Neonatal JaundiceNeonatal Jaundice
Ruben BromikerRuben Bromiker
Department of NeonatologyDepartment of Neonatology
Shaare Zedek Medical CenterShaare Zedek Medical Center
Physiologic JaundicePhysiologic JaundiceHealthy infantsHealthy infants
up to 12mg% in 3rd day; in up to 12mg% in 3rd day; in premature, 5th day.premature, 5th day.
No hemolysis or bleedingsNo hemolysis or bleedings
No underlying metabolic diseaseNo underlying metabolic disease
MechanismMechanism
Production:Production: Volemia,Volemia, RBC span (90 days)RBC span (90 days) Ineffective erythropoyesisIneffective erythropoyesis Turnover of non Hb heme proteinsTurnover of non Hb heme proteins
MechanismMechanism
Enterohepatic recirculation: Enterohepatic recirculation: Glucuronidase Glucuronidase Bilirubin monoglucuronide Bilirubin monoglucuronide Intestinal bacteriaIntestinal bacteria Intestinal motility and stoolingIntestinal motility and stooling
MechanismMechanism
Bilirubin Uptake : ligandinBilirubin Uptake : ligandin
Conjugation : UDPG-T activityConjugation : UDPG-T activity
Hepatic excretion of bilirubinHepatic excretion of bilirubin
Neonatal Neonatal HyperbilirubinemiaHyperbilirubinemia
Visible jaundice: Visible jaundice: Adults: >2mg%Adults: >2mg%Newborns: >6mgNewborns: >6mg
Up to 50% of all newborns may Up to 50% of all newborns may develop jaundicedevelop jaundice
Source of BilirubinSource of BilirubinMetabolism of heme. 6-10 mg/kg/day. Metabolism of heme. 6-10 mg/kg/day. (adults 3-4mg/kg/day)(adults 3-4mg/kg/day)1gr Hemoglobine produces 34mg of 1gr Hemoglobine produces 34mg of bilirubinbilirubin75%: from old RBCs released from RES75%: from old RBCs released from RES25%: from ineffective erythropoyesis, 25%: from ineffective erythropoyesis, myoglobine, cytochromes, catalase, myoglobine, cytochromes, catalase, peroxidase.peroxidase.
MetabolismMetabolism
Heme Biliverdin + CO + FeHeme Biliverdin + CO + Fe
Heme Oxygenase + O2 Heme Oxygenase + O2
Biliverdin reductaseBiliverdin reductase
Indirect Indirect (unconjugated)(unconjugated) bilirubin bilirubinBinds to albumin in plasmaBinds to albumin in plasma
ConjugationConjugation
Liver Uptake (binds to ligandin) Endoplasmic reticullumLiver Uptake (binds to ligandin) Endoplasmic reticullum
Bilirubin Bilirubin Mono and diconjugated bilirubinMono and diconjugated bilirubinUDPG-TUDPG-T
StoolStoolBeta glucuronidaseBeta glucuronidaseBacteriaBacteria
Excretion
Excretion
GutGutEliminationEliminationEnterohepatic recirculationEnterohepatic recirculation
UrobilinoidsUrobilinoids
Indirect bilirubinIndirect bilirubin
LiverLiver
Jaundice: Physical Jaundice: Physical examinationexamination
Blanch skin with a finger Blanch skin with a finger JaundiceJaundice Significant when appears at palms or below knees.Significant when appears at palms or below knees.
Transcutaneous bilirubinometerTranscutaneous bilirubinometer
Bruising, cephalohematoma, others.Bruising, cephalohematoma, others.
OrganomegalyOrganomegaly
Dermal Zones of JaundiceDermal Zones of Jaundice
Dermal Zone Bilirubin range (mg% )1 4.5-82 5.5-123 8-16.54 11-185 > 15
After leaving RES bilirubin binds to After leaving RES bilirubin binds to albumin, initially with low affinity, thus albumin, initially with low affinity, thus bilirubin precipitates in the proximal bilirubin precipitates in the proximal parts of the body before it does it parts of the body before it does it distally. So jaundice appears first distally. So jaundice appears first proximally, and later distally. proximally, and later distally.
