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Original Research |

Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss: A Multicenter Trial With a Minimization Randomization SchemeLMWH and Recurrent Pregnancy Loss

Ekkehard Schleussner, MD, PhD; Gabriele Kamin, MD; Gregor Seliger, MD; Nina Rogenhofer, MD, PhD; Susanne Ebner, MD; Bettina Toth, MD, PhD; Michael Schenk, MD; Melanie Henes, MD; Michael K. Bohlmann, MD, PhD; Thorsten Fischer, MD, PhD; Oana Brosteanu, PhD; Rupert Bauersachs, MD, PhD; David Petroff, PhD, for the ETHIG II group*
[+] Article, Author, and Disclosure Information

* Members of the ETHIG II (Efficacy of Thromboprophylaxis as an Intervention during Gravidity) group are listed in the Appendix.


From Friedrich Schiller University Hospital, Jena, Germany; University Hospital Carl Gustav Carus, Dresden, Germany; St. Elisabeth and St. Barbara Hospital, Halle (Saale), Germany; Ludwig Maximilians University, Munich, Germany; Centre for Human Genetics, Regensburg, Germany; Ruprecht-Karls University of Heidelberg, Heidelberg, Germany; University of Tübingen, Tübingen, Germany; University Hospital Schleswig-Holstein, Lübeck, Germany; Leipzig University, Leipzig, Germany; Klinikum Darmstadt, Darmstadt, Germany; Center for Thrombosis and Hemostasis, Mainz, Germany; Das Kinderwunsch Institut, Dobl, Austria; and Paracelsus Medical University, Salzburg, Austria.

Grant Support: The ETHIG II trial received an unrestricted grant from Pfizer Pharma and was given the multivitamin supplements free of charge from Merck Selbstmedikation.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14-2062.

Reproducible Research Statement:Study protocol: See Supplement. Statistical code and data set: Available from Dr. Petroff (e-mail, david.petroff@zks.uni-leipzig.de).

Requests for Single Reprints: David Petroff, PhD, Clinical Trial Centre, University of Leipzig, 04017 Leipzig, Germany; e-mail, david.petroff@zks.uni-leipzig.de.

Current Author Addresses: Dr. Schleussner: Department of Obstetrics and Gynecology, Friedrich Schiller University Hospital, 07740 Jena, Germany.

Dr. Kamin: Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, 01307 Dresden, Germany.

Dr. Seliger: Klinik und Poliklinik für Geburtshilfe und Pränatalmedizin, Universitätsklinikum Halle (Saale), Medizinische Fakultät, Martin Luther Universität Halle-Wittenberg, 06097 Halle (Saale), Germany.

Dr. Rogenhofer: Division of Gynecologic Endocrinology and Reproductive Medicine, Department of Obstetrics and Gynecology, Ludwig Maximilians University, Campus Grosshadern, 81377 Munich, Germany.

Dr. Ebner: Centre for Human Genetics, Gynecology and Laboratory Medicine, 93047 Regensburg, Germany.

Dr. Toth: Department of Gynecological Endocrinology and Fertility Disorders, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany.

Dr. Schenk: Das Kinderwunsch Institut, A-8143 Dobl, Austria.

Dr. Henes: Department of Obstetrics and Gynecology, University of Tübingen, 72076 Tübingen, Germany.

Dr. Bohlmann: Department of Obstetrics and Gynecology; University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany.

Dr. Fischer: Department of Obstetrics and Gynecology, Paracelsus University Salzburg, A-5020 Salzburg, Austria.

Dr. Brosteanu: Clinical Trial Centre, University of Leipzig, 04017 Leipzig, Germany.

Dr. Bauersachs: Vascular Medicine, Medical Department IV, Klinikum Darmstadt GmbH, 06151 Darmstadt, Germany.

Dr. Petroff: Clinical Trial Centre, University of Leipzig, 04017 Leipzig, Germany.

Author Contributions: Conception and design: E. Schleussner, G. Seliger, N. Rogenhofer, B. Toth, M.K. Bohlmann, T. Fischer, O. Brosteanu, R. Bauersachs.

Analysis and interpretation of the data: E. Schleussner, G. Kamin, G. Seliger, N. Rogenhofer, S. Ebner, B. Toth, M. Schenk, M.K. Bohlmann, O. Brosteanu, R. Bauersachs, D. Petroff.

Drafting of the article: E. Schleussner, N. Rogenhofer, B. Toth, M. Schenk, M.K. Bohlmann, T. Fischer, R. Bauersachs, D. Petroff.

