Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 23 (2021) 91–96

Contents lists available at ScienceDirect

Pregnancy Hypertension: An International

Journal of Women's Cardiovascular Health
journal homepage: www.elsevier.com/locate/preghy

The effect of calcium supplementation on blood pressure in non-pregnant

women with previous pre-eclampsia: A randomized
placebo-controlled study
G Justus Hofmeyr a, Armando Seuc b, Ana Pilar Betrán b, *, Gabriela Cormick c, Mandisa Singata a,
Sue Fawcus d, Simpiwe Mose e, Karlyn Frank e, David Hall f, José Belizán c, James M Roberts g,
Laura A. Magee h, Peter von Dadelszen h, on behalf of the Calcium, Pre-eclampsia Study Group
a
Effective Care Research Unit, Eastern Cape Department of Health/Universities of the Witwatersrand, Walter Sisulu and Fort Hare, South Africa; University of Botswana,
Gaborone, Botswana
b
UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of
Sexual and Reproductive Health and Research, World Health Organization, Geneva, Switzerland
c
Department of Mother and Child Health Research, Institute for Clinical Effectiveness and Health Policy (IECS), Buenos Aires, Argentina
d
Department of Obstetrics and Gynaecology, University of Cape Town, Cape Town, South Africa
e
Department of Obstetrics and Gynaecology, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Soweto, Johannesburg, South Africa
f
Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa
g
Magee-Womens Research Institute, Department of Obstetrics and Gynecology, Epidemiology and Clinical and Translational Research University of Pittsburgh, Pittsburgh,
USA
h
Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, London, UK

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Low dietary calcium is associated with the hypertensive disorders of pregnancy, and evidence
Hypertension suggests that the risks associated with pre-eclampsia are reduced by calcium supplementation. In the general
Calcium (non-pregnant) population, low dietary calcium intake is associated with hypertension with inconsistent evi­
Blood pressure
dence that calcium supplementation may reduce blood pressure. Women with pre-eclampsia are also at risk of
Supplementation
Preeclampsia
hypertension later in life. An exploratory sub-study among early participants enrolled in the WHO long-term
calcium supplementation in women at high risk of pre-eclampsia (CAP) study reported a trend to more blood
pressure reduction with calcium in non-pregnant women with previous severe as opposed to non-severe pre-
eclampsia. The current study reports the effects of low-dose calcium supplementation in non-pregnant women in
the complete trial cohort.
Methods: The CAP Study was a multi-country randomized, double-blind placebo-controlled clinical trial to test
the hypothesis that calcium deficiency may play a role in the genesis of pre-eclampsia in early pregnancy. From
2011 to 2016, non-pregnant women who had pre-eclampsia or eclampsia in their most recent pregnancy were
randomized to receive either 500 mg/day elemental calcium or placebo. In this sub-study we compared the
change in blood pressure from baseline to the 12-week visit between participants receiving calcium versus
placebo for those not pregnant at the 12-week visit.
Results: Of 1355 women randomized, 810 attended a 12-week visit without being pregnant, of whom 791 had
blood pressure measurements available for both baseline and 12-week visits. There was a greater reduction in
blood pressure in the calcium group compared with the placebo group for systolic pressure (difference 3.1
mmHg, 95% CI 0.8 to 5.4) and mean arterial pressure (MAP) (difference 2.0 mmHg, 95% CI 0.1 to 3.8). The
difference in diastolic blood pressure reduction (1.4 mmHg, 95% CI − 0.5 to 3.3) was not statistically significant
(p = 0.140).
For women with previous pre-eclampsia with severe features (n = 447), there was significantly greater reduction
in blood pressure in the calcium than the placebo group (difference for systolic 4.0, 95% CI 0.7 to 7.3; diastolic
3.0, 95% CI 0.5 to 5.5 and mean arterial pressure 3.3, 95% CI 0.8 to 5.9 mmHg). For women with previous pre-
eclampsia without severe features (n = 344), there were no significant differences between calcium and placebo

* Corresponding author.
E-mail address: [email protected] (A.P. Betrán).

