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Pediatrics
April 2010, VOLUME 125 / ISSUE 4

A Systematic Review of Motor and

Cognitive Outcomes After Early Surgery
for Congenital Heart Disease
Suzanne H. Snookes, Julia K. Gunn, Bev J. Eldridge, Susan M. Donath, Rod W. Hunt, Mary
P. Galea, Lara Shekerdemian

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Abstract
CONTEXT: Brain injury is the most common long-term complication of congenital heart
disease requiring surgery during infancy. It is clear that the youngest patients undergoing
cardiac surgery, primarily neonates and young infants, are at the greatest risk for brain injury.
Developmental anomalies sustained early in life have lifelong repercussions.

OBJECTIVE: We conducted a systematic review to examine longitudinal studies of

cognitive and/or motor outcome after cardiac surgery during early infancy.

METHODS: Electronic searches were performed in Medline, the Cumulative Index to

Nursing and Allied Health Literature (Cinahl), and Embase (19982008). The search strategy
yielded 327 articles, of which 65 were reviewed. Eight cohorts provided prospective data
regarding the cognitive and/or motor outcome of infants who had undergone surgery for
congenital heart disease before 6 months of age. Two authors, Ms Snookes and Dr Gunn,
independently extracted data and presented results according to 3 subgroups for age of
follow-up: early development (1 to <3 years); preschool age (35 years); and school age (>5
to 17 years). Weighted analysis was undertaken to pool the results of studies when
appropriate.

RESULTS: All of the identified studies reported results of the Bayley Scales of Infant
Development for children younger than the age of 3. Outcome data as reported by the Bayley
Scales were combined for infants assessed at 1 year of age, revealing a weighted mean
Mental Development Index of 90.3 (95% confidence interval: 88.991.6) and Psychomotor
Development Index of 78.1 (95% confidence interval: 76.479.7). Additional analysis was
limited by a lack of data at preschool and school age.

CONCLUSIONS: With this review we identified a limited number of prospective studies

that systematically addressed outcome in patients at the highest risk. These studies
consistently revealed cognitive and motor delay in children after cardiac surgery during early
infancy. Additional investigation is required to ascertain the consequences of such
impairment during later childhood and into adult life.

cardiac surgery
congenital heart defects
brain injury
developmental disabilities

WHAT'S KNOWN ON THIS SUBJECT:

Survival rates have improved for infants undergoing cardiac surgery in infancy.
Unfortunately, neurologic morbidity is a concern for some survivors. Despite growing
awareness of morbidity, there have been no systematic reviews that have examined such
outcomes in the current surgical era.

WHAT THIS STUDY ADDS:

A systematic review was performed, considering motor and cognitive outcomes after cardiac
surgery at up to 6 months of age. Our detailed analysis of the literature provides an important
update and a template for future studies.
Over the last 2 decades, advances in surgical technique and intensive care for infants
undergoing surgery for congenital heart disease (CHD) have led to a decline in mortality.1 As
survival has improved, long-term disability is now considered a key outcome measure for
these patients. Brain injury is the most significant complication of surgery for CHD.
Neuropathologic specimens24 or cerebral imaging techniques such as ultrasound57 and
MRI8,,16 have revealed a spectrum of congenital and acquired insults in up to half of the
infants who undergo cardiac surgery. Compared with older children, the youngest infants are
at greatest risk of brain injury because of the vulnerability of developing white matter to
acute changes in perfusion and oxygenation,17 the greater complexity of the surgery
performed, and the associated physiology. Although imaging modalities give us valuable
insights into the nature and timing of cerebral injury, the paucity of data correlating findings
with long-term follow-up studies limits our ability to make predictions of neurologic outcome
from these results.

