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Use of Low Molecular Weight Heparin in Acute Venous Thromboembolic Events in Pregnancy
USE OF
Low
MOLECULAR WEIGHT HEPARIN IN ACUTE
VENOUS THROMBOEMBOLIC EVENTS IN PREGNANCY janine C. Malcolm, MD, FRCPC,I Erin j. Keely, MD, FRCPC, 1,2 Alan j. Karovitch, MD, FRCPC,I Philip S. Wells, MD, FRCPC 1,3 I Departments of Medicine, 20bstetrics and Gynaecology,3Clinicai Epidemiology University of Ottawa, Ottawa ON Abstract Objective: To compare the maternal and neonatal outcomes arising from the use of low molecular weight heparin (LMWH) or unfractionated heparin (UFH) in the treatment of acute venous thromboembolism (VTE) in pregnancy. Study Design: A retrospective review of the charts of all women treated for acute VTE in pregnancy at the Ottawa Hospital from January 1990 to December 1999. Results: Twenty-three cases were identified, of which I I were treated with LMWH and 12 with UFH. Maternal and fetal outcomes were similar between the two groups. Hospital length of stay was shorter in the LMWH group. There was no difference in delivery management between the two groups. There was minor bleeding in 2 women in the UFH group and none in the LMWH group. There was one recurrent VTE during treatment in each of the groups. Conclusion: There is no difference in complication rate between LMWH and UFH in the treatment of acute VTE in pregnancy. Resume Objectif : Com parer les issues maternelles et neonatales resultant de I'utilisation de I'heparine de faible poids moleculaire (HFPM) ou de I'heparine non fractionnee (HNF) pour Ie traitement de la thromboembolie veineuse (TEV) aigue durant la grossesse. Conception de I'etude : Revue retrospective des dossiers de toutes les femmes traitees pour une TEV aigue durant leur grossesse it I'H6pitai d'Ottawa, de janvier 1990 it decembre 1999. Resultats : On a releve 23 cas, dont I I ont ete traites it I'HFPM et 12 it I'HNF. Les issues maternelles et fcetales etaient semblables pour les deux groupes. La duree du sejour hospitalier etait plus courte pour Ie groupe HFPM. La prise en charge de I'accouchement etait la meme dans les deux groupes. Deux femmes traitees it I'HNF ont eu de faibles saignements, mais aucune dans Ie groupe HFPM. Dans chacun des deux groupes, iI y a eu un cas de TEV recurrente.
KeyWords Venous thromboembolism, heparin, pregnancy Dr. Wells has received honoraria from several manufacturers of low molecular weight heparin for the provision of educational lectures. Received on February 7, 2002 Revised and accepted on March
22, 2002
Conclusion: II n'y a pas de difference entre Ie taux de complications en rapport avec I'utilisation de I'HFPM ou de I'HNF pour Ie traitement d'une TEV aigue durant la grossesse.
J Obstet Gynaecol Can 2002;24(7):568-71.
INTRODUCTION
Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality with a reponed overall incidence of about ten times the age-adjusted non-pregnancy rate. l ,2 VTE can result in chronic problems such as postphlebitic syndrome3 and pulmonary hypertension. 4 During pregnancy, a number of factors combine to create a procoagulant state. 5These include increases in procoagulant factors,5 resistance to endogenous anticoagulants,5 venous stasis, and possible vascular injury at delivery.5,6 Historically, the treatment ofVTE in pregnancy involved the use of unfractionated heparin (UFH), since warfarin and its derivatives have been shown to be teratogenic at 6 to 12 weeks' gestation, as well as later in pregnancy. 1,7 Recently, the treatment of acute VTE in pregnancy patterns at the Ottawa Hospital has tended toward the use of low molecular weight heparin (LMWH) rather than UFH. This treatment is in parallel with that of acute VTE in the non-pregnant population. Low molecular weight heparin is a relatively new drug and therefore has limited data available on its use for the treatment of acute VTE in the pregnant population. 8,9 LMWH is an attractive option for pregnant patients because of its convenience and ease of use, including its significantly shortened hospitalization requirement, if hospitalization is needed at all. To add to the clinical knowledge of the effectiveness of LMWH over UFH in the treatment of acute VTE in pregnancy, we undertook a retrospective review of the use of both treatment methods at our institution, with the specific goal to compare the maternal and neonatal outcomes. Changes in practice patterns, maternal and fetal outcomes, the influence of the type of anticoagulation on labour and delivery management, and hospitalization trends were also examined.
