Identifying delays in healthcare seeking and provision: The Three Delays-in-Healthcare and mortality among infants and children aged 1-59 months.

Delays in illness recognition, healthcare seeking, and in the provision of appropriate clinical care are common in resource-limited settings. Our objective was to determine the frequency of delays in the "Three Delays-in-Healthcare", and factors associated with delays, among deceased infants and children in seven countries with high childhood mortality. We conducted a retrospective, descriptive study using data from verbal autopsies and medical records for infants and children aged 1-59 months who died between December 2016 and February 2022 in six sites in sub-Saharan Africa and one in South Asia (Bangladesh) and were enrolled in Child Health and Mortality Prevention Surveillance (CHAMPS). Delays in 1) illness recognition in the home/decision to seek care, 2) transportation to healthcare facilities, and 3) the receipt of clinical care in healthcare facilities were categorized according to the "Three Delays-in-Healthcare". Comparisons in factors associated with delays were made using Chi-square testing. Information was available for 1,326 deaths among infants and under 5 children. The majority had at least one identified delay (n = 854, 64%). Waiting >72 hours after illness recognition to seek health care (n = 422, 32%) was the most common delay. Challenges in obtaining transportation occurred infrequently when seeking care (n = 51, 4%). In healthcare facilities, prescribed medications were sometimes unavailable (n = 102, 8%). Deceased children aged 12-59 months experienced more delay than infants aged 1-11 months (68% vs. 61%, P = 0.018). Delays in seeking clinical care were common among deceased infants and children. Additional study to assess the frequency of delays in seeking clinical care and its provision among children who survive is warranted.

Child deaths caused by Klebsiella pneumoniae in sub-Saharan Africa and south Asia: a secondary analysis of Child Health and Mortality Prevention Surveillance (CHAMPS) data.

BACKGROUND: Klebsiella pneumoniae is an important cause of nosocomial and community-acquired pneumonia and sepsis in children, and antibiotic-resistant K pneumoniae is a growing public health threat. We aimed to characterise child mortality associated with this pathogen in seven high-mortality settings. METHODS: We analysed Child Health and Mortality Prevention Surveillance (CHAMPS) data on the causes of deaths in children younger than 5 years and stillbirths in sites located in seven countries across sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and south Asia (Bangladesh) from Dec 9, 2016, to Dec 31, 2021. CHAMPS sites conduct active surveillance for deaths in catchment populations and following reporting of an eligible death or stillbirth seek consent for minimally invasive tissue sampling followed by extensive aetiological testing (microbiological, molecular, and pathological); cases are reviewed by expert panels to assign immediate, intermediate, and underlying causes of death. We reported on susceptibility to antibiotics for which at least 30 isolates had been tested, and excluded data on antibiotics for which susceptibility testing is not recommended for Klebsiella spp due to lack of clinical activity (eg, penicillin and ampicillin). FINDINGS: Among 2352 child deaths with cause of death assigned, 497 (21%, 95% CI 20-23) had K pneumoniae in the causal chain of death; 100 (20%, 17-24) had K pneumoniae as the underlying cause. The frequency of K pneumoniae in the causal chain was highest in children aged 1-11 months (30%, 95% CI 26-34; 144 of 485 deaths) and 12-23 months (28%, 22-34; 63 of 225 deaths); frequency by site ranged from 6% (95% CI 3-11; 11 of 184 deaths) in Bangladesh to 52% (44-61; 71 of 136 deaths) in Ethiopia. K pneumoniae was in the causal chain for 450 (22%, 95% CI 20-24) of 2023 deaths that occurred in health facilities and 47 (14%, 11-19) of 329 deaths in the community. The most common clinical syndromes among deaths with K pneumoniae in the causal chain were sepsis (44%, 95% CI 40-49; 221 of 2352 deaths), sepsis in conjunction with pneumonia (19%, 16-23; 94 of 2352 deaths), and pneumonia (16%, 13-20; 80 of 2352 deaths). Among K pneumoniae isolates tested, 121 (84%) of 144 were resistant to ceftriaxone and 80 (75%) of 106 to gentamicin. INTERPRETATION: K pneumoniae substantially contributed to deaths in the first 2 years of life across multiple high-mortality settings, and resistance to antibiotics used for sepsis treatment was common. Improved strategies are needed to rapidly identify and appropriately treat children who might be infected with this pathogen. These data suggest a potential impact of developing and using effective K pneumoniae vaccines in reducing neonatal, infant, and child deaths globally. FUNDING: Bill & Melinda Gates Foundation.

