Doppler Velocimetry in Maternal Alloimmunization Andrzej Lysikiewicz

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Obstetrical management of isoimmunized pregnancy is determined by the severity of fetal anemia. Early and accurate diagnosis of anemia makes safe and effective clinical management. In fetal Rh disease, fetal anemia leads to cardiovascular changes in blood flow through the major fetal vessels, detectable by Doppler velocimetry. Diagnosis by Doppler velocimetry is par- ticularly attractive since examination can be quick, safe, and cost-effective.

Doppler Velocimetry

as the Preferred Diagnostic Tool

The most accurate assessment of fetal anemia is by direct fetal blood examination obtained by cordocentesis; however, it is also the most invasive diagnostic method with substantial maternal morbidity and fetal mortality reported at 1%±2.7% [1, 2]. Even when no immediate fetal mortality results, lesser complications of the procedure have the potential for delayed fetal adverse effect; therefore, this diagnostic method is used if no safer alternative exists and only when fetal health and survival are in question. Those limitations, however, make clinical diagnosis of fetal anemia less available to the clinician.

Another common diagnostic procedure, amniocentesis, which has become the standard for diagnosis [3] is also not without risks and is less accurate than cordocentesis [4]. These risks have long been recognized and various management schemes have been suggested [5] to minimize maternal/fetal expo- sure in diagnosis. No management proposals, however, eliminate procedure-related risks completely unless invasive procedures can be avoided. Doppler velocimetry measurements are noninvasive and could be superior in terms of safety, patient comfort, and cost.

The natural disease process in alloimmunization leads to increased dynamics of fetal circulation, well suited for Doppler studies. The need for cordocentesis for presumed fetal anemia initially provided an op- portunity to compare fetal Doppler velocimetry before and after the procedure with actual fetal blood hemoglobin values. Such studies have, however, the

disadvantage of cross-sectional data that may not be representative to the extent of prospective longitudinal observations [6]. Prospective longitudinal studies avoid this limitation [7, 8].

Maternal Alloimmunization and Fetal Disease

Most maternal alloimmunizations occur due to the presence of D antigen Rh blood group system incom- patibility, but other fetal antigens will also result in alloimmunization if they are absent in the mother [9]. The clinical picture varies in those cases when fetal anemia is inconsistent with the antibody concen- trations as correlated in Rh disease. There is no evidence, however, that fetal blood velocities are related to any other factors than fetal anemia, and no specific findings of Doppler velocimetry have been reported in alloimmunizations of different antigens.

Fetal Pathophysiology in Alloimmunization

Fetal Anemia

Destruction of fetal red cells by maternal antibodies in the reticulo-endothelial system is the mechanism of fetal Rh disease [9]. Erythrocyte destruction is initially well compensated by fetal intramedullary hema- topoesis. This process increases with increased maternal antibody production leading to increased fetal red cell turnover. As more immature cells are released into the fetal circulation, their maturation decreases.

Eventually, medullary fetal red cell production is complemented by erythropoiesis in the liver and the spleen [10]. Initially this process compensates for red cell destruction with little or no fetal anemia; however, in time, this fetal reserve becomes exhausted and fetal anemia results.

Increased red cell production in the fetal liver is associated with increased hematopoietic cellular mass that affects liver portal circulation, producing portal hypertension, and compromising fetal liver function

Doppler Velocimetry in Maternal Alloimmunization

Andrzej Lysikiewicz

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[11]. Hypoproteinemia that develops from impaired protein synthesis in the liver contributes to development of fetal hypervolemia and hydrops. Fetal hydrops can present as a spectrum of ultrasonographic findings, from a mild form with little fetal circulatory overload to an end-stage disease, involving all major systems that, with no intervention, will progress to fetal death. Development of fetal hydrops is associated with significantly increased fetal loss even if intervention with fetal intravascular transfusion is attempted [12].

The fetus appears to be resistant to decreased oxygen-carrying capacity in fetal anemia as there is little of fetal hypoxemia in anemic fetuses [13]. Increased dynamic of fetal circulation compensates well initially for the decreased fetal erythrocyte mass, maintaining adequate oxygenation. Fetal hypoxia develops relatively late in the process as fetal hemoglobin oxygen- carrying capacity is efficient even at low concentra- tions.

