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Meta-analysis on the effect of aspirin use for prevention of preeclampsia on placental abruption and antepartum hemorrhage

Published:January 03, 2018DOI:https://doi.org/10.1016/j.ajog.2017.12.238

      Objective Data

      Impaired placentation in the first 16 weeks of pregnancy is associated with increased risk of subsequent development of preeclampsia, birth of small-for-gestational-age neonates, and placental abruption. Previous studies reported that prophylactic use of aspirin reduces the risk of preeclampsia and small-for-gestational-age neonates with no significant effect on placental abruption. However, meta-analyses of randomized controlled trials that examined the effect of aspirin in relation to gestational age at onset of therapy and dosage of the drug reported that significant reduction in the risk of preeclampsia and small-for-gestational-age neonates is achieved only if the onset of treatment is at ≤16 weeks of gestation and the daily dosage of the drug is ≥100 mg.

      Study

      We aimed to estimate the effect of aspirin on the risk of placental abruption or antepartum hemorrhage in relation to gestational age at onset of therapy and the dosage of the drug.

      Study Appraisal and Synthesis Methods

      To perform a systematic review and meta-analysis of randomized controlled trials that evaluated the prophylactic effect of aspirin during pregnancy, we used PubMed, Cinhal, Embase, Web of Science and Cochrane library from 1985 to September 2017. Relative risks of placental abruption or antepartum hemorrhage with their 95% confidence intervals were calculated with the use of random effect models. Analyses were stratified according to daily dose of aspirin (<100 and ≥100 mg) and the gestational age at the onset of therapy (≤16 and >16 weeks of gestation) and compared with the use of subgroup difference analysis.

      Results

      The entry criteria were fulfilled by 20 studies on a combined total of 12,585 participants. Aspirin at a dose of <100 mg per day had no impact on the risk of placental abruption or antepartum hemorrhage, irrespective of whether it was initiated at ≤16 weeks of gestation (relative risk, 1.11; 95% confidence interval, 0.52–2.36) or at >16 weeks of gestation (relative risk, 1.32; 95% confidence interval, 0.73–2.39). At ≥100 mg per day, aspirin was not associated with a significant change on the risk of placental abruption or antepartum hemorrhage, whether the treatment was initiated at ≤16 weeks of gestation (relative risk, 0.62, 95% confidence interval, 0.31–1.26), or at >16 weeks of gestation (relative risk, 2.08; 95% confidence interval, 0.86–5.06), but the difference between the subgroups was significant (P=.04).

      Conclusion

      Aspirin at a daily dose of ≥100 mg for prevention of preeclampsia that is initiated at ≤16 weeks of gestation, rather than >16 weeks, may decrease the risk of placental abruption or antepartum hemorrhage.

