Aspirin in the prevention of pre-eclampsia in

high-risk women: a randomised placebo-

controlled PREDO Trial and a meta-analysis
of randomised trials
PM Villa,
a,b
E Kajantie,
c,d
K Ra ikko nen,
e
A-K Pesonen,
e
E Ha ma la inen,
f
M Vainio,
g
P Taipale,
h,i
H Laivuori,
a,j
on behalf of the PREDO Study group
a
Research Programmes Unit, Womens Health, University of Helsinki, Helsinki, Finland
b
Department of Obstetrics and Gynaecology,
University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
c
Department of Chronic Disease Prevention, National
Institute for Health and Welfare, Helsinki, Finland
d
Hospital for Children and Adolescents, Helsinki University Central Hospital and
University of Helsinki, Helsinki, Finland
e
Faculty of Behavioural Sciences, Institute of Behavioural Sciences, University of Helsinki, Helsinki,
Finland
f
HUSLAB and Department of Clinical Chemistry, Helsinki University Central Hospital, Helsinki, Finland
g
Kanta-Hame Central
Hospital, Hameenlinna, Finland
h
Iisalmi Hospital, Iisalmi, Finland
i
Kuopio University Hospital, Kuopio, Finland
j
Haartman Institute,
Medical Genetics, University of Helsinki, Helsinki, Finland
Correspondence: Dr PM Villa, Department of Obstetrics and Gynaecology, University of Helsinki, Helsinki University Central Hospital,
BOX 140, 00029 HUS, Finland. Email pia.villa@helsinki.
Trial registration ISRCTN14030412.
*PREDO Study group members are in Appendix 1.
Accepted 28 June 2012. Published Online 6 November 2012.
Objective To study the effect of aspirin in the prevention of
pre-eclampsia in high-risk women.
Design Randomised, double-blinded, placebo-controlled trial.
Setting Maternity clinics in ten Finnish hospitals participating in
the PREDO Project.
Sample A total of 152 women with risk factors for pre-eclampsia
and abnormal uterine artery Doppler velocimetry.
Methods Participants were randomised to start either aspirin
100 mg/day or placebo at 12 + 0 to 13 + 6 weeks + days of
gestation. Because of the limited power of this trial, we also
conducted a meta-analysis of randomised controlled trials that
included data on 346 women with abnormal uterine artery
Doppler ow velocimetry, and aspirin 50150 mg/day started at
or before 16 weeks of gestation.
Main outcome measure Pre-eclampsia, gestational hypertension
and birthweight standard deviation (SD) score. Outcome
measures for the meta-analysis were pre-eclampsia, severe
pre-eclampsia, preterm (diagnosed <37 + 0 weeks of gestation)
and term pre-eclampsia.
Results From the 152 randomised women, 121 were included in
the nal analysis. Low-dose aspirin did not reduce the rate of
pre-eclampsia (relative risk [RR] 0.7, 95% CI 0.31.7); gestational
hypertension (RR 1.6, 95% CI 0.64.2); early-onset pre-eclampsia
(diagnosed <34 + 0 weeks of gestation) (RR 0.2, 95% CI 0.03
2.1); or severe pre-eclampsia (RR 0.4, 95% CI 0.11.3); and the
results were not statistically signicant in an intention-to-treat
analysis. However, our meta-analysis, including the current data,
suggested that low-dose aspirin initiated before 16 weeks of
gestation reduces the risk of pre-eclampsia (RR 0.6, 95%
CI 0.40.8) and severe pre-eclampsia (RR 0.3, 95% CI 0.10.7).
Conclusions Our trial showed no statistically signicant effect of
aspirin in preventing pre-eclampsia in high-risk women. However,
our meta-analysis suggested that aspirin may reduce the incidence
of pre-eclampsia.
Keywords Acetylsalicylic acid, aspirin, Doppler, intrauterine
growth restriction, meta-analysis, pre-eclampsia, pregnancy,
prevention, uterine artery.
Please cite this paper as: Villa P, Kajantie E, Raikkonen K, Pesonen A-K, Hamalainen E, Vainio M, Taipale P, Laivuori H. Aspirin in the prevention of
pre-eclampsia in high-risk women: a randomised placebo-controlled PREDO Trial and a meta-analysis of randomised trials. BJOG 2013;120:6474.
64 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
DOI: 10.1111/j.1471-0528.2012.03493.x
www.bjog.org
General obstetrics
Background
Pre-eclampsia remains one of the most important chal-
lenges in obstetrics. The disorder affects 35% of pregnan-
cies and is dened according to new-onset hypertension
and proteinuria, which appear after 20 weeks of gestation.
1
It is a multisystem disease with adverse short-term and
long-term outcomes to both the mother and the fetus. In
total, pre-eclampsia and related complications account for
63 000 maternal deaths worldwide every year, 12% of all
maternal deaths.
2
The onset and clinical course are unpre-
dictable, and there is a strong need for tools to predict and
prevent the disorder.
The aetiology of pre-eclampsia remains unknown,
although placental dysfunction, which is due to early pla-
cental developmental abnormality, is central in the disease
process. The early placental disease is followed months later
by the clinical manifestations of pre-eclampsia, which
reect widespread endothelial dysfunction, resulting in
vasoconstriction, end-organ ischaemia and increased vascu-
lar permeability.
