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

  1. Pranom Buppasiri1,*,
  2. Pisake Lumbiganon1,
  3. Jadsada Thinkhamrop1,
  4. Chetta Ngamjarus2,
  5. Malinee Laopaiboon3

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 22 JUN 2011

DOI: 10.1002/14651858.CD007079.pub2


How to Cite

Buppasiri P, Lumbiganon P, Thinkhamrop J, Ngamjarus C, Laopaiboon M. Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD007079. DOI: 10.1002/14651858.CD007079.pub2.

Author Information

  1. 1

    Khon Kaen University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen, Khon Kaen, Thailand

  2. 2

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

  3. 3

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

Publication History

  1. Publication Status: New
  2. Published Online: 5 OCT 2011

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This is not the most recent version of the article. View current version (25 FEB 2015)

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

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.

 FigureFigure 1. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
 FigureFigure 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.

 FigureFigure 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.
 FigureFigure 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).  

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
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 weeks12Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Main analysis
1215615Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

    1.2 Sensitivity analysis by concealment allocation
1014855Risk 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 dose
1660Risk Ratio (M-H, Random, 95% CI)1.55 [1.00, 2.41]

    2.2 High dose
1114955Risk 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 weeks
412766Risk Ratio (M-H, Random, 95% CI)0.97 [0.87, 1.07]

    3.2 Started calcium at 20 weeks or more
82783Risk 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 Carbonate
1115523Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

   4.2 Lactate
00Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    4.3 Gluconate
192Risk 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)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

 9 Maternal bone mineral density (g/cm2) - Second metacarpal (calcium 300 mg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 10 Maternal bone mineral density (g/cm2) - Fourth metacarpal (calcium 300 mg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 11 Maternal bone mineral density (g/cm2) - First phalanx (calcium 600 mg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 12 Maternal bone mineral density (g/cm2) - Second metacarpal (calcium 600 mg)1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 13 Maternal bone mineral density (g/cm2) - Fourth metacarpal (calcium 600 mg)1Mean 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]

 
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 weeks
212901Risk Ratio (M-H, Random, 95% CI)0.98 [0.88, 1.10]

    2.2 Started calcium at 20 weeks or more
3737Risk 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 Gluconate
192Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Carbonate
413546Risk 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)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

    11.1 Total body
2300Mean Difference (IV, Fixed, 95% CI)0.00 [3.45, 0.01]

    11.2 Midshaft radius
1122Mean Difference (IV, Fixed, 95% CI)0.0 [-0.01, 0.01]

    11.3 Lumbar spine
1256Mean Difference (IV, Fixed, 95% CI)0.01 [0.00, 0.02]

 
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 jaundice4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Maternal cholestatic jaundice
1100Risk 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 stones
1518Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.48, 3.85]

    1.4 Headache
18312Risk 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]

 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

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

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms
 

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. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. History
  11. Contributions of authors
  12. Declarations of interest
  13. Sources of support
  14. Differences between protocol and review
  15. Index terms

