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Fetal loss, thrombophilia and heparin: the clinician's dilemma

  1. Top of page
  2. Fetal loss, thrombophilia and heparin: the clinician's dilemma
  3. Conflict of interest statement
  4. References

Every physician caring for women with fetal loss knows how difficult it is to counsel them. The reported association of thrombophilia and fetal loss has raised expectations on the usefulness of antithrombotic therapies. The available data suggest a potential benefit, but published studies have many limitations. How can the clinician make up his mind when even the experts disagree [1–3]? It is important for clinicians to understand the limitations of current available studies and to know what, in the current body of knowledge, is based on strong evidence and what is assumption.

There have been many published studies on the relationship between thrombophilia and fetal loss, with conflicting results. One major limitation of the available data is the fact that many studies include all types of fetal losses, without distinction of timing and number. In some reports, causes of fetal loss other than thrombophilia are not considered. We are dealing with heterogeneous groups of women in which fetal loss may have different etiologies. The clinician must not underestimate the importance of the other causes of fetal loss and should always proceed with an appropriate workup.

Another major problem encountered in the literature is the fact that many studies do not distinguish between thrombophilias, which presents a statistical advantage but is a clinical oversimplification. Thrombophilias cannot be considered as a homogeneous group. Women with factor V Leiden (FVL) and the prothrombin G20210A mutation (FII) have at least twice the risk of recurrent or late fetal loss [4,5]. For the rarer thrombophilias, such as antithrombin, protein C and protein S deficiencies, the accurate risk is difficult to establish but there are data suggesting that they are associated with an increased risk of late fetal loss [4,6]. The thrombophilia with the strongest risk of fetal loss is probably the antiphospholipid antibody syndrome (APS) [7]. By contrast, homozygosity for the C677T MTHFR mutation is not associated with recurrent fetal loss, at least in populations with free access to vitamin supplementation. Finally, even if we accept that the association between some thrombophilias and fetal loss is real, this does not prove causality.

One cannot conclude from the association between thrombophilia and fetal loss that intervention with antithrombotic agents will be beneficial. The benefit or avoidance of antithrombotic agents for the prophylaxis of fetal loss is not problematic in some situations: women with a high risk of thrombosis during pregnancy, such as those with antithrombin deficiency, thrombophilia and a previous thrombotic event, or already on long-term anticoagulation, usually receive antithrombotic prophylaxis based on that indication. In these cases, the uncertainty resides more in the most appropriate intensity of anticoagulation than in the indication itself. On the other hand, pregnant women with less severe thrombophilias but without a history of fetal loss, pregnancy complications or thrombosis are not given heparin during pregnancy.

It is obvious from the literature and from current practice patterns that intervention with antithrombotic agents for the prevention of fetal loss has preceded the acquisition of hard data. The efficacy of heparin combined with aspirin observed in the APS has been readily extrapolated to other thrombophilias. Fortunately, a recent adequately conducted randomized trial showed that, in women with at least one fetal loss after the 10th week of amenorrhoea, a prophylactic dose of a low molecular weight heparin (LMWH) increases the rate of live birth by a factor of 3 in FVL or FII and by a factor of 11 in protein S deficiency when compared with aspirin alone [8]. It is hazardous to extrapolate these results to women with other types of fetal loss or other thrombophilias. Studying different levels of anticoagulation without a control group and without making a distinction between the different thrombophilias does not resolve the fundamental question of whether therapy is beneficial [1].

Standard heparin and LMWHs are not without risk. Even if the risk is very small, women receiving heparin are at risk of skin reactions, heparin-induced thrombocytopenia, osteoporosis and bleeding. Injections are painful, LMWHs are expensive and the follow-up is demanding. Prescribing heparin outside a research protocol in conditions where the benefit is not proven must be weighed against these low but real risks.

Thus, anticoagulation cannot be considered standard or proven therapy for the prevention of fetal loss in all thrombophilias and in all settings. Clinicians and women should be aware of this as well as of the treatment risks. Each situation should be evaluated individually. Well-designed randomized trials with strictly defined inclusion criteria and distinction among thrombophilias are needed, are ethical, and would greatly benefit our patients.

Conflict of interest statement

  1. Top of page
  2. Fetal loss, thrombophilia and heparin: the clinician's dilemma
  3. Conflict of interest statement
  4. References

Dr Rey is author of a research partly funded by Pharmacia Canada. Dr David participated as coinvestigator in a study on the role of deltaparin in pregnancy complications funded by Pharmacia Canada.

References

  1. Top of page
  2. Fetal loss, thrombophilia and heparin: the clinician's dilemma
  3. Conflict of interest statement
  4. References