Long-term outcomes after severe childhood malnutrition in adolescents in Malawi (LOSCM): a prospective observational cohort study.

BACKGROUND: Research on long-term outcomes of severe childhood malnutrition is scarce. Existing evidence suggests potential associations with cardiometabolic disease and impaired cognition. We aimed to assess outcomes in adolescents who were exposed to severe childhood malnutrition compared with peers not exposed to severe childhood malnutrition. METHODS: In Long-term Outcomes after Severe Childhood Malnutrition (LOCSM), we followed up adolescents who had 15 years earlier received treatment for severe childhood malnutrition at Queen Elizabeth Central Hospital in Blantyre, Malawi. Adolescents with previous severe childhood malnutrition included in LOCSM had participated in an earlier follow-up study (ChroSAM) at 7 years after treatment for severe childhood malnutrition, where they were compared to siblings and age-matched children in the community without previous severe childhood malnutrition. We measured anthropometry, body composition, strength, glucose tolerance, cognition, behaviour, and mental health during follow-up visits between Sept 9, 2021, and July 22, 2022, comparing outcomes in adolescents exposed to previous severe childhood malnutrition with unexposed siblings and adolescents from the community assessed previously (for ChroSAM) and newly recruited during current follow-up. We used a linear regression model to adjust for age, sex, disability, HIV, and socioeconomic status. This study is registered with the International Standard Randomised Controlled Trial Number Registry (ISRCTN17238083). FINDINGS: We followed up 168 previously malnourished adolescents (median age 17·1 years [IQR 16·5 to 18·0]), alongside 123 siblings (18·2 years [15·0 to 20·5]), and 89 community adolescents (17·1 years [16·3 to 18·1]). Since last measured 8 years previously, mean height-for-age Z (HAZ) scores had improved in previously malnourished adolescents (difference 0·33 [95% CI 0·20 to 0·46]) and siblings (0·32 [0·09 to 0·55]), but not in community adolescents (difference -0·01 [-0·24 to 0·23]). Previously malnourished adolescents had sustained lower HAZ scores compared with siblings (adjusted difference -0·32 [-0·58 to -0·05]) and community adolescents (-0·21 [-0·52 to 0·10]). The adjusted difference in hand-grip strength between previously malnourished adolescents and community adolescents was -2·0 kg (-4·2 to 0·3). For child behaviour checklist internalising symptom scores, the adjusted difference for previously malnourished adolescents was 2·8 (0·0 to 5·5) compared with siblings and 2·1 (-0·1 to 4·3) compared with community adolescents. No evidence of differences between previously malnourished adolescents and unexposed groups were found in any of the other variables measured. INTERPRETATION: Catch-up growth into adolescence was modest compared with the rapid improvement seen in childhood, but provides optimism for ongoing recovery of height deficits. We found little evidence of heightened non-communicable disease risk in adolescents exposed to severe childhood malnutrition, although long-term health implications need to be monitored. Further investigation of associated home and environmental factors influencing long-term outcomes is needed to tailor preventive and treatment interventions. FUNDING: The Wellcome Trust.

The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) Trial: Protocol for school-age follow-up.

Background: There is a need for follow-up of early-life stunting intervention trials into childhood to determine their long-term impact. A holistic school-age assessment of health, growth, physical and cognitive function will help to comprehensively characterise the sustained effects of early-life interventions. Methods: The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe assessed the effects of improved infant and young child feeding (IYCF) and/or improved water, sanitation and hygiene (WASH) on stunting and anaemia at 18 months. Among children enrolled to SHINE, 1,275 have been followed up at 7-8 years of age (1,000 children who have not been exposed to HIV, 268 exposed to HIV antenatally who remain HIV negative and 7 HIV positive children). Children were assessed using the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox, to measure their growth, body composition, cognitive and physical function. In parallel, a caregiver questionnaire assessed household demographics, socioeconomic status, adversity, nurturing, caregiver support, food and water insecurity. A monthly morbidity questionnaire is currently being administered by community health workers to evaluate school-age rates of infection and healthcare-seeking. The impact of the SHINE IYCF and WASH interventions, the early-life 'exposome', maternal HIV, and contemporary exposures on each school-age outcome will be assessed. We will also undertake an exploratory factor analysis to generate new, simpler metrics for assessment of cognition (COG-SAHARAN), growth (GROW-SAHARAN) and combined growth, cognitive and physical function (SUB-SAHARAN). The SUB-SAHARAN toolbox will be used to conduct annual assessments within the SHINE cohort from ages 8-12 years. Ethics and dissemination: Approval was obtained from Medical Research Council of Zimbabwe (08/02/21) and registered with Pan-African Clinical Trials Registry (PACTR202201828512110, 24/01/22). Primary caregivers provided written informed consent and children written assent. Findings will be disseminated through community sensitisation, peer-reviewed journals and stakeholders including the Zimbabwean Ministry of Health and Child Care.

