Rh Factor

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What is Rh Incompatibility?

Despite advances in medical technology, about 10 percent of women still remain at risk for Rh isoimmunization, which can cause severe hemolytic disease (anemia) or death of the fetus or newborn. Also called Rh sensitization, this phenomenon is the result of an antigen-antibody reaction in the blood and can happen when an Rh negative woman is pregnant with an Rh positive fetus. It can occur through sensitization from a previous pregnancy, inadequate response to prophylaxis, or incompatible blood transfusion.1 The approximate incidence of Rh-related neonatal morbidity is one in 1,000 births.2 Perinatal healthcare providers must understand the pathophysiology and treatments associated with this at-risk population so that the pregnant woman, her fetus, and her newborn can receive appropriate care.
Just as blood is defined by typeA, B, AB, and O,it is also defined by Rh factor. The Rh factor is a distinct protein, an antigen on the red blood cells (RBCs). Presence of the Rh factor makes the blood cell incompatible with blood cells that do not have the antigen. If a person is Rh positive, his or her blood has the Rh factor; if a person is Rh negative, his or her blood does not have the Rh factor. About 85 percent of people are Rh positive and 15 percent are Rh negative. Rh factor causes problems when Rh negative blood comes in contact with Rh positive blood. The immune system of the Rh negative person identifies the Rh positive blood as a harmful invader, an antigen, and produces antibodies to fight it. Antibodies are protein substances produced by the body in response to antigens; they seek to restrict and destroy antigen formation. These antibodies cause pregnancy-related problems.

Sequence of Rh isoimmunization
Rh isoimmunization occurs when an Rh negative woman becomes pregnant with an Rh positive fetus. Although the mother and the fetus have separate circulatory systems, blood from the fetus can cross the placenta and enter the mother's circulation. The woman's body reacts to the fetal blood as it would to a foreign substance and produces antibodies against it. This is referred to as Rh isoimmunization, or Rh sensitization. Anti-Rh positive antibodies are formed in the mother's blood.

These antibodies do not disappear. In a first pregnancy with an Rh positive fetus, the baby is usually delivered before the mother's body produces antibodies although a small percentage do develop fetal pathology, usually during the last trimester. In subsequent pregnancies with an Rh positive fetus, these anti-Rh positive antibodies attack and destroy the fetal Rh positive blood, causing progressively more serious hemolytic disease of the fetus or the newborn.

Sensitization can also occur when an Rh negative woman is exposed to Rh positive blood during the birthing process, an ectopic pregnancy, spontaneous abortion, induced abortion, or blood transfusion. As little as 0.5 ml of Rh positive blood entering the Rh negative maternal bloodstream can cause sensitization and endanger the fetus in future pregnancies.3 There is also a slight chance of developing antibodies after prenatal diagnostic tests or treatments, such as amniocentesis, fetal blood sampling, and intrauterine fetal blood transfusion. Sensitization does not occur when the mother and father are both Rh negative.

Significance of Rh(D) antigen
In genotypic language, there are five major classes of antigens on the human chromosome: C, D, E, c, and e. The C, c, E, and e antigens are significantly less harmful than the D antigen. The presence of the D antigen results in an Rh positive individual and plays a major role in Rh isoimmunization. In an Rh negative woman, the presence of the D antigen in the fetus is responsible for hemolytic disease in fetus and newborn. Hemolytic disease can take the form of mild to severe anemia, or it can be more serious, including erythroblastosis fetalis (grave anemia), hydrops fetalis (severe generalized edema), or even kernicterus (brain damage caused by the breakdown of hemoglobin).

Preventing Rh isoimmunization
Prevention and treatment of hemolytic disease requires constant expert care during the antepartum, intrapartum, postpartum, and newborn periods. The goals of antepartum care are to accurately screen the pregnant woman for Rh incompatibility and sensitization, to start appropriate therapeutic interventions as quickly as possible, and to deliver a mature fetus who has not yet developed severe hemolysis in utero.

Careful screening for women at risk for Rh-related pathology begins with the woman's first prenatal visit. An obstetric history and a prenatal panel of blood tests are routinely obtained during this visit. When the woman is Rh negative, the provider must elicit a careful history of her past pregnancies, including past sensitized pregnancies, and find out if she has ever had a blood transfusion. Fetal circulation is established by four weeks gestation, and the Rh(D) antigen has been found on fetal cells as early as six weeks after conception. Women with irregular menses, or women with a "late" period, may have experienced early spontaneous abortions that can cause Rh sensitization.

The prenatal panel of serologic tests always includes blood typing, Rh factor determination, and an antibody screen. If the maternal blood is Rh negative and the paternal blood is Rh positive or unknown, frequent blood tests (indirect Coombs tests) are obtained from the mother, starting at 16 to 20 weeks gestation. These tests identify the presence of Rh positive antibodies in maternal blood. When the antibody titer rises to 1:16 or greater, the fetus should be monitored by amniocentesis, percutaneous umbilical cord blood sampling (PUBS), or the delta optical density 450 test.

