Expert Review ajog.

org

Prevention of preeclampsia with aspirin

Daniel L. Rolnik, PhD; Kypros H. Nicolaides, MD; Liona C. Poon, MD

Preeclampsia is defined as hypertension arising after 20 weeks of gestational age with proteinuria or other signs of end-organ damage and is
an important cause of maternal and perinatal morbidity and mortality, particularly when of early onset. Although a significant amount of
research has been dedicated in identifying preventive measures for preeclampsia, the incidence of the condition has been relatively un-
changed in the last decades. This could be attributed to the fact that the underlying pathophysiology of preeclampsia is not entirely un-
derstood. There is increasing evidence suggesting that suboptimal trophoblastic invasion leads to an imbalance of angiogenic and
antiangiogenic proteins, ultimately causing widespread inflammation and endothelial damage, increased platelet aggregation, and
thrombotic events with placental infarcts. Aspirin at doses below 300 mg selectively and irreversibly inactivates the cyclooxygenase-1
enzyme, suppressing the production of prostaglandins and thromboxane and inhibiting inflammation and platelet aggregation. Such an
effect has led to the hypothesis that aspirin could be useful for preventing preeclampsia. The first possible link between the use of aspirin and
the prevention of preeclampsia was suggested by a case report published in 1978, followed by the first randomized controlled trial published
in 1985. Since then, numerous randomized trials have been published, reporting the safety of the use of aspirin in pregnancy and the
inconsistent effects of aspirin on the rates of preeclampsia. These inconsistencies, however, can be largely explained by a high degree of
heterogeneity regarding the selection of trial participants, baseline risk of the included women, dosage of aspirin, gestational age of
prophylaxis initiation, and preeclampsia definition. An individual patient data meta-analysis has indicated a modest 10% reduction in
preeclampsia rates with the use of aspirin, but later meta-analyses of aggregate data have revealed a dose-response effect of aspirin on
preeclampsia rates, which is maximized when the medication is initiated before 16 weeks of gestational age. Recently, the Aspirin for
Evidence-Based Preeclampsia Prevention trial has revealed that aspirin at a daily dosage of 150 mg, initiated before 16 weeks of gestational
age, and given at night to a high-risk population, identified by a combined first trimester screening test, reduces the incidence of preterm
preeclampsia by 62%. A secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention trial data also indicated a reduction
in the length of stay in the neonatal intensive care unit by 68% compared with placebo, mainly because of a reduction in births before 32
weeks of gestational age with preeclampsia. The beneficial effect of aspirin has been found to be similar in subgroups according to different
maternal characteristics, except for the presence of chronic hypertension, where no beneficial effect is evident. In addition, the effect size of
aspirin has been found to be more pronounced in women with good compliance to treatment. In general, randomized trials are underpowered
to investigate the treatment effect of aspirin on the rates of other placental-associated adverse outcomes such as fetal growth restriction and
stillbirth. This article summarizes the evidence around aspirin for the prevention of preeclampsia and its complications.
Key words: abruption, adverse pregnancy outcome, algorithm, aspirin, Aspirin for Evidence-Based Preeclampsia Prevention, blood
pressure, competing risk, fetal growth restriction, Fetal Medicine Foundation, first trimester, hypertension, intrauterine growth restriction,
mean arterial pressure, morbidity, mortality, number needed to screen, number needed to treat, perinatal, placental growth factor,
placental insufficiency, prediction, preeclampsia, pregnancy, pregnancy complications, prematurity, preterm, prevention, prophylaxis,
pulsatility index, resistant index, risk factor, safety, stillbirth, uterine artery, uterine artery mean pulsatility index

Introduction notable burden on healthcare systems.1,2 developmental delay, respiratory disor-

Preeclampsia affects 2% to 8% of all One-third of all preeclampsia cases ders, hypertension, renal dysfunction,
pregnancies and is a significant cause of require preterm delivery, and its associa- insulin resistance, obesity, cardiovascular
maternal and perinatal morbidity and tion with fetal growth restriction and disease, and impaired work capacity.3,4
mortality, particularly when of early prematurity often leads to lifelong con- Furthermore, mothers affected by pre-
onset. The disease is responsible for one- sequences for the child, including higher eclampsia are 2 to 5 times more likely to
sixth of all premature births, which are a risk of cerebral palsy and neuro- develop hypertension and cardiovascular

From the Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia (Dr Rolnik); Fetal
Medicine Research Institute, Harris Birthright Centre, King’s College Hospital, London, United Kingdom (Dr Nicolaides); Department of Obstetrics and
Gynaecology, The Chinese University of Hong Kong, Shatin, the Hong Kong Special Administrative Region of the People’s Republic of China (Dr Poon).
Received June 2, 2020; revised Aug. 17, 2020; accepted Aug. 19, 2020.
L.C.P. has received speaker fees and consultancy payments from Roche Diagnostics and Ferring Pharmaceuticals and in-kind contributions from Roche
Diagnostics, PerkinElmer, Thermo Fisher Scientific, and GE Healthcare. The remaining authors report no conflict of interest.
This paper is part of a supplement.
Corresponding author: Liona C. Poon, MD. [email protected]
0002-9378/$36.00
ª 2020 Published by Elsevier Inc.
https://doi.org/10.1016/j.ajog.2020.08.045

