Health Stream Literature Summary - Issue 50 - June 2008

Chlorination disinfection by-products and risk of congenital anomalies in England and Wales.
Nieuwenhuijsen, M.J., Toledano, M.B., Bennett, J., et al.(2008) Environmental Health Perspectives, 116(2); 216-22.

Studies examining disinfection by-products and potential adverse reproductive health effects including low birth weight, spontaneous abortion, stillbirth and congenital anomalies have reported inconsistent results. Most of these studies have had a small sample size and therefore low statistical power. This study is the largest study of its kind to report the relationships between trihalomethane (THM) levels in the public water supply and risk of congenital anomalies across England and Wales. The study area included 12 water companies in the United Kingdom. Areas supplied by each company were divided into water supply zones, each zone covering a population of less than 50,000 people. THM concentrations were used as the marker for chlorine disinfection by-products. Water samples were routinely collected and analysed from each water zone using random samples from consumer’s taps. Modelling was used to calculate the mean annual individual THM concentrations for each water zone and to assign an estimated water source type to each water zone which was dependant on THM levels in four samples taken within each zone.

Information on congenital anomalies was obtained from the National Congenital Anomalies System, regional registries and the national terminations registry. There were 22,828 cases with congenital anomalies; 1,641 (7.2%) of these had a chromosomal defect; 2,249 (9.9%) were classified has having multiple (nonchromosomal) anomalies, and 18,938 (83.0%) were classified as having isolated anomalies only. A postcode to water-zone link was created using geographic information systems (GIS). Postcode of the maternal residence at the year of birth was used to identify the water zone of interest and assign the appropriate exposure status for each birth record. THM exposure was estimated for the first 93 days of pregnancy when birth defects occur in the developing foetus. The weighted average THM estimate associated with each birth record was categorised into one of three predefined exposure categories: concentrations of total THMS (TTHMs; less than 30, 30 to less than 60 and greater than or equal to 60 micro g/L), total brominated THMs (less than 10, 10 to less than 20, and greater than or equal to 20 micro g/L) and bromoform (less than 2, 2 to less than 4, and greater than 4 micro g/L).

After exclusions there were 2,605,226 births left for analysis, including live births, stillbirths and terminations. Analysis was conducted using fixed- and random-effects models for broadly defined groups of anomalies as defined by ICD-9 or ICD-10 codes (cleft palate/lip, abdominal wall, major cardiac, neural tube, urinary and respiratory defects). The authors also defined a more restricted set of anomalies for analysis that were considered to be etiologically coherent and likely to have better ascertainment, and also analysed isolated and multiple anomalies. The data were adjusted for potential confounders including maternal age, socioeconomic status, year of birth and registry.

The mean TTHM concentrations ranged from 16.4 micro g/L in the low-exposure category to 72.2 micro g/L in the high-exposure category. Higher prevalence of each anomaly was found when the most deprived areas were compared to the most affluent areas. There was a U-shaped relationship found between prevalence of congenital anomalies and maternal age, except for neural tube defects (NTDs) where the prevalence decreased with increasing maternal age. There were no statistically significant trends across the three exposure categories for total THMs, total brominated THMs or bromoform for either the broadly defined or more restricted sets of anomalies. The only significant associations (p less than 0.05) for the broadly defined groups of anomalies was a reduced risk of abdominal wall defects in the high TTHM exposure category [odds ratio (OR) = 0.81; 95% confidence interval (CI), 0.68-0.95] and an excess risk of major cardiac defects in the medium (but not high) exposure category of total brominated THMs (OR = 1.12; 95% CI, 1.01-1.23).

When the restricted set of isolated anomalies was considered, statistically significant excess risks were seen for TTHM in the high-exposure category of ventricular septal defects (OR = 1.43; 95% CI, 1.00-2.04) and in the medium- (but not high) exposure category for congenital anomalies of the oesophagus (OR = 1.66; 95% CI 1.12-2.45). For bromoform, there was a significant excess in the high-exposure category for major cardiac defects (OR = 1.18; 95% CI, 1.00-1.39) and gastroschisis (OR = 1.38; 95% CI 1.00-1.92). There were no significant associations between TTHM exposure and any of the potential confounders. Analysis of cases with multiple anomalies showed no significant association with THM concentrations, but the numbers were small.

The study found little evidence of a relationship between concentrations of THMs and a wide range of congenital anomalies. There were no statistically significant exposure-response trends seen across the exposure categories for any of the anomalies considered. The statistically significant excess risks found in this study may have been chance associations as there is still little or no toxicological evidence of reproductive or teratogenic effects of bromoforms or other DBPS. Also the concentrations of bromoform across the study regions were generally very low. The subset analysis of major cardiac defects, ventricular septal defects and gastroschisis may have increased the accuracy of the case definition and further study of these specific anomalies and bromoform exposure may be warranted.

Comment As noted by the authors the large sample size, carefully thought out case definitions and targeted exposure assessment in the first trimester gave strength to the study compared to other registry-based studies. However individual water exposures, many non-water risk factors, and mobility during pregnancy could not be assessed.