Prediction of Recurrent Pregnancy Loss by a New Thrombophilia Based Genetic Risk Score

Overview

Recurrent pregnancy loss (RPL) is a clinical problem affecting 1-5% of couples of reproductive age. The contribution of thrombophilia to RPL is disputed. This controversy is partly due to low sensitivity of the genetic variants currently used to evaluate hereditary thrombophilia: the Leiden mutation (identified as rs6025) in the coagulation factor 5 (F5L) gene and mutation G20210A (identified as rs1799963) in the prothrombin (PT) gene. Our objective was to determine whether a wider algorithm that includes clinic and genetic variants associated with thrombophilia could be more useful in the prediction for RPL than FVL and PT alone.

Recurrent pregnancy loss can affect up to 5% of women in child-bearing age and is considered one of the most common causes of female sterility. In recent years, the association between thrombophilia and pregnancy failure has been observed in a number of studies, varying according to the nature of the thrombophilia (for example the antiphospholipid syndrome as opposed to the hereditary forms) or the type of pregnancy loss (either isolated or recurrent, or early or late). It has therefore been accepted that thrombophilia is detected in a significant number of idiopathic pregnancy losses, reaching 66% of the cases in some series. Since the 1990's, a number of studies have associated recurrent pregnancy loss with FVL mutations (most frequently) and G20210 PT. In a systematic review, it was confirmed that women with thrombophilia have a higher risk of developing thromboembolism and complications in pregnancy. Another recent meta-analysis of prospective cohort studies concluded that women who were carriers of FVL had a higher risk of late pregnancy loss, at 52%, as opposed to non-carriers (OR=1.52), though the differences in absolute risk were discreet (4.2% and 3.2%, respectively). However, the analysis of these 2 single nucleotide polymorphisms (SNPs) showed low discriminative capacity and diagnostic sensitivity. This study hypothesize that the use of the Thrombo inCode® in the screening for hereditary thrombophilia in patients with recurrent pregnancy loss can improve the diagnostic sensitivity and predictive capacity of the routine genetic panel, based on FVL and G20210A PT. Thus, the Thrombo inCode® model can accurately identify more patients with clinical-genetic risk of thromboembolism and therefore establish the appropriate preventive measures. A transversal observational case-control study will be carried out, with retrospective data analysis. The screening for hereditary thrombophilia will be performed through the Thrombo inCode® panel in cases and controls. The results produced from a single genetic analysis will allow comparison to the centres' routine protocol (FV Leiden and G20210A PT) with the complete Thrombo inCode® panel, that also includes the previously-mentioned classical variants.