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and cerebrovascular disease in the future Egyptian papyrus scrolls with compila- report published in 1978, describing
when compared with mothers who do not tions of medical texts dating back to 1534 better outcomes with daily use of
have preeclampsia in their pregnancies.5e7 BCE.19 Around 400 BC, Hippocrates also aspirin from midtrimester in the third
In recent years, a significant amount of utilized extracts from the willow tree and pregnancy of a woman with 2 previous
research has been dedicated to elucidate its leaf tea to treat headache, pain, and pregnancies severely affected by pre-
the pathophysiology of the disorder, fever.20 In 1828, Johann Buchner extrac- eclampsia and fetal growth
develop methods in identifying women at ted the active ingredient of the willow restriction.30
risk through the use of predictive models, bark and called it salicin. A few years later, In the first randomized trial evalu-
and investigate possible preventive stra- in 1853, sodium salicylate was treated ating the effect of aspirin on placenta-
tegies to reduce the incidence of with acetyl chloride to produce acetylsa- mediated complications, Beaufils et al31
preeclampsia.8e10 A robust predictive licylic acid, and the first aspirin tablets randomized 102 women at high risk of
algorithm applied at 11 to 13 weeks of were industrially produced in 1915.21 The preeclampsia and fetal growth restric-
gestational age identifies about 75% of use of aspirin became widespread during tion, mainly based on their obstetrical
the cases of preterm preeclampsia (with the 1918 flu pandemic22 and in the 1960s, history, to receive daily doses of aspirin
delivery before 37 weeks of gestational the first studies on aspirin use for the at 150 mg and dipyridamole at 300 mg
age) and about 90% of the cases of early- prevention of myocardial infarction were from 12 weeks of gestational age or usual
onset disease preeclampsia (with delivery published.22,23 care. There were 6 cases of preeclampsia,
before 34 weeks of gestational age), at a In 1982, Vane, Samuelsson, and Berg- 5 of perinatal death, and another 4 of
10% screen-positive rate.11 This com- ström were awarded the Nobel Prize after fetal growth restriction in the control
bined screening test utilizes maternal elucidating the mechanism of action of arm, and none of these events occurred
characteristics and medical and obstet- the drug24: aspirin belongs to the family of in the treatment arm.31
rical history to calculate the a priori nonsteroidal antiinflammatory drugs, and Numerous randomized trials followed
probability of delivery with preeclampsia its analgesic, antipyretic, and antiin- in the next few decades, with inconsis-
vs that for any other cause at a given flammatory effects are due to the inacti- tent results and conclusions, largely
gestational age, which is then combined vation of the cyclooxygenase (COX)-1 and explained by a high degree of heteroge-
with the measurements of mean arterial COX-2 enzymes, suppressing the pro- neity regarding the selection of trial
pressure, uterine artery mean pulsatility duction of prostaglandins and throm- participants, baseline risk of the included
index on Doppler ultrasound, and serum boxane. This thromboxane reduction also women, dosage of aspirin, gestational
placental growth factor (PlGF) to esti- leads to an inhibition of platelet aggrega- age of prophylaxis initiation, and pre-
mate the posteriori adjusted probability tion, producing an antithrombotic ef- eclampsia definition. A large random-
of preeclampsia development.11 Such fect.25,26 The mechanism of action of the ized trial performed in 1994, named
predictive tests based on competing risks drug is summarized in Figure 2. Collaborative Low-dose Aspirin Study in
have been externally validated in pro- There is increasing evidence suggest- Pregnancy (CLASP), included 9364
spective studies.8,12e14 ing that suboptimal trophoblastic inva- women at risk of preeclampsia or fetal
Despite all these efforts, the preva- sion leads to an imbalance of angiogenic growth restriction because of medical
lence of preeclampsia has remained and antiangiogenic proteins, ultimately history and pregnancies already diag-
relatively unchanged in the last few de- causing widespread inflammation and nosed with these complications. Treat-
cades.15 A large number of very hetero- endothelial damage, increased platelet ment with a daily dosage of 60 mg,
geneous studies have evaluated the aggregation, and thrombotic events with initiated between 12 and 32 weeks of
possible benefit of aspirin intake in placental infarcts.27 It has been hypoth- gestational age, was considered safe but
pregnancy to minimize the risk of pre- esized, therefore, that the effect of aspirin did not lead to a reduction in pre-
eclampsia, with large variations in in the inhibition of inflammation and eclampsia rates. It was observed that
included population risk profile, aspirin platelet aggregation could be useful to there was correlation between rates of
dosage, gestational age of prophylaxis prevent or treat preeclampsia.28 preeclampsia and gestational age at de-
initiation, and disease definition.16 In Nowadays, aspirin is 1 of the most livery; the lower the gestational age, the
this article, we review and summarize commonly prescribed medications, taken lower the rates of preeclampsia.17
the evidence regarding the use of aspirin by more than 50 million people in the
for the prevention of preeclampsia. United States for the prevention of car- Inconsistent effect of aspirin identified in
diovascular disease, and about 40,000 tons meta-analyses. In 2007, Askie et al16
Summary of aspirin history are consumed every year worldwide.29 published an individual patient data
Aspirin is 1 of the oldest medications that meta-analysis on the effect of antiplatelet
is still in widespread use. A timeline of the Effect of aspirin on preeclampsia rates agents (including 24 randomized
history of aspirin is shown in Figure 1. Conflicting results of randomized controlled trials with aspirin alone) on
Aspirin-related compounds were isolated trials. The first possible link between the the incidence of preeclampsia. A modest
from the willow tree (genus, Salix), and use of aspirin and the prevention of 10% risk reduction (relative risk [RR],
reports of willow bark use can be found in preeclampsia was suggested by a case 0.90; 95% confidence interval [CI],

