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Leviton, Alan

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Leviton

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Alan

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Leviton, Alan
Author's Publications: search.filters.isAuthorOfPublication.a69618b3-ded4-4705-9f6c-be90485e218b

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    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
    (Nature Publishing Group UK, 2018) Korzeniewski, Steven J.; Allred, Elizabeth N.; O’Shea, T. Michael; Leviton, Alan; Kuban, Karl C. K.; Lee, Kathleen; McGovern, Anne; Gambardella, Jill; Ursprung, Susan; Ecklund, Ruth Blomquist Kristen; Bassan, Haim; Butler, Samantha; Duplessis, Adré; Hahn, Cecil; Limperopoulos, Catherine; Khwaja, Omar; Soul, Janet S.; Shah, Bhavesh; Christianson, Karen; Hampf, Frederick; Gilmore, Herbert; McQuiston, Susan; Martin, Camilia; Hallisey, Colleen; Hurley, Caitlin; Creixell, Miren; Share, Jane; Van Marter, Linda; Durfee, Sara; Insoft, Robert M.; Wilson, Jennifer G.; Pimental, Maureen; Westra, Sjirk; Krishnamoorthy, Kalpathy; Cole, Cynthia; Fiascone, John M.; Madden, Janet; Nylen, Ellen; McCauley, Anne Furey Roy; Church, Paige T.; Keller, Cecelia; Miller, Karen J.; Bednarek, Francis; Naples, Mary; Powers, Beth; Wellman, Jacqueline; Adair, Robin; Bream, Richard; Miller, Alice; Scheiner, Albert; Stine, Christy; Ehrenkranz, Richard; Williams, Joanne; Romano, Elaine; Miller, Cindy; Close, Nancy; Gordon, Debbie; Harold, Teresa; Specter, Barbara; Allred, Deborah; Dillard, Robert; Goldstein, Don; Hiatt, Deborah; Hounshell, Gail; Waldrep, Ellen; Washburn, Lisa; Welch, Cherrie D.; Engelke, Stephen C.; Moseley, Sherry; Pare, Linda; Smart, Donna; Wilson, Joan; Adler, Ira; Buckwald, Sharon; Helms, Rebecca; Kerkering, Kathyrn; MacGilvray, Scott S.; Resnik, Peter; Bose, Carl; Bose, Gennie; Fordham, Lynn A.; Bostic, Lisa; Marshall, Diane; Milowic, Kristi; Wereszczak, Janice; Poortenga, Mariel; Sutton, Dinah; Betz, Bradford W.; Bezinque, Steven L.; Junewick, Joseph; Burdo-Hartman, Wendy; Fagerman, Lynn; Lohr, Kim; Pastyrnak, Steve; Solomon, Carolyn; Cavenagh, Ellen; Caine, Victoria J.; Olomu, Nicholas; Price, Joan; Paneth, Nigel; Karna, Padmani; Lenski, Madeleine; Schreiber, Michael D.; Yoon, Grace; Feinstein, Kate; Caldarelli, Leslie; O’Connor, Sunila E.; Msall, Michael; Plesha-Troyke, Susan; Batton, Daniel; Kring, Beth; Brooklier, Karen; Oca, Melisa J.; Solomon, Katherine M.
    Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). 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).
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    Are Extremely Low Gestational Age Newborns Born to Obese Women at Increased Risk of Cerebral Palsy at 2 Years?
    (SAGE Publications, 2018) van der Burg, Jelske W.; O’Shea, T. Michael; Kuban, Karl; Allred, Elizabeth N.; Paneth, Nigel; Dammann, Olaf; Leviton, Alan
    The authors hypothesized that the risk of cerebral palsy at 2 years in children born extremely preterm to overweight and obese women is increased relative to the risk among children born to neither overweight nor obese women. In a multicenter prospective cohort study, the authors created multinomial logistic regression models of the risk of diparetic, quadriparetic, and hemiparetic cerebral palsy that included the prepregnancy body mass index of mothers of 1014 children born extremely preterm, cerebral palsy diagnoses of children at 2 years, as well as information about potential confounders. Overweight and obese women were not at increased risk of giving birth to a child who had cerebral palsy. 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).
