- Email: [email protected]
Treatment options in massive pulmonary embolism during pregnancy; A case-report and review of literature
Thrombosis Research 124 (2009) 1–5
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Review Article
Treatment options in massive pulmonary embolism during pregnancy; A case-report and review of literature G. Doreen te Raa a,⁎, Lucie S.M. Ribbert b, Repke J. Snijder c, Douwe H. Biesma a,d a
Department of Internal Medicine, St. Antonius Hospital Nieuwegein Department of Obstetrics, St. Antonius Hospital Nieuwegein Department of Pulmonary Medicine, St. Antonius Hospital Nieuwegein d Division of Internal Medicine and Dermatology, University Medical Centre, Utrecht, the Netherlands b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 27 November 2008 Received in revised form 20 February 2009 Accepted 7 March 2009 Available online 29 March 2009
Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA), streptokinase or urokinase is considered as high-risk treatment in pregnancy. However, several reports have described the successful use of systemic thrombolysis in pregnant patients with massive pulmonary embolism and haemodynamic instability. Case: We describe a 34-year old, pregnant female, who presented at 25 weeks of gestation with an acute collapse with reduced consciousness and shortness of breath caused by massive pulmonary embolism. Because of significant haemodynamic instability, increased right ventricular pressure and no improvement after intravenous heparin, thrombolytic therapy was administered. The response to thrombolytic therapy was excellent. No severe haemorrhagic complications were observed. Anticoagulant therapy with LMWH was continued until delivery. A healthy child was born at term. Review: In English literature, 13 patients received thrombolysis during pregnancy because of pulmonary embolism. No maternal deaths, four non-fatal maternal major bleeding complications, 30.8%;95%CI(9.1-61.4), two fetal deaths, 15.4%;95%CI(1.9-45.5), and five preterm deliveries, 38.5%;95%CI(13.9-68.4), were observed. Surgical embolectomy and catheter embolectomy or catheter thrombolysis has only been performed in 12 patients. Conclusion: The number of reports on thrombolytic therapy, surgical embolectomy and catheter embolectomy or thrombolysis for massive pulmonary embolism during pregnancy are limited. We suggest an international registry for pregnant patients undergoing thrombolysis or embolectomy to gain more information about these treatment options. Nevertheless, complication rates of thrombolytic therapy are acceptable in the light of the underlying disease, and in the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of life-threatening PE. © 2009 Elsevier Ltd. All rights reserved.
Keywords: Pulmonary embolism Venous thromboembolism Pregnancy Thrombolytic therapy Thrombolysis Embolectomy
Contents Introduction . . . . . . Case report. . . . . . . Thrombolytic therapy . . Surgical embolectomy. . Catheter directed therapy Conclusion . . . . . . . Conflict of Interest . . . References . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
1 2 2 3 3 4 4 4
Introduction
⁎ Corresponding author. Department of Internal Medicine, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, the Netherlands. E-mail address: [email protected] (G.D. te Raa). 0049-3848/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2009.03.001
The incidence of venous thromboembolic events (VTE) is the second cause of maternal death in the Netherlands and the most important cause of maternal death in the UK [1,2]. The exact incidence of VTE during pregnancy and puerperium is unknown, but estimations vary from 0.5-3.0 per 1000 pregnant women [3,4] and is up to ten times more common in
2
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5
pregnant women as compared to non-pregnant women [5]. Eighteen percent (35/193) of direct maternal deaths in pregnancy in the Netherlands between 1993 and 2000 were related to VTE [1]. VTE can occur at any stage of pregnancy but there is a higher risk in the puerperium. During pregnancy there are changes in the maternal haemostatic system which tend to prevent haemorrhage, but predispose to thrombosis [6]. Thrombosis is also aggravated by inherited and acquired maternal thrombophilias [6]. Because of the relatively high incidence and mortality rate of VTE in pregnancy, effective primary prevention and adequate management of thromboembolism in pregnancy are important. Treatment of VTE in pregnancy constitutes a challenge in daily clinical practise, because of possible haemorrhagic and teratogenic complications for mother and fetus. Low-molecular-weight heparin (LMWH) and intravenous unfractionated heparin (UFH) are used for prevention and treatment of VTE in pregnancy, with a preference for LMWH [7]. Treatment options for nonpregnant patients with severe, life-threatening pulmonary embolism, with haemodynamic compromise or failure of therapy with heparin include thrombolytic therapy, surgical embolectomy and catheter embolectomy or catheter thrombolysis. These options are considered as high-risk treatment in pregnancy and possibly harmful for mother and fetus. We describe a pregnant patient with massive pulmonary embolism who successfully received thrombolytic therapy and review the available literature on the outcome of aggressive therapy, i.e. thrombolytic therapy and embolectomy, in case of pulmonary embolism during pregnancy. Case report A 34-year-old female, gravida 1, presented at 25 weeks gestation with an acute collapse, reduced consciousness during five minutes and shortness of breath. At physical examination the patient had dyspnoea with a, respiratory rate of 30 per minute and hypoxaemia (O2 saturation 80% on room air), hypotension (blood pressure of 80/30mmHb) and a sinus tachycardia (115 bpm). Heart sounds revealed an ejection murmur. Electrocardiography demonstrated sinus tachycardia with T wave inversion in lead III and V1, V2 and V3. The condition of the fetus, assessed by ultrasound, was normal. The clinical presentation was highly suggestive of pulmonary embolism. Ventilation-perfusion scan showed massive pulmonary embolism with absence of perfusion of almost the entire right lung and a part of the left upper and lower lung. A trans-thoracic echocardiosonography demonstrated a severely enlarged right ventricle and atrium with increased right pressure and moderate tricuspid regurgitation. Therapy was initiated with intravenous heparin, but because of massive pulmonary embolism with significant haemodynamic compromise, increased right ventricular pressure and no improvement after administering heparin, the decision was made to start thrombolytic therapy using streptokinase. The patient received streptokinase as a bolus of 250.000 units followed by a continuous infusion of 100.000 units per hour during 24 hours followed by a weight-adjusted dose of LMWH. The response to thrombolytic therapy was remarkable: the tachycardia and dyspnoea resolved completely and blood pressure and heart rate normalised. Ultrasound revealed no signs of placental or fetal bleeding. The patient developed large subcutaneous haematomas, on the site of the skin injuries due to the collapse, which required two units of red blood cell transfusion. After discharge the pregnancy developed uneventful. LMWH was continued until delivery. A healthy child was born at 41 weeks of gestation by an uncomplicated vaginal delivery with minimal blood loss. A successive lung perfusion scan showed complete resolution of the pulmonary emboli. Acenocoumarol treatment was initiated after delivery and continued for a period of 6 weeks. The total period of anticoagulation therapy was 22 weeks. Thrombolytic therapy In non-pregnant patients, thrombolytic therapy is recommended in case of massive pulmonary embolism and haemodynamic compromise
