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Methotrexate treatment of tubal and interstitial ectopic pregnancy

Last literature review version 17.3: September 2009  |  This topic last updated: July 30, 2009   (More)

INTRODUCTION — Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the mainstay of treatment, advances in early diagnosis facilitated the introduction of medical therapy with methotrexate (MTX) in the 1980s [1]. In one report, approximately 35 percent of women with ectopic pregnancy are eligible for medical treatment [2]. Due to the routine use of early ultrasound among infertile patients who conceive, diagnosis of ectopic pregnancy can be established early and medical treatment can be administered in most cases. The overall success rate of medical treatment in properly selected women is nearly 90 percent [3-5].

Medical treatment of ectopic pregnancy will be reviewed here. Ectopic pregnancy diagnosis, surgical treatment and expectant management are discussed separately. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy" and "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility" and "Expectant management of ectopic pregnancy".)

PHARMACOLOGY — MTX is a folic acid antagonist widely used for treatment of neoplasia, severe psoriasis, and rheumatoid arthritis. It inhibits DNA synthesis and cell reproduction, primarily in actively proliferating cells such as malignant cells, trophoblasts, and fetal cells.

MTX is rapidly cleared from the body by the kidneys, with 90 percent of an intravenous (IV) dose excreted unchanged within 24 hours of administration [6].

The dose of MTX used to treat ectopic pregnancy (50 mg/m2 or 1 mg/kg) is relatively low. High dose MTX (≥500 mg/m2) is used to treat some malignancies.

In some protocols, reduced folates (leucovorin, also called folinic acid, N5-formyl-tetrahydrofolate, citrovorum factor) are given to bypass the metabolic block induced by MTX, and thus rescue normal cells from toxicity. (See "Therapeutic use of high-dose methotrexate", section on 'Clinical pharmacology'.)

CANDIDATES FOR MEDICAL TREATMENT

Optimal candidates — The optimal candidates for MTX treatment of ectopic pregnancy are hemodynamically stable, willing and able to comply with posttreatment follow-up, have a human chorionic gonadotropin beta-subunit (hCG) concentration ≤5000 mIU/mL, and no fetal cardiac activity. Ectopic mass size less than 3 to 4 cm is also commonly used as a patient selection criterion; however, this has not been confirmed as a predictor of successful treatment (see 'Relative contraindications' below.

Contraindications — Some women are not appropriate candidates for medical therapy and should be managed surgically, including women with the following characteristics [7,8]:

  • Hemodynamically unstable
  • Signs of impending or ongoing ectopic mass rupture (ie, severe or persistent abdominal pain or >300 mL of free peritoneal fluid outside the pelvic cavity)
  • Clinically important abnormalities in baseline hematologic, renal or hepatic laboratory values
  • Immunodeficiency, active pulmonary disease, peptic ulcer disease
  • Hypersensitivity to MTX
  • Coexistent viable intrauterine pregnancy
  • Breastfeeding
  • Unwilling or unable to be compliant with post-therapeutic monitoring
  • Do not have timely access to a medical institution

MTX is renally cleared, and in women with renal insufficiency, a single dose of MTX can lead to death or severe complications, including bone marrow suppression, acute respiratory distress syndrome and bowel ischemia. Dialysis does not provide normal renal clearance [9,10].

Relative contraindications

  • High hCG concentration — A high serum hCG concentration is the most important factor associated with treatment failure (table 1). Women with a high baseline hCG concentration (greater than 5000 mIU/mL) are more likely to require multiple courses of medical therapy or experience treatment failure [11,12].

A systematic review of observational studies involved 503 women in which the outcome of single dose MTX therapy was stratified according to initial hCG concentration [11]. There was a statistically significant increase in failure rates in patients with initial hCG levels of greater than 5000 mIU/mL compared with those who had initial levels of less than 5000 mIU/mL (OR 5.5, 95% CI 3.0-9.8). The failure rate for women who had an initial concentration between 5000 and 9999 mIU/mL was significantly higher than for those who had initial levels between 2000 and 4999 mIU/mL (OR 3.8, 95% CI 1.2-12.3). Multiple dose regimens were not evaluated.

