From Phenotype to Endotype: A Systematic Review of Endocrine–Immune–Metabolic Reprogramming in Recurrent Pregnancy Loss Using Single-Cell and Spatial Multi-Omics

A bstract Recurrent pregnancy loss (RPL) continues to challenge clinicians, not only because of its emotional burden but also due to the persistent inability to explain many cases using conventional diagnostic frameworks. Traditional classifications—largely anatomical, genetic, or immunological—offer partial explanations, yet they often fall short when confronted with patients whose investigations appear “normal” despite repeated losses. Over time, it has become increasingly difficult to ignore that endocrine dysregulation, immune imbalance, and metabolic stress rarely act in isolation at the maternal–fetal interface. Rather, they seem to intersect in ways that current models do not fully capture. In this systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, we examined the emerging body of literature applying single-cell and spatial multi-omics technologies to the study of human decidual and placental tissues. Searches were performed across major biomedical databases, with predefined inclusion criteria emphasizing mechanistic relevance and human-derived data. Following screening, 38 studies were included for qualitative synthesis, encompassing single-cell transcriptomics, spatial transcriptomics, and integrative multi-omics analyses. Across these studies, a pattern begins to emerge—though not always neatly—suggesting that RPL may be better understood as a collection of biologically distinct endotypes. These include impaired decidual stromal function linked to progesterone responsiveness, dysregulated decidual immune cell interactions, defective trophoblast differentiation, vascular niche disruption, and metabolic stress states such as ferroptosis. What is striking is not only their individual roles but also how frequently they appear to overlap. Taken together, these findings support a shift toward an endocrine–immune–metabolic framework of RPL, one that may ultimately allow more precise diagnostic stratification and, perhaps cautiously, more targeted intervention.