Abstract
OBJECTIVE: To test the effect on all cause neonatal mortality (aged ≤28 days) of a dose of BCG Danish vaccine and oral polio vaccine (OPV) administered to newborn babies weighing <2000 g. DESIGN: Multicentre, open label, randomised controlled trial SETTING: Three tertiary neonatal intensive care units (NICUs) in southeast India. POPULATION: Newborn babies weighing <2000 g. 7067 were assessed for eligibility and 5420 were randomised (2714 BCG-OPV, 2706 control). INTERVENTIONS: Newborns were randomised 1:1 to receive 0.1 mL of BCG Danish intradermally plus OPV, either within 48 hours of admission to the NICU (early vaccination group) or delayed until at least the time of discharge (control group). Stratification was by NICU, sex, and birth weight (<1000 g, 1000-1499 g, 1500-1999 g). MAIN OUTCOME MEASURES: The primary outcome was all cause neonatal mortality. The main secondary outcome, included a third of the way through the trial, was neonatal mortality due to infection. RESULTS: Of the 5420 newborn babies randomised at a median age of 0.9 days and with a median birth weight of 1560 g, nine were lost to follow-up. Deaths occurred in 238 (8.8%) of 2714 newborn babies in the early vaccination group and 273 (10.1%) of 2706 in the control group. In intention-to-treat Cox survival analysis stratified by NICU and adjusted for postnatal age, birth weight, sex, and gestational age, neonatal mortality per person year was 1.29 in the early vaccination group and 1.50 in the control group (adjusted hazard ratio 0.83, 95% confidence interval (CI) 0.69 to 0.98; P=0.03). The number needed to treat to prevent one death was 21 (95% CI 10 to 245). Infection related neonatal mortality per person year was 0.40 in the early vaccination group and 0.73 in the control group (adjusted hazard ratio 0.53, 95% CI 0.40 to 0.70). No deaths from tuberculosis occurred, and no serious adverse effects were associated with vaccination. CONCLUSIONS: In newborn babies weighing <2000 g in intensive care, BCG-OPV administered at a median age of 0.9 days reduced all cause neonatal mortality owing to a decrease in deaths due to infections other than tuberculosis (a non-specific or off-target effect). A substantial reduction in neonatal mortality could be achieved if a skilled administrator vaccinated a high proportion of newborn babies in high mortality settings on the day of, or soon after, birth. TRIAL REGISTRATION: Clinical Trials Registry India CTRI/2017/01/007676.