1. Neonatal Hyperbilirubinemia: An Update Bryan Burke, MD Arkansas Children’s Hospital University of Arkansas for Medical Sciences

2. Definitions Hyperbilirubinemia: An unusually large amount of bilirubin in the blood resulting in jaundice. Hyperbilirubinemia: An unusually large amount of bilirubin in the blood resulting in jaundice. Acute Bilirubin Encephalopathy: Early stage - lethargy, hypotonia, and poor suck. Intermediate stage - moderate stupor, irritability, hypertonia (retrocollis and opisthotonus), fever, high-pitched cry, which may alternate with drowsiness and hypotonia. Acute Bilirubin Encephalopathy: Early stage - lethargy, hypotonia, and poor suck. Intermediate stage - moderate stupor, irritability, hypertonia (retrocollis and opisthotonus), fever, high-pitched cry, which may alternate with drowsiness and hypotonia.

3. Definitions (cont.) Kernicterus: The chronic form of bilirubin encephalopathy, manifested by a severe form of athetoid cerebral palsy, auditory dysfunction, dental-enamel dysplasia, paralysis of upward gaze, and less often intellectual handicaps. Kernicterus: The chronic form of bilirubin encephalopathy, manifested by a severe form of athetoid cerebral palsy, auditory dysfunction, dental-enamel dysplasia, paralysis of upward gaze, and less often intellectual handicaps.

4. Significance of Topic Kernicterus, though rare, still occurs in America. 1 Kernicterus, though rare, still occurs in America. 1 Newborns are being discharged from the hospital sooner than ever before. Newborns are being discharged from the hospital sooner than ever before. Early discharge means we are less able to observe newborns for the development of jaundice. Early discharge means we are less able to observe newborns for the development of jaundice. 1. Johnson LH, Bhutani VK, Brown AK. System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr. 2002;140:396-403

5. Goals: Accentuate the Positive, Eliminate the Negative Reduce the frequency of severe neonatal hyperbilirubinemia and bilirubin encephalopathy. Reduce the frequency of severe neonatal hyperbilirubinemia and bilirubin encephalopathy. Decrease unintended harm, such as increased anxiety, decreased breastfeeding, unnecessary treatment, excessive cost, and waste. Decrease unintended harm, such as increased anxiety, decreased breastfeeding, unnecessary treatment, excessive cost, and waste.

6. Acknowledgement of the Past To Jon F. Watchko, MD, and Frank A. Oski, MD, for writing “Bilirubin 20mg/dl = Vigintiphobia”, subtitled “Vigintiphobia: A One-Act Play”, in the April 1983 issue of Pediatrics, Vol. 71, No. 4, pages 660-663. To Jon F. Watchko, MD, and Frank A. Oski, MD, for writing “Bilirubin 20mg/dl = Vigintiphobia”, subtitled “Vigintiphobia: A One-Act Play”, in the April 1983 issue of Pediatrics, Vol. 71, No. 4, pages 660-663. To the AAP’s 1994 “Practice Parameter: Management of Hyperbilirubinemia in the Healthy Term Newborn”, which dramatically changed our approach to jaundiced newborns. To the AAP’s 1994 “Practice Parameter: Management of Hyperbilirubinemia in the Healthy Term Newborn”, which dramatically changed our approach to jaundiced newborns.

7. Impetus for this Update The publication in July 2004 of the AAP’s Clinical Practice Guideline “Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation”, a tremendous reference tool. The publication in July 2004 of the AAP’s Clinical Practice Guideline “Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation”, a tremendous reference tool. To understand some of what will follow, you will need to refer to the graphs and charts in your handout. To understand some of what will follow, you will need to refer to the graphs and charts in your handout.

8. The Big Changes Bilirubin values should be assessed against the infant’s age in hours. Bilirubin values should be assessed against the infant’s age in hours. The new guideline is useful in both healthy and sick newborns. The new guideline is useful in both healthy and sick newborns. The new guideline extends down to 35 weeks gestational age. The new guideline extends down to 35 weeks gestational age.