Fetal Cardiovascular Changes in Alloimmunization

A substantial amount of information has been col- lected about fetal circulation during the course of alloimmunization. Fetal anemia consists of reduced red cell mass/cc and ªthinningº of the fetal blood. Signifi- cant fetal anemia has been reported as 5 g/dl below the mean hemoglobin concentration for gestational age, since at this level risk for development of fetal hydrops increases [14]. Lower fetal hemoglobin levels reduce oxygen-carrying capacity that could eventually lead to fetal hypoxia. Hypoxia is, however, not observed until late in the process, presumably due to increased 2,3-diphosphoglycerate concentration and increased cardiac output that maintain adequate tissue oxygen delivery [15]. At this level, anemia leads to reduction of fetal blood viscosity that is further multi- plied by decreased fetal plasma protein production in the fetal liver. The compensatory increase of cardiac output and faster blood circulation, a combination described as the fetal hyperdynamic state [16], pre- vents development of hypoxia and acidosis early in the process.

Increase of the fetal blood flow velocities is not equally consistent in all vessels. Selective redistribution of the blood flow, similar to those of chronic hypoxic growth restriction, has not been confirmed [16]. With terminal hydrops, however, hypoxia is likely and some redistribution of the fetal blood flow may be expected. In early fetal anemia, however, the selection of the most representative vessels reflecting the fetal condition is important to obtain pertinent measurements [17].

Cardiac Blood Flow

In early fetal Rh disease, in the absence of fetal hydrops, there are no indications that fetal anemia of less than 5 g/dl of hemoglobin deficit from the mean hemoglobin concentration expected for gestational age value affects fetal cardiac functions.

At the end stage of alloimmunization generalized fetal hydrops develops. Decreased serum oncotic pressure owing to reduced liver albumin production, umbilical venous and portal hypertension, hypoxic endothelial damage, and congestive heart failure are postulated as mechanisms of hydrops, with congestive heart failure being infrequent. Hecher et al. [15]

examined fetal flow-velocity waveforms from the at- rioventricular valves, ductus venosus, right hepatic vein, inferior vena cava, middle cerebral artery (MCA), and descending thoracic aorta with concur- rent cordocentesis in 38 fetuses with red blood cell isoimmunized pregnancies. Increased blood flow velocities in the thoracic aorta, MCA, and the ductus venosus were consistent with hyperdynamic state. In this study, increased velocity in the thoracic aorta was associated with fetal anemia as in other previous reports [18, 19]. The authors did not notice major changes in the venous blood flow. They concluded that congestive heart failure is not a major factor in development of fetal hydrops and that it happens late in the process, if at all.

Fetal Heart Rate

Fetal hypoxia is often a concern in anemic fetuses in alloimmunization because of presumed reduced oxygen-carrying capacity. Hypoxic fetal response can be expected to involve compensatory tachycardia and redistribution of the fetal blood flow similar to chronic hypoxia in intrauterine growth restriction; however, several studies have shown that the correlation between fetal anemia and fetal acid base is inconsistent [13, 20]. Fetal hypoxia does not appear until late in the process and fetal hemoglobin, even if diluted, can carry a sufficient amount of oxygen. Fetal tachycardia that may be observed is more likely to result from the fetal hyperdynamic state [16]; therefore, only in the very late stage of fetal disease in alloimmunization, reduced oxygen-carrying capacity will lead to hypoxia and fetal tachycardia. With fetal tachycardia a higher end-diastolic flow can be recorded with shortened diastole period. This represents a nonspe- cific finding related to tachycardia itself.

Sinusoidal Fetal Heart Rate

Abnormal cardiac rhythm characteristic for fetal anemia is a sinusoidal rhythm (Fig. 22.1). It has been observed in severely anemic fetuses, regardless of the

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cause of fetal anemia. Intermittent, low-frequency 3- to 5-Hz sinusoidal variations of the fetal heart rate are more likely a result of stressed cardiac neuroregu- lation than actual changes in fetal blood flow [21, 22].The inability of the medullary centers to control the fetal heart rate results in a sinusoidal heart rate pattern. Observations of fetal heart rate in severe anemia, fetal brain maldevelopment, cytomegalovirus in- fection and during alfaprodine or pancuronium bro- mide administration as reported by various authors appear to confirm this mechanism [23, 24].

In the absence of significant hypoxia a mechanism of sinusoidal heart rate pattern is not well under- stood. It is likely that more than one compensatory mechanism is involved in such a severely affected fetus. Decreased fetal blood viscosity, increased blood volume, increased preload, baroreceptor, and volume receptor stimulation all affect fetal heart rate. Hecher et al. [15] reported increased fetal blood viscosity after fetal intravascular transfusion that occurred only in whole blood but not in serum, suggesting that it is increased erythrocyte mass that leads to increased blood viscosity. In anemic fetuses the cumulative effects of increased blood volume and decreased blood viscosity may lead to increased venous blood return and increased preload as reflected by the preload index in inferior vena cava velocimetry.

