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Ultrasound Obstet Gynecol 2013; 41: 479485

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/uog.12470

Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis

The aim of systematic reviews of randomized controlled


trials (RCTs) is to help achieve consensus about the
effects of interventions by summarizing the evidence,
increasing the power to detect differential effects, assessing
consistency of findings and reducing the risk of bias by
using pre-specified, explicit methodology1 .
When it comes to aspirin therapy for prevention of
pre-eclampsia and associated adverse perinatal outcomes,
systematic reviews have brought about as much controversy as they have consensus. Research in this area has
expanded exponentially over the last three decades, from
the first published RCT in 19852 . Data are now available
on over 37 000 women recruited to more than 55 randomized trials. Researchers have sought to meta-analyze
data from aspirin trials on multiple occasions over the
years, initially to justify larger trials and then to quantify treatment effects more precisely. Lately, the focus
seems to have shifted towards trying to resolve uncertainties through subgroup analyses of available data. Our
MEDLINE search for previously published aspirin metaanalyses reporting on either pre-eclampsia or perinatal
death identified no fewer than 21 systematic reviews
published between 1991 and 2013 (Tables 1 and 2),
in addition to one published in this issue of the Journal
by Roberge et al.3 .
The first meta-analysis on aspirin in 1991 summarized
data from six small early studies (394 women) and
showed that aspirin use in the second and third
trimesters significantly reduced the risk of pregnancyinduced hypertension, growth restriction and Cesarean
section4 . The hypothesis generated was tested in larger
trials. Although individual large studies did not show
statistically significant benefits with aspirin therapy5 7 ,
subsequent meta-analysis continued to show that aspirin
improved pregnancy outcome8 .
Contradictory findings between large trials and systematic reviews led to the first contentious issue surrounding
aspirin: should we believe results of large trials or systematic reviews9,10 ? The difficulty in relying on RCTs alone
is that they are often not large enough to allow detection
of modest effects that may still be clinically meaningful.
When trials fail to show significant benefits, insufficient
evidence of effect should not be confused with evidence of
no effect. For example, CLASP (Collaborative Low-dose
Aspirin Study in Pregnancy), the largest aspirin trial to
date, which recruited 9356 women, had an incidence of
pre-eclampsia of 7.6% in the control group and 6.7%
in the aspirin group, with a 12% non-significant reduction in risk of pre-eclampsia5 . To have adequate power

Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.

for this relatively modest effect to reach statistical significance, CLASP would have had to recruit over 25 000
women. Here lies the strength of meta-analysis. Having
obtained raw data for 90% of women in aspirin trials
(36 trials, 34 288 women), the PARIS Collaboration performed the gold standard individual patient data (IPD)
meta-analysis11 , showing a significant reduction in the
risk of pre-eclampsia of 10% (relative risk (RR), 0.90;
95% CI, 0.840.97), which is entirely consistent with
the risk reduction seen in the CLASP trial. The IPD analysis also showed a significant reduction in the risk of
a composite serious adverse outcome (death of mother
or baby, small-for-gestational age baby, preterm birth or
pre-eclampsia) (RR, 0.90; 95% CI, 0.850.96). Importantly, there were no indications of harmful effects on
either mother or baby. It was estimated that 67 highrisk women, with a baseline risk of 15%, would need
to be treated to prevent one case of serious adverse
pregnancy outcome.
Although the benefits of aspirin are modest, in the
absence of alternative beneficial interventions and with
good safety data and low cost, publication of results from
the IPD meta-analyses has been followed by greater consensus about recommending aspirin to high-risk women;
this is reflected in a number of international guidelines on the management of hypertensive disorders in
pregnancy12 16 . How consistently these recommendations are being followed in clinical practice globally is
difficult to assess, but the use of aspirin is still likely to
be patchy.
Since the publication of the IPD review11 and that
of a large aggregate data Cochrane review including
59 trials (37 560 women)17 , a number of systematic
reviews with smaller data sets of aspirin trials have been
published. One may ask why smaller meta-analyses are
continuing to be published, when previously conducted
robust systematic reviews have shown with considerable
precision the small but consistent benefits of aspirin
in pregnancy18 . Perhaps we are still trying to find
explanations for the large swings in effect size among
trials. Maybe we are hoping that if we identify the right
group of women to treat, or the right dose or time at
which to prescribe it, low-dose aspirin might still be
the wonder drug that initial studies suggested it was
going to be.
It is important to remember that systematic reviews also
have limitations and are susceptible to bias. When we are
attempting to resolve uncertainties surrounding aspirin
through meta-analyses of subgroups, we are dealing with
smaller numbers and multiple analyses. This increases

