This chapter should be cited as follows:
Oepkes D, Verweij J, Glob. libr. women's med.,
ISSN: 1756-2228; DOI 10.3843/GLOWM.419143

The Continuous Textbook of Women’s Medicine Series – Obstetrics Module

Volume 18

Ultrasound in obstetrics

Volume Editors: Professor Katia Bilardo, University of Groningen
Dr Valentina Tsibizova, PREIS International School, Firenze, Italy

Chapter

Use of Doppler to Assess Fetal Anemia

First published: January 2024

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INTRODUCTION

Fetal anemia is a potentially life-threatening condition, in particular if it is progressive. Depending on the underlying cause, fetal anemia can often be treated successfully by blood transfusion, either before or after birth. Accurate detection, preferably before irreversible damage has occurred is therefore of vital importance. The true diagnosis of anemia, or gold standard test, is blood sampling and hemoglobin concentration measurement. Since in the fetus, this requires cordocentesis, which is a risky procedure that should only be performed by well-trained experts, there was a need for non-invasive predictive testing in fetuses at risk for anemia, or suspected to have anemia.

This chapter describes the use of Doppler blood flow velocity measurements as the best non-invasive test for fetuses that are possibly suffering from anemia.

PATHOPHYSIOLOGY OF FETAL ANEMIA

Anemia is defined as an abnormally low concentration of hemoglobin, the protein that carries oxygen to the organs and tissues in the body. Since hemoglobin is stored in red blood cells or erythrocytes, anemia is also characterized by a reduced number of red cells, commonly measured by the hematocrit.

Causes of anemia can be divided into:

• Reduced production of red blood cells or hemoglobin, or
• Increased destruction or loss of red cells. In addition,
• Some usually inherited diseases may cause impaired function of hemoglobin by structural alterations of the protein, such as the thalassemia’s, causing anemia-like symptoms but without a low number of red cells.

Examples of reduced production of red cells in fetuses are Kell alloimmunization and Parvovirus B19 infection, where antibodies or a viral infection affect the erythroid precursor cells. Increased destruction of red cells occurs for instance in Rh-D alloimmunization. Acute blood loss happens in cases of placental abruption, trauma or monochorionic twins with a large arterio-arterial anastomosis and/or single fetal demise, while chronic blood loss may occur in twin anemia polycythemia sequence (TAPS).

Irrespective of the cause, fetal anemia results in the fetus trying to compensate for the reduced oxygen-carrying capacity by increasing its cardiac output. This in turn increases the blood flow velocity in all fetal vessels. This flow velocity is also increased because of the lower viscosity of blood containing fewer cells. These two phenomena combined explain the fact that anemia can be detected by measuring the blood flow velocity, in fact in any vessel in the body.

When fetal anemia is chronic and especially if it is also progressive, the increased cardiac demand together with reduced oxygen delivery to the cardiac tissue causes the heart to increase in size and increase ventricular wall thickness. This is called cardiomegaly and is easily seen on ultrasound. The next phase, if anemia remains untreated, is cardiac compromise and ultimately cardiac failure and death. This last stage in a fetus is associated with an interesting and still not completely understood phenomenon called hydrops fetalis.

Hydrops caused by fetal anemia typically starts with a small rim of ascites. This is a reliable sign that the hemoglobin concentration is very low, below 4 g/dl or 7 standard deviations (SD) below the mean for gestational age. This is still a stage where successful treatment with blood transfusion and complete recovery is possible. Further development of hydrops, with skin edema and increasing ascites worsens the prognosis. Even careful slow transfusion may be too much for the compromised heart, and delivery of a severely hydropic and often premature fetus has a high risk of neonatal death. This means that the diagnosis (and treatment) of fetal anemia should be made before hydrops develops. The pitfall that in severely hydropic fetuses, Doppler blood flow measurements can give false negative results (normal or even low flow velocity despite severe anemia) due to decreased cardiac output will be discussed later in this chapter.

