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.

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.

Milk-cereal mix supplementation during infancy and impact on neurodevelopmental outcomes at 12 and 24 months of age: a randomised controlled trial in India.

Inadequate protein intake and lack of micronutrients may affect neurodevelopment in infants. This randomised controlled trial was conducted to measure the effect of two milk-cereal mixes with modest and high amounts of protein and enriched with multiple micronutrients, given between 6 and 12 months, on cognitive, language, motor and behavioural scores at 12 and 24 months of age, compared with no-supplementation. The two supplements were also compared with each other. The study was conducted in urban Delhi, India, and the infants were randomised in a 1:1:1 ratio to the three study groups. At 12 and 24 months of age, 1134 and 1214 children were available, respectively. At 12 months of age, compared with no-supplement group, an increase in the motor scores (mean difference, MD 1·52, 95 % CI: 0·28, 2·75) and a decrease in the infant temperament scores (MD - 2·76, 95 % CI: -4·23, -1·29) in the modest-protein group was observed. Those in the high-protein group had lower socio-emotional scores (MD - 1·40, 95 % CI: -2·43, -0·37) and higher scores on Infant Temperament Scale (MD 2·05, 95 % CI: 0·62, 3·48) when compared with modest-protein group. At 24 months, no significant differences in any of the neurodevelopment scores between the three study groups was found. In conclusion, supplementation with modest amount of protein and multiple micronutrients may lead to short-term small improvements in motor function and infant temperament. There appears no advantage of supplementing with high protein, rather negative effects on infant behaviour were observed.

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.

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).

Prevalence of Underweight, Overweight, and Obesity in Adults in Bhaktapur, Nepal in 2015-2017.

Introduction: There is an increase in the double burden of malnutrition globally, with a particular rise documented in Asia. In Nepal, undernutrition has been prevalent for decades. Today, however, the incidence of overweight and obesity (OWOB) in the country has increased substantially. There is a need to conduct local studies reporting on the concurrent burden of both underweight and OWOB across adult populations. This study addresses this need by describing the distribution of body mass index (BMI) in a defined population of adults living in the peri-urban community of Bhaktapur, Nepal. Material and methods: For this cross-sectional analysis, we used data that were available from 600 women and 445 men whose children were enrolled in an individually randomized, double-blind, placebo-controlled trial assessing the effect of daily vitamin B12 supplementation. Upon enrolment of their 6-11-month old children, mothers and fathers were interviewed about their socio-demographic details. In addition, their weight and height were measured by trained field workers. Each parent's BMI was calculated as the ratio of body weight (in kg) and height squared (in m), expressed as kg/m2, and categorized according to the WHO recommendation. We used linear and multinomial logistic regression models to assess associations between the BMI of the mothers and fathers, and their baseline characteristics. Results: The mean BMI was 23.7 kg/m2 for both the mothers and fathers with a standard deviation (SD) of 3.6 and 3.7, respectively. The proportion categorized as underweight, overweight, and obese was also similar in the two groups with around 5% being underweight, 30% being overweight and 5% being obese. Age was positively associated with BMI in both groups. Those categorized as daily wage earner had a lower mean BMI than those in other occupational groups. Conclusion: Our results contribute to documenting the burden of both under- and overnutrition in a selected group of young adults living in a peri-urban community in Nepal. As Nepal is undergoing an improvement in its economic situation, as well as a nutrition transition, it is important to provide sufficient information to enable timely action, and evidence-based decision-making to prevent a further increase in Nepal's growing double burden of malnutrition.

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.

Acceptability and Reliability of the Bayley Scales of Infant and Toddler Development-III Among Children in Bhaktapur, Nepal.

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.

Cobalamin and Folate Status among Breastfed Infants in Bhaktapur, Nepal.

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

Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania.

INTRODUCTION: As many as 250 million children under the age of 5 may not be reaching their full developmental potential partly due to poor nutrition during pregnancy and the first 2 years of life. Micronutrients, including vitamin B12, are important for the development of brain structure and function; however, the timing, duration and severity of deficiencies may alter the impact on functional development outcomes. Consequently, to fully explore the effect of vitamin B12 on cognitive function, it is crucial to measure neurodevelopment at different ages, in different populations and with vitamin B12 supplementation at different times during the critical periods of neurodevelopment. METHODS AND ANALYSIS: In this project, we follow up children from four recently completed randomised placebo-controlled trials of oral vitamin B12 supplementation, two in India and two in Tanzania, to explore the long-term effects on neurodevelopmental outcomes and growth. All the included trials provided at least two recommended dietary allowances of oral vitamin B12 daily for at least 6 months. Vitamin B12 was supplemented either during pregnancy, early infancy or early childhood. Primary outcomes are neurodevelopmental status, cognitive function and growth later in childhood. We apply validated and culturally appropriate instruments to identify relevant developmental outcomes. All statistical analyses will be done according to intention-to-treat principles. The project provides an excellent opportunity to examine the effect of vitamin B12 supplementation in different periods during early life and measure the outcomes later in childhood. ETHICS AND DISSEMINATION: The study has received ethical approvals from all relevant authorities in Norway, USA, Tanzania and India and complies fully with ethical principles for medical research. Results will be presented at national and international research and policy meetings and published in peer-reviewed scientific journals, preferably open access. TRIAL REGISTRATION NUMBER: NCT00641862 (Bangalore); NCT00717730, updated CTRI/2016/11/007494 (Delhi); NCT00197548 and NCT00421668 (Dar es Salaam).

The effects of vitamin B12 supplementation in pregnancy and postpartum on growth and neurodevelopment in early childhood: Study Protocol for a Randomized Placebo Controlled Trial.

INTRODUCTION: Vitamin B12 is crucial for normal cell division and differentiation, and necessary for the development and myelination of the central nervous system. Pregnant mothers in resource poor settings are at risk for poor vitamin B12 status. Poor vitamin B12 status in infancy is linked to poor growth and neurodevelopment. Brain development starts from conception, and pregnancy is a period of rapid growth and development for the brain. METHODS AND ANALYSIS: The study is an individually randomised double-blind placebo controlled trial in 800 pregnant Nepalese women randomised in a 1:1 ratio. A daily dose of 50 µg of vitamin B12 or placebo is given to women from early pregnancy, not later than week 15, until 6 months after birth. Weekly visits are conducted in order to record compliance, growth and morbidity. The primary outcomes are scores on the cognitive, language and motor subscales of the Bayley Scales of Infant and Toddler Development, Third Edition, measured at 6 and 12 months of age, and growth (length and weight) measured at 6 and 12 months of age. ETHICS AND DISSEMINATION: National Health and Research Council, Nepal (NHRC 253/2016) and Regional Committee for Medical and Health Research Ethics of Western Norway (2016/1620/REK vest) have approved the study. Investigators who have contributed to the conceptualising, conducting, as well as being involved in the data analyses and manuscript writing will be eligible for authorship and be responsible to share outcomes with different stakeholders through publications and workshops. The results from this study may support new dietary guidelines for Nepalese and possibly South Asian pregnant women that can lead to improved pregnancy outcomes, neurodevelopment and cognitive functioning in children. TRIAL REGISTRATION NUMBER: Universal Trial Number: U1111-1183-4093. TRIAL REGISTRATION: clinicaltrials.gov: NCT03071666. Protocol date: version 1.2, 1 June 2017.

The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial.

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.

Vitamin B12 and Folic Acid Improve Gross Motor and Problem-Solving Skills in Young North Indian Children: A Randomized Placebo-Controlled Trial.

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