or cardiogenic shock [8,9]. Several randomised trials have proven that thrombolytic therapy cause more rapid dissolution of the emboli in the first 24 hours and improves haemodynamics earlier as compared to heparin, but without evidence of survival advantage on the long term [8,10,11]. Mortality rates from massive pulmonary embolism in nonpregnant patients are exceptionally high with rates ranging up to 46.3% in patients with a systolic pressure b90 mmHg [15]. Major bleeding complications due to thrombolysis in non-pregnant patients vary from 0.8% to 8.4% [13,16]. The most commonly used thrombolytic agents are streptokinase, urokinase and recombinant tissue plasminogen activator (rt-PA). The safest and most effective treatment is yet unknown, but there seems to be a slight preference for rt-PA because of less haemorrhagic complications and a lower mortality rate [12,13]. Rt-PA is not allergenic and can be administered over a shorter time scale. Rt-PA is a large polypeptide that does not cross the placenta [17,29]. Streptokinase is also a large molecule derived from group C streptococci, which does not cross the placenta in amounts significant enough to induce fetal coagulopathy [14]. Urokinase is a small molecule purified from human urine; it does cross the placenta [17]. It is currently not known whether urokinase induces fetal coagulopathy, but this can not be excluded from its pharmacological profile. We conducted a PubMed (National Library of Medicine, Bethesda, MD) search with the subject headings “thrombolytic therapy”, “thrombolysis”, “pregnancy” and “pulmonary embolism” to identify reports of pregnant women who received treatment with thrombolytic therapy during pregnancy because of pulmonary embolism. Reports with postpartum pulmonary embolism and reports in which therapy was administered after delivery by emergency caesarean section because of pulmonary embolism were excluded. We limited our search to English literature. Data on the type and total dose of thrombolytic agent, gestational week, outcome of mother and child, preterm delivery and bleeding complications were extracted. Twenty-two cases were found till December 2008, two were excluded because of postpartum pulmonary embolism, two were excluded because of initiation of thrombolytic therapy after caesarean section and six cases were excluded because of non-English literature. In summary, we only found 13 cases (including our own case) of patients who received thrombolytic therapy for pulmonary embolism during pregnancy, 6 cases with rt-PA, 5 cases with streptokinase and 2 cases with urokinase (Table 1) [17–28]. Median gestational time was 26 weeks, with a range from 12 to 35 weeks. There have been no maternal deaths, four non-fatal maternal major bleeding complications, 30.8%; 95% CI (9.1-61.4), two fetal deaths, 15.4%; 95% CI (1.9-45.5) and five preterm deliveries, 38.5%; 95% CI (13.9-68.4), all just after initiation of thrombolytic therapy (Table 1). According to the authors, the fetal deaths and preterm deliveries were supposed to be primarily related to the sequelae of pulmonary embolism (Table 1). Three reviews on the use of thrombolysis during pregnancy for different indications, including pulmonary embolism, deep venous thrombosis, thrombosis of cardiac valvular prosthesis, myocardial infarction and stroke, have been published [17,29,30]. Ahearn et al published a review with 172 cases (164 treated with streptokinase, 3 urokinase, 5 rt-PA), including 10 cases of pulmonary embolism (these cases are included in Table 1 with exception of the cases from nonEnglish literature). They reported 5 non-fatal maternal bleeding complications (2.9%) and 3 fetal deaths (1.7%). No maternal deaths from thrombolytic therapy have been reported. Turrentine et al reviewed 172 cases (165 streptokinase, 3 urokinase, 4 rt-PA) with 8.1% maternal bleeding complications, 5.8% pregnancy losses and 5.8% preterm deliveries. They found two maternal deaths (1.2%), which could not be related to thrombolytic therapy, according to the authors. Most cases (n= 155) were described by German investigators, who treated pregnant women with streptokinase because of deep venous thrombosis [14,31,32]. We compared complication rates from patients treated with thrombolysis because of other indications than PE in pregnancy extracted
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5
3
Table 1 Treatment of pulmonary embolism during pregnancy. Author
year
Treatment
Total dose
gestational week
outcome mother
outcome child⁎
preterm delivery⁎
bleeding complications
Thrombolytic therapy Ahearn17 Baudo18 Flossdorf19 Patel20 Yap21 Trukhacheva22 Fagher23 McTaggart24 Hall25 Mazeika26 Te Raa Kramer27 Delclos28
2002 1990 1990 2003 2002 2005 1990 1977 1972 1994 2009 1995 1986
rt-PA rt-PA rt-PA rt-PA rt-PA rt-PA SK SK SK SK SK UK UK
100 mg 100 mg 43 mg 100 mg 100 mg 100 mg 1100.000 U 2900.000 U 1800.000 U 1400.000 U 2650.000 U
12 35 31 20 30 23 28 34 32 25 25 21 28
good good good good good good good good good good good good good
good death (14 d)† good good good good good death (0-8 h)† good good good good good
no yes yes no no no yes yes yes no no no no
no no yes, no no no yes, yes, yes, yes, yes, no yes,
Surgical embolectomy Blegvad35 Duff36 Cohn37 Marcinkevicius38 Becker34 Becker34 Becker34 Taniguchi39
1989 1985 1973 1970 1983 1983 1983 2008
SE SE SE SE SE SE SE SE
28 13 1st trim 24 ? ? ? 22
good good good good good good good good
good death (8 h)† good death (-1 h)† good good death (?)† good
no yes no yes no no yes yes
(?) (7 wk)
no no no no no no no no
15 30 26 26
good good good good
death (24 h)† good good good
yes (24 h) no no no
no no no no
Catheter embolectomy/Catheter Sofocleous44 2001 Bechtel43 2005 Krishnamurthy45 1999 40 Rosenblum 2008
57,200 U/kg
thrombolytic therapy CF rt-PA 34 mg CF rt-PA 15.5 mg CT UK 55,000 U/kg CE
(20 h) (48 h)
(10 h) (18d) (0 h)
(8 h) (20 h)
minor
major minor major major major minor
Legend: rt-PA = recombinant tissue plasminogenactivator, SK = streptokinase, UK = urokinase, SE = surgical embolectomy, CE = catheter directed mechanical embolectomy, CF = catheter directed thrombolytic therapy, preceded by mechanical fragmentation of the clot, CT = catheter directed thrombolytic therapy without mechanical fragmentation, ? = unknown, ⁎(time after intervention). † = cause of death. Baudo et al: cesarean section was accomplished, death due to acute respiratory distress syndrome. No evidence of fetal haemorrhage at autopsy. McTaggert et al: death was thought to be resulted from maternal anoxia following massive embolism. No evidence of fetal haemorrhage at autopsy. Duff et al: death due to premature spontaneous abortion, cause of abortion was not further specified. Marcinkevicius et al: death due to anoxaemia following pulmonary embolism. Becker et al: unknown. Sofocleous et al: death due to spontaneous premature abortion, probably due to maternal haemodynamic compromise because of pulmonary embolism and not due to thrombolytic therapy.
