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Treatment of deep venous thrombosis with low-molecular-weight heparin during pregnancy
Thrombosis Research 106 (2002) 13 – 17
Regular Article
Treatment of deep venous thrombosis with low-molecular-weight heparin during pregnancy Veli-Matti Ulander, Pauliina Stenqvist, Risto Kaaja * Department of Obstetrics and Gynaecology, Helsinki University Hospital, Haartmaninkatu 2, Helsinki 00290, Finland Received 21 December 2001; received in revised form 14 March 2002; accepted 8 May 2002 Accepting Editor: S. Schulman
Abstract Low-molecular-weight (LMW) heparins have been shown to be at least as effective as unfractionated (UF) heparin in the treatment of deep venous thrombosis (DVT) in nonpregnant subjects. LMW heparins have been shown to be safe when used during pregnancy as they do not cross the placenta. Up to now, they have been used mainly in thromboprophylaxis during pregnancy and rarely in the treatment of acute DVT in pregnant women. In a prospective observational study, we compared the effectiveness and safety of the LMW heparin, dalteparin, with UF heparin in the initial treatment (first week) of DVT during pregnancy. After confirmation of DVT by ultrasonography, 10 women were treated with UF heparin (25,430 IU/day, mean) and 21 women with dalteparin (16,000 IU/day, mean) for 7 days and, thereafter, all women were given treatment doses of LMW heparin for another 2 weeks. The dose was then gradually decreased and kept at a high prophylactic dose until delivery. One patient in the dalteparin group had recurrence of DVT 2 weeks after starting the treatment. No differences were observed between the groups in symptoms or bleeding complications during pregnancy and delivery. Our results indicate that LMW heparin is as effective and safe as UF heparin for the first week of treatment, but LMW heparin has the advantage of being easily administered and few laboratory controls are required. D 2002 Elsevier Science Ltd. All rights reserved. Keywords: Low-molecular-weight heparin; Dalteparin; Treatment; Pregnancy; Deep venous thrombosis
1. Introduction Venous thromboembolism (VTE) is the greatest single cause of death in pregnant women in developed countries [1]. Pulmonary embolism (PE) is estimated to cause more than 10 maternal deaths in pregnancy every year in the UK [2]. Low-molecular-weight (LMW) heparins [3,4], like unfractionated (UF) heparin [5], do not cross the placenta and are at present widely used for VTE prophylaxis during pregnancy [6– 9]. Based on the results of large clinical trials in nonpregnant subjects, LMW heparins are at least as effective and safe as UF heparin [10,11] for treatment of VTE. Up to now, no comparative studies have been published on the first week treatment of deep venous thrombosis
Abbreviations: LMW heparin, low-molecular-weight heparin; UF heparin, unfractionated; DVT, deep venous thrombosis; US, ultrasound; VTE, venous thromboembolism; PE, pulmonary embolism. * Corresponding author. Tel.: +358-9-4717-2850; fax: +358-9-47172812. E-mail address: [email protected] (R. Kaaja).
(DVT) with LMW heparins during pregnancy; therefore, we decided to compare UF and LMW heparins in an open observational study.
2. Patients and methods 2.1. Patients Thirty-one patients with thromboembolic disease were enrolled in the study. These patients consisted of all pregnant women treated for acute DVT in one unit (Department of Obstetrics and Gynaecology, Helsinki University Hospital) from 1994 to 2000. This study was approved by the local Ethics Committee. The patients gave informed consent. The first 10 consecutive patients received intravenous UF heparin for treatment of acute DVT, and the next 21 patients received LMW heparin (dalteparin). Most patients (29) had DVT in the lower limbs, but two had DVT in the upper limbs. In all cases, diagnosis was based on ultra-
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V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17
sonography (US; colour Doppler). US examination was repeated if symptoms reoccurred or there was suspicion of recurrence in the affected limb. The initial treatment length was 7 days in both groups. In the UF heparin group, a bolus of 5000 IU was injected and, thereafter, the daily dose was 15,000 IU/500 ml infused at 36 ml/h. Treatment was followed with repeated plasma APTT measurements (every 6 h) and the target value was 70 –100 s. The next 21 patients were treated subcutaneously with a LMW heparin (dalteparin). We used 15% higher treatment doses of dalteparin than recommended by the manufacturer during the first week of treatment to achieve the target level of anti-Xa of 0.5 IU/ml before injection and 1 – 1.5 IU/ml 3 h after injection. Thereafter, the dose was decreased to full treatment doses (200 IU dalteparin/kg divided into two doses) for 2 weeks for patients in both groups. In the beginning of the fourth week, the dose was decreased and given once daily to get an anti-Xa level of 0.7 IU/ml 3 h post injection and at the end of pregnancy, 0.5 – 0.6 IU/ml. Symptomatic patients received higher doses (full treatment doses) with twice-daily injections. Symptoms and anti-Xa values did not always correlate with each other and, when defining dalteparin dose, we were guided by the symptoms. Increasing the dose generally relieved the symptoms, except in one case with recurrence. The LMW heparin doses were halved during delivery day in both groups. The decision to give epidural anaesthesia was made by the anaesthesiologist. After delivery, warfarin treatment was given for a duration of 6 months for proximal DVTs and 3 months for distal DVTs. LMW heparin was discontinued when INR was two to three for at least 2 days. 2.2. Efficacy and safety Efficacy of treatment was evaluated daily by measuring the circumference of the affected limb at mid-femoral and crural level and by asking about occurrence of postthrombotic symptoms (pain, oedema, physical limitations and paraesthesia). The reexamination with US was performed if there was worsening of these symptoms. Pulmonary ventilation scan was performed only in cases with clinical suspicion of PE. Platelet levels were followed during both acute treatment and prophylaxis. Bleeding (haematomas, haematuria, gingival and vaginal bleeding) was recorded. 