Bilirubin and the Brain
Author: Amy Hill, DO | Child Neurology Resident
Column Editor: Kathleen Berg, MD | Co-Director, Office of Evidence-Based Practice | Pediatric Hospitalist, Division of Pediatric Hospital Medicine | Associate Professor of Pediatrics, UMKC School of Medicine
Neonatal jaundice is routine in newborn care, affecting approximately two-thirds of all newborns in the first postnatal week.1 Although common, it requires vigilance, as severe jaundice with bilirubin brain deposits can cause permanent neurologic dysfunction. This article reviews the pathophysiology and prevention of neonatal unconjugated hyperbilirubinemia.
Bilirubin is the final product in heme degradation from senescent red cells and hepatic heme or hemoproteins.2 Bilirubin is a potent cellular antioxidant, which may provide protection in the setting of increased oxidative stress in transition from the relatively hypoxic intrauterine environment.3 Although not all bilirubin is bad, too much can be neurotoxic. Bilirubin is unconjugated in enterohepatic circulation, of which most is bound to albumin. Unbound unconjugated bilirubin can cross the blood-brain barrier and deposit in neural tissues. Bound unconjugated bilirubin can also cross a damaged blood-brain barrier, commonly due to acidosis, hypoxia, hypoperfusion and hyperosmolarity.1
Kernicterus is a term coined in 1903 to describe the yellow staining on brain autopsy of infants with severe jaundice.1 More recently, designation as kernicterus spectrum disorder has been used to encompass hyperbilirubinemia’s range of acute and chronic neurological effects.4 While the disorder is considered a spectrum, awareness of stages of kernicterus may help in recognition of reversible versus permanent symptoms, consideration of management plans, and discussion with families. Acute bilirubin encephalopathy occurs in the first weeks of life when total serum bilirubin (TSB) is greater than 25 mg/dl without hemolysis or greater than 20 mg/dl with hemolysis. Acute bilirubin encephalopathy occurs in three phases. Phase 1 during days 1-2 of onset is characterized by poor suck, high pitched cry, stupor, hypotonia and seizures. Phase 2 ensues through the middle of the first postnatal week with hypertonia of extensor muscles, opisthotonos, retrocollis and fever. Phase 3 follows the first postnatal week with hypertonia.1 Pediatricians should counsel caregivers on these acute neurological signs to monitor during the first postnatal week, especially in infants at elevated risk.
If phototherapy or exchange transfusion is not implemented to reduce severe hyperbilirubinemia, serious permanent central nervous system damage can result. In this chronic disease process often referred to as bilirubin-induced neurologic dysfunction (BIND), unconjugated bilirubin crossing the blood-brain barrier classically deposits in the basal ganglia, thalamus, cerebellum, cerebral gray matter and spinal cord. The exact level of bilirubin required to cause deposition is unknown but is usually above 20 mg/dl in term infants.2 The first phase of BIND appears within postnatal year 1 with hypotonia, hyperactive deep tendon reflexes, obligatory tonic neck reflexes and motor delays. Thereafter, the second phase is characterized as choreoathetotic cerebral palsy, ballismus, tremor, upward gaze, dental dysplasia, sensorineural hearing loss and cognitive impairment.1
The mainstay of treatment for hyperbilirubinemia is phototherapy. However, kernicterus spectrum disorder is rare, and excessive use of labs or phototherapy can cause increased anxiety, decreased breastfeeding and/or bonding with the caregiver, as well as misuse of time and resources. The American Academy of Pediatrics (AAP) Subcommittee on Hyperbilirubinemia recommends clinicians implement routine practices of surveillance and counseling to promote high value care. This recommendation includes measuring TSB or transcutaneous bilirubin (TCB) in the first 24 hours for jaundiced infants.5 TCB is likely sufficient for screening purposes. In a recent study of paired TSB and TCB measurements of infants ≥35 weeks’ gestation, only 1 of 727 were discordant with TCS indicating no need for phototherapy, while TSB did indicate phototherapy, an estimated risk of 1.4 per 1,000 TCB measurements (95% CI 0.03-7.6 per 1,000).6 A systematic review and a meta-analysis, both within the last year, demonstrated strong correlation between TSB and TCB measurements in preterm infants.7,8 Obtained by either method, all bilirubin levels must be interpreted based on age and risk factors. Online nomograms are readily available, such as https://bilitool.org/.
Acute bilirubin encephalopathy and BIND are almost always preventable. Each infant’s risk of severe hyperbilirubinemia should be assessed prior to discharge and follow-up should be planned accordingly. Key points of counseling are to promote and support successful breastfeeding with instruction to feed at least eight times per day in the first several days and to provide written and verbal information on neonatal jaundice.5 A helpful handout on neonatal jaundice FAQs for caregivers in English and Spanish can be found at the AAP’s healthychildren.org website here: https://www.healthychildren.org/English/ages-stages/baby/Pages/Jaundice.aspx.
- Lauer BJ, Spector ND. Hyperbilirubinemia in the newborn. Pediatr Rev. 2011;32(8):341-349. doi:10.1542/pir.32-8-341
- These ND. Chapter 18 Liver and gall bladder. In: Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Elsevier; 2015:852-853.
- Dennery PA. Evaluating the beneficial and detrimental effects of bile pigments in early and later life. Front Pharmacol. 2012;3:115. Published 2012 Jun 22. doi:10.3389/fphar.2012.00115
- Le Pichon JB, Riordan SM, Watchko J, Shapiro SM. The neurological sequelae of neonatal hyperbilirubinemia: definitions, diagnosis and treatment of the kernicterus spectrum disorders (KSDs). Curr Pediatr Rev. 2017;13(3):199-209. doi:10.2174/1573396313666170815100214
- American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation [published correction appears in Pediatrics. 2004 Oct;114(4):1138]. Pediatrics. 2004;114(1):297-316. doi:10.1542/peds.114.1.297
- Konana OS, Bahr TM, Strike HR, Coleman J, Snow GL, Christensen RD. Decision accuracy and safety of transcutaneous bilirubin screening at Intermountain Healthcare. J Pediatr. 2021;228:53-57. doi:10.1016/j.jpeds.2020.08.079
- Hynes S, Moore Z, Patton D, O’Connor T, Nugent L. Accuracy of transcutaneous bilirubin versus serum bilirubin measurement in preterm infants receiving phototherapy: a systematic review. Adv Neonatal Care. 2020;20(6):E118-E126. doi:10.1097/ANC.0000000000000738
- Arman D, Topcuoğlu S, Gürsoy T, Ovalı F, Karatekin G. The accuracy of transcutaneous bilirubinometry in preterm infants. J Perinatol. 2020;40(2):212-218. doi:10.1038/s41372-019-0445-3