https://doi.org/10.1016/j.preghy.2020.11.012
Received 3 July 2020; Received in revised form 27 November 2020; Accepted 27 November 2020
Available online 3 December 2020
2210-7789/© 2020 The Authors. Published by Elsevier B.V. on behalf of International Society for the Study of Hypertension in Pregnancy. This is an open access
article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
G.J. Hofmeyr et al. Pregnancy Hypertension: An International Journal of Women’s Cardiovascular Health 23 (2021) 91–96

groups. ANOVA analysis found no statistically significant interaction between previous pre-eclampsia severity
and treatment, for systolic (p = 0.372), diastolic (p = 0.063) or mean blood pressure (p = 0.103).
Conclusions: Low-dose calcium supplementation significantly reduced systolic and mean arterial pressure in non-
pregnant women with previous pre-eclampsia. We did not confirm a greater calcium effect in women with
previous pre-eclampsia with severe versus non-severe features.
The effect of low-dose calcium is of importance since even modest blood pressure reductions at a population level
may have important benefits in terms of reduced major complications of hypertension. This study adds to the
mounting evidence of health benefits which could be achieved for populations with low dietary calcium through
strategies to increase calcium intake, particularly among women at high risk due to previous pre-eclampsia.
Clinical Trial Registration: The trial was registered with the Pan-African Clinical Trials Registry, registration
number PACTR201105000267371 (https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=267).

1. Background 2. Methods

Pre-eclampsia is associated with low dietary calcium intake, and The CAP trial was a randomized, parallel arm, double-blind placebo-
calcium supplementation in the second half of pregnancy has been controlled clinical trial. Between July 2011 and September 2016, non-
associated with reductions in the prevalence of pre-eclampsia and its pregnant women who had experienced pre-eclampsia or eclampsia in
severe consequences in populations with low dietary calcium intake [1]. their most recent pregnancy were randomly allocated to receive either
Low dietary calcium intake is also associated with hypertension in 500 mg/day elemental calcium or placebo. The methodology of the trial
the non-pregnant population [2,3]. Calcium supplementation has been has been described elsewhere [12]. A brief description is presented
associated with small reductions in blood pressure in some studies of below.
non-hypertensive people [4–7], while the effect in hypertension is un­
clear [8]. A 2020 meta-analysis of the effect of calcium and vitamin D co-
supplementation found no difference in systolic blood pressure and a 2.1. Settings
small reduction in diastolic blood pressure (0.29 mmHg) [9]. Hyper­
tension is exceptionally common among low-income Southern African This was a multi-centre trial in South Africa, Zimbabwe and
populations and is the primary risk factor of the global burden of disease Argentina. The sites in Africa were government secondary or tertiary
[9,10]. urban referral hospitals with large obstetric units serving urban and
As both early and late onset of pre-eclampsia are associated with rural populations. The South African hospitals were located in Cape
long-term metabolic dysfunction and cardiovascular risk including hy­ Town, East London and Johannesburg. In Zimbabwe, the two maternity
pertension, it is important to assess the effect of calcium supplementa­ units included were in Harare. In Argentina, the sites included of one
tion in women from low dietary calcium populations with previous pre- maternity hospital in Tucuman and two in Buenos Aires. These are all
eclampsia [11]. areas with low calcium intake [15–18]. A nutritional interview con­
To investigate whether calcium intake before and in early pregnancy ducted among 312 women enrolled in the trial at 20 weeks gestation
affects the subsequent evolution of pre-eclampsia, we conducted the confirmed that the included population had a low calcium intake (441.0
WHO long term calcium supplementation in women at high risk of pre- ± 97.7 (mean, standard deviation) mg of calcium a day in South Africa
eclampsia (Calcium and Pre-eclampsia, CAP) trial [12,13]. We randomly and 360.5 ± 171.4 mg of calcium a day in Zimbabwe) [17]. The nutri­
allocated non-pregnant women with previous pre-eclampsia or tional assessment in the Argentinean sites did not allow for country-level
eclampsia to calcium supplementation with 500 mg of elemental cal­ estimates. However, evidence outside the CAP trial confirmed the low
cium daily versus placebo before pregnancy and until 20 weeks of levels of calcium intakes in Argentina [15,19].
pregnancy. All participants received 1500 mg calcium supplementation
after 20 weeks according to WHO recommendations. The 20% overall
2.2. Participants
reduction in pre-eclampsia in the calcium group was not statistically
significant. However, for participants with 80% compliance during the
Women were eligible if they had experienced pre-eclampsia or
first half of pregnancy (n = 393), pre-eclampsia was reduced by 34%
eclampsia in their most recent pregnancy, they were in a sexual rela­
(30/144 (21%) versus 47/149 (32%), RR 0.66 (95% CI 0.44 to 0.98), p
tionship, not pregnant, not using reliable contraception and they gave
= 0.037).
informed consent. Exclusion criteria were: less than 18 years of age;
The CAP trial recruited women from July 2011 to September 2016.
chronic hypertension with persistent proteinuria; calcium supplement
Using data available to 9 September 2014, we previously conducted an
intake; and history or symptoms of urolithiasis, renal disease or para­
exploratory study of the effect of low-dose calcium supplementation on
thyroid disease.
blood pressure in non-pregnant women with previous pre-eclampsia
[14]. We found a trend to greater reduction in blood pressure from
baseline to 12 weeks in the calcium group (n = 181) compared to the 2.3. The intervention
placebo group (n = 186) (systolic blood pressure mean difference 1.4,
95% confidence interval (CI) − 1.6 to 4.4; diastolic blood pressure mean Women in the intervention group received one chewable tablet
difference 1.0, 95% CI − 1.3 to 3.4), which was statistically significant containing 500 mg elemental calcium daily from enrolment (before
only for diastolic blood pressure in participants with previous pre- pregnancy) until 20 weeks’ gestation. The women were asked to chew
eclampsia with severe features (mean difference 3.4, 0.4 to 6.4; p = the tablet during the day, not close in time to taking food or iron sup­
0.025) [14]. The objective of the present study is to assess the effect of plements. Women in the control group received placebo tablets identical
low-dose calcium supplementation on blood pressure in non-pregnant in shape, colour and taste to the intervention tablet. The women were
women with previous pre-eclampsia in areas of low calcium intake encouraged not to take any additional calcium supplements. All women
using the data of all women enrolled. received unblinded calcium supplementation (1500 mg) from 20 weeks’
gestation until delivery, according to WHO recommendations [20].
Treatment compliance was calculated by dividing the number of used
tablets by the total number of tablets that should have been taken [12].

