University of Groningen Congenital heart disease : the timing of brain injury Mebius, Mirthe Johanna

Congenital heart disease : the timing of brain injury

Mebius, Mirthe Johanna

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Over the last decades, survival rates have increased tremendously in infants with congenital heart disease (CHD). Focus of attention has therefore gradually shifted from preventing mortality towards optimizing treatment outcome. It is known that infants with CHD may

experience short-term and long-term cardiac complications.1 _{Furthermore, they are at risk}

for neurodevelopmental impairments later in life.2 _{These impairments can manifest itself}

variably, involving various 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.2 _{While several risk factors have been described}

for adverse neurodevelopmental outcome (NDO), such as for example hypoxic-ischemic events, the exact timing of brain injury in infants with CHD is still unknown. The main aim of this thesis was, therefore, to gain more insight into the timing of brain injury in infants with CHD by assessing hemodynamic characteristics regarding cerebral circulation and brain function using non-invasive clinical tools at several moments during the prenatal and early postnatal period. Furthermore, we assessed the association between these non-invasive clinical tools and short-term NDO. Outcome variables of this thesis are presented in Figure 1 and main findings of the thesis are summarized in Table 1.

Figure 1 Outcome variables of the thesis. MRI, magnetic resonance imaging; HC, head circumference;

NIRS, near-infrared spectroscopy; aEEG, amplitude-integrated electroencephalography; Bayley, Bayley scales of infants and toddler development; GMs, general movements. Numbers between parentheses represent chapter numbers.

Prenatal period Preoperative period Intra- and postoperative period Neurodevelopmental outcome

Doppler flow profiles (2,3,6,7,9), MRI (2), HC (3,6)

NIRS (2,4,5,6,7,8,9), aEEG (2,7), MRI (2), HC (6)

NIRS (8,9)

Table 1

M

ain findings of the thesis Pr

ena tal Postna tal pr eoper ativ e In tr a- and post oper ativ e Neur odev elopmen tal out come Chapt er 2 MCA-PI , U A-PI or =, CPR Sig ns of cer ebral de velopmental dela y rc SO 2 Abnor mal aEEG, pr esence of epileptic ac tivit y Sig ns of cer ebral de velopmental dela y Str ok e, WMI, P VL NI Poor er NDO in compar

ison with health

y t

er

m infants

(fr

equently within nor

mal ranges)

MCA-PI + (1 study), MCA-PI - (2 studies), MCA-PI ≠ association (1 study) Cer

ebral de velopmental dela y poor er NDO rc SO 2 poor er NDO Brain injur y on MRI poor er NDO No association with pr eoperativ e aEEG Chapt er 3 MCA-PI /=, U A-PI , CPR HC , A C No association bet w een MCA-PI

and HC No association bet

w een MCA-PI and expec ted O 2 deliv er y t o the brain NI NI NI Chapt er 4 NI rc SO 2

Especially in infants with duc

t-dependent pulmonar y CHD NI NI Chapt er 5 NI Rc SO 2 , Rr SO 2 Not associat ed with dir ec tion of blood flo w in the aor ta in

infants with LSOL

NI NI Chapt er 6 MCA-PI , U A-PI , CPR HC MCA-PI associat ed with expec ted O2 deliv er y t o the brain rc SO 2 HC No association bet w een pr enatal D

oppler and postnatal

rc

SO

2

NI

10

EA: 15% subclinical seizur

es , SW C: 97%, first SW C 10.5h No association bet w een pr enatal D

oppler and postnatal

aEEG NI NI Chapt er 8 NI rc SO 2 indicat or clinical det er ioration ( n=1 ) rc SO 2 and r r SO 2 indicat or clinical det er ioration ( n=1 ) NI Chapt er 9 MCA-PI , U A-PI , CPR rc SO 2 and FT OE rc SO 2 MCA-PI +, CPR +, U A-PI-

