Neonatal jaundice
Yellowish discoloration of skin and sclera because of increase serum level of
bilirubin which may be indirect (unconjugated ) or direct (conjugated ) occur in 60%
of term infant & 80% of preterm infant
bilirubin metabolism
Bilirubin derived from breakdown of heme containing proteins &75% of heme from
senescent RBC Hb in RE system .Other 25% of heme containing protein from Hb of
ineffective erythropoiesis in the BM & from myoglubin , cytochromes , catalase &
free heme .
Each heme containing protein as Hb ,the protein (globulin ) & iron will go to
circulation & heme oxidized by heme oxygenas to biliverdin which reduced by
biliverdin reductase to bilirubine which is indirect (unconjugated ) non polar water
insoluble (not excreted in urin ) that is bind to albumin at specific binding site . This
albumin binded bilirubin is not toxic to CNS .
If the binding sites become saturated with bilirubin (if free unconjugated bilirubin
high ) or competitive compound as sulfonamide , sulfisoxazole & FFA ,these will
lead to increase free bilirubin which may enter CNS & causing
toxicity &
kernicterus
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Non polar water insoluble & fat soluble (unconjugated) indirect bilirubin
dissociated from albumin at hepatocyte where bound to cytoplasmic ligandin (Y
protein ) for transport to smooth endoplasmic reticulum (phenobarbitone increase
ligandin in endoplasmic reticulum ).
Conjugation will occur in liver when indirect water insoluble unconjugated
bilirubin converted by UDPGT (Uridin Diphosphate Glucuronyl Transferase) forming
Conjugated direct bilirubin (monoglucuronide & diglucuronide ) which is water
soluble capable of biliary & renal excretion . UDPGT & ligandin is lower in the new
born ( especially preterm ) in contrast to adult .
Conjugated bilirubin is excreted in the biliary tree & enters GIT where by effect of
intestinal Bacteria that converts bilirubin to urobilinogen & stercobilin that is
excreted in the urine & stool respectively .
Some of the conjugated bilirubin in GIT may be reconverted to unconjugated
bilirubin by intestinal bilirubin glucuronidase then again reabsorbed go back to liver
,this is called enterohepatic circulation .
Enterohepatic circulation may increase in some new born & in patients with pyloric
stenosis, intestinal Atresia, meconium ileus , Hirschprung`s disease & decrease oral
intake . but it decreased by intestina bacteria
Risk Factors for Development of Severe Hyperbilirubinemia in Infants of
35 or More Week's Gestation
Major risk factors
Predischarge TSB ( total serum bilirubin) or level in the high-risk zone
Jaundice observed in the first 24 hr
Blood group incompatibility, other hemolytic disease (G6PD deficiency)
Gestational age 35–36 wk
Previous sibling received phototherapy
Cephalohematoma or significant bruising
Exclusive breast feeding, particularly if nursing is not well and excessive
weight loss excessive
East Asian race
Minor risk factors
Predischarge TSB level in the high intermediate -risk zone
Gestational age 37–38 wk
Jaundice observed before discharge
Previous sibling with jaundice
Macrosomic infant of a diabetic mother
Maternal age ≥25 yr
Male gender
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Decreased risk
TSB or level in the low-risk zone
Gestational age ≥41 wk
Exclusive bottle feeding
Black race
Discharge from hospital after 72 hr
CAUSES INDIRECT (UNCONJUGATED ) NEONATAL HYPERBILIRUBINEMIA
1. Physiolgical jaundice
2. Over production (hemolysis ) include :Blood group incompatibility . ( Rh , ABO , subgroup as kell, Duffy )
RBC enzyme defect as G6PD deficiency , pyruvate kinase deficiency.
Hereditory spherocytosis, elliptocytosis
Hb pathy (alpha thalasemia )
Acquired hemolysis (infection , drug vit K sulfonamide )
Extravascular bleeding as (petechiae , hematoma , pulmonary cerebral ,or
occult hemorrhage
Polycythemia as materno-fetal or feto-fetal transfusion , delay clamping of
umbilical cord .
