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)

Transcript of Premature Babies and Jaundice

  • 1. Premature Babies and JaundiceThe International Neonatology Conference March 5-6, 2013Kiev, UkraineAnn R Stark, MD Professor of PediatricsVanderbilt UniversityNashville, Tennessee, USA

2. Management of Hyperbilirubinemia inPreterm 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 Infants1.2 2.5 kg Peak Level Day of Age at PeakBilling BH. BMJ 1954; 2:1263-5 5. Bilirubin ProductionHeme CatabolismHEME Binds to ferritinNADPH Fe + COExhaledHemeoxygenase BILIRUBINBILIVERDINBiliverdinreductase 6. Heme Catabolism Catabolism of erythrocytes about 80% Turnover of nonhemoglobin hemoproteins Catalase, myglobin, cytochromes, nitric oxidesynthase Ineffective erythropoiesis Newborns have more red blood cells (higherhematocrit) and shorter red blood celllifespan than adults 7. Erythrocyte Lifespan is Shorter in Newborns than Adults Lifespan (days) Adult110-120 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 rateOhls RK in Polin, Fox, Abman (eds). Fetal and Neonatal Physiology, 4th ed. 2011 Saunders Ch 44. 8. Balance of Production and Elimination = Bilirubin LevelProduction EliminationClearance & conjugationRed cell(immature liver)breakdownEnterohepatic 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 diphosphoglucoronatetransferase (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 freebilirubin to enter brain 10. No Consistent Approach to Treatment American Academy of Pediatrics guideline formanagement of hyperbilirubinemia is limitedto infants > 35 weeks gestation Few published guidelines address treatmentthresholds for preterm infants UK (2010); Norway (2010); Netherlands (2011) NICUs typically developed their own guideline Wide range of treatment thresholds at varyinggestation, birth weight, postnatal age 11. Range of Bilirubin Levels Used to StartPhototherapy 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 rangeVan 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 tophototherapy 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%) hadautopsies 4/76 (5%) had kernicterus Birth weight 760-1260 gm; bilirubin 6.5 14 mg/dL(110 238 mol/L)Lipsitz PJ. Pediatrics 1985;75:422 15. Kernicterus at Autopsy Retrospective study of all autopsies 1984-93 atone hospital; < 34 weeks, lived at least 48 hrs;correlated with clinical information and peakserum 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 mol/L) 78 without kernicterus Peak TSB 3.6-22.5 mg/dL (61-382 mol/L), greater than NICHD trial exchange transfusion thresholdWatchko 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)31113.1RDS, possible sepsis, apnea34114.7Low glucose; no neuro signs253 8.7-12 HFOV, IVH, NEC (1)28111.9HFOV, IVH29110.9IMV, 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 TSBClinical Course(wk) (mg/dL)254 10-15.9 RDS, IMV, sepsis, BPD262 7.1-9.6 RDS, IMV, BPD341 17.4 (50d) No complications2417.5 Twin-twin, IMV, IVH, perforation, PDA ligation2619.9 Twin (other acardia), heart failure, IVHOkumara A. Pediatrics 2009; 123:e1052Moll M. Neonatology 2011; 99:90 18. MRI During InfancyT2 weighted imagesHigh intensity in globuspallidus 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 controlgroup; 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 withPoor 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 leveland developmental outcomeOShea TM. Pediatrics 1992; 90:888 21. Is Increased Bilirubin Associated with Poor Neurodevelopmental Outcome? Retrospective study of 128 infants < 27 weeksand < 800 g born 1980-89 Follow-up at 18 months corrected age No association of neurodevelopmentalimpairment and TSB > 200 mol/L (11.7mg/dL) 15 infants were blind: all < 26 weeks Associated with low peak TSB < 160 mol/L andlonger duration of phototherapyYeo KL. Pediatrics 1998; 102:1426 22. Bilirubin and Outcome in Preterm Infants 724 infants 24 to 32 weeks-15 mg/dLgestational age-10 mg/dL 87% evaluated at 2 yr Serum bilirubin fromclinical database Low threshold forphototherapyOnly difference in outcomewas in the highest third in thesmallest infantsMazeiras G. PLoS ONE 2012; e30900 23. Extremely Low Birth WeightObservational Study Retrospective analysis of 2575 infants 401-1000 g birth weight in 12 Neonatal ResearchNetwork 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 orNeurodevelopmental 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