Vestibular brainstem impairment following in utero exposure to high dose paracetamol

Paracetamol (PAR) is an analgesic and antipyretic medication and is regarded as the safest over-the-counter option for relief of pain and fever during pregnancy. Importantly, PAR and its metabolites can reach the fetus through direct placental transfer and subsequently cross the fetal blood brain barrier. While the use of PAR at therapeutic levels during pregnancy is advised to impart no increased risk of neurodevelopmental impairment, in utero exposure to high dose (HD) PAR does result in neurological dysfunction in both human subjects and animal models. To explore the impact of HD in utero PAR exposure on brainstem function, we examined click-evoked auditory brainstem responses (ABR) and found that PAR-exposed animals had delayed ear opening, elevated thresholds, and significant delays in ABR waves I-V, implicating widespread brainstem dysfunction. Since auditory and vestibular dysfunction commonly occur together in neurodevelopmental conditions, we hypothesized that in utero exposure to HD PAR would also result in vestibular impairment. We investigated this hypothesis using a battery of sensorimotor tasks, cervical vestibular-evoked myogenic potentials (cVEMPs) and quantitative morphometrics. PAR-exposed animals had significantly worse performance on sensorimotor tasks, delayed cVEMPs and significantly fewer neurons in the vestibular nuclei. Together, our findings indicate that in utero exposure to HD PAR results in significant functional and structural changes in the vestibular brainstem and suggest that vestibular assessments may be used to screen newborns for congenital brainstem impairments.