Thromboembolism Risk Following Recurrent Miscarriage
Thromboembolism Risk Following Recurrent Miscarriage
Thrombophilia is defined as a disorder associated with an increased tendency to thrombosis. This may be an acquired or congenital tendency, the latter being due to an inherited defect in the coagulation system. In general, acquired thrombophilia is associated with a predisposition to either venous and/or arterial thrombosis, whereas inherited thrombophilia increases mainly the risk of venous thromboembolism. As previously stressed, several studies have analyzed inherited thrombophilic factors that may predispose to arterial and/or venous thrombosis and their possible association with RM. A meta-analysis of 31 studies revealed an association between recurrent (two or more) fetal loss <13 weeks and Factor V Leiden, activated protein C resistance, prothrombin gene mutation and protein S deficiency. Conversely, it was demonstrated that methylene tetrahydrofolate reductase, protein C and antithrombin deficiencies were not associated with RM. A second meta-analysis of 16 studies, reported an association between RM, defined as two or more losses in the first two trimesters, and maternal carriers of Factor V Leiden or prothrombin gene, compared with those without these inherited thrombophilic mutations. However, in another meta-analysis limited to prospective cohort studies, the pooled OR for pregnancy loss in women with factor V Leyden (absolute risk: 4.2%) compared with women without this mutation (absolute risk: 3.2%) was 1.52 (95% CI 1.06–2.19). This meta-analysis also failed to demonstrate or exclude an association between the prothrombin mutation and pregnancy loss (OR: 1.13; 95% CI 0.64–2.01). Therefore, it remains unclear whether screening for inherited thombophilias is, at present, recommended in all women with pregnancy loss. Other studies have shown that the total number of mutations is a significant risk of RM, suggesting that there may be an additive effect of a number of thrombophilic mutations superimposed on the hypercoagulable state of pregnancy and that would increase the risk of clotting.
Although the majority of studies report an increased prevalence of genetic thrombophilic mutations among women with RM, few studies provide evidence of other abnormalities in the hemostatic pathways preceding RM. It has been reported that women with a history of RM at 4–7 of weeks' gestation have an excess of thromboxane production, and between Weeks 8 and 11, they are relatively prostacyclin deficient compared with women with no previous history of pregnancy loss. These changes were greatest among those whose pregnancy ended in abortion. The shift in the thromboxane to prostacyclin ratio in favor of the prothrombotic agent thromboxane may lead to vasospasm and platelet aggregation in the trophoblast, causing the development of microthrombi and placental necrosis.
Other authors reported the cases of two women in whom a significant decrease in the level of protein C and shortening in the rate of fibrinopeptide A generation (indicating activation of coagulation) could be detected several weeks in advance of pregnancy loss. In the second pregnancy of one of these two women, similar hematological changes were documented, but these were reversed by the administration of heparin and the patient went on to deliver at term.
Moreover, our research group recently published that, outside of pregnancy, women with first trimester RM are in a prothrombotic state, manifested by an impaired fibrinolytic response. Other studies have also found impairment of fibrinolysis in RM patients. It has also been described, using global markers of the hemostatic process, that women with RM have increased thrombin generation and an increased maximum clot strength before pregnancy. Furthermore, the authors stressed that women in such a state are at significantly increased risk of miscarriage in future untreated pregnancies. Other studies have also suggested that women with unexplained RM have a hypercoagulable state at baseline consisting in a relative trombomodulin resistance. There is also evidence that circulating placental microparticles are increased in a subgroup of RM patients, indicating an acquired procoagulant state even outside pregnancy.
The hypercoagulable state of RM patients is being increasingly recognized as the cause of long-term health consequences, but few studies have evaluated this issue; thus, several studies have found an increased risk of ischemic heart disease in the subgroup of women with a history of pregnancy loss. A retrospective study of 130,000 women showed that a history of first trimester spontaneous pregnancy loss was associated with a significant increased risk of maternal ischemic heart disease. This risk increased with the number of pregnancy losses. Moreover, among those with three or more pregnancy losses, the risk of death or hospital admission for ischemic heart disease was 2.3-times greater than that among those with no previous history of miscarriage. In contrast, there was no association between therapeutic abortion and the subsequent risk of ischemic heart disease. The authors hypothesized that this may reflect common determinants such as thrombophilic genetic defects or the presence of aPLs. Moreover, the same authors have recently found that there was an increased incidence of ischemic heart disease in the parents of women who experienced multiple miscarriages before their first birth, suggesting that RM and ischemic heart disease may have common pathophysiological pathways and genetic predispositions.
