Update on Perinatal and Pediatric Vitamin D
Michael K. Georgieff M.D., FAAP
Professor of Pediatrics
University of Minnesota School of Medicine
Vitamin D
 Vitamin D is a steroid hormone (not a vitamin)
 Initial form is Vitamin D3 (cholecalciferol)
 Created in dermal cells by UV light exposure
(converts cholesterol to D3)
 Active form is 1,25 di-hydroxy vitamin D
(calcitriol)
Vitamin D
 De Novo synthesis of Vitamin D requires
– Sun exposure +
– Intact liver +
– Intact kidney or…
– Dietary source of calcitriol
How Vitamin D Works
 Enhances intestinal absorption of calcium
and phosphorus
 Increases tubular reabsorption of
phosphorus
 Does not work on bone (PTH does)
 Important mediator of efficient recycling
of calcium and phosphorus so they are
available for bone growth and remodeling
Rickets
 General term refers to abnormal bone
growth and development due to pervasive
lack of calcium and phosphorus substrate
 Vitamin D deficient rickets results in
disorganized cartilage in long bone growth
plates
 What about subclinical vitamin D
deficiency?
Vitamin D Deficient Rickets
 Presents between 6 and 18 months
 Failure to attain or regression of motor
milestones (notably walking or other
weight- bearing activities)
 Bowed legs, flared wrists, pain on major
motor activity, growth failure
 History of lack of sun exposure and
dietary risk factors
Laboratory Findings
 Low serum calcium and phosphorus
 Elevated PTH level (parathyroid hormone)
 Very low 25-OH vitamin D level (hallmark
finding)
– <27.5 nmol/L (11 ng/mL) is low in children
– <37.5 nmol/L (15 ng/mL) causes increase in
PTH level in adults
– Unknown at what level PTH rises in children
Radiological Findings In
Childhood Rickets
 Flared epiphyses
 Bowing of long bones
 Rib changes
 Fractures
What are the Concerns?
• Healthy bone growth
– In childhood
– Bone banking for adulthood
• CNS effects
• Genes regulated by vitamin D
Who is at Risk for Early Vitamin
D Deficiency?
• Infants with low intrauterine accretion
– Born to vitamin D deficient mothers
– IUGR infants
– Premature infants
• Infants with low vitamin D status
– Lack of sun exposure +
– Low dietary sources
Pediatric Vitamin D
Incidence of D deficiency
Populations at Risk
Sources of vitamin D
Breastfeeding
Supplementation (Baby or Mom?)
Prevalence
Rickets thought to be disease of the past
– “Disappeared” in early 1960s due to:
•
Recognition of role of sunlight in vitamin D
homeostasis; fortification of milk
•
Use of multivitamin preps
•
Higher prevalence of formula use
AAP CON recommended 400 IU/d starting
at 2 weeks of age
•
Prevalence
Increased case reports and series of
nutritional rickets since late 1970’s
Exact prevalence remains unknown but
prevalence of risk factors increasing
– Less sun exposure
– Higher prevalence of nursing
– Decreased prescription of vitamins
for nursing infants
Estimated Incidence from
Hospitalized Children
 No national data on incidence in US
 Georgia (1997-99)
 9 per million hospitalized children
 5/9 due to nutritional rickets (all darkly pigmented
children)
 All breastfed
 National Hospital Discharge Survey (NHDS)
 9 per million hospitalized children in US
 75% darkly pigmented children; 50%<12 months
Estimated Incidence from
Office-Seen Children
 Pediatric Research in Office Setting (PROS)
network of AAP
– 23-32 cases per million child office visits
between 1/99 and 6/00.
– Survey (low response rate=26%)
– All darkly pigmented
– All breastfed
– Maternal Vitamin D status unknown
Estimated Incidence from
Literature
 13 articles published between 1996 and 2001
 122 cases reported
 12 US states
 87% darkly pigmented
 Age range from 4 to 58 months at diagnosis
What are the concerns?
•
•
•
•
•
•
Is the scientific evidence solid?
