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Systematic Reviews ajog.org
Aspirin for the prevention of preterm and termpreeclampsia:
systematic review andmetaanalysis
Stephanie Roberge, PhD; Emmanuel Bujold, MD, MSc; Kypros H.
Nicolaides, MD
reeclampsia is a major cause of
OBJECTIVE DATA: Metaanalyses of randomized controlled trials
have reported contra-dictory results about the effect of aspirin in
the prevention of preeclampsia, both in termsof the gestational age
at the onset of treatment and the dose of the drug. The
controversymay be resolved by a metaanalysis that includes several
recently published trials andparticularly the large Combined
Multimarker Screening and Randomized Patient Treat-ment with
Aspirin for Evidence-based Preeclampsia Prevention trial and by
examinationof whether there is a difference of the effect of
aspirin on preterm vs term preeclampsia.STUDY: We performed a
systematic review and metaanalysis that evaluated the pro-phylactic
effect of aspirin during pregnancy.STUDY APPRAISAL AND SYNTHESIS
METHODS: We completed a literature searchthrough PubMed, Cinhal,
Embase, Web of Science, and Cochrane library from 1985 toJune 2017.
Relative risks with random effect were calculated with their 95%
confidenceintervals.RESULTS: Sixteen trials that included 18,907
participants provided data for preterm andterm preeclampsia. Eight
of the included studies were evaluated as being of good quality,and
the other 8 studies were deemed to be of poor or uncertain quality.
There was highheterogeneity within studies (I2 >50%) for preterm
and term preeclampsia, but noheterogeneity was found in the
subgroup of preterm preeclampsia when the onset oftreatment was �16
weeks of gestation and the daily dose of aspirin was �100
mg(I2¼0%). Administration of aspirin was associated with reduction
in the risk of pretermpreeclampsia (relative risk, 0.62; 95%
confidence interval, 0.45e0.87), but there wasno significant effect
on term preeclampsia (relative risk, 0.92; 95% confidence
interval,0.70e1.21). The reduction in preterm preeclampsia was
confined to the subgroup inwhich aspirin was initiated at �16 weeks
of gestation and at a daily dose of �100 mg(relative risk, 0.33;
95% confidence interval, 0.19e0.57). This effect was also
observedin the high-quality studies. The reduction in preterm
preeclampsia that was observed inthe largest trial (Combined
Multimarker Screening and Randomized Patient Treatment
P maternal and fetal morbidity anddeath.1 The adverse
consequences ofpreeclampsia are particularly evident if itis
associated with preterm birth. Severalrandomized studies
investigated thepossibility of preventing preeclampsia bythe
prophylactic use of aspirin, withcontradictory results.2,3
A metaanalysis of individual-participant data reported that the
effectof aspirin in the reduction of pre-eclampsia was 10%; this
was not affectedby the gestational age at the onset oftherapy or
the dose of aspirin.3 Incontrast, other metaanalyses reportedthat
aspirinmay confer greater benefit if itis started at�16 weeks of
gestation ratherthan >16 weeks of gestation, the dailydose is
�100 mg rather than
-
FIGURE 1Selection of the articles
Selection tree for the selection of included articles.
PE, preeclampsia.
Roberge. Aspirin for prevention of preterm preeclampsia. Am J
Obstet Gynecol 2018.
Systematic Reviews ajog.org
dose of aspirin either alone or incombination with dipyridamole
and theother group received placebo or notreatment and (2) data on
the preva-lence of both preterm and term pre-eclampsia were
provided in thepublication or were provided by theauthors. Protocol
was registered inPROSPERO (#71275).
Research strategyMeSH terms and keywords related toaspirin and
preeclampsia were searched
FIGURE 2Quality of the studies
Assessment of risk of bias in studies included acc
Roberge. Aspirin for prevention of preterm preeclampsia. Am
J
288 American Journal of Obstetrics & Gynecology
through PubMed, Embase, Cinahl, Webof science, and the Cochrane
CENTRALlibrary from 1985, when the first trialwas published,8 to
June 2017 and fromreferences of other systematic reviews.No
language restrictions applied.
