Transposition of the Great Arteries: Prenatal Anatomical and Hemodynamic Findings Associated With Perinatal Outcomes
Phase: NA
Conditions: TGA - Transposition of Great Arteries
Sponsor: The Hospital for Sick Children

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Title: 
Transposition of the Great Arteries: Prenatal Anatomical and 
Hemodynamic Findings associated with Perinatal Outcomes 
Short Title 
Fetal TGA 
Sponsor  
Dr. Edgar Jaeggi/The Hospital for Sick Children 
Protocol Date: 
20 November 2018  
 
 
 
 
Site Principal Investigator 
Edgar Jaeggi, MD, FRCP(C)  
Division of Pediatric Cardiology 
Fetal Cardiac Program  
Labatt Family Heart Centre 
The Hospital for Sick Children   
555 University Avenue 
Toronto, ON, M5G1X8 
Phone: (416) 813-7466  
Fax: (416) 813-7547 
email: edgar.jaeggi@sickkids.ca 
 
The document contains confidential and/or proprietary information. Review, disclosure 
and distribution is restricted and requires written approval from: Dr Edgar Jaeggi and Dr 
Mike Seed 
 
 
 
 
 
 
 
 

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Table of Contents 
 
1 
INTRODUCTION                                                                                                                                                                          P5 
2 
BACKGROUND INFORMATION AND RATIONALE  
                                                                                     P5 
2.1 CLINICAL RELEVANCE OF TGA 
 
2.2 PRENATAL CARDIAC IMAGING 
2.3 MATERNAL HYPEROXYGENATION 
2.4  STUDY RATIONALE 
2.5   POTENTIAL BENEFITS AND RISKS OF STUDY PARTICIPATION 
3 
COMPLIANCE STATEMENT                                                                                                                                                    P8 
4 
STUDY OBJECTIVES                                                                                                                                                                 P8 
4.1 PRIMARY OBJECTIVE  
 
4.2 SECONDARY OBJECTIVES  
4.3    STUDY ENDPOINTS  
 
5      INVESTIGATIONAL PLANS                                                                                                                                                      P8 
5.1 GENERAL SCHEMA OF STUDY DESIGN 
 
5.2 PATIENT NUMBERS AND STUDY DURATION 
 
5.3 ELIGIBILITY CRITERIA 
6 
STUDY PROCEDURES                                                   
P9 
6.1   STUDY PROCEDURES 
6.1.1 Consent Process 
6.1.2 Fetal Echocardiography 
 
6.1.3 Fetal MRI 
6.1.4 Neonatal Data 
6.2    DATA SOURCES 
6.3 COLLECTED PATIENT DATA  
A) PRENATAL   
Echocardiography 
Fetal MRI 
Patient Safety During MH 
B) POSTNATAL 
 
7 
ASSESSMENTS OF ADVERSE EVENTS                                                                                                                              P14 
8      STATISTICS                                                                                                                                                                                 P16 
9      STUDY ADMINISTRATION 
                                                                                                                                         P17 
9.1   DATA COLLECTION, MANAGEMENT AND CONFIDENTIALITY 
9.2    DATA & SAFETY MONITORING BOARD (DSMB) 
9.3    REGULATORY AND ETHICAL CONSIDERATIONS  
  9.3.1  Informed Consent 
9.3.2. Study Withdrawal 
9.3.3 Reporting of Adverse Events 
 
10 PUBLICATION 
                                                                                                                                                           P18 
11 REFERENCES 
                                                                                                                                                           P19 
 
 
 
 
 
 
 
 

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ABBREVIATIONS AND DEFINITIONS OF TERMS; ALPHABETICAL ORDER 
AAo 
 
Ascending aorta 
ASO 
 
Arterial switch operation 
BAS 
 
Balloon atrial septostomy 
CO 
 
Cardiac output 
DA 
 
Ductus arteriosus 
DAo 
 
Descending aorta 
FO 
 
Foramen ovale 
IAS 
 
Intact atrial septum 
IVC 
 
Inferior vena cava 
LA 
 
Left atrium 
LV 
 
Left ventricle 
MCA 
 
Middle cerebral artery 
MH 
 
Maternal hyperoxygenation 
PA 
 
Pulmonary artery 
PGE 
 
Prostaglandin 
PI 
 
Pulsatility index (peak systolic velocity – end-diastolic velocity / mean velocity) 
PPHN 
 
Persistent pulmonary hypertension of the newborn 
PV 
 
Pulmonary vein 
RAS 
 
Restrictive atrial septum 
RV 
 
Right ventricle 
SVC 
 
Superior vena cava 
TGA/IVS 
 
Transposition of the great arteries with intact ventricular septum 
UV 
 
Umbilical vein/venous 
VSD 
 
Ventricular septal defect 
VTI 
 
Velocity time integral 
 
 

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PROTOCOL SUMMARY 
Title: 
Transposition of the Great Arteries: Prenatal Anatomical and 
Hemodynamic Findings associated with Perinatal Outcomes 
Short Title 
Fetal TGA  
Sponsor 
Dr. Edgar Jaeggi/The Hospital for Sick Children 
Principal Investigator 
Edgar Jaeggi 
Primary Objective 
Determine the association between response to MH and neonatal 
outcome 
Secondary Objectives 
Determine the change of cerebral perfusion for acute MH 
Study Population 
Pregnant women with a fetal diagnosis of TGA 
Study Design 
Prospective pilot study 
Sample Size 
N = 50  
End points 
Fetal demise or neonatal death or neonatal discharge 
 
