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Randomized Controlled Trial
. 2016 Dec 1;126(12):4702-4715.
doi: 10.1172/JCI89031. Epub 2016 Nov 14.

Early pregnancy vitamin D status and risk of preeclampsia

Hooman Mirzakhani, Augusto A Litonjua, Thomas F McElrath, George O'Connor, Aviva Lee-Parritz, Ronald Iverson, George Macones, Robert C Strunk, Leonard B Bacharier, Robert Zeiger, Bruce W Hollis, Diane E Handy, Amitabh Sharma, Nancy Laranjo, Vincent Carey, Weilliang Qiu, Marc Santolini, Shikang Liu, Divya Chhabra, Daniel A Enquobahrie, Michelle A Williams, Joseph Loscalzo, Scott T Weiss
Randomized Controlled Trial

Early pregnancy vitamin D status and risk of preeclampsia

Hooman Mirzakhani et al. J Clin Invest. .

Abstract

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.

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Conflict of interest statement

The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. VDAART preeclampsia CONSORT diagram.
Figure 2
Figure 2. Dose-response association between maternal serum 25OHD concentrations at 10 to 18 weeks of gestation and the corresponding predicted probability of preeclampsia derived from a logistic regression model adjusted for the identified confounders (Table 2).
The gray zone indicates 0.95 confidence bands (Npreeclampsia= 67, Nhealthy = 749). The minimum predicted risk for the population under study relative to the distribution of pregnant women (vertical tick marks on the x axis) falls at the concentrations of 40 to 50 ng/ml serum vitamin D.
Figure 3
Figure 3. Gene expression study flow chart.
Summary of analysis approach and findings on gene expression analysis, through discovery and replication stages. Gene expression study was conducted using RankPord to identify differentially expressed genes in both discovery and replication cohorts (N = 157 and 30, respectively). PE, preeclampsia; DE, differentially expressed; VDGS, vitamin D gene signatures; PEGS, preeclampsia gene signatures; VDGSPE, vitamin D gene signatures associated with preeclampsia; rVDGSPE, replicated vitamin D gene signatures associated with preeclampsia; PPI, protein-protein interaction.
Figure 4
Figure 4. Functional annotation, tissue specificity, and PPI network mapping of vitamin D signatures associated with preeclampsia obtained from the gene expression study.
GO functional enrichment analysis was based on a hypergeometric test with an FDR adjustment for multiple testing of the identified pathways.
Figure 5
Figure 5. LCC genes (143 genes, highlighted in red) corresponding to the “observable preeclampsia module” among the replicated differentially expressed genes (N = 348) and their biological processes.
The connectivity of the replicated signatures was explored by mapping onto functional protein-protein interaction networks from HumanNet v.1.
Figure 6
Figure 6. Connection among the vitamin D– and IL-10–signaling pathway genes (blue and yellow modules, respectively) within the module.
Only the direct connections between vitamin D and IL-10 pathway genes within the module are shown. The size of the circles corresponds to the degree of genes in the interactome. The closeness of the vitamin D– and IL-10–signaling pathways to the LCC is based on the observed shortest path between each set of genes and the LCC.
See this image and copyright information in PMC

Comment in

  • Prevention of preeclampsia.
    Grotegut CA. Grotegut CA. J Clin Invest. 2016 Dec 1;126(12):4396-4398. doi: 10.1172/JCI91300. Epub 2016 Nov 14. J Clin Invest. 2016. PMID: 27841760 Free PMC article. Review.

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