Kernicterus

Kernicterus, or bilirubin encephalopathy, is bilirubin-induced neurologic damage, typically in infants.[1] The term kernicterus literally means "yellow kern," with kern indicating the most commonly afflicted region of the brain (ie, the nuclear region). Historically, the term refers to an anatomic diagnosis made at autopsy based on a characteristic pattern of staining found in babies who had marked hyperbilirubinemia before they died.

Hervieux first described the condition in 1847, and Schmorl first used the term kernicterus as early as 1903. Regions most commonly affected include the basal ganglia; hippocampus; geniculate bodies; and cranial nerve nuclei, such as the oculomotor, vestibular, and cochlear. The cerebellum can also be affected. Bilirubin-induced neurologic dysfunction (BIND) refers to the clinical signs associated with bilirubin toxicity (ie, hypotonia followed by hypertonia and/or opisthotonus or retrocollis) and is typically divided into acute and chronic phases. The 2 terms are commonly used interchangeably, but this use is not technically accurate because one refers to clinical manifestations and the other to an anatomic diagnosis.

Conventional wisdom characterizes kernicterus as prevalent in the 1950s and 1960s, virtually eradicated in the 1970s and 1980s, only to reappear during the 1990s. It was speculated that early discharge of term infants (before their serum bilirubin concentration peaks) could be a factor in the reemergence of this devastating neurologic affliction, and medical research focused on developing surveillance and treatment paradigms to eliminate the condition. Whereas it is undeniable that kernicterus remains a cause of major neurologic morbidity in the infant population, population studies of children born in California between 1988 and 1997 suggest the prevalence of kernicterus has remained virtually unchanged since 1980.[2]

Much of the traditional teaching regarding hyperbilirubinemia have been questioned as more is learned about bilirubin metabolism and neurologic injury. Kernicterus is now recognized in the premature infant and, very rarely, in the term infant in the absence of profound hyperbilirubinemia[3] ; however, other problems (eg, acidosis or infection) are present in term infants without profound hyperbilirubinemia. Conversely, physiologic jaundice (sometimes to levels previously thought to be universally dangerous) has been recognized to be within the reference range in the first week of life in healthy term babies, particularly those who are breastfed. Jaundice of this type usually spontaneously resolves without sequelae.

Despite the lack of a clear-cut cause-and-effect relationship between kernicterus and the degree of hyperbilirubinemia, laboratory investigations have demonstrated that bilirubin is neurotoxic at a cellular level. Other in vitro studies have shown bilirubin to have more antioxidant capability than vitamin E, which is commonly assumed to be the most potent antioxidant in the human system.[4] This possible role of bilirubin in early protection against oxidative injury, coupled with identification of multiple neonatal mechanisms to preserve and potentiate bilirubin production, has led to speculation about an as-yet-unrecognized beneficial role for bilirubin in the human neonate.

Kernicterus results from an increased concentration of indirect, or unconjugated, bilirubin. The pathophysiology depends on the underlying condition, of which the most common are Crigler-Najjar syndrome, Gilbert syndrome, hemolytic disorders, and a reduced ability to conjugate bilirubin in infants.[1]

Bilirubin staining can be noted on autopsy of fresh specimens in the regions of the basal ganglia, hippocampus, substantia nigra, and brainstem nuclei. Such staining can occur in the absence of severe hyperbilirubinemia; in this situation, factors influencing permeability of the blood-brain barrier (eg, acidosis, infection) and the amount of unbound (versus albumin-bound) bilirubin may play a role.

Characteristic patterns of neuronal necrosis leading to the clinical findings consistent with chronic bilirubin encephalopathy are also essential in the pathophysiology of this entity. Bilirubin staining of the brain without accompanying neuronal necrosis can be observed in babies who did not demonstrate clinical signs of bilirubin encephalopathy but who succumbed from other causes. This staining is thought to be a secondary phenomenon, dissimilar from the staining associated with kernicterus.

Improved brain imaging modalities, such as magnetic resonance imaging (MRI) and ultrasonography, may be emerging as instrumental tools to help clarify the complex picture of kernicterus in contrast with asymptomatic bilirubin staining of brain tissues. Bilirubin staining has been suggested to be visualized on MRI as an increased signal in the posteromedial aspect of the globus pallidus. Despite its theoretical value, however, efforts to use cranial imaging in the clinical setting have remained unsatisfying. A 2008 case series by Gkoltsiou et al reported the inexplicable conclusion that, while all children with severe cerebral palsy and a history of hyperbilirubinemia had abnormal central grey matter on later scans, the characteristic central grey matter MRI features of kernicterus were not seen in early scans.[5]

Familiarity with bilirubin metabolism leads to an understanding of the factors leading to an increased risk of kernicterus (see image below). Bilirubin is produced during the catabolism of the heme component of red blood cells (RBCs). Red cell destruction is usually increased in the immediate neonatal period; it can be pathologically elevated in the presence of immune-mediated or nonimmune-mediated hemolytic disease. The first enzyme in the catabolic cascade leading to bilirubin is heme oxygenase. A constitutive form and an inducible form are recognized and are induced by physiologic stressors. The creation of bilirubin, a potentially toxic water-insoluble compound, from biliverdin, a nontoxic water-soluble substance, consumes energy.

Because of its lipophilic nature, bilirubin must be bound to albumin to travel through the blood stream. In this state, it is not free to cross the blood-brain barrier and cause kernicterus. The albumin-bilirubin complex is carried to the liver, where bilirubin enters the hepatocyte for further metabolism. Once in the liver, bilirubin is conjugated via the action of uridine diphosphate glucuronyl transferase (UDPGT),[6] an enzyme not fully functional until 3-4 months of life.

Conjugated bilirubin is excreted into the intestinal tract via the biliary system. Beta-glucuronidase, present in the intestinal lumen of human neonates, deconjugates the conjugated bilirubin, allowing it to be reabsorbed across the intestinal lipid cell membranes back into the blood stream where it must be re-bound to albumin to repeat the cycle. This process, called enterohepatic recirculation, is a unique neonatal phenomenon and contributes significantly to physiologic jaundice. Feeding and excretion of meconium and stool interrupt the enterohepatic recirculation.

Among infants reported in the US kernicterus registry, 56% had abnormalities known to increase the bilirubin concentration in the blood.[7] Severe hemolytic processes were identified in 25 of 122 babies (20.5%); glucose-6-phosphate dehydrogenase deficiency was diagnosed in 26 babies (21.3%), birth trauma identified in 18 patients (15%), and other causes such as galactosemia, Crigler-Najjar syndrome, and sepsis were diagnosed in 8 babies (7%). In 53 of 122 infants (43.4%), no etiology for the severe hyperbilirubinemia was discovered.

Increased bilirubin production

Most of the circulating bilirubin in the neonate arises from destruction of circulating RBCs. Neonates produce bilirubin at more than double the daily rate of the average adult, primarily because of the larger circulating volume of RBCs and their shorter life span. Any event resulting in increased serum bilirubin load puts the infant at risk for hyperbilirubinemia.

Polycythemia

Prenatal factors, such as maternal smoking, maternal illness, placental insufficiency, and gestation at high altitude, can result in neonatal polycythemia. Obstetric factors, such as delayed clamping of the cord, stripping the cord, or holding the baby below the level of the introitus for a prolonged period, can result in increased RBC mass in the baby. This is particularly true for babies born in the absence of a trained birth attendant.

Hemolysis

Immune hemolytic disease, most often Rh isoimmunization (erythroblastosis fetalis), is the prototype etiology for kernicterus.

ABO isoimmunization, as well as minor blood group antigens, can also causehemolytic disease in the newborn, usually of moderate severity. Infants born to mothers of blood type O negative are at greatest risk, with one series of 249 infants with severe hyperbilirubinemia reporting an odds ratio of 48.6 for infants with Rh incompatibility.[8]

Abnormalities of the red cell itself can also predispose to hemolysis. These can be grouped into membrane defects, such as hereditary spherocytosis and elliptocytosis; enzyme defects, such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and hemoglobinopathies, such as alpha and beta thalassemias.

