Search

Background: Biomarkers such as omega-3 (n-3) PUFAs, urinary iodine concentration (UIC), 1-methylhistidine (1-MH), and trimethylamine N-oxide (TMAO) have been associated with fish intake in observational studies, but data from children in randomized controlled trials are limited. Objectives: The objective of this exploratory analysis was to investigate the effects of fatty fish intake compared with meat intake on various biomarkers in preschool children. Methods: We randomly allocated (1:1) 232 children, aged 4 to 6 y, from 13 kindergartens. The children received lunch meals of either fatty fish (herring/mackerel) or meat (chicken/lamb/beef) 3 times a week for 16 wk. We analyzed 86 biomarkers in plasma (n = 207), serum (n = 195), RBCs (n = 211), urine (n = 200), and hair samples (n = 210). We measured the effects of the intervention on the normalized biomarker concentrations in linear mixed-effect regression models taking the clustering within the kindergartens into account. The results are presented as standardized effect sizes. Results: We found significant effects of the intervention on the following biomarkers: RBC EPA (20:5n-3), 0.61 (95% CI: 0.36, 0.86); DHA (22:6n-3), 0.43 (95% CI: 0.21, 0.66); total n-3 PUFAs, 0.41 (95% CI: 0.20, 0.64); n-3/n-6 ratio, 0.48 (95% CI: 0.24, 0.71); adrenic acid (22:4n-6, -0.65 (95% CI: -0.91, -0.40), arachidonic acid (20:4n-6), -0.54 (95% CI: -0.79, -0.28); total n-6 PUFAs, -0.31 (95% CI: -0.56, -0.06); UIC, 0.32 (95% CI: 0.052, 0.59); hair mercury, 0.83 (95% CI: 0.05, 1.05); and plasma 1-MH, -0.35 (95% CI: -0.61, -0.094). Conclusions: Of the 86 biomarkers, the strongest effect of fatty fish intake was on n-3 PUFAs, UIC, hair mercury, and plasma 1-MH. We observed no or limited effects on biomarkers related to micronutrient status, inflammation, or essential amino acid, choline oxidation, and tryptophan pathways.The trial was registered at clinicaltrials.gov (NCT02331667). Keywords: 1-methylhistidine; biomarkers; fatty fish; mercury; omega-3; polyunsaturated fatty acids; preschool children; targeted metabolomics. © The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.

Background: Mild-to-moderate iodine deficiency is still present in many countries, particularly in pregnant women. Observational studies suggest that mild-to-moderate iodine deficiency during pregnancy may be associated with impaired thyroid function and child neurodevelopment. Randomized-controlled food trials to increase iodine status are scarce. We assessed the impact of an increased intake of cod during pregnancy on maternal iodine status and infant neurodevelopment. Methods: In this randomized-controlled trial, pregnant women in Bergen, Norway, recruited through Haukeland University Hospital, were randomly assigned (1:1) to an intervention of 200 g of cod twice a week for 16 weeks (gestational week 20–36) or to continue with their standard diet (control group). Randomization was done by lottery. Primary outcome was urinary iodine concentration (UIC) (spot samples from six consecutive days) measured postintervention. Secondary outcome was infant neurodevelopment assessed by the cognitive, language, and motor scales of the Bayley Scales of Infant and Toddler Developmental third edition (Bayley-III) at 11 months of age. In addition, maternal thyroid function was measured (thyrotropin [TSH], free triiodothyronine [fT3], free thyroxine [fT4]) at baseline and postintervention. Results: Between January 2016 until February 2017, 137 women were recruited. Postintervention UIC was higher in the intervention group (n = 61) [median (interquartile range, IQR) 98 (64–145) μg/L], compared with control (n = 61) [median (IQR) 73 (52–120) μg/L] (p = 0.028), also after adjusting for baseline UIC (p = 0.048). Infants of mothers in the intervention group had a lower cognitive composite score on the Bayley-III compared with the control group (p = 0.045). There were no group differences in the Bayley III language- or motor composite scores. Maternal thyroid hormones (TSH, fT3, fT4) did not differ between the groups postintervention. Conclusions: Increased cod intake during pregnancy improved the iodine status in women with mild-to-moderate iodine deficiency, however, did not affect thyroid function. The negative effect on cognition should be followed up to assess whether this is a stable effect over time. More studies are warranted to enable good health advice on iodine nutrition in pregnancy. ClinicalTrials.gov NCT02610959. Registered November 20, 2015.

