Antenatal Antecedents of Cognitive Impairment at 24 Months In Extremely Low Gestational Age Newborns

Helderman, Jennifer; O’Shea, T. Michael; Kuban, Karl; Allred, Elizabeth N.; Hecht, Jonathan L.; Dammann, Olaf; Paneth, Nigel; McElrath, Thomas F.; Onderdonk, Andrew; Leviton, Alan

doi:10.1542/peds.2011-1796

Cited by 69 publications

(59 citation statements)

References 57 publications

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“…Recent studies, however, have highlighted a role for both earlier and subtler insults in the majority of cases. For example, the Extremely Low Gestational Age Newborns (ELGAN) Study reported that severe intrauterine growth restriction and evidence of placental vascular thrombosis were associated with impaired neurodevelopmental outcome at 2 y of age (19), consistent with a role for long-standing, prenatal hypoxia. After birth, although low blood pressure is common, the evidence for an association between hypotension and adverse outcomes is limited, as reviewed earlier (20).…”

Section: Mechanisms Of Perinatal Brain Injurymentioning

confidence: 99%

Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth

et al. 2013

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Section: Mechanisms Of Perinatal Brain Injurymentioning

confidence: 99%

Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth

et al. 2013

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“…Nevertheless, there is some evidence for a role of subtle insults, as shown, e.g., by depressed Apgar scores at birth (22). More recently, the Extremely Low Gestational Age Newborns (ELGAN) study reported that severe intrauterine growth restriction and evidence of placental vascular thrombosis consistent with longstanding, prenatal hypoxemia were associated with impaired neurodevelopmental outcome at 2 y of age (23). After birth, although low blood pressure is common, the evidence for an association between hypotension and adverse outcomes is limited, as reviewed in ref.…”

Section: Timing and Etiology Of Preterm Brain Injurymentioning

confidence: 99%

What brakes the preterm brain? An arresting story

et al. 2013

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Children surviving premature birth have a high risk of cognitive and learning disabilities and attention deficit. In turn, adverse outcomes are associated with persistent reductions in cerebral growth on magnetic resonance imaging (MRI). It is striking that modern care has been associated with a dramatic reduction in the risk of cystic white matter damage, but modest improvements in terms of neurodevelopmental impairment. This review will explore the hypothesis that the disability is primarily associated with impaired neural connectivity rather than cell death alone. Very preterm infants exhibit reduced thalamocortical connectivity and cortical neuroplasticity compared with term-born controls. In preterm fetal sheep, moderate cerebral ischemia with no neuronal loss, but significant diffuse failure of maturation of cortical pyramidal neurons, was associated with impaired dendritic growth and synapse formation, consistent with altered connectivity. These changes were associated with delayed decline in cortical fractional anisotropy (FA) on MRI. Supporting these preclinical findings, preterm human survivors showed similar enduring impairment of microstructural development of the cerebral cortex defined by FA, consistent with delayed formation of neuronal processes. These findings offer the promise that better understanding of impairment of neural connectivity may allow us to promote normal development and growth of the cortex after preterm birth. P remature birth is one of the leading causes of morbidity and mortality. Approximately 6-13% of all births are preterm (1), and in the United States, this has been estimated to cost the community more than $26.2 billion in 2005 alone (1). Most of this cost is related not to acute care but to cerebral palsy and long-term neurodevelopmental disability in surviving very premature (≤30 wk gestation) infants. Disability is highly associated with greater prematurity (2,3), but even in "late preterm" infants at 34-36 wk gestation, the risks of injury and disability are increased sevenfold or more compared with term infants (4). Although there is evidence for modest overall improvements in survival without disability in recent cohorts (2,3), others found no apparent improvement in disability after extremely preterm (<25 wk gestation) birth (5).Historically, preterm human autopsy cases typically showed severe necrotic white matter injury (WMI) with evidence of axonal degeneration and loss of cortical neurons (6,7). This necrosis in turn was associated with cerebral palsy. The greater risk of long-term disability in boys is correlated with greater risk of WMI (8). Encouragingly, there is now evidence of a progressive reduction in the severest form of cystic WMI over time (9). In modern cohorts, severe WMI is seen in only ~1% of cases, whereas less severe (nonnecrotic), diffuse WMI is now common (9,10).It is striking that despite this apparent marked reduction in the severity of WMI, that even less severe forms of WMI injury are associated with impaired brain development and disabil...

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“…The clinical relationship between injury and infection is complex and closely intertwined with placental insufficiency [10,11,12]. This complexity is mirrored by preclinical evidence in the neonatal rat that single-dose exposure to lipopolysaccharide (LPS) can either protect or sensitize to injury from other insults [13,14,15,16,17], depending on the time interval between exposure to infection and subsequent ischemia.…”

Section: Introductionmentioning

confidence: 99%

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Dhillon

Gunn

Jung³

et al. 2015

Dev Neurosci

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Acute exposure to subclinical infection modulates subsequent hypoxia-ischemia (HI) injury in a time-dependent manner, likely by cross-talk through Toll-like receptors (TLRs), but the specific pathways are unclear in the preterm-equivalent brain. In the present study, we tested the hypothesis that repeated low-dose exposure to lipopolysaccharide (LPS) before acute ischemia would be associated with induction of specific TLRs that are potentially neuroprotective. Fetal sheep at 0.65 gestation (term is ∼145 days) received intravenous boluses of low-dose LPS for 5 days (day 1, 50 ng/kg; days 2-5, 100 ng/kg) or the same volume of saline. Either 4 or 24 h after the last bolus of LPS, complete carotid occlusion was induced for 22 min. Five days after LPS, brains were collected. Pretreatment with LPS for 5 days decreased cellular apoptosis, microglial activation and reactive astrogliosis in response to HI injury induced 24 but not 4 h after the last dose of LPS. This was associated with upregulation of TLR4, TLR7 and IFN-β mRNA, and increased fetal plasma IFN-β concentrations. The association of reduced white matter apoptosis and astrogliosis after repeated low-dose LPS finishing 24 h but not 4 h before cerebral ischemia, with central and peripheral induction of IFN-β, suggests the possibility that IFN-β may be an important mediator of endogenous neuroprotection in the developing brain.

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Antenatal Antecedents of Cognitive Impairment at 24 Months In Extremely Low Gestational Age Newborns

Cited by 69 publications

References 57 publications

Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth

Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth

What brakes the preterm brain? An arresting story

Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

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