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FIGURE 1
Timeline of events in aspirin history and specific aspects of its use in pregnancy (purple boxes)
Ebers papyrus Hippocrates The Royal Society Joseph Buchner Charles Gerhardt Acetylsalicylic acid is First tablets First studies on
(Egypt) refers (Greece) administers reports on the use of (Germany) extracts the (France) called “Aspirin” and of aspirin are aspirin for prevenon
to willow as willow leaf tea to dried powdered willow acve ingredient of the synthesizes its producon industrially of myocardial
pain reliever relieve pain bark to treat fever willow and calls it “salicin” acetylsalicylic acid process is patented produced infarcon
1918 1938

1500 BC 400 BC 1763 1828 1853 1897-1899 1915 1960’s

1918 Flu pandemic Aspirin
leads to widespread linked to
aspirin use gastris

A series of meta-analyses
Aspirin shown John Vane (UK) Vane, Samuelsson and HOT trial: aspirin Dose-dependant shows that effect of Large RCT shows no
to inhibit describes the Bergström win the reduces cardiovascular effect in aspirin on preeclampsia cardiovascular
platelet mechanism of acon Nobel prize for the events in hypertensive pregnancy rates depends on dose benefit in healthy
funcon of aspirin work with aspirin paents reported and me of iniaon elderly adults
1978 1985 1994 2007 2017

1967 1971 1982 1998 2009 2010-2013 2018

First case report of The first randomized CLASP, a large RCT PARIS meta-analysis ASPRE trial shows a
the use of aspirin to trial showing a benefit of aspirin 60 mg, shows modest effect of 62% reducon in
prevent recurrent of aspirin in prevenng does not show aspirin on preeclampsia rate preterm
preeclampsia preeclampsia benefit of aspirin rate (10% reducon) preeclampsia in
in pregnancy high-risk women
taking 150 mg from
11-14 weeks of
gestaonal age

ASPRE, Aspirin for Evidence-Based Preeclampsia Prevention; CLASP, Collaborative Low-dose Aspirin Study in Pregnancy17; HOT, Hypertension Optimal Treatment study18; PARIS, Perinatal Antiplatelet
Review of International Studies; RCT, randomized controlled trial.
Rolnik. Aspirin for the prevention of preeclampsia. Am J Obstet Gynecol 2022.

0.84e0.97) was identified.16 It is fashion, with the effect maximized at nonresponsive to its effects at a daily
important to note that 15 definitions of daily doses above 100 mg. These later dosage of 162 mg, high-risk women were
preeclampsia were used in the different meta-analyses have been criticized randomly and blindly allocated to
included trials; in most studies, trial because of the use of aggregate data, receive 150 mg of the trial drug daily
medication was given at doses lower than which may overestimate the effect size of or placebo from 11 to 14 weeks of
100 mg (ranging from 50e150 mg, with aspirin as compared with individual gestational age until 36 weeks of gesta-
only 2 studies evaluating aspirin at a patient data meta-analyses, the inclusion tional age or delivery, whichever
dosage of 150 mg)16; and in 59% of the of a small number of heterogeneous occurred first. Aspirin was given at
included pregnancies, trial medication studies, and the fact that the subgroup bedtime, based on a previous chrono-
began after 20 weeks. that received aspirin before 16 weeks of therapy trial including 350 high-risk
A series of subsequent meta-analyses gestational age is likely to have a higher women and comparing different
of aggregate data has revealed that risk profile than the subgroup of women administration times suggesting that the
aspirin is highly effective in reducing who received aspirin after 16 weeks of beneficial effects are dependent on the
preeclampsia rates if initiated before 16 gestational age.35 time of administration, with better
weeks of gestational age (RR, 0.47; 95% regulation of ambulatory blood pressure
CI, 0.34e0.65) but confers no beneficial The Aspirin for Evidence-Based when taken at night.37
effect when started after 16 weeks (RR, Preeclampsia Prevention trial. Because of Innovatively, high-risk women were
0.81; 95% CI, 0.63e1.03)32; the effect on the conflicting results and significant identified by means of a combined al-
preeclampsia rates is mainly because of a heterogeneity of previous studies, and gorithm that takes account of maternal
reduction of the severe and preterm informed by the results of the afore- characteristics, medical and obstetrical
forms of the disorder (RR, 0.11; 95% CI, mentioned meta-analyses revealing that history, biophysical markers (mean
0.04e0.33), with no significant benefi- aspirin is highly effective in reducing arterial pressure and uterine artery
cial effect on term preeclampsia (RR, preeclampsia rates if initiated before 16 Doppler) and biochemical markers
0.98; 95% CI, 0.42e2.33)32,33; and there weeks of gestational age, the Combined (pregnancy-associated plasma protein A
is a dose-response effect when aspirin is multimarker screening and randomized and PlGF).38 Before initiating the ran-
initiated before 16 weeks of gestational patient treatment with Aspirin for domized trial, the predictive algorithm
age.34 Evidence-Based Preeclampsia preven- was prospectively validated in an inde-
The beneficial effect of aspirin is tion (ASPRE) trial was proposed.36 pendent cohort, with similar predictive
therefore optimized when initiated Based on previous data suggesting that performance to that observed in the al-
before 16 weeks, which corresponds to approximately 30% of women are gorithm development studies.11,14,38,39
the time when placentation completes, nonresponsive to the effect of aspirin at a Women with a predicted risk at or
and its action occurs in a dose-response daily dosage of 81 mg but only 5% are higher than 1 in 100 were deemed high

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FIGURE 2
Mechanism of action of aspirin

Cell membrane phospholipids

Phospholipase A2
ASPIRIN
(<300 mg)
Arachidonic acid
X

Cyclooxygenase 1 Cyclooxygenase 2
(COX-1 - physiologic) (COX-2 - inducible) Lipooxygenase

Prostaglandin H2 Hydroperoxyeicosatetraenoic acid

(HPETE)
Thromboxane Prostaglandin
synthase synthase
Glutathione-S-
Prostacyclin transferase
synthase

Thromboxane A2 Prostacyclin Prostaglandins Leukotrienes

TXA2 (PGI2) PGD2, PGE2 and PGF2

Platelets Kidneys Inflamma on Respiratory tract

Ac va on and aggrega on Cytoprotec ve vasodila on Cytokine release Bronchoconstric on
Increase glomerular filtra on Pain Edema

Gastrointes nal tract Central nervous system Endothelium

Protec on of gastric Fever Vasoconstric on
mucosa Nausea and vomi ng Vascular injury

At low doses (below 300 mg), the drug inhibits the COX-1 enzyme, particularly in platelets, leading to a reduction in the production of thromboxane A2
and, to a lesser degree, of prostaglandins and prostacyclin.
COX-1, cyclooxygenase 1; HPETE, hydroperoxyeicosatetraenoic acid; PGD2, prostaglandin D2, PGE2, prostaglandin E2, PGF2, prostaglandin F2; PGI2, prostacyclin; TXA2, Thromboxane A2.
Rolnik. Aspirin for the prevention of preeclampsia. Am J Obstet Gynecol 2022.

risk for developing preterm preeclamp- analysis.41 A secondary analysis of the Safety of aspirin in pregnancy
sia, resulting in a screen-positive rate of ASPRE data revealed a consistent effect Aspirin use in pregnancy is considered
11%. Eventually, 1776 high-risk women size within subgroups according to safe. Large cohort and case-control
were recruited from 13 hospitals across 6 recognized risk factors of preeclampsia studies, which have reported that the
European countries, and treatment with (Figure 3), except in the subgroup of drug is not associated with an increase
aspirin was found to reduce the rate of women with chronic hypertension, in risk of congenital heart defects or
preterm preeclampsia by 62% (1.6% vs where no indication of beneficial effect other structural or developmental
4.3%; odds ratio [OR] in the aspirin was seen, possibly because of preexisting anomalies.44,45 Likewise, the theoretical
group, 0.38; 95% CI, 0.20e0.74; endothelial dysfunction or preestab- risk of premature closure of the fetal
P¼.004). There was a nonsignificant lished suboptimal cardiovascular func- arterial duct with aspirin use has not
trend of greater reduction in the rate of tion.42 In addition, as expected, the been reported.46,47 A recent
preeclampsia the earlier the gestational beneficial effect of aspirin was clearly population-based study from Denmark
age at delivery, and no significant associated with good adherence to reported an increased risk of cerebral
reduction in the rate of term pre- treatment.43 At 90% compliance, the palsy in children of mothers who used
eclampsia was observed.40 effect size of aspirin was even higher at aspirin in pregnancy (adjusted OR
The effect of aspirin on the rate of 76% and could reach 90% when the [aOR], 2.4; 95% CI, 1.1e5.3, control-
preterm preeclampsia was subsequently high-risk woman did not have a history ling for maternal socioeconomic status,
confirmed by an updated meta- of chronic hypertension.43 respiratory infection, urinary infection,

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FIGURE 3
Subgroup analysis of the ASPRE trial on the effect of aspirin on the rate of preterm preeclampsia42

ASPRE, Aspirin for Evidence-Based Preeclampsia Prevention; CI, confidence interval; OR, odds ratio; PE, preeclampsia.
Rolnik. Aspirin for the prevention of preeclampsia. Am J Obstet Gynecol 2022.

