The Effect of Vitamin B12 Supplementation on Leukocyte Telomere Length in Mildly Stunted Nepalese Children: A Secondary Outcome of a Randomized Controlled Trial.

BACKGROUND: Vitamin B12 is essential for deoxyribonucleic acid synthesis and genome stability. A deficiency of vitamin B12 is associated with telomere shortening, genomic aging, and increased risk of chronic disease and mortality. OBJECTIVES: The study aims to determine the effect of vitamin B12 supplementation on leukocyte telomere length (LTL) in infants at risk of vitamin B12 deficiency. METHODS: The study was a predefined secondary analysis of a randomized controlled trial enrolling 600 Nepalese infants aged 6 -11 mo, who were supplemented with 2 µg (2-3 recommended daily allowances) vitamin B12 or placebo daily for 1 y. At the end of the study, LTL was measured in 497 participants. Mean LTL was compared between the treatment arms in the full sample and predefined subgroups based on markers of vitamin B12 status, hemoglobin, sex, and growth indices. RESULTS: LTL at end-study did not differ between the vitamin B12 and placebo arm with a standardized mean difference (95% confidence interval) of 0.04 (-0.14, 0.21). There was no effect of vitamin B12 on LTL in any of the subgroups. CONCLUSIONS: Providing daily vitamin B12 for 1 y during infancy in a population at risk of vitamin B12 deficiency does not affect LTL. This trial was registered at clinicaltrials.gov as NCT02272842.

Vitamin B12 and Folate Status in Pregnant Females and Their Infants in Norway: Secondary Analysis from the Mommy's Food Study.

BACKGROUND: Vitamin B12 and folate are essential micronutrients important for normal infant growth and development. OBJECTIVES: The aims were to describe vitamin B12 and folate status in pregnant females and their infants according to commonly used status cutoffs and examine the associations between maternal status, maternal supplement use, and breastfeeding and infant status. METHODS: Pregnant females were recruited at 18 wk gestation in Bergen, Norway. Maternal vitamin B12 and folate status were measured at gestational weeks 18 (n = 136) and 36 (n = 116), and infant status was measured at ages 3 (n = 73) and 6 (n = 74) mo. RESULTS: At gestational weeks 18 and 36, respectively, 4.4% and 2.6% of the mothers had plasma cobalamin concentrations <148 pmol/L, 0.7% and 6.9% had methylmalonic acid (MMA) concentrations >0.26 µmol/L, and 3.7% and 30% had folate concentrations <10 nmol/L. None of the females had total homocysteine (t-Hcy) concentrations >13 µmol/L or 3 combined indicator of vitamin B12 (cB12) < -0.5. At 3 and 6 mo, respectively, 4.1% and 5.4% of the infants had cobalamin concentrations <148 pmol/L, 63% and 74% had t-Hcy concentrations >6.5 µmol/L, 59% and 66% had MMA concentrations >0.26 µmol/L, and 47% and 60% had cB12 > -0.5. None of the infants had folate concentrations <10 nmol/L. Several of the vitamin B12 biomarkers in infants were associated with maternal vitamin B12 status during pregnancy. Breastfed infants had lower vitamin B12 status (as indicated by plasma cobalamin, t-Hcy, and cB12) than nonbreastfed infants at both 3 and 6 mo. Use of supplements during pregnancy was associated with better vitamin B12 status among infants at 3 and 6 mo, as indicated by infants' cobalamin and t-Hcy concentrations. CONCLUSIONS: Subclinical vitamin B12 deficiency among infants was common and associated with maternal vitamin B12 status during pregnancy and breastfeeding. Among the mothers, an increase in biochemical folate deficiency was discovered toward the end of gestation. Further studies are needed to investigate clinical consequences. This trial was registered at clinicaltrials.gov as NCT02610959.

Effect of Music Therapy on Parent-Infant Bonding Among Infants Born Preterm: A Randomized Clinical Trial.

Importance: Parent-infant bonding contributes to long-term infant health but may be disrupted by preterm birth. Objective: To 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 Participants: This 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. Intervention: Participants 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 Measure: Primary 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. Results: Of 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 Relevance: In 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 Registration: ClinicalTrials.gov Identifier: NCT03564184.

