Ectopic pregnancy: Expectant management of tubal pregnancy

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), intramural, ovarian, or abdominal. Other abnormally implanted pregnancies (eg, hysterotomy [myomectomy, cesarean] scar) can also occur. 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, typically requiring expeditious medical or surgical treatment to reduce the risk of rupture of the fallopian tube or another structure and catastrophic hemorrhage. However, in a small proportion of patients for whom the risk of tubal rupture is minimal, expectant management may be offered. Patients who are candidates for expectant management of ectopic pregnancy require informed consent about the risks of this strategy and close observation until the pregnancy has resolved.

Expectant management of tubal ectopic pregnancy will be reviewed here. 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")

●Treatment (see "Ectopic pregnancy: Choosing a treatment" and "Ectopic pregnancy: Methotrexate therapy" and "Tubal ectopic pregnancy: Surgical treatment")

●Diagnosis and management of uncommon sites of ectopic and abnormally implanted intrauterine pregnancies:

•Abdominal pregnancy (see "Abdominal pregnancy")

•Cervical pregnancy (see "Cervical pregnancy: Diagnosis and management")

•Cesarean scar pregnancy (see "Cesarean scar pregnancy")

•Heterotopic pregnancy (see "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Heterotopic pregnancy' and "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy')

•Interstitial pregnancy (see "Ectopic pregnancy: Methotrexate therapy", section on 'Patients with an interstitial pregnancy: Multiple-dose' and "Tubal ectopic pregnancy: Surgical treatment", section on 'Interstitial pregnancy')

●Patients with pregnancy of unknown location (see "Approach to the patient with pregnancy of unknown location")

PATIENT SELECTION — The most common treatments of tubal ectopic pregnancy are pharmacologic therapy with methotrexate (MTX) or surgical treatment; only a small proportion of patients are candidates for expectant management (algorithm 1). How to choose between these treatment options is discussed in detail separately. (See "Ectopic pregnancy: Choosing a treatment".)

Candidates for expectant management include patients with all of the following:

●No symptoms (eg, abdominal pain) or signs of impending or ongoing ectopic mass rupture (eg, evidence of hemoperitoneum on ultrasound).

●Confirmed or suspected tubal ectopic pregnancy on transvaginal ultrasound (TVUS); findings may include (see "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Diagnosis'):

•A complex inhomogeneous extraovarian adnexal mass.

An extrauterine mass that is characterized as not being suspicious for an ectopic pregnancy (eg, corpus luteum) is not included in this category. (See "Ultrasonography of pregnancy of unknown location".)

•An extraovarian adnexal mass containing an empty gestational sac.

•An extrauterine gestational sac with a yolk sac or embryo (without a heartbeat).

●Serum quantitative beta-human chorionic gonadotropin (hCG) concentration is low (eg, ≤200 milli-international units [mIU]/mL) and decreasing [1]. This is discussed in more detail separately. (See "Ectopic pregnancy: Choosing a treatment", section on 'Medical versus expectant management'.)

●Understand the clinical implications and risks of an ectopic pregnancy and tubal rupture. (See 'Outcomes' below and "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Natural history'.)

●Ready access to a medical facility that can provide emergency surgical treatment, if needed.

●Patient prefers expectant management rather than MTX or surgical treatment.

●Able and willing to comply with close follow-up.

These criteria are discussed in detail separately. (See "Ectopic pregnancy: Choosing a treatment" and "Ectopic pregnancy: Choosing a treatment", section on 'Medical versus expectant management'.)

CLINICAL PROTOCOL — Human chorionic gonadotropin (hCG) levels are followed every two days for three measurements to confirm that the hCG levels continue to decrease (eg, decrease of >10 percent across two consecutive measurements), and then weekly until undetectable. Ultrasound is repeated only as clinically necessary (eg, new or worsening symptoms) and is not needed to confirm pregnancy resolution [2]. Patients must be advised to use reliable contraception during the entire period of hCG monitoring. A new pregnancy during this time makes it difficult to interpret hCG results and complicates management.

Expectant management is abandoned in patients with a plateau or increase in hCG levels (increase of >10 percent across two consecutive measurements) or those with increasing abdominal pain. Such patients require surgery or medical therapy. (See "Ectopic pregnancy: Choosing a treatment", section on 'Choosing between methotrexate and surgery'.):

Patients with hCG levels that are decreasing, but more slowly than expected (eg, decrease of <10 percent), may be offered treatment with MTX or continuation of expectant management. In our practice, we treat such patients with MTX; we also offer MTX to those patients in whom hCG levels have not reach undetectable within 10 weeks. (See "Ectopic pregnancy: Methotrexate therapy", section on 'Preferred approach for most patients: Single-dose'.)

OUTCOMES

Resolution of ectopic pregnancy — Successful expectant management of ectopic pregnancy is defined as reaching an undetectable level of human chorionic gonadotropin (hCG; <5 to 10 milli-international units [mIU]/mL at most laboratories) without complications or conversion to a treatment method (ie, methotrexate [MTX], surgery). Success rates vary widely, in part due to differences in inclusion criteria [1,3-6].

Several randomized trials have evaluated expectant management of ectopic pregnancy and have demonstrated success rates comparable to MTX therapy [1,3,7-10] . However, the level of evidence is low to moderate given low sample size, relatively low (median) hCG levels, and differing protocols used for medical management included in these studies:

●In one trial including 80 patients with tubal ectopic pregnancy and serum hCG <1500 mIU/mL (median hCG: 405 to 465 mIU/mL), patients receiving placebo or MTX (50 mg/m² intramuscular [IM]) had similar rates of uneventful decline of hCG and time to pregnancy resolution (14 to 18 days [median]); patients with embryonic heartbeat or hemoperitoneum were excluded from the study [7]. The rate of surgical intervention was lower with MTX compared with placebo (17 versus 24 percent), and failure rate in patients with a baseline hCG 1000 to 1500 mIU/mL was also lower in the MTX group (38 versus 67 percent), but the study lacked sufficient statistical power to detect these differences. The risk of failure was significantly impacted by hCG level in both groups, with the risk increasing by 0.12 percent for each unit increase in hCG.

●In another trial including 15 patients with a confirmed ectopic pregnancy and a plateauing hCG <1500 mIU/mL (median hCG: 535 and 708 mIU/mL), patients receiving expectant management or MTX (1 mg/kg body weight IM with a maximum of 100 mg) had similar rates of uneventful declines of hCG and hCG clearance times; patients with a viable ectopic pregnancy, signs of tubal rupture, and/or active intraabdominal bleeding were excluded from the study [3]. There were no tubal ruptures or serious complications.

●Other small randomized trials also found comparable success rates for MTX and placebo [1,8]. In one trial including 60 patients with ectopic pregnancy, low-dose (2.5 mg) oral MTX was used for the treatment group [1]. For comparison, therapeutic doses for rheumatoid arthritis are typically at least 15 mg orally per day. Thus, it is not surprising that both groups had similar outcomes.

Prospective studies show similar results. In a literature review of studies including 700 patients with ectopic pregnancy undergoing expectant management, 69 percent of patients experienced ectopic pregnancy resolution [4]. In a subsequent prospective study including 177 patients with ectopic pregnancy managed expectantly, resolution of the ectopic pregnancy by ultrasound occurred two weeks after hCG normalization in 63 percent of patients; longer resolution times (>78 days) occurred in 4.5 percent of patients [11]. There was a positive correlation between resolution time and initial hCG level.

Tubal rupture — Tubal rupture can occur in any patient with ectopic pregnancy, even those with low and declining hCG levels [12].

There are few data to determine the threshold hCG level that allows for expectant management of ectopic pregnancy without unnecessary risk of tubal rupture. In a population-based study including 843 patients with ectopic pregnancy, tubal rupture occurred in 18 percent rate of patients; patients treated with MTX and those with pregnancy of unknown location were excluded from the study [13]. For comparison, rates of rupture after MTX treatment are 7 to 14 percent [14]. (See "Ectopic pregnancy: Choosing a treatment", section on 'Outcomes'.)

