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

previous pre-eclampsia: An exploratory, randomized placebo controlled study

Christopher Doyle
I.

Introduction/Background
Pre-eclampsia is a progressive condition characterized by high blood pressure and
proteinuria occurring after the 20th week of pregnancy. This maternal disorder is among the
leading causes of maternal and infant illness and death worldwide, affecting 5-8% of all
pregnancies and responsible for approximately 76,000 maternal and 500,000 infant deaths per
year (1). Pre-eclampsia is a multisystem disorder characterized by uteroplacental and maternal
endothelial dysfunction. It is widely accepted that placental hypoxia can trigger pre-eclampsia.
However, this is likely secondary to defective placental vasculature (2). This impairment is likely
due to defective trophoblast invasion, in which remodeling of the smooth muscle cell layer of the
maternal vasculature by embryonic cytotrophoblasts causes the placental vasculature to
become dilated, with low resistance under normal circumstances. In pre-eclampsia, shallow
trophoblast invasion results in non-dilated placental blood vessels and high resistance (3).
Although rates of pre-eclampsia have been reduced significantly over the past 50 years,
the rates of pre-eclampsia, eclampsia and maternal mortality remain high in developing
countries (4). The condition is known to be considerably more prevalent in poorer communities
(5). However, two striking exceptions have been identified in which an inverse relationship
between calcium intake and pre-eclampsia was observed. In 1980, it was observed that Mayan
Indians in Guatemala, who traditionally soak their corn in lime before cooking, have a low
prevalence of pre-eclampsia and eclampsia (6). Ethiopians, who also have high calcium levels
in their diets, were found to have lower prevalence of these disorders as well (7). These findings
led to the hypothesis that calcium intake during pregnancy may reduce the incidence of preeclampsia in pregnant women.
Randomized controlled trials testing this hypothesis found that calcium supplementation
of at least 1 gram per day during pregnancy is associated with a reduction in the severe
manifestations of pre-eclampsia (8-11). However, a large trial by the World Health Organization
(WHO) found that calcium supplementation in pregnant women with adequate dietary intake did
not have any significant effects on the proteinuria associated with pre-eclampsia (12). To
reconcile these findings, it was suggested that calcium supplementation in pregnancy reduces
blood pressure, thereby reducing severe manifestations of pre-eclampsia without affecting the
underlying pathology of pre-eclampsia (5). Low calcium intake may cause high blood pressure
by stimulating either the parathyroid hormone or renin release, thereby increasing intracellular
calcium in vascular smooth muscle leading to vasoconstriction (13). Calcium supplementation
can decrease blood pressure by reducing parathyroid hormone release, reducing smooth
muscle contractility. By a similar mechanism, calcium supplementation could reduce smooth
muscle contractility in the uterus, preventing preterm labor (14). Calcium can also increase renal
excretion of dietary NaCl due to competition at reabsorption transporters in the kidney (15), and
can improve insulin sensitivity since insulin secretion is a calcium-dependent process (16).
According to Centeno et al., low calcium diets are associated with hypertension in the general
population (17). Animal studies have shown that high calcium diets can reduce hypertension
related to oral contraceptive use by improving diuresis and vasorelaxant responses (18). A high
dairy diet has also been found to reduce systolic and diastolic blood pressure levels by about 2
mmHg, which is correlated with reduced intracellular calcium (19). In a randomized, placebo
controlled human study, the effect of calcium supplementation on non-hypertensive women with
a mean age of 74 was measured. Results showed an association between 1 g of calcium daily
and a small reduction in systolic blood pressure at 6 months only. The reduction was greater in
a subgroup of women with low dietary calcium (20).

Hofmeyr et al. developed a study on the effects of calcium on non-pregnant women with
previous pre-eclampsia due to a lack of previous randomized human trials on the topic (5). They
deduced that if calcium deficiency is a factor in the genesis of pre-eclampsia, women with
previous pre-eclampsia may be more susceptible to the effects of calcium on blood pressure.
Hofmeyr et al. hypothesized that calcium supplementation in non-pregnant women with previous
pre-eclampsia is associated with reduced systolic and diastolic blood pressure. Additionally,
they hypothesized that the effect of calcium supplementation on blood pressure is greater in
women with previous severe pre-eclampsia/eclampsia (5).
II.

Methods
This study randomized 836 women, with 94% of the women recruited from African sites
and 6% of the women recruited from Argentinean sites. The blood pressures of both the
placebo and experimental group were collected at admission, with no significant differences
between either group at baseline. Due to various exclusions, only 367 of these women were
included in the first subgroup where blood pressures were compared at admission and during
their first follow-up visit 12 weeks after admission. Of these women, 217 previously had severe
pre-eclampsia, while 150 did not. A second follow-up group 24 weeks after admission contained
201 women (5).
WHO conducted this randomized, double-blind placebo-controlled clinical trial examining
the effect of long-term calcium supplementation in women at high risk of pre-eclampsia. The trial
begun in 2011 and is currently on-going. Non-pregnant women who had pre-eclampsia or
eclampsia in their most recent pregnancy are randomized to receive either 500 mg/day
elemental calcium or a placebo. The trial is being conducted in various hospitals in South Africa,
Zimbabwe and Argentina. In the current on-going trial, a nutritional interview was conducted
among all women enrolled in the trial who reach 20 weeks gestation to confirm low calcium
intake in the study population. Inclusion criteria are: females who experienced pre-eclampsia or
eclampsia in their most recent pregnancy, those in a sexual relationship, not pregnant, not using
contraception, and those giving informed consent. Exclusion criteria are: females less than 18
years of age, those with chronic hypertension with persistent proteinuria, females taking calcium
supplements, and those with a history or symptoms of urolithiasis, renal disease or parathyroid
disease (5).
The intervention group took one chewable tablet containing 500 mg calcium daily from
the time of enrollment (before pregnancy) until 20 weeks gestation. Women were asked to take
the tablet during the day and not close to intake of food or iron supplements. The control group
received a placebo tablet identical in shape, color and taste to the tablet given to the
intervention group. The women were told not to intake any additional calcium supplements. All
the women in the trial were given unblinded calcium supplements (1.5 g) from 20 weeks
gestation until delivery (5).
Blood pressure measurement was standardized at the beginning of the trial. Blood
pressure was measured at baseline and subsequently in all following trial visits. Visits were
scheduled every 12 weeks until pregnancy began, and then at 8, 20, and 32 weeks. Baseline
data were compared between the calcium and placebo groups for the study population ensuring
no selective loss. Two comparisons were made: between baseline and 1st trial visit
(approximately 12 weeks after baseline), and between baseline and 2nd trial visit
(approximately 24 weeks after baseline). Changes in systolic and diastolic blood pressures were
calculated by subtracting the measurement at baseline from the measurement at the first and
second follow-up visit. Mean changes in blood pressures, expressed with 95% confidence
intervals, were compared between the calcium and placebo groups (5).

III.
Interpretation of Results
Blood pressure comparisons in the first follow-up visit resulted in reduced systolic and
diastolic blood pressure values for both the calcium and placebo groups, excluding the diastolic
placebo group. Overall, the calcium intervention group yielded greater blood pressure
reductions between the admission and first follow-up visit, with a mean reduction of 4.1 mmHg
systolic and 0.8 mmHg diastolic in the supplementation group compared to a 2.7 mmHg systolic
reduction and 0.2 mmHg diastolic increase in the placebo group. However, these differences
were generally small and not statistically significant. Similar results were noted in the second
follow-up visit, with 5.9 mmHg and 2.5 mmHg reductions in systolic and diastolic blood
pressures of the supplementation group respectively, and 3.3 mmHg systolic and 1.2 mmHg
diastolic reductions in the placebo group. Again, these differences were statistically insignificant.
When the follow-up visit data was stratified based on severe pre-eclampsia in previous
pregnancies, similar trends were noted. However, there was a significant reduction in diastolic
blood pressure in the group with previous severe pre-eclampsia, with a mean difference of -3.4
mmHg at p= 0.025. This result implies that women who previously had severe pre-eclampsia
may be more sensitive to calcium deficiency than women without, perhaps because of either a
greater dietary deficiency or a greater sensitivity to a deficiency. However, the etiology of the
condition cannot be inferred based on this study, as calcium levels were not analyzed prior to
conducting the study.
Calcium is important for healthy blood pressure because it helps blood vessels tighten
and relax when they need to. Manipulations of dietary calcium have been shown to alter blood
pressure in past research. Supplemental dietary calcium lowers blood pressure, whereas diets
restricted in calcium tend to elevate blood pressure. The mechanisms responsible have not
been identified, but numerous possibilities have been proposed. Many of the proposals have
attempted to relate dietary calcium to calcium metabolism in vascular smooth muscle and
altered vascular tone. Other proposals have focused on neural, hormonal, and renal effects of
dietary calcium (21).
Due to the exploratory nature and the multiple comparisons performed, results need to be
interpreted cautiously. An overall effect of calcium supplementation on blood pressure was not
confirmed. Nonetheless, a consistent trend of significant blood pressure reductions in the
calcium in comparison to the placebo group were found at both trial visits (at 12 weeks and
24 weeks after randomization). Differences were not statistically significant except for diastolic
pressure in the sub-group of women with previous severe pre-eclampsia. These women with
previous severe forms of pre-eclampsia may be more sensitive to the effects of calcium
supplementation on diastolic blood pressure than women with previous non-severe preeclampsia. The latter finding is consistent with the hypothesis that women who are susceptible
to pre-eclampsia may be uniquely sensitive to calcium deficiency, either because of greater
dietary deficiency or because of an inherent sensitivity to calcium deficiency (5).
IV.

