ARTICLE

Modifiable Determinants of Serum

25-Hydroxyvitamin D Status in Early Childhood
Opportunities for Prevention
Jonathon L. Maguire, MD, MSc, FRCPC; Catherine S. Birken, MD, MSc, FRCPC; Marina Khovratovich, MD;
Julie DeGroot, MSc; Sarah Carsley, MSc; Kevin E. Thorpe, MMath; Muhammad Mamdani, PharmD, MPH, MA;
Patricia C. Parkin, MD, FRCPC; for the TARGet Kids! Collaboration

Objectives: To determine the effect of modifiable di-

etary intake variables (current vitamin D supplementation and daily cows milk intake) on 25-hydroxyvitamin
D level in early childhood and to evaluate the relationship between these modifiable dietary factors and other
largely nonmodifiable determinants of vitamin D status
including skin pigmentation and season.
Design: Cross-sectional study.
Setting: Primary care pediatric and family medicine practices participating in the TARGet Kids! practice-based research network in Toronto, Ontario, Canada.
Participants: From December 2008 to June 2011,
healthy children 1 to 5 years of age were recruited during a routine physicians visit.
Interventions: Survey, anthropometric measurements, and laboratory data were collected. A multivariable linear regression model was developed to examine
the independent effects of vitamin D supplementation and
daily volume of cows milk on 25-hydroxyvitamin D level.

Author Affiliations are listed at

the end of this article.
Group Information: The
TARGetKids! Collaboration
Clinical Site Investigators are
listed at the end of this article.

Main Outcome Measures: 25-Hydroxyvitamin D level.

Results: Blood was obtained in 1898 children. Two modifiable dietary intake variables, vitamin D supplementation and cows milk, increased 25-hydroxyvitamin D level
by 3.4 ng/mL (95% CI, 2-4 ng/mL) and 1.6 ng/mL per
250-mL cup per day (95% CI, 1-2 ng/mL), respectively.
Two nonmodifiable variables reflecting cutaneous vitamin D synthesis (skin pigmentation and season) were also
strongly associated with 25-hydroxyvitamin D status but
accounted for a much smaller proportion of the explained variation in 25-hydroxyvitamin D level. The effect of vitamin D supplementation and milk intake on
25-hydroxyvitamin D level appeared similar regardless
of skin pigmentation or season.
Conclusion: Two modifiable dietary intake variables (vitamin D supplementation and cows milk intake) are the
most important determinants of 25-hydroxyvitamin D status in early childhood.

JAMA Pediatr. 2013;167(3):230-235.

Published online January 14, 2013.
doi:10.1001/2013.jamapediatrics.226

T IS WELL KNOWN THAT SEVERE VI-

tamin D deficiency causes rickets but less severe vitamin D deficiency (vitamin D levels of
10-30 ng/mL) is emerging as a
risk factor for a number of acute and
chronic illnesses including asthma and allergies in children.1-12 Understanding modifiable determinants of vitamin D status in
early childhood is of practical importance to dietitians, physicians, and parents of young children.13-15
It has been suggested that dietary intake of vitamin D is an important modifiable determinant of vitamin D status in
young children.16-19 Further, a number of
studies have identified that the major dietary sources of vitamin D in young children are vitamin Dfortified cows milk and
vitamin Dcontaining supplements.20-26
JAMA PEDIATR/ VOL 167 (NO. 3), MAR 2013
230

Yet, the effect of cows milk intake and vitamin D supplementation on vitamin D
status is unclear, particularly in the context of known nonmodifiable vitamin D
determinants such as skin pigmentation
and season.
In 2008, the American Academy of Pediatrics Committee on Nutrition recommended that all children older than 1 year
receiving less than 1 L of cows milk per
day be supplemented with 400 IU of vitamin D daily.15 For the first time, healthy
children older than 1 year were recommended to receive supplemental vitamin
D, providing a unique opportunity to study
the effect of vitamin D supplementation
and cows milk intake on the vitamin D status of young children.
The primary objective of this study was
to determine the effect of current vitamin

