Factor V Leiden and the risk of stillbirth in a German population

Summary

An association between the factor V Leiden variant and an increased risk of pregnancy loss has been reported. Most previous studies were performed with clinically recruited patients and controls. This approach may cause selection bias. The present analysis was performed with the aim to investigate the association between the factor V Leiden mutation and the risk of stillbirth in a population-based sample.

The Study of Health in Pomerania (SHIP) is a survey that was carried out in North East Germany. A random sample from the population aged 20 to 79 years was taken. The total SHIP population comprised 4,310 participants. The presence of the factor V Leiden variant was determined by PCR and Mnl I digestion. The presence of the factor V Leiden variant was neither associated with the number of pregnancies nor with the number of children per women. Data from 1,768 females who had at least one pregnancy with known outcome was available for the present analysis. Seventy-three women (4.1%) reported at least one stillbirth. Women with and without the factor V Leiden mutation did not differ with respect to the number of women with at least one stillbirth (OR for factor V Leiden variant 1.57; 95%-CI 0.76 – 3.25). Furthermore, the number of women with two or more stillbirths, the number of stillbirths per affected woman and the number of stillbirths per number of pregnancies per woman was similar between both genotype groups.

In conclusion, there is no association between the factor V Leiden mutation and the risk of stillbirth in a representative population sample.

Keywords

Factor V Leiden - APC resistance - stillbirth - pregnancy loss - SHIP

• References

• 1 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Procl Natl Acad Sci 1993; 90: 1004-8.
• 2 Curvers J, Thomassen CLGD, Rimmer J. et al. Effects of hereditary and acquired risk factors of venous thrombosis on a thrombin generation-based APC resistance test. Thromb Haemost 2002; 88: 5-11.
• 3 Bertina RM, Koelemann BPC, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 4 Rosendaal FR, Koster T, Vandenbrouke JP. et al. High risk of thrombosis in patients homo-zygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-8.
• 5 Clark P, Brennand J, Conkie JA. et al. Activated protein C sensitivity, protein S and coagulation and normal pregnancy. Thromb Haemost 1998; 79: 1166-70.
• 6 Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353: 1258-65.
• 7 Gris JC, Quere I, Monpeyroux F. et al. Case-control study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent. The Nimes Obstetricians and Haematologists Study (NOHA). Thromb Haemost 1999; 81: 891-9.
• 8 Alonso A, Soto I, Urgelles MF. et al. Acquired and inherited thromophilia in women with unexplained fetal loss. Am J Obstet Gynecol 2002; 187: 1337-42.
• 9 Rai R, Regan L, Hadley E. et al. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1996; 92: 489-90.
• 10 Brenner B, Mandel H, Lanir N. et al. Activated protein C resistance can be associated with recurrent fetal loss. Br J Haematol 1997; 97: 551-4.
• 11 Younis JS, Brenner B, Ohel G. et al. Activated protein C resistance and factor V Leiden mutation can be associated with first- as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol 2000; 43: 31-5.
• 12 Grandone E, Margaglione M, Colaizzo D. et al. Factor V Leiden is associated with repeated and recurrent unexplained fetal losses. Thromb Haemost 1997; 77: 822-4.
• 13 Ridker PM, Miletich JP, Buring JE. et al. Factor V Leiden as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998; 128: 1000-3.
• 14 Tormene D, Simioni P, Prandoni P. et al. The risk of fetal loss in family members of pro-bands with factor V Leiden. Thromb Haemost 1999; 82: 1237-9.
• 15 Brenner B, Sarig G, Weiner Z. et al. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 1999; 82: 6-9.
• 16 Meinardi JR, Middeldorp S, de Kam PJ. et al. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130: 736-9.
• 17 Martinelli I, Taioli E, Cetin I. et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 1015-18.
• 18 Tal J, Schliamser LM, Leibovitz Z. et al. A possible role for activated protein C resistance in patients with first and second trimester pregnancy failure. Hum Reprod 1999; 14: 1624-7.
• 19 Murphy RP, Donoghue C, Nallen RJ. et al. Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2000; 20: 266-70.
• 20 Finan RR, Tamim H, Ameen G. et al. Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G202210A gene mutations in a recurrent miscarriage population. Am J Hematol 2002; 71: 300-5.
• 21 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 22 Yusoff NM, Abdullah WZ, Ghazali S. et al. The absence of factor V Leiden mutation in Malays with recurrent spontaneous abortion. Aust N Z J Obstet Gynaecol 2002; 42: 164-6.
• 23 Carp H, Salomon O, Seidman D. et al. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod 2002; 17: 1633-7.
• 24 Dilley A, Benito C, Hooper WC. et al. Mutations in the factor V, prothrombin and MTHFR genes are not risk factors for recurrent fetal loss. J Matern Fetal Neonatal Med 2002; 11: 176-82.
• 25 John U, Greiner B, Hensel E. et al. Study of health in Pomerania (SHIP): a health examination survey in an east German region: objectives and design. Soz-Präventivmed 2001; 46: 186-94.
• 26 Schröder W, Koesling M, Wulff K. et al. Large-scale screening for factor V Leiden mutation in a north-eastern German population. Haemostasis 1996; 26: 233-6.
• 27 Ardelt W, Pasold K, Hillemanns HG. Side effects of drug for thromboembolism prophylaxis. Results from the University Women’s Clinic Freiburg/Br. Fortschr Med 1979; 97: 471-4.
• 28 Wilcox AJ, Weinberg CR, O’Connor JF. et al. Incidence of early loss of pregnancy. N Engl J Med 1988; 319: 189-94.
• 29 Bare SN, Poka R, Balogh I. et al. Factor V Leiden is a risk factor for miscarriage and reduced fertility. Aust N Z J Obstet Gynaecol 2000; 40: 186-190.
• 30 Juul K, Tybjaerg-Hansen A, Nordestgaard BG. Factor V Leiden: relation to fertility?. Lancet 2002; 359: 321.
• 31 Göpel W, Ludwig M, Junge AK, Kohlmann T, Diederich K, Möller J. Selection pressure for the factor V Leiden mutation and embryo implantation. Lancet 2001; 358: 1238-1239.
• 32 Wood SL, Sauve R, Ross S, Brant R, Love EJ. Prediabetes and perinatal mortality. Diabetes Care 2000; 23: 1752-1754.
• 33 De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia: indications and therapeutic implications. Haematologica 2002; 87: 1095-1108.
• 34 Shahar E, Folsom AR, Jackson R. The effect of nonresponse on prevalence estimates for a referent population: insights from a population-based cohort study. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Ann Epidemiol 1996; 6: 498-506.