Sunil Sazawal

Effects of routine prophylactic supplementation with iron and folic acid on admission to hospital and mortality in preschool children in a high malaria transmission setting: community-based, randomised, placebo-controlled trial

BACKGROUND Anaemia caused by iron deficiency is common in children younger than age 5 years in eastern Africa. However, there is concern that universal supplementation of children with iron and folic acid in areas of high malaria transmission might be harmful. METHODS We did a randomised, placebo-controlled trial, of children aged 1-35 months and living in Pemba, Zanzibar. We assigned children to daily oral supplementation with: iron (12.5 mg) and folic acid (50 mug; n=7950), iron, folic acid, and zinc (n=8120), or placebo (n=8006); children aged 1-11 months received half the dose. Our primary endpoints were all-cause mortality and admission to hospital. Analyses were by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59549825. FINDINGS The iron and folic acid-containing groups of the trial were stopped early on Aug 19, 2003, on the recommendation of the data and safety monitoring board. To this date, 24 076 children contributed a follow-up of 25,524 child-years. Those who received iron and folic acid with or without zinc were 12% (95% CI 2-23, p=0.02) more likely to die or need treatment in hospital for an adverse event and 11% (1-23%, p=0.03) more likely to be admitted to hospital; there were also 15% (-7 to 41, p=0.19) more deaths in these groups. INTERPRETATION Routine supplementation with iron and folic acid in preschool children in a population with high rates of malaria can result in an increased risk of severe illness and death. In the presence of an active programme to detect and treat malaria and other infections, iron-deficient and anaemic children can benefit from supplementation. However, supplementation of those who are not iron deficient might be harmful. As such, current guidelines for universal supplementation with iron and folic acid should be revised.

Effect of pneumonia case management on mortality in neonates, infants, and preschool children: a meta-analysis of community-based trials

Pneumonia still causes around two million deaths among children annually (20% of all child deaths). Any intervention that would affect pneumonia mortality is of great public health importance. This meta-analysis provides estimates of mortality impact of the case-management approach proposed by WHO. We were able to get data from nine of ten eligible community-based studies that assessed the effects of pneumonia case-management intervention on mortality; seven studies had a concurrent control group. Standardised forms were completed by individual investigators to provide information on study description, quality scoring, follow-up, and outcome (mortality) data with three age groups (<1 month, <1 year, 0-4 years) and two mortality categories (total and pneumonia-specific). Meta-analysis found a reduction in total mortality of 27% (95% CI 18-35%), 20% (11-28%), and 24% (14-33%) among neonates, infants, and children 0-4 years of age, respectively. In the same three groups pneumonia mortality was reduced by 42% (22-57%), 36% (20-48%), and 36% (20-49%). There was no evidence of publication bias and results were unaltered by exclusion of any study. A limitation of the included studies is that they were not randomised and, because of the nature of the intervention, could not be blinded. Community-based interventions to identify and treat pneumonia have a substantial effect on neonatal, infant, and child mortality and should be incorporated into primary health care.

Zinc Supplementation Reduces the Incidence of Acute Lower Respiratory Infections in Infants and Preschool Children: A Double-blind, Controlled Trial

Background. Increased acute lower respiratory infection incidence, severity, and mortality are associated with malnutrition, and reduced immunological competence may be a mechanism for this association. Because zinc deficiency results in impaired immunocompetence and zinc supplementation improves immune status, we hypothesized that zinc deficiency is associated with increased incidence and severity of acute lower respiratory infection. Methods. We evaluated the effect of daily supplementation with 10 mg of elemental zinc on the incidence and prevalence of acute lower respiratory infection in a double-blind, randomized, controlled trial in 609 children (zinc, n = 298; control, n = 311) 6 to 35 months of age. Supplementation and morbidity surveillance were done for 6 months. Results. After 120 days of supplementation, the percentage of children with plasma zinc concentrations <60 μg/dL decreased from 35.6% to 11.6% in the zinc group, whereas in the control group it increased from 36.8% to 43.6%. Zinc-supplemented children had 0.19 acute lower respiratory infection episodes/child/year compared with 0.35 episodes/child/year in the control children. After correction for correlation of data using generalized estimating equation regression methods, there was a reduction of 45% (95% confidence interval, 10% to 67%) in the incidence of acute lower respiratory infections in zinc-supplemented children. Conclusions. A dietary zinc supplement resulted in a significant reduction in respiratory morbidity in preschool children. These findings suggest that interventions to improve zinc intake will improve the health and survival of children in developing countries.

