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Although umbilical cord infection contributes to neonatal mortality and morbidity and risk can be reduced with topical chlorhexidine, behavioral or other factors associated with cord infection in low-resource settings have not been examined. Data on potential risk factors for omphalitis were collected during a community-based, umbilical cord care trial in Nepal during 2002−2005. Newborns were evaluated in the home for signs of umbilical cord infection (pus, redness, and swelling). Omphalitis was defined as either pus discharge with erythema of the abdominal skin or severe redness (>2 cm extension from the cord stump) with or without pus. Multivariable regression modeling was used to examine associations between omphalitis and maternal, newborn, and household variables. Omphalitis was identified in 954 of 17,198 newborns (5.5%). Infection risk was 29% and 62% higher in infants receiving topical cord applications of mustard oil and other potentially unclean substances, respectively. Skin-to-skin contact (relative risk (RR) • 0.64, 95% confidence interval (CI): 0.43, 0.95) and hand washing by birth attendants (RR • 0.73, 95% CI: 0.64, 0.84) and caretakers (RR • 0.76, 95% CI: 0.60, 0.95) were associated with fewer infections. In this community, unhygienic newborn-care practices lead to continued high risk for omphalitis. In addition to topical antiseptics, simple, low-cost interventions such as hand washing, skin-to-skin contact, and avoiding unclean cord applications should be promoted by community-based health workers.
Infections account for approximately 36 percent of neonatal mortality worldwide (1), and neonatal sepsis may stem from local umbilical cord infections that become systemic (2–4). In developing countries, little is known about risk factors for umbilical cord infection, although unhygienic practices around the time of birth are a likely determinant of disease. Previous work has focused mainly on neonatal tetanus infection, but even where high tetanus toxoid coverage rates have substantially reduced neonatal tetanus, umbilical cord infections are likely to continue if practices at delivery and during the postnatal period do not reduce exposure of the umbilical cord stump to potentially dangerous pathogens (5–7).
The freshly cut umbilical cord is a prime site of bacterial colonization. Omphalitis is proximally caused by colonization that progresses to local signs of infection including pus discharge, redness, swelling, or foul odor. Hospital-based studies from developing countries have reported varying dominance of Gram-positive (mainly Staphylococcus aureus), Gram-negative (mainly Escherichia coli and Klebsiella species), and anerobic bacteria (8–11). Association with low birth weight or early gestational age (12), as well as male sex (10, 11, 13), has been observed.
Intermediate determinants of omphalitis may include hygiene-related practices. These include type of birthing surface (14, 15), cord care (tying, cutting, topical applications) (5–7, 16–18), infant-bathing practices, attendants' hand-washing practices, skin-to-skin contact between mother and newborn, and thermal care of the newborn. Additional distal determinants such as caretaker literacy levels, socioeconomic status, ethnicity, or caste may also be associated with cord infection but, as with the proximal and intermediate determinants, these have not been studied in relation to nontetanus umbilical cord infections.
We recently reported on the protective efficacy of topical antiseptic (chlorhexidine) treatment of the umbilical cord on omphalitis and neonatal mortality (4). Results from that trial illustrate the importance of hygienic cord care and the role of antiseptics, and they highlight the need for greater understanding of the risk factors for nontetanus umbilical cord infection. We provide estimates of the burden of omphalitis among newborns in the community in southern Nepal and describe associations between omphalitis and characteristics of infants and households.
Data were collected during a community-based, cluster-randomized trial of the impact of newborn skin and umbilical cord cleansing with chlorhexidine on neonatal mortality and morbidity. This trial was conducted by the Nepal Nutrition Intervention Project, Sarlahi. Details of the study population, recruitment, and procedures have been provided previously (4). Infants born between September 2002 and March 2005 were randomized within clusters to one of three cord care regimens (umbilical stump cleansing with 4.0 percent chlorhexidine, cleansing with soap and water, or dry cord care only). Women were recruited during the sixth month of pregnancy and given 400 mg of albendazole, iron-folate supplementation (90 days), a clean delivery kit, and tetanus toxoid immunization. All women were provided basic educational messages regarding clean umbilical cord care during delivery and the postnatal period and infant thermal care. The gestational age was estimated from two maternal reports of the time since the last menstrual period; these estimates were provided at enrollment and at the first assessment after delivery. All women provided verbal consent for participation of their infants.
