Pregnancy-related thrombosis and fetal loss in women with thrombophilia Folkeringa, Nienke

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Publication date: 2009 Link to publication in University of Groningen/UMCG research database

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Summary and Discussion

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Pregnancy-related thrombosis and fetal loss in women with thrombophilia

Summary Pregnancy and the puerperium are independent risk factors for venous thromboembolism, which is a major cause of maternal morbidity and mortality. Hereditary thrombophilic defects may increase the overall risk of venous thromboembolism in these conditions. However, their contribution to the absolute risk during pregnancy and the puerperium remains to be established. Most thrombophilic defects are mild risk factors and will have a small effect on the risk of pregnancy related venous thromboembolism, because the latter is low in the normal female population. Women with combinations of thrombophilic defects may be at higher risk of pregnancy related venous thromboembolism than women with a single defect, but there is hardly data available on this issue. Whether thromboprophylaxis should be considered in women with thrombophilic defects during pregnancy and puerperium is still a matter of debate. This is mainly due to the absence of sufficient data on their risk of venous thromboembolism, and the risk reduction by thromboprophylaxis. Nevertheless, thromboprophylaxis is applied in pregnant women, especially when they have a history of venous thromboembolism prior to pregnancy. In addition, it is also considered in women with a thrombophilic defect, but without a history of venous thromboembolism. However, the potential benefit of thromboprophylaxis in women with only a mild thrombophilic defect probably remains small. Strong thrombophilic defects, on the other hand, are associated with a much higher risk of pregnancy related venous thromboembolism. Because these defects are rare, the potential benefit of thromboprophylaxis will be restricted to a small proportion of women. Assuming that thrombophilic defects are involved in the development of placental thrombosis, an association with fetal loss becomes plausible. There is still no convincing evidence, which supports this hypothesis. The pathophysiological mechanisms of early and late fetal loss are different, whereas there may be differences in fetal loss risk associated with various thrombophilic defects, either single or multiple. In clinical practice, antithrombotic drugs, including anticoagulant drugs and aspirin, may be considered to prevent fetal loss in women with prior (recurrent) fetal loss and a thrombophilic defect. However, this application is not evidence based. One should be aware that it may be difficult to perform a properly designed controlled clinical trial in pregnant women, because both women and physicians are reluctant to participate. Moreover, such clinical trials should not only give an answer to the question whether antithrombotic drugs are effective and safe, but should also address the drugs of choice, different dosages, and the time of start and duration of treatment. The here presented studies addressed the absolute risk of pregnancy related venous thromboembolism and fetal loss, respectively, in women with various thrombophilic defects. These defects contained hereditary deficiencies of antithrombin, protein C and protein S, which are established strong risk factors for venous thromboembolism; factor V Leiden and prothrombin G20210A, both known as mild risk

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factors for venous thromboembolism; and high TAFI plasma levels, recently identified as a mild risk factor for venous thrombosis. In a retrospective family cohort study (Chapter 2) we assessed the risk of venous thromboembolism during pregnancy and the puerperium, and the contribution of concomitant thrombophilic defects in families with hereditary antithrombin, protein C or protein S deficiencies. Probands were excluded. Of 222 female relatives, 101 were deficient and 121 non-deficient. Annual incidences of venous thromboembolism were 1.76% in deficient women versus 0.19% in non-deficient women (adjusted relative risk (RR) 11.9; 95% confidence interval (CI), 3.9–36.2). Concomitance of other single and multiple thrombophilic defects increased the risk in deficient women from 1.55% to 2.14% and 2.92%, and in non-deficient women from 0.16% to 0.09% and 0.54%, respectively. Deficient pregnant women were at lower risk (1.37%; 0.80–2.19) than deficient women who had never been pregnant (2.96%; 1.53–5.18); RR 0.5 (0.2– 0.99). This difference was due to the predominance of events related to oral contraceptives in deficient women that had never been pregnant (75%), while 71% of events in deficient women that had had at least one pregnancy were pregnancy-related. This study shows that women with hereditary deficiencies of antithrombin, protein C or protein S are at high risk of pregnancy-related venous thromboembolism. This risk is increased by concomitance of one or more other thrombophilic defects. The absolute risk of fetal loss was assessed in a retrospective family cohort study (Chapter 3). Deficient women were compared to non-deficient relatives. Of 630 women, 317 were evaluable, who had 987 pregnancies (582 in 185 deficient women). Total fetal loss rates were 47% (antithrombin deficiency), 45% (protein C deficiency), 21% (protein S type I deficiency) and 30% (protein S type III deficiency), compared to 32%, 28%, 29% and 27% in non-deficient women, respectively. Adjusted RRs were 2.3 (95% CI, 0.9-6.1), 2.1 (0.9-4.7), 0.7 (0.2-1.8) and 1.1 (0.6-2.0). Differences were mainly due to higher late fetal loss rates in antithrombin deficient (adjusted RR 11.3; 95% CI, 3.0-42.0) and protein C deficient women (adjusted RR 4.7; 95% CI, 1.3-17.4). Cosegregation of factor V Leiden and prothrombin G20210A did not increase the risk, neither in deficient women (29% versus 34%), nor in non-deficient women (24% versus 28%). This was explained by excluding pregnancies after prior venous thromboembolism, because thromboprophylaxis may have influenced outcome of these pregnancies. In excluded women, total fetal loss rates were 39% in deficient women and 0% in nondeficient women. It was concluded that hereditary deficiencies of antithrombin and protein C are associated with a high absolute risk of fetal loss. An additional effect of cosegregation was not demonstrated, maybe because we excluded women with cosegregation, who are at higher risk of venous thromboembolism and thereby we excluded women at high risk of fetal loss.