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.

Background Maternal seafood intake during pregnancy is associated with child neurodevelopment. No randomized controlled trials (RCTs) have examined the effect of maternal lean fish consumption during pregnancy on child neurodevelopment. Objectives The objective of the study was to examine the effect of increased maternal cod intake during pregnancy on infant general and socio-emotional development in the first year of life, and whether any effects observed were mediated by maternal iodine status. Methods In an RCT, 133 pregnant women (≤19 weeks of gestation) were randomly assigned to receive 200 g cod fillet twice weekly (intervention) or to continue with their habitual diet (control) for 16 wk. The mothers completed the developmental screening questionnaires Ages and Stages Questionnaire, 2nd edition (ASQ-2) and Ages and Stages Questionnaire: Social-Emotional (ASQ:SE) when the infants were 3, 6, and 11 mo old. We compared scores between groups using linear mixed-effects models and examined whether iodine status postintervention mediated the effect on child development. Results We found no difference between infants in the intervention and control groups on total ASQ-2 scores (P = 0.633), but a difference on the ASQ:SE scores in favor of the intervention group (20.9 and 20.5 in the intervention group and 26.1 and 26.8 in the control group for 3 and 6 mo, respectively; P = 0.020). There was no difference in change of the scores between the groups over time (P = 0.946). The effect of group on the total ASQ:SE scores was not mediated via maternal urinary iodine concentration postintervention (β = -1.03, SE = 0.68, P = 0.126). Conclusions Our results provide no evidence for an effect of increased cod intake during pregnancy on general child development in the first year of life, but there was a positive effect on socio-emotional problems. More studies are needed to define the role of fish consumption during pregnancy and the effects on child neurodevelopment.This trial was registered at clinicaltrials.gov as NCT02610959.

BACKGROUND One-carbon metabolism (OCM) refers to the transfer of methyl groups central to DNA methylation and histone modification. Insufficient access to methyl donors and B-vitamin cofactors affects epigenetic maintenance and stability, and when occurring in early life may impact future health and neurodevelopment. OBJECTIVE The objective of this study was to examine the relative associations between one-carbon metabolites in Nepalese mother-infant pairs and child cognition measured at 5 y of age. METHODS This is a cross-sectional study from Bhaktapur, Nepal, in a population at high risk of subclinical B-vitamin deficiencies and cumulative infection burden. Venous blood samples from 500 mother-infant pairs were collected when the infants were 2 to 12 mo old, and metabolite concentrations measured by microbiological assays and GC-tandem MS. We re-enrolled 321 of these children at 5 y and assessed cognition by the Ages and Stages Questionnaire, 3rd edition, and subtests from the Developmental Neuropsychological Assessment, 2nd edition (NEPSY-II). The associations of the independent metabolites or unobserved metabolic phenotypes (identified by latent class analysis) with the cognitive outcomes were estimated by seemingly unrelated regression. We explored direct and indirect relations between the OCM pathway and the cognitive outcomes using path analysis. RESULTS Infant cystathionine concentration was inversely associated with 4 cognitive outcomes (standardized βs ranging from -0.22 to -0.11, P values from

Objectives: To assess the extent to which linear growth beyond the early years of life determines later cognitive development. Study design: We revisited children from New Delhi, India, who had participated in a randomized controlled trial 6 years before and assessed neurodevelopment using standardized and validated psychometric tools (Wechsler Intelligence Scale for Children, 4th edition; Crichton Vocabulary Scales; and Neuropsychological test battery). The associations of change in height for age z scores between early (12-36 months) and late (6-9 years) childhood with cognitive outcomes at 6-9 years of age were explored using linear regression models, after adjustment for appropriate confounders. Results: Out of the 1000 North Indian children who were enrolled in the original study, 791 consented to participate in this follow-up. Height for age z scores in the first 2 years of life was significantly associated with both the Wechsler Intelligence Scale for Children-Crichton Vocabulary Scales (standardized β coefficient [β], 0.15; 95% CI, 0.08-0.23), and the Neuropsychological test battery-II z-score (β, 0.09; 95% CI, 0.03-0.18) at 6-9 years of age. There were no significant associations between change in height for age z scores between early and later childhood and Wechsler Intelligence Scale for Children-Crichton Vocabulary Scales (β, -0.03; 95% CI, -0.11 to 0.04) or Neuropsychological test battery-II z-scores (β, -0.04; 95% CI, -0.12 to 0.06). Conclusions: Linear growth between early and late childhood is not associated with later cognitive outcomes. Our findings support the current practice of investing public health efforts to accelerate linear growth in the first 2-3 years of life. Keywords: India; cognition; early childhood; linear growth; middle childhood. publishedVersion publishedVersion

