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      Postmortem investigations and identification of multiple causes of child deaths: An analysis of findings from the Child Health and Mortality Prevention Surveillance (CHAMPS) network

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      1 , 2 , * , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 2 , 4 , 5 , 15 , 7 , 16 , 10 , 13 , 14 , 4 , 5 , 17 , 7 , 18 , 16 , 19 , 11 , 13 , 14 , 7 , 4 , 17 , 11 , 13 , 14 , 12 , 14 , 20 , 11 , 21 , 22 , 7 , 23 , 24 , 25 , 26 , 6 , 4 , 5 , 1 , 2 , the CHAMPS Consortium
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          Abstract

          Background

          The current burden of >5 million deaths yearly is the focus of the Sustainable Development Goal (SDG) to end preventable deaths of newborns and children under 5 years old by 2030. To accelerate progression toward this goal, data are needed that accurately quantify the leading causes of death, so that interventions can target the common causes. By adding postmortem pathology and microbiology studies to other available data, the Child Health and Mortality Prevention Surveillance (CHAMPS) network provides comprehensive evaluations of conditions leading to death, in contrast to standard methods that rely on data from medical records and verbal autopsy and report only a single underlying condition. We analyzed CHAMPS data to characterize the value of considering multiple causes of death.

          Methods and findings

          We examined deaths identified from December 2016 through November 2020 from 7 CHAMPS sites (in Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa), including 741 neonatal, 278 infant, and 241 child <5 years deaths for which results from Determination of Cause of Death (DeCoDe) panels were complete. DeCoDe panelists included all conditions in the causal chain according to the ICD-10 guidelines and assessed if prevention or effective management of the condition would have prevented the death. We analyzed the distribution of all conditions listed as causal, including underlying, antecedent, and immediate causes of death. Among 1,232 deaths with an underlying condition determined, we found a range of 0 to 6 (mean 1.5, IQR 0 to 2) additional conditions in the causal chain leading to death. While pathology provides very helpful clues, we cannot always be certain that conditions identified led to death or occurred in an agonal stage of death. For neonates, preterm birth complications (most commonly respiratory distress syndrome) were the most common underlying condition ( n = 282, 38%); among those with preterm birth complications, 256 (91%) had additional conditions in causal chains, including 184 (65%) with a different preterm birth complication, 128 (45%) with neonatal sepsis, 69 (24%) with lower respiratory infection (LRI), 60 (21%) with meningitis, and 25 (9%) with perinatal asphyxia/hypoxia. Of the 278 infant deaths, 212 (79%) had ≥1 additional cause of death (CoD) beyond the underlying cause. The 2 most common underlying conditions in infants were malnutrition and congenital birth defects; LRI and sepsis were the most common additional conditions in causal chains, each accounting for approximately half of deaths with either underlying condition. Of the 241 child deaths, 178 (75%) had ≥1 additional condition. Among 46 child deaths with malnutrition as the underlying condition, all had ≥1 other condition in the causal chain, most commonly sepsis, followed by LRI, malaria, and diarrheal disease. Including all positions in the causal chain for neonatal deaths resulted in 19-fold and 11-fold increases in attributable roles for meningitis and LRI, respectively. For infant deaths, the proportion caused by meningitis and sepsis increased by 16-fold and 11-fold, respectively; for child deaths, sepsis and LRI are increased 12-fold and 10-fold, respectively. While comprehensive CoD determinations were done for a substantial number of deaths, there is potential for bias regarding which deaths in surveillance areas underwent minimally invasive tissue sampling (MITS), potentially reducing representativeness of findings.

          Conclusions

          Including conditions that appear anywhere in the causal chain, rather than considering underlying condition alone, markedly changed the proportion of deaths attributed to various diagnoses, especially LRI, sepsis, and meningitis. While CHAMPS methods cannot determine when 2 conditions cause death independently or may be synergistic, our findings suggest that considering the chain of events leading to death can better guide research and prevention priorities aimed at reducing child deaths.