No systematic studies of Doppler velocimetry during sinusoidal rhythm have been reported. In our one case fetal Doppler velocimetry in umbilical artery, descending aorta, MCA, and inferior vena cava were recorded. The elevation of ªaº wave in the inferior vena cava was noted, and fetal anemia was confirmed by cordocentesis. Subsequently, sinusoidal rhythm was relieved by fetal intravascular transfusion with the return of the inferior vena cava Doppler waveform to normal values shortly after transfusion. Asso- ciation of abnormal Doppler velocimetry with a sinu-

soidal heart rate pattern has not been definite and needs more observations; however, the presence of fetal sinusoidal rhythm has been reported consistently as an ominous sign and an emergency requiring prompt diagnosis and treatment [21].

Changes in Fetal Systemic Arterial Blood Flow

Doppler Flow Velocity Measurements

Fetal blood flow velocity is the parameter that can be adequately measured, provided that the angle of insonation is known and laminar blood flow is taken into consideration [25]. Accuracy of these measurements depends on the angle of insonation, <608 being ac- ceptable [26]. Volumetric flow measurements are also possible but require accurate data on the size of the vessel that are not easy to obtain. With current tech- nology, they are not of practical use in fetal Rh disease.

According to the law of physics, low viscosity ªthinnedº fetal blood in anemia flows faster in fetal blood vessels [16]. With unchanged peripheral resistance that translates into increased systolic and diastolic velocities. A similar increase in both systolic and diastolic blood flow velocities may be an expla- nation for generally unchanged S/D ratios and other indices in fetal arterial circulation. An increase in blood flow velocity does occur and to measure this change in flow the maximum velocity (or ªpeak velocityº) may be a more appropriate measurement [17]. This single measurement of absolute velocity at its maximum peak is angle dependent and as such requires consistency in the technique of measurements.

In extreme conditions, in a terminally ill fetus, additional factors (hypoxia, neural regulation) may be affecting blood flow distribution and blood flow velocity in specific vessels, but it is not observed in mild to moderate anemia.

Fetal Aortic Arch

Increased fetal blood flow velocity in the aortic arch can be expected in anemic fetuses consistent with increased blood flow velocity in the fetal descending aorta but specific studies are lacking. The standard measurements have not been established for this complex blood flow velocity pattern that varies according to changing physiologic conditions [26].

Fetal Descending Aorta

An example of blood flow velocity measured in the fetal aorta in an anemic fetus is presented in Fig.

22.2.

Fig. 22.1. Sinusoidal fetal heart rate pattern

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Blood flow mean velocity measured in the fetal descending aorta was inversely correlated with fetal hematocrit [27, 28]. Rightmire et al. [27] compared the fetal umbilical artery Pourcelot index with fetal hematocrit and a numerical correlation allowed for retrospective development of a formula predicting fetal hematocrit. Prospective clinical confirmation of the accuracy of this method has not been published.

A similar study by Copel et al. [29] led to development of formulas that had limited accuracy for predicting fetal hematocrit when based on fetal descending aorta Doppler velocities alone.

Descending aorta Doppler velocities were again studied by Nicolaides et al. [17] and the conclusion of this group did not support use of fetal descending aorta Doppler velocities for prediction of fetal hematocrit. A correlation with fetal hematocrit was shown only when descending aorta velocimetry data was analyzed in relation to gestational age [30]. The authors concluded that the correlation, although sta- tistically significant, has no sufficient predictive value for clinical application.

Splenic Artery

The splenic artery, a branch of the celiac axis, can be identified with color Doppler and, within its straight segment, a Doppler velocity measurement can be car- ried out. If done at an insonation angle of close to 08, a high accuracy of such a measurement can be expected [30, 31].

According to this study, the deceleration angle of Doppler waveform correlates well (r=0.68) with fetal hemoglobin deficit (mean expected for gestational age minus actual hemoglobin). Also splenic artery mean velocity is a good predictor of fetal anemia, with sensitivity approaching 100%. Although the authors re-

ported success in obtaining satisfactory blood flow waveforms in 95% of patients, the procedure is highly specialized, which limits its application.

Renal Arteries

Limited information exists on blood flow in renal arteries in Rh disease. Mari et al. [32] indicates improvement in the pulsatility index before fetal intravascular blood transfusion in anemic fetuses and return of absent end-diastolic flow after transfusion.

The authors attribute these findings to fetal increase in renal flow to eliminate excess fluid after transfusion. Diagnostic applications of renal artery velocity measurements in fetal anemia have not been established.

