Impact of cardiac surgical timing on the neurodevelopmental outcomes of newborns with Complex congenital heart disease (CHD)

Abstract

Background: More than half of infants with complex congenital heart disease (CHD)
will have a neurodevelopmental disorder of multifactorial causes. The preoperative
period represents a time-window during which neonates with complex CHD are in
a state of hypoxia and hemodynamic instability, which fosters the emergence of
brain injuries and, thus, affects early brain networks and neurodevelopmental
outcomes. Currently, there is no consensus regarding the optimal age for cardiac
surgery in terms of neurodevelopmental outcomes, and its definition is a real
challenge. Our aim is to determine the relationship between cardiac surgical timing
and long-term neurodevelopmental outcomes for various types of complex CHD.
Methods: We hypothesize that earlier surgical timing could represent a
neuroprotective strategy that reduces perioperative white matter injuries (WMIs) and
postoperative morbidity, leading to improved neurodevelopmental outcomes in
infants with complex CHD. Firstly, our prospective study will allow us to determine
the correlation between age at the time of surgery (days of life) and
neurodevelopmental outcomes at 24 months. We will then analyze the correlation
between age at surgery and (i) the incidence of WMIs (through pre- and
postoperative MRIs), (ii) postoperative morbidity, and (iii) the duration of the hospital stay.
Implications and Dissemination: This research protocol was registered in the Clinical
Trial Registry (National Clinical Trial: NCT04733378). This project aims to help launch
the first Neurocardiac Investigation Clinic in Marseille — AP-HM — to propose an
overall personalized monitoring and treatment program for patients operated on for
complex CHD

Full text

EDITED BY
Petru Liuba,
Lund University, Sweden
REVIEWED BY
Floris E.A. Udink ten Cate,
Radboud University Medical Center,
Netherlands
Liqun Sun,
University of Toronto, Canada
Maria Feldmann,
University Children’s Hospital Zurich,
Switzerland
*CORRESPONDENCE
Béatrice Desnous
beatrice.desnous@ap-hm.fr
SPECIALTY SECTION
This article was submitted to Pediatric
Cardiology, a section of the journal Frontiers in
Pediatrics
RECEIVED 26 July 2022
ACCEPTED 23 January 2023
PUBLISHED 23 March 2023
CITATION
Lenoir M, Beretti T, Testud B, Resseguier N,
Gauthier K, Fouilloux V, Gran C, Paoli F,
El-Louali F, Aldebert P, Blanc J, Soulatges C,
Al-dybiat S, Carles G, Wanert C, Rozalen W,
Lebel S, Arnaud S, Santelli D, Allary C, Peyre M,
Grandvuillemin I, Desroberts C, Alaoui MB,
Boubred F, Michel F, Ovaert C, Milh M,
François C and Desnous B (2023) Impact of
cardiac surgical timing on the
neurodevelopmental outcomes of newborns
with Complex congenital heart disease (CHD).
Front. Pediatr. 11:1003585.
doi: 10.3389/fped.2023.1003585
COPYRIGHT
© 2023 Lenoir, Beretti, Testud, Resseguier,
Gauthier, Fouilloux, Gran, Paoli, El-Louali,
Aldebert, Blanc, Soulatges, Al-dybiat, Carles,
Wanert, Rozalen, Lebel, Arnaud, Santelli, Allary,
Peyre, Grandvuillemin, Desroberts, Alaoui,
Boubred, Michel, Ovaert, Milh, François and
Desnous. This is an open-access article
distributed under the terms of the Creative
Commons Attribution License (CC BY). The use,
distribution or reproduction in other forums is
permitted, provided the original author(s) and
the copyright owner(s) are credited and that the
original publication in this journal is cited, in
accordance with accepted academic practice.
No use, distribution or reproduction is
permitted which does not comply with these
terms.
Impact of cardiac surgical timing on
the neurodevelopmental outcomes
of newborns with Complex
congenital heart disease (CHD)
Marien Lenoir1, Thibault Beretti2, Benoit Testud3,4,
Noémie Resseguier5, Kim Gauthier6, Virginie Fouilloux1, Célia Gran1,
Florent Paoli7, Fedoua El-Louali7, Philippe Aldebert7, Julie Blanc7,
Camille Soulatges7, Sarab Al-dybiat7, Guillaume Carles7,
Chloe Wanert7, William Rozalen6, Stéphane Lebel8, Sophie Arnaud8,
Dominique Santelli8, Chloé Allary8, Marianne Peyre8,
Isabelle Grandvuillemin9, Clotilde Desroberts9, Myriem
Belghiti Alaoui8, Farid Boubred9, Fabrice Michel8, Caroline Ovaert7,
Mathieu Milh6, Clément François10 and Béatrice Desnous2,11*
1
Division of Paediatric Cardiac Surgery, APHM La Timone, Marseille, France,
2
Département de Pédiatrie,
Division de Neurologie, Hôpital de La Timone, Marseille, France,
3
Department of Neuroradiology, APHM La
Timone, Marseille, France,
4
CEMEREM, APHM La Timone, Marseille, France,
5
Aix-Marseille University, Support
Unit for Clinical Research and Economic Evaluation, AP - HM, Marseille, France,
6
Department of Paediatric
Neurology, APHM La Timone, Marseille, France,
7
Department of Paediatric Cardiology, APHM La Timone,
Marseille, France,
8
Department of Paediatric Anesthesia and Intensive Care Unit, APHM La Timone, Marseille,
France,
9
Department of Neonatology, APHM La Conception, Marseille, France,
10
Aix Marseille Univ, CNRS, LPL,
Aix-en-Provence, France,
11
INSERM U1106 Institut de Neurosciences des Systèmes, Marseille, France
Background: More than half of infants with complex congenital heart disease (CHD)
will have a neurodevelopmental disorder of multifactorial causes. The preoperative
period represents a time-window during which neonates with complex CHD are in
a state of hypoxia and hemodynamic instability, which fosters the emergence of
brain injuries and, thus, affects early brain networks and neurodevelopmental
outcomes. Currently, there is no consensus regarding the optimal age for cardiac
surgery in terms of neurodevelopmental outcomes, and its definition is a real
challenge. Our aim is to determine the relationship between cardiac surgical timing
and long-term neurodevelopmental outcomes for various types of complex CHD.
