BMJ neonatal jaundice

Neonatal jaundice Straight to the point of care Last updated: Apr 28, 2020 Table of Contents Summary Basics Definition Epidemiology Aetiology Pathophysiology Classification Prevention Primary prevention Screening Secondary prevention Diagnosis Case history Step-by-step diagnostic approach Risk factors 10 History & examination factors 11 Diagnostic tests 14 Differential diagnosis 15 Treatment 16 Recommendations 16 Treatment details overview 18 Treatment options 20 Emerging 32 Follow up 33 Recommendations 33 Complications 34 Prognosis 35 Guidelines 36 Diagnostic guidelines 36 Treatment guidelines 37 Online resources 40 References 41 Images 49 Disclaimer 52 Summary ◊ Usually noted clinically when serum bilirubin is >85.5 micromol/L (5 mg/dL) Occurs in 50% to 70% of term neonates Most cases physiological ◊ Jaundice in the first 24 hours of life is considered pathological ◊ Treatment for severe hyperbilirubinaemia includes phototherapy and/or exchange transfusion ◊ The major complication of unconjugated hyperbilirubinaemia is kernicterus Neonatal jaundice Basics BASICS Definition Neonatal jaundice is the yellowing discoloration of the skin and sclera of a neonate, which is caused by increased levels of bilirubin in the blood A neonate refers to an infant in the first 28 days of life This topic focuses on recognising and managing early neonatal jaundice, which is most commonly caused by unconjugated hyperbilirubinaemia While prolonged jaundice with conjugated hyperbilirubinaemia may present during this period, appropriate management depends on the pathological cause and detailed commentary is beyond the scope of this material Epidemiology Jaundice is the most common condition in newborns that requires medical attention About 50% to 70% of term babies and 80% of preterm babies develop jaundice in the first week of life.[2] Jaundice usually appears to days after birth and resolves to weeks later without the need for treatment The incidence of hyperbilirubinaemia varies A study in the UK and Ireland showed an incidence of severe hyperbilirubinaemia (maximum unconjugated serum bilirubin ≥510 micromol/L [29.8 mg/dL]) of 7.1 in 100,000.[3] A study in Denmark showed an incidence of extreme hyperbilirubinaemia (492 micromol/L [28.8 mg/dL]) of 25 in 100,000.[4] In the US, severe hyperbilirubinaemia (total serum bilirubin >95th percentile) occurs in 8% to 9% of neonates during the first week; approximately 4% after 72 hours of life.[5] Incidence data for low and middle income countries vary.[6] The incidence of East Asians in a US Washington state population-based study was higher than that of white infants.[7] In studies in the US, a predominantly white and breastfed population in Michigan showed a 95th percentile total serum bilirubin level at 96 hours of life of 224.1 micromol/L (13.1 mg/dL).[8] In studies from Pennsylvania and Northern California, the 95th percentile was 299.3 (17.5 mg/dL).[1] [9] In a mixed population of neonates from the US, Hong Kong, Japan, and Israel, the 95th percentile was 265.1 micromol/L (15.5 mg/dL).[10] The risk for neonatal hyperbilirubinaemia is higher in males and increases progressively with decreasing gestational age Aetiology Physiological jaundice can be a result of: • Increased bilirubin load secondary to increased red blood cell (RBC) volume, decreased RBC life span, or increased enterohepatic circulation • Decreased uptake by the liver because of decreased ligandins or binding of ligandins to other anions • Decreased conjugation in the liver because of decreased uridine diphosphoglucuronyl transferase (UDPGT) activity UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter, which decrease UDPGT enzymatic activity, have been noted to be significant risk factors associated with neonatal hyperbilirubinaemia[11] • Decreased excretion into bile Pathological jaundice with unconjugated hyperbilirubinaemia can be a result of: • Haemolytic anaemias: these result in increased destruction of RBCs, with resultant increased haem, which is converted to excess unconjugated bilirubin; the immature liver is unable to handle the excess load They can be the result of blood group incompatibility (rhesus, ABO), RBC enzyme defects (glucose-6-phosphate dehydrogenase deficiency; pyruvate kinase deficiency), RBC membrane defects This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020 BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com Use of this content is subject to our disclaimer ( Use of this content is subject to our) © BMJ Publishing Group Ltd 2020 All