How to translate neuro-cognitive and behavioural outcome data in animals exposed to paracetamol to the human perinatal setting?
Karel Allegaert 1, 2, 3,   John van den Anker 4, 5, 6
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Department of Development and Regeneration, KU Leuven, Leuven, Belgium
Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
Department of Hospital Pharmacy, Erasmus MC, Rotterdam, The Netherlands
Department of Pediatrics, Pharmacology and Physiology, Children’s National Medical Center, Washington DC, 20010, USA
Intensive Care, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, The Netherlands
Department of Pediatric Pharmacology, University Children’s Hospital Basel, Basel, Switzerland
Submission date: 2020-01-05
Final revision date: 2020-04-19
Acceptance date: 2020-05-05
Online publication date: 2020-11-15
Introduction: There are epidemiological – not necessary causal – observations that link perinatal paracetamol (acetaminophen) exposure to impaired neuro-cognition and behaviour, but animal models may assist to better understand the mechanisms.

Material and methods:
To provide an overview on preclinical data and mechanisms explored, we conducted a structured literature search on animal models and neuro-cognition and behavioural outcome following perinatal paracetamol exposure.

This search resulted in 20 papers [rat (n = 9), zebrafish larvae (n = 6), mice (n = 5)], published between 2009 and 2020. Eight discussed pregnancy/fetal paracetamol exposure, 6 juvenile, 6 studies combined pregnancy and juvenile exposure. Quality assessment (SYRCLE’s bias risk) showed a heterogeneous pattern with blinding issues. Most papers (n = 16) described paracetamol exposure without indication, except for an induced fever and repetitive needle pricking (rat), brain injury (mice), and a zebrafish nociception model. Reported outcomes related to biochemistry (mono-amines, amino acids, protein expression), anatomy (teratogen, morphology, nuclear size) or behaviour (spatial memory, motor, social behaviour and exploration, sexual behaviour). On mechanisms, the cumulative data support an interesting ‘cannabinoid’ hypothesis to link paracetamol to neuro-cognitive and behavioural outcome. Besides limited species diversity, there is relevant within-species paracetamol dosing variability (dose, duration) with undocumented exposure.

Models should further integrate clinical indications, as non-exposure is the obvious safest setting in the absence of an indication. Besides pain and fever and related to the cannabinoid hypothesis, this should include perinatal brain injury, as there is animal experimental evidence that cannabinoids are neuroprotective in newborn brain injury or asphyxia, further supported by evidence from non-perinatal models of paracetamol-related neuroprotective effects.