Adverse effect on breastfeeding
Expense of supplementation
Risks of supplementation
Addressing the multiplicity of issues
Increasing the risk of unhealthy sun
exposure behaviors
What are the questions?
• What level of Vitamin D is adequate?
• What do we really know about sunshine, prevention
of rickets, and risks of skin cancer
• How much does skin pigmentation alter the dose?
• If one were to recommend supplementation:
– Should the mother, the infant, or both receive
supplementation
– Should this be universal or targeted?
– What would be the correct dose?
– What is the right age to start supplements
• Are the benefits worth the expense?
Low Sun Exposure:
Major Risk Factor for Rickets
 Northern climate (but not exclusively)
 Seasonal
 Dark pigmentation (but not exclusively)
 Covered skin
 Sunscreen use
 Proper sunscreen use decreases vitamin D synthesis by 97%
Effects of Latitude and
Season on D Status
• Iowa (41 degrees N) (EH Ziegler et al, 2006)
– During winter, 78% of breastfed infants were D deficient
(25-OH level < 11 ng/ml)
• In South Carolina (32 degrees N) (LA Basile et al, 2007)
– African-American newborns had mean cord serum 25-OH
level of 10.5 ±0.6 ng/ml
– Winter decreased cord serum 25-OH levels in A-A by 25%
and in Caucasians by 35%
Appropriate Sunlight Exposure
Prevents Rickets
• Infants born to mother’s with low Vit D
– Diaper only: 10-30 minutes/week
– Fully clothed, no hat: 2 hours/week
• Infants born to mother’s with adequate Vit D
– Diaper only: < 10 minutes/week
– Fully clothed, no hat: 30 minutes/week
• Outside in the shade doesn’t work
• 6-fold increased need in darkly pigmented infants
In the Absence of Adequate
Sunlight Exposure
 Low dietary intake of Vitamin D becomes a major
issue
 Vitamin D deficient situations in infancy
– Exclusive human milk feeding
– Infants consuming < 500 ml/d of fortified infant
formula
– Not receiving vitamin prep containing vitamin D
– Vitamin D deficient pregnant or nursing mother
Dietary Content of Vitamin D
 Human milk (22 to 100 IU/L)
–
–
–
–
Varies with maternal diet, pigmentation/sun exposure
Light pigmentation 68 IU/L
Dark pigmentation  35 IU/L
Both fall far short of RDA/DRI (infant does not
consume 1L until 14 lbs=5-6 months of age)
– Maternal 3000 IU/d supplement-> 100 IU/L
Relative Importance of Fetal
Stores, Milk and Sun Sources
 Maternal and Infant 25-OH D serum
concentrations highly correlated until 8 weeks of
age
– Combined effects of maternal serum levels on
fetal stores (transplacental) and breastmilk
content
 After 8 weeks, sunlight exposure outweighs effects
of mother’s vitamin D status
Dietary Sources of Vitamin D
 Unfortified cow milk (24 IU/L)
– High variability in measured vitamin D in
fortified cow milk (NEJM)
 Infant formula (400 IU/L)
– Infant must consume 1/2 L per day to receive
DRI of 200 IU/day
– Term infant consumes that amount; preterm
does not
 Tri-vitamin (ADC) prep: 400 IU/dose
Daily Dietary Vitamin D Requirement
to Prevent Rickets (0-36 months)
 Dietary source-USA (IOM, 2001)
– 200 IU/day (5 mcg) is the AI
 Dietary source-Canada
– 400 IU/day in summer
– 800 IU/day in winter
Nutritional Strategies to Improve
Vitamin D Status
 Effective strategies in infants (current recs)
– 200 IU vitamin D/day
1/2 dose tri-vitamin (ADC) prep
• 500 ml of fortified infant formula
• 5 mcg calcitriol
 Recent strategies (experimental)
– Supplementing the pregnant mother
– Supplementing the nursing mother
– Single high dose therapy
•
Maternal Vitamin D Supplementation
During Pregnancy
• IOM (2001) determines
– AI as 200 IU/day
– UL as 2,000 IU/day
• NHANES data: 50% of African-American women
of reproductive age have low vitamin D level
• Infants born to Vitamin D deficient mothers have
lower vitamin D stores
– Dark skin ± skin coverage during pregnancy: 63% rate of
D deficiency in NBs compared to 16% in light skin/no
skin coverage (Dijkstra et al, 2007)
Does Supplementation During
Pregnancy Work?
