Maternal essential and toxic metal mixtures in late pregnancy and neonatal birth weight

BACKGROUND: Prenatal exposure to toxic metals has been consistently associated with impaired fetal growth, yet pregnant individuals are simultaneously exposed to mixtures of essential and toxic metals. Evidence on how such complex metal mixtures in late pregnancy influence birth outcomes in European populations remains limited. METHODS: In a prospective study of 2,754 German mother-infant pairs, 37 metals were measured in maternal blood during late pregnancy. We used elastic net regression, restricted cubic splines, Bayesian kernel machine regression (BKMR), and quantile g-computation to evaluate individual and mixture effects on birth weight, adjusting for key sociodemographic and clinical covariates. RESULTS: Among 2,754 mother-infant pairs (median [IQR] maternal age, 30 [26-34] years; median [IQR] birth weight, 3368.0 [3025.0-3725.0] g), mixture analyses identified manganese (Mn), cobalt (Co), cadmium (Cd), and cesium (Cs) as key metals associated with birth weight. Mn (β = 57.86) and Co (β = 30.11) were positively associated with birth weight, whereas Cd (β = -40.82) and Cs (β = -25.52) were inversely associated. Bayesian kernel machine regression revealed that higher Mn concentrations were associated with weaker negative associations of Cs and Cd with birth weight. Quantile g-computation showed that mixtures dominated by Mn and Co were associated with higher birth weight (37.34 g [95% CI, 5.64 to 69.05 g]; 44.06 g [95% CI, 12.96 to 75.15 g]), while mixtures including Cd and Cs showed nonsignificant negative associations. CONCLUSION: In this large European birth cohort, fetal growth was associated with the combined effects of essential and toxic metals rather than isolated exposures. The positive associations of manganese and cobalt with birth weight were weaker in the presence of co-exposure to cadmium and cesium, highlighting the importance of mixture-oriented environmental risk assessment. Integrated public health strategies that reduce toxic metal exposure while ensuring adequate maternal micronutrient status may be relevant for optimizing birth outcomes.