3
Many of the proposed prediction and
prevention strategies are based on processes involved in
placental development in early pregnancy, although none
of these has been established in clinical practice.
Antiplatelet agents, such as aspirin (acetylsalicylic acid),
are among the most promising candidates for prevention of
pre-eclampsia. They have a positive effect on the balance
between prostacyclin, a vasodilator, and thromboxane, a
vasoconstrictor and stimulant of platelet aggregation. This
process plays a key role in the development of the disease
and is believed to result from shallow placental invasion
and ischaemia that occur shortly after implantation. A
recent meta-analysis, based on 27 trials on 31 678 women,
concluded that aspirin is effective in preventing pre-eclamp-
sia, although the effect was too modest to warrant routine
use in all women.
4
However, if started early in pregnancy,
in high-risk women, the treatment may be effective,
5,6
although studies are few and results are inconsistent.
79
Our aim was to study the effect of aspirin started at
12 + 0 to 13 + 6 weeks + days of gestation on prevention
of pre-eclampsia and intrauterine growth restriction in
high-risk women identied by abnormal uterine artery ow.
We performed the trial in conjunction with the multi-
disciplinary PREDO Project, which we also describe to set
the study in context. In addition, we combined our data
with data from similar previous trials in meta-analysis.
Methods
The Predo Project
The multidisciplinary PREDO Project Prediction and Pre-
vention of Pre-eclampsia had three arms: obstetric (includ-
ing the present aspirin trial), genetic and psychological.
The project was carried out between September 2005 and
December 2009. We recruited 947 pregnant women with
risk factors for pre-eclampsia and 117 pregnant women
without known risk factors as a comparison group at
12 + 0 to 13 + 6 weeks + days of gestation (Figure 1). The
recruitment took place when these women attended the
rst ultrasound screening in one of ten hospital maternity
clinics participating in the PREDO Project; Womens Hos-
pital, Katiloopisto Maternity Hospital and Jorvi Hospital at
Helsinki University Central Hospital, Kanta-Hame Central
Hospital, Paijat-Hame Central Hospital, Tampere Univer-
sity Hospital, Kuopio University Hospital, Northern Karelia
Central Hospital and Iisalmi Hospital. A written informed
consent was obtained from all participants. We also
enrolled the spouse of each study participant (= biological
father of the child) for the genetic arm of the PREDO
Project.
Inclusion criteria and denitions
The inclusion and exclusion criteria of the aspirin trial are
presented in Table 1. Women with one or more risk factors
for pre-eclampsia were invited in arrival order to partici-
pate unless any of the exclusion criteria was present.
Ultrasound measurements and aspirin
We measured uterine artery blood ow by colour Doppler
ultrasound transvaginally from all participants at 12 + 0 to
13 + 6 weeks of gestation. The uterine artery was identied
at the level of the internal cervical os, as it approached the
uterus laterally. We dened the second-degree uterine
artery notch as a notch in the beginning of diastole at least
as deep as the end diastolic notch (see Supplementary
material, Figure S1).
10,11
Women who had bilateral second-
degree notch were allocated to the medication group. They
were randomised (see paragraph Randomisation and
Blinding below) to start either aspirin 100 mg/day or pla-
cebo, which were continued until 35 + 0 weeks of gestation
or delivery, whichever occurred rst. Those women who
did not full the criteria for the medication group were
taken into the follow-up group as described in the ow
chart (Figure 1).
Outcomes
Primary outcomes were pre-eclampsia (blood pressure
140 and/or 90 mmHg in two consecutive measurements
and proteinuria 0.3 g/24 hours),
1
gestational hypertension
(new onset hypertension after 20 weeks of gestation),
1
and
birthweight SD score as a continuous variable calculated
according to Finnish standards.
12
Secondary outcomes were early-onset pre-eclampsia
(pre-eclampsia diagnosed before 34 + 0 weeks of gestation),
severe pre-eclampsia (blood pressure 160 systolic and/or
110 diastolic and/or proteinuria 5 g/24 hours),
1
preterm
PREDO trial aspirin in the prevention of pre-eclampsia
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG 65
pre-eclampsia (pre-eclampsia diagnosed before 37 + 0
weeks of gestation), small for gestational age (SGA) (birth-
weight <)2SD),
12
and length of gestation (continuous vari-
able).
Each individual outcome diagnosis was set by a jury,
which consisted of two physicians and a study nurse. They
met face-to-face and reviewed the hospital and maternity
clinic records of each participant.
Figure 1. Flow-chart of the Prediction and Prevention of Pre-eclampsia (PREDO) Project. The aspirin trial reported in this article is highlighted by
shading.*For a more detailed description of participants who were excluded from analysis, please see text. Aspirin trial only.
