Color coding: Medical focus (CLD, NEC, BP, ABGs, sepsis), ROP/vision focus, Wt/growth/pulmonary/obesity focus, imaging/HUS focus, Placenta/umb cord, pregnancy focus, inflammation/growth factor/endocrine focus, neuro/developmental outcomes, genetic-epigenetic findings, psychiatric d/o

Title & First Author

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Salient points of the publication




175. Anxiety and Depression Correlates at Age 10 in Children Born Extremely Preterm. Moore

J Pediatr Psychol. 2021 Jan 4;jsaa118.

Anxiety and depression rates are elevated in prematurely-born children and adolescents. This prospective study examines demographic, academic, and physical health correlates of anxiety and depression symptoms in a sample of 10-y-o children born EP. Participants were 889 (51.2% male; 62.3% White). Level of prematurity was significantly related to both parent and teacher reports of anxiety. Public health insurance and IEP were associated with both parent and teacher reports of depression. Hispanic ethnicity, public insurance, IEP status, and asthma were significantly associated with both parent-reported anxiety and depression. Gross motor impairment was associated with parent-reported anxiety and teacher-reported depression. Child obesity was associated with teacher reports of anxiety, while male sex was significantly related to teacher reports of depression.

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

Mol Autism. 2020 Dec 11;11(1):97.

We examined associations between placental transcriptomic & epigenomic profiles and assessed their ability to predict intellectual and social impairment at age 10 years in 379 children from the ELGAN cohort. Genes with important roles in neuro-development and placental tissue organization were associated with intellectual and social impairment. Kernel aggregations of placental multi-omics strongly predicted IQ and social function, explaining ~ 8% and 12% of variance in SRS and IQ scores via cross-validation, respectively. Predicted in-sample SRS and IQ showed sign positive and negative associations with ASD case-control status. Aggregating information from biomarkers within and among molecular data types improves prediction of complex traits like social and intellectual ability in children born EP, suggesting that traits within the placenta-brain axis may be omnigenic.

173. Placental programming, perinatal inflammation, and neurodevelopment impairment among those born extremely preterm. Bangma

Pediatr Res. 2020 Nov 12;1-10.

Individuals born EP are at significant risk for impaired neurodevelopment. After discharge from the NICU, associations between child's well-being and factors in the home and social environment become increasingly apparent. We review early life predictors of inter-individual differences in later life neurodevelopment among those born EP. Among biological mechanisms that mediate relationships between early life predictors and later neurodevelopmental outcomes, we highlight evidence for disrupted placental processes, regulated at least in part via epigenetic mechanisms, as well as perinatal inflammation. In relation to these mechanisms, we focus on four prenatal antecedents of impaired neurodevelopment, namely, (1) fetal growth restriction, (2) maternal obesity, (3) placental microorganisms, and (4) socioeconomic adversity. The findings highlighted here may inform efforts to detect and prevent adverse outcomes in infants born extremely preterm.

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

Epigenetics. 2020 Oct 4;1-11.

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.

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

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

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.

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

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

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.

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

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

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.

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




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

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.

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

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

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.

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

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

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.

165. Placental CpG Methylation of Inflammation, Angiogenic, and Neurotrophic Genes and Retinopathy of Prematurity. Bulka

Invest Ophthalmol Vis Sci. 2019 Jul 1;60(8):2888-2894.

We previously identified inflammatory proteins expressed early in life and associated with risk of ROP in EP while angiogenic and neurotrophic growth factors are associated with lower risk of ROP. In this paper, we test hypothesis that placental CpG methylation levels of 12 inflammation-, angiogenic-, and neurotrophic-associated genes predict prethreshold ROP in EP newborns. We used placental CpG methylation data from 395 newborns from ELGAN study.

Placental DNA methylation of 16 CpG sites representing 8 genes associated with prethreshold ROP. Specifically, CpG methylation in serum amyloid A SAA1 and SAA2, brain-derived neurotrophic factor (BDNF), myeloperoxidase (MPO), C-reactive protein (CRP), angiopoietin 1 (ANGPT1), and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) genes. Conversely, CpG methylation within TNF receptor superfamily member 1A (TNFRSF1A) and in BDNF and ANGPT1 genes were associated with increased risk of ROP. CpG methylation may be a useful marker for improving ROP prediction.

164. 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. Clark

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

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.

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

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

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.

162. Microorganisms in the Placenta: Links to Early-Life Inflammation and Neurodevelopment in Children. Tomlinson

Clin Microbiol Rev. 2019;32(3). pii: e00103-18.

Prenatal exposure to stressors can influence childhood health. Microbial infection of intrauterine environment, esp in placenta, is associated with deleterious outcomes. Microbia are associated with epigenetic placental changes. We review research of microbes in placenta and its associations among microbes, placental DNA methylation, perinatal inflammation, and neurodevelopmental outcomes.

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

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

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.

160. Antecedents of Epilepsy and Seizures among Children Born at Extremely Low Gestational Age. Singh

J Perinatol 2019; 39(6):774-783

Of 888 children, 66 had epilepsy and 39 had seizures not associated with epilepsy. Epilepsy was associated with an indicator of low socio-economic status, maternal gestational fever, and early physiologic instability, postnatal exposure to hydrocortisone, cerebral white matter injury and severe bronchopulmonary dysplasia. Seizure without epilepsy was associated with indicators of placental infection and inflammation, and early neonatal hypoxemia. Though both profiles included indicators of infection and inflammation, the profile of risk factors for epilepsy included multiple indicators of endogenous vulnerability.

159. Socioeconomic status and early 1 blood concentrations of inflammation-related and neurotrophic proteins among extremely preterm newborns. Leviton

PLOS ONE 201926;14(3):e0214154

The main objective of this study was to evaluate the relationship between mother’s socioeconomic disadvantage and blood concentrations of inflammation-related proteins among EP newborns. We used 3 indicators/correlates of socioeconomic disadvantage, mother’s eligibility for government-provided medical care insurance (Medicaid), mother’s formal education level, and mother’s IQ. Indicators of socioeconomic disadvantage are associated with modestly increased risk of systemic inflammation in postnatal blood during the first postnatal month and with a slightly reduced risk of a neurotrophic signal, but do not confound relationships between inflammatory proteins and outcomes.

158. Association of circulating pro- and anti-inflammatory protein biomarkers in the first two postnatal weeks with brain MRI volumes and cognitive function at age 10 years in extremely preterm born children. Kuban

J Perinatol. 2019;210:81-90.

To examine elevated neonatal inflammatory and neurotrophic proteins in relation to age-ten brain MRI volumes and cognition in children born extremely preterm.

Adjusting for GA and sex. Children with 3+ elevated IPs had smaller GM, brain stem/cerebellar (CBBS), and total brain (TB) volumes than those without elevated IPs, controlling for NTPs. Controlling for IPs, compared to children with no NTPs, those with 4+ NTPs had larger GM and TB volumes.  Higher GM, WM and CBBS volumes were significantly correlated with higher IQ. Grey and WM volumes were correlated with each other (r=-0.18, p=0.021), and CBBS was highly correlated with GM (r=0.55, p<0.001) and WM (r=0.29, p<0.001). Adjusting for other compartments, CBBS was associated with IQ (p=0.016), but association with WM was marginally significant. GM was not associated with IQ. Controlling for brain volumes, elevated IPs remained significantly associated with lower IQ, while elevated NTPs remained associated with higher IQ. Conclusion: Newborn IP and NP levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

157. Early Postnatal IGF-1 and IGFBP-1 Blood Levels in Extremely Preterm Infants: Relationships with Indicators of Placental Insufficiency and with Systemic Inflammation. Leviton

Am J Perinatol. 2019 Jan 27. doi: 10.1055/s-0038-1677472.

We measured the concentrations of IGF-1 and IGFBP-1, as well as 25 other proteins in blood spots collected weekly from ≥ 880 infants born before 28th week of gestation, and sought correlates of concentrations in the top and bottom quartiles for gestational age and day the specimen was collected. Medically indicated delivery and severe FGR were associated with low concentrations of IGF-1 on first postnatal day and with high IGFBP-1 on almost all days. Elevated IGF-1 and IGFBP-1 were accompanied by elevated concentrations of many other proteins with inflammatory, neurotrophic, or angiogenic properties. Disorders associated with impaired placenta implantation and severe FGR appear to account for a relative paucity of IGF-1 on the first postnatal day. Elevated concentrations of IGF-1 and especially IGFBP-1 were associated with same-day elevated concentrations of inflammatory, neurotrophic, and angiogenic proteins.

156. Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age. Logan

J Perinatol. 2019 Feb;39(2):237-247.

We compared Z-scores ≤-2 on 18 tests of neurocognitive function and academic achievement at 10 years in 245 children arising from twins, 55 from triplets, and 6 septuplets to 568 singletons, from a total of 874 children born before 28 wks.

Children of multifetal pregnancies performed significantly better on one of six subtests of EF than singleton peers. Performance was similar on other assessments of intelligence, language, academic achievement, processing speed, visual perception, & fine motor skills. We found no evidence that children born of multifetal pregnancies had worse scores than singleton peers on neurocognitive and academic function assessments.

155. Antecedents of Obesity Among Children Born Extremely Preterm. Wood

Pediatrics. 2018 Nov;142(5). pii: e20180519. doi: 10.1542/peds. 2018-0519. Epub 2018 Oct 5.

We examined BMI in 871 children and analyzed relationships between antecedents and overweight or obesity at 10 years. Prepregnancy maternal BMI ≥25 and top quartile infant weight gain in the first year were associated with increased risk of overweight and obesity at 10 years. Single marital status and tobacco smoke were risk factor for obesity and being overweight. The risk profiles for overweight and obesity at 10 years of age among ELGAN children is similar to the risk profiles of overweight and obesity among children born at term.

154. Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm. Leviton

J Neuroimmune Pharmacol. 2018 Sep 6. doi: 10.1007/s11481-018-9804-7.

We evaluated the relationship between inflammatory proteins (IP) and neurotrophic proteins (NP) during first postnatal month in 692 ELGAN children and executive function (EF) limitations among 10-year olds who had IQ ≥ 70. Increased risks of executive dysfunction associated with high concentrations of IP (IL-8, TNF-α, and ICAM-1) were modulated by high values of NP. Modulation by NP of increased risk associated with IP was seen for the working memory limitation, but only with high IL-8 and TNF-α, and switching limitation was only seen with high ICAM-1.values. Risks of EF limitations might be explained by perinatal systemic inflammation in absence of adequate neurotrophic capability.

153. Risk factors for chronic lung disease and asthma differ among children born extremely preterm. Jackson

Pediatr Pulmonol. 2018 Aug 29. doi: 10.1002/ppul.24148.

CLD diagnosed during neonatal admission was associated with bronchodilator use at 12 months and 24 months (P < 0.001), but not with an asthma diagnosis at 10 years (Odds Ratio 1.3; 95% confidence interval 0.98-1.8). While risk factors for CLD include lower gestational age (OR 2.7; 1.5-4.7) and fetal growth restriction (OR 2.3; 1.4-3.7), risk factors for asthma include mother's eligibility for public insurance (Medicaid) (OR 1.8; 1.1-2.8), and higher weight gain velocity during the first year (OR 1.5; 1.02-2.2) and between the 2nd and 10th year (OR 1.7; 1.2-2.4).

CONCLUSIONS: Among children born EP, the dx of CLD and its antecedents associated with transient preschool wheezing, but not with asthma. Post-NICU factors, such as growth velocity and socioeconomic disadvantage, appear to have stronger associations with asthma than exposures during NICU admission.

152. Assessing Positive Child Health among Individuals Born Extremely Preterm. Bangma 

J Pediatr. 2018 Aug 2. pii: S0022-3476(18)30836-9.

OBJECTIVE: To assess development of a Positive Child Health Index (PCHI) based on 11 adverse outcomes & evaluate association of PCHI with QoL

RESULTS: Among ELGAN children, higher PCHI scores associated with higher QoL scores for all QoL categories. Children with no disorders and a PCHI of 100% had Pediatric QoL Inventory total scores 11 points higher than children with 1 or more adverse outcomes (PCHI of <100%). Boys had lower QoL scores for the total, psychosocial, social, and school categories.

CONCLUSIONS: PCHI was associated with QoL across the ELGAN cohort at school age. In the current study, the PCHI encompassed 11 outcomes assessed.

151. Among Children Born Extremely Preterm a Higher Level of Circulating Neurotrophins Is Associated with Lower Risk of Cognitive Impairment at School Age. Kuban

J Pediatr. 2018 Jul 18. pii: S0022-3476(18)30677-2.

Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins.

CONCLUSIONS: Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.

150. Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta. Leviton

Acta Paediatr. 2018 Jul 10. doi: 10.1111/apa.14494.

To evaluate the relationship between corticotropin-releasing hormone (CRH) expression in the placenta and the risk of school-related dysfunctions at the age of 10 years among children born extremely preterm (EP).

RESULTS: Only 16 associations statistically significant. Seven of these were social limitations among girls whose placenta CRH mRNA was in top quartile.

CONCLUSION: Overall, placenta CRH mRNA concentrations in the top or bottom quartiles were not associated with increased risks of dysfunctions 10 years later. Girls whose placenta CRH expression was in the top quartile, however, were at increased risk of seven indicators/correlates of social limitations.

149. Neurocognitive and Health Correlates of Overweight and Obesity among Ten-Year-Old Children Born Extremely Preterm. Linthavong

Send to

J Pediatr. 2018 Sep;200:84-90.

BMI category at 10 years was not associated with differences in intelligence, language, or academic achievement. Parents of children with obesity were more likely to report their child had asthma (OR 2.2; 95% CI 1.4-3.5), fair/poor general health (OR 3.2; 95% CI 1.4-7.5), and decreased physical function (OR 1.7; 95% CI 1.1-2.9) but less likely to have physician diagnosed attention-deficit/hyperactivity disorder (OR 0.5; 95% CI 0.3-0.97) or an individualized education plan (OR 0.6; 95% CI 0.4-0.99).

CONCLUSION: Among children born EP, elevated BMI is not associated with a difference in neurocognitive function. However, asthma, fair/poor general health, and decreased physical function more prevalent among participants with obesity, and ADHD and individualized education plan were less prevalent.

148. Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation. Korzeniewski

Transl Psychiatry. 2018 Jun 8;8(1):115.

ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2-5.3) and IL-6 (OR; 95% CI: 2.6; 1.03-6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2-6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3-5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1-3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1-4.2).

147. Accuracy of the Bayley-II mental development index at 2 years as a predictor of cognitive impairment at school age among children born extremely preterm. O’Shea

J Perinatol. 2018 Jul;38:908-916.

Almost two-thirds of children with a low MDI had a normal IQ (≥ 70) at 10 years. Concordance between MDI and IQ was highest among children with major motor and/or sensory impairment, and when MDI was adjusted for gestational age.

CONCLUSION: Most children born extremely preterm with low BSID-II MDI at 2 years have normal intelligence at school age.

146. The risk of neurodevelopmental disorders at age 10 years associated with blood concentrations of interleukins 4 and 10 during the first postnatal month of children born extremely preterm. Leviton

Cytokine. 2018 Oct;110:181-188.

The risks of low scores on the Animal Sorting and Arrows components of the NEPSY-II, both components of the OWLS-II, and the PseudoWord and Spelling components of the WIAT-III were heightened among children who had top quartile concentrations of IL-4 on postnatal days 21 and 28. Children who had high concentrations of IL-10 on days 21 and 28, individually and collectively, were at increased risk of low scores on the WIAT-III Spelling component. High concentrations of IL-4 on day 28 were associated with autism spectrum disorder (ASD). High concentrations of IL-10 on day 28 were also associated with a doubling of ASD risk, but this did not achieve statistical significance. Top quartile concentrations of IL-4 and IL10 on both days were not associated with increased risk of social, language, or behavioral dysfunctions.

145. Socioemotional outcomes at age 10 years in extremely preterm newborns with late-onset bacteremia. Babata

Early Hum Dev. 2018 Jun;121:1-7.

We sought to identify communication and socioemotional characteristics associated with suspected and definite late-bacteremia among 10-y-o children born EP. Definite late-bacteremia was associated with a small but non-statistically significant increased risk of autism on the Autism Diagnostic Observation Schedule-2. Definite late-bacteremia was not associated with behavioral problems identified with the Child Symptom Inventory-4. Compared to peers without bacteremia, those born EP who had suspected or definite late-bacteremia were at increased risk of social and communication impairments identified by SRS and Children's Communication Checklist-2.

144. Antecedents of Screening Positive for Attention Deficit Hyperactivity Disorder in Ten-Year-Old Children Born Extremely Preterm. Leviton

Pediatr Neurol. 2017 Dec 21. pii: S0887-8994(17)30921-9.

We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4. The risk profile of screening positive for attention deficit hyperactivity disorder based on a parent's report differed from risk profile based on teacher's report, whereas risk profile according to physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age, maternal obesity, maternal smoking, singleton, magnesium at delivery, receipt of a sedative, recovery of Mycoplasma  from placenta, low GA, low birth weight, male, mechanical ventilation on day seven, ROP, NEC, antibiotic receipt, and VM on U/S. The multiplicity of risk factors identified can be subsumed as components of 4 broad themes: low SE state, immaturity or vulnerability, inflammation, and epigenetic phenomena.

143. Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life. Tilley

PLoS One. 2018 Mar 7;13(3):e0193271.

Genome-wide placental CpG methylation levels were compared between spontaneous versus indicated deliveries from EP births (EPTBs) (n = 84). Spontaneous EPTB associated with differential CpG methylation levels in 250 CpG sites (217 unique genes) with the majority displaying hypermethylation. The identified genes known to play a role in neurodevelopment. The placental CpG methylation levels for 17 of these sites predicted cognitive function at ten years of age. CONCLUSION: A 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.

142. Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm. Meakin

Horm Behav. 2018 Mar 5. pii: S0018-506X(17)30336-7.

We set out to determine if CpG methylation of HPA axis-associated genes in the placenta was predictive of children’s health outcomes. 14 genes known to play a role in HPA axis function were examined across 84 placental samples from the ELGAN cohort and included in a multi-variable logistic regression model. The methylation levels for a set of nine HPA axis-associated genes were significantly (p<0.05) associated with LPA score at 10 years of age. Overall, 9 HPA axis associated genes were significantly associated with LPA score later in life and play key roles in regulating HPA axis function and also play integral roles in memory, learning, and the development of psychological disorders. Given the plasticity of the epigenome during the prenatal period, these alterations could be influenced by exposure to environmental contaminants, including EDCs.

141. Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage. Leviton

Eur J Paediatr Neurol. 2018 Jan 31. pii: S1090-3798(17)30146-0.

Study participants were 1219 children who had a cranial U/S in NICU and blood specimens during first month. High concentrations of multiple inflammation-related proteins during first 2 weeks associated with increased risk of VM , while high concentrations of just 3 inflammation-related proteins associated with risk of an EL (IL-6, IL-8, ICAM-1), especially on day 7. Concomitant high IL6R and bFGF appeared to modulate the increased risks of VM and EL associated with inflammation.

140. Antenatal and neonatal antecedents of learning limitations in 10-year old children born extremely preterm. Leviton

Early Hum Dev. 2018 Feb 6;118:8-14.

56 children had reading ONLY limitation, 132 children had math ONLY limitation and 89 children had reading AND math limitations. All risk profiles included an indicator of SE disadvantage (e.g., "racial" identity & health care insurance), an indicator of newborn's immaturity/vulnerability (e.g., high illness severity score, hydrocortisone receipt , and/or ventilator-dependence at 36 weeks), and all but the math only limitation included an indicator of fetal growth restriction and inflammation (pregnancy UTI or late ventilator-dependence).

139. Neonatal systemic inflammation and the risk of low scores on measures of reading and mathematics achievement at age 10 years among children born extremely preterm. Leviton

Int J Dev Neurosci. 2018 Feb 1;66:45-53.

We measured 27 inflammatory-related & neurotrophic/angiogenic blood proteins in 1st month from 660 who at age 10 yrs had IQ ≥ 70. We identified 4 groups, a Z-score ≤ -1 on Word Reading assessment only, on Numerical Operations assessment only, on both.RESULTS: The protein profile of low reading scores was confined to the third and fourth postnatal weeks when increased risks were associated with high concentrations of IL-8 and ICAM-1 in the presence of low concentrations of angio-neurotrophic proteins. The profile of low math scores was very similar, except it did not include ICAM-1. In contrast, the profile of low scores on both assessments was present in each of the first four postnatal weeks. The increased risks associated with high concentrations of TNF-α in the first two weeks and of IL-8 and ICAM-1 in the next two weeks were modulated down by high concentrations of angio-neurotrophic proteins.

138. Hand Preference and Cognitive, Motor, and Behavioral Functioning in 10-Year-Old Extremely Preterm Children. Burnett

J Pediatr. 2018 Jan 11. pii: S0022-3476(17)31612-8.

670 children (78%) were classified as right-handed, 49 (6%) had mixed preference, and 145 (17%) were left-handed. Left-handed children performed comparably to right-handed children on measures of cognition, academic, motor, and behavioral function, although at increased risk of poor visual processing and fine motor skill. In contrast, mixed-handed children had greater odds of deficits in verbal and nonverbal intellectual skills, attention, working memory, set-shifting, academic progress, and fine and gross motor skills than right-handed children. Behavior problems including autism spectrum disorder and ADHD were also more common in mixed-handed than right-handed children.

137. Are Extremely Low Gestational Age Newborns Born to Obese Women at Increased Risk of Cerebral Palsy at 2 Years? van der Burg

J Child Neurol. 2018 Mar;33(3):216-224.

Overweight and obese women were not at increased risk of giving birth to a child who had CP. The risk ratios associated with overweight varied between 1.1 for quadriparesis (95% CI = 0.5, 2.1) to 2.0 for hemiparesis (95% CI = 0.4, 9.8). The risk ratios associated with obesity varied between 0.7 for diparesis (95% CI = 0.2, 2.5) to 2.5 for hemiparesis (95% CI = 0.4, 13).

136. Antenatal and Neonatal Antecedents of Executive Dysfunctions in Extremely Preterm Children. Leviton

J Child Neurol. 2018 Mar;33(3):198-208.

The authors assessed 716 children who were 10 years old born extremely preterm whose IQ was ≥ 70. A working memory dysfunction (n = 169), an inhibition dysfunction (n = 360), a switching dysfunction (355), and all 3 (executive dysfunction; n = 107) were defined on the basis of Z-scores ≤ -1 on the DAS-II, and/or NEPSY-II. All risk profiles include socioeconomic disadvantage, newborn's immaturity, and risk profiles of inhibition dysfunction and switching dysfunction also include an indicator of inflammation. Only the switching dysfunction was associated with fetal growth restriction. The risk factors for executive dysfunction can be subsumed under 4 themes of SE disadvantage, immaturity/vulnerability, inflammation, and fetal growth restriction.

135. Co-occurrence and Severity of Neurodevelopmental Burden (Cognitive Impairment, Cerebral Palsy, Autism Spectrum Disorder, and Epilepsy) at Age Ten Years in Children Born Extremely Preterm. Hirschberger

Pediatr Neurol. 2018 Feb;79:45-52.

214 of 873 children (25%) had cognitive impairment, 93 of 849 children (11%) had CP, 61 of 857 children (7%) had ASD, and 66 of 888 children (7%) had epilepsy. Further, 19% of all children had 1 diagnosis, 10% had 2 diagnoses, and 3% had 3 diagnoses. Decreasing GA associated with increasing # of impairments (P < 0.001). Half the children with cognitive impairment and ⅓ with CP, ASD, or epilepsy had a single impairment. Six hundred one (68% [95% CI, 64.5%-70.7%]) children were in category I (not impaired), 74 (8% [95% CI, 6.6%-10.3%]) were in category II (nl cognition with neuro imapairment), and 214 (24% [95% CI 21.7%-27.4%]) were in category III (cognitively impaired). CONCLUSIONS: ¾ had normal intellect at age 10 years; nearly 70% free of neurodevelopmental impairment. 40% with impairments had multiple diagnoses.

134. Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes. Tomlinson

PLoS One. 2017 Dec 14;12(12):e0188664. 

Microorganisms in placenta linked to adverse pregnancy outcomes & neonatal illness. Inflammation in placenta is a contributing factor, but underlying biological mechanisms not understood. Placental epigenome may serve as intermediate between placental microbes & inflammation, contributing to adverse outcomes. In present study, genome-wide DNA methylation (n = 486,428 CpG sites) of 84 placentas analyzed in relation to 16 species of placental microorganisms from ELGAN cohort. The n = 1,789 CpG sites, correspond to n = 1,079 genes, displayed differential methylation (q<0.1) in relation to microorganisms. Altered genes encode for proteins involved in immune/inflammatory responses, esp NF-κB signaling pathway. Data support bacteria-dependent epigenetic patterning in placenta - potential insight into mechanisms associating microorgs & outcomes.

133. Maternal educational status at birth, maternal educational advancement, and neurocognitive outcomes at age 10 years among children born extremely preterm. Joseph

Pediatr Res. 2017 Nov 22. doi: 10.1038/pr.2017.267

To determine if a key marker of SES, maternal ed, is associated with later neurocognitive and academic outcomes among children born EP. Results/Conclusion. Children of mothers in lowest ed stratum at birth more likely to score ≥2 SDs below norms on 17 of 18 tests administered. Children of mothers w/advanced ed (n=199) were at reduced risk for scoring ≥2 SDs on 15 of 18 measures, but significant on only 2 of 18 measures. Among EP children, SE disadvantage at birth is associated with poorer neurocog and academic outcomes at 10 yrs, independent of GA. Maternal ed advancement in child's first 10 years of life is associated with modestly improved neurocog outcomes.

132. Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation. Holm

Invest Ophthalmol Vis Sci. 2017 Dec 1;58(14):6419-6428.

To assess association between inflammation-associated proteins & severe ROP

RESULTS/CONCLUSIONS In first 3 weeks, high VEGF-R1, MPO, IL-8, ICAM-1, MMP 9, erythropoietin, TNF-α, BFG factor associated with risk for prethreshold ROP. On day 28, high SAA, MPO, IL-6, TNF-α, TNF-R1/-R2, IL-8, and ICAM-1 associated with increased risk. Top quartile concentrations of TNF-α & IL-6 associated with ↑risks of ROP when levels of neuroprotective proteins & growth factors, including BDNF, IGF1, IGFBP-1, VEGFR-1 and -2, ANG-1 and PlGF, were not in top quartile. In contrast, high NT-4 and BDNF are protective only in infants w/o elevated inflammatory mediators. Systemic inflammation during first postnatal month associated with increased risk of prethreshold ROP. Elevated concentrations of GF, angiogenic proteins, and NT appear to modulate risk, and capable of reducing the risk even in the absence of systemic inflammation.

131. Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature.


Pediatr Res. 2017 Dec 15. doi: 10.1038/pr.2017.313.

We examined relationships between 25 inflammation-related proteins in blood obtained in first two postnatal weeks and body mass index at 2 years of age.

RESULTS/CONCLUSION: Among children delivered for spontaneous indications (n=734), obesity associated with ↑concentrations of 4 proteins (IL-1β, IL-6, TNF-R1, and MCP-1) on first day; IL-6 on postnatal day 7; and ICAM-3 and VEGF-R1 on postnatal day 14. Among children delivered for maternal or fetal indications (n=148), obesity was associated with elevated concentrations of seven proteins on the 14th postnatal day. In MV models in spontaneous subsample, elevated IL-6 on day 1 predicted obesity (odds ratio: 2.9; 95% confidence limits: 1.2, 6.8), while elevated VCAM-1 on day 14 predicted overweight at 2 years of age (odds ratio: 2.3; 95% confidence limits: 1.2, 4.3).

130. Neurodevelopment at Age 10 Years of Children Born <28 Weeks With Fetal Growth Restriction. Korzeniewski

Pediatrics. 2017 Nov;140(5). pii: e20170697.

We sought to evaluate the relationships between FGR & cognitive, academic, and adaptive behavior brain function at age 10 years. The 52 children whose birth weight z scores were <-2 had severe FGR, and the 113 whose birth weight z scores were between -2 and -1 had less severe FGR.

RESULTS/CONCLUSION: The more severe the growth restriction in utero, the lower the level of function on multiple cognitive and academic achievement assessments performed at age 10 years--children were also more likely than to have social awareness impairments, autistic mannerisms, ASD, language difficulty, and diminished social and psychosocial functioning.

129. Postnatal systemic inflammation and neuro-ophthalmologic dysfunctions in extremely low gestational age children. Holm

Acta Paediatr. 2017 Mar;106(3):454-45

AIM: We explore whether children born very preterm who have visual dysfunctions are at higher risk for having neonatal systemic inflammation.

RESULTS/CONCLUSION: Only one of 80 assessments (16 proteins on five different days) was significant for visual field deficit, and one for impaired fixation at 2 years. No association was found between strabismus and any inflammatory mediator.

128. Academic Achievement Deficits and Their Neuropsychological Correlates in Children Born Extremely Preterm. Akshoomoff

J Dev Behav Pediatr. 2017 Sep 1. [Epub ahead of print]

OBJECTIVE: to examine risks associated with LDs in a large sample of children born EP.

RESULTS / CONCLUSION: risk of low math achievement scores (27%) was 1.5 times higher than risk of low reading achievement scores (17%). LD based on reading only (RD, 6.4% of sample), math only (MD, 16.2%), both reading and math (RD/MD, 8.3%), or no reading or math disabilities (No LD, 69.1%). The RD and MD groups had different patterns of neuropsychological impairment. ELGAN children had higher than expected rates of LD, particularly in mathematics, even after taking SES into consideration. Results indicate specific cognitive weaknesses that differ between EP children with RD and MD.

127. Social Responsiveness Scale Assessment of the Preterm Behavioral Phenotype in 10-Year-Olds Born Extremely Preterm. Korzeniewski

J Dev Behav Pediatr. 2017 Aug 28. [Epub ahead of print]

OBJECTIVE: To evaluate correlates of high score on the SRS in 10-year-old children who were born EP and who did not meet criteria for ASD.

METHODS: After excluding 61 /ASD, children grouped by IQ < or ≥85; neurocognitive & other deficits compared w/SRS scores ≥65 and < 65.

RESULTS / CONCLUSION: Among children w/IQ ≥ 85, prevalence of SRS scores ≥65 was 16% (103/628); among children IQ < 85, it was 27% (40/148) > 4% based on normed population. Among children w/IQ ≥ 85, high SRS scores more often had deficits in attention, EF, language and communication, and  more often had ADHD & emotional sxs (e.g., anxiety and depression) problems. High SRS scores characteristic of children w/intellectual, neurocognitive, language, communication & behavior/emotion regulation probs.

126. Maternal obesity and attention-related symptoms in the preterm offspring. Van der Burg

Early Hum Dev. 2017 Aug 17;115:9-15

AIM:  estimate risk of attention problems at age 10 yrs in children born EP to overweight and obese women .

METHODS: 764 children had IQ≥70 at age 10years when parents and teachers completed CSI-4 that included items about ADHD.

RESULTS / CONCLUSION: Children at increased risk of parent-identified ADHD if mother overweight (odds ratio (OR)=1.9; 95% CI: 1.1, 3.3), or obese (OR=2.3; 95% CI: 1.4, 3.9). No increased risk of teacher-identified ADHD if mother overweight (OR=1.0; 95% CI: 0.6, 1.8), or obese (OR=1.0; 95% CI: 0.6, 1.6). Maternal overweight and obesity are associated with increased risk of parent-identified ADHD characteristics at 10years of age in children born EP.

125. Cumulative Incidence of Seizures and Epilepsy in Ten-Year-Old Children Born Before 28 Weeks' Gestation. Douglass

Pediatr Neurol. 2017 Aug;73:13-19

OBJECTIVE: We evaluated incidence of seizures and epilepsy in first decade of life among children born extremely premature.

RESULTS: By 10 yrs, 12.2% had ≥ 1 seizure, 7.6% had epilepsy, 3.2% had seizure with fever, and 1.3% had a single, unprovoked seizure; incidence increased with ▼GA. In > 75%, seizurs onset was > one year of age. Sz incidence comparable in sexes. ⅔ had other neurological disorders. ⅓ with epilepsy not recorded on questionnaire.

SIGNIFICANCE: Incidence of epilepsy through ten yrs among children born extremely preterm is ~7-14-fold higher than general pediatric pop. Szs under-recognized.

124. Cognitive functioning at age 10 years among children born extremely preterm: A latent profile approach. Heeren

Pediatr Res. 2017 Jun 5. doi: 10.1038/pr. 2017.82. [Epub ahead of print]

BACKGROUND:School-age children born EP are more likely than term peers to have multiple neurocognitive limitations.

METHODS: Based on measures of IQ and EF, subgroups of EP children with common neurocognitive function are identified using LPA. Classification of neurocognitive function using IQ and EF is compared to a standard classification based on IQ .

RESULTS / CONCLUSION: LPA identified four neurocognitive profiles in EP children, with 34% of EP children classified normal, 41% low-normal, 17% moderately impaired, and 8% severely impaired. Impaired children exhibited global impairment across cognitive domains, while children in low-normal group tended to have impaired inhibition relative to their reasoning and working memory skills.Both IQ and EF assessments are needed when describing school-age outcome of EP children

123. Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns. Yanni

Pediatr Res. 2017 May 26. doi: 10. 1038/pr. 2017.128.[Epub ahead of print

BACKGROUND Preterm newborns exposed to IU inflammation are at ▲risk of neurodevelopmental disorders. We hypothesized that adverse outcomes more strongly associated with combination of antenatal and postnatal inflammation than either alone.

RESULTS risk of WM damage increased when placental inflammation followed by elevation of CRP or ICAM-1. We found same for spastic CP when placental inflammation followed by elevation of TNF-α or IL-8. Presence of both placental inflammation & ▲ levels of IL-6, TNF-α, or ICAM-1 associated with microcephaly risk . CONCLUSION Compared to single hit, two inflammatory hits associated with stronger risk for abnormal HUS, spastic cerebral palsy, and microcephaly at 2 years.

122. Neurocognitive Outcomes at 10 Years of Age in Extremely Preterm Newborns with Late-Onset Bacteremia. Bright

J Pediatr. 2017 Aug;187:43-49.

OBJECTIVE: To evaluate difference in 10-year neurocognitive outcomes between E:LGANS with/without suspected or confirmed bacteremia .

STUDY DESIGN: Definite (culture-positive) late-onset bacteremia in postnatal weeks 2-4 was identified in 223 children, and 129 children had suspected bacteremia.

RESULTS / CONCLUSIONS: Infants with lowest GA and B Wt z-score had highest prevalence of definite and suspected late-onset bacteremia. Definite bacteremia associated with worse performance w/IQ, language, academic achievement, and EF. Adjustment for low IQ attenuated associations between bacteremia and dysfunctions at 10 years. Children with suspected bacteremia did not differ from no bacteremia.

121. Antecedents and early correlates of high and low concentrations of angiogenic proteins in extremely preterm newborns. Leviton

Clin Chim Acta. 2017 Aug;471:1-5

BACKGROUND: To identify antecedents & very early correlates of low concentrations of angiogenic proteins in blood of extremely preterm newborns in first postnatal month. RESULTS: Delivery for medical indications or severely IUGR were more likely to have low day-1 blood concentrations of VEGF, VEGF-R2, Ang-1, and PIGF. Systemic inflammation accompanied top quartile concentrations of all 6 angiogenic proteins. CONCLUSIONS: Low day-1 values of angiogenic proteins associated w/placenta insufficiency/dysfunction. High concentrations associated w/inflammation in first month.

120. Genomic biomarkers of prenatal intrauterine inflammation in umbilical cord tissue predict later life neurological outcomes. Tilley

PLoS One. 2017 May 11;12(5):e0176953.

BACKGROUND: Aim to identify genomic biomarkers of IU inflammation in umbilical cord tissue in preterm infants that predict cognitive impairment at 10 years of age. RESULTS / CONCLUSION: Placental indicators of inflammation associated with changes in mRNA expression of 445 genes in umbilical cord. Prenatal intrauterine inflammation is associated with altered gene expression that encode for proteins involved in neuronal umbilical cord tissue. A set of six of the differentially expressed genes predict cognitive impairment later in life, suggesting that the fetal environment is associated with significant adverse effects on neurodevelopment that persist into later childhood.

119. Neurocognitive Correlates of Attention-Deficit Hyperactivity Disorder Symptoms in Children Born at Extremely Low Gestational Age. Scott

J Dev Behav Pediatr. 2017 May;38:249-259.

OBJECTIVE: Our analyses aimed to evaluate the neuropsychological correlates of ADHD symptoms in ELGANs.  METHODS: CSI-4 reports from parents (n = 871) & teachers (n=634) & participants completed standardized neurocognitive & academic function assessments. RESULTS: Children w/ADHD symptoms were at ▲risk for neurocognitive limitations. Associations were weaker if limited to IQ ≥70 or ≥85. Even with IQ ≥85 ADHD sxs more likely have deficits on Working Memory Cluster & NEPSY-II Auditory Response subtest. The risks for impaired academic performance (Z ≤ -1) on components of the WIAT-III were 2-to-3 times higher than ELGANs not having ADHD symptoms. CONCLUSION: In children born EP with ADHD sxs more likely to have neurocognitive impairment. When IQ nl, ADHD associated w/deficits in EF.

118. Systemic Inflammation during the First Postnatal Month and the Risk of Attention Deficit Hyperactivity Disorder Characteristics. among 10 year-old Children Born Extremely Preterm. Allred

J Neuroimmune Pharmacol. 2017 Sep;12:531-543.

Abstract 151 children with ADHD behaviors were identified by parent report, while 128 children were identified by teacher report. Top-quartile concentrations of IL-6R, TNF-α, IL-8, VEGF, VEFG-R1, and VEGF-R2 on multiple days were associated with increased risk of ADHD symptoms as assessed by a teacher. Some of this increased risk was modulated by top-quartile concentrations of IL-6R, RANTES, EPO, NT-4, BDNF, bFGF, IGF-1, PIGF, Ang-1, and Ang-2.

117. Newborn blood gas derangements of children born extremely preterm and neurocognitive dysfunctions at age 10 years. Leviton

Respir Physiol Neurobiol. 2017 Aug;242:66-72

Abstract Among 740 children born extremely preterm, 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 compatible with possibility that blood gas derangements are indicators of physiologic instability/vulnerability/immaturity.

116. Antecedents and correlates of blood concentrations of neurotrophic growth factors in very preterm newborns. Leviton

Cytokine. 2017 Jun;94:21-28

AIM:To identify antecedents and early correlates of low concentrations of neurotrophic growth factors in blood of extremely preterm newborns during the first postnatal month. RESULTS / CONCLUSIONS: The concentrations of 2 neurotrophic proteins, NT4 and BDNF, were low among children delivered for medical (maternal, fetal) indications, and among those who were growth restricted. Children who had top quartile concentrations of NT4, BDNF, and bFGF tended to have elevated concentrations of inflammation-related proteins that day. This pattern persisted for much of the first postnatal month.

115. Observer variability identifying attention deficit/hyperactivity disorder in 10-year-old children born extremely preterm. Leviton

Acta Paediatr. 2017 Aug;106:1317-1322.

AIM: A DSM-5 diagnosis of (ADHD) requires that symptoms be present in two settings. We wanted to see how teachers and parents compare on their assessments.

METHODS: We evaluated how well (CSI-4) reports from 871 parents and 634 teachers of provided information about indicators of school dysfunction.

RESULTS: Kappa values for parent and teacher agreement of any ADHD were at best fair to poor (<0.41). Nevertheless, ADHD identified by each alone provided a moderate amount of information about such indicators of school dysfunction as grade repetition.

CONCLUSION: ADHD identified by a single observer can provide appreciable information about a range of the child's functions needed for success in school.

114. The Relationship of Maternal Prepregnancy Body Mass Index and Pregnancy Weight Gain to Neurocognitive Function at Age 10 Years among Children Born Extremely Preterm. Jensen

J Pediatr. 2017 Aug;187:50-57.

