High-dose vitamin D supplementation in pregnancy and 25(OH)D sufficiency in childhood reduce the risk of fractures and improve bone mineralization in childhood: Follow-up of a randomized clinical trial.

Background: Exposure to vitamin D in early life has been associated with improved bone mineralization, but no studies have investigated the combined effect of pregnancy supplementation and childhood 25(OH)D concentrations on bone health.
Methods: We analyzed the effect of serum 25(OH)D concentrations at age 6 months and 6 years and the combined effect with prenatal high-dose vitamin D (2800 vs. 400 IU/day) on bone mineral density (BMD) and content (BMC) assessed by dual-energy X-ray absorptiometry (DXA) scans at age 3 and 6 years and longitudinal risk of fractures in a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC ₂₀₁₀ ) mother-child cohort with enrollment from March 4, 2009, to November 17, 2010, and clinical follow-up until January 31, 2019 (NCT00856947). All participants randomized to intervention and with complete data were included in the analyses.
Findings: At age 6 months, serum 25(OH)D concentration was measured in 93% ( n  = 541) of 584 children. Children with sufficient (≥ 75 nmol/l) vs. insufficient (< 75 nmol/l) concentrations did not have lower risk of fractures: incidence rate ratio (95% CI); 0.64 (0.37;1.11), p  = 0.11. However, vitamin D sufficient children from mothers receiving high-dose supplementation during pregnancy had a 60% reduced incidence of fractures compared with vitamin D insufficient children from mothers receiving standard-dose: 0.40 (0.19;0.84), p  = 0.02.At age 6 years, serum 25(OH)D concentration was measured in 83% ( n  = 318) of 383 children with available DXA data. Whole-body bone mineralization was higher in vitamin D sufficient children at age 6 years; BMD, adjusted mean difference (aMD) (95% CI): 0.011 g/cm ² (0.001;0.021), p  = 0.03, and BMC, aMD: 12.3 g (-0.8;25.4), p  = 0.07, with the largest effect in vitamin D sufficient children from mothers receiving high-dose vitamin D supplementation; BMD, aMD: 0.016 g/cm ² (0.002;0.030), p  = 0.03, and BMC, aMD: 23.5 g (5.5;41.5), p  = 0.01.
Interpretation: Childhood vitamin D sufficiency improved bone mineralization and in combination with prenatal high-dose vitamin D supplementation reduced the risk of fractures.
Funding: The study was supported by The Lundbeck Foundation R16-A1694, The Danish Ministry of Health 903,516, The Danish Council for Strategic Research 0603-00280B and The European Research Council 946,228.
Competing Interests: All authors declare no conflict of interest regarding the content of this manuscript. The funding agencies did not have any role in design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. JL reports receiving grants from the NIH and the Simons Foundation for Autism and a leadership role in the Metabolomics Society outside of the submitted work. SW reports receiving a grant UH3 OD023268 from the NIH and honoraria from UPTODATE outside of the submitted work. JS reports receiving grants from the NNF and DFF outside of the submitted work. KB reports receiving consulting fees from Sanofi and Astra Zeneca, honoraria from Boehringer Ingelheim and participation in an advisory board from ALK-Abelló Nordic outside of the submitted work.
(© 2021 The Author(s).)