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

study questionIs 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,

methodsTwo 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

findingsOur 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.