  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.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractアブストラクトRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Belizan 1983 {published data only}
  • Belizan JM, Villar J, Zalazar A, Rojas L, Chan D, Bryce GF. Preliminary evidence of the effect of calcium supplementation on blood pressure in normal pregnant women. American Journal of Obstetrics and Gynecology 1983;146:175-80.
Belizan 1991 {published data only}
  • Belizan JM, Villar J, Bergel E, Del Pino A, Di Fulvio S, Galliano SV, et al. Long term effect of calcium supplementation during pregnancy on the blood pressure of offspring: follow up of a randomized controlled trial. BMJ 1997;315:281-5.
  • Belizan JM, Villar J, Gonzalez L, Campodonico L, Bergel E. Calcium supplementation to prevent hypertensive disorders of pregnancy. New England Journal of Medicine 1991;325:1399-405.
  • Bergel E, Gibbons L, Rasines MG, Luetich A, Belizan JM. Maternal calcium supplementation during pregnancy and dental caries of children at 12 years of age: follow-up of a randomized controlled trial. Acta Obstetricia et Gynecologica Scandinavica 2010;89(11):1396-402.
  • Stephens IF. Effect of calcium supplementation during pregnancy on blood pressure of offspring; Authors cannot be sure of effect's generalisability to all children aged 5-9 [letter; comment]. BMJ 1998;316(7126):234.
  • Villar J, Belizan JM, Repke JT. Does calcium supplementation reduce pregnancy-induced hypertension and prematurely?. Proceedings of International Symposium on Advances in the Prevention of Low Birthweight; 1988 May 8-11; Cape Cod, Massachusetts, USA. 1988.
Boggess 1997 {published data only}
Chan 2006 {published data only}
  • Chan GM. The effects of dietary milk on adolescent pregnant mothers and their newborn [abstract]. Pediatric Academic Societies Annual Meeting; 2006 April 29-May 2; San Francisco, CA, USA. 2006.
  • Chan GM, McElllgot K, McNaught T, Gill G. Effects of dietary calcium intervention on adolescent mothers and newborns. Obstetrics & Gynecology 2006;108:565-71.
Crowther 1999 {published data only}
  • Crowther C, Hiller J, Pridmore B, Bryce R, Duggan P, Hague W, et al. Calcium supplementation in nulliparous women for the prevention of pregnancy included hypertension, pre-eclampsia and preterm birth: an Australian randomised trial. 2nd Annual Congress of the Perinatal Society of Australia & New Zealand; 1998 March 30-April 4; Alice Springs, Australia. 1998:101.
  • Crowther CA, Hiller JE, Pridmore B, Bryce R, Duggan P, Hague WM, et al. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: an Australian randomized trial Fracog and the ACT study group. Australian and New Zealand Journal of Obstetrics and Gynaecology 1999;39(1):12-8.
  • Griffith EC, Crowther CA, Hiller JE, Wilson KJ, ACT Study Group. Leg cramps in pregnancy: ineffectiveness of calcium supplementation. 2nd Annual Congress of the Perinatal Society of Australia & New Zealand; 1998 March 30-April 4; Alice Springs, Australia. 1998:99.
  • Hiller JE, Crowther CA, Moore VA, Willson K, Robinson JS. Calcium supplementation in pregnancy and its impact on blood pressure in children and women: follow up of a randomised controlled trial. Australian and New Zealand Journal of Obstetrics and Gynaecology 2007;47(2):115-21.
Ettinger 2009 {published data only}
  • Ettinger AS, Lamadrid-Figueroa H, Tellez-Rojo MM, Mercado-Garcia A, Peterson KE, Schwartz J, et al. Effect of calcium supplementation on blood lead levels in pregnancy: a randomized placebo-controlled trial. Environmental Health Perspectives 2009;117(1):26-31.
Jarjou 2006 {published data only}
  • Hawkesworth S, Sawo Y, Fulford AJ, Goldberg GR, Jarjou LM, Prentice A, et al. Effect of maternal calcium supplementation on offspring blood pressure in 5- to 10-y-old rural Gambian children. American Journal of Clinical Nutrition 2010;92(4):741-7.
  • Jarjou L, Prentice A, Sawo Y, Laskey MA, Bennett J, Goldberg GR, et al. Randomized, placebo-controlled, calcium supplementation study in pregnant Gambian women: effects on breast-milk calcium concentrations and infant birth weight, growth, and bone mineral accretion in the first year of life. American Journal of Clinical Nutrition 2006;83(3):657-66.
