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Premature Babies and Jaundice

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International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)

International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)

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  • 1. Premature Babies and JaundiceThe International Neonatology Conference March 5-6, 2013 Kiev, Ukraine Ann R Stark, MD Professor of Pediatrics Vanderbilt University Nashville, Tennessee, USA
  • 2. Management of Hyperbilirubinemia in Preterm Infants• Evidence to support an approach• Evidence for injury – Kernicterus at autopsy – Kernicterus and imaging – Neurodevelopment and bilirubin• Phototherapy - effective and safe? – Observational data – Randomized trial• New guidelines – expert consensus
  • 3. Epidemiology of Jaundice• 85% of infants > 35 weeks gestation have visiblejaundice due to hyperbilirubinemia in the first weekafter birth – Bhutani, Stark et al, J Pediatr 2012 Epub• Nearly all preterm newborns have hyperbilirubinemia
  • 4. Peak Bilirubin Level Later and Higher in Preterm Infants 1.2 – 2.5 kg Peak Level Day of Age at Peak Billing BH. BMJ 1954; 2:1263-5
  • 5. Bilirubin Production Heme Catabolism HEME Binds to ferritinNADPH Fe + CO Exhaled Hemeoxygenase BILIRUBIN BILIVERDIN Biliverdin reductase
  • 6. Heme Catabolism• Catabolism of erythrocytes – about 80%• Turnover of nonhemoglobin hemoproteins – Catalase, myglobin, cytochromes, nitric oxide synthase• Ineffective erythropoiesis• Newborns have more red blood cells (higher hematocrit) and shorter red blood cell lifespan than adults
  • 7. Erythrocyte Lifespan is Shorter in Newborns than Adults Lifespan (days) Adult 110-120 Term newborn 60 -90 Preterm newborn 35-50**Shorter at lower gestational ages Bilirubin production in newborn approximately 8.5 mg/kg/day, about twice adult rate Ohls RK in Polin, Fox, Abman (eds). Fetal and Neonatal Physiology, 4th ed. 2011 Saunders Ch 44.
  • 8. Balance of Production and Elimination = Bilirubin Level Production Elimination Clearance & conjugation Red cell (immature liver) breakdown Enterohepatic circulation
  • 9. Elimination is also Decreased• Slower hepatic uptake of free bilirubin from blood – Low level of ligandin which controls uptake into hepatocyte• Lower concentration of uridine diphosphoglucoronate transferase (UGT) so decreased conjugation• Increased enteropatic circulation – Beta-glucuronidase in small intestine and often in breast milk – High concentration of unconjuated bilirubin in meconium• Decreased bilirubin binding capacity so more free bilirubin to enter brain
  • 10. No Consistent Approach to Treatment• American Academy of Pediatrics guideline for management of hyperbilirubinemia is limited to infants > 35 weeks gestation• Few published guidelines address treatment thresholds for preterm infants – UK (2010); Norway (2010); Netherlands (2011)• NICUs typically developed their own guideline – Wide range of treatment thresholds at varying gestation, birth weight, postnatal age
  • 11. Range of Bilirubin Levels Used to Start Phototherapy After 72 Hours of AgeMedian and range, 163 hospitals Rennie JM. Arch Dis Child Fetal Neonatal Ed 2009;94:F323
  • 12. Variable Bilirubin Levels Used to Start Phototherapy or Exchange Transfusion10 Dutch NICUsBirth weight 1-1.5 kgMedian and range Van Imhoff DE. Early Hum Dev 2011; 87:521
  • 13. Neurological Injury Caused by Bilirubin• Globus pallidus• VIII (auditory) nerve• Effects on neuronal development
  • 14. Kernicterus at Autopsy in Preterm Infants• NICHD Phototherapy Study 1974-76 – Infants < 2.5 kg birth weight randomly assigned to phototherapy or control at 24 hr of age for 96 hr – Rate of exchange transfusion lower in phototherapy (4.1%) than control (24.4%)• 119/1063 (11%) infants died; 76 (64%) had autopsies• 4/76 (5%) had kernicterus – Birth weight 760-1260 gm; bilirubin 6.5 – 14 mg/dL (110 – 238 µmol/L) Lipsitz PJ. Pediatrics 1985;75:422
