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The Journal of Maternal-Fetal and Neonatal Medicine, 2012; 25(12): 25702574

2012 Informa UK, Ltd.


ISSN 1476-7058 print/ISSN 1476-4954 online
DOI: 10.3109/14767058.2012.715220

Review

 alcium supplementation and prevention of preeclampsia:


C
a meta-analysis
Tito Silvio Patrelli1, Andrea DallAsta1, Salvatore Gizzo1, Giuseppe Pedrazzi3, Giovanni Piantelli1,
Valerio Maria Jasonni2 & Alberto Bacchi Modena1
1Department of Obstetrics, Gynecology and Neonatology, University of Parma, Parma, Italy, 2Department of Obstetrics and

Gynecology, Bologna Toniolo Clinic, Bologna, Italy, and 3Department of Public Health, University of Parma, Parma, Italy

Background: Since the early 1980s, epidemiological evidence


has suggested a connection between low calcium intake and
preeclampsia The purpose of this meta-analysis is to summarize
current evidence regarding calcium supplementation during
pregnancy in predicting preeclampsia and associated maternal
fetal complications. Methods: Literature revision of all RCT (random
allocation of calcium versus placebo) available in MEDLINE/
PUBMED up to 2/29/2012 regarding calcium supplementation
during pregnancy for preventing preeclampsia. We used the
Mantel-Haenszels Method for four subgroup of patients: Adequate
calcium intake; Low calcium intake; Low risk of preeclampsia;
High risk of preeclampsia. We considered p < 0.05 as significant.
Results: There is no consensus in Literature about: (1) the efficacy
of calcium supplementation in the prevention of preeclampsia, (2)
other/adverse/long-term effects of calcium supplementation in
pregnancy. Conclusions: Preeclampsia is likely to be a multifactorial
disease. However, inadequate calcium intake represents a factor
associated with an increased incidence of hypertensive disease.
The results of our meta-analysis demonstrate that the additional
intake of calcium during pregnancy is an effective measure to
reduce the incidence of preeclampsia, especially in populations at
high risk of preeclampsia due to ethnicity, gender, age, high BMI
and in those with low baseline calcium intake.
Keywords: Calcium, high risk patients, low risk patients,
micronutrients, preeclampsia, pregnancy supplementation,
vitamin D

Introduction
Hypertension during pregnancy is currently one of the main
causes of maternal mortality and morbidity and is associated with
prematurity and increased perinatal mortality [1].
Blood pressure measurements taken 6h apart equal to or
greater than 140/90mmHg, in formerly normotensive women,
after the 20th week of pregnancy, without proteinuria, defines
pregnancy-induced hypertension (PIH) [2]. Preeclampsia is a
clinical syndrome of unknown etiology characterized by the
occurrence of hypertension and proteinuria after 20 weeks of
gestation, in formerly normotensive women.
During pregnancy and nursing, calcium requirements are
increased in order to maintain calcium balance and maternal
bone density, and to satisfy fetal growth requirements.

To ensure a normal pregnancy outcome, an adequate maternal


nutritional status is essential as well as a sufficient daily intake of
micronutrients such as folic acid, vitamins, and minerals [3,4].
The currently recommended daily calcium intake during pregnancy is between 300 and 2000mg [5].
Several studies have demonstrated favourable effects of
calcium supplementation during pregnancy in relation to bone
mineralization and fetal growth and prevention of maternal
osteopenia [6].
Presently, the effects of additional calcium intake on other
pregnancy outcomes, such as preterm labour, low birth weight
and intrauterine growth retardation (IUGR), are controversial.
Since the early 1980s, epidemiological evidence has suggested
a connection between low calcium intake and preeclampsia
[710]. This relationship is supported by the following two points
[1113]:
1. The incidence of preeclampsia and eclampsia is low in populations with elevated mean calcium intake, such as native populations in South America and Ethiopia.
2. Preeclamptic patients have calcemia and calciuria levels lower
than normotensive pregnant women.
Several Randomized Controlled Trials (RCT) have tested the
utility of routine calcium supplementation in preventing pregnancy-induced hypertensive disorder [1,5]. These encouraging
results [11] prompted more recent observational studies which
have not shown benefits arising from calcium and vitamin D
intake in preventing preeclampsia [14]. The purpose of this metaanalysis is to summarize current evidence regarding calcium
supplementation during pregnancy in predicting preeclampsia
and associated maternalfetal complications.

Methods
We examined international literature regarding calcium
supplementation for the prevention of preeclampsia. The search
string used by MEDLINE/Pubmed was calcium supplementation
prevention preeclampsia. The electronic research yielded 113
results, 56 reviews. We considered eligible for our meta-analysis
all RCT (random allocation of calcium versus placebo) available
in English-language Journals up to 2/29/2012 regarding calcium
supplementation during pregnancy for preventing preeclampsia,
regardless of the age, parity, clinical and family history of all

Correspondence: Tito Silvio Patrelli, MD, Dipartimento di Scienze Ostetriche, Ginecologiche e di Neonatologia, U.O.C. di Ginecologia e Ostetricia, Viale
Gramsci, 1443100 Parma Italy. Tel.: +39 339 2817381. E-mail: titosilvio.patrelli@gmail.com

2570

Daily calcium intake and preeclampsia onset2571


patients involved in the trials. We applied the Mantel-Haenszels
Method to four subgroup of patients:
1. Adequate calcium intake;
2. Low calcium intake;
3. Low risk of preeclampsia;
4. High risk of preeclampsia.
We considered p < 0.05 as significant.

Results
In total, 16 studies were examined.

risk was 7% in women supplemented with calcium and 12.7%


in women supplemented with placebo (OR = 0.51, 95% CI =
0.280.93) [18].
Adverse effects of calcium supplementation in pregnancy
Adverse effects associated with calcium supplementation were
described as increased incidence of nephrolithiasis, urinary tract
infections and malabsorption of other minerals including iron,
zinc and magnesium [5].
Hofmeyr et al. [19] and Barton et al. [20] reported higher
frequency of HELLP syndrome in patients supplemented with
calcium, probably because of the non-diagnosis or delayed diagnosis of preeclampsia, allowing the disease to progress quicker
and cause complications. Other authors emphasize the absence of
adverse effects associated with calcium supplementation [21,22].

Efficacy of calcium supplementation in the prevention of


preeclampsia
The RCT performed on pregnant women with adequate calcium
intake were six, for a total of 9641 patients. Application of the
Mantel-Haenszels Method demonstrated a statistically insignificant relationship (p = 0.09) between calcium supplementation during pregnancy and the risk of preeclampsia (RR = 0.88;
95% CI=0.771.02) in patients with adequate calcium intake
(Figure1). Conversely, calcium supplementation in pregnant
women with low calcium intake (seven studies, 10 154 patients)
demonstrated a significant reduction in the incidence of
preeclampsia (RR=0.73; 95% CI = 0.610.87) (Figure 2).
Calcium supplementation in patients with high risk of
gestational hypertensive disease (three studies, 346 patients)
significantly reduced the risk of preeclampsia (RR = 0.17; 95%
CI = 0.070.41) (Figure 3).
Moreover, calcium supplementation in low risk patients (seven
studies, 11 059 patients) significantly reduced the incidence of
preeclampsia (RR = 0.74; 95% CI: 0.630.88) (Figure 4).

Discussion

Other effects of calcium supplementation in pregnancy


Jabeen et al. [1] showed that calcium supplementation during
pregnancy did not significantly reduce the incidence of MEF
(RR = 0.81). Hofmeyr et al. [12] also reached similar conclusions. Calcium intake was not protective against low birth weight
(LBW) [15] and IUGR, and had no significant impact on perinatal mortality [1].
The addition of calcium supplementation did not prevent
spontaneous preterm delivery [15]. The risk of prematurity was
reduced only in women at high risk of hypertension (RR = 0.42,
95% CI = 0.230.78) [16]. A recent randomized controlled trial
documented an indirect reduction in the incidence of preterm
labour and of perinatal complications in pregnant women supplemented with calcium (RR = 0.76, 95% CI = 0.600.97) [15]. The

At present, the etiology of hypertensive disease in pregnancy


is unknown, thereby limiting prevention [7]. Preeclampsia is
likely to be a multifactorial disease. To date, several pathogenetic
hypotheses suggest immunological, genetic, and dietetic factors
[25], in addition to growth factors and placental proteins (PP
13) [26]. Hence, it is unlikely that any single intervention will
effectively prevent the occurrence of pregnancy complications.
Due to the heterogeneous causes of preeclampsia, it has been
hypothesised that the pathogenesis is different in women with
multiple risk factors [20]. Furthermore, the possibility that PIH
and preeclampsia are diseases with different pathogenesis must
not be excluded [7]. Knowledge of known risk factors, however,
can help formulate preventative strategies for patients who are
most likely to develop hypertensive disease. Inadequate calcium
intake, defined as a daily intake less than 600mg, represents a

