What is the pathophysiology of hemolytic disease of the newborn (HDN)?

Updated: Dec 28, 2017
  • Author: Sameer Wagle, MBBS, MD; Chief Editor: Muhammad Aslam, MD  more...
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Answer

The exposure of the Rh-negative mother to Rh-positive red cells occurs as a result of asymptomatic fetomaternal hemorrhage during pregnancy. 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. Fetomaternal hemorrhage has been documented in 7%, 16%, and 29% of mothers during their first, second and third trimesters, respectively. 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 the transplacental hemorrhage is less than 0.1 mL in most pregnancies, most women are sensitized as a result of small, undetectable fetomaternal hemorrhage.

After the initial exposure to a foreign antigen, B-lymphocyte clones that recognize the RBC antigen are established. The maternal immune system initially produces antibodies of the immunoglobulin M (IgM) isotype that do not cross the placenta and later produces antibodies of the IgG isotype that traverse the placental barrier. Predominant antibody subclass appears to be IgG1 in one third of individuals whereas a combination of IgG1 and IgG3 subclasses are found in the remaining individuals.

IgG3 is more efficient in binding to reticuloendothelial cells and causing hemolysis because of its longer hinge region. This is termed the primary response and is dose dependent (documented in 15% of pregnancies with 1 mL of Rh-positive cells in an Rh-negative individual compared with 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.

Findings from murine models appear to support a potential role for epitope masking, immune deviation and/or antigen modulation in the mechanism of action of IgG-mediated inhibition of erythrocyte alloimmunization. [7]  Moreover, blends of monoclonal antibodies targeting nonoverlapping epitopes on the RBC surface may have the potential to improve the efficacy of monoclonal antibodies approaching that of polyclonal IgG.

The risk of Rh immunization after the 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 the fetus is 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 compared with 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 are independent of the activation of the complement system.

Reticulocytosis is noted when fetal Hb deficit exceeds 2 gm/dl compared with gestational age norms. Tissue hypoxia develops as fetal anemia becomes severe. When the hemoglobin (Hb) level drops below 8 g/dL, a rise in umbilical arterial lactate occurs. When the Hb level drops below 4g/dL, increased venous lactate is noted. Hydrops fetalis occurs when fetal Hb deficit exceeds 7 g/dL and starts as fetal ascites and evolves into pleural effusions and generalized edema. The various mechanisms responsible for hydrops are hypoalbuminemia secondary to depressed liver function, increased capillary permeability, iron overload secondary to hemolysis, and increased venous pressures due to poor cardiac function. [8]


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