21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate Official reprint from UpToDate® www.uptodate.com ©2017 UpToDate® Ectopic pregnancy: Choosing a treatment and methotrexate therapy Author: Togas Tulandi, MD, MHCM Section Editor: Robert L Barbieri, MD Deputy Editor: Sandy J Falk, MD, FACOG All topics are updated as new evidence becomes available and our peer review process is complete Literature review current through: Jan 2017. | This topic last updated: Apr 13, 2016 INTRODUCTION — An ectopic pregnancy is a pregnancy outside of the uterine cavity. Almost all ectopic pregnancies occur in the fallopian tube (98 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, 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 lifethreatening 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 [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 many cases. The overall success rate of medical treatment in properly selected women is nearly 90 percent [35] Medical treatment of ectopic pregnancy 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: Incidence, risk factors, and pathology") ● Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and diagnosis") ● Surgical management (see "Ectopic pregnancy: Surgical treatment") ● Expectant management (see "Ectopic pregnancy: Expectant management") ● Diagnosis and management of uncommon sites of ectopic pregnancy (see "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy") CHOOSING A TREATMENT — The three approaches to the management of ectopic pregnancy are surgery (salpingostomy or salpingectomy), MTX treatment, or expectant management. Approximately onethird of women with ectopic pregnancies are candidates for MTX treatment [6]. The remaining twothirds of women will require surgery (eg, due to suspicion of a ruptured tube, large ectopic pregnancy, inability to comply with the followup for MTX therapy) and some patients may prefer surgical treatment. A limited proportion of patients are eligible for expectant management Medical versus surgical treatment — MTX therapy is a noninvasive option that has comparable efficacy, safety, and fertility outcomes with surgery. The advantages of surgical treatment are less time for resolution of the ectopic pregnancy and avoidance of the need for prolonged monitoring. Surgery is required when urgent treatment is indicated or MTX therapy is unlikely to be successful https://www.uptodate.com/contents/ectopicpregnancychoosingatreatmentandmethotrexatetherapy/print?source=search_result&search=ectopic%20preg… 1/19 21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate Surgical indications — Surgery is required when emergency treatment is necessary, a concurrent surgical procedure is planned, or there is a relative or absolute contraindication to MTX therapy Surgical indications include: ● Emergency surgery is required: • Hemodynamically unstable • Signs of symptoms of impending or ongoing rupture of ectopic mass (eg, pelvic or abdominal pain or evidence of intraperitoneal bleeding suggestive of rupture) ● Indications for concurrent surgical procedure, including: • Desire for sterilization • Planned in vitro fertilization (IVF) for future pregnancy with known hydrosalpinx (removal of hydrosalpinges increase the likelihood of successful IVF) (see "Reproductive surgery for female infertility", section on 'Salpingectomy before in vitro fertilization') ● Contraindications to MTX therapy (see 'Contraindications' below) ● Failed medical therapy In hemodynamically stable women, surgical intervention should be performed only if a transvaginal ultrasound examination clearly shows a tubal ectopic pregnancy or an adnexal mass suggestive of ectopic pregnancy. If no mass is visualized sonographically, there is a high likelihood that a tubal pregnancy will not be visualized or palpated at surgery. Surgical contraindications are reviewed in detail separately. (See "Ectopic pregnancy: Surgical treatment", section on 'Contraindications'.) Methotrexate therapy — The optimal candidates for MTX treatment of ectopic pregnancy are hemodynamically stable, willing and able to comply with posttreatment followup, have a human chorionic gonadotropin (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 'Factors that impact efficacy' below.) Contraindications — Some women are not appropriate candidates for medical therapy and should be managed surgically, including women with the following characteristics [7,8]: ● Clinically important abnormalities in baseline hematologic, renal, or hepatic laboratory values: 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]. Renal and liver disease may slow metabolism of MTX and result in pancytopenia and skin and mucosal damage [11]. 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, peptic ulcer disease. MTX could be associated with pulmonary toxicity, and the various toxicity of MTX is enhanced in women with immune impairment. Similarly, in those with peptic ulcers, MTX may worsen the condition ● Hypersensitivity to MTX ● Heterotopic pregnancy with coexisting viable intrauterine pregnancy. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy", section on 'Heterotopic pregnancy'.) https://www.uptodate.com/contents/ectopicpregnancychoosingatreatmentandmethotrexatetherapy/print?source=search_result&search=ectopic%20preg… 2/19 21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate ● Breastfeeding ● Unable or unwilling to complete MTX protocol: • Not able or willing to comply with medical therapy posttreatment followup • Lack of timely access to a medical institution for management of tubal rupture Factors that impact efficacy ● 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 [12,13] A systematic review of observational studies involved 503 women in which the outcome of singledose MTX therapy was stratified according to initial hCG concentration [12]. 