CLOMIPHENE CITRATE AND NEURAL-TUBE DEFECTS - A POOLED ANALYSIS OF CONTROLLED EPIDEMIOLOGIC STUDIES AND RECOMMENDATIONS FOR FUTURE STUDIES

Objective: To estimate the degree to which neural tube defects (NTDs) are associated with periconceptional clomiphene citrate (CC) exposure in controlled epidemiologic studies, to investigate the consistency of study findings with respect to this association, and to identify key problems that future studies should address. Design: Pooled analysis of 10 epidemiologic studies. Settings: Hospitals and clinics. Patients: Women undergoing treatment for infertility. Interventions: Oral administration of CC. Main Outcome Measure: Prevalence ratio for NTDs. Results: Ten controlled epidemiologic studies were identified that supplied sufficient data on CC and NTDs for inclusion. The estimated ratio of NTD prevalence among CC-exposed versus unexposed pregnancies ranged from 0.55 to 5.73 among the studies, but the variation was compatible with random fluctuation. The estimated summary prevalence ratio was 1.08, with 95% confidence limits of 0.76 and 1.51. Conclusion: This analysis indicates that an elevation in NTD risk due to CC cannot be ruled out, but any such elevation seems likely to be less than twofold, and there may be no elevation at all. Future studies should be designed to avoid several methodological problems not addressed in studies to date.