If the mother has not been sensitized (has not developed anti-Rh positive antibodies), hemolytic disease of the newborn can be prevented by the antepartum and postpartum administration of Rh immune globulin, also known as anti-Rho(D) gamma globulin, and marketed under the brand name RhoGAM. Given intramuscularly to the mother, Rh immune globulin destroys Rh positive fetal cells as they enter the maternal circulation, before sensitization can occur, and blocks maternal antibody formation.

When the woman is Rh negative and not sensitized and the father's blood type is either Rh positive or unknown, Rh immune globulin should be given at 28 weeks gestation and again after each birth, ectopic pregnancy, abortion, or amniocentesis. When administered as outlined, Rh immune globulin can reduce the incidence of Rh sensitization by up to 97 percent.

Rh immune globulin has been available since 1968. Although it is a blood product derivative, it is marketed as being free of hepatitis risk, and of the approximately half million doses given annually, there have been no verified cases of AIDS transmission. Since it contains traces of plasma proteins, however, allergic reactions are possible. Severe, but rare, anaphylactic reactions have also been reported.

Diagnosing fetal problems
Despite Rh immune globulin prophylaxis, a significant number of fetuses continue to be affected by hemolytic disease, mainly because of atypical antibodies or because prophylaxis was omitted or administered inadequately. The following tests and treatments can help diagnose and treat these fetuses.

If the antibody titer is greater than 1:16, the obstetrician or perinatologist usually performs an amniocentesis and send a specimen of amniotic fluid for a delta OD450 test. To help quantify the severity of the sensitization. Rh isoimmunization leads to increased hemolysis (breakdown) of fetal RBCs. Red blood cell breakdown results in formation of bilirubin that discolors the amniotic fluid. The delta OD450 test measures the concentration of bilirubin pigments. Results are plotted on a graph; rising values indicate worsening hemolysis. PUBS and possible intrauterine fetal transfusion (IUFT) may be recommended if the delta OD450 test shows severe hemolysis.

Ultrasound can be vital in most antepartal fetal surveillance tests and treatments. By itself, however, it is of limited use in the early diagnosis of hemolytic disease of the fetus. Ultrasound evaluations may be done to assess for problems related to Rh isoimmunization, including hydrops fetalis, an advanced stage of erythroblastosis fetalis, polyhydramnios (an excessive amount of amniotic fluid), enlargement of the heart, or distinct shading of the bowel.

PUBS, an invasive procedure, was introduced in 1981 and provides direct access to fetal blood. Fetal blood sampling is the definitive investigation in cases of severe sensitization. The mother may be premedicated to decrease anxiety and to promote cooperation. Under the guidance of ultrasound, a needle is inserted into the umbilical vein approximately 1 to 2 cm from the cord insertion site, and a small amount of fetal blood is aspirated for laboratory analysis. In addition to testing for the presence of maternal cells, the fetal blood may also be tested for hemoglobin and hematocrit, blood gases, pH, bilirubin, platelets, fetal karyotype (chromosomal analysis), and erythropoietin levels (substances that stimulate production of RBCs). After blood sampling, decisions are made about the need for intrauterine fetal transfusion. PUBS can be started at 18 to 20 weeks gestation; fetal loss is approximately 0.5 percent.

Treating fetal problems
More complex, invasive procedures may be undertaken to diagnose or treat fetal isoimmunization. IUFT is such a procedure. It provides a way to directly improve fetal tissue oxygenation by restoring a normal hemoglobin; this prevents or reverses hydrops fetalis. Fetal transfusion also suppresses fetal production of RBCs by the infusion of O negative adult donor RBCs that are fresh, densely packed, washed, irradiated, and screened for infection. Transfusions may be either intraperitoneal or intravascular.

IUFT is usually done in the fetal assessment unit, on an outpatient basis, and under strict asepsis. The woman's abdomen is cleansed as for a surgical procedure, and she may be premedicated with a mild sedative, narcotic, or anti-emetic. Her abdomen is injected with a local anesthetic and, under direct ultrasonic guidance, a spinal needle is inserted into her abdomen, aiming for an appropriate transfusion site. The position of the fetus, the placement of the placenta, and the degree of fetal illness largely determine whether intraperitoneal transfusion (IPT) or intravascular transfusion (IVT) will be undertaken.

