In a large, international study, a single oral dose of the low-cost antibiotic azithromycin during labor lowered the risk of maternal sepsis or death among women delivering vaginally by 33%. The study results were recently published in the New England Journal of Medicine and presented at the Society for Maternal-Fetal Medicine’s 43rd’s Annual Pregnancy Meeting in San Francisco.
While azithromycin administration is common in the United States and elsewhere for women undergoing unplanned cesarean delivery, its effect on those with planned vaginal delivery had been unknown prior to this study, according to the study researchers.
Trial participants were part of a Bill & Melinda Gates Foundation and National Institutes of Health (NIH)-funded trial called Azithromycin Prevention in Labor Use Study (A-PLUS).
The A-PLUS story
The placebo-controlled, randomized A-PLUS trial involved 29,278 pregnant women in Bangladesh, the Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan, and Zambia. Between September 2020 and August 2022, women planning to deliver vaginally were randomly assigned to receive either a 2-gram dose of oral azithromycin or a placebo during labor.
This University of Alabama Birmingham-led study had been designed to include 34,000 women. However, an interim analysis of study data found the treatment had a significant beneficial effect, and enrollment was halted early for maternal effectiveness after ~29,000 women had been studied.
Only 1.6% of women in the study who received prophylactic azithromycin during labor developed sepsis or died within 6 weeks of delivery, compared to 2.4% of those who received placebo, the researchers found. In addition, study results showed a lower risk of maternal endometritis, infections, readmissions, and unscheduled health care visits in the azithromycin group vs placebo. However, the study data on benefits of azithromycin administration did not extend to newborns, the researchers noted, nor did it reduce the risk of stillbirth, newborn sepsis, or newborn death.
The maternal sepsis scourge
During pregnancy, women undergo physiological and anatomical changes and a complicated modulated immune response, which increases the risk of infection (Kourtis et al. 2014). Maternal sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infections during pregnancy, childbirth, post-abortion, or the postpartum period, can lead to organ failure and death (Chen et al. 2021).
Infection, especially sepsis, contributes significantly to global morbidity and mortality—principally in vulnerable populations. Peripartum maternal infections, particularly sepsis, account for 10% of maternal deaths. The World Health Organization (WHO) estimates that sepsis due to obstetric infection is the third most common cause of maternal mortality globally. And while the incidence and death of maternal sepsis are more prevalent in poorer countries, developed countries are not immune to this serious problem. Hensley and colleagues’ study found that 23% of all maternal deaths were sepsis-related in the United States (JAMA, 2019), and Duan and colleagues cite that sepsis accounts for up to 28% of US maternal deaths and up to 15% of maternal admissions to the ICU (Medicine [Baltimore]. 2019).
Prior research in the US by Tita and colleagues found that the use of azithromycin resulted in a lower incidence of maternal infections, including a 50% lower risk of endometritis and wound infections, than with the use of placebo. Azithromycin administration was also associated with fewer readmissions or unscheduled care visits, although outcomes for newborns were not affected (N Engl J Med. 2016).
Some risk, but global promise
The researchers did note that potential harms of adding routine azithromycin for vaginal deliveries include increased antimicrobial resistance, effects of changes to the maternal or neonatal microbiome, and potential drug side effects. However, in their study, no association was found between azithromycin and a higher occurrence of adverse events.
“The top three causes of maternal mortality are infections, hypertensive disorders, and hemorrhage,” stated Professor Esamai, professor of child health and pediatrics at Moi University School of Medicine in Kenya, one of 8 sites in 7 countries which contributed to the A-Plus study. “If widely adopted and scaled-up, this simple intervention could potentially save thousands of lives of new mothers every year.”
“These findings have the potential to change clinical practice by providing a safe, effective, and low-cost approach to reduce the global burden of maternal sepsis and death,” said Diana W. Bianchi, MD, director of NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), in a communique accompanying the study’s presentation at the conference.
“We urgently need effective strategies to prevent pregnancy-related infections, which account for roughly 10 percent of maternal deaths worldwide.”
The complete article, “Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth,” can be found at no cost here.
Clinicians’ Bonus: More To Know
Resources for you and your patients
Maternal sepsis is a significant—but preventable—cause of maternal morbidity and mortality. Find the Society for Maternal-Fetal Medicine (SMFM)’s latest clinical guideline, entitled “SMFM Consult Series #47: Sepsis during pregnancy and the puerperium,” here. The guideline, also endorsed by the American College of Obstetricians and Gynecologists (ACOG), summarizes current about sepsis and empowers healthcare professionals with guidance for its management in pregnancy and the postpartum period.
For further enrichment, don’t miss the SMFM podcast in which Judette Louis, MD, MPH, Chair, College of Medicine Obstetrics & Gynecology at University of South Florida (USF), and obstetrician-gynecologist Tony Kendle, MD, also from USF, review and discuss the SMFM guideline. Listen to the free, on-demand podcast here.
The diagnosis of maternal sepsis remains a challenge as the normal physiologic adaptations of pregnancy can mask the recognition of its common signs and symptoms. In mid-2021, National Institutes of Health (NIH) published its “Top 10 Pearls for the Recognition, Evaluation, and Management of Maternal Sepsis” to raise health care professionals’ awareness of the unique complications of sepsis in critically ill pregnant and postpartum patients, and provide steps to prevent poor outcomes in this population.
For Your Patients
Brenna L. McGuire, MD, Assistant Professor of Assistant Professor of Obstetrics and Gynecology at University of New Mexico, recently penned a brief and measured advisory for women called “Maternal Sepsis: 5 Ways to Reduce Your Risk.” This concise guide can help your patients learn about this rare but serious condition and assist them in advocating for themselves and their babies.
The contents of this feature are not provided or reviewed by NPWH.