Transcript Long Term Effects of In Utero and Early Postnatal Nutrition

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
Overview of Talk
 Why care about early nutrition?
– Emphasis on brain development: Basic Principles
– Concern about long term health
 Nutrient deficiencies and risks to the developing brain
– In utero malnutrition (IUGR)
– Early postnatal nutrition (EUGR)
 Nutrient “excess” and long term health risks
– The “Barker” hypothesis
» Is it really “fetal” programming?
» Risks of overfeeding
 The U-shaped nutrition risk curve
– Striking a balance in feeding young infants
Basic Principles of Nutrient/Brain
Interactions
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)
Nutrient-Brain-Behavior Relationships
Brain regions/processes have different developmental
trajectories
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
Thompson & Nelson, Am Psychol, 200
Early Malnutrition
Early Malnutrition: Clinical Situations
Clinical 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 intake
• Excessive protein-energy needs/losses
Prenatal Malnutrition:IUGR
IUGR 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)
IUGR outcome studies are still confounded by
postnatal events (i.e. outcomes measured at 7 years)
IUGR: Experimental Evidence
from Clinical Studies
Poor 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)
Cognitive rather than motor disabilities
– Consistent with global insults
» PEM, iron deficiency, hypoxia
IUGR: Postnatal Confounders
 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
IUGR: The Strauss and Dietz
Study (1998)
Strauss 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
IUGR: The Strauss and Dietz
Study (1998)
Outcome variables were Wechsler Intelligence Scale
to assess intelligence and Bender-Gestalt Test to
assess visual-motor development
IUGRs had lower IQ (90.6 vs 96.8) and lower B-G
score (57.3 vs 62.3) compared to population cohort
IUGRs 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
IUGRs with OFC<2 SD scored lower in both cohorts
IUGR: The Strauss and Dietz
Study (1998)
Strauss and Dietz concluded “IUGR had little impact
on intelligence and motor development except when
associated with large deficits in head circumference.”
Is the conclusion warranted?
Should we simply not worry about prenatal
malnutrition in spite of the changes in brain anatomy
and neurochemistry?
IUGR: The Strauss and Dietz
Study (1998)
Potential explanations
– Beta error
– Mild IUGR affects neurodevelopmental behaviors
not adequately assessed by Wechsler and BenderGestalt
» broad based evaluations
» single composite score based on multiple subtests of
diverse skills
» not necessarily designed for pathophysiology in question
IUGR: Conclusions
Fetal PEM can reduce head size at birth
Reduced head size likely represents reduced cell
number, size, myelination, synaptogenesis
Behavioral effects include reduced cognitive and
spatial ability
Head sparing during fetal PEM (IUGR) may or may
not constitute a significant neurobehavioral risk
Georgieff, J Pediatr 1998
Postnatal Malnutrition:
Prematurity & “EUGR”
Premature infants have significantly reduced nutrient stores
and growth delays
Neonatologists are not particularly good at growing preterm
infants to match expected intrauterine growth rates
57% of infants <1500 g birthweight become microcephalic
during hospitalization
Catch-up head growth to original percentiles may take years
Is there a relationship between delayed head growth and
developmental outcome?
Nutritional Status at Discharge
• 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?
How Do Our Infants Get So Far Behind?
CPS (1995): Growth Stages
• Transition (0-10d)
• Stable premie grower (10d-d/c)
• Post-discharge (d/c-?)
CPS Stage 1:Transition
• First days of life, but could be much longer
• Sick; Catabolic
- Negative N balance; increased energy needs
- Insulin resistant; counter-regulatory hormones;
down-regulated growth factors
• Nutrient sources  TPN+minimal feeds
• Sick Babies Don’t Grow
CPS Stage 2:Premie 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 when
daily nutritional estimates are made; therefore, minimal
catch-up growth occurs
Post-Discharge Phase
• After 34 weeks PCA
• Healthy, stable (some with BPD)
• Anabolic
• 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
Effect of Mild to Severe Postnatal
Malnutrition on Head Growth in the NICU
and at One-Year Follow-up
Effect of No Prenatal and Mild Postnatal Malnutrition
on Head Size and Development
No DQ
Differences
Georgieff et al, J Pediatr, 1985
Effect of No Prenatal and Moderate Postnatal Malnutrition
on Head Size and Development
3 point DQ
difference
Georgieff et al, J Pediatr, 1985
The effect of combined pre- and
postnatal malnutrition on neonatal and
follow-up head growth
Effect of Pre and Postnatal Malnutrition
on Head Size and Development
-8 DQ
Points
Georgieff et al, J Pediatr, 1985
The effect of chronic illness (BPD) on
weight gain and head growth
1
Weight
Weight z-score
0
Control
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BPD
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10
Postnatal Age (weeks)
deRegnier et al, 1996
1
Head Circumference
OFC Z-score
0
-1
-2
-3
-4
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Postnatal Age (weeks)
deRegnier et al, 1996
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)
 Enriched formula characterized by:
– Higher protein, Ca, P, Vitamins A & D, Zn, Cu, but not Fe
 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
Conclusions
Prenatal and postnatal nutrition have important
impacts on head growth
Early alterations in head growth affect longer term
head size
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
“Fetal” Programming
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)
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
Has broad implications about how we feed IUGR and
preterm infants
Do each of these babies have different adult health fates?
What is the Barker Hypothesis?
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
– Altered hypothalamic/pituitary/adrenal axis regulation (stress
hormones)
– Altered hepatic metabolism (especially CHO handling)
Curhan et al; Circulation, 1996
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)
– 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)
– 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)
Gluckman and Hanson, Science, 2004
Risks of being IUGR
Increased risk of metabolic syndrome
– Type 2 DM
– Insulin resistance
– Obesity (short with abdominal adiposity)
– Hypertension
– Hypercholesterolemia
Asymmetric IUGR > Symmetric IUGR
Metabolic changes eerily reminiscent of chronic cortisol
stimulation
Risks in Infants of Obese or Diabetic Mothers
“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
– 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)
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)
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
THESE ARE STARTLING AND CONCERNING
FINDINGS GIVEN CURRENT NICU PRACTICES!
Is there a middle ground?
Unresolved clinical research question
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)
– Need metabolic markers to monitor side effects (cortisol; body
composition; metabolomics)
Does food composition (quality) make a difference?
– Rat studies suggest low fat, low saturated fat alters
transgenerational epigenetic effects
Summary
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
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