 |
| |
| PATHOPHYSIOLOGY |
|
In
red cell isoimmunized pregnancies, maternal hemolytic antibodies
cross the placenta and attach themselves onto fetal red cells, which
are then destroyed in the fetal reticulo-endothelial system1.
In mild to moderate disease there is a compensatory increase in
intramedullary erythropoiesis, and in severe disease there is recruitment
of extramedullary erythropoietic sites, such as liver and spleen
2,3.
Fetal blood pO2, pCO2 and pH usually remain within the normal
range except in extreme anemia, when hypoxia and acidosis occur
4,5. The fetal blood oxygen content decreases
in proportion to the degree of anemia. The fetal 2,3-diphosphoglycerate
(2,3-DPG) concentration is increased and the consequent decrease
in hemoglobin–oxygen affinity presumably improves delivery
of oxygen to the tissues 6. In moderate anemia,
the umbilical arterial plasma lactate concentration is increased
but this is cleared by a single passage of fetal blood through the
placenta and normal umbilical venous levels are maintained 7.
In severe anemia, when the oxygen content is less than 2 mmol/l,
the placental capacity for lactate clearance is exceeded and the
umbilical venous concentration increases exponentially. These data
suggest that, in the fetus, systemic metabolic acidosis can be prevented,
unless the oxygen content decreases below the critical level of
2 mmol/l 7. When the fetal hemoglobin concentration
deficit exceeds 6 g/dl, hydrops fetalis develops 1. This may be
the result of extensive infiltration of the liver by erythropoietic
tissue, leading to portal hypertension, due to parenchymal compression
of portal vessels, and hypoproteinemia, due to impaired protein
synthesis 8. Furthermore, at this hemoglobin
concentration deficit, the oxygen content decreases below the critical
level of 2 mmol/l.
|
| DIAGNOSIS
AND TREATMENT OF FETAL ANEMIA |
The
severity of fetal hemolysis can be predicted from:
(1)
The history of previously affected pregnancies;
(2)
The level of maternal hemolytic antibodies;
(3)
Changes in the flow velocity waveforms obtained by Doppler studies
of the fetal circulation;
(4)
The altered morphometry of fetus and placenta; and
(5)
The presence of pathological fetal heart rate patterns4.
However,
there is a wide scatter of values around the regression lines describing
the associations between the degree of fetal anemia and the data
obtained from these indirect methods of assessment. The only accurate
method for determining the severity of the disease is blood sampling
by cordocentesis and measurement of the fetal hemoglobin concentration.
Cordocentesis should be performed for all patients with a history
of severe disease and those with a hemolytic antibody level of more
than 15 IU/ml or a titer of 1 in 128 or more9–12. At cordocentesis,
a fetal blood sample is first obtained and the hemoglobin concentration
is determined. If this is below the normal range, the tip of the
needle is kept in the lumen of the umbilical cord vessel and fresh,
packed, rhesus-negative blood compatible with that of the mother
is infused manually into the fetal circulation through a 10-ml syringe
or a transfusion set. At the end of the transfusion, a further fetal
blood sample is aspirated to determine the final hemoglobin concentration13,14.
Subsequent transfusions are given at 1–3-weekly intervals
until 34–36 weeks, and their timing is based on the findings
of non-invasive tests, such as Doppler studies, and the knowledge
that, following a fetal blood transfusion, the mean rate of decrease
in fetal hemoglobin is approximately 0.3 g/dl per day14. |
| DOPPLER
STUDIES |
| |
| Uterine
artery |
In
a longitudinal study of 12 fetuses, Copel et al. included
the uterine artery pulsatility index (PI), together with the descending
thoracic aortic peak velocity, in a multiple regression model to
predict whether the fetal hematocrit was below or above 25% before
the second fetal blood transfusion 15. The authors suggested that
the significant contribution of uterine artery PI to the model could
be explained by the effect of resolving placental edema after the
correction of fetal anemia by the second transfusion. However, this
is unlikely because there was no difference in uterine PI between
hydropic and non-hydropic fetuses. In a series of 95 red cell isoimmunized
pregnancies, impedance in the uterine artery was within the normal
range and there was no significant association between PI and the
degree of fetal anemia. Therefore, it is unlikely that fetal anemia
alters the uteroplacental circulation. |
| Umbilical
artery |
Rightmire
et
al. found a significant inverse correlation between impedance
to flow in the umbilical artery and fetal hematocrit 17
. It was suggested that increased impedance to flow in the fetoplacental
microcirculation may be due to hypoxemia-mediated capillary endothelial
cell damage, or clogging of the placental capillaries by the large
fetal erythroblasts. In contrast, Warren et al . reported
that impedance in the umbilical artery was not abnormal in red cell
isoimmunized pregnancies with high amniotic fluid bilirubin concentration
18. Similarly, in a study of 95 affected
pregnancies, umbilical artery PI, measured immediately before cordocentesis,
was not increased and was not associated with fetal anemia 16. |
| Impedance
to flow in fetal vessels |
| Vyas
et al. measured the PI in the middle cerebral artery of 24
non-hydropic fetuses from red cell isoimmunized pregnancies; there
were no significant associations between PI and either the degree
of fetal anemia or the degree of deficit in oxygen content measured
in samples obtained by cordocentesis 12.
