In the 1960's the first in-utero therapy for hemolytic disease was described. Despite the availability of prophylaxis, it has been estimated that approximately 3.5 fetuses per 1000 live births are at risk for anemia due to alloimmunization1.
Sonographic Evaluation of Significant Fetal Anemia
A number of different sonographic parameters have been evaluated in an attempt to predict significant fetal anemia.
The placenta is enlarged in cases of severe Rh hemolytic disease due to villous edema and hyperplasia2.
While a dilated umbilical vein has been reported as a sonographic sign associated with hydrops, it is not sufficiently sensitive to be used as a marker for severe anemia 3,4.
Roberts et al5 reported that the length of the right lobe of the liver was greater than the 90th percentile in fetuses with a hemoglobin of ?10 gm/dl (Fig. 1). However, the authors were concerned about the reproducibility of liver lengths between centers. Fetal position also played an important role - the right lobe of the liver must be up to obtain an accurate measurement.
Fig 1. Hepatomegaly. Click for larger image.
Splenomegaly due to increased erythropoiesis, congestion and red cell destruction is also an acknowledged late finding of fetal anemia. In fetuses with severe anemia, the splenic perimeter measured at the level of the abdominal circumference, has a sensitivity of 63.6%, specificity of 91.7%, and a positive predictive value of 70% (Fig. 2)6. Since extramedullary erythropoiesis begins between a hemoglobin of 5 and 7 gm/dl, splenomegaly does not predict mild to moderate anemia. After intravascular transfusion the splenic perimeter decreases in size7.
Fig 2. Normal splenic dimensions (markers). Click for larger image.
Prior to the onset of hydrops, the sonographic manifestations of severe anemia are, in order, polyhydramnios, increased placental thickness (Fig. 3), hepatosplenomegaly and ascites (Fig. 4)4. Holosystolic tricuspid regurgitation generally precedes the development of ascites and hydrops8. Unfortunately, none of these sonographic parameters can distinguish mild from severe anemia. The speed with which anemia develops, as well as the individual fetal response to anemia are additional factors that result in the manifestation of hydrops at variable hemoglobin levels9. A fetus may be able to compensate for a gradual onset of anemia with hepatosplenomegaly. However, with a more rapid breakdown of red cells, anemia may occur without hepatosplenomegaly.
Fig 3. Placentomegaly at 30 weeks' gestation due to severe fetal anemia. Polyhydramnios is also present. Click for larger image.
Fig 4. Cadiomegaly due to fetal hydrops. Click for larger image.
Fetal cardiac output increases as a compensatory response to anemia. While the mean cardiac output is increased prior to transfusion, the value is within one standard deviation of a control group10. Hence, the increase in cardiac output cannot be used to reliably predict the extent of fetal anemia. As the severity of anemia increases, cardiomegaly (Fig. 4) gives rise to mitral and/or tricuspid regurgitation (Fig. 5). Marked hypertrophy of the ventricular chambers will eventually occur. After intravascular transfusion to correct anemia, fetal cardiac output declines. It has been postulated that the increase in blood viscosity with transfusion results in an increase in cardiac afterload. As a result, stroke volume declines and cardiac output falls to the normal range11.
Fig 5. Tricuspid regurgitation (arrow) due to fetal anemia and secondary hydrops. Click for larger image.
Rh Titers and Fetal Transfusion
The maternal Rh titer is the initial step in the evaluation of an Rh-sensitized patient.
Since there is a variation in results between laboratories, each institution must determine its "critical titer" - the level at which there is a significant risk of hydrops. Liley12 introduced the spectral analysis of amniotic fluid for bilirubin at 450 nm. His original data divided pregnancies after 27 weeks' gestation into three zones - normal/mild anemia; moderate anemia; and severe anemia. A rising titer that reaches upper zone II or zone III requires percutaneous umbilical blood sampling to accurately determine the fetal hematocrit and possibly perform an intravascular transfusion. Intrasvascular transfusions are continued up to approximately 35 weeks' gestation13.
