1, (pp. 291-311), (2020). [11] Kurjak, Asim; Antsaklis, Panos; Stanojevic, Milan; Vladareanu, Radu; Vladareanu, Simona; Neto, Raul Moreira; Barisic, Lara Spalldi; Porovic, Selma; Delic, Taib Multicentric studies of the fetal neurobehavior by KANET test JOURNAL OF PERINATAL MEDICINE, Volume: 45, Issue: 6, Pages: 717-727, Special Issue: SI DOI: 10.1515/jpm-2016-0409, Published: AUG 2017.

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Fetal Congenital Heart Block Risk in Anti-Ro/SSA Antibodies Positive Pregnancy – How to Prevent

BOIANGIU Andreea Grațiana1,2, BĂLĂNESCU Andra1,3, FILIPESCU George Alexandru1,2, TĂTĂRUȘ Cristina Alina2, VLĂDĂREANU Radu1,2*, VLĂDĂREANU Simona1,4

1 Carol Davila University of Medicine and Pharmacy, Bucharest, (ROMANIA) 2 Obstetrics and Gynaecology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 3 Rheumatology Department, Sf Maria Hospital, Bucharest (ROMANIA) 4 Neonatology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) * Corresponding author: VLĂDĂREANU Radu Email: [email protected]

Abstract

Congenital heart block is caused by a diffuse myocarditis and fibrosis in the region between the atrioventricular node and bundle of His. [1] The damage of atrioventricular conductive tissue results from the placental passage of maternal autoantibodies (anti Ro/SSA). These antibodies are associated with neonatal lupus and are linked to the development of congenital heart block, defined as atrioventricular block diagnosed in utero, at birth or within the neonatal period. [2] The main clinical finding is bradycardia, less than 60 bpm (normal heart beat at birth is 140 bpm) and a pacemaker is immediately necessary, considering that the cardiac lesion is permanent. Is important to perform a cardio-fetal ultrasound and to monitor the fetal heart rate and after birth an electrocardiogram. Mothers with anti-Ro antibodies are diagnosed often with lupus erythematosus, Sjögren syndrome or other autoimmune disease. A standard treatment for congenital heart block does not exist. Research about how to prevent congenital heart block are still ongoing, but there is some evidence for the beneficial effect of hydroxychloroquine. This review aims to offer a broader perspective about the best management of pregnancies with anti Ro/SSA antibodies to reduce neonatal complications, particularly congenital heart block.

Keywords: congenital heart block, neonatal lupus, anti-Ro/SSA antibodies

Introduction

Pregnant women with autoimmune disease have a high risk of developing fetal and maternal complications such as SGA, preeclampsia or preterm delivery. [3] Those complications are a complex model of autoimmunity passively acquired. The mother’s health and fetal development should be monitored frequently during pregnancy. Systemic lupus erythematosus and Sjögren syndrome are chronic autoimmune disease which affects particularly women of reproductive age. Congenital heart block is a passively acquired autoimmune disease caused by antiRo/SSA and anti-La/SSb antibodies. These antibodies cross the placenta beginning with 16 weeks of gestation and might induce myocarditis (macrophage infiltration and giant cell formation), calcification and fibrosis, they may be arrhythmogenic or they can interfere with apoptosis. [4, 5] Complications of neonatal lupus erythematosus are cardiac and cutaneous manifestations (rash, telangiectasia), liver damage (elevated liver enzymes, cholestasis, hepatosplenomegaly) and cytopenia (anaemia,

57 ©Filodiritto Editore – Proceedings thrombocytopenia, neutropenia). [6, 7] Neonatal lupus can occur when mothers are diagnosed with systemic lupus erythematosus and Sjögren Syndrome, but most cases are reported in asymptomatic women. The most severe manifestation is congenital heart block which is usually irreversible.

Anti-Ro/SSA Antigen-Antibody Systems The Ro/La system is a heterogeneous antigenic complex composed of three different proteins (52kDa Ro, 60kDa Ro and La) and four small RNA particles named hY1, hY3, hY4 and hY5. Counterimmunoelectrophoresis is better than immunoblotting and some ELISAs to detect anti- Ro/SSA antibodies, having a high sensitivity (89%) and specificity (100%). On the other hand ELISA is a safe, rapid, sensitive and specific assay. [8] The Ro60 antigen or TROVE2 is located in the nucleus and nucleolus. The Ro 52 autoantigen (TRIM21) is an interferon-inducible protein residing in the cytoplasm, with an important role in regulation of inflammation. Ro52 target interferon regulatory factors 3 and 7 and down regulate proinflammatory nuclear factor kappa-B, therefore inhibits inflammation. [9-11] Anti Ro/SSA and other antibody levels should be determined when a rheumatologic/connective tissue is suspected, especially if the patient is suspected or have the next clinical findings: photosensitivity or subacute cutaneous lupus, primary Sjögren Sindrom vasculitis, cutaneous vasculitis or palpable purpura, interstitial lung disease, neonatal lupus, congenital heart block, nephritis, vasculitis, lymphadenopathy, leukopenia. [12] The prevalence of these antibodies in general population is up to 1-3%. [13] AntiSSA/Ro autoantibodies are found in 85-90% of mothers of children with congenital heart block. [14]

Congenital heart block

Despite the latest findings about congenital heart block, clinical management of these mothers with rheumatologic disease and fetus remains challenging. The symptoms of neonatal lupus due to auto antibodies consist of skin rash, elevated liver enzymes, cytopenia and these manifestations disappear once the maternal auto antibodies are cleared from the fetal circulation, but still congenital heart block represented by the third-degree atrioventricular block is irreversible and requires a pacemaker. [15] Pregnant women with anti-Ro/SSa antibodies and especially those with high titters require careful monitoring of pregnancy which involves serial fetal echocardiography. Congenital heart block is usually diagnosed between 18 and 24 weeks of gestation. It may initially manifest as grade I or II atrioventricular block, but must often manifest as fetal bradycardia and grade III atrioventricular block, the most severe manifestation of neonatal lupus. Echocardiography may reveal ventricular dilatation and myocardial hypertrophy (cardiomyopathy) and/or increased endocardial echogenicity (endocardial fibroelastosis), both with a poor prognosis. [16] Measuring the time interval between the onset of atrial systole and ventricular systole (PR interval) using pulsed wave Doppler helps assess fetal heart rhythm which can rapidly and dramatically change from normal to complete heart block in a few days. [17, 18] Serial echocardiograms should be performs at least every 2 weeks starting with the 16 week of gestation in anti-Ro/SSA positive pregnant women to be able to detect early cardiac abnormalities. [19] Congenital heart block is associated with a high morbidity (65% require lifelong pacing) and with a mortality rate of 20%. [20]

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Molecular mechanism of congenital heart block

The molecular mechanisms underlying congenital heart block pathogenesis are not fully understood. Congenital heart block is characterized by the presence of immune complex deposis, inflammation, calcification and fibrosis at the fetal atrioventricular node. The presence of maternal autoantibodies at the site of fetal heart injury was demonstrate more than 20 years ago. [21] Some data suggest that anti 52-kDa Ro/SSa and anti-La/SSb antibodies are more strongly associated with congenital heart block than anti-60-kDA Ro/SSa alone.[4] A cohort study suggest that it is a correlation between fetal heart block and the levels of Ro antibody, and their mere presence is not enough to cause heart disease. [22] There is a higher prevalence of Ro52 antibodies compared to Ro60 in mothers whose new born are diagnosed with congenital heart block. Despite all that, the risk of fetus developing congenital heart block in a single antiRo/SSA antibody positive pregnancy is only 1-2% and the risk of recurrence of complete atrioventricular block is almost 10 times higher in the following pregnancies. [4, 23] However, the molecular mechanisms by which autoantibodies that cross the placenta affect the fetal cardiac conduction system are not completely elucidated. Anti-Ro60 antibodies are driving inflammation in the fetal heart through opsonization of apoptotic cardiomyocytes, form immune complexes and activate macrophages. Epitope mapping of the immunodominant central region of Ro52 revealed a significant association between the presence of maternal antibodies to amino acids 200-239 (denotes p200) and the risk of congenital heart block. [24, 25] Studies have shown that antibodies specific for Ro52/p200 can bind the surface of live cardiomyocytes and disturb spontaneous calcium oscillations, leading to intracellular accumulation of calcium, loss of contractility and ultimately apoptosis. [15] L- and T-type calcium channels are suggested as potential cross-reactive targets for anti-Ro52 antibodies. The activity of these calcium channels if affected by the maternal antibodies which leads to the cardiac manifestations described in congenital heart block.

Prevention of congenital heart block

The main goal is to detect early fetal cardiac abnormalities that might precede complete atrioventricular block and that might be a target of prevention therapy. [26] Non-fluorinated steroids (prednisone, prednisolone and methylprednisolone) are recommended only for maternal indication. [27] These drugs do not prevent the development of congenital heart block because they do not cross the placenta and they are not active in the fetus. Although fluorinated steroids are not metabolized by the placenta, routine treatment with these drugs is not indicated due to maternal side effects (infection, osteoporosis, osteonecrosis, diabetes, hypertension, pre-eclampsia) and fetal risks (intrauterine growth restriction and oligohydramnios, adrenal suppression), as high doses are required (at least 4mg dexamethasone daily). [27-29, 30] Hydroxychloroquine is a Toll-like receptor agonist often used in lupus treatment, including during pregnancy. Toll-like receptor signalling play a role in the inflammation and fibrosis that appear in congenital hear block. [31, 32] Studies have shown that anti-Ro/SSa positive pregnant women with systemic lupus erythematosus treated with hydroxychloroquine had a reduced risk of fetal cardiac abnormalities. [33] Several retrospective studies demonstrated that pregnant women with anti-Ro/SSa antibodies positive in treatment with hydroxychloroquine are less likely to have a fetus with second- or third-degree atrioventricular block. [34, 35] A prospective single-arm clinical trial conducted by Izmirly demonstrated that hydroxychloroquine reduces the recurrence of congenital heart block in anti-Ro/SSa positive pregnancies by more than one half. [36]

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Intravenous immune globulin is a potential useful tool in prevention of cardiac tissue damage. It increases the elimination of maternal autoantibodies through intravenous immune globulin saturation, decrease placental transport of autoantibodies through FcγRn leading to the modulation of inhibitory signalling on macrophages with consequent reduction of the inflammation and fibrosis. [5] Tonello et al., demonstrated that plasma exchange is efficiently removing antibodies linked to the pathogenesis of congenital heart block. This treatment have a long term efficacy in all women positive for 52-and 60 kDa anti Ro/SSa antibodies. [37, 38, 39, 40] A standard therapy for blocks detected in utero still does not exist.

Conclusion

Management of congenital heart block is still very controversial and there are no standard recommendations on prophylaxis and treatment required during pregnancy. The main goal is to detect early fetal cardiac abnormalities that might precede complete atrioventricular block and that might be a target of prevention therapy. Serial echocardiograms are recommended to detect early fetal heart abnormalities. [38, 40] Non-fluorinated steroids are recommended only for maternal indication while fluorinated steroids are not indicated due to maternal side effects. Hydroxychloroquine reduces the recurrence of congenital heart block. Intravenous immune globulin and plasma exchange are effective in prevention of fetal cardiac disease in pregnancies with anti Ro/SSa antibodies.

REFERENCES

[1] F. Gary Cunningham, K.J.L., Steven L. Bloom, Catherine Y. Spong, Jodi S. Dashe, Barbara L. Hoffman, Brian M. Casey, Jeanne S. Sheffield, Williams Obstetrics. [2] Brucato, A., et al., Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol, 2011. 40(1): pp. 27-41. [3] Soh, M.C. and C. Nelson-Piercy, High-risk pregnancy and the rheumatologist. Rheumatology (Oxford), 2015. 54(4): pp. 572-87. [4] Brucato, A., Prevention of congenital heart block in children of SSA-positive mothers. Rheumatology, 2008. 47(suppl_3): pp. iii35-iii37. [5] Fredi, M., et al., First Report of the Italian Registry on Immune-Mediated Congenital Heart Block (Lu.Ne Registry). Front Cardiovasc Med, 2019. 6: p. 11. [6] Silverman, E. and E. Jaeggi, Non-cardiac manifestations of neonatal lupus erythematosus. Scand J Immunol, 2010. 72(3): pp. 223-5. [7] Lee, L.A., R.J. Sokol, and J.P. Buyon, Hepatobiliary disease in neonatal lupus: prevalence and clinical characteristics in cases enrolled in a national registry. Pediatrics, 2002. 109(1): p. E11. [8] Franceschini, F. and I. Cavazzana, Anti-Ro/SSA and La/SSB antibodies. Autoimmunity, 2005. 38(1): pp. 55-63. [9] Popescu, M.R., et al., A Broader Perspective on Anti-Ro Antibodies and Their Fetal Consequences-A Case Report and Literature Review. Diagnostics (Basel, Switzerland), 2020. 10(7): p. 478. [10] Higgs, R., et al., Self-protection from anti-viral responses-Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral Toll-Like receptors. PLoS One, 2010. 5(7): p. e11776. [11] Wada, K., et al., Ro52-mediated monoubiquitinating of IKK {beta} down-regulates NF-{kappa}B signalling. J Biochem, 2009. 146(6): pp. 821-32. [12] McPherson, R.A., Henry’s Clinical Diagnosis and Management by Laboratory Methods: First South Asia Edition_e-Book. 2017: Elsevier India. [13] Hayashi, N., et al., Prevalence of disease-specific antinuclear antibodies in general population: estimates from annual physical examinations of residents of a small town over a 5-year period. Mod Rheumatol, 2008. 18(2): pp. 153-60.

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[14] Brito-Zerón, P., et al., The clinical spectrum of autoimmune congenital heart block. Nat Rev Rheumatol, 2015. 11(5): pp. 301-12. [15] Ambrosi, A., S.E. Sonesson, and M. Wahren-Herlenius, Molecular mechanisms of congenital heart block. Exp Cell Res, 2014. 325(1): pp. 2-9. [16] Izmirly, P.M., et al., Maternal and fetal factors associated with mortality and morbidity in a multi- racial/ethnic registry of anti-SSA/Ro-associated cardiac neonatal lupus. Circulation, 2011. 124(18): pp. 1927-35. [17] Glickstein, J., et al., The fetal Doppler mechanical PR interval: a validation study. Fetal Diagn Ther, 2004. 19(1): pp. 31-4. [18] Jaeggi, E.T., et al., Is immune-mediated complete fetal atrioventricular block reversible by transplacental dexamethasone therapy? Ultrasound Obstet. Gynecol., 2004. 23(6): pp. 602-5. [19] Brucato, A., R. Cimaz, and M. Stramba-Badiale, Neonatal lupus. Clin Rev Allergy Immunol, 2002. 23(3): pp. 279-99. [20] Friedman, D.M., A. Rupel, and J.P. Buyon, Epidemiology, ethiology, detection, and treatment of autoantibody-associated congenital heart block in neonatal lupus. Curr Rheumatol Rep, 2007. 9(2): pp. 101- 8. [21] Litsey, S.E., et al., Maternal connective tissue disease and congenital heart block. Demonstration of immunoglobulin in cardiac tissue. N Engl J Med, 1985. 312(2): pp. 98-100. [22] Jaeggi, E., et al., The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the development of cardiac neonatal lupus erythematosus a prospective study of 186 antibody-exposed foetuses and infants. J Am Coll Cardiol, 2010. 55(24): pp. 2778-84. [23] Brucato, A., et al., Risk of congenital complete heart block in new-borns of mothers with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis: a prospective study of 100 women. Arthritis Rheum, 2001. 44(8): p. 1832-5. [24] Salomonsson, S., et al., A serologic marker for fetal risk of congenital heart block. Arthritis Rheum, 2002. 46(5): pp. 1233-41. [25] Strandberg, L., et al., Antibodies to amino acid 200-239 (p200) of Ro52 as serological markers for the risk of developing congenital heart block. Clin Exp Immunol, 2008. 154(1): pp. 30-7. [26] Theander, E., et al., Primary Sjögren’s syndrome – treatment of fetal incomplete atrioventricular block with dexamethasone. J Rheumatol, 2001. 28(2): pp. 373-6. [27] Østensen, M., et al., Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis Res Ther, 2006. 8(3): p. 209. [28] Cimaz, R., et al., Neonatal lupus syndromes. Pediatrics in Systemic Autoimmune Diseases, 2000: p. 77. [29] Tseng, C.-E. and J.P. Buyon, Neonatal lupus syndromes. Rheumatic Disease Clinics of North America, 1997. 23(1): pp. 31-54. [30] Petca, A.; Vladareanu, S.; Zvanca, M.; Bot, M.; Vladareanu, R. Timing for the delivery of the growth- restricted fetus: a resolvable issue PROCEEDINGS OF THE 49TH ANNUAL SCIENTIFIC MEETING OF THE EUROPEAN SOCIETY FOR CLINICAL INVESTIGATION Pages: 273-277 Published: 2015. [31] Alvarez, D., et al., A novel role of endothelin-1 in linking Toll-like receptor 7-mediated inflammation to fibrosis in congenital heart block. J Biol Chem, 2011. 286(35): pp. 30444-54. [32] Saxena, A., et al., Prevention and treatment in utero of autoimmune-associated congenital heart block. Cardiol Rev, 2014. 22(6): p. 263-7. [33] Izmirly, P.M., et al., Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in foetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine. Ann Rheum Dis, 2010. 69(10): pp. 1827-30. [34] Tunks, R.D., et al., Maternal autoantibody levels in congenital heart block and potential prophylaxis with anti-inflammatory agents. Am J Obstet. Gynecol., 2013. 208(1): pp. 64.e1-7. [35] Izmirly, P.M., et al., Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti- SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation, 2012. 126(1): pp. 76-82. [36] Izmirly, P., et al., Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti- SSA/Ro-Positive Mothers. J Am Coll Cardiol, 2020. 76(3): pp. 292-302. [37] Tonello, M., et al., Plasma exchange effectively removes 52- and 60-kDa anti-Ro/SSA and anti-La/SSB antibodies in pregnant women with congenital heart block. Transfusion, 2015. 55(7): pp. 1782-6. [38] Vladareanu, Simona; Marin, Alina; Vladareanu, Radu; Popescu, Simona; Bot, Mihaela Fetal and Neonatal Supraventricular Tachycardia ISI Proceedings of the 13th Conference of the Romanian-German Society of Obstetrics and Gynaecology pp. 319-324, 2017

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[39] Berceanu, C.; Vladareanu, S.; Cirstoiu, M. M.; Mehedintu, C.; Comandasu, D.; Berceanu, S.; Bratila, E. The clinical significance of the seronegative antiphospholipid syndrome in pregnancy morbidity b EUROPEAN JOURNAL OF CLINICAL INVESTIGATION 2016, vol. 46, special issue. [40] Berceanu, C.; Bratila, E.; Cirstoiu, M. M.; Mehedintu, C.; Berceanu, S.; Comandasu, D.; Vladareanu, S. Clinical and paraclinical approach in antiphospholipid syndrome-systemic lupus erythematosus-pregnancy interrelationship EUROPEAN JOURNAL OF CLINICAL INVESTIGATION 2016, vol. 46, special issue.

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Current Status of Ultrasound in Cervical Pregnancy

CHICEA Radu1,2, CHICEA Anca3, NIȚĂ Paula1,2

1 Faculty of Medicine, Lucian Blaga University, Sibiu, (ROMANIA) 2 Sibiu County Emergency Clinical Hospital, (ROMANIA) 3 The Engineering Faculty, Lucian Blaga University, Sibiu (ROMANIA) Emails: [email protected], [email protected]

Abstract

Introduction Cervical pregnancy is a form of ectopic pregnancy that can endanger the pregnant woman’s life if not diagnosed and treated in time [1]. Cervical pregnancy was first described in the literature by Rubin in 1911 [2]. It is characterized by the implantation of the trophoblast in the cervical mucosa below the level of the internal cervical orifice.[3]

Etiopathogeny The ethiology of cervical pregnancy remains unknown. The mechanical factors involved are uterine malformations, uterine fibroids, changes in the cervix due to surgery at its level, etc. Ultrasound aspects of cervical pregnancy at the 2D ultrasound evaluation, the empty uterine cavity is highlighted, with the gestational sac located in the cervical canal, the cervical canal of increased dimensions and the absence of the slip sign of the sac. Cervical pregnancy management. Case 1 In October 2019, 21 years old female, presented in the obstetrics and gynaecology clinic of the Sibiu County Emergency Clinical Hospital, with a 2-week history of . The preliminary transvaginal ultrasound report indicated a 6-week cervical pregnancy with cardiac activity. Quantitative beta-human chorionic gonadotrophin (βHCG) concentration was 12.000Ui/ml on admission. Case 2 The 33-year-old CA patient has a history of natural birth, without other associated pathologies. The patient is hospitalized in the obstetrics and gynaecology clinic of the Sibiu County Emergency Clinical Hospital, with the diagnosis of incomplete abortion established following the pelvic examination and ultrasound evaluation. Uterine curettage of the cavity is performed. During uterine curettage, heavy vaginal bleeding sets in, with signs of acute post haemorrhagic anaemia.

Conclusions Cervical ectopic pregnancy remains a major challenge in early pregnancy and the success of conservative treatment depends mainly on early diagnosis.

Keywords: cervical, pregnancy, ultrasound, ectopic etc

Introduction

Cervical pregnancy is a form of ectopic pregnancy that can endanger the pregnant woman’s life if not diagnosed and treated in time [1]. Cervical pregnancy was first described in the literature by Rubin in 1911 [2]. It is characterized by the implantation of the trophoblast in the cervical mucosa below the internal cervical orifice level.[3] In recent years, due to a decreased of fertility

63 ©Filodiritto Editore – Proceedings there was an increase addressability of the population for human assisted reproduction techniques.[1], [4] Ectopic pregnancy and abortion are responsible for 7.9% of maternal mortality. [5] However, cervical pregnancies account for about 1% of all ectopic pregnancies. The incidence of cervical pregnancy is reported in the literature between 1 in 1,000-95,000. [3]

History Data found in the literature show that the location of the pregnancy in the cervical canal was first identified in 1817 and 43 years later it was called cervical pregnancy. In 1911 Rubin published for the first time the diagnostic criteria for cervical pregnancy. Until the 1980s, the clinical diagnosis of cervical pregnancy was established after uterine curettage was performed for alleged incompletely performed abortions, followed by massive haemorrhages, and ending with hysterectomy. [6] In 1978 the cervical pregnancy was highlighted by ultrasound for the first time. [7] With the ultrasound evidence of cervical pregnancy along with dosing of the beta subunit of human chorionic gonadotrophin hormone, there has been a direct increase in the number of cases diagnosed early, which has led to new therapeutic options to preserve fertility. [6]

Etiopathogeny The ethiology of cervical pregnancy remains unknown. There are several factors and theories involved in cervical pregnancy. Of these, an important role is played by human assisted reproduction techniques. Some authors suggest that this may be due to laborious embryo transfer with cervical manipulation at the time of embryo transfer or the use of rigid transfer catheters. [8] Another theory involved in the occurrence of cervical pregnancy refers to the rapid passage of the fertilized egg through the uterine cavity that reaches the cervical canal before it is ready for nidation. [5] Cervical surgery, as well as surgery that leads to the destruction of the basal layer of the endometrium can lead to cervical pregnancies. Among these, an important role is played by repeated uterine curettage as well as the presence of Asherman’s Syndrome. [9], [10] The mechanical factors involved are uterine malformations, uterine fibroids, changes in the cervix due to surgery at its level, etc. [8] The predisposing factors of cervical pregnancy are: surgery in the uterine cavity and cervical canal, human assisted reproduction techniques, birth history by caesarean section, anatomical abnormalities of the uterine cavity, intrauterine device, pelvic inflammatory disease. [11]

Pathology The cervical canal, unlike the uterine body, does not have a decidua. In this situation, chorionic villi invade the cervical tissue and its blood vessels as the pregnancy progresses. Basically, in this situation the cervical pregnancy is characterized as an invasion, like an acreta placenta, with the invasion of neighbouring structures, without a cleavage plan. As the pregnancy progresses, the cervical canal becomes insufficient for it, so it will pass from the internal orifice to the isthmic part of the uterus (around 12 weeks of gestation). This pregnancy with cervical isthmic location has a special importance due to the severity given by the invasion of the isthmic territory which is tributary to the uterine arteries with the appearance of fulminant haemorrhages. [11]

Clinical criteria for cervical pregnancy

In establishing the clinical diagnosis of cervical pregnancy, certain signs and symptoms must be followed. The appearance of painless, vaginal bleeding after a period of is the most

64 ©Filodiritto Editore – Proceedings common symptom in cervical pregnancy. Another sign is the hourglass-shaped uterus, with a visible disproportion of the size of the cervix (cervix in the barrel). In cervical pregnancy, the contents of the cervical canal (pregnancy) are intimately attached to the cervix, and the internal cervical orifice is closed, while the external cervical orifice is open. [8], [12]

Ultrasound aspects of cervical pregnancy

At the 2D ultrasound evaluation, the empty uterine cavity is highlighted, with the gestational sac located in the cervical canal, the cervical canal of increased dimensions and the absence of the slip sign of the sac. In cervical pregnancy, at the transvaginal ultrasound evaluation, the gestational sac is fixed, while in the case of an ongoing abortion, at the mobilization of the uterus with the transducer, the gestational sac slides. Doppler ultrasound shows the gestational sac located below the uterine arteries with the presence of peritrophoblastic blood flow. Regarding the ultrasound evaluation of the cervical pregnancy in addition to the 2D ultrasound evaluation, 3D ultrasound can bring more information by reconstructing the images and by visualizing the coronary sections of the uterine cavity. [11], [13], [14], [15], [16] Ultrasound evaluation is the most accessible and important resource in locating a pregnancy. In addition, the ultrasound examination brings additional information about possible fetal abnormalities, adnexal tumours or unfavourable evolution of pregnancy (for example highlights the restriction of intrauterine growth). [17], [18], [19]

Cervical pregnancy management

Methotrexate Methotrexate is an antagonist of folic acid that inhibits fast-growing tissue. As a mechanism of action, it inhibits the binding of dihydrofolic acid to the enzyme dihydrofolate reductase. As a route of administration, it can be administered orally, intramuscularly, intravenously or injected into the ectopic pregnancy sac. Methotrexate can be given as a single or multiple dose. In a single dose, 50 mg/m² is administered, and in multiple doses, 1 mg/kg is administered on days 1, 3, 5 and 7 in association with Leucovirin 0.1 mg/kg on days 2, 4, 6 and 8. [20], [21], [22] Data published in the literature related to the management of ectopic pregnancies with Methotrexate show an increased success rate.[23], [24] Alleyassin and colleagues conducted a randomized study in 2006 aimed at evaluating the success rate in the treatment of ectopic pregnancy with single or multiple doses of Methotrexate. The success rate was 88.9% in the first group and 92.6% in the second group.[25]

Potassium Chloride Another therapeutic option in cervical ectopic pregnancy is the local administration of Potassium Chloride 2mEq/ml under ultrasound guidance. Studies published in the literature are associated with an increased success rate, however, it should be noted that it has been administered in combination with methotrexate. [26], [27], [28], [29]

Dilatation and curettage Cervical dilation, followed by uterine curettage is a therapeutic option for cervical pregnancy, but this is associated with an increased rate of bleeding. [30] The works published in the literature exposed uterine dilation and curettage as a therapeutic option with good success rates, only after the bilateral embolization of the uterine arteries was performed beforehand. [31], [32], [33]

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Surgical treatment Although data from the literature show increased success rates for methotrexate treatment of cervical pregnancy, surgical treatment (total hysterectomy) remains the treatment of choice in some cases. Surgical treatment of cervical pregnancy is applied in cases where Methotrexate therapy has failed, in patients who have contraindications for Methotrexate administration, advanced gestational age and in cases where massive bleeding endangers the lives of patients. [34], [35] There are data presented in the literature in which total hysterectomy was performed due to the occurrence of massive bleeding after conservative treatment. [36]

Case report

Case 1 In October 2019, 21 years old IIGIIP female with no significant past medical history, sent from a rounded hospital presented in the obstetrics and gynaecology clinic of the Sibiu County Emergency Clinical Hospital, with a 2-week history of vaginal bleeding. The patient had a birth by caesarean section in 2017. The patient’s vital signs were within normal limits both at hospitalization and during the entire period of hospitalization. The pelvic examination revealed a barrel-shape uterine cervix with closed external cervical orifice with reduced vaginal bleeding. The preliminary transvaginal ultrasound report indicated a 6-week cervical pregnancy with cardiac activity as you can see in figure 1. Quantitative beta-human chorionic gonadotrophin (βHCG) concentration was 12.000Ui/ml on admission.

Fig. 1. Transvaginal ultrasound 6-week cervical pregnancy

Fig. 2. Cervical Gestational sac with the presence of peri-trophoblastic blood flow

In an attempt to preserve fertility, we offered the patient conservative management with intravenous administration of Methotrexate in a single dose of 10 mg/kg. An increase in βHCG level was observed after treatment. After the treatment, the ultrasound evaluation performed after a week reveals an enlarged gestational sac with persistent fetal cardiac activity as you can see in figure 3. Following the ultrasound evaluation, the puncture of the ovarian sac and the injection in the bag of Methotrexate 50 mg/m² was decided and the intravenous treatment of Methotrexate is repeated.

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Fig. 3. Cervical pregnancy one week after treatment with Methotrexate

Fig. 4. Ultrasound aspect of pregnancy after puncture and administration of Methotrexate in the ovarian sac

At 3 days after the puncture and injection of the ovarian sac with Methotrexate, the ultrasound evaluation shows an image with a diameter of about 40 mm with irregular contour, hypoechoic, inhomogeneous with transonic center, with peripheral Doppler signal. No embryonic echo is visualized as you can see in Figure 4. The βHCG values performed in the dynamics registered a progressive decrease. The patient was discharged and continued to be monitored monthly by ultrasound and by serial doses of β HCG until its values were negative. At the monthly ultrasound evaluations, the appearance of the image described above was maintained with the decrease of its dimensions and with the maintenance of the presence of the peripheral Doppler signal for 2 months, as you can see in Figure 5. In February 2020, the patient is hospitalized for moderate vaginal bleeding. After administration of styptic treatment, bleeding stops. The ultrasound aspect being suggestive for the vaginal elimination of the contents of the cervical canal. Figure 6 Follow- up ultrasound after 5-6 weeks showed almost normal appearance of cervix and uterus.

Fig. 5. Ultrasound of pregnancy 2 months after injection of the ovarian sac with Methotrexate

Fig. 6. Ultrasound appearance 4 months after pregnancy diagnosis

Case 2 The 33-year-old CA patient has a history of natural birth, without other associated pathologies. The patient is hospitalized in the obstetrics and gynaecology clinic of the Sibiu County Emergency Clinical Hospital, with the diagnosis of incomplete abortion established following the pelvic examination and ultrasound evaluation. Uterine curettage of the cavity is performed. During uterine curettage, heavy vaginal bleeding sets in, with signs of acute post haemorrhagic anaemia. Vaginal suturing of the cervicovaginal arteries is performed for haemostatic purposes, after which the bleeding stops. The material extracted after uterine curettage is sent for

67 ©Filodiritto Editore – Proceedings histopathological examination. On day 1 post-curettage, a control ultrasound is performed, which shows a cervical tumour formation, voluminous with dimensions of 80mm/60mm, intensely vascularized in the cervix and peri cervical as you can see in figure 7 and 8. Taking into account the ultrasound aspect and the unfavourable evolution of the case, the quantitative dosing of βHCG was performed. The values obtained after HCG dosing were elevated 40.000 Ui/ml. Following the corroboration of the clinical data, βHCG values and ultrasound examination, the case is interpreted as primary cervical pregnancy a single dose treatment with Methotrexate is instituted – 50mg/m². The result of the histopathological examination issued one week after uterine curettage establishes the diagnosis of molar pregnancy with cervical location. Resume treatment with Methotrexate with continuous administration of daily doses of 1 mg/Kg on days 1,3,5,7 and 9 with rescue therapy with Leucovorin 0.1 mg/kg which is well tolerated by the patient.

Fig. 7. Ultrasound appearance of the tumor formation one day after uterine curettage

Fig. 8. Highlighting Doppler vascularization in the cervical formation

The ultrasound aspect is stationary after the administration of the treatment. On the 10th day after uterine curettage the patient develops septic condition with Klebsiella pneumonia which is corrected with antibiotic therapy. Pelvic computed tomography (CT) is performed, which shows a tumour formation with cervical location, intensely vascularized. At 7 weeks after uterine curettage, the patient presents with abundant vaginal bleeding, which appeared suddenly with the onset of signs of acute anaemia followed by haemorrhagic shock. Cervico-vaginal message is performed for temporary haemostasis and pelvic CT is performed urgently. The CT evaluation highlights the following aspects: the tumour mass is maintained in the cervix and uterine body with the same morphological characteristics, in dimensional progression with current diameters of about 8.5 cm/54.5 cm/8 cm (craniocaudal diameter/antero posterior/laterolateral) (progression of approximately 3 cm of the caudal cranio diameter), with intralesional aerial inclusions, with predominantly peripheral intralesional turgescent vascularization. The formation does not present a demarcation plan for the uterine bladder and rectum, apparently without invasion of these structures (difficult to assess CT). Vaginal distension with dense inhomogeneous marked content and multiple air inclusions.

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Fig. 9. CT aspect of tumour formation

Considering the installation of the haemorrhagic shock, a surgical treatment for vital purpose is decided. Total hysterectomy is performed with preservation of the fallopian tubes and ovaries. Despite the CT examination describing the removal of the cleavage spaces from the rectum and bladder, there were no intraoperative problems with the preservation of the anatomical planes of delimitation of the cervix.

Fig. 10. Surgical piece obtained after surgery

The postoperative evolution of the patient was favourable. The patient was discharged on the 4th postoperative day with good general condition, afebrile. Abdomen loose, elastic, painless spontaneously or on palpation. Supple surgical wound. Vaginal bleeding absent.

Conclusions

Cervical ectopic pregnancy remains a major challenge in early pregnancy and the success of conservative treatment depends mainly on early diagnosis. In the management of cases of cervical pregnancy, all means of treatment must be considered, both conservative and surgical treatment. Pharmaceutical treatment cannot always prevent significant bleeding that requires surgical treatment. It is also important not to lose sight of the fact that cervical pregnancy can be molar and it is important to use all means of diagnosis for proper case management.

REFERENCES

[1] Sijanović, S., Vidosavljević, D., Topolovec, Z., Milostić-Srb, A., & Mrčela, M. (2014). Management of cervical ectopic pregnancy after unsuccessful methotrexate treatment. Iranian journal of reproductive medicine, 12(4), pp. 285-288. [2] Rubin, IC. (1911). Cervical pregnancy. Am J Obstet. Gynecol.; 13: pp. 625-633. [3] Kirk, E., Condous, G., Haider, Z., Syed, A., Ojha, K. and Bourne, T. (2006), The conservative management of cervical ectopic pregnancies. Ultrasound Obstet. Gynecol., 27: pp. 430-437. doi:10.1002/uog.2693 [4] Moga, M.; Ples, L.; Bigiu, N.; Manitiu, I. (2011) An Overview Of The Risk Of Adverse Reproductive And Developmental Disorders Due To Exposure To Pesticides. 12 (3A), pp. 1311-1319. [5] Filippi V, Chou D, Ronsmans C, et al., (2016) Levels and Causes of Maternal Mortality and Morbidity. In: Black RE, Laxminarayan R, Temmerman M, et al., editors. Reproductive, Maternal, New-born, and Child Health: Disease Control Priorities, Third Edition (Volume 2). Washington (DC): The International Bank for Reconstruction and Development/The World Bank; Apr 5. Chapter 3 https://www.ncbi.nlm.nih.gov/books/NBK361917/ doi: 10.1596/978-1-4648-0348-2_ch3 [6] Leeman, LM. Wendland, CL. (2000) Cervical ectopic pregnancy: diagnosis with endovaginal ultrasound examination and successful treatment with methotrexate. Arch Fam Med; 9: pp. 72-77.

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[7] Raskin MM. (1978) Diagnosis of cervical pregnancy by ultrasound: a case report. Am J Obstet. Gynecol. Jan 15; 130(2): pp. 234-5. doi: 10.1016/0002-9378(78)90377-0. PMID: 619667. [8] Drezett, J., Marques, D., Ottoboni, R., Dzik, A., & Cavagna, M. (2019). Cervical ectopic pregnancy after in vitro fertilization: case report successfully treated with cervical electric aspiration. JBRA assisted reproduction, 23(4), pp. 434-438. https://doi.org/10.5935/1518-0557.20190036 [9] Shinagawa, S., Nagayama, M. (1969) Cervical pregnancy as a possible sequela of induced abortion. Report of 19 cases. Am J Obstet. Gynecol., 105: pp. 282-284. [10] Dicker, D. Feldberg, D. Samuel, N. Goldman, JA. (1985) Ethiology of cervical pregnancy. Association with abortion, pelvic pathology, IUDs and Asherman’s syndrome. J Reprod Med 30: pp. 25-27. [11] Hosni MM, Herath RP, Mumtaz R. (2014) Diagnostic and therapeutic dilemmas of cervical ectopic pregnancy. Obstet. Gynecol. Surv. May; 69(5): pp. 261-76. doi: 10.1097/OGX.0000000000000062. PMID: 25101692. [12] Chen D, Kligman I, Rosenwaks Z. (2001) Heterotopic cervical pregnancy successfully treated with transvaginal ultrasound-guided aspiration and cervical-stay sutures. Fertil Steril. 2001 May; 75(5): pp. 1030- 3. doi: 10.1016/s0015-0282(01)01746-0. PMID: 11334923. [13] RUANO, R et al., (2006) Three-dimensional ultrasonographic diagnosis of a cervical pregnancy. Clinics [online], vol. 61, n. 4 [cited 2020-10-10], pp. 355-358. https://doi.org/10.1590/S1807-59322006000400014. [14] Ushakov, Fedor B.; Elchalal, Uriel; Aceman, Paul J.; Schenker, Joseph G. (1997) Cervical Pregnancy: Past and Future, Obstetrical & Gynaecological Survey: January – Volume 52 – Issue 1 – pp. 45-59. [15] Igbokwe N, Jeyanesan D, Mehta A (2020) Management of Live Cervical Ectopic Pregnancy. Ann Clin Lab Res. Vol. 8 No. 1: p. 310. doi:10.36648/2386-5180.8.1.310 [16] Fylstra DL. (2014) Cervical pregnancy: 13 cases treated with suction curettage and balloon tamponade. Am J Obstet. Gynecol.; 210: p. 581. [17] Pleş L, Sima RM, Burnei A, Albu DF, Bujor MA, Conci S, Teodorescu V, Edu A. Rom J MorpholEmbryol (2016). The experience of our Clinic in laparoscopy for adnexal masses and the correlation between ultrasound findings and pathological results, Rom J Morphol Embryol 57(4): pp. 1337-1341. [18] Stanescu AD, Banica R, Sima RM, Ples L. (2018) Low dose aspirin for preventing fetal growth restriction: a randomised trial. J Perinat Med. 2018 Jan 30. pii: /j/jpme.ahead-of-print/jpm-2017-0184/jpm-2017- 0184.xml. doi: 10.1515/jpm-2017-0184. [Epub ahead of print] [19] Ples, L.; Sima, Romina, M.; Stanescu, A. Daniela; O. Octavian, G. (2017) The Importance of a National Congenital Anomalies Registry – the Role of the Prenatal Diagnosis Proceeding paper for the 5TH ROMANIAN CONGRESS OF THE ROMANIAN SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY pp. 505-510. [20] Hajenius, PJ. Mol, F. Mol, BWJ. Bossuyt, PMM. Ankum, WM. Van der Veen, F. (2007) Interventions for tubal ectopic pregnancy. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD000324. DOI: 10.1002/14651858.CD000324.pub2. [21] F. Mol, B.W. Mol, W.M. Ankum, F. van der Veen, P.J. Hajenius, (2008) Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis, Human Reproduction Update, Volume 14, Issue 4, July-August, Pages 309-319, https://doi.org/10.1093/humupd/dmn012 [22] Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013 Sep; 100(3): pp. 638-44. doi: 10.1016/j.fertnstert.2013.06.013. Epub 2013 Jul 10. PMID: 23849842. [23] Lipscomb, GH. Givens, VM. Meyer, NL. Bran, D. (2005) Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. Am J Obstet. Gynecol. 2005 Jun; 192(6): pp. 1844-7; discussion 1847-8. doi: 10.1016/j.ajog.2004.12.061. PMID: 15970826. [24] Barnhart KT, Gosman G, Ashby R, Sammel M. (2003) The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstet. Gynecol. 2003 Apr; 101(4): pp. 778-84. doi: 10.1016/s0029-7844(02)03158-7. PMID: 12681886. [25] Alleyassin A, Khademi A, Aghahosseini M, Safdarian L, Badenoosh B, Hamed EA. (2006) Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril. 2006 Jun; 85(6): pp. 1661-6. doi: 10.1016/j.fertnstert.2005.11.055. Epub 2006 May 2. PMID: 16650421. [26] Júnior JE, Musiello RB, Araujo Júnior E, Souza E, Fava JL, Guerzet EA, Camano L. (2014) Conservative management of cervical pregnancy with embryonic heart activity by ultrasound-guided local injection: an eight-case series. J Matern Fetal Neonatal Med. 2014 Sep; 27(13): pp. 1378-81. doi: 10.3109/14767058.2013.856413. Epub. 2013 Nov 13. PMID: 24134459.

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[27] Petousis, S., Margioula-Siarkou, C., Kalogiannidis, I., Karavas, G., Palapelas, V., Prapas, N., & Rousso, D. (2015). Conservative management of cervical pregnancy with intramuscular administration of methotrexate and KCl injection: Case report and review of the literature. World journal of clinical cases, 3(1), pp. 81-84. https://doi.org/10.12998/wjcc.v3.i1.81 [28] Yavanasuriya J, Anish Keepanasseril, Kubera NS, Dilip Kumar Maurya, and Gowri Dorairajan. Journal of Gynaecologic Surgery. Oct 2016.290-292 http://doi.org/10.1089/gyn.2016.0003 [29] Dawood A S, Farahat M A, (2019) Intra-cardiac feticide injection for cervical ectopic pregnancy less than 10 weeks of gestation: A case report and review of literature. Indian J Obstet. Gynecol. Res 2019; 6(2): pp. 233-236. [30] Jurkovic, D., Hacket, E. and Campbell, S. (1996), Diagnosis and treatment of early cervical pregnancy: a review and a report of two cases treated conservatively. Ultrasound Obstet. Gynecol., 8: pp. 373-380. doi:10.1046/j.1469-0705.1997. 08060373.x [31] Nakao Y, Yokoyama M, Iwasaka T. (2008) Uterine artery embolization followed by dilation and curettage for cervical pregnancy. Obstet. Gynecol. 2008 Feb; 111(2 Pt 2): pp. 505-7. doi: 10.1097/01.AOG.0000286771.10377.4e. PMID: 18239001. [32] Martinelli P, Maruotti GM, Oppedisano R, Agangi A, Mazzarelli LL, Votino C, Quarantelli M, Iaccarino V. (2007) Is uterine artery embolization for cervical ectopic pregnancy always safe? J Minim Invasive Gynecol. 2007 Nov-Dec; 14(6): pp. 758-63. doi: 10.1016/j.jmig.2007.05.017. PMID: 17980340. [33] Xu B, Wang YK, Zhang YH, Wang S, Yang L, Dai SZ. (2007) Angiographic uterine artery embolization followed by immediate curettage: an efficient treatment for controlling heavy bleeding and avoiding recurrent bleeding in cervical pregnancy. J Obstet. Gynaecol. Res. 2007 Apr; 33(2): pp. 190-4. doi: 10.1111/j.1447-0756.2007.00512. x. PMID: 17441894 [34] Al-Sunaidi M, Tulandi T. (2007) Surgical treatment of ectopic pregnancy. Semin Reprod Med. 2007 Mar; 25(2): pp. 117-22. doi: 10.1055/s-2007-970050. PMID: 17377898. [35] Alammari R, Thibodeau R, Harmanli O. (2017) Vaginal Hysterectomy for Treatment of Cervical Ectopic Pregnancy. Obstet. Gynecol. 2017 Jan; 129(1): pp. 63-65. doi: 10.1097/AOG.0000000000001782. PMID: 27926641. [36] Río de la Loza Cava L, Moyers Arévalo JA. (2012) Embarazo ectópico cervical. Cuando el tratamiento conservador falla. Reporte de un caso y revisión de la bibliografía [Ectopic cervical pregnancy, when conservative treatment fails. Case report and literature review]. Ginecol. Obstet. Mex. 2012 Oct; 80(10): pp. 668-72. Spanish. PMID: 23240232.

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Is Pelvic MRI Required as a Complementary Examination to Ultrasound?

