Distinct pathways drive anterior hypoblast specification in the implanting human embryo.

Development requires coordinated interactions between the epiblast, which generates the embryo proper; the trophectoderm, which generates the placenta; and the hypoblast, which forms both the anterior signalling centre and the yolk sac. These interactions remain poorly understood in human embryogenesis because mechanistic studies have only recently become possible. Here we examine signalling interactions post-implantation using human embryos and stem cell models of the epiblast and hypoblast. We find anterior hypoblast specification is NODAL dependent, as in the mouse. However, while BMP inhibits anterior signalling centre specification in the mouse, it is essential for its maintenance in human. We also find contrasting requirements for BMP in the naive pre-implantation epiblast of mouse and human embryos. Finally, we show that NOTCH signalling is important for human epiblast survival. Our findings of conserved and species-specific factors that drive these early stages of embryonic development highlight the strengths of comparative species studies.

The effect of frozen embryo transfer regimen on the association between serum progesterone and live birth: a multicentre prospective cohort study (ProFET).

STUDY QUESTION: What is the association between serum progesterone levels on the day of frozen embryo transfer (FET) and the probability of live birth in women undergoing different FET regimens? SUMMARY ANSWER: Overall, serum progesterone levels <7.8 ng/ml were associated with reduced odds of live birth, although the association between serum progesterone levels and the probability of live birth appeared to vary according to the route of progesterone administration. WHAT IS KNOWN ALREADY: Progesterone is essential for pregnancy success. A recent systematic review showed that in FET cycles using vaginal progesterone for endometrial preparation, lower serum progesterone levels (<10 ng/ml) were associated with a reduction in live birth rates and higher chance of miscarriage. However, there was uncertainty about the association between serum progesterone levels and treatment outcomes in natural cycle FET (NC-FET) and HRT-FET using non-vaginal routes of progesterone administration. STUDY DESIGN SIZE DURATION: This was a multicentre (n = 8) prospective cohort study conducted in the UK between January 2020 and February 2021. PARTICIPANTS/MATERIALS SETTING METHODS: We included women having NC-FET or HRT-FET treatment with progesterone administration by any available route. Women underwent venepuncture on the day of embryo transfer. Participants and clinical personnel were blinded to the serum progesterone levels. We conducted unadjusted and multivariable logistic regression analyses to investigate the association between serum progesterone levels on the day of FET and treatment outcomes according to the type of cycle and route of exogenous progesterone administration. Our primary outcome was the live birth rate per participant. MAIN RESULTS AND THE ROLE OF CHANCE: We studied a total of 402 women. The mean (SD) serum progesterone level was 14.9 (7.5) ng/ml. Overall, the mean adjusted probability of live birth increased non-linearly from 37.6% (95% CI 26.3-48.9%) to 45.5% (95% CI 32.1-58.9%) as serum progesterone rose between the 10th (7.8 ng/ml) and 90th (24.0 ng/ml) centiles. In comparison to participants whose serum progesterone level was ≥7.8 ng/ml, those with lower progesterone (<7.8 ng/ml, 10th centile) experienced fewer live births (28.2% versus 40.0%, adjusted odds ratio [aOR] 0.41, 95% CI 0.18-0.91, P = 0.028), lower odds of clinical pregnancy (30.8% versus 45.1%, aOR 0.36, 95% CI 0.16-0.79, P = 0.011) and a trend towards increased odds of miscarriage (42.1% versus 28.7%, aOR 2.58, 95% CI 0.88-7.62, P = 0.086). In women receiving vaginal progesterone, the mean adjusted probability of live birth increased as serum progesterone levels rose, whereas women having exclusively subcutaneous progesterone experienced a reduction in the mean probability of live birth as progesterone levels rose beyond 16.3 ng/ml. The combination of vaginal and subcutaneous routes appeared to exert little impact upon the mean probability of live birth in relation to serum progesterone levels. LIMITATIONS REASONS FOR CAUTION: The final sample size was smaller than originally planned, although our study was adequately powered to confidently identify a difference in live birth between optimal and inadequate progesterone levels. Furthermore, our cohort did not include women receiving oral or rectal progestogens. WIDER IMPLICATIONS OF THE FINDINGS: Our results corroborate existing evidence suggesting that lower serum progesterone levels hinder FET success. However, the relationship between serum progesterone and the probability of live birth appears to be non-linear in women receiving exclusively subcutaneous progesterone, suggesting that in this subgroup of women, high serum progesterone may also be detrimental to treatment success. STUDY FUNDING/COMPETING INTERESTS: This work was supported by CARE Fertility and a doctoral research fellowship (awarded to P.M.) by the Tommy's Charity and the University of Birmingham. M.J.P. is supported by the NIHR Birmingham Biomedical Research Centre. S.F. is a minor shareholder of CARE Fertility but has no financial or other interest with progesterone testing or manufacturing companies. P.L. reports personal fees from Pharmasure, outside the submitted work. G.P. reports personal fees from Besins Healthcare, outside the submitted work. M.W. reports personal fees from Ferring Pharmaceuticals, outside the submitted work. The remaining authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT04170517.

