Seminars in Fetal & Neonatal Medicine 19 (2014) 97e104

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Seminars in Fetal & Neonatal Medicine

journal homepage: www.elsevier.com/locate/siny

Review

Growing up after extremely preterm birth: Lifespan mental health

outcomes
Samantha Johnson a, *, Neil Marlow b
a
b

Department of Health Sciences, University of Leicester, Leicester LE1 6TP, UK

Department of Academic Neonatology, Institute for Womens Health, University College London, London, UK

s u m m a r y
Keywords:
Attention decit hyperactivity disorder
Autism spectrum disorders
Comorbidity
Mental health
Outcomes
Preterm birth

There is growing interest in the long-term mental health sequelae of extremely preterm birth. In this paper we
review literature relating to mental health outcomes across the lifespan. Studies conducted in the preschool
years, school age and adolescence, and adulthood show continuity in outcomes and point to an increased risk
for inattention, socio-communicative problems and emotional difculties in individuals born extremely
preterm. Both behavioural and neuroimaging studies also provide evidence of a neurodevelopmental origin
for mental health disorders in this population. Here we summarise contemporary evidence and highlight key
methodological considerations for carrying out and interpreting studies in this eld.
2013 Elsevier Ltd. All rights reserved.

1. Introduction
Extremely preterm (EP) births, before 28 weeks of gestation,
continue to pose the greatest challenge for neonatal medicine.
Providing life-sustaining treatment, minimising environmental
stressors and supporting the family through a traumatic life event are
key challenges for neonatologists and other professionals involved in
perinatal care. For these babies and their families, however, the care
does not end there. The biological vulnerability conferred by EP birth,
which may be amplied through socio-economic disadvantage, can
have a profound impact on development with consequences that
extend across the lifespan. Although EP births comprise just 0.6% of all
births, morbidity is highest among these survivors [1,2]. Cognitive
impairments are the most frequent adverse outcomes [3,4], but there
is growing interest in the impact of preterm birth on mental health
and wellbeing. Here we review literature relating to mental health
outcomes following EP birth. Although we focus on reports from the
most contemporary cohorts, much may be gained through understanding outcomes for older cohorts now in adult life.

2. Studying mental health following extremely preterm birth

Mental health outcomes are generally evaluated as part of longitudinal studies which have, for the most part, sought to identify

* Corresponding author. Address: Department of Health Sciences, University of

Leicester, 22e28 Princess Road West, Leicester LE1 6TP, UK. Tel.: 44 (0) 116 252
5798; fax: 44 (0) 116 252 3272.
E-mail address: sjj19@le.ac.uk (S. Johnson).
1744-165X/$ e see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.siny.2013.11.004

the prevalence of disorders at various ages. Like all outcome

studies, these suffer the inherent problems of selective drop-out.
Some of the issues relating to the maintenance of cohorts have
recently been discussed [5]. Key aspects of cohort evaluations are:

Having a clear denominator in order to evaluate how the ndings may be extrapolated to other studies and how representative they are of the population from which they are drawn.

Evaluating the effect of drop-outs and, where necessary, supplementing the ndings with sensitivity analyses or imputation
techniques.

Having due regard to these in drawing conclusions.
Single centre studies are more practical to manage, but groups
of babies born in individual hospitals may not be representative of
the wider population. Further challenges occur by the simple fact
that populations change over time, such that more contemporary
cohorts comprise a higher proportion of EP children making comparison with historical reports challenging. When studying outcomes it is important that there is a strong underlying hypothesis
and that pre-study power calculations using realistic estimates of
group differences are computed.
It is widely considered preferable to use diagnostic criteria for
studying mental health disorders and to facilitate comparison between studies, yet variation may still exist depending on the
measure used [6]. However, the often insurmountable economic
and practical challenges of implementing diagnostic interviews
mean that most studies have relied solely on behavioural questionnaires (see Johnson [7] and Arpi and Ferrari [8] for reviews).
These typically generate higher rates of individuals that score above

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the cut-off for clinically signicant problems than meet the criteria
for disorders. This is illustrated using data from the UK EPICure
Study (Fig. 1) [9]. As part of a follow-up at 11 years of age,
emotional, conduct, hyperactivity/inattention and peer relationship problems in a cohort of children born EP (<26 weeks) were
assessed using parent and teacher questionnaires; diagnoses of
corresponding disorders were obtained concurrently [10]. For all
domains, parents reported signicantly more problems than disorders and teachers reported more attention and peer problems
(Fig. 1). This begs the question of who is the most appropriate
respondent for assessing childhood psychopathology. It is welldocumented that parent and teacher reports are only modestly
correlated and that parents report higher rates of problems than
teachers or adolescents themselves, particularly for emotional
disorders [11
17]. Obtaining multi-informant data is therefore
advocated for mental health assessment [18,19].
The use of dimensional measures is also advocated for studying
childhood psychopathology in order to quantify the degree to
which symptoms are manifest in individuals and populations [20e
23]. These considerations are particularly important for studying
mental health following EP birth in which there appears to be a
general population shift in psychopathology and a cluster of
symptoms that extends across diagnostic boundaries (see Section
4) [24e26]. As the expression of childhood psychopathology alters
with development, the nature, severity and frequency of behaviours that are considered typical at one age may be rated as pathological at another [20]. It is therefore important to use age- and
gender-specic norms and to obtain contemporaneous reference
data from term-born controls. Where possible, control groups
should be matched, or analyses adjusted, for confounding factors
such as age, sex and socio-economic status. There is controversy
over adjusting for IQ given statistical and theoretical limitations
[27,28] and the comorbidity of neurocognitive sequelae in EP
children (see Section 4.5). Parental mental health may also be a
confounder in light of the higher risk for psychopathology in the
offspring of those with disorders [29]. However, although parents
of preterm children are at risk for parenting stress and poor mental
health [30e32] medical, biological and neurodevelopmental variables are stronger predictors of childhood psychopathology in
preterm samples [33e36], and there is inconsistency in studies of

