Prenatal exposure to nitrate from drinking water and the risk of preterm birth: A Danish nationwide cohort study.

Evidence is emerging that preterm birth (PTB, birth before 37 completed weeks of gestation), a risk factor for neonatal mortality and future morbidity, may be induced by maternal nitrate ( ${NO}_3^{-}$ ) exposure from drinking water. The objective of this study is to assess the association between maternal exposure to nitrate and the risk of PTB in a nationwide study of liveborn singletons.

Methods: We estimated maternal nitrate exposure from household tap water for 1,055,584 births in Denmark to Danish-born parents during 1991-2015 by linkage of individual home address(es) with nitrate concentrations from a national monitoring database. Nitrate exposure during pregnancy was modeled using four categories and continuously. Logistic models adjusted for sex, birth year, birth order, urbanicity, and maternal age, smoking, education, income, and employment, with generalized estimating equations were used to account for sibling clusters.

Results: A total of 1,009,189 births were included, comprising 51,747 PTB. An increase in the risk of PTB was seen across categories of exposure (P < 0.001) with an odds ratio (OR) in the uppermost category (>25 mg/L nitrate) of 1.05 (95% confidence interval [CI] = 1.00, 1.10). Evidence of an exposure-response relationship was observed in models using continuous nitrate (OR = 1.01 [95% CI = 1.00, 1.03] per 10 mg/L nitrate). In sensitivity analyses, results were robust to the addition of variables for short inter-pregnancy interval (<1 year between births), maternal pre-pregnancy body mass index, paternal socioeconomic status and age, season of birth, and inclusion of post-term births. Results were virtually unchanged when the analysis was restricted to women exposed to less than the current European Union standard of 50 mg/L.

Conclusion: We observed an increasing risk of PTB with increases in nitrate in household tap water. These findings add to a growing body of evidence of adverse effects from nitrate in drinking water at levels below current regulatory levels.