  • Jarjou LM, Laskey MA, Sawo Y, Goldberg GR, Cole TJ, Prentice A. Effect of calcium supplementation in pregnancy on maternal bone outcomes in women with a low calcium intake. American Journal of Clinical Nutrition 2010;92(2):450-7.
  • Jarjou LM, Prentice A, Bennett J. Impact of calcium supplementation in the preceding pregnancy on the human milk calcium concentration of Gambian women. Advances in Experimental Medicine and Biology 2004;54:347-9.
  • Jarjou LMA, Bennett J, Laidlow A, Goldberg GR, Prentice A. Changes in bone turnover and calciotropic hormones in lactating Gambian women supplemented with calcium during pregnancy. Journal of Human Lactation 2007;23:86-7.
  • Prentice A, Jarjou LM, Goldberg GR, Bennett J, Cole TJ, Schoenmakers I. Maternal plasma 25-hydroxyvitamin D concentration and birthweight, growth and bone mineral accretion of Gambian infants. Acta Paediatrica 2009;98(8):1360-2.
Karandish 2003 {published data only}
  • Karandish M, Djazayery A, Mahmoudi M, Behrooz A. The effect of calcium supplementation during pregnancy on birth weight. Medical Journal of Reproduction and Infertility 2003;4(3):184.
Levine 1997 {published data only}
  • Harrison-Hohner J, Coste S, Dorato V, Curet LB, McCarron D, Hatton D. Prenatal calcium supplementation and postpartum depression: an ancillary study to a randomized trial of calcium for prevention of preeclampsia. Archives of Women's Mental Health 2001;3:141-6.
  • Hatton DC, Harrison-Hohner J, Coste S, Reller M, McCarron D. Gestational calcium supplementation and blood pressure in the offspring. American Journal of Hypertension 2003;16:801-5.
  • Koo WWK, Walters JC, Esterlitz J, Levine RJ, Bush AJ, Sibai B. Maternal calcium supplementation and fetal bone mineralization. Obstetrics & Gynecology 1999;94:577-82.
  • Levine RJ. Calcium for preeclampsia prevention (CPEP): a double-blind, placebo-controlled trial in healthy nulliparas. American Journal of Obstetrics and Gynecology 1997;176(1 Pt 2):S2.
  • Levine RJ, CPEP Study Group. The trial of calcium for preeclampsia prevention (CPEP). 8th World Congress of the International Society for the Study of Hypertension in Pregnancy; 1992 November 8-12; Buenos Aires, Argentina. 1992:94.
  • Levine RJ, Esterlitz JR, Raymond EG, DerSimonian R, Hauth JC, Ben Curet L. Trial of calcium for preeclampsia prevention (CPEP): rationale, design, and methods. Controlled Clinical Trials 1996;17(5):442-69.
  • Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et al. Trial of calcium to prevent preeclampsia. New England Journal of Medicine 1997;337:69-76.
Lopez-Jaramillo 1989 {published data only}
  • Lopez-Jaramillo P, Narvaez M, Weigel RM, Yepez R. Calcium supplementation reduces the risk of pregnancy-induced hypertension in an Andes population. British Journal of Obstetrics and Gynaecology 1989;96:648-55.
  • Lopez-Jaramillo P, Narvaez M, Yepez R. Effect of calcium supplementation on the vascular sensitivity to angiotensin II in pregnant women. American Journal of Obstetrics and Gynecology 1987;156:261-2.
  • Navaez M, Lopez-Jaramillo P, Weigel M. Calcium (Ca++) supplementation reduces the risk for pregnancy induced hypertension (PIH). 12th FIGO World Congress of Gynecology and Obstetrics; 1988 October 23-28; Brazil. 1988:180-1.
Lopez-Jaramillo 1997 {published data only}
  • Lopez-Jaramillo P, Delgado F, Jacome P, Teran E, Ruano C, Rivera J. Calcium supplementation and risk of preeclampsia in Ecuadorian pregnancy teenagers. Obstetrics & Gynecology 1997;90:162-7.
Niromanesh 2001 {published data only}
Purwar 1996 {published data only}
  • Purwar M, Kulkarni H, Motghare V, Dhole S. Calcium supplementation and prevention of pregnancy induced hypertension. Journal of Obstetrics and Gynaecology Research 1996;22:425-30.
  • Purwar M, Motghare V, Kulkarni H. Calcium supplementation and prevention of pregnancy induced hypertension: randomized double blind controlled trial [abstract]. Journal of Clinical Epidemiology 1996;49 Suppl 1:28S.
Raman 1978 {published data only}
  • Raman L, Rajalakshmi K. Effect of calcium supplementation to undernourished mothers during pregnancy on bone density of the neonates. American Journal of Clinical Nutrition 1978;31:466-9.
