Maternal Alloimmunization and Fetal Hemolytic Disease



Maternal Alloimmunization and Fetal Hemolytic Disease


Mae-Lan Winchester

Carl P. Weiner



Introduction


History

Fetal hemolytic disease was first described in 1609 when a hydropic twin died shortly after birth and its co-twin succumbed to kernicterus a few days later.1 The cause and relationship between hydrops and kernicterus was unrecognized until 1932 when Diamond et al noted that erythroblastosis fetalis was associated with fetal edema, neonatal anemia, and hyperbilirubinemia.2 They demonstrated that these were manifestations of a disease characterized by hepatosplenomegaly, extramedullary erythropoiesis, and erythroblastosis. In 1939, Levine and Stetson were the first to suggest that the hemolysis was due to the maternal development of a blood group antibody directed against a fetal blood group antigen.3 They observed atypical agglutinins in the serum of a woman who had just delivered a hydropic stillborn. These agglutinins were active against her husband’s erythrocytes (same ABO blood group). They postulated that an immunizing agent in the fetus, inherited from the father, entered the maternal circulation and caused her to develop the agglutinin. The discovery of blood group antigens by Landsteiner and Wiener in 1940 laid the foundation for the role of alloimmunization in the pathogenesis of hemolytic disease of the fetus and newborn [HDFN]).4


Red Blood Cell Antigens

There are two main blood group antigens, ABO (with blood types A, AB, AB, and O) and RhD (either positive or negative). There are numerous other antigens identified, with over 50 non-ABO blood group antigens implicated in HDFN.5 The function of many of these antigens remains unknown. However, their presence or absence is apparent when an antigen-negative person is exposed to that specific antigen, potentially triggering a severe allergic reaction (alloimmunization). The most common system causing serious alloimmunization is the Rh antigen system. However, antigen systems other than Rh (so-called minor antigens) are of growing importance as the prevalence of RhD alloimmunization declines as a result of antenatal and postpartum prophylaxis. Excluding RhD, non-D (ie, C, c and E, e) and Kell antibodies are the most frequent antigens implicated in severe cases of HDFN, followed by the Duffy, Kidd, and MNS antigen systems.


Rh Antigen System Nomenclature

The Fisher-Race system, first proposed in the 1940s, presumes the presence of three genetic loci, each with two major alleles—Dd, Cc, Ee.6 An Rh gene complex is described by three letters: Cde, cde, cDE, cDe, Cde, cdE, CDE, CdE. The first three complexes, Cde, cde, and cDE, are the most common, and the last one, CdE, is yet to be demonstrated.

The antigens produced by these alleles (located on chromosome 1p34-36) were originally identified by specific antisera.7 No antiserum to the d antigen has been identified, and it is believed that the d antigen reflects the absence of an allelic product. The presence or absence of the D antigen determines the Rh status. Approximately 45% of D-positive individuals are homozygous for D antigen. For example, offspring conceived by a man who is homozygous D positive (Rh positive) and a woman
who is homozygous D negative (Rh negative) will be D positive; if he is heterozygous, there is an equal chance that the offspring will be D negative or D positive in each pregnancy.

There are alternative classification systems to the Fisher-Race system. The most accurate classification system may be the Wiener system, which is based on the theory that a single locus is occupied by a pair of complex agglutinogens. Eight genotypes are designated (in decreasing order of frequency in the White populations): R1, r, R2, R0, r′, r″, Rz, and rv. Another classification system is the Rosenfield system, which opines that genetic concepts, such as the operon model of gene function with nonlinked regulator genes, are poorly accommodated by the Mendelian model of Fisher-Race.8 Rosenfield proposed an updated system of nomenclature that numbered the Rh antigens as Rh1-Rh48 to explain the quantitative differences in the expression of Rh antigens.


Diversity and Ethnicity

The Rh blood group system is complex, and 42 antigens other than the five mentioned above have been described.9 An allele for C, Cw, is relatively common across all racial and ethnic groups. In black populations, Du, an allele for D, is more common than in other racial groups.10

In the United States, the white non-Hispanic population has a higher incidence of Rh negativity (17.4%) compared to the Hispanic and black non-Hispanic population (7.3% and 7.1%, respectively).11 Global variations exist as well. For example, Rh negativity is 10% to 12% in Finland and 30% to 35% in the Basque population (the highest in the world), but accounts for less than 1% in Asian populations.12,13,14


Immunology

The Rh antigen system is highly immunogenic. Ten different antigenic epitopes have been identified to date. One theory suggests the different epitopes are variably expressed within the erythrocyte membrane, and that this immunologic variation accounts for the spectrum of fetal hemolytic disease.