Long-term effects of calcium supplementation in pregnancy


In the review by Villar and Belizan [16], the possible effects of
calcium intake on the children of women treated were evaluated.
In an RCT conducted by Belizan et al. [23] on the children of
pregnant women, involved in a previous RCT, who were randomized to calcium supplementation with 2g/day versus placebo [24],
it was shown that, at the age of 7, the childrens average systolic
blood pressure was lower if their mothers had been supplemented
with calcium (mean difference = 1.4 mmHg, 95% CI = 3.2 to
0.5 mmHg) as compared to children whose mothers received
a placebo. This effect was greater in children with a body mass
index (BMI) higher than the average population, indicating that
calcium supplementation in pregnancy reduces systolic blood
pressure in children especially if they are overweight.

Figure 1. Calcium supplementation and preeclampsia in adequate calcium intake patients.

2012 Informa UK, Ltd.

2572 T. S. Patrelli et al.


factor associated with an increased incidence of hypertensive
disease [10].
This aspect is particularly relevant in developing countries
and in regions where the diet is traditionally low in calcium. The
recommendation of calcium supplementation during pregnancy is
low cost and devoid of special risks and could significantly reduce
the incidence of PIH, preeclampsia and associated complications.
Lopez-Jaramillo et al. [27] and Crowther et al. [28] demonstrated a beneficial effect of calcium supplementation in preventing
preeclampsia in patients with low baseline intake (RR = 0.21) and in
those with adequate intake (RR = 0.40). In contrast, Levine et al. [29]
and Villar et al. [17] found a significant reduction in the relative risk
only in certain subpopulations, such as those suffering from isolated
eclampsia (RR = 0.68) or with severe early onset preeclampsia,
HELLP syndrome or severe hypertension (RR = 0.76).
Important studies, including the Calcium for Preeclampsia
Prevention trial, have not demonstrated benefits of calcium
supplementation [1].

However, the results of our meta-analysis demonstrate that


the additional intake of calcium during pregnancy is an effective measure to reduce the incidence of preeclampsia, especially
in populations at high risk of preeclampsia due to ethnicity,
gender, age, high BMI and in those with low baseline calcium
intake, as demonstrated by recent and authoritative RCT
(Table I) [18].
Briceo-Perez and colleagues [30] concluded that secondary
prevention with aspirin and calcium during pregnancy is useful
in pregnant women with low calcium intake and/or high risk of
developing early preeclampsia: in groups at increased risk, the
RR for preeclampsia was almost halved (RR = 0.45, 95% CI =
0.310.65) [17]. In addition to clinical history, doppler screening
of the uterine vessels may be helpful in identifying candidates for
calcium supplementation [31]. Regarding the low risk women
and those with adequate intake of calcium, most of the studies
showed the lack/absence of benefits deriving from calcium
supplementation [17,32].

Figure 2. Calcium supplementation and preeclampsia in low intake patients.

Figure 3. Calcium supplementation and preeclampsia in high risk patients.

Figure 4. Calcium supplementation and preeclampsia in low risk patients.


