INTRODUCTION — An ectopic pregnancy is a pregnancy outside of the uterine cavity. The majority of ectopic pregnancies occur in the fallopian tube (96 percent) [1], but other possible sites include cervical, interstitial (also referred to as cornual; a pregnancy located in the proximal segment of the fallopian tube that is embedded within the muscular wall of the uterus), hysterotomy scar (eg, in a patient with a previous cesarean delivery), intramural, ovarian, or abdominal. In addition, in rare cases, a multiple gestation may be heterotopic (include both a uterine and extrauterine pregnancy).

Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the mainstay of treatment, many patients are candidates for medical therapy with methotrexate (MTX) because of advances in early diagnosis [2]. The overall success rate of medical treatment in properly selected patients is nearly 90 percent [3,4].

Treatment of ectopic pregnancy with MTX will be reviewed here. The surgical treatment of ectopic pregnancy is reviewed elsewhere (see "Ectopic pregnancy: Surgical treatment"). Related topics regarding ectopic pregnancy are discussed in detail separately, including:

●Epidemiology, risk factors, and pathology (see "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites")

●Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and diagnosis")

●Choosing a treatment (see "Ectopic pregnancy: Choosing a treatment")

●Surgical management (see "Ectopic pregnancy: Surgical treatment")

●Expectant management (see "Ectopic pregnancy: Expectant management")

●Diagnosis and management of uncommon sites of ectopic and abnormally implanted intrauterine pregnancies (see "Abdominal pregnancy" and "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Heterotopic pregnancy' and "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy' and "Cesarean scar pregnancy")

INDICATIONS — MTX is the main agent used for the pharmacologic therapy of ectopic pregnancy. Some patients require or choose surgical treatment. Only a small proportion are candidates for expectant management (algorithm 1). (See "Ectopic pregnancy: Choosing a treatment".)

The indication for pharmacologic management of ectopic pregnancy is a clinical diagnosis of ectopic pregnancy in a patient who meets the selection criteria for MTX therapy and who prefers pharmacologic management rather than surgical treatment.

The optimal candidates for a single-dose MTX treatment of ectopic pregnancy are patients with the following characteristics:

●Hemodynamically stable.

●No contraindications to MTX therapy.

●Serum beta-human chorionic gonadotropin (hCG) concentration ≤5000 milli-international units/mL.

●No fetal cardiac activity detected on transvaginal ultrasound.

●Willing and able to attend posttreatment follow-up appointments and with access to emergency medical services within a reasonable timeframe in case of a ruptured fallopian tube.

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. Factors that impact the efficacy of MTX are discussed in detail separately. (See "Ectopic pregnancy: Choosing a treatment", section on 'Factors that impact efficacy'.)

CONTRAINDICATIONS — Some patients are not appropriate candidates for MTX therapy and should be managed surgically, including those with the following characteristics [5,6]:

●Desired, viable intrauterine pregnancy.

●Ruptured ectopic pregnancy.

●Clinically important abnormalities in baseline hematologic, renal, or hepatic laboratory values. MTX is renally cleared, and in patients 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 [7,8]. Renal and liver disease may slow metabolism of MTX and result in pancytopenia and skin and mucosal disorders [9]. MTX, especially with chronic administration such as for those with psoriasis or rheumatoid arthritis, can be hepatotoxic. Similarly, it can cause suppression of the bone marrow.

●Immunodeficiency, active pulmonary disease such as tuberculosis, or peptic ulcer disease. The toxicity of MTX is enhanced in patients with immune impairment. MTX may be associated with pulmonary toxicity. In patients with peptic ulcers, MTX may worsen the condition.

●Hypersensitivity to MTX.

●Breastfeeding.

Intermediate-dose MTX is used to treat ectopic pregnancy. Toxicities of high-dose MTX are discussed in detail separately. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Overview of adverse effects'.)

CLINICAL 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 by the kidneys, with 90 percent of an intravenous dose excreted unchanged within 24 hours of administration [10].

Treatment of ectopic pregnancy uses an intermediate MTX dose (50 mg/m² or 1 mg/kg). Low doses (7.5 to 25 mg weekly) are typically used to treat rheumatologic disorders. 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 in combination with MTX to bypass the metabolic block induced by MTX and thus rescue normal cells from toxicity. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Rationale for leucovorin rescue'.)