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 (odds ratio [OR] 5.5, 95% CI 3.09.8). 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 1.212.3). Multipledose 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 [3,13]. In a metaanalysis, sonographic evidence of cardiac activity was significantly associated with treatment failure (OR 9.1, 95% CI 3.822.0) [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 [1316]. Studies have generally restricted use of MTX to women with an ectopic mass less than 3 to 4 cm [13,14]; thus, there are few studies of larger masses [17]. As an example, one observational study found that the success rate for systematic MTX treatment was slightly higher for women with ectopic masses smaller than 3.5 cm compared with masses between 3.5 and 4 cm (93 versus 90 percent) [14] 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 [1315]. Further, ectopic mass size does not appear to correlate with hCG level [18] ● 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 [1921] In a large case series, free fluid confined to the pelvic cavity was not associated with medical treatment failure [13]. 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 culdesac (pouch of Douglas) is controversial [7,22] ● 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 [13,23,24], isthmic location of ectopic mass (rather https://www.uptodate.com/contents/ectopicpregnancychoosingatreatmentandmethotrexatetherapy/print?source=search_result&search=ectopic%20preg… 3/19 21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate than ampullary) [13,25], high pretreatment folic acid level [26], and rate of hCG rise or fall prior to and within several days following treatment [25,27]. 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 Outcome — MTX treatment for ectopic pregnancy has comparable efficacy to laparoscopic salpingostomy, avoids surgical complications, and results in similar fertility outcomes [28,29]. Studies have reported conflicting results regarding whether surgery or medical treatment is more costeffective [5,29]. In a randomized trial of 446 women assigned to salpingotomy or salpingectomy, the cumulative ongoing pregnancy rates after 36 months were comparable [30]. It appears that the fertility rates after treatment of ectopic pregnancy with salpingostomy, salpingectomy, or MTX are similar. In another study, there was no significant difference in the parameters of ovarian response in the subsequent in vitro fertilization cycle after previous treatment of ectopic pregnancy with MTX or salpingectomy [31] A systematic review of randomized trials found that a single systemic dose of systemic MTX (50 mg/m2 or 1 mg/kg) was significantly less successful than laparoscopic salpingostomy (four trials; 71 versus 88 percent; relative risk [RR] 0.82, 95% CI 0.720.94); however, use of additional doses if a single dose was unsuccessful had comparable efficacy to salpingostomy (RR 1.01, 95% CI 0.921.12) [29]. There was no significant difference between systemic MTX in a fixed multipledose regimen and surgery (one trial; 82 versus 71 percent; RR 1.15, 95% CI 0.931.43). In one trial, healthrelated quality of life was significantly more severely impaired after MTX than salpingostomy (eg, more pain, less energy) [32]. The trials were likely underpowered to detect rare surgical complications Subsequent fertility outcomes were reported in 98 women. No significant differences were found between single dose MTX and salpingostomy in the number of intrauterine pregnancies (RR 1.01, 95% CI 0.661.54) or in recurrent ectopic (RR 0.63, 95% CI 0.142.77) [29]. Ectopic pregnancy is likely associated with subfertility since extrauterine pregnancy is usually due to altered tubal function secondary to clinical or subclinical salpingitis Treatment with MTX does not appear to compromise ovarian reserve [33]. In a study of women treated with in vitro fertilization, ovarian responses among women with a history of ectopic pregnancy treated with MTX or salpingectomy were comparable [31] The risk of another ectopic pregnancy appears to be the same for both medical and surgical therapies [34]. (See 'Medical versus surgical treatment' above.) Given the available evidence, for women with tubal pregnancy who are candidates for MTX therapy, we suggest MTX rather than surgical treatment. Surgical treatment is a reasonable option for women who value treatment that is of shorter duration and involves less followup and are willing to take the operative risks and recovery that are involved in surgery Medical 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 For women with suspected ectopic pregnancy, we recommend against expectant management if the serum hCG is >200 mIU/mL. We treat these women with MTX or surgical therapy Expectant management of ectopic pregnancy is discussed in detail separately. (See "Ectopic pregnancy: Expectant management".) METHOTREXATE DRUG INFORMATION https://www.uptodate.com/contents/ectopicpregnancychoosingatreatmentandmethotrexatetherapy/print?source=search_result&search=ectopic%20preg… 4/19 21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate 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 [35] The dose of MTX used to treat ectopic pregnancy (50 mg/m2 or 1 mg/kg) is relatively low. Highdose MTX (≥500 mg/m2) is used to treat some malignancies In some protocols, reduced folates (leucovorin, also called folinic acid, N5formyltetrahydrofolate, 