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Effects of enoxaparin on late pregnancy complications and neonatal outcome in women with recurrent pregnancy loss and thrombophilia: results from the Live-Enox study

2005; Elsevier BV; Volume: 84; Issue: 3 Linguagem: Inglês

10.1016/j.fertnstert.2005.03.048

1556-5653

Benjamin Brenner, Jacob Bar, Martin Ellis, Ilan Yarom, David Yohai, Aaron Samueloff,

Venous Thromboembolism Diagnosis and Management

Women with thrombophilia and a history of recurrent pregnancy loss have poor pregnancy outcomes. Prophylaxis with enoxaparin 40 mg/day or 80 mg/day resulted in favorable gestational and neonatal outcomes. Women with thrombophilia and a history of recurrent pregnancy loss have poor pregnancy outcomes. Prophylaxis with enoxaparin 40 mg/day or 80 mg/day resulted in favorable gestational and neonatal outcomes. Women with a history of recurrent pregnancy loss (RPL) and hereditary thrombophilia have poor pregnancy outcomes and, in the absence of therapeutic intervention, only about 25% of pregnancies result in live births (1Brenner B. Inherited thrombophilia and pregnancy loss.Best Pract Res Clin Haematol. 2003; 16: 311-320Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar). There is evidence from small, uncontrolled studies that the use of low-molecular-weight heparins (LMWHs) during pregnancy may result in improved outcomes in women with thrombophilia and RPL (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar). Furthermore, LMWHs appear to be safe when administered to women during pregnancy (4Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne-Pardonge E. et al.Safety of low-molecular-weight heparin in pregnancy a systematic review.Thromb Haemost. 1999; 81: 668-672PubMed Google Scholar). In one study of 50 women with thrombophilia and RPL, we showed improved live birth rates of 69% and 83% following treatment with enoxaparin 40 mg/day or 80 mg/day, respectively (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar). Although the difference was not significant (P=.37), these data suggested a benefit with the 80 mg/day dose. The Live-Enox study was therefore performed to compare the efficacy and safety of enoxaparin 40 mg/day and 80 mg/day on pregnancy outcomes in women with thrombophilia and a history of RPL. Both doses of enoxaparin were shown to be equally effective and safe, with live birth rates of 84% and 78% in the enoxaparin 40 mg/day and 80 mg/day groups, respectively (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). In this paper, we report data on late pregnancy complications and neonatal outcomes from the Live-Enox study.The Live-Enox study was a multicenter, prospective, randomized, open-label trial between March 2000 and December 2002 at 12 centers in Israel. It was conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983, and approved by the ethics committees of participating centers and the higher ethics committee of the Israeli Ministry of Health. Women aged ≥18 years with thrombophilia and a history of RPL were enrolled at 5–10 weeks of pregnancy. RPL was defined as ≥3 losses during the first trimester, ≥2 in the second trimester, or 1 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 contraindications to LMWH therapy.One hundred eighty women received either enoxaparin 40 mg/day (40 mg once daily (o.d.)) or enoxaparin 80 mg/day (40 mg twice daily (b.i.d.)), self-administered by subcutaneous injection. Study treatment commenced at 5–10 weeks of pregnancy and continued up to 6 weeks postpartum. Follow-up visits were every 4 weeks. The primary efficacy endpoint was the delivery of a healthy infant. Other efficacy endpoints were duration of gestation, birth weight, and incidence of gestational thrombosis and gestational vascular complications (preeclampsia, placental abruption, and intrauterine growth restriction (IUGR)). Safety endpoints were infant and maternal bleeding episodes, maternal thrombocytopenia, infant health (weight, gestational age, Apgar score at 5 minutes), and any drug-related adverse events.Baseline characteristics of the enrolled women were reported previously (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). There were no significant differences in the types of thrombophilia between the groups (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). Women in the enoxaparin 40 mg/day and 80 mg/day groups had similar rates of live births prior to study initiation (28.2% and 28.3%, respectively). The incidence of preeclampsia in the enoxaparin 40 mg/day and 80 mg/day groups was 6.7% and 14.3%, respectively, and the incidence of placental abruption was 13.5% and 8.8%, respectively. Approximately a quarter of the women in both groups had IUGR in previous gestations (22.5% and 24.2%, respectively).Late gestational complications after enoxaparin treatment are shown in Table 1. The incidence of preeclampsia in the enoxaparin 40 mg/day and 80 mg/day groups was 3.4% and 4.4%, respectively. Similarly, the incidence of placental abruption in the enoxaparin 40 mg/day and 80 mg/day groups was 4.5% and 3.3%, respectively.TABLE 1Birth details of mothers and infants after enoxaparin 40 mg/d or 80 mg/d.Enoxaparin 40 mg/dEnoxaparin 80 mg/dPNo. of women in group, n8991Details of mothers Live born neonates, n7065.310 Vaginal delivery, n (%)aPercentages based on the number of live-born neonates.59 (84.3)53 (81.5).717 Gestational period, n (%)aPercentages based on the number of live-born neonates. 36 wk63 (90.0)53 (81.5).076Bleeding episodes, n (%)0 (0)0 (0)NAHeparin-induced thrombocytopenia, n (%)0 (0)0 (0)NAThrombotic episodes, n (%)0 (0)0 (0)NAAllergic reactions, n (%)2 (2.2)3 (3.3).881Postpartum bleeding, n (%)1 (1.1)1 (1.1).779Preeclampsia, n (%)3 (3.4)4 (4.4).722Placental abruption, n (%)4 (4.5)3 (3.3).677Details of newborns Birth weightbData were available on 65 and 63 newborns from the enoxaparin 40 mg/day and 80 mg/day groups, respectively. Mean, g30512998.653 2500 g, n (%)54 (83.1)53 (84.1).513 Apgar score at 5 min, n (%)cData were available on 61 and 60 newborns from the enoxaparin 40 mg/day and 80 mg/day groups, respectively. 70 (0)1 (1.7).912 82 (3.3)1 (1.7).861 921 (34.4)15 (25.0).091 1038 (62.3)43 (71.7).076Neonatal bleeding, n (%)0 (0)0 (0)NANote: NA = not applicable.Brenner. Enoxaparin prophylaxis in pregnancy. Fertil Steril 2005.a Percentages based on the number of live-born neonates.b Data were available on 65 and 63 newborns from the enoxaparin 40 mg/day and 80 mg/day groups, respectively.c Data were available on 61 and 60 newborns from the enoxaparin 40 mg/day and 80 mg/day groups, respectively. Open table in a new tab Both doses of enoxaparin appeared to be safe and well tolerated. The gestation period was longer than 36 weeks in over 80% of patients in each group (Table 1). However, preterm delivery occurred in 10% and 18.5% of women in the enoxaparin 40 mg/day and 80 mg/day groups, respectively. Postpartum bleeding (1.1% of women in each group), and 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 and 80 mg/day, respectively) (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar).The mean birth weight was normal (about 3000 g) in both groups (Table 1). Severe prematurity, with low birth weight (≤1500 g), occurred in only 3.1% and 3.2% of the infants after 40 mg/day and 80 mg/day enoxaparin, respectively. IUGR was uncommon, occurring in 7 out of 65 (10.8%) of infants after 40 mg/day enoxaparin and in 5 out of 63 (7.9%) infants after 80 mg/day enoxaparin. The IUGR was mild in all but one case in both treatment groups (1.5%). Regression analysis showed that birth weight correlated well with gestational week of delivery (P=.003, r =.82 for enoxaparin 40 mg/day group; P=.001, r =.84 for enoxaparin 80 mg/day group). Apgar scores at 5 minutes were within the normal range and were similar irrespective of the dose of enoxaparin (Table 1), indicating that the great majority of live births in this study resulted in normal healthy infants.The outcome of pregnancies in women prior to enrollment in the Live-Enox study was generally poor, with only around 28% of pregnancies resulting in live births. In contrast, after enoxaparin treatment the live birth rate increased to more than 78% (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). The increased incidence of live births was independent of the type of thrombophilia, although the number of women presenting with each specific thrombophilic defect in this study was small (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). The optimal prophylactic regimen for specific defects should be