How to translate neuro-cognitive and behavioural outcome data in animals exposed to paracetamol to the human perinatal setting?

Abstract

IntroductionIntroduction: 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 methodsTo 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.ResultsThis 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.ConclusionsModels 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.

Paracetamol use during pregnancy — a call for precautionary action

“…APAP effects on the cannabinoid and prostaglandin pathways alone or in combination might be the possible mechanisms 1,62,65,69,[152][153][154] . The antipyretic effect of APAP involves inhibition of prostaglandin-synthesizing cyclooxygenase enzymes in the brain 155 .…”

“…However, a particular obstacle is the difficulty in translating human outcomes, such as ADHD and ASD, to behaviour in an animal model. Future studies should include evaluation of brain and behavioural effects in higher order species, from both prenatal and early life exposure, for specific indications and exposure windows 153 .…”

Long-Term Safety of Prenatal and Neonatal Exposure to Paracetamol: A Systematic Review

“…Paracetamol’s analgesic and antipyretic effects are mediated through activation of descending serotonergic pathways, inhibition of prostaglandin synthesis and effects on cannabinoids receptors through its active metabolites [ 8 , 9 , 10 ]. The non-selective inhibition of peripheral cyclooxygenase and the interference with the cannabinoid receptors are among paracetamol’s mechanisms of action that could explain how such causal association could be biologically plausible [ 11 ]. We, therefore, aimed to conduct this review to systematically collate and assess the entirety of primary research on the long-term safety of prenatal and neonatal (within the first four weeks of life) exposure to paracetamol.…”

Ubiquitous Usage of Over the Counter Medications in Pregnancy: Perspectives of Maternal Apprehensiveness

“…High quanta of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological surveys on neurodevelopment in children exposed to paracetamol in utero reveal inconclusive sequences [36,37]. Paracetamol-caffeine is not recommended for use during pregnancy owing to the probable escalated peril of spontaneous abortion consociated with caffeine devour [38,39]…”