ELGAN-ECHO Study Investigators. Long-Term Outcome of Necrotizing Enterocolitis and Spontaneous Intestinal Perforation
Vaidya R, Yi JX, O'Shea TM, Jensen ET, Joseph RM, Shenberger J, Gogcu S, Wagner K, Msall ME, Thompson AL, Frazier JA, Fry R, Singh R; ELGAN-ECHO Study Investigators.
Pediatrics. 2022 Nov 1;150(5):e2022056445. doi: 10.1542/peds.2022-056445. PMID: 36200375; PMCID: PMC9647591.
Abstract
Objectives: Necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) are complications in preterm infants associated with high morbidity, mortality, impaired growth, and neurodevelopmental (ND) outcomes. Few studies have reported growth or ND outcomes of infants born extremely preterm with NEC/SIP beyond early childhood. Here, we compared anthropometric and ND outcomes, at 10 and 15 years, for children with medical NEC, surgical NEC, SIP, and neither NEC nor SIP.
Methods: Participants from the prospective longitudinal extremely low gestational age newborns study were evaluated at ages 10 and 15 years for anthropometrics, neurocognition, attention-deficit/hyperactivity disorder, epilepsy, and gross motor function.
Results: At age 10 years, 889 children were followed-up (medical NEC = 138, surgical NEC = 33, SIP = 29, no NEC/SIP = 689), and 694 children were followed up-at 15 years. Children with medical NEC had similar weight, BMI, height, and head circumference compared with controls at both 10 and 15 years. At 15 years, children with surgical NEC had lower weight z-score (adjusted β: -0.75, 95% confidence interval [CI]: -1.25 to -0.25), lower BMI z-score (adjusted β: -0.55, 95% CI: -1.09 to -0.01), and lower height z-score (adjusted β: -0.65, 95% CI: -1.16 to -0.14). Children with SIP had lower weight and height z-scores at age 10 years when adjusted for sample attrition, but these differences were not significant when adjusted for confounders. We observed no differences in long-term ND outcomes.
Conclusions: Surgical NEC- and SIP-associated growth impairment may persist through late childhood. ND outcomes among school-aged children born extremely preterm with any NEC or SIP are no different from children without NEC/SIP.
Analysis of neurodevelopment in children born extremely preterm treated with acid suppressants before age 2 years
Jensen ET, Yi, J, Jackson W, Singh R, Joseph RM, Kuban KCK, Msall M, Washburn LK, Fry RC, South AM, O’Shea TM
JAMA Network Open 2022 Nov 1;5(11):e2241943. doi: 10.1001/jamanetworkopen.2022.41943
Placental transcriptional signatures associated with cerebral white matter damage in the neonate
Marable CA, Roell K, Kuban KCK, O’Shea TM, Fry RC
Frontiers in Neuroscience - Neuroendocrine Science 2022 Oct 28;16:1017953. doi: 10.3389/fnins.2022.1017953
Association of prenatal modifiable risk factors with ADHD outcomes at age 10 and 15 in an extremely low gestational age cohort
Cochran DM, Jensen ET, Frazier JA, Jalnapurkar I, Kim, Sohye, Roell R, Joseph RM, Hooper Sr, Santos HP Jr, Kuban KCK, Fry RC, O’Shea TM
Frontiers in Human Neuroscience – Brain Health and Clinical Neuroscience 2022 Oct 20;16:911098. doi: 10.3389/fnhum.2022.911098
Caregivers’ perception of the role of the socio-environment on their extremely preterm child’s well-being
Emmanuel CJ, Knafl K, Hodges EA, Docherty SL, Wereszczak JK, Rollins RV, Fry RC, O’Shea TM, Santos HP Jr.
J Pediatr Nurs. 2022 Sep-Oct;66:36-43. doi: 10.1016/j.pedn.2022.05.005. Epub 2022 May 25. PMID: 35623186; PMCID: PMC9427705.
Purpose: The purpose of this qualitative descriptive study was to explore primary caregivers’ perception of how social-environmental characteristics, and their own role as primary caregivers, affected their extremely preterm adolescent’s well-being.
Methods: Participants were 20 mothers who identified as the primary caregiver of an adolescent born extremely prematurely (<28 weeks gestation) enrolled in the ELGAN cohort study. Data was collected through individual interviews and was analyzed using inductive content analysis.
Results: A total of three themes, and five subthemes, were identified. The two main themes were “familial impact to health and well-being,” and “contributors and barriers at the community level.” This study described specific familial and community contributors to child and caregiver well-being, including: the importance of advocacy, participating in community activities, and social and familial support networks.
Conclusions: Overall, while there are individual level characteristics that contribute to well-being, a support structure at the family and community level is essential to children born extremely prematurely, and their mother’s, well-being.
Practice implications: Healthcare providers caring for these families should understand that not only are extremely preterm youth affected by prematurity, but caregivers are also deeply impacted. Therefore, it is essential that maternal and family care is emphasized by nurses and healthcare providers.
Prenatal Exposure to Multiple Metallic and Metalloid Trace Elements and the Risk of Bacterial Sepsis in Extremely Low Gestational Age Newborns: A Prospective Cohort Study
Bulka CM, Eaves LA, Gardner AJ, Parsons PJ, Galusha AL, Roell KR, Smeester L, O’Shea TM, Fry RC.
Front Epidemiol. 2022;2:958389. doi: 10.3389/fepid.2022.958389. Epub 2022 Sep 7. PMID: 36405975; PMCID: PMC9674331.
Background: Prenatal exposures to metallic and metalloid trace elements have been linked to altered immune function in animal studies, but few epidemiologic studies have investigated immunological effects in humans. We evaluated the risk of bacterial sepsis (an extreme immune response to bacterial infection) in relation to prenatal metal/metalloid exposures, individually and jointly, within a US-based cohort of infants born extremely preterm.
Methods: We analyzed data from 269 participants in the US-based ELGAN cohort, which enrolled infants delivered at <28 weeks’ gestation (2002–2004). Concentrations of 8 trace elements—including 4 non-essential and 4 essential—were measured using inductively coupled plasma tandem mass spectrometry in umbilical cord tissue, reflecting in utero fetal exposures. The infants were followed from birth to postnatal day 28 with bacterial blood culture results reported weekly to detect sepsis. Discrete-time hazard and quantile g-computation models were fit to estimate associations for individual trace elements and their mixtures with sepsis incidence.
Results: Approximately 30% of the extremely preterm infants developed sepsis during the follow-up period (median follow-up: 2 weeks). After adjustment for potential confounders, no trace element was individually associated with sepsis risk. However, there was some evidence of a non-monotonic relationship for cadmium, with hazard ratios (HRs) for the second, third, and fourth (highest) quartiles being 1.13 (95% CI: 0.51–2.54), 1.94 (95% CI: 0.87–4.32), and 1.88 (95% CI: 0.90–3.93), respectively. The HRs for a quartile increase in concentrations of all 8 elements, all 4 non-essential elements, and all 4 essential elements were 0.92 (95% CI: 0.68–1.25), 1.19 (95% CI: 0.92–1.55), and 0.77 (95% CI: 0.57–1.06). Cadmium had the greatest positive contribution whereas arsenic, copper, and selenium had the greatest negative contributions to the mixture associations.
Conclusions: We found some evidence that greater prenatal exposure to cadmium was associated with an increased the risk of bacterial sepsis in extremely preterm infants. However, this risk was counteracted by a combination of arsenic, copper, and selenium. Future studies are needed to confirm these findings and to evaluate the potential for nutritional interventions to prevent sepsis in high-risk infants.
Changes in BMI During the COVID-19 Pandemic
Knapp EA, Dong Y, Dunlop AL, Aschner JL, Stanford JB, Hartert T, Teitelbaum SL, Hudak ML, Carroll K, O'Connor TG, McEvoy CT, O'Shea TM, Carnell S, Karagas MR, Herbstman JB, Dabelea D, Ganiban JM, Ferrara A, Hedderson M, Bekelman TA, Rundle AG, Alshawabkeh A, Gilbert-Diamond D, Fry RC, Chen Z, Gilliland FD, Wright RJ, Camargo CA, Jacobson L, Lester BM, Hockett CW, Hodges ML, Chandran A; Environmental Influences on Child Health Outcomes.
Pediatrics. 2022 Sep 1;150(3):e2022056552. doi: 10.1542/peds.2022-056552. PMID: 35768891; PMCID: PMC9444980.
Abstract
Background and objectives: Experts hypothesized increased weight gain in children associated with the coronavirus disease 2019 (COVID-19) pandemic. Our objective was to evaluate whether the rate of change of child body mass index (BMI) increased during the COVID-19 pandemic compared with prepandemic years.
Methods: The study population of 1996 children ages 2 to 19 years with at least 1 BMI measure before and during the COVID-19 pandemic was drawn from 38 pediatric cohorts across the United States participating in the Environmental Influences on Child Health Outcomes-wide cohort study. We modeled change in BMI using linear mixed models, adjusting for age, sex, race, ethnicity, maternal education, income, baseline BMI category, and type of BMI measure. Data collection and analysis were approved by the local institutional review board of each institution or by the central Environmental Influences on Child Health Outcomes institutional review board.
Results: BMI increased during the COVID-19 pandemic compared with previous years (0.24 higher annual gain in BMI during the pandemic compared with previous years, 95% confidence interval 0.02 to 0.45). Children with BMI in the obese range compared with the healthy weight range were at higher risk for excess BMI gain during the pandemic, whereas children in higher-income households were at decreased risk of BMI gain.
Conclusions: One effect of the COVID-19 pandemic is an increase in annual BMI gain during the COVID-19 pandemic compared with the 3 previous years among children in our national cohort. This increased risk among US children may worsen a critical threat to public health and health equity.
Quantitative MRI Characterization of the Extremely Preterm Brain at Adolescence: Atypical vs Neurotypical Developmental Pathways
McNaughton R, Pieper C, Sakai O, Rollins JV, Zhang X, Kennedy DN, Frazier JA, Douglass L, Heeren T, Fry RC, O'Shea TM, Kuban KK, Jara H; ELGAN-ECHO Study Investigators.
Radiology. 2022 Aug;304(2):419-428. doi: 10.1148/radiol.210385. Epub 2022 Apr 26. PMID: 35471112; PMCID: PMC9340244
Background Extremely preterm (EP) birth is associated with higher risks of perinatal white matter (WM) injury, potentially causing abnormal neurologic and neurocognitive outcomes. MRI biomarkers distinguishing individuals with and without neurologic disorder guide research on EP birth antecedents, clinical correlates, and prognoses. Purpose To compare multiparametric quantitative MRI (qMRI) parameters of EP-born adolescents with autism spectrum disorder, cerebral palsy, epilepsy, or cognitive impairment (ie, atypically developing) with those without (ie, neurotypically developing), characterizing sex-stratified brain development. Materials and Methods This prospective multicenter study included individuals aged 14-16 years born EP (Extremely Low Gestational Age Newborns-Environmental Influences on Child Health Outcomes Study, or ELGAN-ECHO). Participants underwent 3.0-T MRI evaluation from 2017 to 2019. qMRI outcomes were compared for atypically versus neurotypically developing adolescents and for girls versus boys. Sex-stratified multiple regression models were used to examine associations between spatial entropy density (SEd) and T1, T2, and cerebrospinal fluid (CSF)-normalized proton density (nPD), and between CSF volume and T2. Interaction terms modeled differences in slopes between atypically versus neurotypically developing adolescents. Results A total of 368 adolescents were classified as 116 atypically (66 boys) and 252 neurotypically developing (125 boys) participants. Atypically versus neurotypically developing girls had lower nPD (mean, 557 10 × percent unit [pu] ± 46 [SD] vs 573 10 × pu ± 43; P = .04), while atypically versus neurotypically developing boys had longer T1 (814 msec ± 57 vs 789 msec ± 82; P = .01). Atypically developing girls versus boys had lower nPD and shorter T2 (eg, in WM, 557 10 × pu ± 46 vs 580 10 × pu ± 39 for nPD [P = .006] and 86 msec ± 3 vs 88 msec ± 4 for T2 [P = .003]). Atypically versus neurotypically developing boys had a more moderate negative association between T1 and SEd (slope, -32.0 msec per kB/cm3 [95% CI: -49.8, -14.2] vs -62.3 msec per kB/cm3 [95% CI: -79.7, -45.0]; P = .03). Conclusion Atypically developing participants showed sexual dimorphisms in the cerebrospinal fluid-normalized proton density (nPD) and T2 of both white matter (WM) and gray matter. Atypically versus neurotypically developing girls had lower WM nPD, while atypically versus neurotypically developing boys had longer WM T1 and more moderate T1 associations with microstructural organization in WM. © RSNA, 2022 Online supplemental material is available for this article.
