Antenatal glucocorticoids and neonatal inflammation-associated proteins
Maheer Faden, Mari Holm, Elizabeth Allred, Raina Fichorova, Olaf Dammann, Alan Leviton, ELGAN Study Investigators
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.
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
Robert M Joseph, Steven J Korzeniewski, Elizabeth N Allred, T Michael O'Shea, Tim Heeren, Jean A Frazier, Janice Ware, Deborah Hirtz, Alan Leviton, Karl Kuban, ELGAN Study Investigators
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.
Predictive Validity of the Modified Checklist for Autism in Toddlers (M-CHAT) Born Very Preterm
So Hyun Kim, Robert M Joseph, Jean A Frazier, Thomas M O'Shea, Katarzyna Chawarska, Elizabeth N Allred, Alan Leviton, Karl K Kuban, Extremely Low Gestational Age Newborn (ELGAN) Study Investigators
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.
Circulating Inflammatory-Associated Proteins in the First Month of Life and Cognitive Impairment at Age 10 Years in Children Born Extremely Preterm
Karl C K Kuban, Robert M Joseph, Thomas M O'Shea, Timothy Heeren, Raina N Fichorova, Laurie Douglass, Hernan Jara, Jean A Frazier, Deborah Hirtz, Julie Vanier Rollins, Nigel Paneth, Extremely Low Gestational Age Newborn (ELGAN) Study Investigators
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).
Systemic endogenous erythropoietin and associated disorders in extremely preterm newborns
Mari Holm, Jon Skranes, Olaf Dammann, Raina N Fichorova, Elizabeth N Allred, Alan Leviton
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.
Girls and Boys Born before 28 Weeks Gestation: Risks of Cognitive, Behavioral, and Neurologic Outcomes at Age 10 Years
Karl C K Kuban, Robert M Joseph, Thomas M O'Shea, Elizabeth N Allred, Timothy Heeren, Laurie Douglass, Carl E Stafstrom, Hernan Jara, Jean A Frazier, Deborah Hirtz, Alan Leviton, Extremely Low Gestational Age Newborn (ELGAN) Study Investigators
J Pediatr. 2016 Jun;173:69-75.e1. doi: 10.1016/j.jpeds.2016.02.048. Epub 2016 Mar 19.
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.
Prevalence and associated features of autism spectrum disorder in extremely low gestational age newborns at age 10 years
Robert M Joseph, Thomas M O'Shea, Elizabeth N Allred, Tim Heeren, Deborah Hirtz, Nigel Paneth, Alan Leviton, Karl C K Kuban
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.
The antecedents and correlates of necrotizing enterocolitis and spontaneous intestinal perforation among infants born before the 28th week of gestation
R Singh, B Shah, E N Allred, M Grzybowski, C R Martin, A Leviton, ELGAN Study co-investigators
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.
Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns
Robert M Joseph, Thomas M O'Shea, Elizabeth N Allred, Tim Heeren, Deborah Hirtz, Hernan Jara, Alan Leviton, Karl C K Kuban, ELGAN Study Investigators
Pediatrics. 2016 Apr;137(4):e20154343. doi: 10.1542/peds.2015-4343. Epub 2016 Mar 22.
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.
Duration of Systemic Inflammation in the First Postnatal Month Among Infants Born Before the 28th Week of Gestation
Olaf Dammann, Elizabeth N Allred, Raina N Fichorova, Karl Kuban, T Michael O'Shea, Alan Leviton, ELGAN Study Investigators
Inflammation. 2016 Apr;39(2):672-7. doi: 10.1007/s10753-015-0293-z.
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.