Decoding Immune-checkpoint Dynamics and Microchimerism in Autoimmune Pregnancy: Systematic Review and Federated Causal Multi-omic Synthesis to Predict and Prevent Adverse Outcomes

A BSTRACT Autoimmune pregnancy lies at a complex intersection of maternal immune tolerance and persistent autoimmunity, where small perturbations can have outsized clinical consequences. Rather than functioning as a static state, immune adaptation in pregnancy appears to evolve through dynamic interactions between immune-checkpoint pathways and bidirectional fetal-maternal microchimerism. This systematic review, conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, synthesizes cross-disease evidence linking immune-checkpoint regulation (programmed cell death protein 1/programmed death-ligand 1, cytotoxic T-lymphocyte antigen-4, T cell immunoglobulin and mucin domain-containing protein 3, LAG-3 (Lymphocyte-activation gene 3), and human leukocyte antigen G with microchimeric cell persistence in autoimmune pregnancy. Comprehensive searches of PubMed, Scopus, and Embase identified 1720 records; 36 studies met predefined inclusion criteria, with 20 prioritized for core synthesis following structured risk-of-bias assessment using ROBIS, risk of bias in non-randomized studies—of interventions (ROBINS-I), and a measurement tool to assess systematic reviews 2. Included evidence spans mechanistic experiments, placental pathology, human cohort studies, and pharmacovigilance analyses, primarily in systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroid disease, and preeclampsia. Across studies, immune-checkpoint dysregulation at the maternal–fetal interface is consistently associated with impaired tolerance, while persistent fetal or maternal microchimeric cells appear to shape immune memory, postpartum autoimmune activity, and offspring immune programming. Beyond summarizing existing evidence, this review integrates findings into six mechanistic themes and proposes a conceptual, translational framework in which multi-omic profiling and causal inference could be applied to study checkpoint–microchimerism interactions across diseases. This framework is explicitly hypothesis-generating and not presented as a validated clinical model, but rather as a research blueprint to guide future longitudinal studies. By clearly distinguishing established evidence from forward-looking synthesis, this review reframes autoimmune pregnancy as a dynamic immune system with implications for risk stratification, monitoring, and the future development of precision approaches in perinatal immunology.