Study Drug/ Intervention 
Description 
 
Transient maternal oxygen administration during 
echocardiographic and MRI imaging 
 
1. 
INTRODUCTION 
In transposition of the great arteries (TGA), a condition that affects ~3/10,000 live-births, the 
aorta arises from the morphological right ventricle (RV) and the pulmonary artery from the left 
ventricle (LV) while the atrio-ventricular connections are concordant. The inverted great arterial 
arrangement can be anatomically corrected by an arterial switch operation (ASO) in early 
infancy with low perioperative mortality and excellent long-term results. In the prenatal 
circulation with the placenta as the sole source of fetal oxygenation, TGA is usually well 
tolerated. With the transition to the postnatal circulation at birth, the lesion may become 
immediately life-threatening as the RV pumps desaturated systemic venous blood back into the 
aorta while oxygenated blood from the lungs is forwarded by the left heart back into the 
pulmonary artery. The neonate with TGA will become profoundly hypoxemic and acidotic 
shortly after birth unless there sufficient shunting of oxygenated pulmonary venous blood into 
the right heart and aorta. TGA is now predominantly detected before birth but reliable prenatal 
prediction of the neonatal hemodynamics and risks by conventional fetal echocardiography has 
remained very challenging. On the other hand, maternal hyper-oxygenation (MH) to increase the 
fetal O2 saturation may be used to mimic the drastic events that occur during the normal 
transition from fetal circulation to the postnatal physiology that includes dilation of the 

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pulmonary vasculature, increase in pulmonary arterial blood flow and left atrial pre-load, 
potentially affecting shunting of blood across the atrial septum. In this prospective pilot study we 
will determine whether MH is a useful diagnostic test to separate fetuses with insufficient 
intracardiac shunting from those with adequate shunting early after delivery.  
 
2.  
BACKGROUND & STUDY RATIONALE 
2.1 
Clinical relevance of TGA 
TGA is the predominant cardiac cause of neonatal cyanosis and affects 5-7% of newborns with 
congenital heart disease (1). The condition is usually repairable with a neonatal ASO, which 
carries a low surgical mortality risk of 2-5% (2, 3). Indeed, morbidity and mortality is nowadays 
greater in the preoperative period. Many preoperative problems are secondary to a restrictive or 
intact atrial septal (RAS) communication, and/or ductal constriction, resulting in inadequate 
shunting of oxygenated blood to the right heart, systemic hypoxemia and rapid progression to 
acidosis, neurological injury and shock (4-7, 9). Yet even with an in-utero patent atrial septum, a 
newborn may become critically ill shortly after birth once the FO closes. Immediate neonatal 
balloon atrial septostomy (BAS) becomes a life-saving procedure in this situation. Of neonatal 
survivors, persistent pulmonary hypertension of newborn (PPHN) is another possible association 
with a poor postnatal outcome, affecting ~1-3% of children with TGA (6, 8).   
2.2 
Prenatal Cardiac Imaging 
Most cases of TGA in Ontario are nowadays detected before birth and referred to the Fetal 
Cardiac Program at the Hospital for Sick Children. All patients undergo repeated assessment 
before birth including a final fetal echocardiogram and a fetal MRI before delivery for prediction 
of the neonatal risk of severe cyanosis. This is standard care and not research-related. 
Better prediction of the neonatal hemodynamics before birth would dramatically facilitate the 
perinatal care of babies with TGA but is not reliably obtained by conventional imaging. 
The prenatal risk assessment of TGA is currently based on the two-dimensional and Doppler 
echocardiographic evaluation of the heart and in particular of possible shunts across the atrial 
septum, the ventricular septum, and the arterial duct. In the fetal circulation, the foramen ovale 
(FO) is an important provider of oxygenated umbilical blood from the placenta to the left heart. 
The crescent shaped FO, located in the central portion of the secundum atrial septum, 
progressively increases in width up to 6 mm at term. The thin, mobile septum primum is 
positioned on the left side of the atrial septum and functions as a flap valve of the FO. During 
most of the cardiac cycle, it is pushed into the left atrium (LA) by the steady stream of blood that 
enters the FO. The fetal echocardiographic evaluation of the atrial septum mainly relies on the 
size of the FO, the position, mobility and shape of the FO flap and the documentation of right-
left shunting across the foramen ovale. The prenatal evaluation of the arterial duct includes the 
echocardiographic assessment of its diameter and documentation of ductal patency and flow 
direction by color and pulse wave Doppler imaging.  
Fetal MRI offers a versatile set of additional tools to assess the fetal physiology and is routinely 
offered to parents at SickKids to examine the hemodynamic alterations of cardiac lesions and the 