Infants with abnor

mal NDO t ended t o ha ve lo w er rc SO 2 and higher FT OE pr eoperativ ely

No association with intraoperativ

e and post operativ e rc SO 2 MCA-PI, pulsatilit y index of the middle cer ebral ar ter y; U A-PI, pulsatilit y index of the umbilical ar ter y; CPR, cer ebr oplacental ratio; rc SO 2 , r eg ional cer ebral ox ygen saturation; aEEG, amplitude -int eg rat ed elec tr oencephalog raph y; WMI, whit e matt er injur y; PVL, per iv entr icular leuk omalacia; NDO , neur ode velopmental out come; HC, head cir cumf er ence; A C, abdominal cir cumf er ence; CHD , congenital hear t disease; LSOL, lef t-sided obstruc tiv e lesions; EA, epileptic ac tivit y; SW C, sleep -wak e-cy cling; FT OE, frac tional tissue o xy gen ex trac

tion; NI, not in

vestigat ed . Table 1 C ontinued

Part I Literature overview

In the first part of this thesis (Chapter 2), we present systematic overview of the literature regarding the association between prenatal or postnatal preoperative cerebral findings and NDO in infants with CHD. Cerebral findings included prenatal cerebral MRI and Doppler

flow patterns, and postnatal cerebral oxygen saturation (r_cSO₂ ), amplitude-integrated

electroencephalography (aEEG), cerebral MRI and cranial ultrasound. Abnormal cerebral findings were common in infants with CHD both prenatally and postnatally. Furthermore, although frequently within the normal ranges, infants with CHD almost always had poorer NDO scores in comparison with healthy term infants. The prenatal period as well as the postnatal period seemed to play an important role in neurodevelopment in infants with CHD. Prenatally, both abnormal Doppler flow patterns and signs of delayed brain

development on MRI were associated with NDO. Postnatally, low r_cSO₂ and signs of brain

injury on MRI were associated with adverse NDO. The association between abnormalities on preoperative cranial ultrasound or aEEG and NDO was less clear.

Part II Prenatal and postnatal cerebral findings

This part of the thesis focuses on prenatal and postnatal hemodynamic characteristics regarding cerebral circulation and brain function in infants with CHD. In several studies, we assessed prenatal Doppler flow patterns (Chapter 3, 6, and 7), head circumferences (HC;

Chapter 3, and 6), postnatal r_cSO₂ (Chapter 4, 5, 6, and 8) and aEEG (Chapter 7) in infants with various types of CHD. Prenatally, fetuses with CHD often showed abnormal Doppler flow patterns, suggestive of preferential brain perfusion (Chapter 3, 6, and 7). Furthermore, fetuses with CHD had smaller HC which only became apparent in the near-term period (Chapter

3, and 6). Doppler flow patterns seemed to be associated with head growth and expected

oxygen delivery to the brain in one study (Chapter 6), while this association could not be

demonstrated in another study (Chapter 3). After birth, neonates with CHD had lower r_cSO₂

in comparison with healthy term infants during the first three days after birth or admission to the NICU (Chapter 4, 5, 6, and 8). In infants with left-sided obstructive lesions, we also observed

lower renal oxygen saturation (r_r SO₂) compared with healthy term infants (Chapter 5)

and in two infants with duct-dependent CHD, r_cSO₂ and/or r_rSO₂ decreased gradually while

other hemodynamic parameters did not indicate that clinical deterioration was imminent

(Chapter 8). Besides lower r_cSO₂, we also observed smaller HC one week after birth (Chapter 6), abnormal aEEG background patterns, and subclinical epileptic activity (Chapter 7). There

was no association between prenatal Doppler flow patterns and postnatal r_cSO₂ (Chapter 6)

and we were also unable to demonstrate an association between prenatal Doppler flow patterns and postnatal aEEG (Chapter 7).

