The results of a multi-country, randomized clinical trial indicate that a single dose of a widely-used, inexpensive antibiotic during childbirth significantly cuts the risk of sepsis or death in pregnant women.
The study, published yesterday in the New England Journal of Medicine, found that women who received an oral dose of azithromycin before a vaginal delivery had a 33% reduced risk of maternal sepsis or death compared with those who received placebo. The outcome was driven primarily by a 35% reduction in the risk of sepsis. The intervention was so successful that the trial was stopped early because of the clear maternal benefit of azithromycin.
The investigators and funders of the trial say the results suggest a single dose of azithromycin could represent a low-cost solution for one the top three causes of maternal death worldwide.
"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," Diana W. Bianchi, MD, director of the National Institute of Health's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), said in a press release.
NICHD was a primary funder of the trial, along with the Bill and Melinda Gates Foundation.
Thirty-five percent reduction in sepsis
Conducted at eight sites in seven countries (Bangladesh, Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan, and Zambia), the Azithromycin Prevention in Labor Use Study (A-Plus) screened more that 44,000 pregnant women at 28 weeks gestation or more who had been admitted to hospital for vaginal delivery from Sep 9, 2020, through Aug 8, 2022.
The trial, which was also funded by the Bill and Melinda Gates Foundation, was part of ongoing efforts to address maternal deaths from pregnancy-related infections and sepsis, which occurs when the immune system overreacts to a bacterial or viral infection, causing tissue damage and organ failure. Sepsis accounts for 10% of maternal deaths worldwide, but the rate in low- and middle-income countries (LMICs) is twice that of high-income countries. Maternal sepsis also increases the risk of neonatal sepsis, which accounts for 16% newborn deaths.
Prophylactic azithromycin is currently recommended for pregnant women delivering via cesarean section by the World Health Organization and other groups, based on a US trial that showed a 50% reduction in the risk of maternal sepsis in women who received intravenous azithromycin. But there are no recommendations for prophylactic antibiotics before vaginal birth.
At a presentation of the study abstract at the annual meeting of the Society for Maternal-Fetal Medicine, lead investigator Alan Tita, MD, PhD, of the University of Alabama at Birmingham, said the trial aimed to build on the findings from the cesarean trial, as well as those from previous test-of-concept studies that suggested a 1- or 2-gram dose of azithromycin given to women giving birth vaginally in LMICs reduced both maternal and neonatal infections.
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
A total of 29,278 women underwent randomization, with 14,590 assigned to receive a single, 2-gram oral dose of azithromycin and 14,688 to receive placebo. The median age in both groups was 24 years. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. The investigators also assessed incidence of specific maternal infections like endometritis, as well as safety outcomes.
Maternal sepsis or death occurred in 1.6% of women in the azithromycin group and 2.4% in the placebo (relative risk, 0.67; 95% confidence interval [CI], 0.56 to 0.79). Since deaths from sepsis occurred in less than 0.1% of the women in each group, the composite results were driven by reduction in maternal sepsis, which occurred in 1.5% in the azithromycin group compared with 2.3% in the placebo group (relative risk, 0.65; 95% CI, 0.55 to 0.77).
Women in the azithromycin group also had lower risk of endometritis (relative risk, 0.66; 95% CI, 0.55 to 0.79), wound infections (relative risk, 0.71; 95% CI, 0.60 to 0.84), and other infections (0.69; 95% CI, 0.56 to 0.85). At least one maternal side effect was reported in 7.1% of women in the azithromycin group and 7.6% of women in the placebo group.
The investigators said the findings indicate that the number of women who would need to be treated with azithromycin to prevent one case of maternal sepsis or death was 125. Tita added that azithromycin also led to reduced use of healthcare resources, as there were fewer hospital readmissions and unscheduled care visits among women in the azithromycin group.
"Azithromycin prevents maternal sepsis deaths…mainly by reducing maternal sepsis and specific infections that lead to sepsis," Tita said. "These findings also suggest the potential to cost-effectively improve maternal outcomes."
No effect on neonatal death or sepsis
Azithromycin did not have an impact on neonatal outcomes, however. Stillbirth or neonatal sepsis within 4 weeks of delivery occurred in 10.5% of infants in the azithromycin group and 10.3% in the placebo group (relative risk, 1.02; 95% CI, 0.95 to 1.09), while neonatal sepsis alone occurred in the 9.8% of infants in the azithromycin group and 9.6% in the placebo group (relative risk, 1.03; 95% CI, 0.96 to 1.10).
Tita and his colleagues noted that additional sub-studies looking at whether adding routine azithromycin for vaginal deliveries increases antibiotic resistance, or induces changes in the maternal or neonatal microbiome, are ongoing. This is a particular concern in the Asian countries where the trial was conducted, which have higher rates of overall antibiotic use than the African countries.
"Although available studies have not shown significant associations between a single azithromycin dose and sustained carriage of resistant organisms or an increase in resistant infections, more long-term data are needed to inform the association between the routine use of oral azithromycin prophylaxis for vaginal delivery and macrolide resistance patterns and subsequent effects on the microbiome," they wrote.