Per- and Polyfluoroalkyl Substances in Umbilical Cord Serum and Key Intermediate Metabolites in Relation to Preterm Birth: A Multicenter Case-Control Study

Evidence from multicenter studies in Chinese populations on prenatal per- and polyfluoroalkyl substance (PFAS) exposure and preterm birth (PTB), and related metabolic mechanisms, remains limited. We conducted a multicenter case-control study including 1990 mother–infant pairs from northern, northwestern, and southern China (2015–2021) to examine associations between umbilical cord serum PFAS levels and PTB risk. In a subcohort ( n = 134), maternal venous blood was analyzed using untargeted metabolomics. Higher levels of most PFAS were associated with an increased PTB risk. Pentacosafluorotridecanoic acid (PFTrDA) showed the strongest association, with a 51% higher PTB risk per interquartile range increase (OR = 1.51; 95% CI: 1.29–1.76), and elevated risks for moderate PTB (OR = 1.66; 95% CI: 1.22–2.25) and late PTB (OR = 1.45; 95% CI: 1.21–1.74). PFAS mixture analyses indicated a positive joint effect (OR = 1.03; 95% CI: 1.01–1.06 per decile increase). Metabolomics identified PFTrDA as the PFAS linked to the most metabolic perturbations (four metabolites). Glycodeoxycholic acid (GDCA) was consistently associated with PFAS exposure and mediated 21–44% of associations between selected PFAS and PTB, suggesting disruptions in bile acid and lipid metabolism.