Oral antifungal drug associated with higher risk of miscarriage

Pregnant women may be at higher risk of miscarriage if they take oral fluconazole to treat vulvovaginal candidiasis (vaginal thrush) infections, the results of a large Danish study published in JAMA
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 suggests.

Previous studies have found no association between oral fluconazole and miscarriage, also known as spontaneous abortion. But as miscarriage is relatively rare, a large number of women need to be included in any analysis to accurately assess a difference in risk.

The researchers had access to data for 1,405,663 pregnancies from the Danish Medical Birth Register and Danish National Patient Register, making it the largest study of its kind. They analysed records for 3,315 women exposed to oral fluconazole during week 7 to 22 of pregnancy and matched them with 13,246 similar women who were not exposed to the drug during this period.

Exposure to fluconazole significantly increased the risk of miscarriage (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.23–1.77). However, overall risk remained low at 4.43% and 4.25%, respectively. The risk of stillbirth (the loss of a pregnancy after week 22) was not increased with exposure to fluconazole.

To account for the possibility that fungal infection increased the risk of miscarriage, the researchers also compared women who used oral fluconazole with women who had thrush but used a topical azole antifungal. Women who had taken fluconazole were still at higher risk of miscarriage compared with the topical treatment group (HR 1.62, 95% CI 1.26–2.07).

“Until more data on the association are available, cautious prescribing of oral fluconazole in pregnancy may be advisable,” say the researchers, led by Ditte Mølgaard-Nielsen of the Statens Serum Institut research centre in Copenhagen.

Pregnant women are more susceptible to vulvovaginal candidiasis due to factors such as altered cell-mediated immunity and raised oestrogen levels, says Chloe Benn, principal pharmacist for women’s and children’s services at the Royal Free London NHS Foundation Trust, who was not involved in the research.

Oral fluconazole is not recommended during pregnancy, particularly in the first 12 weeks because previous research has linked long-term, high-dose fluconazole exposure to craniofacial and skeletal birth defects.

Topical imidazole therapy is recommended for symptomatic cases, for example clotrimazole pessary 100–200mg nightly for at least seven days, says Benn. Low doses of oral fluconazole will be prescribed in difficult-to-treat cases, she explains, adding that oral fluconazole — which is available over the counter in the UK — may be considered more convenient and comfortable by some women. “As is the case with all prescribing in pregnancy, the option with lowest systemic exposure is preferable.”

“This large study adds important information to support women and healthcare professionals making treatment decisions,” Benn concludes, although the researchers note that the results may be confounded by severity of infection.