American Journal of Epidemiology Vol. 153, No. 4 : 325-331
Copyright © 2001 by The Johns Hopkins University School of Hygiene and Public Health
ORIGINAL CONTRIBUTIONS |
Maternal Exposure to Nitrate from Drinking Water and Diet and Risk for Neural Tube Defects
1 March of Dimes Birth Defects Foundation, California Department of Health Services, California Birth Defects Monitoring Program, Emeryville, CA.
2 Present address: Kaiser Permanente, Division of Research, Oakland, CA.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this population-based case-control study conducted in California between June 1989 and May 1991, the authors investigated the association between maternal periconceptional exposure to nitrate from drinking water and diet and risk for neural tube defects. The mothers of 538 cases and 539 nonmalformed controls were interviewed regarding residential history, consumption of tap water at home, and dietary intake during the periconceptional period. Dietary nitrate exposure was not associated with increased risk for neural tube defects. Exposure to nitrate in drinking water at concentrations above the 45 mg/liter maximum contaminant level was associated with increased risk for anencephaly (odds ratio (OR) = 4.0, 95% confidence interval (CI): 1.0, 15.4), but not for spina bifida. Increased risks for anencephaly were observed at nitrate levels below the maximum contaminant level among groundwater drinkers only (OR = 2.1, 95% CI: 1.1, 4.1 for 5–15 mg/liter; OR = 2.3, 95% CI: 1.1, 4.5 for 16–35 mg/liter; and OR = 6.9, 95% CI: 1.9, 24.9 for 36–67 mg/liter compared with <5 mg/liter). Adjustment for identified risk factors for anencephaly did not substantially alter these associations, nor did control for maternal dietary nitrate, total vitamin C intake, and quantity of tap water consumed. The lack of an observed elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater may indicate that something other than nitrate accounts for these findings.
abnormalities; congenital; anencephaly; water pollutants
Abbreviations: BMI, body mass index; CI, confidence interval; CNS, central nervous system; MCL, maximum contaminant level; NTD, neural tube defects; OR, odds ratio
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A substantial number of etiologic investigations have focused on environmental and dietary risk factors for neural tube defects (NTD) (1
). A potential association between NTD risk and exposure to nitrate was first suggested by Knox (2), who reported a positive correlation between quarterly per capita intake of canned and cured meats and spatial and temporal variation in prevalence of anencephaly in England and Wales. Knox postulated that sodium nitrate and nitrite used as meat preservatives were the active agents.
Nitrates and nitrites are precursors to nitrosamines and other N-nitroso compounds that form endogenously after reduction of ingested nitrate to nitrite by bacteria in saliva and the gastrointestinal tract and nitrosation of amines and amides under gastric conditions. These compounds are teratogenic () and can induce central nervous system abnormalities in several animal models (4–9).
Human exposure to nitrate, nitrite, and N-nitroso compounds can occur from a variety of sources, including diet, medications, tobacco smoke, and drinking water (10). In agricultural areas, nitrate contained in inorganic fertilizers and animal manure passes through soil into the groundwater. Septic systems and leaking sewers also contribute to nitrates in groundwater (11). Surface water is less likely to be contaminated by nitrates.
The few studies that have investigated the effect of exposure to nitrate, nitrite, and N-nitroso compounds on NTD risk (12–19) have reported inconsistent results. We conducted a population-based case-control study to investigate the potential association between maternal exposure to nitrate from drinking water and diet and risk of having an NTD-affected pregnancy.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Study population
Study participants were drawn from a population-based case-control study of NTD described previously (20
). Briefly, singleton births occurring between June 1989 and May 1991 to women living in California at the time of delivery were eligible. Liveborn and stillborn infants with a NTD (anencephaly, spina bifida cystica, craniorrachischisis, and iniencephaly) and fetuses electively terminated after prenatal diagnosis of a NTD were ascertained by the California Birth Defects Monitoring Program (21). Controls were nonmalformed infants randomly selected from each area birth hospital in proportion to the hospital's estimated contribution to the total number of livebirths between 1989 and 1991. Women who spoke only languages other than English or Spanish were not eligible for interview. We ascertained 613 infant/fetus cases and 611 controls whose mothers were eligible for interview.
Interviews
Face-to-face interviews were conducted with mothers of 538 (87.8 percent) cases and 539 (88.2 percent) controls and completed on average within 5 months of the actual or estimated date of term delivery. A standardized questionnaire elicited information on maternal medical, reproductive, occupational, and family history and on various maternal and paternal sociodemographic and lifestyle factors. Women were asked to report all addresses and dates of residence for places where they had lived for at least 2 weeks during the periconceptional period, defined as 3 months before through 3 months after conception.
