Medical Therapy for Ectopic Pregnancy

Gary H Lipscomb M.D.


Semin Reprod Med. 2007;25(2):93-98. 

In This Article

Abstract and Introduction

Methotrexate for treatment of ectopic tubal pregnancy has become an accepted alternative to surgical options. Methotrexate is a folic acid analog that interferes with DNA synthesis. Protocols using planned multiple doses of methotrexate alternating with citrovorum rescue factor and one protocol using only a single planned dose are both currently used in the treatment of ectopic pregnancy. In remains unclear which protocol is superior. This article reviews the indications, contraindications, and specifics of using methotrexate for this purpose. Also reviewed are predictors of success and management of usual complications associated with methotrexate therapy.

Until the mid 1980s, treatment for ectopic pregnancy was exclusively surgical. During that decade, medical management with drugs such as methotrexate was first introduced to avoid the need for surgical intervention. The decisions about whether to use medical therapy for ectopic pregnancy, which patients should be treated, which protocol to use, and when to convert to surgical therapy during the course of medical treatment can be difficult choices. The final decision will depend not only on data available in the literature, but also the comfort and experience level of the physician, patient desires, and also the availability of rapid laboratory testing, appropriate hospital services, and physician coverage. This article should aid the physician in making some of these choices.

Although initial medical protocols required prolonged hospitalization, and the multiple doses of methotrexate were associated with significant side effects, refinements in protocols have allowed outpatient therapy and often require only one dose of methotrexate, and are associated with fewer side effects. Protocols using other agents such as potassium chloride, hyperosmolar glucose, dactinomycin, prostaglandins, and RU 486 for the medical management of ectopic pregnancy have also been developed. These agents may be administered by direct injection into the ectopic sac, or in the cases of dactinomycin, prostaglandins, and RU 486, given systemically by oral, intramuscular, or intravenous routes. However, due to the limited experience with these agents, their use must be considered experimental until additional data are available.

Methotrexate is a folic acid analog that has been used extensively in medicine for the treatment of certain neoplastic diseases, severe psoriasis, and adult rheumatoid arthritis. Methotrexate competitively binds to the enzyme dihydrofolic acid reductase, an enzyme that converts dihydrofolate to tetrahydrofolate. This binding prevents the reduction of folate to its active form, tetrahydrofolate. Tetrahydrofolate serves to transport one-carbon groups during the synthesis of purine nucleotides and thymidylate. Without tetrahydrofolate, DNA synthesis, DNA repair, and cellular replication are impaired. Actively proliferating cells such as malignant cells, bone marrow cells, fetal cells, and mucosal cells of the mouth, intestine, and urinary bladder generally are the most sensitive to the effects of methotrexate. Methotrexate is rapidly cleared from the body by the kidneys, with 90% of an intravenous dose excreted unchanged within 24 hours of injection.[1]

Prior to its use for treatment of ectopic pregnancy, methotrexate was used in gynecology only for the treatment of gestational trophoblastic disease. In 1982, Tanaka et al[2] reported treatment of an interstitial ectopic pregnancy in a patient with a 15-day course of intramuscular methotrexate. This was the first report of methotrexate being used in the treatment of an ectopic pregnancy. In the intervening years, methotrexate therapy has become accepted therapy for treatment of ectopic pregnancy.

Initially, all methotrexate protocols for the medical treatment of ectopic pregnancy used multiple doses of methotrexate alternating with reduced folinic acid (citrovorum rescue factor). These protocols generally required prolonged hospital stays, lengthy courses of treatment, and higher than acceptable toxicity rates. Side effects encountered included changes in liver functions, bone marrow suppression, nausea, and stomatitis. Considering these side effects, as well as patient costs, this form of treatment, although perhaps superior to surgical therapy, was not ideal.

In 1989, Stovall et al[3] (University of Tennessee, Memphis, TN) demonstrated that medical management of ectopic pregnancies could be performed safely on an outpatient basis. In their protocol, intramuscular methotrexate, 1 mg/kg of actual body weight, was given on alternating days with citrovorum rescue factor 0.1 mg/kg ( Table 1 ). Methotrexate was continued only until there was a 15% decline in two consecutive daily human chorionic gonadotropin (hCG) titers. A second course of methotrexate/citrovorum was given if previously decreasing levels changed ≤15% or increased between two consecutive hCG titers. Using this outpatient multidose regimen, a success rate of 96% with 100 patients was obtained. Five patients with ectopic cardiac activity were included in this series, with four of five patients (80%) treated successfully. Of the 96 successfully treated patients, 17 patients (17.7%) required only one methotrexate injection, 38 (39.6%) required two doses, 22 (22.9%) required three doses, and 19 (19.8%) received four doses. No major side effects were reported. Minor side effects included three cases of transiently elevated liver functions and two cases of stomatitis.


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