Perinatal inflammation, fetal growth restriction, and long-term neurodevelopmental impairment in Bangladesh.

BACKGROUND: There are limited data on the impact of perinatal inflammation on child neurodevelopment in low-middle income countries and among growth-restricted infants. METHODS: Population-based, prospective birth cohort study of 288 infants from July 2016-March 2017 in Sylhet, Bangladesh. Umbilical cord blood was analyzed for interleukin(IL)-1α, IL-1ß, IL-6, IL-8, and C-reactive protein(CRP). Child neurodevelopment was assessed at 24 months with Bayley-III Scales of Infant Development. We determined associations between cord blood inflammation and neurodevelopmental outcomes, controlling for potential confounders. RESULTS: 248/288 (86%) live born infants were followed until 24 months, among whom 8.9% were preterm and 45.0% small-for-gestational-age(SGA) at birth. Among all infants, elevated concentrations (>75%) of CRP and IL-6 at birth were associated with increased odds of fine motor delay at 24 months; elevated CRP was also associated with lower receptive communication z-scores. Among SGA infants, elevated IL-1α was associated with cognitive delay, IL-8 with language delay, CRP with lower receptive communication z-scores, and IL-1ß with lower expressive communication and motor z-scores. CONCLUSIONS: In rural Bangladesh, perinatal inflammation was associated with impaired neurodevelopment at 24 months. The associations were strongest among SGA infants and noted across several biomarkers and domains, supporting the neurobiological role of inflammation in adverse fetal development, particularly in the setting of fetal growth restriction. IMPACT: Cord blood inflammation was associated with fine motor and language delays at 24 months of age in a community-based cohort in rural Bangladesh. 23.4 million infants are born small-for-gestational-age (SGA) globally each year. Among SGA infants, the associations between cord blood inflammation and adverse outcomes were strong and consistent across several biomarkers and neurodevelopmental domains (cognitive, motor, language), supporting the neurobiological impact of inflammation prominent in growth-restricted infants. Prenatal interventions to prevent intrauterine growth restriction are needed in low- and middle-income countries and may also result in long-term benefits on child development.

Effect of a parenting and nutrition education programme on development and growth of children using a social safety-net platform in urban Bangladesh: a cluster randomized controlled trial.

Background: Although sustainable development goals mandate for quality early childhood development (ECD) interventions for children <8 years, little occurs for children <3 years, especially in urban settings in low-and-middle-income countries (LMICs). Our primary objective was to measure the effect of an ECD-focused parenting and nutrition education on children's development through home visits using a social safety net platform of urban Bangladesh. Methods: A cluster randomized controlled trial was conducted with mothers of children aged 6-16 months in 20 clusters across the Rangpur city, Bangladesh. The intervention group received fortnightly ECD-focused parenting and nutrition education at homes by local Community Health Workers (CHWs) for one year. Bayley-III was used to measure children's cognitive, language and motor development. Data were analyzed using intention to treat. ClinicalTrials.gov Identifier: NCT03753646. Findings: Out of 599 mother-child dyads, 56.6% mothers were aged ≤ 25 years old. After one year, the intervened children had higher cognitive [Effect size Cohen's d; 0.42 SD (95% CI: 0.58-0.25)], language (0.38 SD, 95% CI: 0.55-0.22) and motor (0.17 SD, 95% CI: 0.01-0.34) development. In the intervention group, mothers experienced less violence [Odds ratio; 0.6 (95% CI: 0.4-1.0)] and fathers engaged more (0.23 SD, CI: 0.39-0.06) in ECD activities with their children compared to the comparison group. Total home stimulation and mothers' knowledge on child care were also improved in the intervention. But the children's growth was not improved. Interpretation: This ECD programme improves the development of children of young mothers in urban settings using a social safety-net platform. The evidence may help in increasing ECD coverage in urban areas in LMICs. Funding: Grand Challenges Canada, Saving Brains Programme Grant Number: SB-1810-20176.

Stress biomarkers and child development in young children in Bangladesh.

