This chapter deals primarily with APGO Educational Topic Areas:
TOPIC 17 MEDICAL AND SURGICAL COMPLICATIONS OF PREGNANCY
TOPIC 19 ALLOIMMUNIZATION
Students should be able to identify how pregnancy affects the natural history of various hematologic and immunologic disorders and how a preexisting hematologic and immunologic disorder affects maternal and fetal health. They should be able to outline a basic approach to evaluation and management of hematologic and immunologic disorders in pregnancy. Additionally, the student should understand the pathophysiology behind isoimmunization. They should be able to outline a basic approach to evaluation and prevention.
Clinical Case
A 24-year-old G3P1A1 patient is seen for her initial obstetric visit at about 12 weeks of gestation. She reports a history of a first-trimester loss with her first pregnancy. In her second pregnancy, she had “something in my blood that could make my baby anemic.” She ruptured membranes and delivered at 36 weeks; her infant was anemic and was hospitalized for 6 days. What do you think is going on here? How would you approach the management of the current pregnancy?
HEMATOLOGIC DISEASE
Anemia
The plasma and cellular composition of blood changes significantly during pregnancy, with the expansion of plasma volume proportionally greater than that of the red blood cell (RBC) mass. On average, there is a 1,000 mL increase in plasma volume and a 300 mL increase in RBC volume (a 3:1 ratio). Because the hematocrit (Hct) reflects the proportion of blood made up primarily of RBCs, it demonstrates a “physiologic” decrease during pregnancy; therefore, this decrease is often not actually an anemia but a dilutional effect. Anemia in pregnancy is generally defined as an Hct less than 30% or a hemoglobin (Hb) of less than 10 g/dL.
The direct fetal consequences of anemia are minimal, although infants born to mothers with iron deficiency may have diminished iron stores as neonates. The maternal consequences of anemia are those associated with any adult anemia. If anemia is corrected, the woman with an adequate RBC mass enters labor and delivery better able to respond to acute peripartum blood loss and to avoid the risks of blood or blood product transfusion.
Iron-Deficiency Anemia
Iron-deficiency anemia is by far the most frequent type of anemia seen in pregnancy, accounting for more than 90% of cases. Because the iron content of the standard American diet and the endogenous iron stores of many American women are not sufficient to provide for the increased iron requirements of pregnancy, the National Academy of Sciences recommends 27 mg of iron supplementation (present in most prenatal vitamins) daily for pregnant women. Most prescription prenatal vitamin/mineral preparations contain 60 to 65 mg of elemental iron. It is not clear whether routine iron supplementation for pregnant women consuming a healthy diet actually improves perinatal outcome.
All pregnant women should be screened for iron-deficiency anemia. Severe iron-deficiency anemia is characterized by small, pale erythrocytes (Fig. 23.1) and RBC indices that indicate a low mean corpuscular volume and low mean corpuscular Hb concentration. Additional laboratory studies usually demonstrate decreased serum iron levels, an increased total iron-binding capacity, and a decrease in serum ferritin levels, but these studies are generally reserved for patients unresponsive to treatment of iron-deficiency anemia. This approach is warranted because the vast majority of anemia in pregnancy is of the iron-deficiency type. In evaluating the patient with anemia, a recent dietary history is obviously important, especially if pica (consumption of nonnutrient substances such as starch, ice, or dirt) exists. Such dietary compulsions may contribute to iron deficiency by decreasing the amount of nutritious food and iron consumed.
FIGURE 23.1. Peripheral blood smear of iron-deficiency anemia with microcytic, hypochromic erythrocytes. (From Rubin R, Strayer DS. Rubin’s Pathology: Clinicopathologic Foundations of Medicine. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2007:20–22.)
Treatment
Treatment of iron-deficiency anemia generally requires an additional 60 to 180 mg of elemental iron per day, along with folate to maximize RBC production, in addition to the iron in the prenatal vitamin/mineral preparation. Iron absorption is facilitated by or with vitamin C supplementation or ingestion between meals or at bedtime on an empty stomach. The response to therapy is first seen as an increase in the reticulocyte count approximately 1 week after starting iron therapy. Because of the plasma expansion associated with pregnancy, the Hct may not increase significantly but, rather, stabilizes or increases only slightly.
