Histologic chorioamnionitis and risk of neurodevelopmental impairment at age 10 years among extremely preterm infants born before 28 weeks of gestation

Kartik K Venkatesh, Alan Leviton, Jonathan L Hecht, Robert M Joseph, Laurie M Douglass, Jean A Frazier, Julie L Daniels, Rebecca C Fry, T Michael O'Shea, Karl C K Kuban

Am J Obstet Gynecol. 2020 Nov;223(5):745.e1-745.e10.

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We investigated ass’n between histo chorioamnionitis (CA) & neurodevelopmental (ND) impairment at 10 yrs among children born EP. CA defined by histo stage (early, mod, advanced) and grade (mild/mod, severe) of chorionic plate & umbilical cord inflammation. Children examined for CP, ASD, Cog I, & epilepsy at 10 yrs. Among 805 placentas, 43% (347/805) had histo CA by mod or adv mat stage, 36% (286/805) by severe mat grade, 18% (132/737) by mod or adv fetal stage, and 1% (10/737) by severe fetal grade. Impairment frequencies were 11% (88/767) for CP, 7% (56/773) for ASD, 15% (120/788) for CogI, and 7% (52/763) for epilepsy. Adj OR for association between histo CA & CP was increased with advanced mat stage (adj OR, 2.5; 95% CI, 1.6-3.9), severe mat grade (adj OR, 2.0; 95% CI, 1.2-3.4), mod fetal stage (adj OR, 2.20; 95% CI, 2.1-2.2), and mild or mod fetal grade (adj OR, 1.5; 95% CI, 1.0-2.2). Similarly, adj OR for association between histo CA and epilepsy was increased with advanced mat stage (adj OR, 1.5; 95% CI, 1.3-1.6) and severe fetal grade (adj OR, 5.9; 95% CI, 1.9-17.8). Adj OR for association between histo CA and ASD was increased with mild or mod fetal grade (adj OR, 1.7; 95% CI, 1.0-2.9). Histo CA not associated with CogI. Findings held after adj for delivery GA. In contrast to histo CA, a clinical dx of CA is not associated with ND impairment.

CUE: CpG impUtation ensemble for DNA methylation levels across the human methylation450 (HM450) and EPIC (HM850) BeadChip platforms

Gang Li, Laura Raffield, Mark Logue, Mark W Miller, Hudson P Santos Jr, T Michael O'Shea, Rebecca C Fry, Yun Li

Epigenetics. 2020 Oct 4;1-11.

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Here, we present CpG impUtation Ensemble (CUE), which leverages multiple statistical and modern machine learning methods, to impute from Illumina Human-Methylation450 (HM450) BeadChip to the Illumina Human-Methylation-EPIC (HM850) BeadChip. Data were analyzed from 2 cohorts with methylation measured both by HM450 and HM850: the ELGAN study (n = 127, placenta) and the VA Boston PTSD genetics repository (n = 144, whole blood). Cross-validation results show CUE achieves lowest predicted root-mean-square error (RMSE) (0.026 in PTSD) and highest accuracy (99.97% in PTSD) compared with five methods tested, including k-nearest-neighbors, logistic regression, penalized functional regression, random forest, and XGBoost. Finally, among all 339,033 HM850-only CpG sites shared between ELGAN and PTSD, CUE successfully (RMSE < 0.05 and accuracy >95%in PTSD)  imputed 289,604 (85.4%) sites. In summary, CUE is a valuable tool for imputing CpG methylation from the HM450 to HM850 platform.

A role for microRNAs in the epigenetic control of sexually dimorphic gene expression in the human placenta

Lauren Eaves, Preeyaphan Phookphan, Julia Rager, Jacqueline Bangma, Hudson P Santos Jr, Lisa Smeester, Thomas Michael O'Shea, Rebecca Fry

Epigenomics. 2020 Sep;12(17):1543-1558.

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Aim: The contribution of miRNAs as epigenetic regulators of sexually dimorphic gene expression in the placenta is unknown. Materials & methods: 382 placentas from the extremely low gestational age newborns (ELGAN) cohort were evaluated for expression levels of 37,268 mRNAs and 2,102 miRNAs using genome-wide RNA-sequencing. Results: Sexually dimorphic expression was observed for 128 mRNAs and 59 miRNAs. A set of 25 miRNA master regulators was identified that likely contribute to sexual dimorphic mRNA expression. Conclusion: These data highlight sex-dependent miRNA and mRNA patterning in the placenta and provide insight into a potential mechanism for observed sex differences in outcomes.

