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Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia

Risk factors, clinical manifestations, and neurologic complications of neonatal unconjugated hyperbilirubinemia
Authors:
Ronald J Wong, BA
Vinod K Bhutani, MD, FAAP
Section Editor:
Steven A Abrams, MD
Deputy Editor:
Laurie Wilkie, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Dec 02, 2022.

INTRODUCTION — Nearly all newborn infants develop elevated bilirubin levels (ie, total serum bilirubin [TSB] >1 mg/dL [17 micromol/L], which is the upper limit of normal for adults). As TSB levels increase, the newborn may develop visible jaundice. Neonates with severe hyperbilirubinemia (defined as TSB >25 mg/dL [428 micromol/L] in term and late preterm newborns [gestational age (GA) ≥35 weeks]) are at risk for developing bilirubin-induced neurologic disorders (BIND).

The epidemiology, risk factors, clinical manifestations, and neurologic complications of unconjugated hyperbilirubinemia in term and late preterm newborn infants are reviewed here. Other related issues are discussed separately:

Pathogenesis and etiology of neonatal hyperbilirubinemia (see "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia")

Screening for hyperbilirubinemia in term and late preterm newborns (see "Screening for hyperbilirubinemia in term and late preterm newborn infants")

Management of neonatal hyperbilirubinemia (see "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns" and "Escalation of care for term and late preterm newborns with unconjugated hyperbilirubinemia")

Hyperbilirubinemia in preterm infants (GA <35 weeks) (see "Unconjugated hyperbilirubinemia in preterm infants <35 weeks gestation")

Conjugated (direct) hyperbilirubinemia in neonates (see "Causes of cholestasis in neonates and young infants")

DEFINITIONS

Benign neonatal hyperbilirubinemia is a transient and normal increase in bilirubin levels occurring in nearly all newborn infants and invariably responds to nutritional support. It has been referred to as "physiologic jaundice."

Severe neonatal hyperbilirubinemia is defined as a total serum or plasma bilirubin TSB >25 mg/dL (428 micromol/L). It is associated with an increased risk for developing bilirubin-induced neurologic disorders (BIND).

Extreme neonatal hyperbilirubinemia is defined as a TSB >30 mg/dL (513 micromol/L). It is associated with a higher risk for developing BIND, including irreversible chronic encephalopathy (kernicterus).

BIND results from selective brain damage from free (unbound) bilirubin crossing the blood-brain barrier and binding to brain tissue. The spectrum of neurotoxic injury, including acute and chronic bilirubin encephalopathy (ABE and CBE, respectively), is collectively referred to as BIND. The manifestations of BIND, including subtle dysfunction ABE, and CBE, are described below. (See 'Consequences of severe hyperbilirubinemia' below.)

EPIDEMIOLOGY

Incidence of neonatal hyperbilirubinemia — In the neonate, bilirubin values vary substantially from region to region because of differences in breastfeeding practices, racial composition of the population, and the prevalence of genetic factors that affect bilirubin production and metabolism. These factors as well as the use of different definitions to describe the severity of hyperbilirubinemia may contribute to the following observed global variations in the incidence of severe hyperbilirubinemia.

In studies of term or late preterm infants from a large healthcare system in California, the following incidences of hyperbilirubinemia at different total serum bilirubin (TSB) values were reported from birth data collected between 1995 and 1998 [1,2]:

TSB >20 mg/dL (342 micromol/L) – 2 percent

TSB >25 mg/dL (428 micromol/L) – 0.14 percent

TSB >30 mg/dL (513 micromol/L) – 0.01 percent

The incidence of TSB >20 mg/dL (342 micromol/L) was lower in infants born to mothers who were self-reported as Black compared with White (0.9 versus 1.5 percent, relative risk [RR] 0.62, 95% CI 0.56-0.69) [3]. However, the risk of developing TSB >30 mg/dL (513 micromol/L) was higher in Black infants (0.13 versus 0.03 percent, RR 4.2, 95% CI 1.33-13.2).

