Ectopic pregnancy: Clinical manifestations and diagnosis

Author:
Togas Tulandi, MD, MHCM
Section Editors:
Robert L Barbieri, MD
Howard T Sharp, MD
Deborah Levine, MD
Deputy Editor:
Sandy J Falk, MD, FACOG

Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2017. | This topic last updated: May 02, 2017.
INTRODUCTION An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic
pregnancies occur in the fallopian tube (98 percent) [1], but other possible sites include: cervical,
interstitial (also referred to as cornual; a pregnancy located in the proximal segment of the fallopian
tube that is embedded within the muscular wall of the uterus), hysterotomy (cesarean) scar, intramural,
ovarian, or abdominal. In addition, in rare cases, a multiple gestation may be heterotopic (include both
a uterine and extrauterine pregnancy).
The diagnosis of ectopic pregnancy is based upon a combination of measurement of the serum
quantitative human chorionic gonadotropin and findings on transvaginal ultrasonography.
The clinical manifestations and diagnosis of ectopic pregnancy will be reviewed here. This topic will
focus mainly on the diagnosis of tubal pregnancy. The surgical treatment of ectopic pregnancy is
reviewed elsewhere. Related topics regarding ectopic pregnancy are discussed in detail separately,
including:
Epidemiology, risk factors, and pathology (see "Ectopic pregnancy: Incidence, risk factors, and
pathology")
Management with methotrexate (see "Ectopic pregnancy: Choosing a treatment and methotrexate
therapy")
Surgical treatment (see "Ectopic pregnancy: Surgical treatment")
Expectant management (see "Ectopic pregnancy: Expectant management")
Diagnosis and management of uncommon ectopic pregnancy sites (see "Abdominal pregnancy,
cesarean scar pregnancy, and heterotopic pregnancy")
CLINICAL PRESENTATION The most common clinical presentation of ectopic pregnancy is first-
trimester vaginal bleeding and/or abdominal pain [2]. Ectopic pregnancy may also be asymptomatic.
Clinical manifestations of ectopic pregnancy typically appear six to eight weeks after the last normal
menstrual period, but may occur later, especially if the pregnancy is at an extrauterine site other than
the fallopian tube.
Normal pregnancy discomforts (eg, breast tenderness, frequent urination, nausea) are sometimes
present in addition to the symptoms specifically associated with ectopic pregnancy. There may be a
lower likelihood of early pregnancy symptoms in women with ectopic pregnancy because
progesterone, estradiol, and human chorionic gonadotropin (hCG) may be lower in ectopic pregnancy
than in normal pregnancy [3-5].
In a retrospective study of 2026 pregnant women who presented to the emergency department with
first-trimester vaginal bleeding and abdominal pain, 376 (18 percent) were diagnosed with ectopic
pregnancy. Of these 376 women, 76 percent had vaginal bleeding and 66 percent had abdominal pain
[6]. In a population-based registry of ectopic pregnancy from France, the incidence of rupture was 18
percent [7].
An ectopic pregnancy may be unruptured or ruptured at the time of presentation to medical care. Tubal
rupture (or rupture of other structures in which an ectopic pregnancy is implanted) can result in life-
threatening hemorrhage. Any symptoms suggestive of rupture should be noted. These include severe or
persistent abdominal pain or symptoms suggestive of ongoing blood loss (eg, feeling faint or loss of
consciousness).
Based upon the concern about the risk of rupture at the time or after presentation, clinicians should
consider ectopic pregnancy as a diagnosis in any woman of reproductive age with vaginal bleeding
and/or abdominal pain who has the following characteristics: (1) pregnant, but does not have a
confirmed intrauterine pregnancy (IUP); (2) pregnancy status uncertain, particularly if amenorrhea of
>4 weeks preceded the current vaginal bleeding; (3) in rare cases, a woman who presents with
hemodynamic instability and an acute abdomen that is not explained by another diagnosis.
Vaginal bleeding The volume and pattern of vaginal bleeding vary, and there is no bleeding pattern
that is pathognomonic for ectopic pregnancy. Bleeding may range from scant brown staining to
hemorrhage. Bleeding is typically intermittent, but may occur as a single episode or continuously.
The vaginal bleeding associated with ectopic pregnancy is typically preceded by amenorrhea. However,
some women may misinterpret bleeding as normal menses, and may not realize they are pregnant prior
to developing symptoms associated with ectopic pregnancy. This is particularly true in women who
have irregular menses or who do not keep track of menstrual cycles.
Bleeding occurs in many other conditions in early pregnancy. (See 'Differential diagnosis' below.)
Abdominal pain The pain associated with ectopic pregnancy is usually located in the pelvic area. It
may be diffuse or localized to one side. In cases in which there is intraperitoneal blood that reaches the
upper abdomen or in rare cases of abdominal pregnancy, the pain may be in the middle or upper
abdomen. If there is sufficient intraabdominal bleeding to reach the diaphragm, there may be referred
pain that is felt in the shoulder. Blood pooling in the posterior cul-de-sac (pouch of Douglas) may cause
an urge to defecate.
