Abstract Study question Is the risk of urogenital defects increased in live births where clomiphene citrate is known to have been dispensed by a pharmacist to the individual? Summary answer The risk of urogenital defects is elevated in singletons, and approximately doubled in male babies among women dispensed clomiphene citrate, as compared to unexposed women. What is known already Clomiphene citrate (CC) has been used for ovulation induction since 1967 & is both inexpensive and largely effective. However, CC is a selective estrogen receptor modulator (SERM), which is a class of drugs with the potential for endocrine disruption during fetal development. The link between urogenital defects and CC has previously been reported by ourselves and others. Whether the link continues to exist where individual level pharmaceutical prescribing and dispensing patterns are clearly ascertained has not been determined. Secondly, the interaction of prescribed clomiphene citrate functioning as an endocrine disruptor by fetal sex has not undergone formal statistical testing. Study design, size, duration A population-based cohort study of South Australia was assembled 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. Participants/materials, setting, methods We analysed de-identified pregnancy outcome data for all births in South Australia, 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 2011following 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. Main results and the role of chance We examined 2,264 singleton live births where women were dispensed clomiphene citrate for infertility. Births among women dispensed clomiphene citrate, compared to those without this exposure, had increased urogenital defects (odds ratio (OR) = 1.73, CI = 1.34 - 2.24). This association was slightly reduced after adjustment for maternal characteristics that were potential confounders: age, socio-economic status (based on postcode of residence), Aboriginal ethnicity, born outside Australia in low or middle income country, parity, smoking, pre-existing diabetes or hypertension, pregnancy-induced hypertension and pre-eclampsia (OR = 1.66, CI = 1.28 -, 2.15). There was evidence of an interaction with fetal sex, such that males were at particular risk. Sex-by-clomiphene interaction Male 1.92 (1.47, 2.52) Female 0.88 (0.37, 2.14) Test for interaction χ2(1) = 2.72; p = 0.09 The observed main effects are unlikely to be due to chance, and the sex-specific effect is biologically plausible, but limited in power. Further, there were 280 babies from multiple pregnancies to women exposed to clomiphene citrate that were excluded due to statistical limitations. Limitations, reasons for caution Our data report pharmacy dispensing, but not observed consumption, although infertile women are highly motivated to take this drug and over 5% of pregnancies were multiples, consistent with extensive use. The analysis for interactions and for multiples is currently restricted by power, which may resolve as the cohort number increases. Wider implications of the findings Clomiphene citrate (CC) may be a potent endocrine disruptor inducing urogenital defects, particularly in males. This is important as CC continues to be a WHO essential drug and a first line treatment globally, but with largely unmonitored use and without any industry initiated prospective safety study. Trial registration number Not applicable