Developmental Outcomes of Preterm Infants: Emphasis on Nutrition Michael K. Georgieff, M.D. Professor of Pediatrics and Child Development Director, Center

Developmental Outcomes of Preterm Developmental Outcomes of Preterm Infants: Emphasis on NutritionInfants: Emphasis on Nutrition

Michael K. Georgieff, M.D.Michael K. Georgieff, M.D.

Professor of Pediatrics and Child DevelopmentProfessor of Pediatrics and Child Development

Director, Center for Neurobehavioral DevelopmentDirector, Center for Neurobehavioral Development

Director, NICU Follow-up ProgramDirector, NICU Follow-up Program

University of Minnesota School of MedicineUniversity of Minnesota School of Medicine

Prematurity in the United StatesPrematurity in the United States

In the year 2000: In the year 2000:

– 7.6% of infants born weighed < 2500 grams 7.6% of infants born weighed < 2500 grams

– 1.4% weighed < 1500 grams1.4% weighed < 1500 grams

– Infant mortality dropped to 6.9 per 1000 birthsInfant mortality dropped to 6.9 per 1000 births

Last 8 years, prematurity rates have increasedLast 8 years, prematurity rates have increased

– Role of multiples (IVF)Role of multiples (IVF)

Cognitive Development of Premies in Cognitive Development of Premies in Infancy/Early ChildhoodInfancy/Early Childhood

Theme: Within the normal range, but Theme: Within the normal range, but significantly lower than full term comparisonssignificantly lower than full term comparisons

Specific abilities:Specific abilities:

– immature patterns of visual attentionimmature patterns of visual attention

– memory mostly intact but subtle memory mostly intact but subtle impairmentsimpairments

– slight working memory advantageslight working memory advantage

Cognitive Development of Premies in Cognitive Development of Premies in Middle Childhood/AdolescenceMiddle Childhood/Adolescence

Themes: IQ drops with birth weight & GAThemes: IQ drops with birth weight & GA

– < 2500 g = No MR, no group diffs. in IQ< 2500 g = No MR, no group diffs. in IQ

– < 1500 g = Roughly 10 points below mean< 1500 g = Roughly 10 points below mean

– < 750 g = Roughly 20 points below mean< 750 g = Roughly 20 points below mean Specific deficits:Specific deficits:

– expressive languageexpressive language - memorymemory

– sustained attentionsustained attention - working - working memorymemory

– visual-spatial abilities visual-spatial abilities - set shifting- set shifting

The Vulnerable Preterm BrainThe Vulnerable Preterm Brain

• Rapidly growing tissue Rapidly growing tissue

•exaggerated effect of any insultexaggerated effect of any insult

- vulnerability outweighs “plasticity”vulnerability outweighs “plasticity”

• Vascular instability of the germinal matrixVascular instability of the germinal matrix

• Watershed areas (periventricular area)Watershed areas (periventricular area)

• Selective regional metabolic vulnerability Selective regional metabolic vulnerability (hippocampus)(hippocampus)

Thompson & Nelson, Am Psychol, 2001

Factors Influencing Neurodevelopmental Factors Influencing Neurodevelopmental Outcome in Preterm Infants:Outcome in Preterm Infants:

Which Ones Can We Influence?Which Ones Can We Influence?1. Degree of Prematurity1. Degree of Prematurity

2. Size for Dates (SGA) 2. Size for Dates (SGA)

3. Intraventricular hemorrhage3. Intraventricular hemorrhage

4. (Periventricular) Leukomalacia4. (Periventricular) Leukomalacia

5. Socio-economic Status5. Socio-economic Status

6. Postnatal Nutrition6. Postnatal Nutrition

Major Factors Influencing Major Factors Influencing Neurodevelopmental Outcome in Preterm Neurodevelopmental Outcome in Preterm

InfantsInfants

1. 1. Degree of Prematurity Degree of Prematurity






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24 26 28 30 32 34 36 38 40 42 4424 26 28 30 32 34 36 38 40 42 44

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Gestation (week)Gestation (week)FIG 59-2. Occurrence of spastic diplegia as related to gestational age. FIG 59-2. Occurrence of spastic diplegia as related to gestational age.