Umbilical Arteries

No significant correlation has been found between umbilical artery S/D ratio, pulsatility index, or resistance index and fetal anemia [33, 34]. Perhaps steady placental resistance and consistent umbilical vessel diameter does not alter systolic/diastolic flow ratio even with increased flow of both.

Doppler velocimetry of the fetal umbilical artery reflects fetal placental resistance. There is no evidence that placental vascular resistance is affected by maternal alloimmunization; hence, no changes in umbilical artery indices should be expected.

Internal Carotid Artery

A significant association between the degree of fetal anemia and the increase in mean velocity in the fetal common carotid artery has been reported by Bilardo et al. [34]. In their series of 12 fetuses with primary anemia (previously untransfused) measurements were made immediately before cordocentesis. They suggested that increased fetal cardiac output associated with fetal anemia is an underlying mechanism and not the redistribution in blood flow that occurs in chronic hypoxia in growth-restricted fetuses.

Middle Cerebral Artery

Middle cerebral artery peak blood flow velocity can be visualized on an axial view of the cranium (Fig.

22.3).

Significant and consistent increase of peak flow velocity in the MCA was seen in anemic fetuses when measured at the bifurcation from the circle of Willis and at an angle of insonation of <308 [35]. This finding was reported in several other studies [16, 36, 37], including a multicenter clinical trial [7], and was lin- early correlated with the degree of fetal anemia (Fig.

22.4) [16].

Fig. 22.2. Fetal descending aorta Doppler velocity in the anemic fetus

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The accuracy of Doppler diagnosis of fetal anemia varies depending on previous history of fetal blood transfusions. In anemic, previously untransfused, nonhydropic fetuses, MCA peak velocity correlates well with fetal hemoglobin level obtained at cordocentesis [36]. When there is a history of a previous transfusion given to the fetus, the correlation is not as strong [37]. These cross-sectional studies have also been confirmed recently by observational data of fetal MCA peak velocity in a longitudinal study of fetal blood flow in alloimmunization reported by Zimmer- man [7].

In this multicenter study, 125 fetuses at risk of anemia were longitudinally monitored in 7- to 14-day intervals for abnormal velocimetry or signs of hy-

drops. Cordocentesis or delivery was performed if signs of fetal anemia were detected. Sensitivity of 88%, specificity of 87%, positive predictive value of 53%, and negative predictive value of 98% was achieved. The method was not effective after 35 weeks. The authors' recommendation of this method as primary fetal surveillance in alloimmunization appears well founded and may reduce the need for invasive diagnosis.

Middle cerebral artery peak velocity was compared with other sonographic methods for diagnosis of fetal anemia. In 16 fetuses with isoimmunization, Doppler evaluation of MCA peak systolic velocity was a better predictor than intrahepatic umbilical maximum velocity, liver length, or spleen perimeter [39].

Fig. 22.3. Middle cerebral artery peak velocity

Fig. 22.4. Fetal middle cerebral artery peak velocity in anemic and nonanemic fetuses. Open circles indicate fetuses with either no anemia or mild anemia [0.65 multiples of the median (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 peak systolic velocity in the middle cerebral artery and the dotted curve indicates 1.5 MoM. (From [16])

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Changes in Fetal Venous Blood Flow

High arterial fetal blood flow velocity and increased tissue perfusion in the fetal hyperdynamic cardiovascular state is followed by a blood volume shift from arterial to venous circulation resulting from decreased blood viscosity [40]. The resulting high venous return may lead to right heart overload and right heart failure that can be detectable by Doppler velocimetry [41]; therefore, fetal venous flow has been extensively studied as an indicator of fetal condition in alloimmunization.

Umbilical Vein

An early study by Jouppila reported an inverse correlation between umbilical venous flow and fetal hemoglobin at birth within 4 days from delivery [42]. It was later confirmed by Warren et al. [40] and Iskaros et al. [6] who noted increased venous blood flow in the umbilical vein associated with development of fetal hydrops. Dukkler et al. [39] attempted to correlate intrahepatic umbilical venous maximum velocity and MCA peak velocity with fetal anemia in six fetuses with alloimmunization. They found that in prediction of fetal anemia, the MCA was 100% specific, while intrahepatic umbilical venous blood flow had specificity of 83%.

Inferior Vena Cava Blood Flow

Inferior vena cava blood flow has been described as the A/S index or the atrial flow velocity to atrial re- gurgitation velocity ratio (Fig. 22.5) [41]. This index

is a sensitive indicator of the right cardiac function, especially fetal right heart failure.