  • 15. Kernicterus at Autopsy• Retrospective study of all autopsies 1984-93 at one hospital; < 34 weeks, lived at least 48 hrs; correlated with clinical information and peak serum bilirubin (TSB)• 3 of 81 (4%) infants had kernicterus – 24,25,33 weeks with other illness – Peak TSB 11.3 – 26 mg/dL (192-442 µmol/L)• 78 without kernicterus – Peak TSB 3.6-22.5 mg/dL (61-382 µmol/L), greater than NICHD trial exchange transfusion threshold Watchko JF. Pediatrics 1994; 93:996
  • 16. Kernicterus With Low Bilirubin15/16 preterm infants developed choreoathetosisAll had classic MRI findings of kernicterusGestation n Peak TSB Clinical Course (wk) (mg/dL) 31 1 13.1 RDS, possible sepsis, apnea 34 1 14.7 Low glucose; no neuro signs 25 3 8.7-12 HFOV, IVH, NEC (1) 28 1 11.9 HFOV, IVH 29 1 10.9 IMV, pneumothorax Sugama SS. Pediatr Neurol 2001; 25:328 Govaert P. Pediatrics 2003; 112:1256
  • 17. Kernicterus With Low Bilirubin15/16 preterm infants developed choreoathetosisAll had classic MRI findings of kernicterusGestation n Peak TSB Clinical Course (wk) (mg/dL) 25 4 10-15.9 RDS, IMV, sepsis, BPD 26 2 7.1-9.6 RDS, IMV, BPD 34 1 17.4 (50d) No complications 24 1 7.5 Twin-twin, IMV, IVH, perforation, PDA ligation 26 1 9.9 Twin (other acardia), heart failure, IVHOkumara A. Pediatrics 2009; 123:e1052Moll M. Neonatology 2011; 99:90
  • 18. MRI During Infancy T2 weighted images High intensity in globus pallidus Okimura A. Pediatrics 2009; 123:e1052
  • 19. Is Increased Bilirubin Associated with Poor Neurodevelopmental Outcome?• 6 year follow-up of NICHD phototherapy trial (1974-76)• Evaluated 224/396 (56%) of children in control group; 54 (24%) had exchange transfusions – Neurologic exam; IQ testing (Wechsler)• No association between peak bilirubin levels, duration of hyperbilirubinemia, bilirubin- albumin binding and cerebral palsy or IQ – No athetoid cerebral palsy Scheidt PC. Pediatrics 1991;87:797
  • 20. Is Increased Bilirubin Associated with Poor Neurodevelopmental Outcome?• 495 infants 500-1500 g birth weight• Evaluated at 1 year corrected age• Peak bilirubin level from medical record• Adjusted for intracranial abnormalities (IVH)• No association between peak bilirubin level and developmental outcome O’Shea TM. Pediatrics 1992; 90:888
  • 21. Is Increased Bilirubin Associated with Poor Neurodevelopmental Outcome?• Retrospective study of 128 infants < 27 weeks and < 800 g born 1980-89• Follow-up at 18 months corrected age• No association of neurodevelopmental impairment and TSB > 200 µmol/L (11.7 mg/dL)• 15 infants were blind: all < 26 weeks – Associated with low peak TSB < 160 µmol/L and longer duration of phototherapy Yeo KL. Pediatrics 1998; 102:1426
  • 22. Bilirubin and Outcome in Preterm Infants • 724 infants 24 to 32 weeks -15 mg/dL gestational age -10 mg/dL • 87% evaluated at 2 yr • Serum bilirubin from clinical database • Low threshold for phototherapy… Only difference in outcome was in the highest third in the smallest infants Mazeiras G. PLoS ONE 2012; e30900
  • 23. Extremely Low Birth Weight Observational Study• Retrospective analysis of 2575 infants 401- 1000 g birth weight in 12 Neonatal Research Network Centers, born 1994-97• Peak TSB measured during first 2 weeks• Evaluated at 18-22 months corrected age Oh W. Pediatrics 2003; 112:773
  • 24. Peak TSB is Associated with Death or Neurodevelopmental ImpairmentAdjusted analysis Oh W. Pediatrics 2003; 112:773
  • 25. Peak TSB is Associated with Need for Hearing AidsAdjusted analysis Oh W. Pediatrics 2003; 112:773
  • 26. Peak TSB is Associated with Psychomotor Developmental Index <70Adjusted analysis Oh W. Pediatrics 2003; 112:773
