The first mitotic division of human embryos is highly error prone

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 8, 2022

Human beings are made of ~50 trillion cells which arise from serial mitotic divisions a single cell - the fertilised egg. Remarkably, early human embryo is often chromosomally abnormal, and many mosaic, with karyotype differing one to another. Mosaicism presumably arises chromosome segregation errors during divisions, although these events have never been visualised in living embryos. Here, we establish live imaging using normally embryos an egg-share-to-research programme, as well deselected fertility treatment. We reveal that first division has extended prometaphase/metaphase exhibits phenotypes can cause nondisjunction. These included multipolar segregations lagging chromosomes lead formation micronuclei. Analysis nuclear number size provides evidence equivalent 2-cell gave rise births. Together this shows be tolerated uncovers biological contribute preimplantation mosaicism.

Language: Английский

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PGDIS position statement on the transfer of mosaic embryos 2021

Reproductive BioMedicine Online, Journal Year: 2022, Volume and Issue: 45(1), P. 19 - 25

Published: March 20, 2022

Language: Английский

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Making a good egg: human oocyte health, aging, and in vitro development

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(4), P. 2623 - 2677

Published: May 12, 2023

Mammalian eggs (oocytes) are formed during fetal life and establish associations with somatic cells to form primordial follicles that create a store of germ (the pool). The size this pool is influenced by key events the formation factors influence subsequent activation follicle growth. These regulatory pathways must ensure reserve oocytes within in humans lasts for up 50 years, yet only approximately 0.1% will ever be ovulated rest undergoing degeneration. This review outlines mechanisms govern processes oocyte later growth, ovarian stroma, through ovulation particular reference human oocytes/follicles. In addition, effects aging on female reproductive capacity changes number quality emphasized, both cellular clinical implications discussed. Finally, details current developments culture systems support all stages growth generate mature vitro emerging prospects making new from stem outlined.

Language: Английский

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Opening the black box: why do euploid blastocysts fail to implant? A systematic review and meta-analysis

Human Reproduction Update, Journal Year: 2023, Volume and Issue: 29(5), P. 570 - 633

Published: May 16, 2023

Abstract BACKGROUND A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the strongest predictor of embryo implantation. Yet, its positive predictive value is not higher than 50–60%. This gap knowledge causes euploid blastocysts’ reproductive failure known as ‘the black box implantation’. OBJECTIVE AND RATIONALE Several embryonic, maternal, paternal, clinical, and IVF laboratory features were scrutinized for their putative association with success or implantation blastocysts. SEARCH METHODS systematic bibliographical search was conducted without temporal limits up to August 2021. The keywords ‘(blastocyst OR day5 day6 day7 embryo) (euploid chromosomally preimplantation genetic testing) (implantation miscarriage abortion live birth biochemical pregnancy recurrent failure)’. Overall, 1608 items identified screened. We included prospective retrospective clinical studies randomized-controlled-trials (RCTs) that assessed any feature associated live-birth rates (LBR) and/or (MR) among non-mosaic blastocyst transfer after TE biopsy PGT-A. In total, 41 reviews 372 papers selected, clustered according a common focus, thoroughly reviewed. PRISMA guideline followed, PICO model adopted, ROBINS-I ROB 2.0 scoring used assess bias. Bias across regarding LBR also using visual inspection funnel plots trim fill method. Categorical data combined pooled-OR. random-effect conduct meta-analysis. Between-study heterogeneity addressed I2. Whenever suitable meta-analysis, simply described results. study protocol registered at http://www.crd.york.ac.uk/PROSPERO/ (registration number CRD42021275329). OUTCOMES original (335 studies, 30 7 RCTs) reviews. However, most retrospective, characterized by small sample sizes, thus prone bias, which reduces quality evidence low very low. Reduced inner cell mass (7 OR: 0.37, 95% CI: 0.27–0.52, I2 = 53%), (9 0.53, 0.43–0.67, 70%), overall worse Gardner’s BB-grade (8 0.40, 0.24–0.67, 83%), developmental delay (18 0.56, 0.49–0.63, 47%), (by qualitative analysis) some morphodynamic abnormalities pinpointed time-lapse microscopy (abnormal cleavage patterns, spontaneous collapse, longer time morula formation I, blastulation (tB), duration blastulation) poorer outcomes. Slightly lower LBR, even in context PGT-A, reported women ≥38 years 0.87, 0.75–1.00, 31%), while obesity both (2 0.66, 0.55–0.79, 0%) MR 1.8, 1.08–2.99, 52%). experience previous repeated failures (RIF) (3 0.72, 0.55–0.93, 0%). By analysis, hormonal assessments, only abnormal progesterone levels prior Among protocols used, vitrified-warmed more effective fresh 1.56, 1.05–2.33, 23%) Lastly, multiple vitrification-warming cycles 0.41, 0.22–0.77, 50%) high cells biopsied may slightly reduce simultaneous zona-pellucida opening allowed better results Day 3 hatching-based 1.41, 1.18–1.69, WIDER IMPLICATIONS Embryo selection aims shortening time-to-pregnancy, minimizing risks. Knowing are competence blastocysts therefore critical define, implement, validate safer efficient workflows. Future research should be directed towards: (i) investigations mechanisms involved aging beyond de novo abnormalities, how lifestyle nutrition accelerate exacerbate consequences; (ii) improved evaluation uterine blastocyst-endometrial dialogue, represent boxes themselves; (iii) standardization/automation assessment protocols; (iv) additional invasive preferably non-invasive tools selection. Only filling these gaps we finally crack riddle behind

