Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

 

Characteristics of included studies [ordered by study ID]

Belizan 1991

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Methods	Multicentre 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.
Participants	Nulliparous 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.
Interventions	2 g calcium as 500 mg calcium carbonate tablets, vs identical looking placebo tablets. Compliance was 84% (calcium) and 86% (placebo).
Outcomes	Gestational hypertension (DBP 90 or more; SBP 140 or more mmHg, on 2 occasions 6 hours apart); pre-eclampsia (gestational hypertension + proteinuria > 0.3 g/L on 2 random urine samples 6 hours apart); BP measured with random-zero sphygmomanometers, Korotkoff sound 5. Perinatal death. Follow up: BP > 95th percentile for sex, age and height for children 5-9 years.
Notes	Three 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).
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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CPEP 1997

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Methods	Numbered treatment packs in computer-generated simple randomisation sequence. Loss to follow up: calcium 132/2,295 vs placebo 121/2,294.
Participants	Pregnant nulliparas (45% black, 35% non-Hispanic white, 17% Hispanic white). Passed compliance test (took 75% of placebo over 6-14 days); BP 134/84 mmHg or less; urine protein dipstick negative or trace; 13-21 weeks pregnant. Exclusion criteria: taking medications; obstetric or pre-existing diseases or personal characteristics which could influence study end-points, absorption or metabolism of calcium; any risk associated with calcium supplementation, or compliance; elevated serum creatinine (1.0 mg per decilitre or more) or calcium (10.6 mg per decilitre or more); renal disease; haematuria; history or family history of urolithiasis; frequent use of calcium supplements or antacids. Of 11,959 women screened, 5,703 excluded initially and a further 1,667 after the compliance test. The remaining 4,589 women were enrolled.
Interventions	2 g/day elemental calcium as calcium carbonate, or placebo. Taken until delivery, development of pre-eclampsia or suspicion of urolithiasis. All women took 50 mg calcium per day as normal supplementation and were asked to drink 6 glasses of water per day. Compliance was 64% in the calcium group and 67% in the placebo group. 20% of women took > 90% of the allocated treatment.
Outcomes	Gestational hypertension (DBP sitting, fifth Korotkoff sound unless zero, 90 mmHg or more on 2 occasions, 4 hours-1 week apart); severe gestational hypertension (DBP 110 mmHg twice or treated, or complications); proteinuria (300 mg/24 hours or more, 1+ on 2 occasions 4 hours-1 week apart, 2+ or more, or protein/creatinine ratio 0.35 or more); pre-eclampsia (gestational hypertension + proteinuria within 7 days of each other); severe pre-eclampsia (50/2163 vs 59/2173); renal insufficiency (21/2163 vs 23/2173); urolithiasis (1/2163 vs 3/2173); prematurity (< 37 weeks); baby small for gestational age (124/2163 vs 105/2173); perinatal death. A limited follow up of mothers and infants found reduced systolic blood pressure at two years of age in the calcium supplementation group (Mean 95.4 mmHg, SD 7.6, n = 35 vs 100.2, 7.9, n = 18). The data have not been included in this review because the low and unequal follow-up rate (35 and 18 from 497 invited to participate) limit the reliability of the results.
Notes	Multicentre 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.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Crowther 1999

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Methods	Central telephone randomisation, stratified by centre using variable blocks. Double-blind.
Participants	Inclusion 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.
Interventions	Calcium carbonate 1.8 g daily or lactose placebo tablets, from 20-24 weeks till birth.
Outcomes	Primary: 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.
Notes	Five hospitals in Australia. August 1992 to December 1996. Estimated sample size 948. Trial stopped prematurely for financial reasons. 31% in the calcium group and 24% in the placebo group stopped taking the tablets during the trial. Analysis was by intention to treat.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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L-Jaramillo 1989

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Methods	Assigned 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.
Participants	Inclusion 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.
Interventions	Calcium supplementation with 4 calcium gluconate tablets daily, each containing 500 mg elemental calcium, from after 23 weeks' gestation till delivery, vs identical placebo tablets.
Outcomes	Gestational 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).
Notes	Quito, Ecuador (altitude 2800 m). 1984 to 1986. An earlier report of apparently the same study gave an incidence of gestational hypertension of calcium 3/46 vs placebo 13/46 (Lopez-Jaramillo 1987).
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	D - Not used

