Clomiphene citrate and neural tube defects: a meta-analysis of controlled observational studies.

Background: At the end of the 1980s, several studies suggested a potential increased risk of neural tube defects (NTDs) with ovulation induction/fertility drugs, especially with clomiphene citrate (CC). A previous meta-analysis of observational studies evaluating the risk of NTDs associated with the use of CC performed in 1995 found a risk ratio of 1.08 (95% CI 0.76-1.51). Since then, additional studies have been published and the risk of NTDs associated with periconceptional CC exposure may have changed.
Objective: To perform an updated quantitative meta-analysis of the risk of NTDs associated with periconceptional CC exposure.
Search Strategy: MEDLINE, Web of Science, and Scopus were searched (October 2018).
Selection Criteria: Comparative cohort and case-control studies investigating the risk of NTDs after periconceptional CC exposure.
Data Collection and Analysis: Pooled effect sizes with corresponding 95% CIs were calculated using random effects models, comparing the risk of NTDs between pregnancies exposed and not exposed to CC.
Main Results: Thirteen studies met the inclusion criteria, totalling 218 819 pregnancies. Periconceptional exposure to CC was not significantly associated with an increased risk of NTDs (pooled odds ratio 1.21, 95% CI 0.88-1.66). No heterogeneity between studies was observed (I ²  = 26%). A funnel plot and asymmetry test were not suggestive of publication bias.
Conclusion: Our meta-analysis confirms that exposure to CC before or in early pregnancy was associated with a 21% increased risk of NTD in relation to CC exposure; however, this increased risk is not statistically significant.
Tweetable Abstract: A new meta-analysis finds that clomiphene citrate exposure before or in early pregnancy is not associated with an increased risk of NTDs.
(© 2019 Royal College of Obstetricians and Gynaecologists.)