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International Journal of Nursing Practice 2015; 21 (Suppl. 2), 19–31

ORIGINAL ARTICLE

Calcium supplementation reducing the risk of hypertensive disorders of pregnancy and related problems: A meta-analysis of multicentre randomized controlled trials Li-bin An MD PhD Professor and Dean, School of Nursing, Jilin University, Changchun, China

Wen-tao Li RN MPH Professor and Vice Dean, School of Nursing, Jilin University, Changchun, China

Tie-nan Xie MD PhD Associate Professor, Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, China

Xin Peng RN MM Lecturer, School of Nursing, Jilin University, Changchun, China

Bo Li MD PhD Professor, School of Public Health, Jilin University, Changchun, China

Shu-hong Xie RN BN Postgraduate Students, School of Nursing, Jilin University, Changchun, China

Jing Xu RN BN Postgraduate Students, School of Nursing, Jilin University, Changchun, China

Xiao-hua Zhou RN BN Postgraduate Students, School of Nursing, Jilin University, Changchun, China

Shao-ning Guo RN BN Postgraduate Students, School of Nursing, Jilin University, Changchun, China

Accepted for publication April 2013 An L, Li W, Xie T, Peng X, Li B, Xie S, Xu J, Zhou X, Guo S. International Journal of Nursing Practice 2015; 21 (Suppl. 2): 19–31 Calcium supplementation reducing the risk of hypertensive disorders of pregnancy and related problems: A meta-analysis of multicentre randomized controlled trials

Correspondence: Li-bin An, School of Nursing, Jilin University, Changchun, Jilin 130021, China. Email: [email protected] Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflict of interest: No conflict of interest has been declared by the author. doi:10.1111/ijn.12171

© 2015 Wiley Publishing Asia Pty Ltd

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Hypertensive disorders of pregnancy are closely related to maternal mortality and morbidity. Calcium supplementation during pregnancy seems to reduce the risk of hypertensive disorders. No systematic review on multicentre RCTs of calcium supplementation during pregnancy has been published. The purpose of this study was to report a quantitative systematic review of the effectiveness of calcium supplementation during pregnancy on reducing the risk of hypertensive disorders of pregnancy and related problems. Publications over the years of 1991–2012 were searched through PubMed, Science Direct, EMBASE, CINAHL and Web of Science. The literatures were selected of the multicentre RCTs on calcium supplementation during pregnancy in prevention of hypertensive disorders and related problems. Reference lists from the studies were also examined for additional references. Studies were critically appraised by three independent reviewers, and the Cochrane Handbook was used to assess the quality of those included trials. Four studies were included in this systematic review. All included studies were high quality, with low risk of bias. There was an observed risk reduction in hypertension in calcium group. However, there was no reduction in the risk of severe gestational hypertension, pre-eclampsia, severe pre-eclampsia, preterm birth and low birthweight. Calcium supplementation appears to reduce the risk of hypertension in pregnancy. Key words: calcium supplementation, hypertensive disorders of pregnancy, maternal and child health, multicentre randomized controlled trials.

INTRODUCTION Hypertensive disorders of pregnancy, which includes gestational hypertension, pre-eclampsia and eclampsia, are closely related to maternal mortality and morbidity. About 5% of all pregnancies are complicated with hypertension and 11% of first pregnancies, among of them 50% pregnancies associated with pre-eclampsia.1 The 10–15% of maternal deaths2 and 25.7% of stillbirths and neonatal deaths3 are associated with hypertensive disorders of pregnancy in low- and middle-income countries. The prevention of hypertensive disorders of pregnancy has been an important issue. Belizán first reported that there was a negative relationship between calcium intake and hypertensive disorders of pregnancy.4 The outcome was supported by other epidemiological and clinical studies.5–8 Some studies stated that calcium supplementation could prevent hypertensive disorders during pregnancy by changing the endocrine hormone.7,9 Based on these studies, there is the hypothesis that an increase of calcium intake during pregnancy might reduce the incidence of high blood pressure (BP) and pre-eclampsia. In order to confirm this hypothesis, researchers have conducted further randomized controlled trials (RCTs). Villar and Repke were the first to carry out an RCT of calcium supplementation during pregnancy for nulliparas and report that calcium supplemented group had a dramatic reduction in the risk of preterm birth compared with the placebo group (incidence 7.4% vs. 21.1%).9 Belizán et al. conducted a multicentre RCT and found that the rate of hypertensive disorders of pregnancy was lower in the calcium group than in the placebo © 2015 Wiley Publishing Asia Pty Ltd

