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NEONATAL JAUNDICE- ALL YOU NEED TO KNOW
1. NEONATAL JAUNDICE
A PRESENTATION BY MARY NYAMBURA MUONGOYA
DEFINITION
Neonatal jaundice referstothe yellowishdiscolorationof the white partof the eyes (sclera) andskinina
newbornbabydue to bilirubindepositioninthese tissuessecondary tohighserumbilirubinlevels
(hyperbilirubinemia) thatoccurswhenthe rate of productionexceedsthe rate of elimination.
EPIDEMIOLOGY
Jaundice isa commonneonatal problem.
65% of newbornsdevelopclinical jaundice withabilirubinlevel above 5mg/dLduring the firstweekof
life.
However,significantjaundice occursin6 % of term babies
BILIRUBIN METABOLISM
There are six basicstepsinthe metabolismof bilirubinthese are;
1) Production
Bilirubinisthe endproductof heme( ironprotopophyrin)catabolism.
There are three mainsourcesof heme;
o The firstis the breakdown of effete(senescent) RBCS by cellsof the
reticuloendothelial system.
o The secondis throughineffective erythropoiesis (destruction of developing
erythroidcellsinmarrow.
o The third isa non-erythropoieticcomponent,resultingfromturnoverof
nonhemoglobinsourcesof hemee.g.cytochromes,catalase,peroxidase and
myoglobin.
In the newborninfant,the normal destructionof the circulatingredbloodcellsinthe
RES accounts forapproximately 75% of the dailyproductionof bilirubin.The other25%
of the dailyproductionof bilirubinisderivedfromsourcesother thansenescentred
bloodcells(listedabove)
The conversionof the heme moietytobilirubinrequiresthe sequentialactionof two
enzymes;
o Heme oxygenase-toformbiliverdin,carbonmonoxide andiron
o Biliverdinreductase- thisisareducednicotinamide adeninedinucleotide
phosphate (NADPH) dependentenzymethatcatalyzesconversionof biliverdin
to bilirubin.
Each 1 g of hemoglobinbreakdownresultsinthe productionof 34 mg of bilirubin(1mg/dL=
17.2umol/L of bilirubin).
2. 2) Transport
Bilirubinistransportedinplasmaboundtoalbumin.Humanalbuminhasasingle,tight,high
affinity (orprimary) bindingsite forbilirubinandone ormore weaker,lower affinitybinding
sites.
The capacity of serumalbumintobindbilirubinisknownasthe bindingcapacityandthe
strengthof the bilirubin- albuminbondisreferredtoasthe bindingaffinity.
The amount of free bilirubinisverylow atphysiological pH.
The bindingcapacity,bindingaffinityandamountof free bilirubincanbe estimatedbyIvitro
measurementsandprovidea measure,albeitonlyapproximate,of the amountof bilirubinthat
may be available tocause neuronal injury.
3) Hepaticuptake
Hepatocyteshave aselective andhighlyefficientsystemforremovingunconjugatedbilirubin
fromplasma.Thismechanismrequiresseveral differentorganicaniontransport proteins.
Variantsof one of these,organicaniontransporter2(OATP2),maybe importantindetermining
the riskof severe hyperbilirubinemiainAsianinfants.
In the hepatocyte, the transportedbilirubinisboundtoligandin,acytosolicprotein,that
facilitatestransfertothe endoplasmicreticulum,the site of bilirubinconjugation.
4) Conjugation
Carriedoutby the microsomal enzyme uridine diphosphate glucoronyl transferasewhichis
encodedbythe UGT1A1 gene to formbilirubinmonoglucoronideanddiglucoronide.
5) Excretion
The conjugatedbilirubinisexcretedintothe bile.itisthentransportedtothe small intestine where
In the presence of normal gutflora,the conjugatedbilirubinismetabolizedfurthertostercobilins
and excretedinthe stool.
6) Enterohepaticcirculation
Intestinal betaglucuronidasehydrolyzesthe conjugatedbilirubinthusreleasingfreebilirubin
whichisthenreabsorbedandtransportedbythe portal circulationtothe liver.