BACKGROUND AND OBJECTIVES: Vitamin B12 and folate are important for normal brain development. Our objective for this study was to measure the effects of 6-month supplementation of vitamin B12 and/or folic acid in early childhood on cognition when the children were 6 to 9 years old. METHODS: The study is a follow-up of a factorial randomized, double-blind, placebo-controlled trial in 1000 North Indian children. Children 6 to 30 months of age were randomly assigned to receive a placebo or 1.8 µg of vitamin B12, 150 mg of folic acid, or both daily for 6 months. After 6 years, we re-enrolled 791 of these children for cognitive assessments. We compared the scores of the main outcomes (the Wechsler Intelligence Scale for Children, Fourth Edition [India], the Crichton Verbal Scale, and subtests of the NEPSY-II) between the study groups. We also measured the associations between markers of the B vitamins (plasma cobalamin, folate, and total homocysteine concentrations) in early childhood and the cognitive outcomes. RESULTS: There were no differences between the intervention groups and the placebo group on the cognitive outcomes. Plasma cobalamin, folate, and total homocysteine concentrations in early childhood were associated with the cognitive outcomes at follow-up in the unadjusted models. These associations disappeared in models adjusted for relevant confounders. CONCLUSIONS: Our findings, from both an observational and a randomized design suggest that vitamin B12 and folate in children 6 to 36 months have limited public health relevance for long-term cognition.

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

Purpose. Iodine is an essential trace element necessary for thyroid hormone synthesis. Iodine deficiency is a continuing public health problem despite international efforts to eliminate it. Studies on iodine status in preschoolers are scarce. Thus, the aims of the current study were to determine the iodine status and to investigate possible associations between urinary iodine concentration (UIC) and estimated 24 h iodine extraction (UIE) and iodine-rich foods. Methods. Data are cross-sectional baseline data, obtained from the two-armed randomized controlled dietary trial “Fish Intervention Studies-KIDS” (FINS-KIDS) conducted in Bergen, Norway. UIC was determined by inductively coupled plasma-mass spectrometry in spot urine samples. Inadequate UIC was defined as median

BACKGROUND: Many children worldwide have poor vitamin B12 status. The objective of this study was to estimate association between maternal and infant vitamin B12 status and long-term growth. METHODS: We randomly selected 500 Nepali mother-infant pairs and measured maternal intake and infant and maternal vitamin B12 status using plasma cobalamin, total plasma homocysteine, and methylmalonic acid concentrations. We revisited available children when they were 5 years old and measured growth. The associations between intake and maternal and infant markers of vitamin B12 and growth were estimated in multiple linear regression models adjusting for relevant confounders (n = 331). RESULTS: Maternal vitamin B12 intake and status and vitamin B12 status in infancy predicted linear growth at 5 years of age, but not during infancy. Each microgram increase in the vitamin B12 intake of the mother during infancy was associated with an increase in height of 0.4 (0.2, 0.6) height-for-age z-scores and 1.7 (0.7, 2.7) cm around the child's fifth birthday. CONCLUSION: Vitamin B12 status and intake in early life is an important determinant for linear growth at school age. Our findings should be verified in randomized, placebo controlled trials before translated into public health recommendations. We are grateful for the contributions of the field supervisor Chandrawati Chitrakar and data managers Pravin Rajbhandari and Uma Regmi, and the children and mothers for their invaluable contribution to the study. The present study was funded through grants from the Research Council of Norway (project no. 234495), from the GCRieber Funds, and the South-Eastern Norway Regional Health Authority (grant no. 2012090).

