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

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

Editorial Group: Cochrane Pregnancy and Childbirth Group

Published Online: 5 OCT 2011

Assessed as up-to-date: 22 JUN 2011

DOI: 10.1002/14651858.CD007079.pub2


How to Cite

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

Author Information

  1. 1

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

  2. 2

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

  3. 3

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

*Pranom Buppasiri, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen University, Faculty of Medicine, Khon Kaen, Khon Kaen, 40002, Thailand. bprano@kku.ac.th.

Publication History

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

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Characteristics of included studies [ordered by study ID]
Belizan 1983

MethodsType of study: simple randomisation into 3 groups.
Method of treatment allocation: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.


ParticipantsLocation: outpatient clinic of Guatemala Social Security Hospital.
Time frame: not stated.
Eligible criteria: age 20 to 35 years, single fetus, without evidence of previous pathology and certain date, not receiving any medical treatment during recruitment.
Total recruited: 36 pregnant women.

Treatment group 1 , n = 11, treatment group 2, n = 11, placebo group, n = 14.


Interventions
  • Treatment Group 1 : 1 g calcium/d.
  • Treatment Group 2 : 2 g calcium/d.
  • Compared with placebo tablets.


Started treatment at 15 weeks until delivery.


Outcomes
  1. Blood pressure.
  2. Parathyroid hormone.
  3. Calcium and magnesium level.
  4. Phosphorus level.
  5. Pregnancy outcomes; birthweight, birth length, head circumference.


NotesThe authors did not mention how many tablets were provided in calcium 1 g , 2 g and placebo group.

Missing data = 0%.

For data in  Analysis 2.4 and  Analysis 2.9 the placebo n was halved to enable inclusion of data for treatment groups 1 and 2.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "After the patients volunteers to participate the trial. Simple randomisation were used to devise patient into 3 groups, receive 1, 2 gm calcium comparing with placebo."
Comment: method of random sequence generation was not clearly described.

Allocation concealment (selection bias)Unclear riskComment: allocation concealment was not described.

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: placebo tablets in the same weight, size, organoleptic characteristics.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all enrolled participants were analyses.

MIssing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Belizan 1991

MethodsType of study: multicenter, double-blind, randomised controlled trial.
Method of treatment allocation: randomisation was conducted at each hospital by a random-generator program. A complete set of numbered, sealed, opaque envelopes containing the randomisation codes was sent to each of three hospitals.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 2.3%.

27 women were lost to follow-up after randomisation (14 in the calcium group, 13 in the placebo group) but before they started treatment, and therefore were not included in the followed up analyses. then follow-up was incomplete for 52 women in the calcium group and 46 in placebo group because change of hospital, physician or residence.


ParticipantsLocation: the women enrolled from 3 affiliated hospitals of Centro Rosario de Estudios Perinatales, Rosario, Argentina (two were public hospitals, the another was a private hospital).
Time frame: January 1987 to September 1989.
Eligible criteria: GA < 20 weeks and confirmed by ultrasound, nulliparous, singleton pregnancy, blood pressure < 140/90 mmHg. No evidence of clinical and laboratory of present or past disease, no taking any medications and had normal glucose tolerance test.
Exclusion criteria: gestational date estimated from LMP and ultrasonography different more than 10 days.
Total recruited: 1194 pregnant women; treatment group, n = 593, control group, n = 601. A total of 579 women in the calcium group and 588 in the placebo group were included in final analyses.


Interventions2 g calcium/d (4 tablets/day; each calcium tablet contained 500 mg calcium carbonate and granulated starch). Compared with placebo tablet .
Started treatment at 20 weeks.


Outcomes
  1. Blood pressure.
  2. Serum total calcium.
  3. Serum magnesium.
  4. Urinary calcium excretion.
  5. Serum phosphate.
  6. Serum uric acid.
  7. Pregnancy outcomes; birthweight, birth length, preterm birth, premature rupture of membrane, diabetic mellitus, third trimester bleeding, numbers of hospital admission, perinatal death.
  8. Rate of urinary tract infection.
  9. Rate of maternal anaemia.


NotesTreatment group, n = 593, control group, n = 601. For final analysis, treatment group, n = 579, 588 in placebo group but for other pregnancy outcomes other than pregnancy hypertension, n = 544 in calcium group and n = 554 in control group.

Missing data 27 in 1194 = 2.3%.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "They were randomised at each hospital by a random-generator program."

Allocation concealment (selection bias)Low riskQuote: "A complete set of number, sealed, opaque envelopes containing the randomisation codes was sent to each of three hospital."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The calcium tablets were specially prepared by local pharmaceutical company and placebo tablet contained lactose and granules starch and were identical to calcium tablets with respect to weight, size, flavour and colour. The women, the nurses, and the physician responsible for prenatal care were all unaware of the women's treatment status."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Follow-up was incomplete 52 in treatment group and 46 in placebo group because of change of hospital, physician, or residence. Nonetheless, all were included in analyses up to time when they were lost to follow-up. For the subgroup with incomplete follow-up, information about delivery was available for 17 in calcium group and 12 in placebo group."

Missing data 27 in 1194 = 2.3%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Boggess 1997

MethodsType of study: double-blind randomised controlled trial.
Method of treatment allocation: a computer-generated random number table was used. Using a randomisation schedule in block of 10. All containers and tablets were prepared and dispensed by the University Drug Pharmacy.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no (23 women were randomised and 18 of them completed study). Of the 5, 3 developed preterm labor and one was non compliance, and one self discontinued study medication due to side effects.
Losses to follow-up: 5 in 23 = 21.7%.


ParticipantsLocation: University of Washington Medical Center Women's Clinic.
Time frame: not stated.
Eligible criteria: age 18 to 35 years who received antenatal care.
Exclusion criteria: BP > 140/90 mmHg at 24 weeks, smoking or used illicit drugs, multiple gestation, had history of cardiovascular, renal, or endocrine disorder, hypertension prior to pregnancy, or calcium supplementation.
Total recruited: 23 pregnant women; calcium group, n = 12, placebo group, n =11.


Interventions1.5 g/d of calcium carbonate.
Compared with placebo tablets. Started treatment at 28 to 31 weeks.


OutcomesHemodynamic function measurement.


Notes1. GA was reported as median and range. We changed them into mean and SD.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The study patients were assigned in a double-blind fashion to receive orally either 1.5 element calcium as calcium carbonate or placebo daily, using a randomisation schedule in blocks of ten developed by a computer-generated random number table."

Allocation concealment (selection bias)Low riskQuote: "All containers and tablets were prepared and dispensed by the University Drug Pharmacy."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo tablets were same size, weight, colour, and organoleptic characteristics."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Twenty-three women were randomised and 18 of them completed study. Of the five who failed to complete the study; three developed preterm (all placebo), one was noncompliance (placebo), one discontinues due to side effects (calcium)."

Missing data = 5 in 23 = 21.7 %

Selective reporting (reporting bias)Unclear riskNone identified.

Other biasLow riskNone identified.

Chan 2006

MethodsType of study: computer-generated randomisation.
Method of treatment allocation: the pregnant women were randomly assigned to one of three groups: control, orange juice fortified with calcium, and daily. Computer-generated randomisation was kept in envelopes.
Placebo: no.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up at delivery 8.3% : in control group, missing data at delivery = 0, missed 6 months visit, n = 3 and umbilical cord not collected, n = 2. In orange juice plus calcium missing data = 3, failed to meet required 4 servings, n = 12, misses 6 month visit, n = 3,and mothers blood was not collected, n = 3 and umbilical blood was not collected, n = 3. In daily group, missing data at delivery = 3, missed at 6 month visit, n = 2, mother's blood was not collected, n = 3, and umbilical blood was not collected, n = 5.


