Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

  • Comment
  • Review
  • Intervention

Authors

  • G Justus Hofmeyr,

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

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  • Theresa A Lawrie,

    1. University of the Witwatersrand/University of Fort Hare/East London Hospital Complex, Effective Care Research Unit, East London, South Africa
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  • Álvaro N Atallah,

    1. Universidade Federal de São Paulo / Escola Paulista de Medicina, Brazilian Cochrane Centre, São Paulo, SP, Brazil
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  • Lelia Duley

    1. University of Leeds, Centre for Epidemiology and Biostatistics, Bradford, West Yorkshire, UK
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Abstract

Background

Pre-eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre-eclampsia through a number of mechanisms, and may help to prevent preterm birth.

Objectives

To assess the effects of calcium supplementation during pregnancy on hypertensive disorders of pregnancy and related maternal and child outcomes.

Search methods

We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (May 2010) and contacted study authors.

Selection criteria

Randomised trials comparing at least 1 g daily of calcium during pregnancy with placebo.

Data collection and analysis

We assessed eligibility and trial quality, extracted and double-entered data.

Main results

We included 13 studies of good quality (involving 15,730 women). The average risk of high blood pressure was reduced with calcium supplementation rather than placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81). There was also a reduction in the average risk of pre-eclampsia associated with calcium supplementation (13 trials, 15,730 women: RR 0.45, 95% CI 0.31 to 0.65). The effect was greatest for women with low baseline calcium intake (eight trials, 10,678 women: RR 0.36, 95% CI 0.20 to 0.65) and those selected as being at high risk (five trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42). The variable methods of selecting women as being at high risk limit the clinical usefulness of these pooled results.

The average risk of preterm birth was reduced in the calcium group overall (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97) and amongst women at high risk of developing pre-eclampsia recruited to four small trials (568 women: RR 0.45, 95% CI 0.24 to 0.83).

There was no overall effect on the risk of stillbirth or death before discharge from hospital (11 trials 15,665 babies; RR 0.90, 95% CI 0.74 to 1.09). The composite outcome maternal death or serious morbidity was reduced (four trials, 9732 women; RR 0.80, 95% CI 0.65 to 0.97). Most of the women in these trials were low risk and had a low calcium diet. Maternal deaths were reported in only one trial. One death occurred in the calcium group and six in the placebo group, a difference which was not statistically significant (RR 0.17, 95% CI 0.02 to 1.39). There was an anomalous increase in the risk of HELLP syndrome (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82).

Blood pressure in childhood has been assessed in two studies, only one of which is currently included: childhood systolic blood pressure greater than 95th percentile was reduced (514 children: RR 0.59, 95% CI 0.39 to 0.91).

Authors' conclusions

Calcium supplementation appears to approximately halve the risk of pre-eclampsia, to reduce the risk of preterm birth and to reduce the occurrence of the composite outcome 'death or serious morbidity'. We considered the latter benefit to outweigh the increase in HELLP syndrome, which was small in absolute numbers. There were no other clear benefits, or harms.

Résumé

La supplémentation en calcium durant la grossesse pour la prévention des troubles hypertensifs et des problèmes connexes

Contexte

La pré-éclampsie et l'éclampsie sont des causes courantes de morbidité grave et de décès. La supplémentation en calcium pourrait réduire le risque de pré-éclampsie à travers un certain nombre de mécanismes, et aider à prévenir l'accouchement prématuré.

Objectifs

Évaluer les effets de la supplémentation en calcium durant la grossesse sur les troubles hypertensifs de la grossesse et leurs conséquences pour la santé de la mère et de l'enfant.

Stratégie de recherche documentaire

Nous avons effectué des recherches dans le registre des essais cliniques du groupe Cochrane sur la grossesse et la naissance (mai 2010) et contacté des auteurs d'études.

Critères de sélection

Des essais randomisés comparant une dose d'au moins 1 g de calcium par jour pendant la grossesse à un placebo.

Recueil et analyse des données

Nous avons évalué l’éligibilité et la qualité des essais, et extrait et saisi en double les données.

Résultats Principaux

Nous avons inclus 13 études de bonne qualité (15 730 femmes au total). La supplémentation en calcium avait mieux réduit que le placebo le risque moyen d'hypertension artérielle (12 essais, 15 470 femmes ; risque relatif (RR) 0,65 ; intervalle de confiance (IC) à 95 % 0,53 à 0,81). Il y avait aussi, associée à la supplémentation en calcium, une réduction du risque moyen de pré-éclampsie (13 essais, 15 730 femmes ; RR 0,45 ; IC à 95 % 0,31 à 0,65). L'effet était le plus grand chez les femmes ayant à la base un apport faible en calcium (huit essais, 10 678 femmes ; RR 0,36 ; IC à 95 % 0,20 à 0,65) et chez celles sélectionnées comme étant à haut risque (cinq essais, 587 femmes ; RR 0,22 ; IC à 95 % 0,12 à 0,42). La variabilité des méthodes de sélection des femmes à haut risque limite l'utilité clinique de ces résultats regroupés.

Le risque moyen de prématurité avait été réduit dans le groupe global de calcium (11 essais, 15 275 femmes : RR 0,76 ; IC à 95 % 0,60 à 0,97) et parmi les femmes à risque élevé de développer une pré-éclampsie recrutées pour quatre petits essais (568 femmes ; RR 0,45 ; IC à 95 % 0,24 à 0,83).

Il n'y avait pas d'effet global sur le risque de mortinatalité ou de décès avant la sortie de l'hôpital (11 essais, 15 665 bébés ; RR 0,90 ; IC à 95 % 0,74 à 1,09). Le critère composite « décès de la mère ou morbidité grave » avait été réduit (quatre essais, 9 732 femmes ; RR 0,80 ; IC à 95 % 0,65 à 0,97). La plupart des femmes dans ces essais étaient à faible risque et avaient une alimentation pauvre en calcium. Les décès maternels n'étaient rapportés que dans un seul essai. Un décès était survenu dans le groupe à calcium et six dans le groupe placebo, une différence qui n'était pas statistiquement significative (RR 0,17 ; IC à 95 % 0,02 à 1,39). Il y avait une augmentation anormale du risque de syndrome HELLP (deux essais, 12 901 femmes ; RR 2,67 ; IC à 95 % 1,05 à 6,82).

La pression artérielle dans l'enfance avait été évaluée dans deux études, dont une seule est actuellement incluse : la pression artérielle systolique dans l'enfance supérieure au 95ème percentile avait été réduite (514 enfants ; RR 0,59 ; IC à 95 % 0,39 à 0,91).

Conclusions des auteurs

La supplémentation en calcium semble diminuer environ de moitié le risque de pré-éclampsie et réduire le risque d'accouchement prématuré ainsi que la survenue du résultat composite de « décès ou morbidité grave ». Nous avons considéré que ce dernier avantage l'emportait sur l'augmentation du syndrome HELLP, qui était faible en chiffres absolus. Il n'y avait pas d'autres bénéfice ou avantage clairs.

摘要

孕期補充鈣質避免高血壓疾病及相關問題

背景

妊娠毒血與子癲癇症是嚴重罹病率及死亡的常見成因。鈣質補充可透過許多機制來降低妊娠毒血的風險,並可能有助於避免早產。

目標

評估孕期補充鈣質對於在懷孕期間的高血壓疾病及相關母親與嬰兒成果的影響。

搜尋策略

我們搜尋考科藍孕期與出生群組的試驗註冊(Cochrane Pregnancy and Childbirth Group's Trials Register)(2010年5月),並與研究作者聯絡。

選擇標準

隨機化試驗,至少比較懷孕期間每天補充1克鈣質與安慰劑的效果。

資料收集與分析

我們評估文章合格性與試驗品質,擷取資料,並進行雙重資料輸入。

主要結論

我們納入13個優良品質的研究(共計15,730位婦女)。補充鈣質者,其高血壓的平均風險較使用安慰劑者為降低(12個試驗,15,470位婦女:風險比(RR)0.65,95%信賴區間(CI)0.53到0.81)。在妊娠毒血相關鈣質補充上的平均風險也有降低(13個試驗,15,730位婦女:RR 0.45,95% CI 0.31到0.65)。採用基本鈣質攝取的婦女,其效果最大(8個試驗,10,678名婦女:RR 0.36,95% CI 0.20到0.65),被選為有高風險者(5個試驗,共計587名婦女:RR 0.22,95% CI 0.12到0.42)。選擇有高風險的婦女的方法限制了整體統合結果的臨床有用性。

整體而言,在鈣質補充組的早產平均風險有降低(11個試驗,共計15,275名婦女:RR 0.76,95% CI 0.60到0.97)。在4個小型試驗中招募有發展成為妊娠毒血高風險的婦女(共計568名女性:RR 0.45,95% CI 0.24到0.83)。

在出院前,於死產或死亡的風險上沒有整體的影響(11個試驗,15,665位嬰兒;RR 0.90,95% CI 0.74到1.09)。混合的母親死亡結果或嚴重罹病率也有降低(4個試驗,9,732名婦女;RR 0.80,95% CI 0.65到0.97)。這些試驗中大部分的婦女具有低風險,且攝取低鈣飲食。僅在1個試驗中有顯示有產婦死亡;有1個死亡發生在鈣質組,而6個發生在安慰劑組,其差異並不具統計顯著性(RR 0.17,95% CI 0.02到1.39)。在HELLP併發症風險中有不規則的增加(2個試驗,12,901名婦女;RR 2.67,95% CI 1.05到6.82)。

在2個研究中有評估兒童時期的血壓,其中只有1個是目前所包含的:兒童時期收縮壓大於第第95百分位數有降低(514名兒童:RR 0.59,95% CI 0.39到0.91)。

作者結論

鈣質補充似乎約可減半妊娠毒血的風險,以降低早產的風險,並降低混合結果'死亡或嚴重罹病率'的發生。我們認為後者的益處比HELLP併發症的增加重要,其絕對數值中微小。此外,沒有其它明確的利弊。

Plain language summary

Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

Calcium supplements help prevent pre-eclampsia, preterm birth and lower the risk of the woman dying or having serious problems related to high blood pressure in pregnancy.

Pre-eclampsia is a major cause of death in pregnant women and newborn babies worldwide. Preterm birth (birth before 37 weeks) is often caused by high blood pressure and is the leading cause of newborn deaths, particularly in low-income countries. The review of 13 trials, involving 15,730 women, found that calcium supplementation during pregnancy is a safe and relatively cheap means of reducing the risk of pre-eclampsia in women at increased risk, and women from communities with low dietary calcium. Women were also less likely to die or have serious problems due to pre-eclampsia. Babies were less likely to be born preterm. No adverse effects have been found but further research is needed into the ideal dosage for supplementation.

Résumé simplifié

La supplémentation en calcium durant la grossesse pour la prévention des troubles hypertensifs et des problèmes connexes

La supplémentation en calcium durant la grossesse pour la prévention des troubles hypertensifs et des problèmes connexes

Les suppléments de calcium aident à prévenir la pré-éclampsie et la prématurité, et diminuent le risque pour la femme de mourir ou d'avoir des problèmes graves liés à l'hypertension artérielle pendant la grossesse.

La pré-éclampsie est une cause majeure de mortalité chez les femmes enceintes et les nouveau-nés à travers le monde. La prématurité (naissance avant 37 semaines) est souvent causée par l'hypertension artérielle et est la principale cause de décès des nouveau-nés, en particulier dans les pays à faible revenu. La revue de 13 études, impliquant au total 15 730 femmes, a montré que la supplémentation en calcium durant la grossesse est un moyen sûr et relativement peu onéreux de réduire le risque de pré-éclampsie chez les femmes à risque accru, et chez les femmes appartenant à des communautés où l'apport en calcium alimentaire est faible. Les femmes étaient également moins susceptibles de mourir ou d'avoir des problèmes graves dus à la pré-éclampsie. Les bébés étaient moins susceptibles de naître avant terme. Aucun effet indésirable n'a été trouvé mais des recherches supplémentaires sont nécessaires sur le dosage idéal pour la supplémentation.

