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
![Page 1: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/1.jpg)
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
![Page 2: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/2.jpg)
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
![Page 3: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/3.jpg)
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
![Page 4: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/4.jpg)
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
![Page 5: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/5.jpg)
Bilirubin Production
HEME
BILIVERDIN
Heme oxygenase
NADPH Fe + CO
BILIRUBIN
Biliverdin reductase
Binds to ferritin
Exhaled
Heme Catabolism
![Page 6: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/6.jpg)
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
![Page 7: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/7.jpg)
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
![Page 8: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/8.jpg)
Production
Clearance & conjugation (immature liver)
Enterohepatic circulation
Elimination
Red cell breakdown
Balance of Production and Elimination = Bilirubin Level
![Page 9: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/9.jpg)
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
![Page 10: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/10.jpg)
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
![Page 11: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/11.jpg)
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
![Page 12: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/12.jpg)
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
![Page 13: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/13.jpg)
• Globus pallidus
• VIII (auditory) nerve
• Effects on neuronal development
Neurological Injury Caused by Bilirubin
![Page 14: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/14.jpg)
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
![Page 15: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/15.jpg)
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
![Page 16: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/16.jpg)
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
![Page 17: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/17.jpg)
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
![Page 18: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/18.jpg)
MRI During Infancy
T2 weighted images High intensity in globus pallidus
Okimura A. Pediatrics 2009; 123:e1052
![Page 19: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/19.jpg)
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
![Page 20: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/20.jpg)
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
![Page 21: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/21.jpg)
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
![Page 22: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/22.jpg)
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
![Page 23: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/23.jpg)
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
![Page 24: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/24.jpg)
Peak TSB is Associated with Death or Neurodevelopmental Impairment
Oh W. Pediatrics 2003; 112:773
Adjusted analysis
![Page 25: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/25.jpg)
Peak TSB is Associated with Need for Hearing Aids
Oh W. Pediatrics 2003; 112:773
Adjusted analysis
![Page 26: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/26.jpg)
Peak TSB is Associated with Psychomotor Developmental Index <70
Oh W. Pediatrics 2003; 112:773 Adjusted analysis
![Page 27: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/27.jpg)
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
![Page 28: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/28.jpg)
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
![Page 29: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/29.jpg)
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
![Page 30: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/30.jpg)
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
![Page 31: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/31.jpg)
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
![Page 32: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/32.jpg)
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
![Page 33: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/33.jpg)
Peak Bilirubin and Neurodevelopmental Impairment
Substantial overlap of peak values between groups
Morris BH. N Engl J Med 2008; 359:1885
![Page 34: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/34.jpg)
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
![Page 35: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/35.jpg)
Suggested Use of Phototherapy and Exchange Transfusion - < 35 weeks
Maisels MJ et al. J Perinatol 2012; 32:660
![Page 36: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/36.jpg)
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
![Page 37: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/37.jpg)
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
![Page 38: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/38.jpg)
![Page 39: Premature Babies and Jaundice](https://reader034.vdocuments.us/reader034/viewer/2022042521/556eb6f5d8b42aa32b8b4aee/html5/thumbnails/39.jpg)