The association between adverse pregnancy outcomes and maternal factor V Leiden genotype: a meta-analysis

Summary

The conclusions of studies to date which evaluate a possible association between factor V Leiden and adverse pregnancy outcome have been conflicting. This study was undertaken to further investigate this association. Our objective was to evaluate the association between adverse pregnancy outcomes and maternal factor V Leiden genotype by meta-analysis. Inclusion criteria were: (a) cohort or case control design; (b) outcomes clearly defined as one of the following: first or second/ third trimester miscarriage or intrauterine death, preeclampsia, fetal growth retardation, or placental abruption; (c) both the case and control mothers tested for the factor V Leiden mutation; (d) sufficient data for calculation of an odds ratio. Both fixed and random effect models were used to pool results and heterogeneity and publication bias were checked. For first trimester fetal loss, the pooled odds ratio was heterogeneous (p=0.06) and no dose-response curve could be found. For second/third trimester fetal loss, there was a consistent and graded increase in risk: the odds ratio was 2.4 (95% CI 1.1-5.2) for isolated (non-recurrent) third trimester fetal loss, rising to 10.7 (95% CI 4.0-28.5) for those with 2 or more second/third trimester fetal losses. FactorV Leiden is associated with a 2.9 fold (95% CI 2.0-4.3) increased risk of severe preeclampsia, and a 4.8 fold (95% CI 2.4-9.4) increased risk of fetal growth retardation. These results support factor V Leiden testing for women with recurrent fetal loss in the second/third trimester. Women with only 1 event may also warrant testing if the fetal loss occurred in the third trimester. Conversely, in those women known to have the factor V Leiden mutation, monitoring for adverse pregnancy outcomes is warranted; whether this means increased vigilance or anti-coagulant prophylaxis is still contentious.

Keywords

Factor V Leiden - fetal death - intrauterine growth retardation - preeclampsia - pregnancy - meta-analysis

• References

• 1 Martinelli I, Taioli E, Cetin I. et al.. Thrombophilias and adverse outcomes of pregnancies. What should a clinician do?. N Engl J Med 1999; 340: 50-2.
• 2 Blumenfeld Z, Brenner B. Thrombophiliaassociated pregnancy wastage. Fertil Steril 1999; 72: 765-74.
• 3 Martinelli I, Emanuela T, Cetin I. et al.. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med 2000; 343: 1015-8.
• 4 Rosendaal F. Thrombosis Series: Venous thrombosis: a multi causal disease. Lancet 1993; 353: 1167-73.
• 5 Bertina R, Koelenan B, Koster T. et al.. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 65-7.
• 6 Spina V, Aleandri V, Morini F. The impact of Factor V Leiden on pregnancy. Hum Reprod Update 2000; 06: 301-6.
• 7 De Stephano V, Chiusolo P, Paciaroni K, Leone G. Epidemiology of Factor V Leiden: Clinical Implications. Semin Thromb Hemost 1998; 24: 367-79.
• 8 Hashimoto K, Shizusawa Y, Shimoya K. et al.. The factor V Leiden mutation in Japanese couples with recurrent spontaneous abortions. Hum Reprod 1999; 14: 1872-4.
• 9 Kutteh W, Park V, Deitcher S. Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999; 71: 1048-53.
• 10 Dizon-Townson D, Kinney S, Branch D. et al.. The factor V Leiden mutation is not a common cause of recurrent miscarriage. J Reprod Immunol 1997; 34: 217-23.
• 11 Alfirevic Z, Mousa H, Martlew V. et al.. Postnatal screening for thrombophilia in women with severe pregnancy complications. Obstet Gynecol 2001; 97: 753-9.
• 12 Murphy R, Donoghue C, Nallen R. 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.
• 13 O’Shaughnessy K, Fu B, Ferraro S. et al.. Factor V Leiden and thermalite labelled methylenetetrahydrofolate reductase gene variance in an East Anglian preeclampsia cohort. Hypertension 1999; 33: 1338-41.
• 14 Hatzis T, Cardamakis E, Drivalas E. et al.. Increased resistance to activated protein C and factor V Leiden in recurrent abortions. Review of other hypercoagulability factors. Eur J Contracept Reprod Health Care 1999; 04: 135-44.
• 15 Rothbarth H, Ohel G, Younis J. et al.. High Prevalence of Activated Protein C resistance Due to Factor V Leiden Mutation in Cases of intrauterine fetal Death. J Matern fetal Med 1999; 08: 228-30.
