By Ahizechukwu C. Eke, MD, PhD, MPH
Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore
SYNOPSIS: A single oral dose of azithromycin dramatically reduced the risk of maternal sepsis or death among women planning vaginal deliveries compared to placebo but had little effect on neonatal sepsis or mortality.
SOURCE: Tita AT, Carlo WA, McClure EM, et al. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med 2023;388:1161-1170.
Maternal sepsis, which accounts for 11% of maternal deaths globally, is the third most frequent direct cause of maternal mortality and a significant contributor to severe maternal morbidity.1 With maternal sepsis accounting for 13% of all maternal deaths and a cause-specific maternal mortality ratio of 2.2 deaths per 100,000 live births in the United States, it currently is the fourth most common cause of maternal mortality in the United States.2 Death rates following puerperal sepsis can reach 50% in low- and middle-income countries.3
A U.S. randomized controlled trial that demonstrated a 50% reduction in the incidence of maternal sepsis in women who received intravenous azithromycin prior to cesarean led to the current recommendation by the American College of Obstetricians and Gynecologists (ACOG) that prophylactic azithromycin be given to pregnant individuals having cesarean deliveries.4,5 However, despite some reports of an increased risk of maternal infections after vaginal deliveries and the potential benefit of using azithromycin to prevent maternal sepsis during vaginal births, similar recommendations for prophylactic antibiotics do not exist, including the use of azithromycin prior to vaginal deliveries.6,7 In this trial (Azithromycin Prevention in Labor Use Study [A-Plus]), Tita et al tested the hypothesis that a single oral dose of azithromycin in women in labor who were planning a vaginal delivery would reduce maternal sepsis or death along with stillbirth or neonatal death or sepsis.8
This was a double-blind, multi-country, multicenter, placebo-controlled, randomized clinical trial conducted at eight sites in seven low- or middle-income countries of the Global Network for Women’s and Children’s Health Research of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): Bangladesh, Democratic Republic of the Congo, Guatemala, India, Kenya, Pakistan, and Zambia. Inclusion criteria were pregnant individuals with singleton and multiple gestations, ≥ 28 weeks of gestation, who provided written informed consent, and who were admitted for spontaneous labor or underwent induction of labor. Women were excluded if they had diagnosed puerperal infection warranting the use of antibiotics, cardiac arrhythmia or known cardiomyopathy, allergy to azithromycin or other macrolide antibiotics or the use of these antibiotics within three days, planned cesarean delivery before randomization, advanced stage of labor (cervical dilatation of ≥ 6 cm), and any medical condition that was considered to be a contraindication by the site investigator.8
The primary outcomes were a composite of maternal sepsis or death within six weeks after delivery and a composite of stillbirth or neonatal death or sepsis within four weeks. Secondary maternal outcomes included individual components of the primary outcome, chorioamnionitis, endometritis, wound infections, abdominal or pelvic abscess, mastitis or breast abscess, pneumonia, pyelonephritis, therapeutic use of antibiotics, duration of hospital stay, readmission, admission to a special care unit, and unscheduled healthcare visits.
Secondary neonatal outcomes included any neonatal infection, duration of hospital stay, readmission, admission to a special care unit, unscheduled healthcare visits, and safety outcomes. A sample size of at least 34,000 pregnant individuals would provide the trial with > 90% power to detect a relative difference of 20% between the azithromycin group and the placebo group in the maternal primary outcome on the basis of a baseline incidence of 3% across sites, assuming a type 1 error rate of 5% (two-sided) and a loss to follow-up of 2% to 3%. The primary analysis was by intention-to-treat.
Investigators in the A-Plus study screened > 44,000 pregnant individuals between Sept. 9, 2020, through Aug. 8, 2022. A total of 29,278 women met inclusion criteria and underwent randomization, with 14,590 assigned to receive a single, 2-g oral dose of azithromycin and 14,688 to receive placebo. Overall, the two groups were well balanced with respect to the baseline and demographic characteristics. Administration of 2 g of azithromycin resulted in a 35% reduction in the composite primary outcome (occurred in 1.5% of women in the azithromycin group vs. 2.3% in the placebo group; relative risk [RR], 0.65; 95% confidence interval [CI], 0.55, 0.77). There was a 33% reduction in the risk of maternal sepsis or death in the azithromycin group compared to placebo (1.6% vs. 2.4%; RR, 0.67; 95% CI, 0.56, 0.79). Women in the azithromycin group also had a 34% lower risk of endometritis (RR, 0.66; 95% CI, 0.55, 0.79), 29% lower risk of cesarean and perineal wound infections (RR, 0.71; 95% CI, 0.60, 0.84), and 31% lower risk of other infections (RR, 0.69; 95% CI, 0.56, 0.85). At least one maternal adverse effect was reported (7.1% of women in the azithromycin group and 7.6% of women in the placebo group). Stillbirth or neonatal sepsis within four weeks of delivery were not statistically significant between the azithromycin and placebo groups (10.5% vs. 10.3%; RR, 1.02; 95% CI, 0.95, 1.09). The number of women who would need to be treated with azithromycin to prevent one case of maternal sepsis or death was 125.
