Hyperbilirubinemia and Kernicterus: Not Gone and Not Forgotten M.Jeffrey Maisels, MD, DSc Beaumont Children’s Hospital Royal Oak, MI [email protected] Why worry about jaundice? • Occurs in almost all babies • Source of anxiety and aggravation to families and doctors • Can lead to kernicterus 1 Kernicterus Registry • 125 cases in USA of infants born between 1979 - 2002 and discharged as “healthy newborns” • Sources - parents, physicians, nurses, literature, medico-legal • 69% male • Nearly all breastfed • 97% discharged <72 hr (57.5% <48hr) • 40% <38 weeks Bhutani et al, J Perinatol 2004;24:650 Kernicterus in Healthy Breastfed Term Infants Case Sex BW (g) Gestation (wk) Peak serum bilirubin (mg/dL) 1 M 2820 37 49.7 2 M 3771 37 39.0 5 3 M 4280 39 40.3 10 4 F 4026 37 44.7 7 5 F 3375 38 44.7 4 6 M 3175 37 41.4 6 Age at peek bilirubin (days) 7 Causes of Hyperbilirubinemia in Kernicterus Registry •Idiopathic 37% •Hemolysis 14% •G6PD deficiency 25% •Other 23% Bhutani et al, Pediatr Res 2004;24:650 Kernicterus • Still occurring and can occur in a healthy breastfed infant • Relatively rare disease (8,000 new cases of CP/yr in the US) • But, unlike other causes of CP, almost always preventable Maisels MJ. Pediatrics 1995;96:730 2 Why is this happening? Natural History of Bilirubinemia Have a high degree of humility when you do a visual estimate of the bilirubin level Newsweek Aug 4, 1997 3 RISK OF BEING READMITTED FOR PHOTOTHERAPY 30,000 discharges from well baby nursery 1988-94 4.2/1,000 readmitted for phototherapy RISK FACTOR ODDS RATIO 35 - 36 wks 13.2 36 – 38 wks 7.5 Breast feeding 4.2 Jaundice in nursery 7.8 LOS < 72 h 3.2 Newsweek Aug 4, 1997 Maisels MJ, Pediatrics 1998;101:995 Kernicterus Registry Practitioners do not assess jaundice risks the way they assess other risks • 69% male • Nearly all breastfed • 97% discharged <72 hr (57.5% <48hr) • 40% <38 weeks Bhutani et al, J Perinatol 2004;24:650 Other important risk factors • Jaundice in first 24 hours • Previous sibling jaundiced/phototherapy • Cephalhematoma or bruising (vacuum extraction) • ABO incompatibility with positive DAT • Predischarge bilirubin >95th percentile 4 Effect of Breastfeeding Frequency in First 24 Hours and Bilirubin > 15mg/dL on Day 6 in Japanese Newborns Percent > 15 mg/dL Day 6 Modified from Yamauchi, Pediatrics 1990; 86: 171 Effective breastfeeding is one intervention that could significantly reduce the risk of severe hyperbilirubinemia 30 25 20 15 10 5 0 0-2 3-4 5-6 7-8 Feedings in first 24 hours 9-11 Should you supplement breastfed newborns with water? 5 AMERICAN ACADEMY OF PEDIATRICS Subcommittee on Hyperbilirubinemia Clinical Practice Guideline: Management of Hyperbilirubinemia in the Newborn Infant > 35 Weeks of Gestation Pediatrics 2004 (July);114:297 AAP Jaundice Guideline The 10 Key Elements 1. Promote and support successful breastfeeding. 2. Establish nursery protocols – include circumstances in which nurses can order a bilirubin. 3. Measure TSB or TcB if jaundiced in the first 24 hours. 4. Visual estimation of jaundice can lead to errors, particularly in darkly pigmented infants. 5. Interpret bilirubin levels according to the infant’s age in hours. Risk Assessment New Recommendation by Advisory Group • Do this on every baby -Clinical risk factors (gestation most important) -Measure TcB or TSB AAP Jaundice Guideline The 10 Key Elements (cont) 6. Infants <38 weeks, particularly if breastfed, are high risk 7. Perform risk assessment prior to discharge. 8. Give parents written and oral information . 9. Provide appropriate follow-up based on time of discharge and risk assessment. 