{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T09:08:39Z","timestamp":1788772119795,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>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\u2013brain 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\u2014including ambient environmental heat, infectious fever, behavioral or exogenous heating, and experimentally induced hyperthermia\u2014were 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\u2013brain 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.<\/jats:p>","DOI":"10.3390\/cells15171621","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T08:07:06Z","timestamp":1788768426000},"page":"1621","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Placenta\u2013Brain Axis Under Heat Stress: Inflammatory Pathways Linking Prenatal Thermal Exposure to Offspring Neurodevelopment"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3268-8797","authenticated-orcid":false,"given":"Alina","family":"Liepinaitien\u0117","sequence":"first","affiliation":[{"name":"Department of Environmental Sciences, Faculty of Natural Sciences, Vytautas Magnus University, LT-53361 Kaunas, Lithuania"},{"name":"SMK College of Applied Sciences, Kauno m. sav., 46326 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7365-672X","authenticated-orcid":false,"given":"Nikolaos S.","family":"Avramiotis","sequence":"additional","affiliation":[{"name":"Department of Neurology and Stroke Center, University Hospital Basel, University of Basel, 4031 Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1788-3818","authenticated-orcid":false,"given":"Dimitra","family":"Metallinou","sequence":"additional","affiliation":[{"name":"Midwifery Department, Faculty of Health and Care Sciences, University of West Attica, Egaleo, 122 43 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7458-7500","authenticated-orcid":false,"given":"Eirini","family":"Orovou","sequence":"additional","affiliation":[{"name":"Midwifery Department, University of Western Macedonia, 50 200 Kozani, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angeliki","family":"Bolou","sequence":"additional","affiliation":[{"name":"Midwifery Department, Faculty of Health and Care Sciences, University of West Attica, Egaleo, 122 43 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tzeli","sequence":"additional","affiliation":[{"name":"Midwifery Department, Faculty of Health and Care Sciences, University of West Attica, Egaleo, 122 43 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1653-5398","authenticated-orcid":false,"given":"Aikaterini","family":"Sousamli","sequence":"additional","affiliation":[{"name":"Midwifery Department, Faculty of Health and Care Sciences, University of West Attica, Egaleo, 122 43 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7041-9980","authenticated-orcid":false,"given":"Audrius","family":"D\u0117del\u0117","sequence":"additional","affiliation":[{"name":"Department of Environmental Sciences, Faculty of Natural Sciences, Vytautas Magnus University, LT-53361 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3316-8566","authenticated-orcid":false,"given":"Antigoni","family":"Sarantaki","sequence":"additional","affiliation":[{"name":"Midwifery Department, Faculty of Health and Care Sciences, University of West Attica, Egaleo, 122 43 Athens, Greece"},{"name":"Faculty of Medicine, Kauno Kolegija Higher Education Institution, Kauno m. sav., 50468 Kaunas, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/s41591-024-03395-8","article-title":"A systematic review and meta-analysis of heat exposure impacts on maternal, fetal and neonatal health","volume":"31","author":"Lakhoo","year":"2025","journal-title":"Nat. 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