Unconjugated hyperbilirubinemia

OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal unconjugated hyperbilirubinemia? What are the typical findings for this disease?

Postnatal unconjugated hyperbilirubinemia is a universal phenomenon when an infant's total bilirubin (TB) level exceeds 17.1 μmol/L (1mg/dL), the upper range of normal value for adults. It manifests as jaundice (yellowness of skin) in about 80% of all newborns during the first week after birth. When the TB level is sufficiently elevated, bilirubin can appear in the mucous membranes, sclerae, and body fluids. Elevated unconjugated bilirubin accounts for most of the elevated TB and transcutaneous bilirubin (TcB) in the early neonatal period.

A progressive increase in TB during the first week after birth is usually benign and a function of an infant's age in hours. An excessive rate of TB rise or TB levels >95th percentile for age in hours (as defined in the Bhutani nomogram) is considered significant and likely to require intervention. Excessive TB levels > 428 to 513 μmol/L (25 to 30 mg/dL) are associated with higher risk of bilirubin induced neurologic dysfunction (BIND) in infants >38 weeks of gestation.

What are the usual clinical manifestations?

Bilirubin deposition in the skin and subcutaneous tissues is responsible for the clinical signs of jaundice. The transport of bilirubin across the blood-brain barrier results in the clinical signs of BIND associated with TB levels that exceed the bilirubin-albumin binding capacity.

As a clinical sign, the "visual" presence of jaundice is not a reliable indicator of the TB level or its rate of rise of TB. However, detection of jaundice during the first 24 hours of birth is an index of severe hyperbilirubinemia and requires urgent attention. Thus, all newborn infants should be routinely monitored (every 6 to 8 hours) for development of jaundice in a well lit room.

Jaundice is detected by blanching the skin with digital pressure over the forehead, mid-sternum, iliac crest, patella, and ankles to reveal the underlying skin color. Jaundice usually appears on the nose/face and progresses caudally, but can sometimes fade in and appear as a tan. Color varies from lemony yellow to orange to sienna. Color may be masked and may be hard to detect in low ambient light, skin pigmentation, plethora, exposure to sunlight, or during phototherapy. Inability to detect jaundice or its absence is not indicative of the absence of hyperbilirubinemia.

How do you define the severity of postnatal hyperbilirubinemia

In 2004, the American Academy of Pediatrics recommended the infant's TB level, rather than the unconjugated bilirubin fraction, as a guide to managing newborn jaundice.

The incidence and severity of neonatal hyperbilirubinemia varies by geography, institutions, racial and ethnic mix population, prevalence of hemolytic disorders, and breast feeding and birthing practices, as well as access to timely care.

TB levels have been traditional indicators of severity even though there are other useful and sensitive or specific predictors of BIND.

Table I lists the designation of severity, the reported incidence in the United States, and potential risks for hyperbilirubinemia in term infants managed in accordance with current practice.

Table I.

Definitions of severe neonatal hyperbilirubinemia (age > 72 hours)
Adjective TBlevel (mg/dL) Percentile Incidence Occurrence Risk of Kernicterus
Mild <14 <40th >60% 6 in 10 None reported
Significant >17 to 20 >95th 8.1% to 10% 1 in 10 Unlikely
Severe >20 to 25 >98th 1% to 2% 1 in >70 Cases reported
Extreme >25 to 30 >99.9th 0.14% to 0.16% 1 in >700 Of concern
Hazardous >30 >99.99th 0% to 0.032% 1 in >10,000 Unacceptable risk

The following features suggest severe hyperbilirubinemia:

1. Jaundice within the first 24 hours of birth (indicative of increased production, often due to hemolytic disease).

2. TB >95th percentile for age in hours, as plotted on the hour-specific bilirubin nomogram.

3. Rate of TB rise >0.2 mg/dL/hour (>3.5 μmol/L/hour).

4. Persistence of jaundice after 2 weeks of age in a term infant.

5. Conjugated bilirubin >1.0 mg/dL (17 μmol/L) if the TB is <5.0 mg/dL (86 μmol/L) or >10% to 20% of the TB if TB levels are >5.0 mg/dL (>86 μmol/L). These values are indicative of hemolysis.

What other disease/condition shares some of these signs?

