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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

Background: Since the early 1980s, epidemiological evidencehas suggested a connection between low calcium intake andpreeclampsia The purpose of this meta-analysis is to summarizecurrent evidence regarding calcium supplementation duringpregnancy in predicting preeclampsia and associated maternal

fetal complications.Methods: Literature revision of all RCT (randomallocation of calcium versus placebo) available in MEDLINE/PUBMED up to 2/29/2012 regarding calcium supplementationduring pregnancy for preventing preeclampsia. We used theMantel-Haenszels Method for four subgroup of patients: Adequatecalcium intake; Low calcium intake; Low risk of preeclampsia;High risk of preeclampsia. We consideredp< 0.05 as significant.Results: There is no consensus in Literature about: (1) the efficacyof calcium supplementation in the prevention of preeclampsia, (2)other/adverse/long-term effects of calcium supplementation inpregnancy.Conclusions: Preeclampsia is likely to be a multifactorialdisease. However, inadequate calcium intake represents a factorassociated 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 toreduce the incidence of preeclampsia, especially in populations athigh risk of preeclampsia due to ethnicity, gender, age, high BMIand 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 o the maincauses o maternal mortality and morbidity and is associated withprematurity and increased perinatal mortality [1].

Blood pressure measurements taken 6 h apart equal to orgreater than 140/90mmHg, in ormerly normotensive women,afer the 20th week o pregnancy, without proteinuria, definespregnancy-induced hypertension (PIH) [2]. Preeclampsia is aclinical syndrome o unknown etiology characterized by theoccurrence o hypertension and proteinuria afer 20 weeks ogestation, in ormerly normotensive women.

During pregnancy and nursing, calcium requirements areincreased in order to maintain calcium balance and maternalbone density, and to satisy etal growth requirements.

o ensure a normal pregnancy outcome, an adequate maternalnutritional status is essential as well as a sufficient daily intake omicronutrients such as olic acid, vitamins, and minerals [3,4].

Te currently recommended daily calcium intake during preg-nancy is between 300 and 2000 mg [5].

Several studies have demonstrated avourable effects o

calcium supplementation during pregnancy in relation to bonemineralization and etal growth and prevention o maternalosteopenia [6].

Presently, the effects o additional calcium intake on otherpregnancy outcomes, such as preterm labour, low birth weightand intrauterine growth retardation (IUGR), are controversial.

Since the early 1980s, epidemiological evidence has suggesteda connection between low calcium intake and preeclampsia[710]. Tis relationship is supported by the ollowing two points[1113]:

1. Te incidence o preeclampsia and eclampsia is low in popula-tions with elevated mean calcium intake, such as native popu-lations in South America and Ethiopia.

2. Preeclamptic patients have calcemia and calciuria levels lowerthan normotensive pregnant women.

Several Randomized Controlled rials (RC) have tested theutility o routine calcium supplementation in preventing preg-nancy-induced hypertensive disorder [1,5]. Tese encouragingresults [11] prompted more recent observational studies whichhave not shown benefits arising rom calcium and vitamin Dintake in preventing preeclampsia [14]. Te purpose o this meta-analysis is to summarize current evidence regarding calciumsupplementation during pregnancy in predicting preeclampsiaand associated maternaletal complications.

MethodsWe examined international literature regarding calciumsupplementation or the prevention o preeclampsia. Te searchstring used by MEDLINE/Pubmed was calcium supplementationprevention preeclampsia. Te electronic research yielded 113results, 56 reviews. We considered eligible or our meta-analysisall RC (random allocation o calcium versus placebo) availablein English-language Journals up to 2/29/2012 regarding calciumsupplementation during pregnancy or preventing preeclampsia,regardless o the age, parity, clinical and amily history o all

REVIEW

Calcium supplementation and prevention of preeclampsia: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 andGynecology, Bologna Toniolo Clinic, Bologna, Italy, and 3Department of Public Health, University of Parma, Parma, Italy

Correspondence: ito Silvio Patrelli, MD, Dipartimento di Scienze Ostetriche, Ginecologiche e di Neonatologia, U.O.C. di Ginecologia e Ostetricia, VialeGramsci, 1443100 Parma Italy. el.: +39 339 2817381. E-mail: [email protected]


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patients involved in the trials. We applied the Mantel-HaenszelsMethod to our subgroup o patients:

1. Adequate calcium intake;2. Low calcium intake;3. Low risk o preeclampsia;4. High risk o preeclampsia.

We consideredp< 0.05 as significant.

