In men, cystic fibrosis (CF) leads to infertility in over 95% of cases, due to early and progressive atresia of the vas deferens, resulting in obstructive azoospermia. The advent of highly effective modulator therapy has enabled more men with CF to consider parenthood, raising important questions regarding the impact of these treatments on male fertility. Animal models provide major insights into the mechanism of CF-related reproductive tract abnormalities, yet high interspecies variability complicates model selection. Mouse models display heterogeneous phenotype: knock-in or partial knockout models usually remain fertile, whereas complete knockouts may develop vas deferens atresia with aging. Among currently studied models, CF transmembrane conductance regulator (CFTR)-knockout rats more closely reproduce the human phenotype, showing bilateral absence of the vas deferens and epididymal hypoplasia, although they exhibit more pronounced hypospermatogenesis than observed in men. In larger animal models, including ferrets, pigs, sheep and rabbits, absence of the vas deferens duct and epididymis is frequently observed, often with normal testicular histology; however, most studies in these species have mainly focused on neonatal stages, leaving long-term reproductive outcomes uncharacterized. No single model fully replicates human male reproductive pathology in CF. Combining rodent and large-animal models is probably essential to elucidate the mechanisms of vas deferens absence and to assess the long-term effects of CFTR modulators on male spermatogenesis and reproductive outcomes.

Preterm birth is known to severely impact the neurological development of newborns with long-lasting complications and higher risks of neurological disorders. Sheep (Ovis aries) is well known as a pre-clinical model in therapeutic studies, such as extra-uterine support. The aim of our study was to investigate the relevance of the lamb as a pre-clinical model for preterm birth when cortical maturation of preterm and term lamb is addressed. Cesarean sections were performed on time-dated pregnant ewes to obtain 13 lambs at 100 days and 140 days of pregnancy each (corresponding to 24 and 36 weeks of pregnancy in humans, respectively). Brains were collected and separated in frontal lobe, temporo-parietal lobe, occipital lobe, and cerebellum. Immunohistochemistry staining was used for each brain area by targeting neurons, interneurons, synaptic vesicles, oligodendrocytes, myelin, astrocytes, and microglia. Quantifications were normalized by the surface area of analysis. Overall, 140-days late preterm lambs have significantly higher mean positivity for interneurons, synaptic vesicles, oligodendrocytes, astrocytes, and myelin than 100-days extremely preterm lambs. Similarly, significantly higher mean positivity for neurons was found in the cerebellum of 140-days term lambs. No significant difference was observed regarding microglia. Based on the cellular and structural markers used in this study, brain development in lamb seems to follow an antero-posterior direction similarly to what was reported in humans. Further studies with more specific markers and in-depth analysis will allow for a more accurate and exhaustive description of brain development in lamb.

PIWI proteins and their associated piRNAs constitute a highly conserved pathway that is essential for maintaining germline genome integrity through transposon silencing, viral defence, and RNA protection in germ cells. In mammals, defects in this pathway might lead to meiotic failure and infertility. However, the contributions of individual PIWI genes to human spermatogenesis remain poorly defined. Here, we report on a 29-year-old man with non-obstructive azoospermia and found to carry a homozygous frameshift mutation in PIWIL1 (NM_004764.5:c.1176_1179delAACT). Histological examination of testicular tissue revealed spermatogenic arrest at the spermatocyte stage, and immunohistochemistry confirmed the absence of the full-length PIWIL1 protein and the absence of spermatids. Considering the low reported variant frequency for such a highly conserved mechanism, we evaluated the genetic constraints on PIWIL1. A comparison of mRNA and amino acid sequences in the human vs. the great apes revealed the likely presence of purifying selective pressure. Taken as a whole, these data reinforce the body of evidence showing that PIWIL1 is essential for human spermatogenesis and highlight the importance of the piRNA pathway in safeguarding the male germline. Defects in genome defence mechanisms might therefore constitute an underexplored cause of human male infertility.

