Isoimmunization, or alloimmunization, is an immune reaction where a person produces antibodies against foreign antigens from the same species. In pregnancy, this occurs when the mother’s immune system recognizes specific proteins on the surface of fetal red blood cells as foreign. This difference in blood type between the mother and the fetus can lead to the mother’s body creating antibodies to attack the fetal blood cells. These specialized antibodies can cross the placenta and potentially cause serious health problems for the developing fetus and newborn.
The Sensitization Process
The process of isoimmunization begins with a sensitizing event, which allows fetal red blood cells to enter the mother’s circulation. This transfer of blood, called fetomaternal hemorrhage, most commonly occurs during childbirth when the placenta separates from the uterine wall. However, it can also happen during trauma to the abdomen, invasive prenatal procedures like amniocentesis, miscarriage, or ectopic pregnancy.
When fetal red blood cells enter the mother’s bloodstream, her immune system recognizes the antigens as foreign and mounts an immune response, creating specialized antibodies. These antibodies are initially of the IgM type, which are generally too large to cross the placenta and therefore do not harm the current pregnancy.
Over time, or upon subsequent exposure, the immune system switches to producing smaller, more sustained IgG antibodies. The IgG class of antibodies is small enough to travel across the placenta from the mother to the fetus. If the mother becomes pregnant again with a fetus carrying the same foreign antigen, these circulating IgG antibodies will cross the placenta and begin to target the fetal red blood cells.
Major Types of Blood Incompatibility
Isoimmunization can be caused by incompatibilities in various blood group systems, but the Rh system is the most common and clinically significant. Rh incompatibility occurs when an Rh-negative mother carries an Rh-positive fetus, with the D antigen being the primary cause of the most severe cases. The widespread use of preventive measures for Rh incompatibility has led to other, non-Rh antigens becoming relatively more common causes of the condition.
Other clinically relevant non-Rh antigen systems can also trigger isoimmunization. These include antigens from the Kell, Duffy, and Kidd blood group systems. Anti-Kell antibodies, for instance, can be particularly harmful because they may destroy red blood cell precursors in the fetal bone marrow, not just mature red blood cells in circulation.
ABO incompatibility, where a mother with type O blood carries a fetus with type A, B, or AB blood, is the most frequent type of blood group mismatch. However, the antibodies produced in ABO incompatibility are often of the IgM type or have properties that prevent them from easily crossing the placenta. For this reason, ABO incompatibility is usually much less severe than Rh incompatibility and typically only causes mild symptoms after birth.
Consequences for the Fetus and Newborn
When maternal IgG antibodies cross the placenta and bind to the fetal red blood cells, they mark them for destruction, a process called hemolysis. This destruction leads to a condition known as Hemolytic Disease of the Fetus and Newborn (HDFN), which results in fetal anemia.
As the fetal body attempts to compensate for red blood cell loss, the liver and spleen may become enlarged, and the fetus may produce immature red blood cells. Severe, uncorrected anemia can lead to a state of high-output cardiac failure and a profound, life-threatening condition called Hydrops Fetalis. Hydrops is characterized by an abnormal accumulation of fluid in at least two different fetal body areas, such as the skin, chest, or abdomen.
After birth, the newborn continues to experience red blood cell destruction from the remaining maternal antibodies. The breakdown of red blood cells releases a substance called bilirubin, which the newborn’s immature liver may struggle to process and excrete. High levels of bilirubin in the bloodstream cause jaundice, a yellowing of the skin and eyes. If bilirubin levels become extremely elevated and are left untreated, it can cross the blood-brain barrier and cause a type of irreversible brain damage called kernicterus.
Prevention and Medical Management
The most significant advance in preventing Rh isoimmunization is the use of Rh Immunoglobulin, commonly known as RhoGAM or Anti-D immunoglobulin. This treatment is a concentrated dose of human anti-D antibodies administered to Rh-negative mothers. The injected anti-D antibodies bind to any Rh-positive fetal red blood cells that enter the mother’s circulation, clearing them before her immune system can recognize the antigen and produce long-lasting antibodies.
Standard prevention protocols involve giving Rh Immunoglobulin prophylactically around 28 weeks of gestation and again within 72 hours after the delivery of an Rh-positive baby. It is also administered after any potential sensitizing event, such as a miscarriage, abortion, external cephalic version, or abdominal trauma.
For pregnancies where isoimmunization has already occurred, medical management focuses on closely monitoring the fetus for signs of anemia. This is often done using a specialized ultrasound technique called Doppler assessment, which measures the blood flow velocity in the fetal middle cerebral artery. If the monitoring suggests moderate to severe fetal anemia, the fetus may require an intrauterine blood transfusion, where compatible blood is directly transfused into the umbilical vein. Newborns affected by HDFN may be treated with phototherapy to break down bilirubin or, in severe cases of high bilirubin or persistent anemia, an exchange transfusion to replace the newborn’s blood with compatible donor blood.