Uncharted Territory in Neonatal Hyperbilirubinemia

When to Stop Phototherapy Kernicterus Spectrum Disorders Hyperbilirubinemia in Preterm Infants

Cathy Hammerman Shaare Zedek Med Ctr Hebrew University Faculty of Medicine When Can I Come Out of the Lights?

AAP Subcommittee on Hyperbilirubinemia acknowledges that there is no standard for discontinuation of phototherapy

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1%-13% of infants rebound ~ 3.3 days after PT is stopped

What is REBOUND? Return of total serum bilirubin …

•To levels prior to PT? •To 20 mg/dL? •To 18 mg/dL? •To 15 mg/dL? •To current phototherapy threshold?

14 20

13 15 2018 • 19% of 25,895 [4,920] newborns born at >35 wks received subthreshold PT. • Phototherapy at TSB levels from 0.1 to 3 mg/dL below the appropriate PT threshold during birth hospitalization. • 4.9% of treated vs 12.8% of untreated infants – readmitted for phototherapy • BUT there was a 22-hour-longer length of stay with subthreshold PT, ie. 4526 babies (out of 4920) had to stay an extra day in the hospital unnecessarily The Literature on Stopping Phototherapy • After 2 consecutive total serum bilirubin (TSB) levels of <11 mg/dl over 24 hours [Tan, Clinics in Perinatology 1991] • When the TSB level falls to <14 [AAP hyperbilirubinemia guideline-Appendix] • At ≥2.9 mg/dL below treatment threshold, which could be a TSB as high as 17.5 mg/dL in a full-term infant. [NICE 2010] • At ≥2.9 mg/dL below treatment indication [Norway] • When the TSB falls to half the exchange level [Turkish Archives of Pediatrics] High-threshold: PT stopped when TSB decreased to ≥1 mg/dL below the PT treatment starting threshold Low-threshold group: PT stopped when TSB decreased to ≥3mg/dL below the same limit. High Low Signifi- Threshold Threshold cance [n=25] [n=27] Duration PT 22 ± 13 28 ± 12 p = 0.03 Length of 84 ± 30 h 94 ± 24 h p = 0.05 hospital stay Rebound 20% 18% P = 0.58

Rebound: 28% with hemolysis or G6PD deficiency vs. 8% without (p = 0.06).

When Can I Stop Phototherapy? Practical Application Barak Hi Threshold Started Phototherapy Barak Lo * * Threshold * * NICE AAP

Turkish * Tan 1991 * Should Recommendations Vary by Circumstance?

• AAP has different criteria for initiating PT according to risk – why not apply risk criteria to discontinuation of PT? • Longer phototherapy for those at highest risk for rebound?

•Prediction rule + •Hemolytic disease • Exclusive breastfeeding Unanswered Questions?

Does duration of PT affect rebound? Does intensity of Does rate of phototherapy Does cause of bilirubin decline affect rebound? hyperbilirubine- influence rate of mia affect rebound? rebound?

Kernicterus Spectrum Disorders Kernicterus Spectrum Disorders

Hyperbilirubinemia Reversal 1st Stage • Poor feeding, • Lethargy, • Hypotonia, • HighAcute pitched Bilirubin cry, Chronic 2ndEncephalopathy Stage Bilirubin • Hypertonia of Encephalopathy extensors • Opisthotonus, • Setting sun sign, • Seizures Death (7-20%) [2o Respiratory failure, seizures] Kernicterus Spectrum Disorders

Classic Reversal Kernicterus - Tetrad

Isolated Chronic Auditory Acute Bilirubin Bilirubin Neuropathy Encephalopathy Encephalopathy

Death (7-20%) BIND (Subtle, [2o Respiratory but chronic) failure, seizures] Classic Kernicterus •Pathologic yellow staining of the basal ganglia. •Striking regional cell- specific distribution - distinct different from HIE brain injury although blood supplies are similar. •May reflect regional differences in bilirubin clearance or differential cell sensitivity to injury. Classic Clinical Kernicterus Tetrad

Currently used to refer to permanent, irreversible clinical sequelae attributable to bilirubin neurotoxicity •Oculomotor impairments •Dental enamel hypoplasia •Auditory dysfunction 15 •Choreoathetosis

16 Auditory Neuropathy

• OAEs are normal, while ABRs are abnormal

• Cochlear hair cells remain intact, but auditory nerve center impaired • Dysfunction at the level of the auditory brainstem or nerve with absent or abnormal brainstem auditory evoked potentials. 17 • Auditory processing problem with normal ear function

Classification by Gest. Age and Severity of Bilirubin

50 46 46

44

40 40 41 Classic Kernicterus 39 Auditory Kernicterus 35 Motor Kernicterus 31 30 29 29 28 25 26 24 22

20 21 TotalSerum Bilirubin

10 32 34 36 38 40 42 Gestational Age + Chronologic Age (wks) From: Steve Shapiro Bilirubin Induced Neurologic Dysfunction (BIND) “Subtle Kernicterus” - Wide spectrum of less severe neurologic injury with a history of severe jaundice. •Minimal fine and gross motor incoordination and gait abnormalities, •Fine tremors, •Developmental delay, auditory neuropathy, cognitive impairment, disordered executive function, and behavioral and psychiatric disorders. BIND Score: Scoring Acute Bilirubin Encephalopathy to Predict BIND Score Mental Muscle Tone Cry Pattern Gaze Status 0 Normal Normal Normal Normal 1 Sleepy, poor Hypertonia or High pitched feeding hypotonia cry 2 Lethargic, Hypertonia, neck Shrill cry irritable, stiffness, flexor (may be Jittery spasm, arching intermittent) 3 Unable to Opisthotonus, Weak or Sunsetting feed, apnea, bicycling, absent or or paralysis seizures, twitching, fisting, inconsolable of upward coma hypotonia cry gaze