• 16 Raziel A, Kornberg Y, Friedler S. et al.. Hypercoagulable thrombophilic defects and hyperhomocysteinemia in patients with recurrent pregnancy loss. Am J Reprod Immunol 2001; 45: 65-71.
• 17 Souza S, Ferriani R, Pontes A. et al.. Factor V Leiden and factor II G20210A mutations in patients with recurrent abortion. Hum Reprod 1999; 14: 2448-50.
• 18 Ridker P, Miletich J, Buring J. et al.. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998; 128: 1000-3.
• 19 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.
• 20 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.
• 21 Tal J, Schliamser L, 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.
• 22 Pihusch R, Buchholz T, Lohse P. et al.. Thrombophilic Gene Mutations and Recurrent Spontaneous Abortion: Prothrombin Mutation Increases the risk in the first trimester. AJRI 2001; 46: 124-31.
• 23 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.
• 24 Balasch J, Reverter J, Fabregues F. et al.. First-trimester repeated abortion is not associated with activated protein C resistance. Hum Reprod 1997; 12: 1094-7.
• 25 Tormene D, Simioni P, Prandoni P. et al.. The risk of fetal loss in family members of probands with factor V Leiden mutation. Thromb Haemost 1999; 82: 1237-9.
• 26 Pauer H, Neesen J, Hinney B. Factor V Leiden and its relevance in patients with recurrent abortions. Am J Obstet Gynecol 1998; 178: 629.
• 27 Rai R, Shlebak A, Cohen H. et al.. Factor V Leiden and acquired activated protein C resistance among 1000 women with recurrent miscarriage. Hum Reprod 2001; 16: 961-5.
• 28 Bare S, Poka R, Balogh I, Ajzner E. Factor V Leiden as a risk factor for miscarriage and reduced fertility. Aust NZ J Obstet Gynaecol 2000; 40: 186-90.
• 29 Foka Z, Lambropoulos A, Saravelos H. et al.. Factor V Leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod 2000; 15: 458-62.
• 30 Younis J, 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.
• 31 Preston F, Rosendaal F, Walker I. et al.. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
• 32 Gris J, Quere I, Monpeyroux F. et al.. Casecontrol study of the frequency of thrombophilic disorders in couples with late foetal loss and no thrombotic antecedent – the Nimes Obstetricians and Haematologists Study5 (NOHA5). Thromb Haemost 1999; 81: 891-9.
• 33 Kupferminc M, Eldor A, Steinman N. et al.. Increased frequency of genetic thrombophilia in women with complications in pregnancy. N Engl J Med 1999; 340: 9-13.
• 34 Meinardi J, Middeldorp S, de Kam P. et al.. Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130: 736-9.
• 35 Lindquist P, Svensson P, Marsaal K. et al.. Activated protein C resistance (FV: Q506) and pregnancy. Thromb Haemost 1999; 81: 532-7.
• 36 Mello G, Parretti E, Martini E. et al.. Usefulness of screening for congenital or acquired hemostatic abnormalities in women with previous complicated pregnancies. Haemostasis 1999; 29: 197-203.
• 37 Dizon-Townson D, Nelson L, Easton K. et al.. The factor V Leiden mutation may predispose women to severe preeclampsia. Am J Obstet Gynecol 1996; 175: 902-5.
• 38 Grandone E, Margaglione M, Colaizzo D. et al.. Factor V Leiden, C>T MTHFR polymorphism and genetic susceptibility to preeclampsia. Thromb Haemost 1997; 77: 1052-4.
• 39 Lindoff C, Ingemarsson I, Martinsson G. et al.. Preeclampsia is associated with a reduced response to activated protein C. Am J Obstet Gynecol 1997; 176: 457-60.
• 40 Kobashi G, Yamada H, Asana T. et al.. The factor V Leiden mutation is not a common cause of pregnancy-induced hypertension in Japan. Semin Thromb Hemost 1999; 25: 487-9.
• 41 Nagy B, Toth T, Rigo Jr J. et al.. Detection of factor V Leiden mutation in severe preeclamptic Hungarian women. Clin Genet 1998; 53: 478-81.
• 42 De Groot C, Bloemenkamp K, Duvekot E. et al.. Preeclampsia and genetic risk factors for thrombosis: a case-control study. Am J Obstet Gynecol 1999; 181: 975-80.
• 43 Horstkamp B, Kiess H, Kramer J. et al.. Activated protein C resistance shows an association with pregnancy-induced hypertension. Hum Reprod 1999; 14: 3112-5.