Jaundice: LaboratoryJaundice: Laboratory
Total serum bilirubinTotal serum bilirubin
Blood type, Rh, Coombs infant and Blood type, Rh, Coombs infant and mothermother
Smear (morphology and reticulocytes)Smear (morphology and reticulocytes)
HematocritHematocrit
Jaundice: LaboratoryJaundice: Laboratory
Antibody identificationAntibody identificationDirect bilirubin:Direct bilirubin:
When more than 2 weeks old or signs of cholestasisWhen more than 2 weeks old or signs of cholestasis
If prolonged: If prolonged: LFT, TORCH, sepsis work-up, metabolic, thyroid LFT, TORCH, sepsis work-up, metabolic, thyroid
G6PDG6PD
Non Physiologic JaundiceNon Physiologic Jaundice Onset at < 24 hsOnset at < 24 hs
Bilirubin Bilirubin over levels for phototherapy over levels for phototherapy
Bilirubin rise > 0.5 mg%/hrBilirubin rise > 0.5 mg%/hr
Signs of underlying illnessSigns of underlying illness
Vomiting, lethargy, poor feeding, Vomiting, lethargy, poor feeding, weight weight
Age > 8 days in term or 15 days in Age > 8 days in term or 15 days in prematurepremature
Non Physiologic Jaundice: Non Physiologic Jaundice: AnamnesisAnamnesis
Familial: Familial: G6PD, spherocytosis, metabolic, G6PD, spherocytosis, metabolic,
enzymes.enzymes.Siblings:Siblings:
Immune, breast milk.Immune, breast milk.Pregnancy: Pregnancy:
Infections, drugs, diabetes.Infections, drugs, diabetes.Delivery: Delivery:
Trauma, cord clumping, asphyxia.Trauma, cord clumping, asphyxia.
Bilirubin toxicity:Bilirubin toxicity:
Disrupted BB barrierDisrupted BB barrierHyperosmolarityHyperosmolarityAnoxiaAnoxiaHypercarbiaHypercarbiaPrematurityPrematurity
Cerebral Penetration: Cerebral Penetration: As free indirect bilirubin or bound when As free indirect bilirubin or bound when disrupted BBBdisrupted BBB
Bilirubin toxicity: FactorsBilirubin toxicity: Factors Unbound indirect bilirubinUnbound indirect bilirubin
Albumin concentration Albumin concentration 1gr albumin binds 8.5mg bilirubin1gr albumin binds 8.5mg bilirubin
Displacement from albumin siteDisplacement from albumin siteFFAFFADrugs: SulfonamidesDrugs: SulfonamidesCorrection of acidosisCorrection of acidosis
Bilirubin toxicity: Bilirubin toxicity: KernicterusKernicterus
Basal gangliaBasal gangliaCranial nerve and cerebral nucleiCranial nerve and cerebral nucleiHippocampusHippocampusAnterior horn of spinal cordAnterior horn of spinal cord
Neuronal injury + yellow staining of brainNeuronal injury + yellow staining of brain incidence in hemolytic disease (especially RH)incidence in hemolytic disease (especially RH)
LocalizationLocalization
Bilirubin toxicity: Bilirubin toxicity: Chronic Chronic complicationscomplications
AthetosisAthetosisSensorial deafnessSensorial deafnessLimited upward gazeLimited upward gazeIntellectual deficitsIntellectual deficitsDental dysplasiaDental dysplasia
Bilirubin toxicityBilirubin toxicityHealthy full-term infants: Healthy full-term infants:
Abnormality in ABRAbnormality in ABRHypotony: Hypotony: reverses with reverses with bilirubin bilirubin levelslevelsVery rarely kernicterusVery rarely kernicterus
Low birth weight infants:Low birth weight infants: Damage most probably due to Damage most probably due to accompanying factors than to high accompanying factors than to high bilirubin.bilirubin.
Breast Feeding JaundiceBreast Feeding JaundiceBilirubin Bilirubin after 4 days of age. Healthy infants after 4 days of age. Healthy infants
Resolves after holding breast milk for 1-2 Resolves after holding breast milk for 1-2 daysdays
PresentationPresentationEarly: 2-4 days of ageEarly: 2-4 days of ageLate: after 4 days of age Late: after 4 days of age
Breast Feeding Jaundice: Breast Feeding Jaundice: MechanismMechanism
Interference with hepatic conjugationInterference with hepatic conjugation
Beta glucuronidase in milkBeta glucuronidase in milk
Reduced bacterial colonization of gutReduced bacterial colonization of gut
Caloric intake Caloric intake intestinal motility intestinal motility recirculationrecirculation
FFA suggested to reduce bilirubin metabolismFFA suggested to reduce bilirubin metabolism
Treatment Options for Treatment Options for Jaundiced Breast-fed InfantsJaundiced Breast-fed Infants
OObbsseerrvvee
CCoonnttiinnuuee bbrreeaasstt--ffeeeeddiinngg;; pphhoottootthheerraappyy
SSuupppplleemmeenntt wwiitthh ffoorrmmuullaa wwiitthh oorr wwiitthhoouutt pphhoottootthheerraappyy
IInntteerrrruupptt bbrreeaasstt--ffeeeeddiinngg;; ssuubbssttiittuuttee ffoorrmmuullaa
IInntteerrrruupptt bbrreeaasstt--ffeeeeddiinngg;; ssuubbssttiittuuttee ffoorrmmuullaa;; pphhoottootthheerraappyy
Isoimmune hemolytic disease of the Isoimmune hemolytic disease of the newbornnewborn
Rh , or minor types (Kell, Duffy, E, C,c)Rh , or minor types (Kell, Duffy, E, C,c)
15% of people are Rh-15% of people are Rh-
Coombs +Coombs +
Maternal sensitization d/t previous Maternal sensitization d/t previous pregnancy, transfusion, amniocentesis, pregnancy, transfusion, amniocentesis, abortionabortion
IHDN: Pregnancy IHDN: Pregnancy ManagementManagement
Coombs titers >1/16 or previous history of Coombs titers >1/16 or previous history of severe disease severe disease AmniocentesisAmniocentesis for optical for optical densitydensity
High levels, and clinical signs of hydrops High levels, and clinical signs of hydrops Intrauterine transfusionIntrauterine transfusion
IntraperitonealIntraperitoneal, , intravascularintravascular or or intracardiacintracardiac Repeated transfusions Repeated transfusions switched fetal blood type switched fetal blood type
IHDN: Newborn IHDN: Newborn ManagementManagement
Check immediately after birthCheck immediately after birthHematocritHematocritBilirubinBilirubinBlood typeBlood type
50% will only need 50% will only need phototherapyphototherapy24% will be anemic and cord bilirubin 24% will be anemic and cord bilirubin >4mg%>4mg% exchange transfusionexchange transfusion
IHDN: PreventionIHDN: PreventionAnti D (Rh) immune globulin indicationsAnti D (Rh) immune globulin indications
At 28 weeksAt 28 weeks within 72 hours since birth.within 72 hours since birth.Procedures or suspected Procedures or suspected transplacental hemorrhage.transplacental hemorrhage.
ABO hemolytic disease of the ABO hemolytic disease of the newbornnewborn15% of pregnancies mother O infant A or B15% of pregnancies mother O infant A or B20% will develop significant jaundice20% will develop significant jaundice10% will need phototherapy. 10% will need phototherapy. Presentation:Presentation:
Early jaundice (<24hs of life)Early jaundice (<24hs of life)Many times Combs -, but there are Many times Combs -, but there are antibodiesantibodiesBlood smear: spherocytesBlood smear: spherocytes
Treatment: PhototherapyTreatment: Phototherapy
Bilirubin best absorbs light at 450 Bilirubin best absorbs light at 450 m. m. The best is to provide it with blue light. The best is to provide it with blue light. White range: 380-700 White range: 380-700 m also adequate.m also adequate.Irradiation generates photochemical reaction in Irradiation generates photochemical reaction in the extravascular space of the skinthe extravascular space of the skinA higher illuminated area increases effectivenessA higher illuminated area increases effectiveness
Treatment: Treatment: Phototherapy Phototherapy MechanismMechanism
Photoisomerization: Photoisomerization: Natural Isomer 4Z,15Z Natural Isomer 4Z,15Z 4Z,15E hydrosoluble 4Z,15E hydrosoluble blood blood biliar secretion (unconjugated) biliar secretion (unconjugated) Slow excretion and fast reisomerization Slow excretion and fast reisomerization reabsorbed. reabsorbed.
Photooxydation: Small polar products. SlowPhotooxydation: Small polar products. Slow
Treatment: Treatment: Phototherapy Phototherapy mechanismmechanism
Structural isomerization: Structural isomerization: Ciclization to lumirubin (irreversible) Ciclization to lumirubin (irreversible) bile and urinebile and urine
Fast excretion not reabsorption. Fast excretion not reabsorption. Related to dose of phototherapy Related to dose of phototherapy (intensity of light)(intensity of light)
Treatment:Treatment: Phototherapy mechanism Phototherapy mechanism
Bilirubin Lumirubin
Main PathwayMain Pathway
Phototherapy: TechniquePhototherapy: Technique
Fluorescents ,spots or biliblanketsFluorescents ,spots or biliblanketsMore than 5More than 5w/cm2 at 425-475w/cm2 at 425-475mmNaked , covering eyesNaked , covering eyesIncrease fluids 10-20%Increase fluids 10-20%Check bilirubin every 12-24hsCheck bilirubin every 12-24hsStop: 13Stop: 13±±1mg% in term, 101mg% in term, 10±±1mg% in preterm1mg% in pretermCheck 12-24hs later for reboundCheck 12-24hs later for rebound
Phototherapy: Side effectsPhototherapy: Side effectsIncreased water lossIncreased water lossDiarrheaDiarrheaRetinal damageRetinal damageBronze baby, tanningBronze baby, tanningMutations in DNA? Mutations in DNA? shield scrotum shield scrotumDisturb of mother-infant interaction.Disturb of mother-infant interaction.
