postnatal diagnosis and management of alloimmune hemolytic disease of the newborn

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5/27/2018 PostnatalDiagnosisandManagementofAlloimmuneHemolyticDiseaseoftheN... http://slidepdf.com/reader/full/postnatal-diagnosis-and-management-of-alloimmune-hemolytic-disease- Official reprint from UpToDate ® www.uptodate.com ©2013 UpToDate ® Author Darlene A Calhoun, DO Section Editors Donald H Mahoney, Jr, MD Leonard E Weisman, MD Deputy Editor Alison G Hoppin, MD Postnatal diagnosis and management of alloimmune hemolytic disease of the newborn Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Sep 2013. | This topic last updated: Jun 5, 2013. INTRODUCTION — Alloimmune hemolytic disease of the newborn (HDN) is caused by the destruction of red blood cells (RBCs) of the neonate or fetus by maternal IgG antibodies. These antibodies are produced when fetal erythrocytes, which express an RBC antigen not expressed in the mother, gain access t o the maternal circulation [ 1 ]. Transfer of maternal antibodies across the placenta depends upon the Fc component of the IgG molecule, which is different in IgA and IgM. As a result, only maternal IgG causes HDN. (See "Structure of immunoglobulins", section on 'Antibody fragments' .) The postnatal diagnosis and management of alloimmune HDN in the newborn will be reviewed here. The prenatal diagnosis and management of HDN are discussed separately. (See "Hemolytic disease of the newborn: RBC alloantibodies in pregnancy and associated serologic issues" and "Prevention of Rh(D) alloimmunization" and "Overview of Rhesus (Rh) alloimmunization in pregnancy" and "Significance of minor red blood cell antibodies during pregnancy".) TYPES OF HDN — Alloimmune HDN primarily involves the major blood groups of Rhesus (Rh), A, B, AB, and O. However, minor blood group incompatibilities (Kell, Duffy, MNS system, and P system) can also result in significant disease. Rh hemolytic disease — Individuals are classified as Rh negative or positive based upon the expression of the major D antigen on the erythrocyte. The original description of alloimmune HDN was due to Rh(D) incompatibility, which is associated with t he most severe form of the disease (hydrops fetalis). The frequency of Rh(D)-negative blood types varies with ethnicity. In the United States, about 15 percent of non-Hispanic whites, 7 percent of Hispanics and blacks, and less than 1 percent of Asians are Rh negative. (See "A primer of red blood cell antigens and antibodies", section on 'Rh blood group system'.) Despite the introduction of antenatal Rh(D) immune globulin prophylaxis in the 1960s, which significantly reduced alloimmune sensitization in pregnant women who are Rh(D) negative, Rh incompatibility remains the most common cause of alloimmune HDN because of the lack of uniform administration of prophylactic therapy [2,3]. In 1991, the estimated incidence of Rh alloimmune HDN was 10.6 per 10,000 total births in the United States [3]. (See "Prevention of Rh(D) alloimmunization".) Although Rh(D) incompatibility remains the most frequent cause of Rh HDN, some of the other more than 44 Rh antigens, particularly E and C, have been associated with HDN (table 1) [2 ]. (See "A primer of red blood cell antigens and antibodies", section on 'Rh blood group system' .) Maternal sensitization is due t o a previous exposure to Rh antigen either through transfusion with Rh-positive RBCs, or pregnancy with an Rh-positive offspring. Thus, in the absence of transfusion, Rh alloimmune HDN generally d oes not occur in the first pregnancy. In affected pregnancies, in-utero interventions such as intrauterine transfusions and early delivery have reduced the severity of disease in the newborn, resulting in decreased neonatal morbidity and mortality rates. (See "Overview of Rhesus (Rh) alloimmunization in pregnancy".) In the affected neonate, clinical manifestations of Rh alloimmune HDN range from mild, self-limited hemolytic disease to severe life-threatening anemia (eg, hydrops fetalis). Hyperbilirubinemia usually occurs within the first 24 hours of life. ABO hemolytic disease — Humans have four major blood groups in the ABO system (A, B, AB, O). At about three to six months of age, individuals naturally begin to make A and/or B antibodies to the antigens (found ubiquitously in food and bacteria) they do not possess. As a result, in contrast to Rh disease, ABO alloimmune HDN can occur with the first pregnancy. Although ABO incompatibility occurs in about 15 percent of all pregnancies, it results in neonatal hemolytic disease in only 4 percent of such pregnancies (ie, 0.6 percent of all pregnancies). ABO hemolytic disease is more common and severe in infants of African descent [4]. Infants with ABO HDN generally have less severe disease than those with Rh incompatibility. Hydrops fetalis due to ABO alloimmune HDN is rare and clinically significant hemolysis is uncommon as less than 0.1 percent of infants with evidence of hemolysis will require exchange transfusions [ 4,5]. In one prospective study, maternal IgG anti-A and anti-B titers >512 were associated with severe hyperbilirubinemia that required intervention (eg, phototherapy, intravenous immunoglobulin, or exchange transfusion) [ 6]. Affected infants are usually asymptomatic at birth and have either no or mild anemia. They generally develop hyperbilirubinemia within the first 24 hours of birth. Minor blood groups hemolytic disease — Minor blood group antibodies develop in response to exposure to foreign RBC minor group antigens (eg, Kell, MNS blood system, and Duffy, E) from a previous transfusion or pregnancy, or from exposure to ba cteria or viruses that express these antigens. (See "Hemolytic disease of the newborn: RBC alloantibodies in pregnancy and associated serologic issues".) The clinical disease associated with alloimmune HDN due to minor blood groups ranges from mild (hyperbilirubinemia) to severe including hydrops fetalis. The variability is in part dependent upon the blood group (table 2A-B). In particular, Kell HDN can be severe and may require intrauterine intervention. (See "Significance of minor red blood cell antibodies during pregnancy", section on 'Kell blood group'.) DIAGNOSIS — HDN can be dia gnosed postnatally, which will be reviewed here, or antenatally, which is discussed separately. (See "Overview of Rhesus (Rh) alloimmunization in pregnancy" and "Significance of minor red blood cell antibodies during pregnancy".) The postnatal diagnosis of alloimmune HDN is based upon the following: Demonstration of incompatible blood types between the infant and mother. The most common incompatibilities are: Rh(D) positive infant born to an Rh(D) negative mother A or B blood type in an infant born to a mother with group O blood type Demonstration of hemolysis — Peripheral blood smear findings consistent with HDN include decreased number of RBCs, reticulocytosis macrocytosis, and polychromasia. The normal absolute reticulocyte count in cord blood of term infants is 137.3 ± 33 x 10(9)/L, which corresponds to a reticulocyte fraction of 3.1 ± 0.75 percent [7]. Microspherocytosis (due to partial membrane loss) is commonly seen in the peripheral smear of infants with ABO alloimmune HDN, but it is generally not seen in infants with Rh disease. Demonstration of antibody-mediated hemolysis by either a positive direct or indirect antiglobulin test (Coombs test). A positive direct antiglobulin test demonstrates the presence of maternal antibody on the neonate's RBCs. In this test, agglutination of RBCs from the neonate, when suspended with serum that contains antibodies to IgG, indicates the presence of maternal antibody on the RBC cell surface. A limitation of the direct antiglobulin test is that this may not detect sensitized RBCs in ABO alloimmune HDN because the A and B antigens are less well developed in Postnatal diagnosis and management of alloimmune hemolytic disease ... http://www.uptodate.com/contents/postnatal-diagnosis-and-manageme... 1 of 13 21/10/2013 9:17