Predicting Acute and Post-Recovery Outcomes in Cerebral Malaria and Other Comas by Optical Coherence Tomography (OCT in CM) - A protocol for an observational cohort study of Malawian children.

Cerebral malaria (CM) remains a significant global health challenge with high morbidity and mortality. Malarial retinopathy has been shown to be diagnostically and prognostically significant in the assessment of CM. The major mechanism of death in paediatric CM is brain swelling. Long term morbidity is typically characterised by neurological and neurodevelopmental sequelae. Optical coherence tomography can be used to quantify papilloedema and macular ischaemia, identified as hyperreflectivity. Here we describe a protocol to test the hypotheses that quantification of optic nerve head swelling using optical coherence tomography can identify severe brain swelling in CM, and that quantification of hyperreflectivity in the macula predicts neurodevelopmental outcomes post-recovery. Additionally, our protocol includes the development of a novel, low-cost, handheld optical coherence tomography machine and artificial intelligence tools to assist in image analysis.

Characterising school-age health and function in rural Zimbabwe using the SAHARAN toolbox.

INTRODUCTION: We developed the School-Age Health, Activity, Resilience, Anthropometry and Neurocognitive (SAHARAN) toolbox to address the shortage of school-age assessment tools that combine growth, physical and cognitive function. Here we present i) development, acceptability and feasibility of the SAHARAN toolbox; ii) characteristics of a pilot cohort; and iii) associations between the domains measured in the cohort. METHODS: Growth was measured with anthropometry, knee-heel length and skinfold thicknesses. Bioimpedance analysis measured lean mass index and phase angle. Cognition was assessed using the mental processing index, derived from the Kaufman Assessment Battery for Children version 2, a fine motor finger-tapping task, and School Achievement Test (SAT). Physical function combined grip strength, broad jump and the 20m shuttle-run test to produce a total physical score. A caregiver questionnaire was performed in parallel. RESULTS: The SAHARAN toolbox was feasible to implement in rural Zimbabwe, and highly acceptable to children and caregivers following some minor modifications. Eighty children with mean (SD) age 7.6 (0.2) years had mean height-for-age (HAZ) and weight-for-age Z-scores (WAZ) of -0.63 (0.81) and -0.55 (0.85), respectively. Lean mass index and total skinfold thicknesses were related to WAZ and BMI Z-score, but not to HAZ. Total physical score was associated with unit rises in HAZ (1.29, 95% CI 0.75, 1.82, p<0.001), and lean mass index (0.50, 95% CI 0.16, 0.83, p = 0.004), but not skinfold thicknesses. The SAT was associated with unit increases in the mental processing index and child socioemotional score. The caregiver questionnaire identified high levels of adversity and food insecurity. CONCLUSIONS: The SAHARAN toolbox provided a feasible and acceptable holistic assessment of child growth and function in mid-childhood. We found clear associations between growth, height-adjusted lean mass and physical function, but not cognitive function. The SAHARAN toolbox could be deployed to characterise school-age growth, development and function elsewhere in sub-Saharan Africa.

The current landscape and future of tablet-based cognitive assessments for children in low-resourced settings.

Interest in measuring cognition in children in low-resourced settings has increased in recent years, but options for cognitive assessments are limited. Researchers are faced with challenges when using existing assessments in these settings, such as trained workforce shortages, less relevant testing stimuli, limitations of proprietary assessments, and inadequate parental knowledge of cognitive milestones. Tablet-based direct child assessments are emerging as a practical solution to these challenges, but evidence of their validity and utility in cross-cultural settings is limited. In this overview, we introduce key concepts of this field while exploring the current landscape of tablet-based assessments for low-resourced settings. We also make recommendations for future directions of this relatively novel field. We conclude that tablet-based assessments are an emerging and promising method of assessing cognition in young children. Further awareness and dissemination of validated tablet-based assessments may increase capacity for child development research and clinical practice in low-resourced settings.

Performance of the UNICEF/UN Washington Group tool for identifying functional difficulty in rural Zimbabwean children.

INTRODUCTION: Over one billion people live with disability worldwide, of whom 80% are in developing countries. Robust childhood disability data are limited, particularly as tools for identifying disability function poorly at young ages. METHODS: A subgroup of children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial (a cluster-randomised, community-based, 2x2 factorial trial in two rural districts in Zimbabwe) had neurodevelopmental assessments at 2 years of age. We evaluated functional difficulty prevalence in HIV-exposed and HIV-unexposed children using the Washington Group Child Functioning Module (WGCFM), comparing absolute difference using chi-squared or Fisher's exact tests. Concurrent validity with the Malawi Developmental Assessment Tool (MDAT) was assessed using logistic regression with cohort MDAT score quartiles, linear regression for unit-increase in raw scores and a Generalised Estimating Equation approach (to adjust for clusters) to compare MDAT scores of those with and without functional difficulty. A 3-step, cluster-adjusted multivariable regression model was then carried out to examine risk factors for functional difficulty. FINDINGS: Functional Difficulty prevalence was 4.2% (95%CI: 3.2%, 5.2%) in HIV-unexposed children (n = 1606) versus 6.1% (95%CI: 3.5%, 8.9%) in HIV-exposed children (n = 314) (absolute difference 1.9%, 95%CI: -0.93%, 4.69%; p = 0.14). Functional difficulty score correlated negatively with MDAT: for each unit increase in WGCFM score, children completed 2.6 (95%CI: 2.2, 3.1) fewer MDAT items (p = 0.001). Children from families with food insecurity and poorer housing were more at risk of functional difficulty. INTERPRETATION: Functional difficulty was identified in approximately 1-in-20 children in rural Zimbabwe, which is comparable to prevalence in previous studies. WGCFM showed concurrent validity with the MDAT, supporting its use in early childhood.

Changing Incidence of Invasive Pneumococcal Disease in Infants Less Than 90 Days of Age Before and After Introduction of the 13-Valent Pneumococcal Conjugate Vaccine in Blantyre, Malawi: A 14-Year Hospital Based Surveillance Study.

BACKGROUND: Invasive pneumococcal disease (IPD) in young infants is uncommon but associated with high morbidity and mortality. Accurate data on the burden of IPD in young infants in low-income countries are lacking. We examined the burden of IPD in infants <90 days old in Blantyre, Malawi over a 14-year period and evaluated the indirect impact of the 13-valent pneumococcal conjugate vaccine (PCV13) on vaccine-serotype IPD (VT-IPD) in this population. METHODS: We conducted laboratory-based prospective IPD surveillance in infants <90 days of age admitted to Queen Elizabeth Central Hospital in Blantyre between 2005 and 2018, including 7 years pre-PCV13 and 7 years post-PCV13 introduction. IPD was defined as Streptococcus pneumoniae identified by culture from blood or cerebrospinal fluid. Serotypes were determined by multiplex polymerase chain reaction and latex agglutination testing. RESULTS: We identified 130 cases of culture-confirmed IPD in infants <90 days old between 2005 and 2018. Total IPD incidence was declining before PCV13 introduction. The mean incidence of IPD was significantly lower in the post-PCV13 era. Serotypes 5 (27.8%) and 1 (15.6%) were most prevalent. Even after PCV13 introduction, VTs remained the primary cause of IPD, with serotype 5 accounting for 17.4% and serotype 1 for 13.0% of cases in young infants. CONCLUSION: Vaccine serotypes 1 and 5 were the main cause of IPD in neonates and young infants, both before and after PCV13 introduction. This suggests incomplete indirect protection with persisting VT carriage across the population despite vaccination in this setting. Alternative vaccine schedules and other vaccine introduction approaches need to be considered to protect this vulnerable population.

Global Burden of Childhood Epilepsy, Intellectual Disability, and Sensory Impairments.

BACKGROUND: Estimates of children and adolescents with disabilities worldwide are needed to inform global intervention under the disability-inclusive provisions of the Sustainable Development Goals. We sought to update the most widely reported estimate of 93 million children <15 years with disabilities from the Global Burden of Disease Study 2004. METHODS: We analyzed Global Burden of Disease Study 2017 data on the prevalence of childhood epilepsy, intellectual disability, and vision or hearing loss and on years lived with disability (YLD) derived from systematic reviews, health surveys, hospital and claims databases, cohort studies, and disease-specific registries. Point estimates of the prevalence and YLD and the 95% uncertainty intervals (UIs) around the estimates were assessed. RESULTS: Globally, 291.2 million (11.2%) of the 2.6 billion children and adolescents (95% UI: 249.9-335.4 million) were estimated to have 1 of the 4 specified disabilities in 2017. The prevalence of these disabilities increased with age from 6.1% among children aged <1 year to 13.9% among adolescents aged 15 to 19 years. A total of 275.2 million (94.5%) lived in low- and middle-income countries, predominantly in South Asia and sub-Saharan Africa. The top 10 countries accounted for 62.3% of all children and adolescents with disabilities. These disabilities accounted for 28.9 million YLD or 19.9% of the overall 145.3 million (95% UI: 106.9-189.7) YLD from all causes among children and adolescents. CONCLUSIONS: The number of children and adolescents with these 4 disabilities is far higher than the 2004 estimate, increases from infancy to adolescence, and accounts for a substantial proportion of all-cause YLD.

Early child development in children who are HIV-exposed uninfected compared to children who are HIV-unexposed: observational sub-study of a cluster-randomized trial in rural Zimbabwe.

INTRODUCTION: Exposure to maternal HIV may affect early child development (ECD), although previous studies have reported heterogeneous findings. We evaluated ECD among children who were HIV-exposed uninfected (CHEU) and children who were HIV-unexposed (CHU) recruited to the SHINE trial in rural Zimbabwe. METHODS: SHINE was a community-based cluster-randomized trial of improved infant feeding and/or improved water, sanitation and hygiene. Pregnant women were enrolled between 2012 and 2015. We assessed ECD in a sub-study at 24 months of age, between 2016 and 2017, using the Malawi Developmental Assessment Tool (MDAT; assessing motor, cognitive, language and social development); MacArthur-Bates Communicative Development Inventory (CDI) (assessing vocabulary and grammar); A-not-B test (assessing object permanence); and a self-control task. Mothers and infants were tested longitudinally for HIV. We used generalized estimating equations to compare ECD scores between CHEU and CHU, accounting for the cluster-randomized design. Primary results were adjusted for trial-related factors that could affect measurement reliability of ECD: study nurse, age of child, calendar month of birth, sex and randomized arm. RESULTS: A total of 205 CHEU and 1175 CHU were evaluated. Mean total MDAT score was 90.6 (SD 8.7) in CHEU compared to 92.4 (9.1) in CHU (adjusted mean difference -1.3, 95% CI: -2.3, -0.3), driven mostly by differences in gross motor (-0.5, 95% CI: -0.9, -0.2) and language scores (-0.6, 95% CI: -1.1, -0.1). There was evidence that fine motor scores were lower in CHEU (adjusted mean difference -0.4, 95% CI: -0.8, 0.0) but no evidence of a difference in social scores (0.1, 95% CI: -0.2, 0.4). Mean MacArthur-Bates CDI vocabulary score was 57.9 (SD 19.2) in CHEU compared to 61.3 (18.8) in CHU (adjusted mean difference -2.9 words, 95% CI: -5.7, -0.1). Object permanence and self-control scores were similar between groups. CONCLUSIONS: CHEU in rural Zimbabwe had total child development and vocabulary scores that were approximately 0.15 standard deviations lower than CHU at two years of age. More detailed and specific studies are now needed to unravel the reasons for developmental delay in CHEU and the likelihood that these delays persist in the longer term.

Estimated prevalence of disability and developmental delay among preschool children in rural Malawi: Findings from "Tikule Limodzi," a cross-sectional survey.

BACKGROUND: Early childhood development (ECD) is a critical stage in children's lives, influencing future development and social integration. ECD research among children with disability and developmental delay in low- and middle-income countries is limited but crucial to inform planning and delivery of inclusive services. This study is the first to measure and compare the prevalence of disability and developmental delay among children attending preschool centres in rural Malawi. METHODS: A cross-sectional survey was conducted in 48 preschool centres in Thyolo district, Malawi. Data were collected from parents or guardians of 20 children per centre. Disability was ascertained using the Washington Group/UNICEF Child Functioning Module. Child development was measured using the language and social domains of the Malawi Development Assessment Tool. RESULTS: A total of 960 children were enrolled; 935 (97.4%) children were assessed for disability and 933 (97.2%) for developmental delay; 100 (10.7%) children were identified as having a disability. The prevalence of disability was higher among children 5+ years (n = 60; 29.3%) than children 2-4 years (n = 40; 5.5%); 109 of 933 (11.7%) children were classified as having developmental delay, 41 (4.4%) in "language" and 77 (8·3%) in "social" domains. CONCLUSIONS: This study found that disability and developmental delays are common among preschool children in Malawi. It is one of the first to measure disability and delay among children in a preschool setting in Africa.

Independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved complementary feeding on early neurodevelopment among children born to HIV-negative mothers in rural Zimbabwe: Substudy of a cluster-randomized trial.

BACKGROUND: Globally, nearly 250 million children (43% of all children under 5 years of age) are at risk of compromised neurodevelopment due to poverty, stunting, and lack of stimulation. We tested the independent and combined effects of improved water, sanitation, and hygiene (WASH) and improved infant and young child feeding (IYCF) on early child development (ECD) among children enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial in rural Zimbabwe. METHODS AND FINDINGS: SHINE was a cluster-randomized community-based 2×2 factorial trial. A total of 5,280 pregnant women were enrolled from 211 clusters (defined as the catchment area of 1-4 village health workers [VHWs] employed by the Zimbabwean Ministry of Health and Child Care). Clusters were randomly allocated to standard of care, IYCF (20 g of small-quantity lipid-based nutrient supplement per day from age 6 to 18 months plus complementary feeding counseling), WASH (ventilated improved pit latrine, handwashing stations, chlorine, liquid soap, and play yard), and WASH + IYCF. Primary outcomes were child length-for-age Z-score and hemoglobin concentration at 18 months of age. Children who completed the 18-month visit and turned 2 years (102-112 weeks) between March 1, 2016, and April 30, 2017, were eligible for the ECD substudy. We prespecified that primary inferences would be drawn from findings of children born to HIV-negative mothers; these results are presented in this paper. A total of 1,655 HIV-unexposed children (64% of those eligible) were recruited into the ECD substudy from 206 clusters and evaluated for ECD at 2 years of age using the Malawi Developmental Assessment Tool (MDAT) to assess gross motor, fine motor, language, and social skills; the MacArthur-Bates Communicative Development Inventories (CDI) to assess vocabulary and grammar; the A-not-B test to assess object permanence; and a self-control task. Outcomes were analyzed in the intention-to-treat population. For all ECD outcomes, there was not a statistical interaction between the IYCF and WASH interventions, so we estimated the effects of the interventions by comparing the 2 IYCF groups with the 2 non-IYCF groups and the 2 WASH groups with the 2 non-WASH groups. The mean (95% CI) total MDAT score was modestly higher in the IYCF groups compared to the non-IYCF groups in unadjusted analysis: 1.35 (0.24, 2.46; p = 0.017); this difference did not persist in adjusted analysis: 0.79 (-0.22, 1.68; p = 0.057). There was no evidence of impact of the IYCF intervention on the CDI, A-not-B, or self-control tests. Among children in the WASH groups compared to those in the non-WASH groups, mean scores were not different for the MDAT, A-not-B, or self-control tests; mean CDI score was not different in unadjusted analysis (0.99 [95% CI -1.18, 3.17]) but was higher in children in the WASH groups in adjusted analysis (1.81 [0.01, 3.61]). The main limitation of the study was the specific time window for substudy recruitment, meaning not all children from the main trial were enrolled. CONCLUSIONS: We found little evidence that the IYCF and WASH interventions implemented in SHINE caused clinically important improvements in child development at 2 years of age. Interventions that directly target neurodevelopment (e.g., early stimulation) or that more comprehensively address the multifactorial nature of neurodevelopment may be required to support healthy development of vulnerable children. TRIAL REGISTRATION: ClinicalTrials.gov NCT01824940.

Developmental outcomes in Malawian children with retinopathy-positive cerebral malaria.

OBJECTIVE: To assess children with retinopathy-positive cerebral malaria (CM) for neurocognitive sequelae. METHODS: Participants were selected from an ongoing exposure-control study. Eighty-three Malawian children averaging 4.4 years of age and diagnosed with retinopathy-positive CM were compared to 95 controls. Each child was classified as delayed or not using age-based norms for the Malawi Developmental Assessment Tool (MDAT) for developmental delay on the total scale and for the domains of gross motor, fine motor, language and social skills. Groups were also compared on the Achenbach Child Behaviour Checklist (CBCL) (1.5-5 years). RESULTS: Children with retinopathy-positive CM were delayed, relative to the comparison group, on MDAT total development (P = 0.028; odds ratio or OR = 2.13), with the greatest effects on language development (P = 0.003; OR = 4.93). The two groups did not differ significantly on the Achenbach CBCL internalizing and externalizing symptoms total scores. Stepwise regression demonstrated that coma duration, seizures while in hospital, platelet count and lactate level on admission were predictive of assessment outcomes for the children with retinopathy-positive CM. CONCLUSIONS: Children who suffer retinopathy-positive CM at preschool age are at greater risk of developmental delay, particularly with respect to language development. This confirms previous retrospective study findings with school-age children evaluated years after acute illness. The MDAT and the Achenbach CBCL proved sensitive to clinical indicators of severity of malarial illness.