Pregnancy-induced hypertension and low birth weight:

the role of calcium13

John T Repke and Jose Villar

ABSTRACT Considerable interest has developed regarding blood pressure ofthe population decreased. In 1983 Villar et al
the role of calcium in the regulation of blood pressure. Epide- (5) published his observations on the incidence of eclampsia in
miologic investigations, laboratory evaluations, and clinical trials three populations of women (in the United States, Guatemala,
all confirm that the relationship between calcium and blood and Colombia). The results ofthis trial demonstrated that as the
pressure extends to include the pregnant state. On the basis of incidence of eclampsia increased, the calcium content of the
current information it is clear that calcium supplementation diet was noted to decrease. In fact, it was reported that worldwide,
during pregnancy lowers blood pressure. Additionally, the effect eclampsia incidence varied inversely with dietary calcium intake
of calcium on blood pressure may influence the incidence and/ (1) (Table 1).

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or gestational age ofdevelopment ofpreeclampsia. Additionally, Much evidence has accumulated, both in the form of labo-
the effect on smooth-muscle relaxation detected in calcium-sup- ratory evidence and results of clinical trials, to support the re-
plemented patients may affect the incidence ofprematurity. Al- lationship between calcium and blood pressure. McCarron et al
though the mechanism for these effects has not been entirely (6) identified the relationship between reduced concentrations
elucidated, calcium supplementation appears to affect circulating of serum ionized calcium and hypertension. Additionally, Res-
concentrations of parathyroid hormone and renin, which may nick et al (7) published observations on the relationship between
modulate intracellular ionized calcium, resulting in the observed dlivalent cations and blood pressure as a function ofplasma renin
effect on smooth-muscle relaxation. This effect may also be re- activity. During this same period of time, Belizan et al (8) re-
sponsible for reduced uterine activity and for a lowering of ported on their observations of blood pressure changes in cal-
the incidence of prematurity. Am J C/in Nutr 199 l;54: cium-deprived pregnant rats. It was clear from these observations
2375-415. that after nutritional deprivation of calcium for -4-5 wk, the
mean blood pressure of calcium-deprived rats was significantly
KEY WORDS Calcium, pregnancy, hypertension, prema-
higher than that of rats fed a normal diet.
turity
These observations led to subsequent clinical trials, which re-
ported for the first time the association between nutritional cal-
Introduction
cium intake and blood pressure regulation (9) (Figs 1 and 2)
In 1980 TheAmerican Journa/ofC/inica/Nutrition published (10). These investigations as well as the previous epidemiologic
a report suggesting a relationship between calcium intake and observations led the way to the performance of randomized
edema-proteinuria and hypertension gestosis (I). Since that time clinical trials on healthy pregnant women to ascertain whether
a large body ofdata has accumulated in support ofa relationship calcium supplementation during pregnancy would effectively
between calcium and blood pressure. To understand this rela- lower blood pressure and whether such treatment would have
tionship better and how it affects pregnancy, it is necessary to an effect on the incidence ofpreeclampsia and low birth weight.
have a basic understanding ofthe pathophysiology of pregnancy-
induced hypertension. As early as 1973, Oant et al (2) hypoth- Subjects and methods
esized that pregnancy-induced hypertension was characterized
by an increased vascular sensitivity to the pressor effects of an- The pregnancy-related clinical trials to date have encompassed
giotensin II. A series ofexperiments by Oant et al further defined three separate studies. The initial study was conducted in Oua-
the relationship between angiotensin II sensitivity, locally-pro- temala in a series of healthy, pregnant volunteers who were ran-
domly assigned to receive either placebo, 1 g elemental Ca/d,
duced prostaglandins, and cyclic AMP and pregnancy-induced
hypertension. Additionally, they hypothesized that these sub-
stances exert their effect through a final common pathway me-
I From the Department of Gynecology and Obstetrics, Division of
diated via changes in intracellular ionized calcium (3). This re-
Maternal-Fetal Medicine, The Johns Hopkins University School of
lationship of calcium to blood pressure has served as the basis
Medicine, Baltimore.
for our interest.
2 Supported in part by a grant from the National Dairy Board and
Several epidemiologic studies confirmed a relationship be- National Dairy Council to JTR.
tween blood pressure and calcium. In 1976 Masironi et al (4) 3 Address reprint requests to JT Repke, Department of Gynecology
demonstrated in a population along a river bank in New Guinea & Obstetrics, 218 Houck, The Johns Hopkins Hospital, 600 North Wolfe
that as the calcium content of the water increased, the overall Street, Baltimore, MD 21205.

