Psychosocial Stress as a Maternal Immune Activation-like State: A Systematic Review of Neuroimmune and Fetal Neurodevelopmental Pathways
Wiku Andonotopo, Muhammad Adrianes Bachnas, Mochammad Besari Adi Pramono, Julian Dewantiningrum, Efendi Lukas, I. Nyoman Hariyasa Sanjaya, Anak Agung Gede Putra Wiradnyana, Anak Agung Ngurah Jaya Kusuma, Khanisyah Erza Gumilar, Ernawati Darmawan, Dovy Djanas, Dudy Aldiansyah, Aloysius Suryawan, Ridwan Abdullah Putra, Theresia Monica Rahardjo, Anita Deborah Anwar, Cut Meurah Yeni, Nuswil Bernolian, Laksmana Adi Krista Nugraha, Waskita Ekamaheswara Kasumba Andanaputra, Wibisana Andika Krista Dharma, Milan Stanojevic
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BSTRACT
Maternal immune activation has traditionally been conceptualized in relation to infection, although emerging evidence suggests that severe psychosocial stress during pregnancy may engage partially overlapping inflammatory and neuroimmune pathways. This systematic review examined whether psychosocial stress exposures are associated with maternal immune activation-like signaling relevant to fetal neurodevelopment. Literature searches were conducted across major biomedical databases and supplementary sources in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 principles. Following screening and eligibility assessment, 33 articles were retained for qualitative synthesis, including human cohort studies, experimental investigations, and selected translational or conceptual literature relevant to neuroimmune mechanisms. Across heterogeneous study designs, chronic stress, trauma-related exposures, and adverse affective states were frequently associated with altered cytokine activity, placental inflammatory signaling, oxidative stress responses, and changes in neurodevelopment-related immune pathways. Microglial signaling, chemokine activity, mitochondrial regulation, and inflammatory transcriptional responses emerged as recurrent mechanistic themes, although direct evidence involving fetal interneuron-specific processes remained comparatively limited. Findings varied considerably according to developmental timing, exposure severity, biological sex, and methodological approach, limiting direct causal inference and cross-study comparability. Overall, the available evidence supports the interpretation that psychosocial stress may function, under specific biological conditions, as a maternal immune activation-like state rather than a direct equivalent of infection-driven immune activation. These findings support continued investigation into neuroimmune biomarkers and developmental vulnerability pathways while underscoring the need for longitudinal, mechanistically integrated, and clinically well-characterized pregnancy studies.