In fetal hyperdynamic circulation in anemic fetuses with isoimmunization, an increased venous return could lead to right heart failure. Studies of inferior vena cava blood flow do not, however, support this assumption. In an early study by Rightmire et al.

[27] inferior vena cava average velocity was elevated prior to the first blood transfusion in anemic fetuses, but the correlation with fetal hematocrit was not significant. In our own series, 20 fetal preload index measurements were followed by fetal hematocrit eval- uations by immediate cordocentesis in 13 fetuses in alloimmunized pregnancies (Fig. 22.6) [43]. An asso- Fig. 22.5. Fetal preload index and fetal hematocrit at cordocentesis

Fig. 22.6. Inferior vena cava A/S ratio

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ciation with low fetal hematocrit was weak with 66%

sensitivity, 75% specificity, 50% positive predictive value, and 86% negative predictive value.

Diagnostic use of the preload index is further limited by the difficulty in obtaining consistent measurements from a specific site [44].

Ductus Venosus

The ductus venosus in anemic fetuses demonstrates higher flow, reflecting increased venous return, and cardiac preload. Oepkes found the ductus venosus elevated in anemic fetuses with marked improvement following fetal transfusion [37]. A study by Hecher did not, however, show any significant association with fetal anemia sufficient for use as a diagnostic tool [15].

Maternal Uterine Artery

The pulsatility index of the uterine arteries and thoracic aorta peak velocity were used in a multiple re- gression model to predict fetal hematocrit following fetal transfusion on the assumption that resolving placental edema after transfusion improves uteropla- cental circulation. The uterine artery pulsatility index alone has not been found to change in fetal anemia.

Fetal Morphologic Changes and Doppler Velocimetry in Alloimmunization

Fetal cardiovascular changes reflected in Doppler velocimetry precede development of fetal hydrops. Dur- ing development of anemia in alloimmunization fetal hydrops develops gradually and relatively late in the process. Fetal signs of hydrops appear infrequently if the fetal hemoglobin level is within 5 g of the median value for gestational age. With more severe anemia fetal hydrops appears, often gradually, over a period of days. The following conditions are observed:

1. Increased amniotic fluid volume 2. Increase in placental thickness 3. Fetal liver enlargement 4. Fetal pericardial effusions 5. Ascites

6. Free loops of bowel in ascites 7. Double-walled bladder 8. Scalp edema (ªhaloº) 9. Facial swellings 10. Pleural effusions 11. Extremities edema 12. Umbilical cord pulsation

Moderate increase in amniotic fluid volume enhances the resolution of ultrasound imaging and often facili- tates detection of even small amounts of fluid in fetal body cavities. Findings of fluid in any fetal compart- ment in isoimmunized pregnancy should prompt a complete fetal morphology review for signs of fetal hydrops. Polyhydramnios in alloimmunization may reach a significant degree that is detrimental to the clarity of the imaging. Preterm labor, that often fol- lows, can make fetal examination even more difficult.

Polyhydramnios will frequently regress with correc- tion of fetal anemia.

Placental thickness also increases as part of the process of isoimmunization; however, it is not a reliable indicator of fetal anemia [45].

Liver enlargement is often seen during fetal anemia in alloimmunization as a result of increased fetal extramedullary erythropoiesis [46]. This increased liver size is associated with increased venous Doppler blood flow velocity in fetal intrahepatic venous flow as reported by Oepkes et al. [37]. Although it was postulated by Vintzileos to be a good indicator of fetal compromise [47], it was not as accurate as evaluation with MCA peak velocity measurements [39].

A certain amount of fluid is not unusual in the pericardium. When measured at the valvular level, 2 mm of fluid is often found and is not abnormal.

This small fluid collection is not associated with abnormal Doppler velocimetry; however, large pericardial effusions are one of the signs of fetal hydrops and indicates fetal anemia.

Ascites are defined as sonolucent areas in the fetal abdomen with loops of bowel visible, floating in the ascites and the fetal bladder visible with fluid inside and outside the bladder wall (Fig. 22.7). The presence of ascites is commonly associated with fetal anemia and abnormal Doppler velocimetry of the MCA and other vessels. Pleural effusions when present in hydrops fetalis suggest advanced disease.

Fig. 22.7. Fetal ascites

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Scalp edema and generalized edema are nonspecif- ic changes that may not be related to fetal anemia and changes of Doppler velocimetry.