Results

In total, 16 studies were examined.

Efficacy of calcium supplementation in the prevention ofpreeclampsia

Te RC perormed on pregnant women with adequate calciumintake were six, or a total o 9641 patients. Application o theMantel-Haenszels Method demonstrated a statistically insig-nificant relationship (p = 0.09) between calcium supplementa-tion during pregnancy and the risk o preeclampsia (RR = 0.88;95% CI = 0.771.02) in patients with adequate calcium intake(Figure 1). Conversely, calcium supplementation in pregnant

women with low calcium intake (seven studies, 10 154 patients)demonstrated a significant reduction in the incidence opreeclampsia (RR = 0.73; 95% CI = 0.610.87) (Figure 2).

Calcium supplementation in patients with high risk ogestational hypertensive disease (three studies, 346 patients)signiicantly reduced the risk o preeclampsia (RR = 0.17; 95%CI = 0.070.41) (Figure 3).

Moreover, calcium supplementation in low risk patients (sevenstudies, 11 059 patients) significantly reduced the incidence opreeclampsia (RR = 0.74; 95% CI: 0.630.88) (Figure 4).

Other effects of calcium supplementation in pregnancy

Jabeen et al. [1] showed that calcium supplementation duringpregnancy did not significantly reduce the incidence o MEF

(RR = 0.81). Homeyr et al. [12] also reached similar conclu-sions. Calcium intake was not protective against low birth weight(LBW) [15] and IUGR, and had no significant impact on peri-natal mortality [1].

Te addition o calcium supplementation did not preventspontaneous preterm delivery [15]. Te risk o prematurity wasreduced only in women at high risk o hypertension (RR = 0.42,95% CI = 0.230.78) [16]. A recent randomized controlled trialdocumented an indirect reduction in the incidence o pretermlabour and o perinatal complications in pregnant women supple-mented with calcium (RR = 0.76, 95% CI = 0.600.97) [15]. Te

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 weredescribed as increased incidence o nephrolithiasis, urinary tractinections and malabsorption o other minerals including iron,zinc and magnesium [5].

Homeyr et al. [19] and Barton et al. [20] reported higherrequency o HELLP syndrome in patients supplemented withcalcium, probably because o the non-diagnosis or delayed diag-nosis o preeclampsia, allowing the disease to progress quickerand cause complications. Other authors emphasize the absence oadverse effects associated with calcium supplementation [21,22].

Long-term effects of calcium supplementation in pregnancy

In the review by Villar and Belizan [16], the possible effects ocalcium intake on the children o women treated were evaluated.In an RC conducted by Belizan et al. [23] on the children opregnant women, involved in a previous RC, who were random-ized to calcium supplementation with 2 g/day versus placebo [24],it was shown that, at the age o 7, the childrens average systolic

blood pressure was lower i their mothers had been supplementedwith calcium (mean difference = 1.4 mmHg, 95% CI = 3.2 to0.5 mmHg) as compared to children whose mothers receiveda placebo. Tis effect was greater in children with a body massindex (BMI) higher than the average population, indicating thatcalcium supplementation in pregnancy reduces systolic bloodpressure in children especially i they are overweight.

