DOI: 10.1111/tog.

12111 2014;16:245–50
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Low-dose aspirin and calcium supplementation for the

prevention of pre-eclampsia
a, b
Fionnuala Mone MBBCh BAO MRCOG MRCPI, * Fionnuala M McAuliffe MD FRCOG FRCPI
a
Clinical Fellow, UCD School of Medicine and Medical Science, University College Dublin, National Maternity Hospital, Holles St. Dublin, Ireland
b
Professor in Obstetrics & Gynaecology, UCD School of Medicine and Medical Science, Consultant Obstetrician & Gynaecologist and
Sub-Specialist in Fetal Maternal Medicine, University College Dublin, National Maternity Hospital, Holles St. Dublin, Ireland
*Correspondence: Fionnuala Mone. Email: fmone@nmh.ie

Accepted on 26 March 2014

Key content  To explore the evidence in terms of safety and efficacy of

 Pre-eclampsia is a serious systemic condition, which affects 3–5% low-dose aspirin and calcium use in pregnancy in the prevention
of all pregnancies and accounts for a significant number of of pre-eclampsia.
maternal deaths annually.
Ethical issues
 Administration of anti-platelet agents to women at risk of
 Provision of low-dose aspirin and calcium supplements to
pre-eclampsia leads to a 17% reduction in the risk of developing
pregnant women at risk has the potential to significantly reduce
this condition.
 Calcium supplementation during pregnancy may also be an
maternal mortality and morbidity in addition to rates of perinatal
mortality, not only in the developed world, but also in the
effective measure to reduce the incidence of pre-eclampsia within
developing world.
high-risk populations.
Keywords: aspirin / calcium / placental-like growth factor /
Learning objectives

pre-eclampsia / uterine artery Doppler
To understand the first trimester ultrasound and biochemical
based screening tests available for the prediction of pre-eclampsia.

Please cite this paper as: Mone F, McAuliffe FM. Low-dose aspirin and calcium supplementation for the prevention of pre-eclampsia. The Obstetrician &
Gynaecologist 2014;16:245–50.

Low-dose aspirin commenced prior to 16 weeks of

Introduction
Pre-eclampsia is a serious systemic condition affecting 3–5%
of pregnancies and accounts for more than 50 000 maternal
deaths annually worldwide.1 It is associated with
feto-maternal complications including stroke, eclampsia,
multiple-organ failure, fetal growth restriction, intrauterine
death and preterm labour. Classically defined as new-onset
hypertension and proteinuria in the second half of
pregnancy,2 pre-eclampsia is typically categorised as being
of early (before 34 weeks of gestation) or late onset (after
34 weeks of gestation).3 Origins of the disease process have
been linked with the complex interaction of pregnancy
specific immunological and vascular adaptation, maternal
constitutional factors as well as dysfunctional trophoblastic
development and impaired placentation which is thought to
occur between 8 and 18 weeks of pregnancy.2,4 This
subsequently leads to endothelial dysfunction, organ
ischaemia, widespread inflammation and increased
vascular permeability.
gestation has been demonstrated to have a statistically
significant effect in the prevention of pre-eclampsia, as has
the use of calcium supplementation in women who are
calcium deficient. Other preventative treatments that have
been investigated for pre-eclampsia prevention include the
use of progesterone and anti-oxidants such as vitamins C and
E, however there is a paucity of robust evidence to support
their use in routine practice.5
Screening for pre-eclampsia
It is currently possible to assess a woman’s risk of developing
pre-eclampsia in her index pregnancy from as early as
11 weeks of gestation. Modalities, which can be included in
the first trimester pre-eclampsia risk assessment, include
maternal history, mean arterial pressure (MAP), biochemical
and biophysical markers and uterine artery
Doppler assessment.6
Ideally at the booking visit, a relevant maternal history
should be obtained to define risk factors such as nulliparity,

ª 2014 Royal College of Obstetricians and Gynaecologists 245

 Aspirin for prevention of pre-eclampsia

Afro-Carribean race, history of ovulation induced

Table 1. Table demonstrating the levels of placental biomarkers in the
conception, high body mass index (BMI) and a personal or prediction of onset of pre-eclampsia
family history of pre-eclampsia; particularly if it was
associated with onset or delivery at early gestations. Biomarker First trimester levels

