Study the effect of orally –administered calcium carbonate to

Iraqi J Pharm Sci, Vol.20(1) 2011 Orally - administered calcium and mild pre-eclampsia

The Effect of Orally –Administered Calcium Carbonate to

Pregnant Women with Mild Pre-eclampsia
Sura Sagban

*
, Nada N. Al-Shawi

**,1
, Alia Mohammad

*
, Ashwak Talib

and Utoor Hasson
*

*Department of Obstetrics and Gynecology ,Karbala Hospital, Karbala, Iraq,

** Department of Pharmacology and Toxicology, College of Pharmacy ,University of Baghdad , Baghdad , Iraq

Abstract
Pre-eclampsia is the most common medical complication of pregnancy associated with increased
maternal and infant mortality and morbidity. Its exact etiology is not known, although several

evidences indicate that various elements might play an important role in pre-eclampsia. This study was

carried out to analyze and to compare the concentration of calcium, in mild pre-eclampsia and in

normal pregnant women , and to determine the effect of oral supplementation with calcium on mild

pre-eclampsia , and whether this effect is related to the change in the level of serum calcium. Forty-

five women in the third trimester of pregnancy were selected to participate in this study and divided

into: fifteen apparently healthy, normotensive pregnant women served as a control group; thirty

clinically diagnosed patients with mild pre-eclampsia ( 15 mild pre-eclamptic un-treated group , 15

mild pre-eclamptic treated with calcium carbonate 500 mg twice daily) , the serum calcium were

estimated with an atomic absorption spectrophotometer .the data were analyzed using the un- paired

Student’s-test.The serum calcium in mild pre-eclmpatic un-treated group was significantly lower than

that in normal pregnant women (8.84 ± 1.14 Vs. 9.66 ± 0.87 , p<0.05) , Serum calcium level

significantly increased in mild pre-eclamptic treated with calcium carbonate 500mg twice daily as

compared to mild pre-eclamptic un-treated group (9.76 ±0.96 Vs 8.84±1.14 ,p<0.05) . Systolic

,diastolic, and mean arterial blood pressure were significantly reduced after one month of treatment

with calcium carbonate 500 mg twice daily as compared to mild pre-eclamptic un –treated

group.(134.83 ± 7.5 Vs139.33 ± 5.30, 88.46 ± 3.27 Vs 91 ± 3.38, 103.90 ± 3.8 Vs106.66 ± 3.08

,p<0.05) respectively.This study showed that serum calcium level in mild pre-eclampsia are lower than

in normotensive pregnant women ,this finding support the hypothesis that hypocalcemia is a possible

etiology in pre-eclampsia ; additionally this study showed the possible beneficial effect of calcium

supplementation in controlling pre-eclampsia and reducing blood pressure by increasing serum

calcium level .

Key words: Mild Pre-eclampsia, Calcium carbonate tablet, Pregnant women, Serum calcium

الخالصة
انطثٛح نهحًم يصاحثح نضٚادج انعشس ٔانًٕخ فٙ ٚؼذ يشض اسذفاع ظغػ انذو أٔ يشض عًذيٛح انحًم يٍ أكثش انًعاػفاخ

االو ٔانطفم. الٚضال انغثة انشئٛظ نًشض عًذيٛح انحًم يجٕٓال تانشغى يٍ اٌ ُْانك اثثاذاخ ذذل ػهٗ اٌ يغرٕٚاخ انؼُاصش

استَٕاخ انكانغٕٛو فٙ حانح صًًد ْزِ انذساعح نثٛاٌ انرأثٛش انًحرًم نًادج ك انًخرهفح قذ ذهؼة دٔسا فٙ اسذفاع ظغػ انذو نالو انحايم.

