DOI: 10.1161/CIRCULATIONAHA.115.016024
The Path Forward is to Look Backward in Time – Fetal Physiology:
The New Frontier in Managing Infants with Congenital Heart Defects
Running title: Licht; The path forward - fetal physiology
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
Daniel J. Licht, MD
Children’s Hospital of Philadelphia, Philadelphia, PA
Add
dress for Correspondence:
Corr
Co
rresp
rr
ponden
nden
nce
ce::
Address
Daani
niel
e JJ.. Li
el
ich
cht,
t MD
MD
Daniel
Licht,
Asso
As
soci
so
ciat
ci
atee Professor
at
Prof
Pr
ofes
of
esso
es
sorr of N
so
euro
eu
rolo
ro
logy
lo
gy aand
nd Pediatrics
Ped
edia
iatr
ia
tric
tr
icss
ic
Associate
Neurology
Chil
Ch
ildr
dren
en’ss Hospital
Hos
ospi
piita
tall of Philadelphia
Phi
hila
lade
delp
lphi
hiaa
Children’s
Perelman School of Medicine, University of Pennsylvania
10th Floor Colket Translational Research Bldg., rm. 10030
3501 Civic Center Blvd.
Philadelphia, PA 19104
Tel: 215-590-1719
Fax: 215-590-1771
E-mail: [email protected]
Journal Subject Code:Imaging of the brain and arteries:[61] Other imaging
Key words: heart defects, congenital, brain development, fetal physiology, Editorial, fetal heart,
brain imaging, developmental biology, cerebral blood flow and metabolism
1
DOI: 10.1161/CIRCULATIONAHA.115.016024
The luxury of studying the cognitive outcomes of survivors of infant heart surgery only occurs as
a consequence of the success of the surgeries. The last two decades of improvement in surgical
survival has allowed us to focus our attention beyond survival and cardiac outcomes, to a more
holistic view of the child, their academic achievement and prospects for successful
independence. Most of what we know about long-term outcomes is from the Boston Circulatory
Arrest Study, which began in 1988 and followed the lives of 171 infants with transposition of the
great arteries (TGA) randomized to a surgical strategy that either included hypothermic
circulatory arrest or did not. The most recent report on 139 adolescent survivors (age 16.1 + 0.5
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
years) from this study documented some significant psycho-educational challenges that were not
soo severe as they were prevalent.1 Briefly, grade retention occurred in 17%, spec
special
cia
iall ed
education
duc
ucat
atio
at
ionn iin
io
n
25% and psychotherapy or counseling in 25%. Mostt significantly, the study reports the negative
finding
find
nd
din
ingg th
that
at su
surgical
urgi
giica
call strategy failed to identify in
increased
ncr
c eased risk for th
the
he ou
outcome
utc
tcoome measures. To quote
the
he report
re
“In many
man
anyy respects,
reesppeccts,
ts, the
the similarities
s millaritiess in
si
in th
the
he ooutcomes
uttco
tcome
omes
es ooff tthe
he 2 ggroups
ro
oup
ps have
havee bbeen
e n more
ee
more
striking
differences.”
from
achievement,
fine
motor
tri
riki
king
ki
ng tthan
haan th
thee di
iff
ffer
erren
nce
ces.”” Bo
Both
th ggroups
rooup
upss su
ssuffered
ffer
ff
ered
ed fr
rom po
poor
or aacademic
c de
ca
dem
mi ac
mic
ach
hiev
hiev
evem
em
ment,
ent,, fin
in
ne mo
moto
tor
function, visual
visu
suual spatial
spa
pati
t al skills,
ti
s illls
sk
l , sustained
suust
stai
aiine
n d attention
attte
tent
ntio
nt
ionn and
io
an
nd so
social
oci
c al ccognition.
ogni
og
n tiion
ni
on..
Concurrent with this study, investigations of white matter injury (WMI) have been
ongoing. In 2002, Dr. Mahle and his colleagues reported that nearly 20% of infants with mixed
types of severe congenital heart defects (CHD) had evidence of WMI before surgery despite
optimal medical management from birth.1, 2 This number, it appears, is remarkably robust; study
after study has shown WMI in about 1 in 5 infants before surgery. The second number from
Mahle’s study that is equally robust is the prevalence of WMI after surgery, which rests at about
50%. In more homogeneous populations of infants with CHD, the prevalence of WMI varies. In
populations of infants with transposition of the great arteries (TGA), Petit et al3 reported a pre-
2
DOI: 10.1161/CIRCULATIONAHA.115.016024
operative WMI prevalence of 38% while Beca et al4 report an incidence of 27%. In TGA, all
agree that there is no progression of the injury after surgery, likely due to its corrective nature.
