Rh Incompatibility

The Rh factor (ie, Rhesus factor) is a red blood cell surface antigen that was named after the monkeys in which it was first discovered. Rh incompatibility, also known as Rh disease, is a condition that occurs when a woman with Rh-negative blood type is exposed to Rh-positive blood cells, leading to the development of Rh antibodies.
Rh incompatibility can occur by 2 main mechanisms. The most common type occurs when an Rh-negative pregnant mother is exposed to Rh-positive fetal red blood cells secondary to fetomaternal hemorrhage during the course of pregnancy from spontaneous or induced abortion, trauma, invasive obstetric procedures, or normal delivery. Rh incompatibility can also occur when an Rh-negative female receives an Rh-positive blood transfusion. In part, this is the reason that blood banks prefer using blood type "O negative" or "type O, Rh negative," as the universal donor type in emergency situations when there is no time to type and crossmatch blood.
The most common cause of Rh incompatibility is exposure from an Rh-negative mother by Rh-positive fetal blood during pregnancy or delivery. As a consequence, blood from the fetal circulation may leak into the maternal circulation, and, after a significant exposure, sensitization occurs leading to maternal antibody production against the foreign Rh antigen.
Once produced, maternal Rh immunoglobulin G (IgG) antibodies may cross freely from the placenta to the fetal circulation, where they form antigen-antibody complexes with Rh-positive fetal erythrocytes and eventually are destroyed, resulting in a fetal alloimmune-induced hemolytic anemia. Although the Rh blood group systems consist of several antigens (eg, D, C, c, E, e), the D antigen is the most immunogenic; therefore, it most commonly is involved in Rh incompatibility.

Pathophysiology
The amount of fetal blood necessary to produce Rh incompatibility varies. In one study, less than 1 mL of Rh-positive blood was shown to sensitize volunteers with Rh-negative blood. Conversely, other studies have suggested that 30% of persons with Rh-negative blood never develop Rh incompatibility, even when challenged with large volumes of Rh-positive blood. Once sensitized, it takes approximately one month for Rh antibodies in the maternal circulation to equilibrate in the fetal circulation. In 90% of cases, sensitization occurs during delivery. Therefore, most firstborn infants with Rh-positive blood type are not affected because the short period from first exposure of Rh-positive fetal erythrocytes to the birth of the infant is insufficient to produce a significant maternal IgG antibody response.
The risk and severity of sensitization response increases with each subsequent pregnancy involving a fetus with Rh-positive blood. In women who are prone to Rh incompatibility, the second pregnancy with an Rh-positive fetus often produces a mildly anemic infant, whereas succeeding pregnancies produce more seriously affected infants who ultimately may die in utero from massive antibody-induced hemolytic anemia.
Risk of sensitization depends largely upon the following 3 factors:
Volume of transplacental hemorrhage
Extent of the maternal immune response
Concurrent presence of ABO incompatibility
The incidence of Rh incompatibility in the Rh-negative mother who is also ABO incompatible is reduced dramatically to 1-2% and is believed to occur because the mother's serum contains antibodies against the ABO blood group of the fetus. The few fetal red blood cells that are mixed with the maternal circulation are destroyed before Rh sensitization can proceed to a significant extent. Fortunately, ABO incompatibility usually does not cause serious sequela.
Rh incompatibility is only of medical concern for females who are pregnant or plan to have children in the future. Rh-positive antibodies circulating in the bloodstream of an Rh-negative woman otherwise have no adverse effects.

Frequency
United States
Only 15% of the population lack the Rh erythrocyte surface antigen and are considered Rh-negative. The vast majority (85%) of individuals are considered Rh positive. Rh sensitization occurs in approximately 1 per 1000 births to women who are Rh negative. The Southwest United States has an incidence approximately 1.5 times the national average, which likely is caused by immigration factors and limited access to medical care since blood typing is a routine part of prenatal care. Even so, only 17% of pregnant women with Rh-negative blood who are exposed to Rh-positive fetal blood cells ever develop Rh antibodies.