Am J C/in Nuir l99l;54:237S-4lS. Printed in USA. © 1991 American Society for Clinical Nutrition 237S
2385 REPKE AND VILLAR

TABLE 1 jects in this study were nulliparous or primiparous patients with

Eclampsia incidence as a function of dietary calcium intake- a known last menstrual period between the ages of 18 and 30
worldwide y. A documented negative rollover test was necessary for inclu-
sion into the study. Blood pressure was measured in the left
Eclampsia incidence
Country Calcium intake (per 1000 births) lateral position after 5 mm ofrest. The patients were then placed
in the supine position and the blood pressure was remeasured.
mg-person’ -
A rise in diastolic pressure of < 1 5 mm Hg was considered a
Colombia 240 1.59 negative test. At 26 wk gestation the patients were randomly
Thailand 266 3.7-6.0 assigned to receive 1500 mg Ca/d or placebo. Blood pressure
Jamaica 345 2.5 readings were obtained by a single nurse-midwife and one phy-
India 347 12.0 sician who were recruited for the purposes of blood pressure
Japan 368 High incidence measurement in the study. All blood pressure readings were taken
Israel 884 0.7 while subjects were in the supine and left lateral position by
United Kingdom 1000 0.9
using a random zero sphygmomanometer. A nutritional assess-
Ethiopia 1075 0.9
ment was carried out during each visit. Routine prenatal vitamins
United States 1 100 0.5
were also prescribed to all patients, irrespective of randomization
Guatemala 1 100 0.4
group. Covariates in this analysis included basal blood pressure;
maternal age, weight, and height; race; and weight gain during
pregnancy.
or 2 g elemental Ca/d. This first study was nonblinded. The In the third clinical trial, adolescent patients (considered to
patients were identified at their initial prenatal visit and were be at highest risk for preeclampsia and low birth weight) were

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subsequently enrolled in the study and randomly assigned to recruited from the Johns Hopkins Hospital Adolescent Preg-
one of these three regimens while at 26 wk gestation. Baseline nancy Program. All patients were aged 17 y at the time of
laboratory analysis as well as follow-up laboratory analysis at recruitment. This trial was also approved by the Joint Committee
28 and 36 wk was carried out. The laboratory analysis consisted on Clinical Investigation of the Johns Hopkins Hospital. After
ofa full chemistry panel, including serum magnesium and serum patient and/or parental consent had been obtained, the patients
parathyroid hormone. were randomly assigned at the 20th wk of gestation to receive
The second clinical trial was a double-blind, randomized, either 2 g elemental Ca (as calcium carbonate) per day or placebo.
controlled investigation conducted at two study sites. A total of Once again the design of this study was double blind. A com-
52 subjects were included with 34 ofthese subjects coming from puter-generated list of random numbers was used to assign pa-
the Obstetrics Clinic ofthe Johns Hopkins Hospital and 18 sub- tients to treatment groups. Prenatal care was carried out ac-
jects from the Perinatal Study Center of Rosario, Argentina. cording to the protocols ofthe Johns Hopkins Hospital Adoles-
Informed consent was obtained from all individuals and the cent Pregnancy Program.
subjects studied through the Johns Hopkins Hospital were part The calcium-supplemented group received four tablets per
of a protocol that was approved by the Joint Committee on day of calcium carbonate, each of which contained 500 mg el-
Clinical Investigation of the Johns Hopkins Hospital. The sub- emental Ca (Oscal 500, Marion Laboratories, Kansas City, MO).

,
0/0

10

#5

Blood pressure.
Percntu& changes
from basal values

“ N
- 5.

\ ,\ \
\._ /
- 10- \,#‘

Ptac#{149}bo
group
- --- Calcium group

5 10 15 20

w$ of iupplsmsstation

FIG 1 . Blood pressure reduction after calcium supplementation in men (dorsal position).
 CALCIUM, PREGNANCY, AND HYPERTENSION 2395
0/0

410

+5.

Blood
Pcint
pressure.
chang
0
- lr;:4%..,i/
A ,/P_ ----a
from basal valsi
,/0

-5
.

\ , \ ‘Calcium
\/V - \, V
-10
p.--- Calcsam I . I #{149} #{149} . . 15I . . . 20
0 - .- 5 10
w$ of iupplimintation

FIG 2. Blood pressure reduction after calcium supplementation in nonpregnant women (dorsal position).

