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

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 neurodevelopmental outcomes in offspring. 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 or early-life heat exposure in relation to placental function, inflammatory or oxidative pathways, fetal brain development or offspring neurodevelopment. The included evidence linked prenatal heat exposure or maternal hyperthermia with neural tube defects, neurodevelopmental delay, language impairment, autism spectrum disorder, cerebral palsy and altered brain morphology. Early pregnancy appeared to be the most consistent vulnerability window, although later gestational exposure was also relevant. Experimental evidence suggested disruption of placental barrier function, glucocorticoid and serotonin signaling, inflammatory and oxidative pathways, myelination, apoptosis, and neural progenitor development. Prenatal heat exposure may contribute to neurodevelopmental vulnerability through a heat-related placenta–brain axis. Further prospective and mechanistic studies are needed.