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impact on the perfusion of organs such as the brain (6–8). Our center has significant experience 
with the clinical-research applications of MRI in the human fetus (9). This includes the 
application of fetal MRI in combination with MH (REB No 1000048468).  
Importantly, MRI and echocardiographic imaging pose no known risks to the fetus and the 
mother.   
2.3   Maternal Hyperoxygenation 
This study will examine whether MH is useful as a diagnostic test to more accurately detect TGA 
patients with poor vs. good neonatal intra-cardiac mixing of blood, based on the in-utero 
response to oxygen exposure. Acute maternal oxygen administration will transiently increase the 
fetal oxygen levels to those reached at birth with spontaneous breathing, thus simulating 
conditions that will naturally occur at the time of birth. Echocardiogram and MRI will be used to 
examine the effects on the fetal circulation. This is the research-component of this study.   
It has been discovered 80 years ago that maternal inhalation of oxygen during labour increases 
the oxygen content in the umbilical cord. In the sheep model, e.g., maternal administration of 
100% oxygen increases the fetal arterial pO2 from 20-25 mmHg to 30-35 mmHg and the 
arterial O2 saturation from 65% to 80%. Similarly, MH increased the UV O2 saturation from 75% 
to 95% and UV pO2 from 32-35 mmHg to 40-50 mmHg (10).  
The effects of MH were also studied in the human fetus. Brief maternal administration of 65-
70% O2 via a face mask during the last trimester, which is what will be used in our study, led to a 
significant increase in UV O2 saturation in the normal fetus followed by pulmonary 
vasodilatation. If maternal O2 was administered over a prolonged period in late gestation, the 
effect on the pulmonary vasculature disappeared within a few hours.  
Limited information is available about the most appropriate amount of O2 to be used for MH. 
Experimental data from animal and human subjects showed that increasing FiO2 from room air 
to 40% resulted in the greatest increase in fetal PaO2, and maximal effects on the fetal circulation. 
Furthermore, inhaled O2 up to 15L/min is well tolerated via a simple face mask, which results in 
a FiO2 of ~40 to 50%. While no adverse effects of chronic MH were reported when used to treat 
fetal growth restriction (14-16), a Cochrane review (11) of experimental animal data raised the 
possibility that chronic maternal hyperoxygenation could reduce uterine arterial blood flow, and 
thus recommended further investigations if chronic maternal O2 was to be used for this 
indication. This is not expected with acute hyperoxygenation. Effects on the arterial duct are also 
unlikely to occur due to the short duration of O2 supplementation: it usually takes at least 1-2 
days for spontaneous ductal closure at birth. Ductal constriction was not observed in any of the 
previous studies using MH (12). 
 
In this study, we will examine the added diagnostic value of acute MH in predicting neonatal 
maladaptation due to poor intracardiac mixing of oxygenated blood. MH (70% of O2 by face 
mask) will be administered in late gestation at two separate occasions, during echocardiography 
and MRI. The rate and duration of MH (10 to 15L/min by mask for up to 30-45 minutes/test) is 
considered to be safe to the mother and her fetus. We know that if acute MH is used in the 
normal 3rd trimester fetus with a patent FO, this leads to pulmonary vasodilation, a 30-50% 
increase in pulmonary blood flow and in left atrial load, as well as a reduction in DA flow by 

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fetal MRI (13). Data on the acute effects of MH on fetal TGA are limited and no specific studies 
have been performed to study the response of the pulmonary vasculature to supplementary O2. 
MRI data obtained without the use of MH in 4 fetuses with TGA/IVS and suspected RAS at 
SickKids (14) demonstrated significantly reduced flow across the FO, increased combined 
cardiac output, and increased flow in the ascending (AAo) and descending (DAo) aorta, UV, and 
aorto-pulmonary collaterals when compared with normal fetuses. The fetus with the lowest FO 
shunting and highest aorto-pulmonary collateral flow died from PPHN after birth.  
2.4  
Study Rationale 
To examine the baseline fetal hemodynamics as well as the response to acute MH as an added 
diagnostic test, we will combine various fetal echocardiographic and MR imaging tools. The 
prenatal findings will then be compared to the neonatal presentation.  
We postulate that conditions that predispose newborns to acute neonatal compromise will be 
detectable and distinguishable prior to birth by echocardiography, MRI, or by combining the 
findings of both exams. We expect to encounter the following 4 clinical scenarios:  
1) TGA/IVS with unrestricted atrial shunting before and after birth: we expect fetal baseline 
differences in LV/RV O2 content and DAo/AAo O2 content related to unrestricted right-left 
atrial shunting. MH is expected to further increase the differences in LV/RV O2 content and 
DAo/AAo O2 content, which leads to an increase pulmonary blood flow, LV preload and LV 
stroke volume due to O2-mediated vasodilation of the pulmonary vasculature. As a 
confirmation of pulmonary vaso-reactivity to O2, the branch PA pulsatility index will 
decrease by ≥10% and this will coincide with lower peak systolic flow and reversal of end-
diastolic flow across the DA.  
2) TGA/IVS with in-utero RAS:  In the absence of intracardiac shunting, RV/LV and DAo/AAo 
O2 content will be equal at baseline and with MH and no significant effect on pulmonary 
flow will be observed.  
3) TGA/IVS with postnatal RAS: RV/LV and DAo/AAo O2 content will differ at baseline when 
the FO is still patent. With MH-induced functional closure of the FO by the septal flap, the 
RV load and AAo O2 content will preferentially increase to reach an equal or higher oxygen 
content and saturation when compared with the LV, MPA, DA and DAo.  
4) TGA with PPHN: supplementary maternal O2 will not affect fetal pulmonary blood flow and 
PA pulsatility.  
2.5 
Potential Benefits and Risks of Study Participation 
The potential implications of this study are clinically important. Not only would it help with the 
parental counselling and facilitate the perinatal care of future fetuses with TGA but for TGA/IVS 
with severe RAS it may also offer the possibility of a pre-delivery BAS or a planned delivery 
with ECMO stand-by to prevent hypoxemic organ damage (18). 
The risk to the mother will be the potential of some discomfort related to the oxygen 
administration and the added time of the exams. We may also detect findings that have not been 
detected previously by echocardiography, which will then have to be disclosed to the family and 
may cause additional parental concerns.  
 