Methods: We hypothesize that earlier surgical timing could represent a
neuroprotective strategy that reduces perioperative white matter injuries (WMIs) and
postoperative morbidity, leading to improved neurodevelopmental outcomes in
infants with complex CHD. Firstly, our prospective study will allow us to determine
the correlation between age at the time of surgery (days of life) and
neurodevelopmental outcomes at 24 months. We will then analyze the correlation
between age at surgery and (i) the incidence of WMIs (through pre- and
postoperative MRIs), (ii) postoperative morbidity, and (iii) the duration of the hospital stay.
Implications and Dissemination: This research protocol was registered in the Clinical
Trial Registry (National Clinical Trial: NCT04733378). This project aims to help launch
the first Neurocardiac Investigation Clinic in Marseille —AP-HM —to propose an
overall personalized monitoring and treatment program for patients operated on for
complex CHD.
KEYWORDS
bayley IV, congenital heart disease, white matter injuries, cardiac surgical timing, neonates,
neurodevetlopmental outcomes
TYPE Study Protocol
PUBLISHED 23 March 2023
|
DOI 10.3389/fped.2023.1003585
Frontiers in Pediatrics 01 frontiersin.org

1. Introduction
Congenital heart disease (CHD) is the most common birth defect,
affecting 9 neonates out of every 1,000 live births (i.e., nearly 1% of
births) (1). Half of these children have complex CHD requiring
cardiac surgery during the first months of life (1). Additionally, more
than 50% of them have a neurodevelopmental disorder resulting from
multiple additive, collinear, and interacting risk factors, including
genetic variants, parental education, fetal circulatory disorders,
intraoperative factors, and postoperative complications (2). The
current prognosis for neonates with complex CHD warrants the
development of prevention strategies aimed at improving their
neurodevelopment outcomes and, thus, their quality of life. Cardiac
surgery with its intrinsic risk factors, such as the duration of
extracorporeal circulation (EC) or the realization of circulatory arrest,
does not determine the neurodevelopmental outcomes of these
patients. Indeed, the preoperative period represents a window of time
during which neonates with complex CHD are in a state of hypoxia
and hemodynamic instability, fostering the emergence of brain
injuries (3–5) and, thus, affecting early brain networks (6)and
neurodevelopmental outcomes.
For patients with TGA (Transposition of Great Arteries) or HLHS
(Hypoplastic Left Heart Syndrome), later cardiac surgery leads to a
higher incidence of white matter injuries (WMI) (7,8), which is a
well-known prognostic factor for motor (9–12), language (11), and
cognitive (10,12,13) impairment, as well as behavioral issues (14).
Additionally, Anderson et al. (15) demonstrated that conducting the
arterial switch operation (ASO) on neonates with TGA before the
third day of life reduced the major postoperative morbidity of these
patients in terms of neurological (occurrence of seizures, ischemic
stroke), cardiological, and infection complications. Patients with left
ventricle hypoplasia operated on later in the neonatal period also
presented higher postoperative morbidity (16). Similarly, patients with
TGA given the ASO after 2 weeks of life experienced impaired
perioperative brain growth and slowed language development (17).
Conversely, a major hypotrophy (weight < third percentile) or
hemodynamic instability can delay the surgery, which may then be
considered too risky. The fetal, pre and intraoperative risk factors of
brain injuries are listed in the Table 1. All postoperative morbidities
(Table 2) are deemed as potential risk factors for brain injuries.
There is no consensus regarding the optimal age for surgery in
terms of morbidity and neurodevelopmental outcomes, and its
definition is a real challenge. Importantly, at the present time,
there are no established rules for determining the timing of surgery
in our department. For the most common CHD types, the TGA
are corrected during the first ten days of life. There is a more
pronounced degree of variation for HLHS. This common practice
won’t be changed for our observational study.