Sickle cell disease does not typically cause hemolytic disease in the neonatal period.

Extravasated blood

Significant areas of bruising, such as severe cephalohematoma, subgaleal hemorrhage or peripheral ecchymoses from birth trauma, can result in an increased bilirubin load in the serum as the blood collection resolves. Internal areas of hemorrhage, such as pulmonary or intraventricular bleeds, can also be a significant occult source of serum bilirubin.

Enzyme induction

As mentioned above, heme-oxygenase-one (HO-1) is the inducible form of the first enzyme involved in the creation of bilirubin. This enzyme is activated by physiologic stressors, such as hypothermia, acidosis, hypoxia, and infection (odds ratio 20.6 in sepsis).[8]

Epidemiologic factors

East Asian and Native American babies produce bilirubin at higher rates than do White infants; Black infants have lower production rates than do infants of other racial groups. Male infants have higher serum bilirubin levels than females. Hyperbilirubinemia also runs in families; the etiology is unclear but may relate to genetically increased levels of beta-glucuronidase in the infant, in the mother's breast milk, or both (if the infant is breastfed).

Decreased elimination

Even with normal bilirubin production, abnormalities in transport, excretion, or both can result in an increased level of free bilirubin in the serum.

Albumin binding

Because of its lipophilic nature, bilirubin must be bound to carrier protein to be transported in the aqueous environment of the serum. Albumin has one primary high-affinity binding site for bilirubin and two lower-affinity sites. At physiologic pH, the amount of free bilirubin (eg, bilirubin not bound to albumin) is very low. This is important because only free bilirubin is available to cross the blood-brain barrier and cause neurotoxicity. Decreased albumin binding capacity, decreased albumin binding affinity, or both can serve to increase the amount of free serum bilirubin. Binding affinity is lower in neonates than in older infants and is lower still in premature and sick infants than in healthy term ones.

Some authors advocate including measures of unbound (ie, free) bilirubin when assessing the risk of bilirubin neurotoxicity,[9] in part because some studies have shown a closer association between the unbound bilirubin concentration and auditory abnormalities than those seen with total serum bilirubin, although identifying the neurotoxic unbound bilirubin concentration threshold remains elusive.[10]

Decreased binding capacity can occur in hypoalbuminemia or if the binding sites are filled with other anions. Whether parenterally administered lipid can displace bilirubin from its albumin-binding site is controversial. If faced with dangerously high levels of serum bilirubin, restricting lipid administration to less than maximal levels may be prudent. Drugs, such as sulfisoxazole and ceftriaxone, can also compete for bilirubin-binding sites on the albumin molecule and must be used with caution or avoided in the neonatal period.

Hepatic uptake and conjugation

Albumin carries bilirubin to the liver, where it is incorporated into the hepatocyte by an acceptor protein called ligandin. Hepatic levels of ligandin do not reach adult values until around age 5 days, but they can be induced by administration of phenobarbital.

Once inside the hepatocyte, bilirubin is conjugated to a sugar moiety, glucuronic acid, via the enzyme UDPGT. Inherent neonatal deficiency of this enzyme is the principal etiology of physiologic jaundice. For the first 10 days of life, UDPGT is present at levels about 0.1% of adult values, and hyperbilirubinemia appears to be the primary stimulus to enzyme production.

Beyond physiologic jaundice, congenital inherited defects in UDPGT cause pathologic hyperbilirubinemia of varying severity. Crigler-Najjar syndrome type I is the virtual absence of UDPGT and is characterized by profound refractory hyperbilirubinemia with the ongoing risk of kernicterus at any point during an individual's lifespan. Currently, liver transplantation is the only definitive therapy, although experimental therapies are under investigation. Patients with Crigler-Najjar syndrome type II (ie, Arias syndrome) have a similar clinical presentation as patients with type I. However, patients with type II dramatically respond to therapy with phenobarbital, which is how the diagnosis is made.

Gilbert syndrome is characterized by a benign chronic indirect hyperbilirubinemia without evidence of liver disease or abnormality. The genetic basis for this syndrome was identified as an amplified triplet repeat in the coding gene for UDPGT, and investigations are continuing to clarify the possible role of Gilbert syndrome in infants with neonatal hyperbilirubinemia.

Excretion

Once conjugated, water-soluble bilirubin is excreted in an energy-dependent manner into the bile canaliculi for ultimate delivery into the small intestine. Disruption in this system or obstruction in the biliary system results in accumulation of conjugated bilirubin in the serum, identified by an elevation in the direct fraction of total bilirubin. Direct hyperbilirubinemia in the neonate (defined as a direct fraction greater than one third of total bilirubin) is always pathologic, and an etiology must be pursued.

In the small intestine, conjugated bilirubin cannot be reabsorbed. Intestinal florae convert it into urobilinogen, which is excreted. In the neonate, the paucity of colonic bacteria impedes this conversion. Furthermore, the neonatal gut (but not that of the adult) produces beta-glucuronidase, an enzyme that acts upon conjugated bilirubin, releasing free bilirubin for potential absorption across the intestinal cell lipid membrane into the blood stream. Breast milk also contains beta-glucuronidase, and breast milk feedings increase the level of this enzyme in the neonatal intestine. Combined with slow intestinal motility in the first few days of life, the above factors result in what is called enterohepatic recirculation of bilirubin back into the blood stream.

Systemic factors

Galactosemia

Patients with this rare inborn error of metabolism may primarily present with hyperbilirubinemia, although the direct fraction typically increases during the second week of life. The baby may manifest other characteristic signs, such as hepatomegaly, poor feeding, or lethargy. Urine for reducing substances, but not glucose, is diagnostic. Many state newborn metabolic screens include a test for this disorder.

Hypothyroidism

Although the etiology is unclear, prolonged indirect hyperbilirubinemia is one of the typical features of congenital hypothyroidism, and this diagnosis must be ruled out in any baby with hyperbilirubinemia persisting after age 2-3 weeks. Most state metabolic screens include an assay of thyroid function, although false-negative results and delayed receipt of results may necessitate individual testing in symptomatic infants.

Drugs

Maternal administration of oxytocin, diazepam, or promethazine may result in increased serum bilirubin in the infant. Similarly, neonatal administration of pancuronium and chloral hydrate increases bilirubin levels. Additionally, some drugs, such as sulfonamides and some penicillins, can displace bilirubin from its albumin-binding site, effectively increasing the serum concentration of free bilirubin available to cross the blood-brain barrier.

Acidosis

Systemic acidosis decreases the binding affinity of albumin for bilirubin, resulting in increased levels of free bilirubin in the blood stream. Ready availability of protons promotes the formation of bilirubin acid (free bilirubin anion plus 2 hydrogen ions); that moiety demonstrates increased binding and transport into neural cell membranes.

Disrupted blood-brain barrier

The neonatal blood-brain barrier is more permeable to substances than is the adult's. Administration of hyperosmolar substances, hypercarbia, asphyxia, infection (particularly meningitis), and impaired autoregulation with variations in blood pressure all may weaken capillary tight junctions, increasing capillary permeability. This, in turn, might lower the concentration at which bilirubin is toxic to the CNS.

Breast milk feedings

The well-described physiologic jaundice observed in the first few days of life, particularly in the breastfed infant, is called breastfeeding jaundice. Breastfeeding jaundice is thought to result from multiple mechanisms, described above, which promote production and inhibit excretion of bilirubin, as well as from insufficient milk intake because of reduced mammary gland milk production in the first few days postpartum. Breastfeeding jaundice should be distinguished from breast milk jaundice.

Some breastfed infants, although clinically thriving, continue to manifest an indirect hyperbilirubinemia of unidentifiable etiology for several months. If this is witnessed in a breastfed infant, the exclusion diagnosis of breast milk jaundice may be made. Such hyperbilirubinemia is thought to be caused by persistently high levels of as-yet-unidentified components in some women's breast milk, which result in persistence of the infant's hyperbilirubinemia. One clue may be a history of similar hyperbilirubinemia in other breastfed siblings. This entity is benign.

In general, kernicterus affects Black and South Asian children.[1]

United States data

The exact incidence of kernicterus is unknown.[1] However, Asian, Hispanic, Native American, and Eskimo infants produce higher levels of bilirubin than White infants, whereas bilirubin production is lower in Black infants.[1]

A pilot kernicterus registry monitoring the cases of babies with kernicterus in the United States who have been voluntarily reported shows 125 babies with chronic kernicterus enrolled in the registry from 1984-2002.[11, 12] All but four babies reported in the registry had been discharged from the hospital fewer than 72 hours after birth (97%). Five babies were born at home (4%). No sequelae were identified in nine of 115 infants, and one was lost to follow-up.

International data

In Denmark, eight cases of kernicterus were reported from 1994-2002, whereas no cases had been reported for the preceding 20 years.[13] Following this report, from 2002-2005, a more vigilant approach was taken to the management of newborn jaundice, and no more cases have been reported in Denmark.[14] These combined data result in an overall incidence of kernicterus in Denmark of 1.1 in 100,000 live births from 1994-2005.

In a more recent Danish study (2020) that evaluated data from 408 infants (gestational age ≥35 weeks' gestation) between 2000 and 2015, blood type ABO isohemolytic disease was the most common etiology for extreme neonatal hyperbilirubinemia and kernicterus spectrum disorder.[15] Extreme neonatal hyperbilirubinemia occurred at an incidence of 42 per 100,000 live births (with a falling incidence in 2005-2015), and the incidence of kernicterus spectrum disorder was 1.2 per 100,000 live births(12 of 408 infants).[15]

In June 2003, The Quarterly Bulletin of the Royal College of Paediatrics and Child Health announced the commencement of a surveillance program of cases of severe neonatal hyperbilirubinemia following anecdotal reports throughout Britain and Ireland of increasing observation of kernicterus.[16] A 2004 UK surveillance study reported kernicterus occurring at a rate of 1 in 100,000 live births.

A Canadian survey published in 2004 assessed the frequency of extreme hyperbilirubinemia (serum bilirubin >427 μmol/L or >25 mg/dL) as 1:2,840 live births, of which 13 (2 in 100,000) had abnormal neurological outcomes at the time of discharge.[17]

Using these data, the risk of developing kernicterus in infants manifesting extreme hyperbilirubinemia (>25 mg/dL) can be estimated across populations. In Canada, this risk calculates to 1 in 17.6 infants, whereas in Denmark, the population risk is estimated as 1 in 16.2.[18] When the threshold of extreme hyperbilirubinemia is increased to >30 mg/dL (>513 μmol/L), the risk of developing kernicterus increases to 1 in 5.5-7 live births, depending on the reports. It should be noted that kernicterus also occurs in infants in whom bilirubin levels remained < 25 mg/dL, and the population risk of this occurrence remains unknown.

Hispanic and Asian populations appear to have a greater propensity to develop hyperbilirubinemia, although the underlying explanation for this observation remains elusive. Genetic variants, such as Gilbert disease or G6PD deficiency that occur in sequestered populations, result in geographic and/or ethnic differences in the risk and frequency of kernicterus.

Race-related demographics

Among infants reported in the US kernicterus registry, 58% were White.[12] Asian and Hispanic babies born either in their native countries or in the United States and Native American and Eskimo infants have higher production levels of bilirubin than White infants. Black infants have lower production levels (see image below). The reasons for these racial differences have not been fully elucidated.

Sex-related demographics

Male infants have consistently higher levels of serum bilirubin than do female infants.[1] Among infants reported in the US kernicterus registry, 67% of the patients were male.[12]

Age-related demographics

Acute bilirubin toxicity appears to occur in the first few days of life of the term infant. An estimated 60% of term and 80% of preterm infants develop jaundice in the first week of life.[19] Preterm infants may be at risk of toxicity for slightly longer than a few days. If injury has occurred, the first phase of acute bilirubin encephalopathy appears within the first week of life. 

The pilot kernicterus registry data show that, of 122 infants (all >35 weeks' gestational age at birth), symptoms became apparent in 13 babies (10.6%) aged 3.5 days or younger and in 66 babies (54%) aged 4-7 days.[7] In 36 babies (29.5%), symptoms did not appear until after the first week of life. Most of these babies (76%) were term infants (at least 37 completed weeks' gestation), and no infant was younger than 35 weeks' estimated gestational age. (See the Gestational Age from Estimated Date of Delivery calculator.)

To facilitate the provision of appropriate evaluation and follow-up for babies without recognized risk factors, the American Academy of Pediatrics (AAP) has published an hour-of-age-specific guideline that correlates total serum bilirubin levels with degree of risk and recommendations for follow-up.[20]

The AAP recommends professional medical evaluation in 2-3 days for babies who are discharged from the hospital fewer than 48 hours after birth.[20]  Babies discharged fewer than 72 hours after birth may also be at risk, and they should be closely monitored as well. Other risk factors warranting additional vigilance may include unexplained family history of neonatal hyperbilirubinemia, near-term gestation, low birth weight, excessive bruising or hematomata, and ethnicity at risk for exaggerated hyperbilirubinemia.

Parents should be informed of the importance of keeping these appointments, as well as be familiarized with the symptoms of poor feeding in breastfed babies and how to seek help.

For patient education resources, see the Children's Health Center, as well as Newborn Jaundice and Spinal Tap.

When assessing possible kernicterus, remember that a history of risk for hemolytic disease can be an important clue to a neonate's increased risk of pathologic hyperbilirubinemia, particularly Rh antigen incompatibility between mother and baby[8] . ABO incompatibility and a family history of red blood cell (RBC) abnormalities (ie, glucose-6-phosphate dehydrogenase deficiency, hereditary spherocytosis) are also concerning. A review of neonatal readmissions in Canada showed that, of 258 infants readmitted for severe hyperbilirubinemia from 2002-2004, 87 (34%) demonstrated one of these hematologic abnormalities.[21]

Certain cultural postnatal practices may also contribute to significant hyperbilirubinemia and should be inquired about if culturally relevant. In the Middle East, Peker et al reported in 2010 a case series of 10 severely hypernatremic babies who also presented with kernicterus, two of whom died.[22] Of 112 postpartum women surveyed in Jordan Hospital, Amman, Jordan, almost 50% of them admitted to "salting" their newborns as is the common custom. Women doing this practice broadly represented all socioeconomic and educational strata.[23]

Conversely, if the baby is breastfeeding well and appears healthy and vigorous, this can be reassuring. The mother may have breastfed previous babies who also developed significant jaundice. If so, she may be one of the approximately 20-40% of women who have above-average levels of beta-glucuronidase in their breast milk, which potentiates and prolongs hyperbilirubinemia in their breastfed babies.

Bilirubin-induced neurologic dysfunction (BIND) is the term applied to the spectrum of neurologic abnormalities associated with hyperbilirubinemia. It can be further divided into characteristic signs and symptoms that appear in the early stages (acute) and those that evolve over a prolonged period (chronic).

Acute bilirubin encephalopathy

The clinical features of this diagnosis have been well described and can be divided into three stages. Of babies with BIND, approximately 55-65% present with these features, 20-30% may display some neurologic abnormalities, and approximately 15% have no neurologic signs.

