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Spontaneous abortion linked to oral fluconazole

May 06 2016

Oral fluconazole is used in severe or recurrent cases of vaginal candidiasis during pregnancy, despite concern regarding its safety.  Previous data has demonstrated an association between fluconazole exposure and heart defects (see LIFE news item) and case reports have linked long-term, high-dose treatment to a distinct pattern of craniofacial and skeletal birth defects (e.g. Lopez-Rangel & Van Allen, 2005). Though two previous studies have shown no increased risk of spontaneous abortion or still births with oral fluconazole, small sample sizes indicate a lack of power to detect even a moderate increase in risk. From a cohort of nearly 1.5 million pregnancies, the group from the Staten Serum Institute in Copenhagen, led by Ditte Molgaard-Neilsen therefore investigated the relationship between exposure to oral fluconazole, and risk of spontaneous abortion and still births.

A total of 3315 pregnancies exposed to oral fluconazole between weeks 7 and 22 were compared with 13 246 unexposed pregnancies.  A significant increase in risk of spontaneous abortion was found with fluconazole exposure (HR, 1.48; 95% CI, 1.23-1.77). 5382 pregnancies exposed to oral fluconazole between weeks 7 to birth were compared with 21506 unexposed pregnancies. No significant increase in risk of still birth was found (HR, 1.32; 95% CI, 0.82-2.14]). Topical azole or nystatin therapy is often used in pregnancy and this conferred no risk of spontaneous abortion compared with fluconazole-exposed pregnancies.

Women on higher doses of fluconazole (350-5600 mg) showed no further increased risk of spontaneous abortion, though risk of still birth was significantly elevated. However, the high dose category was heterogeneous with only a few cases in the exposure group (n=15, n=7 for spontaneous abortion and still birth respectively).

It is possible that the results are confounded by severity of vaginal candidiasis, as oral fluconazole is more often used in these cases. In addition, bias may occur if pregnancies are recognised earlier in fluconazole-exposed women, compared to unexposed women – as the risk of spontaneous abortion is higher in early pregnancy and early spontaneous abortion may be mistaken for late menstrual period if pregnancy is not suspected. Despite these potential confounders, the authors believe it likely that oral fluconazole does indeed increase the risk of spontaneous abortion, compared with unexposed women and women with topical azole exposure. The authors advise caution when prescribing oral fluconazole in pregnancy. 


Lopez-Rangel & Van Allen, 2005

Original article