TREATMENT FOR PREGNANT PATIENTS WHO ARE RH D NEGATIVE :
The primary goal of caring for a pregnant patient who is nonimmunized Rh D negative is prevention of alloimmunization. Every patient should have her ABO blood group, Rh type, and antibody screen (indirect Coombs test) checked at the first prenatal visit of each pregnancy. Patients who are found to be Rh D negative with concurrent negative results from antibody screens are candidates for anti-D IgG prophylaxis unless the Rh status of the father of the baby is negative and the paternity certain. In theory, if the Rh D status of the father is known, the patient can be counseled regarding the risk of the fetus having the Rh D antigen; however, because of a 3-5% rate of unknown or false paternity, discussing this issue privately with the patient is of the utmost importance. Anti-D IgG is absolutely contraindicated only in those patients with a documented hypersensitivity to anti-D IgG.
Exogenous administration of IgG to suppress an immune response, as in the case of anti-D IgG prophylaxis, is known as antibody-mediated immune suppression. Although several theories have been proposed to explain the mechanism of action of antibody-mediated immune suppression, the most likely mechanism is via central inhibition, wherein Rh IgG coats fetal erythrocytes, which are then sequestered in the spleen and lymph nodes. The local increase in antigen-antibody complexes interrupts the commitment of B cells to plasma cell clones, thereby suppressing the primary immune response. Additionally, these antigen-antibody complexes stimulate the release of cytokines by immune effector cells that inhibit the proliferation of antigen-specific B cells.
The standard dosing regimen of anti-D IgG is 300 mcg intramuscularly at both 28 weeks' gestation and postpartum within 72 hours of delivery. The 300-mcg dose was determined in 1963 by Pollack et al following experiments in which male volunteers who received Rh D-positive erythrocytes were administered varying doses of anti-D IgG to prevent alloimmunization. In the early days of anti-D IgG prophylaxis, most fetomaternal hemorrhages were known to occur during delivery, and thus, anti-D IgG was administered only in the postpartum period. This continues to be the regimen used in many other countries.
Although this produced a dramatic decrease in the prevalence of alloimmunization, Bowman et al observed that despite this postpartum anti-D IgG prophylaxis, 1-2% of susceptible women continued to become sensitized (Bowman, 1997). They concluded that these women were experiencing fetomaternal hemorrhages prior to delivery, and they conducted experiments in which antepartum doses were added to the prophylaxis regimen. This resulted in a reduction in the number of sensitized women from 1.8% to 0.1% and eventually led to a regimen that includes the additional dose at approximately 28 weeks' gestation, which is used today in the United States.
In settings in which a fetomaternal hemorrhage can be calculated, 10 mcg of anti-D IgG should be administered for every milliliter of fetal blood in the maternal circulation. Thus, the 300-mcg dose is more than adequate for a typical fetomaternal hemorrhage and covers hemorrhage volumes of up to 30 mL of whole fetal blood. In the less than 1% of cases in which the volume of fetomaternal hemorrhage exceeds 30 mL, using the Kleihauer-Betke test to quantitate the volume of fetomaternal hemorrhage and administering the appropriate amount of anti-D IgG (ie, 10 mcg/mL fetal blood) is necessary.
Following delivery, if the infant is found to be Rh negative, the postpartum dose may be omitted. However, if any doubt remains concerning whether to administer anti-D IgG, always administer unless contraindicated. If the fetus if found to be Rh positive, administer anti-D IgG and take care to screen for excess fetomaternal hemorrhage, particularly if cesarean delivery or manual removal of the placenta occurred because both increase the risk and volume of fetomaternal hemorrhage.
Because delivery of an Rh D-positive fetus is not the only means by which transplacental passage of fetal blood can occur, anti-D IgG prophylaxis for nonimmunized women who are Rh D negative is also warranted (1) in cases of first- and second-trimester bleeding, (2) in cases of spontaneous or elective abortion, (3) prior to any invasive procedure (eg, amniocentesis), (4) in evidence of subchorionic or retroplacental hematoma upon ultrasonography, and (5) in cases of intrauterine fetal death. Patients who experience antepartum bleeding or intrauterine fetal death in the third trimester should have a Kleihauer-Betke test to determine whether more RhoGAM (ie, after the prophylactic dose at 28 weeks' gestation) is necessary. If so, patients can be given 10 mcg anti-D IgG per estimated milliliter of whole fetal blood in the maternal circulation.
Because fetal Rh antigens are present as early as the 30th day after conception, anti-D IgG is indicated with ectopic pregnancy and with therapeutic and spontaneous abortions. The risk of alloimmunization in susceptible women undergoing therapeutic or spontaneous abortion is 4-5% and 1.5-2%, respectively. For pregnancies less than or equal to 12 weeks' gestation, 50 mcg of anti-D IgG (also known as MICRhoGAM) is sometimes administered because the entire blood volume of the fetus is usually less than 5 mL. However, pregnancies exceeding 12 weeks' gestation or pregnancies in which the gestational age is unknown should receive the full 300-mcg dose.
Invasive obstetric procedures, such as CVS and amniocentesis (with respective risks of alloimmunization of at least 14% and 7-15%), also necessitate anti-D IgG prophylaxis at the time of the procedure. While a dose of 50 mcg is adequate for first-trimester procedures, the 300-mcg dose should be used for both second- and third-trimester procedures. Additionally, if amniocentesis is performed within 72 hours of delivery, as is often the case with fetal lung maturity determinations, withholding the postpartum anti-D IgG until the fetal Rh status is established postpartum is possible. However, if delivery is to be delayed for more than 72 hours, anti-D IgG should be administered.
Although not an invasive obstetric procedure, external cephalic version is associated with fetomaternal hemorrhage in 2-6% of cases, irrespective of procedure success. In this situation, administering an additional dose or checking for antibody status from the 28-week gestation prophylactic dose and performing a Kleihauer-Betke test shortly afterward to check for fetomaternal hemorrhage is reasonable.
Although the above guidelines have been dramatically successful in reducing the prevalence of Rh D alloimmunization since the introduction of anti-D IgG prophylaxis in 1968, improper management of nonimmunized Rh D-negative patients continues to be problematic. Potential errors and oversights that can result in the patient becoming Rh D alloimmunized include failing to type every patient with the potential for transfusion or fetomaternal hemorrhage, not screening for fetomaternal hemorrhage, not administering anti-D IgG when indicated, or administering an inadequate dosage of anti-D IgG.
TREATMENT FOR PATIENTS WHO ARE ALLOIMMUNIZED :
The goals in managing the alloimmunized pregnancy are 2-fold. First is the detection of fetal anemia prior to the occurrence of fetal compromise. After detection, the goal is to minimize fetal morbidity and mortality by correcting this anemia until fetal lung maturity and delivery can be achieved.
The advent of exchange transfusion for the treatment of Rh (D) hemolytic disease of the fetus and newborn by Wallerstein in 1945 dramatically reduced perinatal mortality. However, because this intervention is only used after the fetus is delivered, those fetuses experiencing severe anemia, particularly those that became hydropic, did not always survive to term delivery. In fact, elective preterm delivery and subsequent emergency exchange transfusion was the standard of care for the fetuses of alloimmunized patients in the early 1960s. Unfortunately, the inability to predict the severity of fetal disease and to manage the complications of prematurity at the time resulted in perinatal mortality rates as high as 25%.
The introduction of measures to predict the severity of fetal disease greatly reduced perinatal mortality rates and augmented survival rates. The decision to use specific interventions should be dictated by the degree of fetal disease. Consider fetal D antigen status, maternal antibody titers, and prior obstetric history in order to individualize and optimize management of an alloimmunized pregnancy. If indicated, the fetus can be assessed and monitored further using amniotic fluid analysis, ultrasound and Doppler studies, and fetal blood analysis.
Assessing fetal risk for Rh D-positive status
Upon confirming maternal Rh D alloimmunization, determining if the fetus is at risk is important because an Rh D-negative fetus is unaffected and requires no intervention irrespective of maternal titers. With certain paternity, if the father is Rh D negative, the fetus is also absolutely Rh D negative. If the father is Rh D positive, he can be homozygous for the D allele or heterozygous. If he is homozygous for the D allele (ie, DD), then the fetus is absolutely Rh D positive.