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3.  
COMPLIANCE STATEMENT 
This study will be conducted in full accordance with all applicable Hospital for Sick Children 
research policies and procedures, International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and all applicable regulations and the PHIPA Privacy Rule. Any episode of 
noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent, 
and will report unanticipated problems in accordance with Hospital for Sick Children REB 
policies and procedures and applicable regulatory requirements. Collection, recording, and 
reporting of data will be accurate and will ensure the privacy, health, and welfare of research 
subjects during and after the study. The protocol, informed consent form(s), recruitment 
materials, and all participant materials will be submitted to the Research Ethics Board (REB) for 
review and approval. 
 
4. 
STUDY OBJECTIVES 
The purpose of the study is to detect prenatal findings that are associated with early postnatal 
morbidity and mortality.  
4.1 Primary Objective  
The primary objective is to examine and characterize the response, or lack thereof, to acute MH 
as a diagnostic test on intracardiac/ductal shunting and pulmonary blood flow among fetuses 
with TGA, and to clarify its associations with measures of neonatal outcomes.  
 
4.2. Secondary Objectives 
A secondary objective will focus on the acute effects of MH on the cerebral perfusion. 
  
4.3 Study Endpoints 
Study endpoints are any of the following outcomes: survival to discharge from Hospital as a 
primary outcome. A secondary outcome will be any evidence of perinatal compromise as defined 
in the protocol. This will be associated with the fetal response to oxygen. For cases with PPHT 
with RV pressure >50% of the systemic pressure at the time of discharge, the outcome to 1 year 
of life will be ascertained.  
 
5.        INVESTIGATIONAL PLAN 
5.1  Study Design 
This is a prospective single centre study on the association between prenatal cardiovascular 
findings, the fetal response to MH and neonatal morbidity and mortality. 
5.2 
Patient Numbers and Study Duration 
Recruitment will be from the time of REB approval of this study to the time 50 patients have 
successfully completed the study. We follow approximately 30 women per year with a fetal 

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diagnosis of simple TGA, defined as TGA either with an intact ventricular septum or with 
ventricular septal defect(s) (VSD). The rate of pregnancy termination is low (<5%) as most 
affected babies do not carry a risk of significant non-cardiac disorders. Parents of a child with 
congenital heart disease are also highly motivated in participating in research that might help 
their or other children with the same condition and we anticipate that at least 80% of eligible 
women will be willing to participate in this research. Based on these assumptions, we anticipate 
being able to successfully recruit 50 participants within ≤ 2.5 years. 
5.3 
Eligibility Criteria  
Inclusion Criteria: 
1) Pregnant mothers ≥18 years of age  
2) Fetal diagnosis of simple TGA and intention of active treatment after birth 
3) Written maternal informed consent 
Exclusion criteria: 
1) Termination of pregnancy 
2) Complex TGA (e.g. Taussig-Bing anomaly or moderate-severe outflow tract obstruction, 
fetal arrhythmia such as frequent premature atrial beats, abnormal baseline heart rate 
(<110 bpm; > 160 bpm) in the third trimester) 
3) Major non-cardiac lesions 
4) Significant maternal co-morbidities that precludes a fetal MRI (e.g. significant obesity, 
claustrophobia) 
 
6.        STUDY PROCEDURES 
6.1 
Study Procedures 
Antenatal diagnosis of TGA followed by a referral to the Fetal Cardiac Program at SickKids is 
typically made during mid-gestation. Fetal echocardiography including a late-gestational MRI is 
routinely used in the assessment of all prenatally diagnosed TGA. 
 
The initial echocardiogram allows differentiating between simple vs complex form of TGA and 
determining whether or not a patient fulfills eligibility criteria to potentially participate in the 
study. The physician will explain the possibility of MH in the last trimester that as a diagnostic 
test may help with the management of future patients with the same condition. If the patient is 
interested in hearing more details about MH, more information will be provided to help families 
decide whether they would like to participate in the study. This will allow coordination of 
echocardiograms and MRI studies on the same day, whenever possible.   
  
Mothers with fetal TGA are routinely seen at SickKids for a final fetal echocardiogram in late 
gestation (≥34 gestational weeks). The final exam includes detailed re-evaluation of all cardiac 
structures including blood flows across the atrial septum, AV and semilunar valves, arterial duct, 
pulmonary and cerebral blood flows, among other. Following the exam, perinatal management 
recommendations are made and discussed with the family. This typically includes the 

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recommendation of 1) delivery at Mount Sinai Hospital, 2) initiation of IV prostaglandin at birth, 
and 3) referral to SickKids critical cardiac care unit for early neonatal care that may include 
preoperative BAS. Whether a mother elects to participate or not in this study, the baseline 
echocardiogram and perinatal management will not be affected by the maternal decision. 
   
