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Abstract Background The European Reference Network for rare Inherited Congenital Anomalies, ERNICA, guidelines for gastroschisis cover perinatal period to help teams to improve care. Method A systematic literature search including 136 publications was conducted. Research findings were assessed following the GRADE methodology. The evidence to decision framework was used to determine the strength and direction of recommendations. Results The mode or timing of delivery do not impact neonatal mortality, risk of NEC or time on parenteral nutrition (PN). Intra or extra abdominal bowel dilatation predict complex gastroschisis and longer length of hospital stay but not increased perinatal mortality. Outcomes after Bianchi procedure and primary fascia closure under anesthesia are similar. Sutureless closure decreases the rate of surgical site infections and duration of ventilation compared to surgical closure. Silo-staged closure with or without intubation results in similar outcomes. Outcomes of complex gastroschisis (CG) undergoing early or delayed surgical repair are similar. Early enteral feeds starting within 14 days is associated with lower risk of surgical site infection. Recommendations The panel suggests vaginal birth between 37 and 39 w in cases of uncomplicated gastroschisis. Bianchi’s approach is an option in simple gastroschisis. Sutureless closure is suggested when general anesthesia can be avoided, sutured closure. If anesthesia is required. Silo treatment without ventilation and general anesthesia can be considered. In CG with atresia primary intestinal repair can be attempted if the condition of patient and intestine allows. Enteral feeds for simple gastroschisis should start within 14 days.

Pregnancy is a state of multiple physiological adaptations. Since methylation of DNA is an epigenetic mechanism that regulates gene expression and contributes to adaptive phenotypic variations, we investigated methylation changes in maternal blood of a longitudinal cohort of pregnant women from the first trimester of gestation to the third. Interestingly, during pregnancy, we found a gain of methylation in genes involved in morphogenesis, such as ezrin, while we identified a loss of methylation in genes promoting maternal-infant bonding (AVP and PPP1R1B). Together, our results provide insights into the biological mechanisms underlying physiological adaptations during pregnancy.

Abstract Background Pregnancy and breastfeeding are associated with bone density loss. Fracture occurrence during pregnancy and post-partum, and its determinants, remain poorly known in Osteogenesis Imperfecta (OI). The aim of this study was to characterize fractures that occurred during pregnancy and post-partum in OI patients. Results We conducted a retrospective multicentric study including a total of 50 previously pregnant OI women from 10 Bone Centers in France. Among these patients, 12 (24%) patients experienced fractures during pregnancy or in the 6 months following delivery, and 38 (76%) did not experience any fracture. The most frequent localizations were: proximal femur (25%), spine (25%), distal femur (12.5%), and pelvis (12.5%). Fractures during pregnancy occurred during the third trimester and post-partum fractures occurred with a mean delay of 2 months following delivery. No fractures occurred during childbirth. We next compared the 12 patients with pregnancy or post-partum fractures with the 38 patients without fractures. Mean age at pregnancy was 32.7 ± 3.1 years-old in the fractured group, vs 29.3 ± 5.0 years-old in the non-fractured group (p = 0.002). Breastfeeding was reported in 85.7% of patients in the fractured group, vs 47.1% in the non-fractured group (p = 0.03). All patients with post-partum fractures were breastfeeding. Bone mineral density was significantly lower in patients with pregnancy-related fractures compared with other patients: spine Z-score − 2.9 ± 1.6DS vs − 1.5 ± 1.7DS (p = 0.03), and total hip Z-score − 2.0 ± 0.7DS vs − 0.5 ± 1.4DS (p = 0.04). At least one osteoporosis-inducing risk factor or disease other than OI was identified in 81.8% vs 58.6% of fractured vs non-fractured patients (not significant). Fracture during pregnancy or post-partum was not associated with the severity of OI. Bisphosphonates before pregnancy were reported in 16.7% and 21.1% of patients with pregnancy-related fractures and non-fractured patients, respectively (not significant). Conclusions OI management during pregnancy and post-partum should aim for optimal control of modifiable osteoporosis risk factors, particularly in patients with low BMD. Breastfeeding should be avoided.

Previous pandemics and related lockdowns have had a deleterious impact on pregnant women's mental health. We studied the impact of the SARS-CoV-2/Covid-19 pandemic and France's first lockdown on pregnant women's mental health. A cross-sectional study was conducted in July 2020 using a web-questionnaire completed by 500 adult women who were pregnant during the first lockdown in France (March-May 2020). Questions focused on their self-perceived psychological state and affects they felt before and during the lockdown and anxiety symptomatology (HAD) two months after it ended. A robust variance Poisson regression model was used to estimate adjusted prevalence ratios (aPR) for anxiety and self-perceived psychological state evolution. One in five respondents (21.1%) reported psychological deterioration during lockdown. Associated determinants were: i) little or no social support (self-perceived) (aRP = 1.77, 95%CI[1.18-2.66]), ii) increased workload (1.65, [1.02-2.66]), and iii) poor/moderate knowledge about SARS-CoV-2 transmission (1.60, [1.09-2.35]). Seven percent of women reporting psychological deterioration had access to professional psychological support during lockdown, while 19% did not despite wanting it. Women reported heightened powerlessness (60.3%), frustration (64%) and fear (59.2%) during lockdown. One in seven respondents (14.2%, 95%CI[10.9-18.2]) had anxiety symptoms. Determinants associated: i) at least one pregnancy-related pathology (aPR = 1.82, 95%CI[1.15-2.88]), ii) overweightness or obesity (1.61, [1.07-2.43]), iii) one child under the age of six years in the household during the lockdown (3.26, [1.24-8.53]), iv) little or no social support (self-perceived) during the lockdown (1.66, [1.07-2.58]), v) friend or relatives diagnosed with Covid-19 or with symptoms of the disease (1.66; [1.06-2.60]), vi) no access to medication for psychological distress (2.86, [1.74-4.71]), and vii) unsuccessfully seeking exchanges with healthcare professionals about their pregnancy during the pandemic (1.66, [1.08-2.55]). Our results can guide prevention and support policies for pregnant women during pandemics, current or future, with or without lockdowns. Preventing perinatal mental health problems is essential to ensure a supportive environment for the child's development.

IntroductionOne of the drawbacks of fetoscopic endoluminal tracheal occlusion (FETO) for congenital diaphragmatic hernia is the need for a second invasive intervention to reestablish airway patency. The "Smart-TO" (Strasbourg University-BSMTI, France) is a new balloon for FETO, which spontaneously deflates when positioned near a strong magnetic field, e.g., generated by a magnetic resonance image (MRI) scanner. Translational experiments have demonstrated its efficacy and safety. We will now use the Smart-TO balloon for the first time in humans. Our main objective is to evaluate the effectiveness of prenatal deflation of the balloon by the magnetic field generated by an MRI scanner.Material and methodsThese studies were first in human (patients) trials conducted in the fetal medicine units of Antoine-Béclère Hospital, France, and UZ Leuven, Belgium. Conceived in parallel, protocols were amended by the local Ethics Committees, resulting in some minor differences. These trials were single-arm interventional feasibility studies. Twenty (France) and 25 (Belgium) participants will have FETO with the Smart-TO balloon. Balloon deflation will be scheduled at 34 weeks or earlier if clinically required. The primary endpoint is the successful deflation of the Smart-TO balloon after exposure to the magnetic field of an MRI. The secondary objective is to report on the safety of the balloon. The percentage of fetuses in whom the balloon is deflated after exposure will be calculated with its 95% confidence interval. Safety will be evaluated by reporting the nature, number, and percentage of serious unexpected or adverse reactions.ConclusionThese first in human (patients) trials may provide the first evidence of the potential to reverse the occlusion by Smart-TO and free the airways non-invasively, as well a safety data.