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Author Aff
Applied He
of the Li Ka
Institute (D
Mamdani a
Departmen
Maguire), S
Paediatric O
Team, Divis
Medicine, T
Children (D
Khovratovi
Mss DeGro
Faculty of M
Departmen
Maguire, Bi
Dalla Lana
Health (Mr
Dan Facult
Mamdani),
Toronto, To
Canada.
Group Info
TARGetKid
Clinical Sit
listed at the

D supplementation and daily cows milk intake on 25hydroxyvitamin D level in a large cohort of healthy urban preschool children. Our secondary objective was to
evaluate the relationship between these modifiable dietary factors and other nonmodifiable determinants of
vitamin D status including skin pigmentation and season.
METHODS

SUBJECTS AND DESIGN

In this prospectively designed, cross-sectional observational
study, healthy children 1 to 5 years of age were recruited during a routine health maintenance physicians visit through the
TARGet Kids! primary care practice-based research network
in Toronto, Ontario, Canada (latitude 43.4!N) between December 2008 and June 2011. TARGet Kids! is a collaboration
between University of Toronto child health outcomes researchers and primary care physicians from the Department of Pediatrics and the Department of Family and Community Medicine. Children were excluded if they had any chronic illnesses
(excluding asthma), were taking a medication known to alter
vitamin D metabolism (ie, phenobarbital), or had a gestational age less than 32 weeks.

SUBJECT RECRUITMENT
AND DATA COLLECTION
Study participants were recruited by research personnel embedded in 7 participating pediatric and family medicine practices. Data were collected prospectively through a standardized parent-completed survey instrument based on the Canadian
Community Health Survey27; anthropometric measurements including height and weight obtained by trained research assistants; and venous blood sampling collected at the primary care
clinic. Medidata RAVE (Medidata Solutions Inc, http://www
.mdsol.com/) was used as the secure electronic data capture system and data repository for all TARGet Kids! data.
The primary outcome for this study was 25-hydroxyvitamin D level. Specimens were sent daily to the Clinical Biochemistry Laboratory at Mount Sinai Hospital in Toronto. Total
25-hydroxyvitamin D level was measured from sera samples
using a competitive 2-step chemiluminescence assay with a DiaSorin LIAISON 25-hydroxyvitamin D TOTAL.28 Extensive testing and validation of this machine has been performed and has
demonstrated an intra-assay imprecision of 7.2% at a concentration of 85 ng/mL (to convert to nanomoles per liter, multiply by 2.496) and an interassay imprecision of 4.9% at 13 ng/
mL, 8.9% at 31 ng/mL, and 17.4% at 85 ng/mL, values that are
well within acceptable limits for biochemical measurements.29,30
The primary predictor variables were vitamin D supplementation and daily volume of cows milk intake. These were
determined from the response to the questions Does your child
take a vitamin Dcontaining supplement regularly? and How
many 250-mL cups of cows milk does your child drink in a
typical day?
Covariates that might influence vitamin D status were identified through a literature review. Covariates were chosen for
inclusion if they were associated with 25-hydroxyvitamin D in
1 or more published studies and included age, sex, season (MaySeptember vs October-April), daily outdoor play time, daily
screen time, and skin pigmentation. Weight was measured using
a precision digital scale ("0.025%; SECA) and standing height
was measured using a stadiometer (SECA). Body mass index
was calculated as weight in kilograms divided by height in me-

7346 Eligible

3950 Did not consent

1884 Declined

3396 Consent obtained

2066 Deferred

1898 Blood obtained

Figure 1. Flow diagram of participant recruitment and retention through the

study.

ters squared.27,31 Body mass index z scores were calculated using

World Health Organization growth standards.32 Skin pigmentation was measured by a trained research assistant using the
Fitzpatrick scale, which is a 6-category skin pigmentation classification system that has been widely used.17,33

