. 2023 Sep 28;23(1):492.

doi: 10.1186/s12887-023-04097-9.

Liver injury in children: signal analysis of suspected drugs based on the food and drug administration adverse event reporting system

Yan Liu^#^{1

2

3

4

5}, Hailong Li^#^{1

2

3

4}, Liang Huang^{1

2

3

4}, Chaomin Wan^{4

6}, Huiqing Wang^{4

6}, Xuefeng Jiao^{1

2

3

4}, Linan Zeng^{1

2

3

4}, Zhijun Jia^{1

2

3

4

5}, Guo Cheng^{4

6

7}, Lei Zhang⁸, Wei Zhang^{9

10}, Lingli Zhang^{11

12

13

14}

Affiliations

¹ Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
² Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
³ NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu, 610041, China.
⁴ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China.
⁵ West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
⁶ Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
⁷ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu, 610041, China.
⁸ College of Computer Science, Sichuan University, Chengdu, 610041, China.
⁹ West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China. zhangwei@wchscu.cn.
¹⁰ Medical Big Data Center, Sichuan University, Chengdu, 610041, China. zhangwei@wchscu.cn.
¹¹ Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. zhanglingli@scu.edu.cn.
¹² Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. zhanglingli@scu.edu.cn.
¹³ NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu, 610041, China. zhanglingli@scu.edu.cn.
¹⁴ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China. zhanglingli@scu.edu.cn.

^# Contributed equally.

PMID: 37770847
PMCID: PMC10537493
DOI: 10.1186/s12887-023-04097-9

Liver injury in children: signal analysis of suspected drugs based on the food and drug administration adverse event reporting system

Yan Liu et al. BMC Pediatr. 2023.

. 2023 Sep 28;23(1):492.

doi: 10.1186/s12887-023-04097-9.

Authors

Affiliations

¹ Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
² Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
³ NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu, 610041, China.
⁴ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China.
⁵ West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
⁶ Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
⁷ Laboratory of Molecular Translational Medicine, Center for Translational Medicine, Sichuan University, Chengdu, 610041, China.
⁸ College of Computer Science, Sichuan University, Chengdu, 610041, China.
⁹ West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China. zhangwei@wchscu.cn.
¹⁰ Medical Big Data Center, Sichuan University, Chengdu, 610041, China. zhangwei@wchscu.cn.
¹¹ Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. zhanglingli@scu.edu.cn.
¹² Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. zhanglingli@scu.edu.cn.
¹³ NMPA Key Laboratory for Technical Research on Drug Products In Vitro and In Vivo Correlation, Chengdu, 610041, China. zhanglingli@scu.edu.cn.
¹⁴ Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, 610041, China. zhanglingli@scu.edu.cn.

^# Contributed equally.

PMID: 37770847
PMCID: PMC10537493
DOI: 10.1186/s12887-023-04097-9

Abstract

Background: Evidence of drug-induced liver injury is abundant in adults but is lacking in children. Our aim was to identify suspected drug signals associated with pediatric liver injury.

Methods: Hepatic adverse events (HAEs) among children reported in the Food and Drug Administration Adverse Event Reporting System were analyzed. A descriptive analysis was performed to summarize pediatric HAEs, and a disproportionality analysis was conducted by evaluating reporting odds ratios (RORs) and proportional reporting ratios to detect suspected drugs.

Results: Here, 14,143 pediatric cases were reported, specifically 49.6% in males, 45.1% in females, and 5.2% unknown. Most patients (68.8%) were 6-18 years old. Hospitalization ranked first among definite outcomes (7,207 cases, 37.2%). In total, 264 disproportionate drug signals were identified. The top 10 drugs by the number of reports were paracetamol (1,365; ROR, 3.6; 95% confidence interval (CI), 3.4-3.8), methotrexate (878; ROR, 2.5; 95% CI, 2.3-2.7), vincristine (649; ROR, 3.0; 95% CI, 2.8-3.3), valproic acid (511; ROR, 3.2; 95% CI, 2.9-3.6), cyclophosphamide (490; ROR, 2.4; 95% CI, 2.2-2.6), tacrolimus (427; ROR, 2.4; 95% CI, 2.2-2.7), prednisone (416; ROR, 2.1; 95% CI, 1.9-2.3), prednisolone (401; ROR, 2.3; 95% CI, 2.1-2.5), etoposide (378; ROR, 2.3; 95% CI, 2.1-2.6), and cytarabine (344; ROR, 2.8; 95% CI, 2.5-3.2). After excluding validated hepatotoxic drugs, six were newly detected, specifically acetylcysteine, thiopental, temazepam, nefopam, primaquine, and pyrimethamine.

Conclusions: The hepatotoxic risk associated with 264 signals needs to be noted in practice. The causality of hepatotoxicity and mechanism among new signals should be verified with preclinical and clinical studies.

Keywords: Children; Liver injury; Pharmacovigilance; Signal analysis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Fig. 1**
Annual cases of hepatic adverse events in children from 2004 to 2020

See this image and copyright information in PMC

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Liver injury in children: signal analysis of suspected drugs based on the food and drug administration adverse event reporting system

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Liver injury in children: signal analysis of suspected drugs based on the food and drug administration adverse event reporting system

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Conflict of interest statement

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