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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 . In one report, approximately 35 percent of women with ectopic pregnancy are eligible for medical treatment . 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 .
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 and toxicity 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]:
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].
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 .
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  (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 . 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 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 , 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 . 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 "First trimester medication abortion (termination of pregnancy)".)
Pretreatment testing — Prior to treatment, the following testing should be performed:
The diagnosis of ectopic pregnancy is discussed in detail separately. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy".)
Precautions during therapy — Patients and clinicians should adhere to the following precautions during MTX treatment :
Single dose protocol — The most efficient approach to medical therapy is administration of a single IM dose of MTX. Approximately 15 to 20 percent of women will require a second dose of MTX and patients should be made aware of this before starting the protocol [3,13]. Fewer than 1 percent of patients need more than two doses  (see 'Side effects and complications' below).
In the single dose protocol (table 2), Day 1 is the day that MTX is administered [1,32]. The dose used is 50 mg per square meter of body surface area (BSA) . 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). Protocols vary slightly; choice of protocol depends on provider preference.
After Day 7, hCG testing is repeated weekly. On Day 14, if there is a <15 percent hCG decline from Days 7 to 14, a third dose of MTX 50 mg/m2 IM is given. 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). 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]. If the hCG does not decline to zero, a new pregnancy should be excluded; if the hCG is rising, a transvaginal ultrasound should be performed. Alternatively, some patients have a slow clearance of serum hCG. In our practice, if three weekly values are similar past 35 days after the last injection, we give an additional dose of MTX (50 mg/m2). This typically accelerates the decline of serum hCG. The risk of gestational trophoblastic disease is low. The causes and evaluation of a persistent low serum hCG are discussed separately. (See "Human chorionic gonadotropin: Testing in pregnancy and gestational trophoblastic disease and causes of low persistent levels", section on 'Causes and evaluation of persistent low levels of hCG'.)
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".)
Folinic acid rescue is not required for women treated with the single dose protocol, even if multiple doses are ultimately given.
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 . 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 . Forty percent of women reported side effects, but these effects were relatively minor and transient .
Ultrasound follow-up — There appears to be no clinical benefit from routine serial ultrasound examinations . 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) . (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 .
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 . 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
Interval to conception — There has been no study addressing when is the earliest and best 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 . However, a retrospective study of controlled ovarian hyperstimulation after methotrexate treatment of ectopic pregnancy reported decreased number of oocytes in the cycle within 180 days after methotrexate compared to that in later days .
Toxicology literature recommends a four to six month washout period [43,44]. A retrospective study of women 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 (mean 3.6±1.7 months) compared with six or more months (mean 23.6±14.7 months) . Thus, since, there is no apparent deleterious effect of previous methotrexate treatment on the offspring, it is reasonable to allow the patients to conceive. Women in this population should take the folate daily, according to routine preconceptual recommendations. (See "Folic acid for prevention of neural tube defects", section on 'Folic acid supplementation for prevention of NTDs'.)
Effect on fertility — There is no evidence of adverse effects of MTX treatment of ectopic pregnancy on future pregnancies [46-49]. In addition, treatment with MTX does not appear to compromise ovarian reserve . 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 . The risk of recurrence appears to be the same for both medical and surgical therapies . (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 .
MEDICAL VERSUS SURGICAL TREATMENT — Approximately 35 percent of women with ectopic pregnancy are eligible for medical treatment . 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 . 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 .
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.
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 pregnancy (located at the junction of the fallopian tube and uterine cavity) with multidose medical therapy (figure 1) [39,55-58], 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 . Success rates of 66 to 100 percent have been reported . In one study, the mean duration to achieve an undetectable serum hCG concentration was 43 ± 64 days .
A residual interstitial mass or heterogeneous area with persistent vascularity on ultrasound has been reported despite complete hCG resolution [59,60]. 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 .
There are also case reports of management of interstitial pregnancy using selective arterial embolization alone or with MTX [62,63].
Surgical treatment of interstitial pregnancy is discussed separately. (See "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility", section on 'Cornuostomy or cornual resection of 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".)
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