1 Department of Epidemiology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
2 Department of Health Care Administration, The Diwan College of Management, Tainan, Taiwan.
3 Section of Epidemiology, Department of Population Health Sciences, National Institute of Public Health, Oslo, Norway.
4 Environmental Health Program, The Nordic School of Public Health, Göteborg, Sweden.
5 Environmental Epidemiology Unit, Department of Public Health, University of Helsinki, Helsinki, Finland.
Received for publication July 6, 2001; accepted for publication April 17, 2002.
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ABSTRACT |
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abnormalities; chlorine compounds; disinfection; water pollution, chemical; water purification
Abbreviations: Abbreviations: CI, confidence interval; ICD-8, International Classification of Diseases, Eighth Revision; OR, odds ratio.
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INTRODUCTION |
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Recent findings suggest that exposure to chlorination by-products increases the risk of birth defects (47). In 19951998, Magnus et al. studied the association between water chlorination and adverse pregnancy outcomes in Norway (8). This study of 141,081 newborns indicated an increased risk of any birth defect related to the use of chlorinated water with a high content of natural organic matter compared with nonchlorinated water with a low amount of organic matter. In particular, an association was found for neural tube defects and for urinary tract defects. We conducted a nationwide cross-sectional study of all births occurring in 19931998 to assess the effect of water chlorination by-products on specific birth defects, particularly defects of the neural tube and urinary tract. In addition, we elaborated the role of natural organic matter in nonchlorinated waters.
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MATERIALS AND METHODS |
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Health outcomes
We assessed the effect of chlorination by-products on the risks of any birth defect and of five groups of defects, including neural tube, cardiac, respiratory system, urinary tract, and oral cleft defects, used in the Magnus et al. study of Norwegian births in 19931995 (8). In the present study with a larger study population, including births in 19931998, we also evaluated the most common specific birth defects, in particular those previously observed to be associated with chlorination: neural tube and urinary tract defects.
All births after the 16th week of gestation are compulsorily reported to The Norwegian Medical Birth Registry. During a childs first week of life, a physician, most often a pediatrician, diagnoses the birth defects to be reported. As a result, birth defects diagnosed later in life are not included in the registry. The International Classification of Diseases, Eighth Revision (ICD-8) is used to code as many as three birth defects for each child. We included all birth defects with ICD-8 codes 740.0759.9 as well as umbilical hernia (ICD-8 code 551.1) and ventral hernia (ICD-8 code 551.2). The following diagnoses were excluded because of poor reliability (8, 9): other anomalies of the nose (ICD-8 code 748.1), congenital hydrocele testis (ICD-8 code 752.4), clubfoot (ICD-8 codes 754.0754.9), congenital dislocation of the hip (ICD-8 code 755.6), and other specified anomalies of muscle, tendon, and fascia (ICD-8 code 756.8).
Exposure assessment
Assessment of exposure was based on municipal-level water quality information on chlorination practices and the humic content of raw water and on the mothers place of residence during pregnancy. Waterworks serving more than 100 persons must report to the National Institute of Public Health in Oslo, Norway. Each municipality was served by one or more waterworks, and the waterworks seldom serve those persons across the municipalitys borders. A total of 233 waterworks serving about 2.7 million people chlorinated their water, and 1,084 waterworks serving about 1.0 million people did not.
The main hypothesis of our study was that exposure to chlorination by-products in tap water increases the risk of birth defects. This exposure was expected to be more likely in municipalities whose waterworks chlorinate the water with dissolved organic compounds. We divided waterworks according to their use of chlorination disinfection and by water color (in mg Pt/liter) as a quantitative measure of the dissolved organic compounds. Water color is highly correlated with the concentration of dissolved organic compounds (r = 0.817, n = 634) (10). The color number is recorded routinely by most of the waterworks. About 28 percent of the municipalities have one waterworks only, 26 percent have two, 16 percent have three, and 30 percent have more than three. For municipalities with more than one waterworks, we calculated the weighted mean color based on the fraction of the population served by each waterworks as a weighting factor. In the main analyses, we focused on municipalities in which all waterworks were either using chlorination or not using chlorination. We constructed exposure categories by using chlorination and three levels of color: low (09.9 mg Pt/liter), medium (1019.9 mg Pt/liter), and high (20 mg Pt/liter). Low color with no chlorination constituted the reference category. Furthermore, we elaborated the effects of natural organic matter by using the three levels of color without chlorination.