group (9.8% vs. 14.8%).10 To evaluate the effects of calcium supplementation during pregnancy, the Cochrane Collaboration has carried out systematic reviews respectively in 2000,11 2002,12 200613 and 2010.14 The results proved that calcium supplementation appeared to reduce the risk of gestational hypertension and preeclampsia. Calcium supplementation during pregnancy (at doses of 1.5∼2.0 g/day) was recommended for the prevention of pre-eclampsia in all women from World Health Organization recommendations.15 However, yet poorly addressed, a possible point is whether the RCT is a single-centre or multicentre trial. As we all know, the results of multicentre trials are always with higher internal and external validity. More positive intervention effects were observed in single-centre RCTs than in multicentre RCTs,16 suggesting that single-centre RCT-based meta-analysis should be moderated. According to the authors’ knowledge, there has no published systematic review focusing on multicentre RCTs of calcium supplementation during pregnancy. The objective of this review was, through meta-analysis of multicentre RCTs, to assess the effectiveness of calcium supplementation during pregnancy, thereby providing better evidence for maternal health-care services.

METHODS The aim of this review was, through meta-analysis of multicentre RCTs, to assess the effectiveness of calcium supplementation during pregnancy on reducing the risk of hypertensive disorders and related problems, thereby providing better evidence for maternal health-care

Meta-analysis of calcium supplementation in pregnancy

services. A quantitative systematic review was carried out, and the principles from Cochrane Handbook for Systematic Reviews of Interventions17 were followed. Review Manager 5.0 software (The Nordic Cochrane Centre, The Cochrane Collaboration, 2008, Copenhagen, Denmark) was applied in this review.

Inclusion criteria Types of studies All multicentre RCTs evaluated the effect of calcium supplementation during pregnancy for prevention of hypertensive disorders. Experimental group received calcium supplementation as compared with control group with placebo.

Types of participants Nulliparous women without diseases such as hypertension, diabetes mellitus or renal disease. Pregnant women with diastolic BP ≤ 90 mmHg and systolic BP ≤ 140 mmHg before interventions.

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whether articles met the inclusion criteria and then compared their results. Any disagreement was resolved by discussion with a third reviewer (L.B.).

Review methods Data source We conducted search for published RCTs that evaluated the effect of calcium supplementation during pregnancy for prevention of hypertensive disorders. The literature search included a comprehensive computer-assisted search through electronic databases of PubMed, Science Direct, EMBASE, CINAHL and Web of Science. Key words used were: ‘calcium supplementation’, ‘pregnant women’, ‘gestational hypertension’, ‘pre-eclampsia’, ‘eclampsia’ and ‘preterm birth’. The search period was restricted in the year 1991–2012 in order to ensure more continuing studies to be included. Furthermore, a manual search was undertaken of references from retrieved articles.

Quality appraisal Types of interventions Intervention group: supplementation with calcium (at least > 1 g/day) from 11∼24 weeks of pregnancy to delivery. Control group: supplementation with the same doses of placebo during the same time.

Types of outcome measures Main outcomes include: the risk of gestational hypertension (defined as a BP of ≥ 140 mmHg systolic and/or ≥ 90 mmHg diastolic), severe gestational hypertension (defined as a BP of ≥ 160 mmHg systolic and/or ≥ 110 mmHg diastolic), pre-eclampsia (defined as pregnancy-induced hypertension with proteinuria of 300 mg/24 h), severe pre-eclampsia (defined as pregnancy-induced hypertension with proteinuria of 3 g/ 24 h), eclampsia, preterm birth, low birthweight, maternal death, caesarean section, admission to neonatal intensive care unit (NICU), neonatal death and health-related problems.

Three reviewers independently did quality assessment of included literatures. The principles from Cochrane Handbook for Systematic Reviews of Interventions17 were followed: Was the study described as randomized? Was the study described as allocation concealment? Was the study described as double blind? Was there the description about withdrawals and dropouts, including numbers and reasons? Did the author selectively report the outcomes? Was there the description about baseline data? In our assessment process, a well-categorized grading system was used, including Grade A: the above criteria were fully met, with ‘low risk’ of bias; Grade B: one or more criteria were partially met, with ‘middle risk’ of bias; Grade C: one or more criteria were not met, with ‘high risk’ of bias. On the basis of the assessment criteria, independent assessments and thorough discussions, the three reviewers came to a decision on data to be used in present study.

