Fetoscopic endoluminal tracheal occlusion with Smart-TO balloon: Study protocol to evaluate effectiveness and safety of non-invasive removal.

INTRODUCTION: One 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 METHODS: These 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. CONCLUSION: These 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.

Iron Metabolism in Normal and Pathological Pregnancies and Fetal Consequences.

Iron is required for energy production, DNA synthesis, and cell proliferation, mainly as a component of the prosthetic group in hemoproteins and as part of iron-sulfur clusters. Iron is also a critical component of hemoglobin and plays an important role in oxygen delivery. Imbalances in iron metabolism negatively affect these vital functions. As the crucial barrier between the fetus and the mother, the placenta plays a pivotal role in iron metabolism during pregnancy. Iron deficiency affects 1.2 billion individuals worldwide. Pregnant women are at high risk of developing or worsening iron deficiency. On the contrary, in frequent hemoglobin diseases, such as sickle-cell disease and thalassemia, iron overload is observed. Both iron deficiency and iron overload can affect neonatal development. This review aims to provide an update on our current knowledge on iron and heme metabolism in normal and pathological pregnancies. The main molecular actors in human placental iron metabolism are described, focusing on the impact of iron deficiency and hemoglobin diseases on the placenta, together with normal metabolism. Then, we discuss data concerning iron metabolism in frequent pathological pregnancies to complete the picture, focusing on the most frequent diseases.

Impact of simulation-based prenatal invasive procedure training on professional practice, a preliminary study.

INTRODUCTION: Amniocentesis and chorionic villus sampling remain the cornerstone of prenatal diagnosis. These procedures are associated with a risk of miscarriage estimated at approximately 0.5 %. Our team has developed a training model for performing simulation-based prenatal invasive procedures. Several simulation sessions are offered each year to obstetricians-gynecologists involved in fetal medicine in France and abroad. This simulation-based learning has already been conclusively evaluated according to levels I and II of the Kirkpatrick model. Here, we carried out a preliminary study according to level III: does participation in training in prenatal invasive procedures through simulation have an influence on professional practice? METHODS: An anonymous online survey was sent to 82 obstetricians-gynecologists who participated in the training in prenatal invasive procedures at the Antoine Béclère maternity hospital between January 1st, 2014 and December 31, 2018. This questionnaire, entitled "Evaluation of the professional impact of training in invasive procedures through simulation", included 20 quantitative and qualitative items. RESULTS: 48 (59 %) obstetricians-gynecologists responded to the questionnaire. 98 % of the participants considered that participation in the training had a significant impact on their professional practice. Half considered this impact to be major. 60 % of the former participants are now attached to a Multidisciplinary Center for Prenatal Diagnosis. CONCLUSION: Participation in training is considered by former participants to have a significant impact on their professional practice. In order to finalize the evaluation of this learning, a study of the benefits for patients and their pregnancy should be discussed.

Preserved efficiency of sickle cell disease placentas despite altered morphology and function.

INTRODUCTION: Pregnant women with sickle cell disease (SCD) are at high risk for sickle cell-related complications, obstetrical complications, and perinatal morbidity. Chronic inflammation and the proangiogenic environment associated with SCD have been associated with endothelial damage. It is unknown whether SCD complications could be associated with placental dysfunction or abnormal placental morphology. Moreover, circulating angiogenic factors in pregnant women with SCD are unexplored. METHODS: Clinical records, placental and blood samples were collected at term delivery for 21 pregnant patients with SCD and 19 HbAA pregnant controls with adapted to gestational age birth weight newborns. Histological and stereological analyses and scanning electron microscopy (SEM) of the placenta, and PlGF and sFlt1 measurements in blood were performed. RESULTS: In the SCD group, the parenchyma-forming villi of placentas were thinner than in controls, and increased fibrinoid necrosis and an overabundance of syncytial knots were seen. SEM revealed elongated intermediate villous endings with a reduction in the number of terminal villi compared to controls, indicating a significant branching defect in SCD placentas. Finally, SCD patients had an imbalance in the angiogenic ratio of sFlt1/PlGF (p = 0.008) with a drop of PlGF concentrations. DISCUSSION: We evidence for the first time both abnormal placenta morphology and altered sFlt1/PlGF ratio in SCD patients, uncorrelated with maintained placental efficiency and fetal growth.