In a subsequent birth cohort of infants born between 1995 and 2011 in the same network, the reported incidence of TSB >30 mg/dL (513 micromol/L) was 8.6 per 100,000 live births [4].

In a Danish population-based study from 2000 to 2015, the incidence of TB ≥26.3 mg/dL (450 micromol/L) was 0.042 percent (42 per 100,000 live births) among term and late preterm newborns (gestational age [GA] ≥35 weeks) [5].

In a prospective population-based study in the United Kingdom and Ireland between 2003 and 2005, the incidence of TSB >30 mg/dL (513 micromol/L) was 7 per 100,000 live births (0.007 percent) [6]. The mean GA of the 108 identified infants was 38.2 weeks.

In a prospective population-based study from Australia performed between 2010 and 2013, the incidence of TSB ≥26.3 mg/dL (450 micromol/L) for newborns greater than 34 weeks GA was 9.4 per 100,000 infants (0.009 percent) [7]. (See 'Risk factors' below.)

Trends over time — The incidence of severe hyperbilirubinemia (TB >25 mg/dL [428 micromol/L]) is decreasing, presumably due to early identification and treatment of at-risk newborns (figure 1). (See "Screening for hyperbilirubinemia in term and late preterm newborn infants" and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Thresholds for treatment'.)

In a study that compared data from the Canadian Paediatric Surveillance Program (CPSP) with previously published reports, the incidence of TSB ≥24.9 mg/dL (426 micromol/L) in Canada declined from 0.04 to 0.01 percent over a 10-year period from 2002 through 2004 to 2011 through 2013 [8].

A report from a multicenter health care system in the United States showed a declining rate of infants with TSB levels >25 mg/dL (428 micromol/L) from 2002 to 2010 [9] (figure 1).

RISK FACTORS

Risk factors for severe hyperbilirubinemia

Predischarge bilirubin level – The strongest predictor of developing severe or progressive hyperbilirubinemia is the newborn's predischarge total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) level, which is typically measured at 24 to 48 hours after birth [10,11]. Additional details regarding newborn bilirubin screening and treatment are provided separately. (See "Screening for hyperbilirubinemia in term and late preterm newborn infants" and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns".)

Risk assessments are based on total bilirubin rather than unconjugated bilirubin levels alone because neonatal hyperbilirubinemia is mostly due to increased bilirubin production, resulting primarily in unconjugated bilirubin. Cholestasis, which presents with primarily elevated conjugated or direct bilirubin, is a rare cause of neonatal hyperbilirubinemia. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia" and "Causes of cholestasis in neonates and young infants".)

Clinical factors associated with increased risk – In addition to the predischarge bilirubin level, the 2022 American Academy of Pediatrics (AAP) clinical practice guideline recognizes the following as key risk factors for developing severe or progressive hyperbilirubinemia [10] (table 1):

Prematurity – The risk increases with each additional week earlier than 40 weeks of gestation [11-14].

Early-onset jaundice (within the first 24 hours after birth) [15].

Known or suspected hemolytic disease due to isoimmune-mediated hemolysis from blood group incompatibilities or inherited hemolytic disorders (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency) [4,7,16]. Hemolysis may be suspected based upon any of the following (see "Alloimmune hemolytic disease of the newborn: Postnatal diagnosis and management" and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency"):

-ABO or Rh incompatibility (regardless of direct antiglobulin test [DAT] status)

-Early-onset jaundice (within in first 24 hours after birth)

-Rapidly rising TSB levels (>0.3 mg/dL [5 micromol/L] per hour in the first 24 hours; >0.2 mg/dL [3 micromol/L] per hour thereafter)

A parent or sibling who required phototherapy or exchange transfusion as a newborn [13,17].

Family history or ancestry suggestive of an inherited hemolytic disorder (eg, G6PD deficiency, hereditary spherocytosis). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Epidemiology'.)

