Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

  • Review
  • Intervention

Authors

  • GJ Hofmeyr,

  • AN Atallah,

  • L Duley


Prof G Justus Hofmeyr, Director/Hon. Professor, Effective Care Research Unit, 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. gjh@global.co.za.

Abstract

Background

High blood pressure during pregnancy is a common cause of serious morbidity and death. Calcium supplementation may reduce the risk of high blood pressure through a number of mechanisms and may help to prevent preterm labour.

Objectives

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

Search strategy

We searched the Cochrane Pregnancy and Childbirth Group trials register (September 2003) and the Cochrane Central Register of Controlled Trials (Issue 3, 2003). We contacted study authors.

Selection criteria

Randomised trials comparing at least one gram daily of calcium during pregnancy with placebo.

Data collection and analysis

Eligibility and trial quality were assessed. Data extraction was carried out and double entered.

Main results

Eleven studies were included, all of good quality. There was a reduction in the incidence of high blood pressure with calcium supplementation (10 trials, 6634 women: relative risk (RR) random effects model 0.58, 95% confidence intervals (CI) 0.43 to 0.79). The effect was greater amongst women at high risk of developing hypertension (four trials, 327 women: RR 0.47, 95% CI 0.22 to 0.97), and those with low baseline dietary calcium (five trials, 1582 women: RR 0.38, 95% CI 0.22 to 0.64).

There was also a reduction in the risk of pre-eclampsia with calcium supplementation (11 trials, 6894 women: RR 0.35, 95% CI 0.20 to 0.60). The effect was greatest in women at high risk of hypertension (five trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42), and those with low baseline calcium intake (six trials, 1842 women: RR 0.29, 95% CI 0.16 to 0.54).

There was no overall effect on the risk of preterm delivery, although there was a reduction in risk amongst women at high risk of developing hypertension (four trials, 568 women: RR 0.45, 95% CI 0.24 to 0.83).

There was no evidence of any effect of calcium supplementation on stillbirth or death before discharge from hospital. There were fewer babies with birthweight, < 2500 g in women at high risk of hypertension (two trials, 449 women: RR 0.45, 95% CI 0.22 to 0.95).

In one study, childhood systolic blood pressure > 95th percentile was reduced (514 women: RR 0.59, 95% CI 0.39 to 0.91).

Authors' conclusions

Calcium supplementation appears to reduce the risk of high blood pressure in pregnancy, particularly for women at high risk of gestational hypertension and in communities with low-dietary calcium intake. Optimum dosage and the effect on more substantive outcomes requires further investigation.

Plain language summary

Plain language summary

Calcium supplements may prevent high blood pressure and help prevent preterm labour

High blood pressure 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 trials found that calcium supplementation during pregnancy is a safe and relatively cheap means of reducing the risk of high blood pressure in women at increased risk, and women from communities with low dietary calcium. No adverse effects have been found but further research is needed into the ideal dosage for supplementation and to confirm the above results, which are influenced by several rather small trials.

Background

High blood pressure with or without proteinuria are major causes of maternal death and morbidity worldwide (NHMRC 1993; HMSO 1994), and perinatal morbidity and mortality. For this reason, strategies to reduce the risk of hypertensive disorders of pregnancy have received considerable attention (Carroli 1994; Bucher 1996; CLASP 1994; ECCPA 1996).

Preterm birth, a common association with hypertensive disorders, 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. 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.

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 (Hamlin 1952; Belizan 1988; Villar 1993; Villar 1987), 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.

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).

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 attractive (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 (Duley 1995; Carroli 1994). A more recent systematic review (Bucher 1996) came to more enthusiastic conclusions, but this optimism was not confirmed by a large trial in the USA (CPEP 1997).

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/neonatal adverse outcomes. Subgroup analyses will test whether these effects are influenced by whether:
(1) Women are at low/average risk of hypertensive disorders, or at high risk.
(2) Women have low or adequate dietary calcium intake prior to trial entry.

