Early BCG-Denmark and Neonatal Mortality Among Infants Weighing <2500 g: A Randomized Controlled Trial

Abstract

Background: BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials.

Methods: In 2008-2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns.

Results: Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval [CI], .47-1.04) and a 34% reduction (0.66; .44-1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35-.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46-.83) within the neonatal period and 16% (0.84; .71-1.00) by age 12 months.

Conclusion: Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates.

Clinical trials registration: NCT00625482.

Figure 1.

Flowchart for the neonatal period (first 28 days of life). The “loss to follow-up” category denotes infants who could not be followed up because their mothers left the hospital without the field assistant and their residence was unknown. The “censored for other reasons” category denotes infants who had been included twice and were excluded on the second inclusion.

Figure 2.

Cumulative mortality curves during the neonatal (28 days) and infant (365 days) periods according to randomization group. (Note differences in scale for the 2 curves.)

Figure 3.

Mortality rates and mortality rate ratios (MRRs) in the 3 trials of early BCG vaccination of low-weight infants in Guinea-Bissau, by trial and combined in a meta-analysis (fixed effect model) with and without censoring for participation in oral poliovirus vaccine (OPV) campaigns. MRRs are given with 95% CIs. Trial I is the small randomized controlled trial (RCT) conducted in Guinea-Bissau in 2002–2004 (n = 104; median age at randomization, 2 days for early BCG and 4 days for controls) [8]; trial II, the RCT conducted in Guinea-Bissau in 2004–2008 (n = 2320) [7]; and trial III, the RCT conducted in Guinea-Bissau in 2008–2013 and presented in the current article (n = 4120; median age at randomization, 2 days for both early BCG and controls). Note differences in scale for the three panels.