FERTILITY AND STERILITY
Vol. 57, No.3, March 1992
Copyright" 1992 The American Fertility Society
Printed on acid·free paper in U.S.A.
Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy
Eyal Schiff, M.D.* Eliezer Shalev, M.D.t+ Moshe Bustan, M.D.t
Avinoam Tsabari, M.D.t Shlomo Mashiach, M.D.* Ehud Weiner, M.D.t
Sheba Medical Center, Tel-Hashomer, and Haemek Medical Center, Afula, Israel
Progress in the diagnostic modalities of ectopic pregnancy (EP), such as vaginal ultrasound and sensitive beta-human chorionic gonadotropin (~-hCG) assays, has been accompanied by a more conservative approach to treatment, with the aim of preserving fertility and reducing surgical interventions and morbidity. Since 1982, successful treatment of EP using parenteral or intramuscular systemic treatment was reported (1, 2). Thus, in selected cases, in which the clinical signs indicate that the tube is unruptured, there is a trend to treat EP medically with methotrexate (MTX). Later on, MTX was successfully injected in cases of EP intratubally under ultrasonographic guidance with apparently no undesirable systemic side effects (3,4). The present study was performed to evaluate the systemic pharmacokinetics of MTX after its local injection intratubally. MATERIALS AND METHODS
Seven women, admitted because of EP over a period of 6 months to the Department of Gynecology, Haemek Medical Center, constituted our study group. All seven patients had clinical signs of unruptured EP. The patients age ranged from 23 to 37
years, with a mean of 27.6 years; gestational age ranged from 6 to 9 weeks, with mean of 7.6 weeks; serum ~-hCG level ranged from 649 to 5,690 mlUjmL, with a mean [±SD] of 2,103 ± 1,798); vaginal ultrasonography demonstrated an adnexal amniotic sac measuring from 10 X 11 mm to 23 X 29 mm (mean of 17 X 17 mm) and no intrauterine amniotic sac. All gave their consent to the MTX treatment. Under vaginal ultrasonographic guidance, 50 mg of MTX was injected via 22-gauge needle directly into the extrauterine amniotic sac. Brachial venous blood samples were withdrawn 1, 2, 6, and 24 hours after the injection and were stored with anticoagulants at 4°C until assayed within 48 hours. Serum levels of MTX were measured by enzyme immunoassay (Emit assay; Syva Company, Maiden Head Derkshire, United Kingdom). The interassay and intra-assay coefficients of variation were 3.5% and 6.5 %, respectively. Two additional patients who were admitted because of persistent hydatidiform mole during the same period were treated by alternate repeated 1M injection of 50 mg of MTX. Levels of the drug in their blood samples were tested after the first injection as in the seven pregnant patients. Student's t-test (two-tailed) was used for statistical analysis. RESULTS
Received August 30, 1991; revised and accepted November 27, 1991. * Department of Obstetrics and Gynecology, Sheba Medical Center. t Department of Obstetrics and Gynecology, Haemek Medical Center. :\: Reprint requests: Eliezer Shalev, M.D., Department of Obstetrics and Gynecology, Haemek Medical Center, Afula 18 101 Israel. 688
Schiff et a1.
Communications-in-brief
None of the seven patients developed complications as a result of the procedure or systemic side effects of the drug. The treatment was successful in all seven cases because ~-hCG levels declined gradually and no further treatment was needed. The mean hospital stay after the injection was 6.5 ± 2.7 days. The decrease in ~-hCG to a level of 0 lasted Fertility and Sterility
14 to 36 days (mean 23.5 days). The serum MTX levels after intratubal injection in seven patients is presented in Figure 1. Maximal serum levels in this group were in the range of 0.35 to 2.1ILmoL/L. In five of the intratubally treated patients, the drug reached its peak level in the serum within 1 hour and in the other two within 2 hours. In all seven patients, serum levels were
Vol. 57, No.3, March 1992
Copyright" 1992 The American Fertility Society
Printed on acid·free paper in U.S.A.