Folate Deficiency
Adequate intake of folic acid (folate) has been found to reduce the risk of neural tube defects (NTDs) in the fetus. The first occurrence of NTDs may be reduced by as much as 36% if women of reproductive age consume 0.4 mg of folate daily both before conception and during the first trimester of pregnancy. The Recommended Dietary Allowance for folate for pregnant women is 0.6 mg. Folate deficiency is especially likely in multiple gestations or when patients are taking anticonvulsive medications. Women with a history of a prior NTD-affected pregnancy or who are being treated with anticonvulsive drugs may reduce the risk of NTDs by more than 80% with daily intake of 4 mg of folate in the months in which conception is attempted and for the first trimester of pregnancy.
Folate is found in green, leafy vegetables and is now an added supplement in cereal, bread, and grain products in the United States. These supplements are designed to enable women to easily consume 0.4 to 1 mg of folate daily. Prescription prenatal vitamin/mineral preparations contain 1 mg of folic acid. Over-the-counter vitamin preparations generally contain less than 1 mg of folate.
Other Anemias
The hemoglobinopathies are a heterogeneous group of single-gene disorders that includes the structural Hb variants and the thalassemias. Hereditary hemolytic anemias are also rare causes of anemia in pregnancy. Some examples are hereditary spherocytosis, an autosomal dominant defect of the erythrocyte membrane; glucose 6-phosphate dehydrogenase deficiency; and pyruvate kinase deficiency.
The Hemoglobinopathies
More than 270 million people worldwide are heterozygous carriers of hereditary disorders of Hb, and at least 300,000 affected homozygotes or compound homozygotes are born each year. The hemoglobinopathies include the thalassemias (α-thalassemia and β-thalassemia) and the sickle cell spectrum: sickle cell trait (Hb AS), sickle cell disease (Hb SS), and sickle cell disorders (Hb SC and sickle cell β-thalassemia) (Table 23.1).
Hb consists of four interlocking polypeptide chains, each of which has an attached heme molecule. The polypeptide chains are called (α) alpha, (β) beta, (γ) gamma, (δ) delta, (ε) epsilon, and (ζ) zeta. Adult Hb consists of two alpha chains and either two beta chains (HbA), two gamma chains (HbF), or two delta chains (HbA2). The beta chains are the oxygen-carrying subunits of the Hb molecule. HbF is the primary Hb of the fetus from 12 to 24 weeks of gestation. In the third trimester, production of HbF decreases as production of beta chains and HbA begins.
Thalassemias α-Thalassemia is generally caused by missing copies of the α-globin gene; however, occasionally point mutations can cause functional abnormalities in the protein. Humans normally have four copies of the α-globin gene. Those with three copies are asymptomatic, those with two copies have mild anemia, and those with one copy have hemolytic anemia. Individuals in whom the gene is absent have Hb Barts disease, which results in hydrops fetalis and intrauterine death.
Phenotypic expressions of β-thalassemia vary because of the many possible mutations in the β-globin gene. Some mutations cause an absence of the protein, whereas others result in a defective globin protein. β-Thalassemia majoroccurs in homozygotes and is a severe disease, whereas a diagnosis of β-thalassemia minor (heterozygotes) may include asymptomatic to clinically anemic patients.
Sickle Cell Disorders The sickle cell disorders are autosomal recessive disorders caused by point mutations that lead to functional abnormalities in the β-globin chains. Instead of normal HbA, individuals with this disorder have abnormal HbS. HbS is unstable, especially under conditions of low oxygen tension. The unstable HbS causes a structural change resulting in deformity of the normal spheroid shape of the RBC into the shape of a “sickle.” These abnormally shaped cells lead to increased viscosity and hemolysis and a further decrease in oxygenation. Sickling that occurs in small blood vessels can cause a vaso-occlusive crisis, in which the blood supply to vital organs is compromised.
Heterozygotic individuals (Hb AS) have sickle cell trait and are asymptomatic. The most severe form of the disease, which occurs in homozygotic individuals (Hb SS), is called sickle cell anemia. Sickle cell disorders are found not only in patients who have Hb SS but also in those who have HbS and one other abnormality of β-globin structure. The most common are Hb SC disease and HbS/β-thalassemia.