Table 1. Inclusion criteria in women randomised to aspirin or placebo in the Prediction and Prevention of Pre-Eclampsia (PREDO) Project
Inclusion criterion Aspirin (n = 61) Placebo (n = 60)
Age under 20 years 2 (3.3%) 0 (0.0%)
Age over 40 years 3 (4.9%) 3 (5.0%)
Obesity (body mass index over 30 kg/m
2
) 25 (41.0%) 27 (45.0%)
Chronic hypertension (140/90 mmHg or medication for hypertension
before 20 weeks of gestation)
8 (13.1%) 12 (20.0%)
Sjo grens syndrome 1 (1.6%) 0 (0.0%)
A history of one of the following conditions:
Gestational diabetes 4 (6.6%) 10 (16.7%)
Pre-eclampsia (blood pressure 140 mmHg systolic or 90 mmHg diastolic
and proteinuria 0.3 g/day or dipstick equivalent in two consecutive measurements)
20 (32.8%) 17 (28.3%)
Small for gestational age (birthweight <)2SD) 6 (9.8%) 9 (15.3%)
Fetus mortus (fetal death after 22 weeks of gestation or >500 g weight in a
previous pregnancy)
3 (4.9%) 1 (1.7%)
An additional inclusion criterion was systemic lupus erythematosus but this was not present in any of the participants.
The exclusion criteria were allergy to aspirin; tobacco smoking (during this pregnancy); multiple pregnancy; and a history of asthma, peptic ulcer,
placental ablation, infammatory bowel diseases (Crohns disease, colitis ulcerosa), rheumatoid arthritis, haemophilia or thrombophilia (previous
venous or pulmonary thrombosis or coagulation abnormality).
In all, 36 women fullled more than one inclusion criteria.
Villa et al.
66 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
Randomisation and blinding
This was an investigator-initiated, randomised, placebo-
controlled, double-blinded trial. The Tampere University
Hospital Pharmacy performed the randomisation. As a paid
service, the aspirin and placebo tablets were prepared by a
pharmaceutical company (Orion, Espoo, Finland) to
appear identical. Tampere University Hospital Pharmacy
repacked and randomised the tablets. The randomisation
was made in blocks of tens by the pharmacists not other-
wise involved in the study. The randomisation code of each
participant was sealed in an envelope and was opened after
the outcome diagnoses of all participants had been set by
the jury, as described above.
Meta-analysis
A computerised search was conducted from January 1965
through January 2012 of the MEDLINE database and the
Cochrane library using the search terms: aspirin, antiplat-
elet, asa, acetylsalicylic, eclamp*, hypertens*, intrauterine
growth restriction, SGA, toxaemia, PIH, pregnancy-induced
hypertension, Doppler, ultrasound, notch, uterine artery.
We did not exclude any manuscript based on language.
We included in the meta-analysis the prospective, rando-
mised, controlled trials, which met the following criteria: 1)
included women with abnormal uterine artery Doppler ow
velocimetry, and 2) started aspirin at or before the 16 weeks
of gestation, with dose between 50 and 150 mg/day. The con-
trol group had to be allocated either to placebo or no treat-
ment. Through the literature search we identied 1414
eligible studies. In addition to our study, only two studies
fullled the inclusion criteria.
7,9
The results were available
for a total of 346 women.
The outcome measures for the meta-analysis were pre-
eclampsia, severe pre-eclampsia, preterm and term pre-
eclampsia. Denition for pre-eclampsia was consistent
between studies (blood pressure 140/90 mmHg, and pro-
teinuria 0.3 g/24 hours). Pre-eclampsia was dened preterm
when diagnosed before 37 completed weeks of gestation.
Severe pre-eclampsia was dened if in addition to above crite-
ria one or more of the following criteria were present: blood
pressure 160 mmHg systolic and/or 110 mmHg diastolic,
or severe proteinuria (denition between studies ranging
from2 g to 5 g/24 hours). Oliguria <500 ml/24 hours, ele-
vated liver enzymes, and platelet count <100 000/mm
3
, or
fetal growth restriction.
Statistical methods
Continuous variables were tested for normality. Highest
proteinuria concentrations per day were log transformed to
attain normality. Continuous variables between study
groups were compared using the independent sample t-test
and categorical variables by chi-square test. Two-tailed
P-values <0.05 were considered statistically signicant.
Relative risks were calculated to compare the risk of each
outcome between aspirin and placebo groups. Based on a
previous study,
7
we expected an incidence of 25% for pre-
eclampsia among the study participants. We calculated that
with a power of 0.80 and an a of 0.05 we would be able to
conrm or exclude a reduction in incidence to 10% in
groups of 80 participants each. For groups of 60 and 61
participants, which was the number included in analysis,
the corresponding power is 0.62.
Studies included in the meta-analysis were combined
and analysed using comprehensive meta-analysis V 2.0
software (Biostat Inc., Englewood, NJ, USA). Individual rel-
ative risks were calculated for each study, and pooled for
global analysis with 95% condence intervals (CI). Global
RR were calculated according to Der Simmonian and Laird
random effect models in case of heterogeneity. Heterogene-
ity between studies was analysed with Higgins I
2
and con-
sidered to be high if >50%. A random effects models was
used for all outcomes, because heterogeneity for both term
and preterm pre-eclampsia was 75%. For pre-eclampsia
heterogeneity was 14%, and for severe pre-eclampsia, it was
0%. Because of the small number of studies, a funnel plot
analysis to assess publication bias was not conducted.
Results
Out of the 947 women recruited, 152 (16.0%) with bilateral
second-degree diastolic notch in the uterine artery ow
were allocated into the aspirin trial. One hundred and
twenty-one women completed the trial.
