Motor Impairment Referrals to an International Child Development Clinic: It is Not Always Cerebral Palsy.

BACKGROUND: The majority of the estimated 50 to 100 million children living with disability worldwide reside in low- or middle-income countries. As families migrate to avoid humanitarian crises, children with developmental disability and delay warrant particular attention in refugee and international health settings. During transitions, medical documentation may be lost and diagnoses may not be fully understood, contributing to the challenges of determining etiologies of motor impairment. METHODS: Of the first 100 refugee children who were referred to the Child Development Clinic, we identified a subset of children referred for motor impairment or cerebral palsy. Data on their presentation, diagnoses following evaluation, and therapeutic services required was collected by retrospective chart review. RESULTS: Twenty children were referred for motor impairment and cerebral palsy. Average age was 8.9 years; 45% were female. Eight children were eventually diagnosed with cerebral palsy, and 12 had alternate or inconclusive diagnoses. Microcephaly was more common in children diagnosed with cerebral palsy. CONCLUSIONS: The frequent differences between referral and final diagnoses in refugee children referred for cerebral palsy highlights the need for pediatricians' careful examination and diagnostic reasoning upon initial presentation.

Academic performance in moderately and late preterm children in the United States: are they catching up?

OBJECTIVE: To determine whether preterm birth of 32-36 6/7 weeks gestation affected school performance from kindergarten through fifth grade. STUDY DESIGN: We assessed 14350 term infants and 1195 32-36 6/7 weeks gestation infants followed in the Early Childhood Longitudinal Study Kindergarten 2011 cohort for classroom performance in kindergarten-fifth grade. Multivariable regression was performed for comparisons, and data were weighted to be representative of the US population. RESULTS: Children born 35-36 6/7 weeks gestation had no significant difference in their academic scores or performance, while 32-34 6/7 weeks' children had lower academic scores and teacher performance scores when compared to term children. Children born between 32 and 36 6/7 weeks gestation had higher odds of individualized education plan needs and had learning disability diagnoses compared to term children. CONCLUSIONS: Children born between 32 and 34 6/7 weeks gestation have poor school performance compared to term children. Children born between 32 and 36 6/7 weeks gestation are at risk for learning disabilities and likely benefit from continued support and services to improve achievement throughout school.

Answering the Rehabilitation 2030 Call.

In 2017, the World Health Organization initiated a global effort to improve rehabilitative services by 2030, with the overall goal of helping individuals with disabilities achieve maximal independence and improved well-being. Though more than 1 billion people worldwide live with a disability, a significant portion do not have access to appropriate rehabilitative services. In low-income countries, such as Zambia, where rehabilitative services are greatly lacking, disability can further exacerbate economic disparities in the context of personal, cultural, and environmental factors that limit participation in society. Therefore, expansion of rehabilitative services in low-income countries is a pressing global need, and such efforts must be tailored to the societal and cultural framework in which they are implemented. Community-based rehabilitation programs are uniquely poised to provide services in similar low-to-middle-income countries as they eliminate travel barriers to care, allow for regular follow-up, and address the societal determinants of disability by encouraging greater community engagement and by decreasing cultural stigma around disability. Special Hope Network (SHN), a community-based rehabilitation organization in Lusaka, Zambia that serves families caring for children with physical and cognitive disabilities, represents a cost-effective, sustainable, and culturally practical model to provide rehabilitative care. We propose this organization's model as one that can be reproduced and expanded upon in other low-to-middle-income countries to answer the World Health Organization's call to action.

Co-recovery of physical size and cognitive ability from infancy to adolescence: A twin study.

This study tested phenotypic and biometric associations between physical and cognitive catch-up growth in a community sample of twins (n = 1285, 51.8% female, 89.3% White). Height and weight were measured at up to 17 time points between birth and 15 years, and cognitive ability was assessed at up to 16 time points between 3 months and 15 years. Weight and length at birth were positively associated with cognitive abilities in infancy and adolescence (r's = .16-.51). More rapid weight catch-up growth was associated with slower, steadier cognitive catch-up growth. Shared and nonshared environmental factors accounted for positive associations between physical size at birth and cognitive outcomes. Findings highlight the role of prenatal environmental experiences in physical and cognitive co-development.

The Early Care (0-3 Years) In Duchenne Muscular Dystrophy Meeting Report.

