early childhood neurodevelopment after intrauterine growth...

Early Childhood NeurodevelopmentAfter Intrauterine Growth Restriction:A Systematic ReviewTerri A. Levine, MSca, Ruth E. Grunau, PhDa,b,c, Fionnuala M. McAuliffe, FRCPI, FRCOG, MDd,RagaMallika Pinnamaneni, MRCPI, MRCPCHe,f, Adrienne Foran, MRCPI, FRCPCH, MDe,f, Fiona A. Alderdice, BSSc, PhDa

abstract BACKGROUND AND OBJECTIVE: Children who experienced intrauterine growth restriction (IUGR) maybe at increased risk for adverse developmental outcomes in early childhood. The objective ofthis study was to carry out a systematic review of neurodevelopmental outcomes from6 months to 3 years after IUGR.

METHODS: PubMed, Embase, PsycINFO, Maternity and Infant Care, and CINAHL databases weresearched by using the search terms intrauterine, fetal, growth restriction, child development,neurodevelopment, early childhood, cognitive, motor, speech, language. Studies were eligiblefor inclusion if participants met specified criteria for growth restriction, follow-up wasconducted within 6 months to 3 years, methods were adequately described, non-IUGRcomparison groups were included, and full English text of the article was available. Aspecifically designed data extraction form was used. The methodological quality of includedstudies was assessed using well-documented quality-appraisal guidelines.

RESULTS: Of 731 studies reviewed, 16 were included. Poorer neurodevelopmental outcomesafter IUGR were described in 11. Ten found motor, 8 cognitive, and 7 language delays. Otherdelays included social development, attention, and adaptive behavior. Only 8 includedabnormal Doppler parameters in their definitions of IUGR.

CONCLUSIONS: Evidence suggests that children are at risk for poorer neurodevelopmentaloutcomes following IUGR from 6 months to 3 years of age. The heterogeneity of primaryoutcomes, assessment measures, adjustment for confounding variables, and definitions ofIUGR limits synthesis and interpretation. Sample sizes in most studies were small, and someexamined preterm IUGR children without including term IUGR or AGA comparison groups,limiting the value of extant studies.

aSchool of Nursing and Midwifery, Queen’s University Belfast, Belfast, Northern Ireland; bDepartment of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; cChildand Family Research Institute, Vancouver, Canada; dDepartment of Obstetrics and Gynaecology, School of Medicine and Medical Science, University College Dublin, National Maternity Hospital,Dublin, Ireland; eDepartment of Neonatology, Rotunda Hospital, Dublin, Ireland; and fChildren’s University Hospital, Temple Street, Dublin, Ireland

Ms Levine conducted the systematic review and drafted the initial manuscript; Drs Grunau and McAuliffe supervised the systematic review process and aided in qualityassessment of included studies; Dr Alderdice supervised the systematic review process and aided in quality assessment of included studies; and all authors revised themanuscript critically for important intellectual content and approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2014-1143

DOI: 10.1542/peds.2014-1143

Accepted for publication Oct 1, 2014

Address correspondence to Fiona A. Alderdice, BSSc, PhD, School of Nursing and Midwifery, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast,UK BT9 7BL. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2015 by the American Academy of Pediatrics

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mailto:[email protected]

Intrauterine growth restriction(IUGR) is defined as a significantreduction in fetal growth rateresulting in birth weight in the lowest10th percentile for gestational age(GA).1 IUGR is estimated to occur in5% to 7% of all pregnancies. It isimportant to distinguish betweeninfants who are small for gestationalage (SGA) and those who haveexperienced true IUGR, which isgenerally caused by placentalinsufficiency and is associated withan abnormal umbilical arterypulsatility index on fetal ultrasound.Although some recent studies includeabnormal fetal umbilical artery bloodflow measured with Dopplerultrasound as a requirement todistinguish SGA from IUGR, many donot, and the terms are often usedinterchangeably.

IUGR is associated with significantneonatal and pediatric morbidity andmortality. Approximately 5% to 10%of all pregnancies complicated byIUGR result in stillbirth or neonataldeath,2 and suboptimal fetal growthis responsible for at least 25% of allstillbirths.3 The most commonidentifiable cause of IUGR is placentalinsufficiency. Placentally restrictedfetuses are chronically hypoxemic andhypoglycemic and have increasedblood lactate concentrations.4

Placental factors include abnormaltrophoblast invasion, placentalinfarcts, placenta previa,circumvallate placenta,chorioangiomata, velamentousumbilical cord insertion, andumbilical-placental vascularanomalies.4 Gray et al5 found infarctsand accelerated villous maturationwere present in the placentae of40% of infants with IUGR, ascompared with 11% of controls. Mostinfants with IUGR show an increasedpostnatal growth velocity withcatch-up growth by 2 to 3 years.6

However, because infants withIUGR have feeding problems anddecreased nutritional stores, ∼10%remain susceptible to sustainedgrowth delay.7

The effects of IUGR continue beyondthe neonatal period and may havea profound impact on childdevelopment. The poorest outcomesare seen after severe or early-onsetIUGR, prematurity, or impaired fetalumbilical arterial flow. Althoughseveral follow-up studies indicateneurodevelopmental deficits inchildren with IUGR, these studieshave not been systematicallyreviewed and the quality of theinformation has not been adequatelyassessed. This systematic reviewevaluates the extent to which IUGR isassociated with poorneurodevelopmental outcomes in thefirst 3 years of life.

METHODS

Search Strategy

The search strategy for the includedstudies is outlined in Appendix 1.We conducted a comprehensiveliterature search to identify studiesthrough to March 2014. The searchstrategy involved searching electronicdatabases and inspectingbibliographies of retrieved articles.We searched the PubMed, Embase,PsycINFO, Maternity and InfantCare, and CINAHL databases. Thefollowing search terms were used:intrauterine, growth restriction, childdevelopment, neurodevelopment,early childhood, cognitive, motor,speech, language. An exampleelectronic search strategy can befound in Appendix 1.

Selection of Eligible Studies

The initial database search returned731 studies. After an initial review oftitles and abstracts, 579 articleswere excluded. Abstracts of theremaining 152 studies were thenreviewed, and a further 35 studieswere excluded. Full-text analysis of117 studies was then conducted, andstudies were determined to beineligible if any of the followingapplied: study participants did notmeet specified criteria for IUGR (birthweight ,10th percentile for GA),

follow-up was not at age 6 months to3 years, study methods were notadequately described, non-IUGRcomparison group was not included,or full English text of the article wasnot available. A total of 101 studiesdid not meet the inclusion criteriafollowing full-text analysis and 16were determined to be eligible forinclusion in this review.

Data Extraction and Synthesis

Data were retrieved by usinga specifically designed data-extractionform that included the authors, yearof publication, and location of study;age at assessment; number andgrowth status of study and controlgroup infants; exclusion criteria;measure(s) used; and results.Available summary results werethen tabulated. A descriptivemethodology was chosen, and theresults presented as a narrativesynthesis of the existing literaturerelated to neurodevelopmentaloutcomes of children whoexperienced IUGR.

Quality Assessment

A suitable outline for assessing thequality of evidence relating toprognostics and health outcomes wasused.8 The outline evaluates 6 areasof potential bias: study participation,study attrition, prognostic factormeasurement, outcomemeasurement, confounding factoranalysis, and data analysis. We alsoused the International Society forPharmacoeconomics and OutcomesResearch (ISPOR) retrospectivedatabase checklist9 to evaluate thequality of data sources in the 1retrospective study included in thisreview. The adapted quality-assessment outline can be found inAppendix 2.

