Calcium supplementation during pregnancy for preventing blood pressure disorders and related problems

What is the issue?

Pre-eclampsia is evident as high blood pressure and protein in the urine. It is a major cause of death in pregnant women and newborn babies worldwide. Preterm birth (birth before 37 weeks) is often caused by high blood pressure and is the leading cause of newborn deaths, particularly in low-income countries.

Why is this important?

Evidence from randomised controlled trials shows that calcium supplements help prevent pre-eclampsia and preterm birth and lower the risk of a woman dying or having serious problems related to high blood pressure in pregnancy. This is particularly for women on low calcium diets.

What evidence did we find?

We searched for evidence on 18 September 2017, and found 27 trials. We found evidence from 13 studies (involving 15,730 women) that calcium supplementation in high doses (at least 1 gram (g) daily) during pregnancy may be a safe way of reducing the risk of pre-eclampsia, especially in women from communities with low dietary calcium and those at increased risk of pre-eclampsia. Women receiving calcium supplements may also be less likely to die or have serious problems related to pre-eclampsia (low-quality evidence) and high blood pressure. Babies may be less likely to be born preterm (low-quality evidence). The syndrome of haemolysis, elevated liver enzymes and low platelets was increased with calcium, but the absolute numbers were small (high-quality evidence). High-dose calcium did not have a clear effect on babies admitted to neonatal intensive care, or the number of stillbirths or deaths before discharge from hospital.

Further research is needed into the ideal dosage of supplementation. Limited evidence from 12 trials (2334 women) suggested that a relatively low dose of calcium may be effective in reducing pre-eclampsia, high blood pressure, and babies admitted to intensive care (however, the quality of the evidence on calcium alone was reduced because eight of the included trials gave other medicines alongside calcium, such as vitamin D, linoleic acid or antioxidants). Low-dose calcium did not have a clear effect on preterm birth, stillbirth or death before discharge from hospital.

One small study compared high-dose calcium with low-dose calcium. Pre-eclampsia appeared to be reduced in the high-dose group, but no other differences were found in preterm birth, or stillbirth.

What does this mean?

In settings where dietary calcium is low, supplementation is an important strategy to reduce the serious consequences of pre-eclampsia. Where high-dose supplementation is not feasible, the option of lower dose supplements (500 milligrams (mg) to 600 mg daily) might be considered in preference to no supplementation.

Authors' conclusions: 

High-dose calcium supplementation (≥ 1 g/day) may reduce the risk of pre-eclampsia and preterm birth, particularly for women with low calcium diets (low-quality evidence). The treatment effect may be overestimated due to small-study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers.

The limited evidence on low-dose calcium supplementation suggests a reduction in pre-eclampsia, hypertension and admission to neonatal high care, but needs to be confirmed by larger, high-quality trials.

Read the full abstract...
Background: 

Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia, and may help to prevent preterm birth. This is an update of a review last published in 2014.

Objectives: 

To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes.

Search strategy: 

We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (18 September 2017), and reference lists of retrieved studies.

Selection criteria: 

We included randomised controlled trials (RCTs), including cluster-randomised trials, comparing high-dose calcium supplementation (at least 1 g daily of calcium) during pregnancy with placebo. For low-dose calcium we included quasi-randomised trials, trials without placebo, trials with cointerventions and dose comparison trials.

Data collection and analysis: 

Two researchers independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two researchers assessed the evidence using the GRADE approach.

Main results: 

We included 27 studies (18,064 women). We assessed the included studies as being at low risk of bias, although bias was frequently difficult to assess due to poor reporting and inadequate information on methods.

High-dose calcium supplementation (1 g/day) versus placebo

Fourteen studies examined this comparison, however one study contributed no data. The 13 studies contributed data from 15,730 women to our meta-analyses. The average risk of high blood pressure (BP) was reduced with calcium supplementation compared with placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81; I² = 74%). There was also a reduction in the risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730 women: average RR 0.45, 95% CI 0.31 to 0.65; I² = 70%; low-quality evidence). This effect was clear for women with low calcium diets (eight trials, 10,678 women: average RR 0.36, 95% CI 0.20 to 0.65; I² = 76%) but not those with adequate calcium diets. The effect appeared to be greater for women at higher risk of pre-eclampsia, though this may be due to small-study effects (five trials, 587 women: average RR 0.22, 95% CI 0.12 to 0.42). These data should be interpreted with caution because of the possibility of small-study effects or publication bias. In the largest trial, the reduction in pre-eclampsia was modest (8%) and the CI included the possibility of no effect.

The composite outcome maternal death or serious morbidity was reduced with calcium supplementation (four trials, 9732 women; RR 0.80, 95% CI 0.66 to 0.98). Maternal deaths were no different (one trial of 8312 women: one death in the calcium group versus six in the placebo group). There was an anomalous increase in the risk of HELLP syndrome in the calcium group (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82, high-quality evidence), however, the absolute number of events was low (16 versus six).

The average risk of preterm birth was reduced in the calcium supplementation group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; I² = 60%; low-quality evidence); this reduction was greatest amongst women at higher risk of developing pre-eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83; I² = 60%). Again, these data should be interpreted with caution because of the possibility of small-study effects or publication bias. There was no clear effect on admission to neonatal intensive care. There was also no clear effect on the risk of stillbirth or infant death before discharge from hospital (11 trials, 15,665 babies: RR 0.90, 95% CI 0.74 to 1.09).

One study showed a reduction in childhood systolic BP greater than 95th percentile among children exposed to calcium supplementation in utero (514 children: RR 0.59, 95% CI 0.39 to 0.91). In a subset of these children, dental caries at 12 years old was also reduced (195 children, RR 0.73, 95% CI 0.62 to 0.87).

Low-dose calcium supplementation (< 1 g/day) versus placebo or no treatment

Twelve trials (2334 women) evaluated low-dose (usually 500 mg daily) supplementation with calcium alone (four trials) or in association with vitamin D (five trials), linoleic acid (two trials), or antioxidants (one trial). Most studies recruited women at high risk for pre-eclampsia, and were at high risk of bias, thus the results should be interpreted with caution. Supplementation with low doses of calcium reduced the risk of pre-eclampsia (nine trials, 2234 women: RR 0.38, 95% CI 0.28 to 0.52). There was also a reduction in high BP (five trials, 665 women: RR 0.53, 95% CI 0.38 to 0.74), admission to neonatal intensive care unit (one trial, 422 women, RR 0.44, 95% CI 0.20 to 0.99), but not preterm birth (six trials, 1290 women, average RR 0.83, 95% CI 0.34 to 2.03), or stillbirth or death before discharge (five trials, 1025 babies, RR 0.48, 95% CI 0.14 to 1.67).

High-dose (=/> 1 g) versus low-dose (< 1 g) calcium supplementation

We included one trial with 262 women, the results of which should be interpreted with caution due to unclear risk of bias. Risk of pre-eclampsia appeared to be reduced in the high-dose group (RR 0.42, 95% CI 0.18 to 0.96). No other differences were found (preterm birth: RR 0.31, 95% CI 0.09 to 1.08; eclampsia: RR 0.32, 95% CI 0.07 to 1.53; stillbirth: RR 0.48, 95% CI 0.13 to 1.83).

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