Characteristics of the women participating in the
aspirin trial
The baseline characteristics of the 61 women allocated ran-
domly into the aspirin group and the 60 women in the pla-
cebo group are presented in Table 2. Table 3 shows their
pregnancy characteristics.
Subjects who discontinued the trial
Of the 152 women initially recruited into the aspirin trial,
31 women were left out of the study (see Supplementary
material, Figure S2). Four of these women had a miscar-
riage, three in the aspirin group and one in the placebo
group. Two of these miscarriages took place at 14 weeks of
gestation and one at 19 weeks of gestation in the aspirin
group and one at 18 weeks of gestation in the placebo
group. Eleven women were lost to follow up or discontin-
ued for various nonmedical reasons; seven of these were in
the aspirin group and four in the placebo group. Five
women decided to discontinue the aspirin trial because of
a medical condition. Three of these women were in the
placebo group and two in the aspirin group. Eleven partici-
pants were additionally excluded from analysis because of
PREDO trial aspirin in the prevention of pre-eclampsia
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG 67
noncompliance with the study protocol. The pregnancy
outcome of all of these 31 women is known. Three women
had one of our primary or secondary outcomes. One
woman, who cancelled her involvement in the trial 1 day
after the entry, and did not start the medication, subse-
quently developed early pre-eclampsia. Another woman
with Factor V Leiden mutation started low-molecular-
weight heparin, and had to discontinue the trial; she gave
birth to a SGA newborn. Both of these women were rando-
mised to aspirin group. One woman from the placebo
group, who discontinued the trial because of thrombocyto-
penia, developed gestational hypertension. We conducted
an intention-to-treat analysis, in which we included all
randomised women, except the ones that had a miscarriage.
The results of our intention-to-treat analysis do not differ
from the results of the analysis made without these
excluded women; risk ratios (RR) in the aspirin group were
as follows for: pre-eclampsia 0.8 (95% CI 0.41.8), gesta-
tional hypertension 1.4 (95% CI 0.63.5), early pre-eclamp-
sia 0.5 (95% CI 0.12.6), preterm pre-eclampsia 0.8 (95%
CI 0.22.8), severe pre-eclampsia 0.5 (95% CI 0.21.6),
SGA newborn 0.5 (95% CI 0.11.9), and severe diagnosis
0.6 (95% CI 0.21.6). None of these associations were sta-
tistically signicant.
Primary outcomes
As shown in Table 4, 19 (15.7%) women were diagnosed
with pre-eclampsia, eight in the aspirin group and 11 in the
placebo group (RR 0.7, 95% CI 0.31.7). Sixteen women
were diagnosed with gestational hypertension, ten in the
aspirin and six in the placebo group (RR 1.6, 95% CI 0.6
4.2). Birthweight SD score in the aspirin group was 0.1
(SD = 1.1) and in the placebo group 0.3 (SD = 1.3)
(P = 0.3). These were not statistically signicant.
Secondary outcomes
There was one woman with early-onset pre-eclampsia in
the aspirin group and four in the placebo group (RR 0.2,
95% CI 0.032.1). Severe pre-eclampsia was diagnosed in
three women in the aspirin group and in eight women in
the placebo group (RR 0.4, 95% CI 0.11.3). In the aspirin
group there were two newborns diagnosed as SGA com-
pared with placebo group with six (RR 0.3, 95% CI 0.1
1.6). These diagnoses were in part seen in the same partici-
pants. Four women in the aspirin group and ten in the pla-
cebo group had one or more of these severe diagnoses
(early-onset pre-eclampsia and/or severe pre-eclampsia
and/or SGA) (RR 0.4, 95% CI 0.11.2). Three women in
the aspirin group and ve women in the placebo group
(RR 0.6, 95% CI 0.22.4) developed preterm pre-eclampsia
(diagnosed before 37 + 0 weeks of gestation). Mean
Table 2. Baseline characteristics
Characteristics Aspirin group
(n = 61)
Placebo group
(n = 60)
Age, years (SD) 30.8 (5.3) 31.0 (5.1)
BMI before
pregnancy, kg/m
2
(SD)
27.9 (6.6) 29.7 (7.8)
Height, cm (SD) 165.7 (5.3) 165.1 (5.2)
Primiparous, n (%) 19 (26.2%) 9 (15.0%)
Educational attainment
Elementary or less 3 (7.5%) 1 (2.4%)
High school or
vocational school
7 (17.5%) 15 (35.7%)
Intermediate 13 (32.5%) 13 (31.0%)
University 17 (42.5%) 13 (31.0%)
BMI, body mass index.
Continuous data presented as mean (standard deviation, SD).
