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

  • Protocol
  • Intervention

Authors

  • G Justus Hofmeyr,

    Corresponding author
    1. University of the Witwatersrand, University of Fort Hare, Eastern Cape Department of Health, Department of Obstetrics and Gynaecology, East London Hospital Complex, East London, Eastern Cape, South Africa
    • G Justus Hofmeyr, Department of Obstetrics and Gynaecology, East London Hospital Complex, University of the Witwatersrand, University of Fort Hare, Eastern Cape Department of Health, Frere and Cecilia Makiwane Hospitals, Private Bag X 9047, East London, Eastern Cape, 5200, South Africa. justhof@gmail.com.

    Search for more papers by this author
  • Sarah Manyame

    1. University of Zimbabwe, Department of Obstetrics and Gynaecology, Harare, Zimbabwe
    Search for more papers by this author

Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To determine the effect of calcium supplementation or food fortification with calcium, given before or very early in pregnancy and at least for the first half of pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, as well as fetal and neonatal outcomes.

Background

Hypertension has been estimated to complicate 5% of all pregnancies and 11% of first pregnancies, half of these being associated with pre-eclampsia, and accounting for up to 40,000 maternal deaths annually (Villar 2003). Pre-eclampsia is defined as high blood pressure and proteinuria occurring after the 20th week of pregnancy.

In general, pre-eclampsia is considerably more prevalent in low-income than in high-income communities. Two striking exceptions have been identified. More than 50 years ago, a low prevalence of pre-eclampsia was reported from Ethiopia where the diet, among other features, contained high levels of calcium (Hamlin 1952). The observation in 1980 that Mayan Indians in Guatemala, who traditionally soaked their corn in lime before cooking, had a low incidence of pre-eclampsia and eclampsia (Belizan 1980), stimulated interest in the concept that the link between poverty and pre-eclampsia might be dietary calcium deficiency.

Subsequent epidemiological, clinical and laboratory studies linking pre-eclampsia to calcium deficiency have been outlined in a Cochrane review (Hofmeyr 2014).

Low dietary calcium intake is also associated with hypertension in the general population (Centeno 2009). A systematic review of randomised trials showed a small reduction in systolic and diastolic blood pressure with dietary and non-dietary calcium supplementation (Griffith 1999). Systolic blood pressure was reduced by -1.44 mm Hg (95% confidence interval (CI) -2.20 to -0.68; P < .001) and diastolic blood pressure by -0.84 mm Hg (95% CI -1.44 to -0.24; P < .001).  Low dietary calcium intake is also considered a risk factor for osteoporosis, renal stones, increased body mass index, insulin resistance and colorectal cancer (Centeno 2009).

The hypothesis that calcium supplementation during pregnancy might reduce the incidence of pre-eclampsia was tested in several randomised trials commencing in the late 1980s. 

The World Health Organization (WHO) conducted a randomised trial of calcium supplementation among low calcium intake pregnant women from 2001 to 2003 (Villar 2006). Results from this trial showed that although 1.5 g calcium/day supplement did not prevent pre-eclampsia, it reduced its severity, maternal morbidity, and neonatal mortality. Supplementation in this trial was only during later pregnancy, starting before the 20th week of pregnancy. This trial was included (along with other randomised trials of calcium supplementation during pregnancy) in the Cochrane review by Hofmeyr 2014. The results showed that calcium supplementation of at least 1 g daily, commencing around mid-pregnancy, was associated with a modest reduction in pre-eclampsia, and notably a reduction in its severe manifestations, particularly among women at increased risk, or with low dietary calcium intake. A review of lower dose calcium supplementation (mainly 500 mg/day in the second half of pregnancy), with or without other supplements, including small trials of variable quality also found a reduction in pre-eclampsia (nine trials, 2234 women, risk ratio (RR) 0·38, 95% CI 0·28 to 0.52) (Hofmeyr 2014a).

WHO has recommended that in populations where dietary calcium intake is low, pregnant women receive 1.5 to 2 g elemental calcium daily, particularly those at increased risk of pre-eclampsia (women with one or more of the following risk factors: obesity, previous pre-eclampsia, diabetes, chronic hypertension, renal disease, autoimmune disease, nulliparity, advanced maternal age, adolescent pregnancy and conditions leading to hyperplacentation and large placentas such as in twin pregnancy) (http://www.who.int/nutrition/publications/micronutrients/guidelines/calcium_supplementation/en/index.html).

