Early pregnancy vitamin D status and risk of preeclampsia.

The Journal of clinical investigation

Dec 2016

DOI: 10.1172/JCI89031

Citations:176

Influential Citations:8

Interventional (Human) Studies

Enhanced Details

Methods

Multicenter randomized, placebo-controlled trial in pregnant women with singleton pregnancies, aged 18-39 years, enrolled at 10-18 weeks gestation; history of asthma, eczema, or allergic rhinitis in mother or father; non-smokers; English- or Spanish-speaking; no chronic hypertension.

Intervention

Vitamin D3 (cholecalciferol) 4,000 IU/day, total 4,400 IU/day with prenatal vitamins providing 400 IU/day; started at 10-18 weeks gestation and continued daily through delivery; taken orally.

Results

Preeclampsia frequency did not differ with vitamin D supplementation in intention-to-treat analysis (8.08% vs 8.33%; RR 0.97, 95% CI 0.61-1.53). However, achieving sufficiency (>=30 ng/mL) in early pregnancy and maintaining into late pregnancy was associated with a significantly lower risk of preeclampsia (P=0.04; adjusted OR 0.28, 95% CI 0.08-0.96). Each 10 ng/mL increase in early-pregnancy 25OHD reduced risk by ~33%; 20 ng/mL by ~54%; 30 ng/mL by ~70% (adjusted OR 0.67, 0.46, 0.30 respectively). No preeclampsia occurred in baseline 25OHD >37 ng/mL, and risk dropped to <5% around 40 ng/mL early in pregnancy. Timing and achieving adequate vitamin D appear critical; starting earlier or using higher doses may be necessary to realize preventive effects, and universal screening/high-dose supplementation in all pregnant women is not yet supported; prepregnancy strategies and frequent vitamin D monitoring for high-risk individuals deserve further testing.

Limitations

Exclusion of vitamin D-sufficient women at baseline; supplementation started after 10-18 weeks may miss critical early placentation; not all participants achieved sufficiency with 4,400 IU/day (about 74% reached >=30 ng/mL by 32-38 weeks); preeclampsia was a prespecified secondary outcome; gene-expression substudy had relatively small sample sizes; findings may not generalize to populations with different baseline vitamin D status or sun exposure.

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. show less