HEMOLYTIC DISEASE OF NEWBORN

Hemolytic Disease of Newborn
A French midwife was the first to report hemolytic disease of the newborn (HDN) in a set of twins in 1609. In 1932, Diamond and colleagues described the relationship of fetal hydrops, jaundice, anemia, and erythroblasts in the circulation, a condition later called erythroblastosis fetalis. Levine later determined the cause after Landsteiner and Weiner discovered the Rh blood group system in 1940. In 1953, Chown subsequently confirmed the pathogenesis of Rh alloimmunization to be the result of passage of Rh-positive fetal red blood cells after transplacental hemorrhage into maternal circulation that lacked this antigen.

Pathophysiology: Although the Rh antibody was and still is the most common cause of severe HDN, other alloimmune antibodies belonging to Kell (K and k), Duffy (Fya), Kidd (Jka and Jkb), and MNSs (M, N, S, and s) systems do cause severe HDN. Rh blood group antigens are determined by at least 2 homologous but distinct membrane-associated proteins. Two separate genes located on chromosome 1 encode Rh proteins. Rh-negative phenotype represents absence of D protein on RBCs and results from deletion of the RHD gene on both chromosomes. Rh antigens exist in 3 loci: Cc, Dd, and Ee. Expression is limited to RBCs, with an increasing density during their maturation, unlike the ABH system, which exists in a wide variety of tissues. Rh antigen is not expressed on RBC progenitors. Of individuals who are Rh positive, 45% are homozygous and 55% are heterozygous.

Frequency of Rh negativity is higher in whites (15%) than in blacks (5%), and it is rare in Asians. The paternal heterozygosity determines the likelihood of an Rh-positive child being born to an Rh-negative mother. The Kleihauer-Betke acid elution technique that determines the proportion of fetal RBCs in maternal circulation has shown the incidence of fetomaternal hemorrhage to be 75% of all pregnancies. Incidence and degree of such hemorrhage appears to increase with gestation. Risk is also increased in pregnancies complicated by placental abruption, spontaneous or therapeutic abortion, and toxemia, as well as after cesarean delivery and ectopic pregnancy.

Procedures such as amniocentesis, chorionic villus sampling, and cordocentesis also increase the risk of alloimmunization. Because in most pregnancies the transplacental hemorrhage is less than 0.1 mL, most women are sensitized as a result of small undetectable fetomaternal hemorrhage.

After the initial exposure to a foreign antigen, the maternal immune system produces antibodies of the immunoglobulin M (IgM) isotype that do not cross the placenta, and later it produces antibodies of the IgG isotype that traverse the placental barrier. This is termed the primary response, and it is dose dependent (documented in 15% of pregnancies with 1 mL of Rh-positive cells in an Rh-negative individual versus 70% of pregnancies after 250 mL). A repeat exposure to the same antigen rapidly induces the production of IgG. This secondary immune response can be induced with as little as 0.03 mL of Rh-positive RBCs.

Risk of Rh immunization after delivery of the first child to a nulliparous Rh-negative mother is 16% if the Rh-positive fetus is ABO compatible with its mother, 2% if ABO incompatible, and 2-5% after an abortion. The ABO-incompatible RBCs are rapidly destroyed in the maternal circulation, reducing the likelihood of exposure to the immune system. The degree of Rh sensitization of the mother is directly related to the amount of fetomaternal hemorrhage (ie, 3% with <0.1 mL versus 22% with >0.1 mL).

After sensitization, maternal anti-D antibodies cross the placenta into fetal circulation and attach to Rh antigen on fetal RBCs, which form rosettes on macrophages in the reticuloendothelial system, especially in the spleen. These antibody-coated RBCs are lysed by lysosomal enzymes released by macrophages and natural killer lymphocytes, and they are independent of the activation of the complement system.

Prolonged hemolysis leads to severe anemia, which stimulates fetal erythropoiesis in liver, spleen, bone marrow, and extramedullary sites, such as skin and placenta. In severe cases, this can lead to displacement and destruction of hepatic parenchyma by erythroid cells, resulting in dysfunction and hypoproteinemia. Destruction of RBCs releases heme that is converted to unconjugated bilirubin. Hyperbilirubinemia becomes apparent only in the delivered newborn because the placenta effectively metabolizes bilirubin. HDN due to Kell sensitization results in hemolysis and suppression of erythropoiesis because the Kell antigen is expressed on the surface of erythroid progenitors.

Hemolysis associated with ABO incompatibility is limited to type O mothers with fetuses who have type A or B blood. In mothers with type A and B blood, naturally occurring antibodies are of IgM class, which do not cross the placenta, whereas in type O mothers, the antibodies are predominantly IgG in nature. Because A and B antigens are widely expressed in a variety of tissues besides RBCs, only small portion of antibodies crossing the placenta is available to bind to fetal RBCs. In addition, fetal RBCs appear to have less surface expression of A or B antigen, resulting in few reactive sites—hence the low incidence of significant hemolysis in affected neonates.

Frequency: In the US: Before the establishment of modern therapy, 1% of all pregnant women developed Rh alloimmunization. Since the advent of routine prophylaxis of at-risk women, incidence of Rh sensitization is reduced to 11 cases per 10,000 births with less than 10% requiring intrauterine transfusion. Alloimmunization due to Kell antigen accounts for 10% of severely affected fetuses. ABO incompatibility frequently occurs during the first pregnancy and is present in approximately 12% of pregnancies, with evidence of fetal sensitization in 3% of live births. Fewer than 1% of births are associated with significant hemolysis.

Mortality/Morbidity: Nearly 50% of the affected newborns do not require treatment. Approximately 25% are born near term but become extremely jaundiced without treatment and either die (90%) or become severely affected by kernicterus (10%). The remaining 25% of affected newborns are severely affected in utero and become hydropic; about half of newborns are affected before 34 weeks' gestation, and the other half are affected between 34 weeks' gestation and term. Before any interventions were available, the perinatal mortality rate was 50%. Wallerstein introduced exchange transfusion in 1945 and reduced the perinatal mortality rate to 25%. Later, Chown suggested the early delivery of those severely affected nonhydropic fetuses by 34 weeks' gestation followed by prompt exchange transfusion, and the mortality rate was further reduced to the current rate of 16%.