• Ditte Mølgaard-Nielsen, Henrik Svanström, Mads Melbye, Anders Hviid, and Björn Pasternak.
• Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark.
• JAMA. 2016 Jan 5; 315 (1): 58-67.

ImportanceVaginal candidiasis is common during pregnancy. Although intravaginal formulations of topical azole antifungals are first-line treatment for pregnant women, oral fluconazole is often used despite limited safety information.ObjectiveTo study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth.Design, Setting, And ParticipantsNationwide register-based cohort study in Denmark, 1997-2013. From a cohort of 1,405,663 pregnancies, oral fluconazole-exposed pregnancies were compared with up to 4 unexposed pregnancies matched on propensity score, maternal age, calendar year, and gestational age (based on gestational age at first day of treatment with eligible controls surviving through this date). To test for confounding by indication, pregnancies exposed to intravaginal formulations of topical azoles were used as an additional comparator group.ExposuresFilled prescriptions for oral fluconazole were obtained from the National Prescription Register.Main Outcomes And MeasuresHazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression.ResultsAmong 3315 women exposed to oral fluconazole from 7 through 22 weeks' gestation, 147 experienced a spontaneous abortion, compared with 563 among 13,246 unexposed matched women. There was a significantly increased risk of spontaneous abortion associated with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). Among 5382 women exposed to fluconazole from gestational week 7 to birth, 21 experienced a stillbirth, compared with 77 among 21,506 unexposed matched women. There was no significant association between fluconazole exposure and stillbirth (HR, 1.32 [95% CI, 0.82-2.14]). Using topical azole exposure as the comparison, 130 of 2823 women exposed to fluconazole vs 118 of 2823 exposed to topical azoles had a spontaneous abortion (HR, 1.62 [95% CI, 1.26-2.07]); 20 of 4301 women exposed to fluconazole vs 22 of 4301 exposed to topical azoles had a stillbirth (HR, 1.18 [95% CI, 0.64-2.16]).Conclusions And RelevanceIn this nationwide cohort study in Denmark, use of oral fluconazole in pregnancy was associated with a statistically significant increased risk of spontaneous abortion compared with risk among unexposed women and women with topical azole exposure in pregnancy. Until more data on the association are available, cautious prescribing of fluconazole in pregnancy may be advisable. Although the risk of stillbirth was not significantly increased, this outcome should be investigated further.

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