TR-05504; No of Pages 6 Thrombosis Research xxx (2014) xxx–xxx

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Thrombosis Research journal homepage: www.elsevier.com/locate/thromres

Regular Article

The incidence and risk factors of recurrent venous thromboembolism during pregnancy Päivi J. Galambosi a,⁎, Veli-Matti Ulander a, Risto.J. Kaaja b a b

Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland Turku University and Satakunta Central Hospital, Pori, Finland

a r t i c l e

i n f o

Article history: Received 24 November 2013 Received in revised form 10 April 2014 Accepted 18 April 2014 Available online xxxx Keywords: Venous thromboembolism Low-molecular-weight heparin Pregnancy Thrombophilia Risk factors

a b s t r a c t Introduction: Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode. Materials and Methods: This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis). Results and Conclusions: The incidence of recurrent VTE was 7.6% (n = 28). Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis. In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p b 0.001; group A vs. C: 5.7% vs. 30.0%, p = 0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p = 0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p = 0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p b 0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population. © 2014 Elsevier Ltd. All rights reserved.

Introduction Pregnancy represents a state of acquired thrombophilia leading to a 4 to 5-fold increased risk of venous thromboembolism (VTE) in comparison with nonpregnant women. [1,2] At present VTE is one of the leading causes of maternal mortality in developed countries. [3] Clinical practice guidelines have been developed to identify women who would benefit from thromboprophylaxis. They also provide recommendations for VTE prophylaxis with low-molecular-weight heparin

Abbreviations: VTE, venous thromboembolism; LMWH, low-molecular-weight heparin; BMI, body mass index; ICD, International Classification of Diseases; gw, Gestational week; DVT, Deep vein thrombosis; ACCP, American College of Chest Physicians; VKAs, vitamin K antagonists. ⁎ Corresponding author at: Helsinki University Central Hospital, PL 100, 00029 HUS, Finland. Tel.: +358 408614037; fax: +358 919125165. E-mail address: [email protected] (P.J. Galambosi).

(LMWH) during pregnancy [4–7]. Most recommendations are based on the results of observational studies in which the study populations and treatment protocols have been heterogeneous [8–11]. This has led to different recommendations about the thromboprophylaxis during and after pregnancy [12]. According to the American College of Chest Physicians (ACCP) [13] LMWH is indicated for all pregnant women with prior VTE. In case of one single episode of VTE associated with a transient risk factor, not related to pregnancy or estrogen-use, postpartum prophylaxis for 6 weeks (prophylactic-or intermediate-dose) is recommended. Antepartum and postpartum prophylaxis for 6 weeks (prophylactic-or intermediate-dose) as soon as pregnancy in confirmed is indicated if women have moderate to high risk of recurrence (single unprovoked VTE, pregnancy- or estrogen-related VTE or multiple prior unprovoked VTE not receiving long-term anticoagulation). Antepartum prophylaxis with weight-adjusted treatment dose or 75% of a weightadjusted treatment dose is recommended for women receiving longterm anticoagulation followed by long-term anticoagulants postpartum.

http://dx.doi.org/10.1016/j.thromres.2014.04.026 0049-3848/© 2014 Elsevier Ltd. All rights reserved.

Please cite this article as: Galambosi PJ, et al, The incidence and risk factors of recurrent venous thromboembolism during pregnancy, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.026

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P.J. Galambosi et al. / Thrombosis Research xxx (2014) xxx–xxx

