Red Cell Alloimmunization Chapter 34 KeNNeth J. MOISe Jr Nomenclature 770 Indications 774 Hemolytic Disease of the Fetus Historic Perspectives 770 Diagnostic Methods 776 and Newborn Due to Non-RhD Incidence 771 Clinical Management 778 Antibodies 781 Pathophysiology 771 First Affected Pregnancy 778 Rhc 781 Rhesus Alloimmunization and Fetal/ Previously Affected Fetus or Infant 778 RhC, RhE, and Rhe 782 Neonatal Hemolytic Disease of the Intrauterine Transfusion 778 Duffy 782 Newborn 772 Technique 778 Kidd 782 Genetics 772 Complications and Outcome 780 Kell 782 Prevention of RhD Hemolytic Disease Neonatal Transfusions 780 in the Fetus and Newborn 773 Neurologic Outcome 780 History 773 Other Treatment Modalities 780 Preparations 773 Future Therapeutic Options 781 KEY ABBREVIATIONS these antibodies across the placenta during pregnancy results in fetal anemia, hyperbilirubinemia, and ultimately hydrops American Association of Blood Banks AABB fetalis. Before the advent of obstetric ultrasound, the perinatal American College of Obstetricians and ACOG effects of maternal red cell alloimmunization could be recog- Gynecologists nized only after birth in the affected neonate. Thus the neonatal Cytomegalovirus CMV consequences of maternal red cell alloimmunization came to be Circulating cell-free fetal DNA ccffDNA known as hemolytic disease of the newborn (HDN). Because the Deoxyribonucleic acid DNA peripheral blood smear of these infants demonstrated a large Diphosphatidylglycerol DPG percentage of circulating immature red cells known as erythro­ Fetal blood sampling FBS blasts, the newborn entity was also known as erythroblastosis Fetomaternal hemorrhage FMH fetalis. Today, ultrasound and fetal blood sampling (FBS) make Grams per deciliter g/dL the detection of the severely anemic fetus a reality. For this Hemolytic disease of the fetus and HDFN reason, the term hemolytic disease of the fetus and newborn newborn (HDFN) would appear more appropriate to describe this Hemolytic disease of the newborn HDN disorder. Intraperitoneal transfusion IPT International unit(s) IU Intrauterine transfusion IUT HISTORIC PERSPECTIVES Intravascular transfusion IVT The first case of HDFN was probably described by a midwife Intravenous immune globulin IVIG in 1609 in the French literature: a twin gestation in which the Kleihauer-Betke KB first fetus was stillborn and the second twin developed jaundice Middle cerebral artery MCA and died soon after birth.1 In 1932, Diamond2 proposed that Microgram µg the clinical entities of erythroblastosis fetalis, icterus gravis neo- Rhesus immune globulin RhIG natorum, and hydrops fetalis represented different manifesta- Single nucleotide polymorphisms SNPs tions of the same disease. Seven years later, Levine and Stetson3 described an antibody in a woman who gave birth to a stillborn fetus. The patient experienced a severe hemolytic transfusion reaction after later receiving her husband’s blood. In 1940, Landsteiner and Weiner4 injected red blood cells from rhesus NOMENCLATURE monkeys into rabbits. The antibody isolated from these rabbits Exposure to foreign red cell antigens invariably results in the was used to test human blood samples from whites, and agglu- production of anti–red cell antibodies in a process known as tination was noted in 85% of individuals. The following year red cell alloimmunization, formerly termed isoimmuniza- Levine and colleagues5 were able to demonstrate a causal rela- tion. The expression sensitization can be used interchange- tionship between Rhesus D (RhD) antibodies in RhD-negative ably with Rhesus alloimmunization. The active transport of women and HDFN in their offspring. 770 Chapter 34 Red Cell Alloimmunization 771 The advent of therapy for HDFN began in 1945 with the 35 description by Wallerstein6 of the technique of neonatal exchange 7 transfusion. Later Liley proposed the use of amniotic fluid bili- 30 31 rubin assessment as an indirect measure of the degree of fetal hemolysis. Sir William Liley’s major contribution to the story of rhesus disease was the introduction of the fetal intraperitoneal 25 transfusion (IPT).8 He learned from a visiting fellow who had 24 returned from Africa that the infusion of red blood cells into the 20 peritoneal cavity of children with sickle-cell disease produced 19 normal-appearing red blood cells on peripheral blood smear. 15 Liley realized that he had previously inadvertently entered the Percentage 15 peritoneal cavity of fetuses at the time of amniocentesis, based 10 on the marked contrast in the yellow hue of the ascitic fluid as 10 compared with amniotic fluid. He postulated that purposeful entry into the fetal peritoneal cavity could be accomplished. 5 After three unsuccessful attempts that resulted in fetal demises, 1/7 the fourth fetus was delivered at 34 weeks’ gestation after 0 undergoing two successful IPTs. Early attempts at IPT used EMDKC fluoroscopy for needle guidance. With the introduction of real- FIG 34-1 Incidence of maternal anti–red cell antibodies associated with time ultrasound in the early 1980s, IPT became a safer proce- hemolytic disease of the fetus and newborn (HDFN) at a tertiary care dure as fluoroscopy was abandoned. Charles Rodeck9 is credited institution between 2007 and 2011. E, M, D, K, and C are antibodies. with the first intravascular fetal transfusion (IVT) using a feto- (Modified from Smith HM, Shirey RS, Thoman SK, Jackson JB. Preva- lence of clinically significant red blood cell alloantibodies in pregnant scope to guide the transfusion needle into a placental plate women at a large tertiary care facility. Immunohematology. 2013;29: vessel. Just 1 year later, investigators in Denmark performed the 127-130.) first ultrasound-guided IVT using the intrahepatic portion of the umbilical vein.10 thought. In this paradigm, maternal RhD-positive red cells gain The 1990s saw the introduction of genetic techniques using access to the circulation of the RhD-negative fetus at the time amniocentesis to determine fetal red cell typing.11 The turn of of delivery. As many as one fourth of RhD-negative babies the century brought the noninvasive detection of fetal anemia have been shown to be immunized in early life as a result through Doppler ultrasound of the fetal middle cerebral artery of their delivery.16,17 The immune response of an Rh-negative (MCA) and the use of fetal typing through cell-free DNA in individual to RhD-positive red cells has been characterized into maternal plasma.12,13 one of three groups: (1) responders, (2) hyporesponders, and (3) nonresponders. About 60% to 70% of individuals are responders who develop an antibody to relatively small volumes INCIDENCE of red cells; in these individuals, the probability of immunization The advent of the routine administration of antenatal and increases with escalating volumes of cells. A small percentage of postpartum rhesus immune globulin (RhIG) has resulted in responders can be called hyperresponders in that they will be a marked reduction in cases of red cell alloimmunization immunized by very small quantities of red cells. The second secondary to the RhD antigen. The Centers for Disease Control group of individuals (10% to 20%), hyporesponders, can be and Prevention (CDC) last required the reporting of rhesus immunized only by exposure to very large volumes of cells. alloimmunization as a medical complication of pregnancy on Finally, the 10% to 20% of individuals who remain appear to U.S. birth certificates in the year 2002.14 In that year, the most be nonresponders. recent for which epidemiologic data are available, the incidence In most cases of red cell alloimmunization, a fetomaternal was reported to be 6.7 cases of rhesus alloimmunization per hemorrhage (FMH) occurs in the antenatal period or, more 1000 live births. commonly, at the time of delivery. If a maternal ABO blood Clearly, a shift to other red cell antibodies associated type incompatibility exists between the mother and her fetus, with HDFN has occurred as a result of the decreasing inci- anti-A and/or anti-B antibodies lyse the fetal cells in the mater- dence of RhD alloimmunization. In a series of over 8000 nal circulation and destroy the RhD antigen.18,19 Even if this pregnant patients between 2007 and 2011, a positive screen protective effect is not present,only 13% of deliveries of RhD- for an antibody associated with HDFN was found in 1.2% of positive fetuses result in RhD alloimmunization in RhD- samples.15 Anti-E was the most common antibody encountered; negative women who do not receive RhIG. The vast majority RhD antibody accounted for only 19% of the significant anti- of RhD-alloimmunized women produce an immunoglobulin G bodies (Fig. 34-1). (IgG) response as their initial antibody. Responders may represent a group of individuals who had their initial exposure to the RhD antigen at birth because of FMH.17 After a sensitizing event, PATHOPHYSIOLOGY the human antiglobulin anti-D titer can usually be detected after Although the placenta was once thought to be an absolute 5 to 16 weeks. However, approximately half of alloimmunized barrier to the transfer of cells between the maternal and fetal patients are sensibilized. In this scenario, an antibody screen will compartments, we now appreciate that the placental interface be negative, but memory B lymphocytes are present that can allows for the bidirectional movement of both intact cells and create an anti-D antibody response. When faced with the chal- free DNA. The putative “grandmother theory” of rhesus red cell lenge of a subsequent pregnancy involving an RhD-positive alloimmunization probably occurs more commonly than first fetus, the anti-D titer becomes detectable. 772 Section V Complicated Pregnancy Chapter 34 Red Cell Alloimmunization The anti-D immune response is the best characterized of the 1p34 anti–red cell antibodies associated with HDFN. In one third of D gene CE gene cases, only subclass IgG1 is produced; in the remainder of cases, 20 D gene CE gene a combination of IgG1 and IgG3 subclasses is found. Anti-D Homozygous IgG is a nonagglutinating antibody that does not bind com- RhD Positive plement.