fever, and rheumatoid arthritis in Although approximately 10% of and the placebo groups.40 Theoretical
pregnancy).48 However, the use of women receiving low-dose aspirin in risks of intracranial bleeding for the
aspirin was defined as “ever used” ac- randomized trials have reported gastro- neonate and postpartum hemorrhage
cording to patient reporting, which not intestinal symptoms, no other major for the mother have never been
only introduced recall bias but also side effects for the women have been confirmed in randomized trials targeting
could not account for dose, frequency, confirmed. In the CLASP trial, there was high-risk populations, even if aspirin
timing, and indication of aspirin use. In no evidence of an increase in the rates of intake is continued until a few days
addition, the authors did not adjust the side effects or adverse events,17 and no before birth17,40,49; however, increased
analyses for preeclampsia, preterm major complications were identified at risk of hemorrhagic events and post-
birth, and small-for-gestational-age 18 months of age in children born to partum hemorrhage have been reported
neonates. Prematurity is by far the mothers who took a daily dosage of 60 in studies evaluating universal aspirin
main cause of cerebral palsy, and mg of aspirin during pregnancy.49 prophylaxis in low-risk populations.50,51
women who used aspirin were likely at Similarly, in the ASPRE trial, the inci- An early randomized trial reported
higher baseline risk of pregnancy com- dence of untoward medication effects that, in 1570 nulliparous women who
plications and preterm birth. was similar between the intervention received 60 mg of daily aspirin and 1565

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women who received placebo from 13 to however, have not been confirmed in factors is significantly lower in those
26 weeks of gestational age, the use of human in vivo studies. Nonetheless, the receiving aspirin 150 mg daily compared
aspirin was associated with an increased beneficial effect of aspirin on pre- with 75 mg daily.66 Furthermore, the
risk of placental abruption (11 cases in eclampsia is now evident, and subse- issue of aspirin nonresponse appears
the aspirin group and 2 cases in the quent modeling of the ASPRE data has more problematic in twin pregnancies,
placebo group).52 This possible adverse revealed a significant interaction be- because rates of nonresponsiveness to
event may have been attributed to the tween the effect size of aspirin and the aspirin have been reported to be as high
late initiation of aspirin therapy. gestational age at delivery with pre- as 65% at a daily dosage of 81 mg.67 A
Placentation is complete mostly by 16 to eclampsia, suggesting, first, that aspirin systematic review and meta-analysis of 6
18 weeks of gestational age, and it is intake shifts the incidence distribution randomized controlled trials with 898
plausible that late initiation of aspirin of preeclampsia to a later gestational multiple pregnancies have reported a
prophylaxis in women with impaired age, and second, the delay in disease significant risk reduction in preeclamp-
placentation leads to an increase in the onset is gestational ageedependent, with sia (RR, 0.67; 95% CI, 0.48e0.94) and
risk of placental abruption. A recent greater delay and benefit in women mild preeclampsia (RR, 0.44; 95% CI,
meta-analysis has suggested a signifi- destined to develop severe early-onset 0.24e0.82) but not severe preeclampsia
cantly higher risk of placental abruption preeclampsia.57 (RR, 1.02; 95% CI, 0.61e1.72) with
when the onset of treatment occurs after aspirin at doses between 60 mg and 100
16 weeks of gestational age than with Prevention of preeclampsia with mg. The reduction of preeclampsia is not
prophylaxis initiation before 16 weeks.53 aspirin in multiple pregnancies significantly different between women
Women with multiple pregnancy are at a randomized before (RR, 0.86; 95% CI,
Mechanism of action in the prevention significantly increased risk of pre- 0.41e1.81) or after 16 weeks of gesta-
of preeclampsia eclampsia when compared with those tional age (RR, 0.64; 95% CI, 0.43e0.96;
Aspirin at doses below 300 mg selectively with a singleton pregnancy, with relative P¼.50).68 The authors conclude that
and irreversibly inactivates the COX-1 risks of 8.7 and 9.1 for preterm pre- there is a low level of evidence support-
enzyme, suppressing the production of eclampsia in dichorionic and mono- ing the use of aspirin for the prevention
prostaglandins and thromboxane and chorionic twin pregnancies, of preeclampsia in multiple pregnancies
inhibiting platelet aggregation24 respectively.58e60 However, because twin and that further studies are required.
(Figure 2). The mechanism by which pregnancies are more likely to be deliv-
aspirin prevents preeclampsia is un- ered prematurely for other indications, Effect of aspirin on other adverse
known, and proposed mechanisms are these relative risks are underestimated pregnancy and cardiovascular
largely speculative and based on in vitro when comparisons are made between outcomes
research, which is consistent with the twin and singleton pregnancies at the Given the common pathophysiology of
lack of understanding of the disease same gestational age.60 The increased preeclampsia and other placental-
pathophysiology. The following possible risk of preeclampsia in multiple preg- associated adverse outcomes, such as
mechanisms have been proposed: (1) nancies may be because of increased fetal growth restriction and stillbirth, it is
improvement in the placentation pro- placental mass rather than true placental reasonable to anticipate that treating
cess, which is supported by the fact that insufficiency, as suggested by the poorer women at high-risk of preeclampsia will
early initiation of therapy indicates a predictive capability of uterine artery also lead to a reduction in other preg-
more prominent reduction in the risk of Doppler and the fact that expression of nancy complications. However, because
preeclampsia; (2) inhibition of platelet antiangiogenic factors is not increased in previous randomized controlled trials
aggregation and its antithrombotic ef- these pregnancies when compared with have focused on preeclampsia as the
fect, thereby leading to lower levels of singleton gestations.61 When the same primary outcome, the evaluation of the
placental infarct; and (3) antiin- combined screening algorithm for treatment effect of aspirin on other
flammatory effects and endothelial sta- singleton pregnancies is applied to twin pregnancy complications, particularly
bilization.54,55 In vitro research with pregnancies, detection of preterm pre- those that are infrequent, such as still-
human choriocarcinoma-derived eclampsia reaches 99%, at the expense of birth, usually lacks statistical power.
(BeWo) cell line treated with serum a high screen-positive rate of about Previous meta-analyses have suggested
from preeclamptic women and aspirin 75%.62 that aspirin prophylaxis initiated before
suggests that the drug modulates cyto- Guidelines from professional organi- 16 weeks of gestational age can halve the
kine secretion, reduces apoptosis to zations list multiple pregnancy as a risk incidence of fetal growth restriction (RR,
levels seen in normotensive serum- factor for preeclampsia and therefore 0.46; 95% CI, 0.33e0.64), perinatal
treated trophoblast cells, upregulates recommend aspirin prophylaxis in these death (RR, 0.41; 95% CI, 0.19e0.92),
trophoblast PlGF production, and pre- cases.35,63e65 Preliminary retrospective and preterm birth (RR, 0.35; 95% CI,
vents premature trophoblast differenti- data from a single center has revealed 0.22e0.57) when compared with placebo
ation commonly observed in that the incidence of preeclampsia in or no treatment.32,69 As mentioned,
preeclampsia.54e56 These findings, twin pregnancies with additional risk these meta-analyses have been criticized

