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Abstract Background Evidence from low- and middle-income countries (LMIC) suggests that home environment is associated with early childhood development outcomes. However, studies from LMIC that have examined how the home environment during middle childhood is associated with intellectual abilities are scarce. The objective of the study was to explore the association between different aspects of the home environment at 7–8 years and fluid reasoning abilities in a rural, high-risk cohort in Pakistan. Methods We employed a cross-sectional research design to examine 1172 children between 7 and 8 years and their families, utilizing the Home Observation for Measurement of Environment for Middle Childhood (HOME-MC) to evaluate various aspects of the home environment and the Fluid Reasoning Index (FRI) of the Wechsler Intelligence for Children (WISC)-5th edition to assess the fluid reasoning abilities of the children. Multivariable regression analyses were used to examine the association between different components of HOME-MC (scored as indices) and FRI scores. Findings Learning materials and opportunities (β = 1.74, 95% CI = 1.15, 2.33) and Responsivity (β = 1.73, 95% CI = 1.07, 2.38) indices had the strongest association with FRI score followed by Family companionship index (β = 1.27, 95% CI = 0.63, 1.90). The eight different indices of the HOME-DC explained 22% of the total variation in FRI scores. Conclusion We conclude that concurrent learning opportunities, parental responsivity and family companionship at home are associated with fluid reasoning abilities during middle childhood which is comparable to what has been found in early childhood years.

Abstract Background The Ages and Stages Questionnaire 3rd edition (ASQ-3) could be a feasible tool in resource-poor settings. Little is known on the relationship between scores on the ASQ-3 and later intellectual abilities in these settings. Aims To examine the relationship between ASQ-3 scores during the first and second year of life and intellectual abilities at 4 years of age in Nepalese children. Methods In a cohort of 600 children at-risk of stunting, the ASQ-3 was performed at 6–11 and 18–23 months, and the Wechsler Preschool and Primary Scales of Intelligence, fourth edition (WPPSI-IV) at 4 years. We examined the relationship between the ASQ-3 scores and WPPSI-IV full scale IQ (FSIQ) using Spearman correlation coefficients and linear regression models. Results Correlations between ASQ-3 total scores and FSIQ was 0.17 (95% CI 0.07, 0.27) at 6–11 and 0.34 (95% CI 0.26, 0.44) at 18–23 months explaining 2 and 12% of the variance respectively. Except for the communication subscale at 18–23 months with moderate correlations, correlations between the ASQ-3 subscales and FSIQ were weak. Conclusion Our findings suggest a modest relationship between ASQ-3 scores in early childhood and intellectual abilities at 4 years.

BackgroundA new and growing body of research has studied bullying among children in early childhood education and care centers (ECECs). The Bernese Program (Be-Prox) is designed to systematically prevent and handle bullying between children in Swiss ECECs. However, the effectiveness of the Be-Prox intervention has not yet been explored in a Norwegian ECEC setting. ObjectiveThis study aims to evaluate the effectiveness of Be-Prox in preventing and handling bullying among peers in Norwegian ECECs. MethodsECECs from 2 Norwegian municipalities were invited to participate in a cluster randomized controlled trial (RCT) to evaluate the effectiveness of the Be-Prox intervention on peer bullying in Norwegian ECECs. After baseline measures were taken, project ECECs were randomized to either an intervention or a control arm. The Be-Prox intervention was introduced to ECECs in the intervention arm through 6 modules over a 9-month period immediately after the randomization. ECECs in the control arm participated in the data collection and were offered the Be-Prox intervention the following year. The primary outcome of the effect evaluation is the mean sum of negative behavior between peers after the Be-Prox training is completed in the intervention arm. Secondary outcomes include child bystander behavior, teacher self-efficacy, and ECEC’s authoritative climate. An extensive implementation and process evaluation, as well as cost-effectiveness analyses, will be conducted alongside the RCT. ResultsBaseline data collection was conducted in September 2023, and the postintervention data collection started in May 2024. At baseline, we collected data on 708 children and 413 personnel from 38 project ECECs in the 2 Norwegian municipalities. The results from the study will be available in late 2024 at the earliest. ConclusionsThe proposed project includes a comprehensive evaluation of the effectiveness of Be-Prox in Norwegian ECECs directly targeting the prevention and handling of bullying, including implementation and cost-effectiveness evaluations. The results from the project have the potential to fill in identified knowledge gaps in the understanding of negative behavior and bullying between peers in ECECs, and how these may be prevented. If proven efficient, our ambition is to offer Be-Prox to Norwegian ECECs as an evidence-based practice to prevent and handle bullying among preschool children. Trial RegistrationClinicalTrials.gov NCT06040437; https://clinicaltrials.gov/study/NCT06040437 International Registered Report Identifier (IRRID)DERR1-10.2196/60626