Furthermore, in a study of 95 fetuses undergoing cordocentesis for
rhesus disease, the PI in both the middle cerebral artery and descending
thoracic aorta was not significantly different from normal controls
and there was no significant association between PI and fetal anemia
16. These findings indicate that impedance
to flow is not affected by anemic hypoxia and by the alterations
of blood constituents, such as hypoproteinemia, or red cell morphology,
such as erythroblastemia, that accompany severe anemia 2,3. |
| Fetal
cardiac Doppler studies |
| Meijboom
et al. measured maximal and mean temporal velocity and early
passive to late active ventricular filling phase (E/A) ratio on
the atrioventricular orifices in 12 fetuses immediately before fetal
blood transfusion 19. There was a non-significant
increase in both maximal and mean temporal velocities. Furthermore,
there was a significant reversal in the E/A ratio in the flow waveforms
from the tricuspid valve. In normal fetuses, these two peaks present
an ‘M’ shape, whereas in anemic fetuses the E peak is
dominant, suggesting that, in fetal anemia, there is an increased
pre-load in the right atrium. Copel et al. found that anemic fetuses
before any intrauterine transfusion had significantly higher stroke
volumes and ventricular outputs than normal controls. The increase
was shared proportionately by both ventricles 20.
However, there was no significant relationship between fetal hematocrit
and cardiac output. Nevertheless, extremely compromised fetuses
demonstrated diminished cardiac function as a terminal finding.
In contrast, Barss et al. reported a case of hydrops fetalis
where the cardiac output measured before an intravascular transfusion
was close to the normal mean for gestation 21.
Rizzo et al. measured right and left cardiac outputs (by
multiplying the tricuspid or mitral mean temporal velocities, valvular
area and heart rate) in 12 anemic fetuses before blood transfusion
by cordocentesis 22. Both left and right
cardiac outputs were significantly higher for gestation than in
187 normal controls. Furthermore, the E/A ratios of both atrioventricular
valves were higher than normal (Figure 1). Lam et al . examined
20 anemic (due to homozygous a-thalassemia-1) fetuses at 12–13
weeks of gestation and reported increased peak velocities at the
pulmonary valve and ascending aorta and an increased inner diameter
of the pulmonary valve 23. The total cardiac
output was increased by one-third and this was mainly due to an
increase of the cardiac output on the right side. The findings of
increased fetal cardiac output in anemia are in agreement with the
results of animal studies and confirm the prediction, from a mathematical
model, that, in fetal anemia, the cardiac output is increased to
maintain an adequate oxygen delivery to the tissues 24.
Possible mechanisms include, first, decreased blood viscosity leading
to increased venous return and cardiac preload and, second, peripheral
vasodilatation as a result of a fall in blood oxygen content and
therefore reduced cardiac afterload. |
 |
 |
| Figure
1 - Flow
velocity waveforms across the tricuspid valve in an anemic fetus
at 28 weeks of gestation. The E/A ratio is increased (0.97 compared
to the expected mean for gestation of 0.75). |
|
| The
high E/A is suggestive of increased cardiac preload. Since right-to-left
cardiac output ratio is normal, there is no evidence of redistribution
in cardiac output similar to that described in hypoxemic growth-restricted
fetuses. These findings suggest that, in fetal anemia, the changes
in fetal cardiac output are mainly due to low blood viscosity. An
alternative explanation is that the symmetrical increase in cardiac
output is secondary to an increase in catecholamine concentrations
in fetal blood induced by anemia 25. |
| Blood
velocity in fetal arteries |
Rightmire
et al . examined 21 fetuses from red cell isoimmunized pregnancies
before fetal blood sampling and reported a significant inverse association
between aortic mean blood velocity and fetal hemoglobin concentration
17. Similarly, from the examination of 68
previously untransfused fetuses at 17–37 weeks of gestation,
Nicolaides et al. reported a significant association between
aortic mean velocity, measured immediately before cordocentesis,
and the degree of fetal anemia 11. However,
separate analysis of non-hydropic and hydropic fetuses demonstrated
that in the former group there was a significant positive correlation
between increased velocity and fetal anemia, whilst in the latter
group there was a significant negative correlation between these
two parameters.