BACKGROUND: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. METHODS: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. RESULTS: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We detected a significant relationship between HPA axis activity and child development, where increased HPA axis activity was associated with poor development outcomes. Specifically, we found that cortisol reactivity (coefficient -0.15, 95% CI (-0.29, -0.01)) and post-stressor levels (coefficient -0.12, 95% CI (-0.24, -0.01)) were associated with CDI comprehension score, post-stressor cortisol was associated with combined EASQ score (coefficient -0.22, 95% CI (-0.41, -0.04), and overall glucocorticoid receptor methylation was associated with CDI expression score (coefficient -0.09, 95% CI (-0.17, -0.01)). We did not detect a significant relationship between SAM activity or oxidative status and child development. CONCLUSIONS: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.

Parental communicative input as a protective factor in Bangladeshi families living in poverty: A multi-dimensional perspective.

Studies from high-income populations have shown that stimulating, supportive communicative input from parents promote children's cognitive and language development. However, fewer studies have identified specific features of input supporting the healthy development of children growing up in low- or middle-income countries. The current study proposes and tests a multi-dimensional framework for understanding whether and how caregiver communicative input mediates the associations between socio-economic conditions and early development. We also examine how caregiver conceptual scaffolding and autonomy support uniquely and synergistically explain variation in child outcomes. Participants were 71 Bangladeshi families with five-year-olds who were exposed to a range of biological and psychosocial hazards from birth. Caregiver-child interactions during snack sharing and semi-structured play were coded for caregiver conceptual scaffolding, autonomy support, and child engagement. Findings indicate that the two dimensions of input were correlated, suggesting that caregivers who provided richer conceptual scaffolds were simultaneously more supportive of children's autonomy. Notably, conceptual scaffolding and autonomy support each mediated associations between maternal education and child verbal intelligence quotient (IQ) scores. Further, caregivers who supported greater autonomy in their children had children who participated in conversations more actively, and these children in turn had higher performance IQ scores. When considered simultaneously, conceptual scaffolding was associated with verbal IQ over and above autonomy support, whereas autonomy support related to child engagement, controlling for conceptual scaffolding. These findings shed new light on how environmental factors may support early development, contributing to the design of family-centered, culturally authentic interventions. A video abstract of this article can be viewed at https://youtu.be/9v_8sIv7ako RESEARCH HIGHLIGHTS: Studies from high-income countries have identified factors mitigating the impacts of socio-economic risks on development. Such research is scarce in low- and middle-income countries. The present study conceptualized and evaluated caregiver communicative input in Bangladeshi families along two interrelated yet distinct dimensions: conceptual scaffolding and autonomy support. Conceptual scaffolding and autonomy support individually mediated associations between maternal education and child verbal IQ, shedding light on protective factors in families living in poverty. Parents providing richer conceptual scaffolds were simultaneously more supportive of children's autonomy. However, the two dimensions each related to cognition and language through unique pathways.

Multidimensional evaluation of the early emergence of executive function and development in Bangladeshi children using nutritional and psychosocial intervention: A randomized controlled trial protocol.

INTRODUCTION: Reversing malnutrition-induced impairment of cognition and emotional regulation is a critical global gap. We hypothesize that brain-targeted micronutrient supplemented nutritional rehabilitation in children with moderate acute malnutrition, followed by 2 years micronutrient supplementation will impact on the cognition and emotion regulation of these children. METHODS: The primary outcome of this prospective, randomized controlled trial is to study the development of executive functions (EFs) and emotion regulation (ER) in this cohort. Moderate acute malnourished (MAM; WLZ/WHZ <-2 and ≥-3 z-score, and/or 11.5 cm ≤ MUAC < 12.5cm; n = 140)children aged around one year (11m-13m) in Mirpur, Dhaka, Bangladesh will be randomized (1:1) to receive either locally produced Ready to Use Supplementary Food (RUSF) or Enhanced Ready to Use Supplementary Food (E-RUSF) until anthropometric recovery (WLZ/WHZ > -1SD), or for 3 months after enrollment (whichever is earlier). The randomized MAMs groups will be given either Small Quantity Lipid Based Nutrient Supplement (SQLNS) or Enhanced Small Quantity Lipid Based Nutrient Supplement (E-SQLNS), respectively until the end of the 2-year follow up period. Standard psychosocial stimulation will be provided to the MAMs intervention groups. Biological samples will be collected, anthropometric and neurocognitive assessments will be performed at 2 (22m-26m) and 3 (34m-38m) years of age. Two control groups will be recruited: 1), non-malnourished one-year (11m-13m) old children (WLZ/WHZ score>-1SD; n = 70); and 2) three-year (34m-38m) old children (n = 70) with untreated MAM (WHZ <-2 and ≥-3 z-score, and/or 11.5≤MUAC<12.5 cm). The 3-year-old MAM reference group will be assessed once and provided with 2 months of nutritional rehabilitation support (RUSF Nutriset's Plumpy'Sup™).

