COMMENTARY: Thrombophilia and pregnancy loss in first intended pregnancy

Recurrent pregnancy loss is a common health problem affecting 1–5% of women at the reproductive age and bears significant emotional, social and economical impact [1]. A number of case–control and cohort studies have suggested an association between inherited thrombophilia and recurrent pregnancy loss while others refuted this occurrence [2–6]. Several recently reported meta-analysis support an association between maternal factor V Leiden (FV Leiden) and factor II G20210A genotypes and pregnancy loss [7–9]. These findings have lead to the introduction of thrombophilia workup in women at risk, particularly in those with recurrent or late pregnancy loss. Documentation of thrombophilic risk factors in womenwith pregnancy complications may have significant therapeutic implications as a number of clinical studies have demonstrated the potential efficacy of prophylaxis with low molecular weight heparin (LMWH) in these settings [10,11]. While interpretation of the results of these studies arose some debate [12–22], it is clear that the field of thrombophilia and pregnancy complications continues to be in the focus of medical research and clinical practice. Studies on the association of thrombophilia and gestational complications in populations of pregnant women have revealed conflicting results [6,23] partly explained by variance in incidence of thrombophilic polymorphisms in different ethnic backgrounds and studies not powered for evaluation of the potential associations. Differences in type of pregnancy loss i.e. primary or secondary, isolatedor recurrent, consecutiveornon-consecutive and timing of its occurrence i.e. first, second or third trimester may also influence the magnitude of these associations [24–26]. In this issue of the Journal of Thrombosis and Haemostasis Lissalde-Lavigne et al. [27] report findings from the NOHA first study, a large carefully designed case–control study nested in a cohort of nearly 32 700 women of who 18% had pregnancy loss with first gestation. After analyzing the characteristics of 3496 pairs of women with an unexplained pregnancy loss and normal pregnancy controls, the authors describe the incidence of FV Leiden and factor II G20210A in these groups. Notably in this study, the greatmajority (85%) of losses were after 10 weeks of gestation partly due to careful exclusion of other causes of pregnancy loss. The findings of the multivariate analysis clearly demonstrate an overall association between unexplained first pregnancy loss and the two thrombophilic risks factors (OR 1⁄4 3.09 and OR 1⁄4 2.34, respectively). The associations results from the 3065 women with losses after 10 weeks of gestation (OR 1⁄4 3.46 and OR 1⁄4 2.60, respectively) but were not found in women with losses between 3 and 9 weeks of gestation. However, the latter should be interpreted with some caution in view of the relatively limited number of women (431) in this group, particularly in view of the low incidence of FV Leiden and factor II G20210A (2% each) in the control population, which is typical for southern France and North Africa [28]. However, In the Middle East, the incidence of FV Leiden is 10–15% and that of factor II G20210A is around 5% [29,30]. It is therefore not unlikely that in these populations early first trimester loss between 6 and 9 weeks of gestation particularly if recurrent may be associated with thrombophilia [31]. The importance of the NOHA first study is in the firm documentation that a first pregnancy loss after 10 weeks of gestation is associated with thrombophilia. As unexplained first pregnancy loss occurred in about 10% of gestations, the findings of this study may have significant clinical impact. Firstly, it is now clear, that women with first unexplained pregnancy loss after 10 weeks of gestation should be screened for thrombophilia. This should result in amendment of currently available guidelines such as the CAP Consensus Conference on Thrombophilia [32] and those recently reported by the Seventh ACCP conference on Antithrombotic and Thrombolytic Therapy [33]. Correspondence: B. Brenner, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa 31096, Israel. Tel.: +972 4 8543520; fax: +972 4 8543886; e-mail: b_brenner@ rambam.health.gov.il Journal of Thrombosis and Haemostasis, 3: 2176–2177