Prior to the institution of IUTs, many severely affected fetuses died in utero or soon after birth. IUT corrects fetal anemia and reduce the risk of congestive heart failure and hydrops fetalis. Fetal bilirubin is cleared very efficiently by the placenta and the mother, so bilirubin removal is not necessary until after birth. Percutaneous intraperitoneal fetal transfusion, pioneered by Liley in the 1960s,5 has been largely replaced by ultrasound-guided direct intravascular transfusion into the umbilical vein.80,87 The intravascular technique circumvents the problem of erratic and often poor absorption of RBCs from the peritoneal cavity in such fetuses. However, intraperitoneal transfusions may be necessary when intravascular access is difficult, as in early pregnancy when the umbilical vessels are narrow or later when increased fetal size prevents access to the umbilical cord.88,89 The first fetal blood sampling with transfusion ideally is performed before hydrops develops. Transfusions are given at fetal hematocrit levels of 25 to 30 percent or less, or if the fetal hemoglobin is 4 to 6 standard deviations below the mean for gestational age. Generally, the hematocrit drops by 1 to 2 percent per day in the transfused hydropic fetus. The fall in hematocrit is rapid in fetuses with severe hemolytic disease, often necessitating a second transfusion within 7 to 14 days. The interval between subsequent transfusions varies, but may be 21 to 28 days. The nonhydropic fetus can tolerate rapid RBC infusions of 5 to 7 mL/min because of the capacitance of the placenta. The hydropic fetus requires slower transfusion rates and can tolerate only smaller, more frequent transfusions. Very low pretransfusion fetal hematocrit levels, rapid large increases in posttransfusion hematocrit level, and increases in umbilical venous pressure during IUTs are associated with fetal death after transfusion.90,91
RBCs for IUT are typically crossmatch compatible with the mother’s plasma and negative for any identified antibody; they should also be irradiated and leukoreduced.92,93 Many centers do not use RBCs heterozygous for sickle hemoglobin to prevent sickling in the fetus at low oxygen tension although direct evidence of its benefit is lacking, and 5 to 7 days old to maximize circulatory half-life. Obtaining RBCs from a rare donor registry may be required in cases of unusual or combination antibodies. In this circumstance, frozen, deglycerolized RBCs may be the only available product. Some centers use maternal RBCs for IUTs, supporting serial maternal donations with iron and folate therapy.94 RBC transfusion is calculated to increase the fetal hematocrit to between 40 and 45 percent. The RBCs are often washed free of additive solutions, and packed to a hematocrit of 70 to 85 percent in a volume calculation based on estimated fetal placental blood volume, fetal hematocrit, and hematocrit of donor RBCs. Various normograms and formulas for the calculation of donor blood volume have been published.95,96 If the hematocrit of the donor unit is approximately 75 percent, multiplying the estimated fetal weight in grams (estimated by ultrasonography) by a factor of 0.02 provides a fairly accurate estimate of the volume of RBCs to be transfused to achieve a fetal hematocrit increment of 10 percent.97
Van Kamp and colleagues estimated procedure-related complication rates of 2.9 percent in the absence of hydrops and 3.9 percent in the presence of hydrops in a cohort study of 254 fetuses treated with 740 IUTs in a single center.98 The most common problem was transient fetal heart rate abnormalities, which occurred in 8 percent of procedures. The procedure-related pregnancy loss rate was calculated to be 1.6 percent per procedure. Fetal distress during or after the procedure may result in emergency cesarean section. Cord accidents such as hemorrhage from the puncture site or rupture of the cord are rare. Additional alloantibodies may develop in already alloimmunized women undergoing IUT; in one study, 25 percent (53 of 212) of “responder” women treated with IUT formed new alloantibodies, 53 percent of which were directed against non-Rh and -K antigens.99
The decision regarding the appropriate time to deliver the baby is based on gestational age, fetal weight and lung maturity, fetal response to the IUTs, ease of performing the transfusions, and antenatal ultrasonography and Doppler studies for fetal anemia. Transfusions usually are provided up to 35 weeks so as to prolong gestation safely until the risks of preterm birth and its attendant complications are minimized, with delivery once adequate lung maturity has occurred.76
In women with severe alloimmunization and with fetal losses or hydrops very early in pregnancy, a variety of methods have been used to suppress the antibody response and prolong survival of the fetus until IUT becomes technically feasible. Use of intravenous immunoglobulin (IVIG), serial plasmapheresis, or plasmapheresis combined with IVIG have been successful in some cases.89,100,101 IVIG may cause nonspecific Fc blockade of the fetal reticuloendothelial system.
