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.


METHODS
Pooled analysis of 10 epidemiologic studies.


METHODS
Hospitals and clinics.


METHODS
Women undergoing treatment for infertility.


METHODS
Oral administration of CC.


METHODS
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.


CONCLUSIONS
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.
Greenland
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Department of Epidemiology, School of Public Health, University of California Los Angeles, USA.
Ackerman
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DL
D000284:Administration, Oral; D016022:Case-Control Studies; D002996:Clomiphene / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D015331:Cohort Studies; D016001:Confidence Intervals; D005260:Female; D005300:Fertility Agents, Female / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D007247:Infertility, Female / Q000188:drug therapy; D009436:Neural Tube Defects / Q000139:chemically induced* / Q000453:epidemiology*; D010062:Ovulation Induction; D011247:Pregnancy; D018873:Pregnancy Rate; D015995:Prevalence; D012307:Risk Factors
D005300:Fertility Agents, Female; D002996:Clomiphene