A detailed beverage consumption questionnaire was administered, focusing on the usual serving size and frequency of each beverage consumed at home during the 3 months before conception. Women were asked about their intake of tap water and of hot and cold beverages prepared with tap water. A detailed dietary history was obtained from the 100-item Block food frequency questionnaire (22) and focused on the usual serving size and frequency of food items consumed during the 3 months before conception.
Estimation of nitrate exposure from drinking water
We obtained a list of all California community water systems (approximately 500), the cities they served, and the geographic coordinates for their coverage area. We first linked each participant's periconceptional residential addresses to water companies by city or geographic coordinates. We then sent to each water company the list of study addresses it potentially served, along with corresponding dates of residence for each address. We requested that the company indicate, for each address 1) whether it served the address during the dates indicated; 2) what type of water (groundwater, surface water, and/or mixed water) was most likely provided; and 3) which specific source(s) (well number, sampling source) most likely supplied the water. The most likely water source was not necessarily that closest to the residence. This information was linked to the Department of Health Services Water Quality Monitoring Database, which contains the results of mandatory routine testing of community drinking water supplies. During the study years, source sampling was required every 3 years for groundwater and annually for surface water. We matched residential addresses to water companies for 442 cases and 441 controls.
For each periconceptional address linked to a water company, only nitrate values from the specific water sources reported to serve the address were used to estimate nitrate exposure. If the specific sources were not reported, nitrate information from all sources sampled by the company was used. Once the appropriate sources were identified, nitrate exposure was estimated based on criteria involving the time period of water sampling. Priority was given to samples taken during the actual dates of residence. If water sampling was not conducted during these dates, samples taken during the same season of residence (either for the same year, if available, or for any year between 1980 and 1995) were used. If no season match was found, samples taken in the year of residence and, if not available, from any year between 1980 and 1995 were used. There was very little difference in the estimated nitrate exposure derived from samples matched by actual dates, season, or year of residence.
Each study subject was assigned a mean drinking water nitrate exposure value (nitrate as milligrams of nitrate/liter) by averaging the nitrate concentrations derived for each maternal periconceptional address. Exposure values derived by a weighted average, where the weighting factor was length of residence at each address, were similar. Sixty-five percent of the case mothers and 72 percent of the control mothers reported only one periconceptional address. Each study subject was also assigned to a water type category. The "groundwater" category was assigned if only groundwater was received at all residences. The "surface water" category was assigned if only surface water was received at all residences. Study subjects were assigned to the "mixed water" category if they received both groundwater and surface water at any one residence (75 percent of all mixed water users) or only groundwater at one residence and only surface water at another residence.
Estimated drinking water nitrate exposure was calculated for 436 (81.0 percent) and 432 (80.1 percent) of interviewed case and control mothers, respectively. For approximately 77 percent of the cases and controls, these estimated exposures were derived from the specific water sources supplying water to the addresses. Sampling data corresponding to the actual date of residence or season of residence were available for approximately 72 percent of the study addresses.
Mean daily water consumption at home (liters/day) was calculated by multiplying the frequency of intake of tap water and all hot and cold beverages prepared with tap water by the serving size and averaging over the 3 months before conception.
Estimation of nitrate exposure from diet and medications
The mothers of 493 cases and 511 controls completed food frequency questionnaires. After excluding questionnaires with errors or incomplete data, we had dietary information for 454 (84.4 percent) case and 462 (85.7 percent) control mothers. The nitrate, nitrite, and N-nitrosamine contents of each reported food item were estimated by a nutritionist who relied on food values published in the scientific literature (23–27). Mean daily dietary intake of nitrate, nitrite, and N-nitrosamines was calculated for each mother by multiplying the frequency of intake of each reported food item by its nitrate, nitrite, and N-nitrosamine content and summing over all foods. Exposure to nitrosatable medications was determined by classifying each medication used during early pregnancy according to its potential for nitrosatability, following the method described by Olshan and Faustman (14).
Statistical analyses
Exposure category cutpoints were chosen by selecting the points on a third-degree polynomial logistic regression curve that marked changes in risk. The adequacy of the third-degree polynomial representation was assessed by contrasting the estimated response curves with those generated from a generalized additive model (nonparametric estimated response curves), and no important differences were observed. Four exposure categories were defined: less than 5, 5–15, 16–35, and more than 35 mg/liter. We categorized dietary intake of nitrates, nitrites, and N-nitrosamines into quartiles based on the distribution of these compounds among controls.