HISTORY OF DOPPLER IN THE DETECTION OF FETAL ANEMIA

When Doppler measurement of fetal blood flow was introduced in obstetrics, early 1980s, the first pathology that investigators tried this technique on was Rh-D alloimmunization. The concept described above of increased flow velocities in fetal anemia was well understood. With relatively low resolution and only B-mode/gray scale ultrasound, the vessel used by these pioneers was the intra-abdominal umbilical vein. Since for the evaluation of absolute velocities, the angle of insonation had to be 0 degrees, or an angle-correction factor needed to be used, the fetus had to be in a favorable position, and scanning was done in a slightly oblique transverse cross-section of the abdomen. The first studies were done without the availability of fetal blood sampling, which only became available in 1984. The Scandinavian researchers Kirkinen, Jouppila and Eik-Nes measured umbilical venous volume flow rates (in ml/min/kg) just before delivery, comparing the values with hemoglobin concentrations from cord blood samples after birth in 12 alloimmunized pregnancies. Their 1981 Lancet publication showed a clear negative linear correlation between volume flow and hemoglobin levels.¹

A few other studies correlated Doppler findings with severity of Rh-D disease using amniotic fluid bilirubin levels or neonatal outcomes. In 1986, Daniel Rightmire, an American research fellow of Nicolaides, Rodeck and Campbell from King’s College in London, UK published Doppler measurements in the umbilical artery, umbilical vein and the aorta in red cell alloimmunization between 18 and 28 weeks’ gestation, and compared the results with fetal hemoglobin and hematocrit obtained by fetoscopic fetal blood sampling prior to intrauterine transfusion (IUT) by fetoscopy.² An inverse correlation was found between the time-averaged mean flow velocity in the descending aorta and fetal hematocrit. Umbilical artery resistance index was also found to be useful in predicting fetal hematocrit before IUT. Larger studies were done by this pioneer group when cordocentesis became available. With Katia Bilardo as first author, this group confirmed in 68 fetuses examined before the first transfusion the positive correlation between aortic mean velocity and degree of anemia.³ They showed that both the blood flow velocities and fetal hemoglobin/hematocrit in healthy fetuses increase with gestational age, necessitating correction for gestational age for both parameters.

Another important finding of this group was a reduced flow velocity in the aorta in the presence of fetal hydrops, all with a hemoglobin deficit >7 g/dl (7SD below the mean for gestational age). This was thought to be due to cardiac decompensation.

In addition, the investigators abandoned the use of estimated volume flow, since the formula to calculate volume flow includes the square of the vessel diameter, a measurement which in a small fetus has a considerable error. Since the vessel diameter is not expected to change due to anemia, it is sufficient to only use flow velocity.

Similar findings were published around the same time by the group of John Hobbins at Yale University, New Haven, Connecticut, USA. With Josh Copel as first author they published a formula to predict fetal hematocrit using aortic flow velocity measures just before IUT,⁴ and subsequently tested this formula in a prospective study.⁵ The results were disappointing, and the group of Nicolaides also concluded that for individual predictive use, Doppler could not replace diagnostic cordocentesis for direct hemoglobin/hematocrit measurement.⁶
Historically interesting is also the research done by the group of King’s College on middle cerebral artery (MCA) Doppler. In 1990, Sanjay Vyas et al. published a series of 24 anemic fetuses in which the mean flow velocity in the MCA was compared to the degree of anemia.⁷ They confirmed that like in other vessels, anemia was correlated with increased flow velocity, which they described as a hyperdynamic circulation, mainly caused by the lower viscosity.

Giancarlo Mari from the group from Baylor College of Medicine in Houston, Texas studies the MCA at the same time as well, first focusing on the pulsatility index.⁸ This index was not correlated to fetal anemia. Interestingly, this group had an abstract accepted at the Society for Gynecologic Investigation 37th annual meeting In St. Louis, where they showed a correlation between the MCA maximal systolic velocity and fetal anemia.⁹ The group performed Doppler studies in many other fetal vessels in various fetal pathologies, but did not find a good predictor of fetal anemia.

