Case-control Study of the Frequency of Thrombophilic Disorders in Couples with Late Foetal Loss and no Thrombotic Antecedent

Jean-Christophe Gris; Isabelle Quéré; Françoise Monpeyrou; Eric Mercier; Sylvie Ripart-Neveu; Marie-Laure Tailland; Méderic Hoffet; Jacques Berlan; Jean-Pierre Daurès; Pierre Marès

doi:10.1055/s-0037-1614594

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1999; 81(06): 891-899
DOI: 10.1055/s-0037-1614594

Letters to the Editor

Schattauer GmbH

Case-control Study of the Frequency of Thrombophilic Disorders in Couples with Late Foetal Loss and no Thrombotic Antecedent

The Nîmes Obstetricians and Haematologists Study⁵ (NOHA⁵)

Jean-Christophe Gris

¹From the Consultation et Laboratoire d’Hématologie, University Hospital, Nîmes

²Laboratoire d’Hématologie, Faculté de Pharmacie, Montpellier

,

Isabelle Quéré

³Service de Médecine Interne B, Médecine Vasculaire, University Hospital, Montpellier

,

Françoise Monpeyrou

⁴Département d’Information Médicale and Nîmes, France

,

Eric Mercier

¹From the Consultation et Laboratoire d’Hématologie, University Hospital, Nîmes

,

Sylvie Ripart-Neveu

⁵Département de Gynécologie et Obstétrique, University Hospital, Nîmes, France

,

Marie-Laure Tailland

⁵Département de Gynécologie et Obstétrique, University Hospital, Nîmes, France

,

Méderic Hoffet

⁵Département de Gynécologie et Obstétrique, University Hospital, Nîmes, France

,

Jacques Berlan

²Laboratoire d’Hématologie, Faculté de Pharmacie, Montpellier

,

Jean-Pierre Daurès

⁴Département d’Information Médicale and Nîmes, France

,

Pierre Marès

⁵Département de Gynécologie et Obstétrique, University Hospital, Nîmes, France

› Author Affiliations

Abstract

Summary

Background: Women with familial thrombophilia have an increased risk of still birth. We postulated that the presence of asymptomatic risk factors for venous thrombosis might be a risk factor for late foetal loss. Methods: We performed a case-control study on the prevalence of heritable thrombophilic defects, of antiphospholipid-related markers and of the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with at least one episode of late unexplained foetal loss and in control women with successful pregnancies. Partners of cases and controls were also studied. Written conclusions of the pathological examination of the placentas, when available, were also reviewed. Results: We found at least one positive biological risk factor for venous thrombosis in 21.1% of the patients and in 3.9% of the controls (p <10^–4). In women, the crude odds ratio for still birth associated with any positive biological risk factor for venous thrombosis was 5.5, 95% confidence interval (_95%CI) [3.4-9.0]. No difference was found between partners of cases and controls (5.2% and 4.7%). Using conditional logistic regression analysis, 4 adjusted risk factors for still birth remained: protein S deficiency, positive anti β₂ glycoprotein I IgG antibodies, positive anticardiolipin IgG antibodies and the factor V Leiden mutation. The C677T mutation in the MTHFR gene was not an individual risk factor but an homozygous genotype was strongly associated with the former 4 risk factors (16.8% of patients vs. 0.9% of controls). In women with such associations, still births always occurred in absence of folic acid supplementation during pregnancy. Available conclusions of pathological analysis of placentas were found to have a very high proportion of “maternal vascular disease of the placenta” in patients with at least one positive risk marker for thromboembolism, specially in case of association with the C677T MTHFR homozygous genotype, compared to patients with negative markers (p <10^–4). Conclusions: Late foetal loss, through placenta thrombosis, may sometimes be the consequence of a maternal multifactorial prothrombotic state associating traditional heritable or acquired thrombosis risk factors to conditions predisposing to an acute mild hyperhomocysteinaemia (coexistence of a genetic predisposition with late pregnancy-related increased folate needs).

Full Text

References

References
1 Sanson BJ, Friederich PW, Simioni P, Zanardi S, Huisman MV, Girolami A, ten Cate JW, Prins MH. The risk for abortion and still birth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost 1996; 75: 387-8.
2 Preston PE, Rosendaal FR, Walker ID, Briët E, Berntorp E, Conard J, Fontcuberta F, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani I, Scharer I, Shulman S, van der Meer FJM. Increased foetal loss in women with heritable thrombophilia. Lancet 1996; 348: 913-6.
3 Gris JC, Ripart-Neveu S, Brun S, Tailland ML, Maugard C, Courtieu C, Biron C, Hoffet M, Hédon B Marès P. Prospective evaluation of the prevalence of haemostasis abnormalities in unexplained primary early recurrent miscarriages – The Nîmes Obstetricians and Haematologists (NOHA) study. Thromb Haemost 1997; 77: 1096-103.
4 Constant G, Gouault-Heilmann M, Martinolli JL. Heparin inactivation during blood storage. Its prevention by blood collection in citric acid, theophylline, adenosine, dipyridamol – CTAD mixture –. Thromb Res 1983; 31: 365-74.
5 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmug der Fibrinogene. Acta Hematol (Basel) 1957; 17: 237-46.
6 Odegard OR, Lie M, Abildgaard U. Heparin cofactors activity measured by an amidolytic method. Thromb Res 1975; 6: 287-94.
7 Martinolli JL, Stocker K. Fast functional protein C assay using protac, a novel protein C activator. Thromb Res 1986; 43: 253-4.
8 Wolf M, Boyer-Neumann C, Martinolli JL. A new functional assay for human protein S activity using activated factor V as substrate. Thromb Haemost 1989; 4: 1144-5.
9 Gris JC, Toulon P, Brun S, Maugard C, Sarlat C, Schved JF, Berlan J. The relationship between plasma microparticles, protein S and anticardiolipin antibodies in patients with human immunodeficiency virus. Thromb Haemost 1996; 76: 38-45.
10 Trossaërt M, Conard J, Horellou MH, Elalamy I, Samama MM, Ireland H, Bayston TA, Lane DA. Modified APC resistance assay in patients on oral anticoagulant therapy. Lancet 1994; 344: 1709.
11 Svensson PJ, Zöller B, Dallbäck B. Evaluation of original and modified APC-resistance test in unselected outpatients with clinically suspected thrombosis and in healthy controls. Thromb Haemost 1997; 77: 332-5.
12 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
13 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 10: 3698-703.
14 Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Mathews RG, Boers GHJ. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 1995; 10: 111-3.
15 Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost 1995; 74: 1185-90.
16 Brandt J, Barna LK, Triplett DA. Laboratory identification of lupus anticoagulants: results of the second international workshop for identification of lupus anticoagulants. Thromb Haemost 1995; 74: 1597-603.
17 Reber G, Arvieux J, Comby E, Degenne D, de Moerloose P, Sanmarco M, Potron G. Multicenter evaluation of nine commercial kits for the quantitation of anticardiolipin antibodies. Thromb Haemost 1995; 73: 444-52.
18 Comp PC. Laboratory evaluation of protein S status. Semin Thromb Haemost 1990; 16: 177-81.
19 Healy AM, Rayburn HB, Rosenberg RD, Weiler H. Absence of the blood clotting regulator thrombomodulin causes embryonic lethality in mice before development of a functional cardiovascular system. Proc Natl Acad Sci USA 1995; 92: 850-4.
20 Malia RG, Kitchen S, Greaves M, Preston FE. Inhibition of activated protein C and its cofactor protein S by antiphopholipid antibodies. Br J Haematol 1990; 76: 101-7.
21 Mercier E, Quéré I, Marès P, Gris JC. Primary recurrent miscarriages: anti-β2-glycoprotein I IgG antibodies induce an acquired activated protein C resistance which can be detected by the modified activated protein C resistance test. Blood 1998; 92: 2993-4.
22 Comp PC, Thurnau RG, Welsh J, Esmon CT. Functional and immunologic protein S levels are decreased during pregnancy. Blood 1986; 68: 881-5.
23 Gruel Y, Moalic P, Durouchet E, Guerois C, Delahousse B, Leroy J. Levels of total and free protein S during normal and pathologic pregnancy and in post-partum. Thromb Haemost 1987; 58: 404.
24 Cumming AM, Tait RC, Fildes S, Yong A, Kenney S, Hay CRM. Development of resistance to activated protein C during pregnancy. Br J Haematol 1995; 90: 725-7.
25 Conard J, Horellou MH, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in ATIII, protein C or protein S: study of 78 women. Thromb Haemost 1990; 63: 319-20.
26 DeStefano V, Leone G, Mastrangelo S, Tripodi A, Rodeghiero F, Castaman G, Barbui T, Finazzi G, Bizzi B, Manuci PM. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb Haemost 1995; 74: 799-800.
27 Mc Coll MD, Ramsay JE, Tait RC, Walker ID, Mac Call F, Conkie JA, Carty MJ, Greer IA. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183-8.
28 De Vries JI, Dekker GA, Huijgens PC, Jakobs C, Blomberg BM, van Geijn HP. Hyperhomocysteinaemia and protein S deficiency in complicated pregnancies. Br J Obstet Gynaecol 1997; 104: 1248-54.
29 Rai R, Regan L, Hadley E, Dave M, Cohen H. Second-trimester pregnancy loss is associated with activated protein C resistance. Br J Haematol 1995; 92: 489-90.
30 Rai RS, Regan L, Chitolie A Donald JG, Cohen H. Placental thrombosis and second trimester miscarriage in association with activated protein C resistance. Br J Obstet Gynaecol 1996; 103: 842-4.
31 Grandone E, Margaglione M, Claizzo D, d’Addedda M, Cappucci G, Vecchione G, Sciannami N, Pavone G, Di Minno G. Factor V Leiden is associated with repeated and recurrent unexplained foetal loss. Thromb Haemost 1997; 77: 822-4.
32 Brener B, Mandel H, Lami N, Yonnis J, Rothbart H, Ohel G, Blumenfeld Z. Activated protein C resistance can be associated with recurrent foetal loss. Br J Haematol 1997; 97: 551-4.
33 Grandone E, Margaglione M, Colaizzo D, Montanaro S, Pavone G, Di Minno G. Presence of factor V Leiden and MTHFR mutation in a patient with complicated pregnancies. Thromb Haemost 1997; 77: 1036-7.
34 De Stefano V, Mastrangelo S, Paciaroni K, Ireland H, Lane DA, Scirpa P, Bizzi B, Leone G. Thrombotic risk during pregnancy and puerperium in women with APC-resistance – Effective subcutaneous heparin prophylaxis in a pregnant woman. Thromb Haemost 1995; 74: 793-4.
35 Hellgren M, Svenson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 1995; 173: 210-5.
36 Hirsch DR, Mikkola KM, Marks PW. Pulmonary embolism and deep vein thrombosis during pregnancy and oral contraceptive use: prevalence of factor V Leiden. Am Heart J 1996; 131: 1145-8.
37 Bokarewa MI, Bremme K, Blömback M. Arg⁵⁰⁶-Gln mutation in factor V and risk for thrombosis during pregnancy. Br J Haematol 1996; 92: 473-8.
38 Cattaneo M, Tsai MY, Bucciarelli P, Taioli E, Zighetti ML, Bignell M, Mannucci PM. A common mutation in the methylenetetrahydrofolate reductase gene (C677T) increases the risk for deep vein thrombosis in patients with mutant factor V (factor V: Q⁵⁰⁶). Arterioscler Thromb Vascul Biol 1997; 17: 1662-6.
39 Aoki KA, Dubkiewicz AB, Matsuura E, Novotny M, Kaberlein G, Gleicher N. Clinical significance of beta2-glycoprotein I-dependent anti- cardiolipin antibodies in the reproductive autoimmune failure syndrome: correlation with conventional antiphospholipid antibody detection system. J Obstet Gynecol 1995; 172: 926-31.
40 Katano K, Aoki A, Sasa H, Ogasawara M, Matsuura E, Yagami Y. Beta 2-glycoprotein I-dependent anticardiolipin antibodies as a predictor of adverse pregnancy outcomes in healthy pregnant women. Hum Reprod 1996; 11: 509-12.
41 Faden D, Tincani A, Tanzi P, Spatola L, Lojacono A, Tarantini M, Balestrieri B. Anti-beta 2 glycoprotein I antibodies in a general population: preliminary results on the prevalence and correlation with pregnancy outcome. Anti-beta 2 glycoprotein I antibodies are associated with some obstetrical complications, mainly pre-eclampsia-eclampsia. Eur J Obstet Gynecol Reprod Biol 1997; 73: 37-42.
42 Cook V, Weeks J, Brown J, Bendon R. Umbilical artery occlusion and fetoplacental thromboembolism. Obstet Gynecol 1995; 85: 870-2.
43 Molloy AM, Daly S, Mills JL, Kirke PN, Whitehead AS, Ramsbotton D, Conley MR, Weir DG, Scott JM. Thermolabile variant of 5,10-methylene-tetrahydrofolate reductase associated with low red-cell folates: implications for folate intake recommendations. Lancet 1997; 349: 1591-3.
44 Quéré I, Wutschert R, Zittoun J, Bellet H, Reber G, Gris JC, Janbon C, Schved JF, de Moerloose P. Association of red-blood methylfolate but not plasma folate with C677T MTHFR polymorphism in venous thromboembolic disease. Thromb Haemost 1998; 80: 707-9.
45 Goddijn-Wessel TA, Wouters MG, van de Molen EF, Spuijbroek MD, Steegers-Theunissen RP, Blom HJ, Boers GH, Eskes TK. Hyperhomocysteinemia: a risk factor for placental abruption or infarction. Eur J Obstet Gynecol Reprod Biol 1996; 66: 23-9.