For the past 2 decades, concerns relating to brain injury in children undergoing open-heart
surgery, and the paucity of neurodevelopmental follow-up data, have been highlighted.18
Griffin et al19 published a comprehensive review of neurodisability after surgery for CHD
between 1980 and 2001. Of the 19 series identified, most concluded that children with CHD
were at increased risk for impaired neurodevelopment regardless of their lesion. However,
there was inconsistency in findings in the preschool- and school-aged populations,
predominantly because of the spectrum of CHD and the age at surgery. The authors
reinforced the lack of available longitudinal data regarding cognitive and neurologic status of
children with complex CHD.

Several elegant reviews have contributed to our current knowledge regarding

neurodevelopmental outcome in the modern era of infant cardiac surgery.20,,25 However, to
our knowledge no systematic analysis of developmental outcome data has been undertaken in
these patients, and no analysis has been performed that specifically targets those having
surgery during early infancy. The objective of this systematic review was to examine the
literature for longitudinal studies of motor and/or cognitive development in infants
undergoing cardiac surgery during the first 6 months of life.

METHODS
Eligibility Criteria

Types of Studies

This review included all randomized, controlled trials or prospective observational cohort
studies or collective reports of multiple prospective cohorts that met the inclusion criteria for
patients and outcome measures.

Patients

Studies of infants undergoing surgical repair or palliation of CHD at up to 6 months of age

were considered for inclusion. Studies for which outcomes related to heart transplant or
isolated arterial duct ligation were excluded. Reports relating to surgery performed before
1988 were excluded, because earlier surgery would now be considered less representative of
the current era with respect to surgical technique, choice of operation, perfusion practice, and
perioperative intensive care. Studies for which the authors reported outcomes solely of
infants diagnosed with syndromes known to affect motor and/or cognitive outcome, such as
trisomy 21 and the 22q deletion spectrum, also were excluded.

Outcome Measures

We included studies for which motor and/or cognitive outcome using a standardized
assessment tool were reported. These tools typically produce a developmental quotient or
mean assessment score, which is available for comparison to normative data.
Nonstandardized methods of evaluating these outcomes were not considered.

Search Strategy

A comprehensive search was undertaken by using Medline, the Cumulative Index to Nursing
and Allied Health Literature (CINAHL), and Embase. Search terms included cardiovascular
surgical procedures or cardiac surgical procedures or heart defects, congenital and
brain injuries or child development or developmental disabilities or motor skills
disorders or psychomotor performance or psychological tests not syndrome or
chromosome disorders or chromosome aberrations. The search was limited to articles
published in English from 1988 to 2008. Two authors, Ms Snookes and Dr Gunn, reviewed
the initial search yield on the basis of title and abstract, and studies that did not meet the
inclusion criteria were excluded. The review authors then examined the full text of the
remaining articles to determine if they met the inclusion criteria. Reference lists from the
included articles were reviewed for additional studies.

Quantitative Analysis

Cognitive and motor outcome data were pooled into 3 age groups: early development (1 to <3
years); preschool age (35 years); and school age (>5 to 17 years). If serial assessments
within the specified age group were reported, data from the most recent assessment was used.
For example, if a study reported cognitive outcomes at 9 and 18 months, then the outcome at
18 months was used. If serial assessments across our specified age groups were reported, data
from the most recent assessment within each age category were used. For each study, mean
outcome values and SDs were reported. For studies for which outcomes using the same
outcome measure at the same time point were reported, a weighted estimate of mean outcome
values was performed. For these studies, heterogeneity was evaluated by using the I2 statistic.
The I2 statistic describes the percentage of total variation across studies that results from
heterogeneity rather than chance.26 A value of 0% indicates no observed heterogeneity, and
larger values show increasing heterogeneity. The possible reasons for heterogeneity were
explored by scrutinizing the studies and performing subgroup analyses when appropriate.
Authors of individual trials were contacted to obtain clarification of items when necessary.

