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  • 1
    In: The Journal of Physiology, Wiley, Vol. 596, No. 23 ( 2018-12), p. 5571-5592
    Abstract: Brain injury around birth is associated with nearly half of all cases of cerebral palsy. Although brain injury is multifactorial, particularly after preterm birth, acute hypoxia–ischaemia is a major contributor to injury. It is now well established that the severity of injury after hypoxia–ischaemia is determined by a dynamic balance between injurious and protective processes. In addition, mothers who are at risk of premature delivery have high rates of diabetes and antepartum infection/inflammation and are almost universally given treatments such as antenatal glucocorticoids and magnesium sulphate to reduce the risk of death and complications after preterm birth. We review evidence that these common factors affect responses to fetal asphyxia, often in unexpected ways. For example, glucocorticoid exposure dramatically increases delayed cell loss after acute hypoxia–ischaemia, largely through secondary hyperglycaemia. This critical new information is important to understand the effects of clinical treatments of women whose fetuses are at risk of perinatal asphyxia.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1475290-6
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  • 2
    In: The Journal of Physiology, Wiley, Vol. 594, No. 5 ( 2016-03), p. 1265-1277
    Abstract: Fetal heart rate variability and changes in the ST segment of the electrocardiogram are used clinically during labour to identify fetuses at risk of severe metabolic acidosis or death. Sympathetic nervous system activity contributes to heart rate variability in healthy normoxic fetuses, and is critical for the rapid haemodynamic adaptations to repeated episodes of asphyxia induced by brief complete umbilical cord occlusions at rates consistent with active labour. We now show that chemical sympathectomy did not alter fetal heart rate variability between episodes of brief repeated asphyxia or elevation of the ST segment during asphyxia. The lack of influence of the sympathetic system on fetal heart rate variability between episodes of brief asphyxia suggests that measures of fetal heart rate variability are unlikely to help monitor changes in sympathetic nervous system activity during active labour.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1475290-6
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  • 3
    In: The Journal of Physiology, Wiley, Vol. 594, No. 17 ( 2016-09), p. 4711-4725
    Abstract: A distinctive pattern of recurrent rapid falls in fetal heart rate, called decelerations, are commonly associated with uterine contractions during labour. These brief decelerations are mediated by vagal activation. The reflex triggering this vagal response has been variably attributed to a mechanoreceptor response to fetal head compression, to baroreflex activation following increased blood pressure during umbilical cord compression, and/or a Bezold–Jarisch reflex response to reduced venous return from the placenta. Although these complex explanations are still widespread today, there is no consistent evidence that they are common during labour. Instead, the only mechanism that has been systematically investigated, proven to be reliably active during labour and, crucially, capable of producing rapid decelerations is the peripheral chemoreflex. The peripheral chemoreflex is triggered by transient periods of asphyxia that are a normal phenomenon associated with all uterine contractions. This should not cause concern as the healthy fetus has a remarkable ability to adapt to these repeated but short periods of asphyxia. This means that the healthy fetus is typically not at risk of hypotension and injury during uncomplicated labour even during repeated brief decelerations. The physiologically incorrect theories surrounding decelerations that ignore the natural occurrence of repeated asphyxia probably gained widespread support to help explain why many babies are born healthy despite repeated decelerations during labour. We propose that a unified and physiological understanding of intrapartum decelerations that accepts the true nature of labour is critical to improve interpretation of intrapartum fetal heart rate patterns. image
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1475290-6
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  • 4
    In: The Journal of Physiology, Wiley, Vol. 596, No. 23 ( 2018-12), p. 5611-5623
