Hemolytic disease of the newborn

• ALSO KNOWN AS: Erythroblastosis fetalis, Rh incompatibility, ABO incompatibility
• ANATOMY OR SYSTEM AFFECTED: Blood, brain, liver, skin
• CAUSES: Blood incompatibilities between mother and fetus
• SYMPTOMS: Pale skin, enlarged liver and spleen, progressive jaundice, and anemia within twenty-four hours of birth, deafness
• DURATION: Varies
• TREATMENTS: Light therapy, drug therapy, blood transfusions, iron and folic acid supplementation

DEFINITION: The destruction of red blood cells in a fetus by antibodies transferred from the mother

Causes and Symptoms

Hemolytic disease of the newborn is a disorder in which maternal antibodies induce hemolysis of the red blood cells of the fetus or newborn, producing jaundice. The most common causes are ABO or Rh incompatibilities. ABO incompatibility occurs when the mother’s blood is type O and the baby’s blood is either type A or type B. The newborn develops jaundice within the first forty-eight hours of birth as a result of increasing bilirubin levels in the blood. Rh incompatibility can arise when an Rh-negative woman is carrying a second Rh-positive fetus. During the delivery of the first Rh-positive baby, blood from the newborn may pass into the mother’s circulation. If no treatment is given, the woman may develop anti-Rh antibodies, which will remain in her circulation. If the fetus in her next pregnancy is also Rh-positive, the anti-Rh antibodies will cross over into the baby’s blood, causing hemolysis of the red blood cells. In severe cases, the hemolysis starts in utero, and the fetus will develop anemia, progressing to generalized edema with heart failure (hydrops fetalis) and death if the anemia is not corrected.

During the pregnancy, a positive Coombs’ test indicates that the woman has been exposed and thus sensitized to Rh factor. A woman who is Rh-negative can become sensitized in three ways: by having delivered an Rh-positive baby following a previous pregnancy and not having received the protein Rhogam; by receiving an erroneous infusion of Rh-positive blood; and by having a spontaneous or induced abortion of an Rh-positive embryo or fetus. A rising concentration of antibodies during the course of the pregnancy indicates that hemolysis is occurring in the fetus. A small amount of amniotic fluid is obtained through a needle inserted through the mother’s abdomen to determine the severity of the disease in the fetus. At birth, the baby may have pale skin and an enlarged liver and spleen. Progressive jaundice and anemia develop within the first twenty-four hours. High levels may cause the bilirubin to enter the brain and produce kernicterus. The baby with kernicterus shows little activity (hypoactivity), refuses to suck milk, and experiences seizures that can progress to permanent neurologic damage or to coma and death. Deafness may be a consequence of high bilirubin levels during the newborn period.

Treatment and Therapy

There is no preventive treatment for ABO incompatibility. Phototherapy, or light therapy, is used to decrease the level of bilirubin. Phototherapy acts on the bilirubin deposited in the skin and makes it water-soluble, so that the pigment can be excreted through the gastrointestinal tract. An exchange transfusion may be required to decrease the concentration of bilirubin if it rises to dangerous levels. These levels will depend on the baby’s maturation and clinical condition.

Preventive treatment for Rh incompatibility consists of giving Rhogam to all Rh-negative pregnant women at twenty-eight weeks of gestation and within the first seventy-two hours after the delivery of an Rh-positive baby. All Rh-negative women who have experienced an abortion or who have erroneously received a transfusion of Rh-positive blood should also receive Rhogam.

An Rh-negative pregnant woman with a positive Coombs’ test needs to have periodic Coombs titers, or antibody concentration measurements, to determine what type of intervention, if any, is required. This test should first be done between sixteen and eighteen weeks of gestation. Rising Coombs titers indicate that hemolysis is occurring in the fetus. Prenatal interventions may include correcting fetal anemia by giving red blood cells directly to the fetus, either into the abdomen or into the umbilical vein. The fetus must be observed with sonography for the development of fetal edema, an ominous sign. At birth, the baby may have severe anemia requiring immediate correction. Phototherapy and an exchange transfusion may be needed if bilirubin rises above acceptable levels. Other modes of therapy, such as phenobarbital, agar gel, and rectal suppositories, are of limited value in reducing bilirubin in infants with hemolytic disease.

Before discharge from the hospital nursery, a hearing test must be done for all infants who have had jaundice during the neonatal period. Anemia may develop during the first six weeks of life as a result of the persistence of antibodies in the baby’s blood. Close follow-up of hemoglobin levels must be done after discharge from the hospital. Blood transfusions may be indicated, as well as iron and folic acid supplementation.

Perspective and Prospects

The incidence of Rh incompatibility has decreased remarkably since the advent of Rhogam. Nevertheless, it still occurs, particularly when unidentified miscarriages have occurred. Rh-negative fetuses can be identified early using special techniques available only in large medical centers. Therapy for hydrops fetalis has improved with the use of cordocentesis. This therapy, which consists of obtaining and transfusing blood directly into the umbilical cord while the fetus is in utero, is available in specialized medical centers and has helped many sensitized babies to survive. Immunoglobulin has been used to block hemolysis, but it cannot be used for treatment. Agents that can metabolize bilirubin are currently under investigation.

In 2021, physicians at Janssen Research & Development began studying a drug, nipocalimab, to treat pregnant women who are at risk of developing severe cases of hemolytic disease of the newborn. The drug may help reduce the number of antibodies in the mother's body and block those antibodies from being transferred to the baby. In February 2024, the US Food and Drug Administration granted Breakthrough Therapy Designation for the drug based on the results of a clinical trial. This designation will expedite the regulatory review of the drug.

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