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Prior preclinical studies and emerging clinical evidence indicate that PAE affects the fetal hypothalamic\u2013pituitary\u2013adrenal (HPA) axis via the maternal\u2010fetal interface in the placenta; however, little is known about the effect of these alterations on neurodevelopmental outcomes. We earlier reported on the effect of PAE and maternal stress on HPA axis biomarkers in placenta and umbilical cord (UC) blood; in the current study, we examined the effect of HPA axis biomarkers on infant neurodevelopmental outcomes at 6\u20139\u2009months of term\u2010equivalent age. Participants in the Ethanol, Neurodevelopment, Infant and Child Health (ENRICH\u20102) prospective cohort were followed from the second trimester of pregnancy until infants were 6\u20139\u2009months of term\u2010equivalent age. Maternal alcohol use was assessed through prospective interviews and a battery of ethanol biomarkers; maternal stress, by a Perceived Stress Scale (PSS). Placenta and UC blood specimens were collected shortly after birth, flash frozen, and analyzed for mRNA and protein expression of placental corticotropin\u2010releasing hormone (pCRH), hydroxysteroid 11\u2010beta dehydrogenase types 1 and 2 (<jats:italic>HSD11B1, HSD11B2<\/jats:italic>) and corresponding proteins (11\u03b2\u2010HSD1 and 11\u03b2\u2010HSD2), and Nuclear receptor subfamily 3 Group C Member 1\u2014alpha (<jats:italic>NR3C1\u2010\u03b1<\/jats:italic>) and corresponding glucocorticoid receptor alpha. UC plasma cortisol and cortisone levels were measured with ELISA. Bayley Scales of Infant Development, fourth edition (BSID\u20104; Motor, Language, Cognitive scores) and Infant Behavior Questionnaire Revised (IBQ\u2010R; Surgency, Orienting\/Regulation, Negative Affect) assessed neurodevelopment at 6\u20139\u2009months of term\u2010equivalent age. Pearson correlation was used to examine associations between placental HPA axis biomarkers and neurodevelopmental outcomes overall and after stratification by group (Alcohol\/Control). Multivariable linear regression assessed the independent effect of placental biomarkers and Alcohol\u2009*\u2009biomarker interactions on infant outcomes after adjusting for Alcohol and maternal stress. Participants (32 Alcohol and 68 Controls) were comparable in sociodemographic characteristics. Activation of the placental HPA axis was correlated with a decrease in BSID\u20104 scores among Controls and an increase in IBQ\u2010R scores (Surgency and Negative Affect) among Alcohol participants. In multivariable analyses, the <jats:italic>HSD11B2\/HSD11B1<\/jats:italic> ratio was associated with a decrease in Cognitive scores, and the Alcohol\u2009*\u2009pCRH interaction was associated with a decrease in Orienting\/Regulation and an increase in Surgency and Negative Affect (all <jats:italic>p<\/jats:italic>'s\u2009&lt;\u2009.05), after adjusting for Alcohol and PSS. A significant independent effect of PSS was also observed on infant motor skills, Orienting\/Regulation, and Negative Affect. This is the first clinical study to characterize the role of placental HPA axis biomarkers and maternal psychosocial stress in PAE\u2010induced changes on infant neurodevelopment, highlighting the importance of a \u201cplacenta\u2013brain axis\u201d. We demonstrated that the effects of mild\u2010to\u2010moderate PAE on infant neurobehavior were observed in participants with the highest quartile of pCRH expression, emphasizing the role of placental biomarkers in PAE\u2010induced effects.<\/jats:p>","DOI":"10.1111\/jne.70071","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T08:40:51Z","timestamp":1753346451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Predictive utility of placental hypothalamic\u2013pituitary\u2013adrenal axis biomarkers and infant neurodevelopment"],"prefix":"10.1111","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-0211","authenticated-orcid":false,"given":"Ludmila N.","family":"Bakhireva","sequence":"first","affiliation":[{"name":"College of Pharmacy Substance Use Research and Education Center, University of New Mexico Health Sciences Center  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingya","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Pharmacy Substance Use Research and Education Center, University of New Mexico Health Sciences Center  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandria","family":"Wiesel","sequence":"additional","affiliation":[{"name":"College of Pharmacy Substance Use Research and Education Center, University of New Mexico Health Sciences Center  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean R.","family":"Lowe","sequence":"additional","affiliation":[{"name":"Department of Pediatrics University of New Mexico, Health Sciences Center  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajani","family":"Rai","sequence":"additional","affiliation":[{"name":"College of Pharmacy Substance Use Research and Education Center, University of New Mexico Health Sciences Center  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Solomon","sequence":"additional","affiliation":[{"name":"Research Service, Raymond G. 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