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.

PubMed Link

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.

Placental epigenetic gestational aging in relation to maternal sociodemographic factors and smoking among infants born extremely preterm: a descriptive study

Clark J, Bulka CM, Martin CL, Roell K, Santos HP Jr., O’Shea TM, Smeester L, Fry RC, Dhingra R.

Epigenetics. 2022 Sep 22;1-15. doi: 10.1080/15592294.2022.2125717. Online ahead of print. PMID: 36134874

PubMed Link Social determinants of health (SDoH) are defined as the conditions in which people are born, grow, live, work, and age. The distribution of these conditions is influenced by underlying structural factors and may be linked to adverse pregnancy outcomes through epigenetic modifications of gestational tissues. A promising modification is epigenetic gestational age (eGA), which captures ‘biological’ age at birth. Measuring eGA in placenta, an organ critical for foetal development, may provide information about how SDoH ‘get under the skin’ during pregnancy to influence birth outcomes and ethnic/racial disparities. We examined relationships of placental eGA with sociodemographic factors, smoking, and two key clinical outcomes: Apgar scores and NICU length of stay. Using the Robust Placental Clock, we estimated eGA for placental samples from the Extremely Low Gestational Age Newborns cohort (N = 408). Regression modelling revealed smoking during pregnancy was associated with placental eGA acceleration (i.e., eGA higher than chronologic gestational age). This association differed by maternal race: among infants born to mothers racialized as Black, we observed greater eGA acceleration (+0.89 week, 95% CI: 0.38, 1.40) as compared to those racialized as white (+0.27 week, 95% CI: -0.06, 0.59). Placental eGA acceleration was also correlated with shorter NICU lengths of stay, but only among infants born to mothers racialized as Black (-0.08 d/week-eGA, 95% CI: -0.12, -0.05). Together, these observed associations suggest that interpretations of epigenetic gestational aging may be tissue-specific.

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.

Frontiers Epidemiology 2022 (accepted)


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.

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

PubMed Link 

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.

Growth during infancy after extremely preterm birth: Associations with later neurodevelopmental and health outcomes

O'Shea TM, Register HM, Yi JX, Jensen ET, Joseph RM, Kuban KCK, Frazier JA, Washburn L, Belfort M, South AM, Santos HP Jr, Shenberger J, Perrin EM, Thompson AL, Singh R, Rollins J, Gogcu S, Sanderson K, Wood C, Fry RC; ELGAN-ECHO Pulmonary/Obesity Group

J Pediatr. 2022 Aug 18:S0022-3476(22)00724-7. doi: 10.1016/j.jpeds.2022.08.015. Epub ahead of print. PMID: 35987367.

PubMed Link

Objective: To evaluate associations between changes in weight, length, and weight/length ratio during infancy and outcomes later in life among individuals born extremely preterm.

Study design: Among participants in the Extremely Low Gestational Age Newborn (ELGAN) study, we measured weight and length at discharge from the neonatal intensive care unit (NICU) and at age 2 years and evaluated neurocognitive, psychiatric, and health outcomes at age 10 years and 15 years. Using multivariable logistic regression, we estimated associations between gains in weight, length, and weight/length ratio z-scores between discharge and 2 years and outcomes at 10 and 15 years. High gain was defined as the top quintile of change; low gain, as the bottom quintile of change.

Results: High gains in weight and weight/length were associated with greater odds of obesity at 10 years, but not at 15 years. These associations were found only for females. High gain in length z-score was associated with lower odds of obesity at 15 years. The only association found between high gains in growth measures and more favorable neurocognitive or psychiatric outcomes was between high gain in weight/length and lower odds of cognitive impairment at age 10 years.

Conclusions: During the 2 years after NICU discharge, females born extremely preterm with high gains in weight/length or weight have greater odds of obesity at 10 years, but not at 15 years. Infants with high growth gains in the 2 years after NICU discharge have neurocognitive and psychiatric outcomes in middle childhood and adolescence similar to those of infants with lower gains in weight and weight/length.

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.

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.

PubMed Link

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.

CpG Methylation Patterns in Placenta and Neonatal Blood are Differentially Associated with Neonatal Inflammation

Eaves LA, Enggasser AE, Camerota M, Gogcu S, Gower WA, Hartwell H, Jackson WM, Jensen E, Joseph RM, Marsit CJ, Roell K, Santos HP Jr, Shenberger JS, Smeester L, Yanni D, Kuban KCK, O'Shea TM, Fry RC.

Pediatr Res. 2022 Jun 28. doi: 10.1038/s41390-022-02150-4. Epub ahead of print. PMID: 35764815.

PubMed Link

Background: Infants born extremely premature are at increased risk for health complications later in life for which neonatal inflammation may be a contributing biological driver. Placental CpG methylation provides mechanistic information regarding the relationship between prenatal epigenetic programming, prematurity, neonatal inflammation, and later-in-life health.

Methods: We contrasted CpG methylation in the placenta and neonatal blood spots in relation to neonatal inflammation in the Extremely Low Gestational Age Newborn (ELGAN) cohort. Neonatal inflammation status was based on the expression of six inflammation-related proteins, assessed as (1) day-one inflammation (DOI) or (2) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 postnatal weeks). Epigenome-wide CpG methylation was assessed in 354 placental samples and 318 neonatal blood samples.

Results: Placental CpG methylation displayed the strongest association with ISSI (48 CpG sites) but was not associated with DOI. This was in contrast to CpG methylation in blood spots, which was associated with DOI (111 CpG sites) and not with ISSI (one CpG site).

Conclusions: Placental CpG methylation was strongly associated with ISSI, a measure of inflammation previously linked to later-in-life cognitive impairment, while day-one neonatal blood methylation was associated with DOI.

Impact: Neonatal inflammation increases the risk of adverse later-life outcomes, especially in infants born extremely preterm. CpG methylation in the placenta and neonatal blood spots were evaluated in relation to neonatal inflammation assessed via circulating proteins as either (i) day-one inflammation (DOI) or (ii) intermittent or sustained systemic inflammation (ISSI, inflammation on ≥2 days in the first 2 weeks). Tissue specificity was observed in epigenetic-inflammatory relationships: placental CpG methylation was associated with ISSI, neonatal blood CpG methylation was associated with DOI. Supporting the placental origins of disease framework, placental epigenetic patterns are associated with a propensity for ISSI in neonates.