Jamie Perin

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000

BACKGROUND Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. METHODS Updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1-59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. FINDINGS Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916-1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610-0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252-0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977-1·176), diarrhoea (9·9%; 0·751 million, 0·538-1·031), and malaria (7·4%; 0·564 million, 0·432-0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339-0·547], 0·363 million [0·283-0·419], and 0·359 million [0·215-0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. INTERPRETATION Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010-15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. FUNDING The Bill & Melinda Gates Foundation.

Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis

BACKGROUND Trend data for causes of child death are crucial to inform priorities for improving child survival by and beyond 2015. We report child mortality by cause estimates in 2000-13, and cause-specific mortality scenarios to 2030 and 2035. METHODS We estimated the distributions of causes of child mortality separately for neonates and children aged 1-59 months. To generate cause-specific mortality fractions, we included new vital registration and verbal autopsy data. We used vital registration data in countries with adequate registration systems. We applied vital registration-based multicause models for countries with low under-5 mortality but inadequate vital registration, and updated verbal autopsy-based multicause models for high mortality countries. We used updated numbers of child deaths to derive numbers of deaths by causes. We applied two scenarios to derive cause-specific mortality in 2030 and 2035. FINDINGS Of the 6·3 million children who died before age 5 years in 2013, 51·8% (3·257 million) died of infectious causes and 44% (2·761 million) died in the neonatal period. The three leading causes are preterm birth complications (0·965 million [15·4%, uncertainty range (UR) 9·8-24·5]; UR 0·615-1·537 million), pneumonia (0·935 million [14·9%, 13·0-16·8]; 0·817-1·057 million), and intrapartum-related complications (0·662 million [10·5%, 6·7-16·8]; 0·421-1·054 million). Reductions in pneumonia, diarrhoea, and measles collectively were responsible for half of the 3·6 million fewer deaths recorded in 2013 versus 2000. Causes with the slowest progress were congenital, preterm, neonatal sepsis, injury, and other causes. If present trends continue, 4·4 million children younger than 5 years will still die in 2030. Furthermore, sub-Saharan Africa will have 33% of the births and 60% of the deaths in 2030, compared with 25% and 50% in 2013, respectively. INTERPRETATION Our projection results provide concrete examples of how the distribution of child causes of deaths could look in 15-20 years to inform priority setting in the post-2015 era. More evidence is needed about shifts in timing, causes, and places of under-5 deaths to inform child survival agendas by and beyond 2015, to end preventable child deaths in a generation, and to count and account for every newborn and every child. FUNDING Bill & Melinda Gates Foundation.

Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review

BackgroundDiarrhea is recognized as a leading cause of morbidity and mortality among children under 5 years of age in low- and middle-income countries yet updated estimates of diarrhea incidence by age for these countries are greatly needed. We conducted a systematic literature review to identify cohort studies that sought to quantify diarrhea incidence among any age group of children 0-59 mo of age.MethodsWe used the Expectation-Maximization algorithm as a part of a two-stage regression model to handle diverse age data and overall incidence rate variation by study to generate country specific incidence rates for low- and middle-income countries for 1990 and 2010. We then calculated regional incidence rates and uncertainty ranges using the bootstrap method, and estimated the total number of episodes for children 0-59 mo of age in 1990 and 2010.ResultsWe estimate that incidence has declined from 3.4 episodes/child year in 1990 to 2.9 episodes/child year in 2010. As was the case previously, incidence rates are highest among infants 6-11 mo of age; 4.5 episodes/child year in 2010. Among these 139 countries there were nearly 1.9 billion episodes of childhood diarrhea in 1990 and nearly 1.7 billion episodes in 2010.ConclusionsAlthough our results indicate that diarrhea incidence rates may be declining slightly, the total burden on the health of each child due to multiple episodes per year is tremendous and additional funds are needed to improve both prevention and treatment practices in low- and middle-income countries.

Global, regional, and national causes of under-5 mortality in 2000–15: an updated systematic analysis with implications for the Sustainable Development Goals

