Abstract Study question Are there significant differences between cumulative live birth rates (CLBR) after a short and an extended embryo culture when comparisons are performed per cycle? Summary answer The CLBR per cycle was significantly lower in the Day-5/6 group and higher per embryo transfer as compared with the Day-2/3 group. What is known already Previous evidence has shown the probability of live birth following a fresh embryo transfer in In Vitro Fertilization (IVF) is higher after extended embryo culture (E-EC: Day-5/6) than after a shorter embryo culture (S-EC: Day-2/3). A further controversy literature has arisen on cumulative pregnancy rates, related to the higher risks of embryo transfer cancellation after E-EC compared with S-EC. Moreover, all of these studies used slow freezing/thawing embryo protocols with a higher survival for Day-2/3 embryos than Day-5/6 embryos. Finally, a recent study combining vitrification highlighted CLBR improvements after E-EC but CLBR were expressed per embryo transfer, not per cycle. Study design, size, duration A French national register study including all IVF cycles with at least one cleaved embryo at day-2 performed in France from 01/2016 to 12/2018 was carried out (n = 165,808 cycles), after exclusion of gamete donation cycles, attempts with preimplantation genetic diagnosis, surgical spermatozoa, viral context, and for which the embryo freezing was performed by slow-freezing. We chose to include only cycles from IVF centers with standardized CLBR similar or above to the national mean (99%CI). Participants/materials, setting, methods From the biomedicine Agency’s registry, two groups were identified: cycles with embryo(s) at Day-2/3 with/without embryo transfer (S-Group) and cycles with all embryos cultured to Day-5/6 with/without embryo transfer (E-Group). The CLBR defined as delivery of at least one live-born infant in fresh or in subsequent frozen-thawed cycles were compared. Only the first delivery was considered. Regression model adjusted for women age, parity, Day-2 embryos, IVF-method and attempt rank was used. Main results and the role of chance In total, 48,293 attempts fulfilled the inclusion criteria. Among them, 31,769 cycles were included in the S-Group and 16,524 in the E-Group. Overall, the CLBR per cycle was significantly lower in the E-Group compared with the S-G group (32.9% versus 33.5%; aOR: 0.89, 95%CI [0.86-0.93], p<.0001). A significant higher rate of fresh embryo transfer cancellation was observed in in the E-Group compared with the S-Group (19.8% versus 3.1%, p < .0001). However, when we performed further comparisons restricted to data from IVF centers with LBR strictly significantly above to the national mean LBR, the CLBR were similar between both groups (36.4% versus 38.5% in S-Group and E-Group, respectively; aOR: 0.97 [0.90-1.04], p = 0.402). Finally, the CLBR in E-group was significantly higher than in S-group when expressed per embryo transfer (aOR: 1.15 [1.10-1.21], p<.0001). Limitations, reasons for caution Main limitations are: the retrospective design and the 1 year follow-up that could not include all frozen embryo cycles performed. Wider implications of the findings Overall, the nationwide results per cycle suggest that extended embyo culture until blastocyst stage, even used in combination with vitrification, could not improve live birth rates. Trial registration number not applicable
Background Risks of maternal morbidity are known to be reduced in pregnancies resulting from frozen embryo transfer (FET) compared to fresh-embryo transfer ( fresh -ET), except for the risk of pre-eclampsia, reported to be higher in FET pregnancies compared to fresh -ET or natural conception. Few studies have compared the risk of maternal vascular morbidities according to endometrial preparation for FET, either with ovulatory cycle (OC-FET) or artificial cycle (AC-FET). Furthermore, maternal pre-eclampsia could be associated with subsequent vascular disorders in the offspring. Methods A 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies was conducted: FET with either OC or AC preparation, and fresh -ET. Data were extracted from the French National Health System database. Results were adjusted for maternal characteristics and infertility (age, parity, smoking, obesity, history of diabetes or hypertension, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency). Results A total of 68025 single deliveries were included: fresh -ET (n=48152), OC-FET (n=9500), AC-FET (n=10373). The risk of pre-eclampsia was higher in AC-FET compared to OC-FET and fresh -ET groups in univariate analysis (5.3% vs. 2.3% and 2.4%, respectively, P <0.0001). In multivariate analysis the risk was significantly higher in AC-FET compared to fresh -ET: aOR=2.43 [2.18-2.70], P <0.0001). Similar results were observed for the risk of other vascular disorders in univariate analysis (4.7% vs . 3.4% and 3.3%, respectively, P =0.0002) and in multivariate analysis (AC-FET compared to fresh -ET: aOR=1.50 [1.36-1.67], P <0.0001). In multivariate analysis, the risk of pre-eclampsia and other vascular disorders were comparable in OC-FET and fresh -ET: aOR=1.01 [0.87-1.17, P = 0.91 and aOR=1.00 [0.89-1.13], P =0.97, respectively).Within the group of FET, the risks of pre-eclampsia and other vascular disorders in multivariate analysis were higher in AC-FET compared to OC-FET (aOR=2.43 [2.18-2.70], P <0.0001 and aOR=1.5 [1.36-1.67], P <0.0001, respectively). Conclusion This nationwide register-based cohort study highlights the possibly deleterious role of prolonged doses of exogenous estrogen-progesterone supplementation on gestational vascular pathologies and the protective role of the corpus luteum present in OC-FET for their prevention. Since OC-FET has been demonstrated not to strain the chances of pregnancy, OC preparation should be advocated as first-line preparation in FET as often as possible in ovulatory women.
