Oral Fluconazole During Pregnancy Increases Risk for Spontaneous Abortion
March 1, 2016 4 minutes read
Approximately 10% of women in the United States develop vaginal candidiasis during pregnancy. Most are treated with intravaginal topical azoles, although oral fluconazole is sometimes prescribed for severe or recurrent symptoms. Previous studies suggested that high-dose fluconazole may lead to birth defects. Therefore, investigators in Denmark sought to determine whether fluconazole use in pregnancy is associated with spontaneous abortion and stillbirth.
The study used national health registries to identify all pregnancies that ended with a singleton live birth, stillbirth, spontaneous abortion, and other abortive outcomes in Denmark between January 1997 and December 2013. Prescription data for oral fluconazole was also obtained from a national prescription register. Dosing was divided into two categories: 150 mg to 300 mg and 350 mg to 5600 mg. The lower doses were based on the standard treatment for vaginal candidiasis, and the higher doses were for more complicated fungal infections such as recurrent vaginal candidiasis. Each fluconazole-exposed pregnancy was matched to up to four non-exposed control pregnancies to avoid potential confounding. Spontaneous abortion was defined as pregnancy loss from 7 through 22 gestational weeks, and stillbirth was defined as pregnancy loss from 23 weeks. Itraconazole exposure during pregnancy was also investigated to determine a class effect for the azoles.
More than 1.4 million pregnancies were included in the cohort. A total of 147 out of 3315 women exposed to oral fluconazole during weeks 7 through 22 of gestation experienced a spontaneous abortion compared to 563 of the 13,246 unexposed matched women. Fluconazole exposure was associated with a significantly increased risk of spontaneous abortion (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.23-1.77). Twenty-one stillbirths occurred in the 5382 pregnancies exposed to fluconazole from week 7 through birth compared to 77 in the 21,506 unexposed matched women. The risk for stillbirth was increased in the fluconazole-exposed women (HR, 1.32; 95% CI, 0.82-2.14) but did not reach statistical significance. Regarding higher-dose vs lower-dose fluconazole, the differences between the HRs of 1.55 (95% CI, 0.94-2.58) and 1.47 (95% CI, 1.22-1.77), respectfully, did not reach statistical significance for spontaneous abortion (P = 0.84). However, the HRs for stillbirth were different between low dose (0.99; 95% CI, 0.56-1.74) and high dose (4.10; 95% CI, 1.89-8.90), which was statistically significant (P = 0.002). Compared to topical azole-exposed pregnancies, there was a significantly increased risk of spontaneous abortion in the oral fluconazole-associated pregnancies (HR, 1.62; 95% CI, 1.26-2.07). Finally, seven of 131 women exposed to itraconazole during pregnancy experienced spontaneous abortions, compared to 34 of 524 matched controls (HR, 1.16; 95% CI, 0.51-2.60).
COMMENTARY
The Infectious Diseases Society of America (IDSA) guidelines on the management of candidiasis state, “Fluconazole, itraconazole, posaconazole, and isavuconazole should be avoided in pregnant women, especially those in the first trimester, because of the possibility of birth defects associated with their use.”1 The study by Molgaard-Nielsen and colleagues lends further support to this recommendation. While miscarriages are often stochastic events, the finding that oral fluconazole significantly increased the risk of spontaneous abortion should make clinicians carefully reflect on the pros and cons of this drug during pregnancy. As the authors note, one possible mechanism of action for the adverse association is that fluconazole can interfere with human CYP450 enzymes, which are expressed during in utero development. Another interesting finding of the study is that higher doses of fluconazole were associated with more stillbirths but not spontaneous abortions. The explanation for this is unclear and could be an undetermined biological mechanism or perhaps statistical imprecision. No clear determination could be made from the data about a class effect of the azoles on pregnancy outcomes, which was not surprising given the small number of pregnancies exposed to itraconazole. Although a larger study might provide an answer to this question, it seems unethical for such an investigation to be conducted given the known risks to the developing fetus. However, a retrospective analysis could be feasible.
Although this was a large cohort, the retrospective design raises the possibility of biases and confounding factors that may have impacted the results. For example, if fluconazole-exposed women sought medical attention for spontaneous abortions more often than the women who were not exposed, this would bias the results toward an increased risk with fluconazole exposure.
Until further safety data emerge, it seems reasonable for clinicians to be very cautious in prescribing oral fluconazole during pregnancy. Topical intravaginal azoles should remain first-line therapy for vaginal candidiasis. For recurrent or refractory cases, longer courses, i.e., 14 days, may be effective; topical nystatin is another option.
REFERENCE
- Pappas PG, et al. Clinical Practice Guidelines for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:e1-e50.
A nationwide cohort study from Denmark found a significantly increased risk of spontaneous abortion associated with oral fluconazole usage. Caution with this medication during pregnancy is advised.
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