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Background: Epigenetic alterations during fetal development have been proposed as key factors explaining associations between maternal lifestyle during pregnancy and later health outcomes in the offspring, pertaining to the developmental origin of health and disease hypothesis.

Objectives: To assess the association of maternal lifestyle with offsprings’ birth weight and underlying epigenetic mediatory mechanisms in the NorthPop prospective birth cohort.

Methods: A three-step analytic pipeline was applied. In 722 mother–child pairs, overall associations between ten maternal lifestyle factors and the offspring’s standardized birth weight were first evaluated by multiple linear regression. Three high-dimensional mediation methods, based on sure independence screening and penalized regression, were then applied on the beta methylation matrix to identify candidate CpG mediators in cord blood driving the significant overall associations. Finally, robust and ordinary least squares (OLS) regression-based classical mediation methods were used with candidate CpG probes to assess single- and multiple (parallel and serial)-mediator models on a low-dimensional space.

Results: Gestational weight gain (GWG) (β-adj = 0.03; p = 2 × 10–5) and maternal BMI at the beginning of pregnancy (β-adj = 0.036; p = 1 × 10–4) were significantly associated with the offspring’s standardized birth weight. High-dimensional mediation analyses identified pooled sets of four (cg19242268 [TCEA2]; cg08461903 [N/A]; cg14798382 [CHERP/C19orf44] and cg21516291 [SLC35C2]) and five (cg17040807 [CYGB]; cg19242268 [TCEA2]; cg26552621 [CIRBP]; cg04457572 [CDH23] and cg06457011 [PLCG1]) candidate CpG mediators related to GWG and BMI at the beginning of pregnancy, respectively. For both exposures, classical mediation analyses revealed a range of significant single- and multiple (both serial and parallel)-mediator models via both robust and OLS regression based approaches. These indicated the likely presence of individual, causally linked multiple, and causally independent multiple mediatory pathways underlying the two significant overall associations.

Conclusions: Our findings support the hypothesis that neonatal health effects related to maternal lifestyle may be partly mediated by epigenetic alterations. Findings also suggest the possible involvement of multiple DNA methylation sites via various mediatory pathways.