Van der Veeken Lennart, Emam Doaa, Bleeser Tom, Valenzuela Ignacio, Van der Merwe Johannes, Rex Steffen, Deprest Jan
Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, Catholic University of Leuven, Leuven, Belgium (Drs Van der Veeken, Emam, and Valenzuela, Dr Van der Merwe, and Dr Deprest); Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium (Drs Van der Veeken and Valenzuela, Dr Van der Merwe, and Dr Deprest); Departement of Obstetrics and Gynecology, University Hospital Antwerp, Belgium (Dr Van der Veeken).
Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, Catholic University of Leuven, Leuven, Belgium (Drs Van der Veeken, Emam, and Valenzuela, Dr Van der Merwe, and Dr Deprest); Department Obstetrics and Gynaecology, University Hospitals Tanta, Tanta, Egypt (Dr Emam).
Am J Obstet Gynecol MFM. 2022 Jan;4(1):100513. doi: 10.1016/j.ajogmf.2021.100513. Epub 2021 Oct 24.
Fetal surgery is part of modern fetal medicine, and some procedures, such as fetal spina bifida repair, are performed under general anesthesia. Fetuses are operated on in a time window when the developing brain is extremely vulnerable to external, potentially harmful factors. To date, little is known about the effect of fetal surgery on fetal brain development.
This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model.
This was a randomized, sham-controlled study in time-mated pregnant does at 28 days' gestation (term, 31 days), which corresponds to the start of the peak of brain development and end of the second trimester of pregnancy in humans. We included 4 different groups in this experiment: no-surgery, general anesthesia, general anesthesia+hysterotomy, and general anesthesia+fetal surgery. In 11 does, anesthesia was induced using propofol and maintained for 75 minutes with 3.6 vol% (4% is the equivalent of 1 minimum alveolar concentration) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO were continuously monitored. For each operated doe, 6 fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac were assigned to fetal surgery: hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision, and suturing. Only hysterotomy was performed on the opposing cornual and third amniotic sacs of the does. The fetus in these experimental sacs was used as internal unmanipulated control (general anesthesia). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no-surgery). At term, the does were delivered by cesarean delivery under ketamine-medetomidine sedation and local anesthesia. The pups underwent standardized motoric and sensory neurologic testing on day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation, and glial cells.
Maternal vital signs were stable during surgery. Survival was similar in the 4 groups (75%-94%), and brain-to-body weight ratio was comparable; only the no-surgery pups had a higher brain weight. On postnatal day 1, the pups in the 4 groups had a comparable neurobehavioral outcome on both motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significantly higher neuron density than pups who underwent maternal surgery, but there was no difference among pups that underwent general anesthesia, hysterotomy, or fetal surgery. The measurements of proliferation had a similar outcome: a higher proliferation rate in the prefrontal cortex of no-surgery pups. Moreover, synaptic density values were higher in the no-surgery pups, but there was no difference observed among pups who underwent general anesthesia, hysterotomy, and fetal surgery. Lastly, there was no difference in gliosis among the 4 groups.
In rabbits, fetal surgery through hysterotomy under maternal general anesthesia did not affect brain development, in addition to the effects of general anesthesia per se.
胎儿手术是现代胎儿医学的一部分，一些手术，如胎儿脊柱裂修复术，是在全身麻醉下进行的。胎儿在发育中的大脑极易受到外部潜在有害因素影响的时间段内接受手术。迄今为止，关于胎儿手术对胎儿大脑发育的影响知之甚少。
本研究旨在评估胎儿手术对兔模型中发育中胎儿大脑的影响。
这是一项在妊娠28天（足月为31天）的同期交配怀孕母兔中进行的随机、假手术对照研究，这相当于人类大脑发育高峰期的开始和妊娠中期的结束。本实验包括4个不同组：未手术组、全身麻醉组、全身麻醉+子宫切开术组和全身麻醉+胎儿手术组。在11只母兔中，使用丙泊酚诱导麻醉，并用3.6体积%（4%相当于1个最低肺泡浓度）的七氟醚维持75分钟。持续监测母兔的血压、心率、血氧饱和度、体温、呼气末二氧化碳。对于每只接受手术的母兔，6只胎儿参与实验。随机分组确定哪些子宫角囊和相对的第三个囊被分配进行胎儿手术：子宫切开术、胎儿注射（阿托品、芬太尼和顺式阿曲库铵）、胎儿皮肤切口和缝合。仅对母兔相对的子宫角和第三个羊膜囊进行子宫切开术。这些实验囊中未操作的胎儿用作内部未处理对照（全身麻醉）。未处理母兔（n = 4）的所有胎儿（n = 38）用作外部对照（未手术）。足月时，母兔在氯胺酮-美托咪定镇静和局部麻醉下通过剖宫产分娩。幼崽在出生第1天接受标准化运动和感觉神经学测试，随后安乐死并取脑进行神经元、突触、增殖和神经胶质细胞的组织学评估。
手术期间母兔生命体征稳定。4组的存活率相似（75%-94%），脑体重比相当；只有未手术的幼崽脑重量更高。在出生后第1天，4组幼崽在运动和感觉测试中的神经行为结果相当。在前额叶皮质，未手术的幼崽神经元密度显著高于接受母兔手术的幼崽，但接受全身麻醉、子宫切开术或胎儿手术的幼崽之间无差异。增殖测量结果相似：未手术幼崽前额叶皮质的增殖率更高。此外，未手术幼崽的突触密度值更高，但接受全身麻醉、子宫切开术和胎儿手术的幼崽之间未观察到差异。最后，4组之间的胶质细胞增生无差异。
在兔中，母兔全身麻醉下通过子宫切开术进行的胎儿手术除了全身麻醉本身的影响外，不影响大脑发育。
