{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T12:40:46Z","timestamp":1793191246191,"version":"4.5.0"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Democritus University of Thrace"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hormones"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Prenatal stress is increasingly recognized as a critical factor influencing fetal brain development, with potential long-term risks for neurodevelopmental and psychiatric disorders. This review explores the effects of prenatal stress on the fetal brain, with particular emphasis on sex differences and the interplay between genetic, epigenetic, and environmental factors. The activation of the hypothalamic\u2013pituitary\u2013adrenal (HPA) axis in response to maternal stress leads to increased levels of glucocorticoids, which can cross the placenta and alter fetal brain structure and function. Key regions affected include the prefrontal cortex, hippocampus, and amygdala, which are crucial for emotional regulation, memory, and cognitive function. Sex differences play a significant role in fetal stress responses, with males exhibiting greater vulnerability to adverse prenatal conditions. Studies suggest that male fetuses exposed to high maternal cortisol levels exhibit alterations in brain connectivity, increased amygdala volume, and heightened stress reactivity, whereas female fetuses may show adaptive mechanisms that confer resilience. Additionally, maternal nutritional status influences fetal neurodevelopment, with both undernutrition and obesity contributing to structural and functional changes in the fetal brain. Advances in neuroimaging techniques, including high-resolution magnetic resonance imaging (MRI) and placental diffusion imaging have provided valuable insights into how prenatal stress affects fetal brain connectivity. Epigenetic modifications, such as DNA methylation and histone modification, are implicated in the long-term programming of stress responses. Furthermore, early-life interventions, including maternal social support and mindfulness-based therapies, may mitigate the adverse effects of prenatal stress on offspring neurodevelopment. Given the profound impact of prenatal stress on fetal brain development, early identification of at-risk populations and the implementation of targeted interventions are crucial. Future research should integrate findings from neuroscience, genetics, and endocrinology to develop preventive strategies that improve neurodevelopmental outcomes and reduce the burden of stress-related disorders in later life.<\/jats:p>","DOI":"10.1007\/s42000-025-00696-6","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T19:59:46Z","timestamp":1753473586000},"page":"5-10","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Prenatal stress, hormones, and fetal brain development: gender differences"],"prefix":"10.1007","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0351-9970","authenticated-orcid":false,"given":"Vasiliki","family":"Georgousopoulou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aspasia","family":"Serdari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Manomenidis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Dacou-Voutetakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"issue":"3","key":"696_CR1","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1111\/eci.12724","volume":"47","author":"S Stavrou","year":"2017","unstructured":"Stavrou S, Nicolaides NC, Critselis E, Darviri C, Charmandari E, Chrousos GP (2017) Paediatric stress: from neuroendocrinology to contemporary disorders. Eur J Clin Invest 47(3):262\u2013269. https:\/\/doi.org\/10.1111\/eci.12724","journal-title":"Eur J Clin Invest"},{"key":"696_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.earlhumdev.2017.09.011","volume":"114","author":"RM Gifford","year":"2017","unstructured":"Gifford RM, Reynolds RM (2017) Sex differences in early-life programming of the hypothalamic-pituitary-adrenal axis in humans. Early Hum Dev 114:7\u201310. https:\/\/doi.org\/10.1016\/j.earlhumdev.2017.09.011","journal-title":"Early Hum Dev"},{"issue":"2","key":"696_CR3","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1017\/S204017441600074X","volume":"8","author":"T Carpenter","year":"2017","unstructured":"Carpenter T, Grecian SM, Reynolds RM (2017) Sex differences in early-life programming of the hypothalamic-pituitary-adrenal axis in humans suggest increased vulnerability in females: a systematic