Evidence for contamination as the origin for bacteria found in human placenta rather than a microbiota.

Until recently the in utero environment of pregnant women was considered sterile. Recent high-sensitivity molecular techniques and high-throughput sequencing lead to some evidence for a low-biomass microbiome associated with the healthy placenta. Other studies failed to reveal evidence for a consistent presence of bacteria using either culture or molecular based techniques. Comparing conflicting "placental microbiome" studies is complicated by the use of varied and inconsistent protocols. Given this situation, we undertook an evaluation of the in utero environment sterility using several controlled methods, in the same study, to evaluate the presence or absence of bacteria and to explain contradictions present in the literature. Healthy pregnant women (n = 38) were recruited in three maternity wards. Placenta were collected after cesarean section with or without Alexis® and vaginal delivery births. For this study we sampled fetal membranes, umbilical cord and chorionic villi. Bacterial presence was analyzed using bacterial culture and qPCR on 34 fetal membranes, umbilical cord and chorionic villi samples. Shotgun metagenomics was performed on seven chorionic villi samples. We showed that the isolation of meaningful quantities of viable bacteria or bacterial DNA was possible only outside the placenta (fetal membranes and umbilical cords) highlighting the importance of sampling methods in studying the in utero environment. Bacterial communities described by metagenomics analysis were similar in chorionic villi samples and in negative controls and were dependent on the database chosen for the analysis. We conclude that the placenta does not harbor a specific, consistent and functional microbiota.

Congenital diaphragmatic hernia has a better prognosis when associated with a hernia sac.

OBJECTIVE: To evaluate neonatal mortality and morbidity up to 6 months in neonates with congenital diaphragmatic hernia (CDH) with or without a hernia sac. METHODS: Seventy-two cases of isolated CDH were included in a retrospective single-center study between January 2010 and December 2016. Hernia sac was defined at the time of surgery or at postmortem examination if the neonate died before surgery. RESULTS: Seventeen newborns (23.6%) had a hernia sac. Survival at 6 months was significantly greater for isolated CDH with a hernia sac: 100% versus 63.6% (P = .003). High-frequency oscillatory ventilation was used significantly more in the no hernia sac group (P = .04). At surgery, the need for patch repair was significantly lower in the hernia sac group: 12% versus 50% (P = .005). The prenatal observed/expected lung-to-head ratio was significantly higher in the hernia sac group than in the no hernia sac group: 49.7% versus 38.6% (P < .05). CONCLUSION: The presence of a hernia sac in CDH is associated with better outcome, especially survival at 6 months. If the presence of a hernia sac is recognized as a particular entity, which carries a good prognosis, it is necessary to be able to diagnose it prenatally, especially in the era of prenatal fetal surgery.

Abnormal pelvic morphology and high cervical length are responsible for high-risk pregnancies in women displaying achondroplasia.

Pregnancies of women displaying achondroplasia are at high risk of adverse events. Early sonographic assessment of affected women can indicate an unusually long cervical length. It is the consequence of pathological anatomy of the pelvis. Thus, there is a foreseeable dystocia owing to cephalopelvic disproportion. Furthermore, this situation could also complicate cervical ripening prior to fetal extraction.

Teaching invasive prenatal procedures: effectiveness of two simple simulators in training.

BACKGROUND: Chorionic villus sampling (CVS) and amniocentesis are the major tools of invasive prenatal diagnosis. We studied the effectiveness of two simulators in training in invasive procedures. METHODS: Two affordable and simple simulators were developed, modelling the maternal abdomen and the different tissue layers crossed by the needle. The trainees were evaluated before and after practical and theoretical training. A score evaluating five criteria for technical quality in performing a procedure safely was established. Initial score of 9 or 10 was excluded. The primary endpoint was improvement defined as the change between pre-test and post-test, expressed as a percentage of the pre-test. RESULTS: A total of 54 residents and 63 specialists in obstetrics and gynaecology participated. Residents improved their scores in the practice of amniocentesis (80% [43-167]) and CVS (100% [29-150]), as well as specialists (100% [25-233] and 67% [33-122]). Specialists who earlier performed one CVS or more than five amniocentesis procedures had a lower increase during training than those who had performed fewer than five procedures (p < 0.01). Being inexperienced in CVS was associated with greater improvement (27% vs 56%, p = 0.003). CONCLUSION: A simple simulator improves the ability of physicians to perform invasive procedures in particular when initial experience is low. © 2016 John Wiley & Sons, Ltd.

