Approach to child with Neonatal Hyperbilirubinemia.pptx

How to assess jaundice in newborns

1. Approach to a child with Neonatal Hyperbillirubinemia Dr . Amit Anand M.D Pediatrics

2. Neonatal Jaundice (Hyperbilirubinemia) Definition: Hyperbilirubinemia refers, excessive level of bilirubin in the blood. Characterized by jaundice, a yellowish discoloration of the skin, sclera, mucous membranes and nails.

3. Visible form of bilirubinemia Adult sclera >2mg / dl Newborn skin >5mg /dl

4. Jaundice more common in newborn INCIDENCE: Full term infants: at least 60%. Preterm infants: over 80%. 6-10% require phototherapy/ other therapeutic options.

5. 1g Hb yields-34mg BR 1g Albumin binds to 8mg BR Newborn : 6-10mg/kg/day Adult : 3-4 mg/kg/day SER

6. Conjugated bilirubin (Direct ) •In bile • Conjugated with glucuronic acid • Polar ,Water soluble , cannot cross B-B-B • Excreted in urine and stool Unconjugated bilirubin (Indirect ) • Bind to albumin in plasma • Non polar ,Fat soluble • Can cross B-B-B (KERNICTERUS !) • High mol wt cannot filter in kidney • Toxic in high level to brain Types of Bilirubun

7. 1. Increased bilirubin production . Hemolytic disease is the most common cause of hyperbilirubinemia . This includes RBC disorders such as isoimmunization (e.g., Rh ,ABO and minor blood group incompatibility), Erythrocyte biochemical abnormalities such as glucose-6-phosphate dehydrogenase or pyruvate kinase deficiencies, ETIOLOGY OF UNCONJUGATED HYPERBILIRUBINEMIA

8. Abnormal erythrocyte morphology such as hereditary spherocytosis (HS). Other: sepsis, sequestered blood due to bruising or cephalohematoma , and polycythemia 2. Decreased bilirubin clearance a. Mutations in the gene that encodes UGT1A1 decrease bilirubin conjugation, reducing hepatic clearance and increasing serum TB levels. b. Crigler-Najjar syndrome due to either absent UGT activity (type I) or reduced UGT activity (type II) results in severe hyperbilirubinemia .

9. c. Gilbert syndrome results from a mutation in the promoter region of the UGT1A1 gene, reducing production of UGT, and is the most common inherited disorder of bilirubin glucuronidation . d . Polymorphisms of the organic anion transporter protein OATP-2 may lead to severe hyperbilirubinemia , especially when combined with a UGT1A1 mutation.

10. e . Decreased clearance may occur in infants of diabetic mothers congenital hypothyroidism, galactosemia , and other inherited metabolic disorders.

11. 3. Increased enterohepatic circulation . Pathologic conditions leading to increased enterohepatic circulation include Decreased enteral intake including breastfeeding failure breast milk jaundice; OR Impaired intestinal motility due to intestinal atresias , meconium ileus , or Hirschsprung disease.

12. Breast feeding jaundice Breast milk jaundice Incidence 5-10 % of newborn 2 . 4 % of newborn Etiology & pathogenesis Decrease intake of breast milk leads to increased enterohepatic circulation WEIGHT LOSS + Due to either a/w Gilbert Syn or a factor in breast milk ( B- glucuronidase  deconjugate intestinal bilirubin & promotes its absorption) Day of appearance Similar to physiological jaundice 4 to 7 days of age Duration of jaundice Less than 3 weeks 3 – 10 weeks. Bilirubin level may reach upto 20-30 mg/dl Treatment Adequate breast feeding Not harmful Good Weight gain Aggravating factors Dehydration Nil as there is no hemolysis

13. Causes of jaundice based on age at onset Within 24 hours Hemolytic disease of new born Rh incompatibility ABO incompatibility Intra uterine infection Toxoplasmosis, CMV, Rubella Deficiency of red cell enzyme G6PD deficiency, pyruvate kinase deficiency Others - Eryhthroblastosis fetalis , concealed hemorrhage ,

14. PHYSIOLOGICAL JAUNDICE CRIGLER- NAJJAR SYNDROME EARLY ONSET BREAST MILK JAUNDICE Onset- 24 to 72 hours of life

15. Onset – after 72 hours of age Septicemia EHBA Breast milk jaundice Metabolic causes Galactosemia Tyrosinemia Hereditary fructosemia Gilbert syndrome Organic acidemia

