Fetal surgery has no additional effect to general anesthesia on brain development in neonatal rabbits.

Abstract Background 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. Until now, little is known if, and how open fetal surgery impacts fetal brain development. Objective To assess the impact of fetal surgery on the developing fetal brain in the rabbit model. Study design This is a randomized, sham-controlled study in time-mated pregnant does at 28 days of gestation (term=31d), which corresponds to the start of the peak of brain development, and to the end of the second trimester in humans. We included four different groups in this experiment: no surgery, general anesthesia (GA), GA + hysterotomy, GA + fetal surgery. In 11 does, anesthesia was induced with propofol and maintained for 75 minutes with 3.6 vol-% (4% is the equivalent of 1 MAC) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO2 were continuously monitored. For each operated doe, six fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac was assigned to fetal surgery, i.e. hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision and suturing. The opposing cornual and third amniotic sacs underwent hysterotomy only. The fetus in between these experimental sacs was used as internal unmanipulated control (GA). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no surgery). At term, does were delivered by cesarean section under ketamine-medetomidine sedation and local anesthesia. Pups underwent standardized motoric and sensory neurologic testing at day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation and glia cells. Results Maternal vital signs were stable during surgery. Survival was similar in the four 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, pups in the four groups had a comparable neurobehavioral outcome both on motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significant higher neuron density, than pups who underwent maternal surgery, but there were no differences between GA, hysterotomy or fetal surgery pups. 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 again no differences were observed between GA-hysterotomy-fetal surgery- pups. Lastly, there was no difference in gliosis between the four groups. Conclusion In rabbits, fetal surgery through hysterotomy under maternal general anesthesia does not affect brain development, in addition to the effects of general anesthesia per se.