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Clinical studies suggest that the use of low-molecular-weight heparins (LMWHs) during pregnancy may result in an improved outcome in women with thrombophilia and recurrent pregnancy loss (RPL) [1–3]. LMWHs also appear to be safe when administered to women during pregnancy [4]. In a study population of 50 women with RPL, our group has previously demonstrated that treatment with enoxaparin 40 mg day−1 or 80 mg day−1 resulted in favorable pregnancy outcomes with live birth rates of 69% and 83%, respectively [1]. The data suggested that the higher dosage of 80 mg day−1 enoxaparin was potentially beneficial for women at a greater risk of thrombosis due to more than one thrombophilic defect [1]. We therefore compared the efficacy and safety of enoxaparin 40 mg day−1 and 80 mg day−1[40 mg twice a day (b.i.d.)] in improving pregnancy outcomes of women with thrombophilia and a history of RPL.

In total, 180 women were enrolled in the LIVE-ENOX study, a multicenter, prospective, randomized, open-label trial, at 12 centers in Israel. Women were enrolled at 5–10 weeks of pregnancy, if aged ≥ 18 years, with thrombophilia and a history of RPL which was defined as three or more losses before the end of the first trimester, two or more in the second trimester or one intrauterine fetal death in the third trimester. Exclusion criteria were: pregnancy loss within 3 months prior to enrollment, prior thromboembolic disease, history of epilepsy, thrombocytopenia, renal or hepatic insufficiency, or contraindication to LMWHs.

Patients received either enoxaparin 40 mg day−1[40 mg o.d. (once daily)] or enoxaparin 80 mg day−1 (40 mg b.i.d), which was self-administered by subcutaneous injection using prefilled syringes. Study treatment commenced at 5–10 weeks of pregnancy, and continued throughout pregnancy and up to 6 weeks postpartum. The primary efficacy endpoint was the delivery of a live, healthy infant. The safety endpoints included maternal thrombocytopenia, and any drug-related adverse events throughout the study.

Over 90% of women in each group completed the study. The baseline characteristics of the patients receiving each dosage of enoxaparin are shown in Table 1. Thrombophilic defects were not significantly different between the two treatment groups (Table 1). In both groups, only about 28% of previous pregnancies had resulted in live births.

Table 1.  Baseline characteristics and outcomes of women enrolled in the LIVE-ENOX study
 Enoxaparin 40 mg day−1 (n = 89)Enoxaparin 80 mg day−1 (n = 91)P-value
  1. APC, Activated protein C; MTHFR, methylene-tetrahydrofolate reductase; NA, not applicable. *Some women were diagnosed with more than one type of thrombophilia.

Baseline characteristics
Mean age, years29.131.60.051
Mean weight, kg64.470.70.047
Mean number of  pregnancy losses
 1st trimester2.912.880.834
 2nd trimester0.580.650.394
 3rd trimester0.330.300.881
Type of thrombophilia, n (%)*
Total number of  thrombophilic defectsn = 138n = 124 
Heterozygous factor  V Leiden mutation30 (21.7)25 (20.2)0.733
APC resistance25 (18.1)20 (16.1)0.818
Antiphospholipid antibodies26 (18.8)25 (20.2)0.752
MTHFR 677TT genotype23 (16.7)23 (18.5)0.614
Protein S deficiency14 (10.1)11 (8.9)0.656
Heterozygous factor II G20210A10 (7.2) 9 (7.3)0.987
Antithrombin III deficiency 3 (2.2) 2 (1.6)0.711
Hyperhomocysteinemia 1 (0.7) 3 (2.4)0.442
Protein C deficiency 2 (1.4) 2 (1.6)0.799
Other 4 (2.9) 4 (3.2)0.770
Efficacy and safety outcomes, n (%)
Evaluable gestationsn = 83n = 83 
Live born neonates70 (84.3)65 (78.3)0.310
Bleeding episodes 0 (0) 0 (0)NA
Heparin-induced  thrombocytopenia 0 (0) 0 (0)NA
Thrombotic episodes 0 (0) 0 (0)NA
Allergic reactions 2 (2.2) 3 (3.3)0.881

Of the 166 women completing the study, 135 gestations resulted in live births: 70 (84.3%) in the 40 mg day−1 group and 65 (78.3%) in the 80 mg day−1 group. There was no significant difference in pregnancy outcome between the 40 mg day−1 and 80 mg day−1 dosages (Table 1). The live birth rate following prophylaxis with enoxaparin was 78.0% for women with activated protein C resistance and factor V Leiden mutation, 84.4% for methylene-tetrahydrofolate reductase gene C677T mutation and hyperhomocysteinemia, 76.9% for antiphospholipid syndrome and 81.3% for other types of thrombophilia. Differences in live birth rate between types of thrombophilia were not statistically significant (P = 0.484). There were no reports of maternal thrombosis, bleeding episodes or thrombocytopenia during enoxaparin use (Table 1). Enoxaparin-related, allergic, local skin reactions at the injection sites were observed in a small number of women (2.2% and 3.3% of those receiving 40 mg day−1 and 80 mg day−1, respectively).