ParticipantsLocation: University of Utah Teen Mother and Child Program.
Time frame: not stated.
Eligible criteria: healthy adolescent (15 to 17 years old) pregnant women. GA < 20 weeks by last normal menstrual period.
Exclusion criteria: hypertension, diabetes, renal or liver diseases, used alcohol, tobacco or medications that would effect Ca metabolism during pregnancy.
Total recruited: 72 healthy pregnant adolescents.


InterventionsThere were 3 groups. Group 1; control (consume usual diet) N = 23. Group 2; orange juice fortified with calcium consumed at least 4 servings of orange juice plus calcium (more than 1200 mg Ca) n = 24. Group 3; daily (consumed at least 4 serving of daily product (Ca more than 1200 mg) e.g., milk, yogurt, cheese, n = 25. Started treatment at 20 weeks.


Outcomes
  1. Maternal weight gain, blood pressure.
  2. Newborn birthweight, lean and fat mass of infant, total body calcium.


NotesMissing data at delivery 6 in 72 = 8.3%.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Pregnant mothers were randomly assigned to one of three groups; control, orange juice fortified with calcium, and daily. Computer-generated randomisation was kept in sealed envelopes."

Allocation concealment (selection bias)Low riskQuote: "Computer-generated randomisation was kept in sealed envelopes."

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "The control group consumed their usual diet while the orange juice plus calcium group were counselled to consume at least four servings of orange juice plus calcium (more than 1,200 mg Ca) so that their Ca intake would be similar to the daily group.The daily group was counselled to consume at least four servings of daily products (more than 1200 mg Ca) daily. Daily products consisted of milk, yogurt, and cheese."

Comment: it was impossible to blind because of different kind of food.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: the authors displayed the flow chart of participants.

Missing data at delivery 6 in 72 = 8.3%.

Selective reporting (reporting bias)Low riskNone identified. Missing data in control group = 13%, in orange juice plus calcium = 12.5 %, in daily product 8%.

Other biasLow riskNone identified.

Crowther 1999

MethodsType of study: placebo-blind trial.
Method of treatment allocation: the randomisation schedule was prepared by the drug company with stratification made by centre using variable blocks.
Placebo: yes, starch tablets.
Sample size calculation: a study of 948 women was estimated to have an 80% probability of detecting differences in the rate of preterm birth at P = 0.05 and an 88% power to detect a 50% difference with the rate of pregnancy-induced hypertension with the same significance level.
Intention-to-treat analyses: yes.

Pre-calculation samples needed 948 women to be recruited in trial but because of shortage of funds, then only 456 pregnant women were recruited.
Losses to follow-up: 0%.


ParticipantsLocation: 5 Australian Medical Centres.
Time frame: August 1992 to December 1996.

Eligible criteria: nulliparous, singleton pregnancy, at less than 24 weeks, with normal blood pressure at trial entry (< 140/90 mmHg) and expected to birth at five collaborating centre were expected for trial but recruitment to the trial was stopped by the steering group without knowledge of study outcomes after 456 women were randomised when the limited financial resources available for the trial were exhausted.
Exclusion criteria: used of antihypertensive or medical disorder where calcium supplementation was contraindicated such as renal failure, hyperparathyroidism or renal calculi.
Total recruitments: 948 pregnant women were planed to be recruited.
Data were performing when pregnancy outcome data were available for all 456 women recruited. Of 456, 227 were assigned to calcium group, 229 were in placebo group.


InterventionsWomen were asked to take 3 tablets daily orally, equivalent 1.8 g calcium or placebo (calcium carbonate, 600 mg of elemental calcium per tablet). Started treatment at 20 weeks until delivery. Compared with 3 tablets of placebo tablets.


Outcomes1. Incidence of PIH.
2. Pregnancy outcomes; preterm birth, premature rupture of membrane, birthweight.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The randomisation schedule was prepared by the drug company with stratification made by centre using variable blocks."

Allocation concealment (selection bias)Low riskQuote: "A study number was given by the central randomisation office. This corresponded to a sealed treatment pack held at the collaboration centre and were provided by Lederle Laboratories "

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Each treatment package contained identically labelled drug container either 600 mg tablets of calcium or placebo tablets of lactose, identical in size, colour and consistency. Data were entered analysed by non clinical members of the research team, and the treatment allocation code broken after exploratory data analyses."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "948 women were expected for trial but recruitment to the trial was stopped by the steering group without knowledge of study outcomes after 456 women were randomised when the limitation financial resource available for the trial were exhaust. Data were performing when pregnancy outcome data were available for all 456 women recruited. Of 456: 227 were assigned to calcium group, 229 were placebo group."

Comment: the number of participants in treatment and control group were equal.

Missing data = 0%.

Selective reporting (reporting bias)High riskTrial stopped before completely enrolled due to a shortage of research funds.

Other biasLow riskNone identified.

Ettinger 2009

MethodsDouble blind RCT.


Participants670 women were randomised in the first trimester of pregnancy.


Interventions1200 mg calcium daily versus placebo.


OutcomesMaternal blood lead levels.


NotesWe have not included outcome data from this study as it specifically focused on the effects of calcium supplementation on blood lead levels. The study does not address any of the review's primary or secondary outcomes.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot described.

Allocation concealment (selection bias)Unclear riskNot described.

Blinding (performance bias and detection bias)
All outcomes
Low riskPlacebo controlled trial.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk670 randomised. 557 included in the analysis (83%).

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Jarjou 2006

MethodsType of study: a randomised, double-blind, placebo controlled study.
Method of treatment allocation: subjects were randomly assigned in double-blind fashion to receive calcium or placebo by using block of 4 from published sets of table in each month and thereby to minimise the potential for seasonal confounding. The code was held by a member of study team who was not directly involved with the collection of data in the field or laboratory and who had no contact with the study participants.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no, final analyses were 61 from 77 in treatment group, 64 from 78 in control group.
Losses to follow-up: 19.3 % (30 in 155).


ParticipantsLocation: Gambian women, in rural village of Keneba and Manduar, in the province of West King.
Time frame: May 1995 to June 1999.
Eligible criteria: nulliparity with no history of any medical condition known to affect calcium or bone metabolism, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation and intended to undergo delivery at the same institution, normal glucose tolerance test and willing to participate in trial, first antenatal visit BP below 140/90 mmHg and free of any underlying medical disorders, based on a comprehensive medical examination and routine laboratory tests.

Exclusion criteria: had history or evidence of renal disease, collagen vascular disease, chronic hypertension and endocrinological disease or if they take any medication.
Total recruited: 155 pregnant women. Treatment group, n = 77 and control group, n = 78 women. In the final analysis only 125 mother-infant pairs were analysed (61 in the treatment group, 64 in the control group).


Interventions1500 mg of calcium (3 chewable tablets of calcium carbonate per day, 500 mg of elemental calcium). 3 tablets of placebo (contained microcrystalline cellulose and lactose) per day, same shape, taste and texture. The study started from 20 weeks until delivery.


Outcomes
  1. Anthropometric measurement (weight, height of pregnant women and fetal birthweight, height, crown-heel, head circumference) in 24 hours postpartum.
  2. Infant bone mineral density.


NotesLost to follow up of infants outcomes: 16 in treatment group then only 61 infants were analysed, 14 in control group then only 64 infants were analysed.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Subjects were randomly assigned in double-blind fashion to receive calcium or placebo by using block of 4 to ensure that equal numbers of subjects were allocated to supplement and placebo groups in each month and thereby to minimize the potential for seasonal confounding. Randomization was achieved by using published sets of tables."

