Predictive utility of placental hypothalamic-pituitary-adrenal axis biomarkers and infant neurodevelopment

Alcohol use remains common in pregnancy with prenatal alcohol exposure (PAE) associated with a plethora of adverse outcomes, including impaired emotional regulation and stress reactivity. Prior preclinical studies and emerging clinical evidence indicate that PAE affects the fetal hypothalamic-pituitary-adrenal (HPA) axis via the maternal-fetal 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 6-9 months of term-equivalent age. Participants in the Ethanol, Neurodevelopment, Infant and Child Health (ENRICH-2) prospective cohort were followed from the second trimester of pregnancy until infants were 6-9 months of term-equivalent 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-releasing hormone (pCRH), hydroxysteroid 11-beta dehydrogenase types 1 and 2 (HSD11B1, HSD11B2) and corresponding proteins (11β-HSD1 and 11β-HSD2), and Nuclear receptor subfamily 3 Group C Member 1-alpha (NR3C1-α) and corresponding glucocorticoid receptor alpha. UC plasma cortisol and cortisone levels were measured with ELISA. Bayley Scales of Infant Development, fourth edition (BSID-4; Motor, Language, Cognitive scores) and Infant Behavior Questionnaire Revised (IBQ-R; Surgency, Orienting/Regulation, Negative Affect) assessed neurodevelopment at 6-9 months of term-equivalent 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 * biomarker 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-4 scores among Controls and an increase in IBQ-R scores (Surgency and Negative Affect) among Alcohol participants. In multivariable analyses, the HSD11B2/HSD11B1 ratio was associated with a decrease in Cognitive scores, and the Alcohol * pCRH interaction was associated with a decrease in Orienting/Regulation and an increase in Surgency and Negative Affect (all p's < .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-induced changes on infant neurodevelopment, highlighting the importance of a "placenta-brain axis". We demonstrated that the effects of mild-to-moderate PAE on infant neurobehavior were observed in participants with the highest quartile of pCRH expression, emphasizing the role of placental biomarkers in PAE-induced effects.