Rogers 1999 {published data only}
Sanchez-Ramos 1994 {published data only}
  • Sanchez-Ramos L, Briones DK, Kaunitz AM, Delvalle GO, Gaudier FL, Walker CD. Prevention of pregnancy induced hypertension by calcium supplementation in angiotensin II sensitive patients. Obstetrics & Gynecology 1994;84:349-53.
  • Sanchez-Ramos L, Del Valle GO, Briones D, Walker RN, Delke I, Gaudier F. Prevention of preeclampsia by calcium supplementation in angiotensin-sensitive patients. American Journal of Obstetrics and Gynecology 1994;170:408.
Sanchez-Ramos 1995 {published data only}
  • Sanchez-Ramos L, Adair CD, DelValle GO, Gaudier F, Delke I. Calcium supplementation in mild preeclampsia remote from term: a prospective randomized double-blind clinical trial. American Journal of Obstetrics and Gynecology 1993;168:385.
  • Sanchez-Ramos L, Adair CD, Kaunitz AM, Briones DK, Del Valle GO, Delke I. Calcium supplementation in mild preeclampsia remote from term: a randomized double clinical trial. Obstetrics & Gynecology 1995;85:915-8.
Taherian 2002 {published data only}
  • Taherin AA, Taherian A, Shirvani A. Prevention of preeclampsia with low-dose aspirin or calcium supplementation. Archives of Iranian Medicine 2002;5:151-6.
Villar 1987 {published data only}
  • Repke JT, Villar J, Anderson C, Pareja G, Dubin N, Belizan JM. Biochemical changes associated with blood pressure reduction induced by calcium supplementation during pregnancy. American Journal of Obstetrics and Gynecology 1989;160:684-90.
  • Villar J, Repke J, Belizan JM, Pareja G. Calcium supplementation reduces blood pressure during pregnancy; results of a randomized control clinical trial. Obstetrics & Gynecology 1987;70:317-22.
Villar 1990 {published data only}
  • Villar J, Belizan JM, Repke J. The effect of calcium supplementation on the incidence of hypertensive disorders of pregnancy and prematurity (Study 1). 7th World Congress of Hypertension in Pregnancy; 1990 October; Perugia, Italy. 1990:54.
  • Villar J, Repke JT. Calcium supplementation during pregnancy may reduce preterm in high-risk populations. American Journal of Obstetrics and Gynecology 1990;163:1124-31.
Villar 2006 {published data only}
  • Abalos E, Merialdi M, Wojdyla D, Carroli G, Campodonico L, Yao SE, et al. Effects of calcium supplementation on fetal growth in mothers with deficient calcium intake: a randomised controlled trial. Paediatric and Perinatal Epidemiology 2010;24(1):53-62.
  • Abdel-Aleem H, Merialdi M, Elsnosy ED, Elsedfy GO, Abdel-Aleem MA, Villar J. The effect of calcium supplementation during pregnancy on fetal and infant growth: a nested randomized controlled trial within WHO calcium supplementation trial. Journal of Maternal-Fetal & Neonatal Medicine 2009;22(2):94-100.
  • Carroli G, Merialdi M, Wojdyla D, Abalos E, Campodonico L, Yao SE, et al. Effects of calcium supplementation on uteroplacental and fetoplacental blood flow in low-calcium-intake mothers: a randomized controlled trial. American Journal of Obstetrics and Gynecology 2010; Vol. 202, issue 1:45.e1-9.
  • Hofmeyr GJ, Mlokoti Z, Nikodem VC, Mangesi L, Ferreira S, Singata M, et al. Calcium supplementation during pregnancy for preventing hypertensive disorders is not associated with changes in platelet count, urate, and urinary protein: a randomized control trial. Hypertension in Pregnancy 2008;27(3):299-304.
  • Villar J, Abdel-Aleem, Merialdi M, Mathai M, Ali MM, Zavaleta N, et al. World Health Organization randomized trial of calcium supplementation among low calcium intake pregnant women. American Journal of Obstetrics and Gynecology 2006;194(3):639-49.
  • Villar J, Aleem HA, Merialdi M, Mathai M, Ali M, Zavaleta N, et al. WHO randomized trial of calcium supplementation among low calcium intake pregnant women [abstract]. American Journal of Obstetrics and Gynecology 2005;193(6 Suppl):S2.
  • Zhang J, Villar J, Sun W, Merialdi M, Abdel-Aleem H, Mathai M, et al. Blood pressure dynamics during pregnancy and spontaneous preterm birth. American Journal of Obstetrics and Gynecology 2007;197(2):162.e1-6.
Wanchu 2001 {published data only}
  • Wanchu M, Malhotra S, Khular M. Calcium supplementation in pre-eclampsia. Journal of the Association of Physician of India 2001;49:795-8.

