Blood transfusion in pregnancies complicated by maternal sickle cell disease. Effects on blood rheology and uteroplacental Doppler velocimetry


Howard, R.J.; Tuck, S.M.; Pearson, T.C.

Clinical and Laboratory Haematology 16(3): 253-259

1994


Doppler ultrasound gives a measure of downstream resistance to blood flow. In this study it has been used to assess the change in placental vascular resistance following blood transfusion in pregnancies complicated by sickle cell disease. Eight women with homozygous sickle cell disease were followed prospectively to assess the effect of transfusion on haemoglobin S percentage, blood and plasma viscosity and uteroplacental Doppler velocimetry. Measurements were made immediately pre and post-transfusion and after several weeks when the desired improvement in haemoglobin S had been achieved. Despite significant changes in haemoglobin S levels and consequent rheological change there was found to be no change in measurements of resistance in the uteroplacental circulation as assessed by Doppler ultrasound.

Clin.
lab.
Haemat.
1994,
16,
253-259
Blood
transfusion
in
pregnancies
complicated
by
maternal
sickle
cell
disease.
Effects
on
blood
rheology
and
uteroplacental
Doppler
velocimetry
RICHARD
J.
HOWARD*,
SUSAN
M.
TUCK*
&
T.C.
PEARSONt
*
University
Department
of
Obstetrics
and
Gynaecology,
The
Royal
Free
Hospital,
London
NW3,
UK
and
t
Department
of
Haematology,
United
Medical
and
Dental
Schools
of
Guy's
and
St
Thomas's
Hospitals,
Lambeth
Palace
Road,
London
SE],
UK
Accepted
for
publication
17
March
1994
Summary
Doppler
ultrasound
gives
a
measure
of
downstream
resistance
to
blood
flow.
In
this
study
it
has
been
used
to
assess
the
change
in
placental
vascular
resistance
following
blood
transfusion
in
pregnancies
complicated
by
sickle
cell
disease.
Eight
women
with
homozygous
sickle
cell
disease
were
followed
prospectively
to
assess
the
effect
of
transfusion
on
haemoglobin
S
percentage,
blood
and
plasma
viscosity
and
uteroplacental
Doppler
velocimetry.
Measurements
were
made
immediately
pre
and
post-transfusion
and
after
several
weeks
when
the
desired
improvement
in
haemoglobin
S
had
been
achieved.
Despite
significant
changes
in
haemoglobin
S
levels
and
consequent
rheological
change
there
was
found
to
be
no
change
in
measurements
of
resistance
in
the
uteroplacental
circulation
as
assessed
by
Doppler
ultrasound.
Keywords:
sickle
cell
disease,
pregnancy,
rheology,
Doppler
velocimetry
Pregnancies
complicated
by
maternal
sickle
cell
disease
are
accompanied
by
fetal
complications
of
prematurity,
growth
retardation
and
increased
perinatal
mortality
(Tuck
et
al.
1983).
The
cause
of
this
is
presumed
to
be
due
to
a
sickling
process
in
the
placental
circulation
where
the
high
degree
of
oxygen
extraction
provides
an
excellent
milieu
for
sickling
and
stasis
(Lukens
1993).
Although
impaired
oxygen
delivery
to
the
fetus
contributes
to
poor
fetal
outcome,
it
is
not
clear
as
to
how
much
the
sickling
process
is
responsible.
It
has
been
theorized
that
it
is
the
chronic
anaemia
of
sickle
cell
disease
resulting
in
poor
oxygen
delivery
which
is
largely
responsible
for
the
fetal
complications
that
are
seen
(Charache
&
Niebyl
1985).
Controversy
exists
as
to
the
role
of
blood
transfusion
in
improving
fetal
outcome
with
some
authors
recommending
prophylactic
transfusion
(Morrison
et
al.
1991)
and
others
advising
transfusion
only
for
obstetric
or
haematological
indications
(Koshy
et
al.
1988).
Correspondence:
Mr
Richard
J.
Howard.
253
254
R.J.
Howard,
S.M.
Tuck
and
T.C.
Pearson
Doppler
ultrasound
gives
a
measure
of
downstream
resistance
to
blood
flow
(Skidmore
et
al.
1980)
and
there
is
some
evidence
that
when
uteroplacental
Doppler
ultrasound
is
raised
it
predicts
hypertension
and
intrauterine
growth
retardation
in
haematologically
normal
pregnancies
(Steel
et
al.
1990).
Recent
reports
have
shown
that
uterine
artery
Doppler
velocimetry
is
abnormal
in
pregnancies
complicated
by
maternal
sickle
cell
disease
(Anyaegbunam
et
al.