STATISTICAL ANALYSES
Descriptive statistics were performed for the main outcome, predictors, and covariates. For our primary analysis, a multivariable linear regression model was developed to examine the independent effects of vitamin D supplementation and daily
volume of cows milk on 25-hydroxyvitamin D level with adjustment of prespecified, clinically relevant covariates (described earlier). All covariates were included in the final model
irrespective of their associated P values.
To reduce the likelihood of overfitting and obtain more conservative estimates of model performance, bootstrap validation of the linear regression model was performed. Additionally, the bootstrap assessment was repeated 100 times to obtain
95% confidence intervals.34 Missing data were handled by single
imputation using conditional means and recursive partitioning.35 A sensitivity analysis including or not including imputed data was also conducted.
For our secondary analyses, we explored the relationship
between vitamin D supplementation and milk intake on
25-hydroxyvitamin D level in the context of childrens skin
pigmentation and season. To accomplish this, we built on the
multivariable linear regression model developed for the primary analyses through the addition of biologically plausible
interactions. These included vitamin D supplementation by
milk intake, vitamin D supplementation by season, vitamin D
supplementation by skin pigmentation, and skin pigmentation by season. To achieve a balance between overfitting and
interpretation and to limit the biases that can result from standard variable selection approaches, these interactions were
tested together. If the joint P value was large (#.30), no further testing was considered. Otherwise, the interactions were
retained in the model. To assess the contribution of each variable and interaction on the variation in 25-hydroxyvitamin D
level, the partial R2 for each was calculated and displayed
graphically.
Data were analyzed using the R project for statistical computing.36 This study was approved by the research ethics board
at The Hospital for Sick Children, and all parents of participating children consented to participation in the study.
RESULTS

STUDY POPULATION
Of the 3396 children who consented to participate, venous blood sampling was obtained in 1898 children
who were included in this analysis (Figure 1). Sev-

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Table 2. Multivariable Linear Regression Model

50

% of Total Population

40

Daily vitamin D
supplementation (yes vs no)
Cows milk intake (per cup/d)
Season (May-Sep vs Oct-Apr)
Outdoor free play (per 1 h/d)
Skin pigmentation
(Fitzpatrick type I-III vs IV-VI)
Age (per year)
BMI z score (per unit)
Screen time (per 1 h/d)

30

20

10

25-Hydroxyvitamin D
Effect, ng/mL (95% CI)

Variable

20

40

60

80

100

120

25-Hydroxyvitamin D, ng/mL

Figure 2. Distribution of study participants 25-hydroxyvitamin D serum levels.

To convert 25-hydroxyvitamin D to nanomoles per liter, multiply by 2.496.

Table 1. Baseline Characteristics

No. (%)
(n = 1898)

Subjects
Age, mo, mean (SD)
Male
BMI z score, mean (SD)
Overweight
Obese
Current breast feeding
Daily milk intake, mL, mean (SD)
Current bottle use
Daily vitamin D supplementation
Daily outdoor play time, min, mean (SD)
Daily screen time, min, mean (SD)
Season (Oct-Apr)
Skin pigmentation (Fitzpatrick type)
1 (lightest)
2
3
4
5
6 (darkest)

37 (18)
964 (51)
0.22 (1.1)
271 (15)
86 (5)
218 (12)
455 (307)
465 (26)
1021 (57)
61 (56)
79 (77)
991 (52)
155 (9)
783 (44)
566 (32)
201 (11)
41 (2)
23 (2)

Abbreviation: BMI, body mass index.

enty-six percent of children had complete survey, anthropometric, and laboratory data. Fifty-seven percent
of the population were regularly consuming a vitamin
Dcontaining supplement. Mean daily cows milk intake was 455 mL. Mean 25-hydroxyvitamin D level was
35 ng/mL (95% CI, 34.86-35.66 ng/mL). Thirty-five
percent (95% CI, 33%-38%) had a 25-hydroxyvitamin
D level less than 30 ng/mL and 6% (95% CI, 5%-7%)
had a 25-hydroxyvitamin D level less than 20 ng/mL
(Figure 2). Subject characteristics are presented in
Table 1. Imputation for missing values did not change
descriptive characteristics.
EFFECT OF VITAMIN D SUPPLEMENTATION
AND COWS MILK INTAKE
ON 25-HYDROXYVITAMIN D LEVEL
For our primary analysis, results of the multivariable linear regression model are shown in Table 2. In the ad-

