Microbiologic and Histologic Characteristics of the Extremely Preterm Infant's Placenta Predict White Matter Damage and Later Cerebral Palsy. The ELGAN Study

Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA.
Pediatric Research (Impact Factor: 2.31). 10/2009; 67(1):95-101. DOI: 10.1203/PDR.0b013e3181bf5fab
Source: PubMed


Inflammatory phenomena seem to contribute to the occurrence of perinatal cerebral white matter damage and CP. The stimulus that initiates the inflammation remains obscure. One thousand two hundred forty-six infants born before the 28th postmenstrual week had a protocol ultrasound scan of the brain read concordantly by two independent sonologists. Eight hundred ninety-nine of the children had a neurologic examination at approximately 24-mo postterm equivalent. The placenta of each child had been biopsied under sterile conditions and later cultured. Histologic slides of the placenta were examined specifically for this study. Recovery of a single microorganism predicted an echolucent lesion, whereas polymicrobial cultures and recovery of skin flora predicted both ventriculomegaly and an echolucent lesion. Diparetic CP was predicted by recovery of a single microorganism, multiple organisms, and skin flora. Histologic inflammation predicted ventriculomegaly and diparetic CP. The risk of ventriculomegaly associated with organism recovery was heightened when accompanied by histologic inflammation, but the risk of diparetic CP was not. Low-virulence microorganisms isolated from the placenta, including common skin microflora, predict ultrasound lesions of the brain and diparetic CP in the very preterm infant. Organism recovery does not seem to be needed for placenta inflammation to predict diparetic CP.

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    • "Detailed analyses of placentas from ELGANs show inflammation is more commonly associated with spontaneous early birth, whereas less inflammation was present in placenta from births induced for maternal health such as pre-eclampsia [16]. Intrauterine infection increases the risk of cerebral palsy in children born preterm [10,17,18], and recent well controlled studies have confirmed that chorioamnionitis is associated with cerebral palsy in children who were born very preterm [19], and with cognitive impairment at 2 years in ELGANs [20]. Together, these human studies of extremely preterm birth reveal a strong correlation between in utero bacterial inflammation and hypoxia-ischemia (HI) and subsequent impaired brain development. "
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    ABSTRACT: Background Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to cerebral palsy, cognitive delay, behavioral issues and epilepsy. Using a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation, we tested our hypothesis that inflammation from HI and LPS differentially affects gliosis, white matter development and motor impairment during the first postnatal month. Methods Pregnant rats underwent laparotomy on embryonic day 18 and transient systemic HI (TSHI) and/or intra-amniotic LPS injection. Shams received laparotomy and anesthesia only. Pups were born at term. Immunohistochemistry with stereological estimates was performed to assess regional glial loads, and western blots were performed for protein expression. Erythropoietin ligand and receptor levels were quantified using quantitative PCR. Digigait analysis detected gait deficits. Statistical analysis was performed with one-way analysis of variance and post-hoc Bonferonni correction. Results Microglial and astroglial immunolabeling are elevated in TSHI + LPS fimbria at postnatal day 2 compared to sham (both P < 0.03). At postnatal day 15, myelin basic protein expression is reduced by 31% in TSHI + LPS pups compared to shams (P < 0.05). By postnatal day 28, white matter injury shifts from the acute injury pattern to a chronic injury pattern in TSHI pups only. Both myelin basic protein expression (P < 0.01) and the phosphoneurofilament/neurofilament ratio, a marker of axonal dysfunction, are reduced in postnatal day 28 TSHI pups (P < 0.001). Erythropoietin ligand to receptor ratios differ between brains exposed to TSHI and LPS. Gait analyses reveal that all groups (TSHI, LPS and TSHI + LPS) are ataxic with deficits in stride, paw placement, gait consistency and coordination (all P < 0.001). Conclusions Prenatal TSHI and TSHI + LPS lead to different patterns of injury with respect to myelination, axon integrity and gait deficits. Dual injury leads to acute alterations in glial response and cellular inflammation, while TSHI alone causes more prominent chronic white matter and axonal injury. Both injuries cause significant gait deficits. Further study will contribute to stratification of injury mechanisms in preterm infants, and guide the use of promising therapeutic interventions.
    Journal of Neuroinflammation 08/2014; 11(1):131. DOI:10.1186/1742-2094-11-131 · 5.41 Impact Factor
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    • "Maternal infection or infection of the placenta is recognised as one of the most important causes of preterm birth, and of cerebral white matter injury (WMI) in the prematurely born baby [1-4]. Consistent with this, histological chorioamnionitis or raised fetal proinflammatory cytokine levels, including tumour necrosis factor-α (TNF-α), are present in the majority of preterm births [2,5]. At present, the specific mechanisms are incompletely understood, and no effective treatment is available. "
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    ABSTRACT: White matter injury (WMI) is the major antecedent of cerebral palsy in premature infants, and is often associated with maternal infection and the fetal inflammatory response. The current study explores the therapeutic potential of glutamate receptor blockade or cyclooxygenase-2 (COX-2) inhibition for inflammatory WMI. Using fetal ovine derived mixed glia cultures exposed to tumour necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS), the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl D-aspartate (NMDA) glutamate receptors and their contribution to inflammation mediated pre-oligodendrocyte (OL) death was evaluated. The functional significance of TNF-alpha and COX-2 signalling in glutamate release in association with TNF-alpha and LPS exposure was also assessed. AMPA and NMDA receptors were expressed in primary mixed glial cultures on developing OLs, the main cell-type present in fetal white matter at a period of high risk for WMI. We show that glutamate receptor expression and configuration are regulated by TNF-alpha and LPS exposure, but AMPA and NMDA blockade, either alone or in combination, did not reduce pre-OL death. Furthermore, we demonstrate that glutamate and prostaglandin E2 (PGE2) release following TNF-alpha or LPS are mediated by a TNF-alpha-COX-2 dependent mechanism. Overall, these findings suggest that glial-localised glutamate receptors likely play a limited role in OL demise associated with chronic inflammation, but supports the COX-2 pathway as a potential therapeutic target for infection/inflammatory-mediated WMI.
    Journal of Neuroinflammation 12/2013; 10(1):153. DOI:10.1186/1742-2094-10-153 · 5.41 Impact Factor
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    • "In a large cohort of extremely preterm infants, the ELGAN cohort, both clinical indicators (McElrath et al., 2009; Martin et al., 2010) and biomarkers of inflammation (Leviton et al., 2010) have been associated with perinatal brain damage and subsequent developmental impairment at 2 years of age. In this cohort, persistent/recurrent elevations of seven inflammation-related proteins, defined as an elevation on at least 2 days a week or more apart in the first 2 weeks of life, are associated with a 2-to 3.9-fold increase in the risk of an attention impairment identified at 2 years of age using the Child Behavioral Checklist [manuscript under review]. "
    Frontiers in Human Neuroscience 09/2013; 7:578. DOI:10.3389/fnhum.2013.00578 · 3.63 Impact Factor
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