3. Increase enterohepatic circulation as pyloric stenosis , meconium plug
syndrome , hirschsprung disease , intestinal atresia or stenosis including
annular pancreas, fasting or hypoperistalses, drug induce paralytic ileus,
swallowed blood .
4. damages or reduces the activity of the transferase enzyme or other
related enzymes (hypoxia, infection, thyroid deficiency , genetic deficiency
that is called Familial non hemolytic defect in conjugation as Crigler najjar ,
Gilbert disease ,also inhibition of conjugation by drug
5. Decrease bilirubin uptake across hepatocyte due to competitive
inhibition
as drug or breast milk jaundice &lucey
Miscellaneous as hypothyroidism , hypoxia, acidosis
Driscoll synd.
6. Breast milk jaundice
7. Miscellaneous as sepsis, UTI ,hypoglycemia , infant of diabetic mother .
8. drug such as oxytocin and chemicals used in the nursery such as phenolic
detergents .
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PHYSIOLOGICAL JAUNDICE
most common cause of jaundice in the neonatal period ,
it is usually appear in
2nd or 3rd day of life in full term infant &
3rd or 4th day in premature
peak usually (6-8 mg/dL ) & not > 12 mg / dL in 3rd day in full term
and usually (10-12 mg/dL) & not > 15 mg/dL in 5th day in preterm .
usually disappear by 4 – 5 days ( rarely by 7 -10 days ) in full term
and usually by 7 - 9 days
( rarely by 10 days - 2wk ) in preterm .
Increase of bilirubin should be not > 5mg/dL/ 24 hr or not > o.5 mg/dL/hr
Physiological jaundice may be attributed to
increase production of bilirubin due to increase RBC volume per kilogram &
decrease RBC survival (70-90 ) days in infant versus 120 days in adult . and
also increase ineffective erythropoiesis and increase turn over of non
hemoglobin heme proteins .
increase enterohepatic circulation by high level of intestinal betaglucuronidase, decrease intestinal bacteria , decrease gut motility with poor
evacuation of bilirubin laden meconium .
defective uptake of bilirubin from plasma by decrease ligandin
defective conjucation due to decrease of UDPG-T
decrease hepatic excretion of bilirubin
Physiological jaundic may be exaggerated (increase peak & duration)
when there is a risk factors as ; breast feeding , male sex , cephal hematoma ,
cutanouse bruising , polycythemia , weigh loss , dehydration , caloric
deprivation , delay bowel movement , maternal DM , drug ( K3 , novobiocin
oxytocin ), trisomy
The jaundice should not regarded as physiological and should
regarded as pathological and must be investigated if
It appeare in the 1st 24 houre
TSB increasing > 5mg/dL/ 24 houre or > o.5 mg/dL/houre
TSB >12 mg /dL in full term or >14mg/ dL in preterm .
Duration of jaundice > 10-14 days or present at or beyond age 2 wk
Jaundice appears excessive for infant's age
Direct bilirubin >2 mg/ dL at any time or pale stool, dark urin +ve bilirubin.
sign of kernicterus ,
Sick infant or associated with vomiting lethergy poor feeding Weigh loss,
apnea bradycardia hypothermia or When there is pallor ,Hsmegally ,
TSB rising rapidly crossing percentiles and unexplained by history and
physical examination
family History of hemolytic disease ,
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TSB concentration approaching exchange levels or not responding to
phototherapy
JAUNDICE IN THE 1ST 24 HOURS
Erythroplastosis fetalis (hemolysis); ABO & Rh . other cause of hemolysis as
G6PD , Pyruvate Kinase deficiency , spherocytosis & so on
Concealed hemorrhage (cephal hematoma ,hepatic &
spleenic hemorrhage
Sepsis .
Congenital infection (CMV, Rubella, Toxoplasmosis
PROLONGED JAUNDICE (DURATION MORE THAN 2 WEEKS & MAY
PERSIST IN AND BEYOND 1ST MONTH CAUSES INCLUDE
Hemolysis
Hypothyroidism
Hereditory glucuronyl transferase defeciency
Breast milk jaundice .