JOGC IiiIJULY 2002
MATERIALS AND METHODS
Medical records from the Ottawa Hospital (Civic and General campuses) were reviewed by asingle observer for all women coded with a discharge diagnosis of deep vein thrombosis (DVT), thromboembolism, or pulmonary embolism during pregnancy. All available inpatient and outpatient charts were reviewed. The study period was from January 1990 to December 1999. Approval for the study was obtained from the Ottawa Hospital Ethics Board. Demographic data; patient risk factors for VTE; time of presentation (gestational age); type and site of VTE; type of imaging study used for diagnosis; therapy for VTE; pertinent antepartum , intrapartum, and postpartum complications; birth weight; mode of delivery; type of anaesthesia; summary oflabour and delivery records; fetal outcomes; and maternal outcomes were recorded. Women were excluded ifVTE had not been objectively diagnosed (i.e., absence of a positive leg ultrasound, high probability V/Q scan, or positive pulmonary angiogram on the chart), or if data on obstetrical outcome were not available. At the Ottawa Hospital, the standard treatment ofVTE with UFH involves the use of a weight-based intravenous bolus of UFH followed by a maintenance dose. The rate of heparin infusion is adjusted to maintain an activated partial thromboplastin time (aPTT) of 1.5 to 2 times that of control levels. After 5 days, an adjusted dose of subcutaneous heparin is then started to maintain the aPTT at 1.5 to 2 times the control values. LMWH became available to our institution in 1995 .
Women were either started on LMWH or admitted to hospital for 24 to 48 hours ofUFH and then switched to LMWH. Treatment doses for LMWH were calculated as 100 IU/kg BID or 200 IV/kg 00 for Dalteperin or 175 IV/kg 00 for Tinzaperin. The dose was not adjusted for increases in body weight. Anti-Xa levels were not consistently requested and could not be included in this study. RESULTS
The study population comprised 30 women, 15 treated with UFH and 15 treated with LMWH. Of the women treated with LMWH , 4 women were treated with Tinzaparin and 11 with Dalteparin. There were no obstetrical outcome data for 3 women treated with UFH and 4 women treated with LMWH as they either delivered elsewhere or had a therapeutic abortion. These were excluded from the analysis, leaving 12 in the UFH group and 11 in the LMWH group. Two women in the LMWH group were initially treated with UFH for 24-48 hours and then switched to LMWH for the remainder of their pregnancy. They were included in the LMWH group for analysis. All women treated with LMWH presented to Ottawa Hospital after 1996. The mean (range) age of the women in the UFH group was 30 (17- 39) years, similar to that of the LMWH group, which was 31 (22-36) years. Both groups were also similar in terms of parity (0-2 in both groups), and history of previous VTE, which occurred in 5 (42%) women in the UFH group and 3 women (27%) in the LMWH group. One woman in
TABLE I MATERNAUFETAL OUTCOMES AND DELIVERY MANAGEMENT IN UFH VS. LMWH GROUPS UFH* = 12
LMWHt n = I I
n
A.MATERNAL Minor bleeding Recurrence of VTE Admitted for VTE Length of stay
2 (17%) I (9%) 9 (75%) 11.2 days (n
B. FETAL Median gestational age at delivery Median birth weight Fetal loss
36 (3 1-41) weeks 3024 (301-4465) g I (8%)
38 (26-41) weeks 3130 (600-4741) g 0
6 (50%) 5 (42%) 4 (33%)
6 (54%) 5 (45%) 4 (36%)
C. DELIVERY MANAGEMENT Regional anaesthesia Induction C-section *UFH: unfractionated heparin tLMWH: Low molecular weight heparin
JOGC _ J U L Y 2002
= 9)
0 I (9%) 6 (54%) 3.4 days (n = 5)
the UFH group had a pulmonary embolism, whereas this occurred in 2 women in the LMWH group. The maternal outcomes are summarized in Table 1. As expected, there was a large difference in length of hospital stay and number of patients admitted. Three women in the UFH group developed VTE after being admitted to hospital for another pregnancy-related complication (placenta previa; pregnancyinduced hypertension). They were excluded from the analysis of length of stay. One woman in each group had a recurrence of VTE during treatment. The woman in the UFH group developed a recurrence of her DVT when the activated partial thromboplastin time was 29 seconds. The recurrent DVT in the woman in the LMWH group occurred 2 weeks after the LMWH dose was decreased from a treatment dose to a prophylactic dose by her treating physician. Two women in the UFH group had minor bleeding episodes, one from the placenta due to a placenta previa and the other from the urethra. Neither required a blood transfusion. The aPTT was greater than 120 seconds in one woman and 86 