Effects of vitamin D supplementation on circulating concentrations of growth factors and immune-mediators in healthy women during pregnancy

Abstract

Background: For the second aim of the Kellogg Foundation grant, this double-blind RCT investigated the impact of plasma vitamin D metabolite 25-hydroxyvitamin D (25(OH)D) on plasma immune-mediators during pregnancy. We hypothesized that higher 25(OH)D concentrations would associate with reduced pro-inflammatory and increased tolerogenic immune-mediator concentrations.

Methods: Pregnant women enrolled at 10-14 weeks gestation were randomized to 400 or 4400 IU vitamin D₃/day. Data on health, safety, circulating 25(OH)D, and 9 immune-mediators were collected at each trimester. Associations between immune-mediators and 25(OH)D at baseline and at second and third trimesters were examined.

Results: Baseline TGF-β and second and third trimesters IFN-γ and IL-2 were associated with baseline 25(OH)D. Baseline immune-mediators were associated with immune-mediators at second and third trimesters for all immune-mediators except IL-5 and IL-10. Race was associated with baseline TGF-β, VEGF and IL-10 and with IL-10 at second and third trimesters.

Conclusions: Both treatment groups had increased 25(OH)D at second and third trimesters, greatest in the 4400 IU group. Though associations between baseline 25(OH)D and baseline TGF-β and second and third trimester IFN-γ and IL-2 were noted, vitamin D supplementation throughout pregnancy did not impact immune-mediators at later trimesters. Supplementing with vitamin D before conception conceivably influences immune-mediator responses during pregnancy.

Impact: In this vitamin D supplementation clinical trial, baseline (first trimester) but not increasing plasma 25(OH)D concentration impacted select plasma immune-mediator profiles in pregnant women. Baseline 25(OH)D was associated with baseline TGF-β and with IFN-γ and IL-2 at second and third trimesters. Baseline IFN-γ, CRP, TGF-β, TNF-α, VEGF, IL-2, and IL-4 were associated with concentrations at second and third trimesters for respective immune-mediators; however, 25(OH)D concentration at second and third trimesters were not. Some racial differences existed in immune-mediator concentrations at baseline and at second and third trimesters. This study assesses the impact of vitamin D supplementation on multiple immune-mediators in pregnant women of different racial/ethnic groups using longitudinal data from a relatively large randomized controlled trial. This study found that race was associated with baseline TGF-β, VEGF, and IL-10 and with IL-10 at second and third trimesters, a novel finding that sheds light where relationships were less well defined. The results of this study suggest that vitamin D supplementation before conception or early in pregnancy, rather than during pregnancy, may be necessary to significantly impact immune-mediator response. This study sets premise for future clinical trials to evaluate the effect of vitamin D supplementation before conception or prior to pregnancy.

Figure 1:

CONSORT flow diagram for Kellogg Pregnancy study

Figure 2:

Boxplots of 25(OH)D concentrations at the 1^st, 2^nd, and 3^rd trimesters for 400 and 4400 IU vitamin D₃/day groups. P-values are for significant difference in 25(OH)D between the 400 and 4400 IU groups at each trimester.

Figure 3:

Mean profiles for observed plasma immune-mediator concentrations at the 1^st, 2^nd, and 3^rd trimesters for 400 and 4400 IU vitamin D₃/day groups. Bars represent standard error. * Baseline immune-mediator is associated with immune-mediator concentrations at 2nd and 3rd trimesters ‡ Baseline 25(OH)D is associated with baseline immune-mediator † Baseline 25(OH)D is associated with immune-mediator concentrations at 2nd and 3rd trimesters