Placenta–Brain Axis Under Heat Stress: Inflammatory Pathways Linking Prenatal Thermal Exposure to Offspring Neurodevelopment

Abstract

Highlights Prenatal thermal exposure was associated with a spectrum of fetal and offspring neurodevelopmental outcomes, with the strongest and most consistent early-pregnancy evidence involving neural tube defects during the periconceptional and neurulation periods. Experimental evidence indicates that heat stress can disrupt placental barrier function, inflammatory and oxidative pathways, glucocorticoid and serotonin-related signaling, and fetal-brain developmental processes, supporting the biological plausibility of a heat-related placenta–brain framework. The placenta may represent a biologically plausible interface linking maternal thermal stress with fetal brain development. Still, current evidence does not establish a causal heat-induced placenta–brain axis in humans. Integrated prospective studies combining individual-level heat assessment, placental biomarkers, fetal-brain imaging, and longitudinal neurodevelopmental follow-up are needed to identify critical gestational windows and test placental mediation. Abstract Climate change is increasing the frequency and intensity of extreme heat events, raising concern about prenatal thermal exposure as a potential risk factor for fetal brain development and offspring neurodevelopment. This systematic review aimed to synthesize evidence on prenatal heat exposure, placental inflammatory or stress-response pathways, and fetal or offspring neurodevelopmental outcomes, while evaluating the placenta–brain axis as a proposed mechanistic hypothesis rather than an established causal pathway. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, Web of Science, Google Scholar, and Embase from database inception to 30 June 2026. Human observational studies, animal experiments, and in vitro mechanistic studies were included when they examined prenatal thermal exposure in relation to either placental function and stress-response mechanisms or fetal-brain and offspring neurodevelopmental outcomes. Ambient environmental heat, infectious fever, behavioral or exogenous heat exposure, experimental maternal hyperthermia, and direct cellular or organoid thermal stimulation were considered separately because these exposures are not biologically equivalent. Across the included studies, distinct prenatal thermal exposures—including ambient environmental heat, infectious fever, behavioral or exogenous heating, and experimentally induced hyperthermia—were associated with congenital central nervous system anomalies, including neural tube defects, as well as later outcomes such as neurodevelopmental delay, language impairment, autism spectrum disorder, cerebral palsy, and altered child-brain morphology. The strongest and most consistent early-pregnancy signal concerned neural tube defects during the periconceptional and neurulation periods, whereas evidence for later neurodevelopmental outcomes identified more heterogeneous susceptibility windows across gestation. Experimental evidence suggested alterations in placental barrier function, glucocorticoid and serotonin-related signaling, inflammatory and oxidative pathways, myelination, apoptosis, and neural-progenitor development. However, only one included experimental study jointly assessed maternal heat stress, placental alterations, and fetal-brain-related outcomes, while the human studies did not measure placental mediators or perform mediation analyses. Evidence from non-heat inflammatory studies therefore provides only indirect mechanistic context. Overall, prenatal heat exposure may contribute to neurodevelopmental vulnerability through multiple direct and indirect pathways, including a biologically plausible but unproven placenta–brain framework. Prospective studies integrating individual-level heat assessment, placental biomarkers, standardized fetal-brain imaging, and longitudinal neurodevelopmental follow-up are required to test this hypothesis.