Discussion

At present, the etiology o hypertensive disease in pregnancyis unknown, thereby limiting prevention [7]. Preeclampsia islikely to be a multiactorial disease. o date, several pathogenetichypotheses suggest immunological, genetic, and dietetic actors

[25], in addition to growth actors and placental proteins (PP13) [26]. Hence, it is unlikely that any single intervention willeffectively prevent the occurrence o pregnancy complications.Due to the heterogeneous causes o preeclampsia, it has beenhypothesised that the pathogenesis is different in women withmultiple risk actors [20]. Furthermore, the possibility that PIHand preeclampsia are diseases with different pathogenesis mustnot be excluded [7]. Knowledge o known risk actors, however,can help ormulate preventative strategies or patients who aremost likely to develop hypertensive disease. Inadequate calciumintake, defined as a daily intake less than 600 mg, represents a

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


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actor associated with an increased incidence o hypertensivedisease [10].

Tis aspect is particularly relevant in developing countriesand in regions where the diet is traditionally low in calcium. Terecommendation o calcium supplementation during pregnancy islow cost and devoid o special risks and could significantly reducethe incidence o PIH, preeclampsia and associated complications.

Lopez-Jaramillo et al. [27] and Crowther et al. [28] demon-strated a beneficial effect o calcium supplementation in preventing

preeclampsia in patients with low baseline intake (RR = 0.21) and inthose with adequate intake (RR = 0.40). In contrast, Levine et al. [29]and Villar et al. [17] ound a significant reduction in the relative riskonly in certain subpopulations, such as those suffering rom isolatedeclampsia (RR = 0.68) or with severe early onset preeclampsia,HELLP syndrome or severe hypertension (RR = 0.76).

Important studies, including the Calcium or PreeclampsiaPrevention trial, have not demonstrated benefits o calciumsupplementation [1].

However, the results o our meta-analysis demonstrate thatthe additional intake o calcium during pregnancy is an effec-tive measure to reduce the incidence o preeclampsia, especiallyin populations at high risk o preeclampsia due to ethnicity,gender, age, high BMI and in those with low baseline calciumintake, as demonstrated by recent and authoritative RC(able I) [18].

Briceo-Perez and colleagues [30] concluded that secondaryprevention with aspirin and calcium during pregnancy is useul

in pregnant women with low calcium intake and/or high risk odeveloping early preeclampsia: in groups at increased risk, theRR or preeclampsia was almost halved (RR = 0.45, 95% CI =0.310.65) [17]. In addition to clinical history, doppler screeningo the uterine vessels may be helpul in identiying candidates orcalcium supplementation [31]. Regarding the low risk womenand those with adequate intake o calcium, most o the studiesshowed the lack/absence o benefits deriving rom calciumsupplementation [17,32].

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

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

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


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According to our study, calcium supplementation does notsignificantly reduce the incidence o unavourable outcomes onlyin patients with adequate calcium intake.

Te importance o the clinical characteristics o the womensupplemented has been demonstrated in the Calcium orPreeclampsia Prevention rial (CPEP) (1997) [29]. Tere hasbeen controversy over the inclusion criteria or the study andother on issues such as conounding actors represented by a latestart o supplementation and poor patient compliance [33].

When to start supplementing? Presently, the most likelyhypothesis on the pathogenesis o preeclampsia (two-stagedisorder) [2] purports that calcium must be administered earlyin the first trimester, i not beore conception, and that initiatingsupplementation in the second trimester seems to be too late [34].

Finally, it is essential to quantiy the minimum effective dosageo calcium to reduce hypertension in pregnancy. E. Oken andcolleagues [14] have ound a significant reduction o RR in PIH

(0.58, 95% CI = 0.220.97) and preeclampsia (0.35, 95% CI =0.200.60) with an intake o at least 1 g/day [17]. Tereore, evenin light o the current recommendations [3], we consider 12 gdaily to be the right dosage.

In conclusion, our study demonstrated the utility o calciumsupplementation in the prevention o preeclampsia, particu-larly in women at high risk and/or with a low calcium diet.Administration o calcium should start early and unlike Homeyret al. [19], we believe that supplementation should be onlyaddressed to people most at risk and not to all pregnant women[34]. Further studies are needed, however, to confirm the benefi-cial effects o these treatments.

Acknowledgments

Te Authors thanks to Mrs. Carolyn David or her precious helpin prooreading the English.

Declaration of Interest: Te authors report no conflicts o interest.

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