• 44 Grandone E, Margaglione M, Colaizzo D. et al.. Prothrombotic genetic risk factors and the occurrence of gestational hypertension with or without proteinuria. Thromb Haemost 1999; 81: 349-52.
• 45 Rigo Jr J, Nagy B, Fintor L. et al.. Maternal and neonatal outcome of preeclamptic pregnancies; the potential roles of factor V Leiden mutation and 5,10 methylenetetrahydrofolate reductase. Hypertens Pregnancy 2000; 19: 163-72.
• 46 van Pampus M, Dekker G, Wolf H. et al.. High prevalence of hemostatic abnormalities in women with a history of severe pre-eclampsia. Am J Obstet Gynecol 2000; 182: 989-90.
• 47 Kupferminc M, Fait G, Many A. et al.. Severe preeclampsia and high frequency of genetic thrombophilic mutation. Obstet Gynecol 2000; 96: 45-9.
• 48 Mimuro S, Lahoud R, Beutler L. et al.. Changes of resistance to activated protein c in the course of pregnancy and the prevalence of factor V mutation. Aust NZ J Obstet Gynaecol 1998; 38: 200-4.
• 49 Von Tempelhoff G, Heilmann L, Spanuth E. et al.. Incidence of the factor V Leiden-mutation, coagulation inhibitor deficiency and elevated antiphospholipid-antibodies in patients with preeclampsia or HELLP-syndrome. Hemolysis, elevated liver-enzymes, low platelets. Thromb Res 2000; 100: 363-5.
• 50 Livingston J, Barton J, Park V. et al.. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol 2001; 185: 153-7.
• 51 Young KimJu, Williamson R, Murray J. et al.. Genetic susceptibility to preeclampsia: Roles of cytosine-to-thymine substitution at nucleotide 677 of the gene for methylenetetrahydro-folate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathionine Beta-synthase, and factor V Leiden. Am J Obstet Gynecol 2001; 184: 1211-7.
• 52 Fatini C, Gensini F, Battaglini B. et al.. Angiotension-converting enzyme DD genotype, angiotensin type 1 receptor CC genotype, and hyperhomocysteinemia increase first-trimester fetal-loss susceptibility. Blood Coagul Fibrinolysis 2000; 11: 657-62.
• 53 Reznikoff-Etievant M, Cayol V, Carbonne B. et al.. Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage. Br J Obstet Gynaecol 2001; 108: 1251-4.
• 54 Public Health Division. New South Wales Mothers and Babies 2000. Sydney. Department of Health. 2001
• 55 American College of Obstetricians and Gynaecologists. Hypertension in Pregnancy. ACOG technical bulletin no 219. Washington DC: American College of Obstetricians and Gynaecologists; 1996
• 56 Martinelli P, Grandone E, Colaizzo D. et al.. Familial thrombophilia and the occurrence of fetal growth restriction. Thromb Haemost 2001; 86: 428-31.
• 57 Wiener-Megnagi Z, Ben-Shlomo I, Goldgerg Y. et al.. Resistance to activated protein C and the Leiden mutation: High prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998; 179: 1565-7.
• 58 Verspyck E, Le Cam-Duchez V, Goffinet F. et al.. Thrombophilia and immunological disorders in pregnancies as risk factors for small for gestational age infants. Br J Obstet Gynaecol 2002; 109: 28-33.
• 59 Glueck C, Kupferminic M, Fontaine R. et al.. Genetic Hypofibrinolysis in Complicated Pregnancies. Obstet Gynecol 2001; 97: 44-8.
• 60 Glueck C, Phillips H, Cameron D. et al.. The 4G/4G Polymorphism of the hypofibrinolytic plasminogen activator inhibitor type 1 gene: an independent risk factor for serious pregnancy complications. Metabolism 2000; 49: 845-52.
• 61 Infante-Rivard C, Rivard G, Yotov W. et al.. Absence of association of thrombophilia polymorphisms with intrauterine growth retardation. N Engl J Med 2002; 347: 19-25.
• 62 Hira B, Pegoraro R, Rom L. et al.. Polymorphisms in various coagulation genes in black South African women with placental abruption. Br J Obstet Gynaecol 2002; 109: 574-5.
• 63 Currie L, Peek M, McNiven M. et al.. Is there an increased maternal-infant prevalence of Factor V Leiden in association with severe pre-eclampsia?. Br J Obstet Gynaecol 2002; 109: 191-6.
• 64 D’Elia A, Driul L, Giacomello R. et al.. Frequency of Factor V, Prothrombin and Methylenetetrahydrofolate reductase gene variants in preeclampsia. Gynecol Obstet Invest 2002; 53: 84-7.