Neonatal hyperbilirubinemia can be missed or not detected when observations are made in a poorly lit room or if the infant is not completely undressed to assess changes in skin tones in cephalo-caudal distribution.

Infants with darker skin (melanin) pigmentation, Hispanics or Asians with yellow chromophores, or infants of mixed ethnic backgrounds are considered most at risk for lack of recognition of jaundice. Thus, a low threshold should be used to measure TB.

Plethora, pallor, shock, or bruises may also confound the detection of jaundice.

The presence of jaundice does not distinguish unconjugated bilirubinemia from conjugated bilirubinemia (cholestasis). Thus, it is appropriate to measure fractionated TB, at least once, to exclude cholestasis.

What caused this disease to develop at this time?

  • Biologic risk factors:Bilirubin at low levels is a known potent anti-oxidant, and at high levels it is a silent neurotoxin.

    Elevated unconjugated bilirubin levels may occur due to increased bilirubin production (degradation of heme moiety of hemoglobin) and/or diminished elimination (hepatic and intestinal) as well as the confounding unique neonatal phenomenon of entero-hepatic reabsorption of bilirubin. Bilirubin and carbon monoxide are equimolar degradation products of heme. The albumin-bound (non-water soluble) bilirubin that is unconjugated is processed in the hepatocyte to a water soluble glucoronidation by the enzyme uridine-di-phospho-glucuronosyl-transferase (UGT) and excreted in the gut. Some of this conjugated bilirubin is reconverted to unconjugated bilirubin by the enzyme β-glucuronidase and reabsorbed in the circulation (entero-hepatic recirculation).

    Risk factors include clinical conditions that delay, interfere, or unbalance this metabolic process (Table II).

Table II.

Biologic risk factors and associated clinical causes of hyperbilirubinemia
Biologic Basis Clinical Conditions
Increased Bilirubin Production isoimmunization: ABO, Rh, and minor groupRBC enzyme defects: G6PD, pyruvate kinase, etc.RBC structural defects: congenital spherocytosis, etc.Sepsis: bacterial, viral, protozoalExtravasated blood: subgaleal, cephalhematoma, etc.Polycythemia
Increased Entero-hepatic Recirculation Prematurity: <38 weeksStarvationDecreased gastro-intestinal motilityDelayed bacterial colonization of the gutPyloric stenosis, gastro-intestinal obstruction
Decreased Elimination Gilbert syndromeArias syndromeLucey-Driscoll syndromeCrigler-Najjar I and II syndromesDubin-Johnson syndromeRotor syndromeDrugs: novobiocin, excessive sedation/paralysis
  • Clinical risk factors: The most frequently recognized risk factors predictive of severe hyperbilirubinemia or need of phototherapy include late prematurity (<38 weeks of gestation), unrecognized hemolysis (ABO incompatibility, congenital spherocytosis, bruising), sub-optimal breast feeding, east Asian race, and racial risk of G6PD deficiency. A more detailed list is given in Table III.

Table III.

Prenatal, natal, and postnatal clinical risk factors for severe hyperbilirubinemia
Prenatal Natal Postnatal
Race Mode of delivery Race and ethnicity
Planned mode of feeding Breast anatomy Sub-optimal lactation
Maternal blood groups Lack of prenatal care Jaundice in first 24 hours
Maternal history Gestation <38 weeks Maternal medications
Reproductive history Birth trauma Macrosomia
  • Genetic risk factors: are described below.

  • Neurotoxicity risk factors: an infant's vulnerability to bilirubin neurotoxicity is influenced by isoimmune hemolytic disorders, G6PD deficiency, significant lethargy, apnea, temperature instability, sepsis, and acidosis. Genetic vulnerability to bilirubin neurotoxicity has yet to be elucidated.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Total Bilirubin: The most frequent test that measures unconjugated bilirubin is the total bilirubin (TB) in the blood. Four forms of bilirubin are present in the blood: unconjugated bilirubin, monoglucuronide, di-glucuronide, and delta bilirubin. Infants exposed to sunlight or phototherapy may also demonstrate photoisomers. Unconjugated bilirubin is insoluble in water.