• Supplementation of pregnant women
–
–
–
–
Improves neonatal calcium handling
Improves 9 year bone status
Improves maternal vit D levels if she was deficient
Does not alter already sufficient maternal D status
• Doses up to 2000 U/day are tolerated, but no trials
to determine efficacy on fetal/neonatal stores
Does Maternal Vitamin D
Supplementation During Lactation Work?
• Human milk vitamin D content is low and reflects
maternal vitamin D status
• Supplementation of deficient mothers increases
milk D levels
• The AI during lactation is 200 IU/day (IOM, 2001)
• The UL is 2,000 IU/day (IOM, 2001)
• 3000 IU/day increases milk levels to 100 IU/L; still
too low
High Dose Supplementation of Lactating
Mothers (CL Wagner et al, 2006)
• Mothers randomized at 1 month to 400 vs 6400
IU/d X 6 months
• Control infants received 300 IU; infants of
supplemented mothers received 0 IU
• Results: anti-rachitic activity of maternal
supplemented infants equaled that of infants
receiving only postnatal dietary supplementation
• No toxicity noted in high dose mothers
• Shows feasibility of maternal supplementation only
Cost to prevent
 Is universal supplementation of infants cost effective?
– Cost of Tri-Vi-Sol ($6.00/month)
– Incidence estimate
• 5 hospitalized per million children
• 25 ambulatory cases per million
– Cost per hospitalization averted: $4,800,000
– Cost per case averted: $958,000
 Cost to prevent far outweighs cost to treat
Summary of Pediatric Vitamin D
• Vitamin D deficiency is increasingly recognized
– Seasonal and Geographical
– Mostly in breastfed infants of color
• Contributors are lack of sunlight exposure and low
levels of D in unsupplemented milk
• Effective therapies include supplementation of
breastfed infants with 200 IU and supplementation of
lactating mothers with >4000 IU/day
– Only the former is currently recommended by AAP
Perinatal Vitamin D
Populations at Risk
Osteopenia of Prematurity
Does Postnatal D work?
Can Prenatal D prevent?
Osteopenia (Rickets) of Prematurity
Staging:
1. Hypodensity of bones
2. Abnormalities of metaphyses
Fraying and cupping
Dense line (healing)
3. Above findings and fractures
1.
2.
3.
Courtesy of Steve Abrams MD
Osteopenia of prematurity: Usually a
disease of inadequate calcium and
phosphorus intake
Calcium intake Calcium
(mg/kg/d)
retention
(%)
Calcium
retention
(mg/kg/d)
In Utero
N/A
N/A
100-120
Human milk
40
60-70
25-30
Routine cow milkbased formula
80-90
40-50
35-45
Total parenteral
nutrition
Up to 80
>95%
70-80
Vitamin D in preterm infants
• Adequate Intake (AI) for vitamin D for full-term infants is 200 IU/day. Upper
limit (UL) is 1000 IU/d (US 1997).
• There is substantial evidence that little Ca absorption is transcellular “active”
(Vitamin D-dependent) in first months of life in premature or even in full-term
infants.
• Multiple studies demonstrate that intake of 160-400 IU/day leads to adequate
vitamin D levels (Cooke 1990, Pittard 1991, Backstrom 1999, Koo JPGN, 1995).
• Preterm formula provides, when fed at 120 cal/kg/d to a 1.5 kg infant: SSC:150
IU/100 kcal = 270 IU/day and EPF: 270 IU/100 kcal = 486 IU/day
• Human milk fortifiers marketed in US provide 150 IU/4 packets.
