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Seminars in Fetal & Neonatal Medicine (2007) 12, 363e373

Cognitive and behavioural outcomesfollowing very preterm birth

Samantha Johnson*

Academic Division of Child Health, E Floor, East Block, Queen’s Medical Centre, Nottingham NG7 2UH, UK

KEYWORDSPreterm;LBW;Cognitive;IQ;Behaviour;ADHD;Outcome;Assessment

Summary This paper provides a review of the cognitive and behavioural outcomes of verypreterm children in middle childhood. Case-controlled studies have shown that very pretermchildren have intelligence quotient (IQ) scores significantly lower than term peers, even forthose who are free of severe disability. Authors have noted a gestational age-related gradientin IQ for those born before 33 weeks and studies have revealed particular problems in non-verbal reasoning and simultaneous information processing. Very preterm children are also atrisk for behavioural problems. There is little consensus regarding the presence of internalisingor externalising behaviours, but most studies show an increased risk of attentional and socialproblems. Studies have also shown a greater prevalence of psychiatric disorders and, specifi-cally, an increased risk for ADHD. Methodological issues are discussed and suggestions aremade for improving the reporting of outcomes to facilitate cross-study comparisons.ª 2007 Elsevier Ltd. All rights reserved.

Introduction

A timely report by the Nuffield Council on Bioethicsexamined the complex ethical and practical decisionsclinicians increasingly face regarding the intensive care ofextremely preterm (EPT) babies.1 This publication is a testa-ment to the vast advances in neonatal care and the markedimprovement in survival of babies born at the limits of via-bility. As increasing numbers graduate from intensive carenurseries, there is warranted concern regarding the future

Abbreviations: LBW, low birthweight (�2500 g); VLBW, very lowbirthweight (�1500 g); ELBW, extremely low birthweight (�1000 g);VPT, very preterm (varying gestational-age based classifications);EPT, extremely preterm (varying gestational-age based classifications).

* Tel.: þ44 (0)115 823 0609; fax: þ44 (0)115 823 0626.E-mail address: sam.johnson@nottingham.ac.uk

1744-165X/$ - see front matter ª 2007 Elsevier Ltd. All rights reservdoi:10.1016/j.siny.2007.05.004

health and well-being of these survivors and an increasinginterest in the long term sequelae of prematurity. Thispaper reviews research relevant to the cognitive andbehavioural outcomes of very preterm (VPT) children inmiddle childhood and considers methodological issues per-taining to outcome monitoring in this population.

Outcome assessments in middle childhood

Although many studies assess outcome at 2 years, it isimportant to monitor progress beyond this point given thetransient or evolving nature of deficits in infancy and thepoor predictive validity of infant tests. Whilst the authorsof early studies sought to catalogue the severe neurologicaland sensory disabilities associated with VPT birth, recentresearch has highlighted a range of more subtle deficitsand has shown that the nature of impairment may bechanging.2 Cognitive and behavioural problems are among

ed.

364 S. Johnson

the most common adverse outcomes and such ‘higher prev-alence/lower severity’ impairments are more evident atschool age, even in those who are free of severe disability.3

The complex demands of the school’s academic and socialenvironment may illuminate emerging sequelae in middlechildhood or exacerbate pre-existing dysfunctions.4 Assess-ments at school age thus provide a timely opportunity tomeasure outcomes when the identification of impairmentsmay be maximised and are likely to be more predictive ofproblems that may persist into adulthood.

IQ in middle childhood

Researchers have typically studied population-basedcohorts of children to define and quantify outcomes forVPT children. As these studies are necessarily large andfrequently have limited time and resources with which toassess survivors, outcomes measures have typically com-prised an assessment of global cognitive function. The needfor objective measures has led to the widespread use ofstandardised intelligence (IQ) tests as indicators of out-come. IQ tests are psychometric measures that yieldstandardised scores on a normalised distribution (typicallymean Z 100, standard deviation (SD) Z 15) and are thusstatistically comparable. Increasingly, studies have imple-mented more domain-specific measures of neuropsycholog-ical abilities but have included these in addition to a globalmeasure. Comparisons between cohorts are facilitated bythe reporting of IQ scores and, for these reasons, the pres-ent review focuses on the results of IQ tests in population-based cohorts.