The three stages are as follows:

• Phase 1 (first few days of life): Decreased alertness, hypotonia, and poor feeding are the typical signs. Obviously, these are quite nonspecific and could easily be indicative of a multitude of neonatal abnormalities. A high index of suspicion of possible BIND at this stage that leads to prompt intervention can halt the progression of the illness, significantly minimizing long-term sequelae. Of note, seizure is not typically associated with acute bilirubin encephalopathy. Among infants reported in the US kernicterus registry, the mean birth weight was 3281 g.[12]

• Phase 2 (variable onset and duration): Hypertonia of the extensor muscles is a typical sign. Patients present clinically with retrocollis (backward arching of the neck), opisthotonus (backward arching of the back), or both. Infants who progress to this phase develop long-term neurologic deficits.

• Phase 3 (infants aged >1 week): Hypotonia is a typical sign.

Chronic bilirubin encephalopathy

The clinical features of chronic bilirubin encephalopathy evolve slowly over the first several years of life in the affected infant. The clinical features can be divided into phases; the first phase occurs in the first year of life and consists of hypotonia, hyperreflexia, and delayed acquisition of motor milestones. The tonic neck reflex can also be observed. In children older than 1 year, the more familiar clinical features develop, which include abnormalities in the extrapyramidal, visual, and auditory systems. Minor intellectual deficits can also occur.

Note the following:

• Extrapyramidal abnormalities: Athetosis is the most common movement disorder associated with chronic bilirubin encephalopathy, although chorea can also occur. The upper extremities are usually more affected than the lower ones; bulbar functions can also be impacted. The abnormalities result from damage to the basal ganglia, the characteristic feature of chronic bilirubin encephalopathy.

• Visual abnormalities: Ocular movements are affected, most commonly resulting in upward gaze, although horizontal gaze abnormalities and gaze palsies can also be observed. These deficits result from damage to the corresponding cranial nerve nuclei in the brain stem.

• Auditory abnormalities: Hearing abnormalities are the most consistent feature of chronic bilirubin encephalopathy and can develop in patients who show none of the other characteristic features. The most common abnormality is high-frequency hearing loss, which can range from mild to severe. These deficits can result from damage both to the cochlear nuclei in the brain stem and to the auditory nerve, which appear to be exquisitely sensitive to the toxic effects of bilirubin, even at relatively low levels. Clinically, this deficit can manifest as delayed language acquisition. Hence, auditory function must be assessed early in any baby at risk for chronic bilirubin encephalopathy.

• Cognitive deficits: Cognitive function is relatively spared in chronic bilirubin encephalopathy. However, individuals with chronic bilirubin encephalopathy are often mistakenly considered to have mental retardation because of their choreoathetoid movement disorders and hearing deficits. The clinician must emphasize that intellectual functioning is not typically severely affected.

• Abnormalities of dentition: Some degree of dental enamel hypoplasia can be observed in about three quarters of patients with chronic bilirubin encephalopathy. A smaller number of individuals develop green-stained teeth.

Hematologic studies

Hematologic laboratory evaluation is the cornerstone of evaluation of the baby with hyperbilirubinemia. Although jaundice can be appreciated clinically, observation alone is not a reliable method to assess the severity or estimate risk factors for the infant.

Total and direct bilirubin

Quantitative measurement of total and direct bilirubin levels should be undertaken in every baby at risk for significant hyperbilirubinemia or kernicterus.

Total bilirubin measures the aggregate of all forms of bilirubin in the serum. The direct fraction measures the amount of conjugated bilirubin. Subtraction of the direct fraction from the total yields the calculated indirect bilirubin, or the unconjugated form. When the indirect/unconjugated bilirubin level exceeds 25 mg/dL in the blood, there is a reduction in elimination and a rise in bilirubin production.[1] Remember that the indirect fraction is composed of bound bilirubin, free bilirubin, and lumirubin, as well as many other clinically unidentifiable isomers if the baby is receiving phototherapy.[25] Only the free bilirubin is available to cross the blood-brain barrier and has the potential to cause neurotoxicity[1] ; if and how the presence of other isomers modulates this process is unclear.

Attempts to measure the amount of bound albumin or to estimate the bound fraction from measures of serum albumin have not proven to be clinically useful, although there has been some renewed interest in the clinical use of this tool.[9, 26, 27]

Serial measurements may be necessary to track the evolution of hyperbilirubinemia; frequency of measurements depends on the baby's gestational age, chronologic age, risk factors, and other clinical characteristics.

In infants who were reported to the US kernicterus registry, total serum bilirubin levels ranged from 20.7-59.9 mg/dL at the time of presentation with the classic physical signs of kernicterus.[12] A similar series of 249 infants in Cairo reported by Gamaleldin et al presented with total serum bilirubin levels ranging from 25-76.4 mg/dL; at presentation, 44 infants (18%) had moderate or severe acute bilirubin encephalopathy.[8]

Every baby with hyperbilirubinemia should have a direct fraction measured at least once to rule out direct hyperbilirubinemia. Direct hyperbilirubinemia in the neonate is defined as a direct fraction of more than 2 mg/dL or more than one third of the total bilirubin concentration and is always pathologic. Subsequently, if the hyperbilirubinemia is established as the indirect type, obtaining a direct fraction with every measurement is unnecessary unless the hyperbilirubinemia develops after the expected time frame for typical neonatal hyperbilirubinemia.

With the advent of early discharge (before the physiologic peak of serum bilirubin) some clinicians are advocating universal bilirubin measurements in all babies prior to discharge. Nomograms have been published that estimate a baby's risk of disease based on measured levels of bilirubin. One nomogram that assessed the risk of critical hyperbilirubinemia in babies leaving the hospital within 24-48 hours of birth adjusted for gestational age and postnatal age in hours (see following image).[20] In 2011, Yu et al published a similar nomogram using transcutaneous measurements in healthy term and late-preterm Chinese infants.[28] However, after reviewing available experimental and observational studies that included comparison groups, the US Preventive Services Task Force concluded there was insufficient evidence to assess the balance of benefits and harms of universal screening for hyperbilirubinemia to prevent bilirubin encephalopathy.[29]

Blood type

The baby's blood type should be determined and compared with that of the mother. Mothers with type O blood may have circulating antibodies to other red cell antigens that can cross the placenta and cause hemolytic disease in a baby with a different blood type, such as blood type A or B. Similarly, mothers who are Rh negative may have antibody to the Rh antigen if they have not been treated with RhoGAM. Antibody to the Rh antigen causes the most fulminant type of hemolytic hyperbilirubinemia, termed erythroblastosis fetalis in its most severe form. ABO incompatibility can cause significant hemolysis as well. Minor antigens on the baby's red blood cells (RBC) are also susceptible to immune-mediated hemolysis from maternally acquired antibody but usually to a lesser extent than the major antigens. Documentation of maternal antibody status during the pregnancy should alert the caretaker about potential risk for hemolytic disease and hyperbilirubinemia.

Reticulocyte count

Babies typically have reticulocyte counts higher than older infants and adults. However, significant elevation in the neonate's reticulocyte count (>7 mg/dL) can indicate the presence of an ongoing hemolytic process.

Direct Coombs test

This test assays for antibody on the RBC membrane. A positive result indicates that antibodies are attached to the RBC, placing it at risk for immune-mediated destruction. This is a qualitative test, so a positive result does not suggest the amount of antibody or the degree of hemolysis. However, pairing these results with the reticulocyte count can provide some idea of the severity of the process. This test, although reliable, does not have 100% sensitivity. Because false-negative results do occur, repeating a test with an initial negative result is not unreasonable if the clinical course supports an ongoing hemolytic process. In a many cases of ABO incompatibility, direct Coombs test findings may be negative. Therefore, an elution test should be performed to demonstrate anti-A or anti-B antibodies in the serum.