عًذيٛح انحًم انثغٛػ ػهٗ يغرٕٖ انكانغٕٛو تانًقاسَح يغ رنك انرشكٛض فٙ انُغاء انحٕايم راخ انعغػ انطثٛؼٙ ٔنرحذٚذ ْزا انرأثٛش

ٍ انحًم ٔذى ذى اخرٛاس خًظ ٔاستؼٌٕ ايشأج فٙ االشٓش انثالثح االخٛشج ي ٔػالقرّ ترغٛٛش فٙ يغرٕٖ انكانغٕٛو فٙ يصم انذو نهُغاء.

ذقغًٍٛٓ انٗ ثالثح يجًٕػاخ: انًجًٕػح االٔنٗ: خًغح ػشش ايشأج حايم رٔاخ ظغػ دو غثٛؼٙ اػرثشٌ كًجًٕػح عٛطشج.

( ايشاج حايم 51انًجًٕػح انثاَٛح: ثالثٌٕ ايشاج حايم يصاتاخ تغًذيٛح انحًم انثغٛػ. قغًد ْزِ انًجًٕػح انٗ يجًٕػرٍٛ )

يهغى يٍ 155( ايشاج حايم يصاتاخ تغًذيٛح انحًم انثغٛػ اػطٍٛ جشػح 51انحًم انثغٛػ ، )شخصد حذٚثا تاصاترٍٓ تغًذيٛح

تُٛد َرائج ْزِ ذى قٛاط يغرٕٖ انكانغٕٛو فٙ يصم انُغاء انحٕايم فٙ انًجًٕػاخ اػالِ . حثٕب كاستَٕاخ انكانغٕٛو يشذاٌ ٕٚيٛا.

خ تغًذيٛح انحًم اقم تصٕسج يؼُٕٚح ػُذ يقاسَرٓا تانحًم انطثٛؼٙ انذساعح اٌ ذشكٛض يغرٕٖ انكانغٕٛو فٙ يصم انُغاء انًصاتا

كًا تُٛد انذساعح اٌ يغرٕٚاخ ظغػ ٔانز٘ صاد ٔتصٕسج يؼُٕٚح تؼذ اعرؼًال كاستَٕاخ انكانغٕٛو نًشظٗ عًذيٛح انحًم انثغٛػ.

يهغى 155رؼًال كاستَٕاخ انكانغٕٛو انذو االَقثاظٙ ، االَثغاغٙ ٔظغػ انذو انششٚاَٙ قذ اَخفط تصٕسج يؼُٕٚح تؼذ شٓش يٍ اع

تُٛد ْزِ انذساعح . يشذٍٛ تانٕٛو تانًقاسَح يغ يجًٕػح انُغاء انحٕايم انًشخصاخ حذٚثا ػهٗ آٍَ يصاتاخ تغًذيٛح انحًم انثغٛػ

نحٕايم رٔاخ ظغػ اٌ يغرٕٖ يصم انكانغٕٛو فٙ انُغاء انحٕايم انًصاتاخ تغًذيٛح انحًم انثغٛػ ْٕ أقم يٍ يغرٕاِ نذٖ انُغاء ا

م انذو انطثٛؼٙ. اٌ انُرائج انرٙ ذى انحصٕل ػهٛٓا يٍ ْزِ انذساعح ذذػى انُظشٚح اٌ قهح يغرٕٖ انكانغٕٛو فٙ انذو قذ ٚكٌٕ انغثة انًحرً

طشج ػهٗ فٙ عًذيٛح انحًم ، تاالظافح انٗ رنك، تُٛد ْزِ انذساعح انٗ انرأثٛش انًفٛذ ٔانًحرًم نًادج كاستَٕاخ انكانغٕٛو فٙ انغٛ

يشض عًذيٛح انحًم انثغٛػ ٔذخفٛط ظغػ انذو ٔذحغٍٛ انرذْٕس انحاصم فٙ يغرٕٖ يصم انكانغٕٛو.