Route of administration — MTX can be given systemically (ie, intravenously, intramuscularly [IM], or orally) or by direct local injection into the ectopic pregnancy sac transvaginally or laparoscopically. IM administration is the most common route for treatment of tubal pregnancy [2].

Local injection is not generally used for tubal pregnancy, and has been found to be less effective than salpingostomy [11]. Local treatment is highly operator dependent. Also, patients bearing the risks of laparoscopic surgery should have definitive treatment (ie, removal of the ectopic gestation via salpingectomy or salpingostomy). Local injection is used in some cases of rare ectopic gestation locations, such as cervical. (See "Cervical pregnancy", section on 'Treatment'.)

When leucovorin is administered as part of the multiple-dose MTX protocol, it is typically administered by IM injection. (See 'Multiple-dose protocol' below.)

Adverse reactions — 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 multiple-dose regimens (40 percent) [3]. (See "Major side effects of low-dose methotrexate".)

CLINICAL PROTOCOL

Pretreatment testing — Prior to treatment, a viable intrauterine pregnancy must be excluded. Otherwise, a viable pregnancy might be exposed to harm from MTX administration [12].

A history and physical examination are performed. The history should include questions regarding contraindications to MTX. (See 'Contraindications' above.)

The following laboratory and imaging tests are performed:

●Serum beta-human chorionic gonadotropin (hCG) – This is part of the diagnostic evaluation and to establish a baseline to monitor the effect of therapy. (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Diagnostic evaluation'.)

●Transvaginal ultrasound – This is part of the diagnostic evaluation.

●Blood type and screen – This is to determine the need for anti-D immune globulin in patients who are RhD-negative, if indicated. (See "RhD alloimmunization: Prevention in pregnant and postpartum patients".)

●Complete blood count and renal and liver function tests – This is to assess for contraindications to MTX therapy. (See 'Contraindications' above.)

The diagnosis of ectopic pregnancy is discussed in detail separately. (See "Ectopic pregnancy: Clinical manifestations and diagnosis".)

Efficacy of single- versus multiple-dose therapy — For patients with tubal pregnancy treated with MTX, we suggest a single-dose protocol in most cases. The two-dose protocol may be beneficial when hCG levels are high (>3000 international units/L) or if an adnexal mass measures >2 cm [13]. We reserve the use of multiple-dose MTX therapy for interstitial or cervical pregnancies. (See 'Interstitial pregnancy' below and "Cervical pregnancy", section on 'Initial therapy: Methotrexate'.)

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 approximately 90 percent for both single- and multiple-dose protocols [3,11,14]. Multiple-dose protocols appear to cause more adverse effects [3]. A single-dose approach is less expensive, requires less intensive monitoring, and does not require leucovorin rescue. The following are systematic reviews of the various regimens:

●A systematic review of two randomized trials compared single-dose with fixed multiple-dose regimens [11]. There was no significant difference between treatment success rates, which ranged from 89 to 91 percent for single-dose and from 86 to 93 percent for multiple-dose therapy [15,16]. There were no consistent findings regarding rates of complications between the two dose regimens.

●Another systematic review included 26 observational studies of 1300 patients with ectopic pregnancy [3]. Overall success rates were lower for single- versus multiple-dose regimens, a result that was statistically significant, but may not be clinically significant. This difference was even larger after adjustment for factors such as hCG level and presence of embryonic cardiac activity (odds ratio [OR] 4.74, 95% CI 1.77-12.62). However, significantly fewer side effects were noted after single-dose versus multiple-dose treatment (31 versus 41 percent).

●In a meta-analysis evaluating randomized controlled trials that compared patients treated for ectopic pregnancy with a single-dose, two-dose, or multidose MTX, the two-dose protocol was associated with higher treatment success compared with the single-dose protocol (OR 1.84, 95% CI 1.13-3.00) [13]. In addition, the two-dose protocol was more successful than single-dose protocol in patients with high hCG levels, defined as hCG levels >3000 international units/L (OR 3.23, 95% CI 1.53-6.84), and in patients with a large adnexal mass, defined as >2 cm (OR 2.93, 95% CI 1.23-6.90). Compared with the single-dose protocol, the multidose protocol was associated with a nonsignificant reduction in treatment failure (OR 0.56, 95% CI 0.28-1.13) and a higher chance of side effects (OR 2.10, 95% CI 1.24-3.54).