Factors associated with children's cognitive, language, and motor development in deprived urban settings in Bangladesh.

BACKGROUND: Children's development is multifactorial. Although there have been several studies exploring the association of children's development with maternal, child, and environmental factors, we are unaware of any study that assessed those factors in children whose mothers were enrolled in a social safety net programme in low- and middle-income countries. This study aimed to identify the factors associated with disadvantaged children's cognitive, language, and motor development at age 6-16 months in deprived settings of urban Bangladesh and to identify relative importance of these factors of children's development. We also explored if there were any gender differences in child development. METHODS: This cross-sectional study was conducted in a deprived setting of urban Bangladesh. Bayley III was used for assessing children's cognitive, language, and motor development. Multivariable linear regression model was used to find the factors associated with children's development, and dominance analysis was used to explore the relative importance of the factors. RESULTS: Out of the total 599 mother-child dyads, 303 (50.58%) were girls. The factors associated with children's development were length-for-age Z-score (cognitive: B = 1.21 [95% CI = 0.31, 2.11], P = 0.008; language: 1.67 [0.79, 2.55] P < 0.001; motor: 2.15 [1.01, 3.29] P < 0.001) and home environment (cognitive: 0.58 [0.27, 0.89] P < 0.001; language: 0.59 [0.27, 0.92], P < 0.001; motor: 0.44 [0.09, 0.79] P = 0.013). Girls had higher cognitive (1.90 [0.17, 3.6], P = 0.031) and language (2.53 [0.55, 4.51], P = 0.013) development compared with boys. Families with a higher number of under five children within the households had lower language (-1.57 [-2.78, -0.36], P = 0.011) development. Violence against the mother and the families' food security status were not associated with the children's development. Children's length-for-age Z-score (27%) and home stimulation environment (23%) were the most important factors of cognitive development. CONCLUSION: Children's nutritional status and home environment are important factors for disadvantaged children's development in deprived urban settings of Bangladesh. Both early child development-focussed parenting and nutrition interventions should be considered when designing child development programmes in urban settings in low- and middle-income countries.

Establishing performance standards for child development: learnings from the ECDI2030.

BACKGROUND: Standards of early childhood development (ECD) are needed to determine whether children living in different contexts are developmentally on track. The Early Childhood Development Index 2030 (ECDI2030) is a population-level measure intended to be used in household surveys to collect globally comparable data on one of the indicators chosen to monitor progress toward target 4.2 of the Sustainable Development Goals: The proportion of children aged 24-59 months who are developmentally on track in health, learning and psychosocial well-being. METHODS: To define performance cut-scores for the ECDI2030 we followed a criterion-referenced standard setting exercise using the modified Angoff method. The exercise gauged the expectations from 15 global experts in ECD and was informed by representative population data collected in Mexico and the State of Palestine. The final calibrated age-specific performance cut-scores were applied to these data to estimate the proportion of children developmentally on track, disaggregated by background characteristics, including the child's sex and attendance to early childhood education. RESULTS: Through a process of standard setting, we generated robust performance standards for the ECDI2030 by establishing five age-specific cut-scores to identify children as developmentally on track. CONCLUSIONS: This paper demonstrated how the standard setting methodology, typically applied to measures in the health and education fields, could be applied to a measure of child development. By creating robust criterion-referenced standards, we have been able to ensure that the cut-scores related to age for the ECDI2030 are based on performance standards set by global experts in the ECD field for defining on and off track development.

Stress Biomarkers and Child Development in Young Children in Bangladesh.

