1. Long Term Effects of In Utero and Early Postnatal 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. Overview of Talk Why care about early nutrition? Why care about early nutrition? –Emphasis on brain development: Basic Principles –Concern about long term health Nutrient deficiencies and risks to the developing brain Nutrient deficiencies and risks to the developing brain –In utero malnutrition (IUGR) –Early postnatal nutrition (EUGR) Nutrient “excess” and long term health risks Nutrient “excess” and long term health risks –The “Barker” hypothesis »Is it really “fetal” programming? »Risks of overfeeding The U-shaped nutrition risk curve The U-shaped nutrition risk curve –Striking a balance in feeding young infants

3. Basic Principles of Nutrient/Brain Interactions

4. Early Nutrition and Brain Development: General Principles Positive or negative nutrient effects on brain development Based on… Timing, Dose and Duration of Exposure Kretchmer, Beard, Carlson (Am J Clin Nutr, 1996)

5. Nutrient-Brain-Behavior Relationships Brain regions/processes have different developmental trajectories Brain regions/processes have different developmental trajectories The vulnerability of a brain region to a nutrient deficit is based on The vulnerability of a brain region to a nutrient deficit is based on –When nutrient deficit is likely to occur –Brain’s requirement for that nutrient at that time Behavioral changes must map onto those brain structures altered by the nutrient deficit Behavioral changes must map onto those brain structures altered by the nutrient deficit

6. Thompson & Nelson, Am Psychol, 2001

9. Early Malnutrition

10. Early Malnutrition: Clinical Situations nClinical conditions early in life include: –Intrauterine growth retardation »Maternal hypertension most common cause »Severe maternal malnutrition –Chronic illness prohibiting adequate feeding (EUGR) »Prematurity/neonatal illness »Chronic renal, hepatic, cardiac, pulmonary, infectious diseases (CHF, cystic fibrosis, HIV) Limited protein-energy intakeLimited protein-energy intake Excessive protein-energy needs/lossesExcessive protein-energy needs/losses

11. Prenatal Malnutrition:IUGR nIUGR due to placental insufficiency is a good model for malnutrition effects on brain growth and development –Brain is in rapid growth phase during last trimester; hence more vulnerable –Placenta as an environmental filter (not an absolute barrier) nIUGR outcome studies are still confounded by postnatal events (i.e. outcomes measured at 7 years)

12. IUGR: Experimental Evidence from Clinical Studies nPoor prenatal head growth=>Poor developmental outcome –Verbal outcome –Visual recognition memory –IQ at 7 years –15% with mild neurodevelopmental abnormalities –Altered neonatal electrophysiology to recognition memory events (LS Black, et al, Exp Neurol; 2004) nCognitive rather than motor disabilities –Consistent with global insults »PEM, iron deficiency, hypoxia

13. IUGR: Postnatal Confounders n Mothers that deliver IUGR infants have a higher prevalence of postnatal non-nutritional risk factors which may also compromise development –less and later prenatal care, higher rate of smoking=> ?less medical care for infant –lower SES –higher rate of personal chronic disease

14. IUGR: The Strauss and Dietz Study (1998) nStrauss and Dietz attempt to control for confounding genetic and environmental factors –45,000 children in National Collaborative Perinatal Project (1959-1976) –2719 IUGR infants compared to 43,104 AGA infants at 7 years of age (standard IUGR paradigm) –220 IUGR infants compared with subsequent AGA sib and also 43,000 non-relatedAGAs Strauss & Dietz, J Pediatr,1998

15. IUGR: The Strauss and Dietz Study (1998) nOutcome variables were Wechsler Intelligence Scale to assess intelligence and Bender-Gestalt Test to assess visual-motor development nIUGRs had lower IQ (90.6 vs 96.8) and lower B-G score (57.3 vs 62.3) compared to population cohort nIUGRs did not have lower IQ (91.0 vs 92.4; p=0.19) or lower B-G score (58.9 vs 60.3; p=0.18) compared to AGA sibling cohort nIUGRs with OFC<2 SD scored lower in both cohorts

16. IUGR: The Strauss and Dietz Study (1998) nStrauss and Dietz concluded “IUGR had little impact on intelligence and motor development except when associated with large deficits in head circumference.” nIs the conclusion warranted? nShould we simply not worry about prenatal malnutrition in spite of the changes in brain anatomy and neurochemistry?

