Number 193, March 2018

(Replaces Practice Bulletin Number 191, February 2018)

Committee on Practice Bulletins—Gynecology. This Practice Bulletin was developed by the

Committee on Practice Bulletins—Gynecology in collaboration with Kurt T. Barnhart, MD, MSCE; and
Jason M. Franasiak, MD, TS (ABB).
This information is designed as an educational resource to aid clinicians in providing obstetric and
gynecologic care, and use of this information is voluntary. This information should not be
considered as inclusive of all proper treatments or methods of care or as a statement of the
standard of care. It is not intended to substitute for the independent professional judgment of the
treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the
treating clinician, such course of action is indicated by the condition of the patient, limitations of
available resources, or advances in knowledge or technology. The American College of Obstetricians
and Gynecologists reviews its publications regularly; however, its publications may not reflect the
most recent evidence. Any updates to this document can be found on www.acog.org or by calling
the ACOG Resource Center.
While ACOG makes every effort to present accurate and reliable information, this publication is
provided “as is” without any warranty of accuracy, reliability, or otherwise, either express or implied.
ACOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or
person. Neither ACOG nor its officers, directors, members, employees, or agents will be liable for
any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or
consequential damages, incurred in connection with this publication or reliance on the information
presented.

INTERIM UPDATE: This Practice Bulletin is updated as highlighted to clarify the guidance on the
assessment of hCG levels after uterine aspiration in women with a pregnancy of unknown location.

PDF Format

Tubal Ectopic Pregnancy

Ectopic pregnancy is defined as a pregnancy that occurs outside of the uterine cavity. The most
common site of ectopic pregnancy is the fallopian tube. Most cases of tubal ectopic pregnancy that
are detected early can be treated successfully either with minimally invasive surgery or with medical
management using methotrexate. However, tubal ectopic pregnancy in an unstable patient is a
medical emergency that requires prompt surgical intervention. The purpose of this document is to
review information on the current understanding of tubal ectopic pregnancy and to provide
guidelines for timely diagnosis and management that are consistent with the best available scientific
evidence.

Background
Epidemiology
According to the Centers for Disease Control and Prevention, ectopic pregnancy accounts for
approximately 2% of all reported pregnancies (1). However, the true current incidence of ectopic
pregnancy is difficult to estimate because many patients are treated in an outpatient setting where
 events are not tracked, and national surveillance data on ectopic pregnancy have not been updated
since 1992 (1). Despite improvements in diagnosis and management, ruptured ectopic pregnancy
continues to be a significant cause of pregnancy-related mortality and morbidity. In 2011–2013,
ruptured ectopic pregnancy accounted for 2.7% of all pregnancy-related deaths and was the leading
cause of hemorrhage-related mortality (2). The prevalence of ectopic pregnancy among women
presenting to an emergency department with first-trimester vaginal bleeding, or abdominal pain, or
both, has been reported to be as high as 18% (3).
Etiology
The fallopian tube is the most common location of ectopic implantation, accounting for more than
90% of cases (4). However, implantation in the abdomen (1%), cervix (1%), ovary (1–3%), and cesarean
scar (1–3%) can occur and often results in greater morbidity because of delayed diagnosis and
treatment (4). An ectopic pregnancy also can co-occur with an intrauterine pregnancy, a condition
known as heterotopic pregnancy. The risk of heterotopic pregnancy among women with a naturally
achieved pregnancy is estimated to range from 1 in 4,000 to 1 in 30,000, whereas the risk among
women who have undergone in vitro fertilization is estimated to be as high as 1 in 100 (5, 6).
Risk Factors
One half of all women who receive a diagnosis of an ectopic pregnancy do not have any known risk
factors (3). Women with a history of ectopic pregnancy are at increased risk of recurrence. The
chance of a repeat ectopic pregnancy in a woman with a history of one ectopic pregnancy is
approximately 10% (odds ratio [OR] 3.0; 95% CI, 2.1–4.4). In a woman with two or more prior ectopic
pregnancies, the risk of recurrence increases to more than 25% (OR, 11.17; 95% CI, 4.0–29.5) (3).
Other important risk factors for ectopic pregnancy include previous damage to the fallopian tubes,
factors secondary to ascending pelvic infection, and prior pelvic or fallopian tube surgery (3, 7).
Among women who become pregnant through the use of assisted reproductive technology, certain
factors such as tubal factor infertility and multiple embryo transfer are associated with an increased
risk of ectopic pregnancy (8, 9). Women with a history of infertility also are at increased risk of
ectopic pregnancy independent of how they become pregnant (7). Other less significant risk factors
include a history of cigarette smoking and age older than 35 years (7).
Women who use an intrauterine device (IUD) have a lower risk of ectopic pregnancy than women who
are not using any form of contraception because IUDs are highly effective at preventing pregnancy.
However, up to 53% of pregnancies that occur with an IUD in place are ectopic (10). Factors such as
oral contraceptive use, emergency contraception failure, previous elective pregnancy termination,
pregnancy loss, and cesarean delivery have not been associated with an increased risk of ectopic
pregnancy (3, 7, 11, 12).
Clinical Considerations and Recommendations
 How is an ectopic pregnancy diagnosed?
The minimum diagnostic evaluation of a suspected ectopic pregnancy is a transvaginal ultrasound
evaluation and confirmation of pregnancy. Serial evaluation with transvaginal ultrasonography, or
serum hCG level measurement, or both, often is required to confirm the diagnosis.

