From maternal distress to fetal brain: A systematic review of psychoimmune–placental extracellular vesicle pathways and their neurodevelopmental signatures

Maternal psychological distress is increasingly recognized as a biologically active exposure rather than a purely psychosocial state. Yet, the mechanistic pathways linking maternal stress to fetal neurodevelopment remain incompletely integrated across disciplines. This systematic review synthesizes current evidence on psychoimmune signaling, placental physiology, and extracellular vesicle (EV) biology to evaluate whether placental vesicle trafficking represents a coherent mechanistic bridge between maternal stress states and fetal neural outcomes. Comprehensive searches of major biomedical databases and study registers identified 1264 records, of which 33 studies met predefined eligibility criteria after duplicate removal, structured screening, and full-text assessment. Across human, animal, and translational models, convergent evidence indicates that maternal stress correlates with inflammatory signaling, endocrine modulation, and altered EV cargo profiles, including regulatory RNAs and proteins capable of influencing placental and fetal cellular pathways. Experimental data suggest that these vesicles can modify neuroimmune tone, synaptic development, and glial maturation, while clinical studies support their potential as minimally invasive biomarkers reflecting intrauterine signaling states. Nevertheless, methodological heterogeneity, limited longitudinal cohorts, and incomplete standardization of vesicle isolation constrain causal inference and clinical implementation. Taken together, the literature supports a system-level model in which placental EVs act as dynamic intermediaries translating maternal physiological context into fetal developmental signals. This integrative perspective reframes maternal stress biology as a measurable, mechanistically tractable component of prenatal medicine. It highlights EVs as candidate targets for biomarker development, risk stratification, and future intervention studies.