Prophylactic use of the Arabin cervical pessary in fetuses with severe congenital diaphragmatic hernia treated by fetoscopic endoluminal tracheal occlusion (FETO): preliminary experience.

OBJECTIVE: The aim of this study was to describe whether the prophylactic use of a cervical pessary decreases the rate of premature birth in congenital diaphragmatic hernia (CDH) fetuses treated with fetoscopic tracheal occlusion (FETO). METHODS: The study concerns a consecutive series of cases with CDH and FETO and a group of CDH without FETO. In a subgroup of the FETO group, a prophylactic cervical pessary was inserted the day following the procedure. Gestational age (GA) at birth was the primary outcome. RESULTS: Fifty-nine fetuses with FETO and 47 expectantly managed were included. The last 15 FETO had a cervical pessary inserted. The median GA at delivery in the FETO group with pessary was 35.1 weeks and was not different from that in the FETO group without a pessary (34.3 weeks; p = 0.28) but was below that in the expectantly managed group (38.3 weeks; p < 0.001). CONCLUSION: Early results suggest that prophylactic use of an Arabin cervical pessary does not prolong gestation of CDH fetuses treated with FETO. © 2015 John Wiley & Sons, Ltd.

Comparing genotoxic signatures in cord blood cells from neonates exposed in utero to zidovudine or tenofovir.

OBJECTIVES: Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero. DESIGN: We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively). METHODS: The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs. RESULTS: Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups. CONCLUSION: Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes.

Advances in prenatal diagnosis of congenital diaphragmatic hernia.

Over the past 20 years, prenatal detection of congenital diaphragmatic hernia (CDH) has improved worldwide, reaching up to 60% in Europe. Pulmonary hypoplasia and persistent pulmonary hypertension are the two main determinants of neonatal mortality and morbidity, so new tools have been focused on their evaluation. Fetal surgery for severe cases requires proper evaluation of the prognosis of fetuses with CDH. Observed-to-expected lung-to-head ratio, liver position, and total lung volume measured by magnetic resonance are the prognostic factors most often used, and have been shown to correlate not only with neonatal mortality but also with morbidity. In daily practice, pulmonary hypertension by itself, although most often associated with lung hypoplasia, is more difficult to predict.

[Vitamin D and pregnancy]. / Vitamine D et grossesse.

Vitamin D insufficiency is characterized, since 2005, by 25(OH)D concentration less than 75 nmol/L (or 30 ng/mL). Vitamin D could interfere with many mechanisms involved in preeclampsia's pathogenesis including trophoblastic invasion and immunomodulation as well as blood pressure control and proteinuria. Occurrence of preeclampsia and gestational diabetes seems to be linked to vitamin D deficiency but recent data in the literature are contradictory. Vitamin D supplementation during pregnancy is controversial. Some societies consider it unnecessary and others recommend up to 2000 UI/d. There is no reported case of teratogenicity linked with vitamin D intake.

Genotoxic signature in cord blood cells of newborns exposed in utero to a Zidovudine-based antiretroviral combination.

