Developmental Outcomes of Preterm
Infants: Emphasis on Nutrition
Michael K. Georgieff, M.D.
Professor of Pediatrics and Child Development
Director, Center for Neurobehavioral Development
Director, NICU Follow-up Program
University of Minnesota School of Medicine
Prematurity in the United States
 In the year 2000:
– 7.6% of infants born weighed < 2500 grams
– 1.4% weighed < 1500 grams
– Infant mortality dropped to 6.9 per 1000 births
 Last 8 years, prematurity rates have increased
– Role of multiples (IVF)
Cognitive Development of Premies in
Infancy/Early Childhood
 Theme: Within the normal range, but
significantly lower than full term comparisons
 Specific abilities:
– immature patterns of visual attention
– memory mostly intact but subtle
impairments
– slight working memory advantage
Cognitive Development of Premies in
Middle Childhood/Adolescence
 Themes: IQ drops with birth weight & GA
– < 2500 g = No MR, no group diffs. in IQ
– < 1500 g = Roughly 10 points below mean
– < 750 g = Roughly 20 points below mean
 Specific deficits:
– expressive language
- memory
– sustained attention
- working memory
– visual-spatial abilities
- set shifting
The Vulnerable Preterm Brain
• Rapidly growing tissue
•exaggerated effect of any insult
- vulnerability outweighs “plasticity”
• Vascular instability of the germinal matrix
• Watershed areas (periventricular area)
• Selective regional metabolic vulnerability
(hippocampus)
Thompson & Nelson, Am Psychol, 200
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants:
Which Ones Can We Influence?
1.
2.
3.
4.
5.
6.
Degree of Prematurity
Size for Dates (SGA)
Intraventricular hemorrhage
(Periventricular) Leukomalacia
Socio-economic Status
Postnatal Nutrition
Major Factors Influencing
Neurodevelopmental Outcome in Preterm
Infants
1.
2.
3.
4.
5.
6.
Degree of Prematurity
Size for Dates (SGA)
Intraventricular hemorrhage
(Periventricular) Leukomalacia
Socio-economic Status
Postnatal Nutrition
P
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10
1
0.1
0.01
24
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40
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44
Gestation (week)
FIG 59-2. Occurrence of spastic diplegia as related to gestational age.
Children In Group (%)
50
<750 g
<750 - 1499 g
Born at term
40
30
20
10
0
C ogn itive
Fu n ction
Acade m ic Vi su al Motor Gross Motor Adapti ve
S k il l s
Fu n ction
Fu n ction
Fu n ction
Outcome of 401-1000g Infants
Vohr et al, 2000
 NICHD Network
 1151 infants evaluated at 18 months
 25% with abnormal neurologic exam
 37% with Bayley II MDI <70
 29% with Bayley II PDI<70
Grim news. Is it representative?
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
1. Degree of Prematurity?
A. Minimal Influence
- Prematurity rates have risen
- Time to delivery with PTL = 4 days
- Prematurity prevention programs->
mixed success
Factors Influencing Neurdevelopmental
Outcome in Preterm Infants
1. Degree of Prematurity
2. Size for Dates (SGA)
3. Intraventricular Hemorrhage
4. (Periventricular) Leukomalacia
5. Socio-economic Status
6. Postnatal Nutrition
Effect of Size for Dates
•
Term Infants: National Collaborative
Prenatal Data Base
- 6.8 point IQ deficit at 7y compared to case controls
• Preterm Infants: with and without postnatal
malnutrition
- 8 point deficit on 1y MDI if postnatal malnutrition > 2
weeks
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
2. Size for Dates (SGA)?
A. Moderate potential influence
- Control maternal BP
- Deliver more prematurely?
- Trading IUGR for EUGR
Factors Influencing Neurdevelopmental
Outcome in Preterm Infants
1. Degree of Prematurity
2. Size for Dates (SGA)
3. Intraventricular Hemorrhage
4. (Periventricular) Leukomalacia
5. Socio-economic Status
6. Postnatal Nutrition
Incidence of Major Handicap with IVH in
<1500g Infants
•
No Hemorrhage: <10%
•
Grade I or II IVH: 12%
•
Grade III IVH: 36%
•
Grade IV IVH: 75%
Is it the lesion or the associated
circumstances?