      Key words

      Impaired placentation in the first 16 weeks of pregnancy is associated with increased risk of the subsequent development of preeclampsia, birth of small-for-gestational-age neonates, and placental abruption.
      • Brosens I.
      • Pijnenborg R.
      • Vercruysse L.
      • Romero R.
      The “Great Obstetrical Syndromes” are associated with disorders of deep placentation.
      • Brosens I.
      • Benagiano G.
      • Brosens J.J.
      The potential perinatal origin of placentation disorders in the young primigravida.
      • Ananth C.V.
      Ischemic placental disease: a unifying concept for preeclampsia, intrauterine growth restriction, and placental abruption.
      • Fisher S.J.
      Why is placentation abnormal in preeclampsia?.
      • Ogge G.
      • Chaiworapongsa T.
      • Romero R.
      • et al.
      Placental lesions associated with maternal underperfusion are more frequent in early-onset than in late-onset preeclampsia.
      • De Wolf F.
      • De Wolf-Peeters C.
      • Brosens I.
      • Robertson W.B.
      The human placental bed: electron microscopic study of trophoplastic invasion of spiral arteries.
      Numerous randomized controlled trials have investigated the potential value of prophylactic use of low-dose aspirin in prevention of preeclampsia; an early meta-analysis reported that the risk of preeclampsia and small for gestational age is reduced by approximately 10%.
      • Askie L.M.
      • Duley L.
      • Henderson-Smart D.J.
      • Stewart L.A.
      Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data.
      A recent individual patient meta-analysis by the same group reported that this modest reduction in risk was unrelated to the gestational age at onset of therapy (<16 vs ≥16 weeks of gestation) or a daily dose of aspirin (≤75 vs >75 mg).
      • Meher S.
      • Duley L.
      • Hunter K.
      • Askie L.
      Antiplatelet therapy before or after 16 weeks’ gestation for preventing preeclampsia: an individual participant data meta-analysis.
      In contrast, other meta-analyses reported that the use of aspirin has a major effect on both preeclampsia and small for gestational age with a greater than 50% reduction in risk, provided that the onset of therapy is ≤16 weeks of gestation and the daily dose of the drug is ≥100 mg; onset of therapy at >16 weeks or daily dose of <100 mg has no significant effect.
      • Roberge S.
      • Bujold E.
      • Nicolaides K.
      Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis.
      • Roberge S.
      • Nicolaides K.
      • Demers S.
      • Hyett J.
      • Chaillet N.
      • Bujold E.
      The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.
      • Bujold E.
      • Roberge S.
      • Lacasse Y.
      • et al.
      Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.
      These results were confirmed by the findings of a recent large multicenter randomized trial (ASPRE) that demonstrated that aspirin (150 mg per day) from 11–14 weeks to 36 weeks of gestation was associated with a >60% reduction in risk of preterm preeclampsia.
      • Rolnik D.L.
      • Wright D.
      • Poon L.
      • et al.
      Aspirin versus placebo in pregnancies at high risk of preterm preeclampsia.
      Placental abruption is a major cause of perinatal death and maternal morbidity.
      • Salihu H.M.
      • Bekan B.
      • Aliyu M.H.
      • Rouse D.J.
      • Kirby R.S.
      • Alexander G.R.
      Perinatal mortality associated with abruptio placenta in singletons and multiples.
      • Ananth C.V.
      • Lavery J.A.
      • Vintzileos A.M.
      • et al.
      Severe placental abruption: clinical definition and associations with maternal complications.
      An early randomized trial on the use of aspirin (60 mg per day) for the prevention of preeclampsia reported that aspirin use was associated with a significant increase in risk of placental abruption, which was attributed to the antiplatelet effect of the drug.
      • Sibai B.M.
      • Caritis S.N.
      • Thom E.
      • et al.
      Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women: The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      Subsequent meta-analyses have reported that aspirin use for prevention of preeclampsia was not associated with increased risk of placental abruption; however, in these meta-analyses the effect of aspirin was not examined in relation to gestational age at onset of therapy or the daily dose of the drug.
      • Askie L.M.
      • Duley L.
      • Henderson-Smart D.J.
      • Stewart L.A.
      Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data.
      • Henderson J.T.
      • Whitlock E.P.
      • O’Connor E.
      • Senger C.A.
      • Thompson J.H.
      • Rowland M.G.
      Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force.
      The objective of this systematic review and meta-analysis was to estimate the effect of aspirin on the risk of placental abruption or antepartum hemorrhage, in relation to gestational age at onset of therapy and the dose of the drug.

      Method

      This is a systematic review and meta-analysis of randomized controlled trials that includes studies that recruited women for the prevention of preeclampsia with the use of aspirin. Treatment includes aspirin or dipyridamole compared with placebo or no treatment. Studies were excluded if pregnant women started treatment before pregnancy or had preeclampsia or fetal growth restriction at randomization.

      Research strategy

      Keywords and MeSH terms related with aspirin for preeclampsia were searched in Embase, PubMed, Cinahl, Web of science, Cochrane CENTRAL library from 1985 to September 2017. No language restrictions were applied.

      Selection of the articles

      Titles were selected for first screening, and abstracts were then reviewed by 2 independent reviewers (S.R., E.B.). All eligible studies were then fully evaluated by the same reviewers; disagreements were resolved by the opinion of a third party (K.N.). Studies that reported placental abruption or antepartum hemorrhage were included in the final analysis.

      Quality evaluation

      The quality of this meta-analysis was assessed with a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) tool,
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      and the quality of each included trial was assessed by the Cochrane Handbook.

      Cochrane Handbook for Systematic Reviews of Interventions In: Higgins J, Green S, editors. The Cochrane Collaboration; 2011. Available at: http://handbook.cochrane.org/. Accessed October 25, 2017.

