Long Term Effects of In Utero and Early Postnatal Nutrition Michael K. Georgieff, M.D. Professor of Pediatrics and Child Development Director, Center for

Long Term Effects of In Utero and Early Long Term Effects of In Utero and Early Postnatal NutritionPostnatal Nutrition

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

Professor of Pediatrics and Child DevelopmentProfessor of Pediatrics and Child Development

Director, Center for Neurobehavioral DevelopmentDirector, Center for Neurobehavioral Development

Director, NICU Follow-up ProgramDirector, NICU Follow-up Program

University of Minnesota School of MedicineUniversity of Minnesota School of Medicine

Overview of TalkOverview of Talk

Why care about early nutrition?Why care about early nutrition?– Emphasis on brain development: Basic PrinciplesEmphasis on brain development: Basic Principles

– Concern about long term healthConcern about long term health

Nutrient deficiencies and risks to the developing brain Nutrient deficiencies and risks to the developing brain – In utero malnutrition (IUGR)In utero malnutrition (IUGR)

– Early postnatal nutrition (EUGR)Early postnatal nutrition (EUGR)

Nutrient “excess” and long term health risksNutrient “excess” and long term health risks– The “Barker” hypothesisThe “Barker” hypothesis

» Is it really “fetal” programming?Is it really “fetal” programming?

» Risks of overfeedingRisks of overfeeding

The U-shaped nutrition risk curveThe U-shaped nutrition risk curve– Striking a balance in feeding young infantsStriking a balance in feeding young infants

Basic Principles of Nutrient/Brain Basic Principles of Nutrient/Brain InteractionsInteractions

Early Nutrition and Brain Development:Early Nutrition and Brain Development:General PrinciplesGeneral Principles

Positive or negative nutrient effects on brain Positive or negative nutrient effects on brain development development

Based on…Based on…

Timing, Dose and Duration of ExposureTiming, Dose and Duration of ExposureKretchmer, Beard, Carlson Kretchmer, Beard, Carlson

(Am J Clin Nutr, 1996)(Am J Clin Nutr, 1996)

Nutrient-Brain-Behavior RelationshipsNutrient-Brain-Behavior Relationships

Brain regions/processes have different developmental Brain regions/processes have different developmental trajectoriestrajectories

The vulnerability of a brain region to a nutrient The vulnerability of a brain region to a nutrient deficit is based on deficit is based on – When nutrient deficit is likely to occurWhen nutrient deficit is likely to occur

– Brain’s requirement for that nutrient at that time Brain’s requirement for that nutrient at that time

Behavioral changes must map onto those brain Behavioral changes must map onto those brain structures altered by the nutrient deficitstructures altered by the nutrient deficit

Thompson & Nelson, Am Psychol, 2001

Early MalnutritionEarly Malnutrition

Early Malnutrition: Clinical SituationsEarly Malnutrition: Clinical Situations

Clinical conditions early in life include:Clinical conditions early in life include:– Intrauterine growth retardationIntrauterine growth retardation» Maternal hypertension most common causeMaternal hypertension most common cause» Severe maternal malnutritionSevere maternal malnutrition

–Chronic illness prohibiting adequate feeding (EUGR)Chronic illness prohibiting adequate feeding (EUGR)» Prematurity/neonatal illnessPrematurity/neonatal illness» Chronic renal, hepatic, cardiac, pulmonary, infectious Chronic renal, hepatic, cardiac, pulmonary, infectious

diseases (CHF, cystic fibrosis, HIV)diseases (CHF, cystic fibrosis, HIV)• Limited protein-energy intakeLimited protein-energy intake• Excessive protein-energy needs/lossesExcessive protein-energy needs/losses

Prenatal Malnutrition:IUGRPrenatal Malnutrition:IUGR

IUGR due to placental insufficiency is a good model IUGR due to placental insufficiency is a good model for malnutrition effects on brain growth and for malnutrition effects on brain growth and developmentdevelopment

–Brain is in rapid growth phase during last Brain is in rapid growth phase during last trimester; hence more vulnerabletrimester; hence more vulnerable

– Placenta as an environmental filter (not an Placenta as an environmental filter (not an absolute barrier)absolute barrier)

IUGR outcome studies are still confounded by IUGR outcome studies are still confounded by postnatal events (i.e. outcomes measured at 7 years)postnatal events (i.e. outcomes measured at 7 years)

