The syncytiotrophoblast is the principal component of the human placenta involved in feto-maternal exchanges and hormone secretion. The syncytiotrophoblast arises from the fusion of villous cytotrophoblasts. We recently showed that functional gap junctional intercellular communication(GJIC) is an important prerequisite for syncytiotrophoblast formation and that connexin 43 (Cx43) is present in cytotrophoblasts and in the syncytiotrophoblast. To determine whether Cx43 is directly involved in trophoblast fusion, we used an antisense strategy in primary cultures of human villous cytotrophoblasts that spontaneously differentiate into the syncytiotrophoblast by cell fusion. We assessed the morphological and functional differentiation of trophoblasts by desmoplakin immunostaining, by quantifying hCG (human chorionic gonadotropin) production and by measuring the expression of specific trophoblast genes (hCG and HERV-W). Furthermore, we used the gap-FRAP (fluorescence recovery after photobleaching) method to investigate functional GJIC. Cytotrophoblasts treated with Cx43 antisense aggregated and fused poorly. Furthermore, less HERV-W env mRNA, hCGβ mRNA and hCG secretion were detected in Cx43 antisense-treated cytotrophoblasts than in cells treated with scrambled antisense. Treatment with Cx43 antisense dramatically reduced the percentage of coupled trophoblast cells. Taken together, these results suggest that Cx43 is directly involved in human trophoblast cell-cell communication, fusion and differentiation.

The glucose-regulated protein 78 (GRP78) is a molecular chaperone that is responsible for protein folding, which belongs to the heat shock protein 70 kDa (HSPA/HSP70). Because of the conjunction of GRP78 transcription with endoplasmic reticulum stress, the chaperone plays an important role in the unfolded protein response (UPR), which is induced after the accumulation of misfolded proteins. In the last years, a significant body of research concentrated on interplay between GRP78 and sexual steroid hormones. Throughout this review, we describe the mechanisms by which GRP78 regulates steroidogenesis at multiple levels and how steroids modulate GRP78 expression in different mammalian reproductive organs. Finally, we discuss the cooperation between GRP78 and steroids for cell survival and proliferation in the context of reproduction and tumorigenesis. This new paradigm offers significant opportunities for future exploration.