Although VPT or very low birthweight (VLBW) childrentypically have group mean IQ scores within the normalrange (�1 SD), these are significantly lower than their termcounterparts. A recent meta-analysis of outcomes for VPT/VLBW children aged 5e14 years pooled data from 15 high-quality studies.5 Weighted mean differences (WMD) forindividual studies ranged from 7.0 to 22.7 points, with anaggregate WMD of 10.9 IQ points (95% confidence interval(CI) 9.2e12.5) between VPT/VLBW children and controls,equating to a 0.73 SD deficit for VPT/VLBW children.Results were unaffected by country, age at assessmentand regional versus hospital-based cohorts. As would beexpected, the highest WMD was found for studies in whichchildren with severe neuro-sensory impairments (NSI)were included.

The deficit in IQ for EPT/extremely low birth weight(ELBW) children is larger than that for VLBW/VPT cohorts. Aregional cohort of ELBW children (<750 g) scored 13 pointslower than term controls and 6 points lower than LBW con-trols matched for age, sex and ethnic group.6 Similarly,Scottish ELBW (<1000 g) children had a mean IQ score12 points lower than controls at 8 years,7 while a Swedishcohort of EPT (<29 weeks) children scored 17 points lowerthan controls.8

The meta-analysis by Bhutta et al. combined studies ofcohorts born from 1975 to 1988,5 prior to the widespreaduse of antenatal steroids, surfactant therapy and improvedventilatory assistance. Follow-up data in middle childhoodare now beginning to emerge for cohorts born in the1990s (Table 1) and continue to highlight the cognitive

disadvantage in these populations. VPT (<32 weeks) chil-dren in mainstream school were found to have a mean IQscore 11 points below that of a matched control group at8 years.9 A marginally larger 13 point difference in IQ scoreshas been noted for 5-year-old VLBW children in the EpipageStudy,10 although these results are yet to be published infull.

Greater deficits have been noted in contemporary EPT/ELBW cohorts,14 with case-controlled studies finding meanIQ scores ranging from 88 to 95 points (Table 1). When chil-dren with NSI are included, mean IQ scores range from 82 to88 points with differences of 9e24 points between casesand controls.12,13,15 When the control group means areregressed to 100 and the index group mean is similarlyadjusted proportionally to enable direct comparisons be-tween studies (VPT mean/control mean � 100), the mean IQfor EPT/ELBW cohorts ranges from 78 to 91points (Table 1).Whilst the magnitude of effect differs between studies, thereremains a robust difference in IQ between VPT/EPT and termchildren in the most recent cohorts.

A number of studies have also demonstrated pooreroutcomes for VPT boys compared to girls.14,17e19 In theEPICure Study, EPT boys had a group mean IQ score 10 pointslower than girls and were more than twice as likely to haveimpaired cognitive function; this sex difference was notfound in the control group.13 However, the cognitive disad-vantage for boys has not been noted in some cohorts.7,16,20

IQ and gestational age

Within-group analyses for VPT children have shown a corre-lation between IQ and gestational age (GA). Bhutta et al.identified a linear relationship between GA and IQ from25 to 40 weeks (R2 Z 0.49, p < 0.001).5 However, whendata for cohorts with a mean GA of 33e40 weeks are ana-lysed, research has shown that this relationship may notbe linear as suggested.21

In the Bavarian Longitudinal Study (BLS) there was norelationship between IQ and GA from 33 to 42 weeks but,below this point, IQ scores decreased linearly by an averageof 2.5 points with each weekly decrease in GA (from 32 to27 weeks).21 Similar population definitions and methodol-ogy permit comparisons between the BLS and the EPICureStudy.13 When control mean scores are regressed to 100and index scores are adjusted accordingly, mean IQ scoresfor the EPICure children born at 23e25 weeks correspondremarkably and confirm the prediction of a 2.5-pointweekly decrement in IQ.22 When the IQ scores of indexgroups in the Bhutta et al. meta-analysis are similarlyadjusted and data are plotted for these children alone,the association between IQ and GA <33 weeks is stronger(R2 Z 0.65, 95% CI 0.43e0.94, p Z 0.002; Fig. 1). The dec-rement in IQ is greater and the slope of the line appearssteeper with a predicted decrease of 1.7 IQ points perweek (95% CI 0.81e2.55).

