Oral intrapartum Azithromycin to prevent sepsis during childbirth: Studies of effectiveness, safety and relevance among women and healthcare providers

Puerperal sepsis is defined as organ dysfunction resulting from infection during pregnancy, childbirth, post-partum, or post-abortion period, and it is a life-threatening condition. (1) As of 2020, global maternal mortality was 223 deaths per 100,000 live births. (2) Puerperal sepsis results in poor outcomes such as fetal or maternal death. Incidence and mortality rates of maternal sepsis differ between geographical regions as well as economic situation, race, and medical conditions. (3) Puerperal sepsis contributes about 11% of the global burden of maternal deaths and is among the top three causes of maternal death worldwide. (4) In Nigeria puerperal sepsis complicates 1% – 8% of all deliveries and is responsible for 15% of maternal deaths. (5) Sepsis cases are typically due to Staphylococcus aureus, Escherichia coli, and Klebsiella spp in most cases. Puerperal sepsis may lead to long-term morbidity even when treated. (6) Maternal infection also, increases the risk of neonatal sepsis which is the third common cause and accounts for 16% of neonatal deaths. (7)(8) The World Health Organization (WHO) does not recommend at present the routine application of antibiotics during spontaneous labour, however, recent advances and trials challenge this recommendation. (9) Azithromycin is an inexpensive broad-spectrum antibiotic that effectively targets the bacteria responsible for maternal sepsis in SSA. Its advantages include a prolonged half-life, high antibiotic levels in placental tissues, easy administration supporting compliance, relatively low cost, and few side effects, (10) (11) and its effect on perinatal morbidity and mortality has been tested in a few trials.

Applied during pregnancy, a randomized trial indicated a reduced risk of low birth weight and prematurity in malaria-endemic settings. (12) A recent multi-country placebo-controlled, randomized trial of 29,278 women found that a single oral dose of azithromycin administered during birth result in a significantly lower risk of maternal sepsis or death of 35% compared to placebo among women planning a vaginal delivery. (2) Similarly, another study in Gambia found a single intrapartum oral dose of 2 g of azithromycin reduced maternal infection by more than 50% and neonatal infection by more than 25% in women who were planning a vaginal delivery. (13) On the contrary, a multicenter, three-group, double-blind, randomized controlled trial in Cameroun found that a single dose of oral azithromycin (1g) with or without 2g of amoxicillin for prolonged labor or rupture of membranes at term did not significantly reduce maternal peripartum or neonatal infection or death. (14)

In view of the conflicting evidence, further studies are needed to evaluate the potential effects in view of concerns about the potential harms of administering routine azithromycin for vaginal deliveries in Low and Middle-income countries (LMIC). This is important against the threat of antimicrobial resistance, effects of changes to the maternal or neonatal microbiome, drug side effects, and costs. It is to note, that the Ministry of Health in Nigeria has requested further studies in the country to demonstrate the effect and safety before amending the national guidance.

In addition, more research is needed to understand potential implementation and scale-up constraints. Awareness of maternal sepsis among healthcare providers is crucial in the control of sepsis. Only if health care providers are appropriately knowledgeable its severity and outcomes implementation and scale-up will be possible to achieve (15) Also, puerperal sepsis-related knowledge and preventive practices among postpartum women are important for the early detection, prevention, and treatment of puerperal sepsis. (16) Further, postpartum infections contribute significantly to social burden by increasing maternal anxiety and the risk of postpartum depression. (17) This is the reason why post-partum depression has been added as a secondary outcome in this trial. The Bill and Melinda Gates foundation has committed to finance a trial in Nigeria and in addition encourages studies to better understand the present knowledge and management around sepsis in Nigeria.

Knowledge gap: In view of the i) favorable pharmacokinetics of Azithromycin, ii) the conflicting results from published trials and the iii) important contribution of sepsis to perinatal morbidity and mortality more research is warranted to assess the safety and effectiveness. Nigeria's maternal mortality rate is one of the highest in the world with sepsis being one of the major drivers of maternal mortality and morbidity, there is a need for evidence-based clinical decisions to improve maternal outcomes.(2)

Overall aim: To assess the effect and safety of single dose intrapartum azithromycin on maternal sepsis, post-partum depression (PPD) among pregnant women undergoing vaginal births in Nigeria as well as to assess the awareness of maternal sepsis among healthcare providers and pregnant women.

Research questions:
1) What is the knowledge of sepsis and what are management practices among trained healthcare providers?
2) What do pregnant women know about sepsis?
3) What is the clinical effectiveness, tolerability, and safety of intrapartum administration of oral azithromycin compared to current routine health facility practice (standard of care) for the prevention of maternal sepsis among pregnant women undergoing vaginal delivery in Nigeria.
4) What is the mental health status of women after vaginal birth and is there an association between sepsis and mental health?