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

Systematic review and meta-analysis of 20 randomized controlled trials in women aged 18 to 50 who were at high risk for preeclampsia and were either planning pregnancy or already pregnant. Risk status was based on prior preeclampsia and/or other clinical risk factors such as chronic hypertension, diabetes, multiple gestation, abnormal uterine artery Doppler findings, or combinations of risk factors.

This systematic review evaluated preconception and pregnancy micronutrient supplementation regimens aimed at preventing preeclampsia in high-risk women. Interventions included calcium (about 500 to 2000 mg/day), vitamin D3 (often 50,000 IU every 2 weeks), vitamin C plus vitamin E (commonly 1000 mg and 400 IU daily), folic acid (4 mg/day or 0.4 mg/day), magnesium citrate (300 mg/day), and multimineral or multivitamin formulations, with treatment starting before conception or in mid-pregnancy and usually continuing until delivery.

Calcium and vitamin D supplementation were associated with a lower rate of preeclampsia in high-risk women, while other micronutrient regimens did not show consistent benefit. Pooled effects were risk difference -0.15 for calcium (95% CI -0.27, -0.03; I2 = 83.41%) and -0.09 for vitamin D (95% CI -0.17, -0.02; I2 = 0.00%). Vitamin C plus vitamin E showed only a small, non-significant trend overall (risk difference -0.04, 95% CI -0.09, 0.00; I2 = 65.76%), and there was no demonstrated effect on severe preeclampsia. One trial also reported more low-birthweight infants with vitamin C and E (387 vs 335, p = 0.023, RR = 1.15, 95% CI = 1.02 to 1.30).

The evidence base was limited by small sample sizes, heterogeneity across trials, and variable methods, doses, timing of initiation, and co-formulations. Arm-level sample sizes and demographic details were inconsistently reported, and some outcomes were available only for a subset of interventions, reducing certainty and comparability across micronutrient classes.