The Association between Serum Bilirubin and Kernicterus Spectrum Disorder: A Systematic Review and Meta-Analysis

Neonatology. 2021;118(6):654-664. doi: 10.1159/000519497. Epub 2021 Nov 3.

Abstract

Background: Total serum bilirubin (TSB) is used in managing neonates with jaundice, but clear evidence on its association with major outcomes is lacking.

Objectives: We evaluated the association between TSB and kernicterus spectrum disorder (KSD).

Methods: We searched PubMed, EMBASE, and CENTRAL till July 2021. Two authors independently selected relevant cohort studies, extracted data (CHARMS checklist), assessed risk of bias (RoB) (QUIPS tool), and rated certainty-of-evidence (Grades of Recommendation, Assessment, Development, and Evaluation). We pooled adjusted odds ratio (aOR) (random-effect) via generic inverse variance methods.

Results: From 2,826 records retrieved, we included 37 studies (n = 648,979). Fifteen studies had low, 16 moderate, and 6 high RoB, with majority having concerns on confounder adjustment and statistical analysis. Twenty-two studies contributed meta-analysis data, and 15 were summarized narratively. TSB appears associated with KSD in infants with certain risk factors (aOR 1.10, 95% CI: 1.07-1.13; 5 studies [n = 4,484]). However, TSB (aOR 1.10, 95% CI: 0.98-1.23; 1 study [n = 34,533]) or hyperbilirubinemia (aOR 1.00, 95% CI: 0.51-1.95; 2 studies [n = 56,578]) have no clear association with kernicterus or neurological diagnosis in overall neonatal population (moderate-certainty-evidence). One study shows that infants with hyperbilirubinemia appear likelier to develop attention-deficit disorder (aOR 1.90, 95% CI: 1.10-3.28) and autistic spectrum disorder (aOR 1.60, 95% CI: 1.03-2.49, n = 56,019) (low-certainty-evidence). Certain clinical factors appear associated with KSD, although very few studies contributed to the analyses.

Conclusions: Despite the importance of this question, there is insufficient high-quality evidence on the independent prognostic value of TSB for adverse neurodevelopmental outcomes in most neonatal populations. Future studies should incorporate all known risk factors alongside TSB in a multivariable analysis to improve certainty-of-evidence.

Keywords: Kernicterus spectrum disorder; Neonatal hyperbilirubinemia; Serum bilirubin.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Bilirubin
  • Cohort Studies
  • Humans
  • Hyperbilirubinemia, Neonatal* / diagnosis
  • Hyperbilirubinemia, Neonatal* / epidemiology
  • Infant
  • Infant, Newborn
  • Kernicterus* / diagnosis
  • Kernicterus* / epidemiology
  • Prognosis
  • Risk Factors

Substances

  • Bilirubin