from the two largest and before mentioned reviews [17,30] with our cohort. Pregnant patients with PE had higher complication rates, 30.8%; 95% CI (9.1-61.4) major bleedings, 15.4%; 95% CI (1.9-45.5) fetal deaths and 38.5%; 95% CI (13.9-68.4) preterm deliveries, as compared to respectively 4%, 3.3% and 2.5% in pregnant patients with thrombolysis for other reasons than PE (not significant). The higher complication rates for PE might be due to the sequelae of the underlying disease; in case of PE, hypoxaemia or haemodynamical instability will have an impact on preterm delivery and fetal deaths. Haemorrhagic complications vary from small haematomas to major bleedings that require blood transfusions. The bleeding complication rate in our cohort is much higher than published in the reviews with various indications for thrombolysis and higher compared to trials of thrombolysis in nonpregnant patients [13,16]. The reason is not known. It is possible that only the successful treatment of PE in pregnant patients with thrombolysis have been reported, leading to an underestimation of maternal deaths. To avoid publication bias, an international registry of thrombolysis in pregnant patients would be helpful. In the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of lifethreatening PE. We recommend rt-PA over streptokinase and urokinase because of presumably less bleeding complications, a shorter duration of administration and no allergic complications.
with facilities for cardiopulmonary bypass surgery and with experienced surgeons. Thoracic surgery during pregnancy is associated with a substantial risk of maternal and fetal morbidity and mortality [34]. We conducted a PubMed (National Library of Medicine, Bethesda, MD) search with the subject headings headings “embolectomy” and/or “thrombolytic therapy”, “pregnancy” and “pulmonary embolism” to obtain reports of pregnant women undergoing surgical embolectomy. The mechanism of literature review and data extraction has been accomplished similar to the description in the section on thrombolytic therapy. We found 22 cases till December 2008, 6 were excluded because of postpartum pulmonary embolism (all after a caesarean section), 4 were excluded because of surgical embolectomy accomplished after an emergency caesarean section because of pulmonary embolism and 4 cases were excluded because of non-English written case-reports. In summary, 8 cases were selected for review (Table 1) [34–39]. Three of these patients were extracted from a report of Becker et al in which they described the results of 68 pregnant women undergoing cardiopulmonary surgery for various reasons [34]. In the eight cases undergoing surgical embolectomy, no maternal deaths, 3 fetal deaths, 37.5%; 95% CI (8.5-75.5), and 4 preterm deliveries, 50%; 95% CI (15.7-84.3), were reported. Maternal survival of surgical embolectomy seems to be acceptable; fetal death rate is, however, substantial, but series are very small.
Surgical embolectomy Catheter directed therapy Surgical embolectomy is indicated when conventional therapy or thrombolytic therapy has failed or when there is a contraindication for thrombolytic therapy [33]. Embolectomy should be limited to centres
Catheter directed therapy includes different techniques with and without pharmacological thrombolysis and mechanical embolectomy,
4
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5
including catheter directed mechanical embolectomy and catheter directed thrombolytic therapy proceeded with or without mechanical fragmentation of the clot [40]. Catheter directed therapies are invasive, experimental procedures, which also requires appropriate facilities and expertise. The main objective of a catheter-based approach with thrombolytic therapy is to improve the rate and efficiency of clot dissolution with minimal risk of systemic fibrinolysis. It has the theoretical advantage of immediate removal or fragmentation of the obstructing clot while avoiding the potential bleeding complications of systemic therapy [41]. However, there is no convincing evidence that catheterdirected thrombolytic therapy is superior to treatment with systemic thrombolytics or standard heparin [42]. The concept of the combination of mechanical fragmentation and thrombolytic therapy is interesting. Mechanical fragmentation increases the surface area of thrombus available for lytic activity, thus improving the efficiency of thrombus dissolution [43]. Mechanical catheter directed embolectomy is also a current alternative to surgical embolectomy. We conducted a PubMed (National Library of Medicine, Bethesda, MD) search with the subject headings “embolectomy” and/or “thrombolytic therapy”, “pregnancy” and “pulmonary embolism” to search for reports of pregnant women with PE treated with catheter therapy. The mechanism of literature review and data extraction has been accomplished similar to the description in the section on thrombolytic therapy. We found six cases of catheter-directed therapy for the treatment of pulmonary embolism during pregnancy till December 2008. One was excluded because of postpartum pulmonary embolism and one was excluded because of initiating the catheter directed intervention after an emergency caesarean section was performed (Table 1) [40,43–45]. In summary, four cases were included for review. In two cases, local catheter directed thrombolytic therapy (rt-PA) was preceded by mechanical embolectomy [43,44]. In another case only catheter directed local thrombolytic therapy using urokinase was performed [45]. In the last case only catheter directed mechanical embolectomy was used [40]. One fetal death, 25%; 95% CI (0.63-80.6), and one preterm delivery, 25%; 95% CI (0.63-80.6), were described. Conclusion Thrombolytic therapy for pregnant patients with PE has been reported in 13 cases (including our case). No maternal deaths occurred and the percentage of major bleeding (30.8%; 95% CI 9.1-61.4) ) and fetal deaths (15.4%; 95% CI 1.9-45.5) are acceptable in the light of the underlying disease. The published experience with thrombolytic therapy (n = 13), surgical embolectomy (n = 8) and catheter directed therapy (n = 4) is limited. We suggest an international registry for pregnant patients undergoing thrombolysis or embolectomy to gain more information about these treatment options. In the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of life-threatening PE. Conflict of Interest None. References [1] Schutte JM, Steegers EAP, Schuitemaker NWE, Santema JG, de Boer K, Briet JW, Pel M, Vermeulen G, Visser W, Roosmalen J. Rise in maternal mortality in the Netherlands 1993-02. [2] Thromboemoblic disease in pregnancy and the puerperium: acute management. RCOG. Green-top Guideline No. 28; 2007. [3] Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94:595–9. [4] Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108–14. [5] Rodger MA, Walker M, Wells PS. Diagnosis and treatment of venous thromboembolism in pregnancy. Best Pract Res Clin Haematol 2003;16:279–96. [6] Rosenberg VA, Lockwood CJ. Thromboembolism in pregnancy. Obstet Gynecol Clin North Am 2007;34:481–500.
