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Is There Any Future for Low-Molecular-Weight Heparin in the Prevention of Pregnancy Loss?The Future of LMWH in Preventing Pregnancy Loss

Jean-Christophe Gris, MD, PhD
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From University Hospital, Nîmes, Nîmes, France.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M15-0564.

Requests for Single Reprints: Jean-Christophe Gris, MD, PhD, Département d'Hématologie, Centre Hospitalier Universitaire, Groupe Hospitalo-Universitaire Carémeau, Place du Professeur Robert Debré, 30029 Nîmes Cedex 9, France; e-mail, jean.christophe.gris@chu-nimes.fr.

Ann Intern Med. 2015;162(9):658-659. doi:10.7326/M15-0564
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In this issue, Schleussner and colleagues found that LMWH does not increase live-birth rates in women with unexplained RPL. The editorialist concurs but suggests that LMWH may still have a role in the prevention of unexplained RPL in certain subgroups of women.

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Similarities and Differences between RCTs in Heparin Prophylaxis for Recurrent Pregnancy Loss
Posted on May 7, 2015
Ekkehard Schleussner, MD PhD, David Petroff, PhD
University Hospital, Jena, University Hospital, Leipzig
Conflict of Interest: None Declared
Jean-Christophe Gris wrote an excellent editorial (1) considering how low-molecular-weight heparin (LMWH) might be used to help avoid pregnancy loss despite mounting evidence showing that it is ineffective in certain situations. He argues convincingly that the cause of previous pregnancy loss needs to be explored before selecting a therapy. He also provides reasons for suspecting that LMWH could help prevent late pregnancy losses.
A large part of the editorial is devoted to helping the reader place the four trials ALIFE, SPIN, HABENOX, and our ETHIGII (2-5) in context. Despite their similarities, Gris points out that “there are subtle and noteworthy differences”, which he goes on to describe. A few further elucidations regarding this point may add useful information.
Pertaining to the ALIFE trial, Gris mentions that women were enrolled earlier than in ETHIGII, “thus allowing observation of an early effect of LMWH on trophoblasts”. Although it is true that ALIFE’s participants were randomized very early on (70% were not even pregnant), use of LMWH began “when a viable intrauterine pregnancy was confirmed on ultrasonography, starting at 6 weeks of gestation” (2). Since this is not very different from our stipulation in ETHIGII that participants have “a viable singleton pregnancy during 5 to 8 weeks' gestation as detected by ultrasonography”, evidence is probably still lacking on the early effects of LMWH.
Regarding HABENOX, it is worth pointing out explicitly that the three randomization arms received LMWH + aspirin, LMWH + placebo and aspirin, meaning there was not a control arm that did not receive medication. This is an important difference in design to the other three trials.
One further similarity between all the trials is that none has yet been powered to examine the effects of LWMH for women with known thrombophilia, meaning that concerted collaborative efforts are still needed.
Ekkehard Schleussner, MD PhD, University Hospital, Jena, Germany
David Petroff, PhD, University Hospital, Leipzig, Germany

1. Gris JC. Is there any future for Low-Molecular-Weight Heparin in the Prevention of Pregnancy Loss? Ann Intern Med. 2015;162: 658-9. doi: 10.7326/M15-0564
2. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyák K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362:1586-96. [PMID: 20335572] doi:10.1056/NEJMoa1000641
3. Clark P, Walker ID, Langhorne P, Crichton L, Thomson A, Greaves M, et al. Scottish Pregnancy Intervention Study (SPIN) collaborators. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115: 4162-7. [PMID: 20237316] doi:10.1182/blood-2010-01-267252.
4. Visser J, Ulander VM, Helmerhorst FM, Lampinen K, Morin-Papunen L, Bloemenkamp KW, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost. 2011; 105:295-301. [PMID: 21103659] doi:10.1160/TH10-05-0334
5. Schleussner E, Kamin G, Seliger G, Rogenhofer N, Ebner S, Toth B, et al. ETHIG II group. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss. A multicenter trial with a minimization randomization scheme. Ann Intern Med. 2015;162: 601-9. doi:10.7326/M14-2062
Posted on May 15, 2015
Jeffrey S. Ginsberg, MD, Jack Hirsh, MD
McMaster University
Conflict of Interest: None Declared
In his Editorial, Dr Gris makes the unhelpful statement that the role of low molecular weight heparin (LMWH) in recurrent pregnancy loss (RPL) is "far from being answered" (1). The statement is ambiguous because it can be interpreted to indicate that there might yet be a role for LMWH for this indication. The apparent "target" for the statement is the small group of individuals who (tragically) suffer a late pregnancy loss. On the heels of describing 4 well designed European randomized trials, and with at least 2 negative North American randomized trials (2,3) evaluating LMWH for prevention of RPL, this statement condoning the use of LMWH for this indication is unjustified. . In conflict with Dr. Gris' statement is the absence of even a signal in subgroup analyses, including the subgroup with a history of one or more later pregnancy losses. Pregnancy loss is devastating for the vast majority of couples. As a clinician caring for these patients, we have all seen many couples who will do almost anything for a normal live birth. Based upon current evidence, the cost of these expensive drugs and the inconvenience of their use in patients with RPL cannot be justified.

