Maternal dietary nitrate intake and risk of neural tube defects: A systematic review and dose-response meta-analysis

Nitrates are naturally occurring compounds in drinking water and foods, especially vegetables and plant foods, and are also used as food additives to delay pathogenic bacteria growth and spoilage. Despite growing evidence for the potential teratogenicity of nitrate, knowledge about the dose-response relationship of dietary nitrate intake and risk of specific birth defects such as neural tube defects (NTDs) is limited. Therefore, the aim of this meta-analysis was to synthesize the knowledge about the dose-response relation between maternal dietary nitrate intake and the risk of NTDs.We conducted a systematic search in PubMed, ISI Web of Science and Scopus up to February 2018 for observational studies. Risk ratios (RRs) and 95% confidence intervals (95% CI) were calculated using a random-effects model for highest versus lowest intake categories. The linear and non-linear relationships between nitrate intake and risk of NTDs were also investigated.Overall, 5 studies were included in the meta-analyses. No association was observed between nitrate intake and NTDs risk in high versus low intake (RR: 1.33; 95% CI: 0.89–1.99, p = 0.158) and linear dose-response (RR: 1.03; 95% CI: 0.99–1.07, p = 0.141) meta-analysis. However, there were positive relationships between nitrate intake and risk of NTDs in non-linear (pnon-linearity < 0.05) model.This meta-analysis has several strengths. The dose-response metaanalysis offers advantages over the conventional methodology. A large number of cases (2008 offspring with NTDs) enhanced the statistical power of this dose-response meta-analysis. Our study contains some limitations. Misclassification of nitrate intake could be a great concern. One study assessed dietary nitrate intake based on self-administered food frequency questionnaire, one study based on pickled vegetables consumption and two studies used an indirect approach to estimate maternal exposure to nitrate in drinking water. The results of subgroup analysis were based on limited number of studies. Findings from this dose-response meta-analysis indicate that maternal nitrate intake higher than ∼3 mg/day is positively associated with NTDs risk.Meta-analysis, Nitrate, Neural tube defects, Systematic review