1 Neonatal hyperbilirubinemia JFK pediatric core curriculum MGH Center for Global HealthPediatric Global Health Leadership FellowshipCredits:Brett Nelson, MD, MPHRachel Siegel, MDSusan O’Brien, MD
2 Discussion outline Bilirubin pathophysiology Physiologic and non-physiologic jaundiceCauses of non-physiologic jaundiceUnconjugated hyperbilirubinemiaConjugated hyperbilirubinemiaWorkupTreatment
3 Bilirubin pathophysiology Bilirubin is breakdown product of heme, from circulating RBCsCarried by albumin to hepatocytes, where processed for excretionIn hepatocytes, uridine diphosphogluconurate glucuronosyltransferase (UGT) catalyzes conjugation of bilirubin with glucuronic acidConjugated bilirubin is now more water soluble and can be excreted in bile (and urine)
5 Epidemiology: neonatal jaundice Neonatal jaundice is quite common>50% of normal newborns and80% of preterm infants have some degree of jaundiceTwo types of neonatal jaundice:Normal / physiologicalAbnormal / non-physiological
6 Reasons for physiologic jaundice In term newborns, bilirubin production is 2-3 times higher than in adultsHematocrit of 50-60%, shorter RBC life span (90 days), and increased turnover of RBCsBilirubin clearance decreased in newborns, mainly due to deficiency of enzyme UGTUGT activity in term infants at 7 days is ~1% of adult liver and doesn’t reach adult levels until 14 weeksIncrease enterohepatic circulation of bilirubin, further increasing bilirubin load
7 Greater concerns in preterm infants Even more RBC turnover and destructionPhysiologically impaired conjugation and elimination of bilirubinAn even less mature liverReduced bowel motility due to inadequate oral intakeDelayed elimination of meconiumIncreased enterohepatic circulation
8 Physiologic jaundice Jaundice appears around 72 hrs of life Bilirubin peaks <14 mg/dlDirect bilirubin <10% of total bilirubinRate of rise <5mg/dL/dayJaundice resolves in 1-2 weeks in term infants, 2 weeks in preterm infantsOtherwise the jaundice is abnormal…
9 Two forms of hyperbilirubinemia Unconjugated / indirect hyperbilirubinemia:Pre-hepatic cause, or impairment in conjugationVS.Conjugated / direct hyperbilirubinemia:Injury at the level of the hepatocytes, or post-hepatic obstructionConsider diagnosis of conjugated hyperbilirubinemia if direct bilirubin is >3mg/dL, or is >10% of total bilirubin
10 Non-physiologic jaundice Early jaundiceStarts on first day of lifeJaundice of long duration>14 days in term or >21 days in preterm infantsDeep jaundicePalms and soles deep yellowObjectively, high bilirubin lab levelsJaundice with fever
11 Differential diagnosis: Unconjugated hyperbilirubinemia Breastfeeding jaundiceOccurs at 1-3 days of age; due to dehydration and lack of stooling (treat by increasing feeding frequency)Breast milk jaundiceOccurs at 4-10 days of age; substance in breast milk inhibits glucuronyl transferase (treat by temporary switch to formula)HemolysisABO/Rh incompatibilityRBC membrane defectsAlpha thalassemiaG6PD deficiencyCephalohematomaPolycythemiaInfectionHypothyroidismGilbert’simpaired conjugation, associated with stress, no overt hemolysisCrigler-Najjar’sabsent (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 biopsyInfectionHepatitis B, TORCHMetabolicGalactosemiaAlpha-1-antitrypsin deficiency: most common genetic causeDubin Johnson or Rotor’s syndrome: defective liver secretion of bilirubinIatrogenicDrug-mediatedTPN-related: occurs in ~2/3 of infants given TPN over 2 weeks of duration; unknown mechanism, possibly mediated by bacterial endotoxins, oxidative stress, glutathione depletionIdiopathicneonatal non-infectious hepatitis (diagnosis of exclusion)
13 The concern: Kernicterus Bilirubin exceeds albumin-binding capacity, crosses BBB, and deposits on basal ganglia and brainstem nucleiRisks increase with levels >20 mg/dlOr lower levels in setting of sepsis, meningitis, hemolysis, hypothermia, hypoglycemia, or prematurityKernicterus is yellow staining of the basal ganglia and brainstem nuclei.Bilirubin encephalopathy is the clinical term to describe the condition that results from accumulation of bilirubin in the brain.Acute phase: infant is severely jaundiced, has a poor suck, lethargy, hypotoniaIf not treated, the infant may become hypertonic (opisthotonus, retrocollis), develop a fever and a high pitched cry.The chronic form: includes choreoathetoid cerebral palsy, upward gaze paresis, hearing loss, and mental retardation.Kernicterus is a devastating usually completely preventable effect of severe hyperbilirubinemia.
15 Cause analysis of kernicterus Early discharge <48hrs without follow-up within 48hrsFailure to check bilirubin level when jaundice within 24hrs of lifeFailure to recognize risk factorsUnderestimating severity by visual assessmentDelay in initiating treatmentFailure to respond to parental concernsA root cause analysis of these recent cases identified the following concerns:Early d/c <48 hrs with no f/u within 48 hrs of d/c.Failure to respond to parental concerns regarding jaundice, poor feeding or lethargy.AAP Subcommittee on Neonatal Hyperbilirubinemia. Pediatrics 2001; 108:
16 Work up: assess risk factors Maternal:Race or ethnic group (Asian, Mediterranean)ABO, Rh incompatibilityPrevious jaundiced infantAdvanced maternal ageDiabetesInfant:Gestation <38 weeksBruising, cephalohematomaInfectionG6PD deficiencyPolycythemiaMale genderNutritional:BreastfeedingWeight lossDecreased feeding frequencyDecreased stoolingDecreased urine outputThese are some of the common maternal clinical risk factors:East Asian, Native American, MediteraneanBlack infants have lower bilirubin levels than white infants but both peak at about 5-6 mg/dl on the 3rd day of life.Asian infants peak on the 4th or fifth day of life at mean levels of 9-12 mg/dl and sustain higher bilirubin levels for longer period of time..Mechanism is not clear but may be due to an increase in bilirubin production or enterohepatic circulation rates in Asian infants.And these are some common infant risk factorsG6PD Deficiency occurs in 11%- to 13% of blacks and is more common among immigrants from the Mediterranean countries and Southeast Asia. It has been associated with kernicterus. Screening of G6PD Deficiency is not routinely performed in most hospitals. (other enzyme, RBC structural defects)(Genetics- Less common- Gilbert’s disease, Crigler-Najaar)Examine infants in well lit area.Look for bruising, cephalohematomas, petechiae, hepatosplenomegaly and other signs of sepsis.Don’t get bili’s on babies who aren’t jaundiced.Normal bili= 5-6 mg/dlClinical jaundice appears when the serum bilirubin levels reach >7 mg/dl.Breastfeeding infants who aren’t feeding well have low levels of intestinal bacteria that are capable of converting bilirubin to to it’s non-resorbable form increases enterohepatic circulationALSO, WHEN DECIDING WHETHER TO TREAT OR DISCHARGE, CONSIDER SOCIAL RISK FACTORS:ParityMaternal ageAccess to medical carePhoneLanguageMaternal depressionSingle parentOverwhelmed householdneed to be considered in planning whether or not to send a family home and in deciding how much support they will require.
17 Work up: laboratory studies Where possible, confirm clinical jaundice with bilirubin levelsPossible additional investigations, depending on likely diagnoses and lab availability:Hemoglobin/hematocrit (PCV) to look for hemolysisBlood smearReticulocyte countWBC to look for signs of infection (WBC <5, WBC>20, or I:T ratio >20%)Blood type of baby and mother, and Coombs testSyphilis serology (e.g. VDRL)G6PD screen, thyroid function tests, liver ultrasoundAdditional laboratories:Reticulocyte to evaluate degree of hemolysisconsider G6PD screenOnce starting:We follow bilirubin values at hour intervals.Frequent feedsMaintain hydration and nutritionKeep parents informedDocumentConsider stopping when:underlying issues are under controlbili trend indicates rebound would be lower than that which requires phototherapySo, it seems straightforward but for many infants the question of who should get phototherapy and for how long still leaves a lot of clinicians biting their fingernails.
18 Treatment options: Unconjugated hyperbilirubinemia Hydration / feedingConsider formula supplementation with temporary interruption of breastfeedingPhototherapy… (see next slide)Antibiotics if suspected infectionAntimalarials 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 signHigh level of suspicion is required!
20 Phototherapy Clinical indications1: Laboratory indications: Jaundice on day 1Jaundice in premature infantDeep jaundice involving palms and soles of the feetLaboratory indications:In full-term infants, bilirubin levels per Bhutani curvesIn 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
21 Bhutani curve: identifying risk Another excellent resource resource we use for guidance in treatment decision-making is a percentile-based bilirubin nomogram developed by Bhutani and published in Pediatrics in 1999.This normogram was developed using:13,000 term and near term infants > 36 weeksno risk factors for hyperbilirubinemiaTSB pre-discharge at hours of life at the time of routine metabolic screeningRacially diverse60% were breastfedFollow-up TSB was obtained 2-4 days after discharge to determine the probability of subsequent, moderately severe hyperbilirubinemia (>17 mg/dl)(F/U on 2976/13,000)Using the nomogram, newborns can be designated ashigh risk (serum bilirubin concentrations >95 %ile)high or low intermediate riskand low risk (serum bilirubin concentrations below 40th % ile)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: )
22 Bhutani curve: phototherapy Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation. (Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114: )
23 WHO guidelines: phototherapy Pocket Book of Hospital Care for Children. WHO
24 Key points regarding treatment: Bilirubin levels above 20 are an emergency that need to be treated emergentlyMultiple unit phototherapy, up to 6-8 lights, if they are available, can and should be usedIf 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 contraindicatedTreat underlying causePhenobarbitalincreases conjugation and excretion of bilirubin; however, could affect cognitive development, therefore used cautiouslyUrsodiolincreases biliary flow and improves cholestatic jaundice
26 Conclusion Neonatal jaundice is a very common condition Important to prevent kernicterusPathologic jaundice is early, deep, quickly progressing, or of long durationAssess jaundice through identifying risk factors and laboratory analysisBhutani curves guide phototherapy treatment for unconjugated hyperbilirubinemiaTreat underlying cause of conjugated hyperbilirubinemia