Factor V Leiden is associated with pre‐eclampsia but not with fetal growth restriction: a genetic association study and meta‐analysis

• Published in: Journal of thrombosis and haemostasis 2008-11, Vol.6 (11), p.1868-1875
• Main Authors: DUDDING, T., HERON, J., THAKKINSTIAN, A., NURK, E., GOLDING, J., PEMBREY, M., RING, S. M., ATTIA, J., SCOTT, R. J.
• Format: Article
• Language: English
• Subjects: adverse pregnancy outcome; ALSPAC; Factor V - genetics; factor V Leiden; Female; fetal growth restriction; Fetal Growth Retardation - epidemiology; Fetal Growth Retardation - etiology; Fetal Growth Retardation - genetics; genetic polymorphisms; Genetic Predisposition to Disease; Genotype; Humans; Infant, Newborn; Mothers; Polymorphism, Genetic; Pre-Eclampsia - epidemiology; Pre-Eclampsia - etiology; Pre-Eclampsia - genetics; Pregnancy; pre‐eclampsia; prothrombin; Prothrombin - genetics; single nucleotide polymorphism; SNP
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2008.03134.x

Background: Adverse pregnancy outcomes have been related to environmental and/or genetic factors. Of interest are genes associated with the clotting system as any perturbation in the balance of thrombotic and thrombolytic cascades could affect the placental circulation and hence the viability of the developing fetus. Several previous reports using relatively small numbers of cases and controls have suggested that there is a relationship between poor pregnancy outcomes and two polymorphisms, one in the factor V gene, the 1691G to A change (rs6025) located on chromosome 1q23 (factor V Leiden, FVL), and the other in the prothrombin gene, 20210G to A change (rs1799963) on chromosome 11p11‐q12 (PT). These results, however, are conflicting. Methods: We genotyped 6755 mother/infant pairs from the Avon Longitudinal Study of Parents and Children (ALSPAC) to determine whether maternal or fetal FVL or PT, either alone or in combination, are associated with fetal growth restriction (FGR) or pre‐eclampsia (PE). We also added the present results to previous cohort studies using meta‐analysis. Results: Smoking, primiparity and lower body mass index (BMI) were all associated with FGR, but neither maternal nor fetal FVL or PT, singly or in combination, were associated with FGR in the ALSPAC cohort. Meta‐analysis confirmed the lack of association between maternal FVL and FGR with a pooled odds ratio (OR) of 1.15 [95% confidence interval (CI) 0.95–1.39]. High BMI, primiparity, diabetes and chronic hypertension were all associated with pre‐eclampsia. Combining ALSPAC results with previous studies in a meta‐analysis indicated that maternal FVL is significantly associated with pre‐eclampsia, with a pooled OR of 1.49 (95% CI 1.13–1.96). Conclusion: Neither maternal nor fetal FVL or PT, singly or in combination, are associated with FGR; this contradicts previous case–control studies and meta‐analyses based on these studies. In a meta‐analysis of all published cohort studies to date, maternal FVL appears to increase the risk of pre‐eclampsia by almost 50%. This result is robust, homogeneous and does not appear to be affected by publication bias.