Background The incidence of non-small cell lung cancer (NSCLC) is increasing in women, including those of childbearing age. While recent drugs such as osimertinib and alectinib have improved the prognosis of specific molecular subtypes (e.g., EGFR-mutant and ALK-rearranged NSCLC), their potential use during pregnancy remains inadequately supported by pharmacological data. Objective To assess the transplacental transfer and placental cotyledon accumulation of osimertinib and alectinib, using a human ex vivo placental perfusion model. Study design Term placentas from normal pregnancies were collected after delivery and perfused with osimertinib or alectinib (in combination with alectinib major active metabolite M4) doses simulating steady state plasma concentrations observed in maternal plasma. Fetal transfer rate, clearance index, and cotyledon accumulation were evaluated, with antipyrine used as a control marker. Samples were collected during a 90-min procedure. Results Significant transplacental transfer of osimertinib was observed, with a fetal transfer rate of 9.5% and a CI of 0.41, and cotyledon accumulation of 28.9%. In contrast, neither alectinib nor M4 were detected in fetal samples, although both were found to accumulate substantially in placental tissues (370.7% and 178.3%, respectively). Conclusion These findings suggest that osimertinib crosses the placenta with a moderate tissue uptake, while alectinib and its metabolite M4 do not appear to be transferred to the fetus but accumulate significantly within the placental tissue. Further studies are needed to guide treatment selection for NSCLC in pregnant women.

RESEARCH QUESTION:How do microsurgical epididymal sperm aspiration (MESA) outcomes in men with cystic fibrosis compare with those with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders (CFTR-RD), and what is the impact of CFTR variants on MESA success rates and subsequent cumulative outcomes after ICSI? DESIGN:A retrospective cohort study, conducted from 2003 to 2023 at Lille University Hospital, involved 147 participants with congenital bilateral absence of vas deferens (cystic fibrosis, n = 70; CFTR-RD, n = 77) who underwent MESA. Epididymal sperm extraction outcomes were compared, followed by an analysis of ICSI results in 108 patients who used their cryopreserved epididymal spermatozoa (cystic fibrosis, n = 49; CFTR-RD, n = 59). RESULTS:MESA outcomes were significantly poorer in the cystic fibrosis group. Extraction failure rates were 18.6% for cystic fibrosis and 3.9% for CFTR-RD (P = 0.01), and good-quality extraction rates were 45.7% for cystic fibrosis and 75.3% for CFTR-RD (P < 0.001). Cystic fibrosis was associated with an increased risk of extraction failure (odds ratio 11.3) and a 60% reduction in the probability of good-quality extraction. Among cystic fibrosis patients, CFTR variants without residual CFTR activity led to poorer outcomes: higher extraction failure rates (27.9% versus 3.7%, P < 0.001), lower good-quality extraction rates (30.2% versus 70.4%, P = 0.002) and reduced sperm concentration (3.5 versus 18.0 million/ml, P = 0.014). Cumulative success rates of ICSI did not differ significantly across groups. CONCLUSIONS:Cystic fibrosis patients exhibit poorer MESA outcomes than CFTR-RD patients, with the absence of residual CFTR activity significantly affecting the results. Cumulative ICSI outcomes were highly favourable for cystic fibrosis patients, showing no significant differences from CFTR-RD patients.

Although maternal obesity influences placental and fetal development, the underlying molecular mechanisms have yet to be determined. Oxidative and inflammatory status at the fetal-placental unit appear to be involved in the early fetal metabolic programming. The objective of the present study is to reveal a potential role of sphingolipids in stablishing an oxidative and inflammatory status in the maternal-placental-fetal unit, as function of fetal sex. Term placenta and maternal and fetal plasma were collected from lean (BMI 18-25 kg/m2) and obese women (BMI 30-40 kg/m2) without gestational diabetes aged from 20 to 40 having undergone a cesarean section. Firstly, key markers of oxidative stress and inflammation were studied with immunoblotting and biochemical assays. Secondly, the maternal-placental-fetal unit's sphingolipid profile was determined by mass spectrometry. Lastly, the placental samples' transcriptome was analyzed by RNA sequencing. Obese mothers showed lower plasma levels of ceramide Cer 20:0 (p = 0.02). Surprisingly, placental ceramide content was not influenced by maternal obesity. Nevertheless, male placentas from obese women showed a higher sphingomyelin content and hypo-inflammation as showed by RNAseq. Both males and female placentas from obese women showed higher levels of oxidative stress as showed by the oxidative stress markers (protein carbonylation and lipid peroxidation). However, RNAseq revealed an upregulation of oxidative stress mechanisms only in female placentas. Whatever the newborn's sex, maternal obesity was associated with higher fetal plasma oxidative stress. In conclusion, our results revealed sex-specific features in the placental transcriptome, highlighted placental metabolic adaptations, and provided insights into the underlying molecular mechanisms of fetal programming.

