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Jewish Home > Cholesterol and Metabolism Center > Research > Repetitive Pregnancy Loss / Very Early Pregnancy Loss

Coagulation disorders and polycystic ovary syndrome, associations with both recurrent pregnancy loss and with very early pregnancy loss (5/14/03).

Introduction:

WHOM CAN WE HELP?:

  1. We are interested in working with women who have had recurrent pregnancy loss (RPL), defined by 3 or more consecutive pregnancy losses before 20 weeks gestation.1
  2. We are also interested in women who, despite normal ovulatory menstrual cycles, no anatomical abnormalities in the reproductive anatomy, with normal husbands' sperm count and motility, have been unable to conceive and those with pregnancy loss before 6 weeks gestation.
  3. Women with polycystic ovary syndrome with RPL.

In women with very early pregnancy loss, there is evidence that although the egg is fertilized and matures to the blastocyst stage, that it cannot implant, and is lost so quickly that the pregnancy-on signal does not get to the pituitary, and the next menstrual cycle appears on schedule without knowledge of the very early pregnancy loss (VEPL).

Both RPL and VEPL appear to be caused, in part, by an increased tendency to form blood clots (thrombophilia), by a reduced ability to dissolve blood clots (hypofibrinolysis), by both, and by a common endocrine syndrome, polycystic ovary syndrome (PCOS). Without treatment with metformin (1.55-2.55 g/day) women with PCOS commonly have RPL, in part due to high levels of plasminogen activator inhibitor activity (PAI-Fx), the major determinant of fibrinolysis.

We are interested in working with women and their physicians who have sustained RPL or VEPL, suggesting which coagulation tests to do, interpreting them, and suggesting therapy for subsequent pregnancies (commonly with Lovenox thromboprophylaxis). We are also interested in working with women and their physicians who may have PCOS as a cause of RPL.

Background: top of page

Recurrent pregnancy loss (RPL) has traditionally been defined by 3 or more consecutive pregnancy losses before 20 weeks gestation.1 RPL has been estimated to occur in approximately 0.3%2 to 1%1 of all couples. Multiple potential etiologies for RPL have been described1-6 including antiphospholipid antibody syndrome, thrombophilia, 7-15 parental karyotype abnormalities, uterine malformations, cervical incompetence, poorly controlled diabetes mellitus, hypothyroidism, and antithyroid antibodies. In most7-15 but not all16-22 studies, the thrombophilic G1691A Factor V Leiden mutation has been identified as an etiology for both RPL and for 2nd and 3rd trimester pregnancy complications.19,23-28 Fetal carriers of the Factor V Leiden mutation are prone to miscarriage and placental infarction.29 Pre-conception identification of maternal Factor V Leiden heterozygosity predicts increased fetal loss.6,30

The presence of the maternal G1691A Factor V Leiden mutation may be a double-edged sword. 22 Dilley et al 22 postulated that the Factor V Leiden mutation may protect against bleeding in early pregnancy. However, two thrombophilic mutations, G1691A Factor V Leiden and the G20210A prothrombin gene, have been implicated in very early pregnancy loss.15 Acquired activated protein C resistance, independent of the Factor V Leiden mutation, is also a risk factor for RPL.31 The G20210A prothrombin gene mutation has been associated with both RPL and 2nd and 3rd trimester pregnancy complications in most 12,19,25,26,32 but not all 33 studies. The thrombophilic C677T mutation of the methylenetetrahydrofolate reductase gene (MTHFR) has also been associated with RPL and 2nd and 3rd trimester pregnancy complications in most 10,25,26,34,35 but not all 12 studies. The thrombophilic antiphospholipid antibody syndrome has been associated with RPL.36-38 Familial and acquired hypofibrinolytic disorders have also been implicated as etiologies for RPL including the 4G/5G mutation of the plasminogen activator inhibitor gene25,39 and its gene product, plasminogen activator inhibitor activity (PAI-Fx).40-43

Women with polycystic ovary syndrome (PCOS) have a high frequency of first trimester spontaneous abortion (SAB), 42-48 ranging from 73%43 to 62%,44 42%,46 35%,47 and 25%48 of pregnancies. Metformin lowers the rate of first trimester SAB in PCOS.43-46 In the largest PCOS-pregnancy study to date (72 women, 84 fetuses),44 metformin during pregnancy safely reduced 1st trimester SAB from 62% to 26%, p<. 0001. On metformin, reductions in serum insulin and PAI-Fx, an independent significant determinant of SAB,42 are correlated.43To date, however, no placebo-controlled, blinded trials of metformin in prevention of SAB in PCOS have been published.

Hyperinsulinemia is an independent, significant risk factor for RPL in PCOS. 44 In 72 women with PCOS, pre-treatment fasting serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 uU/ml rise in insulin), 95% CI 1.09-1.60, p=.0005.44 Craig et al49 have reported that women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls. They speculated49 that the insulin-RPL association was mediated42 through hypofibrinolytic high PAI-Fx, an independent determinant of SAB. PAI-Fx rises with increasing levels of serum insulin and falls when insulin is reduced by metformin.42,43,50,51

In women with recurrent miscarriage, screening reveals a higher than normal incidence of polycystic ovaries. 52 Hence, a high level of fetal loss is characteristic not only of women with RPL with thrombophilia,7-15,19,23-28,31,32,34-39 and/or hypofibrinolysis, 25,39-43 but also of women with PCOS.42-48

Blumenfeld and Brenner 53 have proposed that placental thrombosis may be the final common pathophysiologic pathway for RPL. Prophylactic therapy with low molecular weight heparin54-59 or unfractionated heparin60 in women with heritable and acquired thrombophilia reduces pregnancy wastage compared to their previous pregnancies without thromboprophylaxis. To date, however, no placebo-controlled, blinded trials of low molecular weight heparin in prevention of RPL have been published. The only controlled clinical trials involving heparin and RPL have been carried out in women with antiphospholipid antibody syndrome.17,61

How we can help you top of page

If you meet the criteria, as above for RPL, for VEPL, or have been diagnosed as having polycystic ovary syndrome, then work through your local physicians to get blood drawn for the following blood coagulation tests:

PCR-cDNA: G1691A Factor V Leiden, G20210A Prothrombin, C677T and A 1298C MTHFR, and 4G/5G mutations of the plasminogen activator inhibitor-1 gene. These can be done in a 5 cc purple top tube of blood, and if these cannot easily be done in your locale, they can be done at MDL laboratory in Cincinnati, with the blood sent by overnight courier unrefrigerated. You can call them at 513-475-6631 to set up arrangements to have these assays done. Be sure to arrange for a copy of the laboratory results to be sent to Dr CJ Glueck at the Cholesterol Center and to have these marked RPL-VEPL so that Dr Glueck will know what study group they represent.

Serologic tests (in the liquid blood): Resistance to activated protein C, Proteins C, S, antithrombin III, homocysteine, lupus anticoagulant, APTT, Factors VIII and XI, Lp(a), plasminogen activator inhibitor activity. These analyses can usually be done in major hospital laboratories, or sent to regional and national laboratories.

When the results are available, either email them to us (glueckch@healthall.com) or fax them to us (513-924-8273), and we will interpret them, free of charge, and then send you suggestions as to how to deal with any problems that are found. All information will be entirely confidential. Please be sure to also send us a complete reproductive history including the following:

a. number of pregnancies:__________________

b. number of live births:____________________

c. for each live birth, delivery at gestation week ( ), baby's sex male ( ), female ( ), baby's birth weight ( ), birth length ( ), pre-eclampsia yes ( ) or no ( ), eclampsia yes ( ) or no ( ), toxemia yes ( ) or no ( ), gestational diabetes yes ( ) or no ( ), hypertension of pregnancy requiring blood pressure lowering medications yes ( ), no ( ), caesarian section yes ( ), no ( ).

d. For each pregnancy loss, please provide the following: gestation week, cause of pregnancy loss if specified ( ), Karyotype studies on the abortus yes ( ), no ( ), if yes, chromosomal abnormalities yes ( ), no ( ), karyotype studies in the mother yes ( ), no ( ), karyotype studies in the father yes ( ), no ( )..

e. For each pregnancy loss, please specify if the following information was obtained: antiphospholipid antibody syndrome yes ( ), no ( ), lupus anticoagulant yes ( ), no ( ), uterine malformations yes ( ), no ( ), cervical incompetence yes ( ), no ( ), poorly controlled diabetes mellitus yes ( ), no ( ), hypothyroidism yes ( ), no ( ).

Should you wish to make a 1.5 hour outpatient visit to our Cholesterol Center in Cincinnati for a direct personal evaluation by Dr CJ Glueck and staff, that visit will not be free, but is usually covered by third party insurance. You can check on the mechanics of the third party insurance by calling 513-924-8250 and asking to speak to the receptionist.

References top of page

  1. Lee RM, Silver RM: Recurrent pregnancy loss: summary and clinical recommendations. Semin Reprod Med 2000; 18:433-40.
  2. Babbage SJ, Arkwright PD, Vince GS, et al: Cytokine promoter gene polymorphisms and idiopathic recurrent pregnancy loss. J Reprod Immunol 2001; 51:21-7.
  3. Cramer DW, Wise LA: The epidemiology of recurrent pregnancy loss. Semin Reprod Med 2000; 18:331-9.
  4. Roberts CP, Murphy AA: Endocrinopathies associated with recurrent pregnancy loss. Semin Reprod Med 2000; 18:357-62.
  5. Rushworth FH, Backos M, Rai R, et al: Prospective pregnancy outcome in untreated recurrent miscarriers with thyroid autoantibodies. Hum Reprod 2000; 15:1637-9.
  6. 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.
  7. Younis JS, 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 2002;43:31-35
  8. Wramsby ML, Sten-Linder M, Bremme K: Primary habitual abortions are associated with high frequency of factor V Leiden mutation. Fertil Steril 2000; 74:978-991
  9. Finan RR, Tamim H, Ameen G, et al: Prevalence of factor V G 1691 A (Factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population. Am J Hematol 2002;71:300-5
  10. Murphy RP, Donoghue C, Nallen RJ, et al: Prospective evaluation of the risk conferred by factor V Leiden and thermolabile methylenetetrahydrofolate reductase polymorphisms in pregnancy. Arterioscler Thromb Vasc Biol 2002;20:266-70.
  11. Bare SN, Poka R, Balogh I, et al: Factor V Leiden as a risk factor for miscarriage and reduced fertility. Aust NZ J. Obstet Gynaecol 2000;40:186-190.
  12. Foka ZJ,Lambropoulos AF, Saravelos H, et al: Factor V Leiden and prothrombin G 20210A mutations, but not methylenetetrahydrofolate reductase C 677T, are associated with recurrent miscarriages. Hum Reprod 2000;15:458-62.
  13. Ridker PM, Miletich JP, Buring JE, et al: Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998;128:1000-3.
  14. 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.
  15. Reznikoff-Evievan MF, Cayol V, Carbonne B, et al: Factor V Leiden and G 20210A prothrombin mutations are risk factors for very early recurrent miscarriage. BJOG 2001;108:1251-4.
  16. Dizon-Townson DS, Kinney S, Branch DW, et al: The factor V Leiden mutation is not a common cause of recurrent miscarriage. J Reprod Immunol 1996;34:217-223.
  17. Kutteh WH, Park VM, Deitcher SR: Hypercoagulable state mutation analysis in white patients with early first-trimester recurrent pregnancy loss. Fertil Steril 1999;71:1048-1053.
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  29. Dizon-Townson DS, Meline L, Nelson LM, et al: Fetal carriers of the factor V Leiden mutation are prone to miscarriage and placental infarction. Am J Obstet Gynecol 1998;178:1107-8.
  30. Meinardi JR, Middeldorp S, de Kam PJ, et al: Increased risk for fetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999;130:736-9.
  31. 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;16:961-965.
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  34. Unfeid G, Griesmacher A, Weismuller W, et al: The C677T polymorphism of the methylenetetrahydrofolate reductase gene and idiopathic recurrent miscarriage. Obstet Gynecol 2002;99:614-9.
  35. Nelen WL, Blom HJ, Steegers EA, et al: Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril 2000; 74:1196-9.
  36. Aoki K, Hayashi Y, Hirao Y, Yagami Y: Specific antiphospholipid antibodies as a predictive variable in patients with recurrent pregnancy loss. Am J Reprod Immunol 1993; 29:82-7.
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  40. Gris JC, Neveu S, Tailland ML, et al: Use of a low-molecular weight heparin (enoxaparin) or of a phenformin-like substance (moroxydine chloride) in primary early recurrent aborters with an impaired fibrinolytic capacity. Thromb Haemost 1995; 73:362-7.
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  43. Glueck CJ, Phillips H, Cameron D, et al: Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion: a pilot study. Fertil Steril 2001; 75:46-52.
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  51. Velazquez EM, Mendoza SG, Wang P, et al: Metformin therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoprotein(a), and immunoreactive insulin levels in patients with the polycystic ovary syndrome. Metabolism 1997; 46:454-7.
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  54. Brenner B, Hoffman R, Blumenfeld Z, et al: Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83:693-7.
  55. Empson M, Lassere M, Craig JC, et al: Recurrent pregnancy loss with antiphospholipid antibody: a systematic review of therapeutic trials. Obstet Gynecol 2002; 99:135-44.
  56. Younis JS, Ohel G, Brenner B, et al: The effect of thrombophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation. Br J Obstet Gynecol 2000; 107:415-9.
  57. Bazzan M, Donvito V: Low-molecular-weight heparin during pregnancy. Thromb Res 2001; 101:V175-86.
  58. Sorensen HT, Johnson SP, Larsen H, et al: Birth outcomes in pregnant women treated with low molecular weight heparin. Acta Obstet Scand 2000;79:655-9
  59. Rey E, Rivard GE: Prophylaxis and treatment of thromboembolic diseases during pregnancy with dalteparin. Int J Gynaecol Obstet 2000; 71:19-24.
  60. Bick RL: Recurrent miscarriage syndrome due to blood coagulation protein/platelet defects: prevalence, treatment and outcome results. DRW Metroplex Recurrent Miscarriage Syndrome Cooperative Group. Clin Appl Thromb Hemost 2000; 6:115-25.
  61. Rai R, Cohen H, Dave M, et al: 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.

E-mail: glueckch@healthall.com or cglueck@fuse.net
Fax: 513-924-8273
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