Growth and Development of the of the NICU Graduate NICU Graduate Michael K. Georgieff, M.D. Professor of Pediatrics & Child Development University of Minnesota

Growth and DevelopmentGrowth and Development

of theof the

NICU GraduateNICU Graduate

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

Professor of Pediatrics Professor of Pediatrics

& &

Child DevelopmentChild Development

University of MinnesotaUniversity of Minnesota

Prematurity in the U.S.

• In the year 2000: – 7.6% of infants born weighed less than 2500 grams

– 1.4% weighed less than 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 BrainThe Vulnerable Preterm Brain

• Rapidly growing tissue Rapidly growing tissue exaggerated exaggerated effect of any insult 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)

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

Preterm InfantsPreterm Infants

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 Neurodevelopmental Outcome in

Preterm InfantsPreterm Infants

1. 1. Degree of Prematurity Degree of Prematurity

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

3. Intraventricular hemorrhage3. Intraventricular hemorrhage




1010

11

0.10.1

0.010.01

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

PPeerrcceenntt

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

10

20

30

40

50

CognitiveFunction

AcademicSkills

Visual MotorFunction

Gross MotorFunction

AdaptiveFunction

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

Ch

ildre

n I

n G

rou

p (

%)

Ch

ildre

n I

n G

rou

p (

%)

Outcome of 401-1000g InfantsVohr 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 Neurdevelopmental Factors Influencing Neurdevelopmental Outcome in Preterm InfantsOutcome in Preterm Infants


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

- No deficit compared to AGA sibsNo deficit compared to AGA sibs

• 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








Incidence of Major Handicap with IVH Incidence of Major Handicap with IVH in <1500g Infantsin <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?








Periventricular LeukomalaciaPeriventricular 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 predictive of CP if lesions

extend extend from anterior to from anterior to posteriorposterior

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








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

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

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

• Persistant ostepenia (calcium, Persistant ostepenia (calcium, phosphorus)phosphorus)

• Anemia (Iron)Anemia (Iron)

• Little data on other nutrientsLittle data on other nutrients

Effect of Mild to Severe Postnatal Malnutrition on Head

Growth in the NICU 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 postnatal malnutrition on neonatal and follow-up head

growth

-8 DQ Points

Effect of Pre and Postnatal Malnutrition on Head Size and Development

The effect of chronic illness (BPD) on 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

11

00

-1-1

-2-2

-3-3

-4-4

WeightWeight

ControlControl

BPDBPD

Wei

ght z

-sco

re

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

00

-1-1

-2-2

-3-3

-4-4

Head CircumferenceHead Circumference

OF

C Z

-sco

re

deRegnier et al, 1996

How Do Our Infants Get So Far Behind?

Ehrenkranz et al. Ehrenkranz et al. Reproduced with permission from Pediatrics, Vol 104:280-289, Copyright Reproduced with permission from Pediatrics, Vol 104:280-289, Copyright 1999 by the AAP 1999 by the AAP

Canadian Pediatric Society: Canadian Pediatric Society: Stages of Growth in PretermsStages of Growth in Preterms

• Stage 1: Transition (0-10d)Stage 1: Transition (0-10d)

• Stage 2: Stable premie grower (10d-d/c)Stage 2: Stable premie grower (10d-d/c)

• Stage 3: Post-discharge (d/c-?)Stage 3: Post-discharge (d/c-?)

Is there evidence for different nutritional Is there evidence for different nutritional requirements at each stage ?requirements at each stage ?

Physiology of the infant at each Physiology of the infant at each stage would suggest YES!stage would suggest YES!

1.Early

2. Premie Grower

3. Post-discharge3. Post-discharge

TransitionTransition• First days of lifeFirst days of life

• SickSick

• CatabolicCatabolic

- - Negative N balance; increased energy needsNegative N balance; increased energy needs

- - ?insulin resistant; counter-regulatory hormones?insulin resistant; counter-regulatory hormones

• Nutrient sources Nutrient sources TPN+minimal feeds TPN+minimal feeds

• Goal: Reduce lossesGoal: Reduce losses

- - Can they grow?Can they grow?