Allocation concealment (selection bias)Low riskQuote: "The code was held by a member of study team who was not directly involved with the collection of data in the field or laboratory and who had no contact with the study participants."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "3 tablets of placebo (contained microcrystalline cellulose and lactose) per day, same shape, taste and texture)."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "There were no significant differences between the 2 groups in supplementation period, or compliance."

Comment; all enrolled subjects were completed study.

Missing data 30 in 155 = 19.3%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Karandish 2003

MethodsType of study: double blind, placebo controlled, randomised clinical trial.

Method of treatment allocation: no data.

Placebo: yes (starch tablets).

Intention-to-treat analyses: no, the initial number of participants were 77 pregnant women but by the end of study 68 participants remained .
Losses to follow-up: 11.7 % (9 in 77).


ParticipantsLocation: two prenatal clinics in county of Ahvaz, Iran.

Time frame: no data.

Eligible criteria: pregnant women between the ages of 18 to 35.

Pregnant women in their third trimester before week 28 of their pregnancies.

No history of abortion or stillbirth.

Not suffering from any metabolic or chronic diseases.

Not having previous history of giving birth to twins.

Not being on any other supplements with the exception of iron and folic acid.

Total recruited 77 pregnant women, treatment group, n= 33, placebo group, n= 35.


Interventions1000 mg of calcium (two capsules of 500 mg calcium carbonate) compared with placebo. The study started from 28th-30th week gestation until delivery.


OutcomesAnthropometric parameters of neonates including weight, head circumference and length.


NotesThis paper was written in Farsi. Dr. Reza Navaei kindly translated it to English using the Cochrane Pregnancy and Childbirth Group's translation form.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDouble-blind, placebo-controlled, randomised clinical trial were mentioned but there was no detail of sequencing generation.

Allocation concealment (selection bias)Unclear riskNo detail in allocation concealment.

Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of participants and staff.

Incomplete outcome data (attrition bias)
All outcomes
High riskThe initial participants were 77 pregnant women but the final analyses were 68 women. No detail about 9 women who dropped out from the study.

Selective reporting (reporting bias)Low riskThe preplanned outcomes were reported.

Other biasLow riskNone identified.

Levine 1997

MethodsType of study: computer-generated simple randomisation sequence.

Method of treatment allocation: package of study tablets were prepared and numbered by manufacturer and then shipped to the medical centre.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 253 in 4589 women (5.5%); 132 in the calcium group, 121 in the placebo group.


ParticipantsLocation: The Calcium for Preeclampsia Prevention (CPEP) Trial at 5 U.S medical centres.

Time frame: not stated.
Eligibility criteria: nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 11 to 21 weeks of gestation and intended to undergo delivery at the same institution, normal glucose tolerance test and willing to participate in trial, blood pressure below 134/84 mmHg and free of any underlying medical disorders, based on a comprehensive medical examination and routine laboratory tests.
Exclusion criteria: taking medication, had bad obstetrical conditions, pre-existing disease, elevated serum concentration of creatinine (> 1.0 mg/dl) or calcium (> 10.6 mg /dl), pregnant women with renal disease, hematuria, or history of urolithiasis in themselves or in first-degree relative and who report frequently use of calcium supplementation or antacid.

Total recruited: 4589 pregnant women; treatment group n = 2295, control group n = 2294.


Interventions2 g of calcium (4 chewable tablets of calcium carbonate per day, 500 mg of elemental calcium), start at 13 to 20 weeks until delivery, 2 tablets with morning meal and 2 tablets with evening meal. Compared with 4 tablets of placebo (contained lactose and granulated starch) per day, same size, weight and colour.


Outcomes
  1. Incidence of PIH.
  2. Pregnancy outcomes; preterm birth, premature rupture of membrane, birthweight, birth length, admission to neonatal intensive care unit, perinatal losses.
  3. Urolithiasis, renal insufficiency.


NotesKoo 1999 was another subset report of Levine 1997. Total recruited: 289 pregnant women. 13 refused consent; only 256 women and 256 infants were included (128 in each group).

  1. Fetal bone mineral density, bone mineral content.
  2. Pregnancy outcomes; gestational age, birthweight, birth length, and head circumference.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Package of study tablets were prepared and numbered by manufacturer according to a computer-generated simple randomisation sequence developed by statisticians."

Allocation concealment (selection bias)Low riskQuote: "Package of study tablets were prepared and numbered by manufacturer according to a computer-generated simple randomisation sequence developed by statisticians and then were shipped to the medical centres. Upon enrolment, each woman was assigned the next number packages of medication at the centre and thus was randomised automatically to receive calcium or placebo according to the pre assigned random sequence."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Each woman was assigned the next number packages of medication at the centre and thus was randomised automatically to receive calcium or placebo according to the pre-assigned random sequence. Calcium and placebo tablets were of similar colour and taste."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Of 4589 women enrolled in the study, 253 women (5.5%) were lost to follow-up; 132 in the calcium group, 121 in the placebo group."

Missing data 253 in 4589 = 5.5%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Lopez-Jaramillo 1989

MethodsType of study: prospective, randomised, double-blind, controlled clinical trial.

Method of treatment allocation: table of random numbers. The containers and the calcium tablets for both groups were prepared in Facultad de Quimica y Farmacia.

Stratification: not stated.
Placebo: yes, start tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.

Losses to follow-up: 13.2%.

Only women with no missing values for any of the covariate and outcome variables were included in the analysis. 49 in calcium group and 43 in placebo group. 6 women in calcium group and 8 in placebo group were eliminated from analysis because they were delivered before 38 weeks.


ParticipantsLocation: antenatal outpatient clinic in the Hospital Gineco-Obsterica Isdro Aroya in Quito, Ecuador.

Time frame: 30 months during 1984-1986.

Eligible criteria: nulliparity, age <  25 years, certain last menstrual period, registration at antenatal clinic for the first prenatal visit before 24 weeks gestation and residency in Quito (2800 m altitude) for a period of at least 1 year before conception, blood pressure < 120/80 mmHg and free for of any underlying medical disorders based on a comprehensive medical student examination and routine laboratory tests.

Exclusion criteria: had history of cardiovascular, renal or endocrinological disease or if they took any type of drug or vitamin/mineral preparation.

Total recruited: 106 pregnant women; n = 55 in treatment group, n = 51 in control group.


Interventions2000 mg of calcium (4 tablets of calcium gluconate daily, 500 mg of elemental calcium) compared with 4 tablets of placebo per day, same size, weight and colour. Started treatment at 23 weeks until delivery.


Outcomes
  1. Blood pressure develop PIH.
  2. Pregnancy outcomes; weight gain, preterm birth, birthweight, perinatal mortality.
  3. Serum ionised calcium concentrations.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Using a table of random numbers each patients was assigned independently in sequence to one of two treatment regimens."

Allocation concealment (selection bias)Low riskQuote: "The containers and the calcium tablets for both groups were prepared in Facultad de Quimica y Farmacia."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Treatment assignment was double blind with the composition of the tablets unknown to the patients and to all clinical personnel involved in the study. The placebo group also received four tablets daily of the same size, weight, colour and organoleptic characteristics as calcium tablets."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "106 women satisfactory met the subject selection criteria. Only women with no missing values for any of the covariate and outcome variables were included in these statistical analysis. 49 in the calcium supplemented group and 43 in the placebo group. Six women in calcium supplement group and eight in the placebo group were eliminated from analysis because they were delivery before 38 weeks."

Missing data 14 in 106 = 13.2%.

Selective reporting (reporting bias)Unclear riskComment: not all enrolled participants were analysed.

Other biasLow riskNone identified.

