scholarly journals Evidence for the Placenta-Brain Axis: Multi-Omic Kernel Aggregation Predicts Intellectual and Social Impairment in Children Born Extremely Preterm

2020 ◽  
Author(s):  
Hudson P Santos ◽  
Arjun Bhattacharya ◽  
Robert M Joseph ◽  
Lisa Smeester ◽  
Karl CK Kuban ◽  
...  
Keyword(s):  
Gestational Age ◽  
Complex Traits ◽  
External Validation ◽  
Social Function ◽  
Autism Spectrum ◽  
Intellectual Ability ◽  
Social Impairment ◽  
Neurodevelopmental Outcomes ◽  
Genome Wide ◽  
Extremely Preterm

AbstractBackgroundChildren 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 explain origins of neurodevelopmental outcomes.MethodsWe examined associations between placental genomic 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 (DAS-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 assayed with the Illumina Hiseq 2500, HTG EdgeSeq miRNA Whole Transcriptome Assay, and Illumina EPIC/850K array, respectively. We conducted genome-wide differential mRNA/miRNA and epigenome-wide placenta analyses. These molecular features were integrated for a predictive analysis of IQ and SRS outcomes using kernel aggregation regression. We lastly examined associations between ASD and the genomically-predicted component of IQ and SRS.ResultsGenes with important roles in placenta angiogenesis and neural function 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 the 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 is a cohort of children born pre-term, andgeneralization may be affected by unmeasured confounders associated with low gestational age. We conducted external validation of predictive models, though the sample size of the out-sample dataset (N = 49) and the scope of the available placental datasets are limited. Further validation of the models is merited.ConclusionsAggregating information from biomarkers within and between molecular data types improves prediction of complex traits like social and intellectual ability in children born extremely preterm, suggesting that traits influenced by the placenta-brain axis may be omnigenic.

scholarly journals Evidence for the placenta-brain axis: multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hudson P. Santos Jr ◽  
Arjun Bhattacharya ◽  
Robert M. Joseph ◽  
Lisa Smeester ◽  
Karl C. K. Kuban ◽  
...  
Keyword(s):  
Gestational Age ◽  
Social Function ◽  
Autism Spectrum ◽  
Cpg Methylation ◽  
Intellectual Ability ◽  
Social Impairment ◽  
Neurodevelopmental Outcomes ◽  
Tissue Organization ◽  
Genome Wide ◽  
Extremely Preterm

Abstract Background Children 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. Methods We 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. Results Genes 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. Limitations The 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. Conclusions Aggregating 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.

scholarly journals School-age outcomes following intraventricular haemorrhage in infants born extremely preterm

2020 ◽  
Vol 106 (1) ◽  
pp. 4-8 ◽  
Author(s):  
Nicky Laura Hollebrandse ◽  
Alicia J Spittle ◽  
Alice C Burnett ◽  
Peter J Anderson ◽  
Gehan Roberts ◽  
...  
Keyword(s):  
Cerebral Palsy ◽  
Executive Function ◽  
Motor Function ◽  
Intraventricular Haemorrhage ◽  
Academic Skills ◽  
Intellectual Ability ◽  
Low Grade ◽  
Cranial Ultrasound ◽  
Neurodevelopmental Outcomes ◽  
Extremely Preterm

ObjectiveTo determine the associations of different grades of intraventricular haemorrhage (IVH), particularly grades 1 and 2, with neurodevelopmental outcomes at 8 years of age in children born extremely preterm.DesignPopulation-based cohort study.SettingState of Victoria, Australia.PatientsSurvivors born at <28 weeks’ gestational age (n=546) and matched term-born controls (n=679) from three distinct eras, namely, those born in 1991–1992, 1997 and 2005.ExposureWorst grade of IVH detected on serial neonatal cranial ultrasound.Outcome measuresIntellectual ability, executive function, academic skills, cerebral palsy and motor function at 8 years.ResultsThere was a trend for increased motor dysfunction with increasing severity of all grades of IVH, from 24% with no IVH, rising to 92% with grade 4 IVH. Children with grade 1 or 2 IVH were at higher risk of developing cerebral palsy than those without IVH (OR 2.24, 95% CI 1.21 to 4.16). Increased rates of impairment in intellectual ability and academic skills were observed with higher grades of IVH, but not for grade 1 and 2 IVH. Parent-rated executive functioning was not related to IVH.ConclusionWhile low-grade IVH is generally considered benign, it was associated with higher rates of cerebral palsy in school-aged children born EP, but not with intellectual ability, executive function, academic skills or overall motor function. Higher grades of IVH were associated with higher rates and risks of impairment in motor function, intellectual ability and some academic skills, but not parental ratings of executive function.