How We Get To Stage 3: How We Get To Stage 3: Effects of Stage 1Effects of Stage 1

• Neonatal illness affects protein, energy, calcium, Neonatal illness affects protein, energy, calcium, phosphorus, Na/K/CI, iron statusphosphorus, Na/K/CI, iron status

• Energy requirements increase proportionately to Energy requirements increase proportionately to respiratory distressrespiratory distress

• Protein losses increase with sepsisProtein losses increase with sepsis

• Total daily protein needs are 3.2 g/kg/d; i.e. sum of:Total daily protein needs are 3.2 g/kg/d; i.e. sum of:

-- Intrauterine accretion rate (1.4 g/kg/d) Intrauterine accretion rate (1.4 g/kg/d)

-- Catabolic losses (1.8 g/kg/d) Catabolic losses (1.8 g/kg/d)

• 10 days to 34 weeks post-conception10 days to 34 weeks post-conception

- - Start time varies based on severity of illness Start time varies based on severity of illness (maybe 30 days or more)(maybe 30 days or more)

• Stable, post-neonatal illness (e.g. RDS)Stable, post-neonatal illness (e.g. RDS)

• Anabolic-unique gut physiologyAnabolic-unique gut physiology

• Nutrient source: PT formula or fortified human milkNutrient source: PT formula or fortified human milk

-- Typically, accrued deficits not taken into account Typically, accrued deficits not taken into account

Preemie Growth PhasePreemie Growth Phase

Effects of Stage 2Effects of Stage 2

• Current recommendation likely to be underestimatesCurrent recommendation likely to be underestimates

- - Reference fetal growth rate likely to be low Reference fetal growth rate likely to be low (18-20 v. 10-15 g/kg/d)(18-20 v. 10-15 g/kg/d)

-- Higher energy delivery needed to achieve true fetal Higher energy delivery needed to achieve true fetal growth rate (>130 kcal/kg/d)growth rate (>130 kcal/kg/d)

-- Higher protein delivery needed to support higher Higher protein delivery needed to support higher energy delivery (3.2-3.8 g/kg/d)energy delivery (3.2-3.8 g/kg/d)

• Estimates assume no interruption of growth during Estimates assume no interruption of growth during Phase 1Phase 1

Nutritional Status at Discharge:Nutritional Status at Discharge:Effects of Stage 1 + 2Effects of Stage 1 + 2

• Protein-energy malnutritionProtein-energy malnutrition

- - Cumulative energy deficit: 1000 kcal/kg Cumulative energy deficit: 1000 kcal/kg

- - Cumulative protein deficit: 25 grams/kg Cumulative protein deficit: 25 grams/kg

- - 2000 grams at 37 weeks 2000 grams at 37 weeks

• DemineralizationDemineralization

- - Cumulative calcium deficit Cumulative calcium deficit

• Variable iron statusVariable iron status

• Undocumented nutrientsUndocumented nutrients

-- Cu, Zn, Mg, I, Se, vitamins Cu, Zn, Mg, I, Se, vitamins

Can this pattern of postnatal Can this pattern of postnatal growth failure be reversedgrowth failure be reversed??

• Very preterm infants have minimal nutritional reserves

• Once a preterm infant develops growth failure it is very difficult to recoup the growth loss

• There are few data regarding how to early avoid postnatal malnutrition, let alone how to reverse existing growth failure

Post-Discharge PhasePost-Discharge Phase

• After 34 weeks PCAAfter 34 weeks PCA

• Healthy, stable (some with CLD)Healthy, stable (some with CLD)

• Anabolic-gut physiology more typical of term infantAnabolic-gut physiology more typical of term infant

• Nutrient Source: Several possibilitiesNutrient Source: Several possibilities

- - Unfortified HM, fortified HM, term formula, PT Unfortified HM, fortified HM, term formula, PT formula, follow-up formulaformula, follow-up formula

• Continued growth at term infant rates +recovery from Continued growth at term infant rates +recovery from deficits deficits A TALL ORDERA TALL ORDER

Nutritional Sources:Nutritional Sources:Human MilkHuman Milk

• Gold standard for term infantsGold standard for term infants

• Needs to be fortified for pretermsNeeds to be fortified for preterms

• How does it match needs of discharged How does it match needs of discharged preterm infant?preterm infant?

• Immunologic/infectiousImmunologic/infectious

• IntellectualIntellectual

• Protection from future diseaseProtection from future disease

• Protection of mother from future diseaseProtection of mother from future disease

• Psychological benefitsPsychological benefits

Benefits documented in term infants; which also Benefits documented in term infants; which also apply to preterms?apply to preterms?

Human Milk: AdvantagesHuman Milk: Advantages

Human Milk: ConcernsHuman Milk: Concerns

• Low energy density: can the discharged Low energy density: can the discharged preemie consume enough volume to preemie consume enough volume to make up for density?make up for density?

• Low Ca/P content: longer catch-up of Low Ca/P content: longer catch-up of demineralized bonesdemineralized bones

• Low Na content: is infant home on Low Na content: is infant home on diuretics?diuretics?

• AdvantagesAdvantages

-- Insures energy, protein, mineral, Insures energy, protein, mineral, vitamin delivery when intake volume is vitamin delivery when intake volume is

lowlow

-- Improves weight gain, head growth and Improves weight gain, head growth and mineralization during Phase 2; is mineralization during Phase 2; is

there there carryover to Phase 3?carryover to Phase 3?