further explored.Comparisons of historical data derived from the women before their enrollment to the study should be interpreted with some caution owing to the possibility of confounding. While inclusion of a placebo group was preferred, it was not considered practically feasible given that previous smaller studies have demonstrated a beneficial effect of heparin therapy in improving gestational outcome in women with RPL and thrombophilia (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar, 4Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne-Pardonge E. et al.Safety of low-molecular-weight heparin in pregnancy a systematic review.Thromb Haemost. 1999; 81: 668-672PubMed Google Scholar, 6Younis J.S. Ohel G. Brenner B. Haddad S. Lanir N. Ben-Ami M. The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.Br J Obstet Gynaecol. 2000; 107: 415-419Crossref Scopus (73) Google Scholar, 7Rai R. Cohen H. Dave M. Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).BMJ. 1997; 314: 253-257Crossref PubMed Scopus (975) Google Scholar, 8Gris J.C. Balducchi J.P. Quere I. Hoffet M. Mares P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes.Thromb Haemost. 2002; 87: 536-537PubMed Google Scholar). Although comparisons with historical data have limitations, they can provide important insights in situations where a placebo control is not practical.Live birth rates comparable to those obtained in this study were recently reported in a study of thrombophilic women with 1 or 2 unexplained pregnancy losses from the 10th week of amenorrhea, in which enoxaparin 40 mg/day was compared with low-dose aspirin (86% vs. 29% live births, respectively) (9Gris J.C. Mercier E. Quere I. Lavigne-Lissalde G. Cochery-Nouvellon E. Hoffet M. et al.Low molecular weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-3699Crossref PubMed Scopus (347) Google Scholar). However, the rates of live births, preeclampsia, and placental abruption before enoxaparin treatment were not reported.In the present study, pregnancies continued to full term in the majority of women receiving prophylaxis with enoxaparin, thus increasing the likelihood of delivering a healthy infant. Furthermore, the incidence of preeclampsia, placental abruption, and IUGR in women who received prophylaxis with enoxaparin was lower compared with the historical rates of these complications in the same women. Clinical evidence suggests that women with thrombophilia have an increased risk of pregnancy loss and complications such as preeclampsia, placental abruption, and IUGR (10Kupferminc M.J. Eldor A. Steinman N. Many A. Bar-Am A. Jaffa A. et al.Increased frequency of genetic thrombophilia in women with complications of pregnancy.N Engl J Med. 1999; 340: 9-13Crossref PubMed Scopus (1002) Google Scholar, 11Brenner B. Clinical management of thrombophilia-related placental vascular complications.Blood. 2004; 103: 4003-4009Crossref PubMed Scopus (51) Google Scholar). The low incidence of pregnancy complications following enoxaparin prophylaxis in women with thrombophilia and RPL is beneficial in terms of both fetal and maternal health. Although previous smaller studies have reported the benefits of prophylaxis in improving pregnancy outcomes in women with RPL and thrombophilia (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 6Younis J.S. Ohel G. Brenner B. Haddad S. Lanir N. Ben-Ami M. The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.Br J Obstet Gynaecol. 2000; 107: 415-419Crossref Scopus (73) Google Scholar, 7Rai R. Cohen H. Dave M. Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).BMJ. 1997; 314: 253-257Crossref PubMed Scopus (975) Google Scholar, 8Gris J.C. Balducchi J.P. Quere I. Hoffet M. Mares P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes.Thromb Haemost. 