The available evidence from four trials using a single oral dose of azithromycin showed that routine antibiotic prophylaxis during labour for vaginal birth results in small to moderate reductions across a spectrum of maternal peripartum infections, including maternal sepsis, with no evidence of impact on maternal mortality or clinical benefits for the newborn. The Guideline Development Group (GDG) acknowledged the potential benefit of antibiotic prophylaxis for maternal sepsis in settings with high baseline incidence, with a moderate number-neededto-treat of 167, but it judged the overall desirable effects to be moderate and limited in scope. ƒ In contrast, the GDG identified potentially large undesirable effects, concerning increased risk of antimicrobial resistance. Trial data showed transient increases in resistant pathogens of concern among women and newborns, while modelling projected substantial population-level impacts. Specifically, estimated disability adjusted life years (DALYs) associated with projected increases in macrolide resistance for Staphylococcus aureus (S. aureus) and Streptococcus pneumoniae (S. pneumonia) in the population were substantially higher than the estimated DALYs averted as a result of reduced sepsis due to the intervention. In the African Region, macrolide resistance for S. aureus and S. pneumoniae was estimated to lead to an additional 96 000 DALYs, compared with 11 000 DALYs averted through reduced sepsis. Similarly, in the South-East Asia Region, there was an increase of 42 000 DALYs compared with 1400 prevented and, in the Western Pacific Region, 15 000 additional DALYs compared with 760 prevented. Low- and middle-income countries face a disproportionate burden of antimicrobial resistance with limited implementation of antimicrobial stewardship programmes and policies and limited antimicrobial use surveillance programmes. ƒ The GDG also noted that azithromycin, the main antibiotic used in the trials, is a broad-spectrum WHO AWaRe (Access, Watch, Reserve) “Watch” antibiotic with a high potential for resistance. It should be prioritized for antimicrobial resistance stewardship policies and interventions, making its widespread use without clinical indication concerning from a public health perspective. The GDG also expressed concern about the effects of early life exposure to macrolides on gut microbiota, given evidence of changes in gut bacterial composition and a potentially increased risk of asthma, obesity, food allergies, and inflammatory bowel disease among children. ƒ Women value the prevention of serious infections, but also express concerns about unnecessary medical interventions and the overuse of antibiotics. There was no evidence of important variability in preferences to suggest specific subgroups would benefit from routine antibiotic prophylaxis for vaginal birth. While the direct costs of prophylactic antibiotics are low, the long-term health system and societal costs related to antimicrobial resistance are likely to outweigh any short-term savings. From an equity perspective, routine antibiotic prophylaxis may widen global disparities in antimicrobial resistance burden, and the GDG noted that many health systems lack the surveillance and stewardship capacity needed to mitigate these effects ƒ Although there was no direct evidence on the acceptability of oral antibiotic use during labour, variation across settings is likely, as suggested by differing views in the context of caesarean birth where baseline infection risk is even higher. Administration of an oral antibiotic is likely to be feasible in many settings; regulatory restrictions, however, such as limits on midwives’ prescribing authority in some countries, may pose challenges to universal implementation. ƒ Taking all these factors into account, the GDG concluded that the undesirable consequences of routine antibiotic prophylaxis in labour for vaginal birth outweigh the potential benefits and therefore recommended against its use. ƒ Instead, the GDG expressed support for a multi-pronged strategy that includes strengthening infection prevention and control measures; risk-based assessment for targeted antibiotic prophylaxis when clinically indicated and in line with existing WHO recommendations; and prompt diagnosis and management of infections in the antepartum, intrapartum and postpartum periods. The GDG acknowledged the challenges of resources including the skilled workforce needed to implement these strategies, but it nonetheless prioritized alternative strategies for the prevention of maternal infections. The GDG emphasized that antibiotic prophylaxis in labour for vaginal birth is not recommended for routine administration in any setting or context. Where antibiotic prophylaxis is already indicated in accordance with existing WHO guidance (such as for operative vaginal birth, pre-existing infections, preterm prelabour rupture of membranes, group B streptococcus colonization, or other indications),1 the use of antibiotic prophylaxis should follow these WHO recommendations. ƒ The GDG acknowledged that while azithromycin was the main antibiotic used in the trials underpinning the evidence for this recommendation, the recommendation applies to all classes of antibiotics. ƒ This recommendation is consistent with the WHO recommendation against the routine use of antibiotics after uncomplicated vaginal birth.