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

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.

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.

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.

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.