Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven, Belgium; Clinical Department Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium.
Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium; Department of Cardiovascular Sciences, Group Biomedical Sciences, KU Leuven, Belgium.
Am J Obstet Gynecol. 2019 Oct;221(4):355.e1-355.e19. doi: 10.1016/j.ajog.2019.07.029. Epub 2019 Jul 20.
Recently, the US Food and Drug Administration called for cautious use of anesthetic drugs during pregnancy. In 0.2-2% of pregnancies, nonobstetric surgery is being performed. The consequences of anesthesia during pregnancy on fetal development remain unclear, and preclinical studies in relevant animal models may help to elucidate them.
To assess the effect of maternal anesthesia and surgery during pregnancy on the developing fetal brain, using a rabbit model.
This is a randomized, sham-controlled study in time-mated pregnant does at 28 days of gestation (term = 31 days), which corresponds to the end of the second trimester in humans. Anesthesia was induced in 14 does (155 pups) with propofol and maintained with 4 vol% (equivalent to 1 minimum alveolar concentration) sevoflurane for 2 hours, and a laparotomy with minimal organ manipulation was performed (surgery group). Maternal vital signs (blood pressure, heart rate, peripheral and cerebral oxygen saturation, temperature, end-tidal CO, pH, lactate) were continuously monitored. Sham controls consisted of 7 does (74 pups) undergoing invasive hemodynamic monitoring for 2 hours without sedation. At term, does underwent cesarean delivery under ketamine-medetomidine sedation and local anesthesia. Pups either underwent motor and sensory neurologic testing followed by euthanasia at day 1 or daily neurodevelopment testing for 2 weeks and extensive neurologic assessment at 5 and 7 weeks (open field and object recognition test, T-maze, and radial-arm maze). Brains were harvested for histologic assessment of neuron density and synaptophysin expression.
Blood gases and vital parameters were stable in both groups. On postnatal day 1, surgery pups had significant lower motor (25 ± 1 vs 23 ± 3; P = .004) and sensory (16 ± 2 vs 15 ± 2; P = .005) neurobehavioral scores and lower brain-to-body weight ratios (3.7% ± 0.6% vs 3.4% ± 0.6%; P = .001). This was accompanied by lower neuron density in multiple brain regions (eg, hippocampus 2617 ± 410 vs 2053 ± 492 neurons/mm; P = .004) with lower proliferation rates and less synaptophysin expression. Furthermore, surgery pups had delayed motor development during the first week of life, for example with hopping appearing later (6 ± 5 vs 12 ± 3 days; P = .011). Yet, by 7 weeks of age, neurobehavioral impairment was limited to a reduced digging behavior, and no differences in neuron density or synaptophysin expression were seen.
In rabbits, 2 hours of maternal general anesthesia and laparotomy, with minimal organ and no fetal manipulation, had a measurable impact on neonatal neurologic function and brain morphology. Pups had a slower motoric neurodevelopment, but by 7 weeks the effect became almost undetectable.
最近，美国食品和药物管理局呼吁在怀孕期间谨慎使用麻醉药物。在 0.2-2%的妊娠中，需要进行非产科手术。怀孕期间麻醉对胎儿发育的影响仍不清楚，相关动物模型的临床前研究可能有助于阐明这些问题。
使用兔模型评估母亲在怀孕期间接受麻醉和手术对胎儿大脑发育的影响。
这是一项在妊娠 28 天（足月= 31 天）的时间匹配的妊娠母兔中进行的随机、假手术对照研究，相当于人类妊娠中期的结束。14 只母兔（155 只幼兔）用异丙酚诱导麻醉，并用 4 体积%（相当于 1 最低肺泡浓度）七氟醚维持 2 小时，并进行剖腹术和最小的器官操作（手术组）。监测母兔的生命体征（血压、心率、外周和脑氧饱和度、体温、呼气末 CO、pH 值、乳酸）。假手术对照组包括 7 只母兔（74 只幼兔），进行 2 小时的有创血流动力学监测而不镇静。足月时，母兔在氯胺酮-美托咪定镇静和局部麻醉下进行剖宫产。幼兔或接受运动和感觉神经学测试，然后在第 1 天安乐死，或在 2 周内进行每日神经发育测试，并在 5 和 7 周时进行广泛的神经评估（旷场和物体识别测试、T 迷宫和放射臂迷宫）。采集脑组织进行神经元密度和突触素表达的组织学评估。
两组的血气和生命参数均稳定。在出生后第 1 天，手术组幼兔的运动（25 ± 1 对 23 ± 3；P =.004）和感觉（16 ± 2 对 15 ± 2；P =.005）神经行为评分较低，且大脑与体重比（3.7% ± 0.6% 对 3.4% ± 0.6%；P =.001）较低。这伴随着多个脑区神经元密度降低（例如，海马 2617 ± 410 对 2053 ± 492 个神经元/mm；P =.004），增殖率降低，突触素表达减少。此外，手术组幼兔在生命的第一周运动发育延迟，例如跳跃出现较晚（6 ± 5 对 12 ± 3 天；P =.011）。然而，到 7 周龄时，神经行为损伤仅限于挖掘行为减少，神经元密度或突触素表达无差异。
在兔中，2 小时的母体全身麻醉和剖腹术，伴有最小的器官和胎儿操作，对新生儿的神经功能和大脑形态有明显影响。幼兔的运动神经发育较慢，但到 7 周时，这种影响几乎难以察觉。
