9 January 2017
Neonatal deaths, estimated at 4 million annually, account for almost 40% of under-five mortality. Bacterial sepsis is a leading cause of neonatal deaths with Staphylococcus and Streptococcus species being highly prevalent associated aetiologies in the African continent.
MRC Unit The Gambia embarked on a phase-III, placebo-controlled, randomised clinical trial to evaluate the impact of one oral dose of azithromycin (AZI) given to women during labour on bacterial colonization in the mother and the newborn. The novel underlying hypothesis of the trial was that the mother is the main source for bacterial transmission to newborns and, therefore, decreasing bacterial colonization in the former should impact on the prevalence of colonisation in the latter. The trial was funded by the Medical Research Council (MRC) UK and the UK Department for International Development (DfID) under the MRC/DfID concordat agreement, in collaboration with the European & Developing Countries Clinical Trials Partnership (EDCTP2) programme, supported by the European Union. The study was conceived and designed by Dr Anna Roca (Principal Investigator) and Prof Umberto D’Alessandro (Unit Director and co-Investigator) with the support of both internal and external scientists including support staff from MRCG.
The study started in 2012 and the clinical phase was conducted in 2013-2014 at Jammeh Foundation for Peace (JFP) hospital, a busy public health facility located within peri-urban settlements in Western Gambia. This included a long-term follow-up completed in 2015. 829 women in labour were given 2g of oral AZI. Women and their newborns were followed up for eight weeks and biological samples were collected during the first four weeks (i.e. nasopharyngeal swabs, breast milk and vaginal swabs). Clinical data was collected during the entire follow-up period. The results, published in the Clinical Microbiology & Infection website, supported the initial hypothesis and showed that neonates were protected from bacterial nasopharyngeal carriage of the three study bacteria (i.e. Staphylococcus aureus, Group B Streptococcus and Streptococcus pneumoniae) for at least four weeks when the last samples were collected.
The close follow-up of the patients along with the quality of data collection allowed additional clinical analysis. Although clinical endpoints were defined ad hoc, results are unlikely to be biased because data was collected by study clinicians during the follow-up and thus in a blinded fashion. This clinical analysis showed that the intervention reduced the prevalence of mastitis, occurrence of fever and overall infections among women; and skin infections and overall infections among newborns. The long-term analysis conducted in a sub-group of the study participants, indicated a trend of better anthropometrical measurements (z-scores) among infants born from women who received AZI during labour.
The successful conduct of the trial’s clinical phase was largely attributed to the cooperation and willingness of study mothers and their families. The project had an excellent support from The Gambia Government through the Ministry of Health and Social Welfare and the leadership and staff of JFP. Support was also received from the departments of obstetrics and gynaecology, and paediatrics through the neonatology unit of the Edward Francis Small Teaching Hospital (EFSTH) in Banjul. This study provided the opportunity to conduct several other ancillary analyses such as: AZI excretion in breast milk, dynamics of bacterial transmission among women and newborns, prevalence of bacterial neonatal conjunctivitis and risk factors for bacterial colonisation.
A student has recently started his PhD, aimed at evaluating the effect of the intervention on S. aureus AZI resistance (short and long term effect) and its mechanisms. As a result of the strong baseline data generated by this study, a larger trial awarded by the Joint Global Trials Scheme (co-funded by MRC, Wellcome Trust and DfID) will be conducted in The Gambia and Burkina Faso. The aim of the larger trial will be to examine the effects of the intervention on neonatal mortality and its impact on maternal and neonatal sepsis.