DOI: 10.1111/j.1471-0528.2012.03493.x
www.bjog.org
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
Background
Pre-eclampsia remains one of the most important challenges in obstetrics. The disorder affects 35% of pregnancies and is defined 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 unpredictable, 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 placental developmental abnormality, is central in the disease
process. The early placental disease is followed months later
by the clinical manifestations of pre-eclampsia, which
reflect widespread endothelial dysfunction, resulting in
vasoconstriction, end-organ ischaemia and increased vascular 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-eclampsia, 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 identified by abnormal uterine artery flow.
We performed the trial in conjunction with the multidisciplinary 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 Prevention of Pre-eclampsia had three arms: obstetric (including the present aspirin trial), genetic and psychological.
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
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
65
Villa et al.
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)
2 (3.3%)
3 (4.9%)
25 (41.0%)
8 (13.1%)
Placebo (n = 60)
0
3
27
12
(0.0%)
(5.0%)
(45.0%)
(20.0%)
1 (1.6%)
0 (0.0%)
4 (6.6%)
20 (32.8%)
10 (16.7%)
17 (28.3%)
6 (9.8%)
3 (4.9%)
9 (15.3%)
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 fulfilled more than one inclusion criteria.
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2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
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, antiplatelet, 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, randomised, controlled trials, which met the following criteria: 1)
included women with abnormal uterine artery Doppler flow
velocimetry, and 2) started aspirin at or before the 16 weeks
of gestation, with dose between 50 and 150 mg/day. The control group had to be allocated either to placebo or no treatment. Through the literature search we identified 1414
eligible studies. In addition to our study, only two studies
fulfilled the inclusion criteria.7,9 The results were available
for a total of 346 women.
The outcome measures for the meta-analysis were preeclampsia, severe pre-eclampsia, preterm and term preeclampsia. Definition for pre-eclampsia was consistent
between studies (blood pressure 140/90 mmHg, and proteinuria 0.3 g/24 hours). Pre-eclampsia was defined preterm
when diagnosed before 37 completed weeks of gestation.
Severe pre-eclampsia was defined if in addition to above criteria one or more of the following criteria were present: blood
pressure 160 mmHg systolic and/or 110 mmHg diastolic,
or severe proteinuria (definition between studies ranging
from 2 g to 5 g/24 hours). Oliguria <500 ml/24 hours, elevated liver enzymes, and platelet count <100 000/mm3, 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 significant.
Results
Out of the 947 women recruited, 152 (16.0%) with bilateral
second-degree diastolic notch in the uterine artery flow
were allocated into the aspirin trial. One hundred and
twenty-one women completed the trial.
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
67
Villa et al.
Aspirin group
(n = 61)
Placebo group
(n = 60)
30.8 (5.3)
27.9 (6.6)
31.0 (5.1)
29.7 (7.8)
165.7 (5.3)
19 (26.2%)
165.1 (5.2)
9 (15.0%)
3 (7.5%)
7 (17.5%)
1 (2.4%)
15 (35.7%)
13 (32.5%)
17 (42.5%)
13 (31.0%)
13 (31.0%)
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 significant.
68
Characteristics
Aspirin group
(n = 61)
Placebo
group
(n = 60)
P-value
3 (5.0%)
9 (15.0%)
12.1 (4.9)
0.8
0.6
9 (15.0%)
3 (5.0%)
5 (8.3%)
0.6
146.2 (21.9)
0.3
95.1 (12.5)
0.2
1.3
43 (71.7%)
3 (5.0%)
0.1
0.8
14 (23.3%)
8.9 (0.8)
4 (7.4%)
0.7
0.6
3321 (871)
0.5
585 (150)
0.5
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 compared with placebo group with six (RR 0.3, 95% CI 0.1
1.6). These diagnoses were in part seen in the same participants. Four women in the aspirin group and ten in the placebo 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 five 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
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
Table 4. Study outcomes in aspirin and placebo groups, and relative risk (RR) with 95% confidence intervals (CI) for each outcome.