P Value

3.4 (2 to 4)

$.001

1.6 (1 to 2)
1.6 (0.4 to 2.8)
0.3 (0 to 0.4)
2.7 (1.2 to 4.4)

$.001
.004
.03
.001

%0.2 (%0.4 to 0)
%0.6 (%1.2 to 0)
0.2 (0 to 0.4)

.05
.03
.22

Abbreviation: BMI, body mass index.

SI factor conversion: To convert 25-hydroxyvitamin D to nanomoles per
liter, multiply by 2.496.

justed model, the 2 modifiable dietary intake variables,

vitamin D supplementation and cows milk intake, were
highly significant, with vitamin D supplementation increasing 25-hydroxyvitamin D level by 3.4 ng/mL (95%
CI, 2-4 ng/mL) and cows milk increasing 25hydroxyvitamin D level by 1.6 ng/mL per 250-mL cup
per day (95% CI, 1-2 ng/mL). Two nonmodifiable variables reflecting cutaneous synthesis were also strongly
associated with 25-hydroxyvitamin D level, with summer season increasing 25-hydroxyvitamin D level by 1.6
ng/mL (95% CI, 0.4-2.8 ng/mL) and light skin pigmentation (Fitzpatrick skin pigmentation type I-III vs IVVI) increasing 25-hydroxyvitamin D level by 2.7 ng/mL
(95% CI, 1.2-4.4 ng/mL).
For our secondary analysis, the relationship between
modifiable dietary intake variables (vitamin D supplementation and milk intake) on 25-hydroxyvitamin D level
was evaluated in the context of childrens skin pigmentation and season. A simultaneous test of all hypothesized interactions resulted in P = .59, which is sufficiently large to consider interactions unlikely. The
adjusted effects of vitamin D supplementation, milk intake, season, and skin pigmentation on 25-hydroxyvitamin D level are displayed graphically in Figure 3. The
effect of vitamin D supplementation and milk intake on
25-hydroxyvitamin D level appear similar regardless of skin
pigmentation or season.
To identify the relative contribution of vitamin D
supplementation and cows milk intake on 25hydroxyvitamin D level, the partial R2 for each variable
in the model was calculated (Figure 4). The 2 modifiable dietary variables, cows milk consumption and vitamin D supplementation, appear to account for most of
the explained variation in 25-hydroxyvitamin D level. Sensitivity analysis including or not including imputed data
did not change these results.
COMMENT

In this prospectively designed study, we have examined the contribution of 2 modifiable dietary determinants on 25-hydroxyvitamin D level in the context of
known, and largely nonmodifiable, factors including

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Dark skin pigmentation

Dark skin pigmentation

No supplementation

Vitamin D supplementation

40

40
40

35

Vitamin D

Vitamin D

35

30

25

30

25
12
3

Mi

nth

nta
lk I

Mo

up
e, C

2
0

nta
lk I

Mi

Light skin pigmentation

Light skin pigmentation

No supplementation

Vitamin D supplementation

40

up
e, C

30

25-Hydroxyvitamin D Level, ng/mL

nth

10

Mo

35

12

10

40
25

35

Vitamin D

35

Vitamin D

45

30

25

30

25
12

10

Mo

nth

2
0

Mil

ups

e, C

k
Inta

12

10

Mo

nth

20

2
0

Mil

ups

e, C

k
Inta

Figure 3. The effect of milk intake, skin pigmentation, vitamin D supplementation, and month on 25-hydroxyvitamin D serum levels. Light skin pigmentation
represents Fitzpatrick skin pigmentation types I to III and dark skin pigmentation represents Fitzpatrick skin pigmentation types IV to VI. Effects adjusted for the
average child (age, 37 months; body mass index z score = 0.2; 1 hour of outdoor play; and 1 hour of daily screen time). To convert 25-hydroxyvitamin D to
nanomoles per liter, multiply by 2.496.