Experiences of young girls and women undergoing ovarian tissue cryopreservation: a systematic review and thematic synthesis.

The aim of this study was to explore the experiences of young girls and women who underwent or considered ovarian tissue cryopreservation (OTC) using a systematic review of qualitative studies with thematic synthesis framework. Major electronic databases: MEDLINE, EMBASE, the Cochrane Library, CINAHL and PsycINFO were searched from 1946 to May 2020 and reference lists of relevant articles were hand searched. Any studies that described a qualitative inquiry and highlighted the experiences of women with regards to OTC were included. Two independent reviewers screened the title and abstracts and made a selection against inclusion criteria. Main outcomes measures were experiences of women who have considered and/or undergone OTC, decision making in women who underwent or considered OTC and patient education. Nineteen studies were assessed for full text eligibility and four were included in analysis. 144 verbatim quotations from 85 participants in high income countries (UK, USA and Denmark) were included. Two studies adopted grounded theory approach, one phenomenology and one inductive content analysis. Four themes were generated; participants described their experiences as emotional, involving complex decision-making, helping them prepare for the long-term consequences of potentially losing their fertility and hormonal function, as well as their experience being educational. Additionally, the more practical aspects of the procedure such as OTC being invasive as well as costs implications were highlighted. Women and young girls are often involved in making time-sensitive decisions whether or not to undergo OTC. Healthcare professionals involved in the care of young girls and women undergoing this method need to also take into consideration the emotional wellbeing of the patients as well as the time and expertise it requires to help them make an informed decision.

Fresh and cryopreserved ovarian tissue transplantation for preserving reproductive and endocrine function: a systematic review and individual patient data meta-analysis.

