Early pregnancy vitamin D status and risk of preeclampsia

J Clin Invest. 2016 Dec 1;126(12):4702-4715. doi: 10.1172/JCI89031. Epub 2016 Nov 14.


Background: Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia.

Methods: We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia.

Results: Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity.

Conclusions: Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia.

Trial registration: ClinicalTrials.gov NCT00920621.

Funding: Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Dietary Supplements*
  • Female
  • Humans
  • Incidence
  • Pre-Eclampsia / blood
  • Pre-Eclampsia / epidemiology
  • Pre-Eclampsia / prevention & control*
  • Pregnancy
  • Pregnancy Trimester, First / blood*
  • Pregnancy Trimester, Third / blood*
  • Risk Factors
  • Vitamin D / administration & dosage
  • Vitamin D / analogs & derivatives*
  • Vitamin D / pharmacokinetics


  • Vitamin D
  • 25-hydroxyvitamin D

Associated data

  • ClinicalTrials.gov/NCT00920621