RESULTS
Description of Studies

The search strategy initially identified 327 references, of which 266 were excluded on the
basis of the title and abstract. Six additional articles were identified through hand-searching,
of which 2 were excluded because of cross-sectional study design.27,28 Sixty-five publications
required more detailed examination, of which 40 were excluded for 1 or more of the
following reasons: an absence of developmental assessment tools and/or systematic reporting
of outcome measures at or beyond 1 year of age29,,33; 16 were excluded because of the
inclusion of infants whose age at primary surgery was >6 months, from which it was not
possible to extrapolate data from the younger subgroups32,34,,48; 7 were excluded because of
an indiscernible surgical period or surgical period before 198849,,55; and 12 were excluded
because of cross-sectional or retrospective study design.37,,40,42,45,46,56,,60

The final 25 articles that met all specified inclusion criteria considered only 8 cohorts; as
would be expected from longitudinal studies, many of these cohorts generated multiple
publications. Pertinent details of the publications that arose from these 8 studies, on which
our results are based, are presented in Table 1. Each cohort is discussed in detail below.

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TABLE 1

Details of Included Studies

Study 1

Study 1 was a single-center randomized, controlled trial of infants who underwent an arterial
switch operation for transposition of the great arteries (TGA) with either an intact ventricular
septum or a ventricular septal defect. Infants were randomly assigned to receive either low-
flow cardiopulmonary bypass or deep hypothermic circulatory arrest, with stratification
according to diagnosis and surgeon. Exclusion criteria were a birth weight of <2.5 kg, a
recognizable congenital syndrome, an associated extracardiac anomaly of greater than minor
severity, previous cardiac surgery, or the need for additional aortic arch reconstruction before
the first follow-up. Participants were assessed at 1, 4, and 8 years of age by using the Bayley
Scales of Infant Development I (BSID-I), the Wechsler Preschool and Primary Scale of
Intelligence-Revised (WPPSI-R) and the Peabody Developmental Motor Scale (PDMS), and
the Wechsler Intelligence Scale for Children 3rd Edition, respectively.61,,72

Study 2

This was a prospective cohort study of neurodevelopmental outcome of infants who

underwent the Norwood operation for palliation of hypoplastic left heart syndrome (HLHS).
Exclusion criteria included congenital syndromes known to severely affect
neurodevelopment, and nonEnglish-speaking families. Participants were assessed at 1 year
of age by using the BSID-II.73

Study 3

Study 3 was a single-center prospective cohort study of neurodevelopmental outcome in

relation to apolipoprotein E genotype in infants who underwent surgery before 6 months of
age. Exclusion criteria included multiple congenital anomalies, a recognizable genetic or
phenotypic syndrome other than 22q11 microdeletions, and nonEnglish-speaking families.
Subjects were evaluated at 1 year of age by using the BSID-II.74,,79
Study 4

Study 4 was a single-center randomized, controlled trial of regional cerebral perfusion or

deep hypothermic circulatory arrest in neonates with HLHS. Study participants were
stratified according to surgeon and the presence of 1 or more factors thought to increase the
risk of an adverse outcome, including pulmonary venous obstruction, prematurity (<36
weeks), a birth weight of <2.5 kg, and clinical shock or clinical seizures preoperatively.
Exclusion criteria included a birth weight of <2 kg, a gestational age of <32 weeks, an
identified genetic syndrome known to be associated with abnormal neurodevelopment, or a
history of maternal substance abuse. Development was measured at 1 year of age with the
BSID-II.80

Study 5

This was a single-center prospective cohort study of perioperative predictors of neurologic

injury in infants undergoing cardiac surgery before 4 months of age. Exclusion criteria were a
known chromosomal abnormality, associated extracardiac abnormality, or an abnormal
preoperative neurologic examination. All participants were assessed at 1 year of age by using
the BSID-II.81

Study 6

This was a single-center prospective cohort study of neurodevelopmental outcome in relation

to perioperative predictors in infants who underwent surgery before 6 weeks of age. Infants
who weighed <2.5 kg at birth were excluded. All participants were assessed at 8 months of
age by using the BSID-I and at 5 years of age by using the WPPSI-R or WPPSI 3rd
edition.82,,85