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L-Jaramillo 1990

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Methods	Randomised, double-blind trial. Stated "Each patient was assigned independently in sequence", and "All women completed the study".
Participants	Healthy nulliparous women with positive roll-over test at 28-30 weeks' gestational age - judged at high risk for gestational hypertension.
Interventions	2,000 mg elemental calcium daily, from 28-32 weeks to delivery, vs placebo starch tablets.
Outcomes	Gestational hypertension (BP > 140/90 mmHg on 2 occasions 6 hours apart); proteinuria (300 mg/L); duration of pregnancy (calcium mean 39.2 (SD 1.2) vs placebo 37.4 (2.3) weeks); birthweight (2936 (396) vs 2685 (427) g).
Notes	Quito, Ecuador (altitude 2800 m). Large discrepancy in size of groups not accounted for.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	B - Unclear

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L-Jaramillo 1997

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Methods	Prospective, 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.
Participants	Inclusion 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.
Interventions	Elemental calcium 2 g daily as calcium carbonate from 20 weeks (n = 134), versus placebo tablets (n = 140).
Outcomes	Pre-eclampsia (BP > 140/90 mmHg on 2 occasions > 6 hours apart, and proteinuria > 300 mg/L (> 1+ on dipstick on 2 occasions 4-24 hours apart). BP recorded as mean of 2 measurements, 2 minutes apart, in the right arm, in the sitting position (1st and 5th Korotkoff sounds). Maternal serum ionised calcium at 38 weeks was calcium group mean 1.23, SD 0.02 mM vs placebo 1.16, 0.02; umbilical cord serum ionised calcium levels were calcium 1.44, 0.04 vs placebo 1,37, 0.03; gestational length was calcium 39.6, 0.4 versus placebo 38.7, 0.3.
Notes	Quito, Ecuador (altitude 2800 m). 1990 to 1995.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Niromanesh 2001

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Methods	Double-blind, placebo controlled clinical trial. Women were "randomly assigned".
Participants	Women at high risk for pre-eclampsia: positive 'roll-over' test and at least one risk factor for pre-eclampsia; 28-32 weeks' pregnant; blood pressure < 140/90 mmHg. Exclusion criteria: chronic medical conditions. Not defined as low- or adequate calcium intake (from table 1 dairy intake appears to be about 200 ml + 400 g per day).
Interventions	Elemental calcium 2 g daily (500 mg 6-hourly) or placebo, coded by the pharmacy.
Outcomes	Pre-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 g); weekly maternal weight increase (no difference).
Notes	No loss to follow up.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Purwar 1996

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Methods	Prospective, randomised, double-blind, placebo-controlled trial. Allocated by means of a computer-generated randomisation list. After randomisation, 11/201 (5.5%) women lost to follow up (calcium 6, placebo 5).
Participants	Calcium intake mean 336 mg (calcium) and 352 mg (placebo group) per day. Inclusion criteria: nulliparity; normal single viable pregnancy; known dates; antenatal clinic before 20 weeks; intending to deliver in the same institute; normal glucose tolerance test; no hypertension; no underlying medical disorders. Exclusion criteria: renal disease; collagen vascular disease; chronic hypertension; endocrinological disease; taking medication.
Interventions	Oral calcium containing 2 g elemental calcium daily (n = 103), compared with identical placebo tablets (n = 98), taken from 20 weeks.
Outcomes	Gestational hypertension (SBP > 140 mmHg and DBP > 90 mmHg, twice 6 hours apart) and pre-eclampsia (hypertension + proteinuria =/> 0.3 g/24 hours).
Notes	Nagpur, India.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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S-Ramos 1994

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Methods	Double-blind placebo-controlled trial. Randomisation by computer-generated list. Outcome data entered before breaking the code. 4/33 allocated calcium lost to follow up.
Participants	Normotensive 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.
Interventions	Calcium supplementation with 2 g per day elemental calcium as 500 mg calcium carbonate tablets, versus identical placebo tablets. Compliance checked with electronic pillboxes. Compliance was 79% vs 81%.
Outcomes	Gestational hypertension (BP at least 140/90 mmHg on 2 occasions 4-6 hours apart, on bedrest in hospital); pre-eclampsia (gestational hypertension + proteinuria: 1+ or 300 mg/24 hours); severe pre-eclampsia (pre-eclampsia plus one of BP at least 160 mmHg systolic or 110 mmHg diastolic; proteinuria at least 5 g/24 hours; oliguria < 400 ml per day; elevated liver enzymes; thrombocytopenia < 100,000/microlitre; pulmonary oedema; severe epigastric pain). Birthweight (calcium 3245 (SD 414) vs placebo 3035 (542) g); mean gestational ages (35.6 vs 34.4 weeks); 5 minute Apgar < 7 (1/29 vs 1/34); cord arterial pH (7.25 (0.07) vs 7.20 (0.07)); fetal growth impairment (2/29 vs 4/34).
Notes	Jacksonville, Florida, USA. University hospital serving low-income population.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Villar 1987