Covariates
We used routine birth registry data to construct the following covariates: maternal age (<20, 2034, 35 years) and parity (0, 1, 2,
3 previous deliveries). We received municipal-level data from the Norwegian Social Science Data services, which were used to construct two municipal-level indicators of socioeconomic status: centrality and population density. Centrality indicates urbanicity and geographic placement in relation to a regional center. Population density is a measure of the proportion of the urban population living in the municipality.
Statistical methods
We estimated the prevalence (percentage) of the birth defects (with 95 percent confidence intervals) based on a binomial distribution. We compared the risk of birth defects for three exposure categories (chlorination and low color, chlorination and medium color, chlorination and high color) with the unexposed reference category (no chlorination and low color). We used prevalence odds ratios as a measure of association, and we applied logistic regression analysis to estimate the adjusted odds ratios. Goodness of fit was assessed with likelihood ratio tests to determine whether a variable contributed significantly to the model. First, we fitted a full model with a complete set of covariates. To elaborate sources of confounding, we fitted models with different combinations of covariates and compared the effect estimates from models with and without the covariate of interest. To evaluate the potential role of residual confounding and effect modification, we systematically compared effect estimates on different levels of covariates. In the main analyses, we focused on municipalities in which all waterworks either used chlorination or did not use chlorination. In further analyses, we also included municipalities that had two types of waterworks, taking into account the fraction of the population served by different types. We adopted a similar approach in studying the independent effect of natural organic matter by using the following two exposure categories: no chlorination and medium color, no chlorination and high color; no chlorination and low color was used as the reference.
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RESULTS |
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Cardiac defects
In the present study, 537 (0.29 percent) cardiac defects were identified. Table 4 shows that the risk of cardiac defects was slightly elevated, yielding adjusted odds ratios of 1.38 (95 percent CI: 0.99, 1.93) for the medium-exposure and 1.35 (95 percent CI: 0.89, 2.06) for the high-exposure categories. The estimate for the combined medium- and high-exposure category reached statistical significance (adjusted OR = 1.37, 95 percent CI: 1.00, 1.89). The risk of ventricular septal defects was significantly elevated, with an exposure-response pattern yielding adjusted odds ratios of 1.63 (95 percent CI: 1.02, 2.58) for the medium-exposure and 1.81 (95 percent CI: 1.05, 3.09) for the high-exposure categories. The risk of atrial septal defect was not related to exposure, and other specific cardiac defects were rare (table 4, second footnote). Occurrence of cardiac defects was not systematically related to color in nonchlorinated water.
Respiratory system defects
We identified 192 infants (0.10 percent) with respiratory defects. The adjusted odds ratios for respiratory defects were 1.87 (95 percent CI: 0.96, 3.62) for medium exposure and 1.96 (95 percent CI: 0.89, 4.34) for high exposure to chlorinated humic water. The risk estimate for the combined medium- and high-exposure category reached statistical significance (adjusted OR = 1.89, 95 percent CI: 1.00, 3.58). Estimates for specific defects are not presented in this paper because of small numbers, as shown in the second footnote of table 4. The risk of respiratory defects was not related to color in nonchlorinated water.
Oral cleft defects
There were 343 (0.19 percent) oral cleft defects. The risk of these defects was related to neither chlorinated humic water nor color in nonchlorinated water. Table 4 presents the risk estimates for cleft palate, cleft lip, and cleft palate with cleft lip. None of the estimates reached statistical significance, although those for the risk of cleft lip in relation to chlorinated humic water were substantially elevated.
