Calcium supplementation to prevent pre-eclampsia in Low- and Middle-Income Countries: IPD meta-analysis, network meta-analysis and economic evaluation

WHAT IS THE PROBLEM?
Pre-eclampsia, a condition in pregnancy associated with high blood pressure and protein in the urine, is a major cause of avoidable deaths in mothers and babies, particularly in low and middle-income countries. Calcium supplements in pregnancy could prevent pre-eclampsia and potentially save 21,500 mothers every year from dying in these countries. Although calcium is on the national essential medicines list of these countries, and the World Health Organization (WHO) recommends high-dose calcium (>1.5g/day) to prevent pre-eclampsia, calcium deficiency in pregnancy continues to be a major preventable public health challenge. We can attribute this to the reluctance of mothers to take large, unpalatable high-dose calcium tablets 3-times a day that is often associated with side effects such as vomiting and constipation. Furthermore, large numbers of bulky tablets pose logistical difficulties with transport and storage, limiting their availability in rural areas. The healthcare professionals also have concerns about the large calcium doses affecting the absorption of iron needed to treat anaemia.

WHAT NEEDS TO BE DONE?
There is an urgent need for us to identify a) the group of women who will benefit the most from calcium supplementation (based on individual characteristics) b) the most effective and acceptable minimal dose of calcium, and c) the best time to start the supplement to prevent pre-eclampsia and complications. Policymakers and healthcare professionals also need information on the barriers to the uptake of calcium and its implementation, and the cost implications of supplementation within limited healthcare resources.

WHAT HAS BEEN DONE SO FAR?
To-date, despite over 30,000 women participating in numerous studies on calcium supplementation to prevent pre-eclampsia, we were able to answer the above questions due to differences in the characteristics of women, the dosage and timing of calcium in these studies. Our international collaborative network (i-CIP) has established a partnership between researchers from low, middle- and high-income countries who conducted the above studies, WHO guideline developers, and experts on calcium supplementation in pregnancy to answer the gaps in research.

WHAT DO WE PLAN TO DO?
In this proposal, we plan to combine the data from individuals who participated in studies on calcium supplementation by a technique called 'IPD meta-analysis' to determine if the effects of calcium differed between different groups of women, and if it varied according to the dose and duration of calcium use. We will obtain the views of mothers and healthcare professionals through surveys and interviews on what they consider may hinder the uptake and use of the calcium supplementation strategy that we find to be most effective. We will study the costs of calcium supplementation against the costs saved in low- and middle-income countries by avoiding pre-eclampsia and its complications. This economic model will be provided in a format that can be used by experts in other countries to determine the relevant economic impact. Research capacity strengthening of our partners is the key to the long-term sustainability of the project.

WHAT DO WE EXPECT WILL HAPPEN?
We expect our findings to lead to an update of the existing WHO guidelines on calcium supplementation in pregnancy, inform policymakers on optimal strategies and costs to promote calcium supplementation, reduce calcium deficiency in pregnant women, and improve outcomes for mother and baby by preventing pre-eclampsia. We planned this proposal in partnership with the patient and public involvement groups so that women are involved in the co-development of the study and dissemination. Our collaboration with WHO (Reproductive health, Nutrition, Human Reproduction Programme HRP Alliance) is key to the development and dissemination of our work through guidelines and existing networks.

AIMS AND OBJECTIVES: To determine if the effects of calcium vary according to the maternal characteristics and the intervention type in preventing pre-eclampsia and other complications, to rank various calcium supplementation strategies by effect, to determine the barriers to its uptake and use, and its cost-effectiveness

DESIGN: IPD meta-analysis of randomised trials, network meta-analysis, economic evaluation

DURATION: 21 months

POPULATION: Pregnant women (varied age, parity, pre-eclampsia risk, calcium status)

INTERVENTION: Calcium supplementation (varied dose, timing, duration)

CONTROL: Placebo or usual care

OUTCOMES: Primary: Pre-eclampsia of any onset
Secondary: Early-onset pre-eclampsia (<34 weeks), maternal and offspring complications, side effects from calcium, costs

METHODS
WP1: IPD random-effect meta-analyses to assess overall, and differential effects of calcium supplementation on pre-eclampsia; network meta-analysis to rank intervention effects
WP2: Systematic reviews, Delphi surveys and focus groups on barriers to the uptake and implementation of the effective calcium supplementation regimens to mothers, healthcare professionals and policymakers, with Patient and Public Involvement (PPI)
WP3: Economic evaluation from a healthcare perspective in terms of cost per disability-adjusted life years (DALYs) averted for mothers in LMIC
WP4: Research capacity of partners strengthened through workshops to sustain the living IPD database

