Viewpoint
org
Should we recommend universal aspirin for all
pregnant women?
Fionnuala Mone, MRCOG; Cecilia Mulcahy, MSc; Peter McParland, FRCOG; Fionnuala M. McAuliffe, FRCOG
P reeclampsia is a serious multisystemic maternal condition
that affects 3e5% of pregnancies. Worldwide, pre-
eclampsia and its sequelae are responsible for 10e15% of
maternal and perinatal deaths.1 The denitive cause of pre-
eclampsia remains unknown, although there are several postu-
lated physiologic mechanisms. The underlying disease is
thought to originate from ischemic placental disease, which
leads to a systemic response that is fueled by endothelial damage
and a proposed imbalance between prostacyclin (vasodilator)
and thromboxane A2 (vasoconstrictor) that causes sequelae
precipitated by end-organ damage.2 Rates of preeclampsia in
the United States are increasing; their prevention and manage-
ment have been highlighted in the Presidential Initiative by
the American College of Obstetricians and Gynecologists
(ACOG).3 Low-dose aspirin (LDA) has been found to prevent
preeclampsia if commenced before 16 weeks gestation. It is
believed to act by irreversibly inhibiting cyclooxygenase-1 and -2
in platelets but reversibly in the endothelium; hence, the balance
swings in favor of prostacyclin, which is a potent vasodilator and
inhibitor of platelet aggregation that counteracts the reverse
phenomenon that is associated with preeclampsia.3 There are
emerging screening tests that can predict preeclampsia and
can be performed as early as 11 weeks gestation. The Fetal
Medicine Foundation has devised an algorithm that in-
corporates maternal history, mean arterial blood pressure,
uterine artery Doppler pulsatility index, and placental bio-
markers pregnancy-associated plasma protein A (PAPP-A)
and placental-like growth factor (PLGF), which can detect 96%
of early-onset preeclampsia and 54% of any preeclampsia at a
10% false-positive rate.4,5 Reported performance appears to vary
in differing populations assessed internationally.1,4,5
Point
Should we recommend universal aspirin for all pregnant
women?
Prevention of preeclampsia and fetal growth restriction
LDA that is commenced after the rst trimester has been
demonstrated to reduce the risk of preeclampsia by 24% and
From the Department of Fetal Medicine (all authors) and UCD Obstetrics
and Gynaecology, School of Medicine, University College Dublin
(Drs Mone, McParland, and McAuliffe), National Maternity Hospital,
Dublin, Ireland.
The authors report no conict of interest.
Corresponding author: Fionnuala M. McAuliffe, FRCOG. Fionnuala.
mcauliffe@ucd.ie
0002-9378/$36.00
2016 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2016.09.086
Related editorial, page 95.
ajog.
sequelae, such as pre-term birth and fetal growth restriction, by
14% and 20%, respectively, when given to women who are at
risk of preeclampsia.6 Based on such evidence, the adminis-
tration of LDA is now recommended for women with 1 major
risk factor or 2 moderate risk factors for preeclampsia, as
per guidelines from the National Institute for Health and Care
Excellence, UK.7 These recommendations are echoed by the
US Preventative Services Task Force.8 The ACOG differs
slightly in opinion and recommends LDA usage in women with
a history of preeclampsia in >1 pregnancy or a history of
preeclampsia that required delivery at <34 weeks gestation.3
The use of a maternal history approach for screening, based
on 1 major risk factor (such as a previous preeclamptic preg-
nancy, chronic hypertension, diabetes mellitus, and systemic
lupus erythematosus), which is similar to that proposed by
the ACOG when set at a false-positive rate of 5%, can predict
37% and 28.9% or early-onset and late-onset preeclampsia.
The use of the National Institute for Health and Care Excel-
lence, UK, or US Preventative Task approach can improve these
rates to 89.2% and 93.0% respectively.9
Safety
LDA at a dosage of 60e150 mg has been tried and tested in
pregnancy for decades and has robust safety data to support its
use beyond the rst trimester. The CLASP study (Collaborative
Low-dose Aspirin Study in Pregnancy) was 1 of the original and
largest randomized controlled trials to assess efcacy and safety
of aspirin in the prevention of preeclampsia in at-risk pregnant
women and concluded that, in >9000 subjects, LDA was
generally safe for the fetus and newborn infant, with no evi-
dence of an increased likelihood of maternal or fetal bleeding.10
The ndings of the CLASP study have been supported through
further studies that have concluded that there is no association
between the use of LDA in the third trimester of pregnancy and
neonatal intraventricular hemorrhage, neonatal bleeding, or
antenatal closure of the ductus arteriosus.11-15 Use of aspirin
beyond the rst trimester of pregnancy is not associated with
an increased risk of congenital anomalies,12,16,17 nor is it
associated with increased maternal risk in terms of major
postpartum bleeding, placental abruption, or adverse regional
anesthetic outcome.14,18,19 There is an abundance of robust
data to support the safety of LDA beyond the rst trimester,
most recently a systematic review from the US Preventative
Services Task Force 2014 concluded that LDA usage was not
associated with maternal or neonatal harm, with normal
follow-up to an 18-year period.6
Cost-effectiveness
In addition to being regarded as a safe drug in pregnancy,
LDA is cheap in cost and is available widely. Bearing in mind
FEBRUARY 2017 American Journal of Obstetrics & Gynecology 141
Viewpoint
the high costs to health services worldwide for treatment of
preeclampsia and its sequelae, which encompass care for the
mother and the neonate, it may be suggested that universal
provision of aspirin for prevention of preeclampsia is more
economically viable. The issue is knowing for which group of
women is it more cost-effective to offer preeclampsia pre-
vention, whether it is for all women or just for those with
major risk factors or whether it is for those that test positive
on a formalized screening test algorithm. This may explain
the differing opinions in international guidelines on whom it
is appropriate to offer LDA.20 A recent study has demon-
strated that it is more cost-effective to treat all pregnant
women universally with LDA or via a screened approach
adopting the US Task Force policy.21 As addressed within this
study, the introduction of screening tests have limitations in
terms of their application and interpretation.21 Screening
tests, such as the Fetal Medicine Foundation algorithm,
incorporating rst-trimester uterine artery Doppler assess-
ment, maternal history, mean arterial blood pressure, and
biomarker assessment,4 may introduce additional cost with
resource implications, although a cost-effectiveness analysis
compared with other measures has yet to be assessed.