When the data from cohorts born in the 1990s are addedthis modifies this figure to 1.5 IQ points per week (95% CI0.78e2.29; Fig. 2); as these data do not alter the regressionline significantly it appears that the IQ of VPT cohorts hasnot improved over time. Both Bhutta et al. and the BLShave also found a relationship between BW and IQ, but

justed: indexeanc

Index:% impaired(IQ <70)

Inclusion ofchildren withsevere disabilities

14 Yes

.9 15 Yes. IQ scoreswere substitutedwith a nominalvalue (40) forchildren whowere untestable

.7 21 (usingtest norms);41 (usingcontrol dataas reference

Yes. Scores fromalternative testssubstituted forK-ABC scores,and IQ scores<40 assignednominalvalue (39)

A 9 No. 5% wereunable toparticipate intesting. However,when scores aresubstituted as inMarlow et al.,2005,13 mean IQis reduced by 1point to 95

.0 12 Not stated

.0 5 No. Children withsignificantneurosensoryimpairment werenot assessed, andmissing valueswere not substituted

(continued on next page)

Cogn

itiveand

behavio

ura

loutco

mes

afte

rve

rypre

term

birth

365

Table 1 IQ in middle childhood: population-based studies of cohorts born in the 1990s

Reference Cohort Index (n)a Control (n) Age atfollow-up(years)

IQ testb Control IQ:mean (SD)

Index IQ:mean (SD)

Differencein IQ(95% CI)

AdIQm

Farooqi et al.(2006)11

National,Sweden,1990e1992

< 26 weeks(n Z 86)

Children matchedfor hospital ofbirth, age andsex (n Z 86)

11 Five toFifteen(ParentReport)

e e e e

Hack et al.(2005)12

Hospital-based, US,1992e1995

<1000 g(n Z 219)

School matesmatched for age,race and sex(n Z 176)

8 K-ABC 99.8(15)

87.7(18)

12.1 points 87

Marlow et al.(2005)13

EPICure Study

National,UK andIreland, 1995

<26 weeks(n Z 241)

Class matematched for age,race and sex,mainstreamschools only(n Z 160)

6 K-ABC (orGriffithsScales forseverelyimpaired)

105.7(11.8)

82.1(19.2)

24 points(95% CI20e27)

77

Mikkola et al.(2005)14

Finnish ELBWCohort Study

National,Finland,1996e1997

< 1000 g(n Z 172)

No control group 5 WPPSI-R N/A 96(19)

4 points(from testnorms)

N/

Larroque et al.(2005)10

EPIPAGE Study(Abstract only)

Regional,France,1997

<33 weeks(n Z 1624)

Children born at39 or 40 weeks(n Z 326)

5 K-ABC 106.5(17.8)

93.7(19.3)

12.7points(95% CI10.5e14.9)

88

Anderson et al.(2003)15

Victorian InfantCollaborativeStudy

Regional,Australia,1991e1992

<1000 gand <28 weeks(n Z 258)

Child matched forDOB, sex,language and SES(n Z 220)

8 WISC-III 104.9(14.1)

95.5(16.0)

9.4 points(95% CI12.1e6.7)

91

366 S. Johnson

Table

1(c

onti

nued

)

Refe

rence

Cohort

Index

(n)a

Contr

ol

(n)

Age

at

follow

-up

(years

)

IQte

stb

Contr

ol

IQ:

mean

(SD

)In

dex

IQ:

mean

(SD

)D

iffe

rence

inIQ

(95%

CI)

Adju

sted

IQ:

index

mean

c

Index:

%im

pair

ed

(IQ<

70)

Incl

usi

on

of

childre

nw

ith

seve

redis

abilit

ies

Fould

er-

Hugh

es

and

Cooke

(200

3)9

Regi

onal,

UK,

1991

e19

92

<32

weeks

(nZ

280)

Cla

ssm

ate

matc

hed

for

age

,se

xand

langu

age

(nZ

210)

8W

ISC-I

II10

0.5

(13.

7)89

.4(1

4.2)

11.1

poin

ts(p<

0.00

1)89

.0e

No.

Only

childre

natt

endin

gm

ain

stre

am

schools

incl

uded

Bohm

et

al.

(200

2)16

Stock

holm

Neonata

lPro

ject

Regi

onal,

Sweden,

1988

e19

93

<15

00g

(nZ

143)

Child

matc

hed

for

DO

Band

hosp

ital

of

bir

th(n

Z11

3)

5W

PPSI

-R10

2.3

(11.