A sample of cord blood should be collected from all newborns at the time of delivery. However, specific testing of cord blood samples is performed only if the mother is Rh-negative, if the maternal serum contains red cell alloantibodies of potential clinical significance, or if the neonate develops signs of hemolytic disease. Tests should include ABO and Rh typing and a DAT. Many birth hospitals routinely test cord blood for the infant’s blood type and DAT if the mother is O Rh-positive in order to predict which infants are at increased risk of hyperbilirubinemia. In severe Rh alloimmunization, high titers of maternal antibody may block Rh-antigenic sites on the neonatal red cells, leading to false-negative Rh typing. Antepartum RhIg given to the mother may cause a weakly positive DAT result in the infant at birth. Contamination of the cord blood sample with Wharton jelly during collection can also result in a false-positive DAT result. Although the DAT usually is positive in all forms of alloimmune HDFN, the test cannot predict reliably the degree of clinical severity.102,103 This is especially true for cases resulting from ABO sensitization. When fetomaternal ABO incompatibility is present, the presence of maternally derived IgG anti-A or anti-B in the infant’s serum may be demonstrated by the IAT to support the diagnosis of ABO hemolytic disease. On the other hand, it is important to bear in mind that hemolysis in ABO-incompatible, DAT-negative infants may result from hematologic causes other than alloimmunization or from red cell membrane defects (Chap. 46).104 Elution of maternal antibody from the infant’s red cells, followed by tests to determine the specificity of the antibody in the eluate, may be useful, particularly when several antibodies are present in the maternal serum or when the maternal antibody screen is negative.57 Infants who received IUTs may have mild or moderate anemia with little reticulocytosis. Because most of their circulating red cells are transfused antigen-negative cells, the DAT may be negative, but the IAT will be strongly positive.
Cord blood hemoglobin and indirect bilirubin determinations are useful in determining disease severity. Most infants with cord hemoglobin levels within the age-adjusted normal range do not require exchange transfusion. Usually, a cord hemoglobin level less than 11 g/dL in a term newborn and/or a cord-indirect bilirubin level greater than 4.5 to 5 mg/dL indicate severe hemolysis and often warrant early exchange transfusion. Early exchange transfusion also may be indicated if the rate of rise of bilirubin, measured every 4 to 6 hours, exceeds 0.5 mg/dL per hour. The reticulocyte count usually is greater than 6 percent and may approach 30 to 40 percent in severe Rh disease. The blood film in Rh disease is characterized by increased nucleated RBCs, polychromasia, and anisocytosis. Alternatively, the blood film in ABO HDN is marked by microspherocytes (Fig. 55–4). Severely affected infants may also have thrombocytopenia. Low reticulocyte counts disproportionate to the low hematocrit may be noted in Kell-mediated HDN. Severely affected infants may have hypoglycemia, secondary to hyperinsulinemia. Arterial blood gas analysis may reveal metabolic acidosis and/or respiratory decompensation, and hypoalbuminemia is often present.
Alloimmune hemolytic disease of the newborn. Blood films. A. Infant with ABO blood group alloimmune hemolytic anemia. Note the high prevalence of spherocytes and the large polychromatophilic cells, indicative of reticulocytosis. B. Infant with Rh blood group alloimmune hemolytic anemia. Note spherocytes, reticulocytes, and the nucleated red cells. The intense erythroblastosis is characteristic of Rh blood group alloimmune hemolytic anemia and is less prominent in ABO blood group alloimmune hemolytic anemia. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.)
Immediate Postnatal Management
Results of antenatal monitoring and obstetric interventions during pregnancy and the history of the outcome of previous pregnancies allow the neonatal team to anticipate the needs of the infant born with hemolytic disease. In infants with severe hemolytic disease without the benefit of IUTs, severe anemia and hydrops are the immediate life-threatening concerns and often are accompanied by perinatal asphyxia, surfactant deficiency, hypoglycemia, acidosis, and thrombocytopenia. Exchange transfusions and phototherapy are the mainstays of treatment.