OPINION

Meher and Alfirevic

480

Table 1 Systematic reviews with meta-analyses of all available data from aspirin trials reporting on prevention of pre-eclampsia or perinatal
death
Relative risk (RR) or odds ratio (OR) (95% CI)
Reference
Askie

(2007)11

Duley (2007)17

Kozer (2003)29
Duley (2001)8
Leitich (1997)31
Hauth (1995)32

Sanchez-Ramos (1994)30
Imperiale (1991)4

Focus of analysis

Trials (n)

Women (n)

Pre-eclampsia

Fetal or perinatal death

Individual patient data review


for prevention of PET and
its complications
Cochrane review of
aggregate data for
prevention of PET and its
complications

31

32 217

RR 0.90 (0.840.97)*

RR 0.91 (0.811.03)

59

37 560

RR 0.83 (0.770.89)*

RR 0.86 (0.760.98)*

Effects on pregnancy
outcomes
Prevention of PET and its
complications
Effect on IUGR and perinatal
mortality
Effect on abruptio placentae
and perinatal mortality

38

High risk:
RR 0.75 (0.660.85)*
Moderate risk:
RR 0.86 (0.790.95)*

RR 0.92 (0.811.05)

39

30 563

RR 0.85 (0.780.92)*

RR 0.86 (0.750.98)*

13

13 234

OR 0.84 (0.661.08)

11

15 257

Prevention of PET and its


complications
Prevention of PIH and its
complications

12

5115

OR 0.53 (0.510.55)*

394

RR 0.35 (0.220.55)*

Aspirin vs control:
2.6% vs 2.8%;
P = 0.42
No significant
difference
RR 0.88 (0.322.46)

Only the first author of each study is given. *Statistically significant result. Most up to date Cochrane review listed (three earlier versions of
Cochrane reviews also exist, published in 1995, 2000 and 2003). RR is reported for pregnancy-induced hypertension (PIH) (proteinuric
and non-proteinuric PIH). IUGR, intrauterine growth restriction; PET, pre-eclampsia.

susceptibility to bias, and careful interpretation of findings


in light of potential limitations becomes crucial to avoid
misleading conclusions.
It is important to explore subgroup analyses if there are
potentially large differences between groups in the risk
of a poor outcome with or without treatment, if there is
potential heterogeneity of treatment effect in relation to
pathophysiology, if there are practical questions about
when to treat, or if there are doubts about benefit in
specific groups19 . However, subgroup analyses are not
without hazards, and certain rules need to be followed.
Subgroup analyses should be justified carefully and limited to a small number of research questions because there
is a chance of finding positive effects purely by chance.
As a rule, reports of statistical significance in individual
groups should be ignored, because rates of false positives
and negatives are high, and the only reliable statistical
approach is to perform an interaction test for subgrouptreatment interaction effect. Essentially, subgroup analysis
should be seen as hypothesis generating; the best test
for validity of subgroup findings is confirmation in
subsequent trials19 .
It is important to note that the IPD review11 did not find
any evidence that any one of their pre-specified subgroups
benefited more or less, compared with the others, from
the use of aspirin, based either on risk factors or on
gestation at randomization before or after 20 weeks,
for the outcome of pre-eclampsia. Other meta-analyses
evaluating benefits of aspirin in high-risk and low-risk
women (risk being based mainly on medical and obstetric
history, obstetric factors and ultrasound) have shown

Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.

