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

  • Lennart Van der Veeken
    Affiliations
    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)
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  • Doaa Emam
    Affiliations
    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)
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  • Tom Bleeser
    Affiliations
    Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium (Drs Bleeser and Rex)

    Department of Cardiovascular Sciences, Group Biomedical Sciences, Catholic University of Leuven, Leuven, Belgium (Drs Bleeser and Rex)
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  • Ignacio Valenzuela
    Affiliations
    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)
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  • Johannes Van der Merwe
    Affiliations
    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)
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  • Steffen Rex
    Affiliations
    Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium (Drs Bleeser and Rex)

    Department of Cardiovascular Sciences, Group Biomedical Sciences, Catholic University of Leuven, Leuven, Belgium (Drs Bleeser and Rex)
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  • Jan Deprest
    Correspondence
    Corresponding author: Jan Deprest, MD, PhD, FRCOG.
    Affiliations
    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)

    Institute for Women's Health, University College London, London, United Kingdom (Dr Deprest)
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Published:October 24, 2021DOI:https://doi.org/10.1016/j.ajogmf.2021.100513

      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. To date, little is known about the effect of fetal surgery on fetal brain development.

      OBJECTIVE

      This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model.

      STUDY DESIGN

      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 CO2 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.

      RESULTS

      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.

      CONCLUSION

      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.

      Key words

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