Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes

  • Review
  • Intervention

Authors

  • Pranom Buppasiri,

    Corresponding author
    1. Khon Kaen University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen, Khon Kaen, Thailand
    • Pranom Buppasiri, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen University, Faculty of Medicine, Khon Kaen, Khon Kaen, 40002, Thailand. bprano@kku.ac.th.

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  • Pisake Lumbiganon,

    1. Khon Kaen University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen, Khon Kaen, Thailand
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  • Jadsada Thinkhamrop,

    1. Khon Kaen University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen, Khon Kaen, Thailand
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  • Chetta Ngamjarus,

    1. Faculty of Public Health, Khon Kaen University, Department of Biostatistics and Demography, Khon Kaen, Thailand
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  • Malinee Laopaiboon

    1. Khon Kaen University, Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen, Thailand
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Abstract

Background

Maternal nutrition during pregnancy is known to have an effect on fetal growth and development. It is recommended that women increase their calcium intake during pregnancy and lactation, although the recommended dosage varies among professionals. Currently, there is no consensus on the role of routine calcium supplementation for pregnant women other than for preventing or treating hypertension.

Objectives

To determine the effect of calcium supplementation on maternal, fetal and neonatal outcomes (other than for preventing or treating hypertension) as well as any possible side effects.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (17 March 2011).

Selection criteria

We considered all published, unpublished and ongoing randomised controlled trials (RCTs) comparing maternal, fetal and neonatal outcomes in pregnant women who received calcium supplementation versus placebo or no treatment. We excluded quasi- and pseudo-RCTs.

Data collection and analysis

Two review authors identified studies for inclusion and extracted the data. Two review authors performed data analysis.

Main results

This review includes data from 21 studies (involving 16,602 women). There were no statistically significant differences between women who received calcium supplementation and those who did not in terms of reducing preterm births (less than 37 weeks' gestation) (risk ratio (RR) 0.90; 95% confidence interval (CI) 0.73 to 1.11; 12 studies, 15615 women; random-effects model) and also in less than 34 weeks' gestation (RR 1.11; 95% CI 0.84 to 1.46; three trials, 5145 women). There was no significant difference in infant low birth weight between the two groups (RR 0.91; 95% CI 0.72 to 1.16; four trials, 13449 infants; random-effects). However, compared to the control group, women in the calcium supplementation group gave birth to slightly heavier birth weight infants (mean difference (MD) 64.66 g; 95% CI 15.75 to 113.58; 19 trials, 8287 women; random-effects).

Authors' conclusions

Calcium supplementation is associated with a significant protective benefit in the prevention of pre-eclampsia, and should be used for this indication according to a previous review. This review indicates that there are no additional benefits for calcium supplementation in prevention of preterm birth or low infant birth weight. While there was a statistically significant difference of 80 g identified in mean infant birth weight, there was significant heterogeneity identified, and the clinical significance of this difference is uncertain.

アブストラクト

妊娠アウトカムおよび乳児アウトカム改善に対する(高血圧予防または治療以外の)カルシウム補充

背景

妊娠中の母体栄養が胎児の成長と発達に影響することが知られている。妊娠および授乳中はカルシウム摂取を増加するよう勧められているが、その推奨用量は専門家の間で異なっている。現在、高血圧の予防または治療以外の目的でルーチンにカルシウムを補充することについて合意は得られていない。

目的

母体、胎児および新生児のアウトカムに対するカルシウム補充(高血圧の予防または治療以外)の効果と、起こりうる副作用について検討すること。

検索戦略

Cochrane Pregnancy and Childbirth Group's Trials Register (2011年3月17日)を検索した。

選択基準

カルシウム補充を受けている妊娠女性を対象に、母体、胎児および新生児アウトカムについてプラセボまたは無治療と比較している、発表、未発表および進行中のランダム化比較試験(RCT)とした。準RCTおよび擬似RCTを除外した。

データ収集と分析

2名のレビューアが選択基準を満たす研究を同定しデータを抽出した。2名のレビューアがデータ解析を行った。

主な結果

本レビューには21件の研究(16,602例の女性を含む)からデータが得られた。カルシウム補充を受けた女性と受けなかった女性で、早産(妊娠37週未満)の低下[リスク比(RR)0.90、95%信頼区間(CI)0.73~1.11、12件の研究、15,615例、ランダム効果モデル]、および妊娠34週未満の早産の低下(RR 1.11、95%CI 0.84~1.46、3件の試験、5,145例)に統計学的に有意差はみられなかった。2群間で児の低出生体重に有意差はみられなかった(RR 0.91、95%CI 0.72~1.16、4件の試験、13,449例、ランダム効果)。しかし、コントロール群に比べて、カルシウム補充群では、児の出生体重が若干重かった[平均差(MD)64.66 g、95%CI 15.75~113.58、19件の試験、8,287例、ランダム効果]。

著者の結論

カルシウム補充は、子癇前症の予防において有意な予防的利益と関連しており、以前のレビューに従ってこの適応で使用すべきである。本レビューでは、早産および児の低出生体重の予防において、カルシウム補充の追加的利益はみられなかった。児の平均出生体重において統計学的有意差は65 g*であったが、著しい異質性が同定されているため、この差の臨床的意義は不明である。

訳注

監  訳: 江藤 宏美,2012.2.7

実施組織: 厚生労働省委託事業によりMindsが実施した。

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Résumé scientifique

Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes

Contexte

La nutrition maternelle pendant la grossesse est connue pour avoir un effet sur la croissance et le développement du fœtus. Il est recommandé aux femmes d'augmenter leur apport en calcium durant la grossesse et l'allaitement, bien que la dose recommandée varie entre les professionnels. Actuellement, il n'existe pas de consensus quant au rôle de la supplémentation de routine en calcium pour les femmes enceintes, à part pour la prévention ou le traitement de l'hypertension

Objectifs

Déterminer l'effet de la supplémentation en calcium sur la santé de la mère, du fœtus et du nouveau-né (dans les indications hors prévention et traitement de l'hypertension) ainsi que les éventuels effets secondaires.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre des essais du groupe Cochrane sur la grossesse et l'accouchement (17 mars 2011).

Critères de sélection

Nous avons considéré tous les essais cliniques randomisés (ECR), publiés, inédits ou en cours, comparant la santé de la mère, du fœtus et du nouveau-né chez les femmes enceintes ayant reçu une supplémentation en calcium par rapport à celles ayant reçu un placebo ou n'ayant reçu aucun traitement. Nous avons exclu les quasi- et pseudo-ECR.

Recueil et analyse des données

Deux auteurs de la revue ont identifié des études à inclure et extrait les données. Deux auteurs de la revue ont effectué une analyse des données.

Résultats principaux

Cette revue comprend des données de 21 études (portant sur 16 602 femmes). Il n'y avait aucune différence statistiquement significative entre les femmes ayant reçu une supplémentation en calcium et celles qui n'en avaient pas reçu, en termes de réduction des accouchements prématurés (moins de 37 semaines de gestation) (risque relatif (RR) 0,90 ; intervalle de confiance (IC) à 95% 0,73 à 1,11; 12 études, 15 615 femmes ; modèle à effets aléatoires) ainsi que dans les gestations de moins de 34 semaines (RR 1,11 ; IC 95% 0,84 à 1,46 ; trois essais, 5145 femmes). Il n'y avait pas de différence significative en matière de bas poids de naissance entre les deux groupes (RR 0,91 ; IC 95% 0,72 à 1,16 ; quatre essais, 13 449 nourrissons ; effets aléatoires). Toutefois, comparativement au groupe témoin, les femmes ayant reçu une supplémentation en calcium ont donné naissance à des bébés un peu plus lourds (différence moyenne (DM) 64,66 g ; IC 95% de 15,75 à 113,58 ; 19 essais, 8287 femmes ; effets aléatoires).

Conclusions des auteurs

La supplémentation en calcium est associée à un effet significatif de protection contre la pré-éclampsie et devrait être utilisée pour cette indication d'après une revue précédente. Cette revue indique que la supplémentation en calcium ne présente pas d'avantages supplémentaires pour la prévention des accouchements prématurés ou des bas poids de naissance. Bien qu'une différence statistiquement significative de 80 g ait été identifiée dans le poids de naissance moyen du bébé, une hétérogénéité significative a été identifiée rendant incertaine la signification clinique de cette différence.

Plain language summary

Effect of taking extra calcium (other than preventing or treating high blood pressure) during pregnancy for improving maternal and infant health

Maternal nutrition during pregnancy is known to have a significant effect on fetal growth and development. Another Cochrane review has shown the benefit of taking extra calcium in preventing pre-eclampsia/eclampsia. In our review, regular intake of extra calcium tablets during pregnancy did not improve any maternal outcomes such as the number of preterm births or other infant outcomes, except for a slight increase in infant birth weight in the group of women who received calcium supplementation. Taking calcium supplementation did not appear to have any obvious side effects. Our review included data from 21 randomised controlled studies (involving 16,602 women) although the majority of the comparisons were based on fewer numbers of studies.

Résumé simplifié

Effet de la prise de calcium supplémentaire (prévention et traitement de l'hypertension artérielle non-compris) pendant la grossesse pour améliorer la santé de la mère et du bébé

La nutrition maternelle pendant la grossesse est connue pour avoir un effet significatif sur la croissance et le développement du fœtus. Une autre revue Cochrane a montré le bénéfice de la prise de calcium supplémentaire pour prévenir la pré-éclampsie et l'éclampsie. Dans notre revue, la prise régulière de comprimés de calcium supplémentaires pendant la grossesse n'a eu aucun effet positif sur la mère ou l'enfant (comme le nombre d'accouchements prématurés etc.), à part une petite augmentation du poids de naissance chez les femmes ayant reçu une supplémentation en calcium. La supplémentation en calcium ne semble pas avoir entrainé d'effets secondaires clairs. Notre examen a porté sur les données de 21 études cliniques randomisées (impliquant 16 602 femmes), bien que la majorité des comparaisons fût basée sur un nombre réduit d'études

Notes de traduction

Traduit par: French Cochrane Centre 1st November, 2011
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

Background

Calcium metabolism

Calcium is an essential mineral for many of the body's processes (Trichopoulou 1990). Calcium is a key and important intracellular component for maintaining cell membranes, and has a role in nerve cell function, muscle contraction, enzyme and hormone actions, and is essential for bone mineralisation. Maternal nutrition during pregnancy has a significant effect on fetal growth and development (Luke 1994; Susser 1991). Calcium is transported across the placenta by an active transport process, being important in many developmental functions, including skeletal development (McGuire 2007).

During pregnancy and lactation women require an increase in their calcium intake (Cross 1995; Prentice 1995a; Ritchie 1998). This is not only to maintain maternal calcium balance and bone density, but also to meet the demands of the growing fetus/infant. During pregnancy and lactation, maternal bone mineral density decreases in multiple sites of the body such as the lumbar spine, femoral neck, total hip and wrist. However, this is quickly reversed after cessation of breast feeding (Cross 1995; Kalkwarf 1997; Laskey 1999; Prentice 1995; Sowers 1993; Sowers 1995). Inadequate intake of calcium may harm both the woman and her fetus. Maternal risks of inadequate calcium intake include osteopenia, osteoporosis, tremor, paraesthesia, muscle cramps and tetany. Potential problems for the fetus/infant include delayed fetal growth, low birth weight and poor bone mineralisation (Inzucchi 1999; Koo 1999).

Calcium supplementation

The recommendations for calcium intake during pregnancy and lactation vary from 600 mg to 1425 mg per day, up to 600 mg higher than in non-pregnant women (Prentice 1994). Approximately 200 mg of calcium per day is secreted into breast milk (Prentice 1994).

The increase in calcium requirements may be met through dietary intake. However, supplementation of calcium during pregnancy and lactation has been recommended by some, at doses between 300 mg and 2000 mg per day (Belizan 1991; Koo 1999; Raman 1978). For this review, we have arbitrarily divided calcium supplementation into low dose (1000 mg or less per day) and high dose (1000 mg or more per day) (Jarjou 2006; Kalkwarf 1997; Prentice 1995a; Raman 1978; Villar 1990).

Calcium tablets are inexpensive and readily available. However, side effects have been reported, including difficulty in swallowing, an increase in urinary stones and urinary tract infection, as well as reduced absorption of other minerals such as iron, zinc and magnesium (Hallberg 1992; McGuire 2007).

The effect of calcium supplementation on weight is unclear, with some studies identifying a reduction in body weight, possibly through the combination of calcium with fatty acids which are subsequently not absorbed by the body (Heaney 2002; Sampath 2008; Trowman 2006 ; Yanovski 2009).

Current approach to calcium supplementation in pregnancy

Currently, there is no consensus on the role of routine calcium supplementation for pregnant women.

The Cochrane review evaluating calcium supplementation for the prevention of pre-eclampsia identified a significant beneficial effect, almost halving the risk of women developing pregnancy induced hypertension (Hofmeyr 2006). However, the effect of calcium supplementation on other pregnancy and infant outcomes remains uncertain, with some studies identifying a beneficial effect on fetal growth and bone mineralisation (Chang 2003; Chan 2006; Janakiraman 2003, although this is not universal (Jarjou 2006; Prentice 1995). Calcium also plays a role in smooth muscle function, being important in muscle contraction. Some studies have suggested that calcium supplementation may contribute to altered muscle tone and may therefore contribute to the risk of preterm birth, although the precise effect is unclear (Belizan 1991; Carroli 1994; Lopez-Jaramillo 1989; Villar 1998; Villar 1990). While there is a clear benefit of calcium supplementation in the prevention of hypertension during pregnancy, the effect on other outcomes requires further evaluation.

Objectives

To determine the effect of calcium supplementation on maternal, fetal and neonatal outcomes (other than for preventing or treating hypertension), including the occurrence of side effects.

Methods

Criteria for considering studies for this review

Types of studies

We included all published, unpublished and ongoing simple and cluster-randomised controlled trials (RCTs) comparing maternal, fetal, and neonatal outcomes in pregnant women who received calcium supplementation compared with placebo or no treatment. We excluded quasi- and pseudo-RCTs and crossover studies.

