Antibodies are produced when the body is exposed to an
antigen foreign to the make-up of the body. If a mother is exposed to a foreign antigen and produces IgG (as opposed to
IgM which does not cross the placenta), the IgG will target the antigen, if present in the fetus, and may affect it
in utero and persist after delivery. However, the antibodies of the mother do not go away after the first incompatible pregnancy due to immunological memory. The maternal blood is likely to secrete more antibodies and attack the fetal erythrocytes during subsequent pregnancies because of re-exposure to the antigen. The three most common models in which a woman becomes sensitized toward (i.e., produces IgG
antibodies against) a particular antigen are hemorrhage, blood transfusion, and ABO incompatibility.
Fetal-maternal hemorrhage, which is the movement of fetal blood cells across the placenta, can occur during
abortion,
ectopic pregnancy,
childbirth, ruptures in the
placenta during
pregnancy (often caused by trauma), or medical procedures carried out during pregnancy that breach the uterine wall. In subsequent pregnancies, if there is a similar incompatibility in the fetus, these antibodies are then able to cross the placenta into the fetal bloodstream to attach to the
red blood cells and cause their destruction (
hemolysis). This is a major cause of HDN, because 75% of pregnancies result in some contact between fetal and maternal blood, and 15–50% of pregnancies have hemorrhages with the potential for immune sensitization. The amount of fetal blood needed to cause maternal sensitization depends on the individual's immune system and ranges from 0.1 mL to 30 mL. The woman may have received a therapeutic
blood transfusion.
ABO blood group system and the D antigen of the
Rhesus (Rh) blood group system typing are routine prior to transfusion. Suggestions have been made that women of child-bearing age or young girls should not be given a transfusion with Rhc-positive blood or
Kell1-positive blood to avoid possible sensitization, but this would strain the resources of blood transfusion services, and it is currently considered uneconomical to screen for these blood groups. HDFN can also be caused by antibodies to a variety of other
blood group system antigens, but Kell and Rh are the most frequently encountered. The third sensitization model can occur in women of blood type O. The
immune response to A and B antigens, which are widespread in the environment, usually leads to the production of IgM or IgG anti-A and anti-B antibodies early in life. Women of blood type O are more prone than women of types A and B to making IgG anti-A and anti-B antibodies, and these IgG antibodies are able to cross the placenta. For unknown reasons, the incidence of maternal antibodies against type A and B antigens of the IgG type that could potentially cause hemolytic disease of the newborn is greater than the observed incidence of "ABO disease." About 15% of pregnancies involve a type O mother and a type A or type B child; only 3% of these pregnancies result in hemolytic disease due to A/B/O incompatibility. In contrast to antibodies to A and B antigens, production of Rhesus antibodies upon exposure to environmental antigens seems to vary significantly across individuals. In cases where there is ABO incompatibility and Rh incompatibility, the risk of alloimmunization is decreased because fetal red blood cells are removed from maternal circulation due to anti-ABO antibodies before they can trigger an anti-Rh response.
Rhesus D hemolytic disease of the newborn (often called Rh disease) is the most common and only preventable form of severe HDN. Since the introduction of Rho-D immunoglobulin, (
Rhogam, at 1968, which prevents the production of maternal Rho-D antibodies, the incidence of anti-D HDN has decreased dramatically.
Rhesus c HDFN can range from a mild to severe disease and is the third most common form of severe HDN. Rhesus e and rhesus C hemolytic disease of the newborn are rare. Anti-C and anti-c can both show a negative DAT but still have a severely affected infant. An indirect Coombs must also be run.
Anti-Kell hemolytic disease of the newborn is most commonly caused by anti-K1 antibodies, the second most common form of severe HDN. Over half of the cases of anti-K1 related HDN are caused by multiple blood transfusions. Antibodies to the other Kell antigens are rare. It suppresses the bone marrow by inhibiting the erythroid progenitor cells. Anti-M also recommends antigen testing to rule out the presence of HDN as the direct coombs can come back negative in a severely affected infant. Kidd antigens are also present on the endothelial cells of the kidneys. One study states that it would be unwise to routinely dismiss anti-E as being of little clinical consequence. It also found that the most severe case of anti-E HDFN occurred with titers 1:2, concluding that titers are not reliable for the diagnosis of the anti-E type. ==Diagnosis==