• • • • • •

Exclusion criteria Observational studies and animal experiments were excluded. The participants were excluded who had already diagnosed hypertensive disorders of pregnancy. All the titles and abstracts were read to identify relevant studies and remove apparently irrelevant ones. Two reviewers (W.T. and T.N.) independently assessed

Data extraction Information was extracted by two reviewers (W.T. and T.N.) independently. If there was disagreement between the two reviewers, a third reviewer (L.B.) was consulted. Data were extracted by the Participants, Interventions, Comparison, Outcomes approach: © 2015 Wiley Publishing Asia Pty Ltd

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Participants Study site, inclusion/exclusion criteria, sample size, method and process of randomization, allocation concealment and profile of participants.

Table 1 Exclusion reason for the excluded studies Study

Reason for exclusion

Abdel-Aleem H et al.18

Non-multicentre randomized controlled trial; participants are foetus and infant. Abstract only in a conference. Non-multicentre randomized controlled trial; without clinically relevant outcomes. Non-multicentre randomized controlled trial. Non-multicentre randomized controlled trial; two studies at different period. Secondary analysis based on former study (Levine RJ et al.35). Non-multicentre randomized controlled trial; participants are the offspring of women. Non-multicentre randomized controlled trial without clinically relevant outcomes. Non-multicentre randomized controlled trial. Non-multicentre randomized controlled trial. Non-multicentre randomized controlled trial. Abstract only in a conference. Non-multicentre randomized controlled trial. Abstract only in a conference. Non-multicentre randomized controlled trial. Non-multicentre randomized controlled trial. Abstract only in a conference.

Interventions Dose, onset and duration of calcium supplementation, and the loss of participants.

Aghamohammadi A et al.19 Belizán JM et al.20

Comparison Calcium supplementation in pregnancy compared against placebo.

Outcomes Withdrawals and dropouts, mean and standard deviation used in continuous data, the rate and percentage used in categorical data.

Data synthesis Meta-analysis for the trails was performed with Review Manager 5.0 software. We assessed statistical heterogeneity in each meta-analysis using χ2 statistics and I2. Heterogeneity among trials was with substantial significance if P-value was < 0.1 and I2 was > 50%. When P-value was > 0.1 and I2 was < 50%, the fixed-effect model was used for pooling data. When P-value was < 0.1 and I2 was > 50%, the random-effect model was used. We compared categorical data using risk ratios (RRs) and their 95% confidence intervals (CIs). There was no statistically significant between two groups if the CI included 1, and the P-value was > 0.05.

RESULTS Search outcome Literature search from electronic databases yielded a total of 757 references. Two hundred thirty articles were excluded, which were repetitive publication cross databases. Three hundred sixty-four articles were further excluded due to improper research contents, such as calcium combined with other drugs, dietary intake of calcium and the mechanism of calcium role. By reviewing abstracts, 142 articles were also removed due to case reports, cohort studies, case–control studies, descriptive studies, non-RCTs, animal experiments and narrative reviews. Through reviewing the full texts, 17 relevant studies8,18–34 were further excluded due to or nonmulticentre RCTs or other reasons. The exclusion reason was reported in Table 1. Finally, four studies10,35–37 met © 2015 Wiley Publishing Asia Pty Ltd

Baba DE et al.21 Cong K et al.22

Hauth JC et al.23 Hawkesworth S et al.24

Jarjou LM et al.25

Knight KB et al.26 Kumar A et al.27 López-Jaramillo P et al.28 Nenad S et al.29 Niromanesh S et al.30 Prada JA et al.31 Purwar M et al.32 Sanchez-Ramos L et al.33 Wanchu M et al.34

the inclusion criteria were included. The diagram of review process was in Figure 1.

Characteristics of the included studies The included literatures were published in 1991, 1997, 1999 and 2006, respectively. Women participated in studies were from Argentina, USA, Australia, Egypt, India, Peru, South Africa and Vietnam. All included

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Electronic databases search: n = 757

230 papers were excluded which were repetitive publication cross databases. 364 papers were excluded due to improper research contents.

Papers selected for review of titles: n = 163

142 papers were removed due to case reports, cohort studies, case–control studies, descriptive studies, non-randomized controlled trials, animal experiments and narrative reviews.