Our aim is to determine the relationship between surgical timing
and long-term neurodevelopmental outcomes for various types of
complex CHD. Similarly to Anderson et al. (15) with postoperative
morbidity, we aim to determine a cut-off point for surgical timing
that will improve neurodevelopmental outcomes. For each type of
CHD, we aim to determine a cut-off for surgical timing based on
postoperative morbidity and neurodevelopmental outcomes. We
hope that our findings will contribute to the development of
surgical timing guidelines in the future.
1.1. Hypotheses
We propose an open-design, observational longitudinal study in
which we hypothesize that earlier cardiac surgery may constitute a
preoperative neuroprotective strategy and improve the
neurodevelopmental outcomes of neonates with complex CHD.
1.2. Main objective
The main objective of this study is to assess the correlation
between age at surgery (days of life) of neonates with complex
TABLE 1 Foetal and preoperative risk factors of brain injuries.
Foetal
period
Preoperative
period
Intraoperative
period
Risk Factors
of Brain
injuries
Gestational
Age
Postnatal diagnosis CPB duration (min)
IUGR Lower arterial oxygen
saturation
Aortic clamp time
(min)
Brain
volume
Lower apgar scores at
5 min
DHCA (min)
Selective cerebral
perfusion (min)
Brain
immaturity
Abnormal aEEG
background pattern
Low Flow
Longer time to
surgery
Brain lactates
Low flow
Male sex
CPB, Cardiopulmonary bypass; DHCA, Deep hypothermia with circulatory arrest;
IUGR, Intrauterine growth restriction; aEEG, amplitude EEG.
TABLE 2 Classification of post-op morbidities.
Morbidity
category
Morbidities
Cardiac /
Respiratory
•Cardiac arrest, arrhythmias,
JET
•Low cardiac output syndrom
•Extracorporeal membrane
oxygenation
•Post-op high-output failure
•Re-intubation for acute
respiratory distress
•Neonatal necrotizing
enterocolitis
•Systemic vein
thrombosis
•Acute renal deficiency
with dialysis
•Delayed sternal closure
•Length of intensive care
unit stay
Infectious •Septicemia, fungemia
•Infection of the surgical site,
mediastinitis
•Endocarditis
•Meningitis
•Pneumonia
Neurological •Ischemic cerebrovascular
accident
•Hemorrhagic
cerebrovascular accident
•Epileptic seizure
•Cerebral
thrombophlebitis
Surgical •Recurring diaphragmatic
paralysis/paresis
•Definitive AV block with
device
•Acute hemorrhaging
requiring revision surgery
•Cardiac tamponade
•Unplanned revision
surgery
•Chylothorax
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 02 frontiersin.org

CHD and neurodevelopmental outcomes at 24 months, assessed by
the scores obtained on the subscales of the Bayley Scale of Infant
and Toddler Development®, Fourth Edition® (Bayley-IV test)
exploring motor skills, cognition, and language (18).
Our aim is to determine the optimal threshold for the age at
surgery that discriminates delayed neurodevelopment / normal
neurodevelopment according to the main criterion, i.e.
neurodevelopment at 24 months according to the Bayley-IV scale
(score <80 vs. ≥80).
1.3. Secondary objectives
The secondary objectives of our study are to evaluate the
correlation between age at surgery (days of life) of neonates with
complex CHD and the following outcomes:
i. the presence and severity of WMIs observed on preoperative and
postoperative brain MRI;
ii. postoperative morbidity;
iii. the duration of the postoperative hospital stay;
iv. neurodevelopmental outcomes, including clinical pediatric
neurological assessment (4 months, 12 months, and 24
months) and functional motor skill assessment using the
Alberta Infant Motor Scale (AIMS; 4 months and 12 months).
We will also assess the moderating role of demographic
characteristics and pre-, intra-, and postoperative factors on the
following outcomes:
i. the frequency of pre-, and postoperative WMIs;
ii. postoperative morbidity;
iii. neurodevelopmental outcomes, including clinical pediatric
neurological assessment (4 months, 12 months, and 24
months), functional motor assessment using the AIMS (4
months and 12 months), and the Bayley-IV test (24 months).
2. Methods
2.1. Recruitment
Recruitment will be conducted on a prospective cohort (n= 100)
of neonates with complex CHD requiring cardiac surgery with
cardiopulmonary bypass CPB within the first 2 months of life and
receiving a pre-operate and postoperative brain MRI, standardized
neurological assessments at 4 months, 12 months, and 24 months,
and a neuropsychological assessment with a Bayley-IV test at 24
months.
2.2. Inclusion criteria
In this study, we will recruit infants aged 2 months or less with
complex CHD requiring surgery with extracorporeal circulation
during their first 2 months of life at the La Timone Enfants
Hospital in Marseille. The included patients should be born full-
term (at more than 37 weeks). The eligible complex CHDs
correspond to the anatomical classification of Clancy et al. (19),
(Table 3).
For all patients, we must obtain informed consent from both
parents (except in special cases justifying consent from just one
parent) or from legal representative(s). The parents or legal
representatives must be able to read and speak French.
Additionally, the included patients will need to be affiliated with
French social security.
2.3. Exclusion criteria
Patients will be excluded from this study in cases where they (i)
have not received any preoperative or postoperative brain MRI due to
their poor state of health, because the parents refused, or for another
reason; (ii) have their consent withdrawn.
2.4. Non-inclusion criteria
Patients will not be included if (i) birth weight is less than 2 kilos
and/or gestational age less than 37 weeks (ii) if they have a CCHD
not requiring cardiac surgery with CBP during the first 2 months
of life And (iii) if they have a proven chromosomal abnormality or
genetic syndrome associated with their CCHD.
2.5. Procedure overview
Each recruited patient will participate in the study for 24 months
(Figure 1). Following the recruitment (visit 0, V0) conducted in the
TABLE 3 Classification of complex congenital heart diseases selected for the
study, according to Clancy et al.(19).
Classification
Number
Anatomic
Classification (10)
Complex CHD
I Two-ventricle heart without
arch obstruction
TGA with intact
ventricular septum
TGA/VSD
Tetralogy of Fallot/PA
Truncus Arteriosus
TAPVR
II Two-ventricle heart with arch
obstruction
TGA/VSD/CoAo
VSD/CoAo
VSD/Interrupted
aortic arch
III Single-ventricle heart without
arch obstruction
Unbalanced AVCD
Tricuspid atresia
Mitral atresia
Heterotaxy
Double-outlet left
ventricle
Double-outlet right
ventricle
Single ventricle
(other)
IV Single-ventricle heart with
arch obstruction
HLHS
PA, Pulmonary Atresia; AVCD, Atrioventricular Canal Defect; VSD, Ventricular Septal
Defect; CoAo, Coarctation of the Aorta; HLHS, Hypoplasia of Left Heart Syndrome;
TAPVR, Total Anomalous Pulmonary Venous Return; TGA, Transposition of the
Great Arteries.
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 03 frontiersin.org

neonatal period before cardiac surgery, a preoperative brain MRI will
be performed before surgery (visit 1, V1) if the health of the neonate
allows for this. During the 15 days following the surgery, a
postoperative brain MRI is performed (visit 2, V2). Visits 1 and 2
aim to assess preoperative brain injuries and those that appear or
worsen postoperatively. The preoperative MRI should not delay
cardiac surgery. Visits 3 (V3), 4 (V4), and 5 (V5) will involve
neurodevelopmental assessments at 4 months, 12 months, and 24
months, respectively, conducted by a single child neurologist (Dr.
Desnous) and the Alberta Infant Motor Scale (AIMS) assessment
at 4 months and 12 months. These assessments will be scheduled
and conducted during conventional follow-up cardio-pediatric
appointments. During visit 5 (V5), at 24 months, a standardized
neuropsychological assessment will be performed using the Bayley-
IV test.
2.5.1. Prenatal period
The La Timone Enfants University Hospital (Marseille) is the
regional reference center for pediatric cardiac surgery in the
Provence Alpes Côtes d’Azur (PACA) region, south-east of France.
As part of pregnancy monitoring, and in the event of abnormal
cardiac measurements, parents are referred to an ultrasound
physician specializing in fetal cardiac ultrasounds. When the
parents decide to continue the pregnancy, they meet the cardiac
surgeon, who explains the details of the operation to be performed
after birth and present the study to the parents to explain the
objectives, constraints, and procedures.
2.5.2. Post-partum period
After birth, which takes place in a level 3 maternity ward, patients
are admitted to the Pediatric Intensive Care Unit (PICU) at La
Timone Enfants Hospital for clinical stabilization, cardiac
assessment, and emergency procedures. If the parents or legal
representatives were informed of this study in advance and agreed
to participate, they would be asked to sign the consent form with
the child neurologist. In the unlikely event that the parents could
not be informed prior to the beginning of the study, and where
the study’s procedures would be compatible with treatment within the
framework of the patient’s care, consent will be obtained upon the
child’s admission to the PICU but after a 24-hour reflection period.
2.6. Brain MRI
A pre- and postoperative brain MRI will be performed on a
clinical 3 T Vida MRI system (Siemens Medical Systems) using a
64-channel head coil. Protocol will include 2D T1-weighted,
T2-weighted, and diffusion-weighted imaging and 3D isotropic
T1-weighted imaging to highlight preoperative brain injuries, as
well as those that appear or worsen postoperatively. All MRI
sequences use thin cuts (1 mm), and the entire MRI protocol is
adapted for neonates and infants to optimize contrast. The
preoperative brain MRI will be performed just prior to surgery and
the postoperative one within 15 days following cardiac surgery.
The neonate will be comfortably secured in an adapted cocoon
after administration of a normal food ration, without general
anesthesia or injection of a contrast product. The completion time
for the MRI is between 30 and 45 min.
2.7. Genetic workup
A biobank called SEA-CARREG has been established by the
cardiology department, and all recruited patients will have a genome.
2.8. Neurodevelopmental assessment
Neurodevelopmental evaluations will take place between 4 and
24 months to evaluate cognitive and language outcomes. This
neurodevelopmental assessment will be performed by a single child
neurologist (BD) at 4, 12, and 24 months and will be based on the
AIMS and the Bayley-IV.
