Ultrasound Obstet Gynecol 2015; 46: 414–418

Published online 31 August 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.14889

Early prediction and aspirin for prevention of pre-eclampsia

(EPAPP) study: a randomized controlled trial

A. O. ODIBO*, K. R. GOETZINGER†, L. ODIBO* and M. G. TUULI†

*Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of South Florida, Morsani College of
Medicine, Tampa, FL, USA; †Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Washington University
School of Medicine, St Louis, MO, USA

K E Y W O R D S: acetylsalicylic acid; ASA; aspirin; high-risk; pre-eclampsia

ABSTRACT
Objective To estimate the effect of early administration
of aspirin on the prevention of pre-eclampsia in high-risk
women.
Methods This was planned as a randomized,
double-blind, placebo-controlled trial of aspirin for
women with risk factors for pre-eclampsia. Participants
were randomized to start either aspirin (81 mg/day)
or placebo at 11 + 0 to 13 + 6 weeks of gestation.
The primary outcome was pre-eclampsia and sec-
ondary outcomes included gestational hypertension and
small-for-gestational age at birth.
Results The trial suffered from slow recruitment, leading
to a protocol change to broaden the inclusion criteria
(from a minimum score of multiple risk factors to at
least one risk factor for pre-eclampsia). The trial was
then terminated prematurely due to continuing slow
recruitment and a lack of equipoise given a change in
national guidelines to administer aspirin to high-risk
women. From the 53 women who were randomized,
30 were included in the final analysis. There was no
evidence that the primary outcome of pre-eclampsia was
prevented by low-dose aspirin (relative risk (RR) 0.88,
95% CI 0.21–3.66). Gestational hypertension was seen
in two women, both in the aspirin group. There was no
evidence that the occurrence of small-for-gestational age
was reduced by aspirin (RR 0.88, 95% CI 0.06–12.72).
Conclusions Although this study was underpowered to
show effectiveness of aspirin compared to placebo due to
the premature termination and difficulties encountered,
it highlights practical issues to inform future studies.
Copyright © 2015 ISUOG. Published by John Wiley &
Sons Ltd.
INTRODUCTION
Pre-eclampsia complicates up to 8% of pregnancies
and is a major contributor to maternal mortality and
morbidity. The only effective treatment is delivery, which
leads to significant neonatal morbidity and mortality if
carried out preterm, especially when the disease occurs
early in pregnancy. Several recent studies have shown
improved predictive ability for pre-eclampsia of models
that combine risk factors, biophysical measures and
maternal serum analytes1,2 . However, the utility of these
prediction tests in themselves is limited by the absence of
studies demonstrating effective interventions to reduce the
risk of pre-eclampsia in women identified in this manner
to be at high risk for pre-eclampsia.
Low-dose aspirin has the potential to prevent pre-
eclampsia through the inhibition of thromboxane-
mediated vasoconstriction and immune-modulation. In
a recent systematic review, when studies were stratified
based on gestational age at which aspirin was initiated, a
risk reduction of over 50% was noted when aspirin was
initiated prior to 16 weeks while no benefit was seen when
it was initiated after 16 weeks3 .
We conducted a randomized controlled trial to
estimate the efficacy of low-dose aspirin for preventing
pre-eclampsia in women identified as high risk. We
hypothesized that the risk of pre-eclampsia in women
identified by a first-trimester multiparameter predictive
model to be at high risk would be significantly reduced by
initiating low-dose aspirin early in pregnancy.
METHODS
This was a randomized control trial to estimate the efficacy
of low-dose aspirin in preventing pre-eclampsia in women

Correspondence to: Dr A. Odibo, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, University of South
Florida, Morsani College of Medicine, STC suite 6000, 2 Tampa General Circle, Tampa, FL 33606, USA (e-mail: aodibo@health.usf.edu)
Accepted: 21 April 2015

Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. ORIGINAL PAPER
Early prediction and aspirin for prevention of pre-eclampsia
Table 1 Risk factor scoring system for first-trimester prediction of
pre-eclampsia2
Risk factor
Chronic hypertension
History of prior pre-eclampsia
Diabetes mellitus
Obesity (BMI > 30)
Bilateral uterine artery notches
Low PAPP-A (< 0.52 MoM)
BMI, body mass index; MoM, multiples of the median; PAPP-A,
pregnancy-associated plasma protein-A.
identified in the first trimester to be at high risk. The
study was approved by Washington University School of
Medicine Institutional Review Board, and registered with
clinicaltrials.gov (NCT01547390).
The inclusion criteria were singleton pregnancy under-
going ultrasound examination at 11 + 0 to 13 + 6 weeks
and deemed to be at high risk for pre-eclampsia by the
criteria listed in Table 12 . We excluded pregnancies with
multiple gestation, fetal aneuploidy, major fetal structural
anomaly and bleeding disorder, and women with allergy
to aspirin or already on aspirin or heparin. All eligi-
ble women who presented for first-trimester ultrasound
examination were approached for consent to partici-
pate in the study. Consenting women had the following
assessments between 9 + 0 and 13 + 6 weeks: history for
risk factors, uterine artery Doppler, and measurement of
pregnancy-associated plasma protein-A (PAPP-A). A total
score of at least 6 based on a risk factor scoring system
in first trimester (Table 1) was initially needed to be eligi-
ble for randomization. However, due to slow recruitment
2 years into the study (with only 23 women enrolled)
and following the recommendation from the data safety
monitoring committee, the Institutional Review Board
was asked for permission to revise the inclusion criteria
to the presence of any of the risk factors (as listed in
Table 1).
Women meeting the inclusion criteria were randomized
to receive daily 81 mg aspirin or a placebo pill from
11 + 0 to 13 + 6 weeks until 37 weeks or delivery,
whichever occurred first. Randomization was 1:1 using a
computerized randomization program by the pharmacist
who was otherwise uninvolved in the study. The study
team and the patient were blinded to the intervention the
patient was receiving. The placebo/aspirin was dispensed
by pharmacy at randomization and then again at the
18–24-week ultrasound visit and at the 28–32-week
ultrasound visit. The women were encouraged to take the
study medication with their regular prenatal vitamins.
No specific instructions were given as to the timing of
ingestion of the medication. Compliance was assessed
by having the women complete a pill diary, which
they were asked to return along with any unused
pills, which were counted and returned to pharmacy.
Demographic, previous medical and obstetric history and
current obstetric information were collected from patient
questionnaires and chart abstraction.
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
415
The primary outcome was pre-eclampsia diagnosed per
ACOG criteria at the onset of the study4 . Details of
secondary outcomes were also collected. These included
Score
small-for-gestational-age neonate (birth weight < 10th
4 percentile for gestational age on the Alexander growth
3 standard5 ); early pre-eclampsia (delivery < 34 weeks);
2 severe pre-eclampsia (blood pressure > 160/110 or symp-
2
1
toms including persistent headaches, visual disturbance,
1 or evidence of abnormal renal failure, abnormal liver
enzymes or thrombocytopenia); gestational hyperten-
sion (elevated blood pressure occurring after 20 weeks’
gestation with no evidence of pre-eclampsia); preterm
birth (delivery < 37 weeks); stillbirth; antepartum hem-
orrhage (hemorrhage after 20 weeks’ gestation); neona-
tal death; neonatal intensive care unit admission; and
miscarriage.
Statistical analysis
Statistical analyses for the randomized controlled trial
were originally planned on the ‘intention-to-treat’
principle but, based on the high withdrawal rate, the
analysis was performed on an ‘as-treated’ principle.
The primary outcome and other categorical variables
were compared across groups using the chi-square or
Fisher’s exact test as appropriate. We calculated the
95% confidence intervals around relative risk (RR) of
the primary outcome in the intervention and placebo
groups.
We calculated the required sample size for the trial
based on estimates using our scoring system. Using
a receiver–operating characteristics (ROC) curve we
determined the overall accuracy of our risk factor scoring
system to be 78% (95% CI, 70–86%) and the optimal
cut-off for predicting pre-eclampsia to be a total score of
62 . Based on the anticipated baseline rate of 36% in the
placebo group, a total of 186 women would be needed
for 80% power to detect a 50% reduction in the risk of
pre-eclampsia (two-tailed α of 0.048; incorporating one
interim analysis and using the O’Brien–Fleming stopping
rule6 ). To account for an estimated 15% dropout rate, we
initially estimated that 220 screen-positive women would
need to be randomized. Following the revised inclusion
criteria, a revised sample size of 684 women needed
to be randomized to detect the same 50% reduction
of pre-eclampsia with 80% power and 15% anticipated
dropout rate; this was based on the revised accuracy
of the model of 65%. However, the trial was terminated
prematurely due to slow recruitment and lack of equipoise
given a change to national guidelines to administer
aspirin to high-risk women. All statistical analyses were
performed using STATA software version 13.1 (STATA
Corp., College Station, TX, USA).
RESULTS
Between April 2012 and March 2014, a total of 1470
women were screened. Four hundred and forty-one were
screened with the original algorithm and 1029 with the
Ultrasound Obstet Gynecol 2015; 46: 414–418.
416
modified one. Of these, 138 were screen positive (41 when
using the original algorithm and 97 with the modified
one) and 53 were eligible and consented to participate
in the study and were randomized. Common reasons
for patients declining to participate or being excluded
