Evaluating the heterogeneous effect of extended incubation to blastocyst transfer on the implantation outcome via causal inference

In IVF treatments, extended culture to single blastocyst-transfer is the recommended protocol over cleavage-stage transfer. However, evidence-based criteria for assessing the heterogeneous implications on implantation outcome are lacking. To estimate the causal effect of blastocyst-transfer on implantation outcome, we assembled a multicenter dataset of embryo time-lapse imaging. The data includes a natural source of randomness and has a strong claim for satisfying the assumptions needed for valid causal inference. By fitting a causal forest model, we assessed the Transfer Lift, which quantifies the probability difference in embryo implantation if transferred as a blastocyst versus cleavage-stage. Blastocyst transfer increased the average implantation rate, however we revealed a subpopulation of negative Transfer Lift embryos whose implantation potential is predicted to increase via cleavage-stage transfer. We provide day-of-transfer decision-support tools that are retrospectively estimated to improve implantation rate by 32%, thus demonstrating the efficacy of embryo-level causal inference in reproductive medicine. One Sentence SummaryA causal inference model predicts the heterogeneous effect of prolonged incubation to blastocyst transfer on embryo implantation, thus providing means for optimizing pregnancy rates in IVF treatments.