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
Karl C K Kuban, Hernan Jara, T Michael O'Shea, Timothy Heeren, Robert M Joseph, Raina N Fichorova, Khalid Alshamrani, Adam Aakil, Forrest Beaulieu, Mitchell Horn, Laurie M Douglass, Jean A Frazier, Deborah Hirtz, Julie Vanier Rollins, David Cochran, Nigel Paneth, ELGAN Study Investigators
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.
Antecedents of Epilepsy and Seizures among Children Born at Extremely Low Gestational Age
Rachana Singh, Laurie M Douglass, T Michael O'Shea, Carl E Stafstrom, Elizabeth N Allred, Stephen Engelke, Bhavesh Shah, Alan Leviton, Timothy C Hereen, Karl C K Kuban, ELGAN Study Group
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.
Microorganisms in the Placenta: Links to Early-Life Inflammation and Neurodevelopment in Children
Martha Scott Tomlinson, Kun Lu, Jill R Stewart, Carmen J Marsit, T Michael O'Shea, Rebecca C Fry
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.
Socioeconomic status and early 1 blood concentrations of inflammation-related and neurotrophic proteins among extremely preterm newborns
Alan Leviton, Elizabeth N Allred, Olaf Dammann, Robert M Joseph, Raina N Fichorova, T Michael O'Shea, Karl C K Kuban
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.
Neurocognitive function of 10-year-old multiples born less than 28 weeks of gestational age
J. Wells Logan, Elizabeth N. Allred, Michael E. Msall, Robert M. Joseph, T. Michael O’Shea, Timothy Heeren, Alan Leviton, Karl C. K. Kuban, and ELGAN Study Investigators
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.
Early Postnatal IGF-1 and IGFBP-1 Blood Levels in Extremely Preterm Infants: Relationships with Indicators of Placental Insufficiency and with Systemic Inflammation
Alan Leviton, Elizabeth N Allred, Raina N Fichorova, Deborah K VanderVeen, T Michael O'Shea, Karl Kuban, Olaf Dammann, ELGAN Study Investigators
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.
Antecedents of Obesity Among Children Born Extremely Preterm
Charles T Wood, Olivia Linthavong, Eliana M Perrin, Alan Leviton, Elizabeth N Allred, Karl C K Kuban, T Michael O'Shea, ELGAN Study Investigators
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.
Behavioural dysfunctions of 10-year-old children born extremely preterm associated with corticotropin-releasing hormone expression in the placenta
Alan Leviton, Elizabeth N Allred, Robert M Joseph, Thomas Michael O'Shea, Joseph Majzoub, Karl C K Kuban, ELGAN Study Investigators
Acta Paediatr. 2018 Nov;107(11):1932-1936
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.
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
Alan Leviton, Robert M Joseph, Elizabeth N Allred, Raina N Fichorova, T Michael O'Shea, Karl K C Kuban, Olaf Dammann
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.
Executive Dysfunction Early Postnatal Biomarkers among Children Born Extremely Preterm
Alan Leviton, Robert M Joseph, Raina N Fichorova, Elizabeth N Allred, H Gerry Taylor, T Michael O'Shea, Olaf Dammann
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.