2.8.1. AIMS - Alberta infant motor scale
The AIMS assessment will be performed at 4 months and 12
months. The AIMS is a standardized tool allowing the neuromotor
assessment of infants from 0 to 18 months old and the
identification of children with abnormal motor development. The
scale consists of 58 items exploring the functional motor skills of
infants in sitting, standing, prone, and supine positions. The
FIGURE 1
24-month monitoring of patients born with CCHD operated on within the
first 2 months of life. CPB, Cardiopulmonary bypass; CHD, Congenital
Heart Disease; MRI, Magnetic Resonance Imaging; AIMS, Alberta Infant
Motor scale; BAYLEY scale fourth edition.
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 04 frontiersin.org

interpretation of the results for each position and the overall score
will be completed using percentile ranks according to the age of
the infant. These assessments will be scheduled and performed
during conventional cardio-pediatric follow-up visits.
2.8.2. Bayley-IV
A standardized neuropsychological assessment using a Bayley-IV
test will be performed at 24 months. The Bayley-IV test is used to
assess children aged 1 to 42 months. This is a standardized scale
(mean = 100, standard deviation = 15), which has demonstrated good
sensitivity in detecting neurodevelopmental disorders in patients with
CCHD. The items are organized according to the level of difficulty.
The scale contains five subscales, three of which (cognition, motor
skills, language) require interaction with the child and will be used for
the analysis. The two other subscales will beassessed through
questionnaires completed by the parents or legal representatives and
relate to the socio-emotional sphere, communication of needs, and
self-regulation for the first part and adaptive behavior,
communication, and autonomy for the second part. These results will
not be retained for analysis. This assessment will be scheduled and
performed during a conventional cardio-pediatric follow-up visit.
2.9. Morbidities
An analysis will be conducted for postoperative morbidities (see
Table 2), including cardiac, hemodynamic, surgical, infectious, and
neurological morbidities. Each of these complications will be
analyzed independently.
Perioperative demographic and clinical data, including
postoperative complications, will be collected retrospectively from
prospectively completed medical files. We are particularly
interested in the following data:
(i) demographic, including gender, education level, and economic
status of the parents;
(ii) preoperative, including whether there was a prenatal diagnosis
of complex CHD, gestational age at birth, birth weight, head
circumference at birth, Apgar score at 5 min, type of complex
CHD, whether a Rashkind procedure was performed, the type
of ventilation and its duration in days, hypotension requiring
treatment, cardiac arrest, and arrhythmia.
(iii) intraoperative, including age and weight at the time of surgery,
hematocrit in the operating room, type of surgery, CPB time in
minutes, selective cerebral perfusion time, and circulatory arrest
time in deep hypothermia in minutes.
(iv) postoperative, including ventilation (non-invasive, mechanical),
duration in days, anesthesia, sedatives and exposure to
antiepileptics, medication names and number of days used,
and total and postoperative length of their stay in days.
3. Statistical analysis
3.1. Analytical strategy
The data analysis will be performed blindly using R -3.4.1 for
Windows.
3.1.1. Sample size
Two previously published studies that reported a significant
correlation between age at surgery and the incidence of WMIs
included 26 and 37 patients, respectively (7,8). Based on the active
file of patients with complex CHD operated on each year in
Cardiac Surgery at the La Timone Enfants Hospital, the total
number of subjects included will be 100. With this number of 100
included patients and according to the values of (i) a 5% bilateral
alpha risk and (ii) 80% statistical power, we estimate the minimum
correlation coefficient between age at surgery and Bayley-IV test
scores as 0.39.
According to the same hypotheses (5% bilateral alpha risk and
80% statistical power), and based on the intended number of
patients recruited for each (Clancy) CHD subtypes, the minimum
correlation coefficient that could be highlighted between age at
surgery and Bayley-IV test scores is:
r= 0.38 for class I, two-ventricle heart without arch obstruction
(n= 50)
r= 0.65 for class II, two-ventricle heart with arch obstruction (n= 15)
r= 0.76 for class III, single ventricle heart without arch obstruction
(n= 10)
r= 0.53 for class IV, single ventricle heart with arch obstruction
(n= 25)”
3.1.2. Main analysis
The analysis of the main objective will be based on the evaluation
of the correlation between the age at surgery (in number of days of life)
and the main analysis criteria selected, namely the
neurodevelopmental outcomes at 24 months assessed using the
scores obtained on the Bayley-IV scale. The analysis will be
conducted for the entire cohort and separately for each type of
complex CHD to define the optimal age for surgery for each
complex CHD type. To do this, Pearson’s correlation coefficient will
be estimated with a 95% confidence interval if the application
conditions are met (otherwise, the non-parametric Spearman’s rank
correlation coefficient will be estimated with a confidence interval of
95%). A ROC curve will be plotted to curve to determine (according
to Youden’s method) the optimal threshold for the age at surgery
that discriminates delayed neurodevelopment / normal
neurodevelopment according to the main criterion, i.e.
neurodevelopment at 24 months according to the Bayley-IV scale.
The first secondary endpoint based on the AIMS scores at 4 months
and 12 months will be analyzed using the same previously described
strategy. The next secondary endpoint based on the clinical
assessment by the child neurologist (neurodevelopment considered
normal vs. abnormal) at 4 months, 12 months, and 24 months will
be analyzed using a comparison test for quantitative data.
