CONTEXT:

Brain injury during prenatal and preoperative postnatal life might play a major role in neurodevelopmental impairment in infants with congenital heart disease (CHD) who require corrective or palliative surgery during infancy. A systematic review of cerebral findings during this period in relation to neurodevelopmental outcome (NDO), however, is lacking.

OBJECTIVE:

To assess the association between prenatal and postnatal preoperative cerebral findings and NDO in infants with CHD who require corrective or palliative surgery during infancy.

DATA SOURCES:

PubMed, Embase, reference lists.

STUDY SELECTION:

We conducted 3 different searches for English literature between 2000 and 2016; 1 for prenatal cerebral findings, 1 for postnatal preoperative cerebral findings, and 1 for the association between brain injury and NDO.

DATA EXTRACTION:

Two reviewers independently screened sources and extracted data on cerebral findings and neurodevelopmental outcome. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale.

RESULTS:

Abnormal cerebral findings are common during the prenatal and postnatal preoperative periods. Prenatally, a delay of cerebral development was most common; postnatally, white matter injury, periventricular leukomalacia, and stroke were frequently observed. Abnormal Doppler measurements, brain immaturity, cerebral oxygenation, and abnormal EEG or amplitude-integrated EEG were all associated with NDO.

LIMITATIONS:

Observational studies, different types of CHD with different pathophysiological effects, and different reference values.

CONCLUSIONS:

Prenatal and postnatal preoperative abnormal cerebral findings might play an important role in neurodevelopmental impairment in infants with CHD. Increased awareness of the vulnerability of the young developing brain of an infant with CHD among caregivers is essential.

It has been well established that infants with congenital heart disease (CHD) are at risk for neurodevelopmental impairments. Reports have been published that indicate that in complex CHD, up to 50% of the infants have neurodevelopmental impairments.1 Impairments can manifest themselves variably, involving different aspects such as (mild) impairments in cognition, fine and gross motor skills, executive functioning, visual construction and perception, attention, social interaction, and core communication skills.1 

Threats for the young developing brain can arise at different stages during pre- and postnatal life. Research used to focus on the intraoperative and postoperative period, but we now know that brain injury in infants with CHD may already occur before cardiac surgery.2 Furthermore, there is increasing evidence that suggests that brain injury in infants with CHD already occurs during intrauterine life.3 

The exact mechanism responsible for brain injury in CHD is not yet fully understood. There are 2 main theories. First, the brain could primarily develop differently in infants with CHD because of intrinsic (epi)genetic factors.4 A large part of heart and brain development occurs simultaneously in the human fetus and involves shared genetic pathways. A discrepancy in one of these pathways could lead to abnormal development of both organs and may thus cause neurodevelopmental impairments.5 Second, the heart defect may entail changes in oxygen saturation because of intracardiac or extracardiac mixing, which could in turn lead to circulatory alterations that affect oxygen and nutrient supply to the brain and could therefore disturb normal cerebral development.6 

Although several studies have reported on prenatal brain injury, preoperative brain injury, or neurodevelopmental outcome (NDO) in CHD, a systematic review of brain injury during both prenatal and postnatal preoperative life in relation to NDO is currently not available. The aim of this study was, therefore, to systematically review existing evidence for prenatal and postnatal preoperative brain injury in relation to NDO in infants with complex CHD.

This systematic review was performed according to the PRISMA guidelines for systematic reviews.7 There was no registered protocol available. A systematic search was conducted in PubMed and Embase independently by 2 researchers (M.J.M. and E.M.W.K.) on July 1, 2016. Publications from January 2000 to July 2016 that contained data on prenatal and/or postnatal preoperative cerebral findings and neurodevelopmental outcome in infants with congenital heart disease were selected for this review.

To assess all available literature on prenatal and postnatal preoperative brain injury in relation to NDO, we conducted 3 different searches. We started with a search on cerebral findings in fetuses with congenital heart disease. For this search, we selected all original research articles that were written in English and contained different combinations or synonyms of congenital heart disease, fetus, Doppler, MRI, sonography, and brain. Articles that exclusively focused on head biometry were excluded. For the second search, we used combinations or synonyms of congenital heart disease, neonate, infant, Doppler, MRI, near-infrared spectroscopy, EEG, and brain. Articles were selected if they were written in English, if participants were <3 months of age at the first examination, and if at least part of the study group was diagnosed prenatally with CHD. Articles that focused on infants with chromosomal or syndromal disorders were excluded because we were interested in the effect of the congenital heart defect on NDO in infants with complex CHD. For the purpose of the current review, we were not interested in developmental problems because of chromosomal disorders. In addition, we excluded articles with an interventional study design tailored to evaluate the direct impact of an experimental intervention on cerebral outcome variables. For the third search, we combined the first 2 searches and complemented it with neurodevelopmental outcome and word variants. Articles were selected only if they combined prenatal and/or postnatal preoperative cerebral findings with NDO in infants with CHD. Furthermore, NDO had to be assessed with validated tools such as the Bayley Scales of Infant Development II (BSID II) or the Bayley Scales of Infant and Toddler Development III (Bayley III). The complete search string is available online in Supplemental Information.

In addition to the database search, we screened the reference lists of all retrieved articles for additional relevant publications.

We assessed the quality of the selected articles using the Newcastle-Ottawa Quality Assessment Scale for case-control studies and cohort studies. This scale consists of 3 parts: selection, comparability, and exposure for case-control studies and selection, comparability, and outcome for cohort studies. Each part consists of a different number of items and a different amount of points that can be acquired per item. Selection consists of 4 items with a maximum of 4 points, comparability consists of 1 item with a maximum of 2 points, and exposure or outcome consists of 3 items with a maximum of 3 points. Therefore, the total score ranges from 0 to 9, with 9 being an article of the highest quality. The quality scores of selected articles are presented online in Supplemental Tables 4 and 5.

Our initial search resulted in 503 articles. After removing duplicates, we assessed titles and abstracts of 260 articles, of which 40 were relevant. The main reasons for exclusion were chromosomal or syndromal disorders, not original research, and study being out of scope. From the reference lists, we found 7 additional articles. After reading the full text, 30 articles were included in the prenatal part of the review (Fig 1). Prenatal cerebral findings are presented in Table 1.

FIGURE 1

Prenatal search strategy. NA, not applicable.

FIGURE 1

Prenatal search strategy. NA, not applicable.

TABLE 1

Prenatal Cerebral Findings in Infants with CHD

Study (First Author, Journal, Year of Publication)Study Design, No. InfantsCHDAgeMethodsFindings (Compared With Healthy Controls and/or Reference Values, Unless Otherwise Stated)a
Ruiz et al, Ultrasound Obstet Gynecol, 2016 Retrospective study, N = 119 Mixed Second and third trimester Ultrasound (biometry, Doppler) Normal MCA-PI and CPR during second trimester; 18% MCA-PI and CPR less than fifth percentile at first examination 
Lower MCA-PI in group with severe impairment of cerebral blood flow 
UA-PI increased with GA 
Smaller HC and BPD at diagnosis which remained during pregnancy 
Hahn et alb, Ultrasound Obstet Gynecol, 2016 Retrospective study, N = 133 SVA Second and third trimester Ultrasound (biometry, Doppler) Lower MCA-PI and decreased more as GA progressed 
Smaller HC at 24–29 wk GA and >34 wk GA 
Fetal HC predictor of neonatal HC from 30 wk GA 
MCA-PI not associated with fetal and neonatal HC 
Zeng et al, Ultrasound Obstet Gynecol, 2015 Case-control study, N = 73/168 Mixed Second and third trimester Ultrasound (biometry, Doppler) Lower MCA-PI 
Total intracranial volume, frontal lobe volume, cerebellar volume, and thalamus volume progressively decreased from 28 wk GA 
Largest decrease in frontal lobe volume, followed by total intracranial volume and cerebellar volume 
Smaller HC and BPD from 33 wk GA 
Zeng et alb, Ultrasound Obstet Gynecol, 2015 Case-control study, N = 112/112 Mixed 20–30 wk Ultrasound (Doppler) Lower MCA-PI in HLHS, MCA-PI tended to be lower in LSOL, normal MCA-PI in TGA and RSOL 
Higher cerebral blood flow 
Vascularization index, flow index, and vascularization flow index of the total intracranial volume and 3 main arteries higher in HLHS and LSOL and of the anterior cerebral artery in TGA 
Masoller et al, Ultrasound Obstet Gynecol, 2014 Case-control study, N = 95/95 Mixed 20–24 wk Ultrasound (biometry, Doppler) Lower MCA-PI and CPR and higher fractional moving blood volume 
Fractional moving blood volume >95th percentile in 81% compared with 11% in controls 
No differences in MCA-PI and fractional moving blood volume between CHD diagnostic groups 
Smaller BPD and HC 
No differences in BPD and HC between CHD diagnostic groups 
Williams et alb, Am Heart J, 2013 Cohort study, N = 134 SVA 18–38 wk Ultrasound (Doppler) MCA-PI at first fetal echocardiogram −0.95 ± 1.5 
22% MCA-PI < −2.0 at least once across gestation 
Yamamoto et al, Ultrasound Obstet Gynecol, 2013 Case-control study, N = 89/89 Mixed 32 wk Ultrasound (biometry, Doppler) Lower MCA-PI, higher UA-PI and lower CPR in HLHS and CoA 
CoA with retrograde aortic arch flow, lower MCA-PI and CPR, and higher UA-PI compared with CoA with antegrade flow 
Normal MCA-PI, UA-PI, and CPR in TGA and POTO 
Smaller HC at birth in TGA and CoA 
Szwast et al, Ultrasound Obstet Gynecol, 2012 Retrospective study, N = 131/92 SVA 18–40 wk Ultrasound (Doppler) Lower MCA-PI and lower CPR in aortic arch obstruction compared with controls and compared with pulmonary obstruction 
MCA-PI decreased during gestation for aortic obstruction 
MCA-PI increased during gestation for pulmonary obstruction 
Normal UA-PI 
Williams et alb,c, Ultrasound Obstet Gynecol, 2012 Pilot study, N = 13 Mixed 20–24 wk Ultrasound (Doppler) MCA-PI −1.7 ± 1.1 
56% CPR < 1.0 (no z scores) 
HLHS and TOF lowest MCA-PI (−2.4 and −2.01, respectively), TGA −0.75 
Arduini et al, J Matern Fetal Neonatal Med, 2011 Case-control study, N = 60/65 Mixed 30–38 wk Ultrasound (biometry, Doppler) Lower MCA-PI and CPR (no z scores) 
HLHS and CoA lowest and TOF and TGA highest CPR 
Smaller HC and HC/AC 
HLHS and CoA lowest and TOF and TGA highest HC/AC 
Itsukaichi et al, Fetal Diagn Ther, 20118  Retrospective study, N = 44/140 Mixed 28–34 wk Ultrasound (biometry, Doppler) MCA-RI measurements more often less than fifth percentile and UA-RI >90th percentile 
Similar biometry measurements in fetuses <10th and >10th MCA-RI percentile 
McElhinney et al, Ultrasound Med Biol, 2010 Cohort study, N = 52 HLHS HLHS 20–31 wk Ultrasound (Doppler) Lower MCA-PI and RI in HLHS 
Normal UA-PI and UA-RI 
37% CPR <1.0 (no z scores) 
Berg et al, Ultrasound Obstet Gynecol, 2009 Case-control study, N = 113/1378 Mixed 19–41 wk Ultrasound (biometry, Doppler) Smaller HC at birth, normal MCA-PI and CPR in TGA 
Smaller HC at birth, lower MCA-PI and CPR in HLHS 
Normal biometry and Doppler parameters in PA, AoS, and TOF 
Guorong et al, Fetal Diagn Ther, 2009 Case-control study, N = 45/275 Mixed 20–40 wk Ultrasound (Doppler) Normal MCA-PI 
MCA-PI tended to be lower in LSOL and was lower in congestive heart failure 
Higher UA-PI and higher U/C PI ratios 
No traditional “brain sparing” as MCA-PI was normal, whereas U/C PI was higher 
Chen et al, Am J Perinatol, 2009 Case-control study, N = 11/44 Ebstein anomaly 23–37 wk Ultrasound (Doppler) Lower MCA-PI and CPR (no z scores) 
Higher UA-PI and left ventricular myocardial performance index 
Lower fetal cardiac profile score (median 1 point lower) 
MCA-PI positive correlation with cardiovascular profile score and negative correlation with left ventricular myocardial performance index 
Modena et al, Am J Obstet Gynecol, 2006 Case-control study, N = 71/71 Mixed 24–28 wk Ultrasound (Doppler) Normal MCA-PI, UA-PI, and CPR 
MCA-PI more often less than fifth percentile (5/71 vs 0/71) 
CPR more often less than fifth percentile (8/71 vs 2/71) 
No difference in UA-PI >95th percentile (6/71 vs 3/71) 
Kaltman et al, Ultrasound Obstet Gynecol, 2005 Case-control study, N = 58/114 Mixed 20–40 wk Ultrasound (Doppler) Lower MCA-PI in HLHS 
Higher MCA-PI in RSOL compared with HLHS 
Higher UA-PI in RSOL 
U/C PI-ratio similar between diagnostic groups 
Donofrio et al, Pediatr Cardiol, 2003 Case-control study, N = 36/21 Mixed Second and third trimester Ultrasound (Doppler) Lower MCA-RI and CPR 
Normal UA-RI 
HLHS and HRHS infants had highest incidence of abnormally low CPR (58% and 60%) 
Jouannic et al, Ultrasound Obstet Gynecol, 2002 Case-control study, N = 23/40 TGA 36–38 wk Ultrasound (Doppler) Lower MCA-PI 
Normal UA-PI, DV-PI, and Ao-PI (no z scores) 
Meise et al, Ultrasound Obstet Gynecol, 2001 Case-control study, N = 115/100 Mixed 19–41 wk Ultrasound (Doppler) Normal MCA-PI 
Higher UA-PI 
No difference in UA-PI >95th percentile 
 
Brossard-Racine et alc, Am J Neuroradiol, 2016 Cohort study, N = 103 Mixed Second and third trimester MRI (structural) 16% fetal brain abnormalities (6 mild ventriculomegaly, 4 increased extra-axial spaces, 2 white matter cysts, 2 inferior vermian hypoplasia, 1 white matter signal hyperintensity) 
32% neonatal brain abnormalities, 27% acquired brain injury 
Postnatally, a predominance of punctate white matter injury 
Brossard-Racine et al, Am J Neuroradiol, 2014 Case-control study, N = 144/194 Mixed 18–39 wk MRI (structural) 23% brain injury compared with 1.5% for controls 
Most common: mild unilateral ventriculomegaly and increased extra-axial CSF spaces 
No association between type of brain injury and CHD diagnosis 
Mlczoch et alb, Eur J Paediatr Neurol, 2013 Retrospective study, N = 53 Mixed 20–37 wk MRI
(structural) 39% brain injury (7 malformation, 5 acquired lesion, 9 asymmetry of the ventricles/wider CSF spaces) 
Fetuses with similar PA and Ao size had higher prevalence of brain injury compared with fetuses with PA < Ao or Ao < PA 
Schellen et al, Am J Obstet Gynecol, 2015 Retrospective study, N = 24/24 TOF 25 wk MRI, volume Lower total brain volume and cortical and subcortical volumes from 20 wk GA 
Higher ventricular volumes and cerebrospinal fluid spaces 
Normal intracranial cavity volume and cerebellar volume 
Al Nafisi et al, J Cardiovasc Magn Reson, 20139  Case-control study, N = 22/12 controls Mixed 30–39 wk MRI, volume 6 fetuses brain weights less than fifth percentile, 0 controls brain weights <25th percentile 
19% lower combined ventricular output 
Sun et al, Circulation, 2015 Case-control study, N = 30/30 Mixed 36 wk MRI (volume, O2 saturation) Smaller brain volume 
10% lower aorta oxygen saturation with cerebral blood flow and extraction being normal. As a result, 15% reduction in cerebral oxygen delivery and 32% reduction in oxygen consumption 
Reduced cerebral oxygen consumption associated with a mean 13% reduction in brain volume or 1 SD reduction in estimated brain weight z score 
Limperopoulos et al, Circulation, 2010 Case-control study, N = 55/50 Mixed 25–37 wk MRI (volume, metabolism) Significantly and progressively smaller total brain volume and intracranial cavity volume 
Lower NAA/Cho during the third trimester 
7 CHD fetuses had cerebral lactate compared with 0 controls 
Absence of antegrade aortic flow and presence of lactate predictors of low NAA/Cho 
 
Masoller et al, Fetal Diagn Ther, 2016 Case-control study, N = 58/58 Mixed 36–38 wk Ultrasound (Doppler) Lower MCA-PI and CPR and higher frontal fractional moving blood volume 
MRI (volume, metabolism) Lower MCA-PI and CPR in fetuses with impaired cerebral blood flow than fetuses with near-normal or mildly impaired cerebral blood flow 
Smaller total and intracranial brain volume, decreased cortical development, and altered metabolism 
Fetuses with impairment of blood flow to the cerebrum had more severe abnormalities on MRI than fetuses with near-normal/mildly impaired blood flow to the cerebrum 
Masoller et alb, Ultrasound Obstet Gynecol, 2016 Case-control study, N = 58/58 Mixed 36–38 wk Ultrasound (Doppler) Lower MCA-PI and CPR and higher fractional moving blood volume 
MRI (volume, metabolism) Smaller HC and BPD 
Smaller brain, intracranial, and opercular volume and decreased sulcation 
Increased Ino/Cho and decreased NAA/Cho and Cho/Cr ratios 
MCA-PI, CPR, and fetal HC at mid gestation were independent predictors of abnormal brain development 
Clouchoux et al, Cereb Cortex, 2013 Case-control study, N = 18/30 HLHS 25–37 wk Ultrasound (Doppler) Smaller brain volumes, which became progressively greater after 30 wk GA, smaller gyrification index, and smaller surface area 
MRI, volume 3–4 wk sulcation delay 
Low CPR and absence of antegrade aortic flow associated with decreased cortical gray matter, white matter, subcortical matter, and decreased cortical surface area 
Study (First Author, Journal, Year of Publication)Study Design, No. InfantsCHDAgeMethodsFindings (Compared With Healthy Controls and/or Reference Values, Unless Otherwise Stated)a
Ruiz et al, Ultrasound Obstet Gynecol, 2016 Retrospective study, N = 119 Mixed Second and third trimester Ultrasound (biometry, Doppler) Normal MCA-PI and CPR during second trimester; 18% MCA-PI and CPR less than fifth percentile at first examination 
Lower MCA-PI in group with severe impairment of cerebral blood flow 
UA-PI increased with GA 
Smaller HC and BPD at diagnosis which remained during pregnancy 
Hahn et alb, Ultrasound Obstet Gynecol, 2016 Retrospective study, N = 133 SVA Second and third trimester Ultrasound (biometry, Doppler) Lower MCA-PI and decreased more as GA progressed 
Smaller HC at 24–29 wk GA and >34 wk GA 
Fetal HC predictor of neonatal HC from 30 wk GA 
MCA-PI not associated with fetal and neonatal HC 
Zeng et al, Ultrasound Obstet Gynecol, 2015 Case-control study, N = 73/168 Mixed Second and third trimester Ultrasound (biometry, Doppler) Lower MCA-PI 
Total intracranial volume, frontal lobe volume, cerebellar volume, and thalamus volume progressively decreased from 28 wk GA 
Largest decrease in frontal lobe volume, followed by total intracranial volume and cerebellar volume 
Smaller HC and BPD from 33 wk GA 
Zeng et alb, Ultrasound Obstet Gynecol, 2015 Case-control study, N = 112/112 Mixed 20–30 wk Ultrasound (Doppler) Lower MCA-PI in HLHS, MCA-PI tended to be lower in LSOL, normal MCA-PI in TGA and RSOL 
Higher cerebral blood flow 
Vascularization index, flow index, and vascularization flow index of the total intracranial volume and 3 main arteries higher in HLHS and LSOL and of the anterior cerebral artery in TGA 
Masoller et al, Ultrasound Obstet Gynecol, 2014 Case-control study, N = 95/95 Mixed 20–24 wk Ultrasound (biometry, Doppler) Lower MCA-PI and CPR and higher fractional moving blood volume 
Fractional moving blood volume >95th percentile in 81% compared with 11% in controls 
No differences in MCA-PI and fractional moving blood volume between CHD diagnostic groups 
Smaller BPD and HC 
No differences in BPD and HC between CHD diagnostic groups 
Williams et alb, Am Heart J, 2013 Cohort study, N = 134 SVA 18–38 wk Ultrasound (Doppler) MCA-PI at first fetal echocardiogram −0.95 ± 1.5 
22% MCA-PI < −2.0 at least once across gestation 
Yamamoto et al, Ultrasound Obstet Gynecol, 2013 Case-control study, N = 89/89 Mixed 32 wk Ultrasound (biometry, Doppler) Lower MCA-PI, higher UA-PI and lower CPR in HLHS and CoA 
CoA with retrograde aortic arch flow, lower MCA-PI and CPR, and higher UA-PI compared with CoA with antegrade flow 
Normal MCA-PI, UA-PI, and CPR in TGA and POTO 
Smaller HC at birth in TGA and CoA 
Szwast et al, Ultrasound Obstet Gynecol, 2012 Retrospective study, N = 131/92 SVA 18–40 wk Ultrasound (Doppler) Lower MCA-PI and lower CPR in aortic arch obstruction compared with controls and compared with pulmonary obstruction 
MCA-PI decreased during gestation for aortic obstruction 
MCA-PI increased during gestation for pulmonary obstruction 
Normal UA-PI 
Williams et alb,c, Ultrasound Obstet Gynecol, 2012 Pilot study, N = 13 Mixed 20–24 wk Ultrasound (Doppler) MCA-PI −1.7 ± 1.1 
56% CPR < 1.0 (no z scores) 
HLHS and TOF lowest MCA-PI (−2.4 and −2.01, respectively), TGA −0.75 
Arduini et al, J Matern Fetal Neonatal Med, 2011 Case-control study, N = 60/65 Mixed 30–38 wk Ultrasound (biometry, Doppler) Lower MCA-PI and CPR (no z scores) 
HLHS and CoA lowest and TOF and TGA highest CPR 
Smaller HC and HC/AC 
HLHS and CoA lowest and TOF and TGA highest HC/AC 
Itsukaichi et al, Fetal Diagn Ther, 20118  Retrospective study, N = 44/140 Mixed 28–34 wk Ultrasound (biometry, Doppler) MCA-RI measurements more often less than fifth percentile and UA-RI >90th percentile 
Similar biometry measurements in fetuses <10th and >10th MCA-RI percentile 
McElhinney et al, Ultrasound Med Biol, 2010 Cohort study, N = 52 HLHS HLHS 20–31 wk Ultrasound (Doppler) Lower MCA-PI and RI in HLHS 
Normal UA-PI and UA-RI 
37% CPR <1.0 (no z scores) 
Berg et al, Ultrasound Obstet Gynecol, 2009 Case-control study, N = 113/1378 Mixed 19–41 wk Ultrasound (biometry, Doppler) Smaller HC at birth, normal MCA-PI and CPR in TGA 
Smaller HC at birth, lower MCA-PI and CPR in HLHS 
Normal biometry and Doppler parameters in PA, AoS, and TOF 
Guorong et al, Fetal Diagn Ther, 2009 Case-control study, N = 45/275 Mixed 20–40 wk Ultrasound (Doppler) Normal MCA-PI 
MCA-PI tended to be lower in LSOL and was lower in congestive heart failure 
Higher UA-PI and higher U/C PI ratios 
No traditional “brain sparing” as MCA-PI was normal, whereas U/C PI was higher 
Chen et al, Am J Perinatol, 2009 Case-control study, N = 11/44 Ebstein anomaly 23–37 wk Ultrasound (Doppler) Lower MCA-PI and CPR (no z scores) 
Higher UA-PI and left ventricular myocardial performance index 
Lower fetal cardiac profile score (median 1 point lower) 
MCA-PI positive correlation with cardiovascular profile score and negative correlation with left ventricular myocardial performance index 
Modena et al, Am J Obstet Gynecol, 2006 Case-control study, N = 71/71 Mixed 24–28 wk Ultrasound (Doppler) Normal MCA-PI, UA-PI, and CPR 
MCA-PI more often less than fifth percentile (5/71 vs 0/71) 
CPR more often less than fifth percentile (8/71 vs 2/71) 
No difference in UA-PI >95th percentile (6/71 vs 3/71) 
Kaltman et al, Ultrasound Obstet Gynecol, 2005 Case-control study, N = 58/114 Mixed 20–40 wk Ultrasound (Doppler) Lower MCA-PI in HLHS 
Higher MCA-PI in RSOL compared with HLHS 
Higher UA-PI in RSOL 
U/C PI-ratio similar between diagnostic groups 
Donofrio et al, Pediatr Cardiol, 2003 Case-control study, N = 36/21 Mixed Second and third trimester Ultrasound (Doppler) Lower MCA-RI and CPR 
Normal UA-RI 
HLHS and HRHS infants had highest incidence of abnormally low CPR (58% and 60%) 
Jouannic et al, Ultrasound Obstet Gynecol, 2002 Case-control study, N = 23/40 TGA 36–38 wk Ultrasound (Doppler) Lower MCA-PI 
Normal UA-PI, DV-PI, and Ao-PI (no z scores) 
Meise et al, Ultrasound Obstet Gynecol, 2001 Case-control study, N = 115/100 Mixed 19–41 wk Ultrasound (Doppler) Normal MCA-PI 
Higher UA-PI 
No difference in UA-PI >95th percentile 
 
