First-trimester profiling of maternal plasma metals and vitamins in relation to gestational hypertension.

BACKGROUND

Evidence on exposure to metal-vitamin mixtures in relation to hypertensive disorders of pregnancy (HDP) remains limited. We examined the associations of first-trimester exposure to these mixtures with HDP risk, with stratification by BMI for effect modification analyses.

METHODS

We conducted a nested case-control study within a prospective cohort of 2069 pregnant women. First-trimester plasma concentrations of ten metallic elements (manganese, chromium, cobalt, selenium, arsenic, cadmium, lead, thallium, vanadium, nickel) and two vitamins (vitamins B12 and folate) were measured. After exclusions, 134 HDP cases were matched to 399 controls (1:3 ratio) by maternal age and infant sex. Associations with HDP risk and blood pressure were assessed using conditional logistic regression and linear mixed models with stratification by BMI. Quantile-based g-computation, Bayesian kernel machine regression, and restricted cubic splines were employed to examine mixture effects and non-linear relationships.

RESULTS

Nickel was consistently associated with increased HDP risk (OR: 1.240, 95% CI: 1.118-1.375) and higher perinatal systolic blood pressure (β: 0.589, 95% CI: 0.145-1.032), while vitamin B12 showed protective effects (OR: 0.998, 95% CI: 0.996-1.000) (β: -0.009, 95% CI: -0.017--0.001). Manganese demonstrated a U-shaped relationship with HDP, with the lowest risk at plasma concentrations of 1.44-4.80 μg/L. Mixture analyses identified nickel and chromium as key drivers with opposing effects. BKMR revealed a significant pairwise interaction among manganese, chromium, nickel, and vitamin B12. Associations of nickel and vitamin B12 with HDP were significant only in normal-weight women.

CONCLUSION

First-trimester metal-vitamin mixtures influence HDP risk through concentration-dependent effects of nickel (adverse), chromium and vitamin B12 (protective), and manganese (U-shaped), with modulation by nutrient-metal interactions and maternal pre-pregnancy BMI.