Effect of different dosages of oral
vitamin D supplementation on
vitamin D status in healthy, breastfed
infants: A randomized trial
Sina Gallo¹, Kathryn Comeau¹, Catherine Vanstone¹,
Sherry Agellon¹, Atul Sharma², Glenville Jones3, Mary
L’Abbé4, Ali Khamessan5, Celia Rodd¹²*, Hope Weiler¹*
1School
of Dietetics and Human Nutrition, McGill University, Montréal, Québec
2Montreal Children’s Hospital, McGill University Health Centre, Montréal, Québec
3Departments of Biomedical & Molecular Sciences & Medicine, Queen’s University,
Kingston, Ontario
4Department of Nutritional Sciences, University of Toronto, Toronto, Ontario
5Euro-pharm International Canada Inc., Montréal, Québec
*Senior authors
Role of the Sponsor and
Conflict of Interest Disclosures
• Role of the Sponsor: The funding organizations had no role in
design and conduct of the study; collection, management,
analysis, and interpretation of the data; and preparation, review, or
approval of the manuscript.
– Canadian Institutes of Health Research, Nutricia Research
Foundation and the Canadian Foundation for Innovation
– Fonds de la Recherche en Santé du Québec doctoral
scholarship
– The Canada Research Chairs professor salary award
• Conflict of Interest Disclosures: All authors have completed
and submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. AK is an employee of Europharm
International Canada Inc. All other authors have no conflicts of
interest.
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Vitamin D Sources and Use:
Infant Nutrition and Growth
Maternal Sources: Sun, food
and supplements
Mother’s Skin
25(OH)D
http://www.freedigitalphotos.net
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Vitamin D Sources and Use:
Infant Nutrition and Growth
Maternal Sources: Sun, food
and supplements
Infant Sources: Maternal-fetal
transfer, breast milk, supplements
Infant
Vitamin D
Sources
Mother’s Skin
CYP27A1
(liver)
DBP
25(OH)D
http://www.freedigitalphotos.net
Infant
Vitamin D
Stores
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Vitamin D Sources and Use:
Infant Nutrition and Growth
Maternal Sources: Sun, food
and supplements
Infant Sources: Maternal-fetal
transfer, breast milk, supplements
Infant
Vitamin D
Sources
Mother’s Skin
CYP27A1
(liver)
DBP
25(OH)D
CYP27B1
(kidneys)
Infant
Vitamin D
Stores
DBP
1,25(OH)2D
Healthy
bone growth
“Biologically Active”
http://www.freedigitalphotos.net
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Vitamin D Recommendations and Safety
Levels: year 2006
Prevention of Rickets and for Healthy Infant Growth
Recommendations
200
400
Safety Levels
800
1000
1800
(International Units)
Adequate
Intake,
Institute of
Medicine USA;
American
Academy of
Pediatrics
Health
Canada;
Canadian
Paediatric
Society
Canadian
Paediatric
Society
Tolerable
Upper Intake
Level,
Institute of
Medicine USA
No observed
adverse effect level,
Institute of Medicine
USA
http://www.freedigitalphotos.net
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Vitamin D Status based on Body Stores
and Bone Health: year 2006
Rickets
Arnaud 1976
“Severe”(Canada/US)
Arnaud 1976
Cesur 2003
Molla 2000 “Mild” (Canada/US)
(Turkey)
(Kuwait)
Dawodu 2005
Oginni 1996
(UAE)
Graff 2004
Balasubraman
Garabedian 1983
(Nigeria)
2003 (India)
(Belgium/France)
0
10
20
30
40
50
75
Canadian Paediatric
Society
Recommendation
---------------------------Based on adults and
older children; but
unclear in infants.
150
225
25(OH)D concentrations (nmol/L)
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The study was conducted with the
objectives to:
1. establish a vitamin D dosage which would support
25(OH)D concentrations ≥ 75 nmol/L in 97.5% of
breast fed infants
75 nmol/L = 30 ng/mL
• ≥ 50 nmol/L
50 nmol/L = 20 ng/mL
2. further define the appropriate dosage using:
• weight, length and head circumference growth;
• the addition of mineral to growing bone.
 Ethics: McGill University Institutional Review Board;
 Health Canada Clinical Trials;
 Trial Registration clinicaltrials.gov Identifier: NCT00381914.
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Study Groups: Healthy Infants
 Did not meet criteria
(n= 275)
 Contact declined or
unavailable (n=185)
 Other reason
(n=345)
400 IU/d
(n=39)
Assessed for eligibility (n=937)
Discontinued July 2008 81% of group pl. 25(OH)D
>125 nmol/L after 2 mo
Randomized (n=132)
800 IU/d
(n=39)
1200 IU/d
(n=38)
1600 IU/d
(n=16)
Follow-up 3 mo
n=34
n=35
n=32
n=15
Follow-up 12 mo
n=29
74% retention
n=28
n=29
n=12
Analyzed as intent-to-treat
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Trial Time Course
Infants were randomized to receive
400, 800, 1200 or 1600 IU of vitamin D3 daily
Baseline
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
6
9
Visit 6
Recruitment
Birth
87% on
vitamin D
1
2
3
12
Age (months)
Baseline Characteristics
 Mothers on average 33 y of age, 85% were white
 High income (60% > Canadian average $75,000)
 University educated mothers (89%)
 Infants (58% males)
http://www.freedigitalphotos.net
 Born April-October (60%)
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How many infants met the vitamin D
status target of 75 nmol/L of 25(OH)D?
3 months
800 vs 400 IU
OR 3.5
95% CI, 1.1-11
1200 vs 400 IU
OR 9.7
95% CI, 1.9-49.7
*p<0.01 vs. 400 IU/d at same time; logistic regression at each time point
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How many infants met the vitamin D
status target of 75 nmol/L of 25(OH)D?
3 months
800 vs 400 IU
OR 3.5
95% CI, 1.1-11
1200 vs 400 IU
OR 9.7
95% CI, 1.9-49.7
*p<0.01 vs. 400 IU/d at same time; logistic regression at each time point
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How many infants met the vitamin D
status target of 75 nmol/L of 25(OH)D?
3 months
800 vs 400 IU
OR 3.5
95% CI, 1.1-11
1200 vs 400 IU
OR 9.7
95% CI, 1.9-49.7
*p<0.01 vs. 400 IU/d at same time; logistic regression at each time point
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How many infants met the vitamin D
status target of 50 nmol/L of 25(OH)D?
Recommended
Status Target
IOM, AAP
No differences among treatments over time by logistic regression at each time point
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Assessment of Growth
Girls
13
12
+/-2 Weight-for-age
Z-score (WHO)
12
+ 2SD
11
+ 2SD
11
10
10
9
9
8
8
- 2SD
7
6
5
Weight (kg)
Weight (kg)
Boys
13
7
6
1600 IU/d
1200 IU/d
800 IU/d
400 IU/d
5
4
4
3
3
2
2
1
1
0
- 2SD
0
1
2
3
6
Age (months)
9
12
1
2
3
6
9
12
Age (months)
Mean ± 95% CI; No differences among treatments over time by repeated measures ANOVA
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Assessment of Bone Health
Whole Body
300
1600 IU/d
1200 IU/d
800 IU/d
400 IU/d
Whole Body BMC (g)
250
200
150
100
50
0
1
3
6
9
12
Age (months)
Mean ± SEM; No differences among treatments over time by repeated measures ANOVA
accounting for race after adjustment for multiple comparisons
Vitamin D Recommendations and Safety
Levels: year 2013
400 IU dosage: sufficient to achieve 50 nmol/L of 25(OH)D;
Higher dosages needed if target is 75 nmol/L of 25(OH)D;
No further benefits to growth or bone health of infants.
Healthy Infant Nutrition: Public Policy & Position
Statements for daily vitamin D supplementation
dosages (International Units)
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Vitamin D Recommendations and Safety
Levels: year 2013
400 IU dosage: sufficient to achieve 50 nmol/L of 25(OH)D;
Higher dosages needed if target is 75 nmol/L of 25(OH)D;
No further benefits to growth or bone health of infants.
400
800
1000
1200
Institute of Medicine Canadian
Birth to 6 months
6 to12 months
Health Canada
Paediatric
Tolerable Upper
Tolerable Upper
Canadian Paediatric
Society
Intake Level
Intake Level
Society
Institute of Medicine Institute of Medicine
American Academy of
Healthy Infant Nutrition: Public Policy & Position
Pediatrics
Statements for daily vitamin D supplementation
dosages (International Units)
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Unanswered Questions:
During and beyond infancy
• Identify status targets
– Benefits to bone health
• Underpowered to detect early and longer-term
benefits
– Other health benefits
• Needs of other population groups
– Underrepresented darker skin pigmentation
– Higher risk for deficiency
• Remote geographic location
• Infant born with low vitamin D stores
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This work was made possible by the
following:
Leading Institutions
Funding Agencies
Recruitment and Monitoring
Families and Infants
Recruitment
Five Pediatric Clinics West
Island & Greater Montreal Area
Lakeshore General Hospital
Safety Officer
Dr. J. Mitchell, M.D., F.R.C.P.C.
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