1988).
Resistance
to
flow
in
intermediate
sized
vessels
is
proportional
to
blood
viscosity
and
inversely
proportional
to
the
fourth
power
of
the
vessel
radius.
In
the
microcirculation,
the
deformability
of
the
individual
blood
cells
and
plasma
viscosity
are
factors
in
resistance
to
flow.
Blood
transfusion
in
pregnancy
reduces
haemoglobin
S
percentage
(HbS%)
and
improves
measurements
of
blood
viscosity
(Keiden
et
al.
1988).
The
aim
of
the
present
study
was
to
assess
the
effect
of
blood
transfusion
on
blood
rheology
and
placental
vascular
resistance
as
measured
by
Doppler
flow
velocity
waveforms
in
pregnancies
complicated
by
maternal
sickle
cell
disease.
Patients
and
methods
Approval
for
this
study
was
obtained
from
the
ethical
committees
of
the
partici-
pating
hospitals
and
all
women
gave
their
informed
consent.
Eight
women
with
homozygous
sickle
cell
disease
(HbSS)
were
recruited
into
this
study
which
did
not
alter
any
aspect
of
pregnancy
management;
this
was
decided
by
the
attending
hospital
consultants.
All
blood
used
for
transfusion
was
packed
red
cells
and
the
method
of
transfusion
was
either
a
simple
'top-up'
transfusion
or
an
exchange
transfusion
(a
venesection
of
one
unit
and
a
transfusion
of
two
units).
All
women
had
serial
blood
pressure
measurements
performed
throughout
pregnancy
and
none
had
evidence
of
pre-eclampsia
(defined
by
a
diastolic
blood
pressure
of
90
mmHg
or
more
with
proteinuria)
or
hypertension
(defined
as
a
diastolic
blood
pressure
of
90
mmHg
or
more)
at
the
time
of
transfusion.
Blood
samples
were
taken
immediately
prior
to
transfusion
from
a
peripheral
arm
vein
without
venous
occlusion
or
from
an
existing
indwelling
central
sub-
cutaneous
catheter.
Blood
was
anticoagulated
with
potassium
EDTA
(1.6
mg
EDTA/ml
blood).
Blood
sampling
was
repeated
up
to
72
h
post-transfusion
to
assess
the
immediate
effects
on
haemoglobin
S
percentage
(HbS%),
PCV,
whole
blood
and
plasma
viscosity.
The
long-term
effects
of
transfusion
were
evaluated
by
assessing
a
group
of
four
patients
where
a
large
reduction
in
HbS%
occurred
over
several
weeks.
Four
transfused
patients
with
HbSS
disease,
matched
for
gestational
age,
who
had
constant
levels
of
HbS%
were
used
as
a
control
group.
HbS%
was
measured
by
cellulose
acetate
electrophoresis
at
pH
8.6
and
after
elution
the
absorbance
was
measured
using
a
spectrophotometer
(Phillips
PU8720)
at
413
nanometers
from
which
the
HbS%
was
calculated.
PCV
was
measured
using
a
microhaematocrit
centrifuge
(Hawksley,
Lancing,
Sussex,
UK)
at
15000
g
for
5
min
and
then
read
using
a
microhaematocrit
reader.
This
is
the
Blood
transfusion
in
pregnant
women
with
SCD
255
recommended
technique
for
the
measurement
of
PCV
in
rheological
studies
(ISCH
1986).
The
product
of
the
PCV
and
HbS%
was
used
to
give
the
`sicklecrit'
representing
the
PCV
of
HbS-containing
erythrocytes.
The
absolute
whole
blood
viscosity
(WBV
abs
)
of
oxygenated
samples
was
measured
at
37°C
using
a
Contraves
Low
Shear
30
viscometer
at
high
(94.5
s
-
')
and
low
(0.695
s
-
')
shear
rates.
The
WBV
abs
was
then
corrected
to
a
standard
PCV
of
0.45
(WBV
045
)
by
removing
plasma
from
a
second
sample
and
constructing
a
graph
of
log
viscosity
against
PCV
and
using
the
linear
relationship
to
calculate
the
viscosity
at
a
PCV
of
0.45.
These
corrected
values
were
calculated
in
order
to
exclude
the
consider-
able
effect
of
PCV
on
blood
viscosity.
Corrected
measurements
thereby
assess
change
in
blood
viscosity
almost
entirely
from
an
improved
HbS%.
Plasma
viscosity
was
measured
at
37°C
using
the
same
viscometer
at
high
shear
rate.
