Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

G Justus Hofmeyr; Theresa A Lawrie; Álvaro N Atallah; Maria Regina Torloni

doi:10.1002/14651858.CD001059.pub5

. 2018 Oct 1;2018(10):CD001059. doi: 10.1002/14651858.CD001059.pub5

Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

G Justus Hofmeyr ^1,^✉, Theresa A Lawrie ², Álvaro N Atallah ³, Maria Regina Torloni ³

Editor: Cochrane Pregnancy and Childbirth Group

PMCID: PMC6517256 PMID: 30277579

Abstract

Background

Pre‐eclampsia and eclampsia are common causes of serious morbidity and death. Calcium supplementation may reduce the risk of pre‐eclampsia, and may help to prevent preterm birth. This is an update of a review last published in 2014.

Objectives

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

Search methods

We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (18 September 2017), and reference lists of retrieved studies.

Selection criteria

We included randomised controlled trials (RCTs), including cluster‐randomised trials, comparing high‐dose calcium supplementation (at least 1 g daily of calcium) during pregnancy with placebo. For low‐dose calcium we included quasi‐randomised trials, trials without placebo, trials with cointerventions and dose comparison trials.

Data collection and analysis

Two researchers independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Two researchers assessed the evidence using the GRADE approach.

Main results

We included 27 studies (18,064 women). We assessed the included studies as being at low risk of bias, although bias was frequently difficult to assess due to poor reporting and inadequate information on methods.

High‐dose calcium supplementation (≥ 1 g/day) versus placebo

Fourteen studies examined this comparison, however one study contributed no data. The 13 studies contributed data from 15,730 women to our meta‐analyses. The average risk of high blood pressure (BP) was reduced with calcium supplementation compared with placebo (12 trials, 15,470 women: risk ratio (RR) 0.65, 95% confidence interval (CI) 0.53 to 0.81; I² = 74%). There was also a reduction in the risk of pre‐eclampsia associated with calcium supplementation (13 trials, 15,730 women: average RR 0.45, 95% CI 0.31 to 0.65; I² = 70%; low‐quality evidence). This effect was clear for women with low calcium diets (eight trials, 10,678 women: average RR 0.36, 95% CI 0.20 to 0.65; I² = 76%) but not those with adequate calcium diets. The effect appeared to be greater for women at higher risk of pre‐eclampsia, though this may be due to small‐study effects (five trials, 587 women: average RR 0.22, 95% CI 0.12 to 0.42). These data should be interpreted with caution because of the possibility of small‐study effects or publication bias. In the largest trial, the reduction in pre‐eclampsia was modest (8%) and the CI included the possibility of no effect.

The composite outcome maternal death or serious morbidity was reduced with calcium supplementation (four trials, 9732 women; RR 0.80, 95% CI 0.66 to 0.98). Maternal deaths were no different (one trial of 8312 women: one death in the calcium group versus six in the placebo group). There was an anomalous increase in the risk of HELLP syndrome in the calcium group (two trials, 12,901 women: RR 2.67, 95% CI 1.05 to 6.82, high‐quality evidence), however, the absolute number of events was low (16 versus six).

The average risk of preterm birth was reduced in the calcium supplementation group (11 trials, 15,275 women: RR 0.76, 95% CI 0.60 to 0.97; I² = 60%; low‐quality evidence); this reduction was greatest amongst women at higher risk of developing pre‐eclampsia (four trials, 568 women: average RR 0.45, 95% CI 0.24 to 0.83; I² = 60%). Again, these data should be interpreted with caution because of the possibility of small‐study effects or publication bias. There was no clear effect on admission to neonatal intensive care. There was also no clear effect on the risk of stillbirth or infant death before discharge from hospital (11 trials, 15,665 babies: RR 0.90, 95% CI 0.74 to 1.09).

One study showed a reduction in childhood systolic BP greater than 95th percentile among children exposed to calcium supplementation in utero (514 children: RR 0.59, 95% CI 0.39 to 0.91). In a subset of these children, dental caries at 12 years old was also reduced (195 children, RR 0.73, 95% CI 0.62 to 0.87).

Low‐dose calcium supplementation (< 1 g/day) versus placebo or no treatment

Twelve trials (2334 women) evaluated low‐dose (usually 500 mg daily) supplementation with calcium alone (four trials) or in association with vitamin D (five trials), linoleic acid (two trials), or antioxidants (one trial). Most studies recruited women at high risk for pre‐eclampsia, and were at high risk of bias, thus the results should be interpreted with caution. Supplementation with low doses of calcium reduced the risk of pre‐eclampsia (nine trials, 2234 women: RR 0.38, 95% CI 0.28 to 0.52). There was also a reduction in high BP (five trials, 665 women: RR 0.53, 95% CI 0.38 to 0.74), admission to neonatal intensive care unit (one trial, 422 women, RR 0.44, 95% CI 0.20 to 0.99), but not preterm birth (six trials, 1290 women, average RR 0.83, 95% CI 0.34 to 2.03), or stillbirth or death before discharge (five trials, 1025 babies, RR 0.48, 95% CI 0.14 to 1.67).

High‐dose (=/> 1 g) versus low‐dose (< 1 g) calcium supplementation

We included one trial with 262 women, the results of which should be interpreted with caution due to unclear risk of bias. Risk of pre‐eclampsia appeared to be reduced in the high‐dose group (RR 0.42, 95% CI 0.18 to 0.96). No other differences were found (preterm birth: RR 0.31, 95% CI 0.09 to 1.08; eclampsia: RR 0.32, 95% CI 0.07 to 1.53; stillbirth: RR 0.48, 95% CI 0.13 to 1.83).

Authors' conclusions

High‐dose calcium supplementation (≥ 1 g/day) may reduce the risk of pre‐eclampsia and preterm birth, particularly for women with low calcium diets (low‐quality evidence). The treatment effect may be overestimated due to small‐study effects or publication bias. It reduces the occurrence of the composite outcome 'maternal death or serious morbidity', but not stillbirth or neonatal high care admission. There was an increased risk of HELLP syndrome with calcium supplementation, which was small in absolute numbers.

The limited evidence on low‐dose calcium supplementation suggests a reduction in pre‐eclampsia, hypertension and admission to neonatal high care, but needs to be confirmed by larger, high‐quality trials.

Plain language summary

Calcium supplementation during pregnancy for preventing blood pressure disorders and related problems

What is the issue?

Pre‐eclampsia is evident as high blood pressure and protein in the urine. It is a major cause of death in pregnant women and newborn babies worldwide. Preterm birth (birth before 37 weeks) is often caused by high blood pressure and is the leading cause of newborn deaths, particularly in low‐income countries.

Why is this important?

Evidence from randomised controlled trials shows that calcium supplements help prevent pre‐eclampsia and preterm birth and lower the risk of a woman dying or having serious problems related to high blood pressure in pregnancy. This is particularly for women on low calcium diets.

What evidence did we find?

We searched for evidence on 18 September 2017, and found 27 trials. We found evidence from 13 studies (involving 15,730 women) that calcium supplementation in high doses (at least 1 gram (g) daily) during pregnancy may be a safe way of reducing the risk of pre‐eclampsia, especially in women from communities with low dietary calcium and those at increased risk of pre‐eclampsia. Women receiving calcium supplements may also be less likely to die or have serious problems related to pre‐eclampsia (low‐quality evidence) and high blood pressure. Babies may be less likely to be born preterm (low‐quality evidence). The syndrome of haemolysis, elevated liver enzymes and low platelets was increased with calcium, but the absolute numbers were small (high‐quality evidence). High‐dose calcium did not have a clear effect on babies admitted to neonatal intensive care, or the number of stillbirths or deaths before discharge from hospital.