9. The Big Changes Specific newborn discharge follow-up timeframes are specified, causing a rather dramatic change in our care. Specific newborn discharge follow-up timeframes are specified, causing a rather dramatic change in our care. In addition to clinical assessment of the presence and significance of jaundice, laboratory evaluation is suggested as a possible routine tool. In addition to clinical assessment of the presence and significance of jaundice, laboratory evaluation is suggested as a possible routine tool. Transcutaneous bilirubinometers are mentioned as useful devices. Transcutaneous bilirubinometers are mentioned as useful devices.

10. Primary Prevention Mothers should be advised to nurse their newborns at least 8-12 times per day for the first several days. 2 Mothers should be advised to nurse their newborns at least 8-12 times per day for the first several days. 2 The AAP recommends against routine supplementation of nondehydrated breastfed infants with water or dextrose water. The AAP recommends against routine supplementation of nondehydrated breastfed infants with water or dextrose water. 2. American Academy of Pediatrics, American College of Obstetricians and Gynecologists, Guidelines for Perinatal Care. 5th edition. Elk Grove Village, IL: American Academy of Pediatrics; 2002:220-224.

11. Secondary Prevention Clinicians should perform ongoing systematic assessments during the neonatal period for the risk of an infant developing severe hyperbilirubinemia. Clinicians should perform ongoing systematic assessments during the neonatal period for the risk of an infant developing severe hyperbilirubinemia. Risk factors can be broken into major and minor categories, with an approximate order of importance. Risk factors can be broken into major and minor categories, with an approximate order of importance.

12. Major Risk Factors Total bilirubin or transcutaneous bilirubin in the high-risk zone. 3 Total bilirubin or transcutaneous bilirubin in the high-risk zone. 3 Jaundice observed in the first 24 hours. 4 Jaundice observed in the first 24 hours. 4 Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease, or elevated end-tidal CO 2. Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease, or elevated end-tidal CO 2. 3.Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103:6-14. 4. Newman Liljestrand P, Escobar GJ. Jaundice noted in the first 24 hours after birth in a managed care organization. Arch Pediatr Adolesc Med. 2002;156:1244-1250.

13. Major Risk Factors (cont.) Gestational age 35-36 weeks. 5 Gestational age 35-36 weeks. 5 Previous sibling received phototherapy. 6 Previous sibling received phototherapy. 6 Cephalohematoma or significant bruising. 7 Cephalohematoma or significant bruising. 7 5.Maisels MJ, Kring EA. Length of stay, jaundice, and hospital readmission. Pediatrics. 1998;101:995-998. 6.Ref. Gale R, Seidman DS, Dollberg S, Stevenson DK. Epidemiology of neonatal jaundice in the Jerusalem population. J Pediatr Gastroenterol Nutr. 1990;10:82-86. 7.Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med. 2000:154:1140-1147

14. Major risk factors (cont.) Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive. 8 Exclusive breastfeeding, particularly if nursing is not going well and weight loss is excessive. 8 East Asian race. 9 East Asian race. 9 8.Maisels MJ, Kring EA. Length of stay, jaundice, and hospital readmission. Pediatrics. 1998;101:995-998. 9.Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med. 2000;154:1140- 1147.

15. Minor risk factors Predischarge total serum bilirubin or transcutaneous bilirubin in the high-intermediate risk zone. 10 Predischarge total serum bilirubin or transcutaneous bilirubin in the high-intermediate risk zone. 10 Gestational age 37-38 weeks. 11 Gestational age 37-38 weeks. 11 Jaundice observed before discharge. 11 Jaundice observed before discharge. 11 Previous sibling with jaundice. 11 Previous sibling with jaundice. 11 10.Bhutani, Gourley GR, Adler S, Kreamer B, Dalman C, Johnson LH. Noninvasive measurement of total serum bilirubin in a multiracial predischarge newborn population to assess the risk of severe hyperbilirubinemia. Pediatrics. 2000:106(2). Available at: www.pediatrics.org/cgi/content/full/106/2/e17. 11. Maisels MJ, Kring EA. Length of stay, jaundice, and hospital readmission. Pediatrics. 1998;101:995-998.