• 65 Morrison ER, Miedzybrodzka ZH, Campell DM. et al.. Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results of a large population based study and systematic review. Thromb Haemost 2002; 87: 779-85.
• 66 Finan R, Tamim H, Ameen G. et al.. Prevalence of Factor V G1691A (Factor V–Leiden) and Prothrombin G20210A gene mutations in a recurrent miscarriage population. Am. J. Hematol 2002; 71: 300-5.
• 67 Paternoster D, Stella A, Simioni P. et al.. Activated protein C resistance in normal and pre-eclamptic pregnancies. Gynecol Obstet Invest 2002; 54: 145-9.
• 68 Alonso A, Soto I, Urgelles M. et al.. Acquired and inherited thrombophilia in women with unexplained fetal losses. Am J Obstet Gynecol 2002; 187: 1337-42.
• 69 Grandone E, Colaizzo D, Brancaccio V. et al.. Impact of prothrombotic mutations and family history on the recurrence of intra-uterine fetal deaths. Haematologica 2002; 87: 1118-9.
• 70 Benedetto C, Marozio L, Salton L. et al.. Factor V Leiden and FactoII G210A in preeclamsia and HELLP syndrome. ACTA Obstet Gynecol Scand 2002; 81: 1095-100.
• 71 Kupferminc M, Many A, Bar-Am A. et al.. Mid-trimester severe intruterine growth restriction is associated with a high prevalence of thrombophilia. BJOG 2002; 109: 1373-6.
• 72 Agorastos T, Karavida A, Lambropoulos A. et al.. Factor V Leiden and prothrombin G20210A mutations in pregnancies with adverse outcome. J Matern Fetal Neonatal Med 2002; 12: 267-73.
• 73 Carp H, Salomon O, Seidman D. et al.. Prevalence of genetic markers for thrombophilia in recurrent pregnancy loss. Hum Reprod 2002; 17: 1633-7.
• 74 Yamada H, Kato E, Kobashi G. et al.. Recurrent pregnancy loss: etiology of thrombophilia. Semin Thromb Hemost 2001; 27: 121-9.
• 75 Many A, Yaron Y, Eldor A. et al.. Third-trimester unexplained intrauterine fetal death is associated with inherited thombophilia. Obstet Gynecol 2002; 99: 684-7.
• 76 Pabinger I, Nemes L, Rintelen C. et al.. Pregnancy-associated risk for venous thromboemolism and pregnancy outcome in women homozygous for factor V Leiden. Hematol J 2002; 01: 37-41.
• 77 Sarig G, Younis J, Hoffman R. et al.. Thrombophilia is common in women with idopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002; 77: 342-7.
• 78 Dilley A, Benito C, Hooper W. 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.
• 79 Martinelli I, Emanuela T, Cetin I. et al.. Recurrent late fetal death in women with and without thrombophilia. Thromb Haemost 2002; 87: 358-9.
• 80 vonKries R, Junker R, Oberle D. et al.. Fetal Growth Restriction in Children with Prothrombotic Risk Factors. Thromb Haemost 2001; 86: 1012-6.
• 81 Grandone E, Margaglione M, Colaizzo D. et al.. Lower birth-weight in neonates of mothers carrying factor V G1691A and factor II A mutations. Haematologica 2002; 87: 177-81.
• 82 Yusoff N, Abdullah W, Ghazali S. et al.. The absence of factor V Leiden mutation in Malays with recurrent spontaneous abortions. Aust NZ J Obstet Gynaecol 2002; 42: 164-6.
• 83 McAuley L, Pham B, Tugwell P. et al.. Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?. Lancet 2000; 356: 1228-31.
• 84 Juni P, Holenstein F, Sterne J. et al.. Direction and impact of language bias in meta-analyses of controlled trials: empirical study. Int J Epidemiol 2002; 31: 115-23.
• 85 Moher D, Pham B, Klassen T. et al.. What contributions do languages other than English make on the results of meta-analyses?. J Clin Epidemiol 2000; 53: 964-72.
• 86 Rai R, Backos M, Elgaddal S. et al.. Factor V leiden and recurrent miscarriage-prospective outcome of untreated pregnancies. Hum Reprod 2002; 17: 442-5.
• 87 Suarez-Almazor M, Belseck E, Homik J. et al.. Identifying clinical trials in the medical literature with electronic databases: MEDLINE alone is not enough. Control Clin Trials 2000; 21: 476-87.
• 88 Rey E, Kahn S, David M. et al.. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901-8.