Maternal history at the booking visit alone as a form of

PLGF ↓
first trimester risk assessment for pre-eclampsia can predict s-Flt 1 ↑
47% of cases of both early and late onset pre-eclampsia and PAPP-A ↓
35% of cases of gestational hypertension with a false positive sEND ↑
rate of 10%.6 In terms of maternal history, advancing age VEGF ↓
b-hCG ↑
appears to be the most significant history related risk factor ADAM-12 ↓
for early-onset disease, followed closely by increased
PLGF: Placental like growth factor
maternal BMI.6
s-Flt 1: Soluble fms-like tyrosine kinase 1
The accuracy of the pre-eclampsia probability estimation PAPP-A: Pregnancy associated plasma protein A
can be increased by combining maternal history with a MAP sEND: Soluble Endoglin
measurement in the first trimester. This can increase the VEGF: Vascular endothelial growth factor
b-hCG: Beta-human chorionic gonadotrophin
sensitivity for detection of pre-eclampsia to 60% and
gestational hypertension to 40% with a false positive rate of
10%.7 The advantage of this combined assessment is that it early-onset pre-eclampsia, 45% with late-onset
can be readily performed and incorporated into a logarithmic pre-eclampsia and 50% with gestational hypertension.8 The
equation at the booking appointment. Hence, if such initial elevated resistance within the placental circulation is a result
screening suggests that a woman has a high probability of of the disease process and is reflected in the increased
early onset pre-eclampsia this will have implications in terms measures of impedance, notably resistance index, pulsatility
of necessitating fetal growth and maternal blood pressure index and notching. Both modalities of biomarker screening
surveillance throughout the pregnancy.7 and uterine artery doppler have been demonstrated to predict
Detection rates of of pre-eclampsia in the first trimester pre-eclampsia in low risk populations and can therefore be
can be optimised through the addition of placental utilised as a screening test in either the first or second
biomarkers and maternal history. By combining these trimester.3,6,7 Figure 1 demonstrates a typical uterine artery
results in the first trimester it is possible to detect 80% of Doppler waveform obtained in the first trimester
early onset pre-eclampsia, 64% of late onset pre-eclampsia of pregnancy.
and 39% of gestational hypertension for a false positive rate By combining maternal history, MAP, biochemical marker
of 10%.6 Several biochemical markers have been utilised, but levels (notably PAPP-A and PLGF) and uterine artery
with conflicting results.4 Important biomarkers released from Doppler measurement between 11 and 13+6 weeks of
the villous trophoblast include placental-like growth factor gestation, it is possible to predict 88.5% of pre-eclampsia
(PLGF) and pregnancy associated plasma protein-A requiring delivery before 34 weeks, 46.7% of late
(PAPP-A).3 PLGF is a pro-angiogenic placental biomarker pre-eclampsia and 35.3% of gestational hypertension with a
and, along with the anti-angiogenic biomarkers soluble false positive rate of 5%.6 Therefore, based upon a positive
FMS-like tyrosine kinase-1 (sFLT-1) and soluble endoglin screening test it is possible to tailor aspirin prophylaxis to
(sENG), the balance of these factors has been linked to poor pregnancies that are at greatest risk of pre-eclampsia and
placentation, oxidative stress and maternal endothelial associated adverse outcomes.6,9
dysfunction which subsequently leads to pre-eclampsia and First trimester screening for pre-eclampsia is a
fetal growth restriction.2 It is important when utilising these revolutionary tool in terms of how clinicians can screen for
biomarkers that they are measured against standardised
MoM values to optimise inter-observer accuracy.4 Table 1
demonstrates the relation of biomarkers to
pre-eclampsia risk.
The optimal equation for pre-eclampsia risk in the first
trimester combines all of the above with uterine artery
Doppler studies. It is possible to perform uterine artery
Doppler assessment in both the first and second trimesters to
investigate impaired trophoblastic invasion within the spiral
arteries and hence impaired uterine flow. In isolation, this Figure 1. Example of a first trimester uterine artery Doppler
form of screening is felt to be the most accurate; with a 10% waveform (reproduced with permission of the Fetal
false positive rate it can predict 81% of women with Medicine Foundation).