the relationship between parental mental health and preterm

childrens socio-emotional development [15,30,37,38]. These associations are likely to be bidirectional, potentially mediated by the
quality of parenteinfant interaction [30,39e41]. The importance of
parental mental health as a causal factor in EP childrens psychopathology requires elucidation in longitudinal studies. Parental
mental health is discussed further in this issue by Karli Treyvaud
(Chapter 10).
3. The preschool years
3.1. Behaviour and emotional problems in the preschool years
There is a surprising lack of research regarding behavioural
outcomes during the preschool years. Studies in infancy have
focused on the development of attachment relationships, temperament and parenteinfant interaction (see Korja et al. [42] and
Vanderbilt [43] for reviews). The assessment of early psychopathology becomes more rened from the age of 2e3 years when
well-standardised tools are available to identify clinically signicant difculties, such as the Child Behavior Checklist (CBCL) [44]
and the Strengths and Difculties Questionnaire (SDQ) [45].
Only a few recent studies have investigated outcomes in EP or
extremely low birthweight (ELBW) preschoolers (Table 1). In two
studies, children had more problems on all SDQ scales, suggesting a
generic risk for mental health problems following EP birth [46,47].
Interestingly, Elgen et al. [47] reported that 38% of EP children had
clinically signicant scores yet only 8% had been referred for psychiatric follow-up, highlighting the preponderance of subclinical
symptoms. In a longitudinal study, EP children had signicantly
poorer emotional and behavioural regulation than term-born
children at both 2 and 4 years of age (Table 1); moreover, they
showed less developmental gain than full-term and VP children,
which is suggestive of a specic vulnerability in the development of
early regulatory competence in EP children [48]. More recently,
Scott et al. [49] obtained multi-informant data on EP/ELBW children at 5 years of age. Using both a dimensional and diagnostic
approach, the authors reported greater specicity in outcomes
compared with earlier studies; only attention decit/hyperactivity
disorder (ADHD) symptoms were signicantly and consistently

Fig. 1. Prevalence of parent- and teacher-reported emotional, conduct, attention and peer problems and diagnoses of corresponding psychiatric disorders at 11 years of age among
219 children born extremely preterm (<26 weeks of gestation; EPICure Study) [10]. Asterisks denote signicant between-group differences between informant-rated Strengths and
Difculties Questionnaires and psychiatric diagnoses (P < 0.05). ADHD, attention decit hyperactivity disorder; ASD, autism spectrum disorders.

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99

Table 1
Prospective studies of behavioural and emotional problems and psychiatric disorders in extremely low birthweight (ELBW) or extremely preterm (EP) preschoolers born in the
1990s and beyonda.
Publication

Sample characteristics

Clark et al. [48]

Age (years)

Birth year

Preterm

Control

1998e2001
Single centre

N 39
<28 weeks

N 103

4
Woodward et al.[46]

1998e2000
Single centre

N 43
<28 weeks

N 107

Elgen et al. [47]

1999e2000
National

N 255
<28 weeks/<1000 g

N 1089

Scott et al. [49]

2001e2003
Single centre

N 148
<28 weeks/<1000 g

N 111

Domains with signicantly higher

mean scores in EP/ELBW children

Measure

Regulation

BRS

Regulation
Regulation
Emotional
Conduct
Hyperactivity/inattention
Peer relationship
Total difculties
Emotional
Conduct
Hyperactivity/inattention
Peer relationship
Total difculties
ADHD problems
ADHD problems
Affective problems
ADHD/inattentive
ODD

ERC
BRS
SDQ

SDQ

CBCL
TRF
P-ChIPS

BRS, Behaviour Rating Scale (abbreviated version) of the Bayley Scales of Infant Development, 2nd ed., rated by a researcher. ERC, Emotion Regulation Checklist (modied
version), rated by parents; SDQ, Strengths and Difculties Questionnaire; CBCL, Child Behavior Checklist; TRF, Teacher Report Form; P-ChIPS, Childrens Interview for Psychiatric Syndromes e Parent.
a
Studies are included where they report results for comparisons between EP/ELBW children and term-born controls.

this population [53]. Not only are screening tests associated with a
high rate of false positives, but the high prevalence of cognitive,
motor and sensory impairments in this population further confounds scores on these scales [50e52,54]. Importantly, these
studies have only used screening questionnaires and have not
implemented the M-CHAT follow-up interview to improve specicity. The predictive validity of positive screens and the true
prevalence of ASD in this population require investigation: studies
at school age may hold the answer (see Section 4).

increased, and there was a 2.5-fold increased risk for ADHD diagnoses (Table 1). Although parents and teachers rated higher
scores for affective and oppositional problems, respectively, no
other disorders were increased. These studies highlight an association between EP birth, regulatory problems and ADHD that is
already evident in the early years.
3.2. Early indicators of autism spectrum disorders (ASD)
An area gathering increasing interest is the risk for ASD in EP
infants (Table 2). In recent reports, 21e41% of EP [50,51] infants
screened positive for ASD at 18e24 months using the Modied
Checklist for Autism in Toddlers (M-CHAT) parent questionnaire. In
infants born at <27 weeks, 10e20% screened positive using a range
of ASD screening tools [52]. There is warranted concern that these
studies have substantially overestimated the true risk for ASD in

3.3. Predictive validity of early assessments

There is a paucity of longitudinal studies of behavioural outcomes in EP cohorts. Studies of VLBW children have indicated
moderate stability in problems over the preschool years [55,56] and
there is evidence that early screening is predictive of later mental

Table 2
Cohort studies that have investigated autism spectrum symptoms and disorders in extremely preterm and/or extremely low birthweight children.
Publication

Sample characteristics
Age (years)

The early years

Kuban et al. [50]

Moore et al. [51]

Stephens et al. [52]

School age and adolescence

Treyvaud et al. [60]
7
Hack et al. [24]

Johnson et al. [10]

11

Johnson et al. [25]

11

Prevalence of problems

Measure

M-CHAT

41%

M-CHAT

10%

PDD-2

P 0.08

DAWBA

0.6%
0
0
0
0
2.9%

ns
ns
P < 0.001
P 0.001 ns

CSI-4: autistic disorder

CSI-4: Asperger disorder
DAWBA: any ASD
DAWBA: autistic disorder
DAWBA: atypical autism
SCQ

Birth year

Preterm

Control

Preterm

Control

2002e2004
Regional
2006
National
2008e2009
Regional

N 988
<28 weeks
N 523
<26 weeks
N 554
<27 weeks

21%

e
e

2001e2003
Single centre
1992e1995
Single centre
1995
National

N 177
<30 weeks/<1250 g
N 219
<1000 g
N 219
<26 weeks

1995
National

N 219
<26 weeks

N 65
N 176
N 153

N 153

4.5%
2%
1%
8%
6.5%
1.5%
15.8%

P < 0.001

M-CHAT, Modied Checklist for Autism in Toddlers; PDD-2, Pervasive Developmental Disorders Screening Test, 2nd ed.; CSI-4, Child Symptom Inventory 4; DAWBA,
Development and Well Being Assessment; SCQ, Social Communication Questionnaire; ns, non-signicant.