In summary, it appears that fetal hydropic changes occur as a result of severe fetal anemia. They should not be used as predictors of fetal disease because of their poor predictive value [11, 45]. Abnormal Dop- pler velocimetry detects changes in fetal circulation that precede fetal hydrops and therefore can detect fetal anemia early. According to data by Mari et al. [35]

early detection of fetal anemia is feasible using fetal cardiovascular monitoring with Doppler velocimetry.

A finding of severe fetal hydrops in isoimmunization should be considered as evidence of advanced fetal disease but may be avoidable with intensive fetal diagnosis and active clinical management.

Fetal Blood Redistribution and Fetal Hypoxia in Alloimmunization

Fetal blood redistribution in chronic fetal hypoxia has been reported in growth-restricted fetuses. With decreased oxygen-carrying capacity in fetal anemia, similar findings could be expected due to presumed fetal hypoxia. Initial response to fetal hypoxia is an increase in fetal heart rate [21]. In alloimmunization, however, this heart rate increase may more likely be related to the blood volume increase and blood viscosity decrease resulting in increased fetal circulation [16]. Contrary to expectations, fetal hypoxia is not common in isoimmunized fetuses. Fetal hemoglobin, even if diluted, is able to transport oxygen without developing significant fetal hypoxia [48]. There is no evidence that fetal blood redistribution plays a significant role in fetal cardiovascular changes in isoimmunization [16].

Doppler Velocimetry in Clinical Management of Alloimmunization

Fetal anemia determines the management of alloimmunization.

Use of specific Doppler velocimetry measurements requires a selective, evidence-based approach in choice of measurements. Multiple Doppler-detectable changes of the fetal circulation do not have equal diagnostic value. Methods not adequately studied should only be used with caution, if at all, for diagnostic purposes as those findings often prompt major therapeutic interventions.

The standard of care in alloimmunization has been changing rapidly. The traditional biochemical monitoring is being supplemented by fetal Doppler velocimetry supported by clinical studies.

History of Previous Pregnancy

A history positive for a previous pregnancy with complications should increase the index of suspicion as it is predictive of the general severity of fetal involvement. Maternal history of alloimmunization, previous affected pregnancy or previous neonatal disease are risk factors for development of fetal anemia.

Although the correlation is strong, history alone is not sufficient to guide obstetrical management.

Maternal Antibody Titer

Maternal antibody titer has been a landmark in management of alloimmunization for several decades. Ma- ternal antibody, if present, should prompt paternal blood type zygosity evaluation to determine the likelihood of the presence of an antigen in the fetal blood. If such a risk is not 100%, as in paternal homozygosity, then fetal blood typing should be car- ried out. Absence of an antigen in the fetal blood rules out fetal involvement and makes further testing unnecessary (Fig. 22.8).

Maternal antibody concentration has been correlated with the presence and severity of fetal disease but is not accurate in prediction of specific cases.

High initial titer or rising titer indicates the possibili- ty of fetal anemia, but specific critical titers requiring intervention are difficult to define. Depending on lab- oratory methods, commonly, values 1:16 or higher are being investigated because of the probability of fetal hemolytic anemia. In this range fetal anemia and hemodynamic changes may be better detected by Doppler velocimetry than by antibody titer alone [7].

Amniotic Fluid Densitometry

A change in optical density at 450 nm wavelength detects the presence of bilirubin, an end product of fetal hemolysis. It has been used for four decades in combination with standards developed by Liley [3] to predict severely anemic fetuses that could benefit from intervention. A recent review of values by Queenan et al. improved accuracy of the curve, especially for early pregnancy [5]. According to their report, specificity of detecting severe anemia was 79%. In 21% of fetuses, however, severe anemia would not be detected by this method. This low accuracy of the Liley curves has been a concern in management of fetal anemia [5]. Doppler velocimetry is expected to improve accuracy of this diagnosis.

Detecting Fetal Anemia

For management of alloimmunization an accurate diagnosis of fetal anemia is essential. High specificity is mandatory for this testing to avoid development of

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severe fetal disease and fetal losses. Figure 22.9 pre- sents diagnostic options for detecting fetal anemia in alloimmunization.

Physical signs, such as fetal tachycardia, polyhydramnios, fetal movements, and fetal heart changes have historically guided physicians; those, however, were not accurate enough to assure fetal survival.

Detecting fetal anemia by sonography is not accurate. Morphologic markers do not predict the severity of fetal anemia [11] sufficiently enough to guide clinical management. Detection of fetal anemia using umbilical vein diameter (intrahepatic portion) [49], liver size [46], spleen size [30, 31], placental thickness, abdominal circumference, abdominal diameter, and other parameters have been developed. Although some were reported as accurate predictors, those methods did not gain widespread use. Methodology,

experience and reproducibility were likely limiting factors as much as the fact that fetal hemodynamic changes are first to occur in fetal anemia, preceding other changes. Abnormal fetal morphology occurs as a result of this process and absence of those signs does not prove fetal normality. Monitoring fetal morphology should not be used alone in management of alloimmunization.