scholarly journals 0974 Family-Based Study Of Sleep In Autism Spectrum Disorder Without Intellectual Disability

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A370-A370
Author(s):  
S D Elkhatib Smidt ◽  
A Ghorai ◽  
B Gehringer ◽  
H C Dow ◽  
Z Smernoff ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Inverse Correlation ◽  
Social Function ◽  
Autism Spectrum ◽  
Social Impairment ◽  
Relative Amplitude ◽  
University Of Pennsylvania ◽  
Daytime Activity ◽  
The University

Abstract Introduction Sleep problems are a common concern in children with autism spectrum disorder (ASD) that can persist into adulthood. This study aims to further explore sleep in ASD without intellectual disability (ASD w/o ID). Methods We recruited individuals with ASD w/o ID (probands) and relatives as part of the Autism Spectrum Program of Excellence (ASPE) at the University of Pennsylvania. Actimetry data were collected via a wrist-worn tri-axial accelerometer for 21 days. Data from 212 participants were considered. We analyzed sleep data using the algorithms GGIR, ChronoSapiens, and PennZzz. The sleep traits of proband and sibling pairs were compared using paired t-test or Wilcoxon signed-rank test. We used the Social Responsiveness Scale, Second Edition (SRS-2) to assess social impairment and restricted/repetitive traits. We compared SRS-2 scores to sleep traits using partial Spearman or Pearson correlations adjusting for age (171 participants). Results Probands demonstrated later sleep onset (p = 0.03), decreased M10 average (10-hour period of highest activity/day; p = 0.006), decreased relative amplitude (measure of rest-activity rhythm; p&lt;0.001), and decreased total daytime activity (p = 0.005) compared to siblings. Regarding social function and restricted/repetitive traits, adult males showed an inverse correlation between SRS-2 total score and sleep efficiency (r = -0.2, p= 0.04) and a positive correlation between SRS-2 total score and intradaily variability (r = 0.3, p = 0.02). Adult females showed an inverse correlation between SRS-2 total score and M10 average (r = -0.3, p = 0.02) and between SRS-2 total score and relative amplitude (self-report r = -0.4, p = 0.001; informant r = -0.3, p = 0.005). Conclusion This study focuses on the analysis of sleep traits in ASD including the relationship between social function and sleep. Thus far, the most robust findings are decreased daytime activity and relative amplitude in individuals with ASD w/o ID compared to siblings. We have also shown that ASD social impairment may be related to sleep dysfunction. Support NIH T32HL07713, anonymous donor, and the Institute for Translational Medicine and Therapeutics of the Perelman School of Medicine at the University of Pennsylvania.

scholarly journals Does a Split-Week Gestational Age Model Provide Valuable Information on Neurodevelopmental Outcomes in Extremely Preterm Infants?

Children ◽  
2021 ◽  
Vol 8 (9) ◽  
pp. 731
Author(s):  
Elizabeth Asztalos ◽  
Alberto Nettel Aguirre ◽  
Leonora Hendson ◽  
Paige Church ◽  
Rudaina Banihani ◽  
...  
Keyword(s):  
Gestational Age ◽  
Primary Objective ◽  
Neurodevelopmental Outcomes ◽  
Additional Information ◽  
Extremely Preterm ◽  
Extremely Preterm Infants ◽  
Significant Impairment ◽  
Age Model ◽  
Gestational Week ◽  
Neurodevelopmental Impairment

Our primary objective for this follow-up study was to compare the neurodevelopmental outcomes of a surviving cohort of infants using a split-week gestational model (early versus late) gestational age (GA) and the standard completed GA categorization. Neurodevelopmental outcomes using a split-week GA model defined as early (X, 0–3) and late (X, 4–6), with X being 23–26 weeks GA, were compared to outcomes using completed weeks GA. In total, 1012 infants were included in the study. Statistically significant differences were noted in outcomes between the early and late split of the gestational week at 23 weeks (early vs. late), with 13.3% vs. 54.5% for no neurodevelopmental impairment, and 53.3% vs. 22.7% for significant impairment (p = 0.034), respectively. There were no differences seen in the split week model for 24, 25, and 26 weeks. A trend towards improved neurodevelopmental outcomes was seen with each increasing gestation week. The split-week model did not provide additional information for pregnancies and infants between 24 and 26 weeks gestation. It did, however, provide information for counsel for infants at 23 weeks gestation, showing benefits in the late versus early half of the week.

scholarly journals 4365 Family-Based Study of Sleep in Autism Spectrum Disorder without Intellectual Disability

2020 ◽  
Vol 4 (s1) ◽  
pp. 72-72
Author(s):  
Stacey Elkhatib Smidt ◽  
Arpita Ghorai ◽  
Brielle Gehringer ◽  
Holly Dow ◽  
Zoe Smernoff ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Inverse Correlation ◽  
Social Function ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Spectrum Disorder ◽  
Social Impairment ◽  
Relative Amplitude ◽  
Daytime Activity

