Randomized Controlled Trials to Assess Optimal Aspirin Dose are Warranted.

We thank Drs Ghesquiere, Demuth, and Bujold for their interest in our recent clinical opinion entitled “Low-dose aspirin therapy for the prevention of preeclampsia: time to reconsider our recommendations?” The authors suggest that a randomized trial comparing 81 vs 162 mg of aspirin for the prevention of preeclampsia is ethically challenging and suggest instead a trial comparing 100 vs 162 mg of aspirin would be preferable. We do not agree with the author’s assessment that there is definitive evidence indicating that only aspirin doses >100 mg are effective at reducing the risk of preeclampsia. Their argument is based on the results of meta-analyses. It is imperative to carefully evaluate meta-analyses, which are known to have limitations and susceptibility to bias, to avoid potentially misleading conclusions. The quality of any meta-analysis is dependent on the studies included and multiple subgroup analyses increase susceptibility to bias.1Meher S. Alfirevic Z. Aspirin for pre-eclampsia: beware of subgroup meta-analysis.Ultrasound Obstet Gynecol. 2013; 41: 479-485Crossref PubMed Scopus (21) Google Scholar In their letter, Ghesquiere et al2Ghesquiere L. Guerby P. Marchant I. et al.Comparing aspirin 75 to 81 mg vs 150 to 162 mg for prevention of preterm preeclampsia: systematic review and meta-analysis.Am J Obstet Gynecol MFM. 2023; 5101000Abstract Full Text Full Text PDF Scopus (0) Google Scholar cited 3 meta-analyses that they published between 2017 and 2023.3Roberge S. Bujold E. Nicolaides K.H. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis.Am J Obstet Gynecol. 2018; 218: 287-293.e1Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar,4Roberge 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.Am J Obstet Gynecol. 2017; 216: 110-120.e6Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar In the 2017 meta-analysis, the authors reported that they were unable to determine the optimal dose of aspirin based on the meta-regression, as the number of participants per subgroups was too small and unexplained heterogeneity existed in some subgroups.4Roberge 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.Am J Obstet Gynecol. 2017; 216: 110-120.e6Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar In the 2018 meta-analysis, 8 of 16 included studies were considered to be of poor or uncertain quality.3Roberge S. Bujold E. Nicolaides K.H. Aspirin for the prevention of preterm and term preeclampsia: systematic review and metaanalysis.Am J Obstet Gynecol. 2018; 218: 287-293.e1Abstract Full Text Full Text PDF PubMed Scopus (327) Google Scholar The assessment of aspirin doses <100 and >100 mg was subgroup analyses, which did not include the performance of an interaction test, the most reliable statistical approach for subgroup treatment interaction effect.1Meher S. Alfirevic Z. Aspirin for pre-eclampsia: beware of subgroup meta-analysis.Ultrasound Obstet Gynecol. 2013; 41: 479-485Crossref PubMed Scopus (21) Google Scholar The 2023 meta-analysis comparing 75 to 81 mg of aspirin with 150 to 162 mg of asipirin suggested that the higher doses reduced the risk of preterm preeclampsia.2Ghesquiere L. Guerby P. Marchant I. et al.Comparing aspirin 75 to 81 mg vs 150 to 162 mg for prevention of preterm preeclampsia: systematic review and meta-analysis.Am J Obstet Gynecol MFM. 2023; 5101000Abstract Full Text Full Text PDF Scopus (0) Google Scholar This analysis included only 4 trials with 552 patients, 3 of the trials were noted to have high or unclear risk of bias, and the authors concluded that the lack of large, high-quality studies limited their results.2Ghesquiere L. Guerby P. Marchant I. et al.Comparing aspirin 75 to 81 mg vs 150 to 162 mg for prevention of preterm preeclampsia: systematic review and meta-analysis.Am J Obstet Gynecol MFM. 2023; 5101000Abstract Full Text Full Text PDF Scopus (0) Google Scholar Meta-analyses performed by other groups that reached opposite conclusions were not mentioned by the authors. A 2022 meta-analysis demonstrated that an aspirin dose of 75 mg/day had a better protective effect than other aspirin doses, whereas an individual patient data meta-analysis published in 2007 noted no evidence that aspirin doses >75 mg were superior to lower doses for reducing the risk of preeclampsia.5Wang Y. Guo X. Obore N. Ding H. Wu C. Yu H. Aspirin for the prevention of preeclampsia: a systematic review and meta-analysis of randomized controlled studies.Front Cardiovasc Med. 2022; 9936560Google Scholar,6Askie L.M. Duley L. Henderson-Smart D.J. Stewart L.A. PARIS Collaborative GroupAntiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data.Lancet. 2007; 369: 1791-1798Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar Given the lack of conclusive and robust evidence, we believe that randomized control trials comparing 162 vs 81 mg of aspirin daily for the prevention of preeclampsia are warranted. Optimal dose of aspirin for the prevention of preterm preeclampsiaAmerican Journal of Obstetrics & GynecologyPreviewIt was with great interest that we read the narrative review by Horgan et al1 reporting the difference between scientific evidence and clinical recommendations regarding the optimal dose of aspirin for the prevention of preeclampsia. Based on the meta-analysis by Roberge et al,2 it seems clear that the effective dose for the prevention of preterm preeclampsia would be ≥100 mg per day, with the greatest beneficial effects being observed in randomized trials using a dose of 150 mg per day. Full-Text PDF