Adding neonatal hyperbilirubinemia/bilirubin encephalopathy to the American Society for Apheresis Guidelines on Therapeutic Apheresis

Dear Editor,

Acute bilirubin encephalopathy describes bilirubin toxicity in the “first weeks after birth”, which is likely caused by unbound bilirubin (not bound to albumin) crossing the blood-brain barrier and causing neurotoxicity.¹ Acute bilirubin encephalopathy first manifests with severe jaundice, lethargy, hypotonia, and poor sucking. It then progresses to an intermediate stage which may include moderate stupor, hypertonia, fever, and a high-pitched cry. The advanced phase of acute bilirubin encephalopathy is likely irreversible and may involve pronounced retrocollis-opisthotonus, a shrill cry, the absence of feeding, apnea, coma, seizure, and death. Those surviving acute bilirubin encephalopathy may develop chronic bilirubin encephalopathy and permanent sequalae (together known as “kernicterus”), which may involve deafness, cerebral palsy, paralysis of upper gaze, and other manifestations.¹

In 2004, the American Academy of Pediatrics (AAP) published guidelines for the management of newborn infants with hyperbilirubinemia.¹ In 2009, an update was published because “kernicterus is still occurring in the United States,” but should be a “never event”.² The guidelines include primary and secondary prevention measures and treatment algorithms.¹ Phototherapy treatment reduces the bilirubin level by converting trans-bilirubin to water-soluble cis-bilirubin, which is more easily excreted into bile. Intravenous immunoglobulin (IVIG) can be used in cases of hemolytic disease (HDFN) caused by ABO and Rh antibodies. Modified whole blood exchange transfusion (using red blood cells and plasma) is still recommended, although total serum bilirubin (TSB) levels for initiating exchange transfusion are higher than for phototherapy. The AAP recommends exchange transfusion as “immediate” therapy for the following: (1) patients with signs of acute bilirubin encephalopathy or (2) TSB levels ≥ 5 mg/dL above the risk-appropriate line on the “exchange transfusion bilirubin nomogram”.¹ Still, most patients who receive exchange transfusion failed phototherapy.

We feel that it is imperative that the American Society for Apheresis (ASFA) include severe hyperbilirubinemia/bilirubin encephalopathy in their Guidelines³ for Therapeutic Apheresis. Phototherapy has not eliminated the need for modified whole blood exchange,⁴ and debilitating cases of kernicterus are still occurring. The ASFA Therapeutic Apheresis Guidelines include pediatric indications for apheresis and information about manual exchange transfusion for malaria and sickle cell disease,³ thus neonatal hyperbilirubinemia should also be included. While there is an ASFA guideline for “autoimmune hemolytic anemia, severe”, it describes therapeutic plasma exchange (TPE) for warm autoimmune hemolytic anemia (WAIHA) and cold agglutinin disease (CAD)/cold autoimmune hemolytic anemia (CAIHA).³ The ASFA guideline for “red cell alloimmunization in pregnancy” is for managing hemolytic disease of the fetus and newborn (HDFN) in pregnant women using TPE.³ Thus, these two ASFA guidelines do not describe the apheresis management of neonatal hyperbilirubinemia. Furthermore, the AAP guidelines do not provide detailed recommendations about modified whole blood exchange (ex. the composition of modified whole blood or the volumes of modified whole blood to be exchanged⁵).

In conclusion, neonatal hyperbilirubinemia/bilirubin encephalopathy remains a serious clinical problem. The eighth edition of the ASFA Therapeutic Apheresis Guidelines should include this condition to help physicians provide the most appropriate whole blood exchange transfusion regimen for these patients.