BACKGROUND: Ovarian tissue cryopreservation involves freezing and storing of surgically retrieved ovarian tissue in liquid or vapour nitrogen below -190°C. The tissue can be thawed and transplanted back with the aim of restoring fertility or ovarian endocrine function. The techniques for human ovarian tissue freezing and transplantation have evolved over the last 20 years, particularly in the context of fertility preservation in pre-pubertal cancer patients. Fresh ovarian tissue transplantation, using an autograft or donor tissue, is a more recent development; it has the potential to preserve fertility and hormonal function in women who have their ovaries removed for benign gynaecological conditions. The techniques of ovarian tissue cryopreservation and transplantation have progressed rapidly since inception; however, the evidence on the success of this intervention is largely based on case reports and case series. OBJECTIVE AND RATIONALE: The aim of this study was to systematically review the current evidence by incorporating study-level and individual patient-level meta-analyses of women who received ovarian transplants, including frozen-thawed transplant, fresh or donor graft. SEARCH METHODS: The review protocol was registered with PROSPERO (CRD42018115233). A comprehensive literature search was performed using MEDLINE, EMBASE, CINAHL and Cochrane Central Register of Controlled Trials from database inception to October 2020. Authors were also contacted for individual patient data if relevant outcomes were not reported in the published manuscripts. Meta-analysis was performed using inverse-variance weighting to calculate summary estimates using a fixed-effects model. OUTCOMES: The review included 87 studies (735 women). Twenty studies reported on ≥5 cases of ovarian transplants and were included in the meta-analysis (568 women). Fertility outcomes included pregnancy, live birth and miscarriage rates, and endocrine outcomes included oestrogen, FSH and LH levels. The pooled rates were 37% (95% CI: 32-43%) for pregnancy, 28% (95% CI: 24-34%) for live birth and 37% (95% CI: 30-46%) for miscarriage following frozen ovarian tissue transplantation. Pooled mean for pre-transplant oestrogen was 101.6 pmol/l (95% CI: 47.9-155.3), which increased post-transplant to 522.4 pmol/l (95% CI: 315.4-729; mean difference: 228.24; 95% CI: 180.5-276). Pooled mean of pre-transplant FSH was 66.4 IU/l (95% CI: 52.8-84), which decreased post-transplant to 14.1 IU/l (95% CI: 10.9-17.3; mean difference 61.8; 95% CI: 57-66.6). The median time to return of FSH to a value <25 IU/l was 19 weeks (interquartile range: 15-26 weeks; range: 0.4-208 weeks). The median duration of graft function was 2.5 years (interquartile range: 1.4-3.4 years; range: 0.7-5 years). The analysis demonstrated that ovarian tissue cryopreservation and transplantation could restore reproductive and hormonal functions in women. Further studies with larger samples of well-characterized populations are required to define the optimal retrieval, cryopreservation and transplantation processes. WIDER IMPLICATIONS: Ovarian tissue cryopreservation and transplantation may not only be effective in restoring fertility but also the return of reproductive endocrine function. Although this technology was developed as a fertility preservation option, it may have the scope to be considered for endocrine function preservation.

Human embryo polarization requires PLC signaling to mediate trophectoderm specification.

Apico-basal polarization of cells within the embryo is critical for the segregation of distinct lineages during mammalian development. Polarized cells become the trophectoderm (TE), which forms the placenta, and apolar cells become the inner cell mass (ICM), the founding population of the fetus. The cellular and molecular mechanisms leading to polarization of the human embryo and its timing during embryogenesis have remained unknown. Here, we show that human embryo polarization occurs in two steps: it begins with the apical enrichment of F-actin and is followed by the apical accumulation of the PAR complex. This two-step polarization process leads to the formation of an apical domain at the 8-16 cell stage. Using RNA interference, we show that apical domain formation requires Phospholipase C (PLC) signaling, specifically the enzymes PLCB1 and PLCE1, from the eight-cell stage onwards. Finally, we show that although expression of the critical TE differentiation marker GATA3 can be initiated independently of embryo polarization, downregulation of PLCB1 and PLCE1 decreases GATA3 expression through a reduction in the number of polarized cells. Therefore, apical domain formation reinforces a TE fate. The results we present here demonstrate how polarization is triggered to regulate the first lineage segregation in human embryos.

Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis.

OBJECTIVE: To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Women undergoing FET. INTERVENTION(S): We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET. MAIN OUTCOME MEASURE(S): Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate. RESULT(S): Among the studies analyzing serum progesterone level thresholds <10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs. CONCLUSION(S): Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET. PROSPERO NUMBER: CRD42019157071.

Embryo Screening for Polygenic Disease Risk: Recent Advances and Ethical Considerations.