Down syndrome (DS), the consequence of a third copy of human chromosome 21, is the most common chromosomal disorder. Several comorbidities are inconstantly associated with DS, but intellectual disability (ID) is the constant and major feature of disability. ID might be caused by several defects in neurodevelopmental processes. Among them, neuroinflammation and microglial activation have been reported in DS fetuses and children. Recent studies suggest that anti-inflammatory treatment in mouse models of DS could rescue this phenotype. The Pre-Implantation Factor (PIF) is a peptide known to have immune-modulatory, anti-inflammatory, and neuroprotective effects, and has the advantages of being physiologically secreted by the embryo and to pass the blood brain barrier. We therefore investigated the potential beneficial effect of the peptide on cognitive deficit and microglial activation, in the adult Dp (16)1Yey mouse model of DS. We showed that treatment with synthesized PIF (sPIF) in the adult Dp (16)1Yey mice improves short-term working memory and reduces microglial activation by restoring its ramification. We also showed molecular effects of sPIF treatment on microglia by lowering Iba1, Dyrk1A and EF21 levels, and by upregulating P2Y12 level. In conclusion, sPIF can rescue some aspects of cognitive deficits and modifies positively microglia morphology in a mouse model of DS.

STUDY QUESTION:What other zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) partners are involved in premature ovarian insufficiency (POI)? SUMMARY ANSWER:This study identifies novel pathogenic variants in zinc finger SWIM domain-containing protein 7 (SWS1/ZSWIM7) and its partner, SWSAP1, which impair interhomolog homologous recombination (IH-HR) and lead to isolated POI. WHAT IS KNOWN ALREADY:Knockout mice models of the SWS1-complex (also known as the SWS1-SWSAP1-SPIDR complex or Shu complex) are infertile due to meiotic arrest. Variants of both SWS1/ZSWIM7 and SPIDR are described in POI, but so far, no SWSAP1 variants have been described in female infertility. STUDY DESIGN, SIZE, DURATION:Screening for SWS1-complex variants was performed using exome or genome sequencing data from women with POI as ongoing patient care. In silico modelling, IH-HR assays, and western-blot analysis were performed to test the impact of novel variants identified in genes of the SWS1-complex (SWSAP1 and SWS1/ZSWIM7) on homologous recombination, protein expression, and protein interactions. PARTICIPANTS/MATERIALS, SETTING, METHODS:Five unrelated patients from France were enrolled based on their exome or genome sequencing result as part of ongoing patient care. All the patients were diagnosed with POI and met the European Society of Human Reproduction and Embryology (ESHRE) diagnostic criteria for POI. Functional validation was performed using mouse embryonic stem cells to study the impact of two novel variants found in two patients. MAIN RESULTS AND THE ROLE OF CHANCE:We report five different pathogenic or likely pathogenic variants in five patients. We report the previously described c.231_232del and c.176C>T variants in SWS1/ZSWIM7, as well as two novel variants, c.22del and c.151C>T. Additionally, we report a homozygous frameshift deletion in SWSAP1 (c.353del). All the patients display a similar phenotype of severe isolated POI, associated with primary or early secondary amenorrhea and signs of puberty delay. In silico modelling and IH-HR assays of both SWS1/ZSWIM7 c.176C>T and SWSAP1 c.353del indicated a partial decrease or absence of IH-HR activity in Sws1-/- or Swsap1-/- cells, respectively, and destabilization of the SWSAP1 truncation mutant. LIMITATIONS, REASONS FOR CAUTION:Identification of other patients carrying SWSAP1 variants is needed to evaluate in-depth phenotype to genotype correlations. Future studies should evaluate the role of other genes in the SWS1-complex and explore the potential for therapeutic interventions targeting homologous recombination. WIDER IMPLICATIONS OF THE FINDINGS:These findings provide direct clinical and functional evidence that all three members of the SWS1-complex are implicated in female fertility and recapitulate the observed mouse phenotypes. IH-HR assays provide a relevant functional approach to validate novel variants in homologous recombination genes for POI patients, given the importance of IH-HR for meiotic progression. STUDY FUNDING/COMPETING INTEREST(S):The French Genomic Medicine Initiative PFMG2025 is supported by grants from the French government, notably by the French National Research Agency under the Programme d'Investissments d'Avenir for the CAD (ANR-21-ESRE0001) and the CRefIX (ANR-10-INBS-09-01). M.J. was supported by R01 HD112624 and R35CA253174 grants. E.J.T. was supported by a Norman Beischer Fellowship and a Centre for Research Excellence for Women's Health in Reproductive Life (CRE-WHiRL) fellowship from the National Health and Medical Research Council (NHMRC). J.F.M. was supported by a Research Training Program scholarship from the Australian Government. The authors declare no competing interests. TRIAL REGISTRATION NUMBER:This manuscript included genomic analysis performed in clinical practice in patients with RD/CGP and cancers in France. Consequently, a clinical trial NCT number was not required as we reported in this manuscript results obtained in clinical practice. In compliance with the French law on bioethics (2004-800, 06/08/2004), patients had signed written informed consent forms for clinical practice and had been informed of the research use of what remained of their samples after establishing the molecular diagnosis.