0)91

.1(1

6.7)

11.2

poin

ts(p<

0.00

1)89

.1<

10N

o

SES,

soci

o-e

conom

icst

atu

s;CI,

confidence

inte

rval.

an

indic

ate

sth

enum

ber

of

childre

nadm

inis

tere

dth

eIQ

test

,or

inw

hom

mis

sing

data

were

subst

itute

d.

bIQ

Test

Abbre

viati

ons:

K-A

BC,

Kau

fman

Ass

ess

ment

Batt

ery

for

Childre

n;

WPPSI

-R,

Wech

sler

Pre

schooland

Pri

mary

Scale

of

Inte

llig

ence

-Revi

sed;

WIS

C-I

II,

Wech

sler

Inte

llig

ence

Scale

for

Childre

n3r

dEdit

ion.

cIn

dex

mean

IQadju

sted

pro

port

ionally

for

com

par

ison

wit

hco

ntr

ol

mean

regr

ess

ed

to10

0.

data from these populations are confounded by the inclu-sion of more mature babies with fetal growth restriction.

This relationship underscores the developmental vulner-ability of the preterm baby, even in the absence of majorneurological insult. Disruption to critical stages of braindevelopment are particularly associated with births at<33 weeks and may affect later cognitive outcome.23 Incontrast, a large study based on the US Neonatal Brain Hae-morrhage Study found that GA was not an independent pre-dictor of IQ at 16 years after other risk factors werecontrolled for, although this study included relativelyheavier babies (<2000 g) and many of the variables enteredinto the regression equation were themselves related to GA(e.g. intraventricular haemorrhage (IVH), periventricularleukomalacia (PVL), days of ventilation).24

24 25 26 27 28 29 30 31 32 3370

75

80

85

90

95

100

Mean Gestational Age

Adju

sted

IQ

Adjusted control mean

Figure 2 Correlation between mean gestational age (GA)and mean IQ test score adjusted for comparison with regressedcontrol group mean (mean Z 100) for each cohort identified byBhutta et al. and the most recent case-controlled studies (n Z17, r Z 0.74, p Z 0.001, see Table 2). Only those studies inwhich data for mean GA is available were included.

24 25 26 27 28 29 30 31 32 3370

75

80

85

90

95

100Adjusted control mean

Mean Gestational Age

Adju

sted

IQ

Figure 1 Correlation between mean gestational age (GA)and mean IQ test score adjusted for comparison with regressedcontrol group mean (mean Z 100) for each cohort identified byBhutta et al. (n Z 12, r Z 0.81, p Z 0.002). Only those studiesin which data for mean GA is available were included.

Cognitive and behavioural outcomes after very preterm birth 367

Impact of medical and social factors

VPT children are at increased risk for medical complica-tions and are frequently born to families of lower socio-economic status (SES). Such factors exert independentcumulative influences on later outcomes. Perinatal factorssuch as retinopathy of prematurity (ROP), cerebral ultra-sound abnormalities, chronic lung disease, IVH, PVL, sub-normal head circumference and use of antenatal steroidshave been found to be related to poorer cognitive out-come.14,25e27 IQ is also strongly related to SES for bothterm and VPT populations.14,28e31 The effect of SES isincreasingly evident at school age when the impact ofthe environment plays a more prominent role as the childdevelops.

Despite the strong correlation between SES and IQ,differences in IQ between VPT children and controls remainafter controlling for SES.15,25,30 Even in cases in which termsiblings are used as controls, ELBW children free of NSI havea mean IQ score 10-points lower than their siblings.32 Theinfluence of medical and SES factors on later developmentmay be considered to be additive, such that detrimentaleffects of environmental adversity exacerbate biologicalrisk placing VPT children in ‘double jeopardy’.33 Studieshave shown that VPT children with the lowest SES are themost vulnerable, with IQs of high SES controls being mostdiscrepant from those of low SES VPT children.30,31,34 Italso appears that the impact of environmental factors rea-ches a ceiling limit at which point severe biological risk di-minishes any potentially compensatory effect.35 Biologicalfactors may, therefore, have more impact at the lowergestations. This is borne out in studies of developmentalinterventions that have shown less impact for the most im-mature infants.36

Selective processing deficits

IQ tests yield composite full scale scores (FSIQ). Additionalsub-scales typically comprise Verbal IQ (VIQ) measuringreasoning and conceptual ability with language, andPerformance IQ (PIQ) measuring non-verbal reasoning,spatial-mechanical and perceptual tasks. Within-groupcomparisons for VPT cohorts reveal specific deficits inPIQ, a pattern that is not typically observed in controlgroups, or is of a lesser magnitude. Between-group com-parisons also show greater deficits in PIQ than VIQ.