In an extended series of 95 previously untransfused fetuses undergoing
cordocentesis for rhesus disease, there was a significant increase
in aortic velocity with the degree of fetal anemia 16
. Although, in some hydropic fetuses, aortic velocity was decreased,
in the majority of cases the velocity was increased. In an additional
series of 212 fetuses that had a transfusion 2–3 weeks previously,
the relation between aortic velocity and anemia was weaker.
Copel et al. measured the peak velocity in 16 fetuses immediately
before cordocentesis and derived a series of formulae for the prediction
of whether the fetal hematocrit was above or below 25% 15
. The best prediction was achieved for the untransfused fetuses.
For subsequent transfusions, different formulae had to be used,
presumably because of the different rheological properties of adult,
rather than fetal, blood in the fetal circulation. Bilardo et al.
measured mean velocity in the common carotid artery of 12 previously
untransfused anemic fetuses immediately before cordocentesis 26.
There was a significantassociation between the degree of fetal anemia
and the increase in blood velocity. The authors speculated that
this increase in common carotid artery velocity reflected increased
cardiac output associated with fetal anemia, rather than a chemoreceptormediated
redistribution in blood flow, as seen in hypoxemic growth-restricted
fetuses 27.
Vyas et al ., in a study of 24 previously untransfused,
non-hydropic fetuses from red cell isoimmunized pregnancies at 18–35
weeks of gestation, reported a significant correlation between an
increase in mean velocity in the middle cerebral artery and the
degree of fetal anemia measured in samples obtained by cordocentesis
12. In an extended series of 95 previously
untransfused fetuses undergoing cordocentesis for rhesus disease,
there was a significant association between the increase in mean
velocity in the middle cerebral artery with the degree of fetal
anemia 16. In an additional series of 212
fetuses that had a transfusion 2–3 weeks previously, the relation
between blood velocity and anemia was weaker 16. Mari et al
. found a significant association between the peak systolic
velocity in the middle cerebral artery and fetal hematocrit at cordocentesis.
In a prospective study of 16 fetuses from isoimmunized pregnancies,
they found that all the anemic fetuses had peak velocity values
above the normal mean for gestation, whereas none of the fetuses
with peak velocity below the normal mean was anemic 28.
On the basis of these results, they suggested that, in the management
of isoimmunized pregnancies, the indication for cordocentesis should
be a peak systolic velocity above the normal mean for gestation.
These results were confirmed in a multicenter study involving 111
fetuses from isoimmunized pregnancies; all moderately or severely
anemic fetuses had increased peak velocity in the middle cerebral
artery 29.
Steiner et al . performed 112 fetal blood samplings by cordocentesis
in 33 cases with rhesus isoimmunization and found that the mean
peak systolic aortic velocity of anemic fetuses was significantly
higher than that of unaffected fetuses 30.
Furthermore, there was a good correlation between delta peak velocities
and delta hematocrits for the first procedure. Bahado-Singh
et al. examined the main splenic artery waveforms in 22 nonhydropic
fetuses from red cell isoimmunized pregnancies 31.
The deceleration angle between the line describing the average slope
during the diastolic phase of the cycle and the vertical axis was
measured and expressed in multiples of the median (MoM) for gestational
age. A decrease in the deceleration angle was associated with fetal
anemia and, at a threshold deceleration angle of < 0.60 MoM,
the sensitivity for severe anemia (hemoglobin deficit of 5 g/dl)
was 100%, with an 8.8% false-positive rate. It was concluded that
all cases of severe anemia could be identified before the development
of hydrops, and, if, in the management of red cell isoimmunization,
cordocentesis is only carried out if the deceleration angle is <
0.60 MoM, then the need for cordocentesis would decrease by more
than 90% 31 .
