Basics
Produced by an imbalance between rates of bilirubin production and bilirubin elimination: ‚
- Newborns have higher rate of bilirubin production than adults because of increased RBC mass and shorter RBC life span.
- Newborns, especially preterm infants, have rate limitations in hepatic conjugation and biliary excretion of bilirubin, increased enterohepatic circulation, and diminished bilirubin binding to albumin- and bilirubin-binding protein.
Description
- In most newborns, this represents physiologic jaundice and is not pathologic:
- Bilirubin normally increases from 1.5 mg/dL in cord blood to a mean of 6.5 mg/dL on day 3, followed by a gradual decline to levels of <1.5 mg/dL by day 10 or 12 of life.
- Serum bilirubin may rise to levels exceeding neuroprotective defenses, causing bilirubin tissue binding in basal ganglia, hippocampus, brainstem nuclei, and cerebellum:
- Bilirubin-induced neurologic dysfunction (BIND) caused by increasingly severe hyperbilirubinemia from mild dysfunction to acute bilirubin encephalopathy (ABE) and kernicterus.
- ABE describes the acute manifestations of bilirubin toxicity seen in the 1st wk after birth.
- Kernicterus: Chronic form of BIND, with significant mortality or permanent sequelae including choreoathetoid type of cerebral palsy, gaze abnormalities, hearing loss, and dental dysplasia.
- Rate of progression of BIND depends on rate of increase of bilirubin levels, duration of hyperbilirubinemia, albumin-binding reserves, unbound bilirubin level, host susceptibility, and comorbidities.
- Death is due to respiratory failure and progressive coma or intractable seizures.
- Risk factors for severe hyperbilirubinemia:
- Jaundice observed in 1st 24 hr
- Predischarge total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) (see "Diagnosis " ¯) in high-risk or high " “intermediate-risk zone
- Lower gestational age, 35 " “38 wk
- Exclusive breastfeeding, especially if inadequate with excessive weight loss
- Isoimmune or other hemolytic disease
- Sibling with neonatal jaundice
- Cephalohematoma or excessive bruising
- Ethnicity: East Asian
- Severe hyperbilirubinemia is associated with perinatal factors: Low birth weight, macrosomia from maternal diabetes, infection, polycythemia
- Hyperbilirubinemia neurotoxicity risk factors:
- Isoimmune hemolytic disease
- G6PD deficiency
- Asphyxia
- Sepsis
- Acidosis
- Albumin <3 mg/dL
- Postphototherapy (post-PT) bilirubin rebound to bilirubin levels of concern may occur:
- At high risk are newborns <37 wk gestation, patients with hemolytic disease, patients treated for <72 hr.
Etiology
- Unconjugated hyperbilirubinemia:
- Physiologic jaundice
- Jaundice in breastfed infants:
- Breastfeeding failure jaundice: Exaggeration of physiologic jaundice due to inadequate ingestion/production of sufficient volume of breast milk in the 1st wk of life
- Breast milk jaundice: Begins days 3 " “5, peaks within 2 wk but lasts up to 8 wk; caused by increased ˇ ²-glucuronidase in breast milk
- May be exacerbated by dehydration
- Specific hemolytic conditions:
- Blood group isoimmunization due to ABO, Rh, and minor blood group incompatibility; ABO is most common: Rh disease is unusual (RhoGAM prevents).
- Red cell enzyme deficiencies: G6PD deficiency
- Red cell membrane defects: Hereditary spherocytosis and elliptocytosis
- Sepsis: Bacterial, viral, or protozoal
- Birth trauma:
- Increased heme load from resolving cephalohematoma or ecchymosis
- Polycythemia:
- Caused by maternal " “fetal transfusion
- Fetal " “fetal transfusion
- Infants of diabetic mothers
- Congenital hypothyroidism
- Defective hepatic conjugation:
- Gilbert syndrome (familial partial defect in glucuronyl transferase activity) is benign.
- Crigler " “Najjar syndrome (congenital absence of glucuronyl transferase), lifelong unconjugated hyperbilirubinemia
- Intestinal obstruction such as ileus, functional or anatomic, increases enterohepatic circulation
- Conjugated hyperbilirubinemia:
- Failure of hepatic excretion of conjugated bilirubin
- Causes include neonatal hepatitis, congenital biliary atresia, extrahepatic biliary obstruction, shock liver from neonatal asphyxia, neonatal hemosiderosis
Diagnosis
Signs and Symptoms
History
- Sleepiness, poor intake, and inadequate urine output may be present.
