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The MCA Doppler

and its Role in the


Evaluation of Fetal
Anemia and Fetal
G ro w t h R e s t r i c t i o n
Mauro H. Schenone, MD, Giancarlo Mari, MD*

KEYWORDS
 MCA  Doppler  IUGR  Fetal anemia

DIAGNOSIS OF FETAL ANEMIA BEFORE THE USE OF THE MIDDLE CEREBRAL ARTERY
PEAK SYSTOLIC VELOCITY

Before the widespread use of the middle cerebral artery (MCA) peak systolic velocity
(PSV), the management of maternal red cell alloimmunization was based on an indirect
measurement of fetal hemolysis using spectrophotometric analysis of the amniotic
fluid (optical density [OD] at 450 nm).1 The method to predict the severity of the hemo-
lytic disease of the fetus and neonate was introduced by Liley in 1961.2 The only option
in the diagnosis of anemia from causes other than red cell alloimmunization was the
percutaneous umbilical cord sampling that was initially performed with fetoscopy
and, since 1983, under ultrasound guidance.3

FETAL MCA: 23 YEARS OF LITERATURE

Woo and colleagues4 reported serial Doppler flow velocity-time waveforms of the
MCA at its origin from the internal carotid arteries in 14 patients with normal singleton
pregnancies. The A/B ratio showed a progressive decrease with advancing gesta-
tional age. Kirkinen and colleagues5 recorded blood flow velocity waveforms from
intracranial arteries in 83 normal and 84 high-risk pregnancies. They concluded that
there was a decrease in the resistance index (RI) toward the end of the pregnancy
and that continuous forward flow during diastole was always present in normal cases.
Furthermore, they stated that an RI below the tenth percentile was associated with

The authors have nothing to disclose.


Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, 853
Jefferson Avenue, Room E102, Memphis, TN 38103, USA
* Corresponding author.
E-mail address: gmari@uthsc.edu

Clin Perinatol 38 (2011) 83–102


doi:10.1016/j.clp.2010.12.003 perinatology.theclinics.com
0095-5108/11/$ – see front matter Ó 2011 Elsevier Inc. All rights reserved.
84 Schenone & Mari

newborns that were small for gestational age (SGA) and/or the appearance of subse-
quent cardiotocographic abnormalities.
By 1990, there were 9 published studies in the literature focused on characterizing
the fetal MCA Doppler flow velocity waveform in normal pregnancies, abnormal preg-
nancies (primarily intrauterine growth-restricted [IUGR] fetuses), and pregnancies in
which fetal distress was present.6–13 In 1989, Mari and colleagues10 determined the
pulsatility index (PI) in the middle cerebral, anterior cerebral, and internal carotid
arteries in 30 fetuses (12 normal, 14 IUGR, and 4 post–in utero blood transfusion as
part of the treatment of Rh isoimmunization) between 23 and 37 weeks of gestation.
Their work demonstrated the importance of knowing which cerebral vessel is being
insonated, because the PI was significantly different in the middle cerebral and internal
carotid arteries when compared with the anterior cerebral artery. Since the introduc-
tion of the MCA Doppler to fetal medicine, more than 600 studies have been pub-
lished, covering divergent topics from better known areas (eg, IUGR and fetal
anemia) to less-explored areas, such as the effects of medications on the MCA14–21
and fetal intracranial hemorrhage.22–24