BACKGROUND: The genotoxicity of zidovudine has been established in experimental models. The objective of the study was to identify genotoxicity markers in cord blood cells from newborns exposed in utero to antiretroviral (ARV) combinations containing zidovudine. METHODS: Cells were investigated by karyotyping and gene expression analysis of the CD34(+) hematopoietic stem/progenitor cell (HPC) compartment. RESULTS: Karyotyping of the cord blood cells from 15 ARV-exposed newborns and 12 controls revealed a higher proportion of aneuploid cells in the exposed group (median, 18.8% [interquartile range, 10.0%-26.7%] vs 6.6% [interquartile range, 3.1%-11.7%]; P < .001). All chromosomes were involved, with a random distribution of these alterations. Gene expression profiling of CD34(+) HPCs from 7 ARV-exposed and 6 control newborns revealed that >300 genes were significantly upregulated or downregulated by at least 1.5-fold in the exposed group (P < .05 for all comparisons). Significant alterations of genes involved in cell cycle control, mitotic checkpoints, and DNA repair were identified. Although this study does not allow discrimination between the roles of each of the 3 drugs, both cytogenetic and transcriptional findings are similar to those in cellular experiments that used zidovudine alone. CONCLUSIONS: The cord blood cells, including hematopoietic stem cells, from newborns exposed in utero to a zidovudine-based ARV combination present cytogenetic and transcriptional abnormalities compatible with DNA damage.

Co-occurrence of multifocal chorioangiomatosis and mesenchymal dysplasia in preeclampsia.

Chorioangioma is the most common benign vascular placental tumor. It is often small and has no clinical significance. Large chorioangiomata are rarer and can lead to fetal or maternal complications. Chorioangiomatosis is even rarer and is defined as a focal or multifocal proliferation of placental capillaries permeating villous tissue. Placental mesenchymal dysplasia (PMD) is characterized by the overgrowth of placental mesenchymal tissue and can be associated with fetal or obstetrical complications. We report a case associated with preeclampsia and intrauterine growth restriction, in which both chorioangiomatosis and PMD were present.

Liver-to-thoracic volume ratio: use at MR imaging to predict postnatal survival in fetuses with isolated congenital diaphragmatic hernia with or without prenatal tracheal occlusion.

OBJECTIVE: To evaluate the relationship of the liver-to-thoracic volume ratio (LiTR) by MRI with postnatal survival in foetuses with isolated congenital diaphragmatic hernia (CDH). METHODS: In 30 conservatively managed CDH foetuses and in 31 who underwent fetoscopic endoluminal tracheal occlusion (FETO), logistic regression analysis was used to investigate the effect on postnatal survival of the observed-to-expected (O/E) ratio of total foetal lung volume (TFLV), LiTR, gestational age at delivery, CDH side, intrathoracic position of the liver and, for those who underwent FETO, gestational age at FETO and occlusion period. For 19 foetuses undergoing FETO, a post-FETO MRI was available. The proportionate increase in O/E ratio of TFLV at 3-8 weeks after FETO was compared with the pre-FETO value and correlated with pre-FETO LiTR using linear regression analysis. RESULTS: For conservatively managed foetuses, only LiTR provided a significant prediction of postnatal survival. For foetuses undergoing FETO, LiTR and gestational age at delivery provided a significant independent prediction of postnatal survival. There was a significant inverse association between lung response and pre-FETO LiTR. CONCLUSION: In foetuses with CDH with/without FETO treatment, the LiTR is predictive of postnatal survival at discharge. In foetuses treated with FETO, LiTR is predictive of post-FETO lung response. KEY POINTS: • Congenital diaphragmatic hernia is usually managed conservatively before surgery soon after delivery • Fetoscopic endoluminal tracheal occlusion (FETO) has been introduced for severely affected foetuses • In conservatively managed CDH, the liver-to-thoracic volume ratio (LiTR) predicted postnatal survival best. • In severe CDH with prenatal FETO, LiTR also helped predict postnatal survival. • LiTR should be integrated into the prenatal decision-making for foetuses with CDH.

Clues pointing to simple hysterectomy to treat early-stage cervical cancer.

Radical hysterectomy and pelvic lymphadenectomy is recommended for stage Ia2-Ib1 cervical cancer while parametrial involvement (PI) is rare. Our aim was to evaluate criteria to select women with low risk of PI that could benefit from simple hysterectomy. Factors associated with low risk of PI were analyzed in a series of 37 patients with stage Ia2-Ib1 cervical cancer undergoing radical hysterectomy and sentinel lymph node procedure from 2003 to 2008. PI was associated with tumor size (p<0.001) and lymphovascular space invasion (LVSI) (p=0.007). PI was found in 4.5% of patients with tumor size 2 cm (p=0.04). The negative predictive value was 100% for absence of LVSI (95% CI: 0.83-1) and for combinations: tumor size