Urinary tract defects
There were 232 (0.13 percent) urinary tract defects in the study population. In the logistic regression models, we found a slightly increased risk of urinary tract defects, with adjusted odds ratios of 1.61 (95 percent CI: 0.94, 2.76) for the medium-exposure and 1.35 (95 percent CI: 0.65, 2.80) for the high-exposure categories. The risk estimate for the combined medium- and high-exposure category was 1.55 (95 percent CI: 0.92, 2.61). When we included the municipalities with a mixed type of waterworks, the adjusted odds ratio was 1.46 (95 percent CI: 1.00, 2.13). The risk of obstructive defects of the urinary tract, with adjusted odds ratios of 1.89 (95 percent CI: 0.81, 4.44) for medium exposure and 1.99 (95 percent CI: 0.66, 5.96) for high exposure, showed an exposure-related increase, although the estimates did not reach statistical significance (table 4). The risk of urinary tract defects was not related to color level in nonchlorinated water.
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DISCUSSION |
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Validity of results
The Norwegian Medical Birth Registry provided health information on a large number of newborns, which made it possible to assess the effects of chlorination by-products on some of the most common specific birth defects. We excluded one half of the births because of insufficient water quality data. This exclusion was not likely to introduce selection bias; it was made on the municipality level, and the characteristics of the excluded municipalities and newborns did not differ substantially from those for the included municipalities and newborns, as shown in table 2.
A major limitation of this study was the ascertainment and classification of prenatal exposure to chlorination by-products, including the imprecision of using aggregate municipal measures to classify exposure at the individual level. Residential mobility also raised a potential problem concerning misclassification. Substantial variation in by-product concentrations over time adds another dimension of complexity. The main assumption was that women in municipalities with chlorinated water containing elevated levels of natural organic matter are exposed to chlorination by-products and that the magnitude of exposure is related to the amount of organic compounds in the water. We had no information on the quantities or sources of water that the women consumed, which decreased the accuracy of exposure assessment.
We were not able to take into account confounders such as alcohol consumption; cigarette smoking; vitamin use; or medication, pesticide, and genetic factors. There was no reason to suspect that these confounders were associated with water color or chlorination practices. Adjustment for centrality and population density not only adjusted indirectly for municipal differences in these behavior factors but also partly eliminated detection bias between urban hospitals and rural hospitals. To elaborate the residual confounding and potential effect modification, we systematically conducted stratified analyses by using different categories of exposure and other covariates. Because of reduced group sizes, this procedure was meaningful for only any birth defect and the five birth defect groups. The stratified analyses did not indicate any major confounding or effect modification.
Misclassification of the birth defects was also possible in the present study; diagnosis is difficult because of the rarity of each condition. In general, the birth defects might have been underreported because we did not include those diagnosed after 7 days of age. However, in the presence of a true association, random underreporting would weaken the observed association rather than introduce a spurious effect. In addition, residual confounding by unmeasured parameters such as environmental exposures, including air contaminants and occupational exposures, remains a possible explanation for our results.
Synthesis with previous knowledge
The present study and both previous studies from Massachusetts (4) and New Jersey (5) provide consistent evidence that exposure to chlorination by-products increases the risk of birth defects. All available studies suggest an increased risk of respiratory (4) and urinary tract (4) defects, but the findings are inconsistent for neural tube (4, 5), oral cleft (5, 6), and major cardiac (5, 6) defects. So far, very little is known about the relations between exposure and specific birth defects.
A case-control study in Massachusetts indicated that pregnant women using chlorinated surface water have an increased risk of birth defects, particularly respiratory and urinary tract defects, compared with women using chloraminated water (4). A cross-sectional study in New Jersey found that infants born to women exposed to trihalomethane levels of 80 µg/liter or more tended to have a higher risk of neural tube defects, major cardiac defects, and oral cleft defects than those born to women exposed to trihalomethane levels of 20 µg/liter or less (5). A retrospective cohort study in Nova Scotia provided little evidence that women exposed to trihalomethane levels of 100 µg/liter or more versus 049 µg/liter had an elevated risk of giving birth to infants with neural tube defects (6). In a population-based case-control study in New Jersey, the adjusted odds ratio of neural tube defects was 1.6 (95 percent CI: 0.9, 2.7) for the highest third compared with the lowest third of total trihalomethane exposure levels in the first month of pregnancy (7).
