Comparative effectiveness of lower-dose vs higher-dose aspirin for preeclampsia prevention: a systematic review and meta-analysis of randomized controlled trials

Abstract

OBJECTIVE

To determine whether higher-dose aspirin (150–162 mg/d) reduces preeclampsia risk compared with lower-dose aspirin (75–81 mg/d) in pregnant women at elevated risk, using pooled evidence from all available head-to-head randomized controlled trials.

DATA SOURCES

PubMed/MEDLINE, Cochrane CENTRAL, Embase, Scopus, and ClinicalTrials.gov were searched from inception through April 27, 2026.

STUDY ELIGIBILITY CRITERIA

Parallel-group randomized controlled trials comparing at least two aspirin dose arms (head-to-head dose comparison) in pregnant women at elevated risk for preeclampsia, with a binary preeclampsia outcome reported. Aspirin-vs-placebo trials were excluded.

STUDY APPRAISAL AND SYNTHESIS METHODS

Log odds ratios were pooled using restricted maximum likelihood (REML) estimation with the Hartung–Knapp–Sidik–Jonkman (HKSJ) correction. Risk of bias was assessed using the Cochrane RoB 2 tool; evidence certainty was graded using GRADE. Egger’s test, Duval–Tweedie trim-and-fill, and univariate meta-regression (geography, dose ratio, gestational age at initiation) were performed.

RESULTS

Six randomized controlled trials enrolling 1099 participants across five countries were included. REML+HKSJ pooled OR 1.93 (95% CI 0.84–4.42, P=.096; I²=64.9%), representing approximately 48% lower odds of preeclampsia with higher-dose aspirin, a clinically substantial effect size that did not reach conventional statistical significance, primarily due to limited sample size (N=1099) and substantial between-study heterogeneity. Egger’s test was significant (P=.010); trim-and-fill estimated three missing studies (adjusted OR 1.92, 95% CI 1.47–2.50). No significant dose advantage was seen in North American trials (OR 1.25, 95% CI 0.67–2.34). A safety signal for placental abruption was identified with higher-dose aspirin in one large trial (8 vs 0 events). GRADE certainty: Very Low.

CONCLUSION

Applying conservative statistical methods (REML+HKSJ), higher-dose aspirin (150–162 mg/d) was associated with approximately 48% lower odds of preeclampsia vs lower-dose aspirin (75–81 mg/d; OR 1.93), a clinically meaningful effect that did not reach conventional statistical significance (95% CI 0.84–4.42, P=.096) due to limited sample size and heterogeneity. Clinical significance and statistical significance must be considered independently; the magnitude of this effect warrants serious attention in guideline discussions. A placental abruption safety signal warrants further investigation. Larger, harmonized head-to-head trials with preterm preeclampsia as the primary endpoint are needed.