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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
REVIEW ARTICLE PEDIATRICS Volume 135, number 1, January 2015 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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
PEDIATRICS Volume 135, number 1, January 2015 127 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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
128 LEVINE et al by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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
PEDIATRICS Volume 135, number 1, January 2015 129 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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)
130 LEVINE et al by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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)
PEDIATRICS Volume 135, number 1, January 2015 131 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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)
132 LEVINE et al by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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)
PEDIATRICS Volume 135, number 1, January 2015 133 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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.
134 LEVINE et al by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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
PEDIATRICS Volume 135, number 1, January 2015 135 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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
136 LEVINE et al by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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.
PEDIATRICS Volume 135, number 1, January 2015 137 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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.
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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
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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.
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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
PEDIATRICS Volume 135, number 1, January 2015 141 by guest on July 14, 2018www.aappublications.org/newsDownloaded from
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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