OBJECTIVE: To assess the association between maternal prepregnancy body mass index and adequacy of pregnancy weight gain in relation to neurocognitive function in school-aged children born extremely preterm.

RESULTS: Maternal prepregnancy obesity was associated with increased odds of a lower score for Differential Ability Scales-II Verbal IQ, for Developmental Neuropsychological Assessment-II measures of processing speed and visual fine motor control, and for Wechsler Individual Achievement Test-III Spelling. Children born to mothers who gained an excessive amount of weight were at increased odds of a low score on the Oral and Written Language Scales Oral Expression assessment. Conversely, children whose mother did not gain an adequate amount of weight were at increased odds of a lower score on the Oral and Written Language Scales Oral Expression and Wechsler Individual Achievement Test-III Word Reading assessments.

CONCLUSION: In this cohort of infants born extremely preterm, maternal obesity was associated with poorer performance on some assessments of neurocognitive function.

113. Sexual epigenetic dimorphism in the human placenta: implications for susceptibility during the prenatal period. Smeester

Epigenomics. 2017 Mar;9:267-278

AIM: Evaluate placental epigenome sex-based differences in the ELGAN cohort

METHODS: Placental DNA methylation was assessed at more than 480,000 CpG sites from male and female infants enrolled in the extremely low gestational age newborns cohort (ELGAN) and validated in a separate US-based cohort.

RESULTS: A total of n = 2745 CpG sites, representing n = 587 genes, were identified as differentially methylated (p < 1 × 10-7). The majority (n = 582 or 99%) of these were conserved among the New Hampshire Birth Cohort. The identified genes encode proteins related to immune function, growth/transcription factor signaling and transport across cell membranes.

CONCLUSION: Sex-dependent epigenetic patterning in placenta provide insight into infant outcome differences and responses to perinatal environment.

112. Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm. Logan

J Perinatol. 2017 May;37:606-614

OBJECTIVE: We sought to evaluate to what extent SNAP-II is predictive of cognitive and other neurodevelopmental impairments at 10 years of age.

RESULTS: An undesirably high SNAP-II (30), present in 23% of participants, was associated with an increased risk of cognitive impairment (IQ, executive function, language ability), adverse neurological outcomes (epilepsy, impaired gross motor function), behavioral abnormalities (attention deficit disorder and hyperactivity), social dysfunction (autistic spectrum disorder) and education-related adversities (school achievement and need for educational supports. 

CONCLUSION: Among very preterm newborns, physiologic derangements present in the first 12 postnatal hours are associated with dysfunctions in several neurodevelopmental domains at 10 years of age.

111. Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm. Kuban

J Pediatr. 2016 Oct 24. pii: S0022-3476(16)31038-1.

Early CRP, TNF-a, IL-8, ICAM-1, and epo associated with IQ values >2 SD below expected mean (ORs: 2.0-2.3) and with mod to severe cognitive impairment on a composite measure of IQ and EF (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0), IL-8 (OR: 5.0), ICAM-1 (OR: 6.5), vascular endothelial growth factor-receptor 2 (OR: 3.2), and thyroid-stimulating hormone (OR: 3.1). Mod cognitive impairment most strongly associated with elevations of IL-8, ICAM-1, and VEGF-R 2. When 4 or more inflammatory proteins elevated early, risk of IQ <70 and overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); presence of 4 or more inflammatory protein elevated late strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8).

110. Extremely low gestational age and very low birth weight for GA are risk factors for ASD in a large cohort study of 10-year-old children born at 23-27 weeks gestation. Joseph

Am J Obstet Gynecol. 2016 Nov 12. pii: S0002-9378(16)31989-5

857 assessed for ASD; of these, 840 (98%) assessed for ID. ASD+/ID- diagnosed in 3.2% (27/840), ASD+/ID+ in 3.8% (32/840), and ASD-/ID+ in 8.5% (71/840). Maternal report of cervical-vaginal 'infection' during pregnancy associated with risk of ASD+/ID+ (odd ratio [OR], 2.7). lowest GA category (23-24 weeks) associated with increased risk of ASD+/ID+ (OR, 2.9) and ASD+/ID- (OR, 4.4). Severe FGR strongly associated with increased risk for ASD+/ID- (OR, 9.9), peripartum maternal fever uniquely associated with risk of ASD-/ID+ (OR, 2.9). confirms low GA associated with risk for ASD irrespective of intellectual ability, whereas severe FGR strongly associated with ASD without ID. Cervical-vaginal infection associated with risk of ASD with ID, and peripartum maternal fever associated with risk for ID without ASD.

109. Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm. Kim

J Pediatr. 2016 Nov;178:101-107

Using standard criteria, M-CHAT had a sensitivity of 52%, a specificity of 84%, a PPV of 20%, and an NPV of 96%. False-positive and false-negative rates were high among children with hearing and vision impairments. High false-positive rates also associated with lower SES, motor and cognitive impairments, and emotional/behavioral dysregulation at age 2 years. Among extremely preterm children with ASD, almost one-half were not correctly screened by the M-CHAT at age 2 years.

108. Antenatal glucocorticoids and neonatal inflammation-associated proteins. Faden

Cytokine. 2016 Dec;88:199-208

We measured proteins on postnatal day 1 (N=1118), 7 (N=1138), 14 (N=1030), 21 (N=936) and 28 (N=877) from infants born before 28th week and explored relationship between antenatal steroid receipt and protein concentrations in highest and lowest quartiles. Twenty of 420 assessments [21 (proteins) × 2 (exposure levels: partial and full) × 2 (quartile levels: top and bottom)×5 (days)] were statistically significant without any cohesive pattern. Among infants born before 28 weeks of GA, neither full, nor partial courses of antenatal steroid have sustained anti-inflammatory effect.

107. Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years. Joseph

Autism Res. 2016 May 25. doi: 10.1002/aur.1644

Eight hundred and eighty nine of 966 (92%) participated. Children screening pos on SCQ were evaluated with ADI-R. Those meeting ADI-R criteria were assessed with ADOS-2. A positive ADOS-2 defined ASD. 26 not assessed for ASD because of severe sensory or motor impairment. 61 children met criteria for ASD (prevalence 7.1% (95% CI = 5.5-9.0). ASD risk decreased with increasing gestational age, from 15.0% for 23-24 weeks, 6.5% for 25-26 weeks, to 3.4% for 27 weeks GA; this association was independent of IQ. Among children with ASD, 40% had ID. The male-to-female ratio was 2.1:1, lower than general pop (4:1). ASD prevalence in ELGAN cohort was four times higher than in general pop, and strongly associated with GA.

106. The antecedents and correlates of necrotizing enterocolitis and spontaneous intestinal perforation among infants born before the 28th week of gestation. Singh 

J Neonatal Perinatal Med. 2016 May 19;9(2):159-70

Of 1320 infants, 5% had "medical" necrotizing enterocolitis (mNEC), 6% had "surgical" NEC (sNEC) and 4% had spontaneous intestinal perforation (SIP). Antecedents of mNEC included mother's identification as Black, consumption of aspirin during the pregnancy, and vaginal bleeding after 12th week of gestation. For sNEC the antecedents were maternal self- support, obesity and anemia during the pregnancy, birth before the 24th week, birth weight ≤750gm, and receipt of fresh frozen plasma (FFP) during first postnatal week. Increased risk of SIP associated with increased placental syncytial knots, birth before 24th week, and FFP receipt during first week.

105. Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns.  Holm

Arch Dis Child Fetal Neonatal Ed. 2016 Sep;101(5):F458-63

N=867. Day-1 EPO in highest quartile was associated with increased risk for early and persistent resp dysfunction in first 2 wks of life and NEC requiring surgery. Lowest day 1 EPO quartile was associated with decreased risk of mod BPD. Low EPO associated with decreased resp complication risk persisted on day 7. On day 14, highest EPO quartile associated with increased risk of ROP, and BPD not requiring ventilation.

104. Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns. Joseph

Pediatrics. 2016 Mar 22Epub ahead of print

873 children assessed with well-validated tests of cognitive and academic function. Distributions of test scores were consistently and markedly shifted < normative expectation, with ⅓ to ⅔ performing >1 SD < age expectation. The most extreme downward shifts were on measures of executive control & processing speed. MVA adjusted for SES & growth restriction: risk of poor outcome highest at lowest GA across all 18 measures. CONCLUSIONS: More than ½ of cohort exhibited moderate or severe neurocognitive deficits at age 10 years, with most extensive impairments found among those born at the lowest gestational age.

103. Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years. Kuban

J Pediatr. 2016 Mar 19. Epub ahead.  of print

28% of boys (446) and 21% of girls (428) exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (in 10% of the cohort) or epilepsy (in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population.

102. The Development of Extremely Preterm Infants Born to Women Who Had Genitourinary Infections During Pregnancy Leviton

Am J Epidemiol. 2016 Jan 1;183(1):28-35

The mothers of 989 ELGAN infants who reported a UTI were less likely than others to have a very low MDI (adjusted odds ratio = 0.5; 95% confidence interval: 0.3, 0.8), whereas infants born to women who reported a CVI were more likely than others to have a low PDI (adjusted odds ratio = 1.7; 95% confidence interval: 1.04, 2.7). In this high-risk sample, maternal gestational CVI, but not UTI, was associated with a higher risk of impaired motor development at 2 yrs of age. The apparent protective effect of UTI might be spurious, reflect confounding due to untreated asymptomatic bacteriuria among women who were not given a diagnosis of UTI, or reflect preconditioning.

101. Duration of Systemic Inflammation in the First Postnatal Month Among Infants Born Before the 28th Week of Gestation Dammann

Inflammation. 2015 Dec 16. [Epub ahead of print]

ELGANs that exhibit fetal and neonatal systemic inflammatory responses are at increased risk for developmental adversity, especially if the inflammatory process is sustained. We evaluated PICK patterns in 1220 ELGANs on one or more of postnatal days 1, 7, 14, 21, and 28. ELGANs who have elevated systemic levels of IL-6R, TNF- α, or RANTES on their first postnatal day are twice as likely to have elevated levels of these cytokines at the end of each of the first postnatal month. In some extremely preterm newborns, inflammatory processes can be sustained over weeks.

100. Systemic inflammation on postnatal days 21 and 28 and indicators of brain dysfunction 2years later among children born before the 28th week of gestation. Leviton

Early Hum Dev. 2015 Dec 28;93:25-32.

We measured the concentrations of 16 inflammation-related proteins in blood spots collected on postnatal days 21 (N=749) & 28 (N=697) from ELGAN Study infants. Top quartile concentrations of CRP, IL-1β, IL-6, IL-6R, TNF-R2, IL-8, ICAM-1, and TSH on both days 21 and 28 were associated with neonatal VMeg and MC at 2yrs. Top quartile concentrations of CRP, SAA, IL-6, TNF-R2, IL-8, and ICAM-1 were associated with MDI<55, while top quartile concentrations of CRP, TNF-α (inversely), IL-8, and ICAM-1 were associated with PDI<55. Systemic inflammation during third and fourth postnatal weeks increased risk of VM and MC, and low Bayley Scale scores.

99. Antecedents of inflammation biomarkers in preterm newborns on days 21 and 28. Leviton

Acta Paediatr. 2016 Mar;105(3):274-80.

The purpose of this study was to identify antecedents of systemic inflammation evident during postnatal weeks three and four. We measured protein in blood spots collected on postnatal days 21 (N = 176) and 28 (N = 157) from ELGANs and found that infants born for maternal and fetal indications were more likely than peers to have top quartile concentrations of IL-beta, IL-8, TNF-alpha, and ICAM-1 on days 21 and 28. Similarly, infants whose B. Wt. Z-score was < -2 or between -1 and -2 were also more likely  to have elevated concentrations of these proteins.

98. Weight Status in First 2 Years of Life and Neurodevelopmental Impairment in ELGANs. Belfort

J Pediatr. 2016 Jan;168:30-35.

We examined extent of weight gain and weight status in first 2 yrs of life relate to risk of neurodevelopmental impairment in EP infants. Weight gain in lowest quartile from 7-28 days was not associated with ↑risk of adverse outcomes. Children w/12-mo wt z-score <-2 were at ↑risk for all adverse outcomes in girls, and for MC and GMFCS ≥1 in boys. Excluding children with motor impairment attenuated all associations except wt z-score <-2 w/MC in girls. Most associations of low wt z-score at 24 mos with adverse outcomes were attenuated when excluding children w/motor impairment.

97. Antecedents of the Child Behavior Checklist-Dysregulation Profile in Children Born Extremely Preterm.  Frazier

J Am Acad Child Adolesc Psychiatry. 2015 Oct;54:816-23

We evaluated antenatal & early postnatal antecedents that might mediate association between EP and emotional and behavioral dysregulation (DP) at age 2 years. 9% of 826 ELGAN Study children had a CBCL-DP. Only low maternal education, passive smoking, and recovery of Mycoplasma from placenta were associated with ↑risk, whereas histologic chorioamnionitis was associated with ↓risk, raising possibility that modifiable antenatal and early postnatal phenomena contribute to risk of DP.

96. Strabismus at Age 2 Years in Children Born Before 28 Weeks' Gestation: Antecedents and Correlates. VanderVeen

J Child Neurol. 2016 Mar;31(4):451-60.