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Assuming that placental thrombosis may cause fetal loss, anticoagulant treatment might improve pregnancy outcome. Chapter 4 presents the results of an observational family cohort study, which prospectively assessed the effects of anticoagulant drugs on fetal loss rates in women with hereditary deficiencies of antithrombin, protein C or protein S. The cohort contained 376 women (50 probands and 326 deficient or non-deficient relatives). Probands were consecutive deficient patients with venous thromboembolism. Thromboprophylaxis during pregnancy was recommended in deficient women, irrespective of prior venous thromboembolism, and in non-deficient women with prior venous thromboembolism. Outcome of first pregnancy was analyzed in 55 eligible women. Of 37 deficient women, 26 (70%) received thromboprophylaxis during pregnancy, compared with three of 18 (17%) non-deficient women. Fetal loss rates were 0% in deficient women with thromboprophylaxis versus 45% in deficient women without thromboprophylaxis (p=0.001), and 7% in non-deficient women without thromboprophylaxis (p=0.37). The adjusted RR of fetal loss in women who received thromboprophylaxis versus women who did not was 0.07 (95% CI 0.001– 0.7; p=0.02). Our data suggest that anticoagulant treatment during pregnancy reduces the high fetal loss rate in women with hereditary deficiencies of antithrombin or protein C or protein S. The factor V Leiden and prothrombin G20210A mutations have been associated with late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. In Chapter 5 we assessed the outcome of the second pregnancy after a first loss in women with and without either factor V Leiden or prothrombin G20210A. We selected women with a first pregnancy loss out of two family cohorts of first degree relatives. Probands had factor V Leiden or prothrombin G20210A and a history of documented venous thromboembolism or premature atherosclerosis. Ninety-three women had had a first pregnancy loss and became pregnant a second time. Their risk of loss of the subsequent pregnancy was higher than in 825 women with a successful first pregnancy (25 versus 12%, RR, 2.0; 95% CI, 1.4–3.0). The live birth rate of the second pregnancy after an early first loss (≤ 12 weeks of gestation) was 77% (95% CI, 62–87) for carriers and 76% (95% CI, 57–89) for non-carriers (RR 1.0; 95% CI, 0.8–1.3). After a late first loss (> 12 weeks), the live birth rates were 68% (95% CI, 46–85) and 80% (95% CI, 49–94) for carriers and noncarriers, respectively (RR 0.9; 95% CI 0.5–1.3). Women with a first pregnancy loss have a 2-fold increased risk of loss of the subsequent pregnancy, regardless of their carrier status. More importantly, the outcome of the second pregnancy is rather favourable in absolute terms, even for those with mild thrombophilic defects and a late first loss.