Lopez-Jaramillo 1997

MethodsType of study: a prospective, randomised, double-blind, control clinical trial. Table randomisation was used.

Method of treatment allocation: used a table of random numbers to assigned each patient independently in sequence to one of two treatment regimens.

Treatment assignment was double-blind, with composition of tablets unknown to the patients and to all clinical personnel involved in the study. The containers and tablets were prepared in the Facultad de Quimica y Farmacia, Universidad Central del Ecuador.

Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: yes, 14 in 274 = 5.1%.


ParticipantsLocation: Hospital Gineco-Obstetrico Isidro Ayora in Quito, Ecuador.

Time frame: 56-month period between 1990 to 1995.

Eligible criteria: age < 17.5 years, nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation, residency in Quito (2800 m altitude) for a period of at least 1 year before conception, blood pressure < 120/80 mmHg and free from any underlying medical disorders, based on a comprehensive medical examination and laboratory test.

Exclusion criteria: had history of cardiovascular, renal or endocrinological disease or if they took any type of drugs or vitamin/mineral preparations.

Total recruited: 274 pregnant teenagers were randomised and then 14 women failed to complete the protocol (3 changed the residence, 7 changed to the private hospital, 2 changed to hospital of social insurance, 2 by non-compliance to treatment) then only 260 completed the study, 125 girls received 2000 mg calcium, 135 girls in control group.


Interventions2 g calcium (4 tablets of calcium carbonate per day, 500 mg of elemental calcium) compared with 4 tablets of placebo (contained lactose and granulated starch) per day, same size, weight, colour and organoleptic characteristics to calcium tablets.


Outcomes
  1. Incidence of PIH.
  2. Serum ionised calcium concentrations.
  3. Pregnancy outcomes; gestational age, weight gain, birthweight, fetal mortality.
  4. Side effects of calcium.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "We used a table of random numbers to assigned each patient independently in sequence to one of two treatment regimens."

Allocation concealment (selection bias)Low riskQuote: "The containers and tablets were prepared in the Facultad de Quimica y Farmacia,Universidad Central del Ecuador."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Treatment assignment was double-blind, with composition of tablets unknown to the patients and to all clinical personnel involved in the study. The placebo group also received four tablets daily similar size, weight, colour, and organoleptic characteristics to the calcium tablets."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "274 teenagers were  randomised and then 14 women failed  to completed the protocol (3 changed the residence, 7 changed to the private hospital, 2 changed to hospital of  social insurance, 2 by non-compliance to treatment) then only 260 completed the study, 125 girls received 2000 mg calcium, 135 girls in the control group."

Selective reporting (reporting bias)Low riskNone identified.

Missing data in both groups 14 in 274 = 5.1%. The authors did not provide information about how many people were missing in each group.

Other biasLow riskNone identified.

Niromanesh 2001

MethodsType of study: double blind, placebo controlled clinical trial. Randomly assigned to one of two treatments.

Method of treatment allocation: the manufacturing company coded the tablets. The hospital pharmacy dispensed the tablet among the subjects.

Stratification: not stated.
Placebo: yes, starch tablet.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.


ParticipantsLocation: Mirza-Kochak-Khan Gynecology Hospital.

Time frame: not stated.
Eligible criteria: high risk for pre-eclampsia, positive roll over test, GA 28 to 32 weeks, blood pressure < 140/90 mmHg.
Exclusion criteria: negative for roll-over test and had any chronic condition such as diabetes, renal diseases, cardiovascular disease, hypertension, and severe anaemia.
Total recruited: 30 women at high risk of pre-eclampsia (15 in the calcium group, 15 in the control group).


Interventions2 gm of calcium (4 tablets of 500 mg orally every 6 hours). Compared with placebo.
Started treatment at 28 to 32 weeks.


Outcomes
  1. Incidence of PIH.
  2. Maternal weight gain.
  3. Pregnancy outcomes; duration of pregnancy, birthweight.


NotesNo details about the type of calcium.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Thirty women at high risk of preeclampsia were randomly assigned to 2 g of calcium daily intake and placebo regimen."

Comment: the method of sequence generation was not described.

Allocation concealment (selection bias)Low riskQuote: "The  manufactory company coded the tablets. The hospital pharmacy dispensed the tablet among the subjects."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Randomization and blinding of subjects and the investigator were managed by providing coded tablets of the same packaging and physical characteristics for both calcium and the placebo tablets."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "There was no loss to follow up in the course of study."

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Purwar 1996

MethodsType of study: randomised double blind placebo controlled trial.

Method of treatment allocation: the women were assigned randomly in a double fashion to 1 of 2 treatment groups (calcium/placebo) using computer generated random number table. All the containers and tablets were specially prepared by local Universal pharmaceutical, Nagpur.

Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: yes, 11 in 201 = 5.5%.


ParticipantsLocation: the Government Medical College and Hospital, Nagpur, India.

Time frame: October 1,1993 to December 31, 1994.

Eligible criteria: nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation and intending to undergo delivery at the same institution, normal glucose tolerance test < 140 mg/dl and willing to participate in trial, first antenatal visit below 140/90 mmHg and free of any underlying medical disorders, based on a comprehensive medical examination and routine laboratory tests.  

Exclusion criteria: renal disease, collagen vascular disease, chronic hypertension, endocrinological disease or if on any medication.

Total recruited: 201 pregnant women; treatment group N = 103, control group N = 98. Final number for analysis (treatment group n = 97, control group n = 93).


Interventions2 g calcium (4 tablets of 500 mg calcium carbonate). Placebo (4 tablets of placebo) same size, weight and colour.


Outcomes
  1. Incidence of PIH.
  2. Pregnancy outcomes; preterm birth, birthweight, fetal growth restriction.


NotesMissing data 11 in 201 = 5.5%.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The women were assigned randomly in a double-blind fashion at 20 weeks gestation to 1 of 2 treatment groups (calcium/placebo) using computer-generated random number table."

Allocation concealment (selection bias)Low riskQuote: "All the containers and tablets used were specially prepared for the study by local Universal Pharmaceutical Pvt Ltd, Nagpur."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo tablets were same size, weight and colour."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "A total of 98 women randomly assigned to the placebo groups and 103 in calcium groups. Eleven women (5.47%) were lost to follow-up after randomisation (5 in the placebo group and 6 in the calcium group). The total of 93 women in the placebo group and 98 women in the calcium group were included in the fin final analysis."

Missing data 11in 201 = 5.5%.

Selective reporting (reporting bias)Unclear riskNone identified.

There was inconsistent missing data. The number lost to follow-up is 11 from 201, then it should remained 200 participants in final analysis. But the given number included in final analysis was 201 participants.

Other biasLow riskNone identified.

Raman 1978

MethodsType of study: pregnant women were assigned by strict rotation to one of three groups.

Method of treatment allocation: not clearly stated.

Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: 186 in 273 = 68.1%.


ParticipantsLocation: India, poor segment of the population.

Time frame: not stated.
Eligible criteria: pregnant women who were in low economic status and had regularly consumed supplements were enrolled.
Exclusion criteria: pregnant women suffered from complications such as toxemia, hypertension and diabetes.
Total recruited: 273 pregnant women and divided into 3 groups.


InterventionsCalcium lactate were given in tablet form supplying 150 mg of elemental calcium per tablet. Started treatment at 18 to 22 weeks until delivery.

Group 1: control, n = 38 no treatment.
Group 2: n = 25  received calcium 300 mg/d.
Group 3: n = 24 received calcium 600 mg /d


Outcomes
  1. X-ray left hand (anteroposterior view) of mothers.
  2. X-ray ulna, radius, tibia fibular of neonate.
  3. Densitometry of metacarpal and 4-1 phalangeal of mothers.
  4. Densitometry of ulna, radius, tibia fibular of neonate.


