Prenatal Exposure to Silver is Associated with an Elevated Risk for Neural Tube Defects: A Case Control Study

Abstract Background: Exposure to copper, silver, and titanium has been reported to be associated with a variety of adverse effects on humans. However, few studies have focused on the fetus, which is vulnerable to environmental insults. We investigated the associations between prenatal exposure to the three metals and risk for fetal neural tube defects (NTDs).Methods: Placental samples from 408 women with pregnancies affected by NTDs and 593 women with normal pregnancies were collected from 2003 to 2016 in an NTD high-risk area in northern China. Placental metal concentrations were quantified and used as prenatal exposure markers. Multilevel mixed-effects logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between metal concentrations and risk for NTDs. Single and joint effects of the metals on NTDs were evaluated with Bayesian kernel machine regression (BKMR), which can account for correlation, nonlinearity, and interaction between metals.Results: NTDs had higher concentrations of copper (4.16 μg/g) and silver (0.96 ng/g) than controls (copper: 3.91 μg/g; silver: 0.96 ng/g). Silver was associated with an increased risk for NTDs in a dose-response fashion in single-metal logistic regression, with adjusted ORs (95% CIs) of 1.78 (1.04–3.06) and 1.92 (1.11–3.32) in the second and third tertiles, respectively, compared to the lowest tertile. BKMR revealed toxic effects of silver on NTDs when the concentrations of copper and titanium were fixed at their 25th, 50th, and 75th percentiles, and the association appeared to be linear. No interaction of silver with any of the other two metals was observed. Besides, silver concentration was positively correlated with maternal certain dietary intakes, such as meat or fish, during the periconceptional period.Conclusions: High silver concentrations in placental tissue are associated with an elevated risk for NTDs in offspring. Maternal diet may be a source of silver exposure.