Growth and Development
of the
NICU Graduate
Michael K. Georgieff, M.D.
Professor of Pediatrics
&
Child Development
University 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
– sustained attention
– visual-spatial abilities
- memory
- working memory
- 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)
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
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
e
r
c
e
n
t
10
1
0.1
0.01
24
26
28
30
32
34
36
38
40
42
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
Cognitive
Function
Acade m ic Vi sual MotorGross Motor Adapti ve
Skil l s
Function
Function
Function
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 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
- No deficit compared to AGA sibs
•
Preterm Infants: with and without postnatal
malnutrition
- 8 point deficit on 1y MDI if postnatal malnutrition > 2
weeks
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 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
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
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
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 or premature infant in the
first months of life is to promote
normal growth velocity and body
composition relative to age matched,
healthy infants
•
Prematures: Evidence for PostDischarge Nutrient Deficits
•
Poor first year growth (protein-energy)
• Poorer developmental outcome-related to
growth failure
• Persistant ostepenia (calcium, phosphorus)
• Anemia (Iron)
• Little data on other nutrients
Effect of Mild to Severe
Postnatal Malnutrition on Head
Growth in the NICU and at OneYear 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 preand postnatal malnutrition on
neonatal and follow-up head
growth
Effect of Pre and Postnatal Malnutrition
on Head Size and Development
-8 DQ
Points
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
Postnatal Age (weeks)
deRegnier et al, 1996
10
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
How Do Our Infants Get So Far
Behind?
Ehrenkranz et al. Reproduced with permission from Pediatrics, Vol 104:280-289, Copyright  1999 by the AAP
Canadian Pediatric Society:
Stages of Growth in Preterms
• Stage 1: Transition (0-10d)
• Stage 2: Stable premie grower (10d-d/c)
• Stage 3: Post-discharge (d/c-?)
Is there evidence for different nutritional
requirements at each stage ?
Physiology of the infant at each
stage would suggest YES!
3. Post-discharge
2. Premie
Grower
1.Early
Transition
• First days of life
• Sick
• Catabolic
- Negative N balance; increased energy needs
- ?insulin resistant; counter-regulatory hormones
• Nutrient sources  TPN+minimal feeds
• Goal: Reduce losses
- Can they grow?
How We Get To Stage 3:
Effects of Stage 1
• Neonatal illness affects protein, energy, calcium,
phosphorus, Na/K/CI, iron status
• Energy requirements increase proportionately to
respiratory distress
• Protein losses increase with sepsis
• Total daily protein needs are 3.2 g/kg/d; i.e. sum of:
- Intrauterine accretion rate (1.4 g/kg/d)
- Catabolic losses (1.8 g/kg/d)
Preemie Growth Phase
• 10 days to 34 weeks post-conception
- Start time varies based on severity of illness
(maybe 30 days or more)
• Stable, post-neonatal illness (e.g. RDS)
• Anabolic-unique gut physiology
• Nutrient source: PT formula or fortified human milk
- Typically, accrued deficits not taken into account
Effects of Stage 2
• Current recommendation likely to be underestimates
- Reference fetal growth rate likely to be low
(18-20 v. 10-15 g/kg/d)
- Higher energy delivery needed to achieve true fetal
growth rate (>130 kcal/kg/d)
- Higher protein delivery needed to support higher
energy delivery (3.2-3.8 g/kg/d)
• Estimates assume no interruption of growth during
Phase 1
Nutritional Status at Discharge:
Effects of Stage 1 + 2
• Protein-energy malnutrition
- Cumulative energy deficit: 1000 kcal/kg
- Cumulative protein deficit: 25 grams/kg
- 2000 grams at 37 weeks
• Demineralization
- Cumulative calcium deficit
• Variable iron status
• Undocumented nutrients
- Cu, Zn, Mg, I, Se, vitamins
Can this pattern of postnatal
growth 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 Phase
• After 34 weeks PCA
• Healthy, stable (some with CLD)
• Anabolic-gut physiology more typical of term infant
• Nutrient Source: Several possibilities
- Unfortified HM, fortified HM, term formula, PT
formula, follow-up formula
• Continued growth at term infant rates +recovery from
deficits  A TALL ORDER
Nutritional Sources:
Human Milk
• Gold standard for term infants
• Needs to be fortified for preterms
• How does it match needs of discharged
preterm infant?
Human Milk: Advantages
• Immunologic/infectious
• Intellectual
• Protection from future disease
• Protection of mother from future disease
• Psychological benefits
Benefits documented in term infants; which also
apply to preterms?
Human Milk: Concerns
• Low energy density: can the discharged
preemie consume enough volume to
make up for density?
• Low Ca/P content: longer catch-up of
demineralized bones
• Low Na content: is infant home on
diuretics?
Human Milk: Fortification or
Supplementation after Discharge
• Advantages
- Insures energy, protein, mineral,
vitamin delivery when intake volume is
low
- Improves weight gain, head growth and
mineralization during Phase 2; is there
carryover to Phase 3?