NotesComment: Only 87 subjects completed data: 38, 25, 24 subjects in three groups respectively, high rate of loses to follow-up 186 in 273 = 68.1%.

For data in  Analysis 2.4 the placebo n was halved to enable inclusion of data for treatment groups 1 and 2.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: " the women were assigned by strictly rotation to one of three groups".

Comment: method of sequence generation was not stated.

Allocation concealment (selection bias)Unclear riskComment: method of allocation concealment was not stated.

Blinding (performance bias and detection bias)
All outcomes
High riskComment: no treatment in control group then it was not blind the participants and the intervention was divided in 2 groups which unequal dosage.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskQuote; "Of the 273 mothers registered, data completed in all aspect, could be obtained in 87 subjects (38, 25, 24 respectively)".

Comment: high rate of loss to follow-up.

Missing data 186 in 273 = 68.1%.

Selective reporting (reporting bias)High riskComment: high rate of loss to follow-up:

(in treatment group (calcium 300 mg/d) = 72.5%;

in treatment group (calcium 600 mg/d) = 73.6%;

in control group = 58.2%).

Other biasLow riskNone identified.

Rogers 1999

MethodsType of study: randomisation.
Method of treatment allocation: unsealed envelopes.
Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 18 in 237 =7.6%.


ParticipantsLocation: Chinese Women's Hospital, Hong Kong.
Time frame: July 1992 to December 1994.
Eligible criteria: normotensive, MAP > 80 and < 106 mmHg, second trimester, singleton and used cutoff value 60 mmHg of left lateral position.
Exclusion criteria: MAP < 60 mmHg.
Total recruited: 500 pregnant women (131 patients were excluded only 369 patients were randomised),154 in calcium group, 132 in low-dose aspirin, 83 in control group.


InterventionsCompared 3 groups of total 369 patients.

  1. Calcium (154 patients) 600mg/day from 22 to 32 weeks and 1200 mg/d in dividing dose from 32 weeks to delivery.
  2. Low dose aspirin (132 patients) 80 mg/d starting at 22 weeks until delivery.
  3. Control group were no treatment in 83 patients.


Outcomes
  1. Mean arterial blood pressure.
  2. Pregnancy outcomes; gestational age, birthweight, APGAR score.
  3. Incidence of proteinurics and non proteinurics PIH.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Randomization was into three groups: control, low-dose aspirin, and calcium supplementation in a ratio of 1:2:2 using five unsealed envelope". Of 500 nulliparous screening, 369 were randomisation; 154 were in calcium group, 132 were in low-dose aspirin , and 83 as control group."

Allocation concealment (selection bias)Unclear riskQuote: "Randomization was into three groups; control, low-dose aspirin, and calcium supplementation in a ratio of 1:2:2 using five unsealed envelopes."

Blinding (performance bias and detection bias)
All outcomes
Unclear riskQuote: "All randomisation, data collection, and data entry were undertaken by the same research assistant with the exception of outcome data, which were entered by the first two authors. The research assistant was therefore blinded to the outcome groups."

Comment: It was impossible to blind the participants because difference of drugs and no treatment in control group.

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Fifty (10%) patients eventually delivered in other hospitals and were therefore not subjected to analysis, as they could not reliably be classified into the 3 outcomes groups. 144, 118, and 75 were in calcium group, low-dose aspirin, and control groups respectively were included in final analysis."

Missing data 18 in 237 = 7.6%.

Selective reporting (reporting bias)Unclear riskNone identified.

Other biasLow riskNone identified.

Sanchez-Ramos 1994

MethodsType of study: randomised double-blind, placebo controlled clinical trial.

Method of treatment allocation: women with positive angiotensin test were randomised by means of a computer-generated list. Calcium and placebo tablets were provided by pharmaceutical company.

Stratification: not stated.
Placebo: yes, placebo.
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: 4 in 67 = 6.0%.
Post randomised exclusion: 6 in 67 =  8.9 % did not comply fully the protocol; 4 were excluded from analysis after randomisation because lacking of information, one was admitted to other hospitals (in placebo group), another woman refused to participate after one week of trial (in calcium group).


ParticipantsLocation: University of Florida Health Science Center, Jacksonville, Florida.

Time frame: January 1, 1989 to July 30, 1993.
Eligible criteria: normotensive, nulliparous with increased risk of pregnancy induced hypertension with positive angiotensin sensitivity test  only who were positive roll over test (women supine diastolic blood pressure value were more than 20 mmHg higher than those obtained on her side) received angiotensin infusion at 24 to 28 weeks.

Exclusion criteria: subjects which conditions known to increase the incidence of pregnancy induced hypertension, including history or evidence of renal disease, collagen vascular disease, diabetes mellitus, chronic hypertension and multiple pregnancy.

Total recruited: 281 pregnant women were positive roll-over test; 67 women positive angiotensin sensitivity test; 33 received calcium, 34 received placebo. Final analyses, calcium group, n = 29, control group, n = 34.


Interventions2 g of calcium carbonate, compared with placebo (contained starch and were identical to calcium tablets with respected to weight, size, flavour and appearance).


Outcomes
  1. Incidence PIH.
  2. Pregnancy outcomes; gestational age, preterm birth, birthweight, APGAR score, NICU admission, fetal growth restriction, perinatal death.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Women with positive angiotensin test were randomised by means of  a computer-generated list to receive either 2 g/day of elemental calcium or matching placebo."

Allocation concealment (selection bias)Low riskQuote: "Calcium and placebo tablets were provided by pharmaceutical company."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo contained starch and were identical to calcium tablets with respect to weight, size, flavour and appearance."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Six women (8.9%) did not comply fully the protocol; of these, four were excluded from analysis after randomisation because lack of information. One had a single follow-up prenatal visited and refused to continue participating in the study. She was admitted to another hospital at 35 weeks' gestation with severe preeclampsia and required labour induction (in placebo group). Another woman refused to participate after one week of trial (in calcium group)."

Missing data 4 in 67 = 6%.

Selective reporting (reporting bias)Unclear riskNone identified.

Other biasLow riskNone identified.

Sanchez-Ramos 1995

MethodsType of study: computer-generated list of random numbers.

Method of treatment allocation: the randomisation list was maintain by pharmaceutical personnel. The drug and placebo were delivered by pharmacy to antepartum ward, where nurse administered the medication.

Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: no, because of a decline in perinatal research support, the study was terminated three cases earlier than suggested by power analysis.

Losses to follow-up: 0%.


ParticipantsLocation: University Medical Center.

Time frame: July 1990 - January 1993.

Eligible criteria: nulliparity, 24 to 36 weeks' gestation, mild pre-eclampsia and no evidence of severe pre-eclampsia within 48 hours of admission.

Exclusion criteria: proteinuria > 5 g/d, platelet count < 100,000, oliguria (urine < 500 ml/d), pulmonary edema, elevated liver enzyme > 200 U/L, microangiopathic haemodynamic anaemia, fetal growth retardation, known sensitivity to calcium, chronic hypertension, chronic renal disease, diabetes mellitus,or calcium supplement before admission.

Total recruited: 75 eligible subjects; 36 in treatment group, 39 in control group (because of a decline in perinatal research support, the study was terminated three cases earlier than suggested by power analysis).


Interventions2 g of calcium/d (4 tablets of calcium carbonate per day, 500 mg of elemental calcium). Placebo (4 tablets of placebo per day, same size, weight and colour).


