Hemolytic Disease of the Newborn: A Community Hospitalist Perspective

Recognition and Evaluation

Hemolytic disease of the newborn presents as rapidly developing hyperbilirubinemia and clinical jaundice within the first 12 to 24 hours of life. Severe manifestations include symptomatic anemia and acute bilirubin encephalopathy. Symptoms of acute anemia include pallor, tachycardia, poor nipple feeding, and lethargy. Symptoms occur once RBC mass is inadequate to meet tissue oxygen demand. Severe manifestations include hypoxia, apnea, acidosis, and respiratory distress requiring respiratory support. It is important to note that chronic anemia is often compensated and therefore patients may remain asymptomatic. Untreated acute bilirubin encephalopathy presents with hypertonia, high-pitched cry, apnea, coma, seizures, and potentially death. ⁵ Most community hospital nurseries follow the American Academy of Pediatrics (AAP) guidelines on the management of hyperbilirubinemia in neonates greater than 35 weeks gestation.^4,6

The AAP recommends obtaining DAT, blood type, and Rh (D) type from the infant’s cord blood if the mother is Rh-negative. Optional testing is recommended for infants whose mothers have blood group O. ⁴ Guidelines also recommend serum bilirubin concentration testing prior to discharge or if the infant appears jaundiced. ⁶ At our institution, we obtain DAT, blood type, and Rh (D) type in infants born to blood type O or Rh-negative mothers. ⁷ Jaundice is not always evident early in the course ⁸ ; therefore, we obtain cord bilirubin values in infants who are DAT positive. It is important to keep in mind that the DAT has poor sensitivity for HDN and a negative value does not rule out the diagnosis. ⁴ A 2002 study comparing DAT sensitivities with other established methods (n = 660), cited a sensitivity as low as 38.5%, a specificity of 98.5%, and a positive predictive value of 58.8%. ⁹ This sensitivity was calculated on all neonates and did not specifically consider newborns born to mothers with ABO or Rh-negative blood types. This supports that HDN should be considered in infants with rapidly developing jaundice within the first 24 hours of life, even in those who are DAT negative.

Reasons for the poor sensitivity of the DAT in diagnosing HDN include antibody (IgG) levels below the threshold for detection, removal of antibodies during laboratory preparatory washes, and the presence of antibodies (IgA and IgM) that are not detected by commercial antiglobulin reagents. ¹⁰ Conversely, DAT positivity does not always indicate HDN. In cases where the mother receives RhoGAM for a negative maternal antibody status prior to delivery, the positive DAT in the newborn may reflect maternal Rhogam administration (passive anti-D antibodies) and may not be a true diagnosis of HDN. As this cannot be distinguished from other causes of HDN in most routine laboratories, we advocate that every case of DAT positivity in newborns be approached seriously. ⁷

We obtain repeat bilirubin concentrations, hemoglobin, hematocrit, and reticulocyte counts at 3 to 6 hours of life in infants with suspected HDN. The evaluation algorithm followed by our practice is included for reference in Figure 2 and describes the initial serum tests, 6-hours-of-life studies, and guidelines for phototherapy and IVIG initiation.

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Figure 2.

Evaluation algorithm for patients with suspected HDN.

Acute Management

Phototherapy is the mainstay of treatment for HDN. Decisions to initiate phototherapy in infants above 35 weeks gestation are guided by TSB concentrations, gestational age, and neurotoxicity risk factors. ⁴ Phototherapy is regarded as generally safe, and the risk of toxicity is rare. ⁵ Currently, there is limited evidence to support prophylactic phototherapy in DAT positive infants. ¹¹ While some data exist, more studies are required to provide a threshold for the initiation of phototherapy in infants who are below 35 weeks gestation. ¹²

Intravenous immunoglobulin has been used in conjunction with intensive phototherapy to reduce the need for exchange transfusion. Serious complications can occur, including transfusion-transmitted diseases, anaphylaxis, thrombosis, pulmonary emboli, and renal failure. ⁵ Although several studies have shown that IVIG decreases the need for exchange transfusion, the validity of these studies is in question. One systematic review revealed high degrees of bias in studies showing the efficacy of IVIG, whereas another found insufficient evidence to make a recommendation for its use.^13,14 Nevertheless, this therapy may be considered for infants with HDN who are not responding to intensive phototherapy in preparation for exchange transfusion.