246 ª 2014 Royal College of Obstetricians and Gynaecologists


and subsequently manage pregnancies affected by
pre-eclampsia. Currently not all obstetric units have access
to sonographers trained in uterine artery Doppler studies or
laboratories with placental biomarker assays. Hence in this
case it is important to consider cost effectiveness as well as
patient acceptability, particularly if first trimester screening
will be extended to include low risk pregnancies. Studies are
currently ongoing to assess these factors.
It is also possible to predict risk of pre-eclampsia in the
second trimester of pregnancy and recently second trimester
uterine artery Doppler assessment has been recommended by
the Royal College of Obstetricians and Gynaecologists in
patients with three of more risk factors for fetal growth
restriction.10 The issue with performing screening tests for
pre-eclampsia at this stage is that it is too late for prophylactic
low-dose aspirin to be of any benefit. In line with the principle
proposed by the Fetal Medicine Foundation of turning the
pyramid of care (as demonstrated in Figure 2) to predicting
pregnancy outcome from the first trimester of pregnancy,
focus has moved to predicting the development of
pre-eclampsia from this early stage, as opposed to clustering
visits around the second and third trimesters of pregnancy.
Hence, providing appropriate prophylaxis and focused
surveillance for mothers who are at risk.11
Low-dose aspirin
Current practice
Current guidance from the National Institute for Health and
Care Excellence (NICE) recommends that low-dose aspirin is
reserved for high-risk patients who meet selected criteria. If a
patient has two moderate risk factors or one major risk
factor, clinicians are advised to prescribe 75 mg of aspirin
from 12 weeks of gestation until delivery. These risk factors
are summarised in Table 2.12
12 weeks
Specialist care
20 weeks
12–34 weeks
37 weeks
41 weeks
Figure 2. Inversion of the pyramid of care (reproduced with
permission of KH Nicolaides).
ª 2014 Royal College of Obstetricians and Gynaecologists
Mone and McAuliffe
Mechanism and dosage
In pre-eclampsia, the balance of prostacyclin and
thromboxane A2 are in favour of the latter. Prostacyclin,
which is found mostly in the vascular endothelium, has a
simultaneous anti-aggregatory effect on platelets, in addition
to a systemic vasodilatory effect. Thromboxane A2 is found
primarily in platelets and has an opposing effect to
prostacyclin. Aspirin acts by inhibiting cyclooxygenase and
hence production of both prostacyclin and thromboxane A2.
It does this in an irreversible fashion in platelets but
reversibly in endothelium, hence prostacyclin production
can be re-established while thromboxane production is
inhibited. The dose required to achieve this effect is
unknown, although research has suggested that a dose in
the range of 0.5–2.0 mg/kg/day is sufficient, particularly for
the prevention of early-onset pre-eclampsia.13 Studies have
quoted doses in the range of 50–150 mg with variable
results in terms of prevention of pre-eclampsia and its
sequelae. It would appear that cyclo-oxygenase inhibition is
dose-dependent and cumulative with repeated dosage.
Therefore in relation to dosage, it is important to strike a
balance between efficacy and prolongation in bleeding time.
Efficacy
Recent research suggests that administration of anti-platelet
agents to women at risk of pre-eclampsia can lead to a 17%
reduction in the risk of developing pre-eclampsia. Use of
low-dose aspirin in ‘at risk’ women, compared to placebo
leads to a relative risk (RR) reduction of any pre-eclampsia
and severe pre-eclampsia in the aspirin group (RR 0.6 and 0.3
respectively).14 Among high-risk women only 19 needed to
be treated to prevent one case of the condition as well as
associated reductions in the risk of preterm labour (8%), fetal
or neonatal death (14%), in addition to reduction in rates of
FGR (10%).15 There are low rates of adverse outcome and no
association with placental abruption or fetal intracerebral
bleeding.16 The maximum potential effect in terms of adverse
perinatal outcome is seen when aspirin is commenced before
16 weeks of gestation.17 There is a paucity of research into
Table 2. Indications for low-dose aspirin use in pregnancy for
pre-eclampsia prevention
High risk Moderate risk
Hypertensive disease in Primigravida
previous pregnancy
Chronic kidney disease Age >40 years
Auto immune disease Pregnancy interval >10 years
e.g. anti-phospholipid syndrome
Diabetes mellitus Family history pre-eclampsia
Chronic hypertension Multiple pregnancy
BMI >35 kg/m2 at booking
247
 Aspirin for prevention of pre-eclampsia
outcomes in low-risk patients and whether low-dose aspirin
would be beneficial for more widespread use.15
Safety
Evidence dating back to the Collaborative Low-dose Aspirin
Study in Pregnancy (CLASP)18 suggests that low-dose aspirin
is safe in pregnancy and is associated with essentially
negligible adverse outcome.15Aspirin is currently used
routinely in pregnancies that meet clinical criteria for risk
of pre-eclampsia as outlined by NICE.12 In addition, this
drug has been utilised historically for maternal conditions
including cardiac disease and thrombophilia, often at higher
doses. Although it crosses the placenta, low-dose aspirin is
not linked to teratogenic effects when used in the first
trimester and associations with persistent pulmonary
hypertension with third trimester use are theoretical but
unfounded.19 It is advisable that aspirin is stopped
pre-delivery due to the changes in platelet aggregation and
bleeding times with doses above 40 mg per day and the risk
of postpartum haemorrhage.20 With the exception of one
study, existing research to date has not demonstrated
adverse childhood neurological outcome associated with
low-dose aspirin use in pregnancy.21–23 This, the Extremely
Low Gestational Age Newborns (EGLAN) study,
demonstrated that infants of mothers who had consumed
aspirin during their pregnancy were at increased risk of
cerebral palsy when infants were delivered before the 28th
week of gestation.21
Calcium supplementation
Mechanism
Calcium is a nutrient that must be consumed in adequate
proportions within the diet to ensure adequate serum levels,
as it is not manufactured in the body. In pregnancy serum
levels of calcium tend to fall due to active transport across the
placenta to the fetus, which can accumulate up to 25–30 g
over the course of the pregnancy, notably in the third
trimester. In pregnancy absorption of calcium from the
gastro-intestinal tract is also increased, mainly due to
increased levels of 1,25-dihydroxyvitamin D and urinary
excretion of calcium is increased. Levels of parathyroid
hormone and calcitonin are elevated which subsequently
impacts upon levels of serum calcium.24
The required intake of calcium in pregnancy is 1000 mg
per day, however, it is suggested that only 6% of pregnant
women reach this daily quantity.25 Maternal risks of calcium
deficiency in pregnancy include osteopenia, osteoporosis,
tremor, paraesthesia, muscle cramps and tetany. Calcium also
has a role in fetal bone mineralisation and in the prevention
of fetal growth restriction.26
Serum calcium levels have been found to be reduced in
patients with co-existing pre-elampsia and calcium deficiency
248
has also been linked to other pregnancy morbidities such as
preterm labour.27 The potential pathological mechanism
behind calcium deficiency and pre-eclampsia could
potentially be through parathyroid hormone and renin
release, increasing intracellular calcium levels and leading to
vasoconstriction through smooth muscle vascular
contraction. Further research is required to unveil the
definitive mechanism of action.26
Efficacy
The World Health Organization (WHO) advise calcium
supplements at a dosage of 1.5–2 g per day from 20 weeks of
gestation in populations where calcium intake is low to
prevent the onset of pre-eclampsia, especially amongst
women that are at high-risk of pre-eclampsia. The reason
that it is commenced at 20 weeks of gestation is that this is
the gestation for which most evidence exists; it is most likely
that this is when maternal levels begin to fall. Table 3
summarises the recommended regimen.27
Calcium supplementation has been demonstrated to halve
the risk of pre-eclampsia (RR 0.45), especially in women with
low baseline levels of calcium and at high-risk of the
condition. In addition, risks of preterm labour (RR 0.76) and
maternal death or morbidity are also significantly reduced
(RR 0.80) although the risk of HELLP (haemolyis, elevated
liver enzymes, low platelets) syndrome is increased (RR
2.67).28 A large study by WHO concluded that the
supplementation of calcium to women felt to be deficient
in pregnancy (<600 mg daily intake) had its greatest effect in
the reduction of pre-eclampsia severity, neonatal mortality
and morbidity as opposed to the overall incidence of the
disease.29 Further research is required to define the optimal
dosage and minimal commencement of calcium for the
prevention of pre-eclampsia.
Safety
There are reported maternal side effects associated with
calcium supplements, including difficulty in swallowing,
increased urinary tract stones and infection and reduced
absorption of other minerals. It is advisable that iron and
Table 3. Table demonstrating suggested regimen in pregnancy for
calcium supplementation for the prevention of pre-eclampsia (WHO
guidance)
Dosage 1.5–2.0 g elemental calcium/day
Frequency Daily, with the total daily dosage divided
into three doses (preferably taken at mealtimes)
Duration From 20 weeks of gestation until the end
of pregnancy
Target group All pregnant women, particularly those at
higher risk of gestational hypertension
Settings Areas with low calcium intake
ª 2014 Royal College of Obstetricians and Gynaecologists

