Unconjugated Hyperbilirubinemia

Jaundice often is first evident in the face, particularly in the sclera and the frenulum, and can be noted more caudally at increased levels of hyperbilirubinemia. Estimations of the degree of hyperbilirubinemia have been made based on the level of jaundice observed but are unreliable and require more objective measurement. Many patients with neonatal hyperbilirubinemia are identified through recommended routine screening in the newborn nursery, where the patient’s bilirubin level should be systematically compared with nomograms to determine whether the current level requires intervention. In addition to obtaining routine screening levels, bilirubin levels should be obtained for all infants with jaundice evident in the first 24 hours of life, jaundice that is extensive, or jaundice that appears to be rapidly worsening.

Important historical information in a newborn with jaundice includes feeding and stooling patterns. Dehydration caused by poor feeding or poor maternal milk supply can exacerbate hyperbilirubinemia caused by hemoconcentration and increased enterohepatic circulation. For prevention of hyperbilirubinemia, the American Academy of Pediatrics (AAP) recommends that breastfeeding mothers should nurse their infants at least 8 to 12 times daily for the first several days of life. In addition to detailed feeding and stooling histories, other important parts of the history include level of arousal, presence of fever, and frequency and appearance of urination.

The prenatal and perinatal histories are likewise important. Infants born earlier than 38 weeks of gestational age, of East Asian descent, exclusively breastfed, or with a sibling with a history of neonatal hyperbilirubinemia are at increased risk of hyperbilirubinemia. The mother’s prenatal laboratory study results, including blood type, are also useful if they can be obtained. Jaundice noted before discharge from the newborn nursery, especially if noted within the first 24 hours of life, further elevates the patient’s risk of severe hyperbilirubinemia. Additionally, G6PD deficiency increases the risk of hyperbilirubinemia caused by increased hemolysis after birth and might be noted in the family history. Physical examination findings consistent with hemolytic processes, such as pallor or tachycardia, might increase clinical concern for unconjugated hyperbilirubinemia. Birth trauma resulting in cephalohematomas or significant bruising can lead to increased RBC breakdown, further increasing the infant’s risk. Elevated or low temperature and other signs of infection should also be noted because sepsis is a cause of hyperbilirubinemia.

At severe levels of hyperbilirubinemia, infants may have signs of acute bilirubin encephalopathy, with early signs that include lethargy, hypotonia, decreased activity, and poor suck. Untreated, this can progress over the course of days as infants become irritable, stuporous, and eventually comatose, with decreased or no feeding, hypertonia, retrocollis, opisthotonus, fever, apnea, and a shrill cry. Prolonged severe hyperbilirubinemia results in kernicterus, which is permanent neurologic damage caused by unconjugated hyperbilirubinemia, most notably in the basal ganglia and cranial nerve nuclei. Kernicterus is characterized by athetoid cerebral palsy, auditory disturbances, impaired upward gaze, and dysplasia of the primary teeth (Figure 100-3). Cognitive damage may also occur. Although the risk of kernicterus increases with increased levels of bilirubin, other clinical features appear to modify the risk, including prematurity, albumin binding capacity, duration of hyperbilirubinemia, and the presence of comorbid conditions. Although kernicterus decreased in frequency over the course of the 20th century, new cases continue to be reported, with shortened hospital stays and a resurgence of breastfeeding now requiring a high level of vigilance and the implementation of universal systematic monitoring protocols to avoid further cases of this devastating but preventable disease.

Figure 100-3 Kernicterus.

Conjugated Hyperbilirubinemia

Conjugated bilirubin does not cross the blood–brain barrier, so the primary clinical concern in conjugated hyperbilirubinemia is not the risk of kernicterus but rather the risks associated with a significant underlying disease. Patients with neonatal cholestasis may present with prolonged jaundice, pale stools, and dark urine. Jaundice in these infants may appear greener in tone than infants with unconjugated hyperbilirubinemia. Pertinent findings on physical examination may include jaundice, hepatomegaly, abnormal neurologic examination results caused by infectious or metabolic etiologies, or dysmorphisms suggestive of an underlying syndrome or intrauterine infection. The patient may also exhibit evidence of coagulopathy because of underlying liver disease.