POSSIBLE CLINICAL OUTCOMES OF HYERBILIRUBINEMIA
Jaundice
Acute bilirubinencephalopathy
Chronicbilirubinencephalopathy/kernicterus
RISK FACTORS FOR NNJ (MNEMONIC-JAUNDICE)
Jaundice withinthe first24hours
A siblingwhowasjaundicedasaneonate
Unrecognizedhemolysis
3. Nonoptimal sucking/nursing
Deficiencyof G6PD
Infections
Cephalohematoma/bruising
East Asian/NorthIndian
SYMPTOMS (visible form of bilirubinemia is ≥ 5mg/dl)
Scleral yellowing
Skinyellowing
Mucous membrane yellowing
Nail yellowing
Excesssleepiness
Poorfeeding
Physical examcluestosome etiologies:
o Sepsis:lethargy,temperature instability,poorfeeding,vomiting,apneaortachypnea
o Hemolytic disease: pallor,hepatosplenomegaly
o Extravascularhemolysis: birthtraumaassociatedwithcephalohematomaorbruising
o Polycythemia:ruddycomplexion
o Cholestaticjaundice:persistentjaundicefor3 weeks,darkurine orlight-coloredstools
WHERE TO LOOK FOR SKIN JAUNDICE
Forehead
Tip of the nose
Chest
Knees
Palmsand soles
CLINICAL ASSESSMENT / EVALUATION
VISUALINSPECTION
Examine babyinbrightnatural lightor white fluorescentlight.
Baby shouldbe naked.
Examine blanched skinandgums.
N/B: NORMAL BILIRUBIN LEVELS ARE 1- 1.5mg/dl
Kramer’s rule is usedto determinethe extentof jaundice.
Level 1-headandneck - 5mg/dl
Level 2- upper trunk above the umbilicus - 5-10mg/dl
Level 3- lowertrunkand thighs-10-12mg/dl
5. Measurementof serumbilirubin
o Transcutaneousbilirubinometer
o Serumbilirubinlevels
ETIOLOGY
Causesof neonatal jaundice canbe broadlydividedintotwo;
Causesof unconjugated( indirect) hyperbilirubinemia
Causesof conjugated( direct) hyperbilirubinemia
CAUSES OFUNCONJUGATED (INDIRECT/WATERINSOLLUBLE)HYPERBILIRUBINEMIA
PHYSIOLOGICCAUSES
o IncreasedRBCmass (polycythemia)
o Shorterlife spanof fetal RBCS(80-90 days ina term infant)
o Relativelylowactivityof the enzyme glucoronyl transferase- terminfantshave 1%
of adultactivity,preterminfantshave 0.1%. before birththisenzymeisactively
downregulatedsince bilirubinneedstoremainunconjugatedIordertocross the
palcentato avoidaccumulationinthe fetus.
o Immature hepaticuptake
o Relativelylowconversionof bilirubintourobilinogenbygutflora.
PATHOLOGIC CAUSES
o HEMOLYTIC CAUSES
o CAUSES INTRINSICTOTHE RBCS
Membrane defects- spherocytosis,elliptocytosis,pyknocytosis,and
stomatocytosis
Enzyme defects- G6PDdeficiency,pyruvatekinasedeficiency,hexokinase
deficiency
Globinsynthesisdefects- α thalassemia,sickle celldisease
o CAUSES EXTRINSICTO THE RBCS
Alloimmunity- ABOorrhesusincompatibility,anti-kell,anti-duffy
Systemicconditions- sepsis,sequesteredblood(e.g. cephalohematoma,
bruising,intracranial hemorrhage)
o NON HEMOLYTIC CAUSES
Breastmilkjaundice
a) Breastmilkhas an enzyme calledlipoproteinlipase thatproduceshigh
concentrationsof nonesterifiedfree fattyacidsthatinhibithepatic
glucoronyl transferase ladingtodecreasedbilirubinconjugationand
thushyperbilirubinemia.
6. b) Breastmilkcontainsa metabolite of progesterone called3-α-20beta
pregnanediolthatinhibitsactionof uridine diphosphoglucuronicacid
glucoronyl transferase leadingtodecreasedbilirubinconjugation.
c) At birth,the gut issterile andnormal gutflora take time to establish.In
the absence of gut flora,bilirubinisdeconjugatedbybrushborderbeta
glucuronidase andisreabsorbed.
