The underlying cause for renal and uterine agenesis remains unknown in many cases, whereas recurrence in some families strongly suggests the involvement of genetic factors. Here, we identify 5 affected individuals from 3 families with phenotypes including bilateral or unilateral renal agenesis/hypoplasia, along with variable congenital uterine anomalies and costovertebral defects associated with heterozygous deleterious variants in NR6A1. The variant spectrum includes two inherited missense (c.1175T>G;p.(Met392Arg) and c.196C>T;p.(Arg66Cys)) as well as de novo loss of function, with the latter associated with a perinatal lethal phenotype characterized by bilateral renal agenesis. In vitro studies demonstrated partial loss-of-function for both missense variants. To investigate the role of NR6A1 in development, CRISPR-Cas9 zebrafish mutants for the orthologs nr6a1a and nr6a1b were generated. Mutants recapitulate the human phenotype, exhibiting impaired kidney development, including pronephros segmentation defects and adult kidney hypoplasia, along with axial skeletal abnormalities, cloacal anomalies, and disrupted anteroposterior expression of posterior hox genes. This study provides strong evidence linking NR6A1 heterozygous deleterious variants to renal, uterine and costovertebral defects in humans.

Vasculo-placental disorders include pregnancy complications resulting from placental dysfunction of vascular origin, i.e. pre-eclampsia, HELLP syndrome, intrauterine growth retardation (IUGR), placental abruption and stillbirth of vascular origin. Pre-eclampsia should be investigated for antiphospholipid syndrome (APS) in case of severe pre-eclampsia and premature delivery before 34 weeks of gestation. In addition to testing for APS, pathological report of the placenta can identify some anatomical predispositions to placental vascular malperfusion, as well as chronic placental inflammatory lesions and excess fibrin deposits. The latter two are associated with IUGR and recurrent stillbirth, reflecting a dysimmune process of maternal origin. The internal medicine and obstetrics consultation, organized two months after delivery, combines the postnatal visit with an assessment of the causes of vasculo-placental disorders, and enables to inform patients about the management of future pregnancies and their cardiovascular health. (c) 2024 The Author(s). Published by Elsevier Masson SAS on behalf of Societe Nationale Francaise de Medecine Interne (SNFMI). This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

Introduction Symptomatic postpartum ovarian vein thrombosis (sPOVT), an unusual site of venous thromboembolism (VTE), is a rare complication occurring in 1/500 deliveries, with uncertain prognosis. Objective To evaluate: (i) the risk factors for sPOVT; (ii) the short-term prognosis, in terms of extension to the inferior vena cava and the left renal and association with pulmonary embolism (PE) or deep vein thrombosis (DVT); and (iii) the risk of recurrent VTE after resuming anticoagulation. Method A review of all documented cases of sPOVT was conducted using data of two French multicenter prospective cohorts of 20,238 unselected pregnant women and 7102 adult patients with VTE (NCT02443610–NCT04297085). All sPOVT diagnoses, VTE recurrences and maternal deaths were reviewed and validated by an independent clinical events committee. The Ethics Committee of Brest University Hospital approved the study protocols. Written informed consent was obtained from all participants before inclusion. Results Among the 13 women with sPOVT, the main VTE risk factors were maternal age ≥35 years (n=6;46.2%), obesity (n=3;23.1%), VTE family history (n=4;30.4%), multiple pregnancy (n=3;23.1%), preterm delivery (n=4;30.4%), caesarean delivery (n=3;23.1%) and postpartum infection (n=9;69.2%). At sPOVT diagnosis, four (30.8%) women presented extension to the inferior vena cava or the left renal vein. Among them, one had concomitant PE and one had thrombosis in the contralateral renal vein. None of them had concomitant DVT. During the median (IQR) follow-up of 6.1 years (3.0–7.3), after resuming anticoagulation, one patient had recurrent VTE despite thromboprophylaxis (i.e. muscular vein thrombosis after surgery five years after sPOVT) and one patient died from Hodgkin's lymphoma without VTE recurrence five years after sPOVT. Conclusion sPOVT appeared frequently associated with proximal clot extension and/or with PE or DVT. These observations support that sPOVT requires early diagnosis and effective anticoagulation for a minimum of three months as recommended for proximal DVT and PE. The risk of recurrence was low, so treating sPOVT similarly to provoked PE or DVT for up to six months seems appropriate. Given the close association between postpartum infection and sPOVT, the thrombotic risk needs to be regularly reassessed during postpartum.