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Part III Neurodevelopmental outcome

In this part (Chapter 9) we present the first longitudinal prospective study that assessed the associations between prenatal Doppler flow patterns, postnatal preoperative, intraoperative

and postoperative r_cSO₂ and short-term NDO in infants with CHD. Short-term NDO was

defined as the quality of general movements (GMs) at an age of approximately 3 months. Our main findings were that prenatal Doppler flow patterns, indicative of preferential brain perfusion, were associated with adverse short-term NDO in infants with CHD. Postnatal

preoperative, intraoperative, or postoperative r_cSO₂ and FTOE, on the other hand, were

not clearly associated with NDO. The combination of abnormal Doppler flow patterns

before birth and abnormal r_cSO₂ after birth was associated with a nine-fold increased risk

for abnormal short-term NDO, suggesting a cumulative effect of hypoxic-ischemic events during the prenatal period and early postnatal life.

Etiology of brain injury

The etiology of brain injury in infants with CHD is multifactorial. In Figure 2 we provide a theoretical model of the proposed mechanisms responsible for brain injury in infants with CHD. This model is based on findings from this thesis as well as previous literature. We speculate that there are two main contributors to brain injury in infants with CHD, namely 1) a disruption of genetic pathways and 2) hemodynamic alterations.

Figure 2 Proposed etiology of brain injury in infants with congenital heart disease

Brain damage Increased vulnerability of brain tissue Delayed brain maturation Disruption genetic pathways Hemodynamic alterations Repeated episodes of hypoxia/ischemia

Other factors, such as:

- Impaired autoregulation

The disruption of genetic pathways was not studied in thesis, but previous studies show that development of the heart and brain occur simultaneously in the human fetus and that they share several genetic pathways such as sonic hedgehog, notch, jagged, NKx2.5, fibroblast

growth factor beta, and retinoic acid.3-5 _{A disruption in one of these pathways could affect}

organogenesis of both organs. Recently, several de novo mutations in different genes have

been identified in infants with non-syndromal CHD.6 _{Furthermore, Homsy et al identified de}

novo genetic mutations in infants with CHD and neurodevelopmental impairments. A key finding was that infants with CHD and neurodevelopmental impairments have mutations particularly in genes that are expressed both in heart and brain, suggesting a common

genetic origin for CHD as well as brain anomalies.7

The second contributor to brain injury in infants with CHD, hemodynamic alterations, has been studied in this thesis and will be discussed extensively in the section ‘Timing of brain

injury, the prenatal period’. In summary, CHD can potentially lead to prenatal hemodynamic

alterations due to intracardiac and extracardiac mixing of oxygenated and deoxygenated

blood or due to outflow tract obstructions.8-16 _{These hemodynamic alterations might cause}

(intermittently) impaired cerebral oxygen delivery, inadequate to fulfill the metabolic demand

of the developing brain, which is highly dependent on adequate oxygen and nutrient supply.5

Both the disruption of genetic pathways and hemodynamic alterations might lead to

delayed brain development.3-5,17,18 _{Fetuses with CHD often have smaller HC (Chapter 3 and}

6), smaller brain volumes, lower total brain weight, increased intra-ventricular and

extra-axial cerebrospinal fluid volumes, a sulcation delay of up to 4 weeks and an altered cerebral

metabolism.16,19-27 _{After birth, infants with CHD have smaller HC (Chapter 6) and signs of}

developmental delay of the brain are still present.28-36 _{These signs include an overall reduction}

in brain volume of up to 21%, a lower white matter fractional anisotropy and NAA/Cho

ratio, and a higher mean average diffusivity, lac/Cho ratio, Cho/Cr ratio and Mi/Cr ratio.28-36

