Azithromycin for prevention: How much do we know about its potential to save mothers and infants?
“Mejor prevenir que curar.”
“Heri kuzuia kuliko kuuguza.”
“An ounce of prevention is worth a pound of cure.”
Cultures around the world acknowledge the value of preventing problems before they happen. Many ancient medical traditions, like traditional Ayurvedic medicine from India, are based on preventative health practices like gentle exercise and a healthy diet and rest. Modern preventive health strategies like vaccinations, cancer screenings, and preventive medications have expanded our options for prevention of disease and infection, including for mothers, babies, and children.
For some of these contemporary tools, such as preventative medications, the landscape can be complicated. One such medication is azithromycin, an antibiotic that has been used successfully to prevent and treat infections for decades. With its ability to fight a wide range of bacteria, antimalarial activity, tendency to be absorbed well and last a long time in the body, relatively minor side effects, and excellent tissue penetration in the respiratory tract, skin, placenta, and reproductive organs, azithromycin quickly became a star in the clinical toolbox. It is also relatively inexpensive and on the WHO Model Lists of Essential Medicines and many national formularies, increasing its potential availability at scale and making it a good candidate for mass drug administration (MDA) or systematic drug administration (SDA) programs.
Researchers have spent decades testing the potential role of azithromycin to prevent life-threatening infections, a leading cause of death for both mothers and newborns. The results have excited, disappointed, and then excited again scientists and clinicians the world over, creating a complicated knowledge landscape for use of prophylactic azithromycin among mothers, infants, and children. If you’ve had trouble keeping up with all the emerging science, you’re not alone. The large number of studies and the wide variation in study designs (including timing, dose, medication route, follow-up periods, outcomes of interest, and rationale), has made the evidence particularly challenging to follow!
So, what do we currently know about azithromycin for preventing maternal and newborn infections? Could more routine use of this medication accelerate our progress toward health-related SDGs, especially for moms and babies? We discuss some of the evidence in this post.
A person receives a dose of azithromycin in Ethiopia. Photo credit: Mark Tuschman/ITI – CC BY-NC 2.0
Mass drug administration as a prevention strategy
MDA and SDA programs are preventative strategies that offer safe and inexpensive medicines to entire populations (MDAs) and sub-populations (SDAs) for treatment and prevention of a disease without individual diagnosis. Historically, both have produced positive results.
One of the first documented and effective MDA programs took place in 1910 in the southern United States, where 40% of children were found to be infected with hookworm, an infection that can cause severe anemia and have detrimental effects on growth and development. Health authorities administered an anti-parasite medication via schools, churches, and community centers and rolled out sanitation and education programs. The result was a dramatic drop in infections and an increase in school enrollment.
Could scientists then replicate such positive results with azithromycin for other types of infections?
In 1993, a randomized controlled trial showed that a single dose of azithromycin was equivalent to the arduous 6-week course of tetracycline eye ointment for the treatment of trachoma, a blinding eye infection and one of the most common causes of blindness in low-resource countries. Unsurprisingly, azithromycin MDAs for trachoma became widespread.
Azithromycin and mass drug administration for children
Scientists studying azithromycin in trachoma MDA trials incidentally found reduced diarrhea, skin infections, and malaria in children. Excited by these findings, a flurry of clinical trials ensued, examining child mortality, antibiotic resistance, and gut microbiota to determine if MDAs with azithromycin for decreased child mortality is a smart investment.
A WHO Guideline Development Group (GDG) reviewed this expansive literature and ultimately issued guidelines recommending against universal MDA with azithromycin for prevention of childhood mortality due to mixed results from several studies. However, WHO guidelines do recommend that MDA with azithromycin for reduction in child mortality may be considered under some well-defined circumstances.
Following studies that demonstrated a decrease in childhood mortality with azithromycin MDA programs for trachoma, newborn health researchers hoped they might see drops in infant mortality if they gave a single dose of azithromycin to newborns. They also thought they might see a growth-promoting effect for newborns, which had been demonstrated in previous trials looking at antibiotics in older infants and children.
Unfortunately, these trials showed no impact of neonatal azithromycin administration on reductions in child mortality or growth. And importantly, azithromycin belongs to a class of antibiotics called macrolides that have been linked with a potentially serious newborn condition called pyloric stenosis, a narrowing of the opening leading from the stomach into the small intestine. Since we don’t yet fully understand the link, the risk-benefit calculus of azithromycin in newborns is still unfavorable.
Prophylactic azithromycin for maternal and newborn infections
More recently, researchers have been exploring prophylactic azithromycin as a possible new intervention for all women who present to facilities in early labor. It’s important to note that this approach would be different from prophylaxis strategies already endorsed in global recommendations to provide other antibiotics to women with specific risk factors for maternal or newborn infection, such as preterm premature rupture of membranes (PPROM), prolonged rupture of membranes at term, group B Streptococcus (GBS) colonization, or anticipated cesarean delivery, for example. These recommendations are already well established in many countries that have adopted the WHO recommendations for prevention and treatment of maternal peripartum infections.
Depending on where you live, you might be less familiar with the practice of using azithromycin as part of clinical strategies to address the scenarios mentioned above. In some settings, intravenous azithromycin is provided in addition to a standard antibiotic prophylaxis regimen, usually a first-generation cephalosporin, for women undergoing a nonelective cesarean delivery, due to evidence suggesting a greater reduction in endometritis and wound infection, among other negative outcomes. Azithromycin has also been investigated and used, particularly in higher resource settings, for its activity against Mycoplasma and Ureaplasma bacteria, and its potential to increase the latency period, or the time elapsed between onset of PPROM to delivery.
Given the range of evidence we have around the potential advantages of azithromycin to prevent infections, does it make sense to give azithromycin to all women in early labor?
In 2023, a study on prophylactic azithromycin, the A-PLUS trial, was presented as a late breaker abstract at IMNHC 2023. This randomized trial took place in Bangladesh, Democratic Republic of Congo, Guatemala, India, Kenya, Pakistan, and Zambia, and focused on the use of a single 2-gram oral dose of azithromycin given in early labor. The researchers found that among almost 30,000 pregnant women planning a vaginal birth, those in the azithromycin group were about a third less likely to experience maternal sepsis or death compared to women in the placebo group, a finding consistent with two previous but smaller trials. However, the intervention didn’t appear to have any beneficial impact on reducing stillbirth, neonatal death, or neonatal sepsis. Another randomized clinical trial on prophylactic azithromycin was carried out among nearly 12,000 laboring mothers in Burkina Faso and The Gambia. In that trial, researchers also found that azithromycin given orally during labor did not reduce neonatal sepsis or mortality.
Why did these recent trials show benefit in reducing major infections for laboring women but not their infants? Although azithromycin is a broad-spectrum antibiotic, a 2021 study suggests that it does not cover many of the bacteria that commonly cause neonatal sepsis. As powerful as it is, azithromycin is not the antibiotic of choice to treat infections with group B Streptococcus or E. coli, two leading causes of early-onset neonatal sepsis.
The need to evaluate azithromycin and antibiotic resistance
It is well established that as antibiotic use increases, resistance to antibiotics increases. Many azithromycin MDA programs for trachoma are administered in low-income countries in sub-Saharan Africa, where antibiotic access and use are lower compared to many higher income countries. It is not surprising, then, that trials looking at antibiotic resistance in these particular programs have mixed results, many with low levels of resistance.
However, many questions remain, like what might resistance look like in settings with higher rates of antibiotic use and misuse? What about after years of repeated doses in MDA and SDA programs, or in settings with different distributions of resistance genotypes? What are the impacts on mothers’ and babies’ gut microbiome and subsequent growth, development, or sensitivity to antibiotics? Could new azithromycin SDA programs targeting laboring women be used in countries undertaking MDA without risking an acceleration of macrolide resistance? How do we gauge the balance of risks and benefits, and which strategies to prevent maternal and newborn infections are the most cost-effective for health systems?
In the case of SDA with azithromycin for prevention of maternal infection, the evidence strongly suggests benefit, but we know that emerging evidence on antimicrobial resistance will be critical for estimating the balance of risk and benefit at a population level. For children, the body of evidence for MDA with azithromycin for reduction in mortality is heterogenous and nuanced, and implementation should be thoughtful and based on the current WHO guidance.
MDA and SDA programs with azithromycin and other antibiotics must therefore be studied carefully in varying contexts, and always with robust resistance surveillance systems and substantial inputs from communities in which these trials occur. Fortunately, the A-PLUS study has included a sub-study to assess the effect of the azithromycin intervention on antimicrobial resistance and microbiome diversity. Results of this sub-study are anticipated in the coming year and will likely have a substantial impact on the nature of any guidelines issued by WHO, which is expected to convene a GDG to review the full breadth of literature on the use of prophylactic azithromycin during labor.
Beyond the current evidence for azithromycin
Meanwhile, other studies are looking at the potential impact of prophylactic azithromycin provided in combination with other interventions, such as nutritional supplementation, and its impact at different points along the continuum of care for mothers and newborns. Interest continues in whether azithromycin can improve outcomes related to stillbirth, preterm birth, and infant neurodevelopment. The SANTE study is currently investigating the efficacy of oral azithromycin administered to pregnant women and/or infants during routine care in preventing stillbirths and mortality through 6-12 months of age in Mali, West Africa, where rates of infant and under five mortality are among the highest in the world. We can also look forward to ample new evidence emerging in the coming years from the Global Network for Women’s and Children’s Health Research.
Fortunately, we do have other ways to prevent many serious infections in pregnant and laboring women and newborns. While the global maternal and newborn health community continues to learn more about promising interventions like prophylactic azithromycin, we have ample evidence to continue to accelerate our efforts around infection prevention and control and fight antimicrobial resistance. Those of us working in maternal and newborn health need to advocate for these interventions within a comprehensive, patient-centered model of care.
For a more detailed discussion of the evidence, we recommend taking a look at results from the PeRinatal, neOnatal, and Maternal OuTcomEs with azithromycin prophylaxis in pregnancy and labour (PROMOTE-PROPHYLAXIS) systematic review and meta-analysis, published in this month’s Lancet eClinical Medicine.
For mothers and babies everywhere, WHO’s Guidelines on Core Components of Infection Prevention and Control (IPC) Programmes are a good start, and include recommendations for establishing IPC programs, training, infection surveillance, and auditing. Additionally, the WHO recommendations for prevention and treatment of maternal peripartum infections summarize a range of evidence-based interventions for avoiding maternal infection. Strategies like use of the WHO Labour Care Guide also have the potential to improve quality of intrapartum care and help properly resourced and supported health workers to avoid known risks for maternal and newborn infections, like prolonged labor and overuse of digital vaginal exams.
Dr. Lisa Noguchi is the Director, Maternal, Newborn, and Child Health at Jhpiego and Dr. Bina Valsangkar is a Principal Technical Advisor, Maternal and Newborn Health at Jhpiego.