Papers selected for review of abstracts: RCT n = 21 17 papers were excluded due to the lack of control group or non-multicentre RCT. Papers selected for review of full texts:

Figure 1. Flow diagram of review process.

n=4

studies were multicentre RCTs and double-blind. The participants were nulliparous women without hypertension, diabetes mellitus and renal disease and with a normal BP at trial entry (BP < 140/90 mmHg); One study37 clearly indicated that pregnant women were with low calcium diet. Calcium supplementation (1.0∼2.0 g/day, oral calcium) was given in intervention group while the same dose of placebo was used in control group. Interventions began from 11∼24 weeks of pregnancy to delivery. The loss of target population was clarified in all studies. In one study,36 the loss was high (calcium group, 31%; placebo group, 24%), other three studies at 3.4– 8.7%. The characteristics of the included studies were reported in Table 2.

Quality assessment of literatures The quality assessment of the included studies was done in accordance with the principles from the Cochrane Handbook for Systematic Review of Interventions.17 All the included studies were high quality, with low risk of bias (see in Table 3). They reported the randomization allocation process, double-blinded all outcomes, concealed the allocation plan, checked and assessed the compliance and stated the loss of samples and the reasons. The analysis of data was not selectively reported. Also, all the studies compared the baseline data between two groups, for example maternal age, weight, height, BP, daily calcium intake. They were similar at trial entry.

Effects of calcium supplementation Gestational hypertension The effects of calcium supplementation during pregnancy on risk of gestational hypertension were reported in

four studies. There were a total of 7252 participants in calcium group and 7272 participants in control group. There was no heterogeneity in the pooled data, so the fixed-effect model was used. The average risk of hypertension was reduced with calcium supplementation rather than placebo (RR 0.91, 95% CI 0.84–0.99, Z = 2.16, P = 0.03) (Fig. 2).

Severe gestational hypertension The outcome of severe gestational hypertension was reported by three included trials.35–37 There were a total of 6673 participants in calcium group and 6684 participants in control group. There was no heterogeneity in the pooled data. There was no statistically significant effect on the average risk of severe gestational hypertension associated with calcium supplementation (RR 0.81, 95%CI 0.60–1.09, Z = 1.39, P = 0.16) (Fig. 3).

Pre-eclampsia The effect of calcium supplementation on pre-eclampsia was assessed in four studies. There was no heterogeneity in the pooled data. A fixed-effect model pooled analysis showed no significant reduction in risk of pre-eclampsia in women receiving calcium supplementation (7252 women in calcium group) as compared with those receiving placebo (7272 women in control group) (RR 0.89, 95% CI 0.77–1.02, Z = 1.69, P = 0.09) (Fig. 4).

Severe pre-eclampsia The outcome of severe pre-eclampsia was reported by three included trials.35–37 There were a total of 6673 participants in calcium group and 6684 participants in control © 2015 Wiley Publishing Asia Pty Ltd

© 2015 Wiley Publishing Asia Pty Ltd

1991 The New England Journal of Medicine

1997 The New England Journal of Medicine

1999 Australian and New Zealand Journal of Obstetrics and Gynaecology 2006 American Journal of Obstetrics and Gynecology

Belizán et al.

Levine et al.

Crowther et al.

Villar et al.

Year/journal

Authors

8325

456

Australia/5

Argentina, Egypt, India, Peru, South Africa, Vietnam/6

4589

1194

Sample

America/5

Argentina/3

Site/number

Table 2 Characteristics of the included studies

Intervention group 23.7 ± 5.5 Control group 23.7 ± 5.7 Intervention group 21 ± 4 Control group 21 ± 4 Intervention group 25.1 ± 5.3 Control group 24.3 ± 5.4 Intervention group 22.6 ± 4.4 Control group 22.7 ± 4.4

Age of participant

1.5g/day

1.8g/day

20∼24w to delivery

Before 20w to delivery

1.0g/day

2.0g/day

Dosage

13∼21w to delivery

20w to delivery

Duration of intervention

124 women decided to stop taking the trial medication during the antenatal period. The most frequent reason was that the tablets were too large. 13 women were excluded before intervention, 298 were lost to follow-up without delivery information, but the available data were included for other outcomes.

27 women were lost to follow-up after randomization. 98 women were lost because of a change of hospital, physician, or residence. 253 women were lost to follow-up.