DICULESCU Doru1, MIHU Dan1, NICULA Renata1, MOCAN-HOGNOGI Radu1, MĂLUȚAN Andrei1, IUHAS Cristian1, OANCEA Mihaela1, BUCURI Carmen1, PORUMB Ciprian1, POP Daria1

1 “Iuliu Hațieganu” University of Medicine and Pharmacy Cluj-Napoca, Faculty of Medicine, Department of Obstetrics and Gynaecology II (ROMANIA)

Abstract

Adnexal masses are frequently detected by ultrasound and pose diagnostic problems, because sometimes benign and malignant characteristics overlap. MRI is preferred as a second imaging method for the evaluation of an insufficiently defined adnexal mass, in order to provide the best care. Magnetic resonance imaging allows more accurate and complete diagnosis and staging than ultrasound, especially in cases of deep pelvic endometriosis. In addition, MRI can identify implants at sites difficult to access by laparoscopy. The first-line examination of pelvic venous insufficiency, frequent in multiparous women, is ultrasound and Doppler, but MRI, which is less invasive than venography, allows even a 3D study of pelvic varicose veins. In assessing the pelvic diaphragm, ultrasound and MRI are comparable and demonstrate a moderate value. Non-visualization of ovaries by ultrasound, magnetic resonance-guided focused ultrasound in the non-invasive treatment of uterine fibromas represent other situations that prove the increasingly frequent need to associate pelvic MRI with ultrasound.

Keywords: MRI, gynaecological pathology

Introduction

Ultrasound represents the technique that uses high frequency sound waves to create a live video image visualizing the structure of organs, the movement and flow of the blood through the vessels. When gynaecologists evaluate their patient, they will mainly use ultrasound. MRI uses a strong magnetic field combined with specific radio frequencies to create detailed images of the internal structures of the body by means of a sophisticated calculation system. MRI can be useful for the diagnostic evaluation of endometriosis, pelvic abdominal pain, pelvic masses, the assessment of pelvic venous insufficiency, even in genital prolapse, as well as for the guidance of highly specific treatments.

Frequent gynaecological pathologies evaluated with MRI

Endometriosis is frequent in women of reproductive age. It is important to diagnose and thoroughly evaluate the extension of endometriosis, particularly when surgery is taken into

72 ©Filodiritto Editore – Proceedings consideration. There are three types of pelvic endometriosis: ovarian endometriomas, peritoneal implants, and deep pelvic endometriosis. Ovarian endometriotic cysts are usually diagnosed by ultrasound. However, MRI can be more useful in some cases, because it allows a more specific diagnosis of endometrioma and differentiates blood clots from blood rests in the solid areas of neoplastic cysts (1). MRI specialists will characterize endometriomas as hyperintense cysts in T1 and shadows in T2 (figures 1 and 2). The loss of signal in T2, even if not necessarily present, is an extremely specific sign of endometrioma (2).

Fig. 1. Endometrioma in T1 on MRI after image adjustment; notice the obvious delimitations from surrounding normal tissues (personal collection)

Fig. 2. Same endometrioma as the first image in T2 on MRI (personal collection)

Deep pelvic implants appear as hypointense in T2 and intermediate in T1, when the fibrous component is predominant. The most difficult to diagnose by MRI and impossible to diagnose clinically or ultrasonographically are peritoneal implants several mm in size. They can be diagnosed by MRI when they have a haemorrhagic content and occur in T1 as hyperintense foci. Moreover, MRI can identify endometriotic implants at sites difficult to access laparoscopically or endoscopically (3). On MRI, adenomyosis (which is not included in the concept of deep endometriosis) appears as a thickening of the myometrial junction, highly suggestive when it exceeds 12 mm. However, myometrial involvement can also be nodular, making it difficult to differentiate adenomyosis from myomas by MRI (4). In general, most of the authors agree that the initial imaging exploration should be ultrasound, while MRI is an additional exploration tool in the presence of a suspicion of deep pelvic endometriosis, when ultrasound is inconclusive or when surgical treatment is planned.

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Radiological results should be adequately communicated to gynaecologists in a simple and clear language. Adnexal masses detected incidentally are frequent, posing diagnostic problems because the benign and malignant imaging characteristics overlap. This is why once an adnexal lesion has been detected, the main goal is to best characterize the lesion, which will be subjected or not to surgery (figure 3) (5).

Fig. 3. Adnexal mass in T2 on MRI. A benign ovarian cyst well defined, with no septation or vascularization. Minimal additional value with MRI when compared with ultrasound; on the other hand, the additional hydrosalpinx is more accurately defined compared to ultrasound evaluation (personal collection)

MRI should be preferred as a second imaging opinion regarding the detection of ovarian cancer or for assessing an insufficiently defined adnexal mass, in order to allocate the best care. MRI with an intravenous contrast substance (gadolinium) is useful for the evaluation of complex adnexal lesions, particularly in the presence of a suspicion of malignant lesions. The important contribution of MRI to evaluating adnexal masses is its specificity, which ensures a reliable diagnosis of many benign adnexal lesions (figure 4) (6).

Fig. 4. Adnexal mass in T2 on MRI. An ovarian cancer showing a mixt tumour imprecisely defined with a mixt structure (parenchymatous and liquid) (personal collection)

Practically, MRI should be considered the gold standard technique for the subsequent assessment of an adnexal lesion imprecisely characterized by ultrasound (7). Frequent gynaecological causes of pain during pregnancy include complications related to adnexal masses (ovarian masses, mobile uterine leiomyomas), which have a higher torsion incidence during pregnancy. Adnexal masses are found in 4% of all pregnancies and may cause acute pelvic pain due to haemorrhage or torsion (8).

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Most of the masses can be assessed by ultrasound. MRI can provide more characteristics, such as haemorrhagic content, identification of a pedunculated leiomyoma, characterization of an ovarian mass (8). MRI can also be useful in the diagnosis of conditions mimicking the torsion or rupture of an ovarian tumour, such as appendicitis and inflammatory bowel disease (8, 9, 10).

Special circumstances

Non-visualization of the ovaries by ultrasound poses problems particularly if symptoms are located in the area where the ovary/ovaries cannot be visualized. Non-visualization of the ovaries can be due to a number of factors: experience, diligence, and inadequate functioning of the equipment. The rate in the literature varies between 2-40%. Studies have demonstrated that MRI is a reliable method to exclude malignancy when the ovaries cannot be visualized by ultrasound. Adhesions, which are a frequent cause of pelvic pain, cannot be adequately visualized by either of the methods (11). The gold standard imaging diagnostic instrument for polycystic ovary syndrome, which is ultrasound, can have an important limitation in the case of overweight and obese virgin adolescents. MRI can be a useful alternative (12). Pelvic venous insufficiency is a frequent disease in multiparous women. Diagnosis can be incidental or suspected in the case of symptoms suggesting pelvic congestion syndrome or atypical varicose veins of the lower limbs. The first line of examination is ultrasound and Doppler, but few specialists are able to assess these varicose veins, which collapse in the presence of a full bladder, required for suprapubic evaluation. Ultrasound confirmation would be followed by dynamic venography, which is irradiating, but MRI is less invasive and allows a 3D study of pelvic varicose veins (13). In evaluating the pelvic diaphragm at rest in patients with genital prolapse (GP), it has been shown that the two methods are comparable, with a similar but moderate value (14, 15, 16).

Future methods in use today

High-intensity focused ultrasound (HIFU), guided either ultrasonographically or by MRI (magnetic resonance-guided focused ultrasound = MRgFUS), is used for the non-invasive treatment of symptomatic uterine fibroids. MRgFUS integrates the power of ablation of ultrasounds with magnetic resonance to guide treatment and monitor results. It uses precisely focused ultrasounds to generate and maintain temperatures higher than 56º in the target tissue, resulting in protein denaturation, cell death and coagulative necrosis (17). Not all patients are candidates for this procedure, although it is safe, effective and non-invasive (18). Potential candidates are screened by pelvic MRI (19). MRI can provide a much better characterization of fibroids regarding the location in the pelvis, the position and size of the fibroid, its position in relation to the neighbouring anatomical structures. Injecting a gadolinium-based contrast agent can also be used to evaluate the hemodynamic characteristics of the fibroid (17). MRI can help in the percentage determination of the part of fibroids situated within the cavity, and this information can be useful in deciding hysteroscopic ablation (20, 21).

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Conclusions

1. MRI can help in the selection of optimal treatment for uterine fibroids. 2. Most of the authors agree that the initial imaging exploration should be ultrasound, while MRI is an additional exploration tool useful in the evaluation of endometriosis, particularly when surgery is planned. 3. MRI should be considered the gold standard technique in the subsequent evaluation of an adnexal lesion imprecisely characterized by ultrasound. 4. MRI is not invasive and allows the 3D study of pelvic varicose veins in pelvic venous insufficiency. 5. Radiological results should be adequately communicated to gynaecologists in a simple and clear language.

REFERENCES

[1] R. Méndez Fe rnández, J. Barrera Ortega. Magnetic resonance imaging of pelvic endometriosis. Radiología. 2017;59(4): pp. 286-296 [2] Hottat N, Larrousse C, Anaf V, Noël JC, Matos C, Absil J, et al., Endometriosis: contribution of 3.0-T pelvic MR imaging in preoperative assessment-initial results. Radiology. 2009; 253: pp. 126-34. [3] Koninckx PR, Ussia A, Adamyan L, Wattiez A, Donnez J. Deep endometriosis: definition, diagnosis, and treatment. Fertil Steril. 2012; 98: pp. 564-71. [4] Novellas S, Chassang M, Delotte J, Toullalan O, Chevallier A, Bouaziz J, et al., MRI characteristics of the uterine junctional zone: from normal to the diagnosis of adenomyosis. AJR Am J Roentgenol. 2011; 196: pp. 1206-13. [5] Togashi K. Ovarian cancers: the clinical role of US, CT, and MRI. Eur Radiol 2003; 13 Suppl. 4: pp. 87-104 [6] Kawahara K, Yoshida Y, Kurokawa T, Suzuki Y, Nagahara K, Tsuchida T, et al., Evaluation of positron emission tomography with tracer 18-fluorodeoxyglucose in addition to magnetic resonance imaging in the diagnosis of ovarian cancer in selected women after ultrasonography. J Comput Assist Tomogr 2004; 28(4): pp. 505-16. [7] C. Anthoulakis, N. Nikoloudis. Pelvic MRI as the “gold standard” in the subsequent evaluation of ultrasound- indeterminate adnexal lesions: A systematic review. Gynaecologic Oncology, journal homepage: www.elsevier.com/locate/ygyno, 2013. http://dx.doi.org/10.1016/j.ygyno.2013.10.022 [8] Diculescu Doru, Mihu Dan, Florescu Fulga, Ciortea Razvan, Malutan Andrei, Oancea Mihaela, Bucuri Carmen, Iuhas Cristian. Ultrasound Evaluation and Management of Adnexal Masses During Pregnancy. Proceedings of the 6th Congress of the Ultrasound Society in Obstetrics and Gynaecology/34th Fetus as a patient International Congress, 2018, pp. 155-160. [9] Gabriele Masselli, Lorenzo Derchi, Josephine McHugo, Andrea Rockall, Peter Vock, Michael Weston, John Spencer. Acute abdominal and pelvic pain in pregnancy: ESUR recommendations. Eur Radiol (2013) 23: pp. 3485-3500 DOI 10.1007/s00330-013-2987-7. [10] Tarannum A, Sheikh H, Appiah-Sakyi K, Lindow SW, The Diagnostic use of Magnetic Resonance Imaging for Acute Abdominal and Pelvic Pain in Pregnancy, European Journal of Obstetrics and amp; Gynaecology and Reproductive Biology (2019), doi: https://doi.org/10.1016/j.ejogrb.2019.11.027. [11] Christopher J. Lisanti, Jonathan R. Wood, Ryan B. Schwope. Non-visualization of the ovaries on pelvic ultrasound: does MRI add anything? Abdom Imaging (2014) 39: pp. 162-167 DOI: 10.1007/s00261-013- 0046-0. [12] Simon Kayemba-Kay’s, Armelle Pambou, Anne Heron, Sidi Mohammed Benosman. [13] Polycystic ovary syndrome: Pelvic MRI as alternative to pelvic ultrasound for the diagnosis in overweight and obese adolescent girls. International Journal of Paediatrics and Adolescent Medicine 4 (2017) pp. 147- 152. [14] L.M. Leiber, F. Thouveny, A. Bouvier, M. Labriffe, E. Berthier, C. Aubé, S. Willoteaux. MRI and venographic aspects of pelvic venous insufficiency. Diagnostic and Interventional Imaging (2014) 95, pp. 1091-1102, http://dx.doi.org/10.101/j.diii.2014.01.012

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[15] Xudong Wang, Min Ren, Yujie Liu, Tiecheng Zhang, Jiawei Tian. Perineal Ultrasound Versus Magnetic Resonance Imaging (MRI) Detection for Evaluation of Pelvic Diaphragm in Resting State. Med Sci Monit, 2018; 24: pp. 4449-4454 DOI: 10.12659/MSM.906648. [16] Rada Maria-Patricia, Ciortea Razvan, Malutan Andrei Mihai, Diculescu Doru, Berceanu Costin, Oancea Mihaela, Iuhas Cristian Ioan, Bucuri Carmen Elena, Roman Andrei, Mihu Dan. Transperineal Ultrasound Assessment of a Cystocele’s Impact on the Bladder Neck Mobility in Women with Stress Urinary Incontinence. Medicina 2019, 55, 562; doi: 10.3390/medicina55090562, www.mdpi.com/journal/medicina [17] Magnetic resonance imaging and 3-dimensional transperineal ultrasound evaluation of pelvic floor dysfunction in symptomatic women: a prospective comparative study Dahlia O. El-Haieg, Nadia M. Madkour, Mohammad Abd Alkhalik Basha, et al., Ultrasonography 2019; 38: pp. 355-364 https://doi.org/10.14366/usg.19007 [18] Sang-Wook Yoon, Chan Lee, Sun Hee Cha, Jeong-Sik Yu, Young-Jeong Na, Kyoung Ah Kim, Sang-Geun Jung, Seung-Jo Kim. Patient selection guidelines in MR-guided focused ultrasound surgery of uterine fibroids: a pictorial guide to relevant findings in screening pelvic MRI. Eur Radiol (2008) 18: pp. 2997-3006. DOI 10.1007/s00330-008-1086-7. [19] Cura M, Cura A, Bugnone A. Role of magnetic resonance imaging in patient selection for uterine artery embolization. Acta Radiol (2006) 47: pp. 1105-1114. [20] Samuel A, Stewart EA et al., Avoiding treatment of leiomyosarcomas: the role of magnetic resonance in focused ultrasound surgery. Fertil Steril. (2007) doi: 10.1016/j.fertnstert.2007.08.019 [21] H Marret, F Tranquart. E chographie et IRM pelviennes, ou la surenche re est-elle justifie e? Is over increase in pelvic ultrasound and MRI justified? Gynecologie Obstetrique & Fertilite 38 (2010) pp. 163-165. [22] Dueholm M, Lundorf E, Hanse ES, Ledertoug S, Olesen F. Evaluation of the uterine cavity with magnetic resonance imaging, transvaginal sonography, hysterosonographic examination, and diagnostic hysteroscopy. Fertil Sterilt 2001; 76: pp. 350-7.

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Posterior Urethral Valves and Associated Pop-Off Mechanisms in a New-born – Case Report

FILIPESCU Alexandru-George1,2, MARIN Alina-Gabriela1,2, MUNTEANU Alexandra2, VLĂDĂREANU Radu1,2*, VLĂDĂREANU Simona1,3

1 Carol Davila University of Medicine and Pharmacy, Bucharest, (ROMANIA) 2 Obstetrics and Gynaecology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 3 Neonatology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) * Corresponding author: VLĂDĂREANU Radu Email: [email protected]

Abstract

Posterior urethral valve (PUV) is the most common ethiology of obstructive uropathy in the male pediatric population. It is also acknowledged as Congenital Obstructive Posterior Urethral Membrane (COPUM) [1, 2] for its wide-ranging spectrum of clinical presentation, disease severity involving progressive renal deterioration and developing chronic kidney disease at varying ages as well as associated sequelae. Evolving PUV may lead to pop-off mechanisms in order to prevent the development of high intravesical pressure and to preserve renal function [3]. We present the medical case of a new-born boy diagnosed prenatally with PUV and left vesicoureteral reflux, who underwent vesicoamniotic shunt insertion and postnatal endoscopic PUV ablation and made satisfactory postoperative recovery up to his first month of life, with indication on follow-up of preservation of renal function. The aim of this study was to assess the long-term renal outcome and determine the prognostic significance of various factors in PUV cases.

Keywords: posterior urethral valve, vesicoamniotic shunt, valve ablation, vesico-ureteral reflux

Introduction

Posterior urethral valves (PUV) represent a congenital malformation of the posterior urethra, which stands as the most common cause of lower urinary tract obstruction in male foetuses, occurring in 1 in 4000 to 8000 pregnancies [4-6]. It was first described by Hugh Hampton Young in 1919, who divided PUV into three types [7] (see Fig. 1): • Type I, ~95% of PUVs, in which valves are represented by membranous folds extending inferiorly from the verumontanum to the membranous urethra; it’s believed to result from abnormal insertion and absorption of the most distal aspects of the wolffian ducts during bladder development. In the healthy male, the remnants of these ducts are observed as the plicae colliculi. • Type II, in which valves are bicuspid and are represented as leaflets radiating from the verumontanum cranial to the bladder neck; this type is nowadays very rarely diagnosed among the pediatric population; • Type III, ~5% of PUVs, in which valves are represented as concentric diaphragms within the prostatic urethra, being localized either above or below the verumontanum. It is

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believed to originate from incomplete canalization between the anterior and the posterior urethra and associates the worst prognosis.

Fig. 1. Classification of PUV (from Young, 1919)

The grade of the obstruction determines secondary effects noted on the bladder, ureters and kidneys, PUV being recognized also as the most common cause of chronic kidney disease (CKD) due to lower urinary tract obstruction in children [8]. Morbidity in terms of recurrent urinary tract infection (UTI), worsening of renal functions and growth failure may be decreased by timely and aggressive approach, which implies surgery, pharmacology with or without clean intermittent catheterization. The long-term outcome, however, remains poor if there is associated renal dysplasia.

Medical case

We are going to describe a medical case of a primigravida, 32 years of age, without any significant medical history that could be linked to her new-born’s case, who did not undergo first trimester screening and, therefore, being submitted to a non-invasive prenatal test that cut the risks for the most frequently diagnosed chromosomal abnormalities. The male fetus has been diagnosed during the second trimester screening – at 22 weeks of gestation - with PUV, without any other structural anomalies that could have been observed during the ultrasonographic examination (see Fig. 2). By that moment we noted the presence of the “keyhole sign” – considered a pathognomonic sign for obstructive uropathy due to marked distention of the bladder (47 mm along the greatest diameter) and the urethra immediately proximal to the valve –, the right kidney showed a pelvic dilatation of 6-7 mm that was extending to the primary calyx with a normal echogenic parenchyma of 5 mm depth and the left kidney showed a pelvic dilation of 7-10 mm, with a grade 3 hydronephrosis and a normal echogenic parenchyma of 2-3 mm depth. A very important aspect is that the amniotic fluid quantity by the moment of evaluation was within the normal range; this last fact pleaded for an incomplete urinary obstacle.

a. b. Fig. 2. Ultrasonographic images: a. Male external genital organs; b. Keyhole sign (dilated fetal bladder with dilatation of the vesical neck)

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At 23 weeks of gestation we took a sample of the fetal urine via vesicocentesis and analysed its biochemistry: urine osmotic concentration 164.15 mOsm/kg (normal range: 50-1200 mOsm/kg); urine potassium 2.55 mmol/L (normal range: 20-80 mmol/L); urine sodium 75 mmol/L; urine chloride 63 mmol/L; urine beta 2-microglobuline 5.96 mg/L (normal range <0.2 mg/L). In order to prevent oligohydramnios and subsequent lung underdevelopment or pulmonary hypoplasia, we chose to insert a vesicoamniotic shunt (allowing this way urine to exit the bladder through the shunt and therefore bypassing the obstructed urethra) at 24 weeks of gestation, after which the foetus’s urinary obstruction parameters begun to improve. The fetus was further evaluated via ultrasonography to assess the grade of urinary obstruction and also the possibility of developing other associated anomalies (see Fig. 3) and, 2 weeks later, the shunt appeared to be dislodged; therefore, at 27 weeks of gestation, we took into account the insertion of a second vesicoamniotic shunt in order to maintain the functionality of the urinary tract.

a. b. c. Fig. 3. a. and b. Ultrasound images showing bilateral pyelocaliceal dilation, the left kidney having a markedly dilated calyces and thinning of the renal parenchyma; c. Normal amniotic fluid index.

Birth took place at 33 weeks of gestation, revelling a new-born of 1970 grams, who presented with normal findings on physical examination; on the abdominal ultrasound were described the following parameters: the right kidney of 48 mm/16 mm, parenchyma depth of 7-8 mm, with the notice of a normal corticomedullary differentiation and pyelocaliceal dilation (calyx of 4 mm and pelvis of 3 mm) as well as proximal uretero-hydronephrosis; the left kidney of 45 mm/20 mm, parenchyma depth of 2.4-5 mm, with abnormal corticomedullary differentiation and the presence of renal dysplasia with cortical cysts of maximum 2.2 mm, the left ureter was observed through all of the segments, dilated, with a tortuous pattern; the bladder presented as thick-walled and trabeculated, with endoluminal echoes and an elongated and dilated posterior urethra that reached up to 6.3 mm. We also performed a voiding cystourethrogram (VCUG) which is the best imaging technique regarding the diagnosis of PUV and we noted the bladder with irregular, pseudodiverticula outline, incomplete voiding with left vesicoureteral reflux and dilated, tortuous left ureter and pyelocaliceal system, dilated posterior urethra. Endoscopic valve ablation (via laser fulgurations) is considered the most common surgical procedure for this condition; therefore, the new-born was submitted to the procedure at 12 days after birth. A very important aspect observed during the procedure is that the obstacle was indeed incomplete. Postablation, we monitored renal function and the risk of developing renal tubular acidosis by regular serum creatinine, soda bicarbonate levels and urinalysis, all the levels being within the normal range. After a couple of days the new-born was discharged with normal lab tests (white blood cells ; creatinine 0.36 mg/dL; urea 29 mg/dL; sodium 138 mmol/L; potassium 4.91 mmol/L;

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PCR 0.01 mg/dL; 18.3*109/L; sterile urine culture) having the indication of further evaluating urinalysis and urine culture and assessing postvoid residue and also to monitor the necessity of subsequent surgery.

Discussion

In male embryos, the paramesonephric (Müllerian) ducts suffer degeneration, while the mesonephric (Wolff) ones develop into the ductus deferens, ejaculatory duct and seminal vesicle. Between 4-6 weeks of gestation, the cloaca is divided into the anorectal canal and the urogenital sinus, the last one being subsequently divided by the insertion of the mesonephric duct into the cephalad vesicourethral canal giving rise to the bladder and pelvic urethra, and the caudal portion of the urogenital sinus (known as the genital tubercle) which forms the phallic urethra. In the male fetus, the urethral groove and folds are created as the genital tubercle elongates and as the penile urethra grows, it moves towards the urethral plate of the glans penis. Therefore, complete fusion of the entire urethra occurs at 14 weeks gestation (see Fig. 4) [9].

Fig. 4. Urogenital development (from Langman’s Medical Embryology (11th edition))

Although the exact mechanism resulting in this obstruction is not fully understood, the pathogenesis of PUV appears to be due to a disruption of the normal embryologic development of the male urethra between weeks 9 and 14 of gestation, which results in the obstructing membranous folds within the lumen of the posterior urethra [10]. The morbidity associated to PUV is directly proportional to the moment of appearance of the congenital urinary obstruction during organogenesis (the earlier it appears, the more significant and profound will the urinary system dysfunction be). Also, it is not entirely limited to transient urethral obstruction; this process is characterized by dynamism – the bladder dysfunction can determine ongoing and progressive renal deterioration and even progress to end-stage renal disease (ESRD) in approximately one third of patients born with PUVs. In spite of the physiological changes, the obstructive process determines increased collagen deposition and muscle hypertrophy that leads a significantly thickened bladder wall that limits its compliance during filling [11]. Bladder emptying then occurs at high intravesical pressures, which, in time, can be transmitted to the upper urinary system leading to a grater susceptibility to incontinence, infection, and progressive renal damage; the created pressure can be dissipated or buffered through three possible “pop-off” mechanisms (see Fig. 5) that have as the main result the preservation of a better renal function and therefore allows for normal development of one or even both kidneys:

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1. VURD syndrome (represented by posterior urethral valves, unilateral vesicoureteral reflux and renal dysplasia); 2. Large bladder diverticulum (determining aberrant micturition into the diverticulum); 3. Urinary extravasation with or without urinary ascites (urine leaks from the fornices of the kidneys or from a bladder rupture) [12].

Fig. 5. A voiding cystourethrogram showing posterior urethral valve and pop-off mechanisms. (from Pediatric Surgery, AlSadik Hospital, Qatif, Saudi Arabia)

Although, historically, a “pop-off” mechanism has been regarded as a protective one for long- term renal outcome, its ultimate effect on bladder function has been understudied. D’Oro et al., discovered in their retrospective study that patients with pop-off mechanisms required more extensive interventions in order to achieve continence, and also a greater time to achieve continence and toilet-training than patients without pop-offs. Also, they observed that, at initial presentation, patients with pop-offs had worse bladder dynamics, this fact suggesting that pop- offs might be a manifestation of a much greater intravesical pressure prior to endoscopic valve ablation [3]. As patients with PUV age, bladder decompensation may develop, determining detrusor failure and increased bladder capacity, this fact may be a consequence of overproduction of urine secondary to tubular dysfunction and to the inability to concentrate urine (nephrogenic diabetes insipidus). [11]. Bladder dysfunction can persist even in adulthood for one third of patients, 15% of adults with a history of PUV presenting with urinary incontinence [13]. Renal function in PUV patients depends on a number of risk factors, therefore, renal function deterioration has been linked to age at presentation, glomerular filtration rate (GFR), prenatal diagnosis, renal dysplasia, VUR, renal scarring, nadir creatinine during 1st year of life, upper tract obstruction, bladder dysfunction and UTI. Ansari et al., noted in their study that nadir serum creatinine (P<0.0001 OR 23.79; CI 8.20- 69.05) and the severity of bladder dysfunction (P<0.0001 OR 5.67; CI 1.90-16.93) stand as independent risk factors and also as the main risk factors affecting long-term renal outcome in cases of PUV, with great prediction of progression to ESRD. Serum creatinine level at age 1 year has a much more predictive value than the level at diagnosis, therefore, if initial serum creatinine was ≤1 mg/dl before valve ablation, CRF developed in 23% of cases while it developed in 72% of cases who presented with creatinine above 1 mg/dl (P<0.05) [14-16]; also, serum creatinine level <0.8 mg/dl under the age 3 and 0.5-1.0 mg/dL for children with ages between 3-18 years is considered safe and is associated with practically normal final renal function. [17], whether deterioration of upper function associated with persistent high creatinine levels suggests ESRD

82 ©Filodiritto Editore – Proceedings and the need for renal replacement. Another important marker is GFR which was noted as significantly lower than those without renal failure (P<0.05). [14] Bajpai et al., discovered in their study that CRF developed in 48.8% of patients with renal cortical scars in comparison with 34.8% in patients without renal scars (P=0.099) [14]. Although age at presentation has been considered a predictor of renal function in children with PUV, because prenatal diagnosis was thought to improve the outcome, there are no conclusive studies about the superiority of the long-term outcome in prenatally detected PUV cases compared to the ones detected postnatally. [18-19, 20] Also, early identification of detrimental factors (such as urinary transforming growth factor-beta 1, tumour necrosis factor-alpha and microalbumin levels that were considered to be biomarkers for the early recognition of ongoing renal damage in these particular cases) that cause long-term renal deterioration is necessary in patients with PUV in order to guide future therapy. [21, 22]

Conclusion

Low urinary tract obstruction can lead to significant morbidity and mortality in the fetus. This fact implies prudence from obstetricians in order to understand its general clinical presentation and its main management principles and to choose and customize monitoring protocols suited for each medical case, assuming also the necessity of larger scale studies in order to validate their efficacy in preventing pulmonary hypoplasia and preserving renal function.

REFERENCES

[1] Sahar Zaman Khan, F. Fahim, Khauka Mansoor. Obstructive uropathy: causes and outcome in pediatric patients J Postgrad Med Inst, 26 (2012), pp. 176-182. [2] P. Dewan. Urethral valves or COPUM? Changing the nomenclature Contemp Urol, 11(1999), pp. 15-31. [3] D’Oro A., Meyer T., Gong E. M., Rosoklija I., Liu D.B. Are pressure pop-offs beneficial to the bladder in boys with posterior urethral valves? Journal of Pediatric Urology 2020; 16:488. e1-488.e8. https://doi.org/10.1016/j.jpurol.2020.05.154 [4] Brown T, Mandell J, Lebowitz RL. Neonatal hydronephrosis in the era of sonography. AJR Am J Roentgenol 1987; 148: p. 959. [5] Thakkar D, Deshpande AV, Kennedy SE. Epidemiology and demography of recently diagnosed cases of posterior urethral valves. Pediatr Res 2014; 76: p. 560. [6] Brownlee E, Wragg R, Robb A, et al., Current epidemiology and antenatal presentation of posterior urethral valves: Outcome of BAPS CASS National Audit. J Pediatr Surg 2019; 54: p. 318. [7] Young HH, Frontz WA, Baldwin JC. Congenital obstruction of the posterior urethra. J Urol, 3: pp. 289-365, 1919. J Urol. 2002 Jan. 167(1): pp. 265-7; discussion 268. [8] Warshaw BL, Edelbrock HH, Ettenger RB, et al., Renal transplantation in children with obstructive uropathy. J Urol 1980; 123: 737. [9] Sadler T.W., Langman J. Urogenital development. Langman’s Medical Embryology (11th edition), Ch. 15, pp. 235-263. [10] Krishnan A, de Souza A, Konijeti R, Baskin LS. The anatomy and embryology of posterior urethral valves. J Urol 2006; 175: 1214. [11] Woodhouse CR, Neild GH, Yu RN, Bauer S. Adult care of children from pediatric urology. J Urol. 2012 Apr. 187 (4): pp. 1164-71. [12] Rittenberg MH, Hulbert WC, Snyder HM 3rd, Duckett JW. Protective factors in posterior urethral valves. J Urol. 1988 Nov; 140(5): pp. 993-6. doi: 10.1016/s0022-5347(17)41908-2. PMID: 3139895. [13] Tikkinen KA, Heikkilä J, Rintala RJ, Tammela TL, Taskinen S. Lower urinary tract symptoms in adults treated for posterior urethral valves in childhood: matched cohort study. J Urol. 2011 Aug. 186 (2): pp. 660- 6. [14] Bajpai M, Dave S, Gupta DK. Factors affecting outcome in the management of posterior urethral valves. Pediatr Surg Int. 2001; 17: pp. 11-5.

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[15] Lal R, Bhatnagar V, Mitra DK. Long-term prognosis of renal function in boys treated for posterior urethral valves. Eur J Pediatr Surg. 1999; 9: pp. 307-11. [16] Sarhan O, El-Dahshan K, Sarhan M. Prognostic value of serum creatinine levels in children with posterior urethral valves treated by primary valve ablation. J Pediatr Urol. 2010; 6: pp. 11-4. [17] Ansari MS, Gulia A, Srivastava A, Kapoor R. Risk factors for progression to end-stage renal disease in children with posterior urethral valves. J Pediatr Urol. 2010; 6: pp. 261-4. [18] Reinberg Y, de Castano I, Gonzalez R. Prognosis for patients with prenatally diagnosed posterior urethral valves. J Urol. 1992; 148: pp. 125-6. [19] El-Ghoneimi A, Desgrippes A, Luton D, Macher MA, Guibourdenche J, Garel C, et al., Outcome of posterior urethral valves: To what extent is it improved by prenatal diagnosis? J Urol. 1999; 162: pp. 849-53. [20] Petca, A.; Vladareanu, S.; Zvanca, M.; Bot, M.; Vladareanu, R. Timing for the delivery of the growth- restricted fetus: a resolvable issue PROCEEDINGS OF THE 49TH ANNUAL SCIENTIFIC MEETING OF THE EUROPEAN SOCIETY FOR CLINICAL INVESTIGATION Pages: 273-277, Published: 2015. [21] Mandelia A, Bajpai M, Agarwala S, Gupta AK, Kumar R, Ali A. The role of urinary TGF-β1, TNF-α, IL-6 and microalbuminuria for monitoring therapy in posterior urethral valves. Pediatr Nephrol. 2013; 28: pp. 1991-2001. [22] Paun Silviu, Bernad Elena, Onofriescu Mircea, Vlădăreanu Radu Aspects Regarding Legal Liability of the Physician in Fetal Ultrasonography Proceedings of the 6th Congress of the Ultrasound Society in Obstetrics and Gynaecology 2018, pp. 41-46.

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Hip Ultrasound and Periarticular Alterations in Third Trimester Pregnancy

FILIPESCU Iulia1, BARBU Madalina-Gabriela1*, POPESCU Marius Nicolae1,3, BEIU Cristina3, VLADAREANU Radu2,3

1 Department of Rehabilitation Medicine, Elias Emergency University Hospital, 17 Marasti Blvd., 011461 Bucharest, (ROMANIA) 2 Department of Obstetrics-Gynaecology, Elias Emergency University Hospital, 17 Marasti Blvd., 011461 Bucharest, (ROMANIA) 3 Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Blvd, 050474 Bucharest, (ROMANIA) * Corresponding author: Madalina-Gabriela Barbu Email: [email protected]

Abstract

It is well known that pregnancy determines numerous changes in a woman’s body, from hormonal and vascular physiological modifications, to various musculoskeletal issues that could take a toll on the quality of life of the expectant mother if they are left unattended. There are many reported causes for the predisposition of pregnant women to musculoskeletal lesions. The diagnostic methods of the numerous musculoskeletal injuries and disorders that could occur during pregnancy are limited due to safety concerns for the mother and fetus. While hip pain is often attributed to the stretching of the round ligament of the uterus, there are many serious disorders that should be excluded from the diagnosis during the third trimester of pregnancy. Weight gain, water retention and hyperlaxity of the ligaments can also lead to nerve lesions in the third trimester of pregnancy. After back pain, hip pain is one of the most frequent musculoskeletal complaints pregnant women have and it can greatly affect their daily activities, as well as their psychological state.

Keywords: pregnancy, back pain, hip pain, ultrasound, MRI

1. Introduction

It is well known that pregnancy determines numerous changes in a woman’s body, from hormonal and vascular physiological modifications, to various musculoskeletal issues that could take a toll on the quality of life of the expectant mother if they are left unattended. Studies showed that hip pain was one of the most frequent complaints pregnant women had related to musculoskeletal symptoms, overrun only by back and wrist pain [1]. Moreover, these symptoms were found to appear more frequently in the third trimester of the pregnancy, which might be explained by weight gain, hormonal variations and fluid retention [1]. There are many reported causes for the predisposition of pregnant women to musculoskeletal lesions. Firstly, the increased levels of hormones such as oestrogens and relaxin were linked to ligamentous laxity and joint hypermobility with the scope of preparing the pelvis for birth [2, 3]. However, these changes may also lead to the occurrence of injuries and subluxations [1].

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Relaxin levels were found to be significantly greater in the third trimester than in the first stages of pregnancy, while women reporting pelvic pain were found to have higher levels of relaxin than those without pelvic pain [3]. Secondly, the weight gain that takes place during pregnancy, which is maximal during the last trimester was proved to increase the mechanical stress placed on a joint [4]. Studies showed that throughout pregnancy, an increase of 20% in body mass is to be expected, most of it occurring on the sagittal plane of the abdomen, which together with the ligamentous laxity leads to gait alterations [4-8]. Using joint kinematic analysis, researchers observed that hip adduction and extension were significantly decreased, mostly due to the loss of balance that took place during the later stages of pregnancy [7, 8]. Furthermore, on account of these changes, pregnant women were proved to have a risk of falling 2 times higher than women of the same age that were not pregnant [8]. Thirdly, water retention that intensifies during the last trimester could contribute to joint effusion and nerve entrapment [2]. The diagnostic methods of the numerous musculoskeletal injuries and disorders that could occur during pregnancy are limited due to safety concerns for the mother and fetus. In that regard, magnetic resonance imaging (MRI) and ultrasonography (US) were considered to be the preferred tools for diagnosis during pregnancy, while radiography, fluoroscopy and computed tomography (CT) were limited to cases in which they were deemed necessary [9]. Ultrasonography is a safe method during pregnancy not only for the visualization of pelvic organs and the fetus, but also for the assessment of the musculoskeletal system [9, 10]. It can provide information regarding muscle structure, ligament or tendon injuries and neurovascular lesions, yet its depth could be limited by the amount of overlaying soft tissue present [9, 10].

2. Hip disorders during third trimester pregnancy and the use of ultrasonography as a diagnostic tool

2.1 Pregnancy related transient osteoporosis While hip pain is often attributed to the stretching of the round ligament of the uterus, there are many serious disorders that should be excluded from the diagnosis during the third trimester of pregnancy. Transient osteoporosis is a condition that particularly affects pregnant women in the last trimester and middle-aged men [11-13]. Many theories were proposed to explain the development of transient osteoporosis during pregnancy, amongst them being mechanical stress, microvascular injury, increased maternal demand of calcium, venous stasis, viral infection trauma, venous or pelvic nerves compression by the increased uterus, however the pathogenesis is yet unknown [11, 14-16]. The disorder occurs in the third trimester or early postpartum and it usually affects the hip, provoking acute pain localized in the groin, anterior thigh or greater trochanter, in the absence of trauma or any relevant prior history [11, 16, 17]. The pain was increased by weight bearing and walking without assistive devices [11]. Usually the condition is self-limited, the radiographic signs disappearing in 3 to 6 months postpartum [11]. Secondary stress fractures due to this affliction were reported, the most frequent being femoral neck fractures [14-17]. While the best diagnostic tool for pregnancy related transient osteoporosis is MRI, high-resolution ultrasonography could be helpful in the detection of stress fractures when MRI is not available [18]. The first ultrasound signs that could alert that the patient might have suffered a stress fracture are a hypoechogenic periosteal elevation and hypervascularity, however these findings are limited by the depth of the studied structure [18].

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2.2 The greater trochanteric syndrome The greater trochanteric pain syndrome (GTPS) is another common affliction that can appear during pregnancy. The term refers to a spectrum of diseases that manifest themselves through pain located in the gluteal or great trochanter region or in the lateral thigh, due to tendinopathies, bursal inflammation or gluteal tendon ruptures [11]. The pain is usually chronic and can be exacerbated by prolonged standing, walking, running or by lying on the affected side [11]. The physical examination reveals limited active internal or external rotation of the hip due to pain [19]. While there is not much information on the incidence of GTPS in each trimester of pregnancy, due to the important weight gain and hyperlaxity of the ligaments in the last trimester, this syndrome should be taken into consideration when an expectant mother complains of hip pain that is located as it was described above. The most frequent conditions within the GTPS were described to be gluteus medius and minimus tendinopathies, accompanied by trochanteric bursitis [19, 20]. Ultrasonography was found to be a cost-effective, easily applied and safe diagnostic tool for GTPS during pregnancy [11]. It can assess the anatomy of the gluteus muscles and detect the presence of tendinopathies, bursal effusions or muscle tares [21]. Signs such as heterogenicity, altered architecture of the affected tendon, hypertrophy and calcifications could suggest the development of a tendinopathy, while anechoic or hypoechoic foci and contour defects would point into the direction of tendon ruptures [22, 23]. In addition, US can be used to assess the presence of anechoic collections in the sub-gluteus maximus bursa or sub-gluteus medius bursa, the first one being the most frequent site of trochanteric bursitis in GTPS [19, 22]. Furthermore, US can guide therapeutic procedures such as fluid aspiration and corticosteroid injection when other non-invasive strategies fail to provide pain relief [22, 24, 25].

2.3 Neuropathies in the third trimester Weight gain, water retention and hyperlaxity of the ligaments can also lead to nerve lesions in the third trimester of pregnancy [26]. Other known causes for the development of neuropathies throughout the pregnancy could be gestational diabetes, vasculitis, trauma and repetitive stress, vitamin deficiency, viral infections as well as a genetic predisposition [27]. Studies showed that the carpal tunnel syndrome is the most frequently encountered entrapment neuropathy in both pregnant patients, as well as in the general population [10]. Although less common, several neuropathies of the lower extremity can manifest themselves during pregnancy, resulting in radiating hip pain and an altered quality of life for the expectant mother [10]. While these conditions are often mild in intensity and tend to resolve themselves a few months postpartum, some may evolve in an atypical manner with intense and prolonged pain, demanding close observation which can be made with the help of ultrasonography [10, 26, 28]. Using high-resolution US, the physician can find possible causes for nerve compression such as tenosynovitis, vascular lesions or accessory muscles [29]. Furthermore, US can be used to guide therapeutic procedures such as perineural injections in order to ease the symptoms of the condition [30]. The pathological aspect of a nerve would most often be visualized via US in the form of intraneural edema, the bundle of fibers being more hypoechoic, with less bright surrounding structures than they would normally appear [31, 32]. In addition, proximal to the compression site, the nerve would be enlarged and fusiform, whereas at the location of the entrapment its structure would be flattened or pinched [33]. Other US signs of neuropathy have been described in the literature, such as increased vascularity within the nerve, hyperechoic muscle structure and muscle atrophy, the latter two being suggestive for denervated muscles [33]. Studies showed that meralgia paresthetica is one of the most common compression neuropathies of the lower limb in pregnancy [34, 35]. Caused by the unilateral entrapment or

87 ©Filodiritto Editore – Proceedings compression of the lateral femoral cutaneous nerve at its passing under the inguinal ligament, the clinical manifestations of this condition are usually described as numbness, a tingling sensation or pain located on the lateral side of the thigh [36, 26]. Risk factors for the development of meralgia paresthetica during pregnancy are represented by excessive fetal growth, weight gain and gestational diabetes [26]. This disorder can also be triggered during delivery by the prolonged thigh flexion or by a cutting injury during caesarean delivery [26]. US can aid in the diagnostic of meralgia paresthetica, as well as in the pain management through US guided aesthetic injections at the site of the inguinal ligament [26].

3. Conclusion

After back pain, hip pain is one of the most frequent musculoskeletal complaints pregnant women have and it can greatly affect their daily activities, as well as their psychological state. In that regard, making a correct assessment of the cause behind the reported symptoms would lead to the improvement of the therapeutic approach, thus increasing the patient’s life quality. While most of the diagnostic imaging methods are considered to be unsafe for the expectant mother and fetus, ultrasonography and MRI are considered the preferred tools for the diagnostic of musculoskeletal injuries of the hip during pregnancy. Although it has its limitation pertaining to the difficult access to deep structures, US is an easy to apply, safe, cost and time effective procedure that provides insight into musculoskeletal injuries that occur during pregnancy, as well as aids the therapeutic management.

REFERENCES

[1] Kesikburun, S., et al., Musculoskeletal pain and symptoms in pregnancy: a descriptive study. Ther Adv Musculoskelet Dis, 2018. 10(12): pp. 229-234. [2] Thabah, M. and V. Ravindran, Musculoskeletal problems in pregnancy. Rheumatol Int, 2015. 35(4): pp. 581- 7. [3] Ireland, M.L. and S.M. Ott, The effects of pregnancy on the musculoskeletal system. Clin Orthop Relat Res, 2000(372): pp. 169-79. [4] Anselmo, D.S., et al., Musculoskeletal Effects of Pregnancy on the Lower Extremity A Literature Review. J Am Podiatr Med Assoc, 2017. 107(1): pp. 60-64. [5] Foti, T., J.R. Davids, and A. Bagley, A biomechanical analysis of gait during pregnancy. J Bone Joint Surg Am, 2000. 82(5): pp. 625-32. [6] Forczek, W. and R. Staszkiewicz, Changes of kinematic gait parameters due to pregnancy. Acta Bioeng Biomech, 2012. 14(4): pp. 113-9. [7] Branco, M., et al., Kinematic analysis of gait in the second and third trimesters of pregnancy. J Pregnancy, 2013. 2013: p. 718095. [8] Mei, Q., Y. Gu, and J. Fernandez, Alterations of Pregnant Gait during Pregnancy and Post-Partum. Sci Rep, 2018. 8(1): p. 2217. [9] Cain, U., et al., Musculoskeletal Injuries in Pregnancy. Seminars in Roentgenology, 2020. [10] Brandon, C.J., Musculoskeletal Imaging in the Pregnant and Postpartum Patient, in Musculoskeletal Health in Pregnancy and Postpartum: An Evidence-Based Guide for Clinicians, C.M. Fitzgerald and N.A. Segal, Editors. 2015, Springer International Publishing: Cham. pp. 41-68. [11] Rho, M., F. Shah, and E. Okafor, Hip Disorders in Pregnancy, in Musculoskeletal Health in Pregnancy and Postpartum: An Evidence-Based Guide for Clinicians, C.M. Fitzgerald and N.A. Segal, Editors. 2015, Springer International Publishing: Cham. pp. 135-158. [12] Maliha, G., J. Morgan, and M. Vrahas, Transient osteoporosis of pregnancy. Injury, 2012. 43(8): pp. 1237- 41. [13] Asadipooya, K., L. Graves, and L.W. Greene, Transient osteoporosis of the hip: review of the literature. Osteoporos Int, 2017. 28(6): pp. 1805-1816.