Abstract Background Social withdrawal in infants may be a signal of distress and a precursor for non-optimal development. Objective To examine the relationship between infant social withdrawal and neurodevelopment up to 4 years in Nepalese children. Methods A total of 597 Nepalese infants 6–11 months old were assessed with the modified Alarm Distress Baby Scale (m-ADBB), and of these, 527 with the Bayley Scales of Infant and Toddler Development 3rd edition (Bayley-III) during early childhood, and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) and NEPSY-II subtests at 4 years. We examined whether social withdrawal defined by the m-ADBB was associated with neurodevelopmental scores in regression models. Results Children socially withdrawn in infancy had lower Bayley-III language scores (-2.6 (95% CI -4.5, -0.7)) in early childhood. This association seems to be driven by the expressive communication subscale (-0.7 (95% CI -1.0, -0.3)), but not the receptive communication subscale (-0.2 (95% CI -0.6, 0.1)). There were no differences in the other Bayley-III scores or the WPPSI-IV and NEPSY-II scores at 4 years in children who were socially withdrawn or not. Conclusion Social withdrawal in infancy was reflected in early language development but not cognitive functioning at 4 years.

Abstract Background Treatment fidelity (TF) refers to methodological strategies used to monitor and enhance the reliability and validity of interventions. We evaluated TF in a pragmatic RCT of music therapy (MT) for premature infants and their parents. Methods Two hundred thirteen families from seven neonatal intensive care units (NICUs) were randomized to receive standard care, or standard care plus MT during hospitalization, and/or during a 6-month period post-discharge. Eleven music therapists delivered the intervention. Audio and video recordings from sessions representing approximately 10% of each therapists’ participants were evaluated by two external raters and the corresponding therapist using TF questionnaires designed for the study (treatment delivery (TD)). Parents evaluated their experience with MT at the 6-month assessment with a corresponding questionnaire (treatment receipt (TR)). All items as well as composite scores (mean scores across items) were Likert scales from 0 (completely disagree) to 6 (completely agree). A threshold for satisfactory TF scores (≥4) was used in the additional analysis of dichotomized items. Results Internal consistency evaluated with Cronbach’s alpha was good for all TF questionnaires (α ≥ 0.70), except the external rater NICU questionnaire where it was slightly lower (α 0.66). Interrater reliability measured by intraclass correlation coefficient (ICC) was moderate (NICU 0.43 (CI 0.27, 0.58), post-discharge 0.57 (CI 0.39, 0.73)). Gwet’s AC for the dichotomized items varied between 0.32 (CI 0.10, 0.54) and 0.72 (CI 0.55, 0.89). Seventy-two NICU and 40 follow-up sessions with 39 participants were evaluated. Therapists’ mean (SD) TD composite score was 4.88 (0.92) in the NICU phase and 4.95 (1.05) in the post-discharge phase. TR was evaluated by 138 parents. The mean (SD) score across intervention conditions was 5.66 (0.50). Conclusions TF questionnaires developed to assess MT in neonatal care showed good internal consistency and moderate interrater reliability. TF scores indicated that therapists across countries successfully implemented MT in accordance with the protocol. The high treatment receipt scores indicate that parents received the intervention as intended. Future research in this area should aim to improve the interrater reliability of TF measures by additional training of raters and improved operational definitions of items. Trial registration Longitudinal Study of music Therapy’s Effectiveness for Premature infants and their caregivers – “LongSTEP”. ClinicalTrials.gov Identifier: NCT03564184. Registered on June 20, 2018

Introduction Vitamin B12 (cobalamin) is crucial for optimal child development and growth, yet deficiency is common worldwide. The aim of this study is twofold; (1) to describe vitamin B12 status and the status of other micronutrients in Norwegian infants, and (2) in a randomised controlled trial (RCT), investigate the effect of vitamin B12 supplementation on neurodevelopment in infants with subclinical vitamin B12 deficiency.Methods and analysis Infant blood samples, collected at public healthcare clinics, are analysed for plasma cobalamin levels. Infants with plasma cobalamin 6.5 µmol/L, are given an intramuscular injection of hydroxocobalamin (400 µg). The primary outcomes are cognitive, language and motor development assessed using the Bayley Scales of Infant and Toddler Development at 12 months of age.Ethics and dissemination The study has been approved by the Regional Committee for Medical and Health Research Ethics (ref: 186505). Investigators who meet the Vancouver requirements will be eligible for authorship and be responsible for dissemination of study findings. Results will extend current knowledge on consequences of subclinical vitamin B12 deficiency during infancy and may inform future infant feeding recommendations.Trial registration number NCT05005897.

Using data from a rural cohort in Pakistan (N = 1298), the study examined the predictive validity of the Bayley Scales of Infant and Toddler Development (BSID) 3rd edition on later tests of general abilities. The BSID III subscales (cognitive, language and motor) were administered at 2 years; general ability was assessed using the Verbal, Performance and Full-Scale score from the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) III at 4 years, and the Fluid Reasoning Index (FRI) from the Wechsler Intelligence Scale for Children (WISC) V at 8 years. The combined BSID subscales explained 15% of the variation of the WPPSI III full scale, 16% of the Verbal scale, 7% of the Performance scale and 1% of the FRI. BSID III scores at 24 months should be used with caution to predict future intellectual abilities.

