Paediatric Acute Liver Injury: Signal Detection Using Multiple Healthcare Databases from the EU-ADR Network

Introduction: Data mining in spontaneous reporting databases has shown that drug-induced acute liver injury (ALI) is infrequently reported in children,[1] but such system still has limitations in terms of signal detection. The EU-ADR project aimed to develop and validate a computerised system combining data from multiple European electronic healthcare records (EHR) for early detection of drug safety signals.[2] Aims: To identify drugs potentially associated with ALI in children and adolescents using EHR data. Methods: We extracted data on ALI cases and prescribed/dispensed drugs for individuals 0–18 years old registered with seven European population-based medical records/claims databases of the EU-ADR network during the years 1996–2008. Based on the estimated background incidence rate of ALI, power = 80%, alpha = 5% and the number of person-years (PYs) of drug exposure by ATC classification, we calculated the minimal drug exposure required to detect a signal concerning paediatric ALI.[3] Using the Longitudinal Gamma Poisson Shrinker (LGPS) method,[4] we defined as threshold for potential signals in EU-ADR a value of relative risk (RRLGPS) ‡2 and a lower 95% CI of RRLGPS >1 for each drug associated with at least three events of ALI. We discriminated among potentially relevant new signals and already known signals either in adults or in children by data mining of published literature as well as product labels. Results: Overall 4 838 146 children 0–18 years old contributed 25 575 132 PYs of follow-up time to the EU-ADR database network. Within this population, 1015 events of ALI were identified. The IR of paediatric ALI was estimated to be 3.96 (3.73–4.21)/100 000 PYs. The total amount of drug exposure that is required to detect a weak, moderate and strong association with paediatric ALI (RR‡ 2.0, 4.0 and 6.0) was 202 733 PYs, and 31 041 PYs, and 13 860 PYs, respectively. Among drugs associated with at least three cases, 20 drugs were found to be potential signals for ALI. Except for the anti-asthmatic agent flunisolide, these signals are known to be hepatotoxic in adults. Conclusions: Combining multiple EHR databases increases the power for drug safety signal detection in children. Signals identified by this system include drugs known to be associated with ALI in adults and may further be utilised to characterise ALI in the paediatric population.