Intestinal obstruction . Pyloric stenosis
idiopathic neonatal hepatitis
Hyperalimentation & cholestasis .
Hepatitis, CMV, Syphilis & toxoplasmosis , TORCH
Galactossaemia .
Biliary atresia .
Inspissated bile syndrome follow hemolytic a nemia
Breast milk jaundice
one of the causes of prolonged neonatal unconjugated hyperblilirubinemia
when patient may or may not has physiological jaundice at beginning
develop significance elevation of bilirubin between 1st & 2nd week (usually
after 7th day ) of life reach maximum10-30 mg/ dL ( rarely more than 20
mg/dL ) during 2nd-3rd week. The cause is unclear but in some the milk
contain glucuronidase that increase enterohepatic circulation which lead to
increase unconjugated blilirubin , if breast feeding continue the jaundice
persist for 3-10 weeks at lower level , but if we stop breast feeding there will
be rapid decrease reach normal level within few days with out return of
hyperblilirubinemia when re-start breast feeding
Befor Dx of Breast milk jaundice we have to exclude other causes of
unconjugated hyperblilirubinemia as hemolysis hypothyroidism .
For treatment we have to stop breast feeding for 1-2 days . some times
phototherapy may be needed, very rarely kernicterus has been reported
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THIS
BREAST MILK JAUNDICE SHOULD BE DISTINGUISHED FROM
BREAST-FEEDING JAUNDICE
BREAST-FEEDING JAUNDICE
early-onset, exaggerated phyasiolgical unconjugated hyperbilirubinemia (>12
mg/dL) , in 1st week of life, in breast-fed infants which may be due to decreased
milk intake with dehydration and/or reduced caloric intake. Increased by giving
glucose water that cause reduced caloric intake of breast milk.
Prevented & reduce the incidence by frequent breast-feeding (>10 time /24 hr),
night feeding, discouraging 5% dextrose or water supplementation .
Familial Non Haemolytic Uncojucated Hyperbilirubinaemia :
( inherited deficient conjugation of bilirubin )
• a group of inherited disease associated with different degrees of decrease in hepatic
UDPG-T
• Crigler Najjar type 1 abscence enzyme
• Crigler Najjar type 2 partial defect in hepatic enzyme
Crigler Najjar type 1 abscence enzyme
Rare , transmitted as AR
clinically presented with severe unconj. Hyperbilirubinaemia with no hemolysis ,
develop in 1st 3 days of life which may reach 25 – 35 mg /dL during the 1st month
& may continue after that .
kernicterus is a common complication .
Diagnosis based on
Highe level of unconjogated Bilirubin with no hemolysis
Bilirubin in bile is<10mg/dL in contrast to normal 50 –100 mg / dL
No rseponse to phenobarbitone ( differentiated from type 2 )
Definitive Dx is established by measuring hepatic glucuronyl transferase
activity in liver specimen . Done by close biopsy not open because surgery
& anaesthesia may precipitate kernicterus
DNA Dx .
Treatment
Neonatal period may need continuous phototherapy & repeated exchange
transfusion to prvent kernicterus . After neonatal period risk of kernicterus
still present but with level > 35 mg/dL so we have to put the patient on
phototherapy ( usually we put children during night ) .
Cholestyramine or agar used to bind photobilirubin product & thus
interfere with enterohepatic circulation .
Rx of infection or any illness to prevent development of kernicterus .
Orthotopic hepatic transplant cure disease .
Plasmaphoresis
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Metacloporphyrin may be used which prevent heme oxygenase so inhibit
formation of bilirubin .
Genetic engineered enzyme Replacement
Liver direct gene therapy & hepatocyte transplant remain option in future
Crigler Najjar type 2 partial defect in hepatic enzyme
It is AR , partial defect in hepatic UDPG-T, may be present similar to Type 1 or may
be less severe even occasionally without neonatal manifestation . When present in
neonatal period unconjugated Hyperbilirubinaemia usually occurred in 1st 3 days
, TSB range may compatible with physiological or pathological level , Jaundice
persist in & after 3rd week between 1.5 – 22 mg/dL , K. is unusual , stool color is
normal .
