Ultrasound Obstet Gynecol 2014; 43: 14–24 Published online 10 December 2013 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12526
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*§ *Fetal Medicine Unit, St. George’s Medical School, University of London, London, UK; †Institute for Women’s Health, University College, London, UK; ‡King’s College, London, UK; §Royal Brompton Hospital, London, UK
K E Y W O R D S: brain lesion; congenital heart defects; hypoplastic left heart syndrome; neurodevelopmental outcome; neuroimaging; transposition of the great arteries
ABSTRACT Objectives Studies have demonstrated an association between congenital heart disease (CHD) and neurodevelopmental delay. Neuroimaging studies have also demonstrated a high incidence of preoperative brain abnormalities. The aim of this study was to perform a systematic review to quantify the non-surgical risk of brain abnormalities and of neurodevelopmental delay in infants with CHD. Methods MEDLINE, EMBASE and The Cochrane Library were searched electronically without language restrictions, utilizing combinations of the terms congenital heart, cardiac, neurologic, neurodevelopment, magnetic resonance imaging, ultrasound, neuroimaging, autopsy, preoperative and outcome. Reference lists of relevant articles and reviews were hand-searched for additional reports. Cohort and case–control studies were included. Studies reporting neurodevelopmental outcomes and/or brain lesions on neuroimaging in infants with CHD before heart surgery were included. Cases of chromosomal or genetic abnormalities, case reports and editorials were excluded. Between-study heterogeneity was assessed using the I2 test. Results The search yielded 9129 citations. Full text was retrieved for 119 and the following were included in the review: 13 studies (n = 425 cases) reporting on brain abnormalities either preoperatively or in those who did not undergo congenital cardiac surgery and nine (n = 512 cases) reporting preoperative data on neurodevelopmental assessment. The prevalence of brain lesions on neuroimaging was 34% (95% CI, 24–46; I2 = 0%) in transposition of the great arteries, 49% (95% CI, 25–72; I2 = 65%) in left-sided heart lesions and 46% (95% CI, 40–52; I2 = 18.1%) in
mixed/unspecified cardiac lesions, while the prevalence of neurodevelopmental delay was 42% (95% CI, 34–51; I2 = 68.9). Conclusions In the absence of chromosomal or genetic abnormalities, infants with CHD are at increased risk of brain lesions as revealed by neuroimaging and of neurodevelopmental delay. These findings are independent of the surgical risk, but it is unclear whether the time of onset is fetal or postnatal. Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
INTRODUCTION Congenital heart disease (CHD) remains the leading cause of infant mortality secondary to birth defects1 . Survival rates in neonates with CHD have improved recently2,3 and this has been associated with a shift in focus from cardiac morbidity and mortality towards the risk of brain abnormalities and the integrity of neurodevelopmental outcome4 – 6 . Studies have demonstrated an association between CHD and neurodevelopmental delay, which is attributed in part to the risk of brain injury during cardiac surgery7 – 10 . Neuroimaging studies have also demonstrated a high incidence of preoperative brain abnormalities11 – 24 and neurodevelopmental delay25 – 30 . Early identification of fetuses or neonates at increased risk of brain injury would facilitate appropriate surveillance and targeted intervention. A recent narrative review demonstrated that a considerable proportion of newborns with CHD exhibit neurobehavioral and electrophysiological abnormalities31 . The authors summarize that, using conventional neuroimaging, up to 59% of full-term newborns with CHD have evidence of brain injury31 . Furthermore, studies using quantitative neuroimaging modalities have reported that
Correspondence to: Dr A. Khalil, Fetal Medicine Unit, St George’s University of London, Cranmer Terrace, London SW17 0RE, UK (e-mail:
[email protected]) Accepted: 24 May 2013
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
SYSTEMATIC REVIEW
Brain abnormalities and neurodevelopmental delay in CHD fetuses with CHD have delayed third-trimester brain growth, and that newborns with CHD have impaired white matter maturation, reduced N-acetylaspartate and increased lactate. However, this review did not assess the quality of the studies included and did not quantify the risk of neurodevelopmental delay, which is important in consolidating a management policy and in antenatal counseling. The aim of this study was to perform a systematic review to quantify the non-surgical risk of neurodevelopmental delay and brain abnormalities in newborns and infants with CHD.
METHODS Search strategy This review was performed according to a protocol designed a priori and recommended for systematic reviews and meta-analysis32 – 34 . MEDLINE (1966 − March 2012), EMBASE (1974 − March 2012) and The Cochrane Library (since inception) including The Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and The Cochrane Central Register of Controlled Trials (CENTRAL) were searched electronically on 4 May 2012 utilizing combinations of the relevant MeSH terms, keywords and word variants for ‘congenital heart’, ‘cardiac’, ‘neurologic’, ‘neurodevelopment’, ‘MRI’, ‘ultrasound’, ‘neuroimaging’, ‘autopsy’, ‘preoperative’ and ‘outcome’ (Table S1, available online). No language restrictions were imposed on the search or selection criteria. Reference lists of relevant articles and reviews were hand searched for additional reports.
Study selection Studies were assessed according to the following criteria: population, outcome and study design. Studies reporting brain lesions on neuroimaging and/or neurodevelopmental outcomes in newborns and infants with CHD before heart surgery were included. Studies were excluded if they included data on postoperative outcome only, if the study population had undergone balloon atrial septostomy (BAS) or if the study included preterm infants or those with birth asphyxia, a 5-min Apgar score < 5, associated structural abnormalities (apart from the heart or brain) or infants with genetic/chromosomal anomalies. Studies that included heterogeneous samples and in which the infants had undergone preoperative assessment and/or neuroimaging were included. Outcome measures included structural brain abnormalities revealed by neuroimaging (magnetic resonance imaging (MRI), ultrasound or computed tomography scan) and abnormalities detected on neurological assessment. Neurodevelopmental delay included delay in milestones and disorders affecting the motor or sensory systems, speech or behavior. Prospective and retrospective cohort, case–control studies and case series were included. Case reports and editorials were excluded. Studies reporting data on surrogate markers
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
15
of brain growth, perfusion or maturation such as head size, N-acetylaspartate or lactate levels, changes in cerebral circulation, somatosensory and brainstem evoked potentials and EEG changes were excluded to avoid interpretation of these findings as brain abnormalities. Studies form which data on robust outcomes could be extracted, including brain lesions on neuroimaging and neurodevelopmental delay, were included. The study was registered with the PROSPERO database (Registration number: CRD42012003359, http://www. crd.york.ac.uk/PROSPERO). All abstracts were reviewed independently by two authors. Agreement about potential relevance was reached by consensus, and full-text copies of those papers were obtained. Three reviewers (A.K., N.S. and A.H.) independently extracted data regarding study characteristics, outcome and quality using the criteria of the Strengthening the Reporting of Observational Studies in Epidemiology statement34 . Inconsistencies were discussed by the reviewers and consensus was reached. For those articles in which information was not reported but the methodology was such that this information would have been recorded initially, the authors were contacted.