International impact
Despite advances in the management of preeclampsia and a
reduction in the rates of maternal death in the developed
world, there remains disparity worldwide, with hypertensive
disorders being 1 of the 3 major causes of maternal death
worldwide and remaining the leading cause of death in re-
gions such as Latin America and the Caribbean.22 Countries
where resources are limited, despite the existence of good
world health recommendations for preeclampsia recognition
and management, may nd it a challenge to afford tools to
diagnose and manage the disease or to facilitate safe delivery
and neonatal care.23 Where access to tools for screening,
diagnosis, and treatment of preeclampsia are limited, 1
potential option is the universal provision of LDA, which may
provide a cheaper alternative and could potentially reduce
mortality rates in such countries.
Conclusion
It has been suggested that the most cost-effective approach to
the reduction of preeclampsia is likely to be the provision of
an effective, affordable, and safe intervention that is applied
to all mothers without previous testing to assess levels of
risk.24 Universal aspirin for all may be the answer to this in
terms of efcacy because it is regarded as a safe and cheap
drug that may serve major benet in pregnancy on a
worldwide scale.
Counterpoint
Should we recommend universal aspirin to all pregnant
women?
Efcacy in low-risk populations
There are multiple randomized controlled trials and meta-
analyses that support a risk reduction in preeclampsia and
142 American Journal of Obstetrics & Gynecology FEBRUARY 2017
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sequelae in women who have existing risk factors for the
disease. In terms of such evidence, studies vary in terms of
aspirin dosing, starting times in pregnancy, characteristics of
populations included, combinations of other antiplatelet
agents, types of analyses conducted, and inclusion of studies
that are of variable quality. Hence, metaanalyses provide
variable risk reduction rates for preeclampsia. In terms of risk
reduction of preeclampsia in low-risk women, this has not
been assessed within an appropriately powered randomized
controlled trial, which would likely require >5000 partici-
pants to assess preeclampsia as an outcome. One may suggest
that an evidence-based approach is required on the efcacy of
LDA in terms of preeclampsia risk reduction before pro-
ceeding with a universal aspirin policy.
Aspirin resistance
Some pregnant women may be nonresponsive to aspirin.
Such aspirin resistance may be due to multifactorial reasons
such as (1) genetic polymorphisms, (2) aspirin adherence, (3)
spontaneous regeneration of cyclooxygenase-2 and (4)
increased platelet turnover in pregnancy. Aspirin resistance is
well-established in cardiovascular research, and the reported
prevalence ranges from 5e65%, varying with the assay used
and the populations studied.25,26 A cohort of women is seen
in pregnancy who, despite taking aspirin, still develop pre-
eclampsia; this may represent the aspirin-resistant group. A
clearly dened assessment that combines clinical and
biochemical parameters in pregnancy to determine the
prevalence of aspirin nonresponsiveness is currently the focus
of some research groups.26 Studies suggest that LDA is as
effective as high-dose aspirin in terms of cyclooxygenase
suppression. However, enteric coating, which most prepara-
tions have that are used in pregnancy, can inhibit the
cyclooxygenase inhibitory aspirin effect.27 Pregnant women
differ from standard adults taking aspirin in that they have
increased platelet turnover and production within the bone
marrow, with additional sequestration of platelets in the
placenta, which causes more immature platelets to be released
from the placenta and increases a tendency for platelet ag-
gregation.27 Hence, treating women with universal aspirin in
pregnancy may only target the aspirin-responders, which may
make up a much lower proportion of the population than
previously anticipated.
