Methotrexate is an antimetabolite chemotherapeutic agent that binds to the enzyme dihydrofolate reductase, which is involved in the synthesis of purine nucleotides. This interferes with deoxyribonucleic acid (DNA) synthesis and disrupts cell multiplication. Methotrexate has long been known to be effective in the treatment of leukemias, lymphomas, and carcinomas of the head, neck, breast, ovary, and bladder. It has also been used as an immunosuppressive agent in the prevention of graft versus host disease and in the treatment of severe psoriasis and rheumatoid ahritis. The effectiveness of methotrexate on trophoblastic tissue has been well established and is derived from experience gained in using this agent in the treatment of hydatiform moles and choriocarcinomas. As used in the treatment of ectopic pregnancy, methotrexate is administered in a single or in multiple intramuscular (IM) injections. Treatment with methotrexate is an especially attractive option when the pregnancy is located on the cervix or ovary or in the interstitial or the cornual poion of the tube. Surgical treatment in these cases is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy. Indications Medical therapy for ectopic pregnancy involving methotrexate may be indicated in ceain patients. To determine acceptable candidates for methotrexate therapy, first establish the diagnosis by one of the following criteria: Abnormal doubling rate of the beta-human chorionic gonadotropin (b-HCG) level and ultrasonographic identification of a gestational sac outside of the uterus Abnormal doubling rate of the b-HCG level, an empty uterus, and menstrual aspiration with no chorionic villi A number of other factors must also be considered once the diagnosis is established, as follows: The patient must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum (must be met by every patient) The patient must be reliable, compliant, and able to return for follow-up care (must be met by every patient) The size of the gestation should not exceed 4cm at its greatest dimension (or exceed 3.5 cm with cardiac activity) on ultrasonographic measurement - Exceeding this size is a relative, but not absolute, contraindication to medical therapy Absence of fetal cardiac activity on ultrasonographic findings - The presence of fetal cardiac activity is a relative contraindication No evidence of tubal rupture - Evidence of tubal rupture is an absolute contraindication b-HCG level less than 5000 mIU/mL - Higher levels are a relative contraindication Methotrexate Treatment Protocols A number of accepted protocols with injected methotrexate exist for the treatment of ectopic pregnancy. Multiple-dose regimen Initial experience used multiple doses of methotrexate with leucovorin to minimize adverse effects. Leucovorin is folinic acid that is the end product of the reaction catalyzed by dihydrofolate reductase, the same enzyme inhibited by methotrexate. Normal dividing cells preferentially absorb leucovorin; hence, it decreases the action of methotrexate, thereby decreasing methotrexate's adverse systemic effects. This regimen involves administration of methotrexate as 1 mg/kg IM on days 0, 2, 4, and 6, followed by 4 doses of leucovorin as 0.1 mg/kg on days 1, 3, 5, and 7. Because of a higher incidence of adverse effects and the increased need for patient motivation and compliance, the multiple dosage regimen has fallen out of or in the United States. Single-dose regimen The more popular regimen today is the single-dose injection, which involves injection of methotrexate as 50 mg/m2 IM in a single injection or as a divided dose injected into each buttock. Studies comparing the multiple methotrexate dosage regimen with the single dosage regimen have demonstrated that the 2 methods have similar efficacy. With smaller dosing and fewer injections, fewer adverse effects are anticipated, and the use of leucovorin can be abandoned. The protocol for single-dose methotrexate is detailed below. Using this protocol, Stovall et al achieved a 96% success rate with a single injection of methotrexate. Day 0 Obtain b-HCG level, ultrasonography, and +/- dilatation and curettage. Day 1 Obtain levels of the following: b-HCG Liver function - Eg, aspaate aminotransferase (AST or serum glutamic-oxaloacetic transaminase ), alanine aminotransferase (ALT or serum glutamic-pyruvic transaminase ) Blood urea nitrogen (BUN) Creatinine Evidence of hepatic or renal compromise is a contraindication to methotrexate therapy. Blood type, Rh status, and antibody screening are also performed, and all Rh-negative patients are given Rh immunoglobulin REFERENCE: emedicine.medscape.com