[7] Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood Jul 15 2005;106(2):401–7. [8] Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med 1997;157:2550–6. [9] Goldhaber SZ. Thrombolysis in pulmonary embolism: a debatable indication. Thromb Haemost 2001;86:444–51. [10] Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA 1974;229:1606–13. [11] Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing rightventricular function and pulmonary perfusion. Lancet 1993;341:507–11. [12] Capstick T, Henry MT. Efficacy of thrombolytic agents in the treatment of pulmonary embolism. Eur Respir J 2005;26:864–74. [13] Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50. [14] Pfeifer GW. The use of thrombolytic therapy in obstetrics and gynaecology. Australas Ann Med 1970;19:28–31. [15] Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation 2006;113:577–82. [16] Levine MN. Thrombolytic therapy for venous thromboembolism. Complications and contraindications. Clin Chest Med 1995;16:321–8. [17] Ahearn GS, Hadjiliadis D, Govert JA, Tapson VF. Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options. Arch Intern Med 2002;162:1221–7. [18] Baudo F, Caimi TM, Redaelli R, Nosari AM, Mauri M, Leonardi G, et al. Emergency treatment with recombinant tissue plasminogen activator of pulmonary embolism in a pregnant woman with antithrombin III deficiency. Am J Obstet Gynecol 1990;163:1274–5. [19] Flossdorf T, Breulmann M, Hopf HB. Successful treatment of massive pulmonary embolism with recombinant tissue type plasminogen activator (rt-PA) in a pregnant woman with intact gravidity and preterm labour. Intensive Care Med 1990;16:454–6. [20] Patel RK, Fasan O, Arya R. Thrombolysis in pregnancy. Thromb Haemost 2003;90: 1216–7. [21] Yap LB, Alp NJ, Forfar JC. Thrombolysis for acute massive pulmonary embolism during pregnancy. Int J Cardiol 2002;82:193–4. [22] Trukhacheva E, Scharff M, Gardner M, Lakkis N. Massive pulmonary embolism in pregnancy treated with tissue plasminogen activator. Obstet Gynecol 2005;106:1156–8. [23] Fagher B, Ahlgren M, Astedt B. Acute massive pulmonary embolism treated with streptokinase during labor and the early puerperium. Acta Obstet Gynecol Scand 1990;69:659–61. [24] McTaggart DR, Ingram TG. Massive pulmonary embolism during pregnancy treated with streptokinase. Med J Aust 1977;1:18–20. [25] Hall RJ, Young C, Sutton GC, Cambell S. Treatment of acute massive pulmonary embolism by streptokinase during labour and delivery. Br Med J 1972;4:647–9. [26] Mazeika PK, Oakley CM. Massive pulmonary embolism in pregnancy treated with streptokinase and percutaneous catheter fragmentation. Eur Heart J 1994;15:1281–3. [27] Kramer WB, Belfort M, Saade GR, Surani S, Moise Jr KJ. Successful urokinase treatment of massive pulmonary embolism in pregnancy. Obstet Gynecol 1995;86:660–2. [28] Delclos GL, Davila F. Thrombolytic therapy for pulmonary embolism in pregnancy: a case report. Am J Obstet Gynecol 1986;155:375–6. [29] Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006;21:271–6. [30] Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;50:534–41. [31] Pfeifer GW. Studies on thrombolytic treatment of acute pulmonary embolism in gynecology. Geburtshilfe Frauenheilkd 1966;26:1394–402. [32] Ludwig H. Anticoagulants in pregnancy and puerperium. Geburtshilfe Frauenheilkd 1970;30:337–47. [33] Meneveau N, Seronde MF, Blonde MC, Legalery P, er-Petit K, Briand F, et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest Apr 2006;129(4):1043–50. [34] Becker RM. Intracardiac surgery in pregnant women. Ann Thorac Surg Oct 1983;36(4):453–8. [35] Blegvad S, Lund O, Nielsen TT, Guldholt I. Emergency embolectomy in a patient with massive pulmonary embolism during second trimester pregnancy. Acta Obstet Gynecol Scand 1989;68(3):267–70. [36] Duff P, Greene VP. Pregnancy complicated by solid-papillary epithelial tumor of the pancreas, pulmonary embolism, and pulmonary embolectomy. Am J Obstet Gynecol May 1985 1;152(1):80–1. [37] Cohn LH, Shumway NE. Pulmonary embolectomy during pregnancy. Arch Surg Feb 1973;106(2):214–5. [38] Marcinkevicius A, Sirvydis V, Triponis V, Baublys A, Martinkenas G, Matulionis A. Pulmonary embolectomy during pregnancy. J Cardiovasc Surg (Torino) Sep 1970;11(5):355–8. [39] Taniguchi S, Fukuda I, Minakawa M, Watanabe K, Daitoku K, Suzuki Y. Emergency Pulmonary Embolectomy During the Second Trimester of Pregnancy: Report of a Case. Surg Today 2008;38:59–61. [40] Rosenblum JK, Cynamon J. Mechanical and Enzymatic Thrombolysis of Acute Pulmonary Embolus: Review of the Literature and Cases from Our Institution. Vascular 2008;16(4):213–8.
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5 [41] McCotter CJ, Chiang KS, Fearrington EL. Intrapulmonary artery infusion of urokinase for treatment of massive pulmonary embolism: a review of 26 patients with and without contraindications to systemic thrombolytic therapy. Clin Cardiol Oct 1999;22(10):661–4. [42] Kucher N. Catheter embolectomy for acute pulmonary embolism. Chest Aug 2007;132(2):657–63. [43] Bechtel JJ, Mountford MC, Ellinwood WE. Massive pulmonary embolism in pregnancy treated with catheter fragmentation and local thrombolysis. Obstet Gynecol Nov 2005;106(5 Pt 2):1158–60.
5
[44] Sofocleous CT, Hinrichs C, Bahramipour P, Barone A, Abujudeh H, Contractor D. Percutaneous management of life-threatening pulmonary embolism complicating early pregnancy. J Vasc Interv Radiol Nov 2001;12(11):1355–6. [45] Krishnamurthy P, Martin CB, Kay HH, Diesner J, Friday RO, Weber CA, et al. Catheter-directed thrombolysis for thromboembolic disease during pregnancy: a viable option. J Matern Fetal Med Jan 1999;8(1):24–7.
