Thomas Fréour

Abstract One week after fertilization, human embryos implant into the uterus. This event requires the embryo to form a blastocyst consisting of a sphere encircling a cavity lodging the embryo proper. Stem cells can form a blastocyst model that we called a blastoid 1 . Here we show that naive human pluripotent stem cells cultured in PXGL medium 2 and triply inhibited for the Hippo, TGF-β and ERK pathways efficiently (with more than 70% efficiency) form blastoids generating blastocyst-stage analogues of the three founding lineages (more than 97% trophectoderm, epiblast and primitive endoderm) according to the sequence and timing of blastocyst development. Blastoids spontaneously form the first axis, and we observe that the epiblast induces the local maturation of the polar trophectoderm, thereby endowing blastoids with the capacity to directionally attach to hormonally stimulated endometrial cells, as during implantation. Thus, we propose that such a human blastoid is a faithful, scalable and ethical model for investigating human implantation and development 3,4 .

BACKGROUND: A worldwide increase in the prevalence of obesity has been observed in the past three decades, particularly in women of reproductive age. Female obesity has been clearly associated with impaired spontaneous fertility, as well as adverse pregnancy outcomes. Increasing evidence in the literature shows that obesity also contributes to adverse clinical outcomes following in vitro fertilization (IVF) procedures. However, the heterogeneity of the available studies in terms of populations, group definition and outcomes prevents drawing firm conclusions. A previous meta-analysis published in 2011 identified a marginal but significant negative effect of increased female body mass index (BMI) on IVF results, but numerous studies have been published since then, including large cohort studies from national registries, highlighting the need for an updated review and meta-analysis. OBJECTIVE AND RATIONALE: Our systematic review and meta-analysis of the available literature aims to evaluate the association of female obesity with the probability of live birth following IVF. Subgroup analyses according to ovulatory status, oocyte origin, fresh or frozen-embryo transfer and cycle rank were performed. SEARCH METHODS: A systematic review was performed using the following key words: ('obesity', 'body mass index', 'live birth', 'IVF', 'ICSI'). Searches were conducted in MEDLINE, EMBASE, Cochrane Library, Eudract and clinicaltrial.gov from 01 January 2007 to 30 November 2017. Study selection was based on title and abstract. Full texts of potentially relevant articles were retrieved and assessed for inclusion by two reviewers. Subsequently, quality was assessed using the Newcastle-Ottawa Quality Assessment Scales for patient selection, comparability and assessment of outcomes. Two independent reviewers carried out study selection and data extraction according to Cochrane methods. Random-effect meta-analysis was performed using Review Manager software on all data (overall analysis), followed by subgroup analyses. OUTCOMES: A total of 21 studies were included in the meta-analysis. A decreased probability of live birth following IVF was observed in obese (BMI ≥ 30 kg/m2) women when compared with normal weight (BMI 18.5-24.9 kg/m2) women: risk ratio (RR) (95% CI) 0.85 (0.82-0.87). Subgroups analyses demonstrated that prognosis was poorer when obesity was associated with polycystic ovary syndrome, while the oocyte origin (donor or non-donor) did not modify the overall interpretation. WIDER IMPLICATIONS: Our meta-analysis clearly demonstrates that female obesity negatively and significantly impacts live birth rates following IVF. Whether weight loss can reverse this deleterious effect through lifestyle modifications or bariatric surgery should be further evaluated.

Abstract STUDY QUESTION What recommendations can be provided on the approach to and use of time-lapse technology (TLT) in an IVF laboratory? SUMMARY ANSWER The present ESHRE document provides 11 recommendations on how to introduce TLT in the IVF laboratory. WHAT IS KNOWN ALREADY Studies have been published on the use of TLT in clinical embryology. However, a systematic assessment of how to approach and introduce this technology is currently missing. STUDY DESIGN, SIZE, DURATION A working group of members of the Steering Committee of the ESHRE Special Interest Group in Embryology and selected ESHRE members was formed in order to write recommendations on the practical aspects of TLT for the IVF laboratory. PARTICIPANTS/MATERIALS, SETTING, METHODS The working group included 11 members of different nationalities with internationally recognized experience in clinical embryology and basic science embryology, in addition to TLT. This document is developed according to the manual for development of ESHRE recommendations for good practice. Where possible, the statements are supported by studies retrieved from a PUBMED literature search on ‘time-lapse’ and ART. MAIN RESULTS AND THE ROLE OF CHANCE A clear clinical benefit of the use of TLT, i.e. an increase in IVF success rates, remains to be proven. Meanwhile, TLT systems are being introduced in IVF laboratories. The working group listed 11 recommendations on what to do before introducing TLT in the lab. These statements include an assessment of the pros and cons of acquiring a TLT system, selection of relevant morphokinetic parameters, selection of an appropriate TLT system with technical and customer support, development of an internal checklist and education of staff. All these aspects are explained further here, based on the current literature and expert opinion. LIMITATIONS, REASONS FOR CAUTION Owing to the limited evidence available, recommendations are mostly based on clinical and technical expertise. The paper provides technical advice, but leaves any decision on whether or not to use TLT to the individual centres. WIDER IMPLICATIONS OF THE FINDINGS This document is expected to have a significant impact on future developments of clinical embryology, considering the increasing role and impact of TLT. STUDY FUNDING/COMPETING INTEREST(S) The meetings of the working group were funded by ESHRE. S.A. declares participation in the Nordic Embryology Academic Team with meetings sponsored by Gedeon Richter. T.E. declares to have organized workshops for Esco and receiving consulting fees from Ferring and Gynemed and speakers’ fees from Esco and honorarium from Merck and MSD. T.F. received consulting fees from Vitrolife and Laboratoires Genévrier, speakers’ fees from Merck Serono, Gedeon Richter, MSD and Ferring and research grants from Gedeon Richter and MSD. M.M. received sponsorship from Merck. M.M.E. received speakers’ fees from Merck, Ferring and MSD. R.S. received a research grant from ESHRE. G.C. received speakers’ fees from IBSA and Excemed. The other authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER N/A. DISCLAIMER This Good Practice Recommendations (GPR) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation. ESHRE’s GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type. Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring of any of the included technologies by ESHRE. †ESHRE Pages content is not externally peer reviewed. The manuscript has been approved by the Executive Committee of ESHRE.