Machine learning methods applied to large genomic datasets (such as those used in GWAS) have led to the creation of polygenic risk scores (PRSs) that can be used identify individuals who are at highly elevated risk for important disease conditions, such as coronary artery disease (CAD), diabetes, hypertension, breast cancer, and many more. PRSs have been validated in large population groups across multiple continents and are under evaluation for widespread clinical use in adult health. It has been shown that PRSs can be used to identify which of two individuals is at a lower disease risk, even when these two individuals are siblings from a shared family environment. The relative risk reduction (RRR) from choosing an embryo with a lower PRS (with respect to one chosen at random) can be quantified by using these sibling results. New technology for precise embryo genotyping allows more sophisticated preimplantation ranking with better results than the current method of selection that is based on morphology. We review the advances described above and discuss related ethical considerations.

Embryos are exposed to a significant drop in temperature during the embryo transfer procedure: a pilot study.

RESEARCH QUESTION: During the embryo transfer procedure, to what degree of temperature drop are embryos exposed to between loading the transfer catheter and placing it into the uterus? DESIGN: Twenty-nine simulated embryo transfer procedures were carried out across five clinics. A thermocouple probe was used for standardized measurements inside the embryo transfer catheter to investigate the change in temperature that occurred in the time period between loading and placing the catheter in the uterus. RESULTS: In all cases, the temperature at the loaded catheter tip fell rapidly to ambient temperature during transit from the embryo transfer workstation in the laboratory to the procedure room, even though embryo transfer procedures, ambient temperatures and embryo transfer catheter temperatures at loading varied between clinics. CONCLUSIONS: Given the sensitivity of the pre-implantation embryo to its immediate environment, the rapid and profound drop in temperature observed at the catheter tip that houses the embryo during transit from laboratory to the uterus may affect embryo viability and health. This issue should be addressed to ensure that the tight temperature control aimed for by IVF laboratories continues throughout the embryo transfer procedure, and could improve clinical outcomes.

Plasticity of the human preimplantation embryo: developmental dogmas, variations on themes and self-correction.

BACKGROUND: IVF for the treatment of infertility offers unique opportunities to observe human preimplantation development. Progress in time-lapse technology (TLT) and preimplantation genetic testing (PGT) has greatly expanded our knowledge of developmental patterns leading to a healthy pregnancy or developmental failure. These technologies have also revealed unsuspected plastic properties of the preimplantation embryo, at macromolecular, cellular and multicellular levels. OBJECTIVE AND RATIONALE: This review focuses on the emerging concept of plasticity of the human embryo as revealed by recent evidence derived from TLT and PGT, calling for an updated and more precise redefinition of the boundaries between normal and abnormal development. SEARCH METHODS: PubMed was used to search the MEDLINE database for peer-reviewed English-language original articles and reviews concerning human preimplantation development. Cross-searches were performed by adopting 'fertilisation', 'pronucleus', 'cleavage', 'multinucleation', 'compaction', 'embryo', 'preimplantation genetic testing', 'aneuploidy', mosaicism', 'micromanipulation', 'time-lapse microscopy' and 'IVF/assisted reproduction' as main terms. The most relevant publications, i.e. those concerning major phenomena occurring during normal and abnormal development-with a focus on the human species-were assessed and discussed critically. OUTCOMES: Advances in TLT and PGT have revealed an astonishing plasticity and self-correction ability of the human preimplantation embryo in vitro. At fertilisation, an abnormal number of pronuclei do not always result in the formation of an aneuploid blastocyst. Animal studies and preliminary human observations indicate that combining of parental genomes may occur at the early cleavage stage, if not at fertilisation. Multinucleation occurs with much higher prevalence than previously thought and may be corrected at later cleavage stages. Irregular cleavage (multichotomous, direct, rapid and reverse cleavages) can generate chromosome segregation abnormalities that often lead to developmental arrest, but that sporadically may be confined to cells excluded from the blastocyst, and may sometimes result in viable pregnancy. Mitotic errors can generate mosaic blastocysts, but alternatively normal embryos may form from selective death or clonal depletion of aneuploid cells. WIDER IMPLICATIONS: Deviations from developmental dogmas and the increasing evidence of plasticity of the human embryo challenge current embryological notions and suggest the need to write new rules governing cell cycle, cell determination and chromosome segregation during preimplantation development.