Rh Functionality

Rh antigens are transmembrane proteins thought to maintain appropriate erythrocyte shape and are expressed on the fetal erythrocytes by day 38 of gestation. Expression of these antigens may have a role in maintaining erythrocyte integrity and contributing to electrolyte and volume flux across the erythrocyte membrane. For example, the red blood cells of individuals with Rhnull (lacking all Rh antigens) manifest multiple membrane defects and osmotic fragility and have abnormal shapes.


PATHOGENESIS OF MATERNAL ALLOIMMUNIZATION

Blood transfusion was a common cause of Rh alloimmunization before the discovery of the Rh blood group system. Transfusion remains a relatively common cause of non-D blood group alloimmunization, with rates of alloimmunization ranging from 1% to 10% of transfusions in the general population, and approaches 60% in those with medical conditions requiring chronic transfusions.15,16 An additional proposed mechanism is the “grandmother hypothesis,” whereby an Rh negative woman is sensitived at birth, through exposure to enough Rh-positive cells from her mother at her own birth.17 In this way, an Rh-positive grandmother produces an antigenic simulation to the Rh-negative mother that rivals the pregnancy and birth of an Rh-positive fetus.

For Rh alloimmunization to occur:



  • The woman must be Rh negative and the fetus Rh positive.


  • Fetal erythrocytes must enter the maternal circulation in sufficient quantity.


  • The mother must be immune competent.


Transplacental Hemorrhage

A major cause of maternal alloimmunization is transplacental hemorrhage (TPH), which was shown to cause Rh immunization by Chown in 1954.18,19 Seventy-five percent of women have a fetal TPH at some time during pregnancy or at delivery.20 The hemorrhage volume is usually small, but exceeds 5 mL in 1% and 30 mL in 0.25% of pregnancies. The prevalence and volume of TPH rises with advancing gestation, from 3% (0.03 mL) in the first trimester, to 12% (usually < 0.1 mL) in the second trimester, to 45% (occasionally up to 25 mL) in the third trimester.20 Antenatal invasive procedures, such as chorionic villus sampling or amniocentesis, increase the risk of TPH, although hemorrhage volume remains small.21 Antepartum hemorrhage, cesarean section, manual removal of the placenta, and external cephalic version each increase both the rate and volume of TPH. Spontaneous abortion
has a low risk of TPH (typically < 0.1 mL). However, the risk may be as high as 25% after therapeutic abortion, with volumes exceeding 0.2 mL in 4% of pregnancies.22 Women who become Rh immunized after spontaneous abortion are considered “good responders,” and frequently have very severely affected fetuses in subsequent pregnancies.

In 1957, the Kleihauer acid elution test was developed, which provided a sensitive, but only semiquantitative, method of detecting TPH.23 Currently, more sensitive testing can be accomplished using flow cytometry, which measures directly the concentration of either the Rh antigen or hemoglobin F in maternal circulation. Flow cytometry can detect total blood volumes of <2.0 mL and is especially useful in mothers with hemoglobinopathies, such as sickle cell disease, where the maternal fetal hemoglobin level is higher than that of unaffected women.24 However, flow cytometry is not yet available in all hospitals, perhaps due to equipment and staffing requirements, and many centers only provide the Kleihauer-Betke test.


Maternal Response

At least two factors affect whether alloimmunization occurs. First, 30% of Rh-negative individuals behave as immunologic nonresponders and do not become sensitized, regardless of the Rh-antigen load. Second, ABO incompatibility has a protective effect. One explanation for this phenomenon is that the maternal anti-A or anti-B antibodies alter or mask the fetal Rh antigen so that it is no longer immunogenic.25 Another hypothesis holds that ABO-incompatible fetal cells are more rapidly cleared from the maternal circulation, so that maternal sensitization does not occur.26 Regardless of the mechanism, ABO incompatibility decreases the risk of alloimmunization to 1.5% to 2% after the delivery of an Rh-positive neonate. However, ABO incompatibility provides no protection once Rh immunization has developed.27


Rh Immune Response

The primary Rh immune response develops slowly, typically over 6 to 12 weeks but sometimes up to 6 months. It is usually weak and predominantly consists of IgM, which does not cross the placenta (molecular weight 900,000 kDa). Most immunized women quickly convert IgM to IgG anti-D antibody (molecular weight 160,000 kDa) production, which can readily cross the placenta. The IgG anti-D antibodies coats Rh-positive fetal erythrocytes and trigger extravascular hemolysis.