16. Minor risk factors (cont.) Macrosomic infant of a diabetic mother. 12 Macrosomic infant of a diabetic mother. 12 Maternal age greater than or equal to 25 years. 13 Maternal age greater than or equal to 25 years. 13 Male gender. 13 Male gender. 13 12.Berk MA, Mimouni F, Miodovnik M, Hertzberg V, Valuck J. Macrosomia in infants of insulin-dependent diabetic mothers. Pediatrics. 1989;83:1029-1034. 13.Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med. 2000;154:1140-1147.

17. Decreased risk Total serum bilirubin or transcutaneous bilirubin in the low-risk zone. 14 Total serum bilirubin or transcutaneous bilirubin in the low-risk zone. 14 Gestational age greater than or equal to 41 weeks. 15 Gestational age greater than or equal to 41 weeks. 15 Exclusive bottle feeding. 15 Exclusive bottle feeding. 15 14. Bhutani VK, Johnson L, Sivieri EM. Predictive ability of a predischarge hour-specific serum bilirubin for subsequent significant hyperbilirubinemia in healthy term and near-term newborns. Pediatrics. 1999;103:6-14. 15. Newman TB, Xiong B, Gonzales VM, Escobar GJ. Prediction and prevention of extreme neonatal hyperbilirubinemia in a mature health maintenance organization. Arch Pediatr Adolesc Med. 2000;154:1140-1147.

18. Decreased risk (cont.) Black race. 16 Black race. 16 Discharge from hospital after 72 hours of age. 17 Discharge from hospital after 72 hours of age. 17 16.Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics. 2001;108:31-39. 17.Soskolne EL, Schumacher R, Fyock C, Young ML, Schork A. The effect of early discharge and other factors on readmission rates of newborns. Arch Pediatr Adolesc Med. 1996;150:373-379.

19. Secondary Prevention All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screen for unusual isoimmune antibodies. All pregnant women should be tested for ABO and Rh (D) blood types and have a serum screen for unusual isoimmune antibodies. If the mother was not screened or is Rh-negative, a direct antibody test, blood type, and an Rh type on the infant’s blood is strongly recommended. If the mother was not screened or is Rh-negative, a direct antibody test, blood type, and an Rh type on the infant’s blood is strongly recommended. If the mother is 0-positive, it is an option to test the baby’s type and direct antibody test, but not required if there is good surveillance, risk assessment before discharge, and follow-up. If the mother is 0-positive, it is an option to test the baby’s type and direct antibody test, but not required if there is good surveillance, risk assessment before discharge, and follow-up.

20. Secondary Prevention (cont.) Newborns should be routinely monitored for jaundice and nurseries should have established protocols for jaundice assessment. Newborns should be routinely monitored for jaundice and nurseries should have established protocols for jaundice assessment. Jaundice assessment protocols should include the conditions under which a nurse can obtain a total serum bilirubin or transcutaneous bilirubin level. Jaundice assessment protocols should include the conditions under which a nurse can obtain a total serum bilirubin or transcutaneous bilirubin level.

21. Laboratory Evaluation A bilirubin measurement should be done on any baby less than 24 hours old who is jaundiced. A bilirubin measurement should be done on any baby less than 24 hours old who is jaundiced. The need and timing of another bilirubin test depends on the risk zone into which the bilirubin falls, the age of the infant, and the evolution of the hyperbilirubinemia. The need and timing of another bilirubin test depends on the risk zone into which the bilirubin falls, the age of the infant, and the evolution of the hyperbilirubinemia. A suggested approach to laboratory evaluation is presented in Table 1. A suggested approach to laboratory evaluation is presented in Table 1.

