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Folate and vitamin B12 are essential for growth. Our objective was to estimate their long-term effects on linear growth in North Indian children. This is a follow-up study of a factorial designed, double-blind, randomised, placebo-controlled trial in 1000 young children. Starting at 6–30 months of age, we gave folic acid (approximately 2 RDA), vitamin B12 (approximately 2 RDA), both vitamins or a placebo daily for 6 months. Six years after the end of supplementation, we measured height in 791 children. We used the plasma concentrations of cobalamin, folate and total homocysteine to estimate vitamin status. The effect of the interventions, the association between height-for-age z-scores (HAZ) and baseline vitamin status, and the interactions between supplementation and baseline status were estimated in multiple regression models. Mean (sd) age at follow-up was 7·4 (0·7) years (range 6 to 9 years). There was a small, non-significant effect of vitamin B12 on linear growth and no effect of folic acid. We observed a subgroup effect of vitamin B12 supplementation in those with plasma cobalamin concentration < 200 pmol/l (Pfor interaction = 0·01). The effect of vitamin B12 supplementation in this group was 0·34 HAZ (95 % CI 0·11, 0·58). We found an association between cobalamin status and HAZ in children not given vitamin B12 (Pfor interaction = 0·001). In this group, each doubling of the cobalamin concentration was associated with 0·26 (95 % CI 0·15, 0·38) higher HAZ. Suboptimal vitamin B12 status in early childhood seemingly limits linear growth in North Indian children.

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

IntroductionVitamin 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 B12status and the status of other micronutrients in Norwegian infants, and (2) in a randomised controlled trial (RCT), investigate the effect of vitamin B12supplementation on neurodevelopment in infants with subclinical vitamin B12deficiency.Methods and analysisInfant 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 disseminationThe 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 B12deficiency during infancy and may inform future infant feeding recommendations.Trial registration numberNCT05005897.

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.

Background Biomass fuels are still in use for cooking by many households in resource poor countries such as Nepal and is a major source of household air pollution (HAP). Chronic exposure to HAP has been shown to be associated with shorter telomere length in adults. Objectives To measure the association between exposure related to household biomass fuel in infancy and leukocyte telomere length (LTL) at 18–23 months of age among 497 children from Bhaktapur, Nepal. Methods In a prospective cohort study design, we have collected information on household cooking fuel use and several clinical, anthropometric, demographic, and socioeconomic variables. We estimated the association between biomass fuel use and the relative LTL in multiple linear regression models. Results Most of the families (78%) reported liquified petroleum gas (LPG) as the primary cooking fuel, and 18.7% used biomass. The mean relative (SD) LTL was 1.03 (0.19). Children living in households using biomass fuel had on average 0.09 (95% CI: 0.05 to 0.13) units shorter LTL than children in households with no biomass fuel use. The observed association was unaltered after adjusting for relevant confounders. The association between LTL and biomass use was strongest among children from households with ≤2 rooms and without separate kitchen. Significance Exposure to biomass fuel use in early life might have consequences for longevity, and risk of chronic illnesses reflected in shortening of the telomeres. Our findings support the ongoing effort to reduce exposure to biomass fuel in low-resource settings. Impact statements Biomass for cooking is a leading source of household air pollution in low and middle-income countries, contributing to many chronic diseases and premature deaths. Chronic exposure to biomass fuel through oxidative stress and inflammation has been associated with a shortening of the telomeres, a “biological marker” of longevity. This prospective cohort study describes the association between household biomass fuel use and leukocyte telomere length among 497 toddlers. Leukocyte telomere length was significantly shorter among children living in households with biomass fuel than in children from homes where mainly LPG was used for cooking. Clinical Trial registration Clinicaltrials.gov: NCT02272842, registered October 21, 2014, Universal Trial Number: U1111-1161-5187 (September 8, 2014)

ImportanceParent-infant bonding contributes to long-term infant health but may be disrupted by preterm birth.ObjectiveTo determine if parent-led, infant-directed singing, supported by a music therapist and initiated in the neonatal intensive care unit (NICU), improves parent-infant bonding at 6 and 12 months.Design, Setting, and ParticipantsThis randomized clinical trial was conducted in level III and IV NICUs in 5 countries between 2018 and 2022. Eligible participants were preterm infants (under 35 weeks’ gestation) and their parents. Follow-up was conducted across 12 months (as part of the LongSTEP study) at home or in clinics. Final follow-up was conducted at 12 months’ infant-corrected age. Data were analyzed from August 2022 to November 2022.InterventionParticipants randomized to music therapy (MT) plus standard care or standard care alone during NICU admission, or to MT plus standard care or standard care alone postdischarge, using computer-generated randomization (ratio 1:1, block sizes of 2 or 4 varying randomly), stratified by site (51 allocated to MT NICU, 53 to MT postdischarge, 52 to both, and 50 to neither). MT consisted of parent-led, infant-directed singing tailored to infant responses and supported by a music therapist 3 times per week throughout hospitalization or 7 sessions across 6 months’ postdischarge.Main Outcome and MeasurePrimary outcome was mother-infant bonding at 6 months’ corrected age, measured by the Postpartum Bonding Questionnaire (PBQ), with follow-up at 12 months’ corrected age, and analyzed intention-to-treat as group differences.ResultsOf 206 enrolled infants with 206 mothers (mean [SD] age, 33 [6] years) and 194 fathers (mean [SD] age, 36 [6] years) randomized at discharge, 196 (95.1%) completed assessments at 6 months and were analyzed. Estimated group effects for PBQ at 6 months’ corrected age were 0.55 (95% CI, −2.20 to 3.30; P = .70) for MT in the NICU, 1.02 (95% CI, −1.72 to 3.76; P = .47) for MT postdischarge, and −0.20 (95% CI, −4.03 to 3.63; P = .92) for the interaction (12 months: MT in NICU, 0.17; 95% CI, −2.71 to 3.05; P = .91; MT postdischarge, 1.78; 95% CI, −1.13 to 4.70; P = .24; interaction, −1.68; 95% CI, −5.77 to 2.41; P = .42). There were no clinically important between-group differences for secondary variables.Conclusions and RelevanceIn this randomized clinical trial, parent-led, infant-directed singing did not have clinically important effects on mother-infant bonding, but was safe and well-accepted.Trial RegistrationClinicalTrials.gov Identifier: NCT03564184

OBJECTIVES To evaluate short-term effects of music therapy (MT) for premature infants and their caregivers on mother-infant bonding, parental anxiety, and maternal depression. METHODS Parallel, pragmatic, randomized controlled-trial conducted in 7 level III NICUs and 1 level IV NICU in 5 countries enrolling premature infants ( RESULTS From August 2018 to April 2020, 213 families were enrolled in the study, of whom 108 were randomly assigned to standard care and 105 to MT. Of the participants, 208 of 213 (98%) completed treatment and assessments. Participants in the MT group received a mean (SD) of 10 sessions (5.95), and 87 of 105 participants (83%) received the minimum of 6 sessions. The estimated group effect (95% confidence interval) for PBQ was −0.61 (−1.82 to 0.59). No significant differences between groups were found (P = .32). No significant effects for secondary outcomes or subgroups were found. CONCLUSIONS Parent-led, infant-directed singing supported by a music therapist resulted in no significant differences between groups in mother-infant bonding, parental anxiety, or maternal depression at discharge.

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.