A single cell characterisation of human embryogenesis identifies pluripotency transitions and putative anterior hypoblast centre.

Following implantation, the human embryo undergoes major morphogenetic transformations that establish the future body plan. While the molecular events underpinning this process are established in mice, they remain unknown in humans. Here we characterise key events of human embryo morphogenesis, in the period between implantation and gastrulation, using single-cell analyses and functional studies. First, the embryonic epiblast cells transition through different pluripotent states and act as a source of FGF signals that ensure proliferation of both embryonic and extra-embryonic tissues. In a subset of embryos, we identify a group of asymmetrically positioned extra-embryonic hypoblast cells expressing inhibitors of BMP, NODAL and WNT signalling pathways. We suggest that this group of cells can act as the anterior singalling centre to pattern the epiblast. These results provide insights into pluripotency state transitions, the role of FGF signalling and the specification of anterior-posterior axis during human embryo development.

Integrin ß1 coordinates survival and morphogenesis of the embryonic lineage upon implantation and pluripotency transition.

At implantation, the embryo establishes contacts with the maternal endometrium. This stage is associated with a high incidence of preclinical pregnancy losses. While the maternal factors underlying uterine receptivity have been investigated, the signals required by the embryo for successful peri-implantation development remain elusive. To explore these, we studied integrin ß1 signaling, as embryos deficient for this receptor degenerate at implantation. We demonstrate that the coordinated action of pro-survival signals and localized actomyosin suppression via integrin ß1 permits the development of the embryo beyond implantation. Failure of either process leads to developmental arrest and apoptosis. Pharmacological stimulation through fibroblast growth factor 2 (FGF2) and insulin-like growth factor 1 (IGF1), coupled with ROCK-mediated actomyosin inhibition, rescues the deficiency of integrin ß1, promoting progression to post-implantation stages. Mutual exclusion between integrin ß1 and actomyosin seems to be conserved in the human embryo, suggesting the possibility that these mechanisms could also underlie the transition of the human epiblast from pre- to post-implantation.

A novel test for annexin A5 M2 haplotyping in in vitro fertilization patients and preimplantation embryos.

OBJECTIVE: To develop a test for evaluating the annexin A5 M2 haplotype in in vitro fertilization patients and preimplantation embryos. DESIGN: Test performance was measured by comparing Sanger sequencing of parental blood DNA and quantitative real-time polymerase chain reaction (qPCR) of saliva DNA, 3 fibroblast cell line 7-cell aliquots and their corresponding purified DNA, 123 trophectoderm biopsy samples, and DNA isolated from 1 embryonic stem cell line along with the Mendelian inheritance expectations, embryo Sanger sequencing, and single-nucleotide polymorphism (SNP) microarray-based linkage analysis. SETTING: Preimplantation genetic testing laboratory research on IVF patient and embryo DNA. PATIENT(S): An assay was developed for the detection of the M2 haplotype on saliva samples of 6 in vitro fertilization patients. In addition, 13 patients who underwent preimplantation genetic testing with data on parental and embryo biopsy DNA available for research use were evaluated. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The concordance rates between Sanger sequencing, SNP array-based linkage analysis, and Mendelian inheritance expectations with qPCR. RESULT(S): The concordance rate between Sanger sequencing and qPCR was 100% on parental blood DNA and saliva DNA. The sample concordance rate between all replicates of 7-cell aliquots was 100%. The sample concordance rate between 3 cell lines used to prepare 7-cell aliquots and purified genomic DNA was 100%. The concordance rate between qPCR and Sanger sequencing results from a single trophectoderm biopsy and isolated embryonic stem cell line was 100%. The concordance rate of trophectoderm biopsy qPCR results and expectations from Mendelian inheritance rules was 97%; however, when SNP array-based linkage analysis was included, the concordance rate reached 100%. CONCLUSION(S): This study resulted in the development of a convenient saliva collection method and qPCR-based genotyping method to screen for the M2 haplotype. In addition, a novel method for testing preimplantation embryos has been established, providing an alternative to the use of low molecular weight heparin, through selection of embryos without the M2 haplotype.