In clinical use, protocols may overlap. Fourteen percent of patients on single-dose regimens ultimately receive two or more doses, and 10 percent of patients on multiple-dose regimens receive just a single dose [3].

Single-dose protocol — The single-dose protocol is administration of a single intramuscular (IM) dose of MTX. Approximately 15 to 20 percent of patients will require a second dose of MTX, and patients should be made aware of this before starting the protocol [3,17]. Less than 1 percent of patients need more than two doses [3].

In the single-dose protocol (table 1), day 1 is the day that MTX is administered and an hCG should also be measured [2,18,19]. The dose used is 50 mg per square meter of body surface area (BSA; maximum dose [based on clinical experience] 100 mg in patients with normal renal function). BSA may be calculated based upon height and weight on the day of treatment using a BSA calculator (calculator 1) or the following formula:

Protocols vary slightly; choice of protocol depends on provider or institutional preference.

●In a commonly used protocol, on days 4 and 7, a serum hCG concentration is drawn [5,6,20]. 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. It is common to observe an increase in hCG levels from day 1 through day 4, and this should not cause concern [21]. This is due to continued hCG production by syncytiotrophoblast despite cessation of production by cytotrophoblast.

●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.

Follow-up includes:

●After day 7, hCG testing is repeated weekly. On day 14:

•If there is a ≥15 percent hCG decline from days 7 to 14, check hCG weekly until the level is undetectable (this level varies by laboratory).

-If the hCG does not decline to zero, a new pregnancy should be excluded.

-In our practice, if three weekly values are similar, we give an additional dose of MTX (50 mg/m²). This typically accelerates the decline of serum hCG.

•If there is a <15 percent hCG decline from days 7 to 14, an additional dose of MTX 50 mg/m² IM is given.

•If the hCG is rising, a transvaginal ultrasound should be performed.

We give a maximum of three doses of MTX. In rare cases in which the hCG falls <15 percent between weekly measurements after a third dose, we perform a laparoscopic salpingostomy or salpingectomy. (See "Ectopic pregnancy: Surgical treatment".)

Leucovorin rescue is not required for patients treated with the single-dose protocol, even if a few doses are ultimately given.

The hCG concentration usually declines to less than 15 milli-international units/mL by 35 days postinjection, but may take as long as 109 days [17,22]. Alternatively, some patients have a slow clearance of serum hCG. The risk of gestational trophoblastic disease is low.

There appears to be no clinical benefit from routine serial ultrasound examinations [23]. 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 patients with severe abdominal pain.

Two-dose protocol — The two-dose protocol includes administration of MTX 50 mg/m² on day 1 and a second dose of MTX 50 mg/m² on day 4. Serum hCG levels are obtained on day 7. The goal is for hCG levels to decline more than 15 percent from one measurement to the next before moving to the surveillance phase, which consists of weekly measurement of hCG until it is undetectable.

●On day 7, if the serum hCG declines more than 15 percent from the previous measurement, treatment is stopped, and the surveillance phase begins.

●If the serum hCG measurement declines less than 15 percent, a third dose of MTX may be administered on day 7, and hCG is reassessed on day 11. A fourth dose of MTX may be administered on day 11 for insufficient decline in hCG, with subsequent reassessment on day 14. If there continues to be an insufficient hCG decline at that point, surgery should be considered.

Multiple-dose protocol — The most common multiple-dose regimen is the administration of MTX (1 mg/kg per day IM or intravenously; maximum dose [based on clinical experience] 100 mg per day in patients with normal renal function) on days 1, 3, 5, and 7 and IM leucovorin (0.1 mg/kg) on days 2, 4, 6, and 8 [24]. 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 IM leucovorin 0.1 mg/kg. The hCG is followed until the level is undetectable.

Precautions during therapy — Patients should adhere to the following precautions during MTX treatment [6]:

●Avoid vaginal intercourse and new conception until hCG is undetectable.