We evaluated perinatal factors associated with strabismus at age 2 years in ELGANs. Overall, 14% (n = 141) of children had strabismus at 2 yrs, and 80% of these children had esotropia. Characteristics associated with strabismus were birth before 26 weeks' gestation, severe FGR, maternal Hx of aspirin ingestion. Postnatal factors included a SNAP-II Score ≥30, Vmeg, type I ROP, and ventilator-dependent severe BPD.

95. Brain disorders associated with corticotropin releasing hormone expression in the placenta among children born before the 28th week of gestation. Leviton

Acta Paediatr. 2016 Jan;105(1):e7-e11.

To evaluate relationship between placenta CRH expression & brain structure and function abnormalities in Eps, we evaluated relationship between CRH expression in placenta and risk of HUS abnormalities, low scores on BSID of 900 children at age two years and HC > one and two SD below mean. Infants w/low placenta CRH m-RNA  were at ↑risk of VMeg on HUS. ↑placenta CRH mRNA also associated w/↑risk of inability to walk at 2 years, and a Bayley PDI 3 SD < mean. Placenta CRH mRNA conveys risk information about brain damage in ELGANs.

94. Maternal obesity and development of the preterm newborn at 2 years. van der Burg

Acta Paediatr. 2015 Sep;104(9):900-3.

Compared to mothers with nl BMIs, newborns of obese mothers, but not overweight mothers, were more likely to have Bayley Scales indices > - 3Z-score (mental: OR = 2.1; 95% CI: 1.3, 3.5) (motor: OR = 1.7; 95% CI: 1.1, 2.7). These associations were more prominent in children without intermittent- sustained systemic inflammation (mental: OR = 4.6; 95% CI: 1.6, 14) (motor: OR = 3.7; 95% CI: 1.5, 8.9).Some of impaired development cannot be attributed to confounding due to immaturity, socio-economic correlates, or neonatal systemic inflammation.

93. The breadth and type of systemic inflammation and the risk of adverse neurological outcomes in extremely low gestation newborns Kuban

Pediatr Neurol 2015;52(1):42-8.

We evaluated associations between number and type of proteins elevated on two occasions a week apart and diagnoses of VMeg, MC, MDI < 55, CP, MCHAT+, and sxs of ADHD on CBCL Increasing breadth of early neonatal inflammation, indexed by number of protein elevations or number of protein functional classes elevated, is associated with ↑ risk of d/o of brain structure and function in ELGANS. The risk for most outcomes did not rise until at least four proteins in at least two functional categories were ↑. When focused on 10 proteins previously found associated w/ neurological outcomes, we found risk of low MDI on Bayley Scales, MC, and CBCL-defined ADHD ↑ w/higher numbers of recurrently and/or persistently elevated proteins.

92. Systemic Inflammation and Cerebral Palsy Risk in Extremely Preterm Infants. Kuban

J Child Neurol 2015;52(1):42-8.

Protein elevations within 3 ds of birth not associated with CP. Elevations of TNF-α, TNF-α-R1, IL-8, and ICAM-1 on at least 2 days were associated with DP. Recurrent-persistent elevations of IL-6, E-selectin, or insulin-like GFBP-1 were associated with HP. DP and HP were more likely with at least 4 of 9 protein elevations previously associated with MDI<55 & and MC. Repeated elevated proteins during first 2 postnatal weeks are associated w/increased CP risk.

91. Elevated Endogenous Erythropoietin Concentrations Are Associated with Increased Risk of Brain Damage in Extremely Preterm Neonates. Korzeniewski

PLoS One. 2015 Mar 20;10(3):e0115083

We sought to determine whether elevated perinatal (EPO) is associated with risks ofbrain damage, and whether this risk differs by co-occurrence of (ISSI).

Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) MDI (OR 2.3; 95% CI 1.5-3.5) and/or PDI (OR 2.4; 95% CI 1.6-3.7) Development Indices, and MC at 2 yrs (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of VMeg, CP-HP MC, and MDI & PDI < 55 (ORs ranged from 2.2-6.3), but not WM lesions or other CP forms.

90. Systemic Inflammation in the Extremely Low Gestational Age Newborn Following Maternal Genitourinary Infections Fichorova

Am J Repro Immunol 2015;73(2):162-74

Compared to their peers whose mother had no UTI or CVI, infants whose mother reported a CVI were more likely on day 1 to have a concentration in the top quartile of CRP, SAA, MPO, IL-1β, IL-6, IL-6R, TNF-α, RANTES, ICAM-3, E-selectin and VEGF-R2. Infants whose mother reported UTI were more likely on d 7 to have concentration in the top quartile of MPO, IL-6R, TNF-R1, TNF-R2, and RANTES. Associations were no longer significant 14 days after birth. GU infections in pregnancy appear to increase the very preterm newborn’s risk of systemic inflammation

89. Antecedents and correlates of visual field deficits in children born extremely preterm Holm

Eur J Paediatr Neurol. 2015 Jan;19:56-63.

The VF of 1023 infants assessed by confrontation at age 2 yrs. We compared ante-and postnatal characteristics and exposures of 65 infants with a VFD to peers w/o a VFD. In final regression model, VFD was associated with maternal aspirin use during pregnancy, recurring/persistent acidemia in first 3 postnatal days, cerebral Vmeg, prethreshold ROP, supplemental O2, and vent dependence at 36 wks. Birth before the 27th week was also associated with increased risk, but was diminished by the addition of postnatal variables. Our study supports a multifactorial cause of these deficits.

88. Antenatal and early postnatal antecedents of parent-reported attention problems at 2 years of age Downey

Journal of Pediatrics 2015 166:20-25.

Antenatal antecedents of attention problems included birth to an unmarried mother, maternal secondhand smoke exposure, severe fetal growth restriction, thrombosis of fetal stem vessels in the chorionic plate, and recovery of an organism from placenta.  All but severe SGA were associated with ADHPDSM, too.  Multiple gestation was associated with a lower risk of ADHPDSM. The only postnatal risk factor for attention problems was recovery of bacteria from a tracheal aspirate. Conclusion: Among ELGANs several potentially modifiable antenatal and perinatal antecedents are associated with increased risk for attention problems and ADHPDSM at 2 years.

87. Pre-threshold retinopathy in premature infants with intra-uterine growth restriction Lee

Acta Paediatrica 2015;104(1):27-31.

Low GA (23-24 weeks, OR 11.6 (2.9, 47); 25-26 weeks, 8.1 (2.1, 32)) and severe growth restriction (birth weight Z-score <-2, OR 9.1 (1.1, 76)) were associated with increased risk of pre-threshold ROP.  A sample defined by B. Wt. has an excess of gestationally-older, SGA newborns. Conclusion:  In this sample, low GA and severe growth restriction were associated with increased risk of pre-threshold ROP.

86. The relationship between TSH and systemic inflammation in extremely preterm newborns Soto-Rivera

Endocrine. 2015 Mar;48(2):595-602

Elevated TSH in ill ELGANs attributed to THOP. We evaluated whether high TSH in first 2 weeks follow recovery from inflammation, similar to non-thyroidal illness synd. We evaluated relationships between hyperthyrotropinemia (HTT), TSH in highest quartile, and elevated inflammation-related proteins. Elevated inflammation-related proteins in 1st 2 weeks did not precede day-14 HTT. Inflammation on day 7 associated with day-14 HTT if inflammation persisted for 2 weeks. Hypothesis that HTT follows recovery from severe illness (preceding systemic inflammation), is weakly supported. Findings support hypothesis that TSH conveys info about concomitant inflammation.

85. Endogenous erythropoietin varies significantly with inflammation-related proteins in extremely premature newborns Logan

Cytokine. 2014;69:22-8

We evaluate relationships between endogenous Epo and 25 inflammation-related proteins in ELGANs. The proportion of children with inflammation-associated protein concentrations in top quartile increased with increasing quartile of Epo concentrations on 2 of 3days assessed. The ORs for Epo being in top quartile were significantly elevated among those with an inflammation-related protein concentration in the top quartile. Suggests elevation of Epo is not an epiphenomenon, but instead might promote or reduce inflammation, or promote anti-injury or repair capability.

84. Early blood gas predictors of bronchopulmonary dysplasia in extremely low gestational age newborns. Sriram

Int J Pediatr. 2014;2014:210218.

In models that did not adjust for ventilation, hypoxemia was associated with ↑ risk of severe and very severe BPD; infants with hypercapnea were at increased risk of very severe BPD only. Infants with hypocapnea were at reduced risk of severe BPD. Including ventilation for 14 or more days eliminated associations with hypoxemia and hypercapnea and made the decreased risk of very severe BPD statistically significant.

83. Impaired Visual Fixation at Age 2 yrs in ELGANs: antecedents & Correlates. Phadke

Pediatr Neurol. 2014;51:36-42.

Infants with impaired visual fixation were more likely than those without impaired visual fixation to have been born after shortest gestations (OR, 3.2; 99% CI, 1.4-7.5) and exposed to maternal aspirin (OR, 5.2; 99% CI, 2.2-12). They were also more likely to have had prethreshold retinopathy of prematurity (OR, 4.1; 99% CI, 1.8-9.0). At age 2 years, children with impaired fixation were more likely to be unable to walk (OR, 7.5; 99% CI, 2.2-26) and have a MDI < 55 (OR, 3.6; 99% CIl, 1.4-8.2).

82. Retinopathy of prematurity and brain damage in the very preterm newborn. Allred

J AAPOS. 2014 Jun;18:241-7.

The 173 children w/severe ROP (prethreshold ROP or worse) were more likely than peers without ROP to have brain HUS lesions or CP, and twice as likely to have Bayley Scales scores <55. After adjusting for risk factors common to both ROP and brain disorders, infants with severe ROP were at increased risk of low Bayley Scales only. Exposure to anesthesia was not associated with low Bayley Scales.

81. Are preterm newborns who have relative hyperthyrotropinemia at increased risk of brain damage? Korzeniewski

J Pediatr Endocrinol Metab. 2014;27:1077-88

In univariable models, hyperthyrotropinemia (HTT) not associated with brain damage indicators. In models of HTT only, intermittent or sustained systemic inflammation (ISSI) only, and HTT+ISSI, children with ISSI or HTT+ISSI were at higher risk of VM (OR) 2-6]. Children with HTT only had a higher risk of QP and those with ISSI alone had a higher risk of HP (ORs 1.6-2.4). Elevated risk of MDI <55 associated with ISSI and HTT+ISSI, whereas PDI < 55 & MC associated with HTT+ISSI. Conclusions: The association of HTT with brain damage depends on the presence or absence of ISSI.

80. Comparison of frozen and unfrozen blood spots for gene expression studies. Wei

J Pediatr 2014;164:189-191.E1.

We studied gene expression in 9 pairs newborn blood spots stored 8-10 yrs in frozen or unfrozen state. Fewer genes expressed in unfrozen spots, but avg correlation coeff for gene expression for frozen & unfrozen state was 0.771 (95% CI, 0.700-0.828).

79. Elevated blood levels of inflammation-related proteins are associated with an attention problem at age 24 mo in extremely preterm infants. O’Shea

Pediatr Res. 2014;75:781-7.

A single-day ↑ of ICAM-3 associated w/↑ risk of an attention problem; also persistent-recurrent ↑ of myeloperoxidase, IL-6, TNF-RI, IL-8, ICAM-3, VEGF-R1, and VEGF-R2.

78. Intermittent or sustained systemic inflammation and the preterm brain. Dammann

Pediatr Res. 2014 Mar;75(3):376-80.

We discuss evidence in support of contention that the preterm newborn is capable of intermittent or sustained systemic inflammation (ISSI), and appears to contribute more to adverse neurodevelopmental outcomes than does shorter duration inflammation.

77. Risk factors and correlates of neonatal growth velocity in extremely low gestational age newborns. the ELGAN Study. Barholomew

Neonatology. 2013;104(4):298-304.

In MV model, only ventilator dependence on day 7 (OR 2.2, 95% CI 1.5-3.2), early persistent pulmonary dysfunction (OR 1.8, 95% CI 1.3-2.5), and postnatal exposure to dex (OR 2.8, 95% CI 1.2-6.5) were associated with increased risk of being in lowest GV quartile. Low caloric intake was not associated with low GV (OR 1.3, 95% CI 0.9-1.9). Variables associated with severe pulmonary disease convey more information about risk of reduced GV in first 28 postnatal days than does low caloric intake.

76. Extreme prematurity and attention deficit: epidemiology and prevention. O’Shea

Front Hum Neurosci 2013;7:578.

ELGANs have an increased risk of attention problems. Perinatal systemic inflammation, an antecedent of structural and functional brain disorders in ELGANs, appears to be an antecedent of attention problems. Interventions to prevent initiators

of inflammation or modulate systemic inflammation might decrease the risk of

attention problems among children born extremely preterm.

75. Social-emotional delays at 2 years in ELGA survivors: correlates of impaired orientation-engagement and emotional regulation. Boyd

Early Hum Dev. 2013;89:925-30.

31% of children had a non-optimal (14%) or questionable (17%) Behavior Rating Scale score for Emotional Regulation, and 27% for Orientation/Engagement (O/E). These children were more likely to have MDI and PDI scores <70 and be unable to walk. Antecedents of low scores include multi-fetal pregnancy, indicators of socioeconomic disadvantage, and male sex. Over 25% of children born extremely premature exhibit socio-emotional delays during developmental assessment at age 2 years.

74. Is maternal obesity associated with sustained inflammation in extremely low gestational age newborns? van der Burg

Early Hum Dev. 2013;89:949-55.

Among infants delivered for spontaneous indications, maternal BMI was not related to elevated concentrations of any protein. Among infants delivered for maternal (i.e., preeclampsia) or fetal indications, those whose mother was overweight or obese were more likely than others to have elevated concentrations of inflammation proteins.

