Vitamin B12 Supplementation During Pregnancy on Cognitive Development

Study Overview
=================
Brief Summary
-----------------
Scientific basis: Globally, vitamin B12 deficiency is one of the most common micronutrient deficiencies. The only relevant source of vitamin B12 is animal-source foods and poor gut function may decrease absorption. 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 to pregnant women on neurodevelopment and growth of their children. We also aim to measure the impact of B12 supplementation on several other outcomes. Study design: Individually randomized double-blind placebo controlled trial in pregnant South Asian women at risk of poor vitamin B12 status. Participants will be randomized in a 1:1 ratio. Study participants and site: 800 pregnant women from early pregnancy. Women will be enrolled as early as possible, but no later than in week 15 of pregnancy. Intervention: Daily administration of 50 µg of vitamin B12 from early pregnancy until 6 months after birth. Comparator: Placebo, identical to the vitamin B12 supplements. Outcomes: Primary: (i) neurodevelopment in children measured at 6 and 12 months of age (ii) growth in children measured by weight and length at 12 months. Secondary: (i) neurodevelopment and cognitive functioning in children at 24 months (ii) gestational age at birth, (iii) fetal and infant growth measured by weight and length at birth, after 1 month and then at 3, 6, 9, and 24 months, (iv) hemoglobin concentration in children and mothers. Relevance for programs and public health: The results from this study can suggest new dietary guidelines for South Asian women that again can lead to improved pregnancy outcomes and neurodevelopment and cognitive functioning in South Asian children.

Detailed Description
-----------------
Cobalamin (Vitamin B12) deficiency is common in many low- and middle-income countries. This is not surprising as the main source of vitamin B12 is animal source foods, which are expensive and for cultural and religious reasons often not eaten at all. We have in several studies in women and children demonstrated that poor vitamin B12 status is common in South Asia. There is also compelling evidence that vitamin B12 deficiency occurs frequently in many other settings including pregnant women . Case studies have demonstrated harmful effects of severe vitamin B12 deficiency on the developing infant brain.The consequences of mild or subclinical vitamin deficiency are less clear but it has been shown to be associated with decreased cognitive performance in both elderly and children. Three randomized controlled trials (RCT) have measured the effect of vitamin B12 supplementation on neurodevelopment in children: In a Norwegian trial, an intramuscular injection of B12 substantially improved motor development in six weeks old infants after one month. Another intervention study in low birth weight children in Norway recently confirmed these findings. The infants in these studies had evidence of suboptimal vitamin B12 status, but none were severely deficient. We found a beneficial effect of vitamin B12 supplementation for six months on neurodevelopment in young North Indian children. During pregnancy, vitamin B12 is concentrated in the fetus and stored in the liver. Infants born to vitamin B12-replete mothers have stores of vitamin B12 that are adequate to sustain them for the first several months postpartum. Consequently, vitamin B12 deficiency rarely occurs before the infant is about four months old if the mother has adequate vitamin B12 status during pregnancy. However, many infants of vitamin B12-deficient breastfeeding mothers are vulnerable to B12 deficiency from an early age. In this project we will randomise Nepalese women to receive a supplement containing 50µg cobalamin or a placebo from early pregnancy until 6 months postpartum. Hypothesis to be tested Principal hypothesis: Daily administration of vitamin B12 to pregnant women from early pregnancy until 6 months postpartum will: Increase the scores of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III) by 0.25 SD points measured at 6 and 12 months of age. Increase length for age and weight for length by 0.2 z-scores at 12 months of age. Other hypotheses to be tested (dependent on additional funding): Daily maternal administration of vitamin B12 from the start of the early pregnancy and for 6 months postpartum improves the hemoglobin concentration in the mother and infant. Daily maternal administration of vitamin B12 from early pregnancy and for 6 months postpartum improves plasma vitamin B12 concentration and reduces plasma total homocysteine and methylmalonic acid concentration in the mother and infant. Daily maternal administration of vitamin B12 from early pregnancy and for 6 months postpartum improves insulin sensitivity in the offspring.

Official Title
-----------------
Supplementation of Vitamin B12 in Pregnancy and Postpartum on Growth and Cognitive Functioning in Early Childhood: A Randomized, Placebo Controlled Trial

Conditions
-----------------
Pregnancy Related, Vitamin B 12 Deficiency, Anemia

Intervention / Treatment
-----------------
* Dietary Supplement: cobalamin
* Dietary Supplement: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pregnant mother in early pregnancy and not later than 15 weeks of pregnancy. Current resident and plan to reside in Bhaktapur district for at least the next 2 years. Age of mother between 18 and 40 years. Consent to participate in the study. Exclusion Criteria: Taking or plan to take dietary or multivitamin supplements containing vitamin B12. Known case of chronic disease like asthma, tuberculosis, diabetes, hypertension, hypo or hyperthyroidism or others Known case of current high risk pregnancy Severe anemia (hemoglobin concentration <7 g/dL). Where the study doctor finds it necessary to treat the woman with vitamin B12 or vitamin B12 containing supplements

Ages Eligible for Study
-----------------
Minimum Age: 20 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vitamin B12<br>cobalamin, 50 µg per day throughout pregnancy and during the first 6 months postpartum. | Dietary Supplement: cobalamin<br>* Vitamin supplment tablet containing 50µg cobalamin<br>* Other names: Vitamin B12;|
| Placebo Comparator: Placebo<br>Identical taste and appearance with the Experimental arm. Contains no cobalamin | Dietary Supplement: placebo<br>* A tablet identical to the vitamin supplement but containing no vitamin B12<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Length | Length measured in centimeters and expressed as z-scores | 12 months of age | 
| Neurodevelopment | Cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III) | measured 6 and 12 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Child hemoglobin concentration | Hemoglobin measured by hemocue in full blood | measured 6 and 12 months of age | 
| Child development ASQ | Total and subscale scores of the Ages and Stages Questionnaire - 3rd ed. | 12 first months of life | 
| Child development Bayley | Subscale scores of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III) | measured 6 and 12 months of age | 
| Heart rate variability | Heart rate variability or vagal tone | 12 first months of life | 
| Sleep and activity | Sleep and activity measured by Actigraph (Actiwatch) | 12 first months of life | 
| The Infant Motor Performance | Screening tool to assess motor development | 2 months after birth | 
| Still births | Number of still births | Birth. | 
| Maternal hemoglobin concentration | Hemoglobin measured by hemocue in full blood | at end of pregnancy and 6 and 12 months post party. | 
| Number of complicated births | Number of births that were complicated | Birth. | 
| Children born at small for gestational age | Number of children born at small for gestational age | Birth | 
| Birth weight | weight in g | Birth | 
| Low birth weight | Birthweight < 2,500 g | Birth | 
| Very low birth weight | Birthweight < 2,000 g | Birth | 
| High birth weight | Birthweight > 4,000 g | Birth | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nepal, South Asia, Nutrition, Pregnancy, Neurodevelopment, Growth