Fetal brain growth is altered in congenital heart disease (CHD). The role of disturbed placental and fetal blood flow/oxygenation remains poorly understood. We compared the effect of maternal hyperoxia on cerebral and placental oxygenation in CHD vs control fetuses using blood oxygenation level dependent (BOLD) functional MRI (fMRI).

1. Maternal hyperoxia increases cerebral oxygenation
in fetuses with complex congenital heart disease:
a functional MRI study
WonsangYou, Mary Donofrio, David Wessel, Zungho Zun,
Josepheen De Asis-Cruz, Gilbert Vezina, Dorothy Bulas,
Richard Jonas, Adre du Plessis, Catherine Limperopoulos

2. Congenital Heart Disease (CHD) and Brain Injury
❖ Background
– CHD impairs fetal brain development due to insufficient oxygen supply.
– Placenta is critical for normal brain development.
❖ Unsolved problems
– The mechanism by which CHD disrupts fetal brain development
– The role of placenta in brain injury
❖ Recent studies
– Changes in normal fetal brain & placental oxygenation
during maternal hyperoxia, using fMRI.
– But, hyperoxygenation in CHD, not examined through fMRI.

3. Study Objective
❖ Objective
To compare placental and fetal brain
hemodynamic response to maternal hyperoxia,
between CHD vs healthy fetuses,
using blood oxygenation level dependent
(BOLD) functional MRI
❖ Hypothesis
Maternal hyperoxia would reveal different
oxygenation changes in the fetal brain between
CHD vs control fetuses.
Brain
Placenta
O2
Heart

4. Functional MRI
Neural activity BOLD signal
Deoxyhemoglobin BOLD contrast
depends on the content of oxygen
(deoxyhemoglobin) in blood vessels
modulated by neural tissues .
Neural activity is convolved by hemodynamics in fMRI.
Blood-oxygen-level dependent
𝑂2
Hemodynamics

5. Methods
Brain
Placenta
Normoxia
2 min
Hyperoxia (100% O2)
4 min
Post-normoxia
3:30 min
o 1.5T GE MR scanner
o Echo planar imaging (EPI)

6. Fetal Brain/Placenta Data Processing
ROI
averaging
Motion
correction
ROI
splitting
Statistical
analysis
Raw EPI
ROI
averaging
Motion
correction
Fetal brain
Placenta
Data
imputation
Data
imputation
Defining
ROI masks

7. Study Subjects
Control CHD
N=85 51 34
Mean GA
at MRI (wks)
32 (22-39) 32 (26-38)
❖ Cohort
❖ Inclusion Criteria
• Healthy pregnant women/fetus with normal fetal echo (ECG)
• Pregnant women/fetus who underwent a fetal ECG to confirm CHD
❖ Exclusion Criteria
• Multiple gestations
• Maternal contraindication to MRI
• Congenital infection, dysmorphic
features, dysgenetic brain legions,
other anomalies by ultrasound
• Chromosomal abnormalities by
amniocentesis

8. Study Cohort
Control CHD
N=85 51 34
Mean GA at MRI (wks) 32 (22-39) 32 (26-38)
Single ventricle (1V) 14
HLHS 12
Single LV 2
Two ventricles (2V) 20
dTGA 5
TOF 4
Ebstein’s malformation 4
DORV 3
VSD 2
CoA 1
AVCanal 1

9. Results: Averaged BOLDTime Courses
Normoxia
2 min
Hyperoxia (100% O2)
4 min
Post-normoxia
3:30 min
-20%
-10%
0%
10%
20%
30%
40%
50%
0 100 200 300 400 500
PercentBOLDsignalchange
Time (second)
Brain
Placenta
Early HO Late HO
Early return
NO
Late return
NO

10. Percent Changes in Oxygenation from Baseline
Type Hyperoxia Return to normoxia
Placenta Control 3.7±3.1 (*) 3.9±2.7 (*)
CHD 3.1±3.2 (*) 2.6±5.2 (*)
1-V 4.3±4.6 (*) 4.1±4.3
2-V 2.8±2.6 (*) 2.4±7.4
Brain Control 0.4±1.8 (*) 0.9±1.5 (*)
CHD 0.8±2.0 2.9±3.0 (*)
SV 1.1±1.3 3.4±2.4 (*)
2V 0.6±2.7 0.9±4.0
Unit. %

11. Hyperoxygenation: Control vs CHD
0%
1%
2%
3%
4%
5%
6%
7%
Early
hyperoxia (HO)
Late HO Early return
normoxia (NO)
Late return NO
PercentSignalChangeintheBrain
Control
CHD
0%
2%
4%
6%
8%
10%
12%
14%
Beginning
hyperoxia (HO)
Late HO Early return
normoxia (NO)
Late return NOPercentSignalChangeinthePlacenta
Control
CHD
* p=0.042
Fetal Brain Placenta