2.3. Haemostatic tests APTT was measured with ACL Futura and ACL 2000 equipment (Instrumentarium Laboratory, Helsinki, Finland) and the reagent PTT AUTOMATE (Diagnostica Stago, Paris, France). Anti-Xa measurements were carried out by use of a chromogenic substrate assay based on inhibition of bovine factor Xa by heparin-activated antithrombin III (HEPRN method, DuPont aca IN analyser; DuPont, Wilmington, DE,
USA). APTT (normal range 24 –34 s) was measured by Platelin LS (Organon Teknika, Boxtel, the Netherlands). All patients were analysed for hereditary and acquired thrombophilia. Factor V Leiden was analysed by the method described by Bertina et al. [12], and G20210A prothrombin mutation by the method described by Poort et al. [13]. Lupus anticoagulant was studied by using the Russell Viper Venom Test, with pooled normal plasma in confirmatory tests, anticardiolipin IgG (normal if < 10 GPL) by QUACA Anti-Cardiolipin Elisa (Cheshire Diagnostics, Great Britain), antithrombin by Coamatic AT 400 (normal range 84– 108% of normal control; Chromogenix, Mo¨lndal, Sweden), protein C (normal range 67– 131% of normal control) by Coamatic Protein C (Chromogenix), APC ratio (normal if > 2) by using kits from Chromogenix and protein S (normal range 43 – 126% of normal control) by Liatest Protein S (Diagnostica Stago, Asnieres, France). 2.4. Statistical analysis Continuous variables are presented as means ( F S.D.) and were analyzed by using Student’s t test or the Mann – Whitney test. Categorical data were tested by the v2 test and Fisher’s exact probability test. A probability value of < .05 was considered statistically significant.
3. Results There were no statistical differences in baseline maternal or neonatal data between the groups (Table 1). The time point in pregnancy for diagnosis of DVT tended to be earlier in the LMW heparin group (21 weeks of gestation) than in the UF heparin group (27 weeks of gestation), but the difference did not reach statistical significance. The time from the beginning of symptoms to diagnosis (diagnostic delay) tended to be relatively long in both treatment groups (8 days in the UF heparin group and 7 days in the LMW heparin group; Table 2). In 23 (74%) of all cases, DVT was in the left leg and in 24 (77%) cases, it was in the proximal region of a lower limb (Table 2). There were no statistical differences in thrombophilic data or localisation of the DVT between the groups (Table 2). No PE was detected. It was suspected in three patients using dalteparin (n = 1) and UF heparin (n = 2) during the first week of treatment, but lung scans gave negative results in all three. A 40-year-old woman had had two spontaneous abortions and one normal pregnancy. During her fourth pregnancy, she had superficial thrombophlebitis of the left leg at 25th gestational week and 3 weeks later, she developed a massive venous thrombosis of the same leg, reaching the femoral vein. She was given dalteparin 10,000 IU twice daily for 1 week and thereafter 10,000 IU once daily. Her weight was 80 kg. After 1 week with this reduced dose, her
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17
leg became painful and more swollen and on US examination, slight progression of the thrombosis could be seen. Increasing dalteparin dose to 10,000 IU twice daily for 2 days did not improve the symptoms and, therefore, the patient was given UF heparin intravenously (treatment doses) for 5 days and thereafter dalteparin 10,000 twice daily until the end of pregnancy. She had some postthrombotic symptoms (pain in the leg after 100 m of walking) during rest of her pregnancy. This patient was heterozygous for Factor V Leiden. The treatment data are presented in Table 3. There was no difference in the number of patients having complaints of postthrombotic symptoms in the affected limb after treatment. In 17/31 of the patients (55%), US was repeated (6 in the UF and 11 in LMWH groups) 2– 6 weeks after starting the treatment. In one case (with failure, cf. above), slight progression of the thrombosis could be observed. Thrombocytopenia was not found in either group. One patient in the LMW heparin group had haematuria, but this Table 1 Demographic data
n Age, year, mean (S.D.) BMI, kg/m2, mean (S.D.) Parity: nulliparas, n Maternal diseases, na History of spontaneous abortions, n Pregnancy complications, n Preeclampsia IUGRb Abortion Delivery weeks, mean (S.D.) Mode of delivery; vaginal/Caesarian section, n Birth weight, g, mean (S.D.) Range Apgar at 1 min, mean (S.D.) Range Bleeding during delivery, ml, mean (S.D.) Range Abnormal bleeding (>1000 ml), n Delivery complicationsc, n Epidural, n a
UF heparin
LMW heparin
P
10 31.0 (5.7) 23.4 (4.7) 5 0 1
21 31.6 (4.3) 25.0 (4.6) 16 5 5
NS NS NS NS NS
0 0 0 39.3 (1.1) 8/2
1 1 1 38.7 (3.7) 16/4
NS NS NS NS NS
3575 (352) (2810 – 4050) 8.2 (1.1) (7 – 9) 425 (216)
3516 (939) (340 – 4670) 8.8 (1.3) (4 – 10) 597 (554)
NS
(200 – 1000) 1
(100 – 2200) 2
NS
0
4
NS
5
6
NS
NS NS
Asthma bronchiale, chronic hypertension, arthritis rheumatoides, hypothyreosis, LED and sarcoidosis. b Intrauterine growth retardation ( < mean 2 S.D.), NS = not significant. c One difficulty with Caesarian section due to fibroids, one perineal rupture, one intrapartum asphyxia, one hematoma and infection after Caesarian section.