Background: Hundreds of millions of children in low- and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations between biological measures of chronic stress in early life and developmental outcomes in a large cohort of young children living in rural Bangladesh. Methods: We assessed physiologic measures of stress in the first two years of life using measures of the hypothalamic-pituitary-adrenal (HPA) axis (salivary cortisol and glucocorticoid receptor gene methylation), the sympathetic-adrenal-medullary (SAM) system (salivary alpha-amylase, heart rate, and blood pressure), and oxidative status (F2-isoprostanes). We assessed child development in the first two years of life with the MacArthur-Bates Communicative Development Inventories (CDI), the WHO gross motor milestones, and the Extended Ages and Stages Questionnaire (EASQ). We compared development outcomes of children at the 75th and 25th percentiles of stress biomarker distributions while adjusting for potential confounders (hereafter referred to as contrasts) using generalized additive models, which are statistical models where the outcome is predicted by a potentially non-linear function of predictor variables. Results: We analyzed data from 684 children (49% female) at both 14 and 28 months of age; we included an additional 765 children at 28 months of age. We observed 135 primary contrasts of the differences in child development outcomes at the 75th and 25th percentiles of stress biomarkers, where we detected significant relationships in 5 out of 30 contrasts (17%) of HPA axis activity, 1 out of 30 contrasts (3%) of SAM activity, and 3 out of 75 contrasts (4%) of oxidative status. These findings revealed that measures of HPA axis activity were associated with poor development outcomes. We did not find consistent evidence that markers of SAM system activity or oxidative status were associated with developmental status. Conclusions: Our observations reveal associations between the physiological evidence of stress in the HPA axis with developmental status in early childhood. These findings add to the existing evidence exploring the developmental consequences of early life stress.

Implementing a group-based multi-component early child development intervention through the government health system in rural Bangladesh: A feasibility study.

Children in low- and middle-income countries face an increased risk of impaired cognitive development due to contaminated environments, poor nutrition, and inadequate responsive stimulation from caregivers. Implementing multi-component, community-level interventions may reduce these risks; however, there is little evidence supporting implementation of these interventions at scale. We assessed the feasibility of implementing a group-based intervention that included responsive stimulation, maternal and child nutrition, water and sanitation, and childhood lead exposure prevention through the government health system in Chatmohar, Bangladesh. After implementation, we conducted 17 in-depth interviews with frontline health service providers and 12 key informant interviews with their supervisors and managers to explore the facilitators and difficulties implementing such a complex programme within the health system. Factors facilitating implementation included: high quality training and skill level of providers, support from community members, family, and supervisors, positive relationships between providers and participants, and provision of children's toys and books free of cost. Difficulties included increased workload of the providers, complicated group-based yet stage-specific delivery where providers had to manage a large group of mother-child dyads representing many different child age-groups at once, and logistics difficulties in providing toys and books through a centralised health system process. Key informants made suggestions to ensure effective government-level scale-up including engaging relevant NGOs as partners, identifying feasible ways to make toys available, and offering providers meaningful even if non-monetary rewards. These findings can be used to shape the design and delivery of multi-component child development interventions to be delivered through the health system.

Factors Associated with Reported COVID-like Symptoms and Seroprevalence Data Matched with COVID-like Symptoms in Slums and Non-Slums of Two Major Cities in Bangladesh.

OBJECTIVES: To examine the levels and socio-demographic differentials of: (a) reported COVID-like symptoms; and (b) seroprevalence data matched with COVID-like symptoms. METHODS: Survey data of reported COVID-like symptoms and seroprevalence were assessed by Roche Elecsys® Anti-SARS-CoV-2 immunoassay. Survey data of 10,050 individuals for COVID-like symptoms and seroprevalence data of 3205 individuals matched with COVID-like symptoms were analyzed using bivariate and multivariate logistic analysis. RESULTS: The odds of COVID-like symptoms were significantly higher for Chattogram city, for non-slum, people having longer years of schooling, working class, income-affected households, while for households with higher income had lower odd. The odds of matched seroprevalence and COVID-like symptoms were higher for non-slum, people having longer years of schooling, and for working class. Out of the seropositive cases, 37.77% were symptomatic-seropositive, and 62.23% were asymptomatic, while out of seronegative cases, 68.96% had no COVID-like symptoms. CONCLUSIONS: Collecting community-based seroprevalence data is important to assess the extent of exposure and to initiate mitigation and awareness programs to reduce COVID-19 burden.

Six-Year Follow-up of Childhood Stimulation on Development of Children With and Without Anemia.