Mean total maturation scores are significantly lower in infants with CHD in comparison with

healthy term infants and correspond to a delay of approximately 4 weeks.36

This delay in brain maturation might lead to an increased vulnerability of brain tissue for hypoxic-ischemic insults during the prenatal and early postnatal period. The young developing brain acquires characteristic patterns of injury that reflect the vulnerability of

specific cell populations and the timing of injury.17 _{White matter injury (WMI) is one of the}

most commonly observed lesions in infants with CHD.24,31,32,37,38 _{This type of brain injury is}

usually seen in preterm infants, whereas term infants more often have injury to grey matter

or neuronal structures.39-40 _{The proposed mechanism for WMI in preterm infants is a cellular}

maturation arrest of progenitors of oligodendrocytes that predominate in white matter

during the third trimester.40 _{Early-lineage oligodendrocytes have less defense mechanisms}

(i.e. anti-oxidant capacity) to insults such as hypoxic-ischemic events in comparison with

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Timing of brain injury

The prenatal period

As stated above (section ‘Etiology of brain injury’), CHD can potentially cause prenatal hemodynamic alterations that lead to impaired cerebral oxygen and nutrient supply. This hemodynamic instability could be reflected by prenatal Doppler flow patterns. In response to acute or chronic hypoxia, fetuses redistribute their cardiac output away from

the peripheral vascular beds and towards essential circulations such as the brain.41-45 _This

phenomenon is called brain sparing and is characterized by a lower pulsatility index of the middle cerebral artery (MCA-PI), a higher pulsatility index of the umbilical artery

(UA-PI), and a lower cerebroplacental ratio (CPR).8-16 _{In Chapter 2, 3, 6, 7, and 9 we frequently}

observed prenatal Doppler flow patterns suggestive of brain sparing in fetuses with CHD. Previous studies also observed lower MCA-PI, higher UA-PI and lower CPR in fetuses with CHD, particularly in fetuses with CHD associated with impaired cerebral oxygen supply.

We also studied the association between prenatal Doppler flow patterns and expected cerebral oxygen delivery according to type of CHD in Chapter 3 and 6. In our prospective study (Chapter 6), there seemed to be an association with expected cerebral oxygen delivery, with fetuses with low expected cerebral oxygen delivery showing the lowest MCA-PI. In a larger retrospective study (Chapter 3), however, this association could not be reproduced. This might be due to differences in study methodology. In Chapter 6 we selected one measurement prior to birth and only used descriptive statistics, while in Chapter 3 we used a liner mixed-effects model to assess Doppler trends throughout pregnancy. Furthermore, different classification methods were used to define low, reduced and normal oxygen delivery to the brain. Alternatively, in fetuses with CHD, hypoperfusion might have a more profound effect on cerebral oxygen delivery in comparison with hypoxemia. Differences in oxygen saturation in the ascending aorta between fetuses with expected normal, reduced or low oxygen delivery to the brain are relatively small (65% vs. 60%) and might be too subtle to cause differences in Doppler flow patterns. The effect of hypoperfusion has to be further investigated. One study found lower MCA-PI in fetuses with left-sided obstructive lesions with retrograde blood flow in the ascending aorta in comparison with fetuses with left-sided obstructive lesions with antegrade blood flow in the ascending aorta, suggesting

that brain vessel dilatation may especially occur in the first type of lesions.12

Regarding the association between prenatal Doppler flow patterns and NDO, there are two main theories. Brain sparing might either be a protective mechanism or it might be an insufficient mechanism to compensate for brain underperfusion. Two studies found a negative association between Doppler flow patterns and psychomotor developmental index (Bayley II) suggesting that brain sparing is an adaptive and protective mechanism to compensate for either decreased cerebral oxygen supply or decreased cerebral blood

Doppler flow patterns and cognitive outcome (Bayley III) suggesting that brain sparing

is an insufficient mechanism to compensate for brain underperfusion.15 _{One other study}

could not confirm either one of the theories.14 _{This thesis supports the theory that brain}

sparing in fetuses with CHD is an insufficient compensatory mechanism and a sign of brain vulnerability, as brain sparing was associated with adverse short-term NDO (Chapter 9).