Abstract Background In the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, consultations and pregnancy monitoring examinations had to be reorganised urgently. In addition, women themselves may have postponed or cancelled their medical monitoring for organisational reasons, for fear of contracting the disease caused by SARS-CoV-2 (COVID-19) or for other reasons of their own. Delayed care can have deleterious consequences for both the mother and the child. Our objective was therefore to study the impact of the SARS-CoV-2 pandemic and the first lockdown in France on voluntary changes by pregnant women in the medical monitoring of their pregnancy and the associated factors. Methods A cross-sectional study was conducted in July 2020 using a web-questionnaire completed by 500 adult (> 18 years old) pregnant women during the first French lockdown (March–May 2020). A robust variance Poisson regression model was used to estimate adjusted prevalence ratios (aPRs). Results Almost one women of five (23.4%) reported having voluntarily postponed or foregone at least one consultation or pregnancy check-up during the lockdown. Women who were professionally inactive (aPR = 1.98, CI95%[1.24–3.16]), who had experienced serious disputes or violence during the lockdown (1.47, [1.00–2.16]), who felt they received little or no support (1.71, [1.07–2.71]), and those who changed health professionals during the lockdown (1.57, [1.04–2.36]) were all more likely to have voluntarily changed their pregnancy monitoring. Higher level of worry about the pandemic was associated with a lower probability of voluntarily changing pregnancy monitoring (0.66, [0.46–0.96]). Conclusions Our results can guide prevention and support policies for pregnant women in the current and future pandemics.

Abstract Background Pregnancies in women over 35 years of age are becoming more frequent. The majority of studies point to an age of 35 as a provider of obstetric and neonatal complications. But several confounding factors are not taken into account and this results in contradictory results. Methods The objective was to quantify the strength of the association between maternal age and obstetric and neonatal morbidity. This observational study was based on systematic records of 9 years of pregnancies managed in the Obstetrics and Gynaecology Department of Antoine Béclère Hospital, Clamart, France. In all, 24,674 pregnancies were managed at Antoine Béclère Hospital between April 1, 2007 and December 31, 2015, including 23,291 singleton pregnancies. Maternal age was the age at the beginning of pregnancy, taken as a quantitative variable. The main outcome measure was a composite “unfavourable” pregnancy outcome that included miscarriage, induced abortion, in utero foetal death, stillborn or newborn infant weighing under 500 g or delivered before 24 weeks of gestational age. Obstetric and neonatal morbidity comprised hospitalisation during pregnancy for more than 1 day, pre-eclampsia, gestational diabetes requiring hospitalisation, caesarean delivery, preterm birth, small-for-gestational age, and newborn transfer to the paediatric unit or neonatal intensive care unit. Results Analyses were conducted among singleton pregnancies (n = 23,291) and were adjusted for obesity, assisted reproductive technology and geographical origin of the mother. Unfavourable pregnancy outcome rate tripled with age, from 5% among women aged 25 to 34 to 16% among those over 45. Women over 40 were twice as likely to be hospitalised as those aged 25 to 34. The caesarean section rate reached more than 40% among women over 40 and more than 60% in women over 45. The rate of newborn transfer to paediatric intensive care or a neonatal intensive care unit was doubled in women over 40 and small-for-gestational age was more frequent with age, reaching 34% in women over 45. Conclusions The risk of maternal-foetal complications increases steadily with age and is particularly high after 35 years and closer monitoring appears to be necessary. These results provide additional evidence and information for public health decision-makers.

In 2020, a new coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in China. SARS-CoV-2 infection has been shown to be highly morbid in pregnant women, being a risk factor for several obstetric conditions leading to increased maternal and neonatal mortality. A few studies since 2020 have shown SARS-CoV-2 maternal–fetal transmission and noted placental abnormalities grouped under the term placentitis. We hypothesized that these placental lesions could be responsible for abnormalities in placental exchange and therefore abnormalities in cardiotocographic monitoring, leading to premature fetal extraction. The objective is to identify the clinical, biochemical, and histological determinants associated with the occurrence of non-reassuring fetal heart rate (NRFHR) outside labor in fetuses of SARS-CoV-2-infected mothers. We conducted a retrospective multicenter case series of the natural history of maternal SARS-CoV-2 infections resulting in fetal delivery outside labor due to NRFHR. Collaboration was sought with the maternity hospitals in the CEGORIF, the APHP and Brussels hospitals. The investigators were contacted by e-mail on three successive occasions over a period of one year. Data from 17 mothers and 17 fetuses were analyzed. Most women had a mild SARS-CoV-2 infection; only two women presented severe infection. No woman was vaccinated. We found a substantial proportion of maternal coagulopathy at birth: elevation of APTT ratio (62%), thrombocytopenia (41%) and liver cytolysis (58.3%). Iatrogenic prematurity was noted in 15 of 17 fetuses, and 100% were born by cesarean delivery due to emergency criteria. One male neonate died on the day of birth due to peripartum asphyxia. Three cases of maternal–fetal transmission were recorded following WHO criteria. Placental analysis in 15 cases revealed eight cases of SARS-CoV-2 placentitis, causing placental insufficiency. In total, 100% of the placentas analyzed showed at least one lesion suggestive of placentitis. SARS-CoV-2 maternal infection during pregnancy is likely to generate neonatal morbidity in relation to placental damage resulting in placental insufficiency. This morbidity may be the consequence of induced prematurity as well as acidosis in the most severe situations. Placental damage occurred in unvaccinated women and in women with no identified risk factor, in contrast to severe maternal clinical forms.

Abstract Background Congenital diaphragmatic hernia (CDH) is, depending of the severity, a birth defect associated with significant mortality and morbidity. Prenatal screening by ultrasound may detect this condition and comprehensive assessment of severity is possible, allowing for in utero referral to an experienced centre for planned delivery. In an effort to improve outcomes, prenatal interventions to stimulate lung development were proposed. Along the same lines, new postnatal management strategies are being developed. In order to enable proper comparison of novel perinatal interventions as well as outcomes, a set of uniform and relevant outcome measures is required. Core outcome sets (COS) are agreed, clearly defined sets of outcomes to be measured in a standardised manner and reported consistently. Herein we aim to describe the methodology we will use to define a COS for perinatal and neonatal outcomes of foetuses and newborns with congenital diaphragmatic hernia and to draft a dissemination and implementation plan. Methods We will use the methodology described in the Core Outcome Measures in Effectiveness Trials (COMET) Initiative Handbook. An international steering group will be created to guide the development of the COS. We are systematically reviewing the literature to identify all potential relevant pre- and neonatal outcomes previously used in studies on perinatal interventions for CDH. We will build a consensus on these core outcomes in a stakeholder group using the Delphi method. After completion, a stakeholder meeting will decide on a final COS, using a modified Nominal Group Technique. Thereafter, we will review potential definitions and measurements of these outcomes, and again a consensus meeting will be organised, to finalise the COS before dissemination. Discussion We have started a procedure to develop a COS for studies on perinatal interventions for congenital diaphragmatic hernia, with the purpose of improving the quality of research, guide clinical practice and improve patient care and eventual use in future clinical trials, systematic reviews and clinical practice guidelines. Trial registration We prospectively registered this study in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42019124399 ) and The Core Outcome Measures in Effectiveness Trials (COMET) Initiative (registration number: 1296 ).

