A systematic review and meta-analysis of 20 randomized controlled trials (RCTs) suggests preventive azithromycin in pregnancy and labor has benefits but might not reduce maternal or neonatal mortality, Indian researchers reported late last week in eClinicalMedicine.
The study, led by researchers with the All India Institute of Medical Sciences, is the latest to examine the effect of prophylactic azithromycin, a broad-spectrum macrolide antibiotic, on maternal and neonatal health outcomes.
A US trial in 2016 found that administering azithromycin to pregnant women undergoing cesarean delivery was associated with a 49% reduction in postoperative infections. That finding led to azithromycin prophylaxis being routinely recommended for cesarean births by the American College of Obstetrics and Gynecology and the World Health Organization.
Another RCT, conducted in seven countries, found that women given an oral dose of azithromycin before vaginal birth had a 33% reduced risk of maternal sepsis or mortality compared with those who received placebo.
But that RCT and more recent trials have found prophylactic azithromycin has no impact on neonatal mortality, and subsequent studies have suggested an association with increased carriage of azithromycin-resistant bacteria in newborns, raising questions about the benefits and risks of the practice. The authors of the review also note that observational studies have found an association between antenatal azithromycin exposure and increased risk of stillbirth and congenital malformations in infants.
"The interventions in the antenatal period can be justified if they benefit both mother and fetus or if the benefits are restricted to one of them, the other should not be harmed," they wrote.
Little or no effect on maternal, neonatal mortality
To assess the most up-to-date evidence, the researchers reviewed 20 RCTs involving 56,381 participants. Eighteen of the studies were conducted in low- and middle-income countries, 11 assessed single-dose intrapartum azithromycin administration, and 9 tested antenatal administration.
The meta-analysis found that, compared with placebo or no treatment, intrapartum azithromycin may make little or no difference to maternal mortality (5 RCTs; 44,436 participants; risk ratio [RR], 1.02; 95% confidence interval [CI], 0.86 to 1.20; very low- certainty evidence) or maternal mortality (3 RCTs; 44,131 participants; RR, 1.26; 95% CI, 0.65 to 2.42; low-certainty evidence).
The interventions in the antenatal period can be justified if they benefit both mother and fetus or if the benefits are restricted to one of them, the other should not be harmed.
Similarly, antenatal azithromycin was found to have an uncertain effect on neonatal mortality (3 RCTs; 5,304 participants; RR, 0.74; 95% CI, 0.35 to 1.56; very low-certainty evidence) and maternal mortality (3 RCTs; 8,167 participants; RR, 1.62; 95% CI, 0.67 to 3.91; low-certainty evidence).
But single-dose intrapartum azithromycin did provide some benefit, including possible reduction of some maternal infections (systemic sepsis, endometritis, and surgical-site infections) and neonatal infections (superficial skin infections and omphalitis) and reduced antibiotic use in mothers and newborns. Antenatal azithromycin had little or no effect on preterm birth but was associated with a reduction in the risk of low birth weight.
The researchers also found no evidence of increased risk of miscarriage, stillbirth, congenital abnormalities, cerebral palsy, or childhood asthma, though they note that those events might not have been adequately represented in the RCTs.
The authors say their review supports the recommendation for prophylactic azithromycin for women undergoing elective cesarean delivery and probably extends it to women planning elective vaginal delivery but add that caution is warranted. They say future trials should address timing of administration, dosing schedule, and co-interventions.
"Further trials should also focus on safety aspects, including adequate follow-up of infants for antimicrobial resistance and long-term outcomes," they wrote.