Higher doses of vitamin D?
• No evidence for benefits in preterm infants. One
study evaluating up to 1000 IU found no short or
long-term benefit (up to 11 yrs!) of higher amounts
(Backstrom, JPGN, 1999).
• Some, especially in Europe, recommend providing
up to 1000 IU/d routinely for preterm infants- little
evidence for or against this.
High dose effects
Nako, Pediatrics
International
2004;46:439-443.
• Preterm formula, 2700 IU/L. (1200-1700 IU/L in US)
• Unanswered question is: What is the target 25-OHD?
When might more vitamin D be helpful?
• Vitamin D related absorption increases at 6-8 weeks of age
– when osteopenia worsens. Provide 400-600 IU/d if alk
phos > 800 IU/L.
• Cholestatic babies cannot form 25-hydroxyvitamin D in
their liver. Consider increasing intake for direct bili > 4 to a
maximum of 1000 IU/day total vitamin D.
– If
no response or worsening alk phos, consider adding
1,25 dihydroxyvitamin D (calcitriol, Rocaltrol). Obtain
25-OHD level first and treat if < 20-25 ng/mL.
Assessment and Plans
Prenatal Assessment of Maternal Vitamin D Stores
SUNLIGHT EXPOSURE
FACTORS
Sun-seeking Behaviors
Never outside
Skin Pigmentation
Deep
Geographic Location
Arctic Circle
Cultural Dress
Mostly covered
Elevation
Seaside
Sunscreen Use
Applies to any exposed skin
Always outside
Light
Equato
r
Mostly
uncovered
Mountains
Never Owned Any
DIETARY FACTORS
Diet
No milk, No fish
Diseases assoc. with
Vit D Deficiency
Present
Supplements
No supplements
Vit D fortified Milk, Salmon 3 X a
week
Not present
400 IU Vit D per day
Prenatal Counseling
Either sun exposure or dietary sources
should meet requirements
Good sources &
stores
Acknowledge good
habits
Counsel regarding
appropriate diet and
sun exposure
Questionable
sources & stores
Counsel regarding
appropriate diet and
sun exposure and
consider supplements
Few or no sources
Counsel regarding
appropriate diet and
sun exposure and
prescribe
supplements
Counseling Options for
Mothers
Drink Vitamin D fortified milk
•
• Eat one serving salmon 3 times a week
• Expose hands, face, and arms to sunlight
for 5-15 minutes 2-3 times a week
• Increased time may be necessary for
persons with deeper pigmented skin
• Take Vitamin D supplement of 200 IU
per day
Infant Vitamin D Status - Assessed at 2 months of age
Sun-seeking Behaviors
SUNLIGHT EXPOSURE
FACTORS
Never outside
Skin Pigmentation
Deep
Geographic Location
Arctic Circle
Cultural Dress
Mostly covered
Diaper only
Elevation
Seaside
Mountains
Sunscreen Use
Applies to any exposed
skin
Weather
Long winters
Always outside, frequently in the
sun
Light
Equato
r
Never Owned Any
Long summers
DIETARY FACTORS
Diet
Exclusively breastfeeding
Diseases assoc. with
Vit D Deficiency
Present
Supplements
No supplements
Exclusively formula feeding
Not present
200 IU Vit D per day
Counseling Options for Infants
• Diaper only: 10-30 minutes/week
• Fully clothed, no hat: 2 hours/week
• Increased time may be necessary for babies with
deeper pigmented skin
• Take Vitamin D supplement of 200 IU per day
• When weaning, use only infant formula to replace
breastfeedings
• Vitamin D supplement should be stopped if infant is
consuming 500 ml of formula
Summary
“Upsurge” in rickets is real, but the actual
incidence is unknown (esp. subclinical)
Upsurge is due to inadequate sunlight
exposure, not dietary deficiency
Safe sun exposure can address the problem
Adequate dietary intake will correct the
effect of lack of sunlight exposure
Effective dose is 200 IU starting in first two
months