Brossard-Racine et alc, Am J Neuroradiol, 2016 Cohort study, N = 103 Mixed Second and third trimester MRI (structural) 16% fetal brain abnormalities (6 mild ventriculomegaly, 4 increased extra-axial spaces, 2 white matter cysts, 2 inferior vermian hypoplasia, 1 white matter signal hyperintensity) 
32% neonatal brain abnormalities, 27% acquired brain injury 
Postnatally, a predominance of punctate white matter injury 
Brossard-Racine et al, Am J Neuroradiol, 2014 Case-control study, N = 144/194 Mixed 18–39 wk MRI (structural) 23% brain injury compared with 1.5% for controls 
Most common: mild unilateral ventriculomegaly and increased extra-axial CSF spaces 
No association between type of brain injury and CHD diagnosis 
Mlczoch et alb, Eur J Paediatr Neurol, 2013 Retrospective study, N = 53 Mixed 20–37 wk MRI
(structural) 39% brain injury (7 malformation, 5 acquired lesion, 9 asymmetry of the ventricles/wider CSF spaces) 
Fetuses with similar PA and Ao size had higher prevalence of brain injury compared with fetuses with PA < Ao or Ao < PA 
Schellen et al, Am J Obstet Gynecol, 2015 Retrospective study, N = 24/24 TOF 25 wk MRI, volume Lower total brain volume and cortical and subcortical volumes from 20 wk GA 
Higher ventricular volumes and cerebrospinal fluid spaces 
Normal intracranial cavity volume and cerebellar volume 
Al Nafisi et al, J Cardiovasc Magn Reson, 20139  Case-control study, N = 22/12 controls Mixed 30–39 wk MRI, volume 6 fetuses brain weights less than fifth percentile, 0 controls brain weights <25th percentile 
19% lower combined ventricular output 
Sun et al, Circulation, 2015 Case-control study, N = 30/30 Mixed 36 wk MRI (volume, O2 saturation) Smaller brain volume 
10% lower aorta oxygen saturation with cerebral blood flow and extraction being normal. As a result, 15% reduction in cerebral oxygen delivery and 32% reduction in oxygen consumption 
Reduced cerebral oxygen consumption associated with a mean 13% reduction in brain volume or 1 SD reduction in estimated brain weight z score 
Limperopoulos et al, Circulation, 2010 Case-control study, N = 55/50 Mixed 25–37 wk MRI (volume, metabolism) Significantly and progressively smaller total brain volume and intracranial cavity volume 
Lower NAA/Cho during the third trimester 
7 CHD fetuses had cerebral lactate compared with 0 controls 
Absence of antegrade aortic flow and presence of lactate predictors of low NAA/Cho 
 
Masoller et al, Fetal Diagn Ther, 2016 Case-control study, N = 58/58 Mixed 36–38 wk Ultrasound (Doppler) Lower MCA-PI and CPR and higher frontal fractional moving blood volume 
MRI (volume, metabolism) Lower MCA-PI and CPR in fetuses with impaired cerebral blood flow than fetuses with near-normal or mildly impaired cerebral blood flow 
Smaller total and intracranial brain volume, decreased cortical development, and altered metabolism 
Fetuses with impairment of blood flow to the cerebrum had more severe abnormalities on MRI than fetuses with near-normal/mildly impaired blood flow to the cerebrum 
Masoller et alb, Ultrasound Obstet Gynecol, 2016 Case-control study, N = 58/58 Mixed 36–38 wk Ultrasound (Doppler) Lower MCA-PI and CPR and higher fractional moving blood volume 
MRI (volume, metabolism) Smaller HC and BPD 
Smaller brain, intracranial, and opercular volume and decreased sulcation 
Increased Ino/Cho and decreased NAA/Cho and Cho/Cr ratios 
MCA-PI, CPR, and fetal HC at mid gestation were independent predictors of abnormal brain development 
Clouchoux et al, Cereb Cortex, 2013 Case-control study, N = 18/30 HLHS 25–37 wk Ultrasound (Doppler) Smaller brain volumes, which became progressively greater after 30 wk GA, smaller gyrification index, and smaller surface area 
MRI, volume 3–4 wk sulcation delay 
Low CPR and absence of antegrade aortic flow associated with decreased cortical gray matter, white matter, subcortical matter, and decreased cortical surface area 

AC, abdominal circumference; Ao, aorta; Ao-PI, pulsatility index of the aorta; AoS, aortic stenosis; BPD, biparietal diameter; CoA, coarctation of the aorta; CSF, cerebrospinal fluid; DV-PI, pulsatility index of the ductus venosus; GA, gestational age; HC/AC, head circumference/abdominal circumference; HRHS, hypoplastic right heart syndrome; LSOL, left-sided obstructive lesion; MCA-RI, resistance index of the middle cerebral artery; POTO, pulmonary outflow tract obstruction; RSOL, right-sided obstructive lesion; SVA, single ventricle anomaly; TOF, tetralogy of Fallot; UA-RI, resistance index of the umbilical artery; U/C PI, pulsatility index of the umbilical artery/pulsatility index of the middle cerebral artery.

a

Doppler parameters and biometry measurements are reported as z scores unless otherwise stated.

b

Articles that also address neurodevelopmental outcome.

c

Articles that also address postnatal findings.

The second search resulted in 1347 articles. We assessed titles and abstract of 734 articles after removing duplicates. Reasons for exclusion at this stage were chromosomal or syndromal disorders, not original research, intraoperative or postoperative data, and study being out scope. From the reference lists, we found another 3 articles. Eventually, we read 68 full-text articles, from which 51 were included in the postnatal part of the review (Fig 2). Postnatal cerebral findings are presented in Table 2.

FIGURE 2

Postnatal search strategy. NA, not applicable

FIGURE 2

Postnatal search strategy. NA, not applicable

TABLE 2

Postnatal Cerebral Findings in Infants With CHD

Study (First Author, Journal, Year of Publication)Study Design, No. InfantsCHDAntenatal DiagnosisMethodsFindings (Compared With Healthy Controls and/or Reference Values, Unless Otherwise Stated)
Brossard-Racine et al, ANJR Am J Neuroradiol, 2016 Cohort study, N = 103 Mixed 100% MRI (structural) 32% brain injury (26% acquired) 
WMI most common injury (5 mild and 10 moderate or severe) 
WMI located in the periventricular white matter, centrum semiovale, and frontal white matter 
Second most common injury: nonhemorrhagic parenchymal injury 
McCarthy et al, Pediatr Res, 2015 Retrospective study, N = 72 Mixed MRI (structural) 18% PVL 
The majority of PVL classified as moderate 
Bertholdt et al, Eur J Cardiothorac Surg, 2014 Case-control study, N = 30/20 Mixed 17% MRI (structural) 23% WMI or stroke, 47% intracranial hemorrhage (subdural hematoma or choroid plexus) 
Low Spo2 risk factor for brain injury, BAS not associated with brain injury 
Brain injury associated with poorer neurologic functioning (82% abnormal assessment) 
Owen et ala, J Pediatr, 2014 Cohort study, N = 35 Mixed 51% MRI (structural) 46% evidence of injury or immaturity on MRI (most common: hemorrhage) 
71% suspect or abnormal neurobehavioral assessment (16 suspect, 9 abnormal) 
Goff et al, J Thorac Cardiovasc Surg, 2014 Cohort study, N = 57 HLHS 86% MRI (structural) 19% PVL preoperatively 
Brain immaturity and male sex independent strong predictors of PVL 
Andropoulos et ala, Paediatr Anaesth, 2014 Retrospective study, N = 59 Mixed MRI (structural) 46% preoperative brain injury 
WMI most common injury (31%; 8 mild, 3 moderate, 1 severe) 
Beca et ala, Circulation, 2013 Cohort study, N = 153 Mixed 59% MRI (structural) 26% brain injury (20% WMI, 5% stroke, 4% hemorrhage) 
WMI associated with brain immaturity but not with BAS, diagnostic group, or GA at birth 
WMI and stroke not associated with postoperative brain injury 
Mulkey et al, Pediatr Cardiol, 2013 Retrospective study, N = 73 Mixed 32% MRI (structural) 47% ≥1 type of brain injury, 26% 2–4 injury types 
25% brain injury if hemorrhage was excluded 
Lower Apgar score at 5 min associated with brain injury 
Ortinau et al, J Pediatr, 2013 Case-control study, N = 15/12 Mixed MRI (structural) Reduced cortical surface area and gyrification index for left and right hemispheres 
46% focal signal abnormalities in the white matter 
Glass et al, Cardiol Young, 2011 Cohort study, N = 127 Mixed MRI (structural) 24% white matter injury 
Infants with TGA and blood stream infection might have a higher risk of developing WMI (not significant in the whole group but significant when stroke was excluded) 
Block et al, J Thorac Cardiovasc Surg, 2010 Cohort study, N = 92 TGA MRI (structural) 43% brain injury (23 stroke, 21 WMI, and 7 IVH) 
SVA BAS doubled the risk for brain injury 
 Higher Spo2 protective factor for brain injury (OR = 0.96) 
Andropoulos et al, J Thorac Cardiovasc Surg, 2010 Cohort study, N = 67 Mixed 44% MRI (structural) 28% brain injury (single ventricle and 2 ventricles) 
Brain immaturity associated with preoperative WMI and late death 
58% of lesions partially or completely resolved at late MRI scan (3–6 mo) 
Beca et al, J Am Coll Cardiol, 2009 Cohort study, N = 64 Mixed 32% MRI (structural) 30% brain injury (27% WMI and 5% stroke) 
No differences between cardiac diagnoses 
No association between BAS and brain injury 
Petit et al, Circulation, 2009 Retrospective study, N = 26 (14 BAS) TGA MRI (structural) 38% PVL, 0 strokes 
Arterial oxygen saturation and time to surgery risk factors for brain injury 
No association between BAS and brain injury 
Licht et al, J Thorac Cardiovasc Surg, 2009 Cohort study, N = 42 TGA HLHS 83% HLHS 39% TGA MRI (structural) 21% PVL, 9.5% stroke, 86% incomplete closure of the opercular space (brain immaturity) 
Lower total maturation scores (10.15), ∼1 mo younger than their actual GA 
McQuillen et al, Circulation, 2006 Cohort study, N = 29 TGA MRI (structural) 41% brain injury (5 stroke, 2 WMI, 1 IVH, 4 combination of lesions) 
5 min Apgar score, lowest Spo2, and BAS (12 of 19 infants with BAS had brain injury, 0 of 10 without BAS had brain injury) are risk factors for brain injury 
Durandy et al, Artif Organs, 2011 Cohort study, N = 21 TGA 57% MRI (structural) 42% brain injury (4 infarct, 4 WMI, and 5 hemorrhages in 9 infants) 
55% brain injury in antenatal diagnosis compared with 33% in postnatal diagnosis 
Tavani et al, Neuroradiology, 200310  Cohort study, N = 24 Mixed MRI (structural) 62% of infants delivered vaginally had hemorrhage on MRI 
11 subdural hematomas 
6 blood in the subdural space along the tentorium and falx or more laterally 
7 blood in the choroid plexus 
No relation between intracranial hemorrhage and abnormal neurologic examination 
von Rhein et al, J Pediatr, 2015 Case-control study, N = 19/19 Mixed MRI, volume 21% total brain volume reduction, all regions affected 
Smallest difference: mesencephalon 7.7% smaller 
Biggest difference: cortical gray matter 29.5% smaller and occipital lobes 28.5% smaller 
Ortinau et al, Pediatr Cardiol, 2012 Cohort study, N = 57/36 Mixed MRI, volume Smaller frontal, parietal, cerebellar, and brain stem measures 
Brain growth rate not different 
Differences in volume persisted at 3 mo, except for cerebellar measures 
Somatic growth the greatest predictor of brain growth 
Ortinau et al, J Thorac Cardiovasc Surg, 2012 Cohort study, N = 67/36 Mixed MRI (structural, volume) 42% focal WMI 
Smaller frontal, parietal, cerebellar, and brain stem 
Frontal and brain stem most affected 
Delayed maturation at the microstructural level 
Makki et al, AJNR Am J Neuroradiol, 201311  Case-control study, N = 15/11 TGA MRI (DTI) Higher apparent diffusion coefficient, lower FA genu corpus callosum 
Lower FA splenium corpus callosum 
Hagmann et al, J Child Neurol, 2016 Case-control study, N = 22/22 Mixed MRI (volume, DTI) Corpus callosum 25% (splenium) to 35% (genu) smaller 
Total corpus callosum and splenium significantly smaller 
Splenium lower FA, higher radial diffusion, diffusion coefficient not significant 
No differences in other substructures of the corpus callosum 
Mulkey et al, Pediatr Neurol, 2014 Pilot study, N = 19 Mixed MRI (structural, DTI) 52% brain injury (WMI or stroke) 
Lower FA in multiple major white matter tracts in infants with brain injury compared with infants without brain injury 
Partridge et al, Ann Neurol, 2006 Cohort study, N = 25 Mixed MRI (structural, DTI) 28% brain injury (focal or multifocal) 
Brain injury associated with less change in FA over time in the pyramidal tract compared with newborns with 2 normal MRI scans 
Infants with brain injury had the least dramatic changes with age detected by DTT 
Trend in FA maturation rates across the 3 injury groups: newborns with normal scans had the most rapid changes, those with postoperative injury had intermediate maturation rates, and those with preoperative injury had the least rapid changes 
No differences in directionally averaged diffusion coefficients 
Sethi et al, Pediatr Res, 2013 Cohort study, N = 36 CHD SVA 61% MRI (structural, MRS) 36% brain injury (4 mild WMI, 4 moderate WMI, 2 severe WMI, 6 focal strokes, 5 IVH) 
Higher mean average diffusivity for gray matter and lower FA in the white matter regions 
Lower mean NAA/Cho ratios and higher mean Lac/Cho ratios 
Delayed microstructural brain development 
Park et ala, Pediatr Cardiol, 2006 Case-control study, N = 16/15 TGA MRI (structural, MRS) No abnormal findings on preoperative MRI 
Altered metabolism in parietal white matter (increased Cho/Cr) and occipital gray matter (increased Cho/Cr and Ino/Cr) 
Altered metabolism persisted 1 y after ASO in parietal white matter and normalized for occipital gray matter 
Miller et al, Ann Thorac Surg, 2004 Cohort study, N = 10 TGA MRI (structural, MRS) 40% brain injury (stroke or hemorrhage) 
Higher Lac/Cho 
Similar NAA/Cho between TGA and healthy controls, but those with brain injury on MRI had lower NAA/Cho 
0% focal deficits on neurologic examination 
Abnormalities in tone or reflexes common in newborns with and without brain injury 
Mahle et al, Circulation, 2002 Cohort study, N = 24 Mixed 63% MRI (structural, MRS) 25% ischemic lesions (small cortical watershed infarct, small infarct of the caudate, PVL) 
4% hemorrhagic injury 
16% elevated lactate with diffuse distribution, 25% lactate localized to the basal ganglia, 4% lactate in the peri-insular region 
Elevation of brain lactate associated with brain injury 
Dimitropoulos et al, Neurology, 2013 Cohort study, N = 120 Mixed 33% MRI (structural, DTI, MRS) 41% brain injury 
Lower WM FA and lower NAA/Cho associated with higher injury severity preoperatively 
Higher SNAP-PE, lower Spo2, hypotension, and BAS predictive for higher injury severity 
Shedeed and Elfaytouri, Pediatr Cardiol, 2011 Case-control study, N = 38/20 Mixed MRI (structural, DTI, MRS) 24% white matter injury (PVL and stroke) 
Lower NAA/Cho ratio (0.55 vs 0.67) 
Higher Lac/Cho ratio (0.14 vs 0.09) 
Higher average diffusivity (1.41 vs 1.27) 
Lower white matter FA (0.19 vs 0.25) 
Miller et al, N Engl J Med, 2007 Case-control study, N = 41/16 SVA 17% MRI (structural, DTI, MRS) 32% brain injury 
Decreased NAA/Cho (10%), increased average diffusivity (4%), decreased FA (12%), increased Lac/Cho (28%) 
Nagaraj et al, J Pediatr, 2015 Case-control study, N = 43/58 Mixed 100% MRI (structural, ASL) 32.6% brain injury (64.3% WMI) compared with 0.6% in controls 
All cerebral blood flow parameters lower but not significantly different 
Lower global cerebral blood flow and regional cerebral blood flow in SVA 
Lower regional thalamic cerebral blood flow in cyanotic CHD and lower cerebral blood flow in thalami, occipital white matter, and basal ganglia compared with acyanotic CHD 
Licht et al, J Thorac Cardiovasc Surg, 2004 Cohort study, N = 25 Mixed MRI (volume, ASL) Mean cerebral blood flow 19.7 ± 9.1 mL/100 g per min compared with 50 ± 3.4 mL/100 g per min in controls 
5 neonates cerebral blood flow <10 mL/100 g per min (moderate ischemic changes in piglets) 
24% microcephaly 
Low Hb associated with higher baseline cerebral blood flow 
28% PVL, associated with lower cerebral blood flow and less reactivity to hypercarbia 
 
Van der Laan et al, Pediatr Res, 2013 Retrospective study, N = 21 (12 BAS) TGA NIRS Preductal Spo2 increased immediately after BAS (72%–85%) and stabilized afterward (86%) 
rcSo2 increased immediately after BAS and continued increasing during 24 h after BAS (42%–48% 2 h after BAS to 64% 24 h after BAS) 
Lower baseline rcSo2 in the BAS group, whereas post-BAS rcSo2 was higher compared with infants who did not undergo BAS (64% vs 58%) 
Uebing et al, J Thorac Cardiovasc Surg, 2011 Cohort study, N = 53 HLHS, TGA NIRS 10 h before surgery, HLHS infants had higher rcSo2 than TGA infants (61% vs 56%) 
In HLHS infants, rcSo2 decreased after CPB and recovered to preoperative values within 48 h after CPB 
In TGA infants, rcSo2 decreased after CPB and increased ∼20% above preoperative values within 48 h after CPB 
Kurth et al, Ann Thorac Surg, 2001 Case-control study, N = 91/19 Mixed NIRS Lower rcSo2 (immediately before surgery in the operating room, 1 min recordings) 
Infants with PA had lowest rcSo2 values (38% ± 8%) 
 