MCA-PSV FOR THE DIAGNOSIS OF FETAL ANEMIA: A BRIEF HISTORY OF ITS


CONCEPTION

The use of the MCA-PSV for the diagnosis of fetal anemia is considered one of the few
practice-changing discoveries in fetal medicine. One of the most important contribu-
tions of the MCA-PSV to clinical practice has been the dramatic reduction in the
number of invasive procedures performed in the management of red cell alloimmu-
nized pregnancies.25
Mari and colleagues26 reported that the PI of the MCA decreases within 2 hours
after intrauterine blood transfusion and that the MCA-PSV was a better parameter
than the PI in the assessment of pregnancies complicated by fetal anemia.27 Vyas
and colleagues28 studied 24 Rh-isoimmunized pregnancies and noted an increase
in the MCA mean blood velocity, hypothesizing that the increase of blood flow could
be attributed to a decrease in blood viscosity, as previously suggested by experimen-
tation in dogs.29 A few years later, the same group reported that the MCA mean blood
velocity was not an optimal parameter to assess fetal anemia.30
The reference range for the MCA-PSV was reported in 1995 (Fig. 1).31 In the same
study, it was reported that all the anemic fetuses had an MCA-PSV greater than the
mean of the range of normal values. The false-positive rate was 50%; although
high, had this rate been applied in clinical practice at that time, it would have elimi-
nated 50% of the invasive procedures.
In 1997, MCA Doppler waveforms were examined before and after intrauterine
blood transfusion. It was noted that the increase of the fetal hematocrit was associ-
ated with a decrease in the MCA-PSV, and the results were later reproduced.32,33
A study of 111 fetuses at risk for anemia because of red cell alloimmunization and
265 normal fetuses later changed the practice of how the former were evaluated.25
The hemoglobin concentrations in blood obtained by cordocentesis and MCA-PSV
were measured. A reference range for hemoglobin concentrations in fetuses from
18 to 40 weeks of gestation was established from samples obtained by cordocentesis
from 265 normal fetuses (values are shown in Table 1). Previously reported nomo-
grams of the normal values of the MCA-PSV by gestational age were used.31
The study demonstrated that, based on traditional criteria, approximately 70% of
the fetuses undergoing a cordocentesis were either nonanemic or mildly anemic.
Of the remaining 30%, 40% were hydropic at the time the transfusion was performed.
MCA Doppler and its Applications in Fetal Anemia and Growth Restriction 85

Fig. 1. MCA-PSV with advancing gestation. The curves indicate the median (bottom) and 1.5
multiples of the median (top) for the MCA-PSV. (Reprinted from Mari G, Deter RL, Carpenter
RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to
maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the
Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342(1):9–14; with permission.)

In the same group, an MCA-PSV greater than 1.50 multiples of the median (MoM)
(selected by the receiver operating characteristic curve) would have detected all cases
of significant anemia and would have avoided approximately 70% of the unnecessary
cordocentesis. The false-positive rate was 12%. These results have been reproduced
in many studies.33–42 Fig. 2 shows the number of anemic and nonanemic fetuses by
the MCA-PSV value and gestational age.

HOW DOES THE MCA-PSV COMPARE WITH DELTA OD450 NM IN THE DIAGNOSIS
OF ANEMIA?

In 1997, it was reported that the MCA-PSV was at least as good as the delta OD450 in
diagnosing anemia; however, it had the advantage of being a noninvasive technique.43
Pereira and colleagues44 confirmed these results. Oepkes and colleagues,39 in
a prospective multicenter study, included 165 fetuses of red cell alloimmunized preg-
nancies with indirect antiglobulin titers of at least 1:64 and antigen-positive fetal blood.
The MCA-PSV and delta OD450 methods were applied to all the patients. A total of 74
fetuses were diagnosed with anemia (ie, hemoglobin concentration <5 SD), and the
predictions of each method were compared with the results of the cordocentesis.
The MCA-PSV helped to correctly diagnose anemia in 65 of 74 cases, whereas delta
OD450 did so in 56 of 74 cases. The sensitivity and specificity for the MCA-PSV were
88% and 82%, respectively, whereas for delta OD450, the sensitivity was 76% and the
specificity was 77%. It was concluded that the MCA-PSV can “safely replace invasive
testing” (ie, delta OD450) in the management of Rh-alloimmunized pregnancies.
The American Congress of Obstetricians and Gynecologists has since recognized
that the MCA-PSV is a useful tool in the diagnosis of fetal anemia in the hands of expe-
rienced operators.45
86 Schenone & Mari

Table 1
Reference ranges for fetal hemoglobin concentration in normal and anemic fetuses as
a function of gestational age

Weeks Median 0.55 MoM 0.65 MoM 0.84 MoM


18 10.6 5.8 6.9 8.9
19 10.9 6.0 7.1 9.1
20 11.1 6.1 7.2 9.3
21 11.4 6.2 7.4 9.5
22 11.6 6.4 7.5 9.7
23 11.8 6.5 7.6 9.9
24 12.0 6.6 7.8 10.0
25 12.1 6.7 7.9 10.2
26 12.3 6.8 8.0 10.3
27 12.4 6.8 8.1 10.4
28 12.6 6.9 8.2 10.6
29 12.7 7.0 8.3 10.7
30 12.8 7.1 8.3 10.8
31 13.0 7.1 8.4 10.9
32 13.1 7.2 8.5 11.0
33 13.2 7.2 8.6 11.1
34 13.3 7.3 8.6 11.1
35 13.4 7.4 8.7 11.2
36 13.5 7.4 8.7 11.3
37 13.5 7.5 8.8 11.4
38 13.6 7.5 8.9 11.4
39 13.7 7.5 8.9 11.5
40 13.8 7.6 9.0 11.6

Normal hemoglobin values are >0.84 MoM; fetal anemia is divided into mild (hemoglobin <0.84
MoM), moderate (hemoglobin <0.65 MoM) and severe (hemoglobin <0.55 MoM).
Abbreviation: MoM, multiples of the median.
Reprinted from Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultraso-
nography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for
Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med 2000;342(1):9–14;
with permission.