Types of participants

Pregnant women who received any calcium supplementation compared with placebo or no treatment.

Types of interventions

Calcium supplementation during pregnancy and placebo or no treatment.

Types of outcome measures

Primary outcomes
Maternal outcomes
  1. Preterm birth less than 37 weeks' gestation.

Infant outcomes
  1. Low birthweight (less than 2500 g)

Secondary outcomes
Maternal outcomes
  1. Preterm birth less than 34 weeks' gestation

  2. Maternal weight gain

  3. Maternal bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (osteopenia is classified as BMD between -1 and -2.5 SD; osteoporosis is classified as BMD less than -2.5 SD)

  4. Leg cramps

  5. Backache

  6. Tetany (muscle spasm and twitching)

  7. Incidence of fracture

  8. Duration of breastfeeding

  9. Tremor

  10. Paresthesia

  11. Mother admitted to an intensive care unit

  12. Maternal death

  13. Mode of birth (vaginal birth, Instrumental vaginal birth, cesarean section)

  14. Postpartum hemorrhage

Fetal and neonatal outcomes
  1. Stillbirth or fetal death (fetus died in uterus after 20 weeks' gestation or during labor and delivery)

  2. Neonatal death (baby died in first 28 days of life)

  3. Perinatal mortality (stillbirth and neonatal death)

  4. Admission to neonatal intensive care unit

  5. Birthweight

  6. Birth length

  7. Head circumference

  8. Intrauterine growth restriction

  9. Neonatal BMD (measured by single-photon absorptiometry or dual-energy x-ray absorptiometry)

  10. Osteopenia

  11. Rickets

  12. Fracture

Adverse outcomes
  1. Side effects of calcium supplementation

  2. Compliance

  3. Satisfaction (as defined by the trial authors)

  4. Urinary stones

  5. Urinary tract infection

  6. Nephrocalcinosis

  7. Impaired renal function (as defined by the trial authors)

  8. Maternal anaemia (as defined by the trial authors)

Search methods for identification of studies

We searched the Cochrane Pregnancy and Childbirth Group’s Trials Register by contacting the Trials Search Co-ordinator (17 March 2011). 

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

  1. quarterly 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.  

We did not apply any language restrictions.

Data collection and analysis

Selection of studies

Two review authors, Pranom Buppasiri (PB) and Jadsada Thinkhamrop (JT) independently assessed all potential studies identified as a result of the search strategy. We resolved any disagreement through discussion or by involving the third and fourth review authors, Pisake Lumbiganon (PL), and Malinee Laopaiboon (ML). The fifth review author, Chetta Ngamjarus (CN) was responsible for data analysis.

Data extraction and management

We designed a form to extract data. For eligible studies, PB and JT extracted the data using the agreed form. We resolved discrepancies through discussion and consulted PL and ML if necessary. We entered data into Review Manager software (RevMan 2011) and checked for accuracy. When information on any studies was unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors (PB and JT) assessed the validity of each study independently using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

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

We have described 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 assessed 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) or,

  • unclear risk of bias.   

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

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

We assessed 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) Blinding of participants, personnel and outcome assessors (checking for possible performance and detection bias)

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

We assessed the methods as:

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

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

  • low, high or unclear risk of bias for outcome assessors.

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

We have described for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We 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 was supplied by the trial authors, we have re-included missing data in the analyses which we undertook.

We assessed methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. 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 have described for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

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

We assessed 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 have made 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 have assessed the likely magnitude and direction of the bias and whether we considered it was likely to impact on the findings.  For primary outcomes we have explored the impact of the level of bias through undertaking sensitivity analyses - see ' Sensitivity analysis'. 

Measures of treatment effect

Dichotomous data

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

Continuous data

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

Unit of analysis issues

Cluster-randomised trials

We did not find cluster-randomised trials in the included trials. In future updates of this review, if we identify cluster-randomised trials we will include them in the analyses along with individually randomised trials. We will adjust their sample sizes using the methods described in the Handbook, using an estimate of the intra cluster 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 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 subgroup analysis to investigate the effects of the randomisation unit.

Dealing with missing data

For included studies, we noted levels of attrition. We explored 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 carried out analyses, as far as possible, on an intention-to-treat basis, i.e. we attempted to include all participants randomised to each group in the analyses, and analysed all participants 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 was the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta-analysis using the T2, I2 and Chi2 statistics. We regarded heterogeneity as substantial when I2 was greater than 30% and either T2 was greater than zero, or there was a low P value (less than 0.10) in the Chi2 test for heterogeneity. 

Assessment of reporting biases

When there were 10 or more studies in the meta-analysis we investigated reporting biases (such as publication bias) using funnel plots. We assessed funnel plot asymmetry visually, and used formal tests for funnel plot asymmetry. For continuous outcomes we used the test proposed by Egger 1997, and for dichotomous outcomes we used the test proposed by Harbord 2006. When we detected asymmetry in any of these tests or by a visual assessment, we performed exploratory analyses to investigate it.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2011). We used fixed-effect meta-analysis for combining data where it was reasonable to assume that studies were estimating the same underlying treatment effect: i.e. where trials were examining the same intervention, and the trials’ populations and methods were judged sufficiently similar. When there was clinical heterogeneity sufficient to expect that the underlying treatment effects would differ between trials, or when substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary provided that an average treatment effect across trials was considered clinically meaningful. We treated the random-effects summary as the average range of possible treatment effects and we discussed the clinical implications of treatment effects differing between trials. When we considered that an average treatment effect was not clinically meaningful we did not combine trials.

When we used random-effects analyses, we presented the summary result as the average treatment effect with its 95% confidence interval, and with the estimates of  T2 and I2.

Subgroup analysis and investigation of heterogeneity

When we identified substantial heterogeneity, we investigated it using subgroup analyses and sensitivity analyses.

We carried out the following subgroup analyses:

1. total dose per day of calcium supplementation: low/high (less than 1000 and 1000 or more mg);

2. time supplementation taken during pregnancy (the time that calcium supplementation started):

  • first half of pregnancy (less than 20 weeks);

  • second half of pregnancy (20 weeks or more);

3. type of calcium supplementation preparation; calcium carbonate, lactate, gluconate.

We used the following outcomes in subgroup analysis:

  • preterm birth less than 37 weeks;

  • low birth weight (less than 2500 g).

We assessed differences between subgroups by inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals suggesting a statistically significant difference in treatment effect between the subgroups. Where visual assessment suggested funnel plot asymmetry we assessed differences between subgroups by interaction tests (Higgins 2011).

Sensitivity analysis

We carried out sensitivity analyses to explore the effect of trial quality based on concealment of allocation. We excluded trials rated as 'high risk of bias' or 'unclear risk of bias' for allocation concealment in order to assess for any substantive difference to the overall result.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification.

Results of the search

The search yielded 72 trial reports. After exploring the contents, and grouping for the same study, we included data from 21 trials (54 reports). One further trial that was otherwise eligible for inclusion specifically focused on maternal blood lead levels and did not report any other outcomes, and so has not contributed data to the review (Ettinger 2009). We have provided details of this study in Characteristics of included studies but we have not referred to this study in the discussion of included studies below. We have excluded 14 trials and four trials are 'Awaiting classification' because only the abstracts were available (Almirante 1998; Chames 2002; Galimberti 2001; Repke 1989a) - we tried to contact the authors but unfortunately full papers were not available.

Included studies

For more information about included studies, see: Characteristics of included studies.

Design

All included studies were reported RCTs and one trial (Villar 2006) was stratified by country.

Sample size

The total number of participants included in the trials contributing data to this review was 17,212 pregnant women, but only 16,602 were included in final analyses. MIssing data was 3.5% (610 in 17,212). The sample size varied from 23 to 8325 participants per trial.

Setting

The 21 trials took place in various countries: Argentina, Australia, Egypt, Equador, Gambia, Guatemala, Hong Kong, India, Iran, United Kingdom (East London), United States and Vietnam.

Participants

This review includes data for 16,602 pregnant women. Two trials (Chan 2006; Villar 1990) included only adolescent pregnant women (with a mean age of 17.5 years) but remaining trials were not restricted to adolescents. Two trials (Jarjou 2006; Raman 1978) included only pregnant women from low socioeconomic groups. The largest study (Villar 2006) recruited only pregnant women who received less than 600 mg dietary calcium per day. One study (Lopez-Jaramillo 1997) included pregnant women who had lived at an altitude of 2800 m for a period of at least one year. One study (Sanchez-Ramos 1994) enrolled pregnant women who had normotension but positive roll over and angiotensin tests.

Interventions

Calcium supplementation was used in the treatment groups in all trials and compared with placebo or no treatment control groups. Various types of calcium were used such as calcium carbonate, calcium gluconate, calcium lactate and combined calcium. Calcium carbonate was prescribed in most studies (in 17 of the 21 trials). Calcium lactate was prescribed in one trial and calcium gluconate was prescribed in one trial. Combined calcium supplementation was prescribed in two trials and three trials did not specify the type of calcium used. For timing of calcium supplementation; nine trials (Belizan 1991; Boggess 1997; Crowther 1999; Karandish 2003; Lopez-Jaramillo 1989; Purwar 1996; Sanchez-Ramos 1995; Taherian 2002; Villar 1990) started calcium supplementation at 20 weeks' gestational age (or after) until delivery. Four trials (Belizan 1983; Chan 2006; Levine 1997; Villar 2006) started calcium supplementation at gestational age less than 20 weeks until delivery. For dosage of calcium, 11 trials (Belizan 1991; Boggess 1997; Crowther 1999; Karandish 2003; Levine 1997; Lopez-Jaramillo 1989; Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Villar 1990; Villar 2006) prescribed 1000 mg/d or more (range 1000 to 2000 mg/d). Three trials (Raman 1978; Rogers 1999; Taherian 2002) prescribed calcium less than 1000 mg/d (range 300 mg to 600 mg). In the Taherian 2002 study, calcium supplementation (Caltrate) was prescribed 600 mg at 22 to 32 weeks' gestational age and then 1200 mg from 32 weeks until delivery.

Outcomes

The primary outcomes or objectives of 14 in 21 trials were incidence of pregnancy induced hypertension or changes in blood pressure which were not relevant to this review. However, these studies also reported other outcome data relevant to this review, e.g. preterm birth, maternal weight gain, gestational age, birthweight, birth length, and we have therefore included these data. There were 12 trials with a total of 15,615 participants (Belizan 1991; Boggess 1997; Crowther 1999; Levine 1997; Lopez-Jaramillo 1989; Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Taherian 2002; Villar 1990; Villar 2006; Wanchu 2001) which evaluated the effect of calcium supplementation on preterm birth before 37 weeks. Three trials, with 5145 participants (Crowther 1999; Levine 1997; Wanchu 2001) evaluated the effect of calcium supplementation on preterm birth before 34 weeks. Five of the trials, with 13,638 participants (Crowther 1999; Levine 1997; Lopez-Jaramillo 1989; Villar 1990; Villar 2006) evaluated the effect of calcium supplementation on low birth weight (less than 2500 gm). Seven trials (Belizan 1991; Crowther 1999; Levine 1997; Villar 1987; Villar 1990; Villar 2006; Wanchu 2001) evaluated side effects of calcium supplementation. For further details, see Characteristics of included studies.

No trials reported the effect of calcium supplementation on leg cramps, backache, tetany, tremor, paraesthesia, osteopenia, osteoporosis, fracture in pregnant women, duration of breastfeeding or postpartum haemorrhage, and no trials reported on fetal or neonatal osteopenia, rickets and fracture.

Excluded studies

We excluded 14 trials from this review. The reasons for exclusion include: participants were not appropriate, the interventions were not appropriate or the methodology was not appropriate. For more information, see Characteristics of excluded studies. For more information about the studies which we have not yet assessed for inclusion, see Characteristics of studies awaiting classification.

Risk of bias in included studies

The number of participants in trials ranged from 23 to 8325 per trial.The risk of bias in included studies varied. The overall missing data (lost to final analysis) was 3.5% (610 of 17,212 randomised) ranging from (0% - 68.1%). Seven of the 21 trials had no missing data. Nine of the 21 trials had missing data less than 10%, Only one trial had a very high rate of missing data (68.1%). The largest trial had 0.16% missing data. Most of the studies used methods of sequence generation and allocation concealment which we assessed as being at low risk of bias and overall, the included studies were assessed as low risk of bias for other domains of methodological quality. For an overview of review authors' judgments about each risk of bias item for individual included studies, see Figure 1 and Figure 2.

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Allocation

All studies included in this review were reported as being RCTs. Sample size calculation was clearly stated in only one trial (Crowther 1999). However, the two largest trials (Levine 1997; Villar 2006) had good methodological quality. Adequate sequence generation was performed in 13 trials and these were rated as 'low risk of bias' (Belizan 1991; Boggess 1997; Chan 2006; Crowther 1999; Jarjou 2006; Levine 1997; Lopez-Jaramillo 1989; Lopez-Jaramillo 1997; Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Villar 1990; Villar 2006). The other studies did not report how sequence generation was performed. Thirteen trials had adequate allocation concealment and were rated as 'low risk of bias' (Belizan 1991; Boggess 1997; Chan 2006 Crowther 1999; Jarjou 2006; Levine 1997; Lopez-Jaramillo 1989; Lopez-Jaramillo 1997; Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Villar 1990; Villar 2006).

Blinding

Double-blinding was reported in 16 studies (Belizan 1983; Belizan 1991; Boggess 1997; Crowther 1999; Jarjou 2006; Karandish 2003: Levine 1997; Lopez-Jaramillo 1989; Lopez-Jaramillo 1997; Niromanesh 2001; Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Villar 1987; Villar 1990; Villar 2006). One study (Chan 2006) was unable to blind because the groups consumed different food. The four trials using 'no treatment' as the control group were unable to blind the participants (Raman 1978; Rogers 1999; Taherian 2002; Wanchu 2001).

