Morphometric and morphokinetic differences in the sperm- and oocyte-originated pronuclei of male and female human zygotes: a time-lapse study

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STUDY QUESTION Is spontaneous collapse (SC) by human blastocysts a prognostic factor in IVF treatment? SUMMARY ANSWER SC in human blastocyst is associated with reduced euploid embryo and pregnancy rates. WHAT IS KNOWN ALREADY SC of the human blastocyst is a phenomenon that was revealed relatively recently following the clinical application of time-lapse monitoring in IVF laboratories. The ploidy and clinical prognosis of affected blastocysts are still poorly understood, with inconsistent reports. Systematic reviews and meta-analyses on this topic are currently absent in the literature but its potential as a marker of embryo viability holds great clinical value. In this study, we aimed to comprehensively evaluate the potential of SC as a prognostic factor in regard to ploidy status, and pregnancy, live birth and miscarriage rates. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis were performed according to PRISMA guidelines, with a protocol registered with PROSPERO (CRD42022373749). A search of MEDLINE, EMBASE, and the Cochrane Library for relevant studies was carried out on 10 October 2022, using key words relevant to ‘blastocyst collapse’ and ‘time-lapse imaging’. PARTICIPANTS/MATERIALS, SETTING, METHODS Two independent reviewers systematically screened and evaluated each study in terms of participants, exposure, comparator, and outcomes (PECO). The Quality In Prognosis Studies tool was used for quality assessment. Data were extracted according to Cochrane methods. Pregnancy, live birth, ploidy, or miscarriage data were summarized by risk ratios (RRs) or odds ratios and their 95% CIs. All meta-analyses were performed with random-effects models. MAIN RESULTS AND THE ROLE OF CHANCE Following removal of duplicates, a total of 196 records were identified by the initial search. After screening according to PECO, 19 articles were included for further eligibility assessment. For meta-analysis, seven retrospective cohort studies were eventually included. After data pooling, the incidence of blastocyst SC was 37.0% (2516/6801) among seven studies (ranging from 17.4% to 56.2%). SC was associated with significantly lower clinical pregnancy rates (two studies, n = 736; RR = 0.77, 95% CI = 0.62–0.95; I2 = 30%), ongoing pregnancy rates (five studies, n = 2503; RR = 0.66, 95% CI = 0.53–0.83; I2 = 60%), and reduced euploidy rates (three studies, n = 3569; RR = 0.70, 95% CI = 0.59–0.83; I2 = 69%). Nevertheless, live birth rates (two studies, n = 816; RR = 0.76, 95% CI = 0.55–1.04; I2 = 56%) and miscarriage rate (four studies, n = 1358; RR = 1.31, 95% CI = 0.95–1.80; I2 = 0%) did not differ between blastocysts with or without SC. There was, however, significant heterogeneity between the studies included for evaluation of ongoing pregnancy rates (I2 = 60%, P = 0.04), live birth rates (I2 = 56%, P = 0.13), and ploidy rates (I2 = 69%, P = 0.04). Subgroup analyses were conducted according to different definitions of SC, number of collapse events, and whether the transferred blastocyst had undergone preimplantation genetic testing for aneuploidy; with inconclusive findings across subgroups. LIMITATIONS, REASONS FOR CAUTION All studies in the meta-analysis were retrospective with varying levels of heterogeneity for different outcomes. Not all studies had accounted for potential confounding factors, therefore only unadjusted data could be used in the main meta-analysis. Studies employed slightly different strategies when defining blastocyst SC. Standardization in the definition for SC is needed to improve comparability between future studies. WIDER IMPLICATIONS OF THE FINDINGS Our results indicate that blastocyst SC has negative implications for a pregnancy. Such blastocysts should be given a low ranking when selecting from a cohort for intrauterine transfer. Blastocyst SC should be considered as a contributing variable when building blastocyst algorithms to predict pregnancy or live birth. STUDY FUNDING/COMPETING INTEREST(S) There is no external funding to report. All authors report no conflict of interest. REGISTRATION NUMBER PROSPERO 2022 CRD42022373749

Section: Discussionmentioning

confidence: 99%

Spontaneous collapse as a prognostic marker for human blastocysts: a systematic review and meta-analysis

Bickendorf,

Qi,

Peirce

et al. 2023

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“…However, if a long-term bias were to occur on the embryos selected via black-box DSS, it would be difficult to detect under such a black-box setup in the short term before it is perpetuated and further amplified over time, especially when a surrogate short-time end point, such as ploidy or fetal heart detection (rather than live birth or healthy birth), had been used for training ( Afnan et al , 2021 ). For example, reports have shown sex-linked morphokinetic and morphometric differences in human zygotes/embryos ( Bronet et al , 2015 ; Orevich et al , 2022 ; Kilbee et al , 2023 ). In populations where individuals are selected by algorithms involving such features, this could lead to downstream effects.…”

Section: Ai-driven Dsssmentioning

confidence: 99%

A brief history of artificial intelligence embryo selection: from black-box to glass-box

Lee,

Natalwala,

Chapple

et al. 2023

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With the exponential growth of computing power and accumulation of embryo image data in recent years, artificial intelligence (AI) is starting to be utilized in embryo selection in IVF. Amongst different AI technologies, machine learning (ML) has the potential to reduce operator-related subjectivity in embryo selection while saving labor time on this task. However, as modern deep learning (DL) techniques, a subcategory of ML, are increasingly used, its integrated black-box attracts growing concern owing to the well-recognized issues regarding lack of interpretability. Currently, there is a lack of randomized controlled trials to confirm the effectiveness of such black-box models. Recently, emerging evidence has shown underperformance of black-box models compared to the more interpretable traditional ML models in embryo selection. Meanwhile, glass-box AI, such as interpretable ML, is being increasingly promoted across a wide range of fields and is supported by its ethical advantages and technical feasibility. In this review, we propose a novel classification system for traditional and AI-driven systems from an embryology standpoint, defining different morphology-based selection approaches with an emphasis on subjectivity, explainability, and interpretability.

“…Quantitative parameters, such as embryo morphokinetics, include times to reach a range of biological milestones such as pronuclear appearance, 2-cell stage, and start of blastulation ( Ciray et al , 2014 ). Qualitative traits include morphometric features as early as the pronuclear stage ( Orevich et al , 2022 ), spontaneous collapsing at the blastocyst stage ( Bickendorf et al , 2023 ), and abnormal cleavage (ABNCL) patterns at the cleavage stage such as direct cleavage (DC) ( Rubio et al , 2012 ; Ciray et al , 2014 ), reverse cleavage (RC) ( Liu et al , 2014 ) and less than six intracellular contact points at the 4-cell stage (<6ICCP) ( Liu et al , 2015 ). A recent meta-analysis has highlighted the preferable inter-laboratory transferability of qualitative parameters over quantitative parameters ( Liu et al , 2020 ), potentially due to the varying embryo morphokinetics in response to different culture conditions ( Kasterstein et al , 2013 ) and patient populations ( Fréour et al , 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Abnormal cleavage up to Day 3 does not compromise live birth and neonatal outcomes of embryos that have achieved full blastulation: a retrospective cohort study

Lee,

Peirce,

Natalwala

et al. 2024

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STUDY QUESTION Do embryos displaying abnormal cleavage (ABNCL) up to Day 3 have compromised live birth rates and neonatal outcomes if full blastulation has been achieved prior to transfer? SUMMARY ANSWER ABNCL is associated with reduced full blastulation rates but does not impact live birth rates and neonatal outcomes once full blastulation has been achieved. WHAT IS KNOWN ALREADY? It is widely accepted that ABNCL is associated with reduced implantation rates of embryos when transferred at the cleavage stage. However, evidence is scarce in the literature reporting birth outcomes from blastocysts arising from ABNCL embryos, likely because they are ranked low priority for transfer. STUDY DESIGN, SIZE, DURATION This retrospective cohort study included 1562 consecutive autologous in vitro fertilization cycles (maternal age 35.1 ± 4.7 years) performed at Fertility North, Australia between January 2017 and June 2022. Fresh transfers were performed on Day 3 or 5, with remaining embryos cultured up to Day 6 before vitrification. A total of 6019 embryos were subject to blastocyst culture, and a subset of 664 resulting frozen blastocysts was included for live birth and neonatal outcome analyses following single transfers. PARTICIPANTS/MATERIALS, SETTING, METHODS ABNCL events were annotated from the first mitotic division up to Day 3, including direct cleavage (DC), reverse cleavage (RC) and <6 intercellular contact points at the 4-cell stage (<6ICCP). For DC and RC in combination, the ratios of affected blastomeres over the total number of all blastomeres up to Day 3 were also recorded. All pregnancies were followed up until birth with gestational age, birthweight, and sex of the baby being recorded. MAIN RESULTS AND THE ROLE OF CHANCE Full blastulation rates for embryos showing DC (19.5%), RC (41.7%), <6ICCP (58.8%), and mixed (≥2) ABNCL types (26.4%) were lower than the rates for those without ABNCL (67.2%, P < 0.01 respectively). Subgroup analysis showed declining full blastulation rates with increasing ratios of combined DC/RC affected blastomeres over all blastomeres up to the 8-cell stage (66.2% when 0 affected, 47.0% when 0.25 affected, 27.4% when 0.5 affected, 14.5% when 0.75 affected, and 7.7% when all affected, P < 0.01). However, once full blastulation had been achieved, no difference was detected between DC, RC, <6ICCP, and no ABNCL blastocysts following single frozen transfers in subsequent live birth rates (25.9%, 33.0%, 36.0% versus 30.8%, P > 0.05, respectively), gestational age (38.7 ± 1.6, 38.5 ± 1.2, 38.3 ± 3.5 versus 38.5 ± 1.8 weeks, P > 0.05, respectively) and birthweight (3343.0 ± 649.1, 3378.2 ± 538.4, 3352.6 ± 841.3 versus 3313.9 ± 509.6 g, P > 0.05, respectively). Multiple regression (logistic or linear as appropriate) confirmed no differences in all of the above measures after accounting for potential confounders. LIMITATIONS, REASONS FOR CAUTION Our study is limited by its retrospective nature, making it impossible to control every known or unknown confounder. Embryos in our dataset, being surplus after selection for fresh transfer, may not represent the general embryo population. WIDER IMPLICATIONS OF THE FINDINGS Our findings highlight the incremental impact of ABNCL, depending on the ratio of affected blastomeres up to Day 3, on subsequent full blastulation. The reassuring live birth and neonatal outcomes of ABNCL blastocysts imply a potential self-correction mechanism among those embryos reaching the blastocyst stage, which provides valuable guidance for clinical practice and patient counseling. STUDY FUNDING/COMPETTING INTEREST(S) This research is supported by an Australian Government Research Training Program (RTP) Scholarship. All authors report no conflict of interest. TRIAL REGISTRATION NUMBER N/A.