History

 

 

 

 
 
 
 

 

Physical Exam

Jaundice usually progresses from head to toe.

 

Laboratory Tests

TSB or total cutaneous bilirubin (TcB) levels should be measured in infants who develop jaundice within the first 24 hours, and all bilirubin levels should be interpreted according to the infant’s age (in hours). TcB measurement devices may provide an alternative to frequent blood draws for the accurate assessment of serum bilirubin, although current guidelines indicate variability in the accuracy of TcB instruments from different manufacturers.

When a pathologic cause for jaundice is suspected, laboratory studies should be promptly completed:

  • When jaundice is noticed within the first 24 hours, clinicians should consider a sepsis workup, evaluation for rubella and toxoplasmosis infection, assessment of fractionated serum bilirubin levels, and blood typing to rule out erythroblastosis fetalis. Results of thyroid and galactosemia testing, obtained during the newborn metabolic screening, also should be reviewed.

  • If the level of conjugated bilirubin is >2 mg/dL, a reason for impaired bilirubin excretion should be sought. If conjugated bilirubin is <2 mg/dL, hemoglobin levels and reticulocyte counts should be evaluated. A high hemoglobin concentration indicates polycythemia, whereas a low hemoglobin concentration with an abnormal reticulocyte count suggests hemolysis. If the reticulocyte count is normal, the infant must be evaluated for a nonhemolytic cause of jaundice.

  • Infants with a poor response to phototherapy and those whose family history is consistent with the possibility of glucose-6-phosphate dehydrogenase (G6PD) deficiency require further testing.

  • Maternal prenatal testing should include ABO and Rh (D) typing and a serum screen for unusual isoimmune antibodies. If the mother has not had prenatal blood grouping, or is Rh-negative, a direct Coombs test, blood type, and Rh (D) typing of the infant’s cord blood should be performed. Institutions are encouraged to save cord blood for future testing, particularly when the mother’s blood type is group O.

 

 

Diagnostic Criteria

  • Visible yellowing of the skin, ocular sclera, or both; quantitative testing (serum or transcutaneous) should be completed in infants noted to be jaundiced within the first 24 hours of life.

  • Risk of subsequent hyperbilirubinemia can be assessed by plotting serum bilirubin levels onto a nomogram; all bilirubin levels should be interpreted according to the infant’s age (in hours).

 

 

Several factors are considered as major predictors for the development of severe hyperbilirubinemia among infants of ≥35 weeks’ gestation.

Among the most significant clinical characteristics associated with severe hyperbilirubinemia are predischarge levels in the high-risk zone on the serum bilirubin nomogram (Figure) and jaundice noted within 24 hours of birth.


Nomogram for designation of risk in 2840 well newborns of ≥36 weeks’ gestational age with birth weight of ≥2000 g or ≥35 weeks’ gestational age and birth weight of ≥2500 g based on the hour-specific serum bilirubin value. (Reproduced with permission from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297.)

Image not available.

While the American Academy of Pediatrics currently recommends universal predischarge bilirubin screening using total serum bilirubin (TSB) or total cutaneous bilirubin (TcB) measurements, the United States Preventive Services Task Force (USPSTF) determined that the evidence is insufficient to recommend screening infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy; the American Academy of Family Physicians concurs with the USPSTF position. In clinical practice, however, testing is completed for the vast majority of infants.

American Academy of Pediatrics Subcommittee on Hyper-bilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297. 
[PubMed: [PMID: 15231951]] 
US Preventive Services Task Force. Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy: US preventive services task force recommendation statement. Pediatrics. 2009; 124. 
[PubMed: [PMID: 20704172]] 

 

Other risk factors include various forms of hemolytic disease [eg, ABO incompatibility, glucose-6-phosphate dehydrogenase (G6PD) deficiency], elevated end-tidal carbon monoxide, gestation age of 35–36 weeks, a sibling who required phototherapy, cephalohematoma or significant bruising, exclusive breastfeeding, East Asian race, maternal age ≥25 years, and male gender.