Secondary TPH, which may be very small, produces a rapid immune response (developing within days), which usually consists of IgG antibodies. Additional episodes of TPH typically increase the antibody titer. Long periods between Rh-positive erythrocyte exposure are associated with marked increases in Rh antibody titer, along with increased binding avidity for the D antigen.28 The greater the avidity, the more severe the disease.


Antibody Detection and Measurement Methods

Other methods used to measure and detect antibodies include:



  • Saline—Rh-positive erythrocytes suspended in isotonic saline are agglutinated only by IgM anti-D antibodies. IgG anti-D antibodies cannot bridge the gap between erythrocytes suspended in saline. This method is no longer used in most countries.


  • Colloid—Rh-positive red cells suspended in albumin are agglutinated by IgG anti-D antibodies.29 Because IgM anti-D antibodies also agglutinate colloid-suspended Rh-positive erythrocytes, the albumin titer may not be an accurate measurement of IgG anti-D antibodies. Mixing the serum with dithiothreitol disrupts IgM sulfhydryl bonds, destroying IgM but leaving IgG intact. Subsequent titration allows a true measurement of the IgG anti-D antibody level. This method is rarely used.


  • Indirect antiglobulin test (IAT)30—Antihuman globulin (AHG) antibody (Coombs serum) is produced by the injection of human serum (or specific human IgG) into an animal. IgG anti-D antibodies, if present, adhere to Rh-positive erythrocytes after incubation with the serum being screened for Rh antibodies. The erythrocytes are then washed with isotonic saline and suspended in the AHG antibody serum. The erythrocytes agglutinate if coated with antibody (a positive IAT or indirect Coombs test). The reciprocal of the highest dilution causing agglutination is the indirect antiglobulin titer. IAT screening is more sensitive than albumin screening. IAT titers are usually one to three dilutions higher than albumin titers. A critical titer is defined as the titer associated with a significant risk of fetal hydrops. This varies with the institution and methodology. Most centers have a critical titer between 8 and 32.



  • Enzyme—The incubation of erythrocytes with various enzymes (ie, papain, trypsin, or bromelin) reduces the negative electrical potential of the cells. As a result, the erythrocytes lie closer together in saline and are agglutinated by IgG anti-D antibodies.


  • Autoanalyzer (AA)—AA methods (bromelin31 and low ionic32) are the most sensitive for the detection of Rh antibodies. In this technique, erythrocytes are mixed with agents to enhance agglutination by the anti-D antibodies. Agglutinated cells are separated from nonagglutinated cells and lysed. The amount of released hemoglobin is then compared to an international standard. A modification of the bromelin method is used to measure accurately (µg/mL) the amount of serum anti-D antibodies.33


Prevalence of Rh Immunization

Small amounts of Rh-positive blood (as little as 0.3 mL) can generate Rh immunization in Rh-negative individuals.30 The risk of Rh immunization is dose-dependent: 15% after 1 mL, 33% after 10 mL, and 65% after 50 to 250 mL of Rh-positive erythrocytes.34 A secondary immune response may follow a small, repeat challenge (0.05 mL of Rh-positive erythrocytes). The incidence of Rh immunization 6 months after delivery is 3% in Rh-negative women who, based on serial Kleihauer tests, never had evidence of TPH above 0.1 mL. If the volume is greater than 0.1 mL, the incidence is 14%,29 and it is 22% if the volume is greater than 0.4 mL.35

The incidence of Rh immunization 6 months after delivery of the first Rh-positive ABO-compatible neonate is 8% to 9%.36 An equal number of women are immunized during their first pregnancy, but have no detectable Rh antibodies until challenged again, typically during their next pregnancy (“sensibilization”).37 Therefore, the overall risk of Rh immunization following the first Rh-positive ABO-compatible pregnancy is 16%. An unimmunized Rh-negative woman faces approximately the same risk during a second such pregnancy. As parity increases and the ratio of good responders to poor immune responders decreases, the risk becomes less, such that there is a 50% likelihood that she will be Rh immunized after five Rh-positive ABO-compatible pregnancies. Because the total incidence of Rh immunization is approximately 13% (16% in the 80% carrying ABO-compatible babies, 1.5% to 2% in the 20% carrying ABO-incompatible babies), 13% to 14% of all instances of Rh immunization (1.8 × [100/13]) occur during pregnancy or shortly after delivery.38