Notes de traduction

Traduit par: French Cochrane Centre 25th October, 2012
Traduction financée par: Ministère du Travail, de l'Emploi et de la Santé Français

總結

孕期補充鈣質避免高血壓疾病及相關問題

孕期補充鈣質以避免高血壓疾病及相關問題

鈣質補充有助於避免妊娠毒血、早產,並降低婦女死於或發生嚴重孕期高血壓相關問題的風險。

妊娠毒血在全世界懷孕婦女及新生兒中是主要造成死亡的原因。早產(37週前出生)通常是因高血壓而造成,且會導致新生兒死亡的原因,特別是在低收入國家。13個試驗(包含15,730位婦女)的系統文獻回顧發現: 孕期中的鈣質補充是安全的,且是對風險增加的婦女在降低妊娠毒血風險上相當便宜的方法,也降低低鈣質攝取族群婦女的風險。婦女也可能因為妊娠毒血而死亡或產生嚴重問題。嬰兒也較不傾向於早產。沒有發現任何不良影響,但需要進一步研究,進行有關理想補充劑量的試驗。

譯註

East Asian Cochrane Alliance 翻譯
翻譯由 台灣衛生福利部/台北醫學大學實證醫學研究中心 資助

Background

High blood pressure, with or without proteinuria, is a major causes of maternal death and morbidity (HMSO 1994; NHMRC 1993), and perinatal morbidity and mortality, worldwide. Hypertension has been estimated to complicate 5% of all pregnancies and 11% of first pregnancies, half associated with pre-eclampsia, and accounting for up to 40,000 maternal deaths annually (Villar 2004). For this reason, strategies to reduce the risk of hypertensive disorders of pregnancy have received considerable attention (Bucher 1996; Carroli 1994; CLASP 1994; ECCPA 1996).

Preterm birth, spontaneous and medical, is commonly associated with hypertensive disorders. It is the leading cause of early neonatal death and infant mortality, particularly in low-income countries (Villar 1994). Preterm survivors are at high risk of significant morbidity, especially respiratory disease and its sequelae, and long-term neurological morbidity (Johnson 1993). Interventions to reduce preterm birth have been reviewed by Villar et al (Villar 1998).

During early pregnancy, blood pressure normally falls, climbing slowly in later pregnancy to reach pre-pregnancy levels at term (Villar 1989). These normal changes in blood pressure make the diagnosis of hypertension during pregnancy difficult. Clinical methods of measuring blood pressure are also subject to considerable inaccuracy (Villar 2004). A widely accepted definition, however, is a diastolic blood pressure equal to or greater than 90 mmHg before the onset of labour, or an increase in systolic blood pressure of 30 mmHg or more, or in diastolic blood pressure of 15 mmHg or more. The consequences of high blood pressure are more serious if there is associated proteinuria. Hypertension and significant proteinuria (2+ by dipstick testing, equal to or greater than 300 mg per 24 hours, or equal to or greater than 500 mg per litre) usually indicate the presence of pre-eclampsia. Recently, the urine protein to creatinine ratio has been used increasingly as a measure of proteinuria (Yamasmit 2004). Predictors of poor outcome include low gestational age and high levels of proteinuria (von Dadelszen 2004).

An inverse relationship between calcium intake and hypertensive disorders of pregnancy was first described in 1980 (Belizan 1980). This was based on the observation that Mayan Indians in Guatemala, who traditionally soak their corn in lime before cooking, had a high calcium intake and a low incidence of pre-eclampsia and eclampsia. A very low prevalence of pre-eclampsia had been reported from Ethiopia where the diet, among other features, contained high levels of calcium (Hamlin 1962). These observations were supported by other epidemiological and clinical studies (Belizan 1988; Hamlin 1952; Repke 1991; Villar 1983; Villar 1987; Villar 1993), and led to the hypothesis that an increase in calcium intake during pregnancy might reduce the incidence of high blood pressure and pre-eclampsia among women with low calcium intake. An association has been found between pre-eclampsia and hypocalciuria (Segovia 2004); lower urine calcium to creatinine ratio (Kazerooni 2003); hypocalcaemia (Kumru 2003); lower plasma and higher membranous calcium (Kisters 2000); lower dietary milk intake (Duvekot 2002); and between eclampsia and hypocalcaemia (Isezuo 2004).

Low calcium intake may cause high blood pressure by stimulating either parathyroid hormone or renin release, thereby increasing intracellular calcium in vascular smooth muscle (Belizan 1988) and leading to vasoconstriction. A possible mode of action for calcium supplementation is that it reduces parathyroid release and intracellular calcium, and so reduces smooth muscle contractility. By a similar mechanism, calcium supplementation could also reduce uterine smooth muscle contractility and prevent preterm labour and delivery (Villar 1990). Calcium might also have an indirect effect on smooth muscle function by increasing magnesium levels (Repke 1989). Recent evidence indicates that calcium supplementation affects uteroplacental blood flow (it lowers the resistance index in uterine and umbilical arteries) (Carroli 2010). Supplementation in the second half of pregnancy appears to reduce blood pressure directly, rather than preventing the endothelial damage associated with pre-eclampsia (Hofmeyr 2008).

Calcium supplementation is attractive as a potential intervention to reduce the risk of a woman developing pre-eclampsia. Furthermore, the possibility of a protective effect on the risk of hypertension during childhood makes this even more important (Belizan 1997). It is relatively cheap and readily available. Also, it is likely to be safe for the woman and her child, although this safety would need to be clearly demonstrated in pregnant women before any attempt at widespread introduction into clinical practice. A theoretical risk of increased renal tract stone formation has not been substantiated, and no other adverse effects of calcium supplementation have been documented.

This hypothesis was tested in several randomised trials commencing in the late 1980s which suggested a promising beneficial effect for calcium supplementation. The first systematic reviews highlighted the need for larger trials to assess the effects on important clinical outcomes in addition to pre-eclampsia and preterm delivery, such as perinatal mortality (Carroli 1994; Duley 1995). A subsequent systematic review (Bucher 1996) came to more enthusiastic conclusions, but this optimism was not confirmed by a large trial in the USA (CPEP 1997). These discrepancies have elicited discussion in the literature (Villar 2000). Subsequently, a large trial in communities with low dietary calcium intake has been reported (WHO 2006).

There is thus a need for a systematic review of the current evidence concerning the effectiveness of calcium supplementation in pregnancy.

Objectives

To determine, from the best available evidence, the effect of calcium supplementation during pregnancy on the risk of high blood pressure and related maternal and fetal or neonatal adverse outcomes. Subgroup analyses tested whether these effects were influenced by whether:

  1. women had low or adequate dietary calcium intake prior to trial entry;

  2. women were at low or average risk of hypertensive disorders, or at high risk.

Methods

Criteria for considering studies for this review

Types of studies

All published, unpublished and ongoing trials with random allocation to calcium supplementation during pregnancy versus placebo. We included trials presented only as abstracts if there was enough detail (published and unpublished) to confirm that they were methodologically adequate. We excluded quasi-random designs.

Types of participants

Pregnant women, regardless of the risk of hypertensive disorders of pregnancy. We excluded women with diagnosed hypertensive disorders of pregnancy.

Prespecified subgroups to be compared.

  1. Women at low or average risk of hypertensive disorders of pregnancy (unselected).

  2. Women at above average risk of hypertensive disorders of pregnancy. These included women selected by the trial authors on the basis of an increased risk of hypertensive disorders of pregnancy (e.g. teenagers, women with previous pre-eclampsia, women with increased sensitivity to angiotensin II, women with pre-existing hypertension). Primiparity alone was not regarded as a high-risk factor.

  3. Women or populations with low baseline dietary calcium intake (as defined by trial authors, or if not defined, mean intake less than 900mg per day).

  4. Women or populations with adequate dietary calcium intake (as defined by trial authors, or if not defined, mean intake equal to or greater than 900mg per day).

Types of interventions

Supplementation with calcium from at the latest 34 weeks of pregnancy; compared with placebo treatment. We excluded studies with no placebo. We limited the initial analysis to intended supplementation with at least 1 g of calcium per day. Future updates of this review will include an analysis of effect by dosage, including lower dosage regimens.

Types of outcome measures

In the original protocol we prespecified 15 clinical measures of maternal and fetal or neonatal morbidity and mortality. In October 2004 we added seven additional outcomes (marked * below):

Primary outcomes
For the woman

(1) High blood pressure as defined by trial authors, with or without proteinuria. Ideally, high blood pressure would be defined as diastolic blood pressure equal to or greater than 90 mmHg, or an increase in systolic blood pressure of 30 mmHg or more, or in diastolic blood pressure of 15 mmHg or more.

(2) High blood pressure with significant proteinuria, as defined by trial authors. Ideally, proteinuria would be defined as 2+ by dipstick testing, equal to or greater than 300 mg per 24 hours, or equal to or greater than 500 mg per litre. Although the strict definition of pre-eclampsia includes confirmation of no hypertension or proteinuria outside pregnancy, for convenience the above definition will be referred to in this review as pre-eclampsia.

For the child

(3) Preterm birth (birth before 37 weeks of estimated gestation).

(4) Admission to a neonatal intensive care unit.

(5) Stillbirth or death before discharge from hospital.

Secondary outcomes
For the woman

(1) Maternal death or serious morbidity. Serious morbidity includes eclampsia; renal failure; syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP syndrome); and admission to intensive care. This will be a composite outcome of death or at least one measure of serious morbidity. In addition each individual outcome will be presented.

(2) Placental abruption.

(3) Caesarean section.

(4) *Proteinuria.

(5) *Severe pre-eclampsia as defined by trial authors.

(6) *Eclampsia.

(7) *HELLP syndrome.

(8) *Intensive care unit admission.

(9) *Maternal death.

(10) Mother's hospital stay seven days or more.

For the child

(11) Low birthweight (the first weight obtained after birth less than 2500g).

(12) Neonate small-for-gestational age as defined by trial authors.

(13) Neonate in intensive care unit seven days or more.

(14) *Death or severe neonatal morbidity.

(15) Childhood disability.

(16) Systolic blood pressure greater than 95th percentile during childhood.

(17) Diastolic blood pressure greater than 95th percentile during childhood.

Only those outcomes with data appear in the analysis table.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Pregnancy and Childbirth Group Trials Register by contacting the Trials Search Co-ordinator (May 2010).

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

  4. 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.  

For details of searches carried out in the previous version of the review, see Appendix 2.

Searching other resources

We included additional information obtained from the authors in the previous version of this review (Duley 1995) for five studies (Belizan 1991; L-Jaramillo 1989; Marya 1987; Villar 1987; Villar 1990). We obtained additional information from the authors of the new inclusion (Kumar 2009).

We did not apply any language restrictions.

Data collection and analysis

For the methods used when assessing the trials identified in the previous version of this review, see Appendix 1.

For this update (2010) we used the following methods when assessing the trials identified by the updated search.

Two review authors independently assessed the methodological quality and other inclusion criteria of the identified trials. We resolved disagreements by consensus. The primary assessment for inclusion was based on concealment of allocation and whether the trial was placebo controlled.

Two authors independently extracted and cross-checked the data. Descriptive data included authors, year of publication, country, time span of the trial, maternal age, parity, type of placebo, baseline dietary calcium intake, type, dose, onset and duration of calcium supplementation, compliance, co-interventions, trial quality assessments, and number randomised and analysed.

We compared categorical data using risk ratios and their 95% confidence intervals. We tested for statistical heterogeneity among trials using the I² statistic, with values greater than 50% indicating significant heterogeneity. In the absence of significant heterogeneity, we pooled data using a fixed-effect model. For continuous data, we calculated pooled estimates of effect size from a weighted average, with weight based on the inverse of the variance (Early Breast Cancer Trialists' Group 1990). We identified comparisons, outcomes and subgroups other than those prespecified in the original protocol as 'post hoc' analyses.

Selection of studies

Two review authors (TA Lawrie (TAL) and GJ Hofmeyr (GJH)) independently assessed for inclusion all the potential studies we identified as a result of the search strategy. We would have resolved any disagreement through discussion or, if required, by consulting L Duley (LD).

Data extraction and management

We designed a form to extract data. For eligible studies, TAL and GJH extracted the data using the agreed form. We would have resolved discrepancies through discussion or, if required, by consulting LD. We entered data into Review Manager software (RevMan 2008) and checked it for accuracy.

