Prevention of bacterial infections in the newborn by pre-delivery administration of azithromycin

The last decade has witnessed an important reduction of the mortality in children less than 5 years of age. Nevertheless, such reduction occurred mainly in children older than 1 month; no change was observed in newborns (between birth and one month of age). Mortality in this age group contributes half of all deaths occurring in children below 5 years of age. Sixteen out of the 20 countries with the highest neonatal mortality are in sub-Saharan Africa. In 1990, the United Nations established the Millennium Development Goals (MDG) aiming at improving by 2015 living conditions of the poorest populations. The MDG number 4 aims at reducing by two-thirds the under-five mortality, a result attainable only with a substantial reduction in neonatal deaths.

Severe bacterial disease is among the leading causes of neonatal deaths. In Sub-Saharan Africa, different bacteria are responsible for these deaths during the first month of life. Severe neonatal disease follows bacterial infection. Individuals can be infected without developing disease (carriage stage) but infection is needed to subsequently develop disease. In Sub-Saharan Africa, bacterial carriage (i.e. in the birth canal and/or nasopharyngeal tract) is very common, with the consequence that the occurrence of bacterial disease is one of the highest in the world.

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, if the latter carries bacteria in the nasopharyngeal tract.

If the mother is an important source of bacterial infection to the newborn, treating mothers with a powerful antibiotic during labour should decrease bacterial carriage and therefore diminish the risk of bacterial transmission to the newborn during the first days/weeks of life, which should in turn result in the lower occurrence of severe bacterial disease and hence lower mortality. In the study proposed, we will determine whether a single antibiotic dose given to the mother during labour decreases the bacterial carriage of the newborn during the first month of life.

We have selected an antibiotic (azithromycin) that in Sub-Saharan Africa has already shown both a strong impact on bacterial nasopharyngeal carriage and on all-cause mortality when administered to everybody in a community (mass drug administration). This specific antibiotic has several advantages for being deployable as a simple intervention in rural Africa, i.e. it requires a single oral administration, it has no special storage requirements and it has the potential to eliminate most of the bacteria commonly causing severe disease in newborn.
A clinical trial will be conducted in a rural health facility in Western Gambia to evaluate the effect of treating mothers during labour on bacterial infection in the newborn during the first weeks of life. If an impact is shown, the next step would be to conduct a larger study aiming at establishing if the intervention, implemented at a lower level of care (as most African women deliver at home assisted by traditional birth assistants), decreases the occurrence of neonatal invasive bacterial disease.

Millennium Development Goal number 4 (MDG-4) identifies decreasing childhood mortality as a priority area for international development. Despite important reduction in under-five mortality observed in some countries, neonatal mortality has remained stable, with consequent increase in the proportion of neonatal deaths (40%) among all under five fatalities. MDG-4 is unlikely to be achieved without substantial reduction in neonatal mortality.
Sepsis is a leading cause of neonatal deaths in developing countries, mainly in sub-Saharan Africa (SSA). Neonatal sepsis is a consequence of early bacterial infection. These infections are often transmitted by the mother to the newborn, either intrapartum (vaginal canal) or during the first days of life (nasopharyngeal carriage) when the close physical contact between her and the newborn expose the latter to the risk of being infected.
In SSA, additional benefits of mass-campaigns administering one oral dose of azithromycin (AZI) for trachoma control include lower nasopharyngeal bacterial carriage and lower childhood mortality. AZI is a broad spectrum antibiotic that covers a wide range of bacteria and is suitable for being used in SSA. Though AZI is defined by the Food and Drug Administration as a pregnancy category B drug, extensive published data of randomized clinical trials show no harm for both pregnant women and newborns.
The objective of the study is to evaluate the impact of one dose of AZI given during labour on bacterial carriage of the newborn and the mother. The underlying hypothesis is that this intervention can decrease bacterial carriage both in the mother and the newborn and consequently the risk of invasive bacterial disease in the newborn. Our proof-of-concept - Phase III-b randomized clinical trial - will be conducted in a rural health facility in Gambia. If successful, next step will be a larger study evaluating the same intervention given at the lowest level of care on the incidence of neonatal sepsis.

Our study opens the opportunity to impact on the Millennium Development Goal number 4 of reducing childhood mortality by 2015, a current priority in Global Health. Such an impact on under-five mortality should occur on newborns, the most vulnerable age group, by preventing neonatal bacterial infections and most likely subsequently sepsis. Along with this, the study will expand the worldwide academic knowledge on the prevention of neonatal bacterial infections, subsequent sepsis and associated mortality, using innovate methodologies.

All participants recruited for the study (720 mother/newborn pairs - two groups at very high risk of morbidity and mortality) will benefit from the intervention during birth and the follow-up period (the first month of life) as a healthy effect of the intervention. The impact of such healthy effect is marked in populations where health personnel are scarce. In addition, if our study hypothesis proves correct, children born from treated mothers will have a lower risk of nasopharyngeal bacterial carriage and consequently of sepsis.

This study will offer the opportunity for at least one PhD training fellowship (either a medical doctor to be trained in research methods of infectious diseases and global health or a laboratory-based scientist). Young West-African scientists will be preferentially selected, though the training opportunity will be open to any young researcher with the required expertise and working in an African context.

As any study conducted in a poor-resource setting, capacity building is an important component. Study staff at different levels will receive continuous training on several aspects related to clinical research such as Good Clinical Practices or Ethics. In addition, we will include specific training sessions for the field staff; laboratory technicians will be exposed, as part of the study, to a high-standard microbiological and scientific environment (WHO reference laboratory for microbiology), an almost unique opportunity in the African continent.

The final aim of our trial is to transform the proposed intervention into policy to be implemented at any level of antenatal care in Africa, including delivering women assisted by traditional birth attendants, a common practice in rural Africa where health centres are not easily accessible for a substantial proportion of the population. The potential of a major impact on early neonatal mortality with a relatively simple intervention is high. Assuming favourable results, the intervention could save hundreds of thousands of lives.