Outcomes
  1. Incidence of severe pre-eclampsia.
  2. Pregnancy outcomes; gestational age, birthweight, APGAR score, fetal growth restriction, perinatal death.
  3. Umbilical arterial blood gas.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Patients were assigned using a computer-generated list of random number to receive either calcium or matching placebo."

Allocation concealment (selection bias)Low riskQuote: "The randomisation list was maintained by pharmacy personnel; the drug and placebo were delivered by pharmacy to antepartum ward, where nurse administered the medication."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Patients were assigned to receive either calcium or matching placebo. Clinician caring for study patients were blinded to treatment group allocation."

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "During the studied period, 75 eligible subjects were identified and invited to participate; 36 (48%) were assigned to calcium and 39 (52%) to placebo. Because of decline in perinatal research support, the study was terminated three cases earlier than suggested by power analysis."

Missing data = 0%.

Selective reporting (reporting bias)Low riskTrial was stopped before complete enrolment due to decline of research fund.

Other biasLow riskNone identified.

Taherian 2002

MethodsType of study: randomised controlled study.

Method of treatment allocation: the sampling method was non probability convenience. Use table of random to assign each case independently to one of three group.

Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention to treat analyses: yes.
Losses to follow-up: 0%.


ParticipantsLocation: Isfahan Health Center, Iran.

Time frame: April 1998 to March 2001.
Eligible criteria: nulliparity, single gestation, first antenatal visit before 20 weeks of gestation, BP < 130/80 mmHg and no proteinuria by urine dipstick.
Exclusion criteria: had history of cardiovascular, renal disease or endocrinologic problem, medical or obstetric complications and those with known hazardous condition (multiple gestation, hydatidiform mole).
Total recruited: 990 healthy pregnant women (n = 330 subjects/group).


InterventionsGroup 1: received 75 mg aspirin /day, n = 330.
Group 2: received 500 mg calcium carbonate/day, n = 330.
Group 3: no treatment as control group, n = 330.
Started treatment at 20 weeks until delivery.


Outcomes
  1. Blood pressure.
  2. Pregnancy outcomes; gestational age, birthweight, preterm birth, APGAR score, fetal growth restriction, perinatal death.


NotesComment: the results were reported as mean and 95% CI, then we changed them into SD.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "The sampling method was non probability convenience. We use table of random number to assign each case independently to one of three group."

Allocation concealment (selection bias)Unclear riskComment: the method of allocation concealment was not stated.

Blinding (performance bias and detection bias)
All outcomes
High riskQuote: "Group 1 received 75 mg aspirin; group 2 received 500 mg oral calcium-D daily; and the control group 3 received no medication at all."

Comment: it was impossible to blind because the difference of drug and no treatment in control group.

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all enrolled participants were included in the analyses.

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Villar 1987

MethodsType of study: double-blinded, randomised controlled clinical trial.

Method of treatment allocation: the women were assigned randomly in the double blind fashion at 26 weeks' gestation to one of two treatment groups, using a randomisation schedule prepared in advance for the complete population.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.


ParticipantsLocation: the Johns Hopkins Hospital in Baltimore and Perinatal Study Center of Rosario, Argentina.

Time frame: 1983 to 1985.
Eligible criteria: nulliparous, singleton, known last menstrual period, age 18 to 30 years, free from any underlying medical disorders, negative roll-over test.
Exclusion criteria: history of cardiovascular or renal disease or taking any drug.
Total recruited: 52 pregnant women:
*18 white: 9 in calcium group, 9 in placebo group;
*34 black women: 16 in calcium group, 18 in placebo group.
Total in calcium group, n = 25; in placebo group, n = 27.


Interventions3 tablets of calcium carbonate (500 mg each). Compared with 3 placebo tablets with same size, weight, size, colour and organoleptic characteristics.
Started treatment at 26 weeks.


Outcomes
  1. Incidence of pregnancy induced hypertension.
  2. Birthweight.


NotesComment: the authors provide only mean birthweight but not SD. SD in both groups were imputed by mean.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "The women were assigned randomly in the double blind fashion at 26 weeks gestation to one of two treatment groups, using a randomisation schedule prepared in advance for the complete population."

Allocation concealment (selection bias)Low riskQuote: "The same randomization code, standardization process, and tablets were used in both populations and code was kept in central allocation (Baltimore). Random number in closed envelopes and corresponding medication were distributing to the two hospitals at the beginning. All containers and tablets  were prepared by pharmaceutical."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "Placebo same size, weight, size, colour and organoleptic characteristic."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all enrolled participants were included in the analyses.

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Villar 1990

MethodsType of study: double-blind, randomised placebo-controlled clinical trial.

Method of treatment allocation: computer-generated list of random number. Opaque envelope with the bottle number were located at the clinic and the project coordinator was in charge of the administration of the treatment assigned.
Stratification: not stated.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 0%.


ParticipantsLocation: Adolescent Pregnancy Clinic of the Johns Hopkins Hospital in Baltimore.

Time frame: 1985 to1988.

Eligible criteria: age < 17 year, GA < 20 week, singleton pregnancy, certain last menstrual period, free from any underlying medical disorders determined by history, physical examination, and laboratory tests.

Exclusion criteria: underlying medical disorders determined by history, physical examination, and laboratory tests.

Total recruited: 190 adolescent pregnant women; 95 in the calcium group, 95 in the placebo group.


Interventions2 g of calcium (4 tablets of calcium carbonate per day, 500 mg of elemental calcium) compared with 4 tablets of placebo (contained lactose and granulated starch) per day, same size, weight and colour. Started treatment at 20 weeks until delivery.


Outcomes
  1. Incidence of preterm labor.
  2. Incidence of low birthweight, intrauterine growth restriction, premature rupture of membrane, PIH.
  3. Pregnancy outcomes; gestational age, birthweight , birth length.
  4. Incidence of bacteriuria, pyelonephritis.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "A computer- generated list  of random number was used to allocate the corresponding treatments."

Allocation concealment (selection bias)Low riskQuote: "Opaque envelope with the bottle number were locate at the clinic and project coordinator was in charge of the administration of the  treatment assigned."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The placebo group received four tablets (contained lactose and granulated starch) per day of the same size, weight, colour, and organoleptic characteristics as the calcium tablets."

Incomplete outcome data (attrition bias)
All outcomes
Low riskComment: all enrolled participants were analyses.

Missing data = 0%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Villar 2006

MethodsType of study: multicenter, randomised, placebo-controlled, double trial. Central randomisation at WHO Geneva.

Method of treatment allocation: computer-generated random number blocking with randomly varying groups of 6 to 8 women and were used to restrict randomisation in the strata (country). The technique consisted of allocating consecutively numbered treatment boxes for each woman. Randomisation codes remained at the WHO Clinical trial Unit until the time of analysis and were not available to any person until the analyses were completed. Boxes and tablets were prepared and numbered by Magistra SA, GENEVA and were shipped to each centre.
Stratification: yes, by country.
Placebo: yes, starch tablets.
Sample size calculation: not stated.
Intention-to-treat analyses: yes.
Losses to follow-up: 13 in 8325 = 0.16%.

Before started treatment 2 in calcium were not pregnant, 2 in placebo group, then were excluded from analyses. 143 (3.4%) in calcium group (4157-143 ) lost to follow-up and no delivery information then 4008 pregnancies available for analyses.
155 (3.7%) in placebo group (4168-155) lost to follow-up and no delivery information then 4006 pregnancies available for analyses of preterm labor and 4161 pregnancies  available for analyses of PIH (final analyses) of preterm labor and 4151 pregnancies available for analyses of PIH (final analyses).

Post randomised exclusion: 4 in calcium were not pregnant, 5 in placebo group.


