Fundamentals of fetal toxicity relevant to sevoflurane exposures during pregnancy

Abstract

Over the last three decades, advances in medical and surgical techniques have proven life saving and life‐improving for young children. Consequently, early and repeated exposure to general anesthetics in childhood has increased. However, accumulating evidence suggests that general anesthetics may be neurotoxic in children. Of particular concern is the neurotoxicity fetuses may suffer from maternal exposure to sevoflurane during surgeries and fetal intervention procedures performed during the second trimester, as this can cause neurodevelopmental impairment in offspring. In this review we demonstrate that the pathology associated with fetal toxicity resulting from exposure to sevoflurane during pregnancy involves oxidative stress, neuroinflammation, neuroapoptosis, and alteration of synaptic properties. The mechanisms remain to be elucidated, but may include increased tau protein phosphorylation and abnormal methylation. These findings highlight the need for a global and comprehensive understanding of the potential neurotoxicity of anesthetic exposure in fetuses and its long‐term effects.

Effects of sevoflurane exposure during different stages of pregnancy on the brain development of rat offspring

“…In agreement with these previous studies, this study demonstrated that sevoflurane exposure during early pregnancy in rats damages the neuronal growth of the offspring by affecting the NR4A1/ Most general anesthetics are lipophilic and easily cross the placenta, and neurogenesis, neuronal migration, and corticogenesis are major neurodevelopmental events in early and middle pregnancy [29], which may explain why the neurotoxic effect of anesthesia on the brain development of offspring is greater in early gestation than in late gestation. The long-term neuroinflammatory effect of sevoflurane may be mediated by the release of inflammatory mediators, which would further aggravate the oxidative stress response [20]. These mediators of neuroinflammation could induce neurobehavioral dysfunction, and cause cognitive dysfunction.…”

“…Multiple mechanisms are involved in neuronal damage to offspring, for example neuronal apoptosis [ 16 ], synaptic plasticity [ 17 ], and BDNF-related pathways [ 18 , 19 ]. Chai et al [ 20 ] reviewed the fundamentals of fetal toxicity related to gestational sevoflurane exposure and demonstrated that the pathology associated with fetal toxicity involves oxidative stress, neuroinflammation, neuronal apoptosis, and alteration of synaptic properties. However, existing studies have mainly focused on the effects of sevoflurane exposure in a single stage of pregnancy [ 16 – 19 ].…”

Prenatal sevoflurane exposure causes abnormal development of the entorhinal cortex in rat offspring

“…Thus, based on its inhibition of uterine contraction, which can prevent premature delivery, sevoflurane is the most widely used inhalation anesthetic during pregnancy. Sevoflurane easily impacts fetuses though the placenta [30]. Zheng et al [9] found that with the inhalation of 2.5% sevoflurane for 2 hours and 4.1% sevoflurane for 6 hours, the offspring of pregnant rat showed decreased learning and memory ability, accompanied by the release of inflammatory agents in the hippocampus and abnormal synaptic development.…”

Oxidative stress under general intravenous and inhalation anaesthesia

“…Judging by animal model studies (reviewed in ref. 89 ), exposure to sevoflurane during uterine quiescence can induce neuroinflammation, neuroapoptosis, and eventually memory impairment. Cognitive impairment was also reported in young mice repeatedly exposed to sevoflurane, which caused an increase in proinflammatory proteins IL-6 and TNF-α ( 73 ).…”