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 (see 'Methods of the review'). Quasi-random designs will be excluded.

Types of participants

Pregnant women, regardless of the risk of hypertensive disorders of pregnancy. Women with diagnosed hypertensive disorders of pregnancy will be excluded.

Prespecified subgroups to be compared are:
(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 will include women selected by the trial authors on the basis of an increased risk of hypertensive disorders of pregnancy (eg teenagers, women with previous pre-eclampsia, women with increased sensitivity to angiotensin II, women with pre-existing hypertension).
(3) Women or populations with low baseline dietary calcium intake (as defined by trial authors, or if not defined, mean intake less than 900 mg 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 900 mg per day).

Types of intervention

Supplementation with calcium from at the latest 34 weeks of pregnancy; compared with placebo treatment. Studies with no placebo will be excluded.

The initial analysis will be limited to intended supplementation with at least 1 g of calcium per day. If there is evidence that this dose is beneficial, future updates of this review will include an analysis of effect by dosage, including lower dosage regimens.

Types of outcome measures

Prespecified clinical measures of maternal and fetal/neonatal morbidity and mortality will be sought as follows:

For the women
(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.
(3) Maternal death or serious morbidity (eg eclampsia; renal failure; syndrome of haemolysis, elevated liver enzymes and low platelets; admission to intensive care).
(4) Placental abruption.
(5) Cesarean section.
(6) Mother's hospital stay seven days or more.

For the child
(7) Preterm delivery (delivery before 37 weeks of estimated gestation).
(8) Low birth weight (the first weight obtained after birth less than 2500 g).
(9) Neonate small for gestational age as defined by trial authors.
(10) Admission to neonatal intensive care unit (ICU).
(11) Neonate in intensive care unit seven days or more.
(12) Stillbirth or death before discharge from hospital.

Long-term outcomes
(13) Childhood disability.
(14) Systolic blood pressure greater than 95th percentile during childhood.
(15) Diastolic blood pressure greater than 95th percentile during childhood.

Only those outcomes with data will appear in the analysis table.
The primary outcomes are outcomes 1, 2, 7, 10 and 12. Subgroup analyses will be limited to the primary outcomes.

Search methods for identification of studies

See: Unavailable methods used in reviews.

We searched the Cochrane Pregnancy and Childbirth Group trials register (September 2003).

The Cochrane Pregnancy and Childbirth Group's trials register is maintained by the Trials Search Co-ordinator and contains trials identified from:
1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major conferences;
4. weekly current awareness search of a further 37 journals.

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 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co-ordinator searches the register for each review using these codes rather than keywords.

The Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2003) was also searched using the terms calcium AND pregnan* AND (hypertens* or blood press*).

Additional information obtained from the trialists and included in the previous version of this review (Duley 1995) for five studies (Belizan 1991; L-Jaramillo 1989; Villar 1987; Villar 1990; Marya 1987) was also included in this review.

Methods of the review

The methodological quality and other inclusion criteria of most identified trials were assessed independently by two reviewers who were not associated with any of the trials. Disagreements were resolved by consensus. The primary assessment for inclusion was based on concealment of allocation and whether the trial was placebo controlled.

Most data were independently extracted by two reviewers and cross-checked. 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. Double entry of data was used.

Categorical data were compared using relative risks and their 95% confidence intervals. Statistical heterogeneity between trials was tested for 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 effects 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, pooled estimates of effect size were calculated from a weighted average, with weight based on the inverse of the variance (Early Breast Ca 1990). Comparisons, outcomes and subgroups other than those prespecified in the protocol are identified as 'post hoc' analyses.

Description of studies

See table of 'Characteristics of included studies'. All included studies met the prestated criteria for inclusion in this review.

Methodological quality

See table of 'Characteristics of included studies'. All were well designed, double-blind, placebo-controlled trials. Prespecified 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 Lopez-Jaramillo (L-Jaramillo 1990), a large discrepancy in numbers allocated to each group is not accounted for.