All
Doppler
flow
velocity
waveforms
were
measured
by
the
same
individual
(RJH)
using
a
portable
continuous
wave
Vasoflo
3
Doppler
instrument
(Oxford
Instruments,
Abingdon,
Oxford,
UK)
using
a
4
mHz
transducer
with
the
subject
resting
in
a
semi-recumbent
position.
Uteroplacental
vessel
waveforms
were
obtained
from
the
lower
lateral
border
of
the
uterus
with
the
probe
pointing
downwards
and
medially.
A
uteroplacental
waveform
was
characterized
by
a
waveform
of
low
pulsatility.
Two
measurements
were
taken
from
each
side
of
the
uterus
and
the
average
calculated.
The
resistance
index
(RI)
of
the
flow
velocity
waveform
was
used
as
a
measure
of
downstream
resistance
in
the
uteroplacental
circulation.
Statistical
significance
(P
<
0
.0
5)
was
determined
using
a
paired
t-test,
between
the
pre
and
post-transfusion
mean
values.
In
order
to
allow
for
the
fact
that
the
data
may
not
have
been
normally
distributed
an
analysis
was
also
performed
using
a
non-parametric
test.
Results
A
total
of
20
blood
transfusions
were
followed
prospectively.
Six
of
these
transfusions
were
top-up
transfusions
and
14
were
exchange
transfusions.
Table
1
shows
the
immediate
effects
of
transfusion
on
haematological,
rheological
and
Doppler
parameters
for
these
two
groups.
Both
transfusion
methods
resulted
in
significant
reductions
in
HbS%
and
improvements
in
corrected
whole
blood
viscosity
and
sicklecrit.
There
were
significant
increases
in
absolute
whole
blood
viscosity
in
both
groups.
There
was
no
change
in
uteroplacental
RI
following
either
transfusion
method.
Table
2
shows
the
long-term
effect
of
transfusion
of
four
subjects
where
a
large
reduction
of
HbS%
occurred.
Significant
reductions
in
HbS%
and
sicklecrit,
but
with
a
non-significant
rise
in
absolute
and
fall
in
corrected
blood
viscosity,
were
observed
with
a
small
insignificant
reduction
in
uteroplacental
RI.
A
control
group
of
four
women
with
sickle
cell
disease
who
had
constant
levels
of
HbS%
and
blood
viscosity
over
the
same
gestational
age
range
also
showed
a
small
reduction
in
uteroplacental
RI.
There
were
no
differences
in
statistical
significance
when
this
data
was
assessed
using
non-parametric
statistical
analysis.
o
R
.J
.
H
oward
,
S
.M
.
T
uck
and
T
.C
.
P
e
arson
Table
1.
Immediate
changes
in
haematological,
rheological
and
uteroplacental
Doppler
velocimetry
parameters
as
a
result
of
20
blood
transfusions
in
eight
pregnant
women
with
homozygous
sickle
cell
disease
Mean
Simple
top
up
transfusion
(n
=
6)
Pre
Post
SD
Mean
SD
SEM
Mean
Exchange
transfusion
(n
=
14)
Pre
Post
SD
Mean
SD
SEM
HbS(%)
28.56
5.37
23.16*
5.94
0.70
39.50
13.27
28.93*
10.22
1.098
PCV
0.27
0.04
0.32*
0.04
0.008
0.28
0.03
0.32*
0.01
0.004
Sicklecrit
(HbS%
x
PCV)
7.75
1.85
7.26
1.69
0.209
11.41
3.80
9.10*
3.16
0.323
WBVat,
(94.5
s
-
')
(mPa.$)
3.14
0.32
3.69*
0.42
0.106
3.47
0.20
3.73*
0.33
0.046
WBV„„,
(0.695
s
-
')
(mPa.$)
8.43
1.64
12.49*
1.86
0.338
11.60
1.73
13.09*
2.86
0.467
WBV
045
(94.5
s
-1
)
(mPa.$)
6.02
0.46
5.89
0.49
0.086
6.55
0.77
6.09*
0.48
0.128
WBVO
45
(0.695
s
-
`)
(mPa.$)
33.44
7.58
32.67
6.99
0.822
37.93
6.25
32.85*
4.51
0.993
Plasma
viscosity
(mPa.$)
1.24
0.11
1.21
0.09
0.029
1.31
0.08
1.25*
0.07
0.152
Uteroplacental
RI
0.46
0.06
0.47
0.03
0.024
0.58
0.10
0.57
0.09
0.021
WBV
abs
=
absolute
whole
blood
viscosity.
WBV
045
=
corrected
whole
blood
viscosity.
*P
<
0.05.
SD
=
standard
deviation.
