When Is it Appropriate to Use Methotrexate for Ectopic Pregnancy in the Emergency Department?

Noelle A. Rotondo, DO


August 13, 2008


When is it appropriate to use methotrexate for ectopic pregnancy in the emergency department?

Response from Noelle Rotondo, DO


Response from Noelle Rotondo, DO
Associate Professor, Penn State Hershey Medical Center, Hershey, Pennsylvania; Staff Physician, York Hospital, York, Pennsylvania


Methotrexate is a chemotherapeutic agent used as medical therapy for the treatment of ectopic pregnancy. Although it is most commonly administered intramuscularly, obstetricians may inject the medication directly into the ectopic fetus under ultrasound guidance.[1] This discussion will focus on the use of methotrexate in the emergency department (ED), where it is most commonly administered via intramuscular injection.

Methotrexate is a folic acid antagonist that acts by blocking dihydrofolate reductase. In turn, it prevents cell division in rapidly dividing fetal cells. The decision to use methotrexate in the ED should be made in consultation with the patient's obstetrician, who will be responsible for continued outpatient management.

Indications for methotrexate therapy include[2]:

  • Hemodynamic stability and no evidence of ectopic rupture;

  • Gestational sac ≤ 4 cm if no cardiac activity;

  • Gestational sac ≤ 3.5 cm if cardiac activity is present;

  • Reliable patient, able to follow up for appointments and laboratory studies; and

  • Beta-human chorionic gonadotropin (beta-hCG level) ≤ 5000 mIU/mL.

The failure rate of methotrexate, or the percentage of patients who will require surgical therapy following treatment, increases proportionately as initial beta-hCG levels increase.[3] For patients who have an initial beta-hCG level < 1000 mIU/mL, single-dose methotrexate therapy has a failure rate of just 1.5%. When levels are between 1000 and 5000 mIU/mL, the failure rate is 4%. The failure rate jumps to 14% with initial beta-hCG levels of 5000 to 9999 mIU/mL, and up to 18% with levels between 10,000 and 15,000 mIU/mL.[3]

Contraindications to methotrexate therapy include the following[2]:

  • Evidence of ectopic rupture (clinically or on ultrasound);

  • White blood cell count ≤ 1500/mm3;

  • Creatinine > 1.5 mg/dL;

  • Aspartate aminotransferase (AST) > 2 times upper limits of normal;

  • Platelet count <100,000/mm3; and

  • Patient unreliable or unable to follow up for appointments.

Two commonly used methotrexate protocols are single-dose, which has an 88.1% success rate or multidose, which has a 92.7% success rate.[2,4,5] The single-dose protocol is more commonly used because it is associated with fewer side effects, is less expensive, requires fewer physician visits, and has greater patient compliance.[2,4,5] "Single-dose" therapy is something of a misnomer, however, because approximately 20% of patients will require repeat outpatient injections.[4]

Methotrexate has potentially serious side effects, including bone marrow suppression, liver cirrhosis, renal failure, and pulmonary fibrosis. However, these side effects are generally seen at much higher doses (ie, chemotherapeutic doses) than those used for the treatment of ectopic pregnancy.[4] Regardless, all patients should have a baseline complete blood count, liver function tests, and renal profile checked prior to treatment.

The most common side effects of methotrexate at doses used to treat ectopic pregnancy include excessive flatulence, abdominal pain (that may mimic a ruptured ectopic pregnancy), stomatitis, and sometimes a mild transient elevation of liver enzymes.[1] Patients are instructed to abstain from sexual intercourse (which could increase their risk for rupture), avoid potential gas-producing foods (cabbage, broccoli), and abstain from alcohol. Excessive flatulence is treated with over-the-counter antigas medication. Stomatitis may be treated with "magic mouthwash." The mouthwash formulation we use at our institution consists of one third viscous lidocaine 2%, one third diphenhydramine liquid, and one third aluminum hydroxide-magnesuim hydroxide. Instruct the patient to "swish and spit" 1 to 2 tablespoons every 4 to 6 hours as needed.

Patients are instructed to call their obstetrician with any increased abdominal pain or return to the ED with any worsening symptoms such as dizziness, lightheadedness, or increased abdominal pain, which may suggest a ruptured ectopic pregnancy. The risk for tubal rupture with methotrexate therapy is about 5%. Patients who return to the ED with abdominal pain must be evaluated for possible ruptured ectopic pregnancy.

In summary, methotrexate is appropriate for use as medical therapy for the treatment of ectopic pregnancy in select patients in the ED and is administered as a single-dose intramuscular injection. Patients are instructed to follow up with their obstetrician for continued monitoring, and sometimes they require subsequent doses of methotrexate. The most important predictor of success (termination not requiring surgery) with methotrexate is an initial beta-hCG level of 5000 mIU/mL or less on presentation. Although some abdominal pain is a common side effect of methotrexate therapy, patients who experience increased abdominal pain, lightheadedness, dizziness, or syncope need to be reevaluated for the possibility of tubal rupture.


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