Contradictory results concerning the association between prenatal Doppler flow patterns and NDO outcome in infants with CHD might be due to differences in study design and study methodology. First, NDO was assessed using different validated tests (GMs, Bayley II, and Bayley III) at different ages (3 months to 18 months of age). In Chapter 9, we used the quality of GMs at an age of 3 months according to Prechtl’s method to assess short-term NDO. General movements are spontaneous movements that involve the entire

body and are present from fetal life until approximately 5 months of age.47,48 _Particularly

GMs at an age of 3 months (fidgety period) are an accurate marker to assess the integrity of the young nervous system with a high sensitivity and specificity for neurodevelopment

at an older age.49-52 _{Second, most studies used a single Doppler measurement at various}

moments during pregnancy (first measurement after diagnosis or last measurement before birth), while there is increasing evidence that hemodynamic responses change over

time and particularly late assessments are more representative (Chapter 3).8 _Furthermore,

Doppler flow patterns vary with fetal behavior, fetal heart rate and fetal breathing and recent studies are lacking on the effects of these variables on variability and reproducibility

in fetuses with CHD.53,54 _{Third, various types of CHD were included, which may have different}

pathophysiological and circulatory effects. Brain sparing might be a protective mechanism in some types of CHD, while it is a sign of fetal distress in others.

Postnatal period

After birth, hypoxic-ischemic events form an additional threat to the young developing brain of the infant with CHD. We frequently observed mildly abnormal aEEG background patterns and subclinical epileptic activity prior to surgery (Chapter 7). Furthermore, we

observed low r_cSO₂ values prior to, during, and 24 hours after surgery (Chapter 4-6, 8, and 9).

Their exact contributions to NDO, however, remain unclear.

Previous studies in infants with CHD often reported abnormal aEEG background patterns,

(sub)clinical seizures, and absence of sleep-wake cycling (SWC) prior to surgery.55-58 _While

these abnormalities have been associated with brain injury on preoperative MRI,56 _{a clear}

association between preoperative aEEG abnormalities and NDO could not be demonstrated. We also observed mildly abnormal background patterns and subclinical seizures, but almost all neonates developed SWC during the first 3 days after birth (Chapter 7). Furthermore, we observed less frequent and less severe aEEG abnormalities in comparison with previous studies. In contrast to these studies, we only included neonates diagnosed prenatally with

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CHD, suggesting that immediate treatment after birth may prevent hypoxic-ischemic events and therefore has a beneficial effect on brain function in these infants. In Chapter 7, we also reported a strong association between abnormal preoperative aEEG background patterns and use of sedatives during the first 3 days after birth. Sedatives have been known to cause

a transient depression of electro-cortical activity in several different study populations.59-62

Some authors therefore state that interpreting aEEG recordings in infants who are treated

with sedatives is unreliable and should be avoided.59,61 _{Based on these findings, we speculate}

that there are two explanations for the non-existent association between preoperative aEEG and NDO. First, preoperative aEEG abnormalities are relatively mild in infants with CHD, particularly in prenatally diagnosed cases and are therefore not related to NDO later in life. Alternatively, abnormal aEEG background patterns prior to surgery might be a transient effect of treatment with sedatives instead of a sign of brain injury.

For this thesis, we did not study intraoperative and postoperative aEEG, nor did we assess the association between aEEG abnormalities during this period and NDO. Previous studies reported isoelectric or low voltage activity during deep hypothermic circulatory arrest during surgery. Furthermore, intraoperative seizures were frequently reported in infants with CHD. A significant association was reported between intraoperative seizures

and mortality, but not with NDO.57,58 _{Postoperative aEEG abnormalities, on the other hand,}

did seem to be associated with adverse cognitive and motor outcome in infants with CHD. Both abnormal background patterns, delayed recovery of background patterns and lack of return to SWC within 48 hours after surgery were strongly related to poorer NDO at 2 and

4 years of age.57,58,63 _{Postoperatively, aEEG background abnormalities were more severe in}

comparison with aEEG abnormalities prior to surgery. This might explain why postoperative aEEG abnormalities are associated with NDO while preoperative abnormalities are not.

