Two-Step Theory: A New Approach to Fetal Brain Damage

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  • CHISAKA,Hiroshi
    Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine

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  • (1)胎児脳障害に関与するTwo Step Theoryの検証と予防への治療戦略(シンポジウム3「新生児脳障害の減少に向けて」,<特集>第62回日本産科婦人科学会・学術講演会)

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Abstract

Objectives: Perinatal brain injuries, such as periventricular leukomalacia (PVL), are associated closely with the subsequent development of cerebral palsy and other neurological disabilities. Many studies have shown that the severe hypoxic-ischemic insult was a major cause of perinatal brain damage, but hypoxia alone is an unusual cause of perinatal brain injury. On the other hand, recently, the evidence of 'unexpected brain damage' related with intrauterine infection has been reported. Therefore, we focused on Two-Step Theory, the idea that at least two causative factors, ex), hypoxic insult with uterine infection, are predominately ante-, intra-partum in origin for fetal brain damage. To clarify this theory, we conducted three studies as follows; (Study1) To analyze the effect of intrauterine inflammation occurred with cerebral hemodynamics on PVL in premature fetal sheep. (Study2) To analyze the effect of maternal undernutrition occurred with intrauterine inflammation on the brain in premature fetal mice. (Study3) To analyze the effect of maternal undernutrition occurred with hypoxic insult on the brain in premature fetal mice. Methods: (Study1: intra-uterine inflammation and hypoxic-ischemic insult) Fetuses were given an intravenous infusion of granulocyte colony-stimulating factors (GCSF) from days 105～109 of gestation and an intra-amniotic infusion of endotoxin (LPS, lipopolysaccharide) on day 107 of gestation; the fetuses were then assigned randomly to an acute hemorrhage group induced by approximately 35% of the fetoplacental blood volume withdrawal from a inferior vena cava catheter for 20 minutes (hypoxemia and systemic hypotension), an exchange transfusion group induced by an exchange transfusion of approximately 35% of the fetoplacental blood volume withdrawal and replacement with the same volume of fresh plasma (hypoxemia), or a control (no hemodynamic insult). During each insult, the cerebral hemodynamics was assessed by noninvasive near-infrared spectroscopy (NIRS) and the fetuses were processed for neuropathologic analysis. (Study2; maternal undernutrition and intra-uterine inflammation) Fetuses were maintained with maternal normal nutrition (20% Casein) or undernutrition (10% Casein). On gestational days 14 (E14), pregnant mice were intravaginally injected with 0.1mg/kg LPS or normal saline as a control. Then, the brain on E17 or on postnatal days 7 (P7) was processed for neuropathologic analysis. (Study3: maternal undernutrition and hypoxic insult) Fetuses were maintained with maternal normal nutrition (20% Casein) or undernutrition (10% Casein) as shown in Study 2. On (E17), hypoxic insult was induced by following protocol as three sets of uterine artery clipping for 5 minutes and opening for 5 minutes under fetal electrocardiogram (fECG) measurement (fetal normal heart rate is around 250bpm). Then, the brain on E18 was processed for neuropathologic assessment and analysis for hypoxia related gene expression. Results: (Study 1) Chorioamnionitis were induced in each group. A significant decrease in the blood oxygen content and an increase in the brain total hemoglobin level were observed after the LPS infusion. The fetuses in both the acute hemorrhage and exchange transfusion groups showed an abrupt decrease in the total brain hemoglobin level soon after hemodynamic insult. 4 of the 5 fetuses in each treatment group, but none in the control group, exhibited PVL. (Study 2) On P7, activated astrocytes were exhibited in sub-ventricular zone (SVZ) of fetal brain in the LPS group, which indicated that intra-vaginal LPS injection might have an affect on fetal brain inflammation. In terms of oligodendrocytes precursors (pre-OLs), there were no differences among LPS and maternal undernutrition group on E17. In the other hand, mature OLs on P7 were significantly decreased in LSP injected group under maternal undernutrition. These results suggest that maternal undernutrition w ith intra-uterine inflammation might inhibit the maturation of OLs. (Study 3) On E17, fetal heart rate measured by fECG showed prolonged deceleration down to 70bpm during uterine artery clipping. On E18, about 80% of the fetuses with hypoxic insult under maternal undernutrition exhibited cerebral hemorrhage in SVZ, but about 18% of those with hypoxic insult in control nutrition. These results suggest that maternal undernutrition with hypoxic insult might increase the risks for brain injuries. In addition, the expression of Hypoxia inducible factor 1a (HIF1a) was significantly increased in fetal brain under maternal undernutrion. Conclusions: In terms of study 1, our previous study showed that PVL was not induced by only hypoxemia (only exchange transfusion). However, under the intra-uterine inflammation, hypoxic insult could develop PVL. Study 2 and 3 also indicated that both maternal undernutrition with intra-uterine inflammation and maternal undernutrition with hypoxic insult induced brain damage. These results indicate that in some situations, at least two factors might need to develop perinatal brain injury. Also, maternal undernutrition might mimic the hypoxic condition in fetal brain. In conclusion, a complex of the perinatal stress, such as hemodynamic insult, intra-uterine inflammation and maternal undernutrition, might develop perinatal brain injuries and to prevent fetal brain damage, multi-viewpoint fetal care approach is needed.

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