Decrease in anogenital distance among male infants with prenatal phthalate exposure

Environmental Health Perspectives, August, 2005 by Shanna H. Swan, Katharina M. Main, Fan Liu, Sara L. Stewart, Robin L. Kruse, Antonia M. Calafat, Catherine S. Mao, J. Bruce Redmon, Christine L. Ternand, Shannon Sullivan, J. Lynn Teague

AGD and AGI were modeled as both linear and quadratic functions of age. For babies born at < 38 weeks, age at examination in the first year was calculated from the estimated date of conception instead of the birth date. Once the best fitting model was identified, we plotted the expected AGI and its 25th and 75th percentiles as a function of age. We categorized boys in two ways: We dichotomized boys into those with AGI smaller than or at least as large as expected, and we used the difference between observed and expected AGI to define three groups of boys, short (AGI < 25th percentile for age), intermediate (25th percentile [less than or equal to] AGI < 75th percentile), and long (AGI [greater than or equal to] 75th percentile for age) AGI. We also calculated the proportion of boys in these three groups with normal testicular descent (both testes normal or normal retractile) and normal scrotal (scrotum of normal size and distinct from surrounding tissue). We calculated the correlations between AGD and AGI and penile volume, testicular placement and scrotal parameters (size and distinctness from surrounding tissue). Our decision to use AGI as the measure of genital development was made, and cut points for categorical analyses of outcomes were selected, before obtaining phthalate metabolite values.

We used general linear models to explore the relationships between phthalate metabolite concentration (unadjusted for urine concentration) and genital parameters. Most metabolite concentrations were above the LOD; those below the LOD were assigned the value LOD divided by the square root of 2, which has been recommended when the data are not highly skewed, as was the case here (Hornung and Reed 1990). Metabolite concentrations were logarithmically transformed to normalize distributions. We examined several potentially confounding factors including mother's ethnicity and smoking status, time of day and season in which the urine sample was collected, gestational age at sample collection, and baby's weight at examination.

We also categorized metabolite concentrations into low (< 25th percentile), intermediate (between the 25th and 75th percentiles), and high ([greater than or equal to] 75th percentile) categories and examined the odds ratio (OR) for smaller than expected AGI for babies with high compared with low exposure, and medium compared with low. On the basis of these regression and categorical analyses, we identified the phthalate metabolites most strongly associated with AGI. We refer to these as AGI-associated phthalates.

Because phthalate metabolite concentrations are highly correlated, and because our limited sample size prohibited us from examining multiway interactions, we constructed a summary phthalate score to examine the effect of joint exposure to more than one AGI-associated phthalate. For this purpose, we used quartiles of metabolite concentration; values in the lowest quartile did not contribute to the sum, whereas higher values increased the sum one unit per quartile. We divided this sum into three categories: low (0-1, reflecting little or no exposure to AGI-associated phthalates), intermediate (2-10), and high (11-12, reflecting high exposure to all, or almost all, AGI-associated phthalates). We examined the magnitude of the residual (observed - expected) AGI as a function of this summary phthalate score.