SEM
=
standard
error
of
mean
difference.
Blood
transfusion
in
pregnant
women
with
SCD
257
Table
2.
Long-term
change
in
uteroplacental
RI
in
four
patients
with
homozygous
sickle
cell
disease
where
transfusion
resulted
in
a
significant
fall
in
haemoglobin
S
percentage
and
sicklecrit
Mean
Pre
SD
Mean
Post
SD
SEM
HbS
(%)
61.0
14.30
21.0*
14.40
4.22
PCV
0.28
0.02
0.31*
0.02
0.01
Sicklecrit
(HbS%
x
PCV)
16.97
3.99
6.56*
4.80
0.90
WBV.bs
(9
4
.5
s
-
')
(mPa.$)
3.43
0.19
3.55
0.34
0.20
WBV,
b
,
(0.695
s
-1
)
(mPa.$)
10.02
1.06
13.32
3.14
1.76
WBV
045
(94.5
s
-
`)
(mPa.$)
6.67
0.94
6.04
0.14 0.44
WBV0
45
(0.695
S
-1
)
(mPa.$)
37.37
9.41
34.12
1.36
4.80
Plasma
viscosity
(mPa.$)
1.32
0.03
1.26
0.07
0.06
Uteroplacental
RI
0.54
0.17
0.51
0.03
0.09
Gestational
age
at
the
pre-transfusion
measurements
was
23.50
(SD
3.69)
weeks
and
at
the
post-
transfusion
measurements
was
32.75
(SD
6.39)
weeks.
*
P
<
0.05.
Discussion
Normally,
whole
blood
viscosity
is
dominantly
a
function
of
the
PCV
value
and
to
a
lesser
extent
red
cell
deformability
and
the
effect
of
plasma
proteins.
Blood
viscosity
is
higher
in
sickle
cell
disease
than
normal
blood
at
comparable
PCV
values
due
to
the
presence
of
poorly
deformable
red
cells
(Chein
et
al.
1970).
Table
1
demonstrates
the
overriding
influence
on
blood
viscosity
of
a
rise
in
PCV
following
transfusion.
This
has
the
effect
of
negating
any
benefit
from
the
reduction
in
HbS%,
which
is
reflected
in
the
improved
sicklecrit
value
and
corrected
whole
blood
viscosity
at
high
and
low
shear
rates.
Keiden
et
al.
(1988)
reported
similar
results
and
found
that
the
sicklecrit
value
was
of
use
in
moni-
toring
transfusion
therapy
in
these
pregnancies.
The
upper
limit
of
normal
uteroplacental
RI
has
been
reported
to
be
0.58
and
is
known
to
fall
in
early
pregnancy
but
to
be
constant
from
26
weeks
onwards
(Pearce
1992).
Other
authors
(Anyaegbunam
et
al.
1988)
using
a
similar
con-
tinuous
wave
Doppler
instrument
to
that
used
in
the
present
study
found
that
the
incidence
of
abnormal
velocimetry
in
the
uteroplacental
circulation
was
signifi-
cantly
higher
in
patients
with
homozygous
sickle
cell
disease
than
in
a
control
group.
These
authors
did
not
report
the
effect
of
blood
transfusion
on
the
uteroplacental
waveform
but
there
may
be
implications
for
management
if
blood
transfusion
therapy
improves
Doppler
flow
velocity
waveforms.
The
present
study
showed
no
change
in
uteroplacental
RI
immediately
following
transfusion.
A
small,
clinically
and
statistically
insignificant,
improvement
in
uteroplacental
RI
was
associated
with
large
reductions
of
HbS%
over
time
as
shown
in
Table
2.
However,
a
similar
reduction
in
RI
was
found
in
control
group
indicating
that
any
change
in
RI
was
due
to
advancing
gestational
age
rather
than
improvement
in
HbS%.
258
R.J.
Howard,
S.M.
Tuck
and
T.C.
Pearson
Previous
work
has
shown
that
maternal
blood
viscosity
variables
explain
only
about
10%
of
the
variation
in
the
uteroplacental
resistance
index
in
haematologi-
cally
normal
women
(Steel
et
al.
1988).
Although
resistance
to
flow
is
related
to
fluid
viscosity,
vascular
factors
would
appear
to
be
the
most
important
contribu-
tory
factor
to
the
uteroplacental
waveform
(Steel
et
al.
1988).
The
results
from
the
present
study
show
that
there
is
no
change
in
the
uteroplacental
waveform
following
blood
transfusion
and
significant
improve-
ment
in
HbS%
and
sicklecrit
either
immediately
or
after
several
weeks.