      Analysis

      Subgroup analyses were performed in regards to the dose of aspirin (<100 and ≥100 mg) and the gestational age at onset of treatment (≤16 and >16 weeks).
      • Roberge S.
      • Nicolaides K.
      • Demers S.
      • Hyett J.
      • Chaillet N.
      • Bujold E.
      The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.
      • Pijnenborg R.
      • Dixon G.
      • Robertson W.B.
      • Brosens I.
      Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy.
      Because there are only 2 groups of comparison, subgroup analysis with random effects will be performed.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      The cut-offs of 16 weeks of gestation and 100 mg of the drug were selected because previous meta-analyses reported that aspirin is effective in the prevention of preeclampsia only if the onset of therapy is ≤16 weeks of gestation and if the daily dose of the drug is ≥100 mg.
      • Roberge S.
      • Bujold E.
      • Nicolaides K.
      Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis.
      • Roberge S.
      • Nicolaides K.
      • Demers S.
      • Hyett J.
      • Chaillet N.
      • Bujold E.
      The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.
      • Bujold E.
      • Roberge S.
      • Lacasse Y.
      • et al.
      Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.
      Results was reported by relative risks (RR), calculated with their 95% confidence intervals (CI), with the use of random effects.
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      Sensitivity analyses were performed to evaluate the effect of aspirin alone.
      Publication bias was assessed with funnel plots. Higgins I2 was calculated for heterogeneity and was considered to be high if the score was ≥50%.
      • Higgins J.
      • Thompson S.
      • Deeks J.
      • Altman D.
      Statistical heterogeneity in systematic reviews of clinical trials: a critical appraisal of guidelines and practice.
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      Analyses were carried out with Review Manager software (version 5.3; Nordic Cochrane Center, Cochrane Collaboration, Copenhagen, Denmark).

      Results

      The literature search identified 7143 citations: 161 were reviewed, and 20 trials on a combined total of 12,585 participants met the inclusion criteria (Table 1; Figure 1).
      • Rolnik D.L.
      • Wright D.
      • Poon L.
      • et al.
      Aspirin versus placebo in pregnancies at high risk of preterm preeclampsia.
      • Sibai B.M.
      • Caritis S.N.
      • Thom E.
      • et al.
      Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women: The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

      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. Paper presented at: Proceedings of 9th International Congress, International Society for the Study of Hypertension; March 15-18, 1994; Sydney, Australia.

      • Ayala D.E.
      • Ucieda R.
      • Hermida R.C.
      Chronotherapy with low-dose aspirin for prevention of complications in pregnancy.
      • Beaufils M.
      • Uzan S.
      • Donsimoni R.
      • Colau J.C.
      Prevention of pre-eclampsia by early antiplatelet therapy.
      • Byaruhanga R.N.
      • Chipato T.
      • Rusakaniko S.
      A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia.
      • Caritis S.
      • Sibai B.
      • Hauth J.
      • et al.
      Low-dose aspirin to prevent preeclampsia in women at high risk: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      • Davies N.
      • Gazvani M.
      • Farquharson R.
      • Walkinshaw S.
      Low-dose aspirin in the prevention of hypertensive disorders of pregnancy in relatively low-risk nulliparous women.
      • Gallery E.
      • Ross M.
      • Hawkins M.
      • Leslie G.
      • Gyory A.
      Low-dose aspirin in high-risk pregnancy.
      • Golding J.
      A randomised trial of low dose aspirin for primiparae in pregnancy: The Jamaica Low Dose Aspirin Study Group.
      • Hermida R.C.
      • Ayala D.E.
      • Iglesias M.
      • et al.
      Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women.
      • Hauth J.C.
      • Goldenberg R.L.
      • Parker C.R.J.
      • et al.
      Low-dose aspirin therapy to prevent preeclampsia.
      • Hauth J.C.
      • Goldenberg R.L.
      • Parker Jr., C.R.
      • Cutter G.R.
      • Cliver S.P.
      Low-dose aspirin: lack of association with an increase in abruptio placentae or perinatal mortality.
      • Liu F.
      • Yang H.
      • Li G.
      • Zou K.
      • Chen Y.
      Effect of a small dose of aspirin on quantitative test of 24-h urinary protein in patients with hypertension in pregnancy.
      • McParland P.
      • Pearce J.M.
      • Chamberlain G.V.
      Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension.
      • Morris J.M.
      • Fay R.A.
      • Ellwood D.A.
      • Cook C.M.
      • Devonald K.J.
      A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow.
      • Schiff E.
      • Peleg E.
      • Goldenberg M.
      • et al.
      The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies.
      • Wallenburg H.C.
      • Dekker G.A.
      • Makovitz J.W.
      • Rotmans P.
      Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae.
      • Yu C.K.
      • Papageorghiou A.T.
      • Parra M.
      • Palma Dias R.
      • Nicolaides K.H.
      Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation.
      • Zhao Y.M.
      • Xiao L.P.
      • Hu H.
      • Yang X.N.
      • Xu Y.Q.
      • Guo L.M.
      Low-dose aspirin prescribed at bed time for the prevention of pre-eclampsia in high-risk pregnant women.
      • Zimmermann P.
      • Eirio V.
      • Koskinen J.
      • et al.
      Effect of low dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries: a prospective longitudinal study on a high risk population with persistent notch in the uterine arteries.
      In 2 of the included trials, the data on onset of therapy (≤16 and >16 weeks of gestation) were not included in the original publications, but they were provided by the authors.
      • Sibai B.M.
      • Caritis S.N.
      • Thom E.
      • et al.
      Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women: The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      • Caritis S.
      • Sibai B.
      • Hauth J.
      • et al.
      Low-dose aspirin to prevent preeclampsia in women at high risk: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      In 15 of the 20 studies, the reported outcome was placental abruption,
      • Rolnik D.L.
      • Wright D.
      • Poon L.
      • et al.
      Aspirin versus placebo in pregnancies at high risk of preterm preeclampsia.
      • Sibai B.M.
      • Caritis S.N.
      • Thom E.
      • et al.
      Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women: The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.

