The circle of Willis is composed anteriorly of the anterior cerebral arteries (branches of the internal

This chapter reviews the clinical application of Doppler ultrasound velocimetry of the cerebral blood flow in the fetus. There are two main clinical applications of the fe- tal Doppler cerebral blood flow velocity waveforms:

1. Intrauterine growth restriction (IUGR) pregnan- 2. Diagnosis of fetal anemia cies

Which Is the Cerebral Vessel to Assess in the Fetus?

The circle of Willis is composed anteriorly of the anterior cerebral arteries (branches of the internal

carotid artery that are interconnected by the anterior communicating artery) and posteriorly of the two posterior cerebral arteries (which are branches of the basilar artery and are interconnected on either side with the internal carotid artery by the posterior com- municating artery). These two trunks and the middle cerebral artery (MCA), another branch of the internal carotid artery, supply the cerebral hemispheres on each side. These arteries have different flow velocity waveforms (FVWs) [1, 2] and, therefore, it is impor- tant to know which artery is being studied (Fig. 14.1). The MCA is the vessel of choice to assess the fetal cerebral circulation because it is easy to identify, has a high reproducibility, and provides in-

Cerebral Blood Flow Velocity Waveforms:

Clinical Application

Laura Detti, Maria Segata, Giancarlo Mari

Fig. 14.1A±H. Flow velocity waveforms of the arteries of the circle of Willis. The values indicate the pulsatility index.

(From [2])

formation on the brain-sparing effect [3, 4]. Addi- tionally, it can be studied easily with an angle of zero degrees between the ultrasound beam and the direc- tion of blood flow and, therefore, information on the true velocity of the blood flow can be obtained [5].

Flow velocity waveforms of the middle cerebral artery change with advancing gestation (Fig. 14.2). The pul- satility index (PI) of the MCA is lower between 15 and 20 weeks' gestation, whereas it has a higher value at the end of the second trimester and at the begin- ning of the third trimester (Fig. 14.3) [3]. The lower PI values early and late in gestation may be due to the increased metabolic requirements of the brain in these two periods of gestation [6].

Middle cerebral artery peak systolic velocity (MCA-PSV) increases exponentially with advancing gestation (Fig. 14.4) [5].

Cerebral Blood Flow Velocity Waveforms in the IUGR Fetus

Animal and human experiments have suggested that in the IUGR fetus there is an increase of blood flow to the brain [3, 4, 7±10]. This increase of blood flow can be evidenced by Doppler ultrasound of the MCA [3]. This effect is called the brain-sparing effect and is demonstrated by a lower value of the PI (Fig. 14.5).

The brain-sparing effect appears to be a benign adap- tive mechanism preventing severe brain damage [11].

Small-for-gestational-age (SGA) fetuses with brain- sparing effect less frequently developed intraventricu- lar hemorrhage (IVH) than appropriate-for-gesta- tional-age (AGA) premature fetuses with normal pulsatility index value of the MCA [12]. Following Fig. 14.2. Flow velocity wave- forms of the middle cerebral artery in appropriate-for-gesta- tional-age (AGA) fetuses at dif- ferent gestational ages. (From [4])

Fig. 14.3. Reference range (mean and

predicted values) of the fetal middle

cerebral artery pulsatility index with

advancing gestation. (From [4])

35 weeks' gestation a low PI is physiologically present in the AGA fetus (unpublished data). In IUGR fetuses with a PI below the normal range there is a greater incidence of adverse perinatal outcome [3]. It has also been reported that in SGA fetuses with normal umbil- ical artery PI and abnormal MCA there is an in- creased risk of developing distress and being deliv- ered by emergency cesarean delivery. The risk is in- creased by the presence of abnormal maternal uterine arteries [13]. The brain-sparing effect may be transi- ent, as reported during prolonged hypoxemia in ani- mal experiments, and the overstressed human fetus can also lose the brain-sparing effect [8]. It has been reported that the MCA PI is below the normal range when the pO

is reduced [14]. Maximum reduction in PI is reached when the fetal pO

is 2±4 SD below nor- mal for gestation. When the oxygen deficit is greater there is a tendency for the PI to rise, this presumably reflects the development of brain edema.

