title: The role of aspirin dose on the prevention of preeclampsia and fetal growth restriction: systematic review and meta-analysis.
abstract: BACKGROUND
  Preeclampsia and fetal growth restriction are major causes of perinatal death and handicap in survivors. Randomized clinical trials have reported that the risk of preeclampsia, severe preeclampsia, and fetal growth restriction can be reduced by the prophylactic use of aspirin in high-risk women, but the appropriate dose of the drug to achieve this objective is not certain.
  
  
  OBJECTIVE
  We sought to estimate the impact of aspirin dosage on the prevention of preeclampsia, severe preeclampsia, and fetal growth restriction.
  
  
  METHODS
  We performed a systematic review and meta-analysis of randomized controlled trials comparing the effect of daily aspirin or placebo (or no treatment) during pregnancy. We searched MEDLINE, Embase, Web of Science, and Cochrane Central Register of Controlled Trials up to December 2015, and study bibliographies were reviewed. Authors were contacted to obtain additional data when needed. Relative risks for preeclampsia, severe preeclampsia, and fetal growth restriction were calculated with 95% confidence intervals using random-effect models. Dose-response effect was evaluated using meta-regression and reported as adjusted R2. Analyses were stratified according to gestational age at initiation of aspirin (≤16 and >16 weeks) and repeated after exclusion of studies at high risk of biases.
  
  
  RESULTS
  In all, 45 randomized controlled trials included a total of 20,909 pregnant women randomized to between 50-150 mg of aspirin daily. When aspirin was initiated at ≤16 weeks, there was a significant reduction and a dose-response effect for the prevention of preeclampsia (relative risk, 0.57; 95% confidence interval, 0.43-0.75; P < .001; R2, 44%; P = .036), severe preeclampsia (relative risk, 0.47; 95% confidence interval, 0.26-0.83; P = .009; R2, 100%; P = .008), and fetal growth restriction (relative risk, 0.56; 95% confidence interval, 0.44-0.70; P < .001; R2, 100%; P = .044) with higher dosages of aspirin being associated with greater reduction of the 3 outcomes. Similar results were observed after the exclusion of studies at high risk of biases. When aspirin was initiated at >16 weeks, there was a smaller reduction of preeclampsia (relative risk, 0.81; 95% confidence interval, 0.66-0.99; P = .04) without relationship with aspirin dosage (R2, 0%; P = .941). Aspirin initiated at >16 weeks was not associated with a risk reduction or a dose-response effect for severe preeclampsia (relative risk, 0.85; 95% confidence interval, 0.64-1.14; P = .28; R2, 0%; P = .838) and fetal growth restriction (relative risk, 0.95; 95% confidence interval, 0.86-1.05; P = .34; R2, not available; P = .563).
  
  
  CONCLUSIONS
  Prevention of preeclampsia and fetal growth restriction using aspirin in early pregnancy is associated with a dose-response effect. Low-dose aspirin initiated at >16 weeks' gestation has a modest or no impact on the risk of preeclampsia, severe preeclampsia, and fetal growth restriction. Women at high risk for those outcomes should be identified in early pregnancy.
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, United Kingdom.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Roberge
authors.affiliation: Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, United Kingdom.
authors.forename: Kypros
authors.initials: K
authors.lastname: Nicolaides
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada; Harris Birthright Research Center of Fetal Medicine, King's College Hospital, London, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Demers
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Central Clinical, University of Sydney, Sydney, Australia.
authors.forename: Jon
authors.initials: J
authors.lastname: Hyett
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada.
authors.forename: Nils
authors.initials: N
authors.lastname: Chaillet
authors.affiliation: Department of Obstetrics and Gynecology, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada. Electronic address: emmanuel.bujold@crchudequebec.ulaval.ca.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bujold
mesh_terms: D001241:Aspirin / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005317:Fetal Growth Retardation / Q000517:prevention & control*; D006801:Humans; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D011225:Pre-Eclampsia / Q000517:prevention & control*; D011247:Pregnancy; D012720:Severity of Illness Index
chemical_list: D010975:Platelet Aggregation Inhibitors; D001241:Aspirin
keywords: aspirin; fetal growth restriction; meta-analysis; meta-regression; preeclampsia; pregnancy; systematic review