RESULTS

Included Studies

A total of 16 studies that assessedearly neurodevelopment of childrenwho had experienced IUGR were

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identified and are summarized inTable 1. Among these 16 studies, 15were prospective cohort studies and1 was retrospective. Most studieswere conducted within developednations: Spain (5); the United States(3); and 1 each from Austria, Brazil,Canada, England, Israel, Guatemala,Mexico, and the Netherlands. Theresults of the quality assessment ofincluded studies can be found inTable 2. In 11 of the 16 includedstudies, neurodevelopmentaloutcomes after IUGR are poorer thanthose after normal intrauterinegrowth.

From 6 Months to 1 Year

Four studies examinedneurodevelopment in children withIUGR between 6 months and 1 year ofage. Two of these studies defined IUGRaccording to low birth weight orfetal abdominal circumference withoutreference to Doppler parameters.10,11

Children with IUGR had higher rates ofneuromotor and neurologicabnormalities than controls at 1 year,although most of the abnormalitieswere mild.10 IUGR was the bestpredictor of neurologic impairment at1 year. Fernandez-Carrocera et al10

also found that children with IUGRscored significantly lower thancontrols on the Bayley Scales of InfantDevelopment, version II (Bayley-II),although both groups scored within1 SD of the mean.10 Roth et al11

defined IUGR as a change in fetalabdominal circumference $1.5 SDbetween the first and last scan,whereas SGA was indicated when fetalabdominal circumference changed,1.5 SD, and found no significantdifferences in neurodevelopmentbetween these groups. Even withoptimum obstetric management,approximately one-third of thecombined SGA and IUGR term fetuseshad experienced some neurologicdamage.11

Two of the 4 studies conducted withchildren between 6 months and1 year of age who experienced IUGRincluded abnormal Doppler

parameters in their definition ofIUGR.12,13 In 1 study, preterm infantswith asymmetric IUGR hadsignificantly lower neurobehavioralscores on the habituation, motorsystem, social-interactive, andattention subscales of the NeonatalBehavioral Assessment Scale at40 weeks when compared with bothcontrols and infants with symmetricIUGR.12 Asymmetric fetal growthrestriction occurs late in pregnancy,and infants show weight reductionbut a less marked length reduction.Although generally considered to bea protective “brain-sparing”mechanism, this study suggestsotherwise. Padilla et al13 comparedpreterm children with and withoutIUGR using the Hammersmith InfantNeurologic Examination and theBayley-II at 1 year of age, and foundno significant differences between thegroups in neurodevelopmentalperformance. Thus, 2 of the 4 studiesassessing neurodevelopmentbetween 6 months and 1 yearindicate that these children are atrisk for delay.

From 1 to 2 Years

Of the 8 studies assessingneurodevelopment from 1 to 2 yearsafter IUGR, 7 indicate that thesechildren are at increased risk of delay.Three of the 8 studies defined IUGRaccording to low fetal weight orabdominal circumference withoutreference to Doppler parameters.Batalle et al14 found cognitive,linguistic, and motor deficits by usingBayley-II. Streimish et al15 found thatonly girls with the most severegrowth restriction were at increasedrisk of neurodevelopmentalimpairment at 2 years corrected ageby using the Bayley-II. Procianoyet al16 assessed SGA and appropriatefor gestational age (AGA) very lowbirth weight (VLBW) infants with andwithout severe IUGR by using theBayley-II and found that althoughboth groups demonstratedneurodevelopmental delay, it was notsignificantly related to severe IUGR.

The other 5 studies conducted withchildren from 1 to 2 years of ageincluded abnormal Dopplerparameters in their definition ofIUGR. Baschat et al17 found that 53%of the children with IUGR in theirstudy had linguistic and motor delayat 2 years, and concluded that GAand birth weight remain thepredominant factors for poorerneurodevelopment in infants withIUGR. Esteban et al18 and Padillaet al19 found motor deficits by usingthe Bayley Scales of Infant andToddler Development, third edition(Bayley-III). Esteban et al18 alsoreported lower scores on the adaptivebehavior subscale of the Bayley-III,which is a parent questionnaire thatevaluates aspects of the child’sbehavior, such as health and safety,self-care, self-direction, andcommunity use. Children with IUGRwere at an increased risk for adversecognitive, linguistic, and motorneurodevelopmental outcomes at2 years as measured by vonBeckerath et al20 by using theBayley-II. In a study of 180 preterminfants with IUGR, abnormalneurodevelopmental outcome at2 years was predicted by low birthweight, fetal acidosis, and placentalvillitis. Neurodevelopment at 2 yearswas normal in 76% of theparticipants, and birth weight .835 gprovided the best prediction ofnormal development.21

From 2 to 3 Years

Four studies assessedneurodevelopment after IUGR inchildren from 2 to 3 years of age.Three of these defined IUGRaccording to low birth weight for GAwithout reference to Dopplerparameters. Children with IUGR weremore likely to be developmentallydelayed at age 3 compared withcontrols, and cephalization index,neonatal risk score, and birth weightwere the clinical parameters mostsignificantly correlated withdevelopmental outcome.22 Villaret al23 found that children with

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TABLE1

Included

Studies

Study

StudyGroup(s)

ComparisonGroup

(s)

Ageat

Assessment

ExclusionCriteria

Results

Summary

Measure(s)

Results

From

6moto

1y

Fernandez-

Carrocera

etal

(2003),

Mexico

IUGR

definedby

weight

,10th

centile

forGA

atbirth,

singletons

with

GA$34

wk

(n=77)

Norm

algrow

thdefinedas

AGA

with

weights

.10th

centile

matched

forGA

with

GA$34

wk

(n=77)

12mo

Genetic

abnorm

alities,

congenital

malform

ations,

congenitalin

utero

infection,

orinborn

errors

ofmetabolism.

Infantswhose

families

migratedfrom

the

MexicoCity

area

and

missed$3follow-up

sessions

ordidnot

completeayearly

evaluation.

IUGR

childrenshow

edsignificant

deficits

inneurom

otor

function

andon

both

the

MentalDevelopm

ent

Indexandthe

Psychomotor

Developm

entIndexof

theBayley-II.

Neurom

otor

24(0.32)**

Human

communication

Language

13(0.17)

Auditive

4(0.05)

Bayley-II

MDI

13(0.22)**

PDI

20(0.33)**

Figueras

etal

(2011),S

pain

Preterm

IUGR

definedby

weight,10th

centile

with

abnorm

alUA

Dopplerborn

before

34wkgestation(n

=62)

Preterm

AGA,

matched

forGA

atdelivery(n

=64)

40(6

1)wk

correctedage

Congenital

malform

ations

including

chromosom

alabnorm

alities

and

infections,p

lacental

histologiccriteriafor

chorioam

nionitis,

infant

deathbefore

40wkcorrectedage,and

1of

thefollowing

neurologic

complications

before

40wkof

corrected

age:seizures,

intraventricular

hemorrhage$

Grade

IIIor

periventricular

leukom

alacia.

Preterm

asym

metric

IUGR

infantshad

significantlylower

neurobehavioral

scores

ontheNB

AS.

