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Intrapartum azithromycin reduces maternal infection risk regardless of time to deliveryStudy finds timing of antibiotic in labor may not affect maternal infection prevention

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Key Takeaway
Consider intrapartum azithromycin for maternal infection prevention regardless of delivery timing, but note no neonatal benefit.

This secondary analysis of a randomized controlled trial examined whether the efficacy of intrapartum azithromycin for preventing infections varied by time from administration to delivery. The study included 29,236 pregnant patients at ≥28 weeks gestation presenting in labor for planned vaginal delivery across multiple international centers. Patients received either a single 2g oral dose of azithromycin or placebo during labor.

The analysis found that azithromycin reduced the risk of any maternal infection regardless of time to delivery, with a relative risk of 0.71 (95% CI 0.64-0.79) for administration ≤12 hours before delivery and 0.71 (95% CI 0.54-0.94) for >12 hours. However, in a Sub-Saharan Africa subgroup, greater benefit was observed with administration >12 hours before delivery (RR 0.21, 95% CI 0.08-0.54) compared to ≤12 hours (RR 0.52, 95% CI 0.41-0.66), with an interaction p-value of 0.03. For neonatal infection, azithromycin showed no benefit regardless of timing (RR 1.00, 95% CI 0.95-1.06 for ≤9h; RR 1.01, 95% CI 0.88-1.15 for >9h).

Safety and tolerability data were not reported in this analysis. Key limitations include its nature as a secondary analysis, which increases the risk of false-positive findings, particularly for subgroup analyses. The Sub-Saharan Africa finding requires cautious interpretation as it represents a subgroup analysis with potential confounding factors. While the analysis suggests intrapartum azithromycin benefits maternal infection prevention regardless of anticipated delivery time, clinicians should note the absence of neonatal infection benefit and consider these findings as hypothesis-generating rather than definitive practice guidance.

Researchers looked at data from a large international trial involving over 29,000 pregnant people in labor who were planning vaginal delivery. They wanted to know if the timing of giving a single dose of the antibiotic azithromycin affected how well it worked to prevent infections in mothers and their newborns.

The study found that giving azithromycin during labor reduced the risk of maternal infections by about 29% overall, and this benefit did not depend on how long before delivery the antibiotic was given. However, in a smaller subgroup of participants from Sub-Saharan Africa, the benefit appeared stronger when the antibiotic was given more than 12 hours before delivery. Importantly, the antibiotic showed no benefit in preventing infections in newborns, regardless of timing.

This was a secondary analysis, meaning researchers were looking at existing trial data in a new way rather than conducting a new study specifically designed to answer this timing question. The finding about stronger benefit with longer timing in Sub-Saharan Africa comes from a subgroup analysis, which is less reliable than the main trial results. Readers should understand that while this analysis provides helpful information, it doesn't change the main finding from the original trial: azithromycin helps prevent maternal infections but not newborn infections.

What this means for you:
Antibiotic timing in labor may not change its effectiveness for preventing maternal infections, but shows no benefit for newborns.

Study Details

Study typeRct
EvidenceLevel 2
PublishedApr 2026
View Original Abstract ↓
OBJECTIVE: A multi-centre international trial (A-PLUS), demonstrated that a single dose of 2 g oral azithromycin in labour reduced the risk of maternal sepsis or death, but not neonatal mortality. We aimed to determine whether the efficacy of azithromycin in prevention of any maternal infection or neonatal infection varied by time interval from azithromycin administration to delivery. DESIGN: This is a secondary analysis of a randomized controlled trial. SETTING: Multi-centre international randomized controlled trial. POPULATION: Pregnant patients ≥ 28 weeks gestation (singleton or multiple gestation) presenting in labour for planned vaginal delivery. OUTCOMES: The primary outcome for this secondary analysis was maternal infection and the secondary outcome was any neonatal infection. METHODS: The estimated relative risks (and 95% confidence interval) of any maternal or neonatal infection comparing azithromycin to placebo were obtained by fitting a Poisson model adjusting for site, treatment arm, hours between drug administration and delivery (as continuous measure, and ≤ 12 or > 12 h for maternal and ≤ 9 or > 9 h for neonatal), and the two-way interaction between treatment arm and hours between drug administration and delivery. RESULTS: Included in the analysis were n = 14 569 randomized to azithromycin and n = 14 667 to placebo. There was no evidence that the benefit of azithromycin on reducing the risk of any maternal infection varied by time from dose to delivery (RR 0.71 (0.64-0.79) and RR 0.71 (0.54-0.94) for ≤ 12 and > 12 h respectively, interaction p = 0.987), although there was an observed interaction in Sub-Saharan Africa subgroup with reduced risk observed with administration > 12 vs. ≤ 12 (RR 0.21 (0.08-0.54) vs. RR 0.52 (0.41-0.66), interaction p = 0.03). There was no benefit observed in prevention of infant infection regardless of time from dose to delivery (≤ 9 or > 9 h) (RR 1.00 (0.95-1.06) and RR 1.01 (0.88-1.15) interaction p = 0.997). CONCLUSION: The benefit observed with a single intrapartum dose of azithromycin for prevention of any maternal infection in the setting of planned vaginal delivery was not observed to vary by time interval from azithromycin administration to delivery, although in some populations there may be greater benefit with delivery > 12 h from administration. Pregnant patients presenting for planned vaginal birth benefit from a single dose of 2 g azithromycin regardless of how soon delivery is anticipated.
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