simmons programming of postnatal growth -...
TRANSCRIPT
4/8/2013
1
Programming of Postnatal
Growth
Dr. Mandy Brown Belfort
Nutrition in early life
• How do we optimize early-life growth and
nutrition to promote long term health and
prevent disease:
– Cardiovascular disease
– Obesity / diabetes
– Neurodevelopment
• Research in human populations critical to
informing specific strategies
Postnatal growth
• Epidemic of child and adult obesity
• Link between infant weight gain and obesity
– Might limiting postnatal weight gain in infancy be a viable strategy for prevention?
– What are the risks (e.g. neurodevelopment)?
4/8/2013
2
Overview
• DOHaD and the healthy, full term infant (less)
– Relevance to obesity prevention
• DOHaD and the preterm infant (more)
– Preterm birth
– Fetal growth
– Postnatal growth
• NICU, post-discharge
– Implications for practice
Rapid infant
weight gain
Neurodevelopment
•Cognition
Adiposity-related
•Obesity
Rapid infant
weight gain
Neurodevelopment
•Cognition
Adiposity-related
•ObesityHARM
BENEFIT
4/8/2013
3
Rapid infant
weight gain
Neurodevelopment
•Cognition
Adiposity-related
•ObesityHARM
BENEFIT
Healthy, full term
Healthy, full term
~2.5 fold higher odds of childhood
obesity per additional SD infant
weight gainDruet et al. Paediatr Perinat Epidemiol 2011
Taveras et al, 2009
4/8/2013
4
Healthy, full term
• 872 participants in Project Viva
•Infant weight gain from birth to 8 weeks, 6 months
•PPVT-III at 3 years = cognition
•No association
•Subsequent systematic review: same
Belfort et al. Pediatrics 2010; Beyerlein et al. Am J Clin Nutr 2010
Rapid infant
weight gain
Neurodevelopment
•Cognition
Adiposity-related
•ObesityHARM
BENEFIT
Healthy, full term
Clinical intervention: obesity
prevention in infancy
Paul et al. Obesity 2011
•SLIMTIME Pilot RCT:
SLeeping and Intake
Methods Taught to Infants
and Mothers Early In Life
•Intervention #1 (solids) --
teach hunger/satiety cues,
timing of solid food
introduction
•Intervention #2 (soothe) --
reduce feeding as first
response to fussiness
4/8/2013
5
What about preterm infants?
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – Fetal
– NICU
– After discharge
• Implications for practice– Tradeoffs
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – Fetal
– NICU
– After discharge
• Implications for practice– Tradeoffs
4/8/2013
6
Preterm birth and neurodevelopment
Bhutta et al. JAMA 2002
Cognition: ~11 IQ points
lower than term-born
Motor function: ~0.9 SD
lower than term-born
De Kieviet et al. JAMA 2009
Preterm birth and neurodevelopment
Preterm birth and insulin resistance
Hovi et al. NEJM 2007
•n=163 VLBW young adults: higher glucose, insulin levels vs. n=169 term AGA
•fasting and 2 hours after OGTT
4/8/2013
7
Preterm birth and blood pressure
• Lower birth weight associated with higher
blood pressure later in life
• Historical low birth weight cohorts likely
growth restricted rather than preterm
• Preterm birth also a cause of lower birth
weight
– To what extent related to higher blood pressure?