Zinc Supplementation in Young Children with Acute Diarrhea in India

BACKGROUND In developing countries the duration and severity of diarrheal illnesses are greatest among infants and young children with malnutrition and impaired immune status, both factors that may be associated with zinc deficiency. In children with severe zinc deficiency, diarrhea is common and responds quickly to zinc supplementation. METHODS To evaluate the effects of daily supplementation with 20 mg of elemental zinc on the duration and severity of acute diarrhea, we conducted a double-blind, randomized, controlled trial involving 937 children, 6 to 35 months of age, in New Delhi, India. All the children also received oral rehydration therapy and vitamin supplements. RESULTS Among the children who received zinc supplementation, there was a 23 percent reduction (95 percent confidence interval, 12 percent to 32 percent) in the risk of continued diarrhea. Estimates of the likelihood of recovery according to the day of zinc supplementation revealed a reduction of 7 percent (95 percent confidence interval, -9 percent to +22 percent) in the risk of continued diarrhea during days 1 through 3 and a reduction of 38 percent (95 percent confidence interval, 27 percent to 48 percent) after day 3. When zinc supplementation was initiated within three days of the onset of diarrhea, there was a 39 percent reduction (95 percent confidence interval, 7 percent to 61 percent) in the proportion of episodes lasting more than seven days. In the zinc-supplementation group there was a decrease of 39 percent (95 percent confidence interval, 6 percent to 70 percent) in the mean number of watery stools per day (P = 0.02) and a decrease of 21 percent (95 percent confidence interval, 10 percent to 31 percent) in the number of days with watery diarrhea. The reductions in the duration and severity of diarrhea were greater in children with stunted growth than in those with normal growth. CONCLUSION For infants and young children with acute diarrhea, zinc supplementation results in clinically important reductions in the duration and severity of diarrhea.

Typhoid fever in children aged less than 5 years

BACKGROUND Calculation of the incidence of typhoid fever during preschool years is important to define the optimum age of immunisation and the choice of vaccines for public-health programmes in developing countries. Hospital-based studies have suggested that children younger than 5 years do not need vaccination against typhoid fever, but this view needs to be re-examined in community-based longitudinal studies. We undertook a prospective follow-up study of residents of a low-income urban area of Delhi, India, with active surveillance for case detection. METHODS A baseline census was undertaken in 1995. Between Nov 1, 1995, and Oct 31, 1996, we visited 8172 residents of 1820 households in Kalkaji, Delhi, twice weekly to detect febrile cases. Blood samples were obtained from febrile patients, and those who tested positive for Salmonella typhi were treated with ciprofloxacin. FINDINGS 63 culture-positive typhoid fever cases were detected. Of these, 28 (44%) were in children aged under 5 years. The incidence rate of typhoid per 1000 person-years was 27.3 at age under 5 years, 11.7 at 5-19 years, and 1.1 between 19 and 40 years. The difference in the incidence of typhoid fever between those under 5 years and those aged 5-19 years (15.6 per 1000 person-years [95% CI 4.7-26.5]), and those aged 19-40 years (26.2 [16.0-36.3]) was significant (p<0.001 for both). The difference between the incidence of typhoid at 5-19 years and the incidence at 19-40 years was also significant (10.6 [6.3-14.8], p<0.001). Morbidity in those under 5 and in older people was similar in terms of duration of fever, signs and symptoms, and need for hospital admission. INTERPRETATION Our findings challenge the common view that typhoid fever is a disorder of school-age children and of adults. Typhoid is a common and significant cause of morbidity between 1 and 5 years of age. The optimum age of typhoid immunisation and the choice of vaccines needs to be reassessed.