          Abstract

          In an analysis of data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network, Robert Breiman, Dianna Blau, and colleagues investigate how considering all conditions in the causal chain leading to death informs the identification of deaths attributable to various diagnoses.

          Author summary

          Why was this study done?
          • More than 5 million deaths occur annually in children <5 years of age globally, mostly in low-income settings in Africa and South Asia.

          • There is reason to believe that a substantial proportion of these deaths are preventable if there were effective programs that target the most common causes of death.

          What did the researchers do and find?
          • We studied the causes of death in 7 sites in Africa and South Asia where child mortality is high by conducting surveillance for mortality and then collecting samples of tissue and other diagnostic specimens to perform pathology and diagnostic tests.

          • In each country, a panel of clinical, laboratory, and epidemiological experts determined underlying, intermediate, and immediate causes of death for each child by studying the clinical data available before death, postmortem questionnaire surveys done with parents of the deceased, and postmortem pathology and testing.

          What do these findings mean?
          • Up to now, most programs focus on a single cause of death (CoD) for each child referred to as the underlying condition.

          • However, the findings suggest that most deaths have multiple conditions that contribute to death.

          • Considering all of the conditions, rather than underlying condition alone, markedly changed the proportion of deaths attributed to various diagnoses, especially lower respiratory infection (LRI), sepsis, and meningitis.

          • The findings suggest that considering the full chain of events leading to death can better guide priorities for research and strategies for mortality prevention.

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          Most cited references21

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          Global, regional, and national levels and trends in under-5 mortality between 1990 and 2015, with scenario-based projections to 2030: a systematic analysis by the UN Inter-agency Group for Child Mortality Estimation.

          In 2000, world leaders agreed on the Millennium Development Goals (MDGs). MDG 4 called for a two-thirds reduction in the under-5 mortality rate between 1990 and 2015. We aimed to estimate levels and trends in under-5 mortality for 195 countries from 1990 to 2015 to assess MDG 4 achievement and then intended to project how various post-2015 targets and observed rates of change will affect the burden of under-5 deaths from 2016 to 2030.
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            Mortality by cause for eight regions of the world: Global Burden of Disease Study.

            Reliable information on causes of death is essential to the development of national and international health policies for prevention and control of disease and injury. Medically certified information is available for less than 30% of the estimated 50.5 million deaths that occur each year worldwide. However, other data sources can be used to develop cause-of-death estimates for populations. To be useful, estimates must be internally consistent, plausible, and reflect epidemiological characteristics suggested by community-level data. The Global Burden of Disease Study (GBD) used various data sources and made corrections for miscoding of important diseases (eg, ischaemic heart disease) to estimate worldwide and regional cause-of-death.patterns in 1990 for 14 age-sex groups in eight regions, for 107 causes. Preliminary estimates were developed with available vital-registration data, sample-registration data for India and China, and small-scale population-study data sources. Registration data were corrected for miscoding, and Lorenz-curve analysis was used to estimate cause-of-death patterns in areas without registration. Preliminary estimates were modified to reflect the epidemiology of selected diseases and injuries. Final estimates were checked to ensure that numbers of deaths in specific age-sex groups did not exceed estimates suggested by independent demographic methods. 98% of all deaths in children younger than 15 years are in the developing world. 83% and 59% of deaths at 15-59 and 70 years, respectively, are in the developing world. The probability of death between birth and 15 years ranges from 22.0% in sub-Saharan Africa to 1.1% in the established market economies. Probabilities of death between 15 and 60 years range from 7.2% for women in established market economies to 39.1% for men in sub-Saharan Africa. The probability of a man or woman dying from a non-communicable disease is higher in sub-Saharan Africa and other developing regions than in established market economies. Worldwide in 1990, communicable, maternal, perinatal, and nutritional disorders accounted for 17.2 million deaths, non-communicable diseases for 28.1 million deaths and injuries for 5.1 million deaths. The leading causes of death in 1990 were ischaemic heart disease (6.3 million deaths), cerebrovascular accidents (4.4 million deaths), lower respiratory infections (4.3 million), diarrhoeal diseases (2.9 million), perinatal disorders (2.4 million), chronic obstructive pulmonary disease (2.2 million), tuberculosis (2.0 million), measles (1.1 million), road-traffic accidents (1.0 million), and lung cancer (0.9 million). Five of the ten leading killers are communicable, perinatal, and nutritional disorders largely affecting children. Non-communicable diseases are, however, already major public health challenges in all regions. Injuries, which account for 10% of global mortality, are often ignored as a major cause of death and may require innovative strategies to reduce their toll. The estimates by cause have wide Cls, but provide a foundation for a more informed debate on public-health priorities.
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              Verbal autopsy: current practices and challenges