Background Endometriosis is commonly observed in infertile women and can be staged with regard to severity [e.g. according to the American Fertility Society (AFS) classification]. This condition can cause infertility through impaired oocyte quality, fertilization disorders, tubal lesions, adhesions, deep infiltration, and adenomyosis. Although women with endometriosis often turn to in vitro fertilization (IVF) programs, the literature data on IVF outcomes are sometimes contradictory (i.e. the same as in other etiologies of infertility, or worse). The objective of the present study was to assess and compare pregnancy rates in women with and without endometriosis and according to the endometriosis stage. Methods We retrospectively studied clinical and ongoing pregnancy rates in IVF and the cumulative pregnancy rates after frozen/thawed embryo transfers, in women without endometriosis (group A) or with endometriosis (group B). We further compared groups in which endometriosis was staged according to the revised AFS classification: stage 1/2 (group C), stage 3/4 (group D, without endometrioma), and endometrioma alone (group E). Results We documented 430 cycles in group A and 460 in group B (including 56 in group C, 88 in group D and 316 in group E). After fresh or frozen/thawed embryo transfers, the differences in ongoing pregnancy rates between groups A and B were not significant. However the cumulative rates per couple were significantly lower (p < 0.05) in group D. Conclusions We recommend IVF for women with endometriosis because the pregnancy rates are similar to those observed for women with other types of infertility. This approach is in line with the international guidelines issued by assisted reproductive technology societies. These results again raise the question of whether surgical resection of deep infiltrating endometriosis (stage 3/4) should be recommended before admission to an IVF program. Trial registration This study was approved by an institutional review board (CPP Ouest VI, Brest, France): reference: B2020CE.43

Les pathologies vasculo-placentaires regroupent les complications de grossesse résultant d’une dysfonction placentaire d’origine vasculaire, c’est-à-dire la pré-éclampsie, le HELLP syndrome, le retard de croissance intra-utérin (RCIU) vasculaire, l’hématome rétro-placentaire et la mort fœtale in utero (MFIU) d’origine vasculaire. La pré-éclampsie doit faire rechercher un syndrome des antiphospholipides (SAPL) en cas de critères de sévérité et d’accouchement prématuré avant 34 SA. Au-delà de la recherche de SAPL, l’analyse anatomopathologique placentaire permet d’identifier certaines prédispositions anatomiques à la mal-perfusion vasculaire placentaire, ainsi que des lésions inflammatoires chroniques placentaires et des dépôts de fibrine en excès. Ces deux dernières sont associées au RCIU et la MFIU, volontiers récidivantes, reflet d’un processus dysimmunitaire d’origine maternelle. La consultation conjointe de médecine interne-obstétrique, organisée deux mois après l’accouchement, permet de combiner la visite post-natale au bilan étiologique de pathologie vasculo-placentaire, et d’informer les patientes sur la prise en charge des grossesses futures et leur santé cardio-vasculaire.

