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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 was 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 agreed to participate received calcium 500mg daily or placebo from enrolment until they became pregnant, and up to 20 weeks of pregnancy.  After 20 weeks, all women received calcium supplementation with 1500mg daily according to WHO guidelines.  The primary outcome is pre-eclampsia. The study had a target of enrolling 1350 women in order 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) was to determine the effect of calcium supplementation before, and in the first half of, pregnancy on hypertension and other pregnancy outcomes. 

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 received calcium supplementation with 500 mg elemental calcium daily from enrolment (before pregnancy) until 20 weeks' gestation.The control group received an identical placebo for the same duration. All women received 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:

Recruitment and follow-up is now complete for the CAP study. Overall, 2563 women were screened and 1347 enrolled in the study. Of the 1347 women enrolled, 650 became pregnant during the intervention and 636 were followed up in the trial. The team is currently finalizing the analysis and preparing for publications. 

Publications:

Presentations

  • Hofmeyr GJ on behalf of the CAP study group. Calcium And Pregnancy (CAP) Trial. PRE-EMPT Sixth Annual Meeting, London, UK, 4 October 2017
  • Hofmeyr GJ on behalf of the CAP study group. Calcium in Pregnancy. 2017 Global Pregnancy Collaboration (CoLab) Membership Meeting, London, UK, 2 October 2017 
  • Cormick G. Obesity Worldwide: Different Mechanism in Different Populations? 2017 Global Pregnancy Collaboration (CoLab) Membership Meeting, London, UK, 2 October 2017 
  • Roberts J, Munjanja S. EMPOWER Project - Zimbabwe. 2017 Global Pregnancy Collaboration (CoLab) Membership Meeting, London, UK, 2 October 2017 
  • Hofmeyr GJ on behalf of the CAP study group. The role of calcium in hypertension and pre-eclamsia. Cape Town cardiac disease in Pregnancy symposium, Hatter Institute for cardiovascular Research in Africa, Cape Town, 28 September 2016 
  • Hofmeyr GJ on behalf of the CAP Study Group.Calcium Supplementation in Pre-eclampsia for preventing maternal mortality. International Conference on Maternal and Newborn Health Research – a KLE Centenary Eveny, Belgaum, India 5-6 March 2016. 
  • Singata-Madliki M for the CAP study group. The effect of calcium supplementation on blood pressure in non-pregnant women with previous pre-eclampsia:  an exploratory, randomized placebo controlled study (WHO Study A65750).  34th Priorities in Perinatal Care Conference, Champagne Sports Resort, Drakensberg, KZN 17-20 March 2015 
  • Manyame S, Hofmeyr GJ.  Pre-pregnancy calcium supplementation for the prevention of pre-eclampsia. African Cochrane indaba, Cape Town, 6-8 May 2013 
  • Hofmeyr GJ.  Evidence and global health: constraints and ethical dilemmas. African Cochrane indaba, Cape Town, 6-8 May 2013 
  • Hofmeyr GJ.  Calcium and Pre-eclampsia, Nutrition meeting, Birchwood, Htel Johannesburg, 14 April 2013 
  • Hofmeyr GJ, for the Calcium and Pre-eclampsia (CAP) Study Group.  Low dose calcium supplementation for preventing pre-eclampsia:  A systematic review and commentary.   32nd Conference on Priorities in Perinatal Care in Southern Africa, Mpekweni Beach Resort, 12-15 March 2013. 
  • Hofmeyr GJ, for the Calcium and Pre-eclampsia (CAP) Study Group. Use of calcium and vitamin D for prevention of pre-eclampsia/eclampsia. USAID MCHIP Asia Regional Meeting on Interventions for Impact in Essential Obstetric and Newborn Care, Dhaka, Bangladesh May 3-6, 2012 
  • Hofmeyr GJ, Singata M, Fawcus S, Belizan JM, Oyebajo AB, Munjanja SP, Sawchuck D, von Dadelzsen P, Bergel E, Betran AP, Purnat T, Tahuringana E.Long term calcium supplementation in women at high risk of pre-eclampsia:  a randomized, placebo-controlled trial.  31st Conference on Priorities in Perinatal Care in Southern Africa.  Kruger park, South Africa, 6-9 March 2012. 
  • Hofmeyr GJ, for the Calcium and Pre-eclampsia (CAP) Study Group. Calcium supplementation for preventing pre-eclampsia/eclampsia. Africa Regional Meeting for Interventions for Impact in essential obstetric and newborn care.  Addis Ababa 21-25 February 2011.