Only one case–control study, performed by us, evaluated the long-term risk of thrombotic events after pregnancy among patients with RM associated with inherited thrombophilic factors different than APS and idiopathic RM. This study evaluated the long-term risk for thromboembolic events after RM in APS patients compared with RM patients with thrombophilias different from APS and idiopathic RM patients. It showed a higher risk, although not statistically significant, of thromboembolic events among patients with RM who tested positive only for genetic thrombophilias compared with patients with idiopathic RM. The former control group of patients in this study presented with thrombophilic genetic defects as the only etiologic factor for their pregnancy losses. It consisted of 42 patients with three or more consecutive spontaneous abortions before 10 weeks gestation. Thrombophilia in this group was defined as factor V Leiden mutation (17 patients), prothrombin G20210A gene mutation (12 patients), protein C deficiency (9 patients) or protein S deficiency (4 patients). No woman in this group had combined thrombophilia (two or more findings) and all tested negative for aPL. The idiopathic RM control group was composed of 86 patients with three or more consecutive spontaneous RM who tested negative for fertility studies including routine screening for systemic diseases, diabetes mellitus, thyroid dysfunction, polycystic ovary disease, a chromosome assessment of the woman and her partner, uterine abnormalities, endometrial and hormonal luteal phase defects, endometrial and cervical infection and thrombophilia (plasma levels of protein S and C, antithrombin, factor V Leiden, prothrombin G202010A mutation, acquired protein C resistance and aPL). No patient in the idiopathic RM group (0%) and two patients in the thrombophilic genetic defects group (4.8%) presented with thrombotic events in the 12-year follow-up. The thrombophilic genetic defects group had 7.1 thrombotic events per 1,000 patient-years, which is within the range of estimated risk reported in the literature for patients with inherited thrombophilia.
Inherited thrombophilias such as factor V Leiden and prothrombin mutations are widely accepted in daily clinical practice as a cause of RM because of uteroplacental microvascular thrombosis and hypoperfusion, and thus, thromboprophylaxis is recommended in the next pregnancy in these patients. However, some authors question this approach. The use of long-term thromboprophylaxis in patients with RM having genetic thrombophilias and no previous thrombosis is, generally, not recommended. However, patients with RM having genetic thrombophilias may benefit from counseling about avoiding cardiovascular risk factors. As this group of patients have an increased risk of venous thrombosis, the risk factors associated with venous thrombosis (i.e., the use of contraceptive hormonal methods or hormonal replacement therapy) should be avoided.
Thromboembolism in RM Patients With Congenital Thrombophilia
Congenital Thrombophilia and RM Risk
Thrombophilia is defined as a disorder associated with an increased tendency to thrombosis. This may be an acquired or congenital tendency, the latter being due to an inherited defect in the coagulation system. In general, acquired thrombophilia is associated with a predisposition to either venous and/or arterial thrombosis, whereas inherited thrombophilia increases mainly the risk of venous thromboembolism. As previously stressed, several studies have analyzed inherited thrombophilic factors that may predispose to arterial and/or venous thrombosis and their possible association with RM. A meta-analysis of 31 studies revealed an association between recurrent (two or more) fetal loss <13 weeks and Factor V Leiden, activated protein C resistance, prothrombin gene mutation and protein S deficiency. Conversely, it was demonstrated that methylene tetrahydrofolate reductase, protein C and antithrombin deficiencies were not associated with RM. A second meta-analysis of 16 studies, reported an association between RM, defined as two or more losses in the first two trimesters, and maternal carriers of Factor V Leiden or prothrombin gene, compared with those without these inherited thrombophilic mutations. However, in another meta-analysis limited to prospective cohort studies, the pooled OR for pregnancy loss in women with factor V Leyden (absolute risk: 4.2%) compared with women without this mutation (absolute risk: 3.2%) was 1.52 (95% CI 1.06–2.19). This meta-analysis also failed to demonstrate or exclude an association between the prothrombin mutation and pregnancy loss (OR: 1.13; 95% CI 0.64–2.01). Therefore, it remains unclear whether screening for inherited thombophilias is, at present, recommended in all women with pregnancy loss. Other studies have shown that the total number of mutations is a significant risk of RM, suggesting that there may be an additive effect of a number of thrombophilic mutations superimposed on the hypercoagulable state of pregnancy and that would increase the risk of clotting.
Nonpregnant Women With a History of RM May be in a Prothrombotic State Before and After Pregnancy
Although the majority of studies report an increased prevalence of genetic thrombophilic mutations among women with RM, few studies provide evidence of other abnormalities in the hemostatic pathways preceding RM. It has been reported that women with a history of RM at 4–7 of weeks' gestation have an excess of thromboxane production, and between Weeks 8 and 11, they are relatively prostacyclin deficient compared with women with no previous history of pregnancy loss. These changes were greatest among those whose pregnancy ended in abortion. The shift in the thromboxane to prostacyclin ratio in favor of the prothrombotic agent thromboxane may lead to vasospasm and platelet aggregation in the trophoblast, causing the development of microthrombi and placental necrosis.
