Exposure to metal mixtures and hypertensive disorders of pregnancy: A nested case-control in China*

Exposure to metals has been linked with the risk of hypertensive disorders of pregnancy (HDP), but little is known about the potential effects of exposure to metal mixtures. Thus, our study aimed to investigated the impact of a complex mixture of metals on HDP, especially the interactions among metal mixtures. We did a population-based nested case-control study from October 2013 to October 2016 in Wuhan, China, including 146 HDP cases and 292 controls. Plasma concentrations of Aluminum (Al), Barium (Ba), Cobalt (Co), Copper (Cu), Lead (Pb), Mercury (Hg), Molybdenum (Mo), Nickel (Ni), Selenium (Se), Strontium (Sr), Thallium (Tl), and Vanadium (V) were measured and collected between 10 and 16 gestational weeks. We employed quantile g-computation, conditional logistic regression models, and Bayesian Kernel Machine Regression (BKMR) to assess the association of individual metals and metal mixtures with HDP risk. In the quantile g-computation, the OR for a joint tertile increase in plasma concentrations was 3.67 (95% CI: 1.70, 7.91). Hg contributed the largest positive weights and followed by Al, Ni, and V. In conditional logistic regression models, concentrations of Hg, Al, Ni, and V were significantly associated with the risk of HDP (p-FDR < 0.05). Compared to the lowest tertiles, the ORs (95% CI) for the highest tertiles of these four metals were 2.67 (1.44, 4.95), 3.09 (1.70, 5.64), 5.31 (2.68, 10.53), and 4.52 (2.26, 9.01), respectively. In the BKMR analysis, we observed a linear positive association between Hg, Al, V, and HDP, and a nonlinear relationship between Ni and HDP. A potential interaction between Al and V was also identified. We found that exposure to metal mixtures in early pregnancy, both individually and as a mixture, was associated with the risk of HDP. Potential interaction effects of Al and V on the risk of HDP may exist.