The following are study-related additional procedures, if a mother who fulfils all inclusion and 
none of the exclusion criteria consents in writing to participate in this study: 
1) A fetal echocardiogram during acute MH  
2) A fetal MRI during acute MH  
 
6.1.1 Consent Process 
The study may be explained by the fetal cardiology team prior to the last prenatal encounter.  
Maternal consent will be obtained by a person (research coordinator or another physician) who 
has no direct involvement in the care of this patient at the second last (generally 28-30 weeks) 
visit or at the time of the last fetal exam (≥34 weeks). Moreover, it will be explained that she can 
drop out of the study at any time. Once enrolled, participants (mother and child) will be assigned 
individual study numbers to allow de-identified data entry in a password protected Excel 
database that will be securely stored on the SickKids server and be accessible to the research 
team only. 
 
 
6.1.2 Fetal Echocardiography 
All fetal echocardiograms will be performed with standard GE Voluson E-10 or Philips IU 22 
ultrasound systems within the Echo Lab facility or the Cardiac Diagnostics & Interventions Unit 
(CDIU) at SickKids. Fetal echocardiography poses no known risks to the mother and her fetus. 
At the final visit, the mother will initially undergo a baseline fetal echocardiogram that will 
include the assessment of left and right ventricular outflow tract (peak flow, velocity time 
integral (VTI), heart rate, aortic and pulmonary valve diameters), the arterial duct (systolic and 
end-diastolic flow, forward/reverse flow ratio, VTI, diameter), branch pulmonary artery (peak 
flow, pulsatility index calculated as peak systolic velocity – end-diastolic velocity/mean 
velocity), pulmonary veins (VTI), atrial septum (FO diameter, atrial shunt direction and 
velocities, atrial septal excursion), mid cerebral artery (peak, VTI), as well as ventricular 
dimensions (diameter in 4CV; volumes by 3/4D). These findings will be digitally recorded and 
all measurements will be made offline by the responsible cardiologist to abbreviate the duration 
of the exam. The percent changes in flow VTIs, percent changes in flow PIs and DA 
forward/reverse flow ratios will be calculated using the echocardiography data. 
Immediately following the baseline echocardiogram, maternal oxygen will be administered in the 
same room via a sterile face mask to reach about 65-70% of oxygen and delivered at a rate of 10 
to 15L/minute. After a 5 minute-period to allow fetal steady-state oxygenation, the same 
echocardiographic variables as above will be recorded during continuous maternal O2 
supplementation, which is expected to take maximally 30 minutes or less. During the exam, the 
fetal wellbeing will be continuously monitored by fetal echocardiography, which allows us to 
continuously see the baby’s movements and heart function. Oxygen supplementation will be 

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stopped once the above imaging variables have been obtained or after a maximum of 30 minutes 
(5 minutes initiation + 25 minutes echocardiogram) if the test cannot be completed within this 
time frame. No further research related measurements will be obtained once the MH has 
terminated. 
6.1.3    Fetal MRI 
We routinely perform late-gestational MRI for fetal TGA before birth to examine fetal 
hemodynamics and the brain. Fetal MRI poses no known risks to the mother and her fetus. 
Baseline and MH MRI will be performed as usual with a clinical 1.5T MR system in the CDIU. 
No sedation or invasive techniques will be required to perform MRIs on pregnant women. The 
MRI study will take a maximum of 90 minutes including MH study, which is expected to take 
maximally 45 minutes. The subjects will be fitted with their usual supply of oxygen via a face 
mask during MRI. The same amount of O2 at the same flow rate will be administered as 
described above.  
As with all our fetal MRI studies, a standard multichannel body surface coil will be placed over 
the maternal abdomen and imaging performed for a maximum of one hour.  MR flow 
assessments will be acquired according to our previously published technique to examine the 
distribution of blood flow across the fetal circulation (15).  The PC MR acquisitions will be 
analyzed using a commercial software (Q-flow, Medis) and the oximetry measurements will be 
analyzed using a region of interest placed over the central 50% of the vessel diameter on the T2 
map, according to our previously published techniques (15,16).  The imaging protocol has been 
detailed in previous publications and includes T1 and T2 weighted imaging, diffusion tensor 
imaging, MR spectroscopy and brain volumetry (15,17). MR oximetry will be recorded in the 
ascending aorta (AAo), superior vena cava (SVC), descending thoracic aorta (DAo), umbilical 
vein (UV) and main pulmonary artery (PA).  Oxygen content at baseline and during MH will be 
measured offline at the level of the LV/MPA, RV/AAo and DAo. Blood flow quantifications 
(baseline and MH; cine-phase contrast) will be made in the AAo, DAo, main and branch PAs, 
SVC, IVC, UV and DA. Other variables will include estimated hematocrit (HCT), fluximetry, 
brain volumetry (baseline; 3D steady state), cDO2 and cVO2 (baseline and MH; T2 mapping) to 
measure oxygen consumption. Oxygen supplementation will be stopped once the above imaging 
variables have been obtained or after a maximum of 45 minutes (5 minutes initiation + 40 
minutes MRI) if the test cannot be completed within this time frame. No further research related 
measurements will be obtained once the MH has terminated. 
The MRI data will be used to calculate right ventricle cardiac output, left ventricle cardiac 
output, combined ventricle output, pulmonary artery flow, aorta-pulmonary collateral flow, 
foramen ovale flow and aortic isthmic flow. 
6.1.4   Neonatal Data 
Newborns with antenatally diagnosed TGA are routinely transferred to the Critical Care Unit 
immediately after their delivery for the preoperative management. Unless a VSD is large enough 
to allow discharge home with adequate oxygen saturations and to delay surgery to later in 
infancy, a neonatal ASO is the treatment of choice and mainly completed during the first week of 
life. Early neonatal preoperative procedures may include BAS and/or the use of IV prostaglandin 
to improve the oxygen saturation. Less commonly, intubation, ventilation or even ECMO may 
also be required prior to the surgical intervention. As measure of patient morbidity, a composite 

