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Prostacyclin and Thromboxane Changes Predating Clinical Onset of Preeclampsia
A Multicenter Prospective Study
James L. Mills, MD, MS;
Rebecca DerSimonian, ScD;
Elizabeth Raymond, MD, MPH;
Jason D. Morrow, MD;
L. Jackson Roberts II, MD;
John D. Clemens, MD;
John C. Hauth, MD;
Patrick Catalano, MD;
Baha Sibai, MD;
L. B. Curet, MD;
Richard J. Levine, MD
JAMA. 1999;282:356-362.
Context 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.
Design, Setting, and Participants 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).
Main Outcome Measures 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.
Author Affiliations: Epidemiology Branch (Drs Mills, Clemens, and Levine) and Biometry and Statistics Branch (Dr DerSimonian), Division of Epidemiology, Statistics and Prevention Research, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Md; Family Health International, Clinical Trials Division, Durham, NC (Dr Raymond); Departments of Clinical Pharmacology and Medicine, Vanderbilt University, Nashville, Tenn (Drs Morrow and Roberts); and the Departments of Obstetrics and Gynecology, University of Alabama-Birmingham (Dr Hauth), MetroHealth Medical Center, Cleveland, Ohio (Dr Catalano), University of Tennessee-Memphis (Dr Sibai), and University of New Mexico, Albuquerque (Dr Curet).
RELATED LETTER
Prostacyclin and Thromboxane and the Development of Preeclampsia
Ariela Benigni, Giuseppe Remuzzi, R. M. F. van der Weiden, F. M. Helmerhorst, James L. Mills, Richard J. Levine, and Jason D. Morrow
JAMA. 2000;283(12):1568-1569.
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July 28, 1999
JAMA. 1999;282(4):399-400.
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