Red blood cells carry several types of proteins, called antigens, on their surfaces. The A, B, and O antigens are used to classify a person's blood as type A, B, AB, or O. Each parent passes one A, B, or O antigen gene to their child. How the genes are paired determines the person's blood type.

A person who inherits an A antigen gene from each parent has type A blood; receiving two B antigen genes corresponds with type B blood; and inheriting A and B antigen genes means a person has type AB blood. If the O antigen gene is inherited from both parents, the child has type O blood; however, the pairing of A and O antigen genes corresponds with type A blood; and if the B antigen gene is matched with the O antigen gene, the person has type B blood.

Another red blood cell antigen, called the Rh factor, also plays a role in describing a person's blood type. A person with at least one copy of the gene for the Rh factor has Rh-positive blood; if no copies are inherited, the person's blood type is Rh-negative. In blood typing, the presence of A, B, and O antigens, plus the presence or absence of the Rh-factor, determine a person's specific blood type, such as A-positive, B-negative, and so on.

A person's blood type has no effect on health. However, an individual's immune system considers only that person's specific blood type, or a close match, acceptable. If a radically different blood type is introduced into the bloodstream, the immune system produces antibodies, proteins that specifically attack and destroy any cell carrying the foreign antigen.

Determining a person's blood type is very important if she becomes pregnant. Blood cells from the unborn baby (fetal red blood cells) can cross over into the mother's bloodstream, especially at delivery. If the mother and her baby have compatible blood types, the crossover does not present any danger. However, if the blood types are incompatible, the mother's immune system manufactures antibodies against the baby's blood.

Usually, this incompatibility is not a factor in a first pregnancy, because few fetal blood cells reach the mother's bloodstream until delivery. The antibodies that form after delivery cannot affect the first child. In later pregnancies, fetuses and babies may be in grave danger. The danger arises from the possibility that the mother's antibodies will attack the fetal red blood cells. If this happens, the fetus or baby can suffer severe health effects and may die.

There are two types of incompatibility diseases: Rh incompatibility disease and ABO incompatibility disease. Both diseases have similar symptoms, but Rh disease is much more severe, because anti-Rh antibodies cross over the placenta more readily than anti-A or anti-B antibodies. (The immune system does not form antibodies against the O antigen.) Therefore, a greater percentage of the baby's blood cells are destroyed by Rh disease.

Both incompatibility diseases are uncommon in the United States due to medical advances over the last 50 years. For example, prior to 1946 (when newborn blood transfusions were introduced) 20,000 babies were affected by Rh disease yearly. Further advances, such as suppressing the mother's antibody response, have reduced the incidence of Rh disease to approximately 4,000 cases per year.

Rh disease only occurs if a mother is Rh-negative and her baby is Rh-positive. For this situation to occur, the baby must inherit the Rh factor gene from the father. Most people are Rh-positive. Only 15% of the Caucasian population is Rh-negative, compared to 5–7% of the African-American population and virtually none of Asian populations.

ABO incompatibility disease is almost always limited to babies with A or B antigens whose mothers have type O blood. Approximately one third of these babies show evidence of the mother's antibodies in their bloodstream, but only a small percentage develop symptoms of ABO incompatibility disease.

Rh disease and ABO incompatibility disease are caused when a mother's immune system produces antibodies against the red blood cells of her unborn child. The antibodies cause the baby's red blood cells to be destroyed and the baby develops anemia. The baby's body tries to compensate for the anemia by releasing immature red blood cells, called erythroblasts, from the bone marrow.

The overproduction of erythroblasts can cause the liver and spleen to become enlarged, potentially causing liver damage or a ruptured spleen. The emphasis on erythroblast production is at the cost of producing other types of blood cells, such as platelets and other factors important for blood clotting. Since the blood lacks clotting factors, excessive bleeding can be a complication.

The destroyed red blood cells release the blood's red pigment (hemoglobin) which degrades into a yellow substance called bilirubin. Bilirubin is normally produced as red blood cells die, but the body is only equipped to handle a certain low level of bilirubin in the bloodstream at one time. Erythroblastosis fetalis overwhelms the removal system, and high levels of bilirubin accumulate, causing hyperbilirubinemia, a condition in which the baby becomes jaundiced. The jaundice is apparent from the yellowish tone of the baby's eyes and skin. If hyperbilirubinemia cannot be controlled, the baby develops kernicterus. The term kernicterus means that bilirubin is being deposited in the brain, possibly causing permanent damage.

