Etiology

Fluconazole use during the first trimester of pregnancy was not associated with most major birth defects

Mølgaard-Nielsen D, Pasternak B, Hviid A. Use of oral fluconazole during pregnancy and the risk of birth defects. N Engl J Med. 2013;369:830-9.

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Conclusion

Does use of oral azole antifungal agents during the first trimester of pregnancy increase risk for major birth defects in offspring?

Use of oral fluconazole during the first trimester of pregnancy was not associated with increased risk for major birth defects overall, but it was associated with increased risk for tetralogy of Fallot.

Methods Design: Retrospective, population-based cohort study with individual-level linkage of several national registers. Setting: Denmark. Patients: 976 300 live infants born to 975 588 mothers (mean age 30 y at pregnancy onset) between Jan 1996 and Mar 2011. Infants with missing or implausible gestational ages, chromosomal aberrations, genetic syndromes, or birth defects with known causes were excluded. Risk factors: Filled prescriptions for maternal use of oral fluconazole, itraconazole, and ketoconazole during the first trimester of pregnancy. Infants of women who filled prescriptions for oral antifungal agents in the 4 weeks before pregnancy, and women with fungal infections diagnosed during hospitalization from 4 weeks before pregnancy through the first trimester, were excluded. Outcomes: All major birth defects and 15 individual defects previously associated with azoles (craniosynostosis, cleft palate, cleft lip with or without cleft palate, other craniofacial defects, middleear defects, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects [any], tetralogy of Fallot, pulmonary artery hypoplasia, ventricular septal defects, and hypoplastic left heart).

Main results 8064 infants were exposed to oral azole antifungal agents. Use of fluconazole during the first trimester of pregnancy, regardless of cumulative dose, was not associated with major birth defects (Table). Neither itraconazole nor ketoconazole use during the first trimester of pregnancy was associated with increased risk for major birth defects (Table). Maternal fluconazole use during pregnancy was associated only with the specific birth defect of tetralogy of Fallot (adjusted odds ratio 3.16, 95% CI 1.49 to 6.71) based on 7 events (0.10%) in the exposed group.

Source of funding: Danish Medical Research Council. For correspondence: Ms. D. Mølgaard-Nielsen, Statens Serum Institut, Copenhagen, Denmark. E-mail [email protected]. ■

Commentary Vulvovaginitis is a common ailment to which women are predisposed by pregnancy and antibiotic therapy. Vulvovaginitis is not associated with adverse pregnancy outcome, but treatment relieves symptoms. Trials have not compared azole regimens, but cure rates are ≥ 80% with topical (e.g., clotrimazole) or oral (e.g., fluconazole) azoles. Oral therapy is far more convenient, but is it safe? The retrospective cohort study by Mølgaard-Nielsen and colleagues suggests that there is some element of risk associated with firsttrimester exposure to fluconazole, related to an increased risk for tetralogy of Fallot but not major birth defects overall. The risk is small and can be excluded by routine anatomy scan, providing reassurance for many women who may have taken fluconazole inadvertently in the first trimester. However, the risk is consistent with previous human (1) and animal (2) reproductive studies. Of note, just over half of women exposed to fluconazole were exposed to a single dose of 150 mg (i.e., low dose). This was not a study of high-dose exposures as the single 150-mg dose is the lowest recommended. Ketoconazole or itraconazole was not associated with major or organ-specific malformations. Experimental studies have suggested that azoles may have different teratogenic potential through differential inhibition of cytochrome P450 enzymes responsible for essential synthetic and metabolic functions within human cells (3). However, Mølgaard-Nielsen and colleagues had limited numbers of first-trimester exposures to ketoconazole (n = 72) or itraconazole (n = 687), possibly limiting their statistical power to find drug–malformation relations.

This study should remind clinicians to be cautious about prescribing drugs in pregnancy. Statistical power is often inadequate to exclude increased risk for major malformations and is Association between maternal use of oral azole antifungal agents almost always inadequate to exclude increased risk for organduring the first trimester of pregnancy and risk for major birth defects* specific malformations. Women should be encouraged to use Oral azole antifungal agent Number of Event rate Adjusted alternative effective agents associated with more safety data. pregnancies with (95% CI) odds ratio Topical azoles can be prescribed for 1 to 7 days, or 7 to 14 days exposure for severe or recurrent vulvovaginitis, even with immunocomNo exposure (n = 968 236)† 0 2.60% Reference promise. Courses can be repeated. Thereafter, few women Fluconazole (all doses) 7352 2.86% 1.06 (0.92 to 1.21) would still be at < 10 weeks’ gestation, and recurrent disease Fluconazole (150-mg cumulative dose) 4082 2.62% 0.99 (0.82 to 1.20) could prompt suppressive therapy with oral fluconazole. Fluconazole (300-mg cumulative dose)

2252

3.15%

1.15 (0.91 to 1.46)

Fluconazole (350- to 6000-mg cumulative dose)

1018

3.14%

1.12 (0.79 to 1.59)

Itraconazole

687

3.20%

1.25 (0.82 to 1.92)

Ketoconazole

72

2.78%

1.08 (0.26 to 4.41)

*CI defined in Glossary. Analyses adjusted for several maternal variables. †No filled prescription for oral azole antifungal agents during the first trimester of pregnancy.

JC12

© 2014 American College of Physicians

Laura A. Magee, MD, FRCPC, MSc, FACP University of British Columbia Vancouver, British Columbia, Canada References 1. Lopez-Rangel E, Van Allen MI. Birth Defects Res A Clin Mol Teratol. 2005;73:919-23. 2. Tiboni GM, Marotta F, Del Corso A, Giampietro F. Toxicol Lett. 2006;167:8-18. 3. Marotta F, Tiboni GM. Expert Opin Drug Metab Toxicol. 2010;6: 461-82. 21 January 2014 | ACP Journal Club | Volume 160 • Number 2

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ACP Journal Club. Fluconazole use during the first trimester of pregnancy was not associated with most major birth defects.

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