16. Why does physiological jaundice develop? Increased RBC’s (Polycythemia) Shortened RBC lifespan Immature hepatic uptake & conjugation Increased enterohepatic Circulation

17. Can be aggravated & prolonged by Immaturity Cephalhematoma Birth asphyxia Hypothermia Breast feeding infection Physiological jaundice

18. Physiological versus pathological jaundice Physiological jaundice Jaundice due to physiological immaturity of neonates to handle increased bilirubin production. Pathological jaundice When TSB concentrations are not in ‘physiological jaundice’ range

19. Physiological versus pathological jaundice PHYSIOLOGICAL PATHOLOGICAL Onset More than 24 hours Less than 24 hours Duration Term - <2 wks Preterm- <3 wks Term - >2 wks Preterm- >3 wks Serum bilirubin concentration Raise < 0.2 mg/dl/hr or < 5 mg/dl / day Raise > 0.2 mg/dl/hr or > 5 mg/dl / day TSB < 15mg/dl > 15mg/dl Involvement of palm and soles No Yes Signs of acute bilirubin encephalopathy No Yes Direct bilirubin Less than 2mg/ dl more than 2 mg/dl

20. Presence of one or more of following conditions would qualify a neonate to have pathological jaundice 1. Visible jaundice in first 24 hours of life. However slight jaundice on face at the end of first day (say 18 to 24 hr) is common and can be considered physiological . 2. Presence of jaundice on arms and legs on day 2 3. Yellow palms and soles anytime 4. Serum bilirubin concentration increasing more than 0.2 mg/ dL /hour or more than 5 mg/ dL in 24hours 5. If TSB concentration more than 95th centile as per age-specific bilirubin nomogram 6. Signs of acute bilirubin encephalopathy or kernicterus 7. Direct bilirubin more than 1.5 to 2 mg/ dL at any age 8. Clinical jaundice persisting beyond 2 weeks in term and 3 weeks in preterm neonates

21. Causes of pathological jaundice Common causes: Haemolysis: Blood group incompatibility - ABO, Rh and minor Enzyme deficiencies- G6PD deficiency Decreased conjugation Prematurity Increased enterohepatic circulation Breastfeeding jaundice, GI obstruction Extravasated blood Cephalhematoma, extensive bruising etc

22. EVALUATION OF INFANT WITH HYPERBILIRUBINEMIA

23. 1. Family history a . A family history of jaundice, anemia , splenectomy , or early gallbladder disease suggests hereditary hemolytic anemia (e.g., spherocytosis , glucose-6-phosphatedehydrogenase [G6PD] deficiency). b. A family history of liver disease may suggest galactosemia , α1- antitrypsin deficiency, tyrosinosis , hypermethioninemia , Gilbert disease, Crigler-Najjar syndrome types I and II, or cystic fibrosis. c. Ethnic or geographic origin associated with hyperbilirubinemia (East Asian, Greek, and American Indian) d . A sibling with jaundice or anemia may suggest blood group incompatibility or breast milk jaundice. A. History

24. 2. Pregnancy history a. Illness during pregnancy may suggest congenital viral or toxoplasmosis infection. b. Infants of diabetic mothers are more likely to develop hyperbilirubinemia ). c. Maternal drugs may interfere with bilirubin binding to albumin, making bilirubin toxic at relatively low levels ( sulfonamides ) or may trigger hemolysis in a G6PD-deficient infant ( sulfonamides , nitrofurantoin , antimalarials ).

25. 3. Labor and delivery history a. Birth trauma may be associated with extravascular bleeding and hemolysis . b. Oxytocin use may be associated with neonatal hyperbilirubinemia , although this is controversial. c. Infants with hypoxic-ischemic insult may have elevated bilirubin levels; causes include inability of the liver to process bilirubin and intracranial hemorrhage . d. Delayed cord clamping may be associated with neonatal polycythemia and increased bilirubin load.

26. 4. Infant history a. Delayed or infrequent stooling may be caused by poor caloric intake or intestinal obstruction and lead to increased enterohepatic circulation of bilirubin. b. Poor caloric intake may decrease bilirubin uptake by the liver. c. Vomiting can be due to sepsis, pyloric stenosis , or galactosemia .

