Iowa Neonatology Handbook: Hematology

Hemolytic Disease of the Newborn Due to Maternal Erythrocyte Alloimmunization

1. Historical Perspective & Overview
   
   Hemolytic disease of the newborn has become a less and less common condition due largely to improved preventative measures such as the maternal administration of Rh immune globulin during the early 3rd trimester and the immediate postpartum period. With rare exceptions, it is presently possible to prenatally detect all non-ABO affected fetuses by testing for antibodies in maternal blood.
   
   Most recently fetal cordocentesis has been utilized with increasing success to detect and to treat fetal anemia, i.e., with intravascular transfusion, in pregnancies identified prenatally, perinatal mortality and morbidity have been significantly improved. Infants followed by the High Risk Obstetrical service at the University of Iowa, are most commonly born close to term, have no to mild anemia, and are not jaundice in the first 24 hours. The most common neonatal problem today is that of anemia developing following discharge.
2. Diagnosis
   1. ABO blood group incompatibility:
      Since blood type is not routinely tested at birth, the diagnosis is almost always made after it is recognized that the infant is jaundice. It is uncommon for these infants to be significantly anemic and very rare for them to present with hydrops at birth. The diagnosis is made when the infant is A, B or AB and has a positive direct Coombs test and a positive indirect Coombs result for anti-A or anti-B. The mother will lack the A or B antigen which is positive in the indirect Coombs test.
   2. Rh and other "minor" blood group incompatibilities:
      Due to maternal screening for this condition, these infants are almost recognized prior to delivery. A positive direct Coombs test on the neonates blood with identification of a specific serum antibody known to be associated with hemolytic disease (some blood group antigens, e.g., Lewis are not) makes the diagnosis.
3. Management:
   1. ABO blood group incompatibility:
      Although anemia should be looked for, hyperbilirubinemia is the primary morbidity associated with ABO blood group incompatibility. Management of this condition follows that described elsewhere in this manual (see section on "Management Of Hyperbilirubinemia in the Newborn Period"). The chance for this occurring again in future pregnancies is unpredictable.
   2. Rh and other "minor" blood group incompatibilities
      1. Prior to delivery
         1. obtain a careful history of past and present obstetrical history and a history of previous neonatal outcomes including
            1. Outcome of previous pregnancies, i.e., fetal & neonatal deaths, prematurity, etc.
            2. past & present history of in utero erythrocyte transfusion(s)
            3. past & present hydrops, and
            4. previous neonatal exchange transfusion for hyperbilirubinemia.
         2. In cases where a severely affected, anemic infant is anticipated (a rarity in recent years), packed type O Rh- blood cross-matched against maternal serum should be available for possible immediate booster transfusion (see Neonatal Blood Bank Procedure Manual).
      2. At delivery
         1. Severely Affected Infants: Immediately following birth, the severely affected infant may have problems with circulatory and respiratory failure due to intrapartum depression and anemia, not bilirubin toxicity. Fortunately, this is a rare event with present obstetrical management. If present, ascites may create ventilatory embarrassment and paracentesis should be considered. Pulmonary problems similar in infants with neonatal depression and/or RDS may also occur. After initial stabilization, the infant should be transferred to the NICU. In the rare event that severe anemia is thought to be present and the infant's primary problem, a small exchange transfusion with packed red blood cells, 20-40 mL/kg given in the delivery room, may be indicated.
         2. Mild to Moderately Affected Infants: If the delivery room assessment of infants indicates that the infant is not severely affected but still has some concerning signs, these infants should be transferred to the NICU (or Intermediate Care Nursery if appropriate).
         3. Infants With No Signs Of Clinical Illness Or Jaundice: These infants may be sent to normal nursery if they meet this nursery's other criteria for admission.
         4. Cord Blood Laboratory Determinations: Before the umbilical cord blood clots, an immediate blood sample should be drawn with a large gauge needle and syringe from the placental portion of the umbilical cord and placed in an EDTA anticoagulated tube (lavender top) and red top tube. These samples should be sent to the for the hospital laboratory for blood group and direct Coomb's test.
      3. In the nursery:
         1. Severely Affected Infants: Following transfer to the NICU most severely affected infants warrant having an umbilical or peripheral arterial catheter inserted for monitoring blood pressure, pH and blood gases. As noted above, if severe anemia is present, a small exchange transfusion with packed red cells, 20-40 mL/kg, may be indicated. An infusion of D10W with maintenance electrolytes should be initiated through an arterial line or peripheral IV. A full "two volume" exchange for hyperbilirubinemia should be delayed for several hours until the infant's initial condition has stabilized (see below). If blood is not needed to treat anemia, hypotension may be corrected with Plasmanate®.
         2. Mild to Moderately Affected Infants: Treatment of less severely affected infants starts with correction of hypotension and acidosis. If clinical condition and gestational age allow, oral feedings should be started in first four hours of life.
         3. All Affected Infants, i.e., those which are Coombs positive:
            1. Laboratory Determinations:
               Bilirubin: The frequency of laboratory determinations will depend on the severity of the hemolytic disease, previous values and therapy. Data available on the cord blood sample will be helpful in anticipating these needs as well. In the first 12-24 hours, severely affected jaundiced and/or anemic infants should be started on phototherapy and have their serum total bilirubin levels be measured every 2-4 hours to establish a trend in its rate of rise. Less severely affected and apparently normal infants may be managed without phototherapy but should have serum bilirubin levels measured every four to six hours for the first 24 hours of life. Measurement of direct bilirubin should be one once, preferably during the first day. Infants found to have an elevated direct bilirubin in cord blood should liver enzyme determinations made and be repeated weekly.
               
