Two distinct causes contribute to the low efficiency of human pre-implantation development

∼50% of fertilized eggs arrest during human pre-implantation development, representing a major bottleneck for assisted reproductive technology. The underlying causes remain controversial. By imaging ∼150 live human and monkey fertilized eggs for up to 5 days, we uncovered that the second mitotic divisions are the most error-prone, accounting for early embryonic arrest. Stochastic centriole overduplication, which could be effectively suppressed by transient treatment with PLK4 Inhibitor centrinone, predisposed 2-cell blastomeres to assembling multipolar spindles and missegregating chromosomes. Missegregated chromosomes in turn resulted in the formation of most micronuclei in human embryos and led to the arrest or death of daughter blastomeres. By contrast, late embryonic arrest was largely independent of chromosome missegregations but involved the activation of endoplasmic reticulum stress response, which could impair the expression of subsets of junctional and cell polarity proteins required for blastocyst formation. Thus, two distinct causes contribute to the low efficiency of human pre-implantation development.