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health [57]. In EP children, internalising behaviour problems at 2.5

years were a signicant predictor of disorders at 11 years of age,
whereas externalising difculties were not [10]. Scores on the CBCL
Withdrawn subscale have also been shown to be a signicant
predictor of later ASD symptoms [25], and scores on this and the
Emotionally Reactive subscale have also been associated with
positive M-CHAT screens [58]. Using a VP sample, Treyvaud et al.
[59] have also shown that internalising difculties, sociale
emotional competence and externalising problems at 2 years predicted emotional symptoms, peer problems and conduct problems
at 5 years, respectively. Socialeemotional problems at age 5 years
also predicted psychiatric disorders at age 7 years [60]. With such
specicity in prediction, it may be assumed that there is stability in
outcomes among EP children and that the early problems highlighted above will manifest in attention, emotional problems and
ASD later in childhood.
4. School age and adolescence
4.1. Dimensional studies
EP survivors are at high risk for clinically signicant problems
throughout middle childhood, with prevalence estimates of 18e
38% [24,26,61e63]. Studies have also shown that the mental health
problems of EP children have a greater impact on their daily living
than those of term-born controls [62,64]. Commensurate with the
temporal stability in neurodevelopmental outcomes [65], the rate
of mental health problems remains high despite advances in
neonatal care [61,64]. Whereas there is a greater risk for behaviour
problems in EP versus VP children [3,66], there is little evidence for
a gestation-related gradient within the EP group itself [62,64].
Compared with the preschool years, there is greater consistency
in ndings at school age. In three studies of six EP/ELBW cohorts,
the authors identied an excess of attention, social and thought or
emotional problems despite using different measures [61,64,67]. In
a study using multi-informant data to identify pervasive problems,
EP children had signicantly more problems on all scales but odds
ratios (ORs) were greatest for these three domains [62]. Conrad
et al. [14] also found that only depression/anxiety and hyperactivity/inattention were signicantly increased in ELBW children aged
7e16 years. These ndings thus point to a cluster of attention, social
and emotional problems in EP children [26].
4.2. Diagnostic studies
In a recent meta-analysis of ve studies [68], the authors reported a weighted OR of 3.66 for psychiatric disorders among

preterm children [68]. Three studies of EP/ELBW children report

consistently elevated risks for disorders with prevalence estimates
ranging 23e32% [10,24,60]. These also provide evidence for the
specic risk for attention and social problems in this population
(Table 3) [10,24]. In their VP cohort, Treyvaud et al. [60] did not
report a signicant increase in these disorders which the authors
acknowledge may be a result of low statistical power; however,
there was a trend for a higher rate of ADHD and anxiety disorders.
Thus there appears to be a pattern of elevated risk for symptoms
and disorders associated with ADHD, peer relationship problems
and emotional disorders, the cluster of which has been termed the
preterm behavioural phenotype [26].
The symptoms and correlates of ADHD and ASD in EP children
may indicate a different aetiology that is associated with aberrant
brain development. Indeed, Laucht et al. [29] have shown that
psychosocial and biological risk factors had independent effects on
behavioural outcomes; specically, psychosocial risk was more
strongly associated with externalising difculties whereas biological risk factors, such as preterm birth, were associated with isolated social and attention problems. Other studies have also noted
stronger associations of attention and peer problems with neurodevelopmental impairments [47]. Such studies provide increasing
support for an environmental, neurodevelopmental origin for
ADHD and ASD in EP children. Literature relating to ADHD and ASD
is summarised briey below.
4.3. Attention decit hyperactivity disorder
As noted earlier, Scott et al. [49] reported a 2.5-fold increased
risk for ADHD in EP children at 5 years of age; these ndings are
echoed later in childhood in which authors have reported ORs of
2.6e2.7 for ADHD in VP/VLBW children [69,70] and higher ORs of
4.2e4.3 for ADHD in those born EP/ELBW [10,24]. Dimensional
measures have indicated a generally increased liability to ADHD
symptoms in EP children and an excess of children with problems
who do not meet diagnostic criteria [66,71,72]. Increasing interest
has focused on the expression of ADHD symptoms in this population with a number of studies highlighting a higher risk for inattention relative to hyperactivity/impulsivity in terms of both
symptoms and disorders [10,34,38,73]. There is also a notable
absence of comorbid conduct disorders that are frequently
observed in general population samples (Table 3) [10,61,72]. It has
therefore been suggested that ADHD in preterm populations may
be better described as inattentive subtype disorders with a purer
neurodevelopmental origin [26,67,74]. The cognitive prole of EP
birth is characterised by core decits in working memory and
visuo-spatial skills which have been shown to mediate

Table 3
Mental health disorders in children born extremely preterm (EP) or with extremely low birthweight (ELBW) in the 1990s and beyond.
Publication

Sample characteristics
Age (years)

Scott et al. [49]

Treyvaud et al. [60]

Hack et al. [24]

Johnson et al. [10]

11

Prevalence of any disorder

Birth year

Preterm

Control

Index vs control

OR (95% CI)

2001e2003
Single centre
2001e2003
Single centre
1992e1995
Single centre

N 148
<28 weeks/<1000 g
N 177
<30 weeks/<1250 g
N 219
<1000 g

N 111

N 65

24% vs 9%

3.13 (1.27e7.71)

N 176

32% vs 15%

2.7 (1.6e4.5)

1995
National

N 219
<26 weeks

N 153

23% vs 9%

3.2 (1.7e6.2)

Disorders signicantly
increased in EP/ELBW
children

Measure

ADHD/combined
ADHD/hyperactive
None

P-ChIPS

ADHD (any)
ADHD/inattentive
ADHD/combined
Specic phobia
ADHD (any)
ADHD/inattentive
Emotional disorders
ASD

DAWBA
CSI-4

DAWBA

OR, odds ratio; CI, condence interval; P-ChIPS, Childrens Interview for Psychiatric Syndromes e Parent; CSI-4, Child Symptom Inventory 4; DAWBA, Development and WellBeing Assessment.

