Association of cord plasma metabolites with birth weight: results from metabolomic and lipidomic studies of discovery and validation cohorts.

ABSTRACT

OBJECTIVE: Birth weight is a good predictor of fetal intrauterine growth and long-term health, and several studies have evaluated the relationship between metabolites and birth weight. The aim of this study was to investigate the association of cord blood metabolomics and lipidomics with birth weight, using a two-stage discovery and validation approach. METHODS: Firstly, a pseudotargeted metabolomics approach was applied to detect metabolites in 504 cord blood samples in the discovery set enrolled from the Wuhan Healthy Baby Cohort, China. Metabolome-wide association scan analysis and pathway enrichment were applied to identify metabolites and metabolic pathways that were significantly associated with birth weight adjusted for gestational age Z-score (BW Z-score). Logistic regression models were used to analyze the association of metabolites in the most significantly associated pathways with small-for-gestational age (SGA) at delivery and low birth weight (LBW). Subsequently, 350 cord blood samples in a validation cohort were subjected to targeted analysis to validate the metabolites identified by screening in the discovery cohort. RESULTS: In the discovery set, of 2566 metabolites detected, 2418 metabolites were retained for subsequent analysis after data preprocessing. Of these, 513 metabolites were significantly associated with BW Z-score (P-value adjusted for false discovery rate (PFDR) < 0.05), of which 298 Kyoto Encyclopedia of Genes and Genomes (KEGG)-annotated metabolites were included in the pathway analysis. The primary bile acid biosynthesis pathway was the most relevant metabolic pathway associated with BW Z-score. Elevated cord plasma primary bile acids were associated with lower BW Z-score and higher risk of SGA or LBW in the discovery and validation cohorts. In the validation set, a 2-fold increase in taurochenodeoxycholic acid (TCDCA) and in taurocholic acid (TCA) was associated with a decrease in BW Z-score (estimated ß coefficient, -0.10 (95% CI, -0.20 to 0.00) and -0.18 (95% CI, -0.31 to -0.04), respectively), after adjusting for covariates. In addition, a 2-fold increase in cord plasma TCDCA and of cord plasma TCA was associated with an increased risk of SGA (adjusted odds ratio (OR), 1.52 (95% CI, 1.00-2.30) and 1.77 (95% CI, 1.05-2.98), respectively). The adjusted OR for LBW, for a 2-fold increase in TCDCA and TCA concentration, were 2.39 (95% CI, 1.00-5.71) and 3.21 (95% CI, 0.96-10.74), respectively. CONCLUSIONS: These results indicate a significant association of elevated primary bile acids, particularly TCDCA and TCA, in cord blood with lower BW Z-score, as well as increased risk of SGA and LBW. Abnormalities of primary bile acid metabolism may play an important role in restricted fetal development. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.