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Prevention > The Calcium and Pre-eclampsia (CAP) study: a WHO collaboration

Background

Epidemiological evidence suggests an association between pre-eclampsia and low dietary calcium. Calcium supplementation in the second half of pregnancy reduces the severe consequences of pre-eclampsia with a trend to reduced deaths as well, but does not reduce pre-eclampsia to the extent expected from the epidemiological data.

The purpose of the Calcium and Pre-eclampsia study is to determine whether calcium supplementation before and in early pregnancy, including the time period when the placental origins of pre-eclampsia are thought to evolve, reduces pre-eclampsia.

Women with a history of pre-eclampsia in their most recent pregnancy who agree to participate receive calcium 500mg daily or placebo from enrolment until they become pregnant, and up to 20 weeks of pregnancy.  After 20 weeks all women receive calcium supplementation with 1500mg daily according to WHO guidelines.  The primary outcome is pre-eclampsia. About 1350 women will be enrolled to achieve the sample size of 540 women contributing data to the primary outcome.

Goal 

The goal of this South African, Zimbabwean, and Argentinian RCT (in centres with known dietary calcium deficiency) to determine the effect of calcium supplementation before, and in the first half of, pregnancy on hypertension and other pregnancy outcomes. Between July 2011 and Feb 2012, there was recruitment at 3 sites in South Africa and one in Zimbabwe. In between March 2013 and July 2014, there was recruitment at six sites in Argentina.

Hypothesis

Calcium supplementation commenced before pregnancy will reduce the incidence of pre-eclampsia more effectively than does supplementation starting at 20 weeks’ gestation.

Methods

Study design
Randomised, double-blind placebo-controlled clinical trial.

Inclusion criteria
Women aged 18 to 45 years with a history of pre-eclampsia or eclampsia who plan to become pregnant.

Exclusion criteria

  • Age <18 years or >45 years
  • Chronic hypertension
  • Already pregnant
  • Taking calcium supplementation
  • History or symptoms of urolithiasis, renal disease, or parathyroid disease
  • Not in a sexual relationship
  • Using long-term contraception (eg hormonal, IUD, sterilization)
  • No informed consent.

Intervention

The study group will receive calcium supplementation with 500 mg elemental calcium daily from enrolment (before pregnancy) until 20 weeks' gestation.The control group will receive an identical placebo for the same duration. All women will receive unblinded calcium supplementation at 1000 mg from 20 weeks' gestation until delivery.

Outcomes

The primary outcome is Pre-eclampsia (diastolic blood pressure >90 mmHg on two occasions 4 hours apart, or >110 mmHg once, or systolic blood pressure >140 mmHg on two occasions 4 hours apart, or >160 mmHg once, after 20 weeks gestation in combination with proteinuria 2+ or more on urine dipstick, or >300mg/24 hours, or >500mg/L or urinary protein/creatinine ratio >0.034g/mmol, after 20 weeks' gestation).

Secondary outcomes related to concordance, maternal and neonatal well-being, and mode of delivery will be reported.

Sample size

To show a reduction in pre-eclampsia from 25% to 15% (with alpha-5%, beta=80%) will require 540 participants.

Analysis plan

Analysis will be by intention-to-treat. The results will be reported according to CONSORT guidelines. Categorical data will be presented as risk ratios with 95% confidence intervals.  Continuous data will be presented as mean differences with 95% confidence intervals.

Sub-studies include:

  • The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia
  • The effect of calcium supplementation on conception
  • The effect of calcium supplementation on miscarriage
  • The effect of calcium supplementation on urinary calcium creatinine ratio during pregnancy
  • Pre-eclampsia biomarker study
  • The relationship between inter-pregnancy interval and outcomes in the subsequent pregnancy: Systematic Review
  • The relationship between inter-pregnancy interval and outcomes in the subsequent pregnancy: prospective study
  • Calcium intake assessment of CAP trial participants

Current status:

As of January 2017, we are confident that the 69 women currently pregnant will enable us to reach our target of 540 pregnancies beyond 20 weeks. Over the next 2 months we will discontinue the participation of non-pregnant women in the study, following the procedures set out in our November 2016 report

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