Breastfeedingjaundice
Pyloricstenosis
Polycythemia
a) Due to maternal-fetaltransfusion
b) Fetal-fetaltransfusion
c) Infantsof diabeticmothers
Sepsis
a) bacterial
b) viral
c) protozoa
Hypothyroidism-causesdecreasedbilirubinuptake intothe hepatocyte.
Extravascularhemorrhage (whichresultsinreabsorptionof hemolyzed
blood)
a) Cephalohematoma
b) CNShemorrhage
c) Extensive bruising
CriglerNajjarsyndrome (autosomal recessive diseasescausedbyvarious
mutationsinthe UGT1 gene.CriglerNajjarsyndrome type1refersto
congenital absence of UDP glucuronyl transferasecauseslifelong
unconjugatedhyperbilirubinemia.CriglerNajjartype 2is causedby a
reductioninUDP glucoronyl transferaseandhasa milderphenotype)
Gilbert’ssyndrome (familialpartial defectinglucuronyl transferaseactivity
due to mutationsinthe promotorregioninthe UGT1gene)
Lucy-Driscoll syndrome(severe unconjugatedhyperbilirubinemiathoughtto
be due to inhibitionof infant'sglucuronyltransferasebyunidentified
maternal serumfactors)
N/B: THE CAUSES OF UNCONJUGATED HYPERBILIRUBINEMIA CAN ALSO BE GROUPED
INTO TWO MAIN CATEGORIES: OVERPRODUCTION OF BILIRUBIN AND DECREASED
CONJUGATION OF BILIRUBIN. OVERPRODUCTION COULD BE DUE TO HEMOLYTIC OR NON
7. HEMOLYTIC CAUSES WHILE DECREASED CONJUGATION COULD BE DUE TO THE
SYNDROMES ABOVE OR HYSIOLOGIC JAUNDICE.
DEFINITION OF PATHOLOGIC JAUNDICE
Clinical jaundiceinthe first24 hours of life
Clinical jaundicelasting>14 daysof life
Increase of bilirubin>5 mg / dl / day
Total bilirubin>331.5 ᶙmol/L
Directbilirubin>34ᶙmol/L( > 2 mg / dl)
Stool clay/ white coloredandurine stainingclothesyellow
DEFINITION OF PHYSIOLOGIC JAUNDICE
Appearsafter24 hours
Clinicallynotdetectableafter14 days
Maximumintensityby4th-5thdayinterm & 7th dayin preterm
Serumlevel lessthan15 mg/ dl
Disappearswithoutanytreatment
jaundice occurswhenbilirubinnormally increasesfrom1.5mg/dL incord bloodto a meanof
6.5 mg/dLon day 3, followedbyagradual decline tonormal adultlevelsof 1.5 mg/dLby day 10
or 12 of life
MECHANISMS OF PHYSIOLOGIC JAUNDICE
Increasedproductionof bilirubin ( approx 2-3Xona perkilogrambodyweightbasis,thanadults)
o Increasedineffectiveerythropoiesis
o IncreasedRBCmass/erythrocyte volume
o Short RBC life span(80-90)
Decreasedhepaticuptake- low concentrationof the bindingproteinligandininthe hepatocytes
hence decreaseduptake from intothe hepatocyteendoplasmicreticulum.
Decreasedhepaticconjugation- decreased activityof glucoronyl transferase
Increasedenterohepaticcirculation-conjugatedbilirubinisexcretedthroughthe bileintothe
intestine,where it sisdecconjugatedbyamucosal enzyme,βglucuronidase andreabsorbedinto
the enterohepaticcirculationbefeore itcanbe excretedwiththe stool. Newbornshave a
paucityof gut floraand relative caloricdeprivationinthe firstdaysof life,bothof which
promote physiologichyperbilirubinemiathroughincreasedenterohepaticcirculation.
Diminishedbindingtoalbuminandbilirubinbindingprotein
Physiologicjaundice canbe aggravatedby;
8. Immaturity
Cephalohematoma
Birthasphyxia
Hypothermia
Infection
breastfeeding
CAUSES OFCONJUGATED(DIRECT/WATERSOLUBLE)HYPERBILIRUBINEMIA
HEPATIC CAUSES
o INFECTIONS
o Neonatal idiopathichepatitis
o HepatitisA
o HepatitisB
o TORCH
o Bacterial infectionse.g.E.Coli andurinarytract infections
o METABOLIC
o α1 antitrypsin deficiency
o galactosemia
o tyrosinemia
o Fructosemia
o DubinJohnson syndrome- anautosomal recessive diseasecausedbya
mutationinABCC2 onchromosome 10q24 that resultsinalterationsin
bilirubinexcretionviaMRP2.In normal circumstances,bilirubin
diglucoronideispredominantlyexcretedintothe canaliculusbyacarrier
proteinlocalizedtothe MRP2 on the canalicularmembrane.