0

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CognitiveFunction

AcademicSkills

Visual MotorFunction

Gross MotorFunction

AdaptiveFunction

<750 g<750 g<750 - 1499 g<750 - 1499 gBorn at termBorn at term

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Outcome of 401-1000g InfantsOutcome of 401-1000g InfantsVohr et al, 2000Vohr et al, 2000

NICHD NetworkNICHD Network 1151 infants evaluated at 18 months1151 infants evaluated at 18 months 25% with abnormal neurologic exam25% with abnormal neurologic exam 37% with Bayley II MDI <7037% with Bayley II MDI <70 29% with Bayley II PDI<7029% with Bayley II PDI<70

Grim news. Is it representative?Grim news. Is it representative?

Factors Influencing Neurodevelopmental Factors Influencing Neurodevelopmental Outcome in Preterm InfantsOutcome in Preterm Infants

Which Ones Can We Influence?Which Ones Can We Influence?1.1. Degree of Prematurity?Degree of Prematurity?

A.A. Minimal InfluenceMinimal Influence

- Prematurity rates have risenPrematurity rates have risen

- Time to delivery with PTL = 4 daysTime to delivery with PTL = 4 days

-- Prematurity prevention programs-> Prematurity prevention programs-> mixed successmixed success

Factors Influencing Neurdevelopmental Factors Influencing Neurdevelopmental Outcome in Preterm InfantsOutcome in Preterm Infants

1. Degree of Prematurity1. Degree of Prematurity

2. Size for Dates (SGA)2. Size for Dates (SGA)

3. Intraventricular Hemorrhage3. Intraventricular Hemorrhage




Effect of Size for DatesEffect of Size for Dates

• Term Infants: National Collaborative Term Infants: National Collaborative Prenatal Data BasePrenatal Data Base

- 6.8 point IQ deficit at 7y compared to case controls6.8 point IQ deficit at 7y compared to case controls

• Preterm Infants: with and without postnatal Preterm Infants: with and without postnatal malnutrition malnutrition

- 8 point deficit on 1y MDI if postnatal malnutrition > 2 8 point deficit on 1y MDI if postnatal malnutrition > 2 weeksweeks


Which Ones Can We Influence?Which Ones Can We Influence?2.2. Size for Dates (SGA)?Size for Dates (SGA)?

A. Moderate potential influenceA. Moderate potential influence

- Control maternal BPControl maternal BP

- Deliver more prematurely?Deliver more prematurely?

- Trading IUGR for EUGRTrading IUGR for EUGR








Incidence of Major Handicap with IVH in Incidence of Major Handicap with IVH in <1500g Infants<1500g Infants

• No Hemorrhage: <10%No Hemorrhage: <10%

• Grade I or II IVH: 12%Grade I or II IVH: 12%

• Grade III IVH: 36%Grade III IVH: 36%

• Grade IV IVH: 75%Grade IV IVH: 75%

Is it the lesion or the associated Is it the lesion or the associated circumstances?circumstances?


Which Ones Can We Influence?Which Ones Can We Influence?3.3. Intraventricular hemorrhage?Intraventricular hemorrhage?

A. Almost no influenceA. Almost no influence

- Still unknown etiologyStill unknown etiology

- 60% happen at birth60% happen at birth

- Prophylactic Indocin?Prophylactic Indocin?