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101

performance on executive function and intelligence tests [75,76].

These core decits may also be implicated in the inattention difculties observed in EP children [73,77].
4.4. Autism spectrum disorders
Studies at school age have conrmed a signicantly increased
risk for ASD in EP children, and, as anticipated, the 4e8% prevalence
is markedly lower than the positive screen rate in infancy [24,25]. In
addition, almost twice as many children have clinically signicant
symptoms than have diagnoses [25]. As with ADHD, ASD may also
have a different origin in EP children that is again associated with
aberrant brain development [10,26,50]. ASD in EP children are
more closely associated with a smaller head circumference,
cognitive decits and neurological injuries than are ASD in the
general population [10,50,78,79]. Moreover, EP children have
greater symptoms on the dimensions of impaired social interaction
and communication than repetitive or stereotyped behaviour, the
latter of which is a core symptom domain in diagnostic classications [71,80]. As such, these symptoms may be better characterised
by a social communication disorder. Like ASD, these impairments
may be mediated by EP childrens cognitive decits that adversely
impact on their processing of social and emotional stimuli.
4.5. Comorbidity
The few studies addressing issues of comorbidity have reported
mixed results regarding the rate of comorbid mental health disorders in EP children compared with controls [10,24,49,60]. The most
consistent nding is the lack of comorbid ADHD and conduct disorders. What is perhaps a more pertinent question is to what extent
mental health disorders confer additional morbidity over other
neurodevelopmental sequelae. Numerous studies have shown that
mental health problems are associated with neurosensory, cognitive and motor impairments in this population and, in the majority
of cases, these do not account for the excess of mental health disorders [3,24,56,62]. In the EPICure Study, mental health disorders
conferred only a small degree of additional morbidity over neurodevelopmental disabilities in EP children (Fig. 2). However, it is
important to note that there is a substantial portion of children
whose parents and teachers report clinically signicant difculties
but who do not meet criteria for diagnoses (Fig. 1); thus the true
functional impact of mental health problems is likely to be far
greater than is suggested by the excess of psychiatric disorders
alone.
5. Mental health in adulthood
Emerging data from population registry linkage studies in
Scandinavia indicate a signicant increase in the risk of adult
mental health disorders with decreasing gestational age at birth.
Because of the relatively low population prevalence of these conditions, such large, and necessarily broad, studies are the only ones
to reliably report such ndings. Moster et al. [81] reported an
increased relative risk (RR) of ASD [9.5; 95% condence interval
(CI): 1.5, 36.2] and other disorders of psychological development,
behaviour and emotions (10.5; 5.6, 19.9) in Norwegian adults born
EP. Although the risk of schizophrenia was not signicantly
elevated, it is worth noting that the point prevalence was low even
though the population was censored at 36 years of age. In a further
study of treatment registration among adults in Norway, Halmoy
et al. [82] conrmed that EP survivors remain at increased risk for
ADHD in adulthood (adjusted RR: 5.0; 2.1, 11.8), and a Swedish
study of psychiatric hospitalisations to 23 years also reported
increased risk for non-affective psychosis, depressive disorder and

Fig. 2. Prevalence of moderate/severe neurodevelopmental disability and psychiatric

disorders in 219 11-year-old children born extremely preterm (<26 weeks of gestation)
and a comparison group of 153 classmates born at term (EPICure Study) [4,10].

bipolar affective disorder in adults born <32 weeks [83]. These

latter data conrm the earlier ndings of increased admissions for
psychiatric and addictive disorders [84]. Finally, a study by Crump
et al. [85] conrmed that young adults born EP were more
frequently prescribed psychotrophic medications, specically antipsychotics, antidepressants and hypnotics. As each of these
studies demonstrated a signicant dose effect of prematurity and
a gradation of increased risk with decreasing gestation, there is
apparent continuity of risk from the adolescent studies referred to
above.
Demonstrating this in smaller prospective cohort studies is
more difcult. Saigal et al. [86] reported greater internalised
behaviours in young adults, together with an increased rate of
prescriptions for antidepressants. Several studies of VLBW young
adults have demonstrated a signicant reduction in risk taking
behaviours and social interaction [72,87,88]. Most recently, Burnett et al. [89] have reported a sustained increase in the prevalence of ADHD in EP/ELBW adolescents at 18 years of age, but no
signicant excess of anxiety or mood disorders compared with
normal birth weight controls, using both diagnostic and
dimensional measures. This is somewhat unexpected given that
the majority of previous cohort and population registry linkage
studies have identied increased mood disorders in adolescence
and adulthood. This is therefore encouraging but it remains to be
seen whether such ndings are replicated in other post-1990
cohorts. Taken together, these studies show that although children remain at increased risk of psychiatric disorders in the long