Environmental influences on child health outcomes: cohorts of individuals born very preterm
O'Shea TM, McGrath M, Aschner JL, Lester B, Santos HP Jr, Marsit C, Stroustrup A, Emmanuel C, Hudak M, McGowan E, Patel S, Fry RC; program collaborators for Environmental influences on Child Health Outcomes.
Pediatr Res. 2022 Aug 10:1–16. doi: 10.1038/s41390-022-02230-5. Epub ahead of print. PMID: 35948605
PubMed Link The National Institutes of Health’s Environmental influences on Child Health Outcomes (ECHO) Program was designed to address solution-oriented research questions about the links between children’s early life environment and their risks of pre-, peri-, and post-natal complications, asthma, obesity, neurodevelopmental disorders, and positive health. Children born very preterm are at increased risk for many of the outcomes on which ECHO focuses, but the contributions of environmental factors to this risk are not well characterized. Three ECHO cohorts consist almost exclusively of individuals born very preterm. Data provided to ECHO from cohorts can be used to address hypotheses about (1) differential risks of chronic health and developmental conditions between individuals born very preterm and those born at term; (2) health disparities across social determinants of health; and (3) mechanisms linking early-life exposures and later-life outcomes among individuals born very preterm. IMPACT: The National Institutes of Health’s Environmental Influences on Child Health Outcomes Program is conducting solution-oriented research on the links between children’s environment and health. Three ECHO cohorts comprise study participants born very preterm; these cohorts have enrolled, to date, 1751 individuals born in 14 states in the U.S. in between April 2002 and March 2020. Extensive data are available on early-life environmental exposures and child outcomes related to neurodevelopment, asthma, obesity, and positive health. Data from ECHO preterm cohorts can be used to address questions about the combined effects of preterm birth and environmental exposures on child health outcomes.
The placenta epigenome-brain axis: placental epigenomic and transcriptomic responses that preprogram cognitive impairment
Freedman AN, Eaves LA, Rager JE, Gavino-Lopez N, Smeester L, Bangma J, Santos HP, Joseph RM, Kuban KC, O'Shea TM, Fry RC.
Epigenomics. 2022 Aug;14(15):897-911. doi: 10.2217/epi-2022-0061. Epub 2022 Sep 8. PMID: 36073148; PMCID: PMC9475498.
Abstract
Aim: The placenta-brain axis reflects a developmental linkage where disrupted placental function is associated with impaired neurodevelopment later in life. Placental gene expression and the expression of epigenetic modifiers such as miRNAs may be tied to these impairments and are understudied. Materials & methods: The expression levels of mRNAs (n = 37,268) and their targeting miRNAs (n = 2083) were assessed within placentas collected from the ELGAN study cohort (n = 386). The ELGAN adolescents were assessed for neurocognitive function at age 10 and the association with placental mRNA/miRNAs was determined. Results: Placental mRNAs related to inflammatory and apoptotic processes are under miRNA control and associated with cognitive impairment at age 10. Conclusion: Findings highlight key placenta epigenome-brain relationships that support the developmental origins of health and disease hypothesis.