Resuscitation and stabilization of hydropic infants is challenging. Endotracheal intubation and positive-pressure ventilation with oxygen is usually necessary. Drainage of pleural effusions and ascites may be required to facilitate gas exchange. Metabolic acidosis and hypoglycemia require correction. A partial exchange transfusion may initially be performed using packed red cells to improve hemoglobin levels and oxygenation. A double-volume exchange transfusion is considered only after the initial stabilization.
In a study of 191 infants born alive after IUTs between 1988 and 1999, the hematocrit at birth ranged from 13 to 51 percent.105 Endotracheal ventilation was required more often in babies who had been severely hydropic in utero, but the requirements for exchange transfusion or simple transfusion did not differ between babies who had been hydropic in utero and those without evidence of hydrops. Although some centers report no difference in the frequency of exchange transfusions in babies who have had IUTs compared with babies who have not had IUTs,105,106 other centers report that infants who received multiple IUTs are usually born closer to term and often require less phototherapy and fewer exchange transfusions in the neonatal period.25,107 Nonetheless, many infants with severe HDFN require additional RBC transfusions for severe and prolonged hyporegenerative anemia secondary to suppression of fetal erythropoiesis.21,22,106 Approximately three-quarters of term and near-term infants who had received IUT for Rh HDFN required transfusion within 6 months of age, compared with 26 percent of infants with Rh HDFN who had not received an IUT.106 Thus, careful monitoring of the baby and the baby’s lab values are necessary not only during the initial hospital course but also after hospital discharge.
Exchange transfusion corrects anemia, removes bilirubin and free maternal antibody in the plasma, and replaces the infant’s blood with antigen-negative RBCs that should have normal in vivo survival. Neonatal exchange transfusions can be performed by a continuous technique (simultaneous withdrawal and replacement) or discontinuous technique (alternating withdrawal and replacement). Regardless of the technique, the kinetics of exchange are very similar. A double-blood-volume exchange replaces approximately 85 percent of the infant’s blood volume with antigen-negative RBCs; however, the amount of bilirubin or maternal alloantibody removed by exchange transfusion is significantly less (25 to 45 percent) reflecting the equilibrating tissue-bound plasma pool. Infusion of albumin prior to the exchange transfusion may help bilirubin binding, thus increasing the amount of bilirubin removed. Equilibration of extravascular and intravascular bilirubin, and continued breakdown of red cells by persisting maternal antibodies, result in a rebound of bilirubin following initial exchange transfusion, sometimes requiring repeated exchange transfusions in severe hemolytic disease.
The ideal volume for an exchange transfusion is twice the infant’s blood volume. There is little benefit achieved by exceeding two blood volumes because the efficiency of exchange transfusion declines exponentially as the procedure continues. The volume needed for double-volume exchange depends on the total blood volume (TBV) recognizing differences in term and preterm infants:
Double-blood-volume exchange volume (term) = 85 mL/kg × 2, or 170 mL/kg
Double-blood-volume exchange volume (preterm) = 100 mL/kg × 2, or 200 mL/kg
To perform the exchange transfusion, aliquots of the reconstituted whole blood product are administered while equal amounts of the infant’s blood are withdrawn. Careful attention not to exceed 2 mL/kg per minute (continuous) or 5 mL/kg at a time over 3 to 10 minutes (discontinuous technique) is required to prevent rapid fluctuations in arterial and intracranial pressure.108
The indications for “early” exchange transfusions performed within the first 12 hours of life have remained essentially unchanged over the last 45 years, with minor modifications. Cord hemoglobin levels equal to or less than 11 g/dL, cord bilirubin levels equal to or greater than 5.5 mg/dL, and rapidly rising total serum bilirubin (TSB) equal to or greater than 0.5 mg/dL per hour despite phototherapy are commonly used criteria for early exchange transfusions. Early exchange transfusion has the advantage of replacing sensitized RBCs with normal RBCs, thereby removing not only bilirubin but also the source of future bilirubin. Because bilirubin is distributed in the extracellular fluids, efficiency is enhanced by removing sensitized cells early in the process. Newborns that have been treated with serial IUTs until term often do not require exchange transfusions; however, late anemia is common because of IUT-induced erythropoietic suppression, which may last for many weeks after delivery.109