Background: There are still many people in the world who prepare their meals on open fires or stoves using solid fuels from biomass, especially in low-and middle-income countries. Although biomass cooking fuels have been associated with adverse health impacts and diseases, the association with child linear growth remains unclear. Objectives: In a cohort design, we aimed to describe the association between the use of biomass cooking fuels and linear growth in children aged 18–23 months living in the urban and peri-urban community of Bhaktapur, situated in the Kathmandu valley in Nepal. Methods: Caretakers of 600 marginally stunted children aged 6–11 months were interviewed about their source of cooking fuel and other socio-demographic characteristics at enrolment into a randomized controlled trial. Children’s body length was measured when children were 18–23 months old. In linear regression models, we estimated the association between the use of biomass fuel and length-for-age Z-scores (LAZ), adjusted for relevant confounders. We repeated these analyses in pre-defined sub-groups and different percentiles of LAZ using quantile regression models. Results: Among study participants, 101 (18%) used biomass as cooking fuel. The association between biomass fuel and LAZ was not statistically significant in the full sample (adjusted regression coefficient: –0.14, 95% CI: −0.28, 0.00). The association was stronger in some of the sub-groups and in the lower tail of the LAZ distribution (those who are stunted), but neither reached statistical significance. Discussion: Children from households in poor, urban neighborhoods in Nepal which used biomass fuel for cooking were on average slightly shorter than other children, although the association only approached statistical significance. As this was an observational study, residual confounding cannot be excluded. Further studies are needed to confirm these associations, in particular those seen in certain sub-groups.

The COVID-19 pandemic has affected many aspects of daily life worldwide, but the impact may be higher for impoverished populations. The main aim of this study is to describe the impact of the COVID-19 pandemic on different aspects of daily life in mothers in Nepal. We included 493 mothers of children aged 54–71 months participating in a randomized controlled trial on vitamin B12 supplementation. Mothers answered questions regarding the exposure and impact of the pandemic on their daily lives, and pandemic-related worries and sleep problems. We examined the extent to which worry, and sleep problems differed between mothers according to their exposure to COVID-19, socioeconomic status, and previous symptoms of depression. The mean age (SD) of the mothers was 32.3 (4.6) years and 54% had education below the secondary level. Of the mothers, 5.4% had either been exposed to someone who had tested positive or who had a family member with COVID-19. One-third of the participants responded that the pandemic had affected their economic situation, employment, and family life to a great deal. Both mothers and fathers with educational levels above 10 years or households with higher socioeconomic status had significantly higher average worry scores (maternal p = 0.020 and paternal p = 0.005). Mothers with a history of symptoms of depression had significantly more worry-related sleep problems during the pandemic (p = 0.020) than those without a history of depressive symptoms. Our study underlines the negative impact of the COVID-19 pandemic on diverse aspects of everyday life of mothers in Nepal.

Abstract Background Vitamin D is important for brain function and linear growth. Vitamin D deficiency during pregnancy has been linked with impaired neurodevelopment during early childhood. However, there is limited evidence from population-based studies on the long-term impact of vitamin D deficiency on cognitive development and linear growth. The objective of the current analysis is to examine whether vitamin D deficiency during infancy and early childhood is associated with cognitive development and linear growth measured in school age. Methods This is a follow-up study of a placebo-controlled trial among 1000 North Indian children 6–30 months of age. We measured growth and neurodevelopment in 791 of these children when they were 6–9 years old. Neurodevelopment was measured using the Wechsler Intelligence Scale for Children, 4th edition INDIA, the Crichton Verbal Scale, NEPSY-II subtests, and the BRIEF 2. We categorized vitamin D concentrations during infancy and early childhood according to the US Institute of Medicine’s recommendations; serum 25(OH)D 20 ng/ml as sufficient. In multivariable regression models, adjusting for relevant confounders, we estimated the association between vitamin D status, growth and neurodevelopmental outcomes. Results Among the 791 children, baseline vitamin D status was available for 716. Of these, 45.8% were vitamin D deficient, 32.7% were inadequate, and 21.5% were sufficient. Vitamin D status was not associated with any of the cognitive outcomes or linear growth [Adjusted β coefficient for height for age z-score between deficient and sufficient children was − 0.06 (95% CI − 0.24 to 0.11)] at follow up. Conclusion Our findings do not support the notion that poor vitamin D status in early childhood is an important limitation for cognitive development and linear growth. Trial Registration The trial was first registered at www.clinicaltrials.gov as NCT00717730 in July, 2008, and at CTRI/2010/091/001090 in August, 2010 and then as CTRI/2016/11/007494 in November 2016.

