Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm.
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ABSTRACT:
SUBMITTER: Meakin CJ
PROVIDER: S-EPMC6354776 | biostudies-literature | 2018 May
REPOSITORIES: biostudies-literature
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Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm.
Meakin C J CJ Martin E M EM Santos H P HP Mokrova I I Kuban K K O'Shea T M TM Joseph R M RM Smeester L L Fry R C RC
Hormones and behavior 20180305
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Project description:BackgroundThe placenta is the central regulator of maternal and fetal interactions. Perturbations of placental structure and function have been associated with adverse neurodevelopmental outcomes later in life. Placental CpG methylation represents an epigenetic modification with the potential to impact placental function, fetal development and child health later in life.Study designGenome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from extremely preterm births (EPTBs) (n = 84). The association between the identified differentially methylated CpG sites and neurocognitive outcome at ten years of age was then evaluated.ResultsSpontaneous EPTB was associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes are known to play a role in neurodevelopment and are enriched for basic helix-loop-helix transcription factor binding sites. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age.ConclusionA hypermethylation signature is present in DNA from placentas in infants with spontaneous EPTB. CpG methylation levels of critical neurodevelopment genes in the placenta predicted later life cognitive function, supporting the developmental origins of health and disease hypothesis (DOHaD).
| S-EPMC5841757 | biostudies-literature
Project description:ImportanceInfants born extremely preterm receive transfusions at higher platelet count thresholds than older children and adults due to concerns for intracranial hemorrhage. A recent randomized trial comparing 2 platelet transfusion thresholds showed the higher threshold was associated with increased risk of long-term adverse neurodevelopmental outcomes.ObjectiveTo evaluate the association of platelet transfusion exposure with death and severe neurodevelopmental impairment (NDI) at 2 years' corrected age in a cohort of infants born extremely preterm.Design, setting, and participantsAn observational cohort study and secondary analysis of the Preterm Erythropoietin Neuroprotection Trial, a randomized, placebo-controlled clinical trial of erythropoietin neuroprotection in neonates born extremely preterm, was conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 819 infants born extremely preterm at 24 to 27 completed weeks of gestation who had a documented outcome (death or neurodevelopmental assessment). Analysis was performed in April 2023.ExposuresAny platelet transfusion during neonatal intensive care unit hospitalization.Main outcomes and measuresThe primary composite outcome was death or severe NDI evaluated at 2 years' corrected age using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Gross Motor Function Classification System and was defined as the presence of severe cerebral palsy or a BSID-III composite motor or cognitive score 2 SDs below the mean. Confounding by indication for platelet transfusion was addressed with covariate adjustment and propensity score methods.ResultsOf the 819 infants included in the analysis (429 [52.4%] male; mean [SD] gestational age, 25.5 [1.1] weeks), 245 (30.0%) received at least 1 platelet transfusion during their initial hospitalization. The primary outcome occurred in 46.5% (114 of 245) of infants exposed to a platelet transfusion and 13.9% (80 of 574) of nonexposed infants with a corresponding odds ratio of 2.43 (95% CI, 1.24-4.76), adjusted for propensity score, gestational age at birth, and trial treatment group. The individual components of death and severe NDI were directionally consistent with the overall composite outcome.Conclusions and relevanceThe findings of this study suggest that platelet transfusion in infants born extremely preterm may be associated with an increased risk of death or severe NDI at 2 years' corrected age, although the possibility of residual confounding by indication cannot be excluded.
| S-EPMC10807258 | biostudies-literature
Project description:ObjectiveTo evaluate the correlates of a clinically significant high score on the Social Responsiveness Scale (SRS) in 10-year-old children who were born extremely preterm and who did not meet criteria for autism spectrum disorder (ASD).MethodsAfter excluding 61 participants diagnosed with ASD, we grouped children by IQ < or ≥85 and then compared the prevalence of neurocognitive and other deficits between those who had SRS total and component scores ≥65 and their peers who had lower scores.ResultsAmong children who had IQ ≥ 85, the prevalence of SRS total scores ≥65 was 16% (n = 103/628), and among children who had IQ < 85, it was 27% (n = 40/148), higher than the 4% prevalence expected based on normative population data. Among children who had IQ ≥ 85, those who had high SRS scores more often than their peers had deficits in attention and executive function, and language and communication, and they were more often rated by their parents and teachers as having behavioral (e.g., attention-deficit hyperactivity disorder [ADHD]) and emotional (e.g., anxiety and depression) problems.ConclusionSocial Responsiveness Scale-defined social impairment was much more common in our cohort of 10-year-old children born extremely preterm than was expected based on general population norms. High SRS scores were characteristic of children who had intellectual, neurocognitive, language, and communication limitations, as well as deficits in behavior and emotion regulation.
