Anemia continues to be an uncommon, but life-threatening, condition to the developing fetus. Red cell alloimmunization has historically been the most common cause of fetal anemia in the United States and in many other parts of the world. Alternative causes of fetal anemia include parvovirus infection and other less common conditions.

Fetal anemia is defined as a hemoglobin value below 2 standard deviations from the mean. The fetal hemoglobin increases with advancing gestation (Table 13-1). Reference ranges for fetal hemoglobin have been established using umbilical blood sampling.^1,2

Fetal anemia is categorized as mild, moderate, and severe, based on the degree of deviation from the median for gestational age. Severe anemia may cause hydrops and fetal demise.²

Fetal anemia can result from a large number of pathologic processes (Table 13-2). The most common causes in the United States are maternal alloimmunization and parvovirus infection.³ Other causes include inherited conditions such as alpha-thalassemia, and genetic metabolic disorders, as well as acquired conditions, such as fetal blood loss and infection. Fetal anemia can occur in association with Down syndrome, due to transient abnormal myelopoeisis (TAM), a leukemic condition that occurs in about 10% of infants with Down syndrome.⁴ Vascular tumors and arteriovenous malformations of the fetus or placenta are also rare causes of fetal anemia.⁵

Fetal anemia can occur as a complication of monochorionic twin pregnancies, a condition referred to as twin anemia-polycythemia sequence (TAPS).^6,7 This condition has been reported to occur spontaneously in 3% to 5% of monochorionic twins, or after laser therapy for twin-twin transfusion syndrome (TTTS) in 13% of cases.⁸ TAPS is distinct from TTTS, as it occurs in the absence of amniotic fluid abnormalities characteristic of classical TTTS. Fetal anemia can also result from fetomaternal hemorrhage, which may occur as an isolated acute event, or as a chronic, ongoing hemorrhage.^9,10

Independent of etiology, fetal anemia can be detected by Doppler ultrasonography on the basis of an increase in the peak velocity of systolic blood flow (PSV) in the middle cerebral artery (MCA).^1,2 An MCA-PSV of more than 1.5 MoM is used to identify the severely anemic fetus (see Figure 13-1 and Table 13-3). In one of the first large multicenter studies, including 111 fetuses at risk for anemia and 265 nonanemic fetuses, a sensitivity of a single value of MCA-PSV of nearly 100% was reported (CI: 0.86-1.0) for moderate or severe anemia with a false positive rate of 12%.² Although there is not a strong correlation between MCA-PSV and fetal hemoglobin concentration when the fetus is nonanemic or only mildly anemic, as the hemoglobin decreases, the MCA-PSV increases and can be used to determine the hemoglobin value with a good level of approximation.¹¹ The MCA-PSV has become the standard of care to determine whether pregnancies at risk for fetal anemia should undergo a fetal blood sampling and intrauterine transfusion. This discovery has dramatically reduced the number of invasive procedures performed in the management of pregnancies at risk for anemia.¹²

In 2009, Pretlove et al published a meta-analysis on the diagnostic value of MCA Doppler flow studies for fetal anemia.¹³ Twenty-five studies with 1639 participants were included. Of 9 studies from which the data could be pooled, a sensitivity of 75.5% and a specificity of 90.8% were reported for detecting severe anemia. The use of the MCA-PSV trends (as opposed to a single measurement) may decrease the false positive rate to less than 5%¹⁴ (Figure 13-2).

Although the MCA-PSV was initially developed to screen for fetal anemia caused by red cell alloimmunization, it has been demonstrated to be useful in the assessment of fetal anemia due to other causes, as well. MCA-PSV can predict fetal anemia with a high degree of sensitivity and specificity in cases due to parvovirus infection, TTTS, sacrococcygeal teratoma, cytomegalovirus infection, fetomaternal hemorrhage, Blackfan-Diamond anemia, diffuse neonatal hemangiomatosis with chorangioma, Kaposi-like hemangioendothelioma, elliptocytosis, neonatal hemochromatosis, and mucopolysaccharidosis type VII, as well as unexplained fetal anemia.^3,6,15-17

The MCA-PSV has replaced the delta OD450 measured in the amniotic fluid as the best screening test for detection of fetal anemia.¹⁸

Figure 13-3 shows the algorithm followed at the University of Tennessee in Memphis for patients at risk of fetal anemia due to red cell alloimmunization.

Operators should be trained to sample the MCA-PSV using the proper technique.¹⁹ The steps for correct measurement of the MCA-PSV are reported in Figure 13-4 and they are the following:

1. 
   

   Obtain an axial section of the fetal head at the level of the sphenoid bones during a period of fetal rest.

   
   
2. 
   

   Image the circle of Willis with color Doppler.

   
   
3. 
   

   Select the area of the MCA close to the transducer.

   
   
4. 
   

   The entire length of the MCA should be visualized.

   
   
5. 
   

   Zoom the area of the MCA-PSV in such a way that the MCA occupies more than 50% of the image.

   
   
6. 
   

   The MCA-PSV should be sampled close to its origin from the internal carotid artery.

   
   
7. 
   

   Ideally, the angle between the direction of blood flow and the ultrasound beam should be as close to zero as possible and parallel to the artery for the entire length, without the need for angle correction (Figure 13-5).