The demand for cobalamin (vitamin B12) and folate is increased during pregnancy, and deficiency during pregnancy may lead to complications and adverse outcomes. Yet, the status of these micronutrients is unknown in many populations. We assessed the concentration of cobalamin, folate and their functional biomarkers, total homocysteine (tHcy) and methylmalonic acid (MMA), in 561 pregnant women enrolled in a community-based randomised controlled trial in Bhaktapur, Nepal. Plasma concentrations of cobalamin, folate, tHcy and MMA were measured and a combined indicator of vitamin B12 status (3cB12) was calculated. We report mean or median concentrations and the prevalence of deficiency according to commonly used cut-offs, and assessed their association with indicators of socio-economic status, and maternal and dietary characteristics by linear regression. Among the women at gestational week less than 15, deficiencies of cobalamin and folate were seen in 24 and 1 %, respectively. Being a vegetarian was associated with lower plasma cobalamin, and a higher socio-economic status was associated with a better micronutrient status. We conclude that cobalamin deficiency defined by commonly used cut-offs was common in Nepalese women in early pregnancy. In contrast, folate deficiency was rare. As there is no consensus on cut-off points for vitamin B12 deficiency during pregnancy, future studies are needed to assess the potential functional consequences of these low values.

BackgroundVitamin B12 deficiency is common and affects cell division and differentiation, erythropoiesis, and the central nervous system. Several observational studies have demonstrated associations between biomarkers of vitamin B12 status with growth, neurodevelopment, and anemia. The objective of this study was to measure the effects of daily supplementation of vitamin B12 for 1 year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency.Methods and findingsThis is a community-based, individually randomized, double-blind placebo-controlled trial conducted in low- to middle-income neighborhoods in Bhaktapur, Nepal. We enrolled 600 marginally stunted, 6- to 11-month-old infants between April 2015 and February 2017. Children were randomized in a 1:1 ratio to 2 μg of vitamin B12, corresponding to approximately 2 to 3 recommended daily allowances (RDAs) or a placebo daily for 12 months. Both groups were also given 15 other vitamins and minerals at around 1 RDA. The primary outcomes were neurodevelopment measured by the Bayley Scales of Infant and Toddler Development 3rd ed. (Bayley-III), attained growth, and hemoglobin concentration. Secondary outcomes included the metabolic response measured by plasma total homocysteine (tHcy) and methylmalonic acid (MMA). A total of 16 children (2.7%) in the vitamin B12 group and 10 children (1.7%) in the placebo group were lost to follow-up. Of note, 94% of the scheduled daily doses of vitamin B12 or placebo were reported to have been consumed (in part or completely). In this study, we observed that there were no effects of the intervention on the Bayley-III scores, growth, or hemoglobin concentration. Children in both groups grew on an average 12.5 cm (SD: 1.8), and the mean difference was 0.20 cm (95% confidence interval (CI): -0.23 to 0.63, P = 0.354). Furthermore, at the end of the study, the mean difference in hemoglobin concentration was 0.02 g/dL (95% CI: -1.33 to 1.37, P = 0.978), and the difference in the cognitive scaled scores was 0.16 (95% CI: -0.54 to 0.87, P = 0.648). The tHcy and MMA concentrations were 23% (95% CI: 17 to 30, P < 0.001) and 30% (95% CI: 15 to 46, P < 0.001) higher in the placebo group than in the vitamin B12 group, respectively. We observed 43 adverse events in 36 children, and these events were not associated with the intervention. In addition, 20 in the vitamin B12 group and 16 in the placebo group were hospitalized during the supplementation period. Important limitations of the study are that the strict inclusion criteria could limit the external validity and that the period of vitamin B12 supplementation might not have covered a critical window for infant growth or brain development.ConclusionsIn this study, we observed that vitamin B12 supplementation in young children at risk of vitamin B12 deficiency resulted in an improved metabolic response but did not affect neurodevelopment, growth, or hemoglobin concentration. Our results do not support widespread vitamin B12 supplementation in marginalized infants from low-income countries.Trial registrationClinicalTrials.gov NCT02272842 Universal Trial Number: U1111-1161-5187 (September 8, 2014) Trial Protocol: Original trial protocol: PMID: 28431557 (reference [18]; study protocols and plan of analysis included as Supporting information).

Background: The Ages and Stages Questionnaires, Third Edition (ASQ-3) is becoming a widely used developmental assessment tool. The ASQ-3 can be completed by the caregivers (referred to as “mail out”), or by trained personnel under direct observation of the children (referred to as “home procedure”).Aim: The study was carried out to compare results obtained by the ASQ mail out with those of the ASQ home procedure in a community setting of Bhaktapur, Nepal.Methods: Trained fieldworkers (FWs) performed developmental assessment of 134 children aged 9 months in their homes using the ASQ home procedure. A few days before these assessments, mothers were asked to fill in the same ASQ-3 questionnaire. The concordance correlation coefficient (CCC) was calculated to measure their agreement.Result: The agreement between the ASQ mail out and home procedure was fair for the total score (CCC = 0.54). For the sub-scales, the agreement was good for the gross motor (CCC = 0.65), for the remaining subscales agreement was poor (CCC < 0.4).Conclusion: In resource limited setting like Nepal, the ASQ mail out represents an easy method to assess child development by caretakers at home; however, with the poor agreement between different methods of assessments, we cannot conclude that a single method is superior or most optimal and this question should be investigated further. When either of the method home procedure or mail out is opted, the results should be interpreted with cautions.

