Hum. Reprod. Advance Access originally published online on October 18, 2006
Human Reproduction 2007 22(1):309-311; doi:10.1093/humrep/del350
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Letters to the editor |
Reply: Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage
1 Fertility Clinic 4071, Rigshospitalet, Copenhagen, Denmark 2 Academic Department of Obstetrics and Gynaecology, Royal Free and University College, London Medical School, London, UK 3 Department of Obstetrics and Gynaecology, Liverpool Women’s Hospital, Liverpool, UK and 4 Department of Obstetrics and Gynaecology, Sparne Ziekenhuis, Hoofddorp, the Netherlands
5 To whom correspondence should be addressed at: Fertility Clinic 4071, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. E-mail: obc{at}pregnancyloss.dk
Sir,
Thank you for the opportunity of responding to the comments by Bohlmann et al. to our guidelines (Jauniaux et al., 2006
) for evidence-based management of recurrent miscarriage (RM).
According to the opinion expressed by Bohlmann et al., a clear link between recurrent early miscarriage and maternal hereditary thrombophilia (HT) is already sufficiently established, and such screening should therefore be routine in women with RM.
In our opinion, routine investigation for a factor in patients with RM should only be undertaken if presence of the factor will influence the treatment given to the patients or has a documented prognostic impact on future pregnancy outcome, which is important information for the patient’s decision of whether or not to attempt pregnancy again.
With regard to HT, neither of these requirements are met. Only two small controlled trials of treatment with heparin or aspirin (only one trial compared with placebo) have been conducted in RM patients without antiphospholipid antibodies, and these clearly gave no indication of a treatment effect, and the trials were considered of poor methodological quality (Di Nisio et al., 2005). A randomized trial comparing RM women with neither HT nor antiphospholipid antibodies found similar pregnancy outcomes after treatment with low molecular heparin versus aspirin (Dolitzky et al., in press). No treatment trial including an adequate control group has been carried out in RM patients selected for being HT positive.
Four published studies provide useful information about the impact of the presence of HT on future pregnancy outcome. Rai et al. (2002) first reported a significantly increased miscarriage rate in 25 untreated RM women with the Factor V Leiden mutation, but the same group has recently published another study finding that maternal HT factors when found exclusively in the female exhibit no prognostic impact, and only the combined presence of a series of HT factors in both partners seems to display a negative prognostic impact (Jivrai et al., 2006). In a study of 44 RM patients with and 26 RM patients without HT, Carp et al. (2002) could not find any negative impact of the presence of HT but rather a lower miscarriage rate in patients with HT compared with those without it.
The study by van Dunne et al. (2005) was, as Bohlman et al. correctly point out, not undertaken in patients with RM but patients with a previous thrombotic episode with or without the Factor V Leiden mutation. It was found that patients with the Factor V Leiden mutation had significantly fewer early miscarriages in the history than those without the mutation although this was partially counteracted by a higher rate of late miscarriage. Whereas this study had the weakness that it was not undertaken in RM patients, it had the advantage in comparison to other studies that it focused on women who really through their medical history had documented that they were in an increased risk of thrombosis. The great majority of HT-positive RM patients included in other studies have never suffered any thrombo-embolic episodes.
Overall, these four studies may provide weak support for the belief that the Factor V Leiden mutation increases the risk of late miscarriage but provide no evidence that HT factors increase the risk of recurrent early miscarriage. Therefore, at the moment, there is no evidence-based benefit of undertaking HT screening in women with recurrent early miscarriage.
The meta-analyses by Rey et al. (2003) and Robertson et al. (2006), which comprise almost the same RM patients, found that some HT factors (Factor V Leiden, Prothrombin G20210A mutation) were just significantly associated to early RM (OR 1.9; 95% CI 1.0–3.6 and OR 2.7, 95% CI 1.4–5.3, respectively), but there was a highly statistically significant heterogeneity between the ORs of the individual Factor V Leiden studies, which really prohibits merging of the studies and calculation of an overall average OR. Both meta-analyses found the Factor V Leiden and Prothrombin G20210A mutation to be strongly associated to late RM.
Since these meta-analyses were performed, two other relevant studies have been published. Coulam et al. (2006) found among 150 patients with RM that individual maternal HT factors were not significantly associated with RM, and only if all HT factors were considered in combination, was a significant association detected. Furthermore, Roque et al. (2004) carried out a comparison of the mutual relative risks conferred by a series of hereditary and acquired thrombophilia factors for early and late pregnancy complications. They found that the presence of the Factor V Leiden mutation alone, the presence of one thrombophilia factor and the presence of two or more thrombophilia factors were all significantly protective for developing recurrent early miscarriage, whereas several of the factors including the Factor V Leiden mutation increased the risk of recurrent late miscarriages.
Overall, current evidence does not support a negative role for HTs for recurrent early miscarriage, but they might increase the risk of recurrent late miscarriage. However, more prospective studies and good quality controlled treatment trials are needed in this relatively rare subset of patients before HT screening can be recommended in recurrent late miscarriage.
References
Carp H, Dolitzky M, Tur-Kaspa I, Inbal A. (2002) Hereditary thrombophilias are not associated with a decreased live birth rate in women with recurrent miscarriage. Fertil Steril 78:58–62.[CrossRef][Web of Science][Medline]
Coulam CB, Jeyendran RS, Fishel LA, Roussev R. (2006) Multiple thrombophilic mutations rather than specific gene mutations are risk factors for recurrent miscarriage. Am J Reprod Immunol 55:360–368.
Di Nisio M, Peters LW, Middeldorp S. (2005) Anticoagulants for the treatment of recurrent pregnancy loss in women without antiphospholipid syndrome. The Cochrane Library 2005:Issue 4.
Dolitzky M, Inbal A, Segal Y, Weiss A, Brenner B, Carp H. (2006) A randomized study of thromboprophylaxis in women with unexplained consecutive recurrent miscarriages. Fertil Steril 86:362–366.[CrossRef][Web of Science][Medline]
van Dunne FM, Doggen CJ, Heemskerk M, Rosendaal FR, Helmerhorst FM. (2005) Factor V Leiden mutation in relation to fecundity and miscarriage in women with venous thrombosis. Hum Reprod 20:802–806.
Jauniaux E, Farquharson RG, Christiansen OB, Exalto N. (2006) Evidence-based guidelines for the investigation and medical treatment of recurrent miscarriage. Hum Reprod 21:2216–2222.
Jivrai S, Rai R, Underwood J, Regan L. (2006) Genetic thrombophilic mutations among couples with recurrent miscarriage. Hum Reprod 21:1161–1165.
Rai R, Backos M, Elgaddal S, Shlebak A, Regan L. (2002) Factor V Leiden and recurrent miscarriages – propective outcome of untreated pregnancies. Hum Reprod 17:442–445.
Rey E, Kahn SR, David M, Shrier I. (2003) Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 361:901–908.[CrossRef][Web of Science][Medline]
Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, Walker ID, Greaves M, Brenkel I, Regan L, et al. (2006) The Thrombosis: Risk and Economic Assessment of Thrombophila Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol 132:171–196.[CrossRef][Web of Science][Medline]
Roque H, Paidas MJ, Funai EF, Kuczynski E, Lockwood CJ. (2004) Maternal thrombophilia are not associated with eraly pregnancy loss. Thromb Haemost 91:290–295.[Web of Science][Medline]
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