15
Table 2 Thrombophilic data and localisation of DVT during pregnancy
n Weeks of gestation at diagnosis, mean (S.D.) Personal history of DVT, n (%) Family history of DVT, n (%) Hereditary thrombophilia, n (%) Acquired thrombophilia, n (%) Localisation of DVT, n (%) Lower limb, proximal Lower limb, distal Upper limb Lower left/lower right limb
UF heparin
LMW heparin
P
10 27.0 (8.5)
21 21.0 (9.8)
NS
1 (10)
4 (19)
NS
3 (33)
9 (43)
NS
2 (20)
7 (33)
NS
0 (0)
1 (5)
NS
8 (80) 2 (20) 0 (0) 8/2
16 (76) 3 (14) 2 (10) 15/4
NS NS NS NS
occurred during the prophylactic phase. It disappeared spontaneously after decreasing the dose of LMW heparin. There were no congenital anomalies of infants except for one case of hereditary Treacher –Collins syndrome and one case of sacral dimple, which was not associated with use of heparin. One infant died after premature delivery at 23 gestational weeks (birth weight of 340 g) as a result of severe preeclampsia. The mother had a positive lupus anticoagulant test result and DVT 9 weeks before premature delivery. The decision to give epidural anaesthesia was made by the anaesthesiologist on duty. His/her decision depended mainly on the time and dose of the last LMW heparin injection (given if time length after last dose was at least 12 h and corresponding dose did not exceed 5000 IU of dalteparin), platelet count and possible use of nonsteroidal anti-inflammatory agents. Epidural anaesthesia was given to 35% of our patients without local bleeding.
4. Discussion The established acute phase treatment for DVT during pregnancy has been intravenous heparin [14] (Table 3). There are no randomised studies on the treatment of DVT during pregnancy comparing LMW heparin with UF heparin. According to this observational comparative study, the LMW heparin dalteparin seems to be as good as UF heparin in the acute phase (first week) of treatment of DVT in terms of safety and efficacy. As the number of patients was low (31) and the study was not randomised, we have to interpret our results cautiously. We used higher treatment doses for LMW heparin (dalteparin) than recommended by the manufacturer during the first week of treatment to achieve the target level of antiXa of 0.5 IU/ml before injection and 1 – 1.5 IU/ml 3 h after
16
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17
Table 3 Treatment of acute DVT during pregnancy
n Gestational weeks, mean (S.D.) Delay in diagnosis, days, mean (S.D.)a Dose for acute treatment, IU/24 h, mean (S.D.) Dose for LMW heparin prophylaxis, IU/24 h, mean (S.D.) Failures of treatment, n Symptoms after treatment, n (%) Recanalised thrombi in US, n Haemorrhagic complications during treatment
UF heparin
LMW heparin
P
10 27 (9.9)
21 20 (9.7)
NS
7.9 (9.3)
6.8 (8.1)
NS
25,430 (3786)
16,000 (3491)
NA
7777 (1954)
7875 (2470)
NS
0 4 (40)
1 (recurrent DVT) 8 (38)
NS NS
1/6 0
7/11 0
NS NS
a Time from onset of symptoms to diagnosis and treatment. NA = not applicable; NS = not significant.