Critical revision of the article for important intellectual content: G. Kamin, G. Seliger, N. Rogenhofer, S. Ebner, B. Toth, M. Schenk, M. Henes, M.K. Bohlmann, T. Fischer, O. Brosteanu, R. Bauersachs, D. Petroff.

Final approval of the article: E. Schleussner, G. Kamin, N. Rogenhofer, S. Ebner, B. Toth, M. Schenk, M.K. Bohlmann, T. Fischer, O. Brosteanu, R. Bauersachs, D. Petroff.

Provision of study materials or patients: E. Schleussner, G. Kamin, G. Seliger, N. Rogenhofer, S. Ebner, B. Toth, M. Schenk, M.K. Bohlmann, R. Bauersachs.

Statistical expertise: B. Toth, M.K. Bohlmann, O. Brosteanu, R. Bauersachs, D. Petroff.

Obtaining of funding: E. Schleussner, B. Toth, R. Bauersachs.

Administrative, technical, or logistic support: E. Schleussner, N. Rogenhofer, B. Toth, M. Schenk, M.K. Bohlmann.

Collection and assembly of data: E. Schleussner, G. Kamin, G. Seliger, N. Rogenhofer, S. Ebner, B. Toth, M. Schenk, M. Henes, M.K. Bohlmann, T. Fischer, O. Brosteanu, R. Bauersachs, D. Petroff.


Ann Intern Med. 2015;162(9):601-609. doi:10.7326/M14-2062
Text Size: A A A

Background: A daily injection of low-molecular-weight heparin (LMWH) is often prescribed to women with unexplained recurrent pregnancy loss (RPL), although evidence suggesting a benefit is questionable.

Objective: To determine whether LMWH increases ongoing pregnancy and live-birth rates in women with unexplained RPL.

Design: Controlled, multicenter trial with randomization using minimization conducted from 2006 to 2013. (ClinicalTrials.gov: NCT00400387)

Setting: 14 university hospitals and perinatal care centers in Germany and Austria.

Patients: 449 women with at least 2 consecutive early miscarriages or 1 late miscarriage were included during 5 to 8 weeks' gestation after a viable pregnancy was confirmed by ultrasonography.

Intervention: Women in the control group received multivitamin pills, and the intervention group received vitamins and 5000 IU of dalteparin–sodium for up to 24 weeks' gestation.

Measurements: Primary outcome was ongoing pregnancy at 24 weeks' gestation. Secondary outcomes included the live-birth rate and late pregnancy complications.

Results: At 24 weeks' gestation, 191 of 220 pregnancies (86.8%) and 188 of 214 pregnancies (87.9%) were intact in the intervention and control groups, respectively (absolute difference, −1.1 percentage points [95% CI, −7.4 to 5.3 percentage points]). The live-birth rates were 86.0% (185 of 215 women) and 86.7% (183 of 211 women) in the intervention and control groups, respectively (absolute difference, −0.7 percentage point [CI, −7.3 to 5.9 percentage points]). There were 3 intrauterine fetal deaths (1 woman had used LMWH); 9 cases of preeclampsia or the hemolysis, elevated liver enzyme level, and low platelet count (HELLP) syndrome (3 women had used LMWH); and 11 cases of intrauterine growth restriction or placental insufficiency (5 women had used LMWH).

Limitation: Placebo injections were not used, and neither trial staff nor patients were blinded.

Conclusion: Daily LMWH injections do not increase ongoing pregnancy or live-birth rates in women with unexplained RPL. Given the burden of the injections, they are not recommended for preventing miscarriage.

Primary Funding Source: Pfizer Pharma.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

APL = the antiphospholipid syndrome; LMWH = low-molecular-weight heparin.

Grahic Jump Location
Grahic Jump Location
Appendix Figure.

LMWH use versus group, by time.

LMWH = low-molecular-weight heparin.

Grahic Jump Location
Grahic Jump Location
Figure 2.

Treatment effect.

The effect of LMWH versus control is shown for the primary outcome (ongoing pregnancy rate at 24 weeks' gestation) and secondary outcome (live-birth rate). A potentially different treatment effect for the primary outcome is also analyzed for various subgroups. LMWH = low-molecular-weight heparin.