Systolic blood pressure difference (mmHg)
• Systolic blood pressure 2.5 mmHg (95% CI 1.7, 3.3)
higher in preterm / VLBW vs. full term
• Very preterm (<32 weeks): 3.3 mmHg
•Higher quality studies: 3.8 mmHg
De Jong et al. Hypertension 2012
Systolic blood pressure difference (mmHg)
• Systolic blood pressure 2.5 mmHg (95% CI 1.7, 3.3)
higher in preterm / VLBW vs. full term
• Very preterm (<32 weeks): 3.3 mmHg
•Higher quality studies: 3.8 mmHg
De Jong et al. Hypertension 2012
4/8/2013
8
Preterm birth and blood pressure
• Results support higher blood pressure as
adverse cardiovascular outcome of preterm
birth
– Possible risk for later HTN and sequelae
• Modest effect size
– Similar to effect of dietary sodium
• Limitation: no insight re: mechanism
OutcomeAssociation with
preterm birth
Neurodevelopment ↓
Insulin resistance ↑
Blood pressure ↑
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – Fetal
– NICU
– After discharge
• Implications for practice– Tradeoffs
4/8/2013
9
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – Fetal
– NICU
– After discharge
• Implications for practice– Tradeoffs
Prenatal & perinatal determinants of
blood pressure in preterm infants (1)
• Animal models of fetal growth restriction �
higher offspring blood pressure
• In full term (human) children, higher blood
pressure associated with
– Fetal growth restriction
– Preeclampsia / other hypertensive disorders
– Maternal smoking
• Little data about prenatal and perinatal
influences on blood pressure of preterm infants
Associations of maternal factors with child
systolic BP at 6.5 years
Numbers are mmHg (95% CI)
Age (per 5 years) 0.4 (-0.2, 1.0)
Pre-pregnancy weight (per 5 kg) -0.1 (-0.2, 0.0)
Gestational weight gain (per kg) -0.2 (-0.2, 0.0)
Gestational diabetes 1.2 (-4.9, 7.4)
Preeclampsia -0.7 (-2.4, 1.0)
Smoking (any vs. none) 0.6 (-0.7, 2.0)
Estimates adjusted for maternal and child factors
Belfort et al. J Perinatol. 2012
• 694 infants ≤37 weeks’ gestation (IHDP)
• Medical record review and questionnaire
• Systolic BP x 3 at 6.5 years
4/8/2013
10
Associations of fetal/infant factors with child
systolic BP at 6.5 years
Numbers are mmHg (95% CI)
Birth weight (kg) 0.6 (-0.8, 2.0)
Gestational age (weeks) -0.1 (-0.3, 0.2)
Birth weight z-score 0.7 (-0.1, 1.6)
SGA (vs. AGA) -0.7 (-2.0, 0.6)
Birth order (vs. 1)
2 0.4 (-1.3, 2.1)
3 1.1 (-0.8, 2.9)
Bronchopulmonary dysplasia 1.0 (-1.9, 3.9)
Belfort et al. J Perinatol. 2012
Estimates adjusted for maternal and child factors
Prenatal & perinatal determinants of
blood pressure in preterm infants
• Prior studies of low birth weight and blood pressure did not consider separate effects of gestation length and fetal growth
• In preterm infants, fetal growth restriction, its determinants not related to later BP
– Different from studies of full term infants
– Consistent with few other studies of preterm infants
– Perhaps critical period is late in 3rd trimester?
• For preterm infants, postnatal factors may be more important
Prenatal & perinatal determinants of
blood pressure in preterm infants
• Prior studies of low birth weight and blood pressure did not consider separate effects of gestation length and fetal growth
• In preterm infants, fetal growth restriction, its determinants not related to later BP
– Different from studies of full term infants
– Consistent with few other studies of preterm infants
– Perhaps sensitive period is late in 3rd trimester?
• Preterm infants already born
• Postnatal factors may be more important
4/8/2013
11
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – Fetal
– NICU
– After discharge
• Implications for practice– Tradeoffs
Postnatal growth of preterm infants
• Before term: equivalent to fetal stage of
development (typically in NICU)
• After term: developmentally equivalent to
early postnatal period for full term infant (at
home)
Term = 40 weeks postmenstrual age
TERM =
40 weeks
PMA
Preterm
infant birthNICU
Full term infant still in-utero
POST-NICU
Full term
birth
Postnatal period for full term infant
Postnatal period for preterm infant
4/8/2013
12
Environment: fetus vs. NICU baby
Maturation occurs along the same developmental timeline in-utero and in the NICU
Ehrenkranz et al Pediatrics 1999
NICU vs. fetal weight gain
Ehrenkranz et al Pediatrics 1999
NICU vs. fetal weight gain
Reference
fetus
4/8/2013
13
28-29wk
26-27wk
24-25wk
Ehrenkranz et al Pediatrics 1999
NICU vs. fetal weight gain
Reference
fetus
NICU weight gain
Extra-uterine growth restriction
• occurs at same developmental timing as IUGR in term infant
• post-natal and post-discharge promotion of “catch-up” growth
% with
weight
growth
failure at
discharge
23
0
10
20
30
40
50
60
70
80
90
100
3029282725 2624 333231 34
Gestational age at birth
Growth failure = size less than
10th %ile for postmenstrual age
Clark et al. Pediatrics 2003
Somatic growth correlates with
brain growth at critical period
25 weeks
Hüppi PS. Ann Neurol 1998
28 weeks
40 weeks
125 g 350 g
4/8/2013
14
NICU weight gain and
neurodevelopment
Weight gain quartile (rate of weight gain)
Outcome1
12 g/kg/day
2
16 g/kg/day
3
18 g/kg/day
4
21 g/kg/day
MDI <70 39% 37% 34% 21%
PDI <70 35% 32% 18% 14%
CP 21% 13% 13% 6%
• 495 infants with birth weight <1000g from 12 U.S. NICU’s
• Lower weight gain quartile associated with higher risk of
poor outcome at 18 months
Ehrenkranz et al Pediatrics 2006
Pre-term growth and
neurodevelopment
• 613 infants <33 weeks’ gestation (DINO)
• Greater BMI gain from 1 week to term associated
with higher cognitive, motor scores at 18 months
• Suggests benefit of weight gain out of proportion to
linear growth (adiposity) before termBelfort et al. Pediatrics 2011
Outcome Points per z-score BMI gain (95% CI)
MDI 1.7 (0.4, 3.1)
PDI 2.5 (1.2, 3.9)
Estimates adjusted for maternal and child factors
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – Fetal
– NICU
– After discharge
• Implications for practice– Tradeoffs
4/8/2013
15
Importance of growth after term
• Much research focus on “pre-term” growth
• Post-term period is equivalent to early
postnatal period for full term infant
• Preterm infants leave NICU with deficits
• What are effects of compensation for these
deficits?
TERM =
40 weeks
PMA
Preterm
infant birthNICU
Full term infant still in-utero
POST-NICU
Full term
birth
Postnatal period for full term infant
Postnatal period for preterm infant
EXTRA-UTERINE GROWTH RESTRICTION ???
Growth after term
• Most reach normal size
in first years of life
– Continues through
school age &
adolescence
Casey Semin Perinatol 2008; Hack et al. Pediatrics 2003
4/8/2013
16
Growth after term
• Most reach normal size
in first years of life
– Continues through
school age &
adolescence
• SGA males lighter,
shorter at 20 years
Casey Semin Perinatol 2008; Hack et al. Pediatrics 2003
Growth after term: neurodevelopment
• Healthy full term infants– Early postnatal weight gain not associated with better
neurodevelopment
• Preterm infants in NICU– More rapid weight gain in excess of linear growth
(BMI gain) associated with better outcomes
• Few studies of post-NICU growth and neurodevelopment in preterm infants– What are sensitive periods?
