Calcium supplementation (other than for preventing or treating hypertension) for improving pregnancy and infant outcomes
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effect of calcium supplementation on maternal, fetal and neonatal outcome as well as on possible side effects (other than for preventing or treating hypertension).
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 in nerve, muscle contraction, enzyme and hormone actions. Bone formation is also dependent on calcium levels. Maternal nutrition during pregnancy is known to have a significant effect on fetal growth and development (Luke 1994; Susser 1991). Pregnancy and lactation are the periods when the mother needs to consume a great amount of calcium (Cross 1995; Prentice 1995; Ritchie 1998). Calcium is transported to the fetus by an active transport process across the placenta. The mother has to maintain her calcium levels to keep normal balance and reduce the risk of osteoporosis in later life (Bonner 1994). The fetus needs calcium for skeletal development as well (Thomas 2006). During pregnancy and lactation, maternal bone mineral density (BMD) decreases in multiple sites of body such as the lumbar spine, femoral neck, total hip, and radius wrist. After weaning this is relatively quickly reversed (Cross 1995; Kalkwarf 1997; Laskey 1999; Prentice 1995; Sowers 1993; Sowers 1995). Inadequate intake of calcium may harm both mother and her fetus. Risks include osteopenia, osteoporosis, tremor, paresthesia, muscle cramp, tetany, delayed fetal growth, low birth weight, and poor fetal mineralization (Inzucchi 1999; Koo 1999).
Recommendation for calcium intake during pregnancy and lactation differ around the world from 600 to 1425 mg per day, 400 to 600 mg per day higher than nonpregnant or nonlactating women (Prentice 1994; Prentice 1995). A breastfeeding mother secretes 200 mg calcium into breast milk every day (Prentice 1995).
Calcium supplementation
Calcium supplementation to the daily diet has been recommended to meet the body's demands during pregnancy and lactation to benefit the mother and fetus. The recommended dosages in the literature vary from 300 to 2000 mg/d of elemental calcium (Jarjou 2006; Kalkwarf 1997; Prentice 1995; Villar 1990). Providing extra calcium tablets is attractive because it is cheap, readily available with few side effects, such as difficult swallowing, increase in urinary stones, increase in urinary tract infection, and reduced absorption of other minerals such as iron, zinc and magnesium that could harm the pregnant women (Hallberg 1992).
Current approach to calcium supplementation
Currently, there is no consensus on the role of routine calcium supplementation for pregnant women. Extra calcium tablets are not routinely prescribed for pregnant women because the real benefit is still questionable. In a recent Cochrane meta‐analysis of calcium supplementation for hypertension, a significant beneficial effect in reducing the risk of pregnancy‐induced hypertension was found (Hofmeyr 2006). For maternal bone mineral density and fetal mineralization, there is still conflicting data. Many studies show that fetal femur length, fetal weight and fetal mineralization are significantly better in calcium‐supplemented mothers (Chang 2003; Chan 2006; Janakiraman 2003; Merialdi 2003; Raman 1978). This is in contrast with other studies that suggest that calcium supplementation has no additional effects (Jarjou 2006; Prentice 1995). The effectiveness of calcium supplementation in reducing preterm birth is also uncertain; some studies show a protective effect (Carroli 1994; Villar 1990) while others do not (Belizan 1991; Lopez‐Jaramillo 1989; Villar 1998). Leg cramps are the most common symptom of calcium deficiency, particularly in pregnant women (Hammar 1981). The role of calcium supplementation in reducing leg cramps remains unclear (Hammar 1981; Hammar 1987; Young 2002). Possible explanations for differences in the results of these studies include differences in baseline calcium intake, socioeconomic status, dosage and duration of calcium supplementation, etc.
There is need for a systematic review to evaluate the effectiveness of calcium supplementation during pregnancy for improving maternal, fetal and neonatal outcomes other than preventing or treating hypertension because of the varying results reported in the literature.
Objectives
To determine the effect of calcium supplementation on maternal, fetal and neonatal outcome as well as on possible side effects (other than for preventing or treating hypertension).
Methods
Criteria for considering studies for this review
Types of studies
All published, unpublished and ongoing simple and cluster‐randomized controlled trials comparing maternal, fetal, and neonatal outcomes in calcium supplementation versus placebo or no treatment in pregnant women. We will include studies reported only in abstract form in the "Studies awaiting classification" category and will include them in the analysis when they are published as full reports. We will exclude quasi‐ and pseudo‐randomized controlled trials.