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Methods	Double-blind, randomised controlled trial. Random numbers in closed envelopes.
Participants	Inclusion criteria: nulliparous or primiparous; known menstrual dates; age 18-30 years; singleton pregnancy; negative roll-over test. Exclusion criteria: underlying medical disorders. Mean calcium intake at 26 weeks was; calcium group: 1129 (SD 736) and placebo group 914 (478).
Interventions	Calcium 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.
Outcomes	Weight gain in last trimester of pregnancy; BP increase; gestational hypertension.
Notes	Recruitment 1983-1985. 34 black women from John Hopkins Hospital, Baltimore, USA, 18 white women from Rosario, Argentina.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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Villar 1990

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Methods	Double-blind, randomised trial. Allocation by opaque envelopes, ordered by a computer-generated list of random numbers.
Participants	Pregnant women 17 years or younger; no underlying medical disorders; most were nulliparous with known last menstrual period and singleton pregnancy.
Interventions	2 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.
Outcomes	Preterm 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%).
Notes	John Hopkins Hospital, Baltimore, 1985-1988.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Unclear	D - Not used

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WHO 2006

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Methods	Double-blind, randomised trial. Randomisation stratified by centre, with computer generated blocks of 6-8. Allocation by consecutively numbered treatment packs containing calcium tablets or identical placebo. Treatment packs were prepared centrally.
Participants	Populations with median daily calcium intake < 600 mg; Primiparous women less than 20 weeks pregnant. Exclusion criteria: renal disease or urolithiasis; parathyroid disease; blood pressure > 140 mmHg systolic or > 90 mmHg diastolic; history of hypertension; antihypertensive therapy; diuretic, digoxin, phenytoin or tetracycline treatment.
Interventions	Chewable calcium carbonate tablets with 500 mg elemental calcium, 3 daily, or identical placebo, from enrolment till delivery.
Outcomes	Primary outcomes: preeclampsia (blood pressure diastolic 90 mmHg or more, or systolic 140 mmHg or more, plus proteinuria 2+ on dipsticks or 300 mg per day; preterm birth (< 37 weeks). Secondary outcomes: severe pre-eclampsia (diastolic 110 mmHg or more or systolic 160 mmHg or more); early onset pre-eclampsia (< 32 weeks), pregnancy induced hypertension; eclampsia; placental abruption; birthweight < 2500 g; spontaneous preterm delivery; medically indicated preterm delivery; admission to neonatal ICU for > 2 days; fetal, neonatal and perinatal mortality (before discharge from hospital).
Notes	Multicentre trial in Argentina, Egypt, India, Peru, South Africa and Vietnam. 14,362 women screened, 8325 randomised. Exclusions: 6 calcium (4 not pregnant, 2 lost before treatment started) and 7 placebo (5 not pregnant, 2 lost before treatment started). Loss to follow up: 143 and 155 in calcium and placebo group respectively (some data available on women not followed up to delivery). Treatment compliance 84.5% and 86.2% respectively. Baseline characteristics well matched.
Risk of bias
Item	Authors' judgement	Description
Allocation concealment?	Yes	A - Adequate

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

 

Characteristics of excluded studies [ordered by study ID]

