Effect of High-Dose vs Standard-Dose Vitamin D Supplementation in Pregnancy on Bone Mineralization in Offspring Until Age 6 Years: A Prespecified Secondary Analysis of a Double-Blinded, Randomized Clinical Trial

Abstract

Importance: Studies suggest an association between maternal vitamin D status during pregnancy and offspring anthropometry and bone mineralization, but investigations are few and with mixed results.

Objective: To investigate the effect of a high dose vs standard dose of vitamin D supplementation in pregnancy on anthropometric and bone outcomes until age 6 years in the offspring.

Design, setting, and participants: A prespecified analysis of a double-blinded, randomized clinical trial in the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort that included 623 pregnant mothers and their 584 children. Data were analyzed between January 2019 and September 2019.

Interventions: Vitamin D supplementation of 2800 IU/d (high-dose) vs 400 IU/d (standard-dose) from pregnancy week 24 until 1 week after birth.

Main outcomes and measures: Longitudinal anthropometry assessments including length/height, weight, and body mass index until age 6 years and bone mineral content (BMC) and bone mineral density (BMD) at age 3 years and 6 years from dual-energy radiography absorptiometry scans.

Results: At age 6 years, 517 children (89%) completed the clinical follow-up. All participants were Danish and white; 261 were boys and 256 were girls. A mixed-effects model analysis of dual-energy radiography absorptiometry scan outcomes from ages 3 years and 6 years showed that children in the vitamin D vs placebo group had higher whole-body BMC: mean difference adjusted (aMD) for age, sex, height, and weight was 11.5 g (95% CI, 2.3-20.7; P = .01); higher whole-body-less-head BMC aMD was 7.5 g (95% CI, 1.5-13.5; P = .01); and higher head BMD aMD was 0.023 g/cm2 (95% CI, 0.003-0.004; P = .03). The largest effect was in children from vitamin D-insufficient mothers (<30 ng/mL; to convert to nanomoles per liter, multiply by 2.496) and among winter births. In a post hoc analysis, we found borderline lower incidence of fractures in the vitamin D group (n = 23 vs n = 36; incidence rate ratio, 0.62 [95% CI, 0.37-1.05]; P = .08), but no differences in any anthropometric outcomes. Adjustment for a concomitant ω-3 polyunsaturated fatty acids intervention did not change the results.

Conclusions and relevance: High-dose vitamin D supplementation in pregnancy improved offspring bone mineralization through age 6 years compared with the standard dose, suggesting an increased recommended gestational intake, which may influence peak bone mass, fracture risk, and risk of osteoporosis later in life. We found no supplementation effect on anthropometric outcomes.

Trial registration: ClinicalTrials.gov Identifier: NCT00856947.

Figure 1.. CONSORT Flowchart

Figure 2.. Density Plots of Head and Total Body Bone Mineral Content (BMC) and Bone Mineral Density (BMD) at Age 3 and 6 Years in Children Born to Mothers Receiving High-Dose Vitamin D or Placebo During Pregnancy

Figure 3.. Effect of High-Dose Vitamin D vs Placebo on Head and Total Body Bone Mineral Content (BMC) Stratified by Birth Season at Age 6 Years

A and C, Regular season. B and D, Low vs high vitamin D season.