Non-linear and non-additive associations between the pregnancy metabolome and birthweight

BACKGROUND: Birthweight is an indicator of fetal growth and environmental-related alterations of birthweight have been linked with multiple disorders and conditions progressing into adulthood. Although a few studies have assessed the association between birthweight and the totality of exogenous exposures and their downstream molecular responses in maternal urine and cord blood; no prior research has considered a) the maternal serum prenatal metabolome, which is enriched for hormones, and b) non-linear and synergistic associations among exposures. METHODS: We measured the maternal serum metabolome during pregnancy using an untargeted metabolomics approach and birthweight for gestational age (BWGA) z-score in 410 mother-child dyads enrolled in the PRogramming of Intergenerational Stress Mechanisms (PRISM) cohort. We leveraged a Bayesian factor analysis for interaction to select the most important metabolites associated with BWGA z-score and to evaluate their linear, non-linear and non-additive associations. We also assessed the primary biological functions of the identified proteins using the MetaboAnalyst, a centralized repository of curated functional information. We compared our findings with those of a traditional metabolite-wide association study (MWAS) in which metabolites are individually associated with BWGA z-score. RESULTS: Among 1110 metabolites, 46 showed evidence of U-shape associations with BWGA z-score. Most of the identified metabolites (85%) were lipids primarily enriched for pathways central to energy production, immune function, and androgen and estrogen metabolism, which are essential for pregnancy and parturition processes. Metabolites within the same class, i.e. steroids and phospholipids, showed synergistic relationships with each other. CONCLUSIONS: Our results support that the aspects of the maternal metabolome during pregnancy contribute linearly, non-linearly and synergistically to variation in newborn birthweight.