What is the question?

• The question is: What is the relationship between vitamin D from supplements consumed during infancy and toddlerhood and bone health?

What is the answer to the question?

• Limited evidence suggests no relationship between consumption of 400 IU per day of vitamin D from supplements before age 12 months, compared with higher dosages of up to 1600 IU per day, and biomarkers of bone metabolism in children up to age 36 months. 
• Insufficient evidence is available to determine the relationship between 400 IU per day of vitamin D from supplements, compared with higher dosages, and bone mass, rickets, or fracture. 
• Insufficient evidence is available to determine the relationship between 400 IU per day of vitamin D from supplements, compared with lower dosages, and bone mass, biomarkers of bone metabolism, rickets, or fracture. 
• Insufficient evidence is available to determine the relationship between vitamin D from supplements, compared with no vitamin D from supplements, and bone mass, biomarkers of bone metabolism, rickets, or fracture. 
• Insufficient evidence is available to determine the relationship between vitamin D from supplements, compared with vitamin D from fortified foods, and bone mass, biomarkers of bone metabolism, rickets, or fracture. 

Why was this question asked?

• This important public health question was identified by the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS) to be examined by the 2020 Dietary Guidelines Advisory Committee.

How was this question answered?

• The 2020 Dietary Guidelines Advisory Committee, Birth to 24 Months Subcommittee, conducted a systematic review to answer this question with support from the Nutrition Evidence Systematic Review (NESR) team.

What is the population of interest? 

• Vitamin D supplementation was examined in healthy infants and toddlers (birth to 24 months) with outcomes measured at birth through age 18 years.

What evidence was found? 

• This review includes 6 articles.
• The articles compared infants and toddlers who consumed different dosages of vitamin D from supplements. Most articles compared infants supplemented with 400 International Units (IU) per day (which is the Adequate Intake for infants) with infants supplemented with higher dosages.
• The outcomes of interest were bone mass, biomarkers of bone metabolism, rickets, and fracture from birth to age 18 years. Most articles examined bone mass and biomarkers of bone metabolism in children up to age 36 months.
• Limited evidence suggests that infants who are supplemented with 400 IU per day and infants who are supplemented with higher dosages of up to 1600 IU per day do not have differences in biomarkers of bone metabolism up to age 36 months, but the evidence related to bone mass was inconsistent. 
• There are limitations in the evidence as follows:
  • There were not a lot of articles, and some of the articles studied groups of infants and toddlers that may have been too small to detect a relationship between iron supplementation and growth or size.
  • The studies examined infants who were given supplements for different lengths of time, examined different biomarkers of bone metabolism, and measured the biomarkers at different ages, so comparing the findings of the studies was difficult.
  • In the studies that reported race, most or all infants were white. The findings may or may not be the same in other racial or ethnic groups. 

How up-to-date is this systematic review?

• This review searched for studies from January, 2000 to January, 2020

Background

• This important public health question was identified by the U.S. Departments of Agriculture (USDA) and Health and Human Services (HHS) to be examined by the 2020 Dietary Guidelines Advisory Committee.
• The 2020 Dietary Guidelines Advisory Committee, Birth to 24 Months Subcommittee conducted a systematic review to answer this question with support from the Nutrition Evidence Systematic Review (NESR) team.
• The goal of this systematic review was to examine the following question: What is the relationship between vitamin D from supplements consumed during infancy and toddlerhood and bone health? 

