Abstract
The impact of environmental endocrine disruptors on urogenital anomalies has been reported in numerous species. However, quantifying robust models in humans is difficult due to the lack of precision on exposures and time precedence.
We address these issues by reporting on the therapeutic administration of a selective estrogen receptor modulator (SERM), clomiphene citrate, for the treatment of sub-fertility and the subsequent occurrence of urogenital defects in children born after a defined periconceptional exposure window.
We employed a population-based cohort study of South Australia by linking all records from the state-wide perinatal registry for births between July 2003 and December 2011, including defects coded to ICD9 and BPA, with Commonwealth government data on pharmaceutical dispensing in the national Pharmaceutical Benefits Scheme (PBS), which includes individual level prescribing and dispensing of drugs for ovulation induction, including clomiphene citrate (CC).
De-identified pregnancy outcome data for all births in South Australia were linked to individual level national prescription data to examine the prevalence of urogenital birth defects (>20 weeks gestation) for births occurring between July 2003 and December 2011 following clomiphene citrate dispensing, with 5-years follow-up for defect notifications. Multivariate analysis in STATA within a Secure Unified Research Environment (SURE) was used to calculate odds ratios, adjusted for maternal confounders and socioeconomic circumstance. The analysis was restricted to singleton births.
Following CC exposure proximal to conception, the risk of urogenital defects was elevated in singletons (OR = 1.66, CI=1.28 -, 2.15) and approximately doubled in male babies 1.92 (1.47, 2.52), with no substantial effect in females.
The sex-specific effect is consistent with a causal role for clomiphene citrate. The apparent absence of effect in females is not reassuring as clomiphene citrate is known to cause reproductive anomalies in females, which may may need decades for their full expression.