Risk of liver injury in paediatric population: data mining on electronic healthcare databases in Europe

Introduction: Drugs are one of most important causes of liver injury in paediatrics but so far, the incidence rate of drug-related hepatic injury has only been estimated in the general population. A retrospective population- based cohort study was performed to estimate the incidence rates of hepatic injury in children and to identify the drugs associated with hepatic injury. Methods: Between 1 January 2001 and 31 December 2008 data on population aged 1–18 years were collected using three general practice databases in two European countries: in The Netherlands, the Integrated Primary Care Information (IPCI) database, and in Italy, Pedianet (covering children up to 14), and Health Search/Thales (HSD) (covering children from 14 years). Potential cases of hepatic injury were identified through codes, free text and lab values search. All potential cases were manually validated using specific algorithms by two assessors, blinded to drug exposure. Crude incidence rates (IR; 95% CI) of hepatic injury by country and age and gender-adjusted relative risks (RR; 95% CI) were estimated using Jerboa (http://www.euadr-project.org/). Results: In the study cohort of 319,755 subjects aged 1–18 years, contributing 1,149,066.72 person-years (PY) of follow-up, we identified 871 new definite cases of hepatic injury (46 cases in IPCI, 825 cases in HSD and Pedianet). The incidence rate for hepatic injury was 92.6 (95% CI 86.5–99.2) per 100,000 PY in Italy and 17.9 (13.3–23.6) per 100,000 PY in the Netherlands. Pooled data showed a statistically significant age and gender adjusted increased risk of hepatic injury for antibacterials (RR 13.4; 95% CI 10.9–16.4), followed by corticosteroids for systemic use (11.7;6.3–21.9), drugs for functional gastrointestinal disorders (9.7;3.6– 26.1), NSAIDs (7.6;4.0–14.8), agents for acid related disorders (6.4; 2.7– 15.5), antiepileptics (5.5;3.2–9.5) and drugs for obstructive airway diseases (2.6;1.7–4.1). Conclusions: The incidence of hepatic injury is rare in the paediatric population and heterogeneous between the two European countries. Corticosteroids, antibacterials, NSAIDs, antiepileptics and drugs for obstructive airway diseases are associated with an increased risk of hepatic injury.