672 - Epigenetic Age and Neurodevelopmental Outcomes in Children Born Preterm

Publication Number: 672.4713

Rhandi Christensen, The Hospital for Sick Children, Toronto, ON, Canada; Vann Chau, The Hospital for Sick Children, Toronto, ON, Canada; Anne Synnes, University of British Columbia Faculty of Medicine, Salt Spring island, BC, Canada; Ting Guo, The Hospital for Sick Children, Toronto, ON, Canada; Michael S.. Kobor, University of British Columbia - Department of Medical Genetics, Vancouver, BC, Canada; Ruth Grunau, University of British Columbia Faculty of Medicine, Vancouver, BC, Canada; Steven Miller, University of British Columbia Faculty of Medicine, Vancouver, BC, Canada

Background: Previous studies report epigenetic changes in children born preterm, however predictors of epigenetic age and its association with neurodevelopmental outcomes remain unclear.

Objective: To identify predictors of epigenetic age in children born preterm and to examine the association between epigenetic age and neurodevelopmental outcomes.

Design/Methods: Participants were selected from a prospective cohort of children born preterm (24-32 weeks gestation), well characterized with clinical data, brain MRI, and developmental assessments. From this cohort participants with buccal cell DNA collected at term-equivalent age or 3 years were included (N=105). Epigenetic age (in weeks) was determined using the Pediatric Buccal Epigenetic Clock, using the Illumina platform. Epigenetic age difference (EAD) was calculated by subtracting chronological age from epigenetic age. EAD was used in the analysis to control for variability in participant age. Associations between EAD and factors such as sex, prematurity (extreme vs. very preterm), neonatal morbidities (infection, retinopathy of prematurity [ROP], bronchopulmonary dysplasia, severe brain injury) and neurodevelopmental outcomes at 3 years (Bayley-III) were assessed using multivariable linear regression, controlling for buccal cell proportion.

Results: EAD showed a positive linear association with chronological age at term-equivalent and 3 years of age. Neonatal morbidity was associated with a lower EAD at 3 years (β=-10.8, p=0.03). Sex modified the association between term-equivalent EAD and extreme prematurity (p=0.05) and ROP (p=0.03), with males born extremely preterm or with ROP having a higher EAD (Figure 1). Sex modified the association between 3 year EAD and infection, with males with infection having a higher EAD (p=0.08, Figure 1). EAD at 3 years was associated with cognitive (β=0.1, p=0.003), language (β=0.1, p=0.04) and motor (β=-0.2 p=0.001) scores at 3 years, with a higher EAD being associated with better outcomes (Figure 2).

Conclusion(s): Children born preterm have increasing epigenetic age with advancing chronological age. Higher epigenetic age was associated with better neurodevelopmental outcomes. Neonatal morbidities were associated with lower epigenetic age. However, males born extremely preterm or with neonatal morbidities had a higher epigenetic age, which may reflect an adaptive response to the environmental stressors of prematurity. Epigenetic age, along with established risk factors, contributes to the variability in neurodevelopmental outcomes in children born preterm.

Figure 1 - Sex Differences in Epigenetic Age
Higher epigenetic age in males born extremely preterm (A), in males with retinopathy of prematurity (B), and in males with infection (C).

Figure 2 – Predictors of Neurodevelopmental Outcomes in Children Born Preterm
Epigenetic age is a predictors of cognitive (A), language (B), and motor (C) scores at 3 years in children born preterm. Graphs show the standardized beta coefficients for the independent variables in the linear regression models. × Denotes statistically significant variable.