12. Hyperoxygenation: 1V vs 2V
0%
1%
2%
3%
4%
5%
6%
7%
Early hyperoxia
(HO)
Late HO Early return
normoxia (NO)
Late return NO
PercentSignalChangeintheBrain
Control
2v
1v

13. Hyperoxygenation: CHD subgroup analyses
0%
1%
2%
3%
4%
5%
6%
7%
Late Hyperoxia
(HO)
Late return
normoxia (NO)
PercentSignalChangeintheBrain
Control
2V-CHD
1V-CHD
*p=0.045 * p=0.045
3.3% -1.6%
Single vsTwoVentricle CHD HLHS vsTGA

14. Hyperoxic Oxygen Saturation Curve
70
100
130
160
190
220
250
0% 20% 40% 60% 80% 100%
Saturationtime(second) Saturation ratio
Control
CHD
70
100
130
160
190
220
250
0% 20% 40% 60% 80% 100%
Saturationtime(second)
Saturation ratio
Control
CHD
• Fetal brain is saturated faster in CHD than in healthy controls (in 30~50%).
Placenta Fetal Brain
*

15. Relationship of Placental and Cerebral Oxygenation
Placenta-fetal brain in hyperoxia
BOLD percent signal changes
Control : +1.37% in fetal brain
for +10% in placenta
(p=0.02)
CHD : no significance (p=0.64)

16. Relationship of Oxygenation and GA
Placenta Fetal Brain
Control : +0.8%/wk (p=0.1)
CHD : +1.5%/wk (p=0.04)
Control : +0.2%/wk (p=0.03)
CHD : +0.4%/wk (p=0.1)

17. Relationship of Hyperoxygenation and Basal Condition
Placental BOLD vs UA-PI Cerebral BOLD vs UA-PI
Control : p=0.001
CHD : p=0.04
Placenta BrainUA-PI
Control : p=0.03
CHD : p=0.82
Placenta BrainUA-PI
Control CHD

18. UA-PI: Control vs CHD
R²= 0.2879
R²= 0.2823
0.0
0.5
1.0
1.5
2.0
24 26 28 30 32 34 36 38 40
UA-PI
Gestational age (weeks)
Control
CHD

19. Relationship of BOLD and Doppler Ultrasound Measures
BOLD in hyperoxia
Control CHD
Placenta Brain Placenta Brain
Isthmus 0.001>
(***)
0.001>
(***)
0.699 0.798
UA-RI 0.002
(**)
0.027
(*)
0.268 0.614
UA-PI 0.002
(**)
0.027
(*)
0.343 0.863
CPR 0.065 0.034
(*)
0.455 0.995
MCA-RI 0.530 0.521 0.672 0.464
CCO/wt 0.831 0.895 0.605 0.994
BOLD in post-normoxia
Control CHD
Placenta Brain Placenta Brain
Isthmus 0.115 0.003
(**)
0.986 0.561
UA-RI 0.358 0.060 0.098
(*)
0.823
UA-PI 0.368 0.063 0.148 0.723
CPR 0.716 0.198 0.043
(*)
0.676
MCA-RI 0.689 0.883 0.321 0.679
CCO/wt 0.843 0.574 0.716 0.975

20. Summarized Conclusion from Ultrasound-fMRI Study
Healthy CHD
Change in cerebral
hyperoxygenation
insignificant
significantly elevated
for 1V-CHD fetuses
Relationship of
cerebral oxygenation
with placenta
oxygenation
significant Insignificant
Effects of
basal condition of
placental circulation on
cerebral oxygenation
significant Insignificant

21. Conclusion
• This study provides the first evidence on the effect of
maternal hyperoxia on cerebral oxygenation in CHD fetuses.
• Maternal hyperoxia significantly transiently increases cerebral
oxygenation in the CHD fetuses with 1V.
• But, cerebral oxygenation becomes less dependent to
placental circulation in CHD fetuses, probably due to the
increased resistance by cardiac abnormality as well as
retrograde isthmus flow.

22. Acknowledgement
❖ Collaborators
Catherine Limperopoulos, PhD Marine Bouyssi-Kobar
Adre du Plessis, MD Samantha Bauer
Josepheen Cruz, MD PhD Sonia Dahdouh, PhD
Wesley Zun, PhD Diane Lanham
Iordanis Evangelou, DPhil Caitlyn Loucas
Mary Donofrio, MD Eman Mahdi, PhD
Nickie Andescavage, MD Geraldine Pluviose
Gilbert Vezina, MD Robbie Reese
Dorothy Bulas, MD LauraTinkleman
Shuo-Tse Hsu , MD Yao Wu, PhD
Kushal Kapse Bernard Scalise
❖ Grant Funding
NHLBI R01 (HL116585-01)
National Institutes of Health
CIHR (MOP-81116)
Canadian Institutes of Health
❖ Families
Nurses, Participant families