The fetal inflammatory response syndrome and cerebral palsy: yet another challenge and dilemma for the obstetrician

Svigos, John

doi:10.1111/j.1479-828x.2001.tb01203.x

Cited by 25 publications

(15 citation statements)

References 58 publications

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“…7,8 This injury has been defined as both abnormal cellular morphology and dendritic arborization as well as delayed neurotoxicity 9,10 and is proposed to occur via a pro-inflammatory pathway that is triggered in response to intrauterine inflammation. 11,12 Cytokine response reported by our group and others 10,13–15 has shown in an acute elevation of IL-6, TNF-a and significant increase in IL-1β in the fetal brain and placenta. 10 …”

Section: Introductionmentioning

confidence: 66%

IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury

Leitner

Shammary

McLane

et al. 2014

American J Rep Immunol

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Problem Exposure to intrauterine inflammation, associated with preterm birth, has been linked to a devastating spectrum of neurobehavioral disorders. Mechanisms of this injury are unknown. Using a mouse model of intrauterine inflammation, we have observed a disruption of fetal neuronal morphology along with a marked elevation of Interleukin (IL)-1β in the fetal brain and placenta. In the current study, we hypothesized that IL-1 plays a key role in perinatal brain injury. Method of Study Utilizing a mouse model of inflammation-induced preterm birth, we investigated the role of IL-1 in fetal cortical injury as well as preterm birth. In these studies, dams received systemic treatment with IL-1 receptor antagonist prior to administration of intrauterine inflammation. Results Systemic maternal antagonism of IL-1 improved fetal cortical neuronal injury associated with the exposure to intrauterine inflammation, without affecting the phenotype of preterm birth. IL-1 receptor antagonist blocked activation of neuronal nitric oxide synthase in perinatal cortex, a key enzyme implicated in neurotoxicity. Conclusion Our data suggest that fetal cortical brain injury and preterm birth may occur by divergent mechanisms. Furthermore, our studies indicate maternal administration of IL-1 receptor antagonist (IL-1RA) blocked neuronal nitric oxide synthase activation observed in the brain cortex and, we speculate, that this alteration in activation leads to demonstrated decreased neurotoxicity.

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Section: Introductionmentioning

confidence: 66%

IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury

Leitner

Shammary

McLane

et al. 2014

American J Rep Immunol

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“…15 Intrauterine inflammation associated with preterm birth, placental inflammation, or premature rupture of membrane may lead to a systemic inflammatory condition in the fetus called fetal inflammatory response syndrome (FIRS) through an alteration of pro-inflammatory cytokine levels. 17,18 Maternal intrauterine infection/inflammation resulting in FIRS has been implicated in the development of periventricular leukomalacia (PVL) leading to motor and cognitive impairments in the infant. FIRS is associated with elevated levels of inflammatory cytokines such as interleukin (IL) 6, tumor necrosis factor (TNF) a receptors in the fetal plasma and high cerebrospinal fluid (CSF), and cord blood levels of IL-6 and IL-8.…”

Section: Maternal and Fetal Immune Dysregulation And Impaired Fetal Bmentioning

confidence: 99%

Models of Fetal Brain Injury, Intrauterine Inflammation, and Preterm Birth

Burd

Balakrishnan

Kannan

2012

American J Rep Immunol

221

188

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CitationBurd I, Balakrishnan B, Kannan S. Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol 2012; 67: 287-295 doi:10.1111/j.1600-0897.2012 Intrauterine infection and inflammation are known risk factors for brain damage in the neonate irrespective of the gestational age. Infectioninduced maternal immune activation leads to a fetal inflammatory response mediated by cytokines that has been implicated in the development of not only periventricular leukomalacia and cerebral palsy but also a spectrum of neurodevelopmental disorders such as autism and schizophrenia ( Studies involving animal models of maternal inflammation serve a key role in elucidation of mechanisms involved in fetal brain injury associated with exposure to the maternal milieu. These animal models have been shown to result in fetal microglial activation, neurotoxicity as well motor deficits and behavioral abnormalities in the offspring (J Neurosci

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“…Other than cerebral ischemia, 61 the second most important prenatal factor is most likely intrauterine infection. 49,59,[62][63][64][65][66][67][68][69][70][71] Intrauterine infection stimulates premature delivery and is a common cause of fatal morbidity in preterm infants. For many years, the focus of attention was directed at the involvement of free radical and excitotoxic-mediated damage in PVL.…”

Section: Historical Perspectivementioning

confidence: 99%

Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system

2002

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Periventricular leukomalacia (PVL) occurring in premature infants, represents a major precursor for neurological and intellectual impairment, and cerebral palsy in later life. The disorder is characterized by multifocal areas of necrosis found deep in the cortical white matter, which are often symmetrical and occur adjacent to the lateral ventricles. There is no known cure for PVL. Factors predisposing to PVL include birth trauma, asphyxia and respiratory failure, cardiopulmonary defects, premature birth/low birthweight, associated immature cerebrovascular development and lack of appropriate autoregulation of cerebral blood flow in response to hypoxic-ischemic insults. The intrinsic vulnerability of oligodendrocyte precursors is considered as central to the pathogenesis of PVL. These cells are susceptible to a variety of injurious stimuli including free radicals and excitotoxicity induced by hypoxic-ischemic injury (resulting from cerebral hypoperfusion), lack of trophic stimuli, as well as secondary associated events involving microglial and astrocytic activation and the release of pro-inflammatory cytokines TNF-alpha and IL-6. It is yet unclear whether activated astrocytes and microglia act as principal participants in the development of PVL lesions, or whether they are representatives of an incidental pathological response directed towards repair of tissue injury in PVL. Nevertheless, the accumulated evidence points to a pathological contribution of microglia towards damage. The topography of lesions in PVL most likely reflects a combination of the relatively immature cerebrovasculature together with a failure in perfusion and/or hypoxia during the greatest period of vulnerability occurring around mid-to-late gestation. Mechanisms underlying the pathogenesis of PVL have so far been related to prenatal ischemic injury to the brain initiated within the third trimester, which result in global cognitive and developmental delay and motor disturbances. Over the past few years, several epidemiological and experimental studies have implicated intrauterine infection and chorioamnionitis as causative in the pathogenesis of PVL. In particular, recent investigations have shown that inflammatory responses in the fetus and neonate can contribute towards neonatal brain injury and development-related disabilities including cerebral palsy. This review presents current concepts on the pathogenesis of PVL and emphasizes the increasing evidence for an inflammatory pathogenic component to this disorder, either resulting from hypoxic-ischemic injury or from infection. These findings provide the basis for clinical approaches targeted at protecting the premature brain from inflammatory damage, which may prove beneficial for treating PVL, if identified early in pathogenesis.

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The fetal inflammatory response syndrome and cerebral palsy: yet another challenge and dilemma for the obstetrician

Cited by 25 publications

References 58 publications

IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury

IL‐1 Receptor Blockade Prevents Fetal Cortical Brain Injury but Not Preterm Birth in a Mouse Model of Inflammation‐Induced Preterm Birth and Perinatal Brain Injury

Models of Fetal Brain Injury, Intrauterine Inflammation, and Preterm Birth

Periventricular leukomalacia, inflammation and white matter lesions within the developing nervous system

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