Factor V Leiden and adverse pregnancy outcome

Abstract

Research Doctorate - Doctor of Philosophy (PhD)Intrauterine fetal death, fetal growth restriction (FGR) and pre-eclampsia are major causes of fetal and maternal morbidity and mortality; and placental insufficiency is frequently proposed as the most important underlying mechanism. Given the importance of establishing and maintaining an adequate placental circulation, hereditary thrombophilias are postulated as a possible cause of placental insufficiency. Despite initial reports supporting an association between factor V Leiden (fVL) and adverse pregnancy outcomes, a number of other studies yielded conflicting results. A systematic review and meta-analysis of the literature up to January 2003 was undertaken to address the question of whether the common maternal fVL genotype is associated with an increased risk of adverse pregnancy outcomes (pre-eclampsia, fetal growth restriction and fetal loss). Subsequent meta-analyses were also evaluated. To address the shortfalls observed in the large number of small and possibility underpowered case-control studies, a decision was made to undertake a large nested case-control study within the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. The aim of this study was to evaluate the association between: 1) maternal fVL and intrauterine fetal death, fetal growth restriction and pre-eclampsia; 2) fetal fVL and intrauterine fetal death, fetal growth restriction; 3) maternal prothrombin gene variant (PGV) and intrauterine fetal death, fetal growth restriction and pre-eclampsia and 4) fetal PGV and intrauterine fetal death, fetal growth restriction and pre-eclampsia. Data from other published cohort studies was combined by meta-analysis to increase the power of detecting an association. Overall, the results of the study within the large ALSPAC cohort show no statistically significant association between maternal/fetal fVL or PGV, either alone or in combination with birth weight <10th centile. Furthermore, the FGR meta-analysis which pooled the results of this cohort study and other cohort studies found no evidence of an effect of maternal fVL on FGR. Given the size of the pooled sample, there was 80% power to detect an OR of 1.09, indicating that if an effect of fVL on FGR was missed by this meta-analysis, it would be quite small. The results of this study within the large ALSPAC cohort show no statistically significant association between maternal or fetal fVL or PGV, either alone or in combination with pre-eclampsia. However, increasing the power by combining this study with other cohort studies by meta-analysis revealed a positive association between maternal fVL and pre-eclampsia with an OR of 1.49 (95% CI 1.13-1.96 p=0.003). A narrative review was subsequently published examining the translation from statistical association to change in clinical practice with respect to fVL and adverse pregnancy outcomes. The thesis concludes with a discussion of management in different clinical scenarios relating to fVL and adverse pregnancy outcomes, and the identification of future priority research areas