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Am J Perinatol 2021; 38(12): 1244-1253
DOI: 10.1055/s-0040-1708033
Original Article

Is Neonatal Hyperbilirubinemia Exposure Associated with a Risk of Autism Spectrum Disorder? A Nationwide Cohort Study

Tung-Wei Hung‡   ∗
1   Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
2   School of Medicine, Chung Shan Medical University, Taichung, Taiwan
,
Jeng-Dau Tsai
2   School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3   Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
,
Hui-Hsien Pan‡   ∗
2   School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3   Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
,
Hsuan-Ju Chen
4   Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
5   College of Medicine, China Medical University, Taichung, Taiwan
,
Pen-Fen Liao
2   School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3   Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
,
Ji-Nan Sheu 
2   School of Medicine, Chung Shan Medical University, Taichung, Taiwan
3   Department of Pediatrics, Chung Shan Medical University Hospital, Taichung, Taiwan
› Author Affiliations
Funding This study was supported by Chung Shan Medical University Hospital, Taichung, Taiwan (CSH-2013-C-011), the Taiwan Ministry of Health and Welfare Clinical Trial Centre (MOHW108-TDU-B-212–133004), China Medical University Hospital, Academia Sinica Stroke Biosignature Project (BM10701010021), and the Clinical Trial Consortium for Stroke (MOST 107–2321-B-039-004).
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Abstract

Objective This study aimed to determine whether neonatal hyperbilirubinemia is associated with a risk of autism spectrum disorder (ASD) using a large population-based cohort.

Study Design This retrospective cohort study used data from the children's database (2000–2012) of the National Health Insurance Research Database (1996–2012) in Taiwan. We included neonates who were born between 2000 and 2004 and aged <1 month diagnosed with and without hyperbilirubinemia. The primary outcome was physician-diagnosed ASD. At the end of 2012, multivariate Cox's regression analysis was used to estimate hazard ratios (HRs).

Results A total of 67,017 neonates were included. The neonates with hyperbilirubinemia were associated with 1.28-fold increased risk of ASD (HR = 1.28, 95% confidence interval [CI]: 1.05–1.57) compared with those without hyperbilirubinemia. In subanalysis to determine how phototherapy and exchange transfusion treatment for hyperbilirubinemia were associated with ASD showed no association between treatment and ASD, suggesting the lack of a dose-response effect of hyperbilirubinemia on the risk of ASD. Boys had a nearly six-fold higher risk of ASD than girls (HR = 5.89, 95% CI: 4.41–7.86). Additionally, neonates born with preterm birth and low birth weight were associated with a risk of ASD (HR = 1.46, 95% CI: 1.00–2.13).

Conclusion We did not observe a dose-response effect of hyperbilirubinemia on ASD, but neonatal hyperbilirubinemia may be an independent risk factor for ASD if there is a residual confounding by other perinatal complications. Therefore, this study does not support a causal link between neonatal hyperbilirubinemia exposure and the risk of ASD.

Keywords

autism spectrum disorder - neonatal hyperbilirubinemia - risk factor - boy - preterm birth and low birth weight

Ethical Approval

This study was approved by the hospital's Institutional Review Board (No.: CRREC-103–048) and informed consent was waived because of the retrospective nature of the study.


∗ These authors contributed equally to this work.




Publication History

Received: 30 July 2019

Accepted: 03 February 2020

Article published online:
13 March 2020

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