seconds in the other. There was no documented thrombocytopenia in any of the women in the study. Fetal outcomes are presented in Table 1. There was no difference in gestational age at delivery or median birth weight between the UFH and LMWH groups. There was one fetal death in the UFH group. The death was at 32 weeks of gestational age in a woman treated for a DVT with dose-adjusted UFH (s.c.) from 10 weeks of gestational age. Fetal autopsy revealed that the cause of death was placental infarction secondary to thrombosis of placental vessels. There was no difference in management of delivery between the two groups (Table 1). The induction rates and the Caesarean section rates were increased in both groups compared to the general obstetrical population at our institution (30% induction and 18% Caesarean section). There was no uniform planned management of women on LMWH at the time of delivery. Five women were induced (Table 1). Of these, 2 were induced because of anticoagulation. The other 3 were induced for obstetrical indications. One woman was switched from LMWH to UFH prior to labour. In the UFH group, 5 women were induced: 2 for anticoagulation considerations and 3 for obstetrical indications. Data on the aPTT at days 1, 2, and 3 after initiation ofUFH were only available for 9 of the 12 women treated with UFH as 2 women were discharged immediately on UFH and the third woman was transferred to our institution after the initiation of UFH. Of the 9 women, flllure to achieve a therapeutic aPTT was 66% on day 1, and 37.5% after 72 hours of intravenous UFH. DISCUSSION
Although our study is limited by being retrospective, non-randomized, and having small numbers, it represents the largest JOGC
study on the effectiveness of LMWH for treatment of acute VTE in pregnancy. LMWH, like UFH, does not cross the placenta, 10, II but it has a number of advantages over UFH, including a longer half life, less need for laboratory monitoring (allowing outpatient management), improved bioavailability, less protein binding, and a dose-dependent clearance, which allows for a more predictable response. 1,12,13 In addition to these benefits, LMWH may also cause less heparin-induced thrombocytopenia,14,15 and possibly less osteoporosis.IG-1 8 Studies in non-pregnant populations have shown LMWH to be both safe and effective for the treatment ofDVT and pulmonary embolus. 8 ,9,19 As most studies have excluded pregnant and nursing women,I,20 because of the reluctance to perform proper comparative studies on pregnant women, the use of LMWH for treatment of acute VTE in pregnancy is based primarily on studies of non-pregnant patients, case reports, and small case series. Our review supports the previous smaller studies 21 - 23 that LMWH is safe and effective in pregnant patients. Our case series suggest that fetal and maternal outcomes are similar when LMWH or UFH is used. The study by Sanson et al. 21 in 1999 included only 19 pregnant woman and found no adverse fetal outcomes. A small case series of 4 women, treated for antepartum DVT and pulmonary embolism with enoxaparin until delivery, found no recurrence, bleeding, or adverse events at delivery.22 This finding was supported by the review by Dulitzki et at. 23 with 15% of the 41 women treated for the indication of acute VTE while the remainder were given prophylactic doses. 23 One woman in that series suffered from mild vaginal bleeding. 23 Despite a longer half life with LMWH, there was no difference in delivery management between the two groups of women in our series. The high induction rate in both groups was in part a reflection of increased medical intervention in an attempt to manage the anticoagulation safely and to allow for regional anaesthesia in order to minimize delay between discontinuing heparin and delivery. The lack of uniformity of practice in labour management ofLMWH underlines the need for prospective studies in this area. The use ofLMWH is not without disadvantages. The lack of dosing data in pregnancy is an important problem as the physiological changes in pregnancy, such as increases in glomerular filtration rate and protein binding changes, may alter the pharmacokinetics ofLMWH.24 The dosing of LMWH in this review appeared to be effective, with minimal recurrences or bleeding. The delay in achieving therapeutic concentrations of aPTT with UFH further suggests the superiority of LMWH. LMWH is expensive, with a cost of approximately $30 per day in Canada for therapeutic doses (3 to 4 times higher in the United States). However, this cost may be offset by decreased hospital stay and decreased need for laboratory monitoring.
II
JULY 2002
CONCLUSION
Our results suggest that LMWH can be effectively used for acute VTE in pregnancy and may result in shorter hospital stays. A larger randomized trial should be considered to further assess the safety and efficacy ofLMWH in pregnancy. REFERENCES I. 2.
3. 4. 5. 6.
7.
8.
9.
10.
I I.
12.
13. 14.
15. 16.
17.
18.
Barbour LA. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynecol Clinics North America 1997;24:499-519. Atrash HK, Koonin LM, Lawson HW, Franks AC, Smith jc. Maternal morbidity in the United States 1979-1986. Obstet Gynecol 1990; 76: I055-60. Clagett G,Anderson F, Heitj, Lieberman j,Wheeler H. Prevention of venous thromboembolism. Chest 1998; I 14:531 S-560S. Goldhaber S. Pulmonary embolism. N Engj Med 1998;339:93-104. Greer I.Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353: 1258-65. Dizon-Townson D, Branch DW. Anticoagulation during pregnancy: an update. Seminars in Thrombosis and Hemostasis 1998;24 Suppl 1:55-62. Iturbe-Alessio I, Fonesca MC, Mutchinik 0, Santos MA, Zajarias A, Salazar E. Risks of anticoagulation therapy in pregnant women with artificial heart valves. N Engl j Med 1986;315: 1390--3. Hull RD, Raskob GE, Pineo GF, Green D,Trowbridge AA, Elliott CG. Subcutaneous low-molecular weight heparin compared with continuous intravenous heparin in the treatment of prOXimal vein thrombosis. N Engl j Med 1992;326:975-82. Prandoni P, LensingAYV, Buller HR, Carta M, Cogo A,Vigo M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in prOXimal deep-vein thrombosis. Lancet 1992;339:441-5. Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin does not cross the placenta during the second trimester of pregnancy by direct fetal blood sampling under ultrasound.Thromb Res 1984;34:557-60. Forestier F, Daffos F, Rainaut M,Toulemonde F. Low molecular weight heparin does not cross the placenta during the third trimester of pregnancy.Thromb Haemost 1987;57:234. Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics of a low molecular weight heparin and unfractionated heparin after intravenous and subcutaneous administration.Thromb Res 1985;39:631-6. Weiu j. Low-molecular-weight heparins. N Engl j Med 1997;337:688--98. Warkentin TE, Levine MN, Hirsh j, Horsewood j, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl j Med 1995;332: 1330--5. Magnani HN. Heparin induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran.Thromb Haemost 1993;70:554-61. Melissari E, Parker q,Wilson NV, Monte G, Kanthou C, Pemberton KD, et al. Use of low molecular weight heparin in pregnancy.Thromb Haemost 1992;68:652-65. Shaughnessy SG,Young E, Deschamps P, Hirsh J.The effects of low molecular-weight heparin and standard heparin on calcium loss from fetal rat calvaria. Blood 1995;86: 1368--73. Monreal M, Lafoz E, Olive A, del Rio L,Vedia C. Comparison of subcutaneous unfractionated heparin with low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.Thromb Haemost 1994;71 :7-11.
JOGC
II
19. Gould MK, Dembitzer AD, Doyle RL, Hastie Tj, Garber AM. Low molecular weight heparins compared to unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130:800--9. 20. Lindmarker P. Can all patients with DVT receive low-molecular-weight heparin in an outpatient setting? Haemostasis I999;29(suppl 1):84-8. 21. Sanson B-j, Lensing AWA, Prins M, Ginsberg jS, Barkagan ZS, LavennePardonge E. Safety of low-molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81 :668--2. 22. Thomson Aj,Walker ID, Greer IA. Low-molecular-weight heparin for immediate management of thromboembolic disease in pregnancy. Lancet 1998;352: 1904. 23. Duliuki M, Pauzner R, Langeviu P, Pras M, Many A, Schiff E. Lowmolecular weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 1996;87:380--3. 24. Chan WS, Ray jG. Low molecular weight heparin use in pregnancy: issues of safety and practicality. Obstet Gynecol Surv 1999;54:649-54.
