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

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. We analyzed CHAMPS CoD data from all 7 sites to characterize the distribution of conditions that are listed as causes of death for neonates, infants (<28 days old), and children (12 months to <60 months). Surveillance methods and inclusion criteria for CHAMPS enrollment for MITS [13] have been described previously. Briefly, children who were <5 years of age at the time of death and were residents of a catchment area were eligible for enrollment. Parents or guardians were approached for consent for verbal autopsy and clinical chart abstraction; permission was also sought for specimen collection and testing for children whose deaths were identified within 24 hours of occurrence. The protocol was prospectively developed. Site selection and characteristics have also been previously described [13]. Briefly, the CHAMPS network consists of 7 sites in sub-Saharan Africa and South Asia, each with a geographically defined catchment area: Baliakandi and Faridpur, Bangladesh; Bamako (Djikoroni Para and Banconi), Mali; Kersa and Harar, Ethiopia; Makeni (Bombali Shebora and Bombali Siari Chiefdoms), Sierra Leone; Manhiça, Mozambique; Siaya (Karemo) and Kisumu (Manyatta), Kenya; and Soweto and Thembelihle, South Africa. Sites were selected based on a variety of factors, including demonstrated mortality of greater than 50 deaths per 1,000 live births in children less than 5 years old at the time of site selection (2015), willingness of the local lead investigator to use a common, multisite protocol and to share data globally in real time, as well as ecologic and geographic diversity: We set out to have a distribution of rural, peri-urban, and urban (including informal settlement) sites, prevalence of HIV and malaria, and dispersed locations (geographically, to the degree possible) in sub-Saharan Africa. An additional key consideration was the possibility for a strong relationship between the site and the local ministry of health and/or national public health institute, to ensure that data collected contribute to national public health policy and actions. In addition, limited history of studies to understand disease burden were important components for selecting 2 sites (in Sierra Leone and Ethiopia). Specimen collection and laboratory and pathology testing have also been described [15–18]. The study protocol is available at https://champshealth.org/resources/. Briefly, following written parental/guardian consent, trained CHAMPS technicians collected tissue specimens via standardized needle biopsies from lungs, heart, brain, liver, and bone marrow. Technicians also collected blood, cerebrospinal fluid (CSF), and nasopharyngeal and rectal swabs. Anthropometric data and photographs are also collected during the procedure to evaluate nutritional status and birth defects, respectively. Tissue specimens were reviewed by local and Centers for Disease Control and Prevention (CDC) pathologists using routine histopathology and special stains and immunohistochemistry [18]. Lung tissue, blood, CSF, and rectal and nasopharyngeal swabs were tested for 116 infectious pathogens using multiplexed TaqMan Array Cards [18], and blood and CSF were cultured using standardized microbiological methods. Data were abstracted from available clinical records (both child and maternal when applicable), and trained interviewers used appropriate language translations of the 2016 WHO verbal autopsy instrument to interview caregivers of enrolled deceased children [13,19]. All data for each deceased child from which MITS was collected were reviewed by DeCoDe panels [12] in each country. These local panels consist of clinicians (pediatricians and obstetricians), laboratorians, and public health specialists and determine the causes of death, assigning the underlying, antecedent (intermediate) and immediate causes of death with the appropriate ICD-10 codes following WHO ICD-10 and WHO application of ICD-10 to deaths during the perinatal period (ICD-PM) [19–21]. The ICD-10 codes are then grouped into broad categories based on the Global Burden of Disease groupings [22]. A total of 4,355 deaths (excluding stillbirths) were identified with 3,539 enrolled across CHAMPS sites from 5 December 2016 through 30 November 2020, including 2,823 that were eligible for MITS (i.e., deaths identified within 24 hours of death in which the body was available and parents consented for the procedure) (Fig 1). Of these, MITS was done in 1,765 deaths and results from DeCoDe proceedings were available for 1,260 deaths, which represented the dataset used for this analysis. Stillbirths were excluded since the causes of death typically reflect maternal conditions. Among 4,355 deaths eligible at the 7 CHAMPS sites, MITS was done for 1,765, and DeCoDe results were available for these analyses for 1,260 deaths. CHAMPS, Child Health and Mortality Prevention Surveillance; CoD, cause of death; DeCoDe, Determination of Cause of Death; MITS, minimally invasive tissue sampling. We stratified analyses by deaths occurring during the first 27 days of life (neonates), from 28 days to <12 months of age (infants), and from 12 months to <60 months old (child). We defined the causal chain of mortality for each death to include any condition that appears as the underlying cause or was among antecedent or immediate cause categories, which, together, can include multiple causes. We defined “preterm birth conditions” to include low birth weight, hyaline membrane disease, necrotizing enterocolitis, and pneumothorax following the Global Burden of Disease groupings described above. For neonates with more than 1 type of preterm birth complication, the DeCoDe panels categorized them as having a preterm birth condition as the underlying CoD along with an additional preterm birth condition as either an antecedent or immediate cause. Similarly, other groupings, such as neonatal sepsis and perinatal asphyxia/hypoxia, could be found multiple times in the causal chain for the same death if different etiologies (i.e., multipathogen sepsis) or conditions that fell within that group were identified for that case. We evaluated proportions of deaths by age category associated with each of the conditions listed in the causal chain and evaluated the additional causes in the causal chain for each underlying condition. Finally, we assessed the “attribution gain” (shown as x-fold increases) for each CoD when a causal chain assessment was used for each death by aggregating deaths by age group and comparing with the number of deaths that would be attributed to each cause when relying on underlying condition alone. We used medians, counts, and percentages to summarize data and used χ2 tests as appropriate to describe significant differences among number of causes. All analyses were conducted in SAS v 9.4. Parents or guardians of deceased children provided written informed consent prior to collection of data, specimens, or information on living people (i.e., mothers). Ethics committees overseeing investigators at each site and at Emory University approved overall and site-specific protocols (Emory Institutional Review Board [IRB] #: 00091706). CDC relied for review on the Emory University committee for the overall protocol and on appropriate site ethical review committees where CDC staff were directly engaged at the site. The protocol is available at https://champshealth.org/wp-content/uploads/2021/08/CHAMPS-Mortality-Surveillance-Protocol-v1.3.pdf (S1 Protocol). Data can be accessed at champshealth.org, and requests can be made at the site to access additional datasets. Datasets are publicly available at (CHAMPS, 2021, “CHAMPS De-identified Dataset”; https://dataverse.unc.edu/dataset.xhtml?persistentId=doi:10.15139/S3/PMAAWG). This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist).