The overall risk of birth defects was not increased among infants whose mothers took oral fluconazole during the first trimester of pregnancy, in a large registry study that provides "largely reassuring" results regarding the teratogenicity of this drug, according to the authors.
In the study that included data on more than 7,000 pregnancies exposed to fluconazole in Denmark, fluconazole (largely at the most commonly prescribed 150-mg or 300-mg single doses) was also not associated with an increased risk of 14 of the 15 specific birth defects that have been associated with azole antifungal drugs in human or animal studies. But the risk of tetralogy of Fallot was increased by about threefold, an association that needs to be studied further, concluded Ditte Mølgaard-Nielsen and her associates in the department of epidemiology research, Statens Serum Institut, Copenhagen.
Dr. Ditte Molgaard-Nielsen
The risk of birth defects also was not increased among the smaller number of pregnancies with first-trimester exposure to two other oral azole antifungals, ketoconazole and itraconazole. The study is being published in the Aug. 29 issue of the New England Journal of Medicine (2013;369:830-9).
Most previous studies of the teratogenicity of fluconazole have involved case reports and have suggested that long-term use of fluconazole at high doses may be associated with an increased risk of certain birth defects – the basis of a Food and Drug Administration safety communication in 2011. But while a few epidemiologic studies of oral fluconazole, mostly at the 150-mg dose, have not found an association with birth defects, the studies were not large enough to investigate the risk with different doses or the risk of certain defects, the authors said.
In August 2011, the FDA described the possible association of oral fluconazole, at doses of 400-800 mg/day during the first trimester, and an increased risk of a rare but "distinct set of birth defects," based on case reports. The defects included brachycephaly, abnormal facies, abnormal calvarial development, cleft palate, femoral bowing, thin ribs and long bones, arthrogryposis, and congenital heart disease, which were also seen in animals. As a result, the FDA changed the pregnancy risk category of fluconazole from category C (adverse effects seen in animals but no adequate human data) to D (evidence of human fetal risk based on human data but the potential benefits may justify use in pregnant women with serious or life-threatening conditions) for all indications, except for the 150-mg single dose used for vaginal candidiasis. Because the available human data on that dose do not indicate there is an association with an increased risk of birth defects, the 150-mg dose used for vaginal candidiasis remained in category C.
The Danish study used data on all live-born infants in Denmark between January 1996 and March 2011 from the national birth registry, prescription data from the national prescription registry, and information on birth defects from a national patient registry. The most common cumulative doses of fluconazole were 150 mg (56%) and 300 mg (31%); the remaining percentage of patients were exposed to cumulative doses from 350 mg to 6,000 mg.
Among the 7,352 pregnancies exposed to fluconazole in the first trimester, there were 210 birth defects (2.86%), compared with 25,159 birth defects (2.6%) among 968,236 unexposed pregnancies.
When the investigators looked at 15 different birth defects that have been linked to in utero exposure to fluconazole and other azole antifungal agents, the risk was not significantly increased for defects that included craniosynostosis, cleft palate, cleft lip with or without cleft palate, limb defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects overall, or ventricular septal defects.
However, there were 7 cases of tetralogy of Fallot (0.1%) among pregnancies exposed to fluconazole, compared with 287 cases (0.03%) among those not exposed – a threefold increased risk that was statistically significant. The cases were found in infants exposed to all three cumulative dose categories: four (0.10%) exposed to 150 mg, two (0.09%) exposed to 300 mg, and one (0.10%) exposed to the 350- to 6,000-mg dose range.
Although the increased risk of tetralogy of Fallot could be a chance finding, this was among the birth defects previously associated with exposure to fluconazole, which made the finding more reliable than if this had been the first time the association with this particular birth defect had been reported, the authors noted.
Among 687 pregnancies exposed to itraconazole and 72 pregnancies exposed to ketoconazole in the registry, there was no significantly increased risk of birth defects overall, or any clustering of malformations.
"Our finding that a 150-mg dose of fluconazole was not associated with an increased risk of birth defects overall confirms the results of previous studies; our study also adds to these safety data by reporting risk estimates for doses higher than 150 mg," the authors wrote. "Although fluconazole may confer an increased risk of tetralogy of Fallot, the absolute risk was small and the association needs to be confirmed," they added.