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Neonatal hyperbilirubinemia JFK pediatric core curriculum

Neonatal hyperbilirubinemia JFK pediatric core curriculum. MGH Center for Global Health Pediatric Global Health Leadership Fellowship Credits: Brett Nelson, MD, MPH Rachel Siegel, MD Susan O’Brien, MD. Discussion outline. Bilirubin pathophysiology Physiologic and non-physiologic jaundice

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Neonatal hyperbilirubinemia JFK pediatric core curriculum

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  1. Neonatal hyperbilirubinemiaJFK pediatric core curriculum MGH Center for Global Health Pediatric Global Health Leadership Fellowship Credits: Brett Nelson, MD, MPH Rachel Siegel, MD Susan O’Brien, MD

  2. Discussion outline • Bilirubin pathophysiology • Physiologic and non-physiologic jaundice • Causes of non-physiologic jaundice • Unconjugated hyperbilirubinemia • Conjugated hyperbilirubinemia • Workup • Treatment

  3. Bilirubin pathophysiology • Bilirubin is breakdown product of heme, from circulating RBCs • Carried by albumin to hepatocytes, where processed for excretion • In hepatocytes, uridine diphosphogluconurate glucuronosyltransferase (UGT) catalyzes conjugation of bilirubin with glucuronic acid • Conjugated bilirubin is now more water soluble and can be excreted in bile (and urine)

  4. Bilirubin pathophysiology

  5. Epidemiology: neonatal jaundice • Neonatal jaundice is quite common • >50% of normal newborns and • 80% of preterm infants have some degree of jaundice • Two types of neonatal jaundice: • Normal / physiological • Abnormal / non-physiological

  6. Reasons for physiologic jaundice • In term newborns, bilirubin production is 2-3 times higher than in adults • Hematocrit of 50-60%, shorter RBC life span (90 days), and increased turnover of RBCs • Bilirubin clearance decreased in newborns, mainly due to deficiency of enzyme UGT • UGT activity in term infants at 7 days is ~1% of adult liver and doesn’t reach adult levels until 14 weeks • Increase enterohepatic circulation of bilirubin, further increasing bilirubin load

  7. Greater concerns in preterm infants • Even more RBC turnover and destruction • Physiologically impaired conjugation and elimination of bilirubin • An even less mature liver • Reduced bowel motility due to inadequate oral intake • Delayed elimination of meconium • Increased enterohepatic circulation

  8. Physiologic jaundice • Jaundice appears around 72 hrs of life • Bilirubin peaks <14 mg/dl • Direct bilirubin <10% of total bilirubin • Rate of rise <5mg/dL/day • Jaundice resolves in 1-2 weeks in term infants, 2 weeks in preterm infants • Otherwise the jaundice is abnormal…

  9. Two forms of hyperbilirubinemia • Unconjugated / indirect hyperbilirubinemia: • Pre-hepatic cause, or impairment in conjugation VS. • Conjugated / direct hyperbilirubinemia: • Injury at the level of the hepatocytes, or post-hepatic obstruction • Consider diagnosis of conjugated hyperbilirubinemia if direct bilirubin is >3mg/dL, or is >10% of total bilirubin

  10. Non-physiologic jaundice • Early jaundice • Starts on first day of life • Jaundice of long duration • >14 days in term or >21 days in preterm infants • Deep jaundice • Palms and soles deep yellow • Objectively, high bilirubin lab levels • Jaundice with fever

  11. Differential diagnosis:Unconjugated hyperbilirubinemia • Breastfeeding jaundice • Occurs at 1-3 days of age; due to dehydration and lack of stooling (treat by increasing feeding frequency) • Breast milk jaundice • Occurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by temporary switch to formula) • Hemolysis • ABO/Rh incompatibility • RBC membrane defects • Alpha thalassemia • G6PD deficiency • Cephalohematoma • Polycythemia • Infection • Hypothyroidism • Gilbert’s • impaired conjugation, associated with stress, no overt hemolysis • Crigler-Najjar’s • absent (type 1) or diminished (type 2) UDP-glucoronyl transferase

  12. Differential diagnosis:Conjugated hyperbilirubinemia • Biliary atresia • ~60% of cases; an obliterative process of bile ducts; diagnosed by U/S or biopsy • Infection • Hepatitis B, TORCH • Metabolic • Galactosemia • Alpha-1-antitrypsin deficiency: most common genetic cause • Dubin Johnson or Rotor’s syndrome: defective liver secretion of bilirubin • Iatrogenic • Drug-mediated • TPN-related: occurs in ~2/3 of infants given TPN over 2 weeks of duration; unknown mechanism, possibly mediated by bacterial endotoxins, oxidative stress, glutathione depletion • Idiopathic • neonatal non-infectious hepatitis (diagnosis of exclusion)