Contents lists available at ScienceDirect
Thrombosis Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / t h r o m r e s
Review Article
Treatment options in massive pulmonary embolism during pregnancy; A case-report and review of literature G. Doreen te Raa a,⁎, Lucie S.M. Ribbert b, Repke J. Snijder c, Douwe H. Biesma a,d a
Department of Internal Medicine, St. Antonius Hospital Nieuwegein Department of Obstetrics, St. Antonius Hospital Nieuwegein Department of Pulmonary Medicine, St. Antonius Hospital Nieuwegein d Division of Internal Medicine and Dermatology, University Medical Centre, Utrecht, the Netherlands b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 27 November 2008 Received in revised form 20 February 2009 Accepted 7 March 2009 Available online 29 March 2009
Systemic thrombolysis with recombinant tissue plasminogen activator (rt-PA), streptokinase or urokinase is considered as high-risk treatment in pregnancy. However, several reports have described the successful use of systemic thrombolysis in pregnant patients with massive pulmonary embolism and haemodynamic instability. Case: We describe a 34-year old, pregnant female, who presented at 25 weeks of gestation with an acute collapse with reduced consciousness and shortness of breath caused by massive pulmonary embolism. Because of significant haemodynamic instability, increased right ventricular pressure and no improvement after intravenous heparin, thrombolytic therapy was administered. The response to thrombolytic therapy was excellent. No severe haemorrhagic complications were observed. Anticoagulant therapy with LMWH was continued until delivery. A healthy child was born at term. Review: In English literature, 13 patients received thrombolysis during pregnancy because of pulmonary embolism. No maternal deaths, four non-fatal maternal major bleeding complications, 30.8%;95%CI(9.1-61.4), two fetal deaths, 15.4%;95%CI(1.9-45.5), and five preterm deliveries, 38.5%;95%CI(13.9-68.4), were observed. Surgical embolectomy and catheter embolectomy or catheter thrombolysis has only been performed in 12 patients. Conclusion: The number of reports on thrombolytic therapy, surgical embolectomy and catheter embolectomy or thrombolysis for massive pulmonary embolism during pregnancy are limited. We suggest an international registry for pregnant patients undergoing thrombolysis or embolectomy to gain more information about these treatment options. Nevertheless, complication rates of thrombolytic therapy are acceptable in the light of the underlying disease, and in the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of life-threatening PE. © 2009 Elsevier Ltd. All rights reserved.
Keywords: Pulmonary embolism Venous thromboembolism Pregnancy Thrombolytic therapy Thrombolysis Embolectomy
Contents Introduction . . . . . . Case report. . . . . . . Thrombolytic therapy . . Surgical embolectomy. . Catheter directed therapy Conclusion . . . . . . . Conflict of Interest . . . References . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
. . . . . . . .
1 2 2 3 3 4 4 4
Introduction
⁎ Corresponding author. Department of Internal Medicine, St. Antonius Hospital, P.O. Box 2500, 3430 EM Nieuwegein, the Netherlands. E-mail address: [email protected] (G.D. te Raa). 0049-3848/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.thromres.2009.03.001
The incidence of venous thromboembolic events (VTE) is the second cause of maternal death in the Netherlands and the most important cause of maternal death in the UK [1,2]. The exact incidence of VTE during pregnancy and puerperium is unknown, but estimations vary from 0.5-3.0 per 1000 pregnant women [3,4] and is up to ten times more common in
2
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5
pregnant women as compared to non-pregnant women [5]. Eighteen percent (35/193) of direct maternal deaths in pregnancy in the Netherlands between 1993 and 2000 were related to VTE [1]. VTE can occur at any stage of pregnancy but there is a higher risk in the puerperium. During pregnancy there are changes in the maternal haemostatic system which tend to prevent haemorrhage, but predispose to thrombosis [6]. Thrombosis is also aggravated by inherited and acquired maternal thrombophilias [6]. Because of the relatively high incidence and mortality rate of VTE in pregnancy, effective primary prevention and adequate management of thromboembolism in pregnancy are important. Treatment of VTE in pregnancy constitutes a challenge in daily clinical practise, because of possible haemorrhagic and teratogenic complications for mother and fetus. Low-molecular-weight heparin (LMWH) and intravenous unfractionated heparin (UFH) are used for prevention and treatment of VTE in pregnancy, with a preference for LMWH [7]. Treatment options for nonpregnant patients with severe, life-threatening pulmonary embolism, with haemodynamic compromise or failure of therapy with heparin include thrombolytic therapy, surgical embolectomy and catheter embolectomy or catheter thrombolysis. These options are considered as high-risk treatment in pregnancy and possibly harmful for mother and fetus. We describe a pregnant patient with massive pulmonary embolism who successfully received thrombolytic therapy and review the available literature on the outcome of aggressive therapy, i.e. thrombolytic therapy and embolectomy, in case of pulmonary embolism during pregnancy. Case report A 34-year-old female, gravida 1, presented at 25 weeks gestation with an acute collapse, reduced consciousness during five minutes and shortness of breath. At physical examination the patient had dyspnoea with a, respiratory rate of 30 per minute and hypoxaemia (O2 saturation 80% on room air), hypotension (blood pressure of 80/30mmHb) and a sinus tachycardia (115 bpm). Heart sounds revealed an ejection murmur. Electrocardiography demonstrated sinus tachycardia with T wave inversion in lead III and V1, V2 and V3. The condition of the fetus, assessed by ultrasound, was normal. The clinical presentation was highly suggestive of pulmonary embolism. Ventilation-perfusion scan showed massive pulmonary embolism with absence of perfusion of almost the entire right lung and a part of the left upper and lower lung. A trans-thoracic echocardiosonography demonstrated a severely enlarged right ventricle and atrium with increased right pressure and moderate tricuspid regurgitation. Therapy was initiated with intravenous heparin, but because of massive pulmonary embolism with significant haemodynamic compromise, increased right ventricular pressure and no improvement after administering heparin, the decision was made to start thrombolytic therapy using streptokinase. The patient received streptokinase as a bolus of 250.000 units followed by a continuous infusion of 100.000 units per hour during 24 hours followed by a weight-adjusted dose of LMWH. The response to thrombolytic therapy was remarkable: the tachycardia and dyspnoea resolved completely and blood pressure and heart rate normalised. Ultrasound revealed no signs of placental or fetal bleeding. The patient developed large subcutaneous haematomas, on the site of the skin injuries due to the collapse, which required two units of red blood cell transfusion. After discharge the pregnancy developed uneventful. LMWH was continued until delivery. A healthy child was born at 41 weeks of gestation by an uncomplicated vaginal delivery with minimal blood loss. A successive lung perfusion scan showed complete resolution of the pulmonary emboli. Acenocoumarol treatment was initiated after delivery and continued for a period of 6 weeks. The total period of anticoagulation therapy was 22 weeks. Thrombolytic therapy In non-pregnant patients, thrombolytic therapy is recommended in case of massive pulmonary embolism and haemodynamic compromise