Surgical treatment or varicocele embolization (VE) with sclerosing or mechanical embolic agents have been shown to improve the semen parameters of infertile men. The aim of this study was to evaluate the impact of VE using N-butyl cyanoacrylate (NBCA) glue on semen parameters in infertile men. From January 2014 to June 2018, infertile adult patients with stage 3 varicocele and an initial semen analysis showing at least one abnormal semen parameter, and who were successfully embolized with NBCA Glubran®2 glue, were retrospectively recruited. The availability of a second semen analysis after VE was mandatory for patient inclusion. The primary endpoint was the change in total sperm number (TSN) after VE. The other parameters of interest were progressive and total sperm motilities (Smot) at 1 h (H1), sperm vitality (SV) and morphology (SMor). One hundred and two patients were included. Eight patients presented null TSN before and after VE. Among the remaining 94 patients, a significant improvement in the median TSN after VE was shown (31.79 × 106/ejaculate [IQR: 11.10-127.40 × 106/ejaculate] versus 62.24 × 106/ejaculate [IQR: 17.90-201.60 × 106/ejaculate], p = 0.0295). Significant improvement in TSN was found for the 60 oligo- or azoospermic patients (p = 0.0007), whereas no significant change was found for the 42 patients with normal initial TSN (p = 0.49). Other parameters, such as progressive and total SMot, SV and SMor, also significantly improved after VE (p = 0.0003, 0.0013, 0.0356 and 0.007, respectively). The use of NBCA glue as an embolic agent for VE in infertile men with stage 3 varicocele significantly improves the semen parameters.
A summary is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content.
The oocyte transcriptome follows a tightly controlled dynamic that leads the oocyte to grow and mature. This succession of distinct transcriptional states determines embryonic development prior to embryonic genome activation. However, these oocyte maternal mRNA regulatory events have yet to be decoded in humans. We reanalyzed human single-oocyte RNA-seq datasets previously published in the literature to decrypt the transcriptomic reshuffles ensuring that the oocyte is fully competent. We applied trajectory analysis (pseudotime) and a meta-analysis and uncovered the fundamental transcriptomic requirements of the oocyte at any moment of oogenesis until reaching the metaphase II stage (MII). We identified a bunch of genes showing significant variation in expression from primordial-to-antral follicle oocyte development and characterized their temporal regulation and their biological relevance. We also revealed the selective regulation of specific transcripts during the germinal vesicle-to-MII transition. Transcripts associated with energy production and mitochondrial functions were extensively downregulated, while those associated with cytoplasmic translation, histone modification, meiotic processes, and RNA processes were conserved. From the genes identified in this study, some appeared as sensitive to environmental factors such as maternal age, polycystic ovary syndrome, cryoconservation, and in vitro maturation. In the future, the atlas of transcriptomic changes described in this study will enable more precise identification of the transcripts responsible for follicular growth and oocyte maturation failures.
Abstract The use of Assisted Reproductive Technologies (ART) is consistently rising across the world. However, making an informed choice on which embryo culture medium should be preferred to ensure satisfactory pregnancy rates and the health of future children critically lacks scientific background. Particularly, embryos within their first days of development are highly sensitive to their micro-environment. Here, we aimed to determine the impact of culture media composition on gene expression of human preimplantation embryos. By employing single-embryo RNA-sequencing after 2 or 5 days of post-fertilization culture in different commercially available media, we revealed medium-specific differences in gene expression changes. In particular, we found that culture medium composition can affect the dynamics of expression of developmentally relevant genes at day-2 but the differences were mitigated at the blastocyst stage. This study highlights the ability of embryos conceived in suboptimal in vitro culture media to recover proper transcriptome competency.
The high frequency of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene mutation p.Arg117His in patients with congenital bilateral absence of the vas deferens (CBAVD) and in newborns screened for CF has created a dilemma.Phenotypic and genotypic data were retrospectively collected in 179 non-newborn French individuals carrying p.Arg117His and a second CFTR mutation referred for symptoms or family history, by all French molecular genetics laboratories, referring physicians, CF care centres and infertility clinics.97% of the patients had the intronic T7 normal variant in cis with p.Arg117His. 89% patients were male, with CBAVD being the reason for referral in 76%. In 166/179 patients with available detailed clinical features, final diagnoses were: four late-onset marked pulmonary disease, 83 isolated CBAVD, 67 other CFTR-related phenotypes, including 44 CBAVD with pulmonary and/or pancreatic symptoms and 12 asymptomatic cases. Respiratory symptoms were observed in 30% of the patients, but the overall phenotype was mild. No correlation was observed between sweat chloride concentrations and disease severity. Five couples at risk of CF offspring were identified and four benefited from prenatal or preimplantation genetic diagnoses (PND or PGD). Eight children were born, including four who were compound heterozygous for p.Arg117His and one with a severe CF mutation.Patients with CBAVD carrying p.Arg117His and a severe CF mutation should benefit from a clinical evaluation and follow-up. Depending on the CBAVD patients' genotype, a CFTR analysis should be considered in their partners in order to identify CF carrier couples and offer PND or PGD.