Study 7

Study 7 was a single-center prospective cohort study of neurodevelopmental outcome in

relation to perioperative predictors in infants who underwent an arterial switch operation
before 1 month of age. Exclusion criteria included known preoperative brain damage,
congenital brain abnormalities, and/or other chromosomal abnormalities. Outcome was
evaluated at 3 years of age by using the BSID-II.86

Study 8

Study 8 was a single-center prospective cohort study of the neurodevelopmental outcome of

infants who underwent cardiac surgery before 2 years of age. The subgroup of infants who
required surgery in the first month of life was reported separately. Exclusion criteria included
HLHS, as well as clinical evidence of preexisting neurologic impairment that was attributable
to a cause other than the heart defect. Participants were assessed 12 to 18 months after
surgery by using the PDMS and the Griffiths Mental Development Scale, and at 5 years of
age using the WPPSI-R.30,32,87,88

Cognitive Outcome

Early Development (1 to <3 years)

All 8 studies included cognitive evaluation during early development, generating 18
publications.6365,71,73,,84,86,87 After excluding studies with secondary analyses, primary data
concerning early cognitive outcomes were reported in 11 remaining publications. Five
articles reported cognitive outcome at 1 year of age with the BSID-II Mental Development
Index (MDI).73,75,76,80,81 The average MDI weighted by study sample size was 90.3 (95%
confidence interval [CI]: 88.991.6; I2 = 55.9) (Fig 1). One article reported 1-year cognitive
outcome age with the BSID-I MDI,62 3 articles reported cognitive outcome at 18 months of
age with the BSID-II MDI,8284 1 article reported cognitive outcome at 2 years of age with
the BSID-II MDI,86 and 1 article reported cognitive outcome at 1 to 2 years with the Griffiths
Mental Development Scale.87

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FIGURE 1

Weighted mean BSID-II outcome scores at 1 year of age. Left, PDI; right, MDI. The PDI and
MDI have a mean developmental quotient of 100 (SD: 15).

Preschool Age (35 years)

In 3 of the 8 studies, cognitive evaluation at preschool age was performed, generating 4

publications.65,66,85,88 One article reported cognitive outcome at 4 years with the WPPSI-R,66
and 2 studies reported cognitive outcome at 5 years with the WPPSI-R.85,88

School Age (>5 to 17 years)

For 1 of the 8 studies, cognitive evaluation at school age was reported, generating 7
publications.64,65,67,,70,72 One publication reported the primary data regarding cognitive
outcome at 8 years with the Wechsler Intelligence Scale for Children 3rd edition.68

Motor Outcome

Early Development (1 to <3 years)

Motor evaluation during early development was performed in all of the studies, generating 18
publications.6365,71,73,,84,86,87 After exclusion of articles reporting secondary analyses, there
were 11 publications from 8 studies that reported primary data concerning early motor
development. Five articles reported motor outcome at 1 year of age with the BSID-II
Psychomotor Development Index (PDI).73,75,76,80,81 The average PDI of these studies weighted
according to study sample size was 78.1 (95% CI: 76.479.7; I2 = 69.1) (Fig 1). One article
reported motor outcome at 1 year of age with the BSID-I PDI,62 3 articles reported motor
outcome at 18 months of age with the BSID-II PDI,8284 1 article reported motor outcome at
2 years with the BSID-II PDI,86 and 1 article reported motor outcome between 1 and 2
years with the PDMS.87

Preschool Age (35 years)

Motor evaluation at preschool age using the PDMS was performed in 1 of the 8 studies,
generating 2 publications.65,66

School Age (>5 to 17 years)

There were no articles reporting motor outcome at school age.