Selection of the articlesAll citations were examined to
identifypotentially relevant studies; the abstractsof these studies
were then revised by 2independent reviewers (S.R. and E.B.)who
selected eligible studies for full
ording to the Cochrane handbook.11
Obstet Gynecol 2018.
MARCH 2018
assessment of the complete article. Anydisagreements were
resolved by discus-sion and the opinion of a third party(K.N.). For
articles with incompletedata, the corresponding author wascontacted
for additional information.
Outcome measuresThe primary outcome measure for thisanalysis was
preterm preeclampsia withdelivery at 16 weeks ofgestation) and
daily dose of the drug(
-
FIGURE 3Funnel plot on aspirin for the prevention of preterm
preeclampsia
Funnel plot of distribution of relative risk for preterm
preeclampsia associated with aspirin treatment
for studies included in our analysis.
RR, risk ratio; SE, standard error.
Roberge. Aspirin for prevention of preterm preeclampsia. Am J
Obstet Gynecol 2018.
TABLE 1Risk of preterm and term preeclampsia
Preeclampsia Trials, n Participants, n
Random effect,relative risk(95% confidenceinterval) P value I2,
%
Preterm (50%) for preterm and termpreeclampsia, but no
heterogeneity wasfound in the subgroup of preterm pre-eclampsia
when the onset of treatmentwas�16 weeks of gestation and the
dailydose of aspirin was �100 mg (I2¼0%).Publication bias cannot be
excludedbased on the analysis of the funnel plot(Figure 3).
Administration of aspirin was associ-ated with reduction in the
risk of pre-term preeclampsia (RR, 0.62; 95% CI,0.45e0.87), but
there was no significanteffect on term preeclampsia (RR, 0.92;95%
CI, 0.70e1.21; Table 1, Figure 4).The reduction in preterm
preeclampsiawas confined to the subgroup in whichaspirin was
initiated at �16 weeks ofgestation and at a daily dose of�100
mg(Table 2, Figure 4). There was no sig-nificant reduction in risk
of pretermpreeclampsia in the subgroup in whichaspirin was
initiated at �16 weeks ofgestation and at a daily dose of16 weeks
of gestation, irrespective ofwhether the dose was �100 mg (RR,0.88;
95% CI, 0.54e1.43) or 3times as many studies, including 5
largetrials.7,17,18,21,22
There are 2 possibilities for theapparent effect of aspirin in
thereduction of the risk of preterm pre-eclampsia, but not term
preeclampsia.First, the pathophysiologic effect of
erican Journal of Obstetrics & Gynecology 289
http://www.AJOG.org
-
FIGURE 4Forest plot on aspirin for the prevention of preterm
preeclampsia
Forest plot of effect of low-dose aspirin on risk of preterm
preeclampsia, subgrouped by gestational age at initiation of
treatment and dose of treatment.
CI, confidence interval; M-H, Mantel-Haenszel.
Roberge. Aspirin for prevention of preterm preeclampsia. Am J
Obstet Gynecol 2018.
Systematic Reviews ajog.org
290 American Journal of Obstetrics & Gynecology MARCH
2018
http://www.AJOG.org
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TABLE 2Risk of preterm preeclampsia detailed by onset of
treatment and dose ofaspirin in all studies and in the high-quality
studies
Onset/dose Trials Participants
Random effect,relative risk(95% confidenceinterval) P value I2,
%
All studies
�16 Wk 13 5858 0.45 (0.26e0.79) .005a 5816 Wk 4 8810 0.98
(0.80e1.19) .82 0
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Systematic Reviews ajog.org
women who would benefit from the pro-phylactic use of aspirin.
