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Association of Histologic Chorioamnionitis With Perinatal Brain Injury and Early Childhood Neurodevelopmental Outcomes Among Preterm Neonates.

ABSTRACT: Importance:Understanding the role of chorioamnionitis, a major factor leading to preterm birth, in the pathogenesis of neonatal brain injury and adverse neurodevelopmental outcomes may help in identifying potentially modifiable perinatal variables affecting brain health and outcomes among children born preterm. Objective:To evaluate whether histologic chorioamnionitis among neonates born very preterm is associated with intraventricular hemorrhage (IVH) and punctate white matter injury (WMI) or with adverse neurodevelopmental outcomes during early childhood. Design, Setting, and Participants:Prospective cohort study conducted across 3 academic centers (from April 2006 to September 2013 in Canada, from March 2007 to March 2013 in the Netherlands, and from January 2004 to August 2011 in the United States). Children who were born preterm (24-32 weeks' gestation) and who had undergone a placental pathologic evaluation, magnetic resonance imaging as soon as clinically stable, and Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) assessments between 18 and 24 months' corrected age (CA) were included. Magnetic resonance imaging scans were assessed for grade of IVH and volume of punctate WMI. Data analysis occurred between December 2016 and January 2018. Final multivariable analyses examining the association of chorioamnionitis with motor and cognitive outcomes accounted for academic center and perinatal and postnatal factors. Main Outcomes and Measures:Punctate WMI volume and IVH detected on neonatal magnetic resonance imaging scans; motor and cognitive outcomes defined using Bayley-III assessments conducted among these children between 18 and 24 months' CA. Results:Of 350 neonates (182 male) in the final cohort, 145 (41.4%) had histologic chorioamnionitis. Gestational age was significantly lower among those with chorioamnionitis (median, 26.4 weeks; interquartile range [IQR], 25.6-27.7 weeks) than among those without chorioamnionitis (median, 28.0 weeks; IQR, 27.0-29.7 weeks). Chorioamnionitis was not associated with IVH or WMI, nor was it associated with worse motor outcomes in univariable or multivariable analyses (adjusted Bayley-III motor score, -2.2; 95% CI, -5.6 to 1.3). Cognitive scores were marginally yet statistically significantly lower among children with chorioamnionitis (median, 105; IQR, 95-110) than among those without chorioamnionitis (median, 105; IQR, 100-115) in the univariable model. This difference was attenuated in the multivariable model (adjusted Bayley-III cognitive score, -3.0; 95% CI, -6.4 to 0.4). Conclusions and Relevance:Histologic chorioamnionitis was not associated with IVH or WMI near birth or with worse cognitive or motor outcomes from 18 to 24 months' CA after accounting for perinatal factors. Postnatal factors attenuated the association between chorioamnionitis and neurodevelopmental outcomes, highlighting the importance of preventing postnatal illness, such as infection, to promote optimal outcomes among children born preterm.

SUBMITTER: Bierstone D

PROVIDER: S-EPMC6137531 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Association of Histologic Chorioamnionitis With Perinatal Brain Injury and Early Childhood Neurodevelopmental Outcomes Among Preterm Neonates.

Bierstone Daniel D Wagenaar Nienke N Gano Dawn L DL Guo Ting T Georgio Gregory G Groenendaal Floris F de Vries Linda S LS Varghese Jojy J Glass Hannah C HC Chung Catherine C Terry Jefferson J Rijpert Maarten M Grunau Ruth E RE Synnes Anne A Barkovich A James AJ Ferriero Donna M DM Benders Manon M Chau Vann V Miller Steven P SP

JAMA pediatrics 20180601 6

<h4>Importance</h4>Understanding the role of chorioamnionitis, a major factor leading to preterm birth, in the pathogenesis of neonatal brain injury and adverse neurodevelopmental outcomes may help in identifying potentially modifiable perinatal variables affecting brain health and outcomes among children born preterm.<h4>Objective</h4>To evaluate whether histologic chorioamnionitis among neonates born very preterm is associated with intraventricular hemorrhage (IVH) and punctate white matter in ...[more]

PMID: 29610829

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Project description:ContextNo consensus exists regarding the association between maternal chorioamnionitis and neurodevelopmental outcomes in preterm and very preterm neonates.ObjectivesTo investigate whether maternal chorioamnionitis affects neurodevelopmental outcomes and to identify the factors that may explain these effects.Data sourcesWe used Ovid Medline, EMBASE and Web of Science to conduct a meta-analysis of studies published in English before August 25, 2017, with titles or abstracts that discussed an association between maternal chorioamnionitis and mental/motor development.Study selectionAmong the 603 initially identified studies, we selected those that addressed an association between maternal chorioamnionitis and mental/motor development according to our preselected inclusion criteria as follows: (1) the study compared infants with and without exposure to maternal chorioamnionitis and (2) the neurodevelopmental outcome was followed up using the Bayley Scales of Infant Development 2nd edition.Data synthesisOur meta-analysis included 10 studies. According to a random effect model, infants with maternal chorioamnionitis exposure had poorer mental development (d = -2.25 [95%CI, -4.33, -0.17], p<0.05) than infants without maternal chorioamnionitis, and infants with maternal clinical chorioamnionitis exposure had poorer motor development (d = -2.37 [95%CI, -4.62 to -0.12], p<0.05) than infants without maternal clinical chorioamnionitis exposure. Factors in the meta-analysis that showed differences between the two patient groups included an MDI assessment blinded to medical history, MDI assessment at the correct age, and time of the MDI assessment.ConclusionThis study suggests that maternal chorioamnionitis may affect mental development in preterm and very preterm neonates, and that maternal clinical chorioamnionitis may affect motor development in offspring. Further studies are required to confirm these results and to detect the influence of variables across studies.

Project description:IMPORTANCE:Chorioamnionitis is strongly linked to preterm birth and neonatal infection. The association between histological and clinical chorioamnionitis and cognitive, behavioral, and neurodevelopmental outcomes among extremely preterm neonates is less clear. We evaluated the impact of chorioamnionitis on 18- to 22-month neurodevelopmental outcomes in a contemporary cohort of extremely preterm neonates. OBJECTIVE:To compare the neonatal and neurodevelopmental outcomes of 3 groups of extremely low-gestational-age infants with increasing exposure to perinatal inflammation: no chorioamnionitis, histological chorioamnionitis alone, or histological plus clinical chorioamnionitis. DESIGN, SETTING, AND PARTICIPANTS:Longitudinal observational study at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Two thousand three hundred ninety extremely preterm infants born at less than 27 weeks' gestational age (GA) between January 1, 2006, and December 31, 2008, with placental histopathology and 18 to 22 months' corrected age follow-up data were eligible. MAIN EXPOSURE:Chorioamnionitis. MAIN OUTCOMES AND MEASURES:Outcomes included cerebral palsy, gross motor functional limitation, behavioral scores (according to the Brief Infant-Toddler Social and Emotional Assessment), cognitive and language scores (according to the Bayley Scales of Infant and Toddler Development, Third Edition), and composite measures of death/neurodevelopmental impairment. Multivariable logistic and linear regression models were developed to assess the association between chorioamnionitis and outcomes while controlling for important variables known at birth. RESULTS:Neonates exposed to chorioamnionitis had a lower GA and higher rates of early-onset sepsis and severe periventricular-intraventricular hemorrhage as compared with unexposed neonates. In multivariable models evaluating death and neurodevelopmental outcomes, inclusion of GA in the model diminished the association between chorioamnionitis and adverse outcomes. Still, histological plus clinical chorioamnionitis was associated with increased risk of cognitive impairment as compared with no chorioamnionitis (adjusted odds ratio [OR], 2.38 [95% CI, 1.32 to 4.28] without GA; adjusted OR, 2.00 [95% CI, 1.10 to 3.64] with GA as a covariate). Histological chorioamnionitis alone was associated with lower odds of death/neurodevelopmental impairment as compared with histological plus clinical chorioamnionitis (adjusted OR, 0.68 [95% CI, 0.52 to 0.89] without GA; adjusted OR, 0.66 [95% CI, 0.49 to 0.89] with GA as a covariate). Risk of behavioral problems did not differ statistically between groups. CONCLUSIONS AND RELEVANCE:Antenatal exposure to chorioamnionitis is associated with altered odds of cognitive impairment and death/neurodevelopmental impairment in extremely preterm infants.

Project description:Preterm infants are at high risk for brain injury during the perinatal period. Intraventricular hemorrhage and periventricular leukomalacia, the two most common patterns of brain injury in prematurely-born children, are associated with poor neurodevelopmental outcomes. The hippocampus is known to be critical for learning and memory; however, it remains unknown how these forms of brain injury affect hippocampal growth and how the resulting alterations in hippocampal development relate to childhood outcomes. To investigate these relationships, hippocampal segmentations were performed on term equivalent MRI scans from 55 full-term infants, 85 very preterm infants (born ≤32 weeks gestation) with no to mild brain injury and 73 very preterm infants with brain injury (e.g., grade III/IV intraventricular hemorrhage, post-hemorrhagic hydrocephalus, cystic periventricular leukomalacia). Infants then underwent standardized neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development, 3rd edition at age 2 years, corrected for prematurity. To delineate the effects of brain injury on early hippocampal development, hippocampal volumes were compared across groups and associations between neonatal volumes and neurodevelopmental outcomes at age 2 years were explored. Very preterm infants with brain injury had smaller hippocampal volumes at term equivalent age compared to term and very preterm infants with no to mild injury, with the smallest hippocampi among those with grade III/IV intraventricular hemorrhage and post-hemorrhagic hydrocephalus. Further, larger ventricle size was associated with smaller hippocampal size. Smaller hippocampal volumes were related to worse motor performance at age 2 years across all groups. In addition, smaller hippocampal volumes in infants with brain injury were correlated with impaired cognitive scores at age 2 years, a relationship specific to this group. Consistent with our preclinical findings, these findings demonstrate that perinatal brain injury is associated with hippocampal size in preterm infants, with smaller volumes related to domain-specific neurodevelopmental impairments in this high-risk clinical population.

