Nonphysiologic Neonatal Jaundice

Aka: Nonphysiologic Neonatal Jaundice, Non-physiologic Neonatal Hyperbilirubinemia, Severe Neonatal Hyperbilirubinemia, Severe Neonatal Hyperbilirubinemia Risk Factor

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II. Criteria

  1. Neonatal Jaundice in first 24 hours of life
  2. Serum Bilirubin rises > 5 mg/dl in the first 24 hours
  3. Direct Bilirubin (conjugated) >2 mg/dl
    1. Direct Bilirubin >5 mg/dl suggests cholestasis (e.g. biliary atresia) and requires urgent pediatric GI consult
    2. Direct Bilirubin 2 to 5 mg/dl may be due to Hemolysis, Sepsis, metabolic causes and should be followed
      1. Evaluate for underlying cause (See Neonatal Jaundice Causes)
      2. Recheck serum Direct Bilirubin in several days up to 2 weeks
  4. Term Infant
    1. Serum Bilirubin >17 mg/dl
    2. Neonatal Jaundice persists longer than 1 week
      1. Exception: Breast Feeding Jaundice may persist >1 month
  5. Preterm Infant
    1. Serum Bilirubin >15 mg/dl
    2. Jaundice persist longer than 2 weeks
      1. Exception: Breast Feeding Jaundice may persist >1 month

III. Causes

  1. See Neonatal Jaundice Causes

IV. Risk Factors: Severe Hyperbilirubinemia (Infants 35 weeks gestation or further)

  1. Precautions
    1. Ethnicity is no longer used to determine the risk of Severe Hyperbilirubinemia and its complications
    2. Prior guidelines emphasized increased risk in East Asian patients and decreased risk in african american patients
      1. AAP guidelines as of 2022 no longer use ethnicity to identify high risk patients
  2. Major risk factors
    1. Jaundice in first 24 hours (always pathologic)
      1. Most often due to Hemolysis (esp. Hemolytic Disease of the Newborn, G6PD Deficiency)
      2. Suspect Hemolysis if Bilirubin increase >= 0.3 mg/dl/h in first 24 hours (>= 0.2 mg/dl/h after 24 hours)
    2. ABO or Rh incompatibility and positive Coombs test or Direct Antiglobulin Test (Hemolytic Anemia)
      1. Hemolytic Disease of the Newborn due to Rh Sensitization is most common
    3. G6PD Deficiency
      1. Typically included in most Newborn Screens in U.S.
      2. Consider in children with severe, refractory or late onset Hyperbilirubinemia (esp. formula fed)
    4. Delivery at 35 to 36 weeks gestation or earlier Gestational Age
    5. Significant Birth Trauma
      1. Cephalohematoma
      2. Large Hematomas or significant Bruising
    6. Weight loss >8-10%
    7. Neonatal Sepsis
    8. Serum Albumin <3 g/dl
    9. Infant Breast feeds only
      1. Exclusive Breastfeeding alone does not result in neurotoxicity risk
      2. Breastfeeding Jaundice (peaks days 3 to 5)
        1. Decreased oral intake with weight loss before milk let-down occurs
      3. Breast Milk Jaundice (peaks day 6 to 14 and may persist 2 to 3 months)
        1. Nonesterified long-chain Fatty Acids in Breast Milk competitively inhibit glucuronyl transferase
        2. Results in delayed conjugation of Bilirubin and indirect Hyperbilirubinemia
    10. East Asian or Native American ethnicity
    11. Family History of sibling who required Phototherapy for Neonatal Jaundice
    12. Serum Bilirubin in high risk range for age in hours
  3. Minor risk factors
    1. Male gender
    2. Maternal age over 25 years old
    3. Maternal Gestational Diabetes and Fetal Macrosomia
    4. Delivery at 37 to 38 weeks gestation
    5. Serum Bilirubin in intermediate range for age in hours
    6. Low birth weight
  4. Other risk factors
    1. Polycythemia
    2. Medication exposure
      1. Mother: Diazepam, Oxytocin
      2. Infant: Pediazole, Chloramphenicol

V. Signs

  1. Prematurity
  2. Small for Gestational Age
    1. Polycythemia
    2. Intrauterine Growth Retardation (TORCH Infection)
  3. Microcephaly
    1. Intrauterine Growth Retardation (TORCH Infection)
  4. Extravascular blood
    1. Bruising
    2. Cephalohematoma
  5. Pallor
    1. Hemolytic Anemia
    2. Extravascular blood loss
  6. Petechiae
    1. Congenital infection (TORCH Infection)
    2. Sepsis
    3. Erythroblastosis Fetalis
  7. Hepatomegaly or Splenomegaly
    1. Hemolytic Anemia
    2. Congenital infection (TORCH Infection)
    3. Liver disease
  8. Omphalitis
  9. Chorioretinitis
    1. Congenital infection (TORCH Infection)
  10. Hypothyroidism signs