Cephalohematoma or other significant bruising from birth trauma [11,12]. (See "Neonatal birth injuries", section on 'Cephalohematoma'.)

Down syndrome. (See "Down syndrome: Clinical features and diagnosis".)

Macrosomic (large for gestational age [LGA]) infant of a diabetic mother [11,18,19]. (See "Infants of women with diabetes".)

Need for phototherapy during the birth hospitalization.

Exclusive breastfeeding with suboptimal intake [12,13,20].

For newborns undergoing routine bilirubin screening, these risk factors are used in conjunction with the predischarge TSB or TcB level to assess the newborn's likelihood of developing severe hyperbilirubinemia and to guide appropriate timing of follow-up. The approach is summarized in the table (table 2) and discussed separately. (See "Screening for hyperbilirubinemia in term and late preterm newborn infants", section on 'Risk assessment' and "Screening for hyperbilirubinemia in term and late preterm newborn infants", section on 'Outpatient follow-up'.)

Other reported risk factors that are not included in the 2022 revised AAP clinical practice guideline include:

Polycythemia (see "Neonatal polycythemia", section on 'Hyperbilirubinemia')

Small for gestational age (SGA) [11] (see "Infants with fetal (intrauterine) growth restriction")

Male sex [12]

Maternal age ≥25 years [13]

Newborns cared for at facilities with constrained resources [21]

Factors associated with lower risk – Factors reported to be associated with decreased risk of severe hyperbilirubinemia include:

Gestational age (GA) ≥41 to 42 weeks [12]

Exclusive formula feeding [12,13]

Discharge from the birth hospitalization at >72 hours after birth [13,22]

Planned Cesarean delivery [11]

Risk factors for neurotoxicity — The most important risk factor for neurotoxicity is the severity and duration of bilirubin exposure. Based upon observational studies, the risk of acute and chronic bilirubin encephalopathy (ABE and CBE, respectively) among healthy term and late preterm infants is highest when TSB levels ≥30 mg/dL (513 micromol/L) [4,16,23,24]. Neurotoxicity can occur at lower TSB levels (ie, > 20 to 30 mg/dL (342 to 513 micromol/L) in the setting of Rh disease, severe hemolysis, sepsis, G6PD deficiency, or other acute illnesses. With progressive hyperbilirubinemia, the margins of safety can be diminished by the rate of TSB rise.

In addition to the TSB level, the 2022 AAP clinical practice guideline recognizes the following as key risk factors for developing bilirubin neurotoxicity (table 3) [10]:

GA <38 weeks (the risk increases with decreasing GA)

Hemolytic disorders (alloimmune hemolytic disease of the newborn G6PD deficiency, other inherited hemolytic anemias) [7,25]

Clinical or hemodynamic instability

Bacterial or viral sepsis [25]

Hypoalbuminemia (serum albumin <3.0 g/dL) [26]

For some of these factors (eg, hemolysis), the increased risk of developing bilirubin neurotoxicity is a result of the extreme TSB levels associated with the condition. For others (eg, hypoalbuminemia), the increased risk of neurotoxicity is due to reduced bilirubin-albumin binding, which increases the amount of unbound (free) bilirubin (figure 2). For some factors (eg, sepsis, hemodynamic instability), both mechanisms are likely at play.

Other factors that increase vulnerability to bilirubin neurotoxicity either by reducing bilirubin-albumin binding or increasing permeability of the blood-brain barrier include [27]:

Certain drugs (eg, ceftriaxone, sulfisoxazole, moxalactam)

Metabolic or respiratory acidosis

Hyperosmolality

Factors contributing to neurotoxicity were illustrated in a study of 125 patients with severe CBE (or kernicterus), all of whom were discharged from the birth hospitalization (presumably healthy at discharge) but then readmitted for management of severe hyperbilirubinemia [28]. The following were identified as contributing causes:

No clear underlying risk factor – 42 percent.

G6PD deficiency – 21 percent (when measured).

Other hemolytic condition – 20 percent.

