Rh Incompatibility

Etiology

As mentioned, maternal sensitization occurs in Rh-negative mothers due to exposure to the Rh D antigen. This typically occurs when the Rh-negative mother is carrying an Rh-positive fetus or has been exposed to Rh-positive blood differently. However, if the exposure to the Rh D antigen occurs during the mother’s first pregnancy, the adverse consequences of Rh incompatibility do not typically affect that initial pregnancy because the fetus is often delivered before developing the anti-D antibodies. Once the mother has been sensitized, future pregnancies are at risk for the development of HDN secondary to Rh incompatibility if the fetus is Rh-positive.[1]

Epidemiology

Rh incompatibility depends on the prevalence of Rh-negative blood types, which varies among different populations. Researchers estimate that the frequency of Rh-negativity occurs more frequently among those of Caucasian (North American and European) descent (15% to 17%) compared to those of African (4% to 8%) or Asian descent (0.1% to 0.3%). Worldwide, the prevalence of Rh disease is estimated to be 276 per 100,000 live births, which is significant considering that an estimated 50% of untreated cases of HDN either die or develop brain damage due to the disease. In comparison, the prevalence of Rh disease in developed countries has been reduced to 2.5 per 100,000 live births, which can be attributed to higher-quality perinatal-neonatal care.[2][3]

Pathophysiology

When an Rh-negative mother is exposed to the Rh D antigen, the D antigen is perceived as a foreign threat, similar to how bacteria and viruses are perceived. This leads to a series of activations of immunogenic pathways that culminate in the production of anti-D antibodies. Those antibodies can bind to the D antigen on the erythrocytes of Rh-positive fetuses to further activate immunologic pathways that lead to the hemolysis of the fetal erythrocytes.

History and Physical

Rh-negative mothers who have become sensitized to the D antigen may have been exposed to the D antigen in many ways. Taking a detailed history may reveal potential sensitizing events such as:

Exposure to fetal Rh-positive blood

• Delivery (ie, vaginal, Cesarean section)
• Threatened miscarriage, miscarriage
• Antepartum hemorrhage (eg, placenta previa, abruption, vasa previa, uterine rupture)
• Trauma
• External cephalic version
• Invasive procedures (eg, chorionic villus sampling, amniocentesis)
• Ectopic Pregnancy
• Molar pregnancy 

 Nonfetal exposure to Rh-positive blood

• Transfusion
• Bone marrow transplantation
• Needle-stick injury 

While Rh incompatibility does not typically lead to clinical signs and symptoms in the Rh-negative mother, the consequences on the Rh-positive fetus can be substantial. While the topic of HDN is discussed elsewhere, some clinical features of HDN secondary to Rh incompatibility include lethargy, pallor, jaundice, scleral icterus, tachycardia, tachypnea, and hypotension. Hydrops fetalis is severe, life-threatening hemolytic anemia (that presents with at least 2 of the following: edema, pericardial effusions, pleural effusions, and ascites) and is associated with a significant mortality rate estimated to be more than 50%.[4][5]

Evaluation

As previously mentioned, Rh incompatibility is centered on the Rh status. The United States Preventive Services Task Force (USPSTF) strongly recommends a Rh(D) blood type and antibody screen for all pregnant women at the initial prenatal visit (grade A). Additionally, the USPSTF recommends repeat antibody testing for all unsensitized Rh-negative mothers at 24 to 28 weeks of gestation unless the father is Rh-negative (grade B). Antibody testing should also be performed at delivery. There are numerous outcomes after initial testing:

• If a mother is found to be Rh-positive, there is no risk of alloimmunization regardless of the Rh type of the fetus.
• If the mother is Rh-negative, then alloimmunization can be assessed by an antibody screen.
• If the Rh-negative mother is antibody-positive, then a confirmatory study, such as a Coombs test, is needed to direct further management and monitoring of the pregnancy.
• Paternal Rh testing can also be performed if the mother is antibody-negative.

If the father is also Rh-negative, then there is no risk for alloimmunization and complications of Rh incompatibility. On the other hand, an Rh-positive father gives the fetus a 50% risk of having Rh-positive erythrocytes and a higher risk for the complications of Rh incompatibility. If the father is Rh-positive or the father’s Rh status cannot be determined, then more invasive testing may be needed. For Rh-negative mothers that have potentially been exposed to fetal Rh-positive blood, one must assess fetomaternal hemorrhage. This assessment can be done with the rosette test for screening. Positive screens can be confirmed with the Kleihauer-Betke (KB) test or flow cytometry to determine the percentage of fetal blood cells (based on detecting fetal hemoglobin F) in the maternal circulation and the next steps in management.[6] In a patient’s first affected pregnancy, surveillance of maternal antibody titers is recommended. Titers are repeated every month until 24 weeks of gestation and more frequently in the third trimester. In a patient with a history of HDN, maternal titers are not utilized to determine the appropriate time to initiate fetal surveillance in a subsequent pregnancy. Fetal surveillance includes serial middle cerebral artery dopplers every 1 to 2 weeks beginning at 24 weeks gestation and antenatal testing beginning at 32 weeks gestation. Middle cerebral artery peak systolic velocity greater than 1.5 MoM indicates cordocentesis to determine fetal hematocrit and the need for intrauterine transfusion. 

Treatment / Management

As alluded to earlier, 1 of the main principles of managing Rh incompatibility is preventing maternal sensitization. Rh D immunoglobulin (RhIg) has significantly impacted the prevention of Rh disease. RhIg consists of anti-Rh D antibodies that target Rh-positive erythrocytes to prevent maternal sensitization. It has reduced the rate of alloimmunization from 16% to less than 1%. Furthermore, RhIg immunoprophylaxis has decreased the prevalence of HDN, which is attributed to anti-D antibodies, to less than 1%. If a mother has the potential to have Rh incompatibility during pregnancy, prophylactic RhIg should be administered to unsensitized Rh-negative women at 28 weeks gestation. If the neonate is found to be Rh-positive after delivery, those same unsensitized Rh-negative women should be given RhIg within 72 hours of delivery. The suggested RhIg dose in the United States is 300 mcg, sufficient to cover up to 15 mL of Rh-positive erythrocytes (ie, 30 mL of whole fetal blood). In addition, the American College of Obstetricians and Gynecologists recommends that all Rh-negative women giving birth to Rh-positive infants should initially undergo a qualitative screening test (rosette assay) and, if indicated, proceed with quantitative testing (KB test) to determine the correct number of doses of immune globulin required. The same principle of RhIg immunoprophylaxis can be applied to Rh-negative mothers who have had high-risk events that could have potentially led to fetomaternal hemorrhage, as previously discussed. The recommendations of the American College of Obstetricians and Gynecologists for the dosing of RhIg vary depending on the scenario of potential fetomaternal hemorrhage. Smaller doses are considered for events that occur earlier in the pregnancy since the total fetal-placental blood volume is 3 mL (1.5 mL of fetal erythrocytes) at 12 weeks; therefore, at least 50 mcg should be considered for first-trimester events and 300 mcg if after 12 weeks.[7][8]

Differential Diagnosis

The differential diagnoses for Rh incompatibility include the following:

• Abo incompatibility
• Autoimmune hemolytic anemia
• Alpha thalassemia
• Chronic fetomaternal hemorrhage
• Erythroblastosis fetalis
• Hydrops fetalis
• Hereditary enzyme deficiencies
• Microangiopathic hemolytic anemia
• Spherocytosis
• Twin-twin transfusion