injection. Thereafter, the dose was decreased to full treatment doses for 2 weeks for patients in both groups. At the beginning of the fourth week, the dose was decreased and given once daily to achieve an anti-Xa level of 0.7 IU/ml 3 h postinjection and at the end of pregnancy 0.5– 0.6 IU/ml. With symptomatic patients (n = 4), we gave higher doses (full treatment doses) with twice-daily injections. Our doses after 3 weeks of full treatment doses were lower than earlier recommendations suggesting full treatment doses until the end of pregnancy [15]. Some clinicians give full treatment doses for 6 weeks and thereafter high prophylactic doses (half of the full dose) (Dr. M. de Swiet, personal communication). The optimal dose of LMW heparin for secondary prophylaxis remains to be defined. Evaluation of the efficacy of treatment of DVT during pregnancy can be problematic, especially in cases of PE. Lung scans and spiral CT scans for asymptomatic women are regarded as unethical and D-dimer measurements during pregnancy give unreliable results [16]. On the other hand, clinical suspicion of PE is more rarely confirmed radiologically during pregnancy than outside pregnancy [16]. As PE is still the most common cause of maternal death in pregnancy [17,18], all clinically suspected cases should be confirmed radiologically. In this study, PE was suspected in three patients but lung scans gave negative results in all three. Most of the DVTs in this study were proximal and left-sided, regions known to be more likely to be susceptible to embolism [16]. The efficacy of treatment can also be evaluated by assessing postthrombotic symptoms of the patient and the patency of thrombotic veins. DVT is often massive and proximal during pregnancy and, therefore, the risk of developing venous insufficiency or postthrombotic syndrome in the long term may be higher than in the nonpregnant state [17]. There was no difference in the occurrence of postthrombotic symptoms (pain, physical
limitations, oedema) after either of the heparin treatments during pregnancy (time from symptoms to beginning of treatment). Delayed diagnosis (time from symptoms to beginning of treatment) did not result in increased frequency or altered quality of postthrombotic symptoms and the mean delay was equal in both treatment groups (1 week). In 55% of the patients, US was repeated (6 in the UF heparin group and 11 in the LMW heparin group). The recanalisation rate of the thrombotic vein tended to be higher in the LMW heparin group than in the UF heparin group, but as this evaluation was offered only to patients with symptoms, we cannot give any definitive answer as to whether or not LMW heparin is better in this sense. One woman with progression of DVT (US) after 2 weeks of treatment and with postthrombotic symptoms thereafter was the first to be treated with dalteparin during pregnancy. She was heterozygous for the Factor V Leiden mutation and her dalteparin dose was reduced too quickly (after 2 weeks of treatment) to high prophylactic dose (10,000 IU once daily). After this case, we prolonged the treatment period with full doses to 3 weeks. There were no bleeding complications or heparininduced thrombocytopenia during the treatment period in either of the heparin groups. Although LMW heparins have been shown to be associated with reduced heparin-induced thrombocytopenia [19], our small number of patients prevents us from drawing any relevant conclusions. Secondary thromboprophylaxis was the same (LMW heparin) in all our patients because of the higher risk of osteoporosis with UF heparin compared with LMW heparin in long-term use [20,21]. Epidural anesthesia for delivery was given in 35% of the patients. The decision of the mode of delivery was made with obstetric factors in both groups. Delivery and neonatal data did not differ between the groups and were the same as observed in healthy women at our unit. In conclusion, subcutaneously given LMW heparin seems to be a good and practical substitute for treatment with laborious intravenous UF heparin during the first week of pregnancy. The dose of LMW heparin thereafter until the end of the pregnancy remains to be defined. References [1] Gates S. Thromboembolic disease in pregnancy. Curr Opin Obstet Gynecol 2000;12:117 – 22. [2] Greer IA. Epidemiology, risk factors and prophylaxis of venous thromboembolism in obstetrics and gynaecology. Bailliere’s Clin Obstet Gynaecol 1997;11:403 – 30. [3] Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res 1984;34:557 – 60. [4] Forestier F, So´le Y, Aiach M, Ge´las MA, Daffos F. Absence of transplacental passage of Fragmin during the second and third trimester of pregnancy. Thromb Haemost 1992;67:180 – 1. [5] Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965;93:570 – 3.
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17 [6] Greer IA, de Swiet M. Thrombosis prophylaxis in obstetrics and gynaecology. Br J Obstet Gynaecol 1993;100:37 – 40. [7] Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1995;108:305S – 11S (Suppl). [8] Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108 – 14. [9] Pettila¨ V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 1999;96:275 – 82. [10] Dolovich L, Ginsberg J, Douketis J, Holbrook A, Cheah G. A metaanalysis comparing low molecular weight heparin to unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000;160:181 – 8. [11] Gould M, Dembitzer A, Doyle R, Hastie T, Garper A. Low-molecularweight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomised, controlled trials. Ann Intern Med 1999;130:800 – 9. [12] Bertina RM, Koeleman BPC, Koster T, Rosendal FR, Dirven RJ, De Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64 – 7. [13] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3V-untranslated region of the prothrombin gene is
[14] [15] [16]
[17]
[18] [19]
[20] [21]
17
associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698. Lowe G. Treatment of venous thrombo-embolism. Clin Obstet Gynaecol 1997;11:511 – 21. Ginsberg JS, Greer I, Hirsch J. Use of antithrombotic agents during pregnancy. Chest 2001;119(Suppl 1):122S – 31S. Bombeli T, Raddatz-Mueller P, Fehr J. Coagulation activation markers do not correlate with the clinical risk of thrombosis in pregnant women. Am J Obstet Gynecol 2001;184(3):382 – 9. Greer I. Epidemiology, risk factors and prophylaxis of venous thromboembolism in obstetrics and gynaecology. Clin Obstet Gynaecol 1997;11:403 – 30. Greer I. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353:1258 – 65. Warkentin TE, Levine MN, Hirsh J. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995;332:1330 – 5. Eldor M. Thrombophilia, thrombosis and pregnancy. Thromb Haemost 2001;86:104 – 11. Pettila¨ V, Leinonen P, Markkola A, Hiilesmaa V, Kaaja R. Postpartum bone mineral density in women treated for thromboprophylaxis with unfractionated heparin or LMW heparin. Thromb Haemost 2002; 87:182 – 6.
