Michelle B. Kravitz, MD June 29, 2006

Case 1 You are called by the nurse that a newborn’s TcB is You are called by the nurse that a newborn’s TcB is Is this concerning? Is this concerning? What information do you need to answer that question? What information do you need to answer that question?

Case 2 You are called by the ER to see an infant whose bili is 22. You are called by the ER to see an infant whose bili is 22. Must you admit? Must you admit? What information do you need to answer this question? What information do you need to answer this question?

Outline Review of physiology Review of physiology Kernicterus Kernicterus Risk factors Risk factors Assessing the risk Assessing the risk Therapies Therapies

BILIRUBIN Non-polar, water insoluble compound requiring conjugation with glucuronic acid to form a water soluble product that can be excreted. Non-polar, water insoluble compound requiring conjugation with glucuronic acid to form a water soluble product that can be excreted. It circulates to the liver reversibly bound to albumin It circulates to the liver reversibly bound to albumin

BILIRUBIN PHYSIOLOGY Increased production in neonate due to larger red cell volume, which produces bilirubin as cells are broken down and shorter RBC life span, so broken down faster. Increased production in neonate due to larger red cell volume, which produces bilirubin as cells are broken down and shorter RBC life span, so broken down faster. Heme is catabolized within the reticuloendothelial system by heme oxygenase to form biliverdin. Heme is catabolized within the reticuloendothelial system by heme oxygenase to form biliverdin. Biliverdin is metabolized to bilirubin in the presence of biliverdin reductase Biliverdin is metabolized to bilirubin in the presence of biliverdin reductase

BILIRUBIN PHYSIOLOGY Heme Biliverdin Heme oxygenase Bilirubin Biliverdin reductase

Bilirubin Physiology Ligandins responsible for transport from plasma membrane to endoplasmic reticulum. Ligandins responsible for transport from plasma membrane to endoplasmic reticulum. Bilirubin conjugated in presence of UDPGT (uridine diphosphate glucuronyl transferase) to mono and diglucoronides, which are then excreted into bile canaliculi. Bilirubin conjugated in presence of UDPGT (uridine diphosphate glucuronyl transferase) to mono and diglucoronides, which are then excreted into bile canaliculi.

Enterohepatic Circulation Meconium contains mg of conjugated bilirubin at birth. Meconium contains mg of conjugated bilirubin at birth. Conjugated bilirubin is unstable and easily hydrolyzed to unconjugated bilirubin. Conjugated bilirubin is unstable and easily hydrolyzed to unconjugated bilirubin. This process occurs non-enzymatically in the duodenum and jejunum and also occurs in the presence of beta-glucuronidase, an enteric mucosal enzyme, which is found in high concentration in newborn infants and in human milk. This process occurs non-enzymatically in the duodenum and jejunum and also occurs in the presence of beta-glucuronidase, an enteric mucosal enzyme, which is found in high concentration in newborn infants and in human milk.

Conjugation Since conjugated bilirubin crosses the placenta very little, conjugation is not active in the fetus with levels of UDPGT about 1% of adult levels at weeks gestation Since conjugated bilirubin crosses the placenta very little, conjugation is not active in the fetus with levels of UDPGT about 1% of adult levels at weeks gestation After birth, the levels of UDPGT rise rapidly but do not reach adult levels until 4-6 weeks of age. After birth, the levels of UDPGT rise rapidly but do not reach adult levels until 4-6 weeks of age. Ligandins, which are necessary for intracellular transport of bilirubin, are also low at birth and reach adult levels by 3-5 days. Ligandins, which are necessary for intracellular transport of bilirubin, are also low at birth and reach adult levels by 3-5 days.

CONJUGATED VS UNCONJUNCATED HYPERBILI Conjugated hyperbilirubinemia is always pathologic Conjugated hyperbilirubinemia is always pathologic When the total bili is quite high, the conjugated fraction can rise to as high as 20% of the total, although it usually stays under 1.0. When the total bili is quite high, the conjugated fraction can rise to as high as 20% of the total, although it usually stays under 1.0. Always check a total and direct, so that you can be sure you are excluding conjugated hyperbilirubinemia, which has totally different etiologies and treatments. Always check a total and direct, so that you can be sure you are excluding conjugated hyperbilirubinemia, which has totally different etiologies and treatments.