BackgroundSustained social withdrawal in infancy may have organic and nonorganic causes and could hinder normal development. The Alarm Distress Baby (ADBB) scale is a widely validated screening tool of social withdrawal in children 2–24 months. The aim of the current study was to evaluate the full and modified ADBB in Nepalese infants in a community-based study.MethodsWe enrolled 600 infants who were video recorded during a pediatric examination. The 36 infants first enrolled were scored by an expert rater, and the subsequent 64 infants were scored by two trained staff with the full ADBB scale. Of the 600 enrolled infants, 597 videos (including the 100 infants scored with the full ADBB) were scored with the modified ADBB (m-ADBB) scale by the trained staff, with 7% double scoring. We measured the interrater agreement and psychometric properties of both scales.ResultsIn the 64 infants scored with the full ADBB by two raters, the concordance correlation coefficients (CCCs) indicated poor interrater agreement. For the m-ADBB, the CCCs were better indicating acceptable agreement between raters. The greatest lower bound (GLB) for reliability coefficient for the full ADBB scored by an expert rater indicated good internal consistency, whereas the GLB coefficient for the m-ADBB indicated poorer internal consistency. The Spearman correlation coefficient between the total scores of the two versions was 0.82 (P < 0.001). Among the infants scored with the full ADBB, 25% had a score above cutoff (≥5). Scored with the m-ADBB in the full sample, 11.4% of the infants had a score above the suggested cutoff (≥2). In both versions, children achieved high scores on vocalization.ConclusionOur findings suggest that the m-ADBB is an acceptable approach to achieve adequate interrater agreement in a large community-based study in Nepal. Results indicate high prevalence of social withdrawal in this population. There are, however, uncertainties on the internal consistency of the scales in this setting, and the validity of the scales needs to be investigated further. More effective training strategies for administration and additional cultural-specific instructions could be important measures to explore before implementing the scale further in this setting.

Background: The toxic effects of prenatal methylmercury (MeHg) include neurological abnormalities and developmental delay of which infants and children are particular susceptible. Studies on the effects of low and moderate exposure show conflicting results. Seafood is the main dietary source of MeHg, but also contributes with nutrients regarded as beneficial for development. Objectives: To measure the change in total hair mercury concentration (THHg) after an intervention of lunch meals with fatty fish or meat in Norwegian preschool children, and to examine the associations between THHg and cognitive function. Methods: Children (n = 232) 4–6 years old were randomized to lunch meals with fatty fish (n = 114) or meat (n = 118) three times a week for 16 weeks. THHg was determined using a Direct Mercury Analyzer, and cognitive function was assessed by the Wechsler Preschool and Primary Intelligence Scale-III (WPPSI-III) pre- and post-intervention. Linear mixed effect models were used to analyze changes in THHg and WPPSI-III scores. Results: The mean (SD) THHg pre-intervention was 0.373 (0.204) mg kg−1. Children in the fish group had an increase in THHg (change 0.162, 95% CI 0.111, 0.213 mg kg−1), whereas children in the meat group had decreased THHg (−0.053, 95% CI −0.103, −0.002 mg kg−1). There were no notable associations between THHg and the WPPSI-III raw scores at baseline or after 16 weeks of the fish/meat intervention. Conclusions: Lunch meals including fatty fish led to a significant increase in THHg, but the values remain below the point of departures used for risk assessment by the EFSA, WHO and US-EPA. We observed no associations between THHg and cognitive function. Keywords: Hair mercury, Methylmercury, Fish consumption, Cognitive development, Preschool children

Abstract Background Long chain polyunsaturated fatty acids (LCPUFA) especially docosahexaenoic acid (DHA) and arachidonic acid (AA) are crucial for normal brain development in utero and in early infancy. Data on fatty acid status and cognitive development in infants and children from low-income countries are scarce. Methods We examined the association between the DHA and AA status in infancy (n = 320) and developmental status and cognitive functioning five years later. At five years of age, we measured development by the Ages and Stages Questionnaire 3rd. ed. (ASQ-3) and cognitive functioning by subtests from the neuropsychological test battery NEPSY II. In addition, infant fatty acid composition in red blood cells (RBC) was analyzed. In multiple linear and logistic regression models, we estimated the associations between DHA and AA status in infancy and scores on the ASQ-3 and the NEPSY II subtests. Results There were no notable associations between infant AA and DHA status, and the scores on the ASQ-3 and the NEPSY II subtests five years later. It should be noted that we found better than expected concentrations of erythrocyte DHA and AA among the infants, and the ASQ scores were left-skewed, which limited the ability to identify associations. Conclusion DHA and AA status in infancy is seemingly not related to neurodevelopment measured 5 years later in this peri-urban population from Nepal.