Conclusion statements and grades

• Limited evidence suggests no relationship between consumption of 400 IU per day of vitamin D from supplements before age 12 months, compared with higher dosages of up to 1600 IU per day, and biomarkers of bone metabolism in children up to age 36 months. (Grade: Limited)
• Insufficient evidence is available to determine the relationship between 400 IU per day of vitamin D from supplements, compared with higher dosages, and bone mass, rickets, or fracture. (Grade: Grade not assignable)
• Insufficient evidence is available to determine the relationship between 400 IU per day of vitamin D from supplements, compared with lower dosages, and bone mass, biomarkers of bone metabolism, rickets, or fracture. (Grade: Grade not assignable)
• Insufficient evidence is available to determine the relationship between vitamin D from supplements, compared with no vitamin D from supplements, and bone mass, biomarkers of bone metabolism, rickets, or fracture. (Grade: Grade not assignable)
• Insufficient evidence is available to determine the relationship between vitamin D from supplements, compared with vitamin D from fortified foods, and bone mass, biomarkers of bone metabolism, rickets, or fracture. (Grade: Grade not assignable)

Methods

• A literature search was conducted using 4 databases (PubMed, Cochrane, Embase, and CINAHL) to identify articles that evaluated the intervention or exposure of vitamin D from supplements consumed during infancy and toddlerhood and bone health outcomes. A manual search was conducted to identify articles that may not have been included in the electronic databases searched. Articles were screened by two NESR analysts independently for inclusion based on pre-determined criteria.
• Data extraction and risk of bias assessment were conducted for each included study, and both were checked for accuracy. The Committee qualitatively synthesized the body of evidence to inform development of conclusion statements, and graded the strength of evidence using pre-established criteria for risk of bias, consistency, directness, precision, and generalizability.

Summary of the evidence

• Six articles met the inclusion criteria for this systematic review, which presented evidence from 5 independent randomized controlled trials (1 research group published 2 articles about the same trial). 
• The intervention of interest was vitamin D from supplements consumed during infancy or toddlerhood. Dietary supplements are products that contain one or more dietary ingredients (in this case, vitamin D) intended to be taken by mouth to supplement the diet. In the United States, 400 IU of vitamin D per day is the AI for infants younger than age 12 months, whereas the RDA for ages 12 to 24 months of age is 600 IU per day. To meet this need, the American Academy of Pediatrics currently recommends a supplement of 400 IU per day for infants fed human milk (with the possible exception of infants whose mothers are taking supplements of about 6000 IU per day; maternal vitamin D supplementation during lactation was outside of the scope of this systematic review).
• The comparators of interest were different dosages of vitamin D from supplements and vitamin D from fortified foods. However, no articles were identified that included fortified food comparators. 
• The outcomes of interest were bone mass, biomarkers of bone metabolism, rickets, and fracture through adolescence (i.e., birth through age 18 years). However, no articles were identified that examined fracture or outcomes beyond age 36 months.
• Limited evidence from 3 studies suggests no relationship between 400 IU per day of vitamin D from supplements, compared with higher dosages, and biomarkers of bone metabolism in children up to age 36 months. The ability to draw a stronger conclusion was primarily limited by a small number of studies, small sample sizes, heterogeneous methods, and limited generalizability.  
• Evidence available from 4 studies was insufficient to determine whether a relationship exists between 400 IU per day of vitamin D from supplements, compared with higher dosages, and bone mass. The ability to draw a conclusion was hindered by inconsistent findings from a small number of studies. No studies were available that examined the relationship between 400 IU per day of vitamin D from supplements, compared with higher dosages, and rickets or bone fracture.
• Evidence available from 1 study was insufficient to determine whether a relationship exists between 400 IU per day of vitamin D from supplements, compared with lower dosages, and bone mass or biomarkers of bone metabolism. No studies were available that examined the relationship between 400 IU per day of vitamin D from supplements, compared with lower dosages, and rickets or fracture.
• Evidence available from 1 study was insufficient to determine whether a relationship exists between 200 IU per day of vitamin D from supplements for different durations, compared with no vitamin D from supplements, and biomarkers of bone metabolism or rickets. No studies were available that examined the relationship between 200 IU per day of vitamin D from supplements for different durations, compared with no vitamin D from supplements, and bone mass or fracture. No studies were available that compared other dosages of vitamin D from supplements with no supplementation. It is likely that the evidence that led to the current supplementation recommendation pre-dates our literature search date range of January 2000 to January 2020.