 

A. Physiologic Jaundice

The three classifications of neonatal hyperbilirubinemia are based on the following mechanisms of accumulation: increased bilirubin load, decreased bilirubin conjugation, and impaired bilirubin excretion. In the newborn, unconjugated bilirubin is produced faster and removed more slowly than in the normal adult because of the immaturity of the glucuronyl transferase enzyme system. The main source of unconjugated bilirubin is the breakdown of hemoglobin in senescent red blood cells. Newborns have an increased erythrocyte mass at birth (average hematocrit of 50% vs 33% in the adult) and a shorter lifespan for erythrocytes (90 days vs 120 days in the adult). The newborn cannot readily excrete unconjugated bilirubin, and much of it is reabsorbed by the intestine and returned to the enterohepatic circulation.

Increased production and decreased elimination of bilirubin lead to a physiologic jaundice in most normal newborns. Bilirubin is a very effective and potent antioxidant, and physiologic jaundice may provide a mechanism for protecting the newborn from oxygen free-radical injury. The average full-term white newborn experiences a peak serum bilirubin concentration of 5–6 mg/dL (86–103 μmol/L), which begins to rise after the first day of life, peaks on the third day of life, and falls to normal adult levels by days 10–12. African American infants tend to have slightly lower peaks in serum bilirubin. In Asian infants, serum bilirubin levels rise more quickly than in white infants and tend to reach higher peaks on average (8–12 mg/dL; 135–205 μmol/L). This leads to a longer period of physiologic jaundice among Asian and Native American newborns. Preterm infants (<37 weeks’ gestation) of all races may take 4–5 days to reach peak serum bilirubin levels, and these peaks may be twice those observed among full-term infants.

B. Breastfeeding and Breast Milk Jaundice

Infants who are breastfed may experience exaggerated bilirubin levels as a result of two separate phenomena associated with breastfeeding and breast milk.

Breastfed infants may experience relative starvation in the first few days of life, due to delayed release of milk by the mother and/or difficulties with breastfeeding. This nutritional inadequacy can result in increased enterohepatic circulation of bilirubin, leading to elevated serum bilirubin levels in the first few days of life. Termed breastfeeding jaundice, this finding is considered abnormal and can be overcome by offering frequent feedings (10–12 times per day) and by avoiding water supplementation in breastfed infants.

Breast milk is believed to increase the enterohepatic circulation of bilirubin; however, the specific factor(s) in breast milk that is (are) responsible for this action is (are) unknown. For the first 5 days of life, the serum bilirubin level in breastfed infants parallels that in nonbreastfed infants. Beginning at approximately day 6, breast milk jaundice occurs in breastfed infants as serum bilirubin either rises a little for a few days or declines more slowly. Approximately two-thirds of breastfed infants may be expected to have hyperbilirubinemia from 3 weeks to 3 months of age, with as many as one-third exhibiting clinical jaundice. Breast milk jaundice (unlike breastfeeding jaundice) is considered a form of normal physiologic jaundice in healthy, thriving breastfed infants.

C. Pathologic Jaundice

Exaggerated physiologic jaundice occurs at serum bilirubin levels between 7 and 17 mg/dL (between 104 and 291 μmol/L). Bilirubin levels above 17 mg/dL in full-term infants are no longer considered physiologic, and further investigation is warranted.

The onset of jaundice within the first 24 hours of life or a rate of increase in serum bilirubin exceeding 0.5 mg/dL (8 μmol/L) per hour is potentially pathologic and suggestive of hemolytic disease. Conjugated serum bilirubin concentrations exceeding 10% of total bilirubin or 2 mg/dL (35 μmol/L) are also not physiologic and suggest hepatobiliary disease or a general metabolic disorder.