Regular Article
Treatment of deep venous thrombosis with low-molecular-weight heparin during pregnancy Veli-Matti Ulander, Pauliina Stenqvist, Risto Kaaja * Department of Obstetrics and Gynaecology, Helsinki University Hospital, Haartmaninkatu 2, Helsinki 00290, Finland Received 21 December 2001; received in revised form 14 March 2002; accepted 8 May 2002 Accepting Editor: S. Schulman
Abstract Low-molecular-weight (LMW) heparins have been shown to be at least as effective as unfractionated (UF) heparin in the treatment of deep venous thrombosis (DVT) in nonpregnant subjects. LMW heparins have been shown to be safe when used during pregnancy as they do not cross the placenta. Up to now, they have been used mainly in thromboprophylaxis during pregnancy and rarely in the treatment of acute DVT in pregnant women. In a prospective observational study, we compared the effectiveness and safety of the LMW heparin, dalteparin, with UF heparin in the initial treatment (first week) of DVT during pregnancy. After confirmation of DVT by ultrasonography, 10 women were treated with UF heparin (25,430 IU/day, mean) and 21 women with dalteparin (16,000 IU/day, mean) for 7 days and, thereafter, all women were given treatment doses of LMW heparin for another 2 weeks. The dose was then gradually decreased and kept at a high prophylactic dose until delivery. One patient in the dalteparin group had recurrence of DVT 2 weeks after starting the treatment. No differences were observed between the groups in symptoms or bleeding complications during pregnancy and delivery. Our results indicate that LMW heparin is as effective and safe as UF heparin for the first week of treatment, but LMW heparin has the advantage of being easily administered and few laboratory controls are required. D 2002 Elsevier Science Ltd. All rights reserved. Keywords: Low-molecular-weight heparin; Dalteparin; Treatment; Pregnancy; Deep venous thrombosis
1. Introduction Venous thromboembolism (VTE) is the greatest single cause of death in pregnant women in developed countries [1]. Pulmonary embolism (PE) is estimated to cause more than 10 maternal deaths in pregnancy every year in the UK [2]. Low-molecular-weight (LMW) heparins [3,4], like unfractionated (UF) heparin [5], do not cross the placenta and are at present widely used for VTE prophylaxis during pregnancy [6– 9]. Based on the results of large clinical trials in nonpregnant subjects, LMW heparins are at least as effective and safe as UF heparin [10,11] for treatment of VTE. Up to now, no comparative studies have been published on the first week treatment of deep venous thrombosis
Abbreviations: LMW heparin, low-molecular-weight heparin; UF heparin, unfractionated; DVT, deep venous thrombosis; US, ultrasound; VTE, venous thromboembolism; PE, pulmonary embolism. * Corresponding author. Tel.: +358-9-4717-2850; fax: +358-9-47172812. E-mail address: [email protected] (R. Kaaja).
(DVT) with LMW heparins during pregnancy; therefore, we decided to compare UF and LMW heparins in an open observational study.
2. Patients and methods 2.1. Patients Thirty-one patients with thromboembolic disease were enrolled in the study. These patients consisted of all pregnant women treated for acute DVT in one unit (Department of Obstetrics and Gynaecology, Helsinki University Hospital) from 1994 to 2000. This study was approved by the local Ethics Committee. The patients gave informed consent. The first 10 consecutive patients received intravenous UF heparin for treatment of acute DVT, and the next 21 patients received LMW heparin (dalteparin). Most patients (29) had DVT in the lower limbs, but two had DVT in the upper limbs. In all cases, diagnosis was based on ultra-
0049-3848/02/$ - see front matter D 2002 Elsevier Science Ltd. All rights reserved. PII: S 0 0 4 9 - 3 8 4 8 ( 0 2 ) 0 0 0 7 4 - 9
14
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17
sonography (US; colour Doppler). US examination was repeated if symptoms reoccurred or there was suspicion of recurrence in the affected limb. The initial treatment length was 7 days in both groups. In the UF heparin group, a bolus of 5000 IU was injected and, thereafter, the daily dose was 15,000 IU/500 ml infused at 36 ml/h. Treatment was followed with repeated plasma APTT measurements (every 6 h) and the target value was 70 –100 s. The next 21 patients were treated subcutaneously with a LMW heparin (dalteparin). We used 15% higher treatment doses of dalteparin than recommended by the manufacturer during the first week of treatment to achieve the target level of anti-Xa of 0.5 IU/ml before injection and 1 – 1.5 IU/ml 3 h after injection. Thereafter, the dose was decreased to full treatment doses (200 IU dalteparin/kg divided into two doses) for 2 weeks for patients in both groups. In the beginning of the fourth week, the dose was decreased and given once daily to get an anti-Xa level of 0.7 IU/ml 3 h post injection and at the end of pregnancy, 0.5 – 0.6 IU/ml. Symptomatic patients received higher doses (full treatment doses) with twice-daily injections. Symptoms and anti-Xa values did not always correlate with each other and, when defining dalteparin dose, we were guided by the symptoms. Increasing the dose generally relieved the symptoms, except in one case with recurrence. The LMW heparin doses were halved during delivery day in both groups. The decision to give epidural anaesthesia was made by the anaesthesiologist. After delivery, warfarin treatment was given for a duration of 6 months for proximal DVTs and 3 months for distal DVTs. LMW heparin was discontinued when INR was two to three for at least 2 days. 2.2. Efficacy and safety Efficacy of treatment was evaluated daily by measuring the circumference of the affected limb at mid-femoral and crural level and by asking about occurrence of postthrombotic symptoms (pain, oedema, physical limitations and paraesthesia). The reexamination with US was performed if there was worsening of these symptoms. Pulmonary ventilation scan was performed only in cases with clinical suspicion of PE. Platelet levels were followed during both acute treatment and prophylaxis. Bleeding (haematomas, haematuria, gingival and vaginal bleeding) was recorded. 