SEARCH

SEARCH BY CITATION

The LIVE-ENOX study: building an enoxaparin bridge over troubled maternal waters

  1. Top of page
  2. The LIVE-ENOX study: building an enoxaparin bridge over troubled maternal waters
  3. References

The LIVE-ENOX study reported in this issue of the Journal of Thrombosis and Haemostasis is a randomized trial comparing two different prophylactic doses of enoxaparin in women with thrombophilia and a history of recurrent pregnancy loss (RPL) [1]. There was no significant difference in pregnancy outcome between the two treatment arms. The high live birth rate (84% and 78%, respectively) reported with both doses (30 and 80 mg/day) supports the use of antithrombotic therapy in this setting. However, the optimal management of thrombophilic women with pregnancy complications is controversial, as illustrated by the discordant views expressed by two other experts in this field [2,3]. The LIVE-ENOX investigators and both commentators agree on the importance of prospective trials of antithrombotic therapy in this particular population of pregnant women. They also agree on the need to identify the particular subgroups of women most likely to benefit from prophylaxis. However, they differ in their assessment of the evidence suggesting antithrombotic therapy improves pregnancy outcome. Lindvquist points out that the LIVE-ENOX investigators assume efficacy, prompting their study design comparing two different enoxaparin doses. There are no prospective randomized trials including an untreated control group confirming the benefit of low-molecular-weight heparin in this setting. Unfortunately, because women at risk for a tragic pregnancy outcome are reluctant to accept assignment to no treatment, the optimal placebo-controlled trial may not be feasible.

Nevertheless the favorable results of the LIVE-ENOX study contribute to the accumulating data suggesting low-molecular-weight heparin is beneficial in thrombophilic women with prior fetal loss. Although definitive evidence is still lacking, the concordant results of several cohort and now two prospective randomized trials strongly suggest anticoagulation may improve pregnancy outcome [4–6]. The apparent maternal and fetal safety of low-molecular-weight heparin demonstrated in the current as well as previous studies fuels enthusiasm for additional trials in this population. The evolving consensus in favor of prophylactic anticoagulation is reflected by the recent recommendations of the Seventh American College of Chest Physicians Conference on Antithrombotic Therapy, as well as the increasingly common clinical practice of screening women with RPL for thrombophilia [7].

The comparable outcome in the two treatment groups does not exclude the possibility that a higher enoxaparin dose may be more effective, particularly in high-risk women with multiple thrombophilic defects. Both commentators offer possible methodologic or pathophysiologic reasons for the absence of a ‘dose–response’ effect in the LIVE-ENOX study. Another possibility is that a higher dose than 80 mg per day may be required to demonstrate additional benefit. It is unknown whether the full therapeutic dose of enoxaparin (1 mg per kg b.i.d.) required for effective treatment of venous thromboembolism may also be more effective in high-risk thrombophilic women. Interpretation of the LIVE-ENOX results is also complicated by the inclusion of a large number of women homozygous for the common MTHFR C677T mutation, which may have diluted the benefit of the higher enoxaparin dose. There is no convincing evidence linking the MTHFR mutation to an adverse pregnancy outcome. Based on the results presented, Brenner et al. cannot conclude that ‘a higher dose might be beneficial…for women with a particularly high thrombotic risk’ [1]. Although it is unclear how many women with combined thrombophilia were enrolled in the LIVE-ENOX study, it is unlikely there were enough to compare outcomes with the two doses.

So what are the implications of the LIVE-ENOX study for clinical practice? Gris and Brenner favor prophylactic anticoagulation in thrombophilic women with prior fetal loss. In contrast, Lindqvist cautions against its routine use, arguing it is still ‘too early for clinical implementation’ in the absence of ‘solid evidence.’ This ongoing controversy suggests that for now, decisions about antithrombotic therapy should be based on an individual risk/benefit assessment. For example, enoxaparin prophylaxis may not be appropriate for a women with a homozygous MTHFR C677T mutation and a normal homocysteine level. In contrast, it is justifiable in women with combined thrombophilic disorders, or other single defects convincingly linked to pregnancy loss, after an informed discussion of the risks and the data confirming benefit. Antithrombotic therapy is most like to be effective in women with unexplained fetal loss, after exclusion of other causes. Assessment of the maternal thrombotic risk during pregnancy should also be incorporated into the clinical decision. For example, the indications for prophylactic anticoagulation will be stronger in thrombophilic women with other circumstantial thrombotic risk factors.

Additional studies are urgently needed to identify the thrombophilic profiles and pattern of RPL (first vs. later trimester) most predictive of an improved outcome with antithrombotic therapy. As Lindvquist points out, women with different thrombophilic disorders and timing of fetal loss do not necessarily have the same probability of recurrent loss during a future pregnancy. Although the LIVE-ENOX results shed some light on still murky maternal waters, it is unclear whether they can be extended to thrombophilic women with a single first trimester loss, or other pregnancy complications. It is also unknown whether antithrombotic therapy will improve outcomes in women with unexplained fetal loss without an identifiable thrombophilic disorder, a practice already pioneered by some practicing obstetricians [8]. These specific subgroups of women deserve further study before prophylactic anticoagulation becomes routine and randomized trials more difficult to perform. Perhaps the spirited debate provoked by the LIVE-ENOX results will spark renewed interest in conducting these trials.

References

  1. Top of page
  2. The LIVE-ENOX study: building an enoxaparin bridge over troubled maternal waters
  3. References