ABSTRACT
INTRODUCTION
Objective To compare early vs late administration of lowdose aspirin on the risk of perinatal death and adverse
perinatal outcome.
METHODS
We generated a list of keywords and MeSH terms aspirin,
antiplatelet, acetylsalicylic acid, ASA, pregnancycomplication and pregnancy, for extensive databases
search. EMBASE, PubMed, the Cochrane Central Register
of Controlled Trials (CENTRAL) and Web of Science
Correspondence to: Dr E. Bujold, Department of Obstetrics and Gynecology, Faculty of Medicine, Universite Laval, 2705 boulevard Laurier,
Quebec, QC, Canada, G1V 4G2 (email: emmanuel.bujold@crchul.ulaval.ca)
Accepted: 19 January 2013
SYSTEMATIC REVIEW
Roberge et al.
492
Statistical analysis
Review Manager 5.0.25 software (The Nordic Cochrane
Centre, The Cochrane Collaboration, Copenhagen, Denmark) and the SAS 9.2 software (SAS Institute Inc., Cary,
NC, USA) were used for analysis. Relative risks (RR)
were calculated for each study and were pooled for global
analysis with 95% CIs and stratified according to gestational age at entry ( 16 weeks vs >16 weeks; determined
pre-hoc). Difference between subgroups of gestational age
at entry was evaluated by mixed regression, weighted by
the size of each study. Global RR was calculated according to DerSimonian and Laird random-effect models in
case of significant heterogeneity and with fixed effect in
case of homogeneity between studies20,21 . Heterogeneity
between studies was analyzed using the Higgins I2
statistic22,23 . The distribution of trials was examined
using funnel plots to assess publication bias24 . Sensitivity
analysis was conducted to investigate robustness of
the findings and heterogeneity between studies, with
comparison for the dose of aspirin, use of dipyridamole,
blinding, statistical model, trial size and risk of bias.
RESULTS
The literature search identified 8377 citations from
which we identified 1104 potentially eligible studies
that were completely reviewed (Figure 1). The inclusion
criteria were met by 66 studies, but only 42 of those
were included (27 222 women randomized)25 68 in the
final analysis because several studies recruited over a
range of gestational age overlapping 16 weeks. Studies
included nulliparous women or women identified at
high risk for pre-eclampsia based on medical history
and/or ultrasonographic findings (Table S1). In two
Excluded (n = 24):
Data not available for outcome of interest (n = 2)
Gestational age at treatment not available or overlap (n = 12)
Other reason (other treatment, gestational hypertension at entry) (n = 10)
Study or Subgroup
ASA
Total
Events
Control
Events Total
1
2
7
5
1
2
0
2
0
5
0
1
25
45
82
45
17
19
25
63
50
174
43
60
648
493
Weight
Risk ratio
M-H, Random, 95% CI
0.7%
1.4%
0.7%
0.6%
0.5%
1.0%
Risk ratio
M-H, Random, 95% CI
1.04 (0.0715.73)
0.98 (0.146.65)
0.07 (0.001.15)
0.09 (0.001.50)
0.35 (0.028.08)
0.59 (0.065.96)
Not estimable
0.17 (0.013.54)
Not estimable
0.40 (0.082.01)
Not estimable
0.98 (0.0615.37)
0.41 (0.190.92)
0.6%
2.0%
0.7%
8.3%
Total events
7
26
Heterogeneity: Tau2 = 0.00; chi-square = 5.16, df = 8 (P = 0.74); I2 = 0%
Test for overall effect: Z = 2.17 (P = 0.03)
Studies with treatment > 16 weeks
Byaruhanga42 (1998)
5
114
22
CLASP44 (1994)
1321
0
Davies45 (1995)
58
23
ECPPA46 (1996)
286
4
Gallery48 (1997)
58
40
1253
Golding50 (1998)
1
302
Hauth51 (1993)
1
32
Kim52 (1997)
4
49
McCowan53 (1999)
1
48
McParland54 (1990)
0
21
Omrani57 (1992)
16
Rotchell59 (1998)
747
0
34
Schiff60 (1989)
Schrocksnadel61 (1992)
Trudinger62 (1988)
Wallenburg63 (1986)
Wallenburg64 (1991)
Wang65 (1996)
Yu67 (2003)
Zimmermann68 (1997)
Subtotal (95% CI)
0
0
1
0
0
7
0
22
22
23
18
40
276
13
4737
13
35
0
21
2
35
1
3
3
3
1
15
0
122
1301
60
329
50
1294
302
38
50
52
19
752
32
5.3%
19.0%
1
0
1
0
4
4
1
19
24
23
18
44
278
13
4820
0.5%
0.41 (0.151.12)
0.62 (0.371.05)
Not estimable
1.26 (0.712.23)
1.72 (0.339.02)
1.18 (0.751.85)
1.00 (0.0615.91)
0.40 (0.043.62)
1.36 (0.325.77)
0.36 (0.043.35)
0.30 (0.017.02)
1.07 (0.532.16)
Not estimable
16.3%
1.9%
26.5%
0.7%
1.1%
2.5%
1.1%
0.5%
10.9%
0.29 (0.016.72)
Not estimable
1.00 (0.0715.04)
Not estimable
0.12 (0.012.20)
1.76 (0.525.95)
0.33 (0.017.50)
0.93 (0.731.19)
0.7%
0.6%
3.6%
0.5%
91.7%
Total events
125
143
Heterogeneity: Tau2 = 0.00; chi-square = 13.70, df = 15 (P = 0.55); I2 = 0%
Test for overall effect: Z = 0.56 (P = 0.57)
Total (95% CI)
5397
5468
100.0%
0.87 (0.691.10)
169
132
Total events
Heterogeneity: Tau2 = 0.00; chi-square = 22.49, df = 24 (P = 0.55); I2 = 0%
Test for overall effect: Z = 1.16 (P = 0.24)
0.02
0.1
Favors ASA
10
50
Favors control
Figure 2 Forest plot of effect of low-dose aspirin on risk of perinatal death, subgrouped by gestational age at initiation of treatment. Only
the first author of each study is given. df, degrees of freedom; M-H, Mantel-Haenszel.
Roberge et al.
494
Table 1 Perinatal outcomes associated with low-dose aspirin according to gestational age (GA) at initiation of intervention
Outcome/
GA at initiation
of intervention
Perinatal death
16 weeks
> 16 weeks
Pre-eclampsia
16 weeks
> 16 weeks
Severe pre-eclampsia
16 weeks
> 16 weeks
Fetal growth restriction
16 weeks
> 16 weeks
Preterm birth
16 weeks
> 16 weeks
Placental abruption
16 weeks
> 16 weeks
Participants
(n)
Treated (%)
32
12
20
33
13
20
11
6
5
27
10
17
22
6
16
10
4
6
10 865
1308
9557
12 152
1479
10 673
2143
649
1494
8260
1064
7196
11 302
904
10 398
4175
592
3583
2.4
1.1
2.6
7.5
7.6
7.5
2.8
1.5
3.3
10.7
8.0
11.1
17.4
4.8
18.6
2.3
2.3
2.3
23
10
13
18
9
9
Controls (%)
Relative risk
(95% CI)
(random effect)
I2 (Higgins
test)
3.1
4.0
3.0
9.6
17.9
8.4
7.5
12.3
5.5
12.3
17.6
11.5
20.3
13.4
20.8
1.9
5.1
1.4
NS
0.03
NS
<0.001
<0.001
0.04
<0.001
<0.001
NS
0.04
<0.001
NS
<0.01
<0.001
<0.01
NS
NS
NS
0%
0%
0%
53%
0%
49%
24%
0%
0%
28%
0%
0%
39%
0%
0%
3%
5%
0%
Prevalence
Trials
(n)
2787
1061
1726
1860
959
901
<0.001
<0.001
<0.01
0.01
0.002
NS
45%
69%
0%
88%
93%
55%
P (between
subgroups)
0.02
<0.01
<0.01
<0.001
<0.001
NS
NS
0.048
0.5
SE (logRR)
Allocation concealment
Blinding of outcome assessment
Incomplete outcome data
1.0
Selective reporting
Other bias
1.5
2.0
0.01
0.1
1.0
Relative risk (RR)
10
100
495
DISCUSSION
Our meta-analysis suggests that the prophylactic use of
low-dose aspirin is associated with a significant decrease
in perinatal death, provided the treatment is initiated
at or before 16 weeks of gestation. Low-dose aspirin
initiated at or before 16 weeks is also associated with a
significant and greater reduction of pre-eclampsia, FGR
and preterm birth than is low-dose aspirin started after
Statistical model
Fixed effect (n = 12)
Random effect (n = 12)
Blinding
Yes (n = 7)
No (n = 5)
Dose of aspirin
80 mg daily (n = 3)
81 mg daily (n = 9)
Dipyridamole
No (n = 10)
Yes (n = 2)
Risk of bias
Moderate or high risk of bias (n = 2)
Low risk of bias (n = 10)
Trial size
< 100 participants (n = 7)
100 participants (n = 5)
0.1
0.6
1.1
Relative risk
1.6
Table 2 Perinatal outcomes associated with aspirin started before 16 weeks according to dose of aspirin prescribed
Outcome/
dose of aspirin
Perinatal death
80 mg
100 mg
Pre-eclampsia
80 mg
100 mg
Severe pre-eclampsia
80 mg
100 mg
Fetal growth restriction
80 mg
100 mg
Preterm birth
80 mg
100 mg
Placental abruption
80 mg
100 mg
Controls (%)
Relative risk
(95% CI)
(random effect)
0
1.3
2.4
4.4
NS
NS
NS
401
1078
14.1
5.2
31.8
12.9
<0.001
<0.01
NS
2
4
222
427
0.9
1.8
10.4
13.2
0.01
0.02
NS
4
6
301
763
12.2
6.2
22.8
15.6
0.01
<0.001
NS
2
4
169
735
4.4
4.9
17.7
13.7
0.01
<0.01
NS
0
4
592
2.3
5.1
Prevalence
Trials
(n)
Participants
(n)
Treated (%)
3
9
255
1053
5
8
4
6
321
740
2
6
119
719
NS
P (between
subgroups)
N/A
P
NS
0.001
NS
NS
<0.001
NS
Roberge et al.
496
Table 3 Perinatal outcomes associated with aspirin started before 16 weeks according to whether abnormal uterine artery (UtA) Doppler
was used as an inclusion criterion
Outcome/
inclusion criterion
Perinatal death
Abnormal UtA Doppler
Anamnesis factors only
Pre-eclampsia
Abnormal UtA Doppler
Anamnesis factors only
Severe pre-eclampsia
Abnormal UtA Doppler
Anamnesis factors only
Fetal growth restriction
Abnormal UtA Doppler
Anamnesis factors only
Preterm birth
Abnormal UtA Doppler
Anamnesis factors only
Placental abruption
Abnormal UtA Doppler
Anamnesis factors only
Controls (%)
Relative
risk (95% CI)
(random effect)
0.6
1.2
1.8
4.8
NS
0.04
NS
423
1056
16.6
4.0
34.0
11.6
<0.01
<0.001
NS
3
3
343
306
2.3
0.6
11.4
13.2
<0.01
0.001
NS
3
7
343
721
9.0
7.4
18.1
13.3
0.01
<0.001
NS
2
4
257
647
6.0
4.3
13.0
14.9
NS
<0.001
NS
0
4
592
2.3
5.1
NS
N/A
Prevalence
Trials
(n)
Participants
(n)
Treated (%)
3
9
343
965
4
9
P (between
subgroups)
P
NS
<0.001
NS
NS
0.001
NS
3
7
343
718
46 (115 to 206)
274 (137 to 411)
1
7
86
752
weeks of gestation12,70,71 . Some authors suggest a twowave process: the initial decidual phase being completed
by around 10 weeks and the later myometrial phase
starting at around 1415 weeks72,73 , while others suggest
a continuous process71 . We propose that the beneficial
effect of aspirin is a consequence of an improvement in
the transformation of uterine spiral arteries. This is based
on two facts. First, low-dose aspirin is associated with
a greater reduction of the preterm and severe forms of
pre-eclampsia, which are typically associated with poor
placentation5,6,74 77 . Second, abnormal uterine artery
blood flow is present as early as 12 weeks gestation in
women who will subsequently develop pre-eclampsia,
and low-dose aspirin improves uterine artery blood flow
between the first and the second trimesters10,78,79 . With
these facts in mind, one could suggest that low-dose
aspirin should probably be initiated at around 812
weeks gestation in high-risk women. An individual
patients meta-analysis should be used to establish the
benefits of aspirin in specific gestational-age subgroups
( 16 weeks, 1720 weeks and 2124 weeks gestation)
and could estimate the benefits of initiating aspirin
prophylaxis in women who are first seen after 16 weeks.
This meta-analysis has some limitations. First, none of
the included trials was designed to evaluate perinatal death
and few reported the reasons for perinatal death. Second,
small studies without effect were missing, as seen in
the funnel plot, raising the possibility of publication bias.
ACKNOWLEDGMENTS
Emmanuel Bujold holds a Clinician Scientist Award and
Stephanie Roberge holds a PhD Study Award (Reseau
de formation en recherche perinatale du Quebec) from
the Canadian Institutes of Health Research and from
the Fond de Recherche du Quebec Sante. This study
was supported by the Jeanne and Jean-Louis Levesque
Perinatal Research Chair at Universite Laval, Quebec,
QC, Canada.
497
REFERENCES
1. Geographic variation in the incidence of hypertension in pregnancy. World Health Organization International Collaborative
Study of Hypertensive Disorders of Pregnancy. Am J Obstet
Gynecol 1988; 158: 8083.
2. Duley L. The global impact of pre-eclampsia and eclampsia.
Semin Perinatol 2009; 33: 130137.
3. Bukowski R, Carpenter M, Conway D, Coustan D, Dudley
DJ, Goldenberg RL, Hogue CJ, Koch MA, Parker CB, Pinar
H, Reddy UM, Saade GR, Silver RM, Stoll BJ, Varner MW,
Willinger M; Stillbirth Collaborative Research Network Writing
Group. Causes of death among stillbirths. JAMA 2011; 306:
24592468.
4. Leitich H, Egarter C, Husslein P, Kaider A, Schemper M.
A meta-analysis of low dose aspirin for the prevention of
intrauterine growth retardation. Br J Obstet Gynaecol 1997;
104: 450459.
5. Roberge S, Giguere Y, Villa P, Nicolaides K, Vainio M, Forest
JC, von Dadelzen P, Vaiman D, Tapp S, Bujold E. Early
administration of low-dose aspirin for the prevention of severe
and mild preeclampsia: a systematic review and meta-analysis.
Am J Perinatol 2012; 29: 551556.
6. Roberge S, Villa P, Nicolaides K, Giguere Y, Vainio M, Bakthi
A, Ebrashy A, Bujold E. Early administration of low-dose
aspirin for the prevention of preterm and term preeclampsia: a
systematic review and meta-analysis. Fetal Diagn Ther 2012;
31: 141146.
7. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F,
Marcoux S, Forest JC, Giguere Y. Prevention of preeclampsia
and intrauterine growth restriction with aspirin started in
early pregnancy: a meta-analysis. Obstet Gynecol 2010; 116:
402414.
8. Lyall F. Priming and remodelling of human placental bed spiral
arteries during pregnancy a review. Placenta 2005; 26 Suppl
A: S31S36.
9. Vainio M, Kujansuu E, Koivisto AM, Maenpaa J. Bilateral
notching of uterine arteries at 1214 weeks of gestation for
prediction of hypertensive disorders of pregnancy. Acta Obstet
Gynecol Scand 2005; 84: 10621067.
10. Haapsamo M, Martikainen H, Rasanen J. Low-dose aspirin
reduces uteroplacental vascular impedance in early and mid
gestation in IVF and ICSI patients: a randomized, placebocontrolled double-blind study. Ultrasound Obstet Gynecol
2008; 32: 687693.
11. Espinoza J, Romero R, Mee Kim Y, Kusanovic JP, Hassan S,
Erez O, Gotsch F, Than NG, Papp Z, Jai Kim C. Normal
and abnormal transformation of the spiral arteries during
pregnancy. J Perinat Med 2006; 34: 447458.
12. Pijnenborg R, Dixon G, Robertson WB, Brosens I. Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy.
Placenta 1980; 1: 319.
13. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis
of individual patient data. Lancet 2007; 369: 17911798.
14. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet
agents for preventing pre-eclampsia and its complications.
Cochrane Database Syst Rev 2007; CD004659.
15. Coomarasamy A, Honest H, Papaioannou S, Gee H, Khan K.
Aspirin for prevention of preeclampsia in women with historical
risk factors: a systematic review. Obstet Gynecol 2003; 101:
13191332.
16. Bujold E, Morency AM, Roberge S, Lacasse Y, Forest
JC, Giguere Y. Acetylsalicylic acid for the prevention of
preeclampsia and intra-uterine growth restriction in women
with abnormal uterine artery Doppler: a systematic review and
meta-analysis. J Obstet Gynaecol Can 2009; 31: 818826.
17. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA
statement. PLoS Med 2009; 6: e1000097.
Roberge et al.
498
18. Cochrane Handbook for Systematic Reviews of Interventions,
version 5.1.0 (updated March 2011). Higgins JPT, Green
S (eds). The Cochrane Collaboration, 2011. Available from
www.cochrane-handbook.org.
19. Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical
evidence of bias. Dimensions of methodological quality
associated with estimates of treatment effects in controlled
trials. JAMA 1995; 273: 408412.
20. DerSimonian R, Laird N. Meta-analysis in clinical trials.
Control Clin Trials 1986; 7: 177188.
21. Chevalier P, van Driel M, Vermeire E. Heterogenite dans les
synth`eses methodiques et meta-analyses. Minerva 2007; 6: 160.
22. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring
inconsistency in meta-analyses. BMJ 2003; 327: 557560.
23. Huedo-Medina TB, Sanchez-Meca J, Marin-Martinez F, Botella
J. Assessing heterogeneity in meta-analysis: Q statistic or I2
index? Psychol Methods 2006; 11: 193206.
24. Egger M, Davey Smith G, Schneider M, Minder C. Bias in
meta-analysis detected by a simple, graphical test. BMJ 1997;
315: 629634.
25. August P, Helseth G, Edersheim T, Hutson J, Druzin M.
Sustained relase, low-dose aspirin ameliorates but does not
prevent preeclampsia (PE) in a high risk population. Proceedings
of the 9th International Congress, International Society for the
Study of Hypertension, March 1518, 1994, Sydney, Australia.
Hypertension in Pregnancy, p. 72.
26. Azar R, Turpin D. Effect of antiplatelet therapy in women at
high risk for pregnancy-induced hypertension. Proceedings of
the 7th World Congress of Hypertension in Pregnancy. October
1990, Perugia, Italy, p. 257.
27. Beaufils M, Uzan S, Donsimoni R, Colau JC. Prevention of
pre-eclampsia by early antiplatelet therapy. Lancet 1985; 1:
840842.
28. Benigni A, Gregorini G, Frusca T, Chiabrando C, Ballerini S,
Valcamonico A, Orisio S, Piccinelli A, Pinciroli V, Fanelli R,
Gastaldi A, Remuzzi G. Effect of low-dose aspirin on fetal and
maternal generation of thromboxane by platelets in women at
risk for pregnancy-induced hypertension. N Engl J Med 1989;
321: 357362.
29. Bakhti A, Vaiman D. Prevention of gravidic endothelial
hypertension by aspirin treatment administered from the 8th
week of gestation. Hypertens Res 2011; 34: 11161120.
30. Bakhti A, Vaiman D. Erratum: prevention of gravidic
endothelial hypertension by aspirin treatment administered
from the 8th week of gestation (2012; 34: 1116). Hypertens
Res 2012; 35: 244.
31. Chiaffarino F, Parazzini F, Paladini D, Acaia B, Ossola W,
Marozio L, Facchinetti F, Del Giudice A. A small randomised
trial of low-dose aspirin in women at high risk of pre-eclampsia.
Eur J Obstet Gynecol Reprod Biol 2004; 112: 142144.
32. Dasari R, Narang A, Vasishta K, Garewal G. Effect of maternal
low dose aspirin on neonatal platelet function. Indian Pediatr
1998; 35: 507511.
33. Ebrashy A, Ibrahim M, Marzook A, Yousef D. Usefulness of
aspirin therapy in high-risk pregnant women with abnormal
uterine artery Doppler ultrasound at 1416 weeks pregnancy:
randomized controlled clinical trial. Croat Med J 2005; 46:
826831.
34. Hermida RC, Ayala DE, Iglesias M, Mojon A, Silva I,
Ucieda R, Fernandez JR. Time-dependent effects of low-dose
aspirin administration on blood pressure in pregnant women.
Hypertension 1997; 30: 589595.
35. Hermida RC, Ayala DE, Fernandez JR, Mojon A, Alonso I,
Silva I, Ucieda R, Codesido J, Iglesias M. Administration timedependent effects of aspirin in women at differing risk for
preeclampsia. Hypertension 1999; 34: 10161023.
36. Ayala DE, Ucieda R, Hermida RC. Chronotherapy with lowdose aspirin for prevention of complications in pregnancy.
Chronobiol Int 2012 Sep 24. [Epub ahead of print].
37. Mesdaghinia E, Talari H, Abedzadeh-Kalahroudi M. Effect of
aspirin for prevention of preeclampsia in women with abnormal
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
499
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.