The effect of day 5 blastocyst assessment timing on live birth prediction and development of a prediction algorithm

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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%

Section: Introductionmentioning

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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“…In future studies, a more standardized and accepted criteria should be developed. To achieve this, a numerical model incorporating three aspects of blastocyst morphological grades could be a start point, such as a recent study ( Liu et al , 2022 ), which calculated weightings of each aspect in predicting live birth likelihood.…”

Section: Discussionmentioning

confidence: 99%

Blastocyst quality and reproductive and perinatal outcomes: a multinational multicentre observational study

Zou,

Kemper,

Hammond

et al. 2023

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STUDY QUESTION Does the transfer of single low-grade blastocysts result in acceptable reproductive and perinatal outcomes compared to the transfer of single good-grade blastocysts? SUMMARY ANSWER The transfer of single low-grade blastocysts resulted in a reduced live birth rate of around 30% (14% for very low-grade blastocysts) compared to 44% for single good-grade blastocysts, but does not lead to more adverse perinatal outcomes. WHAT IS KNOWN ALREADY It is known that low-grade blastocysts can result in live births. However, the current studies are limited by relatively small sample sizes and single-centre designs. Furthermore, evidence on perinatal outcomes after transferring low-grade blastocysts is limited. STUDY DESIGN, SIZE, DURATION We conducted a multi-centre, multi-national retrospective cohort study of 10 018 women undergoing 10 964 single blastocyst transfer cycles between 2009 and 2020 from 14 clinics across Australia, China, and New Zealand. PARTICIPANTS/MATERIALS, SETTING, METHODS Blastocysts were graded individually based on assessment of the morphology and development of the inner cell mass (ICM) and trophectoderm (TE), and were grouped into three quality categories: good- (AB, AB, or BA), moderate- (BB), and low-grade (grade C for ICM or TE) blastocysts. CC blastocysts were individually grouped as very low-grade blastocysts. Logistic regression with generalized estimating equation was used to analyse the association between blastocyst quality and live birth as well as other reproductive outcomes. Binomial, multinomial logistic, or linear regression was used to investigate the association between blastocyst quality and perinatal outcomes. Odds ratio (OR), adjusted OR (aOR), adjusted regression coefficient, and their 95% CIs are presented. Statistical significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE There were 4386 good-grade blastocysts, 3735 moderate-grade blastocysts, and 2843 low-grade blastocysts were included in the analysis, for which the live birth rates were 44.4%, 38.6%, and 30.2%, respectively. Compared to good-grade blastocysts, the live birth rate of low-grade blastocysts was significantly lower (aOR of 0.48 (0.41–0.55)). Very low-grade blastocysts were associated with an even lower live birth rate (aOR 0.30 (0.18–0.52)) and their absolute live birth rate was 13.7%. There were 4132 singleton live births included in the analysis of perinatal outcomes. Compared with good-grade blastocysts, low-grade blastocysts had comparable preterm birth rates (<37 weeks, aOR 1.00 (0.65–1.54)), birthweight Z-scores (adjusted regression coefficient 0.02 (0.09–0.14)), and rates of very low birth weight (<1500 g, aOR 0.84 (0.22–3.25)), low birth weight (1500–2500 g, aOR 0.96 (0.56–1.65)), high birth weight (>4500 g, aOR 0.93 (0.37–2.32)), small for gestational age (aOR 1.63 (0.91–2.93)), and large for gestational age (aOR 1.28 (0.97–1.70)). LIMITATIONS, REASONS FOR CAUTION Due to the nature of the retrospective design, residual confounding could not be excluded. In addition, the number of events for some perinatal outcomes was small. Between-operator and between-laboratory variations in blastocyst assessment were difficult to control. WIDER IMPLICATIONS OF THE FINDINGS Patients undergoing IVF should be informed that low-grade blastocysts result in a lower live birth rate, however they do not increase the risk of adverse perinatal outcomes. Further research should focus on the criteria for embryos that should not be transferred and on the follow-up of long-term outcomes of offspring. STUDY FUNDING/COMPETING INTEREST(S) H.Z. is supported by a Monash Research Scholarship. B.W.J.M. is supported by a NHMRC Investigator grant (GNT1176437). R.W. is supported by an NHMRC Emerging Leadership Investigator grant (2009767). B.W.J.M. reports consultancy, travel support, and research funding from Merck. The other authors do not have competing interests to disclose. TRIAL REGISTRATION NUMBER N/A.

“…As mentioned previously, the Gardner blastocyst grading system is considered a traditional embryo selection method. However, varying blastocyst observation timings between laboratories proved to be challenging to control when linking static morphology features to treatment outcomes, considering the dynamic nature of embryo development ( Liu et al , 2022 ). Using a multi-variate logistic regression and incorporating calculated weightings for each contributing variable, the same study presented a numerical scoring system that could potentially minimize operator-related subjectivity at the ranking step ( Liu et al , 2022 ).…”

Section: Ai-driven Dsssmentioning

confidence: 99%

“…However, varying blastocyst observation timings between laboratories proved to be challenging to control when linking static morphology features to treatment outcomes, considering the dynamic nature of embryo development ( Liu et al , 2022 ). Using a multi-variate logistic regression and incorporating calculated weightings for each contributing variable, the same study presented a numerical scoring system that could potentially minimize operator-related subjectivity at the ranking step ( Liu et al , 2022 ). In the study, four variables were input into the logistic regression and coefficients were used as weightings for each of the variables.…”

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.