Version May 2024
INTRODUCTION — An ectopic pregnancy is a pregnancy outside of the uterine cavity. The majority of ectopic pregnancies occur in the fallopian tube, but other possible sites include cervical, interstitial (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 patients with a previous cesarean delivery or myomectomy), intramural, ovarian, or abdominal. In addition, in rare cases, a multiple gestation may be heterotopic (includes both a uterine and extrauterine pregnancy).
Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the gold-standard treatment, advances in early diagnosis in the 1980s facilitated the introduction of medical therapy with methotrexate (MTX) [1]. With the routine use of early ultrasound, 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 patients is nearly 90 percent [2,3]. In a limited proportion of patients with early ectopic pregnancy, expectant management is an option.
Guidance regarding how to choose a treatment for ectopic pregnancy will be reviewed here. Related topics regarding ectopic pregnancy are discussed in detail separately, including:
●Epidemiology, risk factors, and anatomic sites (see "Ectopic pregnancy: Epidemiology, risk factors, and anatomic sites")
●Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and diagnosis")
●Methotrexate therapy (see "Ectopic pregnancy: Methotrexate therapy")
●Surgical management (see "Tubal ectopic pregnancy: Surgical treatment")
●Expectant management (see "Ectopic pregnancy: Expectant management of tubal pregnancy")
●Diagnosis and management of nontubal ectopic or abnormally implanted intrauterine pregnancies (see "Cervical pregnancy: Diagnosis and management" and "Abdominal pregnancy" and "Cesarean scar pregnancy")
●Patients with pregnancy of unknown location (see "Approach to the patient with pregnancy of unknown location")
OVERVIEW — Management of ectopic pregnancy typically requires surgery (salpingostomy or salpingectomy) or methotrexate (MTX) treatment (algorithm 1).
With early diagnosis, most patients with ectopic pregnancy may be treated medically with MTX. The remaining patients will either require (eg, due to suspicion of a ruptured tube, large ectopic pregnancy, inability to comply with the follow-up for MTX therapy) or prefer surgical treatment.
A limited proportion of patients are eligible for expectant management.
MEDICAL VERSUS SURGICAL TREATMENT
Choosing between methotrexate and surgery — Medical treatment with methotrexate (MTX) for ectopic pregnancy has comparable efficacy to surgery and results in similar fertility outcomes [4,5]. (See 'Outcomes' below.)
MTX is the preferred treatment option when all of the following characteristics are present:
●Hemodynamic stability.
●Serum beta-human chorionic gonadotropin (hCG) concentration ≤5000 mIU/mL.
●No fetal cardiac activity detected on transvaginal ultrasound (TVUS). 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 may decrease efficacy' below.)
●Patients are willing and able to comply with post-treatment follow-up and have access to emergency medical services within a reasonable time frame in case of a ruptured fallopian tube.
MTX is contraindicated and surgery is required when the following are present [6,7]:
●Hemodynamic instability.
●Intrauterine pregnancy, including a heterotopic pregnancy with coexisting viable intrauterine pregnancy. (See "Tubal ectopic pregnancy: Surgical treatment", section on 'Indications'.)
●Signs or symptoms of impending or ongoing rupture of ectopic mass (eg, pelvic or abdominal pain or evidence of intraperitoneal bleeding suggestive of rupture).
●Clinically important abnormalities in baseline hematologic, renal, or hepatic laboratory values – In such patients, surgery is recommended given that MTX can cause severe morbidity or mortality. In patients with renal insufficiency, a single dose of MTX can lead to bone marrow suppression, acute respiratory distress syndrome, bowel ischemia, or even death. Dialysis does not provide normal renal clearance [8,9]. Renal and liver disease may slow metabolism of MTX and result in pancytopenia and skin and mucosal disorders [10]. 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.
●Medical conditions such as immunodeficiency, active pulmonary disease (eg, tuberculosis), and peptic ulcer disease – MTX can be associated with pulmonary toxicity, and the toxicities of MTX are enhanced in patients with immune impairment. Similarly, in those with peptic ulcers, MTX may worsen the condition.
●Hypersensitivity to MTX.
●Breastfeeding.
Surgery may also be preferred by some patients who desire a concurrent surgical procedure: for example, sterilization or removal of hydrosalpinx (in a patient desiring future in vitro fertilization). Alternatively, the ectopic pregnancy may be treated with MTX, and surgery for concurrent conditions may be performed electively at a later date. (See "Female infertility: Reproductive surgery", section on 'Salpingectomy before in vitro fertilization'.)