With BIND score >7, almost 100% with irreversible brain damage

Radmacher BMC Pediatrics 2015 More on BIND Scoring •BIND Score predicts neurologic sequelae beyond TSB •4 infants with TSB levels ≥ 36 mg/dL and BIND scores ≤3 had normal outcomes at follow-up. •Conversely, when TSB  with PT, if there signs of moderate to severe acute bilirubin encephalopathy, infants are at risk for long-term impairments Preterm Neonates: Increased Jaundice + Increased Neurologic Vulnerability

12 120

10 100

8 80

6 60

4 40

% Kernicterus by by GA Kernicterus % 2

% Kernicterus Mortality Kernicterus % 20

0 0 Under 30 31-32 wks33-34 wks Under 30 31-32 wks33-34 wks wks wks Increased Jaundice + Increased Vulnerability Serum Albumin <2.5 g/dL Shorter Apgar <3 at 5 RBC Reduced min Lifespan Bilirubin / pH <7.15 for > 1 Albumin hour Binding Capacity Kernicterus Sepsis Spectrum Co- Disorders in Immaturity morbidity Prematures of Bilirubin Co- Conjugation Morbidity [UGT1A1] Increased Blood-Brain Barrier Permeability Is PT Safe in the ELBW? National Collaborative Phototherapy Study •1970s:IVH Infants Associated <2500 g Mortality were assigned in <1000 randomly gm to either 96 hours of PTPhototherapy if TSB >10 (n=Controls637) or no PT with exchange transfusion as needed (n=667). 40 P=0.016

•Mortality:30 <2000 gm BW:

10.1%% 20of PT vs 7.6% of control gp died •Mortality:10 <1000 gm BW:

59% of 0PT vs 39% of controls IVH •The relative risk for death in 1st wk of life with phototherapy was 1.49 (95% CI: 0.93 to 2.40) in ELBW

• Aggressive PT (started when TSB level was >5 mg/dl) vs conservative PT(started when TSB was >8 mg/dl for infants 500 - 750 gm [n=1974] • Death 39% vs 34% with aggressive vs conservative PT [CI: 1.13 (0.96-1.34)] • However, among survivors, aggressive PT associated with  NDI,  hearing loss,  profound impairment.

• The 5% increase in mortality equals the 5% reduction in overall neurodevelopmental impairment.

2008 S E M I N A RS IN P E R INATOLOGY 3 8: 2014 Two studies, 30 years apart, Loss of protective antioxidant show trend to  mortality in effect of mild ELBW with PT hyperbilirubinemia??? Photo-oxidative damage from phototherapy affecting Suppose you conduct a major molecules other than bilirubin??? RCT and find an increase in Photosensitizers, such as in TPN, relative risk of death in the which might increase the treatment group but a benefit vulnerability of ELBW to light??? for an important secondary a) Use the intervention outcome. b) Do not use the intervention c) Use the intervention, but •Is it biologically plausible? perform another major RCT What would you recommend d) Do not use the intervention, • but perform another major26 based on this trial? RCT 2018 Implications for ELBW Infants

Over the years since these studies… •PT dose has dramatically  with new lights •More immature infants with thinner, more translucent skin are being treated with PT. Light can more readily penetrate deeply into the subcutaneous tissue potentially producing oxidative injury to cell membranes and DNA in the tiniest infants.27 Think of phototherapy as a drug!

• Start PT at lower irradiance levels in the ELBW infant • If the TSB continues to rise, increase the surface area exposed before increasing intensity • Measure irradiance and use the least irradiance dose needed to achieve an efficient decrease in bilirubin • DO NOT OVERGENERALIZE THE EFFICACY AND SAFETY DATA CONCERNING PHOTOTHERAPY Thank you

Score: 50 + 15 [if GA <38 wks] - [age in days PT started]*7 – [AAP PT threshold – TSB at PT termination]*4

Hypothetical Case: 37 wks; started on PT DOL 2; taken off when TSB was 6 mg/dL under threshold

Hypothetical Calculation: 50 +15 – [2*7] – [6*4] = 27

Prediction Probability Score of Rebound >20 <10% <20 <4% Management of Hyperbilirubinemia in Prematures Management of Hyperbilirubinemia in Prematures: NICE Guidelines Use postmenstrual age for phototherapy for example, when a 29 week infant is 7 days old, use the TSB level for 30 weeks. Discontinue phototherapy when TSB is 1–2 mg/dl below the initiation level for the infant’s postmenstrual age. Hyperbilirubinemia in the preterm infant; Maisels et al 2012 Retrospective analysis of 2,575 ELBW [400-1,000 gm] infants. Peak TSB levels were directly correlated with the risk of • Death or NDI (OR: 1.068; 95% CI: 1.03 to 1.11), • Hearing impairment (OR: 1.138; 95% CI 1.00 to 1.30) • Psychomotor development index <70 (OR 1.057; 95% CI 1.00 to 1.12)