Oral Antifungal in Pregnancy Increases Miscarriage Risk

Pregnant women who take the oral antifungal drug fluconazole (Diflucan [Pfizer] and generics) for vaginal candidiasis have a significantly increased risk for miscarriage, say Danish investigators.

Of 3315 women who took oral fluconazole during the 7th through 22nd weeks of gestation, 147 had a spontaneous abortion. In contrast, of 13,246 matched controls (pregnant women with no fluconazole exposure), 563 had spontaneous abortions, a difference that translated into a hazard ratio (HR) of 1.48 (95% confidence interval [CI], 1.23 - 1.77).

There was also a trend toward a higher risk for stillbirths among women who took oral fluconazole compared with unexposed matched controls or unexposed unmatched pregnant women, but these differences were not statistically significant, report Ditte Mølgaard-Nielsen, MSc, and colleagues from the Department of Epidemiology Research at Statens Serum Institut in Copenhagen, Denmark.

"Until more data on the association are available, cautious prescribing of oral fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further," the investigators write in JAMA.

Increased secretion of sex hormones during pregnancy increases the risk for vaginal candidiasis, and it's estimated that 1 in 10 pregnant women in the United States will develop the infection, the authors note. Although the infection is typically treated with topical azole antifungals, oral fluconazole may be prescribed for severe or recurrent infections, despite limited data about the teratogenic potential of this agent.

Danish Data Trove

To see whether oral fluconazole use in pregnancy could be associated with risk for spontaneous abortions and stillbirths, the investigators drew on Denmark's comprehensive nationwide birth, patient data, and pharmaceutical registries to create their cohort. They chose week 7 as the starting point for measuring pregnancy because many spontaneous abortions occurring during very early gestation go unrecognized.

Each woman exposed to fluconazole was matched with up to 4 pregnant women with no fluconazole exposure by using propensity score matching, maternal age in 5-year groups, calendar year of pregnancy, and gestational age at the time of first fluconazole exposure, with controls matched for pregnancies surviving to the same gestational age. The final cohort consisted of 1,405,663 pregnancies.

In addition to the increased risk for spontaneous abortion with oral fluconazole exposure vs matched controls noted before, the investigators saw an increased risk for fluconazole use compared with unexposed unmatched pregnancies (HR, 1.49; 95% CI, 1.27 - 1.75).

Additionally, in sensitivity analyses, the risk for spontaneous abortion was higher in women who used oral fluconazole than in those who used a topical azole (HR, 1.62; 95% CI, 1.26 - 2.07) or the antibiotic pivmecillinam (not approved in the United States).

The study was supported by the Danish Medical Research Council. The authors have disclosed no relevant financial relationships.

JAMA. 2016;315:58-67. Abstract

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