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Original Investigation |

Association Between Use of Oral Fluconazole During Pregnancy and Risk of Spontaneous Abortion and Stillbirth

Ditte Mølgaard-Nielsen, MSc1; Henrik Svanström, PhD1; Mads Melbye, MD, DrMedSci1; Anders Hviid, MSc, DrMedSci1; Björn Pasternak, MD, PhD1
[+] Author Affiliations
1Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark
JAMA. 2016;315(1):58-67. doi:10.1001/jama.2015.17844.
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Importance  Vaginal 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.

Objective  To study the association between oral fluconazole exposure during pregnancy and the risk of spontaneous abortion and stillbirth.

Design, Setting, and Participants  Nationwide 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.

Exposures  Filled prescriptions for oral fluconazole were obtained from the National Prescription Register.

Main Outcomes and Measures  Hazard ratios (HRs) for spontaneous abortion and stillbirth, estimated using proportional hazards regression.

Results  Among 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 Relevance  In 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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Figure 1.
Numbers of Pregnancies Included in the Study Cohort and in the Analyses

aMatching 1:4 on gestational age, calendar year, and propensity score.

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Figure 2.
Sensitivity Analyses of the Association Between Fluconazole-Exposed Pregnancies and the Risk of Spontaneous Abortion and Stillbirth Using Matched Control Pregnancies Exposed to Anti-infective Agents
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