PERFORMING AND INTERPRETING THE DOPPLER ASSESSMENT OF THE MCA WHEN


TESTING FOR FETAL ANEMIA

The MCA closest to the ultrasound probe should be sampled soon after its origin from
the internal carotid artery because the measurement at this level has the lowest intra-
observer and interobserver variability, although the peak velocity in the contralateral
MCA would still be valid.46,47 Fig. 3 depicts the area where the spectral Doppler
sample volume should be placed once the MCA has been identified. Fig. 4 shows
normal and abnormal MCA waveforms.
A total of 50 to 100 waveforms in at least 3 sets are examined in the absence of fetal
breathing and movements, and approximately 5 to 10 minutes are spent with the
patient. When the velocity is approximately the same in each set, the measurement
is considered reliable enough for clinical decision making. However, an error of
MCA Doppler and its Applications in Fetal Anemia and Growth Restriction 87

Fig. 2. MCA-PSV in 111 fetuses at risk for anemia because of maternal red cell alloimmuni-
zation. Open circles indicate fetuses with either no anemia or mild anemia (>0.65 MoM
hemoglobin concentration). Triangles indicate fetuses with moderate or severe anemia
(<0.65 MoM hemoglobin concentration). The solid circles indicate the fetuses with hydrops.
The solid curve indicates the median MCA-PSV, and the dotted curve indicates 1.5 MoM.
(Reprinted from Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler
ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative
Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med
2000;342(1):9–14; with permission.)

5% to 10% is possible; therefore, we recommend basing such decisions on trends of


the MCA-PSV after serial exams when possible, rather than using a single
examination.48 This approach has greatly reduced the false-positive rate even after
35 weeks of gestation, and patients who are at risk for fetal anemia can be delivered
successfully between 38 and 40 weeks of gestation when MCA-PSV values are within
an acceptable range. Our group has never missed a case of severe anemia (ie, no
fetus has become hydropic when followed with the MCA-PSV). In the last 7 years,
no unnecessary cordocentesis was performed and no patient was delivered at less
than 38 weeks of gestation when the patient was at risk for anemia and followed
with normal values of the MCA-PSV. We recommend against the use of the angle
corrector because the intraobserver and interobserver variability increases when an
angle corrector is used.49 Our approach to the management of pregnancies compli-
cated by red cell alloimmunization is summarized in Fig. 5.

MCA-PSV FOR THE DIAGNOSIS OF FETAL ANEMIA: IMPORTANT CONSIDERATIONS IN


PARTICULAR SCENARIOS

Important considerations have to be made when using the MCA-PSV for the diagnosis
of anemia in fetuses after one or more intrauterine blood transfusions. Detti and
colleagues50 examined the MCA-PSV before cordocentesis in 64 fetuses that had
previously undergone an intrauterine blood transfusion. Anemia was defined as mild
(hemoglobin concentration between 0.65 and 0.84 MoM), moderate (hemoglobin
88 Schenone & Mari

Fig. 3. Color Doppler ultrasound image showing the MCA. The sample volume (arrow) is
placed in the center of the vessel after its origin from the internal carotid artery. (Reprinted
from Mari G. Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia:
the untold story. Ultrasound Obstet Gynecol 2005;25:323–30; with permission.)