2.3. Haemostatic tests APTT was measured with ACL Futura and ACL 2000 equipment (Instrumentarium Laboratory, Helsinki, Finland) and the reagent PTT AUTOMATE (Diagnostica Stago, Paris, France). Anti-Xa measurements were carried out by use of a chromogenic substrate assay based on inhibition of bovine factor Xa by heparin-activated antithrombin III (HEPRN method, DuPont aca IN analyser; DuPont, Wilmington, DE,
USA). APTT (normal range 24 –34 s) was measured by Platelin LS (Organon Teknika, Boxtel, the Netherlands). All patients were analysed for hereditary and acquired thrombophilia. Factor V Leiden was analysed by the method described by Bertina et al. [12], and G20210A prothrombin mutation by the method described by Poort et al. [13]. Lupus anticoagulant was studied by using the Russell Viper Venom Test, with pooled normal plasma in confirmatory tests, anticardiolipin IgG (normal if < 10 GPL) by QUACA Anti-Cardiolipin Elisa (Cheshire Diagnostics, Great Britain), antithrombin by Coamatic AT 400 (normal range 84– 108% of normal control; Chromogenix, Mo¨lndal, Sweden), protein C (normal range 67– 131% of normal control) by Coamatic Protein C (Chromogenix), APC ratio (normal if > 2) by using kits from Chromogenix and protein S (normal range 43 – 126% of normal control) by Liatest Protein S (Diagnostica Stago, Asnieres, France). 2.4. Statistical analysis Continuous variables are presented as means ( F S.D.) and were analyzed by using Student’s t test or the Mann – Whitney test. Categorical data were tested by the v2 test and Fisher’s exact probability test. A probability value of < .05 was considered statistically significant.
3. Results There were no statistical differences in baseline maternal or neonatal data between the groups (Table 1). The time point in pregnancy for diagnosis of DVT tended to be earlier in the LMW heparin group (21 weeks of gestation) than in the UF heparin group (27 weeks of gestation), but the difference did not reach statistical significance. The time from the beginning of symptoms to diagnosis (diagnostic delay) tended to be relatively long in both treatment groups (8 days in the UF heparin group and 7 days in the LMW heparin group; Table 2). In 23 (74%) of all cases, DVT was in the left leg and in 24 (77%) cases, it was in the proximal region of a lower limb (Table 2). There were no statistical differences in thrombophilic data or localisation of the DVT between the groups (Table 2). No PE was detected. It was suspected in three patients using dalteparin (n = 1) and UF heparin (n = 2) during the first week of treatment, but lung scans gave negative results in all three. A 40-year-old woman had had two spontaneous abortions and one normal pregnancy. During her fourth pregnancy, she had superficial thrombophlebitis of the left leg at 25th gestational week and 3 weeks later, she developed a massive venous thrombosis of the same leg, reaching the femoral vein. She was given dalteparin 10,000 IU twice daily for 1 week and thereafter 10,000 IU once daily. Her weight was 80 kg. After 1 week with this reduced dose, her
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17
leg became painful and more swollen and on US examination, slight progression of the thrombosis could be seen. Increasing dalteparin dose to 10,000 IU twice daily for 2 days did not improve the symptoms and, therefore, the patient was given UF heparin intravenously (treatment doses) for 5 days and thereafter dalteparin 10,000 twice daily until the end of pregnancy. She had some postthrombotic symptoms (pain in the leg after 100 m of walking) during rest of her pregnancy. This patient was heterozygous for Factor V Leiden. The treatment data are presented in Table 3. There was no difference in the number of patients having complaints of postthrombotic symptoms in the affected limb after treatment. In 17/31 of the patients (55%), US was repeated (6 in the UF and 11 in LMWH groups) 2– 6 weeks after starting the treatment. In one case (with failure, cf. above), slight progression of the thrombosis could be observed. Thrombocytopenia was not found in either group. One patient in the LMW heparin group had haematuria, but this Table 1 Demographic data
n Age, year, mean (S.D.) BMI, kg/m2, mean (S.D.) Parity: nulliparas, n Maternal diseases, na History of spontaneous abortions, n Pregnancy complications, n Preeclampsia IUGRb Abortion Delivery weeks, mean (S.D.) Mode of delivery; vaginal/Caesarian section, n Birth weight, g, mean (S.D.) Range Apgar at 1 min, mean (S.D.) Range Bleeding during delivery, ml, mean (S.D.) Range Abnormal bleeding (>1000 ml), n Delivery complicationsc, n Epidural, n a
UF heparin
LMW heparin
P
10 31.0 (5.7) 23.4 (4.7) 5 0 1
21 31.6 (4.3) 25.0 (4.6) 16 5 5
NS NS NS NS NS
0 0 0 39.3 (1.1) 8/2
1 1 1 38.7 (3.7) 16/4
NS NS NS NS NS
3575 (352) (2810 – 4050) 8.2 (1.1) (7 – 9) 425 (216)
3516 (939) (340 – 4670) 8.8 (1.3) (4 – 10) 597 (554)
NS
(200 – 1000) 1
(100 – 2200) 2
NS
0
4
NS
5
6
NS
NS NS
Asthma bronchiale, chronic hypertension, arthritis rheumatoides, hypothyreosis, LED and sarcoidosis. b Intrauterine growth retardation ( < mean 2 S.D.), NS = not significant. c One difficulty with Caesarian section due to fibroids, one perineal rupture, one intrapartum asphyxia, one hematoma and infection after Caesarian section.
