Two blood group systems, Rh (Rh blood group system) and ABO (ABO blood group system), primarily are associated with erythroblastosis fetalis. The Rh system is responsible for the most severe form of the disease, which can occur when an Rh-negative woman (a woman whose blood cells lack the Rh factor) conceives an Rh-positive fetus. Sensitization of the mother's immune system (immunization) occurs when fetal red blood cells that carry the Rh factor (an antigen in this context) cross the placental barrier and enter the mother's bloodstream. They stimulate the production of antibodies (antibody), some of which pass across the placenta into fetal circulation and lyse, or break apart, the red blood cells of the fetus ( hemolysis).

It is rare for a mother to become sensitized during the course of her first Rh-positive pregnancy because the amount of fetal Rh antigen that enters maternal circulation is insufficient to cause sensitization; usually only during labour will exposure be significant. However, because Rh sensitivity is likely to develop during labour, the risk of the disease developing in subsequent Rh-positive pregnancies increases. The risk can be reduced if the mother receives injections of Rh immunoglobulin, which destroys fetal red blood cells in her bloodstream, during her first pregnancy. The fetus also is protected from Rh hemolytic disease if an ABO blood group incompatibility exists concurrently; protection is conferred by ABO antibodies, which destroy fetal blood cells in the maternal circulation before the mother develops Rh sensitivity. Fetal-maternal incompatibilities within the ABO blood group alone are more common than those of the Rh type, but the immune reaction is usually much less severe, unless the fetus is type A and the mother type O.

The severity of erythroblastosis fetalis varies depending on the degree of hemolysis. Symptoms include anemia, with the presence of many immature red blood cells (erythroblasts) in the circulation; jaundice, resulting from a buildup of bilirubin (a breakdown product of hemoglobin from red blood cells); and an enlarged liver and spleen. In its mildest form, the disease manifests only as slight anemia with no other complications; in its most extreme form, the fetus dies in utero. Hydrops fetalis, which is characterized by extreme edema (abnormal accumulation of serous fluid) and congestive heart failure, is the most severe form of the disease in newborns. Usually the infant dies, unless an exchange transfusion (blood transfusion) in which the Rh-positive blood of the infant is replaced by Rh-negative blood is successful. A complication of erythroblastosis fetalis is kernicterus, which is caused by deposition of bilirubin in the brain. Hearing loss, mental retardation, or death may result. Nevertheless, many procedures are available to avert these consequences. If it is determined that the fetus is at risk for erythroblastosis fetalis, amniocentesis can be used to measure bilirubin concentrations and predict the severity of the disease. If levels are elevated, intrauterine transfusions of Rh-negative blood can be given until premature delivery can be induced. These measures, together with the use of Rh immunoglobulin, have almost eliminated the incidence of erythroblastosis fetalis in developed countries.