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score of 10 variables will be used, assigning a value of 1 for each event that occurred between 
birth to hospital discharge or in-hospital death respectively: 1) respiratory distress syndrome 
requiring surfactant; 2) cardiopulmonary resuscitation requiring chest compressions; 3) cerebral 
vascular injury (intra-ventricular or -parenchymal hemorrhage, ischemic stroke); 4) necrotizing 
enterocolitis; 5) need of ECMO; 6) infections associated with health care (bloodstream, surgical 
site, and urinary tract infection); 7) unplanned re-intubation; 8) re-operation for residual cardiac 
lesions; 9) interventional catheterization for residual cardiac lesions; and 10) unplanned intensive 
care readmission. 
 
6.2  Data Sources 
Potential study subjects that will be identified in the Fetal Cardiac Clinic at the Hospital for Sick 
Children (see above). Data will be collected from the patient’s health chart, echocardiography 
images and MRI images.  
 
6.3 Collected Patient Data  
A) Prenatal Echocardiography  
- 
Date of exam (dd/mmm/yyyy) 
- 
Gestational age at exam (weeks/days) 
- 
Estimated fetal weight (g) 
- 
MPA valve diameter 
- 
Aortic valve diameter 
Imaging variables at baseline and with MH: 
Atrial septal morphology (2D; 4D) and foramen flow (color; 4D flow)  
 
FO diameter 
Septal excursion 
Shunt description  
Branch PA flow (mid-portion)  
peak flow  
VTI 
PI (peak systolic velocity – end-diastolic velocity/mean velocity) 
PV Doppler flow:  
VTI 
MPA:  
VTI 
Heart rate 
LCO  
AAo: 
VTI 
Heart rate 
RCO  
DA flow (color and Doppler):  
minimal diameter 
reversed end-diastolic flow: yes – no  
systolic peak flow  
forward-reverse flow ratio 

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flow restriction: yes - no   
 MCA Doppler flow  
peak flow  
VTI 
PI 
UA Doppler flow  
Peak flow  
VTI 
PI 
 
RV and LV (4D): volumes 
 
B) Fetal MRI 
- 
Date of exam 
- 
Gestational age at exam (weeks+days) 
- 
Fetal weight estimation (g) 
- 
Fetal weight Z-score 
- 
Fetal weight percentile 
- 
Brain volumetry (mL) (baseline; 3D steady state) 
- 
Placenta volumetry (mL) 
- 
Estimated HCT 
- 
 
UV 
- 
 
DAo 
- 
 
Ventricle (specify R or L) 
- 
Imaging variables at baseline and with MH 
Cardiovascular oximetry (SatO2): 
LV 
MPA 
RV 
AAo 
DAo 
UV 
SVC 
Fluximetry (ml/min/m2):  
AAo  
DA 
Main PA  
RPA 
LPA 
SVC 
IVC 
UV 
 DA 
 
Brain (ml/min/m2):  

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cDO2 
 
 
cVO2 
Fetus (ml/min/m2) 
                       DO2  
VO2  
 
Placenta Volumetry 
 
 
T2 star 
Patient Safety during MH 
- 
Adverse events 
C) Postnatal Outcomes 
- 
Date of birth (dd/mmm/yyyy) 
- 
Delivery place 
- 
Gestational age at birth   
- 
Weight at birth 
- 
Placental weight at birth 
- 
APGAR score (1 and 5 minutes) 
- 
PaO2 and SpO2 
- 
Age at CCU admission 
- 
Neonatal interventions: stat BAS, oxygen, intubation/ventilation, ECMO, other 
- 
Neonatal PGE: yes – no; time of start  
- 
Neonatal BAS: yes – no; age at procedure 
- 
Pre-op/pre-BAS: hemoglobin; minimal pH; minimal preductal PaO2; peak lactate 
- 
Pre-BAS compromise (defined as minimal pre-BAS pH ≤7.1, SaO2 ≤40%, PaO2 ≤25 
mmHg, maximal serum lactate ≥10 mmol): yes - no  
- 
Pre-BAS echo: ASD and VSD size, shunting, and gradients 
Persistent pulmonary arterial hypertension (defined as combined pre-operative reverse 
differential cyanosis ≥ 30% and/or postoperative RVp ≥ 75% systemic ≥48h post-surgery 
and/or ≥50% at postoperative discharge): yes – no 
- 
Pre-op complications: organ failure; NEC, cerebro-vascular injury; death 
o Date of event 
o Age at event 
- 
Date of surgery 
- 
Age at surgery 
- 
Type of surgical repair: ASO; VSD closure, other 
- 
Outcome to discharge or to 1 year if PPHT  
- 
Morbidity score: 
o RDS requiring surfactant 
o CPR requiring chest compressions 
o Cerebral vascular injury (intra-ventricular or –paranchymal hemorrhage, ischemic 
stroke) 
o NEC 
o ECMO 
o Hospital associated infections 
o Unplanned re-intubation 