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  • Official reprint from UpToDate

    www.uptodate.com 2013 UpToDate

    AuthorDarlene A Calhoun, DO

    Section EditorsDonald H Mahoney, Jr, MDLeonard E Weisman, MD

    Deputy EditorAlison G Hoppin, MD

    Postnatal diagnosis and management of alloimmune hemolytic disease of the newborn

    Disclosures

    All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Sep 2013. | This topic last updated: Jun 5, 2013.INTRODUCTION Alloimmune hemolytic disease of the newborn (HDN) is caused by the destruction of red blood cells (RBCs) of the neonate or fetus by maternal IgGantibodies. These antibodies are produced when fetal erythrocytes, which express an RBC antigen not expressed in the mother, gain access to the maternal circulation [1].Transfer of maternal antibodies across the placenta depends upon the Fc component of the IgG molecule, which is different in IgA and IgM. As a result, only maternal IgGcauses HDN. (See "Structure of immunoglobulins", section on 'Antibody fragments'.)The postnatal diagnosis and management of alloimmune HDN in the newborn will be reviewed here. The prenatal diagnosis and management of HDN are discussedseparately. (See "Hemolytic disease of the newborn: RBC alloantibodies in pregnancy and associated serologic issues" and "Prevention of Rh(D) alloimmunization" and"Overview of Rhesus (Rh) alloimmunization in pregnancy" and "Significance of minor red blood cell antibodies during pregnancy".)TYPES OF HDN Alloimmune HDN primarily involves the major blood groups of Rhesus (Rh), A, B, AB, and O. However, minor blood group incompatibilities (Kell, Duffy,MNS system, and P system) can also result in significant disease.Rh hemolytic disease Individuals are classified as Rh negative or positive based upon the expression of the major D antigen on the erythrocyte. The original description ofalloimmune HDN was due to Rh(D) incompatibility, which is associated with the most severe form of the disease (hydrops fetalis).The frequency of Rh(D)-negative blood types varies with ethnicity. In the United States, about 15 percent of non-Hispanic whites, 7 percent of Hispanics and blacks, and lessthan 1 percent of Asians are Rh negative. (See "A primer of red blood cell antigens and antibodies", section on 'Rh blood group system'.)Despite the introduction of antenatal Rh(D) immune globulin prophylaxis in the 1960s, which significantly reduced alloimmune sensitization in pregnant women who are Rh(D)negative, Rh incompatibility remains the most common cause of alloimmune HDN because of the lack of uniform administration of prophylactic therapy [2,3]. In 1991, theestimated incidence of Rh alloimmune HDN was 10.6 per 10,000 total births in the United States [3]. (See "Prevention of Rh(D) alloimmunization".)Although Rh(D) incompatibility remains the most frequent cause of Rh HDN, some of the other more than 44 Rh antigens, particularly E and C, have been associated withHDN (table 1) [2]. (See "A primer of red blood cell antigens and antibodies", section on 'Rh blood group system'.)Maternal sensitization is due to a previous exposure to Rh antigen either through transfusion with Rh-positive RBCs, or pregnancy with an Rh-positive offspring. Thus, in theabsence of transfusion, Rh alloimmune HDN generally does not occur in the first pregnancy.

    In affected pregnancies, in-utero interventions such as intrauterine transfusions and early delivery have reduced the severity of disease in the newborn, resulting in decreasedneonatal morbidity and mortality rates. (See "Overview of Rhesus (Rh) alloimmunization in pregnancy".)In the affected neonate, clinical manifestations of Rh alloimmune HDN range from mild, self-limited hemolytic disease to severe life-threatening anemia (eg, hydrops fetalis).Hyperbilirubinemia usually occurs within the first 24 hours of life.

    ABO hemolytic disease Humans have four major blood groups in the ABO system (A, B, AB, O). At about three to six months of age, individuals naturally begin to make Aand/or B antibodies to the antigens (found ubiquitously in food and bacteria) they do not possess. As a result, in contrast to Rh disease, ABO alloimmune HDN can occur withthe first pregnancy.

    Although ABO incompatibility occurs in about 15 percent of all pregnancies, it results in neonatal hemolytic disease in only 4 percent of such pregnancies (ie, 0.6 percent of allpregnancies). ABO hemolytic disease is more common and severe in infants of African descent [4].Infants with ABO HDN generally have less severe disease than those with Rh incompatibility. Hydrops fetalis due to ABO alloimmune HDN is rare and clinically significanthemolysis is uncommon as less than 0.1 percent of infants with evidence of hemolysis will require exchange transfusions [4,5]. In one prospective study, maternal IgG anti-Aand anti-B titers >512 were associated with severe hyperbilirubinemia that required intervention (eg, phototherapy, intravenous immunoglobulin, or exchange transfusion) [6].Affected infants are usually asymptomatic at birth and have either no or mild anemia. They generally develop hyperbilirubinemia within the first 24 hours of birth.