Table 3. Pregnancy characteristics
Characteristics Aspirin group
(n = 61)
Placebo
group
(n = 60)
P-value
Antihypertensive medication, n (%)
Before 20 weeks of gestation 4 (6.6%) 3 (5.0%) 0.8
After 20 weeks of gestation 7 (11.5%) 9 (15.0%)
Weight gain during
pregnancy, kg (SD)
11.7 (4.7) 12.1 (4.9) 0.6
Gestational diabetes, n (%)
Diet 10 (16.4%) 9 (15.0%) 0.6
Insulin 1 (1.6%) 3 (5.0%)
Oral glucose tolerance
test not performed, n (%)
6 (9.8%) 5 (8.3%)
Highest systolic
blood pressure,
mmHg (SD)
142.5 (19.6) 146.2 (21.9) 0.3
Highest diastolic
blood pressure,
mmHg (SD)
92.1 (11.8) 95.1 (12.5) 0.2
Highest proteinuria,
g/day*
3.3 1.3 0.1
Mode of delivery, n (%)
Vaginal 47 (77.0%) 43 (71.7%) 0.8
Elective caesarean
section
3 (4.9%) 3 (5.0%)
Caesarean section
during labour
11 (18.0%) 14 (23.3%)
Apgar score at 5 min 9.0 (0.8) 8.9 (0.8) 0.7
Umbilical artery pH
below 7.15,** n (%)
7 (12.5%) 4 (7.4%) 0.6
Newborn birthweight,
g (SD)
3413 (630) 3321 (871) 0.5
Placental weight, g (SD) 602 (131) 585 (150) 0.5
Continuous data presented as mean (SD).
*Geometric mean.
**No umbilical artery pH was below 7.00.
Villa et al.
68 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
gestational age in the aspirin group was 39.1 weeks
(SD = 0.8) and in the placebo group 38.9 weeks (SD = 3.0)
(P = 0.6). None of these differences were statistically signif-
icant (Table 4). One woman in the placebo group had
HELLP syndrome (haemolysis, elevated liver enzymes, and
low platelets) with early pre-eclampsia. None had eclamptic
seizures.
There was no difference in the incidence of pre-eclamp-
sia between the aspirin and placebo groups when women
with body mass index over 30 kg/m
2
were analysed sepa-
rately.
Among the 795 women who were included in the study
but whose uterine artery Doppler ultrasound did not full
the criteria of the aspirin trial (follow-up groups), 66 (8.3%)
developed pre-eclampsia, 24 (3.0%) of these women were
diagnosed with severe pre-eclampsia, and 16 (2.0%) with
early-onset pre-eclampsia. Eighty-nine women were diag-
nosed with gestational hypertension (11.1%). Twenty-four
(3.0%) newborns were born SGA and ten (1.3%) women
both gave birth to an SGA newborn and were diagnosed with
pre-eclampsia.
Adverse effects
One participant reported sudden deafness in one ear at
24 weeks of gestation. The medication was discontinued and
the randomisation code was opened: this participant had
received placebo. No other adverse effects were reported.
Meta-analysis
Our meta-analysis included two additional studies.
7,9
In the
meta-analysis aspirin started at or before 16 weeks of gesta-
tion in women whose uterine artery Doppler ultrasound
indicated an increased risk, signicantly reduced the risk of
pre-eclampsia (RR 0.6, 95% CI 0.370.83) (Figure 2), and
severe pre-eclampsia (RR 0.3, 95% CI 0.110.69) (Fig-
ure 3). Aspirin did not reduce the risk of preterm pre-
eclampsia (RR 0.2, 95% CI 0.021.26) (Figure 4) or term
pre-eclampsia (RR 1.0, 95% CI 0.254.26) (Figure 5).
Discussion
We did not nd statistically signicant benet for the effect
of low-dose aspirin in preventing pre-eclampsia or related
traits in women identied by clinical risk factors and bilat-
eral uterine artery second-degree notch in early pregnancy.
However, our meta-analysis showed that aspirin may be
effective in preventing pre-eclampsia.
Comparisons with previous trials
In recent meta-analyses aspirin and other antiplatelet agents
have shown a moderate but consistent reduction in the risk
of pre-eclampsia. In the Paris collaboration meta-analysis
of 32 217 mothers,
4
which included randomised studies
regardless of their inclusion criteria, the relative risk of pre-
eclampsia was 0.9 in women receiving antiplatelet agents
compared with control women. Whereas this reduction was
not sufcient to warrant treatment for all pregnant women,
the authors recommended low-dose aspirin started in early
pregnancy to women with high-risk of pre-eclampsia.
However, specic criteria for a high-risk group could not
be identied based on the reviewed literature. Cochrane
review of antiplatelet agents for prevention of pre-eclamp-
sia,
13
updated in 2007, demonstrated a 17% reduction in
the incidence when combining studies of different design.
Bujold et al.
5
conducted a meta-analysis (11 348 women)
of 27 studies in which the time of start of aspirin could be
identied. They found a signicant reduction of the inci-
dence of pre-eclampsia. When aspirin was started at
Table 4. Study outcomes in aspirin and placebo groups, and relative risk (RR) with 95% condence intervals (CI) for each outcome.
Aspirin (n = 61) Placebo (n = 60) RR 95% CI
Primary outcomes
Pre-eclampsia 8 (13.1%) 11 (18.3%) 0.7 0.31.7
Gestational hypertension 10 (16.4%) 6 (10.0%) 1.6 0.64.2
Secondary outcomes
Early pre-eclampsia* 1 (1.6%) 4 (6.7%) 0.2 0.032.1
Preterm pre-eclampsia** 3 (4.9%) 5 (8.3%) 0.6 0.22.4
Severe pre-eclampsia*** 3 (4.9%) 8 (13.3%) 0.4 0.11.3
Small for gestational age**** 2 (3.3%) 6 (10.0%) 0.3 0.11.6
Severe diagnosis***** 4 (6.6%) 10 (16.7%) 0.4 0.11.2
*Diagnosed before h34 + 0.
