Abstract

Background: Recurrent pregnancy loss (RPL) remains a significant clinical challenge, with antiphospholipid syndrome (APS) being a major treatable autoimmune cause. Traditional models focused on thrombosis, but evidence now highlights direct inflammatory and immunological insults at the maternal-fetal interface. A substantial number of patients with obstetric APS phenotypes are seronegative by standard criteria, suggesting a role for novel autoantibodies and immune pathways. Objective: This systematic review aimed to synthesize recent evidence on novel autoantibodies, genetic factors, and immunological pathways involved in the pathogenesis of RPL associated with APS. Methods: Following PRISMA guidelines, a systematic search of five databases (PubMed/MEDLINE, Scopus, Web of Science, Embase, Cochrane) was conducted for studies published between January 2019 and December 2024. Studies investigating non-criteria antibodies, genetic polymorphisms, or novel immunological mechanisms in RPL with/without APS were included. Data extraction and risk-of-bias assessment were performed independently by two reviewers. A narrative synthesis was conducted due to study heterogeneity. Results: From 688 screened records, four studies met the inclusion criteria. The findings revealed a multi-layered pathophysiology: 1) Genetic susceptibility via polymorphisms in APOH and NCF1genes; 2) Cellular dysfunction mediated by the long non-coding RNA LncNR_040117 through MAPK pathway activation, impairing trophoblast function; 3) Specific antibody effects, where anti-β2GPI IgG was independently associated with systemic vascular endothelial dysfunction; and 4) Dysregulated inflammatory networks involving cytokines such as TNF-α and IL-6. Conclusion: The pathogenesis of APS-related RPL extends beyond thrombosis, involving a complex interplay of genetic predisposition, novel antibody specificities, non-coding RNA regulation, and inflammatory cytokine networks. These insights advocate for a paradigm shift towards a more integrated, immune-centric model and highlight potential novel biomarkers and therapeutic targets for improving diagnosis and outcomes in RPL.

Key words: Recurrent Pregnancy Loss, Antiphospholipid Syndrome, Non-Criteria Antiphospholipid Antibodies, Immunological Pathways, Genetic Polymorphisms, Long Non-Coding RNA, Endothelial Dysfunction, Trophoblast