Evaluating the heterogeneous effect of extended culture to blastocyst transfer on the implantation outcome via causal inference in fresh ICSI cycles

Purpose: 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 outcomes are lacking. The purpose of this work is to estimate the causal effect of blastocyst transfer on implantation outcome. Methods: We fit a causal forest model using a multicenter observational dataset that includes an exogenous source of variability in treatment assignment and has a strong claim for satisfying the assumptions needed for valid causal inference from observational data. Results: We quantified 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 embryos whose implantation potential is predicted to increase via cleavage-stage transfer. Conclusion: Relative to the current policy, the proposed embryo transfer policy retrospectively improves implantation rate from 0.2 to 0.27. Our work demonstrates the efficacy of implementing causal inference in reproductive medicine and motivates its utilization in medical disciplines that are dominated by retrospective datasets.