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Aspirin for pre-eclampsia: beware of subgroup meta-analysis
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
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
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
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.
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)
10
19 953
Trivedi (2011)34
19
28 237
Ruano (2005)35
22
33 598
27 222
Bujold (2010)39
34
11 348
Bujold (2009)40
1317
Coomarasamy (2003)36
Coomarasamy (2001)37
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)
Roberge (2012)41
Pre-eclampsia
14
346
RR 0.55 (0.370.83)*
392
556
12 416
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.
482
Study or subgroup
Aspirin
Events Total
Control
Events Total
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
24.8%
13.7%
24.2%
0.7%
10.5%
2.8%
76.6%
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.
Opinion
483
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;
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