Complete blood cell (CBC) count

A CBC with manual differential should always be included in the evaluation of a newborn with jaundice. Measurement of the hemoglobin and hematocrit can be helpful to determine if ongoing hemolysis severe enough to cause anemia is present. The peripheral smear inspection is particularly valuable because it may reveal large amounts of nucleated RBCs, suggesting active reticulocytosis; it may reveal abnormally shaped RBCs in the case of hereditary membrane defects such as spherocytosis and elliptocytosis or marked ovalocytosis in the case of hemolytic disease of the newborn. Babies with sepsis can develop hyperbilirubinemia, and, although not conclusive, normal total WBC count and manual differential can be reassuring in a healthy-appearing baby with hyperbilirubinemia.

Serum electrolytes

Breastfed babies are known to normally develop higher levels of serum bilirubin than their formula-fed counterparts. However, with the trend toward earlier discharge, most breastfed babies are being discharged home before breastfeeding is well established, and a concomitant increase in the number of infants readmitted to the hospital in the first week of life with hypernatremic dehydration has occurred. Many of these babies are also significantly hyperbilirubinemic. Therefore, assessing serum sodium, potassium, chloride, bicarbonate, BUN, and creatinine levels is essential; initiate treatment as appropriate. In regions where the cultural practice of newborn salting exists, assessing serum electrolytes is especially important as reports of severe hyperbilirubinemia, kernicterus, and death have been reported with serum sodium levels as high as 194 mEq/dL.[22]

Lumbar puncture

In the initial evaluation of hyperbilirubinemia, sepsis should be included in the differential diagnosis (odds ratio 20.6[8] ). If so, collection of spinal fluid for culture and cell count should be considered to rule out meningitis. If the baby is having neurologic symptoms, cerebral spinal fluid (CSF) evaluation is imperative; depending on the baby's symptoms, expanding the evaluation beyond the normal aerobic bacterial culture may be prudent. If, on the other hand, the baby is vigorous and well-appearing with isolated hyperbilirubinemia as the only symptom (ie, sepsis is not likely to be the cause of the hyperbilirubinemia), a spinal tap may not be necessary.

Transcutaneous bilirubin measurement

Numerous devices that transcutaneously measure total serum bilirubin levels have become commercially available. These devices have been tested in babies of varying ethnicities, skin pigmentations, and gestational ages Correlation with serum bilirubin measurements is generally good. Although this approach is not recommended to replace the criterion standard of serum measurement, it may be a useful adjunct to the clinical management of hyperbilirubinemia in the term and/or preterm infant.

In 2009, Bental et al reported on the correlation of transcutaneous measurements obtained with the Jaundice Meter Minolta/Draeger JM-103 and serum measurements in 1091 paired measurements obtained on 628 infants. Linear regression analysis of the results yielded a correlation coefficient (R2) of 0.846; the group used these data to create a local Bhutani-type TcB nomogram for universal predischarge screening in US populations.[30] Yu et al performed 36,921 measurements in 6,035 healthy term and late-preterm Chinese infants to develop a comprehensive nomogram for this population.[28]

In the acute phase of bilirubin encephalopathy, neuroimaging has no major diagnostic benefit. However, it can help rule out other diagnoses, particularly in the absence of profound hyperbilirubinemia.

Head ultrasonography (HUS)

HUS is particularly well suited to the neonate because it is painless, portable, and noninvasive; also, the neonatal brain is easily imaged through the fontanelles. Ultrasonography is not helpful in diagnosing acute bacterial encephalopathy; however, other entities, such as intraventricular hemorrhage or parenchymal abnormalities, can be ruled out.

Computed tomography (CT) scanning

CT scanning has little place in the evaluation of the neonatal brain. The subtle abnormalities often present in the neonatal period are not well visualized by CT scanning, and false-negative findings are not uncommon.

Magnetic resonance imaging (MRI)

Previously, the neuronal damage characteristic of kernicterus was thought to only be identifiable on histologic examination postmortem. However, experience has revealed that MRI can be used to depict characteristic bilateral symmetric high-intensity signals in the globus pallidus on both T1-weighted and T2-weighted images in patients surviving with chronic bilirubin encephalopathy (see image below).[31, 32] The usefulness and cost-effectiveness of this modality in the diagnosis of more subtle forms of bilirubin-induced neurologic dysfunction (BIND) remains to be fully elucidated.

Brainstem auditory evoked response (BAER)

Hearing impediment is the most common sequela of bilirubin toxicity.[1] Impairment may be subtle and may not be clinically apparent until the baby manifests delayed language acquisition. To maximize the baby's long-term neurologic functioning, early identification of any degree of hearing loss is important so that early developmental assessment and intervention can be initiated in a timely fashion. Serial assessments of hearing function may be necessary. With the advent of mandated universal newborn hearing screening, many newborn hearing screening programs contain specific protocols for infants with significant hyperbilirubinemia designed to identify early hearing loss.

On macroscopic examinations, characteristic yellow staining can be readily observed in fresh or frozen sections of the brain obtained within 7-10 days after the initial bilirubin insult. The regions most commonly involved include the basal ganglia, particularly the globus pallidus and subthalamic nucleus; the hippocampus; the substantia nigra; cranial nerve nuclei, including the oculomotor, cochlear, and facial nerve nuclei; other brainstem nuclei, including the reticular formation and the inferior olivary nuclei; cerebellar nuclei, particularly the dentate; and the anterior horn cells of the spinal cord.

Neuronal necrosis occurs later and results in the clinical findings consistent with chronic bilirubin encephalopathy. Histologically, this appears as cytoplasmic vacuolation, loss of Nissl substance, increased nuclear density with haziness to the nuclear membrane, and pyknotic nuclei (see image below).

Surgical intervention

Stable central venous access is required to successfully perform an exchange transfusion. Surgical placement of appropriate lines may be required to facilitate this procedure if a catheter cannot be placed into the umbilical vein.

Transfer

Reported cases of kernicterus have occurred in near-term or term infants who were discharged from the hospital fewer than 48 hours after birth.

Most infants discharged at fewer than 72 hours after birth have clearly not reached their physiologic peak bilirubin level prior to discharge.

Any infant at risk for significant hyperbilirubinemia and possible neurotoxicity should be cared for in a nursery capable of rendering appropriate care for the hyperbilirubinemia and any contributing diagnoses.

A published nomogram predicts which babies may be at risk for significant disease, based on hour-of-life–specific bilirubin levels (see image below).[20]  Infants whose levels fall in the high-intermediate and high-risk zones should be closely monitored in a nursery capable of caring for sick newborns; they may require transfer from the birth hospital to a regional perinatal center.

The cornerstone of management of hyperbilirubinemia is prevention of neurotoxicity.[1] The definitive method of removing bilirubin from the blood is via exchange transfusion. This is currently the indicated approach in the presence of clinical bilirubin-induced neurologic dysfunction (BIND) when the bilirubin level has reached dangerous levels despite preventive efforts. Phototherapy is the most common method aimed at prevention of bilirubin toxicity. Clinical research efforts evaluating the use of metalloporphyrins to block bilirubin formation by competing with the enzyme heme oxygenase have not yielded a clinically useful intervention to date.

Exchange transfusion

This definitive therapy is used to mechanically remove already-formed bilirubin from the blood. It is indicated whenever clinical signs of acute bilirubin encephalopathy are present in patients who present with critically high serum bilirubin levels that continue to rise despite attempts to reduce it.

