Rhesus conflict during pregnancy

Rhesus incompatibility (Rh) refers to a mismatch between the Rhesus types of the mother and fetus. It is associated with the development of maternal immune sensitization to the Rh antigen and hemolytic disease of the newborn (HDN). An individual can be classified as Rh positive if their red blood cells express the Rhesus D antigen; otherwise, the individual is considered Rh negative if this antigen is absent.[ 1 ] This phenomenon becomes clinically significant if an Rh negative mother is sensitized to the D antigen and subsequently produces antibodies against the D antigen (i.e., aloimmunization), which can bind to and potentially destroy red blood cells with an Rh positive phenotype.[ 2 ] This is of particular concern if an Rh negative mother is expecting a child with an Rh positive phenotype, which can lead to HDN sequelae ranging from self-limited hemolytic anemia to severe hydrops fetalis.

Epidemiology

Rh incompatibility depends on the prevalence of Rh-negative blood types, which varies among populations. Researchers estimate that the incidence of Rh negativity is higher among individuals of Caucasian (North American and European) descent (15% to 17%) than among individuals of African (4% to 8%) or Asian descent (0.1% to 17%; 0.3%). Worldwide, the prevalence of Rh disease is estimated to be 276 cases per 100,000 live births, which is significant considering that approximately 50% of untreated cases of HDN will either die or develop brain damage due to the disease. In comparison, the prevalence of Rh disease in developed countries has decreased to 2.5 per 100,000 live births, which can be attributed to better perinatal-neonatal care.[ 3 ],[ 4 ]

Causes Rh conflict during pregnancy

95% of all clinically significant cases of hemolytic disease of the fetus are caused by incompatibility with the Rh factor, 5% with the AB0 system. [ 5 ] Sensitization with other erythrocyte antigens is also known (more than 10 isoserological systems have been described) - Kell, Kidd, Duffy, Lutheran, Lewis, MNSs, Pp, etc., however, sensitization with the described antigens is extremely rare. [ 6 ]

The Rh factor is a system of allogeneic human erythrocyte antigens that is independent of the factors that determine the blood group (the ABO system) and other genetic markers. [ 7 ]

Maternal sensitization occurs in Rh-negative mothers due to exposure to the Rh D antigen. This usually occurs when an Rh-negative mother carries an Rh-positive fetus or is otherwise exposed to Rh-positive blood. However, if exposure to the Rh D antigen occurs during the mother's first pregnancy, the adverse effects of Rh incompatibility do not usually affect that initial pregnancy because the fetus is often born before anti-D antibodies develop.[ 8 ] Once the mother has become sensitized, future pregnancies are at risk of developing hemolytic disease of the newborn secondary to Rh incompatibility if the fetus is Rh-positive.[ 9 ]

Pathogenesis

There are 6 main Rh antigens. To designate this system of antigens, 2 nomenclatures are used equally: the Wiener nomenclature and the Fisher-Reiss nomenclature.

According to Wiener nomenclature, Rh antigens are designated by the symbols Rh0, rh ^I, rh ^II, Hr0, hr ^I, hr ^II.

The Fisher–Reiss classification is based on the assumption that the Rh chromosome contains 3 sites for 3 genes that determine the Rh factor. Currently, the Fisher–Reiss antigen designation is recommended by the WHO Biological Standards Committee. Each gene complex consists of 3 antigenic determinants: D or absence of D, C or c, E or e in various combinations. The existence of the d antigen has not yet been confirmed, since there is no gene responsible for the synthesis of this antigen. Despite this, the d symbol is used in immunohematology to denote the absence of the D antigen on erythrocytes when describing phenotypes. [ 10 ]

Often two nomenclatures are used simultaneously. In this case, the symbols of one of the designations are placed in brackets, for example Rh0(D).

Thus, 6 genes are known that control the synthesis of the Rh factor, and there are at least 36 possible genotypes of the Rh system. However, a smaller number of antigens (5, 4, 3) can be detected phenotypically, which depends on the number of homozygous loci in an individual. The Rh0(D) antigen is the main antigen of the Rh system, which has the greatest practical significance. It is contained on the erythrocytes of 85% of people living in Europe. It is based on the presence of the Rh0(D) antigen on erythrocytes that the Rh-positive blood type is distinguished. The blood of people whose erythrocytes lack this antigen is classified as Rh-negative. The Rh0(D) antigen is found in 1.5% of cases in a weakly expressed genetically determined variant - the Du variety.

Individuals with Rh-positive blood can be homozygous (DD) and heterozygous (Dd), which has the following practical significance [2]:

• If the father is homozygous (DD), which is the case in 40-45% of all Rh-positive men, then the dominant D gene is always passed on to the fetus. Therefore, in an Rh-negative woman (dd), the fetus will be Rh-positive in 100% of cases.
• If the father is heterozygous (Dd), which is observed in 55–60% of all Rh-positive men, then the fetus can be Rh-positive in 50% of cases, since it is possible to inherit both a dominant and a recessive gene.