Infants with CHD often have low r_cSO₂ values prior to surgery, during surgery and following

surgery.63-70 _{In this thesis, r}

cSO2 values, both before, during and after cardiac surgery, were

frequently below previously established hypoxic-ischemic thresholds in piglets.71,72 _{Prior to}

surgery, infants with abnormal short-term NDO tended to have lower r_cSO₂ values, however,

this difference did not reach statistical significance. There are various explanations for this finding. First, our sample size might have been too small to detect a significant association

between r_cSO₂ and NDO. Previous studies, however, were also unable to demonstrate a clear

association between r_cSO₂ and NDO in infants with different types of CHD. Second, hypoxia

or ischemia duration might have been too short to cause permanent brain injury. Kurth et al. demonstrated that an episode of hypoxia/ischemia of ≥ 2 hours was required to cause

permanent brain injury in neonatal piglets.71 _{In our study, near-infrared spectrometers were}

not blinded to the medical staff, so the staff could have acted on low r_cSO₂ values. Third, we

speculate that neonates with CHD are able to recover from hypoxic-ischemic events during early life. Brain development continues throughout childhood and involves not only the

onset of new pathways and connections, but also elimination of others.73 _{Due to the high}

plasticity of the young brain, previous abnormalities might disappear, at least transiently. There is ongoing debate regarding the association between intraoperative and

postoperative r_cSO₂ and NDO in infants with CHD. We were unable to demonstrate an

association (Chapter 9). Previous studies, on the other hand, reported varying correlations. Cerebral oxygen saturation during and after surgery alone, however, was never a strong

predictor of NDO.64,65,68,74 _{It can be argued that surgical techniques and postoperative}

intensive care have improved in such a way that additional brain injury is prevented. Alternatively, it might be that there is not a single predictor for NDO in infants with CHD, but that NDO is dependent on a combination of prenatal and postnatal factors.

Cumulative effect – Knudson hypothesis

In 1971, Alfred G. Knudson proposed the theory that two mutational events are necessary

to cause cancer.75 _{Since then, the two-hit hypothesis has been put forward in a number}

of diseases where onset of disease cannot clearly be linked to a specific genetic or

environmental insult, such as autism or schizophrenia.76,77

The two-hit hypothesis might also be true for NDO in infants with CHD. While we were unable to demonstrate an association between prenatal Doppler flow patterns and

postnatal r_cSO₂ (Chapter 6) or aEEG (Chapter 7), we did observe a nine-fold increased risk of

having abnormal short-term NDO in infants with CHD with two or more hypoxic-ischemic events during the prenatal and early postnatal period (Chapter 9). The combination of an increased vulnerability of the cerebrum due to a disruption of genetic pathways or circulatory alterations (first hit) and subsequent hypoxic-ischemic events (second hit) might affect NDO in infants with CHD.

Future perspectives

This thesis provides insight into the timing of brain injury in infants with prenatally diagnosed CHD. Particularly the prenatal period seems to be an important contributor to NDO in infants with CHD. Furthermore, there might be a cumulative effect of hypoxic-ischemic events during the prenatal period and early postnatal life. However, many uncertainties regarding brain injury in infants with CHD still exist. The exact role of the early postnatal period remains unclear. Furthermore, the association between hemodynamic characteristics regarding cerebral circulation and brain function and NDO might differ according to the type of CHD. Finally, it is important to assess whether the association between prenatal Doppler flow patterns and NDO is confirmed by larger studies. Future large multicenter studies, including prospectively followed cohorts of fetuses with different types of CHD followed according a strict protocol and with an adequate duration of follow-up (at least until childhood, but preferably until adolescence) are mandatory to allow for risk stratification according to the

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type of CHD. Only after this has been achieved a definitive conclusion on the presence and significance of cerebral hemodynamic changes, on the onset of brain injury and hopefully on possible preventive strategies can be reached.