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o Re-operation for residual cardiac lesions 
o Interventional catheterization for residual lesions 
o Unplanned CCU readmission 
- 
Date of discharge 
- 
Age at discharge 
 
7.  
ASSESSMENT OF ADVERSE EVENTS  
While no adverse events or serious adverse events (AEs or SAEs) have ever been reported in the 
literature and in our own experience (12) with the transient and sustained use of the study drug 
(MH), patient safety is an important aspect of any research study. Acute MH will be considered 
safe if the administration of oxygen is a) well-tolerated by the mother and fetus and b) oxygen 
delivery is maintained or improved during MH. This is particularly important as MH is 
considered a potential long-term prenatal treatment option to improve oxygen delivery to the 
brain.  
Although an AE/SAE related to the fetus is unlikely to occur as a result of research participation, 
if an AE/SAE occurs, the primary physician will be responsible to identify, and to classify the 
seriousness, severity, causality and expectedness as follows:  
a) Assessment if event qualifies as serious: 
Serious Adverse Event (SAE): A SAE is any untoward medical occurrence that at any dose: 
 
Results in death, 
 
Is life-threatening, 
 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
 
Results in persistent or significant disability/incapacity  
 
Results in congenital abnormalities or birth defect 
Other events may be treated as SAEs if the physician considers it to be an important medical 
event that may jeopardize the participant or require intervention to prevent one of the other 
outcomes listed above. 
b) Severity assessment: 
Mild 
Events are considered MILD if signs/symptoms are mild, clinical relevance is 
marginal, laboratory findings are asymptomatic and no specific medical 
intervention is required.  
Moderate 
Events are considered MODERATE if they require minimal, local, or non-
invasive intervention only. 
Severe 
Events are considered SEVERE if they interrupt the participant’s normal daily 
activities and generally require systemic drug therapy or other treatment; they are 
usually incapacitating. 
 
c) Causality assessment: 

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Definitely related 
There is a certainty that the event is related to the study drug(s). 
Probably related 
There is high likelihood that the event is related to the study drug(s).  
Possibly related 
There is a likelihood that the study drug(s) is the cause of the event, but other 
causes cannot be ruled out.  
Unlikely related 
It is not likely that the event is related to the study drug(s), and other more likely 
causes are present. 
Unrelated  
Evidence exists that the event is related to something other than a study drug.  
In the event of an AE, we will use a variety of sources of information to identify possible side 
effects of the MH including direct observations, imaging data, participant reports, laboratory 
reports and other medical reports. The PI and study team will evaluate the circumstances and 
clinical correlation of the events. If a serious and unexpected AE occurs that is deemed to be 
possibly related to the use of MH (e.g. fetal death within a day of the oxygen administration), we 
will discontinue the use of supplementary oxygen to that study participant as applicable, 
immediately place the study on hold indefinitely, and the PI will report the case to the DSMB 
and Health Canada. 
In the case of a moderate AE that is considered possibly related to the intervention (e.g. cardiac 
dysfunction such as fetal bradycardia of less than 90 beats per minute for more than 1 minute), 
we will discontinue the administration of oxygen in that study participant and the DSMB will 
review the event at their next scheduled meeting, and continue to enrol other patients for the 
study.   
 
If an AE is mild, we will discontinue the oxygen supplementation to that study participant, but 
continue enrolling other patients for the study.  Examples of mild maternal AEs that will result in 
discontinuation of oxygen administration for a subject will include fatigue, nasal or oral dryness 
or minor nasal bleeding and skin irritation. 
In the event that oxygen supplementation is discontinued as a result of an AE, the study 
participant will not undergo oxygen supplementation at a later time and will be withdrawn from 
the study. Any data that is collected up until the point of withdrawal will be kept.  
We do not expect ductal occlusion to occur within 45 minutes of fetal exposure to saturations 
that are lower when compared with a neonate. In the unlikely event ductal constriction occurs, it 
will be reversible once the MH is discontinued.  
d) Expectedness assessment: 
Unexpected 
If the nature, severity or frequency of an event is not consistent with the risk 
information listed in the Material Safety Data Sheet  
 

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AEs and SAEs related to oxygen administration will be documented by the site investigator. 
Prior to the start of oxygen administration, a thorough medical history should be obtained to 
document all preexisting maternal symptoms, complaints and health concerns. As many 
pregnancy related symptoms are intermittent in nature, a thorough history including variations in 
severity and frequency should be taken. AEs and SAEs should be reassessed at each participant 
encounter. If signs or symptoms remain similar to baseline or are less in severity, frequency, or 
both, they will be considered within the usual range and do not need to be documented as AEs. In 
contrast, signs and symptoms that are new or, if preexisting, are more frequent/severe, need to be 
documented, assessed for severity and causality, and followed up until resolution.  
In addition, the following table of endpoints will be used for the study: 
Unexpected fetal demise 
Stop the study; review by DSMB, PI and 
collaborators  
Detection of cardiac dysfunction 
Discontinue the exam – observe until resolved 
Review by PI and collaborators   
Fatigue, dry/bloody nose, skin irritation 
Review by PI and collaborators   
 
