Low dose aspirin and low-molecular-weight heparin in the treatment of pregnant Libyan women with recurrent miscarriage

Mohamed O Elmahashi, Aisha M Elbareg, Fathi M Essadi, Bashur M Ashur, Ishag Adam, Mohamed O Elmahashi, Aisha M Elbareg, Fathi M Essadi, Bashur M Ashur, Ishag Adam

Abstract

Background: Recurrent miscarriage is a major women's health problem. Aspirin and heparin have been shown to have potentially beneficial effects on trophoblast implantation. However, few published data on this issue are available from developing countries.

Methods: An open clinical trial was conducted at the Department of Obstetrics and Gynecology at Misurata Teaching Hospital in Libya from January 2009 to December 2010 to investigate the effects of treatment with low dose aspirin (LDA) versus treatment with low-molecular-weight-heparin (LMWH) in combination with LDA on patients with a history of recurrent miscarriages. A total of 150 women were enrolled in the study. Women were eligible for the study if they had a history of three or more consecutive miscarriages. Participants were randomly assigned to receive either LDA (75 mg daily) alone or a combination of LDA and LMWH (75 women per treatment group). The primary outcomes were the rate of miscarriages and live births for each group.

Results: Compared with the group who received LDA alone, the combination group had a significantly lower number of miscarriages (22/75 [29%] vs. 43/75 [47%], P < 0.001) and had a significantly higher number of live births (53/75 [71%] vs. 32/75 [42%], P < 0.001). Two preterm infants in the LDA group and three in the combination group were admitted to the neonatal intensive care unit. There were no significant differences in the mean (SD) birth weights of neonates born in either group (2955.4 ± 560 vs. 3050 ± 540 g for the LDA and combination groups, respectively, P = 0.444). There were no congenital abnormalities detected in either group.

Conclusion: The combination of LDA and LMWH is better than LDA alone for the maintenance of pregnancy in patients with recurrent first trimester miscarriage.

Trial registration: NCT01917799.

