Neonatal Jaundice

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Dr. Kalpana MallaMD Pediatrics

Manipal Teaching Hospital

• Incidence Term—60% Preterm—80%• Bilirubin Source – Hb – 75% Non Hb – 25% (Myoglobin)

Normal Physiology• Bilirubin -breakdown of hemoglobin• Unconjugated bilirubin (insoluble in water)

transported to liver- Bound to albumin • Transported into hepatocyte (Ligandin / y-

protein ) & conjugated - With glucuronic acid → now water soluble

• Secreted into bile

Normal Physiology

• Secreted into bile• In ileum & colon, converted to stercobilin • 10-20% (Deconjugated by β glucuronidase)

reabsorbed into portal circulation (Enterohepatic circulation )and re-excreted into bile or into urine by kidneys - urobilinogen

Bilirubin Metabolism

Glucuronyl TransferaseUnconjugated

(Bilirubin Diglucuronide)

NEWBORN JAUNDICE(PHYSIOLOGICAL)

Etiology1. Decreased RBC survival 90 days, increased RBC

vol /Kg, polycythemia of NB2. Poor hepatic uptake due to immature liver-

decreased ligandin or Y- protein3. Poor conjugation due to enzyme deficiency-

UDPG-T activity

NEWBORN JAUNDICE(PHYSIOLOGICAL)

4. Increased enterohepatic circulation due to - High level of intst beta-glucoronidase - delayed colonization by bacteria - Decreased gut motility5.Decreased hepatic excretion of bilirubin

PHYSIOLOGICAL JAUNDICE• Seen both in term and preterms

• Self limiting

• Develops after 24 hours

• Peaks by day 4- 5 in terms and day 7-8 in preterms

• Peak levels -12mg/dl in term & 15mg/dl in preterm

• Gradually subsides by 10-14 days

• No Treatment necessary

PATHOLOGICAL JAUNDICE

Suspect if...• Jaundice in first 24 hours• Rise of >5mg/24 hours or 0.5

mg/dl/hr• Jaundice beyond

physiological limits• Conjugated bilirubin- >2mg or

20% of total• Beyond 2 weeks• Signs of underlying illness ++

Pathological Jaundice - Hemolytic causes (unconjugated)

Coombs' test positive

–Rh incompatibility

–ABO incompatibility

Coombs' test negative

–Red blood cell membrane defects

–Red blood cell enzyme defects

–Drugs

–Hemoglobinopathies

–Sepsis

Pathological Jaundice - Non-hemolytic (unconjugated)

Extravascular sources

- cephalohematoma

- Polycythemia:- fetal-maternal

transfusion, - delayed cord

clamping- twin-twin

transfusion

Increased Enterohepatic circulation

– Cystic fibrosis– Ileal atresia– Hirschsprung's

disease– Breast milk

jaundice

Pathological Jaundice – Defective

Conjugation(unconjugated)

• Crigler-Najjar syndrome types 1 and 2

• Gilbert syndrome

• Hypothyroidism

• Breast milk jaundice

Pathological Jaundice – Defective Conjugation

Metabolic disorder:

• α1 AT deficiency

• Cystic fibrosis• Galactosemia • Gaucher's disease• Niemann-Pick

disease• Hypothyroidism

Chromosomal disorders

• Turner's syndrome,

• trisomy 18 and 21

Pathological Jaundice – Defective excretion

Biliary obstruction:• biliary atresia• choledochal cyst• Sclerosing

cholangitis • Dubin-Johnson

syndrome • Rotor's syndrome

Infection: • Sepsis• UTI• STORCH

infections

Causes of Jaundice –as per time of onset

Within 24 hrs• HDN—Rh, ABO Incompatibility• IU infections-CMV, HSV, Toxo, Syphilis• RBC Enzyme deficiencies-G-6PD defi, pyruvate kinase deficiency• Drugs—large dose of vit k , syntocin drip, Salicylates, sulphas etc• Hereditary Spherocytosis• Criggler-Najjar syndrome• Alpha thalassemia

24-72 hrs—Physiological Jaundice Exaggerated Physiological

Jaundice

(MATERNAL FACTORS)• -Blood type ABO or Rh incompatibility • -Breastfeeding

• -Drugs: Diazepam, Oxytocin

• -Maternal illness: gestational diabetes

Exaggerated Physiological Jaundice

(neonatal factors)• Birth trauma: cephalohematoma,

cutaneous bruising, instrumented delivery • Drugs: Erythromycin, Chloramphenicol • Immaturity ▪ Birth asphyxia Acidosis ▪ Cretinism

• Hypothermia • Hypoglycemia• Hypothyroidism • Polycythemia

After 72 hrs (within 2 weeks)