8.  
STATISTICS  
This is an observational cohort study to test whether acute MH is a useful diagnostic test for fetal 
TGA. This requires confirmation of the study concept that among TGA fetuses there will be 
specific hemodynamic and structural characteristics and responses that will be associated with 
neonatal compromise shortly after birth. Neonatal compromise is defined as any of these 
outcomes: pre-op/BAS mortality; minimal pre-BAS pH ≤7.1, SaO2 ≤40%, PaO2 ≤25 mmHg, 
maximal serum lactate ≥10 mmol; and/or PPHN (combined pre-operative reverse differential 
cyanosis ≥ 30% and/or postoperative RVp ≥ 75% systemic ≥48h post-surgery or ≥50% at 
postoperative discharge). Twenty-two (31%) of 70 consecutive newborns born at Mount Sinai 
Hospital for fetal TGA/IVS fulfilled at least one of the outcomes (Jaeggi E et al. AEPC 2016). 
PPHT affects 1-3% of children with TGA. Based on these data we would expect about 35 cases 
without severe neonatal compromise, 15 cases with neonatal compromise and 1 case with PPHT.  
Simple descriptive statistics will be adequate for this small feasibility and safety study. Data 
obtained from this study will further help to describe the possible ranges in hemodynamic 
findings at baseline and during MH in a larger cohort of TGA patients and in comparison with 
our previous data. The comparison between pre and post MH variables will be analysed using the 
Brand Altman’s plot. Receiver operating statistics will be used to test the diagnostic value of 
MH.  
 
9.  
STUDY ADMINISTRATION 
9.1  Data Collection, Management and Confidentiality 
Data will be collected by the study investigators using the above described sources and their 
personal usernames and passwords. Study investigators will be responsible for the data 
management and the accuracy of the records.  Only the study team will have access to the 

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database.  Data will be recorded on a Microsoft Excel spreadsheet and will be maintained in a 
locked digital file on the hospital’s secure server.  Data will be backed up on the hospital’s secure 
server.  Any research information obtained about the patient in this study will be kept 
confidential. A patient will not be identified by name, only by unique study ID number. The 
patient’s name or any identifying information will not appear in any reports published as a result 
of this study. All identifying information will be kept behind 2 security measures or as per 
equivalent institutional policy, under the supervision of the study Principal Investigator and will 
not be transferred outside of the hospital. Relevant study records will be archived for 25 years 
following completion of the study, as per the requirements of Health Canada’s Food & Drug Act, 
Part C Division 5. Once the study is complete and the final report has been published, the records 
will be retained and destroyed in accordance with The Hospital for Sick Children Record 
Retention and Destruction policy. All information collected in this study will be kept confidential 
in accordance with institutional policies on subject privacy and PHIPA.  Investigators will not 
use data for any purpose other than conducting the study.  
9.2     Data & Safety Monitoring Board (DSMB) 
An independent DSMB of 4 members will monitor the progress of the study and review the 
safety data. The DSMB will review the result of analyses and other safety data and, if required, 
will provide recommendations to the study sponsor including to stop the trial if there are safety 
concerns. 
9.3     Regulatory and Ethical Considerations 
This study involves an experimental examination for pregnant women and fetuses using 
supplementary oxygen for a limited period of time. Based on earlier experiences by others and 
our center that includes the prolonged use of MH as a potential treatment for fetuses with single 
ventricle physiology, no fetal and maternal AEs occurred. However, data on the use of MH for 
fetal TGA is scarce and therefore fetal and maternal monitoring during oxygenation warranted. 
All participants will be made aware of the experimental aspects of this research, and the time of 
oxygen administration will be kept as short as possible and will be shorter than in previous 
studies. In the unlikely event of a serous complication attributable to the MH we will discontinue 
the study. 
If any incidental findings occur during the study, the study team will share the atypical findings 
and provide recommendations with the SickKids physician. Clinical care will be provided as 
needed.          
9.3.1 Informed Consent 
The study is explained to the patient in detail, including the alternatives to be followed up 
without participation. Any study related questions will be answered prior to signing the consent 
form. The person obtaining consent must co-sign the form with date and time. A copy if the 
consent for must be given to the patient.  
9.3.2 Study Withdrawal 
A subject is free to withdraw from participation in the trial at any time, for any reason, specified 
or unspecified, and without prejudice. If the subject withdraws, data that has already been 

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collected up to that point in time will be kept (as indicated in the patient informed consent). 
9.3.3 Reporting of Adverse Events and Serious Adverse Events  
Subjects will be carefully monitored throughout their study participation. They should stop at 
any time they start to feel uncomfortable; even if they feel as though their ailment is unrelated to 
study intervention. If any unanticipated problems related to the research involving risks to 
subjects or others happen during the course of this study these will be reported to the REB in 
accordance with SickKids Policy. AEs that are not serious but that are notable and could involve 
risks to subjects will be summarized in narrative or other format and submitted to the REB at the 
time of continuing review.  
All serious, unexpected adverse drug reactions to the study medication will be reported to Health 
Canada within 15 calendar days or for death or life-threatening events, within 7 calendar days. In 
the latter case, a follow-up report must be filed within 8 calendar days.  
10.    PUBLICATION 
It is expected that study results will be published in peer reviewed papers. Individual authorship 
will be based on the investigator’s contribution to a study component and journal guidelines of 
authorship. As per the International Committee of Medical Journal Editors 
(http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-
authors-and-contributors.html) authorship will be based on these 4 criteria: a) Substantial 
contributions to the conception or design of the work; or the acquisition, analysis, or 
interpretation of data for the work; AND b) Drafting the work or revising it critically for 
important intellectual content; AND c) Final approval of the version to be published; AND d) 
Agreement to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.  
 
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