Maternal-fetal interface abnormalities in unexplained recurrent pregnancy loss: mechanisms, models, and a framework...

Recurrent pregnancy loss (RPL) is a heterogeneous reproductive condition, and unexplained recurrent pregnancy loss (URPL) denotes repeated pregnancy losses for which no established cause is identified after standard evaluation. Recurrent miscarriage (RM) and recurrent spontaneous abortion (RSA) are overlapping terms used in the literature, whereas recurrent implantation failure (RIF) is a related but distinct infertility context. In this Mini Review, URPL is treated as an exclusion-based clinical category rather than a single disease entity. This review examines the hypothesis that a subset of URPL reflects abnormalities in specific cellular and molecular components of the maternal-fetal interface. We focus on maternal compartments, including endometrial epithelial lineage states, decidual stromal dysfunction, and stromal-immune interactions, as well as fetal/trophoblast compartments such as trophoblast lineage defects and broader maternal-fetal interactions, incorporating insights from recent advances in molecular and cellular technologies and human model systems. Particular attention is given to single-cell, spatial, organoid, assembloid, implantation model, trophoblast stem cell, and placental explant studies published from 2024 to 2026. Current data do not establish clinical subtypes for URPL or support treatment selection in routine practice. However, recent molecular and cellular technologies now make it possible to define interface phenotypes with higher resolution and to test whether patient-derived abnormalities are reproducible and perturbable in experimental systems. An interface-centered framework may therefore help move URPL research from broad exclusion-based labels toward experimentally testable subtype identification based on epithelial, decidual, trophoblast, immune, and embryo-endometrial phenotypes.