Meta-analysis of intervention trials on case-management of pneumonia in community settings

To appraise the effectiveness of the pneumonia case-management strategy in improving child survival, we have done a meta-analysis of six published intervention trials. The results of a seventh published study and two unpublished studies were also reviewed. The six published studies satisfied our criteria for methodological soundness. The reduction in mortality rate (control group minus intervention group) was estimated for each study, and for all the studies together. For total infant mortality, the overall reduction was 15.9 (95% confidence interval 10.6-21.1) deaths per 1000 livebirths; infant mortality due to acute lower respiratory infection was reduced by 10.7 (4.8-16.7) deaths/1000 livebirths. Mortality among children under 5 years was decreased by 36 deaths/1000 livebirths. The pooled estimates of relative risk are consistent with a 20% reduction in infant mortality and a 25% reduction in under-5 mortality. There was no clear association across the studies between the effect of the pneumonia case-management and extent of co-interventions such as immunisation and oral rehydration therapy. The consistency of findings of all the studies, despite differences in design and methods, shows that the case-management strategy has a substantial effect on infant and under-5 mortality, at least in settings with infant mortality rates of 90/1000 livebirths or more. It is important to find out the most efficient ways of implementing this strategy and integrating it into primary health care.

Effect of zinc supplementation on mortality in children aged 1–48 months: a community-based randomised placebo-controlled trial

BACKGROUND Studies from Asia have suggested that zinc supplementation can reduce morbidity and mortality in children, but evidence from malarious populations in Africa has been inconsistent. Our aim was to assess the effects of zinc supplementation on overall mortality in children in Pemba, Zanzibar. METHODS We enrolled 42,546 children aged 1-36 months, contributing a total of 56,507 child-years in a randomised, double-blind, placebo-controlled trial in Pemba, Zanzibar. Randomisation was by household. 21 274 children received daily supplementation with zinc 10 mg (5 mg in children younger than 12 months) for mean 484.7 days (SD 306.6). 21,272 received placebo. The primary endpoint was overall mortality, and analysis was by intention to treat. This study is registered as an International Standard Randomised Clinical Trial, number ISRCTN59549825. FINDINGS Overall, there was a non-significant 7% (95% CI -6% to 19%; p=0.29) reduction in the relative risk of all-cause mortality associated with zinc supplementation. INTERPRETATION We believe that a meta-analysis of all studies of mortality and morbidity, will help to make evidence-based recommendations for the role of zinc supplementation in public health policy to improve mortality, morbidity, growth, and development in young children.

Population Health Metrics Research Consortium gold standard verbal autopsy validation study: design, implementation, and development of analysis datasets

BackgroundVerbal autopsy methods are critically important for evaluating the leading causes of death in populations without adequate vital registration systems. With a myriad of analytical and data collection approaches, it is essential to create a high quality validation dataset from different populations to evaluate comparative method performance and make recommendations for future verbal autopsy implementation. This study was undertaken to compile a set of strictly defined gold standard deaths for which verbal autopsies were collected to validate the accuracy of different methods of verbal autopsy cause of death assignment.MethodsData collection was implemented in six sites in four countries: Andhra Pradesh, India; Bohol, Philippines; Dar es Salaam, Tanzania; Mexico City, Mexico; Pemba Island, Tanzania; and Uttar Pradesh, India. The Population Health Metrics Research Consortium (PHMRC) developed stringent diagnostic criteria including laboratory, pathology, and medical imaging findings to identify gold standard deaths in health facilities as well as an enhanced verbal autopsy instrument based on World Health Organization (WHO) standards. A cause list was constructed based on the WHO Global Burden of Disease estimates of the leading causes of death, potential to identify unique signs and symptoms, and the likely existence of sufficient medical technology to ascertain gold standard cases. Blinded verbal autopsies were collected on all gold standard deaths.ResultsOver 12,000 verbal autopsies on deaths with gold standard diagnoses were collected (7,836 adults, 2,075 children, 1,629 neonates, and 1,002 stillbirths). Difficulties in finding sufficient cases to meet gold standard criteria as well as problems with misclassification for certain causes meant that the target list of causes for analysis was reduced to 34 for adults, 21 for children, and 10 for neonates, excluding stillbirths. To ensure strict independence for the validation of methods and assessment of comparative performance, 500 test-train datasets were created from the universe of cases, covering a range of cause-specific compositions.ConclusionsThis unique, robust validation dataset will allow scholars to evaluate the performance of different verbal autopsy analytic methods as well as instrument design. This dataset can be used to inform the implementation of verbal autopsies to more reliably ascertain cause of death in national health information systems.

Zinc and childhood infectious disease morbidity and mortality

Zinc is an essential mineral and deficiency results in abnormal immune function and higher rates of infectious diseases. Randomized controlled trials of zinc supplementation have been conducted in children in developing countries to determine effects on infectious disease morbidity and mortality. Zinc-supplemented children have been found to have lower rates of diarrhea, pneumonia and malaria in comparison with children not given zinc. Zinc used as an adjunct to fluid and dietary management of acute and persistent diarrhea has been found to reduce diarrheal duration and severity. Preliminary evidence suggests that zinc supplementation in children in poor developing country settings may also reduce infant mortality, but larger trials are needed to address this important issue. Preventive and therapeutic interventions should be implemented in developing countries where zinc deficiency is likely to be prevalent.

Using verbal autopsy to measure causes of death: the comparative performance of existing methods

BackgroundMonitoring progress with disease and injury reduction in many populations will require widespread use of verbal autopsy (VA). Multiple methods have been developed for assigning cause of death from a VA but their application is restricted by uncertainty about their reliability.MethodsWe investigated the validity of five automated VA methods for assigning cause of death: InterVA-4, Random Forest (RF), Simplified Symptom Pattern (SSP), Tariff method (Tariff), and King-Lu (KL), in addition to physician review of VA forms (PCVA), based on 12,535 cases from diverse populations for which the true cause of death had been reliably established. For adults, children, neonates and stillbirths, performance was assessed separately for individuals using sensitivity, specificity, Kappa, and chance-corrected concordance (CCC) and for populations using cause specific mortality fraction (CSMF) accuracy, with and without additional diagnostic information from prior contact with health services. A total of 500 train-test splits were used to ensure that results are robust to variation in the underlying cause of death distribution.ResultsThree automated diagnostic methods, Tariff, SSP, and RF, but not InterVA-4, performed better than physician review in all age groups, study sites, and for the majority of causes of death studied. For adults, CSMF accuracy ranged from 0.764 to 0.770, compared with 0.680 for PCVA and 0.625 for InterVA; CCC varied from 49.2% to 54.1%, compared with 42.2% for PCVA, and 23.8% for InterVA. For children, CSMF accuracy was 0.783 for Tariff, 0.678 for PCVA, and 0.520 for InterVA; CCC was 52.5% for Tariff, 44.5% for PCVA, and 30.3% for InterVA. For neonates, CSMF accuracy was 0.817 for Tariff, 0.719 for PCVA, and 0.629 for InterVA; CCC varied from 47.3% to 50.3% for the three automated methods, 29.3% for PCVA, and 19.4% for InterVA. The method with the highest sensitivity for a specific cause varied by cause.ConclusionsPhysician review of verbal autopsy questionnaires is less accurate than automated methods in determining both individual and population causes of death. Overall, Tariff performs as well or better than other methods and should be widely applied in routine mortality surveillance systems with poor cause of death certification practices.