Aims: To describe the mental health of unaccompanied refugee minors (URMs) settled in Norway and compare their responses to an age- and sex-matched sample of Norwegian young people. Methods: The data were from the Pathways to Independence study of URMs aged 15–20 years (n = 81; 82.7% male; response rate 80%) conducted in 2018–2019 in the Bergen municipality, Norway. The data from the URMs were linked to an age- and sex-matched group of young people from the Norwegian youth@hordaland study conducted in 2012 (n = 324). Mental health was assessed by the Strengths and Difficulties Questionnaire (SDQ). Results: URMs were more likely to agree with most items pertaining to emotional problems, peer problems and prosocial subscales than Norwegian young people. Few differences were found for items on the conduct problems and hyperactivity-inattention problems scales. Poor psychometric properties, including weak factor loadings and low internal consistency, were detected for the SDQ subscales among URMs, except for the emotional problems subscale, indicating that the originally proposed five-factor model fitted the data poorly. Conclusions: URMs appear to have moderately more emotional problems than Norwegian young people. They are more likely to report being alone, getting along better with adults than with their peers and being bullied, but also report being more helpful and sharing with others. Studies with larger samples of URMs should determine the most appropriate factor structure of the SDQ when administered to URM samples. publishedVersion

The most critical period for brain development is before a child’s second birthday. Standardised tests measuring neurodevelopment are more reliable when administered after this period. Severe vitamin B12 deficiency affects brain development and function. In a randomised, double-blind, placebo-controlled trial in 600 Nepalese infants (6–11 months at enrolment), we found no effect of 2 µg vitamin B12 daily for a year on neurodevelopment. The primary objective of the current study was to measure the effect of the intervention on the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-IV) full scale intelligence quotient (FSIQ). We measured the effect on the Bayley Scales of Infant and Toddler Development 3rd edition at age 30–35 months (n 555). At age 42–47 months (n 533), we used the WPPSI-IV and subtests from the Neuropsychological Assessment, 2nd edition (NEPSY-II). We also used the FSIQ to estimate subgroup specific effects. The mean (sd) WPPSI-IV FSIQ in the vitamin B12 group was 84·4 (8·4) and 85·0 (8·6) in the placebo group (mean difference −0·5 (95 % CI -1·97, 0·94), P = 0·48). There were no effect of the vitamin B12 on any of the other neurodevelopmental outcomes and no beneficial effect in any of the subgroups. In conclusion, providing 2 µg of vitamin B12 for a year in infants at risk of vitamin B12 deficiency does not improve preschool cognitive function.

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 Biomass fuel use for cooking is widespread in low to middle income countries. Studies on the association between biomass fuel use and cognitive abilities in children are limited. Objective To examine the association between biomass fuel use for cooking and cognitive abilities in Nepalese children at 4 years of age. Methods In a cohort design we have information on biomass fuel use in the households of 533 children in infancy and cognitive abilities when they were 4 years old from a community-based sample. Cognitive abilities were measured by the Wechsler Preschool and Primary Scale of Intelligence, 4th edition (WPPSI-IV) and the NEPSY-II. We examined the associations between biomass fuel use and scores on the WPPSI-IV Full-Scale IQ (FSIQ) (primary outcome), and WPPSI index and NEPSY-II subtest scores in multiple linear regression models. The associations were also examined in predefined subgroups. Results Ninety-nine (18.6%) of the families used biomass fuel for cooking. Children in these families had lower mean FSIQ than children in families with no biomass use (83.3 (95%CI 81.7, 85.0) vs. 85.3 (95%CI 84.5, 86.0)), with a mean difference of −2.2 (95%CI -3.9, −0.5) adjusting for demographics and socio-economic status. The association between biomass fuel use and cognitive abilities was strongest in subgroups of children from households with more than three rooms, with separate kitchen and bedroom, and with higher wealth-score. These interactions were significant for number of rooms in the home (p = 0.04), if the household had separate bedroom and kitchen (p = 0.05), and for the wealth-score (p = 0.03). Conclusion Biomass fuel use for cooking in Nepalese families was associated with lower overall cognitive abilities at 4 years. Uncertainties include exposure misclassification and unmeasured confounding. The associations between biomass fuel use and neurodevelopment in children needs further investigation with more precise measurements of the exposure. publishedVersion