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    Early Blood Gas Predictors of Bronchopulmonary Dysplasia in Extremely Low Gestational Age Newborns
    (Hindawi Publishing Corporation, 2014) Sriram, Sudhir; Condie, Joy; Schreiber, Michael D.; Batton, Daniel G.; Shah, Bhavesh; Bose, Carl; Laughon, Matthew; Van Marter, Linda; Allred, Elizabeth; Leviton, Alan
    Aim. To determine among infants born before the 28th week of gestation to what extent blood gas abnormalities during the first three postnatal days provide information about the risk of bronchopulmonary dysplasia (BPD). Methods:. We studied the association of extreme quartiles of blood gas measurements (hypoxemia, hyperoxemia, hypocapnea, and hypercapnea) in the first three postnatal days, with bronchopulmonary dysplasia, among 906 newborns, using multivariable models adjusting for potential confounders. We approximated NIH criteria by classifying severity of BPD on the basis of the receipt of any O2 on postnatal day 28 and at 36 weeks PMA and assisted ventilation. Results:. In models that did not adjust for ventilation, hypoxemia was associated with increased risk of severe BPD and very severe BPD, while infants who had hypercapnea were at increased risk of very severe BPD only. In contrast, infants who had hypocapnea were at reduced risk of severe BPD. Including ventilation for 14 or more days eliminated the associations with hypoxemia and with hypercapnea and made the decreased risk of very severe BPD statistically significant. Conclusions:. Among ELGANs, recurrent/persistent blood gas abnormalities in the first three postnatal days convey information about the risk of severe and very severe BPD.
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    Two-hit model of brain damage in the very preterm newborn: small for gestational age and postnatal systemic inflammation
    (2013) Leviton, Alan; Fichorova, Raina; O’Shea, T. Michael; Kuban, Karl; Paneth, Nigel; Dammann, Olaf; Allred, Elizabeth
    Background: We sought to disentangle the contributions of perinatal systemic inflammation and small for gestational age (SGA) to the occurrence of low Bayley Mental Development Indices (MDIs) at age 2 years. Method We measured the concentration of 25 inflammation-related proteins in blood obtained during the first 2 postnatal weeks from 805 infants who were born before the 28th week of gestation and who had MDI measurements at age 2 years and were able to walk independently. Results: SGA newborns who did not have systemic inflammation (a concentration of an inflammation-related protein in the top quartile for gestational age on 2 days a week apart) were at greater risk of an MDI < 55, but not 55–69, than their peers who had neither SGA nor systemic inflammation. SGA infants who had elevated blood concentrations of IL-1beta, TNF-alpha, or IL-8 during the first two postnatal weeks were at even higher risk of an MDI < 55 than their SGA peers without systemic inflammation and of their non-SGA peers with systemic inflammation. Conclusion: SGA appears to place very preterm newborns at increased risk of a very low MDI. Systemic inflammation adds considerably to the increased risk.
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    Early Nutrition and Weight Gain in Preterm Newborns and the Risk of Retinopathy of Prematurity
    (Public Library of Science, 2013) Vanderveen, Deborah; Martin, Camilia; Mehendale, Reshma; Allred, Elizabeth; Dammann, Olaf; Leviton, Alan
    Objective: To identify nutritional and weight gain limitations associated with retinopathy of prematurity (ROP) severity among very preterm newborns. Patients and Methods 1180 infants <28 weeks GA at birth with ROP examination results were grouped and analyzed by quartile of weekly total calorie, carbohydrate, protein, and lipid intake, as well as growth velocity between postnatal days 7 and 28 (adjusted for GA and birth weight Z-score). ROP was categorized by development of no, mild (
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    Are Preterm Newborns Who Have Relative Hyperthyrotropinemia at Increased Risk of Brain Damage?