Enrolled newborns were visited up to 11 times during the neonatal period (days 1−4, 6, 8, 10, 12, 14, 21, and 28) for evaluation of the umbilical cord. Workers assessed the cord for signs of infection, including the presence of pus, redness, and swelling. “Mild” redness (or swelling) was limited to the cord stump, while “moderate” or “severe” was defined as inflammation extending to the skin at the base of the stump (i.e., <2 cm extension onto the abdominal skin) or affecting an area 2 cm or more from the cord, respectively (19).
During two of these follow-up morbidity visits (days 1 and 14), field workers additionally collected information on various potential determinants of infection related to neonatal care practices. The first questionnaire focused on the hand-washing practices of birth assistants, the proper use of items in the clean delivery kit, skin care practices including washing and oil massage, and breastfeeding initiation. The second questionnaire measured general neonatal care practices, such as topical applications to the skin and elements of thermal care including mother-infant skin-to-skin contact. At each follow-up visit, mothers were questioned about materials they had applied to the cord in the previous 24 hours, including mustard oil, ash, mud, antiseptics, and/or other possible applications.
Umbilical cord assessment data collected at each household visit for each child were combined into visit-specific infection status. On the basis of a validation exercise described previously (19), cord infection was defined as follows: presence of pus with either moderate or severe redness, or presence of severe redness with or without pus. Multiple visits that met the criteria for omphalitis were assumed to constitute a single episode of infection.
Home-delivered applications to the cord were grouped into a categorical variable and included a single category for multiple applications. Mustard oil applications to the cord were treated as a separate practice, because 1) the frequency of this application was substantially higher than those of other reported substances and 2) in those cases where multiple applications were reported, mustard oil was included in more than 98 percent of cases. Exposure to these applications was restricted to those occurring within 48 hours of birth to minimize reverse-causation bias that might occur if caretakers applied these substances as a response to perceived infection. To further examine any residual bias, we also conducted a case-cohort analysis to fully adjust for the timing of infection. For each day, x, of follow-up and for each infected infant on day x, 10 controls were randomly selected from among those infants who were not infected by day x; exposure for both cases and controls was then defined as the home-delivered cord application experience prior to selection as a case or control.
For all individual potential risk factors, the risk ratio between infection status and the factor was modeled by use of a binomial regression procedure with robust variance estimation that allowed for adjustment for the randomized treatment allocation. Categorical risk factor variables were analyzed by comparing each value with the “lowest” value. The adjusted analysis was also stratified by cord cleansing allocation in the parent trial to examine the potential for interaction between treatment and potential risk factors for umbilical cord infection.
All analyses were conducted using STATA, version 9.0, software (StataCorp LP, College Station, Texas). The Nepal Health Research Council (Kathmandu, Nepal) and the Committee on Human Research of the Johns Hopkins Bloomberg School of Public Health (Baltimore, Maryland) approved the protocol. This trial is registered at ClinicalTrials.gov (NCT00109616).
Among 17,530 eligible livebirths, 17,198 (98.1 percent) were enrolled in the study, received one or more home visits, and are included in the analysis. There were 157,834 home visits to assess infants for signs of umbilical cord infection, and the mean number of visits per child was 9.2 (standard deviation: 2.1). Visits were missed during periods of uncertain security, military curfews, nationwide strikes, and religious holidays or in the case of late arrival at the home after the birth or death of the infant. In the study population, 91.9 percent of infants were born in the home, there were slightly more males (51.1 percent) than females, 29.5 percent of the sample were low birth weight, and more than 75 percent of newborns' mothers had received no formal education. Additional details on the characteristics of the study population were reported previously (4).
Among all umbilical cord assessments, there were 1,290 (1.0 percent) assessments that met the cord infection definition among 954 individual infants, for a total incidence of 5.5 per 100 neonates. The median time from birth to infection was 2.5 days. More than 75 percent of infections occurred within the first 5 days, and 90 percent occurred in the first week of life (figure 1).