AStudent’s t-test will be used if the application conditions are met;
otherwise, the non-parametric Mann-Whitney test will be used.
3.1.3. Secondary analysis
3.1.3.1. White matter injuries
The correlation between the age at surgery (in number of days of life)
and the presence of WMIs (yes vs. no) will be assessed by describing
and comparing age at surgery according to the presence and absence
of WMIs. Non-contrast 3 Tesla MRIs with 3D-T1 weighted and axial
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 05 frontiersin.org

T2-weighted sequences and diffusion-weighted images will be
performed. Qualitative and quantitative analyses of the MRIs will
be done using a lesion score as previously reported in the literature
(3,20,21); specifically, acquired brain injuries will be characterized
as (i) cerebral vascular accidents, (ii) white matter injuries (WMI),
(iii) intraventricular hemorrhages (IVH), or (iv) global hypoxic-
ischemic injury (HI).
The severity of the injuries will be assessed as follows: 0 = normal,
1 = minimal lesion (minimal WMI and IVH grade I-II), 2 = cerebral
vascular accident (any cerebral vascular accident), and 3 = moderate
or severe lesion (moderate or severe WMI, IVH III, or HI).
Finally, we will assess the severity of the WMIs using the
quartered point system (QPS) (21), the volumetric measurement
and the categorical scale described by Miller et al. (20)asnormal
(no lesion), minimum (≤3WMI,each<2mm),moderate(>3
WMI or WMI measuring >2 mm, but <5% of the hemisphere in
question), or severe (>5% of the affected hemisphere). The same
patient may present several brain injuries, which could also be
bilateral. The most severe lesion will be retained for the lesion
score.
A comparison test for quantitative data will be used. A Student’s
t-test will be used if the application conditions are met; the non-
parametric Mann-Whitney test will be used otherwise. The
correlation between the age at surgery (in number of days of life)
and the severity of WMI (four levels of severity, including normal)
will be conducted using a comparison test for quantitative data.
The analysis of variance will be used if the application conditions
are met; otherwise, the non-parametric Kruskal-Wallis test will be
used.
These analyses will be conducted on the data collected from the
MRIs performed in both the preoperative and postoperative phases.
3.1.3.2. Morbidities
The correlation between age at surgery (in number of days of life)
and the occurrence of at least one of the elements of post-op
morbidity (yes vs. no) will be assessed by describing and
comparing age at surgery according to the presence and absence of
a morbidity criterion. A comparison test for quantitative data will
be used. The Student’s t-test will be used if the application
conditions are met; otherwise, the non-parametric Mann-Whitney
test will be used. This analysis will be conducted with
consideration for each element of morbidity in isolation.
3.1.3.3. Length of hospitalization
The correlation between age at surgery (in number of days of life)
and the length of postoperative hospitalization will be assessed by
estimating the Pearson’s correlation coefficient with a 95%
confidence interval if the application conditions are met
(otherwise, the non-parametric Spearman’s correlation coefficient
will be estimated with a 95% confidence interval).
3.1.3.4. Moderating role of demographic and surgical factors
The moderating role of demographic characteristics and pre-, intra-,
and postoperative factors on the correlation between age at surgery
(in number of days of life) and the various prognostic criteria for
neonates with complex CHD indicated above will be analyzed using
multivariate analyses. For quantitative data (neuropsychological
development assessed using Bayley-IV scale scores,
neurodevelopment assessed using AIMS scores, and length of
postoperative hospitalization), a multivariate linear regression model
will be employed. Each of the criteria previously listed will, in
turn, be considered a dependent variable. Age at surgery, the
explanatory variable of interest, will be systematically incorporated
into the models. The main prognostic factors identified in advance
according to an analysis of data from the literature, will also be
incorporated into the models. Adjusted beta coefficients will be
estimated with a 95% confidence interval. Standardized beta
coefficients will also be presented to assess the relative role of each
factor in the prognosis.
For qualitative data (neurodevelopment judged as normal vs.
abnormal in the neuropediatric clinical assessment, the presence
of WMIs, the element of morbidity), a multivariate logistics
regression model will be utilized. Each of the criteria previously
listed will, in turn, be considered a dependent variable. Age at
surgery, the explanatory variable of interest, will be systematically
incorporated into the models. The main prognostic factors
identified in advance according to an analysis of data from the
literature will also be incorporated into the models. Adjusted
odds ratios will be estimated with a 95% confidence interval. In
order to consider the small sample size, the Firth correction may
be applied.
4. Discussion
The correlation between surgical timing and long-term
neurodevelopmental outcomes in children with complex CHD has
not been fully studied. Moreover, currently, there is no consensus
regarding the optimal surgical timing for neonates with complex
CHD. Our study will allow us to define the optimal time-window
within the neonatal period to perform cardiac surgery to reduce
postoperative morbidity (i.e., postoperative complications) and
optimize the neurodevelopment of infants with complex CHD. We
hope our work will facilitate the evaluation of the risk/benefit ratio
of the chosen therapeutic strategy.
A better understanding of the mechanisms underlying
neurodevelopmental disorders in this population will allow the
identification of other modifiable risk factors and the development
of new prevention and screening strategies to improve the
neurodevelopment and overall health of children and adults.