In Leiden, The Netherlands, one of the largest centers worldwide for the treatment of red cell allommunization, Dick Oepkes and co-workers studied a number of ultrasound and Doppler parameters in the prediction of fetal anemia. Their best-performing parameter was umbilical venous maximum flow velocity, followed by descending aorta time-averaged velocity. A regression model using both parameters had an accuracy of 90%.¹⁰ Although this group published a study on MCA Doppler in normal pregnancies in 1990, they did not think of using the peak velocity to predict fetal anemia.¹¹

Giancarlo Mari moved from Houston to Yale University, to work with Josh Copel, who he convinced to study the MCA peak velocity (MCA-PV) in fetal anemia. In what we now know was a landmark paper, in a collaborative study with the Houston group, they showed a good correlation of MCA-PV with fetal hematocrit.¹² Measurements were done with a 0-degree angle between the ultrasound beam and the blood flow. Their results showed that in fetuses with an MCA-PV below the mean for gestational age, severe anemia was always absent. This would mean that the potentially risky invasive procedure of diagnostic fetal blood sampling could be avoided in many cases. An important remark in their discussion was that these Doppler measurements, in order to be successfully applied, should be done in a population at risk for fetal anemia.

Fortunately, the Yale group decided to follow up this promising result by executing an international multicenter study, published on January 6, 2000 in the NEJM.¹³ This is regarded as the game-changing paper that revolutionized the management of pregnancies at risk for fetal anemia. They measured the fetal hemoglobin concentration using cordocentesis and the peak systolic velocity in the middle cerebral artery (MCA-PSV) in 111 red-cell alloimmunized pregnancies. They constructed a reference range (18–40 weeks) of hemoglobin values in 265 normal fetuses. Sensitivity of MCA-PSV for the prediction of moderate or severe anemia was 100 percent with a false positive rate of 12 percent. The cut-off they used for MCA-PSV was 1.5 Multiples of the Median (MoM). Moderate-to-severe anemia was defined as <0.65 MoM hemoglobin concentration. They concluded that MCA-PSV Doppler provides an accurate noninvasive means to determine the degree of fetal anemia, thereby reducing the need for invasive diagnostic testing using serial amniocentesis for bilirubin levels and cordocentesis for direct hemoglobin measurement.

The ultimate evidence that this noninvasive diagnostic test indeed could replace diagnostic amniocentesis was published in 2006 in the NEJM by Oepkes et al.¹⁴ This prospective study was initiated by the group from Greg Ryan in Toronto, and performed in 10 international fetal therapy centers not involved in Mari’s study. They used the same Doppler technique and the same reference ranges for both fetal hemoglobin and for the MCA-PSV values, and compared the performance of the MCA-Doppler measurements with the until then standard diagnostic test, amniocentesis for bilirubin optical density measurement. In a group of 165 fetuses, of which 74 had severe anemia, sensitivity of MCA Doppler was 88%, while for amniocentesis this was 76%. Specificity was 82% versus 77% respectively. The editorial in the same NEJM issue by Ken Moise Jr., one of the supervisors of Giancarlo Mari, concluded that it was now ‘time to put the needles away’.¹⁵

In the past two decades, MCA-PSV Doppler has been established as the single most accurate noninvasive test for fetal anemia, not only in red cell alloimmunization but in most if not all other pregnancy complications associated with fetal anemia. In the next paragraphs, the use in these various pathologies will be summarized.

