Oral fluconazole use in first trimester ups risks of musculoskeletal malformations

Use of oral fluconazole in the first trimester does not lead to oral clefts or conotruncal malformations but is associated with musculoskeletal malformations, a study has shown.

“Our study confirmed an increase in the risk of musculoskeletal malformations if fluconazole is used during the first trimester, and refuted large increased risks of conotruncal malformations, oral clefts, and other specific types of malformations,” the researchers said.

This population-based cohort study analysed a cohort of pregnancies publicly insured in the US, with data from the nationwide Medicaid Analytic eXtract 2000–2014. Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy. The researchers then examined the risk of musculoskeletal malformations, conotruncal malformations, and oral clefts associated with oral fluconazole exposure, diagnosed during the first 90 days after delivery.

Of the 1,969,954 pregnancies identified, 37,650 (1.9 percent) were exposed to oral fluconazole and 82,090 (4.2 percent) to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95 percent confident interval [CI], 44.8–59.3) per 10,000 pregnancies exposed to fluconazole compared with 37.3 (95 percent CI, 33.1–41.4) per 10,000 pregnancies exposed to topical azoles. [BMJ 2020;369:m1494]

For conotruncal malformations, the risks were 9.6 (95 percent CI, 6.4–12.7) per 10,000 pregnancies exposed to fluconazole compared with 8.3 (95 percent CI, 6.3–10.3) per 10,000 pregnancies exposed to topical azoles. Risks for oral clefts were 9.3 (95 percent CI, 6.2–12.4) vs 10.6 (95 percent CI, 8.4–12.8) per 10,000 pregnancies, respectively.

The adjusted relative risk following fine stratification of the propensity scores was 1.30 (95 percent CI, 1.09–1.56) for musculoskeletal malformations, 1.04 (95 percent CI, 0.70–1.55) for conotruncal malformations, and 0.91 (95 percent CI, 0.61–1.35) for oral clefts overall.

The corresponding adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts based on cumulative doses of fluconazole were 1.29 (95 percent CI, 1.05–1.58), 1.12 (95 percent CI, 0.71–1.77), and 0.88 (95 percent CI, 0.55–1.40) for  fluconazole 150 mg; 1.24 (95 percent CI, 0.93–1.66), 0.61 (95 percent CI, 0.26–1.39), and 1.08 (95 percent CI, 0.58–2.04) for fluconazole >150–450 mg; and 1.98 (95 percent CI, 1.23–3.17), 2.30 (95 percent CI, 0.93–5.65), and 0.94 (95 percent CI, 0.23–3.82) for fluconazole >450 mg.

“The increased risk of musculoskeletal malformations … associated with exposure to fluconazole at common therapeutic doses during the first trimester aligns with the patterns of malformations reported in previous case reports at high doses,” the researchers said. [Pediatr Infect Dis J 1992;11:1062-1064; Clin Infect Dis 1996;22:336-240; Am J Med Genet 1997;72:253-256]

“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 noted.

A first-line treatment for vulvovaginal candidiasis, oral fluconazole is commonly used in women of reproductive age, leading to prenatal exposure. [Curr Infect Dis Rep 2015;17:462; Clin Infect Dis 2016;62:e1-50; Can Fam Physician 2009;55:255-256]