Perinatal Immune Adaptation and Tolerance at the Maternal–Fetal Interface: A Systematic Review

Pregnancy requires the maternal immune system to achieve a delicate balance between protecting the mother and tolerating the semi-allogeneic fetus. Failures in this adaptation are strongly implicated in preeclampsia, recurrent pregnancy loss, fetal growth restriction, and preterm birth, yet the literature on this topic remains fragmented and heterogeneous. We conducted a systematic review to integrate mechanistic, translational, and clinical insights on perinatal immune tolerance at the maternal–fetal interface. Comprehensive searches of PubMed, Embase, Scopus, Web of Science, Cochrane, and Google Scholar up to June 2025 yielded 1245 records. After removal of duplicates and irrelevant reports, 750 studies underwent screening, 120 full texts were assessed, and 50 articles fulfilled predefined criteria. Among these, 20 were identified as core studies through bias assessment using AMSTAR-2, ROBIS, SYRCLE, and an adapted Newcastle–Ottawa scale. Risk of bias ranged from low to moderate across study designs. Synthesis of findings identified regulatory T cells, decidual NK cells, non-classical HLA molecules, and checkpoint pathways such as PD-1/PD-L1 and TIM-3 as central regulators of tolerance. Exosome-mediated communication and metabolic–epigenetic programming emerged as additional layers of immune regulation. Novel themes included microchimerism, B-cell plasticity, and progesterone-driven checkpoint signaling. Translational opportunities span the development of non-invasive biomarkers, immunomodulatory therapies, and machine learning–assisted immune monitoring. This review consolidates the most current evidence on maternal–fetal immune adaptation, demonstrating how mechanistic discoveries can inform clinical innovation. The findings provide a roadmap for future research, highlighting the need for standardized immune profiling, multicenter validation, and ethical translation into perinatal practice.