Exploratory Multi-Compartment Profiling of Steroid and Bile Acid Metabolites in Relation to Maternal Perceived Stress at Term

Maternal stressors during pregnancy are linked to adverse birth outcomes, but the biochemical pathways involved remain poorly defined. We previously reported that the human placenta buffers the fetus from several effects of maternal perceived stress in a cohort of term pregnancies. Here, using the same cohort and no additional participants, we analyze a broader steroid panel and, for the first time, a targeted bile acid metabolomic panel across four maternal–fetal compartments: maternal plasma, placental tissue, cord plasma, and maternal hair. Nulliparous women were recruited during the third trimester at UCSF Mission Bay Hospital; perceived stress was measured using the 10-item Perceived Stress Scale (PSS) and retained as a continuous variable for the primary analysis from 17 women. Of 212 analyte compartment pairs evaluated, 38 metabolites met a predefined detectability criterion and were tested for association with PSS and sociodemographic scores using Kendall’s tau b, with permutation p-values, bootstrap confidence intervals, and Benjamini–Hochberg correction for multiple comparisons. No association survived multiple testing corrections. In exploratory, uncorrected comparisons (p < 0.05), three metabolites were nominally lower in a cohort-derived, higher-PSS group: placental estrone (E1), cord plasma glycochenodeoxycholic acid (GCDCA), and maternal plasma ursodeoxycholic acid (UDCA). Nearly 47.1% of women had gestational diabetes; 20-hydroxyprogesterone (20-OH-PROG) in maternal plasma, dihydroprogesterone (DHP), and pregnenolone (PELN) in placental tissues were nominally decreased in women who developed gestational diabetes compared to women who did not develop gestational diabetes. Maternal hair was not a good compartment for detection of bile acid metabolites. Despite a wide range of perceived stress/sociodemographic scores and a substantial burden of maternal clinical comorbidities in this cohort, all pregnancies resulted in favorable neonatal outcomes at delivery. These findings support the hypothesis that the placenta functions as a buffering organ that protects the developing fetus against broad insults while remaining susceptible to more selective disruptions.