Women with clinical signs and physical symptoms of a ruptured ectopic pregnancy, such as
hemodynamic instability or an acute abdomen, should be evaluated and treated urgently. Early
diagnosis is aided by a high index of suspicion. Every sexually active, reproductive-aged woman
who presents with abdominal pain or vaginal bleeding should be screened for pregnancy, regardless
of whether she is currently using contraception (13, 14). Women who become pregnant and have
known significant risk factors should be evaluated for possible ectopic pregnancy even in the
absence of symptoms.
Transvaginal Ultrasonography
Ultrasonography can definitively diagnose an ectopic pregnancy when a gestational sac with a yolk
sac, or embryo, or both, is noted in the adnexa (15, 16); however, most ectopic pregnancies do not
progress to this stage (15). The ultrasound findings of a mass or a mass with a hypoechoic area that
is separate from the ovary should raise suspicion for the presence of an ectopic pregnancy; however,
its positive predictive value is only 80% (15) because these findings can be confused with pelvic
structures, such as a paratubal cyst, corpus luteum, hydrosalpinx, endometrioma, or bowel.
Although an early intrauterine gestational sac may be visualized as early as 5 weeks of gestation
(17), definitive ultrasound evidence of an intrauterine pregnancy includes visualization of a
gestational sac with a yolk sac or embryo (16). Visualization of a definitive intrauterine pregnancy
eliminates ectopic pregnancy except in the rare case of a heterotopic pregnancy. Although a
hypoechoic “sac-like” structure (including a “double sac sign”) (18) in the uterus likely represents an
intrauterine gestation, it also may represent a pseudogestational sac, which is a collection of fluid or
blood in the uterine cavity that is sometimes visualized with ultrasonography in women with an
ectopic pregnancy (19, 20).
Serum Human Chorionic Gonadotropin Measurement
Measurement of the serum hCG level aids in the diagnosis of women at risk of ectopic pregnancy.
However, serum hCG values alone should not be used to diagnose an ectopic pregnancy and should
be correlated with the patient’s history, symptoms, and ultrasound findings (21, 22). Accurate
gestational age calculation, rather than an absolute hCG level, is the best determinant of when a
normal pregnancy should be seen within the uterus with transvaginal ultrasonography (23, 24). An
intrauterine gestational sac with a yolk sac should be visible between 5 weeks and 6 weeks of
gestation regardless of whether there are one or multiple gestations (25, 26). In the absence of such
definitive information, the serum hCG level can be used as a surrogate for gestational age to help
interpret a nondiagnostic ultrasonogram.
The “discriminatory level” is the concept that there is a hCG value above which the landmarks of a
normal intrauterine gestation should be visible on ultrasonography. The absence of a possible
gestational sac on ultrasound examination in the presence of a hCG measurement above the
discriminatory level strongly suggests a nonviable gestation (an early pregnancy loss or an ectopic
pregnancy). In 50–70% of cases, these findings are consistent with an ectopic pregnancy (27–29).
However, the utility of the hCG discriminatory level has been challenged (24) in light of a case series
that noted ultrasonography confirmation of an intrauterine gestational sac on follow-up when no
sac was noted on initial scan and the serum hCG level was above the discriminatory level (30–32). If
the concept of the hCG discriminatory level is to be used as a diagnostic aid in women at risk of
ectopic pregnancy, the value should be conservatively high (eg, as high as 3,500 mIU/mL) to avoid
the potential for misdiagnosis and possible interruption of an intrauterine pregnancy that a woman
hopes to continue (24, 32). Women with a multiple gestation have higher hCG levels than those with
a single gestation at any given gestational age and may have hCG levels above traditional
discriminatory hCG levels before ultrasonography recognition (24).
Trends of Serial Serum Human Chorionic Gonadotropin
A single hCG concentration measurement cannot diagnose viability or location of a gestation. Serial
hCG concentration measurements are used to differentiate normal from abnormal pregnancies (21,
22, 33, 34). When clinical findings suggest an abnormal gestation, a second hCG value measurement
is recommended 2 days after the initial measurement to assess for an increase or decrease.
Subsequent assessments of hCG concentration should be obtained 2–7 days apart, depending on the
pattern and the level of change.
In early pregnancy, serum hCG levels increase in a curvilinear fashion until a plateau at 100,000
mIU/mL by 10 weeks of gestation. Guidelines regarding the minimal increase in hCG for a
potentially viable intrauterine pregnancy have become more conservative (ie, slower increase) (21,
22) and have been demonstrated to be dependent on the initial value (35). There is a slower than
expected increase in serum hCG levels for a normal gestation when initial values are high. For
example, the expected rate of increase is 49% for an initial hCG level of less than 1,500 mIU/mL,
40% for an initial hCG level of 1,500–3,000 mIU/mL, and 33% for an initial hCG level greater than
3,000 mIU/mL (35). In early pregnancy, an increase in serum hCG of less than a minimal threshold
in 48 hours is suspicious of an abnormal pregnancy (ectopic or early pregnancy loss) because 99% of
normal intrauterine pregnancies will have a rate of increase faster than this minimum. However,
even hCG patterns consistent with a growing or resolving gestation do not eliminate the possibility
of an ectopic pregnancy (36).
Decreasing hCG values suggest a failing pregnancy and may be used to monitor spontaneous
resolution, but this decrease should not be considered diagnostic. Approximately 95% of women
with a spontaneous early pregnancy loss will have a decrease in hCG concentration of 21–35% in 2
days depending on initial hCG levels (34). A woman with decreasing hCG values and a possible
ectopic pregnancy should be monitored until nonpregnant levels are reached because rupture of an
ectopic pregnancy can occur while levels are decreasing or are very low.

