Reducing Mortality at the Neonatal Intensive Care Unit in Guinea-Bissau: A Randomized Trial of Providing BCG Vaccination Immediately

Observational studies in high-mortality areas have shown that the BCG vaccine is associated with marked benefits in child survival. These results cannot be explained by prevention of tuberculosis, which is rare during the firsts years of life. These observations have recently been tested at the Bandim Health Project (BHP) in Guinea-Bissau in randomized trials among low birth weight (LBW, <2500 g) children. According to local practice, BCG is typically postponed in LBW infants until 4-6 weeks of age. Results showed that providing BCG at the time of discharge from the hospital compared with BCG later reduced neonatal mortality by more than 40%. The protective effect started already within the first three days. Based on verbal autopsies, BCG protected the children against neonatal septicemia and pneumonia. Recent immunological studies have indicated that BCG induces epigenetic changes which reprogram the innate immune system to increased pro-inflammatory responses against unrelated pathogens; hence, BCG may indeed have a non-specific beneficial effect protecting against other infections.

BCG is recommended at birth by the World Health Organization (WHO), but is rarely given immediately at birth. In Guinea-Bissau, at the National Hospital's maternity ward, children are currently vaccinated at discharge. For children who are born healthy, this usually means 1-2 days after the delivery. However, very small children and ill children are admitted to the neonatal intensive care unit (NICU), and often stay there for days to weeks before they are discharged - and only receive BCG at the time of discharge. The mortality among children in the NICU is alarmingly high - it was 14% (254/1877) among children admitted to the NICU from November 2007 to May 2013 (unpublished data). A substantial number of children that died had normal birth weight and high Apgar scores. In most cases the underlying cause of death was infectious diseases, which could potentially be affected by BCG vaccination. Hence, the present aim is to conduct a randomized trial at the NICU to study the effect of providing BCG immediately (intervention group) versus BCG at discharge (control group). The primary outcome will be mortality during hospital stay, with cause of death, growth and length of stay as secondary outcomes.

HYPOTHESIS

Providing BCG vaccination upon admission to newborn children in the NICU incubators, rather than at discharge, is associated with 40% reduction in mortality at the NICU for children weighing >1250 g.

METHODS