There are a growing number of reports of neonatal SARS-CoV-2 infections. Here, De Luca and colleagues systematically analyse 176 published cases to better understand the route of transmission, as well as the clinical features and outcomes of neonatal COVID-19.

Résumé Contexte La mise en évidence d’une mosaïque germinale est. un événement rare mais probablement sous-estimé du fait de l’accès limité aux cellules germinales. Les variations génomiques caractéristiques de ce phénomène peuvent être des single nucleotide polymorphismes (SNPs), des copy number variations (CNVs) ou des aneuploïdies. Dans le cas des CNVs, les délétions sont plus fréquentes dans la lignée germinale paternelle tandis que les duplications sont plus fréquemment d’origine maternelle. Le risque de mosaïcisme germinal augmente avec l’âge paternel de part une augmentation du risque de SNPs associée à la division constante des cellules germinales pendant toute la vie d’un homme. Nous rapportons ici un cas de mosaïque germinale chez un donneur de spermatozoïdes ayant entraîné la survenue d’une grossesse pathologique. Résultats Les paillettes d’un même donneur de spermatozoïdes ont été attribuées à sept couples receveurs permettant l’obtention de quatre grossesses évolutives. Pour l’une d’entre elle, l’échographie du deuxième trimestre a permis d’identifier chez le fœtus des pieds bots associés à un retard de croissance intra utérin. L’analyse par hybridation génomique comparative (CGH)-array après amniocentèse a révélé une délétion de 4 MB dans la région 7q32.1q33. Les caryotypes sanguins et les analyses par CGH-array étaient normaux chez la mère et le donneur. Cependant les profils de microsatellites ont montré une origine paternelle du chromosome délété. Une analyse par fluorescent in situ hybridization (FISH) des spermatozoïdes du donneur a révélé la présence de la même délétion dans 12% des spermatozoïdes étudiés. Etant donné le risque de retard mental associé à des remaniements chromosomiques dans cette même région, le couple a préféré interrompre la grossesse. Une amniocentèse a été réalisée pour les autres grossesse en cours et n’a retrouvé aucune anomalie. Conclusions Plusieurs cas de mosaïques germinales ont été rapportés mais leur fréquence réelle reste probablement sous-estimée. En effet, un mosaïcisme germinal ne peut être détecté par les techniques de cytogénétique conventionnelle sur sang. Ce cas illustre la nécessité d’un suivi en temps réel des grossesses obtenues par don de spermatozoïdes étant donné que la survenue d’une grossesse pathologique peut avoir un retentissement sur les autres grossesses issues du même donneur.

Fix data are available on the management of pregnant women infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We conducted a retrospective study of 100 pregnant women with SARS-CoV-2 infection in 4 obstetric units in the Paris metropolitan area of France during March 12–April 13, 2020. Among patients, 52 (52%) were hospitalized, 10 (10%) in intensive care units (ICUs). Women with higher body mass indexes (BMIs; median 30.7 kg/m2) were more likely to be hospitalized in ICUs than other women (median BMI 26.2 kg/m2). Women hospitalized in ICUs had lower lymphocyte count at diagnosis (median 0.77 × 109 cells/L) than women not hospitalized in ICUs (median lymphocyte count 1.15 × 109 cells/L). All women requiring oxygen >5 L/min were intubated. Clinical and laboratory evaluation of SARS-CoV–2−positive pregnant women at the time of diagnosis can identify patients at risk for ICU hospitalization.

Congenital infection of SARS-CoV-2 has been described, but the transmission routes remain unclear. Here, the authors report evidence of transplacental transmission of SARS-CoV-2 in a neonate born to a mother infected in the last trimester and presenting with neurological compromise.

IntroductionPregnant women are at increased risk for COVID-19, and COVID-19 vaccine is the most promising solution to overcome the current pandemic. This study was conducted to evaluate pregnant women's perceptions and acceptance of COVID-19 vaccination.Materials & methodsA cross-sectional study was conducted from February 18 to April 5 2021. An anonymous survey was distributed in 7 French obstetrics departments to all pregnant women before a prenatal visit. All pregnant women attending a follow-up consultation were asked to participate in the study. An anonymous web survey was available through a QR code and participants were asked whether or not they would agree to be vaccinated against SARS-CoV-2, and why. The questionnaire included questions on the patients' demographics and their knowledge of COVID-19 vaccines.ResultsOf the 664 pregnant women who completed the questionnaire, 29.5% (95% CI 27.7; 31.3) indicated they would agree to be vaccinated against COVID-19. The main reason for not agreeing was being more afraid of potential side effects of the SARS-CoV-2 vaccine on the fetus than of COVID-19. Factors influencing acceptance of vaccination were: being slightly older, multiparity, having discussed it with a caregiver and acceptance of the influenza vaccine.DiscussionNearly one-third of pregnant women in this population would be willing to be vaccinated. In addition to studies establishing fetal safety, public health agencies and healthcare professionals should provide accurate information about the safety of COVID-19 vaccines.

During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic lockdown, communication between pregnant women and health professionals may have become complicated due to restrictions on movement and saturated health services. This could have impacts on pregnancy monitoring and women's wellbeing. We aimed to i) describe the unmet need of pregnant women living in France to communicate with health professionals about the pandemic and their pregnancy during the lockdown, ii) assess the socio-demographic, medical and contextual factors associated with this unmet need. The Covimater cross-sectional study, conducted in July 2020, includes data on 500 adult women's experiences of pregnancy during the first lockdown period in France (i.e., from March to May 2020). The women, all residents in metropolitan France, answered a web-based questionnaire about their conversations with health professionals during the lockdown, as well as their social and medical characteristics. A robust variance Poisson regression model was used to estimate crude or adjusted prevalence ratios (aPRs) for their unmet need to communicate with health professionals about the pandemic and their pregnancy. Forty-one percent of participants reported an unmet need to communicate with a health professional during the lockdown, mainly about the risk of transmitting SARS-CoV-2 to their baby and the consequences for the latter. Factors associated were: i) being professionally inactive (aPR = 1.58,CI95%[(1.14-2.21]), ii) having an educational level below secondary school diploma (1.38,[1.05,-1.81]), iii) having experienced serious arguments/violence (2.12,[1.28-3.52]), iv) being very worried about the pandemic (1.41,[1.11-1.78]), v) being primiparous (1.36,[1.06-1.74]) and vi) having had pregnancy consultations postponed/cancelled by health professionals during the lockdown (1.35,[1.06-1.73]). These results can be used to develop targeted strategies that ensure pregnant women are able to i) communicate with health professionals about the potential impact of the SARS-CoV-2 pandemic on their pregnancy, and ii) access up-to-date and reliable information on the consequences of SARS-CoV-2 for themselves and their child.