    Abstract: The fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic–ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely due to a combination of exhaustion of myocardial glycogen and evolving myocardial injury. The chemoreflex is suppressed by relatively long periods of severe hypoxaemia of 1.5–2 min, longer than the typical contraction. Even in this setting, the peripheral chemoreflex is consistently reactivated between contractions. These findings demonstrate that the peripheral chemoreflex is an indefatigable guardian of fetal adaptation to labour. image
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1475290-6
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  • 5
    In: The Journal of Physiology, Wiley, Vol. 594, No. 5 ( 2016-03), p. 1281-1293
    Abstract: Magnesium sulphate is the recommended treatment for pre‐eclampsia and is now widely recommended for perinatal neuroprotection. MgSO 4 has vasodilatory and negative inotropic effects; however, it is unknown whether it impairs the cardiovascular and cerebrovascular adaptations to acute asphyxia in preterm fetuses. Intravenous infusion of a clinically comparable dose of MgSO 4 to the preterm fetus was associated with no change in blood pressure, reduced fetal heart rate and increased femoral arterial conductance and blood flow; femoral arterial waveform height and width were increased, consistent with increased stroke volume during MgSO 4 infusion. During asphyxia MgSO 4 was associated with increased carotid and femoral arterial conductance and blood flows; after asphyxia, fetal heart rate was lower and carotid and femoral blood flows and vascular conductance were greater in MgSO 4 ‐treated fetuses. These data demonstrate that MgSO 4 may increase perfusion of peripheral vascular beds during adverse perinatal events such as asphyxia.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1475290-6
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  • 6
    In: The Journal of Physiology, Wiley, Vol. 595, No. 17 ( 2017-09), p. 6081-6083
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2017
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  • 7
    In: Developmental Medicine & Child Neurology, Wiley, Vol. 60, No. 2 ( 2018-02), p. 126-133
    Abstract: Hypoxia‐ischemia, infection/inflammation, and barotrauma/volutrauma all contribute to preterm brain injury. Multiple different triggers of preterm brain injury are associated with central nervous system dysmaturation. Secondary brain inflammation may be a viable target to improve neurodevelopment after preterm birth. This article is commented on by Paneth on page 115 of this issue. This article's abstract has been translated into Spanish and Portuguese. Follow the links from the abstract to view the translations.
    Type of Medium: Online Resource
    ISSN: 0012-1622 , 1469-8749
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2001992-0
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  • 8
    In: The Journal of Physiology, Wiley, Vol. 592, No. 24 ( 2014-12-15), p. 5493-5505
    Abstract: Mothers at risk of preterm delivery are routinely given synthetic glucocorticoids such as dexamethasone to help mature fetal lungs and improve survival after birth. We have previously shown that dexamethasone given after an acute episode of asphyxia in preterm fetal sheep is associated with greater brain injury. In this study we found that fetal exposure to dexamethasone after asphyxia in preterm fetal sheep was associated with reduced intracerebral oxygenation during the critical latent phase of recovery. In the secondary phase, maternal dexamethasone was associated with increased epileptiform transient activity and evidence of greater mitochondrial oxidation. These findings suggest that fetal exposure to the synthetic glucocorticoid dexamethasone is associated with a critical mismatch between the brain's demand for oxygenation and the supply of oxygen that may contribute to greater brain injury. Abstract Exposure to clinical doses of the glucocorticoid dexamethasone increases brain activity and causes seizures in normoxic preterm fetal sheep without causing brain injury. In contrast, the same treatment after asphyxia increased brain injury. We hypothesised that increased injury was in part mediated by a mismatch between oxygen demand and oxygen supply. In preterm fetal sheep at 0.7 gestation we measured cerebral oxygenation using near‐infrared spectroscopy, electroencephalographic (EEG) activity, and carotid blood flow (CaBF) from 24 h before until 72 h after asphyxia induced by 25 min of umbilical cord occlusion. Ewes received dexamethasone intramuscularly (12 mg 3 ml –1 ) or saline 15 min after the end of asphyxia. Fetuses were studied for 3 days after occlusion. During the first 6 h of recovery after asphyxia, dexamethasone treatment was associated with a significantly greater fall in CaBF ( P   〈  0.05), increased carotid vascular resistance ( P   〈  0.001) and a greater fall in cerebral oxygenation as measured by the difference between oxygenated and deoxygenated haemoglobin (delta haemoglobin; P   〈  0.05). EEG activity was similarly suppressed in both groups. From 6 to 10 h onward, dexamethasone treatment was associated with a return of CaBF to saline control levels, increased EEG power ( P   〈  0.005), greater epileptiform transient activity ( P   〈  0.001), increased oxidised cytochrome oxidase ( P   〈  0.05) and an attenuated increase in [delta haemoglobin] ( P   〈  0.05). In conclusion, dexamethasone treatment after asphyxia is associated with greater hypoperfusion in the critical latent phase, leading to impaired intracerebral oxygenation that may exacerbate neural injury after asphyxia.