ArticlesIncreased fetal loss in women with heritable thrombophilia
Introduction
Until lately, a clear relation with a genetic thrombophilic defect was evident in only 5–10% of patients presenting with venous thromboembolism and was confined to those with deficiencies of antithrombin, protein C, and protein S. The importance of heritable defects as risk factors for venous thromboembolism has increased with the discovery of a genetic thrombophilic disorder that manifests as resistance to activated protein C (APC)1 and the observation that this disorder is present in about 20% of individuals presenting with venous thrombosis.2 Bertina and colleagues3 have shown that in most individuals APC resistance is the result of a single point mutation in the factor V gene at nucleotide 1691, which codes for the APC cleavage site (factor V Leiden mutation). In much of Europe and in the USA the prevalence of the factor V Leiden defect is 3–5%. However, in other parts of the world, such as southeast Asia and Africa, the prevalence of the defect is less than 1%.4
In pregnancy, a successful outcome is highly dependent on satisfactory placental development and sustained placental function. These processes, in turn, require the establishment of an adequate fetomaternal circulatory system. Since this system may be compromised by disturbances of haemostasis leading to a prothrombotic state, we postulated that maternal thrombophilia might be a risk factor for fetal loss. We have therefore studied the relation between heritable thrombophilic defects and fetal loss in a cohort of women who have factor V Leiden or deficiencies of antithrombin, protein C, or protein S (the European Prospective Cohort on Thrombophilia [EPCOT]) and in a control group. Although EPCOT is a prospective follow-up study, the data here were collected at baseline and give information on lifetime occurrence of miscarriage and stillbirth.
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Patients and methods
The women described here were enrolled in EPCOT between January, 1994, and November, 1995. The primary aim of the study is to establish the risk of thrombosis in this group of disorders. A secondary aim is to investigate the possible relation between these disorders and the risk of fetal loss.
The index group consists of male and female individuals of all ages, with or without symptomatic disease. Each participating centre enrolled all registered patients who had hereditary thrombophilia caused
Results
Patients and controls were enrolled by 11 centres from nine countries (Leiden, Barcelona, Bologna, Frankfurt, Glasgow, Malmö, Paris, Rome, Sheffield, Tel-Hashomer, Vienna). On Nov 1, 1995, 1384 women had been enrolled (843 patients, 541 controls). Most of the controls (354 [65%]) were partners of index patients; this proportion was 79% (311/395) among the controls who had been pregnant at least once. The patients were 242 women with protein-C deficiency, 214 with protein-S deficiency, 159 with
Discussion
In this cross-sectional, multicentre study we found an increased risk of fetal loss in women with heritable deficiencies of antithrombin, protein C, or protein S. The risks were greatest for women with antithrombin deficiency and for those with combined defects.
Although the increased risk of fetal loss was found for both miscarriage and stillbirth, analysed jointly and separately, the effect of thrombophilia was especially pronounced for stillbirths. This finding is not unexpected: miscarriage
References (10)
- et al.
Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study
Lancet
(1993) - et al.
World distribution of factor V Leiden
Lancet
(1995) Recurrent miscarriage I: definition and epidemiology
Lancet
(1990)- et al.
High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance)
Blood
(1995) - et al.
Familial thrombophilia due to a previously unrecognised mechanism characterised by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C
Proc Natl AcadSci USA
(1993)