When information regarding any of the above was unclear, we attempted to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

TAL and GJH independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). We resolved any disagreement by discussion.

(1) Sequence generation (checking for possible selection bias)

We 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:

  • adequate (any truly random process, e.g. random number table; computer random number generator);

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

  • unclear.   

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

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

We assessed the methods as:

  • adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

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

  • unclear.   

(3) Blinding (checking for possible performance bias)

We 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 that studies were at low risk of bias if they were blinded, or if we judged that the lack of blinding could not have affected the results. We assessed blinding separately for different outcomes or classes of outcomes.

We assessed the methods as:

  • adequate, inadequate or unclear for participants;

  • adequate, inadequate or unclear for personnel;

  • adequate, inadequate or unclear for outcome assessors.

(4) Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

We 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 stated whether attrition and exclusions were reported, 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 was reported, or could be supplied by the trial authors, we have re-included missing data in the analyses which we undertook. The cut-off level of missing data that was used to assess that a study is adequate was 20%. We assessed methods as:

  • adequate;

  • inadequate;

  • unclear.

(5) Selective reporting bias

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

We assessed the methods as:

  • adequate (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);

  • inadequate (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.

(6) Other sources of bias

We described for each included study any important concerns we had about other possible sources of bias, e.g. whether the trial was stopped early due to some data-dependent process, whether there was extreme baseline imbalance or whether there was a potential source of bias related to the specific study design.

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

  • yes;

  • no;

  • unclear.

(7) Overall risk of bias

We made explicit judgements about whether studies were at high risk of bias, according to the criteria given in the Handbook (Higgins 2009). With reference to (1) to (6) above, we assessed the likely magnitude and direction of the bias and whether we considered it likely to impact on the findings. We 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 present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we used the mean difference if outcomes are 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

Cluster-randomised trials would be included in the analyses along with individually randomised trials. We would adjust their sample sizes using the methods described in the Handbook (section 16.3.4) using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we used ICCs from other sources, we would report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identified both cluster-randomised trials and individually-randomised trials, we would synthesise the relevant information. We would consider it reasonable to combine the results from both if there was little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit was considered to be unlikely.

We would acknowledge heterogeneity in the randomisation unit and perform sensitivity analyses 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 all participants would be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised minus any participants whose outcomes were 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 if T² was greater than zero and either I² was greater than 30% or there was a low P-value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

We investigated reporting biases (such as publication bias) by doing a subgroup analysis based on the sample sizes of the trials.

Data synthesis

We carried out statistical analysis using the Review Manager software (RevMan 2008). 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. If there was clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials, or if substantial statistical heterogeneity was detected, we used random-effects meta-analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random-effects summary was treated as the average range of possible treatment effects and we would discuss the clinical implications of treatment effects differing between trials. If the average treatment effect was not clinically meaningful we would not combine trials.

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

Subgroup analysis and investigation of heterogeneity

When we identified substantial heterogeneity, we investigated it using subgroup analyses. We considered whether an overall summary was meaningful, and if it was, used random-effects analysis to produce it.

We carried out the following subgroup analyses.

  1. Trials in populations with low versus adequate dietary calcium intake;

  2. Trials in subjects with low/average versus high hypertensive risk;

  3. Trials with small versus larger sample sizes.

We used only primary outcomes in subgroup analyses 2 and 3.

For fixed-effect inverse variance meta-analyses we assessed differences between subgroups by interaction tests. For random-effects, we assessed differences between subgroups by inspection of the subgroups’ confidence intervals; non-overlapping confidence intervals indicate a statistically significant difference in treatment effect between the subgroups.

Sensitivity analysis

We undertook sensitivity analysis by considering the results of the larger sample size trials versus the overall results for primary outcomes.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

We included 13 studies. Four were multicentre studies: one in Argentina (Belizan 1991), one in the USA (CPEP 1997), another in Australia (Crowther 1999) and the fourth was international (WHO 2006). Most of the 15,730 women recruited to these studies were low risk (15,143 women) and had a low dietary intake of calcium (10,678). Most studies only recruited women who were nulliparous or primiparous. One study did not state the parity of women recruited (Niromanesh 2001) and another commented that most women were nulliparous (Villar 1990). For most studies the intervention was 1.5 g to 2 g per day of calcium.

Five studies enrolled women considered to be at high risk of pre-eclampsia. The definitions of high risk and the actual risk (rate of pre-eclampsia in the placebo group) were variable: positive 'roll-over test at 28-30 weeks (8/34) (L-Jaramillo 1990); teenagers 17 years or younger (3/88) (Villar 1990); positive 'roll-over' test at 28-32 weeks plus one clinical risk factor (7/15) (Niromanesh 2001); positive 'roll-over' and positive angiotensin II infusion test (15/34) (S-Ramos 1994); and nulliparous teenagers 17.5 years or younger (21/135) (L-Jaramillo 1997). The clinical usefulness of the pooled results in this subgroup is therefore limited.

Two included studies have conducted long-term follow up of the children whose mothers were recruited to these trials (Belizan 1991; Hiller 2007). In Belizan 1991, only the subset of women recruited in private clinics were contacted, and in Hiller 2007, the outcomes reported differed from this review (but unpublished data may be made available by the authors at a later date).

Other studies have reported outcomes for small subsets of women (CPEP 1997: Hatton 2003; WHO 2006: Zhang 2007), but these data did not meet the inclusion criteria for this review.

We excluded 27 studies from the review.

Risk of bias in included studies

See table of Characteristics of included studies. All were well designed, double-blind, placebo-controlled trials. Pre-specified outcome data were not available from all trials. The possibility of reporting bias must be kept in mind for those outcomes with unreported data from some trials.

In L-Jaramillo 1990, a large discrepancy in numbers allocated to each group is not accounted for. In Kumar 2009, we contacted the authors to clarify the imbalance in group size that occurred in their study. We accept their explanation (see notes in Characteristics of included studies) but the imbalance does increase the potential for bias.

In some trials, individual denominators were not given for specific outcomes. Where it was clear that the outcomes were not measured in the entire group, we have adjusted the denominators accordingly.

In other respects, the methodology of the studies included appears sound.

Effects of interventions

In the 13 included studies, significant heterogeneity of results occurred for four outcomes: pre-eclampsia; high blood pressure; preterm birth and birthweight less than 2500 g. Factors accounting for the heterogeneity appeared to be maternal risk at trial entry, dietary calcium and trial size. The small trials have more extreme results than large trials, but as all the small trials recruited high-risk women, this could also be related to risk status. In view of the heterogeneity, we used a random-effects model for these four outcomes.

(1) High blood pressure with or without proteinuria

The results follow a similar pattern to those for pre-eclampsia (see below). Overall there was less high blood pressure with calcium supplementation rather than placebo (12 trials, 15,470 women: risk ratio (RR) random-effects model 0.65, 95% confidence interval (CI) 0.53 to 0.81) Figure 1. The reduction in RR was greatest for the small trials (fewer than 400 women: seven trials, 675 women: RR 0.38, 95% CI 0.21 to 0.68), for women at high risk of developing pre-eclampsia (four trials, 327 women: RR 0.47, 95% CI 0.22 to 0.97), and for those with low baseline dietary calcium (seven trials, 10,418 women: RR 0.44, 95% CI 0.28 to 0.70) (See Figure 2).

Figure 1.

Funnel plot of comparison: 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, outcome: 1.1 High blood pressure (with or without proteinuria).

Figure 2.

Funnel plot of comparison: 2 Routine calcium supplementation in pregnancy by hypertension risk, outcome: 2.1 High blood pressure (with or without proteinuria).

(2) Pre-eclampsia

Overall, there was a reduction in the average risk of pre-eclampsia (13 trials, 15,730 women: RR 0.45, 95% CI 0.31 to 0.65). This reduction in risk ratio was greatest for women at high risk of pre-eclampsia (five trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42), and for those with low baseline calcium intake (eight trials, 10,678 women: RR 0.36, 95% CI 0.20 to 0.65) (See Figure 3, Figure 4).

Figure 3.

Funnel plot of comparison: 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, outcome: 1.2 Pre-eclampsia.

Figure 4.

Funnel plot of comparison: 2 Routine calcium supplementation in pregnancy by hypertension risk, outcome: 2.2 Pre-eclampsia.

When subgrouped by both dietary calcium intake and study size, the effect size appeared to be associated most strongly with study size (in the small studies, risk ratio 0.21 for the low calcium trials and 0.26 for the adequate calcium trials, and in the large studies 0.63 and 0.70 respectively).

(3) Preterm birth

Calcium supplementation reduced the average risk of preterm birth overall (11 trials 15,275 women: RR 0.76, 95% CI 0.60 to 0.97) (See Figure 5) and amongst women at high risk of developing pre-eclampsia recruited to four small trials (568 women: RR 0.45, 95% CI 0.24 to 0.83).

Figure 5.

Funnel plot of comparison: 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, outcome: 1.12 Preterm birth.

(4) Admission to neonatal intensive care unit

There was no overall effect on the RR of admission to a neonatal intensive care unit (four trials, 13,406 women: RR 1.05, 95% CI 0.94 to 1.18).

(5) Stillbirth or death before discharge from hospital

There was no overall effect on the RR of a stillbirth or the baby dying before discharge from hospital (11 trials, 15,665 women: RR 0.90, 95% CI 0.74 to 1.09).

(6) Maternal death or serious morbidity

The risk ratio of having the composite outcome maternal death or serious morbidity was reduced for women allocated calcium supplementation compared with placebo (four trials, 9732 women: RR 0.80, 95% CI 0.65 to 0.97).

(7) Placental abruption

In the five trials reporting this outcome, there was no clear difference between the groups (14,336 women: RR 0.86, 95% CI 0.55 to 1.34).

(8) Caesarean section

There was no statistically significant effect on the risk ratio of caesarean section (eight trials, 15,234 women: RR 0.95, 95% CI 0.89 to 1.02).

(9) *Proteinuria

Only one trial reported proteinuria (WHO 2006), and there was no overall difference between the groups (8312 women: RR 1.04, 95% CI 0.86 to 1.26).

(10) *Severe pre-eclampsia as defined by trial authors

Only one trial reported severe pre-eclampsia (WHO 2006). Again, there was no clear difference between the groups (one trial, 8302 women: RR 0.74, 95% CI 0.48 to 1.15).

(11) *Eclampsia

The two largest trials reported eclampsia (CPEP 1997; WHO 2006) as well as Kumar 2009. There was no clear difference between the groups (three trials, 13,425 women: RR 0.73, 95% CI 0.41 to 1.27).

(12) *HELLP syndrome

Only the two largest studies reported HELLP syndrome (CPEP 1997; WHO 2006). The RR was higher for women allocated calcium supplementation, rather than placebo (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82).

(13) *Maternal intensive care unit admission

Only one trial reported admission to intensive care (WHO 2006). There was no clear difference between the groups (one trial, 8312 women: RR 0.84, 95% CI 0.66 to 1.07).

(14) *Maternal death

Only one trial reported maternal deaths (WHO 2006). One death occurred in the calcium group and six in the placebo group, a difference which was not statistically significant (RR 0.17, 95% CI 0.02 to 1.39).

(15) Mother's hospital stay seven days or more

Data were not available for this outcome.

(16) Birthweight less than 2500 g

There was no overall effect on the risk of having a baby with birthweight less than 2500 g (nine trials, 14,883 women: RR 0.85, 95% CI 0.72 to 1.01).

(17) Neonate small-for-gestational age

There was no overall effect on the risk ratio of the baby being born small-for-gestational age (four trials 13,615 women: RR 1.05, 95% CI 0.86 to 1.29).

(18) Neonate in intensive care unit seven days or more

Data were not available for this outcome.

(19) *Death or severe neonatal morbidity

No data were available for this outcome.

(20) Childhood disability

Data were not available for this outcome.