rights reserved Neonatal jaundice • • • • • (e.g., hereditary spherocytosis, infantile pyknocytosis), thalassaemia, drug-induced (by vitamin K, sulphonamides, nitrofurantoin, anti-malarials, penicillin), or sepsis Extravasation of blood: sequestration of blood in cavities result in increased bilirubin load Examples include cephalhaematoma; intracranial, pulmonary, or gastrointestinal haemorrhage; large haemangiomas; excessive ecchymoses; or petechiae Polycythaemia: increased number of RBCs leads to increased production of bilirubin Increased enterohepatic circulation: delayed gastrointestinal transit increases bilirubin levels Examples include intestinal atresia/stenosis, pyloric stenosis, Hirschsprung's disease, meconium ileus/ plug syndrome Defective conjugation: congenital deficiencies of UDPGT enzyme include Crigler-Najjar syndrome; UDPGT enzyme inhibition can be the result of drugs (e.g., novobiocin), or Lucey-Driscoll syndrome Metabolic conditions (galactosaemia, hypothyroidism, tyrosinosis, hypermethioninaemia, maternal diabetes) Breastfeeding (including failure to establish lactation) Decreased binding of bilirubin to albumin: increased availability of the free (unconjugated) bilirubin to cross the blood-brain barrier This can be caused by drugs (sulphonamides, penicillin, gentamicin), acidosis, asphyxia, hypothermia, increased osmolality, or hypoglycaemia Pathological jaundice with conjugated hyperbilirubinaemia (direct bilirubin is >34.2 micromol/L (2.0 mg/dL)) can be a result of: • Hepatocellular disease: • Metabolic or genetic defects Examples include alpha1-antitrypsin deficiency, cystic fibrosis, Zellweger's syndrome, Dubin-Johnson syndrome (absence of multidrug resistance-associated protein from the canalicular membrane of hepatocytes), Rotor's syndrome (organic-aniontransporting polypeptide [OATP]1B1 and OATP1B3 are absent at the sinusoidal membrane of hepatocytes), and galactosaemia • Infections Examples include rubella, cytomegalovirus, herpes, syphilis, hepatitis A and B, toxoplasmosis, and urinary tract infection with Escherichia coli • Total parenteral nutrition[12] • Neonatal haemochromatosis • Idiopathic neonatal hepatitis • Shock • Intrahepatic biliary disease due to Alagille syndrome (arteriohepatic dysplasia), or inspissated bile syndrome • Extrahepatic biliary disease due to biliary atresia, choledochal cyst, bile duct stenosis, cholelithiasis Pathophysiology Bilirubin is the final product of haem catabolism, which is mostly derived from haemoglobin Breakdown of red blood cell haemoglobin results in haem production (75% of source of bilirubin) Haem can also be derived (25% of source of bilirubin) from breakdown of other proteins such as myoglobin, cytochromes, and nitric oxide synthases In the reticulo-endothelial system, haem is further catabolised by haem oxygenase (rate-limiting step for bilirubin production) to biliverdin This is acted upon by biliverdin reductase to form bilirubin Bilirubin is then bound to serum albumin in the plasma and is transported to the liver Bilirubin dissociates from albumin, and with the help of carrier proteins such as ligandins, is taken up into the This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020 BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com Use of this content is subject to our disclaimer ( Use of this content is subject to our) © BMJ Publishing Group Ltd 2020 All rights reserved BASICS • • Basics Basics BASICS Neonatal jaundice hepatocytes Bilirubin is then conjugated by the uridine diphosphoglucuronyl transferase enzyme in the hepatocytes Bilirubin glucuronide reaches the intestines via the gallbladder and common bile duct In the intestines of the newborn, most of the bilirubin glucuronide is unconjugated by beta glucuronidase Some of this unconjugated bilirubin is reabsorbed and gets into the enterohepatic circulation The rest of the conjugated bilirubin reaches the colon, where the bacteria break it down to urobilinogen, which is then excreted When this normal process of bilirubin formation and excretion is disrupted, hyperbilirubinaemia results.