HEMOLYTIC DISEASE FOLLOW-UP

hemolytic disease follow-up - Further Inpatient Care:
• The stabilization of a hydropic newborn requires a high level of intensive coordinated management by a neonatal team well prepared for the possibly affected infant. In general, immediate intubation followed by draining of pleural effusions and ascites results in immediate improvement in respiratory gas exchange. A cautious correction of anemia with packed RBCs or by exchange transfusion is necessary to prevent circulatory overload. These neonates have normal blood volume but elevated central venous pressure. A close monitoring of metabolic status (eg, watching for hypoglycemia, hypocalcemia, hyperkalemia, acidosis, hyponatremia, renal failure) is absolutely essential to achieve a successful outcome.

• In spite of the first use of phototherapy by Cremer and associates more than 40 years ago, no standard method for delivering phototherapy yet exists.
o Phototherapy units differ widely with respect to the type and size of lamps used. The efficacy of phototherapy depends on the spectrum of light delivered, the blue-green region of visible light being the most effective; irradiance (μW/cm2/nm); and surface area of the infant exposed. High-intensity phototherapy first described by Tan in 1977 uses irradiance greater than 25 μW/cm2/nm up to 40 μW/cm2/nm when a dose-response relationship to bilirubin degradation reaches a plateau. Nonpolar bilirubin is converted into 2 types of water-soluble photoisomers as a result of phototherapy. The initial and most rapidly formed configurational isomer 4z, 15e bilirubin accounts for 20% of total serum bilirubin level in newborns undergoing phototherapy and is produced maximally at conventional levels of irradiance (6-9 μW/cm2/nm).
o The structural isomer lumirubin is formed slowly, and its formation is irreversible and is directly proportional to the irradiance of phototherapy on skin. Lumirubin is the predominant isomer formed during high-intensity phototherapy. Decrease in bilirubin is mainly the result of excretion of these photoproducts in bile and removal via stool. In the absence of conjugation, these photoisomers can be reabsorbed by way of the enterohepatic circulation and diminish the effectiveness of phototherapy.

• Exchange transfusion removes circulating bilirubin and antibody-coated RBCs, replacing them with RBCs compatible with maternal serum and providing albumin with new bilirubin binding sites.
o The process is time consuming and labor intensive, but it remains the ultimate treatment to prevent kernicterus. The process involves the placement of a catheter via the umbilical vein into the inferior vena cava and removal and replacement of 5- to 10-mL aliquots of blood sequentially, until about twice the volume of the neonate's circulating blood volume is reached (ie, double-volume exchange).
o This process removes approximately 70-90% of fetal RBCs. The amount of bilirubin removed varies directly with the pretransfusion bilirubin level and amount of blood exchanged. Because most of the bilirubin is in the extravascular space, only about 25% of the total bilirubin is removed by an exchange transfusion. A rapid rebound of serum bilirubin level is common after equilibration and frequently requires additional exchange transfusions.
o The indications for exchange transfusion are controversial, except for the fact that severe anemia and the presence of a rapidly worsening jaundice despite optimal phototherapy in the first 12 hours of life indicate the need for exchange transfusion. In addition, the presence of conditions that increase the risk of bilirubin encephalopathy lowers the threshold of safe bilirubin levels.
o The following are requirements for exchange transfusion 1. Severe anemia (Hb <10 g/dL) 2. Rate of bilirubin rises more than 0.5 mg/dL despite optimal phototherapy 3. Hyperbilirubinemia o Exchange transfusion is not free of risk, with the estimated morbidity rate at 5% and the mortality rate as high as 0.5% from the procedure. Apnea, bradycardia, cyanosis, vasospasm, and hypothermia with metabolic abnormalities (eg, hypoglycemia, hypocalcemia) are the most common adverse effects.

hemolytic disease follow-up - Deterrence/Prevention:
• Prevention of Rh hemolytic disease
o Rh immunoglobulin (RhIG) was licensed in 1968 in North America after several studies demonstrated its effectiveness in preventing Rh alloimmunization when administered to the mother within 72 hours of delivery. The current standard is to administer RhIG to all unsensitized Rh-negative women at 28 weeks' gestation with an additional dose administered soon after birth if the infant is Rh-positive, irrespective of the ABO status of the baby.
o The standard dose of RhIG is 300 mcg and is increased (300 mcg for every 25 mL of fetal blood in maternal circulation) based on the amount of fetomaternal hemorrhage, which can be quantified using the Kleihauer-Betke technique. Because the time required for the Kleihauer-Betke test usually is longer, most physicians resort to the indirect Coombs test in the mother to assess the adequacy of RhIG dose in a woman with significant fetomaternal hemorrhage. The indirect Coombs test result should become positive in a woman with a prior negative test result, suggesting the presence of excess antibody in circulation. Also administer RhIG to unsensitized Rh-negative women after any event known to be associated with transplacental hemorrhage. The current incidence of Rh immunization stands at 0.1% with the above recommendations.

