Aspirin in preeclampsia prevention: a narrative Review of clinical and mechanistic evidence.

BACKGROUND

Low-dose aspirin reduces preterm preeclampsia, but its mechanisms remain uncertain because circulating concentrations of unchanged aspirin are substantially lower than those used in many experimental studies. This narrative review evaluates proposed mechanisms according to their clinical relevance and compatibility with prophylactic exposure.

METHODS

Evidence concerning platelet inhibition, placentation, inflammatory resolution, angiogenic regulation and epigenetic modification was narratively reviewed, with particular attention to experimental concentrations, model limitations and clinical pharmacological findings.

RESULTS

Clinical pharmacology most strongly supports irreversible platelet cyclooxygenase-1(COX-1) inhibition and sustained suppression of thromboxane A2 (TXA2) generation. These effects may improve uteroplacental perfusion and secondarily influence placental inflammation and endothelial regulation. Experimental studies suggest that aspirin may promote trophoblast migration and survival through protein kinase B (Akt), mitogen-activated protein kinase (MAPK) and cAMP response element-binding protein (CREB) signalling and attenuate nuclear factor kappa B (NF-κB) activation, but these effects were generally observed at concentrations exceeding clinical exposure. Aspirin-associated increases in circulating 15-epi-lipoxin A4 (15-epi-LXA4) and interleukin-10(IL-10) and decreases in interleukin-8(IL-8) provide translational evidence for a pro-resolving response, without establishing a direct placental effect. Preclinical studies suggest effects on soluble fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PlGF)-related pathways; however, a secondary analysis of the Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) analysis found no significant difference in PlGF trajectories between aspirin and placebo. Epigenetic mechanisms remain exploratory.

CONCLUSIONS

Aspirin prophylaxis is most plausibly anchored in sustained platelet COX-1 inhibition, with potential indirect effects on perfusion, inflammation and angiogenic regulation. Direct trophoblast and epigenetic effects at clinical exposure levels remain unproven. Future studies should integrate placental drug exposure with platelet pharmacodynamic and longitudinal placental measurements.