Epigenetic Age Acceleration, Neonatal Morbidities, and Neurobehavioral Responses in Infants Born Very Preterm Open Access

Abstract

Background: Infants born very preterm are at increased risk of experiencing neonatal morbidities and exhibiting nonoptimal neurobehavioral responses. Epigenetic age acceleration is a potential biomarker of developmental maturity that may be useful for this vulnerable population and help identify at-risk neonates for preventative interventions to improve health outcomes.

 

Methods: To understand how neonatal morbidities and neurobehavioral profiles and responses correlated with age acceleration, we utilized data from 519 infants born <30 weeks gestation participating in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) study. Epigenetic age was estimated using the NEOage epigenetic clocks. Morbidities including bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity, severe brain injury, and serious neonatal infections were combined in an additive risk score ranging from 0-4. We regressed post-menstrual age (PMA) and postnatal age (PNA) acceleration on the neonatal morbidities and neurobehavioral profiles and responses separately, controlling for potential confounders. Interaction with sex was also explored. Parameter estimates using the PedBE and Horvath skin-blood epigenetic clocks were obtained to assess for variability across epigenetic clocks.

 

Results: Infants with mild BPD had higher PMA age acceleration (coefficient = 0.36, p-value < 0.01) compared to infants without BPD, and those with moderate-severe BPD had both higher PMA (coefficient = 0.37, p-value < 0.01) and PNA (coefficient = 0.32, p-value = 0.047) age acceleration compared to infants without BPD. Infants exhibiting hypertonicity had higher PNA age acceleration (coefficient = 0.40, p-value = 0.002) compared to those without. In models including interaction, males with moderate-severe BPD had lower PNA age acceleration (coefficient = -0.64, p = 0.025) compared to females with moderate-severe BPD. Additionally, in males, increased handling score was associated with lower (coefficient = -1.09, p-value = 0.02) PNA age acceleration.

 

Discussion: Our analyses revealed associations between age acceleration, neonatal morbidities, and neurobehavioral domains among a cohort of very preterm infants, which is consistent with prior research. Future research may consider collecting DNAm at birth and NICU discharge to assess differences among infants surviving and those who succumb to their adverse health outcomes to better establish the utility of age acceleration as a biomarker of neonatal health.

Table of Contents

Table of Contents

 

Introduction…………………………………………………..……..……………………………1

Methods………………………………………………………...…………………………………4

           Study Population…………………………………………………………………………..4

NICU Neonatal Morbidities………………………………………………………...……..5

NICU Network Neurobehavioral Scale (NNNS) ………………………..….……………..5

Age Metrics………………………………………………………………………………..6

Estimates of Epigenetic Age…………………………………..…………………………..6

Statistical Analyses…………………………..………………..…………………………..6

Results……..……………………………………………………………...………………………7

Study Population…………………………………………………………………………..7

Continuous PMA Age Acceleration……………………………………………………….8

Continuous PNA Age Acceleration…………………………………………….………….8

Interaction by Sex…………………...……………………………………………………….9

Extremes for PMA and PNA Age Acceleration…………………...……...………………….9

Adjustment for Gestational Age………………..…………………...……...………………...10

Comparison to other Epigenetic Clocks………………..………....……...………………...11

Discussion………………………………………………………………………………….……12

References………………………………………………………………………………….……16

Tables and Figures…………………………………………………………………..…….……20

 

About this Master's Thesis

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School	Rollins School of Public Health
Department	Epidemiology
Subfield / Discipline	Epidemiology - MPH & MSPH
Degree	M.P.H.
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Epidemiology
Keyword	Epigenetic Clock Age Acceleration Preterm Infants
Committee Chair / Thesis Advisor	Todd M. Everson, PhD, MPH, Emory University

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