1 School of Developmental and Reproductive Medicine, University of Liverpool, Liverpool, L8 7SS and 2 Liverpool Women's Hospital Trust, Liverpool, L8 7SS, UK
3 To whom correspondence should be addressed. Email: squenby{at}liv.ac.uk
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Abstract |
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Key words: antiphospholipid syndrome/recurrent miscarriage/thrombosis
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Introduction |
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The risk of thrombosis following a positive test for APS in young women is unknown (Cuadrado and Khamashta, 2000; Navarrete et al., 2000
) but has recently been considered to be moderate (Lockshin and Erkan, 2003
). This means that clinicians have no firm evidence on which to base advice regarding need for long-term thromboprophylaxis. The aim of this project was to assess the long-term risk of subsequent thrombosis in young women attending a tertiary recurrent miscarriage clinic. We tested the hypothesis that women diagnosed as having APS as an aetiological factor for their miscarriages were at higher risk of thrombosis than those with idiopathic RM.
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Materials and methods |
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When questionnaires were returned, controls were selected from the idiopathic recurrent miscarriage section of the database. Idiopathic recurrent miscarriage was diagnosed for those for whom the following investigations failed to detect an aetiology for their pregnancy losses: IgG or IgM anticardiolipin, lupus anticoagulant, parental karotype, auto-antibody screen, random blood glucose, thyroid function tests, pelvic ultrasound scan, hysteroscopy, cervical swabs for myoplasma and ureaplasma, high vaginal swab for bacterial vaginosis, and serology for toxoplasmosis, parovirus, rubella and cytomegalovirus (Drakeley et al., 1998). The cases were matched to controls for age, number of years of follow-up and number and type of pregnancy losses (Table II). If the selected controls failed to answer the questionnaire, a further matched control was selected and the questionnaire was sent to them. When 141 case-matched women with idiopathic recurrent miscarriage had answered the questionnaire, recruitment was discontinued.
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The risk of thrombosis between the APS and control group was compared using a statistical test for two independent proportions using StatsDirect (Sale, Cheshire) software for personal computer. P<0.05 was accepted as statistically significant.
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Results |
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Of the 141 women with APS who had no past history of thrombosis prior to referral, six reported a subsequent thrombosis (Table III). No women in the control group had a thrombosis prior to referral, but two women in this group subsequently reported a thrombotic event (Table III). The two women reporting a thrombotic episode were subsequently contacted and agreed to a thrombophilia screen. One was found to be heterozygous for the Leiden factor V mutation and one homozygous for the prothrombin gene mutation 20210A. There was no statistically significant difference in the rate of thrombosis in the APS group [six thromboses per 1000 women-years of follow-up (95% CI 213/1000)] and control group [two thromboses per 1000 women-years (95% CI 0.27/1000)]. There was one non-thrombotic death in each group, reported by the women's partner (Table III). All eight women in the APS subgroup who had had a thrombotic episode prior to referral (Table II) had subsequent thrombotic episodes (Table III).
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Discussion |
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Our study has collected important and challenging data suggesting that women presenting to a recurrent miscarriage clinic do have a long-term thrombosis risk, particularly if APS has been diagnosed. The thrombosis risk in the idiopathic recurrent miscarriage group was found to reflect underlying thrombophilia in women with idiopathic recurrent pregnancy. These thrombophilias were not detected initially as the patient's first visit to the miscarriage clinic pre-dated the discovery of the association between pregnancy loss and thrombophilia (Preston et al., 1996). There are many risk factors for thrombosis which include smoking, oral contraceptive pill use, obesity and hypertension. However, these potential confounding factors were not present in the women reporting thrombosis subsequent to a history of recurrent miscarriage alone.
The incidence of venous thromboembolism in our study was 2/1000 women-years for all women with recurrent miscarriage. It is difficult to compare this rate of thrombosis with that in the published literature because of differences in the methodologies used to detect thrombosis in our study and those previously published. However, a retrospective casecontrol study based on general practitioner records in the UK found that baseline rate of venous thromboembolism for women of reproductive years was 0.27/1000 women-years (Seaman et al., 2003), significantly lower than that detected in our study.
Our study had a good response rate of 74%; however, it is possible that the non-responders had more cerebral thrombosis than the responders so that they were unable to answer the questionnaire. If this were the case then we may have underestimated the thrombosis risk. However, we did know that the most common reason for failing to respond to the questionnaire was change of address and that our postal questionnaires even detected patient death.
Cerebral ischaemia associated with aPL was previously reported to be the most common arterial manifestation of APS (Krnic-Barrie et al., 1997; Shah et al., 1998
; Navarrete et al., 2000
). Most of the thrombotic episodes reported by the patients in the current study were indeed cerebral (Table III). However, the importance of aPL as a risk factor for stroke is controversial. Some studies support an association between aPL and cerebral thrombosis (Levine et al., 1990
; Kushner, 1990
; Camerlingo et al., 1995
; D'Olhaberriague et al., 1998
; Brey et al., 2001
) and others do not (Muir et al., 1994
; Antiphospholipid Antibodies and Stroke Study Group, 1997
; Tanne et al., 1999
). The data presented here suggest that there is an association between APS and cerebral thrombosis.
The efficacy of long-term thromboprophylaxis and its associated risk of bleeding is a complex problem. A recent randomized controlled trial found that high-intensity warfarin was not superior to moderate-intensity warfarin for the prevention of thrombosis in patients with aPL and previous thrombosis (Crowther et al., 2003). Furthermore, the authors reported an annual risk of major bleeding of 3.6% with high-intensity warfarin versus 2.2% with moderate-intensity warfarin. A retrospective study has suggested that low-dose aspirin may be effective in the prevention of thrombosis for asymptomatic APS patients (Erkan et al., 2002
). However, low-dose aspirin has been associated with significant side-effects: a risk of 9% for gastrointestinal bleeding has been reported (Newby et al., 2003
). Therefore, randomized controlled trials are needed to ascertain the efficacy and side-effects of thromboprophylaxis in patients with a history of recurrent miscarriage with and without APS (Lockshin and Erkan, 2003
). Avoidance of other risk factors for thrombosisoral contraceptive pill, smoking, obesity and hypertensionseems to be sensible advice for women with recurrent miscarriage (Cuadrado and Lopez-Pedrera, 2003
).
Presentation with previous thrombosis, recurrent miscarriage and APS was a significant risk factor for recurrent thrombosis. The subgroup results are similar to that of Silver et al. (1994) who also found a significant incidence of cerebral thrombosis in a follow-up study of a similar group of women with APS. Patients with such a high risk of recurrent thrombosis should be referred routinely to a specialist haematology clinic.
In conclusion, our data suggest that a history of recurrent miscarriage is a risk factor for subsequent thrombosis in the long term. In light of these findings, a randomized controlled trial is needed to assess efficacy and bleeding risk for long-term thromboprophylaxis in women with recurrent miscarriage.
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Acknowledgements |
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References |
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Submitted on November 4, 2004; resubmitted on January 31, 2005; accepted on February 11, 2005.