Prostacyclin and thromboxane changes predating clinical onset of preeclampsia - A multicenter prospective study

Context An imbalance in vasodilating (prostacyclin [PGI(2)]) and vasoconstr icting (thromboxane A(2) [TxA(2)]) eicosanoids may be important in preeclam psia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA(2) production have failed to prevent preeclampsia, it is critical to determine whether ei cosanoid changes occur before the onset of clinical disease or are secondar y to clinical manifestations of preeclampsia, Objective To determine whether PGI(2) or TxA(2) changes occur before onset of clinical signs of preeclampsia. Design, Setting, and Participants Multicenter prospective study from 1992 t o 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Pre vention Trial. Women who developed preeclampsia (n =134) were compared with matched normotensive control women (n = 139), Main Outcome Measures Excretion of urinary metabolites of PGI(2) (PGI-M) an d TxA(2) (Tx-M) as measured from timed urine collections obtained prospecti vely before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation . Results Women who developed preeclampsia had significantly lower PCI-M leve ls throughout pregnancy, even at 13 to 16 weeks' gestation (long before the onset of clinical disease); their gestational age-adjusted levels were 17% lower than those of controls (95% confidence interval [CI], 6%-27%; P = 00 5). The Tx-M levels of preeclamptic women were not significantly higher ove rall (9% higher than those of controls; 95% CI, -3% to 23%; P = .14). The r atio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodil ating effects, was 24% higher (95% CI, 6% -45%) n preeclamptic women throug hout pregnancy (P = .007). Conclusions Our results show that reduced PGI(2) production, but not increa sed TxA(2) production, occurs many months before clinical onset of preeclam psia, Aspirin trials may have failed because an increase in thromboxane pro duction is not the initial anomaly. Future interventions should make correc ting prostacyclin deficiency a major part of the strategy to balance the ab normal vasoconstrictor-vasodilator ratio present in preeclampsia.