Objectives: To investigate the association between gestational age, birthweight, and birthweight adjusted for gestational age, with domains of neurocognitive development and behavioral problems in adolescents in Tanzania. Study design: Data from a long-term follow-up of adolescents aged 11-15 years born to women previously enrolled in a randomized controlled trial of prenatal multiple micronutrient supplementation in Dar es Salaam, Tanzania, were used. A battery of neurodevelopmental tests were administered to measure adolescent general intelligence, executive function, and behavioral problems. The INTERGROWTH-21st newborn anthropometric standards were used to derive birthweight for gestational age z-scores. We assessed the shape of relationships using restricted cubic splines and estimated the associations of gestational age, birthweight, and birthweight for gestational age z-score with adolescent development using multivariable linear regressions. Results: Among adolescents studied (n = 421), higher gestational age (per week), birthweight (per 100 grams), and birthweight for gestational age z-score (per SD) were linearly associated with higher intelligence score (adjusted standardized mean difference, 0.05 SD [95% CI, 0.01-0.09], 0.04 SD [95% CI, 0.02-0.06], and 0.09 SD [95% CI, 0.01-0.17], respectively). Birthweight and birthweight for gestational age z-score, but not gestational age, were also associated with improved executive function. Low birthweight (

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. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1937-0) contains supplementary material, which is available to authorized users.

Background: Folate and cobalamin (vitamin B-12) are essential for growth and development. However, few populationbased studies have investigated B-vitamin status in children. Objectives: This study aimed to assess biomarkers of folate and vitamin B-12 status and to explore their dietary determinants in healthy Norwegian children. Methods: Using baseline data obtained from a randomized controlled trial on the effect of fish intake on neurodevelopment in children aged 4–6 y, we measured the plasma concentrations of folate, cobalamin, total plasma homocysteine (tHcy), and methylmalonic acid (MMA). Food-frequency questionnaires (FFQs) were used to assess dietary intake. We used unadjusted and multiple linear regression models to explore the determinants of biomarker concentrations. Results: The median (IQR) of plasma folate (n = 197) and plasma cobalamin (n = 195) concentrations were 15.2 (12.2– 21.1) nmol/L and 785 (632–905) pmol/L, respectively. Plasma folate concentrations of 0.26 μmol/L) and 8 children had elevated tHcy concentrations (>6.5 μmol/L). Plasma folate concentration was inversely correlated with tHcy (ρ = −0.24, P < 0.001); we found no correlation between tHcy and cobalamin (ρ = −0.075, P = 0.30). Children who consumed vitamin supplements had 51% higher plasma folate concentrations (P < 0.0001) than those who did not. Consumption of red meat for dinner more than twice a week was associated with 23% lower plasma folate (P < 0.01). No other significant associations between dietary intake and the biomarkers were observed. Conclusions: The Norwegian preschool children from this cohort had adequate vitamin B-12 status. Poor folate status was common and associated with elevated tHcy. The implications of poor folate status during childhood should be a prioritized research question. This trial was registered at ClinicalTrials.gov as NCT02331667. J Nutr 2020;150:1852–1858. publishedVersion

Background Vitamin 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 findings This 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. Conclusions In 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 registration ClinicalTrials.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)., Tor A. Strand and colleagues measure the effects of daily supplementation of vitamin B12 for one year on neurodevelopment, growth, and hemoglobin concentration in infants at risk of deficiency., Author summary Why was this study done? Many marginalized children fail to reach their cognitive and growth potential. Subclinical vitamin B12 deficiency, which is poor vitamin B12 status without overt clinical symptoms, is common in this population in Nepal. Vitamin B12 deficiency in children is associated with anemia (low hemoglobin concentration), stunted growth, and poor neurodevelopment. What did the researchers do and find? In this population-based, double-blind, randomized controlled trial (RCT), we measured the effects of daily supplementation of vitamin B12 for 1 year in 600 infants. The primary outcomes were neurodevelopment, growth, and hemoglobin concentration. We targeted stunted infants as these children are at risk of vitamin B12 deficiency. Daily supplementation of vitamin B12 for a year resulted in a metabolic profile reflecting substantially improved B12 status (lower total homocysteine (tHcy) and methylmalonic acid (MMA) concentrations) but did not affect neurodevelopment, growth, or hemoglobin concentration. What do these findings mean? In spite of the improved metabolic profile following vitamin B12 supplementation, the findings do not support widespread vitamin B12 supplementation to improve short-term growth, neurodevelopment, or hemoglobin concentration in infants.

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.

ObjectiveTo determine the magnitude of relationships of early life factors with child development in low/middle-income countries (LMICs).DesignMeta-analyses of standardised mean differences (SMDs) estimated from published and unpublished data.Data sourcesWe 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 studiesStudies 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.AnalysesLinear 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.ResultsWe 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.ConclusionsDifferential 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.