    Clinical laboratories usually measure bilirubin in the blood by "diazo reaction," direct spectrophotometry, oxidative, enzymatic or chemical methods, and infrequently by high pressure liquid chromatography. Most analyzers that conform to current College of American Pathologists recommendations have been able to limit the total errors to ± 10% of reference method assay.

  • Transcutaneous Bilirubin (TcB):More recently, TcB measurements have been available by multi-wavelength spectrophotometry. TcB values slightly overestimate the TB and lose their equivalence for TB levels >15 mg/dL (257 μmol/L).

    TcB values are not a substitute for the TB assay, but serve as valuable screening tools. They provide instant point of care results, are non-invasive, and spare the infant of painful heel sticks. Their use decreases the number of TB measurements. However, their accuracy is limited by ±2 mg/dL (34 μmol/L) of TB levels measured by diazo techniques, and TcB cannot be used for infants treated with phototherapy or directly exposed to sunlight.

  • Table IV lists other laboratory tests that are indicated as unconjugated hyperbilirubinemia progresses.

Table IV.

Laboratory evaluation of the jaundiced infant >/= 35 weeks' gestation
Indication Laboratory Assessment
Jaundice at age <24 hours TcB and/or TB
Jaundice excessive for age TcB and/or TB
TB "crossing percentile tracks"- TB >75th percentile for age- TB rate of rise .0.2mg/dL/hour- Infant who is initiated on phototherapy Blood type and Coombs testComplete blood countPeripheral smearDirect bilirubin testRepeat TB to determine rate of riseReticulocyte count and end-tidal carbon monoxide testing are optional
Severe hyperbilirubinemia- TB approaching exchange transfusion threshold- Failure to respond to phototherapy Reticulocyte countSerum albuminBilirubin-Albumin ratioG6PD enzyme quantitative screenAutomated auditory brainstem response (optional)
Associated cholestasis UrinalysisUrine cultureEvaluate for risk sepsisReview state-mandated newborn screening results (such as hypothyroidism, galactosemia)Consider testing for inherited disorders of bilirubin metabolism if cholestasis progresses
Persistent jaundice- Jaundice at age >2 weeks- Jaundiced infant who is ill or has possible sepsis TB and direct bilirubinG6PD enzyme quantitative screenAssess for causes of cholestasisReview state-mandated newborn screening results (such as hypothyroidism, galactosemia)Consider testing for inherited disorders of bilirubin metabolism if cholestasis progresses

Would imaging studies be helpful? If so, which ones?

  • Imaging studies, such as magnetic resonance imaging, are only indicated in infants who were at risk for acute bilirubin encephalopathy, approached or needed an exchange transfusion, or manifested neurologic signs during or subsequent to extreme hyperbilirubinemia. These imaging studies are not indicated during the acute course of the illness, and their potential usefulness has not been validated for prognosis.

  • Radiographic and imaging studies for other clinical conditions that may be associated with severe hyperbilirubinemia are only indicated as deemed necessary for clinical diagnosis of primary conditions and would not usually guide management of hyperbilirubinemia. For example, enclosed hemorrhages such as subdural, subgaleal, hepatic, or those associated with fractures would necessitate specific diagnostic evaluation. Clinical management for bilirubin reduction would be determined by TB and the rate of TB rise. Similarly, gastrointestinal obstruction that promotes entero-hepatic circulation of bilirubin would need specific diagnostic radiographic evaluation.

Confirming the diagnosis


  • A clinical algorithm to prevent and treat unconjugated hyperbilirubinemia is based on a series of AAP recommendations and Agency for Healthcare Research and Quality (AHRQ) evidence reviews that are presented in Table V.

Table V.