Burden of child mortality from malaria in high endemic areas: Results from the CHAMPS network using minimally invasive tissue sampling.

BACKGROUND: Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality. METHODS: Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths. FINDINGS: Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p < 0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p = 0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable. INTERPRETATION: Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures.

Post-mortem investigation of deaths due to pneumonia in children aged 1-59 months in sub-Saharan Africa and South Asia from 2016 to 2022: an observational study.

BACKGROUND: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network programme undertakes post-mortem minimally invasive tissue sampling (MITS), together with collection of ante-mortem clinical information, to investigate causes of childhood deaths across multiple countries. We aimed to evaluate the overall contribution of pneumonia in the causal pathway to death and the causative pathogens of fatal pneumonia in children aged 1-59 months enrolled in the CHAMPS Network. METHODS: In this observational study we analysed deaths occurring between Dec 16, 2016, and Dec 31, 2022, in the CHAMPS Network across six countries in sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and one in South Asia (Bangladesh). A standardised approach of MITS was undertaken on decedents within 24-72 h of death. Diagnostic tests included blood culture, multi-organism targeted nucleic acid amplifications tests (NAATs) of blood and lung tissue, and histopathology examination of various organ tissue samples. An interdisciplinary expert panel at each site reviewed case data to attribute the cause of death and pathogenesis thereof on the basis of WHO-recommended reporting standards. FINDINGS: Pneumonia was attributed in the causal pathway of death in 455 (40·6%) of 1120 decedents, with a median age at death of 9 (IQR 4-19) months. Causative pathogens were identified in 377 (82·9%) of 455 pneumonia deaths, and multiple pathogens were implicated in 218 (57·8%) of 377 deaths. 306 (67·3%) of 455 deaths occurred in the community or within 72 h of hospital admission (presumed to be community-acquired pneumonia), with the leading bacterial pathogens being Streptococcus pneumoniae (108 [35·3%]), Klebsiella pneumoniae (78 [25·5%]), and non-typeable Haemophilus influenzae (37 [12·1%]). 149 (32·7%) deaths occurred 72 h or more after hospital admission (presumed to be hospital-acquired pneumonia), with the most common pathogens being K pneumoniae (64 [43·0%]), Acinetobacter baumannii (19 [12·8%]), S pneumoniae (15 [10·1%]), and Pseudomonas aeruginosa (15 [10·1%]). Overall, viruses were implicated in 145 (31·9%) of 455 pneumonia-related deaths, including 54 (11·9%) of 455 attributed to cytomegalovirus and 29 (6·4%) of 455 attributed to respiratory syncytial virus. INTERPRETATION: Pneumonia contributed to 40·6% of all childhood deaths in this analysis. The use of post-mortem MITS enabled biological ascertainment of the cause of death in the majority (82·9%) of childhood deaths attributed to pneumonia, with more than one pathogen being commonly implicated in the same case. The prominent role of K pneumoniae, non-typable H influenzae, and S pneumoniae highlight the need to review empirical management guidelines for management of very severe pneumonia in low-income and middle-income settings, and the need for research into new or improved vaccines against these pathogens. FUNDING: Bill & Melinda Gates Foundation.

Hepatic Vitamin A Concentrations and Association with Infectious Causes of Child Death.

