What is the pregnancy category of Diflucan (fluconazole)?

Fluconazole (Diflucan) Pregnancy Category

Fluconazole (Diflucan) is classified as FDA Pregnancy Category C for routine vaginal candidiasis treatment (single 150mg dose), but is Category D for all other indications requiring higher doses or prolonged use due to risk of birth defects.

Pregnancy Risk Classification

Fluconazole's pregnancy category depends on the dosage and duration of treatment:

• Category C: Single 150mg dose for vaginal candidiasis
• Category D: All other indications (doses >150mg or prolonged use)

Evidence for Teratogenic Effects

The FDA label clearly indicates that fluconazole has demonstrated teratogenic potential 1:

• High-dose maternal exposure (400-800mg/day) during the first trimester has been associated with a distinctive pattern of birth defects including:

  • Brachycephaly
  • Abnormal facies
  • Abnormal calvarial development
  • Cleft palate
  • Femoral bowing
  • Thin ribs and long bones
  • Arthrogryposis
  • Congenital heart disease

• Animal studies have shown similar effects, including:

  • Increases in fetal anatomical variants
  • Delays in ossification
  • Wavy ribs
  • Cleft palate
  • Abnormal craniofacial ossification

Recent Research on Lower Doses

A 2020 population-based cohort study found that even at lower doses, fluconazole in the first trimester was associated with 2:

• Increased risk of musculoskeletal malformations (adjusted relative risk 1.30)
• Dose-dependent relationship with risk increasing at higher cumulative doses
• No significant association with oral clefts or conotruncal malformations

Clinical Recommendations for Pregnancy

According to the Infectious Diseases Society of America guidelines 3:

1. Avoid fluconazole during the first trimester due to risk of congenital malformations
2. Consider fluconazole use during second and third trimesters only when benefits outweigh risks
3. For cryptococcal infections in pregnancy, use amphotericin B deoxycholate (AmBd) or lipid formulation amphotericin B (LFAmB) instead (these have Category B ratings)
4. For limited pulmonary cryptococcosis, defer antifungal therapy until after delivery when possible

The CDC/NIH/IDSA guidelines for opportunistic infections in HIV-infected adults specifically state 3:

• Single-dose episodic treatment with fluconazole has not been associated with birth defects
• However, high-dose fluconazole (≥400mg) has been linked to "fluconazole embryopathy"
• Substitution of amphotericin B for high-dose fluconazole in the first trimester is recommended

Postpartum Considerations

• Fluconazole is excreted in breast milk at concentrations similar to plasma 3, 1
• Caution should be exercised when administering fluconazole to nursing women

Clinical Decision Algorithm

1. First trimester pregnancy:

   • Avoid fluconazole if possible
   • For vaginal candidiasis: Use topical azoles instead
   • For systemic fungal infections: Consider amphotericin B formulations

2. Second/third trimester pregnancy:

   • For vaginal candidiasis: Single 150mg dose may be considered if benefits outweigh risks
   • For systemic infections: Use amphotericin B when possible
   • If fluconazole is necessary, use lowest effective dose for shortest duration

3. Postpartum:

   • Can resume fluconazole therapy after delivery
   • Monitor for immune reconstitution inflammatory syndrome (IRIS) in immunocompromised patients

Important Caveats

• The risk of birth defects appears to be dose-dependent, with higher risk at doses >450mg 2
• Even with single-dose therapy, patients should be informed of potential risks
• Effective birth control measures should be recommended to all women on azole therapy who are of childbearing potential 3