| S-EPMC5668158 | biostudies-literature
Project description:BackgroundChildren born extremely preterm are at heightened risk for intellectual and social impairment, including Autism Spectrum Disorder (ASD). There is increasing evidence for a key role of the placenta in prenatal developmental programming, suggesting that the placenta may, in part, contribute to origins of neurodevelopmental outcomes.MethodsWe examined associations between placental transcriptomic and epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the Extremely Low Gestational Age Newborn (ELGAN) cohort. Assessment of intellectual ability (IQ) and social function was completed with the Differential Ability Scales-II and Social Responsiveness Scale (SRS), respectively. Examining IQ and SRS allows for studying ASD risk beyond the diagnostic criteria, as IQ and SRS are continuous measures strongly correlated with ASD. Genome-wide mRNA, CpG methylation and miRNA were assayeds with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850 K array, respectively. We conducted genome-wide differential analyses of placental mRNA, miRNA, and CpG methylation data. These molecular features were then integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the multi-omic-predicted component of IQ and SRS.ResultsGenes with important roles in neurodevelopment and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted intellectual and social function, explaining approximately 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed significant positive and negative associations with ASD case-control status.LimitationsThe ELGAN cohort comprises children born pre-term, and generalization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size (N = 49) and the scope of the available out-sample placental dataset are limited. Further validation of the models is merited.ConclusionsAggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits within the placenta-brain axis may be omnigenic.
| S-EPMC7730750 | biostudies-literature
Project description:DNA methylation shifts in Hypothalamic-pituitary-adrenal (HPA) axis related genes is reported in psychiatric disorders including hypersexual disorder. This study, comprising 20 dexamethasone suppression test (DST) non-suppressors and 73 controls, examined the association between the HPA axis dysregulation, shifts in DNA methylation of HPA axis related genes and importantly, gene expression. Individuals with cortisol level ≥ 138 nmol/l, after the low dose (0.5 mg) dexamethasone suppression test (DST) were classified as non-suppressors. Genome-wide methylation pattern, measured in whole blood using the EPIC BeadChip, investigated CpG sites located within 2000 bp of the transcriptional start site of key HPA axis genes, i.e.: CRH, CRHBP, CRHR-1, CRHR-2, FKBP5 and NR3C1. Regression models including DNA methylation M-values and the binary outcome (DST non-suppression status) were performed. Gene transcripts with an abundance of differentially methylated CpG sites were identified with binomial tests. Pearson correlations and robust linear regressions were performed between CpG methylation and gene expression in two independent cohorts. Six of 76 CpG sites were significantly hypermethylated in DST non-suppressors (nominal P < 0.05), associated with genes CRH, CRHR1, CRHR2, FKBP5 and NR3C1. NR3C1 transcript AJ877169 showed statistically significant abundance of probes differentially methylated by DST non-suppression status and correlated with DST cortisol levels. Further, methylation levels of cg07733851 and cg27122725 were positively correlated with gene expression levels of the NR3C1 gene. Methylation levels of cg08636224 (FKBP5) correlated with baseline cortisol and gene expression. Our findings revealed that DNA methylation shifts are involved in the altered mechanism of the HPA axis suggesting that new epigenetic targets should be considered behind psychiatric disorders.
| S-EPMC8505644 | biostudies-literature
Project description:BackgroundChildren born extremely preterm are at increased risk of learning limitations.AimTo identify the antecedents of learning limitations of children born extremely preterm.Study designProspective observational study from birth to age 10 years. Variables entered into the multinomial logistic regression analyses were ordered temporally, with the earliest occurring predictors/covariates of each learning limitation risk entered first and not displaced by later occurring covariates.Subjects874 children who were born before the 28th week of gestation.Outcome measuresA reading limitation was defined as a score one or more standard deviations below the expected mean on the WIAT-III Word Reading and a mathematics limitation was defined as a similarly low score on the Numerical Operations component.Results56 children had a "reading ONLY" limitation, 132 children had a "math ONLY" limitation and 89 children had "reading AND math" limitations. All risk profiles included an indicator of socioeconomic disadvantage (e.g., mother's "racial" identity and eligibility for government-provided health care insurance), an indicator of newborn's immaturity/vulnerability (e.g., high illness severity score, receipt of hydrocortisone, and/or ventilator-dependence at 36 weeks post-menstruation), and all but the math only limitation included an indicator of fetal growth restriction and inflammation (i.e., pregnancy urinary tract infection or late ventilator-dependence).ConclusionsThe themes of socioeconomic disadvantage and immaturity/vulnerability characterize all three risk profiles, while the themes of fetal growth restriction and inflammation are characteristic of a reading limitation only, and the reading and math limitations entity.
