Fluconazole Linked to Increased Risk for Rare Birth Defect

Jenni Laidman

August 28, 2013

An examination of nearly 1 million birth records revealed a 3-fold increased risk for tetralogy of Fallot among infants whose mothers took fluconazole in the first trimester, according to a study published in the August 29 issue of the New England Journal of Medicine.

The study showed no association between the antifungal and 14 other birth defects previously linked to it. However, Ditte Mølgaard-Nielsen, MSc, from the Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark, and colleagues showed that common therapeutic doses of fluconazole in the first trimester resulted in an adjusted odds ratio of 3.16 (95% confidence interval [CI], 1.49 - 6.71) for tetralogy of Fallot. The absolute risk for tetralogy of Fallot remains small, with an estimated 6.5 excess cases per 10,000 infants exposed to the antifungal (95% CI, 1.5 - 17), the authors report.

The odds ratio was adjusted for calendar year, demographic characteristics, socioeconomic variables, smoking status, previous births with malformation, selected coexisting conditions, and treatment with oral antibiotics, immunosuppressive agents, oral corticosteroids, antiepileptic agents, oral contraceptives, or in vitro fertilization drugs.

The study authors looked at the incidence of 15 specific birth defects in 976,300 live births recorded in the Medical Birth Registry in Denmark between January 1, 1996, and March 31, 2011. The study compared prevalence of birth defects among infants exposed prenatally to commonly prescribed doses of fluconazole with the prevalence of birth defects among children who were not exposed.

The authors found no association between oral fluconazole and 14 of 15 birth defects at doses of 150 mg (56% of mothers exposed to fluconazole) and 300 mg (31%). The 14 birth defects were 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.

There were 210 total birth defects reported in 7352 fluconazole-exposed pregnancies (prevalence, 2.86%) compared with 25,159 birth defects among 968,236 unexposed pregnancies (prevalence, 2.60%). The difference in birth defects among the 2 groups did reach significance. Calculating the risk for birth defects at 3 fluconazole dose levels (150, 300, and 350 to 6000 mg) did not change the result.

In a secondary analysis, the authors found no significantly increased risk for birth defects overall among mothers exposed to 2 other azole fungicides: itraconazole (687 pregnancies) and ketoconazole (72 pregnancies).

"The findings from this study are therefore largely reassuring. However, the risk of tetralogy of Fallot was three times as high after fluconazole exposure, and this increased risk was found in all analyses," the authors write.

Previous studies on fluconazole looked at birth defects overall, mostly among women exposed to a single 150-mg dose of the antifungal, for a total of 1650 exposed pregnancies compared with the 7352 exposed pregnancies in this study, the authors note.

The authors have disclosed no relevant financial relationships.

N Engl J Med. 2013;369:830-839.

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