Preimplantation embryos that arrest in vitro: phenotypes, causes and possible therapies

: This review examines the biological basis of human preimplantation embryo developmental arrest, a major limiting factor in reproductive success both in vivo and in vitro. It integrates morphological, genetic, and environmental evidence to hypothesize the origins and consequences of early embryonic failure. Abnormal cleavage-stage phenotypes, including multinucleation, atypical division patterns, and fragmentation, emerge prior to embryonic genome activation and reflect disruptions in mitotic fidelity, chromosome segregation, and cytoskeletal dynamics. These early defects often propagate leading to developmental arrest. Post-genome activation abnormalities, such as blastomere exclusion and impaired blastocyst expansion, represent downstream manifestations of earlier cellular dysfunction. While meiotic aneuploidy contributes primarily to implantation failure and miscarriage rather than in vitro arrest, maternal-effect gene mutations and defects in oocyte-derived molecular machinery further compromise developmental competence. Extrinsic factors related to culture conditions can modulate embryo viability and must be kept under control via strict adherence to international benchmark values for laboratory key performance indicators. Yet, it appears we have reached a plateau in our capacity to improve outcomes, although upcoming automation can further enhance standardization in IVF performance across operators and clinics. Emerging approaches integrating AI-assisted time-lapse imaging with genomic analysis offer new opportunities for high-resolution phenotyping and causal inference. Finally, the review highlights future putative therapeutic strategies aimed at improving mitotic fidelity, particularly through modulation of microtubule dynamics during the first embryonic division, as a promising avenue to enhance blastocyst formation and ultimately IVF success rates.