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term, the societal consequences of EP birth in young adulthood

appear to be somewhat less than anticipated, with better social
adaptation and quality of life than might once have been
predicted.
6. A biological basis for psychiatric morbidity
A biological basis for psychiatric disorders in EP survivors is
perhaps understandable after consideration of the effect of prematurity on brain development, which has been described as a
complex amalgam of destructive and developmental inuences
[90]. Studies using magnetic resonance imaging and computational
techniques have identied differences in the brains of EP children
and adults which may act as biomarkers for these evolving conditions [91]. These include not only ongoing adaptation to destructive
lesions, but more subtle differences in brain size/surface area [92]
and regional volumes such as the frontal and temporal cortex or
hippocampus [93], deep gray matter [94] and corpus callosum [95].
Reduced complexity of brain folding and abnormalities on functional activation imply altered developmental trajectories that
mirror impaired executive functions [96]. As discussed above, such
cognitive decits may underpin mental health symptoms and disorders in EP children [77,97].
Although ex-preterm brain structure and function in relation to
specic psychiatric disorders have not been investigated in large
populations of EP individuals, data from middle childhood suggests that structural alterations may be associated with behavioural ndings, for example with attention and internalising
behaviours (fractional anisotropy in a range of overlapping
areas),[98] socio-emotional development (hippocampal size) [99]
and wellbeing (cerebellar growth) [100]. As yet, such studies
have not been sufciently large or systematic to develop a picture
of the underlying neural basis for psychiatric disorders associated
with preterm birth, but the data suggest that there may be a
biological basis for the clinically observed excess of psychopathology in this population.
7. Conclusions
Studies of mental health outcomes following EP birth have
largely sought to document the prevalence of disorders in
middle childhood and adolescence, but reports of longer-term
outcomes are beginning to surface as contemporary cohorts
reach adulthood. Early attention and regulatory problems are
evident in the preschool years and, by childhood, the greater
specicity in outcomes points to a cluster of inattention, peer
relationship problems and emotional symptoms. Approximately
25% have psychiatric disorders but up to double those numbers
may have signicant difculties that impact on function. This
behavioural phenotype shows continuity into adult life with
increased risk for disorders, yet quality of life and social adaptation are better than may have once been anticipated. Mental
health symptoms appear to have a strong neurodevelopmental
origin which may be mediated by core cognitive decits associated with EP birth. Targeted screening for the cluster of mental
health problems associated with EP birth may be benecial for
detecting children with subclinical difculties, particularly during the preschool years when problems start to become evident.
Future studies are needed to identify resilience and risk factors
for mental health disorders and to further elucidate the role of
parental mental health in the evolution of psychopathology in
EP children. As more EP children continue to enter society, a
greater understanding of the aetiology and functional impact of
these disorders will aid in providing appropriate lifelong
support.

Practice points
 Children born extremely preterm may have attention,
emotional or peer relationship problems that do not meet
diagnostic criteria but which may impact on daily function, for which intervention may be beneficial.
 Screening for behaviour problems from 2 years of age
may aid in detecting children with early difficulties and
those at risk of later mental health disorders.
 Researchers and clinicians should consider including
mental health assessments as part of neurodevelopmental outcome evaluations.

Research directions
 Longitudinal studies are needed to investigate the evolution of mental health sequelae throughout the lifespan.
 The role of parental mental health in the development of
childhood psychopathology requires elucidation in this
population.
 More studies are required to understand the neurological
bases of mental health disorders in extremely preterm
children.

Funding sources
Neil Marlow receives a proportion of funding from the Department of Healths NIHR Biomedical Research Centres funding
scheme at UCLH/UCL.
References
[1] Saigal S, Doyle L. An overview of mortality and sequelae of preterm birth
from infancy to adulthood. Lancet 2008;371:261e9.
[2] MacKay DF, Smith GC, Dobbie R, Pell JP. Gestational age at delivery and
special educational need: retrospective cohort study of 407,503 schoolchildren. PLoS Med 2010;7:e1000289.
[3] Anderson P, Doyle LW. Neurobehavioral outcomes of school-age children
born extremely low birth weight or very preterm in the 1990s. JAMA
2003;289:3264e72.
[4] Johnson S, Fawke J, Hennessy E, Rowell V, Thomas S, Wolke D, et al.
Neurodevelopmental disability through 11 years in children born before
26 weeks of gestation: the EPICure study. Pediatrics 2009;124:e249e57.
[5] Marlow N. Measuring neurodevelopmental outcome in neonatal trials: a
continuing and increasing challenge. Arch Dis Child Fetal Neonatal Ed
2013;98:F554e8.
[6] Angold A, Erkanli A, Copeland W, Goodman R, Fisher PW, Costello EJ.
Psychiatric diagnostic interviews for children and adolescents: a
comparative study. J Am Acad Child Adolesc Psychiatry 2012;51:506e17.
[7] Johnson S. Cognitive and behavioural outcomes following very preterm
birth. Semin Fetal Neonatal Med 2007;12:363e73.
[8] Arpi E, Ferrari F. Preterm birth and behaviour problems in infants and
preschool-age children: a review of the recent literature. Dev Med Child
Neurol 2013;55:788e96.
[9] EPICure Studies. Population based studies of survival and later health
status in extremely premature infants. www.epicure.ac.uk; 2013.
*[10] Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Psychiatric
disorders in extremely preterm children: longitudinal nding at age 11
years in the EPICure study. J Am Acad Child Adolesc Psychiatry 2010;49.
453.e1e463.e1.
[11] Bora S, Pritchard VE, Moor S, Austin NC, Woodward LJ. Emotional and
behavioural adjustment of children born very preterm at early school age.
J Paediatr Child Health 2011;47:863e9.
[12] Dahl LB, Kaaresen PI, Tunby J, Handegard BH, Kvernmo S, Ronning JA.
Emotional, behavioral, social, and academic outcomes in adolescents born
with very low birth weight. Pediatrics 2006;118:E449e59.
[13] van Dulmen MHM, Egeland B. Analyzing multiple informant data on child
and adolescent behavior problems: predictive validity and comparison of
aggregation procedures. Int J Behav Dev 2011;35:84e92.
[14] Conrad AL, Richman L, Lindgren S, Nopoulos P. Biological and environmental predictors of behavioral sequelae in children born preterm. Pediatrics 2010;125:e83e9.