Statistical analysis Between-study heterogeneity was explored graphically within the forest plot and statistically assessed using the I2 statistic, which represents the percentage of betweenstudy variation due to heterogeneity rather than chance35 . A value of 0% indicates no observed heterogeneity, whereas I2 values of ≥ 50% indicate a substantial level of heterogeneity36 . We planned to use a fixed effects model if substantial statistical heterogeneity was not present. Random effects models were also used to test the robustness of results. Subgroup analysis was performed to investigate the heterogeneity of studies. Publication bias was explored using funnel plots and was assessed statistically using Begg and Mazumdar’s rank correlation test (which reports the rank correlation between the standardized effect size and variances of these effects) and the Egger test (which uses actual values of the effect sizes and their precision, rather than ranks)37 . Statistical analyses were performed using Stata 11 (release 11.2, College Station, TX, USA) and Stats Direct (Version 2.7.8, Stats Direct Ltd, Altrincham, Cheshire, UK) statistical software. Most published studies have focused on two defect groups, namely newborns with transposition of the great arteries (TGA) and those with hypoplastic left heart syndrome (HLHS). Subgroup analysis was performed for TGA, left-sided heart lesions (including HLHS, aortic stenosis and coarctation of the aorta) and unspecified/mixed cardiac lesions. We performed the subgroup analysis when three or more articles reported rates.
RESULTS The literature search yielded 9129 possible citations; of these, 9010 were excluded by review of title or
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Khalil et al.
16 Potentially relevant citations identified by searching MEDLINE (1966–March 2012), EMBASE (1974–March 2012), The Cochrane Library (since inception) including The Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and The Cochrane Central Register of Controlled Trials (CENTRAL) and by hand-searching reference lists (n = 9129) Citations excluded (n = 8746) Not relevant Postoperative data only Duplicates Reports of < 5 cases
Citations screened for evaluation of abstract (n = 383) Studies excluded (n = 264) Not relevant Postoperative data only No original data
Citations retrieved for detailed evaluation of full manuscript (n = 119) Studies excluded (n = 100) Postoperative data only Balloon atrial septostomy Data included in another study Studies included in systematic review (n = 19)
Outcome: brain abnormalities (n = 13)∗ (425 CHD cases)
Outcome: neurological development abnormality (n = 9)∗ (512 CHD cases)
Figure 1 Flow chart illustrating identification of studies included in this systematic review. CHD, congenital heart defects. Three studies assessed both structural brain abnormalities and developmental delay.
abstract as not meeting selection criteria or as duplicates (Figure 1). Full manuscripts were retrieved for 119 studies, and a total of 19 studies were included in the review and meta-analysis. A total of 13 studies (n = 425 cases) reported brain abnormalities in newborns or infants with CHD, either preoperative abnormalities or abnormalities in those who did not undergo congenital cardiac surgery. Nine studies (n = 512 cases) reported preoperative data on neurodevelopmental outcomes in newborns or infants with CHD (Figure 1). Table 1 shows characteristics of the studies included that reported structural brain abnormalities, while those showing the neurodevelopmental outcomes are given in Table 2. These findings were reported before any form of cardiac surgery. The brain lesions reported in these studies included ventriculomegaly, white matter injury, ischemic lesions, periventricular leukomalacia, stroke and cerebral atrophy. Subgroup analyses for cases with TGA included five studies for left-sided heart lesions including HLHS and aortic stenosis
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
(n = 71), three studies for coarctation of the aorta (n = 46) and nine studies for mixed/unspecified cardiac lesions (n = 315). The prevalence of brain lesions on neuroimaging was 21/71 (summary estimate from metaanalysis, 34%; 95% CI, 24–46; I2 = 0%) in TGA (Figure 2a), 21/46 (49%; 95% CI, 25–72; I2 = 65%) in left-sided heart lesions (Figure 2b) and 144/315 (46%; 95% CI, 40–52; I2 = 18.1%) in mixed/unspecified cardiac lesions (Figure 2c). The neurodevelopmental abnormalities most commonly reported included seizures, altered tone, reduced level of consciousness and retardation in motor development. The total prevalence of neurodevelopmental delay from the nine studies was 206/512 (42%; 95% CI, 34–51; I2 = 68.9%, Figure 3). The quality of studies is summarized in Figure 4. Among the studies included that reported brain lesions in newborns or infants with CHD, either preoperatively or in those who did not undergo congenital cardiac surgery, study design and eligibility criteria were described in 100% of studies. The sample size was defined in 69%
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Brain abnormalities and neurodevelopmental delay in CHD (a)
Study
17
n/N 11
Tavani (2003)
2/14
0.40 (0.05, 0.85)
Miller (2004)30
4/10
0.40 (0.12, 0.74)
Te Pas (2005)21
4/12
0.14 (0.02, 0.43)
Petit (2009)20
2/14
0.33 (0.10, 0.65)
Durandy (2011)40
9/21
0.43 (0.22, 0.66) 0.34 (0.24, 0.46)
Combined (random) 0.0
0.3
I2 = 0% (95% CI, 0–64.1%)
(b)
0.6
0.9
Proportion (95% CI)
Study
n/N
Tavani (2003)11
5/8
0.63 (0.24, 0.91)
Te Pas (2005)21
10/16
0.63 (0.35, 0.85)
Dent (2006)39
6/22
0.27 (0.11, 0.50)
Combined (random)
0.49 (0.25, 0.72) 0.0
0.2
I = 65% (95% CI, 0–87.9%) 2
(c)
Study
0.4
0.6
0.8
1.0
Proportion (95% CI)
n/N 38
5/15
0.33 (0.12, 0.62)
29/49
0.59 (0.44, 0.73)
7/24
0.29 (0.13, 0.51)
6/9
0.67 (0.30, 0.93)
13/25
0.52 (0.31, 0.72)
Te Pas (2005)
9/20
0.45 (0.23, 0.68)
Partridge (2006)19
7/19
0.37 (0.16, 0.62)
28/62
0.45 (0.32, 0.58)
40/92
0.43 (0.33, 0.54)
McConnell (1990) van Houten
(1996)22
Mahle (2002)15 Tavani Licht
(2003)11
(2004)13 21
McQuillen Block
(2007)17
(2010)23
Combined
0.46 (0.40, 0.52) 0.0
0.2
I2 = 18.1% (95% CI, 0–62.2%)
0.4
0.6
0.8
1.0
Proportion (95% CI)
Figure 2 Pooled prevalence (Forest plot, random-effects model) of brain structural abnormalities in newborns with transposition of the great arteries (a), left-sided heart lesions including hypoplastic left heart syndrome, aortic stenosis and coarctation of the aorta (b) or mixed/unspecified congenital heart defects (c), either preoperatively or in those who did not undergo congenital cardiac surgery. Each study is represented by a line. The box in the middle of the line represents the point effect estimate of this particular study. The midpoint of the box represents the point effect estimate, i.e. the mean effect estimate for each study. The area of the box represents the weight given to the study. The diamond below the studies represents the overall estimate. The width of the line shows the CI of the effect estimate of individual studies. The width of the diamond shows the CI for the overall effect estimate. Only the first author of each study is given. I2 (heterogeneity), diversity between studies; N, total number in group; n, number in group with the outcome.
