Possible mechanisms and clinical innovations of sequential embryo transfer in assisted reproduction

This review comprehensively discusses the innovative value and scientific mechanism of sequential embryo transfer (SET) technology in assisted reproduction. SET, by transferring embryos in stages, offers a novel approach to address clinical challenges in patients with recurrent implantation failure (RIF) and poor ovarian response (POR). The core mechanism involves bidirectional signal regulation between the embryo and endometrium. Extracellular vesicles (EVs) released by embryos during the initial transfer contain bioactive molecules like proteins, microRNA (miRNA), and mRNA. Through bidirectional molecular communication, these EVs interact with the maternal-fetal interface, promoting endometrial decidualization and establishing a molecular memory for 'embryo pre-adaptation,' thereby enhancing endometrial receptivity. Subsequent embryo transfers further optimize the pregnancy microenvironment through cumulative signaling effects, boosting embryo development and implantation success rates. Additionally, the synergistic impact of mechanical injury plays a role. Local micro-injuries induced by the transfer catheter operation trigger an inflammatory response, recruit immune cells, activate tissue repair pathways, stimulate regenerative cell and signaling molecule secretion, and enhance angiogenesis and endometrial remodeling. This 'microtrauma pre-activation' fosters favorable conditions for subsequent embryo implantation. Clinical evidence demonstrates that SET significantly elevates the clinical pregnancy and live birth rates in RIF patients without heightening the risk of multiple pregnancies. In POR patients, SET can reduce cycle cancelation rates. This review not only supports the clinical application of SET but also advances assisted reproduction from empirical to precision medicine guided by molecular mechanisms.