Clinical Review

Thrombophilia in pregnancy: Whom to screen, when to treat

OBG Manag. 2007 January;19(1):50-64

Baha M. Sibai, MD

Helen Y. How, MD

Caroline L. Stella, MD

Despite extensive research on testing and prophylaxis, a cautious approach is warranted

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IN THIS ARTICLE

Prevalence of thrombophilias in women with normal pregnancy outcomes
History of adverse outcomes justifies screening

References

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16. Kupferminc MJ, Fait G, Many A, Girdon D, Eldor A, Lessing JB. Severe preeclampsia: high frequency of genetic thrombophilic mutations. Obstet Gynecol. 2000;96:45-49.

17. Rigo J, Nagy B, Fintor L, et al. Maternal and neonatal outcome of preeclamptic pregnancies: the potential roles of factor V Leiden mutations and 5,10 methylenetetrahydrofolate reductase. Hypertens Pregnancy. 2000;19(2):163-172.

18. von Tempelhoff GF. Incidence of 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;100:363-365.

19. Kupferminc MJ, Peri H, Zwang E, et al. High prevalence of the prothrombin gene mutation in women with intrauterine growth retardation, abruptio placentae and second trimester loss. Acta Obstet Gynecol Scand. 2000;79:963-967.

20. Kim YJ. Genetic susceptibility to preeclampsia: roles of cytosine-to-thymine substitution at nucleotide 677 of the gene for methylenetetrahydrofolate reductase, 68-base pair insertion at nucleotide 844 of the gene for cystathione [beta]-synthase, and factor V Leiden mutation. Am J Obstet Gynecol. 2001;184:1211-1217.

21. Livingston J, Barton JR, Park V, et al. Maternal and fetal inherited thrombophilias are not related to the development of severe preeclampsia. Am J Obstet Gynecol. 2001;185:153-157.

22. 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? BJOG. 2002;109:191-196.

23. Benedetto C, Marozio L, Salton L, et al. Factor V Leiden and factor II G20210A in preeclampsia and HELLP syndrome. Acta Obstet Gynecol. 2002;81:1095-1100.

24. Schlembach D, Beinder E, Zingsem J, et al. Association of maternal and/or fetal factor V Leiden and G20210A prothrombin mutation with HELLP syndrome and intrauterine growth restriction. Clin Sci. 2003;105:279-285.

25. Mello G, Parretti E, Marozio L, et al. Thrombophilia is significantly associated with severe preeclampsia: results of a large-scale, case-controlled study. Hypertension. 2005;46:1270-1274.

26. Branch DW, Andres R, Digre KB, Rote NS, Scott JR. The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol. 1989;73:541-545.

27. Dreyfus M, Hedelin G, Kutnahorsky R, et al. Antiphospholipid antibodies and preeclampsia: a case-control study. Obstet Gynecol. 2001;97:29-34.

28. Kupferminc MJ, Eldor A, Steinman N, et al. Increased frequency of genetic thrombophilia in women with complications of pregnancy. N Engl J Med. 1999;340:9-13.

29. Prochazka M, Happach C, Marsal K, Dahlback B, Lindqvist PG. Factor V Leiden in pregnancies complicated by placental abruption. BJOG. 2003;110:462-466.

30. Infante-Rivard C, Rivard GE, Yotov WV, et al. Absence of association of thrombophilia polymorphisms with intrauterine growth restriction. N Engl J Med. 2002;347:19-25.

31. Howley HE, Walker M, Rodger MA. 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.

32. Martinelli I, Taioli E, Cetin I, et al. Mutations in coagulation factors in women with unexplained late fetal loss. N Engl J Med. 2000;343:1015-1018.

33. Rey E, Kahn SR, David M, et al. Thrombophilic disorders and fetal loss: a metaanalysis. Lancet. 2003;361:901-908.

34. Kupferminc MJ. Mid-trimester severe intrauterine growth restriction is associated with high prevalence of thrombophilia. BJOG. 2002;109:1373-1376.

35. Sibai BM, el-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-eclampsia in young primigravid women: subsequent pregnancy outcome and remote prognosis. Am J Obstet Gynecol. 1986;155:1011-1016.

36. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: recurrence risk and long-term prognosis. Am J Obstet Gynecol. 1991;165:1408-1412.

37. Brenner B. Thrombophilia and fetal loss. Semin Thromb Hemost. 2003;29:165-170.

38. Kupferminc MJ, Fait G, Many A, et al. Low molecular weight heparin for the prevention of obstetric complications in women with thrombophilias. Hypertens Pregnancy. 2001;20:35-44.

39. Cowchock FS, Reece EA, Balaban D, et al. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol. 1992;166:1318-1323.

40. Laskin CA, Bombardier C, Hannah ME, et al. Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med. 1997;337:148-154.

41. Kutteh WH. 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;174:1584-1589.

42. 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.

43. Silver RK, MacGregor SN, Sholl JS, et al. Comparative trial of prednisone versus aspirin alone in the treatment of anticardiolipin antibody-positive obstetric patients. Am J Obstet Gynecol. 1993;169:1411-1417.

44. Pattison NS, Chamley LW, Birdsall M, et al. Does aspirin have a role in improving pregnancy outcome for women with the antiphospholipid syndrome? A randomized controlled trial. Am J Obstet Gynecol. 2000;183:1008-1012.

45. Farquharson RG, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized, controlled trial of treatment. Obstet Gynecol. 2002;100:408-413.

46. Antiphospholipid syndrome. ACOG Practice Bulletin #68. Obstet Gynecol. 2005;106:1113-1121.

47. Gris JC, Mercier E, Quere 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.

48. Ogueh O, Chen MF, Spurll G, Benjamin A. Outcome of pregnancy in women with hereditary thrombophilia. Int J Gynecol Obstet. 2001;74:247-253.

49. Brenner B, Hoffman R, Blumenfeld Z, et al. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated with enoxaparin. Thromb Haemost. 2000;83:693-697.

50. Kupferminc MJ, Fait G, Many A, et al. Low molecular weight heparin for the prevention of obstetric complications in women with thrombophilias. Hypertens Pregnancy. 2001;20:35-44.

51. Verspyck E, Borg JY, Le Cam-Duchez V, et al. Thrombophilia and fetal growth restriction. Eur J Obstet Gynecol Reprod Biol. 2004;113:36-40.

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54. Ridker PM, Miletich JP, Buring JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. 1998;128:1000-1003.

55. Sarig G, Younis J, Hoffman R, et al. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril. 2002;77:342-347.

Fast Track

Antiphospholipid antibody syndrome is the most common acquired thrombophilia of pregnancy

A study of >5,000 asymptomatic gravidas found no association between abruptio placenta and factor V Leiden mutation

Carriers of factor V or prothrombin gene mutations are at higher risk of late fetal loss than noncarriers are

Screen women with a prior adverse pregnancy outcome for thrombophilia; without treatment, their risk of another adverse outcome ranges from 66% to 83%

The risk of VTE during pregnancy and postpartum for women who have antithrombin deficiency and a history of VTE is roughly 40%

Proceed in the half-dark: Your care of the thrombophilic pregnant woman is not yet illuminated by rigorous clinical trials

Thrombophilia has been widely investigated—and that may be one of the main challenges in detecting and managing it during pregnancy: Numerous studies have yielded different estimates of the incidence of various clotting disorders in pregnancy—itself a hypercoagulable state—and conflicting screening and prevention recommendations. The authors offer whatever recommendations have emerged.

Why thrombophilia matters

During pregnancy, clotting factors I, VII, VIII, IX, and X rise; protein S and fibrinolytic activity diminish; and resistance to activated protein C develops.^1,2 When compounded by thrombophilia—a broad spectrum of coagulation disorders that increase the risk for venous and arterial thrombosis—the hypercoagulable state of pregnancy may increase the risk of thromboembolism during pregnancy or postpartum.³

Pulmonary embolism is the leading cause of maternal death in the United States.¹ Concern about this lethal sequela has led to numerous recommendations for screening and subsequent prophylaxis and therapy.

Two types

Thrombophilias are inherited or acquired (TABLE 1). The most common inherited disorders during pregnancy are mutations in factor V Leiden, prothrombin gene, and methylenetetrahydrofolate reductase (MTHFR) (TABLE 2). Caucasians have a higher rate of genetic thrombophilias than other racial groups.

