UROKINASE

Fetal Risk Summary

Urokinase, 100,000 IU/kg intraperitoneal, was not teratogenic in rats or mice (1). The manufacturer cites studies in which doses up to 1000 times the human dose did not impair fertility or produce fetal harm in rats and mice (2). Six reports of its use in human pregnancy have been located.

A woman, at 28 weeks' gestation, was treated with urokinase, 4400 IU/kg for 10 minutes followed by 4400 IU/kg/hour for 12 hours, for pulmonary embolism (3). Heparin therapy was then administered, first IV then SC, for the remainder of the pregnancy. A healthy term infant was delivered 2 months after initiation of therapy.

A 1995 review briefly cited two reports of patients treated with urokinase, apparently without fetal or neonatal complications, for thrombosed prosthetic heart valves (4). A 36-year-old woman was treated at 14 and 32 weeks' gestation and had an uncomplicated cesarean delivery at 34 weeks (4,5). The second patient, a 32-year-old woman, was treated twice with different thrombolytics: at 3 months' gestation with urokinase and at 6 months with streptokinase (4,6). Minor uterine hemorrhage because of placental separation occurred at 3 months and a cesarean section was performed at 7 months. Maternal transfusion and surgical drainage were required following the delivery.

A 27-year-old woman, in premature labor, developed a massive pulmonary embolism at 31 weeks' gestation (7). She was initially treated with a bolus dose of urokinase (200,000 IU) and heparin. Dobutamine was also administered to maintain a stable hemodynamic state. Because her condition continued to deteriorate, she was treated with low-dose alteplase with eventual successful resolution of the embolism. A healthy, preterm, 2100-g male infant was delivered about 3 days after urokinase administration.

A 1994 report described a woman at 26 weeks' gestation who suffered a myocardial infarction (8). Following stabilization, she underwent cardiac catheterization 9 days after the initial infarction, which revealed 90% occlusion of the proximal right coronary artery and mild narrowing of other cardiac arteries. A prolonged intracoronary infusion of urokinase, in preparation for a planned angioplasty, failed to improve the right coronary occlusion, and coronary stents were subsequently placed. A healthy female infant was eventually delivered at 39 weeks.

The treatment of massive pulmonary embolism, diagnosed in a 20-year-old woman at 21 weeks' gestation, with urokinase and heparin was described in a 1995 case report (9). The patient markedly improved after receiving two courses of urokinase, 4400 IU/kg for 10 minutes followed by 4400 IU/kg/hour continuous infusion for 12 hours, approximately 6 hours apart, followed by continuous heparin. No complications of therapy were observed in the fetus, and she eventually delivered a healthy, 3122-g male infant at term.

In summary, the use of urokinase during pregnancy does not appear to represent a major risk to the fetus. The drug is not fetotoxic or teratogenic in rodents. However, only one human case treated with this thrombolytic agent during the 1st trimester (at 3 months) has been reported. It is not known whether the drug crosses the placenta to the fetus, but placental tissue contains proteinase inhibitors that inactivate urokinase (10,11). Placental separation and hemorrhage is a potential complication and has been reported in one case.

Breast Feeding Summary

No data are available. Because of the nature of the indications for urokinase and its very short half-life (20 minutes or less), the opportunities for its use during lactation and the potential exposure of the nursing infant are minimal.

References

1. Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:437–8.
2. Product information. Abbokinase. Abbott Laboratories, 2000.
3. Delclos GL, Davila F. Thrombolytic therapy for pulmonary embolism in pregnancy: a case report. Am J Obstet Gynecol 1986;155:375–6.
4. Turrentine MA, Braems G, Ramirez MM. Use of thrombolytics for the treatment of thromboembolic disease during pregnancy. Obstet Gynecol Survey 1995;50:534–41.
5. Jimenez M, Vergnes C, Brottier L, Dequeker JL, Billes MA, Lorient Roudaut MF, Choussat A, Boisseau MR. Thrombose récidivante d'une prothèse valvulaire aortique chez une femme enceinte. Traitement par urokinase. J Mal Vasc 1988;13:46–9.
6. Tissot H, Vergnes C, Rougier P, Bricaud H, Dallay D. Traitement fibrinolytique par urokinase et streptokinase d'une thrombose récidivante sur double prothèse valvulaire aortique mitrale au cours de la grossesse. J Gynecol Obstet Biol Reprod (Paris) 1991;20:1093–6.
7. 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;16:454–6.
8. Sanchez-Ramos L, Chami YG, Bass TA, DelValle GO, Adair CD. Myocardial infarction during pregnancy: management with transluminal coronary angioplasty and metallic intracoronary stents. Am J Obstet Gynecol 1994;171:1392–3.
9. Kramer WB, Belfort M, Saade GR, Surani S, Moise KJ Jr. Successful urokinase treatment of massive pulmonary embolism in pregnancy. Obstet Gynecol 1995;86:660–2.
10. Holmberg L, Lecander I, Persson B, Ästedt B. An inhibitor from placenta specifically binds urokinase and inhibits plasminogen activator released from ovarian carcinoma in tissue culture. Biochem Biophys Acta 1978;544:128–37.
11. Walker JE, Gow L, Campbell DM, Ogston D. The inhibition by plasma of urokinase and tissue activator-induced fibrinolysis in pregnancy and the puerperium. Thromb Haemost 1983;49:21–3.