Fluconazole While Pregnant Increases Risk of Musculoskeletal Malformations

Yanmin Zhu, MS, PhD

New study findings showed pregnant women who took fluconazole orally had a higher risk of giving birth to a baby with muscle and bone malformations.

Using oral fluconazole in the first trimester was not associated with oral clefts or conotruncal malformations but was associated with musculoskeletal malformations.

“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,” Yanmin Zhu, MS, PhD, and study authors said in a statement.

Zhu and the team of Boston-based colleagues used a cohort of pregnancies publicly insured in the US and data from the nationwide Medicaid Analytic eXtract 2000-14. The investigators examined the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester for the treatment of vulvovaginal candidiasis.

The database contained information on a patient’s Medicaid enrollment, demographics, diagnoses, and all procedures at all outpatient and inpatient settings, and dispensed records for outpatient prescription drugs for reimbursement. In the database, a pregnancy cohort was established to study the safety of drug treatment during pregnancy.

The investigators identified pregnant women aged 12-55 years old who were continuously enrolled in Medicaid from >3 months before the last menstrual period to >1 month after delivery. Also included were those with liveborn infants enrolled from birth to >3 months afterward.

Zhu and the team excluded pregnancies with a chromosomal abnormality or exposure to a teratogenic drug during trimester 1. Among diagnoses of oropharyngeal or esophageal candidiasis, women were also excluded if they had an inpatient diagnosis of fungal infection between 90 days before the last menstrual period and the end of the first trimester.

Pregnant women were identified as taking fluconazole if they filled >1 prescription during the first trimester and had no dispensing for other oral antifungal agents between 90 days before the last period and the end of the first trimester. There was an initial reference group of pregnant women who filled >1 prescription for topical azoles during their first trimester and did not dispense for oral antifungal agents during baseline and the first trimester.

The investigators chose topical azoles including butoconazole, clotrimazole, miconazole, terconazole, tioconazole, and nystatin in the primary reference group to reduce the risk of confounding by indication. The second reference included women with no oral antifungal agent prescriptions during baseline and the first trimester. What’s more, the team classified women exposed to fluconazole into 3 dose groups: 150 mg, >150 mg to <450 mg, and >450 mg.

The primary outcomes of the study were musculoskeletal malformations, oral clefts, and conotruncal malformations. Additional measures included subgroups of such malformations and cardiac malformations overall.

Nearly 2 million pregnancies were included in the cohort, or which, 1.9% were exposed to oral fluconazole and 4.2% were exposed to topical azoles during the first trimester. Those in the fluconazole group were more likely to be black, have a vulvovaginal candidiasis diagnosis or other infections, be overweight or obese and have hypertension and diabetes, use other drugs, and use healthcare facilities more often than women with pregnancies not exposed to fluconazole.

Per 10,000 pregnancies exposed to fluconazole, the risk of musculoskeletal malformations was 52.1 (95% CI, 44.8-59.3) versus 3.8 (95% CI, 37.1-38.9) per 10,000 pregnancies not exposed to fluconazole. There was an unadjusted relative risk of 1.37 (95% CI, 1.19-1.58). For pregnancies exposed to topical azoles, the risk was 37.3 (95% CI, 33.1-41.4).

After comparing oral fluconazole to topical azoles, there was an unadjusted relative risk of 1.4 (95% CI, 1.17-1.67). Overall, after adjusting for all confounding variables, compared with topical azoles, the relative risk was the relative risk compared with topical azoles was 1.3 (95% CI, 1.09-1.56) and the risk difference was 12.15 (95% CI, 3.69-20.6) per 10,000 pregnancies.

For conotruncal malformations, the risk was 9.6 (95% CI, 6.4-12.7) per 10,000 pregnancies exposed to fluconazole, 7.5 (95% CI, 7.1-7.9) per 10,000 pregnancies not exposed to fluconazole, and 8.3 (95% CI, 6.3-10.3) per 10,000 pregnancies exposed to topical azoles. The risk of musculoskeletal malformations was 52.1 (95% CI, 44.8-59.3) per 10,000 pregnancies exposed to fluconazole versus 37.3 (95% CI, 33.1-41.4) per 10,000 pregnancies exposed to topical azoles.

Oral clefts risks were 9.3 (95% CI, 6.2-12.4) for those exposed to fluconazole versus 10.6 (95% CI, 8.4-12.8) for topical azoles. After fine stratification, there was an adjusted relative risk of 1.3 (95% CI, 1.09-1.56) for musculoskeletal malformations, 1.04 (95% CI, .7-1.55) for conotruncal malformations, and .91 (95% CI, .61-1.35) for oral clefts.

“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,” Zhu and the investigators concluded.

The study, “Oral fluconazole use in the first trimester and risk of congenital malformations: population-based study cohort,” was published online in The BMJ.