Women of Mediterranean, Southeast Asian, and African descent are at higher risk for being carriers of hemoglobinopathies and should be offered carrier screening. If both parents are deemed to be carriers of any hemoglobinopathy, genetic counseling is recommended. For individuals of non-African descent, initial testing may be done by complete blood count (CBC). However, ethnicity is not always a good predictor of risk as individuals from at-risk groups may marry outside of their ethnic group. Because individuals of African descent, as well as those of other backgrounds (see Table 23.1) are at high risk for carrying a gene for sickle cell disease, these women should be offered Hb electrophoresis in addition to a CBC. Solubility testing, such as tests for the presence of HbS (Sickledex), isoelectronic focusing, and high-performance liquid chromatography are inadequate for screening and fail to identify important transmissible Hb gene abnormalities affecting fetal outcome.
Although the course of pregnancy can vary according to the type of hemoglobinopathy, there is also individual variation among patients with the same type of disorder. Besides the genetic implications, patients with the sickle cell trait (Hb AS) have an increased risk of urinary infections but experience no other pregnancy complications. Pregnancies in patients with HbS/β-thalassemia are generally unaffected. Patients who are Hb SS or Hb SC, in contrast, may suffer vaso-occlusive episodes. Infections are also more common due to functional asplenia caused by repetitive end-organ damage to the spleen. Infection should be ruled out before attributing any pain to a vaso-occlusive crisis.
Prophylactic maternal RBC transfusions for women with hemoglobinopathies were used in the past. Now, however, transfusions are, for the most part, reserved for complications of hemoglobinopathies, such as congestive heart failure, sickle cell disease crises unresponsive to hydration and analgesics, and severely low levels of Hb. Because fetal outcomes such as preterm labor, intrauterine growth restriction, and low birth weight are more common in women with hemoglobinopathies (except those with sickle cell trait), antenatal assessment of fetal well-being and growth is an important part of managing patients with hemoglobinopathies.
ISOIMMUNIZATION
When any fetal blood group factor inherited from the father is not possessed by the mother, antepartum or intrapartum fetal–maternal bleeding may stimulate an immune reaction in the mother. Maternal immune reactions also can occur from blood product transfusion. The formation of maternal antibodies is called isoimmunization. It can lead to various degrees of transplacental passage of these antibodies into the fetal circulation, causing an antibody response sufficient to destroy fetal RBCs. Although early exposures to maternal antigens during pregnancy may occur in the same pregnancy, isoimmunization more commonly occurs in a subsequent pregnancy. The binding of maternal antibodies to fetal RBC antigens leads to hemolytic disease in the fetus or newborn, characterized by hemolysis, bilirubin release, and anemia. The severity of the illness encountered by the fetus or newborn is determined by a number of factors, including the degree of immune response elicited (i.e., how much antibody is produced), how strongly the antibody binds the antigen, the gestational age at which the diagnosis is made, and the ability of the fetus to replenish the destroyed red cells to maintain an Hct sufficient for growth and development (Table 23.2).
Natural History
Any of the many blood group antigen systems can lead to isoimmunization, but the number of antigens involved in fetal and neonatal hemolytic disease is limited. The most common antigen involved is part of the Rh (CDE) system, specifically the D antigen.
The Rh system is a complex of five antigens—including the C, c, D, E, and e antigens—each of which elicits a unique immune response. These antigens are inherited together in distinctive patterns, reflecting the underlying genotypic makeup of the parents. C and c are alternate forms of the same antigen, as are E and e, but there is no D antigen. The D antigen is either present or absent. Patients with the D antigen are termed Rh D-positive, and those lacking this gene, and hence the antigen, are said to be Rh D-negative. Approximately 15% of whites, 5% to 8% of African Americans, and only 1% to 2% of Asians and Native Americans are Rh D-negative.
A variant of the D antigen called the weak D antigen (formerly Du) also exists. If not appropriately diagnosed, patients can be mistakenly classified as Rh D-negative. For this reason, patients should not be considered Rh D-negative unless efforts have been made to look for the weak D antigen. Patients who are Rh weak D-positive should be managed the same as those who are Rh D-positive.
