Itraconazole in Third Trimester of Pregnancy
Itraconazole can be used in the third trimester when clinically indicated for serious fungal infections, as the teratogenic risk is primarily confined to first-trimester exposure, though amphotericin B remains the preferred agent when feasible. 1, 2
Evidence-Based Recommendations by Trimester
Third Trimester Use
- Azole antifungals including itraconazole are acceptable after the first trimester for conditions requiring systemic antifungal therapy, such as coccidioidomycosis and histoplasmosis 1, 2
- The Infectious Diseases Society of America explicitly recommends azole antifungals (fluconazole or itraconazole at 400 mg daily) for second and third trimester treatment of active nonmeningeal coccidioidomycosis and meningitis 1
- The theoretical teratogenic risk diminishes significantly after organogenesis is complete (after first trimester), though no extensive safety data exist for prolonged third-trimester treatment 1
First Trimester Contraindication
- Itraconazole should be avoided during the first trimester due to teratogenic potential demonstrated in animal studies at doses equivalent to human therapeutic levels 1, 2, 3
- Animal studies showed major skeletal defects in rats and encephaloceles/macroglossia in mice at therapeutic dose equivalents 3
- While the metabolic mechanism causing teratogenicity in animals may not apply to humans, clinical experience remains limited 1
Clinical Context and Decision-Making
When Itraconazole Is Appropriate
- Life-threatening or severe fungal infections (histoplasmosis, coccidioidomycosis, blastomycosis) where benefit outweighs risk 1
- Coccidioidal meningitis in second/third trimester as alternative to intrathecal amphotericin B 1
- Situations where amphotericin B is contraindicated due to maternal renal dysfunction or intolerance 2
Preferred Alternative
- Amphotericin B (lipid formulations preferred) remains the treatment of choice throughout all trimesters for serious systemic fungal infections 1, 2
- Amphotericin B has extensive safety data with no reported teratogenesis, though it causes maternal renal toxicity and hypokalemia 1, 2
- Neonates born to mothers receiving amphotericin B should be evaluated for renal dysfunction and electrolyte abnormalities 1, 2
Important Caveats and Monitoring
Contraception Requirements
- Women of childbearing age receiving itraconazole should use effective contraception during therapy and for 2 months after discontinuation 1
- This reflects the drug's long half-life and tissue accumulation 4
Dosing Considerations
- Standard itraconazole dosing for systemic infections is 200 mg 2-3 times daily 1
- Therapeutic drug monitoring is recommended to ensure adequate drug exposure, particularly given altered pharmacokinetics in pregnancy 1
Breastfeeding
- Women should not breastfeed while receiving itraconazole as it enters breast milk at low concentrations but may accumulate over time 1
Superficial Infections
- For vaginal candidiasis or superficial fungal infections during any trimester, topical azoles (clotrimazole, miconazole) are strongly preferred over systemic agents 1, 5, 6
- Topical therapy achieves 80-90% cure rates with 7-day regimens and has no systemic absorption concerns 5
Key Distinction
The teratogenic concerns with azoles apply specifically to systemic (oral) formulations, not topical preparations, which are safe throughout pregnancy 5, 6