Human Milk: Fortification or
Supplementation
• Disadvantages
- Commits infant to bottle feeding
- Potentially “jeopardizes” breastfeeding
entirely
- Supplementation dilutes positive factors in
human milk
Human Milk: Selective
Supplementation/Fortification
• Healthy LBW infants typically will not
need supplementation if mother’s
milk supply is adequate (>350 ml/day
for 2kg infant at discharge)
- More energy stores at birth
- Less malabsorption
- Less fluid overload issues
- More complete Ca and Fe stores
Human Milk: Selective
Supplementation/Fortification
• VLBW, and especially ELBW, will likely
need fortification or supplementation
after discharge
- Larger accrued deficit (more need for catch-up)
- Lower mineral and iron stores
- More dysfunctional feeders (weaker, longer intubation 
takes smaller volumes)
- Eats to volume rather than to calories (early after discharge)
• Infants with BPD, short gut
Premature Discharge Formula
•Represents hybrid/transitional formula
assuming preterm infant is “turning
into” term infant
Preterm Discharge Formula:
Advantages
• Acknowledges transition in intestinal
physiology
• Energy delivery adjustable based on
volume concerns
• Supplemental in nutrients likely to have
large deficits
- Energy, protein, Ca/P
• Better Phase 3 growth than term formula
Preterm Discharge Formula:
Concerns
•Estimate most likely needs of discharged prematures
- Wide variation in nutrient needs/deliverability in this
population (e.g. Fe)
• Still undermined duration of use
- Safety - nutrient overload
- Efficacy - when is it just as good as term?
• Unknown long term growth and neurodevelopment
effect - Does it make a difference?
What to Feed Healthy LBW Infants
•
Healthy LBW infants should receive
human milk whenever possible
- Group most likely to show catch-up without
supplementation
•
If not human milk, they can receive term
formula
- Will still need closer and earlier nutritional
monitoring than term infants
What to Feed Healthy VLBW
Infants
• VLBW’s can breastfeed but need to show
- Steady growth, crossing percentiles (catch-up)
- Adequate mineralization
- Adequate iron status
• Supplement or fortify if
- Growth is slow (< curve or no catch-up0
- Persistent demineralization
- ELBW or has BPD
Supplementation Fortification of
Breastfed Prematures
• Assuming fortification at end of
hospitalization, continue fortifying (and
bottle feeding the milk) or
supplementing with premature
discharge formula at least 2x/day
• Monitor growth, BUN, prealbumin to decide
whether to increase or decrease
frequency of dosing
What to Feed VLBW Infants
• If exclusively formula fed, VLBW's and
ELBW's should go home on premature
discharge formula rather than term
formula
• Transfer to term formula should be considered
after monitoring shows improvement in
nutritional deficits (I.e. catch-up growth,
mineralization
Monitoring
• The key on what to feed and how long is
monitoring
• Hall and Ehrenkranz have proposed a 1
month post-discharge assessment,
mostly for breastfed but also high risk
(e.g. ELBW, BPD) formula fed infants
• Monitor indices reflect nutritional areas of
highest risk
- Protein-energy, bone mineralization, iron
Nutritional Screening Assessment
Performed 4 - 6 weeks post -hospital D/C:
Growth
Action Values
Weight gain
< 25 g/day
Length growth
< 1 cm/wk
HC growth
< 0.5 cm/wk
(from Hall, 2000)
Nutritional Screening Assessment
Performed 4 - 6 weeks post -hospital D/C:
Biochemical Test
Action Values
Phosphorus
< 4.5 mg/dL
Alkaline phosphatase
> 450 IU/L
BUN
< 5 mg/dL
Prealbumin
< 10 mg/dL
Retinol binding protein
< 2.5 mg/dL
(from Hall, 2000)
Summary
• Nutritional status is still a major
issue at discharge for preterm
infants
• The post-discharge needs are
dictated by the nutritional risks
incurred during hospitalization
Summary
• Although physiologically mature, the
small preterm infant requires
higher deliver of energy, protein,
calcium, phosphorus and iron than
his conceptional age adjusted term
counterpart
• Discharge formulas and fortification
of human milk address these
issues better than term formula
NUTRIE NT
TERM
HUMAN
MILK
TERM
FORMULA
PRET ERM
FORMULA
DIS CHARGE
FORMULA
28 0
52 7
14 00
84 3
42
79
20 8
12 6
14 7
32 1
73 8
48 0
22
48
11 1
72
1
1.6
1.9
1.75
04 2
12
12
9
0.06 ***
1.8
1.8
1.35
22 31/21
20 27/40 5
10 081/17 00
34 55/56 0
33 4/3
30 4/61
15 12/25 4
52 0/84
C ALC IUM
mg/L
Del ive ry* *
(m g/kg/d)
PHO S PHORUS
mg/L
Del ive ry
C a:P ratio
IRON
mg/L
Del ive ry
(m g/kg/d
Vi tami n A/D
IU/L
Del ive ry
(IU/kg/d
*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
NUTRIT ION
ENERGY
Content
Modifi ed
Kcal/oz
Delivery**
(Kcal/kg/d)
PROTEIN
g/L
Delivery
(g/kg/d)
TERM
HUMAN
MILK*
TERM
FORMULA *
PRET ERM
FORMULA *
DISCHARGE
FORMULA *
54% fat/
42% CHO
no
20
100
48.5% fat/
43% CHO
no
20
100
47% fat/
43% CHO
47% fat/
42% CHO
MCT; polymers
MCT; polymer
24
120
22
110
9.1
1.5
14
2.1
23
3.4
20
3.0
* values represent average among 2 or more products
** “Delivery” calculated at 150 cc/kg/day