Pregnancy of Unknown Location

A pregnant woman without a definitive finding of an intrauterine or ectopic pregnancy on ultrasound
examination has a “pregnancy of unknown location” (37). A pregnancy of unknown location should
not be considered a diagnosis, rather it should be treated as a transient state and efforts should be
made to establish a definitive diagnosis when possible (16). A woman with a pregnancy of unknown
location who is clinically stable and has a desire to continue the pregnancy, if intrauterine, should
have a repeat transvaginal ultrasound examination, or serial measurement of hCG concentration, or
both, to confirm the diagnosis and guide management (22, 37). Follow-up to confirm a diagnosis of
ectopic pregnancy in a stable patient, especially at first clinical encounter, is recommended to
eliminate misdiagnosis and to avoid unnecessary exposure to methotrexate, which can lead to
interruption or teratogenicity of an ongoing intrauterine pregnancy (16, 38, 39). The first step is to
assess for the possibility that the gestation is advancing.
When the possibility of a progressing intrauterine gestation has been reasonably excluded, uterine
aspiration can help to distinguish early intrauterine pregnancy loss from ectopic pregnancy by
identifying the presence or absence of intrauterine chorionic villi. Choosing the appropriate time and
intervention should be done through shared decision making, incorporating the patient’s values and
preferences regarding maternal risk and the possibility of interrupting a progressing pregnancy. If
chorionic villi are found, then failed intrauterine pregnancy is confirmed and no further evaluation is
necessary. If chorionic villi are not confirmed, hCG levels should be monitored, with the first
measurement taken 12–24 hours after aspiration. A plateau or increase in hCG postprocedure
suggests that evacuation was incomplete or there is a nonvisualized ectopic pregnancy, and further
treatment is warranted. Although the change at which hCG is considered to have plateaued is not
precisely defined, it would be reasonable to consider levels to have plateaued if they have decreased
by less than 10–15%. Large decreases in hCG levels are more consistent with failed intrauterine
pregnancy than ectopic pregnancy. In two small series of women undergoing uterine aspiration for
pregnancy of unknown location, nearly all women with a decrease in hCG levels of 50% or greater
 within 12–24 hours after aspiration had failed intrauterine pregnancies (29, 40). Patients with a
decrease in hCG of 50% or greater can be monitored with serial hCG measurements, with further
treatment reserved for those whose levels plateau or increase, or who develop symptoms of ectopic
pregnancy. Management of patients with an hCG decrease of less than 50% should be individualized,
as while failed intrauterine pregnancy is more frequent, ectopic pregnancy risk is appreciable. One
study (29) noted 55.6% of patients with ectopic pregnancies had an hCG decrease of more than 10%,
23.5% had a decrease of more than 30%, and 7.1% had a decrease of more than 50%. In a series of
patients who had an initial decrease of hCG levels between 15% and 50% 12–24 hours after office
uterine aspiration for pregnancy of unknown location who were monitored with serial hCG
measurement, 3 of 46 patients had rising or plateauing hCG levels necessitating treatment for
ectopic pregnancy (41). The other patients had resolving hCG levels, and were presumed to have
failed intrauterine pregnancies. Patients with an hCG decline between 15% and 50% 12–24 hours
after aspiration require at least close follow-up with serial hCG measurement, with consideration of
treatment for ectopic pregnancy based on clinical factors such as plateau or increase in hCG,
development of symptoms, or high clinical suspicion or strong risk factors for ectopic pregnancy
(29, 40, 41).
There is debate among experts about the need to determine pregnancy location by uterine
aspiration before providing methotrexate (42, 43). Proponents cite the importance of confirming the
diagnosis to avoid unnecessary exposure to methotrexate and to help guide management of the
current pregnancy and future pregnancies (37, 42). Arguments against the need for a definitive
diagnosis include concern about the increased risk of tubal rupture because of delay in treatment
while diagnosis is established and the increased health-care costs associated with additional tests
and procedures (43). However, with close follow-up during this diagnostic phase, the risk of rupture
is low. In one large series with serial hCG measurement of women with pregnancies of unknown
location, the risk of rupture of an ectopic pregnancy during surveillance to confirm diagnosis was as
low as 0.03 % among all women at risk and as low as 1.7% among all ectopic pregnancies diagnosed
(22). In addition, presumptive treatment with methotrexate has not been found to confer a
significant cost savings or to decrease the risk of complications (44). The choice of performing a
uterine aspiration before treatment with methotrexate should be guided by a discussion with the
patient regarding the benefits and risks, including the risk of teratogenicity in the case of an
ongoing intrauterine pregnancy and exposure to methotrexate.
 Who are candidates for medical management of ectopic pregnancy?
Medical management with methotrexate can be considered for women with a confirmed or high
clinical suspicion of ectopic pregnancy who are hemodynamically stable, who have an unruptured
mass, and who do not have absolute contraindications to methotrexate administration (45). These
patients generally also are candidates for surgical management. The decision for surgical
management or medical management of ectopic pregnancy should be guided by the initial clinical,
laboratory, and radiologic data as well as patient-informed choice based on a discussion of the
benefits and risks of each approach. Women who choose methotrexate therapy should be counseled
about the importance of follow-up surveillance.
Methotrexate
Methotrexate is a folate antagonist that binds to the catalytic site of dihydrofolate reductase, which
interrupts the synthesis of purine nucleotides and the amino acids serine and methionine, thereby
inhibiting DNA synthesis and repair and cell replication. Methotrexate affects actively proliferating
tissues, such as bone marrow, buccal and intestinal mucosa, respiratory epithelium, malignant cells,
and trophoblastic tissue. Systemic methotrexate has been used to treat gestational trophoblastic
disease since 1956 and was first used to treat ectopic pregnancy in 1982 (46). There are no
recommended alternative medical treatment strategies for ectopic pregnancy beyond intramuscular
methotrexate. Although oral methotrexate therapy for ectopic pregnancy has been studied, the
outcomes data are sparse and indicate that benefits are limited (47).
Contraindications

