1. 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

2. Prematurity in the United States In the year 2000: 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 Last 8 years, prematurity rates have increased –Role of multiples (IVF)

3. Cognitive Development of Premies in Infancy/Early Childhood Theme: Within the normal range, but significantly lower than full term comparisons Theme: Within the normal range, but significantly lower than full term comparisons Specific abilities: Specific abilities: –immature patterns of visual attention –memory mostly intact but subtle impairments –slight working memory advantage

4. Cognitive Development of Premies in Middle Childhood/Adolescence Themes: IQ drops with birth weight & GA 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: Specific deficits: –expressive language- memory –sustained attention- working memory –visual-spatial abilities - set shifting

5. The Vulnerable Preterm Brain Rapidly growing tissue exaggerated effect of any insultexaggerated effect of any insult - vulnerability outweighs “plasticity” Vascular instability of the germinal matrix Vascular instability of the germinal matrix Watershed areas (periventricular area) Watershed areas (periventricular area) Selective regional metabolic vulnerability (hippocampus) Selective regional metabolic vulnerability (hippocampus)

6. Thompson & Nelson, Am Psychol, 2001

9. Factors Influencing Neurodevelopmental Outcome in Preterm Infants: Which Ones Can We Influence? 1. Degree of Prematurity 2. Size for Dates (SGA) 3. Intraventricular hemorrhage 4. (Periventricular) Leukomalacia 5. Socio-economic Status 6. Postnatal Nutrition

10. 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

11. 1010.10.01 24 26 28 30 32 34 36 38 40 42 44 PercentPercentPercentPercent Gestation (week) FIG 59-2. Occurrence of spastic diplegia as related to gestational age.

12. <750 g <750 - 1499 g Born at term Children In Group (%)

13. Outcome of 401-1000g Infants Vohr et al, 2000 NICHD Network NICHD Network 1151 infants evaluated at 18 months 1151 infants evaluated at 18 months 25% with abnormal neurologic exam 25% with abnormal neurologic exam 37% with Bayley II MDI <70 37% with Bayley II MDI <70 29% with Bayley II PDI<70 29% with Bayley II PDI<70 Grim news. Is it representative?

14. 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

15. Factors Influencing Neurdevelopmental Outcome in Preterm Infants 1. Degree of Prematurity 1. Degree of Prematurity 2. Size for Dates (SGA) 2. Size for Dates (SGA) 3. Intraventricular Hemorrhage 3. Intraventricular Hemorrhage 4. (Periventricular) Leukomalacia 4. (Periventricular) Leukomalacia 5. Socio-economic Status 5. Socio-economic Status 6. Postnatal Nutrition 6. Postnatal Nutrition

16. Effect of Size for Dates Term Infants: National Collaborative Prenatal Data Base 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 Preterm Infants: with and without postnatal malnutrition - 8 point deficit on 1y MDI if postnatal malnutrition > 2 weeks

17. 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

18. Factors Influencing Neurdevelopmental Outcome in Preterm Infants 1. Degree of Prematurity 1. Degree of Prematurity 2. Size for Dates (SGA) 2. Size for Dates (SGA) 3. Intraventricular Hemorrhage 3. Intraventricular Hemorrhage 4. (Periventricular) Leukomalacia 4. (Periventricular) Leukomalacia 5. Socio-economic Status 5. Socio-economic Status 6. Postnatal Nutrition 6. Postnatal Nutrition

19. Incidence of Major Handicap with IVH in <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 circumstances? Is it the lesion or the associated circumstances?

20. 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?

21. Factors Influencing Neurdevelopmental Outcome in Preterm Infants 1. Degree of Prematurity 1. Degree of Prematurity 2. Size for Dates (SGA) 2. Size for Dates (SGA) 3. Intraventricular Hemorrhage 3. Intraventricular Hemorrhage 4. (Periventricular) Leukomalacia 4. (Periventricular) Leukomalacia 5. Socio-economic Status 5. Socio-economic Status 6. Postnatal Nutrition 6. Postnatal Nutrition

22. (Periventricular) Leukomalacia Hypoxic-ischemic etiology 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 >2mm cysts at 1 month are 95% predictive of CP if lesions extend from anterior to posterior Most common CP is spastic diplegia Most common CP is spastic diplegia

23. Periventricular Hemorrhagic Necrosis

24. 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?)

