Iron Needs of Preterm Infant
Michael K. Georgieff M.D.
Professor of Pediatrics and Child Development
Head, Division of Neonatology
Director, Center for Neurobehavioral Development
University of Minnesota
Overview
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Iron Deficiency: Scope of Problem
Basic Principles of Nutrient-Brain Interactions
Role of Iron in the Developing Brain
Risk of Iron Deficiency in Neonates
– Human
• Preterm
– Rodent
• Risk of Iron Overload in Neonates
• Iron Dosing/Monitoring Recommendations
Why Worry About Iron Deficiency?
• 2 billion people world-wide are iron deficient (WHO)
– 30-50% of pregnant women
• Every cell/organ system needs iron for proper development and subsequent
function
• Iron deficiency anemia is associated with clinical symptoms
– Due to tissue level ID
– Symptoms occur prior to anemia
• Main reason to worry is the effect on the developing brain
– Cognitive and motor effects
– Some temporary (while ID), others long-term (after iron repletion)
Early Nutrition and Brain Development:
General Principles
Positive or negative nutrient effects
on brain development
Based on…
Timing, Dose and Duration of Exposure
Kretchmer, Beard, Carlson, 1996
Nutrient-Brain-Behavior Relationships
• Various brain regions/processes have different
developmental trajectories
• The vulnerability of a brain region to a nutrient
is based on
– When nutrient deficit/overload is likely to occur
– Brain’s requirement for that nutrient at that time
• Behavioral changes must map onto those
brain structures altered by the nutrient effect
Fetus
Late Infancy/Toddler
Pubertal
Thompson & Nelson, 200
Fetus
Late Infancy/Toddler
Pubertal
Iron: A Critical Nutrient for the Developing Brain
– Delta 9-desaturase, glial cytochromes control oligodendrocyte
production of myelin
• Iron Deficiency=> Hypomyelination
– Cytochromes mediate oxidative phosphorylation and
determine neuronal and glial energy status
• Iron Deficiency=> Impaired neuronal growth, differentiation,
electrophysiology
– Tyrosine Hydroxylase involved in monamine neurotransmitter
and receptor synthesis (dopamine, serotonin, norepi)
• Iron Deficiency=> Altered neurotransmitter regulation
Iron: A Significant Risk to the Developing Brain
• Potent oxidant stressor
– Role in Fenton reaction to create reactive oxygen species
• Iron overload associated with neurodegenerative
disorders in adults
– S/P acute hypoxic-ischemic reperfusion injury
– Parkinson’s, Alzheimer’s diseases
• Fetus/premature infant at high risk for iron toxicity
– Underdeveloped anti-oxidant systems
– Low Total Iron Binding Capacity
The U-shaped Nutrition Risk Curve
Deficiency
Adequacy
Risk
Dose
Overload
Iron and the U-shaped Nutrition Risk Curve
Deficiency
Adequacy
Risk
Dose
Overload
Neonatal Iron Deficiency
Fetal Iron: Endowment and Distribution
• Fetuses have 75mg of elemental iron per
kilogram body weight during 3rd trimester
– Term infant: 250mg
– 24 weeker (500g): 37.5 mg
• Majority is in the RBCs (55mg/kg)
• Liver storage pools are relatively large at term
(12 mg/kg); serum ferritin >40 mcg/L
• Non-storage tissues, including brain, heart,
skeletal muscle account for the rest (8 mg/kg)
What Can Negatively Affect Neonatal Iron Status?
• Decreased maternal iron supply
– Fetus with very iron deficient mother (Hgb<8.5)
– Common (>30%) in developing countries
– No studies of newborn brain iron status
• Decreased placental iron transfer during gestation
– Prematurity
• Iron accreted during third trimester
• Generally negative iron balance during NICU stay
– IUGR due to maternal hypertension during pregnancy
• 50% affected
• 75,000 infants per year in US
• 32% decrease in brain iron concentration (Georgieff et al, 1995)
Term Infants: What Can Negatively Affect
Neonatal Iron Status?
• Diabetes Mellitus during pregnancy
– Chronically hypoxic fetus (IDM)=> Increased erythropoeisis
– 65% affected
– 150,000 infants per year in US
– 40% decrease in brain iron concentration (Petry et al, 1992)
• Basic principle:
Iron prioritized to RBCs over brain &
other organs when Fe demand> Fe supply
Preterm Infants: Risk for Iron Deficiency at Birth
Preterm Infants Are Born with Lower Iron Stores
400
Serum Ferritin (mcgs/L)
350
300
1)
Neonates have 75 mg Fe/Kg weight
250
2)
24 weeks EGA= 38mg Fe
200
3)
40 weeks EGA= 225mg Fe
150
4)
20-30% of preterms are IUGR
5)
50% of IUGRs have ferritin <5%ile
100
50
0
20
25
30
35
40
45
Gestational Age (w ks)
Table 1. Percentiles for term and preterm infants.