    Minor blood groups hemolytic disease Minor blood group antibodies develop in response to exposure to foreign RBC minor group antigens (eg, Kell, MNS blood system,and Duffy, E) from a previous transfusion or pregnancy, or from exposure to bacteria or viruses that express these antigens. (See "Hemolytic disease of the newborn: RBCalloantibodies in pregnancy and associated serologic issues".)The clinical disease associated with alloimmune HDN due to minor blood groups ranges from mild (hyperbilirubinemia) to severe including hydrops fetalis. The variability is inpart dependent upon the blood group (table 2A-B). In particular, Kell HDN can be severe and may require intrauterine intervention. (See "Significance of minor red blood cellantibodies during pregnancy", section on 'Kell blood group'.)DIAGNOSIS HDN can be diagnosed postnatally, which will be reviewed here, or antenatally, which is discussed separately. (See "Overview of Rhesus (Rh)alloimmunization in pregnancy" and "Significance of minor red blood cell antibodies during pregnancy".)The postnatal diagnosis of alloimmune HDN is based upon the following:

    Demonstration of incompatible blood types between the infant and mother. The most common incompatibilities are:

    Rh(D) positive infant born to an Rh(D) negative motherA or B blood type in an infant born to a mother with group O blood type

    Demonstration of hemolysis Peripheral blood smear findings consistent with HDN include decreased number of RBCs, reticulocytosis macrocytosis, andpolychromasia. The normal absolute reticulocyte count in cord blood of term infants is 137.3 33 x 10(9)/L, which corresponds to a reticulocyte fraction of 3.1 0.75percent [7]. Microspherocytosis (due to partial membrane loss) is commonly seen in the peripheral smear of infants with ABO alloimmune HDN, but it is generally notseen in infants with Rh disease.

    Demonstration of antibody-mediated hemolysis by either a positive direct or indirect antiglobulin test (Coombs test).

    A positive direct antiglobulin test demonstrates the presence of maternal antibody on the neonate's RBCs. In this test, agglutination of RBCs from the neonate,when suspended with serum that contains antibodies to IgG, indicates the presence of maternal antibody on the RBC cell surface.

    A limitation of the direct antiglobulin test is that this may not detect sensitized RBCs in ABO alloimmune HDN because the A and B antigens are less well developed in

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  • neonates than in older children and adults. In addition, the antigenic sites are fewer and further apart on neonatal RBCs, making agglutination with the Coombs' reagent moredifficult [5].If the direct antiglobulin test is negative, an elution is performed on the infant's RBCs to free any bound maternal antibodies into the serum, then an indirect antiglobulin test isperformed with the eluted serum. In this test, RBCs with a specific antigen, such as Rh(D), A, or B, are incubated with the infant's serum. Antibodies to the specific antigen willadhere to the RBCs. The RBCs are then washed and suspended in serum containing antihuman globulin (Coombs serum). Agglutination of red cells coated with maternalantibody indicates the presence of free maternal antibodies in the neonatal serum [8].In infants with suspected ABO hemolytic disease with both a negative direct antiglobulin test, and indirect test of the infant's eluted serum, other causes for hyperbilirubinemiashould be sought. Specifically, evaluations for glucose-6-phosphate dehydrogenase deficiency, pyruvate kinase deficiency, and the UGT1A1 promoter associated with Gilbertsyndrome should be performed. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn" and 'Differential diagnosis' below.)In infants with Rh alloimmune HDN who have received intrauterine transfusions, the direct antiglobulin test may be negative because the presence of donor Rh-negative RBCsmakes agglutination more difficult. In contrast, the indirect test will remain strongly positive.

    DIFFERENTIAL DIAGNOSIS The differential diagnosis for alloimmune HDN include other causes of neonatal jaundice and/or anemia. Alloimmune HDN is differentiatedfrom the following disorders by the presence of a positive direct or indirect antiglobulin test (Coombs). In addition to being in the differential diagnosis of alloimmune HDN,these disorders can occur concomitantly in an infant with alloimmune HDN. The hyperbilirubinemia may be particularly severe in infants with more than one cause ofhyperbilirubinemia [9]. (See 'Diagnosis' above and "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn".)

    Erythrocyte membrane defects The peripheral blood smear and the negative antiglobulin tests distinguish the inherited erythrocyte membrane defects such ashereditary spherocytosis (picture 1) or elliptocytosis (picture 2) from alloimmune HDN. (See "Hereditary spherocytosis: Clinical features; diagnosis; and treatment" and"Hereditary elliptocytosis: Clinical features and diagnosis".)Erythrocyte enzyme defects Enzyme assays confirm the diagnosis of erythrocyte enzyme defects such as glucose-6-phosphate dehydrogenase (G6PD) or pyruvatekinase deficiencies. The presence of Heinz bodies on peripheral blood smear is consistent with a diagnosis of G6PD deficiency (picture 3). (See "Diagnosis andtreatment of glucose-6-phosphate dehydrogenase deficiency".)Gilbert's syndrome Gilbert's syndrome is the most common inherited disorder of bilirubin glucuronidation. It results from a mutation in the promoter region of theUGT1A1 gene causing a reduced production of UGT, which leads to unconjugated hyperbilirubinemia. A normal hematocrit, reticulocyte count, and peripheral bloodsmear distinguish this disorder from alloimmune HDN. (See "Pathogenesis and etiology of unconjugated hyperbilirubinemia in the newborn", section on 'Gilbert'ssyndrome'.)

    CLINICAL PRESENTATION As discussed previously, clinical manifestations of alloimmune HDN range from mild, self-limited hemolytic disease (eg, hyperbilirubinemia) tosevere life-threatening anemia (eg, hydrops fetalis).

    Hyperbilirubinemia Less severely affected infants typically present with unexpected hyperbilirubinemia within the first 24 hours of life. They may also havesymptomatic anemia (eg, lethargy or tachycardia) but without signs of circulatory collapse. The degree of anemia varies depending upon the type of HDN. Infants withABO incompatibility generally have no or only minor anemia at birth. Whereas, infants with Rh or some minor blood group incompatibilities can present withsymptomatic anemia that require RBC transfusion. (See 'Anemia' below.)Hydrops fetalis Infants with hydrops fetalis present with skin edema, pleural or pericardial effusion, or ascites. Infants with Rh(D) and some minor blood groupincompatibilities, such as Kell, are at risk for hydrops fetalis, especially without antenatal care. ABO alloimmune HDN is generally less severe than that caused by theRh and Kell systems, however, there are case reports of hydrops fetalis due to ABO incompatibility [4]. Neonates with hydrops fetalis may present at delivery with shockor near shock and require emergent transfusion. (See 'Anemia' below.)