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1475290-6
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  • 9
    In: The Journal of Physiology, Wiley, Vol. 601, No. 10 ( 2023-05), p. 1999-2016
    Abstract: Maternal magnesium sulphate (MgSO 4 ) treatment is widely recommended before preterm birth for neuroprotection. However, this is controversial because there is limited evidence that MgSO 4 provides long‐term neuroprotection. Preterm fetal sheep (104 days gestation; term is 147 days) were assigned randomly to receive sham occlusion with saline infusion ( n  = 6) or i.v. infusion with MgSO 4 ( n  = 7) or vehicle (saline, n  = 6) from 24 h before hypoxia–ischaemia induced by umbilical cord occlusion until 24 h after occlusion. Sheep were killed after 21 days of recovery, for fetal brain histology. Functionally, MgSO 4 did not improve long‐term EEG recovery. Histologically, in the premotor cortex and striatum, MgSO 4 infusion attenuated post‐occlusion astrocytosis (GFAP + ) and microgliosis but did not affect numbers of amoeboid microglia or improve neuronal survival. In the periventricular and intragyral white matter, MgSO 4 was associated with fewer total (Olig‐2 + ) oligodendrocytes compared with vehicle + occlusion. Numbers of mature (CC1 + ) oligodendrocytes were reduced to a similar extent in both occlusion groups compared with sham occlusion. In contrast, MgSO 4 was associated with an intermediate improvement in myelin density in the intragyral and periventricular white matter tracts. In conclusion, a clinically comparable dose of MgSO 4 was associated with moderate improvements in white and grey matter gliosis and myelin density but did not improve EEG maturation or neuronal or oligodendrocyte survival. image Key points Magnesium sulphate is widely recommended before preterm birth for neuroprotection; however, there is limited evidence that magnesium sulphate provides long‐term neuroprotection. In preterm fetal sheep exposed to hypoxia–ischaemia (HI), MgSO 4 was associated with attenuated astrocytosis and microgliosis in the premotor cortex and striatum but did not improve neuronal survival after recovery to term‐equivalent age, 21 days after HI. Magnesium sulphate was associated with loss of total oligodendrocytes in the periventricular and intragyral white matter tracts, whereas mature, myelinating oligodendrocytes were reduced to a similar extent in both occlusion groups. In the same regions, MgSO 4 was associated with an intermediate improvement in myelin density. Functionally, MgSO 4 did not improve long‐term recovery of EEG power, frequency or sleep stage cycling. A clinically comparable dose of MgSO 4 was associated with moderate improvements in white and grey matter gliosis and myelin density but did not improve EEG maturation or neuronal or oligodendrocyte survival.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 10
    In: The Journal of Physiology, Wiley, Vol. 596, No. 23 ( 2018-12), p. 6079-6092
    Abstract: We evaluated the effect of magnesium sulphate (MgSO 4 ) on seizures induced by asphyxia in preterm fetal sheep. MgSO 4 did not prevent seizures, but significantly reduced the total duration, number of seizures, seizure amplitude and average seizure burden. Saline‐asphyxia male fetuses had significantly more seizures than female fetuses, but male fetuses showed significantly greater reduction in seizures during MgSO 4 infusion than female fetuses. A circadian profile of seizure activity was observed in all fetuses, with peak seizures seen around 04.00–06.00 h on the first and second days after the end of asphyxia. This study is the first to demonstrate that MgSO 4 has utility as an anti‐seizure agent after hypoxia–ischaemia. More information is needed about the mechanisms mediating the effect of MgSO 4 on seizures and sexual dimorphism, and the influence of circadian rhythms on seizure expression.
    Type of Medium: Online Resource
    ISSN: 0022-3751 , 1469-7793
    URL: Issue
    RVK:
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1475290-6
    SSG: 12
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