Head, Dept of NeonatologyJubilee Mission Medical College

Thrissur, Kerala

DR V C MANOJ

Approach to Hyperbilirubinemia in Preterm

Approach to Hyperbilirubinemia in Preterm

Dr V C Manoj

Head, Dept of Neonatology

Jubilee Mission Medical College

Thrissur, Kerala

Bhutani and Wong: Bilirubin neurotoxicity in premies, Journal of Clinical Neonatology 2013

Extubated from ventilator support by day 14

Discharged subsequently

11 mg/dL

Neurologic examination: signs of

kernicterus

MRI: Increased signals in the globus

pallidus and signs of periventricular

leukomalacia.

ABR: SN hearing impairment

‘Low Bilirubin Kernicterus’

Preterm Jaundice –When is bilirubin level safe?

The problem:80% of preterm babies in the first week of life !

10 and 12 mg/ dl on D – 5

May not reach normal levels until the end of the first month

Why in preterms?

Erythrocyte, hepatic and gastrointestinal immaturity• Large amount of short-lived red blood cells,

• Deficient hepatic conjugation of bilirubin

• Increase in enterohepatic circulation of bilirubin

Delayed enteral nutrition –• restrict intestinal blood flow and enhance the enterohepatic

reuptake

Blood extravasation –• extensive hematomas in upper and lower limbs due to birth

trauma or by IVH

Risk factors for penetration of bilirubin into the brain:Hypoxemia, Acidosis, Hypothermia,Hypoalbuminemia,Hypercapnia, ….

Some basic hard facts !

• Presence of early-onset of jaundice (age <24 hrs) - a medical emergency

• TSB levels at 24-60 hrs predicts severe hyperbilirubinemia and need for PT

• PT reduces the need and/or use of exchange transfusion

• Both PT and exchange transfusion can individually prevent kernicterus

• The persistence of jaundice beyond age 2 wks warrants further inquiry.

• Detection of jaundice or measurement of TSB has not been shown to prevent kernicterus in any randomized control trial !!

(This kind of a study cannot be done ethically and should not be done)

The ultimate Weapon?

When should you treat?

Prophylactic or Therapeutic?

95 babies < 1500 g

Prophylactic PT (from 12 hrs) Vs Therapeutic PT (when TSB < 8.8 mg/dl)

87 survivors – neurological behaviour followed up

82 up to 12 m and

75 up to 18 m (of corrected gestational age)

Cerebral palsy and death were more frequent in the therapeutic PT group.

The authors conclusion: lower bilirubin levels - associated with a better prognosis

Jangaard, et al, Pediatr Res. 2004

• 9 clinical trials - 3449 infants

• “Phototherapy initiated soon after birth (within 36 hours) for preterm or low birth weight infants may prevent the serum bilirubin from reaching a level that would require exchange transfusion and may reduce the risk of impairment of brain and central nervous system development”

• However, further well- designed studies are needed to evaluate the effects of prophylactic phototherapy on brain and central nervous system development and other long-term outcomes.

2013

Should you be Aggressive?

Bilirubin – One of the antioxidants for the immune deficient preterm with under developed scavenger systems

So why not be gentle on jaundice?

1974 ELBW babies randomly assigned to -- aggressive or conservative phototherapy at 12 to 36 hrs of age.

Primary outcome: composite of death or neurodevelopmental impairment (Determined by investigators who were unaware of the treatment assignments)

Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental

impairment.

But it did significantly reduce the rate of neurodevelopmental impairment alone.

This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth.

?

1974 ELBW babies randomly assigned to -- aggressive or conservative phototherapy at 12 to 36 hrs of age.

Primary outcome: composite of death or neurodevelopmental impairment (Determined by investigators who were unaware of the treatment assignments)

Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental

impairment.

But it did significantly reduce the rate of neurodevelopmental impairment alone.

This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth.

?

Modest Elevations in TSB is associated with Neurodevelopmental Impairment(Recent studies of large populations of ELBW infants) Mazeiras G, et al,. PLoS ONE 2012

Oh W, Tyson JE, Fanaroff AA, et al, Pediatrics 2003

Moderate hyperbilirubinemia in

LBW infants poses no risk of neurotoxicity. O’Shea TM, Dillard RG, et al, Pediatrics 1992

Yeo KL, Perlman M, et al,. Pediatrics 1998;.