Standard two-by-two tables and multivariate logistic regression were used to estimate crude and adjusted odds ratios and their 95 percent confidence intervals for each exposure category. Maternal race/ethnicity (White, US-born Latina, foreign-born Latina, Black, and other), age (
19, 20–24, 25–29, 30–34, and 
35 years), education (less than high school, high school graduate, and more than high school), household income ($9,999, $10,000–$29,999, $30,000–$49,999, and $50,000), body mass index (BMI) (29 and >29 kg/m2), periconceptional vitamin use (no use vs. use), tap water consumption (liters per day), and dietary nitrate intake (milligrams per day) were included as covariates in adjusted analyses. Analyses were performed for all NTDs combined and for anencephaly and spina bifida separately. For each case type, analyses were also performed by water type.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Drinking water nitrate
Characteristics of case and control mothers for whom drinking water nitrate information was obtained were similar to characteristics of all interviewed women (20
). Compared with control mothers, case mothers were more likely to be Latina, young, and obese and less likely to have completed high school, to have an income above the poverty line, and to use prenatal vitamins. Mean daily consumption of tap water was higher for case mothers (1,141 ml/day) than for control mothers (976 ml/day). The majority of study mothers received groundwater (51 percent cases and 45 percent controls). Fewer mothers received surface water (24 percent cases and 34 percent controls) and mixed water (25 percent cases and 21 percent controls). The highest mean levels of nitrate were found in groundwater and mixed water (table 1). There was no substantial case–control difference in mean nitrate concentration from groundwater only (13.8 vs. 12.2 mg/liter), surface water only (1.1 vs. 0.82 mg/liter), or mixed water (12.4 vs. 13.4 mg/liter).
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Eight cases and three controls had maternal exposure to nitrate above 45 mg/liter, the maximum contaminant level (MCL) for nitrate in drinking water. Compared with exposure below 45 mg/liter, the odds ratio for NTDs was 2.7 (95 percent confidence interval (CI): 0.76, 9.3). Increased risks were observed among women exposed to drinking water containing more than 5 mg/liter of nitrate (table 2). These increases were accounted for exclusively by groundwater drinkers. Point estimates were virtually unchanged after simultaneous adjustment for maternal race/ethnicity, age, education, income, BMI, and vitamin use. The mean intake of tap water (including beverages prepared with tap water) among groundwater drinkers was 957 ± 851 ml/day. Only 34 of 224 (15.2 percent) case mothers and 20 of 193 (10.4 percent) control mothers drank more than 2 liters of tap water per day. When adjusted for the amount of groundwater consumed (ml/day), effect estimates for nitrate exposure were similar to crude estimates (odds ratio (OR) = 1.2, 95 percent CI: 0.73, 1.9) for 5–15 mg/liter; OR = 1.3, 95 percent CI: 0.79, 2.1 for 16–35 mg/liter, and OR = 2.6, 95 percent CI: 0.76, 8.7 for 36–67 mg/liter nitrate compared with less than 5 mg/liter nitrate).
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We examined risk separately for anencephaly (n = 183) and spina bifida (n = 223). Five anencephaly case mothers were exposed to nitrate in excess of 45 mg/liter (three from groundwater and two from mixed water). Risk for anencephaly associated with exposure exceeding the MCL was 4.0 (95 percent CI: 1.0, 15.4). We observed a doubling in anencephaly risk for maternal exposure to groundwater containing nitrate at 5–15 and 16–35 mg/liter compared with less than 5 mg/liter. An odds ratio of 6.9 (95 percent CI: 1.9, 24.9) was observed for the highest nitrate exposure category, 36–67 mg/liter (table 3). In contrast, no increased risks were evident for anencephaly among mixed water drinkers (either type) or for spina bifida associated with any level of nitrate exposure or among any type of water drinker (table 3). Groundwater drinkers were more likely to have risk factors for NTDs (Hispanic ethnicity, young age, low education, low income, no prenatal vitamin use) than were mixed water drinkers. However, single and multivariable adjustment for maternal race/ethnicity, age, education, income, BMI, and vitamin use did not substantially alter point estimates (data not shown). Water intake did not confound the association between concentration of nitrate in groundwater and risk for anencephaly. The odds ratios for 5–15, 16–35, and 36–67 mg/liter nitrate compared with less than 5 mg/liter nitrate adjusted for amount of tap water consumed were 2.1 (95 percent CI: 1.1, 4.2), 2.4 (95 percent CI: 1.2, 4.9), and 7.9 (95 percent CI: 2.0, 31.4), respectively.
