Vitamin D supplementation during pregnancy: Double‐blind, randomized clinical trial of safety and effectiveness

Journal of Bone and Mineral Research

Oct 2011

DOI: 10.1002/jbmr.463

Citations:781

Influential Citations:54

Interventional (Human) Studies

Enhanced Details

Methods

Single-center, randomized, double-blind trial at MUSC. Participants: pregnant women with singleton pregnancy enrolled between 12 and 16 weeks' gestation, aged 16 years or older; diverse ethnicity (African American, Hispanic, Caucasian). Baseline 25(OH)D measured; intention-to-treat analysis; race-stratified randomization.

Intervention

Vitamin D3 supplementation alongside prenatal vitamins: total daily doses of 400, 2000, or 4000 IU/day from 12-16 weeks' gestation until delivery. Taken as two pills daily: a prenatal vitamin providing 400 IU of vitamin D3 plus an additional vitamin D3 supplement of 0, 1600, or 3600 IU, respectively.

Results

4000 IU/day vitamin D3 produced the highest maternal 25(OH)D levels at one month before delivery and at delivery. Proportion achieving 25(OH)D ≥80 nmol/L around delivery: 50% (400 IU), 70.8% (2000 IU), 82% (4000 IU); with missing data, 52.3%/79.5%/83.9% respectively. RR for ≥80 nmol/L within one month of delivery: 2000 vs 400 IU = 1.52 (95% CI 1.24-1.86); 4000 vs 400 IU = 1.60 (95% CI 1.32-1.95); 4000 vs 2000 = 1.06 (not significant). 25(OH)D directly influenced 1,25(OH)2D; maximum 1,25(OH)2D when 25(OH)D ≥100 nmol/L. Neonatal cord/blood 25(OH)D correlated with maternal 25(OH)D (r^2 ≈ 0.6). No safety concerns; no adverse events attributed to vitamin D. Conclusions: Starting at 12-16 weeks, 4000 IU/day achieved sufficiency in mothers and neonates without toxicity; findings support raising pregnancy vitamin D EAR/RDA to 4000 IU/day.

Limitations

Single-center at latitude 32°N; excludes women with preexisting hypertension or diabetes; supplementation started at 12-16 weeks (safety before organogenesis not assessed); incomplete delivery vitamin D data for some participants; generalizability to other latitudes/populations may be limited.

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 D3 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 D3 [1,25(OH)2D3] 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)2D3 concentrations throughout pregnancy (p < 0.0001), with maximal production of 1,25(OH)2D3 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. © 2011 American Society for Bone and Mineral Research show less