22. Laboratory Evaluation (cont.) Bilirubin should be measured if the jaundice appears excessive for the infant’s age. Bilirubin should be measured if the jaundice appears excessive for the infant’s age. If there is any doubt about the degree of jaundice, measure the bilirubin. If there is any doubt about the degree of jaundice, measure the bilirubin. All bilirubin levels should be interpreted according to the baby’s age in hours. All bilirubin levels should be interpreted according to the baby’s age in hours.

23. Cause of Jaundice The cause of jaundice should be sought in any child receiving phototherapy or whose bilirubin is rising rapidly (crossing percentiles) and is not explained by the H & P. The cause of jaundice should be sought in any child receiving phototherapy or whose bilirubin is rising rapidly (crossing percentiles) and is not explained by the H & P. Infants with an elevated direct or conjugated bilirubin should have a UA and culture. Infants with an elevated direct or conjugated bilirubin should have a UA and culture. Sick infants, or those jaundice at 3 weeks of age or later, should have a total and direct bilirubin measured to identify cholestasis, as well as having their newborn thyroid and galactosemia screen results verified. Sick infants, or those jaundice at 3 weeks of age or later, should have a total and direct bilirubin measured to identify cholestasis, as well as having their newborn thyroid and galactosemia screen results verified.

24. Cause of Jaundice (cont.) If the direct bilirubin is high, look for the cause of cholestasis. If the direct bilirubin is high, look for the cause of cholestasis. Check infant’s G6PD level in infants getting phototherapy whose family, ethnic, or geographic origin suggests an increased chance of G6PD deficiency, or in an infant whose response to phototherapy is poor. Check infant’s G6PD level in infants getting phototherapy whose family, ethnic, or geographic origin suggests an increased chance of G6PD deficiency, or in an infant whose response to phototherapy is poor.

25. Risk Assessment Before Discharge Two options, used individually or in combination. Two options, used individually or in combination. Predischarge measurement of the bilirubin level either by total serum bilirubin or transcutaneous measurement and/or assessment of clinical risk factors. Predischarge measurement of the bilirubin level either by total serum bilirubin or transcutaneous measurement and/or assessment of clinical risk factors. Regardless of whether either or both options is used, appropriate follow-up after discharge is essential. Regardless of whether either or both options is used, appropriate follow-up after discharge is essential.

26. Hospital Policies and Procedures Hospitals should provide written and verbal information for parents at the time of discharge, explaining jaundice, the need to monitor for it, and how to monitor. Hospitals should provide written and verbal information for parents at the time of discharge, explaining jaundice, the need to monitor for it, and how to monitor. Parent information handouts are available at www.aap.org/family/jaundicefaq.htm, both in English and Spanish. Parent information handouts are available at www.aap.org/family/jaundicefaq.htm, both in English and Spanish. www.aap.org/family/jaundicefaq.htm

27. Timing of Follow-up Infants discharged before 24 hours of age should be seen by age 72 hours. Infants discharged before 24 hours of age should be seen by age 72 hours. Discharge between 24-47.9 hours should be seen by age 96 hours. Discharge between 24-47.9 hours should be seen by age 96 hours. Discharge between 48 and 72 hours should be seen by age 120 hours. Discharge between 48 and 72 hours should be seen by age 120 hours.

28. Timing of Follow-up (cont.) If follow-up cannot be ensured in the presence of increased risk for developing severe hyperbilirubinemia, it may be necessary to delay discharge until follow-up can be ensured or the time of greatest risk (72-96 hours of age) has passed. If follow-up cannot be ensured in the presence of increased risk for developing severe hyperbilirubinemia, it may be necessary to delay discharge until follow-up can be ensured or the time of greatest risk (72-96 hours of age) has passed.

