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, 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, usually requiring expeditious surgical or medical treatment to reduce the risk of rupture of the fallopian tube or another structure and catastrophic hemorrhage. However, in a small proportion of cases in which the risk of tubal rupture is minimal, expectant management may be offered [2]. 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 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")
●Choosing a treatment (see "Ectopic pregnancy: Choosing a treatment")
●Methotrexate therapy (see "Ectopic pregnancy: Methotrexate therapy")
●Surgical management (see "Ectopic pregnancy: Surgical treatment")
●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 — The most common treatments of ectopic pregnancy are pharmacologic therapy with methotrexate (MTX) or surgical treatment. Only a small proportion of patients are candidates for expectant management.
The indication for expectant management of ectopic pregnancy is a suspicion of ectopic pregnancy in a patient who meets the selection criteria for expectant management. The patient must also prefer expectant management rather than MTX or surgical treatment.
Selection criteria — When ectopic pregnancy is suspected, in our practice, we offer expectant management only for patients who meet all the following criteria:
●Asymptomatic.
●Understand the clinical implications and risks of an ectopic pregnancy.
●Ready access to a medical facility if emergency surgical treatment is needed.
●Able and willing to comply with close follow-up.
●Transvaginal ultrasound (TVUS) does not show an extrauterine gestational sac or demonstrate an extrauterine mass suspicious for an ectopic pregnancy.
●Serum quantitative beta-human chorionic gonadotropin (hCG) concentration is low (≤200 milli-international units/mL) and decreasing [3]. We define decreasing as a decrease of >10 percent across two consecutive measurements. Some guidelines advise offering expectant management to patients who meet the above criteria and have an hCG <2000 milli-international units/mL [4,5].
Patients with no extrauterine or intrauterine mass on TVUS are described as a pregnancy of unknown location since imaging and laboratory assessment do not clearly distinguish between a failed intrauterine pregnancy and a resolving ectopic pregnancy in an early pregnancy. An extrauterine mass that can be characterized as not being suspicious for an ectopic pregnancy (eg, corpus luteum) is not a contraindication for expectant management. (See "Ultrasonography of pregnancy of unknown location".)
There are few data to determine the threshold hCG level that allows for expectant management of ectopic pregnancy without unnecessary risk of tubal rupture. The rate of tubal rupture without treatment is high. This was illustrated in a population-based study in France that reported an 18 percent rate of tubal rupture among 843 patients with ectopic pregnancy; patients treated with MTX were excluded [6]. Reported rates of rupture after MTX treatment are 7 to 14 percent [7]. (See "Ectopic pregnancy: Choosing a treatment", section on 'Outcomes'.)
Several studies have evaluated use of a hCG threshold up to 1000 to 2000 milli-international units/mL [3,8,9]. The two randomized trials that have evaluated expectant management of suspected ectopic pregnancy used hCG thresholds up to <1500 milli-international units/mL for ectopic pregnancy or <2000 milli-international units/mL for pregnancy of unknown location. However, the trials each included less than 100 participants, and the median hCG was approximately 400 to 500 milli-international units/mL. These trials found resolution of the pregnancy with expectant management alone in 59 and 76 percent of patients [9,10]. One trial found that the risk of failure increased by 0.12 percent for each unit increase in hCG [9]. (See 'Efficacy' below.)
The results of these studies show that with increasing hCG levels there remains a substantial risk of tubal rupture with expectant management. Thus, taking into account the potentially serious risks of tubal rupture and hemorrhage with ectopic pregnancy and the safety and efficacy of medical and surgical treatment (efficacy is approximately 88 percent for MTX or laparoscopy and 97 percent with laparotomy in randomized trials [11]), we recommend that more stringent hCG criterion (≤200 milli-international units/mL) for expectant management.
If expectant management is offered, the patient must be aware of and accept the risk of tubal rupture and be willing and able to comply with follow-up.
CONTRAINDICATIONS — Expectant treatment should not be attempted or management should be converted to pharmacologic or surgical treatment in patients with known or suspected ectopic pregnancy with at least one of the following characteristics:
●Hemodynamically unstable.
●Signs of impending or ongoing ectopic mass rupture (ie, severe or persistent abdominal pain or >300 mL of free peritoneal fluid).
●Human chorionic gonadotropin (hCG) >200 milli-international units/mL (at any time during this pregnancy) and/or increasing. We define increasing as an increase of >10 percent across two consecutive measurements and decreasing as a decrease of >10 percent across two consecutive measurements. There are few data to support how to define an increase or decrease in serial hCG levels, but 10 percent is based on the interassay coefficient of variation, which can be in that range.
●Unwilling or unable to comply with monitoring, including if the patient does not have timely access to a medical institution.
