A model of cerebral palsy from fetal hypoxia-ischemia.
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Disorders of the maternal-placental-fetal unit often results in fetal brain injury, which in turn results in one of the highest burdens of disease, because of the lifelong consequences and cost to society. Investigating hypoxia-ischemia in the perinatal period requires the factoring of timing of the insult, determination of end-points, taking into account the innate development, plasticity, and enhanced recovery. Prenatal hypoxia-ischemia is believed to account for a majority of cerebral palsy cases. We have modeled sustained and repetitive hypoxia-ischemia in the pregnant rabbit in utero to mimic the insults of abruptio placenta and labor, respectively. Rabbits have many advantages over other animal species; principally, their motor development is in the perinatal period, akin to humans. Sustained hypoxia-ischemia at 70% (E22) and 79% (E25) caused stillbirths and multiple deficits in the postnatal survivors. The deficits included impairment in multiple tests of spontaneous locomotion, reflex motor activity, motor responses to olfactory stimuli, and the coordination of suck and swallow. Hypertonia was observed in the E22 and E25 survivors and persisted for at least 11 days. Noninvasive imaging using MRI suggests that white matter injury in the internal capsule could explain some of the hypertonia. Further investigation is underway in other vulnerable regions such as the basal ganglia, thalamus and brain stem, and development of other noninvasive determinants of motor deficits. For the first time critical mechanistic pathways can be tested in a clinically relevant animal model of cerebral palsy. (+info)
Clinical value of lactate measurement and nucleated red blood cell counts in the placental segment of the umbilical vein of premature newborns for diagnosis of hypoxia-ischemia.
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OBJECTIVE: To evaluate the clinical value of lactate measurement and nucleated red blood cell (NRBC) counts when compared to base excess (BE) in the blood collected from the placental segment of the umbilical vein. METHODS: 25 umbilical cords from premature babies were sampled after placental delivery and cord clamping. Babies were followed until discharge. Statistics involved linear regression, Spearman's correlation, ROC curves, and Fisher's exact test. RESULTS: The relationship between lactate in the umbilical vein blood and pH and BE was significant (p < 0.0001). A 4.04 mmol/L lactate level showed a sensitivity of 62.5% and a specificity of 94.1% in detecting pH < 7.2 and BE < -10 mmol/L. NRBC counts were related to BE (p = 0.0095), but with a sensitivity of 37.5% and specificity of 82.4% in detecting BE < -10 mmol/L. CONCLUSIONS: Lactate is a valuable marker of fetal hypoxia when sampled from placental segment veins. NRBC counts demonstrated low sensitivity for the detection of acidosis. (+info)
Use of fetal electrocardiogram for intrapartum monitoring.
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INTRODUCTION: Intrapartum fetal monitoring is essential for the identification of fetal hypoxia to reduce perinatal morbidity and mortality. Cardiotocography is associated with low specificity for fetal acidosis and poor perinatal outcome leading to unnecessary operative deliveries. ST waveform analysis of the fetal electrocardiogram has been shown to be a promising adjunctive intrapartum assessment tool. We aim to present the pathophysiology, the role of intrapartum monitoring and the practical usage of this relatively new technology in our review. METHODS: An electronic search of Medline and OVID was carried out, followed by a manual search of the references identified by the electronic search. RESULTS: The incorporation of ST waveform analysis to cardiotocography has been shown to reduce the rates of neonatal metabolic acidosis, moderate and severe neonatal encephalopathy, thus improving perinatal outcome. The reduction in operative delivery rates due to fetal distress is also significant. The pathophysiology and practical usage of this technology were discussed. CONCLUSIONS: With more accurate identification of fetal hypoxia and reduction of unnecessary intervention rates, incorporation of ST waveform analysis of fetal electrocardiography into cardiotocography can improve the standard of intrapartum fetal monitoring. (+info)
Role of mitochondrial permeability transition in the immature brain following intrauterine ischemia.
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Recirculation following 30 minutes of intrauterine ischemia due to uterine artery occlusion has previously been found to be accompanied by delayed deterioration of the cellular bioenergetic state and of mitochondrial function in the fetal rat brain. The objective of this study was to assess whether the delayed deterioration is due to the activation of mitochondrial permeability transition (MPT), which is observed ultrastructurally as mitochondrial swelling. The respiratory activities and ultrastructure of isolated mitochondria and the cellular bioenergetic state in the fetal rat brain were examined at the end of 30 minutes of intrauterine ischemia and after 1, 2, 3 or 4 hours of recirculation. Cyclosporin A (CsA), a potent and specific MPT blocker, or vehicle was given 1 hour after recirculation. In the vehicle-treated animals, the transient ischemia was associated with a delayed deterioration of the cellular bioenergetic state and mitochondrial activities 4 hours of recirculation. The number of swollen mitochondria increased markedly after 4 hours of recirculation. Both the deterioration and swelling were prevented by CsA. The present study indicates that treatment with CsA improves recovery of energy metabolism and inhibits mitochondrial swelling following transient intrauterine ischemia in the fetal brain. The results suggest that mitochondria and MPT may be involved in the development of ischemic brain damage in the immature rat. (+info)
Comment on "Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery".
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Tyzio et al. (Reports, 15 December 2006, p. 1788) reported that maternal oxytocin triggers a transient excitatory-to-inhibitory switch of gamma-aminobutyric acid (GABA) signaling during labor, thus protecting the fetal rat brain from anoxic injury. However, a body of evidence supports the possibility that oxytocin is released from the fetal pituitary during delivery, not only from the mother, particularly under conditions of hypoxic stress. (+info)
A randomised clinical trial on cardiotocography plus fetal blood sampling versus cardiotocography plus ST-analysis of the fetal electrocardiogram (STAN) for intrapartum monitoring.