A clinical algorithm to manage newborns with unconjugated hyperbilirubinemia
Breast feeding Nurse 8-12/day Quality C: benefit exceeds harm
Use of supplements Routine use of water or dextrose is not indicated Quality B/C: harm exceeds benefit
Infant race and ethnicity as risk factors East Asian and Mediterranean ethnicity are risk factors. African American race is at higher risk for G6PD deficiency Quality B: benefit exceeds harm
Infant Rh blood type, if mother is Rh negative Mandatory testing Quality B: benefit exceeds harm
Infant blood group type, if mother is type O Optional testing Quality C: benefit exceeds harm
Jaundice assessment Assess onset and progression every 6 to 8 hours Quality D: benefit exceeds harm
Laboratory evaluation As listed in Table IV Quality C: benefit exceeds harm
Cause of jaundice As listed in Table II Quality C: benefit exceeds harm
Pre-discharge risk assessment Clinical risk factors and TB/TcB (at age 24 to 48 hours) Quality B: benefit exceeds harm
Hospital policies Provide patient education materials regarding risk and need for timely follow-up Quality D. benefit exceeds harm
Timing of follow-up For all infants, adjust timing on risk status, gestational age (weeks) and postnatal age (hours) at discharge Quality C: benefit exceeds harm
Follow-up assessment Repeat TB/TcB if there is any doubt about jaundice severity or if it has progressed distal to the umbilicus. Quality C: benefit exceeds harm
TREATMENT Use effective phototherapy and/or exchange transfusion in accordance with 2004 AAP guidelines Quality B: benefit exceeds harm
  • The evidence of quality for studies obtained over the past six decades has been summarized by 4 levels: A=Randomized controlled trials (RCT, most deemed unethical based on decades of practice); B=Overwhelming consistent evidence from observational studies or limited RCT; C=Multiple observational studies; D=Expert opinion.

  • Algorithm for follow-up (Table VI) and its timing is based on a recent expert opinion. These decisions are guided by the risk status of the TB/TcB plotted on the hour-specific bilirubin nomogram, gestational age and postnatal age (hours). Table VI outlines these recommendations.

Table VI.

Risk-adjusted follow-up for the first outpatient visit after birth
Bilirubin risk status Infant >37 weeks of gestation Infant <38 weeks of gestation
High Repeat TB (some may need phototherapy)Follow-up in 12 to 24 hours Delay discharge and repeat TB in 4 to 12 hours; likely to need phototherapy
High-Intermediate Follow-up within 48 hours, if discharged at age >48 hoursFollow-up within 24 hours, if discharged at age <48 hours Follow-up within 24 hoursAssess for enteral milk transferAssess for weight lossAssess for phototherapy thresholds
Low-Intermediate Follow-up within 2-3 days, if discharged at age >48 hoursFollow-up within 48 hours, if discharged at age <48 hours Follow-up within 48 hoursAssess for enteral milk transferAssess for weight lossAssess for phototherapy thresholds
Low Follow-up within 2 to 3 days, earlier if discharged <48 hours Follow-up within 48 hoursAssess for enteral milk transferAssess for weight loss

If you are able to confirm that the patient has unconjugated hyperbilirubinemia, what treatment should be initiated?


  • Prevention and treatment options include: a) serial clinical evaluation and assessment of TB/TcB, its rate of rise and decline as plotted on the hour-specific bilirubin nomogram; b) enteral nutritional support to increase milk transfer to the baby; c) use of effective phototherapy; d) rarely, a double volume exchange transfusion by an neonatal intensivist; and lastly e) in some infants and with consultation, the use of chemoprevention with intravenous immune globulin (IVIG) in certain immune-hemolytic disorders among infants at risk for exchange transfusion.

  • Effective phototherapy: A variety of devices are available to deliver effective phototherapy. These are not ultra-violet (UV) lights. Light sources are categorized as: a) light-emitting diodes (LED); b) fluorescent tubes with blue, special blue, or turquoise-green lights; c) metal-halide light bulbs; and d) high intensity LED devices. The ability to deliver effective phototherapy is outlined in Table VII.

Table VII.

Characteristics of effective phototherapy
Parameters Specific Feature Level of Evidence
Light source Blue light spectrum 420 to <500 nm Quality B
Light irradiance >30 μWatts/cm2/nm Quality B
Body surface area 40% to 80% of body exposed to homogeneous lighting Quality B
Response Rate of TB decline (>0.5 mg/dL/hour or > 8.5 μmol/L/hour) Quality B
Duration May be interrupted for feeding after response is documented Quality C
  • Neonatal double-volume exchange transfusion is primarily indicated to remove circulating antibody-coated red blood cells and/or products of hemolysis associated with immune and certain non-immune hemolytic diseases. Concurrent benefits include removal of excessively elevated bilirubin levels, and infusion of fresh blood and plasma to provide additional bilirubin binding sites on the red blood cells and albumin.