Norm

alMCA

Abnorm

alHabituation

6.22

(1.25)

b5.59

(1.53)

Ofthese:

Motor

system

5.40

(0.5)

4.88

(0.82)

Norm

alMCA

(n=29)

Social-interactive

5.55

(1.62)

4.79

(1.76)

Visual

5.23

(1.82)

4.34

(1.87)

Abnorm

alMCA

(n=33)

Auditory

6.00

(1.7)

5.13

(1.74)

Stateorganization

3.97

(0.64)

3.80

(0.83)

Stateregulation

4.09

(1.42)

4.33

(1.45)

Autonomicsystem

5.52

(0.94)

5.50

(1.25)

Attention

5.68

(1.51)

5.11

(1.86)

Padilla

etal

(2010),S

pain

Preterm

severe

IUGR

definedby

anultrasound-estimated

fetalweight,10th

centile

forGA

confirm

edat

birth,

together

with

anabnorm

albloodflow

intheum

bilicalartery

(PI.2SDs)

forGA

(n=37)

Preterm

AGA

matched

for

gender

andGA

atdelivery(n

=36)

12(6

2)mo

correctedage

Chromosom

al,genetic,

orstructural

defects

andsignsof

intrauterine

infection

orneonatal

early-

onsetsepsisas

definedby

positive

bloodculture

within

thefirst72

hof

life

Nosignificant

differences

were

foundusingthe

Hammersm

ithInfant

Neurologic

Exam

inationandthe

Bayley-IIbetween

preterm

childrenwith

andwithoutIUGR.

Bayley-II

MDI

98.8(9.0)b

PDI

91.7(9.9)b

PDI,85,n

(%)

1(2.7)a

MDI

,85,n

(%)

7(18.9)

a


TABLE1

Continued

Study

StudyGroup(s)

ComparisonGroup

(s)

Ageat

Assessment

ExclusionCriteria

Results

Summary

Measure(s)

Results

Roth

etal

(1999),

England

Term

IUGR

asdefinedby

anEFW,10th

centile

forGA

inthethird

trimesterconfirm

edby

repeated

ultrasound

scans,and

achange

inFAC

betweenfirstandlast

scan

greaterthan

–1.5SD

(n=18)

Term

norm

algrow

threferencerange

(n=8)

12mo

Infantsborn

before

36wkof

gestation

Neurodevelopmental

findings

at1ydidnot

differsignificantly.

Neurodevelopmental

assessmentat

1y

Noimpairment

12(66)

SGAdefinedby

anEFW

,10th

centile

forGA

inthethirdtrimester

confirm

edby

repeated

ultrasound

scans,andachange

infetalabdominal

circum

ference

betweenfirstandlast

scan

,1.5SD

(n=49)

Impairment

Withoutdisability

5(28)

With

disability

1(6)

Developm

ental

assessment(Knobloch

etal

1966)

96.8(6.1)

Grossmotor

96.7(10.5)

Fine

motor

97.0(6.1)

Adaptive

97.8(9.0)

Speech

94.1(9.5)

Personal

social

98.2(6.1)

From

1to

2y

Baschatet

al(2009),U

nited

States

IUGR

asdefinedby

FAC

,5thpercentile,

placentaldysfunction

documentedby

anelevated

UAPI(n

=72)

Norm

sfrom

Best

Beginnings

Developm

ental

Screen,C

linical

Adaptive/Clinical

Linguistic

Auditory

MilestoneStage,

Bayley-II

3,6,9,12,18,

and24

mo

Multiplegestation,

deliveryatan

unviable

GA,m

aternaldiabetes,

fetalinfection,

chorioam

nionitis,fetal

anom

alies,abnorm

alfetalkaryotype,

patient

withdraw

aland/or

unavailability

offollow-up

38(53%

)IUGR

infants

had

neurodevelopmental

delayat

twoyears.All

adverseoutcom

eswereconfinedto

neonates

delivered

before

34wkof

gestation.

Significant

differences

were

observed

forbirth

weight,with

adverse

developm

ental

outcom

esconfinedto

neonates

with

abirth

weight,1400

g.

Abnorm

alspeech

developm

ent

20(27.8)

a

Abnorm

almotor

developm

ent

23(31.9)

Cognitive

delay

3(4.2)

Global

delay

17(23.6)

Poor

neurosensory

performance

38(52.8)

Abnorm

alBayley

score

13(18.1)

Batalle

etal

(2012),S

pain

IUGR

definedby

fetal

estim

ated

weight

,10th

centile

accordingto

local

referencestandards

confirm

edat

birth

(n=24)

Norm

algrow

th(10–90th

centile)

accordingto

local

reference

confirm

edat

birthAGA(n

=32)

21(6

3)months

correctedage

Chromosom

al,genetic,

orstructural

defects

andsignsof

intrauterine

infarction

orneonatal

early-

onsetsepsisas

definedby

positive

bloodculture

within

thefirst72

hof

life

IUGR

infantshadpoorer

performance

than

controlson

the

Bayley-II.

Bayley-IIIScores

Cognitive

score

104.3(9.4)*b

Language

score

91.3(12.5)**

Motor

score

100.7(9.6)*

Social-emotional

score

108.6(23.7)

Adaptivebehavior

89.5(18.8)


TABLE1

Continued

Study

StudyGroup(s)

ComparisonGroup

(s)

Ageat

Assessment

ExclusionCriteria

Results

Summary

Measure(s)

Results

Estebanet

al(2010),S

pain

Preterm

,34

wk

gestationIUGR

defined

byan

ultrasound-

estim

ated

fetalw

eight

,10th

centile

forGA

confirm

edat

birth

together

with

abnorm

alDoppler

bloodflow

inthe

umbilical

artery

(n=18)

Term

AGA(n

=15)

18mo

Chromosom

al,genetic,

orstructural

defects

andsignsof

intrauterine

infection

orneonatal

early-

onsetsepsis,any

neonatal

morbidity

Preterm

IUGR

infants

performed

significantlyworse

ontheBayley-III.

Cognitive

score

100.83

(9.27)

Language

score

92.72(12.96)

Preterm

,34

wk

gestationAGAinfants

matched

forGA

(n=15)

Receptive

communication

9.22

(3.07)

Expressive

communication

8.50

(2.64)

Motor

score

93.72(17.31)*

Fine

motor

score

8.83

(3.05)*

Grossmotor

score

9.28

(3.69)

Social

emotional

score

116.39

(24.18)

Adaptivebehavior

score

94.78(13.97)*

Padilla

etal

(2011),S

pain

Preterm

with

severe

IUGR

diagnosed

before

34wk

gestationanddefined

byfetalweight,10th

percentileforGA

confirm

edat

birth

andan

abnorm

alDopplerbloodflow

intheum

bilical

artery

(PI.2SD)(n

=18)

Term

healthyAGA

(n=15)

IUGR:17.83

(66.04)mo

correctedage

Chromosom

al,genetic,

orstructural

defects,

signsof

intrauterine

infection,

neonatal

early-onsetsepsis

IUGR

childrenhad

significantlylower

scores

onthe

Bayley-III.