●Avoid pelvic examinations during surveillance of MTX therapy due to theoretical risk of tubal rupture.

●Avoid sun exposure to limit risk of MTX dermatitis.

●Avoid vitamins containing folic acid.

●It is common advice to avoid nonsteroidal anti-inflammatory drugs (NSAIDs), as the interaction with MTX may decrease renal excretion of MTX and increase the risk of toxicity. However, for rheumatologic disease, low-dose MTX is sometimes given concurrently with NSAIDs along with close monitoring; the dose given for ectopic pregnancy is considered an intermediate dose. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Pharmacology' and "Therapeutic use and toxicity of high-dose methotrexate", section on 'Potential drug-drug-interactions'.)

Pain after treatment — Mild to moderate abdominal pain of short duration (one to two days) at six to seven days after receiving the MTX is common. The pain may be due to tubal abortion or tubal distention from hematoma formation and can usually be controlled with acetaminophen.

A patient with severe pain should 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 patients with ectopic pregnancy: moderate to severe pelvic pain, fluid above the uterine fundus or around the ovary, and hemoglobin concentration <10 g/dL [25]. A patient 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.

Patients 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.

Severe pain alone in a hemodynamically stable patient is not an indication for surgery. As an example, a review of 56 patients 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 [26].

SUBSEQUENT PREGNANCY

Interval to conception — There has been no study addressing the earliest time to conceive after MTX treatment of ectopic pregnancy. One study reported that patients with ectopic pregnancies treated with MTX had a timely return of menses and superior rates of conception compared with those treated with conservative surgical management [27]. However, a retrospective study of controlled ovarian hyperstimulation after MTX treatment of ectopic pregnancy reported decreased number of oocytes in the cycle within 180 days after MTX compared with that in later days [28].

The safe interval from MTX treatment to conception is unclear. Toxicology literature recommends a four- to six-month washout period before attempting to become pregnant [29]. A retrospective study of patients who conceive after MTX treatment for ectopic pregnancy found no difference in fetal malformation and adverse outcome rates in those who conceived within less than six months compared with six or more months [30]. Thus, since there is no apparent deleterious effect of previous MTX treatment on the offspring, it is reasonable to allow the patients to conceive. However, residual MTX may be stored in the liver and kidney for months.

We advise patients not to conceive for three months [6]. On the other hand, there is no evidence of teratogenic risk to those who conceive sooner. Patients trying to conceive should take folate daily, according to routine preconception recommendations. (See "Folic acid supplementation in pregnancy".)

Obstetric outcome — There is no evidence of adverse effects of MTX treatment of ectopic pregnancy on future pregnancies [31].

INTERSTITIAL PREGNANCY — For those with interstitial pregnancy (located at the junction of the fallopian tube and uterine cavity) in whom medical treatment is appropriate, we treat initially with multiple-dose MTX (figure 1 and table 1) [24,32-34], resorting to surgical therapy if there is any deterioration in clinical status. Deciding between medical and surgical treatment is discussed elsewhere.

●(See 'Multiple-dose protocol' above.)

●(See "Ectopic pregnancy: Choosing a treatment", section on 'Medical versus surgical treatment'.)

There are no high-quality data comparing single-dose versus multiple-dose MTX therapy for interstitial pregnancy. A few authors have advocated treatment of interstitial pregnancy by local MTX or potassium chloride (KCl) injection into the ectopic gestation. The dose of MTX is 1 mg/kg body weight or 50 mg/m² body surface area (BSA). The reported success rate is approximately 90 percent [35]. In the presence of fetal cardiac activity or in heterotopic pregnancy, local injection of KCl 20% is preferred [34]. There are also case reports of management of interstitial pregnancy using selective arterial embolization alone or with MTX [36,37].

With multiple-dose MTX for interstitial pregnancy, success rates of 66 to 100 percent have been reported [33]. In one study, the mean duration to achieve an undetectable serum human chorionic gonadotropin (hCG) concentration was 43±64 days [38].

A residual interstitial mass or heterogeneous area with persistent vascularity on ultrasound has been reported despite complete hCG resolution [39,40]. 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 [41].

Surgical treatment of interstitial pregnancy is discussed separately. (See "Ectopic pregnancy: Surgical treatment", section on 'Interstitial pregnancy'.)