(21) Childhood systolic blood pressure greater than 95th percentile

One trial has assessed during childhood a subset of the children recruited whilst in utero (Belizan 1991). At about seven years of age, diastolic blood pressure greater than 95th percentile was reduced (one trial, 514 women: RR 0.59, 95% CI 0.39 to 0.91). While the baseline calcium intake in the original study was low (calcium group mean 646 mg, standard deviation (SD) 396, placebo group 642, SD 448 in a sample assessed during the first four months of the study), the group followed up were only from among the 614 women from the private hospital, not the 580 from the public hospitals. Their dietary calcium intake may have differed from the mean (more likely to be higher in more affluent women). The baseline calcium status of the women in this part of the study therefore cannot be classified.

In the Crowther 1999 trial, a follow up of mothers and offspring was conducted four to seven years later (45% of the original participants) and reported in Hiller 2007. Childhood blood pressure was reported as a continuous variable. It was concluded that calcium supplementation during pregnancy may lower the mean blood pressure of the children of women with hypertension in pregnancy. We have sought additional unpublished data from the authors which may be available/suitable for inclusion in the next update.

A limited follow up of mothers and infants from the CPEP 1997 study found reduced systolic blood pressure at two years of age in the calcium supplementation group (mean 95.4 mmHg, SD 7.6, n = 35 versus 100.2, 7.9, n = 18). We have not included the data in this review because the low and unequal follow-up rate (35 and 18 from 497 invited to participate) limit the reliability of the results. In another report of CPEP 1997 (Hatton 2003), reduced systolic blood pressure was found in the offspring of the calcium supplementation group at two years of age. We have not included these data either because of the high losses to follow up.

(22) Childhood diastolic blood pressure greater than 95th percentile

Data were available only from the Belizan 1991 study. The difference was not statistically significant.

Discussion

Calcium supplementation with at least 1 g of calcium is associated with a halving in the risk ratio of pre-eclampsia, with the confidence intervals putting the true effect anywhere between a 31% reduction and a 65% reduction. Women with an adequate dietary intake of calcium were the only subgroup for which this was not statistically significant, nevertheless the point estimate for this subgroup of women was a 38% reduction. The greatest reduction in risk was for women at high risk (variably defined) and those with low baseline dietary calcium intake. There was also a 35% reduction in the risk of gestational hypertension, with the greatest effect again being amongst women at high risk and those with a low calcium intake at trial entry.

There was a 24% reduction in the risk ratio of preterm birth overall, and by 55% in women at high risk of pre-eclampsia.

Although pre-eclampsia was reduced, this was not clearly reflected in any reduction in severe pre-eclampsia, eclampsia, or admission to intensive care. Nevertheless, the point estimates for these outcomes favoured calcium supplementation, and so moderate reductions in these outcomes remain possible. Also, the risk ratio of the composite outcome 'maternal death or severe morbidity' was reduced by 20% (95% confidence interval 35% to 3%) for women allocated calcium supplementation. In the two trials reporting HELLP syndrome, the RR of this outcome seemed to be increased in association with calcium supplementation. A possible explanation for this apparently anomalous finding, is that calcium supplementation in the second half of pregnancy may have reduced blood pressure rather than the underlying pre-eclamptic process. Lower blood pressures in the calcium group may have reduced the diagnosis of pre-eclampsia and thus interventions to curtail pregnancy, allowing more time for the pre-eclampsia to progress to HELLP syndrome (Hofmeyr 2007).

No side effects of calcium supplementation (other than the increase in HELLP syndrome) have been recorded in the trials reviewed. There remains little information about the long-term follow up of children within these trials, with the exception of a reduction in childhood systolic hypertension in one study that measured this outcome. There is no information about any possible changes in the use of healthcare resources associated with calcium supplementation. It would seem plausible that a reduction in gestational hypertension and pre-eclampsia might lead to fewer antenatal visits, less admission for antenatal care and fewer inductions of labour. However, these trials do not provide data on these outcomes.

Heterogeneity in the results seems to be largely associated with study size, with the small studies having the most positive results (See Figure 6, Figure 7, Figure 8). These 'small study effects' may indicate publication bias or other biases, or be caused by differences between small and large studies. As the small studies tended to recruit high-risk women, at least some of the heterogeneity may be explained by calcium having a greater effect for high-risk women. The data on heterogeneity related to sample size should be interpreted with caution, as the sensitivity analysis was post-hoc, and the cut-off point for sample size (400) was arbitrary.

Figure 6.

Funnel plot of comparison: 3 Routine calcium supplementation in pregnancy by study sample size, outcome: 3.1 High blood pressure (with or without proteinuria).

Figure 7.

Funnel plot of comparison: 3 Routine calcium supplementation in pregnancy by study sample size, outcome: 3.3 Preterm birth.

Figure 8.

Funnel plot of comparison: 4 Routine calcium supplementation in pregnancy by baseline dietary calcium and study sample size, outcome: 4.1 Pre-eclampsia.

There are no clear differences in any other outcomes, although for several outcomes the confidence intervals are approaching statistical significance. So, for caesarean section, a small (5%) reduction in risk ratios associated with calcium supplementation is possible. For stillbirth and death before discharge from hospital the point estimate is for a reduction of 10%, although no effect or a small increase in risk has not been excluded (Figure 9, Figure 10).

Figure 9.

Funnel plot of comparison: 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, outcome: 1.16 Stillbirth or death before discharge from hospital.

Figure 10.

Funnel plot of comparison: 2 Routine calcium supplementation in pregnancy by hypertension risk, outcome: 2.5 Stillbirth or death before discharge from hospital.

Taken together, these trials show a halving in the risk ratio of pre-eclampsia and a significant reduction in the risk of preterm birth for high-risk women and overall, with more modest reductions in the risk ratio of gestational hypertension and of maternal death or serious morbidity. The risk of HELLP syndrome was increased. There are no clear effects on other substantive outcomes at discharge from hospital.

These modest results contrast with the large epidemiological differences between populations with adequate and low dietary calcium intake (Belizan 1980; Hamlin 1952; Hamlin 1962). Possible explanations include the following.

  1. Dietary calcium may be a marker for other aetiological factors.

  2. Starting supplementation in the middle trimester of pregnancy may be too late to be fully effective.

The finding of reduced childhood hypertension needs replication, but if true has far-reaching implications for public health. Although based on only a partial follow up in one study, this finding is supported by a very limited follow up in three studies (CPEP 1997; Crowther 1999), as well as observational (McGarvey 1991) and animal (Bergel 2002) studies.

Authors' conclusions

Implications for practice

The reduction in hypertension, pre-eclampsia and preterm birth, and in the composite outcome maternal death or severe morbidity, support the use of calcium supplementation during pregnancy, particularly for those with low dietary intake or high risk of pre-eclampsia. The increase in the risk of HELLP syndrome was small in terms of absolute numbers, and therefore we considered it to be outweighed by the overall reduction in death or severe morbidity.

Implications for research

The increase in the risk of HELLP syndrome identified by this review requires further investigation. Any future trials should collect information about the use of health service resources, as well as other clinical outcomes. The minimum dose in this review was one gram of calcium daily. It would now be relevant to assess whether supplementation via dietary modification, for women with low calcium intake, has the same benefits as the tablets administered in these trials.

Further research is also needed to provide reassurance that calcium supplementation during pregnancy does not have any adverse effects for the children exposed whilst in utero, and to verify whether it reduces childhood hypertension.

Research into the effects of calcium supplementation combined with low-dose aspirin would be of interest.

Acknowledgements

We thank the trial authors who have contributed additional data for this review, and Jose Villar for constructive criticism of the updated protocol. We also thank Maria Kalousi and Oliver Boothroyd for their assistance with the translation of certain articles to English.

Data and analyses

Download statistical data

Comparison 1. Routine calcium supplementation in pregnancy by baseline dietary calcium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 High blood pressure (with or without proteinuria)1215470Risk Ratio (M-H, Random, 95% CI)0.65 [0.53, 0.81]
1.1 Adequate calcium diet45022Risk Ratio (M-H, Random, 95% CI)0.90 [0.81, 0.99]
1.2 Low calcium diet710418Risk Ratio (M-H, Random, 95% CI)0.44 [0.28, 0.70]
1.3 Dietary calcium not specified130Risk Ratio (M-H, Random, 95% CI)0.91 [0.57, 1.45]
2 Pre-eclampsia1315730Risk Ratio (M-H, Random, 95% CI)0.45 [0.31, 0.65]
2.1 Adequate calcium diet45022Risk Ratio (M-H, Random, 95% CI)0.62 [0.32, 1.20]
2.2 Low calcium diet810678Risk Ratio (M-H, Random, 95% CI)0.36 [0.20, 0.65]
2.3 Dietary calcium not specified130Risk Ratio (M-H, Random, 95% CI)0.14 [0.02, 1.02]
3 Preterm birth1115275Risk Ratio (M-H, Random, 95% CI)0.76 [0.60, 0.97]
3.1 Adequate calcium diet45033Risk Ratio (M-H, Random, 95% CI)0.59 [0.26, 1.33]
3.2 Low calcium diet710242Risk Ratio (M-H, Random, 95% CI)0.81 [0.64, 1.02]
4 Admission to neonatal intensive care unit413406Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.18]
4.1 Adequate calcium diet14336Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.95, 1.26]
4.2 Low calcium diet39070Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.81, 1.19]
5 Stillbirth or death before discharge from hospital1115665Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.09]
5.1 Adequate calcium diet45033Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.66, 1.90]
5.2 Low calcium diet710632Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.70, 1.07]
6 Maternal death/serious morbidity49732Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.65, 0.97]
6.1 Low calcium diet49732Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.65, 0.97]
6.2 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
7 Placental abruption514336Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.55, 1.34]
7.1 Adequate calcium diet34830Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.39, 1.68]
7.2 Low calcium diet29506Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.51, 1.55]
8 Caesarean section815234Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.89, 1.02]
8.1 Adequate calcium diet34981Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.84, 1.07]
8.2 Low calcium diet510253Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.88, 1.04]
9 Proteinuria (gestational with no proteinuria18312Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.86, 1.26]
9.1 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
9.2 Low calcium diet18312Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.86, 1.26]
10 Severe pre-eclampsia18302Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.48, 1.15]
10.1 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
10.2 Low calcium diet18302Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.48, 1.15]
11 Eclampsia313425Risk Ratio (M-H, Fixed, 95% CI)0.73 [0.41, 1.27]
11.1 Adequate calcium diet14589Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.25, 3.99]
11.2 Low calcium diet28836Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.37, 1.26]
12 HELLP syndrome212901Risk Ratio (M-H, Fixed, 95% CI)2.67 [1.05, 6.82]
12.1 Adequate calcium diet14589Risk Ratio (M-H, Fixed, 95% CI)3.50 [0.73, 16.82]
12.2 Low calcium diet18312Risk Ratio (M-H, Fixed, 95% CI)2.26 [0.70, 7.32]
13 Intensive care unit admission18312Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.07]
13.1 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
13.2 Low calcium diet18312Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.07]
14 Maternal death18312Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.02, 1.39]
14.1 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
14.2 Low calcium diet18312Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.02, 1.39]
15 Birthweight < 2500 g914883Risk Ratio (M-H, Random, 95% CI)0.85 [0.72, 1.01]
15.1 Adequate calcium diet45033Risk Ratio (M-H, Random, 95% CI)0.59 [0.31, 1.13]
15.2 Low calcium diet59850Risk Ratio (M-H, Random, 95% CI)0.95 [0.85, 1.05]
16 Neonate small-for-gestational age as defined by trial authors413615Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.86, 1.29]
16.1 Adequate calcium diet14589Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.92, 1.52]
16.2 Low calcium diet39026Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.60, 1.21]
17 Childhood systolic blood pressure > 95th percentile1514Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.39, 0.91]
17.1 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
17.2 Low calcium diet1514Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.39, 0.91]
18 Childhood diastolic blood pressure > 95th percentile1514Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.50, 1.31]
18.1 Adequate calcium diet00Risk Ratio (M-H, Fixed, 95% CI)Not estimable
18.2 Low calcium diet1514Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.50, 1.31]
Analysis 1.1.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 1 High blood pressure (with or without proteinuria).

Analysis 1.2.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 2 Pre-eclampsia.

Analysis 1.3.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 3 Preterm birth.

Analysis 1.4.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 4 Admission to neonatal intensive care unit.

Analysis 1.5.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 5 Stillbirth or death before discharge from hospital.

Analysis 1.6.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 6 Maternal death/serious morbidity.

Analysis 1.7.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 7 Placental abruption.