Studies have shown deficits of 5e10 points in mean PIQscores compared to mean VIQ scores for VPT/EPTcohorts.8,9,14,16 Using a different derivation of normativescores, authors have found the greatest mean differencefrom controls in Perceptual Organisation (�10 points) andFreedom from Distractibility (�8 points) Indices.15 Greaterdeficits in perceptual abilities and non-verbal measureshave also been found in studies using a variety of mea-sures.7,29,37 Two studies have found comparable resultsusing the Kaufman Assessment Battery for Children (K-ABC).38

This is comprised of a Sequential Information Processingsub-scale, measuring the processing of stimuli in a serialorder, and a Simultaneous Information Processing sub-scale, composed of assessments of the ability to processstimuli simultaneously. VLBW children were more likely to

have a discrepancy of at least �1 SD in simultaneous com-pared to sequential processing.30 In contrast to a controlgroup who had similar scores across scales, EPT childrenhad an 8-point deficit in simultaneous compared to sequen-tial processing.13

These results suggest that non-verbal reasoning, visuo-spatial skills and the ability to perceive, integrate andprocess stimuli simultaneously are particularly compro-mised by VPT birth. Such impaired processing capacitymay underlie the behavioural, social and academic diffi-culties frequently observed in this population. Studies haveshown that the frequency of specific learning deficits iscomparable to the normal population25 and that poor per-formance on tests of specific functions can be accountedfor by lowered IQ.30,39 Authors have thus argued that a fun-damental disruption to cortical development and brainorganisation may account for the multiple educationalimpairments in VPT populations.30,40 After adjustment forIQ, studies have highlighted persistent problems with math-ematics, oral-motor skills, verbal working memory and per-ceptual-motor and spatial-organisational abilities.30,39,41,42

This suggests that VPT children may have additional diffi-culties with visually-mediated tasks and tests of motor-related skills that are independent of IQ.

Changes over time

The best predictor of IQ remains IQ as assessed at an earlierage.25 Whether early difficulties represent developmentaldelay or a persistent impairment is equivocal. Longitudinalstudies have typically failed to find evidence of ‘catch-up’growth over time,40,42 with some identifying a trendtowards deteriorating performance in comparison to termpeers.25,43 In contrast, Ment et al.29 found that VLBW chil-dren without NSI showed signs of improvement in receptivevocabulary and IQ, although methodological limitationsmay account for the changes observed in this study.2

Behaviour and psychopathology

VPT children are also at greater risk for long termbehavioural and emotional sequelae. These outcomes arerelatively difficult to compare as the measures used aremore diverse than IQ tests. Assessments are usually con-ducted through self-reports or parental questionnaires andcorroborative information from teacher questionnaires maybe incorporated as multi-informant information is emphas-ised for DSM-IV/ICD-10 categorisation. Information can alsobe obtained from diagnostic interviews, but these can becostly and time consuming to administer. Variability in theconstructs measured between tests also makes it moredifficult compare outcomes (Table 2).

The Child Behaviour Checklist (CBCL)44 is used most fre-quently in the US and European populations. Studies havetypically reported an excess of behavioural and emotionaldisorders and an increased prevalence of abnormal (clini-cally significant) scores in VPT children. There is less con-sensus regarding the prevalence of internalising (anxious/depressed symptoms, withdrawn behaviour and somaticcomplaints) and externalising behaviours (delinquent andaggressive behaviour), but most studies report an excess

Table 2

Assessm Resultsb

AchenbEmpiAsses� Ch

Ch� Tea

For� You

(YS

m Behaviour

g Scale

g Scalenomplaintsepressedt behaviour

e behaviourblemsroblemsproblems

Raw scores, T scores andpercentiles with empiricalcut-offs for identificationof abnormal on each scaleand sub-scale

etence Score

petencempetence

ConnerRevis

rm)nalproblems/inattention

ivityex

Raw scores are convertedto T scores and percentilesfor each scale

StrengtQues

culties (Sum ofes)l symptomsroblems

ivity/inattentiontionship problemsbehaviourpplement

Continuous scores for eachscale and empirical cut-offsfor identification ofborderline and abnormalscores

a Mosb High

368S.