RED CELL ALLOIMMUNIZATION

With the establishment and international consensus of Doppler measurement of MCA-PSV as the tool to evaluate fetuses at risk for anemia, it is important to define its optimal role in the management of this disease. Availability of tests for screening and diagnosis in red cell alloimmunization may vary across the world, and within countries. The issue of availability and access to prophylaxis programs is beyond the scope of this chapter. The use of Doppler to detect anemia only starts to play a role in health care systems where routine screening of pregnant women for blood type and antibodies against fetal red cells are routine. In these screening systems, women with Rh-D, Kell and possibly Rh-c require careful management including serial antibody titer (or alternatives such antibody quantitation or bioassay) testing and when the serum testing puts them in the high-risk group, assessment of the fetal antigen type. In order to maintain the high sensitivity and specificity of MCA-PSV Doppler, this diagnostic test should only be applied to a high-prevalence group, thus the pregnancies with a serum antibody level above a certain cut-off and verified antigen-positivity of the fetus.^12,16

Fetal anemia due to red cell alloantibodies never occurs before 16 weeks’ gestation. However, even in women with a mild history may suddenly have a rise in antibody levels and rapid development of fetal anemia. Especially in Kell immunization, early onset of severe disease is well-known. It is therefore recommended to start surveillance using MCA-PSV from 16–18 weeks onwards. Measurements should be done at least every two weeks, and weekly in case of a severe history, sharp rise in titers, rising Doppler values or reduced fetal movements. With weekly measurements, in the high-risk group, there is virtually no risk of missing fetal anemia requiring intervention.

When performing ultrasound examination in these pregnancies, it is obvious that the sonographer should also evaluate fetal movements, presence of ascites, and cardiac size (cor-thorax ratio). Abnormalities in these parameters however are only expected in very severe anemia, and should normally be preceded by rising MCA-PSV values. False negative MCA-PSV measurements are extremely rare unless the fetus is hydropic, in which case intervention is urgently needed anyway. False positive MCA-PSV measurements do occur, in most series around 10–15%, more likely later in gestation (especially after 35 weeks). In case of a marginally increased MCA-PSV value, and complete absence of reduced movements, ascites or cardiomegaly, it is therefore a valid option not to perform invasive testing but to repeat the MCA Doppler after 3–4 days. If a decision is made to perform a diagnostic cordocentesis with, in case of confirmation of the moderate-to-severe anemia, IUT, it is advised to always combine these interventions. This means that donor blood should be ready for immediate transfusion when a fetal blood sampling is done. The safest way to perform these interventions is to insert the needle into the umbilical vein, take blood sample and rapidly asses hemoglobin/hematocrit, leaving the needle in place. With, ideally, a blood cell counter in the operating room, the need for IUT can be assessed within 1 minute, and blood can be given through the same needle right away. Preparation for IUT, including ordering 0 negative blood, may take several hours and often longer. Unless there is fetal hydrops, the interval between the first detection of an increased MCA-PSV and the IUT can safely be 48 hours.

The primary challenge for fetal therapy centers in the management of red cell alloimmunization is perfect timing of the first intrauterine transfusion. Ideally, fetal anemia should be moderate-to-severe, so a relatively large volume of donor blood can be given. A tiny rim of ascites is acceptable, but true fetal hydrops means the intervention should have been done earlier, since hydrops significantly worsens the prognosis, not only for survival but also for long term health.¹⁷ The routine use of MCA-PSV Doppler has been one of the most important reasons why fetal hydrops is now seldom seen in red cell immunized pregnancies managed by fetal medicine centers.¹⁸

A specific topic is the use of MCA-PSV in the prediction of recurrence of fetal anemia following an IUT. Although with knowledge of the pre and post transfusion hematocrit values and gestational age, a fairly accurate estimate of the transfusion interval can be made, there are exceptions where MCA-PSV measurement may assist in timing the subsequent transfusion. All studies however show a lower accuracy for subsequent transfusions compared to predicting fetal anemia before the first IUT.^19,20,21,22 The high negative predictive value of MCA-PSV may still be used to postpone IUT. Some authors have suggested adapting the cut-off level.^23,24 Whether the presence of adult red blood cells in the fetal circulation plays a role in the declining accuracy with an increasing number of IUTs is unknown. Currently, virtually all experienced fetal therapy centers include MCA-PSV in the post-IUT monitoring, and determine the IUT-interval on an individual basis using all available information, including not only pre and post IUT hematocrits and MCA-PSV, but also fetal size, type and titer of antibody, logistic aspects such as whether adapting the calculated interval means that an additional IUT is needed, or that the delivery will be at a more favorable gestational age etc.

PARVOVIRUS B19 INFECTION

Pregnant women infected with human parvovirus B19 are at significant risk for losing their fetus. In a large prospective series by Enders et al., fetal death rate was 6.3%, and fetal hydrops was found in 3.9%, with the highest risk following infection between 13 and 20 weeks’ gestation.²⁵ Hydrops however has been reported with infections throughout pregnancy. Clinically, the obstetrician can be confronted with pregnant women at risk for fetal anemia due to parvovirus in two ways. A woman can be seen or referred because of reduced fetal movements, with fetal hydrops visible on ultrasound, or a woman has had serum testing for parvovirus infection because of contact with an infected patient/child (often at a daycare center or primary school). In the first example, the work-up for fetal hydrops is often done using a protocol, including testing for viral infections. As outlined above, in fetuses with severe hydrops and cardiac dysfunction, the cardiac output may already be compromised so much that despite very low hemoglobin levels, the MCA-PSV is not increased. Such a fetus is at high risk of imminent death. Still, a careful, slow and low-volume IUT may save its life. A work-up for fetal hydrops may be individualized depending on the specific ultrasound findings and the history. Anemic hydrops is characterized by ascites, in parvo-anemia often a major amount, cardiomegaly and some skin edema. Amniotic fluid volume anemia may be normal or reduced. The placenta is often thick and uniformly gray (‘hydropic’). Such findings, combined with the pregnant woman having a young child in daycare, or working at school or daycare herself, should trigger the clinician to rapidly test for parvovirus infection. Performing an IUT without delay has a high success rate, not only for survival but also for good long-term outcome.^26,27 In our experience, one IUT is almost always sufficient to treat the disease.

Cosmi et al. found a sensitivity and specificity of 94.1 and 93.3% respectively, of MCA-PSV Doppler to predict severe fetal anemia in parvovirus infected pregnancies.²⁸ It is important to realize that fetal anemia caused by parvovirus may occur earlier than in red cell alloimmunization. In addition, several cases have been published of successful IUT at 13–14 weeks gestation already.²⁹ Measuring MCA-PSV before 18 weeks’ gestation requires additional data on normal pregnancies, Since Mari’s nomogram started at 18 weeks. A reliable option appears to be to take the 18-week values of the nomogram, and extrapolate these backwards horizontally, thus, the 1.5 MoM value at 18 weeks remains the same value in the weeks before. Specific nomograms for the early first trimester have been published by Abu-Rustum et al.³⁰

Fetal hydrops with massive hydrothorax, massive skin edema and a relatively small heart very rarely if ever have severe anemia as underlying cause, and work-up may be geared towards genetic causes and in case of hydrothorax, considering thoraco-amniotic shunting.

TWIN ANEMIA POLYCYTHEMIA SEQUENCE

In the distant past, identical twins born with a difference in skin color, pale and red, found to have a large difference in hemoglobin concentration, were considered, by the pediatrician, to suffer from twin-to-twin transfusion syndrome (TTTS). Vascular connections on the placental surface were held responsible. In the 1980s, obstetricians using ultrasound examination in monochorionic twins, found a striking difference in amniotic fluid volume a more common and more interesting phenomenon to diagnose TTTS, and careful analysis showed that various forms of intertwin blood vessel connections resulted in different clinical syndromes.