IntroductionPreterm 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 analysisDesign: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 disseminationThe 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 numberNCT03564184

Poverty adversely affects child development through multiple pathways in low- and middle-income countries. Relationships between diet and child development are poorly understood. In this study, we aimed to explore these associations in a longitudinal cohort of 305 children in rural Nepal (baseline mean age 14 months), evaluating dietary diversity and the consumption of specific food groups at three timepoints over 1.5 years. Child development was assessed using the Ages and Stages questionnaire-version 3 (ASQ-3). Associations between the number of days that children consumed minimum dietary diversity (MDD) (&ge, 4/8 items) and specific food groups over time (range 0&ndash, 3) and total and subscale ASQ scores at age 23&ndash, 38 months were estimated using multiple linear and logistic regression, dichotomizing scores at the lowest quartile. After adjusting for confounders, each additional day of consuming MDD was associated with a 35% reduction in the odds of low total ASQ score [OR 0.65, 95% CI (0.46, 0.92)]. The consumption of animal source foods [OR 0.64, (0.46, 0.89)], and vegetables/fruits [OR 0.60, (0.41, 0.90), but not processed foods [OR 0.99, (0.62, 1.59)] was associated with lower odds of low total development. Vegetables, fruits and animal source foods may be important for child development in this setting.

Objectives The aims of this study were to determine vitamin D status (serum 25-hydroxyvitamin D3 [s-25(OH)D3]) and examine possible associations between vitamin D status and vitamin D–rich dietary sources, sun exposure, and body mass index in preschool children ages 4 to 6 y. Methods This is a cross-sectional study based on baseline data (collected in January-February 2015) from the two-armed randomized controlled trial Fish Intervention Studies-KIDS (FINS-KIDS) conducted in Bergen, Norway. S-25(OH)D3 concentration was determined by liquid chromatography–tandem mass spectrometry. Information regarding habitual dietary intake, recent sun vacations, and body mass index were assessed with questionnaires answered by the children's caregivers. Results The children (n = 212) had a mean (standard deviation) s-25(OH)D3 of 60.7 (13.8) nmol/L; 18.9% had s-25(OH)D3 ≤50 nmol/L. In logistic regression models, non-overweight versus overweight status was inversely associated with s-25(OH)D3 ≤50 nmol/L (odds ratio: 0.41; 95% confidence interval, 0.18–0.95; P = 0.037). Non-sun versus sun vacations were associated with s-25(OH)D3 ≤75 nmol/L (odds ratio: 5.33; 95% confidence interval, 1.93–14.77; P = 0.001). Conclusions The majority of the preschool children (81%) had s-25(OH)D3 >50 nmol/L. Children with overweight status had an increased risk of s-25(OH)D3 ≤50 nmol/L, and children who had not been on sun vacations were at a greater risk of s-25(OH)D3 ≤75 nmol/L.

Background: Many 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. Aim: In 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. Methods: 600 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. Results: There 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. Conclusion: This 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. publishedVersion

Background: The Ages and Stages Questionnaire Third Edition (ASQ-3) may be a feasible and cost-effective tool to screen children's development in resource poor settings. We have assessed the feasibility of the ASQ-3 "home procedure" when conducted by fieldworkers in a community-based nutritional interventional trial on early child development in Nepal. Method: Six hundred children aged 6-11 months at risk of stunting were assessed by trained fieldworkers in their homes by the ASQ-3. Three fieldworkers performed standardization exercises and were double scored with a gold standard during the study period. Intraclass correlations (ICCs) were calculated to measure the interrater agreement. The internal consistency was expressed by standardized Cronbach's alphas. The association between total ASQ score and gestation, low birth weight, and stunted children is presented to give an estimate of the construct validity of the tool. Result: Mean scores of the 600 Nepalese children were consistently lower than in the American norm sample. The ICCs from the standardization exercises were initially good to excellent but declined throughout the study period. The standardized alphas for the total score in the different age groups indicate good internal consistency but varied in the subscales. Children who were preterm, children with low birth weight, and children who were stunted scored substantially lower on the total ASQ score than those who were not. Conclusion: Although the ASQ-3 "home procedure" is low at cost and easily accessible in a Nepalese context, the tool requires rigorous and stringent training to achieve acceptable interrater agreement. Further adjustment is required to achieve satisfactory internal consistency. GC Rieber Funds Thrasher Research Fund. Grant Number: 11512

