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

Takahiro Minato, Takuya Ito, Yoshiyuki Kasahara, Sayaka Ooshio, Tomofumi Fushima, Akiyo Sekimoto, Nobuyuki Takahashi, Nobuo Yaegashi, Yoshitaka Kimura

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5 Citations (Scopus)


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.

Original languageEnglish
Article number478
JournalFrontiers in Physiology
Issue numberMAY
Publication statusPublished - 2018 May 18


  • Cardiac autonomic control
  • Cerebral hemorrhage
  • Fetal electrocardiogram
  • Fetal growth restriction (FGR)
  • Short term variability (STV)


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