Detection of fetal hyperdynamic state indicates fetal anemia. According to a longitudinal study of 125 pregnancies monitored by MCA peak velocity in pregnancies with red cell isoimmunization, 88% sensitivity can be achieved [7].

Methodologic considerations are important. Ap- propriate training and experience is required to cor- rectly measure the peak velocity in the fetal MCA.

Insonation angle is a potential source of error, as is Fig. 22.8. Management of alloimmunization ± maternal antibodies

Fig. 22.9. Management of alloimmunization ± detection of fetal anemia

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selection of the level of measurement outside the bifurcation of the MCA from the circle of Willis. An insonation angle of <308 allows for minimal error.

Other blood flow measurements await clinical vali- dation before they can be adopted as clinical tools;

some already have been shown to be ineffective. For example, the umbilical artery blood flow indices are not informative in alloimmunization and normal values do not represent useful clinical information. A study reported by Bilardo et al. [34] found no correlation between umbilical artery pulsatility index and fetal anemia. A highly specialized measurement of flow velocities within the splenic artery requires specific techniques and experience that may not be uni- versally available. This method of interrogation has not been widely used in clinical management. A study by Dukkler et al. [39] did not show intrahepatic vein velocity to be more predictive than the MCA peak velocity.

Without reliable estimation of fetal blood vessel size, attempts to quantitatively measure fetal blood flow do not yield any new information. In addition, with no changes in vessel size in the process of fetal anemia, blood flow measurements will provide no more information than peak velocities.

Middle cerebral artery peak velocity appears to contain the most accurate information on fetal circulation to allow for noninvasive diagnosis of fetal hyperdynamic circulation in fetal anemia and to select patients for invasive procedures.

A review by Divakaran included eight primary studies with 362 pregnancies affected by red cell alloimmunization evaluated by noninvasive methods. The cumulative metaanalysis of studies with the highest methodologic quality reported a positive likelihood ratio of 8.45 (95% CI 4.69±15.56) and negative likelihood ratio of 0.02 (95% CI 0.001±0.025) [8]. Although those results are encouraging, more clinical data may be needed before Doppler velocimetry will be recom- mended as a primary standard evaluation of fetal anemia.

Diagnostic Invasive Procedures to Detect Fetal Anemia and Doppler Velocimetry

Diagnostic procedures have to be weighted between risk of procedure and quality of information obtained for fetal anemia in alloimmunization.

Amniocentesis is considered a safe procedure with a complication rate of less than 1%. A major risk in using this method lies in the low accuracy of predic- tions. According to Queenan et al. [5], if used for detection of fetal anemia in combination with the OD curve, it is only 89% specific, whereas 21% of anemic fetuses remain undetected. Frigoletto et al. [50] con- servatively managed 11 zone-III fetuses with no ad-

verse fetal outcomes. Fetal Doppler velocimetry of the MCA has the potential to replace amniocentesis in diagnosis of fetal anemia (Fig. 22.8).

Cordocentesis is the most accurate procedure for detection of fetal anemia. It is also the most risky of all procedures with associated fetal loss of 1% [1]

and as high as 4%. If cordocentesis is used as a primary diagnosis, a large number of fetuses will be ex- posed to this risk unnecessarily since only 25% of all fetuses develop severe anemia requiring fetal blood transfusion, but all will have multiple cordocenteses to confirm normal hemoglobin concentration.

With five diagnostic cordocenteses during pregnancy the cumulative fetal mortality risk may reach 10%±20%, too high for a diagnostic procedure.

Clearly, fetal Doppler velocimetry may not be as accurate but is safer and should be considered as an alternative to cordocentesis.

Doppler Monitoring During Cordocentesis

Fetal Intravascular Transfusions

Accurate estimation of fetal anemia by cordocentesis, before and after intravascular blood transfusion, can be compared with Doppler velocimetry and numer- ous cross-sectional data sets were obtained in this fashion.

Fetal MCA Doppler velocimetry can detect fetal anemia and provide timing for initiation of intravascular transfusion prior to the development of fetal hydrops. The role of Doppler velocimetry is to guide timing of transfusions frequently enough to maintain sufficient fetal hemoglobin levels, but not too often, in order to avoid unnecessary risks from the procedure.

