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: 2.84). 10/2009; 67(1):95-101. DOI: 10.1203/PDR.0b013e3181bf5fab
Source: PubMed

ABSTRACT 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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    • "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 · 2.90 Impact Factor
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    • "The lung is also a major potential site of entry for diverse organisms during fetal life, especially in the presence of chorioamnionitis. The latter has been implicated in a significant proinflammatory cascade that may affect neonatal morbidity via both neurodevelopmental as well as respiratory outcomes (Kallapur et al., 2009; Leviton et al., 2010). These clinical observations led us to explore the interrelationship between intrapulmonary endotoxin exposure and an inflammatory response in the developing brain. "
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    ABSTRACT: Perinatal sepsis and inflammation trigger lung and brain injury in preterm infants, and associated apnea of prematurity. We hypothesized that endotoxin exposure in the immature lung would upregulate proinflammatory cytokine mRNA expression in the medulla oblongata and be associated with impaired respiratory control. Lipopolysaccharide (LPS, 0.1mg/kg) or saline was administered intratracheally to rat pups and medulla oblongatas were harvested for quantifying expression of mRNA for proinflammatory cytokines. LPS-exposure significantly increased medullary mRNA for IL-1β and IL-6, and vagotomy blunted this increase in IL-1β, but not IL-6. Whole-body flow plethysmography revealed that LPS-exposed pups had an attenuated ventilatory response to hypoxia both before and after carotid sinus nerve transection. Immunochemical expression of IL-1β within the nucleus of the solitary tract and area postrema was increased after LPS-exposure. In summary, intratracheal endotoxin-exposure in rat pups is associated with upregulation of proinflammatory cytokines in the medulla oblongata that is vagally mediated for IL-1β and associated with an impaired hypoxic ventilatory response.
    Respiratory Physiology & Neurobiology 03/2011; 178(3):458-64. DOI:10.1016/j.resp.2011.03.003 · 1.97 Impact Factor
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    • "infection—The second major upstream mechanism in the pathogenesis of pre-OL injury is infection and systemic inflammation (Volpe, 2008b) (Fig. 6). A number of epidemiological studies have shown an association between PVL and maternal intrauterine infection with fetal systemic inflammation or neonatal systemic infection with neonatal systemic inflammation (Volpe, 2008b; Volpe, 2008c; Wu and Colford, 2000; Shah et al., 2008; Chau et al., 2009; Leviton et al., 2010). Maternal intrauterine infection or neonatal systemic infection or both occur in as many as 65% of VLBW infants (Volpe, 2008b; Stoll et al., 2004; Stoll et al., 2005). "
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    ABSTRACT: Brain injury in the premature infant, a problem of enormous importance, is associated with a high risk of neurodevelopmental disability. The major type of injury involves cerebral white matter and the principal cellular target is the developing oligodendrocyte. The specific phase of the oligodendroglial lineage affected has been defined from study of both human brain and experimental models. This premyelinating cell (pre-OL) is vulnerable because of a series of maturation-dependent events. The pathogenesis of pre-OL injury relates to operation of two upstream mechanisms, hypoxia-ischemia and systemic infection/inflammation, both of which are common occurrences in premature infants. The focus of this review and of our research over the past 15-20 years has been the cellular and molecular bases for the maturation-dependent vulnerability of the pre-OL to the action of the two upstream mechanisms. Three downstream mechanisms have been identified, i.e., microglial activation, excitotoxicity and free radical attack. The work in both experimental models and human brain has identified a remarkable confluence of maturation-dependent factors that render the pre-OL so exquisitely vulnerable to these downstream mechanisms. Most importantly, elucidation of these factors has led to delineation of a series of potential therapeutic interventions, which in experimental models show marked protective properties. The critical next step, i.e., clinical trials in the living infant, is now on the horizon.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 03/2011; 29(4):423-40. DOI:10.1016/j.ijdevneu.2011.02.012 · 2.92 Impact Factor
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