The fetal safety of clomiphene citrate: a population-based retrospective cohort study.
OBJECTIVE
To evaluate whether exposure to clomiphene citrate (CC) for ovulation induction is associated with major malformations overall or with specific fetal anomalies.


METHODS
We conducted a population-based retrospective cohort study. Exposure was defined as CC dispension from 2 months before conception through the first month of pregnancy.


METHODS
Four databases were combined: medication, birth, hospitalization, and terminations of pregnancy.


METHODS
The study included all women in southern Israel who gave birth or underwent termination of pregnancy at Soroka Medical Center, from 1998 to 2009.


METHODS
The rates of major malformations overall and six different subcategories of anomalies were evaluated. The crude odds ratio (OR) was calculated with a 95% confidence interval (95% CI). Subsequently the adjusted odds ratio (aOR) was calculated using multiple logistic regression models controlling for maternal age, pre-pregnancy diabetes, parity, ethnicity, the calendar year in which the birth/termination of pregnancy took place, smoking, and the use of gonadotropins and progesterone.


METHODS
Major malformations overall and specific fetal malformations by organ systems.


RESULTS
Of 114 961 pregnant women, 1872 were exposed to CC. No association was detected between exposure to CC and rates of major malformations overall (aOR 1.08, 95% CI 0.88-1.32) or rates of subcategories of malformations. Exposure was not associated with anencephaly (aOR 2.27, 95% CI 0.44-11.71) or oesophageal atresia (aOR 3.681, 95% CI, 0.65-20.76).


CONCLUSIONS
In this large population-based retrospective cohort study, exposure to CC was not associated with an increased risk of either rates of major malformations overall or rates of specific malformations.


CONCLUSIONS
An observational study: no increased risk for fetal malformations following exposure to clomiphene citrate.
Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration), Beer-Sheva, Israel.
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Weller
Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration), Beer-Sheva, Israel.|Department of Pediatrics, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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Daniel
BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration), Beer-Sheva, Israel.|The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Department of Pediatrics, Hospital for Sick Children and The University of Toronto, Toronto, ON, Canada.
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Koren
The Motherisk Program, Division of Clinical Pharmacology-Toxicology, Department of Pediatrics, Hospital for Sick Children and The University of Toronto, Toronto, ON, Canada.|Department of Obstetrics and Gynecology, Soroka Medical Center, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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Lunenfeld
Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.|BeMORE collaboration (Ben-Gurion Motherisk Obstetric Registry of Exposure collaboration), Beer-Sheva, Israel.
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Levy
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology*; D000293:Adolescent; D000328:Adult; D002996:Clomiphene / Q000009:adverse effects* / Q000627:therapeutic use; D000013:Congenital Abnormalities / Q000453:epidemiology*; D005260:Female; D005300:Fertility Agents, Female / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007247:Infertility, Female / Q000188:drug therapy* / Q000453:epidemiology; D007557:Israel / Q000453:epidemiology; D011247:Pregnancy; D011256:Pregnancy Outcome; D011295:Prenatal Care / Q000379:methods; D012189:Retrospective Studies; D055815:Young Adult
D005300:Fertility Agents, Female; D002996:Clomiphene
Clomiphene citrate; congenital malformations; drug safety; ovulation induction; pregnancy