VI. Causes

  1. See Neonatal Jaundice Causes

VII. Labs

  1. All patients: Total Bilirubin
    1. Total Bilirubin (Serial values; for recommended interval see Phototherapy)
    2. See Neonatal Jaundice for screening indications
    3. See Risk Score for Neonatal Hyperbilirubinemia
  2. All patients on or at risk for Phototherapy
    1. Precautions
      1. Labs are normal in 88% of infants undergoing Phototherapy
      2. Consider labs if additional risks
        1. Jaundice onset in first 48 hours of life and requires Phototherapy
        2. Hyperbilirubinemia not responding normally to Phototherapy
        3. Severe Neonatal Hyperbilirubinemia Risk Factors (see above)
    2. Complete Blood Count with Platelets
    3. Peripheral Smear
    4. Coombs Test (Direct Antiglobulin Test)
    5. Conjugated Bilirubin (Direct Bilirubin)
      1. Conjugated Hyperbilirubinemia is uncommon (1 in 2500 infants)
      2. Direct Bilirubin > 5 mg/dl (>85.5 umol/L) suggest cholestatic causes (e.g. biliary atresia)
      3. Direct Bilirubin <5 mg/dl are more typical of Hemolysis, infection and metabolic causes
    6. Blood Type and Rh (for Hemolytic Disease of the Newborn)
      1. Rhesus Incompatibility (CDE)
        1. anti-D (most severe)
        2. anti-C
        3. anti-E
      2. ABO Incompatibility
        1. A hemolysins
        2. B hemolysins
      3. Anti-Duffy
      4. Anti-Kell
  3. Severe Hyperbilirubinemia (e.g. on or at risk for Exchange Transfusion)
    1. Includes labs as above
    2. Reticulocyte Count
    3. G6PD Enzyme Activity level
    4. Serum Albumin level
    5. Chemistry Panel
    6. End Tidal Carbon Monoxide Level (if available)
  4. Increased Direct Bilirubin (Conjugated Bilirubin) >20% of total (or >2 mg/dl)
    1. Consult pediatric GI for additional recommendations if Direct Bilirubin > 5 mg/dl
    2. Urinalysis and Urine Culture
    3. Neonatal Sepsis evaluation
  5. Prolonged Jaundice >3 weeks
    1. Consider Breast Milk Jaundice (especially if well appearing)
    2. Obtain Direct Bilirubin
      1. If Direct Bilirubin >20% of total, see above evaluation for infection, obstruction, Sepsis, metabolic disorders
    3. Newborn Screen result focused review
      1. Thyroid Stimulating Hormone
      2. Galactosemia Screen

VIII. Evaluation

  1. Term newborn with Jaundice onset Day 1 or after Day 14
    1. See Neonatal Jaundice Causes
  2. Term newborn with Jaundice onset 1 to 14 days of life
    1. Conjugated Bilirubin >20% of total (or >1 mg/dl if Total Bilirubin <5 mg/dl)
      1. Suggests biliary obstruction
      2. See Direct Hyperbilirubinemia
      3. See Neonatal Jaundice Causes
    2. Increased Hemoglobin
      1. Polycythemia
    3. Abnormal Peripheral Smear
      1. Observe for Hemolytic Anemia
    4. Normal Peripheral Smear
      1. See Neonatal Jaundice Causes
      2. Consider decreased conjugation causes
      3. Consider non-hemolytic increased Bilirubin load

IX. Resources

  1. Bilirubin Tool
    1. https://bilitool.org
  2. PediTools
    1. https://peditools.org/bili2022/
  3. Fpnotebook - Newborn Hyperbilirubinemia

X. Management

  1. See Phototherapy for indications
  2. See Exchange Transfusion for indications in severe Hyperbilirubinemia
    1. Indications include Hemolysis and Acute Bilirubin Encephalopathy signs

XI. Complications

  1. Congenital Anemia (Mild Hemolysis)
    1. Pale
    2. Hemoglobin of 13 to 15
    3. Few Reticulocytes
    4. Slight Hepatomegaly and Splenomegaly
    5. No Urobilinogen
  2. Icterus Gravis (Severe Hemolysis)
    1. Jaundice at birth
    2. Anemia
    3. Large Hepatomegaly and Splenomegaly
    4. Urobilinogen positive
  3. Bilirubin Encephalopathy
    1. Acute Bilirubin Encephalopathy
    2. Chronic Bilirubin Encephalopathy (Kernicterus)

XII. References

  1. (2004) Pediatrics 114(1): 297-316 [PubMed]
  2. (2001) Pediatrics 108(3):763-5 [PubMed]
  3. (2023) Am Fam Physician 107(6): 661-4 [PubMed]
  4. Moerschel (2008) Am Fam Physician 77:1255-62 [PubMed]
  5. Muchowski (2014) Am Fam Physician 89(11): 873-8 [PubMed]
  6. Kemper (2022) Pediatrics 150(3): e2022058859 [PubMed]
  7. Par (2023) Am Fam Physician 107(5): 525-34 [PubMed]
  8. Porter (2002) Am Fam Physician 65(4):599-614 [PubMed]

Calculation (FPnotebook.com: DrBits) Open in New Window

Calculation (FPnotebook.com: DrBits) Open in New Window

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