Is azithromycin (Zithromax) safe to use during pregnancy?

Azithromycin Safety During Pregnancy

Azithromycin can be used during pregnancy as an alternative treatment option when clinically indicated, but it should not be considered a first-line agent due to limited safety data. 1

Safety Profile and Recommendations

• Azithromycin is classified as FDA Pregnancy Category B, indicating that animal studies have shown no evidence of harm to the fetus, but adequate well-controlled studies in pregnant women are lacking 2
• The Centers for Disease Control and Prevention (CDC) lists azithromycin as an alternative regimen for treating chlamydia during pregnancy, not as a first-line recommendation 3
• Recommended first-line treatments for chlamydia in pregnancy are erythromycin base 500 mg orally four times a day for 7 days or amoxicillin 500 mg orally three times a day for 7 days 3
• Preliminary data indicate that azithromycin may be safe and effective in pregnancy, but insufficient evidence exists to recommend its routine use in pregnant women 3

Evidence on Fetal Outcomes

• A study of 123 women exposed to azithromycin during pregnancy found no statistically significant increase in major malformations (3.4% in exposed group vs. 2.3% in disease-matched controls and 3.4% in non-teratogen group) 4
• Conflicting evidence exists regarding potential adverse outcomes, with some studies reporting increased risks of spontaneous miscarriage, major congenital malformations, cardiovascular malformations, and preterm birth, while others show no such associations 5
• A 2021 systematic review and meta-analysis found that prophylactic azithromycin during pregnancy actually reduced the risk of 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) 6
• The same meta-analysis noted a potential increase in stillbirth risk, though the confidence interval crossed the null value (Pooled RR 1.39; 95% CI 0.94-2.07) 6

Clinical Use Considerations

• If azithromycin is used for chlamydia treatment during pregnancy, the recommended dosage is 1 g orally in a single dose 3, 1
• Repeat testing (preferably by culture) is recommended 3 weeks after completion of therapy to ensure cure, particularly given the potential consequences of persistent infection for both mother and neonate 3, 1
• Doxycycline and ofloxacin are contraindicated during pregnancy 3
• Erythromycin estolate is specifically contraindicated during pregnancy due to drug-related hepatotoxicity 3

Special Populations

• For women with cystic fibrosis who may be on chronic azithromycin therapy, the potential risk to the infant must be weighed against the potential risk to the mother of treatment discontinuation 7
• HIV-positive pregnant women with chlamydia should receive the same treatment regimen as HIV-negative women 3, 1
• Pharmacokinetic studies show that pregnancy increases the volume of distribution of azithromycin by approximately 86%, but without significant changes in overall drug exposure (AUC) 8

Clinical Decision Algorithm

1. For chlamydia treatment in pregnancy:

   • First-line: Erythromycin base 500 mg orally four times daily for 7 days OR amoxicillin 500 mg orally three times daily for 7 days 3
   • Consider azithromycin (1 g single dose) if:
     • Patient is unlikely to adhere to multi-dose regimens 1
     • Patient has intolerance to first-line agents 1
     • Clinical situation requires rapid treatment 1

2. For other infections requiring macrolide treatment:

   • Consider alternative antibiotics with more established safety profiles in pregnancy when possible 5
   • Use azithromycin only when benefits clearly outweigh potential risks 2, 5
   • Monitor pregnancy outcomes closely when azithromycin is used 5

3. For women on chronic azithromycin (e.g., cystic fibrosis patients):

   • Conduct individualized risk-benefit assessment 7
   • Consider disease severity and potential consequences of discontinuation 7

Common Pitfalls and Caveats

• Do not assume azithromycin is automatically safe in pregnancy simply because it is commonly prescribed 5
• Avoid using azithromycin routinely as first-line therapy for infections in pregnancy when equally effective alternatives with better-established safety profiles exist 3
• Remember that test of cure is essential after treatment of chlamydia in pregnancy, regardless of which antibiotic is used 3, 1
• Be aware that azithromycin may be present in breast milk, though the clinical significance is unclear 2