ParticipantsLocation: Rosiario, Argentina; Assiut , Egypt; Nagpur and Vellor , India; Lima, Peru; East London and Johannesburg, South Africa; Ho Chiminh City, Viet Nam; where population intake calcium < 600 mg/d.

Time frame: November 2001 to July 2003.
Eligible criteria: healthy nulliparity, normal single viable pregnancy with known menstrual period date (LMP), registering at antenatal clinic before 20 weeks of gestation.
Exclusion criteria: blood pressure > 140/90 mmHg, had history or evidence of chronic hypertension, renal disease, signs and symptoms of nephrolithiasis, parathyroid disease and disease that require digoxin, phenytoin, or tetracycline therapy.

Total recruited: 8325 pregnant women were randomised, treatment group, n = 4157, control group, n = 4168.


Interventions1.5 g of calcium carbonate (1 x 500 mg tablet, three times per day at meal time), chewable tablets started at 20 weeks until delivery, and > 3 hours after any iron supplement. Compared with 3 tablets of placebo (contained lactose, sorbitol, cellulose plus other calcium free ingredient) per day, same form, colour and taste.


Outcomes
  1. Incidence of pre-eclampsia/eclampsia.
  2. Pregnancy outcomes; gestational age, preterm birth, birthweight , birth length, maternal admission to intensive care unit, maternal death, stillbirth, neonatal death.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskQuote: "Central randomisation at WHO Geneva. Computer-generated random number blocking with randomly varying groups of 6 to 8  women and were used to restrict randomisation in the strata (country)."

Allocation concealment (selection bias)Low riskQuote: "The technique consisted of allocating consecutively numbered treatment boxes for each woman. Randomization codes remained at the WHO Clinical trial Unit until the time of analysis and were not available to any person until the analyses were completed. Boxes and tablets were prepared and numbered by Magistra SA, GENEVAand were shipped to each centre."

Blinding (performance bias and detection bias)
All outcomes
Low riskQuote: "The placebo tablets were identical in form, colour, and taste ".

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote: "Of 8325 women assigned randomly to group, 4157 were assigned to the calcium group and 4168 were assigned to the placebo group. Nine women (5 in the placebo group; 4 in calcium group) were determined to not be pregnant, and 2 women from each group who were lost to follow-up before starting any treatment were excluded from all analyses. Delivery information was unavailable for 143 (3.4%) in the placebo group; therefore, they did not contribute to the preterm analyses, but the available data were included in the analyses for other outcomes. Thus, 4151 women in the calcium group and 4161 women in the placebo group contribute to the final analyses.

Missing data 13 in 8325 = 0.16%.

Selective reporting (reporting bias)Low riskNone identified.

Other biasLow riskNone identified.

Wanchu 2001

MethodsType of study: randomly assigned to ether group of two treatment groups.

Method of treatment allocation: not stated.
Stratification: not stated.
Placebo: no (no treatment).
Sample size calculation: not stated.
Intention-to-treat analyses: no.
Losses to follow-up: 20 in 120 = 16.7%.


ParticipantsLocation: Post Graduate Institute of Medical Education and Research, Chandigarh.
Time frame: not stated.
Eligible criteria: uncomplicated normotensive primigravida with singleton pregnancy, GA < 20 weeks.
Exclusion criteria: multiple pregnancy, molar pregnancy, hydramnios, congenital malformation, chronic hypertension, chronic renal disease, diabetes mellitus and those already on calcium supplementation.
Total recruited: 120 pregnant women were enrolled, 100 who completed the protocol were analysed. 50 participants in treatment group n = 50, 50 participants in control group. .


Interventions2 g of calcium (4 tablets of calcium carbonate). Compared with no treatment. Started treatment at 20 weeks.


Outcomes
  1. Incidence of pregnancy induced hypertension.
  2. Pregnancy outcomes; gestational age, PROM, preterm birth, birthweight, IUGR, APGAR score.


NotesNo restriction was put on dietary calcium intake in either group.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "Patients were randomly assigned to ether group of two treatment groups."
Comment: the method of sequence generation was not stated.

Allocation concealment (selection bias)Unclear riskComment: the method of allocation concealment was not stated.

Blinding (performance bias and detection bias)
All outcomes
High riskComment: the control group was no treatment.

Incomplete outcome data (attrition bias)
All outcomes
High riskQuote: "120 pregnant women were enrolled in the study, 100 women who completed the protocol were analysed.

Missing data = 20 in 120 = 16.7%.

Selective reporting (reporting bias)Unclear riskNone identified.

Other biasLow riskNone identified.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Duggin 1974The outcomes were not relevant and allocation to groups was not random. Seven primiparas (aged 16-19 years) who were at 32-36 weeks' gestation were included. The participants were divided into control subjects (patient 1-4) and supplemented subjects (patients 5-7) to measure metabolic balance.

Felix 1991There was not random allocation to groups in this trial (women allocated to groups in sequence). The aim of the study was to examine the hypotensive effects of calcium in Andean women.

Hammar 1981The participants were not appropriate. This study was aimed to determine the effect of calcium treatment in pregnant women who suffered from leg cramps. 42 pregnant women who suffered from leg cramps with gestational age 21-38 weeks were included.

Janakiraman 2003This was a crossover study examining bone resorption among pregnant women during received calcium supplementation. 32 pregnant women gestational age 25-35 weeks participated in the study for 20 days. Each women received 1200 mg calcium supplement for 10 days and multivitamin without calcium for 10 days. N-telopeptides of type I collagen (NTX), a biomarker of bone resorption were measured.

Kalkwarf 1997The intervention was not appropriate. The study aimed to examine the effect of calcium supplementation on bone density in postpartum period. The randomised, placebo-controlled trials of 1 g calcium supplementation was conducted in 97 lactating and 99 non-lactating women a mean 16 ± 2 says postpartum (the study of lactation). The other trial (the study of weaning) 95 lactating women who weaned their infants in 2 months after enrolments and 92 non-lactating women were enrolled 5.6 ± 0.8 month postpartum.

Kent 1995The participants were not appropriate. This was a study focusing on the postpartum period and women were not randomised to receive calcium until 36 weeks' gestation. This trial aimed to study the effect of an oral calcium supplement on regional bone loss in normal lactation women. 79 pregnant women at gestational age 36 weeks were randomised to received placebo or 500 mg twice daily of calcium through to 24 weeks' lactation.

Liu 2011The intervention was not appropriate. The participants were provided calcium supplementation until 6 weeks postpartum and measured bone mineral density post-treatment.

Lopez-Jaramillo 1990The participants were not appropriate.The study aimed to examine the effect of calcium supplementation on risk of PIH in pregnant women who had a positive roll-over test.

Mahomed 2000The participants were not appropriate. The study aimed to examine the effect of calcium supplementation on risk of PIH and preterm labor in twin pregnancy.

Mukherjee 1997The participants were not appropriate. The study aimed to examine the effect of calcium supplementation in reduce leg cramps in homogeneous Chinese population. All pregnant women who suffered from leg cramps during January 1994 and May 1995 were enrolled to received either calcium gluconate 600 mg twice daily or two multivitamin tablets twice daily.

Odendaal 1974The participants were not appropriate. Calcium was supplemented only when participants suffered from leg cramps which not relevant to the objective of the review.

Prentice 1995This study did not examine calcium supplementation amongst pregnant women. 60 Gambian mothers consuming a low-calcium were randomised to receive calcium supplement or placebo from 10 days to 78 weeks postpartum.

Qui 1999The intervention was not relevant. Calcium was supplemented from 20 weeks' gestation to postpartum 45 days.

