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Eligibility criteria
FIGURE 2
Studies were included if they random-
ized women at risk of developing pre-
Death of baby: subgroup by randomization at 16 weeks
eclampsia, gestational hypertension, or
intrauterine growth restriction (based
on previous or current obstetric factors
or a preexisting medical disease) to
receive 1 or more antiplatelet agents (eg,
low-dose aspirin or dipyridamole) vs a
placebo or no antiplatelet agent. Qua-
sirandomized trials, and trials that
included women who started treatment
postpartum or had a diagnosis of pre-
eclampsia at trial entry were excluded.
The analysis presented here includes
women enrolled for primary prevention
only (ie, women without gestational
hypertension). Each potentially eligible
study was assessed independently by at
least 2 members of the IPD steering
group, and any differences of opinion
were resolved by discussion.
Four main outcomes were pre-
specied: preeclampsia (hypertension
with new-onset proteinuria at or beyond
20 weeks gestation); death in utero or
death of the baby before discharge from
the hospital; preterm birth at less than 34
weeks gestation; and infant small for
gestational age at birth (as dened by
individual trialists).
TABLE
Systematic reviews with subgroup meta-analysis based on gestational age at randomization before or after
16 weeks for outcome preeclampsia
Results for outcome
preeclampsia Subgroup
Review Type of analysis Number of trials Number of women RR (95% CI) interaction test
PARIS data set Individual participant data <16 wks: 17 <16 wks: 9241 <16 wks: RR, 0.90 No significant
meta-analysis 16 wks: 22 16 wks: 21,429 (0.79e1.03) difference (P .98)a
16 wks: RR, 0.90
(0.83e0.98)a
Xu et al, 201544 Aggregate data 16 wks: 7 16 wks: 1165 16 wks: OR, 0.37 No significant
meta-analysis >16 wks: 14 >16 wks: 3241 (0.27e0.50) difference (P .05)a
>16 wks: OR, 0.77
(0.62e0.97)
Roberge et al, 201317b Aggregate data 16 wks: 13 16 wks: 1479 16 wks: RR, 0.47 Significant difference
meta-analysis >16 wks: 20 >16 wks: 10,673 (0.36e0.62) (P < .01)
>16 wks: RR, 0.78
(0.61e0.99)
a
Statistically significant result for individual subgroups but no statistically significant difference between subgroups; b Earlier version of this meta-analysis was published by the same authors,18 but
data from the most up-to-date meta-analysis is presented here.
Meher. IPD subgroup meta-analysis of antiplatelets for preeclampsia. Am J Obstet Gynecol 2017.
before 16 weeks rather than after 16 weeks Placentation in early pregnancy is not Searches to identify studies for the IPD
(8.8% and 8.7%, respectively). Using in- completely understood, but it is believed meta-analysis were last updated in 2005.
dividual participant data therefore that the rst wave of trophoblast inva- For the updated Cochrane Review,2 7 new
reduced the potential to be misled either sion is already complete around 10 studies have been identied, which ran-
by the play of chance or by bias. weeks, the second wave does not start domized women at or before 16 weeks
As for all subgroup analyses, this until 14e15 weeks, and active endovas- gestation.52-58 These 7 studies were all
analysis by gestation at randomization is cular trophoblast has been seen up to 22 small (totaling 705 women), and several
an indirect comparison and so should be weeks.50,51 If aspirin reduces pre- had an unclear risk of bias and so are
interpreted with caution, as an observa- eclampsia by its impact on endothelial unlikely to change the overall conclusions
tional analysis. Women were not ran- dysfunction, this may explain why it is of our analyses based on individual
domized to early or late administration benecial, even if given at later participant data for more than 9000
of antiplatelet treatment in these trials. gestations. women randomized before 16 weeks.