calcium if both required in pregnancy are taken several hours
apart so as not to affect absorption and that the
recommended upper threshold of 3000 mg intake daily is
not exceeded.
It is the general consensus that the benefits of calcium
supplementation for the prevention of pre-eclampsia in
calcium deficient pregnancies outweigh the risks. No other
risks have been noted and follow up in children has
demonstrated that calcium supplementation in pregnancy
can lead to lower systolic blood pressure in children at
follow-up.30 Due to the alternative mechanisms of aspirin
and calcium, if calcium deficiency co-exists in an individual
who meets the criteria for low-dose aspirin it is permissible to
treat with both simultaneously, although currently there is no
existing evidence to support this.
Conclusion
Low-dose aspirin commenced prior to 16 weeks of gestation
and calcium supplementation after 20 weeks of gestation in
low-intake populations can prevent pre-eclampsia. Treatment
is currently reserved for pregnancies that are ‘at-risk’ of this
condition, based upon clinical risk factors. In the future,
management may be targeted towards the administration of
prophylactic therapy, based on the results of first trimester
screening which will combine clinical history, mean arterial
pressure, uterine artery doppler studies and placental
biomarkers to calculate maternal risk. More research is
needed to see if such therapies are beneficial in
low-risk populations.
Contribution to authorship
F Mone was the primary developer of this article through
critical appraisal of current research in this field to design of
CPD questions. FMcA subsequently edited the draft and
revised it critically for intellectual content and hence
provided final approval.
Disclosure of interests
None declared.
Acknowledgements
None
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