1. Pediatric Iron Deficiency 2017 Update
Holly Knoderer, MD MS
Medical Director, Pediatric Hematology-Oncology - Riley at IU Health North Hospital
Medical Director, Pediatric Services - Riley at IU Health North Hospital
12/27/2017

2. Disclosures No financial disclosures Off-label use of medications
Total Dose Infusion of LMW Iron Dextran
Pediatric use of Ferric Carboxymaltose
12/27/2017

3. Background
Iron deficiency is the world’s most common micronutrient deficiency
In 2011, more than 273 million US children were anemic and over 50% of those were iron deficient1
Higher prevalence of iron deficiency in lower income households
Mexican and Mexican-American ethnicities have high rates
Infants and young children with iron deficiency are more likely to have attention deficits, reduced motor coordination, and language difficulties1
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4. Risk factors for iron deficiency
Prematurity
Low birth weight
Breast fed > 4 months without supplemental iron
Lower socioeconomic status
Excessive cow’s milk consumption
Menorrhagia
Adolescent athletes
Obesity
Acid blockers
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6. Cognitive development
Iron deficiency can impair cognitive development2
not always reversible after correction of deficiency
Limited evidence suggests that iron supplementation in children 2-5 years old (regardless of anemia), produced an improvement in cognitive development in those showing early signs of delay3
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7. Lead Toxicity & Iron Deficiency
Iron deficiency can worsen lead toxicity
PICA symptoms leading to increased lead ingestion
All patients with elevated lead levels should be screened for deficiency and aggressively treated
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8. The infant Physiologic nadir
Term infant –Hgb to ~9.5 by weeks
Preemie – Hgb as low as 7 by 6-8 weeks
Smaller the preemie, the earlier and lower the anemia
Iron stores at birth are dependent on maternal iron status
Was mom anemic during pregnancy?
Did mom take prenatal vitamins?
If breastfeeding, has mom continued to take her vitamins?
How many children (and in what timeframe) has this mother delivered?
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9. Empiric iron supplementation in infants
Exclusively breastfed babies should receive iron supplementation
Term baby: Dose = 1 mg/kg/day starting 4-6 months
Preterm baby: Dose = 2 mg/kg/day starting at 1 month
Continue until predominately formula fed or other food sources provide adequate iron
Formula contains sufficient iron such that additional supplementation is not indicated
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10. The toddler Irritable Picky eater Drinks lots of milk
Contains minimal iron
The iron within milk is poorly absorbed
Child fills up on milk, further limiting other foods that might have higher iron content
Subtle gastritis leads to microscopic blood loss and further decrease in iron absorption
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11. Adolescents Period of rapid growth leading to increased iron needs
Poor diets
Menstrual bleeding
Athletes: Clinical trials in athletes with ferritin < 50 ng/mL given iron replacement had improved athletic performance4,5
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12. Fatigue Most common complaint for iron deficient adolescent
Difficult to distinguish between normal sleep needs in teenage years vs abnormal fatigue
Iron supplementation in adults with normal Hgb but low ferritin reported less fatigue
The lower the starting ferritin, the more dramatic the response
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13. AAP Position on Iron Deficency
Iron-deficiency anemia and iron deficiency without anemia during childhood can have long- lasting detrimental effects on neurodevelopment.
Therefore, pediatricians and other health care providers should strive to eliminate iron deficiency and iron-deficiency anemia.