Differentiating between pathologic and physiologic jaundice requires consideration of historical as well as clinical factors. Important historical features increasing the likelihood that jaundice is pathologic include family history of hemolytic disease, ethnicity suggestive of inherited disease (eg, G6PD deficiency), onset of jaundice in the first 24 hours of life, and jaundice lasting >3 weeks. Clinical assessment requires careful attention to general appearance, vital signs, weight loss, feeding patterns, stool and urine appearance, activity levels, and hepatosplenomegaly, which may be indicative of inborn errors in metabolism, sepsis, or other conditions. A rapid rise in serum bilirubin levels and lack of response to phototherapy are also indicative of pathologic jaundice. Cholestatic jaundice, manifesting as pale-colored stool and dark urine, indicates the need to explore for the presence of biliary atresia or other pathology.

The primary concern with severe hyperbilirubinemia is the potential for neurotoxic effects as well as general cellular injury, which can occur at TSB levels exceeding 20–25 mg/dL. The term kernicterus refers to the yellow staining of the basal ganglia observed postmortem among infants who died with severe jaundice. (Bilirubin deposition in the basal ganglia can also be imaged using magnetic resonance techniques.) The American Academy of Pediatrics (AAP) has recommended that the term acute bilirubin encephalopathy be used to describe the acute manifestations of bilirubin toxicity seen in the first weeks after birth and that the term kernicterus be reserved for the chronic and permanent clinical sequelae of bilirubin toxicity.

Although kernicterus was a common complication of hyperbilirubinemia in the 1940s and 1950s due to Rh erythroblastosis fetalis and ABO hemolytic disease, it is rare today, with the use of Rh immunoglobulin and with the intervention of phototherapy and exchange transfusion. With early discharge to home, however, a small resurgence of kernicterus has been observed in countries in which this complication had essentially disappeared. The reported incidence of chronic kernicterus in the United States is ~1 case/27,000 live births and 1 case/44,000 live births in Canada.

Bilirubin can interfere with various metabolic pathways and may also impair cerebral glucose metabolism. The concentration of bilirubin in the brain and the duration of exposure are important determinants of the neurotoxic effects of bilirubin. Bilirubin can enter the brain when not bound to albumin, so infants with low albumin are at increased risk of developing kernicterus. Conditions that alter the blood-brain barrier such as infection, acidosis, hypoxia, sepsis, prematurity, and hyperosmolarity may affect the entry of bilirubin into the brain.

In infants without hemolysis, serum bilirubin levels and encephalopathy do not correlate well. In infants with hemolysis, TSB levels of >20 mg/dL are associated with worse neurologic outcomes, although some infants with concentrations of 25 mg/dL are normal. Kernicterus has been detected in 8% of infants with associated hemolysis who had TSB levels of 19–25 mg/dL, 33% of infants with levels of 25–29 mg/dL, and 73% of infants with levels of 30–40 mg/dL. It should be noted that the majority of cases of kernicterus described in recent years have been among neonates who had TSB levels of >30 mg/dL at the time of diagnosis, which is well above the recommended treatment thresholds of 15 or 20 mg/dL.

In its acute form, kernicterus (eg, acute bilirubin encephalopathy) may present in the first 1–2 days with poor sucking, stupor, hypotonia, and seizures, although 15% of affected infants may be asymptomatic. During the middle of the first week, hypertonia of extensor muscles, opisthotonus (backward arching of the trunk), retrocollis (backward arching of the neck), and fever may be observed. After the first week, the infant may exhibit generalized hypertonia. Some of these changes disappear spontaneously or can be reversed with exchange transfusion. In most infants with moderate (10–20 mg/dL) to severe (>20 mg/dL) hyperbilirubinemia, evoked neurologic responses return to normal within 6 months. A minority of infants (ranging between 6% and 23%) exhibit persistent neurologic deficits.