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. publishedVersion

Building knowledge on how child welfare services (CWS) should tailor services for unaccompanied refugee minors (URMs) is important. URMs and youth in foster care are high-risk groups taken care of by the CWS in Norway. Little is known on whether knowledge gained from youth in foster care can inform services for URMs, and if these groups are comparable in terms of experiences of potential traumatic events (PTEs) and post-traumatic stress disorder (PTSD) symptom load. Eighty-one URMs reported PTEs and PTSD-symptoms using an adapted version of the Child and Adolescent Trauma Screen (CATS). Responses were described and compared with a sample of 303 youth in foster care in linear regression models. We present relative risks (RR) and standardized mean differences (SMD) for the PTEs and the PTSD subscale and total score between the groups in forest plots. URMs had experienced a mean (standard deviation) of 6.4 (3.4) PTEs and 43.9% reported to have PTSD-symptoms at or above the clinical cut off. Compared to the foster youth, URMs reported more exposures of interpersonal violence outside of the family (RRs ranging from 66.4 [95%CI 18.1; 243.5) to 1.3 (1.0, 1.5)], and more PTSD-symptoms in the re-experiencing subscale [SMD = 0.3 (95% CI 0.1, 0.6)]. The frequency and types of PTEs and the PTSD-symptom load and profile among URMs and youth in foster care differed. Findings underscore the importance of qualified and targeted care for URMs, and that this care should differ to that of other high-risk groups in the CWS.

Background Vitamin B12 deficiency is common worldwide and has been associated with poor sleep. The effect of vitamin B12 supplementation on sleep in infants is not known. Aims To measure the effect of daily supplementation of vitamin B12 for one year on sleep in infants at risk of deficiency. Methods This was an individually randomized double-blind placebo-controlled trial in 600 infants in low-to middle-income neighborhoods in Bhaktapur, Nepal of daily supplementation of vitamin B12 for one year. Infants were included if they were 6–11 month year-old and with a length-for-age less than one z-score. Sleep was a predefined, secondary outcome, and was measured by actigraphy including sleep duration at night and total sleep duration (day and night), sleep onset latency (SOL), and wake after sleep onset (WASO). The effect of vitamin B12 on sleep was additionally assessed in predefined subgroups defined by stunting, underweight, vitamin B12 status, low birthweight, anemia and exclusive breastfeeding for 3 months. Results There was no effect of vitamin B12 supplementation on sleep duration at night, total sleep duration, or WASO. There was a small significant negative effect for SOL. None of the included subgroup analyses revealed effect modification on any of the sleep outcomes. Conclusion Overall, vitamin B12 supplementation did not have an effect on sleep in infants or for high-risk subgroups, with the exception of a small negative effect for SOL. The present study does not support vitamin B12 supplementation to improve sleep in infants. publishedVersion

Building knowledge on how child welfare services (CWS) should tailor services for unaccompanied refugee minors (URMs) is important. URMs and youth in foster care are high-risk groups taken care of by the CWS in Norway. Little is known on whether knowledge gained from youth in foster care can inform services for URMs, and if these groups are comparable in terms of experiences of potential traumatic events (PTEs) and post-traumatic stress disorder (PTSD) symptom load. Eighty-one URMs reported PTEs and PTSD-symptoms using an adapted version of the Child and Adolescent Trauma Screen (CATS). Responses were described and compared with a sample of 303 youth in foster care in linear regression models. We present relative risks (RR) and standardized mean differences (SMD) for the PTEs and the PTSD subscale and total score between the groups in forest plots. URMs had experienced a mean (standard deviation) of 6.4 (3.4) PTEs and 43.9% reported to have PTSD-symptoms at or above the clinical cut off. Compared to the foster youth, URMs reported more exposures of interpersonal violence outside of the family (RRs ranging from 66.4 [95%CI 18.1; 243.5) to 1.3 (1.0, 1.5)], and more PTSD-symptoms in the re-experiencing subscale [SMD = 0.3 (95% CI 0.1, 0.6)]. The frequency and types of PTEs and the PTSD-symptom load and profile among URMs and youth in foster care differed. Findings underscore the importance of qualified and targeted care for URMs, and that this care should differ to that of other high-risk groups in the CWS.

