Dose-Related Adverse Drug Events in Neonates: Recognition and Assessment

Karel Allegaert*, John van den Anker

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
36 Downloads (Pure)


The efficacy and safety of a drug is dose or exposure related, and both are used to assess the benefit-risk balance of a given drug and ultimately to decide on the specific drug license, including its dose and indication(s). Unfortunately, both efficacy and safety are much more difficult to establish in neonates, resulting in very few drugs licensed for use in this vulnerable population. This review will focus on dose-related adverse events in neonates. Besides the regulatory classification on seriousness, adverse event assessment includes aspects related to signal detection, causality, and severity. Disentangling confounders from truly dose-related adverse drug events remains a major challenge, as illustrated for drug-induced renal impairment, drug-induced liver injury, and neurodevelopmental outcome. Causality assessment, using either routine tools (Naranjo algorithm, World Health Organization's Uppsala Monitoring Center causality tool) or a Naranjo algorithm tailored to neonates, still does not sufficiently and reliably document causality in neonates. Finally, very recently, a first neonatal severity-grading tool for neonates has been developed. Following the development of advanced pharmacokinetic approaches and techniques to predict and assess drug exposure, additional efforts are needed to truly and fully assess dose adverse drug events. To further operationalize the recently developed tools on causality and severity, reference databases on a palette of biomarkers and outcome variables and their covariates are an obvious next step. These databases should subsequently be integrated in modeling efforts to truly explore safety outcome, including aspects associated with or caused by drug dose or exposure.

Original languageEnglish
Pages (from-to)S152-S160
JournalJournal of Clinical Pharmacology
Issue numberS1
Publication statusPublished - 29 Jun 2021

Bibliographical note

Publisher Copyright:
© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology


Dive into the research topics of 'Dose-Related Adverse Drug Events in Neonates: Recognition and Assessment'. Together they form a unique fingerprint.

Cite this