Box 1 lists absolute and relative contraindications to methotrexate therapy (45). Before
administering methotrexate, it is important to reasonably exclude the presence of an intrauterine
pregnancy. In addition, methotrexate administration should be avoided in patients with clinically
significant elevations in serum creatinine, liver transaminases, or bone marrow dysfunction indicated
by significant anemia, leukopenia, or thrombocytopenia. Because methotrexate affects all rapidly
dividing tissues within the body, including bone marrow, the gastrointestinal mucosa, and the
respiratory epithelium, it should not be given to women with blood dyscrasias or active
gastrointestinal or respiratory disease. However, asthma is not an exclusion to the use of
methotrexate. Methotrexate is directly toxic to the hepatocytes and is cleared from the body by
renal excretion; therefore, methotrexate typically is not used in women with liver or kidney disease.
Relative contraindications for the use of methotrexate (Box 1) do not serve as absolute cut-offs but
rather as indicators of potentially reduced effectiveness in certain settings. For example, a high
initial hCG level is considered a relative contraindication. Systematic review evidence shows a failure
rate of 14.3% or higher with methotrexate when pretreatment hCG levels are higher than 5,000
mIU/mL compared with a 3.7% failure rate for hCG levels less than 5,000 mIU/mL (48). Of note,
studies often have excluded patients from methotrexate treatment when hCG levels are greater than
5,000 mIU/mL based on expert opinion that these levels are a relative contraindication to medical
management. Other predictors of methotrexate treatment failure include the presence of an
advanced or rapidly growing gestation (as evidenced by fetal cardiac activity) and a rapidly
increasing hCG concentration (greater than 50% in 48 hours) (48–50).
 What methotrexate regimens are used in the management of ectopic pregnancy, and how do they
compare in effectiveness and risk of adverse effects?
There are three published protocols for the administration of methotrexate to treat ectopic
pregnancy: 1) a single-dose protocol (51), 2) a two-dose protocol (52), and 3) a fixed multiple-dose
protocol (53) (Box 2). The single-dose regimen is the simplest of the three regimens; however, an
additional dose may be required to ensure resolution in up to one quarter of patients (54, 55). The
two-dose regimen was first proposed in 2007 in an effort to combine the efficacy of the multiple-
dose protocol with the favorable adverse effect profile of the single-dose regimen (55). The two-
dose regimen adheres to the same hCG monitoring schedule as the single-dose regimen, but a
second dose of methotrexate is administered on day 4 of treatment. The multiple-dose
methotrexate regimen involves up to 8 days of treatment with alternating administration of
methotrexate and folinic acid, which is given as a rescue dose to minimize the adverse effects of the
methotrexate.
The overall treatment success of systemic methotrexate for ectopic pregnancy, defined as resolution
of the ectopic pregnancy without the need for surgery, in observational studies ranges from
approximately 70% to 95% (55). Resolution of an ectopic pregnancy may depend on the
methotrexate treatment regimen used and the initial hCG level. However, there is no clear consensus
in the literature regarding the optimal methotrexate regimen for the management of ectopic
pregnancy. The choice of methotrexate protocol should be guided by the initial hCG level and
discussion with the patient regarding the benefits and risks of each approach. In general, the single-
dose protocol may be most appropriate for patients with a relatively low initial hCG level or a plateau
in hCG values, and the two-dose regimen may be considered as an alternative to the single-dose
regimen, particularly in women with an initial high hCG value.

Single-Dose Versus Multiple-Dose

 Observational studies that compared the
single-dose and multiple-dose regimens have
indicated that although the multiple-dose
regimen is statistically more effective (92.7%
versus 88.1%, respectively; P=.035) (single-
dose failure OR, 1.71; 95% CI, 1.04–2.82), the
single-dose regimen is associated with a
decreased risk of adverse effects (OR, 0.44;
95% CI, 0.31–0.63) (55). However, a more
recent systematic review of randomized
controlled trials showed similar rates of
successful resolution with the single-dose
and multiple-dose regimens (relative risk
[RR], 1.07; 95% CI, 0.99–1.17) and an
increased risk of adverse effects with the
multiple-dose protocol (RR, 1.64; 95% CI,
1.15–2.34) (56). Abbreviation: hCG, human chorionic gonadotropin.

Single-Dose Versus Two-Dose *Stovall TG, Ling FW. Single-dose methotrexate: an expanded

clinical trial. Am J Obstet Gynecol 1993;168:1759-62;

