Vitamin B12 Supplementation During Pregnancy on Cognitive Development

NCT03071666 | Active Not Recruiting Phase 2 DMC

• 2 other identifiers: CISMAC-B12Universal Trial Number
• Study Type: interventional
• Target: 800
• Locations: 1 country
• Sites: 1

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.

Conditions

Pregnancy Related; Vitamin B 12 Deficiency; Anemia

Keywords

Nepal; South Asia; Nutrition; Pregnancy; Neurodevelopment; Growth

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (14)

• Child hemoglobin concentration

  measured 6 and 12 months of age

• Child development ASQ

  12 first months of life

• Child development Bayley

  measured 6 and 12 months of age

• Heart rate variability

  12 first months of life

• Sleep and activity

  12 first months of life

Study Arms (2)

Vitamin B12

EXPERIMENTAL

cobalamin, 50 µg per day throughout pregnancy and during the first 6 months postpartum.

Dietary Supplement: cobalamin

Placebo

PLACEBO COMPARATOR

Identical taste and appearance with the Experimental arm. Contains no cobalamin

Dietary Supplement: placebo

Interventions

cobalamin DIETARY_SUPPLEMENT

Vitamin supplment tablet containing 50µg cobalamin

Also known as: Vitamin B12

Vitamin B12

placebo DIETARY_SUPPLEMENT

A tablet identical to the vitamin supplement but containing no vitamin B12

Placebo

Eligibility Criteria

• Age: 20 Years - 40 Years
• Gender Eligibility Details: The study target pregnant women.
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre For International Health: lead
• Tribhuvan University Teaching Hospital, Institute Of Medicine.: collaborator
• NORCE Norwegian Research Centre AS: collaborator
• Sykehuset Innlandet HF: collaborator

Study Sites (1)

Manjeswori Ulak

Bhaktapur, P.O.Box 40, Nepal

Location

Related Publications (17)

• 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.

  PMID: 18709879 BACKGROUND

• 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.

  PMID: 23344013 BACKGROUND

• 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.

  PMID: 17991639 BACKGROUND

• 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.

  PMID: 24594935 BACKGROUND

• 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.

  PMID: 18454811 BACKGROUND

• 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.

  PMID: 23283502 BACKGROUND

• 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.

  PMID: 24025626 BACKGROUND

• 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.

  PMID: 26098427 BACKGROUND

• 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.

  PMID: 24598885 BACKGROUND

• 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.

  PMID: 23902779 BACKGROUND

• 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.

  PMID: 25802345 BACKGROUND

• 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.

  PMID: 24560137 BACKGROUND

• 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.

  PMID: 17851649 BACKGROUND

• Strand TA, Averina M, Bakken KS, Basnet S, Bottcher Y, Huber S, Hysing M, Kvestad I, Luders T, McCann A, Pokhrel D, Ranjitkar S, Sharma AK, Shrestha M, Ulak M, Chandyo RK. Early-Life Exposures, Neurodevelopment, and Health Outcomes: Protocol for a Birth Cohort Study. JMIR Res Protoc. 2026 Feb 11;15:e78593. doi: 10.2196/78593.

  PMID: 41493372 DERIVED

• Kvestad I, Ulak M, McCann A, Chandyo RK, Hysing M, Schwinger C, Ranjitkar S, Ueland PM, Basnet S, Strand TA. The Effect of Vitamin B-12 Supplementation During Pregnancy on Early Motor Performance: Secondary Analyses From a Double-Blinded Randomized Controlled Trial. J Nutr. 2026 Feb;156(2):101305. doi: 10.1016/j.tjnut.2025.101305. Epub 2025 Dec 27.

  PMID: 41461260 DERIVED

• Chandyo RK, Kvestad I, Ulak M, Ranjitkar S, Hysing M, Shrestha M, Schwinger C, McCann A, Ueland PM, Basnet S, Shrestha L, Strand TA. The effect of vitamin B12 supplementation during pregnancy on infant growth and development in Nepal: a community-based, double-blind, randomised, placebo-controlled trial. Lancet. 2023 May 6;401(10387):1508-1517. doi: 10.1016/S0140-6736(23)00346-X. Epub 2023 Apr 6.

  PMID: 37031691 DERIVED

• 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.

  PMID: 28851784 DERIVED

Related Links

• Centre for Intervention Science in Maternal and Child health

MeSH Terms

Conditions

Vitamin B 12 Deficiency; Anemia

Interventions

Vitamin B 12

Condition Hierarchy (Ancestors)

Vitamin B Deficiency; Avitaminosis; Deficiency Diseases; Malnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Corrinoids; Tetrapyrroles; Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Macrocyclic Compounds; Polycyclic Compounds

Study Officials

• Tor A Strand, MD/PhD

  University of Bergen

  PRINCIPAL INVESTIGATOR

• Laxman Shestha, MD

  Tribhuvan University

  PRINCIPAL INVESTIGATOR

• Ram K Chandyo, MD/PhD

  Kathmandu University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2017
• First Posted: March 7, 2017
• Study Start: March 27, 2017
• Primary Completion: June 28, 2022
• Study Completion (Estimated): December 31, 2029
• Last Updated: April 27, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE

Locations

NE (1)