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.

Results

Significant heterogeneity of results occurred for four outcomes: high blood pressure; pre-eclampsia; preterm delivery and birthweight less than 2500 g. Factors accounting for the heterogeneity appeared to be the predefined subgroups (by risk and baseline dietary calcium), and size of trial, with smaller effects in the larger trials. A random effects model has been used for these outcomes.

(1) High blood pressure with or without proteinuria
Overall there is less high blood pressure with calcium supplementation (10 trials, 6634 women: relative risk (RR) random effects model 0.58, 95% confidence intervals (CI) 0.43 to 0.79), but there is variation in the magnitude of this effect across the sub-groups. A funnel plot of relative risk against sample size shows asymmetry, with smaller effects in the larger trials (more than 1000 subjects). The magnitude of the effect was considerably greater amongst women at high risk of developing hypertension (four trials, 327 women: RR 0.47, 95% CI 0.22 to 0.97), and those with low baseline dietary calcium (five trials, 1582 women: RR 0.38, 95% CI 0.22 to 0.64).

(2) Pre-eclampsia
The results follow a similar pattern to those for gestational hypertension. The overall effect was a reduction in the risk of pre-eclampsia (11 trials, 6894 women: RR 0.35, 95% CI 0.20 to 0.60). The effect was smallest in the largest trial which studied low risk women with adequate baseline calcium diet, and in whom the both groups received routine calcium supplementation (CPEP 1997). The results are strongly influenced by the latter trial. The reduction is significant for women at low risk (six trials, 6307 women: RR 0.49, 95% CI 0.28 to 0.87), but not those with adequate calcium intake (four trials, 5022 women: RR 0.62, 95% CI 0.32 to 1.20). Pre-eclampsia was considerably reduced in women at high risk of hypertension (five trials, 587 women: RR 0.22, 95% CI 0.12 to 0.42), and those with low baseline calcium intake (six trials, 1842 women: RR 0.29, 95% CI 0.16 to 0.54).

(3) Maternal death or serious morbidity
There were too few events for any meaningful conclusions.

(4) Placental abruption
There were too few events for any meaningful conclusions.

(5) Caesarean section
There was no statistically significant effect on the risk of caesarean section.

(6) Mother's hospital stay seven days or more
Data were not available for this outcome.

(7) Preterm delivery
There was no overall effect, but preterm delivery did appear to be reduced among women at high risk of developing hypertension (four trials, 568 women: RR 0.45, 95% CI 0.24 to 0.83).

(8) Birthweight less than 2500 g
There were fewer babies with birthweight, less than 2500 g in women at high risk of hypertension (two trials, 449 women: RR 0.45, 95% CI 0.22 to 0.95), but this was a post hoc subgroup analysis.

(9) Neonate small for gestational age
Data were not available for this outcome.

(10) Admission to neonatal intensive care unit
This outcome was reported in only three trials, and no effect was shown.

(11) Neonate in intensive care unit seven days or more
Data were not available for this outcome.

(12) Stillbirth or death before discharge from hospital
No effect on this outcome was shown.

(13) Childhood disability
Data were not available for this outcome.

(14) Childhood systolic blood pressure greater than 95th percentile at about seven years of age was reduced (one trial, 514 women: RR 0.59, 95% CI 0.39 to 0.91)
Data available from only one study. 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.

(15) Childhood diastolic blood pressure greater than 95th percentile
Data only available from the study discussed above. The difference was not statistically different.

Discussion

Calcium supplementation was associated with: reduced hypertension in all subgroups (though the effect was modest for those at low risk); reduced pre-eclampsia, particularly for those at high risk and with low baseline dietary calcium intake (for those with adequate calcium intake the difference was not statistically significant); reduced preterm delivery and low birthweight for women at high risk of hypertension; and reduced childhood systolic hypertension in the one study to measure this outcome (low risk of hypertension and uncertain calcium intake). No side-effects of calcium supplementation have been recorded in the trials reviewed. There is little information about the long-term follow up of children within these trials (with the exception of blood pressure assessment in one trial), and there is no information about any possible changes in the use of healthcare resources associated with calcium supplementation. Reduction in the risk of hypertension and pre-eclampsia may be regarded as a meaningful outcome in itself. Women may be distressed by these diagnoses, and are commonly subjected to more interventions and hospitalisation (though the latter was not measured in the studies reviewed). There were, however, no documented differences in more substantive outcomes.