Understanding how ageing impacts endometrial function is crucial for preserving fertility in older females. While ageing-related cellular dysfunction and inflammation are observed in the bovine uterus, its effects on endometrial physiology remain unclear. Using an experimental model of young (4-7 years) and old (13-15 years) cloned female cattle, we assessed the effect of ageing on the endometrium through transcriptome profiling and responses of cultured endometrial cells to interferon tau (IFNT) and of cultured endometrial explants to LPS. Progesterone profiles were similar between young and old females. Transcriptomic analysis of endometrial biopsies on day 15 of the estrous cycle identified 859 differentially expressed genes (DEG; p ≤ 0.05, |FC| ≥ 1.5), among which 402 DEG were over-expressed and 457 DEG were under-expresssed in old females. These DEG are linked to immune, inflammatory, metabolic, and cell organization pathways and networks. RT-qPCR validation of selected candidate DEG revealed an increased expression of COL4A3, CPA3, IGFBP1, IGFBP2, RSAD2, SCARA5, and SERPINA14 in young females. In vitro stimulation with IFNT of primary uterine glandular epithelial and stromal cells revealed that glandular epithelial cells exhibit a greater sensitivity to IFNT than stromal cells, both in old and young females. Glandular epithelial cells derived from old females exhibit a weaker response to IFNT, in terms of the number of differentially expressed genes, compared to those from young females. The effect of LPS treatment on cytokine concentrations was lightly more pronounced in young females than in old females, with LPS leading to a significant increase in the concentration of IL-1α, IL-1β, IL-6 and IL-10 in young females. By altering the transcriptomic profile of the endometrium and its capacity to respond to both the embryo's signal and inflammatory factors, we propose that age may be a key factor underlying uterine-related reproductive failures. Further experiments are required to confirm this hypothesis.

Background: In 2015, it was discovered that mutations in the TEX11 gene are associated with azoospermia in general and meiotic maturation arrest in particular. TEX11 is a component of the ZZS complex (comprising Zip2-, Zip4- and Spo16 and originally described in Saccharomyces cerevisiae). During meiosis, this complex is required for the promotion of double-strand break (DSB) repair and thus the maintenance of genomic integrity. Since the initial discovery, several variants and deletions in TEX11 have been reported in patients with spermatogenesis defects. However, many of these new variants have not been functionally validated, which makes it difficult to confirm their direct impact on meiosis. The exonic in-frame deletion TEX11-c.652del237bp has been recurrently identified in infertile men. However, mice models carrying this deletion remain fertile—suggesting that these models may not faithfully replicate human meiotic phenotypes. To address this discrepancy, we functionally validated the TEX11-c.652del237bp variant in vitro. Methods: After amplification in Escherichia Coli DH5α, the pIRES2-EGFP plasmid containing either the wild-type TEX11 sequence or the TEX11-c.652del237bp sequence was transfected into the HEK293 human embryonic kidney cell line. qPCR and Western blot analyses were then used to evaluate the presence and expression levels of TEX11 mRNA and TEX11 protein. Results: The qPCR and Western blot analyses showed that truncated mRNA and protein were produced in cells transfected with the c.652del237bp variant. Hence, the deletion probably leads to the transcription and translation of TEX11 in human testis. Furthermore, in silico modeling suggested that the deletion does not have a significant impact on the ZZS complex. Conclusions: Our in vitro and in silico data demonstrate that the c.652del237bp in-frame deletion results in a truncated TEX11 protein and thus question the deletion’s pathogenic role in human meiosis. However, the absence of a meiotic phenotype in the corresponding mouse model is suggestive of species-specific differences in TEX11 endogenous function. Further studies (such as co-immunoprecipitation experiments with other ZZS complex proteins) are needed to fully assess the functional impact of TEX11-c.652del237bp. These experiments might also provide novel insights into the specific role of the TEX11 SPO22 domain in human spermatogenesis.