- Early phase of ABE:
- Feeding difficulties with poor suck; decreased urine output
- Fussiness, irritability, hypotonia
- Lethargy with altered awake " “sleep pattern
- Intermediate phase of ABE:
- High-pitched cry, irritability
- Increased tone with backward arching of neck (retrocollis) and trunk (opisthotonos) alternating with hypotonia
- Fever
- Signs of advanced ABE:
- Pronounced retrocollis " “opisthotonos
- Semicoma, seizures
- Bicycling movements
Physical Exam
- Yellowish discoloration of skin, sclera, and body fluids due to bilirubin deposition. Indicates elevated serum bilirubin level.
- Evidence of dehydration: Mottled, prolonged capillary refill
- Increasing levels of bilirubin affect skin color progressing in cephalocaudal direction:
- Blanch skin with digital pressure to reveal underlying skin color
- Face: Bilirubin levels >6 " “8 mg/dL
- Feet: Bilirubin levels >12 " “15 mg/dL
- Visual diagnosis of jaundice is unreliable, especially in darkly pigmented infants.
- Neurologic dysfunction is identified by abnormal tone " ”hypotonia, hypertonia, or variability; setting sun sign " ”sclera visible below upper eyelid.
- Clues to contributing conditions
Essential Workup
- Clinical diagnosis considering risk factors
- TSB mandatory in any infant with suspected or obvious jaundice
- Initial TSB should be fractionated into indirect (unconjugated) and direct (conjugated) bilirubin
Diagnosis Tests & Interpretation
Lab
- Interpret TSB according to infants age in hours, not days, to determine risk and need for treatment. Chart progression
- Identify TSB level or TcB
- TcB correlates well with TSB if available.
- Further evaluation is recommended for these newborns with jaundice:
- Occurs in the 1st 24 hr of life
- Persists beyond the 1st wk of life
- TSB levels reach level to initiate intensive PT
- Conjugated bilirubin is >10% or >2 mg/dL.
- Any signs of ABE
- Serum albumin, electrolytes, BUN, Cr, calcium
- CBC with differential and RBC morphology
- Reticulocyte count
- Maternal and infant blood type
- Direct Coombs test on cord blood:
- Hospital routines vary: Some will test newborns from all type O mothers.
- If not available, direct Coombs test on infant's blood
- Sepsis evaluation in ill-appearing infant
- Further inpatient workup is directed at suspected cause:
- Red cell enzyme assay: G6PD
- Liver function tests
- Urine-reducing substances
- Metabolic or endocrine studies
Imaging
- Evaluation for obstructive liver disease (direct hyperbilirubinemia)
- MRI scan of brain with abnormal globus pallidus is pathognomonic of kernicterus; not indicated for emergency management.
Differential Diagnosis
- See "Etiology. " ¯
- Essential to differentiate unconjugated from conjugated hyperbilirubinemia.
Treatment
- Severe newborn hyperbilirubinemia with signs of encephalopathy requires immediate treatment, as outcome is related in part to duration of exposure.
- Initiate PT when TSB exceeds threshold level based on age-in-hours nomogram and risk factors.
Initial Stabilization/Therapy
0.9% normal saline 20 mL/kg bolus if signs of volume depletion. ‚
Ed Treatment/Procedures
- Treatment guidelines for infants ≥35 wk gestation based on TSB plotted vs. age in hours for infants by risk group (below).
- Higher risk are 35 " “37 6/7 wk + risk factors.
- Medium risk are ≥38 wk + risk factors, or 35 " “37 6/7 wk and well.
- Lower risk are ≥38 wk and well.
- Risk factors: Isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, albumin <3 g/dL
- Depending upon the risk group, hospitalization for intensive PT is indicated when TSB (mg/dL) is above:
‚
View LargeAGEHighMediumLow12 hr67.5924 hr7.59.511.536 hr9.511.51348 hr11131560 hr12.514.516.572 hr13.5151896 hr14.517205 " “7 days151821 - BiliTool is an online calculator (http://bilitool.org/) for risk stratification.
- Intensive PT involves use of high level of irradiance delivered to as much of infants surface area as possible (overhead light source and bili blanket beneath) per light source manufacturer. Eyes must be shielded.
- Intensive PT should decrease TSB >0.5 mg/dL/h. Begin as soon as possible.
- Indications for exchange transfusions (ET) are also determined by age in hours and risk stratification, and lack of response to PT in consultation with neonatology. Exchange requires irradiated blood and albumin infusion.
- ET is often recommended regardless of TSB level if infant shows signs of ABE. NICU admission and monitoring.
- If isoimmune hemolytic disease, consider IV immunoglobulin 0.5 " “1 g/kg over 2 hr if TSB level is nearing exchange criteria.
- If any delay in admission/transfer, initiate intensive PT in ED.
