Early Infant Micronutrition and Development

Study Overview
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Brief Summary
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Globally, vitamin B12 deficiency is one of the most common micronutrient deficiencies. Poor status is also seen in affluent countries such as in Norway. Vitamin B12 is crucial for normal cell division and differentiation and necessary for the development and myelination of the central nervous system. Deficiency is also associated with impaired fetal and infant growth. In the proposed study we will measure the effect of daily oral vitamin B12 supplementation infants on neurodevelopment. We also aim to measure the impact of B12 supplementation on several other outcomes. Study design: Individually randomized double-blind placebo-controlled trial breastfed infants who will be assigned to a screening group (in which measurements will be obtained immediately) or a control group (in which serum will be stored and measurements done after one year). Pregnant women will be informed about the study during their first antenatal visit at the clinic and that we will re-approach them on their 6-week visit to their public health nurse. Infants who are deficient will be treated with peroral or intramuscular injections with 400 µg cyano-cobalamin. Infants in the control group will not be offered any intervention their blood sample will be stored for one year and then analyzed for the same nutrients as the intervention group. Outcomes: Primary: (i) neurodevelopment in children measured at 12 months of age (ii) growth in children measured by attained weight and length at 12 months. Secondary: (i) neurodevelopment and cognitive functioning in children later in life

Official Title
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Vitamin B12 Status in Infancy and the Effect of Providing Vitamin B12 to Infants With Signs of Suboptimal Vitamin B12 Status - a Registry-based, Randomized Controlled Trial

Conditions
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Vitamin B 12 Deficiency

Intervention / Treatment
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* Biological: Cyanocobalamin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Availability of informed verbal consent Plan to reside in the defined study area for the next 12 months Mothers intend to breastfeed their children for at least 8 months, and exclusively for 4 months Exclusion Criteria: Severe systemic illness requiring hospitalization Growth retardation Severe congenital malformations Plasma cobalamin concentration <148 pmol/L (These children will be treated for vitamin B12 deficiency and not included in the RCT, but will be included in the cohort design)

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 2 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Screening - treatment<br>From 6 weeks of age, infants will be screened for elevated plasma total homocysteine concentrations. Those who have a concentration above the defined cut-off will be treated with cobalamin (vitamin B12). | Biological: Cyanocobalamin<br>* Intramuscular injection of 400 µg cobalamin to children with elevated thcy at enrollment<br>* Other names: Vitamin B12;|
| No Intervention: Control<br>The control-group sample will be stored and analyzed when the child is 12 months old. Those with elevated tHcy will contribute to the control group. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurodevelopment | Bayley Scales of Infant Development 4th edition | 12 months of age | 
| Prevalence of vitamin B12 deficiency | Number of children with elevated plasma homocysteine or low cobalamin | 1-3 months of age | 
| Prevalence of other vitamin deficiencies | Number of infants with vitamin deficiencies other than vitamin B12 deficiency | 1-3 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurodevelopment measured by the Ages and Stages Questionaire | Ages and Stages Questionnaire version 3 repeated throughout infancy | 4-12 months of age | 
| Vagal tone | Heart rate variability | 12 months of age | 
| Eye tracking | Visual acuity, visuospatial orientation, and attention to social cues | 12 months of age | 
| Neurodevelopment later in childhood | General cognitive abilities (IQ) assessed by the Wechsler Preschool and Primary Scale of Intelligence | 5 years | 
| Adverse events | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 3 months after treatment with vitamin B12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infant, Nutrition, Vitamins, Breastfeeding, Neurodevelopment, Growth, Clinical trial