Unconjugated Hyperbilirubinemia

Transcutaneous or serum bilirubin levels should be measured in all jaundiced infants. A high level on transcutaneous testing should be confirmed with total, unconjugated (indirect), and conjugated (direct) bilirubin levels. Additionally, infant blood type, direct Coombs testing, a complete blood count with smear, and reticulocyte count should be performed in patients requiring phototherapy and in those whose bilirubin levels are increasing rapidly to evaluate for the possibility of a hemolytic process. If hemolysis is suspected in a male infant, G6PD testing should also be considered. A basic metabolic panel can be helpful in a child with associated clinical concern for dehydration. A type and screen as well as an albumin level should be obtained if there is a possibility that the infant needs exchange transfusion.

For unconjugated hyperbilirubinemia, the infant’s total bilirubin level should be plotted according to hour of life on the nomogram developed by Bhutani et al. in 1999 and available in the AAP 2004 guidelines (Figure 100-4). This nomogram determines the age-specific bilirubin level at which phototherapy or exchange transfusion should be initiated in infants who are 35 weeks gestational age or greater. The treatment threshold is based on hour of life, total serum bilirubin level, and presence of additional risk factors, including gestational age, isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, unstable temperatures, acidosis, sepsis, or hypoalbuminemia. The conjugated bilirubin level should not be subtracted from the total bilirubin level when using the nomogram. However, providers should be aware of the risk of bronze baby syndrome, a usually benign discoloration of the skin that occurs in infants with cholestasis receiving phototherapy, and if conjugated bilirubin exceeds 50% of the total bilirubin in an infant requiring phototherapy, expert consultation is advised.

Figure 100-4 American Academy of Pediatrics guidelines for phototherapy and exchange transfusion.

Based on this nomogram, phototherapy should be initiated at moderate levels of hyperbilirubinemia to aid in clearance by photoisomerizing unconjugated bilirubin into a water-soluble form that can be excreted in the bile and urine without further conjugation. Phototherapy is most effective with appropriate wavelengths of light (ideally 460–490 nm), appropriate distance and irradiance, and maximal skin exposure. Phototherapy can be toxic to the immature retina, requiring protective eye shields during treatment (Figure 100-5).

Figure 100-5 Phototherapy and exchange transfusion.

Exchange transfusion is initiated at severe levels of hyperbilirubinemia also based on the infant’s hour of life (see Figure 100-4) and in any infant exhibiting signs of acute bilirubin encephalopathy. Severe hyperbilirubinemia requiring exchange transfusion should be treated as a medical emergency and requires immediate admission to a neonatal intensive care unit for further care (see Figure 100-5). Intravenous γ-globulin may be considered in infants with isoimmune hemolytic disease who are approaching the exchange transfusion threshold.

In addition to these specific treatments for hyperbilirubinemia, it is important to respond appropriately to any concomitant issues, such as dehydration, anemia, or sepsis. Additionally, if hyperbilirubinemia is determined not to require treatment at the time of evaluation, it is important to determine when the total serum bilirubin level should next be obtained, provide the patient’s parents with education about jaundice, and ensure appropriate follow-up for reevaluation.

Conjugated Hyperbilirubinemia

Conjugated hyperbilirubinemia is defined as conjugated bilirubin greater than 1 mg/dL or greater than 20% of the total bilirubin level if total bilirubin is greater than 5 mg/dL. Initial evaluation requires obtaining a thorough history and physical examination as described above, as well as fractionated bilirubin levels and liver function tests, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyl transferase, albumin, and prothrombin time. Evaluation should then occur in a stepwise fashion, focusing first on disease processes requiring urgent treatment, such as sepsis, urinary tract and TORCH (toxoplasmosis or Toxoplasma gondii, other infections, rubella, cytomegalovirus, and herpes simplex virus) infections, hypothyroidism, and metabolic disorders. Next, imaging studies should be considered to localize whether the anatomic site of dysfunction is either intrahepatic or extrahepatic. Ultrasound can provide useful information about the gallbladder; hepatobiliary scintigraphy, however, has better sensitivity for biliary atresia. If no etiology has been found, additional evaluation for other specific etiologies, such as cystic fibrosis and α-1 antitrypsin deficiency, may be helpful.

Therapy for neonatal cholestasis varies depending on the underlying cause. Sepsis requires antibiotic therapy (see Chapter 105), and inborn errors of metabolism require dietary modification or enzyme supplementation. Biliary atresia requires urgent surgical treatment because prognoses are markedly better when the Kasai procedure is performed within the first 60 days of life. In contrast, treatment of patients with many other causes focuses more on supportive care such as nutritional support with caloric and fat-soluble vitamin supplementation along with use of ursodeoxycholic acid, which aims to enhance bilirubin excretion and may reduce associated pruritus. Further management should be conducted in consultation with the appropriate specialist and is beyond the scope of this chapter.