In IUGR fetuses, the disappearance of the brain- sparing effect is a very critical event for the fetus,

and appears to precede fetal death [15±17]. This has been confirmed in a few fetuses in situations where obstetrical interventions were refused by the parents.

Unfortunately, to demonstrate this concept, it is nec- essary to perform a longitudinal study on severely IUGR fetuses up to the point of fetal demise; there- fore, presently we cannot rely on the disappearance of the brain-sparing effect for timing the delivery. It is noted that reversed flow of the MCA velocity wave- forms, although it has been reported in pathological situations [16, 18±20], can be observed in the normal fetus and appears to be a consequence of head com- pression in normal pregnancies (Fig. 14.6) [21]. A number of longitudinal studies have assessed several fetal vessels with Doppler ultrasonography and have reported that the cerebral circulation is one of the first blood flows to become abnormal in IUGR [22±

25].

Fig. 14.4. Reference range of the fetal middle cerebral artery (MCA) peak systolic velocity during gestation. (From [5])

Fig. 14.5. Flow velocity waveform of the MCA obtained in AGA (a) and IUGR fetuses studied at the same gestational age (b)

Fig. 14.6. Flow velocity waveforms of the MCA in an AGA

fetus. The reversed flow is due to head compression

IUGR fetus at 24 weeks

Cerebral±Placental Ratio

It has been reported that the internal carotid/umbilical artery PI ratio has a sensitivity of 70% in identifying growth-restricted fetuses, as opposed to a 60% sensi- tivity for the internal carotid artery and 48% for the umbilical artery alone [26]. Others have selected the middle cerebral artery/umbilical artery ratio and have reported that in AGA fetuses this ratio remains con- stant following 30 weeks' gestation. In AGA fetuses the ratio is equal to 1 [27]. A ratio above 1 is consider- ed pathological. The Cerebral±Placental ratio has also been reported to be a good predictor of neonatal out- come, and could be used to identify fetuses at risk of morbidity and mortality [28, 29]. Another study has reported that in fetuses with suspected IUGR, abnor- mal Cerebral±Placental ratio is strongly associated with low gestational age at delivery, low birth weight, and low umbilical artery pH. Abnormal Cerebral±Placental ratio is also significantly associated with a shorter in- terval to delivery and the need for emergent delivery [30]. A question that arises is: Does the Cerebral±Pla- cental ratio make any difference when compared with the umbilical artery? The answer is that the ratio is use- ful on those conditions characterized by a borderline umbilical artery. If there is absent/reversed flow of the umbilical artery, the ratio is not helpful.

What to Do in Presence

of an Abnormal Cerebral±Placental Ratio?

The management of a pregnancy in the presence of an abnormal cerebral±placental ratio depends on the gestational age. Prior to 34 weeks, steroids and close monitoring with non-stress test (NST) and biophysi- cal profile (BPP) twice a week, and assessment of fetal growth every 2 weeks, is a good management option.

Following 34 weeks' gestation the cerebral±placental ratio does not appear very helpful and, therefore, a clinical decision based on the results of the cerebral±

placental ratio is not recommended [28]; however, others have reported that cerebral±placental ratio continues to be useful [31, 32]; therefore, this re- quires further investigations.

Finally, maternal hyperoxygenation could improve fetal hemodynamics in IUGR fetuses [33].

Prediction of Fetal Hematocrit

Fetal hemoglobin increases with advancing gestation (Table 14.1) [34]. Fetal anemia is categorized as mild, moderate, or severe, based on the degree of deviation from the median for gestational age. Severe anemia may cause hydrops and fetal demise.

There are many causes of fetal anemia (Table 14.2), the most common being red cell alloimmunization in

the United States. The primary cause of red cell alloim- munization is maternal sensitization to D antigen of the rhesus blood group system; however, many other antigens, the so-called irregular antigens, may be re- sponsible for maternal sensitization. Prophylaxis with rhesus immunoglobulins has decreased the incidence of Rh-hemolytic disease; however, this phenomenon is still present.

Several other conditions can lead to fetal anemia.