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Study	Reason for exclusion
Almirante 1998	The method of allocation is not clear from the abstract.
August 2002	Excluded pending full report of results. Inadequate data in abstracts for inclusion.
Belizan 1983	N = 36. No clinically important outcomes presented in format suitable for inclusion in this review. Participants: healthy, 20-35 years, singleton pregnancy. Intervention: calcium 1 g (n = 11), calcium 2 g (n = 11) or placebo (n = 14). Outcomes: DBP 20-24 weeks, and in the third trimester. Study design: randomised, no further information.
Boggess 1997	N = 23. After randomisation, 5/23 (22%) were excluded. Participants: 18-35 years. Excluded if BP > 140/90 mmHg at 24 weeks; smokers; illicit drug use; multiple pregnancy; cardiovascular renal or endocrine disease; hypertension in previous pregnancy; calcium supplementation > 200-250 mg elemental calcium. Intervention: oral calcium carbonate 1.5 g/day for 6 weeks from 28-31 weeks, or placebo tablets. All had 200-250 mg calcium in standard prenatal vitamin-mineral preparations. Outcomes: gestational hypertension (BP at least 140.90 mmHg on 2 occasions, 6 hours apart); pre-eclampsia (gestational hypertension plus at least 1+ proteinuria) Study design: randomised trial. Randomisation schedule in balanced blocks of 10.
Chames 2002	Excluded pending publication of full report. No relevant clinical outcomes reported in the abstract. No difference found in blood lead levels between women receiving calcium 1000 mg daily from 13-19 weeks (n = 24) or placebo (n = 26).
Cong 1995	Beijing Obstetrics and Gynecology Hospital. 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 1991	Excluded 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 1998	Excluded because the intervention was a combination of calcium and linoleic acid.
Kawasaki 1985	N = 94. Not a randomised trial. Interventions: calcium L-aspartate 600 mg/day from 20 weeks to delivery (n = 22) vs no supplementation (n = 72). Outcomes: pregnancy-induced hypertension.
Knight 1992	Excluded because no clinically relevant outcomes reported, placebo not used, and participants not followed till delivery. Normotensive (n = 30 and hypertensive (BP 140/85 mmHg or more, n = 20) nulliparous women "randomly allocated" to receive calcium 1 gram from about 12 weeks to 32 weeks, or a control group. Follow up continued to 36 weeks. Mean diastolic blood pressure reduced in the hypertensive group receiving calcium.
Lavin 1986	Planned trial of calcium versus placebo in women with a positive roll-over test at 28-32 weeks. Trial apparently cancelled.
Marya 1987	N = 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 1990	N = 170. No placebo. Participants: normotensive at 24 weeks' pregnancy. Interventions: calcium 2 g/day from 24 weeks to delivery. Outcomes: pregnancy induced hypertension, pre-eclampsia. Study design: "randomised, single-blinded trial".
Prada 2001	Excluded pending publication of full report. Abstract does not include outcomes specified for this review. Mean blood pressure was reduced in adolescents receiving calcium supplementation 1000 mg daily (n = 62) compared with placebo (n = 62). Not clear whether participants in this report include participants from Prada 2002.
Prada 2002	Excluded pending publication of full report. Abstract does not include outcomes specified for this review. Mean blood pressure was similar in adolescents and women with twin pregnancy receiving calcium supplementation 1000 mg daily (n = 94) compared with placebo (n = 93). Not clear whether participants in this report include participants from Prada 2001.
Raman 1978	N = 273. Allocation was by strict rotation, a quasi-randomised trial. Supplementation with < 1 g/day.
Repke 1989	N = 255. Presented as abstract only. No clinical data available. Interventions: calcium 2 g/day vs placebo, after 20 weeks of pregnancy. Study design: 'randomised clinical trial'.
Rogers 1999	Excluded because: (1) randomisation performed "using five unsealed envelopes"; unequal group numbers suggested that 'something went wrong with the randomisation process'; (2) no placebo used; (3) initial calcium dose 600 mg per day (1200 mg per day after 32 weeks); (4) 10% loss to follow up. Hypertension alone occurred in 21/144 women who received calcium compared with 18/75 controls; pre-eclampsia in 8/144 vs 7/75 respectively.
S-Ramos 1995	N = 75. Excluded because calcium used for treatment of women with pre-eclampsia rather than prevention. Participants: nulliparous, gestation 24-36 weeks; mild pre-eclampsia (BP 140/90-160/100, proteinuria at least 300 mg/day). Interventions: calcium 2 g/day elemental calcium (four tablets of calcium carbonate 1250 mg), versus matching placebo. Outcomes: initial and last BP and biochemical markers; preterm delivery; caesarean section; severe pre-eclampsia; gestation at delivery; birthweight; Apgar < 7 at 1 minute and 5 minutes; cord arterial pH < 7.16; fetal growth restriction; perinatal death. Study design: double-blind, placebo-controlled study using a computer-generated random number list.
Suzuki 1996	N = 152. Not a randomised trial. Interventions: calcium 1 g/day from 20 weeks vs no calcium. Outcomes: pre-eclampsia, gestational hypertension.
Taherian 2002	Inclusion citeria not met: not placebo-controlled, calcium dose < 1 g. Three-way comparison between calcium 500 mg, low-dose aspirin and no treatment. Pre-eclampsia diagnosed in 13/330, 15/330 and 33/330 respectively.
Tamas 1997	Study of treatment of gestational hypertension, not prevention, using the drug dobesilate calcium, not calcium supplementation.
Wanchu 2001	No 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.