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[14] Rozenbaum, M., et al., Uncommon transient osteoporosis of pregnancy at multiple sites associated with cytomegalovirus infection: is there a link? Isr Med Assoc J, 2011. 13(11): pp. 709-11. [15] Daniel, R.S., et al., Bilateral transient osteoporosis of the talus in pregnancy. Osteoporos Int, 2009. 20(11): pp. 1973-5. [16] Kim, Y.L., et al., CT evidence for subchondral trabecular injury of the femoral head in transient osteoporosis of the hip: a case report. J Korean Med Sci, 2010. 25(1): pp. 192-5. [17] Spinarelli, A., et al., Hip fracture in a patient affected by transient osteoporosis of the femoral head during the last trimester of pregnancy. Orthopedics, 2009. 32(5): p. 365. [18] Hoffman, D.F., E. Adams, and S. Bianchi, Ultrasonography of fractures in sports medicine. Br J Sports Med, 2015. 49(3): pp. 152-60. [19] Strauss, E.J., S.J. Nho, and B.T. Kelly, Greater trochanteric pain syndrome. Sports Med Arthrosc Rev, 2010. 18(2): pp. 113-9. [20] Hugo, D. and H. de Jongh, Greater trochanteric pain syndrome %J SA Orthopaedic Journal. 2012. 11: p. 28-33. [21] Connell, D.A., et al., Sonographic evaluation of gluteus medius and minimus tendinopathy. Eur Radiol, 2003. 13(6): pp. 1339-47. [22] Nazarian, L.N., Musculoskeletal ultrasound: applications in the hip. J Dance Med Sci, 2011. 15(4): pp. 173- 6. [23] Ho, G.W. and T.M. Howard, Greater trochanteric pain syndrome: more than bursitis and iliotibial tract friction. Curr Sports Med Rep, 2012. 11(5): pp. 232-8. [24] Martinoli, C., et al., Hip ultrasound. Eur J Radiol, 2012. 81(12): pp. 3824-31. [25] Klauser, A.S., et al., Greater trochanteric pain syndrome. Semin Musculoskelet Radiol, 2013. 17(1): pp. 43- 8. [26] Sax, T.W. and R.B. Rosenbaum, Neuromuscular disorders in pregnancy. Muscle Nerve, 2006. 34(5): pp. 559-71. [27] Mabie, W.C., Peripheral neuropathies during pregnancy. Clin Obstet. Gynecol., 2005. 48(1): pp. 57-66. [28] Rosier, C. and J.P. Camdessanche, Neuropathy and pregnancy: An overview. Rev Neurol (Paris), 2020. [29] Padua, L., et al., Contribution of ultrasound in the assessment of nerve diseases. Eur J Neurol, 2012. 19(1): pp. 47-54. [30] Gooding, M.S., V. Evangelista, and L. Pereira, Carpal Tunnel Syndrome and Meralgia Paresthetica in Pregnancy. Obstet Gynecol Surv, 2020. 75(2): pp. 121-126. [31] Klauser, A.S., et al., Entrapment neuropathies II: carpal tunnel syndrome. Semin Musculoskelet Radiol, 2010. 14(5): pp. 487-500. [32] Tagliafico, A., et al., Contribution of ultrasound in the assessment of patients with suspect idiopathic pudendal nerve disease. Clin Neurophysiol, 2014. 125(6): pp. 1278-84. [33] Cartwright, M.S. and F.O. Walker, Neuromuscular ultrasound in common entrapment neuropathies. Muscle Nerve, 2013. 48(5): pp. 696-704. [34] Beltran, L.S., et al., Entrapment neuropathies III: lower limb. Semin Musculoskelet Radiol, 2010. 14(5): pp. 501-11. [35] Martinoli, C., et al., Imaging of neuropathies about the hip. Eur J Radiol, 2013. 82(1): pp. 17-26. [36] I. Filipescu, M. Berteanu, G.A. Filipescu, R. Vladareanu Low back pain in pregnancy and post-partum period. Principles for medical rehabilitation Revista Ginecologia 6(19) pp. 22-23 (2018)

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Normalisation of Placenta Thickness After Amnio-drainage: Case Report

GORUN Florin1, GORUN Oana2, OLARU Flavius1, GADEA Ramona1, POPA Andreea2, COSTESCU Sergiu1, FORGA Marius1, MOTOI Sorin3

1 Department of Obstetrics-Gynaecology, Victor Babes University of Medicine and Pharmacy Timisoara, P-ta Eftimie Murgu, nr. 2, 300041 Timisoara, (ROMANIA) 2 Department of Obstetrics-Gynaecology, City Emergency Hospital Timisoara, Str. Odobescu, nr. 3, 300202 Timisoara, (ROMANIA) 3 Department of Radiology, Victor Babes University of Medicine and Pharmacy Timisoara, P-ta Eftimie Murgu, Nr. 2, 300041 Timisoara, (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Many causes are mentioned to be involved in the ethiology of amniotic fluid overload (polyhydramnios): congenital anomalies (such obstructions of gastrointestinal tract) (20%), gestational diabetes or anti-D alloimmunisation. Sometimes, despite intensive investigations, no causes are identified (idiopathic polyhydramnios). Diagnosis of polyhydramnios is done based on ultrasound examinations which could be performed along pregnancy in first trimester or later. The scope of our paper was to present the case of a pregnancy of a 42-year-old woman with severe polyhydramnios with placenta thinning, in which amnio-drainage led to normalisation of placenta thickness. We present the case of a 42-year-old woman, second gestation, second parity at 31/32 weeks of pregnancy, with a fetus with trisomy 18, multiple structural anomalies (omphalocele, left heart hypoplastic syndrome and overlapping fingers) and severe polyhydramnios (AFI=55 cm). In order to decompress uterus and reduce the intrauterine pressure, an amniotic drainage was performed with a 22-gauge needle. 2400 ml of amniotic fluid were evacuated until AFI reached a value of 26 cm. Measurement of placenta showed an increase of thickness with 56% from 23 mm to 36 mm after amniotic drainage. Placenta thickness is a simple ultrasonographic marker which should be investigated in each ultrasound examination along pregnancy. In patients with severe polyhydramnios, placenta is thinner and amnio-drainage could normalise placenta thickness. Also, changes in placenta thickness are correlated with fetal hemodynamic effect.

Keywords: Polyhydramnios, placenta thickness, normalisation, amnio-drainage

Introduction

Several causes are mentioned to be involved in the ethiology of amniotic fluid overload (polyhydramnios): congenital anomalies (such obstructions of gastrointestinal tract) (20%), gestational diabetes or anti-D alloimmunisation [1, 2]. Sometimes, despite intensive investigations, no causes are identified (idiopathic polyhydramnios) (60% to 70%) [1, 2]. Diagnosis of polyhydramnios is done based on ultrasound examinations which could be performed during pregnancy in first trimester [3, 4] or later [5]. Most cases are diagnosed in the second half of pregnancies. The cut-off value which is used to define polyhydramnios was set at

90 ©Filodiritto Editore – Proceedings an amniotic fluid index (AFI) above 95.0%, according to internationally recognized nomograms [6]. Amniotic fluid overload leads to an increase in intrauterine pressure and uterine wall distension, which could further lead to an increase in placenta length, respectively, placenta thinning. Placenta thickness is easy to measure and is part of usual ultrasound examinations in first [3, 4] or second trimester [5, 7]. Thinning of placenta could be associated with fetal hemodynamic changes and increase of umbilical cord vessels resistance index [8]. This is why placenta thickness measurement could be used together with (AFI, CTG and Doppler measurement) as an indirect marker of impairment of fetal wellbeing in pregnant women with polyhydramnios, as reported by others, too [8, 9]. The scope of our paper was to present the case of a pregnancy of a 42-year-old woman with severe polyhydramnios with placenta thinning, in which amnio-drainage led to normalisation of placenta thickness.

Case report We present the case of a 42-year-old woman, second gestation, second parity at 31/32 weeks of pregnancy, with a fetus with trisomy 18, multiple structural anomalies (omphalocele, left heart hypoplastic syndrome and overlapping fingers) and severe polyhydramnios (AFI=55 cm). In order to decompress uterus and reduce the intrauterine pressure, an amniotic drainage was performed with a 22-gauge needle. 2400 ml of amniotic fluid were evacuated until AFI reached a value of 26 cm. Measurement of placenta showed an increase of thickness with 56% from 23 mm to 36 mm after amniotic drainage (table 1).

Table 1. Placenta thickness before and after amnio-drainage AFI (cm) Placenta thickness (mm) Thickening (mm/%) 55 23 26 36 13/56%

Discussion

If not treated, polyhydramnios could cause serious complications, such as preterm birth along other factors suc as cervical surgery [10] or inflammation [11]. Moreover, the risk of intrauterine fetal death, premature rupture of membranes, postpartum uterine atony and other several complications is increased [12]. Treatment of polyhydramnios implies amniotic fluid drainage which is an easy to performed procedure. We report in our article how intense the changes in placenta thickness could be after amnio-drainage and speculate that these changes could improve hemodynamic impairment in foetuses. Our results confirm data from the literature and advocate for using amnio-drainage in pregnancies with polyhydramnios [13-15]. The main risks of amnio-drainage are amniotic membrane rupture, preterm birth, placental abruption and fetal death. Depending on frequency, the benefits of amnio-drainage outweigh the risks [15].

Conclusions

Placenta thickness is a simple ultrasonographic marker which should be investigated in each ultrasound examination during pregnancy. In patients with severe polyhydramnios, placenta is thinner and amnio-drainage could normalise placenta thickness. Also, changes in placenta thickness are correlated with fetal hemodynamic effect.

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REFERENCES

[1] Hwang, D.S., Bordoni, B. (2020). Polyhydramnios. In: StatPearls. Treasure Island (FL): StatPearls Publishing. [2] Zeino, S., Carbillon, L., Pharisien, I., Tigaizin, A., Benchimol, M., Murtada, R., Boujenah, J. (2017). Delivery outcomes of term pregnancy complicated by idiopathic polyhydramnios. J Gynecol. Obstet. Hum Reprod. (4), pp. 349-354. [3] Carabineanu, A., Navolan, D., Birsasteanu, F, Cretu, O., Boia, M., Craina, M., Badiu, D.L., Ionescu, C.A., Mehedintu, C., Vladareanu, S., Ciohat, I., Craciunescu, M., Nemescu, D. (2017). The Effect of Chemical Compounds from Cigarettes Smoke on First Trimester Biochemical Markers. Rev Chimie 68(9): pp. 2122- 2124. [4] Nemescu, D., Berescu, A., Onofriescu, M., Navolan, D.B., Rotariu, C. (2015). Safety indices during fetal echocardiography at the time of first-trimester scan are machine dependent. PLOS ONE 10(5): e127570. [5] Navolan, D.B., Vladareanu, S., Lahdou, I., Ciohat, I., Kleist, C., Grigoras, D., Vladareanu, R., Terness, P., Sas, I. (2016). Early pregnancy serum neopterin concentration predict spontaneous preterm birth in asymptomatic pregnant women. J Perinat Med 44(5), pp. 517-522. [6] Krispin, E., Berezowsky, A., Chen, R., Meizner, I., Wiznitzer, A., Hadar, E., Bardin R. (2020). Updating the amniotic fluid index nomograms according to perinatal outcome. The Journal of Maternal-Fetal & Neonatal Medicine 33(1), pp. 113-119. [7] Navolan, D., Craciunescu, M., Ciohat, I., Stoian, D., Badiu, D., Craina, M., Birsesteanu, F., Nemescu, D., Vladareanu, S. (2016). The influence of some biological markers in early pregnancy of patients with birth at term and preterm birth. 67(5), pp. 991-994. [8] Akgündüz, E., Erkılınç, S., Tokmak, A., Güzel Aİ, Özer İ, Danışman N. (2015). Decreased placental thickness and impaired Doppler indices in idiopathic polyhydramnios: a prospective case-control study. J Matern Fetal Neonatal Med. 28(6), pp.722-5. [9] Kurjak, Asim; Antsaklis, Panos; Stanojevic, Milan; Vladareanu, Radu; Vladareanu, Simona; Neto, Raul Moreira; Barisic, Lara Spalldi; Porovic, Selma; Delic, Taib Multicentric studies of the fetal neurobehavior by KANET test JOURNAL OF PERINATAL MEDICINE, Volume: 45, Issue: 6, Pages: 717-727, Special Issue: SI, DOI: 10.1515/jpm-2016-0409, Published: AUG 2017. [10] Hughes, K., Kane, S.C., Araujo Júnior, E., Da Silva Costa, F. Sheehan, P.M. (2016), Cervical length as a predictor for spontaneous preterm birth in high‐risk singleton pregnancy: current knowledge. Ultrasound Obste.t Gynecol. 48, pp. 7-15. [11] Navolan, D., Vladareanu, S., Ciohat, I., Stoian, D., Badiu, D., Craina, M., Tomovici, M., Birsasteanu, F., Nemescu, D., Craciunescu, M. (2016). A preliminary study over second trimester biochemical markers and their clinical utility. Rev Chim 67(6), pp. 1224-1226. [12] Dashe, J.S., Pressman, E.K., Hibbard, J.U. (2018). SMFM Consult Series #46: Evaluation and management of polyhydramnios. Am J Obstet. Gynecol. 219(4): B2-B8 [13] Hamza, A., Herr, D., Solomayer, E.F., Meyberg-Solomayer, G. (2013). Polyhydramnios: Causes, Diagnosis and Therapy. Geburtshilfe Frauenheilkd 73(12), pp. 1241-1246. [14] Kleine, R.T., Bernardes, L.S., Carvalho, M.A., de Carvalho, M.H., Krebs, V.L., Francisco, R.P. (2016). Pregnancy outcomes in severe polyhydramnios: no increase in risk in patients needing amnioreduction for maternal pain or respiratory distress. J Matern Fetal Neonatal Med 29(24), pp. 4031-4034. [15] Greimel, P., Klaritsch, P., Simonis, H., Csapó, B., Pohl, M., Schneditz, D. (2020). Amniodrainage – Induced Circulatory Dysfunction in Women Treated for Twin-To-Twin Transfusion Syndrome. J Clin Med 9(7), p. 2085.

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Reversal of Altered Cerebro-Placental Ratio After Amnio-drainage

GORUN Florin1, GORUN Oana2, COJOCARU Ioana1, GADEA Ramona1, POPA Andreea2, FORGA Marius1, OLARU Flavius1, MOTOI Sorin3

1 Department of Obstetrics-Gynaecology, Victor Babes University of Medicine and Pharmacy Timisoara, P-ta Eftimie Murgu, Nr. 2, 300041 Timisoara, (ROMANIA) 2 Department of Obstetrics-Gynaecology, City Emergency Hospital Timisoara, Str. Odobescu, Nr. 3, 300202 Timisoara, (ROMANIA) 3 Department of Radiology, Victor Babes University of Medicine and Pharmacy Timisoara, P-ta Eftimie Murgu, Nr. 2, 300041 Timisoara, (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Polyhydramnios is defined as a pathologic excess of amniotic fluid volume (AFV) with an amniotic fluid index (AFI) above 95% according to usual nomograms. Diagnosis of polyhydramnios is based on ultrasound. As a result of amniotic fluid overload, the intrauterine pressure increases and several complications may occur: intrauterine fetal death, macrosomia, anormal presentations, cord prolapse, premature rupture of membranes, caesarean delivery, postpartum haemorrhage and preterm birth. Aim of our paper was to present the case of a 42 years old pregnant woman with severe polyhydramnios with a fetus with hemodynamic centralisation, in which amnio-drainage lead to normalisation of cerebro-placental ratio. We present herein the case of a 42 years old woman, 33 weeks of pregnancy, with a fetus with multiple malformations which developed sever polydramnios (AFI=45 cm). Doppler evaluation showed fetal hemodynamic impairment: MCA (medio-cerebral artery) values (pulsatility index PI=1.49, resistance index RI=0.74), UA (umbilical artery values) (PI=2.05, RI=0.90) and CRP (cerebro- placental ratio) of 0.72. After amniotic drainage, hemodynamic values were normalized: medio- cerebral artery values (PI=1.79, RI=0.8), umbilical artery values (PI=1.12, RI=0.60) and CPR of 1.59. Conclusion. Polyhydramnios determines impairment of fetal circulation and amnio-drainage could reverse this impairment. Amnio-drainage could be used to improve fetal well-being and to prolong the time to birth in pregnancies with polyhydramnios his template will assist you in formatting your paper.

Keywords: Polyhydramnios, fetal hemodynamic impairment, reversal, amnio-drainage

Introduction

Polyhydramnios is defined as a pathologic excess of amniotic fluid volume (AFV) with an amniotic fluid index (AFI) above 95% according to usual nomograms [1]. Main causes of polyhydramnios are congenital anomalies (20%), diabetes, alloimmunisation, and idiopathic with no identified underlying causes (60% to 70%) [2, 3]. In pregnant women with polyhydramnios an imbalance of the AFV equilibrium appears (fluid production versus fluid absorption) [2]. As a result of amniotic fluid overload, the intrauterine pressure increases and several complications may occur: intrauterine fetal death, macrosomia, anormal presentations, cord prolapse, premature rupture of membranes, caesarean delivery or postpartum haemorrhage [2]. Polyhydramnios is also

93 ©Filodiritto Editore – Proceedings a cause of preterm birth [4] along with cervical pathology [5] and inflammation [6-8]. For all these reasons, occurrence of polyhydramnios is considered a risk condition in pregnancy [9]. Diagnosis of polyhydramnios is based on ultrasound examination which could be done along regular pregnancy examinations at the time of first trimester screening [10, 11] or later, in second [12] or third trimester [12] of pregnancy. Overdistension of uterus leads to an increase of intrauterine pressure, elongation and thinning of the placenta. As a result, fetal hemodynamic changes may occur [13]. The aim of our paper was to present the case of a 42 years old pregnant woman with severe polyhydramnios with a fetus with hemodynamic centralisation, in which amnio-drainage lead to normalisation of cerebro-placental ratio.

Case report We present herein the case of a 42 years old woman, 33 weeks of pregnancy, second gestation and second parity with a fetus with omphalocele, left hearth hypoplastic syndrome and trisomy 18 which developed sever polydramnios (AFI=45 cm). Doppler evaluation showed fetal hemodynamic impairment: MCA (medio-cerebral artery) values (pulsatility index PI=1.49, resistance index RI=0.74), UA (umbilical artery values) (PI=2.05, RI=0.90) and CRP (cerebro- placental ratio) of 0.72. Because of uterine overload, an amnio-drainage with a 22-gauge needle was performed and 1800 ml of amnionic fluid were evacuated until AFI reach a value of 24 cm. Heart activity was monitorized along amnio-drainage. After amniotic drainage, hemodynamic values were normalized: medio-cerebral artery values (PI=1.79, RI=0.8), umbilical artery values (PI=1.12, RI=0.60) and CPR of 1.59 (table 1).

Table 1. Doppler evaluation of fetal circulation before and after amnio-drainage AFI=45 cm PI RI CPR MCA 1.49 0.74 0.72 UA 2.05 0.90

AFI=24 cm PI RI CPR MCA 1.79 0.80 1.59 UA 1.12 0.60

Discussion

Our report showed that polyhydramnios could be associated with severe impairment of fetal circulation and amnio-drainage could reverse the hemodynamic impairment. Such changes were reported from other physicians, too [13]. Albeit in this case the amnio-drainage did not change the prognostic of the aneuploid fetus in cases of normal foetuses such a procedure could ameliorate the fetal well-being and allow pregnancy prolongation. In most cases, polyhydramyos appears late in pregnancy when the fetus is nearly matured and delay of delivery could ameliorate the prognosis and reduce neonatal morbidity and mortality [14, 15]. Amnio-drainage is a simple technique which could be performed in settings with an ultrasound machine and experimented obstetricians. The main risks of amnio-drainage are represented by amniotic membrane rupture, preterm birth, placental abruption and fetal death [16]. These complications are rare and are overwhelmed by benefits. Amnio-drainage could also lead to uterine decompression and subsequent maternal haemodilution, a phenomen named by Greimel et al., “amnio-drainage-induced circulatory dysfunction” [17].

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Conclusions

Polyhydramnios determines imparriement of fetal circulation and amnio-drainage could reverse this impairment. Amnio-drainage could be used to improve fetal well-being and to prolong the time to birth in pregnancies with polyhydramnios.

REFERENCES

[1] Krispin, E., Berezowsky, A., Chen, R., Meizner, I., Wiznitzer, A., Hadar, E., Bardin R. (2020). Updating the amniotic fluid index nomograms according to perinatal outcome. The Journal of Maternal-Fetal & Neonatal Medicine 33(1), pp. 113-119. [2] Hwang, D.S., Bordoni, B. (2020). Polyhydramnios. In: StatPearls. Treasure Island (FL): StatPearls Publishing. [3] Zeino, S., Carbillon, L., Pharisien, I., Tigaizin, A., Benchimol, M., Murtada, R., Boujenah, J. (2017). Delivery outcomes of term pregnancy complicated by idiopathic polyhydramnios. J Gynecol. Obstet. Hum Reprod. (4), pp. 349-354. [4] Hamza, A., Herr, D., Solomayer, E.F., Meyberg-Solomayer, G. (2013). Polyhydramnios: Causes, Diagnosis and Therapy. Geburtshilfe Frauenheilkd 73(12), pp. 1241-1246. [5] Hughes, K., Kane, S.C., Araujo Júnior, E., Da Silva Costa, F. Sheehan, P.M. (2016), Cervical length as a predictor for spontaneous preterm birth in high‐risk singleton pregnancy: current knowledge. Ultrasound Obstet. Gynecol. 48, pp. 7-15. [6] Navolan, D.B., Vladareanu, S., Lahdou, I., Ciohat, I., Kleist, C., Grigoras, D., Vladareanu, R., Terness, P., Sas, I. (2016). Early pregnancy serum neopterin concentration predict spontaneous preterm birth in asymptomatic pregnant women. J Perinat Med 44(5), pp. 517-522. [7] Navolan, D., Craciunescu, M., Ciohat, I., Stoian, D., Badiu, D., Craina, M., Birsesteanu, F., Nemescu, D., Vladareanu, S. (2016). The influence of some biological markers in early pregnancy of patients with birth at term and preterm birth. 67(5), pp. 991-994. [8] Navolan, D., Vladareanu, S., Ciohat, I., Stoian, D., Badiu, D., Craina, M., Tomovici, M., Birsasteanu, F., Nemescu, D., Craciunescu, M. (2016). A preliminary study over second trimester biochemical markers and their clinical utility. Rev Chim 67(6), pp. 1224-1226. [9] Dashe, J.S., Pressman, E.K., Hibbard, J.U. (2018). SMFM Consult Series #46: Evaluation and management of polyhydramnios. Am J Obstet. Gynecol. 219(4): pp. B2-B8. [10] Carabineanu, A., Navolan, D., Birsasteanu, F, Cretu, O., Boia, M., Craina, M., Badiu, D.L., Ionescu, C.A., Mehedintu, C., Vladareanu, S., Ciohat, I., Craciunescu, M., Nemescu, D. (2017). The Effect of Chemical Compounds from Cigarettes Smoke on First Trimester Biochemical Markers. Rev Chimie 68(9): pp. 2122- 2124. [11] Nemescu, D., Berescu, A., Onofriescu, M., Navolan, D.B., Rotariu, C. (2015). Safety indices during fetal echocardiography at the time of first-trimester scan are machine dependent. PLOS ONE 10(5): e127570. [12] Karakaya, B., Tasci, Y., Erkaya, S. (2019). Fasting and post-prandial plasma glucose screening for gestational diabetes mellitus. East Mediterr Health J 25(4), pp. 282-289. [13] Akgündüz, E., Erkılınç, S., Tokmak, A., Güzel Aİ, Özer İ, Danışman N. (2015). Decreased placental thickness and impaired Doppler indices in idiopathic polyhydramnios: a prospective case-control study. J Matern Fetal Neonatal Med. 28(6), pp. 722-5. [14] da Fonseca, E.B., Damião, R., Moreira, D.A. (2020). Preterm birth prevention. Best Pract Res Clin Obstet. Gynaecol. S1521-6934(20), pp. 30142-5. [15] Kurjak, Asim; Antsaklis, Panos; Stanojevic, Milan; Vladareanu, Radu; Vladareanu, Simona; Neto, Raul Moreira; Barisic, Lara Spalldi; Porovic, Selma; Delic, Taib Multicentric studies of the fetal neurobehavior by KANET test JOURNAL OF PERINATAL MEDICINE, Volume: 45, Issue: 6, Pages: 717-727, Special Issue: SI, DOI: 10.1515/jpm-2016-0409, Published: AUG 2017. [16] Kleine, R.T., Bernardes, L.S., Carvalho, M.A., de Carvalho, M.H., Krebs, V.L., Francisco, R.P. (2016). Pregnancy outcomes in severe polyhydramnios: no increase in risk in patients needing amnioreduction for maternal pain or respiratory distress. J Matern Fetal Neonatal Med 29(24), pp. 4031-4034. [17] Greimel, P., Klaritsch, P., Simonis, H., Csapó, B., Pohl, M., Schneditz, D. (2020). Amnio-drainage – Induced Circulatory Dysfunction in Women Treated for Twin-To-Twin Transfusion Syndrome. J Clin Med 9(7), p. 2085.

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Cytomegalovirus Seroprevalence in Pregnant Women by Age and Environment

GORUN Oana1, GORUN Florin2, COSTESCU Sergiu2, CIOHAT Ioana1, GADEA Ramona2, POPA Andreea1, OLARU Flavius2, MOTOI Sorin3, FORGA Marius2

1 Department of Obstetrics-Gynaecology, City Emergency Hospital Timisoara, Str. Odobescu, Nr. 3, 300202 Timisoara, (ROMANIA) 2 Department of Obstetrics-Gynaecology, Victor Babes University of Medicine and Pharmacy Timisoara, P-ta Eftimie Murgu, Nr. 2, 300041 Timisoara, (ROMANIA) 3 Department of Radiology, Victor Babes University of Medicine and Pharmacy Timisoara, P-ta Eftimie Murgu, Nr. 2, 300041 Timisoara, (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous beta human herpesvirus type 5 which infects 40-100% of the adult population worldwide and cause the most common congenital infection worldwide. Global CMV seroprevalence is estimated at 83% in the general population and 86% among childbearing women. Prenatal detection of new-borns at high risk for congenital CMV infection is important because early diagnosis and treatment of infants with symptomatic congenital cytomegalovirus (CMV) infection may improve outcomes. Fetal abnormalities known to be associated to congenital CMV infection are: ventriculomegaly (4.5-11.6% of cases), microcephaly (14.5%), intracranial calcification (0.6-17.4%), fetal growth restriction (1.9-13%), pericardial effusion (7.2%), ascites (8.7%), hepatomegaly (4.3%) and high intestinal echo- densities. We performed a cross sectional study on 8951 pregnant women from western Romania in two different periods: 2008-2010 (1466 pregnant women) and 2015-2018 (7485 pregnant women). Patients were grouped according the medium of provenience and age. Spearman’s correlation coefficient was used to analyse the strength of the association between seroprevalence and age of pregnant women. In urban areas the CMV seroprevalence showed for both studied pregnant women groups (2008-2010 and 2015-2018) a non-significant decreasing tendency with age: rho=-0.178, p=0.3649 (2008-2010) and rho=-0.2523, p=0.1636 (2015-2018). An increasing but not significant tendency with age was found in participants from the rural area, in both studied groups (2008-2010 and 2015-2018): rho=0.3049, p=0.1572 (2008-2010) and rho=0.1737, p=0.3419 (2015-2018). Conclusion. The screening for congenital CMV infection, by serological or ultrasound methods, is necessary for all age groups regardless of area of residence and age.

Keywords: Cytomegalovirus, seroprevalence, urban area, rural area, age, tendency

Introduction

Human cytomegalovirus (HCMV) is a ubiquitous beta human herpesvirus type 5 which infects 40-100% of the adult population worldwide [1, 2]. Usually the primary infection is asymptomatic

96 ©Filodiritto Editore – Proceedings in healthy individuals but, like all herpesviruses, HCMV establishes lifelong latency that can lead to periodic reactivation [3]. In contrast with the asymptomatic infection of healthy individuals, infection of immunocompromised patients or congenital infection can cause severe disease. Congenital CMV infection is the most common congenital infection worldwide with an incidence in developing countries of 0.6-0.7% of all live births [4]. The vertical transmission rate of the infection corresponds to the gestational age at the time of the primary maternal infection: 8.8% in the preconception period, 30.6% in the first trimester, 34.1% in the second trimester and 40% in the third trimester [5]. Congenital cytomegalovirus (CMV) infection, which results from vertical transmission, can cause health problems that are obvious at birth or that develop later in childhood. CMV can also cause fetal death or miscarriage. At birth, babies with congenital CMV infection may have some signs including: rash, jaundice, microcephaly, low birth weight, hepatosplenomegaly, seizures and retinitis [6]. Long term health problems that can be caused by congenital CMV infection include: hearing loss, developmental and motor delay, vision loss, microcephaly and seizures. Also, CMV infection could determine preterm birth along other factors like inflammation [7, 8] or cervical pathology [9]. Global CMV seroprevalence is estimated at 83% in the general population and 86% among childbearing women [10]. There is also a regional difference in CMV seroprevalence. It has tended to be higher in some regions such as South America, Africa and Asia and the lowest in Western Europe and the United States [11].

Ultrasound Signs of Congenital CMV Infection Prenatal detection of new-borns at high risk for congenital CMV infection is important because early diagnosis and treatment of infants with symptomatic congenital cytomegalovirus (CMV) infection may improve neurological outcomes [12]. The presence of ultrasonographically detected fetal abnormalities at the time of first [13, 14], second [15] or third-trimester ultrasound scan may guide clinicians to suspect a congenital CMV infection. Fetal abnormalities known to be associated to congenital CMV infection are: ventriculomegaly (4.5-11.6% of cases), microcephaly (14.5%), intracranial calcification (0.6-17.4%), fetal growth restriction (1.9-13%), pericardial effusion (7.2%), ascites (8.7%), hepatomegaly (4.3%) and high intestinal echo-densities (4.5-13%) [12].

Material and Methods

A cross sectional study was performed on 8951 pregnant women from western Romania. The participants were tested in two different periods: 2008-2010 (1466 pregnant women tested at the Timisoara Municipal Clinical Hospital) and 2015-2018 (7485 pregnant women tested at SC BIOCLINICA SRL, Timisoara, Romania). IgG- and IgM-anti-CMV antibodies were measured by immunochemiluminescence method using commercial kits: Siemens for 2008-2010 and Abbott for 2015-2018. Data about the year of birth, the age at the time of collection and the environment of the participants were collected from the forms completed at the time of testing. Statistical analysis was performed with Instat GraphPad Prism 8.0.2. Patients were grouped according the medium of provenience and age. Spearman’s correlation coefficient was used to analyse the strength of the association between continuous variables from two non‑Gaussian populations (seroprevalence vs age of pregnant women).

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Results

In urban areas the CMV seroprevalence showed for both studied pregnant women groups (2008-2010 and 2015-2018) a non-significant decreasing tendency with age: rho=-0.178, p=0.3649 (2008-2010) and rho=-0.2523, p=0.1636 (2015-2018) (Table 1). An increasing but not significant tendency with age was found in participants from the rural area, in both studied groups (2008-2010 and 2015-2018): rho=0.3049, p=0.1572 (2008-2010) and rho=0.1737, p=0.3419 (2015-2018) (Table. 1).

Table 1. Trends of CMV seroprevalence according to age and medium of provenience of pregnant women in the two studied groups: 2008-2010 and 2015-2018 seroprevalence vs. age* Urban Rural 2008-2010 rho=-0.178, rho=0.3049 p=0.3649 p=0.1572 2015-2018 rho=-0.2523 rho=0.1737 p=0.1636 p=0.3419 *Spearman’s correlation coefficient was used to analyse the association

Discussions

The seroprevalence of CMV in women of reproductive age, in the western part of Romania, has decreased significantly during the last 10 years, from 94.6% to 91.80% [16]. The risk of primary infection during pregnancy has increased in the last 10 years from 5.4% to 8.2% which may show the need to implement a national screening program and careful ultrasound monitoring of pregnancies at risk of congenital CMV infection. It should be noted that the number of children with congenital disabilities related to CMV is similar to or higher than the number with more well- known conditions, such as Down syndrome or spina bifida. Our results show that there is no significant association between CMV seroprevalence and age, regardless of the environment of origin. Such seroprevalence studies should be done for others materno-foetal infections, too [17].

Conclusion

The screening for congenital CMV infection, by serological or ultrasound methods, is necessary for all age groups regardless of area of residence.

REFERENCES

[1] Kosugi, I. (2010). Cytomegalovirus (CMV). Uirusu. 60(2), pp. 209-20. [2] Hyde, T.B., Schmid, D.S., Cannon, M.J. (2010). Cytomegalovirus seroconversion rates and risk factors: implications for congenital CMV. Rev Med Virol 20(5): pp. 311-326. [3] Brizić, I., Hiršl, L., Britt, W.J., Krmpotić, A., Jonjić, S. (2018). Immune responses to congenital cytomegalovirus infection. Microbes Infect. 20(9-10), pp. 543-551. [4] Marsico, C., Kimberlin, D.W. (2017). Congenital Cytomegalovirus infection: advances and challenges in diagnosis, prevention and treatment. Ital J Pediatr 43(1), p. 38. [5] Picone, O., Vauloup-Fellous, C., Cordier, A., Guitton, S., Senat, M., & Fuchs, F. et al., (2013). A series of 238 cytomegalovirus primary infections during pregnancy: description and outcome. Prenatal Diagnosis, 33(8), pp. 751-758. https://www.cdc.gov/cmv/congenital-infection.html [6] Navolan, D.B., Vladareanu, S., Lahdou, I., Ciohat, I., Kleist, C., Grigoras, D., Vladareanu, R., Terness, P., Sas, I. (2016). Early pregnancy serum neopterin concentration predict spontaneous preterm birth in asymptomatic pregnant women. J Perinat Med 44(5), pp. 517-522.

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[7] Navolan, D., Craciunescu, M., Ciohat, I., Stoian, D., Badiu, D., Craina, M., Birsesteanu, F., Nemescu, D., Vladareanu, S. (2016). The influence of some biological markers in early pregnancy of patients with birth at term and preterm birth. 67(5), pp. 991-994. [8] Hughes, K., Kane, S.C., Araujo Júnior, E., Da Silva Costa, F. Sheehan, P.M. (2016), Cervical length as a predictor for spontaneous preterm birth in high‐risk singleton pregnancy: current knowledge. Ultrasound Obstet. Gynecol. 48, pp. 7-15. [9] Zuhair, M., Smit, G., Wallis, G., Jabbar, F., Smith, C., Devleesschauwer, B., & Griffiths, P. (2019). Estimation of the worldwide seroprevalence of cytomegalovirus: A systematic review and meta-analysis. Reviews in Medical Virology, 29(3), e2034 [10] Cannon, M.J., Schmid, D.S., Hyde, T.B. (2010). Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Rev Med Virol. 20(4), pp. 202-213. [11] Tanimura, K., Yamada, H. (2018). Potential Biomarkers for Predicting Congenital Cytomegalovirus Infection. International Journal of Molecular Sciences 19(12), p. 3760. [12] Carabineanu, A., Navolan, D., Birsasteanu, F, Cretu, O., Boia, M., Craina, M., Badiu, D.L., Ionescu, C.A., Mehedintu, C., Vladareanu, S., Ciohat, I., Craciunescu, M., Nemescu, D. (2017). The Effect of Chemical Compounds from Cigarettes Smoke on First Trimester Biochemical Markers. Rev Chimie 68(9), pp. 2122- 2124. [13] Nemescu, D., Berescu, A., Onofriescu, M., Navolan, D.B., Rotariu, C. (2015). Safety indices during fetal echocardiography at the time of first-trimester scan are machine dependent. PLOS ONE 10(5): e127570. [14] Navolan, D., Vladareanu, S., Ciohat, I., Stoian, D., Badiu, D., Craina, M., Tomovici, M., Birsasteanu, F., Nemescu, D., Craciunescu, M. (2016). A preliminary study over second trimester biochemical markers and their clinical utility. Rev Chim 67(6), pp. 1224-1226. [15] Gorun, F., Motoi, S., Malita, D., Navolan, D.B., Nemescu, D., Olariu, T.R., Craina, M., Vilibic-Cavlek, T., Ciohat, I., Boda, D., Dobrescu, A. (2020). Cytomegalovirus seroprevalence in pregnant women in the western region of Romania: A large-scale study. Exp Ther Med 20(3), pp. 2439-2443. [16] Motoi, S., Navolan, D.B., Malita, D., Ciohat, I., Nemescu, D., Manciuc, C., Gorun, F., Vilibic-Cavlek, T., Boda, D., Craina, M., Dobrescu, A. (2020). A decreasing trend in toxoplasma gondii seroprevalence among pregnant women in Romania – results of a large-scale study. Exp Ther Med. 20(4), pp. 3536-3540.

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Ultrasonographic Evaluation of Abnormal Uterine Bleeding

MĂLUȚAN Andrei Mihai1, DICULESCU Doru1, CIORTEA Răzvan1, MOCAN-HOGNOGI Radu Florin1, IUHAS Cristian1, BUCURI Carmen Elena1, DUDEA Marina1, SUCIU Viorela Elena1, MIHU Dan1

1 2nd Obstetrics and Gynaecology Department, University of Medicine and Farmacy “Iuliu Hațieganu”, Cluj-Napoca (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Abnormal uterine bleeding (AUB) is a common gynaecologic complaint that accounts for one- third of outpatient visits to gynaecologists and more than 70% of all gynaecologic consults in the perimenopausal and postmenopausal years, leading to increased health care costs and decreased quality of life. AUB describes any variation from normal bleeding patterns in nonpregnant, reproductive-aged women beyond menarche lasting for at least 6 months. Transvaginal ultrasound is the first-line imaging test for the evaluation of AUB in both premenopausal and postmenopausal women. Transvaginal ultrasound can be used to diagnose structural causes of abnormal bleeding such as polyps, adenomyosis, leiomyomas, hyperplasia, and malignancy, and can also be beneficial in making the diagnosis of ovulatory dysfunction. Traditional 2-dimensional imaging is often enhanced by the addition of 3-dimension imaging with coronal reconstruction and saline infusion sonohysterography. The availability of newer diagnostic tools has made it possible to promptly diagnose and treat an increasing number of such AUBs in an office setting. Once a proper diagnosis has been established, appropriate management must be implemented. Therefore, AUB should not be under/overestimated and diagnosis, investigations and treatment should be proposed as early as possible, taking into account the scientific data available in the current state of medical knowledge.

Keywords: abnormal uterine bleeding, transvaginal ultrasound, sonohysterography, premenopause, leiomyoma

Introduction

Abnormal uterine bleeding (AUB) is a common gynaecologic complaint that accounts for one- third of outpatient visits to gynaecologists and more than 70% of all gynaecologic consults in the perimenopausal and postmenopausal years, leading to increased health care costs and decreased quality of life. AUB is defined as bleeding from the uterine corpus that is abnormal in regularity, volume, frequency, or duration, and it represents any variation from normal bleeding patterns in nonpregnant, reproductive-aged women beyond menarche lasting for at least 6 months [1, 2]. It is important to determine whether the bleeding problem is acute (may require immediate intervention to prevent further blood loss) or chronic [3]. AUB may affect the woman’s daily activity or cause worry about undetected serious disease [4].

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Terms associated with abnormal uterine bleeding are inconsistently defined in the literature, complicating the approach regarding the evaluation and management [5]. In order to avoid confusion and to facilitate the accurate diagnostic and effective treatment options in AUB, in 2011 the International Federation of Gynaecology and Obstetrics (FIGO) proposed a classification for AUB, known by the acronym PALM-COEIN. PALM involves the structural causes of AUB: polyp, adenomyosis, leiomyoma, malignancy and hyperplasia, whereas COIEN describes the non- structural causes: coagulopathy, ovulatory dysfunction, endometrial disorders, iatrogenic, not yet classified [2, 6-7]. Dysfunctional uterine bleeding is often used to describe a non-structural cause of AUB, which is not included in the PALM-COEIN system, thereby the American Congress of Obstetrics and Gynaecology (ACOG) discourages using this term [8]. Before a diagnosis of “COEIN” causes is made, causes related to uterine structural abnormalities, “PALM” causes, need to be excluded. An exception is the early reproductive period when PALM causes are extremely rare. A possible coagulopathy may be identified in 90% of the women using a structured medical history [9]. Ovulatory disorders are characterized by infrequent or irregular bleeding, which is common in the early and late reproductive period. Other common causes are polycystic ovarian syndrome, hyperprolactinemia, hypothyroidism, and contributing factors such as obesity, anorexia, weight loss, mental stress, and extreme exercise [5].

Diagnostic techniques in AUB

A wide range of imaging techniques may be used to detect the structural causes of AUB, but it is mandatory to possess safe and cost-effective techniques. The first-step diagnostic tool used in AUB is transvaginal ultrasonography (TVU), but the 2-dimensonal (2D) imagining is enhanced by including three-dimensional TVU (3D-TVU), Doppler techniques, contrast hysterosonography (COH) with saline infusion sonohysterography (SIS) or gel infusion sonohysterography (GIS). TVU is often available in the gynaecologic office and it is often integrated in the general gynaecologic examination of women with AUB. The advantage is a fast and immediate diagnosis of the most common structural abnormalities in the uterus and ovaries [5]. SIS has acquired an important role in the diagnosis of AUB, establishing itself as a complementary method to conventional transvaginal sonography in the evaluation of patients. SIS involves the instillation of fluid into the endometrial cavity in order to offer a better image of the endometrial anatomy via ultrasound. The golden rule in performing SIS is that it has to be performed early in the follicular phase of the menstrual cycle, on the last days of menses or first few days after menstruation ends. In this period the endometrium is the thinnest and the endometrial “moguls” are not present yet. The endometrial moguls are thought to be irregularities of the topography of the surface of the functional layer as the endometrium proliferates and becomes secretory. SIS should not be performed during active bleeding, because it may offer a false positive result, due to the small clots or the shedding endometrial lining [10]. There are other invasive and costlier examinations such as hysteroscopy, hysterosalpingography or magnetic resonance imaging (MRI) [10]. Alone or in combination with endometrial sampling (ES) and hysteroscopy, these options are sufficient for the diagnosis of women with AUB [5].

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Structural causes of AUB

Polyps Endometrial polyps are focal epithelial proliferation developed from the endometrium, appearing in 1% of AUB in women under the age of 30 and in 20% in postmenopausal women [11-12]. They may also appear in patients receiving tamoxifen. The incidence of malignant polyps is higher in older women, in cases of postmenopausal bleeding, large polyp size or in women with comorbidities such as obesity, hypertension, diabetes [12]. Endometrial polyps may be single or multiple, measuring from a few millimetres to few centimetres, and may be sessile (when the diameter of the base of the polyp is larger than or the same as the largest diameter of the polyp) or pedunculated (when the diameter of the base of the polyp is smaller than the largest diameter of the polyp) [13]. On TVU detecting a polyp may be challenging. The appearance may vary from a nonspecific endometrial thickening to a focal mass in the endometrial cavity. They can be seen as small, pearl- shaped, echogenic masses. The echogenicity may be similar to that of the surrounding endometrium or it may have a heterogeneous aspect. Regular cystic areas may be observed, and the “bright edge” sign may be observed at the border of the polyps. The bright edge is defined as a sharp and smooth echogenic line positioned at the transitional zone between the myometrium and centrally undefined endometrial echoes [14-15]. Frequently it possesses a distinctive aspect – a dominant central feeder vessel detected with colour flow Doppler, offering a 90% specificity and sensitivity [10]. SIS provides the advantage of differentiating between a focal polypoid lesion and a diffuse thickening of the endometrium. At SIS, polyps may present smooth margins and tent to project off of a stalk. 3D imaging is the only ultrasound option that displays the complete uterine cavity, presenting a longitudinal, transverse and a constructed coronal plane (“Z” plane) (Fig. 1) [10].

Fig. 1. Uterine polyp. (a) TVU 2D long view of a uterus showing an intracavitary polyp. (b) TVU 2D transverse view of the same polyp using colour Doppler showing the presence of blood in the polyp. (c) SIS transverse view showing multiple endometrial polyps.