OBJECTIVES: To assess postmortem vitamin A (VA) concentrations in children under 5 years of age and evaluate the association between VA deficiency (VAD) and infectious causes of death (CoD). STUDY DESIGN: In this cross-sectional study from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network, liver biopsies collected within 72 hours of death were analyzed from 405 stillbirths and children under 5 years in Kenya and South Africa. Total liver VA (TLVA) concentrations were quantified using ultra-performance liquid chromatography, and cutoffs of ≤0.1 µmol/g, >0.1 to <0.7 µmol/g, ≥0.7 to <1.0 µmol/g, and ≥1.0 µmol/g were used to define VAD, adequate VA status, high VA, and hypervitaminosis A, respectively. CoD were determined by expert panel review. RESULTS: Among 366 liver samples with viable extraction, pooled prevalences of VAD, adequacy, high VA, and hypervitaminosis were 34.2%, 51.1%, 6.0%, and 8.7%, respectively. VAD was more common among neonates compared with stillbirths, infants, or children, and among those with low birthweight (LBW), underweight, or stunting (P < .05). When adjusting for site, age, and sex, there was no significant association of VAD with increased infectious CoD (OR 1.9, 95% confidence interval [CI] 0.9, 3.8, P = .073). In stratified analyses, VA deficient boys, but not girls, had an increased risk of infectious CoD (OR 3.4, 95% CI 1.3, 10.3, P = .013). CONCLUSIONS: Definitive postmortem assessment of VA status identified both VAD and VA excess among children under 5 years of age in Kenya and South Africa. VAD in boys was associated with increased risk of infectious mortality. Our findings may inform a transition from universal VA supplementation (VAS) to targeted strategies in certain countries.

Prevalence and Missed Cases of Respiratory Distress Syndrome Disease Amongst Neonatal Deaths Enrolled in the Kenya Child Health and Mortality Prevention Surveillance Network (CHAMPS) Program Between 2017 and 2021.

Objectives. To describe RDS in neonatal deaths at the CHAMPS-Kenya site between 2017 and 2021. Methods. We included 165 neonatal deaths whose their Causes of death (COD) were determined by a panel of experts using data from post-mortem conducted through minimally invasive tissue specimen testing, clinical records, and verbal autopsy. Results. Twenty-six percent (43/165) of neonatal deaths were attributable to RDS. Most cases occurred in low birthweight and preterm neonates. From these cases, less than half of the hospitalizations were diagnosed with RDS before death, and essential diagnostic tests were not performed in most cases. Most cases received suboptimal levels of supplemental oxygen, and critical interventions like surfactant replacement therapy and mechanical ventilation were not adequately utilized when available. Conclusion. The study highlights the urgent need for improved diagnosis and management of RDS, emphasizing the importance of increasing clinical suspicion and enhancing training in its clinical management to reduce mortality rates.

An approach to determining the most common causes of stillbirth in low and middle-income countries: A commentary.

Stillbirth, one of the most common adverse pregnancy outcomes, is especially prevalent in low and middle-income countries (LMICs). Understanding the causes of stillbirth is crucial to developing effective interventions. In this commentary, investigators working across several LMICs discuss the most useful investigations to determine causes of stillbirths in LMICs. Useful data were defined as 1) feasible to obtain accurately and 2) informative to determine or help eliminate a cause of death. Recently, new tools for LMIC settings to determine cause of death in stillbirths, including minimally invasive tissue sampling (MITS) - a method using needle biopsies to obtain internal organ tissue from deceased fetuses for histology and pathogen identification in those tissues have become available. While placental histology has been available for some time, the development of the Amsterdam Criteria in 2016 has provided a useful framework to categorize placental lesions. The authors recommend focusing on the clinical history, the placental evaluation, the external examination of the fetus, and, when available, fetal tissue obtained by MITS, especially of the lung (focused on histology and microbiology) and brain/cerebral spinal fluid (CSF) and fetal blood (focused on microbiological analysis). The authors recognize that this approach may not identify some causes of stillbirth, including some genetic abnormalities and internal organ anomalies, but believe it will identify the most common causes of stillbirth, and most of the preventable causes.

Stillbirths and Neonatal Deaths Caused by Group B Streptococcus in Africa and South Asia Identified Through Child Health and Mortality Prevention Surveillance (CHAMPS).