– Excess adiposity gain vs. linear growth?• Relevant for obesity outcomes
Growth after term: neurodevelopment
PDI points per z-score gain (95% CI)
Term to 4 months 4 to 12 months
Linear growth 2.0 (0.7, 2.3) 0.3 (-1.1, 1.6)
BMI gain 1.2 (-0.2, 2.5) 0.9 (-0.8, 2.6)
• 613 infants <33 weeks’ gestation (DINO)
• Greater linear growth from term to 4 months associated
with higher Bayley motor score at 18 months
• No benefit of excess weight gain
Belfort et al. Pediatrics 2011
Estimates adjusted for pre-term growth and for maternal and child factors
4/8/2013
17
Growth after term: neurodevelopment
IQ points per z-score gain (95% CI)
Term to 4 months 4 to 12 months
Linear growth 2.4 (1.3, 3.5) 0.2 (-1.1, 1.4)
WFL gain 0.7 (-0.1, 1.6) 2.0 (1.1, 2.9)
• 905 infants ≤37 weeks’ gestation (IHDP)
• Greater linear growth from term to 4 months associated
with higher full scale IQ at 8 years
• No benefit of excess weight gain from term to 4 months
Belfort et al. Pediatrics 2010
Estimates adjusted maternal and child factors
Growth after term: neurodevelopment
Odds ratio (95% CI) IQ <85 vs. ≥85
Term to 4 months 4 to 12 months
Linear growth 0.78 (0.65, 0.95) 1.15 (0.92, 1.44)
BMI gain 1.11 (0.92, 1.33) 0.85 (0.69, 1.06)
• 645 infants ≤37 weeks’ gestation (IHDP)
• Greater linear growth from term to 4 months protective
against low IQ at age 18 years
• No benefit of excess weight gain
Estimates adjusted maternal and child factors
Belfort et al. under review
Growth after term: overweight/obesity at age 8
Odds ratio (95% CI) vs. normal weight
Term to 4 months 4 to 12 months
Linear growth 1.27 (1.05, 1.53) 1.10 (0.89, 1.37)
BMI gain 1.36 (1.14, 1.62) 1.66 (1.33, 2.06)
Belfort et al. under review
• 945 infants ≤37 weeks’ gestation (IHDP)
• Greater linear growth from term to 4 months associated
with higher odds of overweight/obesity
• Excess BMI gain also associated with overweight/obesity
• Results similar at age 18 years
4/8/2013
18
Growth after term: systolic BP at 6.5 yrs
mmHg per z-score gain (95% CI)
Term to 4 months 4 to 12 months
Linear growth 1.2 (0.4, 1.9) -0.4 (-1.3, 0.5)
WFL gain 0.1 (-0.5, 0.7) 0.8 (0.1, 1.4)
Belfort et al. Pediatrics 2010
• 666 infants ≤37 weeks’ gestation (IHDP)
• Greater linear growth from term to 4 months associated
with slightly higher systolic BP
Term to 4 months is sensitive period
for growth of preterm infant
Neurodevelopment Obesity Blood pressure
Linear
growth↑ ↑ ↑
BMI
gain↔ ↑ ↔
Term to 4 months is sensitive period
for growth of preterm infant
Neurodevelopment Obesity Blood pressure
Linear
growth↑ ↑ ↑
BMI
gain↔ ↑ ↔
•Does not appear to be advantage of
promoting excess adiposity gain after term
4/8/2013
19
Term to 4 months is sensitive period
for growth of preterm infant
Neurodevelopment Obesity Blood pressure
Linear
growth↑ ↑ ↑
BMI
gain↔ ↑ ↔
•Does not appear to be advantage of
promoting excess adiposity gain after term
•Linear growth more complicated . . .