Primary outcomes
Pre-eclampsia
Gestational hypertension
Secondary outcomes
Early pre-eclampsia*
Preterm pre-eclampsia**
Severe pre-eclampsia***
Small for gestational age****
Severe diagnosis*****
Aspirin (n = 61)
Placebo (n = 60)
RR
95% CI
8 (13.1%)
10 (16.4%)
11 (18.3%)
6 (10.0%)
0.7
1.6
0.31.7
0.64.2
4 (6.7%)
5 (8.3%)
8 (13.3%)
6 (10.0%)
10 (16.7%)
0.2
0.6
0.4
0.3
0.4
0.032.1
0.22.4
0.11.3
0.11.6
0.11.2
1
3
3
2
4
(1.6%)
(4.9%)
(4.9%)
(3.3%)
(6.6%)
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 gestation in women whose uterine artery Doppler ultrasound
indicated an increased risk, significantly 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) (Figure 3). Aspirin did not reduce the risk of preterm preeclampsia (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 find statistically significant benefit for the effect
of low-dose aspirin in preventing pre-eclampsia or related
traits in women identified by clinical risk factors and bilateral uterine artery second-degree notch in early pregnancy.
However, our meta-analysis showed that aspirin may be
effective in preventing pre-eclampsia.
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
69
Villa et al.
Study name
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
8/61
11/60
20.8
36/178
61/168
Villa P 2012
Total
0.72
0.31
1.65
0.55
0.37
0.83
0.01
0.1
Favours experimental
10
100
Favours control
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
flow.
Study name
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
52.3
Villa P 2012
3/61
8/60
Total
5/178
19/168
0.37
0.10
1.32
0.27
0.11
0.69
0.01
0.1
Favours experimental
10
100
Favours control
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 flow.
Study name
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
Total
5/178
43/168
0.59
0.15
2.36
0.16
0.02
1.26
0.01
0.1
Favours experimental
10
100
Favours control
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 flow.
70
with previous suggestions that aspirin in prevention of preeclampsia 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 benefits. 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.
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
Study name
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
Total
5/61
6/60
36.0
31/178
18/168
0.82
0.26
2.54
1.03
0.25
4.26
0.01
0.1
Favours experimental
10
100
Favours control
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 flow.
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 fulfilling 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 first-degree notch in the uterine artery flow velocimetry. In that study those randomised to aspirin started
at 1214 weeks of gestation showed a significant reduction
of pregnancy-induced hypertension (11.6% versus 37.2%,
RR 0.31, 95% CI 0.130.78) and pre-eclampsia (4.7% versus 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 first-degree
notch in the uterine artery flow. In general, caution should
be exercised in evaluating trials with testtreatment combinations.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
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 prostacyclinthromboxane 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 significantly
inhibits the production of thromboxane but leaves prostacyclin 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 (implying 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
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
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Villa et al.
Conclusion
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 Foundation (KR, EK), Sigrid Juselius Foundation (EK), Government 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
In conclusion, although both early-onset and severe preeclampsia, 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 gestation, the differences between the two groups were not statistically significant. However, supported by the results of
our trial and meta-analysis, the role of aspirin in prevention of pre-eclampsia warrants further investigation. We
focused on one specific treatment regimen in women with
clinical risk factors for pre-eclampsia. Together with the
recent rapid development of tools for predicting preeclampsia, our results encourage the use of biochemical risk
markers, possibly in combination with assessment of uterine artery flow, for early identification of women at risk for
future trials to prevent pre-eclampsia.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Figure S1. Uterine artery flow 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
Disclosure of interest
There are no conflicts of interests.
References
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.
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2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
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Appendix 1
The PREDO Study group members are A Aitokallio-Tallberg, 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, University of Helsinki and Helsinki University Central Hospital, 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).
2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG
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Villa et al.
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 scientific community can learn that there comes a time to draw a line, and for aspirin use in
pregnancy that time has come. j
Conflict of interest
No conflicts.
J Thornton
Division of Obstetrics, Gynaecology & Child Health,
Nottingham City Hospital, Nottingham, UK
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2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology 2012 RCOG