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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.

ABSTRACT: 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.

SUBMITTER: Chandyo RK

PROVIDER: S-EPMC5634456 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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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.

Chandyo Ram K RK Ulak Manjeswori M Kvestad Ingrid I Shrestha Merina M Ranjitkar Suman S Basnet Sudha S Hysing Mari M Shrestha Laxman L Strand Tor A TA

BMJ open 20170829 8

<h4>Introduction</h4>Vitamin B<sub>12</sub> 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 B<sub>12</sub> status. Poor vitamin B<sub>12</sub> 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.<h4>Methods and ...[more]

PMID: 28851784

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Project description: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).

Project description:BackgroundVitamin 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 findingsThis 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.ConclusionsIn 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 registrationClinicalTrials.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).

Project description:BackgroundThere is limited research to determine whether vitamin B12 (B12) supplementation during pregnancy and lactation is protective against oxidative stress and pro-inflammatory cytokines and whether this effect is transferred to breastfed infants via milk. In addition, associations among maternal plasma/ milk and infant B12 status and immune function markers are poorly characterized.ObjectivesTo evaluate effects of oral B12 supplementation during pregnancy and postpartum on maternal and infant 8-hydroxy-2'-deoxyguanosine (8-OH-dG, an oxidative stress marker) and proinflammatory cytokine levels, and examine associations between maternal plasma, breastmilk and infant B12 status as well as immune function markers.MethodIn a blinded, placebo-controlled trial, Bangladeshi women (n = 68, 18-35 years, hemoglobin < 11 g/dL, gestational weeks 11-14) received either 250 μg/day B12 or placebo throughout pregnancy up to 3-months postpartum. Samples were collected from mothers at baseline and 3-months postpartum and from infants at 3-months to measure B12 status indicators, 8-OH-dG and proinflammatory cytokines.ResultsMaternal postpartum B12 was positively associated with infant plasma B12. Higher milk B12 concentrations were associated with increased infant B12 (beta (β) = 277, 95% confidence interval (CI) = (132, 423), p<0.001) and lower total homocysteine (β = -7.63, 95% CI = (-12.40, -2.86), p = 0.002) levels. Maternal B12 supplementation reduced plasma 8-OH-dG concentrations among postpartum mothers and infants compared to the placebo group. Supplementation increased plasma TNF-α and IL-6 levels among mothers and IL-10 and IFN-γ levels among infants.ConclusionMilk and maternal plasma B12 at 3 months were associated with infant B12. Maternal B12 supplementation modulates 8-OH-dG and several cytokines which may protect against immune response-induced oxidative stress.Trial registration(clinicaltrials.gov: NCT01795131- 1st posted on 20/02/2013).

Project description:ImportanceObservational studies have reported an association between high maternal vitamin D levels and improved neurodevelopment in offspring, but no randomized clinical trial (RCT) has investigated these observations.ObjectiveTo determine whether high-dose vitamin D supplementation during pregnancy improves offspring neurodevelopment from birth to age 6 years.Design, setting, and participantsThis prespecified secondary analysis of a double-blinded, placebo-controlled RCT of high-dose vitamin D3 supplementation vs standard dose during the third trimester of pregnancy was conducted in the unselected prospective mother-child birth cohort at a single-center research unit in Denmark as part of the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC-2010). Participants included pregnant women; women with vitamin D intake greater than 600 IU/d or an endocrine, heart, or kidney disorder, and those who did not speak Danish fluently were excluded. Neurodevelopmental assessments for offspring of these women were performed at ages 0 to 6 years. Children born prematurely (gestational week <37), with low birth weight (<2500 g), or with a neurological disease affecting neurodevelopment were excluded. Data were analyzed from August 2019 to February 2020.InterventionsHigh-dose (ie, 2800 IU/d) vs standard dose (ie, 400 IU/d) vitamin D3 supplementation from pregnancy week 24 until 1 week after birth.Main outcomes and measuresThe primary outcome of interest was cognitive development assessed at 2.5 years using the Bayley Scales of Infant and Toddler Development. Other neurodevelopmental outcomes included age of motor milestone achievement (Denver Developmental Index and World Health Organization milestone registration), language development (MacArthur-Bates Communicative Development Inventories), general neurodevelopment at age 3 years (Ages and Stages Questionnaire), and emotional and behavioral problems at age 6 years (Strengths and Difficulties Questionnaire).ResultsAmong 623 women randomized, 315 were randomized to high-dose vitamin D3 and 308 were randomized to standard dose placebo. A total of 551 children were evaluated from birth to age 6 years, (282 [51.2%] boys; 528 [95.8%] White), with 277 children in the high-dose vitamin D3 group and 274 children in the standard dose group. There was no effect of the high-dose compared with standard dose of vitamin D3 supplementation during pregnancy on offspring achievement of motor milestones (β = 0.08 [95% CI, -0.26 to 0.43]; P = .64), cognitive development (score difference: 0.34 [95% CI, -1.32 to 1.99]; P = .70), general neurodevelopment (median [IQR] communication score: 50 [50-55] vs 50 [50-55]; P = .62), or emotional and behavioral problems (odds ratio, 0.76 [95% CI, 0.53 to 1.09]; P = .14). There was no effect on language development expressed by the word production at 1 year (median [IQR], 2 [0-6] words vs 3 [1-6] words; P = .16), although a decreased word production was apparent at 2 years in children in the high-dose vitamin D3 group (median [IQR], 232 [113-346] words vs 253 [149-382.5] words; P = .02).Conclusions and relevanceIn this prespecified secondary analysis of an RCT, maternal high-dose vitamin D3 supplementation during the third trimester of pregnancy did not improve neurodevelopmental outcomes in the offspring during the first 6 years of life. These findings contribute essential information clarifying the effects of prenatal exposure to vitamin D on neurodevelopment in childhood.Trial registrationClinicalTrials.gov Identifier: NCT00856947.

Project description:To investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 μg/day for one year in patients with diabetic neuropathy (DN). In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurements of sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and vibration perception threshold (VPT), and they performed cardiovascular autonomic reflex tests (CARTs: mean circular resultant (MCR), Valsalva test, postural index, and orthostatic hypotension). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet (ESCH and ESCF, respectively). We also used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively) and questionnaires to evaluate quality of life (QoL) and level of pain (pain score). B12 levels increased from 232.0 ± 71.8 at baseline to 776.7 ± 242.3 pmol/L at follow-up, p < 0.0001, in the active group but not in the control group. VPT, MNSIQ, QoL, pain score, SNCV, SNAP, and ESCF significantly improved in the active group (p < 0.001, p = 0.002, p < 0.0001, p < 0.000, p < 0.0001, p < 0.0001, and p = 0.014, respectively), whereas CARTS and MNSIE improved but not significantly. MCR, MNSIQ, SNCV, SNAP, and pain score significantly deteriorated in the control group (p = 0.025, p = 0.017, p = 0.045, p < 0.0001, and p < 0.0001, respectively). The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.

Dataset Information

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.

Publications

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.

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