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2.4. Blood pressure measurement

Blood pressure measurement was standardized at the beginning of

the trial according to recommendations by the British Hypertension
Society (http://www.bhsoc.org/latest-guidelines/how-to-measure-
blood-pressure/). Researchers measuring blood pressure were trained
and certified according to the trial procedures and using tools from the
British Hypertension Society. Blood pressure was measured with a
standard mercury sphygmomanometer at the sites in Africa and with an
automated sphygmomanometer at the sites in Argentina.
Blood pressure was measured at recruitment (baseline) and at all
subsequent trial visits. The visits were scheduled every 12 weeks until
the woman became pregnant, then at 8, 20, and 32 weeks of pregnancy.
The first trial visit occurring between 6 and 18 weeks after enrolment
was considered the 12-week visit.

2.4.1. Dietary assessment methods

Dietary intake was assessed in those participants who reached 20-
weeks’ gestation during March 2013 to March 2016. The assessment was
performed using a triple pass 24-h dietary recall adapted and piloted in
South Africa, Zimbabwe and Argentina [17]. The 24-h recall is a guided
interview to assess food intake of the previous day. A detailed descrip­
tion of the methodology for dietary assessment has been published
elsewhere [17].

2.5. Sub-study population and methods Fig. 1. Flowchart of sub-study participants.

For the current prespecified sub-study, routine data collected during reduction in blood pressure in the calcium group compared with the
the trial visits were analysed. Women enrolled in the trial with blood placebo group for systolic (difference 3.1 mmHg, 95% CI 0.8 to 5.4) and
pressure data available for baseline and at least one subsequent follow- mean arterial pressure (MAP) (difference 2.0 mmHg, 95% CI 0.1 to 3.8).
up trial visit while still not pregnant were included. The reduction in the diastolic blood pressure was 1.4 mmHg (95% CI to
Baseline data were compared between the calcium and placebo − 0.5 to 3.3) greater in the calcium group, which was not statistically
groups for the study population to ensure no selective loss to follow-up. significant.
We used an intention-to-treat (ITT) approach for the analysis. For women with previous pre-eclampsia with severe features, there
For each woman, the changes in blood pressures were calculated by was significantly greater reduction in blood pressure in the calcium than
subtracting the measurement at baseline from the measurement at the the placebo group (difference for systolic 4.0, 95% CI 0.7 to 3.3; diastolic
first (ideally at 12 weeks) follow-up visit. The mean changes in systolic, 3.0, 95% CI 0.5 to 5.5 and mean arterial pressure 3.3, 95% CI 0.8 to 5.9
diastolic and mean arterial pressures were compared between the cal­ mmHg). For women with previous pre-eclampsia without severe fea­
cium and placebo groups. The differences were expressed as mean dif­ tures, there were no significant differences between calcium and placebo
ferences with 95% confidence intervals. Mean arterial pressure is groups (Table 2). We used ANOVA analysis to compare the effect of
defined as the average arterial pressure throughout one cardiac cycle. It calcium in the previous severe features group with the effect of calcium
was calculated by doubling the diastolic blood pressure, adding the in the previous non-severe-features group. We found no statistically
systolic blood pressure and dividing that composite sum by three. significant interaction between previous severity and treatment for
Subgroup analyses were performed to compare the effect of calcium systolic (p = 0.372), diastolic (p = 0.063) or mean blood pressure (p =
supplementation on blood pressure change at the 12-week visit between 0.103).
women with a history of pre-eclampsia with severe features and without