Adenomyosis Adenomyosis is a pathology that describes endometrial glands and stroma focally or globally through the uterine musculature, determining a hypertrophy of the myometrium, with a prevalence ranging from 5% to 70% due to inconsistency in diagnostic criteria [16]. It is a common finding in the hysterectomy specimens – up to 70% [17]. Women with adenomyosis are usually asymptomatic, but they may present AUB and dysmenorrhea, dyspareunia, symptoms that are directly proportional to the number of adenomyotic foci and the depth of the invasion. Risk factors for adenomyosis include: previous uterine surgery, oestrogen exposure, history of leiomyomas or endometriosis [10]. Diagnosis of adenomyosis using TVU is based on the presence of at least two or most often three of the next ultrasound features: ectopic endometrial glands and stroma present in the

102 ©Filodiritto Editore – Proceedings myometrium – they appear as cyst/anechoic lacunae, hyperintense foci of endometrial glands, and irregular endometrial outline, with linear striations and buds; features of the adjacent myometrial hypertrophy are irregular myometrial mass with ill-defined borders, often with fan-shaped shading and globular or asymmetrical uterus; Power Doppler can be used to distinguish myometrial cysts from blood vessels. Adenomyosis is characterized by diffusely spread vessels inside the lesions, whereas circular flow along the pseudo-capsule indicates leiomyomas [18] (Fig. 2, Fig. 3). On TVU the most distinctive characteristic in adenomyosis is sub-endometrial echogenic linear striations [19-20]. The diagnosis of adenomyosis using TVU is dependent on its ability to display a clear image, and on the identification of two to three often indistinct criteria. Therefore, TVU is a very observer dependent technique [21]. In the presence of unclear findings by TVU, MRI may be included to make a confident diagnosis [5].

Fig. 2. Ultrasonographic features of adenomyosis (A, B) Ectopic endometrial glands and stroma present in the myometrium. (C, D, E) Asymmetrical uterus with adjacent myometrial hypertrophy. (F) Diffusely spread vessels inside the lesions

Fig. 3. Adenomyosis (A) Sub-endometrial cysts indicated by *. (B) Fan-shape shading indicated by arrow. (C) Cystic spaces within the myometrium with increased blood flow.

Leiomyomas Leiomyomas, also known as myomas or fibroids, are benign tumours that develop from the smooth muscle cells of the myometrium, with a lifetime prevalence of 70% in white women and more than 80% in black women. There is a wide palette of symptoms that may appear in leiomyomas, including: AUB, dysmenorrhea, dyspareunia, chronic pelvic pain, urinary symptoms (polakiuria), digestive symptoms (constipation, bloating), reproductive dysfunction (infertility, obstetrical complications – repeated pregnancy loss, preterm birth, ectopic pregnancy, abnormal placentation, caesarean section necessity due to the location of the fibroid) [22]. Risk factors for developing fibroids are: ethnicity (African American race), early menarche, early use of oral contraceptive, nulliparity, obesity, family history of leiomyomas [23]. The FIGO classification describes the location of the leiomyomas in relationship with the uterine wall, with the following sub classification: submucosal (0-2), other (3-8) and hybrid leiomyomas (impact both endometrium and serosa). Types 0-2 are submucosal fibroids, and they

103 ©Filodiritto Editore – Proceedings are the most frequent type of fibroids that are associated with AUB, but intramural leiomyomas may also cause AUB [24]. TVU is the first tool used to detect leiomyomas, with a 65-99% sensitivity for detecting them depending on the location and the number of fibroids [25]. On ultrasound the pseudo-capsule of the myomas determines a well-defined border; there may also appear a shadowing effect behind the myoma known as the “venetian-blind effect”. The echogenicity is most often low to isoechogenic, but some internal high echogenicity may be present. The main feature that distinguishes leiomyomas from polyps is the vascularity pattern with a circular flow pattern in fibroids, a typical circumferential flow around the lesion, whereas in polyps there is a single central feeder vessel [17]. Leiomyomas may present calcifications, seen as hyperechogenic areas, or degeneration with cystic spaces aspects of different size. In cases of devascularized leiomyomas after uterine artery embolization (UAE), the tumour presents small nitrogen bubbles due to infarction, bubbles that appear as multiple punctate echogenic foci, the leiomyoma having a speckled appearance [26]. In postmenopausal women, leiomyomas are often seen as small distinct hypoechoic areas with a hyperechoic rim and limited vascularity. However, ordinary myomas may also have high vascularity, heterogeneity, and atypical features like in premenopausal women [5]. COH is required to determine the effect of leiomyomas on the endometrial cavity, as SIS describes the most accurate image of a submucosal fibroid, allowing to include it in a FIGO subcategory and to choose the most fitting operative intervention (Fig. 4) [10]. Hysteroscopy is also an important tool in the diagnostic of submucosal fibroids, having the advantage of offering a treatment solution [27]. The main advantage of SIS is its ability to evaluate size and depth of submucosal leiomyomas and, with Doppler, vascularization of the leiomyoma, while hysteroscopy can visualize only a small part of the protruding fibroid in the endometrial cavity.

Fig. 4. (A) Submucosal myoma on 2D US. (B) Submucosal myoma on SIS. (C) Submucosal myoma on 3D US. (D) Recent UAE: echogenig foci with “dirty” shadowing posteriorly

Malignancy and Hyperplasia Malignancy and hyperplasia of the endometrium are common pathologies that affect mostly perimenopausal and postmenopausal women, but also young patients with risk factors, women having a 2.8% lifetime risk of developing endometrial cancer [2]. It is necessary the evaluation of the endometrium in all women over age 45 with AUB, in those who have persistent AUB or do

104 ©Filodiritto Editore – Proceedings not respond to medical therapy, in order to exclude endometrial cancer. Any postmenopausal bleeding should be considered malignancy until proven otherwise [8]. Risk factors for endometrial cancer include: age, hyperestrogenism states (obesity, polycystic ovary syndrome, exclusive oestrogen therapy), family history of Lynch syndrome, treatment with Tamoxifen, diabetes, hypertension [28]. There are no distinct ultrasound features of hyperplasia, and a diagnosis of hyperplasia has to rely on the histology of samples obtained by ES or hysteroscopy. The endometrial outline may be regular or slightly irregular by COH. Hyperplasia may be diffuse or located in small focal areas, with imaging features like polyps [5]. TVU showing a cut-off for endometrium thickness ≤4 mm can be used to exclude malignancy in postmenopausal women and to avoid endometrial sampling. If there is an inadequate image of the endometrium by TVU, SIS can be used. Even tough, there is no agreement on the setup to diagnose women with an increased endometrial thickness, a series of image characteristics can suggest the presence of malignancy: in women with postmenopausal bleeding and an endometrial thickness of >12 mm, endometrial cancer is common; ultrasonographic texture of endometrial cancer may often be heterogenic, and the endo-myometrial junction may be interrupted; vessel morphology by Doppler with multiple vessel pattern is displayed in two-thirds of endometrial cancers; irregular endometrial outline at COH [5] (Fig. 5).

Fig. 5. (A) A thin endometrial lining can exclude in postmenopausal bleeding. (B) Sagittal US view of a 76-year-old patient shows marked irregular thickening of the endometrium. Pathological examination indicated endometrial carcinoma

Non-structural causes of AUB

Coagulopathy Coagulopathy disorders, especially von Willebrand disease, are encountered in 5% to 24% of . This pathology should be suspected in women with history of prolongs menses, of bruising, epistaxis, dental bleeding, postpartum haemorrhage and severe surgical bleeding [9]. Evaluation should begin with a complete blood cell testing.

Ovulatory dysfunction The most frequent cause of AUB due to in young women is polycystic ovarian syndrome (PCOS), whereas in perimenopause oligo-ovulation and anovulation represent the most common causes for AUB due to ovulatory dysfunction. Ultrasound provides just one of the three criteria in the PCOS diagnostic and it describes >12 follicles measuring 2-9 mm in at least one ovary and/or ovarian volume ≥10 ml. Recently it was proposed a cut-off of 25 follicles when performing an ultrasound with high frequency transducer ≥8 MHz [10, 29].

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Endometrial disorders Endometrial disorders are caused by primary dysfunction of local endometrial haemostasis. Patients describe regular and predictable cycles, suggesting normal ovulation, but accuse heavy menstrual bleeding. The endometrium may have an atrophic, eutrophic or hypertrophic aspect [28]. and endometrial inflammation, demonstrated in Chlamydia trachomatis or Ureaplasma infections, represent other non-structural causes of AUB [8].

Iatrogenic Hormonal treatments with oestrogen, progesterone, GnRH agonists, SPRMs and SERMs compose the main cause of AUB with iatrogenic origins. Women who take anticoagulants, antiplatelet treatments or treatments that alter the dopaminergic metabolism may also present AUB [2].

Not yet classified This category is poorly described, rarely, it includes arteriovenous malformation, myometrial hypertrophy, uterine isthmocele secondary to caesarean delivery scar defect [2].

Management

The management of AUB must be focused on two aspects: the symptomatic treatment and the etiological treatment, provided by medical or surgical methods. The first step is to control the acute episode of AUB and includes IV Premarin 25 mg every 4 to 6 hours for 24 hours associated with antiemetic agents [30]. Other alternatives would be oral contraceptive pill with 35-µg oestrogen 3 times daily for 7 days, followed by 1 tablet daily thereafter or medroxyprogesterone acetate 20 mg 3 times daily for 7 days, followed by 1 tablet daily for the next 3 weeks [31]. Tranexamic acid can be used in patients with no history of venous thromboembolism or cerebral vascular disease 10 mg/kg IV (maximum 600 mg/dose) or 1.3 g orally 3 times daily for 5 days [32]. However, there are studies that indicate that during treatment with tranexamic acid the risk of thromboembolic events is not higher than in the general population [33-35]. Nonsteroidal anti-inflammatory drugs (NSAIDs) can also be used in cases of acute bleeding, provided that there are no contraindications, such as gastritis, peptic ulcer disease [28]. Another available alternative to control the acute bleeding is the intrauterine tamponade with a 26F Foley catheter infused with 30 mL fluid [36]. After the acute episode, a choice has to be taken regarding the following management. In cases of non-structural AUB, medical treatment options include combined hormonal contraceptives, oral progestins, levonorgestrel-releasing intrauterine system. GnRH agonists and ulipristal acetate may be used preoperatively in myomas, reducing both the bleeding and the tumour’s size [37-38]. Surgical treatment is recommended in structural causes of AUB that are not controlled by medical treatment, that diminishes the quality of life and in cases when malignancy is suspected, after endometrial sampling. Options of surgical treatments include: endometrectomy, endometrial distruction, resection of polyps and myomas, hysterectomy [28].

Conclusion

AUB is a frequent occurrence encountered in perimenopausal and postmenopausal women and new diagnostic tools offer a prompt diagnose and feasible treatment options that changed the approach in this pathology. AUB should not be under/overestimated and diagnosis, investigations

106 ©Filodiritto Editore – Proceedings and treatment should be proposed as early as possible, taking into account the scientific data available in the current state of medical knowledge. A structured and detailed evaluation of the endometrial cavity and myometrium using TVU and/or with the inclusion of COH is a simple and efficient diagnostic method for women with AUB. Hysteroscopy remains the gold standard in the evaluation of the uterine cavity. However, the high costs and need for qualified professionals to carry out the procedure are factors that limit its use. It is an invasive test that requires professional training and equipment in specialized centers [39]. 2D- and 3D-SIS appears to be a good, less invasive, less costly and more accessible alternative to hysteroscopy, being safe, with a low frequency of side effects, such as discomfort and minor pain, and with high sensitivity and specificity with a high diagnostic accuracy for the detection of endometrial polyps and submucosal uterine leiomyomas in women of reproductive age with AUB [40].

REFERENCES

[1] Khafaga, A, Goldstein, SR. (2019). Abnormal Uterine Bleeding. Obstetrics and Gynaecology Clinics of North America 46(4), pp. 595-605. [2] Marnach, M, Laughlin-Tommaso, S. (2019). Evaluation and Management of Abnormal Uterine Bleeding. Mayo Clinic Proceedings 94(2), pp. 326-335. [3] Munro, MG, Critchley, HO, Broder, MS, Fraser, IS, FIGO Working Group on Menstrual Disorders. (2011). FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. International Journal of Gynaecology and Obstetrics 113(1), pp. 3-13. [4] Dueholm, M, Hjorth, IMD. (2017). Structured imaging technique in the gynaecologic office for the diagnosis of abnormal uterine bleeding. Best Practice & Research Clinical Obstetrics and Gynaecology 40, pp. 23-43. [5] Fraser, IS, Critchley, HO, Munro, MG, Broder, M. (2007). Writing Group for this Menstrual Agreement Process. A process designed to lead to international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding [published correction appears in Fertility and Sterility 88(2), pp. 538]. Fertility and Sterility 87(3), pp. 466-476. [6] Munro, M, Critchley, H, Fraser, I. (2016). Research and Clinical Management for Women with Abnormal Uterine Bleeding in the Reproductive Years: More than PALM-COEIN. BJOG: An International Journal of Obstetrics & Gynaecology 124(2), pp. 185-189. [7] Munro, M, Critchley, H, Fraser, I. (2018). The Two FIGO Systems for Normal and Abnormal Uterine Bleeding Symptoms and Classification of Causes of Abnormal Uterine Bleeding in the Reproductive Years: 2018 Revisions. International Journal of Gynaecology & Obstetrics 143(3), pp. 393-408. [8] American College of Obstetricians and Gynaecologists. (2012). Practice Bulletin No. 128. Obstetrics & Gynaecology 120(1), pp. 197-206. [9] Shankar, M, Lee, C, Sabin, C, Economides, D, Kadir, R. (2004). von Willebrand Disease in Women with Menorrhagia: A Systematic Review. BJOG: An International Journal of Obstetrics and Gynaecology 111(7), pp. 734-740. [10] Wheeler, K, Goldstein, SR. (2017). Transvaginal Ultrasound for the Diagnosis of Abnormal Uterine Bleeding. Clinical Obstetrics and Gynaecology 60(1), pp. 11-17. [11] Dreisler, E, Sorensen, S, Lose, G. Endometrial Polyps and Associated Factors in Danish Women Aged 36- 74 Years. (2009). American Journal of Obstetrics and Gynaecology 200(2), pp. 147.e1-147.e6. [12] Salim, S, Won, H, Nesbitt-Hawes, E, Campbell, N, Abbott, J. (2011). Diagnosis and Management of Endometrial Polyps: A Critical Review of the Literature. Journal of Minimally Invasive Gynaecology 18(5), pp. 569-581. [13] Leone, FPG, Timmerman, D, Bourne, T, Valentin, L, Epstein, E, Goldstein, SR, et al., (2010). Terms, definitions and measurements to describe the sonographic features of the endometrium and intrauterine lesions: a consensus opinion from the International Endometrial Tumour Analysis (IETA) group. Ultrasound in Obstetrics and Gynaecology 35(1), pp: 103-112.

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[14] Hulka, CA, Hall, DA, McCarthy, K, Simenone, JF. (1994). Endometrial polyps, hyperplasia, and carcinoma in postmenopausal women: differentiation with endovaginal sonography. Radiology 191(3), pp. 755-758. [15] Caspi, B, Appelman, Z, Goldchmit, R, Ashkenazi, M, Haruvy, Y, Hagay Z. (2001). The bright edge of the . Ultrasound in Obstetrics & Gynaecology 15(4), pp. 327-330. [16] Dueholm, M. (2006). Transvaginal Ultrasound for Diagnosis of Adenomyosis: A Review. Best Practice & Research Clinical Obstetrics & Gynaecology 20(4), pp. 569-582. [17] Shwayder, J, Sakhel, K. (2014). Imaging for Uterine Myomas and Adenomyosis. Journal of Minimally Invasive Gynaecology 21(3), pp. 362-376. [18] Chiang, CH, Chang, MY, Hsu, JJ, Chiu, TH, Lee, KF, Hsieh, TT et al., (1996). Tumour vascular pattern and blood flow impedance in the differential diagnosis of leiomyoma and adenomyosis by colour Doppler sonography. Journal of Assisted Reproduction and Genetics 16(5), pp. 268-275. [19] Kepkep, K, Tuncay, Y, Göynümer, G, Tutal, E. (2007). Transvaginal Sonography in the Diagnosis of Adenomyosis: Which Findings Are Most Accurate? Ultrasound in Obstetrics and Gynaecology 30(3), pp. 341-345. [20] Cunningham, R, Horrow, M, Smith, R, Springer, J. (2018). Adenomyosis: A Sonographic Diagnosis. RadioGraphics 38(5), pp. 1576-1589. [21] Dueholm, M, Lundorf, E, Sorensen, JS, Ledertoug, S, Olesen, F, Laursen, H. (2002). Reproducibility of evaluation of the uterus by transvaginal sonography, hysterosonographic examination, hysteroscopy and magnetic resonance imaging. Human Reproduction 17(1), pp. 195-200. [22] Stewart, E. (2015). Uterine Fibroids. New England Journal of Medicine 372(17), pp. 1646-1655. [23] Stewart, E, Cookson, C, Gandolfo, R, Schulze-Rath, R. (2017). Epidemiology of Uterine Fibroids: A Systematic Review. BJOG: An International Journal of Obstetrics & Gynaecology 124(10), pp. 1501-1512. [24] Munro, M, Critchley, H, Fraser, I. (2011). The FIGO Classification of Causes of Abnormal Uterine Bleeding in The Reproductive Years. Fertility and Sterility 95(7), pp. 2204-2208.e3. [25] Owen, C, Armstrong, A. (2015). Clinical Management of Leiomyoma. Obstetrics and Gynaecology Clinics of North America 42(1), pp. 67-85. [26] Williams, P, Laifer-Narin, S, Ragavendra, N. (2003). US of Abnormal Uterine Bleeding. RadioGraphics 23(3), pp. 703-718. [27] Munro, M. (2017). Practical Aspects of The Two FIGO Systems for Management of Abnormal Uterine Bleeding in The Reproductive Years. Best Practice & Research Clinical Obstetrics & Gynaecology 40, pp. 3-22. [28] Levy-Zauberman, Y, Pourcelot, A, Capmas, P, Fernandez, H. (2017). Update on The Management of Abnormal Uterine Bleeding. Journal of Gynaecology Obstetrics and Human Reproduction 46(8), pp. 613- 622. [29] Dewailly, D, Lujan, M, Carmina, E, Cedars, M, Laven, J, Norman, R et al., (2013). Definition and Significance of Polycystic Pvarian Morphology: A Task Force Report from The Androgen Excess and Polycystic Ovary Syndrome Society. Human Reproduction Update 20(3), pp. 334-352. [30] Devore, G, Owens, O, Kase, N. (1982). Use of Intravenous Premarin in the Treatment of Dysfunctional Uterine Bleeding. Obstetrical & Gynaecological Survey 37(7), pp. 478-480. [31] Munro, M, Mainor, N, Basu, R, Brisinger, M, Barreda, L. (2006). Oral Medroxyprogesterone Acetate and Combination Oral Contraceptives for Acute Uterine Bleeding. Obstetrics & Gynaecology 108(4), pp. 924- 929. [32] Lukes, A, Moore, K, Muse, K, Gersten, J, Hecht, B, Edlund, M et al., (2010). Tranexamic Acid Treatment for Heavy Menstrual Bleeding. Obstetrics & Gynaecology 116(4), pp. 865-875. [33] Lethaby, A, Farquhar, C, Cooke, I. (2000). Antifibrinolytics for heavy menstrual bleeding. Cochrane Database of Systematic Reviews [CD000249]. [34] Wellington, K, Wagstaff, A. (2003). Tranexamic Acid: A Review of Its Use in The Management of Menorrhagia. Drugs 63(13), pp. 1417-1433. [35] Sundström, A, Seaman, H, Kieler, H, Alfredsson, L. (2008). The Risk of Venous Thromboembolism Associated with The Use of Tranexamic Acid and Other Drugs Tsed to Treat Menorrhagia: A Case-Control Study Using the General Practice Research Database. BJOG: An International Journal of Obstetrics & Gynaecology 116(1), pp. 91-97. [36] James, A, Kouides, P, Abdul-Kadir, R, Dietrich, J, Edlund, M, Federici, A et al., (2011). Evaluation and Management of Acute Menorrhagia in Women with and Without Underlying Bleeding Disorders: Consensus from An International Expert Panel. European Journal of Obstetrics & Gynaecology and Reproductive Biology 158(2), pp. 124-134.

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[37] Friedman, A, Hoffman, D, Comite, F, Browneller, R, Miller, J. (1991). Treatment of Leiomyomata Uteri with Leuprolide Acetate Depot: A Double-Blind, Placebo-Controlled, Multicenter Study. International Journal of Gynecology & Obstetrics 77, pp. 720-725. [38] Donnez, J, Hudecek, R, Donnez, O, Matule, D, Arhendt, H, Zatik, J et al., (2015). Efficacy and Safety of Repeated Use of Ulipristal Acetate in Uterine Fibroids. Fertility and Sterility 103(2), pp. 519-527.e3. [39] Goyal, BK, Gaur, I, Sharma, S, Saha, A, Das, NK. (2015). Transvaginal sonography versus hysteroscopy in evaluation of abnormal uterine bleeding. Medical Journal Armed Forces India 71(2), pp. 120-125. [40] Zinna, M, Gentile, M, Torcia, F, Bianchi, P, Cozza, G, Marziani, R. (2015). Diagnostic accuracy of sonohysterography vs hysteroscopy in benign uterine endocavitary findings. European Review for Medical and Pharmacological Sciences 19(3), pp. 365-371.

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Management in a Case with Leiomyoma of the Uterine Cervix

MITRACHE Danuta1,2, CRAINA Marius1,2, MOZA Andreea1,2, MARINCAS Sebastian1,2, BERNAD Brenda3, BERNAD Elena1,2

1 Department of Obstetrics and Gynaecology of the “Pius Branzeu” Emergency Clinical County Hospital Timisoara (ROMANIA) 2 Department of Obstetrics and Gynaecology, Faculty of Medicine, “Victor Babes” University of Medicine and Pharmacy from Timisoara (ROMANIA) 3 Department of Psychology, West University of Timisoara (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Compared to myomas that occur in the uterine corpus, cervical myomas are closer to other organs such as the bladder, ureter and rectum, and the approach needs to be modified, as the organs that have to be considered differ depending on the location of the myoma. Surgical difficulties associated with these cases are, poor access to the operative field, difficulty in suturing the repairs, increased blood loss, and distortion of the anatomy of the vital neighbouring structures in the pelvic cavity. The objectives of this paper are to explore aspects and possibilities of surgical treatment of women who attempt to preserve fertility.

Keywords: cervix fibroma, vaginal myomectomy, leiomyoma

Introduction

Uterine fibroids are the most common tumours of uterus which develop in 20-40% of reproductive age women, but cervical leiomyomas are less than 5% of all leiomyomas [1]. Congenital cervical anomalies and other benign or malign cervical lesions must be excluded when a cervical tumour is identified [2, 3]. Patients generally have no symptoms; however, those with such symptoms as severe pelvic pain, heavy uterine bleeding, or infertility may be candidates for surgery. We present the case of a sessile cervical myoma in a 37-year-old woman who attempt to preserve fertility.

Method

The article is a case report of a 37-year-old woman who presented in the emergency service with intermittent pelvic pain, heavy menstrual bleeding, dyspareunia, bleeding after sexual contact and . Following the clinical and paraclinical investigations, it has been established the diagnosis of Leiomyoma of Uterine Cervix. The patient was admitted to the IInd Department of Obstetrics and Gynaecology of the “Pius Branzeu” Emergency Clinical Hospital from Timisoara for the specialized treatment.

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Results and discussions

The patient has a history of 4 vaginal births with a physiological evolution. Affirmative, the patient had painful and abundant menstrual cycle with a duration of about 5 days. Routine biochemical and haematological investigations were in normal limit. The general clinical examination did not reveal any pathological changes, the patient presenting a good general condition at the time of admission. Examination of the abdomen revealed a large abdomen increased by volume through fatty panic, sensitive to palpation in the lower abdomen area. Speculum examination revealed a well delimited tumour, bleeding on certain portions (Fig. 1). Bimanual examination estimated a normal uterine size, freely movable and anteverted. It was notable for the presence of a firm mass fixed to the uterine cervix. Rectovaginal examination didn’t detect any nodularity in the cul de sac.

Fig. 1. Cervical fibroid on examination with valves

Pelvic ultrasonography revealed an anteverted uterus with 130/65/50 mm, normal endometrial thickness, on the uterine cervix a sessile vascularised tumour of 44,6/32,4 mm (Fig. 2). The MR Imaging revealed a sessile tumour of 4,6/4/4 cm located anterior of the uterine cervix up to 2 cm. The tumour appears as distinct hypointense masses on T2-weighted images and are homogeneously enhanced. Characteristic high signal intensity on T1-weighted images suggests red degeneration, which is caused by venous thrombosis. The MRI presumptive diagnosis was Leiomyoma of Uterine Cervix.

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Fig. 2. Transvaginal ultrasound – the tumour of the uterine cervix

Because the patient attempt to preserve fertility, the surgical cure of the leiomyoma was decided and vaginal myomectomy was performed. The extracted piece was sent to histopathological examination. The particularity of the case was the sessile implantation of the tumour, so the impossibility of resecting the formation by torsion. The histopathological result was Submucosal fibroleiomyomatous nodule. After 2 months postoperative the ultrasound (Fig. 3A) revealed a hyperechoic image of 1/0.3 cm. The uterus cervix was normal on speculum examination (Fig. 3B).

Fig. 3. Postoperative status

A. Ultrasound aspect B. Speculum examination

General differential considerations for a mass lesion in the uterine cervical region include: prolapsed submucosal uterine leiomyoma, carcinoma, lymphoma or melanoma of the cervix. The ultrasonography with Doppler can help the investigator to assess the local vascularisation characteristics [4, 5]. Laparoscopic Myomectomy and Hysterectomy have been advocated over traditional laparotomy for various benefits in case of uterine leiomyoma [6]. With the advances in laparoscopic techniques, almost all uterine myomas in the uterine corpus can be treated using

112 ©Filodiritto Editore – Proceedings laparoscopic myomectomy. However, the treatment of cervical myoma by laparoscopic operation remains crucial. It is essential to establish techniques for safety in operative laparoscopy, for different types of cervical myomas [7]. Compared to myomas that occur in the uterine corpus, cervical myomas are closer to other organs such as the bladder, ureter, and rectum, and the approach needs to be modified, as the organs that have to be considered differ depending on the location of the myoma. Surgical difficulties associated with these cases are, poor access to the operative field, difficulty in suturing the repairs, increased blood loss, and distortion of the anatomy of the vital neighbouring structures in the pelvic cavity [8]. In our case report, the patient attempt to preserve fertility, so the surgery was classic, vaginal myomectomy. An electronic evidence of more cases can help to create a useful database which can be an important instrument of teaching practical skills for young physicians and students [9, 10]. Pedunculated uterine myomas or submucosal cervical myomas may protrude through the cervical canal and into the vagina and may become necrotic and occasionally infected due to inadequate blood supply [11]. The complications of cervical leiomyomas include pressure effects on the bladder or urethra, degenerative phenomena, , pain (pelvic cramping), prolapse with infection and torsion [12]. Because our patient had a sessile tumour of 4 cm, she had no complication as infection or protruding tumour. Since uterine fibroids are the most common benign tumour in women, it would be important to study the risk factors that lead to this pathology. For example, hormonal imbalance and environmental prenatal exposures to endocrine disrupting chemicals must be studied related in all cases diagnosed with fibroids [13, 14]. Therefore, the study of the effects they could have on reproductive health in women could be the basis for the development of prevention and treatment strategies in the future.

Conclusion

Proper and timely management of cervical myomas increases the patient’s ability to obtain and retain a pregnancy in the future, even the ability to give birth naturally. It is considered that this benign tumour can be prevented, the main solutions remaining its detection through specific investigations and intervention with medical or surgical treatment, when is necessary.

REFERENCES

[1] Buttram Jr VC, Reiter RC. Uterine leiomyomata: Ethiology, symptomatology, and management. Fertil. Steril. 1981; 36: pp. 433-45. [2] Laufer, MR, Goldstein, DP, Hendren, WH. Structural abnormalities of the female reproductive tract. In: Pediatric and Adolescent Gynaecology (Fifth Ed), Emans, SJ, Laufer, MR, Goldstein, DP (Eds), Lippincott Williams & Wilkins Publishing Company, Philadelphia 2005. P. 334. [3] Ples, Liana; Sima, Romina Marina; Stanescu, Anca Daniela; Olaru Octavian-Gabriel. The Importance of a National Congenital Anomalies Registry – the Role of the Prenatal Diagnosis. (2017) Proceeding paper for the 5th Romanian Congress of the Romanian Society of Ultrasound in Obstetrics and Gynaecology, pp. 505- 510. [4] S.I. Bernad, E.S. Bernad, D. Broboana, V.A Albulescu, D. Barbu, C. Balan, Three-dimensional assessment of the fetal flow in a normal and in the presence of the IUGR, Proceedings of the 22th European Congress of Perinatal Medicine, Granada, Spain, May 26-29, 2010, pp. 131-134. [5] Bernad, SI, Bernad, ES, Barbat, T., Barbu, D., Albulescu, V., Assessment of the placental blood flow in the normally developing and growth-restricted fetus, Proceedings of the 22th European Congress of Perinatal Medicine, Granada, Spain, May 26-29, 2010, pp. 1277-130. [6] Matsuoka S, Kikuchi I, Kitade M, Kumakiri J, Kuroda K, Tokita S, et al., Strategy for laparoscopic cervical myomectomy. J Minim Invasive Gynecol. 2010; 17: pp. 301-5.

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[7] Chang WC, Chen SY, Huang SC, Chang DY, Chou LY, Sheu BC. Strategy of cervical myomectomy under laparoscopy. Fertil Steril. 2010; 94: pp. 2710-5. [8] Pleş L, Sima RM, Burnei A, Albu DF, Bujor MA, Conci S, Teodorescu V, Edu A. Rom J MorpholEmbryol (2016). The experience of our Clinic in laparoscopy for adnexal masses and the correlation between ultrasound findings and pathological results, Rom J Morphol Embryol 57(4): pp. 1337-1341. [9] E., Bernad, R., Urda, E., Ilie, C., Bernad, S., Muntean, C., Improve the prenatal care indicators with an electronic patient record system. Proceedings of the European Federation for Medical Informatics Special Topic Conference, Integrating Biomedical Information: From e-Cell to e-Patient, Timisoara, Romania, Apr. 06-08, 2006, pp. 395-397. [10] Vida, M., Lupse, O., Gomoi, V., Stoicu-Tivadar, L., Stoicu-Tivadar, V., Bernad, E., Using Web Services to support the interoperability between healthcare information systems and CDS systems, Control Engineering and Applied Informatics, Volume: 16, Issue: 1, Pages: 106-113, 2014 [11] Golan A, Zachalka N, Lurie S, Sagiv R, Glezerman M. Vaginal removal of prolapsed pedunculated submucous myoma: A short, simple, and definitive procedure with minimal morbidity. Arch Gynecol. Obstet. 2005; 271: pp. 11-3. [12] Cohen DT, Oliva E, Hahn PF et al., Uterine smooth-muscle tumours with unusual growth patterns: imaging with pathologic correlation. AJR Am J Roentgenol. 2007;188 (1): pp. 246-55. [13] Moga, M.; Ples, L.; Bigiu, N.; Manitiu, I. An Overview of The Risk of Adverse Reproductive and Developmental Disorders Due to Exposure to Pesticides (2011). Journal of Environmental Protection and Ecology 12 (3A), pp. 1311-1319. [14] Mahalingaiah S, Hart JE, Wise LA, Terry KL, Boynton-Jarrett R, Missmer SA. Prenatal diethylstilbestrol exposure and risk of uterine leiomyomata in the Nurses’ Health Study II. Am J Epidemiol. 2014 Jan 15; 179(2): pp. 186-91.

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Congenital High Airway Obstruction – See It Once and Never Forget It Case Report

MUNTEANU Alexandra Elena1,2, CONSTANTIN Mona Elena1,2, ZAMFIRESCU Vlad1,2, VLĂDĂREANU Radu1,2*, VLĂDĂREANU Simona1,3, FILIPESCU George Alexandru1,3

1 Carol Davila University of Medicine and Pharmacy, Bucharest, (ROMANIA) 2 Obstetrics and Gynaecology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 3 Neonatology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) * Corresponding author: VLĂDĂREANU Radu Email: [email protected]

Abstract

Congenital high airway obstruction syndrome represents a rare condition in which the fetal glottis, larynx or both are blocked or, worse, absent. The incidence for this congenital anomaly is rare and a few numbers of cases have been reported until now. The constant improvement of the fetal prenatal screening, the techniques and the quality of the operators and the machines have made the diagnosis easier and have reduced the time of the diagnosis starting with the early second trimester. The consequence of the obstruction of the airway at this level is lethal for the fetus and although, ex utero intrapartum procedure (EXIT) shows promises, the search for a cure is ongoing.

Keywords: CHAOS, laryngeal atresia, airway obstruction, EXIT

Introduction

Congenital high airway obstruction syndrome (CHAOS) is defined by agenesis of the glottis, larynx, or both. The importance of this condition is given by the exceedingly poor prognosis that without a treatment leads to certain early neonatal death. The exact incidence of this anomaly is not truly known because of the high grade of mortality, but it seems that fewer than 50 cases were reported since 1989, though some describe it 1 per 50.000 new-borns [1]. The pathology of this condition, at a smaller level, consists of hyperplasia of the alveolar units which are filled with fluid and, therefore, the entrapment of a large amount of fluid within the lungs [2]. The volume of the fetal lungs becomes severely increased, they deform the thorax and reverse the normal convex shape of the diaphragm and displace the last, more mobile, ribs laterally. [3] Soon, the heart is pushed to the middle of the chest, squeezed to a 0-degree cardiac axis. Almost constantly, there is ascites, pleural effusion, and hydrops. The diagnosis is quite easy, the lungs occupy the entire thorax and are very bright compared to the echogenicity of the liver. The prognosis is fatal without treatment, and the association with other anomalies is common. The most frequent non- chromosomal syndrome is Fraser’s syndrome, but it can also be part of Short rib polydactyly syndrome, VATER/VACTERL association, Di George syndrome.

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Case History An 18-year-old woman, gravida 1, parity 0 presented with uterine contractions and lower abdominal pain. Her gestational age was 22 weeks and 4 days. Both she and her family had unremarkable medical histories. Up to that point she was not evaluated by any medical practitioner due to her commitment to the pregnancy. The ultrasound examination showed bilateral enlarged lungs and hyperechoic lung tissue. The heart was displaced, pushed to the middle of the thorax (Fig. 1a, b).

Fig. 1a (left side) Four chamber view of the fetal heart showing enlarged hyperechogenic lungs, fetal heart trapped in the middle. 1b (right side) Post-mortem view of the left lung confirming the enlargement of the pulmonary tissue.

The convexity of the diaphragm was reversed, and the abdomen was filled with fluid (Fig. 2a, b). The left kidney was small and the right one was absent, and the position of the hand was fixed and during the entire scan (Fig. 3a, b).

Fig. 2a (left side) Sagittal sonographic view of the fetal thorax showing the reversed shape of the diaphragm, the hyperechoic lung tissue compared to the liver and the presence of ascites. 2b (right side) Post-mortem caption of the fetal thorax confirming the reversed shape of the diaphragm, the middle- placed heart and the left lobe of the liver pushed to the right side.

The couple was referred to a genetics specialist and an amniocentesis procedure was performed.

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The micro-array performed came back negative and the poor prognosis was discussed with the couple and they chose to remain committed to the pregnancy. Unfortunately, the labor started soon and in 7 days she miscarried a female fetus that weighted 510 g. Post-mortem examination was offered and accepted by the parents. The post-mortem examination confirmed the enlarged lungs, therefore CHAOS, the absent kidney but also revealed anomalies of the gastro-intestinal tract: the sigmoid colon was dilated and the absence of the rectum, and there was an imperforated anus (Fig. 4a, b).

Fig. 3a (left side) Ultrasound view of the left hand, fixed threw out the scan. 3b (right side) Post-mortem caption of the left hand fixed in extension with overlapping fingers

Fig. 4a (left side) Post-mortem caption of the fetal back showing imperforate anus. 4b (right side) Post-mortem caption of the rectum showing the dilated sigmoid colon and agenesis of the rectum.

Discussions

Laryngeal atresia is considered the number one cause for congenital high airway obstruction [1], followed by tracheal agenesis, subglottic stenosis or atresia, and laryngeal webs or cysts. The underlying pathogenesis is not clearly known, but is described as a vascular injury that takes place around the 10th week of gestation with the obstruction of the blood supply necessary for the

117 ©Filodiritto Editore – Proceedings development of the trachea/larynx [4]. The obstruction sets in motion a series of events summarized by the accumulation of fluid in the lungs that become exceedingly enlarged. The unstoppable expansion of the lung volume leads to an increased pressure over the heart function, of the venous flow and the diaphragm. The consequence to that is the constant development of ascites, pleural effusion and finally hydrops. The sonographic diagnosis is quite easy in any section, but routinely best seen on the four- chamber view of the fetal heart. The findings are impressive due to the enlarged, invariable bilateral hyperechoic lungs with the heart pushed in the middle, the loss of the normal convexity of the diaphragm and ascites. Usually, the entrapped fluid dilates the bronchial tree and makes it visible in contrast with the hiperechogenicity of the lungs. The coronal view of the thorax is useful for a better picture of the expansion level of the lungs, the flattened or inverted diaphragm, the distinctive bell-shape given by the lateral displacement of the lower, farely mobile ribs. Our case had all the specific sonographic features, except for polyhydramnios that commonly appears, according to the literature, due to the oesophageal obstruction by the enlargement of the lungs, but if given the time, in association with the bowel obstruction, it’s likely to have developed. The differential diagnosis is undertaken only for educational purpose, because CHAOS has such a unique, unforgettable appearance. From the specific pulmonary lesions, the only one that is bilateral is the microcystic solid form of congenital cystic adenomatoid malformation (CCAM) type III, but the exceedingly large lung volume is not seen in CCAM type III, and, although, the sonographic appearance resembles to bronchial atresia, the latter is, always, a unilateral lesion. It’s useful to keep in mind as a differential diagnosis pulmonary sequestration that has its blood supply from the descending aorta, so finding the feeding vessel clears the diagnosis. Differentiation between laryngeal and tracheal atresia is not possible on ultrasound, so using MRI to locate the obstruction should be the next step. Previously, the precise location or the degree of obstruction, partial or total, were not so important for the outcome of the pregnancy, but now, with the help of an early diagnosis and a multidisciplinary team an EXIT procedure can be performed and a change for survival given. Also, it’s important to separate the intrinsic from extrinsic causes of obstruction such as: cervical tumours, malformation of the lymphatic system and vascular rings. Usually, prognosis indicators are searched and used to analyse the outcome of the pregnancy whenever there is an anomaly, but, in this case, given the mortality of this condition, it seems useless. The risk of association with chromosomal anomalies is low, but, as in the case described, the presence of other anomalies is frequent and increases the risk of non-chromosomal syndromes. The most common genetic syndrome is Fraser’s, characterized by laryngeal atresia, cleft lip and, or palate, microphthalmia, external ear anomalies and bilateral renal agenesis [5]. The only change regarding the prognosis is in a worsening matter, given the fact that the condition is autosomal recession transmitted with an 25% chance of recurrence. The most common associated malformations are trachea-oesophageal fistula, duodenal atresia, hemivertebra, radial aplasia and cardiac anomalies. Until recently, the foetuses with this condition were condemned due to lack of appropriate fetal techniques, but the new EXIT procedure (ex-utero intrapartum technique) remains the only available therapeutical option [6, 7]. The purpose is to obtain a functional, therapeutic airway during the delivery before the blood supply is stopped [8], so the timing of diagnosis, the time of delivery becomes of great importance for the survival and development of the baby. In this procedure, laryngoscope examination followed by tracheostomy is done after partial delivery of the fetal head with the fetus still being attached to the placenta [9]. The other available treatment option is intrauterine fetoscopy laser laryngotomy which is based on the concept of spontaneous

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antenatal improvement of some cases of CHAOS secondary to spontaneous perforation [8, 9]. For the cases that undergo surgical treatment, either in utero or EXIT, MRI could be a required investigation to assess the best option for each case. [10] More than ever, this is a time for an early diagnosis of this condition and, with the help of MRI, clarify the location and the extension of the obstruction. One of the most important and favourable factors for survival is the accurate selection of the cases that could benefit from an intrauterine procedure before EXIT. Long term outcomes and the quality of life of the survivors is still uncertain.

Conclusions

CHAOS is a severe, rare, congenital anomaly with an early neonatal mortality of 100% without treatment. The real incidence and ethiology is not completely known, but some cases are part of genetic conditions, such as Fraser’s syndrome that is autosomal recessive inheritance, with a 25% risk of recurrence. The diagnosis is made quite easy, the sonographic appearance is unique due to the impressive enlargement of the lungs. Not too long ago, the chance of survival soon after birth was nil, but now, with the new EXIT procedure, there are at least 9 survivors reported in the literature after the procedure [11] so, more than ever before, the prenatal diagnosis is vital. One of the challenges after assuring the imminent survival of the neonate remains the reconstruction of the atretic or obstructed part of the airway.

REFERENCES

[1] Royball JL, Liechty KW, Hendrick HL, Bebbington MW, Johnson MP, Coleman BG, et al., Predicting the severity of congenital high airway obstruction syndrome. J Pediatr Surg 2010; 45: pp. 1633-9 [2] Dario P, Paolo V, Ultrasound of Congenital Fetal Anomalies 2017; 13:978 0 415 41444 9. [3] Filipescu, George Alexandru; Burnei-Rusu, Anca; Zvanca, Mona; Solomon, Oana Alina; Clim, Nicoleta; Milulescu, Amelia; Boiangiu, Andreea Gratiana; Vladareanu, Radu Early Detection of Congenital Diaphragmatic Hernia – Case Report and Literature Review 5th Romanian Congress of the Romanian-Society- of-Ultrasound-in-Obstetrics-and-Gynaecology Isi Proceedings pp. 273-277, 2017. [4] D'Eufemia, M. D., Cianci, S., Di Meglio, F., Di Meglio, L., Di Meglio, L., Vitale, S. G., Laganà, A. S., Chiofato, B., Rapisarda, A., Padula, F., La Rosa, V., Coco, C., & Vascone, C. (2016). Congenital high airway obstruction syndrome (CHAOS): discussing the role and limits of prenatal diagnosis starting from a single-center case series. Journal of prenatal medicine, 10(1-2), pp. 4-7. [5] Joshi P, Satija L, George R, Chatterjee S, D’Souza J, Raheem A, Congenital high airway obstruction syndrome- antenatal diagnosis of a rare case of airway obstruction using multimodality imaging, Med J Armed Forces India. 2012 Jan; 68(1): pp. 78-80. [6] Glynn F, Sheahan P, Hughes J, Russell J. Successful ex utero intrapartum treatment (EXIT) procedure for congenital high airway obstruction syndrome (CHAOS) owing to a large oropharyngeal teratoma. Ir Med J 2006; 99: pp. 242-243. [7] Petca, A.; Vladareanu, S.; Zvanca, M.; Bot, M.; Vladareanu, R. Timing for the delivery of the growth-restricted fetus: a resolvable issue PROCEEDINGS OF THE 49TH ANNUAL SCIENTIFIC MEETING OF THE EUROPEAN SOCIETY FOR CLINICAL INVESTIGATION, Pages: 273-277, Published: 2015. [8] Vidaeff AC, Szmuk P, Mastrobattista JM, Rowe TF, Ghelber, More or less CHAOS: case report and literature review suggesting the existence of a distinct subtype of congenital high airway obstruction syndrome Ultrasound Obstet. Gynecol. 2007 Jul; 30(1): pp. 114-7. [9] Sharma R., Dey A. K., Alam S., Mittal K., Thakkar H. A series of congenital high airway obstruction syndrome – classic imaging findings. Journal of Clinical and Diagnostic Research. 2016; 10(3): pp. TD07-TD09. [10] Kurjak, Asim; Antsaklis, Panos; Stanojevic, Milan; Vladareanu, Radu; Vladareanu, Simona; Neto, Raul Moreira; Barisic, Lara Spalldi; Porovic, Selma; Delic, Taib Multicentric studies of the fetal neurobehavior by KANET test JOURNAL OF PERINATAL MEDICINE Volume: 45, Issue: 6, Pages: 717-727, Special Issue: SI, DOI: 10.1515/jpm-2016-0409 Published: AUG 2017.