Isoimmunization can occur when an Rh D-negative woman is pregnant with a fetus who has inherited the Rh D antigen from its father and is, thus, Rh D-positive. Any event associated with fetal–maternal bleeding can potentially lead to maternal exposure to RBCs, which can trigger a maternal immune response. These events include:
• Childbirth
• Delivery of the placenta
• Threatened, spontaneous, elective, or therapeutic abortion
• Ectopic pregnancy
• Bleeding associated with placenta previa or abruption
• Amniocentesis
• Abdominal trauma
• External cephalic version
The amount of Rh D-positive blood required to cause isoimmunization is small—<0.1 mL is sufficient.
Effects of Antibody Development on the Fetus and Newborn
One study indicates that 17% of Rh D-negative women who do not receive anti-D immune globulin prophylaxis during pregnancy will become isoimmunized. As with other antibody-mediated immune responses, the first immunoglobulin (Ig) type produced is of the IgM isoform, which does not cross the placenta to any extent. The chance of significant fetal or newborn disease in a woman’s first at-risk pregnancy is, therefore, low. It is, however, important to consider prior pregnancy losses or terminations as potential exposures, because they could influence the risk of fetal or newborn disease. In a subsequent pregnancy, passage of minute amounts of fetal blood across the placenta into the maternal circulation, a relatively common occurrence, can lead to an anamnestic response of maternal antibody production, which is more robust and rapid than the initial response.
In the case of some antigens, the mother continues to produce predominantly IgM antibodies that fail to cross the placenta. In other cases, the secondary antibody response is characterized by the production of IgG antibodies that freely cross the placenta, enter the fetal circulation, and bind to antigenic sites on fetal red cells. RBCs that are highly bound with antibody are hemolyzed in the fetal reticuloendothelial system and are destroyed via complement-mediated pathways. Hemolysis releases bilirubin, and the fetus excretes the bilirubin and its breakdown products in urine. If the fetus is able to augment erythropoiesis to keep pace with the rate of hemolysis, serious anemia may not develop. However, if large amounts of antibody cross the placenta, resulting in destruction of large numbers of fetal RBCs, the fetus may be unable to sufficiently replenish the RBCs, and anemia may ensue.
Fetal Consequences
Typically, the first-affected pregnancy is characterized by mild anemia and elevated bilirubin at birth, often necessitating treatment for the newborn, such as ultraviolet light and exchange transfusion, because the newborn’s liver may be unable to effectively metabolize and excrete the released bilirubin. Markedly elevated bilirubin levels can lead to kernicterus (bilirubin deposition in the basal ganglia), which can cause permanent neurologic symptoms or even death. This condition is rarely seen today in developed countries.
In some first-affected pregnancies, and in many, but not all, subsequent pregnancies with an antigen-positive fetus, antibody production increases as a result of the anamnestic response, leading to more significant hemolysis and anemia. Assessment of the amount of bilirubin excreted by the fetus into the amniotic fluid is one method used to monitor fetal status (see below). When fetal anemia is significant, fetal hematopoiesis increases, including the recruitment of alternative sites for RBC production. The fetal liver is an important site of extramedullary hematopoiesis. When the liver produces RBCs, the production of other proteins decreases, resulting in a lower oncotic pressure within the fetal vasculature. This consequence, in conjunction with the increase in intravascular resistance to flow caused by islands of hematopoietic cells in the liver, can lead to the development of ascites, subcutaneous edema, or pleural effusion.
Severe anemia affects fetal cardiac function in two ways. First, anemia can lead to a high-output cardiac failure. As the cardiac system attempts unsuccessfully to keep pace with the oxygen delivery demands, the myocardium becomes dysfunctional, resulting in effusions, edema, and ascites due to hydrostatic pressure increases. Second, the anemia itself can cause myocardial ischemia, thereby directly damaging and compromising myocardial function. This combination of fluid accumulation in at least two extravascular compartments (pericardial effusion, pleural effusion, ascites, or subcutaneous edema) is referred to as hydrops fetalis.
Isoimmunization usually progressively worsens in each subsequent pregnancy. Fetal anemia may occur at the same gestational age or earlier than in the prior affected pregnancies.