This
suggests
that
placental
resistance
as
assessed
by
continuous
wave
Doppler
ultra-
sound
is
unchanged
as
a
result
of
prophylactic
blood
transfusion.
Our
findings
concur
with
clinical
evidence
that
has
failed
to
show
a
direct
relationship
between
fetal
outcome
and
the
use
of
prophylactic
blood
transfusion
in
pregnancies
complicated
by
maternal
sickle
cell
disease.
Acknowledgements
The
authors
wish
to
acknowledge
Dr
B.
Wonke,
Dr
A.
Yardumian
and
Dr
A.
Mehta
for
their
assistance
and
permission
to
study
patients
under
their
care.
References
ANYAEGBUNAM
A.,
LANGER
0.,
Lois
B.,
DAMUS
K.,
HALPERT
R.
&
MERKATZ
I.
(1988)
The
application
of
uterine
and
umbilical
artery
doppler
velocimetry
to
the
antenatal
supervision
of
pregnancies
complicated
by
maternal
sickle
hemoglobinopathies.
Am.
J.
Obstet.
Gynecol.
159,
544-547
CHARACHE
S.
&
NIEBYL
J.R.
(1985)
Pregnancy
and
sickle
cell
disease.
Clin.
Haematol.
14,
729-746
CHEIN
S.,
UsAMI
S.
&
BERTLES
J.F.
(1970)
Abnormal
rheology
of
oxygenated
blood
in
sickle
cell
anaemia.
J.
Clin.
Inv.
49,
623-634
INTERNATIONAL
COMMITTEE
FOR
STANDARDIZATION
IN
HAEMATOLOGY
EXPERT
PANEL
ON
BLOOD
RHEOLOGY
(1986)
Guidelines
for
measurement
of
blood
viscosity
and
erythrocyte
deformability.
Clin.
Hemorheol.
6,
439-453
KEIDEN
A.J.,
MARWAH
S.S.,
BAREFORD
D.,
FRANKLIN
I.M.
&
STUART
J.
(1988)
Laboratory
tests
for
monitoring
prophylactic
exchange
transfusion
in
pregnancy
complicated
by
sickle
cell
disease.
Clin.
lab.
Haematol.
10,
243-250
KOSHY
M.,
BURD
L.,
WALLACE
D.,
MOAWAD
A.
&
BARON
J.
(1988)
Prophylactic
red-cell
transfusions
in
pregnant
patients
with
sickle
cell
disease.
NEJM
319,
1447-1452
LUKENS
J.N.
(1993)
Hemoglobinopathies
S,C,D,E
and
0
and
associated
diseases.
In:
Wintrobe's
Clinical
Hematology
(ed.
G.
Richard
Lee)
Lea
&
Febiger,
London
MORRISON
J.C.,
MORRISON
F.S.,
FLOYD
R.C.,
ROBERTS
W.E.,
WAYNE
HESS
L.
&
WISER
W.L.
(1991)
Use
of
continuous
flow
erythrocytapheresis
in
pregnant
patients
with
sickle
cell
disease.
J.
Clin.
Apheresis.
6,
224-229
PEARCE
J.M.F.
(1992)
Doppler
waveforms
in
normal
pregnancy.
In:
Doppler
Ultrasound
in
Perinatal
Medicine
(ed.
J.M.F.
Pearce)
pp.
82-94,
Oxford
University
Press,
Oxford
SKIDMORE
R.,
WOODCOCK
J.P.,
WELLS
P.N.T.,
BIRD
D.
&
BAIRD
R.N.
(1980)
Physiological
interpretation
of
Doppler
shift
waveforms.
III.
Ultrasound
Med.
Biol.
6,
227-31
Blood
transfusion
in
pregnant
women
with
SCD
259
STEEL
S.A.,
PEARCE
J.M.F.,
NASH
G.,
CHRISTOPHER
B.,
DORMANDY
J.
&
BLAND
J.M.
(1988)
Maternal
blood
viscosity
and
uteroplacental
blood
flow
velocity
waveforms
in
normal
and
complicated
pregnancies.
Br.
J.
Obstet.
Gynaecol.
95,
747-752
STEEL
S.A.,
PEARCE
J.M.,
MCPARLAND
P.
&
CHAMBERLAIN
G.V.P.
(1990)
Early
doppler
ultrasound
screening
in
prediction
of
hypertensive
disorders
of
pregnancy.
Lancet.
i,
1548-1551
TUCK
S.M.,
STUDD
J.W.W.
&
WHITE
J.M.
(1983)
Pregnancy
in
sickle
cell
disease
in
the
UK.
Br.
J.
Obstet.
Gynaecol.
90,
112-117.