A clear finding of this thesis is that adverse NDO is common in infants with CHD. When comparing NDO of infants with CHD with other at risk populations, such as infants with hypoxic-ischemic encephalopathy (HIE) or preterm born infants, results are quite similar

(Table 2).78 _{In the Netherlands, infants with HIE and preterm born infants are part of a}

national follow-up program. We believe that infants with CHD should also be incorporated into a follow-up program to allow for early identification and early interventions. In fact,

there is some evidence that NDO improves after early intervention in preterm infants.79

Apart from risk stratification according to type of CHD and early identification and intervention of potential problems, future studies should focus on preventative strategies. Pharmacological neuroprotection and fetal cardiac intervention might be promising for

infants with CHD. A number of medications have been proposed for neuroprotection.80

First, allopurinol is a xanthine oxidase inhibitor that has both neuroprotective as well as cardiovascular protective effects. It can be administered both prenatally and postnatally as it crosses the placenta. In experimental studies neuroprotective effects have been

demonstrated during both periods.81-83 _{In neonates with HIE, there is some evidence}

that allopurinol has beneficial effects on NDO.84 _{In infants with CHD, however, effects of}

allopurinol on NDO have yet to be determined.85 _{Second, another promising medication}

is topiramate, which may have the potential to prevent WMI by protecting progenitors of

oligodendrocytes.86 _{An important mechanism in the development of brain injury in infants}

with CHD might be a maturation arrest of progenitors of oligodendrocytes. Third, caffeine

has potential neuroprotective effects by inhibiting adenosine.87 _{Adenosine is released}

during hypoxic-ischemic events and is involved in WMI.88 _{In preterm infants, caffeine}

administration has been associated with improved NDO.89 _{Randomized-controlled trials}

will be needed to evaluate the full potential of pharmacological neuroprotection in the fetus and neonate with CHD. Finally, the benefits and risks of fetal cardiac interventions should be further explored. Theoretically, some types of CHD might be considered for fetal cardiac intervention in this respect (severe aortic stenosis evolving to hypoplastic left heart syndrome (HLHS), pulmonary atresia with hypoplasia of the right ventricle, and HLHS with

restrictive atrial septum).90 _{Although the procedure nowadays is often technically successful,}

Table 2 Overview of the prevalence of major outcome categories in the largest at-risk populations.

HIE Very preterm CHD

Prevalence 1-6/1000 10/1000 6/1000

Cerebral palsy 30%, TH: 20% 5-10% 2%

IQ < 70 30% 10-20% 10-20%

Mild deficits ~50% ~50% ~30-50%

HIE, hypoxic-ischemic encephalopathy; CHD, congenital heart disease; TH, therapeutic hypothermia. Adapted from: Latal B. Neurodevelopmental Outcomes of the Child with Congenital Heart Disease. Clin Perinatol 2016;43:173-185.

Conclusion

In conclusion, infants with congenital heart disease often have poorer neurodevelopmental outcomes in comparison with healthy term infants. Hemodynamic characteristics of cerebral perfusion and brain function during the prenatal and early postnatal life seem to be associated with neurodevelopmental outcome. Particularly the prenatal period seems to play an important role in neurodevelopmental outcome in infants with congenital heart disease. Postnatally, however, abnormal cerebral oxygen saturation and brain function were also frequently observed. Their exact contribution to neurodevelopmental outcome has yet to be determined. Based on the results of this thesis, we suggest the concept that, in infants with congenital heart disease, the first hit contributing to abnormal neurodevelopment occurs during the fetal period. Developmental delay may be the result of abnormal genetic pathways combined with hemodynamic alterations leading to an increased vulnerability for hypoxic-ischemic events of the young developing brain. Postnatal events may represent the second hit. This thesis further demonstrates that non-invasive clinical investigations can be helpful in identifying fetuses at risk for adverse neurodevelopment. However, longitudinal studies with an adequate duration of follow-up and risk stratification according to type of congenital heart disease are necessary, as brain development is not impaired in all types of congenital heart disease.

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