COMMENTARY
Early diagnosis of sepsis is crucial if lives are to be saved, because late diagnosis and escalating therapy are major causes of maternal morbidity and mortality.1,9 However, only a few evidence-based, pregnancy-specific recommendations are available for healthcare professionals on how to detect, prevent, and manage the early warning symptoms of puerperal sepsis. Early warning sepsis signs, systemic inflammatory response syndrome, and quick sequential organ failure assessment (qSOFA) criteria are just a few of the early warning scoring systems that have been created to help identify sepsis to aid in prompt diagnosis and management.10 Most commonly, the diagnosis of sepsis is based on a qSOFA score of ≥ 2 with a suspicion of infection. The higher the qSOFA score, the higher the probability of morbidity and mortality. Although these sepsis screening methods are efficient for use in nonpregnant individuals for early detection and management of sepsis, there is no optimal method for sepsis screening during pregnancy.11
The early and appropriate use of antibiotics is crucial in the prevention of maternal sepsis during pregnancy. Tita et al argue that the results of this New England Journal of Medicine study have the potential to change clinical practice by providing safe, effective, and low-cost approaches to reduce the global burden of maternal sepsis and death.8 However, there are concerns that prophylactic antibiotics to prevent sepsis after normal vaginal delivery will lead to widespread unnecessary use of antibiotics, which potentially can increase azithromycin antibiotic resistance. To tackle this concern, Tita et al noted that while there are some ongoing studies trying to address the question of whether adding routine azithromycin for all vaginal deliveries would increase antibiotic resistance or induce changes in the maternal or neonatal microbiome, currently available studies have not shown significant associations between a single azithromycin dose and sustained carriage of resistant organisms or an increase in resistant infections, although more long-term data are needed.8
In summary, azithromycin has been shown to prevent maternal death when used for prophylaxis prior to cesarean delivery and currently is recommended by ACOG.4,5 Although this study demonstrates its potential utility in reducing maternal and infant morbidity and mortality when used for sepsis prophylaxis for vaginal deliveries, concerns about antibiotic resistance remain. There are no recommendations from ACOG, the World Health Organization, or other health regulatory bodies at this time regarding prophylactic antibiotics to prevent sepsis during normal vaginal delivery. Until such recommendations are available, healthcare providers should continue to discuss the pros of azithromycin use (prevention of maternal sepsis) vs. the cons (potential for misuse and antibiotic resistance) in women undergoing vaginal delivery.
REFERENCES
- Ali A, Lamont RF. Recent advances in the diagnosis and management of sepsis in pregnancy. F1000Res 2019;8:F1000 Faculty Rev-1546.
- Fan SR, Liu P, Yan SM, et al. New concept and management for sepsis in pregnancy and the puerperium. Maternal-Fetal Med 2020;2:231-239.
- Bonet M, Souza JP, Abalos E, et al. The global maternal sepsis study and awareness campaign (GLOSS): Study protocol. Reprod Health 2018;15:16.
- Tita AT, Szychowski JM, Boggess K, et al. Adjunctive azithromycin prophylaxis for cesarean delivery. N Engl J Med 2016;375:1231-1241.
- Committee on Practice Bulletins-Obstetrics. ACOG Practice Bulletin No. 199: Use of prophylactic antibiotics in labor and delivery. Obstet Gynecol 2018;132:e103-e119.
- Oluwalana C, Camara B, Bottomley C, et al. Azithromycin in labor lowers clinical infections in mothers and newborns: A double-blind trial. Pediatrics 2017;139:e20162281.
- Subramaniam A, Ye Y, Mbah R, et al. Single dose of oral azithromycin with or without amoxicillin to prevent peripartum infection in laboring, high-risk women in Cameroon: A randomized controlled trial. Obstet Gynecol 2021;138:703-713.
- Tita AT, Carlo WA, McClure EM, et al. Azithromycin to prevent sepsis or death in women planning a vaginal birth. N Engl J Med 2023;388:1161-1170.
- Firoz T, Woodd SL. Maternal sepsis: Opportunity for improvement. Obstet Med 2017;10:174-176.
- Churpek MM, Snyder A, Han X, et al. Quick sepsis-related organ failure assessment, systemic inflammatory response syndrome, and early warning scores for detecting clinical deterioration in infected patients outside the intensive care unit. Am J Respir Crit Care Med 2017;195:906-911.
- Cagino SG, Burke AA, Letner DR, et al. Quick sequential organ failure assessment: Modifications for identifying maternal morbidity and mortality in obstetrical patients. Am J Perinatol 2022;39:1-7.
A single oral dose of azithromycin dramatically reduced the risk of maternal sepsis or death among women planning vaginal deliveries compared to placebo but had little effect on neonatal sepsis or mortality.
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