Thrombophilia and severe preeclampsia: time to screen and treat in future pregnancies?

The term thrombophilia is used to describe a heterogenous group of coagulation abnormalities (acquired or inherited) that are generally associated with increased risk of arterial and venous thrombosis.1 Antiphospholipid antibodies (APA) is the most frequent acquired thrombophilic disorder during pregnancy. It is generally diagnosed in the presence of elevated levels of IgG and IgM (GpL or MpL values 20) or the presence of lupus auticoagulant.2 The most common inherited thrombophilic disorders during pregnancy are mutations in factor V Leiden (FVL), prothrombin gene, and tetrahydrofolate reductase. During the past 2 decades, epidemiologic and case-control studies have evaluated the association between thrombophilias and adverse pregnancy outcome (APO), specifically, preeclampsia and intrauterine fetal growth restriction (IUGR).1–5 An association between severe preeclampsia at 34 weeks and APA was first reported by Branch et al in 1989.2 Based on this report, recommendations were made that women with severe preeclampsia at 34 weeks be screened for the presence of APA and be treated if positive in subsequent pregnancies. Since that publication, several studies were published supporting or refuting an association between these antibodies and preeclampsia.6,7 Indeed, a recent report concluded that data do not support routine testing for APA in women with early-onset preeclampsia.6 An association between preeclampsia and inherited thrombophilias was first reported by Dekker et al in 1995.8 Since then, a large number of retrospective and case-controlled studies have examined the association between carriage of thrombophilic mutations and preeclampsia. These studies were the subject of several reviews.1,3,4 Overall, the results of published reports have been inconsistent. However, metaanalysis of all case-control studies suggests that only FVL mutation is associated with an increased risk of preeclampsia (odds ratio, l.18; 95% confidence interval, 1.14 to 2.87).4 The reasons for the differences in findings among various studies are attributable in part to a lack of well-designed prospective studies evaluating the risk of preeclampsia in unselected, asymptomatic pregnant women who are carriers for these thrombophilias, and in part to the heterogenous group of patients studied in case-control studies.4 Almost all studies evaluated the frequency of these thrombophilias in women with complicated cases of severe preeclampsia who were referred to tertiary care obstetric units. In addition, most studies used term-normal pregnancies as control group. Therefore, these studies are subject to bias by overestimating the rate of thrombophilias in the study group and underestimating the rate in the control group. In addition, there are major differences among reported studies regarding the severity of preeclampsia and the gestational age at delivery in the study group,4 as well as differences regarding race and ethnicity. For instance, most studies found an association between severe preeclampsia, particularly at 34 weeks and thrombophilias, but not for mild or term preeclampsia. In addition, a multicenter prospective observational study of 5168 pregnant women found a carrier rate for FVL mutation of 6% among white patients, 2.3% in Asians, 1.6% in Hispanics, and 0.8% in blacks.9 Thus, studies that included exclusively white women will have high association with genetic thrombophilia,8 whereas, studies that included mainly black or Hispanic women will have a low frequency of FVL or prothrombin gene mutations in study and control patients. Mello et al10 report the results of a large, multicenter, case-control study comparing the frequency of thrombophilia between women with preeclampsia and those with normalterm pregnancy. The study populations were 808 white Italian women with preeclampsia and a matched control group (n 808) of women who had normal-term pregnancy. None of the women gave a history of thromboembolic disease, and all had a standardized thrombophilia work-up at 4 to 12 months after the index pregnancy. The authors also divided their study subjects according to the severity of preeclampsia (mild or severe). In addition, among those with severe preeclampsia, maternal and fetal complications were compared between those with and without thrombophilia. The Italian study revealed that the prevalence of inherited or acquired thrombophilia was significantly higher in women with severe preeclampsia (50.7%) compared with control (17.2%) with an odds ratio of 4.9 (95% confidence interval, 3.5 to 6.9). In contrast, they found no association between thrombophilia and mild preeclampsia (16.7% versus 14.9% in control). A surprising finding of this study is that patients with severe preeclampsia and positive thrombophilia work-up had a significantly higher rate of maternal complications such as onset of disease before the 28th week of gestation, abruptio placentae, disseminated intravascular coagulopathy, and acute renal failure compared with preeclamptic women without thrombophilia. In addition, severe preeclamptic women with thrombophilia were more likely to deliver at 28 weeks and had higher perinatal mortality compared with those without thrombophilia. The opinions expressed in this editorial commentary are not necessarily those of the editors or of the American Heart Association. From the Department of Obstetrics and Gynecology, University of Cincinnati, Ohio. Correspondence to Baha M. Sibai, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267. E-mail [email protected] (Hypertension. 2005;46:1252-1253.) © 2005 American Heart Association, Inc.