Health Stream Literature Summary - Issue 53 - March 2009

Maternal exposure to water disinfection by-products during gestation and risk of hypospadias.
Luben TJ, Nuckols JR, Mosley BS, Hobbs C and Reif JS. (2008) Occupational and Environmental Medicine, 65(6); 420-427.

Previous epidemiological studies have provided some evidence of an association between exposure to disinfection by-products (DBPs) and the risk of congenital anomalies. No studies have specifically examined the effect of maternal exposure to DBPs during gestation and risk of hypospadias. This condition is one of the most common congenital anomalies with an estimated prevalence of one in 125 live male births in the USA. Hypospadias is where the urethral opening occurs in an abnormal position (on the ventral side of the penis, near the glans, along the shaft or near the base of the penis) as a result of abnormal urethral closure at approximately week 8 to week 14 of gestation. Hypospadias most likely results from a complex interaction between multiple environmental exposures and genetic susceptibilities. This study evaluated the risk of hypospadias associated with maternal exposure to two groups of DBPs, total trihalomethanes (TTHM) and the sum of the five most prevalent haloacetic acids (HAA).

Birth certificate and birth defect registry data was obtained for 647 cases of hypospadias occurring in Arkansas between 1998 and 2002 and identified by the Arkansas Reproductive Health Monitoring System (ARHMS). Controls (n=1264) were randomly selected from birth certificate records for all male live births of infants without recorded congenital malformations in Arkansas during the same time interval. During the study period monitoring data for quarterly THM and HAA concentrations, including data on six individual species of HAA, were collected from 263 water utilities throughout Arkansas. The residential addresses for each participant were geocoded and linked to the water utility from which they were most likely to receive their tap water. Exposure was estimated by using the average daily DBP concentration for each case and control mother during an exposure window (between 6 and 16 weeks of gestation). Effect estimates were adjusted for race, number of cigarettes smoked per day during pregnancy and maternal education level. Some cases and controls could not be linked to tap water supplies, and some who were linked did not have DBP data to estimate exposure. Data analysis was therefore restricted to 320 cases and 614 controls.

A subset analyses was conducted using data for ARHMS subjects who also participated in the National Birth Defects Prevention Study (NBDPS). The subset analyses aimed to explore the potential effects of exposures to TTHM and HAA based only on an estimate of ingestion (water consumption), and then for TTHM by adding potential dermal and inhalation exposure based on individual showering and/or bathing data. All NBDPS participants were asked about pregnancy and medical history, diet, lifestyle, occupational and environmental exposures and medication use and also water consumption at home and at work and water use behaviours including showering and bathing. Water utility data and the exposure metrics based on ingestion were used to assess exposure for 40 NBDPS cases and 243 NBDPS controls. Two different metrics were used to explore the effects of exposures due to ingestion and then due to showering and bathing. Dose of TTHM and HAA through personal water consumption was estimated as the product of the average concentration in the distribution system during the exposure window and the number of 8-fluid ounce (about 236 ml) glasses of tap water consumed per day. Exposure from ingestion was categorised into tertiles. Mothers who consumed only bottled water or those with average DBP concentrations below detection limits during the exposure window served as the referents. Models were adjusted for body mass index, birth weight, maternal race and plurality.

The prevalence of hypospadias in the study area for the period examined was one per 137 live male births For the ARHMS subjects, there was no evidence that exposure to TTHM, HAA5 or any of the species of HAA was associated with an increase in risk for hypospadias in the unadjusted or adjusted analyses. In the NBDPS subset analysis when exposure was measured by personal water consumption, mothers in the intermediate tertile of exposure to TTHM had a non-significant increased risk of having an infant with hypospadias in the unadjusted analyses (OR 2.11, 95% CI 0.89 to 5.00) which became barely significant in the adjusted analyses (OR 2.79, 95% CI 1.01 to 7.72) compared to women in the referent group. Mothers in the intermediate tertiles of exposure to HAA5 had a significantly increased risk of having an infant with hypospadias in the unadjusted analyses (OR 2.45, 95% CI 1.06 to 5.67) compared to women in the referent group, but this association became insignificant in the adjusted analyses (OR 2.43, 95% CI 0.94 to 6.28). In contrast, women in the highest exposure tertiles had lower ORs than the intermediate tertile. The risk estimates for these analyses were in general imprecise and there was no evidence for a dose-response relationship. The results for bathing and showering exposure to TTHM in the subset analysis were imprecise and also did not follow a dose-response pattern. When ingestion, inhalation and dermal routes of exposure to TTHM in tap water were incorporated, the adjusted analyses using one exposure metric resulted in a non-significant OR of 1.96 (95% CI 0.65 to 6.42) for the highest tertile of exposure with a very weak dose-response relationship suggested. When exposure was classified using a metric that included uptake factors, the risk estimate was slightly lower (OR 1.68, 95% CI 0.55 to 5.13) and there was no evidence of a dose-response relationship.

The results found here provide little evidence of an association between DBP exposure during gestation and an increased risk of hypospadias. Differences in ORs seen when exposure was estimated from tap water DBP levels versus individual water consumption and water use patterns supports the need to use individual-level data when assessing exposure to DBPs.

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