25. Factors Influencing Neurdevelopmental Outcome in Preterm Infants 1. Degree of Prematurity 1. Degree of Prematurity 2. Size for Dates (SGA) 2. Size for Dates (SGA) 3. Intraventricular Hemorrhage 3. Intraventricular Hemorrhage 4. (Periventricular) Leukomalacia 4. (Periventricular) Leukomalacia 5. Socio-economic Status 5. Socio-economic Status 6. Postnatal Nutrition 6. Postnatal Nutrition

26. Combined Effect of SES and Prematurity

27. Moderating Factors For the youngest and smallest infants: For the youngest and smallest infants: –biological factors best predict long-term outcomes For the moderately preterm: For the moderately preterm: –biological factors related to early developmental status, but decline in influence –environmental factors become important after first year of life

28. Home Environment and the Brain The quality of a child’s home environment is associated with global cognitive outcomes 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 has been shown to promote synaptogenesis Experience with a stimulating environment also is related to better performance on a range of learning tasks Experience with a stimulating environment also is related to better performance on a range of learning tasks

29. 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

30. 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

31. 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

32. Canadian Pediatric Society: Growth 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 and nutritional needs

33. Transition: Nutritional and Metabolic Risks Nutrient Source: TPN + Minimal Feeds (Fluid Restriction) Nutrient Source: TPN + Minimal Feeds (Fluid Restriction) Catabolism => High protein turnover Catabolism => High protein turnover –Goal: »2-3g/kg on day 1 »3.8 g/kg average daily intake Insulin Resistance => Energy substrate handling 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?

34. 1. Transition Ehrenkranz et al, 2000

35. 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

36. Premie Grower: Nutritional Risks Protein => Intrauterine rate + deficit from transition Protein => Intrauterine rate + deficit from transition –Target 4g/kg daily –Considerations: »Unknown maternal milk composition »Renal status Energy => Intrauterine weight gain + deficit Energy => Intrauterine weight gain + deficit –Target 135 kcal/kg daily –Considerations: »Fuel source & balance (CHO/Fat) »OMM composition Iron => Phlebotomy losses + Rapid Growth Iron => Phlebotomy losses + Rapid Growth –Target 2-4 mg/kg daily » Is anemia of prematurity iron deficiency?

37. 2. Premie Grower Ehrenkranz et al, 2000

38. Post-Discharge After 34 weeks PCA After 34 weeks PCA Stable, anabolic, mature gut Stable, anabolic, mature gut Nutrient Sources: OMM, Fortified OMM, Post-discharge formula Nutrient Sources: OMM, Fortified OMM, Post-discharge formula

39. Post-Discharge: Nutritional Risks Protein- daily needs + 25 g/kg deficit 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; 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 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

40. 3. Post-discharge Ehrenkranz et al, 2000

41. 1.Early 2. Premie Grower 3. Post-discharge Ehrenkranz et al, 2000

42. Prematures: Evidence for Post- Discharge Nutrient Deficits Poor first year growth (protein-energy) Poor first year growth (protein-energy) Poorer developmental outcome-related to growth failure Poorer developmental outcome-related to growth failure Anemia (Iron) Anemia (Iron)

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

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

45. 3 point DQ difference Effect of No Prenatal and Moderate Postnatal Malnutrition on Head Size and Development

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

47. -8 DQ Points Effect of Pre and Postnatal Malnutrition on Head Size and Development

48. 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

49. 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 post- discharge

50. Conclusions Outcomes of preterm infants are generally better than anticipated based on the biologic lesions 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 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 Pay closer attention to nutrition from birth to post-discharge

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

52. 0 1 2 3 4 5 6 7 8 9 10 10-2-3-4 Weight Control BPD Weight z-score Postnatal Age (weeks) deRegnier et al, 1996

53. Postnatal Age (weeks) 0 1 2 3 4 5 6 7 8 9 10 10-2-3-4 Head Circumference OFC Z-score deRegnier et al, 1996

54. 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

55. What the brain does with protein DNA, RNA synthesis and maintenance DNA, RNA synthesis and maintenance Neurotransmitter production (synaptic efficacy) Neurotransmitter production (synaptic efficacy) Growth factor synthesis Growth factor synthesis Structural proteins Structural proteins –Neurite extension (axons, dendrites) –Synapse formation (connectivity)

56. Why the brain needs fats Cell membranes Cell membranes Synapse formation Synapse formation Myelin Myelin

57. 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)

58. Thompson & Nelson, Am Psychol, 2001