Abstract Background The observed rate of termination of pregnancy (TOP) for Turner syndrome varies worldwide and even within countries. In this vignette study we quantified agreement among ten multidisciplinary prenatal diagnosis centers in Paris. Methods We submitted online three cases of Turner syndrome (increased nuchal translucency, normal ultrasound, aortic coarctation) to fetal medicine experts: one obstetrician, one pediatrician and one geneticist in each of the ten Parisian centers. Each case was presented in the form of a progressive clinical history with conditional links dependent upon responses. The background to each case was provided, along with the medical history of the parents and the counseling they got from medical staff. The experts indicated online whether or not they would accept the parents’ request for TOP. We assessed the percentage of agreement for acceptance or refusal of TOP. We also used a multilevel logistic regression model to evaluate differences among obstetrician-gynecologists, pediatricians and cytogeneticists. Results Overall agreement among the experts to accept or refuse TOP was, respectively, 25 and 28%. The percentage of disagreement was 47%. The percentage of agreement to accept TOP was 33, 8 and 33% for obstetrician-gynecologists, pediatricians and cytogeneticists, respectively. The respective percentages of agreement to refuse TOP were 19, 47 and 26%. Conclusion Our results show the lack of consensus with regard to decisions related to termination of pregnancy for Turner Syndrome. This lack of consensus in turn underscores the importance of multidisciplinary management of these pregnancies in specialized fetal medicine centers.

Abstract Background Patients with atypical values of HCG and/or PAPP-A are at higher risk of chromosomal abnormality and vascular complications of pregnancy. The performance of cfDNA in this particular population has not yet been evaluated. Objectives The primary objective was to evaluate the usefulness and reliability of cfDNA in screening for trisomy 21, 18 and 13 for patients with HCG 5.0 MoM and/or PAPP-A 2.5 MoM. The secondary objective was to evaluate the contribution of cfDNA assay for the prediction of pregnancy’s vascular complications. Method Between June 2016 and July 2017, we analysed a women cohort from all over France who had at least one first trimester serum biomarker outside of normal range, in a retrospective, observational and multicentre study. Patients were included if they had a single pregnancy, normal first trimester ultrasound examination, whatever the result of the combined first trimester screening test was. The cfDNA was analysed by massive parallel sequencing technique. The accuracy of cfDNA assay was evaluated by calculation of sensitivity and specificity, and multivariate regression analysis was used to search for predictive factors for pregnancy’s vascular complications. Results Among the 498 patients who underwent a cfDNA assay in this context, twenty-one (4.2%) were excluded because of loss to follow-up. Out of 477, test failure occurred for four patients initially, reduced to two patients (0.4%) after redrawn. CfDNA was positive for Trisomy 21 (n = 19), Trisomy 18 (n = 6) and Trisomy 13 (n = 1) and negative in 449. The sensitivity of cfDNA assay for trisomy 21 screening was 100% (19/19) (IC 95% 82.4–100) and specificity 100% (458/458) (IC 95% 99.2–100). Among the 447 patients included for prediction of vascular complications, there were four cases of pregnancy induced hypertension and 10 cases of preeclampsia, for which no predictive factor was identified. Intra Uterine growth restriction under 5th percentile (n = 44, 9.8%) was significantly associated with a low fetal fraction (OR = 0.87, IC 95% 0.79–0.96, p = 0.006). Conclusion cfDNA assay is an effective and reliable tool for women with atypical profile of first trimester serum biomarkers.

Abstract Background It is not known if the endogenous surfactant pool available early in life is associated with the RDS clinical course in preterm neonates treated with CPAP. We aim to clarify the clinical factors affecting surfactant pool in preterm neonates and study its association with CPAP failure. Methods Prospective, pragmatic, blind, cohort study. Gastric aspirates were obtained (within the first 6 h of life and before the first feeding) from 125 preterm neonates with RDS. Surfactant pool was measured by postnatal automated lamellar body count based on impedancemetry, without any pre-analytical treatment. A formal respiratory care protocol based on European guidelines was applied. Clinical data and perinatal risk factors influencing RDS severity or lamellar body count were real-time recorded. Investigators performing lamellar body count were blind to the clinical data and LBC was not used in clinical practice. Results Multivariate analysis showed gestational age to be the only factor significantly associated with lamellar body count (standardized β:0.233;p = 0.023). Lamellar body count was significantly higher in neonates with CPAP success (43.500 [23.750–93.750]bodies/μL), than in those failing CPAP (20.500 [12.250–49.750] bodies/μL;p = 0.0003).LBC had a moderate reliability to detect CPAP failure (AUC: 0.703 (0.615–0.781);p

Congenital diaphragmatic hernia (CDH) is associated with abnormal pulmonary development, which is responsible for pulmonary hypoplasia with structural and functional abnormalities in pulmonary circulation, leading to the failure of the cardiorespiratory adaptation at birth. Despite improvement in treatment options and advances in neonatal care, mortality remains high, at close to 15 to 30%. Several risk factors of mortality and morbidities have been validated in fetuses with CDH. Antenatal assessment of lung volume is a reliable way to predict the severity of CDH. The two most commonly used measurements are the observed/expected lung to head ratio (LHRo/e) and the total pulmonary volume (TPV) on MRI. The estimation of total pulmonary volume (TPVo/e) by means of prenatal MRI remains the gold standard. In addition to LHR and TPV measurements, the position of the liver (up, in the thorax or down, in the abdomen) also plays a role in the prognostic evaluation. This prenatal prognostic evaluation can be used to select fetuses for antenatal surgery, consisting of fetoscopic endoluminal tracheal occlusion (FETO). The antenatal criteria of severe CDH with an ascended liver (LHRo/e or TPVo/e < 25%) are undoubtedly associated with a high risk of death or significant morbidity. However, despite the possibility of estimating the risk in antenatal care, it is difficult to determine what is in the child’s best interest, as there still are many uncertainties: (1) uncertainty about individual short-term prognosis; (2) uncertainty about long-term prognosis; and (3) uncertainty about the subsequent quality of life, especially when it is known that, with a similar degree of disability, a child’s quality of life varies from poor to good depending on multiple factors, including family support. Nevertheless, as the LHR decreases, the foreseeable “burden” becomes increasingly significant, and the expected benefit is increasingly unlikely. The legal and moral principle of the proportionality of medical procedures, as well as the prohibition of “unreasonable obstinacy” in all investigations or treatments undertaken, is necessary in these situations. However, the scientific and rational basis for assessing the long-term individual prognosis is limited to statistical data that do not adequately reflect individual risk. The risk of self-fulfilling prophecies should be kept in mind. The information given to parents must take this uncertainty into account when deciding on the treatment plan after birth.