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
3. Intraventricular hemorrhage?
A. Almost no influence
- Still unknown etiology
- 60% happen at birth
- Prophylactic Indocin?
Factors Influencing Neurdevelopmental
Outcome in Preterm Infants
1. Degree of Prematurity
2. Size for Dates (SGA)
3. Intraventricular Hemorrhage
4. (Periventricular) Leukomalacia
5. Socio-economic Status
6. Postnatal Nutrition
(Periventricular) Leukomalacia
• Hypoxic-ischemic etiology
• Periventricular echodensities are
common on early ultrasound and are
not prognostic
• >2mm cysts at 1 month are 95%
predictive of CP if lesions extend from
anterior to posterior
• Most common CP is spastic diplegia
Periventricular Hemorrhagic Necrosis
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
4. (Periventricular) Leukomalacia?
A. Questionable influence
- Keep neonatal blood pressure higher
(hypothetical)
- Reduce fetal hypoxia (earlier delivery?)
Factors Influencing Neurdevelopmental
Outcome in Preterm Infants
1. Degree of Prematurity
2. Size for Dates (SGA)
3. Intraventricular Hemorrhage
4. (Periventricular) Leukomalacia
5. Socio-economic Status
6. Postnatal Nutrition
Combined Effect of SES and Prematurity
Moderating Factors
 For the youngest and smallest infants:
– biological factors best predict long-term outcomes
 For the moderately preterm:
– biological factors related to early developmental status,
but decline in influence
– environmental factors become important after first year
of life
Home Environment and the Brain
The quality of a child’s home environment is
associated with global cognitive outcomes
Experience with a stimulating environment has been
shown to promote synaptogenesis
Experience with a stimulating environment also is
related to better performance on a range of learning
tasks
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
5. Socio-economic Status?
A. No Influence (short-term or
individual)
- Clear economic data that
SES changes in <20% of
people
Major Factors Influencing
Neurdevelopmental Outcome in Preterm
Infants
1. Degree of Prematurity
2. Size for Dates (SGA)
3. Intraventricular Hemorrhage
4. (Periventricular) Leukomalacia
5. Socio-economic Status
6. Postnatal Nutrition
General Principles
The goal of nutritional management of
the sick premature infant in the first
months of life is to promote normal
growth velocity and body composition
relative to age matched, healthy
infants
Canadian Pediatric Society:
Growth Stages in Prematures
 Transition (0-10 days)
 Premie Grower (10 days- 34 weeks PCA)
 Post-discharge (>34 weeks PCA)
Each stage has different metabolic physiology
and nutritional needs
Transition: Nutritional and Metabolic Risks
 Nutrient Source: TPN + Minimal Feeds (Fluid Restriction)
 Catabolism => High protein turnover
– Goal:
» 2-3g/kg on day 1
» 3.8 g/kg average daily intake
 Insulin Resistance => Energy substrate handling
– Glucose and lipid intolerance
– Goals:
» Meet REE (60-70 kcal/kg daily) OR
» Provide energy for weight gain/ “growth” (120 kcal/kg daily)
– Can sick babies grow?
1. Transition
Ehrenkranz et al, 2000
Premie Grower
 10 days to 34 weeks PCA
– Start time varies based on end of illness (could be 30 days or more)




Stable, anabolic
Immature gut physiology
Accrued deficits from previous phase
Nutrient Source: Fortified OMM, PT Formula
Premie Grower: Nutritional Risks
 Protein => Intrauterine rate + deficit from transition
– Target 4g/kg daily
– Considerations:
» Unknown maternal milk composition
» Renal status
 Energy => Intrauterine weight gain + deficit
– Target 135 kcal/kg daily
– Considerations:
» Fuel source & balance (CHO/Fat)
» OMM composition
 Iron => Phlebotomy losses + Rapid Growth
– Target 2-4 mg/kg daily
» Is anemia of prematurity iron deficiency?