2002; 87: 536-537PubMed Google Scholar), the results obtained in this study demonstrate in a large study population that prophylaxis with enoxaparin 40 mg/day or 80 mg/day is safe for both mother and fetus, with the majority of treated pregnancies resulting in a favorable outcome.Our previous study suggested that enoxaparin 80 mg/day might be beneficial in women with multiple severe thrombophilic defects (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar), but the results of the current study showed no differences in pregnancy complications, bleeding complications, or heparin-induced thrombocytopenia (HIT) compared with women receiving the 40 mg/day dose. Together, these two studies suggest that enoxaparin 40 mg/day is sufficient for most women with thrombophilia. Our findings suggest that increasing the dose of enoxaparin from 40 to 80 mg/day does not improve the pregnancy outcome further. However, enoxaparin 80 mg/day might be beneficial and safe in women with a particularly high thrombotic risk (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar).This study did not analyze fetal karyotype. Fetal karyotypic abnormalities have been reported in thrombophilic women with RPL who received prophylaxis with enoxaparin (3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar) and may have been responsible for many of the fetal losses in these women. Although the incidences of IUGR, preeclampsia, and placental abruption were substantially lower in women receiving enoxaparin therapy compared with their historical rates, the incidences remained higher than normal. In addition, although the majority of deliveries were at term, the rate of preterm deliveries was also higher than normal. Future studies should be directed towards optimizing prophylactic strategies to minimize these complications.LMWHs offer a favorable safety profile in pregnancy, as they are associated with a lower risk of maternal and fetal bleeding than warfarin and a lower risk of HIT than UFH (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar, 4Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne-Pardonge E. et al.Safety of low-molecular-weight heparin in pregnancy a systematic review.Thromb Haemost. 1999; 81: 668-672PubMed Google Scholar, 8Gris J.C. Balducchi J.P. Quere I. Hoffet M. Mares P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes.Thromb Haemost. 2002; 87: 536-537PubMed Google Scholar, 12Eldor A. The use of low-molecular-weight heparin for the management of venous thromboembolism in pregnancy.Eur J Obstet Gynecol Reprod Biol. 2002; 104: 3-13Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Gris J.C. Neveu S. Tailland M.L. Courtieu C. Mares P. Schved J.F. 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: 362-367PubMed Google Scholar). This was reflected in the present study, in which both doses of enoxaparin were well tolerated with no clinically significant maternal or neonatal bleeding or HIT. In conclusion, prophylaxis with enoxaparin (40 mg/day or 80 mg/day) is safe and effective for improving pregnancy outcome and reducing late pregnancy complications in thrombophilic women with a history of RPL. Women with a history of recurrent pregnancy loss (RPL) and hereditary thrombophilia have poor pregnancy outcomes and, in the absence of therapeutic intervention, only about 25% of pregnancies result in live births (1Brenner B. Inherited thrombophilia and pregnancy loss.Best Pract Res Clin Haematol. 2003; 16: 311-320Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar). There is evidence from small, uncontrolled studies that the use of low-molecular-weight heparins (LMWHs) during pregnancy may result in improved outcomes in women with thrombophilia and RPL (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar). Furthermore, LMWHs appear to be safe when administered to women during pregnancy (4Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne-Pardonge E. et al.Safety of low-molecular-weight heparin in pregnancy a systematic review.Thromb Haemost. 1999; 81: 668-672PubMed Google Scholar). In one study of 50 women with thrombophilia and RPL, we showed improved live birth rates of 69% and 83% following treatment with enoxaparin 40 mg/day or 80 mg/day, respectively (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar). Although the difference was not significant (P=.37), these data suggested a benefit with the 80 mg/day dose. The Live-Enox study was therefore performed to compare the efficacy and safety of enoxaparin 40 mg/day and 80 mg/day on pregnancy outcomes in women with thrombophilia and a history of RPL. Both doses of enoxaparin were shown to be equally effective and safe, with live birth rates of 84% and 78% in the enoxaparin 40 mg/day and 80 mg/day groups, respectively (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). In