In its chronic form, kernicterus may present in the first year with hypotonia, active deep-tendon reflexes, obligatory tonic neck reflexes, dental dysplasia, and delayed motor skills. After the first year, movement disorders, upward gaze, and sensorineural hearing loss may develop. It has been suggested that long-term effects of severe hyperbilirubinemia on intelligence quotient (IQ) are more likely in boys than in girls. Seidman and colleagues studied 1948 subjects from Hadaasah Hebrew University Medical Center in Jerusalem born in 1970–1971 and drafted into the Israeli army 17 years later and found a higher risk of lowered IQ (< 85) among males with a history of TSB exceeding 20 mg/dL [odds ratio (OR) 2.96; 95% confidence interval (CI) 1.29–6.79] (Seidman et al. 1991).

Carceller-Blanchard  A, Cousineau  J, Delvin  EE Point of care testing: transcutaneous bilirubinometry in neonates. Clin Biochem. 2009;42(3). 
[PubMed: [PMID:18929553]] 
Kaplan  M, Shchors  I, Algur  N  et al. Visual screening versus transcutaneous bilirubinometry for predischarge. jaundice assessment. Acta Paediatr. 2008;97:759–763.
Kuzniewicz  M, Newman  TB Interaction of hemolysis and hyperbilirubinemia on neurodevelopmental outcomes in the collaborative perinatal project. Pediatrics. 2009;123:3. 
[PubMed: [PMID: 19255038]] 
Seidman  DS  et al. Neonatal hyperbilirubinemia and physical and cognitive performance at 17 years of age. Pediatrics. 1991;88:828. 
[PubMed: [PMID: 1896294]] 
Sgro  M, Campbell  DM, Kandasamy  S, Shah  V Incidence of chronic bilirubin encephalopathy in Canada, 2007–2008. Pediatrics. 2012;130:4. 
[PubMed: [PMID: 22966025]] 

 

Nearly every infant is born with a serum bilirubin level higher than that of the normal adult. Approximately 60% of newborns are visibly jaundiced during the first week of life.

 

 

 

 

A. Suspected Pathologic Jaundice

Treatment decisions for both phototherapy (Figure 3-2) and exchange transfusion (Figure 3-3) are based on TSB levels; management options should be discussed with the parents or guardians of the infant.


Guidelines for phototherapy in hospitalized infants of ≥35 weeks’ gestation. (Reproduced with permission from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297.)


Guidelines for exchange transfusion in infants of ≥35 weeks’ gestation. (Reproduced with permission from American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297.)

In infants with isoimmune hemolytic disease, administration of intravenous gamma globulin (0.5–1 g/kg over 2 hours) is recommended if the TSB is rising despite intensive phototherapy or the TSB is within 2–3 mg/dL of the exchange level. If necessary, this dose can be repeated in 12 hours.

Figure 3-2 summarizes the management strategy for hyperbilirubinemia in infants of ≥35 weeks’ gestation. Management decisions regarding phototherapy and exchange transfusion (see Figure 3-3) are based on the infant’s age, risk factors, and TSB levels.

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B. Phototherapy and Exchange Transfusion

1. Phototherapy

This procedure involves exposing the infant to high-intensity light in the blue-green wavelengths. Light interacts with unconjugated bilirubin in the skin, converting it to less toxic photoisomers that are excreted in the bile and urine without conjugation. The efficacy of phototherapy is strongly influenced by the energy output in the blue spectrum, the spectrum of the light, and the surface area of the infant exposed to phototherapy. Commonly used light sources for providing phototherapy are special blue fluorescent tubes, compact fluorescent tubes, and halogen spotlights; however, light-emitting diodes (LEDs) have been shown to be as efficacious as conventional sources, with less heat emission.

Eye protection is placed on the infant, and the bank of lights is placed 15–20 cm from the naked infant. Exposure is increased by placing a fiberoptic blanket under the infant, lightening units all around the infant, or a white sheet around the bassinet to serve as a reflecting surface. If slight warming of the infant is noted, the tubes can be moved away a bit. Phototherapy may be interrupted briefly for parental visits or breastfeeding.