OBJECTIVES/GOALS: Autism spectrum disorder (ASD) is characterized by difficulties in communication and social interaction as well as restricted and repetitive behaviors. Sleep problems are a common concern in children with ASD that can persist into adulthood. This study aims to further explore sleep in ASD without intellectual disability (ASD w/o ID). METHODS/STUDY POPULATION: We recruited individuals of both sexes with ASD w/o ID (probands) and relatives as part of the Autism Spectrum Program of Excellence (ASPE) at the University of Pennsylvania. Actimetry data were collected via a wrist-worn tri-axial accelerometer for 21 days. Data from 212 participants were considered. We analyzed sleep data using the algorithms GGIR, ChronoSapiens, and PennZzz. The sleep traits of proband and sibling pairs were compared using paired t-test or Wilcoxon signed-rank test. We used the Social Responsiveness Scale, Second Edition (SRS-2) to assess social impairment and restricted/repetitive traits. We compared SRS-2 scores to sleep traits using partial Spearman or Pearson correlations adjusting for age (171 participants). RESULTS/ANTICIPATED RESULTS: Probands demonstrated later sleep onset (p = 0.03), decreased M10 average (10-hour period of highest activity/day; p = 0.006), decreased relative amplitude (measure of rest-activity rhythm; p <0.001), and decreased total daytime activity (p = 0.005) compared to siblings. Regarding social function and restricted/repetitive traits, adult males showed an inverse correlation between SRS-2 total score and sleep efficiency (r = −0.2, p = 0.04) and a positive correlation between SRS-2 total score and intradaily variability (r = 0.3, p = 0.02). Adult females showed an inverse correlation between SRS-2 total score and M10 average (r = −0.3, p = 0.02) and between SRS-2 total score and relative amplitude (self-report r = −0.4, p = 0.001; informant r = −0.3, p = 0.005). DISCUSSION/SIGNIFICANCE OF IMPACT: This study focuses on the analysis of sleep traits in ASD including the relationship between social function and sleep. Thus far, the most robust findings are decreased daytime activity and relative amplitude in individuals with ASD w/o ID compared to siblings. We have also shown that ASD social impairment may be related to sleep dysfunction.

Two-year neurodevelopmental outcomes of extremely preterm infants treated with early hydrocortisone: treatment effect according to gestational age at birth

2018 ◽  
Vol 104 (1) ◽  
pp. F30-F35 ◽  
Author(s):  
Olivier Baud ◽  
Clémence Trousson ◽  
Valérie Biran ◽  
Emilie Leroy ◽  
Damir Mohamed ◽  
...  
Keyword(s):  
Gestational Age ◽  
Low Dose ◽  
Age Group ◽  
Neurodevelopmental Outcomes ◽  
Treatment Groups ◽  
Extremely Preterm ◽  
Extremely Preterm Infants ◽  
Gestational Age At Birth ◽  
Age At Birth ◽  
Hydrocortisone Treatment

ObjectiveTo determine whether early hydrocortisone treatment in extremely preterm infants affects neurodevelopmental outcomes at 2 years of age according to gestational age at birth.Patients and methodsThis is an exploratory analysis of neurodevelopmental outcomes by gestational age strata from the PREMILOC trial, in which patients were randomly assigned to receive either placebo or low-dose hydrocortisone and randomisation was stratified by gestational age groups (24–25 and 26–27 weeks of gestation). Neurodevelopmental impairment (NDI) was assessed using a standardised neurological examination and the revised Brunet-Lézine scale at 22 months of corrected age.ResultsA total of 379 of 406 survivors were evaluated, 96/98 in the gestational age group of 24–25 weeks and 283/308 in the gestational age group of 26–27 weeks. Among surviving infants born at 24–25 weeks, significant improvement in global neurological assessment was observed in the hydrocortisone group compared with the placebo group (P=0.02) with a risk of moderate-to-severe NDI of 2% and 18%, respectively (risk difference 16 (95% CI −28% to −5%)). In contrast, no statistically significant difference between treatment groups was observed in infants born at 26–27 weeks (P=0.95) with a similar risk of moderate-to-severe NDI of 9% in both groups. The incidence of cerebral palsy or other major neurological impairments were found similar between treatment groups in each gestational group.ConclusionsIn an exploratory analysis of neurodevelopmental outcomes from the PREMILOC trial, early low-dose hydrocortisone was associated with a statistically significant improvement in neurodevelopmental outcomes in infants born at 24 and 25 weeks of gestation.

scholarly journals Impact of fetal presentation on neurodevelopmental outcome in a trial of preterm vaginal delivery: a nationwide, population-based record linkage study