Pharmacokinetics of methotrexate after local tubal injection for conservative treatment of ectopic pregnancy
Eyal Schiff, M.D.* Eliezer Shalev, M.D.t+ Moshe Bustan, M.D.t
Avinoam Tsabari, M.D.t Shlomo Mashiach, M.D.* Ehud Weiner, M.D.t
Sheba Medical Center, Tel-Hashomer, and Haemek Medical Center, Afula, Israel
Progress in the diagnostic modalities of ectopic pregnancy (EP), such as vaginal ultrasound and sensitive beta-human chorionic gonadotropin (~-hCG) assays, has been accompanied by a more conservative approach to treatment, with the aim of preserving fertility and reducing surgical interventions and morbidity. Since 1982, successful treatment of EP using parenteral or intramuscular systemic treatment was reported (1, 2). Thus, in selected cases, in which the clinical signs indicate that the tube is unruptured, there is a trend to treat EP medically with methotrexate (MTX). Later on, MTX was successfully injected in cases of EP intratubally under ultrasonographic guidance with apparently no undesirable systemic side effects (3,4). The present study was performed to evaluate the systemic pharmacokinetics of MTX after its local injection intratubally. MATERIALS AND METHODS
Seven women, admitted because of EP over a period of 6 months to the Department of Gynecology, Haemek Medical Center, constituted our study group. All seven patients had clinical signs of unruptured EP. The patients age ranged from 23 to 37
years, with a mean of 27.6 years; gestational age ranged from 6 to 9 weeks, with mean of 7.6 weeks; serum ~-hCG level ranged from 649 to 5,690 mlUjmL, with a mean [±SD] of 2,103 ± 1,798); vaginal ultrasonography demonstrated an adnexal amniotic sac measuring from 10 X 11 mm to 23 X 29 mm (mean of 17 X 17 mm) and no intrauterine amniotic sac. All gave their consent to the MTX treatment. Under vaginal ultrasonographic guidance, 50 mg of MTX was injected via 22-gauge needle directly into the extrauterine amniotic sac. Brachial venous blood samples were withdrawn 1, 2, 6, and 24 hours after the injection and were stored with anticoagulants at 4°C until assayed within 48 hours. Serum levels of MTX were measured by enzyme immunoassay (Emit assay; Syva Company, Maiden Head Derkshire, United Kingdom). The interassay and intra-assay coefficients of variation were 3.5% and 6.5 %, respectively. Two additional patients who were admitted because of persistent hydatidiform mole during the same period were treated by alternate repeated 1M injection of 50 mg of MTX. Levels of the drug in their blood samples were tested after the first injection as in the seven pregnant patients. Student's t-test (two-tailed) was used for statistical analysis. RESULTS
Received August 30, 1991; revised and accepted November 27, 1991. * Department of Obstetrics and Gynecology, Sheba Medical Center. t Department of Obstetrics and Gynecology, Haemek Medical Center. :\: Reprint requests: Eliezer Shalev, M.D., Department of Obstetrics and Gynecology, Haemek Medical Center, Afula 18 101 Israel. 688
Schiff et a1.
Communications-in-brief
None of the seven patients developed complications as a result of the procedure or systemic side effects of the drug. The treatment was successful in all seven cases because ~-hCG levels declined gradually and no further treatment was needed. The mean hospital stay after the injection was 6.5 ± 2.7 days. The decrease in ~-hCG to a level of 0 lasted Fertility and Sterility
14 to 36 days (mean 23.5 days). The serum MTX levels after intratubal injection in seven patients is presented in Figure 1. Maximal serum levels in this group were in the range of 0.35 to 2.1ILmoL/L. In five of the intratubally treated patients, the drug reached its peak level in the serum within 1 hour and in the other two within 2 hours. In all seven patients, serum levels were
