Rai R, Cohen H, Dave M, and Regan L.

Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).
BMJ. 1997 Jan 25; 314(7076): 253-257.
Description: This was a randomized, controlled trial that established aspirin and unfractionated heparin as the standard of care in preventing fetal loss in pregnant women with a history of recurrent miscarriages associated with antiphospholipid antibodies.
PubMed citation number: 9022487

Lynch A, Marlar R, Murphy J, Davila G, Santos M, Rutledge J, and Emlen W.

Antiphospholipid antibodies in predicting adverse pregnancy outcome. A prospective study.
Ann Intern Med. 1994 Mar 15; 120(6): 470-475.
Description: This was a prospective study demonstrating that the presence of antiphospholipid antibodies (most notably anticardiolipin IgG) in unselected pregnant women was associated with a higher risk of fetal loss (absolute risk of 15.8% versus 6.5%). However, given that a high proportion of women with antiphospholipid antibodies had successful pregnancies and that studies have not been conducted evaluating the role of intervention in this clinical scenario, routine screening of all pregnant women has not been recommended.
PubMed citation number: 8093135

Rand JH, Wu XX, Andree HA, Lockwood CJ, Guller S, Scher J, and Harpel PC.

Pregnancy loss in the antiphospholipid antibody syndrome – a possible thrombogenic mechanism.
N Engl J Med. 1997 Jul 17; 337(3): 154-160.
Description: This study implicates annexin V, a potent anticoagulant, in the pathogenesis of fetal loss in the antiphospholipid antibody syndrome by showing that incubation of trophoblast and endothelial cells with antiphospholipid antibodies leads to the reduced surface expression of annexin V and the acceleration of coagulation.
PubMed citation number: 9219701

Gerhardt A, Scharf RE, Beckmann MW, Struve S, Bender HG, Pillny M, Sandmann W, and Zotz RB.

Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.
N Engl J Med. 2000 Feb 10; 342(6): 374-379.
Description: This was a retrospective study that showed an increased risk of venous thromboembolism (VTE) during pregnancy and the puerperium for women carrying the factor V Leiden mutation (relative risk 9.3, absolute risk 0.2%) or the prothrombin gene mutation (relative risk 15.2, absolute risk 0.5%) and a disproportionately higher risk of VTE for women carrying both mutations (estimated odds ratio 107, absolute risk 4.6%).
PubMed citation number: 10666427

Friederich PW, Sanson BJ, Simioni P, Zanardi S, Huisman MV, Kindt I, Prandoni P, Buller HR, Girolami A, and Prins MH.

Frequency of pregnancy related venous thromboembolism in anticoagulant factor deficient women: Implications for prophylaxis.
Ann of Intern Med. 1996 Dec 15; 125(12): 955-960.
Description: This was a retrospective study of female family members of patients with a history of VTE and established protein C, protein S, or antithrombin deficiency demonstrating an increased risk of VTE during pregnancy in women with an anticoagulant factor deficiency compared to women without a deficiency (hazard ratio 8.0; absolute risk 4.1% versus 0.5%).
PubMed citation number: 8967705

The above two studies collectively provide a framework on which to make decisions regarding VTE prophylaxis in pregnant women with heritable thrombophilias and provide a basis for future randomized prospective studies addressing VTE prophylaxis in pregnant women with thrombophilia and no history of prior VTE.

Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C, Geerts W, Kovacs M, Weitz JI, Robinson KS, Whittom R, Couture G

Recurrence of Clot in This Pregnancy Study Group. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group.
N Engl J Med. 2000 Nov 16; 343(20): 1439-1444.
Description: This was a prospective study of pregnant women with a prior history of VTE demonstrating that the absolute risk of antepartum VTE was low despite no prophylactic heparin during this time (2.4% of the entire group). However, the risk was higher for women with a prior history of idiopathic VTE and / or VTE associated with a known heritable thrombophilia (5.9%) compared to women without a known heritable thrombophilia and a prior VTE that occurred in association with a temporary risk factor (0%). All patients received post-partum prophylaxis for 4 – 6 weeks.
PubMed citation number: 11078768

Pabinger I, Grafenhofer H, Kyrle P, Quehenberger P, Mannhalter C, Lechner K, and Kaider A.

Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism.
Blood. 2002 Aug 1; 100(3): 1060-1062.
Description: This was a retrospective study of women with a prior history of VTE that demonstrated an increased risk of recurrent VTE during pregnancy compared with recurrence outside of pregnancy(10.9% per 100 patient-years compared with3.7% per 100 patient-years, respectively; relative risk 3.5).
PubMed citation number: 12130523

The above two studies collectively demonstrate an increased risk of antepartum VTE in pregnant women with a history of VTE (at least women with a history of idiopathic VTE and / or a known heritable thrombophilia), thus providing guidance regarding management of these patients.

Preston FE, Rosendaal FR, Walker ID, Briet E, Berntorp E, Conard J, Fontcuberta J, Makris M, Mariani G, Noteboom W, Pabinger I, Legnani C, Scharrer I, Schulman S, and van der Meer FJ.

Increased fetal loss in women with heritable thrombophilia.
Lancet. 1996 Oct 5; 348(9032): 913-916.
Description: This was the first study demonstrating an increased risk of late fetal loss (after 28 weeks of gestation) in women with inherited thrombophilia, particularly in those with more than one heritable thrombophilia or antithrombin deficiency.
PubMed citation number: 8843809

Kupferminc MJ, Eldor A, Steinman N, Many A, Bar-Am A, Jaffa A, Fait G, Lessing JB.

Increased frequency of genetic thrombophilia in women with complications of pregnancy.
N Engl J Med. 1999 Jan 7; 340(1): 9-13.
Description: This was a retrospective study that showed an increased risk of an inherited thrombophilia in pregnant women who had fetal loss, preeclampsia, abruptio placentae, or fetal growth restriction compared to women with uneventful pregnancies.
PubMed citation number: 9878639

Rey, E, Kahn, SR, David, M, Shrier, I.

Thrombophilic disorders and fetal loss: a meta-analysis.
Lancet 2003 March 15; 361(9361):901-908.
Description: This is a meta-analysis of 31 studies evaluating the risk of early versus late and recurrent versus non-recurrent fetal loss for women carrying individual heritable thrombophilias.
PubMed citation number: 12648968

Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, and Younis JS.

Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.
Thromb Haemost. 2000 May; 83(5): 693-697.
Description: While not randomized, this study provides compelling evidence that low-molecular weight heparin prophylaxis of women with a history of recurrent pregnancy loss and an inherited thrombophilia leads to a significantly increased percentage of live births.
PubMed citation number: 10823264

The above four studies are collectively important because they: 1) provide a biologically-relevant rationale for vascular complications of pregnancy in select cases; 2) raise important questions about screening women with recurrent and non-recurrent pregnancy complications; and 3) provide the basis for evaluating the effectiveness of prophylactic anticoagulation for women with a history of pregnancy complications and heritable thrombophilia in a prospective, randomized fashion.

Gris JC, Mercier E, Quere I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, and Mares P.

Low molecular weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.
Blood. 2004 Jan 22 [Epub ahead of print]
Description: This randomized trial demonstrates that low molecular weight heparin (enoxaparin) is significantly superior to aspirin for preventing fetal loss in women with a history of one fetal loss beyond ten weeks gestation and documented heritable thrombophilia (factor V Leiden mutation, prothrombin gene mutation, protein S deficiency).
PubMed citation number: 14739212

Burrows RF, Kelton JG.

Fetal thrombocytopenia and its relationship to maternal thrombocytopenia.
N Engl J Med. 1993 Nov 11; 329(20): 1463-1466.
Description: This was a cross-sectional study demonstrating that the absolute risk of clinically significant thrombocytopenia in neonates born to mothers with incidental thrombocytopenia or idiopathic thrombocytopenic purpura is low, whereas neonates of mothers with platelet alloantibodies are at high risk of severe thrombocytopenia and bleeding events.
PubMed citation number: 8413457

Burrows RF, Kelton JG.

Incidentally detected thrombocytopenia in healthy mothers and their infants.
N Engl J Med. 1988 Jul 21; 319(3): 142-145.
Description: This was a prospective study demonstrating that mild incidental thrombocytopenia is a common finding during pregnancy (8.3% of all pregnancies) and confers no risk of significant thrombocytopenia to the fetus.
PubMed citation number: 3386694

The above two studies are important, because they form the basis for the argument that special obstetrical interventions such as cesarean section or funipuncture are unnecessary in women with incidental thrombocytopenia and idiopathic thrombocytopenic purpura.

Chan WS, Anand S, and Ginsberg JS.

Anticoagulation of pregnant women with mechanical heart valves.
Arch Intern Med. 2000 Jan 24; 160(2): 191-196.
Description: This study provides a thorough review of the effectiveness and hazards of several anticoagulation strategies for pregnant women with prosthetic heart valves.
PubMed citation number: 10647757

Ginsberg JS, Chan WS, Bates SM, and Kaatz S.

Anticoagulation of pregnant women with mechanical heart valves.
Arch Intern Med. 2003 Mar 24; 163(6): 694-698.
Description: This study: 1) challenges the warning issued by Aventis that enoxaparin is not recommended for pregnant women with prothetic heart valves due to a risk of valve thrombosis; 2) refutes the precaution that pregnant women who have received enoxaparin (an agent that does not cross the placenta) have delivered infants with congenital anomalies; and 3) underlines the desperate need for properly designed clinical trials for this group of patients.
PubMed citation number: 12639202

Koshy M, Burd L, Wallace D, Moawad A, and Baron J.

Prophylactic red-cell transfusions in pregnant patients with sickle cell disease. A randomized cooperative study.
N Engl J Med. 1988 Dec 1; 319(22): 1447-1452.
Description: This study demonstrated that perinatal fetal outcomes were no different between women assigned to prophylactic red blood cell transfusion and those who were not, dispelling the long-regarded belief that prophylactic transfusions are essential in pregnant women with sickle cell disease.
PubMed citation number: 3054555

Ginsberg JS, Bates SM.

Management of venous thromboembolism during pregnancy.
J Thromb Haemost. 2003 Jul; 1(7): 1435-42.
PubMed citation number: : 12871278

Ginsberg JS, Greer I, Hirsh J.

Use of antithrombotic agents during pregnancy.
Chest. 2001 Jan; 119(1 Suppl): 122S-131S.
PubMed citation number: 11157646

Brenner B.

Clinical Management of Thrombophilia Related Placental Vascular Complications.
Blood. 2004 Feb 12 [Epub ahead of print]
PubMed citation number: 14962907

McCrae KR, Cines DB.

Thrombotic microangiopathy during pregnancy.
Semin Hematol. 1997 Apr; 34(2): 148-58.
PubMed citation number: 9109217

Branch DW, Khamashta MA.

Antiphospholipid syndrome: obstetric diagnosis, management, and controversies.
Obstet Gynecol. 2003 Jun; 101(6): 1333-44.
PubMed citation number: 12798544

Return to Table of Contents