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 . 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 . 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 . 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.
|Enoxaparin 40 mg day−1 (n = 89)||Enoxaparin 80 mg day−1 (n = 91)||P-value|
|Mean age, years||29.1||31.6||0.051|
|Mean weight, kg||64.4||70.7||0.047|
|Mean number of pregnancy losses|
|Type of thrombophilia, n (%)*|
|Total number of thrombophilic defects||n = 138||n = 124|
|Heterozygous factor V Leiden mutation||30 (21.7)||25 (20.2)||0.733|
|APC resistance||25 (18.1)||20 (16.1)||0.818|
|Antiphospholipid antibodies||26 (18.8)||25 (20.2)||0.752|
|MTHFR 677TT genotype||23 (16.7)||23 (18.5)||0.614|
|Protein S deficiency||14 (10.1)||11 (8.9)||0.656|
|Heterozygous factor II G20210A||10 (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 gestations||n = 83||n = 83|
|Live born neonates||70 (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 . 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 .
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.