The effect of vitamin B12 supplementation during pregnancy on infant growth and development in Nepal: a community-based, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Vitamin B12 is required for healthy infant growth and development, but low and marginal vitamin B12 status is endemic in low-income and middle-income countries. We aimed to measure the effect of vitamin B12 supplementation from early pregnancy until 6 months post partum on infant growth and neurodevelopment. METHODS: In this community-based, double-blind, placebo-controlled trial, we randomly assigned (1:1) 800 pregnant women (aged 20-40 years) who were up to 15 weeks pregnant-recruited from home visits and outpatient departments at three hospitals in Nepal-to daily supplementation with 50 µg oral vitamin B12 or placebo until 6 months postpartum. Independent scientists generated the list that linked allocation to participants' study identification number. Participants were masked to group assignment and all investigators were masked until data cleaning was completed. The primary outcomes were length-for-age Z score (LAZ) at age 12 months and the cognitive composite score of the Bayley Scales of Infant and Toddler Development (3rd edition) at age 6 months and 12 months. The primary and secondary outcomes, including adverse events, were assessed in the intention-to-treat population, for all participants with available outcome data. This trial is registered with ClinicalTrials.gov, NCT03071666. FINDINGS: 800 eligible pregnant women were enrolled in the trial between March 28, 2017, and Oct 15, 2020, with 400 women randomly assigned to each group. Follow-up was completed on May 18, 2022. At baseline, 569 (71%) of 800 women had plasma vitamin B12 indicating low or marginal status (<221 pmol/L). We found no effect of vitamin B12 on the primary outcomes. The mean LAZ at age 12 months were -0·57 (SD 1·03) in the B12 group and -0·55 (1.03) in the placebo group (366 infants in the vitamin B12 group vs 363 infants in the placebo group) with a mean difference of -0·02 (95% CI -0·16 to 0·13). The mean cognitive composite scores were 97·7 (SD 10·5) in the B12 group and 97·1 (10·2) in the placebo group, with a mean difference of 0·5 (95% CI -0·6 to 1·7) measured in 364 and 361 infants. Stillbirths or infant deaths occurred in three (1%) of 374 women in the vitamin B12 group and nine (2%) of 379 women in the placebo group. INTERPRETATION: Although vitamin B12 deficiency was prevalent in our study population and vitamin B12 supplementation from early pregnancy substantially improved vitamin B12 status, supplementation did not improve infant growth or neurodevelopment. Our findings support the current WHO recommendations of no routine vitamin B12 supplementation during pregnancy. FUNDING: Research Council of Norway.

Vitamin B12 status in infancy and the effect of a vitamin B12 injection in infants with subclinical vitamin B12 deficiency: study protocol for a register-based randomised controlled trial.

INTRODUCTION: Vitamin B12 (cobalamin) is crucial for optimal child development and growth, yet deficiency is common worldwide. The aim of this study is twofold; (1) to describe vitamin B12 status and the status of other micronutrients in Norwegian infants, and (2) in a randomised controlled trial (RCT), investigate the effect of vitamin B12 supplementation on neurodevelopment in infants with subclinical vitamin B12 deficiency. METHODS AND ANALYSIS: Infant blood samples, collected at public healthcare clinics, are analysed for plasma cobalamin levels. Infants with plasma cobalamin <148 pmol/L are immediately treated with hydroxocobalamin and excluded from the RCT. Remaining infants (cobalamin ≥148 pmol/L) are randomly assigned (in a 1:1 ratio) to either a screening or a control group. In the screening group, baseline samples are immediately analysed for total homocysteine (tHcy), while in the control group, the baseline samples will be analysed after 12 months. Screening group infants with plasma tHcy >6.5 µmol/L, are given an intramuscular injection of hydroxocobalamin (400 µg). The primary outcomes are cognitive, language and motor development assessed using the Bayley Scales of Infant and Toddler Development at 12 months of age. ETHICS AND DISSEMINATION: The study has been approved by the Regional Committee for Medical and Health Research Ethics (ref: 186505). Investigators who meet the Vancouver requirements will be eligible for authorship and be responsible for dissemination of study findings. Results will extend current knowledge on consequences of subclinical vitamin B12 deficiency during infancy and may inform future infant feeding recommendations. TRIAL REGISTRATION NUMBER: NCT05005897.

Treatment fidelity in a pragmatic clinical trial of music therapy for premature infants and their parents: the LongSTEP study.

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.

Daily Folic Acid and/or Vitamin B12 Supplementation Between 6 and 30 Months of Age and Cardiometabolic Risk Markers After 6-7 Years: A Follow-Up of a Randomized Controlled Trial.

BACKGROUND: Deficiencies of vitamin B12 and folate are associated with elevated concentrations of metabolic markers related to CVDs. OBJECTIVES: We investigated the effect of supplementation of vitamin B12 with or without folic acid for 6 mo in early childhood on cardiometabolic risk markers after 6-7 y. METHODS: This is a follow-up study of a 2 × 2 factorial, double-blind, randomized controlled trial of vitamin B12 and/or folic acid supplementation in 6-30-mo-old children. The supplement contained 1.8 µg of vitamin B12, 150 µg of folic acid, or both, constituting >1 AI or recommended daily allowances for a period of 6 mo. Enrolled children were contacted again after 6 y (September 2016-November 2017), and plasma concentrations of tHcy, leptin, high molecular weight adiponectin, and total adiponectin were measured (N = 791). RESULTS: At baseline, 32% of children had a deficiency of either vitamin B12 (<200 pmol/L) or folate (<7.5 nmol/L). Combined supplementation of vitamin B12 and folic acid resulted in 1.19 µmol/L (95% CI: 0.09; 2.30 µmol/L) lower tHcy concentration 6 y later compared to placebo. We also found that vitamin B12 supplementation was associated with a lower leptin-adiponectin ratio in subgroups based on their nutritional status. CONCLUSIONS: Supplementation with vitamin B12 and folic acid in early childhood was associated with a decrease in plasma tHcy concentrations after 6 y. The results of our study provide some evidence of persistent beneficial metabolic effects of vitamin B12 and folic acid supplementation in impoverished populations. The original trial was registered at www. CLINICALTRIALS: gov as NCT00717730, and the follow-up study at www.ctri.nic.in as CTRI/2016/11/007494.