Further research is needed into the ideal dosage of supplementation. Limited evidence from 12 trials (2334 women) suggested that a relatively low dose of calcium may be effective in reducing pre‐eclampsia, high blood pressure, and babies admitted to intensive care (however, the quality of the evidence on calcium alone was reduced because eight of the included trials gave other medicines alongside calcium, such as vitamin D, linoleic acid or antioxidants). Low‐dose calcium did not have a clear effect on preterm birth, stillbirth or death before discharge from hospital.

One small study compared high‐dose calcium with low‐dose calcium. Pre‐eclampsia appeared to be reduced in the high‐dose group, but no other differences were found in preterm birth, or stillbirth.

What does this mean?

In settings where dietary calcium is low, supplementation is an important strategy to reduce the serious consequences of pre‐eclampsia. Where high‐dose supplementation is not feasible, the option of lower dose supplements (500 milligrams (mg) to 600 mg daily) might be considered in preference to no supplementation.

Summary of findings

for the main comparison.

Calcium supplementation compared with placebo for preventing hypertensive disorders and related problems in pregnancy
Patient or population: pregnant women Settings: outpatient Intervention: high‐dose calcium (≥ 1 g/day) Comparison: placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect  (95% CI)	No of participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	No calcium	Calcium
Pre‐eclampsia	Overall		RR 0.45 (0.31 to 0.65) RR 0.36 (0.20 to 0.65) RR 0.22 (0.12 to 0.42)	15,730  (13) 10,678 (8) 587 (5)	⊕⊕⊝⊝  low¹ ⊕⊕⊝⊝  low¹ ⊕⊕⊝⊝  low¹
	65 per 1000	29 per 1000  (20 to 42)
	Low‐calcium diet
	57 per 1000	21 per 1000  (11 to 37)
	High‐risk women
	176 per 1000	38 per 1000  (21 to 74)
Preterm birth	Overall		RR 0.76 (0.60 to 0.97)	15,275  (11)	⊕⊕⊝⊝  low¹
	104 per 1000	79 per 1000  (62 to 101)
HELLP syndrome	1 per 1000	3 per 1000	RR 2.67 (1.05 to 6.82)	12,901 (2)	⊕⊕⊕⊕  high
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Date	Event	Description
18 September 2017	New search has been performed	The search was updated and three new trials included (Asemi 2012; Asemi 2016; Khan 2013). A new comparison of high‐dose versus low‐dose calcium has been incorporated into this update.
18 September 2017	New citation required but conclusions have not changed	The review includes a total of 27 trials. The conclusions remain unchanged.