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We conducted a series of analyses specifically focused on the risk of anencephaly among groundwater drinkers. When analyses were restricted to study subjects whose estimated nitrate exposure was derived exclusively from specified water sources (68 cases and 133 controls), the OR for the highest exposure category compared with the lowest was 4.4 (95 percent CI: 1.0, 18.9). Analysis restricted to study subjects with nitrate sampling information for the actual dates of residence (48 cases and 89 controls) yielded an OR of 7.7 (95 percent CI: 1.6, 35.1) for the highest exposure category. Among women with only one periconceptional address (70 cases and 140 controls), the OR for the highest exposure category was 3.5 (95 percent CI: 0.8, 14.6). Among women who did not work outside the home (30 cases and 57 controls), the OR for the highest exposure category was 14.0 (95 percent CI: 0.9, 756). Finally, we examined risk among nonsmokers (77 cases and 141 controls) to control for the potential effects of N-nitrosamine exposure from cigarette smoke and observed an OR of 13.7 (95 percent CI: 2.1, 58.1) for the highest water nitrate exposure category. Among the 16 anencephaly cases whose mothers smoked, none were in the highest water nitrate exposure category.
Nitrate exposure from diet and medications
Mean dietary nitrate intake was lower among case mothers than control mothers (64.9 vs. 76.4 mg/day). Vegetables and fruits contributed over 85 percent of the total intake of nitrate from the diet. Dietary nitrate intake was inversely associated with NTD risk (table 4). Single variable adjustment by maternal race/ethnicity; age; education; BMI; income; vitamin use; smoking; alcohol consumption; and dietary folate, zinc, calcium, protein, carotenes, and vitamins A, C, and E did not alter crude estimates of risk. However, after multivariable adjustment for a combination of demographic factors (maternal age, race, education, BMI, income, and vitamin use) and dietary nutrients (folate, zinc, and protein) previously shown to be associated with NTD risk (20, 28, 29), odds ratios were consistent with unity (table 4). Women who consumed foods containing higher levels of nitrite and N-nitrosamines were also not at any increased risk for having an NTD-affected pregnancy (table 4).
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The relation between water nitrate exposure (from all water types combined) and NTD risk was not changed after adjustment for dietary nitrate intake (OR for highest water nitrate category = 1.9, 95 percent CI: 0.73, 4.7). Similarly, risk for anencephaly among groundwater drinkers was not substantially altered after adjustment for dietary nitrate intake (OR = 1.7, 95 percent CI: 0.82, 3.8 for 5–15 mg/liter; OR = 2.1, 95 percent CI: 0.97, 4.5 for 16–35 mg/liter; and OR = 9.2, 95 percent CI: 1.5, 54.1 for 36–67 mg/liter). We examined risk for anencephaly associated with nitrate in groundwater stratified by total vitamin C intake. Two strata (<103 mg/day and
103 mg/day) were defined based on the point on the control distribution corresponding to the lowest quartile of vitamin C intake. Effect estimates ranged from 4.0 (95 percent CI: 0.65, 42.6) to 18.0 (95 percent CI: 1.5, (infinity)) among the low vitamin C intake group and from 1.8 (95 percent CI: 0.87, 3.9) to 5.3 (95 percent CI: 1.2, 23.0) among the high vitamin C intake group. Mothers of 50 cases and 43 controls reported using potentially nitrosatable medications during the periconceptional period. We observed an odds ratio of 1.2 (95 percent CI: 0.77, 1.8) associated with this exposure.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Exposure to nitrate in groundwater at concentrations above the MCL was associated with increased risk for anencephaly. Exposure to drinking water nitrate concentrations below the MCL was also associated with increased risk for anencephaly, but only among groundwater drinkers. Maternal dietary nitrate and quantity of tap water intake in the periconceptional period did not substantially alter this association, nor did adjustment for other identified risk factors for NTDs. Analyses restricted to women with more precise exposure measures resulted in stronger effect estimates. In contrast, exposure to dietary nitrate, nitrite, and N-nitroso compounds and nitrosatable medications was not associated with NTD risk.
Previous studies examining drinking water nitrate reported risks for all central nervous system (CNS) defects combined (13) or NTDs as a group (12, 16) without specifying the subtype of defect examined. Arbuckle et al. (13) reported a twofold risk for CNS anomalies associated with exposure to nitrate in well water (groundwater) containing 26 mg/liter relative to the baseline of 0.1 mg/liter. Increased risks were not seen for public water and spring water, which contained nitrate at much lower concentrations than that observed in well water. In an Australian study (12), an OR of 3.5 was reported for CNS defects among women consuming groundwater compared with rainwater. Defect-specific risks associated with specific levels of nitrate in groundwater were not provided, nor was the amount of water intake taken into consideration. Klotz and Pyrch (16) found no association between NTD risk and nitrate concentration in tap water in New Jersey.