of studies. Characteristics and follow-up were described in only 69% of studies. Efforts to address bias were reported in 92% of studies. Among the included studies
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
that reported data on neurodevelopmental outcomes in newborns or infants with CHD, study design was described in 78% of studies. Eligibility criteria were
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
TGA
Cohort (pro)
7 days (med)
5.1 days (mean)¶¶ 5 days (med)
6 days (med, no injury) 4 days (med, preop injury) 1–8 days (range) Not reported
4.7 days (mean) 6 days (mean, no brain injury) 4 days (mean, preop brain injury) 9.6 days (mean)
9.3 days (mean)
4 days (mean)
4 days (mean)
1 year (med)
Age at assessment
21
12 92
22 66
32
50
25 10
24
24
49
15
Included
21
12 92
22 62
19
50
25 10
24
24
49
15
Assessed
CHD (n)
MRI
MRI MRI
MRI MRI
MRI
US
MRI MRI
MRI
MRI
US
MRI
Assessment method
Total abn, 43%; WMI, 4 (19%); infarct, 4 (19%); hemorrhage, 5 (23%)
Total abn, 42%; widened ventricles and/or SAS, 13 (26%); acute ischemic changes, 4 (8%) (infarction, cerebral edema, PV echodensities, IVH); LSV, 3 (6%); basal ganglion calcifications, 1 (2%) Total abn, 37%; WMI, 4 (21%); infarct, 3 (16%); subependymal germinal matrix IVH, 2 (11%) Total abn, 27%; ischemic lesions, 4 (18%); PVL, 1 (5%); ICH, 1 (5%) Total abn, 45%; ischemic lesions, 23 (37%); WMI, 11 (18%); stroke, 13 (21%); IVH, 5 (8%); subdural hemorrhage, 11 (18%); reduced myelination with immature sulcation, 1 (2%); globally reduced parenchymal volume, 1 (2%) PVL, 4 (33%) Total abn, 43%; stroke, 23 (25%); WMI, 21 (23%); IVH, 7 (8%)
Total abn, 59%; IVH grade I–IV, 8 (16%); subarachnoid hemorrhage, 2 (4%); cerebral atrophy, 13 (27%) subcortical linear echodensities, 10 (20%); PV echo, 4 (8%); IP echo, 4 (8%); SAS enlargement, 1 (2%) Total abn, 46%; ischemic lesions, 6 (25%); PVL, 4 (17%); infarct, 2 (8%); hemorrhage, 1 (4%); open operculum, 4 (17%) Total abn, 54%; hemorrhage, 13 (54%) (subdural, 17; choroid plexus, 7; parenchymal, 1; occipital horns, 1) Total abn, 53%; PVL, 7 (28%); open operculum, 4 (16%) Total abn, 40%; stroke, 3 (30%); hemorrhage, 2 (20%)
Total abn, 30%; ventriculomegaly, 5; left-sided infarction, 1
Findings
Only first author is given. *Chart review. †VSD, TAPVR, PA, TOF, AS, ASD, TGA, VSD, hemitruncus. ‡Most infants had a combination of cardiac lesions, including ASD, AVSD, CoA, DORV, HLHS, interrupted aortic arch, PA, TOF, TAPVR, TGA, TA, VSD. §HLHS, double inlet LV with subaortic stenosis, double outlet RV with mitral atresia, single left ventricle with PA, TGA with right ventricle hypoplasia, TGA, TGA with VSD, VSD with aortic atresia, TA, PA with IVS, CoA with VSD, VSD, AS, VSD, IAA (type B). ¶DORV, MA, HLHS, single left ventricle, unbalanced AVSD, DILV, VSD, TGA, AA with VSD, TA, pulmonary stenosis. **AS, heterotaxy, HLHS, HLHS variant, PA/IVS, TAPVR, TGA/IVS, TOF, TOF/PA, TGA/VSD/CoA, TGA/VSD, TA, VSD/CoA. ††Many had complex CHD in the form of combination of cardiac lesions, including TAPVR, TGA, HLHS, TOF, VSD, PA, DORV, MA, AA, PS, DILV, tricuspid atresia, major aortopulmonary collateral arteries. ‡‡TGA, SV physiology, TA, IAA with VSD, CoA. §§TGA, TA, TGA with VSD, TOF with TAPVD, absent pulmonary valve syndrome, Taussig−Bing anomaly, TOF, TAPVD, PA with IVS, two ventricles with arch obstruction, SV, SV with arch obstruction. ¶¶only the non-BAS group. AA, aortic atresia; abn, abnormalities; AS, aortic stenosis; ASD, atrial septal defect; AVSD, atrioventricular septal defect; BAS, balloon atrial septostomy; CoA, coarctation; DILV, double inlet left ventricle; DORV, double outlet right ventricle; HLHS, hypoplastic left heart syndrome; IAA, interrupted aortic arch; ICH, intracranial hemorrhage; IP, intraparenchymal; IVH, intraventricular hemorrhage; LSV, lenticulostriate vasculopathy; LV, left ventricle; MA, mitral atresia; med, median; MRI, magnetic resonance imaging; PA/IVS, pulmonary atresia with intact ventricular septum; PA, pulmonary atresia; preop, preoperative; pro, prospective; PS, pulmonary stenosis; PV, periventricular; PVL, periventricular leukomalacia; retro, restrospective; RV, right ventricle; SAS, subarachnoid space; SV, single ventricle; TA, truncus arteriosus; TAPVR, total anomalous pulmonary venous return; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; US, ultrasound; VSD, ventricular septal defect; WMI, white matter injury.