“Late” exchange transfusions are performed when serum bilirubin levels threaten to exceed approximately 20 to 22 mg/dL in term infants. The American Academy of Pediatrics (AAP) Subcommittee on Hyperbilirubinemia provided revised guidelines for exchange transfusion in infants 35 or more weeks’ gestation.110 In view of the fact that bilirubin levels rise steadily from birth and peak at approximately 72 to 96 hours of age, exchange transfusion should be considered if serum bilirubin levels reach 15 mg/dL in an infant of 35 weeks’ gestation or 17 mg/dL in an infant of 38 weeks’ gestation despite intensive phototherapy. Immediate exchange transfusion is recommended in infants showing signs of acute bilirubin encephalopathy, even if bilirubin levels are falling.110 Conjugated or direct bilirubin values are not subtracted from total bilirubin levels when considering levels for exchange transfusions. Exchange transfusions are performed at lower bilirubin levels in premature infants, particularly those with hypoxemia, acidosis, and hypothermia, but little data are available to guide intervention in these infants. In infants with birth weights of at least 1500 g, exchange transfusions usually are performed at TSB of 13 to 16 mg/dL but may be considered even at levels as low as 8 to 9 mg/dL in sick babies of 24 weeks’ gestation.111 The bilirubin-to-albumin ratio (mg/dL:g/dL), considered to be a surrogate measure of free bilirubin, may provide additional data in determining the need for exchange transfusion in both term and preterm neonates.112
Blood components chosen for the exchange transfusion should be ABO and Rh compatible (Rh-negative in Rh HDN), negative for offending antibody(ies), and crossmatch compatible with maternal serum. In the case of ABO HDN, O RBCs should be chosen for exchange out of concern that the more developed A or B antigens on any transfused adult donor RBCs may more avidly bind maternal anti-A or anti-B and may result in hemolysis. Either reconstituted whole blood (WB) (e.g., RBCs plus fresh-frozen plasma [FFP]) or stored WB if available can be used for neonatal exchange transfusions. The RBCs are reconstituted with AB or compatible plasma to a final hematocrit of 50 to 60 percent. Fresh (<7 days) RBCs should be used. When fresh RBC units are unavailable, some centers wash the RBCs and transfuse as soon as possible after washing to avoid hyperkalemia. Additionally, the RBC units should be leukoreduced, gamma irradiated, and sickle-negative.113
Potential complications of exchange transfusion include hypocalcemia, hyperglycemia, hypoglycemia, thrombocytopenia, dilutional coagulopathy, neutropenia, disseminated intravascular coagulation, umbilical venous and/or arterial thrombosis, necrotizing enterocolitis, and infection. Thrombocytopenia and hypocalcemia are reported to be the most common complications (incidence ranging from 29 to 47 percent).114,115 Thrombocytopenia results from a dilutional effect of replacing platelet rich neonatal WB with platelet-deficient reconstituted WB. Infants who may be thrombocytopenic from severe HDFN or other comorbidities should be monitored closely after an exchange transfusion as they may require platelet transfusion. Hypocalcemia occurs as a result of the citrate load infused, which an immature neonatal liver has difficulties metabolizing. In anticipation of hypocalcemia, ionized calcium levels should be monitored throughout the exchange transfusion procedure, and intravenous calcium replacement may be needed in sick preterm infants. Furthermore, attempts should be made to correct conditions that may potentiate the symptoms of hypocalcemia such as alkalosis, hypothermia, hypomagnesemia, and hyperkalemia.116
In a retrospective review of exchange transfusions performed in two neonatal intensive care units between 1981 and 1995, the risk of death or permanent serious sequelae was reported to be as high as 12 percent in sick infants, compared with less than 1 percent in healthy infants. Adverse outcomes were more frequent in exchanges done on preterm infants younger than 32 weeks, infants with other significant comorbidities, and when umbilical catheters were used rather than other means of central venous access.117 Another center reported no increase in the number of complications and no exchange transfusion–related deaths over a 21-year period, even though there was a decline in the frequency of exchange transfusions performed over the years.115 Careful clinical judgment is required to balance the potential risk of adverse events from exchange transfusion with the risk of bilirubin encephalopathy in neonates who are premature, sick, or both.
