Risk Factor: BM
Class: Hematological agents/ Hemostatics
Fetal Risk Summary
This hemostatic agent, a competitive inhibitor of plasminogen activation, is used to reduce or prevent hemorrhage in hemophilia and in other bleeding disorders. The drug blocks the action of plasminogen activators (e.g., tissue plasminogen activator [alteplase; t-PA], streptokinase, and urokinase) by inhibiting the conversion of plasminogen to plasmin. No adverse fetal effects were observed in reproductive toxicity testing in mice, rats, and rabbits (1, 2). Both Schardein (3) and Shepard (4) cited a 1971 study in which doses up to 1500 mg/kg/day were given to mice and rats during organogenesis without causing adverse fetal effects.
Tranexamic acid crosses the human placenta to the fetus (5). Twelve women were given an IV dose of 10 mg/kg just before cesarean section. Cord serum and maternal blood samples were drawn immediately following delivery, a mean of 13 minutes after the dose of tranexamic acid. The mean drug concentrations in the cord and maternal serum were 19 g/mL (range
Twelve women with vaginal bleeding between 24 and 36 weeks’ gestation were treated with 7-day courses of tranexamic acid, 1 g orally every 8 hours (6). Additional courses were given if bleeding continued (number of patients with repeat courses not specified). Four women underwent cesarean section (placenta previa in three, breech in one) and the remainder had vaginal deliveries. One of the newborns was delivered at 30 weeks’ gestation, but the gestational ages of the other newborns were not specified. All of the newborns were alive and well. Two of the mothers were receiving treatment at the time of delivery, and the drug concentrations in the cord blood were 9 and 12 g/mL.
A pregnant woman with fibrinolysis was treated with tranexamic acid and fibrinogen for 64 days until spontaneous delivery of a normal 1400-g girl at 30 weeks’ gestation (7). No adverse fetal or newborn effects attributable to the drug were reported. Tranexamic acid was used in a woman with abruptio placentae during her third pregnancy (8). She had a history of two previous pregnancy losses because of the disorder. Treatment with tranexamic acid (1 g IV every 4 hours for 3 days, then 1 g orally 4 times daily) was begun at 26 weeks’ gestation and continued until 33 weeks’ gestation, at which time a cesarean section was performed because of the risk of heavier bleeding. A healthy 1430 g male infant was delivered.
The use of tranexamic acid in a woman with Glanzmann’s thrombasthenia disease was described in an abstract published in 1981 (9). Treatment was started at 24 weeks’ gestation and continued until spontaneous delivery at 42 weeks’ gestation of a healthy boy. A study published in 1980 described the use of tranexamic acid in 73 consecutive cases of abruptio placentae, 6 of which were treated for 112 weeks (10). Six (8.2%) of the newborns were either stillbirths (N=4) or died shortly after delivery (N=2), a markedly reduced mortality rate compared with the expected 33%37% at that time (10). None of the deaths were attributed to the drug. No cases of increased hemorrhage, thromboses, or maternal deaths were observed.
Tranexamic acid (4 g/day) was used in a 21-year-old primigravida at 26 weeks’ gestation for the treatment of vaginal bleeding (11). She also received terbutaline and betamethasone for premature labor. Tranexamic acid was administered as a single dose on admission, and 6 days later a 10-day course was initiated for continued bleeding. Acute massive pulmonary embolism occurred at the termination of tranexamic acid, and following 23 days of treatment with heparin and streptokinase, a preterm 1140-g male infant was spontaneously delivered. No adverse effects in the fetus or newborn attributable to the drug therapy were noted.
A retrospective study published in 1993 examined the question of whether tranexamic acid was thrombogenic when administered during pregnancy (12). Between 19791988 in Sweden, among pregnant women with various bleeding disorders, 256 had been treated with tranexamic acid (mean duration 46 days), whereas 1,846 had not been treated (controls). Two patients (0.78%) in the treated group had pulmonary embolism compared with 4 (0.22%) (3 deep vein thromboses, 1 pulmonary embolism) (odds ratio 3.6, 95% confidence limits 0.717.8) in the control group. In the subgroups of those patients who were delivered by cesarean section (168 treated, 439 controls), the rates of thromboembolism were 1 (0.60%) and 4 (0.91%) (odds ratio 0.65, 95% confidence limits 0.15.8), respectively. Thus, no evidence was found indicating that the use of tranexamic acid during gestation was thrombogenic. Although the purpose of this study did not include examining the effects of the therapy on the fetus or newborn, the authors concluded that in the absence of a thrombogenic risk, there was no reason to change the indications for its use during pregnancy.
In summary, no adverse effects attributable to use of tranexamic acid during pregnancy, either in animals or humans, have been reported in the fetus or newborn. The drug crosses the placenta to the fetus, but its reported lack of effect on plasminogen activator activity in the vascular wall (10,12) (versus its known effect in the peripheral circulation) may protect the fetus and newborn from potential thromboembolic complications.
Breast Feeding Summary
Tranexamic acid is excreted into human milk. One hour after the last dose following a 2-day treatment course in lactating women, the milk concentration of the agent was 1% of the peak serum concentration (13). In adults, approximately 30%50% of an oral dose is absorbed (1). The amount a nursing infant would absorb is unknown, as is the effect of the small amount of drug present in milk.
- Product information. Cyklokapron. Pharmacia, 1996.
- Onnis A, Grella P, Lewis PJ. The Biochemical Effects of Drugs in Pregnancy. Volume 1. Chichester, England: Ellis Horwood, 1984:385.
- Schardein JL. Chemically Induced Birth Defects. 2nd ed. New York, NY: Marcel Dekker, 1993:107.
- Shepard TH. Catalog of Teratogenic Agents. 8th ed. Baltimore, MD: Johns Hopkins University Press, 1995:420.
- Kullander S, Nilsson IM. Human placental transfer of an antifibrinolytic agent (AMCA). Acta Obstet Gynecol Scand 1970;49:2412.
- Walzman M, Bonnar J. Effects of tranexamic acid on the coagulation and fibrinolytic systems in pregnancy complicated by placental bleeding. Arch Toxicol 1982;Suppl 5:21420.
- Storm O, Weber J. Prolonged treatment with tranexamic acid (Cyklokapron) during pregnancy. Ugeskr Laeg 1976;138:17812.
- stedt B, Nilsson IM. Recurrent abruptio placentae treated with the fibrinolytic inhibitor tranexamic acid. Br Med J 1978;1:7567.
- Sundqvist S-B, Nilsson IM, Svanberg L, Cronberg S. Glanzmann’s thrombasthenia: pregnancy and parturition (abstract). Thromb Haemost 1981;46:225.
- Svanberg L, stedt B, Nilsson IM. Abruptio placentaetreatment with the fibrinolytic inhibitor tranexamic acid. Acta Obstet Gynecol Scand 1980;59:12730.
- Fagher B, Ahlgren M, stedt B. Acute massive pulmonary embolism treated with streptokinase during labor and the early puerperium. Acta Obstet Gynecol Scand 1990;69:65962.
- Lindoff C, Rybo G, stedt B. Treatment with tranexamic acid during pregnancy and the risk of thrombo-embolic complications. Thromb Haemost 1993;70:23840.
- Eriksson O, Kjellman H, Nilsson L. Tranexamic acid in human milk after oral administration of Cyklokapron to lactating women. Data on file, KabiVitrum AB, Stockholm, Sweden. (Data supplied by R.G. Leonardi, Ph.D., KabiVitrum, 1987).