from the study included the following: already being on
aspirin, allergy to aspirin, already on anticoagulants for
other indications such as a thrombophilia, concerns about
safety of aspirin, and wanting to be guaranteed aspirin
rather than a placebo. Some women with only one risk
factor such as morbid obesity had the perception that their
risk for pre-eclampsia was not high and therefore declined
to participate. Ten women in the aspirin group and 13
in the placebo group dropped out of the study after
randomization. Seven withdrawals in the aspirin group
were by patient request, one pregnancy was terminated
and two were lost to follow-up (Figure 1). The baseline
characteristics of the 30 women who completed the study
are shown in Table 2. Baseline characteristics were similar
in the two groups except for a higher proportion of
African Americans in the placebo group.
The primary outcome of the study, pre-eclampsia, was
seen in six of the 30 women (20%) with complete
follow-up, three in the aspirin group and three in
the placebo group (RR 0.88, 95% CI 0.21–3.66). All
cases with pre-eclampsia occurred and were delivered
before 34 weeks’ gestation. Gestational hypertension
was seen in two women, both in the aspirin group.
Small-for-gestational age was seen in two of the
randomized women (6.7%), one in the aspirin and one in
the placebo group (RR 0.88, 95% CI 0.06–12.72). With
the exception of the three women reporting rash/hives, no
other adverse effect was reported in either of the groups.
The mean risk score was significantly higher (9.2 ± 1.2)
in the six women who developed early pre-eclampsia vs
4.5 ± 0.4 in the other 24 women enrolled in the study
with complete follow-up (P = 0.0001).
DISCUSSION
This randomized trial, which was terminated prematurely,
was affected by several practical issues that raise questions
regarding the feasibility of conducting future studies
with similar objectives. The findings, which should be
interpreted with caution given that the study was under-
powered to test our original hypothesis, are, however, con-
sistent with the majority of trials using low-dose aspirin
for preventing pre-eclampsia prior to 16 weeks7 – 11 .
The inconclusive results reported by most trials aiming
to use aspirin to prevent pre-eclampsia are mostly due to
the sample size of these studies, as has been demonstrated
by subsequent meta-analyses12 – 16 . Despite the conclu-
sions of these meta-analyses as to the modest benefit
for preventing all forms of pre-eclampsia, international
guidelines have been published recommending the use of
low-dose aspirin17 – 19 .
The main limitation of our study is the small sample
size, similar to other low-dose aspirin trials in early
pregnancy. Our initial scoring system that was validated
Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
Odibo et al.
in our population2 appeared too strict, resulting in very
few high-risk women being assigned a large enough
score to be randomized into the trial. The model was
designed to be highly accurate, balancing the trade-off
between sensitivity and specificity. Our model had a
sensitivity/specificity that depended on the number of risk
factors present and their weighted score. As our analysis
was not based on sensitivity for a fixed false-positive rate,
but on the accuracy of the overall model, it is difficult to
compare the effectiveness of the model to other published
series.
Following the change in the inclusion criteria, the
recommendations of the United States Preventive Services
Task Force that women at risk for pre-eclampsia
should receive low-dose aspirin early in pregnancy was
published19 . With that recommendation, the investigation
team met and determined that we had no equipoise
to continue the trial. Given the small sample size, the
primary goal of randomization, which is to eliminate
potential biases, may not have been achieved. The United
States Preventive Services Task Force recommendation
was based on a systematic review including most of the
data discussed above. It brings up the controversy of
whether clinical decisions should be based on the results
of individual trials or on meta-analysis20 . In addition,
recent reviews have suggested using higher doses of aspirin
and administering these at night time. It is not certain if
taking these steps would have impacted the outcome of
our trial21 – 23 .
We noted a significant dropout rate in the trial. Of the
53 women who were randomized, 23 (43.3%) dropped
out for a number of reasons including the development
of rash or hives or itching, ‘forgetting to take pills’,
being on ‘too many pills’ and termination of pregnancy.
The high dropout rate may be a reflection of our study
population, which includes a high proportion of inner
city low income or indigent patients with social issues
that can reduce attendance for prenatal care. To improve
study retention, our study coordinators called enrolled
patients on a weekly basis to encourage continuation
of study medication and remind them of prenatal visit
appointments. These efforts had little impact on the
overall success of the study. While dropouts were balanced
between the two groups and would not be expected to
affect the results, given the overall small sample size it
resulted in our performing an ‘as-treated’ rather than
an ‘intention-to-treat’ analysis as is the usual case with
trials. The high withdrawal rate also raises a question
of compliance among women prescribed aspirin for
prevention of pre-eclampsia.
Interestingly, all cases of pre-eclampsia in our study
occurred before 34 weeks. The 20% incidence is much
higher than would be expected for an unselected
population. We were unable to estimate the overall
performance of our screening model. This information
would have been helpful if we had been able to collect it.
However, because we are ethically not allowed to follow
those who screened negative (and did not consent to
participate) or withdrew from the study, it is impossible
Ultrasound Obstet Gynecol 2015; 46: 414–418.
Early prediction and aspirin for prevention of pre-eclampsia 417

Multiparameter first-trimester
pre-eclampsia screening
(n = 1470)

Screen negative
(n = 1332)
Screen positive
(n = 138)

79 screen positive
declined
Randomized randomization,
(n = 53) 16 found ineligible*

Treatment group Placebo group

(n = 26) (n = 27)

Dropouts (n = 10) Treatment group with complete Placebo group with complete Dropouts (n = 13)
(7 on patient request, follow-up data (n = 16) follow-up data (n = 14) (10 on patient request,
1 termination, 3 rash/hives)
2 LTF)
Primary outcome: pre-eclampsia (n = 6)

Figure 1 Flowchart of study procedures and enrollment. *Ten women met both criteria. LTF, lost to follow-up.

Table 2 Demographic data and inclusion criteria for the Early Prediction and Aspirin for Prevention of Pre-eclampsia (EPAPP) study

Placebo (n = 14) Aspirin (n = 16) P

Maternal age (years) 31.6 ± 6.1 30.0 ± 5.0 0.45

Body mass index (kg/m2 ) 36.6 ± 6.9 37.4 ± 8.9 0.78
Nulliparous 3 (21.4) 5 (31.2) 0.54
Race/ethnicity 0.013
Black 11 (78.6) 4 (25)
White 3 (21.4) 1 (6.2)
Other 0 (0) 11 (68.8)
Risk score* 5.9 ± 3.2 5.0 ± 2.9 0.40
GA at randomization (weeks) 12.1 ± 1.0 11.7 ± 1.3 0.35
Mean UtA-PI 1.68 ± 0.4 1.57 ± 0.8 0.69
Chronic hypertension 10 (71.4) 6 (37.5) 0.06
Pregestational diabetes 2 (14.3) 4 (25.0) 0.46

Data are given as mean ± SD or n (%). *Risk score as defined by Goetzinger et al.2 . GA, gestational age; UtA-PI, uterine artery pulsatility
index.

to calculate the overall performance of the model. The
mean screening score of the women who developed early
pre-eclampsia was significantly higher than that of the
other women enrolled in the study. It is possible that these
women’s risk was so high that low-dose aspirin could not
prevent them from developing pre-eclampsia. The above
limitations should inform investigators contemplating
future studies for pre-eclampsia prevention. Based on
current guidelines, which may be premature, we wonder
if future trials focused on the primary question of

Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd. Ultrasound Obstet Gynecol 2015; 46: 414–418.
418
pre-eclampsia prevention with aspirin are ethical or
practical given the problems we encountered with this
trial.
The failure to detect a difference in our study should be
interpreted with caution due to the difficulties encountered
with the trial and the study being underpowered to show
a difference. Future trials should focus on the optimal
dose of aspirin or combination of antiplatelet therapy to
potentially optimize the prevention of pre-eclampsia.
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