The authors calculated that for every 10 treatments, there would be one more failure if the hCG level is 5000 to 9999 mIU/mL than there would be if it is 2000 to 4999 mIU/mL.

  • Fetal cardiac activity — The presence of fetal cardiac activity is another relative contraindication to medical treatment [3,12]. In a metaanalysis, sonographic evidence of cardiac activity was significantly associated with treatment failure (OR 9.1, 95% CI 3.8-22.0) [3].
  • Large ectopic size — Although large size of the ectopic pregnancy (≥3.5 cm) is often used as criterion for exclusion in medical treatment regimens, this restriction is based on small studies with inconsistent protocols and results [12-15]. Studies have generally restricted use of MTX to women with an ectopic mass less than 3 to 4 cm [12,13], thus there are few studies of larger masses [16]. As an example, one observational study found that the success rate for systematic MTX treatment was higher for women with ectopic masses smaller than 3.5 cm compared to masses between 3.5 and 4 cm (93 versus 90 percent) [13].

In addition, there are variations within and among studies regarding whether the size used is the actual gestational mass or the mass and surrounding hematoma [12-14]. Further, ectopic mass size does not appear to correlate with hCG level [17].

  • Peritoneal fluid — The sonographic finding of free peritoneal fluid is another commonly used exclusion criterion for MTX treatment of ectopic pregnancy. Peritoneal fluid may be blood, however, this is not diagnostic of tubal rupture; peritoneal blood may also be the result of tubal abortion. Historically, culdocenteses detected blood in the peritoneal cavity of 70 to 83 percent of women with ectopic pregnancies, but only 50 to 62 percent of them had a ruptured fallopian tube [18-20].

In a large case series, free fluid confined to the pelvic cavity was not associated with medical treatment failure [12]. While surgical treatment of patients with free fluid in the paracolic gutters or upper abdomen may be prudent, the amount of allowable free fluid confined to the posterior cul-de-sac (pouch of Douglas) is controversial [7,21].

  • Other — Preliminary reports have cited a variety of other factors which may be associated with treatment failure. These include: sonographic evidence of a yolk sac [12,22,23], isthmic location of ectopic mass (rather than ampullary) [12,24], high pretreatment folic acid level [25], and rate of hCG rise or fall prior to and within several days following treatment [24,26]. Further study is needed to validate these findings.

In addition, women who are planning sterilization may desire concomitant surgical treatment for ectopic pregnancy and tubal ligation.

DRUG ADMINISTRATION — MTX can be given systemically (intravenously, intramuscularly, or orally) or by direct local injection into the ectopic pregnancy sac transvaginally or laparoscopically. Intramuscular (IM) administration is most common.

Intramuscular therapy — Intramuscular MTX administration is the predominant route for treatment of tubal pregnancy [1].

  • Local injection — Local injection of MTX for ectopic pregnancy is rarely used. Local treatment is highly operator dependent and not practical when performed laparoscopically. Women bearing the costs and risks of laparoscopic surgery should have definitive treatment (ie, removal of the ectopic gestation) at the time of the procedure.

A systematic review found that treatment success with local injection of MTX may be higher than with systemic treatment; however, the difference did not reach statistical significance [27]. In addition, local and systemic MTX administration had similar rates of subsequent intrauterine pregnancies or repeat ectopic pregnancies.

Efficacy of single versus multidose therapy — The two most commonly used protocols for MTX administration are single dose and multiple dose (four MTX doses which alternate with oral leucovorin). Fourteen percent of patients on single dose regimens ultimately receive two or more doses and 10 percent of patients on multi-dose regimens receive a single dose [3] (see 'Single dose protocol' below and 'Multiple dose protocol' below.