15
Table 2 Thrombophilic data and localisation of DVT during pregnancy
n Weeks of gestation at diagnosis, mean (S.D.) Personal history of DVT, n (%) Family history of DVT, n (%) Hereditary thrombophilia, n (%) Acquired thrombophilia, n (%) Localisation of DVT, n (%) Lower limb, proximal Lower limb, distal Upper limb Lower left/lower right limb
UF heparin
LMW heparin
P
10 27.0 (8.5)
21 21.0 (9.8)
NS
1 (10)
4 (19)
NS
3 (33)
9 (43)
NS
2 (20)
7 (33)
NS
0 (0)
1 (5)
NS
8 (80) 2 (20) 0 (0) 8/2
16 (76) 3 (14) 2 (10) 15/4
NS NS NS NS
occurred during the prophylactic phase. It disappeared spontaneously after decreasing the dose of LMW heparin. There were no congenital anomalies of infants except for one case of hereditary Treacher –Collins syndrome and one case of sacral dimple, which was not associated with use of heparin. One infant died after premature delivery at 23 gestational weeks (birth weight of 340 g) as a result of severe preeclampsia. The mother had a positive lupus anticoagulant test result and DVT 9 weeks before premature delivery. The decision to give epidural anaesthesia was made by the anaesthesiologist on duty. His/her decision depended mainly on the time and dose of the last LMW heparin injection (given if time length after last dose was at least 12 h and corresponding dose did not exceed 5000 IU of dalteparin), platelet count and possible use of nonsteroidal anti-inflammatory agents. Epidural anaesthesia was given to 35% of our patients without local bleeding.
4. Discussion The established acute phase treatment for DVT during pregnancy has been intravenous heparin [14] (Table 3). There are no randomised studies on the treatment of DVT during pregnancy comparing LMW heparin with UF heparin. According to this observational comparative study, the LMW heparin dalteparin seems to be as good as UF heparin in the acute phase (first week) of treatment of DVT in terms of safety and efficacy. As the number of patients was low (31) and the study was not randomised, we have to interpret our results cautiously. We used higher treatment doses for LMW heparin (dalteparin) than recommended by the manufacturer during the first week of treatment to achieve the target level of antiXa of 0.5 IU/ml before injection and 1 – 1.5 IU/ml 3 h after
16
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17
Table 3 Treatment of acute DVT during pregnancy
n Gestational weeks, mean (S.D.) Delay in diagnosis, days, mean (S.D.)a Dose for acute treatment, IU/24 h, mean (S.D.) Dose for LMW heparin prophylaxis, IU/24 h, mean (S.D.) Failures of treatment, n Symptoms after treatment, n (%) Recanalised thrombi in US, n Haemorrhagic complications during treatment
UF heparin
LMW heparin
P
10 27 (9.9)
21 20 (9.7)
NS
7.9 (9.3)
6.8 (8.1)
NS
25,430 (3786)
16,000 (3491)
NA
7777 (1954)
7875 (2470)
NS
0 4 (40)
1 (recurrent DVT) 8 (38)
NS NS
1/6 0
7/11 0
NS NS
a Time from onset of symptoms to diagnosis and treatment. NA = not applicable; NS = not significant.