results very similar to those in the Cochrane aggregate


data review17 for both risk of pre-eclampsia and fetal or
perinatal death (Table 1), although in some reviews the
risk reduction did not reach statistical significance due
to fewer data and more imprecision in the confidence
intervals (Table 2).
In this issue of the Journal, Roberge et al.3 have
amalgamated and updated their previous publications
and present an eloquent meta-analysis of selected data
comparing the effectiveness of early ( 16 weeks) vs late
(> 16 weeks) administration of aspirin in reducing the
risk of perinatal death and other adverse pregnancy
outcomes including pre-eclampsia. Their meta-analysis
includes 42 studies, with data on 27 222 women.
However, more than 94% of the data are for women
in the >16-week group, whilst all 15 trials recruiting
women at 16 weeks were very small (33350 women
randomized; total, 1517). Their results show that
aspirin administration at 16 weeks significantly reduces
perinatal death, severe pre-eclampsia and fetal growth
restriction. The meta-analysis also shows that aspirin
significantly reduces the risk of pre-eclampsia and preterm
birth regardless of whether it is given before or after
16 weeks, but benefits appear to be greater if it is given
at 16 weeks. It is important to note that the interaction
test between subgroups was statistically significant,
suggesting that the differences in the effect size between
subgroups were more than would be expected to occur
by chance.
This is a well-presented meta-analysis that, if the
conclusions prove correct, has important implications

Ultrasound Obstet Gynecol 2013; 41: 479485.

Opinion

481

Table 2 Systematic reviews with meta-analyses of subsets of data in aspirin trials reporting on prevention of pre-eclampsia or perinatal death
Relative risk (RR) or odds ratio (OR) (95% CI)
Reference

Focus of analysis

Trials (n)

Women (n)

Subgroup meta-analyses based on risk factors


Prevention of PET in high-risk
Rossi (2011)33
vs low-risk women

10

19 953

Trivedi (2011)34

Prevention of PET in high-risk


vs low-risk women

19

28 237

Ruano (2005)35

Prevention of PET in high-risk


vs low-risk women

22

33 598

Subgroup meta-analyses based on GA at randomization to aspirin


Prevention of perinatal death
Roberge (2013)3
42
and other adverse outcomes
with aspirin 16 weeks
and > 16 weeks

27 222

Bujold (2010)39

Prevention of PET and IUGR


with aspirin 16 weeks
and > 16 weeks

34

11 348

Bujold (2009)40

Prevention of PET and IUGR


with aspirin 16 weeks
and > 16 weeks in women
with abnormal uterine
artery Doppler

1317

Coomarasamy (2003)36

Coomarasamy (2001)37

Fetal or perinatal death

High risk: OR 0.72


(0.511.00)
Low risk: OR 0.82
(0.651.04)
High risk: RR 0.79
(0.650.97)*
Low risk: OR 0.86
(0.641.17)
High risk: RR 0.87
(0.790.96)*
Low risk: RR 0.95
(0.811.11)

High risk: OR 0.90


(0.581.40)
Low risk: OR 1.24
(0.90 1.70)
RR 0.94 (0.751.1)

Aspirin 16 weeks: RR
0.47 (0.360.62)*

Aspirin 16 weeks:
RR 0.41
(0.190.92)*
Aspirin > 16 weeks:
RR 0.93 (0.731.19)

Aspirin > 16 weeks: RR


0.78 (0.610.99)*
Aspirin 16 weeks: RR
0.47 (0.340.65)*
Aspirin >16 weeks: RR
0.81 (0.631.03)
Aspirin 16 weeks: RR
0.48 (0.330.68)*

Aspirin 1719 weeks: RR


0.55 (0.171.76)
Aspirin 20 weeks: RR
0.82 (0.621.09)

Meta-analyses in specific groups of women (not comparing subgroups)


Prevention of PET with
3
Villa (2013)38
aspirin 16 weeks in
women with early
abnormal uterine artery
Doppler
Prevention of severe and mild
4
Roberge (2012)22
PET with aspirin 16
weeks

Roberge (2012)41

Pre-eclampsia

Prevention of preterm and


term PET with aspirin 16
weeks

Prevention of PET and


perinatal death in women
with historical risk factors
Prevention of PET in women
with abnormal uterine
artery Doppler

14

346

RR 0.55 (0.370.83)*

392

Severe PET: RR 0.22,


(0.080.57)*

556

Mild PET: RR 0.81,


(0.331.96)
Preterm PET: RR 0.11
(0.040.33)*

12 416

Term PET: RR 0.98


(0.422.33)
OR 0.86 (0.760.96)*

OR 0.79 (0.640.96)*

498

OR 0.55 (0.320.95)*

Only the first author of each study is given. *Statistically significant result. GA, gestational age; IUGR, intrauterine growth restriction; PET,
pre-eclampsia.

regarding when we should start prescribing aspirin in


pregnancy. However, we feel that the results of this metaanalysis should be interpreted with caution, and cannot be
taken as conclusive, because of the inherent limitations of
the dataset analyzed. Firstly, as the authors acknowledge,
all studies in the 16-week subgroup were small. The
chances of the summary estimate changing significantly

Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.

with the addition of new data are, therefore, high.