PATHOGENESIS OF FETAL HEMOLYTIC DISEASE

Fetal blood is produced in the yolk sac beginning the third week of gestation. The Rh antigen is expressed on the red cell membrane by the sixth week. Erythropoiesis begins in the yolk sac but moves to the liver and, finally, to the bone marrow by 16 weeks’ gestation.

Maternal IgG anti-D antibodies cross the placenta and coat D-positive fetal red cells. The fetal red cells are destroyed extravascularly, primarily in the spleen, as anti-D does not fix complement. The resulting anemia stimulates fetal erythropoietin synthesis and release. A reticulocytosis occurs when the fetal hemoglobin deficit exceeds 2 g/dL compared with gestational age-appropriate norms. Should marrow red cell production fail to compensate, extramedullary erythropoiesis occurs, initially in the liver and spleen. Hepatomegaly may become extreme. Cardiac output increases and 2,3-diphosphoglycerate levels are enhanced. Although blood PO2 is unaltered, tissue hypoxia results from the decreased carrying capacity. Umbilical arterial lactate begins to rise when the fetal hemoglobin falls below 8 g/dL, while the umbilical venous lactate begins to rise when the fetal hemoglobin falls below 4 g/dL.35 Erythroblastosis fetalis occurs when nucleated red cell precursors convert from normoblasts to primitive erythroblasts and then are released into the circulation.


Degrees of Rh Hemolytic Disease

The severity of hemolytic disease reflects the amount of maternal IgG anti-D antibodies (the titer) produced, the antibodies’ particular affinity or avidity for the fetal red cell membrane D antigen, and the ability of the fetus to tolerate hypoxemia before developing hydrops secondary to myocardial pump failure. When the globin chain is split from hemoglobin during hemolysis, the remaining heme pigment is converted to biliverdin by hemeoxygenase, and then to the neurotoxic indirect bilirubin by biliverdin reductase. The fetal and newborn liver is deficient in glucuronyl transferase and Y transport protein. As a result, the increased indirect bilirubin is deposited in the perinate’s extravascular fluid compartments.


Indirect bilirubin is water insoluble and can remain in the plasma only when bound to albumin. When the albumin-binding capacity of the perinate’s plasma is exceeded, “free” indirect bilirubin appears and diffuses into fatty tissues. The neuron membrane has a high lipid content, and the free indirect bilirubin penetrates the neuron where it interferes with cellular metabolism. Mitochondria swell, then balloon, and the neuron dies. The dead neurons with accumulated bilirubin appear yellow at autopsy (kernicterus).


Mild Disease

Approximately 50% of affected fetuses do not require treatment postnatally. Their umbilical cord blood hemoglobin is above 12 g/dL, and their umbilical cord serum bilirubin is less than 68 µmol/L (<4 mg/100 mL). In the nursery, their hemoglobin does not drop below 11 g/dL, and their serum indirect bilirubin remains below 340 µmol/L (20 mg/dL) or 260 to 300 µmol/L (15-17.5 mg/dL) if preterm. Postdischarge hemoglobin remains above 7.5 g/dL.


Intermediate Disease

Approximately 25% to 30% of affected fetuses have intermediate disease. They are born at or near term in good condition, with an umbilical cord blood hemoglobin between 9 and 12 g/dL. Extramedullary erythropoiesis is modest and liver function normal.

Some of these infants develop severe hyperbilirubinemia; those with kernicterus are deeply jaundiced. Thankfully, the current incidence of this potentially devastating condition is 1 in 650 to 1000 infants born above 35 weeks’ gestation.39 They become lethargic by day 3 to 5 and then hypertonic. They assume an opisthotonic position with their necks hyperextended; backs arched; and knees, wrists, and elbows flexed. Their vegetative reflexes disappear, and apneic spells develop. The mortality rate approaches 90%. In the remaining 10%, the jaundice fades and spasticity lessens. However, they show severe central nervous system dysfunction over time with profound neurosensory deafness and choreoathetoid spastic cerebral palsy. Developmental delay may be relatively mild, but learning and functioning are hindered by deafness and spastic choreoathetosis.


