Effect of Intrapartum Azithromycin on Early Childhood Microbiome Development A Randomized Placebo-Controlled Trial

Intrapartum and postpartum infections are substantial contributors to morbidity and mortality in both mothers and neonates in SSA, and most countries in the region are likely to fall short of meeting the SDG-3 targets by 2030. Context specific interventions to reduce severe maternal and neonatal infections in SSA are therefore a public health priority. PregnAnZI-1, a proof-of-concept clinical trial conducted in The Gambia, showed that 2g oral intrapartum azithromycin reduces carriage of bacteria commonly associated with severe maternal and neonatal infections in SSA (i.e. Staphylococcus aureus, Streptococcus pneumoniae and Group B Streptococcus). Subsequently, a larger trial (PregnAnZI-2) was conducted in The Gambia and Burkina Faso, to assess the impact of this intervention on neonatal sepsis and mortality. Concurrently, another trial (A-PLUS) of the same intervention was conducted in seven countries across SSA, South Asia, and Latin America to assess the effect on both maternal and neonatal sepsis and mortality. Both the PregnAnZI-2 and A-PLUS trials showed a strong impact on maternal morbidity, with A-PLUS showing a 35% reduction in maternal sepsis. While the trials showed no effect on neonatal sepsis or mortality, other morbidities such as skin infections were reduced. Intrapartum azithromycin prophylaxis has the potential to decrease maternal sepsis and other morbidities in both mothers and neonates, but its effects on the development of the child’s microbiome are unknown. Generating such information is key for a holistic evaluation of the potential public health impact of the intervention before its wider implementation. This PhD is ancillary to the PregnAnZI trials and aims to explore the effects of intrapartum azithromycin on the development of the child’s nasopharyngeal and gut microbiota. The research has three main objectives, addressed in 3 peer-reviewed manuscripts, as follows: 1. Assess the effect of intrapartum azithromycin on the development of the nasopharyngeal bacterial community during infancy. 2. Assess the effect of intrapartum azithromycin on the development of the gut bacterial community during the first 3 years of life. 3. Assess the effect of intrapartum azithromycin on the development of the gut fungal community during the first 3 years of life. My investigations have shown that intrapartum azithromycin has varying effects on the nasopharyngeal and gut microbiota of the child. The intervention showed the potential to control the rapid expansion of Staphylococcus, a major neonatal pathogen, in the nasopharynx during the first week of life. However, in the gut, the intervention increased abundance of Enterobacteriaceae and Enterococcaceae while decreasing Bifidobacterial abundance. Additionally, intrapartum azithromycin showed the potential to increase the abundance of Candida orthopsilosis, a potential fungal pathogen, in the gut, during the wet season. Yet, in both the nasopharynx and the gut, the intervention did not alter the long-term development of the microbiota. Though intrapartum azithromycin showed mostly short-lived effects on the microbiota of the child, the potential impacts of these temporal effects on the health of the child needs careful evaluation. These findings, together with results of the main trial, will provide vital information for a holistic evaluation of risks and benefits for the child associated with the intervention