We prefer an initial approach with single dose therapy for tubal ectopic pregnancy for the following reasons. The overall rate of resolution of ectopic pregnancy reported in the literature is about 90 percent for both single and multiple dose protocols [3,27,28]. Multiple dose protocols appear to cause more adverse effects [3]. The single dose approach is less expensive, requires less intensive monitoring, and does not require folinic acid rescue. The following are systematic reviews of the two regimens:

  • A systematic review of two randomized trials compared single dose with fixed multiple dose regimens [27]. There was no significant difference between treatment success rates, which ranged from 89 to 91 percent for single dose and 86 to 93 percent for multidose therapy [29,30]. There were no consistent findings regarding rates of complications between the two dose regimens.
  • Another systematic review included 26 observational studies of 1300 women with ectopic pregnancy [3]. Overall success rates for single versus multiple dose regimens were 88 and 93 percent, a significant difference. This difference was even larger after adjustment for factors such as hCG concentration and presence of embryonic cardiac activity (OR 4.74, 95 percent CI 1.77-12.62). However, significantly fewer side effects were noted after single dose versus multidose treatment (31 versus 41 percent).

A hybrid of the two protocols, a two-dose MTX regimen (50 mg/m 2 IM on days 0 and 4) has been proposed. A single report on this regimen found an 87 percent treatment success rate [31], infrequent complications and adverse effects, and high patient satisfaction. Further study to evaluate this protocol is needed before it can be recommended.

On the other hand, we use multidose MTX therapy for interstitial pregnancies (see 'Interstitial pregnancy' below.

Combination therapy with mifepristone — Treatment of ectopic pregnancy using a combination of mifepristone and MTX has also been investigated [27]. A systematic review of randomized trials of single dose intramuscular MTX (50 mg/m2) in combination with oral mifepristone (600 mg) versus MTX alone found that combination therapy may increase treatment efficacy. Success rates for MTX or MTX/mifepristone therapy were 81 and 74 percent; the difference approached statistical significance. No differences were found in tubal preservation or tubal patency. No data are available on future fertility. More studies are needed to fully evaluate whether the addition of mifepristone to MTX regimens is beneficial.

We do not recommend the use of this regimen. In addition, mifepristone is not approved for treatment of ectopic pregnancy in the United States. (See "Mifepristone for the medical termination of pregnancy".)

Pretreatment testing — HCG, blood type, complete blood count, renal and liver function tests are drawn prior to starting therapy. A transvaginal ultrasound is performed. (See 'Contraindications' above and "Clinical manifestations, diagnosis, and management of ectopic pregnancy".)

Rh(D) immune globulin should be administered if the woman is Rh(D)-negative. (See "Prevention of Rh(D) alloimmunization".)

We do not perform endometrial sampling in the management of ectopic pregnancy. Treatment with methotrexate is a less invasive option.

Precautions during therapy — Patients and clinicians should adhere to the following precautions during MTX treatment [7]:

  • Avoid vaginal intercourse and new conception until hCG is undetectable
  • Avoid pelvic exams during surveillance of MTX therapy due to theoretical risk of tubal rupture
  • Avoid sun exposure to limit risk of MTX dermatitis
  • Avoid foods and vitamins containing folic acid
  • Avoid nonsteroidal antiinflammatory drugs, as the interaction with MTX may cause bone marrow suppression, aplastic anemia, or gastrointestinal toxicity

Single dose protocol — The most efficient approach to therapy is administration of a single IM dose of MTX (50 mg per square meter of body surface area) [32]. Body surface area (BSA) may be calculated based upon height and weight on the day of treatment using the formula BSA = square root ((cm X kg)/3600) or a BSA calculator (calculator 1).

Approximately 15 to 20 percent of women will require a second dose of MTX and should be made aware of this [3,13]. Fewer than 1 percent of patients need more than two doses [3] (see 'Side effects and complications' below.

Our single dose MTX protocol and another commonly reported protocol are described below and in the table (table 2). Protocols vary slightly; choice of protocol depends on provider preference.

  • In our single dose protocol, Day 1 is the day of MTX treatment [33]. We prefer to draw the second hCG level on Day 7, thereby saving the patient a visit on Day 4. Data from a study of hCG values on Days 1, 4, and 7 suggest that Day 4 serum hCG levels is not an accurate test to predict treatment success [34].

