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  • Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania

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Nutrition and metabolism
Protocol
Does early vitamin B12 supplementation improve neurodevelopment and cognitive function in childhood and into school age: a study protocol for extended follow-ups from randomised controlled trials in India and Tanzania
  1. Brita Askeland Winje1,
  2. Ingrid Kvestad2,
  3. Srinivasan Krishnamachari3,
  4. Karim Manji4,
  5. Sunita Taneja5,
  6. David C Bellinger6,
  7. Nita Bhandari5,
  8. Shruti Bisht3,5,
  9. Anne Marie Darling7,
  10. Christopher P Duggan6,7,
  11. Wafaie Fawzi7,
  12. Mari Hysing2,
  13. Tivendra Kumar5,
  14. Anura V Kurpad3,
  15. Christopher R Sudfeld7,
  16. Erling Svensen8,
  17. Susan Thomas3,
  18. Tor A Strand9,10
  1. 1 Department of Vaccine Preventable Diseases, Norwegian Institute of Public Health, Oslo, Norway
  2. 2 Regional Centre for Child and Youth Mental Health and Child Welfare, Uni Research Health, Bergen, Norway
  3. 3 Division of Mental Health and Neurosciences, St John’s Research Institute, Bangalore, Karnataka, India
  4. 4 Department of Pediatrics and Child Health, Muhibili University of Health and Allied Sciences, Dar es Salaam, Tanzania
  5. 5 Centre for Health Research and Development, Society for Applied Studies, New Delhi, Delhi, India
  6. 6 Division of Gastroenterology, Hepatology and Nutrition, Boston Children’s Hospital, Boston, Massachusetts, USA
  7. 7 Department of Global Health and Population, Harvard T H Chan School of Public Health, Boston, Massachusetts, USA
  8. 8 Haukeland University Hospital, Helse Bergen, Bergen, Norway
  9. 9 Department of Research, Innlandet Hospital Trust, Lillehammer, Norway
  10. 10 Faculty of Medicine, Centre for International Health, University of Bergen, Bergen, Norway
  1. Correspondence to Professor Tor A Strand; tor.strand{at}uib.no

Abstract

Introduction As many as 250 million children under the age of 5 may not be reaching their full developmental potential partly due to poor nutrition during pregnancy and the first 2 years of life. Micronutrients, including vitamin B12, are important for the development of brain structure and function; however, the timing, duration and severity of deficiencies may alter the impact on functional development outcomes. Consequently, to fully explore the effect of vitamin B12 on cognitive function, it is crucial to measure neurodevelopment at different ages, in different populations and with vitamin B12 supplementation at different times during the critical periods of neurodevelopment.

Methods and analysis In this project, we follow up children from four recently completed randomised placebo-controlled trials of oral vitamin B12 supplementation, two in India and two in Tanzania, to explore the long-term effects on neurodevelopmental outcomes and growth. All the included trials provided at least two recommended dietary allowances of oral vitamin B12 daily for at least 6 months. Vitamin B12 was supplemented either during pregnancy, early infancy or early childhood. Primary outcomes are neurodevelopmental status, cognitive function and growth later in childhood. We apply validated and culturally appropriate instruments to identify relevant developmental outcomes. All statistical analyses will be done according to intention-to-treat principles. The project provides an excellent opportunity to examine the effect of vitamin B12 supplementation in different periods during early life and measure the outcomes later in childhood.

Ethics and dissemination The study has received ethical approvals from all relevant authorities in Norway, USA, Tanzania and India and complies fully with ethical principles for medical research. Results will be presented at national and international research and policy meetings and published in peer-reviewed scientific journals, preferably open access.

Trial registration number NCT00641862 (Bangalore); NCT00717730, updated CTRI/2016/11/007494 (Delhi); NCT00197548 and NCT00421668 (Dar es Salaam).

  • vitamin B12
  • neurodevelopment
  • cognitive function
  • event related potential
  • executive function
  • growth

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/bmjopen-2017-018962

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    Footnotes

    • Contributors TAS, IK, CPD and WF took the initiative for the study. TAS, IK, CPD, WF, BAW, SK, KM, ST, MH, NB and ES were involved in developing the design and the study protocol. ST, SK and KM were responsible for setting up the study conduct in each site, with support from AMD, ST, TK, AK and SB. The statistical approach of the study was drafted by CRS, MH, TAS and WF. MH, IK, ES, DCB, and SK were responsible for the cognitive assessments. All authors approved the final version of the protocol. BAW, IK and TAS drafted the current manuscript. All authors have reviewed and accepted the final version of the manuscript.

    • Funding The Vitabeginning study was funded by the Norwegian Research Council Grant number 234495. The original trial in Bangalore was funded by the Indian Council of Medical Research (grant 5/7/192/06-RHN) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant R03 HD054123). The study in Delhi was funded by the Thrasher Research Fund (grant no. 02827) and the Research Council of Norway (grant 172226). The trials in Tanzania were funded by National Institute of Child Health and Human Development (NICHD R01 37701) and the Eunice Kennedy Shriver NIH grant (R01 HD048969-01). CPD is supported by NIH (grants K24DK104676 and P30 DK040561).

    • Competing interests None declared.

    • Patient consent Detail has been removed from this/these case description/s to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

    • Ethics approval Ethical Review Board in Norway (2014/1359, 2015/640), in addition to approvals from partners in USA, Tanzania and India.

    • Provenance and peer review Not commissioned; externally peer reviewed.