Withdraw and dropout

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Table 3 Quality assessment of included studies Included studies

Randomization

Allocation concealment

Blinding

Withdrawal and dropout

Selective reporting

Basic characteristics

Quality grade

Belizán et al. (1991)20 Levine et al. (1997)35 Crowther et al. (1999)36 Villar et al. (2006)37

Yes Yes Yes Yes

Concealed Concealed Concealed Concealed

Double blind Double blind Double blind Double blind

Reported Reported Reported Reported

No No No No

Similar Similar Similar Similar

A A A A

Figure 2. Effect of calcium supplementation on risk of gestational hypertension.

Figure 3. Effect of calcium supplementation on risk of severe gestational hypertension.

group. There was no heterogeneity in the pooled data. So the fixed-effect model was used. There was no difference of effect on the risk of severe pre-eclampsia between two groups (RR 0.80, 95% CI 0.60–1.05, Z = 1.62, P = 0.10) (Fig. 5).

Eclampsia

Villar et al. reported the risk of eclampsia.37 The result showed that 17 cases of eclampsia happened in 4151 participants of calcium group and 25 cases happened in 4161 participants of control group. There was significant effect on the risk of eclampsia associated with calcium supplementation (RR 0.68, 95% CI 0.48–0.97).

Gestational proteinuria without hypertension The impact of calcium supplementation during pregnancy on risk of gestational proteinuria without hypertension was assessed in two studies.35,37 There was no substantial heterogeneity in the pooled data, so the fixed-effect model was used. The analysis comprising 6446 women in intervention group and 6455 women in control group showed no significant reduction (RR 1.03, 95% CI 0.88– 1.21, Z = 0.37, P = 0.71) (Fig. 6).

Maternal death

Only one trial reported the risk of maternal death.37 The result showed that one death occurred in 4151 © 2015 Wiley Publishing Asia Pty Ltd

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Figure 4. Effect of calcium supplementation on risk of pre-eclampsia.

Figure 5. Effect of calcium supplementation on risk of severe pre-eclampsia.

Figure 6. Effect of calcium supplementation on risk of gestational proteinuria without hypertension.

participants of calcium group and six deaths in 4161 participants of control group. There was a difference, which was statistically significant (RR 0.17, 95% CI 0.03–0.76).

Preterm delivery The effect of calcium supplementation on preterm delivery was reported in four studies. There was a substantial heterogeneity in the pooled data, so the random-effect model was used. There were a total of 7139 participants in calcium group and 7153 participants in control group. The average risk of preterm birth was not reduced in the calcium group overall (RR 0.93, 95% CI 0.76–1.13, Z = 0.75, P = 0.45) (Fig. 7). © 2015 Wiley Publishing Asia Pty Ltd

Low birthweight The effect of calcium supplementation on low birthweight was assessed in three studies.35–37 There was a substantial heterogeneity in the pooled data. A random-effect model pooled analysis showed no significant reduction on risk of low birthweight in 6560 women receiving calcium supplementation as compared to 6565 women receiving placebo (RR 0.91, 95% CI 0.72–1.16, Z = 0.74, P = 0.46) (Fig. 8).

Caesarean section The effect of calcium supplementation on Caesarean section was reported in three studies.10,35,36 There was no substantial heterogeneity in the pooled data. A fixed-effect

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Figure 7. Effect of calcium supplementation on risk of preterm delivery.

Figure 8. Effect of calcium supplementation on risk of low birthweight.

Figure 9. Effect of calcium supplementation on risk of Caesarean section.

model pooled analysis showed no significant reduction on risk of Caesarean section in 3066 women receiving calcium supplementation as compared with 3077 women receiving placebo (RR 0.94, 95% CI 0.84–1.06, Z = 1.00, P = 0.32) (Fig. 9).

Neonatal death

Only one trial reported the risk of neonatal death.37 The result showed that 37 cases occurred in 3953 participants of calcium group and 53 cases in 3956 participants of control group. There was a decrease in the risk of neonatal death (RR 0.70, 95% CI 0.56–0.88).

Admission to NICU The outcome of admission to NICU was reported in two studies.10,35 With no substantial heterogeneity in the pooled data, a fixed-effect model pooled analysis showed no significant reduction on risk of admission to NICU in 2839 women receiving calcium supplementation as compared with 2848 women receiving placebo (RR 1.10, 95% CI 0.96–1.25, Z = 1.38, P = 0.17) (Fig. 10).