**Diagnosed before h37 + 0.
***Blood pressure 160 systolic and/or 110 diastolic and/or proteinuria 5 g/24 hr.
****Birthweight <)2SD.
*****Early pre-eclampsia and/or severe pre-eclampsia and/or small for gestational age.
PREDO trial aspirin in the prevention of pre-eclampsia
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG 69
16 weeks of gestation or earlier (n = 764), 36 women
developed pre-eclampsia, and in the control group 80
women developed pre-eclampsia (relative risk 0.47, 95% CI
0.340.65), with little if any heterogeneity between the
studies. This nding is consistent with our meta-analysis. If
aspirin was started after 16 weeks of gestation (n = 10 584)
there was no reduction of the incidence of pre-eclampsia
(relative risk 0.81, 95% CI 0.631.03).
The results of our meta-analysis, together with the results
of the meta-analyses by Bujold et al.
5,6
are in agreement
with previous suggestions that aspirin in prevention of pre-
eclampsia should be started in early gestation, before the
second active phase of trophoblast invasion, which takes
place from 14 weeks of gestation onwards.
14
During that
phase the trophoblast invasion is completed. Although in
our study aspirin was started between 12 + 0 and
13 + 6 weeks of gestation, an even earlier start of treatment
might carry more benets. This was suggested by a recent
study,
15
in which women received aspirin or placebo from
the time of in vitro fertilisation until 12 weeks of gestation.
Study name Statistics for each study MH risk ratio and 95% CI
ASA Control Relative MH Lower Upper
Events/Total Events/Total weight risk ratio limit limit
Vainio M 2002 2/43 10/43 7.5 0.20 0.05 0.86
Ebrashy A 2005 26/74 40/65 71.7 0.57 0.40 0.82
Villa P 2012 8/61 11/60 20.8 0.72 0.31 1.65
36/178 61/168 0.55 0.37 0.83
0.01 0.1 1 10 100
Favours experimental Favours control
Random
Total
Heterogeinity:
2
= 0.03;
2
= 2.32, df = 2 (P = 0.31); I
2
= 14%
Test for overall effect: Z = 2.84 (P = 0.004)
Figure 2. Forest plot of the effect of aspirin started at or before 16 weeks of gestation on pre-eclampsia in women with abnormal uterine artery
ow.
Study name Statistics for each study MH risk ratio and 95% CI
ASA Control Relative MH Lower Upper
Events/Total Events/Total weight risk ratio limit limit
Vainio M 2002 0/43 2/43 9.5 0.20 0.01 4.05
Ebrashy A 2005 2/74 9/65 38.2 0.20 0.04 0.87
Villa P 2012 3/61 8/60 52.3 0.37 0.10 1.32
5/178 19/168 0.27 0.11 0.69
0.01 0.1 1 10 100
Favours experimental Favours control
Random
Total
Heterogeneity:
2
= 0.00;
2
= 0.45, df = 2 (P = 0.80); I
2
= 0%
Test for overall effect: Z = 2.75 (P = 0.01)
Figure 3. Forest plot of the effect of aspirin started at or before 16 weeks of gestation on severe pre-eclampsia in women with abnormal uterine
artery ow.
Study name Statistics for each study MH risk ratio and 95% CI
ASA Control Relative MH Lower Upper
Events/Total Events/Total weight risk ratio limit limit
Vainio M 2002 1/43 5/43 30.7 0.20 0.02 1.64
Ebrashy A 2005 1/74 33/65 32.0 0.03 0.00 0.19
Villa P 2012 3/61 5/60 37.3 0.59 0.15 2.36
0.16 0.02 1.26
0.01 0.1 1 10 100
Favours experimental Favours control
Random
Total 5/178 43/168
Heterogeneity:
2
2.53;
2
= 8.02, df = 2 (P = 0.01); I
2
= 75%
Test for overall effect: Z = 1.7 (0.08)
Figure 4. Forest plot of the effect of aspirin started at or before 16 weeks of gestation on preterm pre-eclampsia in women with abnormal uterine
artery ow.
Villa et al.
70 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
The incidence of hypertensive complications was lower in
the aspirin group (3.6% versus 26.9%, P = 0.02). However,
this was not conrmed in another study
16
in which aspirin
was also started before pregnancy and the incidence of
hypertensive pregnancy complications did not differ signi-
cantly between the low-dose aspirin (n = 52) and placebo
(n = 52) groups (15.4% versus 18.2%, P = 0.7).
Limitations
The most important limitation to this aspirin trial was the
relatively small sample size. The main reason for this was
the use of bilateral second-degree uterine artery notch as a
criterion in selecting women into the medication group
from the group with clinical risk factors. We hypothesised
that this criterion would distinguish those women with
highest risk for pre-eclampsia. However, the number of
women fullling the criterion for medication, 16%, was
unexpectedly small. Further, the number of women who
developed pre-eclampsia was again small, as compared with
previous studies with a similar design. In hindsight a more
lax Doppler criterion, perhaps with focus on nulliparous
women, could have been better in assessing the effect of
aspirin in high-risk women. In the trial by Vainio et al.