Background: Invasive Group B Streptococcus (GBS) is a common cause of early-onset neonatal sepsis and is also associated with stillbirth. This study aimed to determine the proportion of stillborn infants and infants who died between 0 and 90 days attributable to GBS using postmortem minimally invasive tissue sampling (MITS) in 7 low- and middle-income countries (LMICs) participating in Child Health and Mortality Prevention Surveillance (CHAMPS). Methods: Deaths that occurred between December 2016 and December 2021 were investigated with MITS, including culture for bacteria of blood and cerebrospinal fluid (CSF), multipathogen polymerase chain reaction on blood, CSF, and lung tissue and histopathology of lung, liver, and brain. Data collection included clinical record review and verbal autopsy. Expert panels reviewed all information and assigned causes of death. Results: We evaluated 2966 deaths, including stillborn infants (n = 1322), infants who died during first day of life (0 to <24 hours, n = 597), early neonatal deaths (END) (1 day to <7 days; END; n = 593), and deaths from 7 to 90 days (n = 454). Group B Streptococcus was determined to be in the causal pathway of death for 2.7% of infants (79 of 2, 966; range, 0.3% in Sierra Leone to 7.2% in South Africa), including 2.3% (31 of 1322) of stillbirths, 4.7% (28 of 597) 0 to <24 hours, 1.9% (11 of 593) END, and 2.0% (9 of 454) of deaths from 7 to 90 days of age. Among deaths attributed to GBS with birth weight data available, 61.9% (39 of 63) of decedents weighed <2500 grams at birth. Group B Streptococcus sepsis was the postmortem diagnosis for 100% (31 of 31) of stillbirths. For deaths <90 days, postmortem diagnoses included GBS sepsis (83.3%, 40 of 48), GBS meningitis (4.2%, 2 of 48), and GBS pneumonia (2.1%, 1 of 48). Conclusions: Our study reveals significant heterogeneity in the contribution of invasive GBS disease to infant mortality across different countries, emphasizing the need for tailored prevention strategies. Moreover, our findings highlight the substantial impact of GBS on stillbirths, shedding light on a previously underestimated aspect in LMICs.

Provider adherence to clinical care recommendations for infants and children who died in seven low- and middle-income countries in the Child Health and Mortality Prevention Surveillance (CHAMPS) network.

Background: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. Methods: We conducted a retrospective, descriptive study examining clinical data for children aged 1-59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016-June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. Findings: CHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted <24 h. Interpretation: Provision of recommended clinical care for leading causes of death among young children was suboptimal. Further studies are needed to understand the reasons for deficits in clinical care recommendation adherence. Funding: Bill & Melinda Gates Foundation.

Impact of anthropometry training and feasibility of 3D imaging on anthropometry data quality among children under five years in a postmortem setting.

BACKGROUND: The Child Health and Mortality Prevention Surveillance Network (CHAMPS) identifies causes of under-5 mortality in high mortality countries. OBJECTIVE: To address challenges in postmortem nutritional assessment, we evaluated the impact of anthropometry training and the feasibility of 3D imaging on data quality within the CHAMPS Kenya site. DESIGN: Staff were trained using World Health Organization (WHO)-recommended manual anthropometry equipment and novel 3D imaging methods to collect postmortem measurements. Following training, 76 deceased children were measured in duplicate and were compared to measurements of 75 pre-training deceased children. Outcomes included measures of data quality (standard deviations of anthropometric indices and digit preference scores (DPS)), precision (absolute and relative technical errors of measurement, TEMs or rTEMs), and accuracy (Bland-Altman plots). WHO growth standards were used to produce anthropometric indices. Post-training surveys and in-depth interviews collected qualitative feedback on measurer experience with performing manual anthropometry and ease of using 3D imaging software. RESULTS: Manual anthropometry data quality improved after training, as indicated by DPS. Standard deviations of anthropometric indices exceeded limits for high data quality when using the WHO growth standards. Reliability of measurements post-training was high as indicated by rTEMs below 1.5%. 3D imaging was highly correlated with manual measurements; however, on average 3D scans overestimated length and head circumference by 1.61 cm and 2.27 cm, respectively. Site staff preferred manual anthropometry to 3D imaging, as the imaging technology required adequate lighting and additional considerations when performing the measurements. CONCLUSIONS: Manual anthropometry was feasible and reliable postmortem in the presence of rigor mortis. 3D imaging may be an accurate alternative to manual anthropometry, but technology adjustments are needed to ensure accuracy and usability.

Causes of Death Among Infants and Children in the Child Health and Mortality Prevention Surveillance (CHAMPS) Network.