The traditionalapproach has been to define the high-riskgroup based
on factors in maternal char-acteristics and medical history.36,37
How-ever, recent evidence suggests that themost effective way of to
identify the high-risk group is by a combination ofmaternalfactors
with biophysical and biochemicalmarkers,39,40 as was used in the
ASPREtrial.7 Large screening studies demon-strated that the use of
the approachesadvocated by the National Institute forHealth and
Clinical Excellence36 andAmerican College of Obstetricians
andGynecologists37 would identify onlyapproximately 40% and 5%,
respectively,of womenwho would experience pretermpreeclampsia,
compared with 75% by themethod of combined screening at 11e13weeks
of gestation.40,41
ConclusionThe administration of aspirin starting at�16 weeks of
gestation and at a dose of�100mg/day reduces the risk of
pretermpreeclampsia by approximately 70%. -
ACKNOWLEDGMENT
We acknowledge the contribution of authorswho provided
additional data: Affette McCaw-Binn, Alaa Ebrashy, Francesca
Figueras, LianaPles, Pia Villa, Maternal-Fetal Medicine Units(MFMU)
Network.
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APPENDIXCharacteristics of included studies
Study N Inclusion criteria ComplianceaIntervention
Aspirin Controls Onset, wk
Vainio et al, 2002 86 Abnormal uterine arteryDoppler scan
andhistory risk factorsb
N/A 0.5 mg/kg Placebo 12e14
Caritis et al, 1998c 652 History risk factorb 79%>80% 60 mg
Placebo 13e26
Sibai et al, 1993c 644 Nulliparity 73%>80% 60 mg Placebo
13e25
Goldingc 5875 Nulliparity 66% Knowncompliers
60 mg Placebo 12e32
Ebrashy et al, 2005c 136 Abnormal uterine arteryDoppler scan
plushistory risk factorsb
N/A 75 mg No treatment 14e16
Zhao et al, 2012 237 History risk factorb N/A 75 mg Placebo
13e16
Odibo et al, 2015 30 History risk factorb N/A 80 mg Placebo
11e13
August et al, 1994 54 History risk factorsb N/A 100 mg Placebo
13e15
Bakhti and Vaiman, 2011 84 Nulliparity N/A 100 mg No treatment
8e10
Villa et al, 2013c 121 Abnormal uterine arteryDoppler scan
andhistory risk factorsb
9% Excluded fornoncompliance
100 mg Placebo 13e14
Scazzocchio et al, 2017c 155 Abnormal uterine arteryDoppler
scan
100%>90% 150 mg Placebo 11e14
ASPRE 2017 1620 High risk based onFMF screening
80%>90% 150 mg Placebo 11e14
ECPPA 1996 606 History risk factorsb 88% took 75% 60 mg Placebo
12e32
ERASME 2003 3269 Nulliparity Compliancelevel of 80%
100 mg Placebo 13e23
Stanescu et al, 2015c 150 High risk based onFMF screening
N/A 150 mg Placebo 11e14
Yu et al, 2003c 554 Abnormal uterine arteryDoppler scan
N/A 150 mg Placebo 22e24
FMF, Fetal Medicine Foundation; N/A, not available.
a Reported as percentage of women who taken percentage of pills;
b Includes history of chronic hypertension, cardiovascular or
endocrine disease, previous pregnancy hypertension, or fetal
growthrestriction; c Studies in which the authors provided
additional information that was not included in the
publication.
Roberge. Aspirin for prevention of preterm preeclampsia. Am J
Obstet Gynecol 2018.
Systematic Reviews ajog.org
293.e1 American Journal of Obstetrics & Gynecology MARCH
2018
http://www.AJOG.org
Aspirin for the prevention of preterm and term preeclampsia:
systematic review and metaanalysisMethodsResearch strategySelection
of the articlesOutcome measuresQuality
evaluationAnalysesResultsCommentPrincipal findings of this
studyLimitations of the studyComparison with previous metaanalyses
on the use of aspirin for prevention of preeclampsiaClinical
implications of the studyConclusion
AcknowledgmentReferences