severe features. Severe features were defined as: i) eclampsia, or ii) 4. Discussion
haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome
or iii) systolic blood pressure higher than 160 mmHg or iv) diastolic In this population of women with previous pre-eclampsia and low
blood pressure higher than 110 mmHg or v) onset of pre-eclampsia dietary calcium intake, 500 mg per day of calcium supplementation
earlier than 28 weeks, or vi) ICU admission. An ANOVA analysis was compared with placebo significantly lowered systolic and mean blood
conducted controlling for treatment received (placebo vs. calcium) and pressure over a 12-week period. The effect on diastolic blood pressure
history of pre-eclampsia with vs. without severe features. SPSS version was similar in direction but smaller in magnitude, and it did not reach
20 was used for all analyses. statistical significance. In sub-group analysis, there was a significantly
greater reduction in all three elements of blood pressure in the calcium
3. Results group for women with previous pre-eclampsia with severe features, but
not those without severe features. However, the effect difference be­
Fig. 1 shows the trial profile of the sub-study. Among 1355 women tween those with and without severe features did not reach statistical
randomized, 810 attended a 12-week visit without being pregnant, of significance.
whom 791 had blood pressure measurements available for both baseline Our study adds to the body of evidence on the effects of calcium
and 12-week visits. supplementation on blood pressure in non-pregnant individuals.
Baseline data comparing the calcium and placebo groups for all The 500 mg calcium dose provided to our study population with low
women enrolled and for women included in this sub-study are shown in dietary calcium intake [12,16,17] was chosen to reach adequate calcium
Table 1. There were no significant differences between groups. intake levels [21], as recommended in the Dietary Approaches to Stop
Table 2 shows the changes from baseline in blood pressure at the 12- Hypertension (DASH) diet [21]. DASH has been proven to decrease
week visit comparing calcium and placebo groups. There was a greater blood pressure and is recommended as part of a cardiovascular disease

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Table 1
Baseline characteristics of participants at trial entry and of those in the final sample for this sub-study (baseline and 12-week pre-pregnancy blood pressures available)
according to study group.
Outcome All participants at trial entry (n = 1355) Participants included in this sub-study (n = 791)

Calcium (n = 678) Placebo (n = 677) p value Calcium (n = 387) Placebo (n = 404) p value

N n/ %/SD N n/ %/SD N n/ %/SD N n/ %/SD

mean mean mean mean

Maternal age (y) 678 30.2 5.8 677 30.4 5.9 0.518 387 30.5 5,7 404 30.9 5,7 0,315
Maternal weight (kg) 649 76.2 18.5 641 76.9 18.8 0.497 380 76.6 19.1 394 78.1 18.7 0.284
Maternal height (cm) 617 160.2 6.3 613 160.0 6,7 0.489 367 160.7 6.3 380 160.2 6.4 0.275
Systolic BP at randomisation (mm Hg) 675 127.0 19.3 674 127.3 19,2 0.749 387 128.6 18.3 404 127.6 19.1 0.477
Diastolic BP at randomisation (mm 675 81.6 14.1 674 82.3 13,9 0.340 387 82.8 13.9 404 82.7 14,0 0.954
Hg)
Any health complaint at 678 20 (2.9) 677 23 (3⋅4) 0.638 12 3.1% 404 15 3.7% 0.781 12
randomization
Previous severe pre-eclampsia* 403 309 (76.7) 414 343 (82.9) 0.028 217 56.1% 404 230 56.9% 0,864 217
Previous eclampsia 643 107 (16.6) 639 103 (16.1) 0.801 372 55 14.8% 388 65 16.8% 0.519
Previous HELLP syndrome 561 69 (12.3) 561 78 (13.9) 0.426 324 44 13.6% 331 53 16.0% 0.444
Previous live birth 678 349 (51.5) 677 337 (49.8) 0.532 387 195 50.4% 404 189 46.8% 0.346

BP: blood pressure; HELLP: haemolysis, elevated liver enzymes, low platelet count; SD: standard deviation.
*Defined as a systolic BP ≥ 160 mmHg or a diastolic BP ≥ 110 mmHg; * t-test for independent means, or chi-square test with continuity correction.

