Growth and neurodevelopmental

outcomes following fetal growth curves

Mandy Brown Belfort, MD MPH
Associate Professor of Pediatrics, Harvard Medical School
Attending Neonatologist, Brigham and Women’s Hospital
Recorded on November 19, 2021
Faculty Disclosures 2

 I have the following financial relationships with a commercial interest to disclose:

 Grant/Research support from:
 National Institutes of Health
 Gerber Foundation
 Allen Foundation
 March of Dimes
 Altigg Therapeutics / National Science Foundation

 I will not discuss off label use and/or investigational use in my presentation.
Guiding question 3

Which growth
chart should I
use?
 4

Why do we use growth charts?

 5

Why do we use growth charts?

Compare
 6

Why do we use growth charts?

Compare Predict
 7

Why do we use growth charts?

Compare Predict
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth

To whom do we compare?
• Reference = how babies “do” grow
(descriptive)
• Standard = how babies “should” grow
(prescriptive)
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth

To whom do we compare?
• Reference = how babies “do” grow
(descriptive)
• Standard = how babies “should” grow
(prescriptive)
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth

To whom do we compare?
• Reference = how babies “do” grow
(descriptive)
• Standard = how babies “should” grow
(prescriptive)
What do we compare?
• Size at birth – fetal growth
• Change over time – postnatal growth

To whom do we compare?
• Reference = how babies “do” grow
(descriptive)
• Standard = how babies “should” grow
(prescriptive)
Full term infant: from reference to standard 15
 Full term infant: from reference to standard 16

• 2002: CDC reference

• 2006: new WHO standard
• Multicenter Growth Reference Study
• 8440 healthy *breastfed* infants
from 6 countries
• Diverse backgrounds & settings
• Recommended for all children
Full term infant: impact 17

Nommsen-Rivers & Dewey Breastfeed Med 2009

 Full term infant: impact 18

• FACT: growth velocity slower in

breastfed vs. formula fed newborns

• CDC reference  growth faltering 

supplement with formula

• WHO standard  normal  carry on

Nommsen-Rivers & Dewey Breastfeed Med 2009

 Full term infant: impact 19

• FACT: growth velocity slower in

breastfed vs. formula fed newborns

• CDC reference  growth faltering 

supplement with formula

• WHO standard  normal  carry on

Nommsen-Rivers & Dewey Breastfeed Med 2009

 Full term infant: impact 20

• FACT: growth velocity slower in

breastfed vs. formula fed newborns

• CDC reference  growth faltering 

supplement with formula

• WHO standard  normal  carry on

Nommsen-Rivers & Dewey Breastfeed Med 2009

Preterm infant: reference fetus as standard 21
Preterm infant: reference fetus as standard 22

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

Ziegler et. al. Growth 1976

Nutrient accretion based on

chemical analysis
Preterm infant: reference fetus as standard 23

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

Ziegler et. al. Growth 1976

Nutrient accretion based on

chemical analysis
Preterm infant: reference fetus as standard 24

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

Ziegler et. al. Growth 1976

Nutrient accretion based on Compare with “reference fetus” defined

chemical analysis by size at birth across GA range
e.g. Olsen 2010, Fenton 2013
Preterm infant: reality 25

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019
Preterm infant: reality 26

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

Edwards et. al. Pediatrics 2021

Preterm infant: reality 27

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

• Marked improvement over time

• Still well below fetal standard

Edwards et. al. Pediatrics 2021

Preterm infant: reality 28

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

• Marked improvement over time

• Still well below fetal standard

Edwards et. al. Pediatrics 2021

Preterm infant: reality 29

Preterm infants “should”

grow like healthy fetus
AAP Pediatric Nutrition 2019

• Marked improvement over time

• Still well below fetal standard

Wrong standard?

Edwards et. al. Pediatrics 2021

Preterm infant: challenge to dogma 30

Villar et. al. Pediatrics 2018

Preterm infant: challenge to dogma 31

“The idea that the growth of preterm infants should match the growth of healthy
fetuses is not substantiated by data and…is seldom attained.”

Villar et. al. Pediatrics 2018

Preterm infant: challenge to dogma 32

“The idea that the growth of preterm infants should match the growth of healthy
fetuses is not substantiated by data and…is seldom attained.”

“A preterm infant is not, in any nutritional, metabolic, or physiologic sense, a fetus

and should not be managed as such in clinical practice.”

Villar et. al. Pediatrics 2018

Preterm infant: challenge to dogma 33

“The idea that the growth of preterm infants should match the growth of healthy
fetuses is not substantiated by data and…is seldom attained.”

“A preterm infant is not, in any nutritional, metabolic, or physiologic sense, a fetus

and should not be managed as such in clinical practice.”

“Throughout the literature, it is stated that standards cannot be produced for

preterm infants because infants born preterm are neither normal nor healthy.”
Villar et. al. Pediatrics 2018
INTERGROWTH-21ST preterm postnatal standards 34

“We believe it is possible to produce standards based on…preterm infants”

Villar et. al. Pediatrics 2018

 INTERGROWTH-21ST preterm postnatal standards 35

“We believe it is possible to produce standards based on…preterm infants”

Fetal Growth Longitudinal Study (n=4321)
• Accurate gestational age
• Healthy mother, uncomplicated pregnancy
• No congenital abnormalities
• No fetal growth restriction (ultrasound)
• 224 preterm infants

Villar et. al. Pediatrics 2018

 INTERGROWTH-21ST preterm postnatal standards 36

“We believe it is possible to produce standards based on…preterm infants”

Fetal Growth Longitudinal Study (n=4321)
• Accurate gestational age
• Healthy mother, uncomplicated pregnancy
• No congenital abnormalities
• No fetal growth restriction (ultrasound)
• 224 preterm infants

Preterm Postnatal Follow-up Study (n=201)

• 86% late preterm (≥34 weeks )
• 14% early preterm (<34 weeks)
• 41% NICU/SCN admission >1 day
• 22% tube feeding or parenteral nutrition
• 10% RDS
• 1 infant with BPD
• 2 infants with feedings held >3 days Villar et. al. Pediatrics 2018
 INTERGROWTH-21ST preterm postnatal standards 37

“We believe it is possible to produce standards based on…preterm infants”

Fetal Growth Longitudinal Study (n=4321)
• Accurate gestational age
• Healthy mother, uncomplicated pregnancy
• No congenital abnormalities
• No fetal growth restriction (ultrasound)
• 224 preterm infants

Preterm Postnatal Follow-up Study (n=201)

• 86% late preterm (≥34 weeks )
• 14% early preterm (<34 weeks)
• 41% NICU/SCN admission >1 day
• 22% tube feeding or parenteral nutrition
• 10% RDS
• 1 infant with BPD
• 2 infants with feedings held >3 days Villar et. al. Pediatrics 2018
Preterm postnatal standard vs. reference fetal standard 38
Preterm postnatal standard vs. reference fetal standard 39

Estimated fetal weight

Preterm postnatal

Fetal ultrasound

Villar et. al. Pediatrics 2018

Preterm postnatal standard vs. reference fetal standard 40

Estimated fetal weight Fenton/Kim WHO

Preterm postnatal Preterm postnatal

Fetal ultrasound Size at birth

Villar et. al. Pediatrics 2018

Preterm postnatal standard vs. reference fetal standard 41

Estimated fetal weight Fenton/Kim WHO

Preterm postnatal Preterm postnatal

Fetal ultrasound Size at birth

Villar et. al. Pediatrics 2018

Preterm postnatal standard vs. reference fetal standard 42

Estimated fetal weight Fenton/Kim WHO

Preterm postnatal Preterm postnatal

Fetal ultrasound Size at birth

Preterm postnatal vs. fetus

• Weight < fetus during preterm period
• Meets WHO standard by ~65 weeks’ PMA
Villar et. al. Pediatrics 2018
Preterm postnatal standard: impact 43
Preterm postnatal standard: impact 44

z-score decline >1 • Korean Neonatal Network

• <28 weeks’ gestation, n=1356
• Lower prevalence of EUGR by Intergrowth vs. Fenton
EUGR

<10th percentile at discharge

EUGR

Kim et. al. Eur J Pediatr 2021

Preterm postnatal standard: impact 45

z-score change >1 • Korean Neonatal Network

• <28 weeks’ gestation, n=1356
• Lower prevalence of EUGR by Intergrowth vs. Fenton
EUGR

<10th percentile at discharge

EUGR

• Infants identified as EUGR by Intergrowth had more morbidities

Kim et. al. Eur J Pediatr 2021

 46

Why do we use growth charts?

Compare Predict
What do we want to predict? 47

• Slower NICU weight gain predicts poorer neurodevelopmental outcome

• Identify faltering growth in NICU, at discharge  intervene
• Potential to improve long-term outcome
Ehrenkranz et. al. Pediatrics 2005
What do we want to predict? 48

• Slower NICU weight gain predicts poorer neurodevelopmental outcome

• Identify faltering growth in NICU, at discharge  intervene
• Potential to improve long-term outcome
Ehrenkranz et. al. Pediatrics 2005
Preterm postnatal standard & outcomes 49

• Size at 2 years comparable to WHO standard

Villar et. al. Am J Obstet Gynecol 2018

Preterm postnatal standard & outcomes 50

• Size at 2 years comparable to WHO standard

• Developmental motor milestones Fetal growth standards

comparable to fetal growth standard cohort Preterm postnatal standards +/-
corrected age

Villar et. al. Am J Obstet Gynecol 2018

Preterm postnatal standard & outcomes 51

• Size at 2 years comparable to WHO standard

• Developmental motor milestones Fetal growth standards

comparable to fetal growth standard cohort Preterm postnatal standards +/-
corrected age

Adequate growth & development at 2 years

supports validity of this standard
Villar et. al. Am J Obstet Gynecol 2018
Which growth chart is better at prediction? 52
Which growth chart is better at prediction? 53

Cordova Ramos et. al. J Pediatr 2020

Which growth chart is better at prediction? 54

• N=613
• Mean GA 28 weeks
• Poor growth defined as decline in
• Weight: >0.8 SD
• HC: >1 SD
• Length: >2 SD

Cordova Ramos et. al. J Pediatr 2020

Which growth chart is better at prediction? 55

• N=613
• Mean GA 28 weeks
• Poor growth defined as decline in • Olsen & Fenton more predictive of low
• Weight: >0.8 SD Bayley scores vs. preterm postnatal
• HC: >1 SD
• Length: >2 SD

Cordova Ramos et. al. J Pediatr 2020

Guiding question 56

Which growth
chart should I
use?
Implications 57

#1 Theory
• Fetal standard = dogma
• Preterm postnatal challenges dogma
• Biologically plausible
• Good outcomes in preterm postnatal
standard supports validity
• Theoretically amazing!
Implications
#1 Theory
• Fetal standard = dogma
• Preterm postnatal challenges dogma
• Biologically plausible
• Good outcomes in preterm postnatal
standard supports validity
• Theoretically amazing!
58
#2 Practice
• Preterm postnatal growth standard available
as alternative to fetal standard
• Limitations:
• Small # of very preterm infants
• Curves start at 27 weeks
• Likely to reduce number of infants identified
as “growth faltering” in NICU, at discharge
• Pro: reduce “overfeeding”
• Con: missed opportunities
Implications 59

#3 Key knowledge gap

• Impact of shift from fetal standard to preterm
postnatal standard on
• Nutrient delivery
• Growth, body composition
• Neurodevelopment, cardiometabolic health
Implications 60

#3 Key knowledge gap

• Impact of shift from fetal standard to preterm
postnatal standard on
• Nutrient delivery
• Growth, body composition
• Neurodevelopment, cardiometabolic health

Most critical for infants <32 weeks who are

vulnerable to early brain injury, the consequences
of which may be offset by nutritional
interventions during the preterm period
MY QUESTIONS FOR YOU: 61

Which growth
chart do you
use? Why?