pediatrics
July 2017, VOLUME140 /ISSUE 1

Brain Injury and Neurodevelopmental Outcome in Congenital Heart Disease: A Systematic Review

  1. Mirthe J. Mebius, BSca,
  2. Elisabeth M.W. Kooi, MD, PhDa,
  3. Catherina M. Bilardo, MD, PhDb, and
  4. Arend F. Bos, MD, PhDa
  1. aDivision of Neonatology, University of Groningen, University Medical Center Groningen, Beatrix Children’s Hospital, Groningen, Netherlands; and
  2. bDepartment of Obstetrics and Gynecology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
  1. 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.

Abstract

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.

  • Abbreviations:
    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
  • 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.

    Methods

    Search Strategy

    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.

    Quality Assessment

    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.

    Results

    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.

    TABLE 1

    Prenatal Cerebral Findings in Infants with CHD

    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

    TABLE 2

    Postnatal Cerebral Findings in Infants With CHD

    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

    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.

    Prenatal Cerebral Ultrasound

    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.1321 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),13,20,2527 whereas another 5 studies reported similar UA-PI18,22,2830 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

    MRI

    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.3133

    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.21,3338 Another feature of developmental delay was an impaired sulcation with a delay of ∼3 to 4 weeks.21,3638

    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.3942 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).3941,43 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 anisotropy4447 and NAA/Cho4547 were lower, and mean average diffusivity,4547 lactate/choline (Lac/Cho),4547 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.31,46,5069 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.3941,45

    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

    Near-Infrared Spectroscopy

    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.7577 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

    Other Techniques

    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%.8184

    Up to 63% of the neonates had an abnormal preoperative aEEG recording (42%–45% mildly abnormal and 15%–21% severely abnormal).65,8587 In 0% to 19% of the cases, epileptic activity (EA) was registered65,8587 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

    Neurodevelopmental Outcome in Infants With CHD

    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

    Discussion

    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,9294 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.98101 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.

    Conclusions

    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.

    Footnotes

      • Accepted April 3, 2017.
    • Address correspondence to Mirthe J. Mebius, BSc, Division of Neonatology, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. E-mail: m.j.mebius01{at}umcg.nl
    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: No external funding.

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

    References