      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. Paper presented at: Proceedings of 9th International Congress, International Society for the Study of Hypertension; March 15-18, 1994; Sydney, Australia.

      • Beaufils M.
      • Uzan S.
      • Donsimoni R.
      • Colau J.C.
      Prevention of pre-eclampsia by early antiplatelet therapy.
      • Byaruhanga R.N.
      • Chipato T.
      • Rusakaniko S.
      A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia.
      • Caritis S.
      • Sibai B.
      • Hauth J.
      • et al.
      Low-dose aspirin to prevent preeclampsia in women at high risk: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      • Davies N.
      • Gazvani M.
      • Farquharson R.
      • Walkinshaw S.
      Low-dose aspirin in the prevention of hypertensive disorders of pregnancy in relatively low-risk nulliparous women.
      • Hauth J.C.
      • Goldenberg R.L.
      • Parker C.R.J.
      • et al.
      Low-dose aspirin therapy to prevent preeclampsia.
      • Liu F.
      • Yang H.
      • Li G.
      • Zou K.
      • Chen Y.
      Effect of a small dose of aspirin on quantitative test of 24-h urinary protein in patients with hypertension in pregnancy.
      • McParland P.
      • Pearce J.M.
      • Chamberlain G.V.
      Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension.
      • Schiff E.
      • Peleg E.
      • Goldenberg M.
      • et al.
      The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies.
      • Wallenburg H.C.
      • Dekker G.A.
      • Makovitz J.W.
      • Rotmans P.
      Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae.
      • Yu C.K.
      • Papageorghiou A.T.
      • Parra M.
      • Palma Dias R.
      • Nicolaides K.H.
      Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation.
      • Zhao Y.M.
      • Xiao L.P.
      • Hu H.
      • Yang X.N.
      • Xu Y.Q.
      • Guo L.M.
      Low-dose aspirin prescribed at bed time for the prevention of pre-eclampsia in high-risk pregnant women.
      • Zimmermann P.
      • Eirio V.
      • Koskinen J.
      • et al.
      Effect of low dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries: a prospective longitudinal study on a high risk population with persistent notch in the uterine arteries.
      and in 5 studies, the outcome was antepartum hemorrhage.
      • Ayala D.E.
      • Ucieda R.
      • Hermida R.C.
      Chronotherapy with low-dose aspirin for prevention of complications in pregnancy.
      • Gallery E.
      • Ross M.
      • Hawkins M.
      • Leslie G.
      • Gyory A.
      Low-dose aspirin in high-risk pregnancy.
      • Golding J.
      A randomised trial of low dose aspirin for primiparae in pregnancy: The Jamaica Low Dose Aspirin Study Group.
      • Hermida R.C.
      • Ayala D.E.
      • Iglesias M.
      • et al.
      Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women.
      • Morris J.M.
      • Fay R.A.
      • Ellwood D.A.
      • Cook C.M.
      • Devonald K.J.
      A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow.
      Table 1Characteristics of trials included in the meta-analysis
      StudyNInclusion criteriaCompliance
      Reported as percentage of women who took a certain percentage of the total number of prescribed pills
      Intervention
      AspirinControlOnset (wk)
      Zimmermann et al, 1997
      • Zimmermann P.
      • Eirio V.
      • Koskinen J.
      • et al.
      Effect of low dose aspirin treatment on vascular resistance in the uterine, uteroplacental, renal and umbilical arteries: a prospective longitudinal study on a high risk population with persistent notch in the uterine arteries.
      26Abnormal uterine artery Doppler resultsNot reported50 mgNo treatment22–24
      Caritis et al, 1998
      • Caritis S.
      • Sibai B.
      • Hauth J.
      • et al.
      Low-dose aspirin to prevent preeclampsia in women at high risk: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      2503History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      79% of women took >80% of pills60 mgPlacebo13–26
      Hauth et al, 1993
      • Hauth J.C.
      • Goldenberg R.L.
      • Parker C.R.J.
      • et al.
      Low-dose aspirin therapy to prevent preeclampsia.
      • Hauth J.C.
      • Goldenberg R.L.
      • Parker Jr., C.R.
      • Cutter G.R.
      • Cliver S.P.
      Low-dose aspirin: lack of association with an increase in abruptio placentae or perinatal mortality.
      604Nulliparity80% of aspirin group compliant60 mgPlacebo24
      Sibai et al, 1993
      • Sibai B.M.
      • Caritis S.N.
      • Thom E.
      • et al.
      Prevention of preeclampsia with low-dose aspirin in healthy, nulliparous pregnant women: The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
      2911Nulliparity73% of women took >80% of pills60 mgPlacebo13–25
      Golding 1998
      • Golding J.
      A randomised trial of low dose aspirin for primiparae in pregnancy: The Jamaica Low Dose Aspirin Study Group.
      2547Nulliparity66% of women were compliant60 mgPlacebo12–32
      Schiff et al, 1989
      • Schiff E.
      • Peleg E.
      • Goldenberg M.
      • et al.
      The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies.
      65History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      with positive roll-over test
      Not reported100 mgPlacebo28–29
      Wallenburg et al, 1986
      • Wallenburg H.C.
      • Dekker G.A.
      • Makovitz J.W.
      • Rotmans P.
      Low-dose aspirin prevents pregnancy-induced hypertension and pre-eclampsia in angiotensin-sensitive primigravidae.
      44Positive angiotensin II sensitivity testNot reported60 mgPlacebo28
      Byaruhanga et al, 1998
      • Byaruhanga R.N.
      • Chipato T.
      • Rusakaniko S.
      A randomized controlled trial of low-dose aspirin in women at risk from pre-eclampsia.
      230History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      86% of women took >80% of pills75 mgPlacebo20–28
      McParland et al, 1990
      • McParland P.
      • Pearce J.M.
      • Chamberlain G.V.
      Doppler ultrasound and aspirin in recognition and prevention of pregnancy-induced hypertension.
      100Nulliparity with abnormal uterine artery Doppler result26% of women took 100%, median number of tablets missing=275 mgPlacebo24
      Zhao et al, 2012
      • Zhao Y.M.
      • Xiao L.P.
      • Hu H.
      • Yang X.N.
      • Xu Y.Q.
      • Guo L.M.
      Low-dose aspirin prescribed at bed time for the prevention of pre-eclampsia in high-risk pregnant women.
      237History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      Not reported75 mgPlacebo13–16
      Liu et al, 2017
      • Liu F.
      • Yang H.
      • Li G.
      • Zou K.
      • Chen Y.
      Effect of a small dose of aspirin on quantitative test of 24-h urinary protein in patients with hypertension in pregnancy.
      224History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      100% of women were compliant50, 75, 100 mgNo treatment9–16
      August et al, 1994

      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. Paper presented at: Proceedings of 9th International Congress, International Society for the Study of Hypertension; March 15-18, 1994; Sydney, Australia.