• Septicemia• Neonatal Hepatitis, other IU infections• Extra hepatic Biliary atresia• Breast milk jaundice• Metabolic diseases—galactosaemia, CF, alpha-

1 antitrypsin deficiency, hypothyroidism• Hypertrophic Pyloric stenosis

Diagnosis1)History—Antenatal Drugs Trauma Family H/O of jaundice Liver disease H/O delayed feeding Sepsis Sibling jaundice Splenectomy in family

2. General exam

• Cramer’s Index1.Face-4-6 mg/dl2.Chest &Upper trunk – 8-10 mg/dl3.Lower abdomen,thigh-12 -14mg/dl4.Forearms &lower legs -15 -18 mg/dl• Palms & sloes->15-20 mg/dl

Examine • Gestation age-preterm, IUGR• Cephalhematoma, bruising• Pallor-hemolytic anemia• Patechiea -sepsis, erythroblastosis, cong infections• HSM-hemolytic anemia, cong infections• Evidence of hypothyroidism, cong infections

3) Lab investigations

1. Hemoglobin, PCV with peripheral smear2. Total Bilirubin (Total / Direct & Indirect) - >12 mg /<24hr - <12 mg/ >24 hr3. Bilirubin level –Special tests –

– TORCH titres - Thyroid function tests

– Metabolic work up - Sepsis screen– USG / X ray abdomen

• Blood group and Rh typing• Reticulocyte count

Investigations in RH incompatibility

• Antenatal - (mother Rh-ve, previous baby Rh + ve, father Rh +ve.

1) H/o of abortion, H/o having taken Anti D gammaglobulin

2) USG for baby maturation ,HSM, ascites, hydrominos, gen. anasraca

Investigations in RH incompatibility

• Antenatal - - Blood grp (ABO & Rh) of father ,earlier baby - Indirect Coomb’s test – to detect antibodies in mother’s serumIgG Anti body Titre to D TO be estimated at 12-16,28-

32 and 36 weeks. If anti D antibody Titre 1:16 it should be tested serially

- Ab titre in mother’s blood ->1:64 dignostic of HDN- TO CONSIDER TERMINATION OF PREGNANCY.

Investigations in RH incompatibility

• Anmiocentesis:- Look for lecithin sphingomyelin ratio to suggest

maturity.- Shake test for 15 sec. with equal vol etanol 95%-

allowed to stand-ring of buble at the disc- Optical density-by spectrophotometer OD.>0.15

denotes maturity of lungs- Alpha feto protein level increased –rh issoimun- Fetal bloob grp prenatally – amniocentesis

POSTNATAL INVESTIGATION BABY

Cord blood—all babies of Rh-ve mothers, all Unknown blood groups, all with prior h/o jaundice in earlier babies

Blood group-both mother and baby - For evidence of hemolysis – Direct Coombs test Reticulocyte count - >10 suggest hemolysis. Hemoglobin cord Peripheral smear -RBC morphology Bilirubin

Others

RBC membrane defects• RBC enzymes –G-6-PD screenNeonatal hepatitis – LFTMetabolic studies – including hypothyroidismBiliary obstruction – USG,HIDA scan• PCV inc polycythaemia

Flow chart Jaundice >12mg/dl,age <24 hrs

<12mg/dl,age>24 hrs ↓ DCT............................. Negative ↓ ↓Positive Direct bilirubin ↓ >2mg/dlRh, ABO ,Others Hepatitis, TORCH, Sepsis, Biliary obstruction

Negative

Positive

Direct bilirubin < 2mg/dl Htc →high → polycythemia RBC Morpho, Retics ↓Abnormal NormalHemolytic A Breast milk J, Sepsis, IEMH.sperocytosis Hypothyroidism, asphyxia, ∝-

thalassemia physiologic J, DIC,Drugs ,ABO incom H.Pyloric stenosis

lowlow

MANAGEMENT

• Phototherapy• Drugs• Exchange

transfusion

MANAGEMENT OF JAUNDICE• To Decrease Bilirubin: -↑↑ excretion Phototherapy, ET - ↑↑ conjugation phenobarbitone - ↓ enterohepatic circ- Agar, Cholestyramine - Inhibit Bili production—metalloporphyrins - Inhibit haemolysis high dose IVIG - Inc albumin binding—Albumin

PHOTOTHERAPY

Phototherapy -MTH

Phototherapy -MTH

Phototherapy• Safe and effective method for

treatment of neonatal jaundice• Bilirubin absorbs light maximum at

420-460 nm

Mechanism of Action

Conversion of insoluble Bilirubin into soluble bilirubin

1.Photo-isomerization-conversion into soluble form – takes place in extravascular space of skin –conversion to less toxic polar isomer-diffuses into the blood –excreted easily into bile

2.Structural isomerization - conv to lumirubin -rapidly excreted in bile and urine

3. Photo-oxidation- of Bilirubin to water soluble polymers colourless by product.

Indications for Phototherapy

• TSB > 15 mg % in term• TSB > 12 mg% in preterm• TSB > 5 mg% within 24 hours• Adjuvant to exchange transfusion• Prophylactic PT – ELBW, bruised

babies, hemolytic disease of NB,VLBW with Perinatal risk factors

Indications

• Precautions– Cover the eyes and Genitals– Supplemental hydration– Watch for side effects

Procedure

• Best is narrow spectral blue lights (425-475nm)

• White lamps (380-700nm)• Distance from skin – 45cm

• Intensive PT – 15-20 cm• Shield eyes & genitalia• Space of 5-8cm between

phototherapy unit & incubator

• Double surface PT – can be given by fiber-optic blankets (biliblankets)

• Change position once in every 2-4 hrs

• Skin bleached by PT• Level to be checked every 10-20

hrs• Frequent temperature monitoring

& daily weight check

Side Effects

• Immediate – – Loose stools– Dehydration,– Hyperthermia,– ‘Bronze baby’ syndrome,– Rashes,– Upsets maternal infant interactions (bond)

• Late ––Risk of skin malignancies–Damage to intracellular DNA–Retinal damage–Disturbance in circadian rhythm Testicular damage

Biliblanket or glow-worm ?

Home phototherapy

DRUGS

• Phenobarbitone – increase y and z ligands

-induces liver ezymes - ↑↑ conjugation phenobarbitone

• Metalloporphyrins (tin and zinc porphyrins and meso prophyrins)

-inhibits heme oxygenase

• IVIG - Inhibit haemolysis• Oral agar, Cholestyramine-↓ enterohepatic

circ• Albumin infusionsInc albumin binding

• Exchange blood transfusion -- changing the babies blood with the other blood.

• Usually in hemolytic disease of newborn.

• It removes partially hemolysed and antibody coated RBCs and also billirubin

Methods of exchange

• Single volume exchange- 80ml/kg• Double volume exchange-

160ml/kg (87% of infant blood volume exchanged with new blood)

• Triple volume exchange.

Partial exchange transfusion

• Polycythemia• Chronic anemia with heart failure• Hydrops fetalis. • Observed pcv - desired pcv X 100 /

observed pcv.

Exchange Transfusion

Indications:• Rh and ABO incompatibility• Unconjugated billirubin > 20 -25mg/dl

in term, >15 -18mg/dl preterm babies. Sick neonates exchange at lower level

• Septicemia /DIC/ sclerema• Neonatal ITP• Severe anemia due to any cause with HF

Exchange Transfusion(Indications)

• Early Kernicterus• Cong H Sperocytosis• G-6- PD deficiency• Hepatic coma

In Hemolytic disease of the newborn (ABO / Rh)

• H/O previous severely affected infant• Cord Hb <10gm% & bilirubin > 5mg/dl• Rate of rise of bilirubun > 0.5mg/100ml/hr• Jaundice in first 24 hrs of life• Signs of hemolysis-clinical or lab• Maternal ab titer > 1in 64• Positive DCT• Preterm LBW with hyperbilirubinemia• Reticulocyte >10

Rh incompatibility• Due to Rh D-Ag• < 1 mL of Rh-positive fetal blood is sufficient to

sensitize the mother• 90% sensitization during delivery/abortion• So , most first born infants are not affected due

to the short period of exposure which is insufficient to produce a significant maternal Ig G antibody response.

Rh incompatibility

• Sensitized mother produces Ab –IgG types—crosses placenta

• Once sensitized –small doses of Ag stimulate high Ab titer .

• So, risk and severity of sensitization response increases with each subsequent pregnancy with Rh-positive blood fetus

ABO incompatibility• Mother is type O and the baby is either type A or

B. • O +ve Mothers makes antibodies which are IgM

& (IgG) types - IgG types crosses the placenta • No effects if the mother & baby have same blood

group or baby is grp O, as there is nothing to make antibodies against.

ABO incompatibility

• If mother - type A or B Makes antibodies (IgM) type so does not cross the placenta

So, even if baby has a different blood type no effect

Selection of blood

• Blood group O – no antigen Ab –anti -A, anti-B• Blood group A – antigen A Ab - Anti-B• Blood group B –antigen B Ab – anti -A

Blood for exchange transfusion

• Fresh CPD blood• Rh HDN-• ABO incompatibility -

Selection of blood • In Rh incompatibility: (O,A,B,AB-Negative) choice -Rh negative – - Preferably baby’s ABO - O group cross matched against

maternal serum• In ABO incompatibility – “O” blood group same as

baby’s Rh ( +/-) with low titre of Anti A and Anti B antibodies OR ABO type specific blood cross matched against infant serum

- Septicemia – Same as baby’s ABO and Rh

Investigations

• Pre exchange: Hb%, PCV, billirubin, glucose K+, Ca+.

