Impact of Intra-Partum Azithromycin on Neonatal Sepsis and Death and Maternal Infections in the Gambia and Burkina Faso: A Double-Blind Placebo-Controlled Trial

Background: Neonatal sepsis is a leading cause of neonatal mortality. New context-specific interventions are needed to decrease neonatal sepsis and mortality in sub-Saharan Africa where the burden is highest.Methods: A double-blind placebo-controlled randomized clinical trial was conducted in health facilities in West Africa, The Gambia and Burkina Faso, in which women in labour were randomised to receive either 2g of oral azithromycin or placebo (ratio 1:1). The primary outcome was a composite of neonatal sepsis and mortality. Neonatal sepsis was defined as a clinical criteria supported by biochemistry and/or haematology results; or by confirmed microbiology. Neonatal mortality excluded death from those children with 1-min apgar score <4, with major congenital malformatoins or birthweight <1.5Kg.Findings: Overall, 225 newborns out of the 11,783 live-births met the primary endpoint (1.9%) [168 newborns out of 6,516 live-births in The Gambia (2.6%) and 57 out of 5,267 live-births in Burkina Faso (1.1%)]. The overall incidence of the primary composite endpoint was similar in the azithromycin and in the placebo arm (2.0% vs 1.9%, p=0.70); as was the incidence of neonatal mortality (0.8% vs 0.8%, p=0.80) and neonatal sepsis (1.3% vs 1.3%, p=0.92). However, the incidence of clinical skin infections was lower in the azithromycin than in the placebo arm (0.8% versus 1.7%, p<0.001) as was the incidence of bacterially confirmed skin infection (0.4% vs 0.8% p=0.003) and severe skin infections (0.0% vs 0.1% p=0.04). S. aureus was the most common bacteria isolated from confirmed sepsis (8 out of 37, 21.6%) and from bacterially confirmed skin infections (52 out of 67, 77.6%). Incidence of maternal mastitis and puerperal fever were also lower in the azithromycin arm (0.3% vs 0.5% p=0.004 and 0.1% vs 0.3% p=0.004, respectively).Interpretation: The results of this trial do not support the routine introduction of oral intra-partum azithromycin (2g) in sub-Saharan Africa to decrease neonatal sepsis and mortality. However, the intervention reduces other common infections in the newborns and mothers.Trial Registration: ClinicalTrials.gov: NCT03199547Funding: Joint Global Health Trial Scheme (JGHT), reference number MC_EX_MR/P006949/1. AndBill & Melinda Gates Foundation (OPP1196513).Declaration of Interest: The authors declare no conflicts of interest. UNN is currently working with GSK Vaccines Institute for Glboal Health, Italy.Ethical Approval: The trial was approved by The Gambia Government/MRCG (Medical Research Council Unit The Gambia) Joint Ethics Committee, the Comité d’Ethique pour la Recherche en Santé (CERS) and the Ministry of health of Burkina Faso, and the LSHTM Ethics Committee. All women provided a written informed consent during ante-natal care visits.