  • 27. Network Retrospective Study• Peak TSB in first two weeks in extremely low birth weight infants is associated with – Death or neurodevelopmental impairment – Need for hearing aids – Psychomotor Developmental Index < 70• Is not associated with – Cerebral palsy – Mental developmental index < 70 – Neurodevelopmental impairment Oh W. Pediatrics 2003; 112:773
  • 28. Aggresssive vs Conservative Phototherapy – NICHD Network• Extremely low birth weight infants• Randomized at 12 to 36 hours - phototherapy – Aggressive: at enrollment; continue or restart if • 501-750g: 5 mg/dL (85 µmol/L) or higher • 751-1000g: 5 mg/dL (85 µmol/L) in first 7 days, 7 mg/dL (119 µmol/L) in next 7 days – Conservative: • 501-750 g: 8 mg/dL mg/dL (136 µmol/L) or higher • 751-1000g: 10 mg/dL mg/dL (170 µmol/L) or higher• Exchange Transfusion threshold – 501-750 g: 13 mg/dL (222 µmol/L) – 751-1000g: 15 mg/dL (256 µmol/L)• Evaluated at 18-22 months corrected age Morris BH. N Engl J Med 2008; 359:1885
  • 29. Phototherapy Trial Results Aggressive Conservative p n=990 n=984TSB mean (1-14 d) 4.7+1.1 6.2+1.5 <0.001TSB peak (1-14 d) 7.0+1.8 9.8+2.1 <0.001Duration PhotoRx - hr 88+48 35+31 <0.001Exchange Transfusions 2 3 NS Morris BH. N Engl J Med 2008; 359:1885
  • 30. Phototherapy Trial Outcomes AGG % CON % RRDeath or 52 55 0.94 (0.87-1.02)ImpairmentDeath 24 23 1.05 (0.09-1.22)Impairment 26 30 0.86 (0.74-0.99)*Profound 9 13 0.68(0.52-0.89)*impairment (<50)Severe hearing loss 1 3 0.32(0.15-0.68)*Athetosis <1 1 0.20(0.04-0.90)* Morris BH. N Engl J Med 2008; 359:1885
  • 31. Phototherapy Outcomes 500-750 g Aggressive Conservative RR Death 39% 34% 1.13 (0.96-1.34) Impairment 27% 32% 0.86 (0.70-1.05) Rate of death increased by 5% and neurodevelopmental impairment decreased by 5% - neither significant, but potential increase in rate of death is concerningNIH Trial 1974-76 Treatment Control RR<1000 gDeath 59% 40% 1.49 (0.93-2.40)Morris BH. N Engl J Med 2008; 359:1885 Lipsitz PJ. Pediatrics 1985;75:422
  • 32. Bilirubin Levels and Outcomes in Survivors Yes No pNeurodevelopmental Impairment (n) 510 994Mean TSB (14 d) mg/dL 5.4+1.6 5.4+1.5 0.45Peak TSB mg/dl 8.6+2.3 8.3+2.3 0.02Severe hearing loss (n) 35 1870Mean TSB (14 d) mg/dL 6.5+1.7 5.4+1.5 <0.001Peak TSB mg/dl 10.5+2.3 8.4+2.3 <0.001 Morris BH. N Engl J Med 2008; 359:1885
  • 33. Peak Bilirubin and Neurodevelopmental ImpairmentSubstantial overlap of peak values between groups Morris BH. N Engl J Med 2008; 359:1885
  • 34. Unbound Bilirubin• Most bilirubin in circulation is bound to albumin – Binding depends on concentrations of each and binding affinity, which increases with gestational age – Binding affinity may be decreased by sepsis, acidosis, free fatty acids, albumin-binding drugs• Unbound bilirubin might contribute to neurotoxicity – Might be related to both unbound and total – No commercial instrument available
  • 35. Suggested Use of Phototherapy and Exchange Transfusion - < 35 weeks Maisels MJ et al. J Perinatol 2012; 32:660
  • 36. An Approach – but read the footnotes• Operational thresholds – expert consensus• Wide ranges reflect uncertainty• Lower levels if greater risk – Lower gestation, albumin <2.5 g/dL, hemolytic disease, clinically unstable• Exchange transfusion for encephalopathy• Measure albumin• Use postmenstrual age• Use lower irradiance for <1 kg; increase exposed surface area before increasing irradiance Maisels MJ et al. J Perinatol 2012; 32:660
  • 37. Summary• Preterm infants are at risk – kernicterus can occur at low bilirubin levels• Little good evidence is available• Use of unbound bilirubin needs to be tested• Guideline based on expert consensus – Be aware of risk factors – Use phototherapy with care in the smallest infants• Evaluate new recommendations with follow- up

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