By Philip R. Fischer, MD, DTM&H
Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN
SYNOPSIS: In June 2024, the Endocrine Society released new evidence-based guidelines suggesting that all children up to 18 years of age should receive vitamin D supplements, both to prevent rickets and to prevent respiratory tract infections. However, careful review of the data suggests that widespread implementation of this recommendation might not be warranted in North America.
SOURCES: Demay MB, Pittas AG, Bikle DD, et al. Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2024;Jun 3:dgae290.
Shah VP, Nayfeh T, Alsawaf Y, et al. A systematic review supporting the Endocrine Society clinical practice guidelines on vitamin D. J Clin Endocrinol Metab 2024;Jun 3:dgae312.
Vitamin D deficiency has been linked epidemiologically not only to skeletal disorders but also to infectious, autoimmune, metabolic, cardiovascular, and malignant diseases. Nonetheless, whether vitamin D deficiency is causally linked to infectious and other non-skeletal diseases is less clear. Vitamin D testing and supplementation have become much more common in North America, but it is not yet known whether supplementation actually is effective in preventing the non-skeletal effects of vitamin D deficiency.
Thus, experts within the Endocrine Society conducted a systematic review that then informed the preparation of guidelines for vitamin D testing and supplementation directed at preventing complications of low vitamin D levels in various subgroups of the general population. They based their findings and recommendations on evidence arising from randomized controlled trials and from large observational studies that included comparison between groups with and without vitamin D supplementation. Standard, rigorous methods of systematic reviews and evidence grading were employed.
Only for pediatric patients did the researchers find adequate evidence to make recommendations based on the association between vitamin D supplementation and infections. They stated: “In children and adolescents aged 1 to 18 years, we suggest empiric vitamin D supplementation to prevent nutritional rickets and potentially lower the risk of respiratory tract infections.” This recommendation was made with low (grade 2 of 4, with 4 being the highest level) certainty of evidence and low strength of the recommendation (grade 2, with 1 the higher of two options, and level 2 indicating that benefits of supplementation “probably outweigh” the risks, that “clinicians should recognize that different choices will be appropriate for each individual,” and that policy-making “will require substantial debate”).
Most clinicians and nutritionists consider vitamin D supplementation and food fortification with vitamin D to be distinctly different interventions. However, for these papers, the authors combined these interventions, defining their recommended “empiric vitamin D” as including “daily intake of fortified foods, vitamin formulations that contain vitamin D, and/or daily intake of a vitamin D supplement (pill or drops).”
The recommendation to supplement all children and adolescents with vitamin D to prevent respiratory tract infections was based on 12 randomized controlled trials involving 12,951 subjects. These studies were done in Afghanistan, Bangladesh, India, Israel, Japan, Mongolia, Taiwan, and Vietnam. Varying doses of vitamin D supplements were used, and based on this evidence, the authors were unable to recommend specific supplement doses.
Combining the 12 studies, the relative risk of developing a respiratory tract infection with vitamin D supplementation was 0.94, with a 95% confidence interval (CI) of 0.87-1.02. Limiting the analysis to just those with lower respiratory tract infections, the relative risk was 0.93 (95% CI, 0.83-1.04). Two studies considered tuberculosis; the relative risk of developing tuberculosis with vitamin D supplementation was 0.67 (95% CI, 0.14-3.11). Thus, there was not a statistically significant decrease in the risk of developing a single respiratory tract infection (upper, lower, or tuberculous) with vitamin D supplementation. However, in three of the trials, the number of infections was considered, thus counting multiple infections in the same child occurring during the supplementation trials; combined analysis of these three studies revealed that there was a statistically significant reduction in the total number of infections with vitamin D supplementation, with a relative risk of 0.64 (95% CI, 0.51-0.82).
Based on the randomized controlled trials considered, the authors also concluded that “undesirable effects are likely to be trivial” with supplementation of children with vitamin D.
In addition to the pediatric recommendation for vitamin D supplementation based on the reduction in risk of respiratory tract infections, the authors also made other recommendations about vitamin D testing and supplementation in specific population subgroups:
• ages 19-74 years: no empiric vitamin D supplementation and no routine screening of vitamin D status;
• age 75+ years: empiric vitamin D supplementation to reduce mortality;
• pregnant people: empiric vitamin D supplementation to reduce the risks of adverse gestational and neonatal outcomes; and
• people with prediabetes: empiric vitamin D supplementation to reduce progression to diabetes.
COMMENTARY
Rickets still is a global problem, as a result of both vitamin D deficiency and calcium deficiency.1 Vitamin D deficiency still has life-threatening consequences.2 Thus, these new recommendations are valuable and could lead to reductions in rickets and respiratory infections in children around the world.
There is evidence and wisdom behind these new recommendations. But careful consideration of the underlying evidence suggests that these new guidelines should not yet be implemented in North America as a means to prevent respiratory infections.
The authors clearly defined their terms regarding using vitamin D to prevent respiratory tract infections. The grading systems make it clear that the certainty of the evidence is “low” and that the strength of the recommendation is at the lower level. The authors’ definition of “empiric supplementation” makes it clear that “supplementation” also includes dietary ingestion of fortified foods. Thus, formula-fed infants, infants breastfeeding from vitamin D replete mothers, and children consuming adequate vitamin D-fortified milk products would not necessarily require further vitamin D supplementation.3
Unfortunately, rapid readers focusing on the abstract and a colored table will be left simply with the clearly presented conclusion that the Endocrine Society now recommends “empiric vitamin D for those aged 1 to 18 years.” Without careful consideration of the fine print, readers might not realize that the data were entirely from non-North American parts of the world, that the evidence was of “low” certainty, and that the recommendation is attached to caveats about individualizing care and having “substantial debate” before implementing new policies.
To strengthen the rigor of their recommendations, the authors rightly considered good randomized controlled trials. However, they extrapolated the risk of adverse effects of supplementation from research trials to generalized use, leading them to suggest that adverse effects of supplementation are “trivial.” Vitamin D toxicity still occurs in children, and even well-educated parents have become confused with the dosing of various over-the-counter vitamin D formulations, substituting mL for drops and inadvertently overdosing their children.4 The rates of excessively high vitamin D levels also have increased in the adult population as self-directed supplementation has become popular.5
References
- Creo AL, Thacher TD, Pettifor JM, et al. Nutritional rickets around the world: An update. Paediatr Int Child Health 2017;37:84-98.
- Aul AJ, Fischer PR, O’Grady JS, et al. Population-based incidence of potentially life-threatening complications of hypocalcemia and the role of vitamin D deficiency. J Pediatr 2019;211:98-104.e4.
- Lautatzis ME, Keya FK, Al Mahmud A, et al. Maternal vitamin D supplementation and infantile rickets: Secondary analysis of a randomized trial. Pediatrics 2024;153:e2023063263.
- Vogiatzi MG, Jacobson-Dickman E, DeBoer MD, et al. Vitamin D supplementation and risk of toxicity in pediatrics: A review of current literature. J Clin Endocrinol Metab 2014;99:1132-1141.
- Dudenkov DV, Yawn BP, Oberhelman S, et al. Changing incidence of serum 25-hydroxyvitamin D values above 50 ng/mL: A 10-year population-based study. Mayo Clin Proc 2015;90:577-586.