concentration between 0.55 and 0.65 MoM), and severe (hemoglobin concentration
<0.55 MoM).
The MCA-PSV for the prediction of severe, moderate, and mild anemia at a sensitivity
of 100% showed false-positive rates of 6%, 37%, and 70%, respectively. A cutoff of
1.69 MoM was used instead of 1.50 MoM. The investigators concluded that the MCA-
PSV could be reliably used for timing a second intrauterine transfusion; furthermore,
they stated that using this methodology allowed them to effectively delay 94% of
the invasive procedures, whereas using 1.32 MoM as the threshold to predict
moderate anemia would have delayed such procedures in 63% of the cases.
An important question arises after reviewing the data reported by Detti and
colleagues50: in predicting anemia in fetuses, why did the cutoff values used for
fetuses with no prior transfusion differ from those used for fetuses with a prior intra-
uterine blood transfusion? One hypothesis is that the hemoglobin concentration
affects blood viscosity. Other possible factors are described in a study by El Bouh-
madi and colleagues.51 When blood viscosity factors and fetal erythrocyte aggregabil-
ity were assessed in the blood of 119 normal fetuses between 18 and 39 weeks of
gestation using light transmission methods, a progressive increase in blood viscosity
throughout pregnancy was explained not only by a gradual increase in hematocrit
(from 33% to 40%, P<.05) but also by an increase in the Dintenfass Tk red blood
cell rigidity index (a viscometric index of red cell rigidity based on shear-induced eryth-
rocyte elongation) (P<.05).51 Considering that adult red cells are more rigid than fetal
red cells,47 one would expect that the higher the number of adult red cells in the fetal
blood after subsequent intrauterine transfusions, the lower the MCA-PSV would be, at
a constant hemoglobin concentration, and, therefore, the less reliable the MCA-PSV
MCA Doppler and its Applications in Fetal Anemia and Growth Restriction 89

Fig. 4. MCA Doppler waveforms. (A) Borderline, (B) normal, and (C) abnormal MCA wave-
forms. (D) Depiction of a case of reversed flow in the MCA. (Reprinted from Mari G. Doppler
ultrasonography in obstetrics: from the diagnosis of fetal anemia to the treatment of intra-
uterine growth-restricted fetuses. Am J Obstet Gynecol 2009;200(6):613–9; with permission.)
90 Schenone & Mari

Fig. 5. Algorithm for the management of red cell alloimmunization (part I). Although it is
commonly reported that fetal anemia develops with an antibody titer of at least 1:16,
with some antigens, that is, Kell, severe fetal anemia may develop with a lower value
(personal experience [G.M.]). GA, gestational age; PCR, polymerase chain reaction; RhD,
rhesus D. (Reprinted from Mari G. Middle cerebral artery peak systolic velocity for the diag-
nosis of fetal anemia: the untold story. Ultrasound Obstet Gynecol 2005;25:323–30; with
permission.)

thresholds set in normal nontransfused fetuses. In addition, adult red cells are smaller
than fetal red cells, and adult blood differs from fetal blood in the total arterial oxygen
carrying capacity and the capacity of oxygen delivery to the tissues. It is likely that
multiple factors are involved in this process. Retrospective studies have reported
that the MCA-PSV is a useful tool in the diagnosis of anemia after 1 or more intra-
uterine transfusions.
Zimmerman and colleagues52 performed an intention-to-treat multicenter study on
125 fetuses at risk of anemia to evaluate the utilization of the MCA-PSV combined with
B-mode ultrasound imaging to predict anemia in an unselected population of preg-
nancies complicated by alloimmune antibodies known to cause immunological
hydrops. The investigators avoided 90 invasive procedures and missed 2 cases of
fetal anemia. However, the interval between the last Doppler study and delivery was
MCA Doppler and its Applications in Fetal Anemia and Growth Restriction 91

approximately 3 weeks. In the same study, labor was induced in 6 pregnancies after
35 weeks. The neonates were not anemic. The conclusions of this study were (1) the
MCA-PSV may be used to diagnose anemia, (2) the interval between subsequent
studies after 30 weeks of gestation should be less than 3 weeks, and (3) after 34 weeks
of gestation, the trend of the MCA-PSV may decrease the number of cases with false-
positive results. The increase in the false-positive rate after 35 weeks of gestation
could be because of different fetal behavioral states. The MCA-PSV could be falsely
increased when the measurement is performed during a period of rest immediately
after a period of fetal activity.
The MCA-PSV is useful in cases of Kell isoimmunization,25,53 particularly because
the delta OD450 has been proved not to be of help in such cases.54 This is thought
to be related to the pathophysiology of this disease, in which the predominant mech-
anism of anemia is not hemolysis but rather bone marrow suppression of
erythropoiesis.55
The MCA-PSV is also of use in diagnosing anemia secondary to parvovirus
infection,56,57 fetomaternal hemorrhage,58 and a-thalassemia-1.59
The MCA-PSV has been studied in twin pregnancies. In a study of 16 monochorionic
and 32 dichorionic pregnancies, Dashe and colleagues60 concluded that MCA-PSV
values in uncomplicated twin pregnancies are comparable with previously published
singleton norms. Klaritsch and colleagues61 examined 50 uncomplicated monochor-
ionic diamniotic (MCDA) pregnancies for a total of 100 examinations of the
MCA-PSV, assessed biweekly from 15 weeks of gestation, to create normative ranges
from 15 to 37 weeks of gestation. Measurements between 18 and 37 weeks of gesta-
tion were comparable to those in singletons; however, before 18 weeks of gestation,
the MCA-PSV values were higher in MCDA twin pregnancies compared with singleton
references. It would be reasonable to assume that the MCA-PSV, using previously
established reference and cutoff values, could be used for the prediction of anemia
in twin pregnancies between 18 and 35 weeks of gestation, but there exists a lack
of evidence in this area. Evidence is also needed in cases of twin-to-twin transfusion
syndrome (TTTS). In this pathologic condition of twin gestations, the correlation of the
MCA-PSV and hemoglobin concentration has only been tested in pregnancy 24 hours
after the death of 1 monochorionic twin.62 To hypothesize the utility of the MCA-PSV in
cases of TTTS, several researchers have studied these cases to confirm physiologic
principles of the sequential laser technique for TTTS treatment and to create a tool
for post–laser treatment prognosis.63,64

