uog journal club: brain abnormalities and neurodevelopmental delay in congenital heart disease:...

UOG Journal Club: January 2014Brain 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)

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

1. To perform a systematic review to quantify the non-surgical risk of neurodevelopmental delay and brain

abnormalities in newborns and infants with CHD

Objective



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 neuroimaging2.Abnormalities detected on neurologic assessment

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

Methodology

Systematic Review & Meta-Analysis





Results

Potentially appropriate studies identified from search(n=9129)

Citations retrieved for detailed evaluation of full manuscript

(n=119)

Studies included in systematic review(n=19)

Citations excluded based on title or abstract

(n=9010)

Studies excluded(n=100)

Outcome: Brain abnormalities(n=13)

425 CHD cases

Outcome: Neurological developmental abnormality(n=9)

512 CHD cases



Results: Brain Abnormalities on Neuroimaging

Lesion Type n/NPrevalence

(95% CI)I2 p

Transposition of great arteries (TGA)

21/7134%

(24-46)0.0% 0.47

Left-sided lesions 31/4666%

(53-79)0.0% 0.06

Mixed/unspecified lesions

292/58946%

(42-52)18.1% 0.28

There was no evidence of significant publication biasBegg and Mazumdar’s rank correlation test: p=0.66

Egger test: p=0.24



Results: Neurodevelopmental delay

The prevalence of neurodevelopmental

delay was 206/512

42% [95% CI (34-51)]I2=68.9%

There was no evidence of significant

publication bias0.0 0.2 0.4 0.6 0.8 1.0

Combined (random) 0.42 (0.34, 0.51)

proportion (95% confidence interval)

Study n/N

I² = 68.9% (95% CI = 22.3 to 82.8%)

Majnemer 2009 0.46 (0.37, 0.55)60/131

Newburger 1993 0.36 (0.29, 0.44)55/152

Dent 2006 0.65 (0.38, 0.86)11/17

Rufo-Campos 2003 0.25 (0.16, 0.36)21/83

Miller 2004 0.70 (0.35, 0.93)7/10

Tavani 2003 0.41 (0.18, 0.67)7/17

Gessler 2009 0.38 (0.21, 0.56)12/32

Da Rocha 2009 0.25 (0.09, 0.49)5/20

Limperopoulos 1999 0.56 (0.41, 0.70)28/50



Results: Study Quality

Quality MeasureStudies 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%

*Percentage of studies reporting on each quality measure

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



• Meta-analysis used to overcome small sample size issues from prior studies, allowing quantification of risk

• Stratified analysis based on type of lesion

• No evidence of significant publication bias

• Strict inclusion criteria to determine eligible studies

Strengths



• All included studies were observational

• Variable study quality

• Timing of CHD diagnosis is unclear in many of the included studies

• No information available on prenatal neuroimaging

• Brain lesions on imaging do not always correlate with neurodevelopmental delay

Limitations

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?

uog journal club: brain abnormalities and neurodevelopmental delay in congenital heart disease:...

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