Health-related problems

Three studies reported health-related problems10,36,37, including nausea, vomiting, urinary complaints, dyspepsia, abdominal pain and soon. However, there was no data in detail. One trial37 also reported that there were four women diagnosed with kidney stones in the calcium group and none in the placebo group, and five women in © 2015 Wiley Publishing Asia Pty Ltd

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Figure 10. Effect of calcium supplementation on risk of admission to NICU.

the calcium group and three in the placebo group were diagnosed with clinical renal colic.

DISCUSSION Our results compared with Cochrane’s research data The results of this review showed that there was a 16% reduction in the risk of gestational hypertension, whereas there was also a significant reduction of 35% in Cochrane’s results.14 Meanwhile, there was no effect on the risk of Caesarean section, low birthweight and admission to NICU, which were the same as Cochrane’s results in 2010.14 In our review, calcium supplementation did not reduce the risk of pre-eclampsia and preterm birth. However, the Cochrane’s results14 showed that calcium supplementation appeared to approximately reduce the risk of pre-eclampsia and preterm birth. This might be due to the discrepancy between multicentre trial and nonmulticentre trial. Meanwhile, we found that only one trial separately showed that calcium supplementation reduced the risk of maternal and neonatal death. The discrepancy between trials is always a concern in the studies of evidence-based medicine. Biased results of RCTs could be a consequence due to flaws in the design, implementation, analysis, interpretation, or reporting, thereby affecting the results of the meta-analysis that worked on these trials.38 Since the 1990s, the effects of single trial on the meta-analytical results have been explored with a focus on the above aspects.39–41 However, a possible, yet poorly addressed, point is whether the RCT is a single-centre or multicentre trial. A recent study42 showed that single-centre trials were more prone to publication bias than multicentre trials. Moreover, singlecentre trials might be of lower methodological quality than multicentre trials.43,44 On the other hand, single-centre RCTs have smaller sample sizes than multicentre RCTs © 2015 Wiley Publishing Asia Pty Ltd

and tend to include more homogeneous populations.45 In non-pharmacologic interventions, single-centre RCTs are likely to be implemented by highly experienced care providers, and the discrepancy in skill level could have great influence on intervention effects.46 In one word, the results of single-centre trials are not as good as multicentre trials with higher internal and external validity.

Strengths and limitations To the best of the authors’ knowledge, this is the first systematic review focusing on multicentre RCTs of calcium supplementation during pregnancy. All the included multicentre RCTs were high quality and with low risk of bias. The heterogeneity of the included studies during each analysis was tested with I2 ranged from 0% to 64%. All four studies (involving 14 524 women) were large-sample RCT and with low loss rate (0%∼11.2%), which was probably the best way to investigate such effectiveness. The limitation of this review was the limited trials of multicentre RCTs. Among the four studies, the participants came from North America, Australia, South Asia and Africa. It is hoped that more multicentre RCTs with high quality will be conducted at other areas of the world, in order to identify if and how the effect of calcium supplementation during pregnancy might differ between European and Asian ethnicities in reducing the risk of hypertensive disorders and related problems. Additional limitations of this analysis could be publication bias, because it only included published studies.

Implication for research on calcium supplements during pregnancy Role of calcium supplementation in preventing hypertensive disorders during pregnancy can be explained by reduction in the release of parathyroid hormone and

Meta-analysis of calcium supplementation in pregnancy

intracellular calcium in vascular smooth muscle cells, thereby reducing smooth muscle contractility, promoting vasodilatation and lowering BP.47 Low blood calcium is a risk factor leading to gestational hypertensive disorders. However, no study checked participant’s blood calcium level prior and after intervention. Blood calcium level is an objective indicator that is easier measured than daily calcium intake level. In future research, we should measure participant’s blood calcium level before intervention and observe the change of blood calcium level. In addition, exploring the appropriate time and duration of calcium supplementation is also necessary. Meanwhile, we should pay more attention to calcium deficiency symptom such as muscle spasm, leg numb, etc. On the other hand, pregnant women might have different need of calcium with variation of maternal weight and height. So in future research, body mass index (BMI) should be taken into consideration, which might have great influence on the effect of calcium supplementation.

Recommendation for calcium supplementation during pregnancy One negative correlation was observed from Mayan Indians who were used to eat lime soaked corn and had low incidence of pre-eclampsia and eclampsia.4 This was attributed to a long-term intervention effect of high calcium intake. Therefore, health-care workers should guide pregnant women to supplement calcium starting at the early stage of pregnancy and based on their blood calcium level. Individualized calcium supplementation is more effective and safer to pregnant women. According to present studies, calcium supplementation for pregnant women should not exceed 2.0 g/day while carefully monitoring health-related problems, such as nausea, vomiting, abdominal pain, kidney stones and renal colic.