Severe Disease

The remaining 25% are the most severely affected fetuses, who, despite maximal red blood cell production, become progressively more anemic. Ascites with anasarca (generalized edema) occurs. Half these fetuses become hydropic between 18 and 34 weeks’ gestation; the other half between 34 weeks and term.

The mechanism underlying hydrops has become clearer over time. There is always a large hemoglobin deficit.40 Because hemoglobin concentration rises with advancing gestational age, hydrops occurs at higher absolute hemoglobin levels in late compared to early gestation and is rare before 20 weeks’ gestation. Cardiac dysfunction secondary to severe fetal anemia and the resultant inadequate oxygen-carrying capacity is evident in at least 90% of hydropic fetuses. Fetal cardiac dysfunction is characterized by an increase in the biventricular cardiac diameter, systolic atrial-ventricular valve regurgitation, abnormal peak velocity index for veins in the ductus venosus, and an elevated umbilical pressure for gestational age.41 Cardiac dysfunction is detectable prior to the development of hydrops and within 48 hours of transfusion (well before the hydrops resolves), the umbilical venous pressure decreases into the normal range for gestation.42,43 Although hepatomegaly was once thought to cause portal hypertension and decrease cardiac return, it is clear this is not the typical mechanism. Additionally, whereas hypoalbuminemia (secondary to fetal liver failure) was once thought to be a contributing factor, fetal studies have revealed that the albumin concentration is normal in all but premoribund, hydropic fetuses.41,44


Monitoring the Mother and Fetus at Risk

A blood sample is obtained from every woman during her first prenatal visit for blood type and antibody screening. Ideally, all women should have two blood type determinations on record that are in agreement. Mistyping of an Rh-negative woman may have occurred in a prior pregnancy, and an Rh-positive woman, particularly if she has received a transfusion, may have developed a dangerous atypical blood group antibody.

The American College of Obstetricians and Gynecologists recommends routine repeat testing of all women at 28 weeks to detect RhD sensitization due to early fetomaternal hemorrhage.45 Some studies have questioned the utility of additional screening in RhD-positive mothers.46 However, up to 27% of severe fetal hemolytic disease occurs
unexpectedly in RhD-positive mothers with negative first trimester screens.47

The fetal risk is determined once the mother is found to have a clinically significant alloantibody. The first step is to determine the paternal antigen status when an Rh-negative woman is sensitized. If the father is Rh negative, the fetus will also be Rh negative. Rh status should, however, be confirmed at birth. Zygosity must then be determined if the father is Rh positive. If he is homozygous for the antigen, the fetus is at risk for hemolytic disease. However, if the father is heterozygous for the antigen, the risk of fetal hemolytic disease is only 50%. In these cases, or in cases of unknown paternity, additional evaluation is warranted.

Historically, amniocentesis was the preferred method of evaluating fetal antigen status. Furthermore, fetal cells obtained by chorionic villus sampling may also be used. Currently, other methods to determine Rh status include cloning complementary DNA to detect the fetal Rh D genotype and using probes for other known Rh antigens. Although uncommon, point mutations can result in the occasional incorrect diagnosis. Amniocentesis for genetic purposes or for the determination of pulmonary maturity carries a 2% risk of immunization if performed under constant ultrasound guidance.21

Advances in plasma cell-free fetal DNA (cff-DNA) processing have allowed for the accurate determination of fetal antigen status from maternal blood across all three trimesters.48,49,50 Specific primers are used to alleviate the risk of false positives from inactive pseudogenes. False-negative results may occur due to low levels of cff-DNA (usually not an issue after 20 weeks’ gestation) or fetal inheritance of weak D phenotypes. Laboratories have now incorporated internal controls to detect these rare situations. Utilization of cff-DNA has been shown to be >99.3% sensitive at 10 to 11 weeks gestation and remains that high at 24 to 26 weeks.51 In several European countries, Rh-negative mothers with a negative antibody screen are routinely offered cff-DNA testing in the second trimester, which is must more cost-effective than routine—unnecessary for Rh negative fetus—antenatal RhIG prophylaxis.52

At delivery, umbilical cord and maternal blood are tested: umbilical cord blood for ABO, Rh type, and direct Coombs status; and maternal blood for the presence of Rh antibody and fetal red cells. Although most instances of Rh immunization occur after small or undetectable fetal TPH, approximately 1 in 400 women have a fetal TPH of more than 30 mL of whole blood and will not be protected by a single prophylactic dose. Cesarean section and manual removal of the placenta increase the frequency and size of fetal-maternal TPH, increasing the risk of immunization if the fetus is Rh positive.