o Hypopituitarism
o Cysticfibrosis
o Glycogenstorage disorders
o Cerebrohepatorenaldisease ( Zellweger)
o Rotor syndrome- anautosomal recessive diseasecausedbymutationsin
SLCO1B1 andSLCO1B3 on chromosome 12 that resultinthe absence of
OATP1B1 and OATP1B3 on the basolateral surface of hepatocytes.
o DRUGS
o TPN
o Neonatal hemosiderosis
o shockliverfromneonatal asphyxia
POST HEPATIC CAUSES/ EXTRAHEPATIC CAUSES
9. Biliaryatresia- aprogressive diseasecharacterizedbyinflammationandfibrosisof the
extrahepaticbiliarytractresultinginpartial orcomplete obliterationof the extrahepaticbile
ducts.
Choledochal cyst- acysticdilatationof the biliarytract,maybe exclusivelyextrahepaticor
include dilatationsof the intrahepaticbiliarytract.
Alagille syndrome
Bile plugsyndrome
COMPLICATIONS
ACUTE BILIRUBIN ENCEPHALOPATHY
Acute bilirubinencephalopathyis characterizedby;
o Lethargy
o Highpitchedcrying
o Poorfeeding/refusaltofeed
o Irritability
o Jitteriness
o Apnea
o Seizures
o Opisthotonus andretrocolis
o Sunsettingof eyes
o sluggishmoro reflex
KERNICTERUS- causedbybilirubintoxicitytothe basal gangliaandbrainstemnuclei
o Choreoathetoidcerebral palsy
o Upward gaze palsy
o Sensorineural hearingloss
o Dental dysplasia
o Intellectual retardationandlearningdisabilities
MANAGEMENT
PRIMARYPREVENTION
Ensuringadequate feeding
Breastfedinfantsshouldhave 8to 12 feedingdper24 hours.
Formula-fed,full terminfantsshouldconsume 150 kcal per kg perday.
10. DEFINITIVE MANAGEMENT
Treat basedon
TSB
Gestational age and
Cause of jaundice (non-Shemolyticvs.hemolytic)
There are five maintreatmentmodalitiesusedin the managementof jaundice;
PHOTOTHERAPY
AIM: Loweringthe total serumbilirubinconcentration.
LIGHTS: In practice,lightisusedinthe white,blue,turquoise andgreenwavelengths.
Bilirubinabsorbslightprimarilyaround450- 460 nm.
The bestlightis narrow spectrumblue lightsinthe range of 425- 475 nmbut white lampsin
the range of 380-700 nmcouldbe used.
Althoughgreenlighttheoreticallypenetratesskinbetter,ithasnotbeenshown
unequivocallytobe more efficientinclinical use thanblue orwhite light.Besides,green
lightmakesbabieslooksickandisunpleasanttoworkin.
MECHANISMS:
Backgroundknowledge :Thereare fourstructural isomersof bilirubinnamelythe ZZ,ZE,EE
ANDEZ isomerswiththe ZZisomerbeingthe stable more insoluble form.
o Photo-isomerization/configurationalisomerization- thisisaveryrapidand
reversiblereactionthatinvolvesconversionof insoluble toxicformZ isomertonon-
toxicpolarE isomerwhichdiffusesintobloodandisexcretedinbile.
o Structural isomerization- thisisanirreversiblereactionthatinvolves consistingof
intramolecularcyclizationresultingin conversionof bilirubintolumirubinwhichis
rapidlyexcretedinbileandurine. Thisprocessisenhancedbyincreasingthe
intensityof light.Lumirubinisthe primarypigmentfoundinbileduring
phototherapy.
o Photo-oxidation- slow andminorreactioninvolvingphotooxidationof bilirubinto
watersoluble polymersformingacolorlessbyproduct.Thisreactioniscatalyzedby
riboflavin.
INDICATIONS:
o Total serumbilirubin>18mg % in terminfantsand>15 mg % in preterminfants.
o Adjuvanttoexchange transfusion.
o Prophylacticphototherapyfor;ELBW,extremelypreterminfants,babieswithDCT
positivity,baby’swhosemotherisICTpositive
PROCEDURE:
o Selectblue lightsinthe range of 425-475 nm
o Setthe distance fromthe skintobe 45 cm (IPTdistance is15-20 cm)
o Shieldeyes andgenitalia
11. o Change positiononce every2-4hours
o TSB levelscheckedevery10-12hours
o Frequenttemperaturemonitoringanddailyweightcheck
SIDE EFFECTS:
IMMEDIATE LATE
LOOSE STOOLS RISKOF SKIN MALIGNANCY
DEHYDRATION-insensiblewaterlossmay
occur
DAMAGE TO INTRACELLULAR DNA
HYPO/HYPERTHERMIA RETINALDAMAGE
RASHES TESTICULAR DAMAGE
BRONZEBABY SYNDROME
HYPOCALCEMIA
12. EXCHANGE TRANSFUSION
INDICATIONS:
Alloimmune hemolyticdisease of the newborn
o Remove circulatingbilirubintoreduce levelsandpreventkernicterus
o Replace antibody-coatedredcellswithantigen-negativeredcells
o To remove antibodiesassociatedwithredbloodcell hemolysis.
Severe hyperbilirubinaemia secondary to alloimmune haemolyticdiseaseof
the newborn isthe mostcommon reason forexchangetransfusion in the
neonatalintensivecare unit.
Treatment/correctionof Severe anaemia(where there isnormal orincreased
circulatingbloodvolume)
Polycythemia(toreduce haematocrit,usuallyaccomplishedwithpartial exchange
transfusionusingnormal salinereplacement)
Significantunconjugatedhyperbilirubinaemiawithriskof kernicterusdue toany
cause whenintensivephototherapyisunsuccessful
Antibodiesinmaternal autoimmune disease
Severe disturbancesof bodychemistry
PARENTAL CONSENT:
Informedwrittenconsentmustbe obtained.
Consentisdocumentedonaconsentform(AgreementtoTreatmentCR0111).
Consentforbloodisdocumentedonthe reverse side of form CR0111.
In special circumstances (e.g. baby transferred, a shocked anaemic baby with a
parent not available) verbal consent by a parent is acceptable provided it is
documented in baby's clinical record and written consent obtained as soon as
possible
AIM:
Decreasingthe serumbilirubinlevels(thisreducesthe riskof braindamage
(kernicterus))
Decreasingthe sensitizedorabnormal redbloodcells
Remove the offendingantibodysothatongoinghemolysiswill be decreased.
13. EXCHANGE VOLUME:
BloodVolume =70-90 ml/kgfortermand 85-110 ml/kgforpreterminfants
One bloodvolume removes65% of baby's redcells.
Two bloodvolumesremove 88%
ALIQUOTS:
WEIGHT OF NEONATE ALIQUOT VOLUME
<1000 grams 5ml
1000-2000 grams 10ml
>2000 grams 15ml
TECHNIQUE:
Exchange transfusionsare performedusingeither one catheterortwo catheterpush-pull
method. Thisset-upisa jointresponsibilitybetweenmedical andnursingstaff,butthe
specialistdoingthe exchange hasoverall responsibilityforthe procedure.
1. Two Catheter Push-pull Technique
Bloodisremovedfromthe arterywhile infusingfreshbloodthroughaveinatthe same rate.
In Out
Umbilical vein Peripheral artery
or Umbilical vein Umbilical artery
or Peripheral vein Peripheral artery2
or Peripheral vein Umbilical artery
2. One Catheter Push-pull Technique
Thiscan be done throughan umbilical venouscatheter.Exceptionally,anumbilical artery
cathetercan be used.
14. Ideally,the tipof the UVCshouldbe inthe IVC/rightatrium(atorjust above the diaphragm) but
can be usedif itis inthe portal sinus.For 'high'UVC placement,positionshouldbe checkedby
an X-ray.Thisis notalwaysnecessaryfora low position.A low positionedcatheterisusually
removedaftereachexchange.
Withdrawbloodover2 minutes,infuseslightlyfaster.
