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4/8/2013

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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)?

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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

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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

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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

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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


preterm infant



– Cardiovascular


– NICU

– After discharge


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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

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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

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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 ↑


preterm infant



– Cardiovascular


– NICU

– After discharge


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preterm infant



– Cardiovascular


– NICU

– After discharge


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

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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



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


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

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preterm infant



– Cardiovascular


– NICU

– After discharge


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

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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



Reference

fetus

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28-29wk

26-27wk

24-25wk



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

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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


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)



preterm infant



– Cardiovascular


– NICU

– After discharge


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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

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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


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

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IQ points per z-score gain (95% CI)


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)



with higher full scale IQ at 8 years

• No benefit of excess weight gain from term to 4 months


Estimates adjusted maternal and child factors


Odds ratio (95% CI) IQ <85 vs. ≥85


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)


• 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


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



with higher odds of overweight/obesity

• Excess BMI gain also associated with overweight/obesity

• Results similar at age 18 years

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Growth after term: systolic BP at 6.5 yrs

mmHg per z-score gain (95% CI)


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)




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↔ ↑ ↔




Linear

growth↑ ↑ ↑

BMI

gain↔ ↑ ↔

•Does not appear to be advantage of

promoting excess adiposity gain after term

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Linear

growth↑ ↑ ↑

BMI

gain↔ ↑ ↔

•Does not appear to be advantage of

promoting excess adiposity gain after term

•Linear growth more complicated . . .


preterm infant



– Cardiovascular

• Extent to which early growth/nutrition related to these outcomes – NICU

– After discharge


Rapid infant linear

growth

CVD & risk factors

•Blood pressure

Neurodevelopment

•Cognition

Adiposity-related

•Obesity

Preterm

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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?

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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

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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


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

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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

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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

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