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The natural course of women with recurrent fetal loss

2006; Elsevier BV; Volume: 4; Issue: 4 Linguagem: Inglês

10.1111/j.1538-7836.2006.01839.x

1538-7933

Pelle G. Lindqvist, Juan Merlo,

Heparin-Induced Thrombocytopenia and Thrombosis

Habitual miscarriage, usually defined as three consecutive fetal losses, has been shown to be related to between 55% and 70% successful live birth rate [1Poland B.J. Miller J.R. Jones D.C. Trimble BK. Reproductive counseling in patients who have had a spontaneous abortion.Am J Obstet Gynecol. 1977; 127: 685-91Abstract Full Text PDF PubMed Google Scholar]. The definition of habitual miscarriage differs from the wider definition of recurrent fetal loss, which is often defined as at least three first trimester fetal losses and/or ≥ two second trimester fetal losses. Recurrent fetal loss affects 1–2% of the pregnant population, but the pathogenesis of recurrent fetal loss is still unclear in the majority of cases. However, several factors such as chromosome aberrations, thrombophilias, thyroid abnormality, microparticles, and complement activation have been suggested as causative [2Carp H. Dardik R. Lubetsky A. Salomon O. Eskaraev R. Rosenthal E. Inbal A. Prevalence of circulating procoagulant microparticles in women with recurrent miscarriage: a case‐controlled study.Hum Reprod. 2004; 19: 191-5Crossref PubMed Scopus (77) Google Scholar]. As thrombophilia is a major causal candidate for plausible pathogenetic reasons, there have been several studies of the effect of low‐molecular‐weight heparin (LMWH) and low‐dose aspirin for recurrent fetal loss. Some of them have used a ‘before‐and‐after’ design [3Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-7Crossref PubMed Scopus (282) Google Scholar, 4Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE‐ENOX study.J Thromb Haemost. 2005; 3: 227-9Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar], which is rather inappropriate as this design lacks control group and the result might be biased by the phenomenon of ‘regression toward the mean’ [5Lindqvist P.G. Merlo J. Low molecular weight heparin for repeated pregnancy loss: is it based on solid evidence.J Thromb Haemost. 2005; 3: 221-3Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. This phenomenon is a statistical principle stating that, of related measurements, the expected value of the second is closer to the mean than the observed value of the first [6Bland J.M. Altman DG. Regression toward the mean.BMJ. 308. 1994: 1499Google Scholar]. Therefore, in a ‘before‐and‐after’ design, one should expect – independently of any medical treatment – that the group of women with highest rate of recurrent fetal loss would have a lower rate of recurrent fetal loss by natural reasons. Moreover, it has also been reported that the thrombophilic women with one prior fetal loss treated with LMWH enoxaparin have a better outcome that similar women treated with low‐dose aspirin [7Gris J.C. Mercier E. Quere I. Lavigne‐Lissalde G. Cochery‐Nouvellon E. Hoffet M. Ripart‐Neveu S. Tailland M.L. Dauzat M. Mares P. Low‐molecular‐weight heparin versus low‐dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-9Crossref PubMed Scopus (353) Google Scholar]. Unfortunately, this study lacks an untreated control group and cannot inform of the existence of a possible beneficial effect of aspirin or enoxaparin. Until now, however, there have been no published randomized trials trying to answer the relevant question concerning the preventive effect of antithrombotic therapy on fetal loss. In the meanwhile, however, a relevant contribution to this discussion could be to provide a proper estimation of the size of regression toward the mean in untreated women with recurrent fetal loss. Also, it would be useful to describe the natural course of pregnancy among carriers of factor V Leiden (FVL) with at least one prior fetal loss. We are investigating a population‐based prospective cohort that seems very suitable for answering those questions. The cohort includes 2480 gravidae recruited at a mean of 12 weeks of gestation (see elsewhere for a detailed description on this prospective cohort) [8Lindqvist P.G. Svensson P.J. Marsál K. Grennert L. Lutherkort M. Dahlbäck B. Activated protein C resistance (FV:Q506) and pregnancy.Thromb Haemost. 