Oral fluconazole in pregnancy associated with miscarriage

1. Compared to women not receiving treatment, a higher proportion of women on oral fluconazole in early pregnancy experienced miscarriage.

2. Miscarriage was higher among women on oral fluconazole even when compared to women on topical anti-fungals.

Evidence Rating Level: 2 (Good)

Study Rundown: Vaginal candidiasis, commonly known as a yeast infection, affects an estimated 10 percent of pregnant women in the United States. Pregnancy is associated with an increased risk of developing a yeast infection due to an increase in circulating sex hormones, like estrogen. First-line treatment for an uncomplicated yeast infection involves topical formulations azole antifungal medication applied intravaginally. However, for complicated or recurrent infections, most recommend oral azole antifungals, specifically fluconazole (Diflucan). Prior safety studies focusing on oral fluconazole during pregnancy have found no link to birth defects. Two small studies assessed risk of miscarriage (or spontaneous abortion) and stillbirth. In this study, researchers used a large administrative database in attempts to better characterize this relationship.

The use of oral fluconazole in pregnancy was associated with an increased risk of miscarriage prior to 22 weeks gestational age compared to unexposed women, a risk persisted when compared to women exposed to topical anti-fungals. Strengths of this study included large sample size but limitations are numerous and notable. Research from this same large administrative database has historically produced biased and incorrect results, however the methods and analysis make every attempt to address these potential limitations, bias and residual confounding may persist. For example, severity of yeast infection and lack of assessment for co-existent infections such as trichomonas or bacterial vaginosis could bias results away from the null. Future studies might employ a randomized trial to address this question.

Click to read the study in JAMA

Relevant Reading: Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy

In-Depth [retrospective cohort]: Women in the Danish Medical Birth Register from 1997-2013 who were treated with oral fluconazole in pregnancy (n = 5382) were compared with up to 4 unexposed controls matched on a number of characteristics (n = 21 506), including maternal age, calendar year, and gestational age at treatment. An additional comparison group of women exposed to topical and intravaginal antifungal medications in pregnancy were also used. The primary outcomes were spontaneous abortion (pregnancy loss 7-22 weeks gestation) and stillbirth (≥ 23 weeks). Hazard ratios were estimated using proportional hazards regression.

In a retrospective study using an administrative database, the proportion of women on oral antifungal medication who experienced miscarriage was higher than the proportion of women on oral antifungal medications who continued in pregnancy (HR: 1.5, 95% CI: 1.23-1.77). When compared to women who used intravaginal and/or topical azoles, exposure to oral fluconazole was also associated with greater risk of miscarriage (HR: 1.62, 95% CI: 1.26-2.07). Oral fluconazole exposure was not associated with loss after 22 completed weeks of pregnancy.

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