223 - Contributions of prenatal risk factors and neonatal epigenetics to cognitive outcome in children born very preterm

Children born very preterm are at increased risk for neurodevelopmental delay compared to term peers. Prenatal risk factors and neonatal epigenetics could help identify preterm children at highest risk for poor cognitive outcome.

Objective:

To determine the associations among prenatal risk factors, neonatal epigenetics, and cognitive outcome in children born very preterm.

Design/Methods:

We studied 379 neonates born < 30 weeks postmenstrual age (PMA) who participated in the Neonatal Neurobehavioral Outcomes in Very Preterm Infants (NOVI) study and had DNAm measured at NICU discharge along with 3-year follow up data (Table 1). Prenatal risk factors were assessed from medical records and maternal report and included 24 variables (Table 2). We created a cumulative index representing the proportion of prenatal stressors experienced by the mother (M = 0.15, SD = 0.10). Neonatal DNAm was measured from buccal swabs using the Illumina MethylationEPIC BeadArray. Cognitive outcome was measured using the Bayley Scales of Infant and Toddler Development (3^rd Edition). Cognitive composite scores were the primary outcome (M = 93.6, SD = 13.5).

First, generalized estimating equation (GEE) models were used to identify significant associations between DNAm at ~450,000 CpG sites and Bayley cognitive scores (FDR < 10%). Then, we estimated a GEE model with cumulative prenatal risk and DNAm at significant CpG sites predicting 3 year Bayley cognitive scores. All models adjusted for potential confounders (e.g., PMA, sex) and technical covariates (e.g., cell proportions).

Results:

Two CpGs were significantly associated with 3-year cognitive outcome (cg20276927 and cg22358121). These CpGs annotated to TNS3 and TRAPPC4 genes, respectively. TNS3 is associated with birth weight and general cognitive ability and TRAPPC4 is associated with the gut microbiome and neurodevelopmental disorders. We found that cumulative prenatal risk and DNAm of these identified CpGs were both independently associated with cognitive outcome at age 3 (all p < .001). A one standard deviation increase in cumulative prenatal risk was associated with a 2.9 point (95% CI = 1.5 to 4.2) decrease in cognitive scores, on average. One standard deviation increases in methylation of cg20276927 and cp22358121 were associated with a 3.2 (95% CI = 1.9 to 4.4) and 2.7 point (95% CI = 1.6 to 3.8) decrease, respectively, in cognitive scores.

Conclusion(s):

Prenatal risk and neonatal DNA methylation profiles may jointly contribute to risk of poor cognitive outcome in children born very preterm.