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Is there room for randomizing during pregnancy in women with mild inherited thrombophilia and previous fetal losses?

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  2. Is there room for randomizing during pregnancy in women with mild inherited thrombophilia and previous fetal losses?
  3. References

In their interesting research, Brenner et al. [1] randomized women with thrombophilias and previous fetal losses to treatment with different doses of enoxaparin. One of the most interesting findings is that no difference in obstetric outcomes is present between groups treated: 40 mg of enoxaparin are as effective as 80 mg in preventing adverse outcomes. During pregnancy hemorrhagic complications are more frightful for most obstetricians, and the knowledge that lowest doses of low-molecular-weight heparin (LMWH) are effective as higher ones increases the probability that this drug is prescribed also during those pregnancies with hemorrhagic complications (as threatened abortion, abruption placentae).

Moreover, these data are in agreement with recent findings from a study in an animal model of antiphospholipid syndrome (APS) and pregnancy losses [2]. Treatment with unfractioned or LMWH prevents complement activation in vivo, and in vitro protects mice from pregnancy complications induced by aPL antibodies. So, heparins prevent obstetric complications in women with APS because they block activation of complement induced by aPL antibodies targeted to decidual tissues, rather than by anticoagulant effects. This could be one of the reason why subanticoagulant doses of heparin have therapeutic benefits and why Brenner et al. were not able to find a difference between 40 and 80 mg of enoxaparin.

It has been recognized that the association of heparin and low-dose (100 mg) aspirin is the best treatment during pregnancy for preventing fetal losses in women with APS and previous fetal losses [3]. For this reason, we need to concentrate our efforts toward common and mild inherited thrombophilias, as FV Leiden and FII A20210 heterozygosity. We previously described that prophylactic doses of heparins could be efficacious in preventing adverse obstetric outcomes in this setting of women [4]. Interestingly, we described a small subgroup of women who refused heparin and to whom we prescribed aspirin 100 mg. Seven of 31 pregnancies were carried out successfully with aspirin. Probably, it could be useful to investigate about a possible role of aspirin in preventing such complications, in addition to that of heparins. In this, as in our previous work [5], we used strict selection criteria, as recommended by most authors [6]. It is mandatory to collect as much as possible information about previous fetal losses, to exclude other possible causes, especially those more likely affecting viability of fetuses (as an abnormal karyotype).

At variance with Lindqvist and Merlo [7] we believe that some discrepancies, at least those regarding FV Leiden and FII mutations, in data about the association with a history of fetal losses, are mainly due to enrollment criteria, while we fully agree that there is no convincing evidence about the association with MTHFR and homocysteine, too. It is to be kept in mind that the design of a study strongly influences the findings. In this sense, the history of aPL is very similar to this. Studies of small sample size showed an association between aPL and recurrent fetal losses. Later, Infante-Rivard et al. [8] did not find an association between lupus anticoagulants or IgG anticardiolipins and fetal loss in a well-designed study, but with enrollment criteria different from those used by others.

Moreover, no randomized controlled trial (RCT) in literature compare all possible treatments proposed. Nevertheless, we all prescribe heparin plus aspirin since the publication of a study [3]. This small RCT was carried out in pregnant women with aPL and recurrent miscarriage and showed the higher efficacy of heparin plus aspirin vs. aspirin alone. Thus, that study compared not all possible treatments available since then.

In agreement with Gris and Marés [9], we strongly believe that it seems utopian to carry out an RCT for establishing which is the treatment of choice for inherited thrombophilia and such complications, mainly because of lack of interest by drug industries. At this point, we should convince women (who are fertile for a portion of their life) and their families that they have to wait for the results of RCT before having the right therapy, in spite of being prescribed a relatively safe antithrombotic regimen.

References

  1. Top of page
  2. Is there room for randomizing during pregnancy in women with mild inherited thrombophilia and previous fetal losses?
  3. References