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because they may have overestimated the growth restriction, which are the leading lead to a decrease in cardiovascular dis-
effect size of the intervention. However, causes of medically indicated preterm ease. However, if preeclampsia is pri-
the results of the ASPRE trial also sug- delivery. A subset of pregnant women marily caused by a suboptimal
gested a potential reduction in the rates with spontaneous preterm birth has cardiovascular adaptation during preg-
of perinatal death (aOR, 0.59; 95% CI, placental lesions associated with utero- nancy, as suggested by recent studies,77,78
0.19e1.85, controlling for the effect of placental ischemia and abnormal uterine aspirin intake for a short period during
the estimated risk of preeclampsia at artery Doppler, findings that are pregnancy is unlikely to modify cardio-
screening and the participating center) frequently observed in women with vascular outcomes in the future. Large
and birthweight below the 10th preeclampsia, and therefore, it has been population-based studies with long-
percentile (aOR, 0.77; 95% CI, suggested that placental insufficiency term follow-up will be necessary to
0.56e1.06). These reductions of slightly may play a role in the spontaneous onset answer this question.
smaller magnitude were, however, not of preterm labor and be causally associ- Based on the ASPRE trial results, 38
reaching statistical significance, and the ated with spontaneous preterm women at high risk of preterm pre-
trial was not powered to detect differ- birth.72,73 However, the beneficial effect eclampsia need to be treated with aspirin
ences in these secondary outcomes. of aspirin on the rate of spontaneous at 150 mg to avoid 1 case. The RRs for
Investigating the effect of an interven- preterm birth could not be confirmed in the effect of aspirin on adverse preg-
tion on the rates of rare perinatal out- the ASPRE trial. A recent randomized nancy outcomes and the numbers
comes in randomized controlled trials is trial indicated an 11% reduction in needed to treat are summarized in the
problematic. To report a statistically preterm deliveries with a policy of uni- Table.
significant reduction of 40% in peri- versal aspirin prophylaxis at 81 mg daily
natal death in a high-risk population in low- and middle-income countries Identification of pregnancies at
and assuming a 1.7% baseline rate in the (RR, 0.89; 95% CI, 0.81e0.98; P¼.012), increased risk of preeclampsia
placebo group (estimates derived from but this reduction was likely as a result of Because aspirin intake is highly effective
the ASPRE trial) and a 60% recruitment prevention of preeclampsia, as the au- and more than halves the risk of preterm
uptake, about 170,000 pregnancies thors did not distinguish spontaneous and severe forms of preeclampsia in
would have to be screened and 10,000 from iatrogenic preterm birth.74 Existing high-risk populations, an obvious and
women recruited to the randomized evidence is, thus, inconclusive regarding important question is how to best iden-
trial, which would be practically the effect of aspirin on spontaneous tify women at increased risk of devel-
unachievable. preterm birth rates. oping the disorder and associated
A secondary analysis of 2 large The strength of the well-established adverse outcomes. Approaches to pre-
multicenter studies reported that a pol- association of preeclampsia, particularly diction can be broadly divided in risk
icy of screening for preterm preeclamp- of preterm and severe forms of the dis- scoring methods and predictive models,
sia and daily treatment of high-risk ease, with future cardiovascular and the details and performance of such
women with aspirin 150 mg would morbidity and mortality led the Amer- prediction methods are discussed in a
potentially reduce the rate of small-for- ican Heart Association in 2011 to separate article in this issue. However,
gestational-age neonates born before 37 consider a history of preeclampsia or given that the effect of aspirin in
weeks by 20%.70 Another secondary pregnancy-induced hypertension a ma- reducing the risk of preterm pre-
analysis of the ASPRE data revealed that jor risk factor for development of car- eclampsia is maximized when prophy-
neonates from the aspirin arm who diovascular disease.75 In a recently laxis is initiated before 16 weeks of
required admission to the neonatal published advisory, the American Col- gestational age, screening should ideally
intensive care unit had a significantly lege of Obstetricians and Gynecologists be performed in the first trimester and
shorter length of stay than that of neo- and the American Heart Association target women at high risk of developing
nates from the placebo arm who needed recommend cardiovascular disease risk preterm disease.
admission (11.1 vs 31.4 days), with a factors screening for women with prior
mean reduction of 20.3 days (95% CI, preeclampsia that was preterm (<37 Universal aspirin
7.0e38.6; P¼.008). This finding was weeks) or recurrent, with yearly assess- Considering the clear benefit of aspirin
primarily driven by a significant decrease ment of blood pressure, lipids, fasting in reducing the risk of preterm pre-
in the rate of preterm delivery before 32 blood glucose, and body mass index.76 eclampsia, its low cost, and safety profile,
weeks of gestational age (Figure 4), What remains to be determined is some authors advocate for universal
mainly because of the prevention of whether prevention of preeclampsia aspirin prophylaxis for preeclampsia
early-onset preeclampsia.71 with aspirin will lead to lower rates of prevention. It has been suggested that
Although previous meta-analyses cardiovascular events later in life. If this would be a more cost-effective
have also suggested a reduction in the preeclampsia is caused by impaired strategy than the use of aspirin prophy-
rate of preterm birth,69 it is likely that placentation, which then leads to car- laxis in women determined to be at high
this reduction is mediated via a reduc- diovascular damage, then it is plausible risk through a process of screening,
tion in the rate of preeclampsia and fetal that aspirin use during pregnancy will which has been considered to be rather