STUDY QUESTION: Is there an association between dydrogesterone exposure during early pregnancy and the reporting of birth defects? SUMMARY ANSWER: This observational analysis based on global safety data showed an increased reporting of birth defects, mainly hypospadias and congenital heart defects (CHD), in pregnancies exposed to dydrogesterone, especially when comparing to progesterone. WHAT IS KNOWN ALREADY: Intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation in ART. In recent years, randomized controlled clinical trials demonstrated that oral dydrogesterone was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone. Safety profiles in both mother and child were similar. However, concerns have been raised regarding an association between dydrogesterone usage during early pregnancy and CHD in offspring. STUDY DESIGN, SIZE, DURATION: We performed a disproportionality analysis, also called case–non-case study, similar in concept to case–control studies, using the WHO global safety database, VigiBase. The study cohort consisted of individual pregnancy-related safety reports, using the ad hoc standardized query (SMQ ‘Pregnancy and neonatal topics’). Cases of birth defects consisted of safety reports containing terms related to the ‘congenital, familial and genetic disorders’ System Organ Class from the Medical Dictionary for Regulatory Activities. Non-cases consisted of safety reports containing any other adverse event, in pregnancy-related safety reports. PARTICIPANTS/MATERIALS, SETTING, METHODS: Considering reports since database inception to 31 December 2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug on the database, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% CI. For each comparison, two sensitivity analyses were performed. Finally, a case-by-case review was performed to further characterize major birth defects and sort anomalies according to classification of EUROCAT. MAIN RESULTS AND THE ROLE OF CHANCE: Study cohort consisted of 362 183 safety reports in pregnant women, among which 3101 reports were related to the use of drugs for ART, including 145 with dydrogesterone and 1222 with progesterone. Of these, 374 (12.1%) were cases of birth defects: 60 with dydrogesterone and 141 with progesterone, including 48 and 92 cases compatible with major birth defect cases according to EUROCAT classification, respectively. Major birth defects reported with dydrogesterone were mainly genital defects such as hypospadias and CHD. A significantly higher disproportionate reporting of birth defects was found with dydrogesterone when compared to any other drug (ROR 5.4, 95% CI [3.9–7.5]), to any other ART drug (ROR 6.0, 95% CI [4.2–8.5]), and to progesterone (ROR 5.4, 95% CI [3.7–7.9]). Sensitivity analyses found consistent results. LIMITATIONS, REASONS FOR CAUTION: First, under-reporting, being inherent to pharmacovigilance systems, impedes the measurement of the incidence of adverse drug reactions and can limit the sensitivity of signal detection. Second, drug causality, not being the same for all cases, is challenging for such events and requires further assessment. However, sensitivity analyses showed consistent results. WIDER IMPLICATIONS OF THE FINDINGS: This possible safety signal emphasizes the need for further investigation regarding the fetal safety profile of dydrogesterone. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. None of the authors have any financial or personal relationships with other people or organizations that could influence the design, conduct, or reporting of this work. M.B., C.C, C.M and P.S have received institutional funding from Merck, Ferring, Theramex, Gedeon Richter, and Besins. M.B. has received personal honoraria from Merck, Ferring, Gedeon Richter, Theramex, IBSA, and Organon for lectures, presentations, or educational events, and has received non-monetary support for attending meetings from Ferring and Gedeon Richter. C.C has received personal honoraria from Merck, Besins, Gedeon Richter, and Theramex, and non-monetary support for attending meetings from Besins, Gedeon Richter, and Merck. He is the Founder and Past-President of the Society for Endometriosis and Uterine Disorders (SEUD), an unpaid role. C.M. has received personal consulting fees from Gedeon Richter and Ferring and honoraria from Merck Serono, Ferring, Besins, IBSA, and Organon for lectures or educational events. She has received non-monetary support for attending meetings from Ferring, Besins, and Gedeon Richter. P.S. has received personal honoraria from Merck, Ferring, Besins, Gedeon Richter, Theramex, IBSA, and General Electrics Medical Systems for lectures and educational events. He has also received non-monetary support for attending meetings from Merck, Ferring, Besins, Gedeon Richter, Theramex, and IBSA. He is a Board Member of SEUD and serves on the Editorial Boards of RBMO and GOF, all unpaid roles. J.G. has received institutional funding from Pregnomic and DiaSorin. He has received personal honoraria from Elsevier and Merck for lectures and educational events. He is a Board Member of ABA and SFE, an unpaid position. L.C., J.-M.T., and A.H. declare no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

It is now well established that maternal serum markers are often abnormal in fetal trisomy 21. Their determination is recommended for prenatal screening and pregnancy follow-up. However, mechanisms leading to abnormal maternal serum levels of such markers are still debated. Our objective was to help clinicians and scientists unravel the pathophysiology of these markers via a review of the main studies published in this field, both in vivo and in vitro, focusing on the six most widely used markers (hCG, its free subunit hCGβ, PAPP-A, AFP, uE3, and inhibin A) as well as cell-free feto–placental DNA. Analysis of the literature shows that mechanisms underlying each marker’s regulation are multiple and not necessarily directly linked with the supernumerary chromosome 21. The crucial involvement of the placenta is also highlighted, which could be defective in one or several of its functions (turnover and apoptosis, endocrine production, and feto–maternal exchanges and transfer). These defects were neither constant nor specific for trisomy 21, and might be more or less pronounced, reflecting a high variability in placental immaturity and alteration. This explains why maternal serum markers can lack both specificity and sensitivity, and are thus restricted to screening.