Epigenetic gestational age and the relationship with developmental milestones in early childhood.

Shorter gestational age (GA) is a risk factor of developmental delay. GA is usually estimated clinically from last menstrual period and ultrasound. DNA methylation (DNAm) estimates GA using sets of cytosine-guanine-sites coupled with a clock algorithm. Therefore, DNAm-estimated GA may better reflect biological maturation. A DNAm GA greater than clinical GA, known as gestational age acceleration (GAA), may indicate epigenetic maturity and holds potential as an early biomarker for developmental delay risk. We used data from the Upstate KIDS Study to examine associations of DNAm GA and developmental delay within the first 3 years based on the Ages & Stages Questionnaire® (n = 1010). We estimated DNAm GA using two clocks specific to the Illumina Methylation EPIC 850K, the Haftorn clock and one developed from the Effects of Aspirin in Gestation and Reproduction study, in which women were followed to detect pregnancy at the earliest time possible. Among singletons, each week increase in DNAm GA was protective for overall delay (odds ratio:0.74; 95% confidence interval:0.61-0.90) and delay in all domains except for problem-solving skills. Among twins, we observed similar point estimates but lower precision. Results were similar for clinical GA. GAA was largely not associated with developmental delays. In summary, either DNAm GA or clinical GA at birth, but not epigenetic maturity (i.e. GAA), was associated with decreased odds of developmental delay in early childhood. Our study does not support using DNAm GA or GAA as separate risk factors for future risk of developmental delay within the first 3 years of age.