References

    1. Younis J, Ohel G, Brenner B, Ben-Ami M. Familial thrombophilia- the scientific rationale from thromboprophylaxis in recurrent pregnancy loss? Hum Reprod. 1997;12(7):1389–1390. doi: 10.1093/humrep/12.7.1389.
    1. Kutteh W. Antiphospholipid antibodies-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. doi: 10.1016/S0002-9378(96)70610-5.
    1. Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin ad aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies) BMJ. 1997;314(7076):253–257. doi: 10.1136/bmj.314.7076.253.
    1. Clark P, Greer IA, Walker I. Interaction of the protein c/ protein S anticoagulant system, the endothelium and pregnancy. Blood Rev. 1999;13(3):127–146. doi: 10.1054/blre.1999.0114.
    1. Farquharson R, Quenby S, Greaves M. Antiphospholipid syndrome in pregnancy: a randomized controlled trial of treatment. Obstet Gynecol. 2002;100(3):408–413. doi: 10.1016/S0029-7844(02)02165-8.
    1. Wu O, Robertson L, Twaddle S, Lowe GD, Clark P, Greaves M, Walker ID, Langhorne P, Brenkel I, Regan L, Greer I. 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(11):1–110.
    1. Monien S, Kadecki O, Baumgarten S, Salama A, Dorner T, Kiesewetter H. Use of heparin in women with early and late miscarriages with and without thrombophilia. Clin Appl Thromb Hemost. 2009;15(6):636–644. doi: 10.1177/1076029609335501.
    1. Gris JC, Mercier E, Quéré I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Marès P. Low-molecular weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood. 2004;103(10):3695–3699. doi: 10.1182/blood-2003-12-4250.
    1. Rodger MA, Paidas M, McLintock C, Middeldorp S, Kahn S, Martinelli I, Hague W, Rosene Montella K, Greer I. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112(2 pt1):320–324.
    1. Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review. Blood. 2005;106(2):401–407. doi: 10.1182/blood-2005-02-0626.
    1. Clark P, Bates S. North American and British guidelines for anti-thrombotic therapy: are we reaching consensus? Thromb Res. 2009;123(S2):S111–S123.
    1. Rodger M. Thrombophilia and placenta-mediated pregnancy complications: from bench to bedside to policy. Thromb Res. 2009;123(S2):S100–S104.
    1. Hills FA, Abrahams VM, González-Timón B, Francis J, Cloke B, Hinkson L, Rai R, Mor G, Regan L, Sullivan M, Lam EW, Brosens JJ. Heparin prevents programmed cell death in human trophoblast. Mol Hum Reprod. 2006;12(4):237–243. doi: 10.1093/molehr/gal026.
    1. Nelson SM, Greer IA. The potential role of heparin in assisted conception. Hum Reprod Update. 2008;14(6):623–645. doi: 10.1093/humupd/dmn031.
    1. Ellison J, Walker ID, Greer IA. Antenatal use of enoxaparin for prevention and treatment of thromboembolism in pregnancy. BJOG. 2000;107:1116–1121. doi: 10.1111/j.1471-0528.2000.tb11110.x.
    1. Thomson AJ, Walker ID, Greer IA. Low-molecular-weight heparin for immediate management of thromboembolic disease in pregnancy. Lancet. 1904;1998:352.
    1. Shefras J, Farquharson RG. Bone density studies in pregnant women receiving heparin. Eur J Obstet Gynecol Reprod Biol. 1996;65:171–174. doi: 10.1016/0301-2115(95)02358-5.
    1. Warkentin TE, Levine MN, Hirsh J, Horsewood P, Roberts RS, Gent M, Kelton JG. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330–1335. doi: 10.1056/NEJM199505183322003.
    1. Laurent P, Dussarat GV, Bonal J, Jego C, Talard P, Bouchiat C, Cellarier G. Low molecular weight heparins: a guide to their optimum use in pregnancy. Drugs. 2002;62:463–477. doi: 10.2165/00003495-200262030-00004.
    1. Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, Mac Gillavry MR, Hamulyák K, Theunissen IM, Hunt BJ, Büller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost. 1999;81:668–672.
    1. Bates SM, Greer IA, Hirsch J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):627S–644S.
    1. Bussolino F, Bendetto C, Massobrio M, Camussi G. Maternal vascular prostacyclin activity in preeclampsia. Lancet. 1980;ii:702.
    1. Patrono C, García Rodríguez LA, Landolfi R, Baigent C. Low-dose aspirin for the prevention of atherosclerosis. N Engl J Med. 2005;353:2373–2383. doi: 10.1056/NEJMra052717.
    1. Ziakas PD, Pavlon M, Voulgarelies M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115(6):1256–1262. doi: 10.1097/AOG.0b013e3181deba40.
    1. Fouda UM, Sayed AM, Abdou AM, Ramadan DI, Fouda IM, Zaki MM. Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. Int J Gynaecol Obstet. 2011;112(3):211–215. doi: 10.1016/j.ijgo.2010.09.010.
    1. Alalaf S. Bemiparin versus low dose aspirin for management of recurrent early pregnancy losses due to antiphospholipid antibody syndrome. Arch Gynecol Obstet. 2012;285:641–647. doi: 10.1007/s00404-011-2055-y.
    1. Stray-Pedersen B, Stray-Pedersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion. Am J Obstet Gynecol. 1984;148:140–146. doi: 10.1016/S0002-9378(84)80164-7.
    1. Peaceman AM, Rehngerg KA. The effect of aspirin and indomethacin on prostacyclin and thromboxane production by placental tissue incubated with immunoglobulin G fractions from patients with lupus anticoagulant. Am J Obstet Gynecol. 1995;173(5):136–139.
    1. McIntyre JA, Taylor CG, Torry DS, Wagenknecht DR, Wilson J, Faulk WP. Heparin and pregnancy in women with a history of repeated miscarriages. Hemostase. 1993;1(23 Supp):202–211. Review.
    1. Branch DW, Silver RM, Blackwell JL, Reading JC, Scott JR. Outcome of treated pregnancies in women with antiphospholipid syndrome: an update of the Utah experience. Obstet Gynecol. 1992;80:614–620.
    1. De Wolf F, Carreras O, Moerman P, Vermylen J, Van A, Renaer M. Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol. 1982;142(7):829–834.
    1. Out HJ, Kooijman CD, Bruinse HW, Derksen RH. Histopathological findings in placentae from patients with intrauterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Reprod Biol. 1991;41:179–186. doi: 10.1016/0028-2243(91)90021-C.
    1. Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin or anticoagulants for treating recurrent miscarriage in women without antiphospholipid syndrome. Cochrane Database Syst Rev. 2009;1:CD004734.
    1. Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ, Price K, Karumanchi SA, Valdés G. Endothelial dysfunction: a link among preeclampsia, recurrent pregnancy loss, and future cardiovascular events? Hypertension. 2007;49(1):90–95. doi: 10.1161/01.HYP.0000251522.18094.d4.
    1. Santulli G, Trimarco B, Iaccarino G. G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms. High Blood Press Cardiovasc Prev. 2013;20(1):5–12. doi: 10.1007/s40292-013-0001-8.
    1. Santulli G, Cipolletta E, Sorriento D, Del Giudice C, Anastasio A, Monaco S, Maione AS, Condorelli G, Puca A, Trimarco B, Illario M, Iaccarino G. CaMK4 gene deletion induces hypertension. J Am Health Care Assoc. 2012;1(4):e001081.
    1. Izzo R, Cipolletta E, Ciccarelli M, Campanile A, Santulli G, Palumbo G, Vasta A, Formisano S, Trimarco B, Iaccarino G. Enhanced GRK2 expression and desensitization of betaAR vasodilatation in hypertensive patients. Clin Transl Sci. 2008;1(3):215–220. doi: 10.1111/j.1752-8062.2008.00050.x.

Source: PubMed

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