Evolution of embryo selection for IVF from subjective morphology assessment to objective time-lapse algorithms improves chance of live birth.

RESEARCH QUESTION: Does using an objective time-lapse imaging algorithm (TLIA) after IVF relate to conventional morphological assessment of human blastocysts as a prognosticator for live birth? DESIGN: Prospective use of a TLIA to select embryos in multicentre IVF clinics all using the same strictly controlled laboratory protocols. Each blastocyst was given a ranking from A to D, with the highest rank preferred for fresh transfer. This ranking was retrospectively compared with a given morphological score, which was blinded to the TLIA rank; all embryos were cultured under the same conditions. RESULTS: Using multiple variable logistic regression models, TLIA embryo rank enabled greater discrimination between cycles with and without live births than the conventional morphology grade, even when considered in isolation, and when adjusting for covariates related to treatment and patient criteria. Of the 1810 cycles of single blastocyst transfer, 894 (49.4%) resulted in a live birth. A Vuong non-nested test including covariates showed strong evidence of the superiority of the embryo rank model compared with the transfer grade model (P = 0.0008 [raw], P = 0.0003 [Akaike information criterion - corrected]). From the receiver operating characteristic (ROC) curves across all possible thresholds the TLIA rank showed better true positive and true negative rates and had a higher area under the curve [AUC] of 67.43% compared with 61.74% for the blastocyst morphology grade. The same analysis but excluding covariates demonstrated an AUC of 62.86% versus 54.02%, respectively. CONCLUSION: Objective TLIA is superior for selecting embryos for their propensity to generate a live birth over a conventional, subjective blastocyst morphology scoring system.

Cryostorage and retransplantation of ovarian tissue as an infertility treatment.

While still considered an experimental procedure in most countries, ovarian tissue cryopreservation and transplantation has been increasingly applied worldwide to restore fertility in patients with malignant and non-malignant pathologies with risk of premature ovarian insufficiency. It has yielded more than 130 live births up to now and almost all transplanted patients recovered their ovarian function. This study summarizes ovarian tissue cryopreservation and transplantation indications, procedures, their efficacy and main results and proposes different strategies to improve this strategy. Although the main focus of this study is on ovarian tissue cryopreservation and transplantation as a strategy to restore fertility, we believe that it is also important to discuss other applications for this approach.

Breakthroughs and challenges of modern developmental biology and reproductive medicine.

In recent decades we have witnessed unprecedented progress in the field of the developmental biology of mammals. Building on 20th century discoveries, we have managed to increase our understanding of the molecular and cellular mechanisms governing early mammalian embryogenesis and link them to other biological questions, such as stem cells, regeneration, cancer, or tissue and organ formation. Consequently, it has also led to a creation of a completely new branch of reproductive medicine, i.e. assisted reproductive technology (ART). In this Special Issue of The International Journal of Developmental Biology (Int. J. Dev. Biol.) we wished to review state-of-the-art research regarding early mammalian development, from fertilization up to the implantation stage, and discuss its potential meaning for practical applications, including ART. As an introduction to the issue we present a compilation of short essays written by the most renowned scientists in the field, working both in basic and clinical research. The essays are dedicated to the greatest breakthroughs and challenges of 21st century developmental biology and reproductive medicine.

Families Created by Egg Donation: Parent-Child Relationship Quality in Infancy.

Increasing numbers of children are being born through egg donation and thus do not share a genetic relationship with their mother. Parent-infant relationship quality was examined in 85 egg donation families and a comparison group of 65 in vitro fertilization families (infant M = 11 months). Standardized interview and observational measures were used to assess mother-infant and father-infant relationship quality at the representational and behavioral levels. Few differences were found between family types in parents' representations of the parent-infant relationship. Differences were found between family types in the observational assessment of mother-infant relationship quality, indicating less optimal interactions in egg donation families. Findings suggest that egg donation families function well in infancy overall, but there may be subtle yet meaningful differences in mother-infant interaction quality.

Time-lapse imaging algorithms rank human preimplantation embryos according to the probability of live birth.

RESEARCH QUESTION: Can blastocysts leading to live births be ranked according to morphokinetic-based algorithms? DESIGN: Retrospective analysis of 781 single blastocyst embryo transfers, including all patient clinical factors that might be potential confounders for the primary outcome measure of live birth, was weighed using separate multi-variable logistic regression models. RESULTS: There was strong evidence of effect of embryo rank on odds of live birth. Embryos were classified A, B, C or D according to calculated variables; time to start (tSB) and duration (dB{tB - tSB}) of blastulation. Embryos of rank D were less likely to result in live birth than embryos of rank A (odds ratio [OR] 0.3046; 95% confidence interval [CI] 0.129, 0.660; P < 0.005). Embryos ranked B were less likely to result in live birth than those ranked A (OR 0.7114; 95% Cl 0.505, 1.001; P < 0.01), and embryos ranked C were less likely to result in live birth than those ranked A (OR 0.6501, 95% Cl 0.373, 1.118; P < 0.01). Overall, the LRT (Likelihood Ratio Test) p-value for embryo rank shows that there is strong evidence that embryo rank is informative as a whole in discriminating between live birth and no live birth outcomes (p = 0.0101). The incidence of live birth was 52.5% from rank A, 39.2% from rank B, 31.4% from rank C and 13.2% from rank D. CONCLUSIONS: Time-lapse imaging morphokinetic-based algorithms for blastocysts can provide objective hierarchical ranking of embryos for predicting live birth and may have greater discriminating power than conventional blastocyst morphology assessment.

Optimal endometrial thickness to maximize live births and minimize pregnancy losses: Analysis of 25,767 fresh embryo transfers.

RESEARCH QUESTION: What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome? DESIGN: Data were analysed from 25,767 IVF cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses. RESULTS: The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92). CONCLUSIONS: Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.

First in vitro fertilization baby-this is how it happened.

On July 25, 1978, the first human was born following extracorporeal fertilization, an event that opened up a new medical science: expanding our knowledge of and developing novel treatments for infertility, radically changing the opportunities for families with inherited monogenic disorders, generating the new discipline of clinical embryology, and paving the way for studies into stem cell biology. In vitro fertilization (IVF), as it became known in its simplest form, went even further: it engaged the myriad of minds in human society. Not only were books written on the moral status of the human embryo, the ethics of IVF practice, and exercising governments on appropriate-which turned out to be disparate-regulation, it redefined family life! The prediction I made in 1985 that one day we may see five "parents" for one child became a reality quicker than we could have imagined at the time. The new medical science marched inexorably on in almost all countries of the world-a universal human plight at last had an opportunity for remedy: more than 10 million couples seeking a resolution to their infertility became parents, men who had no option to have their own genetic child became genetic fathers, and ever-increasing monogenic conditions were not being passed on to the next generation. The future may well bring to bear the opportunity for in vitro-developed viable gametes to generate successful pregnancies, and other "futuristic" opportunities for IVF science. But its story began over a century ago with seeking an understanding on how an egg matures and how to achieve successful fertilization-a fundamental scientific inquiry. It took one man to go beyond that scientific endeavor, to take head on a society unprepared and unwilling to accept human fertilization in vitro and unempathetic to the plight of the infertile; one man to see what prospects lay ahead for humanity should IVF become a reality, and for that man to battle every step of the way for nearly 2 decades to achieve that dream.