At the time of birth, one or more substances were applied to the cords of 3,236 of 15,755 (20.1 percent) newborns. Throughout the newborn period, 13,827 (80.4 percent) infants received at least one application of mustard oil. Ash (7.1 percent), mud (6.8 percent), and other substances (5.5 percent; breast milk, saliva, water, other oils, herbs, spices, curry) were almost equally applied, while 2,653 (15.4 percent) infants received one or more home-delivered non-study “antiseptics” (table 1). Data on the specific type of reported antiseptic were not collected. Comparisons between cord infection and these and other potential risk factors, adjusted only for treatment group in the randomized trial, are shown in table 2.
Topical applications to the cord may have increased as a result of infection; the use of ash, mud, and home-delivered antiseptics peaked after the appearance of local signs of infection and can lead to spurious associations. For example, infection risk was slightly higher among infants receiving applications of non-study antiseptics but was potentially protective when delivered within the first 48 hours (relative risk (RR) • 0.74, 95 percent confidence interval (CI): 0.55, 0.98). Thus, in table 2, exposure to topical applications was restricted to those occurring within the first 48 hours after birth, when the cord is still attached in most infants. Although neither ash nor mud was associated with cord infection, mustard oil and other substances (breast milk, saliva, water, other oils, herbs, spices, curry) increased the risk of infection. There was an association between birth weight and risk of infection, with more infections in smaller babies (p • 0.03).
A number of intermediate determinants were associated with umbilical cord infection. These included a protective benefit of hand washing, by both the birth assistant (with soap) before delivery (RR • 0.69, 95 percent CI: 0.61, 0.79) and the mother during the first 14 days of life (RR • 0.71, 95 percent CI: 0.56, 0.91), and the reported correct !use of the soap in the clean delivery kit (RR • 0.51, 95 percent CI: 0.45, 0.58). Other items in the kit, such as the new blade and clean string, were not associated with decreased infection, but the almost universal use of these items led to low statistical power to detect any true differences. Thermal care practices such as skin-to-skin contact between mother and newborn (RR • 0.67, 95 percent CI: 0.46, 0.97) and the regular use of a hat (RR • 0.82, 95 percent CI: 0.71, 0.96) were also associated with decreased risk of omphalitis, while infants whose mothers reported regularly warming the room in which the infant was cared for were at slightly elevated risk. There was no evidence that breastfeeding (either feeding colostrum or initiation on the first day of life) or bathing practices protected the newborn from infection. Among the distal determinants assessed, more infections occurred among infants born in the hot season, and newborns born in lower castes (non-Brahmin/Chhetri) were at higher risk of infection. Infants born to mothers in the highest educational category were at slightly less risk, while paternal education and overall ethnic group (Pahadi (originating from the hills of Nepal) vs. Madeshi (originating from the plains)) were not associated with infection risk.
Multivariable models (table 3) were constructed on the basis of these results. Variables showing at least modest statistical evidence for an association (p < 0.10) were included. In the first model, only home-delivered applications to the cord were included. After adjustment, there was little change in the estimates of association for mustard oil, non-study antiseptics, and “other” substances delivered in the first 2 days. Hand-washing and thermal-care variables were added to the second model; the adjusted risk of infection was 27 percent (95 percent CI: 17, 36) lower among infants where the birth assistant washed her hands with soap before delivery. The adjusted risk of infection was also significantly lower when mothers reported “always” washing their hands with soap before handling the newborn (RR • 0.75, 95 percent CI: 0.59, 0.96) or when skin-to-skin contact was practiced (RR • 0.65, 95 percent CI: 0.44, 0.96). After the addition of maternal education, birth weight category (<2,500 g vs. • 2,500 g), season of birth, and caste to the third model, evidence for a protective benefit of non-study antiseptics, inconsistent hand washing by mothers, and the use of a hat to keep the infant warm was low; the latter two variables were removed from the final model. Being born during the hot season, low birth weight, lower caste, and harmful applications to the cord (mustard oil and other substances) were significant risk factors for infection, while hand washing and skin-to skin contact provided protection. Regular room warming remained associated with a higher risk of infection, even after adjustment.
The use of the soap in the clean delivery kit was not included in the multivariable models, because of colinearity with the birth assistant hand-washing variable. When that variable, however, was replaced with the clean delivery kit soap variable, the estimated adjusted risk ratio was 0.49 (95 percent CI: 0.43, 056), further confirming the importance of this hygienic care practice.