Significance of Paternal Antigen Status
Determination of the father’s antigen status is important in assessing whether the fetus is at risk for developing anemia. Any individual can be either homozygous or heterozygous for a particular gene. If the father is heterozygous for the gene for the particular antigen of interest, there is a 50% chance that the fetus will not inherit the gene for that antigen. For many of the antigens, this information can be determined easily by looking at which antigens are expressed on the father’s RBCs. For example, C and c are coded by the same gene but differ by a single base change. An individual can express C, c, or both. If he expresses both, he is heterozygous; if only one antigen is detected, then he must be homozygous. Unfortunately, the situation is not as straightforward with Rh D (because there is no d antigen). However, for antigens other than Rh D, direct genotype testing can be performed to determine if the father is homozygous or heterozygous. In a pregnancy involving an isoimmunized patient, the first step in management is determination of the paternal erythrocyte antigen status. In pregnancies in which there is a heterozygous or unknown paternal genotype, the fetal antigen type should be assessed by genetic analysis of fetal cells obtained by amniocentesis. Regardless of the amount of maternal antibody present, if the subsequent fetus does not carry the antigen (because the father was a heterozygote or there is different paternity), then the fetus has a 98.5% probability of not being at risk.
Diagnosis
All pregnant women should be tested at the time of the first prenatal visit for ABO blood group and Rh D type and screened for the presence of erythrocyte antibodies. These laboratory assessments should be repeated in each subsequent pregnancy. Antibody screening is also recommended before administration of anti-D immunoglobulin at 28 weeks of gestation, postpartum, and the time of any event in pregnancy. Patients who are weak D-positive are not at risk for isoimmunization and should not receive anti-D immunoprophylaxis.
Any antibodies potentially associated with fetal hemolysis found during this routine screening are further evaluated based on the strength of the antibody response, which is reported in titer format (1:4, 1:8, 1:16, etc., or simply as 4, 8, 16, etc.), with higher numbers indicative of a more significant antibody response. Although often encountered during the process of antibody screening, anti-Lewis and anti-Iantibodies are not associated with fetal hemolytic disease and, therefore, are not evaluated further.
Assessment
Although the antibody titer reflects the strength and the amount of the maternal antibody response, its utility in pregnancy management is limited. Titers provide little information about fetal status. In an initial sensitized pregnancy, serial antibody values can assist in determining when the maternal antibody response is strong enough to represent a risk of fetal anemia. A critical titer is that titer associated with a significant risk of severe fetal hemolytic disease and hydrops fetalis. In most centers, this is between 1:8 and 1:32. If the initial antibody titer is 1:8 or less, the Rh D-negative patient can be monitored with titer assessment every 4 weeks. In a first-sensitized pregnancy, titers are generally performed every 4 weeks. With a history of an affected fetus or infant, titers are not helpful in predicting fetal hemolytic disease and further evaluation is warranted.
Amniotic Fluid Assessment
Evaluation for possible fetal anemia is usually undertaken in the second trimester, although management may be individualized depending on history and available expertise. Traditionally, amniotic fluid assessment of the level of bilirubin has been used as a measure of fetal status and an indirect means of estimating the potential for severe fetal anemia. In the second half of a normal pregnancy, the level of bilirubin in the amniotic fluid decreases progressively, whereas in an affected, isoimmunized patient, the amount of bilirubin detected can deviate significantly. The increase in the amniotic fluid bilirubin in affected pregnancies is thought to be a result of fetal urinary excretion of the increased amount of circulating bilirubin. Until recently, serial amniocenteses were performed to determine the level of bilirubin in the amniotic fluid, which in turn reflected the severity of fetal anemia.
Ultrasound Assessment
The current trend in management is the measurement of peak velocity of middle cerebral artery (MCA) flow using Doppler ultrasound. The velocity of flow through the MCA is related to the viscosity of the blood. In the setting of fetal anemia, the blood is less viscous due to fewer cells, and, therefore, the velocity of flow increases. Gestational age–specific peak velocity normal curves have been derived and correlated with the fetal Hct. The degree of peak velocity elevation above the median for that gestational age can be used to estimate the fetal Hct and, thus, the risk of fetal anemia. Using the peak systolic velocity of the MCA, almost all fetuses with moderate to severe anemia can be identified (Figs. 23.2 and 23.3).
FIGURE 23.2. Peak velocity of systolic blood flow in the middle cerebral artery. Red circles indicate fetuses with no anemia or mild anemia; triangles indicate fetuses with moderate or severe anemia; and blue circles indicate fetuses with hydrops. (From Mari G, Deter RL, Carpenter RL, et al. Noninvasive diagnosis by Doppler ultrasonography of fetal anemia due to maternal red-cell alloimmunization. Collaborative Group for Doppler Assessment of the Blood Velocity in Anemic Fetuses. N Engl J Med. 2000;342(1):9–14.)