The LIVE-ENOX data demonstrate, in a large study population of women with thrombophilia and RPL, that prophylaxis with enoxaparin 40 mg day−1 or 80 mg day−1 is effective and safe, with the majority of treated pregnancies resulting in a favorable outcome.

Bleeding and heparin-induced thrombocytopenia (HIT) are the primary safety concerns associated with antithrombotic therapy [1,5–9]. LMWHs, however, are associated with a low risk of bleeding and lower incidence of HIT [1,2,4,10–12]. Indeed, both dosages of enoxaparin were well tolerated, and there were no clinically significant bleeding complications, or HIT. These data concur with existing data showing that prophylaxis with enoxaparin is safe during pregnancy.

Pregnancy outcomes were similar whether 40 mg day−1 or 80 mg day−1 enoxaparin regimens were used. Our previous study suggested that the higher dosage of enoxaparin (80 mg day−1) might be beneficial in women with multiple severe thrombophilic defects [1]. The present results show that enoxaparin 80 mg day−1 did not increase either bleeding complications or HIT compared with the 40 mg day−1 dosage. Combining the data from the present study with our previous report suggests that the lower dosage of enoxaparin (40 mg day−1) may suffice for thrombophilic women with standard risk while a higher dosage of enoxaparin (80 mg day−1) might be beneficial and equally safe in women with a particularly high thrombotic risk [1].

In conclusion, the LIVE-ENOX study demonstrates that enoxaparin 40 mg day−1 and 80 mg day−1 are equally effective and safe in women with thrombophilia and RPL, with the majority of treated pregnancies resulting in a favorable outcome.

References

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  2. References
  3. Appendix
  • 1
    Brenner B, Hoffman R, Blumenfeld Z, Weiner Z, Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin. Thromb Haemost 2000; 83: 6937.
  • 2
    Carp H, Dolitzky M, Inbal A. Thromboprophylaxis improves the live birth rate in women with consecutive recurrent miscarriages and hereditary thrombophilia. J Thromb Haemost 2003; 1: 4338.
  • 3
    Gris JC, Mercier E, Quéré I, Lavigne-Lissalde G, Cochery-Nouvellon E, Hoffet M, Ripart-Neveu S, Tailland ML, Dauzat M, Mares P. Low molecular weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder. Blood 2004; 103: 36959.
  • 4
    Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, MacGillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost 1999; 81: 66872.
  • 5
    Brenner B, Kupferminc MJ. Inherited thrombophilia and poor pregnancy outcome. Best Pract Res Clin Obstet Gynaecol 2003; 17: 42739.
  • 6
    Sarig G, Younis JS, Hoffman R, Lanir N, Blumenfeld Z, Brenner B. Thrombophilia is common in women with idiopathic pregnancy loss and is associated with late pregnancy wastage. Fertil Steril 2002; 77: 3427.DOI: 10.1016/S0015-0282(01)02971-5
  • 7
    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, Van Der Meer FJ. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348: 9136.DOI: 10.1016/S0140-6736(96)04125-6
  • 8
    Ridker PM, Miletich JP, Buring JE, Ariyo AA, Price DT, Manson JE, Hill JA. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med 1998; 128: 10003.
  • 9
    Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 9018.DOI: 10.1016/S0140-6736(03)12771-7
  • 10
    Eldor A. The use of low-molecular-weight heparin for the management of venous thromboembolism in pregnancy. Eur J Obstet Gynecol Reprod Biol 2002; 104: 313.DOI: 10.1016/S0301-2115(02)00239-7
  • 11
    Gris JC, Balducchi JP, Quéré I, Hoffet M, Marès P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes. Thromb Haemost 2002; 87: 5367.
  • 12
    Gris JC, Neveu S, Tailland ML, Courtieu C, Mares P, Schved JF. 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: 3627.

Appendix

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  2. References
  3. Appendix

All the LIVE-ENOX Investigators contributed significantly to the research presented in this letter and the writing, review, and revision of this letter. In addition to the cited authors, the LIVE-ENOX Investigators also include:

A. Samueloff, Shaare Zedek Medical Center, Jerusalem, Israel; D. Yohai, Soroka Medical Center, Beer-Sheva, Israel; J. Bar, Rabin Medical Center, Petah-Tikva, Israel; I. Thaler, Rambam Medical Center, Haifa, Israel; I. Yarom, Haemek Medical Center, Afula, Israel; M. Ellis, Meir Medical Center, Blood Bank, Kfar Sava, Israel; D. Varon, Hadassah Hebrew University Medical Center, Jerusalem, Israel; J. Tal, Bnai-Zion Medical Center, Haifa, Israel; Z. Blumenfeld, Rambam Medical Center, Haifa, Israel; S. Segal, Barzilay Medical Center, Ashkelon, Israel; M. Kupferminc, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.