(Periventricular) Leukomalacia(Periventricular) Leukomalacia

• Hypoxic-ischemic etiologyHypoxic-ischemic etiology

• Periventricular echodensities are Periventricular echodensities are common on early ultrasound and are common on early ultrasound and are

not prognosticnot prognostic

• >2mm cysts at 1 month are 95% >2mm cysts at 1 month are 95% predictive of CP if lesions extend from predictive of CP if lesions extend from

anterior to posterioranterior to posterior

• Most common CP is spastic diplegiaMost common CP is spastic diplegia

Periventricular Hemorrhagic NecrosisPeriventricular Hemorrhagic Necrosis


Which Ones Can We Influence?Which Ones Can We Influence?4.4. (Periventricular) Leukomalacia?(Periventricular) Leukomalacia?

A. Questionable influenceA. Questionable influence

- Keep neonatal blood pressure higher - Keep neonatal blood pressure higher (hypothetical)(hypothetical)

- Reduce fetal hypoxia (earlier delivery?)- Reduce fetal hypoxia (earlier delivery?)








Combined Effect of SES and PrematurityCombined Effect of SES and Prematurity

Moderating FactorsModerating Factors

For the youngest and smallest infants:For the youngest and smallest infants:

– biological factors best predict long-term outcomesbiological factors best predict long-term outcomes For the moderately preterm:For the moderately preterm:

– biological factors related to early developmental status, biological factors related to early developmental status, but decline in influencebut decline in influence

– environmental factors become important after first year environmental factors become important after first year of lifeof life

Home Environment and the BrainHome Environment and the Brain

The quality of a child’s home environment is The quality of a child’s home environment is associated with global cognitive outcomesassociated with global cognitive outcomes

Experience with a stimulating environment has been Experience with a stimulating environment has been shown to promote synaptogenesisshown to promote synaptogenesis

Experience with a stimulating environment also is Experience with a stimulating environment also is related to better performance on a range of learning related to better performance on a range of learning taskstasks


Which Ones Can We Influence?Which Ones Can We Influence?

5.5. Socio-economic Status?Socio-economic Status?

A. No Influence (short-term or A. No Influence (short-term or individual)individual)

- Clear economic data that - Clear economic data that SES changes in <20% of SES changes in <20% of peoplepeople

Major Factors Influencing Major Factors Influencing Neurdevelopmental Outcome in Preterm Neurdevelopmental Outcome in Preterm

InfantsInfants






6. 6. Postnatal NutritionPostnatal Nutrition

General PrinciplesGeneral Principles

The goal of nutritional management of The goal of nutritional management of the sick premature infant in the first the sick premature infant in the first months of life is to promote normal months of life is to promote normal growth velocity and body composition growth velocity and body composition relative to age matched, healthy relative to age matched, healthy infantsinfants

Canadian Pediatric Society: Canadian Pediatric Society: Growth Stages in PrematuresGrowth Stages in Prematures

Transition (0-10 days)Transition (0-10 days) Premie Grower (10 days- 34 weeks PCA)Premie Grower (10 days- 34 weeks PCA) Post-discharge (>34 weeks PCA)Post-discharge (>34 weeks PCA)

Each stage has different metabolic physiology Each stage has different metabolic physiology and nutritional needsand nutritional needs

Transition: Nutritional and Metabolic RisksTransition: Nutritional and Metabolic Risks

Nutrient Source: TPN + Minimal Feeds (Fluid Restriction)Nutrient Source: TPN + Minimal Feeds (Fluid Restriction) Catabolism => High protein turnoverCatabolism => High protein turnover

– Goal: Goal:

» 2-3g/kg on day 1 2-3g/kg on day 1

» 3.8 g/kg average daily intake3.8 g/kg average daily intake

Insulin Resistance => Energy substrate handlingInsulin Resistance => Energy substrate handling– Glucose and lipid intoleranceGlucose and lipid intolerance

– Goals: Goals:

» Meet REE (60-70 kcal/kg daily) OR Meet REE (60-70 kcal/kg daily) OR

» Provide energy for weight gain/ “growth” (120 kcal/kg daily)Provide energy for weight gain/ “growth” (120 kcal/kg daily)

– Can sick babies grow?Can sick babies grow?