Aspirin compliance and patient acceptability
Women typically are advised not to take any medications
during pregnancy; however, up to 80% of women actually
may require medications.28 In terms of compliance with
medications in pregnancy, evidence suggests that, in the
coexistence of chronic illness or new illness, compliance is
high at 90e95% but varies based on drug type and prepa-
ration used.28 In terms of assessment of compliance, methods
include assessment of self-reporting, such as question-
naires, in addition to prescription logs in the pharmacy;
however, these tend to over-estimate compliance, and there
may be a variation in the time taken and if the course of
medication has been completed.29 In short, there is currently
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no robust method to assess aspirin compliance, and there are
no studies unique to pregnancy. Hence, we do not know true
compliance with aspirin specically in pregnancy, notably
compliance in a low-risk population where efcacy is not
known. One must also consider how acceptable it is for
women to take LDA in pregnancy if they have no predis-
posing risk factors for preeclampsia, which is another area
that requires assessment.
Safety
Aspirin safety in pregnancy beyond the rst trimester is
widely known. LDA commenced before the completion of
the rst trimester has been demonstrated to be associated
with a small increase in the incidence of gastroschisis
(approximately 5/100,000 vs 12/100,000 deliveries).30 In
terms of maternal risks, LDA is associated with a 10% in-
crease in gastrointestinal symptoms, hence a specialized
enteric-coated preparation is recommended.12 LDA uncom-
monly can cause hypersensitivity reactions and is contra-
indicated in those women who are aspirin-allergic or have
aspirin-sensitive asthma. LDA is not associated with
elevated rates of placental abruption, major postpartum
hemorrhage, or intracranial neonatal hemorrhage, although
it has been demonstrated to triple rates of vaginal bleeding in
pregnancy (1.3% vs 3.9%; P.004), as demonstrated in the
recent Effects of Aspirin in Gestation and Reproduction
randomized controlled trial that set out to determine
whether the use of LDA (81 mg once daily) that was
commenced preconceptually until 36 weeks gestation
improved live birth rates in women who had had 1 previous
pregnancy loss.31 Although LDA was not associated with an
increased risk of miscarriage, it may not be acceptable to
women with no predisposing risk factors for preeclampsia to
experience additional concern and require further assessment
of bleeding in pregnancy over a small theoretic preeclampsia
risk reduction. This may also have further resource impli-
cations to health services if women attend as an emergency
for assessment of vaginal bleeding in pregnancy. The rec-
ommended dosage of aspirin is unknown, although studies
appear to prescribe it at a dosage of 60e150 mg once daily,
depending on the preparations manufactured in respective
countries. A once-daily dosage appears to be acceptable, and
the effects of LDA do not appear to be half-life dependent but
more so on the individual rate of platelet turnover. Doses of
aspirin <81 mg, as used in the United States, are sufcient in
maintaining COX-1 inhibition in nonpregnant subjects and
hence appears to be sufcient in the absence of aspirin
resistance.27 LDA appears to be most effective if commenced
before placental implantation, typically at <16 weeks gesta-
tion.32 The optimal policy would be to dispense LDA at the
lowest effective dose, which has optimal efcacy and which is
freely and easily acceptable within a population. One must
weigh the potential side-effects and acceptability of universal
LDA for pregnant women and the risks of potential pre-
eclampsia development against a screen-and-treat-all policy,
which may involve additional investigations that are not
acceptable to women.
Viewpoint
Conclusion
The pathologic explanation behind preeclampsia is not fully
understood. The rate of disease reduction is unknown with
LDA use. Hence, one must consider whether universal LDA
for the prevention of a disease, which we do not fully
understand and do not know the efcacy of the proposed
agent, will benet the population. It may not be acceptable to
women who have no risk factors to take a drug that may
increase their risk of vaginal bleeding. Additionally, women
may not be aspirin responders or may not be compliant with
medication. Further research is required to support such a
policy. -
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ajog.org
ABSTRACT
Should we recommend universal aspirin for all
pregnant women?
Low-dose aspirin has been demonstrated to reduce the incidence
of preeclampsia and fetal growth restriction in at-risk populations.
Its role in low-risk populations is as yet unknown. Novel pre-
eclampsia screening tests are emerging that can predict the risk of
the development of preeclampsia from as early as 11 weeks of
gestation. It may be more efficacious, acceptable, and cost-
effective to prescribe low-dose aspirin to all pregnant women
from the first trimester as opposed to performing a screening test
in the first instance. There is variation in opinion: the American
College of Obstetricians and Gynecologists suggests the use of
aspirin only in women who are at risk of preeclampsia, based on
patient history; the National Institute for Health and Clinical
Supplemental Materials Viewpoint
Excellence, UK, and the US Preventative Services Task Force
recommend the use of low-dose aspirin if there is 1 major or 2
moderate risk factors. This point-counterpoint discussion shall
address (1) controversies regarding the real impact of low-dose
aspirin; (2) controversies in the actual guidelines among the
different national societies; (3) controversies regarding emerging
preeclampsia screening tests in terms of cost-effectiveness and
efficacy, and (4) points in favor of the provision of universal vs
screened-positive women.
Key words: fetal growth restriction, low-dose aspirin, preeclampsia,
universal
FEBRUARY 2017 American Journal of Obstetrics & Gynecology 141.e1