    The procedure is conducted in incremental steps to maintain isovolemia and stable hemodynamic well being. A team of experts to place central or peripheral catheters to optimally withdraw and replace equivalent volumes of blood can complete a double volume exchange transfusion within 2 hours of initiation. Traditionally, an umbilical venous catheter is placed for pull-push access. Most neonatologists prefer the use of arterial and venous catheters for the simultaneous and synchronized infusion and withdrawal method. Infants are continuously monitored for their hemodynamic and gas exchange status.

    Follow-up monitoring of electrolytes, complete blood count, platelet count, and coagulation functions are key to recognizing early adverse signs.A crash-cart approach may need to be initiated in an infant with TB>25 mg/dL (427 μmol/L) or those with any neurologic signs.

    These steps, after starting effective phototherapy, include: a) assess for acute bilirubin encephalopathy regardless of TB level; b) check TcB and TB immediately; c) conduct procedures while the infant is under phototherapy; d) prepare for exchange transfusion (such as blood typing, informing blood bank, obtaining informed consent for procedures); e) evaluate for concurrent dehydration, hypernatremia and sepsis; f) continue enteral feeds while providing phototherapy to over 80% of body surface area.

  • Most patients with unconjugated hyperbilirubinemia respond to effective phototherapy. Prolonged use of phototherapy may be necessary among infants with inherited disorders of bilirubin metabolism. Identification of co-morbidities of hypothyroidism, galactosemia and Crigler-Najjar syndrome are likely to require specific interventions for the underlying condition.

What are the adverse effects associated with each treatment option?

Expectant observation: Serial bilirubin monitoring may increase the number of heel sticks in otherwise healthy newborns as the rate of TB rise is monitored; a combined use of TB/TcB may minimize the number of blood tests.

IIncrease enteral intake: Enteral intake of breast milk is a high priority for both family and healthcare provider. Interruption of breast feeding is seldom necessary. Preventive strategies to promote latching along with lactation counseling is associated with increased maternal milk production. Use of expressed maternal breast milk delivered through nipple feedings or other devices may be needed in late preterm infants with discoordinated nippling ability. Use of formula supplements should be rare and for minimal duration.

Phototherapy-related adverse effects are rare and usually not significant. Devices need to perform appropriately in environments of high humidity and oxygen as well as meet electrical and fire safety standards. Infants with known or suspected congenital porphyria or who have been prescribed photosensitizing drugs should not be exposed to phototherapy (particularly white light). Prolonged phototherapy has been associated with an increased risk of oxidant stress, lipid peroxidation, and riboflavin deficiency. Recent reports of malignant melanoma, DNA damage in skin, and skin changes have not yet been validated. Phototherapy does not exacerbate hemolysis. Bronzing of the skin may occur if the infant also has cholestasis.

Exchange transfusion-related adverse effects are serious and include mortality. A risk/benefit assessment for imminent mortality or lifelong irreversible neurologic morbidity is necessary in the context of the potential mortality of the procedure. The rarity of the need and use of this procedure has led to regional recommendations that this procedure be conducted at expert facilities. Timely triage, urgent referral, and emphasis on prevention of exchange transfusion are keys to safer newborn care.

What are the possible outcomes of neonatal unconjugated hyperbilirubinemia?

Benign outcome:Newborns with unconjugated hyperbilirubinemia who are managed expectantly and do not meet the AAP recommended thresholds for phototherapy are most likely to have benign outcomes. Those term infants in whom phototherapy is initiated in a timely manner and do not approach TB thresholds for exchange transfusion are also likely to have benign outcomes.

Adverse outcomes of bilirubin-induced neurologic dysfunction (BIND) are likely to occur among infants admitted with signs of acute bilirubin encephalopathy or any neurological signs associated with severe hyperbilirubinemia. Infants who undergo exchange transfusion, exhibit slow response to phototherapy, experience prolonged severe hyperbilirubinemia, and have TB >25 mg/dL (428 μmol/L) are at risk for BIND.

Subtle long-term effects of BIND have been suspected and debated, but are unproven in infants with diminished bilirubin-albumin binding capacity or prolonged significant hyperbilirubinemia, or in late preterm infants with significant hyperbilirubinemia.