Abstract Background Marine resources including fatty fish are important sources of n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFAs), which are important for brain development. To our knowledge, this is the first randomized controlled trial (RCT) investigating the impact of fatty fish on cognition in preschool children. The purpose of the trial was to investigate whether an increased intake of fatty fish compared to meat improves cognitive function in children 4–6 years old. Methods The children (n = 232) in this two-armed RCT, Fish Intervention Studies-KIDS (FINS-KIDS) were recruited from 13 kindergartens in Bergen, Norway. They were randomly assigned to lunch meals with fatty fish (herring/mackerel) or meat (chicken/lamb/beef) three times a week for 16 weeks. The fish and meat were weighed before and after the meals to record the exact consumption (dietary compliance). The primary outcome was cognitive function measured by the Wechsler Preschool and Primary Scale of Intelligence, 3rd edition (WPPSI-III) and fine-motor coordination measured by the 9-Hole Peg Test (9-HPT) at pre- and post-intervention. Biological samples (blood, urine, hair), and questionnaires to the caregivers were included at both time points. Linear mixed effect models with a random intercept for kindergarten were used to analyze changes from pre- to post-intervention in the primary outcome variables. Results There were 218 children included in the trial (105 in the fish, and 113 in the meat group). The children consumed a mean (standard deviation) of 2070 (978) g fish or 2675 (850) g meat from the study meals (p < 0.0001). The fish group had a significant increase of red blood cell n-3 LC-PUFAs. The intervention had no effect on the WPPSI-III scores (mean change total raw score; fish group 17.7, 95% confidence interval (CI) 14.8–20.7 vs meat group 17.8, 95% CI 15.0–20.6, p = 0.97) in the main analyses. In the sub-analyses, adjusting for dietary compliance, the fish group showed a higher improvement on total raw score (20.4, 95% CI 17.5–23.3) compared to the meat group (15.2, 95% CI 12.4–18.0, p = 0.0060); docosahexaenoic acid mediated this effect. Conclusions There was no beneficial effect of fatty fish compared to meat on cognitive functioning in the preschool children. When considering dietary compliance, we found a beneficial effect of fatty fish on cognitive scores. Trial registration ClinicalTrials.gov, NCT02331667 December 17, 2014.

Abstract Background Iodine is a key component of thyroid hormones that are critical for normal development of the brain and nervous system in utero. Recent results indicate that two thirds of pregnant women in Europe have sub-optimal iodine nutrition. In Norway, milk and seafood are the most important dietary iodine sources and contributes to about 80% of the intake. Method Two-armed randomized trial where 137 pregnant women were randomized to either receiving cod twice weekly, or continue with habitual diet for 16 weeks (pregnancy week 20–36). Socioeconomic- and demographic factors, dietary information and biological (urine, blood, and hair) samples are collected pre- and post-intervention, and at six weeks, three-, six-, and eleven months postpartum. Biological samples (urine, blood, and hair) of the infant are collected at six weeks, three-, six-, and eleven months postnatal. Child development is assessed by The Bayley Scale of Infant and Toddler Development, 3rd edition, at eleven months, and by parent report on the Ages and Stages Questionnaire, 3rd edition, and Ages and Stages Questionnaire: Social Emotional at three-, six-, and eleven months. Discussion The Mommy’s Food study will provide knowledge on changes in iodine nutrition when consuming iodine rich fish during pregnancy and contribute to the understanding of the impact of iodine status in pregnancy on infant neurodevelopment. Trial registration This study is registered in ClinicalTrials.gov (NCT02610959). Registered November 17, 2015.

Abstract Background Vitamin-D deficiency has been linked with impaired development in animal studies; however, the evidence from human studies is scanty. Evidence as to whether vitamin-D deficiency during early childhood affects growth is also limited and conflicting. We examined the extent to which vitamin-D deficiency (

Abstract Background Vitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 is crucial for normal cell division and differentiation, and it is necessary for the development and myelination of the central nervous system. The aim of the present study is to measure the effect of daily supplementation of vitamin B12 on the neurodevelopment and growth of young children in Nepal. Methods/design We are conducting an individually randomized, double-blind, placebo-controlled trial with 600 marginally stunted children 6–11 months old (length for age less than −1 z-score). Children are randomized to receive a lipid-based paste containing vitamin B12 or placebo daily for 12 months. The main outcomes are changes in growth (z-scores) and in neurodevelopment measured by the Bayley Scales of Infant and Toddler Development, Third Edition, from baseline until the end of the study. Discussion If vitamin B12 supplementation benefits early child development and growth, this will have consequences for dietary recommendations for malnourished children worldwide. Trial registrations ClinicalTrials.gov Identifier: NCT02272842 . Registered on 21 October 2014. Universal Trial Number: U1111-1161-5187. Registered on 8 September 2014.