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Placebo tablets were organoleptically similar to the calcium tab- systolic and diastolic pressure were taken in each position and
lets. A nutritional assessment was made at each visit and at three the average value was used as a data point.
separate times during the study; a 24-h recall for complete nu-
tritional assessment was performed by a registered dietitian. Ad-
ditionally, the project coordinator measured compliance with
Results
treatment at each visit and calculated a compliance rate per
The results of these three clinical trials centered mainly on
patient that was also used in the final analysis of compliance
the effect of calcium supplementation on blood pressure, the
rate by group. The project coordinator was also responsible for
incidence of preeclampsia, the circulating concentration of
blood pressure measurements on all patients, again performed
parathyroid hormone and the incidence of premature delivery.
with a random zero sphygmomanometer.
In the initial study it was demonstrated clearly that patients
Gestational age was determined by using the best obstetrical
receiving 2 g elemental Ca/d had a statistically significant re-
estimate, which was a combination of facts including last men-
duction in systolic and diastolic blood pressure (Fig 3) (1 1).
strual period, examination data, and ultrasound data. In this
Coincident with this reduction was the observation that serum
group of patients, preterm labor was defined as four contractions
parathyroid hormone concentrations were reduced by 65% from
within a 20-mm period or eight contractions within a 60-mm
baseline in patients receiving calcium compared with patients
period, irrespective ofcervical change. Blood pressure measure-
receiving placebo. The placebo group experienced a 23% increase
ment was performed as described earlier by a single project co-
in serum parathyroid hormone.
ordinator who measured blood pressure, using a standardized
In the second study the results again supported the notion
technique and the fourth Korotkoff sound, while subjects were
that calcium supplementation effectively reduces blood pressure.
in the supine and left lateral positions. Three measurements of
There was a significant reduction (P = 0.06) in systolic blood
pressure as well as a statistically significant difference (P = 0.05)
in diastolic pressure at term and a statistically significant differ-
75
ence (P = 0.02) in the rate of rise of diastolic pressure in the
third trimester in patients receiving calcium supplementation
(Table 2) (12). Additionally, there were no racial differences in
70
the blood-pressure-lowering effect of calcium. Also of note was
Diastolic
a statistically significant difference (P < 0.01) in serum mag-
Blood
Pressure nesium concentrations in the calcium-supplemented group, with
(mmHg) 65 the calcium-treated patients having higher serum magnesium
concentrations at the completion of the study when compared
with the placebo group. Also noted was an effect on serum pam-
60 thyroid hormone and plasma renin activity, suggesting that pa-
14 16 18 20 22 24 26 28 30 32 34 36 38 tients with initial low plasma renin activity (Fig 4) (15) and
WEEKS OF AMENORRHEA parathyroid hormone are more likely to respond to calcium sup-
P 078 008 008 000 013 010 plementation with blood pressure reduction.
Oof lcyid2
In the third study, involving adolescent patients, once again
FIG 3. Blood pressure reduction after calcium supplementation in the relationship between calcium and blood pressure was af-
pregnant women. Measurements were taken while subjects were seated. firmed. The calcium-supplemented group (2 g elemental Ca/d)
I ± 1 SE. had lower blood pressure readings than did the placebo group.
2405 REPKE AND VILLAR

TABLE 2 calcium, therefore, causing a relaxation of the myocyte. At the

Effect of calcium supplementation during pregnancy on blood arteriolar level this finding may result in reduced blood pressure.
pressure increase: adjusted regression coefficients for the calcium and Studies have demonstrated that the concentration of intracellular
placebo groups5
ionized calcium is higher in hypertensive individuals than in

Lateral Supine normotensive control subjects, and that as blood pressure is

Treatment lowered so is the concentration of intracellular ionized calcium
group Systolic Diastolic Systolic Diastolic (18). At the level of the uterine smooth muscle, a reduction in
uterine contractility may also occur.
mm Hg/wk of gestation With respect to the prevention ofpreeclampsia, several studies
Calcium -0.02 0.36t 0.15 0.10 in the literature suggested that, in fact, calcium supplementation
[23] [231 [24] [24] may reduce the incidence of preeclampsia (12, 13, 19, 20). Our
Placebo 0.35t 0.69t 0.40t 0.6l preliminary investigations would also suggest that preeclampsia
[27] [27] [26] [26] may occur less frequently in calcium-supplemented patients al-
though the numbers are too small to achieve statistical signifi-
S Regression coefficients adjusted for initial blood pressure and race. cance.
n in brackets.
The issue oflow birth weight is also important. Our study on
tP<0.l0.
adolescent patients would suggest that calcium supplementation
P<0.05.
§ P < 0.01. has a significant impact on reducing the incidence of prematurity.
This population of patients has been well studied and the rate
ofprematurity in this population in our clinic was reported pre-
viously (21). Of particular note in this study is that, even when
Compliance with calcium supplementation or placebo was equal