Introduction: Despite medical advances, preterm birth and neonatal intensive care (NICU) hospitalization are demanding and pose risks for infants and parents. Various music therapy (MT) models have suggested parental singing to promote healthy bonding and development in premature infants, but evidence on long-term effects is lacking. Method: We present the theoretical framework and intervention protocol of a resource-oriented MT approach for premature infants and their caregivers used in the international LongSTEP trial (ClinicalTrials.gov NCT03564184). We illustrate how guiding principles manifest in MT sessions, describe frames for phases of intervention, discuss prerequisites and present hypothesized mechanisms of change. Results: The LongSTEP MT approach is resource-oriented, emphasizes parental voice and parent-infant mutual regulation, builds on family-centered care principles, and is relevant in the NICU and beyond. Essential elements include: observation and dialogue on infant and parent needs; voice as the main musical source, with parental voice as the most prominent; active parental participation; modification of music in response to infant states and cues; and integration of the family’s culture and music preferences. The music therapist facilitates and supports interaction between parents and infant. Parents learn how to adapt principles in relation to infant development across NICU hospitalization and post-discharge phases. Discussion: The LongSTEP approach is feasible in culturally diverse countries where consistent parental presence is available, but requires tailoring to local circumstances and culture, particularly in the post-discharge phase. The emphasis on parent-led infant-directed singing places a higher demand on parents than other MT approaches, and requires sufficient psychosocial and musical support for parents. publishedVersion

Aims: The aim of the ‘Pathways to Independence’ study was to gain knowledge of how to facilitate a healthy development for unaccompanied refugee minors (URMs) after settling in Norwegian municipalities. Methods: The project is located in the URM child welfare services (URM CWS) of the Bergen municipality. We invited 101 URMs older than 15 years connected to the URM CWS to participate in a comprehensive survey. Of the invited, 81 consented to participate. The survey included questions on the user’s experiences and satisfaction with the URM CWS, and questions related to schooling, social support and activities after settlement. We also included standardized and validated questionnaires on potential traumatic events, mental and somatic health, protective factors and quality of life. These questionnaires have previously been used in two Norwegian epidemiological studies, the ‘Youth@Hordaland’ and ‘Young in Foster care’, facilitating comparison of the results with other youth populations in Norway. Conclusion: Results from the project will be valuable in the process of reaching knowledge-based recommendations for successful settlement of URMs.

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.

Parental knowledge on child development is important for maximal developmental potential. This study was conducted to assess mothers’ knowledge on child development in Nepal. The Caregivers Knowled...

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: 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. publishedVersion

Vitamin BThe 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 BThere 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.Our findings, from both an observational and a randomized design suggest that vitamin B

Background: Children 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. Objective: The present study aimed to identify determinants of cognitive, language and motor development in 6-11 months old Nepalese infants. Methods: Six hundred infants with a length-for-age z-score

Background: Sustained 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. Methods: We 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. Results: In 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. Conclusion: Our 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. Keywords: ADBB; Nepal; feasibility; infant; social withdrawal. Copyright © 2020 Ulak, Ranjitkar, Shrestha, Braarud, Chandyo, Shrestha, Guedeney, Strand and Kvestad. publishedVersion

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.

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. The study was funded by Thrasher Research Fund (Grant # 11512), Thrasher Early Career Award (Grant # 13988) and the GC Rieber Funds. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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: 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. This work has been supported by the Thrasher Research fund (award 11512) and GC Rieber funds.