Given the potential of the treatment protocol provided in the overall trial to modify the associations between these covariates and the infection outcome, we constructed the final multivariate model separately for each of the treatment methods (chlorhexidine, soap/water, dry cord care). Apart from the association between hand washing and infection, there were no other statistically significant differences in the risk ratio estimates across treatment groups. For hand washing by the birth assistant, the adjusted risk ratio for infection was 0.60 (95 percent CI: 0.49, 0.75) in the dry cord care group compared with 0.87 (95 percent CI: 0.70, 1.08) and 0.79 (95 percent CI: 0.60, 1.03) in the soap/water- and chlorhexidine-cleansing groups, respectively (tests for interaction: p • 0.02, p • 0.10, respectively).
To further examine the potential for reverse-causation bias in the analyses of cord infection and home-delivered applications to the cord, we conducted a nested case-cohort analysis adjusting for timing of exposure, with results shown in table 4. There were no important differences in the estimates of association of the conclusions drawn; potential unclean substances were associated with case status, while there was moderate evidence that non-study antiseptics decreased risk.
This study has demonstrated that signs of moderate to severe omphalitis are seen in approximately 5−6 percent of newborns in southern Nepal and that infections are associated with a number of care-taking practices. There was only slight evidence for an independent association between home-delivered antiseptics and nontetanus umbilical cord infections. In addition to questions of efficacy of topical home antiseptics, this is likely explained by low overall use (<8 percent), inconsistent and/or delayed application, and nonspecificity of caretakers' reports of such substances as “antiseptics.” However, chlorhexidine cord cleansing applied consistently over the first 10 days of life can markedly reduce umbilical cord infection and the risk of neonatal death, especially if initiated early (4). Previous case-control studies have additionally suggested that the use of antiseptics may reduce the risks of neonatal tetanus (6, 17, 20, 21) and neonatal sepsis (5).
Mustard oil was associated with increased risk of infection. This correlates with previous observational studies implicating ghee (clarified butter) in tetanus (7, 22, 23). In light of the almost universal practice of full-body massage of newborns with mustard oil in many south Asian communities (24, 25), the potential for negative impact on overall skin barrier function (26), and the association observed here with omphalitis, further investigation of the impact of mustard oil as a topical application is warranted. Alternative oils that enhance skin barrier function, such as sunflower seed oil, can prevent hospital-acquired sepsis in preterm infants less than 33 weeks' gestational age (27, 28).
Although cow dung ash (11, 18, 29) or ash and burnt earth (16) have been associated with tetanus, there was no parallel correlation observed here. The nonspecific category of applications (“other substances”) was significantly associated with a higher risk of cord infection. As this nonspecific category probably included some substances that are unlikely to increase risk and may even be beneficial, such as breast milk (2, 30), this estimate may substantially underestimate the relation between application of unclean substances and infection. Although the primary analytical approach restricted exposure of home-delivered applications to those occurring within 48 hours, the case-cohort strategy suggests that the associations measured were not a result of reverse-causation bias, nor did the estimates differ substantially in magnitude as the result of misclassification of exposure.
The use of a new blade to cut the cord is widely promoted to prevent neonatal tetanus. The protective nature of this practice likely extends to non-tetanus-related infection but could not be fully analyzed in these data because of the almost universal use (>99 percent) of the blade provided in the clean delivery kit. Use of the soap in the clean delivery kit to wash hands before assisting during delivery was strongly associated (RR • 0.51, 95 percent CI: 0.45, 058) with decreased cord infection risk and correlates with the observation by Bennett et al. (14) of a reduction in tetanus risk with hand washing by birth assistants. The less specific measures of hand washing by birth assistants and mothers' report of consistent hand washing during the first 2 weeks after birth were also associated with decreased cord infection. The latter variable, however, adequately addresses neither the temporal relation between hand washing of caretakers and consequent handling of the infant nor the consistency of the practice over the 2-week period. The responses provided by the mothers may reflect knowledge of advisable hygienic practices rather than actual practices, or they may be a marker for a wider range of positive behaviors that reduce the overall exposure of the infant to pathogens. Nonspecific associations between overall hand-washing practices and infection of infants and children have been reported (31), however, and these data are consistent with those of many prior studies that have highlighted the role of nursery attendant hand-washing practices in quelling nursery outbreaks of umbilical cord infection (32–39). Furthermore, the stratified analyses indicate that the importance of hand washing may be increased when dry cord care is being promoted. Many infants (92 percent) are born at home, and almost all are exposed to substantial infectious challenge during the first days of life. In the absence of topical cord antisepsis, hand washing with soap and water before assisting at delivery may reduce the risk of cord infection; in general, continued emphasis should be placed on promoting this important and simple intervention in community health programs.