Antiphospholipid antibody (APA) syndrome is the most common acquired thrombophilia of pregnancy. It can be diagnosed when the immunoglobulin G or immunoglobulin M level is 20 g per liter or higher, when lupus anticoagulant is present, or both.⁴

TABLE 1

Thrombophilias are inherited or acquired

INHERITED Protein S deficiency Protein C deficiency Protein Z deficiency Antithrombin III Factor V Leiden mutation MTHFR mutation Homozygosity to MTHFR C677T Homozygosity to 4G/4G mutation in PAI-1 gene Prothrombin G20210A mutation Polymorphisms in thrombomodulin gene
ACQUIRED Antiphospholipid antibody syndrome Hyperhomocysteinemia
MTHFR=methylenetetrahydrofolate reductase

TABLE 2

Prevalence of thrombophilias in women with normal pregnancy outcomes

THROMBOPHILIA	PREVALENCE (%)
Factor V Leiden mutation	2–10
MTHFR mutation	8–16
Prothrombin gene mutation	2–6
Protein C and S deficiencies	0.2–1.0*
Anticardiolipin antibodies	1–7
* Combined rate
MTHFR=methylenetetrahydrofolate reductase

Link to adverse pregnancy outcomes

During the past 2 decades, several epidemiologic and case-control studies have explored the association between thrombophilias and adverse pregnancy outcomes,^2-6 which include the following maternal effects:

Venous thromboembolism, including deep vein thrombosis, pulmonary embolism, and cerebral vein thrombosis
Arterial thrombosis (peripheral, cerebral)
Severe preeclampsia

Placental and fetal abnormalities include:

Thrombosis and infarcts
Abruptio placenta
Recurrent miscarriage
Fetal growth restriction
Death
Stroke

Preeclampsia and thrombophilia

The association between preeclampsia and thrombophilia remains somewhat unclear because of inconsistent data. Because of this, we do not recommend routine screening for thrombophilia in women with preeclampsia.

An association between inherited thrombophilias and preeclampsia was reported by Dekker et al in 1995.⁷ Since then, numerous retrospective and case-controlled studies have assessed the incidence of thrombophilia in women with severe preeclampsia.^7-25 Their findings range from:

Factor V Leiden: 3.7% to 26.5%
Prothrombin gene mutation: 0 to 10.8%
Protein S deficiency: 0.7% to 24.7%
MTHFR variant: 6.7% to 24.0%

A meta-analysis of all case-controlled studies suggests that factor V Leiden is the only thrombophilia associated with an increased risk of preeclampsia.⁵ However, almost all studies included in this analysis involved women with severe preeclampsia who were referred to a tertiary-care obstetric center, whereas women in the control groups had a normal term pregnancy. These studies were therefore subject to selection bias because they overestimated the rate of thrombophilias in study groups and underestimated it in control groups.

Other points of contention are the varying levels of severity of preeclampsia and of gestational age at delivery, as well as racial differences. For example, most studies found an association between thrombophilia and severe preeclampsia at less than 34 weeks’ gestation, but not between thrombophilia and mild preeclampsia at term. In addition, a recent prospective observational study at multiple centers involving 5,168 women found a factor V Leiden mutation rate of 6% among white women, 2.3% among Asians, 1.6% in Hispanics, and 0.8% in African Americans.⁸ This large study found no association between thrombophilia and preeclampsia in these women. Therefore, based on available data, we do not recommend routine screening for factor V Leiden in women with severe preeclampsia.

Preeclampsia and APA syndrome

In 1989, Branch et al²⁶ first reported an association between APA syndrome and severe preeclampsia at less than 34 weeks’ gestation. They recommended that women with severe preeclampsia at this gestational age be screened for APA syndrome and treated when the screen is positive. Several later studies supported or refuted the association between APA syndrome and preeclampsia,^26,27 and a recent report concluded that routine testing for APA syndrome in women with early-onset preeclampsia is unwarranted.²⁶ Therefore, we do not recommend routine screening for APA in women with severe preeclampsia.