Placental genomic and epigenomic signatures associated with infant birth weight highlight mechanisms involved in collagen and growth factor signaling

Alexis Payton, Jeliyah Clark, Lauren Eaves, Hudson P Santos Jr, Lisa Smeester, Jacqueline T Bangma, T Michael O'Shea, Rebecca C Fry, Julia E Rager

Reprod Toxicol. 2020 Jul 25;96:221-230.

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Birth weight (BW) can be influenced by endogenous and exogenous factors and is known to be heavily impacted in utero by the health and function of the placenta. We set out to test hypothesis that genes involved in critical placental cell signaling are associated with infant BW, and are likely regulated, in part, through epigenetic mechanisms based on microRNA (miRNA) mediation. This study leveraged a robust dataset based on 390 infants born at low gestational age (ranged 23-27 weeks) to evaluate genome-wide expression profiles of both mRNAs and miRNAs in placenta tissues and relate these to infant BW. A total of 254 mRNAs and 268 miRNAs were identified as associated with BW, the majority of which showed consistent associations across placentas derived from both males and females. BW-associated mRNAs were found to be enriched for important biological pathways, including glycoprotein VI (the major receptor for collagen), human growth, and hepatocyte growth factor signaling, a portion of which were predicted to be regulated by BW-associated miRNAs. These miRNA-regulated pathways highlight key mechanisms potentially linking endogenous/exogenous factors to changes in birth outcomes that may be deleterious to infant and later-in-life health.

Neurocognitive and social-communicative function of children born very preterm at 10 years of age: Associations with microorganisms recovered from the placenta parenchyma.

Martha Scott Tomlinson, Hudson P Santos, Jill R Stewart, Robert Joseph, Alan Leviton, Andrew B Onderdonk, Karl C K Kuban, Timothy Heeren, T Michael O'Shea, Rebecca C Fry, ELGAN Study Investigators

J Perinatol. 2020 Feb;40(2):306-315.

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Study Aim to determine whether specific bacterial species in placenta of EP pregnancies are associated with later neurological deficits. Using data from 807 children in the ELGAN study, risks of a low score on six neurological assessments in relation to 15 microbes quantified with ORs. Certain microbe species in placenta were associated with lower scores on numerical and oral language assessments. Lactobacillus sp. was associated with decreased risk of a low oral language score and on a composite measure of IQ and EF. Placental microorganisms were associated with neurocognitive, but not social-communicative, outcomes at age 10. In contrast, presence of anti-inflammatory Lactobacillus sp. in placenta was associated with lower risk of impaired neurocognitive functions.

Early life antecedents of positive child health among 10- year-old children born extremely preterm

Jacqueline T Bangma, Evan Kwiatkowski, Matt Psioda, Hudson P Santos Jr, Stephen R Hooper, Laurie Douglass, Robert M Joseph, Jean A Frazier, Karl C K Kuban, Thomas M O'Shea, Rebecca C Fry, ELGAN Investigators

Peds Research, 2019;86(6):758-765

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Among children born EP, medical interventions (assisted reproduction, cervical cerclage, and antenatal glucorticoids) and higher SES were associated with improved positive child health index (PCHI) while maternal chronic illness and high BMI is associated with diminished PCHI at 10 years of age.

Psychiatric Symptoms: Prevalence, Co-occurrence, and Functioning Among Extremely Low Gestational Age Newborns at Age 10 Years

Yael Dvir, Jean A Frazier, Robert M Joseph, Irina Mokrova, Phoebe S Moore, T Michael OʼShea, Stephen R Hooper, Hudson P Santos Jr, Karl Kuban, ELGAN Study Investigators

J Dev Behav Pediatr. 2019 Dec;40(9):725-734.

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To evaluate percentage of children born EP who screen positive for ≥1 DSM-IV psychiatric disorders, the co-occurrence of and sex-related differences in these classifications, and the functional correlates of psychiatric symptoms.