INTRODUCTION:Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome with utero-vaginal aplasia is the most severe form of the Müllerian duct anomalies and can be associated with extra-genital abnormalities such as renal or skeletal anomalies, hearing loss, or cardiac defects. The past two decades have witnessed significant advances both in understanding the etiologies of MRKH and in the development of fertility treatments such as uterine transplantation. The present work aimed to determine the rate of women with MRKH syndrome who underwent optimal initial management (after comprehensive malformation assessment) and to establish the rate of patients eligible for uterine transplantation (i.e., those with a vaginal length ≥7 cm without reconstruction using a bowel segment, and an anti-Müllerian hormone level >1.5 ng/mL before 35 years). MATERIAL AND METHODS:Cohort study of 85 women with MRKH syndrome consulting in our tertiary center. RESULTS:62.4% of women with MRKH syndrome had an exhaustive malformative evaluation according to the French guidelines (Protocole National de Diagnostic et de Soin [PNDS]), of which 76.5% had associated malformations (MRKH type II). Pedigree, when available, showed a family history of infertility or a urogenital tract spectrum anomaly in 60% of cases. Concerning the uterine transplantation selection criteria, when evaluated, 22.6% of women had an anti-Müllerian hormone level <1.5 ng/mL and 36% a vaginal length <7 cm. On the 21 women with complete evaluation of both primary and secondary outcomes, 14 of them would be eligible for a uterine transplantation program at the time of consultation according to the main inclusion criteria of uterine transplantation program. CONCLUSIONS:Women with MRKH syndrome are often inadequately explored for associated malformations. Early assessment and monitoring of the ovarian reserve is key for fertility preservation, especially in the era of uterine transplantation.

Hormonal exposure leads to an increased risk of venous thromboembolism (VTE) but the risk of VTE associated with assisted reproductive technology (ART) is not clearly determined. We searched in PubMed, EMBASE, Web of Science, and the Cochrane Library databases and identified all relevant articles published up to February 1, 2021. The primary objective was to determine the frequency of VTE associated with ART. Secondary objectives were to determine (1) the risk of VTE associated with ART as compared to pregnancy without ART; (2) the risk of VTE associated with ovarian hyperstimulation syndrome (OHSS); and (3) to determine potential risk factors of VTE related to ART. Fourteen studies were included. The overall frequency of VTE associated with ART was 0.23% (95% confidence interval [CI]: 0.07-0.46). Women undergoing ART had a two-to threefold increased risk of VTE as compared to spontaneous pregnancy (relative risk [RR]: 2.66; 95% CI: 1.60-4.43). The overall frequency of VTE specifically related to OHSS was < 0.001%. The risk of VTE after ART complicated by OHSS, as compared to ART without OHSS, was higher but not statistically significant (RR: 14.83; 95% CI: 0.86- 255.62). Risk factors of VTE associated with ART were in vitro fertilization procedure (RR, odds ratio [OR], and hazard ratio varying from 1.77, 95% CI: 1.41-2.23 to 4.99, 95% CI: 1.24-20.05), hyperhomocysteinemia (OR: 15.2; 95% CI: 2.0-115.0), polycystic ovarian syndrome (PCOS) (RR: 4.8; 95% CI: 1.7-13.4), successful ART leading to pregnancy (OR: 13.94; 95% CI: 1.41-137.45). Further large prospective studies on risk factors of VTE in women undergoing ART are needed in order to optimize thromboprophylaxis in this context.

There are less than ten cases of deep endometriosis degeneration in the literature. The duration of endometriosis, the ovarian stimulation, the perimenopause and the obesity exposes the woman to an increased risk of endometriosis degeneration.

Early pregnancy loss (EPL) is a spontaneous miscarriage of a clinical pregnancy during the �rst trimester. Several factors of EPL have been studied but results were discordant. We performed a retrospective study in our ART center, comparing baseline data and IVF/ICSI outcomes between cycles with EPL, ongoing pregnancy and without pregnancy. Ectopic pregnancies and biochemical pregnancies (without visualization of a gestational sac on ultrasound) were excluded. The aim of this study is to compare these different cycles, and analyze the risk factors for EPL. We included 2555 IVF/ICSI cycles leading to 2193 oocyte pick-ups and 1806 embryo transfers. Several characteristics (women’s age, infertility diagnosis and duration, estradiol level on the day of hCG-trigger, endometrial thickness, day of embryo transfer) appeared to be risk factors of EPL in univariate analysis. Only women’s age has a signi�cant (p < 0.001) in�uence in multivariate analysis on the rate of EPL, with an OR: 1.71 if the woman’s age ≥ 35 years old (reference < 35 y.o = 1), 2.96 if ≥ 38 y.o and 5.31 if ≥ 40 y.o. In this study, we observed an increase in EPL rate by 4.15% per year in women over 35 years of age.