Description of the condition

The hypertensive disorders of pregnancy include chronic hypertension, gestational hypertension, pre-eclampsia/eclampsia and unclassified hypertension.

Pre-eclampsia is defined as high blood pressure and proteinuria occurring for the first time after 20 weeks' gestation.

Gestational hypertension is defined as diastolic blood pressure > 90 mmHg on two occasions four hours apart, or > 110 mmHg once, and/or systolic blood pressure > 140 mmHg on two occasions four hours apart, or > 160 mmHg once, after 20 weeks’ gestation.

Gestational proteinuria is defined as 2+ or more on urine dipstix, or > 300 mg/24 hours, or > 500 mg/L or urinary protein/creatinine ratio > 0.034, after 20 weeks’ gestation.

Early pregnancy events affecting placentation are thought to contribute to the development of pre-eclampsia (Lyall 2013; Palei 2013) via the following sequence:

  1. failure of cytotrophoblast invasion to remodel uterine spiral arterioles to low-resistance vessels;

  2. impaired uteroplacental blood flow;

  3. syncytiotrophoblast oxidative stress and oversecretion of anti-angiogenic and pro-inflammatory factors from the ischaemic placenta;

  4. widespread maternal endothelial dysfunction with vasoconstriction and renal dysfunction.

This sequence of events has been suggested to be a precursor particularly of early onset pre-eclampsia (Redman 2014).

Description of the intervention

Previous studies and reviews have focused on calcium supplementation during pregnancy. In most studies, calcium supplementation was administered from around 20 weeks of pregnancy, the rationale being to cover the period during which pre-eclampsia is manifest. As set out below, this may be too late to interrupt early pregnancy events which are precursors of pre-eclampsia. This review will focus on interventions to improve calcium intake in early pregnancy. This may be achieved by means of calcium supplementation given to women before or very early in pregnancy and during at least the first half of pregnancy, or food fortification with calcium at an individual or community level.

The possibility of harm from calcium supplementation needs to be considered. Calcium supplementation (but not dietary calcium) has been associated with myocardial infarction risk in the Heidelberg study, an observation at risk of confounding (Li 2012); 1.5 g calcium/day during pregnancy may cause rebound postnatal bone demineralisation (an unexpected finding among multiple trial outcomes assessed) (Jarjou 2010); and an earlier review identified an unexpected increase in the syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP) following calcium supplementation (Hofmeyr 2014), perhaps through the antihypertensive effect of calcium masking the evolution of mild pre-eclampsia into HELLP syndrome (Hofmeyr 2007).

Calcium may be administered in the form of carbonate, citrate, lactate or gluconate, which have good bioavailability. The 19th Expert Committee on the Selection and Use of Essential Medicines recommended the listing of oral solid dosage forms of calcium, providing 500 mg of elemental calcium per dose. http://www.who.int/medicines/EC19uneditedReport.pdf

Food fortification would involve the addition of calcium to staple foods that are low in calcium, such as maize or wheat.

How the intervention might work

Hofmeyr 2008 conducted a randomised trial nested within the large WHO trial of calcium supplementation (1.5 g daily from at least 20 weeks’ gestation) in pregnant women with low dietary calcium intake (Villar 2006) and the nested trial failed to demonstrate an effect of calcium supplementation on biochemical measures commonly elevated in pre-eclampsia: serum urate, platelet count, and urine protein/creatinine ratio.

The lack of effect on proteinuria is consistent with the findings of the main WHO trial (Villar 2006), in which there was a statistically non-significant reduction in pre-eclampsia (8312 women, RR 0.92, 95% CI 0.75 to 1.13) and severe pre-eclampsia (8302 women, RR 0.74, 95% CI 0.48 to 1.15), but no reduction in proteinuria (8312 women, RR for proteinuria 1.01, 95% CI 0.88 to 1.15).  Proteinuria is a hallmark of pre-eclampsia, and a predictor of adverse maternal outcome (von Dadelzsen 2004). 

To reconcile the evidence from the systematic review for reduced pre-eclampsia with calcium supplementation (Hofmeyr 2014), with the absence of evidence of an effect on proteinuria and other markers for pre-eclampsia, we proposed the hypothesis that calcium supplementation in the second half of pregnancy reduces blood pressure and thus the diagnosis and severe manifestations of pre-eclampsia, without a significant effect on the underlying pathology (Hofmeyr 2008).

