Effects of cumulative duration of repeated anaesthesia exposure on foetal brain development in the ovine model.

Objective: Anaesthesia is required in 0.4-1% of pregnant women, and prolonged and repeated exposures to anaesthesia may be required. It is unknown whether these exposures may result in foetal neurotoxicity in humans. As sheep have a gestation comparable to that of humans, the objective of this study was to analyse the neurodevelopmental outcome of ovine foetuses that had been exposed in utero to repeated and prolonged anaesthesia.

Design: Randomized controlled preclinical study.

Setting: Anaesthesia for non-obstetric surgery during pregnancy.

Animals: Twenty-four healthy pregnant Swifter ewes.

Interventions: The ewes were randomized to no anaesthesia exposure (control-group), single exposure (at gestational age 68-70 days), or repeated exposure (at gestational age 68-70 days and 96-98 days) to 2.5 h of sevoflurane anaesthesia and maternal laparotomy. All lambs were delivered at approximately term gestation (gestational age: 140-143 days).

Measurements: The primary outcome was neuron density in the frontal cortex 24 h after birth for the control-group versus the repeated-exposure-group. Key secondary outcome was the time needed to achieve the milestone of standing. Secondary outcomes included other neurobehavioural assessments (e.g., motoric milestones) and histological parameters quantified in multiple brain regions (neuron density, total cell density, proliferation, inflammation, synaptogenesis, astrocytes and myelination).

Main Results: Neuron density in the frontal cortex did not differ between groups (mean ± standard deviation: control-group: 403 ± 39, single-exposure group: 436 ± 23 and repeated-exposure-group: 403 ± 40 neurons/mm, control-group versus repeated-exposure-group: p = 0.986, control-group versus single-exposure-group: p = 0.097). No significant difference was observed for the time needed to achieve the milestone of standing. Only very limited differences were observed for other histological outcome parameters and neurobehavioural assessments.

Conclusions: There is no evidence for foetal neuronal injury or neurobehavioural impairments after a cumulative duration of 5 h repetitive prenatal anaesthesia in sheep.