Dataset Information

Whole genome methylation and transcriptome analyses to identify risk for cerebral palsy (CP) in extremely low gestational age neonates (ELGAN).

ABSTRACT: Preterm birth remains the leading identifiable risk factor for cerebral palsy (CP), a devastating form of motor impairment due to developmental brain injury occurring around the time of birth. We performed genome wide methylation and whole transcriptome analyses to elucidate the early pathogenesis of CP in extremely low gestational age neonates (ELGANs). We evaluated peripheral blood cell specimens collected during a randomized trial of erythropoietin for neuroprotection in the ELGAN (PENUT Trial, NCT# 01378273). DNA methylation data were generated from 94 PENUT subjects (n?=?47 CP vs. n?=?47 Control) on day 1 and 14 of life. Gene expression data were generated from a subset of 56 subjects. Only one differentially methylated region was identified for the day 1 to 14 change between CP versus no CP, without evidence for differential gene expression of the associated gene RNA Pseudouridine Synthase Domain Containing 2. iPathwayGuide meta-analyses identified a relevant upregulation of JAK1 expression in the setting of decreased methylation that was observed in control subjects but not CP subjects. Evaluation of whole transcriptome data identified several top pathways of potential clinical relevance including thermogenesis, ferroptossis, ribosomal activity and other neurodegenerative conditions that differentiated CP from controls.

SUBMITTER: Massaro AN

PROVIDER: S-EPMC7935929 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Whole genome methylation and transcriptome analyses to identify risk for cerebral palsy (CP) in extremely low gestational age neonates (ELGAN).

Massaro An N AN Bammler Theo K TK MacDonald James W JW Perez Krystle M KM Comstock Bryan B Juul Sandra E SE

Scientific reports 20210305 1

Preterm birth remains the leading identifiable risk factor for cerebral palsy (CP), a devastating form of motor impairment due to developmental brain injury occurring around the time of birth. We performed genome wide methylation and whole transcriptome analyses to elucidate the early pathogenesis of CP in extremely low gestational age neonates (ELGANs). We evaluated peripheral blood cell specimens collected during a randomized trial of erythropoietin for neuroprotection in the ELGAN (PENUT Tria ...[more]

PMID: 33674671

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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:Background and objectivesAKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates.Design, setting, participants, & measurementsThe Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin. We included 900 of 941 patients enrolled in Preterm Epo Neuroprotection. Baseline characteristics were compared by primary exposure (severe AKI versus none/stage 1 AKI) using unadjusted logistic regression models. Cox regression models estimated the relationship between severe AKI and death after adjustment for potential confounders. Time-dependent AKI was modeled as a binary outcome and a categorical variable by stage of AKI. We fit Cox models using time-dependent AKI status lagged by <7 days before death. Landmark analyses examined the relationship of death with development of severe AKI.ResultsSevere AKI occurred in 168 of 900 (19%, 95% confidence interval, 17% to 20%) neonates, and stage 3 AKI occurred in 60 (7%, 95% confidence interval, 5% to 8%). Stage 3 AKI occurring 7 days before death (hazard ratio, 3.88; 95% confidence interval, 1.26 to 11.96), intraventricular hemorrhage (hazard ratio, 2.01; 95% confidence interval, 1.01 to 3.99) and sepsis (hazard ratio, 2.85; 95% confidence interval, 1.12 to 7.22) were all independently associated with death. Severe AKI occurring 7 days before death (hazard ratio, 2.21; 95% confidence interval, 0.92 to 5.26) was associated with death but not statistically significant. In a landmark analysis, after adjusting for potential confounders, late (after day 14 and before day 28) severe AKI was strongly associated with higher hazard of death (hazard ratio, 4.57; 95% confidence interval, 1.82 to 11.5).ConclusionsSevere AKI occurs frequently in extremely low gestational age neonates. Stage 3 AKI is associated with mortality, and this association is present 7 days before death.

Project description:IMPORTANCE:Low-grade periventricular-intraventricular hemorrhage is a common neurologic morbidity among extremely low-gestational-age neonates, yet the outcomes associated with this morbidity are not fully understood. In a contemporary multicenter cohort, we evaluated the impact of such hemorrhages on early (18-22 month) neurodevelopmental outcomes of extremely premature infants. OBJECTIVE:To compare neurodevelopmental outcomes at 18 to 22 months' corrected age for extremely low-gestational-age infants with low-grade (grade 1 or 2) periventricular-intraventricular hemorrhage with those of infants with either no hemorrhage or severe (grade 3 or 4) hemorrhage demonstrated on cranial ultrasonography. DESIGN:Longitudinal observational study. SETTING:Sixteen centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. PARTICIPANTS:A total of 1472 infants born at less than 27 weeks' gestational age between January 1, 2006, and December 31, 2008, with ultrasonography results within the first 28 days of life and surviving to 18 to 22 months with complete follow-up assessments were eligible. MAIN EXPOSURE:Low-grade periventricular-intraventricular hemorrhage. MAIN OUTCOME MEASURES:Outcomes included cerebral palsy; gross motor functional limitation; cognitive and language scores according to the Bayley Scales of Infant Development, 3rd Edition; and composite measures of neurodevelopmental impairment. Regression modeling evaluated the association of hemorrhage severity with adverse outcomes while controlling for potentially confounding variables and center differences. RESULTS:Low-grade hemorrhage was not associated with significant differences in unadjusted or adjusted risk of any adverse neurodevelopmental outcome compared with infants without hemorrhage. Compared with low-grade hemorrhage, severe hemorrhage was associated with decreased adjusted continuous cognitive (?, -3.91 [95% CI, -6.41 to -1.42]) and language (?, -3.19 [-6.19 to -0.19]) scores as well as increased odds of each adjusted categorical outcome except severe cognitive impairment (odds ratio [OR], 1.46 [0.74 to 2.88]) and mild language impairment (OR, 1.35 [0.88 to 2.06]). CONCLUSIONS AND RELEVANCE:At 18 to 22 months, the neurodevelopmental outcomes of extremely low-gestational-age infants with low-grade periventricular-intraventricular hemorrhage are not significantly different from those without hemorrhage. Additional study at school age and beyond would be informative.

Dataset Information

Whole genome methylation and transcriptome analyses to identify risk for cerebral palsy (CP) in extremely low gestational age neonates (ELGAN).

Publications

Whole genome methylation and transcriptome analyses to identify risk for cerebral palsy (CP) in extremely low gestational age neonates (ELGAN).

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