Objective: This report summarizes the key discussions from the "Early Care (0-3 years) in Duchenne Muscular Dystrophy" meeting, which aimed to address the challenges and opportunities in the diagnosis and care of Duchenne muscular dystrophy (DMD) and female carriers within the 0-3-year age group. Methods: The meeting brought together experts and healthcare providers who shared insights, discussed advancements in DMD care, and identified research needs. Presentations covered diagnostic challenges, approved therapies, clinical trials, identification of young female carriers, and the importance of clinical care and support for families. Results: The meeting highlighted the importance of timely diagnosis and the lack of evidence-based guidelines for the care of children with DMD aged 0-3 years. Diagnostic challenges were discussed, including delays in receiving a DMD diagnosis and disparities based on ethnicity. The potential benefits and process of newborn screening were addressed.Approved therapeutic interventions, such as corticosteroids and exon-skipping drugs, were explored, with studies indicating the potential benefits of early initiation of corticosteroid therapy and the safety of exon-skipping drugs in DMD. Clinical trials involving infants and young boys were discussed, focusing on drugs like ataluren, vamorolone, and gene therapies.The meeting emphasized the importance of clinical care and support for families, including comprehensive information provision, early intervention services, and individualized support. The identification and care of young female carriers were also addressed. Conclusion: The meeting provided a platform for experts and healthcare providers to discuss and identify key aspects of early care for children with DMD aged 0-3 years. The meeting emphasized the need for early diagnosis, evidence-based guidelines, and comprehensive care and support for affected children and their families. Further research, collaboration, and the development of consensus guidelines are needed to improve early diagnosis, treatment, and outcomes in this population.

Self- and Caregiver-Reported Participation, Quality of Life, and Related Mood and Behavior Challenges in People Living With Dystrophinopathies.

BACKGROUND: Previous studies of quality of life (QOL), mood, and behavior in muscular dystrophy focus on caregiver perceptions. This cross-sectional study aims to determine the prevalence of clinically significant mood and behavior problems by both patient and caregiver report and assess relationship between mood/behavior and QOL. METHODS: Forty-one patients with dystrophinopathies (Duchenne muscular dystrophy [DMD] and Becker muscular dystrophy [BMD]) were recruited through the University of Virginia Neuromuscular Clinic. Each patient and caregiver dyad completed questionnaires, including the Behavior Assessment System for Children, 2nd Edition (BASC-2); the Pediatric Quality of Life Inventory for DMD (PedsQL-DMD); Children's Depression Inventory, 2nd Edition; and Screen for Child Anxiety Related Disorders. RESULTS: Persons with dystrophinopathies rated most of their behavior and adaptive skills similarly to the general population. Sixty-four percent of parent assessments rated clinically significant problems on the BASC-2. Worse BASC-2 scores for self- and parent assessments correlated with lower (worse) scores in the Worry and Communication PedsQL domains. Patient-reported QOL scores were higher than parent-reported scores in each domain except Worry. CONCLUSIONS: Individuals with DMD/BMD rate their adaptive skills, behavioral symptoms, externalizing and internalizing problems, and school problems more positively than parents/caregivers. Obtaining self-report data is a worthwhile endeavor that can add value to intervention planning, with the ultimate goal of optimizing QOL.

Early-Life Enteric Pathogen Exposure, Socioeconomic Status, and School-Age Cognitive Outcomes.

Early-life experiences of enteric infections and diarrheal illness are common in low-resource settings and are hypothesized to affect child development. However, longer-term associations of enteric infections with school-age cognitive outcomes are difficult to estimate due to lack of long-term studies. The objective of this study was to examine the relationship between enteropathogen exposure in the first 2 years of life with school-age cognitive skills in a cohort of children followed from birth until 6 to 8 years in low-resource settings in Brazil, Tanzania, and South Africa. The study included participants from three sites from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health Study who were enrolled just after birth and followed for enteric infections, diarrheal illness, and cognitive development until 2 years of age. When the children were school-age, further data were collected on reasoning skills and semantic/phonemic fluency. We estimated associations between the burden of specific enteric pathogens and etiology-specific diarrhea from 0 to 2 years with cognitive test scores at 6 to 8 years using linear regression and adjusting for confounding variables. In this study, children who carried more enteric pathogens in the first 2 years of life showed overall decreases in school-age cognitive abilities, particularly children who carried protozoa, although this was not statistically significant in this sample. Socioeconomic factors such as maternal education and income were more closely associated with school-age cognitive abilities. Early-life enteric pathogens may have a small, lasting influence on school-age cognitive outcomes, although other socioeconomic factors likely contribute more significantly.