Latal et ala, Dev Med Child Neurol, 2015 Cohort study, N = 77 Mixed 27% CUS 29% brain injury (16% brain edema, 6% PVL, 4% ventricular dilatation, 3% IVH grade I) 
Clinical variables not associated with brain injury 
BAS associated with brain edema (32% vs 6%) 
Gunn et ala, Ann Thorac Surg, 2012 Cohort study, N = 39 SVA 95% aEEG 33% EA, commonly left-sided, predominantly occurring during CPB 
0% preoperative EA 
Gunn et ala, Intensive Care Med, 2012 Cohort study, N = 150 Mixed aEEG 3% preoperative EA 
Te Pas et al, Acta Paediatr, 2005 Retrospective study, N = 50 Mixed CUS 42% abnormal CUS (26% widening ventricles or subarachnoidal space, 8% ischemic changes, 6% lenticulostriate vasculopathy) 
Abnormalities on CUS tended to occur more frequently in HLHS or CoA (63%) than TGA (14%) 
Sigler et al, Ann Thorac Surg, 2001 Cohort study, N = 35 TGA CUS 3% preoperative brain injury (enhanced subependymal echogenicity) 
65% resolved within 2 wk after operation 
Neuron specific enolase not associated with brain injury 
Combination of techniques 
Mulkey et al, Pediatr Neurol, 2015 Cohort study, N = 24 Mixed 100% aEEG 63% abnormal aEEG (42% mildly abnormal, 21% severely abnormal) 
MRI (structural) Abnormal aEEG associated with lower Apgar score at 5 min, CHD surgery at an older age, and male sex 
50% brain injury (infarct and/or white matter injury) 
Infants with brain injury higher odds of having abnormal aEEG (OR = 3.0) 
33% brain atrophy 
Severely abnormal aEEG background pattern associated with brain atrophy (OR = 15.0) 
Dehaes et al, Biomed Opt Express, 2015 Case-control study, N = 11/13 SVA NIRS Lower cerebral oxygen metabolism index, cerebral blood flow index, cerebral oxygen saturation index, and hemoglobin 
DCS Higher cerebral oxygen extraction 
Jain et al, J Cereb Blood Flow Metab, 201412  Cohort study, N = 32 Mixed MRI Lower resting state oxygen extraction fraction, cerebral blood flow, and cerebral metabolic rate for oxygen 
DOS (NIRS) DCS 
Lynch et al, J Thorac Cardiovasc Surg, 2014 Cohort study, N = 37 HLHS MRI (structural) 22% PVL 
DOS (NIRS) DCS Longer time to surgery associated with postoperative PVL 
Lower rcSo2 and higher blood flow index associated with postoperative PVL 
Longer time to surgery associated with lower rcSo2 and higher FTOE 
Rios et al, Pediatrics, 2013 Cohort study, N = 167 Mixed MRI (structural) 3% brain injury ultrasound (4 hemorrhage, 1 PVL) 
CUS 26% brain injury MRI (WMI most common) 
4 infants with hemorrhage on CUS had normal MRI suggesting 80% false positives and a positive predictive value for brain injury of only 20% for HUS before surgery 
Andropoulos et ala, Ann Thorac Surg, 2012 Cohort study, N = 30 Mixed 43% MRI (structural) 33% brain injury 
Mean preoperative rcSo2 56.5% (53.0%–61.9%) 
NIRS rcSo2 < 45% area under the curve 9 (0–191) min 
Williams et ala, Ultrasound Obstet Gynecol, 2012 Pilot study, N = 13 Mixed 100% Ultrasound (Doppler) MCA-PI −0.75 TGA, −2.01 TOF, −2.4 HLHS 
EEG CPR < 1 40% TGA, 67% TOF, 60% HLHS 
MCA-PI positive correlation with neonatal EEG left frontal polar and left frontal β power 
CPR < 1 associated with lower left frontal polar en left frontal β power 
Ter Horst et al, Early Hum Dev, 2010 Cohort study, N = 62 Mixed 15% aEEG 40% normal aEEG, 45% mildly abnormal (DNV), 15% severely abnormal (BS, CLV, FT) 
CUS Similar rate of severely abnormal aEEG in cyanotic and acyanotic CHD (13% vs 16%) 
19% EA, more frequently observed in acyanotic CHD (OR 9.37) 
58% SWC within 72 h 
In acyanotic CHD, SWC more frequent in CoA than in HLHS (92% vs 48%) 
9% ischemia on HUS 
Trend for more severely abnormal background patterns in abnormal HUS (OR 5.4) 
Severely abnormal background pattern and EA associated with more profound acidosis (low pH, more negative base excess, higher lactate) 
McQuillen et al, Stroke, 2007 Cohort study, N = 62 Mixed MRI (structural) 39% preoperative brain injury (18% WMI, 21% stroke, 8% IVH) 
Risk factors for preoperative brain injury: BAS and 5 min Apgar score 
NIRS Preoperative brain injury more common in 2 ventricle anomalies 
Toet et ala, Exp Brain Res, 2005 Cohort study, N = 20 TGA NIRS Lower rcSo2 (27%–52%) 12 h before CPB 
aEEG 100% normal aEEG, 0% EA 
No difference in duration to normalization in aEEG after surgery between preoperative low or high rcSo2 
Robertson et ala, Cardiol Young, 2004 Cohort study, N = 47 Mixed EEG 11% preoperative abnormal EEG (2.8% clinical seizure) 
CUS Nadir CBF velocity 2 h post CPB 
No association between CBF velocity and EEG 
Study (First Author, Journal, Year of Publication)Study Design, No. InfantsCHDAntenatal DiagnosisMethodsFindings (Compared With Healthy Controls and/or Reference Values, Unless Otherwise Stated)
Brossard-Racine et al, ANJR Am J Neuroradiol, 2016 Cohort study, N = 103 Mixed 100% MRI (structural) 32% brain injury (26% acquired) 
WMI most common injury (5 mild and 10 moderate or severe) 
WMI located in the periventricular white matter, centrum semiovale, and frontal white matter 
Second most common injury: nonhemorrhagic parenchymal injury 
McCarthy et al, Pediatr Res, 2015 Retrospective study, N = 72 Mixed MRI (structural) 18% PVL 
The majority of PVL classified as moderate 
Bertholdt et al, Eur J Cardiothorac Surg, 2014 Case-control study, N = 30/20 Mixed 17% MRI (structural) 23% WMI or stroke, 47% intracranial hemorrhage (subdural hematoma or choroid plexus) 
Low Spo2 risk factor for brain injury, BAS not associated with brain injury 
Brain injury associated with poorer neurologic functioning (82% abnormal assessment) 
Owen et ala, J Pediatr, 2014 Cohort study, N = 35 Mixed 51% MRI (structural) 46% evidence of injury or immaturity on MRI (most common: hemorrhage) 
71% suspect or abnormal neurobehavioral assessment (16 suspect, 9 abnormal) 
Goff et al, J Thorac Cardiovasc Surg, 2014 Cohort study, N = 57 HLHS 86% MRI (structural) 19% PVL preoperatively 
Brain immaturity and male sex independent strong predictors of PVL 
Andropoulos et ala, Paediatr Anaesth, 2014 Retrospective study, N = 59 Mixed MRI (structural) 46% preoperative brain injury 
WMI most common injury (31%; 8 mild, 3 moderate, 1 severe) 
Beca et ala, Circulation, 2013 Cohort study, N = 153 Mixed 59% MRI (structural) 26% brain injury (20% WMI, 5% stroke, 4% hemorrhage) 
WMI associated with brain immaturity but not with BAS, diagnostic group, or GA at birth 
WMI and stroke not associated with postoperative brain injury 
Mulkey et al, Pediatr Cardiol, 2013 Retrospective study, N = 73 Mixed 32% MRI (structural) 47% ≥1 type of brain injury, 26% 2–4 injury types 
25% brain injury if hemorrhage was excluded 
Lower Apgar score at 5 min associated with brain injury 
Ortinau et al, J Pediatr, 2013 Case-control study, N = 15/12 Mixed MRI (structural) Reduced cortical surface area and gyrification index for left and right hemispheres 
46% focal signal abnormalities in the white matter 
Glass et al, Cardiol Young, 2011 Cohort study, N = 127 Mixed MRI (structural) 24% white matter injury 
Infants with TGA and blood stream infection might have a higher risk of developing WMI (not significant in the whole group but significant when stroke was excluded) 
Block et al, J Thorac Cardiovasc Surg, 2010 Cohort study, N = 92 TGA MRI (structural) 43% brain injury (23 stroke, 21 WMI, and 7 IVH) 
SVA BAS doubled the risk for brain injury 
 Higher Spo2 protective factor for brain injury (OR = 0.96) 
Andropoulos et al, J Thorac Cardiovasc Surg, 2010 Cohort study, N = 67 Mixed 44% MRI (structural) 28% brain injury (single ventricle and 2 ventricles) 
Brain immaturity associated with preoperative WMI and late death 
58% of lesions partially or completely resolved at late MRI scan (3–6 mo) 
Beca et al, J Am Coll Cardiol, 2009 Cohort study, N = 64 Mixed 32% MRI (structural) 30% brain injury (27% WMI and 5% stroke) 
No differences between cardiac diagnoses 
No association between BAS and brain injury 
Petit et al, Circulation, 2009 Retrospective study, N = 26 (14 BAS) TGA MRI (structural) 38% PVL, 0 strokes 
Arterial oxygen saturation and time to surgery risk factors for brain injury 
No association between BAS and brain injury 
Licht et al, J Thorac Cardiovasc Surg, 2009 Cohort study, N = 42 TGA HLHS 83% HLHS 39% TGA MRI (structural) 21% PVL, 9.5% stroke, 86% incomplete closure of the opercular space (brain immaturity) 
Lower total maturation scores (10.15), ∼1 mo younger than their actual GA 
McQuillen et al, Circulation, 2006 Cohort study, N = 29 TGA MRI (structural) 41% brain injury (5 stroke, 2 WMI, 1 IVH, 4 combination of lesions) 
5 min Apgar score, lowest Spo2, and BAS (12 of 19 infants with BAS had brain injury, 0 of 10 without BAS had brain injury) are risk factors for brain injury 
Durandy et al, Artif Organs, 2011 Cohort study, N = 21 TGA 57% MRI (structural) 42% brain injury (4 infarct, 4 WMI, and 5 hemorrhages in 9 infants) 
55% brain injury in antenatal diagnosis compared with 33% in postnatal diagnosis 
Tavani et al, Neuroradiology, 200310  Cohort study, N = 24 Mixed MRI (structural) 62% of infants delivered vaginally had hemorrhage on MRI 
11 subdural hematomas 
6 blood in the subdural space along the tentorium and falx or more laterally 
7 blood in the choroid plexus 
No relation between intracranial hemorrhage and abnormal neurologic examination 
von Rhein et al, J Pediatr, 2015 Case-control study, N = 19/19 Mixed MRI, volume 21% total brain volume reduction, all regions affected 
Smallest difference: mesencephalon 7.7% smaller 
Biggest difference: cortical gray matter 29.5% smaller and occipital lobes 28.5% smaller 
Ortinau et al, Pediatr Cardiol, 2012 Cohort study, N = 57/36 Mixed MRI, volume Smaller frontal, parietal, cerebellar, and brain stem measures 
Brain growth rate not different 
Differences in volume persisted at 3 mo, except for cerebellar measures 
Somatic growth the greatest predictor of brain growth 
Ortinau et al, J Thorac Cardiovasc Surg, 2012 Cohort study, N = 67/36 Mixed MRI (structural, volume) 42% focal WMI 
Smaller frontal, parietal, cerebellar, and brain stem 
Frontal and brain stem most affected 
Delayed maturation at the microstructural level 
Makki et al, AJNR Am J Neuroradiol, 201311  Case-control study, N = 15/11 TGA MRI (DTI) Higher apparent diffusion coefficient, lower FA genu corpus callosum 
Lower FA splenium corpus callosum 
Hagmann et al, J Child Neurol, 2016 Case-control study, N = 22/22 Mixed MRI (volume, DTI) Corpus callosum 25% (splenium) to 35% (genu) smaller 
Total corpus callosum and splenium significantly smaller 
Splenium lower FA, higher radial diffusion, diffusion coefficient not significant 
No differences in other substructures of the corpus callosum 
Mulkey et al, Pediatr Neurol, 2014 Pilot study, N = 19 Mixed MRI (structural, DTI) 52% brain injury (WMI or stroke) 
Lower FA in multiple major white matter tracts in infants with brain injury compared with infants without brain injury 
Partridge et al, Ann Neurol, 2006 Cohort study, N = 25 Mixed MRI (structural, DTI) 28% brain injury (focal or multifocal) 
Brain injury associated with less change in FA over time in the pyramidal tract compared with newborns with 2 normal MRI scans 
Infants with brain injury had the least dramatic changes with age detected by DTT 
Trend in FA maturation rates across the 3 injury groups: newborns with normal scans had the most rapid changes, those with postoperative injury had intermediate maturation rates, and those with preoperative injury had the least rapid changes 
No differences in directionally averaged diffusion coefficients 
Sethi et al, Pediatr Res, 2013 Cohort study, N = 36 CHD SVA 61% MRI (structural, MRS) 36% brain injury (4 mild WMI, 4 moderate WMI, 2 severe WMI, 6 focal strokes, 5 IVH) 
Higher mean average diffusivity for gray matter and lower FA in the white matter regions 
Lower mean NAA/Cho ratios and higher mean Lac/Cho ratios 
Delayed microstructural brain development 
Park et ala, Pediatr Cardiol, 2006 Case-control study, N = 16/15 TGA MRI (structural, MRS) No abnormal findings on preoperative MRI 
Altered metabolism in parietal white matter (increased Cho/Cr) and occipital gray matter (increased Cho/Cr and Ino/Cr) 
Altered metabolism persisted 1 y after ASO in parietal white matter and normalized for occipital gray matter 
Miller et al, Ann Thorac Surg, 2004 Cohort study, N = 10 TGA MRI (structural, MRS) 40% brain injury (stroke or hemorrhage) 
Higher Lac/Cho 
Similar NAA/Cho between TGA and healthy controls, but those with brain injury on MRI had lower NAA/Cho 
0% focal deficits on neurologic examination 
Abnormalities in tone or reflexes common in newborns with and without brain injury 
Mahle et al, Circulation, 2002 Cohort study, N = 24 Mixed 63% MRI (structural, MRS) 25% ischemic lesions (small cortical watershed infarct, small infarct of the caudate, PVL) 
4% hemorrhagic injury 
16% elevated lactate with diffuse distribution, 25% lactate localized to the basal ganglia, 4% lactate in the peri-insular region 
Elevation of brain lactate associated with brain injury 
Dimitropoulos et al, Neurology, 2013 Cohort study, N = 120 Mixed 33% MRI (structural, DTI, MRS) 41% brain injury 
Lower WM FA and lower NAA/Cho associated with higher injury severity preoperatively 
Higher SNAP-PE, lower Spo2, hypotension, and BAS predictive for higher injury severity 
Shedeed and Elfaytouri, Pediatr Cardiol, 2011 Case-control study, N = 38/20 Mixed MRI (structural, DTI, MRS) 24% white matter injury (PVL and stroke) 
Lower NAA/Cho ratio (0.55 vs 0.67) 
Higher Lac/Cho ratio (0.14 vs 0.09) 
Higher average diffusivity (1.41 vs 1.27) 
Lower white matter FA (0.19 vs 0.25) 
Miller et al, N Engl J Med, 2007 Case-control study, N = 41/16 SVA 17% MRI (structural, DTI, MRS) 32% brain injury 
Decreased NAA/Cho (10%), increased average diffusivity (4%), decreased FA (12%), increased Lac/Cho (28%) 
Nagaraj et al, J Pediatr, 2015 Case-control study, N = 43/58 Mixed 100% MRI (structural, ASL) 32.6% brain injury (64.3% WMI) compared with 0.6% in controls 
All cerebral blood flow parameters lower but not significantly different 
Lower global cerebral blood flow and regional cerebral blood flow in SVA 
Lower regional thalamic cerebral blood flow in cyanotic CHD and lower cerebral blood flow in thalami, occipital white matter, and basal ganglia compared with acyanotic CHD 
Licht et al, J Thorac Cardiovasc Surg, 2004 Cohort study, N = 25 Mixed MRI (volume, ASL) Mean cerebral blood flow 19.7 ± 9.1 mL/100 g per min compared with 50 ± 3.4 mL/100 g per min in controls 
5 neonates cerebral blood flow <10 mL/100 g per min (moderate ischemic changes in piglets) 
24% microcephaly 
Low Hb associated with higher baseline cerebral blood flow 
28% PVL, associated with lower cerebral blood flow and less reactivity to hypercarbia 
 