review. J Dev Orig Health Dis 8(2):244\u2013255. https:\/\/doi.org\/10.1017\/S204017441600074X","journal-title":"J Dev Orig Health Dis"},{"issue":"1","key":"696_CR4","doi-asserted-by":"publisher","first-page":"e1919940","DOI":"10.1001\/jamanetworkopen.2019.19940","volume":"3","author":"Y Wu","year":"2020","unstructured":"Wu Y, Lu YC, Jacobs M, Pradhan S, Kapse K, Zhao L et al (2020) Association of prenatal maternal psychological distress with fetal brain growth, metabolism, and cortical maturation. JAMA Netw Open 3(1):e1919940. https:\/\/doi.org\/10.1001\/jamanetworkopen.2019.19940","journal-title":"JAMA Netw Open"},{"key":"696_CR5","doi-asserted-by":"publisher","first-page":"102380","DOI":"10.1016\/j.nicl.2020.102380","volume":"28","author":"SJ Lehtola","year":"2020","unstructured":"Lehtola SJ, Tuulari JJ, Scheinin NM, Karlsson L, Parkkola R, Merisaari H et al (2020) Newborn amygdalar volumes are associated with maternal prenatal psychological distress in a sex-dependent way. Neuroimage Clin 28:102380. https:\/\/doi.org\/10.1016\/j.nicl.2020.102380","journal-title":"Neuroimage Clin"},{"issue":"10","key":"696_CR6","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1093\/gerona\/glw081","volume":"71","author":"LS Bleker","year":"2016","unstructured":"Bleker LS, de Rooij SR, Painter RC, van der Velde N, Roseboom TJ (2016) Prenatal undernutrition and physical function and frailty at the age of 68 years: The Dutch famine birth cohort study. J Gerontol A Biol Sci Med Sci 71(10):1306\u20131314. https:\/\/doi.org\/10.1093\/gerona\/glw081","journal-title":"J Gerontol A Biol Sci Med Sci"},{"issue":"1","key":"696_CR7","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1111\/j.1467-8624.2009.01385.x","volume":"81","author":"EP Davis","year":"2010","unstructured":"Davis EP, Sandman CA (2010) The timing of prenatal exposure to maternal cortisol and psychosocial stress is associated with human infant cognitive development. Child Dev 81(1):131\u2013148. https:\/\/doi.org\/10.1111\/j.1467-8624.2009.01385.x","journal-title":"Child Dev"},{"issue":"1\u20132","key":"696_CR8","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1002\/jnr.23809","volume":"95","author":"BS McEwen","year":"2017","unstructured":"McEwen BS, Milner TA (2017) Understanding the broad influence of sex hormones and sex differences in the brain. J Neurosci Res 95(1\u20132):24\u201339. https:\/\/doi.org\/10.1002\/jnr.23809","journal-title":"J Neurosci Res"},{"key":"696_CR9","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.yfrne.2017.11.001","volume":"49","author":"BS McEwen","year":"2018","unstructured":"McEwen BS (2018) Redefining neuroendocrinology: Epigenetics of brain-body communication over the life course. Front Neuroendocrinol 49:8\u201330. https:\/\/doi.org\/10.1016\/j.yfrne.2017.11.001","journal-title":"Front Neuroendocrinol"},{"key":"696_CR10","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3389\/fped.2019.00022","volume":"7","author":"P Alur","year":"2019","unstructured":"Alur P (2019) Sex differences in nutrition, growth, and metabolism in preterm infants. Front Pediatr 7:22. https:\/\/doi.org\/10.3389\/fped.2019.00022","journal-title":"Front Pediatr"},{"issue":"4","key":"696_CR11","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1111\/jcpp.13301","volume":"62","author":"ME Norr","year":"2021","unstructured":"Norr ME, Hect JL, Lenniger CJ, Van den Heuvel M, Thomason ME (2021) An examination of maternal prenatal BMI and human fetal brain development. J Child Psychol Psychiatry 62(4):458\u2013469. https:\/\/doi.org\/10.1111\/jcpp.13301","journal-title":"J Child Psychol Psychiatry"},{"key":"696_CR12","doi-asserted-by":"publisher","first-page":"514","DOI":"10.3389\/fnhum.2018.00514","volume":"12","author":"AP Salzwedel","year":"2019","unstructured":"Salzwedel AP, Gao W, Andres A, Badger TM, Glasier CM et al (2019) Maternal adiposity influences neonatal brain functional connectivity. Front Hum Neurosci 12:514. https:\/\/doi.org\/10.3389\/fnhum.2018.00514","journal-title":"Front Hum Neurosci"},{"key":"696_CR13","doi-asserted-by":"publisher","DOI":"10.1515\/jpm-2024-0222","author":"E Takeoka","year":"2025","unstructured":"Takeoka E, Carlson AA, Madan N, Azimirad A, Mahmoud T et al (2025) Impact of high maternal body mass index on fetal cerebral cortical and cerebellar volumes. J Perinat Med. https:\/\/doi.org\/10.1515\/jpm-2024-0222","journal-title":"J Perinat Med"},{"issue":"7","key":"696_CR14","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.25368","volume":"102","author":"M