Neonatal Jaundice Dr Kalpana Malla MD Pediatrics Manipal

Neonatal Jaundice Dr. Kalpana Malla MD Pediatrics Manipal Teaching Hospital Download more documents and slide shows on The Medical Post [ www. themedicalpost. net ]

• 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 / yprotein ) & 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 Unconjugated (Bilirubin Diglucuronide) Glucuronyl Transferase

NEWBORN JAUNDICE (PHYSIOLOGICAL) Etiology 1. Decreased RBC survival 90 days, increased RBC vol /Kg, polycythemia of NB 2. Poor hepatic uptake due to immature liverdecreased ligandin or Y- protein 3. 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 motility 5. 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 -12 mg/dl in term & 15 mg/dl in preterm • Gradually subsides by 10 -14 days • No Treatment necessary

PATHOLOGICAL JAUNDICE Suspect if. . . • Jaundice in first 24 hours • Rise of >5 mg/24 hours or 0. 5 mg/dl/hr • Jaundice beyond physiological limits • Conjugated bilirubin- >2 mg 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 - Nonhemolytic (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: • α 1 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-6 PD 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

Diagnosis 1)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 Index 1. Face-4 -6 mg/dl 2. Chest &Upper trunk – 8 -10 mg/dl 3. Lower abdomen, thigh-12 -14 mg/dl 4. 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 smear 2. Total Bilirubin (Total / Direct & Indirect) - >12 mg /<24 hr - <12 mg/ >24 hr 3. Bilirubin level –Special tests – – TORCH titres – Metabolic work up – USG / X ray abdomen - Thyroid function tests - Sepsis screen • 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 serum Ig. G Anti body Titre to D TO be estimated at 12 -16, 2832 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 HDNTO 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 screen Neonatal hepatitis – LFT Metabolic studies – including hypothyroidism Biliary obstruction – USG, HIDA scan • PCV inc polycythaemia

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

Direct bilirubin < 2 mg/dl Htc →high → polycythemia low RBC Morpho, Retics ↓ Abnormal Normal Hemolytic A Breast milk J, Sepsis, IEM H. sperocytosis Hypothyroidism, asphyxia, ∝thalassemia physiologic J, DIC, Drugs , ABO incom H. Pyloric stenosis

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 (425475 nm) • White lamps (380 -700 nm) • Distance from skin – 45 cm • Intensive PT – 15 -20 cm • Shield eyes & genitalia • Space of 5 -8 cm 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

Home phototherapy Biliblanket or glow-worm ?

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 infusions Inc albumin binding

• Exchange blood transfusion -- changing the babies blood with the other blood. • Usually in hemolytic disease of newborn. • It removes partially hemolysed antibody coated RBCs and also billirubin

Methods of exchange • Single volume exchange- 80 ml/kg • Double volume exchange- 160 ml/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 -25 mg/dl in term, >15 -18 mg/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 <10 gm% & bilirubin > 5 mg/dl Rate of rise of bilirubun > 0. 5 mg/100 ml/hr Jaundice in first 24 hrs of life Signs of hemolysis-clinical or lab Maternal ab titer > 1 in 64 Positive DCT Preterm LBW with hyperbilirubinemia Reticulocyte >10

Rh incompatibility • Due to Rh D-Ag • < 1 m. L 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 –Ig. G 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 Ig. M & (Ig. G) types - Ig. G 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 (Ig. M) 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 to 10 ml -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. Photother Exchange apy( (healthy) apy(sick) healthy) Preterm: <1000 gm. 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 20 -25 12 -15 18 -20 Term: 2500 15 -18

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 -30 mg/dl by 2 nd-3 rd 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 48 hrs. 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 babies 4. Cord blood studies-followed by Phototherapy 5. 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 (D 1 -3) • STAGE 2: hypertonia, opisthotonus, rigidity, oculogyric crisis, retrocollis, fever, seizures. (2 nd week) • Those who survive develop chronic bilirubin encephalopathy • STAGE 3: Hypotonia replaces hypertonia after 3 rd 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 Hepatocyte injury metabolic extrahepatic bile injury EH –biliary atresia viral intrahepatic bile duct paucity idiopathic neonatal hepatitis

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