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

Background: /Objectives: Vitamin D deficiency has been frequently observed in every generation worldwide. Pregnant women are no exception. The associations between maternal vitamin D status and fetal growth, immune system, or metabolism are reported. These infant characteristics are also reported to be associated with epigenetic gestational age at birth. Epigenetic gestational age acceleration at birth longitudinally relates to infant health. This study aimed to investigate the associations between maternal serum vitamin D levels and infants' epigenetic gestational age acceleration 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 2nd trimester to measure serum vitamin D concentration. Cord blood was collected at birth to measure serum vitamin D and to extract DNA. DNA methylation was assessed using Illumina methylation EPIC array. Epigenetic gestational age was calculated using “methylclock” R package. Linear regression analysis was performed to see associations. Results: Maternal serum vitamin D levels in the 2nd 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 results indicate that maternal vitamin D epigenetically programs fetal development which may affect an infant's health after birth.