[13] Metabolic pathway of bilirubin with pathologies relating to unconjugated hyperbilirubinaemia ABO incompatibility, Rhesus incompatibility, shorter RBC lifespan in neonates, bruising during delivery; induced by inflammatory mediators associated with comorbidities of prematurity (e.g., respiratory distress syndrome, infection); dissociation increased by acidosis, ketosis, renal failure; permeable blood-brain barrier in term neonates and premature babies; mutation in UGT1A1 gene results in Gilbert’s syndrome or Crigler-Najjar syndrome I and II; unconjugated bilirubin load increased by decreased gut motility Created by BMJ Knowledge Centre This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020 BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com Use of this content is subject to our disclaimer ( Use of this content is subject to our) © BMJ Publishing Group Ltd 2020 All rights reserved Basics Neonatal jaundice BASICS Detail of liver lobule and its functions, highlighting pathologies that cause conjugated hyperbilirubinaemia Pathologies include: portal vein thrombosis; choledochal cyst; infection (sepsis, E coli urinary tract infection, hepatitis A or B, toxoplasmosis, cytomegalovirus, syphilis, herpes), metabolic (Rotor's syndrome, galactosaemia, tyrosinaemia, alpha-1 antitrypsin deficiency, hypothyroidism, cystic fibrosis, Zellweger's syndrome), drugs, idiopathic neonatal hepatitis, total parenteral nutrition, neonatal haemochromatosis, shock/hypoxia/ischaemia; bile duct paucity, biliary atresia, Alagille syndrome, idiopathic neonatal cholestasis, progressive familial intrahepatic cholestasis, inspissated bile syndrome; MRP2 (also known as ABCC2) gene mutations on the canalicular membrane of hepatocytes result in Dubin-Johnson syndrome, absence of OATP1B1 and OATP1B3 at the sinusoidal membrane of hepatocytes result in Rotor's syndrome Created by BMJ Knowledge Centre Classification Physiological jaundice Physiological jaundice is usually noted at postnatal day 2, peaks on days to 5, and then decreases Serum bilirubin levels up to 205.2 micromol/L (12 mg/dL) are considered physiological in term neonates Pathological jaundice Any jaundice in the first 24 hours of life is considered pathological Bilirubin levels exceeding 95th percentile, as defined by a nomogram, are pathological.[1] This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020 BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com Use of this content is subject to our disclaimer ( Use of this content is subject to our) © BMJ Publishing Group Ltd 2020 All rights reserved Neonatal jaundice Prevention Primary prevention Appropriate support and advice to breastfeeding women, and increasing the frequency of breastfeeding to to 12 times a day for first few days, should be recommended Screening PREVENTION There is insufficient evidence to support universal screening for jaundice to prevent chronic bilirubin encephalopathy.[40] [41] However, screening asymptomatic neonates is important for early recognition of jaundice and/or signs of bilirubin encephalopathy in order to evaluate the aetiology, closely monitor the serum bilirubin levels, and provide therapeutic intervention, if necessary Because jaundice occurs mostly in the first week of life, this is the best time to screen Prior to discharge from hospital, jaundice should be assessed every to 12 hours in the newborn Visual assessment of jaundice alone is considered unreliable and use of transcutaneous bilirubinometer and total serum bilirubin are the usual recommended screening tools.[42] [43] [44] [45] The American Academy of Pediatrics recommends universal pre-discharge bilirubin screening using total serum bilirubin (TSB) or transcutaneous bilirubin (TcB) levels that, when interpreted using the risk zones in the hour-specific nomogram, [Bhutani nomogram for designation of risk based on hour-specific serum bilirubin values] (http://pediatrics.aappublications.org/content/114/1/297#p-152)  provide a measurable assessment of the degree of hyperbilirubinaemia.[43] Combining a pre-discharge measurement of TSB or TcB with clinical risk factors is thought to improve the accuracy of risk prediction A structured approach to management and follow-up according to the pre-discharge TSB/TcB, gestational age, and other risk factors for hyperbilirubinaemia is therefore suggested When there are two or more successive TSB or TcB measurements, it is helpful to plot them on the nomogram to assess the rate of bilirubin elevation If TSB/TcB levels are crossing nomogram percentiles, haemolysis is likely and further investigation and follow-up are indicated Secondary prevention Depending on aetiology, if unconjugated bilirubin levels are high (e.g., in partial conjugation enzyme defects), lifelong intermittent phototherapy is required to prevent neurological damage Specific treatment needs to be continued in most cases of the metabolic/genetic/surgical aetiologies to keep levels of conjugated hyperbilirubinaemia under control Prevention of malnutrition