Genetic thrombophilic mutations and recurrent miscarriage

Recurrent miscarriage (RM) affects 1% of the population. Some cases have a thrombotic aetiology. While it is known that the allele frequency of factor V Leiden (FVL), a thrombophilic gene mutation, is similar between women with and without RM, the miscarriage rate of a subsequent untreated pregnancy is significantly higher in RM women carrying FVL. The studies in the thesis explore the hypothesis that (a) women with FVL and RM, who went on to miscarry again may have an additional thrombophilia that increased their risk of miscarriage (b) thrombophilia genotype inherited by the fetus may determine pregnancy outcome. The first study in the thesis demonstrates that the allele frequencies of FVL, Prothrombin G20210A (pTG) and MTHFR C677T (MTHFR) gene mutations and the prevalence of multiple thrombophilia are similar in couples with RM (n=357), late pregnancy loss (n=69) and a race matched control population (n=68). The second study describes a prospective study which shows that in couples with RM, the miscarriage rate in a subsequent untreated pregnancy was significantly higher if the male or the female partner carried multiple thrombophilic defects than if neither carried a thrombophilic defect (83% vs 44%, RR 1.9; 95% CI, 1.3-2.8). This study suggested that the paternal thrombophilia genotype, and by inference the fetal thrombophilia genotype contributes to determining pregnancy outcome. The third study explores this hypothesis by analysing the allele frequencies of FVL, PTG and MTHFR in miscarried products of conception from first trimester miscarriages (n=31) and umbilical cord blood from live-births (n=89). The allele frequency of PTG was higher in products of conception from first trimester miscarriages than live births (4.8% vs 1.1%, OR 4.47; 95% CI 0.49-54.36). The prevalence of multiple thrombophilic defects was also higher in products of conception from first trimester miscarriages than live births (6.4% vs 2.2% OR 3.00; 95% CI 0.2-42.6) This research suggests that the paternal thrombophilia genotype influences pregnancy outcome. This is a new concept in our understanding of the aetiology of RM and highlights the importance of investigating the male partner with RM. If further studies and larger datasets confirm our findings, the concept of paternal thrombophilia genotype and by inference fetal thrombophilia genotype could lead to a whole new paradigm in the way couples with RM are investigated.EThOS - Electronic Theses Online ServiceGBUnited Kingdo