73. Antecedents of perinatal cerebral WMD with & without IVH in very preterm newborns. Logan

Pediatr Neurol. 2013;49:88-96.

Risk of hypoechoic (HE) lesion with IVH (N = 61) associated with gestation <25 weeks, high SNAP, early recurrent or prolonged acidemia, analgesic exposure, & mech vent at 1 week. Risk of a HE lesion w/o IVH differs from HE lesion with IVH (~PVHI). Suggests HE lesions w/ IVH may have different causal pathway than HE lesions w/o IVH, (~PVL(

72. Perinatal systemic inflammatory responses of growth-restricted preterm newborns. McElrath

Acta Paediatr. 2013 Oct;102(10):e439-42.

Severe SGAs (B Wt Z-score <-2) were not at increased risk of systemic inflammation on day 1. On day 14, however, they were more likely to have elevated CRP, IL-1β, IL-6, TNF-α, IL-8, MCP-4, ICAM-1, ICAM-3, E-SEL, MMP-9, VEGF-R2 and/or IGFBP-1, not attributable to delivery indication, bacteremia or ventilation duration.

71. Early nutrition and weight gain in preterm newborns and the risk of retinopathy of prematurity. VanderVeen

PLoS One. 2013 May 29;8(5):e64325.

Greater risk for Type 1 ROP found for infants with lowest ¼ ile receipt of lipids (2.1/1.1, 3.8), total calories (2.2/1.4, 3.6), and carbohydrates (1.7/1.1, 2.9). Zone 1 ROP was associated with lowest quartile lipid or total calorie intake; stage 3 ROP associated with lowest ¼ ile of total calorie. GV in lowest ¼ ile associated with increased risk of ROP, including type 1 ROP. ROP Risk might be reduced by improving nutritional support.


70. Two-hit model of brain damage in very preterm newborn: fetal growth restriction & postnatal systemic inflammation. Leviton

Pediatr Res. 2013 73:362-70.

SGA newborns who did not have systemic were at a greater risk of an MDI <55 than those with neither SGA nor systemic inflammation. SGA infants with elevated (IL)-1β, TNF-α, or IL-8 in first 2 weeks were at even higher risk of an MDI <55 than SGA peers without systemic inflammation and non-SGA peers with systemic inflammation.

69. Pregnancy disorders appear to modify risk for retinopathy of prematurity associated with neonatal hyperoxemia and bacteremia Lee

J Matern Fetal Neonatal Med. 2013 May;26(8):811-8

Compared to preterm labor, infants delivered after pPROM had reduced risk of plus ds (0.4, 0.2-0.8) and prethreshold/threshold ROP (0.5, 0.3-0.8). Delivery after abruption had reduced risk of zone I ROP and prethreshold/threshold ROP (0.3, 0.1-0.7). Infants born after placental dysfunction had higher severe ROP risks ass’ed with postnatal hyperoxemia & bacteremia than after inflammation-associated pregnancy disorders.

68. Inflammation-initiating illnesses, inflamm-related proteins, and cognitive impairment in extremely preterm infants O’Shea

Brain Behav Immun. 2013 ;29:104-12

The combo of NEC & vent on day 14, and of bacteremia & vent on day 14 elevated risk of MDI <55. Persistently or recurrently elevated concentration of each of the following proteins provided additional information about an increased risk of MDI <55: CRP, SAA, IL-6, TNF-alpha, IL-8, MIP-1beta, ICAM-1, E-SEL, and IGFBP-1.

67. Systemic inflammation associated with mechanical ventilation among extremely preterm infants Bose

Cytokine. 2013;61:315-22

Newborns ventilated for 7-13 days and 14 days (N=330) (v. < 7 days (N=247),  were more likely to have ↑ IL-1β & TNF-α, IL-8, MCP-1ICAM-1, and MMP-9, and less likely to have elevated RANTES & MIP-1β, MMP-1, and VEGF. These relationships were not confounded by chorioamnionitis, antenatal corticosteroid exposure, or bacteremia.

66. Gene Targets for IVH Study Group. Candidate Gene Analysis: Severe Intraventricular Hemorrhage in Inborn Preterm Neonates. Aden

J Pediatr 2013;163(5):1503-6.e1

IVH is a disorder of complex etiology. We analyzed genotypes for 7 genes from 224 inborn preterm neonates treated with antenatal steroids and grade 3-4 IVH and 389 matched controls. Only methylenetetrahydrofolate reductase was more prevalent in cases of IVH, emphasizing the need for more comprehensive genetic strategies.

65. Systemic inflammation, intraventricular hemorrhage, and white matter injury Leviton

J Child Neurol. 2013;28:1637-45

Infants with both IVH and WMI were more likely to have ↑ concentrations of CRP and IL-8 on days 1, 7, and 14, and ↑ SAA and TNF-α on 2 of these days. IVH should be viewed as 2 entities: with-w/o WMI. Each is associated with inflammation, but the combination has a stronger inflammatory signal than hemorrhage alone.

64. Systemic inflammation associated with severe intestinal injury in extremely low gestational age newborns Martin

Fetal Pediatr Pathol. 2013 ;32:222-34

On days 7 & 14, infants with NEC had ↑ levels of CRP, SAA, IL-6 and IL-8. Infants with intestinal perf had ↑ levels of CRP and IGF binding protein-1 on day 7 and elevated CRP, SAA, TNF-receptor-2 and MMP-9 on day 14.

63. Brain damage in preterm newborns and maternal medication:the ELGAN Study Tyler

Am J Obstet Gynecol. 2012;207:192.e1-9

After adjustment for potential confounding the risk of QP CP remained elevated among infants of mothers who consumed aspirin ([OR, 3.0; 95 CI, 1.3-6.9) and NSAIDs (OR, 2.4; 95% CI, 1.04-5.8). The risk of DP CP was also associated with NSAID, but only if consumption was not approved by a physician (OR, 3.5; 95% CI 1.1-11.0).

62. Birth wt- and fetal wt-growth restriction: impact on neurodevelopment Streimish

Early Hum Dev. 2012;88:765-71

Only girls with the most severe growth restriction were at ↑ risk of neurodevelopmental impairment at 24 mos CA in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm.

61. Antenatal antecedents of cognitive impairment at 24 months in extremely low gestational age newborns Helderman

Pediatrics. 2012;129:494-502

103 infants (11%) had MDI <55, and 99 (11%) an MDI between 55-69. No associations between placental orgs & dev delay. Factors strongly associated with MDI <55: fetal vessel thrombosis (OR 3.1; 95% CI 1.2, 7.7), maternal BMI >30 (OR 2.0; 95% CI 1.1, 3.5), mat ed ≤12 years (OR 3.4; 95% CI 1.9, 6.2), nonwhite (OR 2.2; 95% CI 1.3, 3.8), birth wt z score < -2 (OR 2.8; 95% CI 1.1, 6.9), male (OR 2.7; 95% CI 1.6, 4.5).

60. Fetal-placental inflammation, but not adrenal activation, is associated with extreme preterm delivery Trivedi

Am J Obstet Gynecol. 2012;206:236.e1-8

Among ELGANs, spontaneous (vs induced) delivery was associated with less placental CRH expression and more frequent placental inflammation and infection.

Inflammation and infection, rather than premature activation of the fetal adrenal axis, should be the major focus of research to prevent extremely preterm human birth.

59. Intraventricular hemorrhage and developmental outcomes at 24 months of age in extremely preterm infants O’Shea

J Child Neurol. 2012;27:22-9

In logistic regression models that adjusted for GA, sex, and SES, isolated iVH was associated with visual fixation difficulty but no other adverse outcome. Infants with WM lesion unaccompanied by IVH were at increased risk of CP, low MDI and PDI scores, and visual and hearing impairments. Isolated IVH is associated with a modest increase (and possibly no increase) in risk of adverse developmental outcome during infancy.

58. Relationships among the concentrations of 25 inflammation-associated proteins during the first postnatal weeks in the blood of infants born before the 28th week of gestation Leviton

Cytokine. 2012 Jan;57:182-90.

On each of 3 days assessed, ↑ concentrations of 17 proteins were associated with ↑ concentrations of 15 or more of the other 24 proteins. An ↑ concentration of eight proteins on day 1 predicted ↑ concentration of 10 or more proteins on day 7, while an ↑ concentration of two proteins on day 7 were associated with 10 or more proteins on day-14. Few associations seen between days 1 & 14.: Inflammation is a diffuse process in ELGANs, with ↑ concentrations of proteins on same and subsequent days

57. Systemic responses of preterm newborns with presumed or documented bacteraemia Leviton

Acta Paediatr. 2012;101:355-9

Newborns with presumed early (week 1) bacteraemia had ↑ concentrations of only a few inflammation-related proteins, while those who had presumed late (weeks 2-4) bacteraemia did not have any elevations. In contrast, newborns who had documented early bacteraemia or late bacteraemia had a strong inflammatory signal with more protein concentrations elevated on two separate occasions a week apart.

56. Elevated concentrations of inflammation-related proteins in postnatal blood predict severe developmental delay at 2 years of age in extremely preterm infants O’Shea

J Pediatr. 2012;16):395-401

For 17 of 25 inflammation-related proteins, 1 or more significant associations (P<.01) was found between an ↑ blood level of protein and developmental impairment at age 2 years. ↑s on multiple days were more often associated with developmental impairment than on only 1 day. The highest number of ↑s was found in day-14 blood.


55. Blood protein concentrations in the first two postnatal weeks associated with early postnatal blood gas derangements among ELGANs. The ELGAN Study Leviton

Cytokine. 2011;56:392-8

Blood gas derangements on two days were much more likely to be accompanied or followed by sustained or recurrent systemic inflammation than a derangement on only one day. This was most evident for acidemia, and slightly less so for hypercapnia.

54. Neonatal bacteremia and retinopathy of prematurity: the ELGAN study Tolsma

Arch Ophthalmol. 2011;129:1555-63

In MVA, newborns with presumed late bacteremia were at ↑ risk for prethreshold-threshold ROP (OR, 1.8; 95% CI, 1.02-3.2), and those with definite late bacteremia were at ↑ risk for prethreshold-threshold ROP and plus disease ROP (1.8; 1.1-2.9).

53. Placenta microbiology and histology and the risk for severe retinopathy of prematurity Chen

Invest Ophthalmol Vis Sci. 2011 1;52:7052-8

The co-occurrence of bacteria and inflammation was associated with an increased risk for ROP in zone I (OR, 3.1; 95% CI, 1.02-9.5). Among 339 infants with any placental bacteria, the co-occurrence of (1) inflammation and a GA of 23 - 24 weeks and (2) inflammation and hyperoxia were associated with increased risk for all severe ROP.

52. Persistence after birth of systemic inflammation associated with umbilical cord inflammation Leviton

J Reprod Immunol. 2011 ;90:235-43

Seven of nine proteins [CRP, myeloperoxidase , IL1β, IL8, TNFα, ICAM3, and MMP9) were elevated on d 7 among infants with funisitis. Adjusting for GA, SGA, and three postnatal exposures (ventilation on day 7, early bacteremia, and Bell stage III NEC) did not diminish the elevated OR of ↑ MPO, IL1β, TNFα, IL8, ICAM3, and MMP9. The persistence of a relationship between umbilical cord inflammation and inflammation-related proteins on postnatal day 7 suggests sustained systemic inflammation.

51. The M-CHAT in ELGANs: individual items associated with motor, cognitive, vision and hearing limitations Luyster

Paediatr Perinat Epidemiol. 2011;25:366-76

M-CHAT items were failed more frequently by children with concurrently identified impairments (motor, cognitive, vision and hearing). In addition, the frequency of item failure increased with the severity of impairment. Importantly, four of the six M-CHAT 'critical items' were commonly affected by impairments. This suggests that impairments might give rise to false positive M-CHAT screening.

50. Patterns of blood protein concentrations of ELGANs classified by three patterns of respiratory disease in the first 2 postnatal weeks Laughon

Pediatr Res. 2011 ;70:292-6

Two patterns of early lung disease: early and persistent pulmonary dysfunction (EPPD) and nl pulmonary function followed by pulmonary deterioration (PD). 38% (n = 347) of our cohort had PD, and 43% (n = 383) had EPPD. On d 14, elevated RANTES and VEGF associated with ↓ risk of PD. Risk of EPPD ↓ with elevated RANTES, MMP-1, and VEGF on d 14. Risk of EPPD was ↑ if on d 14 IL-8 & ICAM-1 were ↑. Inflammation might influence EPPD and PD risk, or be a consequence of lung damage or therapies.

49.Cluster analysis of placental inflammatory proteins can distinguish preeclampsia from preterm labor and premature membrane rupture in singleton deliveries < than 28 wks of gestation Faupel-Badger

Am J Reprod Immunol. 2011;66:488-94

Placentas from PE had high levels of VEGF combined with low levels of acute inflammatory proteins (IL-1β, IL-18, IL-6, TNF-α), low IL-1 RA, and high transforming growth factor β (TGF-β). PL and pPROM had higher anti-inflammatory IL-1 RA and thrombomodulin combined with lower. Half of the PL and pPROM cases of heightened inflammatory responses (lower TGF-β & higher intensity of inflammatory mediators).