Date	Event	Description
24 May 2013	New citation required and conclusions have changed	Eleven studies have been included for this update (Almirante 1998; Bassaw 1998; Cong 1995; Herrera 1998; Herrera 2006; Jarjou 2004; Li 2000; Marya 1987; Rogers 1999; Rumiris 2006; Taherian 2002).Ten studies of low‐dose calcium added. New meta‐analyses performed. Substantially changed conclusions. Search updated in May 2014, six reports added to Studies awaiting classification (Asemi 2012b; Diogenes 2013; Goldberg 2013; Herrera 2006b; Jarjou 2013; Sulovic 2013a).
28 March 2013	New search has been performed	Search updated. Methods updated.
6 January 2011	Feedback has been incorporated	Feedback from William Stones and Stephen Walkinshaw added with replies from the authors.
5 July 2010	New citation required but conclusions have not changed	New author helped to update the review.
31 May 2010	New search has been performed	Search updated. Fifteen new reports identified: one new study (Kumar 2009) included and four new trials excluded (de Souza 2006; Dizavandy 1998; Herrera 1998a; Karandish 2003).
31 October 2009	Amended	Search updated. Fourteen new reports added to Studies awaiting classification.
1 September 2008	Amended	Converted to new review format.
2 March 2006	New search has been performed	Search updated.
2 March 2006	New citation required and conclusions have changed	A large trial of calcium supplementation in communities with low dietary calcium intake has been added (WHO 2006).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 High blood pressure (with or without proteinuria)	12	15470	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.53, 0.81]
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	7	10418	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.28, 0.70]
1.3 Dietary calcium not specified	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.57, 1.45]
2 Pre‐eclampsia	13	15730	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.31, 0.65]
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	8	10678	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.20, 0.65]
2.3 Dietary calcium not specified	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.02, 1.02]
3 Preterm birth	11	15275	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.60, 0.97]
3.1 Adequate calcium diet	4	5033	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.26, 1.33]
3.2 Low calcium diet	7	10242	Risk Ratio (M‐H, Random, 95% CI)	0.81 [0.64, 1.02]
4 Admission to neonatal intensive care unit	4	13406	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.94, 1.18]
4.1 Adequate calcium diet	1	4336	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.95, 1.26]
4.2 Low calcium diet	3	9070	Risk Ratio (M‐H, Fixed, 95% CI)	0.98 [0.81, 1.19]
5 Stillbirth or death before discharge from hospital	11	15665	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.74, 1.09]
5.1 Adequate calcium diet	4	5033	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.66, 1.90]
5.2 Low calcium diet	7	10632	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.70, 1.07]
6 Maternal death/serious morbidity	4	9732	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.66, 0.98]
6.1 Low calcium diet	4	9732	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.66, 0.98]
6.2 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Placental abruption	5	14336	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.55, 1.34]
7.1 Adequate calcium diet	3	4830	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.39, 1.68]
7.2 Low calcium diet	2	9506	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.51, 1.55]
8 Caesarean section	8	15234	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.89, 1.02]
8.1 Adequate calcium diet	3	4981	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.84, 1.07]
8.2 Low calcium diet	5	10253	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.88, 1.04]
9 Proteinuria (gestational with no proteinuria)	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.86, 1.26]
9.1 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Low calcium diet	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.86, 1.26]
10 Severe pre‐eclampsia	1	8302	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.48, 1.15]
10.1 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Low calcium diet	1	8302	Risk Ratio (M‐H, Fixed, 95% CI)	0.74 [0.48, 1.15]
11 Eclampsia	3	13425	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.41, 1.27]
11.1 Adequate calcium diet	1	4589	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.25, 3.99]
11.2 Low calcium diet	2	8836	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.37, 1.26]
12 HELLP syndrome	2	12901	Risk Ratio (M‐H, Fixed, 95% CI)	2.67 [1.05, 6.82]
12.1 Adequate calcium diet	1	4589	Risk Ratio (M‐H, Fixed, 95% CI)	3.50 [0.73, 16.82]
12.2 Low calcium diet	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	2.26 [0.70, 7.32]
13 Intensive care unit admission	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.66, 1.07]
13.1 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Low calcium diet	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.66, 1.07]
14 Maternal death	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.02, 1.39]
14.1 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 Low calcium diet	1	8312	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.02, 1.39]
15 Low birthweight (birthweight < 2500 g)	9	14883	Risk Ratio (M‐H, Random, 95% CI)	0.85 [0.72, 1.01]
15.1 Adequate calcium diet	4	5033	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.31, 1.13]
15.2 Low calcium diet	5	9850	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.85, 1.05]
16 Neonate small‐for‐gestational age as defined by trial authors	4	13615	Risk Ratio (M‐H, Fixed, 95% CI)	1.05 [0.86, 1.29]
16.1 Adequate calcium diet	1	4589	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.92, 1.52]
16.2 Low calcium diet	3	9026	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.60, 1.21]
17 Systolic blood pressure > 95th percentile during childhood	1	514	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.39, 0.91]
17.1 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
17.2 Low calcium diet	1	514	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.39, 0.91]
18 Diastolic blood pressure > 95th percentile during childhood	1	514	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.50, 1.31]
18.1 Adequate calcium diet	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
18.2 Low calcium diet	1	514	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.50, 1.31]
19 Dental caries in childhood	1	195	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.62, 0.87]
19.1 Low calcium diet	1	195	Risk Ratio (M‐H, Fixed, 95% CI)	0.73 [0.62, 0.87]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia	13	15730	Risk Ratio (M‐H, Random, 95% CI)	0.45 [0.31, 0.65]
1.1 Adequate calcium/small study	2	230	Risk Ratio (M‐H, Random, 95% CI)	0.26 [0.04, 1.50]
1.2 Adequate calcium/large study	2	4792	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.33, 1.46]
1.3 Low calcium/small study	5	675	Risk Ratio (M‐H, Random, 95% CI)	0.21 [0.12, 0.38]
1.4 Low calcium/large study	3	10003	Risk Ratio (M‐H, Random, 95% CI)	0.63 [0.35, 1.14]
1.5 Dietary calcium not specified	1	30	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.02, 1.02]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Uterine artery RI at 32 weeks	1	372	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.02, 0.01]
2 Umbilical artery RI at 32 weeks	1	373	Mean Difference (IV, Fixed, 95% CI)	‐0.01 [‐0.02, 0.01]
3 Low platelet count at 35 weeks	1	667	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.63, 2.18]
4 High serum uric acid at 35 weeks	1	664	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.64, 1.57]
5 High urine protein/creatinine ratio at 35 weeks	1	637	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.76, 1.34]
6 Ultrasound estimate of fetal growth at 32 weeks: femur length (cm)*	1	377	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.04, 0.04]
7 Ultrasound estimate of fetal growth at 32 weeks: biparietal diameter (cm)*	1	377	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.06, 0.06]
8 Ultrasound estimate of fetal growth at 32 weeks: abdominal circumference (cm)*	1	377	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐0.26, 0.26]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 High blood pressure (with or without pre‐eclampsia)	5	665	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.38, 0.74]
1.1 Calcium supplementation alone	3	558	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.39, 0.82]
1.2 Calcium plus vitamin D	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	0.65 [0.24, 1.75]
1.3 Calcium plus linoleic acid	1	48	Risk Ratio (M‐H, Fixed, 95% CI)	0.2 [0.05, 0.82]
2 Pre‐eclampsia	9	2234	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.28, 0.52]
2.1 Calcium supplementation alone	4	980	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.23, 0.57]
2.2 Calcium plus vitamin D	2	1060	Risk Ratio (M‐H, Fixed, 95% CI)	0.49 [0.31, 0.78]
2.3 Calcium plus linoleic acid	2	134	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.09, 0.60]
2.4 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.24 [0.06, 1.01]
3 Preterm birth	6	1290	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.34, 2.03]
3.1 Calcium supplementation alone	1	422	Risk Ratio (M‐H, Random, 95% CI)	0.40 [0.21, 0.75]
3.2 Calcium plus vitamin D	3	760	Risk Ratio (M‐H, Random, 95% CI)	1.59 [1.03, 2.45]
3.3 Calcium plus linoleic acid	1	48	Risk Ratio (M‐H, Random, 95% CI)	0.5 [0.05, 5.15]
3.4 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Random, 95% CI)	0.36 [0.04, 3.23]
4 Admission to neonatal intensive care unit	1	422	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.20, 0.99]
4.1 Calcium supplementation alone	1	422	Risk Ratio (M‐H, Fixed, 95% CI)	0.44 [0.20, 0.99]
4.2 Calcium plus vitamin D	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Calcium plus linoleic acid	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Stillbirth or death before discharge	5	1025	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.14, 1.67]
5.1 Calcium supplementation alone	1	171	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.07, 16.29]
5.2 Calcium plus vitamin D	1	660	Risk Ratio (M‐H, Fixed, 95% CI)	0.2 [0.01, 4.15]
5.3 Calcium plus linoleic acid	2	134	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.08, 4.41]
5.4 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.02, 8.39]
6 Placental abruption	3	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.14, 6.90]
6.1 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Calcium plus vitamin D	2	100	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.14, 6.90]
7 Caesarean section	4	521	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.46, 1.15]
7.1 Calcium supplementation alone	2	387	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.40, 2.22]
7.2 Calcium plus vitamin D	0	0	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
7.3 Calcium plus linoleic acid	2	134	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.35, 0.87]
8 Severe pre‐eclampsia	4	246	Risk Ratio (M‐H, Fixed, 95% CI)	0.40 [0.14, 1.15]
8.1 Calcium supplementation alone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Calcium plus vitamin D	2	100	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.08, 4.39]
8.3 Calcium plus linoleic acid	1	86	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.07, 1.56]
8.4 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.36 [0.04, 3.23]
9 Eclampsia	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.01, 4.06]
9.1 Calcium supplementation alone	1	168	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.01, 4.06]
9.2 Calcium plus vitamin D	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.3 Calcium plus linoleic acid	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Miscarriage	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.00, 1.04]
10.1 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.06 [0.00, 1.04]
11 Low birthweight (birthweight < 2500 g)	2	134	Risk Ratio (M‐H, Fixed, 95% CI)	0.2 [0.05, 0.88]
11.1 Calcium supplementation alone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Calcium plus vitamin D	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.3 Calcium plus linoleic acid	2	134	Risk Ratio (M‐H, Fixed, 95% CI)	0.2 [0.05, 0.88]
12 Neonate small‐for‐gestational age	4	854	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.54, 1.21]
12.1 Calcium supplementation alone	0	0	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Calcium plus vitamin D	1	660	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.58, 1.38]
12.3 Calcium plus linoleic acid	2	134	Risk Ratio (M‐H, Fixed, 95% CI)	0.29 [0.06, 1.32]
12.4 Calcium plus antioxidants	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.07, 16.31]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Pre‐eclampsia	1	262	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.18, 0.96]
2 Preterm birth	1	262	Risk Ratio (M‐H, Fixed, 95% CI)	0.31 [0.09, 1.08]
3 Eclampsia	1	262	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.07, 1.53]
4 Stillbirth	1	262	Risk Ratio (M‐H, Fixed, 95% CI)	0.48 [0.13, 1.83]

Methods	“divided into two groups and followed up until delivery.”
Participants	430 pregnant women who were nulliparas, adolescents and elderly. Dates of recruitment not stated. Setting not stated, Phillipines
Interventions	Group B: 212 women received 500 mg elemental calcium from 16‐20 weeks till delivery. Group A: 210 women served as controls.
Outcomes	Pre‐eclampsia, preterm birth, admission to NICU
Notes	Abstract only
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not specified
Allocation concealment (selection bias)	Unclear risk	Not specified
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No placebo
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No placebo
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No record of loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	No information
Other bias	High risk	Abstract only, no details, no placebo