• Post exchange: Hb%, PCV, billirubin, glucose, Calcium, K+, culture.

Procedure• IN NICU OR OT• Radiant warmer, Monitor HR, BP and

other vitals, infants arms and legs are restrained.

• Assistant to record volume in & out, to check vitals.

• Blood pre warmed to 37 c• Dried umbilical cord soaked with wet

gauze.• Canulation of umbilical vein- 12

o’clock

• Catheter inserted till free flow of blood or SHOULDER UMBILICAL LENGTH.

• Small aliquots of blood removed 5 to10ml -PUSH PULL method.

• Blood in the bag gently mixed.• Procedure over 1 to 2 hr. • Tie around the cord for 1 hr, or hold

tightly at the end of procedure.

Complications• Hypocalcemia and Hypomagnesemia -

Citrate in CPD blood.• Hypoglycemia• Metabolic alkalosis or acidosis.• Hyperkelemia.• CVS: overload and arrythmias• Infections: HBV HIV• Hemolysis• Hypothermia, NEC.

Other roots for exchange

• Umbilical vein cut down- incision above umbilicus in midline.

• Femoral vein canulation with radial artery canulation.

Guidelines for management of hyperbilirubenemia

Gestation and birth wt.

Phototherapy( healthy)

Exchange(healthy)

Phototherapy(sick)

Exchange(sick)

Preterm:

<1000gm. 5-7 11-13 4-7 10-12

1001-1500 7-10 13-15 6-8 11-13

1501-2000 10-12 15-18 8-10 13-15

2001-2500 12-15 18-20 10-12 15-18

Term:

2500 15-18 20-25 12-15 18-20

Breast milk jaundice

• Late onset• Due to factors in breast milk –Interfere with

bilirubin conjugation: - Pregnanediol - Free fatty acids - β-glucoronidase• Instead of ↓by 7 days it continues to rise may

go upto 20-30mg/dl by 2nd-3rd wks of age & return to normal by 4-12 wks

Management

• Stop breast feeding -48 hrs • Again resume it, bilirubin may rise again but

not reach previous high level

Breast feeding jaundice

• Decreased intake of milk leads to increased enterohepatic circulation

• Higher levels on day 4 compared to formula fed babies due decreased intake of milk

Prevention

1. Anti D to be given to the mother after delivery of the baby-within 48hrs. Also can be given to all unsensitized mothers at 28-32 weeks of gestation

2. Amniocentesis and IU transfusion to severely affected babies

3. Preterm delivery of severely affected babies4. Cord blood studies-followed by Phototherapy5. Exchange transfusion

KERNICTERUS

• Entry of unbound bilirubin into brain as free or albumin bound bilirubin

• Acidosis affects bilirubin solubility• Hyperosmolarity, anoxia and

hypercarbia disrupt BBB

• Yellow staining of brain assc with neuronal injury

• Affects basal ganglia, cranial nerve nuclei, brain stem nuclei, hippocampus and AHC of spinal cord (cortex usually spared)

• Necrosis, neuronal loss and gliosis …pathological findings

ACUTE BILIRUBIN ENCEPHALOPATHY

• STAGE 1: hypotonia, lethargy, high pitched cry and poor suck (D1-3)

• STAGE 2: hypertonia, opisthotonus, rigidity, oculogyric crisis, retrocollis, fever, seizures. (2nd week)

• Those who survive develop chronic bilirubin encephalopathy

• STAGE 3: Hypotonia replaces hypertonia after 3rd week age

CHRONIC BILIRUBIN ENCEPHALOPATHY

• Choreo-Athetosis• Partial or complete sensorineural

hearing loss• Limitation of upward gaze• Dental dysplasia• Intellectual deficits

LOW BILIRUBIN KERNICTERUS

• In LBW babies, preterms• Overt changes not seen• Other factors: IVH, drugs, benzyl

alcohol• More likely to suffer from anoxia,

hypercarbia and sepsis

TREATMENT

• Phototherapy• Exchange transfusion• Albumin infusion• Anticonvulsants: phenobarbitone• BERA at follow up

Neonatal cholestasis

Intrahepatic extrahepaticHepatocyte injury bile injury EH –biliary atresiametabolic viral intrahepatic bile duct paucity idiopathic neonatal hepatitis

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