IUGR: Experimental Evidence IUGR: Experimental Evidence from Clinical Studiesfrom Clinical Studies

Poor prenatal head growth=>Poor developmental Poor prenatal head growth=>Poor developmental outcomeoutcome–Verbal outcomeVerbal outcome–Visual recognition memoryVisual recognition memory– IQ at 7 yearsIQ at 7 years– 15% with mild neurodevelopmental abnormalities15% with mild neurodevelopmental abnormalities–Altered neonatal electrophysiology to recognition Altered neonatal electrophysiology to recognition

memory events memory events (LS Black, et al, Exp Neurol; 2004)(LS Black, et al, Exp Neurol; 2004)

Cognitive rather than motor disabilitiesCognitive rather than motor disabilities–Consistent with global insultsConsistent with global insults» PEM, iron deficiency, hypoxiaPEM, iron deficiency, hypoxia

IUGR: Postnatal ConfoundersIUGR: Postnatal Confounders

Mothers that deliver IUGR infants have a higher Mothers that deliver IUGR infants have a higher prevalence of prevalence of postnatalpostnatal non-nutritionalnon-nutritional risk risk factors which may also compromise developmentfactors which may also compromise development

– less and later prenatal care, higher rate of less and later prenatal care, higher rate of smoking=> ?less medical care for infantsmoking=> ?less medical care for infant

– lower SESlower SES

– higher rate of personal chronic diseasehigher rate of personal chronic disease

IUGR: The Strauss and Dietz IUGR: The Strauss and Dietz Study (1998)Study (1998)

Strauss and Dietz attempt to control for confounding Strauss and Dietz attempt to control for confounding genetic and environmental factorsgenetic and environmental factors

– 45,000 children in National Collaborative 45,000 children in National Collaborative Perinatal Project (1959-1976)Perinatal Project (1959-1976)

– 2719 IUGR infants compared to 43,104 AGA 2719 IUGR infants compared to 43,104 AGA infants at 7 years of age (standard IUGR infants at 7 years of age (standard IUGR paradigm)paradigm)

– 220 IUGR infants compared with subsequent 220 IUGR infants compared with subsequent AGA sib and also 43,000 non-relatedAGAsAGA sib and also 43,000 non-relatedAGAs

Strauss & Dietz, J Pediatr,1998


Outcome variables were Wechsler Intelligence Scale Outcome variables were Wechsler Intelligence Scale to assess intelligence and Bender-Gestalt Test to to assess intelligence and Bender-Gestalt Test to assess visual-motor developmentassess visual-motor development

IUGRs had lower IQ (90.6 vs 96.8) and lower B-G IUGRs had lower IQ (90.6 vs 96.8) and lower B-G score (57.3 vs 62.3) compared to population cohortscore (57.3 vs 62.3) compared to population cohort

IUGRs did IUGRs did notnot have lower IQ (91.0 vs 92.4; p=0.19) 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 or lower B-G score (58.9 vs 60.3; p=0.18) compared to AGA sibling cohortto AGA sibling cohort

IUGRs with OFC<2 SD scored lower in both cohortsIUGRs with OFC<2 SD scored lower in both cohorts


Strauss and Dietz concluded “IUGR had little impact Strauss and Dietz concluded “IUGR had little impact on intelligence and motor development except when on intelligence and motor development except when associated with large deficits in head circumference.”associated with large deficits in head circumference.”

Is the conclusion warranted?Is the conclusion warranted? Should we simply not worry about prenatal Should we simply not worry about prenatal

malnutrition in spite of the changes in brain anatomy malnutrition in spite of the changes in brain anatomy and neurochemistry?and neurochemistry?


Potential explanationsPotential explanations

–Beta error Beta error

–Mild IUGR affects neurodevelopmental behaviors Mild IUGR affects neurodevelopmental behaviors not adequately assessed by Wechsler and Bender-not adequately assessed by Wechsler and Bender-GestaltGestalt» broad based evaluationsbroad based evaluations

» single composite score based on multiple subtests of single composite score based on multiple subtests of diverse skillsdiverse skills

» not necessarily designed for pathophysiology in questionnot necessarily designed for pathophysiology in question