Bruising from birth trauma – 14 percent.

Infection – 14 percent (concurrent with other causes).

Crigler-Najjar syndrome or galactosemia – 2 percent.

Breastfeeding difficulties – Nearly all infants (98 percent) were exclusively breastfed. At the time of readmission, 17 percent had lost >10 percent of their birth weight, suggesting inadequate milk intake. (See "Etiology and pathogenesis of neonatal unconjugated hyperbilirubinemia", section on 'Inadequate milk intake' and "Common problems of breastfeeding and weaning", section on 'Inadequate milk intake'.)

Risk factors for readmission — Risk factors for readmission for hyperbilirubinemia for term infants based on data from a large population-based Australian study included [29]:

Early birth hospital discharge (≤48 hours after birth).

GA <39 weeks.

Mother from an Asian country.

Vaginal birth.

First-time mother.

Breastfeeding at the time of birth hospital discharge. Of note, the study did not differentiate between suboptimal or successful initiation of breastfeeding at the time of discharge.

GENETIC PREDISPOSITION — Genetic predisposition may play a contributing role in the development of severe hyperbilirubinemia. Examples include:

Gilbert syndrome – Gilbert syndrome affects approximately 5 to 15 percent of the general population and is more common in individuals of East Asian ancestry [30,31]. It is caused by a common mutation in UGT1A1, which encodes for uridine diphosphate glucuronosyltransferase (UGT), an enzyme that catalyzes the conjugation of bilirubin with glucuronic acid. Thus, affected individuals have decreased bilirubin clearance. The clinical scenario typically presents as persistent jaundice and prolonged unconjugated hyperbilirubinemia at age 10 to 14 days. The relatively high prevalence of this disorder may in part explain why family history is a predictive risk factor for hyperbilirubinemia. In newborns with Gilbert syndrome, reduced bilirubin clearance in combination with any other factor that increases bilirubin (eg, hemolytic disease) can result in severe to extreme hyperbilirubinemia [31,32]. As an example, breastfed infants with Gilbert syndrome have an approximately threefold higher risk for developing severe hyperbilirubinemia compared with breastfed infants without Gilbert syndrome [33]. (See "Gilbert syndrome and unconjugated hyperbilirubinemia due to bilirubin overproduction".)

Inherited hemolytic anemias – Newborns with inherited hemolytic disorders (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency) are at risk of developing severe neonatal hyperbilirubinemia [34]. (See "Overview of hemolytic anemias in children", section on 'Intrinsic hemolytic anemias' and "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Neonatal jaundice'.)

CLINICAL MANIFESTATIONS

Jaundice — Jaundice is the yellow color produced by the deposition of bilirubin in the skin and subcutaneous tissues. It can be assessed visually after digital pressure, using color comparison with standardized color charts. Jaundice may also be assessed in the buccal, gingival, or conjunctival mucosa.

The examination for jaundice should be performed with adequate ambient light or under daylight fluorescent light. Pressing on the skin or oral mucosa with a finger reduces local skin perfusion and facilitates detection of jaundice.

Jaundice usually progresses in a cephalocaudal direction, appearing first in the face with total serum bilirubin (TSB) levels of 4 to 8 mg/dL (68 to 137 micromol/L). The entire body, including palms and soles, can appear jaundiced at TSB >15 mg/dL (257 micromol/L) [35]. However, the extent of visible jaundice on physical examination is not a reliable method to estimate TSB levels or identify infants at risk for rapidly rising TSB, especially in those with darkly pigmented skin [36-40]. If there is uncertainty regarding the presence or extent of jaundice, bilirubin should be measured with a total serum bilirubin (TSB) level or a transcutaneous bilirubin (TcB) device. As discussed separately, routine screening with at least one TSB or TcB measurement during the birth hospitalization (typically between 24 to 48 hours after birth) is suggested for all term and late preterm newborns. Screening should be performed sooner if the newborn appears jaundiced within the first 24 hours. (See "Screening for hyperbilirubinemia in term and late preterm newborn infants".)