A systematic review and meta-analysis of
discussion 1762–5.
three randomized controlled trials showed †Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J,
similar rates of successful resolution for the Chakhtoura N. Use of “2-dose” regimen of methotrexate to
two-dose and single-dose protocols (RR, treat ectopic pregnancy. Fertil Steril 2007;87:250–6.
1.09; 95% CI 0.98–1.20) and comparable risk ‡Rodi IA, Sauer MV, Gorrill MJ, Bustillo M, Gunning JE,
Marshall JR, et al. The medical treatment of unruptured
of adverse effects (RR, 1.33; 95% CI, 0.92–
ectopic pregnancy with methotrexate and citrovorum rescue:
1.94) (56). However, in two of the three trials preliminary experience. Fertil Steril 1986;46:811–3.
included in the review, the two-dose regimen
was associated with greater success among women with high initial hCG levels. In the first trial,
there was a nonstatistically significant trend toward greater success for the two-dose regimen in the
subgroup with an initial hCG level greater than 5,000 mIU/mL (80.0% versus 58.8%, P=.279) (RR,
0.74; 95% CI, 0.47–1.16) (57). The second trial reported a statistically significant higher success rate
for the two-dose regimen versus the single-dose regimen in patients with initial serum hCG levels
between 3,600 mIU/mL and 5,500 mIU/mL (88.9% versus 57.9%, P=.03) (OR 5.80; 95% CI, 1.29–
26.2) (58).
 What surveillance is needed after methotrexate treatment?
After administration of methotrexate treatment, hCG levels should be serially monitored until a
nonpregnancy level (based upon the reference laboratory assay) is reached (51). Close monitoring is
required to ensure disappearance of trophoblastic activity and to eliminate the possibility of
persistent ectopic pregnancy. During the first few days after treatment, the hCG level may increase
to levels higher than the pretreatment level but then should progressively decrease to reach a
nonpregnant level (51). Failure of the hCG level to decrease by at least 15% from day 4 to day 7 after
methotrexate administration is associated with a high risk of treatment failure and requires
additional methotrexate administration (in the case of the single-dose or two-dose regimen) or
surgical intervention (51). Methotrexate treatment failure in patients who did not undergo
pretreatment uterine aspiration should raise concern for the presence of an abnormal intrauterine
gestation. In these patients, uterine aspiration should be considered before repeat methotrexate
administration or surgical management, unless there is clear evidence of a tubal ectopic pregnancy.
 Ultrasound surveillance of resolution of an ectopic pregnancy is not routinely indicated because
findings do not predict rupture or time to resolution (59, 60). Resolution of serum hCG levels after
medical management is usually complete in 2–4 weeks but can take up to 8 weeks (55). The
resolution of hCG levels is significantly faster in patients successfully treated with the two-dose
methotrexate regimen compared with the single-dose regimen (25.7+13.6 versus 31.9+14.1
days; P>.025) (57).
 What are the potential adverse effects of systemic methotrexate administration?
Adverse effects of methotrexate usually are dependent on dose and treatment duration. Because
methotrexate affects rapidly dividing tissues, gastrointestinal problems (eg, nausea, vomiting, and
stomatitis) are the most common adverse effects after multiple doses. Vaginal spotting is expected.
It is not unusual for women treated with methotrexate to experience abdominal pain 2–3 days after
administration, presumably from the cytotoxic effect of the drug on the trophoblastic tissue. In the
absence of signs and symptoms of overt tubal rupture and significant hemoperitoneum, abdominal
pain usually can be managed expectantly by monitoring a woman’s hemoglobin level and
intraperitoneal fluid amount with transvaginal ultrasonography.

Elevation of liver enzymes is a less commonly reported adverse effect and typically resolves after
