Human placentation in the transplanted uterus: mechanisms of maternal–fetal complications and associated clinical challenges

Abstract

Uterus transplantation has evolved from an experimental surgical procedure into a clinically viable treatment option for women with absolute uterine factor infertility. Although successful graft function and an increasing number of live births demonstrate its reproductive potential, pregnancies in transplanted uteri remain clinically challenging. They are frequently associated with hypertensive disorders, preterm birth, and manifestations of abnormal placentation. This review was undertaken to explore whether these adverse outcomes can be better understood through the biological mechanisms of human placentation rather than as isolated obstetric complications. A systematic literature search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using PubMed/MEDLINE, Embase, Scopus, and the Cochrane Library. Studies addressing UTx, placental biology, endocrine regulation, and maternal–fetal outcomes were identified, screened, and assessed for eligibility, resulting in the inclusion of 61 studies for qualitative synthesis. The evidence reveals a consistent pattern indicating that the transplanted uterus does not fully replicate the physiological reproductive environment of a native uterus. Instead, it represents a biologically altered milieu shaped by surgical vascular reconstruction, immunosuppressive therapy, and hormonally programmed endometrial preparation. These factors appear to converge at the maternal–fetal interface, where decidualization, immune tolerance, and spiral artery remodeling are normally orchestrated in a highly coordinated manner but may be only partially reestablished after transplantation. Consequently, implantation is generally successful; however, placentation may be subtly but significantly altered, providing a plausible mechanistic explanation for the increased incidence of maternal and fetal complications reported in UTx pregnancies. From this perspective, ongoing clinical concerns may reflect an incomplete understanding of the underlying biological processes rather than inconsistent reproductive success. Future research should, therefore, move beyond descriptive outcome reporting and focus on integrated mechanistic models that link transplantation biology to placental development and function, thereby informing improved surveillance strategies and targeted therapeutic interventions.