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[11] Joshi P., Satija L., George R. A., Chatterjee S., D'Souza J., Raheem A. Congenital high airway obstruction syndrome antenatal diagnosis of a rare case of airway obstruction using multimodality imaging. Medical Journal Armed Forces India. 2012; 68(1): pp. 78-80. doi: 10.1016/S0377-1237(11) pp. 60111-1. [12] Saadai P, Jelin EB, Nijagal A, Schecter SC, Hirose S, MacKenzie TC, Rand L, Goldstein R, Farrell J, Harrison M, Lee H. Long-term outcomes after fetal therapy for congenital high airway obstructive syndrome. J Pediatr Surg. 2012 Jun; 47(6): pp. 1095-100. doi: 10.1016/j.jpedsurg.2012.03.015. PMID: 22703776.

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Active Management of Gynaecological Malignancies During Pregnancy – Fetal Risk Versus Oncological Safety

PÂRVULEȚU-ALI Saphia1,2*, VLĂDĂREANU Radu1,2**, SOLOMON Oana Alina1,2*, VLĂDĂREANU Simona1,3, BOIANGIU Andreea Grațiana1,2, FILIPESCU George Alexandru1,2*

1 Carol Davila University of Medicine and Pharmacy, Bucharest, (ROMANIA) 2 Obstetrics and Gynaecology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 3 Neonatology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) * All authors have the same contribution ** Corresponding author: VLĂDĂREANU Radu Email: [email protected]

Abstract

The incidence of cancer during pregnancy is considered a rare event up to 0,07-0,1% of all malignant tumours [1], but with the rising of maternal age the number of the pregnant women affected by cancer is growing. Cervical cancer is the most frequent gynaecological tumour diagnosed in pregnant women the types of tumours that occur are the same common tumours that appear in females during reproductive age: cervical cancer, breast tumours, lung cancer, leukaemia, malignant melanoma. [2, 3, 4] Cancer is detected in 1/1000. Women. Among those, cervical cancer is the most often cancer during pregnancy, occurring in 0.8 to 1.5 cases per 10,000 births one half of them being diagnosed prenatally [5]. Hodgkin disease is found in 1:1000-6000 cases and melanoma in 2.6:1000 cases. , part of standard pregnancy care can detect cervical cancer and a routine ultrasound can detect an ovarian cancer. Often the diagnosis is delayed because of the pregnancy symptoms [6]. There are cases in which the type of cancer is demanding chemotherapy and there is poor evidence on this case. Cancer during pregnancy causes ethical and therapeutic challenges, the physician being needed to maintain and regard the wellbeing of the fetus and the maternal prognosis [7]. Because of the lack of exact data’s regarding initiation, dosage the risk of damage cannot be optimum [8]. Physiological changes during pregnancy can affect drug effect especially in second and third trimester, and chemosensitivity of cancer cells ios defined for some anticancer drugs. The purpose of this paper is to describe the impact of anticancer therapy as in short- and long- term effect when administered in pregnant women with malignant disease.

Keywords: pregnancy, cancer, surgery, multidisciplinary

Introduction

Signs and symptoms that commonly occur in cancer may overlap and be hidden by physiological changes specific to pregnancy. There are many procedures that can be used and not harm the fetus. Among those laparoscopic surgery or laparotomy may be safely performed using prophylactic tocolytics cervical coisation requires vaginal length measurement top revent cervical

121 ©Filodiritto Editore – Proceedings incompetence [9]. Patients receiving antenatal chemotherapy must be monitored 2-4 weekly using ultrasounds assessing interval growth, amniotic fluid and cervical length [10]. Staging and treatment should be standard. Chemotherapy should be delayed during the first trimester (14 up to 35 weeks) and radiation therapy is recommended in the postpartum period. Birth may be considered when immediate treatment is required. Future pregnancies do not increase the risk of malignancy recurrence, but subsequent pregnancy rates are lower, depending on the type of cancer. The incidence of cancer during pregnancy is considered a rare event up to 0,07-0,1% of all malignant tumours [1], but with the rising of maternal age the number of the pregnant women affected by cancer is growing. The term “gestational cancer” includes cancer diagnosed during pregnancy and during the first year postpartum according to several studies. The types of tumours that occur are the same common tumours that appear in females during reproductive age: cervical cancer, breast tumours, ovarian cancer, lung cancer, leukaemia, malignant melanoma [2, 3, 4]. Among cancers, cervical cancer 1.4-4.6/100000 cases, ovarian cancer 0.2-3.8/100000 cases, breast cancer during pregnancy, occurred in 1-3 per 3000-10.000 cases, and vaginal cancer in 0.1- 0.5/100000 cases data available in Annals of Oncology online. The risk is lower compared to non- pregnant women. Vulvar neoplasia during pregnancy is rare in corelation with its low incidence before 40-45 years [4, 11, 12, 13, 14, 15, 16, 17]. Hodgkin disease is found in 1:1000-6000 cases and melanoma in 2.6:1000 cases. Pap test, part of standard pregnancy care can detect cervical cancer and a routine ultrasound can detect an ovarian cancer. Often the diagnosis is delayed because of the pregnancy symptoms [6]. There are cases in which the type of cancer is demanding chemotherapy and there is poor evidence on this case. Cancer during pregnancy causes ethical and therapeutic challenges, the physician being needed to maintain the well-being of the fetus and the maternal prognosis [7]. Cancers treatment during pregnancy requires multidisciplinary approach, optimization of the treatment considering the fetal wellbeing. It is highly important to assess precisely the gestational age and the structural development of the fetus and placenta. Foils acid supplements and nutritional counselling is important to reduce maternal-fetal risk. Because of the lack of exact data’s regarding initiation, dosage, the risk of damage cannot be optimum [8]. Physiological changes during pregnancy can affect drug effect especially in second and third trimester, and chemosensitivity of cancer cells is defined for some anticancer drugs. CT scan is not recommended and should be used only if strictly necessary using iv contrast. Fetal exposure is linked to the proper use of the abdominal shield and the quality of the machine. CT comes as a second choice after MRI. Adverse effects depend on the radiotracer, dose and fetus weight [18]. Ionizing radiation should have clear indication and clinical benefit. A study reports that gadolinium-enhanced MRI does not induce congenital anomalies but it was associated with other pathological changes in the offspring as rheumatologic, inflammatory or infiltrative skin conditions and even stillbirth or neonatal death [18] and therefore the use of gadolinium for imaging in MRI is not recommended during pregnancy. A recent study suggests that WB- DWI/MRI (whole-body diffusion-weighted MRI) could replace F-FDG-PET/CT. It reports equal efficacy in the metastasis detection (nodal and distant metastasis) [19] and no adverse effects regarding the fetus. WB-DWI/MRI could be used for staging and for therapeutic response evaluation in pregnant women diagnosed with cancer [20]. Surgery can be performed in any trimester but it is preferred in early second trimester due the size of uterus and the decreased risk of miscarriage [21].

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Cytotoxic chemotherapy Most chemotherapeutic agents have low molecular weight and cross the placenta and are known/suspected teratogens. The timing of exposure to antineoplastic drugs determines the severity of the fetal injury [22], determining a risk of major malformations up to 10%-20% [23]. Chemotherapeutic insult can interfere with the processes of implantation causing miscarriage and spontaneous abortion. If the embryo survives (all-or-nothing period; undifferentiated and totipotent cells), it is expected to develop normally. We must pay attention during organogenesis because of the rapid differentiation that causes increased vulnerability and a risk of major malformation up to 14% [24]. There are organs and systems that maintain to be vulnerable until the end of the first trimester: the eyes, genitals, hematopoietic and central nervous system. During the 2nd and the 3rd trimester chemotherapy can interfere with organ maturation process and determine malformation (3% comparable with the general population) [24], IUGR-intrauterine growth restriction, preterm labor or low birth weight [25]. If initiation of chemotherapy is absolutely necessary pregnancy termination must be considered along with the proper advice on the risk of tetatogenity in case the mother refuses [25, 26, 27]. Pharmacokinetics of the drugs can be modified due to the hypervolemia, enhanced renal/hepatic elimination and reduced albumin levels but current recommendation is to use the same doses (dose/m2 or dose/kg2) as in general population paying attention to dosage due to the weight oscillations [25, 26]. Chemotherapy should be stopped 3 weeks before delivery or after 35 weeks of gestation and therefore weekly regimes should be used [28]. After 14 weeks of gestation, administration of a number of anticancer drugs is available including taxanes, platinum agents, anthracyclines, etoposide and bleomycin. For example, in cervical cancer the regime used is paclitaxel/carboplatin weekly or 3-weekly. Carboplatin is used except germ cell cancers that require cisplatin. Etoposide is used in combination with cisplatin and considered to be safe but documented on few cases [29, 30, 31, 32]. Methotrexate, dacarbazine, cyclophosphamide and cytarabine have a higher teratogenic potential [24, 26, 28]. Tamoxifen is associated with birth defects 1up to 2,6% but the evidence is limited and patients should be counselled about the use and not postpone the treatment [33]. Studies of long-term follow-up of individuals exposed to intrauterine chemotherapy report good outcome regarding growth and development: Sokal et al., 1960, Reynoso-1960, Nulman et al., 2001, Aviles et al., 2001, Amant et al., 2012 [34, 35, 36, 37, 38]. Molecularly targeted agents are more and more used in modern oncology practice. The available evidences report neonatal B cell depletion, oligohydramnios, pre-eclampsia, abortion, stillbirths, premature delivery and a high incidence of infant mortality. The most used targeted immunotherapies are: imatinib, rituximab, transtuzumab, lapatinib, bevacizumab, ipilimumab and PD-1/PD-L1 inhibitors. Immunotherapy immunomodulatory pathways are involved in developing immune tolerance to the presence of a fetus [39]. Inhibition of PD-1/PD-L1, CTLA-4 could trigger an immune response against the fetus so drugs that inhibit these checkpoints can cross the placenta and therefore be toxic for the fetus [40]. In animal models it determined abortion, premature delivery, stillbirths, infant mortality particularly if used in 3rd trimester but no malformations were cited. Doses that were used were much higher than therapeutically and because of the lack of human trials these drugs are not recommended during pregnancy [40, 41, 42].

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Support medications Bisphosphonates are not recommended during pregnancy because it diminishes calcium levels in maternal blood and therefore reduce the calcium delivered towards the fetus determining skeletal malformations and low birth weight [43, 44, 45], but can also affect uterine contraction pattern [46]. GSC-F can cross the placenta but these drugs were used with good safety data’s in cases of severe neutropenia [47]. Radiation therapy effect include malformation, fetal death, growth restriction or carcinogenic effects gestational age and dose related. For pelvic cancers there is no role of RT during pregnancy therapeutic starting from the first fraction, will lead to fetal death and after successful cancer treatment the probability of a new pregnancy decreases.

Conclusions

Delivery should be induced before 37 weeks to avoid morbities and prematurity sequelae. For most cervical and vulvar cancers C section is indicated combined or not with simple or radical hysterectomy using locoregional anaesthesia with careful examination of the placenta. Lymphnodes dissection can be performed after delivery by a gynaecological oncologist to minimize bleeding. Signs and symptoms that commonly occur in cancer may overlap and be hidden by physiological changes specific to pregnancy. Cancers treatment during pregnancy requires multidisciplinary approach, optimization of the treatment considering the fetal wellbeing. [48, 49] MRI is preferred to reduce fetal radiation exposure. Surgery should not be postponed and it can be performed anytime during pregnancy. Iatrogenic prematurity for maternal benefit is the most common complication.

REFERENCES

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[37] Aviles A, Neri N. Haematological malignancies and pregnancy: a final report of 84 children who received chemotherapy in utero. Clin Lymphoma. 2001; 2(3): pp. 173-177. doi: 10.3816/CLM.2001. n. 023. [38] Amant F, Van Calsteren K, Halaska MJ, Gziri MM, Hui W, Lagae L, Willemsen MA. et al., Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study. Lancet Oncol. 2012; 13(3): pp. 256-264. doi: 10.1016/S1470-2045(11)70363-1. [39] Luppi P. How immune mechanisms are affected by pregnancy. Vaccine. 2003; 21(24): pp. 3352-3357. doi: 10.1016/S0264-410X (03)00331-1. [40] Poulet FM, Wolf JJ, Herzyk DJ, DeGeorge JJ. An Evaluation of the Impact of PD-1 Pathway Blockade on Reproductive Safety of Therapeutic PD-1 Inhibitors. Birth Defects Res B Dev Reprod Toxicol. 2016; 107(2): pp. 108-119. doi: 10.1002/bdrb.21176. [41] Johnson DB, Sullivan RJ, Menzies AM. Immune checkpoint inhibitors in challenging populations. Cancer. 2017; 123(11): pp. 1904-1911. doi: 10.1002/cncr.30642. [42] D’Addio F, Riella LV, Mfarrej BG, Chabtini L, Adams LT, Yeung M, Yagita H. et al., The link between the PDL1 costimulatory pathway and Th17 in feto-maternal tolerance. J Immunol. 2011; 187(9): pp. 4530-4541. doi: 10.4049/jimmunol.1002031. [43] Stathopoulos IP, Liakou CG, Katsalira A, Trovas G, Lyritis GG, Papaioannou NA, Tournis S. The use of bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens) 2011; 10(4): pp. 280-291. doi: 10.14310/horm.2002.1319. [44] Patlas N, Golomb G, Yaffe P, Pinto T, Breuer E, Ornoy A. Transplacental effects of bisphosphonates on fetal skeletal ossification and mineralization in rats. Teratology. 1999; 60(2): pp. 68-73. doi: 10.1002/(SICI)1096-9926(199908)60: 2<68: AID-TERA10>3.0.CO; 2-H. [45] Okazaki A, Matsuzawa T, Takeda M, York RG, Barrow PC, King VC, Bailey GP. Intravenous reproductive and developmental toxicity studies of cimadronate (YM175), a novel bisphosphonate, in rats and rabbits. J Toxicol Sci. 1995; 20(Suppl. 1): pp. 1-13. doi: 10.2131/jts.20. SupplementI_1. [46] Minsker DH, Manson JM, Peter CP. Effects of the bisphosphonate, alendronate, on parturition in the rat. Toxicol Appl Pharmacol. 1993; 121(2): pp. 217-223. doi: 10.1006/taap.1993.1148. [47] Cardonick E, Irfan F, Torres N. The use of Neupogen (Filgrastim) or Neulasta (Pegfilgrastim) during pregnancy when chemotherapy is indicated for maternal cancer treatment. Journal of Cancer Therapy. 2012; 3: pp. 157-161. doi: 10.4236/jct.2012.32021. [48] Zervoudis, S.; Tsikouras, P.; Galazios, G.; Liberis, V.; Veduta, A.; Vladareanu, R.; Xaralambous, X.; Konstandinou, S Breast cancer the role of psychology as cofactor. A multicentric study of 278 cases Proceedings of The XV International Congress of The International Society of Psychosomatic Obstetrics and Gynaecology pp. 373-377, 2007. [49] Oprescu, Dana Nuti; Bacalbasa, Nicolae; Balescu, Irina; Filipescu, Alexandru Urinary Tract Resections in Advanced-stage Cervical Cancer – A Series of Eight Cases ANTICANCER RESEARCH, Volume: 37, Issue: 6, Pages: 3271-3276 DOI: 10.21873/anticanres.11691, Published: JUN 2017.

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Managing Invasive Cervical Cancer During Pregnancy

PÂRVULETU ALI Saphia1,2*, VLĂDĂREANU Simona1,3, BOLOCAN Georgiana2, SOLOMON Oana-ALINA1,2, DUMITRASCU Mihai Cristian1,4, BOIANGIU Andreea Gratiana1,2, VLĂDĂREANU Radu1,2

1 Carol Davila University of Medicine and Pharmacy, Bucharest, (ROMANIA) 2 Obstetrics and Gynaecology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 3 Neonatology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 4 Obstetrics and Gynaecology Department Emergency University Hospital, Bucharest, (ROMANIA) * Corresponding author: PÂRVULEȚU-ALI Saphia Email: [email protected]

Abstract

Pregnancy-associated cervical cancer is a challenging and difficult topic in modern onco- gynaecology, which emphasizes the importance of professional experience and the establishment of a multidisciplinary team. Complicated pregnancy with cervical cancer refers to cervical cancer diagnosed during current pregnancy, but also in the first 6-12 months postpartum [1]. The incidence of cervical cancer in pregnant women is low: 1-3% of patients diagnosed with cervical cancer, but it is increasing recently, being age related. Cervical cancer is one of the most common cancers in pregnancy 71.6%, followed by ovarian cancer 7% [1-3].

Keywords: cervical cancer, multidisciplinary team, pregnancy

Introduction

Cervical cancer is the fourth most commonly diagnosed cancer and the second cause of cancer death among females. The estimated incidence is 570,000 new cases in 2018 and the second cause of exitus due to cancer and the only gynaecological cancer staged clinically according to the International Federation of Gynaecology and Obstetrics classification system. The Danish registry revealed a rise regarding the cases of cancer associated with pregnancy from 5.4% to 8.3% over a 30‐year period. An Australian study reported 1798 cancers, 499 during pregnancy and 1299 in the postpartum period, giving an incidence of 137.3/100.000 pregnancies. age explained only a 14% increase in incidence. The overall prognosis is good and regarding all these facts the treatment programmes are curative. Its occurrence during pregnancy has an incidence of approx. 1,200- 10,000 pregnancies, one half of them being diagnosed prenatally.[4] For cervical intraepithelial neoplasia (CIN), reported incidence rates vary between 1.30 and 2.7 per 1000 pregnancies. Almost 2/3 of cervical cancer are diagnosed during the first two trimesters and are early stages. The standardization of treatment is complex and challenging due to rarity of this association. Guideline up to 2012 are based on expert opinions and small trials. [5, 6, 7] Amant, Hunter, Morice et al., published clinical guidelines trying to reach a consensus on treatment during pregnancy. It is a necessary to have a multidisciplinary team due to the lack of consensus and the absence of large cohort studies and randomised controlled trials and take into consideration the histological subtype, the stage, nodal status, gestational age, the patient’s choice and any other obstetrical complications. Nowadays pregnancy preservation and options of

127 ©Filodiritto Editore – Proceedings treatment during pregnancy are common. The purpose of this paper its o gathers treatment guidelines and data’s regarding cervical neoplasia during pregnancy [8, 9-12]. There are many controversial studies about the susceptibility of an onset or progression of cervical cancer during pregnancy. The level of oestrogen, progesterone and human chorionic gonadotropin in pregnant women is correlated with an increased risk of infection with high risk HPV. Also, increased blood and lymph circulation in the genital organs, decreased immunity and dilatation of the cervix are factors that can accelerate the process of metastasis. [13, 14].

Diagnosis

CLINICAL In most cases, patients with stage I cervical cancer are asymptomatic. The most common clinical manifestations are haemorrhage, yellow-smelly discharge, postcoital or spontaneous secretions. Rarely, patients describe pelvic pain. In advanced stages, haematuria, low back pain, intestinal transit disorders may occur [5, 15, 16].

CITOLOGY The pathologist must be informed that the specimen belongs to a pregnant patient. There are some data that show that 1.2% of patients with abnormal cytology have cervical cancer [17, 18].

COLPOSCOPY Extensive professional experience is required for this assessment, due to the physiological changes that occur in pregnancy and it is very important for the physician performing the colposcopy to be familiar with this kind of specimens.

IMAGING 1. MRI is useful for determining tumour size, stromal invasion, vaginal and parametric invasion, but also lymph node invasion 2. Echography Some studies (Epstein et al., 2013, Fischerova et al., 2008) have demonstrated diagnostic accuracy comparable to MRI of transvaginal and transrectal ultrasound. 3. CT The radiation dose should be kept to a minimum during pregnancy and a fetal risk vs. maternal benefit assessment should be performed. However, it is useful in diagnosing lung or pleural metastases. 4. PET-CT Because of potential risks of fetal loss, teratogenicity, intrauterine fetal growth restriction and carcinogenesis, PET-CT with an 18F-2-fluoro-2-deoxy-D-glucose injection (FDG) is generally contraindicated in the pregnant patient. Medical physicists, radiologists and nuclear medicine physicians may be consulted to analyse the potential case and consult with a pregnant patient before or after a PET-CT examination [19-22]. 5. Tumour Markers Two large studies reported an increase of the value of SCC (squamous cell cancer antigen) in the third trimester, but many studies are still ongoing.

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BIOPSY In pregnant patients, the sensitivity and specificity of biopsies in relation to the final diagnosis are 83.7% and 95.9%, respectively. In the case of cervical biopsies performed during pregnancy, the risk of bleeding and effective haemostasis is only 1-3%. Other complications such as early labor or premature rupture of membranes are very rare. Conization is usually postponed postpartum because of the frequent complications: haemorrhage (5% in the first 2 trimesters of pregnancy, 10% in the 3rd trimester), abortion (25%), early labor (12%), infection (2%) [13, 14, 23-26].

TREATMENT Cervical cancer during pregnancy causes therapeutic and ethical dilemmas. The therapeutical approach depends on the gestational age at the time of the diagnosis, disease staging, size of the lesion and the patient's wish to maintain pregnancy and fertility [15, 27]. The most frequent histopathological type of cervical carcinoma found during pregnancy is squamous cell type (responsible for 80% of the lesions), followed by adenocarcinoma. These proportions are similar to those observed among non-pregnant women. According to FIGO, the stage distribution at the time of diagnosis shows that 70 to 80% of pregnant women with cervical cancer are in stage I, 11 to 20% in stage II, 3 to 8% in stage III and 0 to 3% in stage IV [1, 28, 29].

Precursor Lesions Progression of precursor lesions to invasive cancer is very rare 0-0.4%. Colposcopy and cervical biopsy can be performed safely during pregnancy. Endocervical curettage is contraindicated. Physiological changes of the cervix in pregnancy – increased vascularity, hypertrophy, hyperplasia of the endocervical glands – can mimic CIN so colposcopy should be performed by experienced doctors. Aria Stella Phenomenon, changes in trophoblastic cells, can lead to false positive HSIL results if the pathologist is not informed about the pregnant status of the patient [30, 31].

ASC US și LSIL The risk of progressing to CIN 2-3 postpartum is 3.7%. Colposcopy can be delayed up to 6 months postpartum.

HSIL Colposcopy and cervix biopsy are recommended. If the colposcopist certifies the absence of the invasion/the result of the biopsy is CIN 2-3, cytology and colposcopy are performed every 12 weeks to monitor the progression. Spontaneous regression of CIN 2-3 lesions is common: 48-70%.

Invasive lesions In the case of pregnant women with cervical in situ carcinoma, diagnosed using cervical biopsy the doctor may postpone treatment after birth. Delaying therapy for several months does not significantly change the prognosis of the disease (in situ carcinoma). Patients with carcinoma in situ – the doctor may indicate vaginal birth, in the absence of obstetric indications for caesarean section. The presence of cervical in situ carcinoma does not present additional risks for the mother/fetus during vaginal birth [32, 33].

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First trimester

Stage IA2 (T1a2) and IIA (T2a1-2) The doctor must indicate the surgical treatment: Radical hysterectomy (with the product of conception in utero) with pelvic lymphadenectomy. The size of the pregnant uterus in the first trimester does not make it difficult to perform a hysterectomy. Young patients with early cervical cancer may opt for HRLP and avoid radiation therapy. This prevents post-radiotherapy fibrosis and preserves ovarian function. Vaginal radical trachelectomy with pelvic lymphadenectomy, with pregnancy preservation, can be considered an option in selected cases. Imaging of suspect lymph nodes can be verified histopathologically before 24 weeks of pregnancy, preferably by a minimally invasive MRI method. Stage IIB (T2b) and III (T3a-b, IIIC) The doctor must indicate the medical therapeutic abortion as the initial stage of treatment. In stages IIB and III the treatment consists of radiotherapy (RTE + intracavitary) and chemotherapy. Radiotherapy induces the death of the conception product and it is considered unethical to apply it with the conception product in utero. [27, 34]

Second trimester

The doctor must take into account the mother’s desire in the therapeutic decision. The second trimester of pregnancy is the most difficult period in terms of making a therapeutic decision. The physician must obtain the patient’s informed consent before applying the treatment. Postponement of birth and cancer therapy with a few weeks (until fetal viability) does not seem to affect the prognosis. In stages IA2-IIA (T1a2 – T2a1-2) in which the patient chooses to terminate the pregnancy the doctor must indicate HRLP. In stages IA2-IIA (T1a2 – T2a1-2) in which the patient chooses to maintain the pregnancy until fetal viability is reached, the doctor must indicate the completion of the pregnancy by caesarean section at 32-34 weeks of gestation (ultrasound documentation of pregnancy is important) followed by HRLP. In stages IIB-III (T2b – T3a-b) in which the patient chooses to terminate the pregnancy, the doctor must indicate fetal evacuation, followed by chemoradiotherapy. In stages IIB-III (T2b – T3a-b) in which the patient chooses to maintain the course of pregnancy until fetal viability is reached, the doctor must indicate the completion of the pregnancy by caesarean section at 32-34 weeks of amenorrhea followed by chemoradiotherapy.

Third trimester

In stage IA1 (T1a1) the doctor must practice a cervical conization at 6 weeks: after the natural birth (at term) OR after the caesarean section (imposed by obstetric conditions) For stages IA2, IB-IIA (T1a2, T1b-T2a), the doctor must practice HRLP following caesarean section. In stages IIB-IIIB, IIIC the doctor must perform a caesarean section and then direct the patient to the oncology service for chemoradiotherapy [35, 36].

Prognosis

There are some studies on precursor lesions for cervical carcinoma diagnosed during pregnancy that have reported that 10 up to 70% regress and disappear after delivery, while 25 up to 47% persist and 3 up to 30% progress. Monitoring the patient and the progression of the lesion during

130 ©Filodiritto Editore – Proceedings pregnancy is required, and the doctor must consider definitive treatment after childbirth [11, 13, 25, 28, 34]. After a quick review of the literature we discover that pregnant women with invasive cervical carcinoma have a better prognosis than non-pregnant women do. Such findings have been correlated with the larger number of diagnoses during the early stages of pregnancy [5, 7, 10,18]. The maternal prognosis does not seem to be affected in cases of a diagnosis made after 16 weeks of pregnancy with postponement of treatment in order to wait for fetal pulmonary maturity. The rate of recurrence in these cases is similar to those observed among non-pregnant women [4, 15, 11]. The fetal prognosis is influenced by the type of treatment and by the timing since neonatal morbidity and mortality are related to prematurity. In addition, the fetal prognosis also depends on intrauterine exposure to cytotoxic drugs, thus demonstrating the importance of adequate prenatal and perinatal care provided by doctors with experience in such cases in a high-risk unit [5, 10, 32].

Conclusion

Pregnancy is an excellent opportunity for detection of preneoplastic lesions and tumours in the early stages. Progression of precursor lesions to invasive cancer is very rare 0-0.4%. Colposcopy and cervical biopsy can be performed safely during pregnancy. Colposcopy can also rule out or confirm the presence of microinvasion or invasion. Endocervical curettage is contraindicated. Conization is usually postponed postpartum because complications occur frequently. Precursor lesions for cervical carcinoma and in situ carcinoma should be monitored during pregnancy and re-evaluated after delivery. For microinvasive carcinoma, there are no reports in the literature regarding the best approach or the time for treatment and type of delivery. Patient treatment is a priority in cases of invasive carcinoma detected up to the 12th week of pregnancy. When the disease is found in the second trimester, it is possible to wait until fetal pulmonary maturity. Many recent studies have indicated the use of chemotherapy in order to stabilize the disease until the time of delivery, which should preferentially be by caesarean section. [36, 37]

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[33] Al-Halal H., Kezouh A., Abenhaim H. (2012) Incidence and obstetrical outcomes of cervical intraepithelial neoplasia and cervical cancer in pregnancy: A population-based study on 8.8 million births. Arch Gynecol. Obstet., in press. [34] Oprescu, Dana Nuti; Bacalbasa, Nicolae; Balescu, Irina; Filipescu, Alexandru Urinary Tract Resections in Advanced-stage Cervical Cancer – A Series of Eight Cases Anticancer Res. 2017 Jun; 37(6): pp. 3271-3276. doi: 10.21873/anticanres. 11691. [35] Filipescu, Alexandru; Balescu, Irina; Bacalbasa, Nicolae Upper Abdominal Resection for Isolated Metastatic Lesions in Recurrent Cervical Cancer Anticancer Res. 2018 Mar; 38(3): pp. 1659-1663. doi: 10.21873/anticanres.12398. [36] Ghidul SOGR – Cancerul de col uterin – Ministerul Sănătăţii Comisia de Obstetrică şi Ginecologie, Colegiul Medicilor din România Comisia de Obstetrică şi Ginecologie. [37] Skupski, Daniel W.; Chervenak, Frank A.; McCullough, Laurence B.; Bancalari, Eduardo; Haumont, Dominique; Simeoni, Umberto; Saugstad, Ola; Donn, Steven; Arabin, Birgit; Greenough, Anne; Donzelli, Gianpaolo; Levene, Malcolm; Sen, Cihat; Carbonell, Xavier; Dudenhausen, Joachim W.; Vladareanu, Radu; Antsaklis, Aris; Papp, Zoltan; Aksit, Mehmet; Carrapato, Manuel – Ethical dimensions of periviability JOURNAL OF PERINATAL MEDICINE vol 38, issue 6, 10.1515/JPM.2010.098.

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Challenges in Prenatal Diagnosis of Craniosynostosis

PLEȘ Liana1,2, POENARU Mircea-Octavian1,2, STĂNESCU Anca-Daniela1,2, OLARU Octavian-Gabriel1,2, SIMA Romina-Marina1,2

1 Department of Obstetrics and Gynaecology, “Carol Davila” University of Medicine and Pharmacy, Bucur Maternity, Bucharest (ROMANIA) 2 “Sf. Ioan” Emergency Clinical Hospital, Bucharest (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Introduction Ossification of the foetal skull is of membranous type and is completed late after birth. Presence of spaces between bones allow brain growth and foetal head moulding during birth. Premature closure of the sutures is known as craniosynostosis, conditions that ca be detected prenatally by ultrasound or combination of ultrasound MRI, foetal CT.

Material and methods A retrospective observational study was performed on the second trimester anomaly scans performed between 2017-2019 in Bucur Maternity. Ultrasound parameters that we assessed were: head shape, skull ossification, sutures appearance and size of the head including Cephalic Index. All measurements were performed in standard axial section of the foetal head according to the guidelines.

Results From the 4583-anomaly scan performed 28 suspected CNS were identified based on abnormal shape of the head or abnormal cephalic index. After re-evaluation 21 were retained and in two cases termination of pregnancy was performed for Apert syndrome and achondroplasia. After birth only one case of Crouzon syndrome required dedicated management. The most frequent CNS confirmed postpartum were mainly nonsyndromic (dolichocephalic).

Conclusion Craniosynostosis are rare but potentially severe congenital anomalies that can be recognised prenatally. Prenatal diagnosis can be difficult mainly in nonsyndromic cases. The main goal of prenatal diagnosis of craniosynostosis is to as warn about perinatal complications and allow proper counselling of the couple.

Keywords: craniosynostosis, prenatal diagnosis, cephalic index, ultrasound anomaly

Introduction

Foetal skulls recognise a membranous type ossification with the conjunctive tissue present and separating between two bony fronts for a long time during foetal and neonatal life. Proliferate and differentiate into osteocytes. Those spaces are defined as fontanels and sutures [1]. The main

134 ©Filodiritto Editore – Proceedings cranium sutures are: sagittal, coronal, metopic, lambdoid. The main fontanels are: anterior fontanel (bregma), posterior (lambdoid), sphenoidal and mastoid fontanels. Presence of those spaces are important allowing cranium moulding during birth and cerebral normal growth during pregnancy. Fontanels remain opened until postnatal life allowing skull and brain development. [2]. Craniosynostosis (CNS) are defined as premature ossification and closure of the sutures and fontanels. The incidence account for 1/2000-1/5000 births and are producing important consequences- cranium deformities, hydrocephaly, superior airways obstruction, hear and speech impairment, neuro-behaviour delay. [3]. Depending on the association with other structural anomalies, craniosynostosis can be syndrome (20%) or non-syndromic (80%). [3]. The process of growth, suture overlap, and ultimately fusion is tightly regulated by a variety of genes, including several in the fibroblast growth factor receptor (FGFR1, 2, 3) family involved also in other skeletal development processes. In this respect, the nonsyndromic craniosynostosis recognise rarely genetic causes or can be produced by de novo mutation. [4].

Material and method

The aim of the study was to assess the prenatal diagnosis accuracy of foetal craniosynostosis. We performed a retrospective observational cohort study between Jan 2017-dec 2019 in Bucur Maternity. All pregnancies that were scanned in the second trimester for structural anomalies were included. The scans were performed on different ultrasound equipment Mindray, GE Voluson E8, E10, with Trans abdominal probe 3, 5 MHz. We analysed retrospectively the shape of the head, calvarium ossification, sutures appearance and size of the head including Cephalic Index (defined as the ration between parietal diameter BPD and occipitofrontal diameter OFD). Standard axial section of the foetal head (trans- ventricular, trans-thalamic) were used for measurements according to the guidelines. [5] We evaluated also other parameters as inner and outer orbital distance (IOD and OOD) as routine evaluation but included in the study whenever anomalies were suspected. The charts used for comparison of the parameters were published by Chitty. [6] Demographic parameters retained were: patient’s age, gestational age, parity. Whenever suspected anomalies were found detailed analyse of the foetal morphology was performed Presence of structural anomalies others than cranium anomalies were noted and in case of syndrome anomalies, we recommended genetic testing (amniocentesis with karyotype). Pregnancies with abnormal cranium or parameters were scheduled for follow up in the third trimester, pregnancy outcome and confirmation of the craniosynostosis was noted.

Results

From a total of 4583 anomaly scan performed in the mentioned period 28 patients with suspected CNS were identified. 19 of them based on abnormal shape of the head (8 dolichocephalic, 6 brachycephalic, 5 skull deformation). Main patient’s age was 29 years old. Mean GA at time of diagnosis was 23+5 weeks. 22 of the patients (78.5%) were primipara. All patients were re-examined according to the significance of the findings and 21 were retained as true suspect CNS. In one case achondroplasia was diagnosed and karyotype confirmed FGFR2

135 ©Filodiritto Editore – Proceedings mutation. In one case Apert syndrome was diagnosed based on hands anomalies. Both patients underwent TOP and the anomalies were confirmed by forensic examination. From the rest of 19 remained patients after birth we could confirm one Crouzon syndrome which required ICU transfer for superior airways obstruction. In 4 cases the babies had dolichocephalic and in 2 brachycephalic as isolated CNS association. We lost of follow up 8 patients but did not diagnosed at birth prenatally unsuspected craniosynostosis.

Fig. 1. Abnormal skull shape in achondroplasia with premature coronal suture closure

Fig. 2. Scaphocephaly – notice the CI of 63

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Fig. 3. Abnormal shape of the foetal head in Crouzon syndrome in late second trimester – note the normal CI and borderline ventriculomegaly

Fig. 4. Apert syndrome – note the important angulation of the coronal suture and important brain shadowing

Discussion

Craniosynostosis in our experience is a very rare occurrence (1/1000 births) as prenatal diagnosis in concordance to the literature results 3 to 5/10000 [1, 5]. The explanation can be related to the difficult prenatal diagnosis and late onset of the symptoms, usually as a late second trimester or third trimester diagnosis. The real incidence of the craniosynostosis in our country is not known since there is no national malformation register. [7] Diagnosis of the craniosynostosis prenatally is often difficult there is no universal marker and relying on a unique sign is impossible. The main trigger sign of the CNS was in our study the abnormal shape of the cranium mainly the deformity of some parts (at the level of coronal suture, metopic temporal bones). We found that the most affected suture was the sagittal one which induced a dolichocephalic cranium shape. Other studies (Bennis, Harada) also found that the most common affected suture is the sagittal, followed by the coronal [5].

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One of the most important markers of the premature closure of the sagittal or coronal sutures is the Cephalic index with normal ranges between 75 and 85. In all our cases of dolichocephaly CI was below 70 and confirmed the findings of other studies including the fact that in some types CI is not altered (such trigonocephaly or some late Apert syndrome) [8]. Since sutures and fontanels are “windows” through which we can isolate the cerebral structures, and visualise important landmarks as falx cerebri, lateral ventricles, cavum septum pellucidi, thalami etc., premature closure of the foetal skull will make difficult the scan. This observation was made by Krajden Haraz who proposed a novel sign for craniosynostosis “brain shadowing” [9]. In our study we found that sign very useful but we must admit that not always we recognised it as a trigger for CNS. 3D examination of foetal cranium proved valuable as a third stage strategy to routine measurement but it is feasible for screening due to the fact that is time-consuming, requires high operator skills and appropriate equipment as many studies indicate. [8] In our experience the 3D examination of foetal skull was not possible in all cases mainly due to unfavourable condition such anterior position if the foetal spine, thick maternal wall, reduced amniotic fluid. The low incidence of the CNS in our series didn’t allow a proper conclusion toward the syndrome vs nonsyndromic ratio. The nonsyndromic cases were isolated scaphocephaly’s or brachycephalic with good postnatal outcome. As the sagittal suture is the most frequent affected by SNC also other authors reported scaphocephaly as leading the incidence in nonsyndromic CNS [3]. As an overall performance of US in CNS’s prenatal diagnosis, there are different reports in the literature. In a study conducted over 6 years Harada reported 110 suspected cases from which only 41 were confirmed, with a rate of detection of 61%. The relative high detection rate was attained either only by US or the combination of US and further imaging modalities including MRI and/or 3D-CT. [10]. In our study we had a very high rate of false positive reports of CNS, only ¼ being actually confirmed. This was due to lack of specific signs and pitfalls of examination in poor condition as maternal obesity or too much pressure applied on the foetal skull, or familial condition of the foetal cranium shape (i.e., brachycephalic). Another source of misdiagnosis is the late appearance of some syndromes (i.e. Apert syndrome can show the typically aspect late in pregnancy) or lack of trigger associated condition. [11] Associated anomalies are frequent in syndrome CNS as Apert, Crouzon, Pffeifer, Saethre- Chotzen Syndrome etc. The most encountered are skeletal, syndactyly, mitten hands, ventriculomegaly, hypertelorism, exophthalmia, shallow orbits, midface hypoplasia, palate clefts, typical facial appearance [11]. We found association in syndromic cases (mitten hands in Apert syndrome case, exophthalmic face, ventriculomegaly and midface hypoplasia in Crouzon, and skeletal anomalies in achondroplasia). Regarding to the evolution of foetuses with craniosynostosis the potential complication is related to associated condition. The most frequent is related to the foetal growth restriction and requires appropriate evaluation in order to establish the delivery timing. [12] Ultrasound is also in this situation the most useful toll either as many authors demonstrated. [13, 14]. The pregnancy outcome differs according to the type of craniosynostosis. In the syndrome type when multiple association are present the couples could request pregnancy termination (TOP). In Romania foetal anomalies as a reason for TOP is not properly regulated, since the only legal provisions are in found in the Criminal Code. Late onset and late diagnosis of the craniosynostosis is another issue whenever TOP is involved but on the other side can lead to legal litigation for missed prenatal diagnosis. [15]

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Whenever the parents choose to continue pregnancy a proper counselling in multidisciplinary approach ins mandatory mainly for the appropriate surgical management of the baby. An integrated electronic web in order to facilitate the communication between different specialist can be of paramount importance in this situation in our country since the surgical facilities are not available in all tertiary centers. [16] Our study has several limitations: reduced number of cases identified, loss of follow up for some suspected craniosynostosis and lack of genetic tests in all cases due to resource scarcity. Also inexperienced physicians can miss the diagnosis in subtle anomalies overlooked in the second trimester especially when isolated. We must take in account also that CNS is an evolving condition that can worsen throughout pregnancy. That’s why in case of doubt or minor signs the patient must be followed in the third trimester. [17] The prenatal diagnosis of such condition is of paramount importance since in some cases the babies need prompt surgery or appropriate management in order to relive superior airway obstruction.

Conclusion

Craniosynostosis are rare but sometime severe congenital anomalies that can be recognised prenatally. Although there is no unique ultrasound marker appropriate and serial examination of the foetal cranium can trigger the diagnosis. The diagnosis can be difficult in nonsyndromic cases but cephalic index, brain shadowing, skull abnormal shape or 3D abnormal appearance lead to a proper identification of premature suture closure. The main goal of prenatal diagnosis of craniosynostosis is to detect syndromic cases warn about perinatal complications and allow proper counselling of the couple.

REFERENCES

[1] Flaherty K, Singh N, Richtsmeier JT. Understanding craniosynostosis as a growth disorder. Wiley Interdiscip Rev Dev Biol 2015. [2] Aknin JJ. Croissance craniofaciale. In: EMC-Médecine buccale. 2008; pp. 1-21. [3] Bennis Y, Wolber A., Vinchon M., Belkhou A., Duquennoy-Martinot V., Guerreschi P.Les craniosténoses non syndromiques Non syndromic craniosynostosis Annales de Chirurgie Plastique Esthétique Volume 61, Issue 5, October 2016, Pages 389-407. [4] Roscioli T, Elakis G, Cox T, Moon D, Venselaar H, Turner A, et al., Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients. Am J Med Genet C Semin Med Genet 2013; 163(4): pp. 259-70. [5] International Society of Ultrasound in O, Gynaecology Education C. Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’. Ultrasound Obstet. Gynecol. 2007; 29: pp. 109-116. [6] Chitty LS, Altman DG, Henderson A, et al., Charts of fetal size: 2. Head measurements. Br J Obstet. Gynaecol. 1994; 101: pp. 35-43. [7] Ples, Liana; Sima, Romina Marina; Stanescu, Anca Daniela; et al., The Importance of a National Congenital Anomalies Registry – the Role of the Prenatal Diagnosis 5TH ROMANIAN CONGRESS OF THE ROMANIAN SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY Pages: 505-510 [8] J. Cornelissen, Inge Apon, Jacques J. N. M. van der Meulen, Irene A. L. Groenenberg, Mieke N. Kraan – van der Est, Irene M. J. Mathijssen, Gouke J. Bonsel & Titia E. Cohen – Overbeek (2018) Prenatal ultrasound parameters in single-suture craniosynostosis, The Journal of Maternal-Fetal & Neonatal Medicine, 31: 15, pp. 2050-2057, DOI:10.1080/14767058.2017.1335706. [9] Krajden Haratz K, Leibovitz Z, Svirsky R, Drummond CL, Lev D, Gindes L, Lerman-Sagie T, Malinger G. The ‘Brain Shadowing Sign’: A Novel Marker of Fetal Craniosynostosis. Fetal Diagn Ther. 2016; 40(4): pp. 277-284. doi: 10.1159/000444298. Epub 2016 Apr 7. PMID: 27049321.

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[10] Harada A, Miyashita S, Nagai R, Makino S, Murotsuki J. Prenatal sonographic findings and prognosis of craniosynostosis diagnosed during the fetal and neonatal periods. Congenit Anom (Kyoto). 2019 Jul; 59(4): pp. 132-141. doi: 10.1111/cga.12308. Epub 2018 Sep 5. PMID: 30132994. [11] Ketwaroo PD, Robson CD, Estroff JA. Prenatal Imaging of Craniosynostosis Syndromes. Semin Ultrasound CT MR. 2015 Dec; 36(6): pp. 453-64. doi: 10.1053/j.sult.2015.06.002. Epub 2015 Jun 16. PMID: 26614129. [12] Bernad PS.I. Bernad E.S, Broboana D., Albulescu V.A, Barbu D, Balan C, Three-dimensional assessment of the fetal flow in a normal and in the presence of the IUGR, Proceedings of the 22th European Congress of Perinatal Medicine, Granada, Spain, May 26-29, 2010, pp. 131-134. [13] Petca, A.; Vladareanu, S.; Zvanca, M.; Bot, M.; Vladareanu, R. Timing for the delivery of the growth- restricted fetus: a resolvable issue PROCEEDINGS OF THE 49TH ANNUAL SCIENTIFIC MEETING OF THE EUROPEAN SOCIETY FOR CLINICAL INVESTIGATION Pages: 273-277 Published: 2015. [14] Bernad, SI, Bernad, ES, Barbat, T., Barbu, D., Albulescu, V., Assessment of the placental blood flow in the normally developing and growth-restricted fetus, Proceedings of the 22th European Congress of Perinatal Medicine, Granada, Spain, May 26-29, 2010, pp. 1277-130. [15] Octavian, Olaru Gabriel, Ionescu, C, Lesnic, A, Filipescu, GA; Ples, L Ethical and medico-legal aspects of the therapeutic abortion – our experience ROMANIAN JOURNAL OF LEGAL MEDICINE Volume: 26 Issue: 1 MAR 2018 pp. 82-85. [16] Vida, M., Lupse, O., Gomoi, V., Stoicu-Tivadar, L., Stoicu-Tivadar, V., Bernad, E., Using Web Services to support the interoperability between healthcare information systems and CDS systems, Control Engineering and Applied Informatics, Volume: 16, Issue: 1, Pages: 106-113, 2014. [17] Kurjak, Asim; Antsaklis, Panos; Stanojevic, Milan; Vladareanu, Radu; Vladareanu, Simona; Neto, Raul Moreira; Barisic, Lara Spalldi; Porovic, Selma; Delic, Taib Multicentric studies of the fetal neurobehavior by KANET test JOURNAL OF PERINATAL MEDICINE, Volume: 45, Issue: 6, Pages: 717-727, Special Issue: SI DOI: 10.1515/jpm-2016-0409, Published: AUG 2017.

