University of Oulu

Tuovinen S, Räikkönen K, Holmlund-Suila E, et al. Effect of High-Dose vs Standard-Dose Vitamin D Supplementation on Neurodevelopment of Healthy Term Infants: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(9):e2124493,

Effect of high-dose vs standard-dose vitamin D supplementation on neurodevelopment of healthy term infants : a randomized clinical trial

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Author: Tuovinen, Soile1,2; Räikkönen, Katri2; Holmlund-Suila, Elisa3,4;
Organizations: 1Psychology/Welfare Sciences, Faculty of Social Sciences, University of Tampere, Tampere, Finland
2Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
3Children’s Hospital, Pediatric Research Center, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
4Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
5Finnish Institute for Health and Welfare, Helsinki, Finland
6Research Unit for Pediatrics, Pediatric Neurology, Pediatric Surgery, Child Psychiatry, Dermatology, Clinical Genetics, Obstetrics and Gynecology, Otorhinolaryngology, and Ophthalmology, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
7Folkhälsan Research Center, Helsinki, Finland
8Department of Clinical and Molecular Medicine, Norwegian University for Science and Technology, Trondheim, Norway
9Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1 MB)
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Language: English
Published: American Medical Association, 2021
Publish Date: 2021-11-02


Importance: Vitamin D may be important for neurodevelopment. The optimal daily dose of vitamin D for early brain development is not known.

Objectives: To test whether a higher (1200 IU) vs standard (400 IU) dose of vitamin D₃ has beneficial effects on neurodevelopment in the first 2 years of life and whether serum 25-hydroxyvitamin D concentration is associated with neurodevelopment.

Design, Setting, and Participants: This double-blind, interventional randomized clinical trial involved healthy infants born full-term between January 1, 2013, and June 30, 2014, at a maternity hospital in Helsinki, Finland, at the 60th northern latitude. Two-year follow-up was conducted by May 30, 2016. Data analysis was by the intention-to-treat principle. Data were analyzed from November 1, 2020, to May 31, 2021.

Interventions: Randomization of 404 infants to receive 400 IU of oral vitamin D₃ supplementation daily and 397 infants to receive 1200 IU of oral vitamin D3 supplementation daily from 2 weeks to 24 months of age.

Main Outcomes and Measures: Primary outcomes were child total developmental milestone scores at 12 and 24 months of age measured using the Ages and Stages Questionnaire (total score is calculated as a mean of the 5 subscale scores: total score range, 0–60, where 0 indicates delay in all developmental domains and 60 indicates that the child can master all age-specific skills) as well as externalizing, internalizing, and dysregulation problems and competencies scores at 24 months measured using the Infant-Toddler Social and Emotional Assessment (range 0–2, where 0 indicates no problems or no competencies and 2 indicates a high level of problems or a high level of competencies; variables were standardized to the mean [SD] of 0 [1]). Secondary outcomes were specific skills, problems, and competencies derived from these questionnaires.

Results: Of the 987 families recruited, 495 children were randomly assigned to receive 400 IU of vitamin D₃, and 492 children were randomly assigned to receive 1200 IU of vitamin D₃. A total of 801 families participated in the follow-up at 12 and/or 24 months, with 404 children (207 girls [51.2%]) in the 400-IU group and 397 children (198 girls [49.9%]) in the 1200-IU group. All children were of Northern European ethnicity. No differences were found between the 400-IU group and the 1200-IU group in the mean (SD) adjusted Ages and Stages Questionnaire total score at 12 months (45.0 [7.1] vs 46.2 [7.9]; mean difference [MD], 1.17 [95% CI, –0.06 to 2.38]) or 24 months (50.9 [5.3] vs 51.5 [5.5]; MD, 0.48 [95% CI, –0.40 to 1.36]). No differences were found between the 400-IU group and the 1200-IU group at 24 months in the mean (SD) adjusted Infant-Toddler Social and Emotional Assessment externalizing domain score (–0.07 [1.00] vs 0.07 [0.98]; MD, 0.15 [95% CI, –0.01 to 0.31]), internalizing domain score (0.04 [1.06] vs –0.02 [0.98]; MD, –0.07 [95% CI, –0.24 to 0.1.0]), dysregulation domain score (–0.00 [1.04] vs 0.02 [0.96]; MD, 0.02 [95% CI, –0.14 to 0.18]), or competencies score (–0.02 [1.02] vs 0.01 [1.02]; MD, 0.03 [95% CI, –0.13 to 0.20]). The 1200-IU group did have a higher risk in the adjusted model of scoring 1.5 SDs or more on the externalizing domain score (odds ratio, 2.33 [95% CI, 1.19–4.56]; P = .01). Levels of serum 25-hydroxyvitamin D were not associated with the primary outcomes.

Conclusions and Relevance: Higher-than-standard vitamin D₃ doses provide no systematic benefits for child neurodevelopment up to 2 years of age. However, the potential disadvantageous effects of higher doses could not be fully excluded; even if minimal, the potential nonbeneficial effects of higher-than-standard doses warrant further studies in which both safety and benefits should be evaluated.

Trial Registration: Identifier: NCT01723852

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Series: JAMA network open
ISSN: 2574-3805
ISSN-E: 2574-3805
ISSN-L: 2574-3805
Volume: 4
Issue: 9
Article number: e2124493
DOI: 10.1001/jamanetworkopen.2021.24493
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
Funding: This work was supported by the Academy of Finland, Foundation for Pediatric Research, Finska Läkaresällskapet, Finnish Medical Foundation, Governmental Subsidy for Clinical Research, Päivikki and Sakari Sohlberg Foundation, Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne, Sigrid Jusélius Foundation, Folkhälsan Research Foundation, Novo Nordisk Foundation, Orion Research Foundation, Barncancerfonden, and Avohoidon Tutkimussäätiö. Orion Pharmaceuticals is acknowledged for providing the vitamin D supplements gratis for the study.
Copyright information: This is an open access article distributed under the terms of the CC-BY License. © 2021 Tuovinen S et al. JAMA Network Open.