Johnso

n

Commonly used assessments of behaviour and psychopathology in middle childhood

enta Author and publisher Age range Administration Scales

ach System ofrically Basedsment (ASEBA)

ild Behaviourecklist (CBCL)cher Reportm (TRF)th Self ReportR)

Achenbach (1991)44

Achenbach andRescorla (2001)66

ASEBA Research Centrefor Children, Youthand Families

CBCL and TRF:1.5e18 years

YSR: 11e18 years

Parent Report (CBCL)

Teacher Report (TRF)

Child self-report (YSR)

Total Proble

Internalisin

ExternalisinWithdrawSomatic cAnxious/dDelinquenAggressivSocial proThought pAttention

Social CompActivitiesSocial comSchool co

s’ Rating Scales e

ed (CRS-R)Conners (1996)67

Harcourt Assessment

3e17 years

12e17 years

Parent or Teacher Report

Adolescent Self Report

(Short FoOppositioCognitiveHyperactADHD Ind

hs and Difficultiestionnaire (SDQ)

Goodman (1997)50

www.sdqinfo.com

3e16 years Parent or Teacher Report(4e16 years)

Self Report (11e16 years)

Total Diffi1st 4 ScalEmotionaConduct pHyperactPeer relaProsocialImpact su

t recent revisions referenced.er scores represent more impaired function. ADHD, attention deficit/hyperactivity disorder.

Cognitive and behavioural outcomes after very preterm birth 369

of attention and social problems. This is exemplified byBhutta et al.5 who used data from 16 case-controlled stud-ies of VPT/VLBW children aged 5e14 years. There was a sig-nificant excess of total behavioural problems in indexchildren in 81% of studies. On sub-scale analysis, 69% ofstudies reported a higher prevalence of internalising symp-toms and 75% a higher prevalence of externalisingbehaviours.

Studies of ELBW/EPT cohorts have revealed similartrends. Some have reported no differences in internalisingand externalising behaviours between index and controls,45

whilst others have found an excess of internalising andexternalising problems and significantly higher scores forwithdrawal, social, thought and attention problems and de-linquent behaviour, as well as lower levels of social andschool competence.46 Similarly, EPT (<29 weeks) childrenwere found to have significantly higher total problembehaviours, internalising behaviours, attentional problemsand lower social competence than matched controls at10 years.8

These trends are highlighted in an international com-parison of four population-based cohorts of ELBW childrenaged 8e10 years.47 Total problem behaviour scores werehigher for all ELBW children than controls, with significantlyincreased scores in the European cohorts. A significantincrease in internalising behaviours was evident for onlyone ELBW cohort and there were no significant differencesin externalising behaviours between cases and controls inall four countries. However, the authors noted that ELBWcohorts had significantly increased prevalence of social,thought and attention problems, with scores for thesescales being 0.48e1.20 SD higher than controls.

Other measures are more frequently used in UK pop-ulations and have shown an excess of behavioural problemsin LBW children at both 1248 and 14 years.49 More recently,the Strengths and Difficulties Questionnaire (SDQ, Table2)50 has increased in popularity. It is less cumbersomethan the CBCL and has excellent psychometric properties.Studies using the SDQ have reported VPT (<29 weeks) ado-lescents to have significantly higher scores for hyperactiv-ity, emotional and peer problems than controls, althoughadolescents themselves reported only more emotionalproblems than their peers.51

Although a number of cohorts born in the 1990s are nowapproaching middle childhood (Table 3), the publication ofbehavioural outcomes lags behind as most studies willreport first on neurodevelopmental status. In general,these studies have continued to demonstrate the trendsoutlined above. Reijneveld et al.52 found that VPT/VLBWchildren had significantly higher scores on all CBCL scalesexcept for anxious/depressed and sex problems, with thelargest differences being in social and attention problems.The prevalence of abnormal scores was significantly higheronly for the total problem and internalising behaviourscales. Similarly, Anderson and Doyle15 found significantlyhigher scores for total problems and internalising behav-iours but not externalising problems for EPT children, andsignificantly more attention and hyperactivity problemswith poorer social and leadership skills than controls. Asthe prevalence of those with abnormal scores did not differfrom controls this suggests an increased risk of mild behav-ioural dysfunctions.

Attention deficit/hyperactivity disorders

A robust finding is the excess of attentional problems inVPT/VLBW children. Using diagnostic interview schedules,attention deficit/hyperactivity disorders (ADHDs) are themost frequent abnormal psychiatric outcome. In a meta-analysis of data from seven populations, the pooled relativerisk was 2.64 (95% CI 1.85e3.78) compared to controls.5

Increased prevalence of ADHD has been found in 12-year-old VLBW children (23%) compared to matched term con-trols (6%, p < 0.0001)49 and in 10-year-old EPT children(20%) versus controls (8%, p < 0.05).8 In heavier children(LBW, <2000 g) the prevalence of ADHD has been foundto be 10% (versus controls 1%, p Z 0.0001).52