27. B. PHYSICAL EXAMINATION Visual inspection of jaundice Examine the baby in bright natural light or white fluorescent light. No yellow or off white background Make sure the baby is naked Examine blanched skin and gums Note the extent of jaundice (Kramer’s rule) Depth of jaundice (degree of yellowness)

28. Where do you look for jaundice in newborn Forehead Tip of nose Chest Knee Palms and soles

29. Kramer’s rule

30. Kramer’s rule Zone 1= 5mg/dl Zone 2 = 5-10 mg/dl Zone 3 = 10-12 mg/dl Zone 4 = 15mg/dl Zone 5 = >15mg/dl

31. Jaundiced infants should have a bilirubin measurement and be examined for the following contributing factors: 1. Lower gestational age 2. Small for gestational age (SGA ) may be associated with polycythemia and intrauterine infections. 3. Microcephaly may be associated with congenital infections. 4 . Extravascular blood bruising, cephalohematoma , or other enclosed hemorrhage 5 . Pallor associated with hemolytic anemia or extravascular blood loss

32. 6 . Petechiae may suggest congenital infection, sepsis, or erythroblastosis . 7 . Hepatosplenomegal y may be associated with hemolytic anemia , congenital infection, or liver disease. 8. Omphalitis or other sign of infection 9. Chorioretinitis associated with congenital infection 10. Evidence of hypothyroidism

33. C. ADDITIONAL LAB TESTS should be performed when serum TB is ≥95th percentile for age in hours or at or near the threshold for initiation of phototherapy. 1. The mother's blood type, Rh , and antibody screen should have been done during pregnancy and the antibody screen repeated at delivery. 2 . The infant's blood type, Rh , and direct Coombs test to assess for isoimmune hemolytic disease. Infants of Rh-negative women should have a blood type, Rh , and Coombs test performed at birth

34. 3. Peripheral smear for RBC morphology and reticulocyte count to detect causes of Coombs-negative hemolytic disease (e.g., spherocytosis ). HS occurs in about 1 per2,000 births and may be missed if family history alone is used for screening, as many cases are de novo , and HS may be autosomal recessive in infants of Japanese ancestry. In one report, a mean corpuscular hemoglobin concentration (MCHC) of ≥36.0 g/ dL has 82% sensitivity and 98% specificity for diagnosing HS. 4. Hematocrit or hemoglobin measurement will identify polycythemia or suggest blood loss from occult hemorrhage .

35. Measurement of serum bilirubin Transcutaneus bilirubinometry (TcB) Advantage: Reduce invasive blood test Disadvantage: Costly, unreliable- less than 35 weeks, during initial 24 hr of age & TSB more than 14mg/dl Measured by using multiple wave length analysis ➢ End tidal CO → Screen for hemolytic conditions

36. Measurement of TSB Indications Jaundice in first 24 hour Beyond 24 hr: if visually assessed jaundice more than 15 mg/dL If you are unsure about visual assessment During phototherapy, for monitoring progress and after phototherapy Methods : Biochemical: High performance liquid chromatography (HPLC) Micro method: Based on spectrophotometry

37. APPROACH TO A INFANT WITH JAUNDICE

38. Serious jaundice: a.Presence of visible jaundice in first 24 hour b.Yellow palms and soles anytime c.Signs of acute bilirubin encephalopathy or kernicterus: hypertonia, abnormal posturing such as arching, retrocollis, opisthotonus or convulsion, fever, high pitched cry) th d.TcB /TSB value more than 95 centile as per age specific nomogram

39. Management of Indirect Hyperbilirubinemia

40. 1.Infants born at gestation of 35 weeks or more American Academy of Paediatrics (AAP) criteria should be used for deciding need for phototherapy or exchange transfusion. AAP provides two age-specific nomograms - one each for phototherapy and exchange transfusion. The nomograms have lines for three different risk categories of neonates These lines include one each for lower risk babies (38 wk or more and no risk factors), medium risk babies (38 wk or more with risk factors, or 35 wk to 37 wk and without any risk factors) and higher risk (35 wk to 37 wk and with risk factors) MANAGEMENT

41. Isoimmune hemolytic disease G6PD deficiency Asphyxia, Lethargy Temperature instability Sepsis Acidosis Albumin <3 g/ dL (if measured) Neurotoxic Risk Factors

