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Importance Neonatal sepsis causes substantial mortality. Topical antisepsis for laboring women or neonates may reduce pathogenic colonization and sepsis risk.Objective To evaluate the safety and effectiveness of various topical antiseptic regimens to reduce bacterial load in the maternal genital tract and on neonatal skin and assess suitability for future effectiveness trials.Design, Setting, and Participants This randomized clinical trial was conducted from March 7, 2022, to March 29, 2023, at Zomba Central Hospital, Malawi, with 28-day follow-up. Participant populations were laboring women and, separately, facility-born neonates (aged <24 hours and with birth weight >1000 g) not born to a mother recruited to the trial. Data were analyzed from May 17 to December 28, 2023.Interventions Participants were individually randomized in an unblinded factorial design to chlorhexidine 1% (1% CHG), chlorhexidine 2% (2% CHG), or octenidine 0.1% with phenoxyethanol 2% (OHP), each applied either once or multiple times (maternal: antiseptic applied every 4 hours during working hours for up to 6 applications; neonatal: antiseptic applied every 24 hours for up to 3 applications), or to standard of care (SOC; application of sterile water for mothers and no cleansing for neonates). Laboratory staff assessing primary outcomes were blinded.Main Outcomes and Measures Co–primary outcomes were change in total skin bacterial load (log10 colony-forming units [log10CFU]) from baseline at each follow-up, analyzed separately in the maternal and neonatal populations and adjusted for intervention variables. Secondary outcomes included skin condition score (range, 0-12 for neonates and 0-16 for women; lower scores indicate better condition), serious adverse events (SAEs), and neonatal temperature.Results A total of 149 women (mean [SD] age at enrollment, 25.7 [5.9] years) and 147 neonates (mean [SD] age at enrollment, 10.3 [6.3] hours; 82 [56%] male) participated. Mean (SD) infant gestational age was 37.7 (1.5) weeks in the maternal population and 36.7 (3.1) weeks in the neonatal population. Neonates’ mean birth weight was 2729 g (712 g). Among mothers, compared with 1% CHG, bacterial load was higher (worse) with OHP (adjusted log10CFU difference, 1.7; 95% CI, 0.9-2.5) and SOC (3.5; 95% CI, 2.4-4.6); there was no clear log10CFU difference with 2% CHG (−0.6; 95% CI, −1.4 to 0.2). There was no evidence of difference in effectiveness between multiple vs single application (log10CFU difference, −0.4; 95% CI, −1.1 to 0.2). In neonates, 1% CHG showed greater effectiveness than SOC (log10CFU difference, 1.3; 95% CI, 0.2-2.4) but no difference vs 2% CHG (−0.2; 95% CI, −1.1 to 0.7) or OHP (0.7; 95% CI, −0.2 to 1.6). Multiple applications showed increasing benefits over time (frequency × time interaction). Skin scores were low (almost all were 0-1 and none ≥3). There were no significant differences in SAE rates between arms and no signal of postantiseptic neonatal hypothermia.Conclusions and Relevance In this randomized clinical trial of topical antiseptics applied in laboring women and in neonates, 1% CHG reduced maternal and neonatal bacterial colonization without safety concerns, suggesting it would be the optimal regimen to evaluate in a larger pragmatic trial powered for clinical outcomes.Trial Registration ISRCTN Registry Identifier: ISRCTN78026255