In an analysis of Danish health-registry data, the use of oral fluconazole during pregnancy was not associated with an increased risk of birth defects overall or of 14 of 15 birth defects of concern. The absolute risk of tetralogy of Fallot was about 7 cases per 100,000 births.
Assessment of any teratogenic potential of oral azole antifungal agents is important, because pregnant women are at increased risk for vaginal candidiasis, which is the most common clinical indication for these drugs. Although vaginal preparations of topical azole antifungal agents are first-line treatment for vaginal candidiasis during pregnancy, treatment with oral azole antifungal agents is used in cases of recurrence or when topical treatment has failed.
• What led the FDA to change the pregnancy category for fluconazole?
Oral fluconazole treatment has been linked to a distinct pattern of birth defects in five infants of mothers who were treated for severe fungal infections with 400 to 800 mg daily during most or all of the first trimester of pregnancy. Similar defects have been observed in animals exposed to systemic azole antifungal agents. In 2011, the U.S. Food and Drug Administration (FDA) issued a drug-safety announcement concerning the possible teratogenic risks conferred by long-term, high-dose fluconazole treatment. The FDA pregnancy category for fluconazole was consequently changed from C to D, with the exception of the use of fluconazole, at a single dose of 150 mg, for the treatment of vaginal candidiasis. However, concern has been raised about whether common therapeutic doses of oral fluconazole used for frequent fungal infections of the skin or mucous membranes may similarly increase the risk of certain specific defects.
• What were the results of this study with respect to first-trimester fluconazole exposure and overall incidence of birth defects?
No significantly increased risk of birth defects overall was observed among 7352 pregnancies exposed to any fluconazole, as compared with 968,236 unexposed pregnancies (adjusted prevalence odds ratio, 1.06; 95% CI, 0.92 to 1.21); evaluating exposure according to cumulative doses of 150, 300, and 350 to 6000 mg did not change this result.
Morning Report Questions
Q: In the analysis of individual birth defects, which one was significantly increased in the setting of first- trimester fluconazole exposure?
A: In the analysis of 15 birth defects previously linked to azole antifungal agents, the authors found no significantly increased risk of craniosynostosis, cleft palate, cleft lip with or without cleft palate, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, or ventricular septal defects associated with any dose of fluconazole. There were no cases of other craniofacial defects, middle-ear defects, or pulmonary-artery hypoplasia among fluconazole-exposed pregnancies, which is consistent with an absence of increased risk, but the authors were not able to estimate prevalence odds ratios. The adjusted prevalence odds ratio for hypoplastic left heart was 2.03, but it was based on three exposed cases and was nonsignificant. The risk of tetralogy of Fallot was significantly increased, by a factor of three, and was based on seven exposed cases.
Q: What were the results of the analysis of pregnancies exposed to itraconazole or ketoconazole during the first trimester?
A: No significantly increased risk of birth defects overall was observed among the 687 and 72 pregnancies exposed to itraconazole and ketoconazole, respectively, and no apparent clustering of malformations was observed.