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Alloimmunization

What Is It, Causes, Treatment, and More

Author: Corinne Tarantino, MPH

Editors: Ahaana Singh , Ian Mannarino, MD, MBA

Illustrator: Jillian Dunbar

Copyeditor: Joy Mapes


What is alloimmunization?

Alloimmunization refers to an immune response to foreign antigens from another human, most commonly occurring after pregnancy or blood transfusions. In these cases, foreign cells that contain specific antigens, or proteins on the cell surface that can generate an immune response, are present in the body. When these antigens are detected, white blood cells produce antibodies, which signal the immune system to destroy the foreign cell containing the antigen. Usually, this process protects the body against harmful foreign organisms, like bacteria. However, when this occurs in response to another human’s blood products, it is called alloimmunization and may result in serious complications. 

Individuals have various blood types that are classified based on the antigens present on the red blood cells (RBCs). These blood types are classified in accordance with the ABO and Rhesus (Rh) blood group systems. The four blood groups in the ABO system are A, B, AB, and O, which indicate the presence or absence of the A and B antigens on the RBCs. Meanwhile, the Rh system includes approximately 50 antigens that cross the membrane of RBCs. The D antigen is the most frequently tested antigen. Therefore, Rh negative (Rh-) usually refers to RBCs lacking the D antigen, and Rh positive (Rh+) refers to those having the D antigen. A blood type may take both ABO and Rh systems into account. For example, AB+ would indicate the presence of A, B and D antigens on a person’s RBCs.

The immune system responds to the presence of foreign antigens, or any antigens that are not present on their own RBCs, by producing antibodies. Antibodies have several important functions in the immune system, including inactivating the target antigen or marking the antigen for destruction. There are several types of antibodies, which have different shapes and functions. The most common antibodies in blood are Immunoglobulin M (IgM), which is the largest, and Immunoglobulin G (IgG), the smallest. Antibodies to A and B antigens are often produced naturally in the plasma of adults who lack the specific antigen on their own RBCs. This occurs because humans are often exposed to bacterial antigens that are similar to that of A and B antigens. In contrast, Rh antigen exposure generally occurs only  during pregnancy or blood transfusions, which can then lead to alloimmunization.

What is alloimmunization in pregnancy?

Alloimmunization may occur in pregnancy when the pregnant individual and their fetus have different blood types

ABO incompatibility occurs during pregnancy when the mother lacks an A or B antigen on their RBCs, while the fetal blood cells have that specific antigen. This can occur because the fetus would have inherited the opposing blood type from their father. This is unlikely to cause major problems for the baby or mother because the mother produces IgM antibodies which cannot cross the placenta, the organ which provides nutrients to the fetus and separates the fetal and maternal blood. Therefore, the IgM antibodies will protect the mother without harming the baby. 

Rh incompatibility most commonly occurs when the mother is Rh negative (Rh-) and has an Rh positive (Rh+) fetus. When an Rh- mother is exposed to an Rh+ baby during a delivery, the mother’s immune system will develop IgG antibodies. During a second pregnancy with an Rh- baby, the existing antibodies in the mother can cross the placenta and attack the fetuses' RBCs, causing them to burst in a phenomenon known as hemolysis

Alloimmunization during pregnancy may result in a hemolytic disease of the fetus and newborn. The effect of hemolysis on the fetus varies based on the proportion of antibodies in the mother’s blood. When there are few antibodies in the mother, the baby may develop a mild anemia, which is characterized by a decreased number of red blood cells, resulting in less oxygen delivered throughout the body. This may last for two to three months after birth. In severe cases, however, hemolysis may result in a life-threatening condition called “hydrops fetalis” that causes severe swelling in the fetus. After birth, hemolytic disease of the newborn may result in severe anemia or severe jaundice. Symptoms of severe anemia in infants can include pale skin, low energy, or congestive heart failure, while jaundice is a yellow discoloration of the skin from decreased liver function. If a first pregnancy is affected by alloimmunization, future pregnancies have an increased likelihood of developing more severe disease earlier in the pregnancy.

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How common is fetomaternal alloimmune thrombocytopenia?

Fetomaternal alloimmune thrombocytopenia (FMAIT) is a rare condition that occurs when the mother’s immune system attacks the fetus’s platelets, the small cell fragments used for blood clotting. The cause of FMAIT is similar to alloimmunization of RBCs. If the fetal platelets have different antigens from the mother, then the mother’s immune system will make antibodies against those antigens, causing fetal platelet destruction. Due to the reduction in platelets, known as thrombocytopenia, the fetus will have an increased risk for bleeding. As the pregnancy progresses, or during future pregnancies, the thrombocytopenia will generally worsen, with the condition becoming more severe with each subsequent fetus. A fetus with thrombocytopenia may experience severe bleed in the brain (i.e., intracranial hemorrhage) after 20 weeks. A newborn with thrombocytopenia may demonstrate some signs of bleeding, such as small red dots on the skin called “petechiae.” After about 4 weeks, the platelet count for the infant should increase into a normal range, and the bleeding symptoms should stop.