Thus, in a woman with Rh-negative blood, when pregnant by a man with Rh-positive blood, in 55-60% of cases the fetus will have Rh-positive blood. Determining the heterozygosity of the father presents certain difficulties and cannot be introduced into routine practice. Therefore, the pregnancy of a woman with Rh-negative blood by a man with Rh-positive blood should be treated as a pregnancy with a fetus with Rh-positive blood. [ 11 ]

Approximately 1–1.5% of all pregnancies in women with Rh-negative blood are complicated by erythrocyte sensitization during gestation; after delivery, this percentage increases to 10%. This frequency is significantly reduced by the use of anti-Rh0(D) immunoglobulin. [ 12 ]

Symptoms Rh conflict during pregnancy

Although Rh incompatibility does not usually result in clinical signs and symptoms in the Rh-negative mother, the consequences for the Rh-positive fetus can be significant. Some clinical features of HDN secondary to Rh incompatibility include lethargy, pallor, jaundice, scleral icterus, tachycardia, tachypnea, and hypotension.[ 13 ] Hydrops fetalis is a severe, life-threatening hemolytic anemia (which presents with at least two of the following: edema, pericardial effusion, pleural effusion, ascites) and is associated with a significant mortality rate, estimated at greater than 50%.[ 14 ]

Read also: Rhesus conflict during pregnancy - Symptoms

Diagnostics Rh conflict during pregnancy

As mentioned earlier, Rh incompatibility depends on Rh status. The U.S. Preventive Services Task Force (USPSTF) strongly recommends that all pregnant women be tested for Rh(D) blood type and antibodies at their first prenatal visit (Level A). [ 15 ] 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 (Level B). Antibody testing should also be done at delivery. After the initial testing, there are a variety of results:

• If the mother is Rh-positive, there is no risk of alloimmunization regardless of the Rh type of the fetus.
• If the mother is Rh negative, alloimmunization can be assessed using antibody screening.
• If the Rh-negative mother has positive antibodies, a confirmatory test such as a Coombs test is needed to determine further management and monitoring of the pregnancy.
• If an Rh negative mother tests negative for antibodies, the father can also be tested for Rh.

If the father is also Rh negative, there is no risk of alloimmunization and Rh incompatibility complications. On the other hand, an Rh positive father gives a 50% risk of the fetus having Rh positive red blood cells and a higher risk of Rh incompatibility complications. If the father is Rh positive or the father's Rh status cannot be determined, more invasive testing may be required.

In Rh-negative mothers potentially exposed to Rh-positive fetal blood, fetomaternal hemorrhage should be assessed. This assessment can be done using a rosette test for screening. Positive screening results can be confirmed using the Kleihauer-Betke (KB) test or flow cytometry to determine the percentage of fetal blood cells (based on the detection of fetal hemoglobin F) in the maternal circulation and subsequent management steps.[ 16 ]

In the patient's first ruptured pregnancy, maternal antibody titers are recommended to be monitored. Titers are repeated monthly until 24 weeks of gestation and are most frequently repeated in the third trimester. In a patient with a history of HDN, maternal titers are not used to determine the appropriate time to initiate fetal surveillance in a subsequent pregnancy. Fetal surveillance includes serial middle cerebral artery (MCA) Doppler ultrasonography every 1 to 2 weeks beginning at 24 weeks of gestation and antenatal testing beginning at 32 weeks of gestation. A peak MCA systolic velocity greater than 1.5 MoM is an indication for cordocentesis to determine the fetal hematocrit and the need for intrauterine blood transfusion.

Read also: Rhesus conflict during pregnancy - Diagnostics

Screening

Consists of determining the blood type and Rh factor. It should be done for all women planning a pregnancy. In a woman with Rh-negative blood, the blood type and Rh factor of the partner are tested. [ 17 ]

Treatment Rh conflict during pregnancy

One of the main principles of Rh incompatibility management is the prevention of maternal sensitization. Rh D immunoglobulin (RhIg) has had a significant impact on the prevention of Rh diseases. RhIg consists of anti-Rh D antibodies that target Rh positive red blood cells to prevent maternal sensitization. This has reduced the alloimmunization rate from 16% to less than 1%. In addition, RhIg immunoprophylaxis has reduced the prevalence of HDN associated with anti-D antibodies to less than 1%.

If there is a risk of Rh incompatibility in the mother during pregnancy, prophylactic RhIg should be given to unsensitized Rh-negative women at 28 weeks' gestation. If the infant is found to be Rh-positive after delivery, the same unsensitized Rh-negative women should be given RhIg within 72 hours of delivery. The recommended dose of RhIg in the United States is 300 mcg, which should be sufficient to cover up to 15 mL of Rh-positive red blood cells (i.e., 30 mL of fetal whole blood). In addition, the American College of Obstetricians and Gynecologists (ACOG) recommends that all Rh-negative women delivering an Rh-positive infant first undergo a qualitative screening test (rosette test) and, if indicated, proceed to quantitative testing to determine the correct number of doses of immune globulin needed.

The same principle of RhIg immunoprophylaxis can be applied to Rh-negative mothers who have experienced high-risk events that could potentially lead to fetomaternal hemorrhage, as discussed previously. ACOG dosing recommendations for RhIg vary depending on the potential fetomaternal hemorrhage scenario. Lower doses are considered for events occurring earlier in pregnancy because the total fetoplacental blood volume is 3 mL (1.5 mL of fetal red blood cells) at 12 weeks; therefore, at least 50 mcg should be considered for first-trimester events and 300 mcg after 12 weeks.[ 18 ],[ 19 ]

Read also: Rhesus conflict during pregnancy - Treatment