To our knowledge, this is the first study examining nitrate exposures from drinking water to report risk for anencephaly and spina bifida separately. This analytic approach has been advocated by others (30), given that the epidemiology of these phenotypically distinct groups reveals differences for some risk factors. Our finding of increased risk for anencephaly, and not for spina bifida, associated with nitrate in groundwater is preliminary. There are no animal studies linking nitrate or nitrite exposure at lower levels to risk for anencephaly (31). However, several experimental studies have demonstrated an association between exposure to various N-nitroso compounds and occurrence of CNS defects, including anencephaly, in laboratory animals (4, 7, 9).
Why did we not observe an elevation in risk for anencephaly in association with exposure to mixed water containing nitrate at levels comparable with the concentration in groundwater? One possible explanation may be that the estimated nitrate exposure value for mixed water drinkers may be substantially misclassified and bias effect estimates toward the null. Another possibility is that something other than nitrate in groundwater accounts for our findings. However, in our study population, we did not observe a correlation between the levels of nitrate and any other constituents routinely monitored in groundwater, including pesticides. Additionally, exposure to high levels of groundwater nitrate occurred in several different geographic locations, making it unlikely that the increased risks we observed resulted from some other risk factor present among the groundwater group but not among the mixed water group. The lack of consistency in our results by water type requires investigation in future studies.
Our effect estimates could also be biased by exposure misclassification resulting from use of a surrogate measure of exposure. We did not directly measure the concentration of nitrate in residential tap water. Rather, maternal drinking water nitrate exposure was estimated by averaging the nitrate concentration from the community water sources that supplied water to maternal periconceptional addresses. Since nitrate levels in community water supplies are not affected by routine water treatment, nitrate levels at the source should be a good proxy for levels at the tap. However, sources with nitrate levels exceeding the MCL may have been temporarily shut down until lower nitrate levels were achieved. Typical softeners used in the home also do not remove nitrate from water (Rick Sakaji, DHS Drinking Water Program, personal communication, 1999). Two types of point-of-use water treatment systems that can significantly reduce nitrate levels in tap water, reverse osmosis filters and distillers, were not reported by the mothers of any anencephaly cases with nitrate exposure in excess of 5 mg/liter. Furthermore, the concentration of nitrate in the drinking water sources remained fairly constant over the time period from which data were used to estimate exposure. It is unlikely that any exposure misclassification resulting from the use of surrogate measures would be differential with respect to case status.
The daily intake of tap water at home, including beverages prepared with tap water, was, on average, 1 liter, which is similar to previous reports of tap water intake among other populations of pregnant women (32, 33). Because there was very little variability in the amount of tap water consumed in this population, we did not have adequate sample size to examine risk separately for women with high intake. However, there was no evidence of statistical interaction between nitrate concentration and tap water intake, and effect estimates were not changed after adjustment for water intake. We also did not have information on the nitrate levels in tap water consumed outside the home. However, our findings were strongest among women who did not work outside the home and who presumably consumed the majority of tap water at home.
Other methodological considerations in interpreting the observed elevated risks for anencephaly and groundwater deserve mentioning. First, the overall analytic sample comprised approximately 70 percent of the eligible population. We cannot rule out the possibility that our findings may have been affected by selection bias. Second, effect estimates in the highest nitrate exposure category were imprecise owing to small numbers.
The MCL for drinking water nitrate was set at 45 mg/liter based on the risk for infant methemoglobinemia. Our data suggest a possible increased risk for anencephaly among the offspring of women exposed to nitrate in groundwater at concentrations well below the standard. Before the causality of this association can be determined, additional studies with improved exposure assessments need to be conducted.
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ACKNOWLEDGMENTS |
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The authors are grateful to Drs. Andrew Olshan and Elaine Faustman for providing a list of medications with potential for nitrosatability and to Lori Randle for providing estimates of the nitrate content of reported food items.
The opinions expressed are the views of the authors. They do not necessarily reflect the official position of the California Department of Health Services.
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NOTES |
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Reprint requests to Dr. Lisa A. Croen, Kaiser Permanente, Division of Research, 3505 Broadway, Oakland, CA 94611–5714 (e-mail: lac{at}dor.kaiser.org).
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