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ajog.org Expert Review

complex for implementation.79e82

FIGURE 4
Nevertheless, possible benefits of a pre-
ventive strategy need to be balanced with
Secondary analysis of the ASPRE trial71
potential harm because of hemorrhagic
and other adverse events. Benefits of
universal aspirin and long-term safety of
this strategy have not been adequately
studied in randomized trials. In addi-
tion, good adherence to treatment is
paramount to successful prevention.43
Compliance is likely to be lower when
aspirin is given to the whole population
than when recommended to a selected
high-risk group of women counseled
based on individual risk.83 Earlier trials
in which pregnant women received
aspirin on the sole basis of being preg-
nant or nulliparous reported an
increased frequency of bleeding epi-
sodes, low compliance with aspirin at
only about 50%, and no reduction in the
incidence of preeclampsia.51,84 Analo-
gously, universal aspirin for primary
prevention of cardiovascular events in
healthy older adults resulted in a signif-
icantly higher risk of major hemorrhage
but did not significantly reduce the risk
of cardiovascular disease.85 Cumulative length of stay of neonates admitted to the NICU according to gestational age at birth for
placebo (blue circles) and aspirin (red circles) groups.
NICU, neonatal intensive care unit.
Cost effectiveness of aspirin for
Rolnik. Aspirin for the prevention of preeclampsia. Am J Obstet Gynecol 2022.
prevention of preeclampsia
Improving maternal and perinatal
health is a development goal, and
investing resources in preventing sig- combined first trimester screening al- recommendations,88 or universal pro-
nificant public health problems is key gorithm (using maternal characteristics, phylaxis. The authors have suggested
to achieving this goal. The prevalence medical and obstetrical history, serum that a policy of screening by risk factors
and the cost of preeclampsia vary in biomarkers, and uterine artery Doppler) alone and a policy of universal pro-
different world regions. In the United followed by treating high-risk women phylaxis would both lead to similar
States, the estimated average incre- with aspirin prophylaxis, and the au- reductions in the rate of preeclampsia
mental cost for a pregnancy compli- thors concluded that this approach to and cost savings of about US $370
cated by hypertensive disease was US screening and prevention is cost effective million and that, with the screen and
$8200 in 2011.86 Stevens et al2 esti- in various disease prevalence scenarios in treat approach, 76.5% of the women
mated the annual preeclampsia- Israel.87 would not be prescribed aspirin.80
associated costs in the United States However, the low cost of the inter- Mone et al81 have utilized data of
at US $2.18 billion, and this was dis- vention has led to the comparison of a 100,000 low-risk nulliparous women
proportionally driven by healthcare screening and treatment policy vs from Ireland and the United Kingdom to
costs related to premature neonates, universal aspirin prophylaxis in 3 compare combined screening by the
with a cost of US $1311 for a preg- studies. Werner et al80 have performed Fetal Medicine Foundation algorithm
nancy with delivery at 36 weeks and US a cost-effectiveness study, with costs and daily aspirin at 75 mg in high-risk
$150,000 for a pregnancy with delivery based on US healthcare prices. Treat- women vs universal treatment with
at 26 weeks of gestational age. ment involved either no prophylaxis, aspirin at the same dose. The authors
To date, 5 cost-effectiveness studies provision of aspirin to women deemed reported that universal aspirin use would
have been published on the economic high-risk in accordance with the lead to a cost saving of V14.9 million
aspects of preeclampsia prevention with American College of Obstetricians and (equivalent to US $17.5 million) annu-
aspirin. The first study performed an Gynecologists guidelines or the United ally relative to no intervention, whereas
economic evaluation of a comprehensive States Preventive Services Task Force the screen-and-treat strategy would save