1Corresponding author E- mail : nadaalshawi @ yahoo.com

Received : 4/10/2010

Accepted : 17/5/2011

Iraqi J Pharm Sci, Vol.20(1) 2011 Orally - administered calcium and mild pre-eclampsia

Introduction
Preeclampsia is one of the most common

causes of maternal and fetal morbidities and

mortalities
(1)

. Its incidence is 4-8% of

pregnancies
(2)

.The patho physiological

mechanism is characterized by failure of the

trophoblastic invasion of the spiral arteries,

leading to mal adaptation of maternal spiral

arterioles, which may be associated with an

increased vascular resistance of the uterine

artery and decreased perfusion of the

placenta
(3)

. However, the exact etiology of

preeclampsia is still unknown. On the

physiological basis, calcium plays an important

role in muscle contraction and regulation of

water balance in cells. Modification of plasma

calcium concentration leads to the alteration of

blood pressure. The lowering of serum calcium

and the increase of cellular calcium can cause

an elevation of blood pressure in pre-eclamptic

mothers. Therefore, the modification of

calcium metabolism during pregnancy could

be one of the potential causes of

preeclampsia
(4,5).

However, the role and status

of serum calcium, is still being discussed. The

aims of the present study were to measure

serum levels of calcium in mild pre-eclamptic

pregnancy and compared with normal

pregnancy and to investigate whether the oral

supplementation of calcium decrease the

incidence of pre-eclampsia, control the blood

pressure, and affecting the plasma level of

calcium.

Methods
Forty- five women in the third trimester

of pregnancy attending the Karbala hospital;

department of obstetrics and gynecology were

selected to participate in this study with age

ranged between (20-45) years (mean

30.99±0.47). Diagnosis was carried out

according to WHO criteria
(1)

, which are bases

on clinical, laboratory diagnostic measures to

detect hypertension and proteinuria in all

patients. These women were classified into:

1. Fifteen healthy normotensive pregnant
women( blood pressure 120/80) the mean

gestational age ( 32.73 ± 2.49 ) weeks and

mean age (30.46 ± 6.79 )years, mean systolic

blood pressure( 115.33 ± 5.4) mmHg ,

mean diastolic blood pressure(78.66 ±

5.49)mmHg , mean arterial blood pressure

(90.78 ± 4.22) mmHg . These pregnant

women served as control group. Blood

pressure measurement and blood samples

were taken every two weeks until the day of

delivery.

2. Thirty pre- eclamptic pregnant women in
the third trimester of pregnancy, after blood

pressure measurement and protein in urine

assessment in addition to clinical and

diagnostic measures this group can be

classified into two groups

A. Fifteen pre-eclamptic women, their
gestational age mean (31.6 ± .46) weeks

, age mean (31.31 ± 5.89 )years, their

mean systolic blood pressure (139.33 ±

5.30) mmHg ; mean diastolic blood

pressure(91 ± 3.38) ; and mean arterial

blood pressure(106.66 ± 3.08) .they

served as mild pre eclamptic un- treated

control group .

B. Fifteen pregnant women with mild pre-
eclampsia in the third trimester of

pregnancy , They received calcium

carbonate 500 mg twice daily . their

mean gestational age ( 32.6 ± 1.88 )

weeks, mean age(32.13 ± 6.15 )years

,mean systolic blood pressure

(140.83±2.60) mmHg, mean diastolic

blood pressure (91.70 ± 2.85 )mmHg ,

mean arterial blood pressure

(108.05±2.20)mmHg. Blood pressure

measurement and blood samples were

taken every two weeks after starting the

treatment until the day of delivery.

Mid stream urine was collected from women in

a clean plastic tube, and utilized to perform a

test for protein. Venous blood samples were

collected and their sera were isolated by

centrifugation . Measurement of calcium in

serum by colorimetric method , which based

on combination of calcium with reactant O-

cresolphthalein (O-CPC) complexon, to form a

stable , colored reaction product .the developed

colored is measured at 570 nm ; Serum

calcium levels were expressed as mg / dl .

None of the women had cardiac, hepatic or

renal dysfunction .and none had any obstetrical

abnormalities (diabetes mellitus, rhesus

immunization). none had essential

hypertension.

Statistical analysis
Data were presented as mean ± SD .
Comparison of means of parameter tested

between groups was performed by un-paired

Student’s t test and p<0.05 was considered as

statistically significant.