10. Treat newborns, when indicated, with phototherapy or exchange transfusion. Predictive Ability of a Predischarge Hour-specific Serum Bilirubin for Subsequent Significant Hyperbilirubinemia in Healthy Term and Near-Term Newborns Bhutani VK, Johnson L, Sivieri EM. Pediatrics 1999;103:6-14 6 25 Serum Bilirubin (mg/dl) 20 95 th%ile High Risk Zone 75 th%ile e Zon Risk diate rme Inte one Z High k Ris diate rme Inte Low 15 10 40 th%ile Low Risk Zone 5 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Postnatal Age (hours) Bhutani, Pediatrics 1999; 103: 6-14 Newman, Arch Ped Adolesc Med 2005;159:113 Conclusion Risk of developing hyperbilirubinemia can be accurately assessed by measuring predischarge TSB or TcB and gestational age 25 Serum Bilirubin (mg/dl) 20 95 th%ile High Risk Zone 75 th%ile e Zon Risk diate rme Inte e High Zon Risk diate rme Inte 15 40 th%ile Low 10 Low Risk Zone 5 0 0 12 24 36 48 60 72 84 96 108 120 132 144 Postnatal Age (hours) Keren. Pediatrics 2008; 121: e170-e179 Follow-up • Provide appropriate follow-up , according to time of discharge and risk factors • If cannot do this, assess risk and do TcB or TSB level, get outpatient TSB prn. If you discharge an infant before age 72 hours, you or a nurse should see the infant within 2 days of discharge 7 Implementation Give Physicians the Tools to Implement the Guidelines Give Physicians the Tools to Implement the Guidelines Risk assessment tool at bedside Wallet-sized nomogram and guidelines PDA Hospital computer access and website Lab reports of bilirubin to include age in hours and percentile with recommendations for follow up and phototherapy Risk assessment tool at bedside Predischarge Assessment for the Risk of Hyperbilirubinemia in Infants >35 wk Gestation (Pediatrics 2004;114:257-313) Phototherapy Guidelines for Infants >35 wks Gestation 25 Guidelines refer to use of intensive phototherapy. Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin Risk factors*= isoimmune hemolytic disease, G6PD deficiency, asphyxia, 25 Time Age (hrs) TcB TSB Initials Total Serum Bilirubin (mg/dL0 Date 20 Serum Bilirubin (mg/dl) 95 th %ile High Risk Zone 15 Hig h Inte Lo w 10 rm edi Interm ate ed iate ne 75 th%ile ne k Zo Ris 40 th %ile Ris k Zo Low Risk Zone 5 20 respiratory distress, significant lethargy, temperature instability, sepsis, acidosis, or albumin < 3.0 g/dL (if measured) For well infants 35-36 6/7 wk can adjust TSB levels for intervention around the medium risk line. It is an option to intervene at lower TSB levels for infants closer to 35 wks and at higher TSB levels for those closer to 37 6/7 wks. 15 It is an option to provide conventional phototherapy in hospital or at home at TSB levels 2-3 mg/dL below those shown but home phototherapy should not be used in any infant with risk factors. 10 *The risk factors listed above are conditions that might affect the likelihood of brain damage at different bilirubin levels. These factors increase the risk of brain damage because of their negative effects on albumin binding of bilirubin, the integrity of the blood brain barrier, and the susceptibility of the brain cells to damage by bilirubin. 5 Infants at lower risk = > 38 wk. and well Infants at medium risk= > 38 wk. +risk factors or 35 – 37 6/7 wk. & well Bhutani, Pediatrics1999;103:6 Infants at higher risk= 35-37 6/7 wk. + risk factors 0 TcB – Transcutaneous Bilirubin TSB – Total Serum Biilirubin/Direct 0 12 24 36 48 60 72 84 96 108 120 132 0 144 B irth Postnatal Age (hours) 24 h 48 h 72 h 96 h 5 Days 6 Day s 7 Days Age Risk Factors 3 Risk Factors forRisk Development3of Severe Hyperbilirubinemia Major Minor Risk Predischarge TSB or TcB (see nomogram above) In high zone (>95%) In high intermediate zone (>75%) Visible Jaundice First 24 hrs. Before discharge Gestational age 35-36 wks 37-38 wks. Previous sibling Received phototherapy Jaundiced, no phototherapy Blood Groups Hemolytic disease Blood grp. incompatibility with +DAT. Other known hemolytic disease Feeding Exclusive breast (↑risk if poor feeder or ↑ wt. loss ) East Asian Breast fed, nursing well Cephalhematoma or significant bruising Macrosomic infant of IDM,male gender, maternal age >25 yr. Decreased Risk Hispanic (Mexican)? Exclusive formula feeding. African American *unless G^PD def.