References to studies excluded from this review

  1. Top of page
  2. AbstractアブストラクトRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Duggin 1974 {published data only}
Felix 1991 {published data only}
  • Felix C, Jacome P, Lopez A, Moya W, Narvaez M, Lopez-Jaramillo P. The hypotensive effect of calcium supplementation during normal pregnancy in Andean women is not related to vascular production of prostacyclin by umbilical arteries. Journal of Obstetrics and Gynaecology 1991;11:93-6.
Hammar 1981 {published data only}
Janakiraman 2003 {published data only}
  • Janakiraman V, Eittinger A, Mercado-Garcia A, Hu H, Hernandez-Avila M. Calcium supplementations and bone resorption in pregnancy; a randomized cross over trial. American Journal of Preventive Medicine 2003;24:260-4.
Kalkwarf 1997 {published data only}
Kent 1995 {published data only}
  • Kent GN, Price RI, Gutteridge DH, May KD, Allen JR, Smith M, et al. Site specific reduction in bone loss by calcium supplementations in normal lactation. Osteoporosis International 1995;5:315.
Liu 2011 {published data only}
  • Liu Z, Qiu L, Chen YM, Su YX. Effect of milk and calcium supplementation on bone density and bone turnover in pregnant Chinese women: a randomized controlled trial. Archives of Gynecology and Obstetrics 2011;283:205-11.
Lopez-Jaramillo 1990 {published data only}
Mahomed 2000 {unpublished data only}
  • Mahomed K, Marume A, Hammond N, Madzima M. Calcium supplementation for the prevention of pregnancy induced hypertension and preterm labour in twin pregnancy: a randomised controlled trial. Personal communication 1998.
Mukherjee 1997 {published data only}
Odendaal 1974 {published data only}
Prentice 1995 {published data only}
  • Prentice A, Jarjou LM, Cole TJ, Stirling DM, Dibba B, Fairweather-Tait S. Calcium requirements of lactating Gambian mothers: effects of a calcium supplement on breast-milk calcium concentration, maternal bone mineral content, and urinary calcium excretion. American Journal of Clinical Nutrition 1995;62:58-67.
Qui 1999 {published data only}
  • Qiu L, Su Y, Peng Y. Effects of different levels of calcium intake on bone of pregnant women. Chung-Hua Yu Fang i Hsueh Tsa Chih [Chinese Journal of Preventive Medicine] 1999;33:369-71.
Robinson 1947 {published data only}

References to studies awaiting assessment

  1. Top of page
  2. AbstractアブストラクトRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Almirante 1998 {published data only}
  • Almirante CY. Calcium supplementation during pregnancy in prevention of EPH gestosis. Prenatal and Neonatal Medicine 1998;3 Suppl 1:24.
Chames 2002 {published data only}
  • Chames M, Liu H, Bendich A, Bogden J, Sibai B, Prada J. A randomised trial of calcium supplementation effects on blood lead levels in pregnancy. American Journal of Obstetrics and Gynecology 2002;187(6 Pt 2):S137.
Galimberti 2001 {published data only}
  • Galimberti D, Joao M, Bernacchi S, Gimenez S, Carames V. IGF-1 and bone turnover in pregnant women with low calcium intake [abstract]. Journal of Perinatal  Medicine 2001;29 Suppl 1(Pt 1):17.
Repke 1989a {published data only}
  • Repke J, Villar J, Bergel E, Belizan JM. The effect of iron absorption in patients receiving calcium supplementation. Proceedings of 9th Annual Meeting of the Society of Perinatal Obstetricians; 1989 Feb 1-4; New Orleans, Louisiana, USA. 1989:512.

Additional references

  1. Top of page
  2. AbstractアブストラクトRésumé scientifique
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Differences between protocol and review
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. References to studies awaiting assessment
  20. Additional references
Carroli 1994
Chang 2003
  • Chang SC, O'Brien KO, Nathanson MS, Caulfield LE, Mancini J, Witter FR. Fetal femur length is influenced by maternal dairy intake in pregnant African American adolescents. American Journal of Clinical Nutrition 2003;77:1248-54.
Cross 1995
  • Cross NA, Hillman LS, Allen SH, Krause GF, Vieira NE. Calcium homeostasis and bone metabolism during pregnancy, lactation and postweaning: a longitudinal study. American Journal of Clinical Nutrition 1995;61:514-23.
Egger 1997
Hallberg 1992
  • Hallberg L, Rossander-Hulten L, Brune M, Gleerup A. Calcium and iron absorption: mechanism of action and nutritional importance. European Journal of Clinical Nutrition 1992;46:317-27.
Harbord 2006
Heaney 2002
Higgins 2011
  • Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hofmeyr 2006
Inzucchi 1999
  • Inzucchi SE, Burrow GN. Endocrine disorder in pregnancy. Medicine of the Fetus and Mother. 2nd Edition. Lippincott Williams & Wilkins, 1999.
Koo 1999
Laskey 1999
Luke 1994
McGuire 2007
  • McGuire M, Beeman KA. Nutritional Sciences, from Fundamentals to Food. Australia: Thomson Wardworth, 2007.
Prentice 1994
RevMan 2011
  • The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
Ritchie 1998
  • Ritchie LD, Fung EB, Halloran BP, Turnlund JR, Van Loan MD, Cann CE, et al. A longitudinal study of calcium homeostasis during human pregnancy and lactation and after resumption of menses. American Journal of Clinical Nutrition 1998;67:693-701.
Sampath 2008
Sowers 1993
Sowers 1995
Susser 1991
Trichopoulou 1990
  • Trichopoulou A, Vassilakou T. Recommended dietary intakes in the European community member state: an overview. European Journal of Clinical Nutrition 1990;44(Suppl 2):51-125.
Trowman 2006
Villar 1998
  • Villar J, Gulmezoglu M, De Onis M. Nutritional and antimicrobial interventions to prevent preterm birth: an overview of randomized controlled trials. Obstetrical & Gynecological Survey 1998;53:575-85.
Williams 1962
Yanovski 2009
  • Yanovski JA, Parikh SJ, Yanoff LB, Benkinger BI, Calis KA, Reynolds JC, et al. Effects of calcium supplementation on boy weight and adiposity in overweight and obese adult: a randomized clinical trial. Annual Internal Medicine 2009;150:821-W146.