That many VPT children have attentional problems yetfar fewer meet the clinical diagnosis for ADHD54 suggeststhat such symptoms may be sub-clinical or do not fit wellwith the classic ADHD behavioural profile. Studies oftenreport increased attentional problems in the absence ofhyperactivity54 and, although ADHD has been linked tothe development of conduct disorders in the normal popu-lation, there is a notable lack of comorbid disruptive behav-iour conditions in VPT/VLBW children.49,51,53,55,56 Thissuggests that the VPT/VLBW child is susceptible to a ‘purer’form of attentional deficit.35 Neonatal white matter in-juries, particularly parenchymal lesions and ventricular en-largements, have been found to be strongly predictive ofADHD in LBW/ELBW children,57 suggesting a more biologi-cally determined form of ADHD with a neurological aetiol-ogy linked to CNS injury. Indeed, studies have shown thatpreterm birth and medical factors are more strongly associ-ated with ADHD than social factors.49,52,55,58

Sex differences and behaviour

Although some authors have noted similar findings for boysand girls,53,54 studies of VPT cohorts have generally shownthat the excess of behavioural and emotional problemsvaries with sex. Hille et al.47 found a trend for higher totalproblem scores in ELBW boys and, compared to controls,ELBW boys have been found to have more problem behav-iours than girls and significantly more delinquentbehaviour.46 Boys appear to be more susceptible to exter-nalising behaviour problems, whilst girls are more suscepti-ble to internalising problems.52

Other psychopathology

Using informant questionnaires some authors have foundalmost half of all VLBW children have psychiatric symp-toms.54 However, using diagnostic interviews fewer meetcriteria for clinical diagnosis. Despite this, studies haveshown a significantly increased prevalence of psychiatricdisorders in LBW/VLBW children with percentage preva-lence ranging from 25 to 28%.49,53,54 A study of LBW childrenat 6 years also found 22% to have at least one psychiatricdisorder.57

There is less consensus regarding the type of disorderspresent. One case-controlled study reported a significantlyhigher presence of depression but not anxiety disorders,45

whilst others have found significantly higher rates of

Tabl

Refeificantgy:

Prevalence ofclinically significantpsychopathology:index

Difference

Reijn(20 .6%

Internalisingbehaviours: 7.0%

OR 1.1 (95%CI Z 0.7e1.6), NS

.4%Externalisingbehaviours: 11.9%

OR 1.5 (95%CI Z 1.1e2.0),p< 0.05)

.7%Total problembehaviours: 13.2%

OR 1.6 (95%CI Z 1.2e2.2),p< 0.05)

Faro(20

ADHD: 7% Not stated

%Adaptivefunctioning: 26%

p< 0.001

AndeDo

Behaviouralproblems: 7%

NS

Foulan(20

ADHD: 8.9% p Z 0.01

Abbr terval; NS, non-significant; ADHD, attention deficit/hype

370S.

Johnso

n

e 3

rence Cohort Index (n) Control (n) Age atfollow up(years)

Assessment Prevalence ofclinically signpsychopatholocontrol

eveld et al.06)52

Regional <32 weeksor <1500 g(n Z 402)

Normative referencegroup (n Z 6007)

5 CBCL (Parent) Internalisingbehaviours: 6

NetherlandsExternalisingbehaviours: 8

1992e1995Total problembehaviours: 8

oqi et al.06)11

National <26 weeks(n Z 86)

Children matched forhospital, age and sex(n Z 86)

11 Five to Fifteen(Parent)

ADHD: 3%

Sweden CBCL (Teacher) Adaptivefunctioning: 3

1990e1992

rson andyle (2003)15

Regional <1000 g and<28 weeks(n Z 258)

Child matched fordate of birth, sex,language and SES(n Z 220)

8 BASC (Parentand teacher)

Behaviouralproblems: 4%

Australia

1991e1992

der-Hughesd Cooke03)9

Regional <32 weeks(n Z 280)

Classmate matched forage, sex and language(n Z 210)

8 Conners’ RatingScale (Teacher)

ADHD: 2.1%

UK

1991e1992

eviations: CBCL, Child Behavior Checklist; BASC, Behavior Assessment System for Children; OR, odds ratio; CI, confidence inractivity disorder.

