P1.181: Serum Bilirubin as a Biomarker for Neonates with Hypoxic Ischemic Encephalopathy

Background: Prior small cohort studies have reported mixed trends in bilirubin levels among infants with hypoxic ischemic encephalopathy (HIE). Larger population studies are lacking to determine whether bilirubin is associated with HIE severity, therapeutic hypothermia (TH) use, and short- and long-term outcomes such as post-cooling MRI findings and cerebral palsy (CP) diagnosis. We hypothesize that lower bilirubin will be associated with markers of more severe disease since bilirubin is a known antioxidant.

Methods: We conducted a retrospective case control study at the Children’s Hospital Colorado (CHCO) from January 2010 to September 2023. Infants were identified through the Children’s Hospitals Neonatal Database (CHND). Inclusion criteria included gestation age >35 weeks and admission within 24 hours of life. Exclusion criteria consisted of hemolytic disease (e.g. ABO incompatibility) and direct hyperbilirubinemia. Most infants in the control group were transferred for HIE evaluation but were not diagnosed with HIE and treated with expectant management. Infants with HIE were compared based on HIE severity (assigned within 6 hours of life). Data was obtained via CHND and electronic medical record chart review. Data collected included patient diagnoses and demographics, serum bilirubin and albumin values, post-cooling MRIs, abnormal neurological exam by neurologist before 5 years of age, and Ages and Stages Questionnaire (ASQ) scores. Analysis included Student’s t-test, 𝜒2 test, AN(C)OVA, and linear and logistic regression. This study was granted exemption by the University of Colorado/CHCO CO-IRB.

Results: We analyzed 524 infants (353 with HIE and 171 infants in the control group). Neonates with HIE had lower 24 hour and maximum serum bilirubin values than controls (Figure A). Among neonates with HIE, maximum bilirubin (Bmax, mean±SD) decreased with worsening HIE severity (mild HIE n=90, Bmax=8.37±4.6 mg/dL; moderate HIE n=167, Bmax=7.63±3.9 mg/dL; severe HIE n=79, Bmax=5.30±2.4 mg/dL, p< 0.001). A similar inverse relationship was observed for bilirubin levels at 24 hours of life (Figure B, p< 0.05). Bilirubin values were not significantly related to the use of TH (Figure C), but male infants had higher Bmax values than females (Figure D). Serum bilirubin values differed based on encephalopathy severity on EEG (Table, p=0.002). Bmax values trended lower for infants with abnormal neurological exam, low ASQ score, and/or diagnosis of cerebral palsy by age 5 years (Table).

Conclusion: We demonstrate a decline in total serum bilirubin levels with increasing severity of neonatal HIE, suggesting that bilirubin may serve as an acute biomarker of HI injury severity. Maximum serum bilirubin does not correlate with later outcomes such as imaging or neurodevelopmental outcomes, but the degree of decreased bilirubin could help inform a patient’s clinical picture.