48. Blood protein profiles of infants born before 28 weeks differ by pregnancy complication MeElrath

Am J Obstet Gynecol. 2011;204:418.e1-418.e12

Cytokines (IL-1β, IL-6, TNFα), cytokine receptors (IL-6R, TNF-R1, TNF-R2), systemic inflammatory proteins (CRP, SAA, MPO), chemokines (IL-8, MCP-1, MCP-4, MIP-1β, RANTES, I-TAC), adhesion molecules (ICAM-1, ICAM-3, VCAM-1, E-selectin), and metalloproteinases (MMP-1, MMP-9) were ↑ after preterm labor, membrane rupture, abruption, and cervical insufficiency. Such pattern not seen after PE or fetal indication-growth restriction. Inflammatory profiles were also associated with maternal vaginitis.

47.Early postnatal blood concentrations of inflammation-related proteins & microcephaly at two years in infants born before the 28th post-menstrual week Leviton

Early Hum Dev. 2011;87:325-30

↑ SAA on day 1 and ↑of  five proteins on day 14, (IL-6, TNF-R2, IL-8, MCP-1, and ICAM-1) increased risk of microcephaly. The ten proteins ↑ on two separate days a week apart predicted microcephaly, but not when elevated on only one day, were CRP, SAA, IL-1β, IL-6, TNF-α, IL-8, MCP-1, ICAM-1, E-SEL, IGFBP-1.

46. Early postnatal hypotension is not associated with indicators of white matter damage or cerebral palsy in extremely low gestational age newborns Logan

J Perinatol. 2011;31:524-34

21 % of survivors had lowest BP in lowest ¼ ile for GA, 24% txed with pressors & 24% had labile BP . Among these infants, 10% % developed VM and 7% developed an EL lesion. At 2 years, 6% had QP, 4% DP and 2% HP. After adjusting for confounders, no association between indicators of hypotension, and indicators of cerebral WMD or CP.

45. Maternal microbe-specific modulation of inflammatory response in extremely low-gestational-age newborns Fichorova

MBio. 2011 18;2:e00280-10

Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to facultative anaerobes. Prevotella and Gardnerella species, anaerobic streptococci, peptostreptococci, and genital mycoplasmas associated with different patterns of elevated inflammation-related proteins. Lactobacillus associated with low inflammatory response. Microorganisms colonizing placenta provoke distinctive newborn inflammatory responses & Lactobacillus may suppress these responses.

44.The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN study Leviton

J Pediatr. 2011;158:897-903.e1-5

VEGF receptor 1, SAA, and MIP 1β on day 1 and IL-8 on day 7 were associated with increased risk of VM. Elevated MIP 1β on day 1 and ICAM-1 on day 7 were associated with risk of EL lesion. Elevated inflammation-related proteins on two separate days were at significantly ↑ risk for VM, & modestly ↑ risk for EL.

43.Blood protein concentrations in the first two postnatal weeks that predict BPD among infants born before the 28th week of gestation Bose

Pediatr Res. 2011;69:347-53

BPD Risk was associated with ↑ blood cytokines, adhesion molecules, and proteases. ↓ risk was associated with chemokine, RANTES. ↑ of inflammatory proteins associated with BPD risk occurred in first days and intensified thereafter. Exposures that promote inflammation after first days may be more critical in the pathogenesis of BPD. Fetal growth restriction was not accompanied by proteins elevations

42. Early postnatal hypotension and developmental delay at 24 months of age among extremely low gestational age newborns Logan

Arch Dis Child Fetal Neonatal Ed. 2011;96:F321-8

78% of infants in cohort received volume expansion or pressors;. 26% had MDI <70 & 32% had PDI <70. Low MDI & PDI associated with low GA, which in turn, was associated with pressor treatment. After adjusting for potential confounders, none of the indicators of hypotension associated with MDI <70 or PDI <70.

41. Inflamm-related proteins in bld of ELGANs. Contribution of inflammation to the appearance of develop regulation Leviton

Cytokine. 2011;53:66-73

Some blood protein concentrations increase with ↑ GA. More commonly, the inflammation-related proteins decrease with ↑ GA. We observed this pattern regardless of whether or not the placenta is inflamed.

40. Relationship Between Neonatal Blood Protein Concentrations and Placenta Histologic Characteristics in ELGANs Hecht

Pediatr Res. 2011;69:68-73

Placental inflammation had (p< 0.01) ↑ blood cytokines (IL-1β, IL-6, and TNF-α), chemokines (IL-8, MIP-1β, RANTES, and I-TAC), adhesion molecules (ICAM-1, ICAM-3, and E-selectin), matrix metalloproteinases (MMP-1 and MMP-9), VEGF and its receptor VEGF-R2, and SAA and CRP in first 3 d.

39. Does BPD contribute to the occurrence of CP among infants born before 28 weeks of gestation? Van Marter

Arch Dis Child Fetal Neonatal Ed. 2011;96:F20-9

The 536 infants with BPD were at increased risk of all CP phenotypes. Receipt of oxygen without MV at 36 weeks PMA (BPD) was not associated with increased risk of CP. In contrast, BPD accompanied by MV at 36 weeks PMA was associated with a nearly six-fold increased risk of QP and a fourfold increased risk of DP.

38. Early cranial ultrasound lesions predict microcephaly at age 2 years in preterm infants Krishnamoorthy

J Child Neurol. 2011;26:188-94

OR (95% CI) for MC associated with different HUS images were IVH, 1.5 (0.8-3.0); VM, 3.3 (1.8-6.0); an ED, 1.6 (0.7-3.5); and EL, 3.1 (1.5-6.2). VM and EL had similar low PPV (24% and 27%, respectively) and high NPV (91% and 90%, respectively) for MC. VM had higher sensitivity for MC than did EL (24% vs 16%, respectively). Focal WM lesion (EL) and diffuse WMD (VM) predict increased risk of MC.

37. Presumed and definite bacteremia in ELGANs Patel

Acta Paediatr. 2011;100:36-41

Risk patterns did not differ much for presumed and definite bacteremia in first month. While maternal and pregnancy characteristics were associated with early bacteremia, neonatal comorbidities, especially NEC, were the main antecedents/correlates of late bacteremia. Definite and presumed late bacteremias have rather similar risk patterns, while those of early and late bacteremia differ appreciably.

36. Blood gases and retinopathy of prematurity: the ELGAN Study Hauspurg

Neonatology. 2011;99:104-11

MVA indicate exposure to PCO(2) in highest quartile predicts ROP (stage 3- 5: OR = 1.6, - 1.1-2.3); zone 1: 2.0, 1.1-3.6; prethreshold/threshold: 1.9, 1.2-3.0; plus disease: 1.8, 1.1-2.9). Estimates similar for a low pH for zone 1 (2.1, 1.2-3.8), and prethreshold-threshold (1.8, 1.1-2.8). A PaO(2) in highest quartile for GA on at least 2 postnatal days associated with doubled risk of ROP, and 70% risk ↑ for plus disease.

35. Antecedents of chronic lung disease following three patterns of early respiratory disease in preterm infants Laughon

Arch Dis Child Fetal Neonatal Ed. 2011;96:F114-20

CLD 69% of infants with EPPD, 52% with PD, and 17% in the Low FiO(2) group. Birth weight z score <-1 conveyed information about CLD risk in all three groups and was the major risk factor for infants in the Low FiO(2) group (OR 27; 95% CI 7 to 95). MV at 7 days associated with ↑ risk in PD (OR 4.2, 95% CI 2.5 to 6.9) and EPPD groups (OR 2.7, 95% CI 1.5 to 4.7), but not Low FiO(2) group. Among infants with little exposure to oxygen, fetal growth restriction, not MV, is factor with strongest association with CLD

34. Early blood gas abnormalities and the preterm brain Leviton

Am J Epidemiol. 2010;172:907-16

Hypoxemia, hyperoxemia, hypocapnia, hypercapnia, and acidosis were associated with multiple indicators of brain damage. The associations were seen with 1 or with 2 or more days' exposure. Findings suggest individual blood gas derangements do not increase brain damage risk. Rather, the multiple derangements associated with indicators of brain damage might represent immaturity/vulnerability and illness severity.

33. SNAP-II and SNAPPE-II and the risk of structural and functional brain disorders in ELGANs. Dammann

The ELGAN study. Neonatology 2010;97:71-82.

After adjustment for GA, high SNAP-II and SNAPPE-II scores predicted IVH, mod/sev VMeg and EL lesions in cerebral WM. Only 2 highest decile for GA and a Z score >1, predicted EL lesions. Neither SNAP-II nor SNAPPE-II predicted CP. MDI and PDI scores <55 were predicted by both high SNAP-II and SNAPPE-II High SNAP-II and SNAPPE-II inconsistently predicted positive screen for ASD and small HC at 24 mos.

32. The clustering of disorders in infants born before the 28th week of gestation Leviton

Acta Paediatr. 2010;99:1795-800

Adjusted for GA, children with severe NEC (Bell stage IIIb) were at ↑ risk of cerebral WMD, severe ROP (stage 3+), and severe BPD. Children who had early bacteremia were at increased risk of late bacteremia and severe ROP. Those who had severe ROP were at increased risk of severe BPD and both early and late bacteremia.

31. Microbiologic and histologic characteristics of the extremely preterm infant's placenta predict white matter damage and later cerebral palsy. the ELGAN study Leviton

Pediatr Res. 2010;67:95-101

Recovery of single microorganism predicts EL, whereas polymicrobial cultures & skin flora predicted VM and EL. DP CP predicted by single or multiple organisms, and skin flora. Histologic inflammation predicted VM and DP CP. Risk of VM, but not DP CP, associated with organism recovery, heightened by presence of histologic inflammation. Organism recovery not needed for placenta inflammation to predict DP CP

30. Mechanisms of injury to white matter adjacent to a large intraventricular hemorrhage in the preterm brain. Adler

J Clin Ultrasound 2010;38:254-258.

Support was found for possibility that ventricular wall does not function as an efficient barrier, allowing ventricular contents to affect WM where it causes damage. PVHI may not be only or most frequent mechanism of WM damage adjacent to a large IVH.

29. Reader variability in use of diagnostic terms to describe WM lesions seen on HUS: the ELGAN study Westra

J Clin Ultrasound. 2010;38:409-19

Experienced sonologists differ considerably in their tendency to apply diagnostic labels for white matter lesions. This is due to lack of universally agreed-upon definitions.

28. Antenatal antecedents of a small head circumference at age 24-months post-term equivalent in a sample of infants born before the 28th post-menstrual week Leviton

Early Hum Dev. 2010;86:515-21

Risk of MC decreased monotonically with increasing GA. After adjusting, the risk of MC at 2 years included MC at birth [odds ratio: 8.8 ((95% confidence interval: 3.7, 21)], alpha hemolytic Streptococci from placenta [2.9 (1.2, 6.9)], males [2.8 (1.6, 4.9)], and the child's mother un married [2.5 (1.5, 4.3)].

27. Neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia Martin

J Pediatr. 2010;157:751-6

Children with surgical NEC w/o late bacteremia were at increased risk of PDI <70 (OR = 2.7 [1.2, 6.4]), and children with both surgical NEC and late bacteremia were at increased risk of DP CP (OR = 8.4 [1.9, 39]) and MC (OR = 9.3 [2.2, 40]). In contrast, all children with medical NEC were not at increased risk of developmental dysfunction.

26. Factors associated with small head circumference at birth among infants born before the 28th week McElrath

Am J Obstet Gynecol. 2010;203:138.e1-8

Almost 10% of newborns (n = 138), rather than the expected 2.2%, had MC. In MV models, MC was associated with nonwhite race, severe IUGR, preeclampsia, placental infarction, and being female.

25. Nutritional practices and growth velocity in the first month of life in extremely premature infants. Martin

Pediatrics 2009;124:649-57

Protein and fat delivery ~current nutritional recommendations, whereas CBH & total energy intake delivery did not. Yet, GV of infants > current guideline of 15 g/kg per/d. Yet, we found growth restriction (ie, weight for GA < 10th centile) in 75% of infants at 28 d. Early nutrients is important determinant of postnatal growth. Extrauterine growth restriction remains high in ELGANs even when w/GV rate within current guidelines.

24. Patterns of respiratory disease during the first two postnatal weeks in extremely premature infants. Laughon

Pediatrics 2009;123:1124 -1131.

20% of infants had consistently low fraction of inspired oxygen, ~ 38% had pulm deterioration, and remaining 43% had consistently high fraction of inspired O2 (early and persistent lung dysfunction). Infants w/pulm deterioration had lower GA and lower B Wts, had higher SNAP, and received more respiratory support. Gender, multifetal pregnancy, C/S, ACS, chorioamnionitis, & funisitis not associated w/pulm deterioration. Incidence of CLD, O2 tx at 36 wks', was 17% in low fraction of inspired O2 group, 51% in pulm deterioration group, & 67% in early/persistent pulm dysfunction group.

23. Inter-institutional variation in prediction of death by SNAP-II and SNAPPE-II among extremely preterm infants Dammann

Pediatrics. 2009;124:e1001-6

The rate of death before day 28 was 13, whereas overall mortality rate was 18%. SNAP-II, SNAPPE-II, and mortality rates ↓ with increasing GA. Even within GA strata, risk of death ↓ with ↓SNAP-II and SNAPPE-II values. The PPV of most SNAP-II and SNAPPE-II cutoff levels were ~30%, especially in infants with SNAP-II >/=30.

22. Perinatal correlates of Ureaplasma urealyticum in placenta parenchyma of singleton pregnancies that end before 28 weeks of gestation. Olomu

Pediatrics 2009;123:1329-136.

