Rh Incompatibility Patraporn Kinorn

Background The Rh factor (ie, rhesus factor) is an 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 two 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 delivery.

Rh incompatibility can also occur when an Rh-negative female receives a blood transfusion that contains Rh antigens. 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, especially in females

The most common cause of Rh incompatibility is exposure to an Rh-negative mother by Rh-positive fetal blood during pregnancy or delivery, whereby red blood cells from the fetal circulation leak into the maternal circulation. After a significant exposure, sensitization occurs and maternal antibodies are produced 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 has been 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.

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

Race Approximately 15-20% of whites, 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%.

History 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 Mechanism of injury in cases of trauma Presence of vaginal bleeding and/or amniotic discharge Previous invasive obstetrical procedures, such as amniocentesis, cordocentesis, amnionic villous sampling, or ectopic pregnancy

It is important to 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 ED, 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 whether or not an Rh-negative pregnant female can develop Rh incompatibility include the following: Ectopic pregnancy Placenta previa Placental abruption Abdominal/pelvic trauma In utero fetal death Any invasive obstetrical procedure (eg, amniocentesis) Lack of prenatal care Spontaneous abortion

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

Prenatal emergency care Lab Studies Prenatal emergency care Determination of Rh blood type is required in every pregnant female.

In a pregnant woman with Rh-negative blood type, the Rosette screening test often is the first test performed. The Rosette test can detect alloimmunization caused by fetomaternal hemorrhages of as little as 4-7 of RBCs. When a high clinical suspicion of large fetomaternal hemorrhage is present (>30 mL RBCs), the Kleihauer-Betke acid elution test often is performed. The Kleihauer-Betke test is a quantitative measurement of fetal red blood cells in maternal blood, and it can be valuable for determining if additional amounts of Rh IgG should be administered. The amount of Rh IgG required for treatment is at least 20 mcg/mL of fetal RBCs.

Obtaining maternal Rh antibody titers can be helpful for future follow-up care of pregnant females who are known to be Rh-negative and may be initiated from the ED. High levels of maternal Rh antibodies suggest that Rh sensitization has occurred, and further studies, such as amniocentesis and/or cordocentesis, may be necessary to evaluate the health of the fetus.

Postnatal emergency care Immediately after the birth of any infant with an Rh-negative mother in the ED or prehospital setting, examine blood from the umbilical cord of the infant for ABO blood group and Rh type, measure hematocrit and hemoglobin levels, perform a serum bilirubin analysis, obtain a blood smear, and perform a direct Coombs test.

A positive direct Coombs test result confirms the diagnosis of antibody-induced hemolytic anemia, which suggests the presence of Rh incompatibility. Elevated serum bilirubin measurements, low hematocrit, and elevated reticulocyte count from the neonate can help determine if an early exchange transfusion is necessary. An emergent exchange transfusion by a neonatologist specializing in this procedure is required in infants born with erythroblastosis fetalis, hydrops fetalis, or kernicterus

Imaging Studies: In the ED, ultrasound imaging studies of a pregnant female with suspected Rh incompatibility is limited to the pelvic ultrasound. Fetal ascites and soft tissue edema are definite signs of severe involvement. Once hydrops fetalis has developed, the sonographic evidence includes scalp edema, cardiomegaly, hepatomegaly, pleural effusion, and ascites

Other Tests Perform fetal monitoring in cases of suspected fetal distress. Abnormal fetal heart tones and ultrasound evidence of fetal or placental injury are indications of worsening fetal condition requiring emergent delivery, ideally in a center specializing in high-risk obstetrical care.

Prehospital Care When possible, prehospital care personnel should direct their efforts on stabilization of the mother and infant, followed by immediate transport to a facility specializing in high-risk obstetrical and neonatal care.

Emergency Department Care: ED care of the pregnant woman with Rh-negative blood and a suspected fetomaternal hemorrhage varies depending on the presentation of the patient and the gestational age of the fetus. When an infant with Rh incompatibility is delivered in the ED, a more aggressive approach is required, centering on respiratory and hemodynamic stabilization of the infant and determining the need for an emergent exchange transfusion and phototherapy by a neonatologist.

Obtain the Rh status of the pregnant female. If the mother has Rh-negative blood and has not been sensitized previously, administer human anti-D immune globulin (Rh IgG) and refer the woman to an obstetrician for further evaluation.

If the mother has been sensitized previously, as determined by elevated maternal Rh antibodies, administration of Rh IgG is of no value. In this situation, prompt referral to a center specializing in high-risk obstetrics is warranted.

Rh IgG, first released for general use in 1968, has been remarkably successful in the prevention of Rh incompatibility. In the Rh-negative mother, the preparation is administered after a suspected fetomaternal hemorrhage. The exact mechanism by which passive administration of Rh IgG prevents Rh immunization is unknown. The most likely hypothesis is that the Rh immune globulin coats fetal RBCs containing Rh antigens on their surface. These exogenous antibody-antigen complexes cross the placenta before they can stimulate the maternal endogenous immune system B cells to produce IgG antibodies

Since Rh IgG became the standard of care in the US, the risk of Rh incompatibility has been reduced from 10-20% to less than 1%. Because of its short half-life, Rh IgG routinely is administered once at 28-32 weeks gestation and again within 72 hours after birth to all Rh-negative pregnant females as a part of routine prenatal care.

The current recommendation is that every Rh-negative nonimmunized woman who presents to the ED with antepartum bleeding or potential fetomaternal hemorrhage should receive 300 mcg of Rh IgG IM. For every 30 mL of fetal whole blood exposed to maternal circulation, 300 mcg of Rh IgG should be administered. A lower 50-mcg dose preparation of Rh IgG is available and recommended for Rh-negative females who have termination of pregnancy in the first trimester when fetomaternal hemorrhage is believed to be minimal

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Further Inpatient Care: After administering Rh IgG in the ED, promptly refer the Rh-negative pregnant mother of an Rh-positive fetus to an obstetrician at an institution equipped for high-risk obstetrical care.

Deterrence/Prevention Stress the importance of early prenatal care to each pregnant female presenting to the ED. Early administration of Rh IgG in conjunction with early prenatal care is the best means to prevent Rh incompatibility

Complications: Emergent delivery of an infant born with hydrops fetalis should be as nontraumatic as possible. Ideally, a neonatologist who is prepared to perform an exchange transfusion should attend to the infant immediately.

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