The Placenta–Brain–Psychosis Axis in Pregnancy: A Systematic Review of Placental Immunobiology, Maternal Relapse in Schizophrenia and Bipolar Disorder, and Fetal Neurodevelopmental Programming

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BSTRACT

This systematic review addresses the emerging Placenta–Brain–Psychosis Axis, an integrative framework linking placental immunobiology, maternal relapse patterns in severe mental illness, and fetal neurodevelopmental programming – domains that have largely evolved in parallel rather than through coordinated investigation. Comprehensive searches of major biomedical databases were conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guided methodology, resulting in the inclusion of 39 studies spanning epidemiological, mechanistic, and translational research. Collectively, the evidence suggests that the placenta functions not merely as a passive interface but as an active immunological and signaling organ capable of modulating both maternal and fetal physiology. This includes involvement in cytokine signaling, extracellular vesicle communication, and placental serotonin synthesis. While these processes support the concept of a neuro–immune interface, the possibility of bidirectional signaling – particularly effects of placental signaling on maternal neuropsychiatric states – remains biologically plausible but not yet directly established. Clinically, pregnancy and the postpartum period are recognized as phases of increased vulnerability to relapse in schizophrenia and bipolar disorder; however, the underlying biological mechanisms remain insufficiently defined. The integrated synthesis presented here highlights placental signaling as a potential intermediary linking maternal neuroimmune dysregulation with both acute psychiatric relapse and longer-term neurodevelopmental outcomes in offspring. This framework remains provisional and should be interpreted as hypothesis-generating. Nonetheless, it challenges the prevailing brain-centric perspective in perinatal psychiatry by proposing a distributed biological model that may, with further empirical validation, inform biomarker development and anticipatory clinical strategies.