JULY 2002
Low
MOLECULAR WEIGHT HEPARIN IN ACUTE
VENOUS THROMBOEMBOLIC EVENTS IN PREGNANCY janine C. Malcolm, MD, FRCPC,I Erin j. Keely, MD, FRCPC, 1,2 Alan j. Karovitch, MD, FRCPC,I Philip S. Wells, MD, FRCPC 1,3 I Departments of Medicine, 20bstetrics and Gynaecology,3Clinicai Epidemiology University of Ottawa, Ottawa ON Abstract Objective: To compare the maternal and neonatal outcomes arising from the use of low molecular weight heparin (LMWH) or unfractionated heparin (UFH) in the treatment of acute venous thromboembolism (VTE) in pregnancy. Study Design: A retrospective review of the charts of all women treated for acute VTE in pregnancy at the Ottawa Hospital from January 1990 to December 1999. Results: Twenty-three cases were identified, of which I I were treated with LMWH and 12 with UFH. Maternal and fetal outcomes were similar between the two groups. Hospital length of stay was shorter in the LMWH group. There was no difference in delivery management between the two groups. There was minor bleeding in 2 women in the UFH group and none in the LMWH group. There was one recurrent VTE during treatment in each of the groups. Conclusion: There is no difference in complication rate between LMWH and UFH in the treatment of acute VTE in pregnancy. Resume Objectif : Com parer les issues maternelles et neonatales resultant de I'utilisation de I'heparine de faible poids moleculaire (HFPM) ou de I'heparine non fractionnee (HNF) pour Ie traitement de la thromboembolie veineuse (TEV) aigue durant la grossesse. Conception de I'etude : Revue retrospective des dossiers de toutes les femmes traitees pour une TEV aigue durant leur grossesse it I'H6pitai d'Ottawa, de janvier 1990 it decembre 1999. Resultats : On a releve 23 cas, dont I I ont ete traites it I'HFPM et 12 it I'HNF. Les issues maternelles et fcetales etaient semblables pour les deux groupes. La duree du sejour hospitalier etait plus courte pour Ie groupe HFPM. La prise en charge de I'accouchement etait la meme dans les deux groupes. Deux femmes traitees it I'HNF ont eu de faibles saignements, mais aucune dans Ie groupe HFPM. Dans chacun des deux groupes, iI y a eu un cas de TEV recurrente.
KeyWords Venous thromboembolism, heparin, pregnancy Dr. Wells has received honoraria from several manufacturers of low molecular weight heparin for the provision of educational lectures. Received on February 7, 2002 Revised and accepted on March
22, 2002
Conclusion: II n'y a pas de difference entre Ie taux de complications en rapport avec I'utilisation de I'HFPM ou de I'HNF pour Ie traitement d'une TEV aigue durant la grossesse.
J Obstet Gynaecol Can 2002;24(7):568-71.
INTRODUCTION
Venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality with a reponed overall incidence of about ten times the age-adjusted non-pregnancy rate. l ,2 VTE can result in chronic problems such as postphlebitic syndrome3 and pulmonary hypertension. 4 During pregnancy, a number of factors combine to create a procoagulant state. 5These include increases in procoagulant factors,5 resistance to endogenous anticoagulants,5 venous stasis, and possible vascular injury at delivery.5,6 Historically, the treatment ofVTE in pregnancy involved the use of unfractionated heparin (UFH), since warfarin and its derivatives have been shown to be teratogenic at 6 to 12 weeks' gestation, as well as later in pregnancy. 1,7 Recently, the treatment of acute VTE in pregnancy patterns at the Ottawa Hospital has tended toward the use of low molecular weight heparin (LMWH) rather than UFH. This treatment is in parallel with that of acute VTE in the non-pregnant population. Low molecular weight heparin is a relatively new drug and therefore has limited data available on its use for the treatment of acute VTE in the pregnant population. 8,9 LMWH is an attractive option for pregnant patients because of its convenience and ease of use, including its significantly shortened hospitalization requirement, if hospitalization is needed at all. To add to the clinical knowledge of the effectiveness of LMWH over UFH in the treatment of acute VTE in pregnancy, we undertook a retrospective review of the use of both treatment methods at our institution, with the specific goal to compare the maternal and neonatal outcomes. Changes in practice patterns, maternal and fetal outcomes, the influence of the type of anticoagulation on labour and delivery management, and hospitalization trends were also examined.