In hemodynamically stable patients, surgical intervention should be performed only if a TVUS 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, thus resulting in an unnecessary surgery.
Patients may also reasonably choose surgery if they value a treatment that is of shorter duration and involves less follow-up and are willing to take the risks and recovery time associated with surgery.
Surgical contraindications are reviewed in detail separately. (See "Tubal ectopic pregnancy: Surgical treatment", section on 'Contraindications'.)
Methotrexate therapy — MTX may be administered systemically (eg, intravenously, intramuscularly [IM]) as a single dose or with a multiple-dose protocol. In most cases, it is given IM as a single-dose protocol. Alternatively, MTX can be administered by direct local injection into the ectopic pregnancy sac. (See "Ectopic pregnancy: Methotrexate therapy", section on 'Dosing and administration' and "Ectopic pregnancy: Methotrexate therapy", section on 'Comparing single- versus multi-dose therapy'.)
Factors that may decrease efficacy
●High hCG concentration – A high serum hCG concentration is the most important factor associated with MTX treatment failure (table 1). Patients with a high baseline hCG concentration (>5000 mIU/mL) are more likely to require multiple courses of MTX therapy or experience treatment failure [11,12].
A systematic review of observational studies included 503 patients, and 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 >5000 mIU/mL compared with those who had initial levels of less than 5000 mIU/mL (odds ratio [OR] 5.5, 95% CI 3.0-9.8). The failure rate for patients who had an initial concentration between 5000 and 9999 mIU/mL was 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 on TVUS is another relative contraindication to medical treatment. In a meta-analysis, sonographic evidence of cardiac activity was significantly associated with treatment failure (OR 9.1, 95% CI 3.8-22.0) [2].
●Large ectopic size – Although large size of the ectopic pregnancy (≥3.5 cm) is often used as a criterion for exclusion in medical treatment regimens, this restriction is based on small studies with inconsistent protocols and results [12-14]. Studies have generally restricted the use of MTX to patients with an ectopic mass less than 3 to 4 cm [12,13]; thus, there are few studies of larger masses [15]. As an example, one observational study found that the success rate for systematic MTX treatment was slightly higher for patients with ectopic masses smaller than 3.5 cm compared with masses between 3.5 and 4.0 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 [12,13]. Further, ectopic mass size does not appear to correlate with hCG level [16].
●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, culdocentesis detected blood in the peritoneal cavity of 70 to 83 percent of patients with ectopic pregnancies, but only 50 to 62 percent of them had a ruptured fallopian tube [17].
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].
●Other – Preliminary reports have cited a variety of other factors that may be associated with treatment failure including:
•Sonographic evidence of a yolk sac [12,18,19].
•Isthmic location of ectopic mass (rather than ampullary) [12,20].
•High pretreatment folic acid level [21].
•Rate of hCG rise or fall prior to and within several days following treatment [20,22].
•Thickened endometrium (eg, ≥10 or ≥12 mm) [23-26].
•Class III obesity (body mass index [BMI] ≥40 kg/m2) [27]. Compared with patients with BMI <30 kg/m2, BMI ≥30 kg/m2 but <40 kg/m2 does not appear to be associated with higher failure rates [28].
Surgery — When surgery is chosen, there are two options for a surgical approach: salpingectomy (removal of the fallopian tube) and salpingostomy (incising the tube to remove the tubal gestation but leaving the remainder of the tube intact). There is a small risk of retained trophoblastic tissue and an increased risk of recurrent ectopic pregnancy with salpingostomy, but both procedures appear to result in similar subsequent fertility. Traditionally, salpingectomy has been the standard procedure, but salpingostomy is preferred because it is a conservative surgical option. (See "Tubal ectopic pregnancy: Surgical treatment", section on 'Salpingostomy versus salpingectomy'.)
Outcomes — MTX treatment for ectopic pregnancy has comparable efficacy to laparoscopic salpingostomy, avoids surgical complications, and results in similar fertility outcomes [4,5]. Studies have reported conflicting results regarding whether surgery or medical treatment is more cost-effective [3,5].
Relative efficacy of methotrexate versus surgery — MTX treatment of tubal ectopic pregnancy appears to be as effective as laparoscopic salpingostomy, as long as additional doses of MTX are administered if the follow-up hCG levels do not decrease as expected. (See "Ectopic pregnancy: Methotrexate therapy", section on 'Comparing single- versus multi-dose therapy'.)
A systematic review of randomized trials found that a single 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 0.72-0.94). However, when additional doses were given if a single dose was unsuccessful, there was comparable efficacy to salpingostomy (RR 1.01, 95% CI 0.92-1.12) [5]. There was no significant difference between systemic MTX in a fixed multiple-dose regimen and surgery (one trial, 82 versus 71 percent, RR 1.15, 95% CI 0.93-1.43). In one trial, health-related quality of life was significantly more severely impaired after MTX than salpingostomy (eg, more pain, less energy) [29]. The systematic review did not address complication rates, but the trials were likely underpowered to detect rare surgical complications.
Other outcomes
●Tubal rupture – The estimated mortality rate of ectopic pregnancy is 31.9 per 100,000 pregnancies [30]; most of these deaths are due to tubal rupture. The rate of tubal rupture depends on the population studied (rural versus urban, access to a nearby medical facility, and the availability of TVUS and serum hCG measurements). Although the rate of tubal rupture may approach 20 percent in patients who do not receive any form of treatment for their ectopic pregnancy [31], with early detection and close surveillance, the rate of tubal rupture is low.
●Ovarian reserve – Treatment with MTX does not appear to compromise ovarian reserve [32]. In a study of patients treated with in vitro fertilization, ovarian responses among patients with a history of ectopic pregnancy treated with MTX or salpingectomy were comparable [33,34].
●Fertility rates – It appears that the fertility rates after treatment of ectopic pregnancy with salpingostomy, salpingectomy, or MTX are similar. In the systematic review of randomized trials, subsequent fertility outcomes were reported in 98 patients [5]. No significant differences were found between single-dose MTX and salpingostomy in the number of intrauterine pregnancies (RR 1.01, 95% CI 0.66-1.54) or in recurrent ectopic pregnancy (RR 0.63, 95% CI 0.14-2.77). Ectopic pregnancy is likely associated with subfertility since extrauterine pregnancy is usually due to altered tubal function secondary to clinical or subclinical salpingitis. In a subsequent randomized trial of 446 patients assigned to salpingostomy or salpingectomy, the cumulative ongoing pregnancy rates after 36 months were comparable [35]. A study suggested that patients with ectopic first pregnancies had an increased risk of preterm birth (95% CI 1.18-1.37), low birth weight (95% CI 1.1-1.31), placental abruption (95% CI 1.04-1.41), and placenta previa (95% CI 1.1-1.91) [36]. The risk of placental abruption was particularly higher in older patients with a prior ectopic pregnancy (RR 1.42, 95% CI 1.16-1.69).
●Subsequent ectopic pregnancy – The risk of another ectopic pregnancy appears to be the same for both medical and surgical therapies [37]. (See 'Medical versus surgical treatment' above.)
MEDICAL VERSUS EXPECTANT MANAGEMENT — Expectant management is an option only for a small proportion of patients with suspected ectopic pregnancy and a very low risk of tubal rupture. This includes patients with the following (algorithm 1):
●No symptoms (eg, vaginal bleeding, abdominal pain) or signs of impending rupture
●Confirmed or suspected tubal ectopic pregnancy on transvaginal ultrasound (TVUS); findings may include:
•A complex inhomogeneous extraovarian adnexal mass
•An extraovarian adnexal mass containing an empty gestational sac
•An extrauterine gestational sac with a yolk sac or embryo (without a heartbeat)
●Serum beta-human chorionic gonadotropin concentration is low (≤200 mIU/mL) and declining.
We define declining as a decrease of >10 percent across two consecutive measurements. While higher thresholds (eg, 1000 to 2000 mIU/mL) have been studied [38-40], and some guidelines advise offering expectant management to patients who meet the above criteria and have an hCG <2000 mIU/mL [41,42], we recommend that more stringent hCG criterion (ie, ≤200 mIU/mL) be used given that ectopic pregnancy is a potentially life-threatening condition, and treatments for ectopic pregnancy (ie, methotrexate [MTX], surgery) are safe and effective [4]. (See 'Relative efficacy of methotrexate versus surgery' above.)
●Willing and able to attend posttreatment follow-up appointments and have access to emergency medical services within a reasonable time frame in case of a ruptured fallopian tube.
Our protocol for following such patients is described in detail separately. (See "Ectopic pregnancy: Expectant management of tubal pregnancy", section on 'Clinical protocol'.)
In patients with a strong suspicion of ectopic pregnancy and no possibility of an intrauterine pregnancy, a single dose of methotrexate has minimal side effects.
SPECIAL CONSIDERATIONS
Heterotopic pregnancy — In patients with a heterotopic pregnancy in whom the intrauterine gestation is live and desired, systemic medical therapy (ie, methotrexate [MTX]) is contraindicated [43].
