Strand et al. Trials (2017) 18:187 DOI 10.1186/s13063-017-1937-0

STUDY PROTOCOL

Open Access

The effect of vitamin B12 supplementation in Nepalese infants on growth and development: study protocol for a randomized controlled trial Tor A. Strand1,2*, Manjeswori Ulak3, Ram K. Chandyo3, Ingrid Kvestad4, Mari Hysing4, Merina Shrestha3, Sudha Basnet3, Suman Ranjitkar3, Laxman Shrestha3 and Prakash S. Shrestha3

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

Background Micronutrient deficiencies represent a major challenge to child health in many low- and middle-income countries, and they may increase the risk of suboptimal development, impaired cognitive function, and poor growth [1]. Vitamin B12 (cobalamin) deficiency is among the most common micronutrient deficiencies [2, 3] because its main source is animal source foods, which are expensive and for cultural and religious reasons are often not eaten. * Correspondence: [email protected] 1 Department of Research, Innlandet Hospital Trust, 2629 Lillehammer, Norway 2 Centre for International Health, University of Bergen, P.O. Box 78005020 Bergen, Norway Full list of author information is available at the end of the article

Vitamin B12 deficiency is associated with impaired infant and child growth [4, 5]. In several studies of women and children, we have demonstrated that poor vitamin B12 status is common in South Asia [3, 6, 7]. Case studies have demonstrated harmful effects of severe vitamin B12 deficiency on the developing infant brain [8, 9]. The consequences of mild or subclinical vitamin B12 deficiency are less clear, but they have been shown to be associated with decreased cognitive performance in both elderly persons and children [10–13]. Researchers in three randomized controlled trials (RCTs) have measured the effect of vitamin B12 supplementation on neurodevelopment in children. In a Norwegian trial, an intramuscular injection of vitamin B12 substantially improved motor development in 6-week-old infants after

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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1 month [14]. Another trial with low-birth-weight children in Norway recently confirmed these findings [15]. We also found a beneficial effect of vitamin B12 supplementation for 6 months on neurodevelopment in young North Indian children [16]. The infants in these three studies had evidence of suboptimal vitamin B12 status, but none of the children had severe deficiency. Vitamin B12 works with folate, and both are required for cell division, use of energy, and other important metabolic processes. Impaired cell growth is the main mechanism behind anemia in severe cobalamin or folate deficiency. Adequate cell growth is also important for the growing nervous system. Vitamin B12 deficiency may also have consequences through various metabolic pathways that can alter energy use, the production of neurotransmitters, and myelin [8]. Myelin is the principal component of white matter in the brain and is important for nerve conductivity. Disruptions in myelination alter the speed of conduction in multiple systems of the central and peripheral nervous systems [9]. The first 2 years of life is the most important period for brain growth and development of the nervous system [17]. The brain develops rapidly through neurogenesis, axonal and dendritic growth, synaptogenesis, myelination, and gliogenesis. These events happen at different times and build on each other [17]. Small impairments during critical periods can have serious consequences for the brain’s structural and functional capacity, with the possibility of persistence into adult life [18, 19]. In addition to growth and cognitive development outcomes, we will try to estimate long-term effects of vitamin B12 supplementation in the present study. As a secondary outcome, we have therefore included measurements of leukocyte telomere length as a biological marker of future health. Telomeres are the caps located at the ends of chromosomes that promote chromosomal stability [20]. The length of the telomere is an indication of remaining cell cycles of a particular cell line in the body, and it may serve as a biological clock to determine the life span of a cell and an organism [20]. The telomeres shorten by age, and shorter telomeres in the individual are a sign of a shortened life span [21, 22]. Stress may accelerate telomere shortening, and the length of telomeres is often considered to be a biomarker of chronic stress [23]. In children, telomere length has been linked to early adversity and psychological stress [24, 25], family violence [23, 26], lead exposure [27], and cigarette smoking [26], as well as zinc deficiency [28] and disturbances in the one carbon metabolism that occur during folate or B12 deficiency [29]. In a pilot study with Nepalese children, we estimated the relative telomere length in 66 infants and found that the plasma methylmalonic acid (MMA) concentration was inversely associated with the telomere length (unpublished results, personal communication T. Strand). This association, which persisted after

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adjusting for relevant confounders, suggests that poor vitamin B12 status in infancy results in shorter telomeres, possibly linking poor status in infancy to poorer health outcomes later in life. Whether vitamin B12 status causes shortening of telomeres needs to be confirmed using an experimental design such as the one in this trial. Establishing a causal link between vitamin B12 deficiency and neurodevelopment must be done in a randomized, placebo-controlled trial that provides an adequate amount of vitamin B12 for a sufficiently long period. The two RCTs on Norwegian infants were undertaken in patient populations, and in the RCT done in North India, neurodevelopment was a secondary outcome. We designed the present RCT to measure the effect of daily supplementation of vitamin B12 for 1 year in marginally stunted children (length for age less than −1 z-score) on neurodevelopment and growth.

Methods/design Study aim and design

The main aim of the study is to measure to what extent administration of 2 μg of vitamin B12 for 12 months improves neurodevelopment, growth, and hemoglobin (Hb) concentration in children aged 6–11 months at enrollment. The impact of the vitamin B12 supplementation will be measured using a randomized, double-blind, placebocontrolled study design. We will also measure the effect of supplementation on other outcomes important for child health and development. Specific aims of the study

The specific aims of the study are to measure, in infants 6–11 months of age in a population where poor vitamin B12 status and malnutrition is common, the following: 1. To what extent administration of 2 μg of vitamin B12 for 1 year improves developmental scores measured by the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), and the Ages and Stages Questionnaire, Third Edition (ASQ-3) 2. To what extent administration of 2 μg of vitamin B12 improves length-for-age, weight-for-age, and weightfor-length z-scores after 1 year, as well as growth velocity z-scores for the initial 6 months and the last 6 months of supplementation 3. To what extent administration of 2 μg of vitamin B12 for 12 months improves Hb concentration Secondary aims

Secondary aims of the study are the following: 4. Measure to what extent administration of 2 μg of vitamin B12 for 12 months leads to less telomere shortening

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5. To identify subgroups for the above-mentioned outcomes that benefit from vitamin B12 administration 6. Measure to what extent vitamin B12 administration alters plasma cobalamin, MMA, and total homocysteine (tHcy) concentrations 7. In multiple regression analyses, identify predictors for early childhood development scores using variables reflecting socioeconomic status, early stimulation opportunities, morbidity, growth, micronutrient status, self-regulation, sleep, activity, and others

Procedures Exclusion criteria

The following exclusion criteria will be applied: 1. Severe systemic illness requiring hospitalization 2. Severe malnutrition (i.e., weight for height less than −3 z-scores of the World Health Organization standard for this age group); for ethical reasons, these children require micronutrient supplementation and adequate medical care 3. Lack of consent 4. Taking B vitamin supplements that include vitamin B12 5. Severe anemia (Hb

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

Vitamin B12 deficiency is one of the most common micronutrient deficiencies and is associated with poor cognitive development and growth. Vitamin B12 ...
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