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14. Screening Guidelines Centers for Disease Control7:
American Academy of Pediatrics6:
Screen for anemia around 1 year
Screen somewhere between years
Screen for iron deficiency if child deemed high risk
Centers for Disease Control7:
Screen all high risk children
Screen adolescent girls somewhere between years
Screen women every 5 years
American Academy of Family Physicians8:
Insufficient evidence to recommend universal screening
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15. Concerns with current recommendations
AAP
Identifies anemia but can miss iron deficiency
Toddlers: risk increases in the next months with transition to cow’s milk and increasingly picky diets
Misses many teenagers
CDC
Identifies anemia but not latent iron deficiency
AAFP
Misses all but those who present with significant symptoms
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16. Approaches to screening for iron deficiency
CBC
This will miss those with latent, functional iron deficiency
Hgb (lab and age dependent norms)
MCV (lab and age dependent norms)
RDW
Platelet count
Iron Panel
Serum Iron, TIBC, % Saturation
Ferritin
C-reactive protein
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17. Diagnosis Low hemoglobin Microcytosis Elevated RDW Thrombocytosis
Low serum iron
Low transferrin (% saturation)
Elevated TIBC
Low ferritin
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18. Iron Panel
Measures the amount of freely available iron within the blood
Not an ideal marker of overall iron status
Can be normal even when storage pool is low
Influenced by recent iron intake
Quickly turns normal after initiation of replacement therapy
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19. Ferritin Measures the body’s total iron storage
The ONLY cause of low ferritin is low iron
HOWEVER
A normal (or even high) ferritin does not rule-out iron deficiency
Ferritin is an acute phase reactant
CRP can be helpful
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20. 12/27/2017

21. Iron Rich Foods Meat Beans, lentils, and peas Baked potato with skin
Beef
Turkey
Beans, lentils, and peas
Baked potato with skin
Enriched cereals and pasta
Tofu
Raisins
Spinach and other dark green leafy vegetables
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22. Dietary changes to correct deficiency
Dietary changes will never be sufficient to correct iron deficiency
Dietary changes can only prevent future deficiency after repletion of stores
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23. Enteral vs Parenteral Replacement
Advantages of enteral replacement
Effective when taken properly and tolerated
Initial cost is low
Low risk of allergic reactions
Low risk of serious adverse events
Advantages of parenteral replacement
Quickest resolution
Rapid improvement in symptoms
Compliance
Fewer clinic visits
No GI complaints
Total cost may actually be lower
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24. Oral Iron Dosing Calculate doses using mg of elemental iron
Mild anemia or latent iron deficiency – 3 mg/kg daily
Severe anemia – 4-6 mg/kg divided BID
Adolescents – 2-3 mg/kg/day
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25. Oral Iron – complex options
Formulation
Iron Component
Ferrous fumarate
elemental iron
Ferrous gluconate
Ferrous sulfate
Polysaccharide iron
Chew Iron
Iron citrate
Natural Factors
ferric pyrophosphate
VegLife
Iron Glycinate
TwinLab
Ferric Bisglycinate
Nature’s Plus
Iron amino acid complex
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26. Oral: Ferrous Sulfate 15 mg/mL (elemental) solution
325 mg (65 mg elemental) tabs
Typical dose: 3-6 mg/kg/day divided BID or TID
2016 update: no longer covered by Indiana Medicaid and most private insurance carriers
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27. Oral: Polysaccharide iron complex
Dosed as mg of elemental iron
15 mg/mL
125 mg/5 mL
50 mg capsules
Microspheres of iron that remain in solution and are better tolerated and better absorbed
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28. Iron & Vitamin C
Absorption of oral iron is increased in the presence of vitamin C
Recommend taking oral iron supplements with orange juice, or accompanied by fruit
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29. Real World Problems Package Instructions: 1 ml daily
This dose is for general supplementation to avoid iron deficiency
Even when written as a prescription, our experience is that pharmacists often instruct families to take according to package instructions rather than the prescribed dose
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30. Avoid Enteric Coated tabs
Meant to decrease GI side effects
BUT
Coating decreases absorption
Iron is best absorbed high in the duodenum and the coating doesn’t dissolve until farther down the intestinal tract
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31. Oral Iron: Monitoring 4-6 weeks: assess compliance and tolerability
CBC and retic count (no iron studies)
3 months:
CBC, iron panel and ferritin (+/- CRP)
If complete resolution – stop iron
If improving but persistent, re-check in 1-3 months
Consider IV Iron if
No improvement
Poor compliance
Poor tolerance
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32. Duration of Therapy Minimum of three months
Anemia and serum iron levels are the first to correct – must continue beyond that to replete diminished stores
Give until iron panel is normal & ferritin (35-50 ng/mL)