Van der Laan et al, Pediatr Res, 2013 Retrospective study, N = 21 (12 BAS) TGA NIRS Preductal Spo2 increased immediately after BAS (72%–85%) and stabilized afterward (86%) 
rcSo2 increased immediately after BAS and continued increasing during 24 h after BAS (42%–48% 2 h after BAS to 64% 24 h after BAS) 
Lower baseline rcSo2 in the BAS group, whereas post-BAS rcSo2 was higher compared with infants who did not undergo BAS (64% vs 58%) 
Uebing et al, J Thorac Cardiovasc Surg, 2011 Cohort study, N = 53 HLHS, TGA NIRS 10 h before surgery, HLHS infants had higher rcSo2 than TGA infants (61% vs 56%) 
In HLHS infants, rcSo2 decreased after CPB and recovered to preoperative values within 48 h after CPB 
In TGA infants, rcSo2 decreased after CPB and increased ∼20% above preoperative values within 48 h after CPB 
Kurth et al, Ann Thorac Surg, 2001 Case-control study, N = 91/19 Mixed NIRS Lower rcSo2 (immediately before surgery in the operating room, 1 min recordings) 
Infants with PA had lowest rcSo2 values (38% ± 8%) 
 
Latal et ala, Dev Med Child Neurol, 2015 Cohort study, N = 77 Mixed 27% CUS 29% brain injury (16% brain edema, 6% PVL, 4% ventricular dilatation, 3% IVH grade I) 
Clinical variables not associated with brain injury 
BAS associated with brain edema (32% vs 6%) 
Gunn et ala, Ann Thorac Surg, 2012 Cohort study, N = 39 SVA 95% aEEG 33% EA, commonly left-sided, predominantly occurring during CPB 
0% preoperative EA 
Gunn et ala, Intensive Care Med, 2012 Cohort study, N = 150 Mixed aEEG 3% preoperative EA 
Te Pas et al, Acta Paediatr, 2005 Retrospective study, N = 50 Mixed CUS 42% abnormal CUS (26% widening ventricles or subarachnoidal space, 8% ischemic changes, 6% lenticulostriate vasculopathy) 
Abnormalities on CUS tended to occur more frequently in HLHS or CoA (63%) than TGA (14%) 
Sigler et al, Ann Thorac Surg, 2001 Cohort study, N = 35 TGA CUS 3% preoperative brain injury (enhanced subependymal echogenicity) 
65% resolved within 2 wk after operation 
Neuron specific enolase not associated with brain injury 
Combination of techniques 
Mulkey et al, Pediatr Neurol, 2015 Cohort study, N = 24 Mixed 100% aEEG 63% abnormal aEEG (42% mildly abnormal, 21% severely abnormal) 
MRI (structural) Abnormal aEEG associated with lower Apgar score at 5 min, CHD surgery at an older age, and male sex 
50% brain injury (infarct and/or white matter injury) 
Infants with brain injury higher odds of having abnormal aEEG (OR = 3.0) 
33% brain atrophy 
Severely abnormal aEEG background pattern associated with brain atrophy (OR = 15.0) 
Dehaes et al, Biomed Opt Express, 2015 Case-control study, N = 11/13 SVA NIRS Lower cerebral oxygen metabolism index, cerebral blood flow index, cerebral oxygen saturation index, and hemoglobin 
DCS Higher cerebral oxygen extraction 
Jain et al, J Cereb Blood Flow Metab, 201412  Cohort study, N = 32 Mixed MRI Lower resting state oxygen extraction fraction, cerebral blood flow, and cerebral metabolic rate for oxygen 
DOS (NIRS) DCS 
Lynch et al, J Thorac Cardiovasc Surg, 2014 Cohort study, N = 37 HLHS MRI (structural) 22% PVL 
DOS (NIRS) DCS Longer time to surgery associated with postoperative PVL 
Lower rcSo2 and higher blood flow index associated with postoperative PVL 
Longer time to surgery associated with lower rcSo2 and higher FTOE 
Rios et al, Pediatrics, 2013 Cohort study, N = 167 Mixed MRI (structural) 3% brain injury ultrasound (4 hemorrhage, 1 PVL) 
CUS 26% brain injury MRI (WMI most common) 
4 infants with hemorrhage on CUS had normal MRI suggesting 80% false positives and a positive predictive value for brain injury of only 20% for HUS before surgery 
Andropoulos et ala, Ann Thorac Surg, 2012 Cohort study, N = 30 Mixed 43% MRI (structural) 33% brain injury 
Mean preoperative rcSo2 56.5% (53.0%–61.9%) 
NIRS rcSo2 < 45% area under the curve 9 (0–191) min 
Williams et ala, Ultrasound Obstet Gynecol, 2012 Pilot study, N = 13 Mixed 100% Ultrasound (Doppler) MCA-PI −0.75 TGA, −2.01 TOF, −2.4 HLHS 
EEG CPR < 1 40% TGA, 67% TOF, 60% HLHS 
MCA-PI positive correlation with neonatal EEG left frontal polar and left frontal β power 
CPR < 1 associated with lower left frontal polar en left frontal β power 
Ter Horst et al, Early Hum Dev, 2010 Cohort study, N = 62 Mixed 15% aEEG 40% normal aEEG, 45% mildly abnormal (DNV), 15% severely abnormal (BS, CLV, FT) 
CUS Similar rate of severely abnormal aEEG in cyanotic and acyanotic CHD (13% vs 16%) 
19% EA, more frequently observed in acyanotic CHD (OR 9.37) 
58% SWC within 72 h 
In acyanotic CHD, SWC more frequent in CoA than in HLHS (92% vs 48%) 
9% ischemia on HUS 
Trend for more severely abnormal background patterns in abnormal HUS (OR 5.4) 
Severely abnormal background pattern and EA associated with more profound acidosis (low pH, more negative base excess, higher lactate) 
McQuillen et al, Stroke, 2007 Cohort study, N = 62 Mixed MRI (structural) 39% preoperative brain injury (18% WMI, 21% stroke, 8% IVH) 
Risk factors for preoperative brain injury: BAS and 5 min Apgar score 
NIRS Preoperative brain injury more common in 2 ventricle anomalies 
Toet et ala, Exp Brain Res, 2005 Cohort study, N = 20 TGA NIRS Lower rcSo2 (27%–52%) 12 h before CPB 
aEEG 100% normal aEEG, 0% EA 
No difference in duration to normalization in aEEG after surgery between preoperative low or high rcSo2 
Robertson et ala, Cardiol Young, 2004 Cohort study, N = 47 Mixed EEG 11% preoperative abnormal EEG (2.8% clinical seizure) 
CUS Nadir CBF velocity 2 h post CPB 
No association between CBF velocity and EEG 

ASL, arterial spin labeling; ASO, arterial switch operation; BS, burst suppression; CLV, continuous low voltage; CoA, coarctation of the aorta; CPB, cardiopulmonary bypass; CUS, cranial ultrasound; DCS, diffuse correlation spectroscopy; DNV, discontinuous normal voltage; DTI, diffusion tensor imaging; DTT, diffuse tensor tractography; FA, fractional anisotropy; FT, flat trace; FTOE, fractional tissue oxygen extraction; GA, gestational age; IVH, intraventricular hemorrhage; Ino/Cr, myo-inosinotol/creatinine; MRS, magnetic resonance spectroscopy; OR, odds ratio; PVL, periventricular leukomalacia; SNAP-PE, Score for Neonatal Acute Physiology–Perinatal Extension; SpO2, pulse oxygen saturation; SVA, single ventricle anomaly; SWC, sleep-wake cycling; TOF, tetralogy of Fallot; U, unknown; WMI, white matter injury.

a

Articles that also address neurodevelopmental outcome.

The final search resulted in 882 articles. Many articles on neurodevelopmental outcome were not eligible because they did not combine prenatal or postnatal preoperative cerebral findings with neurodevelopmental outcome. Four additional relevant articles were found and added to either the prenatal or the postnatal preoperative part of the review. Results on the association between prenatal or postnatal preoperative cerebral findings and neurodevelopmental outcome are presented in Table 3.