The best test of whether ndings of a Preterm birth prior to 34 weeks A sensitivity analysis including IPD
subgroup analysis reect a true differ- gestation was used as an indicator data and aggregate data from studies
ence or, as here, no difference is by for early-onset or preterm preeclampsia published between 2005 and 2015 showed
conrmation in subsequent randomized in the PARIS Collaborative study, and no signicant difference in overall results
trials.45 Nevertheless, the data presented there was no signicant difference in this whether antiplatelets were given before or
here suggest that for aspirin and other outcome between the subgroups. We after 16 weeks gestation. However, the
antiplatelet agents, a randomized trial have not reported the impact of gestation data should be interpreted with caution
comparing the effects of starting treat- at randomization on severe preeclampsia because the women randomized at 16
ment before or after 16 weeks may not be because sufcient data are not available. weeks in some aggregate data studies could
justied. An aggregate data meta-analysis sug- not be accurately placed in the appropriate
Subgroup analyses may be important gests that early aspirin is associated with subgroup for analysis. Without obtaining
to explore differential effects if they can a signicant reduction in the risk of se- IPD data from these studies, adding them
be carefully justied. It is well known that vere preeclampsia.17 These ndings to the IPD meta-analysis, is problematic
aspirin may suppress aspects of endo- should be interpreted with caution and the ndings are inconclusive.
thelial dysfunction, but whether it also because only a small proportion of
has an impact on placentation remains eligible trials have reported the outcome Implications for clinical practice and
poorly understood.46-49 If the mecha- severe preeclampsia17; therefore, nd- research
nism of action of aspirin in the preven- ings are susceptible to reporting bias, and Our analysis suggests that women at
tion of preeclampsia is indeed related to conclusions could potentially change risk of preeclampsia should be offered
placentation, it is not clear why a specic signicantly if all eligible studies had antiplatelet therapy, usually low-dose
cutoff of 16 weeks should be used. reported this outcome. aspirin, regardless of whether they
are rst seen before or after 16 weeks. It is 2. CLASP (Collaborative Low-dose Aspirin 16. World Health Organization. WHO recom-
unclear whether there is a gestational age Study in Pregnancy) Collaborative Group. mendations for prevention and treatment of
CLASP: a randomized trial of low-dose aspirin pre-eclampsia and eclampsia. World Health Or-
beyond which commencing aspirin ther- for the prevention and treatment of pre- ganization. 2011. Available at: http://whqlibdoc.
apy may not be benecial. Trials have eclampsia among 9364 pregnant women. Lan- who.int/publications/2011/9789241548335_eng.
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based on various gestational age cutoffs at aspirin for primiparae in pregnancy. The Jamaica Bujold E. Prevention of perinatal death and
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across all subgroups (Appendix Figure 1). Study in Pregnancy (BLASP): a ran- vention of preeclampsia and intrauterine growth
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6. Imperiale TF, Petrulis AS. A meta-analysis of tion of pre-eclampsia and its consequences: a
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11. CLASP Collaborative Group. Low dose aspirin aspirin for the prevention of maternal and fetal
ACKNOWLEDGMENTS in pregnancy and early childhood development: complications in high risk pregnancies. BJOG
follow up of the collaborative low dose aspirin study 1996;103:39-47.
We thank the trialists who contributed data to
in pregnancy. BJOG 1994;102:861-8. 23. Uzan S, Beauls M, Breart G, Bazin B,
the PARIS Collaborative Group. The PARIS
12. National Institute for Health and Care Capitant C, Paris J. Prevention of fetal growth
Steering Group gave permission for the PARIS
Excellence. Hypertension in Prenancy. retardation with low-dose aspirin: ndings of the
data set to be used for these analyses. Contri-
Management of Hypertensive Disorders in EPREDA trial. Lancet 1991;337:1427-31.
bution to authorship included the following: L.A.