Complications:
• The 2 major complications of HDN are bilirubin encephalopathy (kernicterus) and late anemia of infancy.
o Bilirubin encephalopathy
􀂃 Before the advent of exchange transfusion, kernicterus affected 15% of infants born with erythroblastosis. Approximately 75% of these neonates died within 1 week of life, and a small remainder died during the first year of life. Survivors had permanent neurologic sequelae and were thought to have accounted for 10% of all patients with cerebral palsy (CP) .
􀂃 The mechanism by which unconjugated bilirubin enters the brain and damages it is unclear. Bilirubin enters the brain as lipophilic free bilirubin unbound to albumin, as supersaturated bilirubin acid that precipitates on lipid membrane in low pH, or as a bilirubin-albumin complex that transfers bilirubin to tissue by direct contact with cellular surface. A damaged blood-brain barrier enhances the entry of all forms of bilirubin into the brain, which is especially important in preterm neonates with respiratory acidosis and vascular injury.
􀂃 Bilirubin has been postulated to cause neurotoxicity via 4 distinct mechanisms: (1) interruption of normal neurotransmission (inhibits phosphorylation of enzymes critical in release of neurotransmitters), (2) mitochondrial dysfunction, (3) cellular and intracellular membrane impairment (bilirubin acid affects membrane ion channels and precipitates on phospholipid membranes of mitochondria), and (4) interference with enzyme activity (binds to specific bilirubin receptor sites on enzymes).
􀂃 The pathologic findings include characteristic staining and neuronal necrosis in basal ganglia, hippocampal cortex, subthalamic nuclei, and cerebellum. The cerebral cortex is s generally pared. About half of these neonates also have extraneuronal lesions, such as necrosis of renal tubular, intestinal mucosal, and pancreatic cells.
􀂃 Clinical signs of bilirubin encephalopathy typically evolve in 3 phases. Phase 1 is marked by poor suck, hypotonia, and depressed sensorium. Fever and hypertonia are observed in phase 2, and at times, the condition progresses to opisthotonus. Phase 3 is characterized by high-pitched cry, hearing and visual abnormalities, poor feeding, and athetosis. The long-term sequelae include choreoathetoid CP, upward gaze palsy, sensorineural hearing loss, and, less often, mental retardation.
􀂃 Currently, the mortality rate stands at 50% in term newborns, but mortality is nearly universal in the preterm population who may simply appear ill without signs specific for kernicterus. Lately, research has indicated that bilirubin production rates may be the critical piece of information identifying jaundiced infants at risk of neurotoxicity. A high bilirubin production rate is thought to result in rapid transfer of bilirubin to tissue, causing high tissue load, in which case any small further increase has great potential to enter the brain. Because the total serum bilirubin represents not only bilirubin production but also distribution and elimination, it is not an absolute indicator of risk of kernicterus. Techniques have been developed to measure the bilirubin production rates accurately and noninvasively using end-tidal carbon monoxide measurement and percutaneous measurement of carboxyhemoglobin.

o Late anemia of infancy
􀂃 Infants with significant hemolytic disease often develop anemia in the first few months of life and frequently require packed RBC transfusion. The etiology of anemia appears to be diminished hypoxic stimulus from transfusion of adult Hb during intrauterine or exchange transfusion, resulting in low erythropoietin levels and reticulocyte count.
􀂃 Continued destruction of neonatal RBCs by high titers of circulating maternal antibodies often contributes to low reticulocyte count and anemia. Administration of recombinant human erythropoietin (rh-EPO) has been shown to minimize the need for transfusion in these newborns.

• Potential complications of exchange transfusion include the following:
o Cardiac - Arrhythmia, volume overload, congestive failure, and arrest
o Hematologic - Overheparinization, neutropenia, thrombocytopenia, and graft versus host disease
o Infectious - Bacterial, viral (CMV, HIV, hepatitis), and malarial o Metabolic - Acidosis, hypocalcemia, hypoglycemia, hyperkalemia, and hypernatremia
o Vascular - Embolization, thrombosis, necrotizing enterocolitis, and perforation of umbilical vessel
o Systemic - Hypothermia

Prognosis:
• Most survivors of alloimmunized gestation are intact neurologically. However, Janssens and colleagues have reported neurologic abnormality to be closely associated with severity of anemia and perinatal asphyxia.

Medical/Legal Pitfalls:
• Failure to provide RhIG therapy to an Rh-negative woman resulting in maternal alloimmunization and affecting the outcome of her future offspring has a very high potential for medicolegal litigation. This warrants that significant attention should be paid to blood type and Rh status of every pregnant woman beginning at the first prenatal visit.
• Explain in detail to every parent the risk of adverse outcome of an alloimmunized gestation irrespective of its severity, including fetal loss, prematurity, brain injury, risk of bilirubin encephalopathy, and subsequent CP.