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

 

Characteristics of ongoing studies [ordered by study ID]

Mahomed 1998

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Trial name or title	Calcium supplementation for the prevention of pregnancy induced hypertension and preterm labour in twin pregnancies: a randomised controlled trial.
Methods
Participants	Women with twin pregnancy.
Interventions	Calcium solution (1 g elemental calcium per 5 ml).
Outcomes	Pregnancy-induced hypertension, preterm labour, perinatal mortality and short-term morbidity, maternal morbidity.
Starting date	Not stated.
Contact information	Prof K Mahomed.
Notes	Sample size 400 per group.

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Comparison 1. Routine calcium supplementation in pregnancy by baseline dietary calcium

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Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

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 1 High blood pressure (with or without proteinuria)

11

14946

Risk Ratio (M-H, Random, 95% CI)

0.70 [0.57, 0.86]

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1.1 Adequate calcium diet

4

5022

Risk Ratio (M-H, Random, 95% CI)

0.90 [0.81, 0.99]

---

1.2 Low calcium diet

6

9894

Risk Ratio (M-H, Random, 95% CI)

0.47 [0.29, 0.76]

---

1.3 Dietary calcium not specified

1

30

Risk Ratio (M-H, Random, 95% CI)

0.91 [0.57, 1.45]

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 2 Pre-eclampsia

12

15206

Risk Ratio (M-H, Random, 95% CI)

0.48 [0.33, 0.69]

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2.1 Adequate calcium diet

4

5022

Risk Ratio (M-H, Random, 95% CI)

0.62 [0.32, 1.20]

---

2.2 Low calcium diet

7

10154

Risk Ratio (M-H, Random, 95% CI)

0.36 [0.18, 0.70]

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2.3 Dietary calcium not specified

1

30

Risk Ratio (M-H, Random, 95% CI)

0.14 [0.02, 1.02]

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 3 Maternal death/serious morbidity

4

9732

Risk Ratio (M-H, Fixed, 95% CI)

0.80 [0.65, 0.97]

---

3.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

3.3 Low calcium diet

4

9732

Risk Ratio (M-H, Fixed, 95% CI)

0.80 [0.65, 0.97]

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 4 Placental abruption

5

14309

Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.55, 1.34]

---

4.1 Adequate calcium diet

3

4830

Risk Ratio (M-H, Fixed, 95% CI)

0.81 [0.39, 1.68]

---

4.3 Low calcium diet

2

9479

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.51, 1.56]

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 5 Caesarean section

7

14710

Risk Ratio (M-H, Fixed, 95% CI)

0.95 [0.88, 1.01]

---

5.1 Adequate calcium diet

3

4981

Risk Ratio (M-H, Fixed, 95% CI)

0.95 [0.84, 1.07]

---

5.3 Low calcium diet

4

9729

Risk Ratio (M-H, Fixed, 95% CI)

0.94 [0.87, 1.03]

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 6 Proteinuria (gestational with no proteinuria

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

1.04 [0.86, 1.26]

---

6.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

6.2 Low calcium diet

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

1.04 [0.86, 1.26]

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 7 Severe pre-eclamsia

1

8302

Risk Ratio (M-H, Fixed, 95% CI)

0.74 [0.48, 1.15]

---

7.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

7.2 Low calcium diet

1

8302

Risk Ratio (M-H, Fixed, 95% CI)

0.74 [0.48, 1.15]

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 8 Eclampsia

2

12901

Risk Ratio (M-H, Fixed, 95% CI)

0.73 [0.41, 1.27]

---

8.1 Adequate calcium diet

1

4589

Risk Ratio (M-H, Fixed, 95% CI)

1.00 [0.25, 3.99]

---

8.2 Low calcium diet

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

0.68 [0.37, 1.26]

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 9 HELLP syndrome

2

12901

Risk Ratio (M-H, Fixed, 95% CI)

2.67 [1.05, 6.82]

---

9.1 Adequate calcium diet

1

4589

Risk Ratio (M-H, Fixed, 95% CI)

3.50 [0.73, 16.82]

---

9.2 Low calcium diet

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

2.26 [0.70, 7.32]

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 10 ICU admission

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

0.84 [0.66, 1.07]

---

10.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

10.2 Low calcium diet

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

0.84 [0.66, 1.07]

---

 11 Maternal death

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

0.17 [0.02, 1.39]

---

11.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

11.2 Low calcium diet

1

8312

Risk Ratio (M-H, Fixed, 95% CI)

0.17 [0.02, 1.39]

---

 13 Preterm birth

10

14751

Risk Ratio (M-H, Random, 95% CI)

0.81 [0.64, 1.03]

---

13.1 Adequate calcium diet

4

5033

Risk Ratio (M-H, Random, 95% CI)

0.59 [0.26, 1.33]

---

13.3 Low calcium diet

6

9718

Risk Ratio (M-H, Random, 95% CI)

0.90 [0.80, 1.02]

---

 14 Birthweight < 2500 g

8

14359

Risk Ratio (M-H, Random, 95% CI)

0.84 [0.68, 1.03]

---

14.1 Adequate calcium diet

4

5033

Risk Ratio (M-H, Random, 95% CI)

0.59 [0.31, 1.13]

---

14.3 Low calcium diet

4

9326

Risk Ratio (M-H, Random, 95% CI)

0.97 [0.86, 1.08]

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 15 Neonate small-for-gestational age as defined by trial authors

3

13091

Risk Ratio (M-H, Fixed, 95% CI)

1.10 [0.88, 1.37]

---

15.1 Adequate calcium diet

1

4589

Risk Ratio (M-H, Fixed, 95% CI)

1.18 [0.92, 1.52]

---

15.3 Low calcium diet

2

8502

Risk Ratio (M-H, Fixed, 95% CI)

0.90 [0.59, 1.38]

---

 16 Admission to neonatal intensive care unit

4

13406

Risk Ratio (M-H, Fixed, 95% CI)

1.05 [0.94, 1.18]

---

16.1 Adequate calcium diet

1

4336

Risk Ratio (M-H, Fixed, 95% CI)

1.09 [0.95, 1.26]

---

16.3 Low calcium diet

3

9070

Risk Ratio (M-H, Fixed, 95% CI)

0.98 [0.81, 1.19]

---

 18 Stillbirth or death before discharge from hospital

10

15141

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.73, 1.09]

---

18.1 Adequate calcium diet

4

5033

Risk Ratio (M-H, Fixed, 95% CI)

1.12 [0.66, 1.90]

---

18.3 Low calcium diet

6

10108

Risk Ratio (M-H, Fixed, 95% CI)

0.86 [0.69, 1.06]

---

 21 Childhood systolic blood pressure > 95th percentile

1

514

Risk Ratio (M-H, Fixed, 95% CI)

0.59 [0.39, 0.91]

---

21.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

21.3 Low calcium diet

1

514

Risk Ratio (M-H, Fixed, 95% CI)

0.59 [0.39, 0.91]

---

 22 Childhood diastolic blood pressure > 95th percentile

1

514

Risk Ratio (M-H, Fixed, 95% CI)

0.81 [0.50, 1.31]

---

22.1 Adequate calcium diet

0

0

Risk Ratio (M-H, Fixed, 95% CI)

Not estimable

---

22.3 Low calcium diet

1

514

Risk Ratio (M-H, Fixed, 95% CI)

0.81 [0.50, 1.31]

---

 

Comparison 2. Routine calcium supplementation in pregnancy by hypertension risk

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 High blood pressure (with or without proteinuria)

11

14946

Risk Ratio (M-H, Random, 95% CI)

0.70 [0.57, 0.86]

---

1.1 Low-risk women

7

14619

Risk Ratio (M-H, Random, 95% CI)

0.78 [0.64, 0.95]

---

1.2 High-risk women

4

327

Risk Ratio (M-H, Random, 95% CI)

0.47 [0.22, 0.97]

---

 2 Pre-eclampsia

12

15206

Risk Ratio (M-H, Random, 95% CI)

0.48 [0.33, 0.69]

---

2.1 Low-risk women

7

14619

Risk Ratio (M-H, Random, 95% CI)

0.68 [0.49, 0.94]

---

2.2 High-risk women

5

587

Risk Ratio (M-H, Random, 95% CI)

