Trimester-specific associations of maternal vitamin D metabolic markers with risks of small vulnerable newborns: a prospective birth cohort study.
5 affiliations
- 1Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- 2Institute of Food Safety and Nutrition Hygiene, Wuhan Center for Disease Prevention and Control, Wuhan, China.
- 3Department of Obstetrics and Gynecology, The Central Hospital of Wuhan, 13 Hangkong Road, Wuhan, 430030, China.
- 4Institute of Food Safety and Nutrition Hygiene, Wuhan Center for Disease Prevention and Control, Wuhan, China. [email protected].
- 5Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [email protected].
Abstract
Background
Vitamin D metabolites beyond total 25(OH)D may influence fetal development, yet their trimester-specific associations with small vulnerable newborns (SVN) remain underexplored. This study examined longitudinal associations of multiple vitamin D metabolic markers with SVN-related outcomes and identified key determinants during pregnancy.Methods
In this prospective cohort of 2,505 mother-infant pairs from China, serum levels of five vitamin D metabolites 25(OH)D₂, 25(OH)D₃, total 25(OH)D, 3-epi-25(OH)D₃, and 24,25(OH)₂D₃] were quantified using HPLC-MS/MS. Two vitamin D metabolite ratios (VMR), VMR1 [24,25(OH)₂D₃/25(OH)D₃] and VMR2 [3-epi-25(OH)D₃/25(OH)D₃], were derived. Outcomes included low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and composite SVN. Associations were evaluated using multivariable logistic regression and restricted cubic spline models. Determinants, including dietary intake, supplementation, season of sample collection, and sociodemographic factors, were evaluated via multivariable linear regression.Results
Vitamin D deficiency decreased from 42.0% in the first trimester to 13.8% in the third trimester. Season and vitamin D intake were major determinants, with supplementation showing stronger correlations than diet. In early pregnancy, higher levels of 25(OH)D₃, total 25(OH)D, 24,25(OH)₂D₃, and VMR1 were linked to lower risks of SVN-related outcomes, particularly PTB and SVN; however, several of these inverse associations were attenuated after FDR-based correction for multiple testing. In contrast, elevated 3-epi-25(OH)D₃ and VMR2 remained robustly associated with increased risks of SGA and SVN after correction. In mid-pregnancy, 25(OH)D₃ and total 25(OH)D were inversely associated with SGA, whereas 25(OH)D₂, 3-epi-25(OH)D₃, and VMR2 were positively associated with PTB, SGA or SVN. Nonlinear patterns included an S-shaped association between 3-epi-25(OH)D₃ and SGA and inverted U-shaped associations between 25(OH)D₂ and multiple outcomes (P nonlinearity < 0.05). In late pregnancy, associations were largely attenuated, with VMR2 showing only marginal inverse trends for SGA (P for trend = 0.058) and SVN (P for trend = 0.064).Conclusions
Trimester-specific vitamin D metabolic profiles showed differential associations with neonatal risks, with stronger corrected evidence for adverse associations related to epimerization-derived markers than for early inverse associations of conventional 25(OH)D metabolites. These findings support comprehensive vitamin D metabolic monitoring and further investigation of tailored supplementation strategies to improve maternal-fetal health.Trial registration
ChiCTR1800016908.
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BibTeX
@article{wang2026trimesterspecific,
title = {{Trimester-specific associations of maternal vitamin D metabolic markers with risks of small vulnerable newborns: a prospective birth cohort study.}},
author = {Shanshan Wang and Yonghua Xiao and Hongjuan Liu and Mingqi Ran and Xinyu Lu and Yundi Mu and Ningning Cui and Jialin Sun and Xudong Wu and Jian Shen and Xuefeng Yang and Xiaomin Wu and Liping Hao},
journal = {BMC medicine},
year = {2026},
month = jul,
doi = {10.1186/s12916-026-05087-1},
url = {https://europepmc.org/article/MED/42897644},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Trimester-specific associations of maternal vitamin D metabolic markers with risks of small vulnerable newborns: a prospective birth cohort study.
AU - Shanshan Wang
AU - Yonghua Xiao
AU - Hongjuan Liu
AU - Mingqi Ran
AU - Xinyu Lu
AU - Yundi Mu
AU - Ningning Cui
AU - Jialin Sun
AU - Xudong Wu
AU - Jian Shen
AU - Xuefeng Yang
AU - Xiaomin Wu
AU - Liping Hao
PY - 2026
DA - 2026/07/01
JO - BMC medicine
DO - 10.1186/s12916-026-05087-1
UR - https://europepmc.org/article/MED/42897644
AB - Background Vitamin D metabolites beyond total 25(OH)D may influence fetal development, yet their trimester-specific associations with small vulnerable newborns (SVN) remain underexplored. This study examined longitudinal associations of multiple vitamin D metabolic markers with SVN-related outcomes and identified key determinants during pregnancy.Methods In this prospective cohort of 2,505 mother-infant pairs from China, serum levels of five vitamin D metabolites 25(OH)D₂, 25(OH)D₃, total 25(OH)D, 3-epi-25(OH)D₃, and 24,25(OH)₂D₃] were quantified using HPLC-MS/MS. Two vitamin D metabolite ratios (VMR), VMR1 [24,25(OH)₂D₃/25(OH)D₃] and VMR2 [3-epi-25(OH)D₃/25(OH)D₃], were derived. Outcomes included low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and composite SVN. Associations were evaluated using multivariable logistic regression and restricted cubic spline models. Determinants, including dietary intake, supplementation, season of sample collection, and sociodemographic factors, were evaluated via multivariable linear regression.Results Vitamin D deficiency decreased from 42.0% in the first trimester to 13.8% in the third trimester. Season and vitamin D intake were major determinants, with supplementation showing stronger correlations than diet. In early pregnancy, higher levels of 25(OH)D₃, total 25(OH)D, 24,25(OH)₂D₃, and VMR1 were linked to lower risks of SVN-related outcomes, particularly PTB and SVN; however, several of these inverse associations were attenuated after FDR-based correction for multiple testing. In contrast, elevated 3-epi-25(OH)D₃ and VMR2 remained robustly associated with increased risks of SGA and SVN after correction. In mid-pregnancy, 25(OH)D₃ and total 25(OH)D were inversely associated with SGA, whereas 25(OH)D₂, 3-epi-25(OH)D₃, and VMR2 were positively associated with PTB, SGA or SVN. Nonlinear patterns included an S-shaped association between 3-epi-25(OH)D₃ and SGA and inverted U-shaped associations between 25(OH)D₂ and multiple outcomes (P nonlinearity < 0.05). In late pregnancy, associations were largely attenuated, with VMR2 showing only marginal inverse trends for SGA (P for trend = 0.058) and SVN (P for trend = 0.064).Conclusions Trimester-specific vitamin D metabolic profiles showed differential associations with neonatal risks, with stronger corrected evidence for adverse associations related to epimerization-derived markers than for early inverse associations of conventional 25(OH)D metabolites. These findings support comprehensive vitamin D metabolic monitoring and further investigation of tailored supplementation strategies to improve maternal-fetal health.Trial registration ChiCTR1800016908.
SN - 1741-7015
ER -