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Giving azithromycin to mothers during labor did not reduce the incidence of neonatal sepsis or mortality, a randomized trial conducted in Gambia and Burkina Faso found.

Of nearly 12,000 live births in the two West African nations, the primary outcome of neonatal sepsis or mortality at 28 days was a similar 2.0% with intrapartum oral azithromycin and 1.9% with placebo (OR 1.06, 95% CI 0.80-1.38, P=0.70), Anna Roca, PhD, of MRC Unit The Gambia at the London School of Hygiene & Tropical Medicine in Fajara, Gambia, and colleagues reported.

Evaluated separately, the rates of neonatal mortality and sepsis were identical in the two study groups, at 0.8% and 1.3%, respectively, according to the findings in .

Fewer cases of culture-confirmed sepsis were identified among newborns in the azithromycin group (13 vs 24 in the placebo group), though this difference was not significant. Gram-positive Staphylococcus aureus was the most commonly isolated bacterium (two cases in the azithromycin group and six in the placebo group), while gram-negative bacteria made up 59.5% of the confirmed cases.

"It is unclear why the effect of intrapartum azithromycin on S. aureus carriage and noninvasive disease did not translate into a reduction in neonatal sepsis or neonatal mortality," Roca and co-authors wrote.

"It may be that sepsis and bacteriologically confirmed sepsis are caused by different pathogens, with gram-negative bacteria, viruses, and/or fungus being more prevalent causes of clinical sepsis," they continued. "An alternative explanation is that a decrease in sepsis caused by some etiologies is balanced by an increase in other etiologies."

Among secondary outcomes in the newborns, the azithromycin group had a significantly lower incidence of clinical skin infections (0.8% vs 1.7% in the placebo group) and less use of antibiotics (6.2% vs 7.8%, P<0.001 for both), as well as a significantly lower odds of any infection (3% vs 4.4%).

In mothers, the azithromycin-treated group experienced a lower incidence of mastitis (0.3% vs 0.5% in the placebo group) and puerperal fever (0.1% vs 0.3%, P=0.04 for both), results "consistent with a conducted in the U.S. that found that azithromycin reduced severe maternal infections by half," the authors noted.

Mothers in the current study () also experienced a significantly lower odds of any infection with the broad-spectrum macrolide (0.4% vs 0.7% with placebo).

"Early evaluations of mass drug administration campaigns to control trachoma in sub-Saharan Africa suggested that azithromycin other than Chlamydia trachomatis and significantly reduced childhood mortality," wrote Roca and colleagues in their introduction.

"A subsequent large-scale cluster-randomized trial in sub-Saharan Africa found that mass azithromycin administration in children younger than 5 years, with a stronger effect in infants younger than 6 months," the team continued. "A recent found that oral azithromycin administered during labor reduced carriage of gram-positive bacteria during the subsequent 4 weeks, and a post hoc analysis found reduced mild to moderate disease in both birthing parents and newborns."

More recently, the randomized A-PLUS trial -- conducted in low- and middle-income countries across Asia, Africa, and Latin America -- showed that a single dose of azithromycin given to mothers during vaginal birth significantly reduced the risk for maternal sepsis or death versus placebo (1.6% vs 2.4%). However, the intervention made no difference on the incidence of stillbirth or neonatal death or sepsis.

"Mortality in the neonatal period remains a stubborn problem," wrote Stephanie Schrag, DPhil, of the CDC, and Cynthia Whitney, MD, MPH, of Emory University, both in Atlanta, in an . "Evidence suggests complications of labor and delivery play a major role in deaths in the first hours after birth, and that preterm delivery and infections also each cause approximately one-third of deaths in the first week of life."

In the current trial, other factors besides sepsis may have affected the mortality rates, they noted. "Deaths were attributed to delivery complications (birth asphyxia) in both sites, and sudden death and aspiration were commonly cited as causes of death in The Gambia."

Despite any benefit the antibiotic might have provided for some secondary endpoints, Schrag and Whitney warned that antibiotic intervention should be approached with "caution," as they "can lead to serious adverse events, such as prolongation of the cardiac QT interval and sudden death reported among a subset of susceptible persons taking azithromycin."

Moreover, antibiotic resistance and growing evidence that antibiotics may disrupt the maternal and newborn microbiome must also be considered. Thus, although the current trial results are "discouraging," said Schrag and Whitney, several other ongoing efforts hold promise to move the field forward.

From October 2017 to May 2021, PregnAnZI-2 randomized 11,983 pregnancies in Gambia (55%) and Burkina Faso (45%) in a 1:1 ratio to the intervention or placebo.

Overall, 11,783 live births met criteria for the primary analysis (neonatal deaths due to asphyxia, low birth weight, and severe congenital malformations were excluded).

Of the 5,889 in the azithromycin group, the combined primary endpoint occurred in 115 newborns, with 79 cases of sepsis and 47 deaths. Of the 5,984 live births in the placebo group, a primary endpoint event occurred in 111 newborns, with 78 cases of sepsis and 45 deaths.

There were eight maternal deaths in the intervention group and six in the placebo group.

Limitations cited by Roca's group included the low proportion of microbiology-confirmed neonatal sepsis; as a result, easy-to-grow bacteria such as S. aureus may have been over-represented.

The study authors also highlighted "striking differences" in early-onset sepsis between participants in Gambia and Burkina Faso, which suggests some cases were missed in the latter due to travel distance to the study health facility. In addition, late-onset sepsis may have been missed in Gambia "because C-reactive protein was measured qualitatively and could not meet the trial criterion of 40 mg/L."

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