Importance: The number of deaths of children younger than 5 years has been steadily decreasing worldwide, from more than 17 million annual deaths in the 1970s to an estimated 5.3 million in 2019 (with 2.8 million deaths occurring in those aged 1-59 months [53% of all deaths in children aged <5 years]). More detailed characterization of childhood deaths could inform interventions to improve child survival. Objective: To describe causes of postneonatal child deaths across 7 mortality surveillance sentinel sites in Africa and Asia. Design, Setting, and Participants: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network conducts childhood mortality surveillance in sub-Saharan Africa and South Asia using innovative postmortem minimally invasive tissue sampling (MITS). In this cross-sectional study, MITS was conducted in deceased children aged 1 to 59 months at 7 sites in sub-Saharan Africa and South Asia from December 3, 2016, to December 3, 2020. Data analysis was conducted between October and November 2021. Main Outcomes and Measures: The expert panel attributed underlying, intermediate, and immediate conditions in the chain of events leading to death, based on histopathologic analysis, microbiological diagnostics, clinical data, and verbal autopsies. Results: In this study, MITS was performed in 632 deceased children (mean [SD] age at death, 1.3 [0.3] years; 342 [54.1%] male). The 6 most common underlying causes of death were malnutrition (104 [16.5%]), HIV (75 [11.9%]), malaria (71 [11.2%]), congenital birth defects (64 [10.1%]), lower respiratory tract infections (LRTIs; 53 [8.4%]), and diarrheal diseases (46 [7.2%]). When considering immediate causes only, sepsis (191 [36.7%]) and LRTI (129 [24.8%]) were the 2 dominant causes. An infection was present in the causal chain in 549 of 632 deaths (86.9%); pathogens most frequently contributing to infectious deaths included Klebsiella pneumoniae (155 of 549 infectious deaths [28.2%]; 127 [81.9%] considered nosocomial), Plasmodium falciparum (122 of 549 [22.2%]), and Streptococcus pneumoniae (109 of 549 [19.9%]). Other organisms, such as cytomegalovirus (57 [10.4%]) and Acinetobacter baumannii (39 [7.1%]; 35 of 39 [89.7%] considered nosocomial), also played important roles. For the top underlying causes of death, the median number of conditions in the chain of events leading to death was 3 for malnutrition, 3 for HIV, 1 for malaria, 3 for congenital birth defects, and 1 for LRTI. Expert panels considered 494 of 632 deaths (78.2%) preventable and 26 of 632 deaths (4.1%) preventable under certain conditions. Conclusions and Relevance: In this cross-sectional study investigating causes of child mortality in the CHAMPS Network, results indicate that, in these high-mortality settings, infectious diseases continue to cause most deaths in infants and children, often in conjunction with malnutrition. These results also highlight opportunities for action to prevent deaths and reveal common interaction of various causes in the path toward death.

Causes of stillbirth and death among children younger than 5 years in eastern Hararghe, Ethiopia: a population-based post-mortem study.

BACKGROUND: Child mortality is high in Ethiopia, but reliable data on the causes of death are scarce. We aimed to gather data for the contributory causes of stillbirth and child deaths in eastern Ethiopia. METHODS: In this population-based post-mortem study, we established a death-notification system in health facilities and in the community in Kersa (rural), Haramaya (rural) and Harar (urban) in eastern Ethiopia, at a new site of the Child Health and Mortality Prevention Surveillance (CHAMPS) network. We collected ante-mortem data, did verbal autopsies, and collected post-mortem samples via minimally invasive tissue sampling from stillbirths (weighing at least 1000 g or with an estimated gestational age of at least 28 weeks) and children who died younger than 5 years. Children-or their mothers, in the case of stillbirths and deaths in children younger than 6 months-had to have lived in the catchment area for the past 6 months to be included. Molecular, microbiological, and histopathological analyses were done in collected samples. Cause of death was established by an expert panel on the basis of these data and classified as underlying, comorbid, or immediate separately for stillbirths, neonatal deaths (deaths aged 0-27 days), and child deaths (aged 28 days to <5 years). FINDINGS: Between Feb 4, 2019, and Feb 3, 2021, 312 deaths were eligible for inclusion, and the families gave consent in 195 (63%) cases. Cause of death was established in 193 (99%) cases. Among 114 stillbirths, the underlying cause of death was perinatal asphyxia or hypoxia in 60 (53%) and birth defects in 24 (21%). Among 59 neonatal deaths, the most common underlying cause was perinatal asphyxia or hypoxia (17 [29%]) and the most common immediate cause of death was neonatal sepsis, which occurred in 27 (60%). Among 20 deaths in children aged 28 days to 59 months, malnutrition was the leading underlying cause (15 [75%]) and infections were common immediate and comorbid causes. Pathogens were identified in 19 (95%) child deaths, most commonly Klebsiella pneumoniae and Streptococcus pneumoniae. INTERPRETATION: Perinatal asphyxia or hypoxia, infections, and birth defects accounted for most stillbirths and child deaths. Most deaths could have been prevented with feasible interventions, such as improved maternity services, folate supplementation, and improved vaccine uptake. FUNDING: Bill & Melinda Gates Foundation.

