Is it time for clinical use of LMWH in women with adverse pregnancy outcome or do we need large-scale prospective studies?
The article by Brenner et al.  touches a topic of hot debate in the obstetric field, i.e. the use of prophylactic antithrombotic measures in those mothers with previous pregnancy losses who are found to be carriers of prothrombotic risk factors.
This issue is very relevant as an association between these risk factors in the mother and a number of pregnancy complications has been reported by several authors [2,3]. Therefore, knowledge of the presence of these thrombophilic conditions could pave the way to anticoagulant prophylaxis in women carrying thrombophilic mutations who have experienced pregnancy losses.
However, this knowledge has been used uncritically in the obstetric world and prompted many clinicians to the use of prophylactic measures from low-dose aspirin to low-molecular-weight heparin LMWH, although still in the absence of prospective randomized studies on the risk–benefit ratio of such treatments. It is hard to blame this behavior, as adverse pregnancy outcome carries a high medical, psychological and social burden and clinicians are asked to do ‘something’. The long-term risks of anticoagulant therapy  are hardly acknowledged, even if explained to the woman.
Therefore, studies investigating the benefits and risks of anticoagulant prophylactic measures are welcome. However, the study by Brenner et al.  does not address the first question, i.e. whether LMWH is indeed beneficial in these patients. This study investigates effects of two different doses of enoxaparin in women with thrombophilia and previous pregnancy losses but lacks indeed a control group taking no therapy. The background that the authors provide for this design is a previous observational study where they reported positive pregnancy outcomes of 69% and 83%, with 40 and 80 mg d−1 enoxaparin, respectively . However, also that study lacked an appropriate control group. We should expect 33% probability of an early pregnancy loss after three previous repetitive events without treatment , leading to an expected pregnancy success rate in the untreated population not quite different from the rates reported by Brenner et al. [1,5].
Other considerations need to be made. The strength of the association between thrombophilia and fetal loss is still controversial and varies according to type of fetal loss and type of thrombophilia .
Moreover, the magnitude of the association is higher when underlying pathologies have been excluded. The selection and definition of the population in the study by Brenner et al.  raise some concern. Women with ≥3 losses in the first trimester, ≥2 in the second trimester or one intrauterine fetal death in the third trimester, carrying different factors of thrombophilia, including methylentetrahydrofolate mutation, protein C and antithrombin deficiencies were included. These criteria identify a quite heterogeneous population, potentially including a number of different mechanistic factors, genetic, endocrine and environmental, that could have an independent role in determining the adverse event.
This leads to a further consideration. The understanding of the pathogenetic mechanisms responsible for fetal loss in the presence of a thrombophilic status is still scanty. Increased thrombosis of placental vessels has been hypothesized but not confirmed. We have previously reported  placental lesions associated with thrombosis in approximately 3/4 of cases of unexplained fetal death, independently from the presence of a maternal trombophilic mutation. A definitive link among adverse pregnancy outcome, thrombotic lesions of the placenta, and a specific thrombophilic condition is not recognized .
Normal placentation, including throphoblast invasion of the maternal circulation, maintenance of blood fluidity in the intervillous space, and separation of the placenta after delivery all require a fine balance between prothrombotic and antithrombotic forces. In a retrospective cohort study, Arias et al.  evidenced the presence of a relationship between adverse pregnancy outcome, thrombotic lesions of the placenta and laboratory abnormalities indicative of a thrombophilic state, suggesting that thrombophilia leading to thrombosis in the maternal and/or fetal circulation is a significant mechanism of disease during pregnancy.
Probably, thrombophilia has a mild adverse impact on placentation and the presence of more than one thrombophilic disorder is associated with a multiplication of the risk for these vascular complications of pregnancy. However, the role of LMWH in the implantation process has not been fully investigated yet, and we cannot exclude that its potential beneficial mechanisms are independent from the thrombophilic state . Therefore, large prospective randomized studies including control groups with no therapy and use of LMWH in women with previous pregnancy losses and no thrombophilic factors are needed to unravel these questions. This requires the attention and support of funding governmental agencies to overcome the ethical concerns related to this clinical problem.