Analysis 1.8.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 8 Caesarean section.

Analysis 1.9.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 9 Proteinuria (gestational with no proteinuria.

Analysis 1.10.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 10 Severe pre-eclampsia.

Analysis 1.11.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 11 Eclampsia.

Analysis 1.12.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 12 HELLP syndrome.

Analysis 1.13.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 13 Intensive care unit admission.

Analysis 1.14.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 14 Maternal death.

Analysis 1.15.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 15 Birthweight < 2500 g.

Analysis 1.16.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 16 Neonate small-for-gestational age as defined by trial authors.

Analysis 1.17.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 17 Childhood systolic blood pressure > 95th percentile.

Analysis 1.18.

Comparison 1 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 18 Childhood diastolic blood pressure > 95th percentile.

Comparison 2. Routine calcium supplementation in pregnancy by hypertension risk
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 High blood pressure (with or without proteinuria)1215470Risk Ratio (M-H, Random, 95% CI)0.65 [0.53, 0.81]
1.1 Low-risk women815143Risk Ratio (M-H, Random, 95% CI)0.71 [0.57, 0.89]
1.2 High-risk women4327Risk Ratio (M-H, Random, 95% CI)0.47 [0.22, 0.97]
2 Pre-eclampsia1315730Risk Ratio (M-H, Random, 95% CI)0.45 [0.31, 0.65]
2.1 Low-risk women815143Risk Ratio (M-H, Random, 95% CI)0.59 [0.41, 0.83]
2.2 High-risk women5587Risk Ratio (M-H, Random, 95% CI)0.22 [0.12, 0.42]
3 Preterm birth1115275Risk Ratio (M-H, Random, 95% CI)0.76 [0.60, 0.97]
3.1 Low-risk women714707Risk Ratio (M-H, Random, 95% CI)0.84 [0.67, 1.05]
3.2 High-risk women4568Risk Ratio (M-H, Random, 95% CI)0.45 [0.24, 0.83]
4 Admission to neonatal intensive care unit413406Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.18]
4.1 Low-risk women313343Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.94, 1.19]
4.2 High-risk women163Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.03, 2.48]
5 Stillbirth or death before discharge from hospital1115665Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.09]
5.1 Low-risk women815153Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.09]
5.2 High-risk women3512Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.20]
Analysis 2.1.

Comparison 2 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 1 High blood pressure (with or without proteinuria).

Analysis 2.2.

Comparison 2 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 2 Pre-eclampsia.

Analysis 2.3.

Comparison 2 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 3 Preterm birth.

Analysis 2.4.

Comparison 2 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 4 Admission to neonatal intensive care unit.

Analysis 2.5.

Comparison 2 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 5 Stillbirth or death before discharge from hospital.

Comparison 3. Routine calcium supplementation in pregnancy by study sample size
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 High blood pressure (with or without proteinuria)1215470Risk Ratio (M-H, Random, 95% CI)0.65 [0.53, 0.81]
1.1 Studies with < 400 participants7675Risk Ratio (M-H, Random, 95% CI)0.38 [0.21, 0.68]
1.2 Studies with =/> 400 participants514795Risk Ratio (M-H, Random, 95% CI)0.83 [0.70, 0.98]
2 Pre-eclampsia1315730Risk Ratio (M-H, Random, 95% CI)0.45 [0.31, 0.65]
2.1 Studies with < 400 participants8935Risk Ratio (M-H, Random, 95% CI)0.21 [0.12, 0.36]
2.2 Studies with =/> 400 participants514795Risk Ratio (M-H, Random, 95% CI)0.71 [0.52, 0.97]
3 Preterm birth1115275Risk Ratio (M-H, Random, 95% CI)0.76 [0.60, 0.97]
3.1 Studies with < 400 participants6810Risk Ratio (M-H, Random, 95% CI)0.43 [0.24, 0.76]
3.2 Studies with =/> 400 participants514465Risk Ratio (M-H, Random, 95% CI)0.86 [0.69, 1.07]
4 Admission to neonatal intensive care unit413406Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.18]
4.1 Studies with < 400 participants163Risk Ratio (M-H, Fixed, 95% CI)0.29 [0.03, 2.48]
4.2 Studies with =/> 400 participants313343Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.94, 1.19]
5 Stillbirth or death before discharge from hospital1115665Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.09]
5.1 Studies with < 400 participants6846Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.02, 9.20]
5.2 Studies with =/> 400 participants514819Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.74, 1.09]
Analysis 3.1.

Comparison 3 Routine calcium supplementation in pregnancy by study sample size, Outcome 1 High blood pressure (with or without proteinuria).

Analysis 3.2.

Comparison 3 Routine calcium supplementation in pregnancy by study sample size, Outcome 2 Pre-eclampsia.

Analysis 3.3.

Comparison 3 Routine calcium supplementation in pregnancy by study sample size, Outcome 3 Preterm birth.

Analysis 3.4.

Comparison 3 Routine calcium supplementation in pregnancy by study sample size, Outcome 4 Admission to neonatal intensive care unit.

Analysis 3.5.

Comparison 3 Routine calcium supplementation in pregnancy by study sample size, Outcome 5 Stillbirth or death before discharge from hospital.

Comparison 4. Routine calcium supplementation in pregnancy by baseline dietary calcium and study sample size (not pre-specified)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Pre-eclampsia1315730Risk Ratio (M-H, Random, 95% CI)0.45 [0.31, 0.65]
1.1 Adequate calcium/small study2230Risk Ratio (M-H, Random, 95% CI)0.26 [0.04, 1.50]
1.2 Adequate calcium/large study24792Risk Ratio (M-H, Random, 95% CI)0.70 [0.33, 1.46]
1.3 Low calcium/small study5675Risk Ratio (M-H, Random, 95% CI)0.21 [0.12, 0.38]
1.4 Low calcium/large study310003Risk Ratio (M-H, Random, 95% CI)0.63 [0.35, 1.14]
1.5 Dietary calcium not specified130Risk Ratio (M-H, Random, 95% CI)0.14 [0.02, 1.02]
Analysis 4.1.

Comparison 4 Routine calcium supplementation in pregnancy by baseline dietary calcium and study sample size (not pre-specified), Outcome 1 Pre-eclampsia.

Comparison 5. Routine calcium supplementation in pregnancy by other outcomes (not pre-specified)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Uterine artery RI at 32 weeks1372Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.02, 0.01]
2 Umbilical artery RI at 32 weeks1373Mean Difference (IV, Fixed, 95% CI)-0.01 [-0.02, 0.01]
3 Low platelet count at 35 weeks1667Odds Ratio (M-H, Fixed, 95% CI)1.19 [0.62, 2.29]
4 High serum uric acid at 35 weeks1664Odds Ratio (M-H, Fixed, 95% CI)1.00 [0.61, 1.65]
5 High urine protein/creatinine ratio at 35 weeks1637Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.70, 1.47]
6 Ultrasound estimate of fetal growth at 32 weeks: femur length (cm)*1377Mean Difference (IV, Fixed, 95% CI)Not estimable
7 Ultrasound estimate of fetal growth at 32 weeks: biparietal diameter (cm)*1377Mean Difference (IV, Fixed, 95% CI)Not estimable
8 Ultrasound estimate of fetal growth at 32 weeks: abdominal circumference (cm)*1377Mean Difference (IV, Fixed, 95% CI)Not estimable
Analysis 5.1.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 1 Uterine artery RI at 32 weeks.

Analysis 5.2.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 2 Umbilical artery RI at 32 weeks.

Analysis 5.3.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 3 Low platelet count at 35 weeks.

Analysis 5.4.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 4 High serum uric acid at 35 weeks.

Analysis 5.5.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 5 High urine protein/creatinine ratio at 35 weeks.

Analysis 5.6.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 6 Ultrasound estimate of fetal growth at 32 weeks: femur length (cm)*.

Analysis 5.7.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 7 Ultrasound estimate of fetal growth at 32 weeks: biparietal diameter (cm)*.

Analysis 5.8.

Comparison 5 Routine calcium supplementation in pregnancy by other outcomes (not pre-specified), Outcome 8 Ultrasound estimate of fetal growth at 32 weeks: abdominal circumference (cm)*.

Appendices

Appendix 1. Methods used to assess trials included in previous versions of this review

Two review authors independently assessed the methodological quality and other inclusion criteria of the identified trials. At least one of these authors had no involvement in the trial. We resolved disagreements by consensus. The primary assessment for inclusion was based on concealment of allocation and whether the trial was placebo controlled.

Two authors independently extracted and cross-checked the data. Descriptive data included authors, year of publication, country, time span of the trial, maternal age, parity, type of placebo, baseline dietary calcium intake, type, dose, onset and duration of calcium supplementation, compliance, co-interventions, trial quality assessments, and number randomised and analysed.

We compared categorical data using risk ratios and their 95% confidence intervals. We tested for statistical heterogeneity between trials using the I-squared statistic, with values greater than 50% indicating significant heterogeneity. In the absence of significant heterogeneity, data were pooled using a fixed-effect model. If there was significant heterogeneity, a random-effects model was used and an attempt made to identify potential sources of heterogeneity (Greenland 1994; Villar 1995) based on subgroup analyses by risk of hypertensive disorders, baseline dietary calcium intake, trial quality and trial size.

For continuous data, we calculated pooled estimates of effect size from a weighted average, with weight based on the inverse of the variance (Early Breast Cancer Trialists' Group 1990). We identified comparisons, outcomes and subgroups other than those prespecified in the original protocol as 'post hoc' analyses.

Appendix 2. Searches carried out in previous versions

Authors searched the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2005, Issue 4) using the terms calcium AND pregnan* AND (hypertens* or blood press*).

Feedback

Stones, 7 December 2010

Summary

Noting that public health programs are now starting to include calcium supplementation, I wonder if the statements in the abstract and plain language summary that "there were no other clear benefits, or harms"/"No adverse effects have been found" should be revised to include mention of the increased risk of HELLP syndrome associated with calcium supplementation. At the very least it would prompt programmers to include surveillance and reporting for this life threatening complication and would help to clarify whether this is a real association.

(Feedback submitted by William Stones, December 2010)

Reply

We agree with the above feedback. We have added emphasis to the effect on HELLP syndrome to the discussion, and added to "Implications for practice":
"..........The increase in the risk of HELLP syndrome was small in terms of absolute numbers, and therefore we considered it to be outweighed by the overall reduction in death or severe morbidity; and to "Implications for research":
"The increase in the risk of HELLP syndrome identified by this review requires further investigation."

To the abstract results we have added "There was an anomalous increase in the risk of HELLP syndrome (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82)."; and to the abstract conclusions we have added "We considered the latter benefit to outweigh the increase in HELLP syndrome, which was small in absolute numbers".

Contributors

Feedback: William Stones

Reply: G Justus Hofmeyr

Walkinshaw, 2 November 2010

Summary

I feel that the conclusion drawn for high-risk women go beyond the data.  Five trials are cited for high-risk women. Of these one trial assessed risk by roll over test, another by roll over test plus angiotensin II infusion, and a third by roll over test plus at least one risk factor. All three of these trials excluded chronic medical conditions.  For the two other trials, data for high-risk women come either from a subgroup analysis or are unpublished data. Villar 1990 includes mainly nulliparous women and excluded medical disease; L-Jaramillo 1990 includes nulliparous women and also excludes underlying medical disease. Thus three of the five trials do not describe high risk in any meaningfully clinically translatable way, and exclude the highest risk women (such as those with previous pre-eclampsia, chronic hypertension, or renal disease). The two additional studies also largely exclude clinical high-risk factors.

To draw a broad conclusion using the very impressive risk reduction in 'high risk' from this is not really translatable to clinical high risk. I think it will confuse clinicians, who will not look at the detail of the trials used and assume that high risk means the usual suspects, when it manifestly does not. The authors should consider some caveat to their conclusion. I actually think the current conclusion misleads.

During the genesis of the NICE guidance we looked in some detail at this to determine if there was evidence of benefit for clinically high-risk women, and concluded that at present those studies had not been performed. I do not feel that it is enough to rely on studies selecting women using research techniques to assess risk.

 The issue in low-risk women is more contentious and I make no comment on that part.