Were the results in agreement with other research (yes or no)?

The overall greater reductions in blood pressure in the supplementation group compared
to the placebo group only loosely supports previous literature findings which suggest calcium
supplementation can reduce blood pressure (13-20), as the unstratified overall differences were
not statistically significant. Furthermore, whereas many of these studies proposed a mechanism
to explain why this reduction could occur, Hofmeyr et al. did not seek to provide any
physiological explanation as to why calcium supplementation could reduce blood pressure.
Unlike Belizan et al., McCarron et al., or Sun et al., Hofmeyr did not measure parathyroid
hormone levels, urinary NaCl excretion, or insulin sensitivity (13,15,16). Therefore, Hofmeyr et
al. did not add any potential physiological observations that could have expanded on previous
literature regarding the pathophysiology of pre-eclampsia.

Despite these limitations, this paper did add significant insight into how calcium
supplementation could be useful specifically for women who have had severe pre-eclampsia in
previous pregnancies. The significant reduction in diastolic blood pressure among previously
diagnosed women supports previous literature, suggesting that calcium supplementation may
reduce the severity of severe pre-eclampsia (8-11). However, while these studies agree that
calcium supplementation can reduce the effects of pre-eclampsia, these studies vary in how
they were conducted, and differ in methods in reducing blood pressure and negative outcomes
associated with pre-eclampsia. For example, Belizan et al.s randomized controlled trial
revealed only a reduction in the systolic blood pressure and was conducted on women who
were currently pregnant (8). Similarly, Crowther et al. demonstrated a reduction in risk of preeclampsia and preterm delivery with calcium supplementation but did not specifically address
systolic or diastolic blood pressure changes (10).
It is also crucial to note that while each of these studies did show various improvements
with calcium supplementation, they were conducted on varying populations. Hofmeyr et al.
mostly examined women from Africa, while Belizan et al., Crowther et al., and Niromanesh et
al., examined women from Argentina, Australia, and Iran respectively (8, 10, 11). Therefore, the
results of this study neither support nor refute the relationship between poverty, calcium intake,
and demographics of pre-eclampsia suggested by other studies (6, 7).
Consequently, the Hofmeyr et al. study is generally in agreement with the existing
literature on calcium supplementation and the reduction of the severity of pre-eclampsia.
However, the study adds only a very specific component to the current literature as it only
provided significant diastolic reductions in women with previous severe pre-eclampsia.
Take for instance a study performed on fifty-two healthy pregnant women who were
enrolled in a double-blind, randomized, controlled clinical trial. After the 26th week of gestation,
the women were given either 1.5 g of elemental calcium per day or a placebo. Subjects in the
calcium group, after adjustment for race and initial blood pressure (BP), had a term mean
systolic and diastolic BP value of 4-5 mmHg lower than those in the placebo group. The
incidence of pregnancy-induced hypertension was 11.1% in the placebo group and 4.0% in the
calcium group, a non-significant difference. Combining these values with previous data, a doseeffect relationship was found between calcium intake and BP reduction during the third trimester
of pregnancy. Further research needs to be conducted to gain an understanding of the
mechanism of this effect, demonstrating a reduction in pregnancy-induced hypertension with
calcium supplementation in a larger population (22).
Interestingly, data from epidemiologic surveys and clinical trials have shown that calcium
metabolism is altered in people with hypertension, indicating a primary role of calcium in the
etiology, prevention, and treatment of hypertension. Investigative efforts worldwide have
identified abnormalities in numerous biochemical parameters of calcium metabolism, and a
consistently low intake of dietary calcium in those with high blood pressure. Calcium
supplementation trials have reported varying results in terms of blood pressure response, and it
is generally concluded that many hypertensive patients may benefit from increased calcium
intake. The blood pressure-lowering effect of calcium may be of particular benefit to the elderly,
people of African origin and pregnant women. Interactions between dietary nutrients have been
shown to be critical in the effect of calcium on blood pressure, particularly sodium and
potassium. Lastly, based on data in this area, calcium intake is postulated to have clinical
application in the treatment of sodium-sensitive, alcohol-associated, and pregnancy-induced
hypertension, and type II diabetes mellitus; and adequate, long-term calcium intake may be a
means of preventing the development of hypertension (23).
V.