Incomplete outcome data

Most studies reported incomplete outcome data. Intention-to-treat analyses was used in 11 trials (Belizan 1983; Belizan 1991; Crowther 1999; Lopez-Jaramillo 1989; Lopez-Jaramillo 1997; Niromanesh 2001; Rogers 1999; Taherian 2002; Villar 1987; Villar 1990; Villar 2006). Ten trials (Boggess 1997; Chan 2006; Jarjou 2006; Karandish 2003: Lopez-Jaramillo 1997; Purwar 1996; Raman 1978; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Wanchu 2001) did not use this analyses.

The rate of losses to follow-up varied from 0% to 68.1%.

One trial (Crowther 1999) recruited 50% of planned sample size and had to stop recruitment because of a shortage of research funds. Another trial (Sanchez-Ramos 1995) recruited 96% of pre-calculated sample size with the same reason. The other 19 trials did not describe their method of sample size calculation.

Selective reporting

We did not have the protocols for all the included studies; therefore we could not address selective reporting.

Other potential sources of bias

None identified.

Effects of interventions

Primary outcomes

Maternal outcomes
1. Preterm birth less than 37 weeks' gestation

Twelve trials (Belizan 1991; Boggess 1997; Crowther 1999; Levine 1997; Lopez-Jaramillo 1989; Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Taherian 2002; Villar 1990; Villar 2006; Wanchu 2001) with data for 15,615 women. There were 7801 women who received calcium supplementation and 7814 women who received placebo or no treatment. Meta-analysis evaluating the effect of calcium supplementation versus placebo or no treatment on preterm birth before 37 weeks revealed that there was no statistically significant difference between the two groups (average risk ratio (RR) 0.90; 95% confidence interval (CI) 0.73 to 1.11; 12 studies, 15,615 women; random-effects model). However, there was substantial heterogeneity between trials (Tau² = 0.04, I² = 54%, P = 0.02) (Analysis 1.1). Therefore, we explored the source of heterogeneity by subgroup analyses stratified by total dose of calcium per day (less than 1000 mg/day or 1000 mg/day or more), starting time of calcium supplementation (before or after 20 weeks) and type of calcium (calcium carbonate, lactate and gluconate).

For total dose of calcium per day, there appeared to be a difference between subgroups (test for subgroup differences I2 82%, P = 0.02); however, only one study was included in the low dose subgroup (Taherian 2002) while 11 studies were in the high dose group, so this apparent difference between groups may have occurred by chance (Analysis 1.2).

For the starting time of calcium supplementation, we found that there was no statistically significant differences between subgroups for women who started calcium before 20 weeks and for women who started calcium at 20 weeks or more (Analysis 1.3).

For type of calcium, there was no statistically significant difference between subgroups when women received calcium carbonate or calcium gluconate; however only one trial gave calcium gluconate to 92 women and in this study there was no preterm birth before 37 weeks in either the treatment or placebo group (Analysis 1.4).

We also conducted sensitivity analyses by removing two included trials (Taherian 2002; Wanchu 2001) whose allocation of concealment was unclear from the analysis and found that the result did not change (average RR 0.84; 95% CI 0.69 to 1.04; 10 trials, 14,855 women; Tau² = 0.04, I² = 53%; random-effects model) (Analysis 1.1; 1.1.2 Sensitivity analysis by allocation concealment).

To investigate possible publication bias we generated a funnel plot (see Figure 3), as well as the Egger's test and the Egger's plot. Visual examination of the funnel plot suggested there might be some asymmetry and the possibility of publication bias. On the other hand, there was no significant asymmetry detected in the result from Egger's test (coefficient of bias = -0.910, 95% CI -2.282 to 0.462, P = 0.168) and Egger’s plot (see Figure 4). Thus, we concluded that there was no strong evidence of publication bias for the outcome of preterm birth before 37 weeks.

Figure 3.

Funnel plot of comparison: 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), outcome: 1.1 Preterm birth (a) Birth prior to 37 weeks.

Figure 4.

Egger's plot for preterm birth (a) Birth prior to 37 weeks.

Infant outcomes
1. Low birth weight (less than 2500 g)

There was no statistically significant protective effect of calcium supplementation on low birth weight (five trials, Crowther 1999; Levine 1997; Lopez-Jaramillo 1989; Villar 1990; Villar 2006, 13,638 women) (average RR 0.83; 95% CI 0.63 to 1.09; random-effects model). However, there was significant heterogeneity between trials (Tau² = 0.04, P = 0.02, I² = 64%) (Analysis 2.1). Women from these trials all received a high dose.

We carried out subgroup analyses for starting time and type of calcium supplementation. There was some evidence that the starting time of supplementation was associated with different treatment effects (test for subgroup differences P = 0.003, I2 = 88.3%). In two studies supplementation started early and there was no evidence of a significant difference between treatment and control groups, whereas the treatment appeared to have a significant effect in studies where supplementation started after 20 weeks' gestation. However, as a total of only four studies contributed estimable data to this subgroup analysis, these differences may have occurred by chance (Analysis 2.2). All of the studies contributing estimable data used calcium carbonate supplements (Analysis 2.3).

We did not conduct sensitivity analyses because all included trials for this outcome were rated as 'low risk of bias' for allocation of concealment.

We did not conduct a funnel plot, the Egger's test and the Egger's plot to investigate publication bias for this outcome because the number of included trials was insufficient (five trials).

Secondary outcomes

Maternal outcomes
1. Preterm birth less than 34 weeks' gestation

There was no statistically significant difference in birth prior to 34 weeks between calcium supplementation versus placebo or no treatment (three trials, Crowther 1999; Levine 1997; Wanchu 2001, 5145 women) (RR 1.11; 95% CI 0.84 to 1.46) (Analysis 1.5). We did not perform subgroup analysis for this outcome as there was no evidence of substantial heterogeneity (I² = 0%).

We performed a sensitivity analyses and removed one included trial (Wanchu 2001) that had 'unclear' risk of bias for allocation concealment. The result did not change (RR 1.10; 95% CI 0.83 to 1.45; 2 trials, 5045 women; I² = 0%) (Analysis 1.6).

2. Maternal weight gain

Three trials (Lopez-Jaramillo 1989; Lopez-Jaramillo 1997; Villar 1987, 404 women) evaluated the effect of calcium supplementation on maternal weight gain. There was no statistically significant difference between treatment versus placebo or no treatment. We found no statistically significant difference between groups (mean difference (MD) -29.46 g per week; 95% CI -119.80 to 60.89 g per week; random-effects model) (Analysis 1.7). There was also substantial heterogeneity between trials (Tau² = 5007.60, I² = 80%).

3. Maternal bone mineral density (BMD)

There was only one trial, involving 273 women (Raman 1978) that evaluated the effect of calcium supplementation and placebo in BMD. The author used radiographic density calculated and expressed in terms of aluminium equivalents as defined by William and Mason (Williams 1962).

We have presented the data for this outcome separately for treatment arms receiving different doses of supplementation:

In calcium 300 mg:

  • first phalanx: there was no statistically significant difference between treatment versus placebo or no treatment (62 women, MD -0.07 g/cm² ; 95% CI -0.29 to 0.15 g/cm² (Analysis 1.8));

  • second metacarpal: there was no statistically significant difference between treatment versus placebo or no treatment (62 women, MD 0.19 g/cm²; 95% CI -0.02 to 0.40 g/cm² (Analysis 1.9));

  • fourth metacarpal: there was no statistically significant difference between treatment versus placebo or no treatment (62 women, MD 0.06 g/cm²; 95% CI -0.17 to 0.29 g/cm² (Analysis 1.10)).

In calcium 600 mg:

  • first phalanx: there was no statistically significant difference between treatment versus placebo or no treatment (63 women, MD 0.09 g/cm²; 95% CI -0.10 to 0.28 g/cm² (Analysis 1.11));

  • second metacarpal: there was no statistically significant difference between treatment versus placebo or no treatment (63 women, MD 0.14 g/cm²; 95% CI -0.11 to 0.39 g/cm² (Analysis 1.12));

  • fourth metacarpal: there was no statistically significant difference between treatment versus placebo or no treatment (63 women, MD 0.07 g/cm²; 95% CI -0.13 to 0.27 g/cm² (Analysis 1.13)).

4. Maternal death

Data for this outcome were reported in only one of the studies (Villar 2006) with 8312 women. Although there appeared to be fewer deaths in the group receiving calcium supplements compared with controls (1/4151 versus 6/4161), the difference between groups was not statistically significant (RR 0.17, 95% CI 0.02 to 1.39).

5. Maternal admission to intensive care unit

One trial involving 8312 women (Villar 2006) reported on this outcome. There was no statistically significant difference between treatment and control groups (RR 0.84; 95% CI 0.66 to 1.07) (Analysis 1.15). 

6. Mode of birth - vaginal birth, Instrumental vaginal birth, cesarean section (non-prespecified outcome)

7. Postpartum haemorrhage (non-prespecified outcome)

Data were not available for this outcome.

Data were not available for the following maternal secondary outcomes: leg cramps; backache; tetany (muscle spasm and twitching); incidence of fracture; duration of breastfeeding; tremor; parasthesia.

Fetal and neonatal outcomes
1. Perinatal mortality

Seven trials (15123 women) reported perinatal mortality (Belizan 1991; Levine 1997; Lopez-Jaramillo 1997; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Taherian 2002; Villar 2006). There was no statistically significant difference between the groups (RR 0.84; 95% CI 0.61 to 1.16; I² = 0%) (Analysis 2.5). 

2. Stillbirth or fetal death

Four trials (Crowther 1999; Levine 1997; Taherian 2002; Villar 2006) involving 14,083 women reported stillbirth or fetal death separately. There was no statistically significant difference between the groups (RR 0.87, 95%; CI 0.72 to 1.06; I² = 0%) (Analysis 2.6).

3. Neonatal death

Data were not available for this outcome.

4. Admission to neonatal intensive care unit

Admission to neonatal intensive care unit was reported in four trials involving 14062 women (Belizan 1991; Levine 1997; Sanchez-Ramos 1994; Villar 2006). There was no statistically significant difference between the groups (RR 1.05; 95% CI 0.94 to 1.18; I² = 0%) (Analysis 2.7). 

5. Birth weight

Mean birthweight was reported in 19 trials involving 8287 women (Belizan 1983; Belizan 1991; Boggess 1997; Chan 2006; Crowther 1999; Karandish 2003; Levine 1997; Lopez-Jaramillo 1989; Lopez-Jaramillo 1997; Niromanesh 2001; Purwar 1996; Raman 1978; Rogers 1999; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Taherian 2002; Villar 1987; Villar 1990; Wanchu 2001). (In the trials by Belizan 1983 and Raman 1978 data were reported separately for women receiving different doses of calcium; in the meta-analysis we have therefore included findings for different doses separately as there was some heterogeneity between the different treatment arms; in both cases we divided the control group between the two entries to avoid double counting.) There was a statistically significant difference in birthweight between the groups (MD 64.66 g ; 95% CI 15.75 to 113.58 g ; Tau² = 7080.52, I² = 78%; random-effects model) (Analysis 2.4) with the women in the calcium supplementation group on average having heavier babies than those in the control group.

6. Birth length

Birth length was reported in six trials (6031 women) (Belizan 1983; Belizan 1991; Karandish 2003; Levine 1997; Raman 1978; Villar 1990). There was no statistically significant difference between the groups (MD -0.08 cm; 95% CI -0.24 to 0.08 cm; I² = 0%) (Analysis 2.8). 

7. Head circumference

Two trials involving 93 women reported head circumference (Belizan 1983; Karandish 2003) (again data for the two treatment arms of the Belizan 1983 trial were entered separately with the control group shared between entries). There was no statistically significant difference between the groups (MD 0.00 cm; 95% CI -0.72 to 0.72 cm; I² = 0%) (Analysis 2.9). 

8. Intrauterine growth restriction

Intrauterine growth restriction was reported in five trials involving 1177 women (Purwar 1996; Sanchez-Ramos 1994; Sanchez-Ramos 1995; Taherian 2002; Villar 1990). There was no statistically significant difference between the groups (RR 0.86; 95% CI 0.61 to 1.22; I² = 0%) (Analysis 2.10). 

9. Neonatal BMD

We presented the data for this outcome separately as subgroups (with subtotals only) due to the different definition of this outcome as defined by authors (Analysis 2.11):

  • total body: there was no statistically significant difference between treatment versus placebo or no treatment in two trials, 300 women (Jarjou 2006; Levine 1997; MD 0.00 g/cm2; 95% CI 0.00 to 0.01 g/cm2; I2 = 0%);

  • midshaft radius: there was no statistically significant difference between treatment versus placebo or no treatment in one trial involving 122 women (Jarjou 2006; MD 0.00 g/cm2; 95% CI -0.01 to 0.01 g/cm2);

  • lumbar spine 1 to 4: there was no statistically significant difference between treatment versus placebo or no treatment in one trial involving 256 women (Levine 1997; MD 0.01 g/cm2; 95% CI 0.00 to 0.02 g/cm2).

We have excluded the data from the Raman 1978 trial from our meta-analysis because they were skewed but have been presented separately in an additional table (see Table 1).  

Table 1. Neonatal bone density (Skewed data)
  1. The standard deviation (SD) was imputed from the standard error of a mean (SEM).

StudyOutcomeTreatmentControl
MeanSDTotalMeanSDTotal
Raman 1978(Ca 300mg)Ulna1.190.81240.640.2638
Raman 1978(Ca 300mg)Fibula1.120.6240.650.4138
Raman 1978(Ca 300mg)Midshaft radius1.170.62240.080.438
Raman 1978(Ca 300mg)Tibia0.910.35240.580.4138
Raman 1978(Ca 600mg)Ulna1.030.53250.640.2638
Raman 1978(Ca 600mg)Midshaft radius1.170.65250.080.438
Raman 1978(Ca 600mg)Tibia1.110.82250.580.4138
Raman 1978(Ca 600mg)Fibula1.510.61250.650.4138

Data were not available for the following secondary fetal and neonatal outcomes: osteopenia; rickets; fracture.

Adverse outcomes, compliance and maternal satisfaction
1. Side effects of calcium supplementation

Four trials reported side effects of calcium supplementation (Belizan 1991; Villar 1987; Villar 2006; Wanchu 2001). We have presented the data for this outcome separately as subgroups (with subtotals only) due to the different definitions of this outcome in the trials (Analysis 3.1).

  • Maternal cholestatic jaundice: there was no statistically significant difference between the groups in one trial involving 100 women (Wanchu 2001) (RR 3.00; 95% CI 0.13 to 71.92).

  • Gastrointestinal symptoms consisting of nausea, heartburn and diarrhoea: there was no statistically significant difference between the groups in one trial involving 52 women (Villar 1987) (RR 2.16; 95% CI 0.43 to 10.78).

  • Gall stones: there was no statistically significant difference between the groups in one trial involving 518 women (Belizan 1991) (RR 1.35; 95% CI 0.48 to 3.85).

  • Headache, vomiting, backache, swelling, vaginal and urinary complaints, dyspepsia, abdominal pain: there was no statistically significant difference between the groups in one trial involving 8312 women (Villar 2006) (RR 1.02; 95% CI 0.93 to 1.12).

2. Urinary stones

Three trials involving 13,419 women reported this outcome (Belizan 1991; Levine 1997; Villar 2006). There was no statistically significant difference between the groups (RR 1.11; 95% CI 0.48 to 2.54; I2 = 39%) (Analysis 3.2).

3. Urinary tract infection

Three trials involving 1743 women reported this outcome (Belizan 1991; Crowther 1999; Villar 1990). There was no statistically significant difference between the groups (RR 0.95; 95% CI 0.69 to 1.30; I2 = 0%) (Analysis 3.3). 

5. Renal colic

This outcome was reported in one trial with 8312 women (Villar 2006). There was no evidence of a statistically significant difference between groups (RR 1.67, 95% CI 0.40 to 6.99) (Analysis 3.4).

5. Impaired renal function

There was no statistically significant difference between the groups for this outcome in one trial, involving 4589 women (Levine 1997) (RR 0.91, 95% CI 0.51 to 1.64) (Analysis 3.8) (Analysis 3.5).

6. Maternal anaemia

One trials, involving 1098 women, reported this outcome (Belizan 1991). There was no statistically significant difference between the groups (RR 1.04; 95% CI 0.9 to 1.22) (Analysis 3.6).

7. Compliance

Data were not available for this outcome.

8. Satisfaction

Data were not available for this outcome.

Discussion

Summary of main results

Calcium supplementation did not reduce preterm birth. Dosage, prescription timing and the type of calcium supplementation did not effect this outcome. Calcium supplementation did not decrease the rate of low birth weight. Timing of supplementation and the type of calcium supplementation did not show any clear protective effect for low birth weight. No trial reported the effect of low dose calcium supplementation (less than 1000 mg) on low birth weight babies. There was no evidence that calcium supplementation had any effect on maternal weight gain during pregnancy. There was no evidence to support the benefit of calcium supplementation in increasing bone mineral density in pregnant women but in infants, there was a statistically significant difference between treatment and placebo or no treatment in total body and tibial BMD. While there was a statistically significant increase in birthweight in the calcium supplementation group, there was also high heterogeneity among the studies, so the results for this outcome should be interpreted with caution. Additionally, the 65 g increase in birth weight might not be clinically important. There was no evidence that calcium supplementation reduced the rate of intrauterine growth restriction, perinatal mortality, stillbirth or fetal death rate. Calcium supplementation also did not increase birth length or fetal head circumference. We found no evidence to show that calcium supplementation was associated with side effects such as postpartum haemorrhage, cholestatic jaundice, gall stones, gastrointestinal symptoms, headache, urinary stones, urinary tract infection or impaired renal function.

Overall completeness and applicability of evidence

Overall missing data was 3.5% (610 in 17,212). One small trial showed a marked loss of follow-up (68.1%, Raman 1978). The loss to follow-up rate in most trials were less than 20%. Most trials prespecified outcomes in included studies especially the primary outcomes, but no data were reported for some of our secondary outcomes. As we mentioned above, the primary objectives of most (14/21 trials) of the included studies was incidence of pregnancy induced hypertension or changes in blood pressure which was not relevant to this review. However, these studies also had other outcomes relevant to this review, e.g. preterm birth, maternal weight gain, gestational age, birth weight, birth length and therefore, we have included them.

The largest trial in this review (Villar 2006) recruited pregnant women from a population who received less than 600 mg of dietary calcium per day. The other two big trials (Belizan 1991; Levine 1997) did not limit daily calcium intake. In addition, there were variations between trials in terms of duration of supplementation. The subgroup analysis to assess the effect on preterm delivery before 37 weeks of calcium supplementation before versus after 20 weeks' gestation revealed no protective effect on either group. There were too few studies to assess other types of calcium prescribed or other outcomes of interest such as preterm delivery before 34 weeks, maternal bone mineral density, and major fetal outcomes. This may be evidence that routine calcium supplementation in pregnant women for preventing preterm birth and low birth weight is not warranted.

Quality of the evidence

Most of the studies (14 of the 21 trials) had good quality evidence (low risk of bias for sequence generation and allocation concealment), see Figure 1 and Figure 2. Six trials did not describe the method of sequence generation clearly and one trial used a method at high risk of bias. However, their main objective was not to assess pregnancy outcomes other than risk of pregnancy induced hypertension.

Potential biases in the review process

We followed methods set out in the Handbook (Higgins 2011) to try to reduce bias in the review process.

Agreements and disagreements with other studies or reviews

A Cochrane review by Hofmeyr 2006 entitled 'Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems' showed that routine calcium supplementation during pregnancy reduced the risk of pre-eclampsia, and death or serious morbidity.

Authors' conclusions

Implications for practice

This review found that calcium supplementation did not reduce preterm birth less than 37 weeks. There is not enough evidence to assess dosage, timing and type of calcium supplementation on pregnancy outcomes other than pregnancy induced hypertension. The review by Hofmeyr 2006 shows a significant protective effect of calcium supplementation on pre-eclampsia/eclampsia, but our review reveals no additional benefits of calcium supplementation. Therefore, calcium supplementation during pregnancy would be primarily considered to prevent pre-eclampsia.

Implications for research

The results from this review found that there are a few short-term additional benefits of calcium supplementation (other than pre-eclampsia prevention) other than slight increases fetal birthweight and neonatal bone mineral density. However, there are limited data to assess its long-term benefits such as osteoporosis in later life. Further research might be needed to provide evidence regarding long-term benefits.

Acknowledgements

The authors would like to thank Professor Caroline Crowther, Phillippa Middleton, Ruth Martis and the SEA-ORCHID project for supporting a fellowship for Pranom Buppasiri, enabling her to complete this systematic review.

We would like to thank Dr. Reza Navaei for translating Karandish 2003.

We thank Lynn Hampson and Jill Hampson for running the search and identifying the articles for consideration.

We thank the following people for their help in editing the review: Jodie Dodd, Therese Dowswell, Frances Kellie, Jason Wasiak and Lisa Cossens.

We also thank the Thai Senior Researcher Fund for support during the development of the review.

Data and analyses

Download statistical data

Comparison 1. Calcium supplementation versus placebo or no treatment (maternal outcomes)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Preterm birth (a) Birth prior to 37 weeks12 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Main analysis1215615Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]
1.2 Sensitivity analysis by concealment allocation1014855Risk Ratio (M-H, Random, 95% CI)0.84 [0.69, 1.04]
2 Preterm birth (a) Birth prior to 37 weeks by dose of calcium1215615Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]
2.1 Low dose1660Risk Ratio (M-H, Random, 95% CI)1.55 [1.00, 2.41]
2.2 High dose1114955Risk Ratio (M-H, Random, 95% CI)0.85 [0.70, 1.04]
3 Preterm birth (a) Birth prior to 37 weeks by started to take calcium1215549Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.10]
3.1 Started calcium before 20 weeks412766Risk Ratio (M-H, Random, 95% CI)0.97 [0.87, 1.07]
3.2 Started calcium at 20 weeks or more82783Risk Ratio (M-H, Random, 95% CI)0.72 [0.45, 1.15]
4 Preterm birth (a) Birth prior to 37 weeks by type of calcium1215615Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]
4.1 Carbonate1115523Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]
4.2 Lactate00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
4.3 Gluconate192Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
5 Preterm birth (b) Birth prior to 34 weeks35145Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.84, 1.46]
6 Preterm birth (b) Birth prior to 34 weeks - Sensitivity analysis by concealment allocation25045Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.83, 1.45]
7 Maternal weight gain (g/w)3404Mean Difference (IV, Random, 95% CI)-29.46 [-119.80, 60.89]
8 Maternal bone mineral density (g/cm2) - First phalanx (calcium 300 mg)1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
9 Maternal bone mineral density (g/cm2) - Second metacarpal (calcium 300 mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
10 Maternal bone mineral density (g/cm2) - Fourth metacarpal (calcium 300 mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
11 Maternal bone mineral density (g/cm2) - First phalanx (calcium 600 mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
12 Maternal bone mineral density (g/cm2) - Second metacarpal (calcium 600 mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
13 Maternal bone mineral density (g/cm2) - Fourth metacarpal (calcium 600 mg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
14 Maternal death18312Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.02, 1.39]
15 Maternal admission to intensive care unit18312Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.07]
16 Vaginal birth86916Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.99, 1.03]
17 Instrumental vaginal birth2675Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.66, 1.20]
18 Cesarean section86916Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.87, 1.08]
Analysis 1.1.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 1 Preterm birth (a) Birth prior to 37 weeks.

Analysis 1.2.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 2 Preterm birth (a) Birth prior to 37 weeks by dose of calcium.

Analysis 1.3.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 3 Preterm birth (a) Birth prior to 37 weeks by started to take calcium.

Analysis 1.4.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 4 Preterm birth (a) Birth prior to 37 weeks by type of calcium.

Analysis 1.5.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 5 Preterm birth (b) Birth prior to 34 weeks.

Analysis 1.6.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 6 Preterm birth (b) Birth prior to 34 weeks - Sensitivity analysis by concealment allocation.

Analysis 1.7.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 7 Maternal weight gain (g/w).

Analysis 1.8.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 8 Maternal bone mineral density (g/cm2) - First phalanx (calcium 300 mg).

Analysis 1.9.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 9 Maternal bone mineral density (g/cm2) - Second metacarpal (calcium 300 mg).

Analysis 1.10.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 10 Maternal bone mineral density (g/cm2) - Fourth metacarpal (calcium 300 mg).

Analysis 1.11.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 11 Maternal bone mineral density (g/cm2) - First phalanx (calcium 600 mg).

Analysis 1.12.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 12 Maternal bone mineral density (g/cm2) - Second metacarpal (calcium 600 mg).

Analysis 1.13.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 13 Maternal bone mineral density (g/cm2) - Fourth metacarpal (calcium 600 mg).

Analysis 1.14.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 14 Maternal death.

Analysis 1.15.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 15 Maternal admission to intensive care unit.

Analysis 1.16.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 16 Vaginal birth.

Analysis 1.17.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 17 Instrumental vaginal birth.

Analysis 1.18.

Comparison 1 Calcium supplementation versus placebo or no treatment (maternal outcomes), Outcome 18 Cesarean section.

Comparison 2. Calcium supplementation versus placebo or no treatment (infant outcomes)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Low birth weight (< 2500 g)513638Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]
2 Low birth weight (< 2500 g) by started to take calcium513638Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]
2.1 Started calcium before 20 weeks212901Risk Ratio (M-H, Random, 95% CI)0.98 [0.88, 1.10]
2.2 Started calcium at 20 weeks or more3737Risk Ratio (M-H, Random, 95% CI)0.41 [0.23, 0.73]
3 Low birth weight (< 2500 g) by type of calcium513638Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]
3.1 Gluconate192Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
3.2 Carbonate413546Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]
4 Birth weight (g)198319Mean Difference (IV, Random, 95% CI)64.66 [15.75, 113.58]
5 Perinatal mortality715123Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.06]
6 Stillbirth or fetal death414083Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.71, 1.15]
7 Admission to neonatal intensive care unit414062Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.18]
8 Birth length (cm)66031Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.24, 0.08]
9 Head circumference (cm)2100Mean Difference (IV, Fixed, 95% CI)-2.42 [-0.72, 0.72]
10 Intrauterine growth restriction51177Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.22]
11 Neonatal bone mineral density (g/cm2)2 Mean Difference (IV, Fixed, 95% CI)Subtotals only
11.1 Total body2300Mean Difference (IV, Fixed, 95% CI)0.00 [3.45, 0.01]
11.2 Midshaft radius1122Mean Difference (IV, Fixed, 95% CI)0.0 [-0.01, 0.01]
11.3 Lumbar spine1256Mean Difference (IV, Fixed, 95% CI)0.01 [0.00, 0.02]
Analysis 2.1.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 1 Low birth weight (< 2500 g).

Analysis 2.2.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 2 Low birth weight (< 2500 g) by started to take calcium.

Analysis 2.3.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 3 Low birth weight (< 2500 g) by type of calcium.

Analysis 2.4.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 4 Birth weight (g).

Analysis 2.5.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 5 Perinatal mortality.

Analysis 2.6.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 6 Stillbirth or fetal death.

Analysis 2.7.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 7 Admission to neonatal intensive care unit.

Analysis 2.8.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 8 Birth length (cm).

Analysis 2.9.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 9 Head circumference (cm).

Analysis 2.10.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 10 Intrauterine growth restriction.

Analysis 2.11.

Comparison 2 Calcium supplementation versus placebo or no treatment (infant outcomes), Outcome 11 Neonatal bone mineral density (g/cm2).

Comparison 3. Calcium supplementation versus placebo or no treatment (adverse outcomes)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Side effects of calcium supplementation - Maternal cholestatic jaundice4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Maternal cholestatic jaundice1100Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 71.92]
1.2 Gatrointenstinal symptoms (including nausea, heartburn and diarrhoea)152Risk Ratio (M-H, Fixed, 95% CI)2.16 [0.43, 10.78]
1.3 Gall stones1518Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.48, 3.85]
1.4 Headache18312Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.93, 1.12]
2 Urinary stones313419Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.48, 2.54]
3 Urinary tract infection31743Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.69, 1.30]
4 Renal colic18312Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.40, 6.99]
5 Impaired renal function14589Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.51, 1.64]
6 Maternal anemia11098Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.90, 1.22]
Analysis 3.1.

Comparison 3 Calcium supplementation versus placebo or no treatment (adverse outcomes), Outcome 1 Side effects of calcium supplementation - Maternal cholestatic jaundice.

Analysis 3.2.

Comparison 3 Calcium supplementation versus placebo or no treatment (adverse outcomes), Outcome 2 Urinary stones.

Analysis 3.3.

Comparison 3 Calcium supplementation versus placebo or no treatment (adverse outcomes), Outcome 3 Urinary tract infection.

Analysis 3.4.

Comparison 3 Calcium supplementation versus placebo or no treatment (adverse outcomes), Outcome 4 Renal colic.

Analysis 3.5.

Comparison 3 Calcium supplementation versus placebo or no treatment (adverse outcomes), Outcome 5 Impaired renal function.

Analysis 3.6.

Comparison 3 Calcium supplementation versus placebo or no treatment (adverse outcomes), Outcome 6 Maternal anemia.

History

Protocol first published: Issue 2, 2008
Review first published: Issue 10, 2011

Contributions of authors

P Buppasiri (PB) developed the protocol. P Lumbiganon (PL) and J Thinkhamrop (JT) edited and commented on the protocol. C Ngamjarus (CN) commented on the protocol.

For the review, PB and JT independently extracted the data. CN conducted the statistical analysis and summarised the results. PB drafted the review. All review authors commented and finalised the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Faculty of Medicine, Khon Kaen University, Thailand.

  • Faculty of Public Health, Khon Kaen University, Thailand.

External sources

  • Thailand Research Fund / Senior Research Scholar, Thailand.

  • SEA-ORCHID Project, Thailand.

  • Department of Nutrition for Health and Development, WHO, Switzerland.

Differences between protocol and review

  1. We have used the Egger's test to investigate publication bias and this is illustrated in an Egger's plot. This was not prespecified in our protocol. For sensitivity analysis, we removed trials that were rated as 'high risk of bias' and 'unclear risk of bias' for adequate concealment from this analysis.

  2. We used stillbirth or fetal death as the same outcome, these were listed as separate outcomes in the protocol.

  3. We added mode of birth (vaginal birth, instrumental birth, cesarean section), postpartum haemorrhage in secondary maternal outcomes.

  4. We deleted limb pain from the list of neonatal outcomes.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Belizan 1983

MethodsType of study: simple randomisation into 3 groups.
Method of treatment allocation: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.
Participants

Location: outpatient clinic of Guatemala Social Security Hospital.
Time frame: not stated.
Eligible criteria: age 20 to 35 years, single fetus, without evidence of previous pathology and certain date, not receiving any medical treatment during recruitment.
Total recruited: 36 pregnant women.

Treatment group 1 , n = 11, treatment group 2, n = 11, placebo group, n = 14.

Interventions
  • Treatment Group 1 : 1 g calcium/d.

  • Treatment Group 2 : 2 g calcium/d.

  • Compared with placebo tablets.

Started treatment at 15 weeks until delivery.

Outcomes
  1. Blood pressure.

  2. Parathyroid hormone.

  3. Calcium and magnesium level.

  4. Phosphorus level.

  5. Pregnancy outcomes; birthweight, birth length, head circumference.

Notes

The authors did not mention how many tablets were provided in calcium 1 g , 2 g and placebo group.

Missing data = 0%.

For data in Analysis 2.4 and Analysis 2.9 the placebo n was halved to enable inclusion of data for treatment groups 1 and 2.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "After the patients volunteers to participate the trial. Simple randomisation were used to devise patient into 3 groups, receive 1, 2 gm calcium comparing with placebo."
Comment: method of random sequence generation was not clearly described.
Allocation concealment (selection bias)Unclear riskComment: allocation concealment was not described.
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: placebo tablets in the same weight, size, organoleptic characteristics.
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Comment: all enrolled participants were analyses.

MIssing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Belizan 1991

Methods

Type of study: multicenter, double-blind, randomised controlled trial.
Method of treatment allocation: randomisation was conducted at each hospital by a random-generator program. A complete set of numbered, sealed, opaque envelopes containing the randomisation codes was sent to each of three hospitals.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 2.3%.

27 women were lost to follow-up after randomisation (14 in the calcium group, 13 in the placebo group) but before they started treatment, and therefore were not included in the followed up analyses. then follow-up was incomplete for 52 women in the calcium group and 46 in placebo group because change of hospital, physician or residence.

ParticipantsLocation: the women enrolled from 3 affiliated hospitals of Centro Rosario de Estudios Perinatales, Rosario, Argentina (two were public hospitals, the another was a private hospital).
Time frame: January 1987 to September 1989.
Eligible criteria: GA < 20 weeks and confirmed by ultrasound, nulliparous, singleton pregnancy, blood pressure < 140/90 mmHg. No evidence of clinical and laboratory of present or past disease, no taking any medications and had normal glucose tolerance test.
Exclusion criteria: gestational date estimated from LMP and ultrasonography different more than 10 days.
Total recruited: 1194 pregnant women; treatment group, n = 593, control group, n = 601. A total of 579 women in the calcium group and 588 in the placebo group were included in final analyses.
Interventions2 g calcium/d (4 tablets/day; each calcium tablet contained 500 mg calcium carbonate and granulated starch). Compared with placebo tablet .
Started treatment at 20 weeks.
Outcomes
  1. Blood pressure.

  2. Serum total calcium.

  3. Serum magnesium.

  4. Urinary calcium excretion.

  5. Serum phosphate.

  6. Serum uric acid.

  7. Pregnancy outcomes; birthweight, birth length, preterm birth, premature rupture of membrane, diabetic mellitus, third trimester bleeding, numbers of hospital admission, perinatal death.

  8. Rate of urinary tract infection.

  9. Rate of maternal anaemia.

Notes

Treatment group, n = 593, control group, n = 601. For final analysis, treatment group, n = 579, 588 in placebo group but for other pregnancy outcomes other than pregnancy hypertension, n = 544 in calcium group and n = 554 in control group.

Missing data 27 in 1194 = 2.3%.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "They were randomised at each hospital by a random-generator program."
Allocation concealment (selection bias)Low riskQuote: "A complete set of number, sealed, opaque envelopes containing the randomisation codes was sent to each of three hospital."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The calcium tablets were specially prepared by local pharmaceutical company and placebo tablet contained lactose and granules starch and were identical to calcium tablets with respect to weight, size, flavour and colour. The women, the nurses, and the physician responsible for prenatal care were all unaware of the women's treatment status."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Follow-up was incomplete 52 in treatment group and 46 in placebo group because of change of hospital, physician, or residence. Nonetheless, all were included in analyses up to time when they were lost to follow-up. For the subgroup with incomplete follow-up, information about delivery was available for 17 in calcium group and 12 in placebo group."

Missing data 27 in 1194 = 2.3%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Boggess 1997

MethodsType of study: double-blind randomised controlled trial.
Method of treatment allocation: a computer-generated random number table was used. Using a randomisation schedule in block of 10. All containers and tablets were prepared and dispensed by the University Drug Pharmacy.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no (23 women were randomised and 18 of them completed study). Of the 5, 3 developed preterm labor and one was non compliance, and one self discontinued study medication due to side effects.
Losses to follow-up: 5 in 23 = 21.7%.
ParticipantsLocation: University of Washington Medical Center Women's Clinic.
Time frame: not stated.
Eligible criteria: age 18 to 35 years who received antenatal care.
Exclusion criteria: BP > 140/90 mmHg at 24 weeks, smoking or used illicit drugs, multiple gestation, had history of cardiovascular, renal, or endocrine disorder, hypertension prior to pregnancy, or calcium supplementation.
Total recruited: 23 pregnant women; calcium group, n = 12, placebo group, n =11.
Interventions1.5 g/d of calcium carbonate.
Compared with placebo tablets. Started treatment at 28 to 31 weeks.
OutcomesHemodynamic function measurement.
Notes1. GA was reported as median and range. We changed them into mean and SD.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The study patients were assigned in a double-blind fashion to receive orally either 1.5 element calcium as calcium carbonate or placebo daily, using a randomisation schedule in blocks of ten developed by a computer-generated random number table."
Allocation concealment (selection bias)Low riskQuote: "All containers and tablets were prepared and dispensed by the University Drug Pharmacy."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo tablets were same size, weight, colour, and organoleptic characteristics."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Twenty-three women were randomised and 18 of them completed study. Of the five who failed to complete the study; three developed preterm (all placebo), one was noncompliance (placebo), one discontinues due to side effects (calcium)."

Missing data = 5 in 23 = 21.7 %

Selective reporting (reporting bias)Unclear riskNone identified.
Other biasLow riskNone identified.

Chan 2006

MethodsType of study: computer-generated randomisation.
Method of treatment allocation: the pregnant women were randomly assigned to one of three groups: control, orange juice fortified with calcium, and daily. Computer-generated randomisation was kept in envelopes.
Placebo: no.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up at delivery 8.3% : in control group, missing data at delivery = 0, missed 6 months visit, n = 3 and umbilical cord not collected, n = 2. In orange juice plus calcium missing data = 3, failed to meet required 4 servings, n = 12, misses 6 month visit, n = 3,and mothers blood was not collected, n = 3 and umbilical blood was not collected, n = 3. In daily group, missing data at delivery = 3, missed at 6 month visit, n = 2, mother's blood was not collected, n = 3, and umbilical blood was not collected, n = 5.
ParticipantsLocation: University of Utah Teen Mother and Child Program.
Time frame: not stated.
Eligible criteria: healthy adolescent (15 to 17 years old) pregnant women. GA < 20 weeks by last normal menstrual period.
Exclusion criteria: hypertension, diabetes, renal or liver diseases, used alcohol, tobacco or medications that would effect Ca metabolism during pregnancy.
Total recruited: 72 healthy pregnant adolescents.
InterventionsThere were 3 groups. Group 1; control (consume usual diet) N = 23. Group 2; orange juice fortified with calcium consumed at least 4 servings of orange juice plus calcium (more than 1200 mg Ca) n = 24. Group 3; daily (consumed at least 4 serving of daily product (Ca more than 1200 mg) e.g., milk, yogurt, cheese, n = 25. Started treatment at 20 weeks.
Outcomes
  1. Maternal weight gain, blood pressure.

  2. Newborn birthweight, lean and fat mass of infant, total body calcium.

NotesMissing data at delivery 6 in 72 = 8.3%.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Pregnant mothers were randomly assigned to one of three groups; control, orange juice fortified with calcium, and daily. Computer-generated randomisation was kept in sealed envelopes."
Allocation concealment (selection bias)Low riskQuote: "Computer-generated randomisation was kept in sealed envelopes."
Blinding (performance bias and detection bias)
All outcomes
High risk

Quote: "The control group consumed their usual diet while the orange juice plus calcium group were counselled to consume at least four servings of orange juice plus calcium (more than 1,200 mg Ca) so that their Ca intake would be similar to the daily group.The daily group was counselled to consume at least four servings of daily products (more than 1200 mg Ca) daily. Daily products consisted of milk, yogurt, and cheese."

Comment: it was impossible to blind because of different kind of food.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Comment: the authors displayed the flow chart of participants.

Missing data at delivery 6 in 72 = 8.3%.

Selective reporting (reporting bias)Low riskNone identified. Missing data in control group = 13%, in orange juice plus calcium = 12.5 %, in daily product 8%.
Other biasLow riskNone identified.

Crowther 1999

Methods

Type of study: placebo-blind trial.
Method of treatment allocation: the randomisation schedule was prepared by the drug company with stratification made by centre using variable blocks.
Placebo: yes, starch tablets.
Sample size calculation: a study of 948 women was estimated to have an 80% probability of detecting differences in the rate of preterm birth at P = 0.05 and an 88% power to detect a 50% difference with the rate of pregnancy-induced hypertension with the same significance level.
Intention-to-treat analyses: yes.

Pre-calculation samples needed 948 women to be recruited in trial but because of shortage of funds, then only 456 pregnant women were recruited.
Losses to follow-up: 0%.

Participants

Location: 5 Australian Medical Centres.
Time frame: August 1992 to December 1996.

Eligible criteria: nulliparous, singleton pregnancy, at less than 24 weeks, with normal blood pressure at trial entry (< 140/90 mmHg) and expected to birth at five collaborating centre were expected for trial but recruitment to the trial was stopped by the steering group without knowledge of study outcomes after 456 women were randomised when the limited financial resources available for the trial were exhausted.
Exclusion criteria: used of antihypertensive or medical disorder where calcium supplementation was contraindicated such as renal failure, hyperparathyroidism or renal calculi.
Total recruitments: 948 pregnant women were planed to be recruited.
Data were performing when pregnancy outcome data were available for all 456 women recruited. Of 456, 227 were assigned to calcium group, 229 were in placebo group.

InterventionsWomen were asked to take 3 tablets daily orally, equivalent 1.8 g calcium or placebo (calcium carbonate, 600 mg of elemental calcium per tablet). Started treatment at 20 weeks until delivery. Compared with 3 tablets of placebo tablets.
Outcomes1. Incidence of PIH.
2. Pregnancy outcomes; preterm birth, premature rupture of membrane, birthweight.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The randomisation schedule was prepared by the drug company with stratification made by centre using variable blocks."
Allocation concealment (selection bias)Low riskQuote: "A study number was given by the central randomisation office. This corresponded to a sealed treatment pack held at the collaboration centre and were provided by Lederle Laboratories "
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Each treatment package contained identically labelled drug container either 600 mg tablets of calcium or placebo tablets of lactose, identical in size, colour and consistency. Data were entered analysed by non clinical members of the research team, and the treatment allocation code broken after exploratory data analyses."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "948 women were expected for trial but recruitment to the trial was stopped by the steering group without knowledge of study outcomes after 456 women were randomised when the limitation financial resource available for the trial were exhaust. Data were performing when pregnancy outcome data were available for all 456 women recruited. Of 456: 227 were assigned to calcium group, 229 were placebo group."

Comment: the number of participants in treatment and control group were equal.

Missing data = 0%.

Selective reporting (reporting bias)High riskTrial stopped before completely enrolled due to a shortage of research funds.
Other biasLow riskNone identified.

Ettinger 2009

MethodsDouble blind RCT.
Participants670 women were randomised in the first trimester of pregnancy.
Interventions1200 mg calcium daily versus placebo.
OutcomesMaternal blood lead levels.
NotesWe have not included outcome data from this study as it specifically focused on the effects of calcium supplementation on blood lead levels. The study does not address any of the review's primary or secondary outcomes.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo controlled trial.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk670 randomised. 557 included in the analysis (83%).
Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Jarjou 2006

MethodsType of study: a randomised, double-blind, placebo controlled study.
Method of treatment allocation: subjects were randomly assigned in double-blind fashion to receive calcium or placebo by using block of 4 from published sets of table in each month and thereby to minimise the potential for seasonal confounding. The code was held by a member of study team who was not directly involved with the collection of data in the field or laboratory and who had no contact with the study participants.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no, final analyses were 61 from 77 in treatment group, 64 from 78 in control group.
Losses to follow-up: 19.3 % (30 in 155).
Participants

Location: Gambian women, in rural village of Keneba and Manduar, in the province of West King.
Time frame: May 1995 to June 1999.
Eligible criteria: nulliparity with no history of any medical condition known to affect calcium or bone metabolism, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation and intended to undergo delivery at the same institution, normal glucose tolerance test and willing to participate in trial, first antenatal visit BP below 140/90 mmHg and free of any underlying medical disorders, based on a comprehensive medical examination and routine laboratory tests.

Exclusion criteria: had history or evidence of renal disease, collagen vascular disease, chronic hypertension and endocrinological disease or if they take any medication.
Total recruited: 155 pregnant women. Treatment group, n = 77 and control group, n = 78 women. In the final analysis only 125 mother-infant pairs were analysed (61 in the treatment group, 64 in the control group).

Interventions1500 mg of calcium (3 chewable tablets of calcium carbonate per day, 500 mg of elemental calcium). 3 tablets of placebo (contained microcrystalline cellulose and lactose) per day, same shape, taste and texture. The study started from 20 weeks until delivery.
Outcomes
  1. Anthropometric measurement (weight, height of pregnant women and fetal birthweight, height, crown-heel, head circumference) in 24 hours postpartum.

  2. Infant bone mineral density.

NotesLost to follow up of infants outcomes: 16 in treatment group then only 61 infants were analysed, 14 in control group then only 64 infants were analysed.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Subjects were randomly assigned in double-blind fashion to receive calcium or placebo by using block of 4 to ensure that equal numbers of subjects were allocated to supplement and placebo groups in each month and thereby to minimize the potential for seasonal confounding. Randomization was achieved by using published sets of tables."
Allocation concealment (selection bias)Low riskQuote: "The code was held by a member of study team who was not directly involved with the collection of data in the field or laboratory and who had no contact with the study participants."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "3 tablets of placebo (contained microcrystalline cellulose and lactose) per day, same shape, taste and texture)."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "There were no significant differences between the 2 groups in supplementation period, or compliance."

Comment; all enrolled subjects were completed study.

Missing data 30 in 155 = 19.3%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Karandish 2003

Methods

Type of study: double blind, placebo controlled, randomised clinical trial.

Method of treatment allocation: no data.

Placebo: yes (starch tablets).

Intention-to-treat analyses: no, the initial number of participants were 77 pregnant women but by the end of study 68 participants remained .
Losses to follow-up: 11.7 % (9 in 77).

Participants

Location: two prenatal clinics in county of Ahvaz, Iran.

Time frame: no data.

Eligible criteria: pregnant women between the ages of 18 to 35.

Pregnant women in their third trimester before week 28 of their pregnancies.

No history of abortion or stillbirth.

Not suffering from any metabolic or chronic diseases.

Not having previous history of giving birth to twins.

Not being on any other supplements with the exception of iron and folic acid.

Total recruited 77 pregnant women, treatment group, n= 33, placebo group, n= 35.

Interventions1000 mg of calcium (two capsules of 500 mg calcium carbonate) compared with placebo. The study started from 28th-30th week gestation until delivery.
OutcomesAnthropometric parameters of neonates including weight, head circumference and length.
NotesThis paper was written in Farsi. Dr. Reza Navaei kindly translated it to English using the Cochrane Pregnancy and Childbirth Group's translation form.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDouble-blind, placebo-controlled, randomised clinical trial were mentioned but there was no detail of sequencing generation.
Allocation concealment (selection bias)Unclear riskNo detail in allocation concealment.
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants and staff.
Incomplete outcome data (attrition bias)
All outcomes
High riskThe initial participants were 77 pregnant women but the final analyses were 68 women. No detail about 9 women who dropped out from the study.
Selective reporting (reporting bias)Low riskThe preplanned outcomes were reported.
Other biasLow riskNone identified.

Levine 1997

Methods

Type of study: computer-generated simple randomisation sequence.

Method of treatment allocation: package of study tablets were prepared and numbered by manufacturer and then shipped to the medical centre.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 253 in 4589 women (5.5%); 132 in the calcium group, 121 in the placebo group.

Participants

Location: The Calcium for Preeclampsia Prevention (CPEP) Trial at 5 U.S medical centres.

Time frame: not stated.
Eligibility criteria: nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 11 to 21 weeks of gestation and intended to undergo delivery at the same institution, normal glucose tolerance test and willing to participate in trial, blood pressure below 134/84 mmHg and free of any underlying medical disorders, based on a comprehensive medical examination and routine laboratory tests.
Exclusion criteria: taking medication, had bad obstetrical conditions, pre-existing disease, elevated serum concentration of creatinine (> 1.0 mg/dl) or calcium (> 10.6 mg /dl), pregnant women with renal disease, hematuria, or history of urolithiasis in themselves or in first-degree relative and who report frequently use of calcium supplementation or antacid.

Total recruited: 4589 pregnant women; treatment group n = 2295, control group n = 2294.

Interventions2 g of calcium (4 chewable tablets of calcium carbonate per day, 500 mg of elemental calcium), start at 13 to 20 weeks until delivery, 2 tablets with morning meal and 2 tablets with evening meal. Compared with 4 tablets of placebo (contained lactose and granulated starch) per day, same size, weight and colour.
Outcomes
  1. Incidence of PIH.

  2. Pregnancy outcomes; preterm birth, premature rupture of membrane, birthweight, birth length, admission to neonatal intensive care unit, perinatal losses.

  3. Urolithiasis, renal insufficiency.

Notes

Koo 1999 was another subset report of Levine 1997. Total recruited: 289 pregnant women. 13 refused consent; only 256 women and 256 infants were included (128 in each group).

  1. Fetal bone mineral density, bone mineral content.

  2. Pregnancy outcomes; gestational age, birthweight, birth length, and head circumference.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Package of study tablets were prepared and numbered by manufacturer according to a computer-generated simple randomisation sequence developed by statisticians."
Allocation concealment (selection bias)Low riskQuote: "Package of study tablets were prepared and numbered by manufacturer according to a computer-generated simple randomisation sequence developed by statisticians and then were shipped to the medical centres. Upon enrolment, each woman was assigned the next number packages of medication at the centre and thus was randomised automatically to receive calcium or placebo according to the pre assigned random sequence."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Each woman was assigned the next number packages of medication at the centre and thus was randomised automatically to receive calcium or placebo according to the pre-assigned random sequence. Calcium and placebo tablets were of similar colour and taste."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Of 4589 women enrolled in the study, 253 women (5.5%) were lost to follow-up; 132 in the calcium group, 121 in the placebo group."

Missing data 253 in 4589 = 5.5%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Lopez-Jaramillo 1989

Methods

Type of study: prospective, randomised, double-blind, controlled clinical trial.

Method of treatment allocation: table of random numbers. The containers and the calcium tablets for both groups were prepared in Facultad de Quimica y Farmacia.

Stratification: not stated.
Placebo: yes, start tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.

Losses to follow-up: 13.2%.

Only women with no missing values for any of the covariate and outcome variables were included in the analysis. 49 in calcium group and 43 in placebo group. 6 women in calcium group and 8 in placebo group were eliminated from analysis because they were delivered before 38 weeks.

Participants

Location: antenatal outpatient clinic in the Hospital Gineco-Obsterica Isdro Aroya in Quito, Ecuador.

Time frame: 30 months during 1984-1986.

Eligible criteria: nulliparity, age <  25 years, certain last menstrual period, registration at antenatal clinic for the first prenatal visit before 24 weeks gestation and residency in Quito (2800 m altitude) for a period of at least 1 year before conception, blood pressure < 120/80 mmHg and free for of any underlying medical disorders based on a comprehensive medical student examination and routine laboratory tests.

Exclusion criteria: had history of cardiovascular, renal or endocrinological disease or if they took any type of drug or vitamin/mineral preparation.

Total recruited: 106 pregnant women; n = 55 in treatment group, n = 51 in control group.

Interventions2000 mg of calcium (4 tablets of calcium gluconate daily, 500 mg of elemental calcium) compared with 4 tablets of placebo per day, same size, weight and colour. Started treatment at 23 weeks until delivery.
Outcomes
  1. Blood pressure develop PIH.

  2. Pregnancy outcomes; weight gain, preterm birth, birthweight, perinatal mortality.

  3. Serum ionised calcium concentrations.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Using a table of random numbers each patients was assigned independently in sequence to one of two treatment regimens."
Allocation concealment (selection bias)Low riskQuote: "The containers and the calcium tablets for both groups were prepared in Facultad de Quimica y Farmacia."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Treatment assignment was double blind with the composition of the tablets unknown to the patients and to all clinical personnel involved in the study. The placebo group also received four tablets daily of the same size, weight, colour and organoleptic characteristics as calcium tablets."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "106 women satisfactory met the subject selection criteria. Only women with no missing values for any of the covariate and outcome variables were included in these statistical analysis. 49 in the calcium supplemented group and 43 in the placebo group. Six women in calcium supplement group and eight in the placebo group were eliminated from analysis because they were delivery before 38 weeks."

Missing data 14 in 106 = 13.2%.

Selective reporting (reporting bias)Unclear riskComment: not all enrolled participants were analysed.
Other biasLow riskNone identified.

Lopez-Jaramillo 1997

Methods

Type of study: a prospective, randomised, double-blind, control clinical trial. Table randomisation was used.

Method of treatment allocation: used a table of random numbers to assigned each patient independently in sequence to one of two treatment regimens.

Treatment assignment was double-blind, with composition of tablets unknown to the patients and to all clinical personnel involved in the study. The containers and tablets were prepared in the Facultad de Quimica y Farmacia, Universidad Central del Ecuador.

Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: yes, 14 in 274 = 5.1%.

Participants

Location: Hospital Gineco-Obstetrico Isidro Ayora in Quito, Ecuador.

Time frame: 56-month period between 1990 to 1995.

Eligible criteria: age < 17.5 years, nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation, residency in Quito (2800 m altitude) for a period of at least 1 year before conception, blood pressure < 120/80 mmHg and free from any underlying medical disorders, based on a comprehensive medical examination and laboratory test.

Exclusion criteria: had history of cardiovascular, renal or endocrinological disease or if they took any type of drugs or vitamin/mineral preparations.

Total recruited: 274 pregnant teenagers were randomised and then 14 women failed to complete the protocol (3 changed the residence, 7 changed to the private hospital, 2 changed to hospital of social insurance, 2 by non-compliance to treatment) then only 260 completed the study, 125 girls received 2000 mg calcium, 135 girls in control group.

Interventions2 g calcium (4 tablets of calcium carbonate per day, 500 mg of elemental calcium) compared with 4 tablets of placebo (contained lactose and granulated starch) per day, same size, weight, colour and organoleptic characteristics to calcium tablets.
Outcomes
  1. Incidence of PIH.

  2. Serum ionised calcium concentrations.

  3. Pregnancy outcomes; gestational age, weight gain, birthweight, fetal mortality.

  4. Side effects of calcium.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "We used a table of random numbers to assigned each patient independently in sequence to one of two treatment regimens."
Allocation concealment (selection bias)Low riskQuote: "The containers and tablets were prepared in the Facultad de Quimica y Farmacia,Universidad Central del Ecuador."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Treatment assignment was double-blind, with composition of tablets unknown to the patients and to all clinical personnel involved in the study. The placebo group also received four tablets daily similar size, weight, colour, and organoleptic characteristics to the calcium tablets."
Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "274 teenagers were  randomised and then 14 women failed  to completed the protocol (3 changed the residence, 7 changed to the private hospital, 2 changed to hospital of  social insurance, 2 by non-compliance to treatment) then only 260 completed the study, 125 girls received 2000 mg calcium, 135 girls in the control group."
Selective reporting (reporting bias)Low risk

None identified.

Missing data in both groups 14 in 274 = 5.1%. The authors did not provide information about how many people were missing in each group.

Other biasLow riskNone identified.

Niromanesh 2001

Methods

Type of study: double blind, placebo controlled clinical trial. Randomly assigned to one of two treatments.

Method of treatment allocation: the manufacturing company coded the tablets. The hospital pharmacy dispensed the tablet among the subjects.

Stratification: not stated.
Placebo: yes, starch tablet.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.

Participants

Location: Mirza-Kochak-Khan Gynecology Hospital.

Time frame: not stated.
Eligible criteria: high risk for pre-eclampsia, positive roll over test, GA 28 to 32 weeks, blood pressure < 140/90 mmHg.
Exclusion criteria: negative for roll-over test and had any chronic condition such as diabetes, renal diseases, cardiovascular disease, hypertension, and severe anaemia.
Total recruited: 30 women at high risk of pre-eclampsia (15 in the calcium group, 15 in the control group).

Interventions2 gm of calcium (4 tablets of 500 mg orally every 6 hours). Compared with placebo.
Started treatment at 28 to 32 weeks.
Outcomes
  1. Incidence of PIH.

  2. Maternal weight gain.

  3. Pregnancy outcomes; duration of pregnancy, birthweight.

NotesNo details about the type of calcium.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Thirty women at high risk of preeclampsia were randomly assigned to 2 g of calcium daily intake and placebo regimen."