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
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Preterm delivery
(a) Birth prior to 37 weeks
(b) Birth prior to 34 weeks
Infant outcomes
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Low birth weight (< 2,500 gm)
Secondary outcomes
Maternal outcomes
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Maternal weight gain
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Maternal bone mineral density (BMD)
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Leg cramps
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Backache
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Tetany (muscle spasm and twitching)
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Osteopenia
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Osteoporosis
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Incidence of fracture
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Duration of breastfeeding
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Tremor
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Paresthesia
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Mother need to admit intensive care unit
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Maternal death
Fetal and neonatal outcomes
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Stillbirth
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Fetal death
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Neonatal death
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Perinatal mortality
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Admission to neonatal intensive care unit
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Birth weight
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Birth length
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Head circumference
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Intrauterine growth restriction
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Neonatal BMD
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Osteopenia
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Limb pain
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Ricket
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Fracture
Adverse outcomes
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Side effects of calcium supplementation
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Compliance
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Satisfaction
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Urinary stones
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Urinary tract infection
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Nephrocalcinosis
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Impair renal function
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Maternal anemia
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register.
The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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weekly searches of MEDLINE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
Details of the search strategies for CENTRAL and MEDLINE, 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 will not apply any language restrictions.
Data collection and analysis
Selection of studies
Two review authors (P Buppasiri (PB) and J Thinkhamrop (JT)) will independently assess for inclusion all potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or by involving the third review author (P Lumbiganon (PL)). The fourth review author (C Ngamjarus (CN)) will be responsible for the planning of the data analysis.
Assessment of methodological quality of included studies
Two review authors (PB and JT) will assess the validity of each study independently using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2006). We will use only the criteria of selection bias and detection bias that are feasible for our review. Methods used for generation of the randomisation sequence will be described for each trial.
(1) Selection bias (randomisation and allocation concealment)
We will assign a quality score for each trial, using the following criteria:
(A) adequate concealment of allocation: such as telephone randomisation, consecutively numbered, sealed opaque envelopes;
(B) unclear whether adequate concealment of allocation: such as list or table used, sealed envelopes, or study does not report any concealment approach;
(C) inadequate concealment of allocation: such as open list of random‐number tables, use of case record numbers, dates of birth or days of the week.
(2) Attribution bias (loss of participants, eg, withdrawal, dropouts, protocol deviation)
We will assess completeness to follow up using the following criteria:
(A) less than 5% loss of participants;
(B) 5% to 9.9 % loss of participants;
(C) 10% to 19.9 loss of participants;
(D) more than 20% loss of participants.
(3) Performance bias (blinding of participants, researchers and outcome assessment)
We will assess blinding using the following criteria:
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blinding of participants (yes /no /unclear);
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blinding of caregiver (yes /no /unclear);
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blinding of outcome assessment (yes/no /unclear).
Data extraction and management
We will adapt the Cochrane Pregnancy and Childbirth Group's data extraction form template to extract data. At least two review authors will extract the data using the agreed form. We will resolve discrepancies through discussion. We will use the Review Manager software (RevMan 2007) to double enter all the data or a subsample.
When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.
Unit of analysis issues
Cluster‐randomised trials
We will include cluster‐randomised trials in the analyses along with individually randomised trials. Their sample sizes will be adjusted using the methods described in Gates 2005 using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), or from another source. If ICCs from other sources are used, this will be reported and sensitivity analyses conducted to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.
We will also acknowledge heterogeneity in the randomisation unit and perform a separate meta‐analysis. Therefore, the meta‐analysis will be performed in two parts as well.
Data analysis
Measures of treatment effect
We will compare categorical data using relative risks and their 95% confidence intervals. For continuous data, we will calculate mean difference with 95% confidence intervals (CI) if the outcomes are measured in the same way among trials. We will use the standardized mean difference to combine trials that measure the same outcome, but use different methods. We will test for statistical heterogeneity between trials using the I‐squared statistic, with values greater than 50% indicating significant heterogeneity. In the absence of significant heterogeneity, we will pool data using a fixed‐effect model. If there is significant heterogeneity, a random‐effects model will be used and an attempt made to identify potential sources of heterogeneity based on subgroup analyses by baseline dietary calcium intake.
Dealing with missing data
We will analyse data on all participants with available data in the group to which they are allocated, regardless of whether or not they received the allocated intervention. If in the original reports participants are not analysed in the group to which they were randomised, and there is sufficient information in the trial report, we will attempt to restore them to the correct group.
Assessment of publication bias
Where sufficient trials are included, we will consider publication bias using funnel plots of between‐treatment effect and its precision on individual trials. If we find asymmetry funnel plots with statistical publication bias, we will further examine the effect of the bias on the meta‐analysis conclusion using sensitivity analyses.
Sensitivity analyses
We will carry out sensitivity analyses to explore the effect of trial quality. The trial quality will involve an analysis based on concealment of allocation. Trials with clearly inadequate allocation of concealment will be excluded in order to assess for any substantive difference to the overall result.
Subgroup analyses
We will conduct the following subgroup analysis:
1. Total dose per day of calcium supplementation: high/low (< 1,000 and ≥ 1,000 mg).
2. Time of supplementation taken from: first half of pregnancy (< 20 weeks); and second half of pregnancy ( > 20 weeks).
3. Type of calcium supplementation preparation: calcium carbonate, lactate, gluconate.