DISCUSSION
In this comprehensive assessment of available literature, we identified 8 studies that provided
objective assessments of motor and/or cognitive outcomes after cardiac surgery during the
first 6 months of life. These cohorts considered infants with TGA (3), infants with a
functionally univentricular circulation (2), and patients with diverse congenital cardiac
malformations (3). All studies assessed motor and cognitive ability at between 1 and 3 years
of age, with all but 1 study reporting cognitive outcomes within 1 SD of the test mean. Motor
outcomes were typically worse, with 5 articles reporting motor quotients within 1 SD of the
expected outcome and 6 reporting scores between 1 and 2 SDs from the expected mean.
Although it was possible to combine data from 5 studies by using the same outcome measure
at 1 year of age, the results themselves are cautioned by the inclusion of heterogeneous
subgroups. The 5 samples showed a mean BSID-II MDI within 1 SD of the test mean and a
mean BSID-II PDI 2 SDs below the test mean; however, calculations represent 2 cohorts of
patients with functionally univentricular circulations and 3 cohorts with a diverse spectrum of
congenital cardiac malformations. Accordingly, moderate heterogeneity was calculated with
the I2 statistic, which, despite our relatively strict inclusion criteria, is reflective of variations
in cardiac diagnoses, as well as outcome variance between samples.

The paucity of longitudinal, long-term follow-up studies limits the interpretation of these
findings into the school years. We would have liked to perform an analysis of published
results at preschool and school age; however, there were inadequate data for children older
than 3 years of age. Cognitive outcomes between 3 and 5 years of age were reported for 3
studies, with only 1 including assessment of gross and fine motor domains. Raw data were
not provided in the motor study; however, patients were reported as on the 9th and 4th
percentiles for gross and fine motor function, respectively.66 Again, cognitive outcomes were
reported within 1 SD of the test mean. Cognitive outcome at school age was reported for only
1 study, with the sample mean being approximately 3 quotient points below the test mean.70
This study included visual-spatial and visual-motor skill testing (including time to complete a
grooved pegboard), and although a large proportion of results were of concern, examining
these outcomes was not a primary aim of this review. It should be noted that despite concerns
of developmental risk spanning decades, there is insufficient longitudinal data of the late
motor outcomes for children who undergo surgery in the first 6 months of life. The literature
may be considered difficult to interpret given the heterogeneity of CHD diagnoses, and the
very variable timing of surgery and follow-up. Indeed, a number of important studies were
excluded from our review for these reasons. As such, future research should be performed
and evaluated only by first defining the subgroup of interest.

Developmental brain disturbances and injury to cortical and deep nuclear gray matter have
been well described after infant cardiac surgery.8991 Typically, the risk of white matter injury
is greatest during the first weeks of postnatal life, during the most active period of
synaptogenesis and myelination.17,89,92 The vulnerability of immature oligodendrocytes is
further compounded by additional cardiovascular risk factors relating to the underlying lesion
and associated physiology and by the fact that the majority of the most complex operations
are performed on the sickest infants. Despite these widely recognized facts, a significant
percentage of the published literature combines neurodevelopmental outcomes of the
youngest patients with older ones. It was for this reason that a number of well-conducted
prospective studies could not be included in our systematic review. We chose to review only
those patients operated on before 6 months, given that surgery beyond this age tended to
largely fall into lower-risk, definitive procedures in infants and children with a more robust
and mature brain.

Attention to surgical variables has shaped the developmental outcome literature for children
with CHD and has influenced intraoperative practice. The Boston Circulatory Arrest Study
led to changes in surgical practice worldwide and stimulated considerable interest in the
association between neurodisability and CHD.62 We noted a wide variation among the studies
with regard to specific surgical factors such as pH strategy and the use and duration of deep
hypothermic circulatory arrest, which have been implicated as potential risk factors for
impaired outcome.35,69,87 We recognize that even within the confines of this review,
perioperative practice has evolved in a plethora of major as well as subtle ways, and this
could influence the findings reported. This is particularly relevant for extrapolation of results
in which changes to clinical practice were made during the time period between surgery and
outcome assessment for a single cohort. Examples of evolving practice over the past decade
include a U-turn in some centers back to circulatory arrest, modified surgical techniques
(eg, surgical strategies for HLHS), and perinatal and perioperative care in patients at high
risk, including the broader use of extracorporeal life support. Patient characteristics
themselves may too have evolved, with a tendency toward more complex surgery for patients
with lesions previously thought to be inoperable. The paramount message is that impairment-
based outcome studies of infants with CHD should be interpreted in light of sample
characteristics before, during, and after surgical intervention. Similarly, data describing
outcomes of children with a specific diagnosis such as TGA should be extrapolated to other
diagnostic groups with educated caution.