In infants with TSB levels of >25 mg/dL, phototherapy should be administered continuously until a response is documented, or until exchange therapy is initiated. If the TSB is not responding to conventional phototherapy (a response is defined as a sustained reduction in TSB of 1–2 mg/dL in 4–6 hours), the intensity should be increased by adding more lights; the intensity of the lights should also be increased while exchange transfusion is prepared. With commonly used light sources, overdose is impossible, although the infant may experience loose stools. Phototherapy is continued until the TSB level is lower than 14–15 mg/dL. The infant may be discharged after the completion of phototherapy. Rebound of TSB following cessation of phototherapy is usually <1 mg/dL.

2. Exchange transfusion

This procedure rapidly removes bilirubin from the circulation. Circulating antibodies against erythrocytes are also removed. Exchange transfusion is particularly beneficial in neonates with hemolysis. One or two central catheters are placed. Small aliquots of blood (8–10 mL per pass) are removed from the infant’s circulation and replaced with equal amounts of donor red cells mixed with plasma. The procedure is repeated until twice the infant’s blood volume is replaced (~160–200 mL/kg). Serum electrolytes and bilirubin are measured periodically during the procedure. In some cases the procedure must be repeated to lower serum bilirubin levels sufficiently. Infusing salt-poor albumin at a dose of 1 g/kg 1–4 hours before exchange transfusion has been shown to increase the amount of bilirubin removed during the procedure.

Complications of exchange transfusion include thrombocytopenia, portal vein thrombosis, necrotizing enterocolitis, electrolyte imbalance, graft-versus-host disease, and infection. Mortality from exchange transfusion approaches 2%, and an additional 12% of infants may suffer serious complications. Therefore, exchange transfusion should be reserved for neonates who have failed intensive phototherapy and should be performed by clinicians and facilities with proper experience.

If exchange transfusion is being considered, the bilirubin/albumin ratio is used in conjunction with the TSB level and other factors in determining the need for exchange transfusion (see Figure 3-3).

C. Suspected Nonpathologic Jaundice

For the management of breastfeeding jaundice, interruption of breastfeeding in healthy full-term newborns is generally discouraged. Frequent breastfeeding sessions (at least 8–10 times in 24 hours) are advised. However, if the mother and physician wish, they may consider using supplemental formula feedings or temporarily interrupting breastfeeding and replacing it with formula feedings. Phototherapy may be initiated, depending on TSB levels.

As discussed previously, breast milk jaundice is seen initially after day 6 of life in the majority of healthy breastfed infants between 3 weeks and 3 months of age. This is a form of normal physiologic jaundice.

Bhutani  VK, Johns  L Kernicterus in the 21st century: frequently asked questions. J Perinatol. 2009; 29:S1. 
[PubMed: [PMID: 19177056]] 
Dijk  PH, Hulzebos  CV An evidence-based view on hyperbilirubinaemia. Acta Paediatrica. 2012; 101:s464 
[PubMed: [PMID: 22404885]] 
Maisels  MJ, McDonagh  AF Phototherapy for neonatal jaundice. N Engl J Med. 2008;358:920–928. 
[PubMed: [PMID: 18305267]] 
Murki  S  et al. Light emitting diodes versus compact fluorescent tubes for phototherapy in neonatal jaundice: a multi-center randomized controlled trial. Indian Pediatr. 2010;47:2. 
[PubMed: [PMID: 19578227]] 

 

 

Intensive phototherapy should produce a decline in TSB of 1–2 mg/dL within 4–6 hours, and the decline should continue thereafter. If the TSB does not respond appropriately to intensive phototherapy, exchange transfusion is recommended. If levels are in a range that suggests the need for exchange transfusion (see Figure 3-3), intensive phototherapy should be attempted while preparations for exchange transfusion are made. Exchange transfusion is also recommended in infants whose TSB levels rise to exchange transfusion levels despite intensive phototherapy. In any of the preceding situations, failure of intensive phototherapy to lower the TSB level strongly suggests the presence of hemolytic disease or other pathologic processes and strongly warrants further investigation or consultation.