      49History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      Not reported100 mgPlacebo13–15
      Ayala et al, 2013
      • Ayala D.E.
      • Ucieda R.
      • Hermida R.C.
      Chronotherapy with low-dose aspirin for prevention of complications in pregnancy.
      350History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      100% of women took >95% of pills100 mgPlacebo12–16
      Morris et al, 1996
      • Morris J.M.
      • Fay R.A.
      • Ellwood D.A.
      • Cook C.M.
      • Devonald K.J.
      A randomized controlled trial of aspirin in patients with abnormal uterine artery blood flow.
      102Nulliparity with abnormal umbilical artery Doppler resultNot reported100 mgPlacebo17–19
      Davies et al, 1995
      • Davies N.
      • Gazvani M.
      • Farquharson R.
      • Walkinshaw S.
      Low-dose aspirin in the prevention of hypertensive disorders of pregnancy in relatively low-risk nulliparous women.
      118NulliparityCompliance was excellent75 mgPlacebo18
      Gallery et al, 1997
      • Gallery E.
      • Ross M.
      • Hawkins M.
      • Leslie G.
      • Gyory A.
      Low-dose aspirin in high-risk pregnancy.
      108History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      ≥80% of women were compliant100 mgPlacebo17–19
      Hermida et al, 1997
      • Hermida R.C.
      • Ayala D.E.
      • Iglesias M.
      • et al.
      Time-dependent effects of low-dose aspirin administration on blood pressure in pregnant women.
      100History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      100% of women were compliant100 mgPlacebo12–16
      Rolnik et al, 2017
      • Rolnik D.L.
      • Wright D.
      • Poon L.
      • et al.
      Aspirin versus placebo in pregnancies at high risk of preterm preeclampsia.
      1620High risk based on combined screening
      Combination of maternal risk factors, serum placental growth factor and pregnancy associated plasma protein-A, mean arterial pressure, and uterine artery pulsatility index
      80% of women took >90% of pills150 mgPlacebo11–14
      Beaufils et al, 1985
      • Beaufils M.
      • Uzan S.
      • Donsimoni R.
      • Colau J.C.
      Prevention of pre-eclampsia by early antiplatelet therapy.
      93History risk factor
      Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      Not reported150 mg
      With dipyridamole 300 mg.
      Placebo14
      Yu et al, 2003
      • Yu C.K.
      • Papageorghiou A.T.
      • Parra M.
      • Palma Dias R.
      • Nicolaides K.H.
      Randomized controlled trial using low-dose aspirin in the prevention of pre-eclampsia in women with abnormal uterine artery Doppler at 23 weeks’ gestation.
      554Abnormal uterine artery Doppler resultNot reported150 mgPlacebo22–24
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.
      a Reported as percentage of women who took a certain percentage of the total number of prescribed pills
      b Includes history of chronic hypertension, cardiovascular or endocrine disease, previous pregnancy hypertension, or fetal growth restriction
      c Combination of maternal risk factors, serum placental growth factor and pregnancy associated plasma protein-A, mean arterial pressure, and uterine artery pulsatility index
      d With dipyridamole 300 mg.
      Figure thumbnail gr1
      Figure 1Selection of the included articles
      Selection tree for selection of included articles.
      PE, preeclampsia.
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.
      All but 1 of the included studies were considered to be of good or unclear quality; 1 study was considered at high risk of bias
      • Zhao Y.M.
      • Xiao L.P.
      • Hu H.
      • Yang X.N.
      • Xu Y.Q.
      • Guo L.M.
      Low-dose aspirin prescribed at bed time for the prevention of pre-eclampsia in high-risk pregnant women.