BACKGROUND AND OBJECTIVES: Previously, in 30 Bangladeshi villages, 2 groups of children with iron-deficiency anemia (IDA) and nonanemic (NA) iron sufficiency aged 6 to 24 months participated in 2 parallel cluster randomized controlled trials of the effect of psychosocial stimulation on neurodevelopment. The intervention was composed of weekly play sessions at home for 9 months. All children with anemia received iron treatment of 6 months. The intervention improved the mental development of NA but not IDA groups. Six years after end line when the children were aged 8 to 9 years, we aimed to determine if benefits were sustained in the NA group or late-onset benefits emerged in the IDA group. METHODS: We relocated 372 (90%) of the initial 412 children from all the clusters (villages), and assessed their IQ with the Wechsler Abbreviated Scale of Intelligence-II, motor development, and school achievement including math, spelling, and reading. Analyses were by intention-to-treat, adjusting for clustering. RESULTS: There was a significant interaction between anemia groups (IDA/NA) and intervention on IQ. The intervention benefitted the NA group's Full-Scale IQ (effect size, 0.43 [95% confidence interval, 0.08-0.79]) and Perceptual Reasoning Index (effect size, 0.48 [95% confidence interval, 0.08-0.89]) but did not affect the IDA group's outcomes. No other outcomes were significant. CONCLUSIONS: The benefits from early childhood psychosocial stimulation on the NA group's IQ, 6 years after intervention ended, adds to the limited evidence on the sustainability of benefits in low- and middle-income countries. Reasons for lack of effect in children with anemia are unknown.

An Integrated Mother-Child Intervention on Child Development and Maternal Mental Health.

OBJECTIVES: To evaluate an integrated, low-cost, facility-based group intervention designed to promote child care, boost maternal mental-wellbeing, reduce harsh discipline, and improve children's health, nutrition, and early development. METHODS: In Dhaka, 30 neighborhood clusters of a low-income urban community were randomized to intervention or control groups. Mothers with children between 6 and 24 months (n = 300) who self-reported negative discipline were identified and enrolled. A 1-year group intervention included integration of responsive caregiving, nutritional supplementation, caregivers' mental health, child protection, and health advice. Child outcomes were cognition (primary) and language, motor and behavioral development, growth, and hemoglobin and iron status (secondary). Maternal outcomes were depressive symptoms, self-esteem, negative discipline, and child care knowledge and practices. RESULTS: Overall, 222 (74%) mother-child dyads participated in the 1-year follow-up. Intervention and control groups differed on wealth, with no other significant differences. The intervention resulted in a 0.75 SD effect on cognition, 0.77 SD on language, 0.41 SD on motor, and 0.43 to 0.66 SDs on behavior during testing (emotion, cooperation, and vocalization) in the intervention arm. Mothers in the intervention group had fewer depressive symptoms (effect size: -0.72 SD), higher self-esteem (0.62 SD), better child care knowledge (2.02 SD), fewer harsh discipline practices (0.25 SD), and better home stimulation (0.73 SD). The intervention showed no effect on child growth or hemoglobin, but significantly improved serum iron status (-0.36 SD). CONCLUSIONS: A comprehensive intervention, delivered through group sessions in health facilities, was effective in promoting child development and reducing maternal depressive symptoms among mothers who reported using negative or harsh discipline.

Concurrent validity of the Ages and Stages Questionnaire Inventory and the Bayley Scales of Infant and Toddler Development in rural Bangladesh.

BACKGROUND: Reliable and valid measurement of early child development are necessary for the design of effective interventions, programs, and policies to improve early child outcomes. One widely used measure in low- and middle-income countries (LMICs) is the Bayley Scales of Infant and Toddler Development III (Bayley-III). Alternatively, the Bangladeshi-adapted Ages and Stages Questionnaire Inventory (ASQ:I) can be administered more quickly, inexpensively, and with less training than the Bayley-III. We aimed to assess the concurrent validity of the Bangladeshi-adapted ASQ:I with the Bayley-III in children 4-27 months old in rural Bangladesh. METHODS: The sample was a sub-sample (n = 244) of endline participants from an evaluation of an early child development intervention (July-August 2018). We assessed concurrent validity between internally age-standardized domain-specific and total scores using Pearson correlations both overall and stratified by age and intervention status. We also assessed correlations between scores and variables theoretically related to child development including maternal education and stimulation in the home. RESULTS: The overall correlation between ASQ:I and Bayley-III total scores was moderate (r = 0.42 95% CI: 0.30-0.53), with no systematic differences by intervention status. Overall, concurrent validity was highest for the gross motor domain (r = 0.51, 0.40-0.60), and lowest for the fine motor domain (r = 0.20, 0.04-0.33). Total ASQ:I and Bayley-III scores were positively correlated with child stimulation and maternal education. CONCLUSION: The Bangladeshi-adapted ASQ:I is a low-cost tool that can be feasibly administered in rural Bangladesh, is moderately correlated with the Bayley-III, and can be used to measure child development when human, time, or financial resources are constrained.

