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

Abstract

Importance: Neonatal sepsis is a leading cause of neonatal mortality. New interventions are needed to decrease neonatal sepsis and mortality in regions with highest burden.

Objective: To evaluate the efficacy of intrapartum azithromycin to reduce neonatal sepsis or mortality, as well as neonatal and maternal infections.

Design, setting, and participants: This double-blind, placebo-controlled, randomized clinical trial enrolled and followed up birthing parents and their infants at 10 health facilities in The Gambia and Burkina Faso, West Africa, between October 2017 and May 2021.

Interventions: Participants were assigned at random to receive oral azithromycin (2 g) or placebo (ratio 1:1) during labor.

Main outcomes and measures: The primary outcome was a composite of neonatal sepsis or mortality, with the former defined based on microbiologic or clinical criteria. Secondary outcomes were neonatal infections (skin, umbilical, eye and ear infections), malaria, and fever; postpartum infections (puerperal sepsis, mastitis), fever, and malaria; and use of antibiotics during 4-week follow-up.

Results: The trial randomized 11 983 persons in labor (median age, 29.9 years). Overall, 225 newborns (1.9% of 11 783 live births) met the primary end point. The incidence of neonatal mortality or sepsis was similar in the azithromycin and placebo groups (2.0% [115/5889] vs 1.9% [110/5894]; risk difference [RD], 0.09 [95% CI, -0.39 to 0.57]), as was the incidence of neonatal mortality (0.8% vs 0.8%; RD, 0.04 [95% CI, -0.27 to 0.35]) and neonatal sepsis (1.3% vs 1.3%; RD, 0.02 [95% CI, -0.38 to 0.43]). Newborns in the azithromycin group compared with the placebo group had lower incidence of skin infections (0.8% vs 1.7%; RD, -0.90 [95% CI, -1.30 to -0.49]) and need for antibiotics (6.2% vs 7.8%; RD, -1.58 [95% CI, -2.49 to -0.67]). Postpartum parents in the azithromycin group had lower incidence of mastitis (0.3% vs 0.5%; RD, -0.24 [95% CI, -0.47 to -0.01]) and puerperal fever (0.1% vs 0.3%; RD, -0.19 [95% CI, -0.36 to -0.01]).

Conclusions and relevance: Azithromycin administered orally during labor did not reduce neonatal sepsis or mortality. These results do not support routine introduction of oral intrapartum azithromycin for this purpose.

Trial registration: ClinicalTrials.gov Identifier: NCT03199547.

Figure 1.. Recruitment, Randomization, and Patient Flow in the Trial of Azithromycin to Prevent Neonatal Sepsis and Mortality

^aOther reasons included being HIV positive (n = 43), taking drugs that increased QT/QTc during the previous 2 weeks (n = 40), planning travel outside of the study area (n = 25), having severe congenital malformation (n = 4), and having a known allergy to macrolides (n = 1). ^bOther reasons included age younger than 16 years (n = 10) and consent not found (n = 6). ^cIndividuals excluded for the following reasons: late arrival to health facility, not enough time to screen/randomize and treat (n = 1149), study staff not available (n = 36), very early preterm or abortion (n = 22), unsure of fetal heart (n = 15), and partner declined participation (n = 9).

Figure 2.. Secondary End Points by Study Group for Newborns and Birthing Parents

Secondary end points for newborns include skin infections, eye infections, ear infections, umbilical infections, malaria, fever, and antibiotic use, and for birthing parents includes puerperal sepsis, mastitis, puerperal fever, malaria, and antibiotic use; additional details are in the Methods section.