Fetal death is defined as the spontaneous cessation of cardiac activity after fourteen weeks of amenorrhea. In France, the prevalence of fetal death after 22 weeks is between 3.2 and 4.4/1000 births. Regarding the prevention of fetal death in the general population, it is not recommended to counsel for rest and not to prescribe vitamin A, vitamin D nor micronutrient supplementation for the sole purpose of reducing the risk of fetal death (Weak recommendations; Low quality of evidence). It is not recommended to prescribe aspirin (Weak recommendation; Very low quality of evidence). It is recommended to offer vaccination against influenza in epidemic periods and against SARS-CoV-2 (Strong recommendations; Low quality of evidence). It is not recommended to systematically look for nuchal cord encirclements during prenatal screening ultrasounds (Strong Recommendation; Low Quality of Evidence) and not to perform systematic antepartum monitoring by cardiotocography (Weak Recommendation; Very Low Quality of Evidence). It is not recommended to ask women to perform an active fetal movement count to reduce the risk of fetal death (Strong Recommendation; High Quality of Evidence). Regarding evaluation in the event of fetal death, it is suggested that an external fetal examination be systematically offered (Expert opinion). It is recommended that a fetopathological and anatomopathological examination of the placenta be carried out to participate in cause identification (Strong Recommendation. Moderate quality of evidence). It is recommended that chromosomal analysis by microarray testing be performed rather than conventional karyotype, in order to be able to identify a potentially causal anomaly more frequently (Strong Recommendation, moderate quality of evidence); to this end, it is suggested that postnatal sampling of the placental fetal surface for genetic purposes be preferred (Expert Opinion). It is suggested to test for antiphospholipid antibodies and systematically perform a Kleihauer test and a test for irregular agglutinins (Expert opinion). It is suggested to offer a summary consultation, with the aim of assessing the physical and psychological status of the parents, reporting the results, discussing the cause and providing information on monitoring for a subsequent pregnancy (Expert opinion). Regarding announcement and support, it is suggested to announce fetal death without ambiguity, using simple words and adapting to each situation, and then to support couples with empathy in the various stages of their care (Expert opinion). Regarding management, it is suggested that, in the absence of a situation at risk of disseminated intravascular coagulation or maternal vitality, the patient's wishes should be taken into account when determining the time between the diagnosis of fetal death and induction of birth. Returning home is possible if it's the patient wish (Expert opinion). In all situations excluding maternal life-threatening emergencies, the preferred mode of delivery is vaginal delivery, regardless the history of cesarean section(s) history (Expert opinion). In the event of fetal death, it is recommended that mifepristone 200mg be prescribed at least 24hours before induction, to reduce the delay between induction and delivery (Low recommendation. Low quality of evidence). There are insufficient data in the literature to make a recommendation regarding the route of administration (vaginal or oral) of misoprostol, neither the type of prostaglandin to reduce induction-delivery time or maternal morbidity. It is suggested that perimedullary analgesia be introduced at the start of induction if the patient asks, regardless of gestational age. It is suggested to prescribe cabergoline immediately in the postpartum period in order to avoid lactation, whatever the gestational age, after discussing the side effects of the treatment with the patient (Expert opinion). The risk of recurrence of fetal death after unexplained fetal death does not appear to be increased in subsequent pregnancies, and data from the literature are insufficient to make a recommendation on the prescription of aspirin. In the event of a history of fetal death due to vascular issues, low-dose aspirin is recommended to reduce perinatal morbidity, and should not be combined with heparin therapy (Low recommendation, very low quality of evidence). It is suggested not to recommend an optimal delay before initiating another pregnancy just because of the history of fetal death. It is suggested that the woman and co-parent be informed of the possibility of psychological support. Fetal heart rate monitoring is not indicated solely because of a history of fetal death. It is suggested that delivery not be systematically induced. However, induction can be considered depending on the context and parental request. The gestational age will be discussed, taking into account the benefits and risks, especially before 39 weeks. If a cause of fetal death is identified, management will be adapted on a case-by-case basis (expert opinion). In the event of fetal death occurring in a twin pregnancy, it is suggested that the surviving twin be evaluated as soon as the diagnosis of fetal death is made. In the case of dichorionic pregnancy, it is suggested to offer ultrasound monitoring on a monthly basis. It is suggested not to deliver prematurely following fetal death of a twin. If fetal death occurs in a monochorionic twin pregnancy, it is suggested to contact the referral competence center, in order to urgently look for signs of acute fetal anemia on ultrasound in the surviving twin, and to carry out weekly ultrasound monitoring for the first month. It is suggested not to induce birth immediately.

AbstractBackgroundDespite recent advances in prenatal genetic diagnosis, medical geneticists still face considerable difficulty in interpreting the clinical outcome of copy‐number‐variant duplications and defining the mechanisms underlying the formation of certain chromosomal rearrangements.Optical genome mapping (OGM) is an emerging cytogenomic tool with proved ability to identify the full spectrum of cytogenetic aberrations.MethodsHere, we report on the use of OGM in a prenatal diagnosis setting. Detailed breakpoint mapping was used to determine the relative orientations of triplicated and duplicated segments in two unrelated foetuses harbouring chromosomal aberrations: a de novo 15q23q24.2 triplication and a paternally inherited 13q14.2 duplication that overlapped partially with the RB1 gene.ResultsOGM enabled us to suggest a plausible mechanism for the triplication and confirmed that the RB1 duplication was direct oriented and in tandem. This enabled us to predict the pathogenic consequences, refine the prognosis and adapt the follow‐up and familial screening appropriately.ConclusionAlong with an increase in diagnostic rates, OGM can rapidly highlight genotype–phenotype correlations, improve genetic counselling and significantly influence prenatal management.

