Vitamin B12 Supplementation During Pregnancy on Cognitive Development (VitaPreg)
Primary Purpose
Pregnancy Related, Vitamin B 12 Deficiency, Anemia
Status
Active
Phase
Phase 2
Locations
Nepal
Study Type
Interventional
Intervention
cobalamin
placebo
Sponsored by
About this trial
This is an interventional prevention trial for Pregnancy Related focused on measuring Nepal, South Asia, Nutrition, Pregnancy, Neurodevelopment, Growth
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
Sites / Locations
- Manjeswori Ulak
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Vitamin B12
Placebo
Arm Description
cobalamin, 50 µg per day throughout pregnancy and during the first 6 months postpartum.
Identical taste and appearance with the Experimental arm. Contains no cobalamin
Outcomes
Primary Outcome Measures
Length
Length measured in centimeters and expressed as z-scores
Neurodevelopment
Cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III)
Secondary Outcome Measures
Child hemoglobin concentration
Hemoglobin measured by hemocue in full blood
Child development ASQ
Total and subscale scores of the Ages and Stages Questionnaire - 3rd ed.
Child development Bayley
Subscale scores of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III)
Heart rate variability
Heart rate variability or vagal tone
Sleep and activity
Sleep and activity measured by Actigraph (Actiwatch)
The Infant Motor Performance
Screening tool to assess motor development
Still births
Number of still births
Maternal hemoglobin concentration
Hemoglobin measured by hemocue in full blood
Number of complicated births
Number of births that were complicated
Children born at small for gestational age
Number of children born at small for gestational age
Birth weight
weight in g
Low birth weight
Birthweight < 2,500 g
Very low birth weight
Birthweight < 2,000 g
High birth weight
Birthweight > 4,000 g
Full Information
NCT ID
NCT03071666
First Posted
February 23, 2017
Last Updated
February 6, 2023
Sponsor
Centre For International Health
Collaborators
Tribhuvan University Teaching Hospital, Institute Of Medicine., NORCE Norwegian Research Centre AS, Sykehuset Innlandet HF
1. Study Identification
Unique Protocol Identification Number
NCT03071666
Brief Title
Vitamin B12 Supplementation During Pregnancy on Cognitive Development
Acronym
VitaPreg
Official Title
Supplementation of Vitamin B12 in Pregnancy and Postpartum on Growth and Cognitive Functioning in Early Childhood: A Randomized, Placebo Controlled Trial
Study Type
Interventional
2. Study Status
Record Verification Date
April 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 27, 2017 (Actual)
Primary Completion Date
June 28, 2022 (Actual)
Study Completion Date
December 31, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre For International Health
Collaborators
Tribhuvan University Teaching Hospital, Institute Of Medicine., NORCE Norwegian Research Centre AS, Sykehuset Innlandet HF
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pregnancy Related, Vitamin B 12 Deficiency, Anemia
Keywords
Nepal, South Asia, Nutrition, Pregnancy, Neurodevelopment, Growth
7. Study Design
Primary Purpose
Prevention
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
We will randomize women in a 1:1 ratio. The vitamin B12 supplements and the placebos will be produced specifically for this trial and be identical in taste and appearance. Each woman will be assigned a packet of medicines according to her id number. This packet will only be labeled with general information about the study and a unique id number. The list that links the id number to the randomization code will be kept with the company that produces the intervention and the placebo, and with the scientist who will generate the randomization code. This scientist will otherwise not be involved in the study. None of the investigators will have access to this list until completion of data collection and cleaning of data for the main outcomes.
Allocation
Randomized
Enrollment
800 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Vitamin B12
Arm Type
Experimental
Arm Description
cobalamin, 50 µg per day throughout pregnancy and during the first 6 months postpartum.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Identical taste and appearance with the Experimental arm. Contains no cobalamin
Intervention Type
Dietary Supplement
Intervention Name(s)
cobalamin
Other Intervention Name(s)
Vitamin B12
Intervention Description
Vitamin supplment tablet containing 50µg cobalamin
Intervention Type
Dietary Supplement
Intervention Name(s)
placebo
Intervention Description
A tablet identical to the vitamin supplement but containing no vitamin B12
Primary Outcome Measure Information:
Title
Length
Description
Length measured in centimeters and expressed as z-scores
Time Frame
12 months of age
Title
Neurodevelopment
Description
Cognitive composite score of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III)
Time Frame
measured 6 and 12 months of age
Secondary Outcome Measure Information:
Title
Child hemoglobin concentration
Description
Hemoglobin measured by hemocue in full blood
Time Frame
measured 6 and 12 months of age
Title
Child development ASQ
Description
Total and subscale scores of the Ages and Stages Questionnaire - 3rd ed.