TGA TGA and SV
Cohort (pro)* Cohort (pro)
HLHS Mixed§§
Cohort (pro) Cohort (pro)
Petit (2009)20 USA Block (2010)23 USA/Canada Durandy (2011)40 France
Mixed‡‡
Cohort (pro)
Partridge (2006)19 USA/Canada Dent (2006)39 USA McQuillen (2007)17 Canada
Mixed** TGA
Cohort (pro) Case–control (pro)
Mixed††
Mixed¶
Cohort (pro)
Cohort (retro)*
Mixed§
Mixed‡
Case–control (retro)*
Cohort (pro)
Mixed†
Cohort (pro)
Te Pas (2005)21 Netherlands
Mahle (2002)15 USA Tavani (2003)11 USA Licht (2004)13 USA Miller (2004)30 USA
McConnell (1990)38 USA van Houten (1996)22 USA
Study
CHD diagnosis
Study design (data collection)
Table 1 Summary of studies included which reported structural brain abnormalities in newborns with congenital heart defects (CHD), either preoperatively or in those who did not undergo congenital cardiac surgery
18
Khalil et al.
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Mixed
Mixed
Cohort (pro)
Cohort (pro)
Cohort (pro)
Da Rocha (2009)42 Brazil
Gessler (2009)43 Switzerland Majnemer (2009)29 Canada Newborns who had surgery in first month of life and infants who had surgery between 1 month and 2 years
Infants
Infants
Newborns
Newborns
Newborns
Newborns
Newborns (assessed within first month of life)
Newborns
Population
9 days (mean)
10 months (med)
7 months (mean)
6 days (mean, no injury); 4 days (mean, preop injury) 4 days (med)
10 days (mean)
9.3 days (mean)
13.9 days (mean)
Not reported
Age at assessment
131
32
20
22
10
83
24
56
180
131
32
20
17
10
83
17
50
152
Assessed
CHD (n) Included
Neurological examination and neuroassessment (neonates assessed with Albert Einstein neonatal neurobehavioral scale; infants assessed with Peabody Developmental Motor Scales)
Neurological assessment; neuroanemnesis and examination Neurological examination
Neurological examination
Neurological and psychological examination (OSD and Early Infancy Carey Temperament Questionnaire) Neurological examination
Neurological examination
ENNAS, neurobehavioral status and neurologic examination
Neurological examination
Assessment method
Total abnormalities, 46%; Neonates: hypo/hypertonia, absent suck reflex, jitteriness, motor asymmetries, microcephaly, poor behavioral state regulation, poor feeding efficiency; predictor variable, acyanotic heart defect; Infants: hypotonia, head preference, motor asymmetry, microcephaly, lethargy, irritability, gross motor delay (26%), fine motor delay (23%)
Total abnormalities, 38%
Total abnormalities, 65%; reduced level of consciousness and increased muscle tone Total abnormalities, 25%
Total abnormalities, 70%; abnormal tone and/or reflexes
Total abnormalities, 56%; hypotonia, 20; hypertonia, 6; jitteriness, 4; no suck, 3; motor asymmetry, 2; decreased muscle power in the extremities, 5; cranial nerve abnormalities, 2; altered states of consciousness, 7; restlessness and agitation, 4; seizures, 4; ENNAS scores abnormal, 29; poor feeding, 35 Total abnormalities, 41%; altered tone in arms and/or legs and lethargy Total abnormalities, 25%; hypotonia, frailness and retardation in motor development
Definite neurological abnormalities, 36%
Abnormalities
Only first author is given. ENNAS, Einstein Neonatal Neurobehavioral Assessment scale; HLHS, hypoplastic left heart syndrome; med, median; OSD, Observational Scale of Development; preop, preoperative; pro, prospective; RCT, randomized controlled trial; TGA, transposition of the great arteries.
Mixed
HLHS
Cohort (pro)
Dent (2006)39 USA
TGA
Mixed
Case–control (pro)
Case–control (pro)
Mixed
Mixed
Cohort (pro)
Cohort (pro)
TGA
CHD diagnosis
RCT (pro)
Study design (data collection)
Miller (2004)30 USA
Tavani (2003)11 USA Rufo-Campos (2003)41 Spain
Newburger (1993)8 USA Limperopoulos (1999)26 Canada
Study
Table 2 Summary of the studies included which reported preoperative neurodevelopmental delay in newborns with congenital heart defects (CHD)
Brain abnormalities and neurodevelopmental delay in CHD 19
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Khalil et al.
20 Study
n/N
Newburger (1993)8
55/152
0.36 (0.29, 0.44)
Limperopoulos (1999)26
28/50
0.56 (0.41, 0.70)
(2003)41
21/83
0.25 (0.16, 0.36)
Tavani (2003)11
7/17
0.41 (0.18, 0.67)
Miller (2004)30
7/10
0.70 (0.35, 0.93)
Dent (2006)39
11/17
0.65 (0.38, 0.86)
Da Rocha (2009)42
5/20
0.25 (0.09, 0.49)
12/32
0.38 (0.21, 0.56)
60/131
0.46 (0.37, 0.55)
Rufo-Campos
Gessler
(2009)43
Majnemer (2009)29 Combined (random)
0.42 (0.34, 0.51) 0.0
0.2
I2 = 68.9% (95% CI, 22.3–82.8)
0.4 0.6 Proportion (95% CI)
0.8
1.0
Figure 3 Pooled prevalence (Forest plot, random-effects model) of preoperative neurodevelopmental delay in newborns with congenital heart defects. Only the first author of each study is given. I2 (heterogeneity), diversity between studies; N, total number in group; n, number in group with the outcome.
described in 89% of studies. The sample size was defined in 44% of studies. Characteristics and followup were described in 78% of studies. Finally, efforts to address bias were reported in 89% of studies. Publication bias, assessed using the Begg and Mazumdar’s rank correlation test and the Egger test, showed no significant bias for the studies reporting brain abnormalities (P = 0.66 and P = 0.24, respectively) or those reporting neurodevelopmental outcomes (P = 0.48 and P = 0.29, respectively). According to the Begg and Mazumdar’s rank correlation test and the Egger test, there was no significant publication bias for the studies reporting brain abnormalities (P = 0.66 and P = 0.24, respectively) or those reporting neurodevelopmental outcomes (P = 0.48 and P = 0.29, respectively). Similarly, there was no evidence of significant publication bias for the subgroup analyses in cases with TGA, left-sided heart lesions or mixed/unspecified cardiac lesions. There was no evidence of significant heterogeneity among studies included for assessment of the imaging of brain lesions in cases with TGA (I2 = 0%; 95% CI, 0–64.1%; P = 0.47), left-sided heart lesions (I2 = 65%; 95% CI, 0–87.9%; P = 0.06) or mixed/unspecified cardiac lesions (I2 = 18.1%; 95% CI, 0–62.2%; P = 0.28).
DISCUSSION The findings of this meta-analysis suggest that CHD is consistently associated with a relatively high prevalence of brain lesions on neuroimaging and a significant risk of preoperative neurodevelopmental delay. Furthermore, the study demonstrates that the prevalence of brain lesions depends on the type of CHD, varying from 34% in cases of TGA to 49% in cases of left-sided heart lesions. The overall prevalence of structural brain abnormalities in this meta-analysis (43%) is lower than that reported (59%) in a recent narrative review by Owen et al.31 . That review included studies recorded in MEDLINE/PubMed
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
between October 1990 and September 2010 and were limited to the English language. Most of the studies included were observational, with their inherent risks of bias and possible over- or under-reporting of brain abnormalities or neurodevelopmental delay in neonates with CHD. The current review was systematic; it included three databases and had no language restriction. In our methodology and meta-analysis, special efforts were made to avoid bias, in particular overestimation of the prevalence of brain abnormalities in cases of CHD. However, despite thorough methodology, this meta-analysis does not provide sufficient information to clarify whether the reported brain lesions apparent on neuroimaging described here occur before or after birth. The explanation for the association between CHD and brain abnormality is not fully established. Block et al.23 suggested that neonates with CHD suffer from preoperative brain injury and that this injury does not worsen postoperatively. One potential explanation for these findings is altered cerebral circulation in utero. Normal fetal brain growth and development relies on adequate delivery of oxygen and substrate, which is influenced by the anatomic structure of the heart and myocardial function. Another possible explanation is that these neonates may have suffered ‘injuries’ postnatally, e.g. when the arterial duct closed. If this were the case, it is possible that, in a proportion of cases reported in this systematic review, the brain abnormalities might not have been a direct effect of having CHD, but rather the result of hemodynamic instability after birth when fetuses are no longer ‘protected’ by the fetal circulation. The latter hypothesis is supported by the finding in this study of a higher prevalence of brain lesions amongst left-sided heart lesions compared to cases of TGA. If fetal and preoperative hypoxemia is indeed the cause of these brain lesions, improvement in the prenatal detection rate of CHD may provide an opportunity to prevent, or at least ameliorate, these effects.
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Brain abnormalities and neurodevelopmental delay in CHD
21
(a)
Source of funding Generalizability Interpretation of results Limitations of study Summary of key results Report of all results and precision Report of number of outcome events Participant characteristics and follow-up time Report of number of individuals in flow diagram Description of all statistical methods Explanation of quantitative variables and their analysis Explanation of study size Efforts to address bias Data sources and methods of assessment Definition of all variables Eligibility and matching criteria Description of setting and recruitment period Study design Introduction states background and objectives Title and abstract appropriate 0
2
4
6 8 Studies (n)
10
12
14
(b)
Source of funding Generalizability Interpretation of results Limitations of study Summary of key results Report of all results and precision Report of number of outcome events Participant characteristics and follow-up time Report of number of individuals in flow diagram Description of all statistical methods Explanation of quantitative variables and their analysis Explanation of study size Efforts to address bias Data sources and methods of assessment Definition of all variables Eligibility and matching criteria Description of setting and recruitment period Study design Introduction states background and objectives Title and abstract appropriate 0
1
2
3
4
5
6
7
8
9
10
Studies (n)
Figure 4 Quality criteria of the included articles, concerning: (a) brain structural abnormalities and (b) preoperative neurodevelopmental delay, as assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. , yes; , no34 .
Pathological studies have reported that 45% of infants with HLHS had hypoxic ischemic lesions and/or intracranial hemorrhage44 . Half of these babies did not undergo surgery44 . Another study by the same authors showed that a significant number of babies with HLHS had associated congenital brain abnormalities such as agenesis of the corpus callosum, holoprosencephaly and abnormal cortical mantle formation45 . Brain lesions detected by cranial ultrasound include cerebral atrophy, widened ventricular or subarachnoid spaces, intraventricular hemorrhage, linear echodensities of the deep gray matter, especially the basal ganglia and the thalamus, and parenchymal echodensities21,22 . Similarly, studies using MRI have reported a range of abnormalities including intracranial hemorrhage, ventriculomegaly with dilation of the subarachnoid spaces representing cerebral atrophy, gray matter injury, cerebral
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
venous thromboses, thromboembolisms, infarctions, periventricular leukomalacia and incomplete closure of the operculum11,13 – 20,23,30,38,46 – 48 . A narrative review by Donofrio et al.6 highlighted the difference between brain lesions in neonates with CHD and in those who sustained hypoxic ischemic injury, suggesting that acquired brain injury in CHD may be related to an abnormality in brain development6 . Miller et al.18 were the first to report brain features quantitatively with preoperative MRI, using specialized techniques of magnetic resonance spectroscopy (MRS) and diffusion tensor imaging, which provided evidence that brain development was delayed in utero in fetuses with CHD. Using these techniques, the authors described a lower ratio of N-acetylaspartate/choline and a higher ratio of lactate/choline in cases of CHD as compared to controls. Using a brain maturation score based on four parameters including myelination, cortical
Ultrasound Obstet Gynecol 2014; 43: 14–24.
22
infolding, involution of glial cell migration bands and the presence of germinal matrix tissues, Licht et al. described a delay in brain development in utero of approximately 1 month in fetuses with CHD14 . The association between abnormal MRS and biochemical findings and poor neurodevelopmental outcome remains to be established, and for this reason we did not include these studies in this systematic review. These studies, in addition to those using Doppler to study the cerebral circulation, if included, might have suggested a higher incidence of brain abnormality and neurodevelopmental delay than that reported in this meta-analysis. Preoperative features of neurodevelopmental delay described in neonates and infants with CHD include seizures, hypotonia, hypertonia, motor asymmetry, inability to suck, feeding difficulties, cranial nerve abnormalities, lethargy, restlessness, agitation and autistic features8,11,26,29,30,39,41 – 43 . These abnormalities are more common in cyanotic infants with oxygen saturation of < 85%26 – 28,49 . A proportion of these abnormalities in infants (up to 1 year of age) might have been secondary to the deleterious effect of, for example, unoperated CHD, particularly as observed in older studies when repair of cyanotic CHD was often delayed. Most studies included mixed types of CHD. However, it seems that babies with coarctation of the aorta or HLHS were at greatest risk of cerebral abnormalities21 . van Houten et al. described cerebral atrophy and deep gray linear echodensities in 71% of neonates with coarctation and ventricular septal defects22 . Infants with HLHS have also been found to be at greater risk of neurodevelopmental delay. However, it seems that all infants with CHD subtypes severe enough to require open heart surgery early in life are at increased risk of developmental delay29 . Complex CHD may be associated with small-forgestational-age fetuses and with small head size50 – 59 . As small head size, on its own, does not necessarily equate to brain abnormalities or neurodevelopmental delay, we have excluded data on small head size unless they were associated with images of brain lesions or neurodevelopmental delay. There is conflicting evidence regarding the effect of BAS on the risk of brain abnormalities in cases with TGA. McQuillen et al. and others demonstrated that BAS is associated with increased risk of stroke in neonates with TGA16,17,23 . In contrast, a recent meta-analysis found no significant association between BAS and brain injury60 . As this possible association was still debated in the literature at the time of planning our systematic review, we decided to exclude cases where BAS was performed, to avoid overestimating the prevalence of preoperative brain injury in cases with TGA. This meta-analysis highlights the importance of prenatal diagnosis of CHD and, if missed prenatally, prompt neonatal diagnosis. Early identification of newborns at increased risk of brain injury and neurodevelopmental delay allows targeted screening and possible intervention. Based on the findings of this meta-analysis, we would recommend that newborns with CHD, in particular HLHS and aortic coarctation, should undergo close
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Khalil et al. periodic developmental surveillance as part of medical follow-up. Established risk factors for preoperative neurologic abnormalities include patient-related factors, e.g. gestational age, 5-min Apgar score14,16 and cardiacrelated factors, with cyanotic defects and coarctation of the aorta being associated with higher risk22,26,31 . Currently, it is not routine to screen for brain abnormalities or neurodevelopmental delay in newborns with CHD. The evidence demonstrated in this meta-analysis and other studies calls for a policy that recommends early assessment of these cases. Owen et al. suggested a two-step approach for screening CHD cases at high risk of brain injury consisting in preoperative bedside neurobehavioral assessment, followed, when results are abnormal, by further evaluation using neuroimaging investigations31 . Brain injury can be assessed even earlier, using neuroimaging techniques during prenatal life. The identification of significant brain abnormalities during fetal life might also influence the parents’ decision following antenatal counseling. Potential early intervention tools to reduce the risk of brain injury include fetal surgery in selected cases61 – 63 . The quality of data available for meta-analysis limits the validity of the current study findings. Small numbers and selection bias of retrospective reviews were the general drawbacks. However, the methodology used in our meta-analysis has reassuringly low heterogeneity, allowing a degree of confidence in the validity of study findings. With specific reference to CHD, the lack of extractable data on clinical subgroups of CHD and the indication for neuroimaging and neurodevelopmental studies are likely to have resulted in over-reporting of these adverse outcomes. Furthermore, the majority of studies lacked information on the timing of CHD diagnosis, raising the possibility that some presurgical cases were not diagnosed with CHD until a postnatal cardiovascular collapse occurred, which in itself may have contributed to the prevalence of brain lesions revealed by neuroimaging and neurodevelopmental delay. Finally, it may be misinterpreted that a brain lesion revealed by neuroimaging confers a high risk of neurodevelopmental handicap and, based on the studies reported, this is far from certain. Prospective large-scale, case–control studies are required to improve the robustness of results by defining clinically meaningful subgroups of CHD with robust ascertainment of brain lesions and the neurodevelopmental outcomes that should be reported. Furthermore, prospective collection of data on predefined brain abnormalities and neurodevelopmental outcomes related to specific CHD diagnoses on a national level would improve our understanding in this area. In the absence of chromosomal or genetic abnormalities, neonates with CHD are at significantly increased risk of brain lesions, as revealed by neuroimaging, and of neurodevelopmental delay. This risk appears to be higher in the presence of left-sided lesions than in the presence of TGA. This association is robust, but the current meta-analysis does not allow us to determine whether the brain injury evident in these infants is of prenatal origin or is a consequence of perinatal or postnatal
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Brain abnormalities and neurodevelopmental delay in CHD cardiovascular compromise. Future prospective studies should be directed towards systematic neuroimaging assessment of fetuses/neonates with CHD, combined with pre- and postsurgical neurodevelopmental evaluation. Only when the mechanism of brain injury is elucidated will it become possible to postulate methods to ameliorate outcome in these infants.
