Emerging evidence suggests that maternal factors during pregnancy can exert effects on offspring. However, the underlying metabolic associations remain insufficiently understood. We investigated associations between first-trimester maternal metabolic profiles and offspring development with large-scale untargeted metabolomics in the prospective Shanghai Birth Cohort (N = 1158). Birth weight and cognitive scores at age four assessed with the Wechsler Preschool and Primary Scale of Intelligence were used as short- and long-term developmental indicators. Here we show maternal fatty acid and phospholipid metabolism in early pregnancy is significantly associated with birth weight. Carnitine, LPE 18:2, and LPG O-13:1 are negatively associated with birth weight, whereas PC 32:2, glycerophosphocholine and several fatty acids show significant positive associations. Several dipeptides have positive associations with cognitive outcomes, while many fatty acids and N-acylethanolamines are negatively associated. Among the six cognitive indices, verbal comprehension has the most metabolite associations, with 4-pyridoxic acid, 1-methylxanthine, and phenylalanyltryptophan being most strongly linked. 4-Pyridoxic acid, a vitamin B6 metabolite, significantly mediates the positive association between multivitamin intake and cognitive development. Several metabolites show sex-specific associations with offspring development, which is consistent with the known sex-related differences in early childhood developmental patterns. Maternal metabolism in early pregnancy is associated with birth weight and long-term cognitive development in offspring. As maternal metabolic profiles reflect both genetic and environmental influences, many metabolites mediate maternal influences on development and reflect sex-specific patterns in child growth. Many maternal factors during pregnancy have been reported to be associated with subsequent child development. The maternal metabolites reflect maternal health status, but the relationship with long-term childhood outcomes remains incompletely understood. This study provides a comprehensive analysis of 499 metabolites across diverse biochemical classes in maternal serum collected during early pregnancy. Utilizing data from a large-scale prospective cohort, we identified short-term metabolic signatures associated with birth weight and long-term signatures linked to cognitive development at four years of age. Several metabolites showed sex-specific association patterns that align with known developmental sex differences, suggesting potential metabolic contributors to these disparities. Our results indicate that maternal metabolism is associated with long-term childhood development, highlighting the importance of maternal health management. Yang, Zeng et al. investigate associations between maternal metabolic profiles during early pregnancy and offspring development using untargeted metabolomics in the Shanghai Birth Cohort. Several metabolites are associated with offspring birth weight and cognitive development in childhood and reflect sex-specific patterns.
Yang et al. (Sat,) studied this question.