Pharmacokinetics of high-dose weekly oral vitamin D3 supplementation during the third trimester of pregnancy in Dhaka, Bangladesh

Abstract

A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27-30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (∆) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ∆[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ∆[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (-15 nmol/L, 95% CI -34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ≥ 50 nmol/L and 90% attained [25(OH)D] ≥ 80 nmol/L; in PL, 89% attained [25(OH)D] ≥ 50 nmol/L but 56% attained [25(OH)D] ≥ 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versus PL (117 nmol/L vs. 98 nmol/L; p = 0.07). Vitamin D3 was well tolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [25(OH)D] ≥ 80 nmol/L in virtually all mothers and newborns. Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D] elevations lead to maternal-infant health benefits.

Figure 1

Blood and urine specimen collection schedules. Participants in groups PH and NH were randomly assigned to either scheduled “A” or “B”. Participants in group PL all followed schedule “C”.

Figure 2

Study flow diagram. Participant screening, enrollment, exclusions, and withdrawal over the course of the study.

Figure 3

Changes in serum 25-hydroxyvitamin D concentration from baseline resulting from weekly vitamin D3 administration to non-pregnant women who received an initial dose of 70,000 IU and then 35,000 IU/week thereafter (NH), pregnant women who received an initial dose of 70,000 IU and then 35,000 IU/week thereafter (PH), and pregnant women who received 14,000 IU/week (PL). Lines connect the group means at each follow-up visit.

Figure 4

Lack of inter-dose fluctuations in mean serum 25-hydroxyvitamin D concentrations among non-pregnant (NH) and pregnant women (PH) during the 10th week of supplementation with 35,000 IU vitamin D3 per week, with the most recent dose administered on day 63. Lines connect the group means at each day; 95% confidence intervals are represented by vertical capped bars.

Figure 5

Negative exponential models predicting serum 25-hydroxyvitamin D concentrations in response to weekly vitamin D3 supplementation in non-pregnant women who received an initial dose of 70,000 IU and then 35,000 IU/week (NH), pregnant women who received an initial dose of 70,000 IU and then 35,000 IU/week (PH), and pregnant women who received a weekly dose of 14,000 IU/week (PL). Vertical bars represent the 95% confidence intervals of the empiric geometric means at each scheduled follow-up time.

Figure 6

Mean albumin-adjusted serum calcium concentrations in the three participant groups. (A) Mean albumin-adjusted serum calcium concentration in pregnant participants who received an initial dose of 70,000 IU and then 35,000 IU/week (PH) and pregnant participants who received a weekly dose of 14,000 IU/week (PL); (B) Mean albumin-adjusted serum calcium concentration in non-pregnant participants who received an initial dose of 70,000 IU and then 35,000 IU/week (NH). Vertical bars represent the 95% confidence intervals of the means at each scheduled follow-up time. Horizontal line indicates the upper limit of the reference range (2.60 mmol/L).

Figure 7

Mean urine calcium:creatinine ratio in the three participant groups.(A) Mean urine calcium:creatinine ratio in pregnant participants who received an initial dose of 70,000 IU and then 35,000 IU/week (PH) and pregnant participants who received a weekly dose of 14,000 IU/week (PL), and (B) Mean urine calcium:creatinine ratio in non-pregnant participants who received an initial dose of 70,000 IU and then 35,000 IU/week (NH). Vertical bars represent the 95% confidence intervals of the means at each scheduled follow-up time.