or cardiogenic shock [8,9]. Several randomised trials have proven that thrombolytic therapy cause more rapid dissolution of the emboli in the first 24 hours and improves haemodynamics earlier as compared to heparin, but without evidence of survival advantage on the long term [8,10,11]. Mortality rates from massive pulmonary embolism in nonpregnant patients are exceptionally high with rates ranging up to 46.3% in patients with a systolic pressure b90 mmHg [15]. Major bleeding complications due to thrombolysis in non-pregnant patients vary from 0.8% to 8.4% [13,16]. The most commonly used thrombolytic agents are streptokinase, urokinase and recombinant tissue plasminogen activator (rt-PA). The safest and most effective treatment is yet unknown, but there seems to be a slight preference for rt-PA because of less haemorrhagic complications and a lower mortality rate [12,13]. Rt-PA is not allergenic and can be administered over a shorter time scale. Rt-PA is a large polypeptide that does not cross the placenta [17,29]. Streptokinase is also a large molecule derived from group C streptococci, which does not cross the placenta in amounts significant enough to induce fetal coagulopathy [14]. Urokinase is a small molecule purified from human urine; it does cross the placenta [17]. It is currently not known whether urokinase induces fetal coagulopathy, but this can not be excluded from its pharmacological profile. We conducted a PubMed (National Library of Medicine, Bethesda, MD) search with the subject headings “thrombolytic therapy”, “thrombolysis”, “pregnancy” and “pulmonary embolism” to identify reports of pregnant women who received treatment with thrombolytic therapy during pregnancy because of pulmonary embolism. Reports with postpartum pulmonary embolism and reports in which therapy was administered after delivery by emergency caesarean section because of pulmonary embolism were excluded. We limited our search to English literature. Data on the type and total dose of thrombolytic agent, gestational week, outcome of mother and child, preterm delivery and bleeding complications were extracted. Twenty-two cases were found till December 2008, two were excluded because of postpartum pulmonary embolism, two were excluded because of initiation of thrombolytic therapy after caesarean section and six cases were excluded because of non-English literature. In summary, we only found 13 cases (including our own case) of patients who received thrombolytic therapy for pulmonary embolism during pregnancy, 6 cases with rt-PA, 5 cases with streptokinase and 2 cases with urokinase (Table 1) [17–28]. Median gestational time was 26 weeks, with a range from 12 to 35 weeks. There have been no maternal deaths, four non-fatal maternal major bleeding complications, 30.8%; 95% CI (9.1-61.4), two fetal deaths, 15.4%; 95% CI (1.9-45.5) and five preterm deliveries, 38.5%; 95% CI (13.9-68.4), all just after initiation of thrombolytic therapy (Table 1). According to the authors, the fetal deaths and preterm deliveries were supposed to be primarily related to the sequelae of pulmonary embolism (Table 1). Three reviews on the use of thrombolysis during pregnancy for different indications, including pulmonary embolism, deep venous thrombosis, thrombosis of cardiac valvular prosthesis, myocardial infarction and stroke, have been published [17,29,30]. Ahearn et al published a review with 172 cases (164 treated with streptokinase, 3 urokinase, 5 rt-PA), including 10 cases of pulmonary embolism (these cases are included in Table 1 with exception of the cases from nonEnglish literature). They reported 5 non-fatal maternal bleeding complications (2.9%) and 3 fetal deaths (1.7%). No maternal deaths from thrombolytic therapy have been reported. Turrentine et al reviewed 172 cases (165 streptokinase, 3 urokinase, 4 rt-PA) with 8.1% maternal bleeding complications, 5.8% pregnancy losses and 5.8% preterm deliveries. They found two maternal deaths (1.2%), which could not be related to thrombolytic therapy, according to the authors. Most cases (n= 155) were described by German investigators, who treated pregnant women with streptokinase because of deep venous thrombosis [14,31,32]. We compared complication rates from patients treated with thrombolysis because of other indications than PE in pregnancy extracted
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5
3
Table 1 Treatment of pulmonary embolism during pregnancy. Author
year
Treatment
Total dose
gestational week
outcome mother
outcome child⁎
preterm delivery⁎
bleeding complications
Thrombolytic therapy Ahearn17 Baudo18 Flossdorf19 Patel20 Yap21 Trukhacheva22 Fagher23 McTaggart24 Hall25 Mazeika26 Te Raa Kramer27 Delclos28
2002 1990 1990 2003 2002 2005 1990 1977 1972 1994 2009 1995 1986
rt-PA rt-PA rt-PA rt-PA rt-PA rt-PA SK SK SK SK SK UK UK
100 mg 100 mg 43 mg 100 mg 100 mg 100 mg 1100.000 U 2900.000 U 1800.000 U 1400.000 U 2650.000 U
12 35 31 20 30 23 28 34 32 25 25 21 28
good good good good good good good good good good good good good
good death (14 d)† good good good good good death (0-8 h)† good good good good good
no yes yes no no no yes yes yes no no no no
no no yes, no no no yes, yes, yes, yes, yes, no yes,
Surgical embolectomy Blegvad35 Duff36 Cohn37 Marcinkevicius38 Becker34 Becker34 Becker34 Taniguchi39
1989 1985 1973 1970 1983 1983 1983 2008
SE SE SE SE SE SE SE SE
28 13 1st trim 24 ? ? ? 22
good good good good good good good good
good death (8 h)† good death (-1 h)† good good death (?)† good
no yes no yes no no yes yes
(?) (7 wk)
no no no no no no no no
15 30 26 26
good good good good
death (24 h)† good good good
yes (24 h) no no no
no no no no
Catheter embolectomy/Catheter Sofocleous44 2001 Bechtel43 2005 Krishnamurthy45 1999 40 Rosenblum 2008
57,200 U/kg
thrombolytic therapy CF rt-PA 34 mg CF rt-PA 15.5 mg CT UK 55,000 U/kg CE
(20 h) (48 h)
(10 h) (18d) (0 h)
(8 h) (20 h)
minor
major minor major major major minor
Legend: rt-PA = recombinant tissue plasminogenactivator, SK = streptokinase, UK = urokinase, SE = surgical embolectomy, CE = catheter directed mechanical embolectomy, CF = catheter directed thrombolytic therapy, preceded by mechanical fragmentation of the clot, CT = catheter directed thrombolytic therapy without mechanical fragmentation, ? = unknown, ⁎(time after intervention). † = cause of death. Baudo et al: cesarean section was accomplished, death due to acute respiratory distress syndrome. No evidence of fetal haemorrhage at autopsy. McTaggert et al: death was thought to be resulted from maternal anoxia following massive embolism. No evidence of fetal haemorrhage at autopsy. Duff et al: death due to premature spontaneous abortion, cause of abortion was not further specified. Marcinkevicius et al: death due to anoxaemia following pulmonary embolism. Becker et al: unknown. Sofocleous et al: death due to spontaneous premature abortion, probably due to maternal haemodynamic compromise because of pulmonary embolism and not due to thrombolytic therapy.
from the two largest and before mentioned reviews [17,30] with our cohort. Pregnant patients with PE had higher complication rates, 30.8%; 95% CI (9.1-61.4) major bleedings, 15.4%; 95% CI (1.9-45.5) fetal deaths and 38.5%; 95% CI (13.9-68.4) preterm deliveries, as compared to respectively 4%, 3.3% and 2.5% in pregnant patients with thrombolysis for other reasons than PE (not significant). The higher complication rates for PE might be due to the sequelae of the underlying disease; in case of PE, hypoxaemia or haemodynamical instability will have an impact on preterm delivery and fetal deaths. Haemorrhagic complications vary from small haematomas to major bleedings that require blood transfusions. The bleeding complication rate in our cohort is much higher than published in the reviews with various indications for thrombolysis and higher compared to trials of thrombolysis in nonpregnant patients [13,16]. The reason is not known. It is possible that only the successful treatment of PE in pregnant patients with thrombolysis have been reported, leading to an underestimation of maternal deaths. To avoid publication bias, an international registry of thrombolysis in pregnant patients would be helpful. In the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of lifethreatening PE. We recommend rt-PA over streptokinase and urokinase because of presumably less bleeding complications, a shorter duration of administration and no allergic complications.
with facilities for cardiopulmonary bypass surgery and with experienced surgeons. Thoracic surgery during pregnancy is associated with a substantial risk of maternal and fetal morbidity and mortality [34]. We conducted a PubMed (National Library of Medicine, Bethesda, MD) search with the subject headings headings “embolectomy” and/or “thrombolytic therapy”, “pregnancy” and “pulmonary embolism” to obtain reports of pregnant women undergoing surgical embolectomy. The mechanism of literature review and data extraction has been accomplished similar to the description in the section on thrombolytic therapy. We found 22 cases till December 2008, 6 were excluded because of postpartum pulmonary embolism (all after a caesarean section), 4 were excluded because of surgical embolectomy accomplished after an emergency caesarean section because of pulmonary embolism and 4 cases were excluded because of non-English written case-reports. In summary, 8 cases were selected for review (Table 1) [34–39]. Three of these patients were extracted from a report of Becker et al in which they described the results of 68 pregnant women undergoing cardiopulmonary surgery for various reasons [34]. In the eight cases undergoing surgical embolectomy, no maternal deaths, 3 fetal deaths, 37.5%; 95% CI (8.5-75.5), and 4 preterm deliveries, 50%; 95% CI (15.7-84.3), were reported. Maternal survival of surgical embolectomy seems to be acceptable; fetal death rate is, however, substantial, but series are very small.
Surgical embolectomy Catheter directed therapy Surgical embolectomy is indicated when conventional therapy or thrombolytic therapy has failed or when there is a contraindication for thrombolytic therapy [33]. Embolectomy should be limited to centres
Catheter directed therapy includes different techniques with and without pharmacological thrombolysis and mechanical embolectomy,
4
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5
including catheter directed mechanical embolectomy and catheter directed thrombolytic therapy proceeded with or without mechanical fragmentation of the clot [40]. Catheter directed therapies are invasive, experimental procedures, which also requires appropriate facilities and expertise. The main objective of a catheter-based approach with thrombolytic therapy is to improve the rate and efficiency of clot dissolution with minimal risk of systemic fibrinolysis. It has the theoretical advantage of immediate removal or fragmentation of the obstructing clot while avoiding the potential bleeding complications of systemic therapy [41]. However, there is no convincing evidence that catheterdirected thrombolytic therapy is superior to treatment with systemic thrombolytics or standard heparin [42]. The concept of the combination of mechanical fragmentation and thrombolytic therapy is interesting. Mechanical fragmentation increases the surface area of thrombus available for lytic activity, thus improving the efficiency of thrombus dissolution [43]. Mechanical catheter directed embolectomy is also a current alternative to surgical embolectomy. We conducted a PubMed (National Library of Medicine, Bethesda, MD) search with the subject headings “embolectomy” and/or “thrombolytic therapy”, “pregnancy” and “pulmonary embolism” to search for reports of pregnant women with PE treated with catheter therapy. The mechanism of literature review and data extraction has been accomplished similar to the description in the section on thrombolytic therapy. We found six cases of catheter-directed therapy for the treatment of pulmonary embolism during pregnancy till December 2008. One was excluded because of postpartum pulmonary embolism and one was excluded because of initiating the catheter directed intervention after an emergency caesarean section was performed (Table 1) [40,43–45]. In summary, four cases were included for review. In two cases, local catheter directed thrombolytic therapy (rt-PA) was preceded by mechanical embolectomy [43,44]. In another case only catheter directed local thrombolytic therapy using urokinase was performed [45]. In the last case only catheter directed mechanical embolectomy was used [40]. One fetal death, 25%; 95% CI (0.63-80.6), and one preterm delivery, 25%; 95% CI (0.63-80.6), were described. Conclusion Thrombolytic therapy for pregnant patients with PE has been reported in 13 cases (including our case). No maternal deaths occurred and the percentage of major bleeding (30.8%; 95% CI 9.1-61.4) ) and fetal deaths (15.4%; 95% CI 1.9-45.5) are acceptable in the light of the underlying disease. The published experience with thrombolytic therapy (n = 13), surgical embolectomy (n = 8) and catheter directed therapy (n = 4) is limited. We suggest an international registry for pregnant patients undergoing thrombolysis or embolectomy to gain more information about these treatment options. In the meantime, current data do not justify withholding pregnant women from thrombolytic therapy in case of life-threatening PE. Conflict of Interest None. References [1] Schutte JM, Steegers EAP, Schuitemaker NWE, Santema JG, de Boer K, Briet JW, Pel M, Vermeulen G, Visser W, Roosmalen J. Rise in maternal mortality in the Netherlands 1993-02. [2] Thromboemoblic disease in pregnancy and the puerperium: acute management. RCOG. Green-top Guideline No. 28; 2007. [3] Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94:595–9. [4] Toglia MR, Weg JG. Venous thromboembolism during pregnancy. N Engl J Med 1996;335:108–14. [5] Rodger MA, Walker M, Wells PS. Diagnosis and treatment of venous thromboembolism in pregnancy. Best Pract Res Clin Haematol 2003;16:279–96. [6] Rosenberg VA, Lockwood CJ. Thromboembolism in pregnancy. Obstet Gynecol Clin North Am 2007;34:481–500.
