FDA Pregnancy Category of Fluconazole
Fluconazole is classified as FDA Pregnancy Category D for most indications, except for single-dose (150mg) treatment of vaginal candidiasis which is classified as Category C. 1
Explanation of FDA Pregnancy Categories
The FDA pregnancy category system classifies medications based on their potential risk to the fetus:
- Category C: Animal studies have shown adverse effects on the fetus, but there are no adequate studies in humans. Potential benefits may warrant use despite potential risks.
- Category D: There is positive evidence of human fetal risk, but potential benefits may warrant use despite risks in serious situations.
Evidence Supporting This Classification
High-Dose Fluconazole Risks
- High-dose fluconazole (≥400 mg daily) has been associated with a pattern of birth defects known as "fluconazole embryopathy" which includes craniosynostosis, characteristic facial abnormalities, digital synostosis, and limb contractures 2, 1
- Exposure to high-dose fluconazole (>150 mg) during the first trimester is associated with an increased risk of cardiac septal closure anomalies (adjusted OR 1.81) 3
Low-Dose Fluconazole Considerations
- Single-dose fluconazole (150 mg) for vaginal candidiasis has historically been considered relatively safer, but recent evidence suggests caution is warranted throughout pregnancy 1
- A 2019 meta-analysis found that oral fluconazole use during the first trimester was associated with an increased risk of heart malformations (OR 1.31) and spontaneous abortion (OR 1.99) 4
Clinical Recommendations
Preferred Alternatives During Pregnancy
- First-line treatment: Topical azole antifungals (clotrimazole, miconazole) are preferred for vaginal candidiasis during pregnancy due to minimal systemic absorption 1
- For systemic infections: Amphotericin B is the preferred agent for systemic fungal infections during pregnancy (FDA Category B) 2, 1
If Fluconazole Is Necessary
- Avoid fluconazole during the first trimester if possible 1
- For invasive or refractory esophageal candidal infections, substitution of amphotericin B for high-dose fluconazole in the first trimester is recommended 2
- If fluconazole is required after the first trimester, use the lowest effective dose for the shortest duration possible 1
Important Precautions
- Women of childbearing potential should use effective contraception while taking fluconazole 1
- Chemoprophylaxis using systemically absorbed azoles should not be initiated during pregnancy and should be discontinued for HIV-infected women who become pregnant 2
- For women requiring fluconazole during pregnancy, monitoring for signs of fetal distress and detailed ultrasound evaluation for potential malformations is advised 1
The FDA pregnancy category classification system has been replaced with the Pregnancy and Lactation Labeling Rule (PLLR) for newer medications, but many clinicians still reference the older category system for medications approved before the change.