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

Sofie Biering-Sørensen, Kristoffer Jarlov Jensen, Ivan Monterio, Henrik Ravn, Peter Aaby, Christine Stabell Benn, Sofie Biering-Sørensen, Kristoffer Jarlov Jensen, Ivan Monterio, Henrik Ravn, Peter Aaby, Christine Stabell Benn

Abstract

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).

Keywords: Bacille Calmette-Guérin vaccine; heterologous immunity; neonatal mortality; nonspecific effects of vaccines; sex differences.

© The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Children enrolled in 3 trials of early BCG effects on neonatal mortality in Guinea-Bissau 2002–2013. Note: The flow of children in each trial has been described in detail elsewhere [3–5]. Abbreviation: BCG, Bacille Calmette-Guérin.
Figure 2.
Figure 2.
Mortality rates split into time intervals since randomization, presented by sex and randomization groups. Abbreviation: BCG, Bacille Calmette-Guérin.
Figure 3.
Figure 3.
Mortality curves for Trials 1, 2, and 3 combined and separately for Trial 2 and Trial 3. Note: It was not possible to calculate a separate mortality curve stratified by sex for Trial 1 due to few deaths within the neonatal period (n = 2 girls, n = 6 boys). Abbreviation: BCG, Bacille Calmette-Guérin.

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Source: PubMed

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