REFERENCES 1 Villar J, Say L, Shennan A et al. Methodological and technical issues related to the diagnosis, screening, prevention and treatment of pre-eclampsia and eclampsia. International Journal of Gynecology & Obstetrics 2004; 85: S28–S41. 2 Duley L. The global impact of pre-eclampsia and eclampsia. Seminars in Perinatology 2009; 33: 130–137. 3 Ngoc NT, Merialdi M, Abdel-Aleem H et al. Causes of stillbirths and early neonatal deaths: Data from 7993 pregnancies in six developing countries. Bulletin of the World Health Organization 2006; 84: 699–705.

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4 Belizán JM, Villar J. The relationship between calcium intake and edema-, proteinuria-, and hypertension-gestosis: An hypothesis. American Journal of Clinical Nutrition 1980; 33: 2202–2210. 5 Villar J, Belizán JM, Fisher PJ. Epidemiologic observation on the relationship between calcium intake and eclampsia. International Journal of Gynecology & Obstetrics 1983; 21: 271–278. 6 Villar J, Repke J, Belizán JM, Pareja G. Calcium supplementation reduces blood pressure during pregnancy: Results of a randomized controlled clinical trial. Obstetrics & Gynecology 1987; 70: 317–322. 7 Belizán JM, Villar J, Repke J. The relationship between calcium intake and pregnancy-induced hypertension: Up-to-date evidence. American Journal of Obstetrics and Gynecology 1988; 158: 898–902. 8 Repke JT, Villar J. Pregnancy-induced hypertension and low birth weight: The role of calcium. American Journal of Clinical Nutrition 1991; 54: 237S–241S. 9 Villar J, Repke JT. Calcium supplementation during pregnancy may reduce preterm delivery in high-risk populations. American Journal of Obstetrics and Gynecology 1990; 163: 1124–1131. 10 Belizán JM, Villar J, Gonzalez L, Campodonico L, Bergel E. Calcium supplementation to prevent hypertensive disorders of pregnancy. New England Journal of Medicine 1991; 325: 1399–1405. 11 Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 2000; (3): CD001059. 12 Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 2002; (1): CD001059. 13 Hofmeyr GJ, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 2006; (3): CD001059. 14 Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database of Systematic Reviews 2010; (8): CD001059. 15 World Health Organization. WHO recommendations for prevention and treatment of pre-eclampsia and eclampsia. WHO Library 2011. Available from URL: http:// whqlibdoc.who.int/publications/2011/9789241548335 _eng.pdf. Accessed 12 April 2003. 16 Dechartres A, Boutron I, Trinquart L, Charles P, Ravaud P. Single-center trials show larger treatment effects than multi-center trials: Evidence from a meta-epidemiologic study. Annals of Internal Medicine 2011; 155: 39–51. 17 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated

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19

20

21

22

23

24

25

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September 2011]. The Cochrane Collaboration 2011. Available from URL: http://www.cochrane-handbook.org. Accessed 20 December 2012. 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 and Neonatal Medicine 2009; 22: 94–100. Aghamohammadi A, Rajabi A. The effect of calcium supplementation during pregnancy on preterm delivery and preeclampsia in nulliparous beyond age 35. Early Human Development 2010; 86: 114S. Belizán JM, Villar J, Bergel E et al. Long-term effect of calcium supplementation during pregnancy on the blood pressure of offspring: Follow up of a randomised controlled trial. British Medical Journa 1997; 315: 281–285. Baba DE, Seyyedi AG, Cordi M. The effect of calcium supplementation in the prevention of hypertensive disorders of pregnancy in nulliparous women. Medical Iournal of the Islamic Republic of Iran 1998; 12: 11–14. Cong K, Chi S, Liu G. Calcium supplementation during pregnancy for reducing pregnancy induced hypertension. Chinese Medical Journal (English Edition) 1995; 108: 57– 59. Hauth JC, Ewell MG, Levine RJ et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Obstetrics & Gynecology 2000; 95: 24–28. Hawkesworth S, Sawo Y, Fulford AJ 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: 741–747. Jarjou LM, Prentice A, Sawo Y et al. Randomized, placebocontrolled, 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: 657–666. Knight KB, Keith RE. Calcium supplementation on normotensive and hypertensive pregnant women. American Journal of Clinical Nutrition 1992; 55: 891–895. Kumar A, Devi SG, Batra S, Singh C, Shukla DK. Calcium supplementation for the prevention of pre-eclampsia. International Journal of Gynecology & Obstetrics 2009; 104: 32–36. López-Jaramillo P, Delgado F, Jácome P, Terán E, Ruano C, Rivera J. Calcium supplementation and the risk of preeclampsia in Ecuadorian pregnant teenagers. Obstetrics & Gynecology 1997; 90: 162–167. Nenad S, Olivera K-V, Goran R, Ljiljana S. Did calcium management prevent preeclampsia? Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 2011; 1: 287.

