NEONATAL JAUNDICE

1. NEONATAL JAUNDICE

2. Outline Introduction • Definition • Epidemiology • Bilirubin metabolism • Aetiopathogenesis/Types • Clinical features • Evaluation of a jaundiced neonate • Management • Complications • Surgical/Cholestaticjaundice

3. Introduction • Neonatal jaundice is a very common condition worldwide, • 60% of term and 80% of preterm new born in the first week of life • Extreme hyperbilirubinaemia is uncommon in developed countries. • It is still a common cause of neonatal morbidity and mortality in developing countries often resulting in kernicterus with its resultant burden, such as medical, economic and social, on the patient family and society at large.

4. definition • : Hyperbilirubinemia refers to an excessive level of accumulated bilirubin in the blood and is characterized by jaundice, a yellowish discoloration of the skin, sclera, mucous membranes and nails.

5. epidemiology • In some LMICs, the incidence of severe neonatal jaundice may be as much as 100 times higher than in higher-income countries. • In Nigeria, it accounts for between 23% and 60% of admission into the Special Care Baby Unit (SCBU), and various factors are responsible for its occurrence. • ),

6. In developed countries feto-maternal blood group incompatibilities are the leading cause of neonatal jaundice • But in developing countries, the case is different as it is mostly prematurity, G6PD deficiency, infective causes as well as effects of herbal medications in pregnancy, application of dusting powder on baby, use of camphor balls to store baby’s clothe that mainly constitute the aetiology in developing countries

7. Severe neonatal jaundice can therefore be said to have modifiable risk factors particularly through maternal education, early and comprehensive antenatal care as well as specialized neonatal care

8. Bilirubin metabolism • Bilirubin is produced in the reticuloendothelial system as the end product of heme catabolism and is formed through oxidation-reduction reactions. • Approximately 75% of bilirubin is derived from hemoglobin, but degradation of myoglobin, cytochromes, and catalase also contributes.

9. In the first oxidation step, biliverdin is formed from heme through the action of hemeoxygenase, the rate-limiting step in the process, releasing iron and carbon monoxide. • The iron is conserved for reuse, whereas carbon monoxide is excreted through the lungs and can be measured in the patient's breath to quantify bilirubin production.

10. Next, water-soluble biliverdin is reduced to bilirubin. • Because of its hydrophobic nature, unconjugated bilirubin is transported in the plasma tightly bound to albumin. • Binding to other proteins and erythrocytes also occurs, but the physiologic role is probably limited. • Binding of bilirubin to albumin increases postnatally with age and is reduced in infants who are ill.

11. When it reaches the liver, bilirubin is transported into liver cells, where it binds to ligandin. • Uptake of bilirubin into hepatocytes increases with increasing ligandin concentrations. • Ligandinconcentrations are low at birth but rapidly increase over the first few weeks of life. • Ligandinconcentrations may be increased by the administration of pharmacologic agents such as phenobarbital.

12. Bilirubin is bound to glucuronic acid in the hepatocyte endoplasmic reticulum in a reaction catalysed by uridinediphosphoglucuronyltransferase (UDPGT). • Monoconjugatesare formed first and predominate in the newborn. • Diconjugatesappear to be formed at the cell membrane and may require the presence of the UDPGT tetramer.

13. Bilirubin conjugation is biologically critical because it transforms a water-insoluble bilirubin molecule into a water-soluble molecule. • Water-solubility allows conjugated bilirubin to be excreted into bile. • UDPGT activity is low at birth but increases to adult values by age 4-8 weeks. • In addition, certain drugs (phenobarbital, dexamethasone, clofibrate) can be administered to increase UDPGT activity.

14. Once excreted into bile and transferred to the intestines, bilirubin is eventually reduced to colorlesstetrapyrroles by microbes in the colon. • However, some deconjugation occurs in the proximal small intestine through the action of B-glucuronidases located in the brush border. • This unconjugated bilirubin can be reabsorbed into the circulation, increasing the total plasma bilirubin pool. • Conjugated bilirubin is not absorbed and instead passes into the colon.

15. There, colonic bacteria deconjugate and metabolize the bilirubin into colourless urobilinogen, which can be oxidized to form urobilin and stercobilin. • Urobilin is excreted by the kidneys to give urine its yellow color and stercobilin is excreted in the faeces giving stool its characteristic brown color. • A trace (~1%) of the urobilinogen is reabsorbed into the enterohepatic circulation to be re-excreted in the bile.

17. Bilirubin metabolism cont’d • This cycle of uptake, conjugation, excretion, deconjugation, and reabsorption is termed 'enterohepatic circulation'. • The process may be extensive in the neonate, partly because nutrient intake is limited in the first days of life, prolonging the intestinal transit time.

18. Bilirubin metabolism Hb → globin + haem 1g Hb = 34mg bilirubin Non – heme source 1 mg / kg Bilirubin Ligandin (Y - acceptor) Intestine Bilirubin glucuronidase Bil glucuronide Bil glucuronide β glucuronidase bacteria Bilirubin Stercobilin

19. Bilirubin metabolism cont’d

20. aetiopathogenesis Neonatal physiologic jaundice results from simultaneous occurrence of the following two phenomena : • Bilirubin production is elevated because of increased breakdown of fetal erythrocytes. This is the result of the shortened lifespan of fetal erythrocytes and the higher erythrocyte mass in neonates. • Hepatic excretory capacity is low both because of : • low concentrations of the binding protein ligandin in the hepatocytes • low activity of glucuronyltransferase, the enzyme responsible for binding bilirubin to glucuronic acid, thus making bilirubin water soluble (conjugation).

21. Summarily,Increasedbilirubin production secondary to accelerated destruction of erythrocytes, • decreased excretory capacity secondary to low levels of ligandin in hepatocytes, • and low activity of the bilirubin-conjugating enzyme uridinediphosphoglucuronyltransferase (UDPGT).

22. TYPES • Two types of neonatal jaundice exist, • Unconjugated (Indirect) • Conjugated (Direct) The unconjugated is further divided into; • Physiologic • Pathologic.

23. Physiologic jaundice (Icterus neonatorum) • This usually appears about the 2nd or 3rd day of life, peaks at about 2-4th day at 5-6mgdl and • decreasing to <2mg/dl between 5-7th after birth • Clinically not detectable after 10-14 days • The serum bilirubin levels are usually <12mg/dl (204umol/l). • The baby is said to be otherwise well. • It is a diagnosis of exclusion

24. Causes of physiological jaundice… They include : • relative high red cell mass and hence increased bilirubin load to the liver(hemolyticanemia,polycythemia,bruising,hemorrhage,reducedred cell life span,increasedentero hepatic circulation) • Reduced hepatic uptake due to low ligandinconcentration(genetic defect,prematurity)

25. Decreased excretory capacity secondary to low ligandin levels in the hepatocytes. • Damage or low activity of the bilirubin-conjugating enzyme uridinediphosphoglucuronyltransferase (UDPGT) (genetic deficiency, hypoxia, Infection,thyroiddeficiency) • Drugs that competes for or block transferase enzyme (drugs that require glucuronic acid conjugation) egSulfisoxazole,moxalactam

26. Pathological jaundice • This occurs in unwell babies. • It is jaundice occurring within the first 24 hour of life. • The total serum bilirubin level >12mg/dl (204umol/l) in term or >5mg/dl (85umol/l)/day. • conjugated bilirubin >2mg/dl (34umol/l), • clinical jaundice lasting >2 weeks, with evidence of haemolysis.

27. causes • Common causes of pathologic unconjugated hyperbilirubinaemiaare: • ABO Incompatibility, G6PD deficiency, • Infections (TORCH,malaria,bacterial) • prematurity • increased haemolysis due to rhesus incompatibility, pyruvate kinase deficiencies, membranopathies, hemolyticagents(such as naphthalene balls, dusting powder) • liver cell membrane defects

28. The risk factors for pathological jaundice are; • Genetics/familial risk : previous sibling with neonatal jaundice, mutations/polymorphisms in the genes that code for enzymes and proteins involved in bilirubin metabolism, and in infants with homozygous or heterozygous glucose-6-phosphatase dehydrogenase (G-6-PD) deficiency and other hereditary hemolyticanemias • maternal diabetes, • maternal drugs (such as oxytocin, diazepam, promethazine)

29. polycythaemia, • Nutrition • prematurity& low birth weight • Blood extravasation (cephalohematoma) • male sex, • trisomy 21 , • Ethnicity/race • geographical location (high altitude)

30. Other forms of Jaundice associated with breastfeeding include: • Breast milk jaundice (BMJ) • Breastfeeding jaundice

31. Breastmilk jaundice • Develops in 2% of breastfed term infants after the 7th day • Maximum concentration as high 10 -30mg/dl is reached during the 2nd - 3rd week • Aetiology is unclear but is attributed to presence of glucuronidase in some breast milk. • β-glucuronidase may play a role by uncoupling bilirubin from its binding to glucuronic acid, thus making it available for reabsorption.

32. If breastfeeding is continued, bilirubin gradually decreases but may persists for 3-10wk at lower levels. • if breastfeeding is discontinued, it falls rapidly reaching normal range in few days seldom returning to previously high level if resumed • Phototherapy may be of benefit • Kernicterus can occur in patients with BMJ

33. Breastfeeding jaundice • Occurs in the 1st week after birth in breastfed infants whose bilirubin levels are normally higher than formula fed infants • In mothers who are experiencing difficulties with establishment of breast feeding , inadequate fluid and nutrient intake often leads to significant postnatal weight loss in the infant. Such infants have an increased risk of developing jaundice through increased enterohepatic circulation.