Ultrasound assessment of the fetus is also helpful in detecting severe signs of hemolysis that have resulted in profound fetal anemia. Occasionally, the first presenting signs of fetal hemolysis may be hydropic changes in the fetus including subcutaneous edema, pericardial and pleural effusions, and ascites. When these findings are identified and hydrops fetalis is diagnosed, the fetal Hct is typically <15%.
FIGURE 23.3. Image of fetal cerebral circulation demonstrating the middle cerebral artery and method of measuring peak flow.
BOX 23.1 Evaluation of a Pregnancy with a Positive Maternal Antibody Screen
Maternal antibody identification and antibody strength (titer)
Careful obstetric history for prior affected fetus
Paternal antigen testing, possible fetal DNA testing
Assessment of risk of fetal anemia if a critical titer is found or if there has been a prior affected child
Amniotic fluid bilirubin assessment
Serial antibody titers, if first-sensitized pregnancy
Middle cerebral artery Doppler
Ultrasound
Cordocentesis/percutaneous umbilical blood sampling if monitoring test is abnormal
Regardless of the methods used to monitor pregnancies at risk for fetal anemia, all techniques are designed to determine the fetal Hct using indirect measures. If the monitoring test indicates a risk of fetal anemia, or if hydrops is diagnosed, cordocentesis or percutaneous umbilical blood sampling (PUBS) is performed to directly measure the fetal Hct. Under ultrasound guidance, a needle is advanced into the umbilical vein, a sample of fetal blood is removed, and the Hct is measured. In general, the average fetal Hct is 36% to 44%, and with severe anemia, it is less than 30% (Box 23.1). In addition to procedures to monitor the fetus for anemia, general tests for fetal well-being are indicated in all isoimmunized women with titers above the critical threshold, because the ability of an affected fetus, even if only mildly anemic, to withstand the stresses of pregnancy and labor may be compromised.
Management
Previously, blood was transfused into the fetal abdominal cavity, where absorption of RBCs could take place over several days through the lymphatic channels. Currently, transfusion of antigen-negative RBCs (depending on the blood group involved) to the fetus is indicated when PUBS determines that the fetus has moderate or severe anemia with an Hct less than 30%. Direct transfusion under ultrasound guidance into the umbilical vein has become the preferred technique. The procedure has a 1% to 3% risk of complications, including fetal death and preterm delivery, which must be weighed against the predicted course of the fetus if left untreated or delivered. The volume of RBCs to be transfused can be calculated based on the gestational age, estimated fetal weight, the Hct of the unit of blood, and the difference between the current fetal Hct and the desired Hct. Because the transfused cells are antigen negative, they are not subject to hemolysis by the maternal antibody and the predicted lifespan of the RBC is the only determinant of how long they persist in the fetal circulation. The timing and need for further transfusions can be based either on the predicted course given the severity of the disease or on MCA Doppler assessments. After two to three transfusions, most of the circulating RBCs in a fetus are transfused cells, because the hematopoietic system in the fetus has been suppressed.
Prevention
Maternal exposure and subsequent sensitization to fetal blood usually occurs at delivery, but it can occur at any time during pregnancy. In the late 1960s, it was discovered that an antibody to the D antigen of the Rh system could be prepared from donors previously sensitized to the antigen. Administration of the anti-D immunoglobulin soon after delivery prevents an active antibody response to the D antigen by the mother in most cases. Anti-D immunoglobulin is effective only for the D antigen of the Rh system. It is not effective in preventing sensitization to other Rh antigens or any other RBC antigens.
It is now standard for Rh D-negative women who deliver Rh D-positive infants to receive a dose of 300 μg of anti-D immunoglobulin within 72 hours of delivery. This practice reduces the risk of sensitization to the D antigen from around 16% to approximately 2%. The residual 2% risk is believed to result from sensitization occurring during the course of pregnancy, especially during the third trimester. For this reason, it is standard practice to administer a 300-μg dose of anti-D immunoglobulin to all Rh D-negative women at about 28 weeks of gestation, unless it is absolutely certain that the father is Rh D-negative.This prophylactic dose reduces the risk of sensitization from 2% to 0.2%. If there is any question regarding the need for prophylaxis, such as the certainty of paternity, anti-D immunoglobulin should be administered. Some authorities recommend that if delivery has not occurred within 12 weeks of the injection at 28 weeks of gestation, a second 300-µg dose of anti-D immunoglobulin should be given at 40 weeks in undelivered patients.
