Purists or pragmatists: how do clinicians manage the mixed messages on miscarriage and thromboprophylaxis?
In this issue of the journal, Brenner et al.  demonstrate that a low-molecular-weight heparin (LMWH), enoxaparin, at doses of either 40 or 80 mg a day, is effective in preventing pregnancy loss in women with thrombophilia and recurrent pregnancy loss (RPL) in comparison with historical, untreated pregnancies in the same women. They show no difference between the two different doses of enoxaparin. As Lindqvist and Merlo  rightly point out the study has many limitations, particularly the absence of an untreated control group, the heterogeneous entry criteria and the risk of ‘regression toward the mean’ with the use of an historic comparison group. They also question the previous observational data supporting a beneficial effect of LMWH in this situation, and indeed whether an association between thrombophilia and RPL really exists. They conclude that it is too early for clinical implementation of LMWH in treatment of RPL. These views, while mostly correct, reflect a purist view of the available data and how to react clinically.
In the real world, clinicians need to manage women with recurrent miscarriage. This is a devasting condition affecting many women: 1–2% of women have three or more miscarriages and 5% have two consecutive losses. We have no established effective treatment. The only prospect on the horizon is antithrombotic therapy, thus the report by Brenner is an important development . This treatment has evolved from the treatment of RPL associated with antiphospholipid syndrome (APAS) where we have evidence of thrombotic placental damage, increased thrombin generation and effective prevention with antithrombotic therapy using LMWH and low-dose aspirin.
Although individual reports linking thrombophilia to RPL are variable due to differences in populations, definitions and timing of RPL , meta-analyses clearly support the association between RPL and heritable thrombophilias, particularly Protein C and S deficiencies, Factor V Leiden and Prothrombin G20210A [4–6]. Acquired thrombophilias other than APAS are also important. Elevated levels of circulating procoagulant microparticles have been reported in 48–59% of women with RPL . These data lend additional support to the hypothesis that a thrombophilic maternal phenotype commonly underlies RPL. Perhaps we have been too specific in our consideration of the mechanisms underlying pregnancy loss, seeking associations with specific genotypes or thrombophilic conditions. Surely it is the clinical thrombophilic phenotype, manifest in these women as RPL, rather the individual's particular defect that is important.
While the pathophysiology of RPL may not be directly related to thrombosis per se in all cases (thrombin has many effects on systems other than hemostasis that could influence RPL), clearly the best available therapeutic intervention to influence the haemostatic system and thrombin generation in pregnancy is LMWH. LMWH has minimal risks for the mother in pregnancy [8,9] and no direct risk to the fetus as it does not cross the placenta. LMWH has significant beneficial effects on trophoblast in vitro . There is evidence of efficacy of LMWH in pregnancy loss not only with APAS but also from an important randomized trial of low-dose aspirin vs. enoxaparin in women with a history of pregnancy loss and associated Protein C deficiency, Protein S deficiency or Factor V Leiden . When coupled with the substantial observational and trial data such as those from Brenner's group [1,12], which is the best evidence we have at present, and the difficulties of conducting randomized controlled trials in this patient group , this represents a significant body of data. The pragmatic view, echoed by Gris and Mares  is that LMWH should be considered in women with RPL, while we await the outcome of randomized controlled trials particularly as there is no other treatment option. Given the extent of the relationship between currently identifiable thrombophilias and RPL, perhaps this should be extended to women with RPL whether or not they have an identifiable thrombophilia . This concept is currently being evaluated in trials such as in the multicenter Scottish Pregnancy Intervention trial in the UK, which will determine whether treatment with low-dose aspirin and LMWH in women with RPL result in a reduction in the rate of expected loss. Whether low-dose aspirin, which appears safe in pregnancy , should be added to LMWH in this situation is controversial. The combination appears effective in APAS, but the one randomized trial on pregnancy loss and heritable thrombophilia suggests that LMWH may be effective alone .
In conclusion, we have no potentially effective treatment for RPL other than LMWH, which carries minimal risk in pregnancy. There is an urgent and unequivocal need for randomized trials of LMWH (+/− low-dose aspirin) in RPL. However, until data from these trials is available, both obstetricians and patients are voting with their feet. After weighing up the limited existing evidence, and the potential benefits and risks of LMWH, they are increasingly siding with the pragmatists and using LMWH for RPL.