La mort fœtale est définie par l’arrêt spontané de l’activité cardiaque à partir de quatorze semaines d’aménorrhée. La prévalence en France de la mort fœtale après 22 SA est comprise entre 3,2 et 4,4/1000 naissances. Concernant la prévention de la mort fœtale en population générale, il est recommandé de ne pas préconiser le repos et de ne pas prescrire une supplémentation en vitamine A, ni en vitamine D, ni en micronutriments dans le seul but de réduire le risque de mort fœtale (Recommandations faibles ; Qualité de la preuve basse). Il est recommandé de ne pas prescrire de l’aspirine (Recommandation faible ; Qualité de la preuve très basse). Il est recommandé de vacciner contre la grippe en période épidémique et contre le SARS-CoV-2 (Recommandations fortes ; Qualité de la preuve basse). Il est recommandé de ne pas réaliser de recherche systématique d’un circulaire du cordon au cours des échographies de dépistage (Recommandation forte ; Qualité de la preuve basse) et de ne pas réaliser de surveillance antepartum systématique par cardiotocographie (Recommandation faible ; Qualité de la preuve très basse). Il est recommandé de ne pas encourager les femmes à réaliser un compte des mouvements actifs fœtaux pour réduire le risque de mort fœtale (Recommandation forte, qualité de la preuve élevée). Concernant le bilan en cas de mort fœtale, Il est proposé qu’un examen externe fœtal soit systématiquement proposé (Avis d’experts). Il est recommandé de réaliser un examen fœtopathologique et anatomopathologique placentaire afin d’en déterminer la cause (Recommandation Forte. Qualité de la preuve modérée). Il est recommandé de réaliser une analyse chromosomique par puce à ADN plutôt qu’un caryotype conventionnel afin d’identifier plus fréquemment une anomalie potentiellement causale (Recommandation forte, qualité de la preuve modérée) ; pour cela, il est proposé de privilégier un prélèvement postnatal à visée génétique sur la face fœtale placentaire (Avis d’experts). Il est proposé de rechercher des anticorps antiphospholipides et de réaliser systématiquement un test de Kleihauer et la recherche d’agglutinines irrégulières (Avis d’experts). Il est proposé de réaliser une consultation de synthèse ayant pour objectifs d’évaluer l’état physique et psychologique des parents, de restituer les résultats, de discuter la cause et d’informer sur la surveillance pour une future grossesse (Avis d’experts). Concernant l’annonce et l’accompagnement, il est proposé d’annoncer la mort fœtale sans ambiguïté, en utilisant des mots simples, en s’adaptant à chaque situation, puis d’accompagner les couples avec empathie dans les différentes étapes de leur prise en charge (Avis d’experts). Concernant la prise en charge, il est proposé, en l’absence de situation à risque de coagulation intravasculaire disséminée ou à risque vital maternel, de prendre en compte le souhait de la patiente pour déterminer le délai entre le diagnostic de la mort fœtale et l’induction de la naissance. Un retour à domicile est possible si souhaité par la patiente (Avis d’experts). La voie d’accouchement à privilégier dans toutes les situations excluant l’urgence vitale maternelle, est la voie basse, que l’utérus soit cicatriciel ou non (Avis d’experts). En cas de mort fœtale, il est recommandé de prescrire un traitement par mifépristone 200mg au moins 24 heures avant de débuter le déclenchement pour réduire le délai déclenchement—accouchement (Recommandation faible. Qualité de la preuve basse). Les données de la littérature sont insuffisantes pour émettre une recommandation concernant la voie d’administration (vaginale ou orale) du misoprostol, ou le type de prostaglandine pour réduire la durée déclenchement—accouchement ou la morbidité maternelle. Il est proposé de mettre en place une analgésie périmédullaire dès le début du déclenchement si la patiente le souhaite, quel que soit l’âge gestationnel. Il est proposé de prescrire de la cabergoline en post-partum immédiat afin d’éviter une montée laiteuse quel que soit l’âge gestationnel, après avoir discuté des effets secondaires du traitement avec la patiente (Avis d’experts). Le risque de récidive de mort fœtale après une mort fœtale inexpliquée ne semble pas augmenté lors de la grossesse suivante et les données de la littérature sont insuffisantes pour émettre une recommandation quant à la prescription d’aspirine. En cas d’antécédent de mort fœtale d’origine vasculaire, il est recommandé de prescrire de l’aspirine à faible dose afin de diminuer la morbidité périnatale, et de ne pas l’associer à une héparinothérapie (Recommandation faible, Qualité de la preuve très basse). Il est proposé de ne pas préconiser un délai optimal avant d’initier une nouvelle grossesse du seul fait de l’antécédent de mort fœtale. Il est proposé d’informer la femme et le co-parent de la possibilité d’un soutien psychologique. La surveillance par enregistrement du rythme cardiaque fœtal n’est pas indiquée du seul fait de l’antécédent de mort fœtale. Il est proposé de ne pas déclencher systématiquement l’accouchement. Cependant, un déclenchement est possible en fonction du contexte et de la demande parentale. L’âge gestationnel sera discuté en tenant compte des bénéfices et des risques, notamment avant 39 SA. En cas de cause de mort fœtale identifiée, la prise en charge sera adaptée au cas par cas (avis d’experts). En cas de mort fœtale dans le cadre d’une grossesse gémellaire, il est proposé qu’une évaluation du jumeau survivant soit réalisée dès que le diagnostic est posé. Il est proposé que le suivi échographique soit mensuel dans les suites d’une mort fœtale en cas de grossesse bichoriale. Il est proposé de ne pas induire de prématurité à la suite de la mort fœtale d’un jumeau. En cas de diagnostic de mort fœtale dans le cadre d’une grossesse gémellaire monochoriale biamniotique, il est proposé d’informer le centre de compétence, de rechercher en urgence des signes d’anémie fœtale aiguë à l’échographie chez le jumeau survivant et de réaliser une surveillance échographique hebdomadaire le premier mois. Il est proposé de ne pas induire la naissance immédiatement.

