Association of Pediatric Buccal Epigenetic Age Acceleration With Adverse Neonatal Brain Growth and Neurodevelopmental Outcomes Among Children Born Very Preterm With a Neonatal Infection

Abstract

ImportanceVery preterm neonates (24-32 weeks’ gestation) remain at a higher risk of morbidity and neurodevelopmental adversity throughout their lifespan. Because the extent of prematurity alone does not fully explain the risk of adverse neonatal brain growth or neurodevelopmental outcomes, there is a need for neonatal biomarkers to help estimate these risks in this population.ObjectivesTo characterize the pediatric buccal epigenetic (PedBE) clock—a recently developed tool to measure biological aging—among very preterm neonates and to assess its association with the extent of prematurity, neonatal comorbidities, neonatal brain growth, and neurodevelopmental outcomes at 18 months of age.Design, Setting, and ParticipantsThis prospective cohort study was conducted in 2 neonatal intensive care units of 2 hospitals in Toronto, Ontario, Canada. A total of 35 very preterm neonates (24-32 weeks’ gestation) were recruited in 2017 and 2018, and neuroimaging was performed and buccal swab samples were acquired at 2 time points: the first in early life (median postmenstrual age, 32.9 weeks [IQR, 32.0-35.0 weeks]) and the second at term-equivalent age (TEA) at a median postmenstrual age of 43.0 weeks (IQR, 41.0-46.0 weeks). Follow-ups for neurodevelopmental assessments were completed in 2019 and 2020. All neonates in this cohort had at least 1 infection because they were originally enrolled to assess the association of neonatal infection with neurodevelopment. Neonates with congenital malformations, genetic syndromes, or congenital TORCH (toxoplasmosis, rubella, cytomegalovirus, herpes and other agents) infection were excluded.ExposuresThe extent of prematurity was measured by gestational age at birth and PedBE age difference. PedBE age was computed using DNA methylation obtained from 94 age-informative CpG (cytosine-phosphate-guanosine) sites. PedBE age difference (weeks) was calculated by subtracting PedBE age at each time point from the corresponding postmenstrual age.Main Outcomes and MeasuresTotal cerebral volumes and cerebral growth during the neonatal intensive care unit period were obtained from magnetic resonance imaging scans at 2 time points: approximately the first 2 weeks of life and at TEA. Bayley Scales of Infant and Toddler Development, Third Edition, were used to assess neurodevelopmental outcomes at 18 months.ResultsAmong 35 very preterm neonates (21 boys [60.0%]; median gestational age, 27.0 weeks [IQR, 25.9-29.9 weeks]; 23 [65.7%] born extremely preterm [<28 weeks’ gestation]), extremely preterm neonates had an accelerated PedBE age compared with neonates born at a later gestational age (β = 9.0; 95% CI, 2.7-15.3; P = .01). An accelerated PedBE age was also associated with smaller cerebral volumes (β = –5356.8; 95% CI, −6899.3 to −2961.7; P = .01) and slower cerebral growth (β = –2651.5; 95% CI, −5301.2 to −1164.1; P = .04); these associations remained significant after adjusting for clinical neonatal factors. These findings were significant at TEA but not earlier in life. Similarly, an accelerated PedBE age at TEA was associated with lower cognitive (β = –0.4; 95% CI, −0.8 to −0.03; P = .04) and language (β = –0.6; 95% CI, −1.1 to −0.06; P = .02) scores at 18 months.Conclusions and RelevanceThis cohort study of very preterm neonates suggests that biological aging may be associated with impaired brain growth and neurodevelopmental outcomes. The associations between epigenetic aging and adverse neonatal brain health warrant further attention.

Biopsychosocial factors in oral and systemic diseases: a scoping review

“…Resilience and coping mechanisms aid in controlling emotions and changing the interaction between the person and the stressor, which reduces the stressor's physiologic effects ( 84 – 86 ). Adverse psychosocial factors in early childhood may also contribute to higher susceptibility to maladaptive stress responses that may manifest in adulthood since it can be imprinted on the developing brain ( 87 , 88 ). For example, individuals who experience chronic stress as children often have a higher prevalence of systemic illnesses as adults, including heart disease ( 89 ) and autoimmune diseases ( 90 ).…”

Mother’s childhood adversity is associated with accelerated epigenetic aging in pregnancy and in male newborns

“…This is notable, as epigenetic aging is a potential indicator of negative health and developmental trajectories for offspring. 48 Epigenetic aging in children has been associated with alterations in brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of brain regions; as well as a range of other offspring developmental and behavioral outcomes. 49 In data from ALSPAC, cumulative and individual ACE exposure of the offspring themselves during childhood (aged 0-14 years), including emotional and physical abuse, were linked to epigenetic age acceleration through 17 years of age, with stronger effect estimates in females.…”

“…This is notable, as epigenetic aging is a potential indicator of negative health and developmental trajectories for offspring. 48 Epigenetic aging in children has been associated with alterations in brain volumes, cortical thickness, cortical surface areas and abnormalities in neuronal microstructure in a range of brain regions; as well as a range of other offspring developmental and behavioral outcomes. 49…”

Parenting Practices May Buffer the Impact of Adversity on Epigenetic Age Acceleration Among Young Children With Developmental Delays

“…Further, the direction of the effects of epigenetic age acceleration suggested that increased levels of positive parenting are related to improved health. Research on the relation between epigenetic age acceleration and prospective child health is limited in pediatric samples; however, emerging science suggests that higher levels of epigenetic age acceleration associates with poor health outcomes (e.g., internalizing disorders, Dammering et al, 2021; reduced neonatal brain growth, Gomaa et al, 2022). Our findings suggest that interventions targeting parenting practices may promote resilience in children exposed to adversity.…”