Conclusion and Relevance to Nutrition Public Health

Hofmeyr et al. (5) determined that while there was an overall trend of reduced blood
pressure, it was not significant. In fact, the only statistically significant finding was in the

difference between diastolic blood pressure of women with previous severe pre-eclampsia who
received treatment (500 mg Ca/day) compared to women with previous severe pre-eclampsia in
the placebo group. In other words, the interaction between treatment and severity of previous
pre-eclampsia was significant (p = 0.20, ANOVA analysis). These results support the
researchers hypothesis that women with previous severe pre-eclampsia are more sensitive to
calcium supplementation. However, this is only their hypothesis and not necessarily the correct
mechanism. They did not look to identify the underlying mechanism in this article, so these
results must be interpreted with caution. Caution must also be taken because of the effect of
genetics on high blood pressure when considering this study took place at multiple sites in
Africa and Argentina. According to WHO, Africa has the highest prevalence of high blood
pressure as 46% of adults have the condition. Therefore, confounding variables that were not
controlled for may be responsible for the significance.
The implements of this study are far reaching for public health for two reasons. Firstly,
being part of the larger WHO calcium and pre-eclampsia (CAP) trials, the results provide
valuable data that the WHO will be able to use in the future regarding blood pressure, calcium
supplementation and/or pre-eclampsia. Therefore, regardless of this studys minimal
significance, its impact will have a greater effect in the large scheme of research. Secondly,
because of the worldwide prevalence of high blood pressure and pre-eclampsia, these two
issues are applicable to a large number in the population. Pre-eclampsia/eclampsia is in the top
three causes of maternal morbidity and mortality, and can impact both maternal and child
health. For example, mothers can suffer from stroke, seizure, and heart failure. Children born to
mothers with eclampsia can be born prematurely and develop learning disabilities, hearing and
vision issues, epilepsy, and cerebral palsy. Worldwide, high blood pressure affects 1 in 3 adults
and increases the risk for heart disease and stroke, two of the leading causes of death. It is
clear the results of this study have worldwide implications relevant to public health (24).
Unfortunately, the significance was minimal, yet the results hint at calcium helping to reduce
blood pressure. If the mechanism could be teased out and better understood, it is possible that
calcium supplementation could be utilized as a treatment option for hypertension, even if only in
the niche of women with previous severe pre-eclampsia. Nutrient supplementation could provide
a far more economically sensible option compared to current drug treatment for high blood
pressure, making treatment available to more people globally.
VI.
Future Studies
Identifying the possible roles of calcium deficiency on the etiology of pre-eclampsia
would be important for reducing prevalence. Proposed, but not yet studied, mechanisms include
improving diuresis and vasorelaxant responses (18), mitigation of the hypertensive effects of
NaCl (15), and changes in vitamin D and parathyroid hormone concentration (13). Vitamin D
may prove to be especially vital for its role in decreasing the risk of hypertension and calcium
homeostasis. Vitamin D regulates calcium in the small intestine, kidney, and in bone (5).
Therefore, designing an experiment that takes vitamin D levels into account when looking at
calcium is critical. Adding a vitamin D group to the current study could have improved
significance because vitamin D levels affect calcium absorption. Low vitamin D levels decrease
the absorption of calcium, so any women with impaired vitamin D levels may not have been as
affected during the present study, not due to calcium. Developing a better understanding of the
biochemical mechanism of calcium and pre-eclampsia would prove vital if calcium is to be
considered in the future as a treatment for high blood pressure.
Additionally, a dose-response relationship must be determined to provide causality.
Therefore, the effective dose of calcium must be identified. This study supplemented at 500
mg/day. Would higher or lower doses change the results? Would smaller doses administered
multiple times a day affect results? Would intravenous administration have different effects in
comparison to oral administration in reducing blood pressure? These questions must be

answered. The genetic component must also be identified to better understand relationships. It
is known that Africans, including African Americans, suffer from higher rates of hypertension.
This study was conducted in sites in Argentina, South Africa and Zimbabwe. Performing this
study again in other parts of the world may deliver different or unexpected outcomes due to both
genetic and environmental factors. Similarly, it would help clarify the relationship between
poverty, calcium deficiency, and the prevalence of pre-eclampsia in certain regions (6, 7).
Lastly, there is a gap in high quality studies with heterogeneity between trials. Therefore,
it is extremely difficult to review and interpret results from similar studies to confidently
determine the effect of calcium on blood pressure. Variations in doses, location, sample size,
and study designs are examples of this heterogeneity. Research must be replicable to have
increasing confidence and sound scientific influence. While further research is necessary, the
results of this study are a meaningful starting point in determining the relationship between
calcium and pre-eclampsia.

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