Phototherapy byproducts are eliminated through urine; therefore, infants with HDN should be adequately hydrated. Still, there is no evidence that IVFs provide additional benefit beyond adequate oral hydration. ¹⁵ A Cochrane Review showed no evidence that IVFs administration alters clinical outcomes of bilirubin encephalopathy in otherwise healthy term infants requiring phototherapy due to unconjugated hyperbilirubinemia. ¹⁵ However, additional studies are needed to assess the role of IVFs in HDN.

Infants with symptomatic anemia may benefit from transfusion of group O, Rh negative–packed RBCs. Case reports have demonstrated successful management with phototherapy and simple transfusion alone. ¹⁶ However, infants with severe hyperbilirubinemia or anemia and cardiovascular collapse, may require exchange transfusion. Whereas the mortality rate of exchange transfusion is less than 0.3% in term neonates, it increases to 10% in preterm neonates. Surprisingly, morbidity rates may reach up to 24% even in term neonates. ⁵ Complications include cardiorespiratory instability, apnea, catheter-related injury, thrombocytopenia, and infection. ⁵

Community hospitals without level 3 or 4 NICUs should have established transfer guidelines. In HDN, the decision to transfer is largely based on clinical stability, the severity of anemia, and the anticipation of exchange transfusion. Shared decision-making should occur between the primary pediatric or newborn hospitalist and the neonatologist at the receiving tertiary care center.

Late Onset Disease

The maternal antibody may continue to cause hemolysis for weeks to months after birth, for as long as it is present in the infant’s circulation. ⁵ Anemia in HDN is divided into early anemia and late anemia. Whereas pediatric hospitalists often manage early anemia, defined as anemia occurring within the first 7 days of life, late anemia does occur in up to 83% of infants whose gestational age is 35 weeks or greater. ⁵ Late anemia is further divided into late hemolytic anemia and late hyporegenerative anemia. Late hemolytic anemia is thought to be antibody mediated, worsened by the natural decline of hemoglobin levels.^2,5 Late hyporegenerative anemia results from a combination of factors, including antibody-mediated destruction of RBCs and RBC precursors, marrow suppression by transfusion, and erythropoietin deficiency.^2,5 Both types of late onset anemia are worsened by the expanding intravascular volume of the growing infant.^2,5 As a result, infants with HDN might require repeat transfusions weeks to months after birth. Late anemia typically resolves by 3 months of age. ⁵ Other potential complications of HDN include thrombocytopenia, cholestasis, and iron overload secondary to transfusion. ⁵

Limitations and Future Considerations

Although the pathology of HDN is well studied, timely management of severe disease is challenging for community hospitals due to limited resources and training. Intravenous immunoglobulin may be available but not routinely used and therefore staff must be adequately trained in appropriate dosing and administration. Intravenous immunoglobulin administration often requires a one-to-one nursing assignment during initiation of the infusion. In smaller NICUs, these therapies might not be possible without additional staffing.

The potential severity of HDN and the rapidity with which it can progress make prioritization of management steps essential. Shared decision-making with neonatology should be initiated early. Discussions should include phototherapy initiation, IVIG administration, and the indications for IVFs. In addition, work up of other diagnoses, including sepsis, should be considered. In this case, hyperbilirubinemia was detected early because a cord bilirubin was obtained, allowing early initiation of phototherapy. We promote starting phototherapy followed by IVIG as soon as possible if there is clinical jaundice and significant hyperbilirubinemia or hemolysis.

The screening policy for hyperbilirubinemia and HDN differs within different institutions. The standardization and development of universal guidelines would be beneficial. Similarly, further study regarding the efficacy of IVIG in preventing exchange transfusions, and the role of IVFs in infants at high risk for acute encephalopathy or kernicterus would also be helpful. Along with these interventions, additional education and training in the delivery of HDN-specific therapeutics in community hospitals without higher level NICUs could lessen the morbidity and mortality associated with this disease.