CLINICAL PROTOCOL — The clinical protocol for expectant management of ectopic pregnancy includes (algorithm 1):
●Diagnosis of pregnancy of unknown location with suspicion of ectopic pregnancy – (See "Ectopic pregnancy: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
●Counseling of patient regarding treatment options – If expectant management is offered, patients must be aware of and accept the risks as well as be willing and able to comply with follow-up. They must also be aware of precautions and reasons to call for medical help. They must be close enough to a medical center that can surgically treat ectopic pregnancy for timely care if impending or ongoing tubal rupture is suspected. (See "Ectopic pregnancy: Choosing a treatment", section on 'Medical versus surgical treatment'.)
●Close monitoring – Tubal rupture has been reported in patients with low and declining human chorionic gonadotropin (hCG) levels [12]. We follow the hCG level every two days for three measurements to confirm that the hCG level continues to decrease (decrease of >10 percent across two consecutive measurements), and then weekly until it is undetectable.
•Expectant management should be abandoned if a patient experiences a significant increase in abdominal pain or the serum hCG starts to increase (increase of >10 percent across two consecutive measurements) or fails to decrease (decrease of >10 percent across two consecutive measurements). These patients should be treated with surgery or methotrexate (MTX), as appropriate for the clinical situation.
•Asymptomatic patients who are managed expectantly and have hCG levels that are slowly declining may be offered continuation of expectant management or MTX injection. In general, in our practice, if the hCG has not reached undetectable within 10 weeks, we offer MTX therapy.
•If the hCG level has plateaued (increase or decrease of ≤10 percent across two consecutive measurements) or is increasing, the patient should be treated with MTX. (See "Ectopic pregnancy: Methotrexate therapy".)
OUTCOME
Efficacy — Successful expectant management of ectopic pregnancy is defined as reaching an undetectable level of beta-human chorionic gonadotropin (hCG, at most laboratories that is less than 5 to 10 milli-international units/mL) with no complications and no conversion to methotrexate (MTX) or surgical treatment. Success rates for expectant management of ectopic pregnancy of 47 to 100 percent have been reported [2]. The wide variation is due, in part, to differences in inclusion criteria as well as the definition of success [3,9,13-15].
Several randomized trials have evaluated expectant management of ectopic pregnancy and have demonstrated success rates comparable to MTX therapy [3,9,10,16]. The amount of time to reach an undetectable hCG was also comparable to MTX. Few patients managed expectantly had complications or had to convert to MTX or surgery.
The available randomized trials included patients with hCG levels higher than the 200 milli-international units/mL threshold we use in our practice, but most did not include an analysis of success rates at different threshold levels of hCG below 1000 milli-international units/mL. Thus, these data do not give information regarding choice of an hCG threshold of 200, 400, 600 milli-international units/mL, or higher. Accordingly, we prefer to use a low hCG level as a criterion to avoid unnecessary risk of unsuccessful treatment or tubal rupture. These trials often included patients with ultrasound evidence of an ectopic gestation, which is also a contraindication based on our practice. Similarly, we prefer to be conservative when offering expectant management.
The two largest randomized trials that compared expectant management with standard MTX therapy (standard dose and intramuscular [IM] route of administration) were:
●One trial (n = 80) assigned patients with a conclusive ultrasound diagnosis (those with an embryonic heartbeat or hemoperitoneum were excluded) of tubal ectopic pregnancy and a serum hCG <1500 milli-international units/mL to MTX (50 mg/m2 IM) or placebo [10]. No significant difference was found in the rate of uneventful decline of hCG (MTX: 83 percent versus placebo: 76 percent) or in the median time to pregnancy resolution (18 versus 14 days). Patients who required additional treatment included: expectant management (24 percent had surgery; one patient had a blood transfusion) and MTX (17 percent had surgery). The risk of failure was impacted by hCG level across both groups; the risk increased by 0.12 percent for each unit increase in hCG. The median hCG was approximately 400 milli-international units/mL in each group. Risk of failure in patients with a baseline hCG 1000 to 1500 milli-international units/mL was lower in the MTX group (38 versus 67 percent); this did not reach statistical significance, but the study lacked sufficient statistical power.