Cognitive

100.83

(9.27)

b

Language

92.72(12.96)

Preterm

AGA(10–90th

centile)matched

for

GAat

delivery(n

=15)

Preterm:19.20

(66.08)mo

correctedage

Receptive

9.22

(3.07)

Expressive

8.50

(2.64)

Term

:19.67

(63.97)mo

correctedage

Motor

93.72(17.31)

Fine

Motor

8.83

(3.05)*

Grossmotor

9.28

(3.69)*

Social

emotional

116.39

(24.18)

Adaptivebehaviors

94.78(13.97)


TABLE1

Continued

Study

StudyGroup(s)

ComparisonGroup

(s)

Ageat

Assessment

ExclusionCriteria

Results

Summary

Measure(s)

Results

Procianoyet

al(2009),B

razil

PretermVLBW

(,1500

g)(n

=96):

Preterm

VLBW

AGA

(birth

weight

10–90th

centile

forGA)(n

=41)

8,12,18,and

24mo

correctedage

Chromosom

alabnorm

alities

ormajor

malform

ations

that

cause

neurodevelopmental

delay,deathbefore

24mo,deafness,

blindness

Assessed

SGAandAGA

VLBW

infantswith

and

withoutsevere

IUGR

usingtheBayley-IIand

foundthat

although

thesegroups

demonstrated

neurodevelopmental

delay,itwas

not

significantly

correlated

with

severe

IUGR.

Bayley-II

MDI,8

mo

78.26

2.2b

Ofthese,preterm

VLBW

SGA(birth

weight

,10th

centile

forGA)

(n=55)

PDI,8mo

77.16

3.5

MDI,12mo

80.16

2.6

PDI,12

mo

80.16

2.7

MDI,18mo

82.16

2.5

PDI,18

mo

83.36

3.1

MDI,24mo

84.06

3.1

PDI,24

mo

85.46

4.0

Streimishet

al(2012),U

nited

States

IUGR

(n=292):b

irth

weightgrow

th-

restricted

asdefined

bySGAaccordingto

birthweightcurves

(n=183),fetalweight

grow

th-restricted

definedby

SGAon

estim

ated

fetalw

eight

curves

butAGAon

birthweightcurves

(n=109)

Norm

algrow

th(n

=1214)

24mocorrected

age

Maternalinfection,

preterm

prem

ature

ruptureof

mem

branes,

chromosom

alabnorm

alities,fetal

deaths,twins/triplets,

andmajor

congenital

anom

alies

B-SGAbutnotF-SGAgirls

wereat

anincreased

risk

ofalow

psychomotor

developm

entindexon

theBayley-II,b

utonly

girlswith

themost

severe

IUGR

wereat

anincreasedrisk

ofneurodevelopmental

impairment.

Bayley-II

MDI

,70

B-SGA

F-SGA

Developm

entally

assessed

IUGR

(n=193):birth

weight

grow

th-restricted

(n=106),fetalweight

grow

th-restricted

(n=87).

Developm

entally

assessed

norm

algrow

th(n

=910)

Boys

2.6(1.2,5.6)*d

1.5(0.6,3.5)

Girls

1.4(0.6,3.3)

1.8(0.8,4.1)

PDI,70

Girls

3.2(1.6,6.5)*

1.9(0.9,4.0)

Boys

2.6(1.1,5.8)*

2.2(1.02,4.7)*

Torrance

etal

(2010),

Netherlands

Preterm

(,34

wk)

IUGR

definedby

birth

weight,10th

percentileforGA

and

antenatalU

API.2SD

from

thereference

rangemean(n

=180)

Developm

ental

quotient

(Griffiths)

and

mental

developm

ental

index(Bayley-II)

norm

s

GriffithsMental

Developm

ent

Scaleat

18and24

moor

Bayley

Scales

ofInfant

Developm

ent-

IIat

24mo

Maternalinfection,

preterm

prem

ature

ruptureof

mem

branes,

chromosom

alabnorm

alities,fetal

deaths,twins/triplets,

andmajor

congenital

anom

alies

Abnorm

alneurodevelopmental

outcom

ewas

predictedby

lowbirth

weight,fetalacidosis,

andplacentalvillitis.

Neurodevelopment

was

norm

alin

76%

oftheparticipants,and

birthweightgreater

than

835gprovided

thebest

predictionof

norm

aldevelopm

ent.

Neurodevelopment

Abnorm

alcranial

ultrasound

26/127

(20.5%

)

Abnorm

alneurological

exam

inationat

term

60(33.3)

c

Survivinginfantsat

2y

156(86.7)

Abnorm

alneurological

exam

inationat

2y

37/156

(23.7%

)

Cerebral

palsy

1(0.6)


TABLE1

Continued

Study

StudyGroup(s)

ComparisonGroup

(s)

Ageat

Assessment

ExclusionCriteria

Results

Summary

Measure(s)

Results

vonBeckerath

etal

(2013),

Austria

Perinatally

analyzed

born

after23

wkwith

birth

weightof

#2500

gand,10th

percentile

forGA.IUG

Rdefined

bypresence

ofdistinct

signsof

placentalinsufficiency

such

aspathologic

Dopplerwaveformsin

theum

bilical

ormiddlecerebral

artery

aswellas

acerebroplacental

Dopplerratio

below1

(n=219),long-term

analyzed

IUGR

(n=146)

Perinatally

analyzed

born

after23

wk

with

birthweight

of#2500

gand

below10th

percentileSGA

(n=299),long-

term

analyzed

(n=215)

24mo

Severe

structural,

genetic,orfunctional

fetalanom

alies

retrospectively

excluded

Comparedwith

6%of

SGAcontrols,25%

ofIUGR

childrenwereat

anincreasedrisk

for

adverse

neurodevelopmental

outcom

es.

Neurodevelopmental

outcom

eNorm

al110(75.34)

Abnorm

al36

(24.66)****

Gradeof

disability

Mild

22(15.07)****

Moderate

8(5.48)

Severe

6(4.11)**

Impaired

domain

Motor

20(13.70)***

Speech

22(15.07)***

Cognition

17(11.64)****

From

2to

3y

Amin

etal

(1997),

Canada

IUGR

definedby

birth

weight.2SD

below

themeanforGA

(n=

52),30

63wGA,842

6232gbirthweight

Birthweight-

matched

AGA,

266

2wGA,872

6201gbirth

weight(n

=55)

4,8,12,18,and

36mo

correctedage

Chromosom

alabnorm

alities,

congenital

intrauterine

infections,and

major

congenital

malform

ations

orsyndromes

Nosignificant

differences

inneurodevelopmental

outcom

esin

IUGR

children.

Persistence

ofmicrocephalywas

associated

with

more

adverse

neurodevelopmental

outcom

es.

Mentaldisability

6(11.5)*a

Abnorm

alspeech

at18

mo

8(15.4)

Infantswith

birthweight

andbirthhead

circum

ference.2SD

belowthemeanfor

GAwereconsidered

tohave

symmetricIUGR.

GA-matched

AGA,

296

2wGA,1094

6142gbirth

weight(n

=56)

Abnorm

alspeech

at36

mo

11(21.2)

Major neurodevelopmental

disabilitiesat

18mo

6/52

(11.5)

Major neurodevelopmental

disabilitiesat

36mo

8/52

(15.4)

Microcephalyandmajor

neurodevelopmental

disabilitiesat

18mo

7/17

(41.2)

Microcephalyandmajor

neurodevelopmental

disabilitiesat

36mo

8/18

(44.4)


TABLE1

Continued

Study

StudyGroup(s)

ComparisonGroup

(s)

Ageat

Assessment

ExclusionCriteria

Results

Summary

Measure(s)

Results

Fattal-Valevski

etal

(1999),

Israel

IUGR

definedby

birth

weightbelowthefifth

centile

forGA,

vascular-inducedas

indicatedby

late

onsetandasym

metric

brain-body

ratio,

supportedby

pathologicstudiesof

theplacentas,which

revealed

placental

pathologyin

more

than

85%

ofcases

(n=85)

AGA(n

=42)

36mo

Genetic

syndromes,

major

malform

ation,

orcongenital

infection.

