Abstract:

The core objective of assisted reproductive technology (ART) is to achieve a healthy live birth; however, recurrent implantation failure (RIF) remains a critical bottleneck limiting the clinical efficacy of ART. Sequential embryo transfer involves the transfer of a cleavage-stage embryo followed by a blastocyst within the same cycle, which offers a novel approach to improve the pregnancy outcomes in RIF patients. Sequential transfer improves endometrial receptivity primarily through three pathways: the embryo-derived leukemia inhibitory factors upregulate HOXA10 expression via the JAK/STAT3 signaling pathway, thereby enhancing embryo-endometrial adhesion; maternal estrogen and progesterone regulate epithelial differentiation through the FGFs-FGFR2 signaling axis that mediated by stromal cells, contributing to the opening and closure of the implantation window; and mechanical stimulation promotes angiogenesis via the TNF-α-MMP pathway while inducing M2-type macrophage polarization to modulate the local immune microenvironment. Clinically, sequential transfer has shown potential in specific populations, including those patients with RIF, advanced age, or polycystic ovary syndrome, without increasing the risks of multiple pregnancies or ectopic pregnancies. However, most current evidence is derived from the retrospective studies with limited randomized controlled trials, and considerable heterogeneity exists across studies regarding the definition of RIF and protocol design, which limits the integration and generalizability of the findings. Overall, current evidence does not support sequential transfer as the routine recommendation in RIF patients, and further studies with refined patient stratification and prospective design are needed to validate its clinical value.

Key words: Sequential embryo transfer, Reproductive techniques, assisted, Recurrent implantation failure, Embryo implantation, Endometrial receptivity, Pregnancy outcome