Drinking water nitrate and risk of pregnancy loss: a nationwide cohort study

Abstract

Background: Nitrate contamination is seen in drinking water worldwide. Nitrate may pass the placental barrier. Despite suggestive evidence of fetal harm, the potential association between nitrate exposure from drinking water and pregnancy loss remains to be studied. We aimed to investigate if nitrate in drinking water was associated with the risk of pregnancy loss.

Methods: We conducted a nationwide cohort study of 100,410 pregnancies (enrolled around gestational week 11) in the Danish National Birth Cohort (DNBC) during 1996-2002. Spontaneous pregnancy losses before gestational week 22 were ascertained from the Danish National Patient Registry and DNBC pregnancy interviews. Using the national drinking water quality-monitoring database Jupiter, we estimated the individual and time-specific nitrate exposure by linking geocoded maternal residential addresses with water supply areas. The nitrate exposure was analyzed in spline models using a log-transformed continuous level or classified into five categories. We used Cox proportional hazards models to estimate associations between nitrate and pregnancy loss and used gestational age (days) as the time scale, adjusting for demographic, health, and lifestyle variables.

Results: No consistent associations were found when investigating the exposure as a categorical variable and null findings were also found in trimester specific analyses. In the spline model using the continuous exposure variable, a modestly increased hazard of pregnancy loss was observed for the first trimester at nitrate exposures between 1 and 10 mg/L, with the highest. adjusted hazard ratio at 5 mg/L of nitrate of 1.16 (95% CI: 1.01, 1.34). This trend was attenuated in the higher exposure ranges.

Conclusion: No association was seen between drinking water nitrate and the risk of pregnancy loss when investigating the exposure as a categorical variable. When we modelled the exposure as a continuous variable, a dose-dependent association was found between drinking water nitrate exposure in the first trimester and the risk of pregnancy loss. Very early pregnancy losses were not considered in this study, and whether survival bias influenced the results should be further explored.

Keywords: Cohort study; Drinking water nitrate; Nitrosatable drug exposure; Pregnancy loss.

Fig.1

Flowchart of enrolled pregnancies in the DNBC 1996–2002 eligible for Cox analysis Model I and II

Fig. 2

Adjusted hazard ratios of pregnancy loss by drinking water nitrate exposure (log scale) in pregnancy with 1 mg/L as reference. Exposures below the highest detection limit 1 mg/L and above 50 mg/L are not shown, but included in the model. Grey scale areas represent the CI. Splines were adjusted for age, education, occupation, population density, BMI, smoking and alcohol. Robust standard errors accounted for dependencies between pregnancies by the same woman