IUGR: ConclusionsIUGR: Conclusions

Fetal PEM can reduce head size at birthFetal PEM can reduce head size at birth Reduced head size likely represents reduced cell Reduced head size likely represents reduced cell

number, size, myelination, synaptogenesisnumber, size, myelination, synaptogenesis Behavioral effects include reduced cognitive and Behavioral effects include reduced cognitive and

spatial abilityspatial ability Head sparing during fetal PEM (IUGR) may or may Head sparing during fetal PEM (IUGR) may or may

not constitute a significant neurobehavioral risknot constitute a significant neurobehavioral risk

Georgieff, J Pediatr 1998

Postnatal Malnutrition: Postnatal Malnutrition: Prematurity & “EUGR”Prematurity & “EUGR”

Premature infants have significantly reduced nutrient stores Premature infants have significantly reduced nutrient stores and growth delaysand growth delays

Neonatologists are not particularly good at growing preterm Neonatologists are not particularly good at growing preterm infants to match expected intrauterine growth ratesinfants to match expected intrauterine growth rates

57% of infants <1500 g birthweight become microcephalic 57% of infants <1500 g birthweight become microcephalic during hospitalizationduring hospitalization

Catch-up head growth to original percentiles may take yearsCatch-up head growth to original percentiles may take years Is there a relationship between delayed head growth and Is there a relationship between delayed head growth and

developmental outcome?developmental outcome?

Nutritional Status at DischargeNutritional Status at Discharge• Protein-energy malnutritionProtein-energy malnutrition

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

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

- 2000 grams at 37 weeks = “EUGR”2000 grams at 37 weeks = “EUGR”

- Osteopenia (Calcium deficit)Osteopenia (Calcium deficit)

- Iron Deficiency (or overload)Iron Deficiency (or overload)

- Other nutrients?Other nutrients?

How Do Our Infants Get So Far Behind?How Do Our Infants Get So Far Behind?

CPS (1995): Growth StagesCPS (1995): Growth Stages

• Transition (0-10d)Transition (0-10d)

• Stable premie grower (10d-d/c)Stable premie grower (10d-d/c)

• Post-discharge (d/c-?)Post-discharge (d/c-?)

CPS Stage CPS Stage 1:Transition1:Transition

• First days of life, but could be First days of life, but could be much longermuch longer

• Sick; CatabolicSick; Catabolic

- - Negative N balance; increased energy Negative N balance; increased energy needsneeds

- - Insulin resistant; counter-regulatory Insulin resistant; counter-regulatory hormones; hormones; down-regulated growth down-regulated growth factorsfactors

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

• Sick Babies Don’t GrowSick Babies Don’t Grow

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

- - Start time varies based on severity of Start time varies based on severity of illness 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 Nutrient source: PT formula or fortified human milkhuman milk

-- Typically, accrued deficits not taken Typically, accrued deficits not taken into account when daily nutritional into account when daily nutritional estimates are made; therefore, minimal estimates are made; therefore, minimal catch-up growth occurscatch-up growth occurs

CPS Stage 2:Premie Growth CPS Stage 2:Premie Growth PhasePhase

Post-Discharge PhasePost-Discharge Phase• After 34 weeks PCAAfter 34 weeks PCA

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

• AnabolicAnabolic

• Nutrient Source: Several Nutrient Source: Several possibilitiespossibilities

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

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

Effect of Effect of Mild to SevereMild to Severe Postnatal Postnatal Malnutrition on Head Growth in the NICU Malnutrition on Head Growth in the NICU

and at One-Year Follow-upand at One-Year Follow-up

No DQDifferences

Effect of No Prenatal and Mild Postnatal Malnutrition on Head Size and Development

Georgieff et al, J Pediatr, 1985

3 point DQdifference

Effect of No Prenatal and Moderate Postnatal Malnutrition on Head Size and Development


The effect of combined The effect of combined pre- and pre- and postnatalpostnatal malnutrition on neonatal and malnutrition on neonatal and

follow-up head growthfollow-up head growth

-8 DQ Points

Effect of Pre and Postnatal Malnutrition on Head Size and Development


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

0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 10 6 7 8 9 10

11

00

-1-1

-2-2

-3-3

-4-4

WeightWeight

ControlControl

BPDBPD

Weight z-score

Postnatal Age (weeks)

deRegnier et al, 1996

Postnatal Age (weeks)Postnatal Age (weeks)0 1 2 3 4 5 0 1 2 3 4 5 6 7 8 9 10 6 7 8 9 10