1. Transition

Ehrenkranz et al, 2000

Premie GrowerPremie 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 RisksPremie Grower: Nutritional Risks

Protein => Intrauterine rate + deficit from transitionProtein => Intrauterine rate + deficit from transition – Target 4g/kg dailyTarget 4g/kg daily– Considerations:Considerations:

» Unknown maternal milk compositionUnknown maternal milk composition» Renal statusRenal status

Energy => Intrauterine weight gain + deficit Energy => Intrauterine weight gain + deficit – Target 135 kcal/kg dailyTarget 135 kcal/kg daily– Considerations:Considerations:

» Fuel source & balance (CHO/Fat)Fuel source & balance (CHO/Fat)» OMM compositionOMM composition

Iron => Phlebotomy losses + Rapid GrowthIron => Phlebotomy losses + Rapid Growth– Target 2-4 mg/kg dailyTarget 2-4 mg/kg daily

» Is anemia of prematurity iron deficiency?Is anemia of prematurity iron deficiency?

2. Premie Grower


Post-DischargePost-Discharge

After 34 weeks PCAAfter 34 weeks PCA Stable, anabolic, mature gutStable, anabolic, mature gut Nutrient Sources: OMM, Fortified OMM, Post-discharge Nutrient Sources: OMM, Fortified OMM, Post-discharge

formulaformula

Post-Discharge: Nutritional RisksPost-Discharge: Nutritional Risks

Protein- daily needs + 25 g/kg deficitProtein- daily needs + 25 g/kg deficit – Target: 3.2 g/kg dailyTarget: 3.2 g/kg daily– Considerations:Considerations:

» OMM commonly used as base; unknown protein contentOMM commonly used as base; unknown protein content

Energy- term growth + 1000 Kcal/kg deficit;Energy- term growth + 1000 Kcal/kg deficit;– Target: 110 kcal/kg dailyTarget: 110 kcal/kg daily– Considerations:Considerations:

» Issue of body proportionality (from low W/L to high W/L; slow linear growth)Issue of body proportionality (from low W/L to high W/L; slow linear growth)

Fe- growth ± status at dischargeFe- growth ± status at discharge – Target 2.25 mg/kg dailyTarget 2.25 mg/kg daily– Considerations:Considerations:

» Issue of wide range of iron status at dischargeIssue of wide range of iron status at discharge» Recent data that 2.25 mg/kg daily is probably lowRecent data that 2.25 mg/kg daily is probably low

3. Post-discharge3. Post-discharge


1.Early

2. Premie Grower

3. Post-discharge3. Post-discharge


Prematures: Evidence for Post-Prematures: Evidence for Post-Discharge Nutrient DeficitsDischarge Nutrient Deficits

• Poor first year growth (protein-energy)Poor first year growth (protein-energy)

• Poorer developmental outcome-related to Poorer developmental outcome-related to growth failuregrowth failure

• Anemia (Iron)Anemia (Iron)

Effect of Effect of Mild to SevereMild to Severe Postnatal Postnatal Malnutrition on Head Growth in the Malnutrition on Head Growth in the

NICU and at One-Year Follow-upNICU and at One-Year Follow-up

No DQDifferences

Effect of No Prenatal and Mild Postnatal Malnutrition on Head Size and Development

3 point DQdifference

Effect of No Prenatal and Moderate Postnatal Malnutrition on Head Size and Development

The effect of combined pre- and The effect of combined pre- and postnatal malnutrition on neonatal postnatal malnutrition on neonatal

and follow-up head growthand follow-up head growth

-8 DQ Points

Effect of Pre and Postnatal Malnutrition on Head Size and Development


Which Ones Can We Influence?Which Ones Can We Influence?6.6. Postnatal NutritionPostnatal Nutrition