Scleral or conjunctival icterus — Scleral icterus is due to bilirubin deposition in the conjunctiva and subsequently in scleral stroma. It can be observed on scleral examination. The finding of scleral icterus generally correlates with clinically significant hyperbilirubinemia, particularly if observed within the first 48 to 72 hours after birth and subsequently lingers. However, the correlation is not always consistent [41,42].

In one study that included 76 infants with scleral icterus, 91 percent had a TSB ≥15 mg/dL (257 micromol/L) [41]. In another study of 689 infants seen in the outpatient setting between 3 and 10 days of age (308 had scleral icterus; 381 did not), the likelihood of having TcB ≥13 mg/dL (222 micromol/L) was far higher among newborns with scleral icterus compared with those without icterus (40 versus 4 percent, respectively) [42]. A limitation of the second study is that it used only TcB measurements, which are less reliable at TSB levels>15 mg/dL (257 micromol/L). (See "Screening for hyperbilirubinemia in term and late preterm newborn infants", section on 'Bilirubin testing methods'.)

Other physical findings — Other findings on physical examination may suggest an underlying condition associated with an increased risk for hyperbilirubinemia such as:

Pallor (in the setting of significant anemia due to hemolysis)

Enclosed hemorrhage (eg, cephalohematoma)

Bruising

Hepatosplenomegaly

CONSEQUENCES OF SEVERE HYPERBILIRUBINEMIA

Bilirubin-induced neurologic disorders (BIND) — The major consequence of severe neonatal hyperbilirubinemia is a spectrum of neurotoxic injuries collectively referred to as BIND.

Pathogenesis – BIND occurs when free (or unbound) bilirubin crosses the blood-brain barrier and binds to brain tissue. This causes both molecular and cytological injuries to brain cells, which can result in cell death by apoptosis (programmed cell death) and/or necrosis (figure 2) [43-45]. The brain regions most often affected include the basal ganglia and the brainstem nuclei for oculomotor and auditory function, accounting for the clinical features seen in infants and children with BIND [46].

Incidence – The true incidence of BIND in the general neonatal population is unknown and varies due to multiple epidemiological factors. Among term and late preterm infants with extreme hyperbilirubinemia (total bilirubin [TB] levels ≥30 mg/dL [513 micromol/L]), reported rates of acute and chronic bilirubin encephalopathy (ABE and CBE, respectively) range from 10 to 30 percent [4,16,23,24].

Risk factors for BIND – Major risk factors for BIND are summarized in the table (table 3) and discussed above. (See 'Risk factors for neurotoxicity' above.)

Clinical spectrum – BIND represents a spectrum of neurologic abnormalities, ranging from subtle findings to severe disability [47,48].

Severe CBE (previously referred to as kernicterus), is the extreme form of BIND associated with permanent neurologic sequelae, such as choreoathetoid cerebral palsy, gaze palsies, and sensorineural impairment [10]. (See 'Incidence' below.)

However, less severe manifestations of BIND can be observed in vulnerable neonates exposed to bilirubin of a lesser degree than typically associated with CBE (generally TSB <25 mg/dL [428 micromol/L]). These subtle clinical neuromotor manifestations may include [47]:

Disorders in visuocortical pathways [49]

Sensorineural hearing loss [50]

Abnormal proprioception (leading to gait abnormalities) [51]

Speech and language disabilities [52]

Processing disorders

Cognitive delays [52]

Acute bilirubin encephalopathy (ABE) — ABE refers to acute signs of bilirubin neurotoxicity in a newborn with severe persistent hyperbilirubinemia.

Incidence — Based on information from population-based studies in resource-rich settings, the estimated incidence of ABE is approximately 0.5 to 1 per 100,000 live-born infants [4,6,7,16]. Among newborn infants with TSB >30 mg/dL (513 micromol/L), reported rates of ABE range from 2 to 10 percent.