Other symptoms that may be present include high levels of insulin and low blood sugar, as well as a condition called hydrops fetalis. Hydrops fetalis is characterized by an accumulation of fluids within the baby's body, giving it a swollen appearance. This fluid accumulation inhibits normal breathing, because the lungs cannot expand fully and may contain fluid. If this condition continues for an extended period, it can interfere with lung growth. Hydrops fetalis and anemia can also contribute to heart problems.

Erythroblastosis fetalis can be predicted before birth by determining the mother's blood type. If she is Rh-negative, the father's blood is tested to determine whether he is Rh-positive. If the father is Rh-positive, the mother's blood will be checked for antibodies against the Rh factor. A test that demonstrates no antibodies is repeated at week 26 or 27 of the pregnancy. If antibodies are present, treatment is begun.

In cases in which incompatibility is not identified before birth, the baby suffers recognizable characteristic symptoms such as anemia, hyperbilirubinemia, and hydrops fetalis. The blood incompatibility is uncovered through blood tests such as the Coombs test, which measures the level of maternal antibodies attached to the baby's red blood cells. Other blood tests reveal anemia, abnormal blood counts, and high levels of bilirubin.

When a mother has antibodies against her unborn infant's blood, the pregnancy is watched very carefully. The antibodies are monitored and if levels increase, amniocentesis, fetal umbilical cord blood sampling, and ultrasound are used to assess any effects on the baby. Trouble is indicated by high levels of bilirubin in the amniotic fluid or baby's blood, or if the ultrasound reveals hydrops fetalis. If the baby is in danger, and the pregnancy is at least 32–34 weeks along, labor is induced. Under 32 weeks, the baby is given blood transfusions while still in the mother's uterus.

There are two techniques that are used to deliver a blood transfusion to a baby before birth. In the first, a needle is inserted through the mother's abdomen and uterus, and into the baby's abdomen. Red blood cells injected into the baby's abdominal cavity are absorbed into its bloodstream. In early pregnancy or if the baby's bilirubin levels are gravely high, cordocentesis is performed. This procedure involves sliding a very fine needle through the mother's abdomen and, guided by ultrasound, into a vein in the umbilical cord to inject red blood cells directly into the baby's bloodstream.

After birth, the severity of the baby's symptoms are assessed. One or more transfusions may be necessary to treat anemia, hyperbilirubinemia, and bleeding. Hyperbilirubinemia is also treated with phototherapy, a treatment in which the baby is placed under a special light. This light causes changes in how the bilirubin molecule is shaped, which makes it easier to excrete. The baby may also receive oxygen and intravenous fluids containing electrolytes or drugs to treat other symptoms.

In many cases of blood type incompatibility, the symptoms of erythroblastosis fetalis are prevented with careful monitoring and blood type screening. Treatment of minor symptoms is typically successful and the baby will not suffer long-term problems.

Nevertheless, erythroblastosis is a very serious condition for approximately 4,000 babies annually. In about 15% of cases, the baby is severely affected and dies before birth. Babies who survive pregnancy may develop kernicterus, which can lead to deafness, speech problems, cerebral palsy, or mental retardation. Extended hydrops fetalis can inhibit lung growth and contribute to heart failure. These serious complications are life threatening, but with good medical treatment, the fatality rate is very low. According to the U.S. Centers for Disease Control and Prevention, there were 21 infant deaths in the United States during 1996 that were attributable to hemolytic disease (erythroblastosis fetalis) and jaundice.

With any pregnancy, whether it results in a live birth, miscarriage, stillbirth, or abortion, blood typing is a universal precaution against blood compatibility disease. Blood types cannot be changed, but adequate forewarning allows precautions and treatments that limit the danger to unborn babies.

If an Rh-negative woman gives birth to an Rh-positive baby, she is given an injection of immunoglobulin G, a type of antibody protein, within 72 hours of the birth. The immunoglobulin destroys any fetal blood cells in her bloodstream before her immune system can react to them. In cases where this precaution is not taken, antibodies are created and future pregnancies may be complicated.