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high-compliance patients were studied separately, the incidence
in the two groups. A nutritional assessment revealed similar in-
ofprematurity was higher in the placebo group with, in fact, no
takes ofprotein, calories, iron, vitamin D, calcium, and vitamin
cases of premature delivery being reported in the high-compli-
C in the two groups.
ance calcium group of patients.
Note that the incidence ofpreeclampsia appeared to be greater
These data suggest that calcium supplementation reduces
in the placebo group than in the calcium-treated group although
blood pressure. The mechanism of this reduction in blood
this difference was not statistically significant. The duration of
pressure appears to be via smooth-muscle relaxation mediated
labor was shorter and the gestational age lower at delivery in the
in turn by alterations in parathyroid hormone and plasma renin
placebo group. With respect to preterm delivery, the incidence
concentrations. Calcium supplementation also appears to re-
ofprematurity (< 37 wk) was statistical significant, being greater
duce the incidence of prematurity possibly through a similar
in the placebo group than in the calcium-treated group (P
mechanism of smooth-muscle relaxation. The incidence of
= 0.007). When each group was analyzed by compliance with
preeclampsia may also be reduced by calcium supplementation
pill taking, it was also demonstrated that even in the high-corn-
although the studies to date have been too small to resolve this
pliance group, the rate ofprematurity was greater in the placebo
issue definitively. There is no question that the calcium ion is
group than in the calcium-treated group. A life-table analysis
an active participant in the final common pathway of virtually
comparing the two groups revealed that the cumulative proba-
all physiologic reactions. The effect of nutritional calcium in-
bility ofdelivery at any gestational age was greater in the placebo
take on outcomes of, for example, hypertension, preeclampsia,
group than in the calcium-treated group (P = 0.02).
and low birth weight, would appear to be real. Larger collab-

Discussion
I.)

0
The above results in their entirety support the concept that U,
>
calcium supplementation, in fact, affects smooth-muscle activity. (no
The blood-pressure-lowering effect ofcalcium supplementation !
was demonstrated clearly by multiple studies on healthy pop- .a
Q,
ulations (9, 1 1-13) as well as in populations with mild to mod- iU) O
Q_ i:
crate hypertension (14). The mechanism ofthis blood-pressure- D’ E
o.Y E
lowering effect remains unclear although mechanisms involving 25
effects on serum parathyroid hormone and plasma renin activity
have been proposed (15, 16). The fact that calcium-supplemented
patients in our first study were observed to have a 65% reduction
in serum parathyroid hormone was significant. The placebo
group in this study experienced a 23% rise in parathyroid hor-
mone, which has been described as occurring during normal P05 L Volui<26 sii#{149}ki55 Lov High

pregnancy (17). N. 4 7 6

This fall in serum parathyroid hormone suggests that one

55Low < MdioeHigh
mechanism of action of nutritional calcium supplementation
may be to mediate serum parathyroid hormone secretion and FIG 4. Mean blood pressure changes between 26 and 38 wk gestation,
thereby mediate intracellular transport ofionized calcium. This and term ofcalcium and placebo (P) groups classified by baseline serum
effect might result in an overall reduction in intracellular ionized plasma renin activity (> or < the median value of 1.7 g- L’ - h’.
 CALCIUM, PREGNANCY, AND HYPERTENSION 2415

orative multicenter trials are required to answer these questions 10. Villar J, Beliz#{225}n
JM, Repke J, et al. The effect ofcalcium intake on
properly. Until such studies are completed, clinicians should the blood pressure of young healthy individuals. Ann NY Acad Sci
emphasize the role ofnutrition in improving outcome of preg- 1984;435:509-l 1.
nancy, paying particular attention to ensuring that all pregnant 1 1. Belizan JM, Villar J, Zalazar A, et al. Preliminary evidence of the
patients are receiving at least the recommended dietary allow- effect of calcium supplementation on blood pressure in normal
ance for calcium through their diet, and with supplementation pregnant women. Am J Obstet Gynecol 1983;l46: 175-80.
when necessary. a 12. Villar J, Repke J, Belizan JM, Pareja G. Calcium supplementation
reduces blood pressure during pregnancy: results of a randomized
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