IUGR

childrenweremore

likelyto

bedevelopm

entally

delayed,and

cephalizationindex,

neonatal

risk

score,

andbirthweightwere

theclinical

parametersmost

significantly

correlated

with

developm

ental

outcom

e.

Neurodevelopment,%

optim

alitems

89.06

9.0***

31%

werepreterm.

36%

werepreterm.

Stanford-Binet

IntelligenceScale

94.96

16.4

Llurba

etal

(2013),U

SABorn

after28

wk

gestationIUGR

defined

bybirthweight,10th

centile

andabnorm

alprenatal

UAor

ICA

Dopplerfindings

(n=87)

SGAborn

after28

wk

gestationwith

norm

alprenatal

Dopplerfindings

(n=122)

3and6y

correctedage

Multiplegestations,fetal

congenitalor

chromosom

alabnorm

alities

orsuspected

intrauterine

infection

Abnorm

alprenatal

umbilical

artery

and

internalcarotid

artery

Dopplerfindings

were

notassociated

with

lower

developm

ental

scores

inlowbirth

weightchildren

delivered

inthethird

trimesterof

pregnancy.

Stanford-Binet

IntelligenceScaleat

3y(n

=209)

IUGR

SGA

n87

122

Totalscore

108.26

22110.36

23Score,85

9(10.3)

13(10.7)

Unable

toperform

2+areasof

SBIS

5(5.7)

2(1.6)

Villaret

al(1984),

Guatem

ala

Full-term

IUGR

definedby

birthweight,10th

centile

forGA,w

ithlowponderal

index

(IUGR-LPI)(n

=21)

Full-term

norm

alweight(10–90th

centile)(n

=146)

36mo

Seriousneonatal

illness

orcongenital

malform

ations,infant

born

before

37wk

gestation,

infant

with

birthweight.90th

percentile,mothers

notknow

ingthedate

oftheirlastmenstrual

period

At24

mo,theIUGR-API

infantsscored

below

theothers

onmental

items.At

3y,theIUGR-

APIinfantshadthe

lowestvalues

on7/8

developm

ental

measuresandon

the

composite

score.

Controls(n)

IUGR-LPI

(n)

IUGR-API

(n)

Perceptual/problem

-solving

Full-term

IUGR

definedby

birthweight,10th

centile

forGA,w

ithadequate

ponderal

index(IU

GR-API)

(n=38)

Embedded

figures

7.76

0.5(110)

6.96

1.2(20)

9.76

0.6(25)

Impossible

puzzle

persistence

10.76

0.3(110)

10.66

0.7(20)

6.26

0.6(25)

Discrimination

learning

15.26

1.1(107)*

12.262.6(19)

9.96

2.3(24)*

Mem

ory

Digitspan

12.560.7(105)*

8.06

1.7(16)*

9.46

1.4(25)*

Sentence

span

16.061.2(108)*

11.762.9(18)

9.16

2.5(25)*

Mem

oryforobjects

2.26

0.1(104)

2.06

0.3(17)

1.76

0.2(23)

Verbal

facility

Namingvocabulary

8.56

0.3(110)**

7.86

0.8(19)

6.16

0.7(25)**

Vocabulary

recognition

21.160.4(110)

20.161.0(19)

19.66

0.9(25)

API,adequate

ponderalindex;B-SGA,sm

allforgestationalageat

birth;EFW,estimated

fetalw

eight;FAC,fetalabdom

inalcircum

ference;F-SGA,sm

allforgestationalageas

fetus;LPI,lowponderalindex;MCA,m

iddlecerebralartery;M

DI,M

ental

Developm

entIndexof

theBayley

Scales

ofInfant

Developm

entII;NB

AS,N

eonatalBehaviourAssessmentScaleNS,N

otsignificant;PDI,Psychom

otor

Developm

entIndexof

theBayley

Scales

ofInfant

Developm

entII;SBIS,Stanford-BinetIntelligence

Scale.*P

,.05,**P,

.01,***P

,.001,****P

,.0001.


TABLE2

Summaryof

Quality

Assessmentof

Included

Studies

PotentialBias

andDomains

Addressed

Amin

etal

Baschat

etal

Batalle

etal

Esteban

etal

Fattal-

Valevski

etal

Fernandez-

Carrocera

etal

Figueras

etal

Llurba

etal

Padilla

etal

(2010)

Padilla

etal

(2011)

Procianoy

etal

Roth

etal

Streimish

etal

Torrance

etal

Villar

etal

Von

Beckerath

etal

Data

source

a

1.Rationaleforusingdata

source

defined

NRNR

NRNR

NRNR

NRNR

NRNR

NRNR

NRNR

NR∼

2.Reliability/validity

described

3.Linkages

betweensources

detailed

Studyparticipationb

++

++

++

++

++

++

++

∼+

4.Source

populationclearly

defined

5.Studypopulationdescribed

6.Studypopulationrepresents

source

populationor

populationof

interest

Studyattrition

b∼

∼2

2+

∼+

++

+2

+2

22

27.Completenessof

follow-up

described

8.Completenessof

follow-up

adequate

Prognosticfactor

measurementb

++

++

++

++

++

++

++

++

9.Prognosticfactorsdefined

10.Prognostic

factorsmeasured

appropriately

Outcom

emeasurementb

++

++

++

++

++

++

++

++

11.O

utcomedefined

12.O

utcomemeasured

appropriately

Confoundingmeasurementand

accountb

++

++

2+

++

++

++

+2

++

13.Confounders

definedand

measured

14.Confounding

accountedfor

Analysisb

++

++

++

++

++

++

++

++

15.Analysisdescribed

16.Analysisappropriate

17.Analysisprovides

sufficient

presentationof

data

+,yes;2,no;∼,partly;N

R,notrelevant.

aISPORchecklistforretrospectivedatabase

studies.9

bGuidelines

forAssessingQuality

inPrognosticStudies.8


asymmetric IUGR scored lower thancontrols, whereas children withsymmetric IUGR scored lower onmental items at 2 years and had thelowest values on 7 of 8developmental measures and on thecomposite score at 3 years. Aminet al24 found no significantdifferences in neurodevelopmentaloutcomes at 3 years between childrenwho had experienced IUGR andmatched controls, althoughpersistence of microcephaly wasassociated with a more adverseneurodevelopmental outcome.

The fourth study, which differentiatedbetween infants with IUGR andinfants who were SGA by usingabnormal umbilical artery or internalcarotid artery Doppler findings, didnot find a difference in developmentalscores on the Stanford-BinetIntelligence Scale at 3 years.25 Thus, 2of the 4 studies available to date thatassess early childhoodneurodevelopment after IUGRidentified these children as at risk fordelay, particularly in the incidence ofasymmetric growth restriction.