    MANAGEMENT In developed countries, routine antenatal care includes screening for maternal antibodies that can potentially cause alloimmune HDN. If such antibodiesare detected, management is directed towards monitoring maternal antibody titers and the condition of the fetus (ie, fetal anemia), and if necessary, intervening with fetal RBCtransfusions. Antenatal care and the prevention of maternal Rh sensitization have significantly reduced the number of infants born with severe manifestations of alloimmuneHDN. (See "Prevention of Rh(D) alloimmunization" and "Overview of Rhesus (Rh) alloimmunization in pregnancy" and "Significance of minor red blood cell antibodies duringpregnancy" and "Intrauterine fetal transfusion of red blood cells".)Postnatal management for affected infants is focused on treating the anemia and hyperbilirubinemia caused by hemolysis of neonatal RBCs.

    Anemia The duration of the anemia in infants with HDN depends on the severity of the anemia at presentation, the timing of onset (early versus late type), and thetreatments that are selected. Early-onset anemia is mediated by alloimmune hemolysis, and may further complicate the natural physiologic hemoglobin nadir that occurs inneonates at four to six weeks of age. Late-onset anemia may be due to immune destruction of erythroid progenitors and/or suppression of erythropoiesis, and may be treatedwith iron supplementation, transfusions, and/or recombinant human erythropoietin.

    Early The severity of the anemia at birth is variable. As discussed above, neonates can present with severe HDN (eg, hydrops fetalis) resulting in significant morbidity ordeath, particularly in the absence of antenatal care. Infants with Rh(D) and some minor blood group incompatibilities, such as Kell, are at risk for hydrops fetalis. (See 'Clinicalpresentation' above and "Postnatal care of hydrops fetalis".)The status of a newborn with HDN due to Rh or Kell incompatibility cannot be predicted with certainty at the time of delivery, even if antenatal care has been provided. As aresult, delivery room management should anticipate the needs of the most severely affected infant including the ability to emergently transfuse packed group O, Rh(D)negative RBCs in neonates with severe life-threatening anemia.

    At delivery, assessment includes evaluation of the infant's respiratory and cardiovascular system, and the severity of hemolysis. Pallor, tachycardia, and tachypnea arefindings suggestive of symptomatic anemia. Respiratory distress may also be due to pleural effusions or pulmonary hypoplasia in infants with hydrops fetalis. (See 'Clinicalpresentation' above.)Thoracentesis or paracentesis may be required in infants with significant respiratory distress due to pleural effusions and/or ascites [10]. Emergent transfusion with group O,Rh(D) negative RBCs is required if the infants is in shock or pending shock due to severe anemia. (See "Postnatal care of hydrops fetalis".)In all cases if alloimmune HDN is suspected or known, cord blood should be sent for the following [10]:

    Blood type and antiglobulin (Coombs) test to confirm the diagnosis.Hematocrit, reticulocyte count, and bilirubin concentration to guide decisions on therapeutic interventions (eg, transfusions and/or phototherapy).Cross match for subsequent transfusion (see "Red cell transfusion in infants and children: Selection of blood products", section on 'Hemolytic disease of the fetus andnewborn').

    Transfusion with cross-matched RBC is indicated in infants with symptomatic anemia (eg, lethargy or tachycardia) but who do not have signs of circulatory collapse.In infants with severe anemia and hyperbilirubinemia, exchange transfusion is preferred over simple transfusion because it not only corrects anemia but also reduceshemolysis by replacing antibody-coated neonatal RBCs with donor RBCs, which do not have the sensitizing antigen, and removes a portion of the unbound maternal antibody.In severely hydropic infants, early exchange transfusion appears to also improve oxygenation [10]. (See "Postnatal care of hydrops fetalis".)Our criteria for exchange transfusion for hyperbilirubinemia are based upon the American Academy of Pediatrics (AAP) guidelines for the management of hyperbilirubinemia(figure 1) [11]. The AAP guidelines for exchange transfusions and a description about the procedure itself including its risk are discussed in detail separately. (See "Treatmentof unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Exchange transfusion'.)

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  • Early exchange transfusions require skilled and available personnel to perform the procedure. If there is a delay or inability to perform an exchange transfusion, simpletransfusion with packed RBCs may be used recognizing that repeat transfusions may be necessary because of ongoing hemolysis. In addition, the use of intravenous gammaglobulin (IVIG) has reduced the need for exchange transfusion especially in infants with ABO hemolytic disease. (See "Treatment of unconjugated hyperbilirubinemia in termand late preterm infants", section on 'Intravenous immunoglobulin'.)In our institution, we perform exchange or simple transfusions based upon the following settings:

    If an infant has severe anemia and hyperbilirubinemia, an exchange transfusion is performed based upon the criteria outlined by the AAP (figure 1). A simpletransfusion may be performed if there is a delay in performing an exchange transfusion.If the hyperbilirubinemia is not severe and the symptoms of anemia are moderate to severe, a simple transfusion is performed.If hyperbilirubinemia is not severe and the symptoms of anemia are mild but the infant is at risk for late anemia, we treat with recombinant erythropoietin (rhEpo)and iron supplementation if the infant is projected to require transfusion without this treatment [12]. However, the indications for and benefits of rhEpo in thesepatients have not been established, as discussed in the next section. (See 'Late' below.)

    The selection of appropriate blood products for RBC transfusions in infants with alloimmune HDN is discussed separately. (See "Red cell transfusion in infants and children:Selection of blood products", section on 'Hemolytic disease of the fetus and newborn'.)If the anemia is asymptomatic, interventions to correct the infant's anemia are not required, but exchange transfusion may still be needed because of hyperbilirubinemia. (See"Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Exchange transfusion' and 'Hyperbilirubinemia' below.)

    Late Late onset anemia presenting one to three weeks after birth may be seen in neonates with ABO [13], minor blood groups (eg, Gerbich [14] and Kell system [15]),and Rh [16] incompatibilities.Late-onset anemia may be due to immune destruction of erythroid progenitors [14] and/or suppression of erythropoiesis [15,16]. In infants who received intrauterinetransfusions, hemolytic anemia may also be delayed until the majority of the donor RBCs is replaced with the RBCs of the affected infant (which express the alloimmuneantigen and therefore, are vulnerable to persistent maternal antibody-mediated hemolysis).Treatment options for late-onset anemia are as follows:

    Asymptomatic infants are treated with iron supplementation (3 to 6 mg/kg/day enterally, depending on amount of enteral feeds), and phlebotomy is minimized to reduceblood loss [12].Infants with symptomatic late-onset anemia are generally treated with simple transfusion.

