BACKGROUND AND PURPOSE:

• Fluconazole is commonly used to treat vulvovaginal candidiasis
  • FDA cautions against use in pregnancy due to concern regarding birth defects and potential risk for stillbirth or miscarriage
• Teratogenicity studies on the use of fluconazole in humans have been inconsistent
• Zhu et al. (BMJ, 2020) assessed the risk of congenital malformations associated with exposure to commonly used doses of oral fluconazole in the first trimester of pregnancy

METHODS:

• Population based cohort study
• Data source
  • The US nationwide Medicaid Analytic eXtract (MAX) 2000 to 2014 (most current data at time of this study)
• Participants
  • Pregnant women ages 12 to 55
  • Enrolled in Medicaid from ≥3 months before the DLMP until 1 month after delivery
  • Infants enrolled for three or more months after birth
• Interventions
  • Use of fluconazole or topical azoles: ≥1 prescriptions during the first trimester of pregnancy
  • Topical azoles (e.g. butoconazole, clotrimazole, miconazole, terconazole, tioconazole, and nystatin) used as primary reference group to minimize confounding based on indication
• Diagnoses made during the first 90 days post delivery
• Primary outcome
  • Risks for the following birth defects associated with fluconazole exposure
    • Musculoskeletal malformations
    • Conotruncal malformations
    • Oral clefts

RESULTS:

• 1,969,954 pregnancies included
  • Exposed to oral fluconazole during first trimester: 1.9%
  • Exposed to topical azoles: 4.2%

Absolute Risks with Fluconazole Versus Topical Azoles

• Musculoskeletal malformations
  • 52.1 (95% CI, 44.8 to 59.3) vs 37.3 (95% CI, 33.1 to 41.4) per 10,000 pregnancies
• Conotruncal malformations
  • 9.6 (95% CI, 6.4 to 12.7) vs 8.3 (95% CI, 6.3 to 10.3) per 10,000 pregnancies
• Oral clefts
  • 9.3 (95% CI, 6.2 to 12.4) versus 10.6 (95% CI, 8.4 to 12.8) per 10,000 pregnancies

Adjusted Relative Risks

• Musculoskeletal malformations: 1.30 (95% CI, 1.09 to 1.56)
• Conotruncal malformations: 1.04 (95% CI, 0.70 to 1.55)
• Oral clefts: 0.91 (95% CI, 0.61 to 1.35)

Adjusted Relative Risks Based on Cumulative Doses of Fluconazole

• 150 mg
  • Musculoskeletal malformations: 1.29 (95% CI,1.05 to 1.58)
  • Conotruncal malformations: 1.12 (95% CI, 0.71 to 1.77)
  • Oral clefts: 0.88 (95% CI, 0.55 to 1.40)
• 150 mg to 450 mg
  • Musculoskeletal malformations: 1.24 (95% CI, 0.93 to 1.66)
  • Conotruncal malformations: 0.61 (95% CI, 0.26 to 1.39)
  • Oral clefts: 1.08 (95% CI, 0.58 to 2.04)
• >450 mg
  • Musculoskeletal malformations: 1.98 (95% CI, 1.23 to 3.17)
  • Conotruncal malformations: 2.30 (95% CI, 0.93 to 5.65)
  • Oral clefts: and 0.94 (95% CI, 0.23 to 3.82)

CONCLUSION:

• Use of oral fluconazole during the first trimester was not associated with oral clefts or conotruncal malformations but was associated with an increased risk for musculoskeletal malformations

Learn More – Primary Sources:

Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study

Related ObG Topics:

Diagnosis and Treatment of Vulvovaginal Candidiasis

Oral Fluconazole Exposure in Pregnancy and Associated Risks for Adverse Events

Oral Fluconazole in First Trimester and Adverse Outcomes

Is Oral Fluconazole Use in Pregnancy Linked to Stillbirths?