FETAL MCA DOPPLER AND IUGR: TRACING THE CONCEPT OF IUGR BACK
TO ITS ORIGIN

Traditionally, babies born with a low birth weight were likely considered preterm. The
concept of IUGR in the literature dates back to the 1960s, when Battaglia and
Lubchenco65 and Lubchenco and colleagues66 published their work in which
outcomes were recorded based on birth weight adjusted for gestational age. Once
such reference values for birth weight by gestational age became available, newborns
could be differentiated as small, adequate, or large for gestational age,67 and the
concept of intrauterine malnourishment affecting birth weight independent of gesta-
tional age gained acceptance. The introduction of ultrasonography in obstetrics
allowed the assessment of fetal biometry.68 There exist numerous publications and
several methods to estimate the fetal weight to the point that it would be impractical
to quote every method in this article. Among the most popular are the methods
described by Shepard and colleagues69 and Hadlock and colleagues.70 Using
92 Schenone & Mari

formulas to assess fetal weight allowed one to establish whether a fetus was
adequately grown for gestational age or not. Alexander and colleagues71 published
an extensive profile of birth weight percentiles for gestational ages between 20 and
44 weeks after analyzing data from more than 3 million live births.
When using large cross-sectional population based growth curves, the reference
values perform best when managing patients from the same population included in
the study but not as well for individuals from other populations in which fetuses and
newborns can be constitutionally smaller or larger, potentially leading to diagnoses
of abnormalities in normal cases. Therefore, attempts have been made to individualize
these curves and diagnose abnormalities only when an individual curve falls below
a projected trend. Deter and colleagues72 have been the first to individualize fetal
growth parameters. Debate of this issue is ongoing, and the definition of IUGR based
on an estimated fetal weight (EFW) less than the tenth percentile for gestational age
continues to be challenged.

DOPPLER ULTRASONOGRAPHY IN THE MANAGEMENT OF IUGR

IUGR represents a threat not only for the fetus but also for the individual as a child and
adult. Barker and Osmond73 have described an association between birth weight
below the tenth percentile and the later development of hypertension, hypercholester-
olemia, coronary heart disease, impaired glucose tolerance, and diabetes mellitus. In
utero diagnosis and treatment becomes an appealing approach to reduce the burden
exerted by IUGR on society. There are more than 10,000 publications in the literature
related to the diagnosis and management of fetuses with IUGR, which is only the tip of
the iceberg in the frenetic quest for a solution to this problem.
Assuring fetal well being and adequately timing delivery of fetuses with IUGR is
paramount; however, the optimal methods are still the subject of much debate.
Doppler ultrasonography for the assessment of fetal hemodynamics is one of the
most important of these methods, considering that one of the principal pathophysio-
logic explanations for IUGR is placental insufficiency, which directly translates into
hemodynamic changes in the fetus. Doppler ultrasonography of the umbilical and
middle cerebral arteries in combination with biometry has been quoted as the best
tool to identify small fetuses at risk for an adverse outcome.74–76
Fitzgerald and Drumm77 pioneered the introduction of Doppler ultrasonography in
obstetrics, specifically in the assessment of IUGR fetuses, when they reported that
umbilical artery (UA) waveforms are abnormal in fetuses with IUGR and that reversed
blood flow of the UA is associated with a poor prognosis.77 Since then, there have
been numerous publications on this topic.
Doppler ultrasonography in the management of IUGR involves the study of multiple
vessels aside from those more commonly assessed (ie, the UA, MCA, and ductus
venosus), and a multitude of vessels have been proposed as part of such manage-
ment. Because of the scope of the topic, discussion is limited to the role of the
MCA in the management of IUGR.