Grahic Jump Location

Tables

References

Letters

NOTE:
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Comments

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Comment
Posted on May 15, 2015
Rucha Patil, M.Sc, Kanjaksha Ghosh, MD, Shrimati Shetty, Ph.D.
KEM Hospital,Parel, Mumbai, India
Conflict of Interest: None Declared
We read with interest the report by Schleussner et al(1) about the multicentric trial on the effect of low molecular weight heparin (LMWH) on pregnancy outcome 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 anticoagulant therapy, the authors have proposed that anticoagulation should not be recommended in such women. A similar observation has been reported in a double blinded placebo controlled trial using enoxaparin(2).
However, while applying the exclusion criteria for different acquired and heritable thrombophilia, one should give due consideration to the recently emerged prothrombotic marker i.e. cell- derived microparticles (MPs), which are basically markers of activation and cell death. As majority of them express phosphatidylserine on their surface, they become thrombogenic. Elevated MP levels in any clinical condition thus suggest some kind of chronic activation or damage. The proof of their procoagulant nature is seen by the shortening of clot time when MP rich plasma is added to the test system; their strong association with different thrombotic disorders also confirms the procoagulant nature of these MPs.
We have earlier shown a strong association of elevated MPs with recurrent pregnancy loss (RPL) in a large series of patients(3) and when such patients with highly elevated MPs were put on LMWH therapy during pregnancy, successful outcome was achieved in patients where MPs gradually normalized(4). Thus, while we completely agree with the authors against administration of LMWH in women with no thrombophilia or presence of a weak inherited thrombophilia, we also propose that in these well designed trials, the role of MPs may not be ignored. The randomized Phase II clinical trials in cancer patients on thromboprophylaxis has proved the efficacy of enoxaparin in reducing the thrombotic events in patients with increased levels of tissue factor MPs(5) and a multicentric trial is currently ongoing to further confirm the role of primary thromboprophylaxis in cancer patients with elevated tissue factor bearing MPs.
While several studies undoubtedly have confirmed the role of MPs in RPL, studies are also emerging on the beneficial role of thromboprophylaxis in patients with pathological levels of MPs of different cell types. MPs are certainly worthy of consideration in larger clinical trials involving thromboprophylaxis in women with unexplained PL. Once the cause and consequence of MPs is fully established, the number of women with idiopathic PL will reduce substantially and evidence based thromboprophylaxis becomes the standard care in majority of these women.


References:
1. 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.
2. 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.
3. Patil R, Ghosh K, Satoskar P, Shetty S. Elevated procoagulant endothelial and tissue factor expressing microparticles in women with recurrent pregnancy loss. PLoS One. 2013;20:e81407.
4. 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.
5. 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.


Recurrent Miscarriage Prevention
Posted on June 1, 2015
Elisabeth Pasquier, MD, PhD, Luc de Saint Martin, MD, PhD
Internal Medicine Brest University Hospital France
Conflict of Interest: None Declared

To the editor,
The results of the open-label trial by Schleussner and colleagues (May 5th issue) are in agreement with those of the recent double-blind placebo-controlled study, reported by our team in April, 2015(1). According to both studies, low-molecular-weight heparin (LMWH) did not improve the chance of a live birth in women with unexplained recurrent miscarriage. Cocooning remains the only validated therapeutic option.
Noteworthy, in the trial by Schleussner et al., the live-birth rate was higher (86 %), compared to that reported in our study (70%) (1) as well as that reported in ALIFE and HABENOX trials (2, 3). Most women with recurrent miscarriage have recurrent early loss with a failure of development before 10 weeks. The anticipated 75% of live-birth rate, used by Schleussner and colleagues for the sample size estimation, was based on longitudinal follow-up studies among women with common recurrent miscarriage (4). This was probably not relevant to the design of their study. Indeed, in Schleussner et al. trial, women were randomized late during pregnancy. The mean gestational age at randomization was 7 weeks (after a viable pregnancy was confirmed by ultrasonography), vs. 5.5 weeks (after a positive pregnancy test) in other trials (1,3). Additionally, only 32 % of women vs. 70% in other trials (1-3) had more than 2 previous early losses. Thus, the women randomized in the open-label trial by Schleussner et al. were at low risk of subsequent pregnancy loss.
Most of the trials, which investigated the benefit of antithrombotic medications in prevention of miscarriage, were not designed to assess the impact of treatment in the early stages of pregnancy. The subcutaneous administration of LMWH hampers its use before conception and early enough during pregnancy in fertile women. It is well known that most of the pathological events are likely to occur very early in pregnancy and may require intervention as early as the initial blastocyst implantation. We would like to emphasize that in a recent study on aspirin therapy before conception, the assessed subgroup of women were at low risk of recurrent loss (one or two previous miscarriages) (5).
Therefore, the nagging question remains: how to reach an optimal management of recurrent miscarriage? In the future, medical caregivers should prefer to investigate more relevant oral or intra-vaginal therapies, given before conception, and consequently at the time of the initial implantation in the prevention of recurrent miscarriage.