We administer a SECOND dose of MTX if the serum hCG concentration on Day 7 has not declined by at least 25 percent from the Day 1 level, and the protocol is repeated.

  • In another commonly used protocol, Day 1 is the day of MTX treatment [1,35]. On Days 4 and 7, a serum hCG concentration is drawn [7,8,36]. If the decrease in hCG between Days 4 and 7 is less than 15 percent, a second dose of MTX 50 mg/m2 IM is administered.
  • Posttreatment laboratory monitoring — It is common to observe an increase in hCG levels in the first several days following therapy (ie, until Day 4) [37]. This is due to continued hCG production by syncytiotrophoblast despite cessation of production by cytotrophoblast.

After Day 7 in both single dose protocols, hCG testing is repeated weekly. If any measurement shows a <25 percent decrease from the level on day 1 OR <15 percent decrease from the level on Day 4, an additional dose of MTX 50 mg/m2 IM is administered [1]. If an additional dose of MTX is indicated, we do not repeat pretreatment laboratory testing (complete blood count, renal and liver function tests); there are no data suggesting that one dose of MTX changes the results of these tests.

Weekly measurements are continued until the hCG is undetectable (this level varies by laboratory). The hCG concentration usually declines to less than 15 mIU/mL by 35 days post-injection, but may take as long as 109 days [13,38].

We give a maximum of three doses of MTX. If the hCG falls <15 percent between weekly measurements after a third dose, we perform a laparoscopic salpingostomy or salpingectomy. (See "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility".)

Multiple dose protocol — The most common multiple dose regimen administers MTX (1 mg/kg per day IM or IV) on Days 1, 3, 5, and 7, and oral leucovorin (0.1 mg/kg) on Days 2, 4, 6, and 8 [39]. HCG levels are drawn on Days 1, 3, 5, and 7. If the serum hCG declines MORE than 15 percent from the previous measurement, treatment is stopped and a surveillance phase begins.

The surveillance phase consists of weekly hCG measurements. If the hCG declines LESS than 15 percent from the previous level, the patient is given an additional dose of MTX 1 mg/kg IM followed the next day with a dose of oral leucovorin 0.1 mg/kg. The hCG is followed until the level is undetectable.

A systematic review of patients treated with multiple dose regimens found a 93 percent success rate [3]. Forty percent of women reported side effects, but these effects were relatively minor and transient [3].

Posttreatment management

Ultrasound follow-up — There appears to be no clinical benefit from routine serial ultrasound examinations [17]. After treatment, the ectopic pregnancy is often noted to increase in size and may persist for weeks on serial ultrasound examinations. This probably represents hematoma, rather than persistent trophoblastic tissue, and is not predictive of treatment failure. However, ultrasound evaluation for peritoneal fluid is indicated for women with severe abdominal pain.

Side effects and complications — Adverse reactions to MTX are usually mild and self-limited. The most common are stomatitis and conjunctivitis. Rare side effects include gastritis, enteritis, dermatitis, pneumonitis, alopecia, elevated liver enzymes, and bone marrow suppression. Approximately 30 percent of patients in the single dose protocol will have side effects; this rate is lower than with multidose regimens (40 percent) [3]. (See "Major side effects of low-dose methotrexate".)

Pain after treatment — Mild abdominal pain of short duration (one to two days) six to seven days after receiving the medication is also common. The pain may be due to tubal abortion or tubal distention from hematoma formation and can usually be controlled with acetaminophen. Nonsteroidal antiinflammatory drugs should be avoided because a clinically significant drug interaction with MTX occurs in some patients taking both drugs.

Occasionally pain may be severe, but women with severe pain who are hemodynamically stable often do not need surgical intervention. As an example, a review of 56 women with abdominal pain severe enough to be evaluated in the clinic or emergency department, or requiring hospitalization, found that only eight patients subsequently required surgery [21].