      because, in 20% of cases, there was loss to follow-up evaluation (Figure 2). The heterogeneity between the studies was low (I2=0–29%). Although the distribution of studies in the funnel plots appears to be good, the small number of studies cannot exclude the possibility of publication bias (Figure 3).
      Figure thumbnail gr2
      Figure 2Risk of bias graph
      Assessment of risk of bias in studies that were included according to the Cochrane handbook.
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.
      Figure thumbnail gr3
      Figure 3Funnel plot on the effect of aspirin on placental abruption or antepartum hemorrhage
      Funnel plot to evaluate the presence of publication bias.
      SE, standard error.
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.
      In the case of aspirin at a daily dose of <100 mg (Table 2; Figure 4), there was no significant effect on risk of placental abruption or antepartum hemorrhage, irrespective of the gestational age at onset of treatment, and no significant difference between the subgroup with onset at ≤16 weeks and those with onset at >16 weeks (P=.72).
      Table 2Risk of placental abruption or antepartum hemorrhage according to dose of aspirin and gestational age at onset of treatment
      Dosage/onsetTrialsParticipantsRandom effect, relative risk (95% confidence interval)P valueI2, %P value (difference between subgroups)
      <100 Mg1194611.20 (0.79–1.81).399.72
       ≤16 Wk416731.11 (0.52–2.36).790
       >16 Wk977881.32 (0.73–2.39).3529
      ≥100 Mg1031470.99 (0.57–1.73).980.04
      Significant at <.05.
       ≤16 Wk623180.62 (0.31–1.26).190
       >16 Wk48292.08 (0.86–5.06).110
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.
      a Significant at <.05.
      Figure thumbnail gr4
      Figure 4Forest plot on the effect of aspirin at a daily dose of <100 mg on placental abruption or antepartum hemorrhage
      Forest plot of effect of low-dose aspirin at a daily dose of <100 mg on risk of placental abruption or antepartum hemorrhage, subgrouped by gestational age at initiation of treatment. Only the first author of each study is given. Cochrane forest plots are commonly used in meta-analyses and details about diamond, size of square, etc. are not typically reported, including in AJOG.
      CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel.
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.
      In the case of aspirin at a daily dose of ≥100 mg (Table 2; Figure 5), onset of therapy at ≤16 weeks of gestation was associated with a nonsignificant reduction in the risk of placental abruption or antepartum hemorrhage (RR, 0.62; 95% CI, 0.31–1.26), whereas onset at >16 weeks of gestation was associated with a nonsignificant increase in the risk of placental abruption or antepartum hemorrhage (RR, 2.08; 95% CI, 0.86–5.06); the subgroup difference was significant (P=.04). After we excluded the study in which dipyridamole was used,
      • Beaufils M.
      • Uzan S.
      • Donsimoni R.
      • Colau J.C.
      Prevention of pre-eclampsia by early antiplatelet therapy.
      the same trends were observed (aspirin ≥100 mg per day; ≤16 weeks: RR, 0.71; 95% CI, 0.34–1.47; vs aspirin ≥100 mg per day; >16 weeks: RR, 2.08; 95% CI, 0.86–5.06), but the difference between subgroups was not significant (P=.07).
      Figure thumbnail gr5
      Figure 5Forest plot on the effect of aspirin at a daily dose of ≥100 mg on placental abruption or antepartum hemorrhage.
      Forest plot of effect of low-dose aspirin at a daily dose of ≥100 mg on risk of placental abruption or antepartum hemorrhage, subgrouped by gestational age at initiation of treatment. Only the first author of each study is given. Cochrane forest plot are commonly used in meta-analyses and details about diamond, size of square, etc. are not typically reported, including in AJOG.
      CI, confidence interval; df, degrees of freedom; M-H, Mantel-Haenszel.
      Roberge. Aspirin use and placental abruption. Am J Obstet Gynecol 2018.

