1. UOG Journal Club: May 2013
Journal Club slides prepared by Dr Leona Poon (UOG
Editor for Trainees)
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
S. Roberge, K. H. Nicolaides, S. Demers, P. Villa and E. Bujold
Volume 41, Issue 5, Date: May 2013, pages 491–499
Opinion:
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
S. Meher, Z. Alfirevic
Volume 41, Issue 5, Date: May 2013, pages 479–485

2. UOG Journal Club: May 2013
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
S. Roberge, K. H. Nicolaides, S. Demers, P. Villa and E. Bujold
Volume 41, Issue 5, Date: May 2013, pages 491–499

3. • Leading causes of perinatal death are preterm birth, fetal abnormality
and impaired placentation leading to PET and FGR
• Meta-analyses of RCTs suggest that prophylactic use of low-dose
aspirin initiated at <16 weeks is associated with significant reduction
in prevalence of severe PET, FGR and preterm birth (Bujold et al. 2010;
Roberge et al. 2012a; Roberge et al. 2012b)
• Mechanism of action of aspirin remains unclear but it could include an
improvement in transformation of uterine spiral arteries, which is
typically incomplete in PET (Fraser et al. 2012; Vainio et al. 2005)
• It is still uncertain whether intervention aimed at improving
placentation could lead to a reduction of placental-related adverse
pregnancy outcomes and to a reduction of perinatal death
Bujold E et al. Obstet Gynecol 2010;116;402-14.
Fraser R et al. J Pathol. 2012;228:322-32.
Roberge S et al. Am J Perinatol 2012a;29:551-6.
Roberge S et al. Fetal Diagn Ther 2012b;31:141-6.
Vainio M et al. Acta Obstet Gynecol Scand 2005;84:1062-7.

4. Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013
Compare effect of early vs. late administration of
low-dose aspirin on the risk of perinatal death and
adverse perinatal outcome
Objective

5. Methodology
• RCTs that evaluated prophylactic
use of low-dose aspirin (50-150
mg/day) during pregnancy
• 1965 – October 2011
• All studies that involved women
who initiated low-dose aspirin at
<16 weeks and at >16 weeks
Inclusion criteria
Perinatal mortality:
Fetal death >16 weeks or
Neonatal death <28 days of age
Primary outcome
Secondary outcomes
Pre-eclampsia
Fetal growth restriction
Preterm birth
Placental abruption
Birth weight
GA at delivery
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013

6. 8,377 potentially appropriate trials from electronic
search
1,104 potentially appropriate trials for inclusion in
meta-analysis
7,273 studies excluded: personal communication,
duplicate, not randomized study with aspirin, allocation
concealment inadequate, relevant outcome not
provided
24 studies excluded: data not available for outcome
of interest, GA at treatment not available or overlap,
other reason
66 studies meeting inclusion criteria
42 studies (27,222 women randomized) with
relevant information included in the systematic
review.
1,038 studies excluded: personal communication,
duplicate, letter, commentary, editorial, meta-analysis,
review, paper retracted, other study design, other
treatment, quality inadequate, relevant outcome not
provided, other reasons

7. • Methodological quality of studies: Cochrane Handbook Criteria tool
• Relative risks (RR) calculated for each study
• Global RR calculated stratified according to GA at entry (≤16 weeks vs >16
weeks):
• Significant heterogeneity: DerSimonian and Laird random effect
• Homogeneity: fixed effect
• Heterogeneity between studies: Higgins’ I2
test
• Weighted difference between subgroups of GA at entry evaluated by mixed
regression
• Publication bias: distribution of RCTs examined using funnel plots
• Robustness of findings and heterogeneity between studies assessed by sensitivity
analysis
Methodology

8. Low-dose aspirin starting at ≤ 16 weeks is associated with a significant
reduction in risk of perinatal death
Aspirin for the prevention of perinatal death
0.02 0.1 1 10 50
Favors aspirin Favors control
No. of study Events Total Events Total
Aspirin ≤16 wks 0.41 (0.19-0.92)12 7 660 26 648
0.93 (0.73-1.19)Aspirin >16 wks 20 125 4,737 143 2,820
Aspirin Control
0.87 (0.69-1.10)Total 132 5,397 169 5,46832
Results