29. Follow-up Assessment Should include the baby’s weight and percent change from birth, adequacy of intake, pattern of voiding and stooling, and the presence or absence of jaundice. Should include the baby’s weight and percent change from birth, adequacy of intake, pattern of voiding and stooling, and the presence or absence of jaundice. Clinical judgment should guide the need for a repeat bilirubin. Clinical judgment should guide the need for a repeat bilirubin. If there is any doubt about the degree of jaundice, measure the bilirubin. If there is any doubt about the degree of jaundice, measure the bilirubin.

30. Treatment Treatment recommendations for phototherapy and exchange transfusion are found in figures 3 and 4. The direct bilirubin should not be subtracted from the total bilirubin. Treatment recommendations for phototherapy and exchange transfusion are found in figures 3 and 4. The direct bilirubin should not be subtracted from the total bilirubin. If the bilirubin does not fall or continues to rise despite intensive phototherapy, hemolysis is likely occurring. If the bilirubin does not fall or continues to rise despite intensive phototherapy, hemolysis is likely occurring.

31. Treatment (cont.) If the bilirubin is at an exchange level or is 25 or more, do not send the baby to the ER. Rather, directly admit the infant and begin intensive phototherapy while awaiting the exchange transfusion to be organized and done. If the bilirubin is at an exchange level or is 25 or more, do not send the baby to the ER. Rather, directly admit the infant and begin intensive phototherapy while awaiting the exchange transfusion to be organized and done.

32. Treatment (cont.) Immediate exchange transfusion is recommended in any jaundiced baby who shows the signs of intermediate to advanced stages of acute bilirubin encephalopathy (hypertonia, arching, retrocollis, opisthotonos, fever, high-pitched cry) even if the bilirubin is falling. Immediate exchange transfusion is recommended in any jaundiced baby who shows the signs of intermediate to advanced stages of acute bilirubin encephalopathy (hypertonia, arching, retrocollis, opisthotonos, fever, high-pitched cry) even if the bilirubin is falling.

33. Table 1. Laboratory Evaluation of the Jaundiced Infant of 35 or More Weeks’ Gestation IndicationsAssessments Jaundice in first 24 h Jaundice appears excessive for infant’s age Infant receiving phototherapy or TSB rising rapidly (ie, crossing percentiles [Fig 2]) rapidly (ie, crossing percentiles [Fig 2]) and unexplained by history and physical and unexplained by history and physical examination examination TSB concentration approaching exchange levels or not responding to phototherapy or not responding to phototherapy Elevated direct (or conjugated) bilirubin level Jaundice present at or beyond age 3 wk, or sick infant sick infant Measure TcB and/or TSB Measure TCB and/or TSB Blood type and Coombs’ test, if not obtained with cord blood cord blood Complete blood count and smear Measure direct or conjugated bilirubin It is an option to perform reticulocyte count, G6PD, and ETCO c, if available G6PD, and ETCO c, if available Repeat TSB in 4-24 h depending on infant’s age and TSB level and TSB level Perform reticulocyte count, G6PD, albumin, ETCO c, if available ETCO c, if available Do urinalysis and urine culture. Evaluate for sepsis if indicated by history and physical examination sepsis if indicated by history and physical examination Total and direct (or conjugated) bilirubin level If direct bilirubin elevated, evaluate for causes of cholestasis cholestasis Check results of newborn thyroid and galactosemia screen, and evaluate infant galactosemia screen, and evaluate infant for signs or symptoms of hypothyroidism for signs or symptoms of hypothyroidism

35. Table 4. Risk Zone as a Predictor of Hyperbilirubinemia 39 TSB Before Discharge Newborns (Total = 2840), n (%) Newborns Who Subsequently Developed a TSB Level >95 th Percentile, n (%) High-risk zone (>95 th percentile) High Intermediate-risk zone Low intermediate-risk zone Low-risk zone 172 (6.0) 356 (12.5) 556 (19.6) 1756 (61.8) 68 (39.5) 46 (12.9) 12 (2.26) 0