If paternity is uncertain, as in 3-5% of pregnancies, or if the father is heterozygous for the D allele, determining fetal D antigen status via polymerase chain reaction assays of fetal cellular elements in amniotic fluid or chorionic villi is possible. While CVS can be performed at earlier gestational ages than amniocentesis, CVS has the disadvantage of potentially worsening maternal titers via fetomaternal hemorrhage that might result from disruption of the chorionic villi during the procedure. Because of the small risk associated with amniocentesis, noninvasive means of determining fetal D antigen status are being investigated. For example, analysis of free fetal DNA, which can be isolated from the maternal circulation, is currently employed in Europe.
In pregnant women who are known to be Rh D alloimmunized or for whom the prenatal antibody screen result is positive, paternal Rh D antigen status should be assessed to determine if the fetus is at risk. If the paternal phenotype is antigen negative and paternity is assured, plans can be made for delivery at term. However, if the paternal phenotype is heterozygous, fetal antigen status should be determined by amniocentesis at 15 weeks' gestation. Again, if the fetus is antigen negative and paternity is assured, delivery can occur at term. However, if paternity is not assured in the setting of negative fetal antigen status, maternal antibody titers should be repeated in 8-10 weeks, as correct paternal samples are necessary to absolutely identify fetal Rh status.
If titers do not undergo a 4-fold increase or greater, delivery can occur at term. If titers do increase 4-fold or greater, management should proceed similar to that of a paternal phenotype that is homozygous (ie, DD), resulting in an Rh D antigen-positive fetus.
The need for absolute certainty regarding paternity in these settings cannot be overemphasized because the outcomes can be disastrous if the fetus is misdiagnosed as Rh D negative. Therefore, emphasize this point with patients in a private manner after they have been isolated from anyone who may have accompanied them on their prenatal visit.
Of note, because of the small risk that amniocentesis poses to an at-risk pregnancy, many women choose to obtain fetal Rh status determination only if their anti-Rh titer reaches the critical value of 1:16 or higher. This is certainly a sensible approach and minimizes the risk of increased sensitization from fetomaternal blood exposure.
Methods for determining fetal status in patients who are alloimmunized
Although not reliably accurate in predicting the severity of fetal disease, past obstetric history can be somewhat prognostic. In general, the severity of fetal disease in a particular pregnancy tends to be similar to, if not more severe than, that of prior pregnancies. Additionally, with a history of a prior hydropic fetus, the chance that the next Rh D-incompatible fetus will also become hydropic if untreated is greater than 80%.
In the Rh D antigen-positive fetus, maternal antibody titer determination is necessary to assess the risk to the fetus and to guide the decision-making process. In general, women with titers higher than 1:4 should be considered Rh alloimmunized. However, the threshold for invasive fetal testing (ie, the critical titer) varies at different institutions and is generally 1:16 or higher because these titers have been associated with fetal hydrops. Titers tend to correlate more reliably with the severity of fetal disease in the first sensitized pregnancy than in subsequent pregnancies. As such, first sensitized pregnancies in which antibody titers are 1:8 or lower can be managed by serially monitoring maternal antibody titers. These are usually performed monthly until 24 weeks of gestation, after which time titers should be repeated every 2 weeks. If titers remain below the critical titer, delivery can occur at term.
Should titers ever rise to 1:16 or higher, fetal assessment via serial amniocentesis for ?OD450, ultrasonography, and/or middle cerebral artery peak systolic velocity (MCA-PSV) Doppler studies is indicated.
Amniocentesis for ?OD450
Analysis of amniotic fluid allows physicians to detect the presence and severity of fetal hemolysis and anemia. Amniotic fluid containing high levels of bilirubin, such as that found in fetuses with severe hemolytic disease, is yellowish-brown. This observation led to the eventual development by Liley in 1961 of a method to predict the severity of fetal hemolysis using spectrophotometric measurements of bilirubin in amniotic fluid. Because the wavelength at which bilirubin absorbs light is 420-460 nm, the amount of shift in optical density from linearity at 450 nm (?OD450) in amniotic fluid samples can be used to estimate the degree of fetal hemolysis. The Queenan curve is a modification of the Liley curve to adjust for the relative inaccuracy of ?OD450 readings in the early-to-middle second trimester.
