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

2. 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)
< 37 weeks’ gestation = Premature
1500 to 2500 grams = Low Birth Weight
only slightly elevated risk for lasting psychological difficulties
< 1500 grams = Very Low Birth Weight
25% develop severe psychological sequelae (CP, MR)
25% develop mild to moderate problems (reduced achievement, ADHD)
Growing public health concern because a small percentage of the population consumes a disproportionate share of limited medical and special education resources
Plasticity of preterm brain: Is prematurity alone enough to alter brain development? (experience-expectant) Or is brain development influenced more by biological & environmental factors (experience-dependent) 3

3. 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
Attention
longer familiarization periods
longer fixation periods
more pauses
fewer shifts of gaze between stimuli
Memory
lower novelty scores (possibly related to reduced speed of processing)
comparable recall for individual actions
reduced recall for temporal order of pairs of actions
Working Memory
mildly preterm infants more successful at longer delays on the AB task
effects lost when not corrected for prematurity - premies may benefit from extra experience 4

4. 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
Incidence of neurological handicap remains stable - Higher rate of MR than in gen. pop
incidence of minor neurodevelopmental impairment increases with age
20% to 59% from 1 to 14
Rose & Feldman found IQ to be associated w/ composite measures of memory & processing speed - accounted for sig. chunk of variance btwn groups for IQ
Expressive language
delays in language onset, speech therapy, verbal reasoning, verbal fluency
Attention - rarely tested explicitly, mostly elevated rates of ADHD inattentive
Memory - at best, selective deficits (pattern recognition, spatial memory span, everyday/episodic memory)
At worst - uniform impairments in visual & verbal, immediate & delayed
Spatial working memory - more errors, less strategy
Set shifting - verbal fluency, Trails B 5

5. 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)

6. Major Factors Influencing Neurodevelopmental 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

7. Major Factors Influencing Neurodevelopmental 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

8. Percent 10 1
0.1
0.01
Gestation (week)
FIG Occurrence of spastic diplegia as related to gestational age.

9. <750 g
< g
Born at term
Children In Group (%)

10. 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?

11. 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

12. 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 > weeks

13. 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

14. 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?

15. 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

16. 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

17. 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

18. 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
Extremely preterm/low birth weight infants
more severe medical complications, worse prognosis, less likely to “catch up” with development
Moderately preterm infants
when predictive, usually as composite measures of neurobiological risk
Environmental factors
Effects of perinatal risk tend to attenuate over time unless caretaking environment is also compromised
Sociodemographic risk & quality of home environment become significant at age 2 and 3.6 (not at 1)
Biological risk - declines in importance, predicts mainly motor outcomes
Environmental risk related to motor, cognitive & social & became stronger with time
Environmental factors can be protective as well as risky 6

19. 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
Quality of home environment is determined by such features as:
level of stimulation
availability of toys & learning materials
density of people in the home
Greenough’s complex environment may not tell us the effects of true “enrichment”, but does suggest that an adequate level of stimulation, relative to isolation, leads to:
increased volume, weight, & thickness in visual cortex
more complex dendritic arborization, increased spine density
higher number of synapses per neuron
higher rate of survival for new neurons in dentate
up-regulation of nerve growth factors in CA1
Improved performance on learning tasks thought to be related to enhanced capacity for learning
utilize wider range of cues to solve cognitive problems
more efficient information processing 9

20. 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

21. 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

22. Prematures: Evidence for Post-Discharge 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

23. Effect of Mild to Severe Postnatal Malnutrition on Head Growth in the NICU and at One-Year Follow-up

24. Effect of No Prenatal and Mild Postnatal Malnutrition
on Head Size and Development
No DQ
Differences

25. Effect of No Prenatal and Moderate Postnatal Malnutrition
on Head Size and Development
3 point DQ
difference

26. The effect of combined pre- and postnatal malnutrition on neonatal and follow-up head growth

27. Effect of Pre and Postnatal Malnutrition on Head Size and Development
-8 DQ
Points

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

29. Control Weight z-score BPD Postnatal Age (weeks) 1 -1 -2 -3 -4 Weight-1 -2 -3 -4
Weight
Control
BPD
Weight z-score
Postnatal Age (weeks)
deRegnier et al, 1996

30. OFC Z-score 1 -1 -2 -3 -4 Postnatal Age (weeks) Head Circumference-1 -2 -3 -4
Head Circumference
OFC Z-score
Postnatal Age (weeks)
deRegnier et al, 1996

31. How Do Our Infants Get So Far Behind?

32. Ehrenkranz et al. Reproduced with permission from Pediatrics, Vol 104: , Copyright  1999 by the AAP

33. 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!

34. 3. Post-discharge
2. Premie Grower
1.Early

35. Transition - Negative N balance; increased energy needs
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?

37. 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)

38. 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

39. Effects of Stage 2 Current recommendation likely to be underestimates
- Reference fetal growth rate likely to be low (18-20 v 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 ( g/kg/d)
Estimates assume no interruption of growth during Phase 1

40. Nutritional Status at Discharge:
Effects of Stage 1 + 2
Protein-energy malnutrition
- Cumulative energy deficit: kcal/kg
- Cumulative protein deficit: 25 grams/kg
grams at 37 weeks
Demineralization
- Cumulative calcium deficit
Variable iron status
Undocumented nutrients
- Cu, Zn, Mg, I, Se, vitamins

41. 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

42. 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

43. Nutritional Sources: Human Milk
Gold standard for term infants
Needs to be fortified for preterms
How does it match needs of discharged preterm infant?

44. 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?

45. 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?

46. 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?

47. Human Milk: Fortification or Supplementation
Disadvantages
- Commits infant to bottle feeding
- Potentially “jeopardizes” breastfeeding entirely
- Supplementation dilutes positive factors in human milk

48. 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

49. 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

50. Premature Discharge Formula
Represents hybrid/transitional formula assuming preterm infant is “turning into” term infant

51. 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

52. 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?

53. 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

54. 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

55. 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

56. 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

57. 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

58. Nutritional Screening Assessment
Performed 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)

59. Nutritional Screening Assessment
Performed 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)

60. 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

61. 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

68. *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

69. * values represent average among 2 or more products
** “Delivery” calculated at 150 cc/kg/day