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30 Niromanesh S, Laghaii S, Mosavi-Jarrahi A. Supplementary calcium in prevention of pre-eclampsia. International Journal of Gynecology & Obstetrics 2001; 74: 17–21. 31 Prada JA, Tsang RC, Guo S. Reduction of blood pressure from calcium supplementation in adolescent pregnancy: A randomized trial. American Journal of Hypertension 2001; 14: A179. 32 Purwar M, Kulkarni H, Motghare V, Dhole S. Calcium supplementation and prevention of pregnancy induced hypertension. Journal of Obstetrics and Gynaecology Research 1996; 22: 425–430. 33 Sanchez-Ramos L, David Adair C, Kaunitz AM, Briones DK, Del Valle GO, Delke I. Calcium supplementation in mild preeclampsia remote from term: A randomized double-blind clinical trial. Obstetrics & Gynecology 1995; 85: 915–918. 34 Wanchu M, Malhotra S, Khullar M. Calcium supplementation in pre-eclampsia. Journal of the Association of Physicians of India 2001; 49: 795–798. 35 Levine RJ, Hauth JC, Curet LB et al. Trial of calcium to prevent preeclampsia. New England Journal of Medicine 1997; 337: 69–77. 36 Crowther CA, Hiller JE, Pridmore B et al. Calcium supplementation in nulliparous women for the prevention of pregnancy-induced hypertension, preeclampsia and preterm birth: An Australian randomized trial. Australian & New Zealand Journal of Obstetrics & Gynaecology 1999; 39: 12–18. 37 Villar J, Abdel-Aleem H, Merialdi M et al. World health organization randomized trial of calcium supplementation among low calcium intake pregnant women. American Journal of Obstetrics and Gynecology 2006; 194: 639–649. 38 Gluud LL. Bias in clinical intervention research. American Journal of Epidemiology 2006; 163: 493–501. 39 Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias. Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. Journal of the American Medical Association 1995; 273: 408–412. 40 Moher D, Pham B, Jones A et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? The Lancet 1998; 352: 609– 613. 41 Tierney JF, Stewart LA. Investigating patient exclusion bias in meta-analysis. International Journal of Epidemiology 2005; 34: 79–87. 42 Von Elm E, Röllin A, Blümle A, Huwiler K, Witschi M, Egger M. Publication and non-publication of clinical trials: Longitudinal study of applications submitted to a research ethics committee. Swiss Medical Weekly 2008; 138: 197–203. 43 Kjaergard LL, Nikolova D, Gluud C. Randomized clinical trials in Hepatology: Predictors of quality. Hepatology 1999; 30: 1134–1138.

Meta-analysis of calcium supplementation in pregnancy

44 Pengel LH, Barcena L, Morris PJ. The quality of reporting of randomized controlled trials in solid organ transplantation. Transplant International 2009; 22: 377–384. 45 Biau DJ, Halm JA, Ahmadieh H et al. Provider and center effect in multi-center randomized controlled trials of surgical specialties: An analysis on patient-level data. Annals of Surgery 2008; 247: 892–898.

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46 Boutron I, Tubach F, Giraudeau B, Ravaud P. Methodological differences in clinical trials evaluating nonpharmacological and pharmacological treatments of hip and knee osteoarthritis. Journal of the American Medical Association 2003; 290: 1062–1070. 47 Villar J, Repke J, Belizan J. Relationship of blood pressure, calcium intake, and parathyroid hormone. American Journal of Clinical Nutrition 1989; 49: 183–184.

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Calcium supplementation reducing the risk of hypertensive disorders of pregnancy and related problems: A meta-analysis of multicentre randomized controlled trials.

Hypertensive disorders of pregnancy are closely related to maternal mortality and morbidity. Calcium supplementation during pregnancy seems to reduce ...
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