Abstract Background Recent studies have suggested a possible association between heparin treatment at the time of cell-free DNA (cfDNA) testing and a non-reportable result. However, these studies lack of proper methodology and had a low level of proof to firmly incriminate heparin. Our objective was to investigate further the relationship between heparin treatment and cfDNA test results. Methods Two complementary approaches were used for the demonstration. First, we conducted a retrospective analysis of a cohort of patients with a singleton pregnancy, screened for aneuploidies by using cfDNA, but with a non-reportable cfDNA result. We included patients between 2013 and 2016 including the patients from the DEPOSA study as controls. CfDNA testing was performed by massive parallel sequencing by using a whole-genome approach. A multiple logistic regression was used to account for the influence of the variables included. Second, we performed in vitro experiments on mimic samples containing increased concentrations of heparin. Results Of 9867 singleton pregnancies tested during the inclusion period, 58 (0.59%) had a non-reportable result and were compared to 295 control patients. Fifteen (25.9%) and 20 (6.8%) patients were treated with heparin in the group with a non-reportable cfDNA result and with a successful assay, respectively. In multivariable analysis, an increased calculated risk at the first-trimester combined screening (OR 28.8 CI 9.76–85.15, p

[This corrects the article DOI: 10.1371/journal.pmed.1002220.].

ObjectiveTo compare maternal complications and describe neonatal outcomes in women with severe preeclampsia at ≤ 26+0 weeks in two countries with different management policies: expectant management (Brazil) versus termination of pregnancy (France).MethodsWe conducted a retrospective comparative study by reviewing the medical records of women with severe preeclampsia at ≤ 26+0 weeks, from January 2010 to June 2018, in two centers: Hospital das Clínicas da Faculdade de Medicina, in Sao Paulo, Brazil (where medical abortion is forbidden in this indication) and Hôpital Antoine-Béclère, Clamart, France (where medical termination is accepted). We collected information on maternal characteristics, laboratory tests, maternal complications and fetal and newborn characteristics. We used Student's t-test and the Mann-Whitney U nonparametric test to compare quantitative variables, and Chi-square test or Fisher's exact test to evaluate the associations between the qualitative variables.ResultsThere was no between-group difference in maternal complications during hospitalization (p = 0.846). In Brazil, the rate of cesarean section was 66.7%, and 20% of patients had vertical incision. The rate of spontaneous fetal death was 35.6% and among the live-born infants 26.6% were discharged from hospital. In France, one patient had a cesarean section with vertical incision.ConclusionWhen comparing termination of pregnancy to expectant management in severe preeclampsia before 26 weeks, maternal complications were equivalent but maternal reproductive future might have been compromised in 20% of cases due to a higher risk of uterine rupture in subsequent pregnancies for patients having classic cesarean (vertical incision). 26.6% of children survived the neonatal period when pregnancy was pursued, however we lack information on their long-term follow-up.

BackgroundPrenatal care providers will play an important role in the acceptance of SARS-Cov-2 vaccination for pregnant women.ObjectiveTo determine the perceptions of French prenatal care providers: midwives, general practitioners (GPs) and obstetricians and gynaecologists (Ob-Gyn) regarding SARS-CoV-2 vaccination during pregnancy.Study designAn anonymous online survey was sent to members of French professional societies representing prenatal practitioners. The participants were asked to answer questions on their characteristics and give their opinions of the SARS-CoV-2 vaccine for themselves and women who are pregnant or willing to become pregnant.ResultsAccess to the survey was opened from January 11th, 2021, to March 1st, 2021. A total of 1,416 responses were collected from 749 Ob-Gyn, 598 midwives and 69 GPs. Most respondents (86.7% overall, 90.4% for Ob-GYN, 81.1% for GPs and 80.1% for midwives) agreed to receive the SARS-CoV-2 vaccine. Vaccination against SARS-CoV-2 would be offered to pregnant women by 49.4% 95%CI [48.1-50.8] of the participants. Midwives were less likely to recommend vaccination than GP and Ob-Gyn (37.5%, 50.7% and 58.8%, respectively). The multinomial logistic regression revealed that being an obstetrician, working in a group, usually offering a flu vaccine and wanting to be vaccinated against SARS-CoV-2 were positively associated with considering pregnant women for SARS-CoV-2 vaccination.ConclusionMost French prenatal healthcare providers are favourable towards vaccinating pregnant women, but a large minority express reservation. More evidence on safety and involvement by professional organisations will be important to encourage the access of pregnant women to vaccination against SARS-CoV-2.

BackgroundThe safety of methods of labor induction in women with previous cesarean deliveries is still debated. We investigated perinatal outcomes associated with labor induction among women with a trial of labor after one cesarean delivery.MethodsThis retrospective study included 339 women with a trial of labor after one prior cesarean and a singleton term fetus in cephalic presentation in 2013-2016 in a French maternity unit. Labor induction was performed with oxytocin, artificial rupture of membranes and/or prostaglandin E2, according to the Bishop score. The primary outcome was a composite of uterine rupture, low Apgar score, neonatal resuscitation or admission to a neonatal unit. The secondary outcomes included cesarean delivery after onset of labor, postpartum hemorrhage and maternal hospital stay after delivery. We used logistic regression to estimate odds ratios adjusted (aOR) for potential confounders.ResultsIn our sample, 67.3% of women had spontaneous labor and 32.7% were induced. More than half of the women received oxytocin during labor regardless of the mode of labor. The proportions of the composite outcome and of cesarean after onset of labor were higher in the induced group compared to the spontaneous group (26.1% vs 15.8%, p = 0.02 and 45.0% vs 27.6%, pConclusionLabor induction after one prior cesarean was associated with a higher risk of adverse perinatal outcome. Nevertheless, the higher proportion of uterine rupture did not differ significantly from that in the spontaneous labor group.

BackgroundTo fight the COVID-19 pandemic, lockdown has been decreed in many countries worldwide. The impact of pregnancy as a severity risk factor is still debated, but strict lockdown measures have been recommended for pregnant women.ObjectivesTo evaluate the impact of the COVID-19 pandemic and lockdown on the seroprevalence and circulation of SARS-CoV-2 in a maternity ward in an area that has been significantly affected by the virus.Study designProspective study at the Antoine Béclère Hospital maternity ward (Paris area, France) from May 4 (one week before the end of lockdown) to May 31, 2020 (three weeks after the end of lockdown). All patients admitted to the delivery room during this period were offered a SARS-CoV-2 serology test as well concomitant SARS-CoV-2 RT-PCR on one nasopharyngeal sample.ResultsA total of 249 women were included. Seroprevalence of SARS-CoV-2 was 8%. The RT-PCR positive rate was 0.5%. 47.4% of the SARS-CoV-2-IgG-positive pregnant women never experienced any symptoms. A history of symptoms during the epidemic, such as fever (15.8%), myalgia (36.8%) and anosmia (31.6%), was suggestive of previous infection.ConclusionsThree weeks after the end of French lockdown, SARS-CoV-2 infections were scarce in our region. A very high proportion of SARS-CoV-2-IgG-negative pregnant women, which is comparable to that of the general population, must be taken into consideration in the event of a resurgence of the pandemic. The traces of a past active circulation of the virus in this fragile population during the spring wave should encourage public health authorities to take specific measures for this independent at-risk group, in order to reduce viral circulation in pregnant patients.