(Summary of comment from Stephen Walkinshaw, Obstetrician and Chair of NICE guideline development group for Hypertension in Pregnancy, November 2010)

Reply

We agree with the points made, and have added the following to the results section: "Five studies enrolled women considered to be at high risk of pre-eclampsia. The definitions of high risk and the actual risk (rate of pre-eclampsia in the placebo group) were variable: positive 'roll-over test at 28-30 weeks (8/34) (L-Jaramillo 1990); teenagers 17 years or younger (3/88) (Villar 1990); positive 'roll-over' test at 28-32 weeks plus one clinical risk factor (7/15) (Niromanesh 2001); positive 'roll-over' and positive angiotensin II infusion test (15/34) (S-Ramos 1994); and nulliparous teenagers 17.5 years or younger (21/135) (L-Jaramillo 1997). The clinical usefulness of the pooled results in this subgroup is therefore limited." To the abstract we have added: "The variable methods of selecting women as being at high-risk limit the clinical usefulness of these pooled results."

Contributors

Feedback: Stephen Walkinshaw

Reply: G Justus Hofmeyr

What's new

DateEventDescription
6 January 2011Feedback has been incorporatedFeedback from William Stones and Stephen Walkinshaw added with replies from the authors.

History

Protocol first published: Issue 2, 1998
Review first published: Issue 3, 1998

DateEventDescription
5 July 2010New citation required but conclusions have not changedNew author helped to update the review.
31 May 2010New search has been performedSearch updated. Fifteen new reports identified: one new study (Kumar 2009) included and four new trials excluded (de Souza 2006; Dizavandy 1998; Herrera 1998; Karandish 2003).
31 October 2009AmendedSearch updated. Fourteen new reports added to Studies awaiting classification.
1 September 2008AmendedConverted to new review format.
2 March 2006New citation required and conclusions have changedA large trial of calcium supplementation in communities with low dietary calcium intake has been added (WHO 2006).
2 March 2006New search has been performedSearch updated.

Contributions of authors

Lelia Duley prepared the original review in the Oxford Database of Perinatal Trials.
Álvaro Atallah and Justus Hofmeyr prepared the protocol for the review.
Justus Hofmeyr prepared the initial data analysis and is primarily responsible for maintaining the review, with input from the other authors. Tess Lawrie prepared the first draft of the 2010 update of the review with input from Justus Hofmeyr, Lelia Duley and Álvaro Atallah.

Declarations of interest

Justus Hofmeyr is a collaborator in the WHO Calcium Trial (WHO 2006), which was included in this review.

Sources of support

Internal sources

  • Universidade Federal de Sao Paulo/Escola Paulista de Medicina, Brazil.

  • Medical Research Council, UK.

  • Department for International Development, UK.

  • (GJH) Effective Care Research Unit, University of the Witwatersrand/Fort Hare, Eastern Cape Department of Health, South Africa.

External sources

  • UNDP/UNFPA/WHO/World Bank (HRP), Switzerland.

  • NHS Programme for Research and Development, UK.

Differences between protocol and review

Additional outcomes were added in 2004, and clearly identified as such.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Belizan 1991

MethodsMulticentre trial. Numbered, sealed opaque envelopes, containing randomisation codes. Of 593 (calcium) vs 601 (placebo) enrolled, 14 vs 13 were lost before starting treatment and excluded from analysis; 577 vs 588 had at least partial follow up. Follow up was incomplete for 52 vs 46, but delivery data were available in 17 vs 12 of these, giving delivery data for 544 vs 554.
ParticipantsNulliparous women, < 20 weeks' pregnant; blood pressure < 140/90 mmHg (mean of 5 measurements); no present or past disease; not taking medication; normal oral glucose tolerance tests.
Interventions2 g calcium as 500 mg calcium carbonate tablets, vs identical looking placebo tablets. Compliance was 84% (calcium) and 86% (placebo).
OutcomesGestational hypertension (DBP 90 or more; SBP 140 or more mmHg, on 2 occasions 6 hours apart); pre-eclampsia (gestational hypertension + proteinuria > 0.3 g/L on 2 random urine samples 6 hours apart); BP measured with random-zero sphygmomanometers, Korotkoff sound 5. Perinatal death.
Follow up: BP > 95th percentile for sex, age and height for children 5-9 years.
Notes

3 hospitals in Rosario, Argentina. Data for preterm birth given as percentages, not clear what the denominators were. Assumed to be the numbers with complete follow up (527 vs 542) as these were the numbers which were divisible by the percentages to give whole numbers. Unpublished placental abruption data obtained from authors.

Babies born in the private hospitals followed up at 7 years. Of 614 randomised (calcium 309/placebo 305), 301/299 completed the first study, 2/6 infant deaths and 1/0 maternal deaths had occurred, leaving 298/293 eligible for follow up. 289/285 were contacted, 10/5 refused to participate, 22/19 lived outside the country, and 257/261 were assessed (88% of those eligible).

Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskComputer-generated random number sequence - Epistats Statistical Package.
Allocation concealment?Low riskComplete set of numbered sealed opaque envelopes was sent to each of 3 hospitals.
Blinding?
All outcomes
Low riskRandomisation code was held centrally such that the woman and her health care providers were blind to her trial group. Tablets were identical in appearance, weight, colour, taste.
Incomplete outcome data addressed?
All outcomes
Low riskAll or partial data available for 579/593 (Ca) and 588/601 (Pl) respectively. Delivery data available for 544 and 554 respectively.
Free of selective reporting?Low riskAll primary outcomes addressed.
Free of other bias?Low riskBalanced group sizes, baseline characteristics including dietary calcium similar in both groups.

CPEP 1997

MethodsNumbered treatment packs in computer-generated simple randomisation sequence. Loss to follow up: calcium 132/2295 vs placebo 121/2294.
Participants

Pregnant nulliparas (45% black, 35% non-Hispanic white, 17% Hispanic white). Passed compliance test (took 75% of placebo over 6-14 days); BP 134/84 mmHg or less; urine protein dipstick negative or trace; 13-21 weeks' pregnant.

Exclusion criteria: taking medications; obstetric or pre-existing diseases or personal characteristics which could influence study end-points, absorption or metabolism of calcium; any risk associated with calcium supplementation, or compliance; elevated serum creatinine (1.0 mg per decilitre or more) or calcium (10.6 mg per decilitre or more); renal disease; haematuria; history or family history of urolithiasis; frequent use of calcium supplements or antacids.

Of 11,959 women screened, 5703 excluded initially and a further 1667 after the compliance test. The remaining 4589 women were enrolled.

Interventions

2 g/day elemental calcium as calcium carbonate, or placebo. Taken until delivery, development of pre-eclampsia or suspicion of urolithiasis. All women took 50 mg calcium per day as normal supplementation and were asked to drink 6 glasses of water per day.

Compliance was 64% in the calcium group and 67% in the placebo group. 20% of women took > 90% of the allocated treatment.

OutcomesGestational hypertension (DBP sitting, fifth Korotkoff sound unless zero, 90 mmHg or more on 2 occasions, 4 hours-1 week apart); severe gestational hypertension (DBP 110 mmHg twice or treated, or complications); proteinuria (300 mg/24 hours or more, 1+ on 2 occasions 4 hours-1 week apart, 2+ or more, or protein/creatinine ratio 0.35 or more); pre-eclampsia (gestational hypertension + proteinuria within 7 days of each other); severe pre-eclampsia (50/2163 vs 59/2173); renal insufficiency (21/2163 vs 23/2173); urolithiasis (1/2163 vs 3/2173); prematurity (< 37 weeks); baby small-for-gestational age (124/2163 vs 105/2173); perinatal death.
A limited follow up of mothers and infants found reduced SBP at 2 years of age in the calcium supplementation group (mean 95.4 mmHg, SD 7.6, n = 35 vs 100.2, 7.9, n = 18). The data have not been included in this review because the low and unequal follow-up rate (35 and 18 from 497 invited to participate) limit the reliability of the results.
NotesMulticentre trial, 5 US university centres. Maternal outcomes reported as percentages of the whole number enrolled. In this review, denominators of 2163 (calcium) and 2173 (placebo) have been used. Neonatal outcomes in the report are based on live births (2134 and 2139). Addition of abortions and fetal deaths brings these numbers to 2156 and 2166. It is not clear why a discrepancy in numbers remains.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskPackages of study tablets prepared and numbered by pharmaceutical manufacturer according to a computer-generated simple randomisation sequence.
Allocation concealment?Low riskOn enrolment, each woman was assigned the next numbered package of medication at one of 5 centres. The blister-packed tablets were identical in appearance.
Blinding?
All outcomes
Low riskDouble-blind. The code was held centrally.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Unclear riskAuthors used total number of women enrolled to each group as denominator instead of total number minus those lost to follow up. Also small discrepancy in overall numbers but unlikely to affect results substantially.
Free of other bias?Low riskBaseline characteristics similar.

Crowther 1999

MethodsCentral telephone randomisation, stratified by centre using variable blocks. Double-blind.
ParticipantsInclusion criteria: nulliparous women; singleton pregnancy; < 24 weeks' gestation; BP < 140/90 mmHg; expected to give birth at a collaborating centre.
Exclusion criteria: antihypertensive therapy; medical contraindication to calcium supplementation.
InterventionsCalcium carbonate 1.8 g daily or lactose placebo tablets, from 20-24 weeks until birth.
OutcomesPrimary: pregnancy-induced hypertension (DBP 90 mmHg or more on 2 consecutive occasions 4 hours apart, or 110 mmHg once; pre-eclampsia (as above plus proteinuria 0.3 g or more per 24 hours or 2+ protein or more on two random clean-catch urine samples); preterm birth (< 37 weeks).
Secondary: severe pregnancy induced hypertension (DBP 110 or more on 2 occasions 4 hours apart, or 120 or more once); severe pre-eclampsia (as above plus proteinuria); very preterm birth (< 32 weeks; extremely preterm birth (< 28 weeks); maternal fetal and infant events after trial entry.
Notes5 hospitals in Australia. August 1992 to December 1996.
Estimated sample size 948. Trial stopped prematurely for financial reasons.
31% in the calcium group and 24% in the placebo group stopped taking the tablets during the trial. Analysis was by intention to treat.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskStratified randomisation centrally co-ordinated using variable blocks.
Allocation concealment?Low riskIdentical sealed treatment packs prepared by drug company.
Blinding?
All outcomes
Low riskDouble-blind. Tablets identical in size, colour and consistency. Code held centrally and only broken after trial closure and exploratory data analyses.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Low riskIntention-to-treat analysis. 227 in calcium group and 229 in placebo group. Baseline characteristics similar.
Free of other bias?Unclear riskOnly achieved 48% of recruitment target (456 instead of 948) due to lack of funds.

Kumar 2009

MethodsRandomised, double-blind, placebo-controlled trial.
Participants

Healthy normotensive primigravid women with uncomplicated single pregnancy; pregnancy 12 to 25 weeks' gestation, known date of the last menstrual period, and intention to deliver at Lok Nayak Hospital, New Delhi. Study population had a low dietary calcium.

Exclusions:  multiple pregnancy, polyhydramnios, fetal malformations, diabetes, chronic hypertension, renal disease, cardiovascular disease, urolithiasis, or blood pressure of 140/90 mmHg or higher at first visit or at enrolment.

Interventions4 tablets (2 g calcium or placebo) were taken daily.
Outcomes

Pre-eclampsia (systolic BP > 140 mmHg and diastolic BP > 90 mmHg on 2 occasions 4 hours apart after 20 weeks' pregnancy in women normotensive previously, together with proteinuria > 300 mg/24 h or 1+ on a clean-catch dipstix in the absence of urinary infection); eclampsia; preterm delivery; caesarean section.

Baseline characteristics comparable.

NotesImbalanced groups: 290 allocated to calcium, 262 to placebo group.  17 and 11 lost to follow up so 273 and 251 analysed respectively. See below.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskSimple randomisation sequence developed manually.
Allocation concealment?Low riskCoded numbers assigned to treatment packets and distributed to participants using the random number sequence. 
Blinding?
All outcomes
Low riskDouble blind. Calcium and placebo tablets were identical. Randomisation code broken after completion of the trial.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Low risk 
Free of other bias?Unclear riskImbalance in size of groups. The authors were contacted regarding the imbalance and they explained that a random sequence was generated for 600 participants (unblocked) but recruiting was stopped at 552 participants and so 48 numbers remained unallocated.