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[Evaluation of infants who develop abnormal signs such as feeding difficulty, behavior changes, apnea, and temperature changes is recommended regardless of whether jaundice has been detected in order to rule out underlying disease.]

Clinical protocols for evaluating jaundice, with assessments to be performed no less than every 8–12 hours in the newborn nursery, should be in place.

Follow up after Hospital Discharge

Follow-up should be provided to all neonates discharged less than 48 hours after birth. This evaluation by a health care professional should occur within 2–3 days of discharge.

Approximately one-third of healthy breastfed infants have persistent jaundice beyond 2 weeks of age. A report of dark urine or light-colored stools should prompt a measurement of direct serum bilirubin. If the history and physical examination are normal, continued observation is appropriate. If jaundice persists beyond 3 weeks, a urine sample should be tested for bilirubin, and a measurement of total and direct serum bilirubin should be obtained.

American Academy of Pediatrics Subcommittee on Hyper-bilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297. 
[PubMed: [PMID: 15231951]] 
Maisels  MJ, Bhutani  VK  et al. Hyperbilirubinemia in the newborn infant ≥35 weeks’ gestation: an update with clarification. Pediatrics. 2009;124:1193–1198. 
[PubMed: [PMID: 19786452]] 

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Shorter hospital stays after delivery limit the time for hospital-based assessment of infant feeding, instruction about breastfeeding, and the detection of jaundice. Hyperbilirubinemia and problems related to feeding are the main reasons for hospital readmission during the first week of life. Among 25,439 infants discharged between 2008 and 2009 from a large medical center in Israel, 143 (0.56%) were readmitted for phototherapy.

Because bilirubin levels usually peak on day 3 or 4 of life, and as most newborns are discharged within 48 hours, most cases of jaundice occur at home. It is therefore important that infants be seen by a health care professional within a few days of discharge to assess for jaundice and overall well-being. This is important in near-term infants (35–36 weeks’ gestation) who are at particular risk for hyperbilirubinemia because of both relative hepatic immaturity and inadequate nutritional intake.

Measuring TSB before discharge and then plotting this value on a nomogram (see Figure 3-1) can be useful for predicting the risk of subsequent moderately severe hyperbilirubinemia (>17 mg/dL) and identify neonates for whom close follow-up is warranted. A study of 17,854 live births reported that neonates in the high-risk group (95th percentile for TSB) at 18–72 hours of life had a 40% chance of developing moderately severe hyperbilirubinemia on discharge, whereas for those in the low-risk group (40th percentile for TSB), the probability for subsequently developing moderately severe hyperbilirubinemia was zero.

Bromiker  R, Bin-Nun  A, Schimmel  MS, Hammerman  C, Kaplan  M Neonatal hyperbilirubinemia in the low-intermediate-risk category on the bilirubin nomogram. Pediatrics. 2012;130(3):e470–e475. 
[PubMed: [PMID: 22926183]] 
Kuzniewicz  MW, Escobar  GJ, Wi  S  et al. Risk factors for severe hyperbilirubinemia among infants with borderline bilirubin levels: a nested case-control study. J Pediatr. 2008;153:2. 
[PubMed: [PMID: 18534217]] 
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Infants who are discharged prior to 48 hours of age, particularly those who are born at <35 weeks’ gestation, should be seen in the office within 2 days of discharge to evaluate jaundice and overall clinical status.

Parental education should emphasize the need to monitor the infant for jaundice, the generally benign course of most cases of jaundice, and associated symptoms such as poor feeding, lethargy, dark urine, and light-colored stools. Family physicians should encourage parents to contact the office with specific questions and concerns. An example of a parent information sheet in English and Spanish is available at http://www.aap.org/family/jaundicefaq.htm

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In 2004, the AAP issued an updated practice parameter for the management of hyperbilirubinemia among newborns of ≥35 weeks’ gestation. Elements of these recommendations are summarized below and can be accessed in full at http://www.aap.org.

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