Association of prenatal modifiable risk factors with attention-deficit hyperactivity disorder outcomes at age 10 and 15 in an extremely low gestational age cohort

Cochran DM, Jensen ET, Frazier JA, Jalnapurkar I, Kim S, Roell KR, Joseph RM, Hooper SR, Santos HP Jr, Kuban KCK, Fry RC, O'Shea TM.

Front Hum Neurosci. 2022 Oct 20;16:911098. doi: 10.3389/fnhum.2022.911098. PMID: 36337853; PMCID: PMC9630552.

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Background: The increased risk of developing attention-deficit hyperactivity disorder (ADHD) in extremely preterm infants is well-documented. Better understanding of perinatal risk factors, particularly those that are modifiable, can inform prevention efforts.

Methods: We examined data from the Extremely Low Gestational Age Newborns (ELGAN) Study. Participants were screened for ADHD at age 10 with the Child Symptom Inventory-4 (N = 734) and assessed at age 15 with a structured diagnostic interview (MINI-KID) to evaluate for the diagnosis of ADHD (N = 575). We studied associations of pre-pregnancy maternal body mass index (BMI), pregestational and/or gestational diabetes, maternal smoking during pregnancy (MSDP), and hypertensive disorders of pregnancy (HDP) with 10-year and 15-year ADHD outcomes. Relative risks were calculated using Poisson regression models with robust error variance, adjusted for maternal age, maternal educational status, use of food stamps, public insurance status, marital status at birth, and family history of ADHD. We defined ADHD as a positive screen on the CSI-4 at age 10 and/or meeting DSM-5 criteria at age 15 on the MINI-KID. We evaluated the robustness of the associations to broadening or restricting the definition of ADHD. We limited the analysis to individuals with IQ ≥ 70 to decrease confounding by cognitive functioning. We evaluated interactions between maternal BMI and diabetes status. We assessed for mediation of risk increase by alterations in inflammatory or neurotrophic protein levels in the first week of life.

Results: Elevated maternal BMI and maternal diabetes were each associated with a 55-65% increase in risk of ADHD, with evidence of both additive and multiplicative interactions between the two exposures. MSDP and HDP were not associated with the risk of ADHD outcomes. There was some evidence for association of ADHD outcomes with high levels of inflammatory proteins or moderate levels of neurotrophic proteins, but there was no evidence that these mediated the risk associated with maternal BMI or diabetes.

Conclusion: Contrary to previous population-based studies, MSDP and HDP did not predict ADHD outcomes in this extremely preterm cohort, but elevated maternal pre-pregnancy BMI, maternal diabetes, and perinatal inflammatory markers were associated with increased risk of ADHD at age 10 and/or 15, with positive interaction between pre-pregnancy BMI and maternal diabetes.

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.

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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.

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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.

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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

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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.

PubMed Link


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.

Sociodemographic Variation in Children’s Health Behaviors During the COVID-19 Pandemic

Bekelman TA, Knapp EA, Dong Y, Dabelea D, Bastain TM, Breton CV, Carroll KN, Camargo CA, Davis AM, Dunlop AL, Elliott AJ, Ferrara A, Fry RC, Ganiban JM, Gilbert-Diamond D, Gilliland FD, Hedderson MM, Hipwell AE, Hockett CW, Huddleston KC, Karagas MR, Kelly N, Lai JS, Lester BM, Lucchini M, Melough MM, Mihalopoulos NL, O'Shea TM, Rundle AG, Stanford JB, VanBronkhorst S, Wright RJ, Zhao Q, Sauder KA; program collaborators for Environmental influences on Child Health Outcomes (ECHO).

Child Obes. 2023 Jun;19(4):226-238. doi: 10.1089/chi.2022.0085. Epub 2022 Jul 19. PMID: 35856858.

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Background: Societal changes during the COVID-19 pandemic may affect children’s health behaviors and exacerbate disparities. This study aimed to describe children’s health behaviors during the COVID-19 pandemic, how they vary by sociodemographic characteristics, and the extent to which parent coping strategies mitigate the impact of pandemic-related financial strain on these behaviors. Methods: This study used pooled data from 50 cohorts in the Environmental influences on Child Health Outcomes Program. Children or parent proxies reported sociodemographic characteristics, health behaviors, and parent coping strategies. Results: Of 3315 children aged 3-17 years, 49% were female and 57% were non-Hispanic white. Children of parents who reported food access as a source of stress were 35% less likely to engage in a higher level of physical activity. Children of parents who changed their work schedule to care for their children had 82 fewer min/day of screen time and 13 more min/day of sleep compared with children of parents who maintained their schedule. Parents changing their work schedule were also associated with a 31% lower odds of the child consuming sugar-sweetened beverages. Conclusions: Parents experiencing pandemic-related financial strain may need additional support to promote healthy behaviors. Understanding how changes in parent work schedules support shorter screen time and longer sleep duration can inform future interventions.

Psychiatric Outcomes, Functioning, and Participation in Extremely Low Gestational Age Newborns at Age 15 Years

Frazier JA, Cochran D, Kim S, Jalnapurkar I, Joseph RM, Hooper SR, Santos HP Jr, Ru H, Venuti L, Singh R, Washburn LK, Gogcu S, Msall ME, Kuban KCK, Rollins JV, Hanson SG, Jara H, Pastyrnak SL, Roell KR, Fry RC, O'Shea TM; ELGAN Study Investigators.

J Am Acad Child Adolesc Psychiatry. 2022 Jul;61(7):892-904.e2. doi: 10.1016/j.jaac.2021.12.008. Epub 2021 Dec 29. PMID: 34973366; PMCID: PMC9240104.

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Objective: To evaluate the prevalence, co-occurrence, sex differences, and functional correlates of DSM-5 psychiatric disorders in 15-year-old adolescents born extremely preterm.

Method: The Extremely Low Gestational Age Newborns (ELGAN) Study is a longitudinal study of children born <28 weeks gestation. At age 15, 670 adolescents completed the Mini-International Neuropsychiatric Interview for Children and Adolescents (MINI-KID), the Youth Self-Report, a disability scale of participation in social roles, and cognitive testing. Parents completed a family psychiatric history questionnaire.

Results: The most prevalent psychiatric disorders were anxiety, attention-deficit/hyperactivity disorder, and major depression. More girls met criteria for anxiety than boys. Though 66% of participants did not meet criteria for a psychiatric disorder, 15% met criteria for 1, 9% for 2, and 8% for ≥3 psychiatric disorders. Participants with ≥2 psychiatric disorders were more likely to have repeated a grade, to have an individualized educational program, and to have a lower nonverbal IQ than those with no psychiatric disorders. Participants with any psychiatric disorder were more likely to use psychotropic medications; to have greater cognitive and functional impairment; and to have mothers who were single, were on public health insurance, and had less than a high school education. Finally, a positive family psychiatric history was identified more frequently among adolescents with ≥3 psychiatric disorders.

Conclusion: Among adolescents born extremely preterm, anxiety, major depression, and attention-deficit/hyperactivity disorder were the most prevalent psychiatric disorders at age 15. Adolescents with >1 psychiatric disorder were at increased risk for multiple functional and participatory challenges.

Family members’ experience of well-being as racial/ethnic minorities raising a child with a neurodevelopmental disorder: A qualitative meta-synthesis

Emmanuel CJ, Knafl KA, Hodges EA, Docherty SL, O'Shea TM, Santos HP Jr.

Res Nurs Health. 2022 Jun;45(3):314-326. doi: 10.1002/nur.22217. Epub 2022 Feb 10. PMID: 35141915.

PubMed Link Raising a child with a neurodevelopmental disorder has often been associated with poorer quality of life and family functioning. Yet, many family members describe themselves as resilient and capable of achieving well-being. Whether and how this occurs in racial/ethnic minority families remains largely unexplored. The aim of this study was to systematically synthesize qualitative studies exploring how families from a racial/ethnic minority background in the United States (1) experienced well-being and (2) responded to challenges they faced while caring for a child diagnosed with three selected neurodevelopmental disorders: autism spectrum disorder, attention deficit hyperactivity disorder, and intellectual disability. A systematic literature search was conducted in November and December of 2019 and updated in October 2021. Three themes were developed based on included studies: “moving toward well-being as a caregiver,” “family and culture: impact on well-being,” and “community and culture: impact on well-being.” The findings in this review indicate that to develop well-being, racial/ethnic minority families faced additional barriers, including racial/ethnic discrimination and stigma within their family and cultural community. The knowledge generated has the potential to identify areas of intervention to promote resilience and well-being in racial/ethnic minority families raising a child with a neurodevelopmental disorder.