skin pigmentation and season in a population of

healthy urban preschoolers at latitude 43.4!N over
multiple seasons.
We have identified that vitamin D supplementation
was associated with an increase in 25-hydroxyvitamin D
level of approximately 3 ng/mL and vitamin Dfortified
cows milk was associated with an increase in 25hydroxyvitamin D level of approximately 2 ng/mL per
250-mL cup. In addition, these 2 modifiable variables appear to account for most of the explained variation in 25hydroxyvitamin D level. The effects of vitamin D supplementation and cows milk intake on 25-hydroxyvitamin
D level appear similar regardless of childrens skin pigmentation and season. We suggest that these findings are
clinically meaningful and underscore the importance of
dietary vitamin D intake to 25-hydroxyvitamin D status
in early childhood.
Early childhood is a critical stage in human development with respect to the cumulative effects of both biologic and lifestyle determinants of health. Achieving

and maintaining optimal vitamin D levels in early childhood may be relevant to health outcomes in later childhood and adulthood.15,37 Dietary records from Canadian infants have demonstrated that at 12 months of
age, average daily intake of vitamin D from complementary food accounts for only 11% of the currently recommended dietary allowance of vitamin D.38,39 Therefore,
other strategies to maintain 25-hydroxyvitamin D level
as children transition from vitamin Dfortified formula or breast milk with vitamin D supplementation
are necessary. To date, there has been limited understanding of modifiable influences on 25-hydroxyvitamin D level in early childhood. Our findings have practical implications for both clinical practice and health
policy.
Our finding that variables reflecting cutaneous production of 25-hydroxyvitamin D (skin pigmentation,
season, and outdoor play time) appear to explain less
variation in 25-hydroxyvitamin D level than dietary
intake variables in early childhood is consistent with

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tion and sensible cows milk intake represent excellent

targets for increasing 25-hydroxyvitamin D level in
young children.

Milk intake
Supplementation
Skin pigmentation
Season
Outdoor play
BMI z score
Screen time
Age
0.000

0.005

0.010

0.015

0.020

0.025

Partial R 2

Figure 4. Partial R 2 of vitamin D determinants on 25-hydroxyvitamin D level.

BMI indicates body mass index.

the findings of Gordon et al19 but may be in contrast to

studies of older children, adolescents, and adults.40-42
We speculate that this could be a consequence of current cultural practice of sun avoidance of young children. If skin exposure to the sun is minimal, cutaneous production of 25-hydroxyvitamin D would also be
expected to be minimal regardless of skin pigmentation, outdoor play time, or season.
Major strengths of this study include the relatively large
sample size, which allowed sufficient statistical power to
assess the independent effect of vitamin D supplementation and cows milk intake, availability of detailed clinical data, and a population of children with a high frequency of vitamin D supplementation. Previous studies
examining predictors of vitamin D level in early childhood have been unable to examine the role of vitamin D
supplementation because of the low frequency of supplement use.16,17,40,43
Limitations of this study include a single geographic
location, although 43.4!N is at similar latitude to several other large North American cities. Additionally, the
absence of geographic variability allowed us to study variables related to cutaneous vitamin D production independent of geographic variability. Another limitation is
the effect of unmeasured confounders that may have introduced bias. These include the amount of vitamin D
consumed in supplements, although all supplemental vitamin D in Canada marketed to children contains 400
IU/dose, as well as background vitamin D dietary intake
aside from that provided through vitamin Dfortified cows
milk and vitamin D supplementation. However, the absence of vitamin D fortification of foods other than milk
in Canada and the generally low consumption of foods
naturally rich in vitamin D by preschoolers (ie, fatty fishes)
make this contribution likely to be small.21,38,44 Finally,
as this was a cross-sectional study, causation cannot be
inferred from the identified associations.
We have identified that 2 modifiable dietary intake
variables (vitamin D supplementation and cows milk
intake) are the most important determinants of
25-hydroxyvitamin D status in early childhood.
Although excessive cows milk intake has been associated with iron deficiency,44 vitamin D supplementa-

Accepted for Publication: August 8, 2012.