●Another trial (n = 73) assigned patients with an ectopic pregnancy or pregnancy of unknown location (those with a viable ectopic pregnancy, signs of tubal rupture and/or active intraabdominal bleeding were excluded) and a plateauing hCG (<50 percent hCG increase or decrease between initial evaluation and four days later) to MTX (1 mg/kg body weight IM with a maximum of 100 mg) or expectant management [9]. The hCG limits were <1500 milli-international units/mL for ectopic pregnancy or <2000 milli-international units/mL for pregnancy of unknown location (median hCG was 535 milli-international units/mL in the MTX group and 708 milli-international units/mL in the expectant group). An uneventful decline of hCG was achieved with initial treatment more often in patients treated with MTX than expectant management (76 versus 59 percent), but this did not reach statistical significance. The median serum hCG clearance time was comparable (MTX: 34 days and expectant: 38 days). Patients who required additional treatment included: expectant management (28 percent of patients were treated with MTX; 13 percent [4 of 32] had surgery) and MTX (22 percent received additional MTX injections; 2 percent [1 of 41] had surgery). There were no tubal ruptures or serious complications. No difference in health-related quality of life was found between groups [17]. This study was limited by the broad definition given to a plateauing hCG (±50 percent).
Other randomized trials include a small series (n = 23) that found comparable success rates for MTX and placebo (90 and 92 percent) [16]. Another trial used oral MTX (2.5 mg for five days) [3]. Mean hCG levels did not differ significantly between groups; in the placebo group, the mean hCG was 211 milli-international units/mL (range 30 to 1343 milli-international units/mL). Ultrasound findings were not reported. In both groups, 77 percent of patients recovered without the need for laparoscopy. A limitation of this trial was the low dose MTX. 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.
In a meta-analysis including two of the randomized trials (103 patients) discussed above [10,16], patients managed with expectant management and MTX treatment experienced similar times to tubal pregnancy resolution and similar rates of avoidance of surgery [18]. However, the level of evidence is low to moderate given low sample size and the relatively low hCG levels required for study inclusion.
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 [2]. In a subsequent prospective study including 177 patients managed expectantly, resolution of the ectopic pregnancy by ultrasound occurred two weeks after hCG normalization in 63 percent of patients (95% CI 55.7-70.4 percent); longer resolution times (>78 days) occurred in 4.5 percent of patients [19]. There was a positive correlation between resolution time and initial hCG level.
Subsequent reproductive function — Following expectant management of suspected ectopic pregnancy, subsequent hysterosalpingography has shown tubal patency of the affected tube in 93 percent of cases [20]. Subsequent intrauterine pregnancy rates of 63 to 88 percent have been reported [20-23].
INTERSTITIAL, NONTUBAL ECTOPIC, AND ABNORMALLY IMPLANTED INTRAUTERINE PREGNANCY — Medical and surgical management of interstitial, heterotopic, cervical, cesarean scar, and abdominal pregnancies are discussed separately.
●(See "Ectopic pregnancy: Surgical treatment", section on 'Interstitial pregnancy'.)
●(See "Ectopic pregnancy: Choosing a treatment", section on 'Heterotopic pregnancy'.)
●(See "Cervical pregnancy".)
●(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 topic (see "Patient education: Ectopic pregnancy (The Basics)")
●Beyond the Basics topic (see "Patient education: Ectopic (tubal) pregnancy (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●An ectopic pregnancy is a pregnancy outside of the uterine cavity. Ectopic pregnancy is a potentially life-threatening condition, generally requiring expeditious surgical or medical treatment. However, in a small proportion of cases in which the risk of tubal rupture is minimal, expectant management is appropriate. (See 'Introduction' above.)
●For patients with a serum beta-human chorionic gonadotropin (hCG) level >200 milli-international units/mL, we recommend methotrexate (MTX) or surgical treatment rather than expectant management (Grade 1B). Based on the risk of tubal rupture and the safety and efficacy of MTX and surgical treatment, we apply stringent criteria to selecting patients for expectant management. We also offer expectant management only to patients with a transvaginal ultrasound with no extrauterine gestational sac or extrauterine mass suspicious for an ectopic pregnancy. (See 'Selection criteria' above.)
●Contraindications to expectant management include hemodynamic instability or signs or symptoms of impending or ongoing tubal rupture. (See 'Contraindications' above.)
●The clinical protocol for expectant management of ectopic pregnancy includes: diagnosis of ectopic pregnancy or pregnancy of unknown location with suspicion of ectopic pregnancy (algorithm 1); counseling of patient regarding treatment options; and close monitoring. (See 'Clinical protocol' above.)
●We follow the hCG level every 48 hours for three measurements to confirm that the hCG level continues to decline, and then weekly until it is undetectable (see 'Clinical protocol' above):
•Expectant management is abandoned if a patient experiences a significant increase in abdominal pain or the serum hCG starts to increase or fails to decrease. These patients should be treated with surgery or MTX, as appropriate for the clinical situation.
•Asymptomatic patients who are managed expectantly and have hCG levels that are slowly declining or have plateaued may be offered continuation of expectant management or MTX injection.
●The rate of an uneventful decline of hCG in patients at low risk of tubal rupture who undergo expectant management is approximately 70 percent. (See 'Efficacy' above.)
