Nienke Folkeringa

Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage

BACKGROUND Aspirin and low-molecular-weight heparin are prescribed for women with unexplained recurrent miscarriage, with the goal of improving the rate of live births, but limited data from randomized, controlled trials are available to support the use of these drugs. METHODS In this randomized trial, we enrolled 364 women between the ages of 18 and 42 years who had a history of unexplained recurrent miscarriage and were attempting to conceive or were less than 6 weeks pregnant. We then randomly assigned them to receive daily 80 mg of aspirin plus open-label subcutaneous nadroparin (at a dose of 2850 IU, starting as soon as a viable pregnancy was demonstrated), 80 mg of aspirin alone, or placebo. The primary outcome measure was the live-birth rate. Secondary outcomes included rates of miscarriage, obstetrical complications, and maternal and fetal adverse events. RESULTS Live-birth rates did not differ significantly among the three study groups. The proportions of women who gave birth to a live infant were 54.5% in the group receiving aspirin plus nadroparin (combination-therapy group), 50.8% in the aspirin-only group, and 57.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, -2.6 percentage points; 95% confidence interval [CI], -15.0 to 9.9; aspirin only vs. placebo, -6.2 percentage points; 95% CI, -18.8 to 6.4). Among 299 women who became pregnant, the live-birth rates were 69.1% in the combination-therapy group, 61.6% in the aspirin-only group, and 67.0% in the placebo group (absolute difference in live-birth rate: combination therapy vs. placebo, 2.1 percentage points; 95% CI, -10.8 to 15.0; aspirin alone vs. placebo -5.4 percentage points; 95% CI, -18.6 to 7.8). An increased tendency to bruise and swelling or itching at the injection site occurred significantly more frequently in the combination-therapy group than in the other two study groups. CONCLUSIONS Neither aspirin combined with nadroparin nor aspirin alone improved the live-birth rate, as compared with placebo, among women with unexplained recurrent miscarriage. (Current Controlled Trials number, ISRCTN58496168.)

Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women

Hereditary thrombophilia is associated with an increased risk of fetal loss. Assuming that fetal loss is due to placental thrombosis, anticoagulant treatment might improve pregnancy outcome. In an observational family cohort study, we 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 tromboembolism. 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 analysed 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 (P = 0·001) and 7% in non‐deficient women without thromboprophylaxis (P = 0·37). The adjusted relative risk of fetal loss in women who received thromboprophylaxis versus women who did not was 0·07 (95% confidence interval 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, protein C or protein S.

High risk of pregnancy-related venous thromboembolism in women with multiple thrombophilic defects

Pregnancy is associated with an increased risk of venous thromboembolism, which probably varies according to the presence of single or multiple thrombophilic defects. This retrospective family cohort study assessed the risk of venous thromboembolism during pregnancy and 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]. 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 women were at lower risk (1·37%; 0·80–2·19) than deficient women that 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. In conclusion, 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 multiple additional thrombophilic defects.

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations

Summary.  Background: The factor V Leiden (FVL) and prothrombin 20210A (PTm) mutations are associated with single late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. Objective: To assess the pregnancy outcome of the second pregnancy after a first loss in women with and without either FVL or PTm mutations. Methods: We selected women with a first pregnancy loss out of two family cohorts of first degree relatives of probands with FVL or PTm mutations and a history of documented venous thromboembolism or premature atherosclerosis. Results: 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 vs. 12%, relative risk (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 non‐carriers, respectively (RR 0.9, 95% CI 0.5–1.3). Conclusions: 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 favorable in absolute terms, even for those with thrombophilia and a late loss, which raises concern regarding the risks and presumed benefits of anticoagulant therapy in these women.

Absolute risk of venous and arterial thromboembolism in thrombophilic families is not increased by high thrombin-activatable fibrinolysis inhibitor (TAFI) levels.

High levels of thrombin-activatable fibrinolysis inhibitor (TAFI) are a supposed risk factor for thrombosis. However, results from previous studies are conflicting. We assessed 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. 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 1,940 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 relative risk [RR] 0.8; 95% confidence interval [CI], 0.5-1.3). For arterial thrombosis these were 0.31% versus 0.23% (adjusted RR 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 interaction with high TAFI levels. High TAFI levels were not associated with an increased risk of venous and arterial thromboembolism in thrombophilic families.

Thrombin activatable fibrinolysis inhibitor (TAFI) is not associated with fetal loss, a retrospective study

a Division of Haemostasis, Thrombosis and Rheology, University Medical Centre Groningen, The Netherlands b Department of Obstetrics and Gynaecology, University Medical Centre Groningen, The Netherlands c Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands d Department of Hematology, University Hospital Maastricht, Maastricht, The Netherlands e Department of Clinical Epidemiology and Medical Technology Assessment, University Hospital Maastricht, Maastricht, The Netherlands

Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study

Please cite this paper as: Korteweg F, Folkeringa N, Brouwer J, Erwich J, Holm J, van der Meer J, Veeger N. Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study. BJOG 2012;119:422–430.

Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study: Fetal loss and multiple thrombophilic defects

Please cite this paper as: Korteweg F, Folkeringa N, Brouwer J, Erwich J, Holm J, van der Meer J, Veeger N. Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study. BJOG 2012;119:422–430.

Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects

Please cite this paper as: Korteweg F, Folkeringa N, Brouwer J, Erwich J, Holm J, van der Meer J, Veeger N. Fetal loss in women with hereditary thrombophilic defects and concomitance of other thrombophilic defects: a retrospective family study. BJOG 2012;119:422–430.

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutation: reply to a rebuttal

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