    Recombinant erythropoietin (rhEpo), or its longer-acting analog darbepoetin, is sometimes used in selected infants in an effort to reduce or prevent the need fortransfusion. This includes infants with Kell, Rh, or ABO incompatibility with progressive anemia but who are not yet sufficiently symptomatic to require transfusion, orfamilies whose religious tradition prohibits transfusion. The rhEpo is given subcutaneously at a dose of 400 U/kg given three times weekly for two weeks [12]. Theseinfants are also treated with supplemental iron (6 mg/kg per day for those infants on enteral feedings). Longer courses of rhEpo also may be beneficial [15,16]. Of note,rhEpo treatment does not usually produce an elevation in hematocrit for at least five days [12]. The indications for and potential benefits of rhEpo for HDN have notbeen established. In our practice we use rhEpo in selected infants in an effort to avoid transfusion, as described above. Some other experts do not recommend thisapproach [17]. The lack of consensus is due to the limited evidence base for use of rhEpo in this population, which consists of case reports with variable results[13,15,16,18-20]. In addition, the likelihood of transfusion depends on regional variations in transfusion and phlebotomy practices.

    Infants with late anemia caused by Rh disease should be monitored until the reticulocyte count recovers, which may take weeks to months, depending on the severity of theanemia and the chosen treatment.

    Hyperbilirubinemia The treatment of unconjugated neonatal hyperbilirubinemia is discussed in greater detail separately. The following is a summary of the management ofhyperbilirubinemia in infants with alloimmune HDN. (See "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants".)In infants with hyperbilirubinemia due to alloimmune HDN, monitoring serum bilirubin levels, oral hydration, and phototherapy are the mainstays of management. For infantswho do not respond to these conventional measures, intravenous fluid supplementation and/or exchange transfusion may be necessary to treat hyperbilirubinemia.Intravenous immunoglobulin (IVIG) also may be useful in reducing the need for exchange transfusion.The duration of clinical symptoms is variable in infants with HDN and depends on several factors. Since there is considerable variation in the strength of the reactivity of thevarious antigens involved in HDN, the degree of initial hemolysis is also variable. Maternal antibody levels are not useful to predict the hemolytic process because they arepoorly correlated with the degree of hemolysis [21]. In addition, the effects of treatment result in variable lengths of clinical symptoms in the infants. Exchange transfusion andthe administration of intravenous immune globulin can result in dramatic improvements in reducing the rate of hemolysis. However, infants with HDN will require continuedmonitoring until their bilirubin concentrations are in a safe range and trending down, without ongoing treatment.

    Phototherapy Phototherapy is the most commonly used intervention to treat and prevent severe hyperbilirubinemia. It is an effective and safe intervention. The AAPhas developed guidelines for the initiation and discontinuation of phototherapy based upon total serum bilirubin (TSB) values at specific hourly age of the patient, gestationalage, and the presence or absence of risk factors for hyperbilirubinemia including alloimmune HDN (figure 2). (See "Treatment of unconjugated hyperbilirubinemia in term andlate preterm infants", section on 'Phototherapy'.)

    Hydration Phototherapy increases insensible skin losses and as a result the fluid requirements of infants undergoing phototherapy are increased. In addition,by-products of phototherapy are eliminated in the urine. If oral hydration is inadequate, intravenous hydration may be necessary. (See "Treatment of unconjugatedhyperbilirubinemia in term and late preterm infants", section on 'Hydration'.)

    Exchange transfusion Exchange transfusion is used to treat severe anemia, as previously discussed, and severe hyperbilirubinemia. Exchange transfusion removesserum bilirubin and decreases hemolysis by the removal of antibody-coated neonatal RBCs and unbound maternal antibody.

    Immediate exchange transfusion is recommended if the infant demonstrates signs of acute bilirubin encephalopathy (ABE), such as lethargy, hypotonia, poor sucking, orhigh-pitched cry. (See "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Exchange transfusion' and "Clinical manifestations ofunconjugated hyperbilirubinemia in term and late preterm infants", section on 'Acute bilirubin encephalopathy'.)The optimal threshold for initiating exchange transfusion in infants with alloimmune HDN to prevent ABE is unknown [10]. Based upon clinical practice, a cord bilirubin levelgreater than 4.5 mg/dL (77 mol/L) has been suggested as an initial threshold for exchange transfusion [22]. However, others have suggested that cord bilirubin levels are notuseful in predicting postnatal TSB levels in neonates with alloimmune HDN [23]. An alternative method uses a rise of TSB greater than 0.5 mg/dL (8 mol/L) per hour, despiteintensive phototherapy, as an indication for exchange transfusion [10,23].As discussed above, the AAP has developed guidelines for exchange transfusion based upon TSB values at specific hourly ages of the patient, gestational age, and thepresence or absence of risk factors for hyperbilirubinemia including alloimmune HDN (figure 1).In our practice, we perform an exchange transfusion if the TSB persists above the threshold values outlined by these guidelines after a trial of phototherapy, IVIG, andintravenous hydration (figure 1). With prenatal diagnosis and management of alloimmune HDN and the use of IVIG, few infants require exchange transfusions. (See"Treatment of unconjugated hyperbilirubinemia in term and late preterm infants", section on 'Exchange transfusion'.)

    Immunoglobulin therapy Several clinical trials have demonstrated that intravenous immunoglobulin (IVIG) reduces the need for exchange transfusion forhyperbilirubinemia in infants with hemolytic disease caused by Rh or ABO incompatibility [24-30]. Although the mechanism of action is uncertain, IVIG is thought to inhibithemolysis by blocking antibody receptors on RBCs. Limited data exist for its use in other blood group incompatibilities such as anti-C and anti-E disease [25,31].We agree with the AAP guidelines, which recommend the administration of IVIG in infants with alloimmune HDN if the TSB is rising despite intensive phototherapy or is within

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  • 2 or 3 mg/dL (34 to 51 micromol/L) of the threshold for exchange transfusion [11]. The recommended dose is 500 to 1000 mg/kg given over 2 hours, and the dose may berepeated in 12 hours if necessary.

    The efficacy of IVIG is supported by two systematic reviews, which pooled data from three [30] and four clinical trials [24]. In the largest trial included in both reviews, IVIG(1000 mg/kg per dose IV) or placebo was randomly assigned to 116 infants with alloimmune HDN. Infants who received IVIG compared with the control group had a lower rateof exchange transfusions (14 versus 38 percent) [28]. Similar results were seen in a second randomized controlled trial of 43 infants, in which IVIG was administered at alower dose (500 mg/kg per dose) [29].By contrast, a separate single center study in a group of 80 infants with Rh-mediated hemolytic disease showed no effect of IVIG [32]. Treatment of infants with IVIG (750mg/kg) did not reduce the rate of exchange transfusion, duration of phototherapy, or maximum bilirubin level as compared with placebo. The lack of efficacy of IVIG in thisstudy might be specific to the Rh-mediated disease of the study population or might be explained by the relatively low dose of IVIG that was used (750 mg/kg for one dose),which is substantially less than the maximum dose recommended by the AAP (up to 1000 mg/kg for two doses). These issues warrant additional investigation which mayrequire a large multicenter evaluation. Until more information is available, we continue our current practice of administering IVIG to infants with severe alloimmune HDNaccording to the AAP guidelines outlined above, in an effort to minimize the need for transfusion support.