Summary Background Despite remarkable progress in the improvement of child survival between 1990 and 2015, the Millennium Development Goal (MDG) 4 target of a two-thirds reduction of under-5 mortality rate (U5MR) was not achieved globally. In this paper, we updated our annual estimates of child mortality by cause to 2000–15 to reflect on progress toward the MDG 4 and consider implications for the Sustainable Development Goals (SDG) target for child survival. Methods We increased the estimation input data for causes of deaths by 43% among neonates and 23% among 1–59-month-olds, respectively. We used adequate vital registration (VR) data where available, and modelled cause-specific mortality fractions applying multinomial logistic regressions using adequate VR for low U5MR countries and verbal autopsy data for high U5MR countries. We updated the estimation to use Plasmodium falciparum parasite rate in place of malaria index in the modelling of malaria deaths; to use adjusted empirical estimates instead of modelled estimates for China; and to consider the effects of pneumococcal conjugate vaccine and rotavirus vaccine in the estimation. Findings In 2015, among the 5·9 million under-5 deaths, 2·7 million occurred in the neonatal period. The leading under-5 causes were preterm birth complications (1·055 million [95% uncertainty range (UR) 0·935–1·179]), pneumonia (0·921 million [0·812 −1·117]), and intrapartum-related events (0·691 million [0·598 −0·778]). In the two MDG regions with the most under-5 deaths, the leading cause was pneumonia in sub-Saharan Africa and preterm birth complications in southern Asia. Reductions in mortality rates for pneumonia, diarrhoea, neonatal intrapartum-related events, malaria, and measles were responsible for 61% of the total reduction of 35 per 1000 livebirths in U5MR in 2000–15. Stratified by U5MR, pneumonia was the leading cause in countries with very high U5MR. Preterm birth complications and pneumonia were both important in high, medium high, and medium child mortality countries; whereas congenital abnormalities was the most important cause in countries with low and very low U5MR. Interpretation In the SDG era, countries are advised to prioritise child survival policy and programmes based on their child cause-of-death composition. Continued and enhanced efforts to scale up proven life-saving interventions are needed to achieve the SDG child survival target. Funding Bill & Melinda Gates Foundation, WHO.

Reduced Susceptibility of Plasmodium falciparum to Artesunate in Southern Myanmar

Background Plasmodium falciparum resistance to artemisinins, the first line treatment for malaria worldwide, has been reported in western Cambodia. Resistance is characterized by significantly delayed clearance of parasites following artemisinin treatment. Artemisinin resistance has not previously been reported in Myanmar, which has the highest falciparum malaria burden among Southeast Asian countries. Methods A non-randomized, single-arm, open-label clinical trial of artesunate monotherapy (4 mg/kg daily for seven days) was conducted in adults with acute blood-smear positive P. falciparum malaria in Kawthaung, southern Myanmar. Parasite density was measured every 12 hours until two consecutive negative smears were obtained. Participants were followed weekly at the study clinic for three additional weeks. Co-primary endpoints included parasite clearance time (the time required for complete clearance of initial parasitemia), parasite clearance half-life (the time required for parasitemia to decrease by 50% based on the linear portion of the parasite clearance slope), and detectable parasitemia 72 hours after commencement of artesunate treatment. Drug pharmacokinetics were measured to rule out delayed clearance due to suboptimal drug levels. Results The median (range) parasite clearance half-life and time were 4.8 (2.1–9.7) and 60 (24–96) hours, respectively. The frequency distributions of parasite clearance half-life and time were bimodal, with very slow parasite clearance characteristic of the slowest-clearing Cambodian parasites (half-life longer than 6.2 hours) in approximately 1/3 of infections. Fourteen of 52 participants (26.9%) had a measurable parasitemia 72 hours after initiating artesunate treatment. Parasite clearance was not associated with drug pharmacokinetics. Conclusions A subset of P. falciparum infections in southern Myanmar displayed markedly delayed clearance following artemisinin treatment, suggesting either emergence of artemisinin resistance in southern Myanmar or spread to this location from its site of origin in western Cambodia. Resistance containment efforts are underway in Myanmar. Trial Registration Australian New Zealand Clinical Trials Registry ACTRN12610000896077

Geophagy is associated with environmental enteropathy and stunting in children in rural Bangladesh.

There is a growing body of literature indicating an association between stunting and environmental enteropathy (EE), a disorder thought to be caused by repeated exposures to enteric pathogens. To investigate the relationship between exposure to enteric pathogens through geophagy, consumption of soil, EE, and stunting, we conducted a prospective cohort study of 216 children under 5 years of age in rural Bangladesh. Geophagy was assessed at baseline using 5 hour structured observation and caregiver reports. Stool was analyzed for fecal markers of intestinal inflammation: alpha-1-antitrypsin, myeloperoxidase, neopterin (all three combined to form an EE disease activity score), and calprotectin. Eighteen percent of children had observed geophagy events by structured observation and 28% had caregiver reported events in the past week. Nearly all households had Escherichia coli (97%) in soil, and 14% had diarrheagenic E. coli. Children with caregiver-reported geophagy had significantly higher EE scores (0.72 point difference, 95% confidence interval [CI]: 0.01, 1.42) and calprotectin concentrations (237.38 μg/g, 95% CI: 12.77, 462.00). Furthermore, at the 9-month follow-up the odds of being stunted (height-for-age z-score < -2) was double for children with caregiver-reported geophagy (odds ratio [OR]: 2.27, 95% CI: 1.14, 4.51). These findings suggest that geophagy in young children may be an important unrecognized risk factor for EE and stunting.