The same is not true in populations of hypoplastic left heart syndrome (HLHS) where WMI is
seen in 15 to 20% before surgery5, 6 but increases to 70% after.7 The palliative nature of the first
heart surgery corrects the direction of flow in the arch and limits the pulmonary diastolic run off
but does nothing to correct the oxygen content of the blood. Nonetheless, there seems to be a
significant benefit in performing the surgery early after birth.7, 8
These investigations on the causes of WMI have led to the recognition that pre-operative
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
factors and patient specific factors (heart diagnosis, age at surgery, prenatal diagnosis) rather
than
han surgical or post-operative factors are the major risks. Questions about how alte
aalterations
lteera
r ti
tion
ons
ns in
fetal circulation may affect brain growth and maturation first appear with Dr. Miller’s
publication
pu
ubl
blic
icat
ic
atio
at
ionn in 2007.
io
200
0077.
00
7.9 Here the authors used diffusion
diffu
fu
usion tensor imaging
imag
gin
i g (MRI)
(M
MRI) and MR
spectroscopy
pecctr
t oscopy tto
o de
demo
demonstrate
mons
nstr
trat
atee significant
at
sign
si
gnif
ific
if
iccan
nt diff
differences
ferrencees in w
white
hitte
hi
te matter
mattteer microstructure
miicr
cros
ostr
trruc
uctu
ture
re and
and
biochemistry
with
infants
without.
Soon
bi
ioc
oche
hemi
he
m sttry bbetween
mi
ettween
ween
n nnewborn
e boorn iinfants
ew
nfaants
nf
antss w
ithh CH
it
CHD
D comp
ccompared
omp
mpar
ared
ar
ed tto
o in
nfa
fant
n s with
nt
w
ithoout.
out.
t S
oon aafter
oo
fte
teer ou
oour
urr
group at CHO
CHOP
OP de
demonstrated,
emo
m ns
nstr
t at
ated
ed, us
ed
usin
using
i g an
in
nM
MRI-based
RI-b
RI
-b
bas
a ed oobservational
bser
bs
erva
er
vati
va
tion
ti
onal
on
a m
al
metric
ettri
ricc ca
call
called
l ed
ll
d tthe
he T
Total
o al
ot
Maturation Scale (TMS), that brain maturation in full-term pre-surgical infants with CHD was
equivalent to expected brain maturation of a 35-week premature infant.10 Others have since
shown that the TMS not only predicted risk for pre- and post-operative WMI, but TMS also
predicted neuro-developmental testing (Bailey scales of infant development) at 2-years.11, 12
The landmark study to seal the question about altered brain growth and development in
fetuses with CHD came from Dr. Limperopoulos and her Boston group.13 Here Dr.
Limperopoulos performed brain MRI in fetuses with and without CHD, to demonstrate that the
brain volumes of infants with CHD diverge from expected normal growth at the beginning of the
3
DOI: 10.1161/CIRCULATIONAHA.115.016024
3rd trimester. Using fetal MR spectroscopy, Dr. Limperopoulos also demonstrated that markers
of white matter maturation (N-acetyl aspartate to choline ratios) lagged normal development and
were most abnormal in the fetuses with left outflow track obstruction (HLHS). These findings
not only validated the findings of Miller and Licht, but also added a time reference as to when
during pregnancy the pathological changes were occurring. This wealth of data on abnormal
brain growth and development suggests that while opportunities for postnatal neuroprotective
interventions exist, their yield might be much less than one would hope for. Novel strategies for
fetal intervention and neuroprotection are needed. Yet, what all the above studies lacked was a
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
clear understanding of the fetal pathophysiology that led to this divergence of brain growth and
maturation. Without this knowledge, progressing to fetal interventions (medicall or
or surgical)
s rg
su
rgic
ical
ic
al)) is
al
is
talled, or at least uninformed.
stalled,
In tthis
In
hiss issu
hi
suee of Circulation, Dr. Sun and co
su
coll
leagues14 from To
T
Toronto
ro
ont
ntoo hospital for Sick
issue
colleagues
Children
C
hiildr
d en publi
publish
ishh th
their
heir
i rresults
ir
essul
ults
lts oon
n fetal
feeta
tall MRI
MR measurements
meaasurrem
men
ntss of
of cerebral
ceere
rebbral
bral blood
blo
loood flow
flo
low
w an
and
nd ce
ccerebral
rebr
brall
oxygenation
with
and
without
serious
CHD.