Dx : - B. in bile is nearly normal , Jaundice respond dramatically to phenobarbital
5 mg / kg / day for 7 – 10 days
Bilirubin encephalopathy
► Kernicterus is a neurological syndrom result from the deposition
of
unconjugated (indirect ) bilirubin in the brain cell especialy basal ganglia . so
unconjugated bilirubin is toxic to CNS & when bilirubin exceed bilirubin Binding
capacity of albumin ,free bilirubin will cross blood brain barrier & diffuse to brain
cell & cause cell damage & Kernicterus.
► The precise level of indirect bilirubin which is toxic to the brain & the duration of
exposure was unknown but Kernicterus is unusual & rare in healthy full term at
bilirubin < 25 mg/dL with no hemolysis .
► There is some risk factor that increase possibility of Kernicterus at lower level
of bilirubin which may damage B.B.B. or decrease bilirubin binding capacity of
albumin as Hemolysis , hyperosmolality , IVH ( intraventricular hemorrhage )
acidosis, hypoalbuminemia , FFA ( free fatty acid ) , hypothermia, drug
,hypoglycemia, hypoxia , sepsis, asphyxia , meningitis , prematurity
► so for example premature LBW ( low birth weigh ) infant develop Kernicterus at
lower bilirubin level than 20-25 mg/dL or even 10mg/dL in very LBW.
►
Clinical manifestation
Onset usually in the 1st wk of life, may be delayed to 2nd–3rd week.
Signs & symptoms of Kernicterus usually appear at 2 –5 days in full term
& 7th day in premature but it can occur at any time in neonatal period .
The early signs are usually indistinguishable from sepsis , asphyxia ,
hypoglycemia & intracranial Hemorrhage .So early signs include poor
feeding , lethargy , loss of moro reflex , hypotonia ,high pitch cry ,
irritability .
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Then at end of 1st week & 2nd week the patient become gravely ill ,
prostrated , respiratory distress , pulmonary Hemorrhage , , bulging
fontanelle ,decrease tendon reflex , twitching of face or limbs , hypertonia
of extensor muscles, opisthotonos, retrocollis, shrill high pitch cry ,
convulsion , rigidity is rare .
Many infant who reach this stage are die & most of survival usually develop
later complete neurological syndromes but may appear to recover for 2–3
month (appear with little abnormality )
Later in the 1st year opisthotonos , muscle rigidity , increase deep tendon
reflexes , irregular movement , hypertonia ,obligatory tonic neck reflex &
convulsion .
In 2nd year opisthotonos , seizure abate but irregular involuntary movement
rigidity , hypertonia or in some hypotonia increase steadily.
By 3 year complete neurological syndrom develop which include
chorioathetosis , involuntary muscle spasm , extrapyramidal signs , fit , MR ,
dysarthritic speech , high frequency hearing loss , spastic quadriplegia , teeth
discoloration , enamel dysplasia .
Pyramidal signs , hypotonia , ataxia may occur in few
►
prevention
Screening for hyperbilirubinemia & presence of risk factors in the 1st 24–
48 hr of life to detect infants at high risk for severe jaundice by physical
examination and lab
early follow-up for jaundice of infant discharged early (<48 hr) within 1st 24 hr
–3 days of discharge .
early measurement & follow up of serum bilirubin level in any jaundiced
neonate treatment accordingly .
check bilirubin in jaundiced infant in 1st 24 hr & evaluated for possible
hemolytic disease;
avoid (visual) assessment in estimation of the severity of jaundice by;
Parental communication to concerns about infant's skin color & education
about potential risks and neurotoxicity.
Mothers should be advised to nurse infant every 2–3 hr in order to ensure
adequate hydration and caloric intake and avoid routine supplementation with
water or glucose water
Treatment of condition that increase risk of K. like sepsis , acidosis , asphyxia
,IVH ….etc .
Prevention of Rh isoimmunization where Any pregnant Rh –ve woman giving
her human Anti D globulin when she delivered Rh +ve baby or develop
abortion.
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