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Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase which suppresses fibrinolysis. TAFI is activated by thrombin, mainly in complex with thrombomodulin, and by plasmin. Since activated TAFI (TAFIa) inhibits fibrinolysis, high plasma levels of TAFI may contribute to the development of thrombosis. However, results from previous studies are conflicting. The absolute risk of venous and arterial thromboembolism in subjects with high TAFI levels (>126 U/dL) versus subjects with normal levels, and the contribution of other concomitant thrombophilic defects were assessed in a study, described in Chapter 6. Relatives from four identical cohort studies in families with either deficiencies of antithrombin, protein C or protein S, prothrombin 20210A, high factor VIII levels, or hyperhomocysteinemia were pooled. Probands were excluded. Of 1940 relatives, 187 had high TAFI levels. Annual incidences of venous thromboembolism were 0.23% in relatives with high TAFI levels versus 0.26% in relatives with normal TAFI levels (adjusted RR 0.8; 95% CI, 0.5-1.3). For arterial thrombosis these were 0.31% versus 0.23% (adjusted relative risk 1.4; 95% CI, 0.9-2.2). High levels of factor VIII, IX and XI were observed more frequently in relatives with high TAFI levels. Only high factor VIII levels were associated with an increased risk of venous and arterial thrombosis, independently of TAFI levels. None of these concomitant defects showed interactions with high TAFI levels. In conclusion, high TAFI levels are not associated with an increased risk of venous and arterial thromboembolism in thrombophilic families. The risk of fetal loss in women with high TAFI levels (>126 U/dL) was assessed in women from the same pooled family cohort (Chapter 7). Of 843 included women, 87 had high TAFI levels. Fetal loss rates in women with high TAFI levels (21%) and in women with normal TAFI levels (28%) were comparable; adjusted RR 0.66 (95% CI, 0.38-1.16). The adjusted RR was 0.74 (95% CI, 0.42-1.33) for early fetal loss and 0.54 (95% CI, 0.14-2.09) for late fetal loss. However, numbers of late fetal loss were small. Comparing quartiles of TAFI levels showed no relationship between fetal loss and TAFI levels (p=0.39). This data suggests that high TAFI levels are not associated with an increased risk of fetal loss. Our observation that the risk of fetal loss was lower rather than higher at high TAFI levels might be explained by another mechanism of fetal loss than placental thrombosis.

Discussion The presented studies addressed venous thromboembolism during pregnancy and puerperium, and fetal loss in women with various thrombophilic defects. Assuming that thrombophilic defects are involved in the pathophysiology of venous thromboembolism, as well as fetal loss as result of placental thrombosis, we expected to find a high risk of pregnancy related venous thromboembolism and fetal loss in women with thrombophilic defects that are known as strong thrombotic risk factors.

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In women with mild thrombophilic defects, the risk of these complications of pregnancy should be low. Moreover, treatment with anticoagulants might reduce the risk of both events. Hereditary deficiencies of antithrombin, protein C and protein S were indeed associated with a high risk of pregnancy related venous thromboembolism. This risk was even higher in deficient women with one or more concomitant thrombophilic defects. However, of these deficiencies, protein S deficiency showed not to be a risk factor for fetal loss, in contrast with deficiencies of antithrombin and protein C. Concomitance of other thrombophilic defects apparently did not influence the risk of fetal loss. The latter finding was attributed to the exclusion of women, who were at highest risk of venous thromboembolism and might have received anticoagulant treatment during pregnancies after a prior episode of venous thromboembolism. High TAFI levels were recently identified as a mild risk factor for venous thromboembolism. As we could not confirm this finding from previous studies, it was not remarkable that high TAFI levels were not associated with an increased risk of fetal loss. To the contrary, our data suggests that high TAFI levels may protect against fetal loss, although this effect did not achieve the level of statistical significance. A possible explanation for a protective effect may be the inhibition of generation of fibrin degradation products and thereby inhibition of apoptosis of trophoblast cells in the placenta. It should be considered that there are differences in pathophysiology of fetal loss and venous thromboembolism in women with hereditary thrombophilic defects. If apoptosis of trophoblast cells is induced by fibrin degradation products, it may contribute to the high risk of fetal loss in women with thrombophilic defects, because these women reveal generation of more thrombin and, consequently, fibrin. Other cytoprotective properties of antithrombin, protein C and protein S may also contribute to fetal loss in deficient women. We showed a low risk of fetal loss in deficient women, who received anticoagulants to prevent venous thromboembolism during pregnancy. Indeed, our study was not designed as a randomized controlled clinical trial. However, whether a proper clinical trial can be performed is questionable. Awaiting convincing evidence, available evidence should be used in clinical practice, weighing the possible benefits and risks of anticoagulant treatment against no-treatment in individual women.

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