In a cohort of infants from a single healthcare system in the United States born between 1995 and 2011, 47 of 525,409 infants (0.01 percent) had at least one TSB level >30 mg/dL (513 micromol/L). Four of these 47 patients (9 percent) had clinical signs of ABE and all had TSB >35 mg/dL (599 micromol/L) [4].

In a Danish population study, five of 224 infants (2 percent) with TSB ≥30 mg/dL (513 micromol/L) developed ABE; three with severe ABE had peak TSB levels of 38 to 57.7 mg/dL (650 to 9987 micromol/L) that resulted in kernicterus or CBE [16].

In another population-based study from the United Kingdom and Ireland, 14 of 108 infants (13 percent) with TSB >30 mg/dL (513 micromol/L) showed evidence of ABE including three who died [6].

The risk may be higher with resource-constrained healthcare systems. In an observational case series from Egypt of 249 infants with TSB >25 mg/dL (428 micromol/L) for unknown duration, moderate or severe ABE was diagnosed in 44 infants (18 percent) and mild ABE in 55 infants (22 percent) based on neurologic assessment using an objective BIND protocol (BIND score, which is discussed below) [53].

Clinical features — ABE typically progresses through three phases [46]:

Early – In the early phase, the clinical signs may be subtle. The infant is sleepy but arousable, and when aroused has mild to moderate hypotonia and a high-pitched cry. It is challenging to diagnosis ABE during this phase [23]. Early ABE may be reversible.

Intermediate – If there is no intervention, the intermediate phase evolves with progression and persistence of hyperbilirubinemia. The infant can be febrile and lethargic with a poor suck or irritable and jittery with a strong suck. The cry can be shrill and the infant can be difficult to console. Mild to moderate hypertonia develops, beginning with backward arching of the neck (retrocollis) and trunk (opisthotonos) with stimulation. An emergent exchange transfusion at this stage might prevent permanent BIND.

Advanced – The advanced phase is characterized by apnea, inability to feed, fever, seizures, and a semicomatose state that progresses to coma. Hypertonicity presents as persistent retrocollis and opisthotonos with bicycling or twitching of the hands and feet. The cry is inconsolable or may be weak or absent. Death can occur, primarily due to respiratory failure or intractable seizures.

Early ABE may be reversible, but if the high TSB level is not addressed promptly, it may result in permanent irreversible neurologic sequelae (CBE). (See 'Chronic bilirubin encephalopathy (kernicterus)' below.)

Clinical signs associated with ABE can be divided into three domains (table 4):

Mental status

Tone

Cry pattern

In neonates with severe hyperbilirubinemia and without any other identifiable cause of neurologic impairment, the severity of each domain is used to determine the overall severity of ABE using the BIND score (table 4).

Brainstem auditory-evoked responses (BAER) can also be used to detect the acute neurologic effects of hyperbilirubinemia and confirm the presence of BIND [54-57]. In one study, elevated TSB levels correlated with prolonged brainstem conduction time [55]. These abnormalities resolve as TSB values decline.

Chronic bilirubin encephalopathy (kernicterus) — CBE (previously referred to as kernicterus) is a permanent post-icteric brain injury characterized by choreoathetoid cerebral palsy and other chronic neurologic impairments.

Incidence — Reported incidence rates of CBE in resource-rich countries (eg, Canada, Denmark, Sweden, and the United States) range from 0.4 to 2.3 per 100,000 live births per year [5,25,34,58,59].

