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

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: ClinicalTrials.gov Identifier: NCT01723852