34. Recent data have shown that breast milk jaundice correlates with higher levels of epidermal growth factor, both in breast milk and in infants' serum. • Levels >12mg/dl develop in 13% of breastfed infants during the 1st week and may be result of decreased milk intake with dehydration and/or reduced caloric intake • Prophylactic glucose water are associated with higher bilirubin levels partly due to reduced intake of high caloric breast milk.

35. Breastfeeding jaundice cont’d • Frequent feeding (>10/24hr) , rooming in for night feeding and on-going lactation support help reduce incidence of earl breastfeeding jaundice. • Breastfeeding should be continued if possible or interrupted temporarily and substituted with formula for a day or two albeit frequently especially if intake is not adequate, dehydrated or excessive weight loss

36. Clinical presentation • Yellowness of the body which progresses in a cephalocaudal progression. • In severe cases ; present with signs of bilirubin encephalopathy • Acute form • Phase one (1-2days) poor suck ,, hypotonia , seizures, lethargy, high pitched cry • Phase 2(middle of first week) hypertonia , opisthotonus , retrocolis , fever • Phase 3 (after the first week) hypertonia • Chronic form /complications

37. KERNICTERUS • Its a neurologic syndrome resulting from deposition of unconjugated (indirect )in the basal ganglia and brain stem. • The pathogenesis involves an interaction between unconjugated bilirubin level, albumin binding levels , passage across blood brain barrier and neuronal susceptibility to injury. • The more immature the infant is , the greater the suceptibility to kenicterus

38. Signs and symptoms usually appear 2-5 days after birth in term infants, and as late as 7days in preterm infant. • Early signs may be subtle and may present as • Lethargy • Poor feeding • Loss of moro reflex. • Subsequently the infant may appear ill and prostate ,with diminished tendon reflex and respiratory distress, opisthotonus with bulging anterior fontanelle, twitching of the face or limbs, and a shrill high pitch cry may follow

39. Evaluation of a child with jaundice • Detailed history; • Family history of jaundice, anemia, liver disease, history of jaundice in other siblings, blood group of mother, • Maternal illness during pregnancy, maternal drug use egsulphonamides, nitrofurantoin, antimalarial, oxytocin, use of phenolic detergents, camphor • Labour and delivery history • Neonatal history eg delayed passage of meconium, cord care, Weight, gestational age • Feeding history eg breastfeeding , consistency, onset of feeding, history of fever,

41. Examination • Jaundice is detected by blanching of the skinwith finger pressures to observe the color of the skin and subcutaneous tissues. • Anaemia or polycythemia • For features suggestive of sepsis • Extravascular blood suggestive of bruising, cephalhematoma, or other enclosed hemorrhage • Petechae associated with congenital infection, sepsis, or erythroblastosisfetalis • Hepatosplenomegaly associated with hemolytic anaemia, or liver disease • Evidence of hypothyroidism

42. Examine and observe for features suggestive of bilirubin encephalopathy • Poor suck • High pitch cry • Stupor • Primitive reflexes • Hypotonia /hypertonia • Excergeration of deep tendon reflexes. • seizures • opisthotinus • Retrocolis • Shrill cry

45. Clinical investigations • Bilirubin measurement; • Transcutaneous bilirubinometry (TCB) • Serum bilirubin (SB)- Total and conjugated • Full blood count • Blood group of mother and baby • Direct antiglobin test (direct coombs test) • Serum albumin levels • Peripheral blood film for RBC morphology • G6PD assay • Reticulocyte count

46. Liver function test • Aspartate aminotransferase-high in hepatocellular disease • Alanine aminotransferase- high in hepatocellular disease • Alkaline phosphatase- often elevated in cholestatic disease • Gamma glutamyltransferase: often elevated in cholestatic disease GGT/ALAT ratio >1 strongly suggests biliary obstruction,but does not distinguish between intrahepatic and extrahepatic cholestasis. • Sepsis screening

47. Arterial blood gases ;Bilirubin encephalopathy is more likely with acidosis • Thyroid function tests • Abdominal ultrasonography • Radionuclide liver scan; uptake of hepatoiminodiacetaic acid is increased in biliary atresia • Liver biopsy

48. Treatment • Most jaundiced babies do very well and may not even require any intervention , however early presentation is important in order to prevent complications. • In those who require treatment the goal is to prevent acute bilirubin encephalopathy . • General treatment • Adequate hydration of baby • Adequate feeding • Sepsis – commence IV antibiotics

49. interventions • Medical care • Phototherapy • Exchange blood transfusion • Intravenous immunoglobulin • Surgical care • pharmacotherapy Mechanism of action of phototherapy • Photo-Isomerization; converts the toxic native unconjugated 4z,15Z bilirubin into a less toxic polar isomer 4Z,15E which can be excreted in bile without conjugation. • Structural isomerization: intramolecularcrystalization of bilirubin to lumibrin which is rapidly excreted and urine • Photo oxidation ;converts bilirubin to small polar products that can be excreted in urine