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Early Diagnosis of Hypoplastic Left Heart Syndrome

POENARU Mircea Octavian1, TALPALARU Alina1, SIMA Romina1, PLEȘ Liana1

1 UMF Carol Davila, Bucur Maternity, (ROMANIA) Email: [email protected]

Abstract

Introduction The early diagnosis of congenital heart anomalies represents another challenge in the obstetric practice. The hypoplastic left heart syndrome (HLHS) has a frequency of 2.8% among congenital heart anomalies and is found in only 0,226% of new-borns. The anomaly is severe, duct dependent, associates a small or non-existent left ventricle, reduced contractility, sometimes with endocardial fibroelastosis, mitral valve disfunction or atresia and/or aortic valve stenosis or atresia. The ascending aorta and the aortic arch are highly narrowed and retrograde blood flow is observed in the aortic arch. HLHS recognizes reconstructive surgical techniques with a success rate of over 85% and a survival at 6 years of age of over 64%.

Materials and method The images recorded at routine ultrasound evaluations in cases of HLHS were retrospectively followed-up. The purpose of the study was to identify any structural or hemodynamic anomalies that could have been identified during standard ultrasound sections at the first trimester screening and/or the reassessment of the heart at 18 weeks.

Results and discussion Only two cases of HLHS were detected in the routine examination in the second trimester (20- 22 weeks). In both cases, correct standard ultrasound images were recorded, both at the first trimester screening and the 18th week reassessment. In both cases, the diagnosis was made on the standard 4-room section. The cause in one case was mitral atresia and the other one, aortic stenosis, confirmed by the anatomo-pathological examination of the parts, in both cases the parents requesting the termination of pregnancy.

Conclusions HLHS is a rare but severe anomaly, whose diagnosis cannot be determined earlier than the time of screening in the second trimester. Although it can be operated with an acceptable success rate, parents usually request the termination of pregnancy.

Keywords: hypoplastic left heart syndrome, mitral atresia, aortic stenosis

Introduction

Hypoplastic left heart syndrome (HLHS) is represented by a wide array of cardiac malformations, which manifest as a severe underdevelopment of the left heart-aorta complex,

141 ©Filodiritto Editore – Proceedings consisting of aortic and/or mitral valve atresia, stenosis, or hypoplasia with marked hypoplasia or absence of the left ventricle (LV), and hypoplasia of the ascending aorta and the aortic arch [1]. If left untreated, the condition is lethal due to the fact that the left heart structures are incapable of sustaining systemic blood flow. In this study we aim to assess the rate of HLHS diagnosis during the first and second trimester ultrasound screening scans in the experience of the Bucur Maternity.

Materials and Method

The purpose of the study was to identify any structural or hemodynamic anomalies that could have been identified during standard ultrasound sections at the first trimester screening and/or the reassessment of the heart at 18 weeks. A retrospective observational cohort study was performed between January 2017 and December 2019 at the Bucur Maternity. All pregnancies that were examined for structural anomalies were included. The images recorded at routine ultrasound evaluations in cases of HLHS were retrospectively followed-up. The scans were performed on different ultrasound equipment: Mindray, GE Voluson E8, E10, with a 3,5 MHz trans-abdominal probe. We obtained standard ultrasound images according to guidelines with a 4-chamber view, respectively a 3-vessel view of the fetal heart. Typical HLHS anomalies, such as hypoplastic left ventricle with diminished capacity and contractility, aortic and mitral valve stenosis or atresia, increased cardiac wall echogenicity specific to endocardial fibroelastosis, narrowing of the ascending aorta and aortic arch and retrograde blood flow through the aortic arch, were searched for. Whenever a case was found, it was referred for second opinion to a maternal foetal medicine specialist and detailed anomaly scan was performed in order to detect associated anomalies. When HLHS anomalies were detected, genetic testing (amniocentesis with karyotype) was indicated. The demographic parameters included in the study were patient age, parity and gestational age.

Results

From a total of 4583 anomaly scans performed only two cases of HLHS were detected in the routine examination in the second trimester (20-22 weeks). In both cases, correct standard ultrasound images were recorded, both at the first trimester screening and the 18th week reassessment. In both cases, the diagnosis was made on the standard 4-room section. Both patients were primiparas, the first patient being 29 years of age, and the second 33 years old. The cause in the first case was mitral atresia, suspected during the first trimester ultrasound scan at 13 weeks of pregnancy and confirmed at the second evaluation at 20 weeks. The second one, aortic stenosis was found at 13 weeks of pregnancy and later confirmed at the 21-week re- evaluation. After the first trimester evaluation, in both cases genetic testing was indicated, but not performed in consideration of poor resources or intention of the couple to terminate the pregnancy. Parents requested the termination of pregnancy, thus in the first case therapeutic abortion was performed at 21 weeks and in the second case at 23 weeks. Following the termination of pregnancy, anatomo-pathological examination of the parts confirmed the HLHS diagnosis in both cases.

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Fig. 1. Ultrasound scan performed in the second trimester – hypoplastic aortic arch illustrated in a sagittal section

Fig. 2. Ultrasound scan during the second trimester – mitral atresia, no inflow through mitral valve and myocardial elastosis of the left ventricle wall

Fig. 3. Atrioventricular blood flow in a fetus with HLHS in the first trimester

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Fig. 4. 3 vessel view section in the second trimester showing a hypoplastic ascending aorta with reversed flow

Discussion

In a clinical context, anatomical forms of the anomaly are characterized by the status of the mitral and aortic valves. Taking this into consideration, the first model consists of atresia of both valves, associated with an absent or extremely hypoplastic LV and a diminutive ascending aorta. Its counterpart is the model in which both the aortic and mitral valves are stenotic, but not atretic. In either form, new-borns with HLHS require a patent ductus arteriosus to maintain normal systemic blood flow. HLHS may occur in otherwise normal new-borns. Although many underlying mechanisms have been proposed for the disease, at the moment the direct cause of HLHS is unknown. Certain genetic anomalies (Turner Syndrome, Jacobsen Syndrome, trisomy 13, trisomy 18, DiGeorge Syndrome) have been associated with HLHS [2-5] and in these cases, the disease usually presents a higher mortality rate and an increase in neurocognitive complications [6, 7]. Routine obstetrical ultrasound screening during the second trimester of pregnancy (between 18 and 24 weeks) is considered the preferred means of prenatal diagnosis of HLHS, if the consulting physician finds the anatomical anomalies described above. The most common variant refers to either both or singular aortic or mitral valve atresia or stenosis, associated with LV hypoplasia. Foetuses with normal left hearts should not be disconsidered, a more careful examination of left to right blood flow through the atrial septum (normally right to left during pregnancy) should be performed [8]. Also, other disturbances such as retrograde flow through the transverse arch should be considered. Prenatal diagnosis of HLHS is obtained in more than 60% of cases [9, 10]. Due to the fact that in Romania no national malformation register exists, it is impossible to assess the frequency of HLHS in the population [11]. Considering the available case series, new born mortality does not seem to be influenced by prenatal or postnatal diagnosis of HLHS. Early HLHS diagnosis is relevant for parental counselling and establishing therapeutic means from an early stage [12]. In case of postnatal diagnosis, the typical anomalies associated with HLHS are easily identifiable while performing an echocardiography. Other examinations, although not conducive to a HLHS diagnosis, may be used so as to assess the severity of physiological changes and include: pulse oximetry, chest radiographies, and electrocardiography’s.

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Currently, the main means of management of HLHS consists of palliative surgery and heart transplant, with a preponderance of palliative surgery due to difficulty in finding transplantation organs and the severe outcome of the disease if left unattended, which leaves both parents and medical practitioners a small amount of time for a therapeutic decision [13, 14]. Surgical palliation of HLHS typically consists of three staged interventions: the first one is performed during the first week of life (the Norwood procedure is the most common), the second at three to six months of age (bidirectional Glenn procedure) and the third at two to five years of age (Fontan procedure) [15-17]. The term palliative is used with these procedures because the patient will not reach a normal biventricular circulation system through them. The purpose of this kind of intervention is to obtain a Fontan circulation, or a total cavo- pulmonary connection. During the first stage an unobstructed pulmonary venous return and controlled arterial pulmonary perfusion should be provided. This can be obtained by means of an ascending arch aortoplasty, an atrial septectomy, followed by providing a source of pulmonary blood flow through a systemic to pulmonary artery shunt or a right ventricle-pulmonary artery conduit. The second procedure is the cavo-pulmonary shunt or the bidirectional Glenn intervention, consisting in the removal of the original shunt and performing an end to side anastomosis between the superior vena cava and the right pulmonary artery. This is usually done when the patient outgrows the original shunt becoming increasingly cyanotic. The third stage of the procedure, or the Fontan operation, redirects the inferior vena cava blood flow into the pulmonary arteries, thus obtaining a total systemic venous return into the pulmonary arteries. HLHS recognizes reconstructive surgical techniques with a success rate of over 85% and a survival at 6 years of age of over 64%. [1] Continuous intravenous prostaglandin E1 administration should be initiated once the diagnosis of HLHS is confirmed in order to maintain a patent ductus arteriosus. Other medications before surgery for infants with ventricular dysfunction may include diuretics, inotropic agents and in case of respiratory distress, mechanical ventilation. Parent counselling should begin immediately after the diagnosis has been made and should include the option of terminating the pregnancy if HLHS is diagnosed during the first and second trimester, choice of delivery and postnatal therapeutic means. [18] If surgery is a viable option, the parents should be informed of the multiple stages of the intervention, unknown long-term complications and the rate of mortality. Parents may use this information to decide whether or not to terminate the pregnancy. In Romania, abortion on demand becomes illegal at 14 weeks of amenorrhea, but during the second trimester, medical discontinuation of pregnancy is allowed for therapeutic reasons, which is why prenatal diagnosis of HLHS through ultrasound screening during this timeframe is imperative [19, 20]. The fetal medicine specialist, being the one to diagnose the anomaly, will also be the first to counsel the expecting parents on whether to continue or end the pregnancy and should adopt a neutral position providing objective information on disease prognosis and treatment options [20, 21].

Conclusions

HLHS is a rare but severe anomaly, whose diagnosis cannot be determined earlier than the time of screening in the second trimester. Although it can be operated with an acceptable success rate, parents usually request the termination of pregnancy.

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Early diagnosis of HLHS allows for parental counselling and education, offering the parents the choice of pregnancy termination, organisation of the birth setting in a centre specialized with dealing with new-borns with HLHS and immediate therapy after delivery. Also, early screening may help in identifying other non-cardiac anomalies found in genetic disorders associated with HLHS. Ultrasound imaging, whether pre or postnatal is a satisfactory method of making a HLHS diagnosis, the typical anatomical features consisting of a hypoplastic left ventricle, stenosis or atresia of the mitral and aortic valves are consistently identified and confirm the diagnosis of HLHS. Many serious forms of HLHS are now detected by fetal echocardiography and the parents may choose to abort these foetuses. In some series as many as 50% of pregnancies with foetuses with HLHS were electively terminated [22]. In another series it was reported that pregnancy termination had a higher rate when first trimester screening was performed compared to second trimester screening [23]. In communities where this practice occurs, we have to take into account these aborted foetuses if we wish to determine the true incidence of HLHS.

REFERENCES

[1] Newburger JW, Sleeper LA, Gaynor JW, et al., Transplant-Free Survival and Interventions at 6 Years in the SVR Trial. Circulation 2018; 137: p. 2246. [2] Allan LD, Sharland GK, Milburn A, et al., Prospective diagnosis of 1,006 consecutive cases of congenital heart disease in the fetus. J AmCollCardiol 1994; 23: p. 1452. [3] Raymond FL, Simpson JM, Sharland GK, Ogilvie Mackie CM. Fetal echocardiography as a predictor of chromosomal abnormality. Lancet1997; 350: p. 930. [4] Hinton RB, Martin LJ, Rame-Gowda S, et al., Hypoplastic left heart syndrome links to chromosomes 10q and 6q and is genetically related to bicuspid aortic valve. J Am CollCardiol 2009; 53: p. 1065. [5] Hinton RB Jr, Martin LJ, Tabangin ME, et al., Hypoplastic left heart syndrome is heritable. J Am CollCardiol 2007; 50: p. 1590. [6] Carey AS, Liang L, Edwards J, et al., Effect of copy number variants on outcomes for infants with single ventricle heart defects. CircCardiovasc Genet 2013; 6: p. 444. [7] Newburger JW, Sleeper LA, Bellinger DC, et al., Early developmental outcome in children with hypoplastic left heart syndrome and related anomalies: the single ventricle reconstruction trial. Circulation 2012; 125: p. 2081. [8] Mäkikallio K, McElhinney DB, Levine JC, et al., Fetal aortic valve stenosis and the evolution of hypoplastic left heart syndrome: patients’ selection for fetal intervention. Circulation 2006; 113: p. 1401. [9] Stasik CN, Gelehrter S, Goldberg CS, et al., Current outcomes and risk factors for the Norwood procedure. J ThoracCardiovascSurg 2006; 131: p. 412. [10] Mahle WT, Clancy RR, McGaurn SP, et al., Impact of prenatal diagnosis on survival and early neurologic morbidity in neonates with the hypoplastic left heart syndrome. Pediatrics 2001; 107: p. 1277. [11] Ples, Liana; Sima, Romina Marina; Stanescu, Anca Daniela; et al., The Importance of a National Congenital Anomalies Registry – the Role of the Prenatal Diagnosis 5TH ROMANIAN CONGRESS OF THE ROMANIAN SOCIETY OF ULTRASOUND IN OBSTETRICS AND GYNECOLOGY, 2017 Pages:505- 510 [12] Morris SA, Ethen MK, Penny DJ, et al., Prenatal diagnosis, birth location, surgical center, and neonatal mortality in infants with hypoplastic left heart syndrome. Circulation 2014; 129: p. 285. [13] Gordon BM, Rodriguez S, Lee M, Chang RK. Decreasing number of deaths of infants with hypoplastic left heart syndrome. J Pediatr 2008; 153: p. 354. [14] Karamlou T, Diggs BS, Ungerleider RM, Welke KF. Evolution of treatment options and outcomes for hypoplastic left heart syndrome over an 18-year period. J ThoracCardiovascSurg 2010; 139: p. 119. [15] Pizarro C, Malec E, Maher KO, et al., Right ventricle to pulmonary artery conduit improves outcome after stage I Norwood for hypoplastic left heart syndrome. Circulation 2003; 108 Suppl. 1: II155-60. [16] Ghanayem NS, Jaquiss RD, Cava JR, et al., Right ventricle to-pulmonary artery conduit versus Blalock- Taussigshunt: a hemodynamic comparison. Ann ThoracSurg 2006; 82: pp. 1603-9; discussion 1609-10.

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[17] Ballweg JA, Dominguez TE, Ravishankar C, et al., A contemporary comparison of the effect of shunt type in hypoplastic left heart syndrome on the hemodynamics and outcome at Fontan completion. J ThoracCardiovascSurg 2010; 140: pp. 537-44. [18] Navolan, Dan; Ionescu, Cringu Antoniu; Carabineanu, Adrian; Birsasteanu, Florin; Cretu, Octavian; Szasz, Florin; Vladareanu, Simona; Ciohat, Ioana; Gidea, Ramona; Nemescu, Dragos; Farcas, Simona; Andreescu, Nicoleta; Simu, Sebastian; Stoian, Dana Influence of Weight of Pregnant Women on First Trimester Biochemical Markers Values REVISTA DE CHIMIE Volume: 69, Issue: 2, Pages: 529-532, Published: FEB 2018. [19] Late Detection of Fetal Congenital Heart Defects – Counseling and Management Issues – Case Report; Ricu Anca, Valcea Ionut, Poenaru Mircea-Octavian, et al., PROCEEDINGS OF THE 6TH CONGRESS OF THE ULTRASOUND SOCIETY IN OBSTETRICS AND GYNECOLOGY/34TH FETUS AS A PATIENT INTERNATIONAL CONGRESS Pages: 557-562, Published: 2018, ISBN 978-88-85813-20-5. [20] Navolan, Dan; Vladareanu, Simona; Ciohat, Ioana; Carabineanu, Adrian; Craina, Marius; Nemescu, Dragos; Birsasteanu, Bogdan; Onofriescu, Alina; Boia, Marioara; Tepetzikiotis, Efstathios; Craciunescu, Mihaela; Birsasteanu, Florin Distribution of Biochemical and Ultrasound Markers Values in the First Trimester Screening Program in Timisoara REVISTA DE CHIMIE, Volume: 68, Issue: 7, Pages: 1636-1639, Published: JUL 2017. [21] Octavian, Olaru Gabriel, Ionescu, C, Lesnic, A, Filipescu, GA; Ples, L – Ethical and medico-legal aspects of the therapeutic abortion – our experience ROMANIAN JOURNAL OF LEGAL MEDICINE, Volume: 26Issue: 1 MAR 2018. Pp. 82-85 [22] Daubeney PE, Sharland GK, Cook AC et al., Pulmonary atresia with intact ventricular septum: impact of fetal echocardiography on incidence at birth and postnatal outcome. UK and Eire Collaborative Study of Pulmonary Atresia with Intact Ventricular Septum. Circulation 1998; 98: pp. 562-6. [23] Jicinska H, Vlasin P, Jicinsky M, et al., Does First-Trimester Screening Modify the Natural History of Congenital Heart Disease? Analysis of Outcome of Regional Cardiac Screening at 2 Different Time Periods. Circulation 2017; 135: p. 1045.

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Is 3D Ultrasound Becoming Mandatory in Future Pregnancy Surveillance?

POP Daria Maria1, NICULA Renata1, PORUMB Ciprian1, MĂLUȚAN Andrei1, MOCAN HOGNOGI Radu Florin1, BLAGA Ligia2, IUHAS Cristian Ioan1, MIHU Dan1, DICULESCU Doru1

1 “IULIU HAŢIEGANU” University of Medicine and Pharmacy, “Mother and Child” Department, Obstetrics and Gynaecology Clinic, Cluj-Napoca, (ROMANIA) 2 “IULIU HAŢIEGANU” University of Medicine and Pharmacy, “Mother and Child” Department, Neonatology Clinic, Cluj- Napoca, (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Since 1989, when first commercial 3D ultrasound device became available, new possibilities were identified for accurate visualization of anatomic fetal structures, with high technological precision and incredible satisfying esthetical features. Still, 3D ultrasound is not a routine evaluation since it requires expensive ultrasound devices and trained personnel. Several advantages of 3D ultrasound can be stated such as: complex assessment of fetal anatomic structures, accurate surface analysis of defects or volumetric measuring of organs. Storage of scanned volumes and images allows later processing of data without the presence of the patient as well as data transfer and analysis via telemedicine. The aim of this article is to review the current applications offered by 3D ultrasound in prenatal evaluation and to identify how this technology can became part in future pregnancy surveillance. As accessibility to 3D ultrasound becomes widely available and the interest of medical professionals continues to increase, a comprehensive ultrasound follow-up of the pregnancy without using this technology seems unlikely. Most likely, 3D ultrasound evaluation will not be included in the minimal requirements for obstetrical ultrasound, but an accurate, modern prenatal diagnosis is unimaginable without 3D.

Keywords: 3D ultrasound, pregnancy surveillance, prenatal diagnosis, telemedicine

Introduction

In modern obstetrics, the use of ultrasound examination occurs on a daily basis, and no one can imagine a correct surveillance of pregnancy without scanning the foetus several times. The beginnings of ultrasound in Obstetrics go back to 1958, when Ian Donald published a paper in the Lancet – “The investigation of abdominal masses by pulsed ultrasound” [1]. All future developments of ultrasound diagnosis in obstetrics and even gynaecology derive from this original paper. Later on, the value of systematic ultrasound screening during pregnancy was demonstrated by several scientific papers [1, 2] and advancements in technology, such as real time scanning machines, led to widespread use of ultrasound in prenatal diagnosis. In 1985, colour Doppler imaging was incorporated into real time equipment [2] and by the end of 1990 harmonic imaging

148 ©Filodiritto Editore – Proceedings was also introduced to specialists [1, 2]. All this improved greatly the image resolution of 2D ultrasound. Studies on 3D imaging began in Japan around 1984 by Kazunon [1], yet we trace the beginnings of 3D ultrasound to the 1989, when the first commercial 3D ultrasound device became available [3]. By 2000, we had modern real time scanning machines with high resolution abdominal and transvaginal transducers, harmonic imaging, colour and power Doppler facilities, also with a 3D/4D option. In time, the machines became less expensive and more available, with better storage capacity which allowed sonographers to become experts in 3D/4D scanning almost overnight. Good quality images obtained by 3D scanning lead to a number of publications highlighting the virtues of this new technique yet evidence-based conclusion of definitive benefits over 2D were hard to obtain, thus 3D ultrasound is not yet a routine evaluation in pregnancy surveillance. The aim of this paper is to review the current literature for convincing evidence that 3D ultrasound offers advantages over 2D and should be included into routine obstetrics practice.

What is 3D/4D ultrasound? 3D ultrasound is a volumetric imaging technology that provides a 3-dimension view of internal structures [4]. It has to do with image data acquisition, volume data analysis and, in the end, volume display. 3D technology permits volume acquisition by several methods, each presenting its advantages and disadvantages: manual acquisition (freehand movements of the probe, but subjected to artefacts if the movements are not performed in a slow and firm manner; nowadays mostly abandoned) [4], automatic 3D acquisition (requires special 3D probe) or matrix array sensors (data is acquired in a single sweep) to help visualize the morphology and size of structures [5]. After volume acquisition, for the purpose of visualisation, one can use the multiplanar mode, surface mode, transparency mode or multiple slice mode. The surface-rendering mode is the display method recognized by non-professionals because of the popular images of foetuses inside the womb. Dynamic volumetric imaging, also known as “4D ultrasound” or “real-time 3D ultrasound” extends the visualization with a time frame so that it is able to display motion instead of a static 3D data set [6]. Thus, 4D ultrasound is defined as 3D ultrasound that is displayed over time (the fourth dimension being the time dimension). 3D data are usually acquired as a large number of consecutive tomographic images through movement of an US transducer array. The merit of the system is real-time acquisition of the anatomic information during the scanning procedure [6, 7]. Three- and four-dimensional (3D/4D) ultrasonography with spatio-temporal image correlation (4D-STIC) is an automated volume acquisition that allows obtaining fetal cardiac volumes and their static and real-time analysis in multiplanar and rendering modes [8]. In the end, we have a single three-dimensional volume throughout a complete cardiac cycle, which results in a four- dimensional volume [8, 9]. STIC in combination with colour Doppler ultrasound is a promising new tool for multiplanar and 3D/4D rendering of the fetal heart. TUI-STIC (spatio-temporal image correlation associated with the tomographic ultrasound imaging mode) refers to a new modality for complete sequential analysis of cardiac structures, that can be displayed on a single panel by showing all echocardiographic transverse views at the same time [10]. However, fascinating it is to employ 3D/4D technology with all its facilities, one needs to remember that good quality 3D ultrasound depends on good quality 2D ultrasound.

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Current applications of 3D in obstetrics We no longer question certain advantages provided by 3D/4D ultrasound in pregnancy scan, especially when it comes to evaluating fetal SNC, heart or facial/skeletal structures. First of all, 3D ultrasound allows operators a simultaneous and less time consuming (compared to 2D) rendering of the anatomical landmarks in three orthogonal planes when using multiplanar mode [11]. Due to technological advancements of 4D ultrasound devices, volume data can be acquired in only a few seconds so that motion artefacts caused by fetal movements may be minimized [9, 11]. 3D ultrasound is superior in demonstrating superficial fetal defects such as facial clefts and studies from several groups have shown that the technique has a high sensitivity for diagnosing defects of the secondary palate which are rarely detected by 2D ultrasound [13]. There is no doubt a dramatic improvement in the study of fetal brain anatomy when compared with conventional 2D ultrasound. With cardio-STIC, volume data sets are obtained in the 3D static mode (no cardiac motion) or using 4D – thus the structures are observed contracting during one or multiple cardiac cycles. A well-executed STIC acquisition contains all the necessary planes necessary for proper evaluation of the five classic transverse planes of fetal echocardiography [14]. Colour Doppler STIC enables the acquisition of volume data sets from the fetal heart that are displayed as a cineloop of a single cardiac cycle [14, 15]. In first trimester scan, 3D ultrasound proves to be more accurate that 2D ultrasound in predicting aneuploidy [16]. 4D scan was successfully used when performing invasive procedures like amniocentesis, chorionic villi sampling, cordocentesis or intrauterine transfusion, because of optimal evaluation of the needle used for this type of procedures, thus resulting in successful sampling with minimal risks [17]. When counselling the parents, the rendered images can help them understand the severity of an existing malformation or, conversely, ensure them of the absence of any fetal abnormality. Also, you can revisit the acquired volumes and get, if needed, a second opinion. More so, volume data can be acquired by a less experienced sonographer on site (standardized plane) and forwarded by telemedicine to an expert for conclusive diagnosis [18], which in today’s globalized environment can only prove to be advantageous. The volume can be reviewed over and over again, can be mailed to an expert, could be shown to consultants (pediatric neurology and neurosurgeons) and also used for teaching purposes. But let’s not forget that this is 3D/4D ultrasound is a challenging technique that requires good equipment and excellent skills as well as targeted experience; it has dramatic legal implications when diagnosis a foetus. There is something to be said about the marketing value of 3D/4D ultrasound, as there is some evidence that it helps create an emotional bond between future parents and their unborn child [19], but false expectations can arise from giving too much credit to cosmetic impact. We already know that in particular situation, when malformations are present and accurate diagnosis is required, 3D ultrasound proves beneficial both for diagnostic purposes and when explanations are necessary [20]. Also, there is a continuous pressure from future parents to employ this kind of technology due to cosmetic benefits as the image presented is better understood by the untrained eye.

Conclusions

The clinical application of 3D ultrasound is likely to advance rapidly due to enhancement of technological features and increased availability of commercial 3D ultrasound devices. Also, the accuracy of the acquired images presented in an attractive, accessible way makes the use of this technology widely accepted and requested. It has already been established that 3D/4D ultrasound

150 ©Filodiritto Editore – Proceedings can enhance the quality of both basic and extended fetal scans, as well as the evaluation of certain congenital anomalies. But as far as its use in regular pregnancy surveillance, we believe that the added value of 3D/4D ultrasound scan needs to be evaluated objectively in large prospective studies that include a wide range of professionals from all over the world. Most likely in the immediate future 3D ultrasound evaluation will not be included in the minimal requirements for regular obstetrical ultrasound, but an accurate, modern prenatal diagnosis is unimaginable without 3D/4D ultrasound scan.

REFERENCES

[1] Campbell, S. (2013). A short history of sonography in obstetrics and gynaecology. Facts Views Vis Obgyn 5(3), pp. 213-229. [2] Grennert, L. (1979). Diagnosis of multiple pregnancy. Br Med J 2(6202), pp. 1439-40. [3] Levaillant, J. (2006). Value of 3D-4D sonography in fetal and gynaecological ultrasound examination: principles and indications. J Radiol 87, pp. 1969-1992. [4] Sedgmen B., McMahon C., Cairns D., et al., (2006). The impact of two-dimensional versus three- dimensional ultrasound exposure on maternal-fetal attachment and maternal health behaviour in pregnancy. Ultrasound Obstet. Gynecol. 27, pp. 245-251. [5] Benacerraf BR., Benson CB., Abuhamad AZ., et al., (2005). Three-and 4-dimesional ultrasound in obstetrics and gynaecology: proceedings of the American institute of ultrasound in medicine consensus conference. J Ultrasound Med 24, pp. 1599-1624. [6] Goncalves LF., Lee W., Espinoza J., et al., Three-and 4-dimesional ultrasound in obstetric practice: does it help? J Ultrasound Med 24, pp. 1587-1597. [7] DeVore, GR. (2005). Three-dimensional and four-dimensional fetal echocardiography: a new frontier. Curr Opin Pediatr 17(5), pp. 592-604. [8] Odeh, M. et al., (2008). Three-dimensional sonographic volumetry of the gestational sac and the amniotic sac in the first trimester. J Ultrasound Med 27(2), pp. 373-378. [9] Tonni, G. et al., (2005). Prenatal screening for fetal face and clefting in a prospective study on low-risk population: can 3- and 4-dimensional ultrasound enhance visualization and detection rate? Oral Surg Oral Med Oral Pathol Oral Radiol Endod 100(4), pp. 420-6. [10] Verwoerd-Dikkeboom, CM. et al., (2008). Reliability of three-dimensional sonographic measurements in early pregnancy using virtual reality. Ultrasound Obstet. Gynecol. 32(4), pp. 910-918. [11] International Society of Ultrasound in Obstetrics & Gynaecology Education Committee. (2007). Sonographic examination of the fetal central nervous system: guidelines for performing the ‘basic examination’ and the ‘fetal neurosonogram’. Ultrasound Obstet. Gynecol. 29(1), pp. 109-16. [12] Espinoza, J. (2011). Contemporary clinical applications of spatio-temporal image correlation in prenatal diagnosis. Curr Opin Obstet. Gynecol. 23(2), pp. 94-102. [13] Kurjak, A. et al., (2007). How useful is 3D and 4D ultrasound in perinatal medicine? J Perinat Med 35(1), pp. 10-27. [14] Rizzo, G. et al., (2011). Collaborative study on 3-dimensional sonography for the prenatal diagnosis of central nervous system defects. J Ultrasound Med 30(7), pp. 003-8. [15] Monteagudo, A. et al., (2000). Three-dimensional transvaginal neurosonography of the fetal brain: ‘navigating’ in the volume scan. Ultrasound Obstet. Gynecol. 16(4), pp. 307-13. [16] Abuhamad, AZ. (2005). Standardization of 3-dimensional volumes in obstetric sonography: a required step for training and automation. J Ultrasound Med 24(4), pp. 397-401. [17] Dikkeboom, CM. et al., (2004). The role of three-dimensional ultrasound in visualizing the fetal cranial sutures and fontanels during the second half of pregnancy. Ultrasound Obstet. Gynecol. 24, pp. 412-16. [18] Chaoui, R. Hoffmann, J. Heling, KS. (2004). Three-dimensional (3D) and 4D colour Doppler fetal echocardiography using spatio-temporal image correlation (STIC). Ultrasound Obstet. Gynecol. 23, pp. 535- 45. [19] Kurjak, A. Azumendi, G. Vecek, N. et al., (2003). Fetal hand movements and facial expression in normal pregnancy studied by four-dimensional sonography. J Perinat Med 31, pp. 496-508. [20] Timor-Tritsch, IE. Han, E. Platt, LD. (2002). Three-dimensional ultrasound experience in obstetrics. Curr Opin Obstet. Gynecol. 14, pp. 569-75.

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Dilated Fetal Coronary Sinus. Case Series and Literature Review

PUIU Serghei1, TAMBALA Carolina2

1 State University of Medicine and Pharmacy “Nicolae Testemitanu” (REPUBLIC OF MOLDOVA) 2 “Ana Maria” Medical Center (REPUBLIC OF MOLDOVA) Emails: [email protected], [email protected]

Abstract

Objective Dilated Coronary Sinus (CS) is an important marker of Congenital Heart Defects (CHD), particularly anomalous drainage of systemic veins. We sought to identify the possible causes of fetal SC dilation, highlighting the ultrasonographic features of these conditions and to review the literature.

Methods The study represents a case series review of 30 of foetuses with dilated CS. The CS was not routinely quantified, being assessed subjectively. When defined arbitrarily as enlarged, an extended cardiac scan was performed.

Results The CS was enlarged between 3.75 and 8.08 mm, depending on the gestational age (GA). The presence of Left Persistent Superior Vena Cava (LPSVC) in 26 cases was the main cause of the dilation, of which 9 cases as an isolated variant, including one case of “unroofed” type SC, and 17 cases associated with other CHD. In two cases the LPSVC and absent Right Superior Vena Cava (RSVC) were seen. Also, one case of Total Anomalous Pulmonary Venous Connection (TAPVC) and one case of anomalous drainage of the Ductus Venosus (DV) into CS were detected. Summarizing own experience, we concluded that the causes of the dilated CS mentioned in the study mainly correspond to the literature data.

Conclusions Dilated CS, usually due to the presence of LPSVC, can be readily detected during routine fetal scan. Other rare cases, such as TAPVC or abnormal drainage of the DV into CS, as well as Coronary Artery Fistula may cause the dilation. Since dilated CS is an important marker of fetal CHD, a detailed fetal ultrasound (US) scan should be performed to rule out possible associated cardiac and extracardiac anomalies.

Keywords: Coronary Sinus, Left Persistent Superior Vena Cava, Ductus Venosus, Anomalous Pulmonary Venous Connection, “Unroofed” Coronary Sinus

Introduction

CS dilation is a relevant sign for abnormalities of central venous drainage, that may not be readily apparent but have a significant impact on prognosis. Dilated CS is the first sign of LPSVC or cardiac type of TAPVC, which commonly are associated with intracardiac (ICAs), extracardiac

152 ©Filodiritto Editore – Proceedings anomalies (ECAs) and isomerism syndromes, where chromosomal anomalies are present in a significant proportion of cases. Therefore, its recognition should prompt a detailed cardiac and extracardiac survey, both prenatally and postnatally.

Material and Methods

The study represents a case series review of 30 of foetuses with dilated CS detected during routine fetal scan in low risk gestations. The CS was assessed subjectively and was not routinely quantified. When defined arbitrarily as being enlarged, extended echocardiography following established guidelines and detailed extracardiac structural survey were performed.

Results

The CS was enlarged between 3.75 and 8.08 mm, depending on the GA. The presence of the LPSVC in 26 cases was the main cause of the dilation, of which 9 cases as an isolated variant, including one case of “unroofed” type SC, and 17 cases associated with other CHD. The associated heart defects in LPSVC were: isolated ventricular septal defects – 7 (41.1%), Coarctation/Hypoplastic Aorta – 5 (29.4%), Double Outlet Right Ventricle – 2 (11.7%), Tetralogy of Fallot – 2 (11.7%), Ostium Primum Atrial Septal Defect (OPASD) – 1 (5.8%), “unroofed” Coronary Sinus – 1 (5.8%), similar to the spectrum described in previous studies on PLSVC associated with dilatation of the CS [1, 2]. In two cases the LPSVC and absent RSVC were seen. Also, one case of TAPVC and one case of anomalous drainage of the DV into CS were detected. All diagnoses were confirmed either by postnatal echocardiography or by autopsy. Summarizing own experience, we concluded that the causes of the dilated CS mentioned in the study mainly correspond to the literature data. In our study, no associated ECAs or isomerism were found, except 5 cases of single Umbilical Artery and one case of Fetal Growth Restriction (FGR). In the CHD associated cases one foetuses died prenatally, 3 pregnancies were terminated and one died in the neonatal period. All cases with isolated PLSVC survived and were doing well at the time of writing.

Case 1 On a routine 19 weeks 3 days’ gestation scan in the four-chamber view the dilated CS (Fig. 1a) raised the suspicion of abnormal PLSVC drainage. But, on tree vessels-trachea view instead both cava veins, only LPSVC was seen (Fig. 1b). In the long-axis view the LPSVC drainage via the CS into the Right Atrium (RA) and absent RSVC in bicaval view (Fig. 1c) were seen. The fetus had no additional anomalies and the neonatal course was uneventful, similar to second reported case.

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Fig. 1. (a) Dilated CS in the four-chamber view. (b) LPSVC and absent RSVC in the tree vessels-trachea view. (c) Absent RSVC in bicaval view.

Case 2 On the 20 and 24 gestational weeks scans we were unable to explain the CS dilation in one of twins in bicorial biamniotic gestation after IVF (Fig. 2a). On the 27 weeks 5 days’ scan we have noticed that on longitudinal view DV has a little bit abnormal direction, running parallel to the Inferior Vena Cava (IVC) and draining into the dilated CS (Fig. 2b). The hepatic, portal and cava veins were normal in appearance. Colour Doppler imaging confirmed the abnormal DV emptying in the CS. The infant after birth was doing well. Postnatal US showed CS dilatation and permeability without any CHD, normal systemic and portal veins.

Fig. 2. (a) Dilated CS in the four-chamber view. (b) Longitudinal view, DV originating from Umbilical Vein, running parallel to the IVC, draining in the CS. (c) Colour Doppler imaging, DV emptying in the CS

Case 3 In 32 weeks, 1 day’ gestation fetal scan for a second opinion due to the dilated CS, we revealed following findings: enlarged CS (Fig. 3a), smooth inner contour of the Left Atrium (LA) and no confluence of Pulmonary Veins (PVs) into the LA (Fig. 3b). Instead, posterior to the heart we found a receiving the PVs and draining into the CS (Fig. 3a). Colour Doppler confirmed the findings (Fig. 3c). The infant after birth has undergone a surgery in a specialized cardiac surgery unit and now is doing well.

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Fig. 3. (a) Confluent vessel (CV) draining into dilated CS in the four-chamber view. (b) Smooth inner contour of the LA and no confluence of PVs. (c) Colour Doppler showing CV draining into CS.

Case 4 On a second opinion scan for a dilated CS (Fig. 4a) and abnormal three-vessels trachea view (Fig. 4b) in a 25 weeks 5 days’ gestation in the longitudinal view in through LPSVC entering the CS clearly shows the communication between CS and LA through the defect – unroofed CS (Fig. 4c). On postnatal echocardiography a coronary sinus atrial septal defect was confirmed. The child is doing well on the follow up to 6 months.

Fig. 4. (a) Dilated CS. (b) Typical appearance of the LPSVC in the three-vessels trachea view. (c) Communication (arrow) between CS and LA through the defect (unroofed CS).

Discussion

The Coronary Sinus is the largest cardiac venous structure, which collects the majority of the cardiac venous blood, while a small portion drains directly into the cardiac chambers. It runs in the atrioventricular groove parallel to the Mitral Valve leaflets, enters the RA below the Foramen Ovale (FO) just above the valve of the inferior vena cava (IVC), measuring between 1 and 3 mm (diastolic diameter) depending on gestational age [3]. Dilated CS is an important sign of abnormal central venous drainage. Dilatation mainly results from volume overload by LPSVC, less frequently by TAPVC into the CS and occasionally by abnormal connections of the DV to the CS, fistula between the Coronary Artery and CS [1, 4-6].

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The LPSVC represents the most common form of anomalous systemic venous return, with 0.2- 0.5% prevalence in persons with normal heart [7, 8]. Oppositely LPSVC occurs in up to 9% of patients with CHD, making it the most common venous anomaly associated with heart defects [7, 9]. In isolated LPSVC the risk of chromosomal and associated anomalies is considered low [9, 10], some ICAs and ECAs being detected occasionally only after birth and missed at the prenatal US in 2% and 7% of cases, respectively [11]. However, even when isolated, the prevalence of aneuploidy is up to 7%, but the real occurrence may be higher, since karyotyping is not done routinely in respective cases [11]. Actually, LPSVC is commonly associated with ICAs and ECAs, detected at the initial or follow-up assessment in 60.7% and 37.8% of cases, respectively [11], chromosomal anomalies occurring in up to 12.5% of such conditions [11]. Among associated CHD [1, 11], the occurrence (up to 21.3% cases) of Aortic Coarctation can be mentioned [12]. Also, LPSVC is a common finding in heterotaxy (50-70% of cases) [11]. A dilated CS usually is the first sign leading to suspicion of this anomaly, confirmed by the finding of supernumerary vessel anterior to Arterial Duct in the three-vessels trachea view [13]. Usually PLSVC runs down to the back of the LA, between the left Atrial Appendage and left PVs and enters the RA through an enlarged CS. In 8% of cases the LPSVC drains directly into the LA, meaning complete unroofing of the CS or coronary sinus ASD [14], a rare variant, where the atrial wall between the CS and LA is either partially or completely absent, resulting in a left-to-right shunt. The morphologic types are: type I, completely unroofed with LPSVC; type II, completely unroofed without LPSVC; type III, partially unroofed midportion; type IV, partially unroofed terminal portion [15]. The prenatal diagnosis of unroofed CS can be achieved in the long axial section of the LPSVC and CS [16]. The combination of LPSVC and absent RSVC is extremely rare and has been reported in 0.05% of autopsied children who died prematurely [17]. Moreover, 11% of patients with right isomerism had LPSVC and absent RSVC [18]. Ectopic connections of the Umbilical Vein (UV) have been described in a number of studies, particularly in cases of DV agenesis. In extrahepatic forms most frequently reported are those to the Iliac Vein, IVC, RA, and, rarely, CS [6, 19, 20]. In the latter case, the UV and portal system flow are unaffected, without systemic shunt and, therefore, without risk of heart failure. Blood from the DV arrives in the RA by an abnormal orientation that does not facilitate shunting to the FO. This condition has no consequences for fetal emodynamics and does not require any particular management during the neonatal period [21]. The TAPVC is a condition that has little impact prenatally, but having serious clinical consequences postnatally. TAPVC can be an isolated anomaly but is very often found in heterotaxy, mainly in right atrial isomerism. There are different types of TAPVC: supracardiac, intracardiac and connections to RA or CS [22]. Isolated TAPVR is rare, occurring in less than 1% of CHD [23, 24]. The detection rates on prenatal screening vary from only 1.9% to 60% of cases [25, 26]. US features of TAPVC are: absent PVs connections to the LA; vertical vein confluence draining into enlarged CS; absent Coumadin ridge, causing the smooth aspect of inner LA contour [27] and increased post-LA space index [28]. Due its close proximity to the insertion of the atrioventricular valve a dilated CS may be misinterpreted as OPASD (or Partial Atrio-Ventricular Septal Defect). US diagnosis is based by lack of normal cardiac crux and atrioventricular valves appearance in the four-chamber view and appear to dome towards the ventricles. Also, for differentiation, the junction where the LPSVC enters the CS appears in cross section as a round intraluminal structure adjacent to the lateral wall of the LA [29].

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Fig. 5. In the four-chamber view the OPASD (long arrows) is evident above the closed (a) and opened (b) atrioventricular valve, abnormal heart crux. (c) The dilated CS in case of LPSVC (short arrow) mimics the OPASD, normal appearance of heart crux. (d) The round structure (arrow head) on the LA lateral wall represents the cross- section where LPSVC joins the CS.

Dilatation of the CS also can extremely rarely result by abnormal connections of the Coronary Artery and the CS. Coronary Artery Fistula is a rare malformation (1 in 50,000 live births), seldom diagnosed in utero. 84% of which draining into the Right Ventricle [30].

Conclusions

Dilated fetal CS, mainly due to the presence of LPSVC, can be easily detected during routine fetal scan. Other rare cases, such as TAPVC or abnormal drainage of the DV into CS may cause the dilation. Dilated CS may be an important sign of abnormalities of central venous drainage and should be considered as a marker of abnormal development (for both ICAs and/or ECAs). The mentioned condition prompt meticulous prenatal screening for developmental anomalies. Follow- up should be arranged after birth in order to rule out additional cardiac and extracardiac anomalies.

REFERENCES

[1] Machevin-Surugue E, David N, Verspyck E, Labadie G, Blaysat G, Durand I, Ickowicz V, Marpeau L. Dilated coronary sinus in prenatal echocardiography; identification, associations and outcome. Prenat Diagn 2002; 22: pp. 898-902. [2] Chaoui R, Heling KS, Kalache KD. Caliber of the coronary sinus in foetuses with cardiac defects with and without left persistent superior vena cava and in growth-restricted foetuses with heart-sparing effect. Prenat Diagn 2003; 23: pp. 552-557. [3] Abello KC, Stewart PA, Baschat AA. Two-dimensional and M-Mode echocardiography of the fetal coronary sinus. Ultrasound Obstet. Gynecol. 2002; 20: pp. 137-41. [4] Karl K, Kainer F, Knabl J, Chaoui R. Prenatal diagnosis of total anomalous pulmonary venous connection in the coronary sinus. Ultrasound Obstet. Gynecol. 2011; 38: pp. 729-731. [5] Foued Ben Brahim, Tristan Hazelzet, Laurence Cohen, Isabelle Durand, Julie Blanc, Elise Barre, Marie Brasseur Daudruy, Nadine David. Aberrant Drainage of the Umbilical Vein into the Coronary Sinus Without Ductus Venosus Agenesis. J Ultrasound Med 2014; 33: pp. 535-542. [6] Kiener, C. Kaihura, C. Cavalli, N. Volpe, T. Frusca, V. Zidere A fistula connecting the coronary artery to the coronary sinus identified by prenatal diagnosis: case report and literature review. Ultrasound in Obstetrics & Gynaecology 2015; 46 (Suppl. 1): pp. 122-184. [7] P. G. Postema, L. A. J. Rammeloo and J. Hruda. Clinical significance of a persistent left superior vena cava. Ultrasound Obstet. Gynecol. 2008; 31: pp. 111-114. [8] Cherian SB, Ramesh BR, Madhyastha S. Persistent left superiorvena cava. Clin Anat 2006; 19: pp. 561-565.