This procedure is not without risk. Whereas exchange transfusion remains the definitive therapy, as recommended in the AAP's Clinical Practice Guideline “Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation” published in 2004, all babies should undergo a trial of phototherapy, if only while the blood is being prepared, prior to initiating exchange transfusion.[20] In the presence of Rh isoimmunization, a cord bilirubin level of more than 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. This relationship has not been demonstrated in hyperbilirubinemia of other etiologies. A report of supplemental intravenous fluid administration in 74 term babies with nonhemolytic severe hyperbilirubinemia (total serum bilirubin level, 18-25 mg/dL) demonstrated a decreased rate of exchange transfusion in babies receiving the extra fluid (16%) compared with controls (54%).[33]

The procedure involves removing the baby's native blood and replacing it with citrate phosphate dextrose (CPD) banked blood that does not contain bilirubin. Obviously, this must be performed gradually. Using an estimate of 80-90 mL/kg total blood volume, double this amount is usually removed and replaced sequentially in aliquots (10-15 mL in term babies; 5-10 mL in smaller preterm babies) over several hours. This approach, called a double volume exchange transfusion, harvests the most efficient amount of bilirubin from the blood for the amount of intervention and results in a decrease in total serum bilirubin levels by about 40%.

Because of ongoing pathology and equilibrium between the intravascular and extravascular spaces, having to repeat the procedure at least once is not uncommon.

Using O negative blood rather than the baby's blood type is important because not all circulating antibodies may be removed. Packed RBCs resuspended in fresh frozen plasma must be used for this procedure. Irradiated RBCs are used to decrease the risk of graft-versus-host reaction.

This procedure carries both inherent risks and iatrogenic ones and should be carefully performed. The reported overall mortality rate is about 3:1000; the risk of significant morbidity has been reported at about 5:100. In babies who were very ill, the risks are higher. One series of 25 infants who were ill reported a mortality rate of 20%. As exchange transfusion is becoming an increasingly rare intervention, iatrogenic complications can be expected to increase.

A review of 183 exchange transfusions performed in 165 neonates in Bangkok, Thailand, from 1994-2003 reported an overall morbidity of 15.3%, of which 67% was attributed to infection associated with the procedure.[34] Infants who were sick at the time of the procedure (31.3%) were more likely to develop complications than were infants who were basically healthy but hyperbilirubinemic (6.8%). Preterm infants who required exchange transfusion also developed procedure-related complications of anemia, apnea, and cardiac arrest; overall, basically healthy preterm infants were more likely to develop some morbidity than were similarly treated full-term infants. Morbidities were identified in infants at the same rate regardless of gestational age (preterm vs term). No mortalities were reported. In Iran, exchange transfusions performed from 2001-2004 in 68 infants for hyperbilirubinemia resulted in one death directly related to complications from the procedure.[35]

Transfusing with banked blood products carries a risk of infection. Currently, the risk of infection with known pathogens is exceedingly small. However, a risk of infection with pathogens that have not yet been discovered (ie, hepatitis C) continues.

During the procedure, continually monitor for attendant physiologic aberrations, such as hypoglycemia, thrombocytopenia (reported in 6% of patients in the Iranian series[35] ), hyperkalemia (particularly if the banked blood is >5 d), and hypocalcemia (if ethylenediamine tetra-acetic acid [EDTA] preservative is used in the banked blood).

Mechanical issues can contribute to the overall mortality and morbidity of the procedure. The need for central access, catheter-related and infusion-related problems, and human error during infusion are all areas that can pose potentially significant risk. Since the advent of phototherapy and obstetric treatment of Rh disease, the need for exchange transfusion has diminished. As fewer contemporary clinicians are familiar with exchange transfusion, the risk of iatrogenic complications increases.

As mentioned above, no clear-cut level of bilirubin above which encephalopathy is assured and below which neurologic safety is assured has been determined. Birthweight, gestational age, and chronologic age are all important, as are a baby's systemic condition, fluid and nutritional status, acid-base status, and the presence or absence of known pathology.

In 2004, the AAP published revised practice parameters for the management of hyperbilirubinemia in healthy infants aged 35 weeks' gestation or older.[20] In this document, the AAP presented recommendations for exchange transfusion for serum bilirubin levels greater than 20-25 mg/dL, depending on the postconceptional age of the infant and the bilirubin-to-albumin ratio, a tool that is not widely incorporated into the decision algorithm. The series by Gamaleldin et al of 249 infants with severe hyperbilirubinemia (≥25 mg/dL) suggested that when neurotoxicity risk issues such as Rh incompatibility or sepsis were present, 90% of infants who developed BIND manifested total serum bilirubin levels of greater than 25.4 mg/dL. However, in the 111 infants without risk factors, neurotoxicity was first observed with total serum bilirubin levels greater than 31.5 mg/dL.[8]

Studies have reported neurologically normal outcomes in healthy term infants with histories of serum bilirubin levels as high as 46 mg/dL. However, kernicterus has been reported to occur in near-term infants with serum bilirubin levels as low as 20.7 mg/dL and in preterm infants with peak total serum bilirubin as low as 13.1 mg/dL.[10] The level at which to intervene is a clinical question that remains to be answered. A survey answered by 163 hospitals in the United Kingdom in 2009 yielded a range of 20-30 mg/dL as thresholds for exchange transfusion in otherwise healthy term infants.[24] The procedure should be strongly considered in babies with significant risk factors predisposing for kernicterus (eg, sepsis, acidosis, hemolytic disease) if the bilirubin level has approached the range of 20-25 mg/dL.

Phototherapy

Phototherapy induces a conformational change in the bilirubin molecule, rendering it water-soluble. Formation of lumirubin is irreversible, whereas the formation of other water-soluble isomers is reversible upon cessation of phototherapy. Protect the infant's eyes during phototherapy to prevent irreversible retinal damage.[1] Typically, phototherapy is initiated at the following total serum bilirubin levels in neonates aged[1] :

• 25-48 hours old: ≥15 mg/dL
• 49-72 hours old: ≥18 mg/dL
• Older than 72 hours: ≥20 mg/dL

Postphototherapy rebound is a well-recognized phenomenon that must be considered in all patients receiving phototherapy for hyperbilirubinemia due to a hemolytic process or prematurity. One series of 226 term and near-term neonates treated in Israel between January 2001 and September 2002 reported significant rebound hyperbilirubinemia in 13.3% of patients.[36]  Risk factors of excessive rebound included a positive direct Coombs test and a gestation less than 37 weeks.

Enteral interventions

Administration of agar has been tried in an attempt to decrease the enterohepatic recirculation of conjugated bilirubin. It has not proved to be clinically useful and may cause intestinal obstruction.

Parenteral administration of immunoglobulin G (IgG) has been shown in controlled clinical trials to reduce the need for exchange transfusion in both Rh and ABO immune-mediated hemolytic disease. Its mechanism of action is not entirely clear.

Administration in hyperbilirubinemia resulting from isoimmune hemolytic disease that is unresponsive to phototherapy and/or is approaching exchange level has been recommended by the AAP in its 2004 revised clinical practice guideline.

Accelerated meconium evacuation

Administration of glycerin suppositories to facilitate stooling has been evaluated as a potential method of ameliorating hyperbilirubinemia. Although a controlled trial demonstrated earlier passage of meconium, no effect was demonstrated on total serum bilirubin levels, except for a small statistically significant effect identified in males with blood type A positive. Whether this was a statistical aberration or a true treatment effect is unclear.

Enteral prebiotics

Enterohepatic recirculation and delayed stooling contribute to perpetuation of hyperbilirubinemia. Investigations have focused on the role of oligosaccharides (galactose and fructose) naturally occurring in breastmilk as a modulator of intestinal flora and function. As a result, major infant formula manufacturers are now adding these so-called prebiotics to their formulations. A randomized, double-blind trial of formula and prebiotics versus formula and maltodextrine placebo was examined the effect of the investigational formula on stooling frequency. For the first 28 days of life, 76 newborns were randomly assigned to receive one of the formulations. Transcutaneous bilirubin measurements and number of stools per day were recorded. Infants in the prebiotic group showed significantly more stools per day for the duration of the trial period, as well as lower transcutaneous bilirubin levels (p< 0.05).[37]

Beta-glucuronidase inhibition

L-aspartic acid and enzymatically hydrolyzed casein (EHC) are known inhibitors of beta glucuronidase, the enzyme that promotes enterohepatic recirculation of conjugated bilirubin in the neonatal intestine. A randomized controlled trial of enteral administration of these substances (2 treatment groups) compared with babies who received nothing (group 3) or enteral whey/casein (no known enzymatic activity, group 4) showed significantly lower transcutaneous bilirubin measurements in breastfed babies aged 3-7 days who received the enzyme inhibitors when compared with the controls.[38] However, a similar treatment effect observed in group 4 raises some questions regarding the value of these therapies.