The interface between the different zones has a negative slope; this is secondary to the increased ability of the fetus to metabolize the breakdown products of hemoglobin. Thus, the same value of ?OD450 is more worrisome for hemolysis at a later gestation. Because amniocentesis is an invasive procedure, the risks associated with it include preterm premature rupture of the membranes, fetal bleeding, fetal bradycardia requiring emergency cesarean delivery, chorioamnionitis, preterm labor, spontaneous abortion, and worsening of alloimmunization due to induced fetomaternal hemorrhage.
Ultrasonography
Ultrasonographic evaluation of the fetus is a significant part of managing an Rh-incompatible pregnancy. Accurate determination of gestational age via ultrasonography is critical because management is guided in large part by gestational age. Although it cannot help predict the impending development of hydrops, ultrasonography can help unequivocally diagnose the presence of hydrops-a diagnosis that would greatly affect the course of treatment. The sonographic findings consistent with hydrops include ascites, pleural and pericardial effusions, and edema.
Several other sonographic findings have been proposed as possible indicators of the future development of hydrops. These include polyhydramnios, increased placental thickness (>4 cm), dilation of the cardiac chambers, dilation of the umbilical vein, chronic enlargement of the spleen and liver, and visualization of both sides of the fetal bowel wall. However, none of these findings has proven predictive. Ultrasonography can be utilized in the management of Rh-incompatible pregnancies to assess fetal well-being; diagnose hydrops; and guide amniocenteses, FBS, and IUTs. In this capacity, ultrasonography has improved both the safety and success rate of invasive procedures and has helped to minimize invasive testing.
MCA Doppler for MCA-PSV
The use of Doppler flow measurements in various fetal blood vessels has been studied to help predict the severity of fetal anemia. The anemic fetus attempts to enhance oxygenation by increasing cardiac output, thus increasing the velocity of blood flow. Anemia also results in decreased blood viscosity, which in turn, results in increased velocity of blood flow. In their studies of the middle cerebral artery (MCA) in 2000, Mari et al demonstrated that increases in peak velocity of systolic blood flow in the MCA can be used to detect moderate and severe anemia in nonhydropic fetuses. The MCA is utilized because it can be evaluated using a minimal angle of insonation. Generally, a threshold value of 1.5 multiples of the median (MoMs) is used to determine when FBS with possible IUT should be employed. Serial MCA Doppler studies are obtained every 1-2 weeks depending on the trend.
Reliable MCA-PSV values can be obtained as early as 18 weeks' gestation, but care should be taken after 35 weeks' gestation, after which time the false-positive rate of MCA-PSV increases, and consideration should be given to converting to amniocentesis for surveillance. If MCA Doppler studies are routinely employed, an estimated 70% of invasive testing could be avoided.
Fetal blood sampling
The previously discussed predictive measures are indirect measures of fetal disease. The only definitive means of diagnosing fetal anemia and acidosis is via FBS, also known as cordocentesis or PUBS, which was first performed in the early 1980s. FBS helps provide direct and accurate diagnosis of anemia and fetal acidosis, especially in cases of anti-Kell alloimmunization and before 26-28 weeks' gestational age when ?OD450 values of amniotic fluid are not as reliable. The other advantage of FBS is that by providing direct access to the umbilical vein, the same procedure can be used to transfuse the fetus. Despite the wealth of information afforded by FBS, routine use is not universal because of concerns regarding fetal and maternal complications. These include fetomaternal hemorrhage, fetal loss (0.5-2% per procedure), placental abruption, acute refractory fetal distress, and amnionitis with maternal adult respiratory distress syndrome.
Management scheme for patients who are alloimmunized with an at-risk fetus
Depending on the technology available to individual institutions, fetal surveillance can be undertaken with serial amniocentesis, MCA Doppler studies, or commonly, both.
Traditional management of alloimmunized patients with serial amniocenteses is based on which zone the ?OD450 measurement falls into on the Liley or Queenan curves. Evidence from several studies, including Liley's original work, indicates that mild or no hemolytic disease occurs in zone 1; intermediate disease in zone 2 (transitional between mild and severe hemolysis); and severe disease, including the development of hydrops within the week, in zone 3.