BACKGROUND: Postpartum hemorrhage is a major component of perinatal morbidity and mortality that affects young women worldwide and is still often unpredictable. Reducing the incidence of postpartum hemorrhage is a major health issue and identifying women at risk for postpartum hemorrhage is a key element in preventing this complication.OBJECTIVE: This study aimed to estimate postpartum hemorrhage prevalence after vaginal delivery and to identify postpartum hemorrhage risk factors.STUDY DESIGN: Unselected pregnant women >16 years of age admitted to 1 of 6 maternity wards in Brittany (France) for vaginal birth after 15 weeks of gestation were recruited in this prospective, multicenter cohort study between June 1, 2015, and January 31, 2019. Postpartum hemorrhage was defined as blood loss >500 mL in the 24 hours following delivery. Independent risk factors for postpartum hemorrhage were deter-mined using logistic regression. Missing data were imputed using the Mul-tivariate Imputation by Chained Equations method.RESULTS: Among 16,382 included women, the postpartum hemor-rhage prevalence was 5.37%. A first-degree family history of postpartum hemorrhage (adjusted odds ratio, 1.63; 95% confidence interval, 1.24-2.14) and a personal transfusion history (adjusted odds ratio, 1.90; 95% confidence interval, 1.23-2.92) were significantly associated with postpartum hemorrhage. The use of oxytocin during labor was also a risk factor for postpartum hemorrhage (adjusted odds ratio, 1.24; 95% confi-dence interval, 1.06-1.44). Inversely, smoking during pregnancy and intrauterine growth restriction were associated with a reduced risk for postpartum hemorrhage (adjusted odds ratio, 0.76; 95% confidence inter -val, 0.63-0.91, and 0.34; 95% confidence interval, 0.13-0.87, respectively).CONCLUSION: In addition to classical risk factors, this study identified a family history of postpartum hemorrhage and personal transfusion history as new characteristics associated with postpartum hemorrhage after vaginal delivery. The association of postpartum hemorrhage with a family history of postpartum hemorrhage suggests a hereditary hemorrhagic phenotype and calls for genetic studies. Identifying women at risk for postpartum hemorrhage is a key element of being prepared for this complication.

Many studies failed to show a predictive impact of AMH levels on the chances of pregnancy; however, acceptable pregnancy rates for young women with low AMH levels were observed in IVF + / - ICSI. The objectives of this retrospective study were to evaluate the clinical pregnancy and live birth rates in the first IVF + / - ICSI cycle in women under 38 years old with AMH level < 1.2 ng/ml and to determine the arguments for care. We classified the women into three groups: group A: AMH < 0.4 ng/ml (n: 86); group B: AMH: 0.4 to 0.8 ng/ml (n: 90); and group C: AMH > 0.8 to < 1.2 ng/ml (n: 92). We recorded data on the patients' characteristics, stimulation cycles, embryo cultures, and ongoing pregnancies. No difference was observed between the three groups for the number of embryos transferred, the clinical pregnancy, and the live birth rates (LBR) per embryo transfer (LBR/transfer: 24.1% in group A, 25.9% in group B, and 28.1% in group C). The young age of the women reassures about the oocyte quality, but a low level of AMH may raise concerns about a lower quantitative oocyte yield, leading to accelerated management of the couple in IVF + / - ICSI.