Sn-mesoporphyrin

Experimental therapy with Sn-mesoporphyrin inhibits bilirubin production by interfering with heme-oxygenase, an essential enzyme in the catabolic pathway of hemoglobin. This therapy is in clinical trials but has not been approved for use by the Food and Drug Administration (FDA). A report of a single case of compassionate use in the United States in a very low birth weight infant with severe growth restriction who was not a candidate for exchange transfusion showed a more than 25% reduction in total serum bilirubin levels after administration of a single dose at 46 hours of life.[39] Although more extensively studied in other countries, the safety and possible long-term sequelae of this therapeutic modality remain to be elucidated.

Diet and activity

Depending on the degree of neurologic impairment, infants or children may have limitations in their ability to eat normally. Diet and nutrition must be individualized with the help of the neurodevelopmental team caring for the patient.

Some neurologic deficits typically appear during the phase of motor skill acquisition by the infant. Motor deficits should be identified early, and appropriate intervention should be initiated to maximize the infant's ability in this critical area. 

Obtaining input from a pediatric neurologist during the acute presentation of BIND may be useful. However, the history and clinical presentation may make the diagnosis apparent.

In the chronic phase, involving neurodevelopmental specialists in the care and evaluation of the infant is important. Developmental potential can be maximized by early identification of and intervention for neurologic deficits.

If the patient develops hydrocephalus, consultation with a neurosurgeon is recommended.

Prevention

Prevention of hyperbilirubinemia is the best way to minimize the incidence of kernicterus. However, because some babies develop kernicterus with relatively modest bilirubin levels, no known absolute level of bilirubin below which the infant is completely safe is recognized. Additionally, because other factors contribute to the ability of bilirubin to cross the blood-brain barrier, management of these components must be appropriately considered.

In 2009, Newman et al reported the numbers needed to treat with phototherapy to prevent kernicterus, based on the AAP 2004 guideline phototherapy threshold. Assessment of 22,547 infants from a cohort of 281,898 infants born in a California hospital system from 1995-2004 resulted in various NNTs for different subpopulations of infants. Averaging 222 for boys and 339 for girls, the subgroup NNTs ranged from 10 for less than 24-hour-old, 36–week-gestation boys to 3,041 for older than or 3-day-old, 41-week-gestation girls.[40]

Serum bilirubin

Total serum bilirubin comprises a conjugated fraction (loosely called direct bilirubin) and an unconjugated fraction (indirect bilirubin). They are additive. However, the indirect fraction is composed of bound bilirubin (bound to albumin), lumirubin and other isomers if the baby is under phototherapy (unbound but water-soluble and unlikely to cross the blood-brain barrier), and free bilirubin. The free component is potentially toxic, but its exact serum level cannot be readily measured.

Risk of reduction of serum bilirubin

The current level of knowledge does not recognize the physiologic benefits of bilirubin, despite the multiple mechanisms operant in the neonate to promote and preserve hyperbilirubinemia. In vitro experiments have demonstrated a potent antioxidant capability of bilirubin, more so than the currently identified mechanisms.

An emerging field of research in human medicine is the role of oxidative injury in the development of various pathologic processes, which may be contributory to many neonatal diseases, such as retinopathy of prematurity, periventricular leukomalacia, bronchopulmonary dysplasia, and necrotizing enterocolitis. Observational studies in the neonate have demonstrated an inverse correlation between peak serum bilirubin levels and the development of these various pathologies. Investigation into this line of research continues.

Phototherapy

Irradiance with light in the blue-green spectrum (440-480 nm) induces a photochemical reaction that changes the bilirubin molecule into other photoisomers that are water-soluble, readily excretable, and unlikely to cross the blood-brain barrier into the lipid-rich neuronal tissue. Such conversion begins immediately upon exposure of the skin surface to the light.

The most important photoreaction is an irreversible structural isomerization of bilirubin into a water-soluble substance called lumirubin, which is then excreted in the bile. Reversible configurational isomerization and photo-oxidation also contribute somewhat to the effectiveness of phototherapy to reduce free bilirubin in the baby.

To be effective, adequate skin surface must be exposed to the appropriate wavelength, with enough intensity (lux) to induce the desired reaction. The AAP included recommendations for wavelength (430-490 nm) and irradiance (>30 µW/cm2) in their 2004 clinical practice guideline.[20]

Serum bilirubin levels should be closely monitored during phototherapy. A 1-mg/dL to 2-mg/dL decrease of measured bilirubin levels over a period of 4-6 hours is an appropriate response to phototherapy. If an inadequate response has been observed, lining the baby's bedding with aluminum foil or white material can increase the surface area of exposure and may increase the effectiveness of phototherapy.

Various devices are commercially available to facilitate provision of phototherapy. Models include overhead lights, blankets, and swaddling devices; selection is based on abilities to cover a broad surface area, ease of administration, and personal preference. The assortment of commercially available phototherapy devices continues to expand, and each new market entry is advertised as superior to the previous entry. Head-to-head clinical trials repeatedly show that time, irradiance, and skin surface area are the most significant factors in efficacy of phototherapy.[41, 42, 43]

In 2004, the AAP revised its clinical practice guideline for the management of hyperbilirubinemia in the healthy infant older than 35 weeks' estimated gestational age.[20]  The guideline incorporates a nomogram that delineates serum bilirubin levels by hour of life with subsequent risk for significant disease (see following image).

An Internet-based tool, BiliTool, is now available to help clinicians assess and treat hyperbilirubinemia based on the hour-specific nomogram and published guidelines.

This reference should be used when deciding how closely to monitor babies being discharged home before their bilirubin levels have peaked. Since its development, some experts have recommended universal bilirubin screening (performed with the state metabolic screen to minimize blood draws) before discharge.

Although falling short of recommending universal bilirubin measurement, the AAP guideline does recommend assessment of risk of severe hyperbilirubinemia in every baby prior to hospital discharge. This assessment can include either a bilirubin measurement (serum or transcutaneous), a clinical assessment of risk factors, or a combination of these 2 approaches. Further prospective analysis of these strategies found that the hour-specific nomogram was a better predictor than a clinical risk factor approach and that predischarge bilirubin level combined with gestational age most accurately predicted an infant's risk of developing severe hyperbilirubinemia.[44, 45]

Current quantization of bilirubin has been limited to direct serum measurement. Transcutaneous measurement devices are commercially available and are slowly being integrated into clinical use. The manufacturers claim excellent reliability and validity in babies of all skin types and colors.

Risks of phototherapy

Phototherapy by itself is generally considered safe in babies, except in some rare genetic skin disorders and congenital porphyria. However, some risks are associated with its use.

Exposure to phototherapy can increase insensible fluid loss and lead to dehydration, especially in babies in open warmers if fluid intake and output are not closely monitored. This, in turn, potentiates hyperbilirubinemia.

Some extremely premature infants have reportedly experienced skin burns from fiberoptic blankets on which they were lying. Such devices should be used cautiously in infants with vulnerable skin.