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BACKGROUND: Cardiotocography (CTG) is worldwide the method for fetal surveillance during labour. However, CTG alone shows many false positive test results and without fetal blood sampling (FBS), it results in an increase in operative deliveries without improvement of fetal outcome. FBS requires additional expertise, is invasive and has often to be repeated during labour. Two clinical trials have shown that a combination of CTG and ST-analysis of the fetal electrocardiogram (ECG) reduces the rates of metabolic acidosis and instrumental delivery. However, in both trials FBS was still performed in the ST-analysis arm, and it is therefore still unknown if the observed results were indeed due to the ST-analysis or to the use of FBS in combination with ST-analysis. METHODS/DESIGN: We aim to evaluate the effectiveness of non-invasive monitoring (CTG + ST-analysis) as compared to normal care (CTG + FBS), in a multicentre randomised clinical trial setting. Secondary aims are: 1) to judge whether ST-analysis of fetal electrocardiogram can significantly decrease frequency of performance of FBS or even replace it; 2) perform a cost analysis to establish the economic impact of the two treatment options. Women in labour with a gestational age > or = 36 weeks and an indication for CTG-monitoring can be included in the trial. Eligible women will be randomised for fetal surveillance with CTG and, if necessary, FBS or CTG combined with ST-analysis of the fetal ECG. The primary outcome of the study is the incidence of serious metabolic acidosis (defined as pH < 7.05 and Bdecf > 12 mmol/L in the umbilical cord artery). Secondary outcome measures are: instrumental delivery, neonatal outcome (Apgar score, admission to a neonatal ward), incidence of performance of FBS in both arms and cost-effectiveness of both monitoring strategies across hospitals. The analysis will follow the intention to treat principle. The incidence of metabolic acidosis will be compared across both groups. Assuming a reduction of metabolic acidosis from 3.5% to 2.1 %, using a two-sided test with an alpha of 0.05 and a power of 0.80, in favour of CTG plus ST-analysis, about 5100 women have to be randomised. Furthermore, the cost-effectiveness of CTG and ST-analysis as compared to CTG and FBS will be studied. DISCUSSION: This study will provide data about the use of intrapartum ST-analysis with a strict protocol for performance of FBS to limit its incidence. We aim to clarify to what extent intrapartum ST-analysis can be used without the performance of FBS and in which cases FBS is still needed. TRIAL REGISTRATION NUMBER: ISRCTN95732366. (+info)
The ontogeny of hemodynamic responses to prolonged umbilical cord occlusion in fetal sheep.
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There is evidence that preterm fetuses have blunted chemoreflex-mediated responses to hypoxia. However, the preterm fetus has much lower aerobic requirements than at term, and so moderate hypoxia may not be sufficient to elicit maximal chemoreflex responses; there are only limited quantitative data on the ontogeny of chemoreflex and hemodynamic responses to severe asphyxia. Chronically instrumented fetal sheep at 0.6 (n = 12), 0.7 (n = 12), and 0.85 (n = 8) of gestational age (GA; term = 147 days) were exposed to 30, 25, or 15 min of complete umbilical cord occlusion, respectively. At all ages, occlusion was associated with early onset of bradycardia, profoundly reduced femoral blood flow and conductance, and hypertension. The 0.6-GA fetuses showed a significantly slower and lesser fall in femoral blood flow and conductance compared with the 0.85-GA group, with a correspondingly reduced relative rise in mean arterial blood pressure. As occlusion continued, the initial adaptation was followed by loss of peripheral vasoconstriction and progressive development of hypotension in all groups. The 0.85-GA fetuses showed significantly more sustained reduction in femoral conductance but also more rapid onset of hypotension than either of the younger groups. Electroencephalographic (EEG) activity was suppressed during occlusion in all groups, but the degree of suppression was less at 0.6 GA than at term. In conclusion, the near-midgestation fetus shows attenuated initial (chemoreflex) peripheral vasomotor responses to severe asphyxia compared with more mature fetuses but more sustained hemodynamic adaptation and reduced suppression of EEG activity during continued occlusion of the umbilical cord. (+info)
New Doppler index for prediction of perinatal brain damage in growth-restricted and hypoxic fetuses.
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OBJECTIVE: To evaluate the new vascular score, hypoxia index (HI), in the prediction of sonographically detected structural brain lesions in neonates within the first week after delivery of growth-restricted fetuses. METHODS: This prospective study included 29 growth-restricted fetuses delivered between 31 and 40 gestational weeks. Doppler umbilical artery (UA) and middle cerebral artery (MCA) resistance indices (RI) were recorded at 48-h intervals for at least 2 weeks before delivery. The cerebroumbilical ratio (C/U ratio = MCA-RI/UA-RI) and the HI (the sum of the daily reductions in C/U ratio, i.e. percentage below the cut-off value of 1, over the period of observation) were calculated. After delivery, neonatal outcome was evaluated according to obstetric parameters and ultrasound examinations of the brain. Doppler indices, C/U ratio and HI, as well as neonatal clinical and biochemical parameters, were tested as potential predictors of brain lesions using the C4.5 data-mining algorithm. RESULTS: Neonatal brain lesions were detected in 13 growth-restricted fetuses. Of all the parameters tested by the C4.5 data-mining algorithm, only HI was identified as a predictor of neonatal brain lesions. HI also showed better correlation with neonatal biochemical parameters, such as umbilical venous partial pressure of oxygen and umbilical venous pH, compared with the C/U ratio. CONCLUSIONS: HI, which takes into account cumulative oxygen deficit, could significantly improve the prediction of a poor neurological outcome in pregnancies complicated by growth restriction and hypoxia. (+info)