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. 2016 Feb 25;4:e1701.
doi: 10.7717/peerj.1701. eCollection 2016.

A Systematic Review of Pediatric Clinical Trials of High Dose Vitamin D

Free PMC article

A Systematic Review of Pediatric Clinical Trials of High Dose Vitamin D

Nassr Nama et al. PeerJ. .
Free PMC article


Background. Due to inadequate UV exposure, intake of small quantities of vitamin D is recommended to prevent musculoskeletal disease. Both basic science and observational literature strongly suggest that higher doses may benefit specific populations and have non-musculoskeletal roles. Evaluating the evidence surrounding high dose supplementation can be challenging given a relatively large and growing body of clinical trial evidence spanning time, geography, populations and dosing regimens. Study objectives were to identify and summarize the clinical trial literature, recognize areas with high quality evidence, and develop a resource database that makes the literature more immediately accessible to end users. Methods. Medline (1946 to January 2015), Embase (1974 to January 2015), and Cochrane databases (January 2015), were searched for trials. All pediatric (0-18 years) trials administering doses higher than 400 IU (<1 year) or 600 IU (≥1 year) were included. Data was extracted independently by two of the authors. An online searchable database of trials was developed containing relevant extracted information ( Sensitivity and utility were assessed by comparing the trials in the database with those from systematic reviews of vitamin D supplementation including children. Results. A total of 2,579 candidate papers were identified, yielding 169 trials having one or more arms meeting eligibility criteria. The publication rate has increased significantly from 1 per year (1970-1979) to 14 per year (2010-2015). Although 84% of the total trials focused on healthy children or known high risk populations (e.g., renal, prematurity), this proportion has declined in recent years due to the rise in trials evaluating populations and outcomes not directly related to the musculoskeletal actions of vitamin D (27% in 2010s). Beyond healthy children, the only pediatric populations with more than 50 participants from low risk of bias trials evaluating a clinically relevant outcome were prematurity and respiratory illness. Finally, we created and validated the online searchable database using 13 recent systematic reviews. Of the 38 high dose trials identified by the systematic review, 36 (94.7%) could be found within the database. When compared with the search strategy reported in each systematic review, use of the database reduced the number of full papers to assess for eligibility by 85.2% (±13.4%). Conclusion. The pediatric vitamin D field is highly active, with a significant increase in trials evaluating non-classical diseases and outcomes. Despite the large overall number there are few high quality trials of sufficient size to provide answers on clinical efficacy of high-dose vitamin D. An open access online searchable data should assist end users in the rapid and comprehensive identification and evaluation of trials relevant to their population or question of interest.

Keywords: High-dose; Online database; Pediatrics; Systematic review; Vitamin D.

Conflict of interest statement

Margaret Sampson is an Academic Editor for PeerJ.


Figure 1
Figure 1. Flow chart of study selection based on inclusion and exclusion criteria.
The stages of a systematic selection scheme include: identification, screening, eligibility, and final included studies.
Figure 2
Figure 2. Evolution of pediatrics trials of high dose vitamin D over time.
Exponential increase in number of trials (A, R2 = 0.96, p < 0.001). (B) Comparison of studied populations among the different decades (p < 0.001). (C) Comparison of form of vitamin D administered among different decades (p < 0.001). (●) Healthy/subclinical VDD; (○) Classical; (▾) Non-classical; (□) Cholecalciferol; (■) Ergocalciferol.
Figure 3
Figure 3. Comparison of trials among geographical regions.
Number of published trials per region (A, p < 0.001), and patients (B, p < 0.001). (C–F) North America and Europe (■) compared to the other regions (□), in terms of route (C, p < 0.001), form (D, p = 0.003), dosage (E, p < 0.001), frequency of supplementation (F, p < 0.001), and population (G, p = 0.81). AI, Adequate Intake; C/S, Central/southern; D2, Ergocalciferol; D3, Cholecalciferol; IM, Intramuscular; IV, Intravenous; NZ, New Zealand; PO, Oral; RDA, Recommended Dietary Allowance.

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Grant support

Nassr Nama received an Undergraduate Research Opportunity Program (UROP) from the University of Ottawa. Nassr Nama and Klevis Iliriani received Summer Studentships from the Children’s Hospital of Eastern Ontario Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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