    Breastfeeding Although maternal antibodies are present in breast milk, very little antibody is absorbed [33]. Thus, mothers should be encouraged to breastfeed.SUMMARY AND RECOMMENDATIONS Alloimmune hemolytic disease of the newborn (HDN) is caused by the destruction of red cells of the neonate or fetus by maternalIgG antibodies. Incompatibility between mother and offspring of a major blood group (Rhesus [Rh] and ABO) or minor blood group (Kell, Duffy, MNS system, and P system)causes HDN that may result in clinically significant neonatal anemia and/or hyperbilirubinemia.

    Clinical presentation and diagnosis

    Rh HDN Although the introduction of Rh immune globulin prophylaxis has significantly reduced sensitization in pregnant Rh-negative women, Rh incompatibility isthe most common cause of alloimmune HDN. Clinical manifestations of Rh HDN range from mild, self-limited hemolytic disease to hydrops fetalis. Antenatal care,including intrauterine transfusion, has decreased the rates of neonatal morbidity and mortality due to Rh alloimmune HDN. (See 'Rh hemolytic disease' above and"Overview of Rhesus (Rh) alloimmunization in pregnancy".)ABO HDN Infants with ABO HDN generally have less severe disease than those with Rh hemolytic disease. Affected infants are usually asymptomatic at birth anddevelop hyperbilirubinemia within the first 24 hours of birth. Anemia is usually either absent or mild. (See 'ABO hemolytic disease' above.)Minor blood groups The clinical disease associated with alloimmune HDN due to minor blood groups ranges from mild (hyperbilirubinemia) to severe manifestations,including hydrops fetalis (table 2A-B). In particular, Kell HDN can be severe and may require intrauterine intervention. (See 'Minor blood groups hemolytic disease'above and "Significance of minor red blood cell antibodies during pregnancy".)The diagnosis of alloimmune HDN is based upon demonstrating incompatible blood types between the mother and her infant, and the presence of antibody-mediatedhemolysis by either a positive direct or indirect antiglobulin tests (Coombs test), and evidence of hemolysis on a peripheral blood smear of the infant. (See 'Diagnosis'above.)The differential diagnosis for alloimmune HDN includes other causes of neonatal jaundice and/or anemia. Alloimmune HDN is differentiated from these disorders by thepresence of a positive direct and/or indirect antiglobulin test. (See 'Differential diagnosis' above.)The degree of anemia varies in infants with alloimmune HDN. Anemia may present at birth (early) or not until one to three weeks of age (late). (See 'Management'above.)In infants with alloimmune HDN, hyperbilirubinemia generally presents within the first 24 hours of life. (See 'Clinical presentation' above.)

    Management

    In infants with alloimmune HDN with shock or pending shock due to severe anemia, emergent transfusion is required at delivery. We recommend using group O, Rh (D)negative red blood cells (RBCs) versus cross-matched RBCs (Grade 1C).In infants who have early symptomatic anemia without signs of circulatory compromise, we recommend cross-matched RBCs transfusion (Grade 1C).In our institution, we perform exchange or simple transfusions based upon the following considerations: (See 'Early' above.)

    If an infant has severe anemia and hyperbilirubinemia, an exchange transfusion is performed, based upon the criteria outlined by the American Academy ofPediatrics (figure 1). A simple transfusion may be performed if there is a delay in performing an exchange transfusion.If the hyperbilirubinemia is not severe and the symptoms of anemia are moderate, a simple transfusion is performed.If hyperbilirubinemia is not severe and the symptoms of anemia are mild but the infant is at risk for late anemia, we treat with recombinant erythropoietin (rhEpo)and iron supplementation if the infant is projected to require transfusion without this treatment. However, the indications for and benefits of rhEpo in these patientshave not been established. (See 'Late' above.)

    In infants with late onset symptomatic anemia, we recommend simple transfusion of cross-matched blood rather than no intervention (Grade 1C). (See "Indications forred blood cell transfusion in infants and children", section on 'Less than 4 months of age' and "Red cell transfusion in infants and children: Selection of blood products",section on 'Hemolytic disease of the fetus and newborn'.)Management of hyperbilirubinemia due to HDN includes monitoring serum bilirubin levels, oral hydration, and phototherapy, which is based on the criteria outlined bythe American Academy of Pediatrics (figure 2). For infants who do not respond to conventional measures, intravenous fluid supplementation, intravenousimmunoglobulin, and exchange transfusion may be used. (See "Treatment of unconjugated hyperbilirubinemia in term and late preterm infants" and 'Hyperbilirubinemia'above.)We recommend immediate exchange transfusion if the infant demonstrates signs of acute bilirubin encephalopathy (ABE) (Grade 1B). (See "Treatment ofunconjugated hyperbilirubinemia in term and late preterm infants" and 'Hyperbilirubinemia' above.)

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    REFERENCES

    Medearis AL, Hensleigh PA, Parks DR, Herzenberg LA. Detection of fetal erythrocytes in maternal blood post partum with the fluorescence-activated cell sorter. Am JObstet Gynecol 1984; 148:290.

    1.

    Geifman-Holtzman O, Wojtowycz M, Kosmas E, Artal R. Female alloimmunization with antibodies known to cause hemolytic disease. Obstet Gynecol 1997; 89:272.2.Chvez GF, Mulinare J, Edmonds LD. Epidemiology of Rh hemolytic disease of the newborn in the United States. JAMA 1991; 265:3270.3.McDonnell M, Hannam S, Devane SP. Hydrops fetalis due to ABO incompatibility. Arch Dis Child Fetal Neonatal Ed 1998; 78:F220.4.McKenzie, S. Anemia In: Intensive Care of the Fetus and Newborn Second Edition, Spitzer AR (Ed), Elsevier Mosby, 2005. p.1289.5.Bakkeheim E, Bergerud U, Schmidt-Melbye AC, et al. Maternal IgG anti-A and anti-B titres predict outcome in ABO-incompatibility in the neonate. Acta Paediatr 2009;98:1896.

