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