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[9] Galindo A, Gutierrez-Larraya F, Escribano D, Arbues J, Velasco JM. Clinical significance of persistent left superior vena cava diagnosed in fetal life. Ultrasound Obstet. Gynecol. 2007; 30: pp. 152-161. [10] Berg C, Knuppel M, Geipel A, Kohl T, Krapp M, Knopfle G, Germer U, Hansmann M, Gembruch U. Prenatal diagnosis of persistent left superior vena cava and its associated congenital anomalies. Ultrasound Obstet. Gynecol. 2006; 27: pp. 274-280. [11] S. Gustapane, M. Leombroni, A. Khalil, F. Giacci, L. Marrone, F. Bascietto, G. Rizzo, G. Acharya, M. Liberati and F. D’Antonio. Systematic review and meta-analysis of persistent left superior vena cava on prenatal ultrasound: associated anomalies, diagnostic accuracy and postnatal outcome. Ultrasound Obstet. Gynecol. 2016; 48: pp. 701-708. [12] Pasquini L, Fichera A, Tan T, Ho SY, Gardiner H. Left superior caval vein: a powerful indicator of fetal coarctation. Heart 2005; 91: pp. 539-540. [13] Yoo SJ, Lee YH, Kim ES, Ryu HM, Kim MY, Choi HK, Cho KS, Kim A. Three-vessel view of the fetal upper mediastinum: an easy means of detecting abnormalities of the ventricular outflow tracts and great arteries during obstetric screening. Ultrasound Obstet. Gynecol. 1997; 9: pp. 173-182. [14] Vydt T, Cools F, Rademakers FE. Absent right and persistent left superior vena cava. Acta Cardiol 2003; 58: pp. 421-423. [15] Kirklin JW, Kouchoukos NT: Kirklin/Barratt‐Boyes Cardiac Surgery: Morphology, Diagnostic Criteria, Natural History, Techniques, Results, and Indication. 3rd ed. Philadelphia, PA: Churchill Livingstone: 2003. [16] L. Chen. Prenatal ultrasound diagnosis of unroofed coronary sinus and literature review. Ultrasound in Obstetrics & Gynaecology 2018; 52 (Suppl. 1): pp. 138-193. [17] Minniti S, Vincentini S, Procacci C. Congenital anomalies of the venae cavae: embryological origin, imaging features and report of three new variants. Eur Radiol 2002; 12: pp. 2040-2055. [18] Pasquini L, Belmar C, Seale A, Gardiner HM. Prenatal diagnosis of absent right and persistent left superior vena cava. Prenat Diagn 2006; 26: pp. 700-702. [19] Yagel S, Kivilevitch Z, Cohen SM, et al., The fetal venous system, part II: ultrasound evaluation of the fetus with congenital venous system malformation or developing circulatory compromise. Ultrasound Obstet. Gynecol. 2010; 36: pp. 93-111. [20] Barrea C, Ovaert C, Moniotte S, Biard JM, Steenhaut P, Bernard P. Prenatal diagnosis of abnormal cardinal systemic venous return without other heart defects: a case series. Prenat Diagn 2011; 31: pp. 380-388. [21] Kiserud T, Eik-Nes SH, Blaas HG, Hellevik LR. Foramen ovale: an ultrasonographic study of its relation to the inferior vena cava, ductus venosus and hepatic veins. Ultrasound Obstet. Gynecol. 1992; 2: pp. 389-396. [22] Abuhamad A, Chaoui R. Anomalies of the systemic and pulmonary venous connections. In A Practical Guide to Fetal Echocardiography: Normal and Abnormal Hearts. Lippincott- Williams and Wilkins: Philadelphia, PA, 2010; pp. 226-242. [23] Volpe P, Campobasso G, De Robertis V, et al., Two- and four-dimensional echocardiography with B-flow imaging and spatiotemporal image correlation in prenatal diagnosis of isolated total anomalous pulmonary venous connection. Ultrasound Obstet. Gynecol. 2007; 30: pp. 830-837. [24] Allan LD, Sharland GK. The echocardiographic diagnosis of totally anomalous pulmonary venous connection in the fetus. Heart 2001; 85: pp. 433-437. [25] Porres DV, Morenza OP, Pallisa E, Roque A, Andreu J, Martínez M. Learning from the pulmonary veins. Radiographics 2013; 33: pp. 999-1022. [26] Ganesan S, Brook MM, Silverman NH, Moon-Grady AJ. Prenatal findings in total anomalous pulmonary venous return: a diagnostic road map starts with obstetric screening views. J Ultrasound Med 2014; 33: pp. 1193-1207. [27] Richelle Olsen, Zoe Doyle, Denis Levy, Tracy Anton, RDMS, Delaram Molkara, Maryam Tarsa, Mark Sklansky, Dolores H. Pretorius. Anomalous Pulmonary Venous Return. Insights into Prenatal Detection. J Ultrasound Med 2016; 35: pp. 1193-1206. [28] Kawazu Y, Inamura N, Shiono N, et al., “Post-LA space index” as a potential novel marker for the prenatal diagnosis of isolated total anomalous pulmonary venous connection. Ultrasound Obstet. Gynecol. 2014; 44: pp. 682-687. [29] Paladini, P. Volpe, G. Sglavo, M. G. Russo, V. de Roberts, I. Penner and C. Nappi. Partial atrioventricular septal defect in the fetus: diagnostic features and associations in a multicentre series of 30 cases. Ultrasound Obstet. Gynecol. 2009; 34: pp. 268-273. [30] Kiener, C. Kaihura, C. Cavalli, N. Volpe, T. Frusca, V. Zidere. A fistula connecting the coronary artery to the coronary sinus identified by prenatal diagnosis: case report and literature review. Ultrasound in Obstetrics & Gynaecology 2015; 46 (Suppl. 1): pp. 122-184.

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The Role of Ultrasound in the Preoperative Evaluation of Pelvic Inflammatory Disease Sequelae

SIMA Romina-Marina1,2, RĂDUCANU Georgiana2, POENARU Mircea-Octavian1,2, OLARU Octavian-Gabriel1,2, BADIU Dumitru-Cristinel1,3, PLEȘ Liana1,2

1 “Carol Davila” University of Medicine and Pharmacy, Bucur Maternity, Bucharest (ROMANIA) 2 “Sf. Ioan” Emergency Clinical Hospital, Bucharest (ROMANIA) 3 “Bagdasar-Arseni” Clinical Emergency Hospital, Bucharest (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Introduction The exact incidence of pelvic inflammatory disease (PID) in the United States of America is unknown. It is estimated that PID is responsible for 400,000 annual ambulatory visits as a first diagnosis and it represents between 5% and 20% of all gynaecological hospitalizations. In Romania, there are no exact data about the incidence. The clinical evaluation is supplemented by imaging, and the gold standard is represented by transvaginal ultrasound.

Material and methods We realized a 3-year retrospective study in Bucur Maternity, which included hospitalized patients for sequellary pelvic inflammatory disease symptoms such as: tubo-ovarian abscesses, sactosalpinx, chronic pelvic pain or infertility that required laparoscopic surgery.

Results The study included 320 patients with PID symptoms. Out of these, a total of 67 presented long- term manifestations and required exploratory laparoscopy. In 5% of women with sequelae of PID the perihepatitis syndrome known as Fitz-Hugh-Curtis syndrome was observed. Laparoscopy identified fibrous “violin-string” adhesions that appeared between the diaphragm dome and liver. 7.8% of the patients had bilateral piosalpinx and one case had relapsed piosalpinx. 84.3% of patients had pelvic adhesions of different degrees and 48% of women had bilateral tubal obstruction. The correlation between the ultrasound images of hydrosalpinx, piosalpinx and and the laparoscopic aspect averaged 96.5%, and for tubo-ovarian abscess the average was about 98%.

Conclusions Preoperative ultrasound evaluation in patients with symptomatology of sequellary pelvic inflammatory disease is essential. The accuracy of this technique guides the surgical approach and counselling of the patient regarding the surgical intervention and possible complications.

Keywords: pelvic inflammatory disease, surgical intervention, Fitz-Hugh-Curtis syndrome, hydrosalpinx

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Introduction

Pelvic inflammatory disease (PID) is an inflammation of the female upper genital tract that affects the uterus, fallopian tubes, ovaries and adjacent pelvic structures. The ethiology is polymicrobial, most commonly involved pathogens are sexually transmitted germs (Neisseria gonorrhoeae, Chlamydia trachomatis) and organisms associated with , which spread to superior genital tract ascending from the cervix or vagina. [1] The diagnosis of PID is most often based on clinical examination. The symptoms and signs may vary from subtle to severe. Because of the differences in the clinical manifestation, the Centers for Disease Control and Prevention (CDC) has proposed minimal criteria for the diagnosis of pelvic inflammatory disease. [2] Additional tests can be useful in diagnosing the pelvic inflammatory disease. Laparoscopy can confirm the diagnosis but despite being considered the standard for the diagnoses of PID its routine use is limited by the costs and the risks of intervention. The procedure allows visualization of tubal and ovarian lesions and bacteriological sampling for germ detection. [3] Ultrasonography is commonly used in the diagnosis and evaluation of complications of pelvic inflammatory disease, which may impact the surgical approach. Ultrasound criteria for diagnosis of pelvic inflammatory disease have been described by Timor-Tritsch and Rottem, and include thickened/dilated fallopian tubes, incomplete septa in the tube, increased vascularity around the tube, echogenic fluid in the tube, cogwheel sign, beads on a string sign. [4] The complications and sequelae of PID are represented by tubo-ovarian abscess, pelvic peritonitis, Fitz-Hugh-Curtis syndrome, chronic pelvic pain, infertility, ectopic pregnancy.

Material and methods

We realized a 3-year retrospective study in the Bucur Maternity. We included all patients hospitalized for sequellary pelvic inflammatory disease symptoms such: tubo-ovarian abscesses, sactosalpinx, chronic pelvic pain or infertility that required laparoscopic surgery. Transvaginal sonography was used in all patients with symptoms for sequelae of PID. The results of the ultrasound diagnosis were compared with the laparoscopic diagnosis.

Results

The study included 320 patients with PID symptoms. Out of these, a total of 67 presented long- term manifestations and required exploratory laparoscopy. The mean age for study group was 27.3 years (ranges 19 and 45). The majority of 72,3% patients presented repeated episodes of pelvic pain and vaginally discharge treated with antibiotics and pain killers. A percentage of 5.6% had a previous laparoscopy for hydrosalpinx. The ultrasound examination revealed unilateral hydrosalpinx in 45.2%, bilateral hydrosalpinx in 17.6% cases and tubo-ovarian abcces in 8.3% cases. All patients underwent explorative laparoscopy. In 5% of women with sequelae of PID the perihepatitis syndrome known as Fitz-Hugh-Curtis syndrome was observed. Laparoscopy identified fibrous “violin-string” adhesions that appeared between the diaphragm dome and liver. The laparoscopic examination revealed unilateral hydrosalpinx in 43.8%, bilateral hydrosalpinx in 15.4% cases and tubo-ovarian access in 8.3% cases, 7.8% of the patients had bilateral piosalpinx and one case had relapsed piosalpinx. 84.3% of patients had pelvic adhesions of different degrees and 48% of women had bilateral tubal obstruction. The correlation between the ultrasound images of hydrosalpinx, piosalpinx and

160 ©Filodiritto Editore – Proceedings hematosalpinx and the laparoscopic aspect averaged 96.5%, and for tubo-ovarian abscess the average was about 98%. The most frequent surgical intervention was adhesiolisis in 88.3% patients followed by unilateral salpingectomy in 32.2% cases followed. It was just one case that required conversion to laparotomy due to extensive pelvic process.

Fig. 1. Ultrasound aspect of left hydrosalpinx (bilocular) Fig. 2. Ultrasound aspect of right hydrosalpinx Fig. 3. 3D-Ultrasound aspect of right hydrosalpinx

Fig. 4. Laparoscopic aspect of right hydrosalpinx Fig. 5. Laparoscopic aspect of pelvic adhesions Fig. 6. Laparoscopic aspect of Fitz-Hugh-Curtis syndrome

Discussion

The annually estimated number of pelvic inflammatory disease cases in the US is around 1 million women who suffer at least an episode of PID. The variations in the clinical manifestations make the real diagnosis of patients with pelvic inflammatory disease a challenge. In addition to the criteria developed by CDC, various diagnostic imaging methods have been proposed to improve the accuracy of the diagnosis. Ultrasonography is the most frequently used imaging examination in the diagnosis of PID, being non-invasive and widely available. Transvaginal ultrasonography (TVS) helps to detect tubal and ovarian lesions and to identify markers of pelvic inflammatory disease. This allows the clinicians to diagnose and choose the appropriate therapy. It also helps to differentiate between acute and chronic characteristics, and to evaluate the complications of the disease. [5] The results have an impact on therapeutic approach. Ultrasonography allows detailed visualization of fallopian tubes, ovaries and adjacent pelvic structures. A study that included 30 patients with laparoscopically confirmed PID compared with 20 clinically healthy patients showed that tubal hyperaemia had a sensitivity of 100% and a specificity of 80% for pelvic inflammatory disease. Most patients with piosalpinx had changes of the shape, structure, and thickness of the fallopian tube walls. Radiology-performed studies show that in the case of tubo-ovarian abscess (TOA) ultrasonography has a moderate sensitivity of 56-93% and a high specificity of 86-98%. [14, 15] Ultrasound images suggestive of TOA include loss of tissue

161 ©Filodiritto Editore – Proceedings boundaries between the pelvic organs; the fallopian tubes dilated with thickened walls; and formation of complex masses with irregular edges. [4, 16] Studies have shown that TVS can be nonspecific in mild and atypical PID, with low sensitivity (81%) and specificity (78%). [6] For the last three decades, laparoscopy became the gold standard in pelvic inflammatory disease evaluation, offering the possibility to diagnose and manage the complications. It allows operative procedures including adhesiolysis, drainage of purulent collections, lavage of the peritoneal cavity, establish the tubal patency, evaluation of the fertile prognosis and adhesion process. In a study of 30 patients hospitalized with clinically suspected pelvic inflammatory disease, Tukeva et al., [6] compared transvaginal ultrasonography, MRI and laparoscopy. All patients underwent laparoscopy. 21 patients were diagnosed by laparoscopy with PID. They reported that 17 of 21 patients were diagnosed by transvaginal ultrasound (TVS) with PID, finding that TVS had an 81% sensitivity and a 78% specificity. Maleckiene et al., reported a low sensitivity of laparoscopy in mild disease. [7, 8] In our study it was observed that the correlation between the images obtained on transvaginal ultrasound and the laparoscopic aspect was on average 96,5% for hydrosalpinx, piosalpinx and hematosalpinx, and for the images suggestive of tubal ovarian abscess the average was 98%. In our clinic it was also observed a strong correlation between ultrasonographic, histopathologic and laparoscopic diagnosis. [17]. The results are similar with worldwide data reported.

Conclusions

Preoperative ultrasound evaluation in patients with suggestive symptomatology of sequelae of pelvic inflammatory disease is essential. The accuracy of this technique guides the surgical approach and counselling of the patient regarding the surgical intervention and possible complications. In the presence of complicated disease surgery can be postponed or set up must be made in order to insure the best results.

REFERENCES

[1] Haggerty CL, Ness RB. (2008) Diagnosis and treatment of pelvic inflammatory disease. Women’s Health. 4(4): pp. 383-97. [2] Centers for Disease Control and Prevention. (2010) Sexually transmitted diseases treatment guidelines. Morbidity and Mortality Weekly Report, vol 59, no RR-12 [3] Wolner-Hanssen P, Svensson L, Mardh P-A, et al., (1985) Laparoscopic findings and contraceptive use in women with signs and symptoms suggestive of acute . Obstet. Gynecol. 66: pp. 233-239. [4] Timor-Tritsch IE, Lerner JP, Monteagudo A, et al., (1998) Transvaginal sonographic markers of tubal inflammatory disease. Ultrasound Obstet. Gynecol. 12: pp. 56-66. [5] Thomassin-Naggara I., Darai E., Bazot M. (2012) Gynaecological pelvic infections: what is the role of imaging? Diagn. Interv. Imaging, 93(6): pp. 491-9. [6] Tukeva TA, Aronen HJ, Karjalainen PT, Molander P, Paavonen T, Paavonen J. (1999) MR imaging in pelvic inflammatory disease: comparison with laparoscopy and US. Radiology. 210(1): pp. 209-16. [7] 7.Malekiene L, Kajenas S, Nadisauskiene RJ, Railaite DR. (2009) Comparison of clinical and laparoscopic diagnoses of pelvic inflammatory disease. Int J Gynaecol. Obstet. 104(1): pp. 74-5. [8] Jaiyeoba O, Soper D.E. (2011) A practical approach to the diagnosis of pelvic inflammatory disease. Infectious Diseases in Obstetrics and Gynaecology. Vol 2011. [9] Chandra S. Role of laparoscopy in the management of pelvic inflammation disease/tubo-ovarian abscess compare to other modalities. Available from https://www.imperial.ac.uk/media/imperial-college/administration-and-support- services/library/public/vancouver.pdf [10] Jennings LK, Krywko DM. Pelvic Inflammatory Disease (PID). Available from:

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https://www.ncbi.nlm.nih.gov/books/NBK499959/ [11] Mitchell C, Prabhu M Pelvic Inflammatory Disease: Current concepts in pathogenesis, diagnosis and treatment, Infect Dis Clin North Am. 2013 December; 27(4). [12] Cacciatore B, Leminen A, Ingman-Friberg S, Ylöstalo P, Paavonen J. (1992) Transvaginal sonographic findings in ambulatory patients with suspected pelvic inflammatory disease. Obstet. Gynecol. 80(6): pp. 912- 6. [13] Molander P, Finne P, Sjöberg J, Sellors J, Paavonen J. (2003). Observer agreement with laparoscopic diagnosis of pelvic inflammatory disease using photographs. Obstet. Gynecol. 101(5 Pt 1): pp. 875-80. [14] Lee DC, Swaminathan AK. (2011) Sensitivity of ultrasound for the diagnosis of tubo-ovarian abscess: a case report and literature review. J Emerg Med. 40(2): pp. 170-5. [15] Lambert MJ, Villa M. (2004) Gynecologic ultrasound in emergency medicine. Emerg Med Clin North Am. 22(3): pp. 683-696. [16] Adhikari S, Blaivas M, Lyon M. (2008) Role of bedside transvaginal ultrasonography in the diagnosis of tubo-ovarian abscess in the emergency department. J Emerg Med. 34(4): pp. 429-433. [17] Pleş L, Sima RM, Burnei A, Albu DF, Bujor MA, Conci S, Teodorescu V, Edu A. Rom J MorpholEmbryol (2016). The experience of our Clinic in laparoscopy for adnexal masses and the correlation between ultrasound findings and pathological results, Rom J Morphol Embryol 57(4): pp. 1337-1341.

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To Screen or Not to Screen for CMV in 1st Trimester Pregnancy?

SOCOLOV Demetra, ROSIN Oana, FLOREA Gabriela, MURĂRAȘU Mara, PANCU Doina, PĂDURARU Luminița, DAVID Cristina, SOCOLOV Razvan, MIHĂLCEANU Elena

University of Medicine and Pharmacy “Grigore T. Popa” (ROMANIA) “Cuza Voda” University Hospital (ROMANIA) Email: [email protected]

Abstract

The CMV infection in pregnancy is highly discussed due to its complicated outcome. The CMV infection is one of the most frequent causes of neonatal neurological and neurosensorial deficit. We hereby present 3 clinical cases with different outcomes, all having in common first trimester seroconversion for CMV during pregnancy. The first case presents a first trimester seroconversion with ultrasonographic findings during the second trimester, without any in utero therapy, which led to the birth of a foetus with neurological and neurosensorial deficit. The second case observed is a non-primary seroconversion for CMV, with a positive IgG and a negative IgM at the first trimester screening, discovered based on a suggestive ultrasonography finding: a periventricular hyper echogenicity, which was later confirmed by amniocentesis with CMV-DNA positive result. The patient decided to terminate the pregnancy. The third case puts an emphasis on the treatment options. The patient was diagnosticated with the infection during the first trimester, and was treated with hyperimmunoglobulin at 13 weeks’ gestation, following which she had the amniocentesis at 21 weeks negative for CMV-DNA, with an excellent neurological and neurosensorial outcome. Since the main guidelines do not recommend CMV screening to all pregnant patients, based on the different outcomes at birth, it would be perhaps a good idea to be taken into consideration, given the extensive implication this infection could have on the future infant.

Case presentation We analysed 3 recent cases of first trimester seroconversion for CMV, all with different outcomes, but, nevertheless, showing the importance for the correct diagnosis of such an infection, given the serious consequences it can draw regarding both the future mother and the infant. Firstly, we analysed the case of a 25-year-old woman, 2G 1P, partially monitored during her pregnancy, who didn’t perform TORCH screening in the first trimester of pregnancy, with a second trimester morphology showing unilateral ventriculomegaly, oligohydramnios, enlarged cisterna magna and cerebellar hypoplasia. CMV serology at 22 weeks was positive for IgM (1,17 UI/l (n<0.9)) and IgG (15,7 UI/l (n<0,9)) with an IgG avidity of 13,5UI/ml=50,82%, which pleaded for an infection dating from the first trimester. An amniocentesis was performed at 25 weeks, showing a positive CMV-DNA testing and a normal karyotype. The woman was admitted for rupture membrane at 39 weeks and the ultrasound identified unilateral ventriculomegaly, chandelier-like cerebral calcifications (fig. 1) and fetal hepatosplenomegaly (fig. 2), with fetal growth restriction at 4,8 percentiles. The fetus was

164 ©Filodiritto Editore – Proceedings extracted through C-section due to acute fetal distress and weighted 2570g with an APGAR score of 7 and meconial amniotic fluid. She was discharged on the fourth day following her surgery.

Fig. 1. Ventriculomegaly, cerebral calcifications

The infant presented with acrocyanosis at birth but adapted well. He was monitored by ultrasound in the following days, during which the ventriculomegaly with thrombi and microcephaly were confirmed, along with a distended abdomen due to hepatosplenomegaly and congenital bilateral hydrocele. In the first day of life, the new-born presented a desaturation episode down to 80%, but the recovery was quick under oxygen administration. The EEG showed no pathological waves. Serology tested positive for CMV IgG (106UI/ml), negative for IgM (0,027UI/ml) and CMV was not present in the urine. The transaminases and conjugated bilirubin were elevated: TGP(ALT)=77 UI/l, TGO(AST)=180 UI/l, direct bilirubin=4,8mg/dl. The platelets and indirect bilirubin values were normal. The audiometry showed a bilateral deficit. He was discharged after 11 days, in good general state, with facial jaundice, slightly enlarged abdomen, microcephaly, normotensive anterior fontanelle and a weight of 2550g. This was a first trimester primary seroconversion for CMV with ultrasound signs of fetal CMV infection, which was confirmed by amniocentesis. The pregnant woman did not receive antiviral treatment and the neurological and neurosensorial prognostic was unfavourable.

Fig. 2. Foetal hepatomegaly

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Secondly, we observed the case of a 36-year-old patient, 2G IP, with a first trimester screening performed for TORCH, showing a positive IgG and a negative IgM for CMV. At the 23 weeks morphological scan, a cerebral periventricular hyperechogenic image (fig. 3) was noticed, highly suggestive for an ongoing CMV infection. A serological screening was repeated, with a positive result for both IgM and IgG. After that, an amniocentesis was performed, showing positive CMV- DNA in the amniotic fluid. Given the circumstances, the patient opted for a therapeutic pregnancy termination. This case was a nonprimary first trimester seroconversion for CMV suspected based on an ultrasound pathognomonic sign: periventricular hyper echogenicity and confirmed by amniocentesis.

Fig. 3. Periventricular hyperechogenic image

The third case was of A 30-year-old pregnant patient, 4G 0P, with a history of 3 pregnancy losses in the first trimester and a biochemical pregnancy, diagnosed with hyperhomocysteinemia, factor V Leiden heterozygote for thrombophilia, under LWMH during pregnancy. She performed a TORCH test at 9 weeks of gestation and tested negative for CMV IgG<4.0 UA/mL (n<4,0) and positive for CMV IgM=2,310 Index (<0,700). CMV serology was repeated at 11 weeks with the following results: Ig G=10UA/ml (n<4,0) and IgM=2,260 Index (n<0,700). CMV IgG avidity index was 0,068, which pleaded for a first trimester CMV infection. She received treatment with a single dose of HIG 10.000UI at 13 weeks of gestation. An amniocentesis was performed at 21 weeks of pregnancy and CMV DNA was absent in the amniotic fluid. The growth rate was normal throughout the pregnancy and there were no ultrasound abnormalities. She delivered vaginally a 3880g baby, APGAR score of 9, at 40 weeks. The new-born clinical outcome was favorable, with positive serology for CMV IgG and negative CMV IgM, transfontanelar ultrasound without pathological signs, normal audiogram, and normal eye fundus exam.

Discussion

The CMV is responsible for the most common congenital infection, compromising 0.5%-2% of all live births, and is the main non-genetic cause of congenital hearing loss and neurological impairment. Sensorial and neurological morbidity is specific to the first trimester seroconversion, with up to 40-50% of neonates who contracted the virus having future sequelae. The seroconversion during pregnancy is up to 4% and the vertical transmission is 30-50% for the primary infection and 2-3% for secondary ones.

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Systematic detection of CMV infection among pregnant women or targeted screening in a high- risk population is not routinely recommended. Nevertheless, CMV serologic assay for IgM and IgG antibody is often indicated at the onset of pregnancy as part of TORCH complex test [1]. Otherwise, it is performed when maternal mononucleosis-like symptoms, fever of unknown ethiology or fetal ultrasound anomalies suggestive for CMV infection are present. «Recurrent» or secondary infections are often present, and they could mean a viral reactivation, a reinfection or a persistent active state from a recent primary infection. The non-primary maternal infection rate may vary a lot among different populations, from 0.1% to 1% or more. Even though the CMV infection rate is low, under 2%, it should be considered when characteristic echographic signs occur. The ultrasonographical and MRI findings show over 95% sensibility for the nervous system abnormalities. Once such a finding is identified, an amniocentesis is recommended, for the detection of CMV-DNA in the amniotic fluid. The neonates can have different outcomes at birth: 90% are asymptomatic, with 95% evolving as normal children and 5% present sequelae. 10% can be symptomatic, from which 40% evolve as normal new-borns and 60% have sequelae. The serological screening before 14 weeks’ gestation is particularly important for the identification of the primary infection, but not so specific in women already immune. That is why a close attention must also be payed to CMV- related ultrasound signs. The sensitivity of the routine ultrasound examination is 25% in predicting neonatal symptoms [2]. However, serial targeted examinations and MRI of known infected foetuses demonstrate 95% sensitivity for brain anomalies [3]. MRI can also be used to detect prognostic factors like polymicrogyria, which is associated with an unfavourable outcome [4]. The highest specificity for the diagnosis of the congenital infection is the detection of the virus’ DNA in the amniotic fluid culture or PCR. Amniocentesis can be performed starting with 17 weeks of gestation [3]. As CMV targeted vaccines failed to provide more than 75% protection for more than 2 years’ time, prophylactic measures are limited to prevention through hygiene measures (both partners avoiding contact with body fluids from infected persons, especially children, before conception, up until 14 weeks of pregnancy) [3]. There are two strategies that can be applied in case of CMV infection during the first trimester of pregnancy: the prevention of fetal transmission of CMV (secondary prevention) and the treatment of an already infected fetus in order to reduce the risk of developing sequelae (tertiary prevention). The current available therapeutical options include the hyperimmune globulin and the antiviral agents. Valganciclovir given to symptomatic children has been proven efficient in easing hearing and neurological symptoms [3]. Ganciclovir and valganciclovir are very efficient against CMV, but they seem to have a teratogenic and genotoxic effect in vitro and are not approved for administration during pregnancy [5]. Administration of acyclovir and valaciclovir during pregnancy is not associated with an increased risk of major birth defects, they are not genotoxic nor carcinogenic in vitro or in animals, although there are no controlled studies documenting their safety [6], [7]. Valaciclovir administered from the diagnosis of primary infection until the amniocentesis, has shown a decrease in vertical transmission from 29,8% to 11,1%, in a treatment group of a randomized controlled trial of 90 pregnant women. In a second phase open-label trial, oral valaciclovir administered to patients with a mildly symptomatic foetus was associated with a higher chance of an asymptomatic neonate (82%) at the time of birth, compared to the untreated historical group (43%). Moreover, pregnant women with early primary cytomegalovirus infection (during the periconceptional period and first trimester) recruited in a randomized, double-blind,

167 ©Filodiritto Editore – Proceedings placebo-controlled study that received 8g/day of Valaciclovir had a 71% reduced rate of vertical transmission [8]. Another therapy option is represented by Hyperimmune globulin. Immunoglobulins have been safely used in pregnancy for more than forty years and CMV hyperimmune globulin has not been found to have obstetrical adverse effects [9]. Administration of cytomegalovirus hyperimmune globulin in pregnancy was associated with a significantly lower risk of congenital disease and infection [10], [11] and it appears to prevent maternal-fetal transmission in cases of first trimester CMV primary maternal infection when it is done in the first 20 weeks of gestation [12], [13], [14]. Despite of the frequent and severe sequelae caused by CMV infection, screening in pregnancy is not included in routine practice. [15, 16] Recent studies have demonstrated the screening importance given the fact that an infection detected in the first pregnancy weeks could help the mother make an informed decision regarding the future, knowing the possible implication of CMV [17]. A second trimester found-out could mean little possibilities, as an advanced pregnancy would mean a more difficult termination. Also, even if the women chose to keep the child, she could face a tough outcome at birth, if the detected lesions would be extensive [18]. Also, if CMV infection is detected in the first trimester, infected mothers and foetuses can benefit from antiviral treatment or hyperimmune globulin administration. There is evidence that the hyperimmune globulin administered in high doses prevents congenital CMV disease, decreases the maternal viremia and is beneficial to neurodevelopmental outcomes in infants [14], although a randomized placebo-controlled trial to confirm this has yet to be completed. In our third case, HIG treatment seemed to be very efficient, as there were no neurological sequalae or ultrasound abnormalities and DNA-CMV was negative at the time of amniocentesis. By comparison, the patients that received no treatment during the pregnancy after a first trimester seroconversion, had significant neurologic sequelae and hearing disability.

Conclusion

Given the cumulated information on diagnosis, pre- and postnatal management suggesting that early detection and treatment of CMV infection reduces the maternal-fetal transmission as well as fetal sequelae and long-term disability, we propose that routine CMV screening in the first trimester should be performed in an effort to decrease the negative consequences of this disease. After years of experience on cases with good and bad neonatal outcomes, we have come to the conclusion that this potentially serious congenital infection should be more carefully considered in the daily clinical practice when recommending the first trimester screening panel.

REFERENCES

[1] Baer, H. R., McBride, H. E., Caviness, A. C., & Demmler-Harrison, G. J. (2014). Survey of congenital cytomegalovirus (cCMV) knowledge among medical students. Journal of Clinical Virology, 60(3), pp. 222- 242. [2] Faure-Bardon, V., Magny, J. F., Parodi, M., Couderc, S., Garcia, P., Maillotte, A. M., ... & Pladys, P. (2019). Sequelae of congenital cytomegalovirus following maternal primary infections are limited to those acquired in the first trimester of pregnancy. Clinical infectious diseases, 69(9), pp. 1526-1532. [3] Leruez-Ville, M., Foulon, I., Pass, R., & Ville, Y. (2020). Cytomegalovirus infection during pregnancy: State of the science. American Journal of Obstetrics and Gynaecology. [4] Bonalumi S, Trapanese A, Santamaria A, D’Emidio L, Mobili L. Cytomegalovirus infection in pregnancy: review of the literature. J Prenat Med. 2011; 5(1): pp. 1-8. http://www.ncbi.nlm.nih.gov/pubmed/22439067%0Ahttp://www.pubmedcentral.nih.gov/articlerender.fcgi? artid=PMC3279147

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[5] Khalil, A., Heath, P., Jones, C., & Soe, A. (2018). Ville YG on behalf of the Royal College of Obstetricians and Gynaecologists. Congenital Cytomegalovirus Infection: Update on Treatment: Scientific Impact Paper No. 56. BJOG, 125(1), e1-e1. [6] Pasternak, B., & Hviid, A. (2010). Use of acyclovir, valacyclovir, and famciclovir in the first trimester of pregnancy and the risk of birth defects. Jama, 304(8), pp. 859-866. [7] Wutzler, P., & Thust, R. (2001). Genetic risks of antiviral nucleoside analogues – a survey. Antiviral research, 49(2), pp. 55-74. [8] Shahar-Nissan, K., Pardo, J., Peled, O., Krause, I., Bilavsky, E., Wiznitzer, A., ... & Amir, J. (2020). Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial. The Lancet, 396(10253), pp. 779-785. [9] Delle Chiaie, L., Neuberger, P., Vochem, M., Lihs, A., Karck, U., & Enders, M. (2018). No evidence of obstetrical adverse events after hyperimmune globulin application for primary cytomegalovirus infection in pregnancy: experience from a single centre. Archives of Gynaecology and Obstetrics, 297(6), pp. 1389-1395. [10] Maloney, J. M., & Sicherer, S. H. (2006). Passive Immunization During Pregnancy for Congenital Cytomegalovirus Infection. Paediatrics, 118(Supplement 1), pp. S54-S54. [11] Nigro, G. (2017). Hyperimmune globulin in pregnancy for the prevention of congenital cytomegalovirus disease. Expert Review of Anti-infective Therapy, 15(11), pp. 977-986. [12] Kagan, K. O., Enders, M., Schampera, M. S., Baeumel, E., Hoopmann, M., Geipel, A., ... & Brucker, S. (2019). Prevention of maternal – fetal transmission of cytomegalovirus after primary maternal infection in the first trimester by biweekly hyperimmunoglobulin administration. Ultrasound in Obstetrics & Gynaecology, 53(3), pp. 383-389. [13] Revello, M. G., Lazzarotto, T., Guerra, B., Spinillo, A., Ferrazzi, E., Kustermann, A., ... & Arossa, A. (2014). A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. New England Journal of Medicine, 370(14), pp. 1316-1326. [14] Nigro, G., & Adler, S. P. (2020). High-Dose Cytomegalovirus (CMV) Hyperimmune Globulin and Maternal CMV DNAemia Independently Predict Infant Outcome in Pregnant Women with a Primary CMV Infection. Clinical Infectious Diseases, 71(6), pp. 1491-1498. [15] Navolan, Dan; Ionescu, Cringu Antoniu; Carabineanu, Adrian; Birsasteanu, Florin; Cretu, Octavian; Szasz, Florin; Vladareanu, Simona; Ciohat, Ioana; Gidea, Ramona; Nemescu, Dragos; Farcas, Simona; Andreescu, Nicoleta; Simu, Sebastian; Stoian, Dana Influence of Weight of Pregnant Women on First Trimester Biochemical Markers Values REVISTA DE CHIMIE, Volume: 69, Issue: 2, Pages: 529-532, Published: FEB 2018. [16] Navolan, Dan; Vladareanu, Simona; Ciohat, Ioana; Carabineanu, Adrian; Craina, Marius; Nemescu, Dragos; Birsasteanu, Bogdan; Onofriescu, Alina; Boia, Marioara; Tepetzikiotis, Efstathios; Craciunescu, Mihaela; Birsasteanu, Florin Distribution of Biochemical and Ultrasound Markers Values in the First Trimester Screening Program in Timisoara REVISTA DE CHIMIE, Volume: 68, Issue: 7, Pages: 1636-1639, Published: JUL 2017. [17] Schleiss, M. R. (2018). Congenital cytomegalovirus: Impact on child health. Contemporary paediatrics, 35(7), p. 16. [18] Kagan, K. O., & Hamprecht, K. (2017). Cytomegalovirus infection in pregnancy. Archives of gynaecology and obstetrics, 296(1), pp. 15-26.

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Giant Uterine Fibroid and Postoperative Outcome

STERIU Liliana1, IZVORANU Silvia1, NOUR Corina1, PENCIU Roxana1, BALTĂȚESCU Gabriela2, TICA Vlad1

1 Institute of Doctoral Studies, Doctoral School of Medicine, Faculty of Medicine, “Ovidius” University of Constanta; Emergency County Hospital, Department of Obstetrics and Gynaecology, Constanta, (ROMANIA) 2 Institute of Doctoral Studies, Doctoral School of Medicine, Faculty of Medicine, “Ovidius” University of Constanta Emergency County Hospital, Department of Pathology, Constanta, (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

We present the case of a 61-year-old woman, at climacterium for 13 years, who was admitted for abdominal pain and increased size of the abdomen. We suspected ovarian neoplasm associated with a cervical neoplasm after imagistic investigations. During the surgery, there was a giant uterus, with the uterine fundus to the xiphoid appendix, which required a xipho-pubic incision. Total hysterectomy was performed with bilateral adnexectomy. The frozen sample pathological examination revealed benignity. A particularity of this case was the difficult evolution of the postoperative wound, with infection and dehiscence. That needed care for a long period of time. Other particularities were the increase size of the uterus and the preoperative ambiguity of the diagnosis.

Keywords: giant leiomyoma, dehiscence, infection

Introduction

Uterine fibroids are frequently diagnosed in older women; a lot of them are incidentally discovered. They are common benign tumours that cause abnormal bleeding, inflammatory pelvic symptoms, urinary and digestive disorders. The differential diagnosis includes a multitude of abdominal tumoral pathologies [1-4] or those inducing pelvic pain [5-7], especially adenomyosis [8-10]. This, especially as uterine signalling pathways are still not, completely, understood [11, 12]. The preferred imagistic method for this pathology is ultrasonography, but in some cases, we have to use superior imagistic methods, like computer tomography (CT) and even magnetic resonance (MRI). Many authors recommend expectant management for asymptomatic patients. The appropriate treatment could be medical or/and surgical [13], under general or regional anaesthesia [14].

Case presentation We present a case of a 61 years-old woman who came to the hospital for increased volume of the abdomen associated with pain. The woman has been in menopause for 13 years. After clinical and biological examination, the diagnose was uncertain. The biological exams showed no major modifications. The ultrasound revealed a big tumour that occupied the entire abdomen with the

170 ©Filodiritto Editore – Proceedings sizes of 35/45 cm. After CT scan we suspected ovarian and cervical cancer. The MRI offered us no clarification. During the surgery was, therefore, performed, we found a big uterine tumour that filled the entire abdomen. The incision was a large one, xipho-pubic (Fig. 1, Fig. 2). We performed total hysterectomy with bilateral adnexectomy. The frozen section pathological examination of the specimen concluded for benignity. The tumour was a large leiomyoma.

Fig. 1. Uterine fibroid during the surgery Fig. 2. Uterine fibroid during surgery

The surgery resulted in a big wound that required a lot of effort to care and cure (Fig. 3, Fig. 4).

Fig. 3. Day 1after surgery Fig. 4. Day 5after surgery

Daily, we cleaned it, but the infection and dehiscence occurred on the 7th day after surgery (Fig. 5). We opened the wound, cleaned it for another 14 days. When the wound probe was sterile, we sutured it (Fig. 6). At present the patient is surgically cured (Fig. 7).

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Fig. 5. Day 7 after surgery Fig. 6. Day 21 after surgery Fig. 7. Day 32 after surgery

Discussions

Most of fibroids are asymptomatic and not require treatment. Some of them have increased volume and cause pain, bleeding or/and anaemia. For symptomatic fibroids hysterectomy offers a definitive solution [15]. The embolization of uterine fibroids using emboli to obturate the uterine arteries seems to be an alternative treatment, conserving the uterus [16, 17]. Both treatments – hysterectomy and uterine artery embolization – have improved the quality of life, but the complications were higher in the patients that underwent hysterectomy than in those that underwent embolization. The symptoms rapidly disappear after hysterectomy despite the complications [18, 19]. The treatment for our case was surgical due to the size of uterus and the preoperative diagnostic ambiguity.

Conclusion

The particularity of this case was the difficult evolution of the postoperative wound, with infection and dehiscence. This needed wound care for a long period of time. Other particularities were the increased size of the uterus and the preoperative ambiguity of the diagnosis.

REFERENCES

[1] Tica AA, Tica OS, Saftoiu A, Camen D, Tica VI. Large Pancreatic Mucinous Cystic Neoplasm during Pregnancy: What Should Be Done? Gynecol. Obstet. Invest. 2013; 75(2): pp. 132-138. [2] Tica I, Tica OS, Nicoară AD, Tica VI, Tica A-A. Ovarian teratomas in a patient with Biedl Bardet syndrome, a rare association. Rom J Morphol Embryol. 2016; 57(4): pp. 1403-1408. [3] Tica I, Niculescu C, Mocanu L, Iliescu MG, Tica VI (corresponding author), Niculescu Z. Nodular subcutaneous lesion – an alarming sign for an upcoming pancreatic disorder. Rom J Morphol Embryol 2019, 60(4): pp. 1343-1347. [4] Tica I, Morosan V, Micu LG, Niculescu C, Mehedinti MC, Coman M, Craitoiu S, Iacov-Craitoiu MM, Tica VI, Niculescu Z. Giant abdominal tumour – would you think adrenal? Romanian Journal of Morphology and Embryology, 2019; 60(2): pp. 691-695.

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[5] Izvoranu S, Penciu R, Mocanu ID, Tica V. Chronic Pelvic Pain of Gynaecological Cause. Proceedings of the 14th National Congress of Urogynaecology and the National Conference of the Romanian Association for the Study of Pain, Ed. Bratila E; Cirstoiu M. Filodiritto Publisher, Bologna, Italy, 2017: pp. 463-465. [6] Penciu RC, Postolache I, Steriu L, Izvoranu S, Tica AA, Mocanu ID, Sarbu V, Deacu M, Tica I, Baltatescu GI, Tica OS, Tica VI. Is there a relationship in-between ovarian endometriosis and ovarian cancer? Immunohistochemical profile of four cases with coexisting ovarian endometriosis and cancer. Romanian Journal of Morphology and Embryology, 2020; 61(1): pp. 157-165. [7] Penciu RC, Izvoranu S, Mocanu, D, Tica V. Correlation Between Dysmenorrhea and Endometriosis: Case Report. Proceedings of the 14th National Congress of Urogynaecology and the National Conference of the Romanian Association for the Study of Pain, Ed. Bratila E; Cirstoiu M. Filodiritto Publisher, Bologna, Italy, 2017: pp. 569-570. [8] Penciu RC, Steriu L, Izvoranu S, Postolache I, Tica AA, Mocanu D, Tica OS, Sarbu V, Deacu M, Baltatescu G, Tica I, Petcu L, Tica VI. CD10, CD34 and Ki67 Immunohistochemical Markers Expression in Endometriosis and Adenomyosis. Rev Chim-Bucharest. 2019; 70(4): pp. 1323-1327. [9] Penciu RC, Postolache I, Steriu L, Izvoranu S, Postolache I, Tica AA, Steriu L, Izvoranu S, Mocanu D, Tica OS, Sarbu V, Tica O, Deacu M, Baltatescu G, Petcu L, Tica I, Tica VI. Gynaecological Symptoms Correlated with Immunohistochemical Aspects of Endometriosis and Adenomyosis. Rev Chim-Bucharest, 2019; 70(8): pp. 3053-3057. [10] Penciu RC, Izvoranu S, Mocanu, D, Tica V. Pelvic Chronic Pain in Endometriosis Versus Adenomyosis. Proceedings of the 14th National Congress of Urogynaecology and the National Conference of the Romanian Association for the Study of Pain, Ed. Bratila E; Cirstoiu M. Filodiritto Publisher, Bologna, Italy, 2017: pp. 566-568. [11] Tica AA, Dun E, Tica V, Cojocaru V, Tica OS, Berceanu S. The autonomic innervation of the uterus. A short review on pharmacological aspects. Gineco.ro. 2011;7(24): pp. 86-91. [12] Tica AA, Tica VI, Tica O, Dun E, Berceanu S, Tica I. Endothelin I activate the NAADP signalling complex on myometrial smooth muscle cell. Gineco.ro. 2010; 6(22): pp. 254-255. [13] De La Cruz MS. Uterine Fibroids: Diagnosis and Treatment. Am Fam Physician 2017; 95(2): pp. 100-107. [14] Tica V. A new method of anaesthesia – Piritramide used intrathecally as a sole analgesic in surgery. Anesthesist. 1988; 37(10): pp. 116-116. [15] Lefebvre G, Vilos G, Allaire C, Jeffrey J, Arneja J, Birch C, Fortier M, Wagner MS. The management of uterine leiomyomas. J Obstet. Gynaecol. Can 2003; 25(5): pp. 396-418. [16] Bradley L. Am J Obstet. Gynecol., 2009; 201(2): pp. 127-135. [17] Levy B. Modern management of uterine fibroids. Acta Obstet. Gynecol. Scand. 2008; 87(8): pp. 812-823. [18] Marshburn P, Matthews M., Hurst B. (2006). Uterine artery embolization as a treatment option for uterine myomas. Obstet. Gynecol. Clin North Am 2006; 33(1): pp. 125-144. [19] Vilos G, Allaire C, Laberge PY, Leyland N. J Obstet. Gynaecol. Can 2015; 37(2): pp. 157-178.

