Thrombolytic
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
The limited use of alteplase during pregnancy does not suggest a significant fetal risk. Although only one of the reported human exposures occurred during organogenesis, the high molecular weight probably precludes the transfer of alteplase to the embryo. Moreover, teratogenicity was not observed in animals. Hemorrhage is a risk of therapy at any time during gestation, but careful monitoring of the mother can prevent this from becoming a significant risk to the fetus. Therefore, it appears that alteplase may be used during gestation if the mother’s condition requires this therapy.
FETAL RISK SUMMARY
Alteplase (tissue plasminogen activator; t-PA; rt-PA), an enzyme formed by recombinant DNA technology, is a thrombolytic agent used for the treatment of acute conditions such as myocardial infarction, pulmonary embolism, and ischemic stroke. The agent is a glycoprotein composed of 527 amino acids (1).
No maternal or fetal toxicity was observed in rats and rabbits dosed with 1 mg/kg (approximately 0.65 times the human dose for acute myocardial infarction [HD]) during organogenesis (1). An embryocidal effect was noted in rabbits administered an IV dose of 3 mg/kg (about 2 times the HD) (1). Shepard (2) cited two studies in which no teratogenicity or other toxicity was observed in the offspring of pregnant rats and rabbits administered t-PA during organogenesis.
Ten case reports have described the use of alteplase in human pregnancy (3–12). A 27-year-old woman in premature labor at 31 weeks’ gestation was treated with urokinase and heparin, supplemented with continuous dobutamine to maintain a stable hemodynamic state, for massive pulmonary embolism (3). Because she failed to improve, low-dose alteplase therapy was initiated at 10 mg/hour for 4 hours, followed by 2 mg/hour for 1.5 hours (total dose 43 mg). The patient’s clinical condition markedly improved with complete reperfusion of the right upper and middle lobe and partial reperfusion of the left lower lobe. Coagulation tests (prothrombin time, partial thromboplastin time, and thrombin time) during alteplase therapy remained within or close to the normal range. A healthy, premature, 2100-g male infant was delivered 48 hours after thrombolysis. A 38-year-old woman at 32 weeks’ gestation developed a superior vena caval thrombosis during total parenteral hyperalimentation (4). Treatment with alteplase, 2 mg/hour for 48 hours resulted in clinical resolution of her symptoms (swelling of face and arms) within 24 hours. No evidence of placental bleeding was observed. Labor was induced 2 days later, and a healthy premature infant was delivered. A 29-year-old woman with severe pulmonary embolism and congenital antithrombin III deficiency was treated at 35 weeks’ gestation with 100 mg alteplase for 3 hours followed by IV heparin (5). Nearly complete reperfusion of the right lung and the lower two-thirds of the left lung was observed at the end of the alteplase infusion. No placental bleeding was noted. The male infant, delivered by cesarean section 20 hours later, died at 14 days of age secondary to intracranial hemorrhage, a complication thought to be caused by prematurity and unrelated to the thrombolytic therapy.
Brief details of a case (6) of t-PA therapy during pregnancy were described in a 1995 review (8). A 30-year-old woman in her 11th week of gestation was treated with alteplase for pulmonary embolism. No complications were observed, and she had a normal, term delivery (6). A 30-year-old woman at 21 weeks’ gestation had an acute myocardial infarction that was treated with a total dose of 100 mg alteplase given IV for 90 minutes (7). Immediate relief of her chest pain occurred and the other effects of cardiac reperfusion (arrhythmias and hypotension) were successfully treated. A cesarean section was performed at 33 weeks’ gestation for premature labor unresponsive to magnesium sulfate, and a 1640-g male infant who has done well was delivered. A 20% abruptio placentae was noted during surgery. The cause of the abruption was thought to be either alteplase or the aspirin (81 mg/day) the mother had received after her initial treatment (7).
A 32-year-old pregnant woman had two episodes of a thrombosed St. Jude mitral valve prosthesis (8). The first event, at 20 weeks’ gestation, was successfully treated by clot removal under cardiopulmonary bypass. About 8 weeks later, another clot formed on the valve and it was treated with 50 mg alteplase. An anterior placental hematoma was noted on ultrasound during treatment, but it resolved spontaneously within 2 weeks. At 38 weeks’ gestation, the patient delivered vaginally a healthy girl with Apgar scores of 10 at 1 and 5 minutes (8). A 31-year-old patient developed a pulmonary embolism at 12 weeks’ gestation (9). The woman was initially treated with IV heparin. However, because of continued hemodynamic deterioration, IV alteplase 100 mg over 2 hours was administered with rapid clinical improvement. SC heparin was given for the remainder of the pregnancy. At 33 weeks’ gestation, placental abruption was diagnosed and a cesarean section delivered a normal 2325-g female infant with Apgar scores of 7 and 8 at 1 and 5 minutes, respectively (9). The last case report involved a 28-year-old woman who underwent in vitro fertilization because of long-standing infertility (10). Approximately 7 days after embryo transfer, she experienced a middle cerebral artery thrombosis secondary to ovarian hyperstimulation syndrome induced by the fertility medications. Treatment with 15.5 mg of intra-arterial alteplase over 68 minutes dissolved the clot but a hematoma developed in the right basal ganglia resulting in worsening the stroke. She improved over the next 3 months with only mild residual effects of the stroke and eventually delivered a healthy male infant by spontaneous vaginal delivery at term (10).
