An inexpensive and easy-to-deliver intervention — a single dose of the antibiotic azithromycin — could sharply reduce the number of pregnant people in low- and middle-income countries who develop the life-threatening condition sepsis in childbirth, a study published Thursday reported.
The results of an international trial, published in the New England Journal of Medicine, showed that administration of the antibiotic during labor cut the risk of the mother developing sepsis by about 35% — a large effect for such a simple intervention. The study was stopped early when a planned interim analysis found the clear benefit for those getting the drug.
One funder of the study, the Foundation for the National Institutes of Health (FNIH), estimates that if the approach is adopted widely in low- and middle-income countries, as many as 2 million cases of maternal sepsis could be averted annually.
The study, called A-PLUS — short for the Azithromycin Prophylaxis in Labor Use Study — followed up on earlier work in the United States that showed use of the same antibiotic during a planned cesarean section delivery cut the risk of the mother developing sepsis in half, explained Alan Tita, the lead author of both studies. Since the U.S. trial results were published in the New England Journal of Medicine in 2016, administration of azithromycin during C-sections has become recommended practice.
“We were hopeful because the U.S. study was remarkable,” Tita told STAT in an interview. “Here what we are looking at is a … 35% or so reduction of maternal sepsis. So it’s within the ballpark.”
The publication of the new paper was timed to correspond with the presentation of the findings at the Society for Maternal-Fetal Medicine’s 43rd annual pregnancy meeting in San Francisco on Thursday.
The study was conducted at eight sites in seven countries, mostly in Sub-Saharan Africa and Asia: Bangladesh, the Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, and Zambia. It was conducted by the Global Network for Women’s and Children’s Health Research, part of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
More than 29,000 women who were planning to have a vaginal birth were randomly assigned to either receive a 2-gram oral dose of azithromycin, consisting of four 500 millligram pills, or a placebo when they were in labor.
Sepsis is a dangerous condition that occurs when a response to an infection goes awry. Immune reactions meant to protect against infection instead attack the body itself, impairing blood flow to the brain and other vital organs. Most people survive mild sepsis. But if it isn’t treated promptly, septic shock can develop; it has a fatality rate of about 40%.
Maternal infections, particularly sepsis, rank among the top three causes of maternal deaths, causing about 10% of such deaths globally. And maternal sepsis increases the risk of sepsis in newborns, which accounts for about 16% of neonatal deaths.
Azithromycin is a broad-spectrum antibiotic with a long half-life, which means the drug is not quickly flushed from the body. It does not require refrigeration and is a generic drug, characteristics that make it well-suited to the goal of the study — to find a feasible way to lower the risk of maternal sepsis in low-resource settings.
“It’s a huge effect. If you were to apply any intervention that had an effect size of 35% to such a large population of people, the potential is enormous,” said Julie Gerberding, CEO of FNIH. “And the fact that it is affordable, available, and we’re not talking about a long course of treatment — we’re talking about a dose — so it’s very practical from that standpoint.”
Denise Jamieson, who chairs the department of gynecology and obstetrics at Emory University, agreed, saying the intervention will be feasible to use in many settings.
“I was pleased to see some good news in the area of global maternal mortality,” she said, adding that the study was carefully conducted. Jamieson was not involved in the study.
There is some reason to think the effect on maternal sepsis might actually be bigger. Many of the women enrolled in the Asian sites were using other antibiotics at the time of delivery, Tita said. That may have lowered their risk of developing sepsis, thereby dampening the impact of the intervention in the trial. The majority of the trial participants — 55% — were enrolled in Asia. The study noted that the effect in the African countries was greater than what was seen in the Asian settings.
Michael Santos, vice president for science for FNIH, said the result was especially impressive because the trial didn’t focus exclusively on women at high risk of a difficult birth, instead enrolling anyone planning a vaginal birth at the trial sites. Focusing solely on high-risk women would have made it easier to see an impact, if there was one; that such a large effect was seen in a population of women of all risk levels was striking, he suggested.
The trial did not observe a lower rate of maternal deaths among women who got the antibiotic versus those who got the placebo. But the number of deaths in both groups was low. Tita said it would have taken a larger sample size to see there was a statistically significant difference in deaths between the two groups.
Likewise, the study did not show that use of azithromycin in the mothers lowered the risk of sepsis or neonatal death in their babies. Tita noted that the U.S. study testing use of IV azithromycin in women giving birth by C-section did not see an impact on sepsis rates among the newborns either.
However, the new study showed lower rates of other problems among the women who received the antibiotic; lower risk of maternal endometritis, a uterine infection; and lower rates of hospital readmission and unscheduled medical visits after birth among the women who received the drug. Tita said the group would like to do a cost-benefit analysis. One such study done in the United States showed that for every dose of intravenous azithromycin given to a woman having a C-section, more than $300 in other medical costs were averted, he said.
Tita said the group also plans to reach out to the World Health Organization to try to get the global health agency to recommend that use of this intervention becomes standard practice in planned vaginal births in appropriate settings.
Interestingly, one of them may not be the United States. Jamieson said that while infection is a major cause of maternal mortality in the U.S. as well, the country has a lower rate and pattern of sepsis in delivery than what was seen in the study sites, and much higher antibiotic use as well. “This is not necessarily a solution for the U.S.,” she said.
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the FNIH, and the Bill & Melinda Gates Foundation.
A previous version of this article misstated the number of pills used in the study. It is a single dose given in four pills, not a single pill.