Fecal Markers of Environmental Enteropathy are Associated with Animal Exposure and Caregiver Hygiene in Bangladesh

Undernutrition is estimated to be an underlying cause of over half of all deaths in young children globally. There is a growing body of literature suggesting that increased exposure to enteric pathogens is responsible for environmental enteropathy (EE), a disorder associated with impaired growth in children. To determine if household unsanitary environmental conditions were significantly associated with EE and stunting in children, we conducted a cohort of 216 children (≤ 30 months) in rural Bangladesh. Stool was analyzed for four fecal markers of EE: alpha-1-antitrypsin, myeloperoxidase, and neopterin combined to form an EE disease activity score, and calprotectin. We observed a significant association between having an animal corral in a childs sleeping room and elevated EE scores (1.0 point difference, 95% confidence interval [CI]: 0.13, 1.88) and a two times higher odds of stunting (height-for-age z-score < -2) (odds ratio [OR]: 2.53, 95% CI: 1.08, 5.43) after adjusting for potential confounders. In addition, children of caregivers with visibly soiled hands had significantly elevated fecal calprotectin (μg/g) (384.1, 95% CI: 152.37, 615.83). These findings suggest that close contact with animals and caregiver hygiene may be important risk factors for EE in young children. These findings are consistent with the hypothesis that unsanitary environmental conditions can lead to EE in susceptible pediatric populations.

Diarrhea as a risk factor for acute lower respiratory tract infections among young children in low income settings

Background Diarrhea and acute lower respiratory tract infections (ALRI) are leading causes of morbidity and mortality among children under 5 years of age. We sought to quantify the correlation of diarrhea and respiratory infections within an individual child and to determine if infection with one illness increases the risk of infection with the other during the same time period. Methods We quantified the likelihood of an ALRI and a diarrhea episode occurring during the same week compared to the likelihood of each occurring independently in two cohorts of children under 3 years of age using a bivariate probit regression model. We also quantified the likelihood of an ALRI episode conditioned on a child’s diarrhea history and the likelihood of a diarrhea episode conditioned on a child’s ALRI history using Cox Proportional Hazard models. Results In Indian and Nepali children, diarrhea and ALRI occurred simultaneously more than chance alone. Incidence of ALRI increased in both cohorts as the number of days with diarrhea in the prior 28 days increased; the greatest incident rate ratio was reported among children with 20 or more days of diarrhea (1.02, 95% confidence interval (CI) 1.01 – 1.03 in Nepal and 1.07, 95% CI 1.05 – 1.09 in South India). Incidence of diarrhea was affected differently by ALRI prevalence depending on season. Conclusions Diarrhea may be a direct risk factor for ALRI among children under 3 years of age. The risk of comorbidity increases as disease severity increases, providing additional rationale for prompt community case–management of both diarrhea and pneumonia.

Trends in causes of death among children under 5 in Bangladesh, 1993-2004: an exercise applying a standardized computer algorithm to assign causes of death using verbal autopsy data

BackgroundTrends in the causes of child mortality serve as important global health information to guide efforts to improve child survival. With child mortality declining in Bangladesh, the distribution of causes of death also changes. The three verbal autopsy (VA) studies conducted with the Bangladesh Demographic and Health Surveys provide a unique opportunity to study these changes in child causes of death.MethodsTo ensure comparability of these trends, we developed a standardized algorithm to assign causes of death using symptoms collected through the VA studies. The original algorithms applied were systematically reviewed and key differences in cause categorization, hierarchy, case definition, and the amount of data collected were compared to inform the development of the standardized algorithm. Based primarily on the 2004 cause categorization and hierarchy, the standardized algorithm guarantees comparability of the trends by only including symptom data commonly available across all three studies.ResultsBetween 1993 and 2004, pneumonia remained the leading cause of death in Bangladesh, contributing to 24% to 33% of deaths among children under 5. The proportion of neonatal mortality increased significantly from 36% (uncertainty range [UR]: 31%-41%) to 56% (49%-62%) during the same period. The cause-specific mortality fractions due to birth asphyxia/birth injury and prematurity/low birth weight (LBW) increased steadily, with both rising from 3% (2%-5%) to 13% (10%-17%) and 10% (7%-15%), respectively. The cause-specific mortality rates decreased significantly due to neonatal tetanus and several postneonatal causes (tetanus: from 7 [4-11] to 2 [0.4-4] per 1,000 live births (LB); pneumonia: from 26 [20-33] to 15 [11-20] per 1,000 LB; diarrhea: from 12 [8-17] to 4 [2-7] per 1,000 LB; measles: from 5 [2-8] to 0.2 [0-0.7] per 1,000 LB; injury: from 11 [7-17] to 3 [1-5] per 1,000 LB; and malnutrition: from 9 [6-13] to 5 [2-7]).ConclusionsPneumonia remained the top killer of children under 5 in Bangladesh between 1993 and 2004. The increasing importance of neonatal survival is highlighted by the growing contribution of neonatal deaths and several neonatal causes. Notwithstanding the limitations, standardized computer-based algorithms remain a promising tool to generate comparable causes of child death using VA data.

Randomized controlled trial of hospital-based hygiene and water treatment intervention (CHoBI7) to reduce cholera

This intervention significantly reduced symptomatic Vibrio cholerae infection.