17. IUGR: The Strauss and Dietz Study (1998) nPotential explanations –Beta error –Mild IUGR affects neurodevelopmental behaviors not adequately assessed by Wechsler and Bender- Gestalt »broad based evaluations »single composite score based on multiple subtests of diverse skills »not necessarily designed for pathophysiology in question

18. IUGR: Conclusions nFetal PEM can reduce head size at birth nReduced head size likely represents reduced cell number, size, myelination, synaptogenesis nBehavioral effects include reduced cognitive and spatial ability nHead sparing during fetal PEM (IUGR) may or may not constitute a significant neurobehavioral risk Georgieff, J Pediatr 1998

19. Postnatal Malnutrition: Prematurity & “EUGR” nPremature infants have significantly reduced nutrient stores and growth delays nNeonatologists are not particularly good at growing preterm infants to match expected intrauterine growth rates n57% of infants <1500 g birthweight become microcephalic during hospitalization nCatch-up head growth to original percentiles may take years nIs there a relationship between delayed head growth and developmental outcome?

20. Nutritional Status at Discharge Protein-energy malnutrition Protein-energy malnutrition - Cumulative energy deficit: 1000 kcal/kg - Cumulative protein deficit: 25 grams/kg - 2000 grams at 37 weeks = “EUGR” - Osteopenia (Calcium deficit) - Iron Deficiency (or overload) - Other nutrients?

21. How Do Our Infants Get So Far Behind?

22. CPS (1995): Growth Stages Transition (0-10d) Stable premie grower (10d-d/c) Stable premie grower (10d-d/c) Post-discharge (d/c-?) Post-discharge (d/c-?)

23. CPS Stage 1:Transition First days of life, but could be much longer Sick; Catabolic Sick; Catabolic - Negative N balance; increased energy needs - Negative N balance; increased energy needs - Insulin resistant; counter-regulatory hormones; down-regulated growth factors - Insulin resistant; counter-regulatory hormones; down-regulated growth factors Nutrient sources  TPN+minimal feeds Nutrient sources  TPN+minimal feeds Sick Babies Don’t Grow Sick Babies Don’t Grow

24. 10 days to 34 weeks post-conception 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) Stable, post-neonatal illness (e.g. RDS) Anabolic-unique gut physiology Anabolic-unique gut physiology Nutrient source: PT formula or fortified human milk Nutrient source: PT formula or fortified human milk - Typically, accrued deficits not taken into account when daily nutritional estimates are made; therefore, minimal catch-up growth occurs CPS Stage 2:Premie Growth Phase

25. Post-Discharge Phase After 34 weeks PCA After 34 weeks PCA Healthy, stable (some with BPD) Healthy, stable (some with BPD) Anabolic Anabolic Nutrient Source: Several possibilities 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 Continued growth at term infant rates +recovery from deficits  A TALL ORDER

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

27. No DQ Differences Effect of No Prenatal and Mild Postnatal Malnutrition on Head Size and Development Georgieff et al, J Pediatr, 1985

28. 3 point DQ difference Effect of No Prenatal and Moderate Postnatal Malnutrition on Head Size and Development Georgieff et al, J Pediatr, 1985

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

30. -8 DQ Points Effect of Pre and Postnatal Malnutrition on Head Size and Development Georgieff et al, J Pediatr, 1985

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

32. 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

33. 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

34. Benefits of Discharge Formula for Premature Infants (J Carver et al, 2001) 125 preterm infants (30 weeks EGA, 1275 g) randomized to enriched vs standard term formula (74 assessed at 6 mos CGA; 53 at 12 mos CGA) 125 preterm infants (30 weeks EGA, 1275 g) randomized to enriched vs standard term formula (74 assessed at 6 mos CGA; 53 at 12 mos CGA) Enriched formula characterized by: Enriched formula characterized by: –Higher protein, Ca, P, Vitamins A & D, Zn, Cu, but not Fe Infants fed discharge formula had: Infants fed discharge formula had: –Greater W, L, OFC at 6 mos –Greater W, OFC at 12 mos –Effects most pronounced in <1250g BW group and males

35. Conclusions Prenatal and postnatal nutrition have important impacts on head growth Prenatal and postnatal nutrition have important impacts on head growth Early alterations in head growth affect longer term head size Early alterations in head growth affect longer term head size Smaller OFC’s in follow-up associated with poorer developmental outcome Smaller OFC’s in follow-up associated with poorer developmental outcome Clearly, promotion of continued normal growth velocity in and after the NICU is important Clearly, promotion of continued normal growth velocity in and after the NICU is important

37. “Fetal” Programming Programming refers to process (often epigenetic) by which early environmental stimuli (e.g. nutrition) alter how genes are expressed throughout the lifetime Programming refers to process (often epigenetic) by which early environmental stimuli (e.g. nutrition) alter how genes are expressed throughout the lifetime Best described in fetal period with effect of prenatal nutrition=> adult cardiovascular health (D. Barker) Best described in fetal period with effect of prenatal nutrition=> adult cardiovascular health (D. Barker) May also apply to postnatal nutrition in term and preterm infants May also apply to postnatal nutrition in term and preterm infants Suggests vulnerable period based on post-conceptional age irrespective of in utero vs ex utero Suggests vulnerable period based on post-conceptional age irrespective of in utero vs ex utero Has broad implications about how we feed IUGR and preterm infants Has broad implications about how we feed IUGR and preterm infants

