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Neurocognitive sequelae of antenatal corticosteroids in a late preterm rabbit model

  • Johannes van der Merwe
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium

    Division Woman and Child, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium
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  • Lennart van der Veeken
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium

    Division Woman and Child, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium
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  • Annalisa Inversetti
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium
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  • Angela Galgano
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium
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  • Ignacio Valenzuela
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium
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  • Thomas Salaets
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium

    Division Woman and Child, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
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  • Sebastiano Ferraris
    Affiliations
    School of Biomedical Engineering and Imaging Sciences, King’s College London, London, United Kingdom
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  • Tom Vercauteren
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium

    School of Biomedical Engineering and Imaging Sciences, King’s College London, London, United Kingdom
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  • Jaan Toelen
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium

    Division Woman and Child, Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
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  • Jan Deprest
    Correspondence
    Corresponding author: Jan Deprest, MD, PhD.
    Affiliations
    Department of Development and Regeneration, Cluster Woman and Child, Group Biomedical Sciences, KU Leuven University of Leuven, Belgium

    Division Woman and Child, Department of Obstetrics and Gynaecology, University Hospitals Leuven, Leuven, Belgium

    Institute for Women’s Health, University College London, London, United Kingdom
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Published:December 04, 2021DOI:https://doi.org/10.1016/j.ajog.2021.11.1370

      Background

      Late preterm birth is associated with short-term respiratory and adaptive problems. Although antenatal corticosteroids seem to reduce the respiratory burden, this may come at the cost of adverse neuropsychological outcomes later in life. This impact has not been investigated.

      Objective

      Herein, we investigate what the short- and long-term neurodevelopmental effects of a single course of betamethasone in simulated late preterm birth.

      Study Design

      Time-mated pregnant does received 0.1 mg/kg betamethasone (n=8) or 1 mL saline intramuscular (n=6) at the postconceptional ages of 28 and 29 days. The antenatal corticosteroid dose and scheme were based on previous studies and were comparable with routine clinical use. Cesarean delivery was done on postconceptional age 30 days (term=31 days), and new-born rabbits were foster-cared for 28 days and were thereafter cared for in group housing. Neonatal lung function testing and short-term neurobehavioral testing was done. Open field, spontaneous alternation, and novel object recognition tests were subsequently performed at 4 and 8 weeks of age. On postnatal day 1 and at 8 weeks, a subgroup was euthanized and transcardially perfuse fixated. Ex vivo high-resolution Magnetic Resonance Imaging was used to calculate the Diffusion Tensor Imaging-derived fractional anisotropy and mean diffusivity. Fixated brains underwent processing and were serial sectioned, and a set of 3 coronal sections underwent anti-NeuN, Ki67, and terminal deoxynucleotidyl transferase dUTP nick end labeling staining.

      Results

      Antenatal corticosteroid exposure was associated with improved neonatal lung function, yet resulted in a long-term growth deficit that coincided with a persistent neurobehavioral deficit. We demonstrated lower neonatal motor scores; a persistent anxious behavior in the open field test with more displacements, running, and self-grooming episodes; persistent lower alternation scores in the T-Maze test; and lower discriminatory indexes in the novel object recognition.
      On neuropathological assessment, antenatal corticosteroid exposure was observed to result in a persistent lower neuron density and fewer Ki67+ cells, particularly in the hippocampus and the corpus callosum. This coincided with lower diffusion tensor imaging-derived fractional anisotropy scores in the same key regions.

      Conclusion

      Clinical equivalent antenatal corticosteroid exposure in this late preterm rabbit model resulted in improved neonatal lung function. However, it compromised neonatal and long-term neurocognition.

      Key words

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