We now understand that monochorionic twins with only tiny arteriovenous anastomoses (<1 mm) are at risk for this syndrome with the striking neonatal feature of a red and pale baby. This disease is called Twin Anemia Polycythemia Sequence (TAPS).³¹ Unlike in TTTS, the amniotic fluid volume in these twins is often not different. The diagnosis can be made prenatally by measuring the MCA-PSV, just like in other fetal anemia diseases.³² The same reference range can be used, although specific monochorionic twin nomograms have been published.³³ The well-known correlation between flow velocity and degree of anemia also applies to the prediction of polycythemia, although in many cases of TAPS the polycythemic fetus has an MCA-PSV values in the lower range of the normal distribution.³⁴ Definitions, updated over the years, and staging have been published by the Leiden group. The most recent staging uses the difference in MCA-PSV value between the twins (delta MCA-PSV >0.5 MoM) as the leading parameter.³⁵

FETOMATERNAL HEMORRHAGE

A well-known cause of severe and potentially lethal fetal anemia is fetomaternal hemorrhage (FMH). This can occur due to abdominal trauma such as traffic accidents (seatbelt), but may also occur spontaneously and even asymptomatically to the pregnant woman. Reduced fetal movements and abnormal fetal heart rate patterns on cardiotocography are common. The fetus may become hydropic. MCA-PSV can be used to detect fetal anemia, with identical cut-off levels and nomograms as in red cell alloimmunization.^36,37,38 Detecting and quantifying fetal cells in maternal blood i.e., with the Kleihauer-Betke test can confirm the diagnosis. IUT can be used to treat fetal anemia due to FMH, but serial MCA-PSV measurements to rule out recurrence after treatment is advised.

FETAL AND PLACENTAL TUMORS

Highly vascularized tumors of the fetus or placenta, sometimes with arteriovenous shunts, may cause a fetal hyperdynamic circulation with often a milder degree of anemia than would be expected from the MCA-PSV Doppler measurement. Still, some of these cases may benefit from an IUT of from techniques aimed to stop or reduce the abnormal blood flow, such as radiofrequency ablation and laser coagulation. Examples are chorioangioma^39,40,41 and sacrococcygeal teratoma.⁴² MCA-PSV Doppler can also be used to follow-up the fetal condition following interventions.

ALPHA-THALASSEMIA

Homozygous alpha-thalassemia-1 is a relatively common and severe, most often lethal genetic condition. Carrier-screening can be done and in pregnancies of couples at-risk invasive genetic or hematologic (fetal blood sampling) can be offered. However, noninvasive prediction can be useful either in non-screened pregnant women or in those wanting to avoid invasive testing. In the past, the diagnosis alpha-thalassemia often led to the request to terminate the pregnancy. However, the affected fetus may be saved by IUTs, with postnatal treatment using (lifelong) blood transfusions with chelation therapy, similar to beta-thalassemia management. The first in human studies have also been performed using gene-therapy. MCA-PSV-Doppler has been shown to work well as a diagnostic tool for alpha-thalassemia.^43,44 Since the fetus suffers from a low hemoglobin level but also from abnormally functioning hemoglobin, the severity of disease may be underestimated by using MCA-PSV estimated hemoglobin levels only. IUT treatment needs to be adapted to the percentage functioning hemoglobin.⁴³ Diagnostic performance of MCA-PSV in alpha-thalassemia-1 was shown to be improved by using a cut-off level of 1.30 MoM.⁴⁵

FETAL GROWTH RESTRICTION

In fetal growth restriction (FGR), MCA Doppler is often used in combination with umbilical artery Doppler, a combination that may show ‘brain sparing’, for which commonly the pulsatility index is used. Increased MCA-PSV can be found in FGR, as part of the hypoxemia-induced increased blood flow to the brain, but some of these fetuses are also found to be anemic. One study in pregnancies with FGR showed that MCA-PSV was correlated significantly with the fetal hemoglobin level.⁴⁶ However, its’ predictive values were insufficient for meaningful clinical use.

