Background & question
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), with a long half-life and the potential for endocrine disruption during fetal development. The FDA (1965) found it to be embryocidal and teratogenic at high doses. The link between CC and human birth defects has previously been reported by ourselves and others. There has never been a prospective safety study in humans.
Whether the link with urogenital defects exists where contemporary prescribing and dispensing patterns are clearly ascertained has not been determined.
Secondly, the interaction of prescribed clomiphene citrate by fetal sex has not undergone formal statistical testing.
Methods
We employed a population-based cohort study of 161,295 births in South Australia including 2,264 singleton CC exposed live births between July 2003 and December 2011, including defects coded to ICD9 and BPA, and dispensing in the national Pharmaceutical Benefits Scheme (PBS). Multivariate analysis in STATA was used to calculate odds ratios.
Results
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 and potential confounders: (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
Conclusion
Clomiphene citrate (CC) is associated with urogenital defects, particularly in males. This is important as CC continues to be widely used, is a WHO essential drug and a first line treatment globally, but with largely unmonitored use contrary to FDA mandated safety requirements. Further studies across jurisdictions and clinical application are warranted.