TABLE 3

Prenatal and Preoperative Cerebral Findings and Their Relation With NDO

Study (First Author, Journal, Year of Publication)Study Design, No. InfantsCHDAge at NDO Testing, MoMethodsOutcomeFindings (Compared With Healthy Controls and/or Reference Values, Unless Otherwise Stated)Relation
Ultrasound 
Hahn et al, Ultrasound Obstet Gynecol, 2016 Retrospective study, N = 133 SVA 14 Ultrasound (Doppler and biometry) BSID II MDI 88.5 ± 16.6 and PDI 76.4 ± 19.8 ± 
First MCA-PI negatively associated with PDI 
HC/AC negatively associated with PDI 
Zeng et al, Ultrasound Obstet Gynecol, 2015 Case-control study, N = 112/112 Mixed 12 Ultrasound (three dimensional, Doppler) BSID II Lower MDI (85.2 vs 99.1) and PDI (72.8 vs 99.4) ± 
No correlation between MCA-PI and NDO 
Total intracranial flow index positively correlated with PDI and MDI 
Williams et al, Am Heart J, 2013 Cohort study, N = 134 SVA 14 Ultrasound (Doppler) BSID II MDI 88.5 ± 16.6 and PDI 76.4 ± 19.8 
62% PDI < 85 and 35% MDI < 85 
MCA-PI correlated negatively with PDI but not with MDI 
MCA-PI < −2.0, on average, with 11-point-higher PDI scores compared with MCA-PI > −2.0 (84.7 vs 73.6) 
Latal et al, Dev Med Child Neurol, 2015 Cohort study, N = 77 Mixed 12 HUS BSID II MDI 89 (49–107) and PDI 69 (49–113) − 
Isolated CHD: MDI 91 (50–107) and PDI 70 (49–113) 
No association between brain injury on ultrasound and NDO 
MRI 
Masoller et al, Ultrasound Obstet Gynecol, 2016 Case-control study, N = 58/58 Mixed MRI Bayley III Lower cognitive (91 vs 103), language (97 vs 108), motor (86 vs 100), social-emotional (85 vs 106), and adaptive (89 vs 97) score 
Average Bayley III score associated with total blood volume, left and right singulate depth, frontal Ino/Cho ratio, and NAA/Cho ratio 
Andropoulos et al, Paediatr Anaesth, 2014 Retrospective study, N = 59 Mixed 12 MRI Bayley III Composite scores: cognitive 102 ± −13.3, language 87.8 ± −12.5, motor 89.6 ± 14.1 ± 
Preoperative brain injury not associated with NDO 
Preoperative rcSo2 values associated with cognitive and motor score 
Beca et al, Circulation, 2013 Cohort study, N = 153 Mixed 3 and 24 MRI Bayley III Composite scores: cognitive 94 ± 15, language 94 ± 16, motor 97 ± 12 
Delay in maturation of the posterior limb of the internal capsule on the first MRI associated with lower motor scores 
Lower brain maturity associated with reduced performance on all domains 
Amplitude-integrated EEG 
Gunn et al, Ann Thorac Surg, 2012 Cohort study, N = 39 SVA 24 aEEG Bayley III Composite scores: cognitive 92.4 ± 13.5, language 94.3 ± 17.7, motor 93.8 ± 10.6 ± 
Seizures associated with mortality but not associated with NDO 
Recovery of background pattern within 48 h: 14 points increase in motor score 
Gunn et al, Intensive Care Med, 2012 Cohort study, N = 150 Mixed 48 aEEG Bayley III Composite scores: cognitive 93.2 ± 13.7, language 93.5 ± 16.2, motor 96.7 ± 12.7 − 
Preoperative background pattern not associated with NDO 
Combination of techniques 
Andropoulos et al, Ann Thorac Surg, 2012 Cohort study, N = 30 TGA 12 NIRS Bayley III Composite scores: cognitive 104.8 ± 15, language 90.0 (83.0–94.0), motor 92.3 ± 14.2 
MRI Lower preoperative rcSo2 associated with lower cognitive score 
Preoperative brain injury associated with lower language score 
Preoperative brain injury, lower preoperative rcSo2, associated with lower motor score 
Williams et al, Ultrasound Obstet Gynecol, 2012 Pilot study, N = 13 Mixed 18 Ultrasound (Doppler) Bayley III Composite scores: cognitive 95, language 84, motor 87 
EEG Language and motor scores in HLHS and TOF >1 SD below population mean 
MCA-PI correlated positively with cognitive scores 
EEG left frontal polar and left frontal β power correlated positively with cognitive scores 
MCA-PI correlated positively with neonatal EEG left frontal polar and left frontal β power 
Toet et al, Exp Brain Res, 2005 Cohort study, N = 20 TGA 30 NIRS BSID II rcSo2 ≤ 35%: MDI 97 and PDI 95 ± 
aEEG rcSo2 > 35%: MDI 101 and PDI 106 
Low rcSo2 associated with lower MDI and PDI 
Robertson et al, Cardiol Young, 2004 Cohort study, N = 35 Mixed 12 BSID II BSID II Preoperatively: MDI 103 ± 5 (all infants within normal range) and PDI 99 ± 8 (2 infants below 80) − 
EEG 12 mo follow-up: MDI 94 ± 13 and PDI 89 ± 20 
Transcranial Doppler 57% both MDI and PDI in normal range 
No association between EEG abnormalities, reduced cerebral blood flow, and NDO 
Study (First Author, Journal, Year of Publication)Study Design, No. InfantsCHDAge at NDO Testing, MoMethodsOutcomeFindings (Compared With Healthy Controls and/or Reference Values, Unless Otherwise Stated)Relation
Ultrasound 
Hahn et al, Ultrasound Obstet Gynecol, 2016 Retrospective study, N = 133 SVA 14 Ultrasound (Doppler and biometry) BSID II MDI 88.5 ± 16.6 and PDI 76.4 ± 19.8 ± 
First MCA-PI negatively associated with PDI 
HC/AC negatively associated with PDI 
Zeng et al, Ultrasound Obstet Gynecol, 2015 Case-control study, N = 112/112 Mixed 12 Ultrasound (three dimensional, Doppler) BSID II Lower MDI (85.2 vs 99.1) and PDI (72.8 vs 99.4) ± 
No correlation between MCA-PI and NDO 
Total intracranial flow index positively correlated with PDI and MDI 
Williams et al, Am Heart J, 2013 Cohort study, N = 134 SVA 14 Ultrasound (Doppler) BSID II MDI 88.5 ± 16.6 and PDI 76.4 ± 19.8 
62% PDI < 85 and 35% MDI < 85 
MCA-PI correlated negatively with PDI but not with MDI 
MCA-PI < −2.0, on average, with 11-point-higher PDI scores compared with MCA-PI > −2.0 (84.7 vs 73.6) 
Latal et al, Dev Med Child Neurol, 2015 Cohort study, N = 77 Mixed 12 HUS BSID II MDI 89 (49–107) and PDI 69 (49–113) − 
Isolated CHD: MDI 91 (50–107) and PDI 70 (49–113) 
No association between brain injury on ultrasound and NDO 
MRI 
Masoller et al, Ultrasound Obstet Gynecol, 2016 Case-control study, N = 58/58 Mixed MRI Bayley III Lower cognitive (91 vs 103), language (97 vs 108), motor (86 vs 100), social-emotional (85 vs 106), and adaptive (89 vs 97) score 
Average Bayley III score associated with total blood volume, left and right singulate depth, frontal Ino/Cho ratio, and NAA/Cho ratio 
Andropoulos et al, Paediatr Anaesth, 2014 Retrospective study, N = 59 Mixed 12 MRI Bayley III Composite scores: cognitive 102 ± −13.3, language 87.8 ± −12.5, motor 89.6 ± 14.1 ± 
Preoperative brain injury not associated with NDO 
Preoperative rcSo2 values associated with cognitive and motor score 
Beca et al, Circulation, 2013 Cohort study, N = 153 Mixed 3 and 24 MRI Bayley III Composite scores: cognitive 94 ± 15, language 94 ± 16, motor 97 ± 12 
Delay in maturation of the posterior limb of the internal capsule on the first MRI associated with lower motor scores 
Lower brain maturity associated with reduced performance on all domains 
Amplitude-integrated EEG 
Gunn et al, Ann Thorac Surg, 2012 Cohort study, N = 39 SVA 24 aEEG Bayley III Composite scores: cognitive 92.4 ± 13.5, language 94.3 ± 17.7, motor 93.8 ± 10.6 ± 
Seizures associated with mortality but not associated with NDO 
Recovery of background pattern within 48 h: 14 points increase in motor score 
Gunn et al, Intensive Care Med, 2012 Cohort study, N = 150 Mixed 48 aEEG Bayley III Composite scores: cognitive 93.2 ± 13.7, language 93.5 ± 16.2, motor 96.7 ± 12.7 − 
Preoperative background pattern not associated with NDO 
Combination of techniques 
Andropoulos et al, Ann Thorac Surg, 2012 Cohort study, N = 30 TGA 12 NIRS Bayley III Composite scores: cognitive 104.8 ± 15, language 90.0 (83.0–94.0), motor 92.3 ± 14.2 
MRI Lower preoperative rcSo2 associated with lower cognitive score 
Preoperative brain injury associated with lower language score 
Preoperative brain injury, lower preoperative rcSo2, associated with lower motor score 
Williams et al, Ultrasound Obstet Gynecol, 2012 Pilot study, N = 13 Mixed 18 Ultrasound (Doppler) Bayley III Composite scores: cognitive 95, language 84, motor 87 
EEG Language and motor scores in HLHS and TOF >1 SD below population mean 
MCA-PI correlated positively with cognitive scores 
EEG left frontal polar and left frontal β power correlated positively with cognitive scores 
MCA-PI correlated positively with neonatal EEG left frontal polar and left frontal β power 
Toet et al, Exp Brain Res, 2005 Cohort study, N = 20 TGA 30 NIRS BSID II rcSo2 ≤ 35%: MDI 97 and PDI 95 ± 
aEEG rcSo2 > 35%: MDI 101 and PDI 106 
Low rcSo2 associated with lower MDI and PDI 
Robertson et al, Cardiol Young, 2004 Cohort study, N = 35 Mixed 12 BSID II BSID II Preoperatively: MDI 103 ± 5 (all infants within normal range) and PDI 99 ± 8 (2 infants below 80) − 
EEG 12 mo follow-up: MDI 94 ± 13 and PDI 89 ± 20 
Transcranial Doppler 57% both MDI and PDI in normal range 
No association between EEG abnormalities, reduced cerebral blood flow, and NDO 

HC/AC, head circumference/abdominal circumference; SVA, single ventricle anomaly; TOF, tetralogy of Fallot.

Prenatally, 1 study included a small percentage of infants with nonisolated CHD, 13% of the studies did not report on whether they included infants with nonisolated CHD, and 84% focused exclusively on infants with isolated CHD. Postnatally, 32% of the studies did not report on including or excluding infants with nonisolated CHD and 1 study included a small percentage of infants with nonisolated CHD. When possible, only the results of infants with isolated CHD were presented.

Twenty-two articles reported on Doppler parameters (Table 1). In general, these studies were case-control studies or cohort studies that compared Doppler parameters of fetuses with CHD with either healthy controls or reference values from the literature. Almost all studies used z scores to adjust for gestational age (the amount of SDs from the mean for a given gestational age).

The vast majority (86%) of the 22 studies that reported on Doppler parameters found the pulsatility index (PI) of the middle cerebral artery (MCA) to be lower in the entire study group (13 articles) or in selected CHD diagnoses (6 articles). In particular, fetuses with hypoplastic left heart syndrome (HLHS) or cardiac lesions that are associated with impaired cerebral oxygen supply had a lower pulsatility index of the middle cerebral artery (MCA-PI) compared with healthy controls.13,21 Fetuses with right-sided obstructive lesions14,15,19,20 often had a MCA-PI similar to healthy controls. Contradictory results were reported concerning MCA-PI in fetuses with transposition of the great arteries (TGA). On the one hand, TGA is one of the lesions associated with impaired cerebral oxygen supply because venous blood from the brain is redirected to the brain. This may lead to brain sparing, as suggested by the lower MCA-PI found by some studies.13,21,22 On the other hand, 3 studies specifically looking into the MCA-PI of fetuses with TGA found values similar to healthy controls.14,15,19 

None of the studies on Doppler parameters in fetuses with CHD reported higher MCA-PI compared with healthy controls. Abnormally low MCA-PI was present from the second trimester onwards23 and tended to decrease more than would be expected for gestational age.24 

Cerebroplacental ratio (CPR) was also reported to be lower in the majority of fetuses with CHD (75% of the selected articles). Again, fetuses with HLHS tended to have a lower CPR than fetuses with right-sided obstructive lesions and TGA.15,19 Two articles that did not use z scores found CPR values of <1.0 in 37% to 56% of the cases.16,18 

Concerning PI of the umbilical artery (UA), which reflects intraplacental resistance to flow, 11 articles reported contradictory results. Five studies reported a higher pulsatility index of the umbilical artery (UA-PI),13,20,25,27 whereas another 5 studies reported similar UA-PI18,22,28,30 in fetuses with CHD compared with healthy controls. One study reported both higher UA-PI (coarctation of the aorta and HLHS) as well as normal UA-PI (right-sided obstructive lesions and TGA) in different parts of the study group.15 

Prenatal MRI

The main findings on MRI in fetuses with different types of CHD (majority TGA, HLHS, tetralogy of Fallot, single ventricle anomaly) were features of developmental delay of the cerebrum. In 16% to 39% of the cases, lesions such as (unilateral) mild ventriculomegaly and increased extra-axial cerebrospinal fluid spaces were present. These abnormalities are both thought to be markers of delay of cerebral development.31,33 

In addition to these lesions, other signs of developmental delay of the cerebrum such as a smaller head circumference (HC) and biparietal diameter, lower total brain weight, lower total brain volumes, higher ventricular volumes, and higher cerebrospinal fluid volumes were also common in fetuses with CHD.21,33,38 Another feature of developmental delay was an impaired sulcation with a delay of ∼3 to 4 weeks.21,36,38 

Furthermore, cerebral metabolism was altered in fetuses with CHD and included an increased myo-inositol/choline (Ino/Cho), decreased n-acetylaspartate/choline (NAA/Cho), and decreased choline/creatinine (Cho/Cr) ratio.21,33,37 These metabolic alterations are also in accordance with cerebral developmental delay.

Fetuses with CHD associated with impaired oxygen supply to the cerebrum (HLHS, critical aortic stenosis, interrupted aortic arch, and TGA) showed more pronounced developmental delay in comparison with fetuses with CHD associated with sufficient blood flow to the cerebrum.21,34,37 Infants with HLHS showed a progressive decline in volumetric growth of the cortical and subcortical gray matter in comparison with healthy controls. These differences in brain volumes became significant from a gestational age of 30 weeks.38 Because of the study design of most studies, a further differentiation according to the type of CHD was impossible.

