In the Journals

Any exposure to fluconazole during pregnancy increases risk for spontaneous abortions

Any maternal exposure to fluconazole during pregnancy — whether in low or high doses — may increase the risk for spontaneous abortion, and high-dose fluconazole during the first trimester may increase the risk for cardiac septal closure anomalies, researchers reported recently in the Canadian Medical Association Journal.

In 2011, the FDA issued a safety warning for fluconazole in pregnant women, stating that high doses of the antifungal taken in the first trimester may be associated with “a rare and distinct set of birth defects,” although the risk did not appear to be associated with low doses used to treat vaginal yeast infections, the agency said at the time.

The Infectious Diseases Society of America published revised guidelines in 2015 on the treatment and management of invasive Candida infection, including the recommendation that several treatments, including fluconazole, “be avoided in pregnant women, especially those in the first trimester, because of the possibility of birth defects associated with their use.” And in 2016, after a Danish study showed an association between the drug and the risk for miscarriages, the FDA said it would review the safety of oral fluconazole in pregnant women.

“Treatment with high-dose fluconazole in pregnancy has been linked to a distinct pattern of craniofacial, skeletal and heart defects. Animal studies have confirmed the teratogenicity of fluconazole at high doses,” Anick Bérard, PhD, pharmacy professor at the University of Montreal and a researcher at the CHU Sainte-Justine Research Center, and colleagues wrote in the CMAJ study.

“Specifically, use of high-dose fluconazole during pregnancy has been linked to a pattern of major congenital malformations resembling the Antley-Bixler syndrome, a genetic disorder associated with reduced activity of [the fungal cytochrome P451 enzyme] owing to genetic mutations. As such, use of high-dose fluconazole during pregnancy is contraindicated.”

However, “low-dose fluconazole is frequently used in pregnancy, given that vulvovaginal candidiasis in pregnancy may be more severe and treatment resistant,” they wrote.

Bérard and colleagues conducted three case-control studies within the Quebec Pregnancy Cohort to examine the effect of exposure to low- (150 mg or less) and high-dose (more than 150 mg) fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. They identified women exposed to low- and high-dose fluconazole and matched each case of spontaneous abortion or stillbirth with up to five controls, according to the study. All liveborn babies were considered as controls for cases of congenital malformation.

In total, 320,868 pregnancies were included in the analysis of spontaneous abortions, 226,599 in the analysis of major congenital malformations and 7,832 in the analysis of stillbirths, Bérard and colleagues reported. According to the study, 69.5% of women exposed to fluconazole during pregnancy received low-dose fluconazole and the remainder of women received a dose more than 150 mg.

Results of the study showed that use of oral fluconazole during early pregnancy was associated with an increased risk for spontaneous abortion in both low (n=345; adjusted OR = 2.23; 95% CI, 1.96–2.54) and high (n=245; adjusted OR = 3.20; 95% CI 2.73–3.75) doses when compared with no exposure.

Additionally, “Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR = 1.81, 95% CI 1.04–3.14; 13 exposed cases) compared with no exposure,” Bérard and colleagues wrote. “No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth.”

In a related commentary, Vanessa Cristine Paquette, PharmD, and Chelsea Elwood, MD, of the British Columbia Women's Hospital and Health Centre, said the study “validates what is already known about the use of oral fluconazole in pregnancy: it may be associated with spontaneous abortion but not stillbirth. The study re­emphasizes 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.” – by Caitlyn Stulpin

Disclosures: Bérard reports receiving grants from the Canadian Institutes of Health Research (the Canadian Network for Advanced Interdisciplinary Methods for comparative effectiveness research), the Quebec Health Research Fund and the Quebec Network for Drug Research. Paquette and Elwood report no relevant financial disclosures.

Any maternal exposure to fluconazole during pregnancy — whether in low or high doses — may increase the risk for spontaneous abortion, and high-dose fluconazole during the first trimester may increase the risk for cardiac septal closure anomalies, researchers reported recently in the Canadian Medical Association Journal.

In 2011, the FDA issued a safety warning for fluconazole in pregnant women, stating that high doses of the antifungal taken in the first trimester may be associated with “a rare and distinct set of birth defects,” although the risk did not appear to be associated with low doses used to treat vaginal yeast infections, the agency said at the time.

The Infectious Diseases Society of America published revised guidelines in 2015 on the treatment and management of invasive Candida infection, including the recommendation that several treatments, including fluconazole, “be avoided in pregnant women, especially those in the first trimester, because of the possibility of birth defects associated with their use.” And in 2016, after a Danish study showed an association between the drug and the risk for miscarriages, the FDA said it would review the safety of oral fluconazole in pregnant women.

“Treatment with high-dose fluconazole in pregnancy has been linked to a distinct pattern of craniofacial, skeletal and heart defects. Animal studies have confirmed the teratogenicity of fluconazole at high doses,” Anick Bérard, PhD, pharmacy professor at the University of Montreal and a researcher at the CHU Sainte-Justine Research Center, and colleagues wrote in the CMAJ study.

“Specifically, use of high-dose fluconazole during pregnancy has been linked to a pattern of major congenital malformations resembling the Antley-Bixler syndrome, a genetic disorder associated with reduced activity of [the fungal cytochrome P451 enzyme] owing to genetic mutations. As such, use of high-dose fluconazole during pregnancy is contraindicated.”

However, “low-dose fluconazole is frequently used in pregnancy, given that vulvovaginal candidiasis in pregnancy may be more severe and treatment resistant,” they wrote.

Bérard and colleagues conducted three case-control studies within the Quebec Pregnancy Cohort to examine the effect of exposure to low- (150 mg or less) and high-dose (more than 150 mg) fluconazole during pregnancy on the occurrence of spontaneous abortions, major congenital malformations and stillbirths. They identified women exposed to low- and high-dose fluconazole and matched each case of spontaneous abortion or stillbirth with up to five controls, according to the study. All liveborn babies were considered as controls for cases of congenital malformation.

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In total, 320,868 pregnancies were included in the analysis of spontaneous abortions, 226,599 in the analysis of major congenital malformations and 7,832 in the analysis of stillbirths, Bérard and colleagues reported. According to the study, 69.5% of women exposed to fluconazole during pregnancy received low-dose fluconazole and the remainder of women received a dose more than 150 mg.

Results of the study showed that use of oral fluconazole during early pregnancy was associated with an increased risk for spontaneous abortion in both low (n=345; adjusted OR = 2.23; 95% CI, 1.96–2.54) and high (n=245; adjusted OR = 3.20; 95% CI 2.73–3.75) doses when compared with no exposure.

Additionally, “Exposure to fluconazole during the first trimester did not increase the risk of overall major congenital malformations; however, exposure to a high dose during the first trimester was associated with an increased risk of cardiac septal closure anomalies (adjusted OR = 1.81, 95% CI 1.04–3.14; 13 exposed cases) compared with no exposure,” Bérard and colleagues wrote. “No association was found between exposure to fluconazole during pregnancy and the risk of stillbirth.”

In a related commentary, Vanessa Cristine Paquette, PharmD, and Chelsea Elwood, MD, of the British Columbia Women's Hospital and Health Centre, said the study “validates what is already known about the use of oral fluconazole in pregnancy: it may be associated with spontaneous abortion but not stillbirth. The study re­emphasizes 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.” – by Caitlyn Stulpin

Disclosures: Bérard reports receiving grants from the Canadian Institutes of Health Research (the Canadian Network for Advanced Interdisciplinary Methods for comparative effectiveness research), the Quebec Health Research Fund and the Quebec Network for Drug Research. Paquette and Elwood report no relevant financial disclosures.