The findings of increased blood velocity in the fetal arteries with
anemia (Figure 2
and Figure 3) are compatible
with the data from the fetal cardiac Doppler studies. If it is assumed
that, in anemia, the cross-sectional area of the fetal descending
aorta and middle cerebral arteries does not change, the increased
velocity would reflect an increase in both central and peripheral
blood flow due to increased cardiac output. The decreased aortic
velocity in some hydropic fetuses may be the consequence of cardiac
decompensation, presumably due to the associated hypoxia and lactic
acidosis and to the impaired venous return due to liver infiltration
with hemopoietic tissue 2. |
 |
Figure
2: Blood velocity in the fetal thoracic aorta (left)
and middle cerebral artery (right) in red cell isoimmunized
pregnancies plotted on the appropriate reference range (mean,
95th and 5th centiles) for gestation. Fetal anemia is associated
with a hyperdynamic circulation. |
|
 |
Figure
3: Flow
velocity waveformin the fetal middle cerebral artery in
a severely anemic fetus at 22 weeks (left) and in a normal
fetus (right). In fetal anemia, blood velocity is increased
|
|
| Blood
velocity in fetal veins |
|
Rightmire et al . measured the fetal inferior vena caval
time averaged mean velocity immediately before the first intravascular
fetal blood transfusion in 19 rhesus-affected pregnancies at 18–28
weeks of gestation 17. Although the velocity
was higher than in non-anemic controls, there was no significant
correlation with fetal hematocrit. In the same study, the intrahepatic
umbilical venous velocity was not significantly different from non-anemic
controls. In contrast, Kirkinen et al. examined 18 rhesus
isoimmunized pregnancies within 4 days before delivery and reported
that, in anemic fetuses, the volume flow in the intrahepatic umbilical
vein was significantly increased due to both increased blood velocity
and vessel diameter 32. Similarly,Warren
et al. performed serial measurements of fetal blood flow
in 51 rhesus isoimmunized pregnancies and reported that increased
flow was associated with subsequent development of fetal hydrops
or rise in amniotic fluid bilirubin concentration. It was postulated
that the increased flow was the result of reduced blood viscosity
due to the reduced hematocrit. Iskaros et al. performed serial
measurements of umbilical vein maximal flow velocity and found that
elevated velocities prior to delivery were predictive of the need
for exchange blood transfusion 33. They concluded
that pregnancies with a mild or no history of fetal anemia may be
monitored by a combination of serial antibody quantification and
Doppler measurement of umbilical vein maximal flow velocities. Oepkes
et al ., in a study of 21 previously transfused fetuses from
red cell isoimmunized pregnancies, reported increased peak systolic
and time averaged maximum velocities in the ductus venosus before
intravascular fetal blood transfusion, which returned to normal
values the following day 34.
It was suggested that the increase in ductus venosus blood flow
in anemic fetuses reflects increased venous return and therefore
cardiac preload. Hecher et al. recorded flow velocity waveforms
from the ductus venosus, right hepatic vein, inferior vena cava,
middle cerebral artery and descending thoracic aorta from 38 red
cell isoimmunized pregnancies and found that only the velocity in
the thoracic aorta was significantly associated with the degree
of fetal anemia 35. Furthermore, this study
showed that heart failure is not the primary mechanism for the development
of hydrops, but rather the end-stage of severe anemia, because the
pulsatility of venous blood flow waveforms was not increased. Hydrops
may be due to reduced colloid osmotic pressure, hypoxia-induced
endothelial damage and increased permeability. Severe fetal anemia,
with consequent cardiac failure, is associated with a reversed ‘a’
wave in the ductus venosus. Under these conditions, pulsations are
also present in the venous portal system (which in normal fetuses
is characterized by a continuous flow). The pulsatile pattern present
in the venous system corresponds to findings in children with portal
hypertension 36. Since, in fetal anemia,
resistance to flow in the fetal circulation and placenta is unchanged,
an increase of umbilical venous blood flow is in accordance with
high cardiac output and elevated arterial velocities.
|
| Hemodynamic
changes following fetal blood transfusion |
|
Warren et al. and Kirkinen et al. found that, immediately
after a fetal intraperitoneal blood transfusion, there was
a temporary increase in umbilical venous blood flow and subsequent
gradual decrease from above to within the normal range 18,32.
It was suggested that the gradual decrease in flow, coinciding with
resolution of fetal ascites, was the result of absorption of the
transfused blood and correction of the fetal anemia. Copel et
al. measured impedance to flow in the uterine and umbilical
arteries and peak velocity in the descending thoracic aorta immediately
before and 12 hours after fetal blood exchange transfusion by
cordocentesis; no differences were found 15.
Doppler studies of impedance to flow in the umbilical artery before
and soon after intravascular top-up transfusion provided
conflicting results. In a study of 43 cases, Bilardo et al.
found no significant changes 26. In contrast,
Weiner and Anderson and Hanretty et al. reported a significant
decrease in impedance immediately after fetal blood transfusion
in 19 and 22 fetuses, respectively 37,38.