Methods	RCT described as single‐blind controlled clinical trial Individual randomisation
Participants	Setting: maternity clinics in Kashan Iran. Dates of recruitment: April 2011 to February 2012. Inclusion criteria: pregnant nulliparous women at risk of pre‐eclampsia, singleton pregnancy, 18‐35 years in third trimester. High risk was defined as nulliparous, with environmental, socioeconomic factors or obesity (not clear). 54 women recruited. Exclusion criteria: women with severe pre‐eclampsia, intrauterine fetal death, placental abruption, preterm birth or GDM.
Interventions	Experimental intervention: calcium‐vitamin D supplements for 9 weeks (500 mg calcium carbonate plus 200 IU vitamin D per day). Total number randomised: n = 27 women (24 analysed). Control/comparison intervention: placebo. Total number randomised: n = 27 women (25 analysed).
Outcomes	Compliance monitored weekly. Dietary intake (from diaries). Maternal weight, BMI, blood biochemical outcomes (fasting plasma glucose, cholesterol, high and low density lipoprotein‐cholesterol).
Notes	Funding: the study was supported from a grant (university or government). Grant from the Vice‐chancellor for Research, Kashan University of Medical Sciences (KUMS). Study placebo provided by Share Darou Co, Tehran, Iran and supplements by Darou Pakhsh Co. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The method of sequence generation was not described.
Allocation concealment (selection bias)	Unclear risk	This was a placebo controlled study but it was not clear how women were assigned to groups. Although the supplements and placebo packs were described as identical it was not clear whether or not staff were aware of allocation.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Described as a single‐blind trial. It was not clear what this meant. Women were provided with active or placebo drugs in identical packs. Only participants were blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	It was not clear if outcome assessment was blind but as most outcomes were biochemical lack of blinding may not have impacted on outcomes.
Incomplete outcome data (attrition bias)   All outcomes	High risk	54 women were recruited, 49 included in the analyses (25 in placebo group, 24 in calcium/vitamin D group). Women with severe pre‐eclampsia, preterm birth and GDM were excluded — it was not clear if these exclusions were after randomisation — these outcomes may have related to the intervention.
Selective reporting (reporting bias)	Unclear risk	We did not have access to the study protocol. It was not clear if all outcome data collected was reported.
Other bias	Unclear risk	Women in the placebo group had slightly lower weights pre‐pregnancy (and throughout pregnancy).

Methods	Double‐blind parallel‐arm RCT, individual randomisation, placebo controlled
Participants	Setting: clinics in Kashan, Iran. Dates of recruitment: March‐September 2012. Inclusion criteria: 46 women, 18‐40 with singleton pregnancy. Exclusion criteria: women with pre‐eclampsia, placental abruption and GDM (it appeared that women were excluded after randomisation).
Interventions	Experimental intervention: calcium‐vitamin D for 9 weeks from 25 weeks (500 mg calcium, 200 IU vitamin D per day). Total number randomised: n = 23. Control/comparison intervention: placebo pills of similar appearance. Total number randomised: n = 23. Women in both groups took iron and folic acid supplements.
Outcomes	Fasting plasma glucose, insulin metabolism, biomarkers of oxidative stress, vitamin D levels, BP, birth size, gestational age, mode of birth.
Notes	Author contacted re information about women excluded after randomisation. Funding: reported to be funded by a grant from the vice‐chancellor for research, Kashan university of medical sciences. Reported that supplements and placebo were provided by Shahre Daru Co, Tehran. CoI: reported no conflict of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	It was reported that randomisation was by random numbers “taken from a computer”.
Allocation concealment (selection bias)	Unclear risk	Placebo controlled but method at point of randomisation not described
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Not clear if staff blind. Placebo controlled but it was not clear if staff were aware.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Not clear if outcome assessors blind, some outcomes may not be affected by lack of blinding.
Incomplete outcome data (attrition bias)   All outcomes	High risk	4 women were excluded post‐randomisation for reasons that may have related to the intervention (participants that developed complications during the trial were excluded – we have added these back in and collected these data for our analysis).
Selective reporting (reporting bias)	Unclear risk	We had no protocol. Women were excluded post‐randomisation and no ITT.
Other bias	Unclear risk	Author contacted re post‐randomisation exclusions.

Methods	Numbered treatment packs in computer‐generated simple randomisation sequence. Loss to follow‐up: calcium 132/2295 vs placebo 121/2294.
Participants	Setting: medical centres in the USA. Dates of recruitment not clear. 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 dL or more) or calcium (10.6 mg per dL or more); renal disease; haematuria; history or family history of urolithiasis; frequent use of calcium supplements or antacids. Of 11,959 women screened, 5703 were excluded initially and a further 1667 after the compliance test. The remaining 4589 women were enrolled.
Interventions	2 g/day elemental calcium as calcium carbonate, or placebo. Taken until delivery, development of pre‐eclampsia or suspicion of urolithiasis. All women took 50 mg calcium per day as normal supplementation and were asked to drink 6 glasses of water per day. Compliance was 64% in the calcium group and 67% in the placebo group. 20% of women took > 90% of the allocated treatment.
Outcomes	Gestational hypertension (DBP sitting, fifth Korotkoff sound unless zero, 90 mmHg or more on 2 occasions, 4 hours to 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 to 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 to have reduced SBP at 2 years of age in the calcium supplementation group (mean 95.4 mmHg, SD 7.6, n = 35 vs 100.2, 7.9, n = 18). The data have not been included in this review because of 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 2163 (calcium) and 2173 (placebo) have been used. Neonatal outcomes in the report are based on live births (2134 and 2139). Addition of abortions and fetal deaths brings these numbers to 2156 and 2166. It is not clear why a discrepancy in numbers remains. Sources of funding: supported by The National Institute of Child Health and Human Development and the National Heart, Lung and Blood Institute. Study medications were industry provided. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Packages of study tablets were prepared and numbered by pharmaceutical manufacturer according to a computer‐generated simple randomisation sequence.
Allocation concealment (selection bias)	Low risk	On enrolment, each woman was assigned the next numbered package of medication at 1 of 5 centres. The blister‐packed tablets were identical in appearance.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind. The code was held centrally.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind. The code was held centrally.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition < 10%
Selective reporting (reporting bias)	Unclear risk	Authors used total number of women enrolled to each group as denominator instead of total number minus those lost to follow‐up. Also small discrepancy in overall numbers but unlikely to affect results substantially.
Other bias	Low risk	Baseline characteristics similar

Methods	Prospective, randomised, double‐blind, placebo‐controlled trial. Allocated by means of a computer‐generated randomisation list. After randomisation, 11/201 (5.5%) women were lost to follow‐up (calcium 6, placebo 5).
Participants	Women attending a hospital clinic in Nagpur, India. Recruitment between 1993 and 1994. 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 Source of funding: not stated. Supplements and placebos were provided by a pharmaceutical company. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random number table
Allocation concealment (selection bias)	Low risk	Adequate
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind. Containers and tablets prepared by a pharmaceutical firm in Nagpur. Tablets were the same size, weight and colour.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind. Containers and tablets prepared by a pharmaceutical firm in Nagpur. Tablets were the same size, weight and colour.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition < 10%
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	Apart from 11 women lost to follow‐up, there are no missing data. Otherwise baseline characteristics and compliance were similar; balanced loss to follow‐up.

Methods	Randomised controlled trial
Participants	Inclusion criteria: nulliparity; age ≥ 35 years; previous pre‐eclampsia; family history of pre‐eclampsia; multiple pregnancy; time between pregnancies ≥ 10 years; body mass index ≥ 25; diastolic pressure ≥ 80 mmHg before 20 weeks' gestation; proteinuria ≥+ on more than 1 occasion or ≥ 300 mg/24 h before 20 weeks' gestation; underlying medical conditions (pre‐existing hypertension; pre‐existing renal disease; pre‐existing diabetes; presence of antiphospholipid antibodies; chronic autoimmune disease); male sex partner's predecessor wife has previous pre‐eclampsia. The inclusion criteria include women who already have hypertension, but it may be that women that are actually recruited may not have these specific risk factors.
Interventions	This is a calcium supplement dose comparison 600 mg versus 1200 mg; it is not a placebo controlled trial.
Outcomes	Pre‐eclampsia.
Notes	This is a trial registration — the study is specifically about prevention of pre‐eclampsia — recruitment should have ended (2015) but there are no subsequent updates of the registration or publications. Awaiting assessment pending further publications.