0.22 [0.12, 0.42]

---

 13 Preterm birth

10

14751

Risk Ratio (M-H, Random, 95% CI)

0.81 [0.64, 1.03]

---

13.1 Low-risk women

6

14183

Risk Ratio (M-H, Random, 95% CI)

0.91 [0.74, 1.12]

---

13.2 High-risk women

4

568

Risk Ratio (M-H, Random, 95% CI)

0.45 [0.24, 0.83]

---

 16 Admission to neonatal intensive care unit

4

13406

Risk Ratio (M-H, Fixed, 95% CI)

1.05 [0.94, 1.18]

---

16.1 Low-risk women

3

13343

Risk Ratio (M-H, Fixed, 95% CI)

1.06 [0.94, 1.19]

---

16.2 High-risk women

1

63

Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.03, 2.48]

---

 18 Stillbirth or death before discharge from hospital

10

15141

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.73, 1.09]

---

18.1 Low-risk women

7

14629

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.73, 1.09]

---

18.2 High-risk women

3

512

Risk Ratio (M-H, Fixed, 95% CI)

0.39 [0.02, 9.20]

---

 

Comparison 3. Routine calcium supplementation in pregnancy by study sample size

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 1 High blood pressure (with or without proteinuria)

11

14946

Risk Ratio (M-H, Random, 95% CI)

0.70 [0.57, 0.86]

---

1.1 Studies with < 400 participants

7

675

Risk Ratio (M-H, Random, 95% CI)

0.38 [0.21, 0.68]

---

1.2 Studies with =/> 400 participants

4

14271

Risk Ratio (M-H, Random, 95% CI)

0.90 [0.81, 1.00]

---

 2 Pre-eclampsia

12

15206

Risk Ratio (M-H, Random, 95% CI)

0.48 [0.33, 0.69]

---

2.1 Studies with < 400 participants

8

935

Risk Ratio (M-H, Random, 95% CI)

0.21 [0.12, 0.36]

---

2.2 Studies with =/> 400 participants

4

14271

Risk Ratio (M-H, Random, 95% CI)

0.85 [0.69, 1.05]

---

 13 Preterm birth

10

14751

Risk Ratio (M-H, Random, 95% CI)

0.81 [0.64, 1.03]

---

13.1 Studies with < 400 participants

6

810

Risk Ratio (M-H, Random, 95% CI)

0.43 [0.24, 0.76]

---

13.2 Studies with =/> 400 participants

4

13941

Risk Ratio (M-H, Random, 95% CI)

0.93 [0.76, 1.13]

---

 16 Admission to neonatal intensive care unit

4

13406

Risk Ratio (M-H, Fixed, 95% CI)

1.05 [0.94, 1.18]

---

16.1 Studies with < 400 participants

1

63

Risk Ratio (M-H, Fixed, 95% CI)

0.29 [0.03, 2.48]

---

16.2 Studies with =/> 400 participants

3

13343

Risk Ratio (M-H, Fixed, 95% CI)

1.06 [0.94, 1.19]

---

 18 Stillbirth or death before discharge from hospital

10

15141

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.73, 1.09]

---

18.1 Studies with < 400 participants

6

846

Risk Ratio (M-H, Fixed, 95% CI)

0.39 [0.02, 9.20]

---

18.2 Studies with =/> 400 participants

4

14295

Risk Ratio (M-H, Fixed, 95% CI)

0.89 [0.73, 1.09]

---

 

Comparison 4. Routine calcium supplementation in pregnancy by baseline dietary calcium and study sample size

---

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

---

 2 Pre-eclampsia

12

15206

Risk Ratio (M-H, Random, 95% CI)

0.48 [0.33, 0.69]

---

2.1 Adequate calcium/small study

2

230

Risk Ratio (M-H, Random, 95% CI)

0.26 [0.04, 1.50]

---

2.2 Adequate calcium/large study

2

4792

Risk Ratio (M-H, Random, 95% CI)

0.70 [0.33, 1.46]

---

2.3 Low calcium/small study

5

675

Risk Ratio (M-H, Random, 95% CI)

0.21 [0.12, 0.38]

---

2.4 Low calcium/large study

2

9479

Risk Ratio (M-H, Random, 95% CI)

0.89 [0.74, 1.09]

---

2.5 Dietary calcium not specified

1

30

Risk Ratio (M-H, Random, 95% CI)

0.14 [0.02, 1.02]

---