The heterogeneity of results is difficult to ascribe to a particular feature of the trials, as there is overlap between the classification of trials according to sample size, risk of hypertension and baseline dietary calcium intake. Most of the included trials employed sound methodology, being double-blind and placebo controlled. The potential for being misled by bias was thus small.

Authors' conclusions

Implications for practice

The lack of convincing evidence of effectiveness from the largest trial to date (CPEP 1997) may discourage the use of calcium supplementation. It should be borne in mind that the latter trial included women with a low risk of hypertension, adequate dietary calcium intake and, in addition, all women in both groups received low-dose calcium supplementation as part of their routine prenatal supplementation. Data from this trial are not necessarily applicable to the care of women who may be more likely to benefit from calcium supplementation.

The data included in this review support calcium supplementation for women at high risk of gestational hypertension, and in communities with low dietary calcium intake, provided that reduction in the diagnosis of hypertension or pre-eclampsia is regarded as important. Whether lower dosages of calcium than used in the trials reviewed may have similar effects, cannot be determined from this review.

Implications for research

Future research should focus on the ideal dosage for calcium supplementation during pregnancy. Further randomised trials should concentrate on women at high risk of gestational hypertension, and communities with low dietary calcium intake, and the effect on substantive outcomes should be determined. They should also include long-term follow up of the children and measures of the use of health service resources. The WHO multicentre randomised trial of calcium supplementation to prevent pre-eclampsia will address some of these issues (WHO).

Potential conflict of interest

Justus Hofmeyr is a collaborator in the WHO Calcium Trial (WHO) which will be considered for inclusion in this review. He will not participate in decisions regarding that trial.

Acknowledgements

We thank the trial authors who have contributed additional data for this review, and Jose Villar for constructive criticism of the protocol.

Characteristics of included studies

StudyBelizan 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.
NotesThree 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.

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).
Allocation concealmentA
StudyCPEP 1997
MethodsNumbered treatment packs in computer-generated simple randomisation sequence. Loss to follow up: calcium 132/2,295 vs placebo 121/2,294.
ParticipantsPregnant 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, 5,703 excluded initially and a further 1,667 after the compliance test. The remaining 4,589 women were enrolled.
Interventions2 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.
NotesMulticentre trial, 5 US university centres. Maternal outcomes reported as percentages of the whole number enrolled. In this review, denominators of 2,163 (calcium) and 2,173 (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.
Allocation concealmentA
StudyCrowther 1999
MethodsCentral telephone randomisation, stratified by
centre using variable blocks. Double blind.
ParticipantsInclusion criteria: Nulliparous women; Singleton pregnancy; < 24 weeks' gestation; Blood pressure < 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 till birth.
OutcomesPrimary: pregnancy-induced hypertension (diastolic blood pressure 90 mmHg or more on two 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 (diastolic blood pressure 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.
NotesFive 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.
Allocation concealmentA
StudyL-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).
Allocation concealmentD
StudyL-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.
Interventions2,000 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/litre); 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). Large discrepancy in size of groups not accounted for.
Allocation concealmentB
StudyL-Jaramillo 1997
MethodsProspective, randomised, double-blind, placebo controlled trial. 14 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.
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).
OutcomesPre-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.
Allocation concealmentA
StudyNiromanesh 2001
MethodsDouble-blind, placebo controlled clinical trial. Women were "andomly assigned".
ParticipantsWomen at high risk for pre-eclampsia: positive 'roll-over' test and at least on 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.
InterventionsElemental calcium 2 g daily (500 mg 6-hourly) or placebo, coded by the pharmacy.
OutcomesPre-eclampsia: an increase (30 mmHg) of systolic blood pressure above 14 mmHg and an increase (15 mmHg) of diastolic blood pressure 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 grams); weekly maternal weight increase (no difference).
NotesNo loss to follow up.
Allocation concealmentA
StudyPurwar 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).
ParticipantsCalcium 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.
Allocation concealmentA
StudyS-Ramos 1994
MethodsDouble-blind placebo-controlled trial. Randomisation by computer-generated list. Outcome data entered before breaking the code. 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).
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%.
OutcomesGestational 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.
Allocation concealmentA
StudyVillar 1987
MethodsDouble-blind, randomised controlled trial. Random numbers in closed envelopes.
ParticipantsInclusion 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.
Allocation concealmentA
  1. a