| S-EPMC5869147 | biostudies-literature
Project description:BackgroundTo identify modifiable antecedents during pre-pregnancy and pregnancy windows associated with a positive child health at 10 years of age.MethodsData on 889 children enrolled in the Extremely Low Gestational Age Newborn (ELGAN) study in 2002-2004 were analyzed for associations between potentially modifiable maternal antecedents during pre-pregnancy and pregnancy time windows and a previously described positive child health index (PCHI) score at 10 years of age. Stratification by race was also investigated for associations with investigated antecedents.ResultsFactors associated with higher PCHI (more positive health) included greater gestational age, birth weight, multiple gestation, and medical interventions, including assisted reproduction and cervical cerclage. Factors associated with lower PCHI included correlates of lower socioeconomic status, pre-pregnancy chronic medical disorders in the mother such as pre-pregnancy body mass index (BMI), and maternal asthma. When stratified by race, variation in significant results was observed.ConclusionsAmong children born extremely preterm, medical interventions and higher socioeconomic status were associated with improved PCHI, while chronic illness and high BMI in the mother is associated with lower PCHI at 10 years of age. Knowledge of such antecedent factors could inform efforts to develop interventions that promote positive child health outcomes in future pregnancies.
| S-EPMC6802282 | biostudies-literature
Project description:Among 740 children born extremely preterm, we evaluated the relationship between the highest and lowest quartiles of the distributions of PaO2 and PaCO2, as well as the lowest quartile of pH on one day, and separately on two days, and the risk of neurocognitive, language, and behavioral dysfunctions at age 10 years. Children who had hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidemia, sometimes on only one day, and sometimes on two or more days, were more likely than others to have a high illness severity score (within the first 12 postnatal hours), and 10 years later to have multiple dysfunctions. The tendency of blood gas derangements to be associated with high illness severity scores and with multiple dysfunctions 10 years later is compatible with the possibility that blood gas derangements are indicators of physiologic instability/vulnerability/immaturity rather than contributors to brain damage.
| S-EPMC5502708 | biostudies-literature
Project description:BackgroundAlthough survival rates for infants born extremely preterm (gestation < 28 weeks) have improved significantly in recent decades, neurodevelopmental impairment remains a major concern. Children born extremely preterm remain at high risk for cognitive impairment from early childhood to adulthood. However, there is limited evidence on genetic factors associated with cognitive impairment in this population.MethodsFirst, we used a latent profile analysis (LPA) approach to characterize neurocognitive function at age 10 for children born extremely preterm. Children were classified into two groups: (1) no or low cognitive impairment, and (2) moderate-to-severe cognitive impairment. Second, we performed TOPMed-based genotype imputation on samples with genotype array data (n = 528). Third, we then conducted a genome-wide association study (GWAS) for LPA-inferred cognitive impairment. Finally, computational analysis was conducted to explore potential mechanisms underlying the variant x LPA association.ResultsWe identified two loci reaching genome-wide significance (p value < 5e-8): TEA domain transcription factor 4 (TEAD4 at rs11829294, p value = 2.40e-8) and syntaxin 18 (STX18 at rs79453226, p value = 1.91e-8). Integrative analysis with brain expression quantitative trait loci (eQTL), chromatin conformation, and epigenomic annotations suggests tetraspanin 9 (TSPAN9) and protein arginine methyltransferase 8 (PRMT8) as potential functional genes underlying the GWAS signal at the TEAD4 locus.ConclusionsWe conducted a novel computational analysis by utilizing an LPA-inferred phenotype with genetics data for the first time. This study suggests that rs11829294 and its LD buddies have potential regulatory roles on genes that could impact neurocognitive impairment for extreme preterm born children.
| S-EPMC8903548 | biostudies-literature
Project description:ObjectiveTo assess the burden of invasive infection following surgery (surgery-associated infections [SAI]) among infants born extremely premature.Study designThis was an observational, prospective study of infants born at gestational age 22-28 weeks hospitalized for >3 days, between April 1, 2011, to March 31, 2015, in academic centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. SAI was defined by culture-confirmed bacteremia, fungemia, or meningitis ≤14 days following a surgical procedure.ResultsOf 6573 infants, 1154 (18%) who underwent surgery were of lower gestational age (mean [SD]: 25.5 [1.6] vs 26.2 [1.6], P < .001), lower birth weight (803 [220] vs 886 [244], P < .001), and more likely to have a major birth defect (10% vs 3%, P < .001); 64% had 1 surgery (range 1-10 per infant). Most underwent gastrointestinal procedures (873, 76%) followed by central nervous system procedures (150, 13%). Eighty-five (7%) infants had 90 SAIs (78 bacteremia, 5 fungemia, 1 bacteremia and meningitis, 6 meningitis alone). Coagulase-negative staphylococci were isolated in 36 (40%) SAI and were isolated with another organism in 5 episodes. Risk of SAI or death ≤14 days after surgery was greater after gastrointestinal compared with central nervous system procedures (16% vs 7%, adjusted relative risk [95% CI]: 1.95 [1.15-3.29], P = .01). Death ≤14 days after surgery occurred in 141 of the 1154 infants; 128 deaths occurred after gastrointestinal surgeries.ConclusionsSurgical procedures were associated with bacteremia, fungemia, or meningitis in 7% of infants. The epidemiology of invasive postoperative infections as described in this report may inform the selection of empiric antimicrobial therapy and postoperative preventive care.
| S-EPMC8712381 | biostudies-literature