Nonlinear Catch-Up Growth in Height, Weight, and Head Circumference from Birth to Adolescence: A Longitudinal Twin Study.

Owing to high rates of prenatal complications, twins are, on average, substantially smaller than population norms on physical measurements including height, weight, and head circumference at birth. By early childhood, twins are physically average. This study is the first to explore the process of catch-up growth by fitting asymptotic growth models to age-standardized height, weight, and head circumference measurements in a community sample of twins (n = 1281, 52.3% female) followed at up to 17 time points from birth to 15 years. Catch-up growth was rapid over the first year and plateaued around the population mean by early childhood. Shared environmental factors accounted for the majority of individual differences in initial physical size (57.7-65.5%), whereas additive genetic factors accounted for the majority of individual differences in the upper asymptotes of height, weight, and head circumference (73.4-92.6%). Both additive genetic and shared environmental factors were associated with variance in how quickly twins caught up. Gestational age and family SES emerged as important environmental correlates of physical catch-up growth.

Association of Circulating Biomarkers with Growth and Cognitive Development in Rural Tanzania: A Secondary Analysis of the Early Life Interventions in Childhood Growth and Development In Tanzania (ELICIT) Study.

BACKGROUND: Children in low-resource areas experience nutritional and infection challenges delaying growth and cognitive development. OBJECTIVES: Our goal was to assess for associations of circulating biomarkers related to nutrition and inflammation, with growth and developmental outcomes among children in a birth cohort in a resource-poor area in rural Tanzania. METHODS: We assessed data from 1,120 children participating in the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) study. At age 12 and 18 mo, participants had blood tests performed for hemoglobin, collagen-X, insulin-like growth factor-1 (IGF-1), fibroblast growth factor-21 (FGF21), thyroglobulin, ferritin, soluble transferrin receptor (sTFR), retinol binding protein-4 (RBP4), C-reactive protein (CRP), α1-acid glycoprotein (AGP), and CD14. At 18 mo, participants had anthropometry measured and converted to z-scores for length-for-age (LAZ), weight-for-age (WAZ) and head-circumference-for-age (HCZ) and had the Malawi Developmental Assessment Tool (MDAT) performed to evaluate cognitive development. We performed linear regression assessing biomarkers (predictor variable) on anthropometry and MDAT scores (dependent variables), adjusted for sex, socioeconomic status, and baseline values. RESULTS: There was a high degree of intrafactor correlation between 12 and 18 mo and interfactor correlation between biomarkers. IGF-1 and sTFR were positively and FGF21 and ferritin negatively associated with LAZ at 18 mo, whereas collagen-X and CD14 were additionally associated with recent linear growth. Only markers predominantly related to nutrition were consistently linked with WAZ at 18 mo, while RBP4 and AGP were additionally associated with recent change in WAZ. IGF-1 was positively and thyroglobulin, RBP4, and CD14 negatively linked to MDAT scores. IGF-1 was the only factor linked to both 18-mo LAZ and MDAT. CONCLUSIONS: Individual biomarkers were consistently linked to growth and cognitive outcomes, providing support for relationships between nutrition and inflammation in early child development. Further research is needed to assess overlaps in how biomarker-related processes interact with both growth and learning. REGISTERED AT CLINICALTRIALS.GOV: NCT03268902.

Nonlinear Catch-Up Growth in Height, Weight, and Head Circumference from Birth to Adolescence: A Longitudinal Twin Study.

Owing to high rates of prenatal complications, twins are, on average, substantially smaller than population norms on physical measurements including height, weight, and head circumference at birth. By early childhood, twins are physically average. This study is the first to explore the process of catch-up growth by fitting asymptotic growth models to age-standardized height, weight, and head circumference measurements in a community sample of twins ( n = 1,281, 52.3% female) followed at up to 17 time points from birth to 15 years. Catch-up growth was rapid over the first year and plateaued around the population mean by early childhood. Shared environmental factors accounted for the majority of individual differences in initial physical size (57.7%-65.5%), whereas additive genetic factors accounted for the majority of individual differences in the upper asymptotes of height, weight, and head circumference (73.4%-92.6%). Both additive genetic and shared environmental factors were associated with variance in how quickly twins caught up. Gestational age and family SES emerged as important environmental correlates of physical catch-up growth.

