Alteplase]]>

Risk Factor: CM
Class: Hematological agents/ Thrombolytics

Contents of this page:
Fetal Risk Summary
Breast Feeding Summary
References

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) during organogenesis (1). An embryocidal effect was noted in rabbits administered an IV dose of 3 mg/kg (about 2 times the human dose for acute myocardial infarction) (1). Shepard cited two studies in which no teratogenicity or other toxicity was observed in the offspring of pregnant rats and rabbits administered tissue plasminogen activator during organogenesis (2).

Five case reports have described the use of alteplase in human pregnancy (3,4,5,6 and 7). 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, and after alteplase, she was treated with continuous IV heparin. Complete reperfusion of the right upper and middle lobe and partial reperfusion of the left lower lobe was demonstrated on subsequent repeat pulmonary angiography. Coagulation tests (prothrombin time, partial thromboplastin time, and thrombin time) during alteplase therapy remained within or close to the normal range. A healthy, premature, 2,100-g male infant was spontaneously delivered 48 hours after thrombolysis.

A 38-year-old woman at 32 weeks’ gestation was receiving total parenteral nutrition because of subacute intestinal obstruction (4). She developed a superior vena caval thrombosis 5 days after the start of hyperalimentation. The patient was treated with alteplase, 2 mg/hour for 48 hours. Clinical resolution of her symptoms (swelling of her face and arms) occurred within 24 hours, and repeat venography demonstrated re-canalization of the thrombosis. 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 the fourth 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 (6). No complications were observed, and she had a normal term delivery.

In a 1997 case report, 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).

In summary, the limited use of alteplase (t-PA) during pregnancy does not support a teratogenic risk. Because of the high molecular weight, it is doubtful if this enzyme crosses the placenta to the fetus. Although there is a major risk of maternal hemorrhage if alteplase is given at the time of delivery, there does not appear to be a similar risk when therapy occurs outside of the intrapartum period. No complications of therapy were observed in the four cases described above. Moreover, a 1995 review found no increased risk with thrombolytic agents (streptokinase, urokinase, or alteplase) for preterm rupture of membranes, placental hemorrhage, or premature labor (8). In seven women administered thrombolytic therapy before 14 weeks’ gestation, pregnancy loss occurred in one case (8). 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. Based on these data, however, it appears that alteplase may be used during gestation if the mother’s condition requires this therapy.

Breast Feeding 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 (less than 5 minutes), the opportunities for its use during lactation or the possibility of exposure to a nursing infant are minimal.

References

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  1. Product information. Activase. Genentech, 2001.
  2. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:416.
  3. Flobdorf Th, 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;16:4546.
  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;66:398400.
  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;163:12745.
  6. Seifried E, Gabelmann A, Ellbrck D, et al. Thrombolytische Therapie einer Lungenarterienembolie in der Frhschwangerschaft 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;50:53441.
  7. Schumacher B, Belfort MA, Card RJ. Successful treatment of acute myocardial infarction during pregnancy with tissue plasminogen activator. Am J Obstet Gynecol 1997;176:7169.
  8. Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Surv 1995;50:53441.

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