L-Jaramillo 1989

MethodsAssigned independently in sequence using a table of random numbers. All 106 women enrolled completed the study (calcium 55, placebo 51), 14 women who delivered at 36-38 weeks excluded (calcium 6, placebo 8), none developed gestational hypertension. These women are included in this review.
ParticipantsInclusion criteria: nulliparity; age 25 years or less; certain menstrual dates; clinic attendance before 24 weeks' gestation; residence in Quito; normotensive; no medical disorders; not taking medication or vitamin/mineral preparations.
InterventionsCalcium supplementation with 4 calcium gluconate tablets daily, each containing 500 mg elemental calcium, from after 23 weeks' gestation till delivery, vs identical placebo tablets.
OutcomesGestational hypertension (BP 140/90 mmHg or more, or rise of 30 mmHg systolic or 15 mmHg diastolic, on 2 occasions 6 hours apart); weekly weight gain, mean (SEM) (calcium 412 (26) vs placebo 452 (28) g); birthweight (3097 (40) vs 2832 (50) g); length of gestation (39.3 (0.08) vs 38.7 (0.07) weeks).
NotesQuito, Ecuador (altitude 2800 m). 1984 to 1986. An earlier report of apparently the same study gave an incidence of gestational hypertension of calcium 3/46 vs placebo 13/46 (Lopez-Jaramillo 1987).
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskAssigned using a random number table.
Allocation concealment?Unclear riskNot described.
Blinding?
All outcomes
Low riskDouble-blind. Identical containers and tablets prepared by the Faculty of Chemistry and Pharmacy, Central University of Ecuador.
Free of selective reporting?High risk14 women excluded from the report because they delivered before 38 weeks leaving 43/49 women in the calcium and placebo groups respectively. Data from the 14 excluded women are included in this review.

L-Jaramillo 1990

MethodsRandomised, double-blind trial. Stated "Each patient was assigned independently in sequence", and "All women completed the study".
ParticipantsHealthy nulliparous women with positive roll-over test at 28-30 weeks' gestational age - judged at high risk for gestational hypertension.
Interventions2000 mg elemental calcium daily, from 28-32 weeks to delivery, vs placebo starch tablets.
OutcomesGestational hypertension (BP > 140/90 mmHg on 2 occasions 6 hours apart); proteinuria (300 mg/L); duration of pregnancy (calcium mean 39.2 (SD 1.2) vs placebo 37.4 (2.3) weeks); birthweight (2936 (396) vs 2685 (427) g).
NotesQuito, Ecuador (altitude 2800 m). 22 in calcium group, 34 in placebo group.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskAuthors state that this was a randomised controlled trial but no details of sequence generation are provided.
Allocation concealment?Unclear riskNo details given about how concealment was achieved or whether tablets looked identical.
Blinding?
All outcomes
Unclear riskStated double-blind.
Free of other bias?Unclear riskLarge discrepancy in size of groups not accounted for.

L-Jaramillo 1997

MethodsProspective, randomised, double-blind, placebo controlled trial.
ParticipantsInclusion criteria: age < 17.5 years; nulliparous; first prenatal visit before 20 weeks' gestation; certain menstrual dates; residency in Quito for at least 1 year; BP =/< 120/80 mmHg; no underlying medical disorders; no drug, mineral or vitamin therapy. Average daily calcium intake in this population is 51% of the recommended dietary allowance.
InterventionsElemental calcium 2 g daily as calcium carbonate from 20 weeks (n = 134), versus placebo tablets (n = 140).
Outcomes

Pre-eclampsia (BP > 140/90 mmHg on 2 occasions > 6 hours apart, and proteinuria > 300 mg/L (> 1+ on dipstick on 2 occasions 4-24 hours apart). BP recorded as mean of 2 measurements, 2 minutes apart, in the right arm, in the sitting position (1st and 5th Korotkoff sounds).

Maternal serum ionised calcium at 38 weeks was calcium group mean 1.23, SD 0.02 mM vs placebo 1.16, 0.02; umbilical cord serum ionised calcium levels were calcium 1.44, 0.04 vs placebo 1,37, 0.03; gestational length was calcium 39.6, 0.4 versus placebo 38.7, 0.3.

NotesQuito, Ecuador (altitude 2800 m). 1990 to 1995.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskRandom number table used to assign each patient independently in sequence to calcium or placebo regimen.
Allocation concealment?Low riskAdequate. Tablets similar in weight, colour, size. Containers and tablets prepared by the Department of Chemistry and Pharmacy, Central University of Ecuador.
Blinding?
All outcomes
Low riskDouble-blind.
Incomplete outcome data addressed?
All outcomes
Unclear risk274 recruited, 260 analysed.
Free of selective reporting?Unclear riskOnly participants with no missing values were included in the analyses (125 in calcium group and 135 in placebo group).
Free of other bias?Unclear risk14 withdrawals after randomisation: 12 by change to another hospital or private medical doctor, 2 by non-compliance. 9/134 (6.7%) were from the calcium group and 5/140 (3.6%) from the placebo group.

Niromanesh 2001

MethodsDouble-blind, placebo controlled clinical trial.
ParticipantsWomen at high risk for pre-eclampsia: positive 'roll-over' test and at least 1 risk factor for pre-eclampsia; 28-32 weeks' pregnant; blood pressure < 140/90 mmHg. Exclusion criteria: chronic medical conditions.
Not defined as low- or adequate calcium intake (from table 1 dairy intake appears to be about 200 ml + 400 g per day).
InterventionsElemental calcium 2 g daily (500 mg 6-hourly) or placebo, coded by the pharmacy.
OutcomesPre-eclampsia: an increase (30 mmHg) of SBP above 14 mmHg and an increase (15 mmHg) of DBP above 90 mmHg, twice 4-6 hours apart, with proteinuria 1+; duration of pregnancy (39.5 SD 0.8 vs 37.7 SD 2.5 weeks); birthweight (3316 SD 308 vs 2764 SD 761 g); weekly maternal weight increase (no difference).
NotesNo loss to follow up.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear riskWomen were "randomly assigned".
Allocation concealment?Low riskAdequate. Manufacturer coded the tablets which had same packaging and physical characteristics. Pharmacy dispensed the tablets.
Blinding?
All outcomes
Low riskDouble-blind.
Incomplete outcome data addressed?
All outcomes
Low riskNo incomplete outcome data (sample size = 30).
Free of selective reporting?Low risk 
Free of other bias?Unclear riskNo incomplete data or loss to follow up.

Purwar 1996

MethodsProspective, randomised, double-blind, placebo-controlled trial. Allocated by means of a computer-generated randomisation list. After randomisation, 11/201 (5.5%) women lost to follow up (calcium 6, placebo 5).
Participants

Calcium intake mean 336 mg (calcium) and 352 mg (placebo group) per day.
Inclusion criteria: nulliparity; normal single viable pregnancy; known dates; antenatal clinic before 20 weeks; intending to deliver in the same institute; normal glucose tolerance test; no hypertension; no underlying medical disorders.

Exclusion criteria: renal disease; collagen vascular disease; chronic hypertension; endocrinological disease; taking medication.

InterventionsOral calcium containing 2 g elemental calcium daily (n = 103), compared with identical placebo tablets (n = 98), taken from 20 weeks.
OutcomesGestational hypertension (SBP > 140 mmHg and DBP > 90 mmHg, twice 6 hours apart) and pre-eclampsia (hypertension + proteinuria =/> 0.3 g/24 hours).
NotesNagpur, India.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskComputer-generated random number table.
Allocation concealment?Low riskAdequate.
Blinding?
All outcomes
Low riskDouble-blind. Containers and tablets prepared by a pharmaceutical firm in Nagpur. Tablets same size, weight and colour.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Low risk 
Free of other bias?Unclear riskApart from 11 women lost to follow up, there are no missing data. Otherwise baseline characteristics and compliance similar; balanced loss to follow up.

S-Ramos 1994

MethodsDouble-blind placebo-controlled trial. 4/33 allocated calcium lost to follow up.
ParticipantsNormotensive nulliparas; positive roll-over test (281/1065) and positive angiotensin II infusion test at 20-24 weeks' gestation (67/281). 67 allocated to calcium (33) or placebo (34).
Exclusion criteria: factors increasing the risk of gestational hypertension, including renal disease, collagen vascular disease, diabetes mellitus, chronic hypertension, multifetal pregnancy.
InterventionsCalcium supplementation with 2 g per day elemental calcium as 500 mg calcium carbonate tablets, versus identical placebo tablets. Compliance checked with electronic pillboxes. Compliance was 79% vs 81%.
Outcomes

Gestational hypertension (BP at least 140/90 mmHg on 2 occasions 4-6 hours apart, on bedrest in hospital); pre-eclampsia (gestational hypertension + proteinuria: 1+ or 300 mg/24 hours); severe pre-eclampsia (pre-eclampsia plus one of BP at least 160 mmHg systolic or 110 mmHg diastolic; proteinuria at least 5 g/24 hours; oliguria < 400 ml per day; elevated liver enzymes; thrombocytopenia < 100,000/microlitre; pulmonary oedema; severe epigastric pain).

Birthweight (calcium 3245 (SD 414) vs placebo 3035 (542) g); mean gestational ages (35.6 vs 34.4 weeks); 5 minute Apgar < 7 (1/29 vs 1/34); cord arterial pH (7.25 (0.07) vs 7.20 (0.07)); fetal growth impairment (2/29 vs 4/34).

NotesJacksonville, Florida, USA. University hospital serving low-income population.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskRandomisation by computer-generated list.
Allocation concealment?Low riskAdequate
Blinding?
All outcomes
Low riskDouble-blind. Tablets prepared by pharmaceutical company and were identical with respect to weight, size, flavour and appearance.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Low risk 
Free of other bias?Low riskData entered before breaking the code. Intention-to-treat analysis. 4/33 in the calcium group lost to follow up so 29 in calcium and 34 in placebo, however even if the four lost to follow up had PIH, results would still have significantly favoured the calcium group.

Villar 1987

MethodsDouble-blind, randomised controlled trial.
Participants

Inclusion criteria: nulliparous or primiparous; known menstrual dates; age 18-30 years; singleton pregnancy; negative roll-over test.

Exclusion criteria: underlying medical disorders.

Mean calcium intake at 26 weeks was; calcium group: 1129 (SD 736) and placebo group 914 (478).

InterventionsCalcium carbonate 1.5 g (500 mg tablets) from 26 weeks' gestation vs placebo tablets. Women at John Hopkins Hospital also received vitamin preparations containing 200 mg calcium and 100 mg magnesium per day.
OutcomesWeight gain in last trimester of pregnancy; BP increase; gestational hypertension.
NotesRecruitment 1983-1985. 34 black women from John Hopkins Hospital, Baltimore, USA, 18 white women from Rosario, Argentina.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Unclear risk'Randomly assigned' - no other details.
Allocation concealment?Low riskRandom numbers in closed envelopes.
Blinding?
All outcomes
Low riskTablets same weight, size and colour, prepared by The John Hopkins pharmacy and distributed to the 2 hospitals.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Low risk 
Free of other bias?Unclear riskWomen at John Hopkins Hospital only also received vitamin preparations containing 200 mg calcium/day.

Villar 1990

MethodsDouble-blind, randomised trial.
ParticipantsPregnant women 17 years or younger; no underlying medical disorders; most were nulliparous with known last menstrual period and singleton pregnancy.
Interventions2 g elemental calcium as 500 mg calcium carbonate tablets, vs placebo tablets. All women were prescribed prenatal vitamin tablets containing 200 mg calcium and 100 mg magnesium per day.
OutcomesPreterm labour; preterm delivery < 37 weeks (calcium 7.4 vs placebo 21.1%); delivery 30-37 weeks; idiopathic prematurity; spontaneous prematurity; low birthweight (< 2500 g) (calcium 9.6% vs placebo 21.1%); postdates > 42 weeks (calcium 7.4 vs placebo 5.3%); impaired fetal growth (3.2 vs 3.2%); premature rupture of membranes (2.1 vs 1.0%); Apgar score < 8 at 5 minutes (4.4 vs 10.5%).
NotesJohn Hopkins Hospital, Baltimore, 1985-1988.
Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskComputer-generated list of random numbers.
Allocation concealment?Low riskOpaque envelopes with bottle numbers; project co-ordinator responsible for assigning treatment. Identical tablets and containers prepared at The John Hopkins Hospital pharmacy.
Blinding?
All outcomes
Low riskDouble-blind.
Incomplete outcome data addressed?
All outcomes
Low risk 
Free of selective reporting?Low risk 
Free of other bias?Unclear riskBaseline characteristics similar except for maternal weight (higher in placebo group - P < 0.01).