The Journal of Maternal-Fetal and Neonatal Medicine

Daily calcium intake and preeclampsia onset2573


Table I. Studies included in this meta-analysis and their features.
Studies
Features
CPEP [29]
Study performed on nulliparous patients, G.A. between 13 and 21 weeks, with BP < 135/85 mmHg, albustick: negative/trace.
Supplemented with calcium carbonate 2g/day.
Crowther et al. [28]
Study performed on nulliparous patients, singleton pregnancy, G.A.: <24 weeks; BP < 140/90 mmHg. Supplemented with
calcium carbonate 1.8g/day.
Villar et al. [43]
Controlled double-blind study conducted on nulliparous and primiparous patients singleton pregnancy, between 18- and
30-year-old, roll-over test: negative. Supplemented with calcium carbonate 2g/day.
Villar and Repke [35]
Controlled double-blind study on healthy pregnant women <18-year-old; singleton pregnancy. Supplemented with calcium
carbonate 2g/day.
Sanchez-Ramos et al. [36]
Controlled double-blind study nulliparous patients, normotensive. Roll-over test: positive. ATII infusion test at 2024 weeks:
positive. Supplemented with calcium carbonate 2g/day.
Purwar et al. [37]
Controlled double-blind study on nulliparous patients; G.A.: <20 weeks; singleton pregnancy, not hypertensive, Glucose
Tolerance Test: normal; healthy. Supplemented with elemental calcium 2g/day.
Lopez-Jaramillo et al. [27]
Controlled double-blind study, on nulliparous patients; age <17.5-year-old; G.A.: <20 weeks, residing in Quito at least one year;
BP 120/80 mmHg. Supplemented with calcium carbonate 2g/day.
Lopez-Jaramillo et al. [38]
Controlled double-blind study on healthy nulliparous patients. Roll-over test within 24 weeks: positive; considered at risk of
gestational hypertension. Supplemented with elemental calcium 2g/day starting from 2832 weeks.
Lopez-Jaramillo et al. [39]
Randomized study performed on nulliparous patients, age <26-year-old, evaluated within 24 weeks, normotensive, healthy,
residing in Quito, no supplementation/therapy. Supplemented with calcium gluconate 2g/day.
Belizan et al. [24]
Multicentric study performed on nulliparous patients. G.A.: <20 weeks; PB < 140/90 mmHg. Supplemented with calcium
carbonate 2g/day.
Niromanesh et al. [40]
Controlled double-blind study on high preeclampsia risk patients. Roll-over test: positive. Minimum one risk factor for
preeclampsia. G.A.: 2832 weeks. BP < 140/90 mmHg. Supplementated with elemental calcium 2g/day.
Levine et al. [29]
Controlled randomized trial on healthy nulliparous women. G.A.: 1321 weeks. Random allocation: supplementation with
elemental calcium 2g/day versus placebo.
Villar et al. [17]
Controlled double-blind study on population with low calcium intake (<600mg/day), primiparous patients, G.A.: <20 weeks,
not hypertensive, not nephropathic, negative for urolithiasis and for parathyroid disease. Supplemented with calcium 1.5g/day.
Kumar et al. [18]
Study performed on primigravida patients with G.A.: between 12 and 25 weeks, low daily calcium intake (<900mg/day).
Supplemented starting from 1225 weeks until the day of delivery with calcium 2g/day.
Wanchu et al. [41]
Study performed on nulliparous patients with G.A.: <20 weeks, not comorbidity, low calcium intake (<900mg/day).
Supplemented with Calcium 2g/day until the day of delivery.
Taherian et al. [42]
Study performed on nulliparous patients with G.A.: <20 weeks, no comorbidity, low calcium intake (<900mg/day).
Supplemented with calcium 500mg/day until the day of delivery.

According to our study, calcium supplementation does not


significantly reduce the incidence of unfavourable outcomes only
in patients with adequate calcium intake.
The importance of the clinical characteristics of the women
supplemented has been demonstrated in the Calcium for
Preeclampsia Prevention Trial (CPEP) (1997) [29]. There has
been controversy over the inclusion criteria for the study and
other on issues such as confounding factors represented by a late
start of supplementation and poor patient compliance [33].
When to start supplementing? Presently, the most likely
hypothesis on the pathogenesis of preeclampsia (two-stage
disorder) [2] purports that calcium must be administered early
in the first trimester, if not before conception, and that initiating
supplementation in the second trimester seems to be too late [34].
Finally, it is essential to quantify the minimum effective dosage
of calcium to reduce hypertension in pregnancy. E. Oken and
colleagues [14] have found a significant reduction of RR in PIH
(0.58, 95% CI = 0.220.97) and preeclampsia (0.35, 95% CI =
0.200.60) with an intake of at least 1g/day [17]. Therefore, even
in light of the current recommendations [3], we consider 12g
daily to be the right dosage.
In conclusion, our study demonstrated the utility of calcium
supplementation in the prevention of preeclampsia, particularly in women at high risk and/or with a low calcium diet.
Administration of calcium should start early and unlike Hofmeyr
et al. [19], we believe that supplementation should be only
addressed to people most at risk and not to all pregnant women
[34]. Further studies are needed, however, to confirm the beneficial effects of these treatments.

2012 Informa UK, Ltd.

Acknowledgments
The Authors thanks to Mrs. Carolyn David for her precious help
in proofreading the English.
Declaration of Interest: The authors report no conflicts of interest.

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