   
   
8. 
   

   The MCA flow velocity waveforms are displayed, and the highest point of the waveform (PSV) is measured.

This sequence should be repeated at least 3 times in each fetus, with the highest MCA-PSV used for clinical care. The time required for the procedure is approximately 5 to 10 minutes. The use of an angle corrector is associated with higher intra- and interobserver variability and is not recommended.¹⁹

How often the MCA-PSV should be repeated depends on prior history, gestational age, and measured MCA-PSV MoM level. Surveillance should be reserved for when the pregnancy is advanced enough such that a fetal blood sampling procedure or intrauterine transfusion can technically be completed, typically between 15 and 18 weeks of gestation. After 24 weeks of gestation, routine testing is usually done on a weekly basis.

Once an intrauterine transfusion has been performed, a second transfusion is often necessary, especially if the fetus is remote from term. The need for serial or subsequent transfusions is typically less in the setting of parvovirus infection compared to alloimmunization. After a transfusion in an alloimmunized pregnancy, the fetal hemoglobin will drop at approximately 0.4 g/dL/day, and hematocrit at approximately 1%/day.³ The timing of a second transfusion can be difficult to determine with certainty, but it appears that using the MCA-PSV can give an accurate assessment of when to resample the fetus. Detti et al reported that MCA-PSV was able to detect severe anemia with 100% sensitivity and a false positive rate of 6%, and thus accurately predict the need for and timing of the second transfusion.²⁰ A prospective multicenter randomized trial has shown that the MCA-PSV may be used for timing the next transfusions in fetuses previously transfused (unpublished data). As an alternative, if the posttransfusion hematocrit is known or can be estimated, the timing of the next transfusion can be calculated using the expected decline in fetal hematocrit.

In pregnant women with parvovirus infection the MCA peak systolic velocity is followed on a weekly basis for 10 consecutive weeks. If the value remains below 1.5 MoM, no intervention is needed. In anemia due to parvovirus infection, anemia and hydrops when it is present, usually resolve following 1 or 2 transfusions.

The definition of hydrops is excessive fluid accumulation within 2 or more fetal extravascular compartments and body cavities. Hydrops is divided into immune and nonimmune. Nonimmune hydrops represents more than 80% of all reported cases of hydrops fetalis. There are 14 diagnostic categories of hydrops (Table 13-4).²¹

Doppler ultrasonography of the umbilical artery, umbilical vein, and ductus venosus in presence of hydrops varies from normal to abnormal.

If the ductus venosus velocity waveforms present reversed flow, the heart is almost always affected either by abnormal anatomy (eg, tricuspid atresia) or by an abnormal function of it, for example, cardiomyopathy, as in case of TTTS (Figure 13-6), or an abnormal rhythm of it.

The most common causes of hydrops are the following:

1. 
   

   Rhythm abnormalities

   
   
2. 
   

   Congenital heart disease

   
   
3. 
   

   Chromosomal abnormalities

   
   
4. 
   

   Anemia

   
   
5. 
   

   Fetal abnormalities

   
   

   Infections

   
   

   CCAM

   
   

   AV malformations

   
   
6. 
   

   Errors of the metabolism

For the evaluation of hydrops, patient history and ultrasound represent the initial steps. The next step is represented by the MCA-PSV.

If the MCA-PSV is below the 1.5 MoM, anemia is not the cause of hydrops, and a fetal blood sampling is not necessarily needed. The fetal liver function tests are rarely altered in cases of hydrops, and therefore it is not practical to check their values with a fetal blood sampling.

For the metabolic errors of the metabolism and for chromosome analysis, with a few exceptions, the amniocentesis may replace the fetal blood sampling.

1. 
   

   In case of TTTS, following successful laser therapy, the hydrops may require weeks to resolve. It resolves initially in the subcutaneous tissue and next in the other cavities.

   
   
2. 
   

   In hydrops secondary to parvovirus infection, the hydrops may resolve spontaneously in 30% of the cases. If the MCA-PSV decreases or it is normal, discussion with the patient and offering no intervention may be an option because it indicates that the hydrops is resolving. Figure 13-5 shows one of those cases. The patient was referred for fetal blood sampling due to hydrops secondary to anemia due to parvovirus infection. At the evaluation, the MCA-PSV was normal. The hydrops resolved, and no procedures were done. The patient and the fetus did well.

Testing for fetal lung maturity is beneficial in selected situations, such as those in which the risk of pregnancy continuation is comparable to the risk associated with prematurity due to delivery before 39 weeks of gestation.

A great effort has been made to predict fetal lung maturity to determine when a fetus is likely to develop neonatal complications as a result of pulmonary immaturity (eg, respiratory distress syndrome of the newborn or death). Several methods to evaluate fetal lung maturity have been described, and the standard of care today involves performing an amniocentesis.²² Third trimester amniocenteses carry risks and complications in approximately 0.7% of cases; such complications include preterm labor and delivery, preterm premature rupture of membranes, placental abruption, and fetomaternal hemorrhage.²³ To avoid the risks associated with amniocentesis, a noninvasive test is desirable.

There are more than 80 attempts recorded in the literature to discover the ideal noninvasive method of assessment of fetal lung maturity, and among the most researched methods are placental grading, biparietal diameter, and lung echotexture (Table 13-5).