B159 - Factor V Leiden and adverse pregnancy outcome - 01/03/2004

B number: 
Principal applicant name: 
Dr Tracy Dudding (University of Newcastle, ROW)
Prof Rodney Scott (University of Newcastle, ROW), Dr John Attia (University of Newcastle, ROW)
Title of project: 
Factor V Leiden and adverse pregnancy outcome.
Proposal summary: 

The aetiology of adverse pregnancy outcomes such as pre-eclampsia and fetal growth retardation is likely to be multifactorial and influenced by a complex interplay between maternal, fetal and placental factors. Given that a successful pregnancy outcome is highly dependent on the establishment and maintenance of an adequate placental circulation, it is possible that abnormalities of placental vasculature, leading to inadequate fetomaternal circulation, may be responsible for at least some poor pregnancy outcomes. This has led to an interest in the thrombophilias as risk factors for adverse pregnancy outcome. The factor V Leiden mutation is the most common form of inherited thrombophilia.1 A point mutation in the factor V gene at nucleotide position 1691, resulting in an arginine to glutamine substitution, reduces the sensitivity of the factor V protein to inactivation by activated protein C (activated protein C resistance) resulting in a pro-coagulant state and an increased risk of thrombosis.2 The trait is inherited in an autosomal dominant manner with the risk of thrombosis increased seven times in heterozygotes and 80 times in homozygotes. 3 Studies have shown that the distribution of the factor V Leiden mutation varies in different populations, being present in about 5% of Caucasian individuals (Europeans, Jews, Arabs and Indians) and virtually absent in Africans and Asians.

Rey et al 2003 published a meta-analysis confirming the association between recurrent fetal loss and the factor V Leiden mutation.4 Rai et al 2002 aimed to tease out the isolated contribution of factor V Leiden by comparing FVL+ women with recurrent fetal loss to FVL- women with the same history of fetal loss. The live birth rate was significantly lower among the women who carried the mutation confirming that factor V Leiden independently increases the risk of fetal loss.5 Data from our recently published meta-analysis concludes that factor V Leiden is also associated with a 2.9 fold (95%CI 2.0-4.3) increased risk of severe pre-eclampsia and a 4.8 fold (95% CI 2.4-9.4) increased risk of fetal growth retardation6.

A function enhancing mutation in the Prothrombin gene (Prothrombin G20210A) results in higher circulating levels of prothrombin, the precursor of thrombin. This mutation is present in 2.3 % of the general population is associated with a 3-4 fold increased risk of thromboembolism. The Leiden thrombophilia study reported a relative risk of 2.8 with the 20210A Prothrombin gene variant in 2.3% of healthy carriers and 6.2% of consecutive controls.

A meta-analysis with pooled data from nine studies (n=2087) indicated a significant association between the prothrombin G20210A mutation with late non-recurrent fetal loss (2.30,1.09-4.87) 4 A number of small case-control studies have conflicting results with respect to a possible association between prothrombin and the risk of pre-eclampsia and intrauterine growth restriction; and larger prospective studies are needed to clarify a possible relationship. There have been no studies evaluating a possible risk of adverse pregnancy outcome associated with the fetal Prothrombin G20210A mutation.

Most of the research in this area has been in the form of case-control studies which are notoriously subject to bias. We are therefore proposing a nested case-control study, which is methodologically more vigorous.

Placental thrombi resulting in placental infarction may occur on either side of the maternal-fetal interface, and theoretically the fetal as well as the maternal factor V Leiden genotype may influence the risk of adverse pregnancy outcome. Therefore, we aim to address the effect, not only of maternal factor V Leiden and prothrombin G20210A mutation, but also of fetal factor V Leiden and prothrombin G20210A mutation on pre-eclampsia, intrauterine growth retardation and late fetal death.

1 Rosendaal F. Thrombosis Series: Venous thrombosis: a multi causal disease. Lancet 1993;353:1167-73.

2 Bertina R, Koelenan B, Koster T, Rosendall FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:65-67.

3 Spina V, Aleandri V, Morini F. The impact of Factor V Leiden on pregnacy. Hum Reprod Update 2000;6: 301-306.

4 Rey E, Kahn S, David M, Shier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361:901-908.

5 Rai R, Backos M, Elgaddal S, Shlebak A, Regan L. Factor V leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Human Reproduction 2002;17:442-445.

6 Dudding TE, Attia J. The association between adverse pregnancy outcomes and maternal factor V ledien genotype: a meta-analysis. Thromb Haemost 2004;91:700-11.

Date proposal received: 
Monday, 1 March, 2004
Date proposal approved: 
Monday, 1 March, 2004
Genetics, Obstetrics, Pregnancy
Primary keyword: