Vitamin B12 Supplementation During Pregnancy on Cognitive Development

Anemia Clinical Trial

— VitaPreg  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03071666
• Other study ID #: CISMAC-B12
• Secondary ID: Universal Trial
• Status: Active, not recruiting
• Phase: Phase 2/Phase 3
• Start date: March 27, 2017
• Est. completion date: December 31, 2029

Study information

• Verified date: April 2024
• Source: Centre For International Health
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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:

1. 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.

2. 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):

1. 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.

2. 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.

3. Daily maternal administration of vitamin B12 from early pregnancy and for 6 months postpartum improves insulin sensitivity in the offspring.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 800
• Est. completion date: December 31, 2029
• Est. primary completion date: June 28, 2022
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 20 Years to 40 Years

Eligibility

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

Related Conditions & MeSH terms

• Anemia
• Pregnancy Related
• Vitamin B 12 Deficiency

Intervention

Dietary Supplement:
• cobalamin
Vitamin supplment tablet containing 50µg cobalamin
• placebo
A tablet identical to the vitamin supplement but containing no vitamin B12

Locations

Country	Name	City	State
Nepal	Manjeswori Ulak	Bhaktapur

Sponsors (4)

Lead Sponsor	Collaborator
Centre For International Health	NORCE Norwegian Research Centre AS, Sykehuset Innlandet HF, Tribhuvan University Teaching Hospital, Institute Of Medicine.

Country where clinical trial is conducted

Nepal, 

References & Publications (13)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

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

External Links

•   Centre for Intervention Science in Maternal and Child health