Brenner1  recently reviewed thrombophilia-related placental vascular complications, notably including preeclampsia and intrauterine growth restriction, and dealt baldly with the question of the potential benefit of aspirin in prevention of preeclampsia, claiming it was raised and refuted in the 1980s. Of course, when preeclampsia occurs in association with factor V (FV) Leiden mutation, factor II 20210G>A, or methylenetetrahydrofolate reductase TT polymorphisms, a specific treatment is required. However, the efficacy of low-dose aspirin in prevention of preeclampsia and related complications was still recently confirmed,2  and an abundant literature contributed to define now the groups of women who can benefit from low-dose aspirin.

This effect was first demonstrated in high-risk patients accurately selected by close analysis of their historic risk factors.3-5  In these first trials, the approach of the investigators was justified in view of the low mean birth weight or high preeclampsia incidence in the placebo groups, and the gain was substantial. Subsequently, several large-scale trials including heterogeneous groups of women at low or moderate risk aimed to test the preventive action of low-dose aspirin either in a high proportion or even in the whole population of the pregnant women. Moreover, gestational age at entry was very variable, until 32 weeks of gestation. Given the low incidence of preeclampsia and the normal mean birth weight in the placebo groups, these large trials not surprisingly either reported a mild benefit or were negative. However, some of them usefully determined that the specific risk attributable to such conditions as primiparity, twin pregnancy, and nonsevere diabetes or hypertension can probably not be avoided by means of low-dose aspirin.6  In the complex network of the mechanisms involved in the pathogenesis of preeclampsia and related disorders, thromboxane is probably one of the factors leading from defective placentation and placental ischemia to platelet aggregation and placental thrombosis and finally to the clinical stage of the disease. Low-dose aspirin selectively inhibits thromboxane production in the woman's circulation, and this inhibition parallels the clinical effect.4,5  However, the abnormalities of the uteroplacental circulation development that constitute uteroplacental insufficiency are early established. So, the early excess of placental production of thromboxane reported in women with uteroplacental insufficiency may explain that low-dose aspirin only acts optimally when aspirin treatment is started before placentation is completed, and clinical data support this view.7  Thus, the baseline risk of preeclampsia or intrauterine growth retardation should be estimated and low-dose aspirin started early on the presence of significant historic risk factors, such as previous severe preeclampsia or moderate to severe renal insufficiency.8  A 2-stage Doppler artery screening in first and second trimester could also define a high-risk population,9  and promising results have been published for aspirin prevention with first-trimester uterine artery Doppler selection in high-risk pregnancies.10 

Role of aspirin in women with thrombophilia

Carbillon and Uzan suggest that aspirin has a positive effect on prevention of preeclampsia in selected high-risk patients. Since my review1  was focused on management of placental vascular complications in women with thrombophilia, the role of aspirin was only briefly mentioned.

In women with antiphospholipid syndrome and previous complications, aspirin is given with unfractionated heparin (UFH) or low–molecular-weight heparin (LMWH).2  However, whether a regimen of UFH or LMWH alone without aspirin is sufficient has not been adequately determined in this setting.

The association of inherited thrombophilia with placental vascular complications set the stage for antithrombotic prophylaxis. Aspirin alone has not been found to be of significant value in thrombophilic women with previous pregnancy complications.3  Moreover, aspirin crosses the placenta into the fetus and combinations of UFH or LMWH with aspirin may also increase bleeding tendency in the mother. Thus, the routine use of aspirin in thrombophilic women cannot be advocated.

Correspondence: Benjamin Brenner, Department of Hematology, Rambam Medical Center, Haifa 31096, Israel; e-mail: b_brenner@rambam.health.gov.il.

1
Brenner B. Clinical management of thrombophilia-related placental vascular complications.
Blood
.
2004
;
103
:
4003
-4009.
2
Tincani A, Branch W, Levy RA, et al. Treatment of pregnant patients with antiphospholipid syndrome.
Lupus
.
2003
;
12
:
524
-529.
3
Gris JC, Mercier E, Quere I, et al. Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.
Blood
.
2004
;
103
:
3695
-3699.
1
Brenner B. Clinical management of thrombophilia-related placental vascular complications.
Blood
.
2004
;
103
:
4003
-4009.
2
Duley L, Henderson-Smart DJ, Knight M, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications.
Cochrane Database Syst Rev
.
2004
;(1):
CD004659
.
3
Uzan S, Beaufils M, Breart G, Bazin B, Capitant C, Paris J. Prevention of fetal growth retardation with low-dose aspirin: findings of the EPREDA trial.
Lancet
1991
;
337
:
1427
-1431.
4
Schiff E, Peleg E, Goldenberg M, et al. The use of aspirin to prevent pregnancy-induced hypertension and lower the ratio of thromboxane A2 to prostacyclin in relatively high risk pregnancies.
N Engl J Med
.
1989
;
321
:
351
-356.
5
Benigni A, Gregorini G, Frusca T, et al. Effect of low-dose aspirin on fetal and maternal generation of thromboxane by platelets in women at risk for pregnancy-induced hypertension.
N Engl J Med
.
1989
;
321
:
357
-362.
6
Caritis S, Sibai B, Hauth J, et al. Low-dose aspirin to prevent preeclampsia in women at high risk: National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units.
N Engl J Med
.
1998
;
338
:
701
-705.
7
Sullivan M, Elder M, de Swiet M. Too little, too late.
Am J Obstet Gynecol
.
1999
;
181
:
508
-509.
8
Coomarasamy A, Braunholtz D, Song F, Taylor R, Khan KS. Individualising use of aspirin to prevent pre-eclampsia: a framework for clinical decision making.
BJOG
.
2003
;
110
:
882
-888.
9
Carbillon L, Uzan M, Largilliere C, et al. Prospective evaluation of uterine artery flow velocity waveforms at 12-14 and 22-24 weeks of gestation in relation to pregnancy outcome and birth weight.
Fetal Diagn Ther
.
2004
;
19
:
381
-384.
10
Vainio M, Kujansuu E, Iso-Mustajarvi M, Maenpaa J. Low dose acetylsalicylic acid in prevention of pregnancy-induced hypertension and intrauterine growth retardation in women with bilateral uterine artery notches.
BJOG
.
2002
;
109
:
161
-167.