Abstract Background Congenital diaphragmatic hernia is an orphan disease with high neonatal mortality and significant morbidity. An important cause for this is pulmonary hypertension, for which no effective postnatal therapy is available to date. An innovative strategy aiming at treating or preventing pulmonary hypertension more effectively is urgently needed. Prenatal sildenafil administration to expectant mothers prevented fetal and neonatal vascular changes leading to pulmonary hypertension in several animal models, and is, therefore, a promising approach. Before transferring this antenatal medical approach to the clinic, more information is needed on transplacental transfer and safety of sildenafil in humans. Methods This is a randomized, investigator-blinded, double-armed, parallel-group, phase I/IIb study with as a primary objective to measure the in-vivo transplacental transfer of sildenafil in women in the second and early third trimester of pregnancy (sub-study 1; weeks: 20.0–32.6) and at term (sub-study 2; weeks: 36.6–40). Participants will be randomized to two different sildenafil doses: 25 or 75 mg. In sub-study 1, a single dose of the investigational product will be administered to women undergoing termination of pregnancy, and maternal and fetal blood samples will be collected for determination of sildenafil concentrations. In sub-study 2, sildenafil will be administered three times daily from 3 days before planned delivery until actual delivery, following which maternal and umbilical cord samples will be collected. Proxies of maternal and fetal tolerance as well as markers of fetal pulmonary vasodilation will also be measured. Discussion This is the first study evaluating in-vivo transplacental passage of sildenafil in humans. Trial registration EU Clinical Trials Register 2016–002619-17, validated on 12 August 2016. Trial sponsor: UZ Leuven, Herestraat 49, 3000 Leuven.

Abstract Background There are many reasons to think that epigenetics is a key determinant of fetal growth variability across the normal population. Since IGF1 and INS genes are major determinants of intrauterine growth, we examined the methylation of selected CpGs located in the regulatory region of these two genes. Methods Cord blood was sampled in 159 newborns born to mothers prospectively followed during their pregnancy. A 142-item questionnaire was filled by mothers at inclusion, during the last trimester of the pregnancy and at the delivery. The methylation of selected CpGs located in the promoters of the IGF1 and INS genes was measured in cord blood mononuclear cells collected at birth using bisulfite-PCR-pyrosequencing. Results Methylation at IGF1 CpG-137 correlated negatively with birth length (r = 0.27, P = 3.5 × 10−4). The same effect size was found after adjustment for maternal age, parity, and smoking: a 10% increase in CpG-137 methylation was associated with a decrease of length by 0.23 SDS. Conclusion The current results suggest that the methylation of IGF1 CpG-137 contributes to the individual variation of fetal growth by regulating IGF1 expression in fetal tissues.

Using an organotypic culture system termed human Fetal Testis Assay (hFeTA) we previously showed that 0.01 μM BPA decreases basal, but not LH-stimulated, testosterone secreted by the first trimester human fetal testis. The present study was conducted to determine the potential for a long-term antiandrogenic effect of BPA using a xenograft model, and also to study the effect of BPA on germ cell development using both the hFETA and xenograft models.Using the hFeTA system, first trimester testes were cultured for 3 days with 0.01 to 10 μM BPA. For xenografts, adult castrate male nude mice were injected with hCG and grafted with first trimester testes. Host mice received 10 μM BPA (~ 500 μg/kg/day) in their drinking water for 5 weeks. Plasma levels of total and unconjugated BPA were 0.10 μM and 0.038 μM respectively. Mice grafted with second trimester testes received 0.5 and 50 μg/kg/day BPA by oral gavage for 5 weeks.With first trimester human testes, using the hFeTA model, 10 μM BPA increased germ cell apoptosis. In xenografts, germ cell density was also reduced by BPA exposure. Importantly, BPA exposure significantly decreased the percentage of germ cells expressing the pluripotency marker AP-2γ, whilst the percentage of those expressing the pre-spermatogonial marker MAGE-A4 significantly increased. BPA exposure did not affect hCG-stimulated androgen production in first and second trimester xenografts as evaluated by both plasma testosterone level and seminal vesicle weight in host mice.Exposure to BPA at environmentally relevant concentrations impairs germ cell development in first trimester human fetal testis, whilst gonadotrophin-stimulated testosterone production was unaffected in both first and second trimester testis. Studies using first trimester human fetal testis demonstrate the complementarity of the FeTA and xenograft models for determining the respective short-term and long term effects of environmental exposures.

OBJECTIVE:To assess whether antibiotics used for treatment in asymptomatic second-trimester women positive for Mycoplasma or Ureaplasma spp. detected by amniotic-fluid PCR prevents preterm delivery. DESIGN:A randomized, double-blind, placebo-controlled trial. SETTING:10 maternal fetal medicine centers in France. POPULATION:Women with a singleton pregnancy who underwent amniocentesis between 16 and 20 weeks' gestation (weeks) for Down syndrome screening. A sample of 238 women with PCR-positive findings per treatment group was needed to show a 50% reduction in the preterm delivery rate. METHODS:Amniotic fluid was tested. Women with positive findings on real-time PCR of amniotic fluid for Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma urealyticum and Ureaplasma parvum were randomized to receive josamycin or placebo. Amniotic fluid was also tested for 16S PCR. MAIN OUTCOME MEASURES:The primary outcome was delivery before 37 weeks. RESULTS:In total, 1043 women underwent amniotic-fluid screening with specific PCR detection between July 2008 and July 2011: PCR detection failed in 27 (2.6%), and 20 (1.9%) underwent termination of pregnancy. Among the 1016 women with PCR results, 980 had available data for the primary outcome (delivery before 37 weeks) and 29 (3.0%) were positive for Ureaplasma and/or Mycoplasma spp. Because of the low rate of women with PCR-positive findings, the trial was stopped prematurely. In total, 19 women were randomized to receive placebo (n = 8) or josamycin (n = 11) and their characteristics were comparable, as was the rate of preterm delivery and secondary outcomes. In comparing all PCR-positive and -negative women regardless of treatment, PCR positivity for Ureaplasma and/or Mycoplasma spp. was not associated with any adverse pregnancy or neonatal outcome. Amniotic-fluid screening by 16S PCR showed no other bacterial colonization associated with preterm birth. CONCLUSIONS:Because of a low amniotic fluid colonization rate, the trial was interrupted. Maternal amniotic-fluid colonization by Mycoplasma and/or Ureaplasma spp. at 16-20 weeks in asymptomatic women is rare and not associated with adverse pregnancy outcomes. TRIAL REGISTRATION:ClinicalTrials.gov NCT00718705.

Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients’ lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired. Genetic complementation of patient's cells with wild-type FANCM improved their resistance to MMC re-establishing FANCD2 monoubiquitination. FANCM was more strongly expressed in human fetal germ cells than in somatic cells. FANCM protein was preferentially expressed along the chromosomes in pachytene cells, which undergo meiotic recombination. This mutation may provoke meiotic defects leading to a depleted follicular stock, as in Fancm-/- mice. Our findings document the first Mendelian phenotype due to a biallelic FANCM mutation.

[This corrects the article DOI: 10.1371/journal.pmed.1002220.].

