Prostacyclin and thromboxane changes predating clinical onset of preeclampsia: a multicenter prospective study.
BACKGROUND
An imbalance in vasodilating (prostacyclin [PGI2]) and vasoconstricting (thromboxane A2 [TxA2]) eicosanoids may be important in preeclampsia, but prospective data from large studies needed to resolve this issue are lacking. Because most trials using aspirin to reduce TxA2 production have failed to prevent preeclampsia, it is critical to determine whether eicosanoid changes occur before the onset of clinical disease or are secondary to clinical manifestations of preeclampsia.


OBJECTIVE
To determine whether PGI2 or TxA2 changes occur before onset of clinical signs of preeclampsia.


METHODS
Multicenter prospective study from 1992 to 1995 of subjects from the placebo arm of the Calcium for Preeclampsia Prevention Trial. Women who developed preeclampsia (n = 134) were compared with matched normotensive control women (n = 139).


METHODS
Excretion of urinary metabolites of PGI2 (PGI-M) and TxA2 (Tx-M) as measured from timed urine collections obtained prospectively before 22 weeks', between 26 and 29 weeks', and at 36 weeks' gestation.


RESULTS
Women who developed preeclampsia had significantly lower PGI-M levels 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=.005). The Tx-M levels of preeclamptic women were not significantly higher overall (9% higher than those of controls; 95% CI, -3% to 23%; P=.14). The ratio of Tx-M to PGI-M, used to express relative vasoconstricting vs vasodilating effects, was 24% higher (95% CI, 6%-45%) in preeclamptic women throughout pregnancy (P=.007).


CONCLUSIONS
Our results show that reduced PGI2 production, but not increased TxA2 production, occurs many months before clinical onset of preeclampsia. Aspirin trials may have failed because an increase in thromboxane production is not the initial anomaly. Future interventions should make correcting prostacyclin deficiency a major part of the strategy to balance the abnormal vasoconstrictor-vasodilator ratio present in preeclampsia.
Mills
J L
JL
Epidemiology Branch, Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
DerSimonian
R
R
Raymond
E
E
Morrow
J D
JD
Roberts
L J
LJ
Clemens
J D
JD
Hauth
J C
JC
Catalano
P
P
Sibai
B
B
Curet
L B
LB
Levine
R J
RJ
D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives / Q000652:urine; D000328:Adult; D015415:Biomarkers; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D006801:Humans; D011225:Pre-Eclampsia / Q000378:metabolism* / Q000517:prevention & control / Q000652:urine; D011247:Pregnancy; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000031:analogs & derivatives / Q000652:urine
D015415:Biomarkers; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C049235:11-dehydro-thromboxane B2; D011464:Epoprostenol