ABSTRACT
There has been an sudden increase of knowledge about thrombophilias in the last decade as new thrombophilias are discovered and new associations are explored. It is now evident that thrombophilias are common and that the clinical consequences of having a thrombophilia do not appear to be limited to venous thromboembolism. The placenta-mediated pregnancy complications are also common (more than one in six pregnancies are affected) and include pregnancy loss, preeclampsia, placental abruption, and intrauterine growth restriction. These complications as a whole are the leading causes of maternal and neonatal morbidity in the developed world. Evidence has emerged to suggest that thrombophilic women may be at higher risk of developing these placenta-mediated pregnancy complications. However, is this evidence mature enough to claim that a causal association is proven? Is the evidence strong enough to recommend anticoagulant prophylaxis? We suggest that causality is not yet proven and that the data to support management with anticoagulant prophylaxis in thrombophilic pregnancies is too immature to consider this an established intervention.
KEYWORDS
Thrombophilia - intrauterine growth restriction (IUGR) - preeclampsia - pregnancy loss - placental abruption
REFERENCES
1
van der Meer F J, Koster T, Vandenbroucke J P, Briet E, Rosendaal F R.
The Leiden Thrombophilia Study (LETS).
Thromb Haemost.
1997;
78
631-635
2
Rodeghiero F, Tosetto A.
The epidemiology of inherited thrombophilia: the VITA Project. Vicenza Thrombophilia and Atherosclerosis project.
Thromb Haemost.
1997;
78(1)
636-640
3
Souto J C, Coll I, Llobet D et al..
The prothrombin 20210A allele is the most prevalent genetic risk factor for venous thromboembolism in the Spanish population.
Thromb Haemost.
1998;
80
366-369
4
Brown K, Luddington R, Williamson D, Baker P, Baglin T.
Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene.
Br J Haematol.
1997;
98
907-909
5
Poort S R, Rosendaal F R, Reitsma P H, Bertina R M.
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;
88
3698-3703
6
Koster T, Blann A D, Briet E, Vandenbroucke J P, Rosendaal F R.
Role of clotting factor VIII in effect of von Willebrand factor on occurrence of DVT.
Lancet.
1995;
345
152-155
7
Kraaijenhagen R A, Anker P S, Koopman M MW et al..
High plasma concentration of Factor VIIIc is a major risk factor for venous thromboembolism.
Thromb Haemost.
2000;
83(1)
5-9
8
Halbmayer W M, Haushofer A, Schon R et al..
The prevalence of moderate and severe FXII (Hageman factor) deficiency among the normal population: evaluation of the incidence of FXII deficiency among 300 healthy blood donors.
Thromb Haemost.
1994;
71
68-72
9
den Heijer M, Koster T, Blom H J et al..
Hyperhomocysteinemia as a risk factor for deep-vein thrombosis.
N Engl J Med.
1996;
334(12)
759-762
10
Ridker P M, Miletich J P, Hennekens C H, Buring J E.
Ethnic distribution of factor V Leiden in 4047 men and women. Implications for venous thromboembolism screening.
JAMA.
1997;
277
1305-1307
11 Department of Health WO, Scottish Department of Health .Why mothers die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994-1996 . Drife J, Lewis G London; The Stationary Office 1998
12
Berg C J, Atrash H K, Koonin L M, Tucker M.
Pregnancy-related mortality in the United States, 1987-1990.
Obstet Gynecol.
1996;
88
161-167
13 Rusen I D, Liston R, Wen S W, Bartholomew S. Special Report on Maternal Mortality and Severe Morbidity in Canada Enhanced Surveillance: The Path to Prevention. Cat. No. H39-4/44-2004E. Minister of Public Works and Government Services Canada 2004
14
Helewa M E, Burrows R F, Smith J, Williams K, Brain P, Rabkin S W.
Report of the Canadian Hypertension Society Consensus Conference: 1. Definitions, evaluation and classification of hypertensive disorders in pregnancy.
CMAJ.
1997;
157
715-725
15
Strauss R S.
Adult functional outcome of those born small for gestational age: twenty-six-year follow-up of the 1970 British Birth Cohort.
JAMA.
2000;
283
625-632
16
Ghidini A, Salafia C M, Pezzullo J C.
Placental vascular lesions and likelihood of diagnosis of preeclampsia.
Obstet Gynecol.
1997;
90(4 pt 1)
542-545
17
Salafia C M, Vintzileos A M, Silberman L, Bantham K F, Vogel C A.
Placental pathology of idiopathic intrauterine growth retardation at term.
Am J Perinatol.
1992;
9(3)
179-184
18
Salafia C M, Ernst L M, Pezzullo J C, Wolf E J, Rosenkrantz T S, Vintzileos A M.
The very low birthweight infant: maternal complications leading to preterm birth, placental lesions, and intrauterine growth.
Am J Perinatol.
1995;
12(2)
106-110
19
Salafia C M, Pezzullo J C, Lopez-Zeno J A, Simmens S, Minior V K, Vintzileos A M.
Placental pathologic features of preterm preeclampsia.
Am J Obstet Gynecol.
1995;
173(4)
1097-1105
20
Isermann B, Sood R, Pawlinski R et al..
The thrombomodulin-protein C system is essential for the maintenance of pregnancy.
Nat Med.
2003;
9(3)
331-337
21
Li W, Zheng X, Gu J M et al..
Extraembryonic expression of EPCR is essential for embryonic viability.
Blood.
2005;
106(8)
2716-2722
22
Evans A S.
Causation and disease: a chronological journey. The Thomas Parran Lecture.
Am J Epidemiol.
1978;
108(4)
249-258
23
Parascandola M, Weed D L.
Causation in epidemiology.
J Epidemiol Community Health.
2001;
55(12)
905-912
24
Hill A B.
The environment and disease: association or causation?.
Proc R Soc Med.
1965;
58
295-300
25
Thygesen L C, Andersen G S, Andersen H.
A philosophical analysis of the Hill criteria.
J Epidemiol Community Health.
2005;
59(6)
512-516
26
Lin J, August P.
Genetic thrombophilias and preeclampsia: a meta-analysis.
Obstet Gynecol.
2005;
105(1)
182-192
27
Wu O, Robertson L, Twaddle S et al..
Screening for thrombophilia in high-risk situations: systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study.
Health Technol Assess.
2006;
10
1-110
28
Howley H E, Walker M, Rodger M A.
A systematic review of the association between factor V Leiden or prothrombin gene variant and intrauterine growth restriction.
Am J Obstet Gynecol.
2005;
192
694-708
29
Alfirevic Z, Roberts D, Martlew V.
How strong is the association between maternal thrombophilia and adverse pregnancy outcome? A systematic review.
Eur J Obstet Gynecol Reprod Biol.
2002;
101(1)
6-14
30
Rey E, Kahn S R, David M, Shrier I.
Thrombophilic disorders and fetal loss: a meta-analysis.
Lancet.
2003;
361(9361)
901-908
31
Burke W, Thomson E, Khoury M J et al..
Hereditary hemochromatosis. Gene discovery and its implications for population-based screening.
JAMA.
1998;
280
172-178
32
Infante-Rivard C, Rivard G E, Yotov W V et al..
Absence of association of thrombophilia polymorphisms with intrauterine growth restriction.
N Engl J Med.
2002;
347(1)
19-25
33
Meinardi J R, Middeldorp S, de Kam P J et al..
Increased risk for fetal loss in carriers of the factor V Leiden mutation.
Ann Intern Med.
1999;
130
736-739
34
Preston F E, Rosendaal F R, Walker I D et al..
Increased fetal loss in women with heritable thrombophilia.
Lancet.
1996;
348
913-916
35
Redman C W.
Current topic: pre-eclampsia and the placenta.
Placenta.
1991;
12(4)
301-308
36
Kramer M S.
Determinants of low birth weight: methodological assessment and meta-analysis.
Bull World Health Organ.
1987;
65(5)
663-737
37
Hills F A, Abrahams V M, Gonzalez-Timon B et al..
Heparin prevents programmed cell death in human trophoblast.
Mol Hum Reprod.
2006;
12(4)
237-243
38
Huhle G, Geberth M, Hoffmann U, Heene D L, Harenberg J.
Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin.
Gynecol Obstet Invest.
2000;
49(1)
67-69
39
Lepercq J, Conard J, Borel-Derlon A et al..
Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.
BJOG.
2001;
108
1134-1140
40
Greer I A, Nelson-Piercy C.
Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy.
Blood.
2005;
106
401-407
41
Howell R, Fidler J, Letsky E, de Swiet M.
The risks of antenatal subcutaneous heparin prophylaxis: a controlled trial.
Br J Obstet Gynaecol.
1983;
90(12)
1124-1128
42
Greer I A.
The use of LMWH in pregnancies at risk: new evidence or perception?.
J Thromb Haemost.
2005;
3
781-782
43
Gates S, Brocklehurst P, Ayers S, Bowler U.
Thromboprophylaxis and pregnancy: two randomized controlled pilot trials that used low-molecular-weight heparin.
Am J Obstet Gynecol.
2004;
191
1296-1303
44
McColl M D, Ramsay J E, Tait R C et al..
Risk factors for pregnancy associated venous thromboembolism.
Thromb Haemost.
1997;
78(4)
1183-1188
45
Bates S M, Greer I A, Hirsh J, Ginsberg J S.
Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
Chest.
2004;
126(3 suppl)
627S-644S
46
Rai R, Cohen H, Dave M, Regan L.
Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).
BMJ.
1997;
314
253-257
47
Kutteh W H.
Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone.
Am J Obstet Gynecol.
1996;
174(5)
1584-1589
48
Farquharson R G, Quenby S, Greaves M.
Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment.
Obstet Gynecol.
2002;
100
408-413
49
Empson M, Lassere M, Craig J, Scott J.
Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant.
Cochrane Database Syst Rev.
2005;
(2)
CD002859
50
Gris J-C, Mercier E, Quéré I et al..
Low-molecular-weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.
Blood.
2004;
103
3695-3699
51
Rodger M.
Important publication missing key information.
Blood.
2004;
104(10)
3413-3414
52
Di Nisio M, Peters L, Middeldorp S.
Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome.
Cochrane Database Syst Rev.
2005;
(2)
CD004734
53
Walker M C, Ferguson S E, Allen V M.
Heparin for pregnant women with acquired or inherited thrombophilias.
Cochrane Database Syst Rev.
2003;
(2)
CD003580
Dr. Marc A Rodger
Division of Hematology, The Ottawa Hospital, General Campus
501 Smyth Rd., Ottawa, Ontario, Canada K1H 8L6
Email: mrodger@ohri.ca