Calcium supplementation commencing before or early in pregnancy, or food fortification with calcium, for preventing hypertensive disorders of pregnancy

Background Pre-eclampsia is considerably more prevalent in low- than high-income countries. One possible explanation for this discrepancy is dietary diKerences, particularly calcium deficiency. Calcium supplementation in the second half of pregnancy reduces the serious consequences of pre-eclampsia and is recommended by the WorldHealthOrganization (WHO) for women with low dietary calcium intake, but has limited eKect on the overallrisk of pre-eclampsia. It is important to establish whether calcium supplementation before and in early pregnancy has added benefit. Such evidence would be justification for population-level fortification of staple foods with calcium. Objectives To determine the eKect of calcium supplementation or food fortification with calcium, commenced before or early in pregnancy and continued at least until mid-pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, as well as fetal and neonatal outcomes. Search methods We searched the Cochrane Pregnancy and Childbirth Trials Register (10 August 2017), PubMed (29 June 2017), ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 August 2017) and reference lists of retrieved studies. Selection criteria Randomised controlled trials of calcium supplementation orfood fortification which include women of child bearing age not yet pregnant, or in early pregnancy. Cluster-RCTs, quasi-RCTs and trials published in abstract form only would have been eligible for inclusion in this review but none were identified. Cross-over designs are not appropriate for this intervention. The scope of this review is to consider interventions including calcium supplementation with or without additional supplements or treatments, compared with placebo or no intervention. Data collection and analysis Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Main results This review is based on one RCT (involving 60 women) which looked at calcium plus additional supplements versus control. The women (who had lowantioxidant status)were in the early stages of pregnancy.We did notidentify any studieswhere supplementation commenced pre-pregnancy. Another RCT comparing calcium versus placebo is ongoing but not yet complete. We did not identify any studies looking at any of our other planned comparisons. Calcium plus antioxidants and other supplements versus placebo We included one small study (involving 60 women with low antioxidantlevels) which was conducted in an academic hospital in Indondesia. The study was at low risk of bias for all domains with the exception of selective reporting, for which it was unclear. Women in the intervention group received calcium (800 mg) plus N-acetylcysteine (200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg) and selenium (100 mcg) and vitamins A (1000 IU), B6 (2.2 mg), B12 (2.2 mcg), C (200 mg), and E (400 IU) versus the placebo control group of women who received similar looking tablets containing iron and folic acid. Both groups received iron (30 mg) and folic acid (400 mcg). Tablets were taken twice daily from eight to 12 weeks of gestation and then throughout pregnancy. The included study found that calcium supplementation plus antioxidants and other supplements may slightly reduce pre-eclampsia (gestational hypertension and proteinuria) (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.06 to 1.01; low-quality evidence), but this is uncertain due to wide confidence intervals just crossing the line of no eKect, and small sample size. It appears that earlypregnancy loss before 20 weeks' gestation (RR 0.06, 95% CI 0.00 to 1.04; moderate-quality evidence) may be slightly reduced by calcium plus antioxidants and other supplements, but this outcome also has wide confidence intervals, which just cross the line of no eKect. Very few events were reported under the composite outcome, severe maternal morbidity and mortality index and no clear diKerence was seen between groups (RR 0.36, 95% CI 0.04 to 3.23; low-quality evidence). However, the included study observed a reduction in the composite outcome pre-eclampsia and/or pregnancy loss at any gestational age (RR 0.13, 95% CI 0.03 to 0.50; moderate-quality evidence), and pregnancy loss/stillbirth at any gestational age (RR 0.06, 95% CI 0.00 to 0.92;moderate-quality evidence)in the calcium plus antioxidant/supplement group. Other outcomes reported (placental abruption, severe pre-eclampsia and preterm birth (less than 37 weeks' gestation)) were too infrequent for meaningful analysis. No data were reported for the outcomes caesarean section, birthweight less 2500 g, Apgar score less than seven at five minutes, death or admission to neonatal intensive care unit (ICU), or pregnancy loss, stillbirth or neonatal death before discharge from hospital. Authors' conclusions The results of this review are based on one small study in which the calcium intervention group also received antioxidants and other supplements. Therefore, we are uncertain whether any of the eKects observed in the study were due to calcium supplementation or not. The evidence in this review was graded low to moderate due to imprecision. There is insuKicient evidence on the eKectiveness or otherwise of pre- or early-pregnancy calcium supplementation, or food fortification for preventing hypertensive disorders of pregnancy. Furtherresearch is needed to determine whether pre- or early-pregnancy supplementation, orfood fortification with calcium is associated with a reduction in adverse pregnancy outcomes such as pre-eclampsia and pregnancy loss. Such studies should be adequately powered, limited to calcium supplementation, placebo-controlled, and include relevant outcomes such as those chosen for this review. There is one ongoing study of calcium supplementation alone versus placebo and this may provide additional evidence in future update