Of potentially greater concern with respect to extremely premature infants is the report of increased mortality associated with phototherapy. A study conducted by the NICHD Neonatal Network as reported by Watchko evaluated the outcomes of aggressive versus conservative phototherapy in extremely low birth weight infants. Although aggressive phototherapy seemed to improve neurodevelopmental outcomes in the 751- to 1000-g cohort, aggressive phototherapy used in the group with birth weights of 501-750 g showed a 5% higher mortality rate, with a post-hoc Bayesian analysis estimating an 89% probability that aggressive phototherapy increased the rate of death in this cohort. The authors speculate that greater light penetration deeper into subcutaneous tissues and possible oxidative injury to cell membranes may be responsible.[10]

Concern exists about the risk of retinal damage in infants exposed to the extremely bright light of phototherapy. Accordingly, all infants should wear protective eye coverings while being treated.

An observed increase in the prevalence of patent ductus arteriosus (PDA) has been shown to occur in premature infants receiving phototherapy, and foil shields to the chest have been shown to ameliorate this increase. The operant mechanism has not been fully elucidated.

Bilirubin photosensitizes the skin, and skin damage is a theoretical risk. Bullous eruptions have been described in several infants with porphyrin abnormalities; congenital porphyria is a contraindication to the use of phototherapy. In 2011, Csoma et al from Hungary reported on 59 sets of twins, one of which received blue-light phototherapy and the other of which did not. Neonatal phototherapy was associated with a significantly higher prevalence of both cutaneous and uveal melanocytic lesions, after controlling for sun exposure and other confounders.[46]

Bronze baby syndrome occurs in infants with direct hyperbilirubinemia who are exposed to phototherapy. This seems likely to be the result of dermal accumulation of coproporphyrins. Measurement of the direct fraction of total bilirubin should be performed in every baby before starting phototherapy.

Phototherapy can interfere with maternal-child bonding at a critical time in the dyad's development. If a mother is breastfeeding, initiation of phototherapy introduces mechanical barriers to the breastfeeding process, which can be overwhelming at this critical time. Any comments about the role of breast milk in the development of hyperbilirubinemia may further sabotage this process. Altered parental perceptions of their infant from healthy to ill may further influence their short-term and long-term interactions with their infant. The pediatrician should address these issues with the family.

Phototherapy may be associated with ileus and/or feeding intolerance in premature infants treated with overhead (but not fiberoptic) devices. Doppler flow studies of splanchnic blood flow performed on babies receiving overhead phototherapy showed increased resistance to flow in the superior mesenteric artery (SMA) compared with prephototherapy measurements; no such effect was observed in babies being treated with fiberoptic devices. A retrospective review of 52 consecutive extremely low birth weight infants showed a higher incidence of ileus (abdominal distention, bilious aspirates) in babies receiving phototherapy (63.4%) compared with those who did not (9%).[47]  Outcomes between the 2 groups were comparable.

Breastfeeding

The link between hyperbilirubinemia and breastfeeding has long been recognized, and, until relatively recently, breastfeeding was typically interrupted in infants with jaundice. Randomized controlled trials have shown that offering formula or dextrose water to the breastfed infants with jaundice actually increases total serum bilirubin levels and, thus, should not be advocated. The AAP recommends against this practice, with evidence quality B and C in its 2004 clinical practice guideline.[20]  Furthermore, this practice has also been shown to result in a decrease in breast milk intake after breastfeeding is reestablished. Study of the effect of continuing breastfeeding versus its interruption has not shown any untoward effect of continued breastfeeding. Because of the clear short-term and long-term advantages to the infant of breast milk feeds, the evidence would indicate that breastfeeding should be continued in the infant who is well enough to have enteral feedings.

Infant massage

In 2011, Chen et al reported from Niigata, Japan the results of a randomized controlled trial of the benefits of infant massage on hyperbilirubinemia. Forty-two healthy term breastfed infants ranging in weight from 2800-3600 g were randomized to massage or no massage (control). Infants receiving massage had a significantly higher frequency of stooling on days 1 and 2 (P < .05) and a lower total serum bilirubin on day 4 compared with the control group.[48]

Clinical algorithms

A Journal of Pediatrics supplement devoted exclusively to hyperbilirubinemia and prevention of kernicterus advocated 2 models for public health policy aimed at eliminating kernicterus from the population.[49, 50]  To date, notwithstanding the efforts of some hospital systems and the American Academy of Pediatrics to standardize this aspect of newborn care, approaches to the surveillance and management of hyperbilirubinemia remain individualized, both throughout the United States and elsewhere.[24]

To help ensure that infants may reach their maximum neurodevelopmental potential, referring babies with bilirubin-induced neurologic dysfunction (BIND) to a neurodevelopmental pediatrician skilled in caring for these patients is important. Early identification of and intervention for neurodevelopmental deficits has been shown to positively impact an infant's long-term neurodevelopmental prognosis.

The numerous areas of uncertainty surrounding the diagnosis and treatment of hyperbilirubinemia in the infant, coupled with the infrequency of sequelae, make it easy to become cavalier about the evaluation of an infant with jaundice. However, remember that physiologic hyperbilirubinemia is a diagnosis of exclusion, and kernicterus, when it occurs, is a devastating and legally indefensible sequela.

Sepsis must always be excluded in the infant with jaundice. Uncommon, but treatable, metabolic causes of jaundice include hypothyroidism and galactosemia. The first sign of occult immune or nonimmune hemolytic disease may be hyperbilirubinemia.

In its 2004 clinical practice guideline, the AAP included recommendations regarding interval between hospital discharge and outpatient follow-up evaluation by a qualified health care professional.[20]  Recommendations are based on the infant's age (in hours of life) at discharge, presence or absence of risk factors for exaggerated hyperbilirubinemia, and the presence of other neonatal problems. Recommendations for follow-up range from as early as prior to 72 hours of life (if discharged before 24 h) to no later than 120 hours (5 d) if discharged before 72 hours.

No medications are available to treat the symptoms of acute or chronic bilirubin encephalopathy. Pharmacologic intervention is aimed at prevention. Current therapies are indicated as adjuncts to phototherapy when total bilirubin is approaching exchange level; experimental therapy continues with the use of bilirubin production inhibitors.

Class Summary

These methods decrease the amount of free bilirubin in the intravascular space, thus theoretically reducing the risk of neurotoxicity. Bilirubin is produced via induction of its enzymatic pathway and by RBC degradation. Inhibition of either of those 2 mechanisms can decrease the amount of bilirubin in the blood.

Albumin (Albuminar, Albutein, Plasbumin)

Because bilirubin bound to albumin is not available to cross the blood-brain barrier, increasing the amount of serum albumin theoretically increases the amount of available binding sites and decreases free bilirubin. Efforts to quantify albumin-binding capability or serum levels of bound bilirubin have not proved to be clinically useful, although assessment of the bilirubin-to-albumin ratio have been incorporated into the decision-making algorithm for exchange transfusion. However, administration of albumin for the purpose of increasing bilirubin-binding capacity is not a recommended standard of care. It may be considered in cases of significant hypoalbuminemia. Measured albumin levels < 3 g/dL may be considered an additional risk factor for BIND when considering therapeutic interventions.

Immune globulin intravenous (Gamimune, Gammagard S/D, Gammar-P, Polygam S/D)

Parenteral administration has been shown in controlled clinical trials to reduce the need for exchange transfusion in both Rh and ABO immune-mediated hemolytic disease. Its mechanism of action is not entirely clear.

Administration in hyperbilirubinemia resulting from isoimmune hemolytic disease that is unresponsive to phototherapy and/or is approaching exchange level has been recommended by the AAP in its 2004 revised clinical practice guideline.

Class Summary

Phenobarbital may increase hepatic conjugation and excretion. Decreased hepatic conjugation caused by normal delay in enzyme induction increases the amount of unconjugated bilirubin in the blood stream. Conjugated bilirubin does not pose a threat of neurotoxicity. Once conjugated, this nontoxic form of bilirubin proceeds toward intestinal excretion.

Phenobarbital (Luminal, Solfoton)

Induces the hepatic enzymes involved in bilirubin conjugation and increases biliary excretion.

Do not administer intra-arterially. Dosing can be enteral or parenteral.