11

00

-1-1

-2-2

-3-3

-4-4

Head CircumferenceHead Circumference

OFC Z-score

deRegnier et al, 1996

Benefits of Discharge Formula for Benefits of Discharge Formula for Premature InfantsPremature Infants (J Carver et al, 2001)(J Carver et al, 2001)

125 preterm infants (30 weeks EGA, 1275 g) randomized to 125 preterm infants (30 weeks EGA, 1275 g) randomized to enriched vs standard term formula (74 assessed at 6 mos CGA; enriched vs standard term formula (74 assessed at 6 mos CGA; 53 at 12 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 FeHigher protein, Ca, P, Vitamins A & D, Zn, Cu, but not Fe Infants fed discharge formula had:Infants fed discharge formula had:

– Greater W, L, Greater W, L, OFCOFC at 6 mos at 6 mos

– Greater W, Greater W, OFCOFC at 12 mos at 12 mos

– Effects most pronounced in <1250g BW group and malesEffects most pronounced in <1250g BW group and males

ConclusionsConclusions

Prenatal and postnatal nutrition have important Prenatal and postnatal nutrition have important impacts on head growthimpacts on head growth

Early alterations in head growth affect longer term Early alterations in head growth affect longer term head sizehead size

Smaller OFC’s in follow-up associated with poorer Smaller OFC’s in follow-up associated with poorer developmental outcomedevelopmental outcome

Clearly, promotion of continued normal growth Clearly, promotion of continued normal growth velocity in and after the NICU is importantvelocity in and after the NICU is important

““Fetal” ProgrammingFetal” Programming

Programming refers to process (often epigenetic) by which Programming refers to process (often epigenetic) by which early environmental stimuli (e.g. nutrition) alter how genes early environmental stimuli (e.g. nutrition) alter how genes are expressed throughout the lifetimeare expressed throughout the lifetime

Best described in Best described in fetalfetal period with effect of prenatal period with effect of prenatal nutrition=> adult cardiovascular health (D. Barker)nutrition=> adult cardiovascular health (D. Barker)

May also apply to May also apply to postnatalpostnatal nutrition in term and preterm nutrition in term and preterm infantsinfants

Suggests vulnerable period based on post-conceptional age Suggests vulnerable period based on post-conceptional age irrespective of in utero vs ex uteroirrespective of in utero vs ex utero

Has broad implications about how we feed IUGR and Has broad implications about how we feed IUGR and preterm infantspreterm infants

Do each of these babies have different adult health fates?

What is the Barker Hypothesis?What is the Barker Hypothesis?

Observations by David BarkerObservations by David Barker– Cohorts of adults in Britain with heart disease, diabetes mellitus, Cohorts of adults in Britain with heart disease, diabetes mellitus,

hypertensionhypertension

– Risk of these related in part to birth weightRisk of these related in part to birth weight

– Lower birth weight (particularly <6.5 lbs) increased riskLower birth weight (particularly <6.5 lbs) increased risk

Concept of altered metabolic setpoints in uteroConcept of altered metabolic setpoints in utero– Altered hypothalamic/pituitary/adrenal axis regulation (stress Altered hypothalamic/pituitary/adrenal axis regulation (stress

hormones)hormones)

– Altered hepatic metabolism (especially CHO handling)Altered hepatic metabolism (especially CHO handling)

Curhan et al; Circulation, 1996

Refinement of the Barker HypothesisRefinement of the Barker Hypothesis

Barker’s associations much stronger if difference between Barker’s associations much stronger if difference between degree of IUGR and rapidity of postnatal growth is degree of IUGR and rapidity of postnatal growth is considered (considered (Lucas et alLucas et al))– High weight gain in first year after IUGRHigh weight gain in first year after IUGR– But, isn’t that “catch-up growth?”But, isn’t that “catch-up growth?”

