Associations of DNA Methylation Mortality Risk Markers with Congenital Microcephaly from Zika Virus: A Study of Brazilian Children Less than 4 Years of Age.

BACKGROUND: Zika virus (ZIKV)-associated congenital microcephaly is an important contributor to pediatric death, and more robust pediatric mortality risk metrics are needed to help guide life plans and clinical decision making for these patients. Although common etiologies of pediatric and adult mortality differ, early life health can impact adult outcomes-potentially through DNA methylation. Hence, in this pilot study, we take an early step in identifying pediatric mortality risk metrics by examining associations of ZIKV infection and associated congenital microcephaly with existing adult DNA methylation-based mortality biomarkers: GrimAge and Zhang's mortality score (ZMS). METHODS: Mortality measures were calculated from previously published HumanMethylationEPIC BeadChip data from 44 Brazilian children aged 5-40 months (18 with ZIKV-associated microcephaly; 7 normocephalic, exposed to ZIKV in utero; and 19 unexposed controls). We used linear models adjusted for chronological age, sex, methylation batch and white blood cell proportions to evaluate ZIKV and mortality marker relationships. RESULTS: We observed significant decreases in GrimAge-component plasminogen activator inhibitor-1 [PAI-1; ß = -2453.06 pg/ml, 95% confidence interval (CI) -3652.96, -1253.16, p = 0.0002], and ZMS-site cg14975410 methylation (ß = -0.06, 95% CI -0.09, -0.03, p = 0.0003) among children with microcephaly compared to controls. PAI-1 (ß = -2448.70 pg/ml, 95% CI -4384.45, -512.95, p = 0.01) and cg14975410 (ß = 0.01, 95% CI -0.04, 0.06, p = 0.64) results in comparisons of normocephalic, ZIKV-exposed children to controls were not statistically significant. CONCLUSION: Our results suggest that elements of previously-identified adult epigenetic markers of mortality risk are associated with ZIKV-associated microcephaly, a known contributor to pediatric mortality risk. These findings may provide insights for efforts aimed at developing pediatric mortality markers.

Associations of PM2.5 exposure with emergency department visits and readmissions among preterm infants with bronchopulmonary dysplasia.

OBJECTIVES: To quantify the association of ambient air pollution (particulate matter, PM2.5) exposure with medically attended acute respiratory illness among infants with bronchopulmonary dysplasia (BPD). STUDY DESIGN: Single center, retrospective cohort study of preterm infants with BPD in Metropolitan Philadelphia. Multivariable logistic regression quantified associations of annual mean PM2.5 exposure (per µg/m3) at the census block group level with medically attended acute respiratory illness, defined as emergency department (ED) visits or hospital readmissions within a year after first hospital discharge adjusting for age at neonatal intensive care unit (NICU) discharge, year, sex, race, insurance, BPD severity, and census tract deprivation. As a secondary analysis, we examined whether BPD severity modified the associations. RESULTS: Of the 378 infants included in the analysis, 189 were non-Hispanic Black and 235 were publicly insured. Census block PM2.5 level was not significantly associated with medically attended acute respiratory illnesses, ED visits, or hospital readmissions in the full study cohort. We observed significant effect modification by BPD grade; each 1 µg/m3 higher annual PM2.5 exposure was medically attended acute respiratory illness (adjusted odds ratio [aOR] 1.65, 95% CI: 1.06-2.63) among infants with Grade 1 BPD but not among infants with grade 3 BPD (aOR 0.83, 95% CI: 0.47-1.48) (interaction p = .024). CONCLUSIONS: Cumulative PM2.5 exposure in the year after NICU discharge was not significantly associated with medically attended acute respiratory illness among infants with BPD. However, infants with Grade 1 BPD had significantly higher odds with higher exposures. If replicated, these findings could inform anticipatory guidance for families of these infants to avoid outdoor activities during high pollution days after NICU discharge.

Environmental Determinants of Post-Discharge Acute Respiratory Illness among Preterm Infants with Bronchopulmonary Dysplasia.

OBJECTIVE: To analyze the association of components of the Centers for Disease Control and Prevention (CDC) Environmental Justice Index (EJI) with respiratory health outcomes among infants with bronchopulmonary dysplasia (BPD) within one year after discharge from the neonatal intensive care unit. METHODS: This was a retrospective cohort study of a cohort of preterm infants with BPD. Multivariable logistic regression models estimated associations of EJI and its components with medically attended acute respiratory illness, defined as an ED visit or inpatient readmission, within one year of discharge from the neonatal intensive care unit. A mediation analysis was conducted to evaluate how environmental injustice may contribute to racial disparities in acute respiratory illness. RESULTS: Greater EJI was associated with an increased risk of medically attended respiratory illness (per EJI standard deviation increment, aOR 1.38, 95% CI: 1.12-1.69). Of the index's components, the Environmental Burden Module's Air pollution domain had the greatest association (aOR 1.44, 95% CI: 1.44-2.61). With respect to individual indicators within the EJI, Diesel Particulate Matter (DSLPM) and Air Toxic Cancer Risk (ATCR) demonstrated the strongest relationship (aOR 2.06, 95% CI: 1.57-2.71 and aOR 2.10, 95% CI: 1.59-2.78, respectively). Among non-Hispanic Black infants, 63% experienced a medically attended acute respiratory illness as compared to 18% of non-Hispanic White infants. DSLPM mediated 39% of the Black-White disparity in medically attended acute respiratory illness (p = 0.004). CONCLUSIONS: Environmental exposures, particularly air pollution, are associated with post-discharge respiratory health outcomes among preterm infants with BPD after adjusting for clinical, demographic, and social vulnerability risk factors. Certain types of air pollutants, namely, DSLPM, are more greatly associated with acute respiratory illness. Environmental exposures may contribute to racial disparities in medically attended acute respiratory illness among infants with BPD.

Place-Based Strategies Addressing Neighborhood Environments to Improve Perinatal and Preterm Infant Outcomes.

Preterm birth (defined as birth <37 weeks of gestation) is a significant health concern globally, with lasting implications for individuals, families, and society. In the United States, high preterm birth rates among Black and low-income populations likely result from differences in environmental exposures. Structural racism and economic disadvantage have led to unequal distribution of polluting industrial sites and roadways across society as well as differential access to health-promoting resources which contribute to preterm birth risk. Once born, preterm infants remain at risk for numerous environmentally responsive adverse health outcomes that affect growth and development throughout childhood and adulthood. In this commentary, we describe associations of neighborhood environments with pregnancy and preterm infant health outcomes and propose strategies to address harmful exposures that affect families across the lifespan.