Exchange transfusion: Exchange transfusion: TechniqueTechniqueIrradiated PC < 7 days + FFP. WarmedIrradiated PC < 7 days + FFP. WarmedDouble of blood volume.Double of blood volume.Open incubator, monitorsOpen incubator, monitorsRoute Route
UV: push-pull, over > 1hrUV: push-pull, over > 1hrArtery-vein: IsovolumetricArtery-vein: Isovolumetric
Exchange transfusion: Exchange transfusion: ComplicationsComplications
Hypocalcemia-hypomagnesemia (CPD)Hypocalcemia-hypomagnesemia (CPD)Hypoglycemia (monitor Dx after exchange)Hypoglycemia (monitor Dx after exchange)Acid base disturbancesAcid base disturbancesHyperkalemiaHyperkalemiaCardiovascular:Cardiovascular:
Embolizations, arrhythmia, perforation, arrest.Embolizations, arrhythmia, perforation, arrest.
Exchange transfusion: Exchange transfusion: ComplicationsComplicationsBleedingBleeding
Thrombocytopenia, loss of factors.Thrombocytopenia, loss of factors.
InfectionsInfectionsHemolysisHemolysisGVHDGVHDOtherOther
Fever, hypothermia, NEC?Fever, hypothermia, NEC?
Neonatal Jaundice:Neonatal Jaundice:Other treatmentsOther treatments
Phenobarbital: Phenobarbital: conjugation conjugationOral agar: Oral agar: enterohepatic circulation enterohepatic circulationMetalloporphyrins: inhibit bilirubin Metalloporphyrins: inhibit bilirubin production.production.
Competitors of heme oxygenaseCompetitors of heme oxygenase
IVIGg: inhibits hemolysis.IVIGg: inhibits hemolysis.Binds to FC receptor of reticuloendothelial Binds to FC receptor of reticuloendothelial cellscells
Management of Hyperbilirubinemia Management of Hyperbilirubinemia in the Healthy Term Newborn*in the Healthy Term Newborn*
Age,hours TSB Level, mg/ dL (pmol/ L) Consider
PhototherapyPhototherapy Exchange
Transfusion ifIntensive Photo
therapy Fails
ExchangeTransfusion and
IntensivePhototherapy
<=24§ ... ... ... ...25-48 >12 (170) >15 (260) >20 (340) >25 (430)49-72 >15 (260) >18 (310) >25 (430) >30 (510)>72 >17 (290) >20 (340) >25 (430) >30 (510)* TSB mdicates total serum bilirubin.
§ Term infants who are clinically jaundiced at <=24 hours old are notconsidered healthy and require further evaluation.
Diagnostic approach to neonatal jaundiceDiagnostic approach to neonatal jaundiceJaundiceJaundice
Measure BilirubinMeasure BilirubinNon physiologic Non physiologic
Blood type, Rh, CoombsBlood type, Rh, CoombsHematocrit, Smear, ReticulocytesHematocrit, Smear, Reticulocytes
Increased direct biliIncreased direct bili Increased indirect biliIncreased indirect biliCoombs +Coombs +Coombs -Coombs -ABOABO
RhRhminor groupminor group
SepsisSepsisTORCHTORCHBiliary AtresiaBiliary AtresiaCholestasisCholestasisInspissated BiInspissated BiHepatitisHepatitisCFCFTyrosinosisTyrosinosisGalactosemiaGalactosemia
ororHematocriHematocritt
HematocritHematocritPolycytemiaPolycytemia
RC shapeRC shape NormalNormal
AbnormalAbnormal
BleedingsBleedingsEnterohepaticEnterohepaticMetabolicMetabolicDrugsDrugsOtherOtherSpecific and non specificSpecific and non specific
AbnormalitiesAbnormalities