BackgroundPerinatal mortality and morbidity continue to be major global health challenges strongly associated with prematurity and reduced fetal growth, an issue of further interest given the mounting evidence that fetal growth in general is linked to degrees of risk of common noncommunicable diseases in adulthood. Against this background, WHO made it a high priority to provide the present fetal growth charts for estimated fetal weight (EFW) and common ultrasound biometric measurements intended for worldwide use.Methods and findingsWe conducted a multinational prospective observational longitudinal study of fetal growth in low-risk singleton pregnancies of women of high or middle socioeconomic status and without known environmental constraints on fetal growth. Centers in ten countries (Argentina, Brazil, Democratic Republic of the Congo, Denmark, Egypt, France, Germany, India, Norway, and Thailand) recruited participants who had reliable information on last menstrual period and gestational age confirmed by crown-rump length measured at 8-13 wk of gestation. Participants had anthropometric and nutritional assessments and seven scheduled ultrasound examinations during pregnancy. Fifty-two participants withdrew consent, and 1,387 participated in the study. At study entry, median maternal age was 28 y (interquartile range [IQR] 25-31), median height was 162 cm (IQR 157-168), median weight was 61 kg (IQR 55-68), 58% of the women were nulliparous, and median daily caloric intake was 1,840 cal (IQR 1,487-2,222). The median pregnancy duration was 39 wk (IQR 38-40) although there were significant differences between countries, the largest difference being 12 d (95% CI 8-16). The median birthweight was 3,300 g (IQR 2,980-3,615). There were differences in birthweight between countries, e.g., India had significantly smaller neonates than the other countries, even after adjusting for gestational age. Thirty-one women had a miscarriage, and three fetuses had intrauterine death. The 8,203 sets of ultrasound measurements were scrutinized for outliers and leverage points, and those measurements taken at 14 to 40 wk were selected for analysis. A total of 7,924 sets of ultrasound measurements were analyzed by quantile regression to establish longitudinal reference intervals for fetal head circumference, biparietal diameter, humerus length, abdominal circumference, femur length and its ratio with head circumference and with biparietal diameter, and EFW. There was asymmetric distribution of growth of EFW: a slightly wider distribution among the lower percentiles during early weeks shifted to a notably expanded distribution of the higher percentiles in late pregnancy. Male fetuses were larger than female fetuses as measured by EFW, but the disparity was smaller in the lower quantiles of the distribution (3.5%) and larger in the upper quantiles (4.5%). Maternal age and maternal height were associated with a positive effect on EFW, particularly in the lower tail of the distribution, of the order of 2% to 3% for each additional 10 y of age of the mother and 1% to 2% for each additional 10 cm of height. Maternal weight was associated with a small positive effect on EFW, especially in the higher tail of the distribution, of the order of 1.0% to 1.5% for each additional 10 kg of bodyweight of the mother. Parous women had heavier fetuses than nulliparous women, with the disparity being greater in the lower quantiles of the distribution, of the order of 1% to 1.5%, and diminishing in the upper quantiles. There were also significant differences in growth of EFW between countries. In spite of the multinational nature of the study, sample size is a limiting factor for generalization of the charts.ConclusionsThis study provides WHO fetal growth charts for EFW and common ultrasound biometric measurements, and shows variation between different parts of the world.

To validate a model predicting the risk of threatened preterm delivery and to establish the optimal threshold for this risk scoring system.Two cohorts were studied: one of singleton pregnancies without preterm premature rupture of membranes (PPROM) and no cervical cerclage (cohort 1) and one of twin pregnancies without PPROM and no cervical cerclage (cohort 2). Patients were included from January 1st 2013 until December 31st 2013 by the Regional Perinatal Network of Ile de France with patients transferred because of threatened preterm delivery at 22 to 32 weeks of gestation. The individual probability of delivery within 48 hours of admission was calculated using the nomogram for every patient. Discrimination and calibration of the nomogram as well as the optimal threshold were determined using R studio.The nomogram accurately predicted obstetric outcome. Discrimination and calibration were excellent, with an area under the curve (AUC) of 0.88 (95% CI 0.86-0.90) for cohort 1 and 0.73 (95% CI 0.66-0.80) for cohort 2. The optimal threshold would be 15% for cohort 1 and 10% for cohort 2. Using these thresholds, the performance characteristics of the nomogram were: sensitivity 80% (cohort 1) and 69% (cohort 2), negative predictive value 94.8% (cohort 1) and 91.3% (cohort 2). Use of the nomogram would avoid 253 unnecessary transfers in cohort 1.The nomogram was efficient and clinically relevant in our high risk population. A threshold set at 15% would help minimize the risk of preterm deliveries in singleton pregnancies and should reduce unnecessary, costly and stressful in utero transfer.

Acute hepatitis E virus infections occurred during the third trimester in 2 pregnant women in France who sought treatment with nonspecific symptoms or asymptomatic elevation of liver enzymes. Infection cleared quickly in both women. We detected no hepatitis E RNA in 1 newborn’s feces at 3 weeks of age.

RATIONALE:Congenital diaphragmatic hernia (CDH) is associated with a high incidence of respiratory problems, even after initial hospital discharge. These problems are likely to lead to re-hospitalization during infancy, although actual frequency of readmissions is unknown. OBJECTIVE:We aimed to determine the rate of hospitalization for wheezing in infants with CDH between the time of initial discharge and 24 months of age, and to identify factors associated with readmission. METHODS:Data about infants with CDH born in three French reference tertiary centers between January 2009 and March 2013 who were alive at hospital discharge, were extracted from a prospective national database. RESULTS:Ninety-two children were identified, and 86 were included in the analysis. In total, 116 wheezing episodes requiring a doctor's visit occurred in 50 infants (58%) before 24 months of age. Twenty-two children (26%) were readmitted at least once for wheezing exacerbations. RSV was present in 6 of 15 (40%) of children with available nasal samples at first readmission, and 1 of 5 (20%) at second readmission. Thoracic herniation of the liver, low gestational age, longer initial hospitalization, need for oxygen therapy at home, and eczema were all significantly associated with readmission for wheezing exacerbations. Fifty-three infants (62%) received palivizumab prophylaxis, but there was no association with the overall rate of readmission for wheezing exacerbations or RSV-related hospitalization. CONCLUSIONS:The rate of readmission for wheezing among infants with CDH is high, and significantly influenced by several prenatal and neonatal factors. Palivizumab prophylaxis was not associated with the rate of readmission.

After publication of the original article [1], it came to the publishers’ attention that the below author’s corrections provided at the proofing stage had been misinterpreted.

PURPOSE: To evaluate the accuracy of ultrasonography and magnetic resonance imaging (MRI) in the diagnosis of placenta accreta and to define the most relevant specific ultrasound and MRI features that may predict placental invasion. MATERIAL AND METHODS: This study was approved by the institutional review board of the French College of Obstetricians and Gynecologists. We retrospectively reviewed the medical records of all patients referred for suspected placenta accreta to two university hospitals from 01/2001 to 05/2012. Our study population included 42 pregnant women who had been investigated by both ultrasonography and MRI. Ultrasound images and MRI were blindly reassessed for each case by 2 raters in order to score features that predict abnormal placental invasion. RESULTS: Sensitivity in the diagnosis of placenta accreta was 100% with ultrasound and 76.9% for MRI (P = 0.03). Specificity was 37.5% with ultrasonography and 50% for MRI (P = 0.6). The features of greatest sensitivity on ultrasonography were intraplacental lacunae and loss of the normal retroplacental clear space. Increased vascularization in the uterine serosa-bladder wall interface and vascularization perpendicular to the uterine wall had the best positive predictive value (92%). At MRI, uterine bulging had the best positive predictive value (85%) and its combination with the presence of dark intraplacental bands on T2-weighted images improved the predictive value to 90%. CONCLUSION: Ultrasound imaging is the mainstay of screening for placenta accreta. MRI appears to be complementary to ultrasonography, especially when there are few ultrasound signs.

