Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: the untold story

The use of the middle cerebral artery peak systolic velocity (MCA-PSV) for the diagnosis of fetal anemia has been one of the few discoveries in fetal medicine that is changing the standard of care in the management of affected pregnancies1. This has led to a more than 70% reduction in the number of invasive tests, which often cause fetal death, in the assessment of red-cell alloimmunized pregnancies1. Up to 2 years ago, I thought that only a few doctors in the world were relying upon the MCA-PSV for the diagnosis of fetal anemia. However, in 2003 at the Society for Maternal–Fetal Medicine (SMFM) meeting in San Francisco and a few months later at the American Institute of Ultrasound in Medicine (AIUM) meeting in Montreal, during my lectures on fetal anemia, I asked my colleagues, ‘how many of you are using the middle cerebral artery peak systolic velocity in fetuses at risk of anemia?’, and I was pleasantly surprised to see that about 70% of the participants raised their hands. I then realized that the use of the MCA-PSV in fetal medicine had become a reality. A recent article published in the New England Journal of Medicine entitled ‘Who's on first?—medical discoveries and scientific priority’, illustrates that each achievement in science is usually attributed to the person who made the final contribution to a discovery2. However, behind this person there is the work of many other researchers who prepared the basis for the discovery, and without that work, the discovery would not have been possible. It is for this that I acknowledge the important contribution of many investigators that over the last 20 years have applied Doppler ultrasonography to describe the association between fetal anemia and a hyperdynamic fetal circulation3-11. For me, it all started in 1987 at Baylor College of Medicine, Houston, TX, USA. Along with other investigators, Dr Robert L. Carpenter, Dr Russell L. Deter, Dr Kenneth J. Moise, Jr and Dr Theodor Stefos, I was studying the effects of intravascular transfusion on the circulation of the fetus. We were using two-dimensional (2D) ultrasound equipment (GE PASS II, Milwaukee, WI, USA) that did not have a color Doppler system. I noticed that, in all fetal anemia cases, the MCA waveforms (following transfusion) had a lower PSV value than before transfusion. We reported this concept a number of years later12, 13. I could obtain a clear and good signal from this vessel by placing the sample volume parallel to the greater wing of the sphenoid bone. The anatomy of the MCA suggested that this vessel could be sampled with an angle of zero degrees and, therefore, the blood velocity could be measured. We were able to confirm in every case that the velocity in anemic fetuses was higher than that found following transfusion. Our first study was presented at the Society for Gynecologic Investigation in 199014. In this study, we suggested that, for the diagnosis of fetal anemia, the MCA-PSV was a better parameter than the pulsatility index. In 1995, we reported in this Journal the first comprehensive study on the MCA-PSV15. Our data indicated that we could diagnose fetal anemia in all cases due to red-cell alloimmunization; however, the false-positive rate was approximately 50%. In any case, the measurement of the MCA-PSV could spare 50% of the fetuses at risk for anemia from invasive procedures. I started to apply the MCA-PSV in my practice and I was able to reduce the number of invasive procedures. However, I did not yet understand something related to its application in clinical practice. When I worked at Yale, Dr Uku Oz—a fellow of mine—and I were looking at the correlation between the MCA-PSV and fetal hemoglobin. The data showed that a cubic function described the relationship between the two parameters (Figure 1). Suddenly, I understood what I had missed for a long time: the MCA-PSV does not diagnose all cases of fetal anemia because, in mildly anemic cases, the velocity does not necessarily change. However, the correlation between hemoglobin and MCA-PSV becomes more accurate as the severity of anemia increases16. Furthermore, when the anemia becomes very severe (hemoglobin levels of 1–3 g/dL), the velocity does not increase further. With this information in hand, I organized a study at different medical centers, carried out by several investigators—expert sonologists or good sonographers acquainted with the sampling of the MCA. We measured the velocity prior to cordocentesis in fetuses that were suspected to have anemia, based on traditional criteria. This multicenter study demonstrated that 70% of the invasive procedures performed to diagnose anemia were not necessary because the fetuses were either non-anemic or only slightly anemic1. If we had used the MCA-PSV as the criterion for intervention, we could have avoided approximately 70% of the procedures (Figure 2). In this study, we reported that an exponential function expresses the changes of fetal hemoglobin with advancing gestation, and classified the degrees of anemia as follows: mild, moderate, and severe (Table 1). Because we did not base our decision to perform an invasive procedure on the value of the velocity, I therefore participated in another study with Dr Roland Zimmerman, chairman of Obstetrics and Gynecology at the University of Zurich, Switzerland, Dr Robert L. Carpenter from the Houston Medical Center, and Dr Peter Duerig from Bern University, Switzerland. Dr Zimmerman and I had discussed this project in 1996 but we had not pursued it. Now the time was right. In this study, we based our decision to perform an invasive procedure on an elevated MCA-PSV value17. We included 125 women at risk for having a fetus with anemia, and avoided any invasive procedure in 90 women. We detected all but two cases of moderate and severe anemia. The first was a case in which the last value of velocity was assessed 3.5 weeks prior to delivery. The fetus was delivered at 35.5 weeks and the hematocrit was 24.5%. The second case was that of a patient serially followed up to 35 weeks when the last measurement was obtained. The fetus was then delivered 2.5 weeks later and the hematocrit was 15%. The neonates were transfused and did well. We also induced labor in six patients after 35 weeks' gestation because the value of the velocity was above our cut-off point. The neonates were not anemic. This study taught us that in some fetuses the MCA-PSV should be evaluated more frequently than every 2–3 weeks, and following 35 weeks' gestation, the MCA-PSV false-positive rate increases. I believe that the reason why the MCA-PSV, following 35 weeks' gestation, may be falsely increased in normal, non-anemic fetuses is due to different behavioral states of the fetus in this period of gestation. For example, the MCA-PSV may be falsely increased when the measurement is performed during a period of rest that follows a period of fetal activity. For the management of the fetus at risk for anemia following 35 weeks, see Figures 3 and 4. Cubic function describing the relationship between middle cerebral artery peak systolic velocity (MCA-PSV) and fetal hemoglobin (Hb). The values are expressed as multiples of the median (MoM). y = 0.6835 + MCA-PSV MoM × 1.2794 − 1.2885 MCA-PSV2 + 0.2861 × MCA-PSV3. Peak velocity of systolic blood flow in the middle cerebral artery (MCA) with advancing gestation. The curves indicate the median (below) and 1.5 multiples of the median (MoM) (above) peak systolic velocity (PSV) in the MCA. (Reprinted from G. Mari et al. N Engl J Med 2000; 342: 9–141, with permission. Copyright © 2000 Massachusetts Medical Society). 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, i.e. Kell, severe fetal anemia may develop with a lower value (personal experience). MCA-PSV, middle cerebral artery peak systolic velocity; PCR, polymerase chain reaction; RhD, rhesus D. Algorithm for the management of red-cell alloimmunization (Part II). GA, gestational age; MoM, multiples of the median; MCA-PSV, middle cerebral artery peak systolic velocity. In a subsequent study, Detti et al. reported that the MCA-PSV could be used to diagnose anemia even in fetuses previously transfused once18. The Rh blood group system was discovered by Landsteiner and Weiner in 194019 and its involvement in maternal alloimmunization and hemolytic disease of the fetus and neonate (HDFN) was first described by Levine et al. in 194120. In 1953, Bevis first recognized that spectrophotometric measurements of amniotic fluid appeared to change at optical density 450 nm in fetuses who were shown to have HDFN21. In 1956, Liley performed the first amniocentesis in a human to assess the fetal bilirubin through a spectrophotometric analysis in a pregnancy at risk for anemia, and in 1960 he described the technique and complications of amniocentesis22. In 1961, Liley described a method which uses the observed change in the optical density at 450 nm (delta OD450) to predict the severity of HDFN in fetuses23, and in 1963 this investigator performed the first intrauterine transfusion (intraperitoneal) in an anemic fetus using X-ray guidance24. In 1964, Freda et al. performed the first intravascular transfusion in a fetus at 26 weeks' gestation25. This was the first case of open fetal surgery. Early in the 1970s, Carlo Valenti performed the first fetoscopy and also the first umbilical blood sampling under fetoscopy guidance26, 27. This technique was extensively used in Europe by Dr Charles Rodeck and his group28, and in the United States by Dr John Hobbins and Dr Jeremiah Mahoney29. In 1983, fetal blood sampling under ultrasound guidance was described by Daffos et al.30 and it remains the current technique used for fetal blood transfusion. Despite the introduction of Rh(D) immune globulin for the prevention of hemolytic disease of the fetus/newborn following the studies of Vincent Freda and collaborators31-33, who received the Lasker award in 1980, Rh alloimmunization remains a major problem in several areas of the world. Maternal Rh alloimmunization occurs when a pregnant woman develops an immunological response to a paternally derived red blood cell antigen (D) foreign to the mother and inherited by the fetus. The antibodies may cross the placenta, bind to antigens present on the fetal erythrocytes, and cause hemolysis. Hemolysis of the erythrocytes causes anemia in the fetus, and if severe, may result in edema, hydrops fetalis, and fetal death. Hemolytic disease of the fetus/neonate can also be caused by other antigens of the Rh blood group system and by the so-called ‘irregular antigens’ of the non-rhesus blood group system. Therefore, the term red-cell alloimmunization is more commonly used. Red-cell alloimmunization remains the most common cause of fetal anemia even in the USA, as a recent review of the 2001 birth certificates by the Centers for Disease Control and Prevention indicates that Rh sensitization still affects 6.7 out of every 1,000 live births34. This number, added to the other causes of red-cell alloimmunization (Kell, Kidd, Duffy, etc.), suggests that each year in the USA there are more than 30 000 fetuses at risk for anemia due to red-cell alloimmununization. In 1997, we reported that the MCA-PSV is superior to amniocentesis in detecting anemia in cases at risk of anemia35. Pereira et al. in 2003, confirmed these results36. A recent, comprehensive, multicenter study by Oepkes et al., in which MCA-PSV and amniocentesis were performed prior to cordocentesis, has reported that the sensitivity and specificity of the MCA-PSV for detection of anemia are better than amniocentesis, which was considered the standard of care to diagnose fetal anemia in red-cell alloimmunization cases, and MCA can be safely used for timing a cordocentesis and possible fetal transfusion37. In their study, the authors used both the Liley23 and the Queenan38 curves. Bullock et al. have reported, in this issue of the Journal, that MCA-PSV and delta OD450 have similar test accuracy in detecting fetal anemia39. However, they conclude that the MCA-PSV is a preferable screening method for fetal anemia because it is non-invasive. The MCA-PSV diagnoses fetal anemia, even in cases of Kell sensitization, in which the problem is not the hemolysis but the suppression of the erythroid precursor in the bone marrow. We found a good correlation between the blood velocity and the hemoglobin values (R2 = 55%)1. Van Dongen et al., in this issue of the Journal, concisely confirm that MCA-PSV can be used even in cases of Kell alloimmunization40. This is another advantage of using the MCA-PSV, because in cases of Kell alloimmunization, delta OD450 is not accurate41-43. I do not see any problem with investigators expressing the concept of anemia in SD or in absolute values, or when they develop reference ranges for the MCA-PSV in the normal fetuses in their population. However, I do see a problem when investigators—not trained to correctly sample this parameter—perform a study on fetuses at risk for anemia, and try to predict this condition by using the MCA-PSV. This can be misleading, which is highlighted in the article by Bartha et al., reported in this issue of the Journal44. The sensitivity of the MCA-PSV for the diagnosis of fetal anemia ranged from 7% to 100% in the hands of different operators1, 40, 44-50. Therefore, the operators should be trained to correctly sample the MCA-PSV, for if the measurement is done well, the intra- and interobserver variabilities are small. Another important issue is determining what part of the MCA should be sampled. I completed a study on the intra- and interobserver variabilities of the MCA with Dr Alfred Abuhamad, Dr Mekibib Altaye, and three of my former fellows: Dr Erich Cosmi, Dr Maria Segata, and Dr Masashi Akiyama51. The results indicate that any segment of the MCA, with the exception of the area close to its division into terminal branches, can be sampled with good results. The reason why the distal area of the MCA does not have good reproducibility is due to a technical factor: any minimal movement of the fetal head can displace the sample volume in one of the terminal branches. There are usually two or three terminal branches but in my experience there can be as many as five (Figure 5). The MCA-PSV should be sampled at its proximal point, soon after its origin from the internal the for angle because measurement at this is with the intra- and interobserver The sample volume should be at the of the vessel (Figure If this Doppler parameter is correctly the in the MCA-PSV reference ranges that different investigators would be Although the that I may a case of severe anemia in the I very because, to patients at risk for fetal anemia using the MCA-PSV reference ranges previously reported, I have missed a case of moderate or severe anemia. Therefore, I do not believe that the cut-off we have previously should be the was with data by several investigators at different Doppler ultrasound the middle cerebral artery The into two terminal branches by 1 and it into five terminal branches to MCA color Doppler of the MCA flow velocity waveforms of the MCA the and the Doppler ultrasound the middle cerebral The sample volume is in the of the vessel after its origin from the internal When the MCA is it is important to be and the possible of this vessel or the waveforms of its (Figure 5). I believe that the blood velocity is increased in any vessel of the anemic fetus, as also suggested by the study by Van Dongen et al. reported in this issue of the The advantage of studying the MCA is that it is to an angle of zero degrees between the ultrasound and the of blood In the diagnosis of severe anemia, there is one the of and of this parameter could be of in the If a fetus at risk for anemia has a normal MCA-PSV and is it would be important to that fetus very because it could be anemic. Although can be found in normal and non-anemic in my it is very to be found in fetuses at risk for anemia, when there is I believe that if a is trained in the measurement of the MCA-PSV, the management of a patient at risk for fetal anemia can be based on the if the is not trained it is better to use a different to diagnose fetal anemia. For example, the patient could be to the that has sonologists or sonographers trained to correctly the MCA-PSV. If there are close that perform the MCA-PSV the patient should be of this The of fetal anemia with an invasive and procedure than MCA-PSV as amniocentesis, should be presented to the It is important to that MCA-PSV assessment should be for patients who are at risk of having an anemic use of the MCA-PSV without a clear may cause more than It is good medical care to every patient with the MCA-PSV and if the value is to that the fetus is anemic. This may and For example, if is because of fetal and fetal rate an elevated MCA-PSV may the the other hand, an elevated MCA-PSV, in the of a fetal rate and anemia does not indicate may a false-positive Therefore, is indicated when an elevated MCA-PSV value is found in the of the risk of fetal anemia. our first studies on the cerebral circulation of the anemic fetus, we have sampled the MCA following its origin from the internal we have the for the measurement of the an of the head is at the of the sphenoid color Doppler the of the of the of is the color is the the MCA is the MCA flow velocity waveforms are and the of the (PSV) is measured. The waveforms should be all The above is at least three in each I have trained many sonographers and sonologists on the use of the MCA-PSV. In the USA, it is not to to their in the measurement of the MCA-PSV. However, I that each and in the measurement of the MCA-PSV should have the of one for I believe that the first for good should be a on the application of MCA-PSV for the diagnosis of fetal this should be followed by i.e. to the measurement with that by a trained or Our in USA, is for review of both and to sonographers and sonologists in their I patients at risk for anemia because of red-cell alloimmunization, as indicated in Figures 3 and 4. are used in the studies of the MCA-PSV in these flow The first method a for the first I a patient who is at risk of having an anemic fetus due to red-cell alloimmunization, I the MCA-PSV. If the value is 1.5 multiples of the median (MoM) (Figure I the MCA-PSV in 1 If the value remains 1.5 MoM, I the parameter the following I perform a analysis on the three values, and if the is to the of the shown in I the study at that between 2 and weeks, based on the risk of the For example, if I see a patient for the first time at weeks and has an value of 1 : 16, the of is for the is not in having an amniocentesis to if the fetus is and does not have a of a affected by anemia, I the MCA-PSV in I base my decision for a test on the of the MCA-PSV. If the remains to the of the shown in and the value remains 1 : I the every 2 weeks 35 this gestational if the value remains the cut-off of 1.5 MoM, I to the MCA-PSV on a If the value is above 1.5 MoM, I the of the MCA-PSV and if it following the of to the I as indicated in 4. for non-anemic fetuses y = + mildly anemic fetuses y = + and anemic fetuses y = + (Reprinted from Detti L. et © with from is that, if the patient is Rh I perform a maternal blood test to for of the fetus. This technique is very accurate and the risk of the to the above management is to assess the MCA-PSV on a If it becomes higher than 1.5 MoM, one should the study in 2–3 and if the value to one should perform a cordocentesis and be for intravascular transfusion. The median and 1.5 MoM are reported in MCA-PSV can be used to diagnose fetal anemia due to other et and et reported that this parameter is in cases of fetal anemia to et reported that MCA-PSV diagnoses anemia to transfusion and have reported that MCA-PSV diagnoses anemia to and fetal In cases with I perform an ultrasound every for weeks following the I for of anemia and I the MCA-PSV. If the value of the velocity becomes higher than 1.5 MoM, I the ultrasound a and for and I do not in cases of based on the MCA-PSV because the fetus would not necessarily become and the anemia without usually occurs in the When I diagnose I perform a delivery. The MCA-PSV is elevated in cases of but as indicated I other that of fetal in the fetal rate prior to the MCA-PSV. In if the MCA-PSV is the cut-off of 1.5 MoM, I do not perform a The data of et al. for the use of MCA-PSV in the management of following the of the et al. have reported that in from to occurs in of cases with as a result of of Therefore, this parameter should be used for cases of following In the MCA-PSV has been shown to be an for the diagnosis of fetal anemia. The for correctly this parameter is the of sonographers and I believe that anemic fetuses should become with the diagnosis of fetal anemia using the MCA-PSV. I would to Dr Russell L. and Dr for their and

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