Maternal Vitamin D Deficiency Is a Risk Factor for Infants' Epigenetic Gestational Age Acceleration at Birth in Japan: A Cohort Study.

Background/objectives: The DNA methylation of neonatal cord blood can be used to accurately estimate gestational age. This is known as epigenetic gestational age. The greater the difference between epigenetic and chronological gestational age, the greater the association with an inappropriate perinatal fetal environment and development. Maternal vitamin D deficiency is common in Japan. The aim of this study was to investigate the associations between maternal serum vitamin D levels and epigenetic gestational age acceleration at birth in Japan.

Methods: The data were obtained from the hospital-based birth cohort study conducted at the National Center for Child Health and Development in Tokyo, Japan. Maternal blood was collected in the second trimester to measure the serum vitamin D concentration. Cord blood was collected at birth to measure serum vitamin D and to extract DNA. DNA methylation was assessed using an Illumina methylation EPIC array. Epigenetic gestational age was calculated using the "methylclock" R package. Linear regression analysis was performed to see associations.

Results: Maternal serum vitamin D levels in the second trimester were negatively associated with epigenetic gestational age acceleration at birth when calculated by Bohlin's method (regression coefficient [95% CI]: -0.022 [-0.039, -0.005], n = 157), which was still significant after considering infants' sex (-0.022 [-0.039, -0.005]). Cord blood serum vitamin D levels were not associated with epigenetic age acceleration. Maternal age at delivery and birth height were associated in positive and negative ways with epigenetic gestational age acceleration, respectively (0.048 [0.012, 0.085] and -0.075 [-0.146, -0.003]).

Conclusions: Maternal vitamin D deficiency was related to an infant's epigenetic gestational age acceleration at birth. These findings suggest that the association between fetal development and maternal vitamin D levels may involve the fetal epigenetic regulation of the fetus.