In such patients, treatment should be tailored to the site of implantation of the ectopic pregnancy, utilize the least invasive therapy, and preserve the concomitant intrauterine pregnancy.
●Salpingectomy is the standard surgical approach for a coexistent tubal pregnancy and should be the first line of treatment in patients with hemodynamic instability or other signs of tubal rupture [44,45]. A laparoscopic approach is desirable if the patient is hemodynamically stable. (See "Tubal ectopic pregnancy: Surgical treatment".)
●In expert hands, an unruptured ectopic pregnancy can alternatively be treated with local feticidal injection under sonographic guidance. Substances for injection should have high therapeutic effectiveness with low toxicity for the concurrent intrauterine pregnancy and produce no lasting damage to the fallopian tube [46]. Two options are potassium chloride (KCl; eg, 2 mL of 2 mEq/mL [47]) and hyperosmolar glucose [46,47].
In a literature review including 11 cases of heterotopic tubal and intrauterine pregnancy treated with KCl injection, 6 of 11 cases (55 percent) failed this therapy and required surgical intervention [44].
With either approach, an ultrasound examination to confirm cardiac activity of the intrauterine fetus is performed one to two weeks after the procedure.
There appears to be a higher risk of spontaneous abortion of the intrauterine pregnancy of a heterotopic pregnancy than in an isolated intrauterine pregnancy [43,45,48].
Other abnormally implanted pregnancies — Medical and surgical management of other abnormally implanted (eg, interstitial, cervical, cesarean scar, abdominal) pregnancies are discussed separately.
●(See "Ectopic pregnancy: Methotrexate therapy", section on 'Patients with an interstitial pregnancy: Multiple-dose' and "Tubal ectopic pregnancy: Surgical treatment", section on 'Interstitial pregnancy'.)
●(See "Cervical pregnancy: Diagnosis and management".)
●(See "Cesarean scar pregnancy".)
●(See "Abdominal 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 5th to 6th 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 10th to 12th 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
●General principles
•An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic pregnancies occur in the fallopian tube. Tubal ectopic pregnancy may be treated medically (methotrexate [MTX]), surgically, or in a small proportion of patients with expectant management (algorithm 1). (See 'Introduction' above.)
•For patients with tubal pregnancy who are candidates for MTX therapy, we suggest MTX rather than surgical treatment (Grade 2B). (See 'Medical versus surgical treatment' above.)
●Patients requiring surgery – Surgery is required for patients with the following characteristics (see 'Choosing between methotrexate and surgery' above and 'Surgery' above):
•Hemodynamically unstable
•Suspected or impending tubal rupture (eg, evidence of intraperitoneal bleeding, pelvic or abdominal pain)
•Heterotopic pregnancy with coexisting viable intrauterine pregnancy
•Contraindications to MTX therapy or failed MTX therapy
Patients may also reasonably choose surgery if they need a concurrent surgical procedure or if they value a treatment that is of shorter duration and involves less follow-up and are willing to take the risks and recovery time associated with surgery.
●Candidates for MTX – Candidates for MTX treatment are patients with ectopic pregnancy who meet the following criteria (see 'Choosing between methotrexate and surgery' above):
•Hemodynamically stable
•Have no renal, hepatic, or hematologic disorders
•Able and willing to attend post-treatment appointments and have access to medical care in case of a ruptured fallopian tube
•Pretreatment serum human chorionic gonadotropin (hCG) concentration ≤5000 mIU/mL
•No fetal cardiac activity on transvaginal ultrasound
●Factors that may decrease efficacy of MTX – Factors that may decrease the efficacy of MTX treatment of ectopic pregnancy include hCG >5000 mIU/mL, large ectopic size (eg, ≥3.5 cm), presence of fetal cardiac activity, and sonographic finding of peritoneal fluid. (See 'Factors that may decrease efficacy' above.)
●Role of expectant management – Expectant management is an option only for a small proportion of patients with ectopic pregnancy and a very low risk of tubal rupture. Generally accepted criteria for expectant management include (see 'Medical versus expectant management' above):
•No symptoms or signs of impending rupture (eg, pelvic or abdominal pain)
•Confirmed or suspected tubal pregnancy on TVUS (without cardiac activity)
•hCG is low and declining (variable thresholds are used, as discussed below)
•Patient can comply with close follow-up and has ready access to emergency surgical treatment, if necessary
For patients who otherwise meet these criteria but have a serum hCG is >200 mIU/mL, we suggest MTX or surgery rather than expectant management (Grade 2C). Other experts offer expectant management to patients who meet the above criteria and have an hCG <2000 mIU/mL. (See 'Medical versus expectant management' above.)
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