Department of Reproductive Science and Medicine, Imperial College School of Medicine at St Mary's, Mint Wing, Praed Street, London W2 1PG, UK
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Abstract |
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Key words: aspirin/recurrent miscarriage
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Introduction |
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Low dose aspirin is an anti-platelet agent which irreversibly inhibits platelet cyclo-oxgenase and thereby decreases the production of thromboxane A2 (TXA2), a potent vasoconstrictor. Aspirin has been widely used in attempts to treat pregnant women with recurrent miscarriage associated with antiphospholipid antibodies (aPL), an acquired thrombophilic defect, and other auto-immune conditions (Kutteh, 1996; Laskin et al., 1997
; Rai et al., 1997
). The aim of this study was to assess the value of low dose aspirin in improving the subsequent livebirth rate amongst women with either unexplained recurrent early miscarriage or unexplained late pregnancy loss.
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Materials and methods |
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Management during pregnancy
Women were divided into two groupsthose who chose to take low dose aspirin (75 mg daily) and those who did not take aspirin. Aspirin was started within 5 weeks of amenorrhoea and continued until delivery. Both groups of women took folic acid (400 µg daily) until 14 weeks gestation as prophylaxis against neural tube defects. No woman took heparin. All were encouraged to attend a dedicated early pregnancy clinic at which supportive care was offered and serial first trimester ultrasound scans were performed.
Our clinic is a national referral centre. Accordingly, the overwhelming majority of women that we see have been previously counselled by a variety of doctorsboth general practitioners and gynaecologists. Many of these individuals recommend aspirin treatment on an empirical basis. One of the primary aims of this study was to provide data in order that clinicians may have some basis, or lack of basis, for recommending aspirin therapy during pregnancy.
Statistical analysis
Normally distributed continuous variables were analysed using Student's t test; otherwise the Mann Whitney U test was used. Discrete variables were analysed using the 2 test.
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Results |
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Discussion |
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Aspirin inhibits the action of the enzyme cyclo-oxygenase and thereby suppresses the production of TXA2 in platelets. In vascular cell walls, cyclo-oxygenase is also responsible for the conversion of arachidonic acid to prostacyclin (PGI2). TXA2 induces platelet aggregation and vasoconstriction, whilst PGI2 inhibits platelet aggregation and induces vasodilation. Women with a history of recurrent early miscarriage in weeks 47 of gestation have an excess of TXA2 production and between weeks 811 they are relatively PGI2 deficient, compared with women with no previous history of pregnancy loss (Tulpalla et al., 1991). These changes are greatest amongst those whose pregnancies end in miscarriage. The shift in the TXA2:PGI2 ratio, in favour of TXA2, may lead to vasospasm and platelet aggregation in the trophoblast, causing the development of microthrombi and placental necrosis. In a small study of women with early miscarriages it was reported that whilst aspirin corrects these biochemical abnormalities, it does not affect the miscarriage rate (Tulppala et al., 1997
).
There are several possible reasons for the lack of efficacy of low dose aspirin in improving the pregnancy outcome of women with recurrent early miscarriages. First, a proportion of women with recurrent early miscarriages have lost three consecutive pregnancies purely by chance alone and have no underlying pathological abnormality; second, aspirin may truly have no effect; third, the dose of aspirin may be too low; and finally aspirin may only be of benefit to a subgroup of women with recurrent early miscarriage associated with a thrombophilic defect. Indeed, randomized controlled studies have only shown aspirin to be of benefit to women with aPL, which are an acquired thrombophilic defect (Kutteh, 1996; Rai et al., 1997
).
In this study, women took a low dose of aspirin (75 mg daily). This dose of aspirin, or an even lower dose of 60 mg daily, has often been used in pregnancy studies examining the effect of aspirin on the incidence of pre-eclampsia (CLASP Collaborative Group, 1994; Sibai, 1998). This dose derives from studies examining the effect of aspirin on myocardial re-infarction rates. In these cardiovascular studies, lower doses of aspirin (60150 mg/day) were found to be as effective as higher doses (up to 1000 mg/day) with fewer side-effects (Antiplatelet Trialists' Collaboration, 1994a
). This may not be the case in pregnancy, and indeed the mechanisms underlying the cardio-protective effects of aspirin may not be applicable to pregnancy.
In contrast to its lack of efficacy amongst women with unexplained recurrent early miscarriage, low dose aspirin significantly increased the prospective livebirth rate amongst women with a previous late miscarriage. This supports the hypothesis that a number of cases of second trimester miscarriage and later pregnancy complications have a thrombotic aetiology.