              Cause-of-death data derived from verbal autopsy (VA) are increasingly used for health planning, priority setting, monitoring and evaluation in countries with incomplete or no vital registration systems. In some regions of the world it is the only method available to obtain estimates on the distribution of causes of death. Currently, the VA method is routinely used at over 35 sites, mainly in Africa and Asia. In this paper, we present an overview of the VA process and the results of a review of VA tools and operating procedures used at demographic surveillance sites and sample vital registration systems. We asked for information from 36 field sites about field-operating procedures and reviewed 18 verbal autopsy questionnaires and 10 cause-of-death lists used in 13 countries. The format and content of VA questionnaires, field-operating procedures, cause-of-death lists and the procedures to derive causes of death from VA process varied substantially among sites. We discuss the consequences of using varied methods and conclude that the VA tools and procedures must be standardized and reliable in order to make accurate national and international comparisons of VA data. We also highlight further steps needed in the development of a standard VA process.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: SupervisionRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: Investigation
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: Supervision
                Role: InvestigationRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                30 September 2021
                September 2021
                : 18
                : 9
                : e1003814
                Affiliations
                [1 ] Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America
                [2 ] Emory Global Health Institute, Emory University, Atlanta, Georgia, United States of America
                [3 ] Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [4 ] South African Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit, University of the Witwatersrand, Johannesburg, South Africa
                [5 ] Department of Science and Innovation/National Research Foundation: Vaccine Preventable Diseases, University of the Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa
                [6 ] US Centers for Disease Control and Prevention-Kenya, Kisumu, Kenya
                [7 ] Centro de Investigação em Saúde de Manhiça [CISM], Manhica, Mozambique
                [8 ] Instituto Nacional de Saúde [INS], Manhiça, Mozambique
                [9 ] Crown Agents, Freetown, Sierra Leone
                [10 ] Centre pour le Développement des Vaccins (CVD-Mali), Ministère de la Santé, Bamako, Mali
                [11 ] Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
                [12 ] Department of Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, United Kingdom
                [13 ] College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
                [14 ] International Center for Diarrhoeal Diseases Research (icddr,b), Dhaka, Bangladesh
                [15 ] Kisumu County, Kenya Department of Health, Kisumu, Kenya
                [16 ] ICAP–Columbia University, Makeni, Sierra Leone
                [17 ] Kenya Medical Research Institute (KEMRI) Center for Global Health Research, Kisumu, Kenya
                [18 ] Universitat de Barcelona, Barcelona, Spain
                [19 ] World Hope International, Makeni, Sierra Leone
                [20 ] Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
                [21 ] Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
                [22 ] Ministry of Health and Sanitation, Freetown, Sierra Leone
                [23 ] ISGlobal, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain
                [24 ] Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
                [25 ] Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital de Sant Joan de Deu, University of Barcelona, Barcelona, Spain
                [26 ] Consorcio de Investigacion Biomedica en Red de Epidemiologia y Salud Publica (CIBERESP), Madrid, Spain
                University of Southampton, UNITED KINGDOM
                Author notes

                I have read the journal’s policy and the authors of this manuscript have the following competing interests: QB, a co-author of this paper is also a Guest Editor on this special issue on Global Child Health: From Birth to Adolescence and Beyond. QB was not directly involved in editorial decisions regarding this paper. JAGS reports current funding for other projects to his institution (London School of Hygiene & Tropical Medicine) from the UK Medical Research Council, Wellcome Trust, Gavi, Bill & Melinda Gates Foundation, and the UK National Institute for Health Research.