For 871 10-year-old children in The ELGAN Study, parents completed the CSI-4, and the Pediatric Quality of Life Inventory (PedsQL). At age 10 years, ELGANs were more likely to screen positive for a number of psychiatric disorders when compared with normative expectations, with a few sex-related differences. 15% screened positive for 1 disorder, 7% for 2, 3% for 3, and 4% for ≥4 psychiatric disorders. Children who screened positive for ≥3 psychiatric disorders were twice as likely to repeat a grade, have an IEP, have a school aide, and to require special remediation classes. Children who screened positive for any psychiatric disorder were 4 times more likely to use 1 or more psychotropic medication, and those who screened positive for ≥2 psychiatric disorders had lower PedsQL scores.

Associations between placental CpG methylation of metastable epialleles and childhood BMI across ages one, two and ten in the Extremely Low Gestational Age Newborns (ELGAN) cohort

Jeliyah Clark, Elizabeth Martin, Catherine M Bulka, Lisa Smeester, Hudson P Santos, T Michael O'Shea, Rebecca C Fry

Epigenetics. 2019 Nov;14(11):1102-1111.

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The Developmental Origins of Health and Disease hypothesis posits in utero and early life conditions can disrupt normal fetal development & program susceptibility to later-life disease. Metastable epialleles are genomic loci in which CpG methylation patterning is responsive to maternal diet and conserved across time and tissues, and could serve as ‘signatures’ of gestational environment conditions. We determine if methylation of metastable epialleles was associated with changes in childhood BMI z-scores at one, two and ten years in the ELGAN cohort. 26/250 probes associated (p < 0.05) with changes in BMI z-score, including Mesoderm Specific Transcript (MEST) and Histone Deacetylase 4 (HDAC4), which have been associated with childhood obesity and adipogenesis. Significant association found within female placentas for imprinted gene PLAG1 Like Zinc Finger 1 (PLAGL1). Epigenetic marks may be involved in programming susceptibility to obesity in utero and placental tissues may predict growth among premature infants.

Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort

Kezia A Addo, Catherine Bulka , Radhika Dhingra, Hudson P Santos Jr, Lisa Smeester, T Michael O'Shea, Rebecca C Fry

Environ Epigenet. 2019 Aug 6;5(2):dvz010.

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Acetaminophen is considered safest antipyretic/analgesic medication for pregnant women, although prenatal exposure associated with early life epigenetic changes and later life health outcomes. We evaluated epigenome-wide CpG methylation in placental tissue in relation to maternal acetaminophen use in pregnancy in cohort of 286 newborns born prior to 28 weeks gestation. More than half of the newborns had acetaminophen exposure in utero. 42 CpGs were identified to be differentially methylated at a false discovery rate < 0.05, with most displaying increased methylation. A significantly associated gene is the prostaglandin receptor (PTGDR), which plays essential role mediating placental blood flow and fetal growth. 6 of the 42 CpGs, were significantly different between male and female placentas; 3 sites associated in the male placenta and 3 associated in the female placenta (P interaction < 0.2). Findings highlight maternal acetaminophen use in pregnancy is associated w/placental epigenome and some are sex dependent.

Epigenome-wide DNA methylation in placentas from preterm infants: association with maternal SES

Hudson P Santos Jr, Arjun Bhattacharya, Elizabeth M Martin, Kezia Addo, Matt Psioda, Lisa Smeester, Robert M Joseph, Stephen R Hooper, Jean A Frazier, Karl C Kuban, T Michael O'Shea, Rebecca C Fry

Epigenetics. 2019 Aug;14(8):751-765.

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Hypothesis: prenatal maternal SES adversity is associated with DNA methylation in placenta. SES adversity defined by four factors: college education, marital status, nutritional service assistance, and health insurance. Epigenome-wide DNA methylation in 426 placentas from ELGAN cohort found associations between SES adversity and DNA methylation at 33 CpG sites: 19 (57.6%) increased methylation and 14 (42.4%) decreased methylation in association with ≥ one SES factor. Placentas from female pregnancies showed more robust differential CpG methylation than placentas from male pregnancies. Maternal SES adversity was associated with differential methylation of genes involved in gene transcription and placental function potentially altering immunity and stress response.