Use of oral fluconazole during pregnancy and the risk of birth defects.

BACKGROUND Case reports suggest that long-term, high-dose fluconazole treatment for severe fungal infections during pregnancy causes a pattern of birth defects. It is unclear whether commonly used lower doses increase the risk of specific birth defects. METHODS In a registry-based cohort of liveborn infants in Denmark, we evaluated first-trimester oral fluconazole exposure and the risk of birth defects overall and of birth defects previously linked to azole antifungal agents. RESULTS The majority of fluconazole-exposed pregnancies were in women who received common therapeutic doses of 150 mg (56% of pregnancies) or 300 mg (31%). Oral fluconazole exposure was not associated with an increased risk of birth defects overall (210 birth defects among 7352 fluconazole-exposed pregnancies [prevalence, 2.86%] and 25,159 birth defects among 968,236 unexposed pregnancies [prevalence, 2.60%]; adjusted prevalence odds ratio, 1.06; 95% confidence interval [CI], 0.92 to 1.21). In addition, oral fluconazole exposure was not associated with a significantly increased risk of 14 of 15 types of birth defects previously linked to azole antifungal agents: craniosynostosis, other craniofacial defects, middle-ear defects, cleft palate, cleft lip, limb defects, limb-reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, pulmonary-artery hypoplasia, ventricular septal defects, and hypoplastic left heart. A significantly increased risk of tetralogy of Fallot was observed (7 cases in fluconazole-exposed pregnancies [prevalence, 0.10%] as compared with 287 cases in unexposed pregnancies [prevalence, 0.03%]; adjusted prevalence odds ratio, 3.16; 95% CI, 1.49 to 6.71). CONCLUSIONS Oral fluconazole was not associated with a significantly increased risk of birth defects overall or of 14 of the 15 specific birth defects of previous concern. Fluconazole exposure may confer an increased risk of tetralogy of Fallot. (Funded by the Danish Medical Research Council.).