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