Cognitive Development.

Cognitive development in children begins with brain development. Early life exposures may both positively and negatively influence cognitive development in children. Infants, toddlers, and children learn best in secure, nurturing environments and when attachment to a consistent caregiver is present. Pediatricians can screen for both social determinants of health and developmental milestones at office visits to address barriers to care and promote positive cognitive and learning outcomes. Pediatricians may model developmental stimulation during office visits to talk with an infant/child, asking questions of a child, singing and pointing to pictures in books, and modeling responsive listening. Pediatricians may support caregivers to talk with their children, read to their children, and avoid/reduce screen time. Pediatricians can help point caregivers to resources for parent training, Head Start, and quality preschool programs. School readiness has both pre-academic and socioemotional components and can have long-term effects on a child's school success, health, and quality of life. School readiness depends on both the child and the caregiver being ready for school, taking into account caregiver and child health and mental health and child cognitive development.

Early Childhood Stimulating Environment Predicts Later Childhood Resilience in an Indian Longitudinal Birth Cohort Study.

BACKGROUND: Human resilience is dynamic and generated through myriad interactions starting from early childhood. Resilience can improve quality of life and longevity. OBJECTIVE: The current analysis evaluates childhood resilience at 9 years of age and its associations with concurrent cognition and early childhood factors, using longitudinal follow-up of a community birth cohort in Vellore, south India. METHODS: Resilience was assessed using the Child and Youth Resilience Measure and cognition utilizing the Malin's Intelligence Scale for Indian Children. Early childhood variables included growth stunting, maternal depression scores, home environment scores, and socio-economic status (SES) at 2 years of age. Statistical evaluation included bivariate analysis with further multi-variate regression for each resilience domain and the total resilience score. FINDINGS: Out of 251 newborns recruited into the original birth cohort, 205 (81.7%) children were available for the 9-year follow-up. Mean (SD) scores in individual, caregiving, and context domains of resilience were 26.34 (3.2), 19.52 (1.6), and 20 (1.8) respectively. Individual resilience domain was associated with verbal cognition scores at 9 years of age (0.07, p = 0.019) and total home environment scores (0.16, p = 0.027) at 2 years of age, when adjusted for stunting, maternal depression, and SES. The total resilience score was associated only with concurrent verbal intelligence (0.08, p = 0.026) after adjustment with early childhood factors. Analysis of individual home environment factors showed that daily stimulation was associated with the individual domain of resilience. CONCLUSIONS: Follow-up of an Indian birth cohort showed that in addition to concurrent cognitive abilities, childhood resilience was related to early childhood stimulating home environment. Promoting optimal stimulating home environments in low-resource settings to nurture holistic childhood development including mental health is essential.

Upper Extremity Examination for Neuromuscular Diseases (U-EXTEND): Protocol for a Multimodal Feasibility Study.

BACKGROUND: Neuromuscular diseases, such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD), may result in the loss of motor movements, respiratory failure, and early mortality in young children and in adulthood. With novel treatments now available, new evaluation methods are needed to assess progress that is not currently captured in existing motor scale tests. OBJECTIVE: With our feasibility study, our interdisciplinary team of investigators aims to develop a novel, multimodal paradigm of measuring motor function in children with neuromuscular diseases that will revolutionize the way that clinical trial end points are measured, thereby accelerating the pipeline of new treatments for childhood neuromuscular diseases. Through the Upper Extremity Examination for Neuromuscular Diseases (U-EXTEND) study, we hypothesize that the novel objective measures of upper extremity muscle structure and function proposed herein will be able to capture small changes and differences in function that cannot be measured with current clinical metrics. METHODS: U-EXTEND introduces a novel paradigm in which concrete, quantitative measures are used to assess motor function in patients with SMA and DMD. Aim 1 will focus on the use of ultrasound techniques to study muscle size, quality, and function, specifically isolating the biceps and pronator muscles of the upper extremities for follow-ups over time. To achieve this, clinical investigators will extract a set of measurements related to muscle structure, quality, and function by using ultrasound imaging and handheld dynamometry. Aim 2 will focus on leveraging wearable wireless sensor technology to capture motion data as participants perform activities of daily living. Measurement data will be examined and compared to those from a healthy cohort, and a motor function score will be calculated. RESULTS: Data collection for both aims began in January 2021. As of July 2022, we have enrolled 44 participants (9 with SMA, 20 with DMD, and 15 healthy participants). We expect the initial results to be published in summer 2022. CONCLUSIONS: We hypothesize that by applying the described tools and techniques for measuring muscle structure and upper extremity function, we will have created a system for the precise quantification of changes in motor function among patients with neuromuscular diseases. Our study will allow us to track the minimal clinically important difference over time to assess progress in novel treatments. By comparing the muscle scores and functional scores over multiple visits, we will be able to detect small changes in both the ability of the participants to perform the functional tasks and their intrinsic muscle properties. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/40856.