OBJECTIVE: To determine if bilateral absent or reverse end-diastolic (ARED) flow in the two umbilical arteries (UAs) at the perivesical (PVC) segment represents a more severe degree of hemodynamic compromise than unilateral ARED flow at the PVC segment in singleton pregnancies complicated by intrauterine growth restriction (IUGR). METHODS: This was a prospective observational study. One hundred nine fetuses with IUGR underwent a total of 225 ultrasound (US) examinations. We measured the pulsatility index (PI) from the two UAs at the PVC segment, UA in the free floating cord (FFC), middle cerebral artery (MCA), ductus venosus (DV) and the aortic isthmus blood flow index (IFI). Three groups were classified according to bilateral positive end-diastolic (PED) flow, unilateral ARED flow or bilateral ARED flow in the UAs at the PVC segment. RESULTS: The proportions of US examinations with PED flow, unilateral ARED flow and bilateral ARED flow in the UAs were 54.7%, 20.4%, and 24.9%, respectively. At the last US examination, the IFI z-scores were significantly lower in the bilateral ARED group (-6.28 ± 4.30) compared to the unilateral ARED group (-1.72 ± 3.18, p

Endocrine disruptors (ED) have been incriminated in the current increase of male reproductive alterations. Bisphenol A (BPA) is a widely used weak estrogenic environmental ED and it is debated whether BPA concentrations within the average internal exposure are toxic. In the present study we investigated the effects of 10(-12) to 10(-5) M BPA concentrations on fetal Leydig cell function, as fetal life is a critical period of sensitivity to ED effects on male reproductive function. To this aim, fetal testes from human at 6.5-10.5 gestational weeks (GW) or from rat and mouse at a comparable critical period of development (14.5 days post-coitum (dpc) for rat and 12.5 dpc for mouse) were explanted and cultured using our validated organotypic culture system in the presence or absence of BPA for 1-3 days. BPA concentrations as low as 10(-8) M reduced testosterone secretion by human testes from day 1 of culture onwards, but not by mouse and rat testes where concentrations equal to 10(-5) M BPA were required. Similarly, 10(-8) M BPA reduced INSL3 mRNA levels only in human cultured testes. On the contrary, 10(-5) and 10(-6) M diethylstilbestrol (DES), a classical estrogenic compound, affected testosterone secretion only in rat and mouse testis cultures, but not in human testis cultures. Lastly, contrarily to the DES effect, the negative effect of BPA on testosterone produced by the mouse fetal testis was maintained after invalidation of estrogen receptor α (ERα). In conclusion, these results evidenced i) a deleterious effect of BPA on fetal Leydig cells function in human for concentrations from 10(-8) M upwards, ii) species-specific differences raising concerns about extrapolation of data from rodent studies to human risk assessment, iii) a specific signaling pathway for BPA which differs from the DES one and which does not involve ERα.

Phthalates have been shown to have reprotoxic effects in rodents and human during fetal life. Previous studies indicate that some members of the nuclear receptor (NR) superfamilly potentially mediate phthalate effects. This study aimed to assess if expression of these nuclear receptors are modulated in the response to MEHP exposure on the human fetal gonads in vitro.Testes and ovaries from 7 to 12 gestational weeks human fetuses were exposed to 10(-4)M MEHP for 72 h in vitro. Transcriptional level of NRs and of downstream genes was then investigated using TLDA (TaqMan Low Density Array) and qPCR approaches. To determine whether somatic or germ cells of the testis are involved in the response to MEHP exposure, we developed a highly efficient cytometric germ cell sorting approach. In vitro exposure of fetal testes and ovaries to MEHP up-regulated the expression of LXRα, SREBP members and of downstream genes involved in the lipid and cholesterol synthesis in the whole gonad. In sorted testicular cells, this effect is only observable in somatic cells but not in the gonocytes. Moreover, the germ cell loss induced by MEHP exposure, that we previously described, is restricted to the male gonad as oogonia density is not affected in vitro.We evidenced for the first time that phthalate increases the levels of mRNA for LXRα, and SREBP members potentially deregulating lipids/cholesterol synthesis in human fetal gonads. Interestingly, this novel effect is observable in both male and female whereas the germ cell apoptosis is restricted to the male gonad. Furthermore, we presented here a novel and potentially very useful flow cytometric cell sorting method to analyse molecular changes in germ cells versus somatic cells.

BACKGROUND: Alveolarization requires coordinated extracellular matrix remodeling, a process in which matrix metalloproteinases (MMPs) play an important role. We postulated that polymorphisms in MMP genes might affect MMP function in preterm lungs and thus influence the risk of bronchopulmonary dysplasia (BPD). METHODS AND FINDINGS: Two hundred and eighty-four consecutive neonates with a gestational age of

BACKGROUND: Pulmonary hypoplasia and persistent pulmonary hypertension account for significant mortality and morbidity in neonates with congenital diaphragmatic hernia (CDH). Global lung immaturity and studies in animal models suggest the presence of surfactant deficiency that may further complicate the pathophysiology of CDH. However, data about surfactant status in human fetuses with CDH at birth are contradictory. The lack of a chronological study of surfactant content in late pregnancy has been a significant limitation. The appropriateness of administering surfactant supplements to neonates with CDH is therefore a debated question. METHODS AND FINDINGS: We investigated surfactant content in human fetuses with CDH compared to age-matched fetuses with nonpulmonary diseases used as controls. Concentrations of disaturated phosphatidylcholine and surfactant proteins were found to be similar at a given stage of pregnancy, with both components showing a similar pattern of increase with progressing pregnancy in fetuses with CDH and in control fetuses. Thyroid transcription factor 1, a critical regulator of surfactant protein transcription, similarly displayed no difference in abundance. Finally, we examined the expression of three glucocorticoid-regulated diffusible mediators involved in lung epithelial maturation, namely: keratinocyte growth factor (KGF), leptin, and neuregulin 1 beta 1 (NRG1-beta1). KGF expression decreased slightly with time in control fetuses, but remained unchanged in fetuses with CDH. Leptin and NRG1-beta1 similarly increased in late pregnancy in control and CDH lungs. These maturation factors were also determined in the sheep fetus with surgical diaphragmatic hernia, in which surfactant deficiency has been reported previously. In contrast to the findings in humans, surgical diaphragmatic hernia in the sheep fetus was associated with decreased KGF and neuregulin expression. Fetoscopic endoluminal tracheal occlusion performed in the sheep model to correct lung hypoplasia increased leptin expression, partially restored KGF expression, and fully restored neuregulin expression. CONCLUSIONS: Our results indicate that CDH does not impair surfactant storage in human fetuses. CDH lungs exhibited no trend toward a decrease in contents, or a delay in developmental changes for any of the studied surfactant components and surfactant maturation factors. Surfactant amounts are likely to be appropriate to lung size. These findings therefore do not support the use of surfactant therapy for infants with CDH. Moreover, they raise the question of the relevance of CDH animal models to explore lung biochemical maturity.