A. Large potential influence!!A. Large potential influence!!

- Limit degree and duration of initial illness- Limit degree and duration of initial illness

Prenatal steroids, control infectionsPrenatal steroids, control infections

- Initiate early nutrition- Initiate early nutrition

Early protein, trophic feedsEarly protein, trophic feeds


Which Ones Can We Influence?Which Ones Can We Influence?6.6. Postnatal NutritionPostnatal Nutrition

- Make up deficits during premie growth- Make up deficits during premie growth

Calculate and replace deficits; adequate Calculate and replace deficits; adequate monitoring of key “brain” nutrient statusmonitoring of key “brain” nutrient status

- Continue nutritional management post-- Continue nutritional management post-dischargedischarge

ConclusionsConclusions

Outcomes of preterm infants are generally Outcomes of preterm infants are generally better than anticipated based on the biologic better than anticipated based on the biologic lesionslesions

– Outcomes still poor in <25 week babiesOutcomes still poor in <25 week babies– NICHD network data are overly pessimisticNICHD network data are overly pessimistic

Use more pathophysiologically precise tools in Use more pathophysiologically precise tools in preterm follow-up studies to better identify preterm follow-up studies to better identify factors that can be altered in the NICUfactors that can be altered in the NICU

Pay closer attention to nutrition from birth to Pay closer attention to nutrition from birth to post-dischargepost-discharge

The effect of chronic illness (BPD) The effect of chronic illness (BPD) on weight gain and head growthon weight gain and head growth

0 1 2 3 4 5 6 7 8 9 100 1 2 3 4 5 6 7 8 9 10

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00

-1-1

-2-2

-3-3

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WeightWeight

ControlControl

BPDBPD

Wei

ght z

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Postnatal Age (weeks)

deRegnier et al, 1996

Postnatal Age (weeks)Postnatal Age (weeks)0 1 2 3 4 5 6 7 8 9 100 1 2 3 4 5 6 7 8 9 10

11

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Head CircumferenceHead Circumference

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deRegnier et al, 1996

Major Factors Influencing Major Factors Influencing Neurodevelopmental Outcome in Preterm Neurodevelopmental Outcome in Preterm

InfantsInfants




4. Periventricular Leukomalacia4. Periventricular Leukomalacia



What the brain does with proteinWhat the brain does with protein

DNA, RNA synthesis and maintenanceDNA, RNA synthesis and maintenance Neurotransmitter production (synaptic Neurotransmitter production (synaptic

efficacy)efficacy) Growth factor synthesisGrowth factor synthesis Structural proteinsStructural proteins

– Neurite extension (axons, dendrites)Neurite extension (axons, dendrites)

– Synapse formation (connectivity)Synapse formation (connectivity)

Why the brain needs fatsWhy the brain needs fats

Cell membranesCell membranes Synapse formationSynapse formation MyelinMyelin

Iron: A Critical Nutrient for theIron: A Critical Nutrient for the Developing Human Brain Developing Human Brain

Iron containing enzymes and hemo-proteins are Iron containing enzymes and hemo-proteins are involved in important cellular processes in involved in important cellular processes in developing braindeveloping brain– Delta 9-desaturase, glial cytochromesDelta 9-desaturase, glial cytochromes control control

oligodendrocyte production of myelinoligodendrocyte production of myelin

– CytochromesCytochromes mediate oxidative phosphorylation and mediate oxidative phosphorylation and determine neuronal and glial energy statusdetermine neuronal and glial energy status

– Tyrosine HydroxylaseTyrosine Hydroxylase involved in monamine involved in monamine neurotransmitter synthesis (dopamine, serotonin, neurotransmitter synthesis (dopamine, serotonin, norepi)norepi)

Thompson & Nelson, Am Psychol, 2001

Documents

Developmental Outcomes of Preterm Infants: Emphasis on Nutrition Michael K. Georgieff, M.D. Professor of Pediatrics and Child Development Director, Center