A patient with severe pain may be further evaluated with transvaginal ultrasonography. Findings suggestive of hemoperitoneum raise clinical suspicion of tubal rupture. In one study, three parameters predicted hemoperitoneum ≥300 mL in women with ectopic pregnancy: moderate to severe pelvic pain, fluid above the uterine fundus or around the ovary, and serum hemoglobin concentration <10 g/dL [40]. A woman with none of these three criteria had a probability of 5.3 percent of hemoperitoneum ≥300 ml. When two or more criteria were present, the probability for hemoperitoneum ≥300 ml reached 92.6 percent.

Women with severe pain should be closely observed for hemodynamic changes which may accompany a tubal rupture. Falling hCG levels do not preclude the possibility of tubal rupture. If tubal rupture is suspected, immediate surgery is required.

SUBSEQUENT REPRODUCTIVE PERFORMANCE — There is no evidence of adverse effects of MTX treatment of ectopic pregnancy on future pregnancies [41-44]. In addition, treatment with MTX does not appear to compromise ovarian reserve [45]. Attempts to conceive may be resumed after the hCG level is undetectable.

Extrauterine pregnancy is usually due to altered tubal function secondary to clinical or subclinical salpingitis; the functional disorder is bilateral and irreversible. Therefore, it is not surprising that ectopic pregnancy can be followed by infertility and recurrent ectopic pregnancy.

The incidence of recurrent ectopic pregnancy is approximately 15 percent and rises to 30 percent following two ectopic pregnancies [46]. The risk of recurrence appears to be the same for both medical and surgical therapies [47]. (See 'Medical versus surgical treatment' below.)

The initial level of hCG >5000 mIU/mL may be associated with increased risk of subsequent tubal obstruction, regardless of treatment approach [48].

MEDICAL VERSUS SURGICAL TREATMENT — Approximately 35 percent of women with ectopic pregnancy are eligible for medical treatment [2]. In these women, systemic treatment with MTX is as effective as laparoscopic salpingostomy, and results in similar success rates for tubal patency and future intrauterine pregnancy [49]. Although adverse effects are increased with MTX over surgery, depending on the MTX regimen (fixed multiple dose versus single/variable dose), patient recovery may be improved with medical treatment. Medical treatment costs approximately $3000 less than surgery per resolved ectopic pregnancy [5].

In patients who are eligible for either medical or surgical treatment, the choice of therapy should be guided by the patient's preference after a detailed discussion of risks, benefits, outcome, and monitoring requirements of both medical and surgical approaches. Informed consent is obtained before administration of MTX, as well as before surgery.

A systemic review of randomized trials compared methotrexate therapy with laparoscopic salpingostomy; major findings are listed below [49]:

  • Intramuscular MTX therapy (single or multiple dose) and salpingostomy yielded similar treatment success rates, ranging from 82 to 95 percent for MTX therapy versus 80 to 92 percent for salpingostomy. Transvaginal injection of MTX was significantly less effective than salpingostomy.
  • Adverse effects and complications were more common in women treated with systemic MTX than with surgery (60 versus 12 percent in one study). However, the studies were likely underpowered to detect a difference in rare perioperative complications.
  • Physical and psychological functioning after treatment was improved for patients treated with single dose MTX compared to laparoscopic salpingostomy; however, women treated with multidose regimens showed greater functional impairment than their surgical counterparts.
  • The time required for hCG concentrations to reach undetectable levels is faster after laparoscopic surgery, thus reducing the period of posttreatment monitoring, based on the only randomized trial to report this outcome.
  • Posttreatment tubal patency and intrauterine pregnancy rates were similar.
  • Risk of recurrent ectopic pregnancy did not differ by treatment approach.

MEDICAL TREATMENT VERSUS EXPECTANT MANAGEMENT — Expectant management should only be considered by women with unknown location of their pregnancy or suspected ectopic pregnancy, and low and declining serum hCG levels. (See "Expectant management of ectopic pregnancy".)

INTERSTITIAL PREGNANCY — We initially treat interstitial (located at the junction of the fallopian tube and uterine cavity) pregnancy with multidose medical therapy [39,50-52], resorting to surgical therapy if there is any deterioration in clinical status. There are no high quality data comparing single versus multidose MTX therapy for interstitial pregnancy.