Among newborns with hyperbilirubinemia, the risk of developing CBE depends upon the severity and duration of hyperbilirubinemia. Based upon population data from resource-rich countries, the estimated risk according to predischarge TSB levels is as follows [21,58,60]:

TSB >20 and ≤25 mg/dL (342 and 428 micromol/L) – CBE is extremely rare

TSB >25 and ≤30 mg/dL (428 and 513 micromol/L) – Approximately 5 percent

TSB >30 and ≤35 mg/dL (513 and 599 micromol/L) – Approximately 10 to 25 percent

TSB >35 mg/dL (599 micromol/L) – Almost all infants will develop signs of CBE

Two advances in medical care have impacted how hyperbilirubinemia is managed and have altered the associated morbidity and mortality. They include the widespread use of Rh(D) immunoglobulin to Rh-negative mothers, which dramatically decreased the incidence of Rh-isoimmune neonatal hemolytic disease, and the introduction of phototherapy, which significantly reduced the need for exchange transfusions and the risk of developing severe hyperbilirubinemia. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients" and "Initial management of unconjugated hyperbilirubinemia in term and late preterm newborns", section on 'Initial intervention (phototherapy)'.)

Thus, an infant's risk of developing CBE has declined considerably from its peak in the 1950s through the 1970s. Nevertheless, isolated cases of CBE, a mostly preventable condition, continue to be reported despite the implementation of practice guidelines [9,61-64]. In particular, infants with hemolytic diseases (eg, glucose-6-phosphate dehydrogenase [G6PD] deficiency) are at risk for developing severe hyperbilirubinemia and CBE [10,64-66].

Reported cases of CBE have declined in many parts of the world after the adoption of universal newborn bilirubin screening. However, there still is a significant risk for death in infants with CBE [28,67]. In the United States, 31 deaths associated with CBE were reported during the period between 1979 and 2006 (0.28 deaths per million live births) [67].

Clinical features — CBE usually develops during the first year after birth [46,68].

The characteristic findings of CBE include:

Choreoathetoid cerebral palsy (chorea, ballismus, tremor, and dystonia). (See "Hyperkinetic movement disorders in children".)

Sensorineural hearing loss due to auditory neuropathy (abnormal BAER with normal OAE) [69,70]. (See "Hearing loss in children: Etiology", section on 'Hyperbilirubinemia'.)

Gaze palsies, especially limitation of upward gaze.

Dental enamel hypoplasia.

In general, cognitive function is relatively spared. The major neurologic features of CBE reflect the classic affected areas of the brain (basal ganglia and the brainstem nuclei for oculomotor and auditory functions). Abnormal findings on magnetic resonance imaging typically involve the cerebellum, hippocampus, and brainstem [71,72].

Most infants who develop CBE will have manifested signs of ABE during the neonatal period [36]. However, there are reported cases of infants who developed CBE with few or no signs of ABE [73,74].

Hyperbilirubinemia and autism — Whether hyperbilirubinemia is associated with increased risk of autism spectrum disorders (ASD) remains uncertain. The available reports have reached variable conclusions:

Studies reporting no association – In a retrospective nested case-control study from a single healthcare system that included 2155 children (338 with ASD and 1817 matched controls without ASD), the proportion of children who had been exposed to TSB >20 mg/dL (342 micromol/L) was similar in both groups (2.1 percent versus 2.5 percent) [75]. After adjusting for other factors (gestational age, sex, birth facility, maternal age, maternal race/ethnicity, maternal education), neonatal hyperbilirubinemia did not appear to be a significant predictor of ASD later in childhood. Exposure to phototherapy was also not associated with risk of ASD.

Similarly, an earlier case-control study from the same healthcare system also did not find an association between ASD and neonatal exposure to various degrees of hyperbilirubinemia (TSB 15 to <20 mg/dL [257 to 342 micromol/L], TSB 20 to <25 mg/dL [342 to 428 micromol/L], or TSB ≥25 mg/dL [≥428 micromol/L]) [76].

Studies reporting a possible association – In a population-based study from Denmark using data collected from four national registries including 733,826 infants born between 1994 and 2004, neonatal hyperbilirubinemia was associated with an increased risk of neurobehavioral disorders, including ASD (hazard ratio [HR] 1.67, 95% CI 1.03-2.71) [77].

Another population-based study from Nova Scotia that included 61,238 infants born between 1994 and 2000 reported an association between neonatal exposure to TSB >19 mg/dL (325 micromol/L) and later development of ADHD, developmental delay, and ASD [78]. However, the association between hyperbilirubinemia and ASD was of borderline statistical significance (adjusted risk ratio [aRR] 1.6, 95% CI 1.0-2.5).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neonatal jaundice".)