and vitamin deficiencies is important in addition to promotion of bile flow and avoidance of bleeding This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020 BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com Use of this content is subject to our disclaimer ( Use of this content is subject to our) © BMJ Publishing Group Ltd 2020 All rights reserved Neonatal jaundice Diagnosis Case history Case history #1 A baby boy of approximately 36 weeks gestational age is born to a primigravida mother Pregnancy and delivery are uncomplicated, with Apgar scores of at and minutes Mother's and baby's blood groups are both O+ Mother chooses to exclusively breastfeed the baby At 24 hours of life, the baby is noted to be jaundiced and the total serum bilirubin is noted to be 119.7 micromol/L (7 mg/dL) He is discharged home later the same day with an appointment for follow-up with the paediatrician at week of age However, 48 hours later, the baby is brought to the emergency department History from the mother reveals that the baby has progressively become more jaundiced, is not breastfeeding well and is lethargic Examination also reveals evidence of moderate volume depletion and significant jaundice (including the soles) The neurological examination is normal and total serum bilirubin is 342.1 micromol/L (20 mg/dL) Case history #2 A term baby is born to a mother who had a previous baby with a history of jaundice in the newborn period, not requiring hospitalisation Pregnancy and delivery are uncomplicated, with Apgar scores of and at and minutes, respectively Mother's and baby's blood groups are O+ and B+, respectively At 12 hours of life, the baby is noted to be jaundiced and the total serum bilirubin is 85.5 micromol/L (5 mg/dL) Tests reveal direct Coombs' test to be positive and presence of microspherocytes on the peripheral smear Other presentations DIAGNOSIS The neonate may present with clinical signs of bilirubin encephalopathy These include irritability with a high-pitched cry, possibly fever and increased muscle tone (usually involving the extensor group of muscles), and characteristically intermittent backwards arching of the neck (retrocollis) and trunk (opisthotonus) Decreased tone and abnormal Moro reflex are possible manifestations Step-by-step diagnostic approach Jaundice is usually noted by yellow discoloration of the skin and sclera with the naked eye.[34] [35] [36] [37] However, visual estimation of the degree of jaundice can lead to errors, particularly in darkly pigmented neonates Therefore, every jaundiced neonate should have a transcutaneous bilirubin measurement Jaundice is physiological if it happens in postnatal day and resolves by a week of life and transcutaneous measurement is normal All neonates with jaundice in the first 24 hours of life and those with increased transcutaneous bilirubin after 24 hours of life need further evaluation Evaluation of pathological jaundice If child is younger than 24 hours of age or transcutaneous bilirubin measurement is 205.2 micromol/ L (12 mg/dL), total serum bilirubin should be measured If total serum bilirubin is >205.2 micromol/L (12 mg/dL) or >95th percentile for age (in hours) on a nomogram, a Coombs' test should be done.[1] [Bhutani nomogram for designation of risk based on hour-specific serum bilirubin values] (http:// pediatrics.aappublications.org/content/114/1/297#p-152)  If the Coombs' test is positive, mother's and neonate's ABO and Rh blood groups must be checked If there is no incompatibility (incompatibility This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 28, 2020 BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com Use of this content is subject to our disclaimer ( Use of this content is subject to our) © BMJ Publishing Group Ltd 2020 All rights reserved Neonatal jaundice Diagnosis occurs when mother is blood group O and neonate is A or B or when the mother is Rhesus -ve and the neonate is Rhesus +ve), minor blood group antigens incompatibility should be considered If negative, direct serum bilirubin must be checked Direct bilirubin >34.2 micromol/L (2 mg/dL) If direct bilirubin is >34.2 micromol/L (2 mg/dL), various causes of conjugated hyperbilirubinaemia such as hepatocellular disease secondary to infections/metabolic or genetic causes and extrahepatic biliary disease needs to be considered and investigated.[38] Tests include liver function tests, blood culture, urine for reducing substances, plasma amino acids, urine amino acids, urine culture, abdominal ultrasound, and percutaneous liver biopsy Direct bilirubin