1. Copyright restrictions may apply Risk of Mortality Associated With Neonatal Hypothermia in Southern Nepal Mullany LC, Katz J, Khatry SK, LeClerq SC, Darmstadt GL, Tielsch JM. Risk of mortality associated with neonatal hypothermia in southern Nepal. Arch Pediatr Adolesc Med. 2010;164(7):650-656.

2. Copyright restrictions may apply Introduction Hypothermia is thought to be an important contributing factor to neonatal mortality in low-resource settings. Community-based data on mortality risk subsequent to hypothermia are lacking. Current World Health Organization (WHO) definitions of mild, moderate, and severe hypothermia are not risk based, and new cutoffs are needed.

3. Copyright restrictions may apply Methods Sample –Observational study among newborns in southern Nepal: Axillary temperature collected during in-home visits. Vital status measured through neonatal period. Daily ambient temperature measured. –23 240 newborns (>90% home births) between 2002 and 2006.

4. Copyright restrictions may apply Methods Analysis –Mortality-hypothermia relationship examined: Using WHO cutoffs for mild, moderate, and severe hypothermia. For risk associated with each quarter-degree interval between 32.0°C and 36.5°C With binomial risk regression using continuous axillary measures. –New hypothermia classification system proposed. –Multivariate binomial models used to adjust for potential confounders. –Models stratified by preterm status.

5. Copyright restrictions may apply Results Infants with hypothermia by WHO classification: –Mild hypothermia: 25.6%. –Moderate hypothermia: 31.6%. Table 1. Associations Between Mortality and First Temperature Observed for Standard WHO Categories

6. Copyright restrictions may apply Results Mortality Risk Associated With Hypothermia Figure. Association between first temperature observed and mortality, adjusted for age and ambient temperature at measurement. Error bars indicate 95% confidence interval; *normal temperature.

7. Copyright restrictions may apply Results Mortality Associated With Hypothermia Modified by Gestational Age Table 2. Multivariate Model of Overall Risk and Risk Stratified by Birth Status

8. Copyright restrictions may apply Comment Study Limitations –Some infants died prior to home visit and had no axillary measures— they were excluded from analysis. –Some misclassification in gestational age estimate is possible (last menstrual period was reported by the mother at mid-pregnancy). –Other temperature collection methods (ie, rectal) may be more accurate for newborns.

9. Copyright restrictions may apply Comment Early exposure to hypothermia is among the most important risk factors for subsequent neonatal mortality. Mortality risk varies substantially within the current WHO moderate hypothermia category. We recommend new temperature thresholds/categories: –Normal:36.5°C-37.5°C –Grade 1:36.0°C-36.5°C –Grade 2:35.0°C-36.0°C –Grade 3:34.0°C-35.0°C –Grade 4:<34.0°C

10. Copyright restrictions may apply Comment Under the new classification system, the most severe category is expanded to 34.0°C (grade 4). The remaining interval within the WHO’s moderate category is split into grade 3 (34.0°C-35.0°C) and grade 2 (35.0°C-36.0°C). Example applications of new categorization: –Infants with grade 3 or 4 hypothermia require immediate and skilled care plus referral. –Preterm infants with grade 2 hypothermia or term infants with grade 3 hypothermia require immediate, targeted, in-home demonstration of improved thermal care.

11. Copyright restrictions may apply Comment Further research is urgently required to identify risk factors for early neonatal hypothermia. Evaluation of low-cost thermal care interventions in community- and hospital-based settings is needed. Reducing exposure to neonatal hypothermia has the potential to substantially reduce the global neonatal mortality burden.

12. Copyright restrictions may apply Contact Information If you have questions, please contact the corresponding author: Luke C. Mullany, PhD (lmullany@jhsph.edu).lmullany@jhsph.edu Funding/Support This study was supported by grants HD 553466, HD 44004, and HD 38753 from the National Institutes of Health; grant 810-2054 from the Bill and Melinda Gates Foundation; and Cooperative Agreements between Johns Hopkins University and the Office of Health and Nutrition, US Agency for International Development (HRN-A-00-97-00015-00 and GHS-A-00-03- 000019-00).