    (Walter de Gruyter GmbH, 2014-11) Korzeniewski, Steven J.; Soto-Rivera, Carmen L.; Fichorova, Raina; Allred, Elizabeth N.; Kuban, Karl C. K.; O’Shea, T. Michael; Paneth, Nigel; Agus, Michael; Dammann, Olaf; Leviton, Alan
    Background We sought to disentangle the contributions of hyperthyrotropinemia (an indicator of thyroid dysfunction) (HTT) and intermittent or sustained systemic inflammation (ISSI) to structural and functional indicators of brain damage. Methods We measured the concentrations of TSH on day 14, and of 25 inflammation-related proteins in blood collected during the first 2 postnatal weeks from 786 infants born before the 28th week of gestation who were not considered to have hypothyroidism. We defined hyperthyrotropinemia (HTT) as a TSH concentration in the highest quartile for gestational age on postnatal day 14 and ISSI was defined as a concentration in the top quartile for gestational age of a specific inflammation-related protein on two separate days a week apart during the first two postnatal weeks. We first assessed the risk of brain damage indicators comparing 1) neonates who had HTT to those without (regardless of ISSI), and 2) neonates with HTT only, ISSI only, or HTT+ ISSI, to those who were exposed to neither HTT nor ISSI. HTT was defined as a TSH concentration in the highest quartile for gestational age on postnatal day 14. Results In univariable models that compared those with HTT to those without, HTT was not significantly associated with any indicator of brain damage. In models that compared HTT only, ISSI only, and HTT+ISSI, to those with neither, children with ISSI only or with HTT+ISSI were at significantly higher risk of ventriculomegaly [odds ratios (OR) ranged from 2–6], while those with HTT only were at significantly reduced risk of a hypoechoic lesion [ORs ranged from 0.2–0.4]. Children with HTT only had a higher risk of quadriparesis and those with ISSI alone had a higher risk of hemiparesis [ORs ranged from 1.6–2.4]. Elevated risk of a very low mental development score was associated with both ISSI only and with HTT+ISSI while a very low motor development score and microcephaly were associated with HTT+ISSI. Conclusions The association of HTT with increased or decreased risk of indicators of brain damage depends upon the presence or absence of ISSI.
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    Elevated Endogenous Erythropoietin Concentrations Are Associated with Increased Risk of Brain Damage in Extremely Preterm Neonates
    (Public Library of Science, 2015) Korzeniewski, Steven J.; Allred, Elizabeth; Logan, J. Wells; Fichorova, Raina; Engelke, Stephen; Kuban, Karl C. K.; O’Shea, T. Michael; Paneth, Nigel; Holm, Mari; Dammann, Olaf; Leviton, Alan
    Background: We sought to determine, in very preterm infants, whether elevated perinatal erythropoietin (EPO) concentrations are associated with increased risks of indicators of brain damage, and whether this risk differs by the co-occurrence or absence of intermittent or sustained systemic inflammation (ISSI). Methods: Protein concentrations were measured in blood collected from 786 infants born before the 28th week of gestation. EPO was measured on postnatal day 14, and 25 inflammation-related proteins were measured weekly during the first 2 postnatal weeks. We defined ISSI as a concentration in the top quartile of each of 25 inflammation-related proteins on two separate days a week apart. Hypererythropoietinemia (hyperEPO) was defined as the highest quartile for gestational age on postnatal day 14. Using logistic regression and multinomial logistic regression models, we compared risks of brain damage among neonates with hyperEPO only, ISSI only, and hyperEPO+ISSI, to those who had neither hyperEPO nor ISSI, adjusting for gestational age. Results: Newborns with hyperEPO, regardless of ISSI, were more than twice as likely as those without to have very low (< 55) Mental (OR 2.3; 95% CI 1.5-3.5) and/or Psychomotor (OR 2.4; 95% CI 1.6-3.7) Development Indices (MDI, PDI), and microcephaly at age two years (OR 2.4; 95%CI 1.5-3.8). Newborns with both hyperEPO and ISSI had significantly increased risks of ventriculomegaly, hemiparetic cerebral palsy, microcephaly, and MDI and PDI < 55 (ORs ranged from 2.2-6.3), but not hypoechoic lesions or other forms of cerebral palsy, relative to newborns with neither hyperEPO nor ISSI. Conclusion: hyperEPO, regardless of ISSI, is associated with elevated risks of very low MDI and PDI, and microcephaly, but not with any form of cerebral palsy. Children with both hyperEPO and ISSI are at higher risk than others of very low MDI and PDI, ventriculomegaly, hemiparetic cerebral palsy, and microcephaly.