MCA DOPPLER IN THE ASSESSMENT OF IUGR FETUSES

The structure of the MCA makes it a convenient target for in utero flow velocimetry
studies and, at the same time, opens a window to observe the circulation within the
central nervous system of the fetus, which is involved in many, if not all, pathologic
processes in fetal medicine, including IUGR.
One of the earliest reports on this subject was by Echizenya and colleagues.7 They
used pulsed Doppler ultrasonography to examine the significance of MCA flow
MCA Doppler and its Applications in Fetal Anemia and Growth Restriction 93

velocimetry as a fetal assessment tool and examined the association between


abnormal blood flow values and perinatal morbidity in normal and abnormal pregnan-
cies (including IUGR). They reported abnormal values in 71.7% of the abnormal preg-
nancy group in contrast to a 23.7% rate in normal pregnancies. It was concluded that
velocimetry of the MCA was the most reliable method to diagnose fetal distress. The
following section addresses each of the MCA Doppler–derived parameters relevant to
the study of IUGR.

MCA PI AND RI

The RI and PI were used in most of the initial studies on MCA Doppler in IUGR fetuses,
and they continue to represent the mainstay of the assessment in such cases. Ishi-
matsu and colleagues8 reported lower values of the MCA RI in asymmetrical SGA
fetuses when compared with normal and symmetric SGA fetuses. van den Wijngaard
and colleagues11 demonstrated a reduced PI in IUGR fetuses when compared with
normal fetuses, and these findings were later reproduced.78,79
Chiba and Murakami80 performed Doppler studies of the MCA and cordocentesis to
determine the levels of venous cord blood gases in 17 fetuses with IUGR. They
reported a significant positive correlation between the MCA RI and PO2 and pH,
whereas a negative correlation was noted between the MCA RI and PCO2.
The MCA Doppler has also been assessed as a predictor of perinatal outcomes.
Mari and Deter77 compared outcomes of SGA fetuses with a normal MCA PI with
outcomes of those with an abnormal value and concluded that SGA fetuses with
a normal MCA PI are at a lower risk for adverse outcomes than those with an abnormal
PI. In the same study, the investigators emphasized that the reference ranges of the PI
in appropriate-for-gestational-age (AGA) fetuses have a parabolic shape with
advancing gestation. The lowest PI values were observed during the 2 periods of brain
growth spurt. In these 2 periods, the brain demands more nutrients because of the
increased metabolic requirement.
Bahado-Singh and colleagues81 studied 203 IUGR fetuses and measured the MCA
PI and UA PI. Perinatal outcome was categorized as (1) birth weight less than the tenth
percentile, (2) birth weight less than the fifth percentile, (3) perinatal complications
(meconium-stained fluid, cesarean delivery for fetal distress, 5-minute Apgar score
<7, perinatal death, neonatal intensive care unit stay of more than 24 hours, hypogly-
cemia, or polycythemia), (4) birth weight less than the tenth percentile with perinatal
complications, or (5) birth weight less than the fifth percentile with perinatal complica-
tions. They reported a statistically significant increase in adverse perinatal outcomes
in cases with an abnormal cerebroplacental ratio (the MCA PI divided by the UA PI).
In 2000, Baschat and colleagues82 studied Doppler velocimetry of the UA, MCA,
inferior vena cava, ductus venosus, and free umbilical vein in 121 IUGR fetuses. Peri-
natal outcomes including mortality, respiratory distress, bronchopulmonary dysplasia,
intraventricular hemorrhage, necrotizing enterocolitis, circulatory failure, and levels of
UA blood gases were recorded. The only statistically significant association noted was
that between the abnormal ductus venosus flow and fetal death.
Ulrich and colleagues83 reported that the brain sparing effect represented a risk
factor for early neurological morbidity in fetuses with absent or reverse end-diastolic
flow of the UA.
One study addresses the use of the MCA PI as a prognostic factor for long-term
outcomes. Roza and colleagues84 reported that a higher UA to MCA ratio (using the
MCA PI) correlated with higher scores of internalizing and somatic complaints scales
in toddlers.
94 Schenone & Mari

REVERSAL OF BRAIN SPARING EFFECT

An IUGR fetus with a previously low PI that suddenly presents with an elevated MCA PI
has been linked to poor outcomes.74 Konje and colleagues85 reported reversal of the
brain sparing effect in 8 fetuses, 4 of which ended as stillbirths and the remainder died
during the neonatal period.
Rowlands and Vyas86 published a study that included 5 IUGR fetuses that were
longitudinally monitored until the time of fetal death. Of the 5 fetuses, 2 developed
reversal of the brain sparing effect 48 hours before death. This finding has been repro-
duced by others.87,88

REVERSE END-DIASTOLIC FLOW IN THE MCA: WHAT DOES IT MEAN?

