Maternal vitamin D deficiency may accelerate fetal aging and impact newborn health

By Vijay Kumar MalesuReviewed by Susha Cheriyedath, M.Sc.Jan 22 2025

New study reveals low maternal vitamin D levels may ‘fast-forward’ fetal biological clocks, raising questions about long-term health risks and prenatal care strategies.

Research: Maternal Vitamin D Deficiency Is a Risk Factor for Infants’ Epigenetic Gestational Age Acceleration at Birth in Japan: A Cohort Study. Image Credit: Fida Olga / Shutterstock

In a recent study published in the journal Nutrients, researchers in Japan investigated the association between maternal vitamin D levels during pregnancy and epigenetic gestational age acceleration at birth in a Japanese cohort.

Background

Vitamin D deficiency is widespread globally, with pregnant women in Asia particularly affected. Beyond its role in bone health, vitamin D deficiency has been linked to respiratory infections, obesity, and adverse birth outcomes.

Emerging evidence highlights its epigenetic effects, including programming fetal development and influencing immune cell function. Deoxyribonucleic acid (DNA) methylation, an epigenetic mechanism, predicts biological age and reflects developmental processes. Epigenetic gestational age acceleration, a potential biomarker of fetal development, has been associated with adverse neonatal and adult health outcomes.

Further research is essential to elucidate how maternal vitamin D deficiency impacts epigenetic regulation and long-term health trajectories.

About the study

The study participants were recruited from a hospital-based birth cohort conducted at the National Center for Child Health and Development in Tokyo, Japan, between 2010 and 2013. Pregnant women were enrolled during the first trimester, and informed consent was obtained for their participation and that of their newborns.

Maternal blood samples were collected during the second trimester (24-28 weeks of gestation), and cord blood samples were obtained at delivery. Mother-child pairs were excluded if the mothers smoked, had pre-existing diseases, experienced pregnancy complications, or used medications during pregnancy.

Newborns included were delivered after 37 weeks of gestation and had appropriate birth weights for gestational age, excluding those in the top (>90th percentile) or bottom (<10th percentile) ranges. Mother-child pairs were selected based on maternal serum vitamin D levels, ensuring a median concentration of 20 ng/mL, considered adequate by the Institute of Medicine guidelines.

Pre-pregnancy body mass index (BMI) was calculated from self-reported weight and height. Gestational age was determined using a combination of last menstrual period and ultrasound data. Birth weight and height z-scores were calculated using Japanese reference data.

Serum 25-hydroxyvitamin D (25(OH)D) levels in maternal and cord blood were measured using a competitive protein-binding assay. DNA was extracted from cord blood samples, and methylation was analyzed using the Infinium MethylationEPIC BeadChip array. Notably, the EPIC array lacked some CpG probes used in Bohlin’s and Knight’s original algorithms, which may affect gestational age estimates.

Epigenetic gestational age was calculated using Bohlin and Knight's algorithms, implemented via the ‘methylclock’ package in R.

Statistical analyses included linear regression to assess associations and Spearman correlation tests to examine relationships between characteristics and epigenetic age acceleration.

Study results

The median serum 25(OH)D level of the 157 participants during mid-gestation was 20.5 ng/mL. Among these, 76 participants had serum 25(OH)D levels below 20 ng/mL, the threshold defined by the Institute of Medicine (IOM) as adequate.

Maternal and paternal age, pre-pregnancy BMI, gestational weight gain, gestational weeks at birth, birth height, birth weight, and cord blood 25(OH)D levels were documented to provide a comprehensive dataset for analysis.

Epigenetic gestational ages (DNAmGAs), as calculated using Bohlin and Knight’s methods, showed significant correlations with chronological gestational ages. The correlation was stronger using Bohlin’s method (r = 0.71) compared to Knight’s method (r = 0.48). Bohlin’s method also consistently estimated older DNAmGAs.

Linear regression analysis revealed significant negative associations between maternal mid-gestation 25(OH)D levels and epigenetic gestational age acceleration (calculated by Bohlin’s method), with a regression coefficient of −0.022 (95% CI: −0.039 to −0.005). No such associations were observed with cord blood 25(OH)D levels.

Additionally, maternal age at delivery and birth height were significantly associated with age acceleration, showing positive (0.049, 95% CI: 0.013 to 0.085) and negative (−0.071, 95% CI: −0.142 to −0.005) correlations, respectively. These associations remained significant after adjusting for infant sex.

Gender differences were noted in the correlations between maternal serum 25(OH)D levels and DNAmGA accelerations. The correlation coefficients were −0.227 (p = 0.037) in male infants and −0.170 (p = 0.153) in female infants.

Despite the significant associations of maternal serum 25(OH)D levels and birth height with epigenetic gestational age acceleration, no correlation was found between these factors themselves (p = 0.248). Furthermore, maternal 25(OH)D levels were not correlated with gestational age at delivery (p = 0.409).

These findings suggest that maternal vitamin D levels during mid-gestation influence epigenetic age acceleration at birth, highlighting a potential link between maternal nutritional status and fetal epigenetic programming. However, cord blood 25(OH)D levels appear unrelated to this outcome.

Conclusions

To summarize, this study found a stronger correlation between chronological gestational age and DNAmGA using Bohlin’s method compared to Knight’s. Maternal serum 25(OH)D levels negatively correlated with gestational age acceleration, suggesting vitamin D deficiency may improperly accelerate fetal development.

Factors like genetic variants, ultraviolet B (UV-B) exposure, and obesity influence 25(OH)D levels, while prior research (Chen et al., 2020) showed vitamin D3 supplementation had a protective effect.

Maternal age and birth height were also associated with DNAmGA acceleration, reflecting impacts on skeletal growth. No link was observed with birth weight.

The authors caution that the study’s sample size and selection method (prioritizing participants from vitamin D extremes) may limit generalizability.