According to the Practice Bulletin clinical management guidelines for Obstetrician-Gynecologists [14] LMWH with prophylactic, intermediate -or weight-adjusted treatment dose is recommended for the women with high-risk thrombophilia with a single previous VTE episode - not receiving long-term anticoagulation therapy. Weightadjusted treatment dose of LMWH for women with two or more previous episodes of VTE (with or without trombophilia) - receiving long-term anticoagulation is recommended. The Obstetric Thromboprophylaxis Swedish Guidelines [15] assesses the VTE risk during pregnancy and the puerperium by means of a scoring system of various risk factors. This guideline recommends high-dose antepartum prophylaxis and at least 12 weeks postpartum prophylaxis to the women at very high risk (i.a. recurrent VTE or antiphospholipid antibodies with VTE). Well-known strong risk factor for pregnancy-related VTE beside prior VTE is thrombophilia [16]. Other significant risk factors include age older than 35 years, heart disease, sicle cell disease, lupus erythematosus, obesity (body mass index [BMI] N 30kg/m2 and smoking [16]. In a study by Jacobsen ante-and postnatal risk factors for VTE have viewed separately and the risk factors differed markedly during antepartum and postpartum. Antenatal age older than 35 years had a moderately increased risk factor for VTE, whereas gestational diabetes and assisted reproduction displayed higher risk for antepartum VTE. Cesarean section and preeclampsia were strong risk factors for postpartum VTE [2]. What is the risk of recurrence of VTE during pregnancy? Some studies limited to women with a history of VTE exist [10, 17–20]. In these studies the risk of antepartum VTE if LMWH was withheld was 2.4–6.2% and the postpartum risk was 6.7–8.3% [10,17,18]. With LMWH prophylaxis the risk of antepartum VTE was 0.0–3.0% and the postpartum risk 0.0–6.3%[10,19,20]. In studies with more heterogeneous populations and with LMWH at least postpartum the risk of recurrent antepartum VTE was 0.24–1.6% and it was 0.36–4.0% postpartum [9,11,21,22]. We conclude, that the populations in these studies differed in terms of risk factors, thrombophilia status and LMWH dosage. In a cohort study of 648 LMWH-treated pregnant women with heterogeneous indications the incidence of recurrent antepartum VTE was 2.5% [23]. Because at present there are only a few reports on recurrent VTE during pregnancy we conducted a substudy in which we closely evaluated a subgroup of 270 pregnant women with at least one previous episode of VTE (369 pregnancies). The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode. Materials and methods This is a substudy of a larger previously published retrospective cohort study on the safety of low-molecular-weight heparin during pregnancy [23]. In this cohort study the subgroup of 270 pregnant women (369 pregnancies) with a history of at least one previous VTE was evaluated closely (Fig. 1). Before subgroup selection one woman with previous VTE was excluded, because the suspected VTE during the index pregnancy was not accurately diagnosed by imaging. All women delivered at ≥ 22 weeks of gestation between February 1994 and January 2007 at the Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Finland. Relevant baseline characteristics of the patients and pregnancy data were retrieved from the electronic hospital database by using The International Classification of Diseases (ICD) codes I74, I81, I82 and D68. The following data were collected: age, gravidity, parity and BMI in connection with the first prenatal care visit of the index pregnancy, amount and types of previous VTEs, duration of pregnancy, primary diseases, thrombophilia and risk factors at first and current VTE. The type, dose, time of initiation and duration of LMWH and other types of concomitant medication were documented.

Fig. 1. Disposition of study participants. No. of pregnancies (no. of women) are shown. The definitions for groups A, B and C are given in the text. 1One woman (two different pregnancies) was analyzed in groups A and C (one pregnancy with successful LMWHprophylaxis and one with recurrence before the aimed LMWH-initiation). 2One woman (two different pregnancies) was analyzed in groups B and C (one pregnancy with recurrence despite LMWH-prophylaxis and one with recurrence before the aimed LMWH-initiation).

Normal prophylactic LMWH doses were standardized: enoxaparin, 40 mg/day or dalteparin, 5000 IU/day. Weight-adjusted treatment doses were defined as full-treatment doses of LMWH (dalteparin, 200 IU/kg/day or enoxaparin, 1 mg/kg twice daily). Intermediate doses were 50% of weight-adjusted treatment doses, i.e. enoxaparin, 1 mg/kg/day or dalteparin, 100 IU/kg/day. The indications for starting antepartum LMWH-prophylaxis preferably as soon as possible during the first trimester (pregnancy test positive) were history of idiopathic VTE, pregnancy-or estrogen-related VTE, multiple prior VTEs and history, VTE in combination with hereditary or acquired thrombophilia. The special attention was paid to the initiation of LMWH prophylaxis as early as possible in women with combined thrombophilias or antithrombin (AT) deficiency. In cases of long-term anticoagulation with vitamin K antagonists (VKAs) it was replaced with LMWH immediately after the positive pregnancy test. Starting LMWH prophylaxis from the late third trimester (gestational weeks [gw] 34-36) was indicated in cases of history of VTE related to pure acquired thrombophilia such as operations (mainly orthopedic) in which the causal factor was not more present during pregnancy. The principal outcome variable was recurrent antepartum VTE. Postpartum data after hospital discharge was unfortunately not available, because patients were lost to follow-up after delivery, as the treatment of postpartum VTEs took place in different departments. Only objectively diagnosed definite VTEs were included (Doppler ultrasonographic examination of lower or upper limb veins, or spiral computer tomography in cases of suspected pulmonary embolism). The population was divided into three different groups: women with at least one previous VTE with no recurrent VTE during the index pregnancy (group A), women who suffered recurrent VTE despite ongoing LMWH prophylaxis (group B) and women with recurrent VTE before the planned LMWH treatment in the index pregnancy (group C). The risk factors, numbers and types of previous VTEs, thrombophilia status, age, BMI, LMWHdosing details and initiation of the LMWH prophylaxis in index pregnancies were compared between the groups. Group A was used as a control group for groups B and C when comparing risk factors in connection with recurrent VTEs. The population was classified retrospectively according to the risk of recurrent VTE (low, moderate or high) based on the ACCP guidelines [13]. The realized initiation-times of thromboprophylaxis was compared to the recommended ones. [13] When comparing variables not

Please cite this article as: Galambosi PJ, et al, The incidence and risk factors of recurrent venous thromboembolism during pregnancy, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.026

P.J. Galambosi et al. / Thrombosis Research xxx (2014) xxx–xxx

dependent on the index pregnancy (number, types and risk factors of previous VTEs and thrombophilia) we included only the last pregnancy, gathering the most amount of information on that particular patient’s pregnancy history. The gestational weeks (gw) were determined from the last normal menstruation and/or by ultrasound. The criteria of the antiphospholipid antibodies carrier was determined as lupus anticoagulants, Anticardiolipin antibody or Anti-β glycoprotein-1 antibody on two or more occasions at least 12 weeks apart without clinical manifestations[24]. Antiphospholipid syndrome is an clinical entity featuring one or more clinical episodes of arterial or venous thrombosis in any tissue or organ with no alternative cause of thrombosis or fetal loss and, and presence of antiphospholipid antibodies[24]. Statistical analyses were undertaken by using the Statistical Package for the Social Sciences Version 21 (SPSS Inc., Chicago, IL, USA). Quantitative variables were reported as means, when the data was normally distributed, medians and range, when the data deviated from the normal distribution. Variables were compared by using Student’s t-test or the Mann–Whitney U-test. Frequencies were compared by using the Chi-squared test, only valid percentage was calculated. All tests were

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two-tailed and p-values b0.05 were considered to be statistically significant. Results After exclusion of one woman, 270 women with at least one previous antepartum VTE (369 pregnancies) were included. Seventy-one women had had two and 9 women had had three previous pregnancies. One woman had had six and one had had seven previous pregnancies. In connection with these 369 pregnancies there were 12 antepartum recurrent VTEs in 10 women (3.3%) before the planned LMWH treatment (group C). Sixteen recurrent antepartum VTEs were diagnosed in 15 women (4.3%) despite LMWH prophylaxis (group B). The overall incidence of recurrent antepartum VTE was 7.6%. One woman suffered recurrent VTE before initiation of the planned LMWH treatment, plus recurrent VTE despite LMWH prophylaxis in another pregnancy (included in groups B and C). Another woman had one pregnancy with successful VTE prophylaxis and one pregnancy with recurrent VTE before LMWH treatment (included in groups A and C).

Table 1 Characteristics of the study population (n = 270; 369 pregnancies), type of first venous thromboembolism (VTE), thrombophilia and associated risk factors Group A: women without recurrent venous thromboembolism VTE, Group B: women with recurrent VTE despite prophylaxis, Group C: women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis. Group A No. of women n (%) No. of pregnancies n (%) Previous VTE episodes 1 ≥2 Long-term anticoagulation with VKAs before the pregnancy n(%) Type of previous VTE n (%) DVT alone (no thrombophilia) PE alone (no thrombophilia) DVT with PE (no thrombophilia) DVT or PE with thrombophilia Atypical location of VTE (±thrombophilia)a Thrombophilia n (%)b FV Leiden heterozygous FV Leiden homozygous Prothrombin G20210A AT III deficiency Protein C or S deficiency Antiphospholipid antibodies Combined abnormalities FVIII Risk factors at first VTE n (%) None or unknown Oral contraceptives Pregnancy Postpartum/After cesarean section Other transient risk factorsc Hormonal risk factors Average BMId BMI N30 n (%) Average age (years) Age N35 years n (%) Average dalteparin dose (IU per day)e Average enoxaparin dose (mg per day)e Initiation of LMWH (gestational weeks) Duration of LMWH treatment (weeks) Initiation of LMWH on gwf 4-5 (moderate risk) Initiation of LMWH on gwf 4-5 (high risk) † ‡ a b c d e f

245 (90.7) 341 (92.4)

Group B

p-value†

15 (5.6) 16 (4.3)

Group C 10 (3.7) 12 (3.3)

b0.001 231 (94.3) 14 (5.7) 18 (7.3)