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is the most severe form of congenital malformation of the inner female reproductive tract. It is diagnosed as such when the uterus, the upper vagina and optionally the Fallopian tubes are absent. It accounts for approximately 1 in 5000 live-born females and has been classified in two subtypes: type 1 in the presence of isolated uterovaginal aplasia and type 2 when associated in various combinations with extragenital malformations of the kidneys, skeleton, heart and auditory system. Most cases of MRKH syndrome are sporadic, although a significant number of many familial cases have been reported to date. Despite numerous studies, the genetics of the syndrome remains largely unknown and appears to be heterogeneous: chromosomal abnormalities and some candidate gene variants appear to be associated with a few cases; others have been suggested but not yet confirmed. To date, mainly the GREB1L gene appears to be a serious candidate. Among the remaining hypotheses, the controversial contribution of partial duplications of the SHOX gene is still puzzling, as the deficiency of this gene is a major cause of skeletal adysplasia syndromes. We have attempted to resolve this controversy in a study of 60 MRKH cases. Our results tend to show that SHOX duplications can be the origin of a genetic mechanism responsible for MRKH syndrome.

Dietary supplementation is commonly used in men with male infertility but its exact role is poorly understood. The aim of this multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the impact of high-dose folic acid supplementation on IVF-ICSI outcomes. 162 couples with male infertility and an indication for IVF-ICSI were included for one IVF-ICSI cycle. Male partners of couples wishing to conceive, aged 18–60 years old, with at least one abnormal spermatic criterion were randomized in a 1:1 ratio to receive daily supplements containing 15 mg of folic acid or a placebo for 3 months from Day 0 until semen collection for IVF-ICSI. Sperm parameters and DNA fragmentation before and after the treatment and the biochemical and clinical pregnancy rates after the fresh embryo transfer were analyzed. We observed an increase in the biochemical pregnancy rate and a trend for a higher clinical pregnancy rate in the folic acid group compared to placebo (44.1% versus 22.4%, p = 0.01 and 35.6% versus 20.4%, p = 0.082, respectively). Even if no changes in sperm characteristics were observed, a decrease in DNA fragmentation in the folic acid group was noted (8.5 ± 4.5 vs. 6.4 ± 4.6, p < 0.0001). High-dose folic acid supplementation in men requiring IVF-ICSI for male infertility improves IVF-ICSI outcomes.

Congenital uterine anomalies (CUA) may have major impacts on the health and social well-being of affected individuals. Their expressivity is variable, with the most severe end of the spectrum being the absence of any fully or unilaterally developed uterus (aplastic uterus), which is a major feature in Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). So far, etiologies of CUA remain largely unknown. As reports of familial occurrences argue for strong genetic contributors in some cases, we performed whole exome sequencing in nine multiplex families with recurrence of uterine and kidney malformations, a condition called hereditary urogenital adysplasia. Heterozygous likely causative variants in the gene GREB1L were identified in four of these families, confirming GREB1L as an important gene for proper uterine and kidney development. The apparent mode of inheritance was autosomal dominant with incomplete penetrance. The four families included fetuses with uterovaginal aplasia and bilateral renal agenesis, highlighting the importance to investigate GREB1L in such phenotypes. Subsequent sequencing of the gene in a cohort of 68 individuals with MRKH syndrome or uterine malformation (mostly sporadic cases) identified six additional variants of unknown significance. We therefore conclude that heterozygous GREB1L variants contribute to MRKH syndrome and this probably requires additional genetic or environmental factors for full penetrance.