Ideally, fetal intervention should occur before the onset of hydrops. In a review Schumacher and Moise14 reported the survival after intravascular transfusion of 75% and 94% for hydropic and non-hydropic fetuses, respectively. As a result, non-invasive methods that predict severe anemia before the onset of hydrops have been sought.
Doppler Investigation in Fetal Anemia
Through the years multiple vessels have been evaluated in an attempt to better predict severe anemia. An increase in blood velocity with fetal anemia has been recorded in the carotid arteries, descending aorta and umbilical vein. Copel et al15 developed a formula utilizing the peak systolic velocity in the descending aorta that had a 75% efficiency for detecting a fetal hematocrit < 25%. Hydrops does not generally occur until the hematocrit falls below 15%. By setting the formula to detect a hematocrit < 25%, the false positive rate would be increased. In a follow-up prospective study of 13 patients with severe Rh disease, an angle corrected fetal descending aorta peak velocity did not improve the predictive accuracy of hydrops in the diagnosis of severe anemia16.
Intracardiac and venous Doppler studies cannot accurately predict anemia9. The fetal aorta16 and splenic artery17 have also been evaluated with variable success. The use of angle independent indices or measurements that require angle correction are not sufficiently sensitive to detect the velocity changes associated with anemia1.
Middle Cerebral Artery
The middle cerebral artery has become the vessel of choice when assessing a fetus for anemia. However, the technique for obtaining the peak systolic velocity in the middle cerebral artery is critical in obtaining reliable results. The fetal vertex is imaged on an axial plane that includes the cavum septum pellucidum and thalami. The transducer is then moved toward the base of the skull until the Circle of Willis is visualized. The angle of vessel insonation should be close to zero and the Doppler gate placed in the center of the vessel immediately above its demarcation from the Circle of Willis (Fig 6)18 . The PSV should not be measured in the distal branches of the middle cerebral artery (Fig 7). The PSV is lower in these vessels than in the main branch of the MCA. The MCA should be zoomed to occupy, at least, 50% of the image (Fig. 8). An angle of insonation of zero degrees insures the most accurate measurement of the PSV1. The PSV is measured in the MCA closest to the transducer. The fetus should not be active or breathing during the examination. If the MCA is measured with this technique, there is a low intraobserver and interobserver variability in the values obtained18.
Fig 6. Circle of Willis at 24 weeks' gestation. The appropriate place to measure peak systolic velocity is marked (arrow). Click for larger image.
Fig 7. Distal branches (arrows) of the middle cerebral artery. Click for larger image.
Fig 8. Normal peak systolic velocity (marker) in the middle cerebral artery at 24 weeks' gestation. Click for larger image.
The MCA-PSV may not increase with mild anemia. As the severity of anemia increases, the correlation with MCA-PSV improves. Once the fetal hemoglobin falls to 1-3gm/dl, the velocity in the MCA does not continue to rise19.
MCA-PSV has also been evaluated with Kell sensitization, in which there is a suppression of erythroid precursor rather than hemolysis. The resulting anemia is accurately reflected in an elevated MCA-PSV20.
Anemia secondary to fetal maternal hemorrhage21, twin-to-twin transfusion22, and parvo- virus23 has also been accurately predicted with MCA-PSV. In fetuses with non-immune hydrops, a normal MCA-PSV can be used to exclude anemia as a possible etiology for the sonographic findings8.
The use of middle cerebral artery peak systolic velocity has resulted in a 70%1 to 80%24 reduction in invasive fetal testing (i.e. amniocentesis or percutaneous umbilical blood sampling).
In isoimmunized pregnancies an MCA-PSV of mean plus 1.5 SD detects 96%24 to 100%1 of severely anemic fetuses with a 12%1 to 14%24 false positive rate.
MCA-PSV is not performed before 18 weeks' gestation. Prior to this gestational age the reticuloendothelial system is too immature to successfully destroy enough antibody coated erythrocytes to result in significant anemia24.
After the correction of fetal anemia with an intravascular transfusion, the MCA-PSV immediately returns to normal25. Even after two intrauterine transfusions, MCA-PSV remains a reliable test for recurring fetal anemia26.
Healthy fetuses have up to a 10% rise in MCA-PSV during the active state. This increase could contribute to part of the reported false positive rate of MCA-PSV in detecting fetal anemia27.
After 35 weeks' gestation, MCA-PSV is not a reliable predictor of severe anemia28. A physiologic mechanism for this finding has not yet been elucidated.
MCA-PSV has been found to be similar29 or better30 than amniotic fluid OD450 in the prediction of anemia.
The measurement of MCA-PSV has revolutionized the management of fetuses with suspected anemia. With appropriate training, the accurate measurement of the MCA-PSV can reduce invasive fetal testing for anemia by up to 80%.
- Mari G, Deter RL, Carpenter RL, Rahman F, Zimmermann R et al. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. Fetal blood flow velocity of the middle cerebral artery in the anemic fetus. N Engl J Med 2000;342:9-14.
- Saltzman DH, Frigoletto FD, Harlow BL, Barss VA, Benacerraf BR. Sonographic evaluation of hydrops fetalis. Obstet Gynecol 1989;74:106-110.
- Reese EA, Gabrielli S, Abdalla M, O'Connor TZ, Hobbins JC. Reassessment of the utility of fetal umbilical vein diameter in the management of isoimmunization. Am J Obstet Gynecol 1988;159:937-938.
- Chitkara U, Wilkins I, Lynch L, Mehalek K, Berkowitz RL. The Role of Sonography in Assessing Severity of Fetal Anemia in Rh- and Kell-Isoimmunized Pregnancies. Obstet Gynecol 1988;71:393-398.
- Roberts AB, Mitchell JM, Pattison NS . Fetal liver length in normal and isoimmunized pregnancies. Am J Obstet Gynecol 1989;161:42-46.
- Bahado-Singh R, Oz U, Mari G, Jones D, Paides M, Onderoglu L. Fetal splenic sizes in anemia due to Rh-alloimmunization. Obstet Gynecol 1998;92:828-832.
- Oepkes D, Meerman RH, Vandenbussche RPHA, Van Kamp IL, Kok FG, Kanhai HHH. Ultrasonographic fetal spleen measurements in red blood cell-alloimmunized pregnancies. Am J Obstet Gynecol 1993;169:121-128.
- Mari G (Opinion). Middle cerebral artery peak systolic velocity for the diagnosis of fetal anemia: the untold story. Ultrasound Obstet Gynecol 2005;25:323-330.
- Hecher K, Snijder R, Campell S, Nicolaides K. Fetal venous, arterial, and intrauterine blood flows in red blood cell isoimmunization. Obstet Gynecol 1995;85:122-128.
- Rizzo G, Nicolaides KH, Arduini D, Campbell S. Effects of intravascular fetal blood transfusion on fetal intracardiac Doppler velocity waveforms. Am J Obstet Gynecol 1990;113:1231-1238.
- Moise KJ, Mari G, Fisher DJ, Huhta J, Cano LE, Carpenter RJ, Jr. Acute fetal hemodynamic alterations after intrauterine transfusion for treatment of severe red blood cell alloimmunization. Am J Obstet Gynecol 1990;163:776-784.
- Liley AW. Intrauterine transfusion of foetus in haemolytic disease. Br Med J 1963;2:1107-1109.
- Klumper FJ, Van Kamp IL, Vandenbussche FP, Meerman RH, Oepkes D, et al. Benefits and risks of fetal red-cell transfusion after 32 weeks gestation. Eur J Obstet Gynaecol Reprod Biol 2000;92:91-96.
- Schumacher B, Moise KJ. Fetal transfusion for fetal red blood cell alloimmunization in pregnancy. Obstet Gynecol 1996;88:137-150.
