Do thrombophilias cause early first-trimester miscarriages? Yes.

CONTROVERSIES IN OB/GYN Do thrombophilias cause early first-trimester miscarriages? By Michael J. Kupferminc, MD Yes. Both direct and indirect evidence support this hypothesis. About 15% of all pregnancies end in miscarriage, mainly because of chromosomal abnormalities in the fetus. Recurrent miscarriage (RM)defined as three consecutive miscarriagesaffects 1% to 2% of women of reproductive age and up to 5% of all women have two or more recurrent losses. RM is a heterogeneous condition, with a number of different origins, including prothrombotic states, structural uterine anomalies, chromosomal anomalies, and endocrinologic defects. In up to 80% of cases, the underlying cause is unexplained. Currently available evidence, however, suggests an association between first-trimester RM and thrombophilias. Thrombophilia and pregnancy Thrombophilia is an inherited or acquired tendency to venous or arterial thrombosis. Pregnancy is a hyper-coagulable state, and women with thrombophilia may be at increased risk for thrombosis and adverse maternal and fetal outcomes. The most common acquired thrombophilia is antiphospholipid syndrome (APS). The most common inherited thrombophilias are factor V Leiden (FV), prothrombin mutation, and the methylenetetrahydrofolate reductase mutation (MTHFR), which is the most common cause of hyperhomocysteinemia. More rare thrombophilias include deficiencies of antithrombin, protein C, and protein S. The hemostatic system plays an important role in the success of pregnancy, implantation, and placentation. When the fertilized egg implants into the uterine decidua, it comes into contact with the maternal circulation, and this connection is crucial to a successful pregnancy. Prothrombotic states such as thrombophilia may interfere with this process, producing thrombosis that leads to miscarriage. The direct and indirect evidence supporting the association between miscarriage and thrombophilias is outlined below. Indirect evidence Women with a history of RM are at greater risk of preeclampsia, fetal growth restriction (FGR), and intrauterine fetal death, which suggests that these disorders share a common origin. Indeed, these late adverse outcomes are characterized by the presence of placental thrombosis and infarction and are associated with thrombophilias. Women with a history of RM who are not pregnant are in a prothrombotic state.1 They have significantly higher levels of thrombin antithrombin complexes and their endothelium is chronically stimulated because of activation of the coagulation system. At 4 to 7 weeks' gestation, women with a history of RM produce excess thromboxane; at 8 to 11 weeks' gestation, they are relatively deficient in prostacyclin compared with women with no previous history of RM. Direct evidence Studies have found a higher prevalence of thrombophilias in women with first-trimester miscarriage who have the following conditions. Antiphospholipid syndrome. Prospective studies have demonstrated an increased prevalence of antiphospholipid antibodies (aPL) among women with first-trimester RM.1 Some 15% of women with RM have positive tests for aPL. Several studies have reported a 50% to 70% rate of early fetal loss in women with aPL. Most miscarriages in aPL-positive women occurred in the first trimester of pregnancy after fetal heart activity was established. With antithrombotic therapy, the live-birth rate for women with APS and RM increases from 20% to 80%.1 Deficiencies of protein S, C, and antithrombin III. Brenner studied a group of 129 women who had been pregnant at least once and who had a family member with documented venous thrombosis associated with a deficiency of antithrombin III, protein S, and protein C.2 One hundred eighty-eight of the pregnancies (22.3%) in the 60 women who were themselves deficient resulted in miscarriage or stillbirth, compared to 11.4% of the 202 pregnancies in the 69 nondeficient subjects. The relative risk of abortion and stillbirth per pregnancy for deficient women as compared to nondeficient women was 2.0 (95% CI, 1.23.3). Women with dysfibrinogenemia also are candidates for miscarriage, and of 64 pregnancies in subjects with that condition, 39% ended in miscarriage.2 Factor V Leiden. Ridker and colleagues compared the frequency of FV in 113 women with RM to 437 controls and found the mutation in 8% of those with RM and 3.7% of the controls (OR 2.3, 95% CI, 1.05.2).3 In a subgroup of patients with three or more pregnancy losses and no successful pregnancies, mutation prevalence was 9% (OR 2.6, 95% CI, 1.06.7). Younis and colleagues evaluated FV mutations in women with first-trimester recurrent embryonic loss and with second-trimester loss, and in controls.4 FV prevalence was significantly higher in women with first-trimester RM than in controls. Finan and colleagues tested 110 women with unexplained first-trimester (> two) losses and 67 controls.5 Fortyone carried FV, versus 16.4% of the controls, (P=0.002) and 13.6% carried the prothrombin mutation, compared to 3% of the controls (P=0.001). Foka and colleagues tested 80 women with recurrent (> two) losses and 100 controls.6 Of the 80, 61 had a first-trimester loss. FV and prothrombin mutations were significantly more prevalent in the women with RM (19% vs. 4%; P=0.003 and 9% vs. 2%, P=0,038, respectively). They also were more prevalent in the 61 women with first-trimester losses than in the controls (14.7% vs. 4%, P=0.01 and 8.1% vs. 2%, P=0.06, respectively). Reznikoff-Etievan and colleagues investigated 260 women with two or more losses before 10 weeks of pregnancy and 240 controls.7 They found an association between FV and prothrombin mutations and RM before 10 weeks' gestation (OR 2.4 and 2.7, respectively). MTHFR gene mutation. Nelen and colleagues performed a meta-analysis to evaluate the relationship between early RM and hyperhomocysteinemia and evaluated fasting or afterload homocysteine concentrations and the MTHFR C677T mutation.8 The pooled odds ratios were 2.7 (1.55.2) for elevated fasting homocysteine, 4.2 (2.08.8) for afterload homocysteine, and 1.4 (1.02.0) for MTHFR. These data support hyperhomocysteinemia as a risk factor for recurrent early RM, while homozygosity for the MTHFR mutation represents a small increase in risk for RM. Prothrombin mutation. In addition to the three studies previously mentioned, Pihusch and colleagues studied 102 patients with two or more consecutive abortions and 128 women without miscarriage.5-7,9 In patients with RM, the prothrombin mutation occurred more often, and the association was significant in 75 women whose abortions occurred exclusively in the first trimester (6.7% vs. 0.8%, P=0.027, OR 8.5). Conclusion Indirect and direct evidence supports the opinion that acquired and inherited thrombophilia causes first-trimester miscarriage. REFERENCES 1. Regan L, Rai R. Thrombophilia and pregnancy loss. J Reprod Immunol. 2002;55:163-180. 2. Brenner B. Inherited thrombophilia and fetal loss. Curr Opin Hematol. 2000;7:290-295. 3. Ridker PM, Miletich JP, Buring JE, et al. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss. Ann Intern Med. 1998;128:1000-1003. 4. Younis JS, Brenner B, Ohel G, et al. Activated protein C resistance and factor V Leiden mutation can be associated with first-as well as second-trimester recurrent pregnancy loss. Am J Reprod Immunol. 2000;43:31-35. 5. Finan RR, Tamim H, Ameen G, et al. Prevalence of factor V G1691A (factor V-Leiden) and prothrombin G20210A gene mutations in a recurrent miscarriage population. Am J Hematol. 2002;71:300-305. 6. Foka ZJ, Lambropoulos AF, Saravelos H, et al. Factor V leiden and prothrombin G20210A mutations, but not methylenetetrahydrofolate reductase C677T, are associated with recurrent miscarriages. Hum Reprod. 2000;15:458-462. 7. Reznikoff-Etievan MF, Cayol V, Carbonne B, et al. Factor V Leiden and G20210A prothrombin mutations are risk factors for very early recurrent miscarriage. BJOG. 2001;108:1251-1254. 8. Nelen WL, Blom HJ, Steegers EA, et al. Hyperhomocysteinemia and recurrent early pregnancy loss: a meta-analysis. Fertil Steril. 2000;74:1196-1199. 9. Pihusch R, Buchholz T, Lohse P, et al. Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester. Am J Reprod Immunol. 2001;46:124-131. Dr. Kupferminc is Head of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Controversies in OB/GYN focuses on controversial issues pertaining to the clinical practice of obstetrics and gynecology and reproductive medicine. The authors have been selected for their ability to articulate a particular point of view, regardless of their own personal convictions. We hope that these short essays will provoke discussion and help Contemporary OB/GYN's readers clarify and refine their own practice management. You can join in the dialogue by completing and faxing in the response form at the end of this article or sending us your opinion (pro or con) via e-mail to jorvos@advanstar.com. A summary of the correspondence we receive will be published in a future issue. David B. Seifer, MD, Department Editor Department of Obstetrics, Gynecology, and Reproductive Sciences UMDNJ-Robert Wood Johnson Medical School New Brunswick, N.J. Michael Kupfermine. Do thrombophilias cause early first-trimester miscarriages? Contemporary Ob/Gyn Mar. 1, 2004;49:51-59.