NONTUBAL ECTOPIC PREGNANCY — Medical and surgical management of heterotopic, cervical, or abdominal pregnancy, or an abnormally implanted intrauterine pregnancy (ie, cesarean scar pregnancy) are discussed separately. (See "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy' and "Cervical pregnancy" and "Abdominal pregnancy" and "Cesarean scar pregnancy".)

COMBINED USE WITH OTHER MEDICATIONS — Combined use of MTX with other medications has been studied. However, combination therapy is not commonly used since it adds cost and potential complications, while MTX alone is an effective therapy.

Mifepristone — Treatment of ectopic pregnancy using a combination of mifepristone and MTX has been investigated [11]. A systematic review that included two randomized trials that compared single-dose MTX (50 mg/m²) alone with intramuscular (IM) MTX in combination with oral mifepristone (600 mg) found a statistically lower success rate for MTX alone (61 versus 72 percent; odds ratio [OR] 0.59, 95% CI 0.35-0.99), but the trials were small (n = 124 and 138). 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 use mifepristone in combination with MTX for treatment of ectopic pregnancy.

Other agents — Preliminary research has been done to investigate use of a combination of MTX and gefitinib, a medication used in the treatment of non-small cell lung cancer and breast cancer [42,43]. Gefitinib selectively inhibits the tyrosine kinase domain of epidermal growth factor receptor and the placenta has the highest expression of epidermal growth factor of all nonmalignant tissues. In a small case series of 12 patients with an ectopic pregnancy, combination therapy with MTX plus gefitinib resulted in a faster decline of serum human chorionic gonadotropin, a marker of trophoblastic activity, than treatment of historical controls with MTX alone [43]. Gefitinib may result in interstitial lung disease, particularly in patients of Japanese ancestry. Further study is needed before gefitinib can be used to treat ectopic pregnancy.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Ectopic pregnancy".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Ectopic pregnancy (The Basics)")

●Beyond the Basics topics (see "Patient education: Ectopic (tubal) pregnancy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic pregnancies occur in the fallopian tube (96 percent). (See 'Introduction' above.)

●For patients with tubal pregnancy treated with methotrexate (MTX), we suggest a single-dose over multiple-dose regimen (Grade 2B). However, we use a multiple-dose regimen for interstitial and cervical pregnancies. (See 'Efficacy of single- versus multiple-dose therapy' above and 'Interstitial pregnancy' above.)

●The ideal candidates for MTX treatment are patients with ectopic pregnancy who meet the following criteria (see 'Indications' above):

•Hemodynamically stable.

•Have no renal, hepatic, or hematologic disorders.

•Able and willing to attend posttreatment appointments.

•Pretreatment serum beta-human chorionic gonadotropin (hCG) concentration less than 5000 milli-international units/mL.

•Tubal size of less than 3 to 4 cm and no fetal cardiac activity (these are not independent predictors of MTX treatment success).

●Pretreatment testing includes serum hCG, complete blood count, and renal and liver function tests. (See 'Pretreatment testing' above.)

●In most patients, we suggest a one-dose rather than two-dose or multidose protocols of MTX (Grade 2C) due to comparable efficacy but improved tolerability. However, some patients, particularly those with baseline hCG levels of >3000 international units/L or adnexal masses >2 cm, may be better candidates for a two-dose protocol than a single-dose protocol, given higher likelihood of benefit. (See 'Efficacy of single- versus multiple-dose therapy' above.)

●In single-dose protocols, intramuscular (IM) MTX 50 mg/m² is given followed by an hCG level on treatment days 4 and 7 and then weekly. If the decrease in hCG between days 4 and 7 is less than 15 percent, a second dose of MTX is administered. Additional doses of MTX are given if the hCG does not decline sufficiently. The hCG is followed until the level is undetectable. (See 'Single-dose protocol' above.)

●In two-dose protocols, MTX is given on days 1 and 4. If serum hCG levels decline more than 15 percent from the previous measurement, treatment is stopped, and hCG is followed weekly until the level is undetectable. If hCG levels decline less than 15 percent, subsequent doses of MTX may be administered, up to a total of four doses. (See 'Two-dose protocol' 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.)

●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.)