Risks and Benefits. Parents should receive the FAQ (frequently asked questions) instruction sheet regarding newborn jaundice. These are available on the AAP and CDC websites in both English and Spanish. Parents should be reassured that with implementation of current AAP guidelines and post-discharge surveillance, infants will have a benign outcome. The risk of brain damage or need of exchange transfusion is usually preventable and rare with US guidelines. In the event an infant has an unusually acute and unpredictable course of unconjugated hyperbilirubinemia, the risks and benefits of interventions of individual procedures should be reviewed in the context of risks of lifelong irreversible post-icteric sequelae or kernicteric mortality.

How do these pathogens/genes/exposures cause the disease?


  • Inherited non-hemolytic hyperbilirubinemic syndromes include: a) genetic glucuronidation defects that encompass Gilbert and Crigler-Najjar syndromes and b) defects of canalicular transport and hepatocellular storage such as Dubin-Johnson and Rotor syndromes. Arias syndrome is similar to Gilbert syndrome but reported as autosomal dominant with variable penetrance. The Lucey-Driscoll syndrome, a rare disorder, was attributed to a yet unidentified inhibitor of UGT from maternal breast milk.

  • Gilbert syndrome (also called Meulengracht syndrome) is characterized by mild, fluctuating non-hemolytic unconjugated hyperbilirubinemia that is not associated with hepatic inflammation. In the United States, about 9% of the population is homozygous and 42% is heterozygous for the Gilbert mutation.

    In the neonatal population, neonatal hyperbilirubinemia is exacerbated with concurrent increased production or increased entero-hepatic recirculation. It is often a co-morbid condition with ABO incompatibility or G6PD deficiency. It is the most frequent basis for jaundice between ages 2-4 weeks, especially in breast-fed infants.

    Gilbert syndrome is benign and confirmed by genotyping for polymorphisms of the UGT gene. Absence of the UG1TA1 enzyme is a drastic variant of the conjugation disorder (Crigler-Najjar type 1 disease) and is often fatal (unless treated with lifelong phototherapy) and is associated with mutations of exons 2, 3 and 4 of the UG1TA1 gene. Decreased conjugation ability to <30% of enzyme activity characterizes Crigler-Najjar type 2 disease associated with mutations in exon 1 of the UG1TA1 gene.

    Gilbert syndrome probably represents a wider spectrum of UG1TA1 gene defects with the most severe form manifesting as Crigler-Najjar type 1 disease.

    Table VIII compares the more frequent non-hemolytic causes of mildly but persistently elevated neonatal jaundice.

Table VIII.

Comparison of some inherited causes of persistent unconjugated hyperbilirubinemia
Gilbert syndrome Dubin-Johnson syndrome Rotor syndrome
Genetics UG1TA1 OATP Not known
Inheritance Autosomal recessive Autosomal recessive Autosomal recessive
Defect Decreased conjugation Biliary transport deficiency Defective storage of conjugated bilirubin
Hyperbilirubinemia Unconjugated Conjugated > unconjugated bilirubinemia Conjugated>unconjugated bilirubinemia
Severity (mild) fluctuates fluctuates fluctuates
Urine features Normal (75% coproporphyrin III) Normal (80% coproporphyrin I) 2- to 5-fold higher excretion of coproporphyrin
Hepato-biliary transport Impaired uptake possible Biphasic bromsulfphthalein (BSP) clearance Increased retention of BSP
Histology Normal "Black liver": lysosomal pigment Normal
Prognosis Benign Benign Benign

Other clinical manifestations that might help with diagnosis and management


Acute bilirubin encephalopathy presents as progressive changes in the infant's mental, muscle tone, and crying status. Signs progress from drowsiness, poor feeding, and hypotonia that alternates with increased tone (dystonia), especially the extensor muscles. The latter progress to retrocollis and then to opisthotonos. Paralysis of upward gaze and mask-like kernicteric facies have been reported. Mortality is due to progressive coma or intractable seizures causing respiratory failure. The rate of progression of these signs depends on the rate of TB rise, duration of hyperbilirubinemia and associated co-morbidities.

Chronic bilirubin encephalopathy, or kernicterus, is an irreversible athetoid variety of cerebral palsy. It is characterized by generalized dystonia, paralysis of upward gaze, movement disorders, dental enamel of dysplasia of deciduous teeth, and varying severity of sensorineural hearing loss. Cognition is spared unless bilirubin encephalopathy is complicated by co-morbidities.

BIND refers to a wider spectrum of disorders that are confined to discrete neural pathways. For example, damage to auditory pathways may not result in sensorineural hearing loss, but might cause auditory neuropathy (dyssynchrony). More recently, visual-motor changes have been reported in moderately jaundiced infants.

What complications might you expect from the disease or treatment of the disease?

Extreme bilirubin neurotoxicity can be fatal, with necropsy signs of yellow staining of the basal ganglia. Cellular evidence of damage occurs in the basal ganglia, specifically, the globus pallidus and also observed in the sub-thalamus, central and peripheral auditory pathways, hippocampus, diencephalon, midbrain, pontine nuclei for respiratory, neuro-humoral and electrolyte control, brainstem nuclei for oculomotor and auditory function, and in the cerebellum (mostly vermis).

Clinical signs manifest as acute bilirubin encephalopathy, chronic bilirubin encephalopathy, isolated hearing loss, and other subtle disorders.

Are additional laboratory studies available; even some that are not widely available?

Tests listed in the laboratory evaluation (Table IV) are sufficient to identify and manage most causes of jaundice.

Further investigation for unexplained or suspected hemolytic disorders, RBC structural defects, and RBC enzyme disorders may require specialized tests.

Infants at risk for diagnosis of G6PD deficiency or inherited persistent unconjugated hyperbilirubinemia may require further non-invasive testing such as G6PD genotype, UG1TA1 polymorphisms, and BSP and urine coproporphyrin assays. There are no indications for invasive diagnosis.

Infants at risk of adverse outcomes will need automated ABR, comprehensive ABR, and magnetic resonance imaging as a component of their follow-up during infancy and childhood.

How can neonatal unconjugated hyperbilirubinemia be prevented?

The primary and secondary prevention strategies listed above, implemented through a systems approach, has been shown to be the most effective process to prevent need for exchange transfusion, TB levels >30 mg/dL (513 μmol/L), and possibly kernicterus.

What is the evidence?

Bhutani, VK, Gourley, GR, Adler, S. "Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia". Pediatrics. vol. 106. 2000. pp. E17.

Bhutani, V, Chima, R, Sivieri, EM. "Innovative neonatal ventilation and meconium aspiration syndrome". Indian J Pediatr. vol. 70. 2003. pp. 421-7.

Keren, R, Bhutani, VK, Luan, X. "Identifying newborns at risk of significant hyperbilirubinaemia: a comparison of two recommended approaches". Arch Dis Child. vol. 90. 2005. pp. 415-21.

Wennberg, RP, Ahlfors, CE, Bhutani, VK. "Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns". Pediatrics. vol. 117. 2006. pp. 474-85.

Keren, R, Luan, X, Friedman, S. "A comparison of alternative risk-assessment strategies for predicting significant neonatal hyperbilirubinemia in term and near-term infants". Pediatrics. vol. 121. 2008. pp. E170-9.

Johnson, L, Bhutani, FK, Karp, K. "Clinical report from the pilot US Kernicterus Registry (1992 to 2004)". J Perinatol. vol. 29. 2009. pp. S25-45.

Mishra, S, Chawla, D, Agarwal, R. "Transcutaneous bilirubinometry reduces the need for blood sampling in neonates with visible jaundice". Acta Paediatr. vol. 98. 2009. pp. 1916-9.

Bhutani, VK, Vilms, RJ, Hamerman-Johnson, L. "Universal bilirubin screening for severe neonatal hyperbilirubinemia". J Perinatol. vol. 30. 2010. pp. S6-15.

"Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy: US Preventive Services Task Force recommendation statement". Pediatrics. vol. 124. 2009. pp. 1172-7.

"Prevention of acute bilirubin encephalopathy and kernicterus in newborns. Position Statement #3049". Adv Neonatal Care. vol. 10. 2010. pp. 112-8.

Bratlid, D, Nakstad, B, Hansen, TW. "National guidelines for treatment of jaundice in the newborn". Acta Paediatr. vol. 100. 2001. pp. 499-505.