this paper, we report data on late pregnancy complications and neonatal outcomes from the Live-Enox study. The Live-Enox study was a multicenter, prospective, randomized, open-label trial between March 2000 and December 2002 at 12 centers in Israel. It was conducted in accordance with the Helsinki Declaration of 1975, as revised in 1983, and approved by the ethics committees of participating centers and the higher ethics committee of the Israeli Ministry of Health. Women aged ≥18 years with thrombophilia and a history of RPL were enrolled at 5–10 weeks of pregnancy. RPL was defined as ≥3 losses during the first trimester, ≥2 in the second trimester, or 1 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 contraindications to LMWH therapy. One hundred eighty women received either enoxaparin 40 mg/day (40 mg once daily (o.d.)) or enoxaparin 80 mg/day (40 mg twice daily (b.i.d.)), self-administered by subcutaneous injection. Study treatment commenced at 5–10 weeks of pregnancy and continued up to 6 weeks postpartum. Follow-up visits were every 4 weeks. The primary efficacy endpoint was the delivery of a healthy infant. Other efficacy endpoints were duration of gestation, birth weight, and incidence of gestational thrombosis and gestational vascular complications (preeclampsia, placental abruption, and intrauterine growth restriction (IUGR)). Safety endpoints were infant and maternal bleeding episodes, maternal thrombocytopenia, infant health (weight, gestational age, Apgar score at 5 minutes), and any drug-related adverse events. Baseline characteristics of the enrolled women were reported previously (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). There were no significant differences in the types of thrombophilia between the groups (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). Women in the enoxaparin 40 mg/day and 80 mg/day groups had similar rates of live births prior to study initiation (28.2% and 28.3%, respectively). The incidence of preeclampsia in the enoxaparin 40 mg/day and 80 mg/day groups was 6.7% and 14.3%, respectively, and the incidence of placental abruption was 13.5% and 8.8%, respectively. Approximately a quarter of the women in both groups had IUGR in previous gestations (22.5% and 24.2%, respectively). Late gestational complications after enoxaparin treatment are shown in Table 1. The incidence of preeclampsia in the enoxaparin 40 mg/day and 80 mg/day groups was 3.4% and 4.4%, respectively. Similarly, the incidence of placental abruption in the enoxaparin 40 mg/day and 80 mg/day groups was 4.5% and 3.3%, respectively. Note: NA = not applicable. Brenner. Enoxaparin prophylaxis in pregnancy. Fertil Steril 2005. Both doses of enoxaparin appeared to be safe and well tolerated. The gestation period was longer than 36 weeks in over 80% of patients in each group (Table 1). However, preterm delivery occurred in 10% and 18.5% of women in the enoxaparin 40 mg/day and 80 mg/day groups, respectively. Postpartum bleeding (1.1% of women in each group), and 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 and 80 mg/day, respectively) (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). The mean birth weight was normal (about 3000 g) in both groups (Table 1). Severe prematurity, with low birth weight (≤1500 g), occurred in only 3.1% and 3.2% of the infants after 40 mg/day and 80 mg/day enoxaparin, respectively. IUGR was uncommon, occurring in 7 out of 65 (10.8%) of infants after 40 mg/day enoxaparin and in 5 out of 63 (7.9%) infants after 80 mg/day enoxaparin. The IUGR was mild in all but one case in both treatment groups (1.5%). Regression analysis showed that birth weight correlated well with gestational week of delivery (P=.003, r =.82 for enoxaparin 40 mg/day group; P=.001, r =.84 for enoxaparin 80 mg/day group). Apgar scores at 5 minutes were within the normal range and were similar irrespective of the dose of enoxaparin (Table 1), indicating that the great majority of live births in this study resulted in normal healthy infants. The outcome of pregnancies in women prior to enrollment in the Live-Enox study was generally poor, with only around 28% of pregnancies resulting in live births. In contrast, after enoxaparin treatment the live birth rate increased to more than 78% (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). The increased incidence of live births was independent of the type of thrombophilia, although the number of women presenting with each specific thrombophilic defect in this study was small (5Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss the Live-Enox study.J Thromb Haemost. 