Impact of prothrombotic mutations and family history on the occurrence of intra-uterine fetal deaths.

The role of inherited thrombophilias in the occurrence of fetal loss has been established.1-4 We do not know whether the risk of recurrence of late fetal loss is higher in women carrying inherited thrombophilia. Women (n=84) with at least one previous intra-uterine fetal death (IUFD)5 who were enrolled between February 1998 and July 2001 in three Atherosclerosis and Thrombosis Centers, were screened for acquired and inherited thrombophilias. A comprehensive work up for recurrent fetal loss was performed in all cases. Unexplained fetal loss was defined as previously described.1 As controls, 108 healthy parous women with uneventful pregnancies were enrolled. All were Caucasian women from Southern Italy. Information about personal and family history (first-degree relatives) of IUFD, pre-eclampsia (PE), and fetal growth restriction (FGR) was collected by interviews and confirmed by means of the patients’ records. The study was carried out according to the principles of the Declaration of Helsinki. Blood samples were collected in 3.8% trisodium citrate and treated as previously described.1 Antiphospholipid antibodies-lupus anticoagulant (LA) and IgG anticardiolipin antibodies (aCL), antithrombin, protein C, amidolytic and immunologic and total and free protein S antigen were determined in all patients, as reported.6 Leukocyte DNA was obtained from frozen blood and factor V Leiden and factor IIA20210 mutations investigated, as described.6 All the analyses were performed according to the Statistical Package for Social Science (SPSS 6.1 for Macintosh). The significance of differences in means was evaluated by non-parametric tests, whereas the significance of any difference in proportions was tested by χ2 statistics. A multivariate regression analysis was performed to correct the associations found for potential confounding variables such as age, gravidity, FV Leiden, FII A20210 allele and a family history of obstetric complications. Table 1 shows the features of all cases and controls. Twentytwo (26.2%) women suffered from an IUFD in the second trimester (i.e. ≤ 24 weeks), while 63 did so in the third trimester. Ten (11.9%) cases showed the FV Leiden (all heterozygous), while 11 (13.1%, 1 with both the mutations) were heterozygous for the FII A20210 allele. Six (7.1%) women had a confirmed presence of antiphospholipid antibodies. Of them, 2 also showed the FV Leiden mutation and 1 both the mutations. Among controls, 2 (1.9%) carried the FV Leiden (OR: 7.9; 95% CI: 1.7-36.8) and 5 the FII A20210 allele (4.6%, OR: 3.1; 95% CI: 1.0-9.2). Multivariate analysis (Table 2), correcting for the potential confounding variables, age, gravidity, FV Leiden or FII A20210 allele, and family history, showed that prothrombotic mutations were independently associated with IUFD (OR 6.3; 95%CI: 1.0-41.1 and OR: 4.2; 95%CI: 1.0-17.1 for FV Leiden and FII A20210 , respectively). Moreover, a family history of obstetric complications was also independently associated with the occurrence of a first IUFD (OR: 8.4; 95%CI: 1.5-46.4). Four cases suffered from venous thrombosis (of them, two with the FV Leiden and one with both the prothrombotic mutations). Fourteen (16.7%) cases had a recurrent IUFD. Four out of these 14 (28.6%) women with recurrence showed an inherited thrombophilia. When we compared thrombophilic women with one IUFD to thrombophilic women with recurrence, a not significant difference of inherited risk factors was recorded. No woman with more than one risk factor had a recurrence of IUFD. Family history of obstetric complications (1 IUFD, 4 PE, 2 sine causa FGR) was registered in 7 (8.3%) cases : one of them carried the FII A20210 allele and 2 the FV Leiden. In the control group, 2 (1.9%, OR: 4.8; 95%CI: 1-23.8) women showed a family history (2 IUFD) of obstetric complications: none of them carried a prothrombotic mutation. As shown in Table 2, family history showed a significant association with IUFD. This study confirms, in a selected sample, that prothrombotic mutations are associated with IUFD. Identification of conditions carrying an increased risk of recurrent IUFD is important for pharmacologic management of the subsequent pregnancies. At present, prospective evaluations of pregnancies in women carrying one prothrombotic mutation are lacking, and this is probably due also to the habit that physicians have of using heparin in the subsequent pregnancies of these women. Nevertheless, to know whether women with prothromTable 1. Clinical features and coagulation screening of cases and controls.