    6.

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  • Paterakis GS, Lykopoulou L, Papassotiriou J, et al. Flow-cytometric analysis of reticulocytes in normal cord blood. Acta Haematol 1993; 90:182.7.Desjardins L, Blajchman MA, Chintu C, et al. The spectrum of ABO hemolytic disease of the newborn infant. J Pediatr 1979; 95:447.8.Maisels, MJ. Jaundice. In: Avery's Neonatology: Pathophysiology and Management of the Newborn, McDonald, MG, Mullett, MD, Seshia, MM (Eds), Lippincott, Williams& Williams, Philadelphia 2005. p.800.

    9.

    Peterec SM. Management of neonatal Rh disease. Clin Perinatol 1995; 22:561.10.American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation.Pediatrics 2004; 114:297.

    11.

    Calhoun DA, Christensen RD, Edstrom CS, et al. Consistent approaches to procedures and practices in neonatal hematology. Clin Perinatol 2000; 27:733.12.Lakatos L, Csthy L, Nemes E. "Bloodless" treatment of a Jehovah's Witness infant with ABO hemolytic disease. J Perinatol 1999; 19:530.13.Arndt PA, Garratty G, Daniels G, et al. Late onset neonatal anaemia due to maternal anti-Ge: possible association with destruction of eythroid progenitors. Transfus Med2005; 15:125.

    14.

    Dhodapkar KM, Blei F. Treatment of hemolytic disease of the newborn caused by anti-Kell antibody with recombinant erythropoietin. J Pediatr Hematol Oncol 2001;23:69.

    15.

    Ohls RK. The use of erythropoietin in neonates. Clin Perinatol 2000; 27:681.16.Mainie P. Is there a role for erythropoietin in neonatal medicine? Early Hum Dev 2008; 84:525.17.Wacker P, Ozsahin H, Stelling MJ, Humbert J. Successful treatment of neonatal rhesus hemolytic anemia with high doses of recombinant human erythropoietin. PediatrHematol Oncol 2001; 18:279.

    18.

    Ovali F, Samanci N, Daolu T. Management of late anemia in Rhesus hemolytic disease: use of recombinant human erythropoietin (a pilot study). Pediatr Res 1996;39:831.

    19.

    Pessler F, Hart D. Hyporegenerative anemia associated with Rh hemolytic disease: treatment failure of recombinant erythropoietin. J Pediatr Hematol Oncol 2002;24:689.

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    Grundbacher FJ. The etiology of ABO hemolytic disease of the newborn. Transfusion 1980; 20:563.21.Blanchette, V, Dror, Y, Chan, A. Hematology. In: Avery's Neonatology: Pathophysiology and Management of the Newborn, McDonald, MG, Mullett, MD, Seshia, MM(Eds), Lippincott, Williams & Williams, Philadelphia 2005. p.1169.

    22.

    Wennberg RP, Depp R, Heinrichs WL. Indications for early exchange transfusion in patients with erythroblastosis fetalis. J Pediatr 1978; 92:789.23.Gottstein R, Cooke RW. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88:F6.24.Sato K, Hara T, Kondo T, et al. High-dose intravenous gammaglobulin therapy for neonatal immune haemolytic jaundice due to blood group incompatibility. Acta PaediatrScand 1991; 80:163.

    25.

    Rbo J, Albrecht K, Lasch P, et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 1992; 121:93.26.Hammerman C, Kaplan M, Vreman HJ, Stevenson DK. Intravenous immune globulin in neonatal ABO isoimmunization: factors associated with clinical efficacy. BiolNeonate 1996; 70:69.

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    Alpay F, Sarici SU, Okutan V, et al. High-dose intravenous immunoglobulin therapy in neonatal immune haemolytic jaundice. Acta Paediatr 1999; 88:216.28.Daolu T, Ovali F, Samanci N, Bengisu E. High-dose intravenous immunoglobulin therapy for rhesus haemolytic disease. J Int Med Res 1995; 23:264.29.Alcock GS, Liley H. Immunoglobulin infusion for isoimmune haemolytic jaundice in neonates. Cochrane Database Syst Rev 2002; :CD003313.30.Wagner T, Resch B, Legler TJ, et al. Severe HDN due to anti-Ce that required exchange tranfusion. Transfusion 2000; 40:571.31.Smits-Wintjens VE, Walther FJ, Rath ME, et al. Intravenous immunoglobulin in neonates with rhesus hemolytic disease: a randomized controlled trial. Pediatrics 2011;127:680.

    32.

    BOWMAN JM. Gastrointestinal absorption of isohemagglutinin. Am J Dis Child 1963; 105:352.33.

    Topic 5933 Version 8.0

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  • GRAPHICS

    Non-Rh(D) antibodies and risk of associated hemolytic disease of the fetus and newborn

    Antigen system Specific antigen Antigen system Specific antigen Antigen system Specific antigen

    Frequently associated with severe disease

    Kell K (K1)

    Rhesus c

    Infrequently associated with severe disease

    Colton Coa MNS Mta Rhesus HOFM

    Co3 MUT LOCR

    Diego ELO Mur Riv

    Dia Mv Rh29

    Dib s Rh32

    Wra sD Rh42

    Wrb S Rh46

    Duffy Fya U STEM

    Kell Jsa Vw Tar

    Jsb Rhesus Bea Other antigens HJK

    k (K2) C JFV

    Kpa Ce JONES

    Kpb Cw Kg

    K11 Cx MAM

    K22 ce REIT

    Ku Dw Rd

    Ula E

    Kidd Jka Ew

    MNS Ena Evans

    Far e

    Hil G

    Hut Goa

    M Hr

    Mia Hr0

    Mit JAL

    Associated with mild disease

    Dombrock Doa Gerbich Ge2 Scianna Sc2

    Gya Ge3 Other Vel

    Hy Ge4 Lan

    Joa Lsa Ata

    Duffy Fyb Kidd Jkb Jra

    Fy3 Jk3

    Reproduced with permission from: Moise KJ. Hemolytic disease of the fetus and newborn. In: Maternal-Fetal Medicine Principles and Practice, 5th ed, Creasy RK, Resnik

    R, Iams JD (Eds), Saunders, Philadelphia 2004. p. 555. Copyright 2004 Elsevier Science.

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  • Minor red blood cell antibodies associated with hemolytic disease of the newborn

    Blood system Specific antigens Severity of hemolytic disease of the newborn (HDN)

    Kell K Mild to severe

    k Mild

    Ko Mild

    Kp(a) Mild

    Kp(b) Mild

    Js(a) Mild

    Js(b) Mild

    Duffy Fy(a) Mild to severe

    Fy(b) Not a cause of HDN

    Fy(3) Mild

    Kidd Jk(a) Mild to severe

    Jk(b) Mild to severe

    Jk(3) Mild

    Lewis Le(a) Not a cause of HDN

    Le(b) Not a cause of HDN

    I I Not a cause of HDN

    i Not a cause of HDN

    MNSs M Mild to severe

    N Mild

    S Mild to severe

    s Mild to severe

    U Mild to severe

    Mi(a) Moderate

    Mt(a) Moderate

    Vw Mild

    Mur Mild

    Hil Mild

    Hut Mild

    Lutheran Lu(a) Mild

    Lu(b) Mild

    Diego Di(a) Mild to severe

    Di(b) Mild to severe

    Xg Xg(a) Mild

    P PP1P(k) Mild to severe

    P1 Not a cause of HDN

    Adapted from data in Weinstein L. Clin Obstet Gynecol 1982; 25:327 and Reid ME, Toy PTCY. In: Hematology of Infancy and Childhood, 5th ed, Nathan DG, Orkin SH

    (Eds), WB Saunders, Philadelphia, 1998, p. 1768.

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  • Minor red blood cell antibodies associated with hemolytic disease of the newborn

    Blood system Specific antigens Severity of hemolytic disease of the newborn (HDN)

    Public antigens Yt(a) Moderate to severe

    Yt(b) Mild

    Lan Mild

    En(a) Moderate

    Ge Mild

    Jr(a) Mild

    Co(a) Severe

    Co(a-b-) Mild

    Private antigens Batty Mild

    Becker Mild

    Berrens Mild

    Biles Moderate

    Ch/RG Not a cause of HDN

    Cromer Mild

    Dombrock Mild

    Evans Mild

    Gerbich Not a cause of HDN

    Gonzales Mild

    Good Severe

    H Not a cause of HDN

    Heibel Moderate

    Hunt Mild

    Indian Not a cause of HDN

    Jobbins Mild

    Knops Not a cause of HDN

    LW Mild

    Radin Moderate

    Rm Mild

    Scianna Not a cause of HDN

    Ven Mild

    Wright(a) Severe

    Wright(b) Mild

    XK Not a cause of HDN

    Zd Moderate

    Adapted from data in Weinstein L. Clin Obstet Gynecol 1982; 25:327 and Reid ME, Toy PTCY. In: Hematology of Infancy and Childhood, 5th ed, Nathan DG, Orkin SH

    (Eds), WB Saunders, Philadelphia, 1998, p. 1768.

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  • Spherocytes

    Peripheral blood smear shows multiple spherocytes which are

    small, dark, dense hyperchromic red cells without central pallor

    (arrows). These findings are compatible with hereditary

    spherocytosis or autoimmune hemolytic anemia.Courtesy of Carola von Kapff, SH (ASCP).

    Normal peripheral blood smear

    High power view of a normal peripheral blood smear. Several

    platelets (black arrows) and a normal lymphocyte (blue arrow)

    can also be seen. The red cells are of relatively uniform size and

    shape. The diameter of the normal red cell should approximate

    that of the nucleus of the small lymphocyte; central pallor (red

    arrow) should equal one-third of its diameter.Courtesy of Carola von Kapff, SH (ASCP).

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  • Elliptical red cells in hereditary elliptocytosis

    Peripheral blood smear from a patient with hereditary elliptocytosis

    shows multiple elliptocytes.Courtesy of Carola von Kapff, SH (ASCP).

    Normal peripheral blood smear

    High power view of a normal peripheral blood smear. Several

    platelets (black arrows) and a normal lymphocyte (blue arrow)

    can also be seen. The red cells are of relatively uniform size and

    shape. The diameter of the normal red cell should approximate

    that of the nucleus of the small lymphocyte; central pallor (red

    arrow) should equal one-third of its diameter.Courtesy of Carola von Kapff, SH (ASCP).

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  • Peripheral smear in Heinz body hemolytic anemia

    showing Heinz bodies and bite cells

    Split screen view of a peripheral smear from a patient with Heinz

    body hemolytic anemia. Left panel: red cells with characteristic

    bite-like deformity (arrows). Right panel: Heinz body preparation

    which reveals the denatured hemoglobin precipitates.Courtesy of Carola von Kapff, SH (ASCP).

    Normal peripheral blood smear

    High power view of a normal peripheral blood smear. Several

    platelets (black arrows) and a normal lymphocyte (blue arrow)

    can also be seen. The red cells are of relatively uniform size and

    shape. The diameter of the normal red cell should approximate

    that of the nucleus of the small lymphocyte; central pallor (red

    arrow) should equal one-third of its diameter.Courtesy of Carola von Kapff, SH (ASCP).

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  • Guidelines for exchange transfusion in infants 35 or more weeks

    gestation

    The dashed lines for the first 24 hours indicate uncertainty due to a wide range of

    clinical circumstances and a range of responses to phototherapy. Immediate

    exchange transfusion is recommended if infant shows signs of acute bilirubin

    encephalopathy (hypertonia, arching, retrocollis, opisthotonos, fever, high pitched

    cry) or if TSB is 5 mg/dL (85 micromol/L) above these lines. Risk factors include

    isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy,

    temperature instability, sepsis, acidosis. Measure serum albumin and calculate

    B/A ratio. Use total bilirubin. Do not subtract direct reacting or conjugated

    bilirubin. If infant is well and 35 to 37 6/7 wk (median risk) can individualize TSB

    levels for exchange based on actual gestational age. Note that these suggested

    levels represent a consensus of most of the committee but are based on limited

    evidence, and the levels shown are approximations. During birth hospitalization,

    exchange transfusion is recommended if the TSB rises to these levels despite

    intensive phototherapy. For readmitted infants, if the TSB level is above the

    exchange level, repeat TSB measurement every two to three hours and consider

    exchange if the TSB remains above the levels indicated after intensive

    phototherapy for six hours.Reproduced with permission from: Subcommittee on Hyperbilirubinemia. Management of

    Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation. Pediatrics 2004;

    114:297. Copyright 2004 The American Academy of Pediatrics.

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  • Guidelines for phototherapy in hospitalized infants of 35 or more

    weeks gestation

    Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin. Risk

    factors include isoimmune hemolytic diseases, G6PD deficiency, asphyxia,

    significant lethargy, temperature instability, sepsis, acidosis, or albumin