Causes of death identified in neonates enrolled through Child Health and Mortality Prevention Surveillance (CHAMPS), December 2016 -December 2021.

Each year, 2.4 million children die within their first month of life. Child Health and Mortality Prevention Surveillance (CHAMPS) established in 7 countries aims to generate accurate data on why such deaths occur and inform prevention strategies. Neonatal deaths that occurred between December 2016 and December 2021 were investigated with MITS within 24-72 hours of death. Testing included blood, cerebrospinal fluid and lung cultures, multi-pathogen PCR on blood, CSF, nasopharyngeal swabs and lung tissue, and histopathology examination of lung, liver and brain. Data collection included clinical record review and family interview using standardized verbal autopsy. The full set of data was reviewed by local experts using a standardized process (Determination of Cause of Death) to identify all relevant conditions leading to death (causal chain), per WHO recommendations. For analysis we stratified neonatal death into 24-hours of birth, early (1-<7 days) and late (7-<28 days) neonatal deaths. We analyzed 1458 deaths, 41% occurring within 24-hours, 41% early and 18% late neonatal deaths. Leading underlying causes of death were complications of intrapartum events (31%), complications of prematurity (28%), infections (17%), respiratory disorders (11%), and congenital malformations (8%). In addition to the underlying cause, 62% of deaths had additional conditions and 14% had ≥3 other conditions in the causal chain. The most common causes considering the whole causal chain were infection (40%), prematurity (32%) and respiratory distress syndrome (28%). Common maternal conditions linked to neonatal death were maternal hypertension (10%), labour and delivery complications (8%), multiple gestation (7%), placental complications (6%) obstructed labour and chorioamnionitis (5%, each). CHAMPS' findings showing the full causal chain of events that lead to death, in addition to maternal factors, highlights the complexities involved in each death along with the multiple opportunities for prevention. Highlighting improvements to prenatal and obstetric care and infection prevention are urgently needed in high-mortality settings.

Prioritizing Health Care Strategies to Reduce Childhood Mortality.