JOGC IiiIJULY 2002
MATERIALS AND METHODS
Medical records from the Ottawa Hospital (Civic and General campuses) were reviewed by asingle observer for all women coded with a discharge diagnosis of deep vein thrombosis (DVT), thromboembolism, or pulmonary embolism during pregnancy. All available inpatient and outpatient charts were reviewed. The study period was from January 1990 to December 1999. Approval for the study was obtained from the Ottawa Hospital Ethics Board. Demographic data; patient risk factors for VTE; time of presentation (gestational age); type and site of VTE; type of imaging study used for diagnosis; therapy for VTE; pertinent antepartum , intrapartum, and postpartum complications; birth weight; mode of delivery; type of anaesthesia; summary oflabour and delivery records; fetal outcomes; and maternal outcomes were recorded. Women were excluded ifVTE had not been objectively diagnosed (i.e., absence of a positive leg ultrasound, high probability V/Q scan, or positive pulmonary angiogram on the chart), or if data on obstetrical outcome were not available. At the Ottawa Hospital, the standard treatment ofVTE with UFH involves the use of a weight-based intravenous bolus of UFH followed by a maintenance dose. The rate of heparin infusion is adjusted to maintain an activated partial thromboplastin time (aPTT) of 1.5 to 2 times that of control levels. After 5 days, an adjusted dose of subcutaneous heparin is then started to maintain the aPTT at 1.5 to 2 times the control values. LMWH became available to our institution in 1995 .
Women were either started on LMWH or admitted to hospital for 24 to 48 hours ofUFH and then switched to LMWH. Treatment doses for LMWH were calculated as 100 IU/kg BID or 200 IV/kg 00 for Dalteperin or 175 IV/kg 00 for Tinzaperin. The dose was not adjusted for increases in body weight. Anti-Xa levels were not consistently requested and could not be included in this study. RESULTS
The study population comprised 30 women, 15 treated with UFH and 15 treated with LMWH. Of the women treated with LMWH , 4 women were treated with Tinzaparin and 11 with Dalteparin. There were no obstetrical outcome data for 3 women treated with UFH and 4 women treated with LMWH as they either delivered elsewhere or had a therapeutic abortion. These were excluded from the analysis, leaving 12 in the UFH group and 11 in the LMWH group. Two women in the LMWH group were initially treated with UFH for 24-48 hours and then switched to LMWH for the remainder of their pregnancy. They were included in the LMWH group for analysis. All women treated with LMWH presented to Ottawa Hospital after 1996. The mean (range) age of the women in the UFH group was 30 (17- 39) years, similar to that of the LMWH group, which was 31 (22-36) years. Both groups were also similar in terms of parity (0-2 in both groups), and history of previous VTE, which occurred in 5 (42%) women in the UFH group and 3 women (27%) in the LMWH group. One woman in
TABLE I MATERNAUFETAL OUTCOMES AND DELIVERY MANAGEMENT IN UFH VS. LMWH GROUPS UFH* = 12
LMWHt n = I I
n
A.MATERNAL Minor bleeding Recurrence of VTE Admitted for VTE Length of stay
2 (17%) I (9%) 9 (75%) 11.2 days (n
B. FETAL Median gestational age at delivery Median birth weight Fetal loss
36 (3 1-41) weeks 3024 (301-4465) g I (8%)
38 (26-41) weeks 3130 (600-4741) g 0
6 (50%) 5 (42%) 4 (33%)
6 (54%) 5 (45%) 4 (36%)
C. DELIVERY MANAGEMENT Regional anaesthesia Induction C-section *UFH: unfractionated heparin tLMWH: Low molecular weight heparin
JOGC _ J U L Y 2002
= 9)
0 I (9%) 6 (54%) 3.4 days (n = 5)
the UFH group had a pulmonary embolism, whereas this occurred in 2 women in the LMWH group. The maternal outcomes are summarized in Table 1. As expected, there was a large difference in length of hospital stay and number of patients admitted. Three women in the UFH group developed VTE after being admitted to hospital for another pregnancy-related complication (placenta previa; pregnancyinduced hypertension). They were excluded from the analysis of length of stay. One woman in each group had a recurrence of VTE during treatment. The woman in the UFH group developed a recurrence of her DVT when the activated partial thromboplastin time was 29 seconds. The recurrent DVT in the woman in the LMWH group occurred 2 weeks after the LMWH dose was decreased from a treatment dose to a prophylactic dose by her treating physician. Two women in the UFH group had minor bleeding episodes, one from the placenta due to a placenta previa and the other from the urethra. Neither required a blood transfusion. The aPTT was greater than 120 seconds in one woman and 86 seconds in the other. There was no documented thrombocytopenia in any of the women in the study. Fetal outcomes are presented in Table 1. There was no difference