1.Gris JC. Is there any future for Low-Molecular-Weight Heparin in the Prevention of Pregnancy Loss? Ann Int Med. 2015;162: 658-9. doi10.7326/M15-0564.

2.Rodger MA, Hague WM, Kingdom J, Kahn SR, Karovitch A, Sermer M, et al. Antepartum dalteparin versus no antepartum dalteparin for the prevention of pregnancy complications in pregnant women with thrombophilia (TIPPS): a multinational open-label randomised trial. Lancet. 2014 Nov 8;384(9955):1673-83.

3.Laskin CA1, Spitzer KA, Clark CA, Crowther MR, Ginsberg JS, Hawker GA, et al. Low molecular weight heparin and aspirin for recurrent pregnancy loss: results from the randomized, controlled HepASA Trial. J Rheumatol. 2009 Feb;36(2):279-87.

Posted on May 22, 2015
Rucha Patil, M.Sc, Kanjaksha Ghosh, M.D., Shrimati Shetty, Ph.D.
Kem Hospital, Mumbai, India
Conflict of Interest: None Declared
We read with interest the editorial by Gris (1) on the recently concluded multicentric trial (2) on the effect of low molecular weight heparin (LMWH) in women with unexplained pregnancy loss (PL). Based on the absence of a significant difference in the live birth rates between women on and not on LMWH, the authors have proposed that LMWH should not be recommended in such women.
While we partly agree with the author, we are also intrigued by the results obtained in a study done at our centre (4) which included 32 patients, with a history of PL (n= 2-9 PL) or with deep vein thrombosis in early pregnancy. They were treated with heparin along with aspirin on account of a strong solitary or a combination of genetic and acquired thrombophilia markers. 16 of the 23 patients treated with unfractionated heparin (UFH) and all 9 patients treated with LMWH had successful pregnancy outcome without any major adverse reactions. Subsequently in a second study, when women with highly elevated procoagulant microparticles (MPs) were initiated on heparin and aspirin, live birth was achieved in 19 women, where the MP levels normalized (5). Though all these studies lacked a control group without anticoagulant therapy (ACT), the fact that when not on ACT these women had multiple pregnancy loss, supports the beneficial role of ACT. An important point to note is that all patients were on a combination of heparin and aspirin.
As Gris mentions that PL is a syndrome and not a molecularly defined disease, it is very important to understand the pathophysiology of this syndrome. Procoagulant MPs may be one such marker which will guide us one step closer. In a randomized Phase II clinical trial in cancer patients on thromboprophylaxis, the efficacy of enoxaparin was shown in reducing thrombotic events in patients with increased tissue factor MPs (6) and a multicentric trial is currently ongoing to validate primary thromboprophylaxis in cancer patients with elevated tissue factor bearing MPs. MPs are certainly worthy of consideration in larger clinical trials involving thromboprophylaxis in women with unexplained PL.
Though the comment of Gris is evidence based, it is little too early to stop LMWH in women with unexplained PL. Unexplained PL itself is an arbitrary classification as there are still many causes yet to be identified. Until the whole pathophysiology of unexplained PL is unraveled, any recommendation to drop the LMWH needles should be kept on hold.

1. Gris JC. Is there any future for low molecular-weight heparin in the prevention of pregnancy loss? Ann Intern Med. 2015;162:658-659.
2. Schleussner E, Kamin G, Seliger G, Rogenhofer N, Ebner S, Toth B, et al; ETHIG II group. Low-molecular-weight heparin for women with unexplained recurrent pregnancy loss: a multicenter trial with a minimization randomization scheme. Ann Intern Med. 2015;162:601-9.
3. Pasquier E, de Saint Martin L, Bohec C, Chauleur C, Bretelle F, Marhic G, et al. Enoxaparin for prevention of unexplained recurrent miscarriage: a multicenter randomized double-blind placebo-controlled trial. Blood. 2015;125:2200-5.
4. Ghosh, K., Shetty, S., Vora, S., Salvi, V. Successful pregnancy outcome in women with bad obstetric history and recurrent fetal loss due to thrombophilia: effect of unfractionated heparin and low-molecular weight heparin. Clin Appl Thromb Hemost. 2008;14:174-179.
5. Patil R, Ghosh K, Damania K, et al. Effect of anticoagulant therapy on cell-derived microparticles (MP) and pregnancy outcome in women with pregnancy loss. Br J Haematol. 2015.
6. Zwicker JI, Liebman HA, Bauer KA, Caughey T, Campigotto F, Rosovsky R, et al. Prediction and prevention of thromboembolic events with enoxaparin in cancer patients with elevated tissue factor-bearing microparticles: a randomized-controlled phase II trial (the Microtec study). Br J Haematol. 2013;160:530-7.

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