Because even a minute amount of fetal RBCs can result in sensitization to the Rh D antigen, in any circumstance when a fetal–maternal hemorrhage can occur, a prophylactic dose of 300 μg of anti-D immunoglobulin should be administered. Each dose of anti-D immunoglobulin provides protection against sensitization for up to 30 mL of fetal blood or 15 mL of fetal RBCs.
In cases of trauma or bleeding during pregnancy in which there is a potential for more than a 30-mL fetal–maternal transfusion, the extent of the fetal–maternal hemorrhage can be assessed using the Kleihauer-Betke test. This test identifies fetal erythrocytes in the maternal circulation. The number of fetal cells as a proportion of the total cells can be determined, and the volume of fetal–maternal hemorrhage can be estimated. Based on this estimation, the appropriate dose of Rh immunoglobulin can be determined. An indirect Coombs test can also be used to determine if the patient has received sufficient antibody. A positive test indicates that she has received an adequate dose.
Management of Isoimmunization to Other Red Cell Antigens
Although the routine use of Rh immunoglobulin has decreased isoimmunization due to the D antigen, isoimmunization due to other blood group antigens has proportionally increased. The frequency of these antibodies varies depending on the frequency of the antigen in the general population and in various ethnic groups. In addition, the likelihood that these antibodies will result in significant fetal hemolytic disease depends on several factors, including the size of the sensitizing antigenic stimulus, the relative potency of the antigen, and the isoform (IgG or IgM) of antibody response.
Kell Antigen
Sensitization to any of these antigens can occur in any exposed woman lacking the particular antigen, regardless of her ABO or Rh type. An antibody screen will detect the presence of these antibodies. The most important cause of hemolytic disease of the fetus not associated with the D antigen is isoimmunization to the Kell antigen (see Table 23.2). This sensitization commonly results from a prior blood transfusion. If a maternal antibody screen reveals the presence of an anti-Kell antibody, paternal blood typing for the Kell antigen should be performed. Because the direct phenotype of the erythrocyte for the Kell antigen and its complement—the Cellano antigen—can be performed, genotyping is not necessary. Ninety percent of individuals are Kell negative, so if paternity is certain, no further evaluation is required. Even among those who carry the Kell antigen, 98% are heterozygous, so consideration should be given to fetal genotype determination.
Anemia resulting from Kell isoimmunization is unique in that the predominant effect of the antibody is destruction and suppression of hematopoietic precursor cells; hemolysis is only a minimal component of the fetal problem. For this reason, amniotic fluid surveillance of bilirubin may not be as useful in monitoring these pregnancies, and MCA Doppler is the preferred surveillance method. Most providers use a critical titer measurement of 1:8 to initiate further evaluation in Kell-sensitized pregnancies.
ABO Hemolytic Disease
ABO hemolytic disease, due to maternal–fetal incompatibility for the major blood group antigens, can occur. It is usually associated with mild fetal and newborn hyperbilirubinemia. Typically, it is not associated with severe fetal disease, because there are fewer A and B antigenic sites on fetal RBCs than on adult blood cells. In addition, much of the anti-A and anti-B antibody produced is of the IgM isoform that does not cross the placenta to any extent.
Clinical Follow-Up
In the case presented at the beginning of this chapter, the most likely diagnosis is isoimmunization. The initial sensitization could have occurred with her first-trimester loss. No mention of the patient having received prophylactic immunoglobulin is given. Inquiry into the father of each pregnancy is important in management, insofar as they each could possess different antigens. At this point in her current pregnancy, immediate management would consist of ultrasound to accurately assess her gestational age and blood type and screen for potentially dangerous antibodies. Paternal antigen testing is also important. Subsequent management would depend on laboratory information. Close follow-up would likely be needed, to include periodic ultrasound examinations for fetal growth and to assess for evidence of fetal anemia. Intrauterine transfusions, steroid administration to promote fetal pulmonary maturity, and early delivery may be required.
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