discontinuing methotrexate use (61). Alopecia also is a rare adverse effect of the low doses used to
treat ectopic pregnancy. Cases of pneumonitis also have been reported, and women should be
counseled to report any fever or respiratory symptoms to their physicians (62).
 How should women be counseled regarding the treatment effects of methotrexate?
Patients treated with methotrexate should be counseled about the risk of ectopic pregnancy rupture;
about avoiding certain foods, supplements, or drugs that can decrease efficacy; and about the
importance of not becoming pregnant again until resolution has been confirmed. It is important to
educate patients about the symptoms of tubal rupture and to emphasize the need to seek
immediate medical attention if these symptoms occur. Vigorous activity and sexual intercourse
should be avoided until confirmation of resolution because of the theoretical risk of inducing
rupture of the ectopic pregnancy. Additionally, practitioners should limit pelvic and ultrasound
examinations when possible. Patients should be advised to avoid folic acid supplements, foods that
contain folic acid, and nonsteroidal antiinflammatory drugs during therapy because these products
may decrease the efficacy of methotrexate. Avoidance of narcotic analgesic medications, alcohol,
and gas-producing foods are recommended so as not to mask, or be confused with, escalation of
symptoms of rupture. Sunlight exposure also should be avoided during treatment to limit the risk of
methotrexate dermatitis (63).
Before treatment with methotrexate, women should be counseled about the potential for fetal death
or teratogenic effects when administered during pregnancy. The product labeling approved by the
U.S. Food and Drug Administration recommends that women avoid pregnancy during treatment and
for at least one ovulatory cycle after methotrexate therapy (63). Methotrexate is cleared from the
serum before the 4–12 weeks necessary for the resolution of the ectopic gestation and ovulation in
the next cycle (64, 65). However, there are reports of methotrexate detectable in liver cells 116 days
past exposure (66). Limited evidence suggests that the frequency of congenital anomalies or early
pregnancy loss is not elevated in women who have become pregnant shortly after methotrexate
exposure (66). However, perhaps based on the timing of methotrexate’s clearance from the body,
some experts continue to recommend that women delay pregnancy for at least 3 months after the
last dose of methotrexate (67).
 How does methotrexate treatment affect subsequent fertility?
 Patients can be counseled that available evidence, although limited, suggests that methotrexate
treatment of ectopic pregnancy does not have an adverse effect on subsequent fertility or on ovarian
reserve. A prospective observational study noted no difference in anti-müllerian hormone levels or
reproductive outcomes after administration of methotrexate (68). Furthermore, a systematic review
of women undergoing fertility treatment found no significant differences in the mean number of
oocytes retrieved during the cycles before and after methotrexate administration (69).
 Who are candidates for surgical management of ectopic pregnancy?
In clinically stable women in whom a nonruptured ectopic pregnancy has been diagnosed,
laparoscopic surgery or intramuscular methotrexate administration are safe and effective
treatments. The decision for surgical management or medical management of ectopic pregnancy
should be guided by the initial clinical, laboratory, and radiologic data as well as patient-informed
choice based on a discussion of the benefits and risks of each approach. Surgical management of
ectopic pregnancy is required when a patient is exhibiting any of the following: hemodynamic
instability, symptoms of an ongoing ruptured ectopic mass (such as pelvic pain), or signs of
intraperitoneal bleeding.