S. Johnson, N. Marlow / Seminars in Fetal & Neonatal Medicine 19 (2014) 97e104

[15] Spiker D, Kraemer HC, Constantine NA, Bryant D. Reliability and validity of
behavior problem checklists as measures of stable traits in low birth
weight, premature preschoolers. Child Dev 1992;63:1481e96.
[16] Gardner F, Johnson A, Yudkin P, Bowler U, Hockley C, Mutch L, et al.
Behavioral and emotional adjustment of teenagers in mainstream school
who were born before 29 weeks gestation. Pediatrics 2004;114:676e82.
[17] Saigal S, Pinelli J, Hoult L, Kim MM, Boyle M. Psychopathology and social
competencies of adolescents who were extremely low birth weight. Pediatrics 2003;111:969e75.
[18] Renk K. Cross-informant ratings of the behavior of children and adolescents: the gold standard. J Child Fam Stud 2005;14:457e68.
[19] Ford T, Goodman R, Meltzer H. The British child and adolescent mental
health survey 1999: the prevalence of DSM-IV disorders. J Am Acad Child
Adolesc Psychiatry 2003;42:1203e11.
[20] Hudziak JJ, Achenbach TM, Althoff RR, Pine DS. A dimensional approach to
developmental psychopathology. Int J Methods Psychiatr Res
2007;16(Suppl. 1):S16e23.
[21] Goodman A, Goodman R. Strengths and difculties questionnaire as a
dimensional measure of child mental health. J Am Acad Child Adolesc
Psychiatry 2009;48:400e3.
[22] Nigg JT. Future directions in ADHD etiology research. J Clin Child Adolesc
Psychol 2012;41:524e33.
[23] Coghill D, Sonuga-Barke EJ. Annual research review: categories versus
dimensions in the classication and conceptualisation of child and
adolescent mental disorders e implications of recent empirical study. J
Child Psychol Psychiatry Allied Discipl 2012;53:469e89.
*[24] Hack M, Taylor HG, Schlichter M, Andreias L, Drotar D, Klein N. Behavioral
outcomes of extremely low birth weight children at age 8 years. J Dev
Behav Pediatr 2009;30:122e30.
[25] Johnson S, Hollis C, Kochhar P, Hennessy E, Wolke D, Marlow N. Autism
spectrum disorders in extremely preterm children. J Pediatr 2010;156:
525e31.
*[26] Johnson S, Marlow N. Preterm birth and childhood psychiatric disorders.
Pediatr Res 2011;69:11re8r.
[27] Dennis M, Francis DJ, Cirino PT, Schachar R, Barnes MA, Fletcher JM. Why
IQ is not a covariate in cognitive studies of neurodevelopmental disorders.
J Int Neuropsychol Soc 2009;15:331e43.
[28] Taylor HG. Children born preterm or with very low birth weight can have
both global and selective cognitive decits. J Dev Behav Pediatr 2006;27:
485e6. author reply 6e7.
[29] Laucht M, Esser G, Baving L, Gerhold M, Hoesch I, Ihle W, et al. Behavioral
sequelae of perinatal insults and early family adversity at 8 years of age. J
Am Acad Child Adolesc Psychiatry 2000;39:1229e37.
[30] Treyvaud K, Anderson VA, Lee KJ, Woodward LJ, Newnham C, Inder TE,
et al. Parental mental health and early socialeemotional development of
children born very preterm. J Pediatr Psychol 2010;35:768e77.
[31] Miles MS, Holditch-Davis D, Schwartz TA, Scher M. Depressive symptoms
in mothers of prematurely born infants. J Dev Behav Pediatr 2007;28:36e
44.
[32] Glazebrook C, Marlow N, Israel C, Croudace T, Johnson S, White IR, et al.
Randomised trial of a parenting intervention during neonatal intensive
care. Arch Dis Child Fetal Neonatal Ed 2007;92:F438e43.
[33] Indredavik MS, Vik T, Heyerdahl S, Kulseng S, Fayers P, Brubakk AM.
Psychiatric symptoms and disorders in adolescents with low birth weight.
Arch Dis Child 2004;89:F445e50.
[34] Botting N, Powls A, Cooke RWI, Marlow N. Attention decit hyperactivity disorders and other psychiatric outcomes in very low birthweight
children at 12 years. J Child Psychol Psychiatry Allied Discipl 1997;38:
931e41.
[35] Indredavik MS, Vik T, Evensen AI, Skranes J, Taraldsen G, Brubakk A.
Perinatal risk and psychiatric outcome in adolescents born preterm with
very low birth weight or term small for gestational age. J Dev Behav
Pediatr 2010;31:286e94.
*[36] Spittle AJ, Treyvaud K, Doyle LW, Roberts G, Lee KJ, Inder TE, et al. Early
emergence of behavior and socialeemotional problems in very preterm
infants. J Am Acad Child Adolesc Psychiatry 2009;48:909e18.
[37] Huhtala M, Korja R, Lehtonen L, Haataja L, Lapinleimu H, Rautava P.
Parental psychological well-being and behavioral outcome of very low
birth weight infants at 3 years. Pediatrics 2012;129:e937e44.
[38] Jaekel J, Wolke D, Bartmann P. Poor attention rather than hyperactivity/
impulsivity predicts academic achievement in very preterm and full-term
adolescents. Psychol Med 2013;43:183e96.
[39] Jaekel J, Wolke D, Chernova J. Mother and child behaviour in very preterm
and term dyads at 6 and 8 years. Dev Med Child Neurol 2012;54:716e23.
[40] Forcada-Guex M, Pierrehubert B, Borghini A, Moessinger A, MullerNix CM. Early dyadic patterns of mothereinfant interactions and outcomes of prematurity at 18 months. Pediatrics 2006;118:107e14.
[41] Assel M, Landry S, Swank P, Steelman L, Miller-Loncar C, Smith K. How do
mothers childrearing histories, stress and parenting affect childrens
behavioural outcomes? Child Care Health Dev 2002;28:359e68.
[42] Korja R, Latva R, Lehtonen L. The effects of preterm birth on mothereinfant interaction and attachment during the infants rst two years. Acta
Obstet Gynecol Scand 2012;91:164e73.
[43] Vanderbilt D, Gleason MM. Mental health concerns of the premature infant through the lifespan. Pediatr Clin North Am 2011;58:815e32.