Elisabeth Pasquier*, M.D., Ph.D., Luc de Saint Martin*, M.D., Ph.D
* EA 3878 (GETBO) , Department of Internal Medicine and Chest Diseases, Brest University Hospital, La Cavale Blanche Hospital, 29609 Brest, France.      elisabeth.pasquier@chu-brest.fr

No potential conflict of interest relevant to this letter was reported.

References

1. 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 Apr 2;125:2200-5.
2. Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulya´k K, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362:1586-96.
3. 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.
4. Brigham SA, Conlon C, Farquharson RG. A longitudinal study of pregnancy outcome following idiopathic recurrent miscarriage. Hum Reprod. 1999;14(11):2868-2871
5. Schisterman EF, Silver RM, Lesher LL, Faraggi D, Wactawski-Wende J, Townsend J, et al. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial. Lancet. 2014 Jul 5;384:29-36. Preconception low-dose aspirin and pregnancy outcomes: results from the EAGeR randomised trial.

Author's Response
Posted on June 26, 2015
Ekkehard Schleussner and David Petroff
Univeristy of Leipzig
Conflict of Interest: None Declared
Two interesting letters concerning our recent article (1) on recurrent miscarriage prevention are being published in the current issue of this journal.
In the first, Patil, Ghosh and Peti propose looking at microparticles to assess risk. This interesting approach was not well established when our trial was designed, but we certainly agree that research in that direction should be followed.

In the second, Pasquier and Saint Martin note that low-molecular-weight heparin (LMWH) does not increase live birth rates in the populations being considered and also propose exploring specific new avenues. They remark that in our recently published trial (1), the women were “at low risk of subsequent pregnancy loss”, since the mean week of gestation at inclusion was thought to be high and because the proportion of women with more than 2 previous early losses was ostensibly low. Indeed, the overall miscarriage rate in our trial was low, but we included sub-group analyses of higher risk groups.
Regarding the time of inclusion, we designed our trial based on the hypothesis that the effect of LMWH on placental vascularization is at the root of its putative benefit and thus randomized during this stage (5-8 weeks’ gestation) after ultrasonographic confirmation of a fetal heartbeat. The SPIN trial included women after confirmation of pregnancy before the 7th week (2), resulting in mean inclusion about a week earlier than in our case. The ALIFE trial randomized most of the women before pregnancy, but only began LMWH therapy after “pregnancy was confirmed on ultrasonography, starting at 6 weeks of gestation”, (3) thus providing evidence for the effects of LMWH beginning much later than randomization and comparable to our trial. Pasquier et al. are to be commended for providing important data with their PREFIX trial on the effects of LMWH at earlier stages of pregnancy (4).

In terms of miscarriage history, about 60% of the women in ALIFE had had more than two previous miscarriages (not 70%), in SPIN it was about 43%, which is almost identical to the 44% in our paper (8% with 1 late and > 1 early; 3% with >1 late and > 0 early; 33% with 0 late and >2 early miscarriages). The HABENOX trial mentioned by Pasquier and Saint Martin did not include any women with 2 early pregnancy losses and is thus not comparable regarding miscarriage history (5). Given the distribution of pregnancy loss in the population and at the obstetrician's, it is something of a surprise that there are so few women with 2 early pregnancy losses in the PREFIX trial, given that this was an inclusion criterion.

Pasquier and Saint Martin’s letter to the editor demonstrates how important it is to discuss and compare the trials on this topic openly, since subtle differences in design and local patient characteristics can have a large effect on clinically relevant parameters.

References

1. Schleussner E, Kamin G, Seliger G, et al. Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss: A Multicenter Trial With a Minimization Randomization Scheme. Ann Int Med. 2015: 162: 601-9.

2. Clark P, Walker ID, Langhorne P, et al. 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.

3. Kaandorp SP, Goddijn M, van der Post JA, et al. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010;362:1586-96.

4. Visser J, Ulander VM, Helmerhorst FM, et al. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. HABENOX: a randomised multicentre trial. Thromb Haemost. 2011; 105:295-301.

5. 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 Apr 2;125:2200-5.



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Summary for Patients

Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss

The full report is titled “Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss. A Multicenter Trial With a Minimization Randomization Scheme.” It is in the 5 May 2015 issue of Annals of Internal Medicine (volume 162, pages 601-609). The authors are E. Schleussner, G. Kamin, G. Seliger, N. Rogenhofer, S. Ebner, B. Toth, M. Schenk, M. Henes, M.K. Bohlmann, T. Fischer, O. Brosteanu, R. Bauersachs, and D. Petroff, for the ETHIG II group.

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