1. SARAH PIXTON AUGUST 2013 ORANGE BASE HOSPITAL Low Dose Aspirin In Pregnancy

2. Pathophysiology The endothelial activation and injury in preeclampsia may also disturb the finely tuned balance of physiological coagulation, fibrinolysis and platelet activation. There’s increased production of thromboxane (TxA) by platelets and placental tissue, and a reduced placental synthesis of prostacyclin (PGI) Elevated platelet thromboxane synthesis and reactivity is an important mechanism in the development of the utero- placental circulatory insufficiency that may accompany hypertension in pregnancy

3. Aspirin Mechanism of Action Aspirin breaks down into salicylic acid and acetic acid. The acetic acid irreversibly binds to COX-1 within the platelets, preventing the formation of thromboxane A 2 (a potent vasoconstrictor and induces platelet aggregation), resulting in a decrease in the ability to form clots and increase bleeding time. Since platelets are non-nucleated cells and incapable of synthesizing new COX enzymes, the effect lasts for the life of the platelet which is about 7 days at which time new platelets are formed. The salicylic acid portion has the analgesic and anti-inflammatory actions. A dose of aspirin as small as 40 mg will prolong the bleeding time for up to 5 days

4. In normal pregnancy the synthesis of prostacyclin (PGI), an endothelium-derived vasodilator and inhibitor of platelet aggregation, increases markedly, which leads to a dominance in the biological balance with platelet derived thromboxane A, (TxA), a strong vasoconstrictor and inductor of platelet aggregation. Some women fail to develop or maintain these physiological adaptational responses to pregnancy; in these women a relative dominance of TXA, over PGI, results in vasocontriction and platelet aggregation “Action via Cox-1 inhibition” “TxA2= vasoconstrictor and platelet aggregator”

5. In pre-eclampsia… Aspirin level of action Imbalance between vasodilator mediators (prostaglandin, NO) and vasoconstrictor mediators (thromboxane) results in endothelial dysfunction

6. Under normal conditions, the remodeling of maternal spiral arteries is favoured by high availability of nitric oxide (NO) In preeclampsia, there is an improper remodeling of spiral arteries during placentation causing endothelial dysfunction

7. History Behind The Evidence Because of the hypothesis that the maternal/ uteroplacental circulatory disturbance in PIH / IUGR depends at least in part on a functional imbalance between two prostaglandins-thromboxane and prostacyclin, it was attempted to correct the imbalance by means of dietary and pharmacologic manipulation of prostaglandin synthesis, in particular with low-dose aspirin. Review of early small trials of low-dose aspirin suggested reductions of about three-quarters in the incidence of preeclampsia, but these results were not always confirmed in larger trials." Because of this apparent discrepancy, a large randomized trial of low-dose aspirin for the prevention and treatment of preeclampsia (Collaborative Low-dose Aspirin Study in Pregnancy [CLASP]) was designed

8. CLASP The Collaborative Low·dose Aspirin Study in Pregnancy (CLASP) was performed from 1988-1993 as a randomized, double-blind, placebo-controlled trial of low-dose aspirin for the prevention or treatment of pre-eclampsia and /or fetal growth retardation. Women between 12 and 32 weeks of pregnancy received a daily dose of 60 mg of aspirin or matching placebo until delivery if they were thought to be at higher than average risk of developing severe preeclampsia. A total of 9364 women from 213 centers in 16 countries were randomized. The impact of low-dose aspirin on the prevention of preeclampsia and its sequelae was smaller in CLASP than in the earlier reports possibly due to the inclusion of relatively low-risk patients in the CLASP- trial.

9. CLASP Results The prophylactic use of aspirin was associated with a decrease of 12% in the incidence of proteinuric preeclampsia, but the reduction was not statistically significant. No significant effect on birth weight or stillborn rate was detected. Aspirin did, however, significantly reduce the likelihood of preterm delivery (19.7% aspirin vs 22.2% control) There was a significant trend (p = 0.004) towards progressively greater reductions in proteinuric pre-eclampsia the more preterm the delivery. There was no evidence of a therapeutic effect of low-dose aspirin. Finally, CLASP provided support with regard to the safety of aspirin for the pregnant woman and her baby

10. However..NICE Guidelines A Cochrane systematic review of 59 RCTs (randomized controlled trials) showed a significant benefit of low dose aspirin in prevention of pre-eclampsia as compared to placebo in both risk populations. Duley L, Henderson-Smart DJ, Meher S et al. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database of Systematic Reviews 2007;(2) The Guideline Development group at NICE (National Institute for Health and Care Excellence) used evidence from an HTA report 1 and developed its own health economic analysis which showed an unequivocal economic benefit in women on aspirin versus no aspirin in the risk groups Meads CA, Cnossen JS, Meher S et al. Methods of prediction and prevention of pre-eclampsia: systematic reviews of accuracy and effectiveness literature with economic modelling. Health Technology Assessment 2008; 12:(6)

11. Our Evidence Statement: Aspirin prophylaxis reduces the occurrence of pre-eclampsia, preterm birth and fetal and neonatal mortality in women at moderate or high risk of developing the condition. There was no significant risk of ante-or postpartum haemorrhage in the group on aspirin versus the one without. There was no statistically significant difference in risk of long term neonatal adverse effects at 12-18 months for children born to mothers on low dose aspirin in pregnancy.

12. From the NICE Guidelines..

13. Suggested practice for OBH Initial Contact with Health Services via GP/ Midwife 1) Assess risk factors2) Commence aspirin Risk factors for pre-eclampsia Moderate: _ First pregnancy _ Age ≥ 40 years _ Pregnancy interval > 10 years _ BMI ≥ 35 kg/m2 at first visit _ Family history of pre-eclampsia _ Multiple pregnancy High: _ Hypertensive disease during previous pregnancy _ Chronic kidney disease _ Autoimmune disease such as systemic lupus erythematosis or antiphospholipid syndrome _ Type 1 or type 2 diabetes _ Chronic hypertension If one HIGH risk factor OR 2 or more MODERATE risk factors To commence low dose aspirin (100mg/ day) at 12 weeks 3) Early referral to Obstetric Clinic at OBH

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