Parsaei","year":"2024","unstructured":"Parsaei M, Hashemi SM, Moghaddam HS, Peterson BS (2024) A systematic review of MRI studies on the effects of maternal obesity on offspring brain structure and function. J Neurosci Res 102(7):e25368. https:\/\/doi.org\/10.1002\/jnr.25368","journal-title":"J Neurosci Res"},{"issue":"6","key":"696_CR15","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1177\/09637214231201079","volume":"32","author":"CA Nelson","year":"2023","unstructured":"Nelson CA, Fox NA, Zeanah CH (2023) Romania\u2019s abandoned children: the effects of early profound psychosocial deprivation on the course of human development. Curr Dir Psychol Sci 32(6):515\u2013521. https:\/\/doi.org\/10.1177\/09637214231201079","journal-title":"Curr Dir Psychol Sci"},{"key":"696_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.dcn.2019.100632","volume":"36","author":"MD Wheelock","year":"2019","unstructured":"Wheelock MD, Hect JL, Hernandez-Andrade E, Hassan SS et al (2019) Sex differences in functional connectivity during fetal brain development. Dev Cogn Neurosci 36:100632. https:\/\/doi.org\/10.1016\/j.dcn.2019.100632","journal-title":"Dev Cogn Neurosci"},{"key":"696_CR17","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.neubiorev.2013.12.004","volume":"39","author":"AN Ruigrok","year":"2014","unstructured":"Ruigrok AN, Salimi-Khorshidi G, Lai MC, Baron-Cohen S et al (2014) A meta-analysis of sex differences in human brain structure. Neurosci Biobehav Rev 39:34\u201350. https:\/\/doi.org\/10.1016\/j.neubiorev.2013.12.004","journal-title":"Neurosci Biobehav Rev"},{"issue":"4","key":"696_CR18","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1586\/eem.12.33","volume":"7","author":"CA Sandman","year":"2012","unstructured":"Sandman CA, Davis EP (2012) Neurobehavioral risk is associated with gestational exposure to stress hormones. Expert Rev Endocrinol Metab 7(4):445\u2013459. https:\/\/doi.org\/10.1586\/eem.12.33","journal-title":"Expert Rev Endocrinol Metab"},{"issue":"6","key":"696_CR19","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/nrn3818","volume":"16","author":"TL Bale","year":"2015","unstructured":"Bale TL (2015) Epigenetic and transgenerational reprogramming of brain development. Nat Rev Neurosci 16(6):332\u2013344. https:\/\/doi.org\/10.1038\/nrn3818","journal-title":"Nat Rev Neurosci"},{"issue":"5","key":"696_CR20","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1016\/j.jaac.2017.03.001","volume":"56","author":"C Buss","year":"2017","unstructured":"Buss C, Entringer S, Moog NK, Toepfer P et al (2017) Intergenerational transmission of maternal childhood maltreatment exposure. J Am Acad Child Adolesc Psychiatry 56(5):373\u2013382. https:\/\/doi.org\/10.1016\/j.jaac.2017.03.001","journal-title":"J Am Acad Child Adolesc Psychiatry"},{"key":"696_CR21","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s13148-021-01054-0","volume":"13","author":"TK Kallak","year":"2021","unstructured":"Kallak TK, Br\u00e4nn E, Fransson E et al (2021) DNA methylation in cord blood in association with prenatal depressive symptoms. Clin Epigenet 13:78. https:\/\/doi.org\/10.1186\/s13148-021-01054-0","journal-title":"Clin Epigenet"},{"key":"696_CR22","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2021.101507","volume":"73","author":"J Lin","year":"2022","unstructured":"Lin J, Epel E (2022) Stress and telomere shortening: insights from cellular mechanisms. Ageing Res Rev 73:101507. https:\/\/doi.org\/10.1016\/j.arr.2021.101507","journal-title":"Ageing Res Rev"},{"key":"696_CR23","doi-asserted-by":"publisher","first-page":"675","DOI":"10.1016\/j.jad.2023.08.074","volume":"340","author":"PJW Naud\u00e9","year":"2023","unstructured":"Naud\u00e9 PJW, Stein DJ, Lin J, Zar HJ (2023) Investigating the association of prenatal psychological adversities with telomere length. J Affect Disord 340:675\u2013685. https:\/\/doi.org\/10.1016\/j.jad.2023.08.074","journal-title":"J Affect Disord"},{"key":"696_CR24","doi-asserted-by":"publisher","DOI":"10.1016\/j.psychres.2020.113565","volume":"295","author":"S Takahashi","year":"2021","unstructured":"Takahashi S, Arima H, Nakano M, Ohki T, Morita J, Tabata K, Takayama Y, Tanno K, Yamamoto T (2021) Telomere shortening as a stress-related biomarker in children exposed to maternal chronic stress in utero measured 7 years after the Great East Japan Earthquake. Psychiatry Res 295:113565. https:\/\/doi.org\/10.1016\/j.psychres.2020.113565","journal-title":"Psychiatry