SAMPLE SIZE: i-CIP (Calcium In pregnancy to prevent Pre-eclampsia) IPD collaborators have so far agreed to share data of 27,824 women (11 trials). Assuming heterogeneity of 1-8% in pre-eclampsia rates in the low-risk group in each trial, we have over 98% power to detect an interaction OR of 0.62 in our IPD meta-analysis for differential effect by maternal risk-status

DISSEMINATION: WHO guidelines, conferences, publications, links with WHO regional hubs, Collaborating Centres and LMIC policymaker

IMPACT GOALS (IG)

IG1: UPDATED WHO GUIDELINES: The critical evidence resource will result in the updating of WHO recommendations on calcium supplementation in pregnancy to prevent pre-eclampsia.
IG2: IMPROVED CALCIUM UPTAKE IN PREGNANCY: Our evidence on personalised prevention of pre-eclampsia with calcium to groups that benefit the most, in a dose that is effective and acceptable to women, is expected to increase the uptake of calcium in pregnancy.
IG3: REDUCTION IN THE RATES OF PRE-ECLAMPSIA AND COMPLICATIONS: If calcium supplementation for calcium-deficient women is taken to scale, the prevalence of pre-eclampsia in this at-risk group in LMIC may be halved to achieve the Sustainable Developmental Goals in maternal and offspring mortality for 2030.
IG4: OPEN-ACCESS FLEXIBLE ECONOMIC MODEL: The economic model will be developed by adapting the existing model of our Dutch partner will be freely accessible for use by health economists in other countries.
IG5: IMPROVED IMPLEMENTATION: Global, national, and regional level policies will be updated to incorporate the optimal calcium supplementation strategy to prevent pre-eclampsia identified by us, and informed by our economic model.
IG6: LIVING IPD DATABASE: Our research capability strengthening work (IPD and aggregate meta-analysis and large database management) will lead to a sustained living IPD database so that rapid and timely update of the evidence base can be performed as new evidence is published.
IG7: STRONG PARTNERSHIPS BETWEEN WHO AND I-CIP PARTNERS: The i-CIP partnerships will be strengthened within the framework of WHO HRP Alliance and lay the foundations for similar IPD meta-analyses of other essential nutritional supplements such as iron.
IG8: PATIENT AND PUBLIC INVOLVEMENT (PPI) IN LMIC: Our work will establish a framework for Women's Health PPI engagement in LMIC on prevention of pre-eclampsia based on the model in East London, UK.

WHO WILL BENEFIT AND HOW FROM THE RESEARCH?

- Women, who will ultimately have access to an optimised and more acceptable calcium supplementation regimen in pregnancy. When translated into practice and policy, this is expected to reduce maternal and perinatal morbidity and mortality (particularly those related to hypertensive disorders of pregnancy), particularly in high-burden, low-resource settings.
- WHO guideline developers - our evidence will inform updating of global recommendations and address a major research priority identified in the 2018 guideline.
- Clinicians and public health Programme managers in low-calcium intake areas. Policymakers can implement evidence-informed, targeted/nuanced policies to optimise calcium intake in pregnancy with more efficient use of available data.
- Global Programmes on nutrition in pregnancy, particularly ongoing programs in LMICs will benefit from information on how best to deliver calcium to pregnant women. WHO's ongoing research Programme into food fortification with calcium will benefit from our work on the total minimum calcium dose exposure required in pregnancy to prevent pre-eclampsia.
- LMIC society is expected to have positive economic and social impacts through disease prevention, reduced hospital admissions for women and newborns, and lowered long-term costs with chronic health conditions due to hypertensive disorders in pregnancy and prematurity related complications.
- Research community (please see section on academic benefits).
- Other stakeholder groups: Policymakers and Professional bodies-WHO regional and country offices and relevant country Ministries, National Guideline Alliance (NGA) UK; International Study of Hypertension in Pregnancy (ISSHP); Global Obstetric Network (GONET), IPPIC (International Prediction of Complications in Pregnancy); PPI groups-APEC, Katie's Team; NGO (Non-Governmental Organisations) and community groups in the targeted countries.
Please see Pathways to Impact document on our proposed activities and ODA statement.