Table 2
Blood pressure change according to study group. Change in blood pressure (mmHg) at the 12-week visit compared with baseline, expressed as mean values with
standard deviation (SD) and 95% confidence intervals (CI). Differences between calcium and placebo groups expressed as mean differences with 95% CI), for all
women and for women with and without severe features of pre-eclampsia in the previous pregnancy.
Calcium Placebo Difference (Placebo - Calcium) p (*)

N Mean (SD) 95% CI N Mean (SD) 95% CI 95% CI

All
Systolic 387 − 5.3 (15.0) − 6.8, − 3.8 404 − 2.2 (17.8) − 3.9, − 0.5 3.1 0.8, 5.4 0.009
Diastolic 387 − 2.6 (13.0) − 6.8, − 3.8 404 − 2.2 (17.8) − 3.9, − 0.5 1.4 − 0.5, 3.3 0.140
**
MAP 387 − 3.5 (12.4) − 4.7, − 2.2 404 − 1.5 (14.1) − 2.9, − 0.1 2.0 0.1, 3.8 0.038
With Severe pre-eclampsia
Systolic 217 − 6.2 (15.2) − 8.2, − 4.1 230 − 2.2 (20.1) − 4.8, 0.4 4.0 0.7, 7.3 0.018
Diastolic 217 − 3.7 (12.2) − 5.3, − 2.0 230 − 0.6 (14.8) − 2.6, 1.3 3.0 0.5, 5.5 0.019
MAP** 217 − 4.5 (12.0) − 6.1, − 2.9 230 − 1.2 (15.4) − 3.2, 0.8 3.3 0.8, 5.9 0.011
Without Severe pre-eclampsia
Systolic 170 − 4.1 (14.8) − 6.4, − 1.9 174 − 2.3(14.2) − 4.4, − 0.1 1.9 − 1.2, 5.0 0.229
Diastolic 170 − 1.3 (13.8) − 3.4, 0.8 174 − 1.9 (13.1) − 3.9, 0.1 − 0.6 − 3.5, 2.2 0.673
**
MAP 170 − 2.2 (12.9) − 4.2, − 0.3 174 − 2.0 (12.3) − 3.9, − 0.2 0.2 − 2.5, 2.9 0.873
*
p-value.
**
MAP: mean arterial pressure.

reduction strategy for hypertensive and normotensive individuals at supplementation in a dose that could be achieved by food fortification
increased risk of hypertension [22]. In contrast, calcium supplementa­ and dietary intake [12]. With 791 participants, our trial increases by
tion above adequate calcium intakes is not recommended to prevent or 25% the data available in the 2015 Cochrane review of calcium sup­
treat hypertension. There is contradictory evidence from cohort studies plementation to prevent hypertension and is almost double the size of
regarding the use of calcium supplementation above recommended the subgroup less than 35 years of age (9 trials; 399 women) [7]. Also,
levels which may actually increase coronary artery calcification and blood pressure was measured in a standardized fashion and analysis was
cardiovascular risk in older ages [23–26]. by intention-to-treat.
Addressing modifiable risk factors is a key element of preventing The baseline characteristics of the participants of this sub-study
future morbidity. Women with previous pre-eclampsia, particularly if provided reassurance that the effectiveness of randomization was pre­
the disease was of early onset or recurrent, are at increased risk of served in this group of women. However, interpretation of our results
developing cardiovascular disease later in life [11,27,28]. Therefore, the should take into account the fact that pre-pregnancy effects of calcium
reduction in systolic and mean arterial pressure with low-dose calcium supplementation was not the primary purpose of the main trial.
supplementation in these non-pregnant women is of clinical importance. In conclusion, modest calcium supplementation (500 mg/day)
The magnitude of the blood pressure reduction observed in our trial is designed to achieve levels associated with adequate dietary intake was
similar to the average 2.6/1.5 mmHg reduction seen following recom­ associated with a clinically important reduction in systolic and mean
mended reductions in dietary sodium intake [29]. Small changes (as low arterial pressure among women with prior pre-eclampsia, who are at
as a 2 mmHg reduction in systolic blood pressure) at a population level increased cardiovascular risk. Our results would support strategies to
are associated with important reductions in vascular disease, including improve calcium intake in women from low dietary calcium intake
stroke, ischemic heart disease, and all-cause mortality [30–32]. The populations at higher risk for hypertension due to previous pre-
large dietary calcium intake deficiencies seen in low- and middle- eclampsia. Such approaches could include food fortification [21] or
income countries such as our trial sites [16] may be difficult to ach­ individualized supplementation of women with previous pre-eclampsia
ieve without staple food fortification. or eclampsia.
The strengths of this study are the double masked, randomized na­
ture of calcium supplementation, recorded dietary calcium intake, and

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