                ¶ Membership of the CHAMPS Consortium is provided in the Acknowledgments.

                Author information
                https://orcid.org/0000-0002-7099-2936
                https://orcid.org/0000-0001-7518-2855
                https://orcid.org/0000-0002-1078-2187
                https://orcid.org/0000-0002-0670-6026
                https://orcid.org/0000-0002-5372-5932
                https://orcid.org/0000-0002-3948-3121
                https://orcid.org/0000-0002-1634-0531
                https://orcid.org/0000-0001-8914-3638
                https://orcid.org/0000-0002-8219-6259
                https://orcid.org/0000-0003-4282-5572
                https://orcid.org/0000-0003-2200-8954
                https://orcid.org/0000-0003-4774-5416
                https://orcid.org/0000-0002-7693-2491
                https://orcid.org/0000-0003-1327-9090
                https://orcid.org/0000-0003-1251-6621
                https://orcid.org/0000-0003-0341-2329
                https://orcid.org/0000-0001-9140-5983
                https://orcid.org/0000-0001-7533-5006
                https://orcid.org/0000-0002-8648-9403
                https://orcid.org/0000-0003-0875-7596
                https://orcid.org/0000-0001-5877-2968
                https://orcid.org/0000-0002-7629-0636
                Article
                PMEDICINE-D-21-00711
                10.1371/journal.pmed.1003814
                8516282
                34591862
                c4fe1bd5-4645-4cfb-a0aa-bb700f5947e0

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 11 February 2021
                : 14 September 2021
                Page count
                Figures: 2, Tables: 13, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000865, Bill and Melinda Gates Foundation;
                Award ID: OPP1126780
                Award Recipient :
                This work was funded by the Bill and Melinda Gates Foundation (Grant number: OPP1126780) to RFB and CGW. https://www.gatesfoundation.org The funder participated in discussions of study design and data collection. They did not participate in analysis or conclusions of this work and did not play a role in decision to publish and preparation of this manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Women's Health
                Maternal Health
                Birth
                Preterm Birth
                Medicine and Health Sciences
                Women's Health
                Obstetrics and Gynecology
                Birth
                Preterm Birth
                Medicine and Health Sciences
                Women's Health
                Maternal Health
                Pregnancy
                Pregnancy Complications
                Preterm Birth
                Medicine and Health Sciences
                Women's Health
                Obstetrics and Gynecology
                Pregnancy
                Pregnancy Complications
                Preterm Birth
                Medicine and Health Sciences
                Pediatrics
                Child Health
                Medicine and Health Sciences
                Public and Occupational Health
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                People and Places
                Population Groupings
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                Medicine and Health Sciences
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                Pulmonology
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                Biology and Life Sciences
                Developmental Biology
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                Clinical Medicine
                Signs and Symptoms
                Sepsis
                Neonatal Sepsis
                Medicine and Health Sciences
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                Infectious Diseases
                Infectious Diseases of the Nervous System
                Meningitis
                Medicine and Health Sciences
                Neurology
                Infectious Diseases of the Nervous System
                Meningitis
                Medicine and Health Sciences
                Medical Conditions
                Inflammatory Diseases
                Meningitis
                Medicine and Health Sciences
                Medical Conditions
                Congenital Disorders
                Custom metadata
                vor-update-to-uncorrected-proof
                2021-10-14
                Data can be accessed at champshealth.org and requests can be made at that site to access additional datasets. Datasets are publicly available at (Child Health and Mortality Prevention Surveillance, 2021, "CHAMPS De-identified Dataset: https://dataverse.unc.edu/dataset.xhtml?persistentId=doi:10.15139/S3/PMAAWG.

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