Cord serum ferritin percentiles for term and preterm infants
Percentile
Siddappa et al., Neonatology, 2007
Gestational
Age
Term (37
wks), n =308
Pre-Term (< 37
wks), n = 149
5% 25%
50%
75% 95%
40
84
134
200
309
35
80
115
170
267
Preterm Infants: Risk for Negative Iron Balance
During Hospitalization
Factors that Determine Preterm Infant
Iron Balance in the NICU
Positive Iron Balance
Negative Iron Balance
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Low Endowment (IUGR)
Phlebotomy Losses
Iron Rx at 2 months
Iron Rx < 2mg/kg/d
rhEpo Rx
Rapid Postnatal Growth
1)
2)
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Older gestation & AGA
RBC Transfusion
Iron Rx at 2 weeks
Iron Rx @ 2-4 mg/kg/d
Iron Rx @ 6mg/kd/d c rhEpo
Parenteral Iron
Slow Postnatal Growth Rate
Preterm infants have elevated ZnPP at 34 weeks PCA (Winzerling &Kling)
Does anemia of prematurity have an iron deficiency component?
Preterm Infants: Risk of ID/IDA after Discharge
Iron Status after NICU Discharge
35
2 mos CGA
Hemoglobin in
<1750g Preterms
# of infants
30
Lower total body iron
stores & higher serum
TfR at 2 mos of age
Shah et al, PAS 2006
25
20
15
10
5
0
HB < 11
HB > 11
sTFR<8, ferritin>20
sTFR>8, ferritin<20
Up to 69% ID at follow-up
if in hospital iron therapy
delayed until 2 months
postnatal age
Hall et al, 1993
Neurobehavioral Risks of Early ID
Neurobehavioral Sequelae of Perinatal ID
• Behavioral abnormalities
– Term infants with low neonatal iron stores have poorer school
age neurodevelopment (Tamura et al, 2002)
– Iron deficient infants born to IDA mothers have altered
temperament (Wachs et al, 2005)
– Preterm infants with lowest quartile of ferritin concentration at
discharge have abnormal neurologic reflexes (Armony-Sivan,
2004)
– Preterm infants with low ferritins have slower central nerve
conduction speeds (Amin, 2010)
• Electrophysiologic abnormalities
– Term IDM with ferritin concentrations <35 mcg/L have impaired
auditory recognition memory processing (Siddappa et al, 2004)
Assessing Memory Function
in ID Newborn Infants
(How do we do this and why?)
Mom: “Hi Baby”
Stranger: “Hi Baby”
Event related potentials (ERPs) in infants
Iron Sufficient
Iron Deficient
Siddappa et al., 2004, Pediatr. Res.
Perinatal Iron Deficiency: What is the Biology?
Early Postnatal ID:
Myelin Effects in the Rat
• Altered fatty acid profile in myelin fraction
• Decreased myelin proteins, including myelin basic protein
• Decreased oligodendrocyte proliferation
• Transcripts for myelin basic protein affected
– short term (while ID)
– long term (at P180 after iron repletion)
• Likely accounts for ABR findings in premies (Amin et al, 2010)
Neurotransmitter Effects in the Rat
• Effects on monoamines, esp dopamine, known
since late 1970’s (Yehuda, Youdim, Beard)
• While ID: Decreased DAT, D1R, D2R
• Regional differences- Large effects in striatum
– Changes related to timing and severity
– Behavioral effects include hesitancy, wariness
• Likely accounts for reduced engagement and
altered temperament in ID newborns (Wachs et al,
2005)
Hippocampal Effects
• Short and long-term genomic changes (ES Carlson et al, 2007)
– Dendrite structure, synaptic efficacy, oxidative metabolism
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Reduced energy status (M deUngria et al, 2000)
Altered dendrite morphology (ES Carlson et al, 2009)*
Long-term suppression of BDNF and its receptor (P Tran et al, 2009)
Reduced LTP (long-term potentiation) (LA Jorgenson et al, 2005)
Reduced learning and memory
– Morris Water Maze (B Felt and B Lozoff, 1996)
– Radial Arm Maze (AT Schmidt et al, 2007)
• Likely accounts for recognition memory deficits (Siddappa et al, 2004)
Sufficient
Deficient
Excess Iron
Brain Iron Overload:
Which Infants are at Risk?
• Birth Asphyxiated Newborns
– Increased free (non-protein bound) iron in cord blood
(Perrone et al, 2002)
– Increased NPBI and thio-barbituric-acid-reactive species
(TBARS) in plasma suggesting increased lipid
peroxidation (Yu et al, 2003)
– Plasma NPBI >15.2mcmol/L is 100% sensitive and
specific for neurologic impairment (Buonocore et al, 2003)
– NPBI elevated in CSF and correlated with oxidized
proteins and Sarnat stage (Ogihara et al., 2003)
Brain Iron Overload:
Which Infants are at Risk?
• Preterm Infants
– Parenteral iron (Pollak et al, 2001)
– RBC transfusion (with hemolysis)
– Relationship between RBC transfusions and other “oxidant
diseases” (e.g. BPD, ROP)
Inder et al, 1997; Cooke et al, 1997
Human studies have not assessed specific
neurodevelopment as a function of area of iron overload
Concerns About Excess Iron in the Term Neonate
• Newborn term infants with highest quartile of cord blood
ferritin concentration have poorer outcome than middle
quartiles (Tamura et al, 2002)
– But not as bad as lowest quartile
– High ferritin; iron or inflammation?
• Infants with high normal hemoglobins at 6-9 months
receiving formula with 12 mg Fe/L have lower IQs at age
10 (Lozoff et al, 2008 PAS abstract)
– Not true for infants with normal or low hemoglobins
How well regulated is enteral iron uptake in the neonate?
» Term
» Preterm
Early Iron Overload: Animal Models
• Free iron=>Reactive oxygen species
– Astrocyte dysfunction
– NMDA receptor impairment
– Damaged mitochondrial DNA
– Peroxidation of immature myelin sheaths
• Increased perivascular iron deposition in neonatal
rat brain following severe hypoxia-ischemia
(Palmer et al, 1999)
– Within hours of neonatal stroke
– Long term iron deposition and neuronal loss
– Protective effect of iron chelators
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Palmer et al, 1994
Iron Supplements and Memory in IS Rodents
• Increasing levels of high dose (2.5 to 30 mg/kg/d)
iron administration to iron sufficient neonatal rats
results in worse memory performance as adults
(Schroder et al, 2001)
– Dose responsive increase in brain iron content
– No specific regional structural/functional assessment
(e.g. LTP)
Iron Overload: Summary
• There are plenty of theoretical reasons based on
animal studies to be concerned
• Further research needs to explore this potential
link in human infants, especially treatment of iron
sufficient infants with supplemental iron
– Reviews by Buonocoare (2003) and Gressens (2002)
Iron Dosing
Treatment and Monitoring Iron Status
in the Preterm Infant
• Current AAP dosing recommendations appear appropriate
for preterms in NICU
– 2-4 mg/kg/day enteral iron
• 4mg/kg if <30 weeks
• 2-3 mg/kg if >30 weeks
– 6 mg/kg/day if on rhEpo
• Post-discharge recommendations (2.25 mg/kg/d) appear
low and should be increased to 3.3 mg/kg/d
• Consider monitoring ferritin at birth, at discharge and at
follow-up (along with hemoglobin & indices)
Iron Dosing for Neonates and Infants
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Term AGA
Term SGA
Preterm >30 w EGA
Preterm <30 w EGA
Preterm on rhEpo
Preterm; ferritin <35
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1 mg/kg daily
2 mg/kg daily
2 mg/kg daily
4 mg/kg daily
6 mg/kg daily
+2 mg/kg daily
Conundrums in preterms:
1. Anemic, no retics, ferritin >350
2. Breastfed infants
Monitoring Iron Status
• AAP recommends hemoglobin screening at 9 months
of age
– Earlier screening for premies, SGAs
– sTfR, ZnPP, MCV might screen pre-anemia
• sTfR, ZnPP not available everywhere, lacking standards for <
12 month olds
• Ferritin is good pre-anemic screen
– But, infant cannot have acute illness (acute phase reactant)
• NHANES and CDC testing sTfR/Heme ratio
Summary
• Iron has an important role in late gestational
and early postnatal brain development
• Iron is regulated within a narrow range
• Iron deficiency and iron overload present
risks to developing brain
• Risks can be global or regionally specific
• Abnormal behaviors in ID “map onto”
regional brain areas at risk
Acknowledgements
• U of Minnesota
– Raghu Rao
– Lyric Jorgenson
– Erik Carlson
– Adam Schmidt
– Jane Wobken
– Tracy deBoer
– Charles Nelson
• NICHD
• NINDS
• Jack Widness (U of Iowa)
• Betty Leibold (U of Utah)
• Rick Eisenstein (U of Wisconsin)
• Jim Connor, John Beard (Penn State)
• Betsy Lozoff, Barb Felt (U of Michigan)
• At HCMC& U of Minnesota
– Asha Siddappa
• Raye-Ann deRegnier, Malika Shah
(Northwestern U)