Metabolic signatures of prenatal gestational diabetes exposure and childhood lung function in a prospective birth cohort

Prenatal gestational diabetes mellitus (GDM) exposure has been associated with altered respiratory outcomes in offspring, but the metabolic correlates underlying this relationship remain unclear. We investigated whether GDM exposure was associated with distinct metabolomic signatures in mid-childhood and whether GDM-related metabolites were associated with lung function. Untargeted plasma metabolomic profiling was conducted in 699 children aged 6 years (172 GDM-exposed, 527 controls) from a prospective birth cohort in Wuhan, China. Multivariable regression was used to identify metabolites associated with GDM exposure and examine associations between GDM-related metabolites and spirometric indices. Pathway enrichment analyses were performed to identify shared metabolic pathways associated with maternal glycemia and childhood lung function. Exploratory statistical indirect-effect analyses were conducted to evaluate whether selected candidate metabolites showed statistical indirect associations in models relating maternal glycemia to childhood lung function. We identified 69 annotated metabolites associated with prenatal GDM exposure, primarily involving amino acid and peptide metabolism, lipid metabolism, and bile acid–related pathways. Several GDM-related metabolites, including Leu-Tyr-Arg, sphingomyelin d34:1, prostaglandin F2α, and L-cysteine-glutathione disulfide, were associated with lung function in mid-childhood. Pathway analyses highlighted shared enrichment of histidine metabolism, primary bile acid biosynthesis, and related metabolic pathways across maternal glycemia and offspring lung function. Exploratory statistical indirect-effect analyses identified selected metabolites with statistical indirect associations in models of maternal glycemia and childhood lung function; however, temporality between metabolites and lung function could not be established. Prenatal GDM exposure was associated with distinct metabolic profiles in children at 6 years of age, several of which were cross-sectionally associated with lung function. These findings identified candidate metabolic pathways related to prenatal GDM exposure and childhood lung-function and provide leads for future longitudinal and experimental validation.