injection. Thereafter, the dose was decreased to full treatment doses for 2 weeks for patients in both groups. At the beginning of the fourth week, the dose was decreased and given once daily to achieve an anti-Xa level of 0.7 IU/ml 3 h postinjection and at the end of pregnancy 0.5– 0.6 IU/ml. With symptomatic patients (n = 4), we gave higher doses (full treatment doses) with twice-daily injections. Our doses after 3 weeks of full treatment doses were lower than earlier recommendations suggesting full treatment doses until the end of pregnancy [15]. Some clinicians give full treatment doses for 6 weeks and thereafter high prophylactic doses (half of the full dose) (Dr. M. de Swiet, personal communication). The optimal dose of LMW heparin for secondary prophylaxis remains to be defined. Evaluation of the efficacy of treatment of DVT during pregnancy can be problematic, especially in cases of PE. Lung scans and spiral CT scans for asymptomatic women are regarded as unethical and D-dimer measurements during pregnancy give unreliable results [16]. On the other hand, clinical suspicion of PE is more rarely confirmed radiologically during pregnancy than outside pregnancy [16]. As PE is still the most common cause of maternal death in pregnancy [17,18], all clinically suspected cases should be confirmed radiologically. In this study, PE was suspected in three patients but lung scans gave negative results in all three. Most of the DVTs in this study were proximal and left-sided, regions known to be more likely to be susceptible to embolism [16]. The efficacy of treatment can also be evaluated by assessing postthrombotic symptoms of the patient and the patency of thrombotic veins. DVT is often massive and proximal during pregnancy and, therefore, the risk of developing venous insufficiency or postthrombotic syndrome in the long term may be higher than in the nonpregnant state [17]. There was no difference in the occurrence of postthrombotic symptoms (pain, physical
limitations, oedema) after either of the heparin treatments during pregnancy (time from symptoms to beginning of treatment). Delayed diagnosis (time from symptoms to beginning of treatment) did not result in increased frequency or altered quality of postthrombotic symptoms and the mean delay was equal in both treatment groups (1 week). In 55% of the patients, US was repeated (6 in the UF heparin group and 11 in the LMW heparin group). The recanalisation rate of the thrombotic vein tended to be higher in the LMW heparin group than in the UF heparin group, but as this evaluation was offered only to patients with symptoms, we cannot give any definitive answer as to whether or not LMW heparin is better in this sense. One woman with progression of DVT (US) after 2 weeks of treatment and with postthrombotic symptoms thereafter was the first to be treated with dalteparin during pregnancy. She was heterozygous for the Factor V Leiden mutation and her dalteparin dose was reduced too quickly (after 2 weeks of treatment) to high prophylactic dose (10,000 IU once daily). After this case, we prolonged the treatment period with full doses to 3 weeks. There were no bleeding complications or heparininduced thrombocytopenia during the treatment period in either of the heparin groups. Although LMW heparins have been shown to be associated with reduced heparin-induced thrombocytopenia [19], our small number of patients prevents us from drawing any relevant conclusions. Secondary thromboprophylaxis was the same (LMW heparin) in all our patients because of the higher risk of osteoporosis with UF heparin compared with LMW heparin in long-term use [20,21]. Epidural anesthesia for delivery was given in 35% of the patients. The decision of the mode of delivery was made with obstetric factors in both groups. Delivery and neonatal data did not differ between the groups and were the same as observed in healthy women at our unit. In conclusion, subcutaneously given LMW heparin seems to be a good and practical substitute for treatment with laborious intravenous UF heparin during the first week of pregnancy. The dose of LMW heparin thereafter until the end of the pregnancy remains to be defined. References [1] Gates S. Thromboembolic disease in pregnancy. Curr Opin Obstet Gynecol 2000;12:117 – 22. [2] Greer IA. Epidemiology, risk factors and prophylaxis of venous thromboembolism in obstetrics and gynaecology. Bailliere’s Clin Obstet Gynaecol 1997;11:403 – 30. [3] Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight (PK 10169) does not cross the placenta during the second trimester of pregnancy study by direct fetal blood sampling under ultrasound. Thromb Res 1984;34:557 – 60. [4] Forestier F, So´le Y, Aiach M, Ge´las MA, Daffos F. Absence of transplacental passage of Fragmin during the second and third trimester of pregnancy. Thromb Haemost 1992;67:180 – 1. [5] Flessa HC, Kapstrom AB, Glueck HI, Will JJ. Placental transport of heparin. Am J Obstet Gynecol 1965;93:570 – 3.
V.-M. Ulander et al. / Thrombosis Research 106 (2002) 13–17 [6] Greer IA, de Swiet M. Thrombosis prophylaxis in obstetrics and gynaecology. Br J Obstet Gynaecol 1993;100:37 – 40. [7] Ginsberg JS, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 1995;108:305S – 11S (Suppl). [8] Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108 – 14. [9] Pettila¨ V, Kaaja R, Leinonen P, Ekblad U, Kataja M, Ikkala E. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 1999;96:275 – 82. [10] Dolovich L, Ginsberg J, Douketis J, Holbrook A, Cheah G. A metaanalysis comparing low molecular weight heparin to unfractionated heparin in the treatment of venous thromboembolism: examining some unanswered questions regarding location of treatment, product type, and dosing frequency. Arch Intern Med 2000;160:181 – 8. [11] Gould M, Dembitzer A, Doyle R, Hastie T, Garper A. Low-molecularweight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomised, controlled trials. Ann Intern Med 1999;130:800 – 9. [12] Bertina RM, Koeleman BPC, Koster T, Rosendal FR, Dirven RJ, De Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64 – 7. [13] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3V-untranslated region of the prothrombin gene is
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