Pregnancy. NICE clinical guideline no. 107. 24. Subtil D, Goeusse P, Puech F, et al. Aspirin
and L.D. supplied the data from the PARIS
Issued 2010, updated January 2011. Available (100 mg) used for prevention of pre-eclampsia in
Collaboration; L.A. and S.M. conducted the
at: http://www.nice.org.uk/nicemedia/live/ nulliparous women: the Essai Regional Aspirine
analysis; and S.M. and K.H. entered and
13098/50418/50418.pdf. Accessed May 8, Mere-Enfant study (ERASME) (Part 1). BJOG
checked the data. All authors contributed to and
2015. 2003;110:475-84.
agreed to the manuscript. S.M. is the guarantor
13. Magee L, Pels A, Helewa ME, Rey E, von 25. Vainio M, Kujansuu E, Iso-Mustajarvi M,
for the manuscript, and L.A. is the guarantor for
Dadelszen P. Diagnosis, evaluation, and man- Maenpaa J. Low dose acetylsalicylic acid in
the data from the PARIS Collaborative Group.
agement of the hypertensive disorders of preg- prevention of pregnancy-induced hypertension
Ethics approval was not required for this analysis
nancy. SOGC Practice Bulletin no. 307, May and intrauterine growth retardation in women
because the IPD data used in the systematic
2014. Executive Summary. Obstet Gynaecol with bilateral uterine artery notches. BJOG
review have been published previously. Funding
Can 2014;36:416-38. 2002;109:161-7.
for the original PARIS IPD analysis is reported
elsewhere.10 14. Lowe SA, Bowyer L, Lust K, et al. 26. Uzan S, Beauls M, Bazin B, Danays T.
SOMANZ guideline for the management of Idiopathic recurrent fetal growth retardation and
hypertensive disorders of pregnancy 2014. aspirin-dipyridamole therapy. Am J Obstet
Available at: https://somanz.org/documents/ Gynecol 1989;160:763-4.
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APPENDIX TABLE 1
Sensitivity analysis for outcome preeclampsia based on trials characteristics
Characteristics RR (95% CI) Subgroup interaction test
Relative risk of preeclampsia in main analysis 0.90 (0.84e0.97)
PARIS definition of preeclampsia (SBP 140 mm Hg or 0.90 (0.83e0.97) Sensitivity analysis only
DBP 90 mm Hg and trialist-defined proteinuria)
Trialists own definition of preeclampsia 0.88 (0.81e0.96)
Placebo-controlled studies 0.90 (0.84e0.97) P .52
No placebo 0.71 (0.41e1.25)
Aspirin dose 75 mg 0.92 (0.85e0.99) P .23
Aspirin dose >75 mg 0.77 (0.61e0.97)
CI, confidence interval; DBP, diastolic blood pressure; SBP, systolic blood pressure; PARIS, Perinatal Antiplatelet Review of International Studies; RR, relative risk.
Meher. IPD subgroup meta-analysis of antiplatelets for preeclampsia. Am J Obstet Gynecol 2017.
APPENDIX TABLE 2
Sensitivity analysis: IPD data meta-analysis combined with aggregate data from studies published between
2005 and 2015
Gestation at randomization <16 wks Gestation at randomization >16 wks
Outcome RR (95% CI) RR (95% CI) Subgroup interaction test
Preeclampsia RR 0.78 (0.63 to 0.97) RR 0.88 (0.78 to 0.99) P .36
Death of baby RR 0.81 (0.67 to 0.98) RR 0.92 (0.79 to 1.07) P .31
Preterm birth <34 wks RR 0.84 (0.73 to 0.97) RR 0.91 (0.82 to 1.00) P .39
SGA baby RR 0.68 (0.50 to 0.92) RR 0.95 (0.84 to 1.07) P .05
CI, confidence interval; RR, relative risk; SGA, small for gestational age.
Meher. IPD subgroup meta-analysis of antiplatelets for preeclampsia. Am J Obstet Gynecol 2017.
APPENDIX FIGURE 1
Preeclampsia: subgroups by gestational age at randomization
Meher. IPD subgroup meta-analysis of antiplatelets for preeclampsia. Am J Obstet Gynecol 2017.