Boston—Vulvovaginal candidiasis, commonly known as thrush, often occurs during pregnancy, and expectant mothers usually are prescribed a short course of topical antifungal agents or one dose of oral fluconazole.

Now, a report in The BMJ suggests that pregnant women who use oral thrush treatment might have a higher risk of delivering a baby with muscle and bone malformations. Brigham and Women’s Hospital–led researchers emphasize, however, that the absolute risk is small and that they did not demonstrate any association between the therapy and heart defects or oral clefts in babies, which had been feared.

The researchers note that topical antifungal treatment is available OTC in many countries, but that patients often opt for oral fluconazole because of the convenience of taking one oral dose.

Researchers sought to examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.

To do that, they focused on a cohort of 1.9 million pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14. Participants included pregnant women enrolled in Medicaid from 3 or more months before the last menstrual period to 1 month after delivery, and their infants enrolled for 3 or more months after birth. During the first trimester, 37,650 (1.9%) pregnancies were exposed to oral fluconazole and 82,090 (4.2%) pregnancies were exposed to topical azoles.

Researchers established use of fluconazole and topical azoles by requiring one or more prescriptions during the first trimester of pregnancy. The study team was looking for increased risk of musculoskeletal malformations, conotruncal malformations, and oral clefts, associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery.

Results indicate the following:
• The risks of musculoskeletal malformations were 52.1 (95% CI, 44.8 to 59.3) per 10,000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10,000 pregnancies exposed to topical azoles.
• The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10,000 pregnancies exposed to fluconazole and topical azoles, respectively.
• The risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively.

The authors calculated the adjusted relative risk after fine stratification of the propensity score at 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, they note, adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.

The risk of musculoskeletal malformations was double in women taking the highest dose in early pregnancy (above 450 mg), but absolute risks were still small (12 incidents per 10,000 exposed pregnancies overall). A 30% increased risk among women who had taken a smaller cumulative dose of 150 mg of oral fluconazole also was identified.

“Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10,000 exposed pregnancies overall,” the researchers conclude.

“Oral fluconazole during the first trimester, especially prolonged treatment at higher than commonly used doses, should be prescribed with caution, and topical azoles should be considered as an alternative treatment,” they add.

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