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    Systems approach to the study of brain damage in the very preterm newborn
    (Frontiers Media S.A., 2015) Leviton, Alan; Gressens, Pierre; Wolkenhauer, Olaf; Dammann, Olaf
    Background:: A systems approach to the study of brain damage in very preterm newborns has been lacking. Methods:: In this perspective piece, we offer encephalopathy of prematurity as an example of the complexity and interrelatedness of brain-damaging molecular processes that can be initiated inflammatory phenomena. Results:: Using three transcription factors, nuclear factor-kappa B (NF-κB), Notch-1, and nuclear factor erythroid 2 related factor 2 (NRF2), we show the inter-connectedness of signaling pathways activated by some antecedents of encephalopathy of prematurity. Conclusions:: We hope that as biomarkers of exposures and processes leading to brain damage in the most immature newborns become more readily available, those who apply a systems approach to the study of neuroscience can be persuaded to study the pathogenesis of brain disorders in the very preterm newborn.
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    Perturbation of Gene Expression of the Chromatin Remodeling Pathway in Premature Newborns at Risk for Bronchopulmonary Dysplasia
    (BioMed Central, 2007) Cohen, Jennifer Naomi; Van Marter, Linda; Sun, Yao; Allred, Elizabeth; Leviton, Alan; Kohane, Isaac
    Background: One-third to one-half of all infants born before the 28th week of gestation develop bronchopulmonary dysplasia (BPD). Inflammatory regulators appear to be involved in the pathogenesis of BPD, possibly beginning in fetal life. To evaluate the feasibility of using expression profiling in umbilical cord tissue to discover molecular signatures for developmental staging and for determining risk of BPD, we conducted a cross-sectional study of infants born at less than 28 weeks of gestation (n = 54). Sections of umbilical cord were obtained at birth from 20 infants who later developed BPD and from 34 of their peers who did not develop BPD. Results: Umbilical cord expression profiles at birth exhibited systematic differences in bioenergetic pathways with respect to gestational age. Infants who subsequently developed BPD had distinct signatures involving chromatin remodeling and histone acetylation pathways, which have previously been implicated in several adult onset lung diseases. These findings are consistent with prior work on inflammatory processes and bioenergetics in prematurity. Conclusion: This study of gene expression of the newborn umbilical cord implicates the chromatin remodeling pathways in those premature infants who subsequently develop BPD. Larger sample sizes will be required to generate prognostic markers from umbilical cord profiles.
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    Cognitive Functioning at Age 10 Years Among Children Born Extremely Preterm: A Latent Profile Approach
    (2017) Heeren, Timothy; Joseph, Robert M.; Allred, Elizabeth N.; O'Shea, Thomas M.; Leviton, Alan; Kuban, Karl C. K.
    Background: School-age children born extremely preterm (EP) are more likely than their term peers to have multiple neurocognitive limitations. We identify subgroups of EP children who share similar profiles on measures of IQ and executive function (EF), and describe the nature and prevalence of cognitive impairment in EP children. Methods: Based on measures of IQ and EF, subgroups of EP children with common neurocognitive function are identified using latent profile analysis (LPA). Based on these subgroups, we describe the nature and prevalence of impairment in EP children, and examine associations between cognitive function, gestational age, and academic achievement. Classification of neurocognitive function using IQ and EF is compared to a standard classification based on IQ z-scores. Results: 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 the low-normal group tended to have impaired inhibition relative to their reasoning and working memory skills. Conclusion: Within categories of EP children defined in terms of IQ, there is substantial variation in EF; thus both IQ and EF assessments are needed when describing school-age outcome of EP children.