This hypothesis also serves to explain another anomaly identified in the systematic review:  whereas pre-eclampsia was reduced overall by 22% (12 trials, 15,206 women; RR 0.78, 95% CI 0.68 to 0.89) and the composite outcome ‘maternal death or severe morbidity’ was reduced by 20% (five trials, 9734 women, RR 0.80, 95% CI 0.65 to 0.97), HELLP syndrome was increased 2.7 times with calcium supplementation (two trials, 12,901 women, RR 2.67, 95% CI 1.05 to 6.82) (Hofmeyr 2014).  If calcium supplementation in the second half of pregnancy reduces only blood pressure, this would reduce the diagnosis and some of the hypertension-related complications of pre-eclampsia, while the effects on other organ systems, such as the endothelium, platelets and liver might continue for a longer time in the calcium supplementation group in which fewer early deliveries for hypertension would take place.

The second anomaly requiring explanation is the modest effect of calcium supplementation in late pregnancy on pre-eclampsia, in contrast to the striking epidemiological differences in populations with good and poor dietary calcium.  Deficient dietary calcium before and during early pregnancy may place populations at risk for pre-eclampsia, and the potential to reverse this effect by supplementation in later pregnancy may be limited (Hofmeyr 2008).

Based on the epidemiological association of pre-eclampsia with low dietary calcium and the current understanding of pre-eclampsia as having its origins in early pregnancy events, it is hypothesised that calcium supplementation in early pregnancy may reduce the risk of pre-eclampsia (Hofmeyr 2008).

Why it is important to do this review

The benefits of calcium supplementation in the second half of pregnancy in the prevention of severe pre-eclampsia and other severe morbidity have been proven by systematic reviews. However, there is no evidence to prove or disprove the potential benefits of pre- and early pregnancy calcium supplementation or food fortification in preventing pre-eclampsia. Evidence for such an effect would create the opportunity to have a major impact on pre-eclampsia at a population level, for example by food fortification with calcium among communities at risk. There has not to our knowledge been a previous systematic review on this subject.

Objectives

To determine the effect of calcium supplementation or food fortification with calcium, given before or very early in pregnancy and at least for the first half of pregnancy, on pre-eclampsia and other hypertensive disorders, maternal morbidity and mortality, as well as fetal and neonatal outcomes.

Methods

Criteria for considering studies for this review

Types of studies

Randomised trials (including cluster-randomised trials) will be included. Quasi-randomised trials will be included with due caution and sensitivity analysis. Abstract reports will be included if sufficient information is given to assess trial quality and results. Cross-over designs are not appropriate for this intervention.

Types of participants

Women of child bearing age not yet pregnant, or in early pregnancy. Women might be at low/average risk of pre-eclampsia, or high risk as predicted by their previous pregnancies, nulliparity or being from a high-risk population.

Types of interventions

A Calcium supplementation

B Calcium food fortification

C Different doses of calcium supplementation or food fortification

D Placebo

E No supplementation

F Dummy food fortification

G No food fortification

Comparisons

Comparisons will include A versus D or E, B versus F or G, A versus B and C versus C.

Studies of calcium plus other supplements will be included and subjected to subgroup analysis.

Types of outcome measures

We will consider both maternal and fetal outcomes which might be related to the effects of the calcium supplements or food fortification.

Primary outcomes
  1. Pre-eclampsia (gestational hypertension and proteinuria, as defined below)

  2. Pre-elampsia and/or pregnancy loss/stillbirth at any gestational age

  3. Severe maternal morbidity and mortality index: one or more of secondary outcomes marked # below

Secondary outcomes
Maternal
  1. No conception during study period

  2. Pregnancy loss before 24 weeks' gestational age

  3. Pregnancy loss/stillbirth at any gestational age

  4. Gestational hypertension (diastolic blood pressure > 90 mmHg on two occasions four hours apart, or > 110 mmHg once, and/or systolic blood pressure > 140 mmHg on two occasions four hours apart, or > 160 mmHg once, appearing after 20 weeks’ gestation)

  5. Gestational proteinuria (2+ or more on urine dipstix, or > 300 mg/24 hours, or > 500 mg/L or urinary protein/creatinine ratio > 0.034, appearing after 20 weeks’ gestation)

  6. * Severe gestational hypertension (systolic blood pressure > 160 mmHg on two occasions four hours apart, or once followed by antihypertensive therapy, and/or diastolic blood pressure > 110 mmHg on two occasions four hours apart, or once followed by antihypertensive therapy, appearing after 20 weeks' gestation)