2005; 3: 227-229Crossref PubMed Scopus (172) Google Scholar). The optimal prophylactic regimen for specific defects should be further explored. Comparisons of historical data derived from the women before their enrollment to the study should be interpreted with some caution owing to the possibility of confounding. While inclusion of a placebo group was preferred, it was not considered practically feasible given that previous smaller studies have demonstrated a beneficial effect of heparin therapy in improving gestational outcome in women with RPL and thrombophilia (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar, 4Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne-Pardonge E. et al.Safety of low-molecular-weight heparin in pregnancy a systematic review.Thromb Haemost. 1999; 81: 668-672PubMed Google Scholar, 6Younis J.S. Ohel G. Brenner B. Haddad S. Lanir N. Ben-Ami M. The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.Br J Obstet Gynaecol. 2000; 107: 415-419Crossref Scopus (73) Google Scholar, 7Rai R. Cohen H. Dave M. Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).BMJ. 1997; 314: 253-257Crossref PubMed Scopus (975) Google Scholar, 8Gris J.C. Balducchi J.P. Quere I. Hoffet M. Mares P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes.Thromb Haemost. 2002; 87: 536-537PubMed Google Scholar). Although comparisons with historical data have limitations, they can provide important insights in situations where a placebo control is not practical. Live birth rates comparable to those obtained in this study were recently reported in a study of thrombophilic women with 1 or 2 unexplained pregnancy losses from the 10th week of amenorrhea, in which enoxaparin 40 mg/day was compared with low-dose aspirin (86% vs. 29% live births, respectively) (9Gris J.C. Mercier E. Quere I. Lavigne-Lissalde G. Cochery-Nouvellon E. Hoffet M. et al.Low molecular weight heparin versus low-dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-3699Crossref PubMed Scopus (347) Google Scholar). However, the rates of live births, preeclampsia, and placental abruption before enoxaparin treatment were not reported. In the present study, pregnancies continued to full term in the majority of women receiving prophylaxis with enoxaparin, thus increasing the likelihood of delivering a healthy infant. Furthermore, the incidence of preeclampsia, placental abruption, and IUGR in women who received prophylaxis with enoxaparin was lower compared with the historical rates of these complications in the same women. Clinical evidence suggests that women with thrombophilia have an increased risk of pregnancy loss and complications such as preeclampsia, placental abruption, and IUGR (10Kupferminc M.J. Eldor A. Steinman N. Many A. Bar-Am A. Jaffa A. et al.Increased frequency of genetic thrombophilia in women with complications of pregnancy.N Engl J Med. 1999; 340: 9-13Crossref PubMed Scopus (1002) Google Scholar, 11Brenner B. Clinical management of thrombophilia-related placental vascular complications.Blood. 2004; 103: 4003-4009Crossref PubMed Scopus (51) Google Scholar). The low incidence of pregnancy complications following enoxaparin prophylaxis in women with thrombophilia and RPL is beneficial in terms of both fetal and maternal health. Although previous smaller studies have reported the benefits of prophylaxis in improving pregnancy outcomes in women with RPL and thrombophilia (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 6Younis J.S. Ohel G. Brenner B. Haddad S. Lanir N. Ben-Ami M. The effect of thromboprophylaxis on pregnancy outcome in patients with recurrent pregnancy loss associated with factor V Leiden mutation.Br J Obstet Gynaecol. 2000; 107: 415-419Crossref Scopus (73) Google Scholar, 7Rai R. Cohen H. Dave M. Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies).BMJ. 1997; 314: 253-257Crossref PubMed Scopus (975) Google Scholar, 8Gris J.C. Balducchi J.P. Quere I. Hoffet M. Mares P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes.Thromb Haemost. 