These data provide evidence that umbilical cord cleansing with chlorhexidine can markedly reduce the risk of omphalitis. The risk of cord infection was reduced by 32−75% with greater effect on more severe grades of infection, and an 87% reduction in risk of the most severe grade of omphalitis was seen in those whose treatment was initiated within the first 24 h after birth. The time to first cleansing was an important modifying factor, with stronger evidence of protection against infection in infants enrolled within 24 h of birth for all three grades of infection severity. In infants receiving 4·0% chlorhexidine applications to the cord, the risk of mortality was 24% lower than dry cord care alone. As with cord infection, reduction in mortality was greater (34%) for those treated with chlorhexidine on the first day of life. An association between early application of antiseptics and reduced odds of neonatal tetanus death compared with late or no antiseptics has been noted previously.37
Interventions to reduce exposure of the infant to bacterial colonisation and infection of the cord stump should take place at the earliest possible time, with a primary focus beyond the prevention of omphalitis. In this high mortality setting, although identifying and treating severe omphalitis must remain an important priority, visible signs of cord infection could in fact, for many infants, signal a successful immune response which limits infection to a local process. In the absence of such a response, however, acquisition of infectious pathogens might lead directly to a systemic infectious process without producing visible signs of omphalitis.
A similar process arises with exposure to Clostridium tetani
at the umbilical cord stump, producing neonatal tetanus without concurrent signs of local cord infection.38
During the initial days of life, rapid colonisation of the moist stump tissue might lead to direct exposure of the bloodstream to pathogens, since the umbilical vessels remain patent at this time. Therefore, early application of chlorhexidine to the umbilical cord stump not only reduces omphalitis, but also reduces mortality risk by preventing exposure to pathogens that might otherwise lead to a systemic infectious process and death, with or without signs of local cord infection. The 34% difference in mortality between treatment and control infants who were reached within the first 24 h of life and the increased protective effect of early chlorhexidine treatment on omphalitis incidence lend support to this argument. This trial, the first designed to assess the effect of cord antisepsis on mortality, suggests that previous studies have focused on the less important outcome—signs that might signal local containment of cord infection—and thus, until now, the benefits of cord antisepsis have been underestimated.
There was no evidence that the full-body cleansing assignment33
modified the relation between cord-care regimen and risk of infection or mortality. Also, these data provide no evidence that applications of a non-antiseptic soap and water-cleansing solution to the cord reduces infection or mortality risk compared with a dry cord-care regimen. The soap and water regimen might transiently reduce surface bacteria via mechanical removal of loosely adherent microorganisms. For residual and cumulative effects, however, non-antibacterial agents are substantially less effective than antibacterial agents such as chlorhexidine.39–42
In this study, the soap and water cord-care regimen probably shares this characteristic inefficiency of non-medicated cleansing agents, and cannot be further recommended, whereas the residual effect of chlorhexidine cord cleansing might have significantly reduced exposure of the infant to infectious pathogens.
There were some limitations to this study. The umbilical cord stump of infants was not cultured to examine bacterial colonisation because it was not possible to include this as a corollary sign of umbilical cord infection in this rural setting. The cord-cleansing intervention and cord assessment was done by the same workers. All were masked, however, to the treatment codes. Confounding is unlikely to explain these results, since the randomisation achieved balance across the treatment clusters; slightly imbalanced variables did not confound the relative risk estimates. Selection bias was also unlikely because 96% of eligible infants participated in the study.
The predominately rural farming communities of Sarlahi district share cultural, social, and economic characteristics with a broad population in southern Asia, and thus the results might be applicable not only within the Terai region of southern Nepal, but also in northern India, Pakistan, and northwestern Bangladesh. In these and in other low-resource settings where a high proportion of women deliver at home without skilled assistance, and exposure of the newly cut umbilical cord to environmental pathogens is high, chlorhexidine cord cleansing could provide a protective benefit similar to that seen in this study. Where neonatal mortality rates are higher or neonatal tetanus remains a public health problem, or both, the intervention could have a larger effect because the proportion of deaths from umbilical sepsis might be higher. Research on the effectiveness of this intervention in communities of sub-Saharan Africa is also warranted.
Although this study provides evidence that early use of chlorhexidine will reduce omphalitis and mortality risk, further information is needed about the frequency of cord cleansing during the first week of life to confer maximum protection. For example, a more simple programmatic approach, limiting cleansing to the first 3 days of life, or possibly even the first day of life alone, could provide substantial protection against infection and mortality. Furthermore, in view of the reductions in neonatal mortality among infants receiving this simple intervention within the first day of life, investigations designed to identify optimum models for community-based delivery near the time of birth are urgently needed.
Umbilical cord cleansing with chlorhexidine is regarded to be safe.3,30
Trace levels of the compound have been detected in the blood of infants after umbilical cord cleansing43,44
without any related clinical consequence. Contact dermatitis has been reported in up to 15% of infants after placement of a 0·5% chlorhexidine impregnated dressing over a central venous catheter.45
These exceptional reactions, however, might have resulted from the circumstances in which infants of less than 28 weeks gestational age and less than 1000 g at birth had the occlusive dressing in place for more than 7 days. Despite widespread use in clinical and community settings for over 30 years, no adverse events associated with topical applications to the cord stump have been reported in neonates.
The strong safety record, low cost, and ease of implementation make cord cleansing with 4·0% chlorhexidine an ideal intervention, even for mothers, traditional birth attendants, or other people with little training who might assist with deliveries in low-resource settings. To increase coverage and ensure the earliest possible intervention time, topical antiseptics could be incorporated into clean delivery kits for use by skilled birth attendants or caretakers in low-resource settings, or implemented within comprehensive community outreach efforts to improve newborn care. Although well accepted in our study population, qualitative investigations to determine potential barriers to uptake should be included in any well-designed neonatal care programme that includes topical antiseptic applications to the cord.
These results suggest that the current WHO recommendation for dry cord care is inappropriate for many low-resource settings where the baseline risk of omphalitis and mortality associated with a portal of entry through the cord is high. Furthermore, prevention of local cord infections could be secondary to the role that cord cleansing with chlorhexidine might have in reducing the risk of early neonatal sepsis and death. Continued efforts to identify and implement efficacious, affordable, and feasible community-based interventions to reduce neonatal infections and mortality are needed in order to meet the challenge of Millennium Development Goal 4 for child survival.46
We believe that the use of 4·0% chlorhexidine for topical cord antisepsis represents an important intervention with the potential for substantial effect on public health.