Results
The present study enrolled 45 pregnant
women. The clinical characteristics of the

participant shown in Table 1. There were no

statistical difference between mild pre-

eclamptic un-treated group and normotensive

control group for age and gestational period.

The results showed that systolic, diastolic ,and

mean arterial blood pressures were

Iraqi J Pharm Sci, Vol.20(1) 2011 Orally - administered calcium and mild pre-eclampsia

significantly higher in mild pre-eclamptic un-

treated group when compared with the normal

pregnant women , serum calcium levels in

mild pre-eclamptic un-treated women were

significantly lower when compared to

normotensive pregnant controls(p<0.05).

Table 1 : Clinical characteristics of the

study population.

variables

Normotensiv

e pregnant

controls

n=15

Mild pre-

eclamptic un-

treated group

n=15

Maternal

Age(years)
30.46 ± 6.79 31.31 ±5.89 NS

Systolic B.P.

(mmHg)
115 .33 ± 5.4

139.33 ±5.30*

Diastolic

B.P.

(mmHg)

78.66 ± 5.49 91 ± 3.38 *

Mean

Arterial

B.P.(mmHg)

90.78 ± 4.22 106.66 ± 3.08*

Gestational

age

(weeks)

32.73 ± 2.49 31.6 ± 2.46 NS

Serum

Calcium

(mg/d)

9.66 ± 0.87 8.84 ± 1.14*

Data are shown as mean ±SD ; *: p < 0.05

compared to normotensive control group; NS:no

significant differences.

Figure 1 shows that in mild pre-eclamptic

women, mean arterial blood pressure levels

were inversely correlated with serum calcium

level ( r = - 0.811 ) (p<0.05).

Figure 1: Relation between Mean Arterial

Blood Pressure and serum calcium in mild

pre-eclamptic patients.

Mild pre-eclamptic women treated with oral
tablets calcium carbonate 500 mg tablets twice

daily showed a significant decrease in the

levels of systolic - , diastolic -, and mean

arterial blood pressures compared to mild pre-

eclamptic un- treated control group ( p < 0.05)

as shown in table 2. The levels of

systolic - , diastolic- and mean arterial blood

pressures in mild pre-eclamptic treated with

calcium carbonate twice daily showed a

significant difference with the corresponding

levels in normotensive controls (p< 0.05).as

shown in table 2 and figures 2,3 and 4.

Table 2: Systolic- ,Diastolic- , and Mean arterial- blood pressures in mild pre-eclamptic women

treated with calcium carbonate (500mg tablets) compared to mild pre-eclamptic un-treated

control group and normotensive pregnant control groups.

Data shown as mean ± SD ; Values with non- identical subscripts ( a, b, c ) within each parameter

are significantly different (p < 0.05).

p<0.05
r = - 0.811

100

105

110

115

120

0 5 10 15M
e

a
n

A
rt

e
ri

a
l B

lo
o

d
P

re
ss

u
re

m
H

g
)

Serum Calcium mg/dl

Systolic blood

pressure

mmHg

Diastolic Blood

pressure

mmHg

Mean Arterial Blood

pressure

mmHg

Mild Pre-eclamptic treated

with Calcium carbonate

n=15

134.83±75
c

88.46±27
c

103.90 ±3.8
c

Mild pre-eclamptic Un -

treated Control

n=15

139.33±5.3
b

91 ± 3.38
b

106.6±0.08
b

Normoten-sive Pregnant

Control

n=15

115 ± 5.49
a

78.6±5.49
a

90.87 ± 4.2
a

Iraqi J Pharm Sci, Vol.20(1) 2011 Orally - administered calcium and mild pre-eclampsia

Figure2:The effect of treatment with

calcium carbonate 500 mg tablet on systolic

blood pressure levels in mild pre-eclamptic

women .

Figure 3: The effect of treatment with calcium

carbonate 500 mg tablet on diastolic blood

pressure levels in mild pre-eclamptic women.

Figure 4: The effect of treatment with calcium

carbonate 500 mg tablet on mean arterial blood

pressure level in mild pre-eclamptic women .

Figure 5: The effect of treatment with calcium

carbonate 500 mg tablet in mild pre-eclamptic

women on serum calcium level.

Table 3: serum calcium in mild pre-eclamptic treated with calcium carbonate 500 mg tablet compared to

mild pre-eclamptic un-treated and normotensive control groups.

Normotensive pregnant

Control

n=15

Mild pre-eclamptic Un-

treated Control

n=15

Mild pre-eclamptic treated

with Calcium carbonate 500

mg tablet n=15

Serum Calcium

(mg/dl)

9.66±0.87
a
8.84±1.14

9.76±0.76
a

Data shown as mean ± SD ; Values with non- identical subscripts ( a,b ) within each parameter
are significantly different (p < 0.05).

A significant increase in the serum calcium

level were seen in mild pre-eclamptic women

treated with calcium carbonate 500 mg tablet

compared to pre-eclamptic un –treated control

group ( p< 0.05 ) , the level of serum calcium

were reached levels of corresponding

normotensive pregnant control group as

shown in table 3. and Figure 5.

Iraqi J Pharm Sci, Vol.20(1) 2011 Orally - administered calcium and mild pre-eclampsia

Discussion
It has been proposed that the
pathophysiological processes in pre-eclampsia

began with a reduction in placental perfusion
(6,7)

and, ultimately, placental ischemia and

infarction
(8).

The resultant placental damage is

believed to result in the release of a variety of

placental factors
(9)

such as Soluble fms- like

tyrosine kinase (sFlt1), the angiotensin II type-

1 receptor autoantibody (AT1-AA), and

cytokines such as tumor necrosis factor

(TNF)-α that generate widespread dysfunction

of the maternal vascular endothelium
(10)

Which in turn resulted in enhance formation

of factors such as endothelin, reactive oxygen

species (ROS), thromboxane, , and

augmentation the sensitivity to vascular

angiotensin II, In addition, preeclampsia is

also associated with the decreased formation

of vasodilators such as nitric oxide (NO) and

prostacyclin
(11)

.These alterations in vascular

function not only lead to hypertension but

multi- organ dysfunction, especially in women

with early onset preeclampsia
(12).

In the

present study , in mild cases of preeclampsia

showed an elevation in systolic ,diastolic ,and

mean arterial blood pressures compared to

normotensive control pregnancies (p< 0.05),

Table1.Deficient or excessive levels of blood

electrolytes and trace elements can be an

adverse factor on human pregnancy. The

results from many clinical studies

demonstrated the relationship between the

aggravation of the hypertensive complication

of pregnancy and the change in the serum

concentration of electrolytes
( 13-15)

.In the

present study, Mean serum calcium levels in

mild pre-eclamptic un-treated women were

significantly lower than normotensive pregnant

women (p< 0.05), Table1. This finding is

similar to the previous studies
(16,17)

, and is

contradictory to others
(18-20)

, where no

significant differences in serum calcium levels

in pre-eclampsia were observed compared to

normal pregnancy. Furthermore, our study

showed an inverse relationship between serum

calcium level and mean arterial blood pressure

in mild pre-eclamptic patients, Figures 1.The

biochemical mechanism responsible for the

possible decrease in extracellular calcium and

concomitant increase in intracellular calcium is

presently unclear. It has been suggested that

parathyroid hormone plays a crucial role in

influencing cation transport
(21)

. it was

postulated that, in preeclampsia, the defective

placenta is unable to produce sufficient levels

of 1,25 (OH)2 D, resulting in inadequate

gastrointestinal calcium absorption, low

ionized calcium levels, and a secondary rise in

PTH, which in turn may increase cytoplasmic

Ca
+2

or alter the production of endothelium –

derived vasoactive factors
(31)

. Low calcium

levels may also contribute to hypertension via

stimulation of renin release from the kidney
(22)