Quality Assessment of Studies

Our assessment of the quality ofstudies included in this review usingthe ISPOR Retrospective DatabaseChecklist9 and guidelines forassessment of prognostic studies8 issummarized in Appendix 2. Onestudy20 used an existing data set, butdid not fully outline the qualityassessment of the original datasources. Nonstandardized outcomemeasures increased the possibility ofmeasurement bias and madecomparability between studiesproblematic. Adjustment forpotentially confounding perinatal,maternal, and socioeconomic factorsand neonatal and childhoodcomorbidities was inadequatelyoutlined in 2 of the 16 studies.21,22

Although the number of participantslost to follow-up was generallyrecorded, attempts to collectinformation on participants whodropped out of the study, reasons for

loss to follow-up, and keycharacteristics of participants lost tofollow-up were adequately describedin only 6 of the 16studies.11–13,19,22,25 Eight studiesused fetal or birth weight orabdominal circumference to defineIUGR without reference to Dopplerparameters,10–16,22–24 and 8 requiredabnormal Dopplerparameters.12,13,17–21,25

DISCUSSION

This systematic review identified 16studies that evaluated earlychildhood neurodevelopment up to3 years after IUGR: 4 of the studieswere conducted with childrenbetween 6 months and 1 year of age,8 up to 2 years, and 4 up to 3 years.Eleven of the 16 included studiesreported poorerneurodevelopmental outcomes inthese children. Ten of these 11studies found motor delay, 8 foundcognitive delay, and 7 foundlanguage delay. Esteban et al18 alsoreported reduced adaptive behaviorskills, including self-care, self-direction, and community use.Neonatal risk factors associated withneurodevelopmental delay afterIUGR were low birth weight, fetalacidosis, and placental villitis. Onestudy found that only girls with themost severe growth restriction wereat increased risk ofneurodevelopmental impairment at2 years.15 This finding suggests thatit may be useful to attend moreclosely to the potential influence ofgender. Interestingly, 2 studies foundthat asymmetric IUGR, generallyconsidered to be a protective, brain-sparing mechanism, preceded moreadverse neurodevelopmentaloutcomes.12,23 Four studies12,16,19,21

examined neurodevelopmentaloutcomes in preterm infants afterIUGR without includinga comparison group of term IUGRinfants, which makes it difficult todetermine whether growth or GAhad a more significant detrimental

effect on the neurodevelopmentaloutcomes of the children in thesestudies.

Eight of the 16 studies includedabnormal Doppler ultrasoundparameters in their definition ofIUGR: 2 were conducted from6 months to 1 year, 5 up to 2 years,and 1 up to 3 years of age. Six of these8 studies found that children are atincreased risk of neurodevelopmentaldelay after IUGR, whereas 5 of the 8studies that did not include Dopplerparameters in their definitions ofIUGR found significant differences inneurodevelopmental outcomes afterIUGR. Within the context of thisreview, it is difficult to determinewhether including Dopplerparameters in the definition of IUGRallows for more sensitivity indetecting differences in earlychildhood neurodevelopmentaloutcomes. Increasingly, research intoneonatal outcomes indicates thata stricter definition of IUGR thatrequires abnormal Dopplerultrasound parameters as well asestimated fetal weight ,3rd centile isimportant.26 In 1 study of 1116fetuses, abnormal Doppler wassignificantly associated with adverseobstetric and neonatal outcomes,regardless of estimated fetal weightor abdominal circumferencemeasurements.26 Additional researchis required to determine whetherrequiring stricter diagnostic criteriafor IUGR may lead to more effectiveresource allocation, better pregnancyoutcomes, or improvedneurodevelopmental outcomes inearly childhood.

Although it was beyond the remit ofthis systematic review, studiesdemonstrate that theseneurodevelopmental delays continueinto later childhood. Preterm childrenwith IUGR scored lower on verbal IQand full-scale IQ tests at 5 to 8 yearsin 1 study than preterm or termchildren who were AGA.27 Thesedeficits were more marked in boysthan in girls, but remained significant


regardless of parental education, GA,or neonatal morbidity. Leitner et al28

found significant differences ingrowth parameters,neurodevelopmental scores, and IQat 6 years in children with IUGR,which were best predicted by weight,height, and neonatal risk scores.These children presented witha specific profile of difficulties,including spatial and graphomotorskills, lateralization, coordinationproblems,28 and inferior spatialorientation abilities29 that wereassociated with lower academicachievements at 9 to 10 years.30 Gevaet al31 found that children with IUGRhad lower IQs and moreneuropsychological difficulties at9 years, including difficulties withlanguage, creativity, and executivefunctioning that are believed toindicate frontal lobe dysfunction, andshort-term memory problems thataffected serial verbal processing andsimultaneous processing ofvisuospatial stimuli.32,33 Learningdisabilities, lower academicachievements, and difficulties withverbal knowledge, reading decodingand comprehension, and arithmetichave been found in children withIUGR, as well as a correlationbetween head circumference and IQscores at most ages.31 Long-termneurodevelopmental outcomes afterIUGR have not been systematicallyreviewed; however, research to dateindicates that these children are atgreater risk of delay into laterchildhood and adolescence.

The recent availability ofneuroimaging data for children withIUGR is particularly interesting andcan be a useful augmentation toclinical neuropsychologicalassessments. Several studies havereported specific structural andfunctional consequences ofIUGR.14,34–36 In 3 studies,14,17,18

imaging results correlated withlower neurodevelopmentalassessment scores in children withIUGR. Another area requiring furtherresearch is the development of

interventional strategies to improvethe outcomes of these children. Oneinterventional strategy that hasshown promise is the NewbornIndividualized Developmental Careand Assessment Program.37

Participation of preterm infants withIUGR in this program improved self-regulation and motor function anddecreased motor stress signals.Whether benefits of this interventionpersist into childhood, and whetherother strategies may be beneficial,remains to be evaluated.

This systematic review has severallimitations. The heterogeneity ofprimary outcome and assessmentchoices, adjustment for confoundingvariables, and definition of IUGRused in these studies limits thesynthesis and interpretation of thecurrent literature. Sample sizes inmost of the included studies weresmall and thus had low power todetect meaningful differencesbetween groups; only 3studies15,20,21 included more than100 children with IUGR. These 3studies all found significantdifferences in early childhoodneurodevelopmental outcomes afterIUGR. The definition of IUGR variedconsiderably across studies, rangingfrom fetal or birth weightrequirements in the lowest 3rd to10th percentiles or reducedabdominal circumferences toabnormal Doppler parameters. It isalso possible that a number of theoriginal studies had selection bias.For example, Procianoy et al16

selected their samples from withina VLBW group. Arnold et al38 foundthat if a cohort is defined primarilyby birth weight, this leads toconfounding of growth status andmaturity (or GA). In studiesassessing the impact of fetal growth,cohorts should be based primarilyon GA, with groups differing bygrowth status, rather thanintroducing a more arbitrary birthweight criterion. Neglecting toinclude abnormal Dopplerparameters in the definition of IUGR

results in a failure to differentiatebetween infants who arepathologically growth-restrictedand those who are merely SGA.Similarly, many studies examineinfants with IUGR born pretermwithout including term IUGR orterm AGA comparison groups. Thelack of term infants with IUGR asa comparison group in studiesexamining preterm infants withIUGR13 or neglecting to comparesubgroups of infants with IUGR atfollow-up with infants whoexperienced normal intrauterinegrowth5 also limits the value ofthese studies.