BACKGROUND: There is growing evidence that nutritional interventions in the first 1000 days of life may influence long-term health and development outcomes. Few studies have examined the effect of maternal and infant micronutrient supplementation on development outcomes in sub-Saharan Africa. METHODS: We conducted a follow-up study of two randomized trials of antenatal and infant micronutrient supplementation conducted in Dar es Salaam, Tanzania. We assessed the effect of maternal multiple micronutrient (MMN) supplementation in pregnancy on development of children at 11-14 years of age. We also examined the effect of infant zinc and MMN supplementation on development at 6-8 years of age. We used generalized linear models to assess standardized mean differences (SMDs) in general intelligence, executive function, and mental health scores. RESULTS: We followed up 446 children whose mothers were enrolled in the maternal MMN supplementation trial and 365 children who were enrolled in the infant zinc and MMN supplementation trial. We found no effect of maternal MMN supplementation on general intelligence (SMD: -0.03; 95% CI: -0.15, 0.09), executive function (SMD: 0.00; 95% CI: -0.11, 0.11), and mental health scores (SMD: 0.06; 95% CI: 10.10, 0.22). We also found no effect of either infant zinc or MMN supplementation on any of the three development domains (p-values > 0.05). CONCLUSIONS: We found that antenatal MMN supplementation and infant zinc and MMN supplementation did not have a large effect on development outcomes in middle childhood and early adolescence in Tanzania. The development follow-up study was funded by the Norwegian Research Council Grant number 234495. The parent randomized trials were funded by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) (R01 37701 and R01 HD048969–01). CPD was supported by K24DK104676 and P30 DK040561.

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.

Cobalamin and folate are crucial micronutrients during infancy and they are required for growth and cognitive development. Due to the monotonous and predominantly vegetarian-based complementary feeding and poor maternal micronutrient status, infants from low- and middle-income countries are susceptible to cobalamin deficiency. However, data on plasma cobalamin and folate and the functional markers methylmalonic acid and total homocysteine from breastfed infants in Nepal are still needed. We collected plasma samples from 316 6–11-month-old breastfed infants with a length-for-age of less than minus one z-score and analyzed blood for plasma folate, cobalamin, methylmalonic acid and total homocysteine concentrations. Cobalamin deficiency (plasma cobalamin 10 µmol/L) and methylmalonic acid (>0.28 µmol/L) indicating functional cobalamin deficiency were found among 53% and 75% of the infants, respectively. Based on a combined indicator of cobalamin status, 58% were found to have low cobalamin status. However, folate deficiency (

IntroductionAs many as 250 million children under the age of 5 may not be reaching their full developmental potential partly due to poor nutrition during pregnancy and the first 2 years of life. Micronutrients, including vitamin B12, are important for the development of brain structure and function; however, the timing, duration and severity of deficiencies may alter the impact on functional development outcomes. Consequently, to fully explore the effect of vitamin B12on cognitive function, it is crucial to measure neurodevelopment at different ages, in different populations and with vitamin B12supplementation at different times during the critical periods of neurodevelopment.Methods and analysisIn this project, we follow up children from four recently completed randomised placebo-controlled trials of oral vitamin B12supplementation, two in India and two in Tanzania, to explore the long-term effects on neurodevelopmental outcomes and growth. All the included trials provided at least two recommended dietary allowances of oral vitamin B12daily for at least 6 months. Vitamin B12was supplemented either during pregnancy, early infancy or early childhood. Primary outcomes are neurodevelopmental status, cognitive function and growth later in childhood. We apply validated and culturally appropriate instruments to identify relevant developmental outcomes. All statistical analyses will be done according to intention-to-treat principles. The project provides an excellent opportunity to examine the effect of vitamin B12supplementation in different periods during early life and measure the outcomes later in childhood.Ethics and disseminationThe study has received ethical approvals from all relevant authorities in Norway, USA, Tanzania and India and complies fully with ethical principles for medical research. Results will be presented at national and international research and policy meetings and published in peer-reviewed scientific journals, preferably open access.Trial registration numberNCT00641862 (Bangalore);NCT00717730, updated CTRI/2016/11/007494 (Delhi);NCT00197548andNCT00421668(Dar es Salaam).