Importance: Although child mortality trends have decreased worldwide, deaths among children younger than 5 years of age remain high and disproportionately circumscribed to sub-Saharan Africa and Southern Asia. Tailored and innovative approaches are needed to increase access, coverage, and quality of child health care services to reduce mortality, but an understanding of health system deficiencies that may have the greatest impact on mortality among children younger than 5 years is lacking. Objective: To investigate which health care and public health improvements could have prevented the most stillbirths and deaths in children younger than 5 years using data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network. Design, Setting, and Participants: This cross-sectional study used longitudinal, population-based, and mortality surveillance data collected by CHAMPS to understand preventable causes of death. Overall, 3390 eligible deaths across all 7 CHAMPS sites (Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) between December 9, 2016, and December 31, 2021 (1190 stillbirths, 1340 neonatal deaths, 860 infant and child deaths), were included. Deaths were investigated using minimally invasive tissue sampling (MITS), a postmortem approach using biopsy needles for sampling key organs and fluids. Main Outcomes and Measures: For each death, an expert multidisciplinary panel reviewed case data to determine the plausible pathway and causes of death. If the death was deemed preventable, the panel identified which of 10 predetermined health system gaps could have prevented the death. The health system improvements that could have prevented the most deaths were evaluated for each age group: stillbirths, neonatal deaths (aged <28 days), and infant and child deaths (aged 1 month to <5 years). Results: Of 3390 deaths, 1505 (44.4%) were female and 1880 (55.5%) were male; sex was not recorded for 5 deaths. Of all deaths, 3045 (89.8%) occurred in a healthcare facility and 344 (11.9%) in the community. Overall, 2607 (76.9%) were deemed potentially preventable: 883 of 1190 stillbirths (74.2%), 1010 of 1340 neonatal deaths (75.4%), and 714 of 860 infant and child deaths (83.0%). Recommended measures to prevent deaths were improvements in antenatal and obstetric care (recommended for 588 of 1190 stillbirths [49.4%], 496 of 1340 neonatal deaths [37.0%]), clinical management and quality of care (stillbirths, 280 [23.5%]; neonates, 498 [37.2%]; infants and children, 393 of 860 [45.7%]), health-seeking behavior (infants and children, 237 [27.6%]), and health education (infants and children, 262 [30.5%]). Conclusions and Relevance: In this cross-sectional study, interventions prioritizing antenatal, intrapartum, and postnatal care could have prevented the most deaths among children younger than 5 years because 75% of deaths among children younger than 5 were stillbirths and neonatal deaths. Measures to reduce mortality in this population should prioritize improving existing systems, such as better access to antenatal care, implementation of standardized clinical protocols, and public education campaigns.

Mixed-methods analysis of select issues reported in the 2016 World Health Organization verbal autopsy questionnaire.

BACKGROUND: Use of a standardized verbal autopsy (VA) questionnaire, such as the World Health Organization (WHO) instrument, can improve the consistency and reliability of the data it collects. Systematically revising a questionnaire, however, requires evidence about the performance of its questions. The purpose of this investigation was to use a mixed methods approach to evaluate the performance of questions related to 14 previously reported issues in the 2016 version of the WHO questionnaire, where there were concerns of potential confusion, redundancy, or inability of the respondent to answer the question. The results from this mixed methods analysis are discussed across common themes that may have contributed to the underperformance of questions and have been compiled to inform decisions around the revision of the current VA instrument. METHODS: Quantitative analysis of 19,150 VAs for neonates, children, and adults from five project teams implementing VAs predominately in Sub-Saharan Africa included frequency distributions and cross-tabulations to evaluate response patterns among related questions. The association of respondent characteristics and response patterns was evaluated using prevalence ratios. Qualitative analysis included results from cognitive interviewing, an approach that provides a detailed understanding of the meanings and processes that respondents use to answer interview questions. Cognitive interviews were conducted among 149 participants in Morocco and Zambia. Findings from the qualitative and quantitative analyses were triangulated to identify common themes. RESULTS: Four broad themes contributing to the underperformance or redundancy within the instrument were identified: question sequence, overlap within the question series, questions outside the frame of reference of the respondent, and questions needing clarification. The series of questions associated with one of the 14 identified issues (the series of questions on injuries) related to question sequence; seven (tobacco use, sores, breast swelling, abdominal problem, vomiting, vaccination, and baby size) demonstrated similar response patterns among questions within each series capturing overlapping information. Respondent characteristics, including relationship to the deceased and whether or not the respondent lived with the deceased, were associated with differing frequencies of non-substantive responses in three question series (female health related issues, tobacco use, and baby size). An inconsistent understanding of related constructs was observed between questions related to sores/ulcers, birth weight/baby size, and diagnosis of dementia/presence of mental confusion. An incorrect association of the intended construct with that which was interpreted by the respondent was observed in the medical diagnosis question series. CONCLUSIONS: In this mixed methods analysis, we identified series of questions which could be shortened through elimination of redundancy, series of questions requiring clarification due to unclear constructs, and the impact of respondent characteristics on the quality of responses. These changes can lead to a better understanding of the question constructs by the respondents, increase the acceptance of the tool, and improve the overall accuracy of the VA instrument.

Insights on the differentiation of stillbirths and early neonatal deaths: A study from the Child Health and Mortality Prevention Surveillance (CHAMPS) network.

