High factor XI, recurrent pregnancy loss, enoxaparin Of the 149 women with 0 pregnancy losses, 7 (5%) had factor XI level R150% versus 5 of 31 (16%) women with recurrent pregnancy loss. Three of the 5 women with high factor XI and recurrent pregnancy loss, with 19 previous pregnancy losses and 0 live births, were given enoxaparin during 5 subsequent pregnancies, and had 6 term live births and 1 miscarriage. (Fertil Steril 2010;94:2828–31. 2010 by American Society for Reproductive Medicine.) Key Words: Factor XI, thrombophilia, recurrent pregnancy loss, enoxaparin
Heritable and acquired thrombophilia and hypofibrinolysis are well-documented risk factors for recurrent pregnancy loss (defined as three or more consecutive pregnancy losses before 20 weeks gestation), spontaneous abortion, and intrauterine growth retardation (1–10). Three thrombophilic mutations, factor V Leiden (9–12), 20210G>A prothrombin (10, 13, 14), and MTHFR 677 C>T homozygosity or MTHFR 677C>T-1298A>C compound heterozygosity (13, 15–17), have been associated with recurrent pregnancy loss. The hypofibrinolytic 4G4G mutation of the plasminogen activator inhibitor-1 gene is associated with fetal loss (18) and pregnancy complications (7, 19–21). Placental thrombosis may be a major final common pathway in recurrent pregnancy loss (12, 22, 23), interacting with the physiologic thrombophilic hyperestrogenemia of pregnancy to increase risk for thrombosis of the spiral arteries of the uterus, placental ischemia, and fetal loss (5, 7, 24, 25). High factor XI level is predominantly familial (26–28), is a significant independent risk factor for venous thrombosis (29–32), but has not been studied previously in women with recurrent pregnancy loss. Meijers et al. (29) reported a 2.2-fold
Charles J. Glueck, M.D. Joel Pranikoff, M.D. Naseer Khan, M.D. Kashif Riaz, M.D. Kirti Chavan, M.D. Pavithra Raj, M.D. Muhammad Umar, M.D. Ping Wang, Ph.D. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio Received October 22, 2009; revised November 28, 2009; accepted December 19, 2009; published online June 17, 2010. C.J.G. has nothing to disclose. J.P. has nothing to disclose. N.K. has nothing to disclose. K.R. has nothing to disclose. K.C. has nothing to disclose. P.R. has nothing to disclose. M.U. has nothing to disclose. P.W. has nothing to disclose. Supported in part by the Medical Research Council and by the Lipoprotein Research Fund of the Jewish Hospital of Cincinnati. Reprint requests: Charles J. Glueck, M.D., Cholesterol Center, ABC Building, 3200 Burnet Avenue, Cincinnati OH, 45229 (FAX: 513-585-7950; E-mail:
[email protected]).
2828
increased risk of venous thrombosis in subjects with top decile factor XI and a dose-response relation between factor XI and risk of venous thrombosis. Documentation of high factor XI as a newly recognized risk factor for recurrent pregnancy loss would provide an option to optimize subsequent live birth outcomes with low-molecular-weight heparin (LMWH) (22, 33–35). In our current study, having excluded women with major thrombophilias associated with recurrent pregnancy loss: factor V (9–12), prothrombin (10, 13, 14), and MTHFR 677 C>T homozygosity or MTHFR 677C>T-1298A>C compound heterozygosity (13, 15–17), our specific aim was to assess whether thrombophilic high factor XI was associated with recurrent pregnancy loss. Our second specific aim, in three women with high factor XI and with recurrent pregnancy loss (19 previous pregnancies, 19 miscarriages), was to determine whether subsequent enoxaparin would facilitate healthy live births. This study followed a protocol approved by the Jewish Hospital Institutional Review Board. Enoxaparin therapy was considered standard clinical care in recurrent pregnancy loss (35–39). Coagulation profiles were obtained in 391 women, 234 with R1 live birth pregnancy and 0 pregnancy losses, 108 with 1 sporadic pregnancy loss, and 49 with R3 pregnancy losses. The 234 women with R1 live birth pregnancy and 0 pregnancy losses had been evaluated during studies of familial thrombophilia and hypofibrinolysis. The 108 women with 1 sporadic pregnancy loss and the 49 women with R3 pregnancy losses were studied after referral for assessment of etiologies of pregnancy loss. To enter the study, women had to be free of the following known etiologies for recurrent pregnancy loss: anatomic uterine abnormalities, cervical incompetence, poorly controlled diabetes, and hypothyroidism (40). To avoid other major thrombophilias whose contributions might interact with the thrombophilia of high factor XI to cause recurrent pregnancy loss, women had to be free of factor V (9–12), prothrombin (10, 13, 14), and MTHFR 677 C>T homozygosity or MTHFR 677C>T-1298A>C compound heterozygosity (13, 15–17). With use of these selection criteria, the current report was a consecutive case series of 149 women with R1 live birth pregnancy and 0 pregnancy losses (324 pregnancies, 312 live births), 82 women with 1 sporadic pregnancy loss (213 pregnancies, 120 live births, 82 pregnancy losses), and 31 women with R3 pregnancy losses (186 pregnancies, 49 live
Fertility and Sterility Vol. 94, No. 7, December 2010 Copyright ª2010 American Society for Reproductive Medicine, Published by Elsevier Inc.
0015-0282/$36.00 doi:10.1016/j.fertnstert.2009.12.084
births, 132 pregnancy losses, 5 very early A prothrombin, 1691 G>A factor V Leiden, and MTHFR 677 C>T-1298A>C gene mutations (5, 7, 21, 44, 46) and for the hypofibrinolytic 4G4G polymorphism of the PAI-1 gene (7, 19–21). Serologic studies for the following thrombophilic factors were done: resistance to activated protein C, proteins C and S (total and free), antithrombin III, homocysteine, anticardiolipin antibodies IgG and IgM, dilute Russell’s viper venom time, partial thromboplastin time, and factors VIII and XI (5, 7, 21, 44, 46, 47). Serologic studies were done for hypofibrinolytic plasminogen activator inhibitor activity and lipoprotein a (44, 45). Factor XI activity (47) in fresh plasma was determined with use of an activated partial thromboplastin time–based one-stage clotting time assay. Three women with recurrent pregnancy loss and high factor XI, with 19 antecedent pregnancy losses and no live births, were treated with enoxaparin (40 mg every 12 hours) throughout 5 subsequent pregnancies. Fisher’s test was used to compare the frequency of high factor XI levels (R150%) in 262 women with R1 pregnancy, 149 with R1 live birth pregnancy and 0 pregnancy losses, 82 with 1 sporadic pregnancy loss, and 31 with recurrent pregnancy loss. McNemar’s test was used to compare previous pregnancy outcomes without enoxaparin in 3 women with 19 antecedent pregnancy losses and no live births versus 5 subsequent pregnancies with enoxaparin. Of the 49 women with recurrent pregnancy loss in the overall cohort of 391 women before exclusions of women with the factor V Leiden, prothrombin, and/or MTHFR mutations, 8 (16%) were excluded because of factor V Leiden heterozygosity and 10 (20%) because of MTHFR 677 C>T homozygosity or MTHFR 677C>T-1298A>C compound heterozygosity, respectively, leaving 31 with recurrent pregnancy loss. The factor V Leiden mutation was more common (8/49, 16%) in the 49 women with recurrent pregnancy loss than in the 234 women with no pregnancy losses (8/234, 3.4%), Fisher’s P¼.002. After excluding women with factor V Leiden, prothrombin, and MTHR mutations, the remaining cohort included 149 women with R1 live birth pregnancy and 0 pregnancy losses, 82 women with 1 sporadic pregnancy loss, and 31 women with R3 pregnancy losses. Of the 149 women with 0 pregnancy losses, 7 (5%) had factor XI R150%, versus 5 of 31 (16%) of women with recurrent pregnancy loss (Fisher’s P¼.036), versus 4 of 82 women with 1 sporadic pregnancy loss (5%), P>.5. The recurrent pregnancy loss group had a third peak of factor XI (140% to 160%) and a longer tail of values out to 200% versus women with no miscarriage (Fig. 1).
Fertility and Sterility
Glueck. Correspondence. Fertil Steril 2010.
Three of the 5 women with recurrent pregnancy loss and high factor XI, 19 previous pregnancy losses, 0 live births without enoxaparin, were given treatment with enoxaparin (80 mg/d) throughout 5 subsequent uneventful pregnancies. With enoxaparin, they had 6 term live births and 1 miscarriage (McNemar’s S ¼ 28, PA prothrombin (10, 13, 14), MTHFR 677 C>T homozygosity, or MTHFR 677C>T-1298A>C compound heterozygosity (13, 15–17), thrombophilic mutations associated with recurrent pregnancy loss. Our current study suggests that measurement of factor XI be added to the roster of thrombophilias associated with recurrent pregnancy loss. Recognition of factor XI as a contributor to recurrent pregnancy loss provides an option toward subsequent use of LMWH. In our study, 3 of the 5 women with recurrent pregnancy loss and high factor XI, with 19 antecedent pregnancy losses and no live births, taking enoxaparin in 5 subsequent pregnancies, had 6 term live births and 1 miscarriage (P