MCA-PSV DOPPLER TECHNIQUE AND REFERENCE RANGE

The middle cerebral artery is a small vessel in the base of the fetal brain. With good knowledge of anatomy and appropriate ultrasound equipment, the pulsating vessel can be visualized on B-mode ultrasound,¹¹ however, the introduction of color Doppler has greatly improved the ease to find the vessel. Although the position of the fetal head can be extremely variable, especially in early gestation, it is often possible to find a position for the transducer (preferably a curved array one) to make the angle of insonation close to 0 degrees. If it is impossible to keep the angle less then 10 degrees, the error in the measurement is negligible for practical use when on-screen angle-correction is applied, with an angle of at most 30 degrees. In addition, the sample volume which is also set on-screen should have a width of about the diameter of the vessel, and be placed at about one-third of the length of the vessel, as measured from its origin from the internal carotid artery at the circle of Willis. When it is set too close to the internal carotid artery, this may interfere with the flow velocity waveform. When the measurement is done too far from the origin of the MCA, the velocity may decrease. When five identical consecutive waveforms are seen on the screen, the peak velocity on one of these waveforms can be used to place the measurement caliper, preferably by hand and when automated, by visual check for correctness. The gain setting is important as well. This should be set so that a faint background of fine dots is visible outside de actual waveform, to ensure that the true peak is no missed. A too low gain setting may ‘cut off’ the peak of the wave. An example is given in Figure 1.

These guidelines, summarized in Table 1, make it clear that the operator needs to have sufficient training and experience in the use of ultrasound and Doppler in obstetrics.

Reference ranges used in ultrasound and Doppler diagnostic testing ideally should be constructed with the same machine and technique, and the same population with which the patient is evaluated. Any deviation from this principle will lower the accuracy. This is often a reason for centers to construct their own reference range, and many such publications exist for MCA-PSV Doppler. Although it is not expected that Switzerland,⁴⁷ Ireland⁴⁸ and Poland⁴⁹ should have significantly different ranges a nomogram for use in for instance Niger⁵⁰ could well serve the population in Northern Africa better. An example of serial MCA-PSV measurements in an actual patient requiring two IUTs is given in Figure 2.

NEW DOPPLER MEASUREMENTS IN FETAL ANEMIA

As outlined at the beginning of this chapter, blood flow in many other fetal vessels were studied before it was shown that the MCA-PSV had the highest accuracy. This parameter has gained a solid place in modern management of red cell alloimmunization. Still, technology and innovation never stop, and additional Doppler parameters and tools have recently been studied in fetal anemia. An interesting observation was explored by the group from Zurich.⁵¹ They noticed appearance of a second systolic peak in the MCA flow profile following IUT in the majority of fetuses. The primary wave is caused by left ventricle ejection and the secondary wave, by a (temporary) response to the circulatory challenge of IUT, after reflection in vasoconstricted peripheral arteries . The authors concluded that monitoring of this particular Doppler sign might be of clinical benefit in fetal treatment, but remains to be evaluated in systematic clinical studies.

The team from Karolinksa Institute in Sweden studies the use of automated cardiac tissue Doppler (cTDI) in anemic fetuses.⁵² They concluded that peak myocardial velocities assessed by cTDI are increased in fetuses before IUT reflecting the physiology of hyperdynamic circulation. The fetal heart appears able to adapt and efficiently handle the volume load caused by IUT by altering its myocardial function.

SUMMARY AND CONCLUSION

The days when pregnancies at risk for fetal alloimmune hemolytic disease were monitored by serial amniocentesis and diagnostic cordocentesis are long gone. Middle cerebral artery peak systolic velocity is now the primary diagnostic tool in the monitoring for fetal anemia, not only in red cell alloimmunization but in virtually all pregnancy complications possibly leading to fetal anemia. A few aspects are important in order to ensure a high accuracy of MCA Doppler to detect fetal anemia. First, the measurements should be restricted to populations with a high prevalence of fetal anemia. Second, meticulous technique, training and experience are required, meaning that the best performance will be observed in centers with a high volume of at-risk pregnancies. Third, there is still room for additional parameters to use in decision-making, in particular in timing of IUTs. Type of antibody, titer, obstetric history, logistic and technical aspects, parents’ wishes, view of the neonatologist and many other details make the management of pregnancies at risk a highly individualized type of medicine, again a plea for centralization. There is no doubt however that the introduction of noninvasive Doppler evaluation of the fetus at risk for anemia has led to a major decrease in invasive procedures, thereby reducing complications and saving lives.

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