If ferritin is high, but iron saturation is low – base treatment decision on iron panel
In this case, ferritin acting as an acute phase reactant
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33. Treatment Failure Not taking
Reduced absorption (H2 blocker, PPI, taking with milk)
Failure to reduce milk intake
Incorrect diagnosis or multiple diagnoses
Inflammatory state with block in intestinal iron absorption
Celiac disease, irritable bowel, H. pylori
Anemia of chronic disease
Ongoing or recurrent blood loss
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34. Treatment success
Ferritin > 35 when not acting as an acute phase reactant
Normal RDW
Normal hemoglobin
+/- normal iron panel
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35. Parenteral Replacement
1950’s: Iron Dextran. “Death by dextran”
Removed from the US market in 1989
2000: Iron Sucrose
2009: LMW Iron Dextran
2013: Ferric Carboxymaltose
Mamula, Powers
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36. IV Iron Sucrose Most widely used product world wide
Must be delivered in small doses
Usually requires multiple doses to replenish deficit
Test dose recommended over minutes and can’t be the same day
Remaining infusions take minutes
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37. LMW Iron Dextran
Least expensive drug option for rapid replacement, but for pediatrics, multiple visits still required
Approved dosing in pediatrics
Max 100 mg per dose
Total dose replacement approved for pediatrics in Europe and done at some US centers9
Total dose calculated by iron deficit
Max dose 1000 mg
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38. LMW Iron Dextran Administration
Test dose required (same visit)
Give mg IV over 5-10 minutes
If no reaction, proceed to remainder of infusion
Dilute in mL 0.9% NaCl
Administration time is 1-2 hours
30 post-infusion monitoring recommended
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39. Ferric Carboxymaltose
Shell coating causes slow delivery of iron to transport proteins rather than rapid exposure saturating transferrin and mediating free iron toxicity – less toxic
First agent approved for rapid, high dose replacement in adults
Not approved for pediatrics
Several retrospective and case series of use in children10-15
> 200 pediatric patients in the literature
No serious adverse reactions reported
Riley at IU North: > 70 doses
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40. Ferric Carboxymaltose
Standard Dose: 15 mg/kg (max 750 mg)
Estimate based on weight and starting Hgb:
Under 50 kg with mild anemia:
singe dose
Under 50 kg with moderate or severe anemia:
two doses given at least 1 week apart
Over 50 kg:
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41. Parenteral Iron Preparations
Generic
Name
Iron
Sucrose
LMW Iron
Dextran
Ferric Carboxymaltose
Trade Name
VenoFer
INFeD
Injectafer
FDA Approved for peds
> 2 years
> 4 months
No (US)
> 14 yr (Europe)
Black Box Warning No
Yes
Standard Dose
7 mg/kg
10 mg/kg
15 mg/kg
Max approved daily dose
200 mg
100 mg
750 mg
TDI for children
Yes (1000 mg)
Approved in Europe
Case series in US
Yes (750 mg)
Infusion time
min
60-90 min
5-15 min
Test Dose Required
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42. FDA Box Warnings Highest possible risk of anaphylaxis
However, no reports of such with any of the current formulations
Adverse event (backache, myalgias, fever, hypotension) rate of 1 per 200,000 infusions
Only Ferric carboxymaltose lacks the black-box warning
but, clear guidelines that the “office should have adequately trained personnel and equipment to manage anaphylaxis including immediate access to ICU”
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43. Premedication No routine premedication for any of the IV iron products
Exceptions (Pre-treat with methylprednisolone):
Asthma
Multiple drug allergies
Juvenile inflammatory arthritis
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44. Rapid Improvement After Therapy
PICA symptoms resolve during the infusion
Patients feel better within days
MCV and RBC pallor improves ~ 3 days
Reticulocytosis begins within 2 days – peaks around 7 days
Hgb rise in ~2 weeks
2 gm rise by 4 weeks
Normal value in 4-6 weeks
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45. IV Iron: longterm follow-up
4-6 weeks after infusion to ensure adequate correction
Re-check at 6 and 12 months after infusion as recurrence of deficiency is not uncommon
Ongoing menstrual loss
Rapid growth continues
Poor diets continue
Goal is ferritin > 35 (closer to 50)
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46. Recent ASPHO discussion
“One of the biggest lessons of my clinical career has been to appreciate the subtle but real effects of iron deficiency WITHOUT anemia.  I think this is absolutely under appreciated.  To attain optimal health and wellbeing for growing children, I think it crucial to treat iron deficiency even before it leads to anemia.”
Your patients will thank you!
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48. References International. Nutritional Anemia Consultative Group. 1998.
WHO/UNICEF. 2001, 2011
Pediatrics (4)
Am J Dis Child (2)
Am J Dis Child (2)
Pediatrics (5)
Centers for Disease Control and Prevention. MMWR (40)
Pediatrics (4)
Pediatr Blood Cancer
Pediatr Blood Cancer (S38)
Personal Communication (Manuscript submitted)
Ann Pharmacother (e63)
BMC Gastroenterol (184)
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