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Low Molecular Weight Heparin Therapy in Placental Insufficiency

TICA Vlad1,2, COCOS Adelina1, STERIU Liliana1,2, BADIU Diana1,2, IZVORANU Silvia1,2, BANARIU Gheorghe2, NOUR Corina1,2, PENCIU Roxana1,2

1 Department of Obstetrics & Gynaecology, “Sf. Apostol Andrei” Emergency Clinic County Hospital, Constanta, (ROMANIA) 2 Institute of Doctoral Studies, Doctoral School of Medicine, Faculty of Medicine, “Ovidius” University of Constanta, (ROMANIA) Email: [email protected]

Abstract

Placental insufficiency may cause numerous, severe, complications, which could lead to substantial fetal or neonatal morbidity or mortality. Morpho pathological complications involved are necrosis/placental infarction, haemorrhage and thrombosis – up to extensive fetal villous vessels thrombosis. This thrombosis and the results of some in vitro studies support the use of low-molecular weight heparin (LMWH). Some authors report positive results in pregnant women, but others (heterogenous) do not support them. It is difficult, therefore, to establish a definitive conclusion of the benefit of LMWH use in placental insufficiency. Large, well-conceived trials are clearly needed – and, meanwhile, LMWH treatment in placental insufficiency is restricted to research.

Introduction

Normal placental development. Placentation usually occurs in a hypoxic environment – which is essential and appropriate for the embryonic development during early pregnancy. At around 10-12 weeks of gestation, the intervillous blood flow increases. This is the result of the exposure of the trophoblast to an increased oxygen tension. Previously, low oxygen tension prevents trophoblast differentiation to an invasive phenotype. For a healthy pregnancy, the fetal-maternal interactions, during early pregnancy, are very important. The cytotrophoblast cells proliferates and differentiates in order to form the multinucleate syncytiotrophoblast layer or it breaks the syncytium in selected places and creates multi-layered columns of cells non-polarized extravillous trophoblast. This transformation connects the embryo to the uterine wall. The cells of the extravillous trophoblast invade the uterine wall down to the first third of the myometrium and its spiral arteries. These cells replace the vascular wall by disrupting the endothelium and the smooth muscle layer. These changes convert the narrow caliber arteries and results in distended uteroplacental arteries and alteration of the process could lead to pregnancy-induced hypertension, for which we, still, do not have an efficient prophylaxis [1]. These arteries offer increases blood flow in the placenta and provide oxygen and nutrients for the growing fetus [2].

Placental insufficiency The abnormal placenta appears in 5-10% of pregnancies and represents an abnormal thin placenta (less than 1cm). The type of circumvallate placenta appears in 1% of normal placentas; amnion cell metaplasia (amnion nodosum) is found in 65% of normal placentas. Also, the

174 ©Filodiritto Editore – Proceedings definition includes increased syncytial knots, calcifications and infarction which are due to the focal or diffuse thickening of blood vessels. About 50% of the villi volume is filled by villi capillaries [3]. The causes involved in placental insufficiency are: diabetes, autoimmune diseases, renal diseases, thrombophilia, low socioeconomic status, viral infections (e.g.: cytomegalovirus, rubella, malaria), structural anomalies, chromosomal or genetic diseases, placental abnormalities and multiple pregnancies [4, 5]. The complications that might appear are numerous: migraine, uterine contractions, high risk of arterial hypertension, diabetes, preeclampsia. Preeclampsia causes low contribution of oxygen and reduces nutrient transport, then it causes placental insufficiency and fetal restriction growth, that lead to substantial fetal or neonatal morbidity or mortality – hypoxia, hypothermia, hypoglycaemia, hypocalcaemia, polycythemia, fetal distress and death [4]. Morpho pathological complications caused by placental insufficiency are: necrosis/placental infarction, haemorrhage and thrombosis – up to extensive fetal villous vessels thrombosis [6].

Low-molecular weight heparin (LMWH) use The use of LMWH in placental insufficiency can be supported by the already described thrombotic lesions associated with that condition. More, several in vitro studies report LMWH- induced angiogenesis [7-9]. Placenta growth factor seems also to be elevated by LMWH [10]. On the other hand, there are studies reporting suppression of the trophoblastic invasion [11, 12]. Some studies involving pregnant women favour the LMWH use – for reducing the placenta- related recurrent complications [13], including on the neonatal weigh in case of placental insufficiency [14, 15]. In other studies, during pregnancy, there was no positive influence [16-24]. More, prolonged use could have caused haemorrhagic problems, related immunity effects or, even, osteoporosis [25]. On the positive side, common surgical procedures, including caesarean section and regional anaesthesia [26] can be done, under LMWH.

Conclusions

It is difficult to establish a definitive conclusion of the benefit of LMWH use in placental insufficiency. Some studies show in vitro arguments in favour the concept and, some, report positive results in pregnant women, but others (heterogenous), on pregnant women, do not support them. Large, well-conceived trials are clearly needed – and, meanwhile, LMWH treatment in placental insufficiency is restricted to research.

REFERENCES

[1] Tica V. Preeclampsia – an unsolved prophylaxis chapter. Gineco.ro. 2012; 8(27): pp. 3-4. [2] Caniggia I, Winter J, Lye SJ, Post M. Oxygen and placental development during the first trimester: implications for the pathophysiology of pre-eclampsia. Placenta 2000; 21 Suppl A: S25. [3] Brant, W., Core Curriculum, The: Ultrasound. Publication 2001, 1st, Ed. Publisher: Lippincott Williams & Wilkins (LWW). [4] Cetin I., Taricco E., Clinical causes and aspects of placental insufficiency 2011, Cambridge University Press. [5] Tica AA, Tica OS, Georgescu CV, Mixich F, Tica VI, Berceanu S, Ebanca E, Patrascu A, Simionescu C. Recurrent partial hydatidiform mole, with a first twin pregnancy, after treatment with clomiphene citrate. Gynecological Endocrinology. 2009; 25(8): pp. 514-519. [6] Franco C, Walker M, Robertson J, et al., Placental infarction and thrombophilia. Obstet. Gynecol. 2011; 117(4): pp. 929-34.

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[7] Bose P, Black S, Kadyrov M, Bartz C, Shleb, et al., Adverse effects of lupus anticoagulant positive blood sera on placental viability can be prevented by heparin in vitro. Am J Obstet. Gynecol. 2004; 191: pp. 2125- 31. [8] Bose P, Black S, Kadyrov M, Weissenborn U, et al., Heparin and aspirin attenuate placental apoptosis in vitro: implications for early pregnancy failure. Am J Obstet. Gynecol. 2005; 192: pp. 23-30. [9] Sobel ML, Kingdom J, Drewlo S. Angiogenic response of placental villi to heparin. Obstet. Gynecol. 2011; 117: pp. 1375-83. [10] Yinon Y, Ben Meir E, Margolis L, et al., Low molecular weight heparin therapy during pregnancy is associated with elevated circulatory levels of placental growth factor. Placenta 2015; 36: pp. 121-4. [11] Ganapathy R, Whitley GS, Cartwright JE, Dash PR, Thilaganathan B. Effect of heparin and fractionated heparin on trophoblast invasion. Hum Reprod 2007; 22: pp. 2523-7. [12] Quenby S, Mountfield S, Cartwright JE, Whitley GS, Vince G. Effects of low-molecular weight and unfractionated heparin on trophoblast function. Obstet. Gynecol. 2004;104: pp. 354-61. [13] Rodger, M.A., Carrier, M., Le Gal, G., Martinelli, I., Perna, A., Rey, E., de Vries, J.I. & Gris, J.C. Meta- analysis of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. Blood, 2014, 123, pp. 822-828. [14] Zaman Z, Imran F, Iqbal MJ. J. Soc. Obstet. Gynaecol. Pak. 2018; Vol 8. No 4 “Role of Enoxaparin to Improve Obstetrical Outcome in Patients with IUGR and Oligohydramnios” [15] Rodger MA, Gris JC, de Vries JIP, et al., Low molecular – weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. Lancet 2016; 388: pp. 2629-41. [16] Dilmen G, Aytac S, Toppare MF, Ozturk M, Goksin E. Umbilical artery blood flow characteristics in normal pregnancies. Gynecol. Obstet. Invest 1994; 38: pp. 96-9. [17] Abheiden CNH, Van Hoorn ME, Hague WM, Kostense PJ, van Pampus MG, de Vries JIP. Does low- molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomized controlled trial results. BJOG 2016; 123: pp. 797-805. [18] de Vries JI, van Pampus MG, Hague WM, Bezemer PD, Joosten JH; FRUIT Investigators. Low-molecular- weight heparin added to aspirin in the prevention of recurrent early-onset preeclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J Thromb Haemost 2012; 10: pp. 64-72. [19] Rey E, Garneau P, David M, Gauthier R, Leduc L, Michon N, et al., Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. J Thromb Haemost 2009; 7: pp. 58-64. [20] Martinelli I, Ruggenenti P, Cetin I, et al., Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial. Blood 2012; 119: pp. 3269-75. [21] Haddad B, Winer N, Chitrit Y, et al., Enoxaparin and aspirin compared with aspirin alone to prevent placenta-mediated pregnancy complications: a randomized controlled trial. Obstet. Gynecol. 2016; 128: pp. 1053-63. [22] Visser J, Ulander VM, Helmerhorst FM, et al., Thromboprophylaxis for in women with or without thrombophilia. HABENOX: a randomized multicenter trial. Thromb Haemost 2011; 105: pp. 295-301. [23] Kaandorp SP, Goddijn M, van der Post JA, et al., Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. NEngl J Med 2010; 362: pp. 1586-96. [24] Groom KM, McCowan LM, Mackay LK, et al., Enoxaparin for the prevention of preeclampsia and intrauterine growth restriction in women with a history: a randomized trial. Am J Obstet. Gynecol. 2017; 216: 296.e1-14. [25] Ganapathy R, Whitley GS, Cartwright JE, Dash PR, Thilaganathan B. Effect of heparin and fractionated heparin on trophoblast invasion. Hum Reprod 2007; 22: pp. 2523-7. [26] Tica V. A new method of anaesthesia – Piritramide used intrathecally as a sole analgesic in surgery. Anesthetist. 1988; 37(10): pp. 116-116.

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IOTA Criteria for Diagnosis of Ovarian Masses – Cases Analysis

TÎRNOVANU Mihaela Camelia1, TOMA Bogdan2, MUCILENIŢA Cerasela2, CORDUNEANU Roxana2, IOV Alexandra3, TÎRNOVANU Vlad Gabriel3

1 University of Medicine and Pharmacy “Gr. T. Popa” Iaşi (ROMANIA) 2 Clinical Hospital of Obstetrics and Gynaecology “Cuza Vodă” Iaşi (ROMANIA) 3 Student University of Medicine and Pharmacy “Gr. T. Popa” Iaşi (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

50% of adnexal masses are usually instantly recognisable at transvaginal ultrasound examination using simple descriptors. If the ovarian mass does not fit one of these categories, we must use IOTA (International Ovarian Tumour Analysis) simple rules to discriminate benign and malignant masses. The simple rules were conclusive in about 75% of adnexal masses. If we have inconclusive cases, we can use subjective opinion by expert or ADNEX (Assessment of Different NEoplasias in the adneXa) – IOTA risk of malignancy model. For ADNEX optimum cut-off is 26,1%, but subjective appearance by expert is superior to ADNEX.

Aim To establish a prospective validation of IOTA group criteria.

Material and methods We analysed 250 patients admitted in 1st Clinic of Gynaecology Iasi for surgical treatment in a 3-year period.

Results 55.2% of adnexal masses were recognisable using simple descriptors. Simple Rules were applicable in 70.53% of the rest of tumours. We had 33 inconclusive cases. The malignancy rate was 5% in cases classified as benign, 89% in cases classified as malignant, and 37% in inconclusive cases. Feature B1 (unilocular cyst) was most predictive of a benign tumour, while feature B3 (acoustic shadows) was least predictive. Feature M2 (ascites) was most predictive of malignancy and feature M4 (irregular multilocular-solid tumour with largest diameter ≥100 mm) was least predictive.

Conclusion The Simple Rules must be used on the assessment and management of ovarian masses. The ability to provide accurate risk estimates is highly relevant for risk stratification and individualized patient management. Important limitations of the Simple Rules are the inconclusive results for some cases and the absence of an estimated risk of malignancy. The simple rules cannot replace training and experience in ultrasonography.

Keywords: IOTA, ovarian neoplasms, ultrasonography

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Introduction

Ovarian cancer is the most aggressive gynaecological malignancy. The five-year survival rate of patients is around 40% and the disease accounts for approximately half of all deaths related to gynaecological cancer [1]. Accurately characterizing ovarian pathology prior to deciding on surgical intervention is important for the optimization of patient management. Benign pathology may be best treated conservatively or in a general gynaecology unit using a minimal access approach. Conversely, suspected malignant masses should be referred to specialized units for further management. Transvaginal ultrasonography is an excellent tool for discriminating between benign and malignant adnexal masses. Ultrasonography has developed many scoring systems to predict ovarian malignancy, which is: Sassone Morphology Index (1991), Risk of Malignancy Index (Jacob, 1991), and International Ovarian Tumour Analysis (IOTA, 2000-2013) [2]. About 50% of adnexal masses are ‘easy’ to diagnose (instant) using information that should be obtainable by most clinicians (simple descriptors). Timmerman et al., demonstrated that simple rules method (IOTA criteria) had sensitivity of 95% and specificity of 91% [3]. Validation of this system by Kaijser et al., showed a sensitivity of 90% [4]. A criticism of these prediction models is that they were developed and validated by experts in characterizing adnexal pathology [5]. Some adnexal masses are almost impossible to confidently and correctly classify as benign or malignant. From a practical point of view, Daemen et al., considers that does not seem reasonable to refer more than 10% of patients with an adnexal mass for a second-stage test (that patients with inconclusive ultrasonography) [6].

Objective

To establish a prospective validation of IOTA group criteria of the benign or malignant nature of an adnexal mass.

Methods

We analysed 250 patients admitted in 1st Clinic of Gynaecology Iasi for surgical treatment during three years. Transvaginal sonography was carried out by ultrasound examiners specialized in gynaecological ultrasound. The ultrasound examiner used subjective evaluation of grey-scale and Doppler ultrasound findings to classify each mass as benign or malignant. The examiner also stated whether the diagnosis was certainly benign, probably benign, uncertain, probably malignant or certainly malignant. We applied the simple rules [7]. Briefly, we used five ultrasound-based variables collected in the study to predict a malignant tumour (M-features): irregular solid tumour (M1), ascites (M2), at least four papillary structures (M3), irregular multilocular solid tumour with a largest diameter of at least 100 mm (M4) and very high colour content on colour Doppler examination (M5). We also used five ultrasound features to predict a benign tumour (B-features): unilocular cyst (B1), presence of solid components for which the largest solid component was <7 mm in largest diameter (B2), acoustic shadows (B3), smooth multilocular tumour (B4), and no detectable blood flow on Doppler examination (B5). If one or more M-features were present in the absence of a B-feature, we classified the mass as malignant (Rule 1). If one or more B-features were present in the absence of an M-feature, we

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classified the mass as benign (Rule 2). If both M-features and B-features were present, or if none of the features was present, the simple rules were inconclusive (Rule 3). The risk of malignancy or benignity was compared for all cases with the histological diagnosis of the surgically removed adnexal mass (the gold standard). Tumours were classified according to the criteria recommended by the International Federation of Gynaecology and Obstetrics.

Results

Both the sonographic morphological and vascular characteristics of a mass can give very useful information about its nature. 55.2% of adnexal masses were recognisable using simple descriptors. Simple Rules were applicable in 70.53% of the rest of tumours. We had 33 inconclusive cases. The malignancy rate was 5% in cases classified as benign, 89% in cases classified as malignant, and 37% in inconclusive cases. Feature B1 (unilocular cyst) was most predictive of a benign tumour, while feature B3 (acoustic shadows) was least predictive. Feature M2 (ascites) was most predictive of malignancy and feature M4 (irregular multilocular-solid tumour with largest diameter ≥100 mm) was least predictive. We will give some examples of cases from our study. Case 1 was a young woman 18-year old which was admitted in our clinic for a huge abdominal mass and the tumour rapidly grew during last month. On ultrasonography we found an irregular solid tumour – M1 (fig. 1), and a small quantity of ascites – M2 (fig. 2). Regarding vascular score there were some vessels, but not very high colour content (fig. 3). The diagnosis was malignant tumour and was confirmed by pathological exam – immature teratoma (fig. 4, 5).

Fig. 1. Irregular solid tumour – M1 Fig. 2 Ascites (arrow) – M2 Fig. 3. Low colour content in tumour

Fig. 4. Immature teratoma external surface Fig. 5. Immature teratoma on section

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The second case was a patient with an adnexal mass detected during a routine gynaecological examination. At ultrasonography we detected unilocular cyst – B1 (fig. 6), presence of solid components for which the largest solid component was <7 mm in largest diameter – B2 (fig. 7), and no detectable blood flow on Doppler examination – B5 (fig. 8). The imaging diagnosis was of course benign ovarian mass and the same was the histological diagnosis – papillary ovarian cystadenoma (fig. 9, 10).

Fig. 6. Unilocular cyst – B1 Fig. 7. Papillation <7 mm – B2 Fig. 8. No detectable blood flow – B5

Fig. 9. External surface of the cyst Fig. 10. internal surface of the cyst

The third case was a woman 25-year old with a giant mass on the left ovary. At ultrasonography we found an irregular solid tumour – M1 (fig. 11), in the other part of the tumour irregular multilocular solid tumour with a largest diameter of at least 100 mm – M4 (fig. 12), presence of ascites – M2 (fig. 13), but at colour Doppler exam no detectable blood flow – B5 (fig. 14). So, we were in front of an inconclusive case. Considering the age of patient and the absence of vessels inside the tumour we appreciated that is a benign mass. It was established during the surgery by frozen section that the left ovarian mass had three distinct parts: ovarian fibroma (fig. 15), ovarian fibroma with cystic degeneration and oedema (fig. 16), and ovarian serous cyst (fig. 17).

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Fig. 11. The solid part of tumour – M1 Fig. 12. Feature M4 the same tumour

Fig. 13. Presence of ascites – M2 Fig. 14. No detectable blood flow – B5

Fig. 15. Ovarian fibroma Fig. 16. Fibroma with cystic Fig. 17. Ovarian serous cyst degeneration

The rules seem to work less well for abscesses, fibromas, and stage I serous borderline tumours. These conditions are also difficult to classify with subjective assessment of ultrasonic findings. This was the situation for this case and we had a few more. The fourth case a 39-year old presented a cyst with accelerated growth in the last year, from 4 cm to 11 cm, with a papillary projection of 6 cm, CA125=75ui/ml, and was nulliparous. Ultrasonography evaluation found unilocular cyst – B1 (fig. 18), by simple descriptors it seems to be endometriosis and the big papillary projection because did not contained vessels was appreciated as B5 (fig. 19). We interpreted the ovarian mass as a benign one – unilocular solid endometrioma. The pathological result was endometrioid ovarian cancer developed on endometriosis. For most of our cases with malignant transformation of endometrioma we could not diagnose the malignancy by ultrasound exam. Maybe for this case it would have been better

181 ©Filodiritto Editore – Proceedings to use the proportion of solid tissue in the tumour (the ADNEX model) to obtain the probability of tumour type. The mathematical multiclass model uses three clinical predictors (age, serum CA- 125 level, type of centre) and six ultrasound predictors (maximal diameter of lesion, proportion of solid tissue, more than 10 cyst locules, number of papillary projections, acoustic shadows, and ascites) [8, 9].

Fig. 18. Unilocular cyst – B1 Fig. 19. Papillation without blood vessels – B5

In practice, all ultrasound examiners go through a mental process when carrying out a scan. For some masses we will immediately identify a specific appearance and recognize the nature of a lesion, without the need to measure specific structures in the tumour. Always we must take into account clinical characteristic of patient and measurements of serum CA 125 levels or ROMA (Risk of Ovarian Malignancy Algorithm) score. For example, in women older than 50 years, an adnexal mass associated with a serum CA 125 level of over 100 U/mL is very often a carcinoma.

Conclusions

Our results suggest that the current approach used to characterize adnexal masses may not be optimal. The Simple Rules must be used on the assessment and management of ovarian masses. The ability to provide accurate risk estimates is highly relevant for risk stratification and individualized patient management. Important limitations of the Simple Rules are the inconclusive results for some cases and the absence of an estimated risk of malignancy. The simple rules cannot replace training and experience in ultrasonography.

REFERENCES

[1] Siegel R, Ma J, Zou Z, Jemal A. (2014). Cancer statistics, 2014. CA Cancer J Clin 64, pp. 9-29. [2] Twickler DM, Moschos E. (2010). Ultrasound and assessment of ovarian cancer risk. AJR Am J Roentgenol 194(2), pp. 322-329 [3] Timmerman D, Testa AC, Bourne T et al., (2008). Simple ultrasound-based rules for the diagnosis of ovarian cancer. Ultrasound Obstet. Gynecol. 31, pp. 681-690. [4] Kaijser J, Bourne T, Valentin L et al., (2013). Improving strategies for diagnosing ovarian cancer: a summary of the International Ovarian Tumour Analysis (IOTA) studies. Ultrasound Obstet. Gynecol. 41, pp. 9-20. [5] Van Holsbeke C, Van Calster B, Bourne T et al., (2012). External validation of diagnostic models to estimate the Risk of Malignancy in adnexal masses. Clin Cancer Res 18, pp. 815-825. [6] Daemen A, Valentin L, Fruscio R et al., (2011). Improving the preoperative classification of adnexal masses as benign or malignant by second-stage tests. Ultrasound Obstet. Gynecol. 37, pp. 100-106. [7] Timmerman D, Ameye L, Fischerova D et al., (2010). Simple ultrasound rules to distinguish between benign and malignant adnexal masses before surgery: prospective validation by IOTA group. BMJ 341, c6839.

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[8] Van Calster B, Van Hoorde K, Valentin L., et al., (2014). Evaluating the risk of ovarian cancer before surgery using the ADNEX model to differentiate between benign, borderline, early and advanced stage invasive, and secondary metastatic tumours: prospective multicentre diagnostic study. BMJ 349: g5920 doi: 10.1136/bmj. g5920 [9] Epstein E, Van Calster B, Timmerman D, Nikman S. (2016). Subjective ultrasound assessment, the ADNEX model and ultrasound-guided tru-cut biopsy to differentiate disseminated primary ovarian cancer from metastatic non-ovarian cancer. Ultrasound Obstet. Gynecol. 47, pp. 110-116.

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The Role of Ultrasonography for Operability Evaluation of Cervical Cancer

TÎRNOVANU Mihaela Camelia1, IOV Alexandra2, TÎRNOVANU Vlad Gabriel2, HIMINIUC Loredana3, TOMA Bogdan3

1 University of Medicine and Pharmacy “Gr. T. Popa” Iaşi (ROMANIA) 2 Student University of Medicine and Pharmacy “Gr. T. Popa” Iaşi (ROMANIA) 3 Clinical Hospital of Obstetrics and Gynaecology “Cuza Vodă” Iaşi (ROMANIA) Emails: [email protected], [email protected], [email protected], [email protected], [email protected]

Abstract

Background Cervical cancer is the third most common cancer in women in the world (first place in Romania) Clinicians depend on diagnostic imaging in the triage and the treatment management of the patients. In recent years ultrasound has gained increased attention in preoperative staging of cervical cancer.

Aim The objective was to study the tumour size, colour score and the possible invasion of tissue and to predict the operability of cases with cervical carcinoma.

Methods The study group comprised forty-eight patients with histologically confirmed invasive carcinoma of the cervix. A prospective study was performed and included patients diagnosed with invasive cervical cancer admitted in 1st Gynaecology Department Iaşi during the period of 2017- 2019. Maximum cervical tumour length, anterior-posterior diameter and width have been measured and tumour. Intratumoral blood flow was subjectively evaluated by colour Doppler examination. We evaluated the tumour extension at the level of parametrium.

Results The median age of the patients was 53.2 years, ranging from 29 to 81 years. 12 (25%) patients were diagnosed with IB2 stage (FIGO) cervical cancer and 36 (75%) with stage IIB or higher. Histologically, 42 (87.5%) cases were squamous cell carcinoma and 6 (12.5%) were adenocarcinoma. Sonographic findings suggesting parametrial invasion are extension of the cervical tumour beyond the cervical stroma with the presence of hypoechoic irregular tissue infiltrating the peri-cervical tissue. The surrounding cervical tissue with invasion usually had very scarce vascularization. Agreement between ultrasound assessment of parametrial invasion and MRI was good (sensitivity 76%; specificity 86%; agreement 85%).

Conclusions The results of this study demonstrate that transvaginal ultrasound, an inexpensive procedure, easily accepted by patients, could be carried out quickly and could be used to evaluate the local

184 ©Filodiritto Editore – Proceedings extension of cases with big cervical tumours and to monitor the effectiveness of cervical cancer treatment widely as alternative method to MRI.

Keywords: Cervical cancer, ultrasonography, operability

Introduction

EUROCARE-5 study shows that five-year relative survival for European women diagnosed with cervical cancer in 2000-2007 was 62%, ranging from 57% in Eastern Europe to 67% in Northern Europe. Survival was particularly low (<55%) in Bulgaria, Latvia, and Poland and highest in Norway (71%) [1]. Unfortunately, Romania has a low survival rate also because many patients present at gynaecologists in advanced stages. Cervical cancer is the third most common cancer in women worldwide. In the last few years, the overall 5-year survival rate has been reported to be 73% but the prognosis for patients with locally advanced cervical cancer is poor [2]. The extent of disease when compared with pathological specimens is underestimated in 17% to 32% of cases of FIGO (International Federation of Gynaecology and Obstetrics) stage IB and in up to 67% of cases of more advanced FIGO stages [3]. Cervical cancer has become less common in Europe but is still a major public health problem. The number of new cases of cervical cancer in Europe in 2018 was 61000, with 25800 deaths [4]. An accurate diagnosis guides patient management and informs prognosis. Hoffman et al., showed 52% and 45% accuracy for tumour diameter estimation by clinical examination and pelvic examination [5]. Because of the discrepancies between clinical staging and pathological findings, more sophisticated imaging methods have been suggested: magnetic resonance imaging (MRI) for measuring tumour volume and local extent, computed tomography (CT) and positron emission tomography (PET/CT) for evaluation of metastatic disease. However, the FIGO Gynaecologic Cancer Committee has accepted these sophisticated methods only reluctantly, because MRI, CT and PET/CT are not universally available. Ramirez congratulates and recognizes ESGOs’ (European Society of Gynaecological Oncology) massive effort to provide guidance in establishing measures of care for women with cervical cancer [6]. According to ESGO-ESTRO (European Society for Radiotherapy and Oncology)-ESP (European Society of Pathology) guidelines [7, 8]: • Pelvic examination and biopsy, with or without colposcopy, are mandatory components for the diagnosis of cervical cancer, • Clinicians depend on diagnostic imaging in the management of patients to triage them to treatment, • Magnetic resonance imaging is the mandatory initial investigation for assessment of the extent of a pelvic tumour and guide treatment options, • Endovaginal/transrectal ultrasound is an option if it is performed by a properly trained sonographer. In recent years ultrasound has gained increased attention in preoperative staging of cervical cancer [9].

Aim

The objective was to study the tumour size, colour score and the possibly invasion of parametrium tissue, to predict the operability of cases with cervical carcinoma by 2D ultrasound examination. Precise tumour size evaluation is critical for determining the best course of therapy.

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In addition to being highly accurate, the ideal diagnostic method should also be fast, widely available, and inexpensive. Ultrasound examinations take less time, do not require any special preparation, and are cheaper and more widely available than MRI.

Methodology

The study group comprised 48 patients with histologically confirmed invasive carcinoma of the cervix. It was a prospective study and included patients diagnosed with invasive cervical cancer admitted in 1st Gynaecology Department Iaşi between 2017-2019. Assessment of these women was made by transvaginal transducer, approach which provided a better visualization of the cervical mass. Maximum cervical tumour length, antero-posterior diameter and width have been measured and tumour echogenicity was assessed in real-time 2D ultrasound examination. Intratumoral blood flow was subjectively evaluated by colour Doppler examination. Tumour extension to the parametrium was also evaluated. Sonographic findings suggestive for parametrial invasion during the 2D ultrasound examination are extension of the cervical tumour beyond the cervical stroma and the presence of hypoechoic irregular spiculae infiltrating the peri-cervical tissue.

Results

The median age of the patients was 53.2 years, ranging from 29 to 81 years. The largest number of cases was for group of age 56-65 years followed by group 46-55 years (Fig. 1).

No. cases 16 14 12 10 8

6

4

2 0 under 35 years 36-45 years 46-55 years 56-65 years over 65 years age Fig. 1. Distribution of cases by age

12 (25%) patients were diagnosed with IB stage (FIGO) cervical cancer and 36 (75%) with stage IIB or higher. Mean tumour dimensions for cases with stage IB variated between 9-38.66 mm and was greater for cases with endocervical tumours. Mean tumour dimensions for cases with stage IIB or higher was between 37.33-52.48 mm. At pathological exam 42 (87.5%) cases were squamous cell carcinoma (SCC) and 6 (12.5%) adenocarcinomas (AC). The surrounding cervical tissue with invasion usually had very scarce vascularization for squamous cell carcinoma. For adenocarcinoma we find an increased vascular score inside the tumour (fig. 2) and increased vascularization in the invasion zone (fig. 3) comparing with squamous cell carcinoma.

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Fig. 2. 66-years women with adenocarcinoma Fig. 3. Posterior invasion zone was confirmed with many vessels during surgery at the level of uterosacral ligaments

We illustrate a case with stage IIB – a tumour around 71 mm (cervical adenocarcinoma) which had a “splash” image during colour Doppler exam and vessels in the left parametrial invasion (fig. 4 a, b, c).

a b c Fig. 4. a) a big endocervical tumour, b) “splash” image in tumour, c) vessels in parametrial invasion

During ultrasound evaluation we must look very carefully after the posterior limit of the tumour regarding mesorectal (fig. 5). Colour Doppler examination helps us to identify this limit easier (fig. 6). We must always evaluate any region of interest with Doppler.

Fig. 5. Posterior limit of the tumour Fig. 6. Tumoral vessels don’t show rectal invasion

Agreement between ultrasound assessment of parametrial invasion and MRI in our study was good (sensitivity 76%; specificity 86%; agreement 85%). To illustrate this fact, we present a case of a 62-year-old woman with stage IIB established by ultrasonography with 100% agreement with

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MRI (table.1). Both methods show that the greatest dimension of tumour was around 4cm (fig. 7), and the upper limit was at isthmus (fig. 8, 10).

Table. 1 A case concordance between ultrasound exam and MRI Ultrasonography Magnetic resonance imaging Location cervical channel in the posterior part of the cervix Dimensions 23/39/27mm 33/42/23mm Upper limit superior limitation at isthmus superior limitation at isthmus Infiltration of parametrium left left Posterior contact with yes yes mesorectal fascia

Fig. 7. The greatest tumoral dimension and left Fig. 8. Ultrasound – tumoral upper limit and

parametrial spread – 2D ultrasound 2 mm distance to mesorectal fascia

Fig. 9. MRI – left parametrium invasion Fig. 10. MRI – tumoral upper limit

One month after radiotherapy the patient’s evaluation was made in both ways again. Clinical rectal exam revealed a cervical tumour about 2 cm, without infiltration around (uterosacral ligaments and parametrium). At ultrasound examination we found a 10/14.6/6.6mm tumour and a possible 5 mm infiltration in the left parametrium. MRI report described tumour after radiotherapy 25/21 mm. Final pathology of surgical specimen established posterior cervical wall tumour of 2 cm very well limitated, without infiltration in parametrium or lymph node metastases. Ultrasonography is a useful instrument for patients follow up. In this case, one year after surgical treatment we evaluated the vaginal cuff and it was normal. At other case we detected recurrence at the level of the vaginal cuff (fig. 11) and metastases in an external iliac lymph node (fig. 12).

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Fig. 11. Vaginal cuff recurrence Fig. 12. Pelvic lymph node metastases

Discussions

The most common type of cervical cancer is SCC, previously reported to account for 85% of the cases [10]. SCC can be categorized depending on invasiveness and grade of differentiation. The incidence of AC has shown an increase over the last three to four decades. In our study large portion of cervical cancers were squamous cell carcinomas too – 87.5%. Sonography was able to provide accurate measurements, characteristics of tissue appearance, and potential spread of the condition. Sonography typically shows a mass in the cervical region, usually with significant vascularity [11, 12]. We found similar aspects in cases from our study. Sonography, in combination with other imaging methods, has been shown to be an advantageous and favourable evaluation technique for analysis of ordinary and pathologic anatomy. Chiappa et al., believe that 2D and 3D ultrasound should be regarded as complementary techniques. While 2D dynamic ultrasound can be used to detect the presence of infiltration, 3D ultrasound volumes can be used to define more precisely the location and degree of tumour invasion in those cases for which tailored surgery is planned. The found agreement between 2D ultrasound and MRI was moderate (76%; kappa, 0.46) [13]. We didn’t used 3D analysis but our results regarding staging were good with agreement 85% between 2D ultrasound and MRI.

Conclusions

We found that colour Doppler is a very valuable sonographic technique in the assessment of cervical tumours, because the vast majority (95%) of such tumours are vascularized, which will make it easier to detect them and to determine their borders. Tumour vascularization is related to cervical tumour size. The results of this study, even if we have a small number of cases, demonstrate that transvaginal ultrasound, an inexpensive procedure, easily accepted by patients, could be carried out quickly and could be used to evaluate the local extension of cases with big cervical tumours and to monitor the effectiveness of cervical cancer treatment widely as alternative method to MRI. Of course, for a good evaluation of patients and increasing of our expertise we need for a while external auditing of ultrasonography performance by MRI.

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REFERENCES

[1] Sant M, Chirlaque Lopez MD, Agresti R, et al., (2015). Survival of women with cancers of breast and genital organs in Europe 1999-2007: results of the EUROCARE-5 study. Eur J Cancer 51, pp. 2191-2205. [2] Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. (2009). Cancer statistics. CA Cancer J Clin 59, pp. 225- 249. [3] Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F (1990). Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: A Gynaecologic Oncology Group study. Gynecol. Oncol 38, pp. 352-357. [4] Ferlay J, Colombet M, Soerjomataram I, et al., (2018). Cancer incidence and mortality patterns in Europe: estimates for 40 countries and 25 major cancers in 2018. Eur J Cancer 103, pp. 356-387. [5] Hoffman M S, Cardosi R J, Roberts, et al., (2004). Accuracy of pelvic examination in the assessment of patients with operable cervical cancer. Am J Obstet. Gynecol. 190, pp. 986-993. [6] Ramirez PT (2020). Quality indicators in cervical cancer surgery: a valiant step in the right direction. Int J Gynecol. Cancer 30, pp. 1-2. [7] Cibula D, Potter R, Planchamp F, et al., (2018). The European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology guidelines for the management of patients with cervical cancer. Int J Gynecol. Cancer 28, pp. 641-655. [8] Cibula D, Planchamp F, Fischerova D, et al., (2020). European Society of Gynaecological Oncology quality indicators for surgical treatment of cervical cancer. Int J Gynecol. Cancer 30, pp. 3-14. [9] Gaurilcikas A, Vaitkiene D, Cizauskas A, et al., (2011). Early-stage cervical cancer: agreement between ultrasound and histopathological findings with regard to tutor size and extent of local disease. Ultrasound Obstet. Gynecol. 38, pp. 707-715. [10] Thaxton L, Waxman AG (2015). Cervical cancer and prevention: immunization and screening. Med Clinics North Amer 99(3), pp. 469-477. [11] Alcazar JL, Castillo G, Jurado M, Lopez-Garcia G (2003). Intratumoral blood flow in cervical cancer as assessed by transvaginal colour Doppler ultrasonography: correlation with tumour characteristics. Intern J Gynecol. Cancer 13(4), pp. 510-514. [12] Chappell CE, Fisher K (2016). Sonographic Detection of Cervical Carcinoma with Metastases. Journal of Diagnostic Medical Sonography 32(2), pp. 117-124 [13] Chiappa V, Di Legge A, Valentini AL et al., (2015). Agreement of two-dimensional and three-dimensional transvaginal ultrasound with magnetic resonance imaging in assessment of parametrial infiltration in cervical cancer. Ultrasound Obstet. Gynecol. 45, pp. 459-469.

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Onco-fertility Outcomes After Fertility-Sparing Treatment and Factors that Predict Recurrence in Young Patients with Serous Borderline Ovarian Tumour

VLĂDĂREANU Radu1,2, BOIANGIU Andreea Grațiana1,2*, DUMITRASCU Mihai Cristian1,3, APOSTEANU Antonia2, TRĂISTARU Andrei Vlad1,2, VLĂDĂREANU Simona1,4

1 Carol Davila University of Medicine and Pharmacy, Bucharest, (ROMANIA) 2 Obstetrics and Gynaecology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) 3 Obstetrics and Gynaecology Department Emergency University Hospital, Bucharest, (ROMANIA) 4 Neonatology Department, University Emergency ELIAS Hospital, Bucharest, (ROMANIA) * Corresponding author: BOIANGIU Andreea Gratiana Email: [email protected]

Abstract

Fertility sparing surgery represents a challenging topic nowadays because epithelial ovarian cancer (EOC) continues to represent one of the most lethal conditions in women in western countries, and because more and more women are prioritizing their professional careers and are trending to extend the day of conception and expand childbirth towards higher ages. [1] The well- known consequence of cancer treatment has established a negative impact on the quality of life of cancer survivors due to infertility and premature menopause and so the field of onco-fertility generated a substantial part of gynaecologic oncology, making the treating physician both life- saver and protector-of-future fertility. [2]

Keywords: Fertility, pregnancy, cancer

Introduction

Serous borderline ovarian tumours (SBOTs) represent the most frequent histological subtype of borderline ovarian tumours and are more likely to be associated with: • bilateral tumours, • a micro-papillary pattern, • advanced FIGO stage, • peritoneal implants, • a high recurrence rates. Bilateral SBOTs are also widely reported to be associated with a higher frequency of surface involvement, the micro-papillary pattern and extra-ovarian implants, all of which adversely impact disease progression [3]. Over the last decade, fertility-sparing surgery (FSS) that preserves the uterus and at least part of the ovary has become the gold standard for women with borderline ovarian tumours who desire to maintain their fertility. [4, 5] Fertility-sparing approaches are becoming the standard management of young patients with unilateral SBOTs and other borderline histological subtypes.

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Current Indications for FSS Selecting optimal candidates for FSS is a tricky part, because the amount of evidence has been too small to accurately estimate the risk of leaving a microscopic tumour in the contralateral ovary, especially in high-grade disease with positive peritoneal cytology. [6] According to the 2007 guidelines of the American College of Obstetrics and Gynaecology (ACOG), fertility-sparing surgery for reproductive-age patients with invasive EOC is recommended for highly or moderately differentiated stage IA disease with non-clear-cell histology [7]. Authors identified stage Ia EOC patients with favourable histology, that is, mucinous, serous, endometrioid, or mixed histology and grade 1 or 2, as the optimal candidates to safely undergo fertility-sparing surgery even without a mandatory subsequent platinum-based adjuvant chemotherapy. [8]

Optimal candidates for FSS • highly or moderately differentiated stage IA disease, • non-clear-cell histology, • unilateral stage I tumour, • without dense adhesions.

SBOT’S treatment Fertility spearing surgery involves preserving the uterus and at least partially an ovary. The treatment for serous borderline ovarian tumours (SBOTs) include: 1. FSS with BOC (bilateral ovarian cystectomy); 2. FSS with UAC (unilateral anexectomy with contralateral cystectomy); 3. Radical surgery, including bilateral anexectomy with or without hysterectomy. Complete peritoneal surgical staging was considered when all peritoneal surfaces were carefully explored by cytology, multiple random or targeted biopsies, and omentectomy. [9] Lymph node dissection is not mandatory because there is no evidence to support this procedure in borderline ovarian tumours [10]. Adjuvant chemotherapy was offered based on the pathological findings of the surgical sample. The follow-up of the patient consisted of physical and gynaecological examinations, determination of CA-125 and an ultrasound every 3 months during the first year after surgery, every 6 months for 2 years and then yearly subsequent.

Recurrence

Study involving 127 patients with bilateral SBOTs were identified and 33 patients were excluded due to older age (n=28) or insufficient follow-up data remaining 94 patients for further analysis, from which: • 15 women underwent radical surgery during their treatment (16%) • 79 patients (84.0%) had a fertility-sparing procedure, with a - BOC (48 patients) 51% - UAC (31 patients) 33% Regarding pathological features, 63 (67%) women had micro-papillary patterns, and nearly half of the patients (n=46, 49%) had extra-ovarian implants, including invasive and non-invasive implants in 10 (11%) and 36 (38%) of affected patients, respectively.

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During a medium follow-up of 5 years that consisted in both physical and gynaecological examinations, determination of CA-125 and an ultrasound every 3 months in the first year after surgery, every 6 months for 2 years and then annually thereafter, (65%) patients developed primary relapse of borderline or invasive disease accordingly: • (20%) of patients that had radical surgery, • (84%) of patients that had unilateral anexectomy with contralateral cystectomy (UAC), • (67%) of patients that had bilateral ovarian cystectomy (BOC). Concerning the patients who underwent FSS procedures, approx. 75% experienced recurrence. The 5-year disease-free survival (DFS) rate of patients who underwent BOC was 14%, compared with 35% in patients with UAC. Additionally, more than three quarters patients had been treated conservatively for their primary relapses, from which more than half patients had a further recurrence after conservative treatment of their first relapse, and a quarter of them suffered a third recurrence. Notably, subjects from the UAC group had a significantly higher need of radical intervention for recurrence than the BOC group (65 versus 28%).

Factors that predict recurrence

Most studies involve the following factors that contribute to relapse and to a significantly poorer prognosis for SBOT progression [11, 12, 13] • younger age at diagnosis, • patients aged <30 years, • patients with a preoperative CA-125 >300 U/mL, • patients with SBOT-MPs (micro-papillary pattern), • bilateral involvement, • FSS procedure, • incomplete staging, • tumour residuals, • extra-ovarian implants.

Reproductive Outcomes after Fertility-Sparing Surgery in EOC

Data regarding reproductive outcome after FSS in EOC are summarized from a study that included: • 440 patients, with a mean age of 28 years old, • FIGO stages IA-IC, • Successful conception- 127 patients (29%). Literature data concerning the rate of women with successful conception after FSS accounts approximately 30% of all patients, but if we take into consideration only the women with childbearing wish who actively tried to conceive, then rates of successful conception are substantially higher, range from 66% to 100%, indicating that no relevant reproductive impairment exists after FSS. [14, 15, 16, 17,18, 19]

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Regarding the FSS in women with SBOT’s

Among the 79 women who underwent FSS procedures, 10 patients (13%) were diagnosed as infertile before their ovarian tumours, and 49 patients (62%) attempted to conceive after surgery. During the median follow-up of 85 months (range, 18-243 months), 23 patients (47%) obtained 27 pregnancies (24 spontaneous and 3 after IVF-ET), resulting in 19 live births.

Future Perspectives

The onco-gynaecologist is in a unique position to provide young cancer patients with up-to- date fertility preservation information and fertility-sparing surgical alternatives [2]. However, even after FSS, many young patients fail to fulfil their childbearing wish, due to various reasons, such as early relapse in the remaining ovarian tissue or due to diminished ovarian reserve. Additional techniques like cryopreservation of ovarian tissue, oocytes, or even embryos are called to offer an additional safety option to young women. [20]

Conclusion

The objective of our article was to establish the feasibility of fertility preservation in young women with bilateral SBOTs, as well as their oncological and reproductive outcomes, based on extensive mainly retrospective studies series worldwide. Comparing the FSS procedures, the ultra-conservative BOC approach was more effective than the standard UAC approach in terms of reproductive outcomes. In conclusion, FSS is feasible for young women with BiSBOT’s who desire fertility, with an acceptable oncological outcome and meaningful rates of pregnancy. The ultraconservative BOC procedure should be proposed when technically feasible. FSS in early-stage of epithelial ovarian cancer (EOC) appears an absolutely viable and safe option for women younger than 40 years who wish to preserve their childbearing potential after careful consideration of histologic subtypes. The optimal indication is referring to stage Ia G1/G2 disease, as well as stage Ic with favourable, that is, non-clear-cell histology.

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