Language: Английский

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Does recurrent implantation failure exist? Prevalence and outcomes of five consecutive euploid blastocyst transfers in 123 987 patients

Human Reproduction, Journal Year: 2024, Volume and Issue: 39(5), P. 974 - 980

Published: March 7, 2024

Abstract STUDY QUESTION What are the clinical pregnancy and live birth rates in women who underwent up to two more euploid blastocyst transfers after three failures absence of another known factor that affects implantation? SUMMARY ANSWER The fourth fifth resulted similar 40% 53.3%, respectively, culminating a cumulative rate 98.1% (95% CI = 96.5–99.6%) five transfers. WHAT IS KNOWN ALREADY first blastocysts have implantation provide 92.6%. DESIGN, SIZE, DURATION An international multi-center retrospective study was conducted at 25 individual clinics. period spanned between January 2012 December 2022. A total 123 987 patients with 64 572 were screened for inclusion. PARTICIPANTS/MATERIALS, SETTING, METHODS Patients history any embryo transfer clinic, unscreened participating clinics, parental karyotype abnormalities, use donor oocytes or gestational carrier, untreated intracavitary uterine pathology (e.g. polyp, leiomyoma), congenital anomalies, adenomyosis, communicating hydrosalpinx, endometrial thickness <6 mm prior initiating progesterone, testicular sperm due non-obstructive azoospermia male partner, an reported intermediate chromosome copy number (i.e. mosaic), preimplantation genetic testing cycles monogenic disorders, structural rearrangements excluded. Ovarian stimulation protocols embryology laboratory procedures including trophectoderm biopsy followed usual practice each center. ploidy status determined comprehensive screening. Endometrial preparation centers included programmed cycles, natural modified cycles. MAIN RESULTS AND THE ROLE OF CHANCE 105 (0.085% population) met criteria least one additional failing achieve positive test consecutive Outcomes across centers. Overall, (40% vs relative risk 1.33, 95% 0.93–1.9, P value 0.14). Sensitivity analyses excluding biopsied on Day 7 postfertilization, BMI >30 kg/m2, using non-ejaculate sperm, double-embryo which day receptivity assay result yielded results. Where data available, had (relative 0.84, 0.58–1.21, 0.29). 96.5–99.6%). LIMITATIONS, REASONS FOR CAUTION Retrospective design has its own inherent limitations. continuing further dropping out from treatment failed can be systematically different, perhaps regard ovarian reserve economic status. WIDER IMPLICATION FINDINGS Implantation failure seems mainly embryonic factors. Given stable high blastocysts, unexplained recurrent should prevalence <2%. Proceeding best next step once etiology is ruled out. FUNDING/COMPETING INTEREST(s) None. TRIAL REGISTRATION NUMBER N/A.

