Recurrent miscarriages: Caution regarding development of clinical trials using low molecular weight heparin and pregnancy
Authors: Dipika Misra, Louis Aledort
Journal: American Journal of Hematology (2010)

Over the past few years, several large negative randomized control trials have been published showing no benefit with prophylactic doses of low molecular weight heparin (LMWH) in women with recurrent miscarriages [1, 2]. Furthermore, among pregnant women with antiphospholipid syndrome, there has been conflicting data to show benefit of LMWH to prevent recurrent miscarriages [3, 4]. We are concerned that these protocols do not provide a standardized assessment of the activity of prophylactic doses of LMWH in pregnancy using anti-Xa levels. Pharmacokinetics studies of fixed doses of LMWH have shown that anti-Xa levels vary during the course of pregnancy [5-8]. Lebaudy et al. studied anti-Xa levels in 75 pregnant women and 38 nonpregnant women who were receiving enoxaparin. Pregnant women demonstrated significantly higher drug clearance and had dramatic changes in their volume of distribution. Among women receiving enoxaparin 40 mg every day, there was a 24% decrease in peak anti-Xa levels during the course of their pregnancy (Fig. 1). These changes in pharmacokinetics have been attributed to the normal physiologic changes that occur in pregnancy, specifically an increase in weight, increase in plasma volume, changes in renal function, and possible changes in protein expression within the placenta that may have an affinity to bind with LMWH [7]. Although these pharmacokinetic studies are small with no clear evidence of how these differences in peak anti-Xa levels may affect a women's risk of developing a recurrent thrombosis, the 2008 American College of Chest Physicians guidelines have offered a grade 1C recommendation for monitoring anti-Xa levels in pregnant women receiving therapeutic doses of LMWH [9]. Typical anti-Xa kinetics profile with repeated administration of enoxaparin at 40 mg/day, in relation to pregnant state and gestational age [7]. We present a case to further support anti-Xa testing for pregnant women on LMWH therapy. Recently, a 21-year-old female (G1P0) presented to our institution at 30 weeks of pregnancy with worsening lower extremity pain after being starting 1 week prior on enoxaparin 60 mg (1 mg/kg) for a right lower extremity DVT. Despite treatment for 1 week with appropriate weight based dosing of LMWH, a repeat Doppler revealed further extension of the common femoral vein thrombus. Blood levels of antifactor-Xa that were assessed 4 hours after enoxaparin injection were found to be 0.32 (therapeutic dosing 0.5-1.0). We empirically increased her enoxaparin dosage by 70% to obtain a peak anti-Xa level of 0.60, and we suspect that the patient's clot extended because her enoxaparin dose was subtherapeutic, despite receiving the appropriate weight based dose. Our patient's history and the above pharmacokinetic studies we have presented strongly suggest we need to re-evaluate how we design and evaluate clinical trial protocols that involve the use of LMWH in pregnancy. Dipika Misra*, Louis Aledort*, * Division of Hematology and Oncology, Mount Sinai School of Medicine, One Gustave L. Levy, New York, New York.