Secondly, it is well recognized that meta-analyses of small
studies are more likely to overestimate treatment effects
due to publication bias: trials with significant findings
are more likely to be published, whilst small negative
studies remain unpublished and unavailable for inclusion
in meta-analysis20 . Funnel plots are used to investigate the

Ultrasound Obstet Gynecol 2013; 41: 479485.

Meher and Alfirevic

482

Study or subgroup

Aspirin
Events Total

Control
Events Total

Study size 350 women or fewer


Byaruhanga42 (1998)
5
114
13
Davies43 (1995)
58
0
0
58
2
Gallery44 (1997)
4
Kim45 (1997)
32
3
1
McCowan46 (1999)
49
3
4
48
3
McParland47 (1990)
1
Omrani48 (1992)
21
1
0
34
0
Schiff49 (1989)
0
Schrocksnadel50 (1992)
22
1
0
Trudinger51 (1988)
22
0
0
Wallenburg52 (1986)
23
1
1
Wallenburg53 (1991)
18
0
0
Wang54 (1996)
40
4
0
Zimmerman55 (1997)
13
1
0
Subtotal (95% CI)
552
16
Total events
32
Heterogeneity: Chi2 = 5.53, df = 9 (P = 0.79); I2 = 0%
Test for overall effect: Z = 2.14 (P = 0.03)

122
60
50
38
50
52
19
32
19
24
23
18
44
13
564

Weight
8.8%
1.5%
1.9%
2.1%
2.0%
1.1%
1.1%
0.7%
3.0%
1.1%
23.4%

Risk ratio
M-H, Fixed, 95% CI

Risk ratio
M-H, Fixed, 95% CI

0.41 (0.15, 1.12)


Not estimable
1.72 (0.33, 9.02)
0.40 (0.04, 3.62)
1.36 (0.32, 5.77)
0.36 (0.04, 3.35)
0.30 (0.01, 7.02)
Not estimable
0.29 (0.01, 6.72)
Not estimable
1.00 (0.07, 15.04)
Not estimable
0.12 (0.01, 2.20)
0.33 (0.01, 7.50)
0.54 (0.31, 0.95)

Study size more than 350 women


CLASP5 (1994)
35 1301
22 1321
23
ECPPA56 (1996)
329
21
286
Golding6 (1998)
40 1253
35 1294
1
Hauth57 (1993)
302
1
302
16
Rotchell7 (1998)
752
15
747
7
Yu58 (2003)
278
4
276
Subtotal (95% CI)
4185
4256
Total events
111
109
Heterogeneity: Chi2 = 5.17, df = 5 (P = 0.39); I2 = 3%
Test for overall effect: Z = 0.14 (P = 0.89)

24.8%
13.7%
24.2%
0.7%
10.5%
2.8%
76.6%

0.62 (0.37, 1.05)


1.26 (0.71, 2.23)
1.18 (0.75, 1.85)
1.00 (0.06, 15.91)
1.07 (0.53, 2.16)
1.76 (0.52, 5.95)
1.02 (0.79, 1.32)

Total (95% CI)


Total events

0.91 (0.72, 1.15)


4737
4820 100.0%
143
125
Heterogeneity: Chi2 = 13.70, df = 15 (P = 0.55); I2 = 0%
Test for overall effect: Z = 0.82 (P = 0.41)
Test for subgroup differences: Chi2 = 4.00, df = 1 (P = 0.05), I2 = 75.0%

0.01

0.1
1
10
100
Favors aspirin
Favors control

Figure 1 Forest plot of subgroup analysis based on study size from trials administering aspirin after 16 weeks gestation that were included
in the analysis by Roberge et al.3 . Only the first author of each study is given.

presence of such publication bias in systematic reviews


and, for aspirin meta-analyses, have consistently shown
asymmetry, suggesting that small negative trials may be
missing21 . While it is possible that aspirin may be more
beneficial if it is given before 16 weeks, it remains equally
possible that, were large trials to be conducted with
early aspirin administration, the effects could be far more
modest than currently suggested.
To illustrate the impact of study size, we have
performed a subgroup analysis based on study size for
trials that administered aspirin after 16 weeks that were
included in the analysis of Roberge et al.3 . We used 350
randomized women as the cut-off for study size, as this
was comparable to the RCTs included in the 16-week
subgroup. The subgroup analysis clearly demonstrates
benefit of late aspirin in small RCTs and lack of
benefit when RCTs are large (Figure 1). The forest plot
looks very similar to Figure 2 in the meta-analysis of
Roberge et al.

Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.

Moreover, the meta-analysis by Roberge et al.3 does not


include data from all women randomized at 16 weeks.
A number of studies were excluded because gestational
age at randomization overlapped 16 weeks. Data on
perinatal death from the three largest aspirin trials that
recruited women from 12 to 32 weeks5 7 seem to have
been available separately for inclusion in the > 16-week
subgroup but not in the 16-week group. A more robust
and complete dataset based on gestation at randomization
should be available from the PARIS Collaboration IPD
data11 , and further analyses and publication of those data
may help reduce uncertainty in this area.
The review could also have been influenced by
systematic differences between the populations of women
in the two subgroups. There was a marked imbalance
between the baseline risk of pre-eclampsia in the
control groups for the 16-week subgroup (17.9%)
and the >16-week subgroup (8.4%). For the primary

Ultrasound Obstet Gynecol 2013; 41: 479485.

Opinion

483

outcome of perinatal death, as the authors acknowledge,


definitions were variable and underlying causes unclear.
Reports of significant reductions in risk of severe preeclampsia with early aspirin administration should also
be interpreted with caution, not only in this review but
also in other reviews reporting this outcome22 . Systematic
reviews can overestimate treatment effects when data
on important outcomes are missing from a significant
number of trials, because statistically significant results
have higher odds of being reported than do non-significant
findings23,24 . Only a small proportion of eligible trials
have reported on severe pre-eclampsia (6/15 in 16week and 5/27 in > 16-week groups); therefore, findings
are susceptible to reporting bias and conclusions could
change significantly if all eligible studies were to report the
outcome.
Finally, for any subgroup analysis, there should be a
clear rationale and justification. Evidence that suggests
aspirin may have an effect on placentation is tenuous
at best25,26 , and it is equally possible that aspirin may
also have a beneficial effect on endothelial dysfunction
later in gestation. Even if we assume that aspirin has
an effect purely on placentation, it is not clear why 16
weeks has been chosen as the cut-off; the first wave of
trophoblast invasion is complete by around 10 weeks,
the second wave does not start until 1415 weeks and
active endovascular trophoblast has been seen in uterine
myometrial vasculature up to 22 weeks gestation27,28 .

Summary
Findings from this most recent review by Roberge et al.3
cannot be taken as conclusive, given the relatively small
amount of data, and missing data, in the 16-week
subgroup, as well as the potential impact of other factors
such as variable outcome definitions for perinatal death
and possible systematic differences between the women in
the two gestational age subgroups. It would be reassuring
to see these data confirmed by the currently available IPD
data. We would appeal to the PARIS Collaboration to
make these data publicly available to reduce uncertainty
in this area. Although multiple subgroup analyses carry
the risk of finding significant effects by chance, we feel
the current debate justifies further analysis of the IPD
data in this case.
Finally, we predict an avalanche of small RCTs and
subgroup meta-analyses based on biomarker risk factors
as the search to find better tests for prediction of preeclampsia continues. Whether women identified in this
way benefit from low-dose aspirin will remain unknown
for some time. We would, therefore, appeal to those
undertaking research in this area to ensure that sample
sizes are adequate in order to answer this question with
certainty, rather than resorting to subgroup meta-analyses
of small trials.
S. Meher* and Z. Alfirevic
Department of Women and Childrens Health,
University of Liverpool, Liverpool, UK;

Copyright 2013 ISUOG. Published by John Wiley & Sons Ltd.

Queen Charlottes and Chelsea Hospital,


Imperial College Healthcare NHS Trust,
London, UK
*Correspondence.
(e-mail: smeher@liv.ac.uk)

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