2. Premie
Grower
Ehrenkranz et al, 2000
Post-Discharge
 After 34 weeks PCA
 Stable, anabolic, mature gut
 Nutrient Sources: OMM, Fortified OMM, Post-discharge
formula
Post-Discharge: Nutritional Risks
 Protein- daily needs + 25 g/kg deficit
– Target: 3.2 g/kg daily
– Considerations:
» OMM commonly used as base; unknown protein content
 Energy- term growth + 1000 Kcal/kg deficit;
– Target: 110 kcal/kg daily
– Considerations:
» Issue of body proportionality (from low W/L to high W/L; slow linear growth)
 Fe- growth ± status at discharge
– Target 2.25 mg/kg daily
– Considerations:
» Issue of wide range of iron status at discharge
» Recent data that 2.25 mg/kg daily is probably low
3. Post-discharge
Ehrenkranz et al, 2000
3. Post-discharge
2. Premie
Grower
1.Early
Ehrenkranz et al, 2000
Prematures: Evidence for PostDischarge Nutrient Deficits
•
Poor first year growth (protein-energy)
• Poorer developmental outcome-related to
growth failure
• Anemia (Iron)
Effect of Mild to Severe Postnatal
Malnutrition on Head Growth in the
NICU and at One-Year Follow-up
Effect of No Prenatal and Mild Postnatal Malnutrition
on Head Size and Development
No DQ
Differences
Effect of No Prenatal and Moderate Postnatal Malnutrition
on Head Size and Development
3 point DQ
difference
The effect of combined pre- and
postnatal malnutrition on neonatal
and follow-up head growth
Effect of Pre and Postnatal Malnutrition
on Head Size and Development
-8 DQ
Points
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
6. Postnatal Nutrition
A. Large potential influence!!
- Limit degree and duration of initial illness
Prenatal steroids, control infections
- Initiate early nutrition
Early protein, trophic feeds
Factors Influencing Neurodevelopmental
Outcome in Preterm Infants
Which Ones Can We Influence?
6. Postnatal Nutrition
- Make up deficits during premie growth
Calculate and replace deficits; adequate
monitoring of key “brain” nutrient status
- Continue nutritional management postdischarge
Conclusions
Outcomes of preterm infants are generally
better than anticipated based on the biologic
lesions
– Outcomes still poor in <25 week babies
– NICHD network data are overly pessimistic
Use more pathophysiologically precise tools in
preterm follow-up studies to better identify
factors that can be altered in the NICU
Pay closer attention to nutrition from birth to
post-discharge
The effect of chronic illness (BPD)
on weight gain and head growth
1
Weight
Weight z-score
0
Control
-1
BPD
-2
-3
-4
0
1
2
3
4
5
6
7
8
9
10
Postnatal Age (weeks)
deRegnier et al, 1996
1
Head Circumference
OFC Z-score
0
-1
-2
-3
-4
0
1
2
3
4
5
6
7
8
9
10
Postnatal Age (weeks)
deRegnier et al, 1996
Major Factors Influencing
Neurodevelopmental Outcome in Preterm
Infants
1.
2.
3.
4.
5.
6.
Degree of Prematurity
Size for Dates (SGA)
Intraventricular hemorrhage
Periventricular Leukomalacia
Socio-economic Status
Postnatal Nutrition
What the brain does with protein
DNA, RNA synthesis and maintenance
Neurotransmitter production (synaptic
efficacy)
Growth factor synthesis
Structural proteins
– Neurite extension (axons, dendrites)
– Synapse formation (connectivity)
Why the brain needs fats
Cell membranes
Synapse formation
Myelin
Iron: A Critical Nutrient for the
Developing Human Brain
Iron containing enzymes and hemo-proteins are
involved in important cellular processes in
developing brain
– Delta 9-desaturase, glial cytochromes control
oligodendrocyte production of myelin
– Cytochromes mediate oxidative phosphorylation and
determine neuronal and glial energy status
– Tyrosine Hydroxylase involved in monamine
neurotransmitter synthesis (dopamine, serotonin,
norepi)
Thompson & Nelson, Am Psychol, 200