9 (60.0) 6 (40.0) 7 (46.7)

144 (58.8) 28 (11.4) 14 (5.7) 64 (26.1) 11 (4.5) 235 64 (27.2) 34 (14.5) 2 (0.9) 3 (1.3) 4 (1.7) 9 (3.8) 6 (2.6) 5 (2.1) 1 (0.4)

6 (40.0) 0 1 (6.7) 8 (53.3) 0 15 8 (53.3) 2 (13.3) 1 (6.7) 0 1 (6.7) 1 (6.7) 3 (20.0) 0 0

62 (25.3) 113 (46.1) 17 (6.9) 18 (7.3) 64 (26.1) 148 (60.4) 25.1 49 (14.4) 31.7 79 (23.2) 4760 (n = 312) 51 (n = 23) 15 24 12 (5.0) 22 (38.6)

0 10 (66.7) 3 (20.0) 1 (6.7) 6 (40.0) 14 (93.3) 25.8 3 (18.8) 30.6 1 (6.3) 5420 (n = 12) 80 (n = 2) 7 30 0 7 (58.3)

p-value‡

b0.001

0.022 7 (70.0) 3 (30.0) 0

1.000

0.183 0.382 0.600 0.034

5 (50.0) 1 (10.0) 0 3 (30.0) 1 (10.0)

0.725 0.388

0.040 1.000 0.170 1.000 0.268 0.468 0.012 1.000 1.000

4 (40.0) 2 (20.0)

0.471 0.644

1 (10.0)

0.346

1 (10.0)

0.223

b0.001 0.182 0.097 1.000 0.242 0.011 0.839 0.443 0.406 0.135 0.065 0.08 b0.001 0.005 1.000 0.335

0 2 (20.0) 3 (30.0) 0 2 (20.0) 9 (90.0) 25.3 0 32.1 2 (16.7) 8100 (n = 9) 113 (n = 3) 10 29 0 0

0.746 1.000

0.051 0.035 1.000 0.094 0.838 0.386 0.780 0,741 0.005 0.030 0.003 0.001 1.000 0.572

Group A vs. group B. Group A vs. group C. sinus, subclavian vein, central retinal vein or auricular vein thrombosis. Thrombophilia status determined in 235 women (95.9%) in no recurrent VTE group and 15 women (100%) in recurrent VTE group. immobilization, long flight or train journey. determined in 340 pregnancies (group A) and 14 pregnancies (group B). Six women (group A) and 2 (group B) whose medication was changed from dalteparin to enoxaparin, or vice versa, were excluded from the analysis. gestational weeks.

Please cite this article as: Galambosi PJ, et al, The incidence and risk factors of recurrent venous thromboembolism during pregnancy, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.026

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P.J. Galambosi et al. / Thrombosis Research xxx (2014) xxx–xxx