Postnatal Preoperative MRI

Forty studies used MRI to examine preoperative cerebral findings in infants with different types of CHD (Table 2). Signs of delayed development of the cerebrum were also common during this period. Infants with CHD had an overall reduction of 21% in total brain volume,39 with all brain regions being affected.39,42 The largest regional difference between neonates with CHD and healthy controls seemed to be in the corpus callosum (31% smaller), cortical gray matter (29.5% smaller), and the occipital lobes (28.5% smaller).39,41,43 These differences in brain volumes persisted to an age of 3 months. Brain growth rate, however, did not seem to differ between neonates with CHD and healthy controls in 1 study.40 

Brain metabolism and microstructural development were also in accordance with delayed cerebral development. White matter fractional anisotropy44,47 and NAA/Cho45,47 were lower, and mean average diffusivity,45,47 lactate/choline (Lac/Cho),45,47 Cho/Cr,48 and myo-inosinotol/creatinine48 were higher. The mean total maturation scores were significantly lower than reported normative data in neonates without CHD and corresponded to a delay of ∼4 weeks in structural brain development.49 In infants with TGA, the altered metabolism was still present in the white matter and disappeared in the gray matter 1 year after the arterial switch operation.48 

Apart from delayed cerebral development, the most commonly observed lesions on MRI were (punctate) white matter injury, periventricular leukomalacia, and stroke. Such brain lesions were reported in 19% to 52% of the cases.31,46,50,69 Although the type of CHD was associated with the occurrence of developmental delay or brain injury on MRI, most studies did not specify these differences.39,41,45 

There were multiple clinical factors associated with preoperative brain injury. Risk factors for preoperative brain injury included brain immaturity,53,54,59,64,70 lower arterial oxygen saturation values,53,63,71,72 lower Apgar scores at 5 minutes,56,61,70 abnormal amplitude-integrated electroencephalography (aEEG) background pattern,65 longer time to surgery,72 male sex,73 and presence of brain lactate.74 A higher Score for Neonatal Acute Physiology–Perinatal Extension, hypotension, lower white matter fractional anisotropy, and lower NAA/Cho were associated with higher brain injury severity.53 Balloon atrial septostomy (BAS) was found to be an independent risk factor for brain injury in 4 studies,53,58,61,70 whereas 4 other studies did not find an association between BAS and brain injury.54,60,71,72 

Only a few studies examined regional cerebral oxygen saturation (rcSo2) by means of near-infrared spectroscopy (NIRS) before surgery. Neonates with CHD had significantly lower preoperative rcSo2 compared with healthy controls.75,77 Neonates with HLHS had higher rcSo2 than neonates with TGA,78 and neonates with a pulmonary atresia (PA) had the lowest rcSo2.75 In HLHS, neonates in whom cerebral oxygen saturation was monitored by NIRS had higher arterial oxygen saturation, were less often mechanically ventilated, and were less often intubated for a presumed circulatory mismatch.79 In TGA, rcSo2 increased immediately after BAS and continued increasing during the 24 hours after BAS. Neonates in need of BAS had lower baseline rcSo2 but higher post-BAS rcSo2 compared with neonates who did not undergo BAS.80 

Brain injury on transcranial ultrasound was reported in up to 42% of the cases. The positive predictive value of transcranial ultrasound for the presence of brain injury, however, was very low with a value of 20%.81,84 

Up to 63% of the neonates had an abnormal preoperative aEEG recording (42%–45% mildly abnormal and 15%–21% severely abnormal).65,85,87 In 0% to 19% of the cases, epileptic activity (EA) was registered65,85,87 before surgery. EA was more frequently observed in neonates with acyanotic CHD.85 An abnormal aEEG recording was associated with lower Apgar scores at 5 minutes, surgery at an older age, and male sex.65 Furthermore, neonates with brain injury had higher odds of having abnormal aEEG recordings.65 

Sixteen prenatal or preoperative postnatal studies reported on NDO in infants with CHD. Fourteen of these studies used the BSID II or Bayley III at an age of 6 to 48 months. Thirteen studies assessed the association between prenatal or preoperative postnatal cerebral findings and NDO and were included in Table 3. Although scores were frequently within the normal range reported in healthy term infants (mean, SD 100 ± 15), almost all studies reported poorer NDO scores in infants with CHD compared with healthy controls or normative data. For the BSID II, the psychomotor developmental index (PDI) was more affected than the mental developmental index (MDI). Mean composite scores for the PDI ranged from 69.0 to 103.0 in infants with CHD14,24,81,88,89 and for the MDI from 85.2 to 103.5.14,24,81,88,89 The mean composite scores for the Bayley III were slightly higher compared with the composite scores for the BSID II. Mean cognitive scores ranged from 91.0 to 104.8, mean language scores ranged from 87.8 to 97.0, and mean motor scores ranged from 86.0 to 97.0.37,52,54,62,85,86 

There were many prenatal and postnatal preoperative factors associated with neurodevelopmental outcome in infants with CHD. Two articles found a negative correlation between MCA-PI and NDO.24,88 MCA-PI < 2.0 was associated with an increase of PDI of 11 points.88 One article found a positive correlation between MCA-PI and Bayley III cognitive scores16 and 1 article did not find any association between MCA-PI and NDO.14 A delayed development of the cerebrum was also associated with poorer NDO.38,54 Preoperative brain injury on MRI was associated with lower language and motor scores,62 whereas brain injury on preoperative ultrasound was not associated with NDO.81 Lower preoperative rcSo2 was associated with lower cognitive scores and lower motor scores62 and with lower BSID II scores.76 

There was little evidence on the association between preoperative EEG or aEEG and NDO. One study found a positive association between preoperative left frontal polar and left frontal β power and cognitive scores.16 Three other studies did find an association between intraoperative or postoperative aEEG and NDO, but not between preoperative aEEG and NDO outcome.85,86,88 

This systematic review demonstrates that prenatal and postnatal preoperative brain injury are common in infants with CHD. More importantly, this review demonstrates that abnormal cerebral findings during these periods might be associated with poorer neurodevelopmental outcomes in later life.

One major finding of this review was the presence of cerebral developmental delay in many infants with CHD during both the prenatal as well as the postnatal preoperative period. All cerebral regions were affected and a delay of up to 4 weeks compared with healthy controls was described.49 It has been well established that preterm-born infants are at risk for developing brain injury because of the complex mechanisms of destructive events and developmental issues. The preterm brain is associated with vulnerable white matter, immature vasculature, and impaired autoregulation.90 Moreover, signs of cerebral developmental delay are associated with adverse NDO in preterm infants. In infants with CHD, cerebral developmental delay was associated with the occurrence of brain injury on preoperative MRI and also with the severity of brain injury.53,59,64 We speculate, therefore, that cerebral developmental delay might lead to an increased vulnerability of the brain and could therefore be an important contributor to brain injury in infants with CHD.

Another major finding was that many fetuses with CHD had abnormal Doppler parameters. PI of the middle cerebral artery and CPR were low, whereas UA-PI was high compared with healthy fetuses in the majority of studies that reported on Doppler parameters. These findings are in accordance with redistribution of blood flow to enhance cerebral perfusion, also called the brain-sparing effect.30 Brain sparing might be a consequence of low cerebral oxygen content (hypoxemia) or low cerebral blood volume (ischemia). In fetuses with intrauterine growth restriction, brain sparing is a sign of severely impaired oxygen and/or nutrient supply and is associated with mortality and poor outcome.91 In fetuses with CHD, this association seems to be less clear8,14,16,24,88 and might even be a protective factor.24,88 Moreover, it has been reported that up to 23.8% of fetuses with CHD are also growth restricted,92,94 and variable degrees of impaired placental function may concurrently modulate cerebral vascular resistance. Brain sparing in fetuses with CHD could be an adaptive mechanism to compensate for either hypoxemia (low po2 because of placental insufficiency), hypoxia (low oxygen saturation because of intra- and extracardiac mixing), or ischemia.95 In all 3 situations, changes in cerebral vascular resistance may occur to compensate for poor oxygenation and to meet cerebral metabolic demands.14 Unfortunately, to date there are no studies looking systematically at uteroplacental (UA) and fetal (MCA, ductus venosus) flow to clarify if and to what extent brain sparing is determined by the effect of the cardiac lesion on oxygen saturation in fetuses with CHD.

Postnatally, brain injury was frequently reported (up to 52%) before cardiac surgery in infants with CHD. The most commonly observed lesions were all associated with decreased cerebral blood flow (ischemia) and included (punctate) white matter injury, periventricular leukomalacia, and stroke.30 Another indicator of an ischemic state was the presence of cerebral lactate in some infants with CHD.34,74 In addition to ischemia, hypoxia might also play a role in the development of early acquired brain injury in infants with CHD. Multiple studies found low arterial oxygen saturation values to be an independent risk factor for preoperative brain injury and high arterial oxygen saturation values to be a protective factor for preoperative brain injury.53,58,61,71,72 

In general, infants with CHD scored lower on neurodevelopmental tests compared with healthy infants. Their mean scores, however, were frequently within the normal ranges reported in healthy term infants (mean, SD 100 ± 15). A possible explanation for these normal scores might be that most infants were examined during early childhood (6–48 months). Certain capacities and skills such as memory function and abstract-logic thinking mature during the course of childhood, and problems might only become apparent at an older age.96 Children with CHD at school age on average score lower on motor skills, higher-order language, visual-spatial skills, vigilance, and sustained attention. These deficits often persist through adolescence into adulthood. Furthermore, children and adolescents with complex CHD often have difficulties with social cognition and executive functioning, which might lead to psychosocial disorders and a lower quality of life.97 

We found numerous associations between prenatal and postnatal preoperative cerebral findings and neurodevelopmental outcome in infants with CHD. Both prenatally as well as postnatally we were unable to identify specific cerebral findings that were responsible for poorer neurodevelopmental functioning in infants with CHD. We speculate, therefore, that neurodevelopmental impairment in CHD is the cumulative effect of delayed microstructural development in combination with multiple hypoxic and/or ischemic events during prenatal and postnatal preoperative life rather than being caused by a single independent factor.

Research to further clarify the actual mechanisms responsible for neurodevelopmental impairment in infants with CHD is essential. Nowadays, the adult population with CHD is larger than the pediatric population with CHD. Many adults with CHD still experience psychosocial and cognitive challenges that may impact emotional functioning, academic achievement, and even quality of life.98,101 To explore pathophysiological mechanisms and to optimize treatment protocols, large (multicenter) prospective trials should be conducted that include the prenatal to the postoperative period with an adequate duration of follow-up. Furthermore, increasing awareness of the vulnerability of the young developing brain of an infant with CHD is also essential among physicians and other caregivers that are involved in the treatment to prevent neurodevelopmental impairment later in life.

This systematic review has several limitations. First, most studies included in this review were observational studies. This type of study is unequivocally associated with a risk of bias of under- or overestimating outcome measures. The vast majority of studies, however, were of reasonable to very good quality according to the Newcastle-Ottawa Quality Assessment Scale. Second, comparisons between studies were difficult because various techniques and methods were used to assess cerebral abnormalities in infants with complex CHD. Reference values for antenatal Doppler parameters, for example, were different from one study to another. In addition to various techniques and methods, numerous different types of CHD were included with different pathophysiology, circulatory effects, and treatment protocols. This also made comparisons between studies more difficult. Future studies should differentiate between cardiac lesions to make risk stratification of infants with CHD possible and counseling perhaps a little more specific.102 Finally, an effect of chromosomal abnormalities on cerebral development and NDO cannot be ruled out completely since not all studies stated whether they included infants with chromosomal abnormalities with CHD. For future studies, it would also be interesting to assess differences in cerebral abnormalities and NDO between infants with isolated CHD and infants with nonisolated CHD.

The current systematic review suggests that prenatal and postnatal preoperative abnormal cerebral findings may play an important role in neurodevelopmental impairment in infants with CHD. Physicians and other caregivers should be more aware of this vulnerability of the brain and of the possible effect repeated episodes of hypoxia and/or ischemia during early life may have in infants with CHD. Prenatal and postnatal counseling remains challenging when CHD is diagnosed.102 Targeted investigation in each individual case may help clarify which injuries are already present prenatally and which are due to the postnatal course of the condition.

     
  • aEEG

    amplitude-integrated electroencephalography

  •  
  • BAS

    balloon atrial septostomy

  •  
  • Bayley III

    Bayley Scales of Infant and Toddler Development III

  •  
  • BSID II

    Bayley Scales of Infant Development II

  •  
  • CHD

    congenital heart disease

  •  
  • Cho/Cr

    choline/creatinine

  •  
  • CPR

    cerebroplacental ratio

  •  
  • EA

    epileptic activity

  •  
  • HC

    head circumference

  •  
  • HLHS

    hypoplastic left heart syndrome

  •  
  • Ino/Cho

    myo-inositol/choline

  •  
  • Lac/Cho

    lactate/choline

  •  
  • MCA

    middle cerebral artery

  •  
  • MCA-PI

    pulsatility index of the middle cerebral artery

  •  
  • MDI

    mental developmental index

  •  
  • NAA/Cho

    n-acetylaspartate/choline

  •  
  • NDO

    neurodevelopmental outcome

  •  
  • NIRS

    near-infrared spectroscopy

  •  
  • PA

    pulmonary atresia

  •  
  • PDI

    psychomotor developmental index

  •  
  • PI

    pulsatility index

  •  
  • rcSo2

    cerebral oxygen saturation

  •  
  • TGA

    transposition of the great arteries

  •  
  • UA

    umbilical artery

  •  
  • UA-PI

    pulsatility index of the umbilical artery

Ms Mebius conceptualized and designed the study, screened databases for eligible studies, drafted the initial manuscript, and revised the manuscript after feedback from coauthors; Dr Kooi conceptualized and designed the study, screened databases for eligible studies, and critically reviewed and revised the manuscript; Prof Dr Bilardo and Prof Dr Bos conceptualized and designed the study and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

FUNDING: No external funding.

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

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