Project Summary There is growing evidence that fetal exposure to glucocorticoids may contribute to a variety of adverse birth outcomes. Recent concern has emerged regarding the fetal effects of antenatal corticosteroids (AC) administered as preventive care to women who are at risk of preterm birth. Although they effectively reduce the likelihood of certain neonatal morbidities, our previous research found that neonates whose mothers were prescribed corticosteroids had significantly depleted and unusual gut microbiota in the first month of life, in contrast to neonates whose mothers did not receive them. We also found that a mother's symptoms of depression predicted a significant amount of variance in infant gut microbiota composition, with both more severe depression and higher levels of stress associated with a greater abundance of bacterial species that modulate metabolism of steroids. Importantly, sex differences also emerged. The bacterial taxa of male infants were significantly depleted in contrast to girls; and their microbial compositions differed. Lastly, our research indicates that bacterial structure of the maternal vaginal microbiome (a key source of microbes for the neonatal microbiome) is affected by maternal stress. Transmission of altered bacterial communities during vaginal delivery may disrupt neonatal microbial environments that are essential for health. To validate and extend our preliminary findings, we propose to determine: 1) if AC or maternal emotional distress in pregnancy are associated with a distinct neonatal gut microbiome that differs from neonates whose mothers did not receive AC or were not distressed, and 2) if distinct microbial genes and gene pathways identified at birth are sustained or increased through early life. Our primary focus will be on microbial species that metabolize glucocorticoids. We will also determine if AC and emotional distress are associated with a distinct maternal vaginal microbiome and whether these vaginal microbes are found in the neonatal gut microbiome. Finally, we will examine the moderating effect of fetal/infant sex in all analyses. 160 women will complete measures of depressive symptoms and stress, provide a vaginal specimen, and covariate measures in pregnancy. Stool samples will be acquired from infants at birth and at 1 month and 3 months postnatal, along with further measures of maternal stress, depressive symptoms and covariates. The medical record will provide data on AC as well as additional covariates that will be controlled for in analyses. Multilevel regression modeling will be used to examine the aims, along with elastic, net and weighted network analyses, in addition to integrated analyses of metagenomics and metabolomics for maternal vaginal and neonatal gut datasets. Exposure to AC and maternal emotional distress during pregnancy could have implications for early programming of the infant's microbiome and future disruption of adaptive function that is critical to the c...