The characteristics and risk profiles of the study groups are shown in Table 1. When comparing groups A and B together, the incidence of two or more previous VTEs was significantly higher in group B (group A: 5.7% vs. group B: 40.0%, p b 0.001), as was previous VTE in combination with antiphospholipid antibody carrier status (group A:2.6% vs. group B: 20.0%, p = 0.012). Because all women with antiphospolipid antibodies had an episode of vascular thrombosis in the group B, they met the criteria of antiphospolipid syndrome. The incidence of previous VTE in combination with other thrombophilias like Factor V Leiden (group A:14.5% vs. group B:13.3%, p = 1.000) or Prothrombin mutations (group A: 1.3% vs. group B: 0%, p = 1.000) did not differ between the groups. The percentage of women with long-term anticoagulation with VKAs was significantly higher in group B (group A: 7.6% vs. group B: 46.7%, p b 0.001). Hormonal reasons (oral contraceptives, pregnancy, puerperium) related to previous VTE were notable in group B (group A: 60.4% vs. group B: 93.3%, p = 0.011). Every woman in group B had at least one known risk factor related to previous VTE, contrary to group A, in which 25% of previous VTEs were idiopathic, or the data regarding to the possible risk factor related to previous VTE was missing. When comparing groups A and C together, the incidence of two or more previous VTEs was higher in group C (group A: 5.7% vs. group C: 30.0%, p = 0.022), as was previous pregnancy-related VTE (group A: 6.9% vs. group C: 30.0%, p = 0.035). Regarding thrombophilia, there was no statistically significant difference between groups A and C. No differences in age, BMI or LMWH doses were seen between the groups A, B and C. When we classified the women according to the risk of recurrent VTE: 8.8% (n = 30) in group A, 0% in group B and 8.3% (n = 1) in group C were at low risk. The incidence of women at moderate risk was 74.5% (n = 254) in group A, 25% (n = 4) in group B and 66.7% (n = 8) in group C. Almost one fifth of the women (16.7%, n = 57) in group A, majority (75.0%, n = 12) in group B and 25% (n = 3) in group C were at high risk. When comparing the percentages of the women (moderate or high risk) who initiated the LMWH prophylaxis early in the first trimester (gw 4-5) no significant differences existed between to groups A and B (moderate risk; group A: 5.0% vs. group B: 0%, p = 1.000, high risk group A: 38.6% vs. group B: 58.3%, p = 0.335) neither groups A and C (moderate risk; group A: 5.0% vs. group C: 0%, p = 1.000, high risk; group A: 38.6% vs. group C: 0%, p = 0.572). There were sixteen recurrences in 15 women despite LMWH prophylaxis. All cases were deep venous thromboses in a lower limb (left side 56.0%, information on the side is missing in one case). The mean initiation time of LMWH prophylaxis was 7.2 gw (range 4-18 gw) and duration before the recurrence was 15 gw (gestational weeks) (range 4–32 gw). Majority (93.3%, n = 14) of the women had a history of hormonal-related prior VTE. The incidence of multiple prior VTEs was 40.0% (n = 6). One woman with DVT (deep vein thrombosis; left popliteal vein) in the 10th gw experienced recurrence in the 13th gw and was treated by means of thrombolysis followed by weight-adjusted treatment dose of LMWH. Primarily she received only one week’s weight-adjusted treatment dose of LMWH and then 2 weeks of prophylactic dose of LMWH. One event occurred in a women with DVT (left popliteal vein) in the 9th gw and despite weightadjusted treatment dose of LMWH she developed recurrent DVT in the 10th gw (left femoral vein), which necessitated addition to the LMWH dose. Twelve cases of recurrent VTE occurred in 10 women before the planned initiation of LMWH prophylaxis. Nine of these were DVTs in a lower limb (66.7% left-sided), plus one submassive pulmonary embolism (PE) and two cases of subclavian vein thrombosis (one related to In vitro fertilization and the other to protein C deficiency). The mean gw at diagnosis was 10 (range 6–22). Three women were treated by means of thrombolysis following weight-adjusted treatment dose of LMWH, 7 by means of weight-adjusted treatment dose of LMWH, one with intermediate dose LMWH and one with prophylactic-dose

LMWH (local muscle vein thrombosis). Majority (90.0%, n = 9) of these women had a history of hormonal-related prior VTE. The incidence of multiple prior VTEs was 30.0% (n = 3). We also compared the women based on the amount of prior VTEs. The incidence of recurrent VTE was 0% with one prior VTE and prophylactic dose LMWH (n = 287). One tenth (10.1%, n = 29) of those women were at high risk of recurrent VTE. With multiple prior VTEs and different doses of LMWH (n = 37) the incidence of recurrent VTE was 24.3% (n = 9). Majority of those women (91.9%, n = 34) were at high risk of recurrent VTE. Table 2 presents the characteristics of LMWH treatment during and after the index pregnancies. Almost half of the women in group B (46.7%, n = 7) had had long-term anticoagulation therapy with VKAs before the pregnancy. VKAs were replaced with LMWH immediately after the positive pregnancy test. One of the women with long-term anticoagulation had a history of two previous VTEs and one had a history of two previous VTEs and antiphospholipid antibody syndrome together. Four women had long-term anticoagulation because of a history of previous VTE in combination with a high risk thrombophilia (FV Leiden homozygous, antithrombin III deficiency, antiphospholipid antibody syndrome and Protein C defiency). One women with longterm anticoagulation had a history of DVT plus multiple pulmonary embolism in the same time. Thus 29% (n = 2) of the women with longterm anticoagulation had two or more prior VTEs and 57% (n = 4) had high risk thrombophilia. Because of the high-risk profile in group B, 25% had used intermediate and 6.3% weight-adjusted treatment dose of LMWH in the index pregnancy before recurrent VTE. The majority of the women (83.3%) in group C received weight-adjusted treatment dose of LMWH-treatment due to the acute VTE diagnosis before the aimed initiation of LMWH prophylaxis. The mean initiation time of LMWH was earlier in groups B and C (gw 7 and 10 respectively) than in group A (gw 15). In group A only 10.9% (n = 34) of the women at moderate or high risk initiated LMWH early in the first trimester (gw 4-5). Correspondingly 43.8% of the women at high or moderate risk in group B and 0% in group C initiated LMWH in gw 4-5. In group A 4.7% and in group B 12.5% used aspirin as co-medication, mostly because of antiphospholipid antibodies or arterial disease.