Clinical guidance for fetal intravascular transfusions currently rely on clinical findings and the ob- servation that fetal hematocrit decreases at the rate of 0.3%±1.0% per day. Using mathematical formulas and known hematocrit at the time of cordocentesis, an es- timate can be made regarding appropriate amount of time for repeated intrauterine intravascular fetal transfusion. Longitudinal Doppler velocimetry assessment of fetal anemia is the other alternative in guid- ing frequency and timing of fetal intravascular transfusions.

Several management schemes have been developed to guide frequency of transfusions. Less frequent, larger volume transfusions can be safer by reducing the total number of fetal intravascular blood transfusions [51], thereby reducing the risk of fetal blood volume overload [52]. Use of Doppler velocimetry during transfusion to assess fetal condition has not

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been widely used except for detecting acute fetal bra- dycardia.

Posttransfusion hemodynamic changes can be detected by Doppler velocimetry. Rizzo et al. reported changes consistent with transient right and left heart overload following transfusion that lasted up to 2 h after transfusion [53] and overall reduction of the hyperdynamic state.

In our own series [43], in 18 cases that required blood transfusion due to hematocrit level, a less significant decrease in the fetal preload index was noted following fetal intravascular transfusion p<0.05.

There is a fall in the fetal preload index following fetal intravascular transfusion. The fetal preload index predicts fetal anemia with a sensitivity of 66% and a negative predictive value of 86% (Fig. 22.5).

Increased blood viscosity, congestive heart failure, and cardiac humoral regulation are likely all involved in the posttransfusion changes. It is still unclear if such changes can be used to guide the physician regarding the amount of blood necessary to be transfused and the timing for consecutive transfusion.

Posttransfusion changes occurred immediately but delayed effects are also observed:

n Immediate posttransfusion changes:

± Increase of fetal red cell mass

± Increase of blood viscosity and peripheral resistance

± Vascular overload

± Decreased cardiac output

± Fetal humoral response n Delayed changes:

± Fetal fluid resorption and loss within hours after transfusion

± Decrease of fetal venous return

± Relief of the acute fluid overload and hyperdynamic state.

Rizzo et al. [53] found a temporary decrease in cardiac output after intravascular transfusions due to an increase in fetal vascular resistance that returned to normal 2 h later. Similarly, Mari et al. [54] found decreased middle cerebral peak velocity following fetal intravascular transfusion. Copel et al. [29] studied blood flow velocities in the descending aorta and found no significant changes following the transfusion. In a series by Weiner et al., a decrease in resistance after blood transfusion was attributed to vaso- dilatory humoral fetal response [52].

Clearly more than one fetal physiologic response is observed after blood transfusion. Severity of fetal anemia, amount of blood transfused, dynamic of transfusion, and fetal humoral response all have an effect on fetal Doppler velocimetry and represent limitations in fetal evaluation.

Early Delivery

Historically early delivery has been advised for severe alloimmunization; however, prematurity, fetal anemia, and hydrops are associated with high mortality and morbidity. Early delivery is therefore advised after fetal lung maturity can be confirmed or if additional fetal indices are non-reassuring and fetal conditions worsen despite adequate intrauterine treatment. Fetal biophysical profile is often used for fetal surveillance.

Decreased fetal activity unresponsive to fetal transfusions may result from additional pathology other than alloimmunization, requiring delivery. Biophysical fetal assessment has been used in those circumstances as a primary method of fetal surveillance. Fetal umbilical artery blood flow can occasionally reveal absent end-diastolic flow that is more likely to be a reflection of placental vascular pathology. Abnormal umbilical Doppler indices are often difficult to inter- pret in severe fetal anemia. If fetal lung maturity can be confirmed, an early delivery is preferable.

Noninvasive Therapies, Gamma Globulin, Plasmapheresis, Nonintervention

None of these treatments have gained wide use, and since advances in fetal diagnosis and intravascular transfusion therapy have been developed, these methods have been largely abandoned.

Conclusion

Fetal anemia with low fetal blood viscosity and hyperdynamic fetal circulation is a mechanism of fetal disease in isoimmunization. Doppler-detectable changes occur in arterial and venous circulation.

Doppler velocimetry in specific vessels and specific measurements can be used in clinical management.

Fetal MCA peak velocity is the best studied, specific Doppler marker for fetal anemia, and is preferable to other Doppler-based diagnostic methods.

Intravascular fetal blood transfusions are associated with temporary cardiovascular overload that can be detected by Doppler velocimetry.

The role of Doppler velocimetry in technical as- pects of fetal intravascular transfusions remains to be determined.

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