Safety of High-Dose Vitamin D Supplementation Among Children Aged 0 to 6 Years: A Systematic Review and Meta-analysis

Nicklas Brustad, Sina Yousef, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, Bo Lund Chawes, Nicklas Brustad, Sina Yousef, Jakob Stokholm, Klaus Bønnelykke, Hans Bisgaard, Bo Lund Chawes

Abstract

Importance: Several health benefits of vitamin D have been suggested; however, the safety of high-dose supplementation in early childhood is not well described.

Objective: To systematically assess the risk of adverse events after high-dose supplementation with vitamin D reported in published randomized clinical trials.

Data sources: PubMed and ClinicalTrials.gov were searched through August 24, 2021.

Study selection: Randomized clinical trials of high-dose vitamin D supplementation in children aged 0 to 6 years, defined as greater than 1000 IU/d for infants (aged 0-1 year) and greater than 2000 IU/d for children aged 1 to 6 years.

Data extraction and synthesis: Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 reviewers independently extracted the data from the eligible studies. Summary risk ratio (RR), 95% CI, and P values were derived from random-effects meta-analysis.

Main outcomes and measures: Adverse events, serious adverse events (SAEs), and/or levels of 25-hydroxyvitamin D, calcium, alkaline phosphatase, phosphate, parathyroid hormone, and/or the ratio of urine calcium to creatinine levels.

Results: A total of 32 randomized clinical trials with 8400 unique participants were included. Different clinical outcomes of children receiving high-dose vitamin D supplements ranging from 1200 to 10 000 IU/d and bolus doses from 30 000 IU/week to a single dose of 600 000 IU were evaluated. Eight studies with 4612 participants were eligible for meta-analysis using a control group receiving either low-dose vitamin D supplementation (≤400 IU/d) or placebo when investigating the risk of SAEs such as hospitalization or death. No overall increased risk of SAEs in the high-dose vitamin D vs control groups was found (RR, 1.01 [95% CI, 0.73-1.39]; P = .89, I2 = 0%). In addition, risk of hypercalcemia (n = 726) was not increased (RR, 1.18 [95% CI, 0.72-1.93]; P = .51). Clinical adverse events potentially related to the vitamin D supplementation reported in the studies were rare.

Conclusions and relevance: This meta-analysis and systematic review found that high-dose vitamin D supplementation was not associated with an increased risk of SAEs in children aged 0 to 6 years, and that clinical adverse events potentially related to the supplementation were rare. These findings suggest that vitamin D supplementation in the dose ranges of 1200 to 10 000 IU/d and bolus doses to 600 000 IU to young children may be well tolerated.

Conflict of interest statement

Conflict of Interest Disclosures: None reported.

Figures

Figure 1.. Study Flowchart
Figure 1.. Study Flowchart
RCT indicates randomized clinical trial.
Figure 2.. Summary Risk Ratio (RR) of…
Figure 2.. Summary Risk Ratio (RR) of the Association Between High-Dose Vitamin D Supplementation and Serious Adverse Events
Different sizes of markers indicate weights of the studies; whiskers, 95% CIs.
Figure 3.. Summary Risk Ratio (RR) of…
Figure 3.. Summary Risk Ratio (RR) of the Association Between High-Dose Vitamin D Supplementation and Serious Adverse Events Stratified by Bolus and Daily Supplementation
Different sizes of markers indicate weights of the studies; whiskers, 95% CIs.

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Source: PubMed

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