Linear Growth and Neurodevelopment

Neonatal Nutrition, Growth and
Neurodevelopment: It's not all
about weight gain!
Sara Ramel, MD
Division of Neonatology
University of Minnesota Masonic Children’s Hospital
Minneapolis, MN
Optimizing Neurodevelopment
Gestational Age
• Understand the impact of linear growth and
FFM gains, as well as weight gain on later
neurodevelopment in preterm infants.
• Discuss the impact of both caloric and
protein intake on later growth and
developmental outcomes in preterm infants,
as well as available methods of fortification
for optimizing outcomes.
Brain Development through
Term Gestation
Brain Development throughout
Infancy and Childhood
Thompson & Nelson, 2001
Critical Periods
• All nutrients are important for brain growth and
• Nutrients that support basic neuronal metabolism and
– Proteins, glucose, specific fats
– Iron, Zinc, Copper, Iodine
• Rapidly developing systems at the time of preterm
– Hippocampus learning and memory
– Myelin speed of processing
– Cerebellum balance, motor integration and cognition
Preterm Infants Undergo Postnatal Growth
• Growth is a marker of
macronutrient status
• Postnatal growth failure
is common among
VLBW infants
– Unable to recover prior
to discharge
– Not restricted to those
extremely small infants
Ehrenkranz et al. Pediatrics 1999
Growth Failure continues to be a
• Growth failure
rates are
• Growth failure
is still a
• Growth failure
is occurring at a
critical time in
Horbar et al. Pediatrics 2015.
Greater Postnatal Weight Gain Benefits
Neurodevelopment in Premature Infants
Any Neurodevelopmental
Bayley Mental
Development Index <70
Development Index <70
Cerebral Palsy
Percent with Outcome at 18 mos
Quartile 1 Quartile 2 Quartile 3 Quartile 4
Ehrenkranz et al., Pediatrics, 2006
Linear Growth in VLBW infants
Ramel SE et al. Neonatology. 2012; 102:19-24.
Linear Growth Failure Studies
• Belfort; birth <33 wks: Mean length z-score (LZ) is 1-SD
below reference population at term and 4 months,
equal to reference by 18 months CGA
• Belfort; birth ≤37 wks: Length remained lower than
reference population out to 18 months CGA
• Ramel; birth AGA <30 wks: Reduction in LZ from birth
to discharge, did not return to baseline by 24 months
Belfort et al. J Pediatr 2013;163(6):1564–9.e2
Belfort et al. Pediatrics 2011;128:e899–906.
Ramel et al. Neonatology 2012;102:19–24.
• 62 AGA VLBW infants (<30
weeks GA)
• Improved linear growth
throughout the first year of
life →Improved
neurodevelopment at 24
• ↑ 1 z-score at discharge =
↑ 8 points (language)
• ↑ 1 z-score at 4 and 12
months = ↑ 4.5 points
Linear Growth and Neurodevelopment
• Infants born <33 weeks (mean=30 weeks)
• Linear growth from term to 4 months CGA associated with
higher motor scores at 18 months
• Infants born ≤37 weeks and LBW (mean=33 weeks and
1800 grams)
• Increased linear growth from term to 4 months CGA,
decreased odds of IQ <85 at 8 and 18 years
• <1250g AGA and SGA infants
• Linear growth from birth to 2 years of age correlated with
PDI and CP
Belfort et al. Pediatrics 2011;128:e899–906.
Belfort et al. J Pediatr 2013;163(6):1564–9.e2
Latal-Hajnal et al. J Pediatr 2003;143(2):163-7.
• Linear growth prior to 1 year of age has the
highest impact on long term
neurodevelopment in preterm
• Critical time period for intervention based on
developmental window of brain.
Thompson and Nelson. American Psychologist. 2001
Body Composition
• Preterm infants have increased adiposity and
decreased FFM at term CGA compared to term
• Abnormal distribution – increased intra-abdominal
fat at term
Ramel et al. JPGN 2011;53(3):333-8.
Johnson et al. Pediatrics 2012; 130 (3):E640-9.
