Department of Family Medicine, University of California, Riverside, Riverside, CA, USA
Transfer of nutrients, proteins, and antibodies between the mother and fetus generally occurs across the placenta without direct transfer of blood. Although the maternal and fetal blood supplies are separated from each other, they are, of necessity, in relative proximity and can, under certain circumstances, come into contact with each other. Under these circumstances, exposure to foreign proteins may elicit an immune response with potential health effects for either the mother or fetus.
Rh isoimmunization represents a serious maternal–fetal complication. All red blood cells are produced with a variety of surface antibodies that serve to identify one’s own red cells from those of others. The presence of red blood cells from an outside source will elicit an immune response with subsequent hemolysis/removal of the foreign cells. This response may be relatively minor or may represent a significant medical complication.
The primary surface proteins serve to identify blood within the ABO blood type categories. Exposure to immunologically incompatible blood types within the ABO category will result in significant hematological complications. A second set of proteins (rhesus factor) also provide significant identification. Rh-negative ([Rh−] those without Rh factor) patients exposed to blood containing Rh factor (Rh positive [Rh+]) will produce an antibody response to that blood. It is this incompatibility that results in the complications of Rh isoimmunization. An initial exposure will lead to development of antibodies. Subsequent exposures will yield a significant antibody response and an associated reaction.
Pregnant Rh-negative patients exposed to fetal Rh-positive blood may also develop such an antibody response (approximately 20 % will isoimmunize if not treated). Because such antibodies can cross the placenta and reach the fetus, all subsequent pregnancies that involve Rh-positive fetuses will potentially result in hemolysis and in complications for the fetus.
Rh factor is a genetically inherited trait with an autosomal-dominant inheritance pattern. An Rh-negative mother is, by definition, homozygous (Rh−/Rh−). An Rh-positive father may be homozygous (Rh+/Rh+) or heterozygous (Rh+/Rh−). As all children will receive one Rh-negative gene from such mothers, the Rh status of the child is dependent on the Rh status of the father. All children of homozygous Rh-positive fathers will be Rh positive. One-half of all children of heterozygous fathers will be Rh positive.
Fetal Consequences of Isoimmunization
Although maternal blood does not generally cross the placenta, maternal antibodies do. The placental transmission of maternal antibodies to Rh factor will result in fetal hemolysis and subsequent anemia. In addition, the red blood cell destruction results in the release of heme and bilirubin. These breakdown products are cleared by the maternal circulation after crossing the placenta. The results for the fetus are generally related to complications of severe anemia (erythroblastosis fetalis) and may include heart failure, acute pericardial effusion, hypoxia, acidosis, and death.
Newborn Consequences of Isoimmunization
Following delivery, Rh-isoimmunized infants lose access to the maternal circulation but will continue to have circulating maternal antibodies. Under these circumstances, the neonate may be incapable of adequately clearing the bilirubin and heme that result from continued red blood cell destruction. The potential complications for infants will include those anemia, cardiac complications, acidosis, and death, as well as deposition of heme within the basal ganglia of the developing brain (kernicterus).
The Rh status of the infant is usually unknown; therefore, particular care should be taken to note the Rh status of the mother. When known, the Rh status of the father should also be noted. Prior pregnancies should be recorded, including the Rh status of the resulting infant. If the patient has had prior pregnancies, any administration of Rh immunoglobulin (discussed later) should be recorded. As noted previously, the initial exposure is less significant than subsequent exposures. For this reason, the history is particularly important in second and subsequent pregnancies.
In general, the physical examination will not contribute to the diagnosis of Rh isoimmunization, but careful monitoring of fetal growth and development is critical in the management of pregnancies complicated by Rh isoimmunization.
Rh factor should be documented for all pregnant patients. For those patients found to be Rh negative, paternal testing may be indicated. If paternity is uncertain or paternal testing cannot be performed, the infants should be assumed to be Rh positive and management should proceed accordingly.
Management Prior to Isoimmunization
Overall management of Rh− patients is outlined in Fig. 12.1. The management of pregnancies with the potential for isoimmunization consists of the following three key principles:
Evaluation and management of Rh− patient
At 28 weeks’ gestation, Rh-negative patients should be tested for evidence of Rh antibodies. If no antibodies are detected, patients should receive 300 μg of Rh immunoglobulin as a single intramuscular dose. Following delivery, the Rh status of the infant should be determined. If the infant is found to be Rh positive, a second dose of Rh immunoglobulin should be administered within the first 72 h postpartum.
Under all circumstances where maternal–fetal transfusion is possible or suspected, patients should receive Rh immunoglobulin. In general, a single dose is sufficient for most exposures. If a larger-than-usual transfusion is suspected, further testing should be performed to determine the extent of exposure and additional doses of immunoglobulin may be necessary. This occurs in less than 1 out of 200 cases.
Management of Pregnancies with Rh-Sensitized Mothers
Management of the first pregnancy associated with isoimmunization is generally uncomplicated and will follow the guidelines for usual pregnancy management. Infants may require additional monitoring postpartum but can be expected to follow the usual newborn course. All Rh-sensitized mothers, however, should be informed of the development, the nature of the problem, and its potential effects in subsequent pregnancies. Critical discussions of contraception, preconception counseling, and future pregnancy planning should begin in the immediate postpartum period.
Patients known to be previously Rh sensitized require careful management and involvement of a skilled maternal–fetal medicine provider. Although a full discussion of the management of such patients is beyond the scope of this text, the general course of management is reviewed here.
For previously sensitized patients, antibody titers should be drawn at intake, at 20 weeks’ gestation, and every 4 weeks thereafter. If antibody titers remain below 1:8, careful antenatal monitoring and continued routine prenatal care are recommended. When titers rise above a critical threshold (1:8–1:32), management will proceed as described below:
Amniotic Fluid Assessment
Beginning in the second trimester, bilirubin levels in the amniotic fluid decrease. In patients with significant isoimmunization, levels of bilirubin will rise as the pregnancy progresses. Serial measurement of bilirubin in the amniotic fluid can be used to determine the presence and severity of rising bilirubin levels. Fetal involvement is graded as mild, moderate, or severe based on the results of these studies. Mild involvement will require amniocentesis every 2–3 weeks with delivery at term in the absence of a worsening of the fetal condition. Moderate involvement requires amniocentesis every 1–2 weeks with delivery when fetal lung maturity can be demonstrated (see Chap. 7). Severe disease requires weekly amniocentesis and may also require intrauterine transfusion. In all cases assessment of fetal well-being is necessary (see Chap. 17).
With advances in fetal ultrasonography, assessment of blood flow in the middle cerebral artery now allows for noninvasive assessment of fetal status. The decrease in blood viscosity (due to red blood cell lysis) results in higher velocity blood flow. Normalized values correlated with fetal hematocrit allow for identification affected fetuses with moderate or severe anemia.
Percutaneous Umbilical Blood Sampling
Under circumstances requiring direct measurement of fetal hematocrit, sampling of the umbilical vein allows for such measurement. Normal fetal hematocrit is approximately 40 % (36–44 %) but may be <30 % in severe anemia.