Effect of Intrapartum Azithromycin vs Placebo on Neonatal Sepsis and Death A Randomized Clinical Trial

ABSTRACT Sepsis is a leading cause of neonatal mortality, and rates have not decreased in recent years despite medical advances. Azithromycin has been shown in previous research to be effective in reducing infection and sepsis; in particular, a recent study showed that administration of the drug during labor reduced gram-positive bacteria over the next 4 weeks, along with reduced disease in mothers and newborns. This study was designed to assess the effectiveness of azithromycin administered during labor in reducing instances of neonatal sepsis and mortality. The primary outcome for this study was neonatal sepsis or death within the first 28 days of life. Deaths that were identifiably due to severe birth asphyxia, low birth weight, and severe congenital malformations were excluded. Secondary outcomes included neonatal sepsis, neonatal mortality, culture-confirmed sepsis, fever, skin infections, bacterially confirmed skin infections, conjunctivitis, umbilical infection/omphalitis, malaria, prescribed antibiotics, and hospitalization. Secondary outcomes for parents included postpartum sepsis, bacterially confirmed postpartum sepsis, mastitis, malaria, puerperal fever, prescribed antibiotics, hospitalization, and mortality. The final analysis included 11,625 parents and 11,783 neonates; baseline characteristics between the azithromycin and placebo groups were not significantly different. Of the total sample, 225 instances of neonatal sepsis or death occurred. The incidence of either mortality or sepsis was similar between groups (odds ratio [OR], 1.06; 95% confidence interval [CI], 0.80–1.38; P = 0.70), as well as the individual outcomes of mortality (OR, 1.05; 95% CI, 0.70–1.60; P = 0.80) and sepsis (OR, 1.02; 95% CI, 0.74–1.40; P = 0.92). Incidence of neonatal skin infections ( P < 0.001), bacterially confirmed skin infections ( P = 0.003), and need for antibiotics ( P < 0.001) were all significantly reduced in the azithromycin group. Azithromycin reduced instances of both mastitis ( P = 0.04) and puerperal fever ( P = 0.04), but there were no other significant differences between groups. These results indicate no effect of azithromycin on neonatal sepsis or mortality. There were reductions in some instances of infection in both parents and newborns, specifically newborn skin infections, but there was no effect on the primary outcome. These results are in contrast to the previous proof-of-concept trial that showed azithromycin to reduce the amount of gram-positive bacteria carried by mothers and infants. Recent studies from different countries have found some conflicting results in longer-term outcomes, but the differing time periods limit comparison of results. This study was limited by underestimation of incidence of infections due to follow-up design, as well as slight differences between the 2 countries involved in the study. Overall, the results of this analysis do not support a change in clinical practice to introduce azithromycin to prevent neonatal sepsis and mortality.