Micronutrient supplementation interventions in preconception and pregnant women at increased risk of developing pre-eclampsia: a systematic review and meta-analysis

Abstract

Background: Pre-eclampsia can lead to maternal and neonatal complications and is a common cause of maternal mortality worldwide. This review has examined the effect of micronutrient supplementation interventions in women identified as having a greater risk of developing pre-eclampsia.

Methods: A systematic review was performed using the PRISMA guidelines. The electronic databases MEDLINE, EMBASE and the Cochrane Central Register of Controlled trials were searched for relevant literature and eligible studies identified according to a pre-specified criteria. A meta-analysis of randomised controlled trials (RCTs) was conducted to examine the effect of micronutrient supplementation on pre-eclampsia in high-risk women.

Results: Twenty RCTs were identified and supplementation included vitamin C and E (n = 7), calcium (n = 5), vitamin D (n = 3), folic acid (n = 2), magnesium (n = 1) and multiple micronutrients (n = 2). Sample size and recruitment time point varied across studies and a variety of predictive factors were used to identify participants, with a previous history of pre-eclampsia being the most common. No studies utilised a validated prediction model. There was a reduction in pre-eclampsia with calcium (risk difference, -0.15 (-0.27, -0.03, I² = 83.4%)), and vitamin D (risk difference, -0.09 (-0.17, -0.02, I² = 0.0%)) supplementation.

Conclusion: Our findings show a lower rate of pre-eclampsia with calcium and vitamin D, however, conclusions were limited by small sample sizes, methodological variability and heterogeneity between studies. Further higher quality, large-scale RCTs of calcium and vitamin D are warranted. Exploration of interventions at different time points before and during pregnancy as well as those which utilise prediction modelling methodology, would provide greater insight into the efficacy of micronutrient supplementation intervention in the prevention of pre-eclampsia in high-risk women.

Fig. 1. PRISMA Flow Diagram.

Flow diagram showing the study selection process.

Fig. 2. Forest plot of risk difference (95% CI) for overall pre-eclampsia, stratified by supplementation.

Forest plot assessing risk of overall pre-eclampsia with calcium, folic acid, vitamin C and E, vitamin D or multi-micronutrient supplementation. Key: (1) includes linoleic acid (2) includes calcium (3) includes L-arginine (4) all participants given ferrous sulfate tablets.

Fig. 3. Forest plot of risk difference (95% CI) for severe pre-eclampsia only, stratified by supplementation.

Forest plot assessing risk of severe pre-eclampsia with calcium, folic acid or vitamin C and E supplementation.