  7. * Early onset pre-eclampsia (< 32 weeks' gestation)

  8. * # Severe pre-eclampsia (proteinuria plus severe diastolic and/or systolic hypertension)

  9. Moderately severe thrombocytopenia (< 100 x 109/L or as defined by trial authors)

  10. Uric acid > reference values for gestational age

  11. # Renal failure (serum creatinine > 120 mmol/L or as defined by trial authors)

  12. # Pulmonary oedema

  13. # Cerebrovascular accident

  14. Liver failure (serum AST > 70 U/L or as defined by trial authors)

  15. # Intensive care unit (ICU) admission > 24 hours

  16. * # Eclampsia

  17. * # HELLP syndrome (haemolysis (LDH > 600 U/L or bilirubin > 1.2 mg/dl), elevated liver enzymes (AST > 70 U/L), and low platelet count (< 100 x 109/L))

  18. * # Placental abruption

  19. # Maternal death

  20. Mother’s hospital stay seven days or more after birth

  21. Caesarean section

  22. Severe pre-eclamptic complications index (Villar 2006): one or more of outcomes marked * above

Neonatal
  1. Birthweight < 2500 g

  2. Preterm birth (< 37 weeks' gestation)

  3. Early preterm birth (< 32 weeks’ gestation)

  4. Apgar score less than seven at five minutes

  5. Death or admission to neonatal ICU for 24 hours or more

  6. Stillbirth

  7. Pregnancy loss, stillbirth or neonatal death before discharge

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co-ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co-ordinator and contains trials identified from:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of Embase;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.

In addition, we will carry out a supplementary search of PubMed (inception to current) using the strategy given in Appendix 1.

Searching other resources

We will search the reference lists of retrieved papers.

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

Both review authors will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person.

Data extraction and management

We will design a form to extract data. For eligible studies, both review authors will extract the data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2014) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Both review authors will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.   

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. less than 20% missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. 20% or more missing outcome data, numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their standard errors using the methods described in the Handbook [Section 16.3.4 or 16.3.6] using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.

Cross-over trials

Cross-over trials are not appropriate for this intervention.

Studies with multiple arms

For multi-armed studies, pairs of arms relevant to the review will be compared. Where one arm appears more than once on a meta-analysis, the outcomes and denominators will be divided by the number of times it appears to avoid multiple counting.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis, we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually.  If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2014). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses.

  1. Women at high risk of pre-eclampsia, low risk or risk unclear/mixed

  2. Women with low dietary calcium, adequate dietary calcium or dietary calcium unclear/mixed

  3. High-dose calcium supplementation (1 g daily or more) or low-dose supplementation

  4. Supplementation or food fortification

  5. Calcium alone or calcium plus other supplements

The following outcomes will be used in subgroup analysis: (1) and (2): all outcomes; (3) and (4): primary outcomes.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2014). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

We will perform sensitivity analysis by examining the effect on results of excluding:

  1. trials at high risk of bias based on allocation concealment;

  2. trials with small sample sizes (less than 200);

  3. trials with no pre-registered protocols.

Acknowledgements

As part of the pre-publication editorial process, this protocol has been commented on by three peers (an editor and two referees who are external to the editorial team), members of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

This review was conducted as an activity of the Calcium and Pre-eclampsia study, objective 1 of the PRE-EMPT program of the University of British Columbia, a grantee of the Bill & Melinda Gates Foundation.

Appendices

Appendix 1. PubMed search strategy

(Calcium supplementation) AND ((preeclampsia) OR (eclampsia) OR (hypertension AND (pregnancy OR pregnant OR pregnancies)))

Contributions of authors

GJ Hofmeyr (GJH) conceived the review. S Manyame wrote the first draft of the protocol. GJH revised the protocol and the response to reviewers.

Declarations of interest

The review authors are conducting a trial that could potentially be included in this review. Two external experienced systematic reviewers, who are not directly involved with the trial, will evaluate the trial for inclusion, risk of bias, and carry out data extraction.

Sources of support

Internal sources

  • Eastern Cape Department of Health, South Africa.

    Salary support (GJH)

External sources

  • The PRE-EMPT Program, University of British Columbia, funded by the Bill & Melinda Gates Foundation, UK.

    (GJH and SM)

Ancillary