MONITORING AND DOCUMENTATION:
1. Recordbaseline observationspriortocommencingexchangetransfusion.
- Axilla/rectal temperature
- Heart rate
- Respiratoryrate
- Bloodpressure
- Oxygensaturationandcolour
2. Continuouslymonitorandrecordat 15 minute intervalsonthe recordof Exchange
Transfusionsheet(CR5730),the followingobservations:
- Skintemperature
- Heart rate
- Respiratoryrate
- Oxygensaturation
- BloodPressure (non-invasive)
3. Recordaxilla/rectal temperaturerecorded15minutes aftereach donor pack is
commenced,and then every30 minutesduring the transfusion.
4. Observe foranychangesinneurological status - drowsiness,irritability.
5. Recordbloodin/bloodoutonthe Recordof Exchange Transfusionsheet(CR5730).Keepa
runningtotal.
6. Recordbloodresultsonthe Exchange TransfusionResultsSheet(CR5729)
7. Maintaincontinuouselectronicmonitoringof vital signsforatleasttwohourspost
transfusion(orlongerif baby'sconditionisnot stable).
The entire procedure shouldtake 1-2hoursand shouldbe performedusingaseptic
technique
15. COMPLICATIONS
Be aware of thispossibility,observe the babycarefully andhave resuscitation
equipmentready
During Exchange
Air embolus Ensure the linesare correctlysetup.
Watch the linescontinuouslyforair.
Turn the line off instantlyif airisseen.
Neverhave a3 way tap opentoair and the baby
Be verycareful if there are large swingsinintrathoracicpressure.
Volume imbalance The nurse is responsible forrecordingthe volume balance throughoutthe
exchange.
Arrhythmias Can occur from a varietyof causes.
Setthe monitortohave an audible QRScomplex.
Acidosis Bloodfor exchange transfusionispreservedinCPD(citrate,phosphate,
dextrose) andcanbe quite acidotic.
Checkthe baby's bloodpHbefore,during (usually half way),andafterthe
exchange
Checkmore frequentlyforasick,unstable orsmall baby.
16. Respiratory distress MonitorrespirationandSpO2 constantly.
Hyperkalemia CPD bloodcan have highpotassium[K+] levels.
Check[K+] at the start of each bag.
Monitorthe QRS complex.(forarrhythmia,wideningQRS)
MonitorK+ witheachbloodgas.
Anemia/Polycythemia Checkthe PCV of eachbloodbag.
Agitate the bagevery 15 minutes.
FluctuatingBP and
cerebral blood flow
Monitorrate of bloodinandout carefully.
After Exchange
Infection Prophylacticantibioticsare notindicated.
Observe closelyforsignsof infection.
Hypocalcaemia Monitorcalcium[Ca++] and give replacementCa++in IV fluidsasper
clinical guidelines
Hypoglycaemia Unlikelyduringthe exchange asCPDbloodhas19mmol/L [glucose].
Howeverreboundhypoglycaemiamayoccurafterwards.
Commence a10% glucose infusionpostexchange,orif the exchange is
interrupted.
Hypernatraemia CPD bloodhasa high[Na+].Monitor [Na+] witheachgas.
Thrombocytopenia Verycommon,andmore severe aftermore exchanges(due toincreased
plateletconsumption).
Recoversina few days.
Monitorplatelets seriallyforaweekpostexchange.
17. Polycythaemiaor
anaemia
From poorlymixedorpackedblood.
Coagulopathy or
neutropenia
More likelythe multiple transfusions.
Necrotisingenterocolitis Umbilical catheterrelated(especiallywithalow UVC) and maybe due to
BP and bloodvolume fluctuations.
Take care withfeedingpostexchange
Blood transmitted
infections
For a detailedlistrefertoBloodProducts - RBC guideline
Graft versusHost
disease
There have beenseveral case reports.
It seemstobe more likelywithmore preterminfants,intrauterine
transfusions,multiple exchanges,andrelateddonors.
Irradiate the donorblood.
Drug therapy
IVIG
Metallopophyrintin/zinc
REASONS OF REFERRAL
Onsetof jaundice within24hours
Rapidlyrisingbilirubingreaterthan6mg/dl/day(103umol/L/day)
Clinical jaundicebelowumbilicus(12-15mg/dl /205-257umol/L)
Clinical jaundicetill the solesof the feet
G6PD deficiency
s/sx of sepsis