2021 ◽  
Author(s):  
Anna Toijonen ◽  
Seppo Heinonen ◽  
Mika Gissler ◽  
Laura Seikku ◽  
Georg Macharey
Keyword(s):  
Autism Spectrum Disorders ◽  
Record Linkage ◽  
Autism Spectrum ◽  
Linkage Study ◽  
Neurodevelopmental Outcomes ◽  
Breech Delivery ◽  
Very Preterm ◽  
Vaginal Breech Delivery ◽  
Extremely Preterm ◽  
Spectrum Disorders

Abstract Purpose To assess the risk of adverse neurodevelopmental outcomes at the age of four after an attempted vaginal delivery according to the fetal presentation in birth. Methods This retrospective record linkage study evaluated the risks of cerebral palsy, epilepsy, intellectual disability, autism spectrum disorder, attention-deficit/hyperactivity disorder, and speech, visual, and auditory disabilities among preterm children born after an attempted vaginal breech delivery. The control group comprised children born in a cephalic presentation at the same gestational age. This study included 23 803 singleton deliveries at gestational weeks 24 + 0–36 + 6 between 2004 and 2014. Results From 1629 women that underwent a trial of vaginal breech delivery, 1122 (66.3%) were converted to emergency cesarean sections. At extremely preterm and very preterm gestations (weeks 24 + 0—31 + 6), no association between a trial of vaginal breech delivery and neurodevelopmental delay occurred. At gestational weeks 32 + 0—36 + 6, the risks of visual disability (aOR 1.67, CI 1.07—2.60) and autism spectrum disorders (aOR 2.28, CI 1.14—4.56) were increased after an attempted vaginal breech delivery as compared to vaginal cephalic delivery. Conclusion A trial of vaginal breech delivery at extremely preterm and very preterm gestations appears not to increase the risk of adverse neurodevelopmental outcomes at the age of four. In moderate to late preterm births, a trial of vaginal breech delivery was associated with an increased risk of visual impairment and autism spectrum disorders compared to children born in cephalic presentation. A trial of vaginal preterm breech delivery requires distinctive consideration and careful patient selection.

Hearing and Neurodevelopmental Outcomes of Young Infants with Parechovirus-A and Enterovirus Meningitis: Cohort Study in Singapore Children and Literature Review

2020 ◽  
Author(s):  
Elis Yuexian Lee ◽  
Jessica Hui Yin Tan ◽  
Chew Thye Choong ◽  
Nancy Wen Sim Tee ◽  
Chia Yin Chong ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Oropharyngeal Dysphagia ◽  
Significant Risk ◽  
Developmental Outcomes ◽  
Autism Spectrum ◽  
Clinical Findings ◽  
Cortical Blindness ◽  
Speech Delay ◽  
Neurodevelopmental Outcomes ◽  
Young Infants

Abstract Parechovirus-A (PeV-A) and Enterovirus (EV) commonly cause childhood aseptic meningitis. Bacterial meningitis in children has been associated with devastating long-term sequelae. However, developmental outcomes are unclear in Parechovirus meningitis. This study aims to review the clinical findings and developmental outcomes of infants with PeV-A and EV meningitis. We performed a retrospective study of infants aged 90 days or younger being admitted to our hospital with PeV-A meningitis between November 2015 and July 2017, with positive cerebrospinal fluid (CSF) PeV-A PCR and negative blood and CSF bacterial cultures. Hearing and neurodevelopmental outcomes were compared with a previous cohort of infants aged 90 days or younger with EV meningitis admitted from January 2015 to December 2015. A total of 161 infants were included in our study, of which 68 infants (42.2%) had PeV-A meningitis and 93 infants (57.8%) had EV meningitis. We assessed their developmental outcome at 6 months, 1 year, and 2 years post-meningitis. At 2 years post-meningitis, three infants with PeV-A meningitis had developmental delay (5.5%), whereas none with EV meningitis had developmental delay. One patient had speech delay and autism spectrum disorder, while two had mild speech delay. When compared with our cohort of EV meningitis ≤90 days old, children with PeV-A meningitis ≤90 days old were more likely to have developmental delay 2 years post-meningitis (odds ratio 2.4, 95% confidence interval 2.0–3.0, p = 0.043). None of the patients with PeV-A or EV meningitis had sensorineural hearing loss or neurological sequelae, such as cortical blindness, oropharyngeal dysphagia, hydrocephalus, epilepsy, or cerebral palsy. Infants with PeV-A meningitis had a significant risk of developmental delay 2 years post-meningitis compared with those with EV meningitis. It is important to follow-up the developmental milestones of infants diagnosed with PeV-A meningitis for at least 2 years; and when they develop developmental delay, to ensure that they receive appropriate intervention.

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