BACKGROUND: Preeclampsia (PE) and fetal growth restriction (FGR) are major causes of perinatal death and handicap in survivors. Randomized clinical trials (RCTs) have reported that the risk of PE, severe PE and FGR 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: To estimate the impact of aspirin dosage on the prevention of PE, severe PE and FGR.
STUDY DESIGN: We performed a systematic review and meta-analysis of RCTs comparing the effect of daily aspirin or placebo (or no treatment) during pregnancy. We searched MEDLINE, EMBASE, Web of Science and Cochrane CENTRAL up to December 2015, and study bibliographies were reviewed. Authors were contacted to obtain additional data when needed. Relative risks (RR) for PE, severe PE and FGR were calculated with 95% confidence intervals (CI) using random-effect models. Dose-response effect was evaluated using meta-regression and reported as an adjusted R-square (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: Forty-five RCTs including a total of 20,909 pregnant women randomized to between 50 mg and 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 PE (RR: 0.57; 95%CI: 0.43-0.75; p<0.001; R2=44%; p=0.036), severe PE (RR: 0.47; 95%CI: 0.26-0.83; p=0.009; R2=100%; p=0.008) and FGR (RR: 0.56; 95%CI: 0.44-0.70; p<0.001; R2=100%; p=0.044), with higher dosages of aspirin being associated with greater reduction of the three 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 PE (RR: 0.81; 95%CI: 0.66-0.99; p=0.04) without relationship with aspirin dosage (R2= 0%; p=0.941). Aspirin initiated at >16 weeks was not associated with a risk reduction or a dose-response effect for severe PE (RR: 0.85; 95%CI: 0.64-1.14; p=0.28; R2=0%; p=0.838) and FGR (RR: 0.95; 95%CI: 0.86-1.05; p=0.34; R2=not available; p=0.563).
CONCLUSION: Prevention of PE and FGR using aspirin in early pregnancy is associated with a dose-response effect. Low-dose aspirin initiated after 16 week's gestation has a modest or no impact on the risk of PE, severe PE and FGR. Women at high-risk for those outcomes should be identified in early pregnancy.