Antenatal and Neonatal Antecedents of Executive Dysfunctions in Extremely Preterm Children
Alan Leviton, Robert M Joseph, Elizabeth N Allred, T Michael O'Shea, H Gerry Taylor, Karl K C Kuban
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.
Antenatal and neonatal antecedents of learning limitations in 10-year old children born extremely preterm
Alan Leviton, Robert M Joseph, Elizabeth N Allred, T Michael O'Shea, Karl K C Kuban
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).
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
Alan Leviton, Olaf Dammann, Elizabeth N Allred, Robert M Joseph, Raina N Fichorova, T Michael O'Shea, Karl C K Kuban
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.
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
Rachel G Hirschberger, Karl C K Kuban, Thomas M O'Shea, Robert M Joseph, Tim Heeren, Laurie M Douglass, Carl E Stafstrom, Hernan Jara, Jean A Frazier, Deborah Hirtz, Julie V Rollins, Nigel Paneth, ELGAN Study Investigators
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.
Circulating biomarkers in extremely preterm infants associated with ultrasound indicators of brain damage
Alan Leviton, Elizabeth N Allred, Raina N Fichorova, T Michael O'Shea, Lynn A Fordham, Karl K C Kuban, Olaf Dammann
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.
Hand Preference and Cognitive, Motor, and Behavioral Functioning in 10-Year-Old Extremely Preterm Children
Alice C Burnett, Peter J Anderson, Robert M Joseph, Elizabeth N Allred, T Michael O'Shea, Karl C K Kuban, Alan Leviton, ELGAN Study Investigators
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.
Antecedents of Screening Positive for Attention Deficit Hyperactivity Disorder in Ten-Year-Old Children Born Extremely Preterm
Alan Leviton, Stephen R Hooper, Scott J Hunter, Megan N Scott, Elizabeth N Allred, Robert M Joseph, T Michael O'Shea, Karl Kuban, ELGAN Study Investigators
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.
Elevations of inflammatory proteins in neonatal blood are associated with obesity and overweight among 2-year-old children born extremely premature.
Eliana M Perrin, T Michael O'Shea, Asheley Cockrell Skinner, Carl Bose, Elizabeth N Allred, Raina N Fichorova, Jelske W van der Burg, Alan Leviton
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).
Microorganisms in the human placenta are associated with altered CpG methylation of immune and inflammation-related genes
Martha Scott Tomlinson, Paige A Bommarito, Elizabeth M Martin, Lisa Smeester, Raina N Fichorova, Andrew B Onderdonk, Karl C K Kuban, T Michael O'Shea, Rebecca C Fry
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.
Systemic Inflammation-Associated Proteins and Retinopathy of Prematurity in Infants Born Before the 28th Week of Gestation
Mari Holm, Tora S Morken, Raina N Fichorova, Deborah K VanderVeen, Elizabeth N Allred, Olaf Dammann, Alan Leviton, ELGAN Study Neonatology and Ophthalmology Committees
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.