Maternal surgery during pregnancy has a transient adverse effect on the developing fetal rabbit brain.

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Publisher: Elsevier B.V.
Document Type: Report
Length: 734 words

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Key words brain; cognition; development; fetus; general anesthesia; long term; maternal surgery; motor; neurobehavior; pregnancy; rabbit Background 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. Objective To assess the effect of maternal anesthesia and surgery during pregnancy on the developing fetal brain, using a rabbit model. Materials and Methods 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.sub.2, 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. Results Blood gases and vital parameters were stable in both groups. On postnatal day 1, surgery pups had significant lower motor (25 [plus or minus] 1 vs 23 [plus or minus] 3; P = .004) and sensory (16 [plus or minus] 2 vs 15 [plus or minus] 2; P = .005) neurobehavioral scores and lower brain-to-body weight ratios (3.7% [plus or minus] 0.6% vs 3.4% [plus or minus] 0.6%; P = .001). This was accompanied by lower neuron density in multiple brain regions (eg, hippocampus 2617 [plus or minus] 410 vs 2053 [plus or minus] 492 neurons/mm.sup.2; 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 [plus or minus] 5 vs 12 [plus or minus] 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. Conclusion 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. Author Affiliation: (a) Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven, Belgium (b) Clinical Department Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium (c) Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium (d) Department of Cardiovascular Sciences, Group Biomedical Sciences, KU Leuven, Belgium (e) Institute for Women's Health, University College London, London, UK * Corresponding author: Jan Deprest, MD, PhD, FRCOG. Article History: Received 27 February 2019; Revised 22 June 2019; Accepted 16 July 2019 (footnote) Drs Rex and Deprest are joint last authors. (footnote) This study was performed at the Katholieke Universiteit Leuven, Leuven, Belgium. (footnote) The authors report no conflict of interest. (footnote) JvdM and LvdV are funded by the Erasmus + Programme of the European Union (Framework Agreement number: 2013-0040). This publication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein. Work is funded by the Wellcome Trust (WT101957) and Engineering and Physical Sciences Research Council (ESPRC) (NS/A000027/1). JDP is funded by the Great Ormond Street Hospital Charity Fund. (footnote) Cite this article as: Van der Veeken L, Van der Merwe J, Devroe S, et al. Maternal surgery during pregnancy has a transient adverse effect on the developing fetal rabbit brain. Am J Obstet Gynecol 2019;221:355.e1-19. Byline: Lennart Van der Veeken, MD (a,b), Johannes Van der Merwe, MD (a,b), Sarah Devroe, MD (c,d), Annalisa Inversetti, MD (a), Angela Galgano, MD (a), Tom Bleeser, MD (a,c), Roselien Meeusen, MS (c), Steffen Rex, MD, PhD (c,d), Jan Deprest, MD, PhD [] (a,b,e,*)

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Gale Document Number: GALE|A600794883