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Expert Review ajog.org

TABLE
Relative risk and number needed to treat with 95% CIs for different adverse pregnancy outcomes with the use of
aspirin initiated before 16 weeks compared with placebo or no treatment
Outcome Relative risk (95% CI) Number needed to treat (95% CI)
Preeclampsia <37 wk a
0.38 (0.20e0.72) 38 (24e102)
Preeclampsia <34 wk a
0.20 (0.06e0.71) 69 (41e233)
Birthweight <10th percentileb 0.77 (0.65e0.91) 16 (10e43)
Birthweight <5th percentile b
0.73 (0.59e0.91) 19 (12e63)
Birthweight <3rd percentile b
0.77 (0.59e0.99) 30 (15e846)
Neonatal intensive care unit >14 d b
0.34 (0.15e0.75) 51 (30e167)
c
Stillbirth or neonatal death 0.26 (0.11e0.60) 34 (22e80)
ASPRE, Aspirin for Evidence-Based Preeclampsia Prevention; CI, confidence interval; SPREE, Screening Program for Preeclampsia.
a
Estimates calculated based on the ASPRE trial data35; b Estimates based on secondary analysis of data from the ASPRE trial and the SPREE study70,71; c Estimates calculated based on reported
numbers in random effects meta-analysis of aspirin use initiated before 16 weeks of gestational age.69
Rolnik. Aspirin for the prevention of preeclampsia. Am J Obstet Gynecol 2022.

only V3.1 million (equivalent to US $3.6 prophylaxis.83 Most importantly, the $5,600,000 (US $560 per pregnancy
million).82 strategy of universal aspirin has not screened), based on neonatal intensive
Another recent study has also sug- been adequately evaluated in random- care unit stay alone.71
gested that universal aspirin prophylaxis ized trials. None of the studies on cost effective-
would be the most cost-effective strat- Finally, before implementing first ness of selective or universal aspirin
egy.81 A decision analysis was used to trimester combined screening for pre- prophylaxis have adequately considered
compare 4 strategies: no aspirin use, eclampsia, a Canadian group performed long-term consequences of preeclampsia
aspirin use initiated before 16 weeks of a cost-effectiveness study from the local for women and lifelong morbidity for
gestational age guided by biomarkers healthcare system perspective using a children. Cost-effectiveness analyses
and ultrasound (estimates were based on decision-tree model to compare com- investigating the value of the first
the performance of combined screening bined screening and treatment of high- trimester screen-and-prevent program
and on the ASPRE trial results11,40), risk women with aspirin 150 mg daily in different populations, accounting for
aspirin use initiated before 16 weeks of vs current practice in Canada (treatment differences in prevalence and healthcare
gestational age guided by the United with aspirin 81 mg daily based on iden- models, are needed, and future cost-
States Preventive Services Task Force tification of risk factors). First trimester effectiveness research should take into
recommendations,88 or universal aspirin screening led to a significant reduction in account not only the estimates of
initiated before 16 weeks of gestational the rate of early-onset preeclampsia and compliance with different strategies but
age. The dose of aspirin was not speci- a cost saving of CaD $14.4 million.89 also the full spectrum of long-term car-
fied. The authors reported that, Screening cost has been estimated at diovascular disease for women and
compared with universal aspirin CaD $668.84 per pregnancy, but where prematurity-related complications for
administration, the use of the United screening for fetal aneuploidy is per- children.
States Preventive Services Task Force formed, the cost of screening for pre-
guidelines was associated with US eclampsia is lower at approximately CaD Conclusion
$8,011,725 higher healthcare costs and $100.00 per pregnancy, leading to a Aspirin is highly effective in preventing
346 additional cases of preeclampsia per further cost reduction of CaD $220 preterm preeclampsia when adminis-
100,000 pregnant women; combined million.89 tered to high-risk women at doses above
screening was associated with an addi- In the ASPRE trial, the shorter length 100 mg and initiated before 16 weeks of
tional US $19,216,551 and 308 addi- of stay in the neonatal intensive care unit gestational age, reducing its incidence by
tional cases.81 in women treated with aspirin resulted in more than 60%. Identification of high-
These 3 cost-effectiveness studies significant estimated cost savings, which risk women should, therefore, be per-
on universal aspirin prophylaxis have far outweigh the cost of screening.71 formed in the first trimester of preg-
not, however, accounted for the likely Assuming a screen-positive rate of 10% nancy, ideally with the use of predictive
lower compliance with treatment, pre- and the daily cost of a stay in neonatal algorithms. Combined screening with
sumed smaller effect size of aspirin on intensive care unit at US $4,000, the maternal factors, mean arterial pressure,
the rates of preeclampsia, and possible estimated cost savings from screening uterine artery Doppler, and serum PlGF
serious complications with universal 10,000 pregnancies would be US for early prediction of preeclampsia has

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ajog.org Expert Review

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