Subsequent reproductive function — Patients with ectopic pregnancy who are managed expectantly appear to have similar subsequent reproductive outcomes as those managed medically or surgically, but data are limited. In a prospective study including 30 patients with ectopic pregnancy managed expectantly, subsequent hysterosalpingography demonstrated tubal patency of the affected tube in 93 percent of cases [15]. The subsequent intrauterine pregnancy rate was 88 percent, and one patient (4 percent) had an ectopic pregnancy. Other studies have reported intrauterine pregnancy rates between 63 and 84 percent of patients [15-18].

CONSIDERATIONS FOR FUTURE PREGNANCY — The safe interval from resolution of ectopic pregnancy to conception of another pregnancy is unclear and there are no studies addressing the earliest time to conceive after expectant management of ectopic pregnancy. We advise patients that they may try to conceive again following their next menstrual period.

As with all patients with a history of ectopic pregnancy, subsequent pregnancies should be monitored closely with serial measurement of human chorionic gonadotropin (hCG) levels and early transvaginal ultrasound. We use the same clinical protocol as for patients with a pregnancy of unknown location and start with the first missed menses or after embryo transfer for those undergoing in vitro fertilization. The goal is to establish the diagnosis early and avoid tubal rupture. (See "Approach to the patient with pregnancy of unknown location", section on 'Hemodynamically stable patients'.)

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 topic (see "Patient education: Ectopic pregnancy (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●Clinical context – Ectopic pregnancy is a potentially life-threatening condition typically requiring expeditious medical or surgical treatment (algorithm 1). However, in a small proportion of patients in whom the risk of tubal rupture is minimal, expectant management may be an option. How to choose between these treatment options is discussed in detail separately. (See 'Introduction' above and "Ectopic pregnancy: Choosing a treatment".)

●Patient selection – Candidates for expectant management should have all of the following (see 'Patient selection' above and "Ectopic pregnancy: Choosing a treatment"):

•No symptoms (eg, abdominal pain) or signs of impending or ongoing ectopic mass 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 quantitative beta-human chorionic gonadotropin (hCG) concentration is low (eg, ≤200 milli-international units [mIU]/mL) and decreasing.

•Understand the clinical implications and risks of an ectopic pregnancy and tubal rupture.

•Ready access to a medical facility that can provide emergency surgical treatment, if needed.

•Patient prefers expectant management rather than methotrexate [MTX] or surgical treatment.

•Able and willing to comply with close follow-up.

●Clinical protocol – hCG levels are followed every 48 hours for three measurements to confirm that the hCG level continues to decline, and then weekly until it is undetectable. Ultrasound is repeated only as clinically necessary (eg, new or worsening symptoms) and is not needed to confirm pregnancy resolution. (See 'Clinical protocol' above.)

•For patients who experience a plateau or increase in hCG levels or have increasing abdominal pain, expectant management is abandoned; these patients require definitive treatment for ectopic pregnancy (ie, with surgery or MTX), as appropriate for the clinical situation. This is discussed separately. (See "Ectopic pregnancy: Choosing a treatment", section on 'Choosing between methotrexate and surgery'.)

•For asymptomatic patients who are managed expectantly and have hCG levels that are declining, but more slowly than expected (eg, decrease of <10 percent or not yet undetectable by 10 weeks), we suggest treatment with MTX rather than continuation of expectant management (Grade 2C).

●Outcomes

•Resolution – Success rates (ie, reaching an undetectable level of hCG) of expectant management appear to be similar to MTX therapy. (See 'Resolution of ectopic pregnancy' above.)

•Tubal rupture – Tubal rupture can occur in any patient with ectopic pregnancy, even those with low and declining hCG levels. The threshold hCG level that allows for expectant management of ectopic pregnancy without unnecessary risk of tubal rupture is uncertain. (See 'Tubal rupture' above.)

•Subsequent pregnancy – Patients with ectopic pregnancy who are managed expectantly appear to have similar subsequent reproductive outcomes as those managed medically or surgically, but data are limited. (See 'Subsequent reproductive function' above.)

●Future pregnancy – We advise patients that they may try to conceive again following their next menstrual period. As with all patients with a history of ectopic pregnancy, subsequent pregnancies should be monitored closely with serial measurement of hCG levels and early TVUS. (See 'Considerations for future pregnancy' above.)