BackgroundChildren in low and middle income countries may have many risk factors for poor cognitive development, and are accordingly at a high risk of not reaching their developmental potential. Determinants for cognitive development in early life can be found among biological and socioeconomic factors, as well as in stimulation and learning opportunities.ObjectiveThe present study aimed to identify determinants of cognitive, language and motor development in 6–11 months old Nepalese infants.MethodsSix hundred infants with a length-for-age z-score

Objective To determine the magnitude of relationships of early life factors with child development in low/middle-income countries (LMICs).Design Meta-analyses of standardised mean differences (SMDs) estimated from published and unpublished data.Data sources We searched Medline, bibliographies of key articles and reviews, and grey literature to identify studies from LMICs that collected data on early life exposures and child development. The most recent search was done on 4 November 2014. We then invited the first authors of the publications and investigators of unpublished studies to participate in the study.Eligibility criteria for selecting studies Studies that assessed at least one domain of child development in at least 100 children under 7 years of age and collected at least one early life factor of interest were included in the study.Analyses Linear regression models were used to assess SMDs in child development by parental and child factors within each study. We then produced pooled estimates across studies using random effects meta-analyses.Results We retrieved data from 21 studies including 20 882 children across 13 LMICs, to assess the associations of exposure to 14 major risk factors with child development. Children of mothers with secondary schooling had 0.14 SD (95% CI 0.05 to 0.25) higher cognitive scores compared with children whose mothers had primary education. Preterm birth was associated with 0.14 SD (–0.24 to –0.05) and 0.23 SD (–0.42 to –0.03) reductions in cognitive and motor scores, respectively. Maternal short stature, anaemia in infancy and lack of access to clean water and sanitation had significant negative associations with cognitive and motor development with effects ranging from −0.18 to −0.10 SDs.Conclusions Differential parental, environmental and nutritional factors contribute to disparities in child development across LMICs. Targeting these factors from prepregnancy through childhood may improve health and development of children.

Introduction Preterm birth has major medical, psychological and socioeconomic consequences worldwide. Music therapy (MT) has positive effects on physiological measures of preterm infants and maternal anxiety, but rigorous studies including long-term follow-up are missing. Drawing on caregivers’ inherent resources, this study emphasises caregiver involvement in MT to promote attuned, developmentally appropriate musical interactions that may be of mutual benefit to infant and parent. This study will determine whether MT, as delivered by a qualified music therapist during neonatal intensive care unit (NICU) hospitalisation and/or in home/municipal settings following discharge, is superior to standard care in improving bonding between primary caregivers and preterm infants, parent well-being and infant development.Methods and analysis Design: international multicentre, assessor-blind, 2×2 factorial, pragmatic randomised controlled trial; informed by a completed feasibility study. Participants: 250 preterm infants and their parents. Intervention: MT focusing on parental singing specifically tailored to infant responses, will be delivered during NICU and/or during a postdischarge 6-month period. Primary outcome: changes in mother–infant bonding at 6-month corrected age (CA), as measured by the Postpartum Bonding Questionnaire. Secondary outcomes: mother–infant bonding at discharge and at 12-month CA; child development over 24 months; and parental depression, anxiety and stress, and infant rehospitalisation, all over 12 months.Ethics and dissemination The Regional Committees for Medical and Health Research Ethics approved the study (2018/994/REK Nord, 03 July 2018). Service users were involved in development of the study and will be involved in implementation and dissemination. Dissemination of findings will apply to local, national and international levels.Trial registration number NCT03564184

Introduction: Nepal suffered from major earthquakes in April 2015 resulting in great damage to the society. The objective of the current study is to describe the earthquake exposure, the impact on family’s daily life and the symptoms of post-traumatic stress disorder (PTSD) and their association in Nepalese mothers 20 months following the earthquakes.Methods: In a clinical trial in Bhaktapur, Nepal, 558 mothers responded to an inventory on earthquake exposure and the Impact of Event Scale – Revised (IES-R) 20 months after the earthquakes. In multiple linear regression models, we estimated the associations between the earthquake exposure and the impact on the families’ life and the IES-R score.Results: Over 60% reported that the earthquakes had a great deal of negative impact on their family’s life. In 4.7%, close family members died, and in 10.5%, family members were injured. 24% had IES-R scores indicating PTSD symptoms within clinical concern or a possible diagnosis. Lower levels of education were associated with higher scores on the total IES-R. Mothers who report that the earthquakes had a great deal of negative impact had higher total IES-R scores [9.8, 95% CI (5.9, 13.6)] compared to mothers that reported no such negative impact. Mothers with family members who were killed had higher IES-R scores [3.6, 95% CI (1.6, 5.5)] than those with no family members who died. Mothers assisting in rescue efforts had lower IES-R scores [2.8, 95% CI (0.8, 4.8)] than those not assisting.Conclusion: Our study demonstrates high levels of exposure to traumatic events, large negative impact on the everyday life of the families, and a high level of PTSD symptoms. There was a consistent and graded association between the exposure variables and PTSD symptoms. The large impact of the earthquakes on these Nepalese mothers underscore the importance of awareness of mental disorders following major natural catastrophes for marginalized families.