Time Frame
12 first months of life
Title
Child development Bayley
Description
Subscale scores of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley-III)
Time Frame
measured 6 and 12 months of age
Title
Heart rate variability
Description
Heart rate variability or vagal tone
Time Frame
12 first months of life
Title
Sleep and activity
Description
Sleep and activity measured by Actigraph (Actiwatch)
Time Frame
12 first months of life
Title
The Infant Motor Performance
Description
Screening tool to assess motor development
Time Frame
2 months after birth
Title
Still births
Description
Number of still births
Time Frame
Birth.
Title
Maternal hemoglobin concentration
Description
Hemoglobin measured by hemocue in full blood
Time Frame
at end of pregnancy and 6 and 12 months post party.
Title
Number of complicated births
Description
Number of births that were complicated
Time Frame
Birth.
Title
Children born at small for gestational age
Description
Number of children born at small for gestational age
Time Frame
Birth
Title
Birth weight
Description
weight in g
Time Frame
Birth
Title
Low birth weight
Description
Birthweight < 2,500 g
Time Frame
Birth
Title
Very low birth weight
Description
Birthweight < 2,000 g
Time Frame
Birth
Title
High birth weight
Description
Birthweight > 4,000 g
Time Frame
Birth
10. Eligibility
Sex
Female
Gender Based
Yes
Gender Eligibility Description
The study target pregnant women.
Minimum Age & Unit of Time
20 Years
Maximum Age & Unit of Time
40 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tor A Strand, MD/PhD
Organizational Affiliation
University of Bergen
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Laxman Shestha, MD
Organizational Affiliation
Tribhuvan University
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ram K Chandyo, MD/PhD
Organizational Affiliation
Kathmandu University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Manjeswori Ulak
City
Bhaktapur
ZIP/Postal Code
P.O.Box 40
Country
Nepal
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data will be shared with other researchers upon request after completion of the study (data collection) and after publication of the main outcomes. And if the ethical review boards approve the use of the data for other purposes that what is described in the proposal.
Citations:
PubMed Identifier
18709879
Citation
Allen LH. Causes of vitamin B12 and folate deficiency. Food Nutr Bull. 2008 Jun;29(2 Suppl):S20-34; discussion S35-7. doi: 10.1177/15648265080292S105.
Results Reference
background
PubMed Identifier
23344013
Citation
Samuel TM, Duggan C, Thomas T, Bosch R, Rajendran R, Virtanen SM, Srinivasan K, Kurpad AV. Vitamin B(12) intake and status in early pregnancy among urban South Indian women. Ann Nutr Metab. 2013;62(2):113-22. doi: 10.1159/000345589. Epub 2013 Jan 22.
Results Reference
background
PubMed Identifier
17991639
Citation
Taneja S, Bhandari N, Strand TA, Sommerfelt H, Refsum H, Ueland PM, Schneede J, Bahl R, Bhan MK. Cobalamin and folate status in infants and young children in a low-to-middle income community in India. Am J Clin Nutr. 2007 Nov;86(5):1302-9. doi: 10.1093/ajcn/86.5.1302.
Results Reference
background
PubMed Identifier
24594935
Citation
Ulak M, Chandyo RK, Adhikari RK, Sharma PR, Sommerfelt H, Refsum H, Strand TA. Cobalamin and folate status in 6 to 35 months old children presenting with acute diarrhea in Bhaktapur, Nepal. PLoS One. 2014 Mar 3;9(3):e90079. doi: 10.1371/journal.pone.0090079. eCollection 2014.
Results Reference
background
PubMed Identifier
18454811
Citation
Dror DK, Allen LH. Effect of vitamin B12 deficiency on neurodevelopment in infants: current knowledge and possible mechanisms. Nutr Rev. 2008 May;66(5):250-5. doi: 10.1111/j.1753-4887.2008.00031.x.