Concept of a “thrifty phenotype” in utero Concept of a “thrifty phenotype” in utero (Gluckman and Hanson(Gluckman and Hanson; ;

Science , 2004Science , 2004))– Designed to preserve vital systems during periods of relative Designed to preserve vital systems during periods of relative

nutrient insufficiency (IUGR)nutrient insufficiency (IUGR)– Not designed to handle sudden large amounts of nutrient Not designed to handle sudden large amounts of nutrient

delivery (rapid postnatal refeeding)delivery (rapid postnatal refeeding)

Gluckman and Hanson, Science, 2004

Risks of being IUGRRisks of being IUGR

Increased risk of metabolic syndromeIncreased risk of metabolic syndrome– Type 2 DMType 2 DM

– Insulin resistanceInsulin resistance

– Obesity (short with abdominal adiposity)Obesity (short with abdominal adiposity)

– HypertensionHypertension

– HypercholesterolemiaHypercholesterolemia

Asymmetric IUGR > Symmetric IUGRAsymmetric IUGR > Symmetric IUGR Metabolic changes eerily reminiscent of chronic cortisol Metabolic changes eerily reminiscent of chronic cortisol

stimulationstimulation

Risks in Infants of Obese or Diabetic MothersRisks in Infants of Obese or Diabetic Mothers

““Programming” is present during fetal lifeProgramming” is present during fetal life– IDMs risk of subsequent obesity and diabetes is a function of IDMs risk of subsequent obesity and diabetes is a function of

maternal glycemic controlmaternal glycemic control

– NIH interested in “long-term metabolic consequences in NIH interested in “long-term metabolic consequences in offspring of obese or diabetic mothers”offspring of obese or diabetic mothers”

Evidence that postnatal diet modifies riskEvidence that postnatal diet modifies risk– Breast milk from diabetic mothers has higher glucose and Breast milk from diabetic mothers has higher glucose and

insulin concentrationsinsulin concentrations

– Increased risk of glucose intolerance at 2 years after exposure Increased risk of glucose intolerance at 2 years after exposure to this milk (compared with banked human milk)to this milk (compared with banked human milk)

Risks in Premature InfantsRisks in Premature Infants

Extremely preterm (<1000g) premies may have greater Extremely preterm (<1000g) premies may have greater insulin resistance and blood vessel reactivity changes at 18 insulin resistance and blood vessel reactivity changes at 18 months to two years (Denne et al)months to two years (Denne et al)

Dutch study: early weight gain and late infancy weight Dutch study: early weight gain and late infancy weight gain in <32 weekers associated with higher BMI and gain in <32 weekers associated with higher BMI and abdominal fat at age 19 yearsabdominal fat at age 19 years

Undernutrition of preterm infants in first 2 weeks Undernutrition of preterm infants in first 2 weeks associated with less long-term insulin resistanceassociated with less long-term insulin resistance

THESE ARE STARTLING AND CONCERNING THESE ARE STARTLING AND CONCERNING FINDINGS GIVEN CURRENT NICU PRACTICES!FINDINGS GIVEN CURRENT NICU PRACTICES!

Is there a middle ground?Is there a middle ground?

Unresolved clinical research questionUnresolved clinical research question Need enough intake to sustain adequate head growth for Need enough intake to sustain adequate head growth for

neurodevelopmentneurodevelopment– >85 Kcal/Kg/d; 3g of amino acids/kg/d>85 Kcal/Kg/d; 3g of amino acids/kg/d

Potentially avoid rapid overfeeding (quantity) after period Potentially avoid rapid overfeeding (quantity) after period of malnutrition (IUGR; EUGR)of malnutrition (IUGR; EUGR)– Need metabolic markers to monitor side effects (cortisol; body Need metabolic markers to monitor side effects (cortisol; body

composition; metabolomics)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 Rat studies suggest low fat, low saturated fat alters

transgenerational epigenetic effectstransgenerational epigenetic effects

SummarySummary

Nutritional status in the perinatal period has a potentially Nutritional status in the perinatal period has a potentially profound effect on long-term health and profound effect on long-term health and neurodevelopmentneurodevelopment

Lack of early head growth confers long-term Lack of early head growth confers long-term developmental risks; need to find strategies to keep brain developmental risks; need to find strategies to keep brain growth on track during IUGR or EUGR periodsgrowth on track during IUGR or EUGR periods

Rapid shifts in nutritionally delivery are associated with Rapid shifts in nutritionally delivery are associated with long-term cardiovascular health risks; overfeeding after long-term cardiovascular health risks; overfeeding after growth restriction may be dangerous due to resetting of growth restriction may be dangerous due to resetting of metabolic setpointmetabolic setpoint

However… Need more research to define upper limits of However… Need more research to define upper limits of intakeintake

Documents

Long Term Effects of In Utero and Early Postnatal Nutrition Michael K. Georgieff, M.D. Professor of Pediatrics and Child Development Director, Center for