KERNICTERUS Why we care about indirect hyperbilirubinemia Why we care about indirect hyperbilirubinemia Staining of the brain by bilirubin Staining of the brain by bilirubin Early symptoms-acute bilirubin encephalopathy- poor feeding, abnormal cry, hypotonia, Early symptoms-acute bilirubin encephalopathy- poor feeding, abnormal cry, hypotonia, Intermediate phase-stupor, irritability, hypertonia Intermediate phase-stupor, irritability, hypertonia Late – shrill cry, no feeding, opisthotonus, apnea, seizures, coma, death Late – shrill cry, no feeding, opisthotonus, apnea, seizures, coma, death

KERNICTERUS Late sequelae can include Late sequelae can include gaze abnormalities feeding difficulties dystoniaincoordinationchoreoathetosis sensorineural hearing loss painful muscle spasms

KERNICTERUS Incidence of bilirubin levels>30 1/10,000 Incidence of bilirubin levels>30 1/10,000 Over 120 cases kernicterus documented since 1990 Over 120 cases kernicterus documented since 1990 Overwhelming majority term, breastfed Overwhelming majority term, breastfed Majority of those had levels in high 30s to 40s. Majority of those had levels in high 30s to 40s. Lowest level recorded in case series of 111 from was 20.7, but the mean was 38. Lowest level recorded in case series of 111 from was 20.7, but the mean was 38. Many cases had no planned follow up and had been discharged early (<48 hours). Many cases had no planned follow up and had been discharged early (<48 hours).

KERNICTERUS AND FREE BILIRUBIN An article published this year in Pediatrics makes the case for establishing free bilirubin levels rather than total serum bilirubin levels to monitor jaundice and assess risk for kernicterus. An article published this year in Pediatrics makes the case for establishing free bilirubin levels rather than total serum bilirubin levels to monitor jaundice and assess risk for kernicterus. Since bilirubin travels bound to albumin predominantly, the free bilirubin is inversely proportional to the albumin concentration. Since bilirubin travels bound to albumin predominantly, the free bilirubin is inversely proportional to the albumin concentration.

ALBUMIN A low albumin level could possibly be the reason behind kernicterus occurring in some infants at relatively low bilirubin levels. A low albumin level could possibly be the reason behind kernicterus occurring in some infants at relatively low bilirubin levels. There was a report of a 29 week infant whose peak bilirubin level was only 15.7 and yet developed classic kernicterus with spasticity, dystonia, ballismus, and gaze abnormalities. There was a report of a 29 week infant whose peak bilirubin level was only 15.7 and yet developed classic kernicterus with spasticity, dystonia, ballismus, and gaze abnormalities. Her bilirubin/albumin molar ratio was It has been suggested that a ratio of >0.5 might be a threshold in sick preterm infants. Her bilirubin/albumin molar ratio was It has been suggested that a ratio of >0.5 might be a threshold in sick preterm infants.

ALBUMIN Wenneberg et. al. suggest that an infant with an albumin level of 2 would be at the same risk for kernicterus with a bilirubin of 15 as an infant with a bilirubin of 30 and an albumin level of 4. Wenneberg et. al. suggest that an infant with an albumin level of 2 would be at the same risk for kernicterus with a bilirubin of 15 as an infant with a bilirubin of 30 and an albumin level of 4. We do not have data on albumin levels in healthy term infants, but most likely, hypoalbuminemia is a concern in extremely preterm or otherwise sick infants. We do not have data on albumin levels in healthy term infants, but most likely, hypoalbuminemia is a concern in extremely preterm or otherwise sick infants.

RISK FACTORS FOR SIGNIFICANT JAUNDICE Gestational Age Gestational Age Race Race Family history of jaundice requiring phototherapy Family history of jaundice requiring phototherapy Hemolysis (ABO or other) Hemolysis (ABO or other) Severe bruising Severe bruising Breastfeeding Breastfeeding

TIME COURSE OF JAUNDICE Pathologic by definition if significant in first 24 hours Pathologic by definition if significant in first 24 hours Usually begins to peak by 48 hours and continues until 96 hours Usually begins to peak by 48 hours and continues until 96 hours In Asian infants and preterm infants, peak can continue out to 5-7 days. In Asian infants and preterm infants, peak can continue out to 5-7 days.

RISK FACTORS-RACE Asians-highest risk Asians-highest risk Levels peak at as opposed to average Caucasian levels of 6-8. There is also a later peak which can occur at 5-7 days. Levels peak at as opposed to average Caucasian levels of 6-8. There is also a later peak which can occur at 5-7 days. Black infants have a lower peak, rarely exceeding 12. (but they have a much higher incidence of G6PD deficiency) Black infants have a lower peak, rarely exceeding 12. (but they have a much higher incidence of G6PD deficiency) Caucasians are in the middle. Caucasians are in the middle.

RISK FACTORS- GESTATIONAL AGE The younger the gestation, the higher the risk of jaundice. The younger the gestation, the higher the risk of jaundice. 37 weeks more prone to jaundice than 40 weeker who is more prone than a 42 weeker. 37 weeks more prone to jaundice than 40 weeker who is more prone than a 42 weeker. 35 and below is much more prone 35 and below is much more prone Extreme preemies also more prone to kernicterus and are treated at much lower levels. Extreme preemies also more prone to kernicterus and are treated at much lower levels.

RISK FACTORS-FAMILY HX A child whose sibling needed phototherapy is 12 times more likely to also have significant jaundice. A child whose sibling needed phototherapy is 12 times more likely to also have significant jaundice. Frequently peak bilirubin levels correlate between siblings. Frequently peak bilirubin levels correlate between siblings.

RISK FACTORS- HEMOLYSIS ABO Incompatibility is the most common cause of hemolysis causing jaundice. ABO Incompatibility is the most common cause of hemolysis causing jaundice. Only 10-20% of infants with ABO mismatch develop significant jaundice. Only 10-20% of infants with ABO mismatch develop significant jaundice. Some of these infants, however, develop very significant jaundice quickly. Some of these infants, however, develop very significant jaundice quickly. Coombs positive ABO is more likely to cause hemolysis, but many babies will be asymptomatic. Conversely, Coombs negative ABO mismatch does occasionally cause significant hemolysis, but this is rather rare. Coombs positive ABO is more likely to cause hemolysis, but many babies will be asymptomatic. Conversely, Coombs negative ABO mismatch does occasionally cause significant hemolysis, but this is rather rare.

RISK FACTORS- PATHOLOGIC G6PD Deficiency G6PD Deficiency Hereditary Spherocytosis Hereditary Spherocytosis Glucuronyl Transferase Deficiency Type 1 (Crigler Najar Syndrome) Glucuronyl Transferase Deficiency Type 1 (Crigler Najar Syndrome) GT deficiency Type 2 (Arias Syndrome) GT deficiency Type 2 (Arias Syndrome) Polycythemia Polycythemia

BREASTMILK/BREASTFEEDING JAUNDICE Breastfeeding jaundice occurs early Breastfeeding jaundice occurs early It is due to the lack of breast milk It is due to the lack of breast milk It is often associated with poor passage of meconium. It is often associated with poor passage of meconium. Treatment should be aimed at supporting breastfeeding while supplementing as needed to avoid extreme weight loss, dehydration, and worsening jaundice. Treatment should be aimed at supporting breastfeeding while supplementing as needed to avoid extreme weight loss, dehydration, and worsening jaundice.

BREASTMILK/BREASTFEEDING JAUNDICE Breast milk jaundice is a different, more benign entity, which tends to occur late in the first week or afterwards. Breast milk jaundice is a different, more benign entity, which tends to occur late in the first week or afterwards. It is actually due to something in the breast milk which tends to prolong jaundice. It is actually due to something in the breast milk which tends to prolong jaundice. Usually weight gain is good, and the baby is otherwise well. Usually weight gain is good, and the baby is otherwise well. Jaundice might persist as late as 3-4 weeks, but usually will peak by 2 weeks. Jaundice might persist as late as 3-4 weeks, but usually will peak by 2 weeks. Textbook treatment is to interrupt breastfeeding (I usually do not do this). Textbook treatment is to interrupt breastfeeding (I usually do not do this).

ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS Bhutani curve Bhutani curve

ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS Maisels’ and Kring’s study showed that not all early higher TcB will continue going up. Maisels’ and Kring’s study showed that not all early higher TcB will continue going up. They divided the rate of rise to be concerned with into They divided the rate of rise to be concerned with into 6-24hr>0.22/hr 6-24hr>0.22/hr 24-48>0.15/hr 24-48>0.15/hr 48+>0.06/hr 48+>0.06/hr

Copyright ©2004 American Academy of Pediatrics Subcommittee on Hyperbilirubinemia, Pediatrics 2004;114: Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation

ASSESSING THE RISK OF JAUNDICE BY THE NUMBERS Palm downloadable! Palm downloadable!

THERAPIES- PHOTOTHERAPY Phototherapy has been the mainstay of treating hyperbilirubinemia since the 1960s. Phototherapy has been the mainstay of treating hyperbilirubinemia since the 1960s. Phototherapy causes structural isomerization, forming lumirubin, which is then excreted in the bile and urine. Phototherapy causes structural isomerization, forming lumirubin, which is then excreted in the bile and urine. Since photoisomers are water soluble, they should not be able to cross the blood-brain barrier, so starting phototherapy should decrease the risk of kernicterus by turning 20-25% of bilirubin into a form unable to cross, even before the level has lowered significantly. Since photoisomers are water soluble, they should not be able to cross the blood-brain barrier, so starting phototherapy should decrease the risk of kernicterus by turning 20-25% of bilirubin into a form unable to cross, even before the level has lowered significantly.

THERAPIES- PHOTOTHERAPY Bilirubin absorbs light best at 450 nm, but longer wavelenths penetrate skin better. Bilirubin absorbs light best at 450 nm, but longer wavelenths penetrate skin better. Make sure skin is as exposed as possible and that light is not too far from baby. Make sure skin is as exposed as possible and that light is not too far from baby. Fiberoptic light (bili blanket) is much less efficacious on its own. Fiberoptic light (bili blanket) is much less efficacious on its own.

THERAPIES-EXCHANGE TRANSFUSION Double volume exchange transfusion was a common procedure prior to advent of Rhogam and phototherapy. Double volume exchange transfusion was a common procedure prior to advent of Rhogam and phototherapy. Now fortunately a rare occurrence Now fortunately a rare occurrence Used for bilirubin >25 in a term infant and not decreasing despite phototherapy Used for bilirubin >25 in a term infant and not decreasing despite phototherapy

THERAPIES-Sn Mesoporphyrin SnMP is a structural analog of heme SnMP is a structural analog of heme It blocks the site on heme oxygenase where conversion of heme to bilirubin occurs. It blocks the site on heme oxygenase where conversion of heme to bilirubin occurs. Still under investigation (why?) Still under investigation (why?) Administered parenterally in a small dose (6 micromoles/kg) Administered parenterally in a small dose (6 micromoles/kg) In term infants, obviated need for phototherapy In term infants, obviated need for phototherapy Some preterm infants still needed phototherapy but none needed exchange transfusion Some preterm infants still needed phototherapy but none needed exchange transfusion Virtually 100% efficacy Virtually 100% efficacy

THERAPIES-Sn Mesoporphyrin Can also be used repeatedly for patients with Crigler-Najar (effects last several days). Can also be used repeatedly for patients with Crigler-Najar (effects last several days). Stanate ® -currently being patented Stanate ® -currently being patented Ongoing study at Children’s Hospital of Columbus in newborns at risk of exchange transfusion Ongoing study at Children’s Hospital of Columbus in newborns at risk of exchange transfusion Accepting patients until September, 2006 Accepting patients until September, 2006 Richard McCleod, MD, Principal Investigator Richard McCleod, MD, Principal Investigator

Review of Case 1 How old is the patient? What is the gestational age? What other risk factors are present? –1–1–1–12 hours old –F–F–F–Full term –A–A–A–ABO incompatible

Review of Case 2 How old is the patient? What is the fractionation? Breast or bottle fed? Other risk factors? –1–1–1–10 days –2–2–2–22 total / 0.8 direct –B–B–B–Breast fed –N–N–N–None

MANAGING JAUNDICE- TAKE HOME POINTS Consider the risk factors, particularly prematurity and hemolysis Consider the risk factors, particularly prematurity and hemolysis Follow up is key! Follow up is key! Consider how well baby is feeding, parents’ ability to return, reliability, etc Consider how well baby is feeding, parents’ ability to return, reliability, etc The higher the number of risk factors, the lower the level at which to intervene The higher the number of risk factors, the lower the level at which to intervene Sometimes, you will be surprised. We can’t always prevent hyperbilirubinemia, but we should always prevent kernicterus. Sometimes, you will be surprised. We can’t always prevent hyperbilirubinemia, but we should always prevent kernicterus.

REFERENCES Tate, M, Neonatal Hyperbilirubinemia, Revised, June 2001 in MICC Curriculum. Tate, M, Neonatal Hyperbilirubinemia, Revised, June 2001 in MICC Curriculum. Maisels MJ and E Kring, Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of >/= 35 weeks’ gestation. Pediatrics. 2006, 117(4): Maisels MJ and E Kring, Transcutaneous bilirubin levels in the first 96 hours in a normal newborn population of >/= 35 weeks’ gestation. Pediatrics. 2006, 117(4): Wennberg et. al., Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics. 2006, 117(2): Wennberg et. al., Toward understanding kernicterus: a challenge to improve the management of jaundiced newborns. Pediatrics. 2006, 117(2):

Watchko JF, Vigintophobia revisited. Pediatrics, 2005, 115(6): Watchko JF, Vigintophobia revisited. Pediatrics, 2005, 115(6): Gourley GR et. al., A controlled, randomized, double blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics, 2005, 116(2): Gourley GR et. al., A controlled, randomized, double blind trial of prophylaxis against jaundice among breastfed newborns. Pediatrics, 2005, 116(2): Merhar SL and DL Gilbert, Clinical Findings and Cerebrospinal fluid neurotransmitters in 2 children with severe chronic bilirubin encephalopathy, including a former preterm infant without marked hyperbilirubinemia. Pediatrics, 2005, 116(5): Merhar SL and DL Gilbert, Clinical Findings and Cerebrospinal fluid neurotransmitters in 2 children with severe chronic bilirubin encephalopathy, including a former preterm infant without marked hyperbilirubinemia. Pediatrics, 2005, 116(5):

M Herschel et. al., Isoimmunization is unlikely to be the cause of hemolysis in ABO- incompatible but direct antiglobulin test-negative neonates. Pediatrics. 2002, 110(1): M Herschel et. al., Isoimmunization is unlikely to be the cause of hemolysis in ABO- incompatible but direct antiglobulin test-negative neonates. Pediatrics. 2002, 110(1): LD Eggert et. al., The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006, 117(5):e LD Eggert et. al., The effect of instituting a prehospital-discharge newborn bilirubin screening program in an 18-hospital health system. Pediatrics. 2006, 117(5):e

A Kappas, A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 2004, 113(1) A Kappas, A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 2004, 113(1) D Alexander, Commentary on “A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 113(1):135. D Alexander, Commentary on “A method for interdicting the development of severe jaundice in newborns by inhibiting the production of bilirubin. Pediatrics. 113(1):135.

J Grupp-Phelan et. Al., Early newborn hospital discharge and readmission for mild and severe jaundice. Arch Pediatr Adolesc Med. 1999;153: J Grupp-Phelan et. Al., Early newborn hospital discharge and readmission for mild and severe jaundice. Arch Pediatr Adolesc Med. 1999;153: P Goevaert et. al. Changes in globus pallidus with pre(term) kernicterus. Pediatrics. 2003, 112 (6): P Goevaert et. al. Changes in globus pallidus with pre(term) kernicterus. Pediatrics. 2003, 112 (6): S Ip et. al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004, 114(1):e S Ip et. al. An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics. 2004, 114(1):e

T WR Hansen, Neonatal Jaundice. eMedicine.com/ped/topic1061.htm, updated June 8, T WR Hansen, Neonatal Jaundice. eMedicine.com/ped/topic1061.htm, updated June 8, 2006.