Trial name or title	Combined therapy with low‐dose aspirin and calcium supplements during second trimester to reduce the risk of superimposed pre‐eclampsia in pregnant women with chronic hypertension: a randomised‐controlled trial
Methods	Placebo controlled randomised trial
Participants	104 women with chronic hypertension Inclusion criteria Pregnant woman with chronic hypertension aged 20 years or more Attending antenatal care and planning to delivery at Khon Kaen Hospital and Srinagarind Hospital Carrying a live structurally normal singleton fetus between 13 to16 weeks of gestation Participants give informed consent Exclusion criteria History of bleeding disorders Thrombocytopenia platelet count 140,000 mm3 Placenta previa Asthma Allergy to aspirin Planning to delivery in other hospitals
Interventions	Low‐dose aspirin (81 mg) and calcium carbonate 1500 mg per day compared with placebo
Outcomes	Pre‐eclampsia, neonatal outcomes
Starting date	01 July 2017 (anticipated). Reported completion date: 31 May 2018.
Contact information	Sukanya Chaiarach, sukanyatanoorat@hotmail.com
Notes

Methods	Randomised clinical trial. Participants were alternately allocated to either the supplemented or to the control groups in order to match for age, parity, ethnic group and BMI. Data from the 'control' group were not used in this analysis. Randomisation was conducted by the pharmacist using a table of random numbers, and supplements were distributed to the participants in sealed envelopes. Clinicians were unaware whether the participants were in the supplemented or control groups, and which supplementation was administered.
Participants	Women attending a hospital in Trinidad between 1992 and 1995. Pregnant women recruited into the study before 20 weeks’ gestation primigravidae, or multigravidae with obstetric history of pre‐eclampsia. Participants were normotensive and urinalysis was negative for albuminuria. None had any underlying medical disorders such as chronic hypertension, renal disease, diabetes mellitus and collagen vascular disorders.
Interventions	2 calcium tablets (1200 mg elemental calcium), a combination of 1 calcium tablet and 1 baby Cafenol (80 mg aspirin) or 1 baby Cafenol daily. All participants, including the controls, received the routine haematinics which were ferrous sulphate (200 mg) and folic acid (5 mg) daily. There were 114 primigravidae amongst the controls. Of the supplemented groups, 45 primigravidae received aspirin, 36 had calcium and aspirin, and calcium tablets were administered to 42 primigravidae. All of these women were less than 24 years of age. For this review we have used only data for calcium (600 mg) and Cafenol (80 mg aspirin) vs Cafenol daily (80 mg aspirin).
Outcomes	DBP (measured by the same observer with the participants in a sitting position, recorded at the onset of muffing ‐phase 4 Korotkoff sound), PIH (BP ≥ 140/90 mmHg), pre‐eclampsia (hypertension plus proteinuria).
Notes	8 participants were unavailable for analysis. Source of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The supplement vs control group were allocated by alternation, but it was clear that various supplemented groups were randomised by the pharmacist using random number tables. In this review we use only data for calcium plus aspirin vs aspirin, which were randomised.
Allocation concealment (selection bias)	Low risk	Supplements were distributed in sealed envelopes.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Clinicians were unaware whether the participants were in the supplemented or control groups, and which supplementation was administered. Participants were not blinded as placebos were not used.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Reported that clinicians recording outcomes were unaware of treatment group
Incomplete outcome data (attrition bias)   All outcomes	High risk	8 participants were unavailable for analysis.
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	None noted

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; BP < 140/90 mmHg (mean of 5 measurements); no present or past disease; not taking medication; normal oral glucose tolerance tests. Recruitment between 1987 and 1989.
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	3 hospitals in Rosario, Argentina. Data for preterm birth given as percentages, not clear what the denominators were. Assumed to be the numbers with complete follow‐up (527 vs 542) as these were the numbers which were divisible by the percentages to give whole numbers. Unpublished placental abruption data obtained from authors. Babies born in the private hospitals followed up at 7 years. Of 614 randomised (calcium 309/placebo 305), 301/299 completed the first study, 2/6 infant deaths and 1/0 maternal deaths had occurred, leaving 298/293 eligible for follow‐up. 289/285 were contacted, 10/5 refused to participate, 22/19 lived outside the country, and 257/261 were assessed (88% of those eligible). Funded by a research grant from The International Development Research Centre, Canada. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated random number sequence ‐ Epistats Statistical Package
Allocation concealment (selection bias)	Low risk	Complete set of numbered sealed opaque envelopes was sent to each of 3 hospitals.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Randomisation code was held centrally such that the woman and her healthcare providers were blind to her trial group. Tablets were identical in appearance, weight, colour, taste.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Randomisation code was held centrally such that the woman and her healthcare providers were blind to her trial group. Tablets were identical in appearance, weight, colour, taste.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All or partial data available for 579/593 (Ca) and 588/601 (Pl) respectively. Delivery data were available for 544 and 554 respectively.
Selective reporting (reporting bias)	Low risk	All primary outcomes addressed
Other bias	Low risk	Balanced group sizes, baseline characteristics including dietary calcium similar in both groups

Methods	“Healthy antepartum cases were randomized and divided into 3 groups.”
Participants	Healthy primipara. Setting and dates of recruitment not stated (China)
Interventions	A: 120 mg calcium daily; B: 240 mg calcium daily; C: no calcium (D: 1 g calcium; E: 2 g calcium; E: no calcium: not included as trials with high risk of bias not included in high calcium dose review).
Outcomes	Biochemical studies; hypertension, pre‐eclampsia, birthweight, gestational age, method of delivery.
Notes	First period (low dose) April 1987 to June 1988 (groups A, B, C); second period (high dose) April 1989 to June 1990 (groups C, D, F). Similar results for groups A and B, which were combined in this meta‐analysis Source of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not described
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No placebo
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No placebo
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Loss to follow‐up not reported
Selective reporting (reporting bias)	Unclear risk	Limited information
Other bias	High risk	Very limited description of methods

Methods	Central telephone randomisation, stratified by centre using variable blocks. Double‐blind.
Participants	Inclusion criteria: nulliparous women; singleton pregnancy; < 24 weeks' gestation; BP < 140/90 mmHg; expected to give birth at a collaborating centre.  Exclusion criteria: antihypertensive therapy; medical contraindication to calcium supplementation.
Interventions	Calcium carbonate 1.8 g daily or lactose placebo tablets, from 20‐24 weeks until birth.
Outcomes	Primary: PIH (DBP 90 mmHg or more on 2 consecutive occasions 4 hours apart, or 110 mmHg once; pre‐eclampsia (as above plus proteinuria 0.3 g or more per 24 hours or 2+ protein or more on 2 random clean‐catch urine samples); preterm birth (< 37 weeks).  Secondary: severe PIH (DBP 110 or more on 2 occasions 4 hours apart, or 120 or more once); severe pre‐eclampsia (as above plus proteinuria); very preterm birth (< 32 weeks; extremely preterm birth (< 28 weeks); maternal fetal and infant events after trial entry.
Notes	5 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 ITT Sources of funding: a grant from the Queen Victoria Hospital Foundation and The Women's and Children's Hospital Foundation, Australia. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Stratified randomisation centrally co‐ordinated using variable blocks
Allocation concealment (selection bias)	Low risk	Identical sealed treatment packs prepared by drug company
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind. Tablets identical in size, colour and consistency. Code held centrally and only broken after trial closure and exploratory data analyses.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind. Tablets identical in size, colour and consistency. Code held centrally and only broken after trial closure and exploratory data analyses.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition < 10%
Selective reporting (reporting bias)	Low risk	ITT analysis. 227 in calcium group and 229 in placebo group. Baseline characteristics similar.
Other bias	Unclear risk	Only achieved 48% of recruitment target (456 instead of 948) due to lack of funds.