An added challenge for this field is the recruitment of
patients with various types of CHD to define a general optimal
age for cardiac surgery and an optimal age for each CHD type
and not only for TGA and HLHS, which have been studied in
more depth.
Moreover, the patients in our study will receive a
neurodevelopmental follow-up at 4 months, 12 months, and 24
months. They will benefit from early screening for
neurodevelopmental disorders with an orientation toward adapted
rehabilitation structures, thereby supporting improvements in their
overall neurodevelopmental outcome. The aim is to extend this
treatment process to all patients with complex CHD who undergo
surgery in their first weeks of life. This project, initially internal in
hospitals in Marseille, could be extended with the collaboration of
pediatric cardiology and neurology teams across France.
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 06 frontiersin.org

5. Limitation
As Complex CHD are characterized by their heterogeneity, the
monocentric nature of our protocol study may be considered a
limitation, as well as the relatively low number of participants to
be recruited (n= 100). This preliminary work may allow us to
define an optimal surgery timing only for those CHDs that recruit
frequently (e.g., TGA, aortic arch hypoplasia). The extension of
this project to other pediatric cardiology and neurology teams in
France will enable more reliable results to be obtained.
6. Conclusion
We will conduct a preliminary observational study to determine
the most appropriate surgical timing for each type of complex CHD.
This project aims to determine whether an earlier surgery would be a
beneficial neuroprotective strategy to reduce brain injuries and
postoperative morbidities and improve neurodevelopmental
outcomes. This research should be useful in developing guidelines
for optimal surgical timing for complex CHDs in the near future.
Based on the balance between benefit and risk, these guidelines
will make it easier to determine the optimal surgical timing for a
newborn or infant with a complex CHD. Secondly we will conduct
an interventional study to reduc the age at surgery.
Ethics statement
A copy of the signed informed consent is provided to all
participants. Our local ethics committee approved this protocol on
the 2th of July 2020 (Reference 2020-041), and it has been
registered on ClinicalTrials.gov as NCT04733378.
Author contributions
ML contributed to the protocol development, methodology,
literature review, redaction, and revision of the manuscript. BT
contributed to the protocol development, methodology, literature
review, redaction, and revision of the manuscript. NR contributed
to the protocol development, methodology, literature review,
redaction, and revision of the manuscript. KG contributed to the
literature review, redaction and revision of the manuscript. SL
contributed to the redaction, and revision of the manuscript.
SA contributed to the redaction, and revision of the manuscript.
DS contributed to the redaction, and revision of the
manuscript. CA contributed to the redaction, and revision of the
manuscript. FE contributed to the redaction, and revision of
the manuscript. FP contributed to the redaction, and revision of
the manuscript. MP contributed to the redaction, and revision
of the manuscript. JB contributed to the redaction, and revision of
the manuscript. GC contributed to the redaction, and revision of
the manuscript. CW contributed to the redaction, and revision
of the manuscript. CG contributed to the redaction, and revision
of the manuscript. KG contributed to the literature review,
redaction and revision of the manuscript. FM contributed to the
redaction, and revision of the manuscript. VF contributed to
the redaction, and revision of the manuscript. CO contributed to
the revision of the manuscript. MM contributed to the
methodology, redaction, and revision of the manuscript. CF
contributed to the methodology, redaction, and revision of the
manuscript. BD contributed to the conceptualization and design of
the study, protocol development, methodology, literature review,
redaction, and revision of the manuscript. All authors contributed
to the article and approved the submitted version.
Funding
AORC Jeune Chercheur to BD, AP-HM
Conflict of interest
The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be
construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
claim that may be made by its manufacturer, is not guaranteed or
endorsed by the publisher.
References
1. Hoffman JI, Kaplan S. The incidence of congenital heart disease. J Am Coll Cardiol.
(2002) 39(12):1890–900. doi: 10.1016/s0735-1097(02)01886-7
2. Rollins CK, Newburger JW. Correction of D-transposition of the great arteries
sooner rather than later. Circulation. (2019) 139(24):2739–41. doi: 10.1161/
CIRCULATIONAHA.119.040012
3. Dimitropoulos A, McQuillen PS, Sethi V, Moosa A, Chau V, Xu D, et al. Brain
injury and development in newborns with critical congenital heart disease. Neurology.
(2013) 81(3):241–8. doi: 10.1212/WNL.0b013e31829bfdcf
4. Andropoulos DB, Hunter JV, Nelson DP, Stayer SA, Stark AR, McKenzie ED, et al..
Brain immaturity is associated with brain injury before and after neonatal cardiac
surgery with high-flow bypass and cerebral oxygenation monitoring. J Thorac
Cardiovasc Surg (2010) 139(3):543–56. doi: 10.1016/j.jtcvs.2009.08.022
5. Beca J, Gunn JK, Coleman L, Hope A, Reed PW, Hunt RW, et al. New white matter
brain injury after infant heart surgery is associated with diagnostic group and the use of
circulatory arrest. Circulation. (2013) 127(9):971–9. doi: 10.1161/CIRCULATIONAHA.
