Clinical and genetic risk factors associated with neonatal severe hyperbilirubinemia: a case-control study based on the China Neonatal Genomes Project

Xiao Wang; Tiantian Xiao; Jin Wang; Bingbing Wu; Huijun Wang; Yulan Lu; Yaqiong Wang; Bin Chen; Liyuan Hu; Yun Cao; Rong Zhang; Guoqiang Cheng; Laishuan Wang; Zhihua Li; Xinran Dong; Lin Yang; Wenhao Zhou

doi:10.3389/fgene.2023.1292921

Clinical and genetic risk factors associated with neonatal severe hyperbilirubinemia: a case-control study based on the China Neonatal Genomes Project

Front Genet. 2024 Jan 11:14:1292921. doi: 10.3389/fgene.2023.1292921. eCollection 2023.

Authors

Xiao Wang^#¹, Tiantian Xiao^#², Jin Wang³, Bingbing Wu¹, Huijun Wang¹, Yulan Lu¹, Yaqiong Wang¹, Bin Chen³, Liyuan Hu³, Yun Cao³, Rong Zhang³, Guoqiang Cheng³, Laishuan Wang³, Zhihua Li³, Xinran Dong¹, Lin Yang^{3

4}, Wenhao Zhou^{1

3

5}

Affiliations

¹ Center for Molecular Medicine, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
² Chengdu Women's and Children's Central Hospital, The Affiliated Women's and Children's Hospital, School of Medicine, University of Electronic Science and Technology of China (UESTC), Chengdu, China.
³ Department of Neonatology, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁴ Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai, China.
⁵ Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.

^# Contributed equally.

Abstract

Objective: We aimed to investigate the clinical and genetic risk factors associated with neonatal severe unconjugated hyperbilirubinemia. Methods: This was a retrospective, 1:1 matched, case-control study. We included 614 neonates diagnosed with severe unconjugated hyperbilirubinemia (serum total bilirubin level ≥425 μmol/L or serum total bilirubin concentration that met exchange transfusion criteria) from the China Neonatal Genomes Project in Children's Hospital of Fudan University. Clinical exome sequencing data were analyzed using a data analysis pipeline of Children's Hospital of Fudan University. The factors associated with severe unconjugated hyperbilirubinemia were assessed using univariable and multivariable logistic regression analyses. Interaction analyses were examined between clinical and genetic risk factors. Results: ABO/Rh incompatibility hemolysis (odds ratio [OR] 3.36, 95% confidence interval [CI] 2.32-4.86), extravascular hemorrhage (OR 2.95, 95% CI 2.24-3.89), weight loss (OR 5.46, 95% CI 2.88-10.36), exclusive breastmilk feeding (OR 3.56, 95% CI 2.71-4.68), and the homozygous mutant of UGT1A1 211G>A (OR 2.35, 95% CI 1.54-3.59) were all identified as factors significantly associated with severe unconjugated hyperbilirubinemia. The presence of UGT1A1 211G>A mildly increased the risk of severe unconjugated hyperbilirubinemia caused by ABO/Rh incompatibility hemolysis (OR 3.98, 95% CI 2.19-7.23), although the effect is not statistically significant. Conclusion: ABO/Rh incompatibility hemolysis, extravascular hemorrhage, weight loss, exclusive breastmilk feeding, and the homozygous mutant of UGT1A1 211G>A were found to be risk factors for severe unconjugated hyperbilirubinemia. Clinical factors remain the most crucial and preventable determinants in managing severe unconjugated hyperbilirubinemia, with a minimal genetic contribution. The establishment of preconception care practices and the reinforcement of screening for the aforementioned risk factors are essential steps for preventing severe unconjugated hyperbilirubinemia.

Keywords: UGT1A1 polymorphism; case-control analysis; generalized linear model; neonatal unconjugated hyperbilirubinemia; risk factors.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The study was supported by grants from the Shanghai Municipal Science and Technology Major Project (Grant No. 20Z11900600) to WZ and the Ministry of Science and Technology National Key Research and Development Program (Grant No. 2020YFC2006402) to WZ.