Methods	Allocation sequence was generated using random number tables, and prepared by an administrative staff member.
Participants	Recruitment May 1995 to May 1996, 3 hospital outpatient clinics in Cali, Colombia. 676 healthy primigravid women screened. Primigravidas with risk factors for pre‐eclampsia (high biopsychosocial risk, positive roll‐over test and high mean BP (> 85 mmHg) selected).
Interventions	450 mg linoleic acid plus 600 mg calcium (n = 44) vs identical looking placebos (n = 45) in the third trimester.
Outcomes	Biochemical studies; maternal and neonatal clinical outcomes.
Notes	1 study group excluded for taking ASA; 2 from control group lost to follow‐up Source of funding: the study was supported by a grant from the National Institute of Science and Technology of Colombia. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“ allocated randomly.”
Allocation concealment (selection bias)	Low risk	“ allocated randomly.”
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	“Double blind, placebo controlled trial.”
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	“Double blind, placebo controlled trial.”
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 from study group excluded for taking ASA; 2 from control group lost to follow‐up.
Selective reporting (reporting bias)	Low risk	Main outcomes reported
Other bias	Low risk	“Double blind, placebo controlled trial.”

Methods	"The participants were allocated in two random groups."
Participants	March 2001 to March 2003; 4 outpatient clinics in Bangladesh and Colombia. 220 primigravid women screened for abnormal Doppler ultrasound in uterine or arcuate arteries (diastolic notch) from week 18 to 22 of gestation. Primigravidas < 19 years or > 35 years, 18 to 22 weeks with risk factors for pre‐eclampsia including reliable family history of PE were included. Those with DBP of 85 mm Hg or more at the first antenatal visit, cardiovascular or renal disease, or hypertensive or taking any medication at the time were excluded. Mean daily calcium intake was also similar at study entry (601.5 mg [range, 310—1101 mg] vs 576.0 mg [314—936 mg]; P = 0.94).
Interventions	450 mg conjugated linoleic acid plus 600 mg calcium (n = 25) vs placebo (n = 25) from 18 to 22 weeks.
Outcomes	Biochemical studies.
Notes	220 women screened; eco‐Doppler ultrasound positive in 53 women; 3 eligible women refused to participate 1 woman from the control group was lost during the follow‐up (change of residence) and 1 woman from the supplemented group withdrew. Source of funding: Columbia Institute for Science and Technology and Partners in Population and Development Institute, Dhaka, Bangladesh. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“random cards were prepared and sealed by an independent administrative staff member using a random number table prepared with the True Epistat statistical package version 5.0.”
Allocation concealment (selection bias)	Low risk	“allocated in two random groups….sequentially numbered, sealed, opaque envelope containing a card that indicated the study allocation.”
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	“allocated in two random groups….sequentially numbered, sealed, opaque envelope containing a card that indicated the study allocation.” ‐ it appears the study was not double‐blinded.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	“allocated in two random groups….sequentially numbered, sealed, opaque envelope containing a card that indicated the study allocation.” ‐ it appears the study was not double‐blinded.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1 loss to follow‐up in each group
Selective reporting (reporting bias)	Unclear risk	No information
Other bias	Low risk	Low to moderate (appears not double‐blind)

Methods	Randomised double‐blind placebo‐controlled trial conducted in The Gambia between 1995 and 2000.
Participants	662 pregnant women were randomised; 452 of 546 live born children were followed up.
Interventions	1500 mg calcium (Ca) orally per day or placebo from 20 weeks' gestation until delivery.
Outcomes	1. Maternal BP at 36‐38 weeks' gestation  2. Breast‐milk calcium concentration during lactation  3. Postpartum bone mineral content of mother and baby 4. Cardiovascular risk in offspring 5. BP in offspring (Hawkesworth 2011). Follow‐up of 350 children (64%). There were no differences in mean BP measurements 6. Maternal plasma 25 hydroxyvitamin D, birthweight and infant growth and bone mineral accretion (Prentice 2009)
Notes	Source of funding: UK Medical Research Council. (Supplements and placebos were provided by a pharmaceutical company.) CoI: none of the authors reported a personal or financial conflict of interest.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random permuted blocks of 4
Allocation concealment (selection bias)	Low risk	Sealed opaque envelopes
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias)   All outcomes	High risk	> 20% missing data
Selective reporting (reporting bias)	Unclear risk	Maternal hypertension outcomes have not yet been reported
Other bias	High risk	Of 155 women randomised, 125 who had normal pregnancy were selected for the sub‐studies. It's not clear whether bias could have been introduced by this selection.

Methods	Described as prospective randomised clinical trial
Participants	Setting: women attending the antenatal clinic of a tertiary care hospital in West Bengal, India (described as serving a population with low socio‐economic status). Dates of recruitment: May 2010–April 2011. Inclusion criteria: 272 women. Healthy nulliparous women (18‐30 years) with singleton pregnancy, with BP < 140/90 mmHg and no proteinuria at first antenatal visit before 20 weeks.
Interventions	Experimental intervention: 127 women. High‐dose calcium supplements (2 g oral elemental calcium, 4 tablets daily) from 20 weeks’ gestation. Comparison intervention: 145 women. Low‐dose calcium (500 mg plus placebo, 1 active and 3 placebo tablets of similar appearance daily).
Outcomes	(Prespecified outcomes were not clear; it was stated what was recorded at subsequent antenatal visits but it was not clear if these were study outcomes). Reported: eclampsia and pre‐eclampsia, preterm birth, gestational age at birth, birthweight, IUGR, stillbirth, mean systolic and mean BP (not clear when the reported values were measured).
Notes	Funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Reported using a computer‐generated randomisation table
Allocation concealment (selection bias)	Unclear risk	This was reported to be a placebo controlled trial but it was not clear staff were aware of allocation at the point of randomisation.
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Placebo was supplied so women may have been blind to which arm they were in. It was not clear whether staff were aware of the treatment group.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	It was not clear if it was recorded in notes whether women were in the intervention or placebo groups.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	10/272 were lost to follow up.
Selective reporting (reporting bias)	Unclear risk	We had no trial protocol and it was not clear what the study outcomes were (much data that was collected were not reported). Several outcomes were not well defined (e.g. not clear when mean BP values were recorded).
Other bias	Unclear risk	No baseline characteristics reported

Methods	Randomised, double‐blind, placebo‐controlled trial
Participants	Women were recruited between January 2005 and December 2007 at a hospital in New Delhi, India. Healthy normotensive primigravid women with uncomplicated single pregnancy; pregnancy 12 to 25 weeks' gestation, known date of the last menstrual period, and intention to deliver at Lok Nayak Hospital, New Delhi. Study population had a low dietary calcium. Exclusions: multiple pregnancy, polyhydramnios, fetal malformations, diabetes, chronic hypertension, renal disease, cardiovascular disease, urolithiasis, or BP of 140/90 mmHg or higher at first visit or at enrolment.
Interventions	4 tablets (2 g calcium or placebo) were taken daily.
Outcomes	Pre‐eclampsia (SBP > 140 mmHg and DBP > 90 mmHg on 2 occasions 4 hours apart after 20 weeks' pregnancy in women normotensive previously, together with proteinuria > 300 mg/24 h or 1+ on a clean‐catch dipstick in the absence of urinary infection); eclampsia; preterm delivery; caesarean section. Baseline characteristics comparable.
Notes	Imbalanced groups: 290 allocated to calcium, 262 to placebo group. 17 and 11 lost to follow‐up so 273 and 251 analysed respectively. See below. Source of funding: University Grant Commission, New Delhi, India. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Simple randomisation sequence developed manually
Allocation concealment (selection bias)	Low risk	Coded numbers assigned to treatment packets and distributed to participants using the random number sequence.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind. Calcium and placebo tablets were identical. Randomisation code broken after completion of the trial.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind. Calcium and placebo tablets were identical. Randomisation code broken after completion of the trial.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Attrition < 10%
Selective reporting (reporting bias)	Low risk	Expected outcomes reported.
Other bias	High risk	Imbalance in size of groups. The authors were contacted regarding the imbalance and they explained that a random sequence was generated for 600 participants (unblocked) but recruiting was stopped at 552 participants and so 48 numbers remained unallocated.

