The Association of Factor V Leiden and Prothrombin Gene Mutation and Placenta-Mediated Pregnancy Complications: A Systematic Review and Meta-analysis of Prospective Cohort Studies

Marc Rodger and colleagues report the results of their systematic review and meta-analysis of prospective cohort studies that estimated the association of maternal factor V Leiden and prothrombin gene mutation carrier status and placenta-mediated pregnancy complications.Background: Factor V Leiden (FVL) and prothrombin gene mutation (PGM) are common inherited thrombophilias. Retrospective studies variably suggest a link between maternal FVL/PGM and placenta-mediated pregnancy complications including pregnancy loss, small for gestational age, pre-eclampsia and placental abruption. Prospective cohort studies provide a superior methodologic design but require larger sample sizes to detect important effects. We undertook a systematic review and a meta-analysis of prospective cohort studies to estimate the association of maternal FVL or PGM carrier status and placenta-mediated pregnancy complications. Methods and Findings: A comprehensive search strategy was run in Medline and Embase. Inclusion criteria were: (1) prospective cohort design; (2) clearly defined outcomes including one of the following: pregnancy loss, small for gestational age, pre-eclampsia or placental abruption; (3) maternal FVL or PGM carrier status; (4) sufficient data for calculation of odds ratios (ORs). We identified 322 titles, reviewed 30 articles for inclusion and exclusion criteria, and included ten studies in the meta-analysis. The odds of pregnancy loss in women with FVL (absolute risk 4.2%) was 52% higher (OR = 1.52, 95% confidence interval [CI] 1.06–2.19) as compared with women without FVL (absolute risk 3.2%). There was no significant association between FVL and pre-eclampsia (OR = 1.23, 95% CI 0.89–1.70) or between FVL and SGA (OR = 1.0, 95% CI 0.80–1.25). PGM was not associated with pre-eclampsia (OR = 1.25, 95% CI 0.79–1.99) or SGA (OR 1.25, 95% CI 0.92–1.70). Conclusions: Women with FVL appear to be at a small absolute increased risk of late pregnancy loss. Women with FVL and PGM appear not to be at increased risk of pre-eclampsia or birth of SGA infants. : Please see later in the article for the Editors' Summary Background: The death of a baby at any stage of pregnancy is heartbreaking and, sadly, a quarter of women lose their baby during pregnancy or birth. A pregnancy can go wrong for many reasons but complications that are caused by problems with the placenta affect more than one in 20 pregnancies. The placenta is the organ that links the mother to her baby. It is full of blood vessels that transfer oxygen and nutrients from the mother to her baby and that take carbon dioxide and waste products away from the baby. If the placenta does not circulate blood efficiently between the mother and baby (placental insufficiency), the result can be pregnancy loss (spontaneous miscarriage or still birth), pre-eclampsia (a sudden rise in blood pressure in late pregnancy that is life-threatening for both mother and baby), a small for gestational age pregnancy (the baby does not grow properly during pregnancy), or placental abruption (separation of the placenta from the wall of the womb, a condition that deprives the baby of oxygen and nutrients and can cause severe maternal blood loss). Why Was This Study Done?: One possible cause of placental insufficiency is inherited thrombophilia, an increased tendency to form blood clots that occurs in more than 10% of people. The commonest inherited thrombophilias are factor V Leiden (FVL) and prothrombin gene mutation (PGM). Comparisons of the frequencies of these thrombophilias in women who have had placenta-mediated pregnancy complications with the frequencies in women who have not had complications (“retrospective case control studies”) have found an association between thrombophilia and pregnancy complications. As a result, doctors sometimes give heparin to women with thrombophilia who have had a poor pregnancy outcome to reduce blood clotting during subsequent pregnancies (anticoagulant therapy). However, a better way to determine whether thrombophilia and pregnancy problems are associated is to recruit groups of women with and without thrombophilia and follow them during pregnancy to see whether they develop complications —“prospective cohort studies.” In this study, the researchers undertake a systematic review (a search that uses predefined criteria to identify all the research on a given topic) and meta-analysis (a statistical method for combining the results of studies) of prospective cohort studies to estimate the risk of placenta-mediated pregnancy complications in women with FVL or PGM. What Did the Researchers Do and Find?: The researchers identified ten prospective cohort studies that examined the association between FVL/PGM and placenta-mediated pregnancy complications and that met their predefined criteria. In their meta-analysis of these studies, they estimated that the absolute risk of pregnancy loss in women with FVL was 4.2% whereas the absolute risk of pregnancy loss in women without FVL was 3.2%. In other words, women with FVL had a 52% higher risk of pregnancy loss than women without FVL (an odds ratio of 1.52). The absolute increased risk, however, was 1%. There was no significant association (a significant association is one that is unlikely to have occurred by chance) between PGM and pregnancy loss. Similarly, there was no significant association between either of the thrombophilias and pre-eclampsia, small for gestational age pregnancies, or placental abruption. Finally, there was no significant association between either FVL or PGM and the composite outcome of any placenta-mediated pregnancy complication (pregnancy loss, pre-eclampsia, small for gestational age, and placental abruption). What Do These Findings Mean?: These findings suggest that women with FVL have a small absolute increased risk of pregnancy loss but that neither FVL nor PGM increase a woman's risk of pre-eclampsia or of giving birth to a small for gestational age infant. Although there seems to be no increased risk of pregnancy loss with PGM, more research is needed to confirm this finding and to confirm the lack of an association between thrombophilia and placental abruption. The researchers also warn that all these reassuring findings should be treated cautiously because of variability between the studies in how complications were defined. Importantly, however, these findings suggest that the introduction of anticoagulant therapies for women with thrombophilia and a history of pregnancy complications on the basis of retrospective case control studies might have been premature. Anticoagulant therapy should be considered experimental, therefore, until controlled trials of the approach have been completed. Additional Information: Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000292.