1999; 81: 532-7Crossref PubMed Scopus (215) Google Scholar]. The women were interviewed about prior pregnancies, and blood was drawn for measuring coagulation FVL. An FVL status was not known in advance and blood samples were not analyzed until at least 6 months post partum. Therefore, the data were blind regarding FVL status. In the cohort, recurrent fetal loss was defined as ≥3 first trimester fetal losses and/or ≥2 second trimester fetal losses (13–26 weeks). Table 1 presents the data on prior and current live birth rates calculated in our population cohort and in other relevant investigations. Although we included all women with recurrent fetal loss and not only those with thrombophilia, it is obvious that the size of the regression toward the mean is substantial, as – without treatment – the women with very low prior live birth rates (i.e. 28%) show a rather high current live birth rate (i.e. 89%). Our results are very similar to those obtained in treatment trials without randomization and with ‘before‐and‐after’ designs. Thus, without a valid a control group, it is not possible to draw conclusions. The large effect of the ‘regression toward the mean’ jeopardizes any conclusions drawn from studies using the ‘before‐and‐after’ design.Table 1Pregnancy outcome in different subgroups of women with prior fetal lossPrior live birth rate (%)Present live birth rate (%)Recurrent fetal lossEnoxaparin 40 or 80 mg (n = 50) [3Brenner B. Hoffman R. Blumenfeld Z. Weiner Z. Younis JS. Gestational outcome in thrombophilic women with recurrent pregnancy loss treated by enoxaparin.Thromb Haemost. 2000; 83: 693-7Crossref PubMed Scopus (282) Google Scholar]*2075Enoxaparin 40 mg (n = 89) [4Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE‐ENOX study.J Thromb Haemost. 2005; 3: 227-9Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]*2884Enoxaparin 80 mg (n = 91) [4Brenner B. Hoffman R. Carp H. Dulitsky M. Younis J. Efficacy and safety of two doses of enoxaparin in women with thrombophilia and recurrent pregnancy loss: the LIVE‐ENOX study.J Thromb Haemost. 2005; 3: 227-9Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar]*2878No treatment (n = 37)†,**2889Second trimester fetal loss1 prior (n = 43) no treatment**4998≥2 prior (n = 10) prior no treatment**3080Nulliparous women with one prior fetal losses and carriers of factor V Leiden (FVL)Low‐dose Asprin (n = 36) [7Gris J.C. Mercier E. Quere I. Lavigne‐Lissalde G. Cochery‐Nouvellon E. Hoffet M. Ripart‐Neveu S. Tailland M.L. Dauzat M. Mares P. Low‐molecular‐weight heparin versus low‐dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-9Crossref PubMed Scopus (353) Google Scholar]029Enoxaparin 40 mg (n = 36) [7Gris J.C. Mercier E. Quere I. Lavigne‐Lissalde G. Cochery‐Nouvellon E. Hoffet M. Ripart‐Neveu S. Tailland M.L. Dauzat M. Mares P. Low‐molecular‐weight heparin versus low‐dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-9Crossref PubMed Scopus (353) Google Scholar]094No treatment (n = 20)‡,**095No treatment (n = 52)§,**4098Recurrent fetal loss ≥3 first trimester and/or ≥2 second trimester fetal loss. *Includes or/and ≥1 stillbirth.†Includes women with and without thrombophilia. ‡Nulliparous carriers of FVL with at least 1 prior fetal loss.§FVL carriers with at least 1 prior fetal loss.**Present study. Open table in a new tab Recurrent fetal loss ≥3 first trimester and/or ≥2 second trimester fetal loss. *Includes or/and ≥1 stillbirth. †Includes women with and without thrombophilia. ‡Nulliparous carriers of FVL with at least 1 prior fetal loss. §FVL carriers with at least 1 prior fetal loss. **Present study. Although not completely comparable in our cohort, the women with prior fetal loss who were FVL carriers had similar outcome as those similar women treated with enoxaparin in the study by Gris et al. [7Gris J.C. Mercier E. Quere I. Lavigne‐Lissalde G. Cochery‐Nouvellon E. Hoffet M. Ripart‐Neveu S. Tailland M.L. Dauzat M. Mares P. Low‐molecular‐weight heparin versus low‐dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-9Crossref PubMed Scopus (353) Google Scholar]. This comparison indicates that women with prior fetal loss and carrying FVL seem to have a good prognosis. The authors' write that, in the development of their investigation, the creation of a control group ‘was tried out, but failed’ [7Gris J.C. Mercier E. Quere I. Lavigne‐Lissalde G. Cochery‐Nouvellon E. Hoffet M. Ripart‐Neveu S. Tailland M.L. Dauzat M. Mares P. Low‐molecular‐weight heparin versus low‐dose aspirin in women with one fetal loss and a constitutional thrombophilic disorder.Blood. 2004; 103: 3695-9Crossref PubMed Scopus (353) Google Scholar] . The authors also argue that it would be a ‘theoretical argument’ to include women in a placebo‐controlled trial, but that it would be a more ‘humane ethical option’ to compare two antithrombotic treatments. We do not agree. As there is no evidence of efficient treatment, the only ethical option is to compare with placebo. Many of us remember when immunotherapy was the ‘true’ treatment, until it was shown not to be of substantial value [9Scott JR. Immunotherapy for recurrent miscarriage.Cochrane Database Syst Rev. 2003; Crossref Google Scholar]. We conclude that, for both scientific and ethic reasons, only well‐designed trials including comparison to an untreated group may increase our knowledge regarding the preventive effect of antithrombotic therapy on fetal loss in general and the effect of an LMWH in particular.