Objectives.-Based on data from a vast medical-psychopathological research study proposed to girls suffering from utero-vaginal agenesis Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH), the value and the function of a frequently occurring (10%) bulimic disorder (with weight gain) at the announcement of the diagnosis are analyzed from a psychodynamic perspective. The psychic implications of the diagnosis and its consequences in terms of the modalities of the sessions with these adolescents, alongside genital sexuality, are underlined. The analysis of two cases studies, put into perspective, allows us to refine our understanding of the meaning of this food-related symptom. Therefore, this could both constitute a defensive modality signaling the impasses of the process of construction of the feminine as it could be a lever of psychic transformation of the traumatic repercussions of this process. Methods.-Forty young MRKH women aged 19 to 34 (with an average age of 25 1/2) are met. The research is offered to them from two to 17 years after their diagnostic announcement; clinical reflection consists of a retrospective analysis of their adolescent traumatic experience. The patients' stories are collected using a clinical research non-directive interview. Two projective methods Rorschach and Thematic Apperception Test (TAT) are also proposed to better understand the modalities of their psychic functioning at the time of the clinical encounters. Interview data are subjected to a thematic clinical analysis. The protocols of the Rorschach and of the TAT are analyzed according to the method of interpretation of the French School, which refers to the psychoanalytic theory of psychic functioning. The material, resulting from sessions with two patients diagnosed with MRKH at the age of 17 and having gained 10 kg in the aftermath of this announcement, is compared in a thorough way. Results. - The contrasts in terms of problematics and of levels of elaboration between the interview and the projective protocols are striking for each patient. With the analysis of the interview, the bulimic symptom of the first patient occurs in a psychic context where feminine interiority seems unrepresentable. On the contrary, projective protocols reveal access to conflicting and symbolic feminine work. In the same way, the second patient's discourse about her symptom is at first sight much more elaborate than that of the first patient; she establishes a subjective link between the renunciation of maternity inherent in the announcement of MRKH and the compensatory dimension provided by weight gain. However, the discrepancy with the projective tests is surprising in this second patient. Indeed, her productions reflect fragilities in her identity and an insufficient symbolization of the sexual that testify to the defensive value of the excessive symbolization of her speech, evident in the interview. Discussion. - These contrasts lead us to consider binge-eating as an attempt to treat an already conflicting female sexuality, even in deadlock, before the discovery of MRKH. Its traumatic accents are updated and potentiated with the diagnostic announcement. The different levels of identified problems can coexist in a same woman, whether it is a feminine that has neither been constructed nor integrated; an impossible investment of the internal body; or a counter-investment of an impossible maternity. In this context, the etiopathogeny of weight gain subsequent to the announcement of the diagnosis is unique for each young woman, but always in connection with an affected or wounded feminine and/or maternal. Conclusion. - In conclusion, if the weight gain following the diagnosis reflects a hindrance or even an impasse (possibly punctual) of the psychic treatment of its effects, this medical announcement in adolescence can constitute, afterwards, a new chance for these girls, with a potentially mutative value. (C) 2020 Elsevier Masson SAS. All rights reserved.

Although it has been clearly stated that vaginal dilation must be considered the first-line treatment for clinical conditions characterized by an absent or hypoplastic vagina, mainly Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, a great number of scientific papers on surgical vaginal reconstructions are reported every year. This wide variety of surgical techniques (more than 10) are recognized and performed worldwide, making it difficult to compare results and define an evidence-based approach. Standardized treatment should be considered even more important in the pediatric and adolescent population for the implications offered by the uterus transplantation scenario.

Sperm and embryos cryopreservation is a commonly applied technique for several years. Recently authorized in France, vitrification tends to replace gradually the conventional technique of slow freezing, so upsetting the practices in the management of patients. It allows from now on the cryopreservation of oocytes and opens new perspectives in egg donation either still in fertility preservation. This review thus attempted to examine the contribution of vitrification in the freezing of oocytes and human embryos at various stages of development. If obviously vitrification appears as the current method of choice for the cryopreservation of oocytes as well as blastocystes, the results are less cut as regards embryos to early stages. No increase in adverse obstetric and perinatal outcomes in children conceived from vitrified oocytes or embryos is noted in the literature. (C) 2015 Elsevier Masson SAS. All rights reserved.

Germline mutations BRCA1&2 are responsible in women for breast and ovarian cancers that commonly occur at a young age: as such, there are strong interactions between the oncological risks and the events of reproductive life, pregnancy, breastfeeding, and management of infertility.A review of the international literature from the PubMed database was conducted, and recommendations of French health agencies were exposed. Published studies are case-control and cohort studies in the majority, with a low level of evidence.Pregnancy and lactation have no effect on breast and ovaries or even decreases the risk. The sex ratio among patients carrying the mutation is in favor of girls. It is not observed more infertility in patients carrying a mutation despite a strong suspicion of premature ovarian failure, and infertility treatments do not increase breast and ovarian risk. There are ethical debates concerning the place of pre-natal diagnosis: both experts and concerned patients recommend a case-by-case analysis of the requests.