Rapid Protective Effects of Early BCG on Neonatal Mortality Among Low Birth Weight Boys: Observations From Randomized Trials

BACKGROUND: Three randomized trials (RCTs) in low-weight (<2.5 kg) infants have shown that Bacille Calmette-Guérin (BCG) vaccine nonspecifically reduces all-cause mortality in the neonatal period. METHODS: Using data from 3 RCTs of early BCG (n = 6583) we examined potential sex differences in the timing of the mortality reduction in the neonatal period, presenting metaestimates of the main outcome mortality rate ratios (MRR) for BCG-vaccinated and controls. RESULTS: Among controls, boys had a particularly high mortality during the first week after randomization: male–female MRR 2.71 (95% CI, 1.70–4.50). During the first week, BCG had a marked beneficial effect for boys, reducing mortality 3-fold (MRR [BCG/no BCG] = 0.36 [0.20–0.67]). In weeks 2–4 the effect waned for boys (MRR = 0.91 [0.51–1.69]). In girls, the pattern was opposite with a limited effect in the first week (MRR = 0.85 [0.46–1.54]), but a significant reduction in weeks 2–4 (MRR = 0.56 [0.31–1.00]). This was consistent in all 3 trials. Verbal autopsies linked early benefit to fewer sepsis-related deaths among BCG-vaccinated boys. DISCUSSION: The marked reduction in mortality in the days after BCG vaccination in boys emphasizes the importance of providing BCG soon after birth. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT00146302) and ClinicalTrials.gov (NCT00625482).