               Hemoglobin and hematocrit values should be determined at 8-12 hours of age, before and after each exchange transfusion and daily until stable. Since the severely affected infant often has ß-cell hyperplasia, the infant should be monitored and treated in a similar manner to infants of diabetic mothers. In addition, blood glucose levels should be monitored 1 and 2 hours after each exchange transfusion in which CPDA-1 blood is used.
            2. Phototherapy:
               Phototherapy should be initiated within the first 4 hours of life based on the cord bilirubin level and the subsequent rate of rise of the serum bilirubin concentration. This may avoid the need for an exchange transfusion. It is essential that the infant continue to have serum bilirubin levels monitored while under phototherapy.
            3. Exchange Transfusions:
               The need for and timing of exchange transfusions should be done in consultation with the attending physician. Criteria for exchange transfusion do not change because of phototherapy. After exchange transfusion, serum bilirubin levels should be measured by the chemical method at 2-4 hours after the exchange, and then every 4-6 hours.
            4. Intravenous Immune Globulin Therapy
               Although the mortality rate for exchange transfusion is probably lower than 1%, treatments as effective but less invasive and which have fewer risks would be appealing. One such treatment appears to be evolving.
               Rh antibodies do not fix compliment and do not induce intravascular hemolysis. The mechanism of destruction of antibody-sensitized red blood cells is probably antibody-dependent cellular cytotoxic effects mediated by cells of the RE system. Thus, erythrocyte destruction is similar to destruction of antibody-sensitized platelets in neonatal isoimmune thrombocytopenia. It has been shown in this latter disease that high dose intravenous immune globulin therapy can produce beneficial effects. Accordingly, it seemed plausible that similar therapy might alter the course of bilirubin production and reduce the rate of exchange transfusions in infants with Rh isoimmunization. The results of a recent study that tested this hypothesis concluded that, although the mechanisms was yet unknown, that indeed, high dose intravenous immune globulin therapy (500 mg/kg i.v. over 2-3h as soon as Rh incompatibility is established) did reduce serum bilirubin levels and the need for blood exchange transfusions in children with Rh hemolytic disease (J PEDIATR 1992;121:93-7). The optimum dose of intravenous immune globulin, the most efficacious number of infusions, and the best preparation remain to be determined. Undoubtedly, some of these questions are being answered in trials currently in progress. We would encourage ongoing dialogue of house staff with attendings on the neonatology services to ascertain the current status of this treatment.
      4. At Discharge: Post-hospital Care Plan
         1. Parents: Parents need to be aware that affected infants who may or may not have been anemic at birth (especially those who received one or more in utero erythrocyte transfusions) are at considerable risk for developing clinically significant anemia during the first 3-4 months of life. Their infants should have weekly hematocrit and reticulocyte counts performed and receive simple packed erythrocyte transfusions (20-25 mL/kg of PRBCs) if clinical symptoms appear if Hb levels fall below 6-7 gm/dL without evidence of a reticulocytosis, i.e., reticulocyte count <1%, or <100,000 per µL. Although infants can become sufficiently anemic to develop congestive heart failure, more often they manifest evidence of poor feeding or lack of activity. Life threatening clinical signs can occur in the presence of superimposed acute illnesses, i.e., viral infections.
         2. Local Physician: S/he should be contacted and given the same information as the parents along with an offer to provide the opportunity for future telephone consultation with an NICU staff neonatologist (Dr. Widness or Bell are particularly interested in following these infants).

References:

Millard DD, Gidding SS, Socol ML, et al. Effects of intravascular, intrauterine transfusions on prenatal and postnatal hemolysis and erythropoiesis in severe fetal isoimmunization. J Pediatr 1990;117:447-454.

Weiner CP, Williamson RA, Wenstrom KD, Sipes S, Grant SS, Widness JA. Management of fetal hemolytic disease by cordocentesis: I. Prediction of fetal anemia. Am J Obstet Gynecol 1991;165:546-553.

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