    BP: blood pressure
    CI: confidence interval
    DBP: diastolic blood pressure
    RR: relative risk
    SBP: systolic blood pressure
    SEM: standard error of the mean
    vs: versus

StudyVillar 1990
MethodsDouble-blind, randomised trial. Allocation by opaque envelopes, ordered by a computer-generated list of random numbers.
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); delivery 30 - 37 weeks; idiopathic prematurity; spontaneous prematurity; low birthweight (< 2500 g); 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.
Allocation concealmentD

Characteristics of excluded studies

StudyReason for exclusion
  1. a

    BP: blood pressure
    DBP: diastolic blood pressure
    IU: international unit
    vs: versus

Almirante 1998The method of allocation is not clear from the abstract.
Belizan 1983N = 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 1997N = 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.
Cong 1995Beijing Obstetrics and Gynecology Hospital. Three 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.
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.
Kawasaki 1985N = 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 subjects 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.
Marya 1987N = 400. The method for allocating women to the two 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 1990N = 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".
Raman 1978N = 273. Allocation was by strict rotation, a quasi-randomised trial. Supplementation with < 1 g/day.
Repke 1989N = 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 1999Excluded 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 1995N = 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 1996N = 152. Not a randomised trial.

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

StudyMahomed 1998
Trial name or titleCalcium supplementation for the prevention of pregnancy induced hypertension and preterm labour in twin pregnancies: a randomised controlled trial.
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.
StudyWHO
Trial name or titleWHO multicentre randomised trial of calcium supplementation for the prevention of pre-eclampsia.
ParticipantsNulliparous, normotensive women who are less than 20 weeks pregnant at enrolment.
InterventionsCalcium 1.5 g daily, versus placebo.
OutcomesPrimary outcomes: pre-eclampsia; hypertension.
Starting dateRecruitment started in November 2001.
Contact informationJose Villar and Mario Merialdi, Reproductive Health and Research, WHO, Geneva.
NotesSample size 8500 women

Analyses

Comparison 01. Routine calcium supplementation in pregnancy by hypertension risk
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 High blood pressure (with or without proteinuria)106634Relative Risk (Random) 95% CI0.58 [0.43, 0.79]
02 Pre-eclampsia116894Relative Risk (Random) 95% CI0.35 [0.20, 0.60]
03 Maternal death/serious morbidity31420Relative Risk (Fixed) 95% CI0.39 [0.02, 9.20]
04 Placental abruption31408Relative Risk (Fixed) 95% CI1.52 [0.43, 5.37]
05 Caesarean section66332Relative Risk (Fixed) 95% CI0.94 [0.84, 1.05]
07 Preterm delivery96671Relative Risk (Random) 95% CI0.66 [0.43, 1.01]
08 Birthweight < 2500g76491Relative Risk (Random) 95% CI0.69 [0.47, 1.01]
09 Neonate small for gestational age as defined by trial authors1190Relative Risk (Fixed) 95% CI0.72 [0.26, 1.99]
10 Admission to neonatal intensive care unit35497Relative Risk (Fixed) 95% CI1.09 [0.96, 1.24]
12 Stillbirth or death before discharge from hospital96763Relative Risk (Fixed) 95% CI1.04 [0.65, 1.66]
15 Childhood systolic blood pressure > 95th percentile1514Relative Risk (Fixed) 95% CI0.59 [0.39, 0.91]
16 Childhood diastolic blood pressure > 95th percentile1514Relative Risk (Fixed) 95% CI0.81 [0.50, 1.31]
Analysis 01.01.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 01 High blood pressure (with or without proteinuria)