Based on this evidence, once serial measurements are started, if a zone 1 reading is obtained, monitoring the ?OD450 approximately every 3 weeks is reasonable. However, with a trend into zone 2, the frequency of testing should increase to every 1-2 weeks depending on the steepness of the slope of the curve and the closeness of the measurement to zone 3.
Once the ?OD450 measurements have entered high zone 2 or zone 3 or the fetus has been diagnosed with hydrops based on ultrasound findings, a decision should be made to either perform an FBS with possible IUT if hematocrit is less than 30% or to deliver if beyond 34 weeks' gestation (32 wk with mature lung indices). A number of important factors must be considered when preparing a patient for FBS and possible IUT; these include gestational age, the possibility of delivery, fetal maturation with corticosteroids, and the likelihood of transfusion.
If a patient is beyond viability (24th wk of gestation), a discussion regarding the management of fetal bradycardia should occur. Even though 24 weeks' gestation is considered the cusp of viability, the outcomes are likely to be even more dismal if the fetus is hydropic. In this setting, consultation with a neonatologist is important, as is fully informing the patient of the description and probabilities of different outcomes.
If the fetus is at a gestational age at which the patient would desire immediate delivery if signs of fetal distress occurred, the procedure may be performed with the patient under epidural or spinal anesthesia to avoid the risks associated with general anesthesia and to decrease the amount of time required to deliver the fetus. In addition, also consider regional anesthesia in the setting of likely transfusion because this procedure can be time consuming and uncomfortable for the patient. Because of the possibility of immediate delivery, a 48-hour course of betamethasone to accelerate fetal maturity, particularly the lungs, is usually administered before the first 2 procedures.
MCA Doppler studies can be initiated at 18 weeks' gestation and repeated every 1-2 weeks. If the MCA-PSV exceeds 1.5 MoMs, the concern for developing fetal anemia is high and FBS with possible IUT should be undertaken. Of note, after 35 weeks' gestation, fetal surveillance should be undertaken via serial amniocenteses given the high rate of false-positive results using MCA Doppler studies at this gestational age.
It is not uncommon for both serial amniocentesis and MCA-PSV measurements to be obtained. While using both methodologies may increase the combined sensitivity, it also may increase the rate of false-positive results. Large, prospective studies comparing the risks, benefits, and costs of these screening modalities alone or combined have yet to be performed.
FBS and IUT
The first IUTs were performed intraperitoneally in 1963. However, since the advent of FBS and intravenous transfusions into the umbilical vein, use of the intraperitoneal transfusion (IPT) has diminished in the management of anemic fetuses. Benefits of IVT over IPT include direct measurement of the fetal hemoglobin and acid-base status, lower failure rate (particularly in hydropic fetuses), lower rates of procedure-related morbidity and mortality, and better efficacy at earlier gestational ages. The only benefit offered by IPT is the ability to drain fetal ascites during the procedure, but this is of minimal benefit in hydropic fetuses.
When preparing to perform an FBS, a number of details must be accomplished before the procedure itself. As mentioned previously, the patient must have a consultation with a neonatologist and anesthesiologist. The blood for possible transfusion must be typed and cross-matched against the mother's serum to help rule out any other possible hemolytic antibodies. This can require several hours. The large variety of equipment, such as transfusion tubing, a blood warmer, heparinized syringes, and an accurate machine to obtain a rapid hematocrit value, must be prepared and calibrated. Unless the procedure is being performed in a unit that routinely performs these procedures, these issues should be discussed and reviewed in detail with the team of nurses, physicians, and technologists involved in the procedure.
Once all of the consultants and equipment are prepared, the actual FBS can be performed. After regional anesthesia is obtained, the patient is placed in the supine position with a left lateral tilt to prevent the uterus from occluding the inferior vena cava. The abdomen is carefully prepared, often using both povidone-iodine solution (Betadine) and alcohol because an intrauterine infection can be as disastrous as hydrops itself. A sterile sleeve is placed over the ultrasound transducer used to guide the procedure.
The best location for the FBS is near the umbilical cord insertion into the placenta. This location is relatively stable, and the needle is less likely to be dislodged once access is gained. If the placenta is anterior, the risk of the fetus dislodging the needle is unlikely. However, this risk is increased with a posterior placenta and an active fetus. In this setting, the fetus may be administered a subcutaneous injection of a neuromuscular blocking agent to decrease its activity.