Down syndrome (DS) is a genetic disease characterized by a supernumerary chromosome 21. Intellectual deficiency (ID) is one of the most prominent features of DS. Central nervous system defects lead to learning disabilities, motor and language delays, and memory impairments. At present, a prenatal treatment for the ID in DS is lacking. Subcutaneous administration of synthetic preimplantation factor (sPIF, a peptide with a range of biological functions) in a model of severe brain damage has shown neuroprotective and anti-inflammatory properties by directly targeting neurons and microglia. Here, we evaluated the effect of PIF administration during gestation and until weaning on Dp(16)1Yey mice (a mouse model of DS). Possible effects at the juvenile stage were assessed using behavioral tests and molecular and histological analyses of the brain. To test the influence of perinatal sPIF treatment at the adult stage, hippocampus-dependent memory was evaluated on postnatal day 90. Dp(16)1Yey pups showed significant behavioral impairment, with impaired neurogenesis, microglial cell activation and a low microglial cell count, and the deregulated expression of genes linked to neuroinflammation and cell cycle regulation. Treatment with sPIF restored early postnatal hippocampal neurogenesis, with beneficial effects on astrocytes, microglia, inflammation, and cell cycle markers. Moreover, treatment with sPIF restored the level of DYRK1A, a protein that is involved in cognitive impairments in DS. In line with the beneficial effects on neurogenesis, perinatal treatment with sPIF was associated with an improvement in working memory in adult Dp(16)1Yey mice. Perinatal treatment with sPIF might be an option for mitigating cognitive impairments in people with DS.

Azoospermia (the complete absence of spermatozoa in the semen) is a common cause of male infertility. The etiology of azoospermia is poorly understood. Whole-genome analysis of azoospermic men has identified a number of candidate genes, such as the X-linked testis-expressed 11 (TEX11) gene. Using a comparative genomic hybridization array, an exonic deletion (exons 10-12) of TEX11 had previously been identified in two non-apparent azoospermic patients. However, the putative impact of this genetic alteration on spermatogenesis and the azoospermia phenotype had not been validated functionally. We therefore used a CRISPR/Cas9 system to generate a mouse model (Tex11Ex9-11del/Y) with a partial TEX11 deletion that mimicked the human mutation. Surprisingly, the mutant male Tex11Ex9-11del/Y mice were fertile. The sperm concentration, motility, and morphology were normal. Similarly, the mutant mouse line's testis transcriptome was normal, and the expression of spermatogenesis genes was not altered. These results suggest that the mouse equivalent of the partial deletion observed in two infertile male with azoospermia has no impact on spermatogenesis or fertility in mice, at least of a FVB/N genetic background and until 10 months of age. Mimicking a human mutation does not necessarily lead to the same human phenotype in mice, highlighting significant differences species.