Keenan WJ, et al. Pediatrics 1972

Lipsitz PJ, et al, Pediatrics 1985

Govaert P, et al, Pediatrics 2003

Moll M, et al, Neonatology 2011

Sugama S, et al, Pediatr Neurol

2001Mazeiras G, et al, PLoS ONE 2012

‘Low Bilirubin Kernicterus’

Low bilirubin levels may be associated with a better

prognosis in VLBW newborns

Jangaard A, et al, Pediatr Res. 2004

Number needed to harm: 10638 In Downs syndrome - 1285.

(5144849 infants born ≥35 wks POG in California hospitals --1998 – 2007)

Pediatrics, 2016

Why should we be aggressive?

Phototherapy in newborns, according to this review, may increase the odds of developing any cancer by 1.3 times, the odds of leukemia in general by 1.7 times, the odds of myelocytic leukemia by 2.9 times and the odds of kidney cancer by 2.5 times.

Number of studies: 10

Study design: 5 case control and 5 cohort

Total no. of children: 6637417

Five countries: Sweden , USA, UK ,Canada and Taiwan.

A SYSTEMATIC REVIEW AND META-ANALYSIS By Dr Mohammed Abdellatif

BEWARE !!!

What are the Guidelines available?

Comparison of TSB thresholds for the use of phototherapy in preterm infants

Guidelines (in the Management of Preterm Hyperbilirubinemia)

The NICE guidelines

Recommendations for < 23 or POG

TSB based PT thresholds formula:

PT threshold bilirubin (μmol/L) = (gestational age × 10) − 100

Separate nomograms - for infants from 23 to 37 wks POG

The thresholds rise from 40 μmol/L at birth to a plateau TSB level after 72 hours.

The American “Approach”

AAP Committee on Fetus and Newborn (2007) tasked a group of experts to develop guidelines for the Mgt of jaundice <35 weeks POG

High level of evidence in preterm infants is lacking, - The recommendations of Maisels et al. did not meet AAP requirements for guidelines (2012)

Hence called “approach”

TSB treatment thresholds are lower when compared to the NICE guideline, especially for infants of lower GA

TSB treatment thresholds are lower when compared to the NICE guideline, especially for infants of lower GA

Maisels MJ, Watchko JF, Bhutani VK, et al, J Perinatol 2012

Suggested use of phototherapy and exchange transfusion in preterm infants < 35 weeks GA

Norwegian guidelines: Treatment - based on bilirubin levels and birth weight. (Postnatal age is also factored)

Following the introduction of these guidelines, fewer babies in Norway receive PT, and no cases of chronic kernicterus have been reported during this period.

Message

Another Parameter: Bilirubin/Albumin (B/A) ratio

• High bilirubin/albumin (B/A) ratios increase the risk of bilirubin neurotoxicity.

• Is B/A ratio a valuable measure, in addition to the total serum bilirubin (TSB), in the management of hyperbilirubinemia?

Bilirubin Albumin Ratio (BAR) Trial

The Bilirubin Albumin Ratio in the Management of Hyperbilirubinemia in Preterm Infants to Improve Neurodevelopmental Outcome:

A Randomized Controlled Trial – BAR Trial (Netherlands)

615 preterm infants < 32 weeks' gestation or less: Randomly assigned to treatment based on either B/A ratio and TSB thresholds (consensus-based), whichever threshold was crossed first, or on the TSB thresholds only.

The primary outcome: Neurodevelopment at 18 to 24 months' corrected age (Bayley Scales of ID III)

The additional use of B/A ratio in the management of hyperbilirubinemia in preterm infants did not improve their neurodevelopmental outcome.

…. Apps in the Age of Smart Medicine !

Created to provide clinical decision support for treatment of indirect hyperbilirubinemia

• Preterms (27 wks 0 days - 34 wks 6 days)

• PBR serves to operationalize the Maisels 2012 Approach

• As phototherapy and exchange transfusion thresholds are lower at early postnatal age, the tool is intended for use in infants greater than 48 hours of age only.

14

28 6

so finally………..

Newborn infants should have their bilirubin levels screened and assessment of risk factors done prior to hospital discharge

and again within 48 to 72 hours after discharge. (Maisels et al., 2012)

Systematic screening guidelines have been found to significantly decrease the incidence of kernicterus (Christensen et al., 2012).

…… the final word ?

“There is no level, there probably never was a level, nor will there be a level” of bilirubin to exclude the disease.

Lucey 1982

Lucey JF. Bilirubin and brain damage: a real mess. Pediatrics. 1982;69:381-2.

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