~12% are G6PD deficient Other factors 25 20 15 Infants at lower risk = > 38 wk. and well Infants at medium risk= > 38 wk. +risk factors or 35 – 37 6/7 wk. & well Follow-up should be provided as follows Any infant discharged before age 72 hours should be seen within 2 days of discharge. *If an infant is discharged before age 72 hours AND if you plan to follow up in more than 2 days, please document your reasons in the chart. The dashed lines for the first 24 hours indicate uncertainty due to a wide range of clinical circumstances and a range of responses to phototherapy Perform immediate exchange if infant shows signs of acute bilirubin encephalopathy, ( hypertonia, arching, retrocollis, opisthotonos, fever, high pitched cry)or if TSB is >5 mg/dL above these lines. Risk factors = isoimmune hemolytic disease, G6PD deficiency, asphyxia, respiratory distress, significant lethargy, temperature instability, sepsis, acidosis. Measure serum albumin and evaluate B/A ratio = bilirubin ( mg/dL) / albumin (g/dL). See the table below. Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin If TSB above exchange transfusion line, repeat every 2-3 hrs until TSB decreases for 2 consecutive measurements. In isoimmune hemolytic disease give IVIG 0.5 – 1g/kg over 2-3 hours if TSB is rising and within 2-3 mg/dL of exchange level. This can be repeated in 12 hr. If infant is well and 35-36 6/7 wk (medium risk) can individualize TSB levels for exchange based on actual gestational age Infants at higher risk= 35-37 6/7 wk. + risk factors 10 Birth 24 h Discharged from hospital after 72 hrs. *The more risk factors present, the greater the risk of developing severe hyperbilirubinemia **If considering phototherapy or exchange transfusion please refer to the back of this page for guidelines and information. Guidelines for Exchange Transfusion in infants > 35 wk Gestation 30 >41 wk (eg. G^PD deficiency) Race 3 Low risk zone (<40%) Total Serum Bilirubin (mg/dL) • • • • • If many risk factors, see earlier. If few risk factors, can see later but document your reasons in chart 48 h 72 h 96 h 5 Days 6 Days 7 Days Age The risk factors listed above are conditions that might affect the likelihood of brain damage at different bilirubin levels. These factors increase the risk of brain damage because of their negative effects on albumin binding of bilirubin, the integrity of the blood brain barrier, and the susceptibility of the brain cells to damage by bilirubin During birth hospitalization, exchange transfusion is recommended if the TSB rises to these levels despite intensive phototherapy. For readmitted infants, if the TSB level is above the exchange level, repeat TSB measurement every 2 to 3 hours and consider exchange, if the TSB remains above the levels indicated after intensive phototherapy for 6 hours. The following B/A ratios can be used together with but not in lieu of the TSB level as an additional factor in determining the need for exchange transfusion. Risk Category B/A Ratio at Which exchange Transfusion Should be considered Lower Risk Medium Risk Higher Risk TSB mg/dL 8.0 7.2 6.8 If the TSB is at or approaching the exchange level, send blood for immediate type and cross match. Blood for exchange transfusion is modified whole blood. (red cells and plasma) cross matched against the mother and compatible with the infant. 8 Give Physicians the Tools to Implement the Guidelines Wallet-sized nomogram and guidelines Quality improvement programs Tony Burgos, MD, MPH Stanford University and Packard Children’s Hospital Chris Longhurst, MD, MS Stanford University and Packard Children’s Hospital Stuart Turner, DVM University of California Davis 9 % infants Scheduled follow up < 3 days after discharge William Beaumont Hospital 100 90 80 70 60 50 40 30 20 10 0 Length of Stay < 48 hrs >48 hrs 1994 Chart review & letter to pediatricians re: guidelines 1995 Data presented to MD’s. Follow up letter 1998 QI monitor 1999 Presentation to MD’s/ Memo to all MD’s. QI monitor and letter to MD if noncompliant 2000 If have a very jaundiced baby, send baby to pediatric floor or NICU not to emergency department 2003 Continue QI monitor and letters to MD’s if not compliant Jaundice is now predominantly an outpatient problem Newborn follow up in one to two weeks is abandonment Drive through deliveries should not be a problem as long as you don’t abandon the baby Need a high degree of humility when assessing jaundice clinically. 10 Follow The AAP Guidelines “This is an age in which one cannot find common sense without a search warrant” No system is perfect, use common sense References: • • • • • • Maisels MJ, Baltz RD, Bhutani VK, et al: Neonatal jaundice and kernicterus. Pediatrics 2001; 108:763 Bhutani VK, Johnson LH, Maisels MJ, et al: Kernicterus: Epidemiological strategies for its prevention through systems-based approaches. J Perinatol 2004;24:650. Johnson LH, Bhutani VK, Brown AK: System-based approach to management of neonatal jaundice and prevention of kernicterus. J Pediatr 2002;140:396 Maisels MJ, Baltz RD, Bhutani V, et al: Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297. 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 Newman TB, 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 George Will • • • • • • References: Moyer VA, Ahn C, Sneed S: Accuracy of clinical judgment in neonatal jaundice. Arch Pediatr Adolesc Med 2000;154:391 Maisels MJ, Ostrea EJ Jr, Touch S, et al: Evaluation of a new transcutaneous bilirubinometer. Pediatrics 2004;113:1628 Rubaltelli FF, Gourley GR, Loskamp N, et al: Transcutaneous bilirubin measurement: A multicenter evaluation of a new device. Pediatrics 2001;107:1264 Newman TB, Escobar GJ, Gonzales VM, et al: Frequency of neonatal bilirubin testing and hyperbilirubinemia in a large health maintenance organization. Pediatrics 1999;104:1198 Newman TB, Liljestrand P, Escobar GJ: Combining clinical risk factors with bilirubin levels to predict hyperbilirubinemia in newborns. Arch Pediatr Adolesc Med 2005;159:113 Ip S, Chung M, Kulig J, O’Brien R, et al: An evidence-based review of important issues concerning neonatal hyperbilirubinemia. Pediatrics 2004;114:e130 References • • • • • • • Huang M-J, Kua K-E, Teng H-C, Tang K-S, Weng H-W, Huang C-S. Risk factors for severe hyperbilirubinemia in neonates. Pediatr Res 2004; 56:682-689. Kaplan M., Hammerman C., Maisels M.J. Bilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation. Pediatrics 2003; 111:886-893. Kaplan M, Hammerman C, Renbaum P, Klein G, Levy-Lahad E. Gilbert's syndrome and hyperbilirubinaemia in ABOincompatible neonates. Lancet 2000; 356:652-653. Watchko J.F. Vigintiphobia revisited. Pediatrics 2005; 115:1747-1753. Maisels M.J., Watchko J.F. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatol Ed 2003; 88:F459-F463. Watchko J.F., Maisels M.J. Jaundice in low birth weight infants pathobiology and outcome. Arch Dis Child Fetal Neonatol Ed 2003; 88:F456-F459. Kaplan M., Hammerman C. Glucose-6-phosphate dehydrogenase-deficient neonates: A potential cause for concern in North America. Pediatrics 2000; 106:1478-1480. References • Sgro M, Campbell D, Shah V. Incidence and causes of severe hyperbilirubinemia in Canada. CMAJ 2006; 175: 587-90 • Canadian Pediatric Society. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks’ gestation) Pediatr Child Health 2007; 12: 1B-112B (suppl). • Manning D et al Prospective surveillance of severe hyperbilirubinemia in the newborn in the UK and Ireland. Arch Dis Child Fetal Neonatal Ed 2007; 92: 342-346 11
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