in gestational age at delivery or median birth weight between the UFH and LMWH groups. There was one fetal death in the UFH group. The death was at 32 weeks of gestational age in a woman treated for a DVT with dose-adjusted UFH (s.c.) from 10 weeks of gestational age. Fetal autopsy revealed that the cause of death was placental infarction secondary to thrombosis of placental vessels. There was no difference in management of delivery between the two groups (Table 1). The induction rates and the Caesarean section rates were increased in both groups compared to the general obstetrical population at our institution (30% induction and 18% Caesarean section). There was no uniform planned management of women on LMWH at the time of delivery. Five women were induced (Table 1). Of these, 2 were induced because of anticoagulation. The other 3 were induced for obstetrical indications. One woman was switched from LMWH to UFH prior to labour. In the UFH group, 5 women were induced: 2 for anticoagulation considerations and 3 for obstetrical indications. Data on the aPTT at days 1, 2, and 3 after initiation ofUFH were only available for 9 of the 12 women treated with UFH as 2 women were discharged immediately on UFH and the third woman was transferred to our institution after the initiation of UFH. Of the 9 women, flllure to achieve a therapeutic aPTT was 66% on day 1, and 37.5% after 72 hours of intravenous UFH. DISCUSSION
Although our study is limited by being retrospective, non-randomized, and having small numbers, it represents the largest JOGC
study on the effectiveness of LMWH for treatment of acute VTE in pregnancy. LMWH, like UFH, does not cross the placenta, 10, II but it has a number of advantages over UFH, including a longer half life, less need for laboratory monitoring (allowing outpatient management), improved bioavailability, less protein binding, and a dose-dependent clearance, which allows for a more predictable response. 1,12,13 In addition to these benefits, LMWH may also cause less heparin-induced thrombocytopenia,14,15 and possibly less osteoporosis.IG-1 8 Studies in non-pregnant populations have shown LMWH to be both safe and effective for the treatment ofDVT and pulmonary embolus. 8 ,9,19 As most studies have excluded pregnant and nursing women,I,20 because of the reluctance to perform proper comparative studies on pregnant women, the use of LMWH for treatment of acute VTE in pregnancy is based primarily on studies of non-pregnant patients, case reports, and small case series. Our review supports the previous smaller studies 21 - 23 that LMWH is safe and effective in pregnant patients. Our case series suggest that fetal and maternal outcomes are similar when LMWH or UFH is used. The study by Sanson et al. 21 in 1999 included only 19 pregnant woman and found no adverse fetal outcomes. A small case series of 4 women, treated for antepartum DVT and pulmonary embolism with enoxaparin until delivery, found no recurrence, bleeding, or adverse events at delivery.22 This finding was supported by the review by Dulitzki et at. 23 with 15% of the 41 women treated for the indication of acute VTE while the remainder were given prophylactic doses. 23 One woman in that series suffered from mild vaginal bleeding. 23 Despite a longer half life with LMWH, there was no difference in delivery management between the two groups of women in our series. The high induction rate in both groups was in part a reflection of increased medical intervention in an attempt to manage the anticoagulation safely and to allow for regional anaesthesia in order to minimize delay between discontinuing heparin and delivery. The lack of uniformity of practice in labour management ofLMWH underlines the need for prospective studies in this area. The use ofLMWH is not without disadvantages. The lack of dosing data in pregnancy is an important problem as the physiological changes in pregnancy, such as increases in glomerular filtration rate and protein binding changes, may alter the pharmacokinetics ofLMWH.24 The dosing of LMWH in this review appeared to be effective, with minimal recurrences or bleeding. The delay in achieving therapeutic concentrations of aPTT with UFH further suggests the superiority of LMWH. LMWH is expensive, with a cost of approximately $30 per day in Canada for therapeutic doses (3 to 4 times higher in the United States). However, this cost may be offset by decreased hospital stay and decreased need for laboratory monitoring.
II
JULY 2002
CONCLUSION
Our results suggest that LMWH can be effectively used for acute VTE in pregnancy and may result in shorter hospital stays. A larger randomized trial should be considered to further assess the safety and efficacy ofLMWH in pregnancy. REFERENCES I. 2.
3. 4. 5. 6.
7.
8.
9.
10.
I I.
12.
13. 14.