Impact of Shigella infections and inflammation early in life on child growth and school-aged cognitive outcomes: Findings from three birth cohorts over eight years.

BACKGROUND: Shigella infections cause inflammation, which has been hypothesized to mediate the associations between Shigella and child development outcomes among children in low-resource settings. We aimed to assess whether early life inflammation and Shigella infections affect school-aged growth and cognitive outcomes from 6-8 years of age. METHODOLOGY/PRINCIPAL FINDINGS: We conducted follow-up assessments of anthropometry, reasoning skills, and verbal fluency in 451 children at 6-8 years of age in the Brazil, Tanzania, and South Africa sites of MAL-ED, a longitudinal birth cohort study. We estimated the associations between Shigella burden and inflammation with linear growth at 2, 5, and 6-8 years of age, and with the cognitive test scores using linear regression and adjusting for potential confounding variables. We also assessed whether inflammation mediated the associations between Shigella and school-aged outcomes using a regression-based approach to mediation analysis. A high prevalence of Shigella was associated with a 0.32 (95% CI: 0.08, 0.56) z-score lower height-for-age z-score (HAZ) at 6-8 years compared to a low prevalence of Shigella. Intestinal inflammation had a smaller association with HAZ at 6-8 years. Shigella burden had small and consistently negative associations with cognitive outcomes in Brazil and Tanzania, but not South Africa, and the estimates were not statistically significant. Systemic inflammation was strongly associated with lower verbal fluency scores in Brazil (semantic fluency z-score difference: -0.57, 95% CI: -1.05, -0.10; phonemic fluency z-score difference: -0.48, 95% CI: -0.93, -0.03). There was no evidence that intestinal inflammation mediated the association between Shigella and HAZ or cognitive outcomes. CONCLUSIONS/SIGNIFICANCE: While Shigella infections were consistently associated with long-term deficits in linear growth, the estimates of the negative associations between Shigella and cognitive outcomes were imprecise and only observed in the Brazil and Tanzania sites. Systemic inflammation was strongly associated with lower semantic and phonemic fluency scores in Brazil only, highlighting the site-specificity of effects.

The Hidden Disease: Delayed Diagnosis in Duchenne Muscular Dystrophy and Co-Occurring Conditions.

OBJECTIVE: Early diagnosis of Duchenne muscular dystrophy (DMD) is important for timely intervention to prolong function and preserve quality of life. The prevalence of various neurocognitive disorders is known to be higher in patients with DMD than the general population. In this study, we highlight cases of delayed DMD diagnosis that resulted from misattribution of early motor symptoms to co-occurring neurocognitive conditions. We also investigate the difference in age at DMD diagnosis in the setting of specific co-occurring neurocognitive conditions. METHOD: In this study, we reviewed 40 consecutive patients seen at a Certified Duchenne Care Center, excluding siblings of already-diagnosed patients. We highlight cases of significant delay in DMD diagnosis in the setting of co-occurring neurocognitive diagnoses. We also investigate the association of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), intellectual disability, and speech/language delay on age of DMD diagnosis. RESULTS: The prevalence of co-occurring neurocognitive diagnoses was 73.1% in patients diagnosed at or after age 5 years vs. 35.7% in those diagnosed before age 5 years. The average age of DMD diagnosis was 6.6 years in patients with any co-occurring neurocognitive diagnoses and 4.9 years in patients without ( p = 0.09). Individual analysis of ASD and ADHD showed significant differences. A greater number of co-occurring conditions were associated with an increased age at DMD diagnosis ( R2 = 0.87, p < 0.001). CONCLUSION: The data suggest an association between the presence of co-occurring neurocognitive conditions and a later age of DMD diagnosis. One cost-effective diagnostic step that can be implemented by all pediatric practitioners is testing serum creatinine kinase (CK) in any child with motor delays or hypotonia, even in the context of other behavioral or cognitive disabilities.