The effect of infant vitamin B12 supplementation on neurodevelopment: a follow-up of a randomised placebo-controlled trial in Nepal.

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.

The association between household biomass fuel use and leukocyte telomere length among toddlers in Bhaktapur, Nepal.

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).

Vitamin B12 and/or folic acid supplementation on linear growth; a 6 years follow-up study of a randomised controlled trial in early childhood in North India.

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, randomized placebo-controlled trial in 1,000 young children. Starting at 6-30 months of age, we gave folic acid (∼2 RDAs), vitamin B12 (∼2 RDAs), both vitamins, or a placebo daily for six 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 (P 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 (P interaction = 0.001). In this group, each doubling of the cobalamin concentration was associated with 0.26 (95% CI: 0.15 to 0.38) higher HAZ. Suboptimal B12 status in early childhood seemingly limits linear growth in North Indian Children.

Short-term Music Therapy for Families With Preterm Infants: A Randomized Trial.

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 (<35 weeks gestational age at birth) and their parents. MT included 3 sessions per week with parent-led, infant-directed singing supported by a music therapist. Primary outcome was mother-infant bonding as measured by the Postpartum Bonding Questionnaire (PBQ) at discharge from NICU. Secondary outcomes were parents' symptoms of anxiety measured by General Anxiety Disorder-7 (GAD-7) and maternal depression measured by Edinburgh Postpartum Depression Scale (EPDS). Group differences at the assessment timepoint of discharge from hospital were tested by linear mixed effect models (ANCOVA). 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 effect of vitamin B12-supplementation on actigraphy measured sleep pattern; a randomized control trial.

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. TRIAL REGISTRATION: clinicaltrials.gov: NCT02272842. UNIVERSAL TRIAL NUMBER: U1111-1161-5187.

Impact of the COVID-19 pandemic on daily life and worry among mothers in Bhaktapur, Nepal.

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.

Gestational Age, Birth Weight, and Neurocognitive Development in Adolescents in Tanzania.

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 (<2500 g) was associated with lower intelligence and executive function scores. Associations between birthweight and executive function were stronger among adolescents born to women with higher education. CONCLUSIONS: The duration of gestation and birthweight were positively associated with adolescent neurodevelopment in Tanzania. These findings suggest that interventions to improve birth outcomes may also benefit adolescent cognitive function.

Longitudinal Study of Music Therapy's Effectiveness for Premature Infants and Their Caregivers (LongSTEP): Feasibility Study With a Norwegian Cohort.

Premature infants and their parents experience significant stress during the perinatal period. Music therapy (MT) may support maternal-infant bonding during this critical period, but studies measuring impact across the infant's first year are lacking. This nonrandomized feasibility study used quantitative and qualitative methods within a critical realist perspective to evaluate the feasibility, acceptability, and suitability of the treatment arm of the Longitudinal Study of music Therapy's Effectiveness for Premature infants and their caregivers (LongSTEP) (NCT03564184) trial with a Norwegian cohort (N = 3). Families were offered MT emphasizing parent-led infant-directed singing during neonatal intensive care unit (NICU) hospitalization and across 3 months post-discharge. We used inductive thematic analysis of semi-structured interviews with parents at discharge from NICU and at 3 months and analyzed quantitative variables descriptively. Findings indicate that: (1) parents of premature infants are willing to participate in MT research where parental voice is a main means of musical interaction; (2) parents are generally willing to engage in MT in NICU and post-discharge phases, finding it particularly interesting to note infant responsiveness and interaction over time; (3) parents seek information about the aims and specific processes involved in MT; (4) the selected self-reports are reasonable to complete; and (5) the Postpartum Bonding Questionnaire appears to be a suitable measure of impaired maternal-infant bonding. Parents reported that they were able to transfer resources honed during MT to parent-infant interactions outside MT and recognized parental voice as a central means of building relation with their infants. Results inform the implementation of a subsequent multinational trial that will address an important gap in knowledge.

Effects of vitamin B12 supplementation on neurodevelopment and growth in Nepalese Infants: A randomized controlled trial.

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).

Dietary Intake and Biomarkers of Folate and Cobalamin Status in Norwegian Preschool Children: The FINS-KIDS Study.

BACKGROUND: Folate and cobalamin (vitamin B-12) are essential for growth and development. However, few population-based 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 <10 nmol/L were observed in 13% of the children. No child had a cobalamin concentration <148 pmol/L. Two children were identified with elevated plasma MMA concentrations (>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.

Vitamin B12, Folate, and Cognition in 6- to 9-Year-Olds: A Randomized Controlled Trial.

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.

Longitudinal Study of music Therapy's Effectiveness for Premature infants and their caregivers (LongSTEP): protocol for an international randomised trial.

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

Effect of antenatal and infant micronutrient supplementation on middle childhood and early adolescent development outcomes in Tanzania.

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.