  13. The concern: Kernicterus • Bilirubin exceeds albumin-binding capacity, crosses BBB, and deposits on basal ganglia and brainstem nuclei • Risks increase with levels >20 mg/dl • Or lower levels in setting of sepsis, meningitis, hemolysis, hypothermia, hypoglycemia, or prematurity

  14. Signs of kernicterus • Acute sequelae: • Poor suck, lethargy, hypotonia, seizure • Then hypertonia (opisthotonus, retrocollis), fever, high-pitched cry • Chronic sequelae: • Choreoathetoid CP, gaze paresis, sensorineural hearing loss, mental retardation

  15. Cause analysis of kernicterus • Early discharge <48hrs without follow-up within 48hrs • Failure to check bilirubin level when jaundice within 24hrs of life • Failure to recognize risk factors • Underestimating severity by visual assessment • Delay in initiating treatment • Failure to respond to parental concerns AAP Subcommittee on Neonatal Hyperbilirubinemia. Pediatrics 2001; 108: 763-765.

  16. Maternal: Race or ethnic group (Asian, Mediterranean) ABO, Rh incompatibility Previous jaundiced infant Advanced maternal age Diabetes Infant: Gestation <38 weeks Bruising, cephalohematoma Infection G6PD deficiency Polycythemia Male gender Nutritional: Breastfeeding Weight loss Decreased feeding frequency Decreased stooling Decreased urine output Work up: assess risk factors

  17. Work up: laboratory studies • Where possible, confirm clinical jaundice with bilirubin levels • Possible additional investigations, depending on likely diagnoses and lab availability: • Hemoglobin/hematocrit (PCV) to look for hemolysis • Blood smear • Reticulocyte count • WBC to look for signs of infection (WBC <5, WBC>20, or I:T ratio >20%) • Blood type of baby and mother, and Coombs test • Syphilis serology (e.g. VDRL) • G6PD screen, thyroid function tests, liver ultrasound

  18. Treatment options:Unconjugated hyperbilirubinemia • Hydration / feeding • Consider formula supplementation with temporary interruption of breastfeeding • Phototherapy… (see next slide) • Antibiotics if suspected infection • Antimalarials if fever and positive smear • (Exchange transfusion) • (IVIG in immune-mediated red cell destruction)

  19. Diagnosis of jaundice can be very difficult in dark-skinned babies • Scleral icterus may be more sensitive marker but is a later sign • High level of suspicion is required!

  20. Phototherapy • Clinical indications1: • Jaundice on day 1 • Jaundice in premature infant • Deep jaundice involving palms and soles of the feet • Laboratory indications: • In full-term infants, bilirubin levels per Bhutani curves • In premature infants, when bilirubin level ≥5x weight (e.g. threshold for 3kg newborn = 3kg x 5 = 15mg/dl) 1. Pocket Book of Hospital Care for Children. WHO. 2005.

  21. Bhutani curve: identifying risk Nomogram for designation of risk in 2840 well newborns at 36 or more weeks' gestational age with birth weight of 2000 g or more or 35 or more weeks' gestational age and birth weight of 2500 g or more based on the hour-specific serum bilirubin values. (Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316)

  22. Bhutani curve: phototherapy Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation. (Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114:297-316)

  23. WHO guidelines: phototherapy Pocket Book of Hospital Care for Children. WHO. 2005.

  24. Key points regarding treatment: • Bilirubin levels above 20 are an emergency that need to be treated emergently • Multiple unit phototherapy, up to 6-8 lights, if they are available, can and should be used • If bilirubin is high, need to provide multi-unit therapy, encouragement of frequent feeding and possibly IV fluids as well

  25. Treatment:Conjugated hyperbilirubinemia • Phototherapy is contraindicated • Treat underlying cause • Phenobarbital • increases conjugation and excretion of bilirubin; however, could affect cognitive development, therefore used cautiously • Ursodiol • increases biliary flow and improves cholestatic jaundice

  26. Conclusion • Neonatal jaundice is a very common condition • Important to prevent kernicterus • Pathologic jaundice is early, deep, quickly progressing, or of long duration • Assess jaundice through identifying risk factors and laboratory analysis • Bhutani curves guide phototherapy treatment for unconjugated hyperbilirubinemia • Treat underlying cause of conjugated hyperbilirubinemia

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