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	Women recruited at a hospital antenatal clinic in Quito, Ecuador. Dates of recruitment 1984‐1986. 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). Source of funding: the study was supported by the Consejo Nacional de Ciencia y Technologia and Consejo Nacional de Universidades y Escuclas Polieenicas, Ecuador. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Assigned using a random number table
Allocation concealment (selection bias)	Unclear risk	Not described
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Double‐blind. Identical containers and tablets prepared by the Faculty of Chemistry and Pharmacy, Central University of Ecuador.
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Double‐blind. Identical containers and tablets prepared by the Faculty of Chemistry and Pharmacy, Central University of Ecuador.
Incomplete outcome data (attrition bias)   All outcomes	High risk	14 women excluded from the report because they delivered before 38 weeks leaving 43/49 women in the calcium and placebo groups respectively. Data from the 14 excluded women are included in this review.
Selective reporting (reporting bias)	Unclear risk	Not clear
Other bias	Unclear risk	Not clear

PERMALINK

Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems

G Justus Hofmeyr

Theresa A Lawrie

Álvaro N Atallah

Maria Regina Torloni

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

for the main comparison.

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

For the woman

For the child

Secondary outcomes

For the woman

For the child

Outcomes for 'Summary of findings' table

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

(1) Random sequence generation (checking for possible selection bias)

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

(3.1) Blinding of participants and personnel (checking for possible performance bias)

(3.2) Blinding of outcome assessment (checking for possible detection bias)

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

(5) Selective reporting (checking for reporting bias)

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

(7) Overall risk of bias

Assessment of the quality of the evidence using the GRADE approach

Measures of treatment effect

Dichotomous data

Continuous data

Unit of analysis issues

Cluster‐randomised trials

Cross‐over trials

Other unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

High‐dose calcium supplementation

Low‐dose calcium supplementation

Sensitivity analysis

Results

Description of studies

Results of the search

1.

Included studies

High‐dose calcium supplementation (1 g/day or more)

Low‐dose calcium supplementation (less than 1 g/day)

High‐dose versus low‐dose calcium supplementation (1 g/day or more versus less than 1 g/day)

Excluded studies

Risk of bias in included studies

2.

3.

Allocation

Methods	Randomised, double‐blind trial. Stated "Each patient was assigned independently in sequence", and "All women completed the study".
Participants	Women attending a hospital in Quito, Ecuador. Dates of recruitment not stated. Healthy nulliparous women with positive roll‐over test at 28‐30 weeks' gestational age ‐ judged at high risk for gestational hypertension.
Interventions	2000 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). 22 in calcium group, 34 in placebo group. Source of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Authors state that this was a RCT but no details of sequence generation are provided.
Allocation concealment (selection bias)	Unclear risk	No details given about how concealment was achieved or whether tablets looked identical
Blinding of participants and personnel (performance bias)   All outcomes	Unclear risk	Stated double‐blind but no further information
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Stated double‐blind but no further information
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Not clear
Selective reporting (reporting bias)	Unclear risk	Not clear
Other bias	Unclear risk	Large discrepancy in size of groups not accounted for

Methods	"Patients were divided into 3 groups."
Participants	Women recruited at the outpatient clinic and labour ward of the First Afifliated Hospital of Xi’an Medical University between Aug 1996 to Dec 1998. High‐risk women with a predisposition to PIH. Participants were required to be at 20‐24 weeks' gestation when entering the study, with a BMI index of < 24, and an arterial pressure of < 11.3 kPa. Study states only that participants were "selected from our hospital outpatient clinic and labour ward".
Interventions	The first group (n = 29) received a daily dose of 600 mg of Calictrate‐D, the second group (n = 29) received 1200 mg if Calcitrate‐D daily, and the third group (n = 30), the control group, received nothing. From 20‐24 weeks till birth
Outcomes	Hypertension; biochemical studies
Notes	The outpatient clinic and labour ward of the First Afifliated Hospital of Xi’an Medical University. Aug 1996 to Dec 1998. No information on consent or ethical approval Source of funding: not clear (original article not in English). CoI: not clear.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported
Allocation concealment (selection bias)	Unclear risk	Not reported
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No placebo
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No placebo
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	Loss to follow‐up not reported
Selective reporting (reporting bias)	Unclear risk	No information
Other bias	High risk	Methods not reported

Methods	"Randomly selected." Information from authors indicated that it was actually a consecutive series.
Participants	Women attending the antenatal hospital of a hospital in India. Dates of recruitment not stated. 400 pregnant women 20 to 35 years old attending antenatal clinic. Dietary intake about 500 mg calcium and 40 IU vitamin D daily.
Interventions	200 women daily supplement calcium 375 mg plus vitamin D 1200 IU from 20 to 24 weeks of pregnancy onwards, vs 200 women no supplement.
Outcomes	"Toxaemia", biochemical studies, mean BP
Notes	Medical College Hospital, Rohtak, India Souce of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Not specified. Information from authors indicated that it was actually a consecutive series.
Allocation concealment (selection bias)	High risk	Not specified. Information from authors indicated that it was actually a consecutive series.
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No placebo
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No placebo
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	No record of losses to follow‐up
Selective reporting (reporting bias)	Unclear risk	No report of registered protocol
Other bias	High risk	Very limited reporting of methods

Methods	Double‐blind, placebo‐controlled clinical trial.
Participants	Women attending a hospital in Tehran, Iran. Dates of recruitment not stated Women at high risk for pre‐eclampsia: positive 'roll‐over' test and at least 1 risk factor for pre‐eclampsia; 28‐32 weeks' pregnant; BP < 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 SBP above 14 mmHg and an increase (15 mmHg) of DBP above 90 mmHg, twice 4‐6 hours apart, with proteinuria 1+; duration of pregnancy (39.5 SD 0.8 vs 37.7 SD 2.5 weeks); birthweight (3316 SD 308 vs 2764 SD 761 g); weekly maternal weight increase (no difference).
Notes	No loss to follow‐up Source of funding: not stated; supplements and placebo tablets were provided by a pharmaceutical company. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Women were "randomly assigned".
Allocation concealment (selection bias)	Low risk	Adequate. Manufacturer coded the tablets which had same packaging and physical characteristics. A pharmacy dispensed the tablets.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No incomplete outcome data (sample size = 30)
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	No incomplete data or loss to follow‐up

Methods	Randomised to control vs aspirin vs calcium in ratio 1; 2; 2, using 5 unsealed envelopes, selected by participants. Imbalance suggested that ‘something went wrong’, perhaps a tendency for participants to select from a certain part of the pile of envelopes.
Participants	Women attending a clinic in Hong Kong. Recruitment: July 1992 to Dec 1994. 500 primiparous Chinese women in 2^nd trimester with sitting MAP 80 to 106 mmHg screened at 22‐24 weeks with rested left lateral automated BP (cut‐off MAP 60 mmHg). 369 selected: calcium 154, aspirin 132, control 83. 32 delivered elsewhere and were excluded, leaving 337.
Interventions	Aspirin 80 mg daily from 22 weeks vs calcium 600 mg daily from 22 to 32 weeks, then 1200 mg daily vs control
Outcomes	Hypertension, pre‐eclampsia, mean BP
Notes	Source of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	5 open envelopes
Allocation concealment (selection bias)	High risk	Unsealed envelopes
Blinding of participants and personnel (performance bias)   All outcomes	High risk	No placebo
Blinding of outcome assessment (detection bias)   All outcomes	High risk	No placebo
Incomplete outcome data (attrition bias)   All outcomes	High risk	10% loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	No information
Other bias	High risk	See above