Relevance of DOHaD paradigm to the
preterm infant
• Impact of preterm birth on outcome– Neurodevelopment
– Obesity-related / metabolic
– Cardiovascular
• Extent to which early growth/nutrition related to these outcomes – NICU
– After discharge
• Implications for practice– Tradeoffs
Rapid infant linear
growth
CVD & risk factors
•Blood pressure
Neurodevelopment
•Cognition
Adiposity-related
•Obesity
Preterm
4/8/2013
20
Rapid infant linear
growth
CVD & risk factors
•Blood pressure
Neurodevelopment
•Cognition
Adiposity-related
•Obesity
HARM
BENEFIT
Preterm
Rapid infant linear
growth
CVD & risk factors
•Blood pressure
Neurodevelopment
•Cognition
Adiposity-related
•Obesity
HARM
BENEFIT
Preterm
Preterm infant linear growth after term
• Greater linear growth associated with
neurodevelopmental benefit but also
overweight/obesity and higher systolic BP
• Optimal strategy will depend on magnitude of
effect, relative value of outcomes
– Is higher IQ “worth” trading for higher risk of
overweight/obesity and higher systolic BP?
4/8/2013
21
Strengths & Limitations
• Large cohorts of preterm infants– Multiple growth measures in infancy
– IHDP• Outcomes at school age, 18 yrs
• Born in 1980’s, outdated nutritional practices
– DINO• Contemporary cohort
• Outcomes at 18 months
• Growth ≠ nutriWon– Need to study determinants of growth e.g. specific
nutrients (macro, micro), energy
Strengths & Limitations
• BMI ≠ adiposity
– Body composition measures would be better
• Observational design
– Able to control for multiple potential confounders
• Possible residual confounding by unmeasured factors
– Cannot establish causality
• Develop and test hypotheses
• Inform RCT’s
Take home message #1:
Infancy is potentially sensitive window for
prevention of CVD and obesity, and for
enhancing neurodevelopment
Rapid infant
weight gain
CVD & risk factors
•Blood pressure
Neurodevelopment
•Cognition
Adiposity-related
•Obesity
HARM
BENEFIT
4/8/2013
22
Take home message #2:
Balance of risks & benefits depends on
population
• Full term / healthy
– Associations of early postnatal weight gain with
obesity, higher blood pressure
– No association with neurodevelopment
– Balance in favor of pressing need for obesity
prevention strategies
Take home message #2:
Balance of risks & benefits depends on
population
• Preterm
– Promoting rapid BMI gain before term but NOT
after term beneficial to neurodevelopment
– Associations of post-term linear growth with
obesity, blood pressure, AND neurodevelopment
• ‘Optimal’ linear growth pattern not clear
• Further work to incorporate relative value of outcomes
Acknowledgements
IHDP
Marie McCormick
Cami Martin
Vincent Smith
Stephen Buka
Patrick CaseyFunding: R01 HD27344, RWJF 039543,
MCJ060515, 360593,
Pew Charitable Trust 91-01142
DINO
Maria Makrides
Carmel Collins
Robert Gibson
Tom Sullivan
Philip RyanFunding: Australian National Health
and Medical Research Council (grant
250322), Channel 7, Children’s
Research Foundation of S Australia Inc.
Project Viva
Matthew Gillman
Emily Oken
Sheryl Rifas-Shiman
Ken KleinmanFunding: R01 HD 34568, HL 68041
Preterm BP meta
analysis
Femke de Jong
Ruurd van Elburg
Michael Monuteaux
4/8/2013
23
Next steps
• Decision analysis provides quantitative
framework for examining risks/benefits using
data from many sources
• Particularly useful when other study designs
not practical
– Large study
– Multiple outcomes
– Long time frame to assess impact to adulthood
Newborn Preterm Infant
Rapid weight gain
Moderate weight gain
Childoverweight/
obesity
Child high blood
pressure
Childcognitive
advantage
Death or Disability
Coronary Heart
Disease
Adult Cognitive
Advantage
Adult overweight/
obesity
Adult hypertension
Stroke
Adult cognitive
advantage
INFANCY
CHILDHOOD
ADULTHOOD
4/8/2013
24
Pre-term growth and insulin resistance
• Limited data
• Subset (100/163) of young adults in Finnish
VLBW cohort with birth-to-term weight gain
• No evidence for relationship of pre-term
weight gain with insulin resistance
– Did not examine excess adiposity gain vs. linear
growth