It would be convenient to assume that patient characteristics and perioperative care

predictably determine functional outcome. However, as the Boston study showed, outcome
differences between study arms altered over time, as did the contribution of specific factors
such as postoperative seizures.63 It is increasingly appreciated that early environmental
factors can have positive and negative effects on the structure of the brain and on early child
development.93,94 In other words, the positive predictive validity of assessment tools is
limited by the fact that the rate of skill development is not constant and linear, and early
delays do not always predict later problems. Significant variability in early development has
been observed within normally developing infants over time and among healthy infants
assessed at the same time point.95 In patients with CHD, this variability is magnified by the
burden of repeated hospital admissions and the limitation of assessments occurring only at a
single time point. In addition, the administrators of the tools and the tools themselves may
influence the outcomes reported. Ferry18 highlighted a higher rate of abnormalities reported
by neurologists compared with clinicians directly managing the infants with CHD. Moreover,
the sensitivity of identifying patients with developmental delay is poor: a recent study
showed that >70% of physicians almost always use clinical assessment without a formal
screening tool,96 which may detect less than half of the children in need of developmental
services.97 It is important to note that a seemingly normal 1-year-old who had cardiac surgery
in early infancy may display significant abnormalities of neurodevelopment at 4 or 8 years of
age.64 Also contributing to this variability are limitations of the sensitivity of early
developmental scales compared with more established and sophisticated tests of intelligence,
behavior, and higher cortical function that are assessed from school age in children who are
likely more accustomed to test situations.

The scope of this review was limited by a number of important factors, including the paucity
of prospective studies, the fact that most assessments occurred at only 1 time point, the poor
sensitivity of early assessment tools, and that the assessment tools themselves changed over
time. Thus, the contribution of specific risk factors to outcome could not be examined.

CONCLUSIONS
This systematic review has shown that well-designed longitudinal studies form a rare but
potentially valuable basis for research into techniques for reducing the incidence of brain
injury or for modifying its long-term impact after cardiac surgery. Within a subgroup of
infants receiving cardiac surgery at <6 months of age, cognitive and motor developmental
domains were below the expected mean at all ages studied. Our review has shown that at 1
year of age, the risk of motor delay was greater than the risk of cognitive disability.

In an evolving field of medical and surgical management, more definitive outcomes are
critical for parent counseling and the provision of timely intervention for the individual.
Despite widespread awareness and concern regarding neurodisability in survivors of surgery
for CHD, this systematic review has identified the absolute need for focused long-term
studies to investigate the neurodevelopmental outcome of these infants at high risk.

ACKNOWLEDGMENTS
We thank Drs Catherine Limperopoulos, Annette Majnemer, and Frank Pigula for prompt
correspondence regarding data presented in published studies.

Footnotes
o Accepted November 24, 2009.
 Address correspondence to Lara Shekerdemian, MD, MRCP, FRACP, Royal
Children's Hospital, Flemington Road, Parkville, Victoria 3052, Australia. E-mail:
lara.shekerdemian@rch.org.au
FINANCIAL DISCLOSURE: Dr Gunn receives a postgraduate health research
scholarship from the Murdoch Children's Research Institute; the other authors have
indicated they have no financial relationships relevant to this article to disclose.
CHD =
congenital heart disease
TGA =
transposition of the great arteries
BSID =
Bayley Scales of Infant Development
WPPSI =
Wechsler Preschool and Primary Scale of Intelligence
PDMS =
Peabody Developmental Motor Scale
HLHS =
hypoplastic left heart syndrome
MDI =
Mental Developmental Index
CI =
confidence interval
PDI =
Psychomotor Developmental Index

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