Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness

Abstract

The need, safety, and effectiveness of vitamin D supplementation during pregnancy remain controversial. In this randomized, controlled trial, women with a singleton pregnancy at 12 to 16 weeks' gestation received 400, 2000, or 4000 IU of vitamin D(3) per day until delivery. The primary outcome was maternal/neonatal circulating 25-hydroxyvitamin D [25(OH)D] concentration at delivery, with secondary outcomes of a 25(OH)D concentration of 80 nmol/L or greater achieved and the 25(OH)D concentration required to achieve maximal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] production. Of the 494 women enrolled, 350 women continued until delivery: Mean 25(OH)D concentrations by group at delivery and 1 month before delivery were significantly different (p < 0.0001), and the percent who achieved sufficiency was significantly different by group, greatest in 4000-IU group (p < 0.0001). The relative risk (RR) for achieving a concentration of 80 nmol/L or greater within 1 month of delivery was significantly different between the 2000- and the 400-IU groups (RR = 1.52, 95% CI 1.24-1.86), the 4000- and the 400-IU groups (RR = 1.60, 95% CI 1.32-1.95) but not between the 4000- and. 2000-IU groups (RR = 1.06, 95% CI 0.93-1.19). Circulating 25(OH)D had a direct influence on circulating 1,25(OH)(2)D(3) concentrations throughout pregnancy (p < 0.0001), with maximal production of 1,25(OH)(2)D(3) in all strata in the 4000-IU group. There were no differences between groups on any safety measure. Not a single adverse event was attributed to vitamin D supplementation or circulating 25(OH)D levels. It is concluded that vitamin D supplementation of 4000 IU/d for pregnant women is safe and most effective in achieving sufficiency in all women and their neonates regardless of race, whereas the current estimated average requirement is comparatively ineffective at achieving adequate circulating 25(OH)D concentrations, especially in African Americans.

Conflict of interest statement

All other authors (DDJ, TCH, ME, and CLW) state that they have no conflicts of interests.

Copyright © 2011 American Society for Bone and Mineral Research.

Figures

Figure 1. Flow Diagram of Pregnancy Study

1IU denotes International Units

Figure 2. Circulating vitamin D3, its metabolites and intact parathyroid hormone as a function of vitamin D3 dose and time during pregnancy

Panels A, B, C and D show the mean (± S.E.M.) circulating concentrations of vitamin D3, 25(OH)D, 1,25(OH)2D and intact parathyroid hormone at defined time points during pregnancy.

Figure 2. Circulating vitamin D3, its metabolites and intact parathyroid hormone as a function of vitamin D3 dose and time during pregnancy

Panels A, B, C and D show the mean (± S.E.M.) circulating concentrations of vitamin D3, 25(OH)D, 1,25(OH)2D and intact parathyroid hormone at defined time points during pregnancy.

Figure 2. Circulating vitamin D3, its metabolites and intact parathyroid hormone as a function of vitamin D3 dose and time during pregnancy

Panels A, B, C and D show the mean (± S.E.M.) circulating concentrations of vitamin D3, 25(OH)D, 1,25(OH)2D and intact parathyroid hormone at defined time points during pregnancy.

Figure 2. Circulating vitamin D3, its metabolites and intact parathyroid hormone as a function of vitamin D3 dose and time during pregnancy

Panels A, B, C and D show the mean (± S.E.M.) circulating concentrations of vitamin D3, 25(OH)D, 1,25(OH)2D and intact parathyroid hormone at defined time points during pregnancy.

Figure 3. Substrate-Product Relationships of Vitamin D Metabolites during Pregnancy

Panel A demonstrates the relationship between circulating vitamin D3 to control the production of 25(OH)D during pregnancy. Panel B demonstrates the relationship of circulating 25(OH)D to control the production of 1,25(OH)2D during pregnancy. All data points for all subjects in all groups were included in this analysis.

Figure 3. Substrate-Product Relationships of Vitamin D Metabolites during Pregnancy

Panel A demonstrates the relationship between circulating vitamin D3 to control the production of 25(OH)D during pregnancy. Panel B demonstrates the relationship of circulating 25(OH)D to control the production of 1,25(OH)2D during pregnancy. All data points for all subjects in all groups were included in this analysis.

Figure 4. Serum Calcium and Urinary Calcium/Creatinine Ratio as a Function of Vitamin D3 Dose and Time during Pregnancy

Panels A and B show the mean (± S.D.) serum calcium and urinary calcium/creatinine ratio at defined time points during pregnancy.

Figure 5. Relationship of Circulating 25(OH)D on the Urinary Calcium: Creatinine Ratio during Pregnancy

All data points are included for all study patients. Urinary calcium and urinary creatinine were measured in mmol/L. Ratio was calculated from measurement of urinary calcium (mmol/L) divided by measurement of urinary creatinine (mmol/L).