WHO 2006

  1. a

    BP: blood pressure
    CI: confidence interval
    DBP: diastolic blood pressure
    ICU: intensive care unit
    PI: pulsatility index
    PIH: pregnancy-induced hypertension
    RI: resistance index
    RR: risk ratio
    SBP: systolic blood pressure
    SD: standard deviation
    SEM: standard error of the mean
    vs: versus

MethodsDouble-blind, randomised trial. Randomisation stratified by centre, with computer-generated blocks of 6-8. Allocation by consecutively numbered treatment packs containing calcium tablets or identical placebo. Treatment packs were prepared centrally.
ParticipantsPopulations with median daily calcium intake < 600 mg; Primiparous women less than 20 weeks' pregnant. Exclusion criteria: renal disease or urolithiasis; parathyroid disease; blood pressure > 140 mmHg systolic or > 90 mmHg diastolic; history of hypertension; antihypertensive therapy; diuretic, digoxin, phenytoin or tetracycline treatment.
InterventionsChewable calcium carbonate tablets with 500 mg elemental calcium, 3 daily, or identical placebo, from enrolment till delivery.
OutcomesPrimary outcomes: pre-eclampsia (BP diastolic 90 mmHg or more, or systolic 140 mmHg or more, plus proteinuria 2+ on dipsticks or 300 mg per day; preterm birth (< 37 weeks). Secondary outcomes: severe pre-eclampsia (diastolic 110 mmHg or more or systolic 160 mmHg or more); early onset pre-eclampsia (< 32 weeks), pregnancy induced hypertension; eclampsia; placental abruption; birthweight < 2500 g; spontaneous preterm delivery; medically indicated preterm delivery; admission to neonatal ICU for > 2 days; fetal, neonatal and perinatal mortality (before discharge from hospital).
Notes

Multicentre trial in Argentina, Egypt, India, Peru, South Africa and Vietnam. Enrolment from 2001-2003.
14,362 women screened, 8325 randomised. Exclusions: 6 calcium (4 not pregnant, 2 lost before treatment started) and 7 placebo (5 not pregnant, 2 lost before treatment started). Loss to follow up: 143 and 155 in calcium and placebo group respectively (some data available on women not followed up to delivery). Treatment compliance 84.5% and 86.2% respectively. Baseline characteristics well matched.

An ancillary study in Argentina assessed 510 of the participants by Doppler Ultrasound for RI, PI in uterine and umbilical arteries, and for bilateral uterine artery notching (Carroli 2010). Similarly, a group of 708 participants in South Africa were assessed for serum and urine parameters of endothelial damage (Hofmeyr 2008).

Risk of bias
BiasAuthors' judgementSupport for judgement
Adequate sequence generation?Low riskComputer-generated randomisation lists for each site with random blocks of 6 to 8 women.
Allocation concealment?Low riskConsecutively numbered identical treatment boxes were allocated for each woman enrolled. Randomisation codes remained at the WHO Clinical Trial Unit until analysis.
Boxes and tablet bottles were prepared and numbered by Magistra SA, Geneva and shipped to trial centres. Placebo and calcium tablets identical.
Blinding?
All outcomes
Low riskDouble-blind.
Incomplete outcome data addressed?
All outcomes
Low risk143/4151 and 155/4161 women in calcium and placebo groups respectively were missing delivery data but were included in other analyses.
Free of selective reporting?Low risk 
Free of other bias?Low riskIntention-to-treat principle. Baseline characteristics, compliance and drop-out rates similar.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    ASA: acetylsalicylic acid
    BP: blood pressure
    DBP: diastolic blood pressure
    IU: international unit
    RCT: randomised controlled trial
    vs: versus

Almirante 1998The method of allocation is not clear from the abstract.
August 2002Excluded pending full report of results. Inadequate data in abstracts for inclusion.
Belizan 1983

N = 36. No clinically important outcomes presented in format suitable for inclusion in this review.

Participants: healthy, 20-35 years, singleton pregnancy.
Intervention: calcium 1 g (n = 11), calcium 2 g (n = 11) or placebo (n = 14).
Outcomes: DBP 20-24 weeks, and in the third trimester.
Study design: randomised, no further information.

Boggess 1997

N = 23. After randomisation, 5/23 (22%) were excluded.

Participants: 18-35 years. Excluded if BP > 140/90 mmHg at 24 weeks; smokers; illicit drug use; multiple pregnancy; cardiovascular renal or endocrine disease; hypertension in previous pregnancy; calcium supplementation > 200-250 mg elemental calcium.
Intervention: oral calcium carbonate 1.5 g/day for 6 weeks from 28-31 weeks, or placebo tablets. All had 200-250 mg calcium in standard prenatal vitamin-mineral preparations.
Outcomes: gestational hypertension (BP at least 140.90 mmHg on 2 occasions, 6 hours apart); pre-eclampsia (gestational hypertension plus at least 1+ proteinuria).
Study design: randomised trial. Randomisation schedule in balanced blocks of 10.

Chames 2002Excluded pending publication of full report. No relevant clinical outcomes reported in the abstract. No difference found in blood lead levels between women receiving calcium 1000 mg daily from 13-19 weeks (n = 24) or placebo (n = 26).
Cong 1995

Beijing Obstetrics and Gynecology Hospital. 3 studies reported, but due to serious uncertainty about the method of randomisation in these studies, all have been excluded from this review.

Study 1: calcium 120 mg vs 480 mg vs no calcium.
Study 2: calcium 1 g vs 2 g vs no calcium.
Study 3: calcium 2 g vs no calcium.

de Souza 2006Participants randomised to calcium AND aspirin (ASA).
Dizavandy 1998Excluded due to the unexplained large and imbalanced loss to follow up (6/58 in calcium group and 24/85 in placebo group). Hypocalciuric women in Iran randomised to receive calcium (2 g) or identical placebo but method of randomisation is unclear. Attempts to contact authors for more details failed.
Felix 1991Excluded as allocation was by alternation, not random. 14 women received calcium supplementation and 11 received placebo. No women developed hypertension or pre-eclampsia. The production of 6-keto-prostaglandin F1alpha by umbilical arteries was similar between groups.
Herrera 1998Excluded because the intervention was a combination of calcium AND linoleic acid.
Karandish 2003No details of randomisation available (attempts were made to contact the author) and outcome assessed (birthweight) is not a review outcome. Study compared 1 g calcium to placebo in 68 women from 28-30 weeks' gestation.
Kawasaki 1985

N = 94. Not a randomised trial.

Interventions: calcium L-aspartate 600 mg/day from 20 weeks to delivery (n = 22) vs no supplementation (n = 72).
Outcomes: pregnancy-induced hypertension.

Knight 1992Excluded because no clinically relevant outcomes reported, placebo not used, and participants not followed till delivery. Normotensive (n = 30 and hypertensive (BP 140/85 mmHg or more, n = 20) nulliparous women "randomly allocated" to receive calcium 1 gram from about 12 weeks to 32 weeks, or a control group. Follow up continued to 36 weeks. Mean diastolic blood pressure reduced in the hypertensive group receiving calcium.
Lavin 1986Planned trial of calcium versus placebo in women with a positive roll-over test at 28-32 weeks. Trial apparently cancelled.
MacDonald 1986An RCT of calcium AND vitamin D versus placebo in 55 Asian women with no method or results provided in this personal communication from 1986. Attempts to contact the author for more details were unsuccessful.
Marya 1987

N = 400. The method for allocating women to the 2 groups was not clear from the report. Additional information obtained from the first author indicated that alternate allocation was used.

Interventions: calcium 375 mg per day plus vitamin D 1200 IU per day from 20-24 weeks onward, and no supplementation.
Outcomes: 'toxaemia'.

Montanaro 1990

N = 170. No placebo.

Participants: normotensive at 24 weeks' pregnancy.
Interventions: calcium 2 g/day from 24 weeks to delivery.
Outcomes: pregnancy-induced hypertension, pre-eclampsia.
Study design: "randomised, single-blinded trial".

Prada 2001Excluded pending publication of full report. Abstract does not include outcomes specified for this review. Mean BP was reduced in adolescents receiving calcium supplementation 1000 mg daily (n = 62) compared with placebo (n = 62). Not clear whether participants in this report include participants from Prada 2002.
Prada 2002Excluded pending publication of full report. Abstract does not include outcomes specified for this review. Mean blood pressure was similar in adolescents and women with twin pregnancy receiving calcium supplementation 1000 mg daily (n = 94) compared with placebo (n = 93). Not clear whether participants in this report include participants from Prada 2001.
Raman 1978N = 273. Allocation was by strict rotation, a quasi-randomised trial. Supplementation with < 1 g/day.
Repke 1989

N = 255. Presented as abstract only. No clinical data available.

Interventions: calcium 2 g/day vs placebo, after 20 weeks of pregnancy.
Study design: 'randomised clinical trial'.

Rogers 1999

Excluded because: (1) randomisation performed "using five unsealed envelopes"; unequal group numbers suggested that 'something went wrong with the randomisation process'; (2) no placebo used; (3) initial calcium dose 600 mg per day (1200 mg per day after 32 weeks); (4) 10% loss to follow up.

Hypertension alone occurred in 21/144 women who received calcium compared with 18/75 controls; pre-eclampsia in 8/144 vs 7/75 respectively.

S-Ramos 1995

N = 75. Excluded because calcium used for treatment of women with pre-eclampsia rather than prevention.

Participants: nulliparous, gestation 24-36 weeks; mild pre-eclampsia (BP 140/90-160/100, proteinuria at least 300 mg/day).
Interventions: calcium 2 g/day elemental calcium (four tablets of calcium carbonate 1250 mg), versus matching placebo.
Outcomes: initial and last BP and biochemical markers; preterm delivery; caesarean section; severe pre-eclampsia; gestation at delivery; birthweight; Apgar < 7 at 1 minute and 5 minutes; cord arterial pH < 7.16; fetal growth restriction; perinatal death.
Study design: double-blind, placebo-controlled study using a computer-generated random number list.

Suzuki 1996

N = 152. Not a randomised trial.

Interventions: calcium 1 g/day from 20 weeks vs no calcium.
Outcomes: pre-eclampsia, gestational hypertension.

Taherian 2002Inclusion criteria not met: not placebo-controlled, calcium dose < 1 g. 3-way comparison between calcium 500 mg, low-dose aspirin and no treatment. Pre-eclampsia diagnosed in 13/330, 15/330 and 33/330 respectively.
Tamas 1997Study of treatment of gestational hypertension, not prevention, using the drug dobesilate calcium, not calcium supplementation.
Wanchu 2001No placebo used. 120 consecutive nulliparous women less than 20 weeks' pregnant "randomly assigned" to receive 2 g elemental calcium daily, or no treatment. Analysis restricted to 100 women who "completed the protocol". Mild pre-eclampsia occurred in 9/50 vs 6/50 and severe pre-eclampsia in 0/50 vs 2/50 study vs control groups respectively.

Characteristics of ongoing studies [ordered by study ID]

Mahomed 1998

Trial name or titleCalcium supplementation for the prevention of pregnancy-induced hypertension and preterm labour in twin pregnancies: a randomised controlled trial.
Methods 
ParticipantsWomen with twin pregnancy.
InterventionsCalcium solution (1 g elemental calcium per 5 ml).
OutcomesPregnancy-induced hypertension, preterm labour, perinatal mortality and short-term morbidity, maternal morbidity.
Starting dateNot stated.
Contact informationProf K Mahomed.
NotesSample size 400 per group.

Ancillary