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.

Maternal and neonatal health are priority areas for international development. Puerperal and neonatal sepsis are leading causes of maternal and neonatal deaths in sub-Saharan Africa (SSA).

We propose a double-blind randomized trial giving 2g of azithromycin to women in labour. This intervention should impact on neonatal mortality by clearing maternal bacterial carriage and thus reducing bacterial transmission and subsequent neonatal sepsis. The intervention should lower puerperal sepsis.

We have generated robust baseline by conducting a first proof-of-concept study where 829 Gambian women in labour were randomly allocated to either 2g of azithromycin or placebo. The prevalence of bacteria was lower in the nasopharyx, breast milk and vaginal tract of mothers and the nasopharynx of the newborns from the azithromycin arm. We also observed a 50% reduction of skin and umbilical infections in the babies and 70% reduction of mastitis and fever in the mothers during the puerperal period.
Our proof-of-concept trial was not designed to assess severe clinical endpoints. Thus, we propose to conduct a multi-country Phase III trial (12,500 pregnant women) to assess the effect of azithromycin given to women in labour on neonatal mortality. As secondary objectives, we will measure the effect on maternal/neonatal hospitalization during the neonatal period and; the effect on bacterial resistance and transmission. The efficacy results will be used in a decision analytic model for estimating the cost-effectiveness of the intervention.

The advantages of our approach are its simplicity, the low cost, the possibility of targeting several bacteria and the integrated approach of protecting mothers and babies. The trial will be conducted in The Gambia and Burkina Faso to increase representativeness of the results. These two African institutions are unique in the region in having the infrastructures required for this trial. The MRCG is the only institution with baseline data.

Our study will evaluate a novel approach for preventing an important proportion of maternal and neonatal deaths in sub-Saharan Africa (SSA). The proposal has been developed in response to the current Sustainable Development Goal number 3 in which Maternal and Neonatal Health are global health priorities. The beneficiaries of the proposed intervention are women in labour attending health facilities for delivery and their offspring in SSA; they represents approximately two thirds of all deliveries occurring in The Gambia and in other SSA countries. The intervention is easy to implement (one dose of azithromycin given when the woman arrives at the health facility in labour) and low cost.

Azithromycin has been used in several randomized trials and interventions with different purposes, showing the high potential of this drug to decrease morbidity and mortality. However, we believe that azithromycin given to women in labour can have an impact on neonatal outcomes. Such new concept has been explored by the proof-of-concept study we carried out in The Gambia, in which 829 women and their offspring were included. The proof-of-concept study was designed to assess the effect of the intervention on bacterial colonization in both the women and their babies. Besides the strong impact of colonization, the study showed also a decrease on clinical outcomes in mothers and babies in the intervention arm. However, the study was too small to determine the impact of the intervention on neonatal mortality and severe morbidity. Therefore, we are proposing an adequately powered trial that will specifically evaluate the effect of the intervention on clinical outcomes, including severe morbidity and mortality.

Beyond the potential impact on public health, this trial has the opportunity to expand academic knowledge on maternal and neonatal health. We will generate a large amount of data on risk factors for maternal and neonatal morbidity and mortality, and on the aetiology of sepsis that can be prevented using innovative interventions. We will also learn if preventing infections during early life results into a better growth in infancy (another common cause of mortality) in SSA.

Building on the encouraging results of our proof-of-concept trial, the current trial includes social science, health systems research and a cost-effectiveness analysis. If the trial proves that neonatal sepsis and episodes of maternal or neonatal hospitalization and death can be prevented by a single administration of azithromycin to women in labour, we will evaluate the cost per episode prevented, the overall cost-effectiveness of the intervention and the feasibility of implementing this new intervention into the current health system in SSA.

As the proposed study will be conducted in a poor-resource setting, capacity building will be an important component. This study will offer the opportunity for African medical doctors and laboratory-based staff to have hands-on training in research methods of infectious diseases and global health. All study staff will receive continuous training on clinical research, such as Good Clinical Practices, Good Laboratory Practices and Ethics. In addition, we will include specific training sessions for the field staff; laboratory technicians will be working to the highest microbiological and scientific standards (the MRCG microbiology laboratory is the WHO reference for the West African region).

Translation of research findings into practice would be facilitated by the inclusion of representatives of the Burkina and Gambian Ministries of Health. If the trial is successful, their support will be key for the involvement of international policy-makers and public health organizations to accelerate the intervention's scale up.