The MCA Doppler and its Role in the Evaluation of Fetal Anemia and Fetal Growth Restriction

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 hemolytic 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 gestational 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: [email protected] 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.

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newborns that were small for gestational age (SGA) and/or the appearance of subsequent 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 pregnancies (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 introduction of the MCA Doppler to fetal medicine, more than 600 studies have been published, 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 contributions 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 alloimmunized 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 experimentation 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 eliminated 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 associated 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 nomograms 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

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 pregnancies 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 experienced operators.45

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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 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.

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 intraobserver 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

Fig. 2. MCA-PSV in 111 fetuses at risk for anemia because of maternal red cell alloimmunization. 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 complicated 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

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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 MCAPSV 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 intrauterine blood transfusion? One hypothesis is that the hemoglobin concentration affects blood viscosity. Other possible factors are described in a study by El Bouhmadi and colleagues.51 When blood viscosity factors and fetal erythrocyte aggregability 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 erythrocyte 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

Fig. 4. MCA Doppler waveforms. (A) Borderline, (B) normal, and (C) abnormal MCA waveforms. (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 intrauterine growth-restricted fetuses. Am J Obstet Gynecol 2009;200(6):613–9; with permission.)

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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 diagnosis 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 intrauterine 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 pregnancies 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

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 falsepositive 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 mechanism 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 monochorionic 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 gestation 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 gestational 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

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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, hypercholesterolemia, 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 pathophysiologic 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 management. 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

velocimetry as a fetal assessment tool and examined the association between abnormal blood flow values and perinatal morbidity in normal and abnormal pregnancies (including IUGR). They reported abnormal values in 71.7% of the abnormal pregnancy 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. Ishimatsu 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, hypoglycemia, or polycythemia), (4) birth weight less than the tenth percentile with perinatal complications, or (5) birth weight less than the fifth percentile with perinatal complications. 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. Perinatal 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.

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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 reproduced 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 MCAPSV in 30 growth-restricted fetuses with an EFW less than the third percentile. Perinatal 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% confidence 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 MCAPSV 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 nonanemic 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 hemoglobin 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

related to a decreased fetal hemoglobin concentration that is thought to be responsible for the decrease in blood viscosity and consequently an increased cardiac output. In IUGR fetuses, the MCA-PSV increase is related to hypoxemia and hypercapnia 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 ultrasound 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 wellbeing 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 elucidate 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 understand the vascular changes occurring in IUGR fetuses, while being practical enough for sonographers to complete the studies even in a busy ultrasonography unit. The

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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 represent a transitional phase. This transitional phase precedes the abnormal phase.98 In the presence of IUGR cases with an abnormal PI value, investigators and clinicians 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 methodology 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. REFERENCES

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