Uthaya et al. Pediatric Research 2005; 57(2):211-5.
FFM Gains and Neurodevelopment
• 16 AGA infants, mean birth GA ~30 weeks
• Body Composition measurements via ADP at
Term and 4 months CA
• Visual pathway assessment via pattern
reversal Visual Evoked Potentials
FFM Gains and Neurodevelopment
• Increased FFM at term and 4 months CGA is
associated with faster speed of visual
processing at 4 months CGA
Bold line = Visual
Evoked Potential in
infant with relatively
high FFM
Dashed line = Visual
Evoked Potential in
infant with relatively
low FFM
From Pfister KM et al. Pediatr Res 2013;74(5):576–83
Birth to Term FFM gains and
• Increased FFM
gains (10gms/wk)=
Improved motor
(2pts) and
cognitive (3pts)
• Increased FM gains
did not improve
Ramel et al. E-PAS 2015:753028.
Manuscript under review.
FFM gains and Neurodevelopment
• FFM gains in preterm
infants (<36 weeks)
from 4 months CA to 4
years were positively
associated with
cognition at 4 years of
• These associations were
not seen in term infants
or for FM changes
Scheurer et al. E-PAS 2015: 752440
Manuscript in preparation
Nutrition Matters!
Weight gain,
Linear Growth
Fat-Free Mass Gains
• Energy intake is the primary determinant of
weight gain
• Carbohydrates (ie. glucose) are the main fuel
source for the brain
• Improved caloric intake associated with
– Increased FFM accretion prior to discharge
– increased FFM accretion at 4 months CGA
– increased linear growth out to 24 months CGA
• Increases in caloric intake NOT associated with
increased FM
Ramel et al. Manuscript under review.
Ramel et al. Neonatology 2012;102:19–24
Ramel et al. JPGN 2011;53(3):333-8
• Diet A: 3.7 g/kg/d of
protein and 129
• Diet B: 4.2 g/kg/d
and 150 kcal/kg/d
• Diet C: 4.7 g/kg/d
and 150 kcal/kg/d
• Similar gains in FFM
to reference fetus
Costa-Orvay et al. J Nutr 2011
• Introduction of new
– Higher max amounts
of protein and IL
– Earlier enteral feeds
and faster more
frequent adjustment
– New prescription
ordering system
• Findings:
– Higher caloric intake
– Improved weight gain
– Improved HC
– Similar % body fat
– Lower rates of sepsis
Energy has an independent effect
on MDI
Every 10 kcal/kg/d increase in
energy during week 1  4.6point increase in MDI on 18
month Bayley
Stephens et al, Pediatrics 2009;123(5):1337-43
• n=76
• Standard nutrient
– term formula
– Un-supplemented DEBM
High nutrient group
Neurologically normal at 8y
MRI (1.5T) – T1 images
– brain volume & segmentation
Isaacs et al Ped Res 2008
• Fats are necessary for efficient neural processing
– Myelin synthesis, cell membrane fluidity, synaptasome
• Fear of providing lipids early
– Lung disease, increased sepsis, thrombocytopenia,
CNS damage, hyperbilirubinemia
– Recent evidence that IL (up to 2-3 g/kg/day) on DOL 1
are well-tolerated by preterm infants
Viaardingerbroek H et al. AJCN 2012
Salama GS et al. Clin Med Insights Pediatr 2015
• 110 VLBW AGA preterm infants (26-32 weeks)
• 0.5 vs 2 g/kg/day IL on first day of TPN
• Experimental group:
– Increased energy intake
– Decreased NEC and ROP
– Increased rate of AGA at discharge
Drenckpohl D. Pediatrics. 2008
• 48 VLBW preterm infants born <28 weeks
• Infants received a mean of 4.2±1.3 grams/kg/day
• Increased lipid intake in first 14 days is associated
with improved DQ at 1 year of age
dit Trolli et al. Early lipid supply and neurological development
at one year in VLBW preterm infants. Early Hum Dev 2012.