Once intraumbilical vascular access is gained, stabilizing the needle is enormously important so that access is not lost. This can be accomplished more easily if tubing is attached to the hub of the needle, rather than connecting and disconnecting syringes. A sample of the fetal blood is taken. Usually, part of the sample is used to obtain a rapid hematocrit value from the unit and the rest is sent to the laboratory for confirmation. Usually, the transfusion of Rh D-negative packed erythrocytes is begun even before the hematocrit results are returned, unless some strong possibility exists that the fetus does not require blood.
The amount to be transfused can be calculated once the hematocrit/hemoglobin results are returned. In general, 30-60 mL/kg of nonhydropic fetal weight is transfused because volumes higher than this may be difficult for the fetus to tolerate. During the transfusion, the turbulent flow of the blood being infused should be monitored via ultrasonography to ensure that the needle is still in place. If intravascular access is lost and the transfusion is inadequate, repeat access may be attempted.
In the setting in which repeat access cannot be gained or with a posterior placenta in which intravascular access could not be gained initially, performing an IPT is reasonable. These transfusions require a greater volume of blood, roughly calculated as the following:
(Number of weeks' gestation - 20) X 10 mL
If an IPT is attempted, take care to avoid the umbilical vessels and to ensure that intra-abdominal access is indeed intraperitoneal. This can be accomplished by watching the blood as it is transfused into the fetal abdomen.
Once the transfusion is accomplished (if via IVT), a final blood sample is often taken to estimate the final hematocrit value of the fetus, although this measurement is an underestimation of the hematocrit secondary to the large volume infused during the transfusion. The fetus should be monitored with continuous fetal monitoring for the ensuing 4 hours (both during the procedure and immediately after because decelerations of the fetal heart rate are common and must be managed cautiously).
If the initial hematocrit value was extremely low, a repeat procedure may be necessary as soon as within a week; otherwise, the procedure can be performed every 2-4 weeks based on the posttransfusion hemoglobin value. Because the goal is to maintain the fetal hemoglobin value at greater than 9 g/dL and because it drops at approximately 1 g/dL every 3 days, these values can be used to calculate how much time can be allotted until the next procedure. Serial IUTs are usually performed until 34 weeks' gestation, beyond which time the risk of the procedure likely outweighs the benefits. This leads to delivery of the fetus at 34-37 weeks' gestation and, occasionally, even earlier if fetal lung maturity is documented.
Timing of delivery
Regardless of the mode of surveillance, in a woman with antibody titers at or above the critical level, antenatal testing should be initiated at 32 weeks' gestation. At 35-36 weeks' gestation, amniocentesis should be performed to assess ?OD450 and fetal lung maturity. If fetal lung maturity is confirmed and the ?OD450 does not indicate an upper affected zone (eg, Liley zone II), induction of labor should be undertaken in 2 weeks to allow time for hepatic maturity. If fetal lung maturity has not been achieved and the fetus is not in an upper affected zone, amniocentesis should be repeated in 2 weeks.
If fetal lung maturity has not been achieved but the fetus is found to be in an upper affected zone, consideration should be given to administration of oral phenobarbital (30 mg PO tid) to accelerate hepatic maturity in an effort to minimize hyperbilirubinemia, and labor should be induced in 1 week. However, many clinicians deliver at this point to minimize risk from further hemolysis.
ALLOIMMUNIZATION RELATED TO NON-RH D ANTIGENS :
While alloimmunization to the Rh D erythrocyte antigen has historically been the most common etiology of severe hemolytic disease of newborns, it is becoming a rarity in developed countries because of routine prophylaxis with anti-D IgG. However, hemolysis may also be caused by the presence of antibodies to atypical erythrocyte antigens. No screening program or prophylaxis is available for these atypical erythrocyte antigens in antigen-negative patients. Sensitization to these atypical erythrocyte antigens can lead to fetal hemolysis; consequently, the rate of hemolytic disease related to these more rare antibodies is either stable or rising.
