Unexplained Recurrent Pregnancy Loss and Emerging Endometrial Biology: A Clinically Oriented Narrative Review

Abstract

Abstract

A substantial proportion of couples who experience recurrent pregnancy loss (RPL) complete a full guideline-based evaluation without an identifiable cause and are given a diagnosis of unexplained RPL. This category should be interpreted as the current limitation of clinically validated biological explanation rather than as the absence of underlying pathology, and it is within this diagnostic gap that interest in emerging endometrial biology has grown. Recent advances in endometrial biology have generated substantial interest in three closely related investigational domains: the endometrial microbiome, chronic endometritis (CE), and the endometrial immune milieu. Each domain has independently been associated with reproductive failure in observational research, and growing evidence suggests potential biological interactions among them. However, significant methodological heterogeneity, absence of standardized diagnostic criteria, and insufficient prospective validation currently preclude routine clinical implementation. This narrative review synthesizes current evidence in each of these domains and weighs their relevance to how unexplained RPL is managed. The review concludes that abnormalities involving endometrial microbial composition, chronic endometrial inflammation, and local immune dysregulation represent biologically plausible contributors to unexplained pregnancy loss in selected women, but that the principal barriers to clinical adoption are reproducibility, methodological standardization, and demonstrated clinical utility rather than biological plausibility alone. Major professional guidelines currently advise against routine use of these tests outside a research context. Emerging endometrial biology should therefore be interpreted as a framework for ongoing scientific inquiry, not as a basis for expanded clinical testing. Incorporation into routine practice will require standardized methodology, independent multicenter validation, and prospective demonstration that diagnosis and treatment improve clinically meaningful reproductive outcomes.