UOG Journal Club: Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis

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. BujoldVolume 41, Issue 5, Date: May 2013, pages 491–499

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

S. Meher, Z. AlfirevicVolume 41, Issue 5, Date: May 2013, pages 479–485

UOG Journal Club: May 2013Prevention 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. BujoldVolume 41, Issue 5, Date: May 2013, pages 491–499

• 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.


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

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 usinglow-dose aspirin: a meta-analysis


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

• 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

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

Results

Comparison of perinatal outcomes: GA at initiation of aspirin

OutcomeTrial 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)

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



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



Results



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)

• 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



• 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



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



UOG Journal Club: May 2013Opinion:

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

S. Meher, Z. AlfirevicVolume 41, Issue 5, Date: May 2013, pages 479–485

• The aim of systematic reviews of RCTs is to help achieve consensus about effects of interventions by:

1. Summarizing the evidence2. Increasing power to detect differential effects3. 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?

• 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



What is known?

• 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 pathophysiology3. Practical questions about when to treat4. 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



• 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



Subgroup analyses

• 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



Summary

• 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



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?



Opinion Aspirin for pre-eclampsia: beware of

subgroup meta-analysisMeher and Alfirevic, UOG 2013

Health & Medicine

UOG Journal Club: Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis