Is azithromycin (Zithromax) safe to use during pregnancy?

Azithromycin Safety in Pregnancy

Azithromycin should be used during pregnancy only when clinically indicated and when benefits outweigh potential risks, as it is classified as FDA Pregnancy Category B with no conclusive evidence of harm to the fetus. 1, 2

Safety Profile

• Azithromycin is classified as FDA Pregnancy Category B, indicating that animal reproduction studies have not demonstrated fetal risk, but there are no adequate well-controlled studies in pregnant women 2
• Reproduction studies in rats and mice at doses up to 4 and 2 times the human daily dose (500 mg) respectively showed no evidence of harm to the fetus 2
• Unlike clarithromycin (which has shown teratogenic effects in animal studies), azithromycin does not require dose adjustment during pregnancy and does not affect the cytochrome P450 system, making it safer to use with other medications during pregnancy 1

Specific Clinical Indications

Azithromycin is specifically recommended for:

1. First-line treatment for chlamydial infections in pregnancy:

   • Recommended as a single 1g oral dose 1
   • Preferred due to high compliance rate, demonstrated safety, and proven efficacy 1

2. MAC (Mycobacterium avium complex) prophylaxis in HIV-infected pregnant women 1

Potential Concerns and Monitoring

• Current evidence on fetal and neonatal outcomes following prenatal azithromycin exposure has yielded conflicting results 3
• Some studies have reported potential risks including spontaneous miscarriage, major congenital malformations, and cardiovascular malformations, but these findings have not been consistent across studies 3
• The most recent large-scale trial (A-PLUS) found that azithromycin reduced maternal sepsis without significant adverse effects on newborns 4
• One systematic review noted a potential signal for increased stillbirth risk, though the confidence interval crossed the null value (Pooled RR 1.39; 95% CI 0.94-2.07) 5

Precautions

• Azithromycin should not be used concomitantly with medications that can prolong the QT interval due to risk of cardiac arrhythmias 1
• Close monitoring for known side effects such as liver enzyme abnormalities and hearing impairment is warranted, especially when co-administered with medications like nelfinavir 2
• Prothrombin times should be carefully monitored when patients receive azithromycin and oral anticoagulants concomitantly 2

Pharmacokinetics in Pregnancy

• Pregnancy increases the volume of distribution of azithromycin by approximately 86% relative to bioavailability, but without significant change in overall drug exposure (AUC) 6
• The terminal elimination half-life is estimated at approximately 77-78 hours in both pregnant and non-pregnant women 6

Benefits in Specific Populations

• In women with cystic fibrosis, the potential risks of discontinuing chronic azithromycin therapy during pregnancy must be weighed against potential risks to the fetus 7
• A systematic review found that prophylactic azithromycin during pregnancy reduces low birth weight (Pooled RR 0.79; 95% CI 0.68-0.93) and prematurity (Pooled RR 0.87; 95% CI 0.78-0.98) 5

Alternative Treatments When Indicated

For chlamydial infections when azithromycin cannot be used:

• Amoxicillin 500mg orally three times daily for 7 days
• Erythromycin base 500mg orally four times daily for 7 days
• Ceftriaxone 250 mg IM as a single dose (for patients who cannot tolerate oral medications) 1

Note that doxycycline, fluoroquinolones, and erythromycin estolate are contraindicated during pregnancy 1.