Commonly, patients with antibodies to the rarer erythrocyte antigens are recognized by the antibody screen performed upon initial presentation to prenatal care. If the results of the screen are positive, the laboratory isolates the exact antibody. If the antibody is known to cause hemolysis in the fetus, such as anti-c, anti-Kell, and anti-E antibodies, these patients are treated similarly to those who are Rh sensitized. Initial management involves monitoring serial maternal antibody titers, which leads to an assessment of the fetus for hemolysis using amniocentesis or MCA Doppler studies as indicated by rising antibody titers, ultrasound findings, and possibly, the results from FBS.
If the antibody has not been known to cause fetal hemolysis, such as anti-Lea and anti-Leb (the Lewis antigens), no reason exists to follow antibody titers. One proposition is that patients with antibodies known to cause only mild hemolysis, such as anti-Hil, anti-Hu, and anti-Vw antibodies, can be treated expectantly because the risk of invasive testing likely outweighs the risk of disease. In the rare case of finding a new erythrocyte antibody, conservative management entails monitoring the patient as if the antibody would cause hemolysis. However, patients should be counseled carefully regarding the risks and benefits of either management plan.
In only 2 situations are patients not monitored identically to patients who are Rh sensitized. The first is that of alloimmunization to the c, E, or, C antigens. Some concern exists that hemolysis may occur in these patients with a lower than 1:16 titer. Thus, if the initial titer is 1:4 and stable but increases at 26 weeks' gestation to 1:8, assessing with amniocentesis for ?OD450 at that point is reasonable. However, if the patient presents in the first trimester with a 1:8 titer that remains stable at 1:8 throughout the second trimester, continued serial antibody titers are indicated.
The second situation in which patients should not be treated identically to patients who are Rh sensitized is that of Kell isoimmunization because several cases of severe fetal hemolysis with anti-Kell antibodies have occurred in the setting of low ?OD450 values. The proposed etiology for this is that the anti-Kell antibodies may attack and destroy erythroid precursors that have low levels of hemoglobin. This leads to fetal anemia, but not with the concomitant rise in bilirubin breakdown products, thus leading to relatively normal values of the ?OD450 and rendering amniotic fluid studies ineffective. However, MCA Doppler flow studies can be utilized in these patients to assess fetal anemia.
Association of atypical erythrocyte antibodies and hemolytic disease of the newborn (with disease frequency and antibodies) is as follows:
" Common - Kell, c, E
" Uncommon - e, C, cE, Ce, Cw, Kpa, Kpb, k, Jka, s, Wra, Fya
" Rare - Biles, Coa, Dia, Dib, Doa, Ena, Fyb, Good, Heibel, Jkb, Lua, Lub, M, Mia, Mta, N, Radin, S, U, Yta, Zd
" No documented cases - Lea, Leb, P
ABO incompatibility
Sensitization to an Rh D-positive fetus is much less likely in the setting of a mother who is making anti-A or anti-B antibodies to the fetal erythrocytes. This is likely because the erythrocytes are cleared by the ABO incompatibility before the maternal immune system has an opportunity to recognize the other foreign antigen, Rh D. This type of ABO incompatibility can also lead to mild fetal hemolysis. Because most of the anti-A and anti-B antibodies are IgM, which does not cross the placenta, the fetal hemolysis does not lead to severe anemia and hydrops. However, even with mild anemia, the hemolysis may lead to hyperbilirubinemia and even kernicterus; thus, closely monitor the neonate postpartum for jaundice. No particular antepartum management needs to be addressed in the setting of ABO incompatibility.
CONCLUSION :
The prevention and treatment of alloimmunization leading to fetal hydrops is a true success story in obstetrics. While this problem only occurred in a minority of pregnancies, the outcomes were disastrous in patients who were affected. With the discovery of the Rh (D) antigen and anti-D IgG and with the fact that prophylaxis with the latter could prevent sensitization 99% of the time, women who are Rh D negative no longer need to fear the complications of alloimmunization. Furthermore, in patients who have become sensitized, close monitoring of antibody titers, the use of ?OD450 or MCA-PSV to recognize hemolysis or anemia, and treatment with IUT have led to a dramatic decrease in perinatal morbidity and mortality rates. The development of noninvasive modalities to assess fetal anemia has allowed increasing avoidance of amniocentesis and its associated risks, and it is hoped that with continued research, more noninvasive modalities will be possible in the future.