A 2005 report described the use of alteplase in an 18-year-old woman with nephritic syndrome who was treated with cyclosporine and prophylactic enoxaparin from 9 weeks’ gestation (11). At 26 weeks’, a subtotal thrombus of the right main renal vein was found. Enoxaparin was stopped and a continuous infusion of alteplase and low-dose heparin was begun. After 24 hours, the thrombus had decreased by 25%. On hospital day 7 (27 weeks’), a cesarean section performed for a prolonged fetal heart rate deceleration delivered a 720-g female infant with Apgar scores of 5 and 6 at 1 and 5 minutes, respectively. Alteplase and heparin were discontinued intraoperatively. The infant, with repeated normal head ultrasound scans, went home on the 83rd day of life with no evidence of focal neural deficits (11).
A 2006 report described the use of alteplase in a 34-year-old woman at 10 weeks’ gestation who developed a fulminate pulmonary thromboembolism (12). Treatment with alteplase removed most of the thrombotic material in the pulmonary arteries. The patient was treated with heparin and then danaparoid and gave birth to a healthy female infant at term (12).
A 1995 review found no increased risk for preterm rupture of membranes, placental hemorrhage, or premature labor from thrombolytic agents (streptokinase, urokinase, or alteplase) (13). In seven women administered thrombolytic therapy before 14 weeks’ gestation, pregnancy loss occurred in one case. Because of the small number of exposures, the concern that thrombolytics may interfere with placental implantation cannot be completely excluded and, indeed, one such case has been reported, although the exact cause was not determined (13).
BREASTFEEDING SUMMARY
It is not known whether alteplase (t-PA) crosses into human milk. Because of the nature of the indications for this agent and its very short initial half-life (<5 minutes), the opportunities for its use during lactation or the possibility of exposure of a nursing infant is minimal.
References
1.Product information. Activase. Genentech, 2001.
2.Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:416.
3.Flossdorf T, Breulmann M, Hopf H-B. 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.
4.Barclay GR, Allen K, Pennington CR. Tissue plasminogen activator in the treatment of superior vena caval thrombosis associated with parenteral nutrition. Postgrad Med J 1990;66:398–400.
5.Baudo F, Caimi TM, Redaelli R, Nosari AM, Mauri M, Leonardi G, deCataldo F. 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.
6.Seifried E, Gabelmann A, Ellbrück D. Thrombolytische Therapie einer Lungenarterienembolie in der Frühschwangerschaft mit rekombinantem Gewebe-Plasminogen-Aktivator. Geburtshilfe Frauenheilkd 1991;51:655. As cited in Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;50:534–41.
7.Schumacher B, Belfort MA, Card RJ. Successful treatment of acute myocardial infarction during pregnancy with tissue plasminogen activator. Am J Obstet Gynecol 1997;176:716–9.
8.Fleyfel M, Bourzoufi K, Huin G, Subtil D, Puech F. Recombinant tissue type plasminogen activator treatment of thrombosed mitral valve prosthesis during pregnancy. Can J Anaesth 1997;44:735–8.
9.Huang WH, Kirz DS, Gallee RC, Gordey K. First trimester use of recombinant tissue plasminogen activator in pulmonary embolism. Obstet Gynecol 2000;96:838.
10.Elford K, Leader A, Wee R, Stya PK. Stroke in ovarian hyperstimulation syndrome in early pregnancy treated with intra-arterial rt-PA. Neurology 2002;59:1270–2.
11.Song JY, Valentino L. A pregnant patient with renal vein thrombosis successfully treated with low-dose thrombolytic therapy: a case report. Am J Obstet Gynecol 2005;192:2073–5.
12.Weilbach C, Rahe-Meyer N, Raymondos K, Piepenbrock S. Delivery of a healthy child 30 weeks after resuscitation for thromboembolism and treatment with danaparoid: 5-year follow up. J Perinat Med 2006;34:505–6.
13.Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;50:534–41.