CONCLUSIONS

IUGR is a major public healthproblem that can increase the risk ofdeveloping diabetes, hypertension,stroke, and coronary heart diseasein later life. The purpose of thisreview was to identify whetherIUGR also predicts significantneurodevelopmental delay inearly childhood from 6 months to3 years of age. The 16 studiesreviewed here indicate that IUGRoften results in neurodevelopmentaldelay. However, IUGR itself isinconsistently defined acrossstudies and often is usedinterchangeably with SGA, whichis merely an indication of size andnot of the placental insufficiencyfundamental to IUGR etiology. Due inpart to inconsistent differentiationamong infants with IUGR, infants whoare SGA, and extremely low birthweight infants, findings differ acrossstudies. Further follow-up studieswould be helpful to expand existingknowledge of the effects of IUGRon neurodevelopment in earlychildhood, but it is essential tostandardize definitions, study designs,and outcome measures. Moreover,there is a great need for additionalneuroimaging data and thedevelopment of interventions designedto improve neurodevelopmentaloutcomes in children who haveexperienced IUGR.


FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Ms Levine receives a PhD studentship from Queen’s University Belfast in Northern Ireland.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

REFERENCES

1. Alfirevic Z, Neilson JP. Dopplerultrasonography in high-riskpregnancies: systematic review withmeta-analysis. Am J Obstet Gynecol.1995;172(5):1379–1387

2. McIntire DD, Bloom SL, Casey BM, LevenoKJ. Birth weight in relation to morbidityand mortality among newborn infants.N Engl J Med. 1999;340(16):1234–1238

3. Morrison I, Olsen J. Weight-specificstillbirths and associated causes ofdeath: an analysis of 765 stillbirths. Am JObstet Gynecol. 1985;152(8):975–980

4. McMillen IC, Adams MB, Ross JT, et al.Fetal growth restriction: adaptations andconsequences. Reproduction. 2001;122(2):195–204

5. Gray PH, O’Callaghan MJ, Harvey JM,Burke CJ, Payton DJ. Placental pathologyand neurodevelopment of the infant withintrauterine growth restriction. DevMed Child Neurol. 1999;41(1):16–20

6. Karlberg J, Jalil F, Lam B, Low L, YeungCY. Linear growth retardation in relationto the three phases of growth. Eur JClin Nutr. 1994;48(suppl 1):S25–S43,discussion S43–S44

7. Lee PA, Chernausek SD, Hokken-KoelegaAC, Czernichow P; International Small forGestational Age Advisory Board.International Small for Gestational AgeAdvisory Board consensus developmentconference statement: management ofshort children born small for gestationalage, April 24-October 1, 2001. Pediatrics.2003;111(6 pt 1):1253–1261

8. Hayden JA, Côté P, Bombardier C.Evaluation of the quality of prognosisstudies in systematic reviews. Ann InternMed. 2006;144(6):427–437

9. Motheral B, Brooks J, Clark MA, et al.A checklist for retrospective databasestudies—report of the ISPOR Task Forceon Retrospective Databases. ValueHealth. 2003;6(2):90–97

10. Fernandez-Carrocera LA, Chavez-TorresR, Casanueva E, Barrera-Reyes RH,Ibarra-Reyes MP, Martinez-Cruz C.Intrauterine growth retardation and

neurodevelopment at one year of age inMexican children. Nutr Res. 2003;23:1–8

11. Roth S, Chang TC, Robson S, Spencer JA,Wyatt JS, Stewart AL. Theneurodevelopmental outcome of terminfants with different intrauterinegrowth characteristics. Early Hum Dev.1999;55(1):39–50

12. Figueras F, Cruz-Martinez R, Sanz-CortesM, et al. Neurobehavioral outcomes inpreterm, growth-restricted infants withand without prenatal advanced signs ofbrain-sparing. Ultrasound ObstetGynecol. 2011;38(3):288–294

13. Padilla N, Perapoch J, Carrascosa A,Acosta-Rojas R, Botet F, Gratacós E.Twelve-month neurodevelopmentaloutcome in preterm infants withand without intrauterine growthrestriction. Acta Paediatr. 2010;99(10):1498–1503

14. Batalle D, Eixarch E, Figueras F, et al.Altered small-world topology ofstructural brain networks in infants withintrauterine growth restriction and itsassociation with laterneurodevelopmental outcome.Neuroimage. 2012;60(2):1352–1366

15. Streimish IG, Ehrenkranz RA, Allred EN,et al; ELGAN Study Investigators. Birthweight- and fetal weight-growthrestriction: impact onneurodevelopment. Early Hum Dev. 2012;88(9):765–771

16. Procianoy RS, Koch MS, Silveira RC.Neurodevelopmental outcome ofappropriate and small for gestationalage very low birth weight infants. J ChildNeurol. 2009;24(7):788–794

17. Baschat AA, Viscardi RM, Hussey-GardnerB, Hashmi N, Harman C. Infantneurodevelopment following fetalgrowth restriction: relationship withantepartum surveillance parameters.Ultrasound Obstet Gynecol. 2009;33(1):44–50

18. Esteban FJ, Padilla N, Sanz-Cortés M,et al. Fractal-dimension analysis detectscerebral changes in preterm infantswith and without intrauterine growth

restriction. Neuroimage. 2010;53(4):1225–1232

19. Padilla N, Falcón C, Sanz-Cortés M, et al.Differential effects of intrauterinegrowth restriction on brain structureand development in preterm infants:a magnetic resonance imaging study.Brain Res. 2011;1382:98–108

20. von Beckerath A, Kollmann M, Rotky-FastC, Karpf E, Lang U, Klaritsch P. Perinatalcomplications and long-termneurodevelopmental outcome of infantswith intrauterine growth restriction. AmJ Obstet Gynecol. 2013;208(2):130.e1–e6

21. Torrance HL, Bloemen MC, Mulder EJ,et al. Predictors of outcome at 2 years ofage after early intrauterine growthrestriction. Ultrasound Obstet Gynecol.2010;36(2):171–177

22. Fattal-Valevski A, Leitner Y, Kutai M, et al.Neurodevelopmental outcome inchildren with intrauterine growthretardation: a 3-year follow-up. J ChildNeurol. 1999;14(11):724–727

23. Villar J, Smeriglio V, Martorell R, BrownCH, Klein RE. Heterogeneous growth andmental development of intrauterinegrowth-retarded infants during the first3 years of life. Pediatrics. 1984;74(5):783–791

24. Amin H, Singhal N, Sauve RS. Impact ofintrauterine growth restriction onneurodevelopmental and growthoutcomes in very low birthweightinfants. Acta Paediatr. 1997;86(3):306–314

25. Llurba E, Baschat AA, Turan OM, HardingJ, McCowan LM. Childhood cognitivedevelopment after fetal growthrestriction. Ultrasound Obstet Gynecol.2013;41(4):383–389

26. Unterscheider J, Daly S, Geary MP, et al.Optimizing the definition of intrauterinegrowth restriction: the multicenterprospective PORTO study. Am J ObstetGynecol. 2013;208(4):290.e1–e6

27. Morsing E, Asard M, Ley D, Stjernqvist K,Marsál K. Cognitive function afterintrauterine growth restriction and very


preterm birth. Pediatrics. 2011;127(4).Available at: www.pediatrics.org/cgi/content/full/127/4/e874

28. Leitner Y, Fattal-Valevski A, Geva R, et al.Six-year follow-up of children withintrauterine growth retardation: long-term, prospective study. J Child Neurol.2000;15(12):781–786

29. Leitner Y, Heldman D, Harel S, Pick CG.Deficits in spatial orientation of childrenwith intrauterine growth retardation.Brain Res Bull. 2005;67(1-2):13–18