INTRODUCTION: The high burden of stillbirths and neonatal deaths is driving global initiatives to improve birth outcomes. Discerning stillbirths from neonatal deaths can be difficult in some settings, yet this distinction is critical for understanding causes of perinatal deaths and improving resuscitation practices for live born babies. METHODS: We evaluated data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network to compare the accuracy of determining stillbirths versus neonatal deaths from different data sources and to evaluate evidence of resuscitation at delivery in accordance with World Health Organization (WHO) guidelines. CHAMPS works to identify causes of stillbirth and death in children <5 years of age in Bangladesh and 6 countries in sub-Saharan Africa. Using CHAMPS data, we compared the final classification of a case as a stillbirth or neonatal death as certified by the CHAMPS Determining Cause of Death (DeCoDe) panel to both the initial report of the case by the family member or healthcare worker at CHAMPS enrollment and the birth outcome as stillbirth or livebirth documented in the maternal health record. RESULTS: Of 1967 deaths ultimately classified as stillbirth, only 28 (1.4%) were initially reported as livebirths. Of 845 cases classified as very early neonatal death, 33 (4%) were initially reported as stillbirth. Of 367 cases with post-mortem examination showing delivery weight >1000g and no maceration, the maternal clinical record documented that resuscitation was not performed in 161 cases (44%), performed in 14 (3%), and unknown or data missing for 192 (52%). CONCLUSION: This analysis found that CHAMPS cases assigned as stillbirth or neonatal death after DeCoDe expert panel review were generally consistent with the initial report of the case as a stillbirth or neonatal death. Our findings suggest that more frequent use of resuscitation at delivery and improvements in documentation around events at birth could help improve perinatal outcomes.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Causes of death in HIV-infected and HIV-uninfected children aged under-five years in western Kenya.

OBJECTIVES: Describe the causes of death among infants and children less than 5 years stratified by HIV status. DESIGN: Cross-sectional analysis of causes of death ascertained through minimally invasive tissue sampling (MITS) in the Kenya Child Health and Mortality Prevention Surveillance site. METHODS: We included decedents aged 28 days to less than 5 years, whose death was reported within 36 h, underwent MITS, and had HIV test results and causes of death determined. MITS specimens were tested using Taqman Array Cards, culture, cytology, histopathology and immunohistochemistry and HIV PCR. A panel evaluated epidemiologic, clinical, verbal autopsy and laboratory data to assign causes of death using ICD-10 guidelines. Causes of death and etiological agents were stratified by HIV status. RESULTS: Of 176 included decedents, 14% (n = 25) were HIV-infected, median viral load was 112 205 copies/ml [interquartile range (IQR) = 9349-2 670 143). HIV-disease (96%; n = 24) and malnutrition (23%; n = 34) were the leading underlying causes of death in HIV-infected and HIV-uninfected decedents, respectively. Malnutrition was more frequent in the causal chain of HIV-infected (56%; n = 14) than HIV-uninfected decedents (31%; n = 49) (P value = 0.03). Viral pneumonia was twice as common in HIV-infected (50%; n = 9) than HIV-uninfected decedents (22%; n = 7) (P value = 0.04). CONCLUSION: Nearly all HIV-infected decedents' underlying cause of death was HIV disease, which was associated with malnutrition. Our findings underscore the need for strengthening early identification and management of HIV-infected children. Prevention, early diagnosis and treatment of malnutrition could be instrumental in improving the survival of HIV-infected and HIV-uninfected children.

Guidance for Systematic Integration of Undernutrition in Attributing Cause of Death in Children.

Minimally invasive tissue sampling (MITS) is increasingly being used to better understand causes of death in low-resource settings. Undernutrition (eg, wasting, stunting) is prevalent among children globally and yet not consistently coded or uniformly included on death certificates in MITS studies when present. Consistent and accurate attribution of undernutrition is fundamental to understanding its contribution to child deaths. In May 2020, members of the MITS Alliance Cause of Death Technical Working Group convened a panel of experts in public health, child health, nutrition, infectious diseases, and MITS to develop guidance for systematic integration of undernutrition, as assessed by anthropometry, in cause of death coding, including as part of the causal chain or as a contributing condition, in children <5 years of age. The guidance presented here will support MITS and other researchers, public health practitioners, and clinicians with a systematic approach to assigning and interpreting undernutrition in death certification.