Cognitive and behavioural outcomes after very preterm birth 371

anxiety disorders but not major depressive episodes inVLBW children.49,54 Other studies have not found increasedrates of depression or anxiety disorders in VPT children.53

Deficits in social skills and social competence area frequent finding and most studies show the greatestdifference from controls in social problems.52 The preva-lence of Autistic Spectrum Disorders has been less wellinvestigated in VPT/VLBW populations. The authors of onewell conducted study report significantly higher scores ona parental rating scale of Autistic Spectrum symptomatol-ogy compared to term controls (p < 0.001). In two studies,the authors have found one VLBW child to meet criteria forAsperger disorder compared to none of the controls.53,54

Studies assessing self-esteem in VPT children have oftenfailed to find a significant difference in self-esteem andglobal self-worth between ELBW46,59 and VPT adolescents51

and young adults60 using self-report questionnaires. How-ever, Elgen et al.53 found 11-year-old LBW children to havelowered self-esteem when using a diagnostic interview.

How should we report outcomes?

Variability in outcomes may be attributed to variations instudy quality that reflect differences in population defini-tions, the application of comparator data and the selectionof outcome measures. An appreciation of study methodol-ogy is important in interpreting results and a number ofmethodological considerations are noted briefly below withrecommendations for improving the reporting of outcomes.

Population definitions

� Population denominators and sample characteristicsshould be clearly described.� As single-centre cohorts may be subject to selection

bias,61 larger population-based cohorts are preferable.� It is better practice to define populations by GA for in-

vestigating the effects of VPT birth. SD scores for BWmay be used as a covariate for controlling for fetalgrowth restriction.� For those with severe NSI who are unable to participate

fully in standardised assessments, IQ scores may besubstituted with a nominal value to quantify functionin the significantly impaired range.6,13,20

� As subject attrition may bias outcomes,62,63 follow-uprates and analyses of non-responders on variables likelyto affect outcomes should be reported.

Comparator data

� Concurrent comparator data should be reported whenassessing childhood outcomes.� The use of classmates matched for age, sex and ethnic

group is advantageous as this will also select childrenfrom the same social neighbourhood and with sharededucational input.� Control groups should be assessed at each time point to

determine whether changes in index groups reflect thetypical developmental trajectory or are cohort-specific.

� IQ scores for VPT children should be considered in com-parison to contemporary norms. Given the secular up-ward drift in IQ test scores over time, the comparisonof outcomes to obsolete test norms may underestimatethe extent of impairment.64 When data obtained fromcurrent control groups are applied to define outcomethe prevalence of impairment has been shown toincrease markedly.13

Selection of outcome measures

� Recently standardised outcome measures with goodpsychometric properties should be used.� The administration of standardised tests should be

quality assured (e.g. inter-rater reliability), as system-atic differences between assessors may bias results.� ‘Non-verbal’ tests that are less reliant on verbal admin-

istration and responses minimise cultural and languagebias and facilitate assessments of children with speech,language and hearing impairments.� It is advantageous to use formal standardised psychiat-

ric assessments that yield DSM-IV/ICD-10 classificationsin addition to questionnaire methods.� Multi-informant reports are beneficial as adolescents

may self-report fewer problems65 and corroborativeevidence is emphasised for diagnostic classification.

Summary and conclusions

There is no question that VPT birth is a major reproductiverisk for cognitive and behavioural sequelae, even in childrenwithout significant NSI. Whilst VPT children have groupmean IQ scores within the normal range, these are signifi-cantly lower than their term peers. Cognitive outcome ismost compromised in those born at <33 weeks in whom IQdecreases by an average of 1.5e2.5 points for each decreas-ing week of gestational age. VPT children appear to have thepoorest performance on tests of visuo-spatial skills and non-verbal reasoning and to have specific difficulties in the si-multaneous processing of complex stimuli.

In addition, the VPT child is at increased risk for sub-clinical behavioural problems and can most often be de-scribed as inattentive, shy or withdrawn, and with poor socialskills. VPT children are more likely to have psychiatricdisorders, of which ADHD is the primary abnormal outcome.The lack of comorbid hyperactivity and conduct disorderssuggests a ‘purer’ form of attentiondeficit. There is also someevidence of increased risk for Autistic Spectrum Disorders inVPT children but this requires further investigation.

Variations in methodology can make direct comparisonsacross studies problematic. The use of contemporarycomparator data and a consensus regarding populationdenominators, age at assessments and outcome measureswould facilitate comparison of outcomes. The reporting ofoutcomes by each week of gestational age would alsofacilitate meta-analyses. The continued longitudinal mon-itoring of outcomes through middle childhood for the mostcontemporary cohorts will aid in defining the long termsequelae of VPT birth and in identifying the later health andeducational needs of these children.

372 S. Johnson

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