PREDICTING THE SEVERITY OF RH HEMOLYTIC DISEASE


Medical History

The severity of hemolytic disease may remain similar from pregnancy to pregnancy (mild, moderate, or severe), but is more likely to progress in severity with each Rh-positive pregnancy. The risk of hydrops is 8% to 10% in a first sensitized pregnancy. If a woman has had a hydropic fetus, there is a 90% chance that the next affected fetus will also develop hydrops without intervention, typically at the same or an earlier time in gestation.


Rh Antibody Titers

If Rh antibody titers are measured in the same laboratory by the same experienced personnel using the same methods, the results are reproducible and of some value in predicting the risk of severe hemolytic disease. Because the binding constant of the Rh antibody varies from fetus to fetus, as may the density of Rh antigen on the red blood cell membrane and the ability of the fetus to compensate for RBC hemolysis, the titer indicates only which fetus is at risk. The maternal antibody titer that puts the fetus at risk must be determined by each laboratory. However, in general, an albumin titer of 16 or an indirect antiglobulin titer of 32 to 64 carries a 10% risk that the fetus will become hydropic without intervention. The exact titer threshold that is deemed critical will vary by lab. Titers of at-risk women should be repeated monthly after the first prenatal visit.


Fetal Blood Sampling

Maternal history and antibody titer alone are inadequate for the proper management of the Rh-immunized pregnancy, and fetal blood sampling by cordocentesis may be necessary. Fetal blood sampling is by far the most accurate means of determining the degree of severity of hemolytic disease. Cordocentesis is available in many tertiary perinatal centers. This procedure, which usually precedes
fetal intravascular transfusion (IVT), allows for the measurement of all blood parameters typically measured after birth (ie, hemoglobin, hematocrit, serum bilirubin, direct and indirect platelet count, leukocyte count, serum proteins, and blood gases). Fetal blood sampling has an associated mortality rate of less than 1%43 (0.2% in the authors’ hands for Rh disease using a needle guide). Other complications, such as prolonged bradycardia, umbilical cord hematoma, amnionitis with maternal adult respiratory distress syndrome, and placental abruption, occur in approximately 5% of patients sampled using a freehand technique.53,54 Cordocentesis can be performed as early as 16 to 18 weeks; it is usually feasible by 20 to 21 weeks.


Ultrasound

Ultrasound has a central role in the management of the alloimmunized pregnancy because it establishes gestational age, can predict moderate and severe anemia, and can detect hydrops fetalis.55,56,57,58,59,60


Doppler Ultrasonography

A number of investigators found that decreasing fetal hemoglobin levels, which would be associated with a lower blood viscosity and increased cardiac output, also produce higher blood velocities.61,62,63 Vessels studied include the descending aorta, the umbilical vein, the splenic artery, the common carotid artery, and the middle cerebral artery (MCA). The most commonly interrogated vessel is the MCA.






In 2000, Mari et al first demonstrated the utility of the peak systolic velocity (PSV) of the fetal MCA as a noninvasive marker of fetal anemia.64 This method has largely replaced serial amniocentesis. The Society for Maternal-Fetal Medicine recommends that MCA-PSV be used as the primary technique to detect fetal anemia, with MCA-PSV greater than 1.5 MoM (multiples of median) as the threshold for cordocentesis to confirm that a fetal IVT is needed.65 More than 70% of invasive tests can be avoided using this threshold.

A 2009 meta-analysis demonstrated that the MCA-PSV > 1.5 MoM has a 75.5% sensitivity and 90.8% specificity for the detection of severe anemia.66 MCA-PSV is also useful in timing of intrauterine transfusion (IUT), which is discussed later in this chapter. Figures 22.1 and 22.2 are interrogations of the MCA doppler in the same fetus, 3 weeks apart. Cordocentesis was performed when the MCA-PSV was found to be 1.6 MoM (Figure 22.2).

Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Maternal Alloimmunization and Fetal Hemolytic Disease
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