Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal

Alan T N Tita, et al. Azithromycin to Prevent Sepsis or Death in Women Planning a Vaginal Birth. N Engl J Med. 2023.

https://www.nejm.org/doi/full/10.1056/NEJMoa2212111

Background

The use of azithromycin reduces maternal infection in women during planned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death.

Methods

In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks’ gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit.

Results

A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P=0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events.

Conclusions

Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491

Comments from Dr. Karpagambal Sairam Venugopalan

We understand that sepsis is emerging as one of the leading causes of maternal death all over the world inspite of majority of institutional deliveries and safe childbirth practices. As we have WHO safe surgical procedures checklist, we do have safe, clean delivery checklist protocols to be followed in every labour room and home birth centres.

The article highlights the value of Single dose Azithromycin 2 g as a preventive strategy for maternal sepsis. The concern is the randomisation with regard to gestational age. Infection is a proven cause of preterm labour (PTL) and preterm prelabour rupture of membranes (PPROM). According to most evidence-based guidelines, the source of infection in PTL and PPROM has to identify (like getting a high vaginal swab, urine culture done or searching for other sources of infection) and empiric broad-spectrum antibiotics are indicated.

We concur with the fact that Azithromycin can be the drug of choice in Pelvic inflammatory disease in both non-pregnant and nonpregnant women as it is a broad-spectrum antibiotic with a wide coverage of organisms that can colonise the pelvis and the reproductive tract. According to the article, 12.6% in the azithromycin group and 12.9% in the placebo group were PRETEM (gestational age <37 weeks) and 8.5 and 8.7%, respectively were randomised as high risk for sepsis prior to treatment. Even though the numbers may seem small, they are at the highest risk of Chorioamnionitis, endometritis, maternal, neonatal sepsis, and death. Regarding neonatal sepsis, any symptoms, signs, parameters suggestive of sepsis in the first week of life, the source could be transmission of infection from the mother especially from the birth canal. Hence, neonatologists are behind our vaginal swab reports to check if the same organism is growing in the neonates blood culture. Any infection after 1st week of life nosocomial infection has to be ruled out.

World Health Organisation (WHO) released a labour care guide manual in August 2021 highlighting that uncomplicated term deliveries do not require any antibiotic even if an episiotomy is needed. So why the need for Azithromycin for all?

So, to conclude the number needed to treat is really very high to prevent 1 maternal death (not mentioned in the article) from sepsis which is really worth the effort as prevention of one maternal death will change the life of the neonate and family and will make a difference in the national and global health care indices. The availability, cost, adverse effects, increasing antimicrobial resistance are the points to ponder before adopting this prophylactic antibiotic therapy. The benefits vs risks need to be balanced before implementing this into routine clinical practice. As an obstetrician, we are eager to adopt any strategy to save mothers lives.

Dr. Karpagambal Sairam Venugopalan

Obstetrician and Gynecologist