Brain abnormalities and neurodevelopmental delay in congenital heart disease: systematic review and meta-analysis A. Khalil, N. Suff, B. Thilaganathan, A. Hurrell, D. Cooper and J.S. Carvalho Link to free access article: http://onlinelibrary.wiley.com/doi/10.1002/uog.12526/abstract

1. UOG Journal Club: January 2014
Brain abnormalities and neurodevelopmental delay in congenital
heart disease: systematic review and meta-analysis
A. Khalil, N. Suff, B. Thilaganathan, A. Hurrell, D. Cooper
and J.S. Carvalho
Volume 43, Issue 1, Date: January 2014, pages 14-24
Journal Club slides prepared by Dr. Katherine
Goetzinger
(UOG Editor for Trainees)

2. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
•
Congenital heart disease (CHD) is the leading cause of infant
mortality, secondary to birth defects
•
As CHD mortality rates have decreased, more attention has
turned to neurologic morbidities in surviving CHD neonates
•
While neurologic injury in CHD patients previously has been
attributed to brain injury during cardiac surgery, recent studies
have suggested a high incidence of abnormal neuroimaging
and neurodevelopmental delay in the pre-operative setting

3. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Objective
1. To perform a systematic review to quantify the nonsurgical risk of neurodevelopmental delay and brain
abnormalities in newborns and infants with CHD

4. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Methodology
Systematic Review & Meta-Analysis
Search Strategy: Medline, EMBASE and The Cochrane Library
Study Type: Prospective/retrospective cohort studies, case-control
studies and case series
Inclusion Criteria: Studies reporting brain lesions on neuroimaging
and/or neurodevelopmental outcomes in newborns and infants with
CHD before heart surgery
Outcomes:
1.Structural brain abnormalities revealed by neuroimaging
2.Abnormalities detected on neurologic assessment

5. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Methodology
Systematic Review & Meta-Analysis
Analysis:
•Forest plots: fixed and random effects models
•Between-study heterogeneity: Higgin’s I2
•Publication bias: Funnel plots, Begg and Mazumdar’s rank
correlation test and the Egger test
•Subgroup analysis based on lesion type
•Transposition of the great vessels (TGA)
•Left-sided heart lesions
•Unspecified/mixed cardiac lesions

6. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Results
Potentially appropriate studies identified from search
(n=9129)
Citations excluded based on
title or abstract
(n=9010)
Citations retrieved for detailed evaluation of full
manuscript
(n=119)
Studies excluded
(n=100)
Studies included in systematic review
(n=19)
Outcome: Brain abnormalities
(n=13)
425 CHD cases
Outcome: Neurological developmental abnormality
(n=9)
512 CHD cases

7. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Results: Brain Abnormalities on Neuroimaging
n/N
Prevalence
(95% CI)
I2
p
Transposition of
great arteries (TGA)
21/71
34%
(24-46)
0.0%
0.47
Left-sided lesions
31/46
66%
(53-79)
0.0%
0.06
Mixed/unspecified
lesions
292/589
46%
(42-52)
18.1%
0.28
Lesion Type
There was no evidence of significant publication bias
Begg and Mazumdar’s rank correlation test: p=0.66
Egger test: p=0.24

8. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Results: Neurodevelopmental delay
Study
Newburger 1993
n/N
55/152
0.36 (0.29, 0.44)
Limperopoulos 1999 28/50
0.56 (0.41, 0.70)
Rufo-Campos 2003 21/83
0.25 (0.16, 0.36)
Tavani 2003
7/17
0.41 (0.18, 0.67)
Miller 2004
7/10
0.70 (0.35, 0.93)
Dent 2006
11/17
0.65 (0.38, 0.86)
Da Rocha 2009
5/20
0.25 (0.09, 0.49)
Gessler 2009
12/32
0.38 (0.21, 0.56)
Majnemer 2009
60/131
0.46 (0.37, 0.55)
The prevalence of
neurodevelopmental
delay was 206/512
Combined (random)
0.42 (0.34, 0.51)
0.2
0.4
0.6
0.8
1.0
I² = 68.9% (95% CI = 22.3 to 0.0
82.8%)
proportion (95% confidence interval)
42% [95% CI (34-51)]
I2=68.9%
There was no evidence
of significant
publication bias

9. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Results: Study Quality
Studies Reporting
Data on
Neuroimaging*
Studies Reporting
Data on
Neurodevelopmental
Outcomes*
Study Design
100%
78%
Eligibility Criteria
100%
89%
Sample Size
69%
44%
Follow Up
69%
78%
Efforts to Reduce Bias
92%
89%
Quality Measure
*Percentage of studies reporting on each quality measure

10. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Conclusions
• There is a high prevalence of brain lesions on neuroimaging as well as a
significant risk of pre-operative neurodevelopmental delay in CDH infants
• The prevalence of brain lesions appears to be dependent on the type of
CHD, with a higher prevalence noted with left-sided cardiac lesions
Implications for Practice
• This study highlights the importance of diagnosis of fetal CHD to allow
identification of newborns at increased risk for neurodevelopmental delay
• Providers may consider close periodic developmental surveillance as
part of medical follow up for infants with CHD, especially left-sided lesions

11. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Strengths
•
Meta-analysis used to
overcome small sample size
issues from prior studies,
allowing quantification of risk
Limitations
•
All included studies were
observational
•
Variable study quality
•
Timing of CHD diagnosis is
unclear in many of the included
studies
•
Stratified analysis based on
type of lesion
•
No evidence of significant
publication bias
•
No information available on
prenatal neuroimaging
•
Strict inclusion criteria to
determine eligible studies
•
Brain lesions on imaging do not
always correlate with
neurodevelopmental delay

12. Brain abnormalities and neurodevelopmental delay in congenital heart disease:
systematic review and meta-analysis
Khalil et al., UOG 2014
Discussion Points
•
•
•
•
•
•
What is the biological basis for the hypothesis that CHD predisposes to
brain abnormalities and neurodevelopmental delay in the newborn?
Why do babies with left-sided cardiac lesions appear to be at greatest
risk?
How would over- or under-reporting of brain abnormalities and
developmental delay affect the results of this meta-analysis?
Is there a role for more detailed neuroimaging with sonography and/or
MRI in fetuses with CHD? At what point in gestation should this occur?
How do brain abnormalities observed on neuroimaging correlate to
degree of neurodevelopmental handicap?
Should pediatric providers routinely incorporate neurodevelopmental
screening into their postnatal follow up of infants with CHD?