What is the mechanism of action of aspirin (acetylsalicylic acid) in preventing preeclampsia?

Mechanism of Action of Aspirin in Preventing Preeclampsia

Aspirin prevents preeclampsia primarily through its anti-inflammatory, antiangiogenesis, and antiplatelet properties that counteract the pathophysiological processes of poor placentation, endothelial dysfunction, and imbalance between thromboxane A2 and prostacyclin. 1

Pathophysiology of Preeclampsia

Preeclampsia develops through a two-stage process:

1. Poor Placentation Stage:

   • Inadequate trophoblastic invasion of the myometrium
   • Poor remodeling of spiral arteries leading to reduced uteroplacental perfusion
   • Shallow invasion causes restricted blood flow to the placenta 1
   • Two waves of trophoblastic invasion occur: decidual invasion at 8-10 weeks and myometrial invasion at 16-18 weeks 1

2. Maternal Systemic Response Stage:

   • Placental hypoxia and ischemia trigger oxidative stress
   • Release of inflammatory mediators into maternal circulation
   • Endothelial dysfunction develops throughout maternal vasculature
   • Vasoconstriction and increased maternal blood pressure 1

Specific Mechanisms of Aspirin Action

1. Prostanoid Pathway Modulation

• Aspirin selectively and irreversibly inhibits cyclooxygenase-1 (COX-1) enzyme 2
• This inhibition suppresses thromboxane A2 (TXA2) production, a potent vasoconstrictor and platelet aggregator 3
• At low doses, aspirin preferentially inhibits platelet COX-1 while preserving endothelial prostacyclin (PGI2) production 2
• This corrects the imbalance between thromboxane A2 and prostacyclin that characterizes preeclampsia 3

2. Improved Placentation

• Enhances blood flow velocity in uterine and ovarian arteries 4
• Reduces pulsatility index values in uterine arteries 4
• Improves implantation environment and trophoblast invasion 4
• Modulates inflammatory factors affecting endometrium and vasculature 4

3. Anti-inflammatory Effects

• Reduces systemic inflammation associated with preeclampsia 1
• Counteracts the inflammatory response to placental ischemia 2
• Helps regulate immune responses at the maternal-fetal interface 4

4. Vascular Effects

• Corrects pathologic increase in angiotensin II sensitivity that precedes clinical preeclampsia 3
• Improves endothelial function by reducing oxidative stress 2
• Enhances vasodilation and reduces vasoconstriction 1

Timing and Dosage Considerations

The effectiveness of aspirin in preventing preeclampsia depends on:

• Timing: Most effective when started before 16 weeks of gestation, ideally between 12-16 weeks 1, 4

  • Starting before conception may provide additional benefits for implantation 4
  • Starting after 16 weeks shows reduced effectiveness 1

• Dosage: Higher doses appear more effective 1

  • 81-100 mg daily is standard in the US 4
  • Doses ≥100 mg show greater reduction in preeclampsia when started before 16 weeks 1
  • 150 mg daily showed 62% reduction in preterm preeclampsia in the ASPRE trial 2

Special Considerations

• Obesity: May limit aspirin effectiveness due to:

  • Limited absorption of aspirin
  • Higher rate of platelet regeneration
  • Increased renewal of cyclooxygenase-1 1

• Chronic Hypertension: Evidence suggests limited effectiveness in women with chronic hypertension 1, 2

  • Altered pharmacokinetics in pregnancy may require higher doses 1
  • Preexisting vascular damage may limit aspirin's preventive effects 1

Clinical Implications

The understanding of aspirin's mechanism explains why:

• Early initiation (before 16 weeks) is crucial for optimal effect
• Higher doses (≥100 mg) may be more effective than traditional low doses
• Certain populations (obesity, chronic hypertension) may have reduced response
• Nighttime administration may enhance effectiveness due to circadian effects on platelet activity 2

By targeting the fundamental pathophysiological processes of preeclampsia, aspirin represents one of the few effective preventive strategies for this serious pregnancy complication, particularly in high-risk women.