Language: Английский

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Single-cell DNA sequencing reveals a high incidence of chromosomal abnormalities in human blastocysts

Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: 134(6)

Published: Jan. 4, 2024

Aneuploidy, a deviation from the normal chromosome copy number, is common in human embryos and considered primary cause of implantation failure early pregnancy loss. Meiotic errors lead to uniformly abnormal karyotypes, while mitotic chromosomal mosaicism: presence cells with at least two different karyotypes within an embryo. Knowledge about mosaicism blastocysts mainly derives bulk DNA sequencing multicellular trophectoderm (TE) and/or inner cell mass (ICM) samples. However, this can only detect average net gain or loss above detection threshold 20-30%. To accurately assess mosaicism, we separated TE ICM 55 good quality surplus successfully applied single-cell whole genome (scKaryo-seq) on 1057 cells. Mosaicism involving numerical structural abnormalities was detected 82% embryos, where most affected less than 20% Structural abnormalities, potentially caused by replication stress damage, were observed 69% embryos. In conclusion, our findings indicated that prevalent good-quality blastocysts, these would likely be identified as current techniques used for preimplantation genetic testing aneuploidy (PGT-A).

Language: Английский

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Maternal selection of human embryos in early gestation: Insights from recurrent miscarriage

Seminars in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 131, P. 14 - 24

Published: Jan. 31, 2022

Compared to most mammals, human pregnancy is unusual in that it involves chromosomally diverse embryos, cyclical breakdown and regeneration of the uterine mucosa, intimate integration fetal maternal cells at uteroplacental interface. Not surprisingly, often falters early gestation. Whether these losses result clinical miscarriages depends on origins impacts chromosomal errors development ability decidualizing endometrium engage embryo biosensing selection. Aneuploidy originating oocytes during meiosis drives age-related risk miscarriage. By contrast, frequency endometrial cycles with an impaired decidual response may account for stepwise increase miscarriage rates each loss independently age. Additional physiological mechanisms operate gestation ensure failing pregnancies are lost before vascular maternal-fetal connections established by end first trimester. Here, we summarise how investigations into cause led new insights processes govern selection embryos

Language: Английский

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On the reproductive capabilities of aneuploid human preimplantation embryos

The American Journal of Human Genetics, Journal Year: 2022, Volume and Issue: 109(9), P. 1572 - 1581

Published: Sept. 1, 2022

Language: Английский

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IVF outcomes of embryos with abnormal PGT-A biopsy previously refused transfer: a prospective cohort study

Human Reproduction, Journal Year: 2022, Volume and Issue: 37(6), P. 1194 - 1206

Published: March 28, 2022

What are the outcomes for patients who choose to move embryos diagnosed as abnormal by preimplantation genetic testing aneuploidy (PGT-A) a new institution transfer after diagnosing refused them?Many seek have selected with PGT-A trophectoderm biopsies transferred recognizing that these can still offer chance of pregnancy and live birth.: is widely practiced method selecting based on biopsy few cells. Many clinical practices refuse even when there no other 'normal' available.This prospective cohort 69 couples who, since 2014, moved total 444 previously at their parent institutions our practice. Among these, 50 have, thus far, undergone 57 cycles 141 embryos.Embryos (mostly using next generation sequencing) were academically affiliated private fertility research center in New York City. Female age retrieval was 41.35 ± 3.98 years, 74% Caucasian, 12% Asian 10% African descent. All identified among prospectively recorded center's registry.Among 144 102 (72.3%) had only 1 or 2 chromosomal abnormalities, 30 (21.3%) 3 more 9 (6.4%) 'undiagnosed' because degraded DNA, yet been transfer. Transfer resulted 8 births, 11 miscarriages voluntary terminations. One child born segmental duplication required repair coarctation aorta newborn. willing such transfers result establishment ongoing euploid pregnancies births.Findings this case series represent chose having elsewhere may not be representative wider population undergoing IVF general. Not all phenotypes present immediate postnatal period so it will important continue follow development children.PGT-A clinics refusal biopsies, those mosaic findings, consequently large numbers infertile women prematurely advised motherhood through third-party egg-donation.This work supported intramural funds from Center Human Reproduction not-for-profit Foundation Reproductive Medicine, both York, NY, USA. N.G. D.H.B. listed co-inventors several U.S. patents. patents (US Patent# 7,615,544) relates pre-supplementation hypo-androgenic androgens, DHEA testosterone and, therefore, least peripherally related subject manuscript. D.F.A. also received travel speaker honoraria pharmaceutical medical device companies, though none here presented shareholder Fertility Nutraceuticals he receive royalty payments LLC.N/A.

Language: Английский

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ESHRE survey results and good practice recommendations on managing chromosomal mosaicism

Human Reproduction Open, Journal Year: 2022, Volume and Issue: 2022(4)

Published: Jan. 1, 2022

Abstract STUDY QUESTION How should ART/preimplantation genetic testing (PGT) centres manage the detection of chromosomal mosaicism following PGT? SUMMARY ANSWER Thirty good practice recommendations were formulated that can be used by ART/PGT as a basis for their own policy with regards to management ‘mosaic’ embryos. WHAT IS KNOWN ALREADY The use comprehensive chromosome screening technologies has provided variety data on incidence at preimplantation stage development and evidence is accumulating clarifies clinical outcomes after transfer embryos putative mosaic results, implantation, miscarriage live birth rates, neonatal outcomes. DESIGN, SIZE, DURATION This document was developed according predefined methodology ESHRE recommendations. Recommendations are supported from literature, large survey evaluating current published guidance documents. literature search performed using PubMed focused studies between 2010 2022. through web-based questionnaire distributed members special interest groups (SIG) Reproductive Genetics Embryology, PGT Consortium members. It included questions ART PGT, reporting, embryo follow-up transfers. final dataset represents 239 centres. PARTICIPANTS/MATERIALS, SETTING, METHODS working group (WG) 16 expertise process mosaicism. based expert opinion WG, while taking into consideration results survey. MAIN RESULTS AND THE ROLE OF CHANCE Eighty percent biopsy three or more cells report mosaicism, even though only 66.9% all have validated technology 61.8% these specifically calling criteria designating reporting policies vary significantly across replying WG how in practice, considering validation, risk assessment, policies, prenatal follow-up. Guidance also essential elements constitute consent forms report, covered counselling. As there several unknowns it recommended monitor emerging topic adapt refine whenever new insights available evidence. LIMITATIONS, REASONS FOR CAUTION Rather than providing instant standardized advice, help developing towards practice. WIDER IMPLICATIONS FINDINGS will facilitate knowledge-based approach dealing different In addition future research formulated. Following up direct existing gaps translation Emerging improving guidance, evidence-based managing FUNDING/COMPETING INTEREST(S) received technical support ESHRE. M.D.R. participated EQA advisory group, outside submitted work, chair Belgian society human genetics. D.W. declared receiving salary Juno Genetics, UK. A.C. an employee Igenomix, Italy C.R. Spain. C.S. grant FWO, Belgium, not related work. I.S. being Co-founder IVFvision Ltd, J.R.V. patents ‘Methods haplotyping single-cells’ ‘Haplotyping copy number typing polymorphic variant allelic frequencies’, board member Preimplantation Genetic Diagnosis International Society (PGDIS) Prenatal (ISPD). K.S. reported Chair-elect other authors had nothing disclose. DISCLAIMER Good Practice (GPR) views ESHRE, which result consensus relevant stakeholders scientific time preparation. GPRs information educational purposes. They interpreted setting standard care deemed inclusive proper methods care, exclusive reasonably directed obtaining same results. do replace need application judgement each individual presentation, variations locality facility type. Furthermore, imply endorsement, favouring, any

Language: Английский

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