103

[44] ASEBA. Achenbach system of empirically based assessment. http://www.

aseba.org/; 2012.
[45] Goodman R. The strengths and difculties questionnaire: a research note.
J Child Psychol Psychiatry 1997;38:581e6.
[46] Woodward LJ, Moor S, Hood KM, Champion PR, Foster-Cohen S, Inder TE,
et al. Very preterm children show impairments across multiple neurodevelopmental domains by age 4 years. Archs Dis Childh Fetal Neonatal
Ed 2009;94:F339e44.
[47] Elgen SK, Leversen KT, Grundt JH, Hurum J, Sundby AB, Elgen IB, et al.
Mental health at 5 years among children born extremely preterm: a national population-based study. Eur Child Adolesc Psychiatry 2012;21:
583e9.
[48] Clark CAC, Woodward LJ, Horwood LJ, Moor S. Development of emotional
and behavioral regulation in children born extremely preterm and very
preterm: biological and social inuences. Child Dev 2008;79:1444e62.
*[49] Scott MN, Taylor HG, Fristad MA, Klein N, Espy KA, Minich N, et al.
Behavior disorders in extremely preterm/extremely low birth weight
children in kindergarten. J Dev Behav Pediatr 2012;33:202e13.
[50] Kuban KCK, OShea TM, Allred EN, Tager-Flusberg H, Goldstein DJ,
Leviton A. Positive screening on the Modied Checklist for Autism in
Toddlers (M-CHAT) in extremely low gestational age newborns. J Pediatr
2009;154:535e40.
[51] Moore T, Johnson S, Hennessy E, Marlow N. Screening for autism in
extremely preterm infants: problems in interpretation. Dev Med Child
Neurol 2012;54:514e20.
[52] Stephens BE, Bann CM, Watson VE, Sheinkopf SJ, Perata-Carcelen M,
Bodnar A, et al. Screening for autism spectrum disorders in extremely
preterm infants. J Dev Behav Pediatr 2012;33:535e41.
[53] Johnson S, Marlow N. Positive screening results on the modied checklist
for autism in toddlers: implications for very preterm populations. J Pediatr
2009;154:478e80.
[54] Luyster RJ, Kuban KCK, OShea TM, Paneth N, Aldred EN, Leviton A. The
modied checklist for autism in toddlers in extremely low gestational age
newborns: individual items associated with motor, cognitive, vision and
hearing limitations. Paediatr Perinat Epidemiol 2011;25:366e76.
[55] Gray RF, Indurkhya A, McCormick MC. Prevalence, stability, and predictors
of clinically signicant behavior problems in low birth weight children at
3, 5, and 8 years of age. Pediatrics 2004;114:736e43.
[56] Delobel-Ayoub M, Arnaud C, White-Koning M, Casper C, Pierrat V,
Garel M, et al. Behavioral problems and cognitive performance at 5 years
of age after very preterm birth: the EPIPAGE study. Pediatrics 2009;123:
1485e92.
[57] Briggs-Gowan MJ, Carter AS. Socialeemotional screening status in early
childhood predicts elementary school outcomes. Pediatrics 2008;121:
957e62.
[58] Limperopoulos C, Bassan H, Sullivan NR, Soul JS, Robertson RL, Moore M,
et al. Positive screening for autism in ex-preterm infants: prevalence and
risk factors. Pediatrics 2008;121:758e65.
[59] Treyvaud K, Doyle LW, Lee KJ, Roberts G, Lim J, Inder TE, et al. Sociale
emotional difculties in very preterm and term 2 year olds predict specic
socialeemotional problems at the age of 5 years. J Pediatr Psychol
2012;37:779e85.
[60] Treyvaud K, Ure A, Doyle LW, Lee KJ, Rogers CE, Kidokoro H, et al. Psychiatric outcomes at age seven for very preterm children: rates and predictors. J Child Psychol Psychiatry Allied Discipl 2013;54:772e9.
[61] Farooqi A, Hagglof B, Sedin G, Gothefors L, Serenius F. Mental health and
social competencies of 10- to 12-year-old children born at 23 to 25 weeks
of gestation in the 1990s: a Swedish national prospective follow-up study.
Pediatrics 2007;120:118e33.
[62] Samara M, Marlow N, Wolke D. Pervasive behavior problems at 6 years of
age in a total-population sample of children born at 25 weeks of
gestation. Pediatrics 2008;122:562e73.
[63] Grunau R, Whiteld MF, Fay TB. Psychosocial and academic characteristics
of extremely low birth weight (<800g) adolescents who are free of major
impairment compared with term-born control subjects. Pediatrics
2004;114:e725e32.
[64] Hutchinson EA, De Luca CR, Doyle LW, Roberts G, Anderson PJ. Victorian
Infant Collaborative Study G. School-age outcomes of extremely preterm
or extremely low birth weight children. Pediatrics 2013;131:e1053e61.
[65] Moore T, Hennessy EM, Myles J, Johnson S, Draper ES, Costeloe KL, et al.
Neurological and developmental outcome in extremely preterm children
born in England in 1995 and 2006: the EPICure studies. BMJ 2012;345:
e7961.
[66] Taylor HG, Klein N, Minich N, Hack M. Middle school-age outcomes in
children with very low birth-weight. Child Dev 2000;71:1495e511.
*[67] Hille ETM, den Ouden AL, Saigal S, Wolke D, Lambert M, Whitaker A, et al.
Behavioural problems in children who weigh 1000 g or less at birth in four
countries. Lancet 2001;357:1641e3.
*[68] Burnett AC, Anderson PJ, Cheong J, Doyle LW, Davey CG, Wood SJ. Prevalence of psychiatric diagnoses in preterm and full-term children, adolescents and young adults: a meta-analysis. Psychol Med 2011;41:2463e
74.
[69] Bhutta A, Cleves M, Casey P, Cradock M, Anand K. Cognitive and behavioral
outcomes of school-aged children who were born preterm. A metaanalysis. J Am Med Assoc 2002;288:728e37.