cannot
ox
xyg
ygen
enat
en
atio
io
on in
in ffetuses
etuuses
usess w
ithh an
it
nd wi
with
thou
th
ouut se
seri
riou
ri
ouss CH
ou
HD. Th
Thee ssignificance
ign
gnif
gn
iffic
ican
ance
an
cee ooff tthis
hiss re
hi
rreport
port
po
rt ca
annot
ann
not be
overstated and
nd
d it
it go
goes
e w
es
well
e l be
el
beyo
beyond
y nd tthe
yo
h ffindings
he
indi
in
d ng
di
ngss th
tthey
ey ob
oobserved
seerv
rved
ed iin
n th
the 60 ppatients
atiien
at
ents
tss ((30
30 w
with
i h and 30
it
without CHD) studied. It is the technical achievement of being able to make non-invasive
measurements of vascular and metabolic physiology in a moving fetus that is the most eyeopening. The introduction of metric optimized gating (MOG) by co-author Dr. MacGowan has
allowed for phase contrast measurements of blood flow and oximetry in fetal vessels.15 There are
some assumptions made for the calculations used in this manuscript, but they are equitably applied
to the CHD fetuses and controls. Eventually numbers like the T20 (T2 of fully oxygenated blood)
of fetal blood will be measured and the absolute quantification of oxygen saturations will be
known. For now these numbers are good, if not perfect, and suffice for comparisons with normal.
4
DOI: 10.1161/CIRCULATIONAHA.115.016024
We must consider that it has only been 7 years since the multislice snapshot technique for
measuring fetal brain volumes was published16 and only 5 years since Dr. Limperopoulos
demonstrated discrepant in brain growth in fetuses with CHD.13 These leaps in technology take
time.
The main findings in this report by Sun and colleagues highlight the limitations of our
perhaps simplistic understanding of how CHD alters fetal physiology. The most striking example
of this is the finding that umbilical venous saturations in CHD fetuses were lower than in controls
suggesting placental pathology may be an important contributor to the central nervous system
Downloaded from http://circ.ahajournals.org/ by guest on June 18, 2017
changes observed in the newborn with CHD. These MRI findings support some preliminary
findings by Goff et al17 who demonstrated gross differences in
n placental weights aand
nd vvascularity.
nd
ascula
cu
ula
lari
rity
ri
ty.
Also unexpected was the finding that cerebral oxygen consumption was significantly lower in
fetuses
fe
etu
use
sess with
with CHD,
CHD
D, while
w ile oxygen delivery was not
wh
noot (though
(thhough trendedd to
(t
ttowards
ward
wa
rdss significance).
rd
Both the
he aabnormal
bnorrmaal ce
bnor
cere
cerebral
rebbral
re
brall ooxygen
xy
ygen cconsumption
onsum
mptio
on an
andd plac
pplacental
lacen
nta
tall fu
ffunction
nction
ncti
on rraise
aisse cchicken/egg
ai
hick
hi
ken
en/e
/ gg
/e
questions
that
will
need
with
MRI
techniques.
Currently
ques
qu
e ti
es
tion
o s th
on
hat w
ill ne
nee
ed tto
o be cclarified
lari
la
rifi
ri
fied
fi
ed w
ithh th
it
thee ad
aadvancement
vancem
van
emen
em
entt of tthese
en
hese M
hese
RI te
tech
c ni
ch
n qu
ques
es. Curr
es
C
urr
r en
ntlyy
the
he major limitation
limi
miita
tati
t on of
ti
of these
th
hesse MR sequences
seq
que
u nc
nces
es is
is certain
cert
ce
rttaiin types
type
ty
pess off m
pe
movement
ovem
ov
em
men
entt an
andd vessel
veess
ssel
el size.
siz
i e. As such,,
all measurements are restricted to late gestation fetuses where motion is limited and vessels are
larger. But instead of focusing on the limitations, we need to revel in the quantum leap of the
advancements the authors bring. Studies in more homogeneous populations (just TGA or HLHS)
will follow, as will comparison of fetal and neonatal physiology. Eventually, the refined techniques
will allow longitudinal study across the entire gestation. The authors are to be congratulated for
such remarkable accomplishments. Implementation of these fetal imaging techniques will improve
our understanding of fetal development and will give birth to a new field of fetal medical
intervention.
5
DOI: 10.1161/CIRCULATIONAHA.115.016024
Funding Sources: The author is funded by NIH for research related to brain injury in neonates
with severe congenital heart defects.
Conflict of Interest Disclosures: None.
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7
The Path Forward is to Look Backward in Time−−Fetal Physiology: The New Frontier in
Managing Infants with Congenital Heart Defects
Daniel J. Licht
Circulation. published online March 11, 2015;
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Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2015 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
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