Early pregnancy vitamin D status and risk of preeclampsia

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 casecontrol 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.