REFERENCES 1. Mensah GA and Brown DW. An Overview Of Cardiovascular Disease Burden In The United States. Health Affairs 2007; 26: 38–48. 2. Hoffman J, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39: 1890–1900. 3. Knowles RL, Bull C, Wren C, Dezateux C. Mortality with congenital heart defects in England and Wales, 1959–2009: exploring technological change through period and birth cohort analysis. Arch Dis Child 2012; 97: 861–865 4. Wernovsky G. Outcomes regarding the central nervous system in children with complex congenital cardiac malformations. Cardiol Young 2005; 15 (Suppl 1) 132–133. 5. Donofrio MT, Massaro AN. Impact of congenital heart disease on brain development and neurodevelopmental outcome. Int J Pediatr 2010; 2010. pii: 359390. doi: 10.1155/2010/359390. 6. Donofrio MT, Duplessis AJ, Limperopoulos C. Impact of congenital heart disease on fetal brain development and injury. Curr Opin Pediatr 2011; 23: 502–511. 7. Burrows F, Hillier SC, McLeod ME, Iron KS, Taylor MJ. Anterior fontanel pressure and visual evoked potentials in neonates and infants undergoing profound hypothermic circulatory arrest. Anesthesiology 1990; 73: 632–636. 8. Newburger J, Jonas RA, Wernovsky G, Wypij D, Hickey PR, Kuban K, Farrell DM, Holmes GL, Helmers SL, Constantinou J, Carrazana E, Barlow JK, Walsh AZ, Lucius KC, Share JC, Wessel DL, Hanley FL, Mayer JE, Jr., Castaneda AR, Ware JH. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low-flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 1993; 329: 1057–1064. 9. O’Hare B, Bissonnette B, Bohn D, Cox P, Williams W. Persistent low cerebral blood flow velocity following profound hypothermic circulatory arrest in infants. Can J Anesthesia 1995; 42: 964–971. 10. Ferry PC. Neurologic sequelae of open-heart surgery in children. Am J Dis Child 1990; 144: 369–373. 11. Tavani F, Zimmerman RA, Clancy RR, Licht DJ, Mahle WT. Incidental intracranial hemorrhage after uncomplicated birth: MRI before and after neonatal heart surgery. Neuroradiology 2003; 45: 253–258. 12. Beca J, Gunn J, Coleman L, Hope A, Whelan LC, Gentles T, Inder T, Hunt R, Shekerdemian L. Pre-operative brain injury in newborn infants with transposition of the great arteries occurs at rates similar to other complex congenital heart disease and is not related to balloon atrial septosomy. J Am Coll Cardiol 2009; 553: 1807–1811. 13. Licht D, Wang J, Silvestre DW, Nicolson SC, Montenegro LM, Wernovsky G, Tabbutt S, Durning SM, Shera DM, Gaynor JW, Spray TL, Clancy RR, Zimmerman RA, Detre JA. Preoperative cerebral blood flow is diminished in neonates with severe congenital heart defects. J Thorac Cardiovasc Surg 2004; 128: 841–849. 14. Licht D, Shera DM, Clancy RR, Wernovsky G, Montenegro LM, Nicolson SC, Zimmerman RA, Spray TL, Gaynor JW, Vossough A. Brain maturation is delayed in infants with complex congenital heart defects. J Thorac Cardiovasc Surg 2009; 137: 529–537. 15. Mahle W, Tavani F, Zimmerman RA, Nicolson SC, Galli KK, Gaynor JW, Clancy RR, Montenegro LM, Spray TL, Chiavacci
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
23
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
RM, Wernovsky G, Kurth CD. An MRI study of neurological injury before and after congenital heart surgery. Circulation 2002; 106 (Suppl 1) 109–114. McQuillen P, Hamrick SEG, Perez MJ, Barkovich AJ, Glidden DV, Karl TR, Teitel D, Miller SP. Balloon atrial septostomy is associated with preoperative stroke in neonates with transposition of the great arteries. Circulation 2006; 113: 280–285. McQuillen P, Barkovich AJ, Hamrick SEG, Perez M, Ward P, Glidden DV, Azakie A, Karl T, Miller SP. Temporal and anatomic risk profile of brain injury with neonatal repair of congenital heart defects. Stroke 2007; 38: 736–741. Miller S, McQuillen PS, Hamrick S, Xu D, Glidden DV, Charlton N, Karl T, Azakie A, Ferriero DM, Barkovich AJ, Vigneron DB. Abnormal brain development in newborns with congenital heart disease. N Engl J Med 2007; 357: 1928–1938. Partridge S, Vigneron DB, Charlton NN, Berman JI, Henry RG, Mukherjee P, McQuillen PS, Karl TR, Barkovich AJ, Miller SP. Pyramidal tract maturation after brain injury in newborns with heart disease. Ann Neurol 2006; 59: 640–651. Petit C, Rome JJ, Wernovsky G, Mason SE, Shera DM, Nicolson SC, Montenegro LM, Tabbutt S, Zimmerman RA, Licht DJ. Preoperative brain injury in transposition of the great arteries is associated with oxygenation and time to surgery, not balloon atrial septostomy. Circulation 2009; 119: 709–716. Te Pas A, Van Wezel-Meijler G, Bokenkamp-Gramann R, Walther FJ. Preoperative cranial ultrasound findings in infants with major congenital heart disease. Acta Paediatr 2005; 94: 1597–1603. van Houten J, Rothman A, Bejar R. High incidence of cranial ultrasound abnormalities in full-term infants with congenital heart disease. Am J Perinatol 1996; 13: 47–53. Block A, McQuillen PS, Chau V, Glass H, Poskitt KJ, Barkovich AJ, Esch M, Soulikias W, Azakie A, Campbell A, Miller SP. Clinically silent preoperative brain injuries do not worsen with surgery in neonates with congenital heart disease. J Thorac Cardiovasc Surg 2010; 140: 550–557. Andropoulos D, Hunter JV, Nelson DP, Stayer SA, Stark AR, McKenzie ED, Heinle JS, Graves DE, Fraser CD Jr. Brain immaturity is associated with brain injury before and after neonatal cardiac surgery with high-flow bypass and cerebral oxygenation monitoring. J Thorac Cardiovasc Surg 2010; 139: 543–556. Limperopoulos C, Majnemer A, Rosenblatt B, Shevell MI, Rohlicek C, Tchervenkov C. Agreement between the neonatal neurological examination and a standardized assessment of neurobehavioural performance in a group of high-risk newborns. Pediatr Rehabil 1997; 1: 9–14. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurologic status of newborns with congenital heart defects before open heart surgery. Pediatrics 1999; 103: 402–408. Limperopoulos C, Majnemer A, Shevell MI, Rosenblatt B, Rohlicek C, Tchervenkov C. Neurodevelopmental status of newborns and infants with congenital heart defects before and after open heart surgery. J Pediatr 2000; 137: 638–645. Limperopoulos C, Majnemer A, Rosenblatt B, Shevell MI, Rohlicek C, Tchervenkov C, Gottesman R. Association between electroencephalographic findings and neurologic status in infants with congenital heart defects. J Child Neurol 2001; 16: 471–476. Majnemer A, Limperopoulos C, Shevell MI, Rohlicek C, Rosenblatt B, Tchervenkov C. A new look at outcomes of infants with congenital heart disease. Pediatr Neurol 2009; 40: 197–204. Miller S, McQuillen PS, Vigneron DB, Glidden DV, Barkovich AJ, Ferriero DM, Hamrick SE, Azakie A, Karl TR. Preoperative brain injury in newborns with transposition of the great arteries. Ann Thorac Surg 2004; 77: 1698–1706. Owen M, Shevell M, Majnemer A, Limperopoulos C. Abnormal brain structure and function in newborns with complex
Ultrasound Obstet Gynecol 2014; 43: 14–24.
Khalil et al.
24
32.
33.
34.
35.