30. Leitner Y, Fattal-Valevski A, Geva R, et al.Neurodevelopmental outcome ofchildren with intrauterine growthretardation: a longitudinal, 10-yearprospective study. J Child Neurol. 2007;22(5):580–587

31. Geva R, Eshel R, Leitner Y, Valevski AF,Harel S. Neuropsychological outcome ofchildren with intrauterine growth

restriction: a 9-year prospective study.Pediatrics. 2006;118(1):91–100

32. Geva R, Eshel R, Leitner Y, Fattal-ValevskiA, Harel S. Verbal short-term memoryspan in children: long-term modalitydependent effects of intrauterine growthrestriction. J Child Psychol Psychiatry.2008;49(12):1321–1330

33. Geva R, Eshel R, Leitner Y, Fattal-ValevskiA, Harel S. Memory functions of childrenborn with asymmetric intrauterinegrowth restriction. Brain Res. 2006;1117(1):186–194

34. Lodygensky GA, Seghier ML, Warfield SK,et al. Intrauterine growth restrictionaffects the preterm infant’s hippocampus.Pediatr Res. 2008;63(4):438–443

35. Borradori-Tolsa C, Zimine S, Warfield SK,et al. Early alteration of structural andfunctional brain development inpremature infants born with

intrauterine growth restriction. PediatrRes. 2004;56(1):132–138

36. Batalle D, Muñoz-Moreno E, Figueras F,Bargallo N, Eixarch E, Gratacos E.Normalization of similarity-basedindividual brain networks from graymatter MRI and its association withneurodevelopment in infants withintrauterine growth restriction.Neuroimage. 2013;83(1):901–911

37. Als H, Duffy FH, McAnulty G, et al. NIDCAPimproves brain function and structurein preterm infants with severeintrauterine growth restriction.J Perinatol. 2012;32(10):797–803

38. Arnold CC, Kramer MS, Hobbs CA, McLeanFH, Usher RH. Very low birth weight:a problematic cohort for epidemiologicstudies of very small or immatureneonates. Am J Epidemiol. 1991;134(6):604–613


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http://www.pediatrics.org/cgi/content/full/127/4/e874

APPENDIX 1 SEARCH STRATEGY

(“humans”[MeSH Terms] OR “humans”[All Fields] OR “human”[All Fields]) AND (“fetal growth retardation”[MeSH Terms]OR (“fetal”[All Fields] AND “growth”[All Fields] AND “retardation”[All Fields]) OR “fetal growth retardation”[All Fields] OR(“intrauterine”[All Fields] AND “growth”[All Fields] AND “restriction”[All Fields]) OR “intrauterine growth restriction”[AllFields]) AND (“growth and development”[Subheading] OR (“growth”[All Fields] AND “development”[All Fields]) OR“growth and development”[All Fields] OR “development”[All Fields]) AND outcome[All Fields]

APPENDIX 2 Quality Assessment Outline

Potential Bias Items to Be Considered for Assessment

Data source: there is sufficient detail on thedata source to limit selection andmeasurement bias (yes, partly, no, orunsure)a

Relevance: have the data attributes been described insufficient detail for decision-makers to determinewhether there was a good rationale for using thedata source, the data source’s overallgeneralizability, and how the findings can beinterpreted in the context of their own organization?

Reliability and validity: have the reliability and validityof the data been described, including any dataquality checks and data-cleaning procedures?

Linkages: have the necessary linkages among datasources and/or different care sites been carried outappropriately taking into account differences incoding and reporting across sources?

Eligibility: have the authors described the type of dataused to determine member eligibility?

Study participation: the study samplerepresents the population of interest onkey characteristics sufficient to limitpotential bias to the results (yes, partly,no, or unsure)b

The source population or population of interest isadequately described for key characteristics.

The sampling frame and recruitment are adequatelydescribed, possibly including methods to identify thesample (number and type used [eg, referralpatterns in health care]), period of recruitment, andplace of recruitment (setting and geographiclocation).

Inclusion and exclusion criteria are adequatelydescribed (eg, including explicit diagnostic criteriaor “zero-time” description).

There is adequate participation in the study by eligiblesubjects.

Study attrition: loss to follow-up (fromsample to study population) is notassociated with key characteristics (ie,the study data adequately represent thesample), sufficient to limit potential bias(yes, partly, no, or unsure)b

Response rate (ie, proportion of study samplecompleting the study and providing outcome data) isadequate.

Attempts to collect information on participants whodropped out of the study are described. Reasons forloss to follow-up are provided.

Participants lost to follow-up are adequately describedfor key characteristics.

There are no important differences between keycharacteristics and outcomes in participants whocompleted the study and those who did not.

Prognostic factor measurement: theprognostic factor of interest isadequately measured in studyparticipants to sufficiently limit bias(yes, partly, no, or unsure)b

A clear definition or description of the prognosticfactor measured is provided (eg, including dose,level, duration of exposure, and clear specification ofthe method of measurement).

Continuous variables are reported or appropriate(ie, not data-dependent), and cut points are used.

An adequate proportion of the study sample hascomplete data for prognostic factors. The method andsetting of measurement are the same for all studyparticipants. Appropriate methods are used ifimputation is used for missing prognostic factor data.


APPENDIX 2 Continued

Potential Bias Items to Be Considered for Assessment

Outcome measurement: the outcome ofinterest is adequately measured in studyparticipants to sufficiently limit potentialbias (yes, partly, no, or unsure)b

A clear definition of the outcome of interest is provided,including duration of follow-up and level and extentof the outcome construct.

The outcome measure and method used are adequatelyvalid and reliable to limit misclassification bias(eg, may include relevant outside sources ofinformation on measurement properties, and mayinclude characteristics, such as blind measurementand confirmation of outcome with valid and reliabletest).

Confounding measurement and account:important potential confounders areappropriately accounted for, limitingpotential bias with respect to theprognostic factor of interest (yes, partly,no, or unsure)b

All important confounders, including treatments (keyvariables in conceptual model), are measured.

Clear definitions of the important confoundersmeasured are provided (eg, including dose, level,and duration of exposures).

Measurement of all important confounders isadequately valid and reliable (eg, may includerelevant outside sources of information onmeasurement properties, and may includecharacteristics, such as blind measurement andlimited reliance on recall).

Analysis: the statistical analysis isappropriate for the design of the study,limiting potential for presentation ofinvalid results (yes, partly, no, orunsure)b

There is sufficient presentation of data to assess theadequacy of the analysis.

The strategy for model-building (ie, inclusion ofvariables) is appropriate and is based ona conceptual framework or model.

The selected model is adequate for the design of thestudy.

There is no selective reporting of results.a ISPOR checklist for retrospective database studies.9

b Guidelines for Assessing Quality in Prognostic Studies.8


DOI: 10.1542/peds.2014-1143 originally published online December 29, 2014; 2015;135;126Pediatrics

Pinnamaneni, Adrienne Foran and Fiona A. AlderdiceTerri A. Levine, Ruth E. Grunau, Fionnuala M. McAuliffe, RagaMallika

Systematic ReviewEarly Childhood Neurodevelopment After Intrauterine Growth Restriction: A

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DOI: 10.1542/peds.2014-1143 originally published online December 29, 2014; 2015;135;126Pediatrics

Pinnamaneni, Adrienne Foran and Fiona A. AlderdiceTerri A. Levine, Ruth E. Grunau, Fionnuala M. McAuliffe, RagaMallika

Systematic ReviewEarly Childhood Neurodevelopment After Intrauterine Growth Restriction: A

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