[7] Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood Jul 15 2005;106(2):401–7. [8] Dalen JE, Alpert JS, Hirsh J. Thrombolytic therapy for pulmonary embolism: is it effective? Is it safe? When is it indicated? Arch Intern Med 1997;157:2550–6. [9] Goldhaber SZ. Thrombolysis in pulmonary embolism: a debatable indication. Thromb Haemost 2001;86:444–51. [10] Urokinase-streptokinase embolism trial. Phase 2 results. A cooperative study. JAMA 1974;229:1606–13. [11] Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, et al. Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing rightventricular function and pulmonary perfusion. Lancet 1993;341:507–11. [12] Capstick T, Henry MT. Efficacy of thrombolytic agents in the treatment of pulmonary embolism. Eur Respir J 2005;26:864–74. [13] Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50. [14] Pfeifer GW. The use of thrombolytic therapy in obstetrics and gynaecology. Australas Ann Med 1970;19:28–31. [15] Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Massive pulmonary embolism. Circulation 2006;113:577–82. [16] Levine MN. Thrombolytic therapy for venous thromboembolism. Complications and contraindications. Clin Chest Med 1995;16:321–8. [17] Ahearn GS, Hadjiliadis D, Govert JA, Tapson VF. Massive pulmonary embolism during pregnancy successfully treated with recombinant tissue plasminogen activator: a case report and review of treatment options. Arch Intern Med 2002;162:1221–7. [18] Baudo F, Caimi TM, Redaelli R, Nosari AM, Mauri M, Leonardi G, et al. Emergency treatment with recombinant tissue plasminogen activator of pulmonary embolism in a pregnant woman with antithrombin III deficiency. Am J Obstet Gynecol 1990;163:1274–5. [19] Flossdorf T, Breulmann M, Hopf HB. Successful treatment of massive pulmonary embolism with recombinant tissue type plasminogen activator (rt-PA) in a pregnant woman with intact gravidity and preterm labour. Intensive Care Med 1990;16:454–6. [20] Patel RK, Fasan O, Arya R. Thrombolysis in pregnancy. Thromb Haemost 2003;90: 1216–7. [21] Yap LB, Alp NJ, Forfar JC. Thrombolysis for acute massive pulmonary embolism during pregnancy. Int J Cardiol 2002;82:193–4. [22] Trukhacheva E, Scharff M, Gardner M, Lakkis N. Massive pulmonary embolism in pregnancy treated with tissue plasminogen activator. Obstet Gynecol 2005;106:1156–8. [23] Fagher B, Ahlgren M, Astedt B. Acute massive pulmonary embolism treated with streptokinase during labor and the early puerperium. Acta Obstet Gynecol Scand 1990;69:659–61. [24] McTaggart DR, Ingram TG. Massive pulmonary embolism during pregnancy treated with streptokinase. Med J Aust 1977;1:18–20. [25] Hall RJ, Young C, Sutton GC, Cambell S. Treatment of acute massive pulmonary embolism by streptokinase during labour and delivery. Br Med J 1972;4:647–9. [26] Mazeika PK, Oakley CM. Massive pulmonary embolism in pregnancy treated with streptokinase and percutaneous catheter fragmentation. Eur Heart J 1994;15:1281–3. [27] Kramer WB, Belfort M, Saade GR, Surani S, Moise Jr KJ. Successful urokinase treatment of massive pulmonary embolism in pregnancy. Obstet Gynecol 1995;86:660–2. [28] Delclos GL, Davila F. Thrombolytic therapy for pulmonary embolism in pregnancy: a case report. Am J Obstet Gynecol 1986;155:375–6. [29] Leonhardt G, Gaul C, Nietsch HH, Buerke M, Schleussner E. Thrombolytic therapy in pregnancy. J Thromb Thrombolysis 2006;21:271–6. [30] Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;50:534–41. [31] Pfeifer GW. Studies on thrombolytic treatment of acute pulmonary embolism in gynecology. Geburtshilfe Frauenheilkd 1966;26:1394–402. [32] Ludwig H. Anticoagulants in pregnancy and puerperium. Geburtshilfe Frauenheilkd 1970;30:337–47. [33] Meneveau N, Seronde MF, Blonde MC, Legalery P, er-Petit K, Briand F, et al. Management of unsuccessful thrombolysis in acute massive pulmonary embolism. Chest Apr 2006;129(4):1043–50. [34] Becker RM. Intracardiac surgery in pregnant women. Ann Thorac Surg Oct 1983;36(4):453–8. [35] Blegvad S, Lund O, Nielsen TT, Guldholt I. Emergency embolectomy in a patient with massive pulmonary embolism during second trimester pregnancy. Acta Obstet Gynecol Scand 1989;68(3):267–70. [36] Duff P, Greene VP. Pregnancy complicated by solid-papillary epithelial tumor of the pancreas, pulmonary embolism, and pulmonary embolectomy. Am J Obstet Gynecol May 1985 1;152(1):80–1. [37] Cohn LH, Shumway NE. Pulmonary embolectomy during pregnancy. Arch Surg Feb 1973;106(2):214–5. [38] Marcinkevicius A, Sirvydis V, Triponis V, Baublys A, Martinkenas G, Matulionis A. Pulmonary embolectomy during pregnancy. J Cardiovasc Surg (Torino) Sep 1970;11(5):355–8. [39] Taniguchi S, Fukuda I, Minakawa M, Watanabe K, Daitoku K, Suzuki Y. Emergency Pulmonary Embolectomy During the Second Trimester of Pregnancy: Report of a Case. Surg Today 2008;38:59–61. [40] Rosenblum JK, Cynamon J. Mechanical and Enzymatic Thrombolysis of Acute Pulmonary Embolus: Review of the Literature and Cases from Our Institution. Vascular 2008;16(4):213–8.
G.D. te Raa et al. / Thrombosis Research 124 (2009) 1–5 [41] McCotter CJ, Chiang KS, Fearrington EL. Intrapulmonary artery infusion of urokinase for treatment of massive pulmonary embolism: a review of 26 patients with and without contraindications to systemic thrombolytic therapy. Clin Cardiol Oct 1999;22(10):661–4. [42] Kucher N. Catheter embolectomy for acute pulmonary embolism. Chest Aug 2007;132(2):657–63. [43] Bechtel JJ, Mountford MC, Ellinwood WE. Massive pulmonary embolism in pregnancy treated with catheter fragmentation and local thrombolysis. Obstet Gynecol Nov 2005;106(5 Pt 2):1158–60.
5
[44] Sofocleous CT, Hinrichs C, Bahramipour P, Barone A, Abujudeh H, Contractor D. Percutaneous management of life-threatening pulmonary embolism complicating early pregnancy. J Vasc Interv Radiol Nov 2001;12(11):1355–6. [45] Krishnamurthy P, Martin CB, Kay HH, Diesner J, Friday RO, Weber CA, et al. Catheter-directed thrombolysis for thromboembolic disease during pregnancy: a viable option. J Matern Fetal Med Jan 1999;8(1):24–7.