Supplementation With Iron Syrup or Iron-Containing Multiple Micronutrient Powders Alters Resting Brain Activity in Bangladeshi Children.

BACKGROUND: Anemia and iron deficiency have been associated with poor child cognitive development. A key rationale for the prevention of anemia using supplementation with iron has been the benefits to neurodevelopment. However, little causal evidence exists for these gains. OBJECTIVES: We aimed to examine effects of supplementation with iron or multiple micronutrient powders (MNPs) on brain activity measures using resting electroencephalography (EEG). METHODS: Children included in this neurocognitive substudy were randomly selected from the Benefits and Risks of Iron Supplementation in Children study, a double-blind, double-dummy, individually randomized, parallel-group trial in Bangladesh, in which children, starting at 8 mo of age, received 3 mo of daily iron syrup, MNPs, or placebo. Resting brain activity was recorded using EEG immediately after intervention (month 3) and after a further 9-month follow-up (month 12). We derived EEG band power measures for delta, theta, alpha, and beta frequency bands. Linear regression models were used to compare the effect of each intervention with that of placebo on the outcomes. RESULTS: Data from 412 children at month 3 and 374 at month 12 were analyzed. At baseline, 43.9% were anemic and 26.7% were iron deficient. Immediately after intervention, iron syrup, but not MNPs, increased the mu alpha-band power, a measure that is associated with maturity and the production of motor actions (iron vs. placebo: mean difference = 0.30; 95% CI: 0.11, 0.50 µV2; P = 0.003; false discovery rate adjusted P = 0.015). Despite effects on hemoglobin and iron status, effects were not observed on the posterior alpha, beta, delta, and theta bands, nor were effects sustained at the 9-month follow-up. CONCLUSIONS: The effect size for immediate effects on the mu alpha-band power is comparable in magnitude with psychosocial stimulation interventions and poverty reduction strategies. However, overall, we did not find evidence for long-lasting changes in resting EEG power spectra from iron interventions in young Bangladeshi children. This trial was registered at www.anzctr.org.au as ACTRN12617000660381.

Effects of iron supplementation on neural indices of habituation in Bangladeshi children.

BACKGROUND: Iron deficiency and anemia have been associated with poor cognition in children, yet the effects of iron supplementation on neurocognition remain unclear. OBJECTIVE: We aimed to examine the effects of supplementation with iron on neural indices of habituation using auditory event-related brain potentials (ERPs). METHODS: This substudy was nested within a 3-arm, double-blind, double-dummy, individual randomized trial in Bangladesh, in which 3300 8-mo-old children were randomly selected to receive 3 mo of daily iron syrup (12.5 mg iron), multiple micronutrient powders (MNPs) (including 12.5 mg iron), or placebo. Children were assessed after 3 mo of intervention (mo 3) and 9 mo thereafter (mo 12). The neurocognitive substudy comprised a randomly selected subset of children from the main trial. Brain activity elicited during an auditory roving oddball task was recorded using electroencephalography to provide an index of habituation. The differential response to a novel (deviant) compared with a repeated (standard) sound was examined. The primary outcome was the amplitude of the mismatch response (deviant minusstandard tone waveforms) at mo 3. Secondary outcomes included the deviant and standard tone-evoked amplitudes, N2 amplitude differences, and differences in mean amplitudes evoked by deviant tones presented in the second compared with first half of the oddball sequence at mo 3 and 12. RESULTS: Data were analyzed from 329 children at month 3 and 363 at mo 12. Analyses indicated no treatment effects of iron interventions compared with placebo on the amplitude of the mismatch response (iron syrup compared with placebo: mean difference (MD) = 0.07µV [95% CI: -1.22, 1.37]; MNPs compared with placebo: MD = 0.58µV [95% CI: -0.74, 1.90]) nor any secondary ERP outcomes at mo 3 or 12, despite improvements in hemoglobin and ferritin concentrations from iron syrup and MNPs in this nested substudy. CONCLUSION: In Bangladeshi children with >40% anemia prevalence, iron or MNP interventions alone are insufficient to improve neural indices of habituation. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12617000660381.

