Antifungal drug during pregnancy tied to miscarriage, birth defects

New findings from a large study of pregnant women in Quebec suggests that use of an oral antifungal treatment for vaginal yeast infections during pregnancy is associated with increased risk of miscarriage, researchers reported today in the Canadian Medical Association Journal.

The findings, from the Quebec Pregnancy Cohort, on ongoing population-based grouping that researchers use to study medication use in pregnant women, show that women who received a single dose of oral fluconazole during early pregnancy had a more than twofold increase in the risk of miscarriage compared with women who were not exposed to the drug.

In addition, exposure to a higher dose (150 milligrams [mg] or higher) of oral fluconazole during the first trimester was associated with an increased risk of having a newborn with a heart defect.

Vaginal yeast infections caused by Candida affect an estimated 10% of women during pregnancy, and topical antifungal creams are recommended as the first-line treatment for these infections. While a single dose of oral fluconazole (150 mg or less ) is also sometimes prescribed for more serious or persistent infections, concerns about potential links to miscarriage and birth defects have arisen in recent years.

In 2016, a Danish study published in the Journal of the American Medical Association (JAMA) reported an increased risk of miscarriage associated with low-dose oral fluconazole exposure compared with no exposure or with topical azole exposure. Case reports have also linked high doses of oral fluconazole taken during pregnancy to skeletal malformations in children.

The US Food and Drug Administration (FDA), which is reviewing the results of the Danish study, advises caution in prescribing oral fluconazole during pregnancy.

Both low, high doses assessed

For the study, researchers with McGill University and the Universite de Montreal conducted three case-control studies using Quebec Pregnancy Cohort data from 1998 through 2015.

From the data, which include all pregnancies covered by the Quebec Prescription Drug Insurance Plan, they were able to identify women who were prescribed oral fluconazole during pregnancy and those who weren't. They were looking to assess the impact of exposure to low-dose (150 mg or less) or high-dose (more than 150 mg) fluconazole during pregnancy on the occurrence of miscarriage, major congenital malformations, and stillbirths.

From 441,949 potentially eligible pregnancies, 320,868 were included in the analysis of miscarriages, 226,599 for congenital malformations, and 7,832 for stillbirths. Of the women who received fluconazole, 69.5% received a common single dose of 150 mg, and the remainder received a dose of more than 150 mg.

Adjusting for potential confounders, the researchers found that exposure to low-dose fluconazole was associated with an increased risk of miscarriage compared with no exposure (adjusted odds ratio [aOR] for 345 women exposed to low-dose treatment, 2.23; 95% confidence interval [CI], 1.96 to 2.54). In the 249 women exposed to high-dose treatment, the associated risk was even greater (aOR, 3.20; 95% CI, 2.73 to 3.75).

When the researchers looked at congenital malformations, they found that low-dose fluconazole exposure was not associated with increased risk of overall congenital malformation. But exposure to high-dose treatment in 13 women during the first trimester was associated with increased risk of cardiac septic closure anomalies (aOR, 1.81; 95% CI, 1.04 to 3.14).

"Any maternal exposure to fluconazole during pregnancy may increase the risk of spontaneous abortion and doses higher than 150 mg during the first trimester may increase the risk of cardiac septal closure anomalies," lead study author Anick Berard, PhD, and her co-authors write.

No association was found between exposure to low- or high-dose oral fluconazole and risk of stillbirth.

Findings need replication

Berard and her colleagues say that while the findings are consistent with the Danish study and with other previous research, including a 2018 study of pregnant women in Norway and Sweden—also in JAMA— that found no association between oral fluconazole and increased risk of stillbirth, they need to be replicated. Limitations include missing information on potential confounders such as smoking, alcohol intake, and use of over-the-counter folic acid.

Writing in an accompanying commentary, Vanessa Paquette, PharmD, of Children's and Women's Health Center of British Columbia, and Chelsea Elmwood, MD, of the University of British Columbia, say the study validates what is already known about the use of oral fluconazole in pregnancy and "re-emphasizes safe prescribing practices in pregnancy, which include confirming the correct diagnosis and then choosing the safest medication with the largest body of data in pregnancy at the lowest appropriate doses."

They conclude that while topical azoles should be the treatment of choice in early pregnancy for vulvovaginal candidiasis, oral fluconazole treatment should not be deterred if it is indicated for women with invasive fungal infections, and a risk-benefit discussion should take place, with treatment risks considered within the context of the health of the mother.

"A healthy mom is required for a healthy baby," they write.

See also:

Feb 19 Can Med Assoc J study

Feb 19 Can Med Assoc J commentary

Jan 5, 2016, JAMA study in Denmark

Jun 12, 2018, JAMA study in Norway and Sweden

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