Overview--Hemolytic Disease of the New Born.pptx

Overview--Hemolytic Disease of the New Born

1. Hemolytic disease of the newborn

2. Blood group system Rh blood group system MNS blood group system Kell blood group system ABO blood group system Duffy blood group system Kidd blood group system Lewis, P1P(K), GLOB, and I blood group systems Lutheran blood group system Vel blood group system Chido -Rodgers blood group Gerbich blood group system Colton blood group system Diego blood group system Cartwright ( Yt ) blood group system Knops blood group system

3. ALLOANTIBODIES NOT ASSOCIATED WITH HDFN maternal antibodies will not cause hemolytic disease of the fetus and newborn (HDFN) if they cannot cross the placenta ( eg , IgM), or if they are directed against an antigen not expressed on fetal red blood cells (RBCs). This includes antibodies to the Lewis blood group antigens, the I antigens, and the P antigen P1. Maternal titers and fetal assessment for anemia are unnecessary for pregnancies associated with these alloantibodies. Lewis  — The Lewis antigens are not associated with HDFN. This includes Le(a), Le(b), and four rare associated antigens. Antibodies to Lewis antigens are IgM, and fetal RBCs lack Lewis antigens, which develop later in childhood [ 14 ]. However, Lewis antibodies commonly are detected during pregnancy and often may lead to confusion regarding HDFN. I  — The I antigens are not associated with HDFN. The I blood group includes "I" and " i " antigens, neither of which has been associated with HDFN. Fetal and newborn RBCs strongly express the i antigen, with only small amounts of I antigen. P1  — The P1 antigen often elicits an IgM alloantibody in women who express P2; anti-P1 is not associated with HDFN. In contrast, women who have the very rare "p" phenotype can produce clinically significant alloantibodies to other P antigens. (See  'P'  below.)

4. ALLOANTIBODIES THAT CAN BE ASSOCIATED WITH HDFN Antibodies to blood group systems that have been associated with hemolytic disease of the fetus and newborn (HDFN) are listed in the table; however, the presence of antibodies to these blood group systems does not necessarily result in HDFN. Some of these blood group systems are discussed in more detail below. Kell  — The most antigenic of the Kell group is K; K is present in approximately 9 percent of Caucasian blood donors. K-sensitized pregnancies are responsible for approximately 10 percent of severe cases of HDFN. In a large series that included 19 K-sensitized pregnancies, severe HDFN was seen in five (26 percent) [ 11 ]. Other Kell antigens include k, Kp (a), Kp (b), Ko, Js(a), Js(b), and a large number of other rare antigens; these are rarely a cause of Kell incompatibility [ 15 ]. The genotype frequencies in Caucasians are approximately: Kk (8.7 percent), kk (91.1 percent), and KK (0.2 percent) [ 14 ]. By comparison, the frequencies for African-Americans are Kk (2 percent), and kk (98 percent), and KK is extremely rare. Blood transfusion is likely the most common mechanism of K sensitization in reproductive-age women. Antigen testing for K antigens is not routinely performed on blood donors in the United States, although it is in some countries ( eg , Australia, the Netherlands) [ 16 ]. In one series, 8 of 12 K-sensitized women with K-positive babies had a prior blood transfusion [ 17 ]. Alloimmunization during a previous pregnancy may account for anti-K in women who have not received a transfusion.

5. HDFN due to anti-K can be severe. One reason for this is the ability of anti-K to cause destruction of red blood cell (RBC) precursors and maturing erythrocytes in the bone marrow as well as circulating mature fetal RBCs. Anti-K can be particularly troublesome because the titer of the alloantibody correlates poorly with the likelihood of fetal anemia, and the severity of anemia can change dramatically over the course of a single week [ 17-22 ]. Hydrops fetalis can develop before the third trimester. The severity of HDFN from K alloimmunization was illustrated in a large cohort study that identified 1026 K-sensitized pregnancies in the Netherlands [ 23 ]. Of these, there were 124 cases in which a mother with anti-K was pregnant with a K-positive child (in one case, twins). After exclusion of pregnancies with multiple alloantibodies, there were 92 remaining pregnancies (93 neonates) with K sensitization and signs of HDFN. Findings from these pregnancies included the following: ●Intrauterine transfusion was required for 48 fetuses (52 percent). An additional neonate received a transfusion after birth. ●There were three perinatal deaths related to anti-K. ●Of the 16 pregnancies with titers <4, none had severe HDFN. ●Use of a cutoff maternal antibody titer of 4 provided the best sensitivity (100 percent), specificity (36 percent), positive predictive value (64 percent), and negative predictive value (100 percent). ●The first antibody titer obtained (median gestational age, 14 weeks) had the highest power to predict the need for transfusions, and subsequent titers did not change substantially during the pregnancies. Other series have reported similar findings [ 19 ]. One case of fetal hydrops has been reported in the second trimester when the maternal titer was 2 [ 24 ]. Management of K-sensitized pregnancies thus requires a lower threshold antibody titer, as discussed below.