Human Milk: Fortification or Human Milk: Fortification or Supplementation after DischargeSupplementation after Discharge

Human Milk: Fortification or Human Milk: Fortification or SupplementationSupplementation

• DisadvantagesDisadvantages

-- Commits infant to bottle feedingCommits infant to bottle feeding

- - Potentially “jeopardizes” breastfeeding Potentially “jeopardizes” breastfeeding entirelyentirely

-- Supplementation dilutes positive factors in Supplementation dilutes positive factors in human milkhuman milk

Human Milk: Selective Human Milk: Selective Supplementation/FortificationSupplementation/Fortification

• Healthy LBW infants typically will not Healthy LBW infants typically will not need supplementation if mother’s need supplementation if mother’s milk supply is adequate (>350 ml/day milk supply is adequate (>350 ml/day for 2kg infant at discharge)for 2kg infant at discharge)

-- More energy stores at birthMore energy stores at birth

-- Less malabsorption Less malabsorption

-- Less fluid overload issuesLess fluid overload issues

-- More complete Ca and Fe storesMore complete Ca and Fe stores

• VLBW, and especially ELBW, will likely VLBW, and especially ELBW, will likely need fortification or supplementation need fortification or supplementation after discharge after discharge

-- Larger accrued deficit (more need for catch-up) Larger accrued deficit (more need for catch-up)

-- Lower mineral and iron stores Lower mineral and iron stores

-- More dysfunctional feeders (weaker, longer intubation More dysfunctional feeders (weaker, longer intubation takes smaller volumes)takes smaller volumes)

-- Eats to volume rather than to calories (early after discharge) Eats to volume rather than to calories (early after discharge)

• Infants with BPD, short gut Infants with BPD, short gut

Human Milk: Selective Human Milk: Selective Supplementation/FortificationSupplementation/Fortification

•Represents hybrid/transitional formula Represents hybrid/transitional formula assuming preterm infant is “turning assuming preterm infant is “turning into” term infantinto” term infant

Premature Discharge FormulaPremature Discharge Formula

Preterm Discharge Formula: Preterm Discharge Formula: AdvantagesAdvantages

• Acknowledges transition in intestinal Acknowledges transition in intestinal physiologyphysiology

• Energy delivery adjustable based on Energy delivery adjustable based on volume concernsvolume concerns

• Supplemental in nutrients likely to have Supplemental in nutrients likely to have large deficitslarge deficits

-- Energy, protein, Ca/P Energy, protein, Ca/P

• Better Phase 3 growth than term formulaBetter Phase 3 growth than term formula

•Estimate most likely needs of discharged prematuresEstimate most likely needs of discharged prematures

-- Wide variation in nutrient needs/deliverability in this Wide variation in nutrient needs/deliverability in this population (e.g. Fe)population (e.g. Fe)

• Still undermined duration of useStill undermined duration of use

-- Safety - nutrient overload Safety - nutrient overload

-- Efficacy - when is it just as good as term? Efficacy - when is it just as good as term?

• Unknown long term growth and neurodevelopment Unknown long term growth and neurodevelopment effect - Does it make a difference? effect - Does it make a difference?

Preterm Discharge Formula: Preterm Discharge Formula: ConcernsConcerns

What to Feed Healthy LBW InfantsWhat to Feed Healthy LBW Infants

• Healthy LBW infants should receive Healthy LBW infants should receive human milk whenever possiblehuman milk whenever possible

-- Group most likely to show catch-up without Group most likely to show catch-up without supplementationsupplementation

• If not human milk, they can receive term If not human milk, they can receive term formulaformula

-- Will still need closer and earlier nutritional Will still need closer and earlier nutritional monitoring than term infantsmonitoring than term infants

• VLBW’s can breastfeed but need to showVLBW’s can breastfeed but need to show

-- Steady growth, crossing percentiles (catch-up) Steady growth, crossing percentiles (catch-up)

-- Adequate mineralization Adequate mineralization

-- Adequate iron status Adequate iron status

• Supplement or fortify ifSupplement or fortify if

-- Growth is slow (< curve or no catch-up0 Growth is slow (< curve or no catch-up0

-- Persistent demineralization Persistent demineralization

-- ELBW or has BPD ELBW or has BPD

What to Feed Healthy VLBW What to Feed Healthy VLBW InfantsInfants

• Assuming fortification at end of Assuming fortification at end of hospitalization, continue fortifying (and hospitalization, continue fortifying (and bottle feeding the milk) bottle feeding the milk) or or supplementing with premature supplementing with premature discharge formula at least discharge formula at least 2x/day2x/day

• Monitor growth, BUN, prealbumin to decide Monitor growth, BUN, prealbumin to decide whether to increase or decrease whether to increase or decrease frequency of dosingfrequency of dosing

Supplementation Fortification of Supplementation Fortification of Breastfed PrematuresBreastfed Prematures