7
women with clinical risk factors similar to those in our
study were allocated into the medication group if they had
a bilateral rst-degree notch in the uterine artery ow ve-
locimetry. In that study those randomised to aspirin started
at 1214 weeks of gestation showed a signicant reduction
of pregnancy-induced hypertension (11.6% versus 37.2%,
RR 0.31, 95% CI 0.130.78) and pre-eclampsia (4.7% ver-
sus 23.3%, RR 0.2, 95% CI 0.050.86) with aspirin started
at 1214 weeks of gestation. In Vainios study 70% of
women with clinical risk factors had bilateral rst-degree
notch in the uterine artery ow. In general, caution should
be exercised in evaluating trials with testtreatment combi-
nations.
17
Our trial and others with similar design do not
reveal how Doppler ultrasound measurement performs in
prediction of pre-eclampsia. Nor does this kind of study
design nd out whether women with normal uterine artery
nding would benet from aspirin. The rationale of con-
ducting meta-analysis was to overcome the small sample
size of the present study. The main limitation for the
meta-analysis was the small number of eligible studies.
Moreover, the heterogeneity for term and preterm pre-
eclampsia suggests variability between studies. However,
great homogeneity for pre-eclampsia and severe pre-
eclampsia suggests valid ndings.
Possible mechanisms
Placental dysfunction is a result of the shallow invasion of
trophoblasts into the placental bed spiral arteries,
18
which
leads to reduced placental perfusion and ischaemia. This
activates platelets and causes an imbalance of the prostacy-
clinthromboxane ratio in favour of vasoconstrictive and
aggregatory thromboxane. Prostacyclin is produced by
endothelial cells and is vasodilatory and anti-aggregatory.
The hypothesis of aspirin in preventing pre-eclampsia is
based on its effect on prostaglandin production. Low-dose
aspirin inhibits thromboxane production of platelets but
the production of prostacyclin by endothelial cells stays
intact. The dosage of 0.52.0 mg/kg of aspirin signicantly
inhibits the production of thromboxane but leaves prosta-
cyclin production unaffected.
19
It is however of note that
this process is most likely to be active in early-onset, severe
pre-eclampsia. The meta-analyses, performed by us and
others, support the hypothesis that aspirin started early is
effective in preventing pre-eclampsia. However, further
studies are needed, especially to assess the effectiveness of
aspirin on early-onset pre-eclampsia. Aspirin may delay the
onset of pre-eclampsia.
Our study included by design a larger proportion of
women with a history of select pregnancy disorders (imply-
ing an excess of multiparous women), obesity and chronic
hypertension, and who would be expected to be at an
increased risk of the late-onset form of the disease.
20
That
said, it should also be noted that because there is excess
Study name Statistics for each study MH risk ratio and 95% CI
ASA Control Relative MH Lower Upper
Events/Total Events/Total weight risk ratio limit limit
Vainio M 2002 1/43 5/43 23.1 0.20 0.02 1.64
Ebrashy A 2005 25/74 7/65 41.0 3.14 1.45 6.77
Villa P 2012 5/61 6/60 36.0 0.82 0.26 2.54
31/178 18/168 1.03 0.25 4.26
0.01 0.1 1 10 100
Favours experimental Favours control
Random
Total
Heterogeneity:
2
= 1.13;
2
= 8.05, df = 2 (P = 0.02); I
2
= 75%
Test for overall effect: Z = 0.04 (P = 0.97)
Figure 5. Forest plot of the effect of aspirin started at or before 16 weeks of gestation on term pre-eclampsia in women with abnormal uterine
artery ow.
PREDO trial aspirin in the prevention of pre-eclampsia
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG 71
inammatory action in obesity, obese women might benet
from the anti-inammatory action of aspirin,
21
which how-
ever was not seen in our study.
Many women who develop severe pre-eclampsia are nul-
liparous with no other known clinical risk factor. To
include them in a prevention trial, an early predictive bio-
chemical, or genetic marker, or a combination of predictive
tests would be necessary. Although we did not use a bio-
chemical risk marker in the present study, this area has
developed substantially in previous years. The risk calculat-
ing programs, which take into account risk factors, one or
more biochemical measurements and ultrasound measure-
ments, hold promise.
21,22
Conclusion
In conclusion, although both early-onset and severe pre-
eclampsia, as well SGA newborns, were more common in
the placebo group than in the group receiving 100 mg daily
dose of aspirin from approximately 1235 weeks of gesta-
tion, the differences between the two groups were not sta-
tistically signicant. However, supported by the results of
our trial and meta-analysis, the role of aspirin in preven-
tion of pre-eclampsia warrants further investigation. We
focused on one specic treatment regimen in women with
clinical risk factors for pre-eclampsia. Together with the
recent rapid development of tools for predicting pre-
eclampsia, our results encourage the use of biochemical risk
markers, possibly in combination with assessment of uter-
ine artery ow, for early identication of women at risk for
future trials to prevent pre-eclampsia.
Disclosure of interest
There are no conicts of interests.