We were able to study nine of the most common specific birth defects as outcomes. Two, ventricular septal defect and obstructive defects of the urinary tract, were related to exposure to chlorinated water with a high amount of organic matter. One previous study has provided effect estimates for specific birth defects. Consistent with our results, Klotz and Pyrch (11) found no significant association between exposure to chlorination by-products and risk of spina bifida. Interestingly, we found that the risk of spina bifida was related to high amounts of organic matter in nonchlorinated water.
A study of 21 Norwegian waterworks using chlorination reported exposure levels for chlorination by-products (12). The average concentration of total trihalomethanes was 9.4 µg/liter and of halogenated acetic acid was 14.6 µg/liter, which were relatively lower compared with concentrations reported in US (5, 7) and Canadian (6) drinking water sources, although the mean color was 22 mg Pt/liter for these selected Norwegian waterworks.
We studied a relatively large number of health outcomes, which may have influenced interpretation of our results. However, we considered the hypotheses of the effects on the a priori defined birth defect groups, which are independent and mutually exclusive and thus do not require multiple-inference procedures (13). Following a suggestion by Rothman and Greenland (13), we presented all single-inference procedures with point estimates and confidence intervals (or numbers of birth defects when too few to produce an estimate) rather than selected effect estimates from an unknown number of estimates. Each reported association should be considered in the light of previous epidemiologic and toxicologic evidence (14, 15). Our finding suggested a small effect of prenatal exposure to chlorination by-products on ventricular septal defects, one of the most homogeneous cardiac defect categories. This finding is consistent with toxicologic evidence of the effects of haloacetic acids and haloacetoniriles (16).
The risk of neural tube defects was related to color level, with an exposure response pattern. Of the risk for specific birth defects, that for spina bifida showed a similar pattern. We did not have sufficient information on the quality of unchlorinated water to elaborate potential, specific causal agents. From previous literature, we know that nitrate levels are higher in humic waters and could increase the risk of neural tube defects (17, 18). In addition, hardness of water has been reported to be associated with the risk of neural tube defects, particularly anencephaly (1922). Any known or unknown determinant of birth defects related to the amount of natural organic matter could be responsible for the observed association between color level and risk of neural tube defects. This problem was common in all previous studies assessing the effects of chlorination by-products on the risk of birth defects, because persons exposed to chlorination by-products were also exposed to substances in water with natural organic matter. Unlike in the previous study areas of the United States and Canada, Norwegian waterworks commonly distribute unchlorinated surface water with a relatively high content of natural organic matter. This unusual setting made it possible to assess the effect of organic matter independently from the effect of chlorination. Further studies should determine the role of different water quality parameters related to the content of natural organic matter.
Conclusion
In summary, the present study indicates that exposure to chlorinated surface waters with a high content of natural organic matter increases the risk of birth defects. The current body of evidence, including the present and five previous studies (48), suggests small effects on the risk of urinary tract, respiratory system, and major cardiac defects. The studies of neural tube and oral cleft defects are inconclusive, probably explained by qualitative geographic differences in the levels of natural organic matter or lower concentrations of chlorination by-products in Norwegian drinking water than in US and Canadian drinking water. Additionally, the risk of ventricular septal defects was found to be associated with exposure to chlorinated surface water containing natural organic matter. This type of information emphasizes the importance of focusing on specific birth defects rather than using broad categories of outcomes based on organ systems. The present findings also suggest that natural organic matter in nonchlorinated tap water contains substances that may increase the risk of congenital birth defects.
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NOTES |
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REFERENCES |
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