104

S. Johnson, N. Marlow / Seminars in Fetal & Neonatal Medicine 19 (2014) 97e104

[70] Linnet KM, Wisborg K, Agerbo E, Secher NJ, Thomsen PH, Henriksen TB.
Gestational age, birth weight, and the risk of hyperkinetic disorder. Arch
Dis Child 2006;91:655e60.
*[71] Johnson S, Wolke D. Behavioural outcomes and psychopathology during
adolescence. Early Hum Dev 2013;89:199e207.
[72] Hack M, Flannery DJ, Schluchter M, Cartar L, Borawski E, Klein N. Outcomes in young adulthood for very-low-birth-weight infants. N Engl J
Med 2002;346:149e57.
[73] Shum D, Neulinger K, OCallaghan M, Mohay H. Attentional problems in
children born with very preterm or with extremely low birth weight at 7e
9 years. Arch Clin Neuropsychol 2008;23:103e12.
[74] Martel MM, von Eye A, Nigg JT. Revisiting the latent structure of ADHD: is
there a g factor? J Child Psychol Psychiatry 2010;51:905e14.
[75] Mulder H, Pitchford NJ, Hagger MS, Marlow N. Development of executive
function and attention in preterm children: a systematic review. Dev
Neuropsychol 2009;34:393e421.
[76] Aarnoudse-Moens CS, Duivenvoorden HJ, Weisglas-Kuperus N, Van
Goudoever JB, Oosterlaan J. The prole of executive function in very
preterm children at 4 to 12 years. Dev Med Child Neurol 2012;54:247e53.
[77] Nadeau L, Boivin M, Tessier R, Lefebvre F, Robaey P. Mediators of behavioral problems in 7-year-old children born after 24 to 28 weeks of
gestation. J Dev Behav Pediatr 2001;22:1e10.
[78] Hack M, Youngstrom EA, Cartar L, Schluchter M, Taylor HG, Flannery D,
et al. Behavioral outcomes and evidence of psychopathology among very
low birth weight infants at age 20 years. Pediatrics 2004;114:932e40.
[79] Skranes J, Vangberg TR, Kulseng S, Indredavik MS, Evensen KA,
Martinussen M, et al. Clinical ndings and white matter abnormalities
seen on diffusion tensor imaging in adolescents with very low birth
weight. Brain 2007;130:654e66.
[80] American Psychiatric Association. Diagnostic and statistical manual of
mental disorders (DSM-V). 5th ed. Washington DC: APA; 2013.
[81] Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med 2008;359:262e73.
[82] Halmoy A, Klungsoyr K, Skjaerven R, Haavik J. Pre- and perinatal risk
factors in adults with attention-decit/hyperactivity disorder. Biol Psychiatry 2012;71:474e81.
*[83] Nosarti C, Reichenberg A, Murray RM, Cnattingius S, Lambe MP, Yin L, et al.
Preterm birth and psychiatric disorders in young adult life. Arch Gen
Psychiatry 2012;69:E1e8.
[84] Lindstrom K, Lindblad F, Hjern A. Psychiatric morbidity in adolescents and
young adults born preterm: a Swedish national cohort study. Pediatrics
2009;123:e46e53.
[85] Crump C, Winkleby MA, Sundquist K, Sundquist J. Preterm birth and
psychiatric medication prescription in young adulthood: a Swedish national cohort study. Int J Epidemiol 2010;39:1522e30.
*[86] Saigal S, Stoskopf B, Streiner DL, Boyle M, Pinelli J, Paneth N, et al. Transition of extremely low-birth weight infants from adolescence to young

[87]

[88]
*[89]

[90]

[91]
[92]

[93]

[94]

[95]

[96]

[97]

[98]

[99]

[100]

adulthood. Comparison with normal birth-weight controls. JAMA

2006;295:667e75.
Hallin AL, Stjernqvist K. Follow-up of adolescents born extremely preterm: self-perceived mental health, social and relational outcomes. Acta
Paediatr 2011;100:279e83.
Cooke RW. Health, lifestyle, and quality of life for young adults born very
preterm. Archs Dis Childh 2004;89:201e6.
Burnett A, Davey CG, Wood SJ, Wilson-Ching M, Molloy C, Cheong JL, et al.
Extremely preterm birth and adolescent mental health in a geographical
cohort born in the 1990s. Psychol Med 2013 Aug;28:1e12 [Epub ahead of
print].
Volpe JJ. Brain injury in premature infants: a complex amalgam of
destructive and developmental disturbances. Lancet Neurol 2009;8:110e
24.
Ment LR, Hirtz D, Huppi PS. Imaging biomarkers of outcome in the
developing preterm brain. Lancet Neurol 2009;8:1042e55.
Skranes J, Lohaugen GC, Martinussen M, Haberg A, Brubakk AM, Dale AM.
Cortical surface area and IQ in very-low-birth-weight (VLBW) young
adults. Cortex 2013;49:2264e71.
de Kieviet JF, Zoetebier L, van Elburg RM, Vermeulen RJ, Oosterlaan J. Brain
development of very preterm and very low-birthweight children in
childhood and adolescence: a meta-analysis. Dev Med Child Neurol
2012;54:313e23.
Boardman JP, Counsell SJ, Rueckert D, Kapellou O, Bhatia KK, Aljabar P,
et al. Abnormal deep grey matter development following preterm birth
detected using deformation-based morphometry. Neuroimage 2006;32:
70e8.
Northam GB, Liegeois F, Tournier JD, Croft LJ, Johns PN, Chong WK, et al.
Interhemispheric temporal lobe connectivity predicts language impairment in adolescents born preterm. Brain 2012;135:3781e98.
Smyser CD, Snyder AZ, Shimony JS, Blazey TM, Inder TE, Neil JJ. Effects of
white matter injury on resting state FMRI measures in prematurely born
infants. PLoS One 2013;8:e68098.
Mulder H, Pitchford NJ, Marlow N. Processing speed mediates executive
function difculties in very preterm children in middle childhood. J Int
Neuropsychol Soc 2011 Mar;28:1e10 [Epub ahead of print].
Loe IM, Lee ES, Feldman HM. Attention and internalizing behaviors in
relation to white matter in children born preterm. J Dev Behav Pediatr
2013;34:156e64.
Rogers CE, Anderson PJ, Thompson DK, Kidokoro H, Wallendorf M,
Treyvaud K, et al. Regional cerebral development at term relates to schoolage socialeemotional development in very preterm children. J Am Acad
Child Adolesc Psychiatry 2012;51:181e91.
Parker J, Mitchell A, Kalpakidou A, Walshe M, Jung HY, Nosarti C, et al.
Cerebellar growth and behavioural and neuropsychological outcome in
preterm adolescents. Brain 2008;131:1344e51.