42. Bhutani Curve- phototherapy

43. Bhutani Curve- Exchange transfusion

44. 2. Preterm babies

45. Therapeutic Management Purposes: reduce level of serum bilirubin and prevent bilirubin toxicity Modalities : Phototherapy- Reduction of bilirubin levels Exchange transfusion- Reduction of bilirubin levels IV IG- prevent- Lysis of RBC’s by blocking immune mediated antibody Metalloporphyrin tin/ zinc- Prevent breakdown of Hb by inhibiting heme oxidase Phenobarbitone/ UDCA- Conjugation of bilirubin

46. Phototherapy Safe and effective method for treatment of neonatal jaundice Bilirubin absorbs light maximum at 420-4 7 nm

47. Phototherapy

48. Mechanism of Action Conversion of insoluble Bilirubin into soluble bilirubin  Excretion of bilirubin Photo- isomerisation Structural isomerisation Photo- oxidation

49. Photo-isomerisation Reversible reaction. Conversion of insoluble, toxic form Z isomer  non toxic polar (water soluble) E isomer  diffuses into the blood  excreted easily into bile without conjugation

50. Structural isomerisation Main Mechainism Irreversible reaction Bilirubin  lumirubin Rapidly excreted in bile and urine Main responsible for phototherapy induce decline of TSB Reduction of bilirubin directly proportional to dose of phototherapy

51. Ph o t o- o xid a tion Minor reaction Photo-oxidation of Bilirubin to water soluble polymers Colourless by product Riboflavin- catalyze the dermal photo- oxidation

52. Phototherapy

53. CHARACTERSTICS OF DEVICES The most effective are characterized by the following: Light emission in the blue-green spectrum (460 to 490 nm), which includes the region (460 nm) where bilirubin most strongly absorbs light 2. Irradiance of at least 30 μW /cm 2 /nm 3. Illumination of maximal body surface area shown to decrease TB during first 4 to 6 hours of exposure

54. 1. Fluorescent blue light : most effectively because they deliver light in the blue-green spectrum, providing maximal absorption and good skin penetration. 1500 hours , cheap but irradiance changes with time . 2. Blue light-emitting diodes (LEDs) - optimal high-intensity light in the absorption spectrum of bilirubin , 3,000 hours life span ,better than Fluorescent bulbs . m/c used nowdays 3. Fiberoptic blankets or pads can be placed directly under the infant, generate little heat, but provide lower irradiance → not in intensive PTx 4. Halogen lights Usage of CFL is not recommended LIGHT SOURCES

55. P r oced u r e Best is narrow spectral blue lights (4 60-490 nm) Distance from skin – 30 to 45cm Intensive PT – 15-20 cm Shield eyes & genitalia Change position once in every 2-4 hrs Level to be checked every 10-12 hrs Frequent temperature monitoring & daily weight check

56. Side Effects Immediate: Loose stools Dehydration Hypo or hyperthermia Rashes Bronze baby syndrome Late: Risk of skin malignancies Damage to intracellular DNA Retinal damage Testicular damage

57. 1)IVIG may act by occupying the Fc receptors on macrophages, decreasing removal of antibody-coated red cells from the circulation → reduces hemolysis 0.5 to 1 g/kg IVIG can be given over 2 hours 2)Heme oxygenase inhibitors : rate limiting step heme → biliverdin TIN-MESOPORPHYRIN (SNMP) for phototherapy resistant jaundice. A single i /m dose on day 1 may reduce need for subsequent phototheraphy Phenobarbitone, clofibrate or steroids → NOT recommended Pharmacotheraphy

58. Exchange transfusion The procedure involves the incremental removal of the patient's blood and simultaneous replacement with fresh donor blood, saline or plasma T h e E T s hou l d be pe rf o rm e d by pu l l a n d pu s h t e c h n i q u e us in g u m bi l i cal venous route Indications - infants with Rh isoimmunnisation include: Cord bilirubin 5mg/ dl or more Cord Hb 10g/ dl or less

59. Exchange transfusion Complications Hypocalcaemia and Hypomagnesaemia - Citrate in CPD blood Hypoglycaemia Metabolic alkalosis or acidosis Hyperkelemia CVS: overload and arrhythmias Infections: HBV HIV Haemolysis Hypothermia, NEC.

60. P r e v e n tion Early and frequent breast feeding Adequate hydration Administration of Anti‐D injection in case of Rh Incompatibility

61. Neurologic manifestations of bilirubin toxicity. 1. ABE is the clinical manifestation of bilirubin toxicity seen in the neonatal period. The clinical presentation consists of three phases: a)Early phase:- Signs are subtle and may include lethargy hypotonia high-pitched cry poor suck.

62. B) Intermediate phase progresses in the absence of intervention for hyperbilirubinemia and is characterized by hypertonia of extensor muscles (rigidity, opisthotonus, and retrocollis), oculogyric crisis, irritability, fever, and seizures. Some infants die in this phase. All infants who survive this phase are likely to develop chronic bilirubin encephalopathy (clinical diagnosis of kernicterus).

63. c. Advanced phase. Signs include pronounced opisthotonus and retrocollis, cry that can be weak or shrill, apnea , seizures, and coma. Affected infants die from intractable seizures or respiratory failure

64. 2. Kernicterus refers to the chronic and permanent sequelae of bilirubin toxicity that develop during the first year of age. Most infants who develop kernicterus have had signs of ABE in the neonatal period although some have a history of high TB level with few or no signs of ABE. The signs of kernicterus are as follows: a. Choreoathetoid cerebral palsy with neuromotor impairments b. Sensorineural hearing loss (auditory neuropathy), characterized by abnormal brainstem auditory evoked response with normal otoacoustic emission testing c. Limitation of upward gaze d. Dental enamel dysplasia

65. K ernic t erus: * Bilirubin deposits typically in basal ganglia, hippocampus, substantia nigra, etc.

66. Prolonged jaundice Definition : Persistence of significant jaundice for more than 2 weeks in term or More than 3 weeks in preterm babies

67. Causes of prolonged jaundice Common: Inadequacy of breast feeding Breast milk jaundice Cholestasis Rare causes: Hypothyroidism Criggler-Najjar syndrome GI obstruction due to malrotation Gilbert syndrome

68. / CHOLESTASIS • Direct bilirubin level >1 mL/dL or >15% of the TB level • Defects in intrahepatic bile production • Defects in transmembrane transport of bile or mechanical obstruction to flow to flow CONJUGATED HYPERBILIRUBINEMIA / CHOLESTASIS LAB Abnormal LFT , Raised GGT USG- Atresia , Choledochal cyst , Malformations HIDA scan , -Hepatobiliary scintigraphy Liver biopsy CLINICAL POINTERS Pale stools Dark Urine Hepatomegaly, Splenomegaly

69. 1. Obstructive bile duct disorders. Biliary atresia : frequent cause and must be identified promptly so that intervention ( hepatoportoenterostomy ) can be performed before 2 months of age. This condition may be associated with situs inversus, polysplenia or asplenia, and cardiac anomalies Alagille syndrome : characterized by unusual facial appearance, ocular abnormality (posterior embryotoxon ), cardiac abnormalities (pulmonic stenosis), and vertebral anomalies (butterfly vertebrae). Choledochal duct cysts are an uncommon but surgically treatable cause of cholestasis. 2. Infectious causes include sepsis and urinary tract infections as well as infections caused by numerous viral, bacterial, and other organisms.

70. 3. Metabolic disorders include α1- antitrypsin deficiency, cystic fibrosis, galactosemia, tyrosinemia, galactosemia, storage diseases (Gaucher, Niemann-Pick), Zellweger syndrome, mitochondrial disorders, and congenital disorders of glycosylation. 4. Immunologic disorders include gestational alloimmune liver disease (formerly neonatal hemochromatosis) and neonatal lupus erythematosus. 5. Endocrine disorders include hypothyroidism and panhypopituitarism. 6. Toxic disorders. A frequent cause of cholestasis in the NICU occurs in infants unable to take enteral feeding who have prolonged courses of TPN including lipid. This condition typically resolves with introduction of enteral feedings.

71. Inherited disorders Unconjugated Hyperbilirubinemia Conjugated Hyperbilirubinemia Gilbert Syndrome Dubin - Johnson Syndrome Crijglar Nijjar Syndrome Rotor Syndrome

72. Summa r y: Hyperbilirubinemia is a common and potential serious issue in neonates Important to recognize and diagnose early in order to initiate prompt treatment when possible