Fetal death is defined as the spontaneous cessation of cardiac activity after 14 weeks gestational age (GA). Regarding prevention of fetal death in the general population, it is not recommended to counsel or prescribe rest, aspirin, vitamin A, vitamin D, or micronutrient supplementation; systematically look for nuchal cord during prenatal screening ultrasound; or perform systematic antepartum monitoring by cardiotocography for the sole purpose of reducing the risk of fetal death. It is recommended to offer vaccination against influenza in epidemic periods and against SARS-CoV-2. Regarding evaluation in the event of fetal death, it is recommended that a fetal autopsy and anatomopathologic examination of the placenta be performed; chromosomal analysis be performed by microarray testing, rather than by conventional karyotype (with postnatal sampling of the fetal placental surface preferred for genetic purposes); testing for antiphospholipid antibodies be performed, with systematic Kleihauer-Betke testing and for irregular agglutinins; and summary consultation to discuss these examination results be offered. Regarding announcement and support, it is recommended that fetal death be announced without ambiguity, using simple words adapted to each situation, after which the couple should be supported with empathy across the different stages of their care. Regarding patient management in cases of fetal death, it is recommended that: in the absence of risks for disseminated intravascular coagulation or maternal demise, the patient's wishes regarding the timing between the fetal death diagnosis and labor induction should be considered; return home is possible, according to the patient's wishes; in all situations except maternal life-threatening emergencies, the preferred mode of delivery is vaginal, regardless of previous cesarean section(s); mifepristone 200 mg be prescribed at least 24 h before induction; and perimedullary analgesia be initiated at the start of induction if requested by the patient, regardless of GA. Of note, there is insufficient evidence to recommend either the administration route (i.e., vaginal or oral) of misoprostol or prostaglandin type. Regarding the risk of recurrence after unexplained fetal death: the incidence does not appear to be increased in subsequent pregnancies; in cases with a history of fetal death due to vascular problems, low-dose aspirin is recommended to reduce perinatal morbidity (otherwise, evidence is insufficient to recommend the prescription of aspirin); no optimal delay in initiating another pregnancy should be recommended based solely on a history of fetal death; fetal heart rate monitoring is not indicated based solely on a history of fetal death; although systematic labor induction is not recommended, induction may be considered depending on the context and parental request, and considering fetal age, benefits, and risks, especially before 39 weeks GA. Note that if the cause of fetal death is identified, management should be adjusted on a case-by-case basis. Regarding fetal death in a twin pregnancy, it is recommended that the surviving twin be examined immediately upon fetal death diagnosis; in a dichorionic twin pregnancy, preterm delivery induction is not recommended; in a monochorionic twin pregnancy, the surviving twin should be immediately evaluated for signs of acute fetal anemia, with weekly ultrasound monitoring for the first month, though immediate labor induction is not recommended.

Objectives The performance of non-invasive prenatal screening using cell-free DNA testing of maternal blood in twin pregnancy is underevaluated, while serum marker-based strategies yield poor results. This study aimed to assess the performance of non-invasive prenatal screening for trisomy 21 in twin pregnancy as a first-tier test. Secondary objectives were to assess its failure rate and factors associated with failure. Methods This retrospective cohort study included twin pregnancies in which non-invasive prenatal screening using cell-free DNA was performed as the primary screening strategy between May 2017 and October 2019. We used the NIPT VeriSeq (R) test for in-vitro diagnosis and set a fetal fraction cut-off of 4% for monochorionic pregnancies and 8% for dichorionic ones. Clinical data and pregnancy outcome were collected from physicians or midwives via a questionnaire or were retrieved directly on-site. We calculated the performance of non-invasive cell-free DNA screening for trisomy 21, analyzed its failure rate and assessed potentially associated factors. Results Among 1885 twin pregnancies with follow-up, there were six (0.32%) confirmed cases of trisomy 21. The sensitivity of non-invasive prenatal screening for trisomy 21 was 100% (95% CI, 54.1-100%) and the false-positive rate was 0.23% (95% CI, 0.06-0.59%). The primary failure rate was 4.6%, with 4.0% being due to insufficient fetal fraction. A successful result was obtained for 65.4% of women who underwent a new blood draw, reducing the overall failure rate to 2.8%. Maternal body mass index, gestational age at screening as well as chorionicity were significantly associated with the risk of failure. Conclusion This study provides further evidence of the high performance, at an extremely low false-positive rate, of non-invasive prenatal screening in twins as part of a primary screening strategy for trisomy 21. (c) 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.