Comment: the method of sequence generation was not described.

Allocation concealment (selection bias)Low riskQuote: "The  manufactory company coded the tablets. The hospital pharmacy dispensed the tablet among the subjects."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Randomization and blinding of subjects and the investigator were managed by providing coded tablets of the same packaging and physical characteristics for both calcium and the placebo tablets."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "There was no loss to follow up in the course of study."

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Purwar 1996

Methods

Type of study: randomised double blind placebo controlled trial.

Method of treatment allocation: the women were assigned randomly in a double fashion to 1 of 2 treatment groups (calcium/placebo) using computer generated random number table. All the containers and tablets were specially prepared by local Universal pharmaceutical, Nagpur.

Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: yes, 11 in 201 = 5.5%.

Participants

Location: the Government Medical College and Hospital, Nagpur, India.

Time frame: October 1,1993 to December 31, 1994.

Eligible criteria: nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation and intending to undergo delivery at the same institution, normal glucose tolerance test < 140 mg/dl and willing to participate in trial, first antenatal visit below 140/90 mmHg and free of any underlying medical disorders, based on a comprehensive medical examination and routine laboratory tests.  

Exclusion criteria: renal disease, collagen vascular disease, chronic hypertension, endocrinological disease or if on any medication.

Total recruited: 201 pregnant women; treatment group N = 103, control group N = 98. Final number for analysis (treatment group n = 97, control group n = 93).

Interventions2 g calcium (4 tablets of 500 mg calcium carbonate). Placebo (4 tablets of placebo) same size, weight and colour.
Outcomes
  1. Incidence of PIH.

  2. Pregnancy outcomes; preterm birth, birthweight, fetal growth restriction.

NotesMissing data 11 in 201 = 5.5%.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The women were assigned randomly in a double-blind fashion at 20 weeks gestation to 1 of 2 treatment groups (calcium/placebo) using computer-generated random number table."
Allocation concealment (selection bias)Low riskQuote: "All the containers and tablets used were specially prepared for the study by local Universal Pharmaceutical Pvt Ltd, Nagpur."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo tablets were same size, weight and colour."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "A total of 98 women randomly assigned to the placebo groups and 103 in calcium groups. Eleven women (5.47%) were lost to follow-up after randomisation (5 in the placebo group and 6 in the calcium group). The total of 93 women in the placebo group and 98 women in the calcium group were included in the fin final analysis."

Missing data 11in 201 = 5.5%.

Selective reporting (reporting bias)Unclear risk

None identified.

There was inconsistent missing data. The number lost to follow-up is 11 from 201, then it should remained 200 participants in final analysis. But the given number included in final analysis was 201 participants.

Other biasLow riskNone identified.

Raman 1978

Methods

Type of study: pregnant women were assigned by strict rotation to one of three groups.

Method of treatment allocation: not clearly stated.

Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: 186 in 273 = 68.1%.

Participants

Location: India, poor segment of the population.

Time frame: not stated.
Eligible criteria: pregnant women who were in low economic status and had regularly consumed supplements were enrolled.
Exclusion criteria: pregnant women suffered from complications such as toxemia, hypertension and diabetes.
Total recruited: 273 pregnant women and divided into 3 groups.

Interventions

Calcium lactate were given in tablet form supplying 150 mg of elemental calcium per tablet. Started treatment at 18 to 22 weeks until delivery.

Group 1: control, n = 38 no treatment.
Group 2: n = 25  received calcium 300 mg/d.
Group 3: n = 24 received calcium 600 mg /d

Outcomes
  1. X-ray left hand (anteroposterior view) of mothers.

  2. X-ray ulna, radius, tibia fibular of neonate.

  3. Densitometry of metacarpal and 4-1 phalangeal of mothers.

  4. Densitometry of ulna, radius, tibia fibular of neonate.

Notes

Comment: Only 87 subjects completed data: 38, 25, 24 subjects in three groups respectively, high rate of loses to follow-up 186 in 273 = 68.1%.

For data in Analysis 2.4 the placebo n was halved to enable inclusion of data for treatment groups 1 and 2.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: " the women were assigned by strictly rotation to one of three groups".

Comment: method of sequence generation was not stated.

Allocation concealment (selection bias)Unclear riskComment: method of allocation concealment was not stated.
Blinding (performance bias and detection bias)
All outcomes
High riskComment: no treatment in control group then it was not blind the participants and the intervention was divided in 2 groups which unequal dosage.
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk

Quote; "Of the 273 mothers registered, data completed in all aspect, could be obtained in 87 subjects (38, 25, 24 respectively)".

Comment: high rate of loss to follow-up.

Missing data 186 in 273 = 68.1%.

Selective reporting (reporting bias)High risk

Comment: high rate of loss to follow-up:

(in treatment group (calcium 300 mg/d) = 72.5%;

in treatment group (calcium 600 mg/d) = 73.6%;

in control group = 58.2%).

Other biasLow riskNone identified.

Rogers 1999

MethodsType of study: randomisation.
Method of treatment allocation: unsealed envelopes.
Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 18 in 237 =7.6%.
ParticipantsLocation: Chinese Women's Hospital, Hong Kong.
Time frame: July 1992 to December 1994.
Eligible criteria: normotensive, MAP > 80 and < 106 mmHg, second trimester, singleton and used cutoff value 60 mmHg of left lateral position.
Exclusion criteria: MAP < 60 mmHg.
Total recruited: 500 pregnant women (131 patients were excluded only 369 patients were randomised),154 in calcium group, 132 in low-dose aspirin, 83 in control group.
Interventions

Compared 3 groups of total 369 patients.

  1. Calcium (154 patients) 600mg/day from 22 to 32 weeks and 1200 mg/d in dividing dose from 32 weeks to delivery.

  2. Low dose aspirin (132 patients) 80 mg/d starting at 22 weeks until delivery.

  3. Control group were no treatment in 83 patients.

Outcomes
  1. Mean arterial blood pressure.

  2. Pregnancy outcomes; gestational age, birthweight, APGAR score.

  3. Incidence of proteinurics and non proteinurics PIH.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "Randomization was into three groups: control, low-dose aspirin, and calcium supplementation in a ratio of 1:2:2 using five unsealed envelope". Of 500 nulliparous screening, 369 were randomisation; 154 were in calcium group, 132 were in low-dose aspirin , and 83 as control group."
Allocation concealment (selection bias)Unclear riskQuote: "Randomization was into three groups; control, low-dose aspirin, and calcium supplementation in a ratio of 1:2:2 using five unsealed envelopes."
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

Quote: "All randomisation, data collection, and data entry were undertaken by the same research assistant with the exception of outcome data, which were entered by the first two authors. The research assistant was therefore blinded to the outcome groups."

Comment: It was impossible to blind the participants because difference of drugs and no treatment in control group.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Fifty (10%) patients eventually delivered in other hospitals and were therefore not subjected to analysis, as they could not reliably be classified into the 3 outcomes groups. 144, 118, and 75 were in calcium group, low-dose aspirin, and control groups respectively were included in final analysis."

Missing data 18 in 237 = 7.6%.

Selective reporting (reporting bias)Unclear riskNone identified.
Other biasLow riskNone identified.

Sanchez-Ramos 1994

Methods

Type of study: randomised double-blind, placebo controlled clinical trial.

Method of treatment allocation: women with positive angiotensin test were randomised by means of a computer-generated list. Calcium and placebo tablets were provided by pharmaceutical company.

Stratification: not stated.
Placebo: yes, placebo.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: 4 in 67 = 6.0%.
Post randomised exclusion: 6 in 67 =  8.9 % did not comply fully the protocol; 4 were excluded from analysis after randomisation because lacking of information, one was admitted to other hospitals (in placebo group), another woman refused to participate after one week of trial (in calcium group).

Participants

Location: University of Florida Health Science Center, Jacksonville, Florida.

Time frame: January 1, 1989 to July 30, 1993.
Eligible criteria: normotensive, nulliparous with increased risk of pregnancy induced hypertension with positive angiotensin sensitivity test  only who were positive roll over test (women supine diastolic blood pressure value were more than 20 mmHg higher than those obtained on her side) received angiotensin infusion at 24 to 28 weeks.

Exclusion criteria: subjects which conditions known to increase the incidence of pregnancy induced hypertension, including history or evidence of renal disease, collagen vascular disease, diabetes mellitus, chronic hypertension and multiple pregnancy.

Total recruited: 281 pregnant women were positive roll-over test; 67 women positive angiotensin sensitivity test; 33 received calcium, 34 received placebo. Final analyses, calcium group, n = 29, control group, n = 34.

Interventions2 g of calcium carbonate, compared with placebo (contained starch and were identical to calcium tablets with respected to weight, size, flavour and appearance).
Outcomes
  1. Incidence PIH.

  2. Pregnancy outcomes; gestational age, preterm birth, birthweight, APGAR score, NICU admission, fetal growth restriction, perinatal death.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Women with positive angiotensin test were randomised by means of  a computer-generated list to receive either 2 g/day of elemental calcium or matching placebo."
Allocation concealment (selection bias)Low riskQuote: "Calcium and placebo tablets were provided by pharmaceutical company."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo contained starch and were identical to calcium tablets with respect to weight, size, flavour and appearance."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Six women (8.9%) did not comply fully the protocol; of these, four were excluded from analysis after randomisation because lack of information. One had a single follow-up prenatal visited and refused to continue participating in the study. She was admitted to another hospital at 35 weeks' gestation with severe preeclampsia and required labour induction (in placebo group). Another woman refused to participate after one week of trial (in calcium group)."

Missing data 4 in 67 = 6%.

Selective reporting (reporting bias)Unclear riskNone identified.
Other biasLow riskNone identified.

Sanchez-Ramos 1995

Methods

Type of study: computer-generated list of random numbers.

Method of treatment allocation: the randomisation list was maintain by pharmaceutical personnel. The drug and placebo were delivered by pharmacy to antepartum ward, where nurse administered the medication.

Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no, because of a decline in perinatal research support, the study was terminated three cases earlier than suggested by power analysis.

Losses to follow-up: 0%.

Participants

Location: University Medical Center.

Time frame: July 1990 - January 1993.

Eligible criteria: nulliparity, 24 to 36 weeks' gestation, mild pre-eclampsia and no evidence of severe pre-eclampsia within 48 hours of admission.

Exclusion criteria: proteinuria > 5 g/d, platelet count < 100,000, oliguria (urine < 500 ml/d), pulmonary edema, elevated liver enzyme > 200 U/L, microangiopathic haemodynamic anaemia, fetal growth retardation, known sensitivity to calcium, chronic hypertension, chronic renal disease, diabetes mellitus,or calcium supplement before admission.

Total recruited: 75 eligible subjects; 36 in treatment group, 39 in control group (because of a decline in perinatal research support, the study was terminated three cases earlier than suggested by power analysis).

Interventions2 g of calcium/d (4 tablets of calcium carbonate per day, 500 mg of elemental calcium). Placebo (4 tablets of placebo per day, same size, weight and colour).
Outcomes
  1. Incidence of severe pre-eclampsia.

  2. Pregnancy outcomes; gestational age, birthweight, APGAR score, fetal growth restriction, perinatal death.

  3. Umbilical arterial blood gas.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Patients were assigned using a computer-generated list of random number to receive either calcium or matching placebo."
Allocation concealment (selection bias)Low riskQuote: "The randomisation list was maintained by pharmacy personnel; the drug and placebo were delivered by pharmacy to antepartum ward, where nurse administered the medication."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Patients were assigned to receive either calcium or matching placebo. Clinician caring for study patients were blinded to treatment group allocation."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "During the studied period, 75 eligible subjects were identified and invited to participate; 36 (48%) were assigned to calcium and 39 (52%) to placebo. Because of decline in perinatal research support, the study was terminated three cases earlier than suggested by power analysis."

Missing data = 0%.

Selective reporting (reporting bias)Low riskTrial was stopped before complete enrolment due to decline of research fund.
Other biasLow riskNone identified.

Taherian 2002

Methods

Type of study: randomised controlled study.

Method of treatment allocation: the sampling method was non probability convenience. Use table of random to assign each case independently to one of three group.

Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention to treat analyses: yes.
Losses to follow-up: 0%.

Participants

Location: Isfahan Health Center, Iran.

Time frame: April 1998 to March 2001.
Eligible criteria: nulliparity, single gestation, first antenatal visit before 20 weeks of gestation, BP < 130/80 mmHg and no proteinuria by urine dipstick.
Exclusion criteria: had history of cardiovascular, renal disease or endocrinologic problem, medical or obstetric complications and those with known hazardous condition (multiple gestation, hydatidiform mole).
Total recruited: 990 healthy pregnant women (n = 330 subjects/group).

InterventionsGroup 1: received 75 mg aspirin /day, n = 330.
Group 2: received 500 mg calcium carbonate/day, n = 330.
Group 3: no treatment as control group, n = 330.
Started treatment at 20 weeks until delivery.
Outcomes
  1. Blood pressure.

  2. Pregnancy outcomes; gestational age, birthweight, preterm birth, APGAR score, fetal growth restriction, perinatal death.

NotesComment: the results were reported as mean and 95% CI, then we changed them into SD.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "The sampling method was non probability convenience. We use table of random number to assign each case independently to one of three group."
Allocation concealment (selection bias)Unclear riskComment: the method of allocation concealment was not stated.
Blinding (performance bias and detection bias)
All outcomes
High risk

Quote: "Group 1 received 75 mg aspirin; group 2 received 500 mg oral calcium-D daily; and the control group 3 received no medication at all."

Comment: it was impossible to blind because the difference of drug and no treatment in control group.

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Comment: all enrolled participants were included in the analyses.

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Villar 1987

Methods

Type of study: double-blinded, randomised controlled clinical trial.

Method of treatment allocation: the women were assigned randomly in the double blind fashion at 26 weeks' gestation to one of two treatment groups, using a randomisation schedule prepared in advance for the complete population.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.

Participants

Location: the Johns Hopkins Hospital in Baltimore and Perinatal Study Center of Rosario, Argentina.

