Placental DNA methylation mediates the prenatal maternal stress‐childhood allergy association: A cohort study

BACKGROUND: Prenatal maternal stress is a common exposure implicated in childhood allergies. However, evidence for placental DNA methylation as a mediator is limited, with prior studies focusing narrowly on HPA-axis genes. This study aimed to examine the impact of prenatal maternal stress on offspring allergic diseases and placental DNA methylation's mediating role from an epigenome-wide perspective. METHODS: Within the Shanghai Parent-Child Cohort (n = 3883 pairs), maternal stress and childhood allergic diseases were assessed via questionnaires and medical records. Latent class analysis identified allergic trajectories. Specific CpG sites were identified using genome-wide placental DNA methylation analysis and bisulfite pyrosequencing validation. Associations were examined using multivariate log-binomial regression, linear regression, and logistic regression; mediation effects were assessed using causal mediation analysis with nonparametric bootstrapping. RESULTS: Maternal total stress in early pregnancy was associated with increased risks of atopic dermatitis (RR: 1.23, 95% CI: 1.04-1.45), asthma (RR: 1.42, 95% CI: 1.07-1.88) and persistent allergy (RR: 1.36, 95% CI: 1.13-2.84), while late-pregnancy total stress associated with atopic dermatitis (RR: 1.39, 95% CI: 1.10-1.77), allergic rhinitis (RR: 1.56, 95% CI: 1.16-2.11) and persistent allergy (RR: 1.30, 95% CI: 1.03-1.45). Genome-wide analysis and pyrosequencing validation identified specific placental CpG site hypermethylation associated with both prenatal maternal stress and childhood allergic outcomes. Stress effects on persistent allergic trajectory were partially mediated through HLA-DRA methylation, with a mediation proportion of 8.89%, and on asthma through IPCEF1 methylation (12.8%). CONCLUSION: Prenatal maternal stress may adversely impact childhood allergy outcomes, partially mediated by alterations in placental DNA methylation.