Pre-delivery administration of azithromycin to prevent neonatal sepsis and death: a phase III double-blind randomized clinical trial

Though maternal and neonatal health are high priority areas for international development, worldwide there are 1 million maternal and 4 million neonatal deaths every year and half of them occur in sub-Saharan Africa. Bacterial infections, namely sepsis, are a leading cause of maternal and neonatal deaths in sub-Saharan Africa. Newborns can be infected during labour - when passing through the birth canal - and also during the first days/weeks of life, as a consequence of the close physical contact with the mother, when the latter carriers bacteria even when she does not show any symptoms. As the mother is an important source of bacterial transmission to the newborn, treating mothers with antibiotics during labour should reduce the occurrence of severe bacterial disease and mortality in the newborn. In many high-income countries, pregnant women are screened during pregnancy for vaginal carriage of Group B Streptococcus, the bacteria responsible for the vast majority of neonatal sepsis in the developed world. If women are carriers, they are treated with intravenous antibiotics during labour to reduce transmission and subsequent risk of severe disease to their off-spring. Although this intervention has been successful in developed countries, infrastructure and resource limitations in regions like sub-Saharan Africa prevent both screening and use of intravenous antibiotics. Also, in sub-Saharan Africa several bacterial pathogens are responsible for neonatal sepsis and antibiotics, to be effective, would need to cover a wide range of bacteria. We propose to conduct a large trial in The Gambia and Burkina Faso to determine if a single dose of an oral antibiotic given to women during labour decreases newborn mortality. The trial will also assess whether giving the antibiotic reduces hospitalisations in mothers and their newborns during the first few weeks after birth. We will use an antibiotic (azithromycin) that has already been used to eliminate other diseases in sub-Saharan Africa, such as trachoma (the most important cause of blindness caused by infection), and has the potential to eliminate most of the bacteria commonly causing severe disease in the region. An advantage of using this antibiotic in sub-Saharan Africa is that it can be stored at room temperature without the need of a fridge. Importantly, since this antibiotic is not widely used in clinical care in sub-Saharan Africa, any temporary increase in resistance, as a result of using the antibiotic, will have small impact on clinical care. We have generated robust preliminary data on the effect of the intervention in a smaller trial conducted in The Gambia (829 women recruited). We found that, babies born to mothers who had taken this antibiotic during labour were less likely to carry bacteria that can cause severe disease. Furthermore, these babies were also less likely to have bacterial skin and umbilical infections, both of which are common among newborns in sub-Saharan Africa. And in mothers who had taken azithromycin, fevers and mastitis (both common after giving birth) were less frequent. The preliminary data confirm our hypothesis that azithromycin can be used to reduce bacterial transmission but it was too small to assess the effect of the antibiotic on mortality and hospitalizations. If we find that azithromycin prevents severe bacterial infections in mothers and newborns, then it could be an effective intervention since it is cheap and simple to administer.