Sepulveda and colleagues89 describe a case of IUGR with brain sparing effect, in
which the MCA PI increased back to normal limits at 29 weeks of gestation. One
week later, reverse end-diastolic flow of the MCA was seen on the day of in utero fetal
death. Caution must be exerted when interpreting these data because only 1 case is
described, and reverse end-diastolic flow of the MCA can be iatrogenically induced by
applying excessive pressure over the fetal cranium.

MCA-PSV: A NEW PARAMETER IN THE ASSESSMENT OF IUGR FETUSES

Mari and colleagues90 performed a longitudinal assessment of the MCA PI and MCA-
PSV in 30 growth-restricted fetuses with an EFW less than the third percentile. Peri-
natal mortality was recorded, and MCA PI and PSV values were classified as normal
or abnormal. Forward stepwise logistic regression indicated that the MCA-PSV was
the best parameter in the prediction of perinatal mortality (odds ratio, 14; 95% confi-
dence interval, 1.4–130, P<.05; Nagerlke R[2] 5 31). This finding may be explained by
the fact that the MCA PI in IUGR fetuses can normalize in later stages after becoming
abnormally low (ie, reversal of the brain sparing effect); conversely, once the MCA-
PSV becomes abnormal, it remains as such.

WHY IS THE MCA-PSV INCREASED IN IUGR FETUSES?

Plausible mechanisms that explain the increase of the MCA-PSV in anemic fetuses
have been elucidated, but IUGR fetuses are not necessarily anemic. There must be
another reason for the increase in the MCA-PSV in this group of fetuses.
Akalin-Sel and colleagues91 postulated that hypoxemia alone or with hypercapnia is
responsible for cerebral vascular responses as part of the complex group of regulatory
mechanisms that play a role in the circulatory redistribution in human fetal growth
restriction.
Hanif and colleagues92 performed a study demonstrating that the mechanisms that
determine increased MCA-PSV in anemic AGA fetuses are different from those in non-
anemic IUGR fetuses. Two groups of fetuses were studied: one included 14 fetuses at
risk for anemia because of red cell alloimmunization and the other included 22 IUGR
fetuses. The hemoglobin concentration and level of umbilical vein blood gases were
determined in both groups. The relationship between the MCA-PSV and the hemo-
globin concentration, PO2, PCO2, and pH values were assessed by regression analysis
using multiples of the mean in the 2 groups. In the group at risk for anemia, the fetal
hemoglobin concentration was the only parameter related to the MCA-PSV (R2 5
0.34, P<.05). In fetuses with IUGR, the PCO2 (R2 5 0.36, P<.01) and the PO2 (R2 5 0.30,
P<.01) correlated well with the MCA-PSV, but no relationship was found between the
MCA-PSV and the hemoglobin concentration. In anemic fetuses, the high MCA-PSV is
MCA Doppler and its Applications in Fetal Anemia and Growth Restriction 95

related to a decreased fetal hemoglobin concentration that is thought to be respon-


sible for the decrease in blood viscosity and consequently an increased cardiac
output. In IUGR fetuses, the MCA-PSV increase is related to hypoxemia and hyper-
capnia and thus to brain autoregulation.

WHERE DO THE MCA DOPPLER ABNORMALITIES FIT IN THE SEQUENCE OF ABNORMAL


FETAL TESTING IN IUGR?