Analysis 01.02.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 02 Pre-eclampsia

Analysis 01.03.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 03 Maternal death/serious morbidity

Analysis 01.04.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 04 Placental abruption

Analysis 01.05.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 05 Caesarean section

Analysis 01.07.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 07 Preterm delivery

Analysis 01.08.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 08 Birthweight < 2500g

Analysis 01.09.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 09 Neonate small for gestational age as defined by trial authors

Analysis 01.10.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 10 Admission to neonatal intensive care unit

Analysis 01.12.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 12 Stillbirth or death before discharge from hospital

Analysis 01.15.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 15 Childhood systolic blood pressure > 95th percentile

Analysis 01.16.

Comparison 01 Routine calcium supplementation in pregnancy by hypertension risk, Outcome 16 Childhood diastolic blood pressure > 95th percentile

Comparison 02. Routine calcium supplementation in pregnancy by baseline dietary calcium
Outcome titleNo. of studiesNo. of participantsStatistical methodEffect size
01 High blood pressure (with or without proteinuria)96604Relative Risk (Random) 95% CI0.53 [0.37, 0.75]
02 Pre-eclampsia106864Relative Risk (Random) 95% CI0.37 [0.21, 0.64]
03 Maternal death/serious morbidity31420Relative Risk (Fixed) 95% CI0.39 [0.02, 9.20]
04 Placental abruption31408Relative Risk (Fixed) 95% CI1.52 [0.43, 5.37]
05 Caesarean section66332Relative Risk (Fixed) 95% CI0.94 [0.84, 1.05]
07 Preterm delivery96670Relative Risk (Random) 95% CI0.66 [0.43, 1.01]
08 Birthweight < 2500g76491Relative Risk (Random) 95% CI0.69 [0.47, 1.01]
09 Neonate small for gestational age as defined by trial authors1190Relative Risk (Fixed) 95% CI0.72 [0.26, 1.99]
10 Admission to neonatal intensive care unit35497Relative Risk (Fixed) 95% CI1.09 [0.96, 1.24]
12 Stillbirth or death before discharge from hospital96763Relative Risk (Fixed) 95% CI1.04 [0.65, 1.66]
15 Childhood systolic blood pressure > 95th percentile00Relative Risk (Fixed) 95% CINot estimable
16 Childhood diastolic blood pressure > 95th percentile00Relative Risk (Fixed) 95% CINot estimable
Analysis 02.01.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 01 High blood pressure (with or without proteinuria)

Analysis 02.02.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 02 Pre-eclampsia

Analysis 02.03.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 03 Maternal death/serious morbidity

Analysis 02.04.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 04 Placental abruption

Analysis 02.05.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 05 Caesarean section

Analysis 02.07.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 07 Preterm delivery

Analysis 02.08.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 08 Birthweight < 2500g

Analysis 02.09.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 09 Neonate small for gestational age as defined by trial authors

Analysis 02.10.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 10 Admission to neonatal intensive care unit

Analysis 02.12.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 12 Stillbirth or death before discharge from hospital

Analysis 02.15.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 15 Childhood systolic blood pressure > 95th percentile

Analysis 02.16.

Comparison 02 Routine calcium supplementation in pregnancy by baseline dietary calcium, Outcome 16 Childhood diastolic blood pressure > 95th percentile

Sources of support

External sources of support

  • UNDP/UNFPA/WHO/World Bank (HRP) SWITZERLAND

Internal sources of support

  • 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

Ancillary