- Copel JA, Grannum PA, Belanger K, Green J, Hobbins JC. Pulsed Doppler flow-velocity waveforms before and after intrauterine intravascular transfusion for severe erythroblastosis fetalis. Am J Obstet Gynecol 1988;158:768-774.
- Copel JA, Grannum PA, Green JJ, Belanger K, Hobbins JC. Pulsed Doppler flow-velocity waveforms in the prediction of fetal hematocrit of the severely isoimmunized pregnancy. Am J Obstet Gynecol 1989;161:341-344.
- Bahado-Singh R, Oz U, Deren O, Pirhonana J, Kovanci E et al. A new splenic artery Doppler velocimetric index for prediction of severe fetal anemia associated with Rh alloimmunization. Am J Obstet Gynecol 1999;180:49-54.
- Mari G, Adrignolo A, Abuhamed AZ, Pirhonen J, Jones DC et al. Diagnosis of fetal anemia with Doppler ultrasound in the pregnancy complicated by maternal blood group immunization. Ultrasound Obstet Gynecol 1995;5:400-405.
- Mari G, Detti L, Oz U, Zimmermann R, Duerig P, Stefos T. Accurate prediction of fetal hemoglobin by Doppler ultrasonography. Obstet Gynecol 2002;99:589-593.
- Van Dongen H, Klumper FJCM, Sikkel E, Vandenbussche FPHA, Oepkes D. Non-invasive tests to predict fetal anemia in Kell-alloimmunized pregnancies. Ultrasound Obstet Gynecol 2005;25:341-345.
- Sueters M, Arabin B, Oepkes D. Doppler sonography for predicting fetal anemia caused by massive fetomaternal hemorrhage. Ultrasound Obstet Gynecol 2003;22:186-189.
- Senat MV, Loizeau S, Couderc S, Bernard JP, Ville Y. The value of middle cerebral artery peak systolic velocity in the diagnosis of fetal anemia after intrauterine death of one monochorionic twin. Am J Obstet Gynecol 2003;189:1320-1324.
- Cosmi E, Mari G, Delle CL, Detti L, Akiyama M et al. Non-invasive diagnosis by Doppler ultrasonography of fetal anemia resulting from parvovirus infection. Am J Obstet Gynecol 2002;187:1290-1293.
- Scheier M, Hernandez-Andrede E, Carmo A, Dezereya V, Nicolaides KH. Prediction of fetal anemia in rhesus disease by measurement of fetal middle cerebral artery peak systolic velocity. Ultrasound Obstet Gynecol 2004;23:432-436.
- Stefos T, Cosmi E, Detti L, Mari G. Correction of fetal anemia on the middle cerebral artery peak systolic velocity. Obstet Gynecol 2002;99:211-215.
- Mari G, Zimmermann R, Moise KJ, Jr, Deta RL. Correlation between middle cerebral artery peak systolic velocity and fetal hemoglobin after 2 previous intrauterine transfusions. Am J Obstet Gynecol 2005;193:1117-1120.
- Sallout BI, Fung KFK, Wen SW, Medd LM, Walker MC. The effect of fetal behavioral states on middle cerebral artery peak systolic velocity. Am J Obstet Gynecol 2004;191:1283-1287.
- Zimmermann R, Durig P, Carpenter RJ, Jr, Mari G. Longitudinal measurement of peak systolic velocity in the fetal middle cerebral artery for monitoring pregnancies complicated by red cell alloimmunization: a prospective multicentre trial with intention-to-treat. Br J Obstet Gynaecol 2002;109:746-752.
- Bullock R, Martin WL, Coomarasamy A, Kilby MD. Prediction of fetal anemia in pregnancies with red-cell alloimmunization: comparison of middle cerebral artery peak systolic velocity and amniotic fluid OD450. Ultrasound Obstet Gynecol 2005;25:331-334.
- Pereira L, Jenkins TM, Berghalla V. Conventional management of maternal red cell alloimmunization compared with management by Doppler assessment of middle cerebral artery peak systolic velocity. Am J Obstet Gynecol 2003;189:1002-1006.