The most common multiple dose regimen administers MTX (1 mg/kg per day IM or IV) on Days 1, 3, 5, and 7 with leucovorin (0.1 mg/kg orally) on Days 2, 4, 6, and 8; a second course of MTX/leucovorin may be given seven days after the last dose [39]. Success rates of 66 to 100 percent have been reported [52]. In one study, the mean duration to achieve an undetectable serum hCG concentration was 43 ± 64 days [51].

A residual interstitial mass or heterogeneous area with persistent vascularity on ultrasound has been reported despite complete hCG resolution [53,54]. Close follow-up in patients treated medically is advised. In those with increasing abdominal pain, early surgical intervention should be considered. After medical treatment of an interstitial pregnancy, there is an unknown risk of uterine rupture in a future pregnancy [55].

There are also case reports of management of interstitial pregnancy using selective arterial embolization alone or with MTX [56,57].

Surgical treatment of interstitial pregnancy is discussed separately. (See "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility", section on Interstitial pregnancy.)

NONTUBAL ECTOPIC PREGNANCIES — Medical and surgical management of heterotopic, cervical, cesarean scar, or abdominal pregnancy are discussed separately. (See "Cervical pregnancy" and "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".)

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Ectopic (tubal) pregnancy".) We encourage you to print or e-mail this topic review, or to refer patients to our public web site, www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS

Summary

  • The ideal candidates for MTX treatment are women with ectopic pregnancy who meet the following criteria:

  • - Hemodynamically stable
  • - Able and willing to comply with posttreatment monitoring
  • - Pretreatment serum hCG concentration less than 5000 mIU/mL
  • - Tubal size of less than 3 to 4 cm and no fetal cardiac activity (these are not independent predictors of MTX treatment success)

(See 'Candidates for medical treatment' above.)

  • Renal, hepatic, or hematologic disorders are contraindications to treatment with MTX. (See 'Contraindications' above.)

  • In multiple dose protocols, MTX is given on Days 1, 3, 5, and 7 and leucovorin on Days 2, 4, 6, and 8. If the serum hCG concentration plateaus or increases in two consecutive measurements, a second course may be given seven days after the previous dose. HCG is followed weekly until undetectable. (See 'Multiple dose protocol' above.)

  • Routine ultrasound follow-up is not necessary during treatment. After treatment, the ectopic pregnancy often increases in size and may persist for weeks. However, ultrasound evaluation for peritoneal fluid is indicated for women who develop severe abdominal pain.
  • Mild abdominal pain of short duration (one to two days) that occurs six to seven days after receiving the medication is common. Women with severe pain should be observed closely for hemodynamic changes which may accompany a tubal rupture. Clinical suspicion of a tubal rupture is an indication for immediate surgery. (See 'Pain after treatment' above.)

  • Treatment with MTX does not appear to compromise future fertility or pregnancy outcome, or increase the risk of recurrent ectopic pregnancy. (See 'Subsequent reproductive performance' above.)

  • Women with a pregnancy of unknown location or suspected ectopic pregnancy, and low and declining serum hCG levels may be candidates for expectant management. There are no high quality studies which compare expectant and medical treatment. (See 'Medical treatment versus expectant management' above.)

Recommendations

  • In women with tubal ectopic pregnancy, who are good candidates for MTX therapy (hemodynamically stable, able to comply with follow-up, hCG <5000 mIU/mL, no fetal cardiac activity), we suggest MTX therapy rather than laparoscopic surgery (Grade 2B). In stable women who do not meet these criteria, we suggest laparoscopic surgery rather than MTX (Grade 2C). (See 'Medical versus surgical treatment' above.)

  • In women who have been treated with methotrexate for tubal or interstitial pregnancy, we suggest that attempts to conceive may be resumed after the hCG level is undetectable rather than waiting for one or more ovulatory cycles (Grade 2C). (See 'Subsequent reproductive performance' above.)

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