Results Reference
background
PubMed Identifier
23283502
Citation
Strand TA, Taneja S, Ueland PM, Refsum H, Bahl R, Schneede J, Sommerfelt H, Bhandari N. Cobalamin and folate status predicts mental development scores in North Indian children 12-18 mo of age. Am J Clin Nutr. 2013 Feb;97(2):310-7. doi: 10.3945/ajcn.111.032268. Epub 2013 Jan 2.
Results Reference
background
PubMed Identifier
24025626
Citation
Torsvik I, Ueland PM, Markestad T, Bjorke-Monsen AL. Cobalamin supplementation improves motor development and regurgitations in infants: results from a randomized intervention study. Am J Clin Nutr. 2013 Nov;98(5):1233-40. doi: 10.3945/ajcn.113.061549. Epub 2013 Sep 11.
Results Reference
background
PubMed Identifier
26098427
Citation
Kvestad I, Taneja S, Kumar T, Hysing M, Refsum H, Yajnik CS, Bhandari N, Strand TA; Folate and Vitamin B12 Study Group. Vitamin B12 and Folic Acid Improve Gross Motor and Problem-Solving Skills in Young North Indian Children: A Randomized Placebo-Controlled Trial. PLoS One. 2015 Jun 22;10(6):e0129915. doi: 10.1371/journal.pone.0129915. eCollection 2015.
Results Reference
background
PubMed Identifier
24598885
Citation
Duggan C, Srinivasan K, Thomas T, Samuel T, Rajendran R, Muthayya S, Finkelstein JL, Lukose A, Fawzi W, Allen LH, Bosch RJ, Kurpad AV. Vitamin B-12 supplementation during pregnancy and early lactation increases maternal, breast milk, and infant measures of vitamin B-12 status. J Nutr. 2014 May;144(5):758-64. doi: 10.3945/jn.113.187278. Epub 2014 Mar 5.
Results Reference
background
PubMed Identifier
23902779
Citation
Taneja S, Strand TA, Kumar T, Mahesh M, Mohan S, Manger MS, Refsum H, Yajnik CS, Bhandari N. Folic acid and vitamin B-12 supplementation and common infections in 6-30-mo-old children in India: a randomized placebo-controlled trial. Am J Clin Nutr. 2013 Sep;98(3):731-7. doi: 10.3945/ajcn.113.059592. Epub 2013 Jul 31.
Results Reference
background
PubMed Identifier
25802345
Citation
Strand TA, Taneja S, Kumar T, Manger MS, Refsum H, Yajnik CS, Bhandari N. Vitamin B-12, folic acid, and growth in 6- to 30-month-old children: a randomized controlled trial. Pediatrics. 2015 Apr;135(4):e918-26. doi: 10.1542/peds.2014-1848.
Results Reference
background
PubMed Identifier
24560137
Citation
Kumar T, Taneja S, Yajnik CS, Bhandari N, Strand TA; Study Group. Prevalence and predictors of anemia in a population of North Indian children. Nutrition. 2014 May;30(5):531-7. doi: 10.1016/j.nut.2013.09.015. Epub 2013 Oct 15.
Results Reference
background
PubMed Identifier
17851649
Citation
Yajnik CS, Deshpande SS, Jackson AA, Refsum H, Rao S, Fisher DJ, Bhat DS, Naik SS, Coyaji KJ, Joglekar CV, Joshi N, Lubree HG, Deshpande VU, Rege SS, Fall CH. Vitamin B12 and folate concentrations during pregnancy and insulin resistance in the offspring: the Pune Maternal Nutrition Study. Diabetologia. 2008 Jan;51(1):29-38. doi: 10.1007/s00125-007-0793-y. Epub 2007 Sep 13.
Results Reference
background
PubMed Identifier
28851784
Citation
Chandyo RK, Ulak M, Kvestad I, Shrestha M, Ranjitkar S, Basnet S, Hysing M, Shrestha L, Strand TA. 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. BMJ Open. 2017 Aug 29;7(8):e016434. doi: 10.1136/bmjopen-2017-016434.
Results Reference
derived
Links:
URL
http://cismac.org
Description
Centre for Intervention Science in Maternal and Child health
Learn more about this trial
Vitamin B12 Supplementation During Pregnancy on Cognitive Development
We'll reach out to this number within 24 hrs