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SUMMARY AND RECOMMENDATIONS

Clinical significance – Elevated total serum bilirubin (TSB) levels occur in nearly all newborn infants and may present with visible jaundice. Infants with TSB levels >25 mg/dL [428 micromol/L] are at risk for developing bilirubin neurotoxicity. If hyperbilirubinemia in this range is not treated promptly, it can result in severe permanent neurologic injury. (See 'Introduction' above and 'Consequences of severe hyperbilirubinemia' above.)

Epidemiology – The estimated incidence of severe hyperbilirubinemia (defined as TSB >25 mg/dL [428 mmol/L]) varies globally, ranging from approximately 10 to 40 per 100,000 live births. The variation may be due to differences in breastfeeding practices and genetic factors that affect bilirubin production and metabolism. (See 'Incidence of neonatal hyperbilirubinemia' above.)

Risk factors

For severe hyperbilirubinemia – The strongest predictor for developing severe hyperbilirubinemia is the newborn’s predischarge TSB or transcutaneous bilirubin (TcB) level, which is typically measured at 24 to 48 hours after birth. Additional factors associated with increased risk of severe or progressive hyperbilirubinemia are summarized in the table (table 1). (See 'Risk factors for severe hyperbilirubinemia' above.)

For neurotoxicity – The most important risk factor for neurotoxicity is the severity and duration of bilirubin exposure. The risk is highest with TSB ≥30 mg/dL (513 micromol/L). Additional factors associated with increased risk of bilirubin neurotoxicity are summarized in the table (table 3). (See 'Risk factors for neurotoxicity' above.)

Clinical manifestations – The main clinical features of neonatal hyperbilirubinemia are jaundice and scleral icterus. (See 'Jaundice' above and 'Scleral or conjunctival icterus' above.)

However, the extent of visible jaundice is not a reliable method to estimate TSB levels or identify newborns at risk for rapidly rising bilirubin, especially in those with darkly pigmented skin. If there is uncertainty regarding the presence or extent of jaundice, TSB or TcB should be measured. As discussed separately, at least one screening TSB or TcB measurement is suggested for all newborns during the birth hospitalization, typically between 24 to 48 hours after birth, or sooner if the newborn appears jaundiced. (See "Screening for hyperbilirubinemia in term and late preterm newborn infants".)

Neurologic consequences of severe hyperbilirubinemia – The major consequence of neonatal hyperbilirubinemia is a spectrum of neurotoxic injuries collectively referred to as bilirubin-induced neurologic disorders (BIND). The clinical spectrum of BIND ranges from subtle findings to severe permanent disability. (See 'Bilirubin-induced neurologic disorders (BIND)' above.)

Acute bilirubin encephalopathy (ABE) – ABE refers to acute signs of neurotoxicity. Clinical findings may be subtle initially (sleepiness, mild hypotonia, high-pitched cry). Without intervention, ABE can progress to more severe manifestations (apnea, seizures, severe hypertonia) and ultimately coma or death (table 4). (See 'Acute bilirubin encephalopathy (ABE)' above.)

The incidence of ABE is approximately 1 per 100,000 live births. Among newborns with extreme hyperbilirubinemia (TSB >30 mg/dL [513 micromol/L]), reported rates of ABE range from 2 to 10 percent. (See 'Incidence' above.)

Chronic bilirubin encephalopathy (CBE) – CBE (formerly called kernicterus) is a permanent post-icteric brain injury characterized by choreoathetoid cerebral palsy, sensorineural hearing loss, gaze palsies, and other chronic neurologic impairments. (See 'Chronic bilirubin encephalopathy (kernicterus)' above.)

CBE is rare, with reported incidence rates ranging from 0.4 to 2.3 per 100,000 live births. (See 'Incidence' above.)

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References