Differential effects of prenatal depression and anxiety on infant sleep: dual-pathway mechanisms involving the hypothalamic–pituitary–adrenal axis and the gut-brain axis

Abstract Study Objectives Prenatal psychological distress is associated with adverse offspring outcomes, including infant sleep disturbances (ISD) and altered gut microbiota, yet the mediating roles of the neonatal gut microbiome and tryptophan metabolism remain underexplored. Materials and Methods This prospective birth cohort study enrolled 2288 mother-infant pairs, using questionnaires to assess prenatal anxiety/depression and infant sleep patterns up to 12 months. A 112-pair sub-cohort underwent multi-omics analyses: meconium microbiota profiling via 16S rRNA sequencing and cord blood tryptophan metabolite quantification via liquid chromatography–tandem mass spectrometry. Least absolute shrinkage and selection operator (LASSO) regression, mediation analyses, and XGBoost modeling were applied. Results Prenatal depression alone was a significant risk factor for ISD (fully adjusted OR = 1.53, 95% CI: 1.04–2.25), with a stronger effect in female infants (OR = 2.11, p = .022). Cord blood cortisol partially mediated this link (Average Causal Mediation Effect = –7.47, 95% CI: [–14.82, –0.12], p = .048). Prenatal anxiety correlated with reduced meconium microbial alpha-diversity, lower Bifidobacterium abundance, and decreased 3-HAA/serotonin levels, which were associated with sleep disturbance; serial mediation confirmed the gut microbiota-tryptophan metabolism pathway. The XGBoost predictive model achieved an AUC of 0.727, with microbial diversity, Streptococcus abundance, dopamine, and 3-HAA as top contributors. Conclusions This study identifies distinct mediating pathways for depression and anxiety, providing targets for personalized infant sleep health interventions. Statement of Significance This study reveals that prenatal depression and anxiety impair infant sleep through distinct biological pathways. Depression was associated with elevated fetal cortisol (HPA axis), while anxiety may influence the neonatal gut microbiome and its production of sleep-regulating tryptophan metabolites. These findings contribute to a novel dual-pathway model that helps clarify previously unresolved mechanistic questions. By integrating these biomarkers into a machine learning model, we offer a translational tool for early risk prediction. The work bridges a critical gap between epidemiological observation and biological mechanism, paving the way for personalized interventions—targeting stress hormones for depression or gut health for anxiety—to improve infant neurodevelopmental outcomes.