Associations of plasma manganese with adverse pregnancy outcomes: Nested case-control studies in a Chinese birth cohort

Both insufficient and excessive manganese exposure are associated with adverse pregnancy outcomes. However, no systematic research has established a standardized reference range for manganese levels with the consideration of the associated health risks during pregnancy. To verify the associations of prenatal manganese exposure with adverse outcomes and to identify a proper reference range for manganese based on health risks, we designed three nested case-control studies on three adverse outcomes including hypertensive disorders of pregnancy (HDP), preterm birth (PTB), and low birth weight (LBW) to investigate the associations with manganese levels. Plasma manganese concentrations in early pregnancy were measured. Conditional logistic regression analyses were used to estimate the associations of manganese levels with adverse outcomes. Restricted cubic spline (RCS) models were used to characterize the dose-response relationship of manganese and each outcome. Nonlinear associations were observed for manganese and adverse outcomes. Compared with women in the middle tertile of plasma manganese, we found that those in the highest tertile had a significantly higher risk of HDP (OR = 1.72, 95% CI: 1.02 to 2.89), that women in the lowest tertile had almost a tripled risk of delivering LBW infants (OR = 2.93, 95% CI: 1.67 to 5.17), and that women both in the lowest and the highest tertiles had significantly higher risks of PTB [OR = 1.83 (95% CI: 1.14 to 2.95); OR = 1.70 (95% CI: 1.05 to 2.76)]. U-shaped associations were found between plasma manganese and risk of PTB and infant LBW. Based on the results of RCS models, we identified a proper plasma manganese range of 1.72-3.18 μg/L, with relatively lower risks of adverse pregnancy outcomes. In conclusion, our study found U-shaped associations between manganese exposure and adverse pregnancy outcomes, and provided an optimal range of manganese concentration for pregnant women, based on health risk considerations.