Mental health and sleep problems are prevalent in children during preschool years. The aim of the current study was to investigate if increased intake of fatty fish compared with meat improves mental health and sleep in four- to six-year-old children. The children (n = 232) in the two-armed randomized controlled trial, Fish Intervention Studies-KIDS (FINS-KIDS), 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 in grams (dietary compliance). Mental health problems were assessed by the strengths and difficulties questionnaire (SDQ) and sleep by parent report pre- and post-intervention. There was no significant statistical difference between changes in mental health and sleep for the fish eating group compared with the meat eating group, neither in the crude analysis nor after adjusting for intake of fish or meat (dietary compliance). publishedVersion

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. Electronic supplementary material The online version of this article (10.1186/s12916-018-1020-z) contains supplementary material, which is available to authorized users.

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. 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. 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. This study is registered in ClinicalTrials.gov ( NCT02610959 ). Registered November 17, 2015.

OBJECTIVES: The extent to which vitamin-D deficiency (

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 (

INTRODUCTION: Vitamin B12 is crucial for normal cell division and differentiation, and necessary for the development and myelination of the central nervous system. Pregnant mothers in resource poor settings are at risk for poor vitamin B12 status. Poor vitamin B12 status in infancy is linked to poor growth and neurodevelopment. Brain development starts from conception, and pregnancy is a period of rapid growth and development for the brain. METHODS AND ANALYSIS: The study is an individually randomised double-blind placebo controlled trial in 800 pregnant Nepalese women randomised in a 1:1 ratio. A daily dose of 50 µg of vitamin B12 or placebo is given to women from early pregnancy, not later than week 15, until 6 months after birth. Weekly visits are conducted in order to record compliance, growth and morbidity. The primary outcomes are scores on the cognitive, language and motor subscales of the Bayley Scales of Infant and Toddler Development, Third Edition, measured at 6 and 12 months of age, and growth (length and weight) measured at 6 and 12 months of age. ETHICS AND DISSEMINATION: National Health and Research Council, Nepal (NHRC 253/2016) and Regional Committee for Medical and Health Research Ethics of Western Norway (2016/1620/REK vest) have approved the study. Investigators who have contributed to the conceptualising, conducting, as well as being involved in the data analyses and manuscript writing will be eligible for authorship and be responsible to share outcomes with different stakeholders through publications and workshops. The results from this study may support new dietary guidelines for Nepalese and possibly South Asian pregnant women that can lead to improved pregnancy outcomes, neurodevelopment and cognitive functioning in children. TRIAL REGISTRATION NUMBER: Universal Trial Number: U1111-1183-4093. TRIAL REGISTRATION: clinicaltrials.gov: NCT03071666. Protocol date: version 1.2, 1 June 2017. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted. KEYWORDS: Cobalamin; Nepal; Pregnancy; Supplementation Funding This study has been granted funding from the Centre of Excellence Scheme and the University of Bergen (UiB), Norway to the Centre for Intervention Science in Maternal and Child Health (CISMAC; project number 223269).

Objective and background For large epidemiological studies in low and middle-income countries, inexpensive and easily administered developmental assessment tools are called for. This report evaluates the feasibility of the assessment tool Ages and Stages Questionnaire 3.edition (ASQ-3) “home procedure” in a field trial in 422 North Indian young children. Methods ASQ-3 was translated and adjusted for a North Indian Hindi setting. Three examiners were trained by a clinical psychologist to perform the assessments. During the main study, ten % of the assessments were done by two examiners to estimate inter-observer agreement. During all sessions, the examiners recorded whether the scoring was based on observation of the skill during the session, or on caregiver’s report of the child’s skill. Intra class correlation coefficient was calculated to estimate the agreement between the raters and between the raters and a gold standard. Pearson product moment correlation coefficient and standardized alphas were calculated to measure internal consistency. Principal findings Inter-observer agreement was strong both during training exercises and during the main study. In the Motor subscales and the Problem Solving subscale most items could be observed during the session. The standardized alphas for the total ASQ-3 scale across all ages were strong, while the alpha values for the different subscales and age levels varied. The correlations between the total score and the subscale scores were consistently strong, while the correlations between subscale scores were moderate. Conclusions/significance We found that the translated and adjusted ASQ-3 “home procedure” was a feasible procedure for the collection of reliable data on the developmental status in infants and young children. Examiners were effectively trained over a short period of time, and the total ASQ scores showed adequate variability. However, further adjustments are needed to obtain satisfying alpha values in all subscales, and to ensure variability in all items when transferred to a North Indian cultural context.