Hematological disorders can lead to fetal anemia and they are implicated in approximately 10±27% of cases of nonimmune hydrops [35±37]. Fetal anemia may also result from excessive erythrocyte loss by hemoly- Table 14.1. Increase of fetal hemoglobin with advancing gestation

Weeks Mean 95 5 0.55 MoM 0.65 MoM

18 10.6 11.8 9.4 5.8 6.9

19 10.9 12.2 9.6 6.0 7.1

20 11.1 12.5 9.8 6.1 7.2

21 11.4 12.8 9.9 6.2 7.4

22 11.6 13.0 10.1 6.4 7.5

23 11.8 13.3 10.2 6.5 7.6

24 12.0 13.6 10.3 6.6 7.8

25 12.1 13.8 10.4 6.7 7.9

26 12.3 14.0 10.5 6.8 8.0

27 12.4 14.3 10.6 6.8 8.1

28 12.6 14.5 10.7 6.9 8.2

29 12.7 14.7 10.7 7.0 8.3

30 12.8 14.9 10.8 7.1 8.3

31 13.0 15.1 10.8 7.1 8.4

32 13.1 15.3 10.9 7.2 8.5

33 13.2 15.5 10.9 7.2 8.6

34 13.3 15.7 10.9 7.3 8.6

35 13.4 15.8 10.9 7.4 8.7

36 13.5 16.0 10.9 7.4 8.7

37 13.5 16.2 10.9 7.5 8.8

38 13.6 16.4 10.9 7.5 8.9

39 13.7 16.5 10.9 7.5 8.9

40 13.8 16.7 10.9 7.6 9.0

Table 14.2. Causes of fetal anemia Red cell alloimmunization Alpha-thalassemia Enzyme disorder

Pyruvate kinase deficiency

Glucose phosphate isomerase deficiency G6PD deficiency

Kasabach-Merritt sequence

Fetomaternal hemorrhage

Intracranial hemorrhage

Parvovirus B19 infection

Twin-to-twin transfusion

Blackfan-Diamond syndrome

Transient myeloproliferative disorder

Congenital leukemia

sis or hemorrhage, or erythrocyte underproduction [36].

In Southeast Asia homozygous alpha-thalassemia-1 (hemoglobin Bart's) is the most common cause of fe- tal hydrops, accounting for 60±90% of cases [38].

This condition, however, has become more frequent in Canada and in North America due to an increased number of immigrants from Southeast Asia [39, 40].

Massive fetomaternal hemorrhage, defined as loss of more than 150 ml, is a rare condition that may re- sult in severe fetal anemia with or without hydrops, and fetal death [41±43]. Red blood cell enzymopa- thies, such as autosomal-recessive inherited deficien- cies of pyruvate kinase and glucose phosphate iso- merase, and G6PD deficiency, are rare conditions that may cause fetal anemia and hydrops [36, 44±46].

Parvovirus infection can lead to severe fetal ane- mia and consequently hydrops because of virus trop- ism for immature erythrocytes in the bone marrow or fetal liver [47]. Conditions such as large placental chorioangioma, twin±twin transfusion syndrome, transient myeloproliferative disorder, congenital leu- kemia, intracranial hemorrhage, and Blackfan-Dia- mond syndrome, may also cause fetal anemia [48±

50]. Noninvasive diagnosis of fetal anemia has been the goal of many investigators for more than 20 years.

The pulsatility index of fetal cerebral vessels does not have good parameters to diagnose fetal anemia [51].

The PI of the cerebral arteries can become abnormal when the hematocrit is close to 10%. In such a condi- tion, the pulsatility index of the middle cerebral ar- tery decreases, suggesting hypoxemia in the severely anemic fetus. The MCA PI in 101 cases of fetal ane- mia was below 2 SD in 7 anemic fetuses (unpublished data). In these fetuses the hematocrit was <15%.

When the anemia is severe, there is an increase of blood flow to the brain, which is reflected by a low MCA PI; however, this phenomenon is not always present and it allows recognition of only a small number of anemic fetuses. The assessment of the MCA plays the most important role in the noninva- sive diagnosis of fetal anemia [5, 34].

Red Cell Alloimmunization and MCA Peak Systolic Velocity

Amniocentesis and cordocentesis are invasive tools for diagnosis and management of fetal anemia due to red cell alloimmunization. They are associated with significant complications. Both invasive procedures could worsen maternal alloimmunization due to sec- ondary fetal hemorrhage. It has been reported that more than 70% of fetuses that underwent invasive procedures, because they were defined as severely anemic based on traditional criteria, were found to be either non-anemic or mildly anemic [34]. The use of MCA-PSV could have detected all the cases of sig- nificant fetal anemia requiring transfusion and would have avoided approximately 70% of the unnecessary invasive procedures [34].

