Abstract
Brief but severe asphyxia in late gestation or at the time of birth may lead to neonatal hypoxic ischemic encephalopathy and is associated with long-term neurodevelopmental impairment. We undertook this study to examine the consequences of transient in utero asphyxia in late gestation fetal sheep, on the newborn lamb after birth. Surgery was undertaken at 125 days gestation for implantation of fetal catheters and placement of a silastic cuff around the umbilical cord. At 132 days gestation (0.89 term), the cuff was inflated to induce umbilical cord occlusion (UCO), or sham (control). Fetal arterial blood samples were collected for assessment of fetal wellbeing and the pregnancy continued until birth. At birth, behavioral milestones for newborn lambs were recorded over 24 h, after which the lambs were euthanased for brain collection and histopathology assessments. After birth, UCO lambs displayed significant latencies to (i) use all four legs, (ii) attain a standing position, (iii) find the udder, and (iv) successfully suckle - compared to control lambs. Brains of UCO lambs showed widespread pathologies including cell death, white matter disruption, intra-parenchymal hemorrhage and inflammation, which were not observed in full term control brains. UCO resulted in some preterm births, but comparison with age-matched preterm non-UCO control lambs showed that prematurity per se was not responsible for the behavioral delays and brain structural abnormalities resulting from the in utero asphyxia. These results demonstrate that a single, brief fetal asphyxic episode in late gestation results in significant grey and white matter disruption in the developing brain, and causes significant behavioral delay in newborn lambs. These data are consistent with clinical observations that antenatal asphyxia is causal in the development of neonatal encephalopathy and provide an experimental model to advance our understanding of neuroprotective therapies.
Highlights
Notwithstanding the recent debate over the appropriateness of the terms Neonatal Encephalopathy and Hypoxic-Ischemic Encephalopathy [1,2,3], there continues to be uncertainty about the contribution of antenatal hypoxic-ischemic events to the functional and structural brain pathology that can arise after birth at term [4], [5]
In this study we show that a brief fetal asphyxia in utero late in gestation increases the probability of preterm birth, and the lambs have significant behavioral deficits following birth that appear to arise from the underlying neuropathology caused by the asphyxia, and not from the preterm birth per se
Immunohistochemical and histological analysis confirmed previous findings in fetal sheep that certain brain areas are vulnerable to hypoxic damage in late gestation; viz., the corpus callosum, subcortical white matter, striatal regions responsible for sensorimotor integration and movement control [13], [26,27,28], consistent with the view that acute antepartum hypoxic events can induce brain damage that manifest as neuromotor and cognitive disabilities in the newborn
Summary
Notwithstanding the recent debate over the appropriateness of the terms Neonatal Encephalopathy and Hypoxic-Ischemic Encephalopathy [1,2,3], there continues to be uncertainty about the contribution of antenatal hypoxic-ischemic events to the functional and structural brain pathology that can arise after birth at term [4], [5]. We [10], [11], and others [12,13,14] have described the distribution and type of brain injury that arises from brief asphyxia in utero in late gestation fetal sheep, produced by transiently occluding the umbilical cord. The distribution and type of brain injury that arises from this global fetal asphyxia has been described in detail for the 24–72 h period after the fetal insult [10], [13], [14], but it is not known if the brain pathology partly resolves by the time of birth, or evolves further and has neurodevelopmental and behavioral consequences for the newborn animal
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