Project description:ObjectivesFirst, to apply a recently extended scoring system for preterm brain injury at term-equivalent age (TEA-)MRI in a regional extremely preterm cohort; second, to identify independent perinatal factors associated with this score; and third, to assess the prognostic value of this TEA-MRI score with respect to early neurodevelopmental outcome.Study design239 extremely preterm infants (median gestational age [range] in weeks: 26.6 [24.3-27.9]), admitted to the Wilhelmina Children's Hospital between 2006 and 2012 were included. Brain abnormalities in white matter, cortical and deep grey matter and cerebellum and brain growth were scored on T1- and T2-weighted TEA-MRI using the Kidokoro scoring system. Neurodevelopmental outcome was assessed at two years corrected age using the Bayley Scales of Infant and Toddler Development, third edition. The association between TEA-MRI and perinatal factors as well as neurodevelopmental outcome was evaluated using multivariable regression analysis.ResultsThe distribution of brain abnormalities and brain metrics in the Utrecht cohort differed from the original St. Louis cohort (p < .05). Mechanical ventilation >7 days (β [95% confidence interval, CI]: 1.3 [.5; 2.0]) and parenteral nutrition >21 days (2.2 [1.2; 3.2]) were independently associated with higher global brain abnormality scores (p < .001). Global brain abnormality scores were inversely associated with cognitive (β in composite scores [95% CI]: -.7 [-1.2; -.2], p = .004), fine motor (β in scaled scores [95% CI]: -.1 [-.3; -.0], p = .007) and gross motor outcome (β in scaled scores [95% CI]: -.2 [-.3; -.1], p < .001) at two years corrected age, although the explained variances were low (R2 ≤.219).ConclusionPatterns of brain injury differed between cohorts. Prolonged mechanical ventilation and parenteral nutrition were identified as independent perinatal risk factors. The prognostic value of the TEA-MRI score was rather limited in this well-performing cohort.

Project description:Inflammasomes are cytosolic multiprotein complexes that orchestrate inflammation in response to pathogens and endogenous danger signals. Herein, we determined whether the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis (1) express major inflammasome components; (2) express caspase (CASP)-1 and CASP-4 as well as their active forms; (3) exhibit apoptosis-associated speck-like protein containing a CARD (ASC)/CASP-1 complex formation; and (4) release the mature forms of interleukin (IL)-1? and IL-18. We utilized quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, immunoblotting, and immunohistochemistry to determine the messenger RNA (mRNA) and protein expression of major inflammasome components, nucleotide-binding oligomerization domain (NOD) proteins, and the pro- and mature/active forms of CASP-1, CASP-4, IL-1?, and IL-18. The ASC/CASP-1 complex formation was determined using an in situ proximity ligation assay. When comparing the chorioamniotic membranes from women in spontaneous preterm labor with acute histologic chorioamnionitis to those without this placental lesion, we found that (1) the mRNA of NLR family pyrin domain-containing protein ( NLRP) 1, NLRP3, NLR family CARD domain-containing protein 4 ( NLRC4), and NOD2 were higher; (2) the NLRP3 protein was increased; (3) the mRNA and active form (p10) of CASP-1 were greater; (4) the mRNA and active form of CASP-4 were increased; (5) the mRNA and mature form of IL-1? were higher; (6) the mature form of IL-18 was elevated; and (7) ASC/CASP-1 complex formation was increased. In conclusion, spontaneous preterm labor with acute histologic chorioamnionitis is characterized by an upregulation of NLRP3 and the active form of CASP-4, as well as increased ASC/CASP-1 complex formation, which may participate in the activation of CASP-1 and the maturation of IL-1? and IL-18 in the chorioamniotic membranes. These findings provide the first evidence that supports a role for the inflammasome in the pathological inflammation implicated in spontaneous preterm labor with acute histologic chorioamnionitis.

Dataset Information

Association of Histologic Chorioamnionitis With Perinatal Brain Injury and Early Childhood Neurodevelopmental Outcomes Among Preterm Neonates.

Publications

Association of Histologic Chorioamnionitis With Perinatal Brain Injury and Early Childhood Neurodevelopmental Outcomes Among Preterm Neonates.

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