The role of vitamin D deficiency in fetal growth restriction: a systematic review

Background: Fetal Growth Restriction (FGR) and Small-for-Gestational-Age (SGA) are major contributors to perinatal morbidity and mortality. Maternal vitamin D deficiency has been proposed to impair placental development and fetal growth through mechanisms involving angiogenesis, immune regulation, and oxidative stress. Increasing evidence suggests that maternal 25-hydroxyvitamin D [25(OH)D] status may play a significant role in the pathogenesis of impaired fetal growth. Objective: To synthesize evidence on the association between maternal 25-hydroxyvitamin D [25(OH)D] concentrations and the risk of FGR and SGA, and to evaluate the impact of vitamin D supplementation on fetal growth outcomes. Methods: A systematic search of PubMed, Cochrane Library, Springer, ScienceDirect, and DOAJ was performed following PRISMA 2020 guidelines. Observational studies and randomized controlled trials examining maternal vitamin D status and fetal growth outcomes were included. Results: The 48 included studies showed consistent evidence linking low maternal 25(OH)D concentrations with increased risk of FGR and SGA, with several analyses demonstrating dose-response patterns at lower vitamin D thresholds. Associations with preterm birth were directionally similar but less consistent. Findings from intervention trials assessing vitamin D supplementation were heterogeneous, influenced by variations in dosage, timing of initiation, baseline vitamin D status, adherence, and co-nutrient exposures. Experimental and mechanistic studies further supported biological plausibility, demonstrating vitamin D-mediated effects on placental angiogenesis, immune modulation, endocrine signaling, and oxidative stress pathways. Conclusion: Maternal vitamin D deficiency is consistently associated with impaired fetal growth, although findings from supplementation trials remain variable. Standardized dosing strategies, harmonized diagnostic cut-offs, and better-controlled interventions are needed to clarify the optimal role of vitamin D in preventing FGR and SGA. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024622395.