• Providing adequate calories promotes
improved growth in weight, length and fatfree mass gains
• Increased calories and lipids provided early
are associated with improved
• Increased calories provided prior to term have
not been associated with increased gains in fat
• Protein is necessary for neurogenesis, dendritic
arborization, synaptogenesis and myelin production
• Protein accretion is indexed by linear growth and FFM
• Historically limited due to safety concerns
• Parenteral amino acid administration of 3-3.5 g/kg/d
on the first day of life is safe and results in increased
protein accretion
– 4.5-5.5g/kg/day on subsequent days are now thought to
be safe and associated with improved linear growth
Ibrahim HM. J Pernatology, 2004.
Thureen PJ. Pediatr Res, 2003.
Olsen IE. JPGN, 2014.
• Cumulative hospital protein deficit negatively associated
with FFM at term and 4 months CGA
• Increased protein provision in first week associated with
increased gains in FFM, not FM, throughout
Ramel et al. JPGN 2011;53(3):333-8
Ramel et al. Manuscript under review
Protein and Growth
• Biasini, 2012: infants 23-30 weeks
– normal vs extra protein supplementation (enteral)
– Improved in-hospital and post*
discharge head and linear growth
– Improved developmental testing
at 3 months CGA
• Olsen, 2014: randomized trial of new fortifier
– High protein group: 4.6-5.5 g/kg/day
– Improved length z-scores without
increased weight z-scores
Biasini et al. J Matern Fetal Neonatal Med, 2012
Olsen et al. JPGN, 2014
Protein intake – independent
effect on MDI
Every 1 g/kg/d increase in
protein during week 1  8.2point increase in MDI on 18
month Bayley
Stephens et al, Pediatrics 2009;123(5):1337-43
• Influence of change in TPN solutions on later
growth and neurodevelopment
• No difference between before and after groups in:
 clinical outcome
 growth z-scores at 4 weeks
 18 month developmental scores
• Levels of protein given were below recommended
levels in both groups
• Enteral protein intake in the first two weeks of life
was positively associated with neurodevelopment
(both cognitive and motor) at 18 months
• Protein provided at 4-4.5 (possibly up to 5.5)
grams/kg/day is safe
• Adequate provision of protein leads to improved
gain in weight, length, head circumference and
• Increased provision of protein is associated with
improved developmental outcomes
Enteral Nutrition:
Breast Milk Fortification
• Breast milk is best…
Immunoprotective properties
Improved developmental outcomes
Improved tolerance and lower rates of NEC
Nutrient content is variable
Nutrient content is insufficient
• Standard vs. Adjustable vs Target Fortification
– Close growth monitoring
– Frequent lab draws
– Breast Milk Analyzers
Adamkin. Clin Perinatol. 2014
Rochow. Current Opinion. 2015
Breast Milk Fortification
Adamkin. Clin Perinatol. 2014
Post-Term Supplementation
• Randomized infants to
fortification at discharge or solely
mom’s milk
• Found improved growth in
weight, length and head
• Improved weight gain and linear
growth persisted throughout the
1st year
• No differences in body
Aimone A. JPGN. 2009
Post-Term Supplementation
• Few studies have
evaluated the influence
of post-discharge
nutrition on
– Improved visual
development at 4 and 6
– No differences on 18
month Bayley
• Multiple Cochrane
– preterm formula and
fortified breast milk after
discharge from the NICU
improve growth, but not
enough evidence for
Post-Term Supplementation
• Reasons??
• ESPGHAN Committee
on Nutrition
– Lack of data
recommends until 40– Continued inadequate
52 weeks in those with
– Inappropriately balanced
suboptimal weight
strategy (energy vs
– Missed the crucial
window for intervening
Aggett P.J. JPGN. 2006
Groh-Wargo. ICAN. 2014
Monitor closely and optimize early!
• Avoid early deficits when able
– Optimize TPN
• Protein and Lipids begin on DOL 1
– Continue TPN while advancing feeds
• Do not stop TPN before fortifying milk
• Monitor growth closely
– Not only weight gain… monitor length, proportionality and
body composition as able
• Increase calories and protein when growth is poor
– Increased nutrition ≠increased fat in preterm neonates
• Consider post-discharge supplementation for at-risk