The combination of prophylactic heparin and low-dose aspirin was shown in the 1990s to improve pregnancy outcome in patients with antiphospholipid antibodies and recurrent pregnancy loss (RPL). Antiphospholipid antibodies induce placental thrombosis. When associations between hereditary thrombophilias and RPL were reported in the early 2000s, we and other physicians (Rodger MA J Obstr Gyn Canada 2002) began empirically prescribing prophylactic low molecular weight heparin, low-dose aspirin, or the combination to pregnant women with thrombophilia and unexplained RPL. We observed high live birth rates. Data emerged showing live birth rates of 70.2-94% in pregnant women with RPL treated with low-dose low molecular weight heparin and/or low-dose aspirin. Only one report has addressed treatment after failure of low-dose low molecular weight heparin: Brenner and colleagues (Thromb Haemost 2000) treated 3 pregnant women with multiple thrombophilic defects with enoxaparin 60 mg x 2/day after failure of enoxaparin 40 mg x 2/day; all 3 pregnancies yielded live births. We report cases of a live term birth and two ongoing viable pregnancies with therapeutic enoxaparin,1.5 mg/kg SC, (TEP) and aspirin after failure of prophylactic enoxaparin, 40 mg SC, (PEP) and aspirin in two women with thrombophilia and RPL.
A 33 year-old woman with a history of 2 unexplained miscarriages at 6 weeks (Patient 1) and a 42 year-old woman with a history of 3 unexplained miscarriages at 8 weeks (Patient 2) presented in April 2006 and in August 2007 respectively. Uterine malformations, acquired uterine defects, and hormonal abnormalities were ruled out. Parental karyotypes were normal. Thrombophilia evaluation included: factor V Leiden, prothrombin gene mutation, methylene tetrahydrofolate reductase (MTHFR) gene mutation, fasting homocysteine, protein C, protein S, antithrombin, IgG anticardiolipin antibody, IgM anticardiolipin antibody, lupus anticoagulant, plasminogen activator inhibitor-1 (PAI-1), and PAI-1 4G/5G polymorphism. Positive results were: one copy each of the C677T and A1298C MTHFR mutations in Patient 1 and Patient 2; PAI-1 120 ng/mL and PAI-1 4G/4G polymorphism in Patient 2. The following describes the clinical course in both patients.
Patient 1 was started on aspirin 81 mg daily and on clomiphene citrate to improve fertility. She conceived but miscarried at 7 weeks in June 2006. She underwent in vitro fertilization (IVF) in December 2006 while continuing on aspirin. She started on PEP daily within 24 hours of egg retrieval. She miscarried twins at 6 and 8&1/2 weeks. In May 2007, she conceived through IVF while continuing on aspirin. She started on TEP daily within 24 hours of egg retrieval. Anti-Xa level was monitored monthly. Enoxaparin was adjusted to maintain the anti-Xa level between 0.6 and 1.2 ui/mL. She delivered a healthy term baby on January 10, 2008. She continued to take aspirin daily. She conceived naturally in February 2009. She started on TEP daily with monthly anti-Xa monitoring when her pregnancy was confirmed. She currently has a live 24-week gestation.
Patient 2 was started on aspirin 81 mg daily. She conceived through IVF in May 2008. She started on PEP daily within 24 hours of egg retrieval. She miscarried in a few weeks. She conceived through IVF in October 2008 while continuing on aspirin. She started on PEP daily within 24 hours of egg retrieval. After two weeks when her pregnancy was confirmed PEP was increased to TEP. She miscarried in a few weeks. She conceived in May 2009 through IVF while continuing on aspirin. TEP with monthly anti-Xa monitoring was started prior to IVF when she started her ovarian stimulation medications. She currently has a live 16-week gestation.
Our report corroborates the findings by Brenner and colleagues of a benefit of an increased enoxaparin dose after failure of a low dose. It is possible that the higher dose leads to better control of a placental thrombotic state. While the timing of initiation of thromboprophylaxis has been established for natural pregnancies (aspirin is started pre-conception; enoxaparin is started at pregnancy confirmation or at detection of the fetal heartbeat), optimal time for initiation of thromboprophylaxis in IVF pregnancies has not been determined. Ovarian stimulation for IVF leads to a hyperestrogenic state which increases thrombotic risk. It is possible that starting TEP at the time of initiation of ovarian stimulation in Patient 2 enabled her ongoing viable second-trimester pregnancy by optimizing placental conditions.
Off Label Use: Aspirin and enoxaparin during pregnancy to prevent recurrent fetal loss.
Asterisk with author names denotes non-ASH members.