IPT, introduced in 1963, may be used to treat the less severely ill fetuses. IPT is inappropriate in the presence of hydrops, because the absorption of the transfused blood is very unpredictable. It is also inappropriate when the fetus is even more gravely ill, because there may be little or no absorption at all. To perform IPT, an amniocentesis is done and, under ultrasonic guidance, a large bore needle is used to introduce an epidural catheter into the peritoneal cavity of the fetus. Packed RBCs, which are crossmatched against maternal serum, are transfused through the catheter. The blood is absorbed into fetal circulation through subdiaphragmatic lymphatics and the thoracic duct. It takes about eight to nine days for two-thirds of the transfused blood to be absorbed. A second IPT is done in nine to 12 days, and subsequent transfusions are scheduled about every four weeks until 32 weeks gestation. Delivery is planned at about 36 weeks gestation. Up to 86 percent of nonhydropic transfused fetuses survive.

Intravenous fetal transfusion, introduced in 1981, is a more effective treatment modality than IPT and has replaced IPT in most centers. IVT may be undertaken as early as 17 to 20 weeks gestation. It replaces fetal RBCs with donor blood that does not undergo hemolysis by maternal antibodies. The mother is prepared as described earlier, and the fetus is injected intramuscularly or intravenously with a neuromuscular blocking agent designed to decrease fetal movement for about 40 to 50 minutes. Because of its stability, an umbilical vein or artery in the placental cord root is the best transfusion site, but the intrahepatic vein may also be used.

The intracardiac route is an option in extreme circumstances only. Throughout the procedure, the fetal heart rate is continuously monitored by ultrasound.

Once the needle is inserted into the umbilical vein, a small amount of blood is aspirated for stat hemoglobin or hematocrit analysis. A transfusion volume formula is then used to calculate the amount of blood to be transfused. The blood is administered via a 30 ml syringe, over a 20-minute period, at a rate of 1 to 3 ml per minute. Donor red cells are crossmatched against maternal serum. Subsequent transfusions may be given at two-day to four-week intervals, depending on the severity of fetal disease. Overall IVT survival rate is about 93 percent.

During post-procedure, the mother and fetus are observed for six to 24 hours. If the fetus has reached viability, the mother is given specific discharge instructions. She is carefully coached regarding the signs and symptoms of fetal distress or preterm labor. She is taught how to detect and record daily fetal movement and kick counts. She is advised to immediately contact her healthcare provider if she notices decreased fetal movement, vaginal bleeding, premature rupture of membranes, or preterm labor.

Fetal transfusion has contributed greatly to the prolongation of sensitized pregnancies and to the delivery of healthy infants at a gestation of 36 weeks or more.

Intrapartum care
The goal of intrapartum management of the Rh negative woman is to minimize opportunity for maternal-fetal bleeds. The physician or nurse-midwife and the bedside nursing staff should be aware of the patient's Rh-related history, should avoid manual removal of the placenta if possible, and should clamp the cord immediately after birth. They should ensure that a Kleihauer-Betke blood test is drawn from the mother shortly after birth to test for the presence and quantity of Rh positive blood in her circulation. They also should give a thorough report to the postpartum and neonatal personnel assuming care of the mother and newborn upon transfer from labor and delivery.

Postpartum and newborn care
The goals of postpartum management are to prevent sensitization in the as yet unsensitized woman and to quickly diagnose and treat hemolytic disease in the newborn.

The Rh negative woman whose indirect Coombs test is negative, and who has delivered an Rh positive child whose direct Coombs test is also negative, should receive an intramuscular injection of Rh immune globulin within 72 hours of birth. These test results indicate that neither mother nor baby has been sensitized. Rh immune globulin will prevent the mother from forming antibodies to any Rh positive fetal blood cells that might have entered her circulation during delivery.

The normal dose of Rh immune globulin, 300 micrograms, should suppress the immune response to approximately 30 ml of Rh positive blood. If the Kleihauer-Betke shows a larger fetal-maternal bleed, repeated doses of Rh immune globulin are necessary. An additional 300 micrograms is given for every 30 ml of Rh positive blood or for every 15 ml of fetal red cells in the maternal circulation. These additional doses may be given at one time, using multiple injection sites, or at 12-hour intervals.

If the mother's indirect Coombs test is positive, indicating Rh positive antibodies present in her blood, and her Rh positive newborn has a positive direct Coombs test, indicating sensitized maternal Rh positive antibodies present in fetal cord blood, Rh immune globulin should not be given to the mother. But the newborn should be monitored for signs of hemolytic disease and treated appropriately.

Phototherapy, exchange transfusion, albumin infusion, or drug therapy may be used to treat hemolytic disease in newborns.

Recent decades have seen advances in our understanding of the pathophysiology and treatment of Rh-related disease. As medical and therapeutic techniques continue to improve, nurses continue to be central players in the continuum of care provided to the Rh negative mother and her Rh positive baby. As the nurse listens, observes, teaches, encourages, and provides direct care to the patient and her family, the nurse makes invaluable contribution to their quality of life.

 
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