An important finding, which demands further investigation, was the significantly higher number of late miscarriages amongst women who took aspirin compared with those who did not. An explanation for this may lie in our understanding of the development of placental intervillous blood flow. Clearly, in order for maternal thrombophilic defects to cause placental thrombosis and subsequent pregnancy loss, there must be a maternal intervillous circulation. Recent histological data suggest that this only develops after 8 weeks gestation (Burton et al., 1999). Amongst women who had a further late miscarriage, aspirin at a dose of 75 mg daily may be sufficient to maintain the pregnancies until after 14 weeks gestation, but insufficient to maintain them to the stage of viability. It is possible that higher doses of aspirin may lead to a higher livebirth rate. Whilst no study has examined the effect of variable dose aspirin in the treatment of women with recurrent miscarriage, a study on aspirin and pre-eclampsia reported excellent livebirth rates amongst those in whom the dose of aspirin was titrated during pregnancy against the mean platelet volume (Sullivan et al., 1998
).
There is now convincing evidence that many cases of recurrent miscarriage and later pregnancy complications have a thrombotic aetiology. Whilst the empirical use of low dose aspirin in women with unexplained recurrent early miscarriage cannot be justified, we are currently investigating the role of higher doses of aspirin in the treatment of both women with early miscarriages associated with thrombophilic abnormalities and in those with late pregnancy losses.
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Notes |
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References |
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Antiplatelet Trialists' Collaboration (1994b) Collaborative overview of randomised trials of antiplatelet therapy I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br. Med. J., 308, 81106.
Burton, G.J., Jauniaux, E. and Watson, A.L. (1999) Maternal arterial connections to the placental intervillous space during the first trimester of human pregnancy: the Boyd collection revisited. Am. J. Obstet. Gynecol., 181, 718724.[ISI][Medline]
CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group (1994) CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet, 343, 619629.[ISI][Medline]
Clifford, K., Rai, R., Watson, H. and Regan, L. (1994) An informative protocol for the investigation of recurrent miscarriage: preliminary experience of 500 consecutive cases. Hum. Reprod., 9, 13281332.[Abstract]
Dizon, T.D., Meline, L., Nelson, L.M. et al. (1997) Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am. J. Obstet. Gynecol., 177, 402405.[ISI][Medline]
Khamashta, M.A. and Hughes, G.R. (1993) ACP Broadsheet no. 136: February 1993. Detection and importance of anticardiolipin antibodies. J. Clin. Pathol., 46, 104107.[ISI][Medline]
Kupferminc, M.J., Eldor, A., Steinman, N. et al. (1999) Increased frequency of genetic thrombophilia in women with complications of pregnancy. N. Engl. J. Med., 340, 913.
Kutteh, W.H. (1996) Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am. J. Obstet. Gynecol., 174, 15841589.[ISI][Medline]
Laskin, C.A., Bombardier, C., Hannah, M.E. et al. (1997) Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N. Engl. J. Med., 337, 148153.
Lupus Anticoagulant Working Party on behalf of the BCSH Haemostasis and Thrombosis Taskforce (1991) Guidelines on testing for the lupus anticoagulant. . J Clin. Path., 44, 885889.[ISI][Medline]
Preston, F.E., Rosendaal, F.R., Walker, I.D. et al. (1996) Increased fetal loss in women with heritable thrombophilia. Lancet, 348, 913916.[ISI][Medline]
Rai, R.S., Regan, L., Clifford, K., Pickering, W. et al. (1995) Antiphospholipid antibodies and Beta2-glycoprotein-I in 500 women with recurrent miscarriage: results of a comprehensive screening approach. Hum. Reprod., 10, 20012005.[Abstract]
Rai, R.S., Regan, L., Chitolie, A. et al. (1996) Placental thrombosis and second trimester miscarriage in association with activated protein C resistance. Br. J. Obstet. Gynaecol., 103, 842844.[ISI][Medline]
Rai, R., Cohen, H., Dave, M. and Regan, L. (1997) Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br. Med. J., 314, 253257.
Rushton, D.I. (1988) Placental pathology in spontaneous miscarriage. In: Beard, R.W. and Sharp, F. (eds), Early Pregnancy Loss: Mechanisms and Treatment. RCOG, London, pp. 149158.
Sibai, B.M. (1998) Prevention of preeclampsia: a big disappointment. Am. J. Obstet. Gynecol., 179, 12751278.[ISI][Medline]
Sullivan, M.H., Clark, N.A., De Swiet, M. et al. (1998) Titration of antiplatelet treatment in pregnant women at risk of preeclampsia. Thromb. Haemost., 79, 743746.[ISI][Medline]
Tulpalla, M., Viinikka, L. and Ylikorkaka, O. (1991) Thromboxane dominance and prostacyclin deficiency in habitual abortion. Lancet, 387, 879.
Tulppala, M., Marttunen, M., Soderstrom-Anttila, V. et al. (1997) Low-dose aspirin in prevention of miscarriage in women with unexplained or autoimmune related recurrent miscarriage: effect on prostacyclin and thromboxane A2 production. Hum. Reprod., 12, 15671572.[Abstract]
Submitted on March 21, 2000; accepted on June 30, 2000.