Prenatal exposure to mixtures of metals and metalloids and risk of spontaneous preterm birth: Critical exposure windows and susceptibility factors.

Limited research has evaluated how prenatal exposure to mixtures of metals and metalloids influences the risk of spontaneous preterm birth (SPB), and the critical exposure windows and susceptibility factors remain unclear. In this nested case-control study, we measured serum concentrations of 41 metals/metalloids in 580 pregnant women from Shanxi Province, China-including 135 SPB cases and 445 term controls-to evaluate associations for individual metals/metalloids and for the overall mixture with SPB risk. Using multivariable logistic regression with elastic-net regularization, we identified four metals associated with SPB: iron (Fe), copper (Cu), mercury (Hg), and antimony (Sb). Fe, Cu, and Hg were positively associated with SPB, whereas Sb showed an inverse association. Bayesian kernel machine regression (BKMR) and quantile g-computation (QGC) corroborated that higher overall metal/metalloid mixture exposure was associated with a significant increase in SPB risk. Specifically, increasing mixture concentrations from the 50th to 90th percentiles was associated with a 1.503-fold increase in SPB risk (BKMR; 95 % CI: 1.109-2.036) and a 2.943-fold increase (QGC; 95 % CI: 1.726-5.016), consistent with a dose-response relationship. Stratified analyses indicated that the first trimester appears to be a critical exposure window, with heightened susceptibility among women carrying male fetuses and among multiparous women. This study provides new evidence on the prenatal impacts of metal/metalloid mixtures on SPB. These findings highlight early pregnancy as a window of vulnerability and underscore the need for targeted public-health interventions to mitigate exposure, particularly in susceptible subgroups.