U urealyticum was recovered from 6% and bacteria from 47%; 47% of placentas had no bacteria detectable. The presence of U urealyticum in placental parenchyma before 28 weeks is associated with increased risk of preterm labor and delivery, higher risk of fetal and maternal inflammation, and increased risk of intraventricular hemorrhage and echolucent brain lesions but not of early neonatal death.

21. Antenatal Complications and the Risk of Neonatal Cerebral White Matter Damage and Later Cerebral Palsy in Children Born at an Extremely Low GA. McElreth

Am J Epidemiol 2009;170:819-828.

Infants w/ACS had lower risks of VMeg & EL (10% vs. 23%, P < 0.001 & 7% vs. 11%, P = 0.06). Risk of VMeg ↑ w/preterm labor: OR = 2.3, 95% CI: 1.1, 4.9), PROM (OR = 3.6, 95% CI: 1.5, 8.7), and cervical insuff (OR = 2.8, 95% CI: 1.4, 5.5) compared w/ infants delivered for PE. Risk of EL lesion was ↑ w/ preterm labor (OR = 2.7, 95% CI: 1.2, 5.7) and IUGR (OR = 3.3, 95% CI: 1.2, 9.4). Doubling of DP risk w/preterm labor & PROM not sign, nor was doubling of QP and tripling of DP risk ass’ed w/ cervical insuff

20. The ELGAN study of the brain and related disorders in extremely low gestational age newborns O’Shea

Early Hum Dev. 2009;85:719-25

The following are associated with ultrasongraphically detected WMD, CP, or both: preterm labor-preterm delivery, prelabor PROM, or cervical insufficiency; microorgs in placenta, including human skin microflora; placental inflammation; lower GA; greater neonatal illness severity; severe CLD; neonatal bacteremia; and NEC.

19. Chronic lung disease and developmental delay at two years of age in children born before 28 weeks gestation. Laughon

Pediatrics 2009;124:637-48.

49% of ELGANs had CLD; of these, 14% received MV at 36 wks PM age. ELGANs w/o CLD had lowest risk of a MDI or PDI <55, followed by ELGANs with CLD not receiving MV, and ELGANs with CLD receiving MV (9%, 12%, and 18% for the MDI and 7%, 10%, and 20% for the PDI, respectively). In TORM models, the risk of an MDI of <55 ass’ed w/following variables: GA <25 wks; single mother; late bacteremia; PTX; and NEC. The risk of PDI of <55 ass’ed w/single mother, complete course of ACS, early & persistent pulm dysfunction, pulm deterioration during 2nd postnatal wk, PTX, and PIE. CLD, without or with MV, not ass’ed w/risk of either low MDI or low PDI.

18. Fetal Growth Restriction and Chronic Lung Disease among infants born before the 28th week of gestation. Bose

Pediatrics 2009;124;e450-e458

Among the prenatal factors, B. Wt z scores, used as a marker of FGR, provided most information about CLD risk. Indicators of placental inflammation and infection not associated with ↑risk of CLD. W/i ~all strata of prenatal, placental, and neonatal variables, FGRs infants were at ↑CLD risk. FGR was the only maternal or prenatal characteristic that was highly predictive of CLD after adjustment for other risks.

17. Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children who were born at extremely low gestational age. Kuban

J Child Neurol 2009;24:63-72

HUS in 1053 infants were read with respect to IVH, VMeg, and EL. Standardized neuro exams classified CP, and functional impairment. 44% w/ VMeg and 52% w/ EL developed cerebral palsy. Compared with no ultrasound abnormalities, children with were 24 X > likely to have QP and 29 X > likely to have HP. Children w/VMeg were 17 X > likely to have QP or HP. 43 % w/CP had nl HUS. EL, late VMeg had ↑probability of CP, esp QP. Nearly ½ w/CP had no HUS abnormality.

16. Developmental correlates of head circumference at birth and at two years in a cohort of ELGANs. Kuban

J Pediatr 2009;155:344-9.e1-3 

A total of 11% of infants in our sample had MC at 2 years. MC at 2 years, but not at birth, predicts severe motor and cognitive impairments at 2 years. A total of 71% of children with congenital MC had a normal HC at 2 years and had neurodevelopmental outcomes ~ those with nl HC at birth and 2 years. Among children with MC at 2 years, more than half had a MDI <70, and nearly a third had CP. The risks were increased if child also had cerebral WM damage on neonatal HUS.Among ELGANs, MC at 2 yrs, but not at birth, is associated with motor and cognitive impairment at age 2.

15.Maternal antenatal complications and the risk of neonatal cerebral WMD and later CP in ELGANs McElrath

Am J Epidemiol. 2009;170:819-28

Mothers that received antenatal steroids tended to have lower risks of VM and EL (10% vs. 23%, P < 0.001 and 7% vs. 11%, P = 0.06). Risk of VM was ↑ for infants delivered because of PL (OR = 2.3, 95% CI: 1.1, 4.9), PPROM (OR = 3.6, 95% CI: 1.5, 8.7), and cervical insufficiency (OR = 2.8, 95% CI: 1.4, 5.5) compared to infants delivered because of PE. Risk of an EL was ↑ for infants with PL (OR = 2.7, 95% CI: 1.2, 5.7) and IUGR (OR = 3.3, 95% CI: 1.2, 9.4).

14. Positive screening on the Modified-Checklist for Autism in Toddlers (M-CHAT) in Extremely Low Gestational Age Newborns. Kuban

J Pediatr 2009;154:535-540.e1

Odds for screening + on M-CHAT ↑ 23-fold for those unable to sit or stand and 7-fold if unable to walk. Children with QP were 13 X more likely to screen +, and those with HP 4 X more likely to screen +. Children with major vision or hearing impairments were 8 X more likely to screen +. Odds for screening + were increased 13-fold with MDI <55 and > than 4-fold for MDI 55-69. Even after motor, cognitive, visual, & hearing impairments eliminated, 10% screened +: double expected rate.

13. Characterization of chorioamnionitis in second trimester C-section placentas and correlation with microorganism recovery from subamniotic tissues. Hecht

Pediatr Dev Pathol 2008;11:15-22

Subamniotic parenchyma of 835 placentas delivered by c/s cultured and evaluated in blinded fashion. Microbes recovered from 41% of placentas. Microbes found more frequently in placentas with high-grade chorionic plate inflammation: Actinomyces, Prevotella bivia, Corynebacterium sp., Escherichia coli, Peptostreptococcus magnus, multiple species of Streptococci, and Mycoplasma sp., including Ureaplasma urealyticum. These microorganisms were also associated with fetal vasculitis.

12. Histologic characteristics of singleton placentas delivered before the 28th week of gestation. Hecht

Pathology 2008;40:372-6

Lesions of uteroplacental circulation (abruption, extensive infarction/thrombosis, basal or perivillous fibrin deposition, ↑syncytial knots) inversely related to membrane & cord inflammation. Earlier GA favored inflamm; older age favored charact of ↓blood flow. Inflammation of chorionic plate in 43%, cord in 19%, & chorionic plate vessels in 30%. Of placentas w/umb cord inflammation, 8% had no inflammation of chorionic plate.

11. Pregnancy disorders that lead to delivery before the 28th week of gestation: and epidemiologic approach to classification. McElrath

Am J Epidemiol 2008;168:980-9

We enrolled 1,006 women who delivered a liveborn singleton ELGAN infants. Each delivery classified by presentation: preterm labor (40%), prelabor premature rupture of membranes (23%), preeclampsia (18%), placental abruption (11%), cervical incompetence (5%), and fetal indication/intrauterine growth restriction (3%). Using factor analysis, the authors found 2 broad patterns. One pattern, characterized by histo chorioamnionitis and placental microbe recovery, was associated with preterm labor, prelabor PROM, placental abruption, and cervical insufficiency. The other, had paucity of orgs and inflammation but presence of histo features of abnl placentation, & ass’ed w/PET and IUGR. Preterm delivery disorders may be separated into two groups: those with intrauterine inflammation and those associated with aberrations of placentation.

10. An algorithm for identifying and classifying cerebral palsy in young children. Kuban

J Pediatr 2008;153:466-472

Of 1056 children examined, 11.4% had an algorithm-based CP. Of these, 31% had DP, 17% had HP, and 52% had QP. Children with QP were 9 X more likely than DP (76% versus 8%) to be more highly impaired and 5 X more likely to be microcephalic (43% versus 8%). They were > than 2 X as likely as children with DP to have MDI <70 and were MCHAT+ 76% compared with DP (30%) and w/oCP (18%).

9. Colonization of second trimester placenta parenchyma. Onderdonk

Am J Obstet Gynecol 2008;199:52.e1-52.e10

Bx specimens of chorion from 1083 placentas cultured, and placentas examined. Placentas delivered by c/s w/ PET had lowest bacteria (25%). Preterm labor had highest rates, which ↓with ↑GA from 79% at 23 weeks to 43% at 27 wks. Microorgs in placenta associated w/wbc in fetal stem vessels of chorion or in vessels of umb cord.

8.Detection of Bacteria in Placental Tissues Obtained from Extremely Low Gestational Age Neonates (ELGAN) Onderdonk

Am J Obstet Gynecol 2008;198:110.e1-7

The culture + rate was higher for vaginal deliveries (333/489; 68%) than for cesarean sections (363/876; 41%). 30% of culture-positive samples had only aerobic bacteria, 21% had only anaerobic bacteria, and 9% had only Mycoplasma/Ureaplasma. Staph and Corynebacterium & organisms associated w/bacterial vaginosis most frequently recovered. Approximately 1/2 of 2nd trimester placentas had orgs w/i chorionic plate.

7. Neonatal Cranial Ultrasound Lesions and Developmental Delays at 2 Years of Age Among Extremely Low Gestational Age Children. O’Shea

Pediatrics 2008;122:e662-e669

26% of all children had MDI < 70, and 31% had PDI < 70. HUS more associated with low PDI than with low MDI. Children w/o HUS abnormality had lowest probability (23% and 26%) of delayed development. Mod/severe Vmeg associated with 4-fold risk of low PDI and 3-fold risk of low MDI. EL was next best predictor of delay At particularly high risk were infants with bilat cerebellar hemorrhage, Vmeg and bilat/post EL

6. Perturbation of gene expression of the chromatin remodeling pathway in premature newborns at risk for BPD. Cohen

Genome Biol 2007;8:R210

To evaluate expression profiling in umbilical cord tissue to discover molecular signatures for staging and determine risk for BPD, we conducted cross-sectional study of ELGANs (n = 54). Sections of umb cord obtained at birth f/ 20 infants w/BPD & 34 peers who did not. Infants who developed BPD had distinct signatures involving chromatin remodeling and histone acetylation pathways, implicated in adult lung ds.

5. Factors associated with tx for hypotension in extremely low gestational age newborns during the first postnatal week. Laughon

Pediatrics 2007;119:273-80.

The goals to ID the BP of ELGANs that prompt intervention & to ID other infant characteristics of BP therapies. At each GA, the lowest MAP in treated and untreated infants tended to increase with advancing postnatal age. The proportion of infants receiving any tx decreased with increasing GA from 93% at 23 wks to 73% at 27 wks. Lower GA lower B Wt ,male sex, and higher SNAP-II values associated with tx.

4. Reference weights for placentas delivered before the 28th week of gestation.  Hecht

Placenta 2007;28:987-90

We measured the weight of 930 singleton placentas delivered < 28th week, and examined distributions of wts. We excluded 90 IUGR, resulting in normative sample of 840 placentas. Placenta weight varied with B Wt. Placentas from pregnancies ending due to preeclampsia, fetal indications or with poor perfusion on histology were among smallest and weights correlated with the smallest birth weights for gestational age.

3. Observer variability assessing US scans of the preterm brain: The ELGAN Study. Kuban

Pediatric Radiology 2007;37:1201-8.

We sought to evaluate observer variability among experienced neurosonologists. We collected all protocol US scans of 1,450 infants born before the 28th postmenstrual week. Each set of scans read by 2 sonologists for presence of IVH and mod/sev vmeg, & EL &EG: in WM. Scans read discordantly sent to a tie-breaking third sonologist.

Vmeg, EL and IVH had similar rates of positive agreement (68-76%), negative agreement (92-97%), and kappa values (0.62 to 0.68). EG had lower values of positive agreement (48%), negative agreement (84%), and kappa (0.32).

2.Thymus involution and cerebral white matter damage in extremely low gestational age neonates. Kuban, J

Biol Neonate 2006;90:252-7

Among newborns who die, those who have cerebral white matter damage are more likely than others to have thymus involution and low thymus weights. We sought to evaluate in a population of preterm newborns who did not die if those who developed a cerebral white matter damage (defined by echolucency) are more likely than others to have thymus involution assessed on chest radiographs. Infants with an EL were more likely to have had early involution than infants without an EL (89% vs. 44%) (p = 0.01).

1.Video and CD-ROM as a training tool for performing neurologic examinations of 1-year-old children in a multicenter epidemiologic study. Kuban

J. Child Neurol 2005;20:829-31

In lieu of traditional training of examiners to identify cerebral palsy on a neurologic examination at age 1 year, we proposed an alternative approach using multimedia training video. Interactive CD-ROM examination training is an efficient and cost-effective means of training both neurologists and non-neurologists to perform structured neurologic examinations in 1-year-old children.





2005-2008 -- 13 publications

2009 ---------- 12 publications

2010 ---------- 8 publications

2011 ---------- 21 publications

2012 ---------- 8 publications

2013 ----------14 publications

2014 ---------- 8 publications

2015----------- 16 publications