BackgroundMany young children in developing countries do not reach their developmental potential. Traditional methods for assessing developmental outcome are time consuming, thus, physiological measures that can contribute to the prediction of developmental outcomes in high risk groups have been suggested. Vagally mediated heart rate variability (vmHRV) is considered a neurophysiological or peripheral proxy for prefrontal and executive functioning and might serve as a supplement for traditional measurements of developmental status and as a potential useful risk indicator.AimIn the present study, we wanted to describe the vmHRV in Nepalese infants and relate it to the Bayley Scales of infant and toddler development, 3. edition (Bayley-III) subscales.Methods600 Nepalese infants were included in the study. At 6–11 and 17–24 months, we measured neurodevelopmental and socio-emotional outcomes by the Bayley-III. Inter-beat intervals were recorded at two measurement points when the children were 17–24 months.ResultsThere was a high intraclass correlation between HRV indices generated from the two measurement points. No significant associations between vmHRV and Bayley-III sub scales were found at any time.ConclusionThis study is the first to describe vmHRV in healthy infants and the relationship between Bayley-III scores. Our results suggest that vmHRV is not associated with measures of general development in infancy.

Background: The Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley-III) is the most widely used developmental assessment tool for infants and toddlers worldwide, but less is known about its psychometric properties and feasibility in low and middle-income countries.Aim: To assess the psychometric properties and feasibility of the Bayley-III when used in a large scale randomized controlled intervention trial in Nepal.Methods: The participating infants were part of a randomized, doubled blind, placebo-controlled trial to measure the efficacy of vitamin B12 supplementation on growth and neurodevelopment. A total of 600 children aged 6–11 months were enrolled and included for developmental assessment. The Bayley-III measures child development across five domains: cognition, receptive and expressive language, fine and gross motor skills. Some items were culturally adapted. To measure and ensure appropriate inter-observer agreement, standardization exercises were performed during the initial training, and double scoring of 7% of test sessions were conducted throughout the study by two examiners.Results: The inter-rater agreement was excellent for both the standardization exercises before the start of the study, and for the quality control throughout the study with intraclass correlation coefficient ranging from 0.95 to 0.99. The internal consistency measured by the Cronbach’s alpha coefficient ranged between 0.57 and 0.87. The subtests raw scores as well as scaled scores were significantly correlated (p < 0.001). The means and SDs of the scaled scores compared with American norms were similar to the distribution in the American sample, with the exception of the receptive (Mean = 7.7, SD = 2.2) and expressive (Mean = 7.3, SD = 1.9) language subtests that were lower than the American norms.Conclusion: The inter-rater reliability between the scorers on the Bayley-III was excellent both during standardization and for the quality control. The distributions for the cognitive and motor subscales are comparable to the American norms, while caution is needed in the interpretation of the language scales. The results suggest that Bayley-III is a feasible tool for the assessment of neurodevelopmental status in nutritional studies in low resource settings such as Nepal. Cultural adaptations, training and standardization are prerequisites for a valid and reliable assessment using the Bayley-III.

ObjectivesDeficiencies of vitamin B12 and folate are associated with delayed development and neurological manifestations. The objective of this study was to measure the effect of daily supplementation of vitamin B12 and/or folic acid on development in young North Indian children.MethodsIn a randomized, double blind trial, children aged six to 30 months, received supplement with placebo or vitamin B12 and/or folic acid for six months. Children were allocated in a 1:1:1:1 ratio in a factorial design and in blocks of 16. We measured development in 422 children by the Ages and Stages Questionnaire 3rd ed. at the end of the intervention.ResultsCompared to placebo, children who received both vitamin B12 and folic acid had 0.45 (95% CI 0.19, 0.73) and 0.28 (95% CI 0.02, 0.54) higher SD-units in the domains of gross motor and problem solving functioning, respectively. The effect was highest in susceptible subgroups consisting of stunted children, those with high plasma homocysteine (> 10 μmol/L) or in those who were younger than 24 at end study. With the exception of a significant improvement on gross motor scores by vitamin B12 alone, supplementation of either vitamin alone had no effect on any of the outcomes.ConclusionOur findings suggest that supplementation of vitamin B12 and folic acid benefit development in North Indian Children.Trial registrationClinicalTrials.gov NCT00717730.

Background and objectiveInfants and young children in low to middle-income countries are at risk for adverse neurodevelopment due to multiple risk factors. In this study, we sought to identify stimulation and learning opportunities, growth, and burden of respiratory infections and diarrhea as predictors for neurodevelopment.MethodsWe visited 422 North Indian children 6 to 30 months old weekly for six months. Childhood illnesses were assessed biweekly. At end study, we assessed neurodevelopment using the Ages and Stages Questionnaire 3rd ed. (ASQ-3) and gathered information on stimulation and learning opportunities. We identified predictors for ASQ-3 scores in multiple linear and logistic regression models.ResultsWe were able to explain 30.5% of the variation in the total ASQ-3 score by the identified predictors. When adjusting for child characteristics and annual family income, stimulation and learning opportunities explained most of the variation by 25.1%. Height for age (standardized beta: 0.12, pConclusionOur results support the importance of early child stimulation and general nutrition for child development. Our study also suggests that diarrhea is an additional risk factor for adverse neurodevelopment in vulnerable children.