Microbiome-related metabolites in early to midpregnancy and risk of fetal growth extremes: a metabolome-wide association study

Background: Small for gestational age (SGA) and large for gestational age (LGA) are fetal growth extremes that predispose an individual to a plethora of short- and long-term adverse health consequences. Perturbations to the intrauterine metabolic milieu and microbiome have been linked to both SGA and LGA. However, the roles of microbiome-related metabolites as the end products of microbial metabolism in fetal growth remain understudied. Objectives: We aimed to examine the prospective association of microbiome-related metabolites in early to midpregnancy with risk of SGA and LGA. Methods: We drew a random sample of singleton pregnancies with 140 SGA, 134 LGA, and 140 appropriate for gestational age (AGA) births from the Pregnancy Environment and Lifestyle Study. Untargeted metabolites were measured by gas chromatography/time-of-flight mass spectrometry, reversed-phase liquid chromatography/quadrupole time-of-flight mass spectrometry, and hydrophilic interaction liquid chromatography/quadrupole time-of-flight mass spectrometry using fasting serum collected at gestational weeks (GW) 10–13 and GW 16–19. Chemical enrichment analysis examined the associations of metabolites with SGA and LGA compared with AGA risk, with false discovery rate (FDR) adjustment. Results: We detected 135 microbiome-related metabolites. At GW 10–13, clusters of basic amino acids (AAs), branched-chain AAs, and dicarboxylic acids were significantly and positively associated with risk of SGA, after adjusting for covariates and multiple testing (all P_FDR <0.05). At GW 16–19, branched-chain AAs and hydroxybutyrates were positively associated with SGA risk, whereas dicarboxylic acids were inversely associated with SGA risk. For LGA, at GW 10–13, 4 clusters (basic AAs, cyclic AAs, dicarboxylic acids, and hydroxybutyrates) were associated with an increased risk. At GW 16–19, lysophosphatidylcholines, sugar alcohols, and phenylacetates were inversely associated with LGA risk, whereas carnitines were positively associated with LGA risk. Conclusions: This study identifies common and unique microbiome-related metabolites associated with risk of fetal growth extremes. Given that microbiota is malleable, our findings may inform strategies to optimize the intrauterine microbial-metabolic profile and fetal growth.