Chlorhexidine May Reduce Neonatal Mortality and Infection in LMICs

RATIONALE: The umbilical cord, composed of blood vessels and connective tissue, connects the fetus to the placenta during pregnancy. After birth, the remaining cord stump may serve as an entry point for harmful bacteria, potentially leading to serious infection (neonatal sepsis) and death, particularly in low- and middle-income countries (LMICs). Applying antiseptics - substances that prevent the growth of microorganisms on living tissues - may help reduce the risk of infection through the umbilical stump. OBJECTIVES: To evaluate the benefits and harms of the application of antiseptics on a newborn's umbilical cord versus no antiseptics for the prevention of morbidity and mortality in infants in low- or middle-income countries (LMICs), and high-income countries (HIC). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS and trial registries in December 2025. We checked reference lists of included studies and/or studies/systematic reviews where subject matter related to the intervention or population examined in this review. ELIGIBILITY CRITERIA: We included individual and cluster-randomized controlled trials comparing any antiseptic with no antiseptic applied to the umbilical cord of newborns (0 to 28 days of life), regardless of gestational age, birthweight, delivery setting, or maternal infection risk. We excluded studies involving newborns with congenital malformations, quasi-randomized or observational designs, trials comparing different formulations or concentrations of the same antiseptic, and studies involving only topical antibiotics or antiseptic-antibiotic combinations. OUTCOMES: Our outcomes were all-cause neonatal mortality, omphalitis, and cord separation time. All the outcomes were measured during the neonatal period (i.e. from birth to 28 days of life). RISK OF BIAS: The risk of bias was assessed by using the Cochrane risk of bias tool (RoB 1). SYNTHESIS METHODS: Two review authors independently assessed studies for inclusion and evaluated the risk of bias. One review author extracted the data, and a second author verified the extraction for accuracy. We analyzed studies conducted in low- and middle-income countries (LMICs) separately from those in high-income countries (HICs), given the differing baseline risks. Where appropriate, we synthesized results using random-effects meta-analysis. We assessed the certainty of the evidence for each outcome using the GRADE approach. INCLUDED STUDIES: We included 18 trials in the review (143,150 participants), two studies are awaiting classification and four studies are ongoing trials. The included studies evaluated antiseptics such as 70% alcohol, 4.0% chlorhexidine (CHX), silver sulfadiazine, and povidone iodine in LMICs. In HIC, the studies evaluated CHX and alcohol. SYNTHESIS OF RESULTS: Five population-based trials looking at CHX in LMICs reported data on all-cause mortality that comprised 2280 deaths in 129,381 participants. Combined results showed that topical application of CHX may lead to a small reduction in all-cause neonatal mortality from 18/1000 to 15/1000 participants (average risk ratio (RR) 0.86; 95% confidence interval (CI) 0.73 to 1.01; 129,381 participants, 5 studies; low-certainty evidence). Among the CHX studies that took place in an LMIC, the topical application of CHX likely reduces the risk of omphalitis from 87/1000 participants in the control group to 62/1000 participants in the CHX group (RR 0.71; 95% CI 0.60 to 0.85; 128,486 participants, 5 studies; moderate-certainty evidence). The topical application of CHX likely increases cord separation time by 1.85 days in the CHX group compared with control (mean difference (MD) 1.85 days; 95% CI 0.81 to 2.90; 47,533 participants, 6 studies; moderate-certainty evidence) in studies conducted in LMICs. One study evaluated CHX in a HIC and did not report all-cause neonatal mortality data. The evidence was very uncertain about the use of topical application of CHX for the prevention of omphalitis (RR 0.28; 95 % CI 0.06 to 1.35; 669 participants, 1 study; very low-certainty evidence), indicating that the findings should be interpreted with caution. Similarly, the effect on cord separation time (MD: -0.80; 95 % CI -1.21 to -0.39; 669 participants, 1 study; very low-certainty evidence) was very uncertain. Four studies in LMICs evaluated the topical application of alcohol but none of them reported data on all-cause mortality. The evidence for the prevention of omphalitis from topical application of alcohol is very uncertain based on two studies (RR 1.22; 95% CI 0.34 to 4.44; 270 participants, 2 studies; very low-certainty evidence). The effect of alcohol on cord separation time is very uncertain based on data from four trials (MD -0.00 days; 95% CI -1.75 to 1.75; 598 participants, 4 studies; very low-certainty evidence). Four studies conducted in a HIC evaluated the topical application of alcohol. The pooled results showed that cord separation time was likely increased by 1.63 days in the alcohol group compared to the control group (MD 1.63 days; 95 % CI 1.11 to 2.15; 2117 participants, 4 studies; moderate-certainty evidence). None of the four studies in HIC that evaluated the topical application of alcohol reported data on the prevention of all-cause mortality or omphalitis. Overall, the included studies had a moderate risk of selection and attrition bias, a high risk of detection and performance bias, and unclear risk of reporting bias. AUTHORS' CONCLUSIONS: Topical application of 4.0% chlorhexidine to the umbilical cord likely reduces the risk of cord infection and may reduce neonatal mortality in low- and middle-income countries, though it probably delays cord separation by about two days. In high-income countries, evidence for chlorhexidine is very uncertain. For 70% alcohol, evidence from low- and middle-income countries is very uncertain for prevention of infection, and its use may result in little or no difference in cord separation time. In high-income countries, moderate-certainty evidence suggests that alcohol likely delays cord separation slightly. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: 2010 Protocol available doi.org/10.1002/14651858.CD008635 2013 published review available doi.org/10.1002/14651858.CD008635.pub2.