Medical Therapy for Ectopic Pregnancy

Gary H Lipscomb M.D.


Semin Reprod Med. 2007;25(2):93-98. 

In This Article

Single-Dose Methotrexate Protocol

Because most patients treated with multidose methotrexate responded with decreasing levels before the peak effect of the second and third injection, it was theorized that many patients could be treated successfully with only a single dose of methotrexate. Subsequently, a protocol using only single-dose methotrexate without the use of citrovorum rescue factor was developed at the University of Tennessee, Memphis.[4] This protocol is detailed in Table 2 . Because the majority of patients receive only one dose of methotrexate, this protocol is commonly referred to as single-dose methotrexate. Compared with previous multidose methotrexate protocols, single-dose methotrexate is less expensive, has fewer side effects, requires less intensive patient monitoring, and has greater patient acceptance. More than 600 patients to date have been treated with this protocol, with a success rate of ~90%. A detailed analysis of success rates of various subgroups from the first 315 patients from this database has been published and is listed in Table 3 .[5]

This success rate is particularly noteworthy because there was no upper limit placed on hCG levels and the limits on the size of an ectopic gestation that could be treated were liberalized several times. In addition, for purposes of this particular protocol, size is defined as including only the gestational sac if it can be delineated from surrounding hematoma. If a gestational sac cannot be distinguished, the size of the entire mass is used. Currently, the upper limit of ectopic size for medical therapy at our institution is 4 cm if cardiac activity is not present and 3.5 cm if cardiac activity is present. The upper limit on ectopic size has been empiric, and some information suggests that ectopic size may not be a significant risk factor for failure.[6]

Before treatment with methotrexate, patients must be counseled extensively about the risk and benefits of treatment, the expected course and duration of treatment, and the importance of follow-up. Traditionally, all patients at our institution are screened with a base line hCG, Rh factor, complete blood count (CBC), aspartate aminotransferase (AST), creatinine, and blood urea nitrogen (BUN). White-cell counts <1500 µ/L, abnormal renal function, or elevation in the liver function values more than twice the upper limit of normal are contraindications to methotrexate. To date, no patient without known medical problems has failed to meet these screening criteria, and it has been suggested by some that in the absence of a history of renal disease, previous hepatitis, liver dysfunction, or evidence of a depressed immune system, there is no need for a screening CBC, AST, creatinine, or BUN prior to initial methotrexate dosing. However, these tests should be performed prior to a second dose of methotrexate even if results initially are normal.

The presence of fluid in the pelvis on ultrasound, presumably blood, is considered by many to be a contraindication to medical therapy because of fears that this may indicate ongoing tubal rupture. In the older literature, ~70 to 83% of all ectopic pregnancies had nonclotting blood in the pelvis when a culdocentesis was performed.[7,8,9] Interestingly, 50 to 62% of the patients with positive culdocentesis were found to have an unruptured fallopian tube. This blood may also produce mild peritoneal signs (i.e., rebound) on abdominal examination. Based on these data, fluid confined to the pelvis and rebound in an otherwise hemodynamically stable patient are not considered reasons for surgical intervention in the protocol used at the University of Tennessee. Although there are no data to indicate that increasing amounts of blood in the pelvis is associated with increasing failure rates with methotrexate,[6] we empirically consider blood in the upper abdomen a strong relative contraindication to medical therapy. Hemodynamically stable patients with smaller amounts of blood confined to the pelvis are routinely treated medically at our institution. If there is concern that this blood is the result of active bleeding, hospitalization with observation and serial hematocrits is indicated.

In the single-dose protocol used at the University of Tennessee, Memphis, methotrexate is given intramuscularly in a dose of 50 mg/m2. This is based on actual body weight as opposed to most chemotherapy protocols that use ideal body weight. For the average patient, this results in dosages of 75 to 100 mg, although obese patients will require significantly more methotrexate. Methotrexate is generally available in concentrations of 25 mg/cm3. Using this concentration, a total volume of 3 to 4 cm3 is generally required to deliver the needed dose of methotrexate. Volumes greater than 3 cm3 are usually given with more than one injection, but can be administered in only one injection if necessary.

The day methotrexate is given is considered day 1 in our protocol. A repeat hCG is performed on days 4 and 7. If the hCG level declines <15% between days 4 and 7, a second dose of methotrexate is given and the protocol is restarted at a new day 1. A repeat CBC and AST are obtained before retreatment. We routinely obtain these laboratory tests with the hCG level on all day-7 patients to prevent delays if retreatment is needed. If the hCG level declines ≥15%, hCG titers are then observed weekly until titers reach <15 mIU/mL. Although we have never had a complication using this end point, many physicians choose to follow hCG titers to negative, generally 3 to 5 mIU/mL, depending on the assay used. If the hCG level declines <15% in any week, repeat methotrexate dosing is performed and the protocol is again restarted at a new day 1. Although this protocol is referred to as single-dose methotrexate, ~20% of patients will require more than one treatment cycle.[5] The mean time to resolution in successfully treated patients is ~35 days.[5] However, resolution may take as long as 109 days. Tubal rupture also may be delayed, with the longest time from initial treatment to rupture in our database occurring at 31 days.

Ultrasound generally is not repeated for patients except to evaluate severe separation pain or for patients with positive ectopic cardiac activity. As noted later in this article, the ectopic mass frequently will increase in size over time with methotrexate therapy.[10] This increase, in an otherwise asymptomatic patient, is not an indication for surgery. For patients with cardiac activity, ultrasound is repeated weekly until absence of cardiac activity is demonstrated. Patients with persistent cardiac activity on day 7 are re-treated even if hCG titers are declining appropriately. No data exist on the number of doses of methotrexate that can be given safely. In patients with gestational trophoblastic disease, one common protocol uses a similar dose of methotrexate weekly until hCG levels are negative. Minimal side effects have been observed during this type of treatment. Nevertheless, our institution traditionally has restricted ectopic treatments to a maximum of three injections.

During treatment, patients are required to avoid alcohol and folate-containing vitamins. Sexual intercourse or pelvic examinations could potentially rupture the tubal hematoma commonly noted on ultrasound after methotrexate treatment and therefore should be avoided. Patients are also requested to avoid cabbage, onions, leeks, and other potential gas-producing foods to avoid the gastrointestinal distress from excess intestinal gas production that seems to be common following methotrexate treatment. Patients are instructed to use over-the-counter simethicone-containing antigas agents as needed for this problem.


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