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For additional articles relating to hyperbilirubinemia and treatment options, see our additional reading by topic page.
Intervention for hyperbilirubinemia includes phototherapy based on cord bilirubin, serial determinations, and the rate of rise. A cord bilirubin of ⩾2.05 mg/dL (pre-term) to 2.15 mg/dL (full-term) indicates need for phototherapy 60. Serum bilirubin should be assessed regularly during phototherapy. It is important to note that infants with HDFN will have rebounding hyperbilirubinemia. When phototherapy is stopped, levels will increase rapidly and the infant will frequently require additional phototherapy. To help prevent this, it is better to use continuous phototherapy vs intermittent phototherapy. Because home phototherapy is not an option for infants with HDFN, a 12 or 24 hour trial without lights before discharge is advisable to reduce hospital readmissions.
The implementation of intravenous immune globulin (IVIG) in the newborn is employed by many neonatal units in the treatment of HDFN after birth 46. IVIG is given when bilirubin levels are rising despite intensive phototherapy, or when levels are approaching the levels necessitating an exchange transfusion. Early studies indicated that high-dose IVIG (0.5g/kg IV immediately after HDFN is confirmed) does reduce serum bilirubin levels and subsequent need for exchange transfusion 47. A recent meta-analysis confirmed these findings in studies where IVIG doses ranged from 0.5g/kg to 1.5g/kg in one to three administrations 48. Adverse effects of IVIG can include: fever, allergic reactions, rebound hemolysis, and fluid overload 88. IVIG can affect the efficacy of some live-virus vaccines for 11-12 months. This can affect administration of the rotavirus vaccine.
Exchange transfusion should be conducted if bilirubin reaches or exceeds critical levels as shown below (infants with HDFN are medium or high risk)45. A cord bilirubin level of >5 mg/dL, or a rate of rise in serum bilirubin of more than 0.5-1 mg/dL/h is predictive of the ultimate need for exchange transfusion 84. IVIG may prevent the need for an exchange transfusion if initiated early enough.
While phototherapy and exchange transfusions are effective treatments for hyperbilirubinemia after it forms, much can be done to optimize treatment of infants with HDFN to prevent and eliminate the development of kernicterus. Studies are currently underway on a multitude of pharmacotherapeutic agents to prevent or treat neonatal hyperbilirubinemia, including metalloporphyrins. The increased hemolysis occuring in infants with HDFN is associated with increased bilirubin production and a greater risk for neurologic injury. Preventing the formation of bilirubin via heme oxygenase (the rate-limiting enzyme responsible for the production of bilirubin), is possible with both natural and synthetic metalloporphyrins 87. Clinical studies of SnMP show that it prevents excessive hyperbilirubinemia and reduces the duration and need for phototherapy in both term and near-term infants 86. The use of metalloporphyrins reduces the risk of Kernicterus and BIND, however side effects such as photosensitivity and potential inhibition of several other enzymes that have essential roles in metabolism have been known to occur 86. While multiple metalloporphyrins have been studied in animal models, only two have been studied in human neonates: tin protoporphyrin (SnPP) and tin mesoporphyrin (SnMP). SnPP was highly efficacious, but abandoned due to its photosensitizing properties85. SnMP can be used at lower doses with minimal photoreactivity 87. Metalloporphyrins are currently being studied and administered on a compassionate basis, particularly in regards to patients with religious objections to blood products 89.
Elevated levels of circulating maternal antibodies in the neonatal circulation in conjunction with suppression of the fetal bone marrow production of red cells often results in the need for neonatal red cell “top-up” transfusions after discharge from the nursery. This results in a 1- to 3-month period in which up to 75% of these infants may need “top-up” red cell transfusions 96. Weekly reticulocyte counts and hematocrit levels should be assessed until a rising reticulocyte count is noted for at least 2 consecutive weeks. The threshold-for-transfusion includes a hematocrit value of less than 30% in the symptomatic infant or less than 20% in the asymptomatic infant have been suggested by some experts. Typically, only one neonatal transfusion is required, although a maximum of up to three has been reported.
Erythropoietin has been in use since the 1990s as an adjunct treatment for late anemia and to increase a reduced reticulocyte count. In limited single-arm studies and case reports, erythropoietin has been shown to be safe 33, 38 and may reduce the need for transfusion in neonates with HDFN 46, 66, 68, 69, 70. In one 6-week study of 20 infants with HDFN due to anti-D, the “number of erythrocyte transfusions was significantly lower than that of the control group (1.8 versus 4.2). The reticulocyte counts and Hb levels rose earlier in the treatment group" 13. This may also be a treatment option for children whose parents object to the use of blood products for religious reasons 67. For additional articles relating to erythropoietin, see our additional reading by topic page.
Active hemolysis consumes folate; folate is a key ingredient in erythropoiesis. As a result, folic acid is frequently prescribed for infants with HDFN in order to encourage the creation of new RBCs. Various approaches supplement folic acid at a dosage between 50 µg/day and 300µg/day for 3 months 56.