The creation of the Global Scales for Early Development (GSED) for children aged 0-3 years: combining subject matter expert judgements with big data.

INTRODUCTION: With the ratification of the Sustainable Development Goals, there is an increased emphasis on early childhood development (ECD) and well-being. The WHO led Global Scales for Early Development (GSED) project aims to provide population and programmatic level measures of ECD for 0-3 years that are valid, reliable and have psychometrically stable performance across geographical, cultural and language contexts. This paper reports on the creation of two measures: (1) the GSED Short Form (GSED-SF)-a caregiver reported measure for population-evaluation-self-administered with no training required and (2) the GSED Long Form (GSED-LF)-a directly administered/observed measure for programmatic evaluation-administered by a trained professional. METHODS: We selected 807 psychometrically best-performing items using a Rasch measurement model from an ECD measurement databank which comprised 66 075 children assessed on 2211 items from 18 ECD measures in 32 countries. From 766 of these items, in-depth subject matter expert judgements were gathered to inform final item selection. Specifically collected were data on (1) conceptual matches between pairs of items originating from different measures, (2) developmental domain(s) measured by each item and (3) perceptions of feasibility of administration of each item in diverse contexts. Prototypes were finalised through a combination of psychometric performance evaluation and expert consensus to optimally identify items. RESULTS: We created the GSED-SF (139 items) and GSED-LF (157 items) for tablet-based and paper-based assessments, with an optimal set of items that fit the Rasch model, met subject matter expert criteria, avoided conceptual overlap, covered multiple domains of child development and were feasible to implement across diverse settings. CONCLUSIONS: State-of-the-art quantitative and qualitative procedures were used to select of theoretically relevant and globally feasible items representing child development for children aged 0-3 years. GSED-SF and GSED-LF will be piloted and validated in children across diverse cultural, demographic, social and language contexts for global use.

Protocol for validation of the Global Scales for Early Development (GSED) for children under 3 years of age in seven countries.

INTRODUCTION: Children's early development is affected by caregiving experiences, with lifelong health and well-being implications. Governments and civil societies need population-based measures to monitor children's early development and ensure that children receive the care needed to thrive. To this end, the WHO developed the Global Scales for Early Development (GSED) to measure children's early development up to 3 years of age. The GSED includes three measures for population and programmatic level measurement: (1) short form (SF) (caregiver report), (2) long form (LF) (direct administration) and (3) psychosocial form (PF) (caregiver report). The primary aim of this protocol is to validate the GSED SF and LF. Secondary aims are to create preliminary reference scores for the GSED SF and LF, validate an adaptive testing algorithm and assess the feasibility and preliminary validity of the GSED PF. METHODS AND ANALYSIS: We will conduct the validation in seven countries (Bangladesh, Brazil, Côte d'Ivoire, Pakistan, The Netherlands, People's Republic of China, United Republic of Tanzania), varying in geography, language, culture and income through a 1-year prospective design, combining cross-sectional and longitudinal methods with 1248 children per site, stratified by age and sex. The GSED generates an innovative common metric (Developmental Score: D-score) using the Rasch model and a Development for Age Z-score (DAZ). We will evaluate six psychometric properties of the GSED SF and LF: concurrent validity, predictive validity at 6 months, convergent and discriminant validity, and test-retest and inter-rater reliability. We will evaluate measurement invariance by comparing differential item functioning and differential test functioning across sites. ETHICS AND DISSEMINATION: This study has received ethical approval from the WHO (protocol GSED validation 004583 20.04.2020) and approval in each site. Study results will be disseminated through webinars and publications from WHO, international organisations, academic journals and conference proceedings. REGISTRATION DETAILS: Open Science Framework https://osf.io/ on 19 November 2021 (DOI 10.17605/OSF.IO/KX5T7; identifier: osf-registrations-kx5t7-v1).

Gestational and childhood urinary iodine concentrations and children's cognitive function in a longitudinal mother-child cohort in rural Bangladesh.