Contribution to authorship
The authors made the following substantial contributions
to this work: conception and design: PV, EK, KR, AKP,
EH, MV, PT, HL; acquisition of data: PV, MV, PT, AAT,
AMH, VKH, TK, LKN, EK, MK, RM, PS, RS, TS, SSK, SS,
VMU, JU, TV, TW, HL, or analysis and interpretation of
data: PV, EK, HL; drafting the article: PV, EK, HL; and
revising it critically for important intellectual content: all
authors. Final approval of the version to be published was
given by all authors.
Details of the ethics approval
The PREDO Project was approved by the Ethics Commit-
tee of Obstetrics and Gynaecology, Hospital District of Hel-
sinki and Uusimaa (Dnro HUS 3/E8/05). It is registered as
an International Standard Randomised Controlled Trial
number ISRCTN14030412.
Funding
This work was supported by Academy of Finland (KR,
A-KP, EK, HL), Clinical Graduate School in Paediatrics
and Obstetrics/Gynaecology, University of Helsinki (PV),
Finnish Medical Society Duodecim (PV), Emil Aaltonen
Foundation (EK), Finnish Concordia Fund (PV), Finnish
Foundation For Paediatric Research (EK), Finnish Medical
Foundation (EK, HL), Signe and Ane Gyllenberg Founda-
tion (KR, EK), Sigrid Juselius Foundation (EK), Govern-
ment Special Subsidy for Health Sciences at Helsinki and
Uusimaa Hospital District (PT, HL, PREDO Project), Jane
and Aatos Erkko Foundation (HL), Orion Foundation
(PV), Paivikki and Sakari Sohlberg Foundation (PV, HL),
Yrjo Jahnsson Foundation (KR).
Acknowledgements
We thank all our study nurses for their enthusiastic efforts
in recruitment, data acquisition and data recording. We are
grateful to the women who participated in the PREDO
Project.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Uterine artery ow measured medially after
the crossover with iliac artery. The notch in the beginning
of diastole (indicated by an arrow) is second degree in this
measurement.
Figure S2. Flow chart presenting women randomised to
aspirin or placebo in the Prediction and Prevention of
Pre-eclampsia (PREDO) Project. j
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Appendix 1
The PREDO Study group members are A Aitokallio-Tall-
berg, A-M Henry, VK Hiilesmaa, T Karipohja, R Meri,
S Sainio, T Saisto, S Suomalainen-Konig, V-M Ulander,
T Vaitilo (Department of Obstetrics and Gynaecology, Uni-
versity of Helsinki and Helsinki University Central Hospi-
tal, Helsinki, Finland). L Keski-Nisula (Kuopio University
Hospital, Kuopio Finland). E Koistinen, T Walle, R Solja
(Northern Karelia Central Hospital, Joensuu, Finland).
M Kurkinen (Paijat-Hame Central Hospital, Lahti,
Finland). P Staven (Iisalmi Hospital, Iisalmi, Finland).
J Uotila (Tampere University Hospital, Tampere, Finland).
Commentary on Aspirin in the prevention of pre-eclampsia in
high-risk women
Why is BJOG publishing a randomised trial of low-dose aspirin for the prevention of pre-eclampsia involving only 152
women when there is already, not just a Cochrane review (Duley et al. Cochrane Database Syst Rev 2007;2:CD004659)
involving 37 560 women dealing with the same question, but also an individual patient meta-analysis (Askie et al. Lancet
2007;369:17918) involving 32 217 women? These both showed with considerable precision, that aspirin reduces
pre-eclampsia, preterm delivery and severe adverse outcomes.
Did participants really understand the results of the previous trials? How was ethical approval justied in light of
previous results? The trial recruitment started in 2005 and the trial registration document (www.controlled-trials.com/
ISRCTN14030412/) showed a planned sample size of 1000 participants, but only 152 were eventually randomised. No
less than 31 (20%) of participants were excluded from analysis for various reasons after randomisation, leaving only
121 in the analysis group. The small sample size of the present trial is not the only problem. In the trial registration
document no < 43 primary outcomes are listed! The paper reports three primary outcomes, only one of which was
also listed in the trial registration document. No explanation is given for either discrepancy in the paper.
Informed readers may raise their eyebrows, but what can we learn. The trial is now completed and nothing can be
changed. We learn rst that women had participated and the data they had generated should not be wasted, so there
PREDO trial aspirin in the prevention of pre-eclampsia
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG 73
is an ethical ground for publication. Second, the trial results could be pooled with two other small trials into a new
meta-analysis of the effect of aspirin in a subgroup of high-risk women who also have abnormal uterine artery
Doppler waveforms at 14 weeks. We learn that it differs little from its effect in other high-risk groups. Third, we learn
that overall results of the kind reported in previous comprehensive reviews (Cochrane Database Syst Rev
2007;2:CD004659; Lancet 2007;369:17918) cannot be trumped by trials or meta-analyses within subgroups. We hope
that through this, the scientic community can learn that there comes a time to draw a line, and for aspirin use in
pregnancy that time has come. j
Conict of interest
No conicts.
J Thornton
Division of Obstetrics, Gynaecology & Child Health,
Nottingham City Hospital, Nottingham, UK
Villa et al.
74 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG