Sina Gallo¹, Kathryn Comeau¹, Catherine Vanstone¹, Sherry Agellon¹, Atul Sharma², Glenville...

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, Québec2Montreal 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, Ontario5Euro-pharm International Canada Inc., Montréal, Québec

*Senior authors

Effect of different dosages of oral vitamin D supplementation on

vitamin D status in healthy, breastfed infants: A randomized trial

Effect of different dosages of oral vitamin D supplementation on

vitamin D status in healthy, breastfed infants: A randomized trial

• 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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Role of the Sponsor andConflict of Interest DisclosuresConflict of Interest Disclosures

Role of the Sponsor andConflict of Interest DisclosuresConflict of Interest Disclosures

25(OH)D

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Mother’s Skin

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Maternal Sources: Sun, food and supplements

Maternal Sources: Sun, food and supplements

Vitamin D Sources and Use:Infant Nutrition and Growth

Vitamin D Sources and Use:Infant Nutrition and Growth

Infant Vitamin D Sources

25(OH)D

CYP27A1(liver)

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Mother’s Skin

4

Maternal Sources: Sun, food and supplements

Maternal Sources: Sun, food and supplements

Infant Sources: Maternal-fetal transfer, breast milk, supplements

Infant Sources: Maternal-fetal transfer, breast milk, supplements

Vitamin D Sources and Use:Infant Nutrition and Growth

Vitamin D Sources and Use:Infant Nutrition and Growth

DBP

Infant Vitamin D

Stores

Infant Vitamin D Sources

25(OH)D

CYP27A1(liver)

1,25(OH)2D

CYP27B1(kidneys)

“Biologically Active”

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Mother’s Skin

DBP

5

Maternal Sources: Sun, food and supplements

Maternal Sources: Sun, food and supplements

Infant Sources: Maternal-fetal transfer, breast milk, supplements

Infant Sources: Maternal-fetal transfer, breast milk, supplements

Vitamin D Sources and Use:Infant Nutrition and Growth

Vitamin D Sources and Use:Infant Nutrition and Growth

DBP

Healthy bone growth

Healthy bone growth

Infant Vitamin D

Stores

(International Units)

6

Prevention of Rickets and for Healthy Infant GrowthPrevention of Rickets and for Healthy Infant Growth

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

Vitamin D Recommendations and Safety Levels: year 2006

Vitamin D Recommendations and Safety Levels: year 2006

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RecommendationsRecommendations Safety LevelsSafety Levels

25(OH)D concentrations (nmol/L)

Oginni 1996 Graff 2004(Nigeria)

Dawodu 2005(UAE)

Garabedian 1983(Belgium/France)

Rickets

Molla 2000(Kuwait)

Cesur 2003(Turkey)

Arnaud 1976“Severe”(Canada/US)

Arnaud 1976“Mild” (Canada/US)

Balasubraman 2003 (India)

Canadian Paediatric Society

Recommendation----------------------------Based on adults and older children; but unclear in infants.

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Vitamin D Status based on Body Stores and Bone Health: year 2006

Vitamin D Status based on Body Stores and Bone Health: year 2006

1. establish a vitamin D dosage which would support 25(OH)D concentrations ≥ 75 nmol/L in 97.5% of breast fed infants• ≥ 50 nmol/L

2. further define the appropriate dosage using:• weight, length and head circumference growth; • the addition of mineral to growing bone.

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Ethics: McGill University Institutional Review Board; Health Canada Clinical Trials; Trial Registration clinicaltrials.gov Identifier: NCT00381914.

The study was conducted with the objectives to:

The study was conducted with the objectives to:

75 nmol/L = 30 ng/mL50 nmol/L = 20 ng/mL

Randomized (n=132)

800 IU/d (n=39)

1600 IU/d (n=16)

400 IU/d (n=39)

n=29

1200 IU/d (n=38)

n=34

Follow-up 3 mo

Follow-up 12 mo

n=28

n=35 n=32

n=29

n=15

n=12

Discontinued July 2008 - 81% of group pl. 25(OH)D >125 nmol/L after 2 mo

Analyzed as intent-to-treat

Did not meet criteria (n= 275)

Contact declined or unavailable (n=185)

Other reason (n=345)

74% retention 9

Study Groups: Healthy InfantsStudy Groups: Healthy InfantsStudy Groups: Healthy InfantsStudy Groups: Healthy Infants

Assessed for eligibility (n=937)

Visit 2

87% on vitamin D87% on

vitamin D Birth

3

Age (months)

Visit 4 Visit 5 Visit 6

6 9 12

RecruitmentVisit 3

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BaselineVisit 1

Infants were randomized to receive 400, 800, 1200 or 1600 IU of vitamin D3 daily

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) Born April-October (60%)

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) Born April-October (60%)

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Trial Time CourseTrial Time CourseTrial Time CourseTrial Time Course

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*p<0.01 vs. 400 IU/d at same time; logistic regression at each time point 11

How many infants met the vitamin D How many infants met the vitamin D status target of 75 nmol/L of 25(OH)D?status target of 75 nmol/L of 25(OH)D?

How many infants met the vitamin D How many infants met the vitamin D status target of 75 nmol/L of 25(OH)D?status target of 75 nmol/L of 25(OH)D?

3 months800 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 12

How many infants met the vitamin D How many infants met the vitamin D status target of 75 nmol/L of 25(OH)D?status target of 75 nmol/L of 25(OH)D?

How many infants met the vitamin D How many infants met the vitamin D status target of 75 nmol/L of 25(OH)D?status target of 75 nmol/L of 25(OH)D?

3 months800 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 13

How many infants met the vitamin D How many infants met the vitamin D status target of 75 nmol/L of 25(OH)D?status target of 75 nmol/L of 25(OH)D?

How many infants met the vitamin D How many infants met the vitamin D status target of 75 nmol/L of 25(OH)D?status target of 75 nmol/L of 25(OH)D?

3 months800 vs 400 IU OR 3.5 95% CI, 1.1-11

1200 vs 400 IU OR 9.7 95% CI, 1.9-49.7

No differences among treatments over time by logistic regression at each time point 14

How many infants met the vitamin D How many infants met the vitamin D status target of 50 nmol/L of 25(OH)D?status target of 50 nmol/L of 25(OH)D?

How many infants met the vitamin D How many infants met the vitamin D status target of 50 nmol/L of 25(OH)D?status target of 50 nmol/L of 25(OH)D?

Recommended Status Target

IOM, AAP

Assessment of GrowthAssessment of GrowthAssessment of GrowthAssessment of Growth

0

1

2

3

4

5

6

7

8

9

10

11

12

13

Age (months)

We

igh

t (k

g)

1 2 3 6 9 12

+ 2SD

- 2SD

0

1

2

3

4

5

6

7

8

9

10

11

12

13

Age (months)

We

igh

t (k

g)

1 2 3 6 9 12

+ 2SD

- 2SD

400 IU/d800 IU/d1200 IU/d1600 IU/d

+/-2 Weight-for-ageZ-score (WHO)

Girls Boys

Mean ± 95% CI; No differences among treatments over time by repeated measures ANOVA 15

0

50

100

150

200

250

300

1200 IU/d 800 IU/d 400 IU/d

Age (months)

Wh

ole

Bo

dy

BM

C (

g)

1 3 6 9 12

Whole Body

1600 IU/d

Assessment of Bone HealthAssessment of Bone HealthAssessment of Bone HealthAssessment of Bone Health

Mean ± SEM; No differences among treatments over time by repeated measures ANOVA accounting for race after adjustment for multiple comparisons

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.

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Healthy Infant Nutrition: Public Policy & Position Statements for daily vitamin D supplementation

dosages (International Units)

Healthy Infant Nutrition: Public Policy & Position Statements for daily vitamin D supplementation

dosages (International Units)

Vitamin D Recommendations and Safety Levels: year 2013

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.

6 to12 monthsTolerable Upper

Intake LevelInstitute of Medicine

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Institute of Medicine Health Canada

Canadian Paediatric Society

American Academy of Pediatrics

Canadian Paediatric

Society

Birth to 6 monthsTolerable Upper

Intake LevelInstitute of Medicine

Healthy Infant Nutrition: Public Policy & Position Statements for daily vitamin D supplementation

dosages (International Units)

Healthy Infant Nutrition: Public Policy & Position Statements for daily vitamin D supplementation

dosages (International Units)

Vitamin D Recommendations and Safety Levels: year 2013

Vitamin D Recommendations and Safety Levels: year 2013

• 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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Unanswered Questions:During and beyond infancy

Unanswered Questions:During and beyond infancy

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Leading InstitutionsLeading Institutions Funding AgenciesFunding Agencies

Recruitment and MonitoringRecruitment and Monitoring Families and InfantsFamilies and Infants

RecruitmentFive Pediatric Clinics West Island & Greater Montreal AreaLakeshore General HospitalSafety OfficerDr. J. Mitchell, M.D., F.R.C.P.C.

This work was made possible by the following:

This work was made possible by the following:

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