The decreased MCA PI has been historically regarded as an early finding in the
sequence of abnormal testing in IUGR, whereas its reversal and an abnormal increase
have been described as a late finding.86–88 Reverse end-diastolic flow in the MCA has
been anecdotally described in the literature as an agonal sign, although it is possible to
iatrogenically create this when applying pressure over the fetal cranium with the ultra-
sound probe.89 Hecher and colleagues93 serially assessed 93 IUGR fetuses and
reported a sequence of appearance of abnormal findings in fetal testing. The first
parameter to become abnormal was the amniotic fluid index, followed by the PI in
the UA, MCA, and aorta, and lastly ductus venosus, inferior vena cava and fetal heart
rate short term variability. Baschat and colleagues94 reported changes in fetal well-
being testing related to the time of delivery or stillbirth. Doppler abnormalities
preceded biophysical profile deterioration. The researchers noted 3 patterns of
Doppler deterioration. Most patients (72%) followed a particular sequence: abnormal
UA PI and brain sparing effect followed by venous Doppler deterioration, which is
compatible with what Hecher and colleagues reported. Ferrazi and colleagues95
obtained similar results. Mari and colleagues96 reported that the above mentioned
sequence in 10 fetuses with IUGR followed this order: abnormal UA PI, MCA PI,
ductus venosus, and then MCA-PSV. Once again the pattern was reproduced.
After following 104 fetuses with IUGR, Turan and colleagues97 reported that the
characteristics of the cardiovascular changes in IUGR depend on gestational age at
onset and severity of the placental disease.
There is an important limitation to the evidence available. IUGR cases are studied as
a single noxa, which may explain the conflicting areas in the literature. We believe that
IUGR fits better into the category of a syndrome, in which the restriction of growth is
the end point (something in common) for different pathologic entities. To better eluci-
date the causes and consequences of IUGR, studies should discriminate among the
different causes that lead to the syndromic IUGR.74 Our group believes that IUGR
fetuses should be divided into several categories, based on the specific maternal or
fetal abnormality or the absence of any abnormality.74

PERFORMING AND INTERPRETING FETAL MCA DOPPLER WHEN IUGR IS SUSPECTED

The literature on Doppler is saturated with many studies that have performed Doppler
analysis on 3 continuous waveforms, selected more often from a group of 5 to 15
waveforms. We believe this is insufficient, especially when basing clinical decisions
on these results. This belief has been supported by the results of recent studies.98–100
Several vessels can have abnormal waveforms following maternal contractions or
following a fetal deceleration.101,102 Therefore, incorrect or unreliable data can be
obtained if clinicians limit themselves to 3 waveforms.
In our institution, a Doppler examination usually ranges between 20 and 60 minutes.
In severe IUGR fetuses, between 500 and 1000 waveforms are obtained for each
vessel at each exam. By studying so many waveforms, it is more likely to clearly under-
stand the vascular changes occurring in IUGR fetuses, while being practical enough
for sonographers to complete the studies even in a busy ultrasonography unit. The
96 Schenone & Mari

best approach is one that includes the assessment of the UA and the MCA on 1 to 3
different occasions and 5 to 10 minutes apart in the absence of fetal movements and
breathing. In each set, at least 10 to 15 waveforms should be obtained. If the quality of
the waveforms is good, the analysis can be performed either on all the waveforms or
on 3 waveforms from each set.
There are 3 possible scenarios. First, the first set of waveforms has a normal PI. If
this is the case, then it is not necessary to obtain the next 2 sets and the PI value is
considered normal. In such cases, the UA and the MCA Doppler are repeated in 2
weeks if the gestational age is less than 30 weeks and in 1 week if the gestational
age is greater than 30 weeks. If the PI values remain normal at the following Doppler
exam, the fetus is considered to be a constitutionally small fetus and further Doppler
scans are not carried out.
Second, if the UA or the MCA has an abnormal PI in the first set of waveforms, the
other 2 sets of waveforms are obtained. If the PI is abnormal in the following 2 sets
also, an average of the 3 sets is obtained, and the conclusion is that the overall value
is abnormal.
Third, if the waveforms have different values, that is, an abnormal PI in the first set
and a normal PI in the second or third set, the conclusion is that the waveforms repre-
sent a transitional phase. This transitional phase precedes the abnormal phase.98
In the presence of IUGR cases with an abnormal PI value, investigators and clini-
cians use different protocols because there are no clear data on the subject to suggest
the use of one approach versus another. We have previously reported our method-
ology when managing IUGR cases with an abnormal UA Doppler.25

SUMMARY

The MCA Doppler examination is a great resource in the diagnosis and management
of fetal anemia and IUGR. As a window into the hemodynamics of the fetal central
nervous system, its potential is clearly unlimited. In cases of IUGR, the MCA Doppler
flow velocimetry shows early and late changes. The PSV is proposed as a desirable
parameter in every evaluation of IUGR fetuses, particularly because it has been
demonstrated to perform better than other parameters in the prediction of perinatal
mortality. Further research is needed, especially studies that discriminate among
the different types of IUGR. In cases of fetal anemia, it is widely accepted that the
MCA-PSV should be used in the diagnosis and management of cases. Further
research is suggested to address the utility of this method in the prediction of anemia
in fetuses after 35 weeks of gestation.

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