Johnson, L, Bhutani, VK. "The clinical syndrome of bilirubin-induced neurologic dysfunction". Semin Perinatol. vol. 35. 2011. pp. 101-13.

Eggert, LD, Wiedmeier, SE, Wilson, J, Christensen, RD. "The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system". Pediatrics. vol. 117. 2006. pp. e855-62.

Amin, SB, Lamola, AA. "Newborn jaundice technologies: unbound bilirubin and bilirubin binding capacity in neonates". Semin Perinatol. vol. 35. 2011. pp. 134-40.

Stevenson, DK, Vreman, HJ, Wong, RJ. "Bilirubin production and the risk of bilirubin neurotoxicity". Semin Perinatol. vol. 35. 2011. pp. 121-6.

Bartlett, MG, Gourley, GR. "Assessment of UGT polymorphisms and neonatal jaundice". Semin Perinatol. vol. 35. 2011. pp. 127-33.

Atkinson, M, Budge, H. "Review of the NICE guidance on neonatal jaundice". Arch Dis Child Educ Pract Ed. vol. 96. 2011. pp. 136-40.

Bhutani, VK, Maisels, MJ, Stark, AR. "Management of jaundice and prevention of severe neonatal hyperbilirubinemia in infants >or=35 weeks gestation". Neonatology. vol. 94. 2008. pp. 63-7.

Mah, MP, Clark, SL, Akhigbe, E. "Reduction of severe hyperbilirubinemia after institution of predischarge bilirubin screening". Pediatrics. vol. 125. 2010. pp. e1143-8.

Maisels, MJ. "Screening and early postnatal management strategies to prevent hazardous hyperbilirubinemia in newborns of 35 or more weeks of gestation". Semin Fetal Neonatal Med. vol. 15. 2010. pp. 129-35.

Bhutani, VK, Johnson, LH, Schwoebel, A, Gennaro, S. "A systems approach for neonatal hyperbilirubinemia in term and near-term newborns". J Obstet Gynecol Neonatal Nurs. vol. 35. 2006. pp. 444-55.

Newman, TB. "Universal bilirubin screening, guidelines, and evidence". Pediatrics. vol. 124. 2009. pp. 1199-202.

Trikalinos, TA, Chung, M, Lau, J, Ip, S. "Systematic review of screening for bilirubin encephalopathy in neonates". Pediatrics. vol. 124. 2009. pp. 1162-71.

Newman, TB. "Data suggest visual assessment of jaundice in newborns is helpful". J Pediatr. vol. 154. 2009. pp. 466-7.

Kuzniewicz, MW, Escobar, GJ, Newman, TB. "Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use". Pediatrics. vol. 124. 2009. pp. 1031-9.

Newman, TB, Liljestrand, P, Escobar, GJ. "Combining clinical risk factors with serum bilirubin levels to predict hyperbilirubinemia in newborns". Arch Pediatr Adolesc Med. vol. 159. 2005. pp. 113-9.

Bhutani, VK, Johnson, LH, Jeffrey Maisels, M. "Kernicterus: epidemiological strategies for its prevention through systems-based approaches". J Perinatol. vol. 24. 2004. pp. 650-62.

Newman, TB, Liljestrand, P, Escobar, GJ. "Infants with bilirubin levels of 30 mg/dL or more in a large managed care organization". Pediatrics. vol. 111. 2003. pp. 1303-11.

Newman, TB, Liljestrand, P, Escobar, GJ. "Jaundice noted in the first 24 hours after birth in a managed care organization". Arch Pediatr Adolesc Med. vol. 156. 2002. pp. 1244-50.

Ongoing controversies regarding etiology, diagnosis, treatment

In view of an established practice and access to reasonably safe and effective bilirubin reduction strategies that have evolved over the past seven decades, ongoing and currently unresolved controversies include:

#1. Does exchange transfusion prevent kernicterus in the absence of multiple RCTs?

#2. Does phototherapy prevent kernicterus in the absence of multiple RCTs?

#3. Does universal bilirubin screening prevent kernicterus in the absence of evidence for practices listed #1 and #2?

#4. Is the evidentiary ability of universal bilirubin screening to predict severe hyperbilirubinemia and need for phototherapy sufficient to implement mandatory pre-discharge screening?

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