9. Results
Comparison of perinatal outcomes: GA at initiation of aspirin
Outcome
Trial Women Prevalence
RR P-value
(n) (n) Treated (%) Controls (%)
Perinatal death 32 10,865 2.4 3.1 0.87 (0.69-1.10)
≤16 wks 12 1,308 1.1 4.0 0.41 (0.19-0.92) 0.02
>16 wks 20 9,557 2.6 3.0 0.93 (0.73-1.19)
PET 33 12,152 7.5 9.6 0.62 (0.49-0.78)
≤16 wks 13 1,479 7.6 17.9 0.47 (0.36-0.62) <0.01
>16 wks 20 10,673 7.5 8.4 0.78 (0.61-0.99)
FGR 27 8,260 10.7 12.3 0.86 (0.75-0.99)
≤16 wks 10 1,064 8.0 17.6 0.46 (0.33-0.64) <0.001
>16 wks 17 7,196 11.1 11.5 0.98 (0.88-1.08)
Preterm birth 22 11,302 17.5 20.3 0.81 (0.71-0.92)
≤16 wks 6 904 4.8 13.4 0.35 (0.22-0.57) <0.001
>16 wks 16 10,398 18.6 20.8 0.90 (0.83-0.97)
Abruption 10 4,175 2.3 1.9 1.24 (0.79-1.95)
≤16 wks 4 592 2.3 5.1 0.55 (0.21-1.47) NS
>16 wks 6 3,583 2.3 1.4 1.56 (0.96-2.55)

10. Results
There is a possibility of
publication bias
because small studies
with no beneficial effect
were missing
Funnel plot of distribution of RR for perinatal death
associated with aspirin treatment (black circles =
aspirin started ≤16 weeks, white circles = aspirin
started >16 weeks
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013

11. The majority of included studies were deemed low / unclear risk of bias, except
for one study with >20% of individuals lost to follow-up and two with a risk of
selective reporting.
Assessment of risk of bias in studies included in the analysis
(low , unclear , high ) following the Cochrane Handbook
Results
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013

12. Results
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013
No statistical difference
observed between any of
the subgroups identified in
sensitivity analysis
Sensitivity analysis of RR for perinatal death for studies
where aspirin was initiated ≤ 6 weeks (dashed vertical
line = RR from random effects meta-analysis)

13. • Effect of low-dose aspirin started at ≤ 6 weeks on perinatal death was
significant and homogeneous according to I2
test and sensitivity analysis
• Similar effects of early aspirin prophylaxis on perinatal outcomes were
observed:
• in women who received ≤ 80 mg daily and those who received ≥ 100
mg daily.
• in women who were selected using abnormal uterine artery Doppler
as an inclusion criterion as compared with those selected using
anamnesis factors only.
Results
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013

14. • The beneficial effect of aspirin is a consequence of an improvement in
transformation of uterine spiral arteries. This statement is based on:
1. Low-dose aspirin has a greater reduction of preterm and severe
PET, which are associated with poor placentation
2. Abnormal uterine artery blood flow is present as early as 12
weeks in women who will subsequently develop PET and aspirin
improves such blood flow between 1st
and 2nd
trimesters
• Low-dose aspirin should probably be initiated in the first trimester in
high-risk women
Discussion
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013

15. 1. None of the included trials was designed to evaluate perinatal death
and few reported the reasons for perinatal death
2. Small studies without effect were missing, raising the possibility of
publication bias
3. Definition of perinatal death was heterogeneous between studies
4. Six largest trials that could have had the power to examine the impact
of low-dose aspirin on perinatal death recruited women mostly >16
weeks
5. Findings were limited by the small size of the studies that recruited at
<16 weeks: each of them individually was underpowered to address
perinatal death
Limitations
Prevention of perinatal death and adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013

16. UOG Journal Club: May 2013
Opinion:
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
S. Meher, Z. Alfirevic
Volume 41, Issue 5, Date: May 2013, pages 479–485

17. • The aim of systematic reviews of RCTs is to help achieve consensus about
effects of interventions by:
1. Summarizing the evidence
2. Increasing power to detect differential effects
3. Assessing consistency of findings
4. Reducing risk of bias by using pre-specified, explicit methodology
• However, systematic reviews have brought about as much controversy as they
have consensus, when it comes to aspirin for prevention of PET and adverse
perinatal outcome
Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
Meher and Alfirevic, UOG 2013
What is known?

18. • Data are now available on >37,000 women recruited to >55 RCTs
• The PARIS Collaboration performed the ‘gold standard’ individual patient data
(IPD) meta-analysis, showing a significant 10% reduction in PET and
composite serious adverse outcome
• Estimated NNT is 67 high-risk women to prevent one case of serious
adverse pregnancy outcome
• Recent focus is shifted towards trying to resolve uncertainties through
subgroup analyses of available data
Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
Meher and Alfirevic, UOG 2013
What is known?

19. • Smaller numbers and multiple analyses, which increase susceptibility to bias
• Important to explore subgroup analyses if:
1. Potential large differences between groups in the risk of a poor outcome
with or without treatment
2. Potential heterogeneity of treatment effect in relation to pathophysiology
3. Practical questions about when to treat
4. Doubts about benefit in specific groups
• It should be justified carefully and limited to a small number of research
questions (high risk of +ve effects purely by chance)
Subgroup analyses
Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
Meher and Alfirevic, UOG 2013

20. • As a rule, reports of statistical significance in individual groups should be
ignored, because rates of false +ve and –ve are high, and the only reliable
statistical approach is to perform an interaction test for subgroup-treatment
interaction effect
• From the review by Roberge et al, the interaction test between subgroups
was statistically significant, suggesting that differences in the effect size
between subgroups were more than would be expected to occur by
chance
• Subgroup analyses should be seen as ‘hypothesis generating’; the best test
for validity of subgroup findings is confirmation in subsequent trials
Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
Meher and Alfirevic, UOG 2013
Subgroup analyses

21. • The review by Roberge et al has potential important implications regarding when
we should start aspirin in pregnancy
• However, the findings cannot be taken as conclusive because:
• Relatively small amount of data (6% of all data) and the data missing from
the ≤16 week subgroup
i. Chances of summary estimate changing significantly with the
addition of new data are high
ii. Small studies are more likely to overestimate treatment effects due
to publication bias: trials with significant findings are more likely to be
published
iii. Data on perinatal death from the three largest RCTs seem to have
been available separately for inclusion in the >16 week subgroup but
not in ≤ 16 week subgroup
Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
Meher and Alfirevic, UOG 2013
Summary

22. • Potential impact of other factors such as variable outcome definitions and
possible systematic differences between the women in the two GA subgroups
i. Marked imbalance between baseline risk of PET in controls for <16
week subgroup (18%) vs >16 week subgroup (8%)
• Choice of 16 weeks as a cut-off is arbitrary
• Although multiple subgroup analyses carry the risk of finding significant effects
by chance, the research question can potentially be confirmed by further
analyses of PARIS Collaboration IPD data
• Future research must ensure that sample sizes are adequate, rather than
resorting to subgroup meta-analyses of small trials
Summary
Opinion
Aspirin for pre-eclampsia: beware of subgroup meta-analysis
Meher and Alfirevic, UOG 2013

23. Discussion points
• Should we be using low-dose aspirin to prevent perinatal death and
adverse perinatal outcome ?
• When is the optimal gestational age for starting low-dose aspirin?
• How do we identify women at risk?
• What proportion of women would fit our definition of high risk?
• Should low-dose aspirin ever be started after 16 weeks?
• What is the optimal dosage of aspirin for the prevention of perinatal
death perinatal death and adverse perinatal outcome?
Prevention of perinatal death and
adverse perinatal outcome using
low-dose aspirin: a meta-analysis
Roberge et al., UOG 2013
Opinion
Aspirin for pre-eclampsia: beware of
subgroup meta-analysis
Meher and Alfirevic, UOG 2013