Are early childhood stunting and catch-up growth associated with school age cognition?-Evidence from an Indian birth cohort.

BACKGROUND: Millions of children worldwide especially in the Asian subcontinent are vulnerable to early childhood stunting. There are contradictory reports of the association between catch-up growth in childhood and school age cognition. METHODS: A community-based birth cohort recruited between 2010 and 2012 from urban slums in Vellore, India was followed up until 9 years of age. From regular anthropometric measurements, stunting status for each individual child was calculated at 2, 5 and 9 years. Cognition was assessed at 9 years of age using the Malin's Intelligence Scale for Indian Children (MISIC). Children were divided into groups based on stunting at each time point as well as catch-up growth, and a regression model was utilised to evaluate their association with cognition at 9 years. RESULTS: Among 203 children included in this analysis, 94/203 (46.31%) children were stunted at 2 years of age, of whom 39.36% had a catch-up growth at 5 years of age, and 38.30% at 9 years. Around 10% of the cohort remained stunted at all time points. In the multivariable analysis, children who were stunted at 2, 5 and 9 years had a significantly lower verbal and total intelligence quotient (IQ) scores by 4.6 points compared to those who were never stunted. Children with catch up growth following stunting at 2 years had higher cognition scores than those who were persistently stunted throughout the childhood. CONCLUSIONS: This study showed persistent stunting in childhood was associated with lowering of 4-5 IQ points in childhood cognition at 9 years of age. Recovery from early life stunting in children with catch up growth prevented further lowering of cognition scores in these children compared to persistently stunted children. Nutritional supplementation during late infancy and early toddlerhood in addition to continuing nutritional supplementation programmes for preschool and school children can improve childhood stunting and cognitive abilities in vulnerable populations.

Sex Differences in Early Childhood Growth in a Resource-Limited Setting: A Secondary Analysis of the Early Life Interventions in Childhood Growth and Development in Tanzania (ELICIT) Study.

BACKGROUND: In population-based growth surveys in sub-Saharan Africa, boys have higher rates of growth failure than girls. OBJECTIVES: Our goal was to assess for the presence, timing, and potential etiology of sex-based differences in length-for-age z score (LAZ), weight-for-age z score (WAZ), and head circumference-for-age z score (HCZ) in a birth cohort in rural Tanzania. METHODS: We performed a secondary analysis of randomized controlled trial data on 1084 children followed from age <2 wk to 18 mo, assessing anthropometry (measured every 3 mo), illness (hospitalization and monthly maternal report of symptoms), and feeding [monthly maternal report of exclusive breastfeeding (EBF) and complementary solids and liquids (CSLs)]. We used linear regression to assess sex differences in LAZ, WAZ, and HCZ over time. RESULTS: Although male and female infants had similar anthropometry measures at study entry, males exhibited poorer growth through 6 mo (e.g., 3-mo mean LAZ: males -0.94, females -0.74, P < 0.01; 3-mo mean WAZ: males -0.63, females -0.48, P < 0.05), without significant worsening from 6 to 18 mo. Males had lower HCZ only at 9 mo. In evaluating possible etiologies, mediation analysis failed to identify illness or hospitalization as mediators of poorer growth among males, although at age 3 mo, males with recently reported illness exhibited greater decline in WAZ than females with illness (ΔWAZ: males -0.24, females 0.03, heterogeneity test P = 0.01). Differences in EBF and introduction of CSL did not explain the sex-based growth outcomes. CONCLUSIONS: In longitudinal analysis, males exhibited more severe growth failure by 3 mo than girls and did not exhibit catchup growth between 6 and 18 mo. Reported symptoms of illness and early introduction of CSL did not appear to be mediators of these sex-based differences, although likely not all sickness was captured by monthly maternal report. Given the early nature of these deficits, LAZ and WAZ measures at 6 mo may be good outcomes for intervention studies targeting improvements in early childhood growth and thriving.

Cognitive Outcomes at 18 Months: Findings from the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) Trial.

Micronutrient deficiencies and enteric infections negatively impact child growth and development. We enrolled children shortly after birth in a randomized, placebo-controlled, 2 × 2 factorial interventional trial in Haydom, Tanzania, to assess nicotinamide and/or antimicrobials (azithromycin and nitazoxanide) effect on length at 18 months of age. Cognitive score at 18 months using the Malawi Developmental Assessment Tool (MDAT), which includes gross motor, fine motor, language, and social assessments, was a secondary outcome. Here, we present the MDAT results of 1,032 children. There was no effect of nicotinamide (change in development-for-age Z score [DAZ] -0.08; 95% CI: -0.16, 0) or antimicrobials (change in DAZ 0.04; 95% CI: -0.06, 0.13) on overall MDAT score. The interventions had no effect on cognitive outcomes in subgroups defined by gender, socioeconomic status, birthweight, and birth season or on MDAT subscores. Further analyses are needed to identify targetable risk factors for impaired cognitive development in these settings.

Effect of scheduled antimicrobial and nicotinamide treatment on linear growth in children in rural Tanzania: A factorial randomized, double-blind, placebo-controlled trial.

BACKGROUND: Stunting among children in low-resource settings is associated with enteric pathogen carriage and micronutrient deficiencies. Our goal was to test whether administration of scheduled antimicrobials and daily nicotinamide improved linear growth in a region with a high prevalence of stunting and enteric pathogen carriage. METHODS AND FINDINGS: We performed a randomized, 2 × 2 factorial, double-blind, placebo-controlled trial in the area around Haydom, Tanzania. Mother-child dyads were enrolled by age 14 days and followed with monthly home visits and every 3-month anthropometry assessments through 18 months. Those randomized to the antimicrobial arm received 2 medications (versus corresponding placebos): azithromycin (single dose of 20 mg/kg) at months 6, 9, 12, and 15 and nitazoxanide (3-day course of 100 mg twice daily) at months 12 and 15. Those randomized to nicotinamide arm received daily nicotinamide to the mother (250 mg pills months 0 to 6) and to the child (100 mg sachets months 6 to 18). Primary outcome was length-for-age z-score (LAZ) at 18 months in the modified intention-to-treat group. Between September 5, 2017 and August 31, 2018, 1,188 children were randomized, of whom 1,084 (n = 277 placebo/placebo, 273 antimicrobial/placebo, 274 placebo/nicotinamide, and 260 antimicrobial/nicotinamide) were included in the modified intention-to-treat analysis. The study was suspended for a 3-month period by the Tanzanian National Institute for Medical Research (NIMR) because of concerns related to the timing of laboratory testing and the total number of serious adverse events (SAEs); this resulted in some participants receiving their final study assessment late. There was a high prevalence of stunting overall (533/1,084, 49.2%). Mean 18-month LAZ did not differ between groups for either intervention (mean LAZ with 95% confidence interval [CI]: antimicrobial: -2.05 CI -2.13, -1.96, placebo: -2.05 CI -2.14, -1.97; mean difference: 0.01 CI -0.13, 0.11, p = 0.91; nicotinamide: -2.06 CI -2.13, -1.95, placebo: -2.04 CI -2.14, -1.98, mean difference 0.03 CI -0.15, 0.09, p = 0.66). There was no difference in LAZ for either intervention after adjusting for possible confounders (baseline LAZ, age in days at 18-month measurement, ward, hospital birth, birth month, years of maternal education, socioeconomic status (SES) quartile category, sex, whether the mother was a member of the Datoga tribe, and mother's height). Adverse events (AEs) and SAEs were overall similar between treatment groups for both the nicotinamide and antimicrobial interventions. Key limitations include the absence of laboratory measures of pathogen carriage and nicotinamide metabolism to provide context for the negative findings. CONCLUSIONS: In this study, we observed that neither scheduled administration of azithromycin and nitazoxanide nor daily provision of nicotinamide was associated with improved growth in this resource-poor setting with a high force of enteric infections. Further research remains critical to identify interventions toward improved early childhood growth in challenging conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT03268902.