What to Feed VLBW InfantsWhat to Feed VLBW Infants

• If exclusively formula fed, VLBW's and If exclusively formula fed, VLBW's and ELBW's should go home on premature ELBW's should go home on premature discharge formula rather than term discharge formula rather than term formulaformula

• Transfer to term formula should be considered Transfer to term formula should be considered after monitoring shows improvement in after monitoring shows improvement in nutritional deficits (I.e. catch-up growth, nutritional deficits (I.e. catch-up growth, mineralizationmineralization

• The key on what to feed and how long is The key on what to feed and how long is monitoringmonitoring

• Hall and Ehrenkranz have proposed a 1 Hall and Ehrenkranz have proposed a 1 month post-discharge assessment, month post-discharge assessment, mostly for breastfed but also high risk mostly for breastfed but also high risk (e.g. ELBW, BPD) formula fed infants(e.g. ELBW, BPD) formula fed infants

• Monitor indices reflect nutritional areas of Monitor indices reflect nutritional areas of highest riskhighest risk

-- Protein-energy, bone mineralization, iron Protein-energy, bone mineralization, iron

MonitoringMonitoring

Nutritional Screening AssessmentNutritional Screening Assessment Performed 4 - 6 weeks post -hospital D/C:Performed 4 - 6 weeks post -hospital D/C:

Growth Action ValuesGrowth Action Values

Weight gain < 25 g/dayWeight gain < 25 g/day

Length growth < 1 cm/wk Length growth < 1 cm/wk

HC growth < 0.5 cm/wkHC growth < 0.5 cm/wk

(from Hall, 2000) (from Hall, 2000)

Nutritional Screening AssessmentNutritional Screening Assessment Performed 4 - 6 weeks post -hospital D/C:Performed 4 - 6 weeks post -hospital D/C:

Biochemical Test Action ValuesBiochemical Test Action Values

Phosphorus < 4.5 mg/dLPhosphorus < 4.5 mg/dL

Alkaline phosphatase > 450 IU/L Alkaline phosphatase > 450 IU/L

BUN < 5 mg/dLBUN < 5 mg/dL

Prealbumin < 10 mg/dLPrealbumin < 10 mg/dL

Retinol binding protein < 2.5 mg/dLRetinol binding protein < 2.5 mg/dL

(from Hall, 2000)(from Hall, 2000)

SummarySummary

• Nutritional status is still a major Nutritional status is still a major issue at discharge for preterm issue at discharge for preterm infantsinfants

• The post-discharge needs are The post-discharge needs are dictated by the nutritional risks dictated by the nutritional risks incurred incurred during hospitalizationduring hospitalization

SummarySummary• Although physiologically mature, the Although physiologically mature, the

small preterm infant requires small preterm infant requires higher deliver of energy, protein, higher deliver of energy, protein, calcium, phosphorus and iron than calcium, phosphorus and iron than his conceptional age adjusted term his conceptional age adjusted term counterpartcounterpart

• Discharge formulas and fortification Discharge formulas and fortification of human milk address these of human milk address these issues better than term formulaissues better than term formula

NUTRIENT TERMHUMAN

MILK

TERMFORMULA

PRETERMFORMULA

DISCHARGEFORMULA

CALCIUM

mg/L

Delivery**

(mg/kg/d)

280

42

527

79

1400

208

843

126

PHOSPHORUS

mg/L

Delivery

Ca:P ratio

147

22

1

321

48

1.6

738

111

1.9

480

72

1.75

IRON

mg/L

Delivery

(mg/kg/d

042

0.06***

12

1.8

12

1.8

9

1.35

Vitamin A/D

IU/L

Delivery

(IU/kg/d

2231/21

334/3

2027/405

304/61

10081/1700

1512/254

3455/560

520/84

*values represent average among 2 or more products**”Delivery” calculated at 150 cc/kg/day***5-10x higher bioavailability than from cow milk based formula

NUTRITION TERMHUMANMILK*

TERMFORMULA*

PRETERMFORMULA*

DISCHARGEFORMULA*

ENERGYContent

ModifiedKcal/oz

Delivery**(Kcal/kg/d)

54% fat/42% CHO

no20

100

48.5% fat/43% CHO

no20100

47% fat/43% CHO

MCT; polymers24120

47% fat/42% CHO

MCT; polymer22110

PROTEINg/L

Delivery(g/kg/d)

9.11.5

142.1

233.4

203.0

* values represent average among 2 or more products* values represent average among 2 or more products

** “Delivery” calculated at 150 cc/kg/day** “Delivery” calculated at 150 cc/kg/day

Documents

Growth and Development of the of the NICU Graduate NICU Graduate Michael K. Georgieff, M.D. Professor of Pediatrics & Child Development University of Minnesota