Time frame: 1983 to 1985.
Eligible criteria: nulliparous, singleton, known last menstrual period, age 18 to 30 years, free from any underlying medical disorders, negative roll-over test.
Exclusion criteria: history of cardiovascular or renal disease or taking any drug.
Total recruited: 52 pregnant women:
*18 white: 9 in calcium group, 9 in placebo group;
*34 black women: 16 in calcium group, 18 in placebo group.
Total in calcium group, n = 25; in placebo group, n = 27.

Interventions3 tablets of calcium carbonate (500 mg each). Compared with 3 placebo tablets with same size, weight, size, colour and organoleptic characteristics.
Started treatment at 26 weeks.
Outcomes
  1. Incidence of pregnancy induced hypertension.

  2. Birthweight.

NotesComment: the authors provide only mean birthweight but not SD. SD in both groups were imputed by mean.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "The women were assigned randomly in the double blind fashion at 26 weeks gestation to one of two treatment groups, using a randomisation schedule prepared in advance for the complete population."
Allocation concealment (selection bias)Low riskQuote: "The same randomization code, standardization process, and tablets were used in both populations and code was kept in central allocation (Baltimore). Random number in closed envelopes and corresponding medication were distributing to the two hospitals at the beginning. All containers and tablets  were prepared by pharmaceutical."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo same size, weight, size, colour and organoleptic characteristic."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Comment: all enrolled participants were included in the analyses.

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Villar 1990

Methods

Type of study: double-blind, randomised placebo-controlled clinical trial.

Method of treatment allocation: computer-generated list of random number. Opaque envelope with the bottle number were located at the clinic and the project coordinator was in charge of the administration of the treatment assigned.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.

Participants

Location: Adolescent Pregnancy Clinic of the Johns Hopkins Hospital in Baltimore.

Time frame: 1985 to1988.

Eligible criteria: age < 17 year, GA < 20 week, singleton pregnancy, certain last menstrual period, free from any underlying medical disorders determined by history, physical examination, and laboratory tests.

Exclusion criteria: underlying medical disorders determined by history, physical examination, and laboratory tests.

Total recruited: 190 adolescent pregnant women; 95 in the calcium group, 95 in the placebo group.

Interventions2 g of calcium (4 tablets of calcium carbonate per day, 500 mg of elemental calcium) compared with 4 tablets of placebo (contained lactose and granulated starch) per day, same size, weight and colour. Started treatment at 20 weeks until delivery.
Outcomes
  1. Incidence of preterm labor.

  2. Incidence of low birthweight, intrauterine growth restriction, premature rupture of membrane, PIH.

  3. Pregnancy outcomes; gestational age, birthweight , birth length.

  4. Incidence of bacteriuria, pyelonephritis.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "A computer- generated list  of random number was used to allocate the corresponding treatments."
Allocation concealment (selection bias)Low riskQuote: "Opaque envelope with the bottle number were locate at the clinic and project coordinator was in charge of the administration of the  treatment assigned."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The placebo group received four tablets (contained lactose and granulated starch) per day of the same size, weight, colour, and organoleptic characteristics as the calcium tablets."
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Comment: all enrolled participants were analyses.

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Villar 2006

Methods

Type of study: multicenter, randomised, placebo-controlled, double trial. Central randomisation at WHO Geneva.

Method of treatment allocation: computer-generated random number blocking with randomly varying groups of 6 to 8 women and were used to restrict randomisation in the strata (country). The technique consisted of allocating consecutively numbered treatment boxes for each woman. Randomisation codes remained at the WHO Clinical trial Unit until the time of analysis and were not available to any person until the analyses were completed. Boxes and tablets were prepared and numbered by Magistra SA, GENEVA and were shipped to each centre.
Stratification: yes, by country.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 13 in 8325 = 0.16%.

Before started treatment 2 in calcium were not pregnant, 2 in placebo group, then were excluded from analyses. 143 (3.4%) in calcium group (4157-143 ) lost to follow-up and no delivery information then 4008 pregnancies available for analyses.
155 (3.7%) in placebo group (4168-155) lost to follow-up and no delivery information then 4006 pregnancies available for analyses of preterm labor and 4161 pregnancies  available for analyses of PIH (final analyses) of preterm labor and 4151 pregnancies available for analyses of PIH (final analyses).

Post randomised exclusion: 4 in calcium were not pregnant, 5 in placebo group.

Participants

Location: Rosiario, Argentina; Assiut , Egypt; Nagpur and Vellor , India; Lima, Peru; East London and Johannesburg, South Africa; Ho Chiminh City, Viet Nam; where population intake calcium < 600 mg/d.

Time frame: November 2001 to July 2003.
Eligible criteria: healthy nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation.
Exclusion criteria: blood pressure > 140/90 mmHg, had history or evidence of chronic hypertension, renal disease, signs and symptoms of nephrolithiasis, parathyroid disease and disease that require digoxin, phenytoin, or tetracycline therapy.

Total recruited: 8325 pregnant women were randomised, treatment group, n = 4157, control group, n = 4168.

Interventions1.5 g of calcium carbonate (1 x 500 mg tablet, three times per day at meal time), chewable tablets started at 20 weeks until delivery, and > 3 hours after any iron supplement. Compared with 3 tablets of placebo (contained lactose, sorbitol, cellulose plus other calcium free ingredient) per day, same form, colour and taste.
Outcomes
  1. Incidence of pre-eclampsia/eclampsia.

  2. Pregnancy outcomes; gestational age, preterm birth, birthweight , birth length, maternal admission to intensive care unit, maternal death, stillbirth, neonatal death.

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskQuote: "Central randomisation at WHO Geneva. Computer-generated random number blocking with randomly varying groups of 6 to 8  women and were used to restrict randomisation in the strata (country)."
Allocation concealment (selection bias)Low riskQuote: "The technique consisted of allocating consecutively numbered treatment boxes for each woman. Randomization codes remained at the WHO Clinical trial Unit until the time of analysis and were not available to any person until the analyses were completed. Boxes and tablets were prepared and numbered by Magistra SA, GENEVAand were shipped to each centre."
Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The placebo tablets were identical in form, colour, and taste ".
Incomplete outcome data (attrition bias)
All outcomes
Low risk

Quote: "Of 8325 women assigned randomly to group, 4157 were assigned to the calcium group and 4168 were assigned to the placebo group. Nine women (5 in the placebo group; 4 in calcium group) were determined to not be pregnant, and 2 women from each group who were lost to follow-up before starting any treatment were excluded from all analyses. Delivery information was unavailable for 143 (3.4%) in the placebo group; therefore, they did not contribute to the preterm analyses, but the available data were included in the analyses for other outcomes. Thus, 4151 women in the calcium group and 4161 women in the placebo group contribute to the final analyses.

Missing data 13 in 8325 = 0.16%.

Selective reporting (reporting bias)Low riskNone identified.
Other biasLow riskNone identified.

Wanchu 2001

  1. a

    BP = Blood pressure
    Ca = Calcium
    g = gram
    g/d = grams per day
    GA = gestational age
    IUGR = intrauterine growth restriction
    LMP = last menstrual period
    MAP = mean arterial pressure
    Mg = magnesium
    ml/d = millilitres per day
    mmHg = millimetres mercury
    PIH = pregnancy induced hypertension
    PROM = preterm rupture of the membranes
    SD = standard deviation
    U/L = units per litre
    WHO = World Health Organisation

Methods

Type of study: randomly assigned to ether group of two treatment groups.

Method of treatment allocation: not stated.
Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: 20 in 120 = 16.7%.

ParticipantsLocation: Post Graduate Institute of Medical Education and Research, Chandigarh.
Time frame: not stated.
Eligible criteria: uncomplicated normotensive primigravida with singleton pregnancy, GA < 20 weeks.
Exclusion criteria: multiple pregnancy, molar pregnancy, hydramnios, congenital malformation, chronic hypertension, chronic renal disease, diabetes mellitus and those already on calcium supplementation.
Total recruited: 120 pregnant women were enrolled, 100 who completed the protocol were analysed. 50 participants in treatment group n = 50, 50 participants in control group. .
Interventions2 g of calcium (4 tablets of calcium carbonate). Compared with no treatment. Started treatment at 20 weeks.
Outcomes
  1. Incidence of pregnancy induced hypertension.

  2. Pregnancy outcomes; gestational age, PROM, preterm birth, birthweight, IUGR, APGAR score.

NotesNo restriction was put on dietary calcium intake in either group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned to ether group of two treatment groups."
Comment: the method of sequence generation was not stated.
Allocation concealment (selection bias)Unclear riskComment: the method of allocation concealment was not stated.
Blinding (performance bias and detection bias)
All outcomes
High riskComment: the control group was no treatment.
Incomplete outcome data (attrition bias)
All outcomes
High risk

Quote: "120 pregnant women were enrolled in the study, 100 women who completed the protocol were analysed.

Missing data = 20 in 120 = 16.7%.

Selective reporting (reporting bias)Unclear riskNone identified.
Other biasLow riskNone identified.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    g = grams
    PIH = Pregnancy induced hypertension

Duggin 1974The outcomes were not relevant and allocation to groups was not random. Seven primiparas (aged 16-19 years) who were at 32-36 weeks' gestation were included. The participants were divided into control subjects (patient 1-4) and supplemented subjects (patients 5-7) to measure metabolic balance.
Felix 1991There was not random allocation to groups in this trial (women allocated to groups in sequence). The aim of the study was to examine the hypotensive effects of calcium in Andean women.
Hammar 1981The participants were not appropriate. This study was aimed to determine the effect of calcium treatment in pregnant women who suffered from leg cramps. 42 pregnant women who suffered from leg cramps with gestational age 21-38 weeks were included.
Janakiraman 2003This was a crossover study examining bone resorption among pregnant women during received calcium supplementation. 32 pregnant women gestational age 25-35 weeks participated in the study for 20 days. Each women received 1200 mg calcium supplement for 10 days and multivitamin without calcium for 10 days. N-telopeptides of type I collagen (NTX), a biomarker of bone resorption were measured.
Kalkwarf 1997The intervention was not appropriate. The study aimed to examine the effect of calcium supplementation on bone density in postpartum period. The randomised, placebo-controlled trials of 1 g calcium supplementation was conducted in 97 lactating and 99 non-lactating women a mean 16 ± 2 says postpartum (the study of lactation). The other trial (the study of weaning) 95 lactating women who weaned their infants in 2 months after enrolments and 92 non-lactating women were enrolled 5.6 ± 0.8 month postpartum.
Kent 1995The participants were not appropriate. This was a study focusing on the postpartum period and women were not randomised to receive calcium until 36 weeks' gestation. This trial aimed to study the effect of an oral calcium supplement on regional bone loss in normal lactation women. 79 pregnant women at gestational age 36 weeks were randomised to received placebo or 500 mg twice daily of calcium through to 24 weeks' lactation.
Liu 2011The intervention was not appropriate. The participants were provided calcium supplementation until 6 weeks postpartum and measured bone mineral density post-treatment.
Lopez-Jaramillo 1990The participants were not appropriate.The study aimed to examine the effect of calcium supplementation on risk of PIH in pregnant women who had a positive roll-over test.
Mahomed 2000The participants were not appropriate. The study aimed to examine the effect of calcium supplementation on risk of PIH and preterm labor in twin pregnancy.
Mukherjee 1997The participants were not appropriate. The study aimed to examine the effect of calcium supplementation in reduce leg cramps in homogeneous Chinese population. All pregnant women who suffered from leg cramps during January 1994 and May 1995 were enrolled to received either calcium gluconate 600 mg twice daily or two multivitamin tablets twice daily.
Odendaal 1974The participants were not appropriate. Calcium was supplemented only when participants suffered from leg cramps which not relevant to the objective of the review.
Prentice 1995This study did not examine calcium supplementation amongst pregnant women. 60 Gambian mothers consuming a low-calcium were randomised to receive calcium supplement or placebo from 10 days to 78 weeks postpartum.
Qui 1999The intervention was not relevant. Calcium was supplemented from 20 weeks' gestation to postpartum 45 days.
Robinson 1947The intervention was not appropriate. Calcium was given to treat women with leg cramps which was not relevant to the objective of the review.

Characteristics of studies awaiting assessment [ordered by study ID]

Almirante 1998

MethodsParticipant were divided into 2 groups.
Participants430 pregnant women in first trimester who were nulliparous, adolescents and elderly.
Interventions

Treatment group, n = 212 were given 500mg elemental calcium per day on the 16th-20th week until delivery.

Control group, n = 210 were not given calcium supplementation.

OutcomesEarly pregnancy hypertension, prematurity, number of babies admitted to NICU.
NotesAbstract only. We have contacted the authors but have not had a reply. We will reconsider this trial for inclusion once the full publication is available, or the authors have provided more information.

Chames 2002

MethodsRandomised double-blind placebo control trial.
Participants50 pregnant women with 13-19 weeks pregnancy.
Interventions

1000 mg calcium per day compared with placebo.

Control group, n = 26, treatment group, n = 24.

OutcomesBlood lead level.
NotesAbstract only. We have contacted the authors but have not had a reply. We will reconsider this trial for inclusion once the full publication is available, or the authors have provided more information.

Galimberti 2001

MethodsThe author did not state clearly about randomisation but the participant were divided into 2 groups.
Participants44 pregnant women (calcium intake 310-720 mg/d).
Interventions

Treatment group , n = 26 were given calcium supplementation 750 mg/d (as calcium citrate) until delivery.

Contron group, n = 18 received placebo.

OutcomesSerum level of Ca and markers of bone turn-over.
NotesAbstract only. We have contacted the authors but have not had a reply. This trial will be reconsidered for inclusion once the full publication is available, or the authors have provided more information.

Repke 1989a

  1. a

    Ca = Calcium
    g/d = grams per day
    NICU = Neonatal intensive care unit

MethodsRandomised clinical trial.
ParticipantsAfter 20-week pregnancy.
Interventions2 g/d versus placebo. Treatment group, n = 125. Control group, n = 130.
OutcomesHaemoglobin level.
NotesAbstract only. We have contacted the authors but have not had a reply. We will reconsider this trial for inclusion once the full publication is available, or the authors have provided more information.

Ancillary