15. 16.
17.
18.
Barbour LA. Current concepts of anticoagulant therapy in pregnancy. Obstet Gynecol Clinics North America 1997;24:499-519. Atrash HK, Koonin LM, Lawson HW, Franks AC, Smith jc. Maternal morbidity in the United States 1979-1986. Obstet Gynecol 1990; 76: I055-60. Clagett G,Anderson F, Heitj, Lieberman j,Wheeler H. Prevention of venous thromboembolism. Chest 1998; I 14:531 S-560S. Goldhaber S. Pulmonary embolism. N Engj Med 1998;339:93-104. Greer I.Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999;353: 1258-65. Dizon-Townson D, Branch DW. Anticoagulation during pregnancy: an update. Seminars in Thrombosis and Hemostasis 1998;24 Suppl 1:55-62. Iturbe-Alessio I, Fonesca MC, Mutchinik 0, Santos MA, Zajarias A, Salazar E. Risks of anticoagulation therapy in pregnant women with artificial heart valves. N Engl j Med 1986;315: 1390--3. Hull RD, Raskob GE, Pineo GF, Green D,Trowbridge AA, Elliott CG. Subcutaneous low-molecular weight heparin compared with continuous intravenous heparin in the treatment of prOXimal vein thrombosis. N Engl j Med 1992;326:975-82. Prandoni P, LensingAYV, Buller HR, Carta M, Cogo A,Vigo M, et al. Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in prOXimal deep-vein thrombosis. Lancet 1992;339:441-5. Forestier F, Daffos F, Capella-Pavlovsky M. Low molecular weight heparin does not cross the placenta during the second trimester of pregnancy by direct fetal blood sampling under ultrasound.Thromb Res 1984;34:557-60. Forestier F, Daffos F, Rainaut M,Toulemonde F. Low molecular weight heparin does not cross the placenta during the third trimester of pregnancy.Thromb Haemost 1987;57:234. Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics of a low molecular weight heparin and unfractionated heparin after intravenous and subcutaneous administration.Thromb Res 1985;39:631-6. Weiu j. Low-molecular-weight heparins. N Engl j Med 1997;337:688--98. Warkentin TE, Levine MN, Hirsh j, Horsewood j, Roberts RS, Gent M, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl j Med 1995;332: 1330--5. Magnani HN. Heparin induced thrombocytopenia (HIT): an overview of 230 patients treated with orgaran.Thromb Haemost 1993;70:554-61. Melissari E, Parker q,Wilson NV, Monte G, Kanthou C, Pemberton KD, et al. Use of low molecular weight heparin in pregnancy.Thromb Haemost 1992;68:652-65. Shaughnessy SG,Young E, Deschamps P, Hirsh J.The effects of low molecular-weight heparin and standard heparin on calcium loss from fetal rat calvaria. Blood 1995;86: 1368--73. Monreal M, Lafoz E, Olive A, del Rio L,Vedia C. Comparison of subcutaneous unfractionated heparin with low molecular weight heparin (Fragmin) in patients with venous thromboembolism and contraindications to coumarin.Thromb Haemost 1994;71 :7-11.
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19. Gould MK, Dembitzer AD, Doyle RL, Hastie Tj, Garber AM. Low molecular weight heparins compared to unfractionated heparin for treatment of acute deep venous thrombosis: a meta-analysis of randomized, controlled trials. Ann Intern Med 1999; 130:800--9. 20. Lindmarker P. Can all patients with DVT receive low-molecular-weight heparin in an outpatient setting? Haemostasis I999;29(suppl 1):84-8. 21. Sanson B-j, Lensing AWA, Prins M, Ginsberg jS, Barkagan ZS, LavennePardonge E. Safety of low-molecular weight heparin in pregnancy: a systematic review. Thromb Haemost 1999;81 :668--2. 22. Thomson Aj,Walker ID, Greer IA. Low-molecular-weight heparin for immediate management of thromboembolic disease in pregnancy. Lancet 1998;352: 1904. 23. Duliuki M, Pauzner R, Langeviu P, Pras M, Many A, Schiff E. Lowmolecular weight heparin during pregnancy and delivery: preliminary experience with 41 pregnancies. Obstet Gynecol 1996;87:380--3. 24. Chan WS, Ray jG. Low molecular weight heparin use in pregnancy: issues of safety and practicality. Obstet Gynecol Surv 1999;54:649-54.
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