Res"},{"key":"696_CR25","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.neuroscience.2015.07.068","volume":"342","author":"JA DiPietro","year":"2017","unstructured":"DiPietro JA, Voegtline KM (2017) The gestational foundation of sex differences in development and vulnerability. Neuroscience 342:4\u201320. https:\/\/doi.org\/10.1016\/j.neuroscience.2015.07.068","journal-title":"Neuroscience"},{"key":"696_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2024.106009","volume":"192","author":"S Mandl","year":"2024","unstructured":"Mandl S, Alexopoulos J, Doering S, Wildner B et al (2024) The effect of prenatal maternal distress on offspring brain development: A systematic review. Early Hum Dev 192:106009. https:\/\/doi.org\/10.1016\/j.earlhumdev.2024.106009","journal-title":"Early Hum Dev"},{"issue":"3","key":"696_CR27","doi-asserted-by":"publisher","first-page":"971","DOI":"10.1017\/S0954579418000147","volume":"30","author":"M Deuschle","year":"2018","unstructured":"Deuschle M, Hendlmeier F, Witt S et al (2018) Cortisol, cortisone, and BDNF in amniotic fluid in the second trimester of pregnancy. Dev Psychopathol 30(3):971\u2013980. https:\/\/doi.org\/10.1017\/S0954579418000147","journal-title":"Dev Psychopathol"},{"issue":"12","key":"696_CR28","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1007\/s11920-018-0961-4","volume":"20","author":"TL Bale","year":"2018","unstructured":"Bale TL (2018) Sex differences in vulnerability to prenatal stress: A review of the recent literature. Curr Psychiatry Rep 20(12):102. https:\/\/doi.org\/10.1007\/s11920-018-0961-4","journal-title":"Curr Psychiatry Rep"},{"key":"696_CR29","doi-asserted-by":"publisher","unstructured":"Graham AM, Moyer E, Martin J, Gilmore JH, Styner M, Shuffrey LC, Bost BM, Degnan AJ, Monk C, Thomason ME (2024) Brain structural and functional outcomes in the offspring of women experiencing psychological distress during pregnancy. Mol Psychiatry. Advance online publication. https:\/\/doi.org\/10.1038\/s41380-024-02449-0","DOI":"10.1038\/s41380-024-02449-0"},{"issue":"2","key":"696_CR30","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1159\/000362414","volume":"82","author":"T Kuiri-H\u00e4nninen","year":"2014","unstructured":"Kuiri-H\u00e4nninen T, Sankilampi U, Dunkel L (2014) Activation of the hypothalamic-pituitary-gonadal axis in infancy: Minipuberty. Horm Res Paediatr 82(2):73\u201380. https:\/\/doi.org\/10.1159\/000362414","journal-title":"Horm Res Paediatr"},{"issue":"4","key":"696_CR31","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1210\/endrev\/bnae003","volume":"45","author":"J Rohayem","year":"2024","unstructured":"Rohayem J, Alexander EC, Heger S, Nordenstr\u00f6m A, Howard SR (2024) Mini-puberty, physiological and disordered: Consequences, and potential for therapeutic replacement. Endocr Rev 45(4):460\u2013492. https:\/\/doi.org\/10.1210\/endrev\/bnae003","journal-title":"Endocr Rev"},{"issue":"10","key":"696_CR32","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1016\/j.biopsych.2022.11.023","volume":"93","author":"S Nolvi","year":"2023","unstructured":"Nolvi S, Merz EC, Kataja EL, Parsons CE (2023) Prenatal stress and the developing brain: Postnatal environments promoting resilience. Biol Psychiatry 93(10):942\u2013952. https:\/\/doi.org\/10.1016\/j.biopsych.2022.11.023","journal-title":"Biol Psychiatry"}],"container-title":["Hormones"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s42000-025-00696-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s42000-025-00696-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s42000-025-00696-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T19:28:51Z","timestamp":1774380531000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s42000-025-00696-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,25]]},"references-count":32,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["696"],"URL":"https:\/\/doi.org\/10.1007\/s42000-025-00696-6","relation":{},"ISSN":["1109-3099","2520-8721"],"issn-type":[{"value":"1109-3099","type":"print"},{"value":"2520-8721","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,25]]},"assertion":[{"value":"20 April 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 June 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 July 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors have no conflicts of interest to declare.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interest"}}]}}