Infants receiving skin-to-skin contact were 36 percent less likely to have umbilical cord infection (RR • 0.64, 95 percent CI: 0.43, 0.95) after adjustment for other!factors. Skin-to-skin contact could reduce the risk of cord infection by increasing the rate of colonization with normal skin flora (40). Skin-to-skin contact has been associated with a decreased risk of infectious morbidity among infants, especially low-birth-weight infants (41, 42), but there are no previous reports of the role that skin-to-skin contact may play in reducing umbilical cord infection.
Male and female newborns were at equivalent risk for omphalitis in this study, contrasting with two hospital-based reports from developing countries that reported increased risk among males (10, 11). Low birth weight was independently associated with infection after adjustment, but the magnitude of association was small (16 percent). Preterm birth may be a more specific risk factor for cord infection, as has been suggested elsewhere (8). Our gestational age data do not provide strong evidence for such a relation, but they may be insufficiently precise for valid interpretation. After adjustment, lower caste infants were at 21 percent greater risk of cord infection, suggesting that there may be other unmeasured, potentially harmful behaviors practiced among lower caste families.
Although our household visit completion rate was high (mean: 9.2 of 11 visits), missing cord assessments can underestimate incidence. This was probably minimal, as the most commonly missed visits (days 1, 21, 28) corresponded to the period of lowest risk. Some of the cord assessments likely resulted in misclassification of signs of infection (19); however, such misclassification likely reduced the magnitude of observed associations between determinants and infection. Differential misclassification may have occurred with some risk factors; for example, workers may have found that smaller infants were more difficult to assess consistently. Evidence for a relation between caste status and cord infection, even after adjustment, suggests that unobserved harmful behaviors or unmeasured elements of the physical environment may further affect exposure risk. For example, the composition of the birthing surface may increase infection risk (14, 15), yet was not adequately measured in this study.
Generalization of these findings to other settings is potentially problematic, given the variation in hygienic practices and the environmental context of those practices. For example, although ash applications to the cord were not associated with increased risk of cord infection in this setting, previous evidence suggests that such a practice may significantly increase risk in other settings (11, 18). Differences in the complex interaction of newborn care practices, environmental exposures, and household and community resources and educational levels may modify the relation between these factors and umbilical cord infection.
In summary, the evidence presented here indicates that use of mustard oil and other unclean substances can increase the risk of subsequent nontetanus-related cord infection and should be discouraged. Hand washing with soap and skin-to-skin contact may provide substantial protection against omphalitis. These newborn care practices are likely to be most important in settings where topical antiseptics are not being delivered and where the current World Health Organization recommendation of dry cord care is being promoted. Programs promoting the improvement of neonatal care in the community should raise awareness of nontetanus-related umbilical cord infection among community members, emphasize hand washing with soap among birth assistants before assisting with delivery, discourage the application of unclean substances to the umbilical cord, and promote the use of skin-to-skin contact for its potential to reduce infection in addition to its many other potential benefits, including improving the thermal status of the newborn (43). Given the impact of early and consistent cleansing of the cord with 4.0 percent chlorhexidine (4) on both infection and mortality, the delivery of topical chlorhexidine to the cord should also be integrated into programs in low-resource settings where the risk of cord infection is high.
This study was supported by the US National Institute of Child Health and Human Development (grants HD44004 and HD38753); the Bill and Melinda Gates Foundation (grant 810-2054); and cooperative agreements between the Johns Hopkins Bloomberg School of Public Health and the Office of Heath and Nutrition, US Agency for International Development (grants HRN-A-00-97-00015-00 and GHS-A-00-03-000019-00).
The funding sources played no role in the study design, collection, data analysis, writing of the report, or decision to submit the paper for publication.
Conflict of interest: none declared.