Methods	Double‐blind, placebo‐controlled trial. Participants randomised according to a computer‐generated random number sequence by an independent third party who had no conflict of interest in the study.
Participants	Women attending a university hospital in Indonesia between March 2003 and June 2004 60 pregnant women with low antioxidant status at 8 to 12 weeks of gestation Exclusion criteria: 1) history or current use of anti‐hypertensive medication or diuretics; 2) use of vitamin C > 150 mg and/or vitamin E > 75 IU per day; 3) known placental abnormalities; 4) current pregnancy as a result of in vitro fertilisation; 5) regular use of platelet active drugs or non‐steroidal anti‐inflammatory drugs (NSAIDs); 6) known fetal abnormalities; 7) documented uterine bleeding within a week of screening; 8) uterine malformations; 9) history of medical complications.
Interventions	Supplementation with calcium (800 mg), N‐acetylcysteine (200 mg), Cu (2 mg), Zn (15 mg), Mn (0.5 mg), and selenium (100 mcg) and vitamins A (1000 IU), B6 (2.2 mg), B12 (2.2 mcg), C (200 mg), and E (400 IU), from 8 to 12 weeks of gestation throughout pregnancy Both groups received Fe (30 mg) and folic acid (400 mcg). Placebo supplement’s size and appearance were matched with those of antioxidants.
Outcomes	Maternal: pre‐eclampsia, hypertension, proteinuria and abortion. Perinatal: IUGR, intrauterine fetal death, preterm delivery (before 37 weeks).
Notes	Source of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Participants were randomised according to a computer‐generated random number sequence by an independent third party who had no conflict of interest in the study.
Allocation concealment (selection bias)	Low risk	Participants were randomised according to a computer‐generated random number sequence by an independent third party who had no conflict of interest in the study.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind, placebo‐controlled trial
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind, placebo‐controlled trial
Incomplete outcome data (attrition bias)   All outcomes	Low risk	No loss to follow‐up
Selective reporting (reporting bias)	Unclear risk	Unable to comment
Other bias	Low risk	None noted

Methods	Double‐blind placebo‐controlled trial. 4/33 allocated calcium lost to follow‐up.
Participants	Women attending a hospital in Jacksonville, Florida, USA between 1989 and 1993. University hospital serving low‐income population Normotensive nulliparas; positive roll‐over test (281/1065) and positive angiotensin II infusion test at 20‐24 weeks' gestation (67/281). 67 were allocated to calcium (33) or placebo (34).  Exclusion criteria: factors increasing the risk of gestational hypertension, including renal disease, collagen vascular disease, diabetes mellitus, chronic hypertension, multifetal pregnancy.
Interventions	Calcium supplementation with 2 g per day elemental calcium as 500 mg calcium carbonate tablets, vs 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 1 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 Source of funding: not stated. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation by computer‐generated list
Allocation concealment (selection bias)	Low risk	Adequate
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind. Tablets were prepared by a pharmaceutical company and were identical with respect to weight, size, flavour and appearance.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind. Tablets were prepared by a pharmaceutical company and were identical with respect to weight, size, flavour and appearance.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% attrition
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	Data entered before breaking the code. ITT analysis. 4/33 in the calcium group lost to follow‐up so 29 in calcium and 34 in placebo, however even if the 4 lost to follow‐up had PIH, results would still have significantly favoured the calcium group.

Methods	Double‐blind, RCT
Participants	Recruitment 1983‐1985. 34 black women from Johns Hopkins Hospital, Baltimore, USA, 18 white women from Rosario, Argentina 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 Johns 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	Source of funding: grants from the National Dairy Board and the National Dairy Council. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	'Randomly assigned' ‐ no other details
Allocation concealment (selection bias)	Low risk	Random numbers in closed envelopes
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Tablets were the same weight, size and colour, prepared by The Johns Hopkins pharmacy and distributed to the 2 hospitals.
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Tablets were the same weight, size and colour, prepared by The Johns Hopkins pharmacy and distributed to the 2 hospitals.
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% attrition
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	Women at Johns Hopkins Hospital only also received vitamin preparations containing 200 mg calcium/day.

Methods	Double‐blind, randomised trial
Participants	Johns Hopkins Hospital, Baltimore, 1985‐1988 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 (calcium 7.4 vs placebo 21.1%); delivery 30‐37 weeks; idiopathic prematurity; spontaneous prematurity; low birthweight (< 2500 g) (calcium 9.6% vs placebo 21.1%); postdates > 42 weeks (calcium 7.4 vs placebo 5.3%); impaired fetal growth (3.2 vs 3.2%); premature rupture of membranes (2.1 vs 1.0%); Apgar score < 8 at 5 minutes (4.4 vs 10.5%)
Notes	Source of funding: grants from the National Dairy Board and the National Dairy Council. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated list of random numbers
Allocation concealment (selection bias)	Low risk	Opaque envelopes with bottle numbers; project co‐ordinator responsible for assigning treatment. Identical tablets and containers were prepared at The Johns Hopkins Hospital pharmacy.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	< 10% attrition
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Unclear risk	Baseline characteristics similar except for maternal weight (higher in placebo group, P < 0.01)

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	Multicentre trial in Argentina, Egypt, India, Peru, South Africa and Vietnam. Enrolment from 2001‐2003 Populations with median daily calcium intake < 600 mg; primiparous women less than 20 weeks' pregnant Exclusion criteria: renal disease or urolithiasis; parathyroid disease; BP > 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: pre‐eclampsia (BP diastolic 90 mmHg or more, or systolic 140 mmHg or more, plus proteinuria 2+ on dipsticks or 300 mg per day; preterm birth (< 37 weeks). Secondary outcomes: severe pre‐eclampsia (diastolic 110 mmHg or more or systolic 160 mmHg or more); early onset pre‐eclampsia (< 32 weeks), PIH; eclampsia; placental abruption; birthweight < 2500 g; spontaneous preterm delivery; medically indicated preterm delivery; admission to neonatal ICU for > 2 days; fetal, neonatal and perinatal mortality (before discharge from hospital).
Notes	Multicentre trial in Argentina, Egypt, India, Peru, South Africa and Vietnam. Enrolment from 2001‐2003  14,362 women screened, 8325 randomised. Exclusions: 6 calcium (4 not pregnant, 2 lost before treatment started) and 7 placebo (5 not pregnant, 2 lost before treatment started). Loss to follow‐up: 143 and 155 in calcium and placebo group respectively (some data available on women not followed up to delivery). Treatment compliance 84.5% and 86.2% respectively. Baseline characteristics were well matched. An ancillary study in Argentina assessed 510 of the participants by Doppler ultrasound for RI, PI in uterine and umbilical arteries, and for bilateral uterine artery notching (Carroli 2010). Similarly, a group of 708 participants in South Africa were assessed for serum and urine parameters of endothelial damage (Hofmeyr 2008). Source of funding: the study was supported by UNDP/UNFPA/World Health Organization/World Bank Special Programme of Research, Development and Research Training. CoI: not stated.
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation lists for each site with random blocks of 6 to 8 women
Allocation concealment (selection bias)	Low risk	Consecutively numbered identical treatment boxes were allocated for each woman enrolled. Randomisation codes remained at the WHO Clinical Trial Unit until analysis.  Boxes and tablet bottles were prepared and numbered by Magistra SA, Geneva and shipped to trial centres. The placebo and calcium tablets were identical.
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind
Blinding of outcome assessment (detection bias)   All outcomes	Low risk	Double‐blind
Incomplete outcome data (attrition bias)   All outcomes	Low risk	143/4151 and 155/4161 women in calcium and placebo groups respectively were missing delivery data but were included in other analyses.
Selective reporting (reporting bias)	Low risk	Expected outcomes reported
Other bias	Low risk	ITT principle. Baseline characteristics, compliance and dropout rates were similar.