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During pregnancy, red blood cells from the fetal circulation leak into the maternal circulation. If the mother is Rh negative, her system will not tolerate the presence of Rh positive cells. Her immune system treats the Rh positive fetal cells as if they were a foreign protein or substance and makes antibodies against the fetal blood cells. These anti-Rh positive antibodies may cross the placenta into the fetus where they destroy the fetus' circulating red blood cells. First-born infants are often not affected (unless the mother has had previous interrupted pregnancies, which could have sensitized her system) as it takes time for the mother to develop antibodies against the fetal blood.

Rh incompatibility may cause symptoms ranging from very mild to fatal. In its mildest form, Rh incompatibility causes hemolysis (destruction of the red blood cells) with the release of free hemoglobin into the infant's circulation. Hemoglobin is converted into bilirubin, which causes an infant to become yellow (jaundiced). The jaundice of Rh incompatibility, measured by the level of bilirubin in the infant's bloodstream, may range from mild to dangerously high levels.

Hydrops fetalis is a complication of a severe form of Rh incompatibility in which massive fetal red blood cell destruction (a result of the Rh incompatibility) causes a severe anemia resulting in fetal heart failure, total body swelling, respiratory distress (if the infant has been delivered), and circulatory collapse. Hydrops fetalis often results in death of the infant shortly before or after delivery.

Kernicterus is a neurological syndrome caused by deposition of bilirubin into the brain (CNS) tissues. Kernicterus develops in extremely jaundiced infants, especially those with severe Rh incompatibility. It occurs several days after delivery and is characterized initially by loss of the Moro (startle) reflex, poor feeding, and decreased activity. Later a high-pitched shrill cry may develop along with unusual posturing, a bulging fontanel, and seizures. Infants may die suddenly of kernicterus. If they survive they later develop decreased muscle tone, movement disorders, high-pitched hearing loss, seizures, and decreased mental ability.

Rh incompatibility develops only when the mother is Rh negative and the infant is Rh positive. Special immune globulins, called RhoGAM, are now used to prevent this sensitization. Hydrops fetalis and kernicterus have decreased markedly in frequency as a result of these preventive measures.