6. ABO  The ABO system contains the A and B antigens, which are assembled on the H antigen. Type O represents the absence of A and B ( ie , H alone). The A and B antigens are codominantly expressed, resulting in blood types A, B, O, and AB. Thus, an individual who is type A can be heterozygous or homozygous for the A antigen; a type B individual can be heterozygous or homozygous for B. Naturally occurring IgM antibodies to A and B develop early in life in individuals lacking the corresponding antigen, following exposure to bacterial antigens in the gut. These IgM antibodies do not cross the placenta and do not cause HDFN. However, IgG ABO antibodies may exist, particularly in group O mothers who have been exposed to a non-O fetus [ 41 ]. —In contrast to other IgG alloantibodies, severe hemolysis due to ABO incompatibility is usually a problem for the neonate and rarely affects the fetus [ 42-46 ]. However, hemolysis may be particularly pronounced in group B African-American fetuses, in whom the B antigen is more developed at birth than in other populations [ 42-44,47,48 ]. An issue may arise when a type A or B, Rh(D)-negative fetus of a type O, Rh(D)-negative mother is typed for Rh(D). Apparent weak Rh(D)-positivity may be seen at the antiglobulin stage due to ABO incompatibility even though the fetus is Rh(D)-negative. This weak Rh(D) typing is often a false positive reaction, and Rh(D)  immune globulin  generally is not indicated. An exception can occur when the newborn is Rh(D)-positive but types as Rh(D)-negative because of a high level of attachment of maternal anti-Rh(D) to the newborn's RBCs (called "blocked Rh"); this is very rare. An elution technique can be performed using the baby's cells and reagent anti-D to definitively determine whether the baby's cells are weakly Rh(D) positive. Additional information about Rh(D) variants and their typing is presented separately.

7. Rh(c) and Rh(E) The Rh system includes many antigens other than Rh(D), the most clinically significant of which are "c" and "E." Other Rh antigens include "C" and "e"; there is no "d" antigen. Importantly, administration of anti-Rh(D)  immune globulin  does not protect the mother from developing antibodies directed against these other Rh antigens. The likelihood of HDFN due to other Rh antigens was illustrated in a large series that included 118 Rh(c)-sensitized pregnancies; of these, severe HDFN was seen in 12 (10 percent) [ 11 ]. The hemolytic effect of Rh(c) is similar to Rh(D) [ 16 ]. In various case series, mortality rates up to 10 percent have been reported; intrauterine transfusions have been required in 1 to 17 percent, and neonatal transfusions have been required in approximately 10 to 30 percent [ 25-28 ]. Special mention should be made of the Rh(D)-negative pregnant women presenting with what appears to be anti-"C+D." The patient may actually have an antibody to the G antigen, which is present on any RBC that expresses Rh(C) and/or Rh(D). Immunohematology reference laboratories can readily distinguish between these possibilities. The clinical importance of this distinction is that the woman may be negative for Rh(D) and has not been actively alloimmunized to the Rh(D) antigen and thus is a candidate for Rh(D)  immune globulin .

8. P  The P system consists of the P1 and P2 antigens, which are present in 79 and 21 percent of Caucasians, respectively. Women with the very rare "p" phenotype can produce anti-P1+P+P(k), an antibody that has been associated with severe HDFN and recurrent early pregnancy loss [ 40 ]. Women with the P2 antigen commonly produce anti-P1 antibodies, which are IgM antibodies that do not cross the placenta. (See  'P1'  above.) Duffy  The Duffy antigens, Fy (a) and Fy (b), are encoded by codominant alleles, giving the phenotypes Fy ( a+b +), Fy (a-b-), Fy ( a+b -), or Fy (a-b+). Only anti- Fy (a) antibody has been associated with HDFN, which may range from mild to severe [ 29 ]. Of interest, 82 percent of blacks are Fy (a-b-), likely because Fy (b) antigen serves as a receptor for malaria [ 30 ]. MNS The MNS system contains the M, N, S, s, and U antigens, as well as 32 other rare antigens. Naturally occurring antibodies to M and N are seen in a small percentage of the general population in the absence of exposure to allogeneic blood. ●Anti-S, anti-s, and anti-U have been reported to cause mild to severe HDFN; anti-N may cause mild hemolysis. ●Anti-Mur, which is especially common in Southeast Asians, can cause mild or severe disease [ 31,32 ]. ●Anti-M rarely causes fetal anemia since it is typically IgM. Severe HDFN due to anti-M may occur if the antibody is a high-titer IgG that is active at 37°C rather than room temperature or a mixture of IgM and IgG [ 33-38 ]. Asians, especially those with Chinese or Japanese ancestry, appear to be prone to develop moderate HDFN, as summarized in a case report and review of the literature published in 2019 [ 39 ]. Affected fetuses and newborns have shown hypoproliferative anemia out of proportion to that expected based on the antibody titer, similar to that seen with anti-Kell.

9. PREPREGNANCY COUNSELING If a nonpregnant woman is found to have an alloantibody to a red blood cell (RBC) antigen, she should be counseled regarding the potential effects of the antibody on a future pregnancy. Details of this counseling will depend on the class of the antibody (IgG versus IgM); the specificity ( ie , the target antigen); and the antigen type of the biologic father, which determines the risk to the fetus. Parental testing  — Individuals with a history of hemolytic disease of the fetus and newborn (HDFN) require further testing to determine the specificity and the potential father's antigen status. In some situations, such as the detection of an anti-M antibody, further consultation with a blood bank pathologist is indicated to determine if the antibody is of the IgG or IgM class. The antibody titer prepregnancy is not useful, since the titer may rise several-fold during pregnancy. If the antibody is capable of producing HDFN ( eg , IgG, concerning specificity) and the potential father of the future pregnancy is known, it is reasonable to determine whether he carries the associated RBC antigen and, if so, whether he is homozygous or heterozygous for the allele. Prevention of HDFN  — HDFN can be prevented by avoiding pregnancy with fetal RBC antigen-maternal RBC antibody incompatibility. Prevention is rarely attempted because of the costs and complexities involved and because HDFN can be treated successfully in most cases. Fetal RBC antigen-maternal RBC antibody incompatibility can be avoided in the following ways: ●In vitro fertilization with preimplantation genetic diagnosis – If the potential biologic father is heterozygous for the antigen, in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD) can be used to identify antigen-negative embryos, and only these embryos are considered for embryo transfer [ 49 ]. ●Use of a gestational carrier – If the potential biologic father is homozygous for the antigen, the intended parents can conceive by IVF and the embryo can be carried by a gestational carrier who is not alloimmunized . ●Use of donor sperm – Sperm from an antigen-negative donor can be used for intrauterine insemination of the alloimmunized mother.

10. PRENATAL MANAGEMENT Our general approach to diagnosis and management of non-Rh(D) alloimmunization in pregnancy is illustrated in the algorithm and outlined below. The efficacy of this approach has been demonstrated in several case series; however, there is limited evidence on which to base management [ 29,50 ]. This approach is consistent with recommendations of the American College of Obstetricians and Gynecologists (ACOG), which advise that the care of patients with non-Rh(D) alloantibodies should be the same as for women with Rh(D) alloimmunization, with the possible exception of Kell sensitization [ 10 ]. Antibody screening   Follow up a positive antibody screen -Evaluate the antibody Eliminate unimportant antibodies ,For clinically important antibodies, determine maternal antibody level -Determine fetal antigen status   -Kell-sensitized pregnancy Assessing for fetal anemia

11. Overview of Rhesus (D) alloimmunization in pregnancy Rhesus (Rh; D)-negative women who deliver an Rh(D)-positive baby or who are otherwise exposed to Rh(D)-positive red cells are at risk of developing anti-D antibodies. Rh(D)-positive fetuses/neonates of these mothers are at risk of developing hemolytic disease of the fetus and newborn (HDFN), which can be associated with serious morbidity or mortality. the Rhesus blood group system consists of 48 antigens; the most common antigens that induce antibodies are D (there is no d antigen), C, c, E, e; C/c and E/e are alternate alleles with codominant expression. Some combination of DCE is inherited as a haplotype from each parent. A woman who is "Rh-negative" (meaning no D antigen) can form anti-C, c, E, and/or e antibodies if exposed to fetal red cells with C, c, E, and/or e antigens inherited from the father that she does not share. Since she is Rh(D) negative, she may have received prophylactic anti-D immune globulin  in previous pregnancies, but this would not prevent c alloimmunization.

12. Prevalence of Rh(D)-negative blood type  — The prevalence of Rhesus antigens varies among populations. The following examples illustrate ethnic variation in prevalence of phenotypically Rh(D)-negative individuals [ 3 ]: ●Basques – 30 to 35 percent ●Caucasians in North America and Europe – 15 percent ●African Americans – 8 percent ●Africa – 4 to 6 percent ●India – 5 percent ●Native Americans and Inuit Eskimos – 1 to 2 percent ●Japan – 0.5 percent ●Thailand – 0.3 percent ●China – 0.3 percent Zygosity  — About 40 percent of Rh(D)-positive individuals are homozygous for the D antigen (DD); the remainder is heterozygous (Dd).

13. PATHOGENESIS AND CONSEQUENCES By 38 days of gestation, the Rh(D) antigen is expressed as part of the red blood cell (RBC) membrane [ 10 ], and, in contrast to most other antigens ( eg , A,B,M,N), Rh(D) is only present on RBCs. Maternal Rh(D) alloimmunization develops as a result of maternal immune system exposure to Rh(D)-positive RBCs [ 11 ]. Once anti-D IgG antibodies are present in the pregnant woman's circulation, they can cross the placenta and opsonize fetal RBCs, which are then phagocytized by macrophages in the fetal spleen. Events that can cause maternal alloimmunization include: Transplacental fetomaternal bleeding during any pregnancy Injection with needles contaminated by Rh(D)-positive blood Inadvertent transfusion of Rh(D)-positive blood D-mismatched allogeneic hematopoietic stem cell transplantation Transplacental fetomaternal bleeding accounts for virtually all cases of maternal Rh(D) alloimmunization. Tiny (0.1 mL) quantities of fetal RBCs gain access to the maternal circulation in nearly all pregnancies. Early predictors of fetomaternal bleeding remain largely unknown, and no cause can be identified in over 80 percent of cases 

14. SCREENING Rh(D) typing and an antibody screen should be performed at the first prenatal visit. For Rh(D)-negative women with an initially negative antibody screen and uncomplicated pregnancy, the antibody screen is repeated at about 28 weeks of gestation, and at delivery Screening tests Indirect Coombs Gel microcolumn assay  Automated enzymatic methods

15. DIAGNOSIS The diagnosis of Rh(D) alloimmunization is based upon detection of anti-Rh(D) antibody in maternal blood. Identification of an alloantibody means that the fetus is at risk for HDFN, not that it has occurred or will develop. False positive  — Screening for anti-D antibodies may not be helpful in identifying alloimmunization if the patient has received  anti-D immune globulin within the past few weeks. Titration can be helpful in these cases: women who received anti-D immune globulin at 28 weeks will have a low (≤4) antibody titer at term; a high titer suggests the presence of allo -anti-D. Also, new allo -anti-D is associated with IgM antibodies, whereas exogenous anti-D is IgG.

16. NEONATAL ISSUES In a report of hemolytic disease of the newborn detected, managed and treated by the Regional Blood Transfusion Center of France over a 30 year interval, 62 percent of Rh(D)-positive newborns of women with Rh(D)-alloimmunization underwent exchange transfusion [ 34 ]. If the neonatal hematocrit is near normal because of a recent intrauterine transfusion (IUT), neonatal exchange transfusion may not be necessary. With senescence of the transfused red cells, approximately 50 percent of infants transfused in utero will require a "top-up" transfusion at one month of age due to suppression of fetal erythropoiesis from IUT and persistence of maternal antibody not removed by exchange transfusion [ 35 ]. In some cases, up to four top-up transfusions are necessary before reticulocytosis begins and anti-red cell antibodies disappear [ 36 ]. A detailed discussion of the evaluation and management of neonates of alloimmunized women is available elsewhere. 

17. PREVENTION Most, but not all, Rh(D) alloimmunization can be prevented by administration of  anti-D immune globulin  to women exposed or at high risk of being exposed to Rh(D)-positive red blood cells (RBCs). All D-negative pregnant women should undergo an antibody screen at the first prenatal visit. If the initial screen is negative, a repeat screen at 28 weeks of gestation should be performed prior to the administration of  anti-D immune globulin . Once alloimmunization has occurred,  anti-D immune globulin  is not effective for preventing or reducing the severity of HDFN. The three options for prevention of an affected fetus in this setting are: Pregnancy by insemination with sperm from a Rh(D)-negative donor In vitro fertilization and preimplantation genetic testing for selection of  RHD  negative embryos (if father is heterozygous for  RHD ) Use of a gestational carrier Given the success of intrauterine fetal transfusion for treatment of HDFN, one of these options is usually considered only by women at risk for very early, severe fetal anemia where intrauterine fetal transfusion is more risky and less successful

18. If the fetus is  RHD -positive, the indirect Coombs titer ( ie , indirect antiglobulin test) is repeated monthly as long as it remains stable; rising titers should be repeated every two weeks. The critical titer (the titer associated with a risk for development of severe anemia and hydrops fetalis) varies among laboratories and by methodologies; however, in most centers, an anti-D titer between 16 and 32 is considered critical. In Europe and the United Kingdom, a threshold value of 15 international units/mL is the critical value, based upon comparison with an international standard. When the critical titer is reached or exceeded and the fetus is  RHD -positive, further assessment by Doppler velocimetry is performed to determine whether the fetus is severely anemic. Doppler interrogation of the fetal middle cerebral artery (MCA) peak systolic velocity (PSV) is the best tool for predicting moderate to severe fetal anemia in at-risk pregnancies. We measure MCA-PSV at one- to two-week intervals. The frequency is increased if indicated by multiples of the median ( MoMs ) approaching 1.5. An MCA-PSV ≤1.5 MoMs for gestational age is consistent with absence of moderate to severe anemia. If MCA-PSV remains at this level, we schedule delivery at 37 to 38 weeks of gestation. In addition, we begin weekly antenatal testing at 32 weeks of gestation. For pregnancies with MCA-PSV >1.5 MoMs for gestational age, we obtain fetal blood by cordocentesis for hemoglobin determination and perform an intrauterine fetal transfusion if fetal hemoglobin is two standard deviations below the mean value for gestational age. Intrauterine transfusion is generally limited to pregnancies <35 weeks of gestation because after 35 weeks, intrauterine transfusion is considered riskier than delivery followed by postnatal transfusion therapy. At ≥35 weeks of gestation we would deliver a fetus with MCA-PSV >1.5 MoMs for gestational age.

19. Postnatal diagnosis and management of hemolytic disease of the fetus and newborn Clinical manifestations of HDFN range from mild, self-limited hemolytic disease ( eg , hyperbilirubinemia with mild to moderate anemia) to severe life-threatening anemia ( eg , hydrops fetalis). Mild to moderate disease  — Less severely affected infants typically present with self-limited hemolytic disease, manifested as hyperbilirubinemia within the first 24 hours of life. They may also have symptomatic anemia ( eg , lethargy or tachycardia) but without signs of circulatory collapse. The degree of anemia varies depending upon the type of HDFN. Infants with ABO incompatibility generally have no or only minor anemia at birth. In contrast, infants with Rhesus (Rh) or some minor blood group incompatibilities can present with symptomatic anemia that requires red blood cell (RBC) transfusion. Hydrops fetalis  — Infants with severe life-threatening anemia ( eg , hydrops fetalis) present with skin edema, pleural or pericardial effusion, or ascites. Infants with Rh(D) and some minor blood group incompatibilities, such as Kell, are at risk for hydrops fetalis, especially pregnancies without antenatal care. ABO HDFN is generally less severe than that caused by the Rh and Kell systems; however, there are case reports of hydrops fetalis due to ABO incompatibility [ 3 ]. Neonates with hydrops fetalis may present at delivery with shock or near shock and require emergent transfusion.

20. Postnatal diagnosis  HDFN is clinically suspected when the following two criteria are fulfilled when a diagnosis has not been made antenatally: ●Demonstration of incompatible blood types between the infant and mother. The most common incompatibilities are: •Rhesus D (Rh[D]) positive infant born to an Rh(D)-negative mother •Group 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 HDFN include decreased number of red blood cells (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 [ 9 ]. Microspherocytosis (due to partial membrane loss) is commonly seen in the peripheral smear of infants with ABO alloimmune HDFN, but it is generally not seen in infants with Rh disease.

21. DIFFERENTIAL DIAGNOSIS The differential diagnosis for HDFN includes other causes of neonatal jaundice and hemolytic anemia. HDFN is differentiated from the following disorders by the presence of a positive direct or indirect antiglobulin test (DAT/IAT; Coombs test). These disorders can occur concomitantly in an infant with HDFN. Hyperbilirubinemia may be particularly severe in infants with more than one cause of hyperbilirubinemia. The differential diagnosis of unconjugated hyperbilirubinemia and/or anemia during the neonatal period includes the following disorders. Additional characteristics and diagnostic steps are discussed in separate topic reviews: ●Erythrocyte membrane defects – The peripheral blood smear and the negative antiglobulin tests distinguish the inherited erythrocyte membrane defects, such as hereditary spherocytosis [ 19 ] or elliptocytosis, from HDFN. ●Erythrocyte enzyme defects – Enzyme assays confirm the diagnosis of erythrocyte enzyme defects, such as glucose-6-phosphate dehydrogenase (G6PD) or pyruvate kinase deficiencies. For patients with G6PD deficiency, the peripheral blood smear reveals microspherocytes , eccentrocytes or "bite cells," and "blister cells" with hemoglobin puddled to one side. ●Gilbert syndrome – Gilbert syndrome is the most common inherited disorder of bilirubin glucuronidation. It results from a mutation in the promoter region of the  UGT1A1  gene causing a reduced production of UGT, which leads to unconjugated hyperbilirubinemia. A normal hematocrit, reticulocyte count, and peripheral blood smear distinguish this disorder from HDFN.

22. Management The postnatal management for HDFN is dependent on both the severity of anemia and hyperbilirubinemia: ●For infants with HDFN with shock or pending shock due to severe anemia (hydrops fetalis), we recommend emergent transfusion using group O, Rh(D)-negative red blood cells (RBCs) versus cross-matched RBCs. ●For infants who have early moderate to severe symptomatic anemia without signs of circulatory compromise, we recommend a transfusion with cross-matched RBCs. Selection of RBCs for transfusion depends on the type of HDFN. In these patients, the choice between exchange and simple transfusion is based upon the following considerations : •If an infant has findings suggestive of acute bilirubin encephalopathy (ABE) and hyperbilirubinemia, we recommend an exchange transfusion be performed. •If an infant has severe anemia and hyperbilirubinemia without signs of ABE, we suggest performing an exchange transfusion for hematocrit <25 percent or based upon the bilirubin threshold levels as outlined by the American Academy of Pediatrics (AAP). •If the hyperbilirubinemia is not severe and the symptoms of anemia are moderate, we suggest performing a simple transfusion. •A simple transfusion may be performed if there is a delay in performing an exchange transfusion.

23. ●If hyperbilirubinemia is not severe and the symptoms of early anemia are mild, but the infant is at risk for late anemia, we suggest administering darbepoetin and iron .Recombinant erythropoietin ( rhEPO ) is a reasonable alternative but requires more frequent dosing. ●For infants with late-onset symptomatic anemia, we suggest simple transfusion of cross-matched blood rather than no intervention. ●Management of hyperbilirubinemia due to HDFN includes monitoring serum bilirubin levels, oral hydration, and phototherapy, which is based on the criteria outlined by the AAP. For infants who do not respond to conventional measures, intravenous (IV) fluid supplementation, intravenous  immune globulin  (IVIG), and exchange transfusion may be used.

24. END