38. Do each of these babies have different adult health fates?

39. What is the Barker Hypothesis? Observations by David Barker Observations by David Barker –Cohorts of adults in Britain with heart disease, diabetes mellitus, hypertension –Risk of these related in part to birth weight –Lower birth weight (particularly <6.5 lbs) increased risk Concept of altered metabolic setpoints in utero Concept of altered metabolic setpoints in utero –Altered hypothalamic/pituitary/adrenal axis regulation (stress hormones) –Altered hepatic metabolism (especially CHO handling)

40. Curhan et al; Circulation, 1996

41. Refinement of the Barker Hypothesis Barker’s associations much stronger if difference between degree of IUGR and rapidity of postnatal growth is considered ( Lucas et al ) Barker’s associations much stronger if difference between degree of IUGR and rapidity of postnatal growth is considered ( Lucas et al ) –High weight gain in first year after IUGR –But, isn’t that “catch-up growth?” Concept of a “thrifty phenotype” in utero (Gluckman and Hanson ; Science, 2004 ) Concept of a “thrifty phenotype” in utero (Gluckman and Hanson ; Science, 2004 ) –Designed to preserve vital systems during periods of relative nutrient insufficiency (IUGR) –Not designed to handle sudden large amounts of nutrient delivery (rapid postnatal refeeding)

42. Gluckman and Hanson, Science, 2004

43. Risks of being IUGR Increased risk of metabolic syndrome Increased risk of metabolic syndrome –Type 2 DM –Insulin resistance –Obesity (short with abdominal adiposity) –Hypertension –Hypercholesterolemia Asymmetric IUGR > Symmetric IUGR Asymmetric IUGR > Symmetric IUGR Metabolic changes eerily reminiscent of chronic cortisol stimulation Metabolic changes eerily reminiscent of chronic cortisol stimulation

44. Risks in Infants of Obese or Diabetic Mothers “Programming” is present during fetal life “Programming” is present during fetal life –IDMs risk of subsequent obesity and diabetes is a function of maternal glycemic control –NIH interested in “long-term metabolic consequences in offspring of obese or diabetic mothers” Evidence that postnatal diet modifies risk Evidence that postnatal diet modifies risk –Breast milk from diabetic mothers has higher glucose and insulin concentrations –Increased risk of glucose intolerance at 2 years after exposure to this milk (compared with banked human milk)

45. Risks in Premature Infants Extremely preterm (<1000g) premies may have greater insulin resistance and blood vessel reactivity changes at 18 months to two years (Denne et al) Extremely preterm (<1000g) premies may have greater insulin resistance and blood vessel reactivity changes at 18 months to two years (Denne et al) Dutch study: early weight gain and late infancy weight gain in <32 weekers associated with higher BMI and abdominal fat at age 19 years Dutch study: early weight gain and late infancy weight gain in <32 weekers associated with higher BMI and abdominal fat at age 19 years Undernutrition of preterm infants in first 2 weeks associated with less long-term insulin resistance Undernutrition of preterm infants in first 2 weeks associated with less long-term insulin resistance THESE ARE STARTLING AND CONCERNING FINDINGS GIVEN CURRENT NICU PRACTICES!

46. Is there a middle ground? Unresolved clinical research question Unresolved clinical research question Need enough intake to sustain adequate head growth for neurodevelopment Need enough intake to sustain adequate head growth for neurodevelopment –>85 Kcal/Kg/d; 3g of amino acids/kg/d Potentially avoid rapid overfeeding (quantity) after period of malnutrition (IUGR; EUGR) Potentially avoid rapid overfeeding (quantity) after period of malnutrition (IUGR; EUGR) –Need metabolic markers to monitor side effects (cortisol; body composition; metabolomics) Does food composition (quality) make a difference? Does food composition (quality) make a difference? –Rat studies suggest low fat, low saturated fat alters transgenerational epigenetic effects

47. Summary Nutritional status in the perinatal period has a potentially profound effect on long-term health and neurodevelopment Nutritional status in the perinatal period has a potentially profound effect on long-term health and neurodevelopment Lack of early head growth confers long-term developmental risks; need to find strategies to keep brain growth on track during IUGR or EUGR periods Lack of early head growth confers long-term developmental risks; need to find strategies to keep brain growth on track during IUGR or EUGR periods Rapid shifts in nutritionally delivery are associated with long-term cardiovascular health risks; overfeeding after growth restriction may be dangerous due to resetting of metabolic setpoint Rapid shifts in nutritionally delivery are associated with long-term cardiovascular health risks; overfeeding after growth restriction may be dangerous due to resetting of metabolic setpoint However… Need more research to define upper limits of intake However… Need more research to define upper limits of intake