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 highdose methotrexate", section on 'Clinical pharmacology'.) Routes of administration — MTX can be given systemically (intravenously, intramuscularly, or orally) or by direct local injection into the ectopic pregnancy sac transvaginally or laparoscopically. Intramuscular administration is most common. Intramuscular MTX administration is the predominant route for treatment of tubal pregnancy [2] Local injection of MTX for tubal 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 [36]. In addition, local and systemic MTX administration had similar rates of subsequent intrauterine pregnancies or repeat ectopic pregnancies. Local injection is not generally used for tubal pregnancy, but is used for cervical gestations. (See "Cervical pregnancy", section on 'Treatment'.) Adverse reactions — Adverse reactions to MTX are usually mild and selflimited. 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 singledose protocol will have side effects; this rate is lower than with multidose regimens (40 percent) [3]. (See "Major side effects of lowdose methotrexate".) Combination with other medications Mifepristone — Treatment of ectopic pregnancy using a combination of mifepristone and MTX has also been investigated [36]. A systematic review that included two randomized trials that compared singledose MTX (50 mg/m2) alone with intramuscular MTX in combination with oral mifepristone (600 mg) found a statistically lower success rate for MTX alone, but the success rates were clinically comparable (61 versus 72 percent; odds ratio 0.59, 95% CI 0.350.99) and 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 recommend the use of this regimen. In addition, mifepristone is not approved for treatment of ectopic pregnancy in the United States. (See "Firsttrimester medication abortion (termination of 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 nonsmall cell lung cancer and breast cancer [37,38]. Gefitinib selectively inhibits the tyrosine kinase domain of epidermal growth factor receptor and the placenta has the highest expression of EGF of all nonmalignant tissues. In a small case series of 12 women with an ectopic https://www.uptodate.com/contents/ectopicpregnancychoosingatreatmentandmethotrexatetherapy/print?source=search_result&search=ectopic%20preg… 5/19 21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate 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 [38]. 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 CLINICAL PROTOCOL Pretreatment testing — Prior to treatment, viable intrauterine pregnancy must be excluded. Otherwise, a woman with a viable pregnancy might be subjected to MTX administration [39]. The following testing should be performed: ● Serum human chorionic gonadotropin (hCG) as part of the diagnostic evaluation and to establish a baseline to monitor the effect of therapy ● Transvaginal ultrasound as part of the diagnostic evaluation ● Blood type and screen to determine the need for antiD immune globulin in women who are Rh(D)negative (see "Prevention of Rh(D) alloimmunization in pregnancy") ● Complete blood count and renal and liver function tests 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 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 singledose regimens ultimately receive two or more doses, and 10 percent of patients on multidose regimens receive a single dose [3]. (See 'Singledose protocol' below and 'Multipledose protocol' below.) We prefer an initial approach with singledose 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 multipledose protocols [3,36,40]. Multipledose protocols appear to cause more adverse effects [3] The singledose 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 singledose with fixed multipledose regimens [36] There was no significant difference between treatment success rates, which ranged from 89 to 91 percent for singledose and from 86 to 93 percent for multidose therapy [41,42]. 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 multipledose 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 (odds ratio [OR] 4.74, 95 percent CI 1.7712.62). However, significantly fewer side effects were noted after singledose versus multidose treatment (31 versus 41 percent) A hybrid of the two protocols, a twodose MTX regimen (50 mg/m2 intramuscularly (IM) on Days 0 and 4) has been proposed. A single report on this regimen found an 87 percent treatment success rate [43], infrequent complications and adverse effects, and high patient satisfaction. Further study to evaluate this protocol is needed before it can be recommended https://www.uptodate.com/contents/ectopicpregnancychoosingatreatmentandmethotrexatetherapy/print?source=search_result&search=ectopic%20preg… 6/19 21/2/2017 Ectopic pregnancy: Choosing a treatment and methotrexate therapy UpToDate On the other hand, we use multidose MTX therapy for interstitial pregnancies as well as for cervical pregnancy (See 'Interstitial pregnancy' below.) Singledose 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 [3,14]. Less than 1 percent of patients need more than two doses [3] In the singledose protocol (table 2), Day 1 is the day that MTX is administered [2,44]. The dose used is 50 mg per square meter of body surface area (BSA) [45]. 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 ● In a commonly used protocol, on Days 4 and 7, a serum hCG concentration is drawn [7,8,46]. 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 in the first several days following therapy (ie, until Day 4) [47]. 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 After Day 7, hCG testing is repeated weekly. On Day 14, if there is a