2002; 87: 536-537PubMed Google Scholar), the results obtained in this study demonstrate in a large study population that prophylaxis with enoxaparin 40 mg/day or 80 mg/day is safe for both mother and fetus, with the majority of treated pregnancies resulting in a favorable outcome. Our previous study suggested that enoxaparin 80 mg/day might be beneficial in women with multiple severe thrombophilic defects (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar), but the results of the current study showed no differences in pregnancy complications, bleeding complications, or heparin-induced thrombocytopenia (HIT) compared with women receiving the 40 mg/day dose. Together, these two studies suggest that enoxaparin 40 mg/day is sufficient for most women with thrombophilia. Our findings suggest that increasing the dose of enoxaparin from 40 to 80 mg/day does not improve the pregnancy outcome further. However, enoxaparin 80 mg/day might be beneficial and safe in women with a particularly high thrombotic risk (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar). This study did not analyze fetal karyotype. Fetal karyotypic abnormalities have been reported in thrombophilic women with RPL who received prophylaxis with enoxaparin (3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar) and may have been responsible for many of the fetal losses in these women. Although the incidences of IUGR, preeclampsia, and placental abruption were substantially lower in women receiving enoxaparin therapy compared with their historical rates, the incidences remained higher than normal. In addition, although the majority of deliveries were at term, the rate of preterm deliveries was also higher than normal. Future studies should be directed towards optimizing prophylactic strategies to minimize these complications. LMWHs offer a favorable safety profile in pregnancy, as they are associated with a lower risk of maternal and fetal bleeding than warfarin and a lower risk of HIT than UFH (2Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis J.S. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-697PubMed Google Scholar, 3Carp 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: 433-438Crossref PubMed Scopus (176) Google Scholar, 4Sanson B.J. Lensing A.W. Prins M.H. Ginsberg J.S. Barkagan Z.S. Lavenne-Pardonge E. et al.Safety of low-molecular-weight heparin in pregnancy a systematic review.Thromb Haemost. 1999; 81: 668-672PubMed Google Scholar, 8Gris J.C. Balducchi J.P. Quere I. Hoffet M. Mares P. Enoxaparin sodium improves pregnancy outcome in aspirin-resistant antiphospholipid/antiprotein antibody syndromes.Thromb Haemost. 2002; 87: 536-537PubMed Google Scholar, 12Eldor A. The use of low-molecular-weight heparin for the management of venous thromboembolism in pregnancy.Eur J Obstet Gynecol Reprod Biol. 2002; 104: 3-13Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar, 13Gris J.C. Neveu S. Tailland M.L. Courtieu C. Mares P. Schved J.F. 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: 362-367PubMed Google Scholar). This was reflected in the present study, in which both doses of enoxaparin were well tolerated with no clinically significant maternal or neonatal bleeding or HIT. In conclusion, prophylaxis with enoxaparin (40 mg/day or 80 mg/day) is safe and effective for improving pregnancy outcome and reducing late pregnancy complications in thrombophilic women with a history of RPL. The help of Hadas Goshen and Yael Segal in coordination, Chana Sternberg and Daphna Menashe in monitoring, and Gil Harari in the statistical analysis of this study is greatly appreciated. In addition to the cited authors, Live-Enox investigators who also contributed significantly during preparation and review of this manuscript are Ron Hoffman, M.D., Israel Thaler, M.D., and Zeev Blumenfeld, M.D., Rambam Medical Center, Haifa; Howard Carp, M.B.B.S., F.R.C.O.G., and Mordechai Dulitsky, M.D., Sheba Medical Center, Tel Hashomer; David Varon, M.D., Hadassah Hebrew University Medical Center, Jerusalem; Joseph Tal, M.D., Bnai-Zion Medical Center, Haifa; Shmuel Segal, M.D., Barzilay Medical Center, Ashkelon; Michael Kupferminc, M.D., Tel Aviv Sourasky Medical Center, Tel Aviv; and Johnny Younis, M.D., Poriah Medical Center, Tiberias.