Prostacyclin, Thromboxane A2, and the Effect of Low-Dose ASA in Pregnancies at High Risk for Hypertensive Disorders

Abstract

In preeclampsia, underperfusion of the uteroplacental circulation and placental ischemia combine to damage the placenta. This in turn is thought to cause widespread endothelial cell damage and also an imbalance in eicosanoids, the vasodilator prostacyclin, and the vasoconstrictor thromboxane A2. Although low-dose acetylsalicylic acid (ASA) restores the balance in favor of prostacyclin, the clinical results of administering ASA remain uncertain. The present longitudinal study sought to find whether the prostanoids have a pathophysiological role in pregnancy-induced hypertension (PIH) and intrauterine growth restriction (IUGR). In addition, ASA was given in a daily dose of 0.5 mg/kg. Participants were 90 women at risk of preeclampsia or IUGR who had bilateral notching in the uterine arteries when screened by Doppler ultrasonography at 12 to 14 weeks gestation. After assigning these women to ASA or a placebo, 43 women in both groups were followed up throughout pregnancy. Urine samples were taken at baseline and at 24 to 26 weeks and 32 to 34 weeks of gestation, and analyzed for metabolites of thromboxane A2 and prostacyclin. ASA treatment significantly prevented PIH, especially before 37 weeks vacation, as well as preeclampsia, regardless of whether bilateral notches persisted. If bilateral notching disappeared by 24 to 26 weeks gestation, ASA-treated women less often had PIH and preeclampsia than did placebo recipients. ASA did not alter outcomes when bilateral notches persisted at 32 to 34 weeks gestation. When notches were absent at this time, ASA-treated women had lower rates of PIH and preeclampsia. When PIH developed before 37 gestational weeks, the ratio of prostacyclin metabolite to thromboxane A2 metabolite did not increase as much as in other pregnancies. In placebo patients with preeclampsia, levels of prostacyclin metabolite were significantly lower than in other pregnancies at 12 to 14 weeks gestation. In placebo recipients, the metabolite ratio did not change in the course of pregnancy and was not influenced by adverse outcomes. Metabolite ratios increased in ASA-treated women whether the outcome was normal or abnormal. These findings suggest that the balance between vasodilating and vasoconstricting prostanoids shifts in an unfavorable manner in pregnant women with PIH. Treatment with ASA may help to restore a normal balance. It is best given beginning early in pregnancy.