Other authors reported the cases of two women in whom a significant decrease in the level of protein C and shortening in the rate of fibrinopeptide A generation (indicating activation of coagulation) could be detected several weeks in advance of pregnancy loss. In the second pregnancy of one of these two women, similar hematological changes were documented, but these were reversed by the administration of heparin and the patient went on to deliver at term.
Moreover, our research group recently published that, outside of pregnancy, women with first trimester RM are in a prothrombotic state, manifested by an impaired fibrinolytic response. Other studies have also found impairment of fibrinolysis in RM patients. It has also been described, using global markers of the hemostatic process, that women with RM have increased thrombin generation and an increased maximum clot strength before pregnancy. Furthermore, the authors stressed that women in such a state are at significantly increased risk of miscarriage in future untreated pregnancies. Other studies have also suggested that women with unexplained RM have a hypercoagulable state at baseline consisting in a relative trombomodulin resistance. There is also evidence that circulating placental microparticles are increased in a subgroup of RM patients, indicating an acquired procoagulant state even outside pregnancy.
Do Nonpregnant Patients With Inherited Thrombophilias & a History of RM Have a Higher Risk of Thrombosis?
The hypercoagulable state of RM patients is being increasingly recognized as the cause of long-term health consequences, but few studies have evaluated this issue; thus, several studies have found an increased risk of ischemic heart disease in the subgroup of women with a history of pregnancy loss. A retrospective study of 130,000 women showed that a history of first trimester spontaneous pregnancy loss was associated with a significant increased risk of maternal ischemic heart disease. This risk increased with the number of pregnancy losses. Moreover, among those with three or more pregnancy losses, the risk of death or hospital admission for ischemic heart disease was 2.3-times greater than that among those with no previous history of miscarriage. In contrast, there was no association between therapeutic abortion and the subsequent risk of ischemic heart disease. The authors hypothesized that this may reflect common determinants such as thrombophilic genetic defects or the presence of aPLs. Moreover, the same authors have recently found that there was an increased incidence of ischemic heart disease in the parents of women who experienced multiple miscarriages before their first birth, suggesting that RM and ischemic heart disease may have common pathophysiological pathways and genetic predispositions.
Only one case–control study, performed by us, evaluated the long-term risk of thrombotic events after pregnancy among patients with RM associated with inherited thrombophilic factors different than APS and idiopathic RM. This study evaluated the long-term risk for thromboembolic events after RM in APS patients compared with RM patients with thrombophilias different from APS and idiopathic RM patients. It showed a higher risk, although not statistically significant, of thromboembolic events among patients with RM who tested positive only for genetic thrombophilias compared with patients with idiopathic RM. The former control group of patients in this study presented with thrombophilic genetic defects as the only etiologic factor for their pregnancy losses. It consisted of 42 patients with three or more consecutive spontaneous abortions before 10 weeks gestation. Thrombophilia in this group was defined as factor V Leiden mutation (17 patients), prothrombin G20210A gene mutation (12 patients), protein C deficiency (9 patients) or protein S deficiency (4 patients). No woman in this group had combined thrombophilia (two or more findings) and all tested negative for aPL. The idiopathic RM control group was composed of 86 patients with three or more consecutive spontaneous RM who tested negative for fertility studies including routine screening for systemic diseases, diabetes mellitus, thyroid dysfunction, polycystic ovary disease, a chromosome assessment of the woman and her partner, uterine abnormalities, endometrial and hormonal luteal phase defects, endometrial and cervical infection and thrombophilia (plasma levels of protein S and C, antithrombin, factor V Leiden, prothrombin G202010A mutation, acquired protein C resistance and aPL). No patient in the idiopathic RM group (0%) and two patients in the thrombophilic genetic defects group (4.8%) presented with thrombotic events in the 12-year follow-up. The thrombophilic genetic defects group had 7.1 thrombotic events per 1,000 patient-years, which is within the range of estimated risk reported in the literature for patients with inherited thrombophilia.
Should Nonpregnant Patients With Inherited Thrombophilias and a History of RM Receive Long-term Thromboprofilaxis?
Inherited thrombophilias such as factor V Leiden and prothrombin mutations are widely accepted in daily clinical practice as a cause of RM because of uteroplacental microvascular thrombosis and hypoperfusion, and thus, thromboprophylaxis is recommended in the next pregnancy in these patients. However, some authors question this approach. The use of long-term thromboprophylaxis in patients with RM having genetic thrombophilias and no previous thrombosis is, generally, not recommended. However, patients with RM having genetic thrombophilias may benefit from counseling about avoiding cardiovascular risk factors. As this group of patients have an increased risk of venous thrombosis, the risk factors associated with venous thrombosis (i.e., the use of contraceptive hormonal methods or hormonal replacement therapy) should be avoided.