Surgical management is necessary when a patient meets any of the absolute contraindications to
medical management listed in Box 1 and should be considered when a patient meets any of the
relative contraindications. Surgical management should be employed when a patient who initially
elects medical management experiences a failure of medical management. Surgical treatment also
can be considered for a clinically stable patient with a nonruptured ectopic pregnancy or when there
is an indication for a concurrent surgical procedure, such as tubal sterilization or removal of
hydrosalpinx when a patient is planning to undergo subsequent in vitro fertilization.

Surgical management generally is performed using laparoscopic salpingectomy (removal of part or

all of the affected fallopian tube) or laparoscopic salpingostomy (removal of the ectopic pregnancy
while leaving the affected fallopian tube in situ). Laparotomy typically is reserved for unstable
patients, patients with a large amount of intraperitoneal bleeding, and patients in whom
visualization has been compromised at laparoscopy.

 How do medical management and surgical management of ectopic pregnancy compare in

effectiveness and risk of complications?
Medical management of ectopic pregnancy avoids the inherent risks of surgery and anesthesia.
However, compared with laparoscopic salpingectomy, medical management of ectopic pregnancy
has a lower success rate and requires longer surveillance, more office visits, and phlebotomy.
Randomized trials that compared medical management of ectopic pregnancy with methotrexate to
laparoscopic salpingostomy have demonstrated a statistically significant lower success rate with the
use of single-dose methotrexate (relative rate for success, 0.82; 95% CI, 0.72–0.94) and no
difference with the use of multidose methotrexate (relative rate for success, 1.8; 95% CI, 0.73–4.6)
(70). Comparing systemic methotrexate with tube-sparing laparoscopic surgery, randomized trials
have shown no difference in overall tubal preservation, tubal patency, repeat ectopic pregnancy, or
future pregnancies (70).
Medical management of ectopic pregnancy is cost effective when laparoscopy is not needed to make
the diagnosis and hCG values are less 1,500 mIU/mL (71). Surgical management of ectopic
pregnancy is more cost effective if time to resolution is expected to be prolonged, or there is a
relatively high chance of medical management failure, such as in cases with high or increasing hCG
values or when embryonic cardiac activity is detected (72, 73).
 How do salpingostomy and salpingectomy compare in effectiveness and fertility outcomes in the
management of ectopic pregnancy?
The decision to perform a salpingostomy or salpingectomy for the treatment of ectopic pregnancy
should be guided by the patient’s clinical status, her desire for future fertility, and the extent of
fallopian tube damage. Randomized controlled trials that compared salpingectomy with
salpingostomy for the management of ectopic pregnancy have found no statistically significant
difference in the rates of subsequent intrauterine pregnancy (RR, 1.04; 95% CI, 0.899–1.21) or
repeat ectopic pregnancy (RR, 1.30; 95% CI, 0.72–2.38) (74). In contrast, cohort study findings
indicate that salpingostomy is associated with a higher rate of subsequent intrauterine pregnancy
(RR, 1.24; 95% CI, 1.08–1.42) but also with an increased risk of repeat ectopic pregnancy (10%
versus 4%; RR, 2.27; 95% CI, 1.12–4.58) compared with salpingectomy (74).
In general, salpingectomy is the preferred approach when severe fallopian tube damage is noted and
in cases in which there is significant bleeding from the proposed surgical site. Salpingectomy can be
considered in cases of desired future fertility when the patient has a healthy contralateral fallopian
tube. However, salpingostomy should be considered in patients who desire future fertility but have
damage to the contralateral fallopian tube and in whom removal would require assisted
reproduction for future childbearing. When salpingostomy is performed, it is important to monitor
the patient with serial hCG measurement to ensure resolution of ectopic trophoblastic tissue. If there
is concern for incomplete resection, a single prophylactic dose of methotrexate may be considered
(45).

 Who are candidates for expectant management of diagnosed ectopic pregnancy?

There may be a role for expectant management of ectopic pregnancy in specific circumstances.
Candidates for successful expectant management of ectopic pregnancy should be asymptomatic;
should have objective evidence of resolution (generally, manifested by a plateau or decrease in hCG
levels); and must be counseled and willing to accept the potential risks, which include tubal rupture,
hemorrhage, and emergency surgery. If the initial hCG level is less than 200 mIU/mL, 88% of
patients will experience spontaneous resolution; lower spontaneous resolution rates can be
anticipated with higher hCG levels (75). In a single small randomized trial of women with hCG levels
less than 2,000 mIU/mL, expectant management was not associated with a statistically significant
lower treatment success than single-dose methotrexate for the management of ectopic pregnancy
(59% versus 76%, respectively) (RR, 1.3; 95% CI, 0.9–1.8) (76). Reasons for abandoning expectant
management include intractable or significantly increased pain, insufficient decrease of hCG levels,
or tubal rupture with hemoperitoneum.
Summary of Recommendations
The following recommendations are based on good and consistent scientific evidence (Level A):
 In clinically stable women in whom a nonruptured ectopic pregnancy has been diagnosed,
laparoscopic surgery or intramuscular methotrexate administration are safe and effective
treatments. The decision for surgical management or medical management of ectopic pregnancy
should be guided by the initial clinical, laboratory, and radiologic data as well as patient-informed
choice based on a discussion of the benefits and risks of each approach.
 Surgical management of ectopic pregnancy is required when a patient is exhibiting any of the
following: hemodynamic instability, symptoms of an ongoing ruptured ectopic mass (such as pelvic
pain), or signs of intraperitoneal bleeding.
The following recommendations are based on limited or inconsistent scientific evidence (Level B):
 Serum hCG values alone should not be used to diagnose an ectopic pregnancy and should be
correlated with the patient’s history, symptoms, and ultrasound findings.
 If the concept of the hCG discriminatory level is to be used as a diagnostic aid in women at risk of
ectopic pregnancy, the value should be conservatively high (eg, as high as 3,500 mIU/mL) to avoid
the potential for misdiagnosis and possible interruption of an intrauterine pregnancy that a woman
hopes to continue.
 The decision to perform a salpingostomy or salpingectomy for the treatment of ectopic pregnancy
should be guided by the patient’s clinical status, her desire for future fertility, and the extent of
fallopian tube damage.
 The choice of methotrexate protocol should be guided by the initial hCG level and discussion with
the patient regarding the benefits and risks of each approach. In general, the single-dose protocol
may be most appropriate for patients with a relatively low initial hCG level or a plateau in hCG
values, and the two-dose regimen may be considered as an alternative to the single-dose regimen,
particularly in women with an initial high hCG value.
 Failure of the hCG level to decrease by at least 15% from day 4 to day 7 after methotrexate
administration is associated with a high risk of treatment failure and requires additional
methotrexate administration (in the case of the single-dose or two-dose regimen) or surgical
intervention.
 Patients can be counseled that available evidence, although limited, suggests that methotrexate
treatment of ectopic pregnancy does not have an adverse effect on subsequent fertility or on ovarian
reserve.
 There may be a role for expectant management of ectopic pregnancy in specific circumstances.
The following recommendations are based primarily on consensus and expert opinion (Level C):
 The minimum diagnostic evaluation of a suspected ectopic pregnancy is a transvaginal ultrasound
evaluation and confirmation of pregnancy. Serial evaluation with transvaginal ultrasonography, or
serum hCG level measurement, or both, often is required to confirm the diagnosis.
 A woman with a pregnancy of unknown location who is clinically stable and has a desire to continue
the pregnancy, if intrauterine, should have a repeat transvaginal ultrasound examination, or serial
measurement of hCG concentration, or both, to confirm the diagnosis and guide management.
 Medical management with methotrexate can be considered for women with a confirmed or high
clinical suspicion of ectopic pregnancy who are hemodynamically stable, who have an unruptured
mass, and who do not have absolute contraindications to methotrexate administration.
 After administration of methotrexate treatment, hCG levels should be serially monitored until a
nonpregnancy level (based upon the reference laboratory assay) is reached.
 Patients treated with methotrexate should be counseled about the risk of ectopic pregnancy rupture;
about avoiding certain foods, supplements, or drugs that can decrease efficacy; and about the
importance of not becoming pregnant again until resolution has been confirmed.
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Tubal ectopic pregnancy. ACOG Practice

Bulletin No. 193. American College of
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