      Comment

      Principal findings of this study

      The findings of this study suggest that aspirin at <100 mg per day does not influence the risk of placental abruption or antepartum hemorrhage, irrespective of the gestational age at onset of therapy. However, in the case of aspirin at ≥100 mg per day, we observed a significant difference in the risk of placental abruption or antepartum hemorrhage between women who started the treatment at ≤16 weeks of gestation and those who started at >16 weeks, with a nonsignificant tendency of benefit for the former and harm for the latter.

      Limitations of the study

      Data for placental abruption or antepartum hemorrhage in relation to dosage and timing of aspirin were reported in only 20 of the 65 trials that examined the effect of aspirin on the prevention of preeclampsia; consequently, in our meta-analysis, there is a potential risk of selection bias. Results are also limited by the low prevalence of placental abruption or antepartum hemorrhage, which was reported in only 173 of the 11,585 participants (1.5%) in the included trials.
      Placental abruption or antepartum hemorrhage was a secondary outcome in all the included trials, and, although aspirin did not have a significant effect on the risk of placental abruption or antepartum hemorrhage, none of the trials was powered adequately for such an outcome. Our approach for further subdivision of the study population according to dose and timing of onset of therapy could have resulted in even greater reduction of power to demonstrate significant effects. However, in the context of aspirin use for the prevention of preeclampsia, our previous subgroup analyses had demonstrated the importance of subdividing the population according to both the dose and timing of onset of therapy.
      • Roberge S.
      • Nicolaides K.
      • Demers S.
      • Hyett J.
      • Chaillet N.
      • Bujold E.
      The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.
      • Bujold E.
      • Roberge S.
      • Lacasse Y.
      • et al.
      Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.
      In the ASPRE trial, the beneficial effect of aspirin in the prevention of preterm preeclampsia appeared to depend on compliance.
      • Wright D.
      • Poon L.C.
      • Rolnik D.L.
      • et al.
      Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia.
      In our meta-analysis, it was not possible to evaluate the effect of compliance on the risk of placental abruption or antepartum hemorrhage because, in 8 of the 20 trials, compliance was not reported and because 10 of the remaining 12 trials did not report results separately according to compliance.

