premature babies and jaundice
DESCRIPTION
International conference «Actual approaches to the extremely preterm babies: International experience and Ukrainian realities» (Kyiv, Ukraine, March 5-6, 2013)TRANSCRIPT
Premature Babies and Jaundice The International Neonatology Conference
March 5-6, 2013 Kiev, Ukraine
Ann R Stark, MD Professor of Pediatrics Vanderbilt University
Nashville, Tennessee, USA
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
Epidemiology of Jaundice
• 85% of infants > 35 weeks gestation have visible jaundice due to hyperbilirubinemia in the first week after birth – Bhutani, Stark et al, J Pediatr 2012 Epub
• Nearly all preterm newborns have hyperbilirubinemia
1.2 – 2.5 kg
Peak Bilirubin Level Later and Higher in Preterm Infants
Billing BH. BMJ 1954; 2:1263-5
Peak Level Day of Age at Peak
Bilirubin Production
HEME
BILIVERDIN
Heme oxygenase
NADPH Fe + CO
BILIRUBIN
Biliverdin reductase
Binds to ferritin
Exhaled
Heme Catabolism
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
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
Ohls RK in Polin, Fox, Abman (eds). Fetal and Neonatal Physiology, 4th ed. 2011 Saunders Ch 44.
Bilirubin production in newborn approximately 8.5 mg/kg/day, about twice adult rate
Production
Clearance & conjugation (immature liver)
Enterohepatic circulation
Elimination
Red cell breakdown
Balance of Production and Elimination = Bilirubin Level
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
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
Range of Bilirubin Levels Used to Start Phototherapy After 72 Hours of Age
Median and range, 163 hospitals
Rennie JM. Arch Dis Child Fetal Neonatal Ed 2009;94:F323
Variable Bilirubin Levels Used to Start Phototherapy or Exchange Transfusion
10 Dutch NICUs Birth weight 1-1.5 kg Median and range
Van Imhoff DE. Early Hum Dev 2011; 87:521
• Globus pallidus
• VIII (auditory) nerve
• Effects on neuronal development
Neurological Injury Caused by Bilirubin
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
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
Kernicterus With Low Bilirubin
Gestation(wk)
n Peak TSB (mg/dL)
Clinical Course
31 34
1 1
13.1 14.7
RDS, possible sepsis, apnea Low glucose; no neuro signs
25 28 29
3 1 1
8.7-12 11.9 10.9
HFOV, IVH, NEC (1) HFOV, IVH IMV, pneumothorax
Sugama SS. Pediatr Neurol 2001; 25:328 Govaert P. Pediatrics 2003; 112:1256
15/16 preterm infants developed choreoathetosis All had classic MRI findings of kernicterus
Kernicterus With Low Bilirubin
Gestation(wk)
n Peak TSB (mg/dL)
Clinical Course
25 26 34
4 2 1
10-15.9 7.1-9.6
17.4 (50d)
RDS, IMV, sepsis, BPD RDS, IMV, BPD No complications
24
26
1
1
7.5
9.9
Twin-twin, IMV, IVH, perforation, PDA ligation Twin (other acardia), heart failure, IVH
15/16 preterm infants developed choreoathetosis All had classic MRI findings of kernicterus
Okumara A. Pediatrics 2009; 123:e1052 Moll M. Neonatology 2011; 99:90
MRI During Infancy
T2 weighted images High intensity in globus pallidus
Okimura A. Pediatrics 2009; 123:e1052
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
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
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
Bilirubin and Outcome in Preterm Infants
-10 mg/dL
-15 mg/dL • 724 infants 24 to 32 weeks gestational age • 87% evaluated at 2 yr • Serum bilirubin from clinical database • Low threshold for phototherapy…
Mazeiras G. PLoS ONE 2012; e30900
Only difference in outcome was in the highest third in the smallest infants
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
Peak TSB is Associated with Death or Neurodevelopmental Impairment
Oh W. Pediatrics 2003; 112:773
Adjusted analysis
Peak TSB is Associated with Need for Hearing Aids
Oh W. Pediatrics 2003; 112:773
Adjusted analysis
Peak TSB is Associated with Psychomotor Developmental Index <70
Oh W. Pediatrics 2003; 112:773 Adjusted analysis
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
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
Phototherapy Trial Results
Aggressive n=990
Conservative n=984
p
TSB mean (1-14 d) 4.7+1.1 6.2+1.5 <0.001
TSB peak (1-14 d) 7.0+1.8 9.8+2.1 <0.001
Duration PhotoRx - hr 88+48 35+31 <0.001
Exchange Transfusions 2 3 NS
Morris BH. N Engl J Med 2008; 359:1885
Phototherapy Trial Outcomes AGG % CON % RR
Death or Impairment
52 55 0.94 (0.87-1.02)
Death 24 23 1.05 (0.09-1.22)
Impairment 26 30 0.86 (0.74-0.99)*
Profound impairment (<50)
9 13 0.68(0.52-0.89)*
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
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)
Morris BH. N Engl J Med 2008; 359:1885
Rate of death increased by 5% and neurodevelopmental impairment decreased by 5% - neither significant, but potential increase in rate of death is concerning
NIH Trial 1974-76 Treatment Control RR
<1000 g
Death 59% 40% 1.49 (0.93-2.40)
Lipsitz PJ. Pediatrics 1985;75:422
Bilirubin Levels and Outcomes in Survivors
Yes No p
Neurodevelopmental Impairment (n) 510 994
Mean TSB (14 d) mg/dL 5.4+1.6 5.4+1.5 0.45
Peak TSB mg/dl 8.6+2.3 8.3+2.3 0.02
Severe hearing loss (n) 35 1870
Mean TSB (14 d) mg/dL 6.5+1.7 5.4+1.5 <0.001
Peak TSB mg/dl 10.5+2.3 8.4+2.3 <0.001
Morris BH. N Engl J Med 2008; 359:1885
Peak Bilirubin and Neurodevelopmental Impairment
Substantial overlap of peak values between groups
Morris BH. N Engl J Med 2008; 359:1885
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
Suggested Use of Phototherapy and Exchange Transfusion - < 35 weeks
Maisels MJ et al. J Perinatol 2012; 32:660
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
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