Also The decreased serum total calcium

concentration in preeclampsia may be an

alteration of the plasma protein concentration

(primarily albumin ) results in parallel changes

in total plasma calcium
(23)

.It is widely accepted

that vascular smooth muscle contraction is

triggered by increases in intracellular free Ca
+2

concentration due to Ca
+2

release from the

intracellular stores and Ca
+2

entry from the

extracellular space
(24,25

). Several studies have

investigated the role of angiotensin II as an

agonist for receptor-mediated intracellular

calcium transients in vascular smooth

muscle
(26)

. These studies have consistently

shown an increase of intracellular free calcium

concentration in platelets and lymphocytes in

response to stimulation with angiotensin II and

vasopressin in patients with pre-eclampsia
(27)

In addition ,Ang II may enhance Ca
+2

entry

through plasma membrane Ca
+2

channels
(28)

Furthermore, there is evidence that several

ion-transport pathways are highly sensitive to

oxidative stress, and the resulting modulation

of ion transport by ROS will affect Ca
+2

homeostasis
(29)

.Treatment of mild cases of

pre-eclampsia with calcium carbonate 500 mg

tablet twice daily for one month resulted in a

significant decrease in the level of systolic

,diastolic , and mean arterial blood pressure (

p< 0.05) ,Table 2. figures 2,3,and4.. Our

findings were similar to those reported by

others
(30,31).

Calcium supplementation

enhances vasodilation and reduces blood

pressure
(3,4)

by suppression of the parathyroid

hormone
(21)

, which in turn reduces the

intracellular calcium concentration in vascular

smooth muscle cells ,diminishing their

responsiveness to pressure stimuli and

reducing angiotensin II sensitivity in women

with pre-eclampsia
(32)

.However, several

different mechanisms have been proposed by

which Ca supplementation could reduce blood

pressure in pre-eclampsia. Some have focused

on neural ,humoral, and renal effects ,whereas

others have attempted to relate the

antihypertensive action of Ca
+2

supplementation to improved vascular

function
(33)

. It has been thought that the

improved vascular function following Ca

supplementation in experimental animals has

been attributed to decreased α-adrenoceptor

responsiveness
(34,35)

, reduced permeability of

plasma membrane to Ca and other cations
(36)

improved function of cell membrane Na-K

ATPase
(37)

, improved vasodilator function of

the vascular endothelium ,and to increased

Iraqi J Pharm Sci, Vol.20(1) 2011 Orally - administered calcium and mild pre-eclampsia

sensitivity of the smooth muscle NO
(38)

.An

interesting link between the intake and

metabolism of calcium and the control of

arterial tone may be the extracellular receptor ,

the activation of which cause vasorelaxation

via the release of hyperpolarizing mediators
(39).

The results of this study showed that mild pre-

eclamptic patients treated with calcium

carbonate showed a significant increase in

serum calcium level (p< 0.05) Table 3.

,Figure 5., and the result of increasing serum

calcium is consistent with the others
(40)

which demonstrated that calcium

supplementation for women with a low

baseline calcium intake was associated with an

increase in serum calcium concentration. thus

calcium supplementation could have a

meaningful impact on calcium metabolism

regulation by maintaining serum calcium

level within the narrow physiological range

and reducing serum PTH
(21)

. Moreover ,when

calcium is present in optimal concentration, it

stabilizes vascular membranes, blocks its own

entry into cells and reduces

vasoconstriction
(41)

, Calcium in combination

with other ions such as Na+, K+ ,Cl- and

Mg2+ provides ionic balance to the vascular

membrane
(42)

, since membrane potential in

vascular smooth cells is governed by the

membrane permeability to these ions, and they

are act as a major determinant of membrane

potential under resting condition.From this

study we conclude that the reduction in serum

level of calcium during pregnancy might be

possible contributor in etiology of pre-

eclampsia, and supplementation of this

micronutrients may be of value to prevent pre-

eclampsia by controlling blood pressure

,improving endothelial function , and

modulating the deterioration of serum level of

calcium.

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