It was postulated that simple needling of fetal blood vessels stimulates
a humoral vasodilator mechanism. Supportive evidence was provided
by the finding that fetal blood levels of vasoactive substances
with vasodilatatory effects, like prostaglandins and atrial natriuretic
peptide, are increased after an intravascular blood transfusion
39,40. However, as Welch et al. Pointed
out, the possible changes in indices of impedance after an intrauterine
transfusion may not be simply due to vasodilatation but due to the
complex influences of altered fetal whole blood viscosity, increased
number of scattering particles (red cells) and vasoactive compounds
41. Bilardo et al. performed fetal
Doppler studies in 43 cases immediately before and within 30 minutes
of an intravascular top-up transfusion 26.
There was a significant decrease in mean blood velocity in both
the descending thoracic aorta (Figure
4 ) and common carotid artery. Similarly, Mari et
al. found that intrauterine transfusion is associated with a
significant decrease in the peak velocity in the middle cerebral
artery and this decrease is proportional to the increase in fetal
hematocrit 42. These findings are likely
to be the result of a decrease in cardiac output following the transfusion
due to:
(1)
Increased blood hemoglobin concentration and viscosity, and consequent
decrease in venous return;
(2)
Congestive heart failure due to overloading of the fetal circulation;
or
(3)
Cardio-inhibition due to increased baroreceptor activity.
Confirmatory
evidence of a decrease in cardiac output following blood transfusion
was provided by Rizzo et al.22. They
measured left and right cardiac outputs before and at 15-min intervals
for 2 hours after an intravascular top-up transfusion in 12 fetuses.
After transfusion, there was a significant temporary fall in both
right and left cardiac outputs. Furthermore, the E/A ratios in both
the tricuspid and mitral valves were increased suggesting that cardiac
preload was also increased. Within 2 hours after transfusion, both
parameters had returned towards the normal range. The fall in cardiac
output was significantly related to the amount of expansion of the
fetoplacental volume due to the transfusion. The most likely explanation
for these findings is that transfusion results in temporary cardiovascular
overload. Animal studies have also shown that the fetal heart has
very limited reserve capacity to increase its output in response
to acute overload, and that massive increases in fetal blood volume
are associated with a decrease in cardiac output. After transfusion,
there is a rapid rate of fluid loss and this explains the rapid
recovery in E/A ratios and cardiac output 43.
|
 |
Figure
4: Flow velocity waveform in the fetal descending
thoracic aorta in an anemic fetus demonstrating high velocities
and Doppler ‘window’ for low velocities during
systole (top). After blood transfusion, there is a decrease
in peak systolic velocity and the Doppler ‘window’
has disappeared (bottom). |
|
The
short-lived nature of the hemodynamic effects of intravascular transfusion
can also explain the findings of Mari et al. who reported
that the middle cerebral artery PI, internal carotid artery PI and
umbilical artery PI before and the day after fetal transfusion were
not significantly different 44. Similarly,
Copel et al., in a study of cardiac output at 12 hours after
intravascular blood transfusion, found no significant differences
from the pretransfusion levels 20. |
| CONCLUSIONS |
-
In
red cell isoimmunized pregnancies, placentation is normal and
therefore indices of impedance to flow in the uterine and umbilical
arteries are normal, irrespective of the severity of fetal anemia.
-
In
red cell isoimmunized pregnancies, normal placental perfusion
results in normal fetal blood pO2, pCO2 and
pH and therefore there is no evidence of redistribution
in the fetal circulation; the PI in the middle cerebral artery,
thoracic aorta and renal arteries is normal.
-
In
red cell isoimmunized pregnancies, the left and right cardiac
outputs and blood velocity in the umbilical vein, middle cerebral
artery, thoracic aorta, renal arteries and the fetal venous
system are ncreased in proportion to the degree of fetal anemia.
The most likely mechanism for the hyperdynamic circulation of
anemic fetuses is decreased blood viscosity, leading to increasedvenous
return and cardiac preload.
-
In
red cell isoimmunized pregnancies, fetal heart failure is not
the primary mechanism for the development of hydrops. However,
severe anemia with consequent end-stage cardiac failure may
be associated with high pulsatility or even reversed ‘a’
wave in the ductus venosus and pulsations in portal sinus.
-
In
red cell isoimmunized pregnancies, intravascular fetal blood
transfusion results in temporary cardiovascular overload with
a temporary fall in both right and left cardiac outputs.
|
| |
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