BACKGROUND: Severe iodine deficiency adversely affects neurodevelopment; however, evidence regarding the association of non-severe deficiency and child cognitive functioning is inconclusive. METHODS: This prospective mother-child cohort study was nested in a population-based nutritional supplementation trial in Bangladesh (Maternal and Infant Nutrition Interventions in Matlab [MINIMat]). Participants with data on cognitive abilities at 5 and 10 years of age (n = 1530) and at least one measurement of urinary iodine concentration (UIC) (gestational week 8, 5, and 10 years) were selected. Cognitive abilities were assessed using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and Wechsler Intelligence Scale for Children (WISC-IV). UICs were measured with inductively coupled plasma mass spectrometry and thereafter adjusted for specific gravity. RESULTS: Median UICs in our population: (282 µg/L [pregnancy]; 406 µg/L [5 years]; 294 µg/L [10 years]) indicated that iodine intake corresponded to above 'adequate' or even 'excessive', according to the WHO classification. Maternal 'UIC <150 µg/L' was associated with lower full-scale and verbal scores at 5 and 10 years, although the associations were weakened in the fully adjusted models. A tendency of decreased verbal scores was also observed for maternal 'UIC ≥500 µg/L' but not for the corresponding child iodine category (≥300 µg/L). Child 'UIC <100 µg/L' was associated with lower processing speed (B=-3.1, 95% CI [-6.2, -0.1]; P-value = 0.041) compared with the reference group (100 µg/L≤ UIC <300 µg/L). CONCLUSIONS: Current findings add to the growing evidence of a causal association of early-life iodine intake with cognitive development, indicating that low iodine intake during childhood is associated with reduced processing speed and non-optimal gestational iodine intake is weakly associated with slightly poorer verbal development outcomes.

A comprehensive intervention package improves the linear growth of children under 2-years-old in rural Bangladesh: a community-based cluster randomized controlled trial.

Approximately one-third of children under the age of five are stunted in developing countries and many of them are micronutrient-deficient. We designed a comprehensive intervention package including egg/milk-based snacks to improve linear growth and dietary diversity among 6 to 12-month-old children in rural Bangladesh. In this 1-year community-based cluster randomized controlled longitudinal experiment, 412 mother-infant pairs were randomly assigned to receive either monthly food vouchers (for eggs, milk, semolina, sugar, and oil) to prepare egg and milk-based snacks for their children, along with multiple micronutrient powder (MNP), counseling on child feeding and handwashing, or regular government health communication alone (control; n = 206, treatment; n = 206). The trial was conducted in 12 clusters (small administrative units of sub-district). The primary inclusion criteria were ultra-poor households with limited resources and having children under 2-years-old. The primary and secondary outcomes were differences in children's length gain and dietary diversity. The effect of intervention on child growth was examined using a mixed effect linear regression model. Mean weight and length of the children did not significantly differ between groups at baseline. Around 90% of the children in both groups were breastfed. After receiving intervention for 12 months, LAZ score increased by 0.37 (CI 0.24, 0.51, p < 0.001) and risk of stunting reduced by 73% (OR: 0.27, CI 0.13, 0.58, p = 0.001). This comprehensive intervention package improved the growth and dietary diversity of children in extremely poor Bangladeshi households. A scaling-up of this intervention in contexts with limited resources should be taken into consideration.Trial registration: This trial registered retrospectively at ClinicalTrials.gov as NCT03641001, 21/8/2018.

Rethinking Responsive Feeding: Insights from Bangladesh.

Young children's growth is influenced by food and feeding behavior. Responsive feeding has been shown to promote healthy growth and development, to prevent under- and overfeeding, and to encourage children's self-regulation. However, most measures of responsive feeding do not incorporate bidirectional mother-infant responsivity or early learning principles and have not been validated against observations. To overcome these gaps, we laid the groundwork for a responsive feeding measure based on a community sample of 67 mothers and their 6-18-month-old children in Bangladesh. Children were weighed and measured. Mothers reported on their child's dietary intake and responded to a 38-item responsive feeding questionnaire developed through a 2-phase Delphi procedure. Based on a video-recorded feeding observation, mother-child dyads were categorized into proximal (43%) and distal (57%) responsivity groups. Using stepwise logistic regression, a 9-item model from the responsive feeding questionnaire had excellent fit (AUC = 0.93), sensitivity (90%), specificity (89%), positive predictive value (87%), and negative predictive value (93%). Proximal responsivity was characterized by maternal concerns about children's dietary intake. Distal responsivity was characterized by maternal perception of children's happy mood during feeding. Findings support responsive feeding as modulating between proximal and distal responsivity, promoting autonomy, self-regulation, and enabling children to acquire and practice healthy eating behaviors.