Discussion In this retrospective observational cohort study of 270 unique women (369 pregnancies) with at least one previous VTE, we observed Table 2 Characteristics of LMWH medication during the index pregnancies. Group A

Group B

Group C

Type of LMWH n (%) Dalteparin Enoxaparin

318 (93.3) 23 (6.7)

14 (87.5) 2 (12.5)

9 (75.0) 3 (25.0)

Dose of LMWH n (%) Prophylaxis Intermediate Weight-adjusted Initiation of LMWH gw (range) Duration of LMWH gw (range)

310 (90.9) 23 (6.7) 8 (2.3) 15 (4-39)a 24 (0-37)

11 (68.8) 4 (25.0) 1 (6.3) 7 (4-18)b 30 (16-36)

1 (8.3) 1 (8.3) 10 (83.3) 10 (6-22) 29 (18-33)

Co-medicationc Aspirin n (%) Thrombolysis n (%)

16 (4.7) 0

2 (12.5) 1 (6.3)

0 3(25.0)

a+b 7.3% (Group A) and 46.7% (Group B) had long-term anticoagulation with VKAs before the pregnancy, which was replaced with LMWH immediately after the positive pregnancy test. The gestational weeks (gw) were determined from the last normal menstruation. The positive pregnancy test result is detectable at gw 4 (four weeks after the last menstruation). c LMWH was changed to heparin (n = 1) and to orgaran (n = 1) because of allergic reaction.

Please cite this article as: Galambosi PJ, et al, The incidence and risk factors of recurrent venous thromboembolism during pregnancy, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.026

P.J. Galambosi et al. / Thrombosis Research xxx (2014) xxx–xxx

28 antepartum VTEs (7.6%). Twelve recurrences (3.3%) occurred in early pregnancy before initiation of LMWH prophylaxis (group C) and 16 (4.3%) occurred despite LMWH prophylaxis (group B). These incidences are notably more frequent than in previously published literature, implying significant treatment failure in our department. A possible explanation for this might be dosing, that was too conservative in high or moderate risk women, and too late initiation in the 1990s and early 2000s as a result of lack of experience and lack of consistent recommendations concerning LMWH treatment in different risk groups. The principal aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode. The incidence of a history of two or more previous VTEs, previous VTE in connection with antiphospholipid antibody syndrome and previous VTE related to hormonal risk factors was significantly higher among the women with recurrent antepartum VTE compared to women with successful LMWH prophylaxis. The percentage of long-term anticoagulation users was significantly high (46.7%) in the group with recurrent antepartum VTE despite ongoing LMWH prophylaxis, compared to those with successful LMWH prophylaxis. Understandably, these women are partially same than the women with a history of two or more previous VTEs or antiphospholipid antibody syndrome. Risk for recurrence of VTE in these patients could also occur in cases of too low dose of LMWH (intermediated or even with prophylactic dose of LMWH). Unexpectedly the incidence of age N35 years, BMI N30 kg/m2 nor initiation of the LMWH prophylaxis later than early in the first trimester (gw 4-5) did not differ between the groups. We have to point out, that young women with more than one prior VTE are candidates for long-term anticoagulation mainly with VKAs. [25,26] Fortunately these young women have low risk of bleeding. [25] The young women with antiphospholipid antibody syndrome often are on long-term anticoagulation with VKAs. [27] Due to risk for embryopathy this treatment should be replaced to LMWH when pregnancy is achieved (preferably before gw 6). [13] In a study by Pabinger et al. 2005[10] the probability of recurrent antepartum VTE in women with a history of VTE was 6.2% without thrombosis prophylaxis and 0.0% with prophylaxis. The authors concluded that the risk of recurrent VTE was substantial in women with a history of previous VTE. The incidence of recurrent VTE was lower in a study by Brill-Edwards et al. 2000, 2.4% [17], where the population was limited to low-risk women included in mid-pregnancy (mean gw 15 ± 6 at enrollment). Thus early VTEs could have been missed. In addition, women with known thrombophilia excluded and the majority had previous VTE secondary to a temporary risk factor, in contrast to the high-risk population in our study. In a study by Roeters van Lennep et al. [22] the subjects were placed in one of two risk-groups: pregnant women at intermediate risk, who received low-dose LMWH for 6 weeks postpartum, and women at high risk, who received low-dose LMWH antepartum and for 6 weeks postpartum. Of 126 pregnancies, all VTE recurrences occurred in highrisk women, 1.6% antepartum and 4.0% postpartum. In a prospective trial [11] with 810 pregnant women divided into three risk-groups as regards history of VTE and thrombophilic profile, symptomatic VTE occurred in five women (0.6%). All events occurred in high-risk or very high-risk patients with weight-adjusted ante-and postpartum LMWH treatment (2 cases antepartum and 3 postpartum). In another prospective trial [15] the VTE recurrence rate was 1.2% with prophylactic dose LMWH initiated early in the pregnancy or in mid-pregnancy (women with antiphospholipid antibody syndrome, antithrombin deficiency or ongoing anticoagulation therapy excluded). In our study VTE recurrences were concentrated to the high-risk population, 24.3% of women with multiple prior VTEs and different doses of LMWH - correspondingly the incidence of recurrent VTE was 0% in women with one prior VTE and prophylactic dose. Previously cited reports on this issue are studies with heterogeneous populations as regards risk profile, anticoagulation treatment strategy

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and history of thrombosis – which makes comparison demanding. Most of them are observational retrospective studies with emphasis on the incidence of recurrent VTE, and with no controls. A limitation of our study is its retrospective design with possible confounding factors, such as possible smoking during pregnancy, which data was missing due to incomplete medical records. The lack of data concerning possible postpartum recurrent VTEs is also a limitation, as we know the risk is higher in the puerperal period than antepartum. Data on the risk factors at the time of the first VTE in the control group (A) is underreported, which is a limitation as well. Contrary to what we expected, we did not find the significance for BMI N 30 kg/m2 or age N 35 years to be risk factors - indicating the study is probably underpowered for that kind of weaker risk factors. Even though the majority of women in our study initiated the LMWH prophylaxis later than ACCP guideline recommends, no significant differences between the groups A, B and C were observed related to the time of LMWH initiation. More cases are needed to identify the effect of the late initiation of the LMWH prophylaxis to the recurrence rate. Due to small number of patients in the groups B and C we are cautious in interpreting our results regarding risk factors and consider them as preliminary. The strength of our study is the large sample size restricted to women with a history of previous VTE, treated in the same hospital by a few specialists in accordance with unchanging guidelines. Owing to accurate electronic hospital records, data on characteristics, thrombophilia, VTE history and treatment of the study population is nearly complete. As far as we know, no previously published studies with this kind of design exist, which is also a strength. There are two different patient groups of recurrent antepartum VTE, those who get it despite LMWH prophylaxis, and those who get it before the initiation of LMWH prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The high incidence of recurrent VTEs in our cohort was due to insufficient LMWH-prophylaxis. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in these high risk women. Our findings are in line with the current guidelines, which recommend individual risk assessment and even weight-adjusted treatment dose of LMWH in case of high recurrence risk, initiated immediately after a positive pregnancy test result. [13–15] Prospective trials comparing different dosing regimens are still needed. Addendum Data analysis, study design, concept and writing the manuscript was carried out by P. Galambosi. V-M. Ulander and R. Kaaja contributed writing the article. R. Kaaja also contributed to study design and interpretation of data. Conflict of interest Veli-Matti Ulander and Risto Kaaja have participated congresses by the sponsors Leopharma and Pfizer. Acknowledgements The authors thank Ms. Eija Kortelainen for assistance in data collection, Mr. Szabolcs Galambosi for help in data analysis and Mr. Nick Bolton for correction of the language. References [1] Liu S, Rouleau J, Joseph KS, Sauve R, Liston RM, Young D, et al. Epidemiology of pregnancy-associated venous thromboembolism: a population-based study in Canada. J Obstet Gynaecol Can 2009;31:611–20.

Please cite this article as: Galambosi PJ, et al, The incidence and risk factors of recurrent venous thromboembolism during pregnancy, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.026

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[2] Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium–a register-based case-control study. Am J Obstet Gynecol 2008;198(233):1–7. [3] Cantwell R, Clutton-Brock T, Cooper G, Dawson A, Drife J, Garrod D, et al. Saving Mothers' Lives: Reviewing maternal deaths to make motherhood safer: 20062008. The Eighth Report of the Confidential Enquiries into Maternal Deaths in the United Kingdom, 118 Suppl 1. BJOG; 2011. p. 1–203. [4] Kent N, Leduc L, Crane J, Farine D, Hodges S, Reid GJ, et al. Prevention and Treatment of Venous Thromboembolism (Vte) in Obstetrics. J SOGC 2000;22:736–49. [5] Nicolaides AN, Breddin HK, Fareed J, Goldhaber S, Haas S, Hull R, et al. Cardiovascular Disease Educational and Research Trust and the International Union of Angiology. Prevention of venous thromboembolism. International Consensus Statement. Guidelines compiled in accordance with the scientific evidence. Int Angiol 2001;20:1–37. [6] Samama CM, Albaladejo P, Benhamou D, Bertin-Maghit M, Bruder N, Doublet JD, et al. Committee for Good Practice Standards of the French Society for Anaesthesiology and Intensive Care (SFAR). Venous thromboembolism prevention in surgery and obstetrics: clinical practice guidelines. Eur J Anaesthesiol 2006;23:95–116. [7] Lussana F, Dentali F, Abbate R, d'Aloja E, D'Angelo A, De Stefano V, et al. Italian Society for Haemostasis and Thrombosis. Screening for thrombophilia and antithrombotic prophylaxis in pregnancy: Guidelines of the Italian Society for Haemostasis and Thrombosis (SISET). Thromb Res 2009;124:19–25. [8] Dulitzki M, Pauzner R, Langevitz P, Pras M, Many A, Schiff E. Low-molecular-weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 1996;87:380–3. [9] Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, et al. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG 2001;108:1134–40. [10] Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005;3:949-54.[11] Bauersachs RM, Dudenhausen J, Faridi A, Fischer T, Fung S, Geisen U, et al. EThIG Investigators. Risk stratification and heparin prophylaxis to prevent venous thromboembolism in pregnant women. Thromb Haemost 2007;98:1237–45. [11] Okoroh EM, Azonobi IC, Grosse SD, Grant AM, Atrash HK, James AH. Prevention of venous thromboembolism in pregnancy: a review of guidelines, 2000-2011. J Womens Health (Larchmt) 2012;21:611–5. [12] Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. American College of Chest Physicians: VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:

[13] [14] [15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23] [24] [25] [26]

American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:S691–736. James A. Committee on Practice Bulletins-Obstetrics. Practice bulletin no. 123: thromboembolism in pregnancy. Obstet Gynecol 2011;118:718–29. Lindqvist PG, Hellgren M. Obstetric thromboprophylaxis: the Swedish guidelines. Adv Hematol 2011;2011:157483. James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol 2006:1311–5. Brill-Edwards P, Ginsberg JS, Gent M, Hirsh J, Burrows R, Kearon C, et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. Recurrence of Clot in This Pregnancy Study Group. N Engl J Med 2000;343:1439–44. De Stefano V, Martinelli I, Rossi E, Battaglioli T, Za T, Mannuccio Mannucci P, et al. The risk of recurrent venous thromboembolism in pregnancy and puerperium without antithrombotic prophylaxis. Br J Haematol 2006;135:386–91. Rozanski C, Lazo-Langner A, Kovacs MJ. Prevention of Venous Thromboembolism (VTE) Associated with Pregnancy in Women with a Past History of VTE. 51st ASH Annual Meeting and Exposition; 2009. Lindqvist PG, Bremme K, Hellgren M. Working Group on Hemostatic Disorders (Hem-ARG), Swedish Society of Obstetrics and Gynecology. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. Acta Obstet Gynecol Scand 2011;90:648–53. Nelson-Piercy C, Powrie R, Borg JY, Rodger M, Talbot DJ, Stinson J, et al. Tinzaparin use in pregnancy: an international, retrospective study of the safety and efficacy profile. Eur J Obstet Gynecol Reprod Biol 2011;159:293–9. van Lennep JE Roeters, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost 2011;9:473–80. Galambosi PJ, Kaaja RJ, Stefanovic V, Ulander VM. Safety of low-molecular-weight heparin during pregnancy: a retrospective controlled cohort study. Eur J Obstet Gynecol Reprod Biol 2012;163:154–9. Reddy P. Laboratory diagnosis of antiphospholipid syndrome. South Med J 2013;106:439–46. Palareti G. Recurrent venous thromboembolism: what is the risk and how to prevent it. Sci (Cairo) 2012;2012:391734. Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000;27(160):769–74. Ruiz-Irastorza G, Hunt BJ, Khamashta MA. A systematic review of secondary thromboprophylaxis in patients with antiphospholipid antibodies. Arthritis Rheum 2007;57:1487–95.

Please cite this article as: Galambosi PJ, et al, The incidence and risk factors of recurrent venous thromboembolism during pregnancy, Thromb Res (2014), http://dx.doi.org/10.1016/j.thromres.2014.04.026