Open Access Research article

Adverse drug reactions and off-label and unlicensed medicines in children: a nested case?control study of inpatients in a pediatric hospital

Jennifer R Bellis3*, Jamie J Kirkham2, Signe Thiesen1, Elizabeth J Conroy2, Louise E Bracken3, Helena L Mannix3, Kim A Bird4, Jennifer C Duncan3, Matthew Peak3, Mark A Turner1, Rosalind L Smyth5, Anthony J Nunn1 and Munir Pirmohamed6

Author Affiliations

1 Department of Women?s and Children?s Health, University of Liverpool, First Floor, Liverpool Women's Hospital, Crown Street, Liverpool L8 7SS, UK

2 Department of Biostatistics, University of Liverpool, Shelley's Cottage, Brownlow Street, Liverpool L69 3GS, UK

3 Research and Development, Alder Hey Children?s NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK

4 Oncology Unit, Alder Hey Children?s NHS Foundation Trust, Eaton Road, Liverpool L12 2AP, UK

5 Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK

6 Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK

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BMC Medicine 2013, 11:238  doi:10.1186/1741-7015-11-238

Published: 7 November 2013



Off-label and unlicensed (OLUL) prescribing has been prevalent in pediatric practice. Using data from a prospective cohort study of adverse drug reactions (ADRs) among pediatric inpatients, we aimed to test the hypothesis that OLUL status is a risk factor for ADRs.


A nested case?control study was conducted within a prospective cohort study. Details of all medicines administered were recorded, including information about OLUL status. The odds ratio for OLUL medicines being implicated in a probable or definite ADR was calculated. A multivariate Cox proportional hazards regression model was fitted to the data to assess the influence that OLUL medicine use had on the hazard of an ADR occurring.


A total of 10,699 medicine courses were administered to 1,388 patients. The odds ratio (OR) of an OLUL medicine being implicated in an ADR compared with an authorized medicine was 2.25 (95% confidence interval (CI) 1.95 to 2.59). Medicines licensed in children but given to a child below the minimum age or weight had the greatest odds of being implicated in an ADR (19% of courses in this category were implicated, OR 3.54 (95% CI 2.82 to 4.44). Each additional OLUL medicine given significantly increased the hazard of an ADR (hazard ratio (HR) 1.3 95% CI 1.2 to 1.3, P <0.001). Each additional authorized medicine given also significantly increased the hazard (HR 1.2 95% CI 1.2 to 1.3, P <0.001).


OLUL medicines are more likely to be implicated in an ADR than authorized medicines. The number of medicines administered is a risk factor for ADRs highlighting the need to use the lowest number of medicines, at the lowest dose for the shortest period, with continual vigilance by prescribers, in order to reduce the risk of ADRs.

Adverse drug reactions; Pediatrics; Prescribing; Off-label; Unlicensed