Effects of antibiotic prophylaxis during labour on maternal and neonatal outcomes in women planning vaginal birth

Abstract

Rationale: Maternal sepsis is the third leading cause of maternal mortality globally. However, the risk of maternal sepsis can be reduced by administering antibiotics prophylactically before infection occurs. Previous research has assessed the effects of azithromycin prophylaxis during pregnancy, but evidence is lacking on the effects of other types of antibiotics, and the potential for antimicrobial resistance.

Objectives: To assess the effects of antibiotic prophylaxis in women in labour after 28 weeks' gestation on the prevention of maternal and neonatal infections and mortality.

Search methods: We used CENTRAL, MEDLINE, Embase, one other database, and two trial registries, together with reference checking, citation searching, and contact with study authors to identify eligible studies. We did not restrict the search by publication type or language. The latest search date was 30 July 2024.

Eligibility criteria: We included randomised controlled trials involving pregnant women in labour after 28 gestational weeks, comparing any antibiotic prophylaxis with placebo or no treatment. We included trials of women anticipating a vaginal delivery, irrespective of baseline risk factors (unselected, lower-risk, or higher-risk), and without an indication for antibiotic prophylaxis in any care setting. We excluded trials that enroled only women with a planned caesarean section or a known bacterial infection (such as group B Streptococcus), and trials evaluating antibiotics for treatment rather than prevention.

Outcomes: Our key outcomes of interest, as presented in the summary of findings table, were: incidence of maternal sepsis, maternal mortality, neonatal sepsis, neonatal mortality, wound infection (perineal), adverse effects of antibiotics, and neonatal intensive care unit (NICU) admission.

Risk of bias: We used the revised Cochrane risk of bias tool for randomised trials (RoB 2) to assess the risk of bias.

Synthesis methods: We synthesised results for each outcome using random-effects meta-analysis in Review Manager. Meta-analyses were conducted using the inverse-variance method for dichotomous and continuous outcomes. We used a narrative synthesis following the SWiM (Synthesis Without Meta-analysis) reporting guideline for outcomes that could not be pooled statistically due to heterogeneity or limited data. We summarised key findings from individual studies descriptively and structured by outcome domain. We used GRADE to assess the certainty of evidence for each outcome.

Included studies: We included four trials with 42,846 participants (21,501 in the intervention groups versus 21,345 in the control groups). All were individually randomised trials conducted in low- and middle-income countries. Three trials used a single oral dose of azithromycin in the intervention group, while the fourth used a combination of azithromycin and amoxicillin. All four trials used a placebo control.

Synthesis of results: We judged three trials to have an overall low risk of bias, and the remaining trial to be at 'some concerns', due to reporting bias. Below, we report on the key outcomes of interest, as presented in the summary of findings table. Compared to placebo, any antibiotic use: • probably reduces maternal sepsis (1.8% in the placebo group versus 1.2% in the antibiotic group; risk ratio (RR) 0.65, 95% confidence interval (CI) 0.56 to 0.77; I² = 0%; 4 studies, 42,430 participants; moderate-certainty evidence). • likely results in little to no difference in maternal mortality (RR 1.21, 95% CI 0.63 to 2.33; I² = 0%; 4 studies, 42,371 participants; moderate-certainty evidence). • results in little to no difference in neonatal sepsis (RR 1.03, 95% CI 0.96 to 1.10; I² = 0%; 4 studies, 42,862 participants; high-certainty evidence). • results in little to no difference in neonatal mortality (RR 1.03, 95% CI 0.87 to 1.21; I² = 0%; 4 studies, 42,678 participants; high-certainty evidence). • results in little to no difference in perineal wound infection (1.5% in the placebo group versus 1.0% in the antibiotic group; RR 0.80, 95% CI 0.64 to 0.99; 1 study, 25,114 participants; high-certainty evidence). • results in little to no difference in NICU admission (RR 1.03, 95% CI 0.94 to 1.12; I² not applicable; 1 study, 29,084 participants; high-certainty evidence). The evidence is very uncertain about the effects of antibiotic use on antimicrobial resistance (AMR). One trial showed higher short-term detection of azithromycin-resistant bacteria in some maternal samples, but no persisting differences at 11 to 13 months, while in neonates, AMR was rare (very low-certainty evidence).

Authors' conclusions: Offering a single oral dose of prophylactic antibiotics to pregnant women in labour after 28 gestational weeks or more probably reduces maternal sepsis. It likely results in little to no difference in maternal mortality, and results in little to no difference in neonatal sepsis, neonatal mortality, perineal wound infection, and NICU admission. Evidence on antimicrobial resistance is very uncertain: short-term increases in resistant organisms were observed in some maternal samples, but no persisting between-group differences were found at 11 to 13 months' follow-up. Implementation should be cautious and accompanied by antimicrobial stewardship and AMR surveillance, and future research should better quantify AMR effects and identify optimal antibiotic strategies.

Funding: This work was partially funded by UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a co-sponsored programme executed by the World Health Organization (WHO) and partially supported by JST Grant Number JPMJPF2108.

Registration: Registration: PROSPERO (2024) CRD42024582129.