      Clinical implications of the study

      National guidelines recommend that women who were identified by their demographic characteristics and medical history as being at high-risk for development of preeclampsia should be advised to take aspirin at a daily dose that varies between 75 and 80 mg, depending on the country.
      • Henderson J.T.
      • Whitlock E.P.
      • O’Connor E.
      • Senger C.A.
      • Thompson J.H.
      • Rowland M.G.
      Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force.

      NICE Clinical Guideline. National Collaborating Centre for Women’s and Children’s Health. Commissioned by the National Institute for Health and Clinical Excellence. Hypertension in pregnancy: The management of hypertensive disorders during pregnancy. CG107. Available at: http://guidance.nice.org.uk/CG107. 2010. Accessed November 7, 2017.

      American College of Obstetricians and Gynecologists
      Task Force on Hypertension in Pregnancy; Hypertension, Pregnancy-Induced-Practice Guideline, American College of Obstetrician and Gynecologist.
      However, on the basis of the results of our meta-analyses that aspirin is effective in reducing the risk of preeclampsia only if the daily dose is ≥100 mg and with the results of the ASPRE trial,
      • Roberge S.
      • Bujold E.
      • Nicolaides K.
      Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis.
      • Roberge S.
      • Nicolaides K.
      • Demers S.
      • Hyett J.
      • Chaillet N.
      • Bujold E.
      The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.
      • Rolnik D.L.
      • Wright D.
      • Poon L.
      • et al.
      Aspirin versus placebo in pregnancies at high risk of preterm preeclampsia.
      it is likely that the recommended daily dose of aspirin will become 150 mg. It would then be important to emphasize that, although such therapy is beneficial if treatment is initiated before 16 weeks of gestation, it may increase the risk of abruption or antepartum hemorrhage without reducing the risk of preeclampsia if treatment is initiated after 16 weeks of gestation.
      Placental abruption has been considered, together with preeclampsia, to be the consequence of impaired placentation.
      • Neiger R.
      Long-term effects of pregnancy complications on maternal health: a review.
      • Farr A.
      • Chervenak F.A.
      • McCullough L.B.
      • Baergen R.N.
      • Grunebaum A.
      Human placentophagy: a review.
      In this respect, aspirin administration in women at increased risk of impaired placentation actually may lead to a reduction in the risk of abruption, as it does for preeclampsia, provided the dose is ≥100 mg and the gestational age at onset of the treatment is ≤16 weeks of gestation. Placentation is completed mostly by 18 weeks of gestation;
      • Pijnenborg R.
      • Dixon G.
      • Robertson W.B.
      • Brosens I.
      Trophoblastic invasion of human decidua from 8 to 18 weeks of pregnancy.
      if the mechanism whereby aspirin reduces the risk of preeclampsia is mediated by improving placentation, it should not be surprising that aspirin therapy that is initiated at >16 weeks of gestation is not beneficial. In cases of persistent abnormal placentation, the use of aspirin at ≥100 mg per day, through its antiplatelet proprieties, could increase the risk of hemorrhage and abruption. It is therefore doubtful that universal use of aspirin is beneficial, and it may actually be harmful.
      • Mone F.
      • Mulcahy C.
      • McParland P.
      • McAuliffe F.M.
      Should we recommend universal aspirin for all pregnant women?.

      Conclusion

      This study demonstrated that the prophylactic use of aspirin at a daily dose of ≥100 mg may have different effects on the risk of placental abruption or antepartum hemorrhage, depending on the gestational age at onset of treatment; if the onset of treatment is at ≤16 weeks of gestation, rather than >16 weeks, the risk is decreased.

      Acknowledgment

      We acknowledge the Maternal-Fetal Medicine Units (MFMU) Network for the data that they provided and Amelie Boutin for the statistical review.

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