Mortality/Morbidity
During the course of Rh incompatibility, the fetus is primarily affected. The binding of maternal Rh antibodies produced after sensitization with fetal Rh-positive erythrocytes results in fetal autoimmune hemolysis. As a consequence, large amounts of bilirubin are produced from the breakdown of fetal hemoglobin and are transferred via the placenta to the mother where they are subsequently conjugated and excreted by the mother. However, once delivered, low levels of glucuronyl transferase in the infant preclude the conjugation of large amounts of bilirubin and may result in dangerously elevated levels of serum bilirubin and severe jaundice.
Mildly affected infants may have little or no anemia and may exhibit only hyperbilirubinemia secondary to the continuing hemolytic effect of Rh antibodies that have crossed the placenta.
Moderately affected infants may have a combination of anemia and hyperbilirubinemia/jaundice.
In severe cases of fetal hyperbilirubinemia, kernicterus develops. Kernicterus is a neurologic syndrome caused by deposition of bilirubin into central nervous system tissues. Kernicterus usually occurs several days after delivery and is characterized by loss of the Moro (ie, startle) reflex, posturing, poor feeding, inactivity, a bulging fontanelle, a high-pitched shrill cry, and seizures. Infants who survive kernicterus may go on to develop hypotonia, hearing loss, and mental retardation.
Another serious life-threatening condition observed in infants affected by Rh incompatibility is erythroblastosis fetalis, which is characterized by severe hemolytic anemia and jaundice. The most severe form of erythroblastosis fetalis is hydrops fetalis, which is characterized by high output cardiac failure, edema, ascites, pericardial effusion, and extramedullary hematopoiesis. Newborns with hydrops fetalis are extremely pale with hematocrits usually less than 5. Hydrops fetalis often results in death of the infant shortly before or after delivery and requires an emergent exchange transfusion by a neonatologist if there is to be any chance of infant survival.

Race
Approximately 15-20% of Caucasians, as opposed to 5-10% of African Americans, have the Rh-negative blood type.
Among individuals of Chinese and American Indian descent, the incidence of Rh-negative blood type is less than 5%.

CLINICAL

History of prior blood transfusion
Rh blood type of the mother
Rh blood type of the father (55% of Rh-positive men are genetically heterozygous for the Rh antigen and, therefore, produce Rh-negative offspring when mating with Rh-negative women 50% of the time.)
Previous pregnancies, including spontaneous and elective abortions
Previous administration of Rh IgG (RhoGAM)
Mechanism of injury in cases of maternal trauma during pregnancy
Presence of vaginal bleeding and/or amniotic discharge
Previous invasive obstetric procedures, such as amniocentesis, cordocentesis, chorionic villous sampling, or ectopic pregnancy
Note that a large fetal-maternal hemorrhage may occur without symptoms and with little or no evidence of trauma. Therefore, a high index of suspicion is warranted and a low threshold for treatment is indicated.

Physical
Evaluation of the vital signs and primary survey of the airway and cardiovascular system are indicated to ensure maternal stability.
A thorough pelvic examination is required.
In situations in which abdominal and/or pelvic trauma is a consideration, inspect for evidence of bruising that may suggest the possibility of significant fetomaternal hemorrhage.
When an infant with an Rh-negative mother is delivered in the emergency department, a thorough physical examination of the infant must be performed after initial stabilization, and a neonatologist must be consulted immediately.
Physical findings may vary from mild jaundice to extreme pallor and anemia with hydrops fetalis.

Causes
Factors that influence an Rh-negative pregnant female's chances of developing Rh incompatibility include the following:
Ectopic pregnancy
Placenta previa
Placental abruption
Abdominal/pelvic trauma
In utero fetal death
Any invasive obstetric procedure (eg, amniocentesis)
Lack of prenatal care
Spontaneous abortion

DIFFERENTIALS
Other Problems to be Considered
ABO incompatibility Autoimmune hemolytic anemia Microangiopathic hemolytic anemia Spherocytosis Hereditary enzyme deficiencies Alpha thalassemia Chronic fetomaternal hemorrhage Twin-twin transfusion Erythroblastosis fetalis Hydrops fetalis
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