112.001089
6. Ni Bhroin M, Abo Seada S, Bonthrone AF, Kelly CJ, Christiaens D, Schuh A, et al.
Reduced structural connectivity in cortico-striatal-thalamic network in neonates
with congenital heart disease. Neuroimage Clin. (2020) 28:102423. doi: 10.1016/j.nicl.2020.
102423
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 07 frontiersin.org

7. Lynch JM, Buckley EM, Schwab PJ, McCarthy AL, Winters ME, Busch DR, et al.
Time to surgery and preoperative cerebral hemodynamics predict postoperative white
matter injury in neonates with hypoplastic left heart syndrome. J Thorac Cardiovasc
Surg. (2014) 148(5):2181–8. doi: 10.1016/j.jtcvs.2014.05.081
8. Petit CJ, Rome JJ, Wernovsky G, Mason SE, Shera DM, Nicolson SC, et al.
Preoperative brain injury in transposition of the great arteries is associated with
oxygenation and time to surgery, not balloon atrial septostomy. Circulation. (2009)
119(5):709–16. doi: 10.1161/CIRCULATIONAHA.107.760819
9. Peyvandi S, Chau V, Guo T, Xu D, Glass HC, Synnes A, et al. Neonatal brain injury
and timing of neurodevelopmental assessment in patients with congenital heart disease.
J Am Coll Cardiol. (2018) 71(18):1986–96. doi: 10.1016/j.jacc.2018.02.068
10. Claessens NHP, Algra SO, Ouwehand TL, Jansen NJG, Schappin R, Haas F, et al.
Perioperative neonatal brain injury is associated with worse school-age
neurodevelopment in children with critical congenital heart disease. Dev Med Child
Neurol. (2018) 60(10):1052–8. doi: 10.1111/dmcn.13747
11. Andropoulos DB, Easley RB, Brady K, McKenzie ED, Heinle JS, Dickerson HA, et al.
Changing expectations for neurological outcomes after the neonatal arterial switch operation.
Ann Thorac Surg. (2012) 94(4):1250–5. discussion 5-6. doi: 10.1016/j.athoracsur.2012.04.050
12. Hoskote A. Neurodevelopmental outcomes in children with congenital heart
disease: the role of perioperative neuroimaging. Dev Med Child Neurol. (2018) 60
(10):974–5. doi: 10.1111/dmcn.13781
13. Andropoulos DB, Ahmad HB, Haq T, Brady K, Stayer SA, Meador MR, et al. The
association between brain injury, perioperative anesthetic exposure, and 12-month
neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort
study. Paediatr Anaesth. (2014) 24(3):266–74. doi: 10.1111/pan.12350
14. Mahle WT, Tavani F, Zimmerman RA, Nicolson SC, Galli KK, Gaynor JW, et al.
An mri study of neurological injury before and after congenital heart surgery.
Circulation. (2002) 106(12 Suppl 1):I109–14. doi: 10.1161/CIRCULATIONAHA.113.
003312
15. Anderson BR, Ciarleglio AJ, Hayes DA, Quaegebeur JM, Vincent JA, Bacha EA.
Earlier arterial switch operation improves outcomes and reduces costs for neonates
with transposition of the great arteries. J Am Coll Cardiol. (2014) 63(5):481–7. doi: 10.
1016/j.jacc.2013.08.1645
16. Anderson BR, Ciarleglio AJ, Salavitabar A, Torres A, Bacha EA. Earlier stage 1
palliation is associated with better clinical outcomes and lower costs for neonates with
hypoplastic left heart syndrome. J Thorac Cardiovasc Surg. (2015) 149(1):205–10 e1.
doi: 10.1016/j.jtcvs.2014.07.094
17. Lim JM, Porayette P, Marini D, Chau V, Au-Young SH, Saini A, et al. Associations
between age at arterial switch operation, brain growth, and development in infants with
transposition of the great arteries. Circulation. (2019) 139(24):2728–38. doi: 10.1161/
CIRCULATIONAHA.118.037495
18. Bayley N, Aylward GP. Bayley scales of infant and toddler development (4th ed.)
technical manual. Bloomington, MN: NCS Pearson (2019).
19. Clancy RR, McGaurn SA, Wernovsky G, Spray TL, Norwood WI, Jacobs ML, et al.
Preoperative risk-of-death prediction model in heart surgery with deep hypothermic
circulatory arrest in the neonate. J Thorac Cardiovasc Surg. (2000) 119(2):347–57.
doi: 10.1016/S0022- 5223(00)70191-7
20. Miller SP, Ferriero DM, Leo nard C, Piecuch R, Glidden DV, Partridge JC, et al.
Early brain injury in pre mature n ewborns detec ted wit h magnetic reso nance imaging
is associated with adverse early neurodevelopmental outcome. JPediatr. (2005) 147
(5):609–16. doi: 10.1016/j.jpeds.2005.06.033
21. McCarthy AL, Winters ME, Busch DR, Gonzalez-Giraldo E, Ko TS, Lynch JM,
et al. Scoring system for periventricular leukomalacia in infants with congenital heart
disease. Pediatr Res. (2015) 78(3):304–9. doi: 10.1038/pr.2015.99
Lenoir et al. 10.3389/fped.2023.1003585
Frontiers in Pediatrics 08 frontiersin.org