The Nepal Newborn Washing Study was a cluster-randomized, placebo-controlled, community-based trial that began in September 2002 among newborn infants who were delivered to women who lived in Sarlahi District in south-central Nepal. This area is typical of much of the Indian subcontinent. The population is considered poor, even in Nepal; almost three fourths of families live below the poverty line.23
The area was divided into sectors (N
= 413) on the basis of the population that 1 local female worker (ward distributor [WD]) could service, ~40 to 50 households.
Pregnancies in the study area were identified by the WDs, who went door to door on a monthly basis. At ~6 months' gestation, women were recruited for participation. At the time of recruitment, all women received weekly vitamin A supplementation, iron–folic acid supplements, and albendazole. These benefits were provided because previous research in this area had demonstrated their efficacy. Tetanus immunization history was assessed and, when deficient, provided by study staff, and all women were provided with a clean birthing kit. Workers provided education regarding proper nutrition during pregnancy and hygienic delivery and neonatal care, including clean cord care and prevention of hypothermia. Although the prevalence of HIV infection and group B streptococcal colonization in pregnant women is not known in this area, they are likely to be very low.
Eligibility and Randomization
Infants in this population typically are delivered by family members or untrained, traditional birth attendants, and >95% of births occur in the home. The WD was notified by families as soon as possible after the birth of a child. The WD then walked to the home to enroll the newborn infant and conducted the skin-cleansing.
Randomization was conducted at the sector level, stratified by geographic area and tertiles of infant mortality risk as measured during an antenatal micronutrient supplementation trial that was completed in the same area 1 year before the start of this study.24
Concurrent with this trial, a subset of infants were included in a nested trial of 3 approaches to care of the umbilical cord using omphalitis and mortality as end points (). Details of this trial were presented in a separate article.25
FIGURE 1 Study design. Results of the nested trial of umbilical cord care treatments (gray boxes) are reported separately.25
Informed consent was obtained at the community, household, and individual levels. Community consent was obtained during meetings with community leaders. In addition, verbal consent was obtained at the household level from the parents of enrolled infants.
Newborn infants were sector-randomized to receive 1 of 2 skin-cleansing regimens when the WD arrived at the house after delivery: (1) wiping of the total body excluding the eyes and ears with Pampers infant wipes (Procter and Gamble Co, Cincinnati, OH) that released a solution that contained 0.25% free chlorhexidine (equivalent to 0.44% chlorhexidine digluconate) or (2) wiping with the same infant wipes that lacked chlorhexidine (placebo). All wipes were alcohol-free, produced by Procter and Gamble Co, and packaged in sterile plastic sachets that contained 6 wipes. The allocation codes were kept at Proctor and Gamble, and investigators and all study staff were masked to the treatment assignment. Demonstrations with life-sized dolls and an instructional video were used to train WDs to deliver the intervention using a standard protocol.26
Definition and Measurement of Outcome
The primary outcome was all-cause mortality within the first 28 days of life. Cause of death was assessed by verbal autopsy and classified by an algorithmic approach defined previously.27
Sepsis deaths were defined by the presence of 2 or more of the following signs or symptoms: (1) caregiver's report of fever; (2) vomiting more than half of feeds; (3) unconsciousness; (4) bulging fontanelle; (5) feeding difficulty (not able to suck before death or feeding less than normal); (6) skin or umbilical cord infection (pus discharge from the cord stump); (7) jaundice; and (8) difficulty breathing and either rapid breathing or chest indrawing. A hierarchy of diagnoses was applied during cause-of-death analysis as follows: congenital abnormality, tetanus, prematurity, birth asphyxia, sepsis, acute lower respiratory infection, and diarrhea.27
For deaths that were attributed to congenital abnormality or tetanus, a confirmation by physician review of the verbal autopsy record was required.
Community-level data on the presence of economic, educational, and health facilities were collected during interviews with community leaders. Household-level data on socioeconomic status, education, maternal health indicators including reproductive history, and household structure were collected during a household interview. After the intervention visit to the home, a staff member (not the WD) visited to collect data on the delivery process and the condition and immediate care of the newborn infant and to weigh the infant using a digital infant scale. Visits were conducted on days 2, 3, 4, 6, 8, 10, 12, 14, 21, and 28 to assess infant vital status and morbidity. At each visit, the staff member examined the infant for signs of umbilical cord and skin infection, measured the axillary temperature and respiratory rate, and recorded other morbidity symptoms and signs. On day 14, an interview was conducted with the mother on newborn care practices. Infants who had specific sets of signs and symptoms at the time of household visits were referred to the local health system for care. All infants who were alive at 28 days were discharged from the study.
The study originally was designed to detect a minimum reduction in all-cause neonatal mortality of 20% (relative risk [RR]: 0.80) given 80% power, a 2-sided type I error of 5%, 5% loss to follow-up, and a neonatal mortality rate of 50 per 1000 live births in the placebo group. Because neonatal mortality did not cluster at the sector level during a previous study,24
no adjustment was made for intracluster correlation. This resulted in a sample size of 13 500 live births. A lower-than-expected neonatal mortality rate by the time of the first Data and Safety Monitoring Board (DSMB) meeting prompted the recommendation that the sample size be expanded to ~17 000 live births.
Statistical analysis was performed using Stata 8.0 (Stata Corp, College Station, TX). Treatment groups were compared on baseline household, maternal, and delivery characteristics. Treatment effect on neonatal mortality was done on 2 populations. The first used all live births that occurred in the cluster irrespective of whether they received their assigned intervention. The second used only newborns who were alive at the time of the WD visit to the home and who received their assigned intervention. Mortality was compared using live births as the denominator and deaths within the first 28 days as the numerator. Survival analysis, including Kaplan-Meier survival curves, also was conducted. Multivariable binomial regression with a log link function was used to model the risk for mortality adjusted for potentially confounding factors imbalanced across treatment groups and to model effect modification. Estimates of the RRs and their SEs were adjusted to account for the clustered randomization using generalized estimating equations with an exchangeable correlation structure.28
Children who migrated out of the study area or whose parents refused additional participation before day 28 were censored at the time when they left the study. Stratified analyses were planned for selected variables that are known to be important risk factors for neonatal mortality, such as LBW, previous child death in the family, gender, and ethnic group.
Ethical Review and Data and Safety Monitoring
This study received approval from the Nepal Health Research Council and the Committee on Human Research of the Johns Hopkins Bloomberg School of Public Health. It is registered at www.clinicaltrials.gov
(NCT00109616). An independent DSMB met 3 times to review the protocol and the data for safety and efficacy. At the meeting in January 2005, the DSMB recommended that the study be stopped because of adequate evidence for a beneficial effect of chlorhexidine newborn skin-cleansing among LBW infants. The ethical committees approved this decision, and from March 8, 2005, through January 2006 (end of enrollment), all newborn infants in the study area received skin-cleansing with the chlorhexidine solution.
Role of Funders
Financial supporters and the commodity supplier played no role in the design, conduct, management, analysis, or interpretation of the results or in the preparation, review, or approval of this article.