Robinson 1947The intervention was not appropriate. Calcium was given to treat women with leg cramps which was not relevant to the objective of the review.

 
Characteristics of studies awaiting assessment [ordered by study ID]
Almirante 1998

MethodsParticipant were divided into 2 groups.

Participants430 pregnant women in first trimester who were nulliparous, adolescents and elderly.

InterventionsTreatment group, n = 212 were given 500mg elemental calcium per day on the 16th-20th week until delivery.

Control group, n = 210 were not given calcium supplementation.

OutcomesEarly pregnancy hypertension, prematurity, number of babies admitted to NICU.

NotesAbstract only. We have contacted the authors but have not had a reply. We will reconsider this trial for inclusion once the full publication is available, or the authors have provided more information.

Chames 2002

MethodsRandomised double-blind placebo control trial.

Participants50 pregnant women with 13-19 weeks pregnancy.

Interventions1000 mg calcium per day compared with placebo.

Control group, n = 26, treatment group, n = 24.

OutcomesBlood lead level.

NotesAbstract only. We have contacted the authors but have not had a reply. We will reconsider this trial for inclusion once the full publication is available, or the authors have provided more information.

Galimberti 2001

MethodsThe author did not state clearly about randomisation but the participant were divided into 2 groups.

Participants44 pregnant women (calcium intake 310-720 mg/d).

InterventionsTreatment group , n = 26 were given calcium supplementation 750 mg/d (as calcium citrate) until delivery.

Contron group, n = 18 received placebo.

OutcomesSerum level of Ca and markers of bone turn-over.

NotesAbstract only. We have contacted the authors but have not had a reply. This trial will be reconsidered for inclusion once the full publication is available, or the authors have provided more information.

Repke 1989a

MethodsRandomised clinical trial.

ParticipantsAfter 20-week pregnancy.

Interventions2 g/d versus placebo. Treatment group, n = 125. Control group, n = 130.

OutcomesHaemoglobin level.

NotesAbstract only. We have contacted the authors but have not had a reply. We will reconsider this trial for inclusion once the full publication is available, or the authors have provided more information.

 
Comparison 1. Calcium supplementation versus placebo or no treatment (maternal outcomes)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Preterm birth (a) Birth prior to 37 weeks12Risk Ratio (M-H, Random, 95% CI)Subtotals only

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

    1.2 Sensitivity analysis by concealment allocation
1014855Risk Ratio (M-H, Random, 95% CI)0.84 [0.69, 1.04]

 2 Preterm birth (a) Birth prior to 37 weeks by dose of calcium1215615Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

    2.1 Low dose
1660Risk Ratio (M-H, Random, 95% CI)1.55 [1.00, 2.41]

    2.2 High dose
1114955Risk Ratio (M-H, Random, 95% CI)0.85 [0.70, 1.04]

 3 Preterm birth (a) Birth prior to 37 weeks by started to take calcium1215549Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.10]

    3.1 Started calcium before 20 weeks
412766Risk Ratio (M-H, Random, 95% CI)0.97 [0.87, 1.07]

    3.2 Started calcium at 20 weeks or more
82783Risk Ratio (M-H, Random, 95% CI)0.72 [0.45, 1.15]

 4 Preterm birth (a) Birth prior to 37 weeks by type of calcium1215615Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

    4.1 Carbonate
1115523Risk Ratio (M-H, Random, 95% CI)0.90 [0.73, 1.11]

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

    4.3 Gluconate
192Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 5 Preterm birth (b) Birth prior to 34 weeks35145Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.84, 1.46]

 6 Preterm birth (b) Birth prior to 34 weeks - Sensitivity analysis by concealment allocation25045Risk Ratio (M-H, Fixed, 95% CI)1.10 [0.83, 1.45]

 7 Maternal weight gain (g/w)3404Mean Difference (IV, Random, 95% CI)-29.46 [-119.80, 60.89]

 8 Maternal bone mineral density (g/cm2) - First phalanx (calcium 300 mg)1Mean Difference (IV, Fixed, 95% CI)Subtotals only

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

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

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

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

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

 14 Maternal death18312Risk Ratio (M-H, Fixed, 95% CI)0.17 [0.02, 1.39]

 15 Maternal admission to intensive care unit18312Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.66, 1.07]

 16 Vaginal birth86916Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.99, 1.03]

 17 Instrumental vaginal birth2675Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.66, 1.20]

 18 Cesarean section86916Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.87, 1.08]

 
Comparison 2. Calcium supplementation versus placebo or no treatment (infant outcomes)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Low birth weight (< 2500 g)513638Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]

 2 Low birth weight (< 2500 g) by started to take calcium513638Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]

    2.1 Started calcium before 20 weeks
212901Risk Ratio (M-H, Random, 95% CI)0.98 [0.88, 1.10]

    2.2 Started calcium at 20 weeks or more
3737Risk Ratio (M-H, Random, 95% CI)0.41 [0.23, 0.73]

 3 Low birth weight (< 2500 g) by type of calcium513638Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]

    3.1 Gluconate
192Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    3.2 Carbonate
413546Risk Ratio (M-H, Random, 95% CI)0.83 [0.63, 1.09]

 4 Birth weight (g)198319Mean Difference (IV, Random, 95% CI)64.66 [15.75, 113.58]

 5 Perinatal mortality715123Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.06]

 6 Stillbirth or fetal death414083Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.71, 1.15]

 7 Admission to neonatal intensive care unit414062Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.94, 1.18]

 8 Birth length (cm)66031Mean Difference (IV, Fixed, 95% CI)-0.08 [-0.24, 0.08]

 9 Head circumference (cm)2100Mean Difference (IV, Fixed, 95% CI)-2.42 [-0.72, 0.72]

 10 Intrauterine growth restriction51177Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.61, 1.22]

 11 Neonatal bone mineral density (g/cm2)2Mean Difference (IV, Fixed, 95% CI)Subtotals only

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

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

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

 
Comparison 3. Calcium supplementation versus placebo or no treatment (adverse outcomes)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Side effects of calcium supplementation - Maternal cholestatic jaundice4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Maternal cholestatic jaundice
1100Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 71.92]

    1.2 Gatrointenstinal symptoms (including nausea, heartburn and diarrhoea)
152Risk Ratio (M-H, Fixed, 95% CI)2.16 [0.43, 10.78]

    1.3 Gall stones
1518Risk Ratio (M-H, Fixed, 95% CI)1.35 [0.48, 3.85]

    1.4 Headache
18312Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.93, 1.12]

 2 Urinary stones313419Risk Ratio (M-H, Fixed, 95% CI)1.11 [0.48, 2.54]

 3 Urinary tract infection31743Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.69, 1.30]

 4 Renal colic18312Risk Ratio (M-H, Fixed, 95% CI)1.67 [0.40, 6.99]

 5 Impaired renal function14589Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.51, 1.64]

 6 Maternal anemia11098Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.90, 1.22]

 
Table 1. Neonatal bone density (Skewed data)

StudyOutcomeTreatmentControl


MeanSDTotalMeanSDTotal

Raman 1978(Ca 300mg)Ulna1.190.81240.640.2638

Raman 1978(Ca 300mg)Fibula1.120.6240.650.4138

Raman 1978(Ca 300mg)Midshaft radius1.170.62240.080.438

Raman 1978(Ca 300mg)Tibia0.910.35240.580.4138

Raman 1978(Ca 600mg)Ulna1.030.53250.640.2638

Raman 1978(Ca 600mg)Midshaft radius1.170.65250.080.438

Raman 1978(Ca 600mg)Tibia1.110.82250.580.4138

Raman 1978(Ca 600mg)Fibula1.510.61250.650.4138

 The standard deviation (SD) was imputed from the standard error of a mean (SEM).