Phototherapy is the mainstay of treatment for unconjugated hyperbilirubinemia; the objective of treatment is preventing bilirubin neurotoxicity. Exposure of bilirubin to light results in structural and configurational isomerization of bilirubin to less toxic and less lipophilic products that are excreted efficiently without hepatic conjugation. The effectiveness of phototherapy is influenced by the wavelength and irradiance of light, the surface area of exposed skin, and the duration of exposure. Intensive phototherapy involves the use of high levels of irradiance (≥30 μW/cm2) in the 430- to 490-nm band, delivered to as much of the infant’s surface area as possible. Intensive phototherapy effectively reduces bilirubin levels and decreases the need for exchange transfusions for hyperbilirubinemia in ABO and Rh HDN.118,119 Early and intensive phototherapy should be initiated in infants with moderate or severe hemolysis or in infants with rapidly rising bilirubin levels (>0.5 mg/dL per hour). In full-term infants (at least 38 weeks’ gestation) with HDFN, intensive phototherapy should be initiated if TSB levels are 5 mg/dL or greater at birth, 10 mg/dL at 24 hours after birth, or approximately 13 to 15 mg/dL at 48 to 72 hours after birth.110 Phototherapy is recommended at lower levels for preterm or sick infants. Therapy often is initiated at TSB less than 5 mg/dL in preterm infants with HDFN so as to avoid potentially risky exchange transfusions.110,111
A number of small studies have reported on the successful administration of high-dose IVIG as an adjuvant treatment to standard therapy for HDN as way to prevent the need for exchange transfusions.109 The decreased bilirubin levels in infants treated with IVIG is attributed to reduction in hemolysis secondary to blockade of mononuclear phagocyte Fc receptors. A Cochrane meta-analysis of the three largest studies demonstrated that IVIG administration (0.5 to 1.0 g/kg) may prevent exchange transfusion for many term infants with HDN, which contributed to an AAP published recommendation that IVIG be considered in Rh HDN when TSB continues to rise despite aggressive phototherapy or when the TSB is within 2 to 3 mg/dL of the exchange level.110 However, a prospective randomized control trial showed that prophylactic IVIG (0.75 g/kg) did not decrease the duration of phototherapy, maximum bilirubin levels, need for RBC transfusion or for exchange transfusion in Rh HDN.120 Although, the majority of the infants included in this study were treated with IUT, IVIG was not effective at reducing the need for exchange transfusion in either the group treated with IUTs or those who were not. Thus, there is no universal approach to the use of IVIG in patients with HDN; it seems justified as a temporizing measure to exchange transfusion in neonates with severe HDN unmodified by IUT or neonates with HDN where a previous sibling had suffered from severe disease requiring exchange transfusion.109
Recombinant human erythropoietin (rHuEPO) given subcutaneously at a dose of 200 to 400 U/kg given three times weekly for 2 weeks is sometimes administered to infants in an effort to reduce or prevent transfusion for late-onset anemia from HDN. Some studies show its use to decrease the need for postnatal transfusions in infants with late hyporegenerative anemia of Rh HDN and in neonates with Kell HDN.21,121,122 In one study of 103 patients with Rh HDN, administration of 200 U/kg of rHuEPO, three times per week for 6 weeks, reduced the number of RBC transfusions to a mean of 1.5, and 55 percent of patients did not require any transfusions.121 rHuEPO is more effective in decreasing future transfusion needs in neonates that never received IUTs suggesting that IUTs may decrease the neonatal response to rHuEPO.123 Despite encouraging reports in relatively small numbers of neonates, it remains unclear whether rHuEPO, or the longer-acting analogue darbepoetin, offer a distinct clinical benefit in regard to decreasing donor exposures or improvement of morbidity and/or mortality in this population. rHuEPO has been shown to lessen neurologic sequelae in term infants with hypoxic ischemic encephalopathy, therefore it may have a role as a potential treatment for perinatal brain injury in the future.124