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Front. Physiol. | doi: 10.3389/fphys.2018.00478

Relationship between Short term variability (STV) and onset of cerebral hemorrhage at ischemia–reperfusion load in fetal growth restricted (FGR) mice

 Takahiro Minato1, Takuya Ito2,  Yoshiyuki Kasahara1, Sayaka Ooshio1,  Tomofumi Fushima3, Akiyo Sekimoto3,  Nobuyuki Takahashi3, Nobuo Yaegashi4 and  Yoshitaka Kimura1*
  • 1Graduate School of Medicine, Tohoku University, Japan
  • 2Center for Development of Advanced Medical Technology, Jichi Medical University, Japan
  • 3Graduate School of Pharmaceutical Sciences and Faculty of Pharmaceutical Sciences, Tohoku University, Japan
  • 4Department of Gynecology and Obstetrics, Tohoku University Hospital, Japan

Fetal growth restriction (FGR) is a risk factor exacerbating a poor neurological prognosis at birth. A disease exacerbating a poor neurological prognosis is cerebral palsy. One of the cause of this disease is cerebral hemorrhage including intraventricular hemorrhage. It is believed to be caused by an inability to autoregulate cerebral blood flow as well as immaturity of cerebral vessels. Therefore, if we can evaluate the function of autonomic nerve, cerebral hemorrhage risk can be predicted beforehand and appropriate delivery management may be possible. Here dysfunction of autonomic nerve in mouse FGR fetuses was evaluated and the relationship with cerebral hemorrhage incidence when applying hypoxic load to resemble the brain condition at the time of delivery was examined. Furthermore, FGR incidence on cerebral nerve development and differentiation was examined at the gene expression level. FGR model fetuses were prepared by ligating uterine arteries to reduce placental blood flow. To compare autonomic nerve function in FGR mice with that in control mice, fetal short-term variability (STV) was measured from electrocardiograms. In the FGR group, a significant decrease in the STV was observed and dysfunction of cardiac autonomic control was confirmed. Among genes related to nerve development and differentiation, Ntrk and Neuregulin 1, which are necessary for neural differentiation and plasticity, were expressed at reduced levels in FGR fetuses. Under normal conditions, Neurogenin 1 and Neurogenin 2 are expressed mid-embryogenesis and are related to neural differentiation, but they are not expressed during late embryonic development. The expression of these two genes increased in FGR fetuses, suggesting that neural differentiation is delayed with FGR. Uterine and ovarian arteries were clipped and periodically opened to give a hypoxic load mimicking the time of labor, and the bleeding rate significantly increased in the FGR group. This suggests that FGR deteriorates cardiac autonomic control, which becomes a risk factor for cerebral hemorrhage onset at birth. This study demonstrated that cerebral hemorrhage risk may be evaluated before parturition for FGR management by evaluating the STV. Further, this study suggests that choosing an appropriate delivery timing and delivery method contributes to neurological prognosis improvement.

Keywords: fetal growth restriction, Cerebral Hemorrhage, fetal electrocardiogram, Short-term variability, cardiac autonomic control, cerebral blood flow

Received: 15 Sep 2017; Accepted: 16 Apr 2018.

Edited by:

Ahsan H. Khandoker, Khalifa University, United Arab Emirates

Reviewed by:

Kathleen M. Gustafson, University of Kansas Medical Center, United States
Antonio Paolo Beltrami, University of Udine, Italy  

Copyright: © 2018 Minato, Ito, Kasahara, Ooshio, Fushima, Sekimoto, Takahashi, Yaegashi and Kimura. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: MD, PhD. Yoshitaka Kimura, Tohoku University, Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan, ykimura@med.tohoku.ac.jp