Emerging plastic additives in umbilical cord serum, metabolomic profiles, and fetal growth restriction: A case-control study

BACKGROUND: Fetal growth restriction (FGR) is associated with substantial perinatal and long-term health risks. As traditional plasticizers are being restricted, exposure to emerging plastic additives is increasing, yet their associations with FGR and related metabolic profiles remain poorly characterized. METHODS: This case-control study included 90 FGR cases and 100 controls from the "Early Life Plan" cohort. A total of 117 plastic additives were measured in umbilical cord serum, and untargeted metabolomics was performed using UHPLC-HRMS. Multivariable logistic regression, restricted cubic splines, Bayesian kernel machine regression (BKMR), and quantile g-computation were used to evaluate the effects of single and mixed exposures of these chemicals on fetal growth outcomes. Meet-in-the-middle (MITM) analysis and pathway enrichment analysis were performed to identify associated metabolic features. RESULTS: UV-360 was positively associated with FGR (OR = 1.35, 95% CI: 1.11-1.64), while 2,6-DtBEP was negatively associated with FGR (OR = 0.72, 95% CI: 0.61-0.84). Neither BKMR nor quantile g-computation provided clear evidence of an overall association between the 21-chemical mixture and FGR. Exploratory class-specific BKMR analyses suggested positive and negative associations for UV stabilizers and antioxidants, respectively. Differential metabolites were mainly enriched in amino acid, lipid, and one-carbon metabolism. MITM analyses suggested that six metabolites, including Valine, Proline, Palmitoylcarnitine, Ornithine, Xanthine, and (25 R)-Delta(4)-dafachronic acid, may be involved in the associations of UV-360 and DiBA/DnBA with FGR. CONCLUSIONS: Concentrations of selected plastic additives in umbilical cord serum were associated with FGR, with UV-360 being consistently associated with higher odds of FGR. Metabolomic findings suggest that amino acid and lipid metabolism may be involved in these associations, warranting further validation in future studies.