In a multicenter study, the sensitivity of MCA-PSV for prediction of moderate and severe anemia prior to the first cordocentesis was 100%, with false-posi- tive rates of 12% at 1.50 multiples of the median (Fig. 14.7) [34].

Other robust data for the use of MCA-PSV have been reported in a multicenter trial with intention to treat. In this study, the authors monitored pregnan- cies complicated by red cell alloimmunization by studying MCA-PSV longitudinally. The MCA-PSV was used for timing cordocentesis [52]. This prospective

120 110 100 90 80 70 60 50 40 30 20 10

15 17 19 21 23 25 27 29 31 33 35 37 39

MCA peak s y st olic v elocit y

Gestational Age (wks)

1.5 MoM

Median

Fig. 14.7. Middle cerebral artery

peak systolic velocity values used

for detection of anemia. Fetuses

with a MCA-PSVvalue above 1.5

multiples of the median are likely to

be anemic. (From [34])

study confirmed that MCA-PSV is an accurate meth- od of monitoring pregnancies complicated by red cell antibodies. In this study two anemic fetuses were missed in a group of 125 fetuses at risk of anemia.

The interval between the last assessment of MCA-PSV and the delivery in those two fetuses was 3.5 and 2.5 weeks. This suggested that a closer assessment of MCA-PSV is necessary. This study also demonstrated that the number of false positives increased following 35 weeks' gestation. A recent prospective study com- pared MCA-PSV with Delta OD 450 in the prediction of moderately and severely anemic fetuses [53]. The authors concluded that both procedures are useful in the prediction of fetal anemia, but Doppler ultra- sound assessment remains a method that has the ad- vantage of being less expensive and noninvasive than amniocentesis. The MCA-PSV represents a more suit- able tool in the diagnosis and management of preg- nancy complicated by alloimmunizations than Delta OD 450 [24, 54, 55].

The MCA-PSV performed prior to the first transfu- sion has been used to estimate the real value of fetal he- moglobin [56]. The difference between the observed and calculated hemoglobin was lower in fetuses that ex- hibited moderate to severe anemia compared with cases when the fetus was mildly anemic (Fig. 14.8);

therefore, MCA-PSV performs better in cases of clini- cally significant anemia. The explanation is that initial small decreases in fetal hemoglobin only slightly change cardiac output and blood viscosity. When the anemia becomes more severe, these compensatory

mechanisms operate more to maintain the oxygen and metabolic equilibrium in the various organs.

Intrauterine transfusion decreases fetal anemia sig- nificantly and normalizes the value of fetal MCA-PSV (Figs. 14.9, 14.10) due to an increased blood viscosity and an increased oxygen concentration in fetal blood [57]. The MCA-PSV may also be used for timing the second fetal transfusion and the cut-off point to de- tect severe anemia is higher than that used for never- transfused fetuses [58]. This is probably the conse- quence of the different blood viscosity of the adult blood when compared with the fetal blood.

Several other studies have confirmed the utility of MCA-PSV for diagnosing fetal anemia [59±62]. This parameter may also diagnose fetal anemia in dichori- onic twin pregnancies complicated by red blood cell alloimmunization [63].

The above studies have used only one value of MCA-PSV, which indicates whether the fetus is ane- mic or not at the time of the evaluation; however, it does not predict whether the fetus will become ane- mic. In a longitudinal study, it has been shown that the MCA slope is an excellent tool for identifying those fetuses that will become severely anemic and, therefore, need to be followed up more closely during the pregnancy (Fig. 14.11) [64]. The same author sug- gested the following protocol for monitoring preg- nancies at risk for fetal anemia due to red cell alloim- munization [65]:

1. MCA-PSV should be performed in fetuses at risk of fetal anemia on a weekly basis for three consec- utive weeks.

2. Cordocentesis is indicated when the MCA-PSV val- ue is over 1.5 MoM.

3. If the MCA-PSV remains below 1.5 MoM a regres- sion line has to be obtained from the following three values.

If the plotted regression line is to the right of the dotted line shown in Fig. 14.11, the examination has to be repeated every 2 or 4 weeks based on the initial risk of the patient ± with a lower initial risk (e.g., a Coombs titer between 1:16 and 1:32) the examina- tion can be repeated every 4 weeks, but with a higher initial risk it should be repeated every 2 weeks. If the plotted regression line is between the dotted and the thin line (Fig. 14.11), the examination has to be re- peated every 1±2 weeks based on the initial risk to the patient. If the plotted regression line is to the left of the thin line and the MCA-PSV value is below 1.50 MoM, the examination has to be repeated in 1 week. Figure 14.12 represents the algorithm we use for the management of pregnancies at risk of fetal anemia because of red cell alloimmunization.

Centers with minimal experience with the assess- ment of MCA-PSV should initially perform these Fig. 14.8. Quadratic function expressing the correlation of

percentage difference between the predicted and the ac-

tual hemoglobin value and the hemoglobin multiples of

the median. (From [56]) Y=0.2876 ± 0.922 ´0.9498´2

Fig. 14.9. Middle cerebral ar- tery peak systolic velocity be- fore and after transfusion in a group of fetuses never trans- fused. The values are com- pared to the reference range for gestational age. (From [57])

Fig. 14.10. Middle cerebral ar-

tery peak systolic velocity be-

fore and after transfusion in a

group of fetuses previously

transfused. (From [57])

measurements in conjunction with serial amniocente- sis for Delta OD 450 because of the learning curve as- sociated with performing MCA Doppler [66].

Alloimmunization is also discussed in Chap. 22.

MCA-PSV in Other Causes of Fetal Anemia Delle Chiaie et al. [59] found an inverse correlation between MCA-PSV measurements and hemoglobin values in fetuses at risk for fetal anemia due to red cell alloimmunization and fetal parvovirus infection.

In a longitudinal multicenter study on fetuses at risk for anemia resulting from parvovirus infection, the measurement of MCA-PSV predicted fetal anemia with a sensitivity of 94.1%. All cases with moderate and severe anemia were detected either by MCA-PSV alone or in combination with real-time ultrasonogra- phy [67].

MCA-PSV may also be a useful test in cases of se- verely anemic fetuses due to fetomaternal hemor- rhages [43]. An increased peak blood flow velocity

has been reported in cases of acute severe fetomater- nal hemorrhage [68].

Recently, it has also been reported that MCA-PSV may be helpful for the diagnosis of anemia in twin±

twin transfusion syndrome following laser coagula- tion of the placental vessels [69].

The MCA-PSV appears to be the best test for the noninvasive diagnosis of fetal anemia. It is important to emphasize that training sonographers and sonolo- gists is the ªconditio sine qua nonº for the correct sampling of MCA-PSV.

The following steps are necessary for the correct assessment of the MCA.

1. The fetus needs to be in a period of rest (no breathing or movements).

2. The circle of Willis is imaged with color Doppler.

3. The sonographer zooms the area of the MCA so that it occupies more than 50% of the screen. The MCA should be visualized for its entire length (Fig. 14.13).

4. The sample volume (1 mm) is placed soon after the origin of the MCA from the internal carotid artery (1±2 mm).

5. The angle between the direction of blood flow and the ultrasound beam is as close as possible to zero degrees. The angle corrector should not be used.

6. The waveforms (between 15 and 30) should be similar to each other. The highest PSV is measured (Fig. 14.14).

7. Repeat the above steps at least three times.

The MCA distal to the transducer can be an alterna- tive to the MCA proximal to the transducer [70];

however, the latter is preferable because it has the lowest intra- and interobserver variability [71].

Maternal Antibody Titer (Indirect Coombs) > Critical Value

Fetus‘ Father Genotype

Homozygous Negtive for antigen Heterozygous or not available

Not other test necessary

A) Amniocentesis for fetal blood typing by PCR B) Free fetal DNA in maternal plasma

Fetus does not have the antigen Fetus has the antigen

MCA-PSV sequential studies Fig. 14.11. Slopes for normal fetuses (dotted line), mildly anemic fetuses (thin line), and severely anemic fetuses (thick line). (From [64])

Fig. 14.12. Management algo-

rithm in pregnancies at risk of

having an anemic fetus be-

cause of red cell alloimmuniza-

tion

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