36. 37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
congenital heart defects before open heart surgery a review of the evidence. J Child Neurol 2011; 26: 743–755. Henderson LK, Craig JC, Willis NS, Tovey D, Webster AC. How to write a Cochrane systematic review. Nephrology (Carlton) 2010; 15: 617–624. NHS Centre for Reviews and Dissemination. Systematic reviews: CRD’s guidance for undertaking reviews in health care, University of York York, UK, 2009 (http://www.york. ac.uk/inst/crd/pdf/Systematic_Reviews). von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. PLoS Med 2007; 4: e296. Guyatt G, Rennie D, Meade MO, Cook DJ (eds) Making Sense of Variability in Study Results. Users’ Guides to the Medical Literature: A Manual of Evidence-Based Clinical Practice, (2nd edn), JAMA Press: Chicago, IL, 2002 (http://jmvertiz.posgrado.unam.mx/pmdcmos02/convocatorias/ Users_guide_medical_literature.pdf). Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560. Sterne JAC, Egger M. Funnel plots for detecting bias in metaanalysis: guidelines on choice of axis. J Clin Epidemiol 2001; 54: 1045–1046. McConnell JR, Fleming WH, Chu WK, Hahn FJ, Sarafian LB, Hofschire PJ, Kugler JD. Magnetic resonance imaging of the brain in infants and children before and after cardiac surgery. A prospective study. Am J Dis Child 1990; 144: 374–378. Dent CL, Spaeth JP, Jones BV, Schwartz SM, Glauser TA, Hallinan B, Pearl JM, Khoury PR, Kurth CD. Brain magnetic resonance imaging abnormalities after the Norwood procedure using regional cerebral perfusion. J Thorac Cardiovasc Surg 2006; 131: 190–197. Durandy Y, Rubatti M, Couturier R, Rohnean A. Pre- and postoperative magnetic resonance imaging in neonatal arterial switch operation using warm perfusion. Artif Organs 2011; 35: 1115–1118. ´ Rufo-Campos M, Rojas-P´erez I, Gomez de Terreros M, Grueso´ Montero J, Alvarez-Madrid A, Gomez de Terreros I, Rufo˜ Munoz M, Gil-Fournier M. The psychoneurological status of newborn infants with congenital heart disease before surgical intervention. Rev Neurol 2003; 37: 705–710. Da Rocha TS, Guardiola A, Piva JP, Ricachinevski CP, Nogueira A. Neuropsychomotor development before and after open-heart surgery in infants. Arq Neuropsiquiatr 2009; 67: 457–462. Gessler P, Schmitt B, Pr`etre R, Latal B. Inflammatory response and neurodevelopmental outcome after open-heart surgery in children. Pediatr Cardiol 2009; 30: 301–305. Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Acquired neuropathologic lesions associated with the hypoplastic left heart syndrome. Pediatrics 1990; 85: 991–1000. Glauser TA, Rorke LB, Weinberg PM, Clancy RR. Congenital brain abnormalities associated with the hypoplastic left heart syndrome. Pediatrics 1990; 85: 984–990. Ashwal S, Holshouser B, Hinshaw DB Jr, Schell R, Bailey L. Proton magnetic resonance spectroscopy in the evaluation of children with congenital heart disease and acute central nervous
system injury. J Thorac Cardiovasc Surg 1996; 112: 403–414. 47. Ashwal S, Holshouser BA, Del Rio MJ, Tong KA, Applegate RL, Bailey LL. Serial proton magnetic resonance spectroscopy of the brain in children undergoing cardiac surgery. Pediatr Neurol 2003; 29: 99–110. 48. Limperopoulos C. Disorders of the fetal circulation and the fetal brain. Clin Perinatol 2009; 36: 561–577. 49. Chock VY, Reddy VM, Bernstein D, Madan A. Neurologic events in neonates treated surgically for congenital heart disease. J Perinatol 2006; 26: 237–242. 50. Spiers PS. Does growth retardation predispose the fetus to congenital malformation? Lancet 1982; 1: 312–314. 51. Rosenthal GL, Wilson PD, Permutt T, Boughman JA, Ferencz C. Birth weight and cardiovascular malformations a populationbased study. The Baltimore-Washington Infant Study. Am J Epidemiol 1991; 133: 1273–1281. 52. Rosenthal GL. Patterns of prenatal growth among infants with cardiovascular malformations: possible fetal hemodynamic effects. Am J Epidemiol 1995; 143: 505–513. 53. Richards MR, Merritt KK, Samuels MH, Langmann AG. Congenital malformations of the cardiovascular system in a series of 6053 infants. Pediatrics 1955; 15: 12–29. 54. Naeye RL. Anatomic features of growth failure in congenital heart disease. Pediatrics 1967; 39: 433–440. 55. Mehrize A, Drash A. Birth weight of infants with cyanotic and acyanotic congenital malformations of the heart. J Pediatr 1961; 59: 715–718. 56. Levy RJ, Rosenthal A, Fyler DC, Nadas AS. Birthweight of infants with congenital heart disease. Am J Dis Child 1978; 132: 249–252. 57. Kramer HH, Trampisch HJ, Rammor S, Giese A. Birth weight of children with congenital heart disease. Eur J Pediatr 1990; 149: 752–757. 58. Khoury MJ, Erickson JD, Cordero JF, McCarthy BJ. Congenital malformations and intrauterine growth retardation a population study. Pediatrics 1988; 82: 83–89. 59. Heyman MA, Rudolph AM. Effects of congenital heart disease on fetal and neonatal circulations. Prog Cardiovasc Dis 1972; 15: 115–143. 60. Polito A, Ricci Z, Fragasso T, Cogo PE. Balloon atrial septostomy and pre-operative brain injury in neonates with transposition of the great arteries a systematic review and a meta-analysis. Cardiol Young 2012; 22: 1–7. 61. Tworetzky W, McElhinney DB, Marx GR, Benson CB, Brusseau R, Morash D, Wilkins-Haug LE, Lock JE, Marshall AC. In utero valvuloplasty for pulmonary atresia with hypoplastic right ventricle: techniques and outcomes. Pediatrics 2009; 124: e510−e518. 62. McElhinney D, Marshall AC, Wilkins-Haug LE, Brown DW, Benson CB, Silva V, Marx GR, Mizrahi-Arnaud A, Lock JE, Tworetzky W. Predictors of technical success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome. Circulation 2009; 120: 1482–1490. 63. Marshall A, Levine J, Morash D, Silva V, Lock JE, Benson CB, Wilkins-Haug LE, McElhinney DB, Tworetzky W. Results of in utero atrial septoplasty in fetuses with hypoplastic left heart syndrome. Prenat Diagn 2008; 28: 1023–1028.
SUPPORTING INFORMATION ON THE INTERNET Table S1 may be found in the online version of this article.
Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.
Ultrasound Obstet Gynecol 2014; 43: 14–24.