Published Online: January 14, 2013. doi:10.1001/2013
.jamapediatrics.226
Author Affiliations: The Applied Health Research Centre of the Li Ka Shing Knowledge Institute (Drs Maguire
and Mamdani and Mr Thorpe) and Department of Pediatrics (Dr Maguire), St Michaels Hospital, Paediatric Outcomes Research Team, Division of Paediatric Medicine,
The Hospital for Sick Children (Drs Birken, Khovratovich, and Parkin and Mss DeGroot and Carsley), and Faculty of Medicine, Department of Pediatrics (Drs Maguire, Birken, and Parkin), Dalla Lana School of Public
Health (Mr Thorpe), and Leslie Dan Faculty of Pharmacy (Dr Mamdani), University of Toronto, Toronto, Ontario, Canada.
Correspondence: Jonathon L. Maguire, MD, MSc, FRCPC,
Department of Pediatrics, St Michaels Hospital, 30 Bond
St, 15-014 Cardinal Carter, Toronto, ON M5B 1W8,
Canada (jonathon.maguire@utoronto.ca).
Author Contributions: Dr Maguire had primary responsibility for final content. All authors read and approved
the final manuscript. Study concept and design: Maguire,
Birken, and Parkin. Acquisition of data: Birken,
Khovratovich, and Parkin. Analysis and interpretation of
data: Maguire, DeGroot, Carsley, Thorpe, Mamdani, and
Parkin. Drafting of the manuscript: Maguire and DeGroot.
Critical revision of the manuscript for important intellectual content: Maguire, Birken, Khovratovich, Carsley,
Thorpe, Mamdani, and Parkin. Statistical analysis: Thorpe
and Mamdani. Obtained funding: Maguire, Birken, and
Parkin. Administrative, technical, and material support:
Khovratovich, DeGroot, Carsley, and Parkin. Study supervision: Maguire and Khovratovich.
TARGetKids! Collaboration Clinical Site Investigators:
Tony Barozzino, MD; Douglas Campbell, MD; Brian
Chisamore, MD; Karoon Danayan, MD; Anh Do, MD; Mark
Feldman, MD; Sloane Freeman, MD; Moshe Ipp, MD; Sheila
Jacobson, MD; Eddy Lau, MD; Sharon Naymark, MD;
Patricia Neelands, MD; Michael Peer, MD; Marty Perlmutar,
MD; Navindra Persaud, MD; Michelle Porepa, MD; Alana
Rosenthal, MD; Janet Saunderson, MD; Michael Sgro, MD;
Susan Shepherd, MD; Carolyn Taylor, MD.
Conflict of Interest Disclosures: None reported.
Funding/Support: Overall support for the TARGet Kids!
program was provided by the Canadian Institutes of Health
Research Institute of Human Development, Child and
Youth Health and the Institute of Nutrition, Metabolism, and Diabetes as well as the St Michaels Hospital
Foundation. The Paediatric Outcomes Research Team is
supported by a grant from The Hospital for Sick Children Foundation.
Role of the Sponsors: Funding agencies had no role in
the design, collection, analyses, or interpretation of results of this study.
Additional Contributions: We thank Azar Azad, PhD,
Tonya DAmour, MSc, Kanthi Kavikondala, MSc,
Tarandeep Malhi, MSc, Magda Melo, MSc, Subitha
Rajakumaran, BSc, Juela Sejdo, BSc, and Laurie

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Thompson, BSc, for administrative and technical support for the TARGetKids! program.
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