What is alloimmunization in blood transfusion?

In blood transfusions, a common procedure in which a person receives blood donated by another person through an intravenous (IV) line, antibodies may develop in the recipient against the blood donor’s RBC antigens. The process for alloimmunization due to blood transfusion is similar to exposure of pregnant mothers to their infants. The more blood transfusions received, the greater the risk for alloimmunization reactions to occur. Alloimmunization in blood transfusions may result in an acute (immediate) or delayed hemolytic transfusion reaction that presents with several symptoms, including fever, chills, backaches or headaches, shortness of breath, and increased heart rate. Transfusion reactions can cause significant clinical problems, such as development of blood clots in different parts of the body (i.e., disseminated intravascular coagulation) and acute kidney failure. The most severe reactions result from ABO incompatibility, but Rh incompatibility is more common. 

Is there a difference between alloimmunization and isoimmunization?

No, there is no difference between alloimmunization and isoimmunization. The terms are often used interchangeably when referring to alloimmunization during pregnancy, particularly regarding the Rh factor.

How is alloimmunization diagnosed?

The first step for diagnosis of alloimmunization is assessment of a person’s medical history and any signs or symptoms. In addition, there are several types of diagnostic tests for alloimmunization, most involving blood samples. The test used varies depending on the individual’s current condition. Only antibodies for the ABO and Rh antigens are routinely tested, but there are other blood antigens that may rarely cause alloimmunization. 

During pregnancy, a maternal antibody screening may be conducted to determine if the mother has developed any antibodies to the fetus’ antigens. Additionally, ultrasounds may help to diagnose conditions associated with alloimmunization during pregnancy, such as hydrops fetalis.

After birth, newborns of mothers with confirmed alloimmunization will be assessed for signs and symptoms of anemia, like pale skin. If newborns present with symptoms or have a mother with a different blood type, screenings may be conducted to accurately diagnose which antibodies are present.

Individuals who receive a blood transfusion will be monitored for an acute hemolytic transfusion reaction, which presents with fever and chills. If they demonstrate signs and symptoms of a reaction to the transfusion, an antibody screening may be conducted to diagnose alloimmunization

How is alloimmunization treated?

Treatment for alloimmunization will vary depending on the cause and severity of the reaction. In mild cases, a newborn may only be monitored for signs of heart problems, such as sudden sweating or shortness of breath. Occasionally, a newborn with a mild anemia may be provided iron supplementation.

In cases of severe anemia during early pregnancy, generally before 24 weeks, IV immunoglobulin or steroids may be administered. Later in pregnancy, an intrauterine blood transfusion may be performed. A blood transfusion may also be required after birth. 

When alloimmunization occurs during a blood transfusion, the transfusion should immediately be stopped, and a blood sample should be drawn to test for a new blood donor match. The individual should be continuously hydrated but may also require treatment with mannitol, a type of sugar alcohol that can increase urination and prevent water retention in the lungs.

How can you prevent alloimmunization?

For pregnant individuals who are RhD negative, formation of antibodies to D antigen can be prevented by giving them anti-D immune globulin (RhoGAM) in the third trimester. This will clear the RhD positive red blood cells from the body before delivery of the baby, when exposure to the D antigen would otherwise occur.

To prevent alloimmunization during a transfusion, several screening tests should be performed. The initial blood test screening will check for the individual’s blood type and antibodies. If the antibody screen is positive, further testing may occur to determine the particular antibodies that are present within the person’s blood. Then the individual who requires a transfusion will be matched to a donor’s blood that is the same blood type and does not contain the specific antigens the recipient has antibodies against. This screening process will minimize the risk of alloimmunization during future blood transfusions.

What are the most important facts to know about alloimmunization?

Alloimmunization is a response by an individual’s immune system to foreign human antigens that most frequently occurs during pregnancy or blood transfusions. During pregnancy, alloimmunization is most common when the fetus and mother have different Rh blood types. Alloimmunization during pregnancy may result in a hemolytic disease of the fetus and newborn, during which the fetus or newborn’s red blood cells burst, causing anemia and, in severe cases, fetal death. Rarely, fetomaternal alloimmune thrombocytopenia (FMAIT) may occur. In the case of FMAIT, the fetus or infant’s immune system attacks cells involved in blood clotting instead of red blood cells, thereby increasing the risk of bleeding. With blood transfusions, alloimmunization may cause an immediate reaction from blood type incompatibility. Alloimmunization may be diagnosed based upon signs and symptoms of a reaction, ultrasounds during pregnancy, or blood sample antibody testing. Treatment generally depends on the underlying cause and severity. Prevention may include providing anti-D immune globulin to RhD negative individuals who are pregnant with an RhD positive fetus and by matching blood types between donors and recipients prior to blood transfusions. 

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Related links

Routine prenatal care: Clinical practice
Blood groups and transfusions
Hemolytic disease of the newborn
Blood products and transfusion: Clinical practice

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