Hemolytic disease of the newborn


Hemolytic disease of the newborn, also known as hemolytic disease of the fetus and newborn, HDN, HDFN, or erythroblastosis foetalis, is an alloimmune condition that develops in a fetus at or around birth, when the IgG molecules produced by the mother pass through the placenta. Among these antibodies are some which attack antigens on the red blood cells in the fetal circulation, breaking down and destroying the cells. The fetus can develop reticulocytosis and anemia. This fetal disease ranges from mild to very severe, and fetal death from heart failure can occur. When the disease is moderate or severe, many erythroblasts are present in the fetal blood, and so these forms of the disease can be called erythroblastosis fetalis.
HDFN represents a breach of immune privilege for the fetus or some other form of impairment of the immune tolerance of pregnancy. Various types of HDFN are classified by which alloantigen provokes the response. In order of incidence, the types include ABO, anti-RhD, anti-RhE, anti-Rhc, anti-Rhe, anti-RhC, multiantigen combinations, and anti-Kell.

Signs and symptoms

Signs of hemolytic disease of the newborn include a positive direct Coombs test, elevated cord bilirubin levels, and hemolytic anemia. It is possible for a newborn with this disease to have neutropenia and neonatal alloimmune thrombocytopenia as well. Hemolysis leads to elevated bilirubin levels. After delivery bilirubin is no longer cleared from the neonate's blood and the symptoms of jaundice increase within 24 hours after birth. Like other forms of severe neonatal jaundice, there is the possibility of the neonate developing acute or chronic kernicterus, however the risk of kernicterus in HDN is higher because of the rapid and massive destruction of blood cells. It is important to note that isoimmunization is a risk factor for neurotoxicity and lowers the level at which kernicterus can occur. Untreated profound anemia can cause high-output heart failure, with pallor, enlarged liver and/or spleen, generalized swelling, and respiratory distress.
HDN can be the cause of hydrops fetalis, an often-severe form of prenatal heart failure that causes fetal edema.

Complications

Complications of HDN could include kernicterus, hepatosplenomegaly, inspissated bile syndrome and/or greenish staining of the teeth, hemolytic anemia and damage to the liver due to excess bilirubin. Conditions that may cause similar symptoms in the newborn period include: acquired hemolytic anemia, congenital toxoplasma, congenital syphilis infection, congenital obstruction of the bile duct, and cytomegalovirus infection.
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, the IgG will target the antigen, if present in the fetus, and may affect it in utero and persist after delivery. The three most common models in which a woman becomes sensitized toward 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, 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. 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 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, that 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, Rhesus antibodies are generally not produced from exposure to environmental antigens. 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.

Antibody specific

The diagnosis of HDN is based on history and laboratory findings:
Blood tests done on the newborn baby
Blood tests done on the mother
Blood tests done on the father
Types of HDN are classified by the type of antigens involved. The main types are ABO HDN, Rhesus HDN, Kell HDN, and other antibodies. ABO hemolytic disease of the newborn can range from mild to severe, but generally it is a mild disease. It can be caused by anti-A and anti-B antibodies. Rhesus D hemolytic disease of the newborn is the most common form of severe HDN. Rhesus c hemolytic disease of the newborn can range from a mild to severe disease – is the third most common form of severe HDN. Rhesus e and rhesus C hemolytic disease of the newborn are rare. Combinations of antibodies, for example, anti-Rhc and anti-RhE occurring together can be especially severe.
Anti-Kell hemolytic disease of the newborn is most commonly caused by anti-K 1 antibodies, the second most common form of severe HDN. Over half of the cases of anti-K 1 related HDN are caused by multiple blood transfusions. Antibodies to the other Kell antigens are rare.

Prevention

In cases of Rho incompatibility, Rho immunoglobulin is given to prevent sensitization. However, there is no comparable immunotherapy available for other blood group incompatibilities.
Early pregnancy
Mid- to late- pregnancy
Rhesus-negative mothers who are pregnant with a rhesus-positive infant are offered Rho immune globulin at 28 weeks during pregnancy, at 34 weeks, and within 48 hours after delivery to prevent sensitization to the D antigen. It works by binding any fetal red blood cells with the D antigen before the mother is able to produce an immune response and form anti-D IgG. A drawback to pre-partum administration of RhIG is that it causes a positive antibody screen when the mother is tested, which can be difficult to distinguish from natural immunological responses that result in antibody production. Without Rho immunoglobulin, the risk of isoimmunization is approximately 17%; with proper administration the risk is reduced to less than 0.1–0.2%.

After birth testing

In some cases, the direct Coombs will be negative but severe, even fatal HDN can occur. An indirect Coombs needs to be run in cases of anti-C, anti-c, and anti-M. Infants with Anti-M are also recommended to receive antigen testing to rule out the presence of HDN. The below tests are often useful in cases of hemolytic disease of the newborn, but are not required for treatment of all newborns.
After birth, treatment depends on the severity of the condition, but could include temperature stabilization and monitoring, phototherapy, transfusion with compatible packed red blood, exchange transfusion, sodium bicarbonate for correction of acidosis and/or assisted ventilation.
Once a woman has antibodies, she is at high risk for a future transfusion reaction if she is in need of a blood transfusion. For this reason, she must carry a medical alert card at all times and inform all doctors and emergency personnel of her antibody status. The absence of antibodies however does not preclude a woman from having a transfusion reaction:
"Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions. Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures."
For a summary of transfusion reactions in the US, see reference.

Epidemiology

In 2003, the incidence of Rh sensitization in the United States was 6.8 per 1000 live births; 0.27% of women with an Rh incompatible fetus experience alloimmunization.

Other animals

Hemolytic disease of the newborn is most commonly seen in kittens and foals. It has also been reported in puppies.