- Treat comorbid disease (sepsis, liver dysfunction, polycythemia, hypothyroidism)
- Encourage increased frequency of feeding with breast milk or formula; supplemental dextrose " “water is not useful. May need to enter supplementation or IV fluids.
- Breastfeeding failure and breast milk jaundice:
- Most infants can continue to breastfeed.
- Encourage mothers to nurse at least 8 " “12 times per day for 1st several days.
- Supplementation with formula and/or IV fluids may be temporarily required.
- 2 " “3 day cessation of breastfeeding is recommended for infants with breast milk jaundice and levels not responding to PT.
- Encourage mother to maintain lactation by use of breast pump or manual expression during period of cessation.
- Physiologic jaundice: Reassurance and arrange appropriate follow-up
Medication
First Line
IV immunoglobulin 0.5 " “1 g/kg over 2 hr in isoimmune hemolytic disease if TSB level is nearing exchange criteria and not responding to intensive PT. ‚
Second Line
- Phenobarbital increases bilirubin conjugation and excretion slowly; may adversely impact cognitive development; not routinely used
- Ursodeoxycholic acid increases bile flow and is useful in the treatment of cholestatic jaundice.
Follow-Up
Disposition
Admission Criteria
- Infants requiring intensive PT
- Evidence of significant anemia, sepsis, dehydration, or evidence of obstructive liver disease requires hospitalization for diagnostic evaluation and treatment
- Rapid transport to NICU; transport PT if transport time >30 min
Discharge Criteria
- Stable infant with hyperbilirubinemia not requiring PT
- Stable term infant with uncomplicated nonhemolytic hyperbilirubinemia with no risk factors and TSB 2 " “3 mg/dL below levels recommended for intensive PT; may have home PT arranged if appropriate timely follow-up can be ensured.
- Direct communication with primary care provider and neonatal consultant.
Issues for Referral
Breastfeeding failure: Lactation consultants are available at many hospitals. ‚
Followup Recommendations
Follow-up with primary care provider: ‚
- Within 12 hr: Stable infant with hyperbilirubinemia not requiring PT and with no risk factors
- Within 8 hr: Stable infant with uncomplicated nonhemolytic hyperbilirubinemia with home PT arranged
Pearls and Pitfalls
- TSB must be interpreted according to the newborns age in hours, not days, and with regard for risk factors for severe hyperbilirubinemia.
- PT needs to be initiated when the TSB exceeds the threshold level.
- Infant feeding and hydration must be assessed and corrected.
Additional Reading
- Maisels ‚ MJ, Bhutani ‚ VK, Bogen ‚ D, et al. Hyperbilirubinemia in the newborn infant > or = 35 wk gestation: An update with clarifications. Pediatrics. 2009;124:1193 " “1198.
- Schwartz ‚ HP, Haberman ‚ BE, Ruddy ‚ RM. Hyperbilirubinemia: Current guidelines and emerging therapies. Pediatr Emerg Care. 2011;27(9):884 " “889.
See Also (Topic, Algorithm, Electronic Media Element)
- Neonatal Sepsis
- Online access to AAP guidelines available at: http://aappolicy.aappublications.org/cgi/content/full/pediatrics;114/1/2970 Factors, in order to prevent BIND dysfunction.
Codes
ICD9
- 774.6 Unspecified fetal and neonatal jaundice
- 774.7 Kernicterus of fetus or newborn not due to isoimmunization
- 774.39 Other neonatal jaundice due to delayed conjugation from other causes
- 773.1 Hemolytic disease of fetus or newborn due to ABO isoimmunization
- 277.4 Disorders of bilirubin excretion
- 774.30 Neonatal jaundice due to delayed conjugation, cause unspecified
- 774.31 Neonatal jaundice due to delayed conjugation in diseases classified elsewhere
- 774.5 Perinatal jaundice from other causes
ICD10
- P57.9 Kernicterus, unspecified
- P59.3 Neonatal jaundice from breast milk inhibitor
- P59.9 Neonatal jaundice, unspecified
- P55.1 ABO isoimmunization of newborn
- E80.4 Gilbert syndrome
- E80.5 Crigler-Najjar syndrome
- P59.8 Neonatal jaundice from other specified causes
SNOMED
- 387712008 Neonatal jaundice (disorder)
- 359007 Kernicterus due to isoimmunization (disorder)
- 82696006 Neonatal jaundice due to delayed conjugation from breast milk inhibitors (disorder)
- 32858009 Hemolytic disease of fetus OR newborn due to ABO immunization
- 206454000 Neonatal jaundice with Crigler-Najjar syndrome (disorder)
- 206456003 Neonatal jaundice with Gilberts syndrome (disorder)