The timing, character, and severity of abdominal pain vary, and there is no pain pattern that is
pathognomonic for ectopic pregnancy. The onset of the pain may be abrupt or slow, and the pain may
be continuous or intermittent. The pain may be dull or sharp; it is generally not crampy. The pain may
be mild or severe. Tubal rupture may be associated with an abrupt onset of severe pain, but rupture may
also present with mild or intermittent pain.
DIAGNOSTIC EVALUATION
Overview Any women with a possible pregnancy who has vaginal bleeding and/or abdominal pain
should be evaluated for ectopic pregnancy. The main goals and steps of the evaluation of a woman with
a suspected ectopic pregnancy are:
Confirm that the patient is pregnant. (See 'Serial hCG' below.)
Evaluate the patient for hemodynamic instability, since rupture of the structure in which the ectopic
pregnancy is implanted may cause hemorrhage. Failure to diagnose ectopic pregnancy before tubal
rupture limits the treatment options and increases maternal morbidity and mortality.
Determine whether the pregnancy is intrauterine or ectopic (in rare cases, the pregnancy is
heterotopic). Determine the site of the ectopic pregnancy.
Determine whether the structure in which the pregnancy is implanted (most commonly, the fallopian
tube) has ruptured and whether the patient is hemodynamically stable.
Perform additional testing to guide further management (eg, blood type and antibody screen,
pretreatment testing for methotrexate therapy).
Step one: Confirm pregnancy and symptoms suggestive of ectopic pregnancy
History A menstrual history should be taken and the estimated gestational age should be calculated.
(See "Prenatal assessment of gestational age and estimated date of delivery".)
Risk factors for ectopic pregnancy should be elicited, including prior ectopic pregnancy, current use of
an intrauterine device, prior tubal ligation, and in vitro fertilization (IVF) (table 1). However, over 50
percent of women are asymptomatic before tubal rupture and do not have an identifiable risk factor for
ectopic pregnancy [8]. A population-based French study identified four factors that increased the risk
of rupture when an ectopic pregnancy was suspected: (1) never having used contraception, (2) history
of tubal damage and infertility, (3) induction of ovulation, and (4) high level of human chorionic
gonadotropin (hCG, at least 10,000 international units/L) [7]. (See "Ectopic pregnancy: Incidence, risk
factors, and pathology", section on 'Risk factors'.)
The medical and surgical history should be reviewed, since this may impact treatment. The focus
should be on obstetric history and pelvic or abdominal surgical history and medical comorbidities that
are potential contraindications for surgery or methotrexate therapy (eg, renal or hepatic disease).
Human chorionic gonadotropin Measurement of hCG is performed initially to diagnose pregnancy
and then followed serially to assess for ectopic pregnancy.
The initial test to diagnose pregnancy may be either a urine or serum hCG. Once a pregnancy is
confirmed, if ectopic pregnancy is suspected, the serum quantitative hCG is then repeated serially
(typically every two days) to assess whether the increase in concentration is consistent with an
abnormal pregnancy. In some cases, the diagnosis of ectopic pregnancy can be made after a single
measurement of hCG in combination with transvaginal ultrasound, if the hCG is above the
discriminatory zone and transvaginal ultrasound shows no evidence of an intrauterine pregnancy and
the presence of findings that suggest an ectopic pregnancy. However, a finding of the absence of an
intrauterine pregnancy with an hCG level within the discriminatory zone is not always reliable. In
stable patients, we repeat hCG measurement and ultrasound before providing the treatment. (See
'Transvaginal ultrasound' below and 'Clinical protocol' below.)
In pregnant women, hCG can be detected in serum and urine as early as eight days after the luteinizing
hormone surge (approximately 21 to 22 days after the first day of the last menstrual period in women
with 28-day cycles). The hCG concentration in a normal intrauterine pregnancy (IUP) rises in a
curvilinear fashion until about 41 days of gestation, after which it rises more slowly until
approximately 10 weeks, and then declines until reaching a plateau in the second and third trimesters
[9]. It is not possible to determine whether a pregnancy is normal from a single hCG level because
there is a wide range of normal levels at each week of pregnancy [10]. (See "Clinical manifestations
and diagnosis of early pregnancy", section on 'Serum pregnancy test' and "Human chorionic
gonadotropin: Testing in pregnancy and gestational trophoblastic disease and causes of low persistent
levels", section on 'Pregnancy'.)
Step two: Evaluate hemodynamic stability Women with ectopic pregnancy may become
hemodynamically unstable if there is a rupture of and hemorrhage from the structure in which the
pregnancy is implanted, usually the fallopian tube. Young patients may not exhibit unstable vital signs
until they have lost a large volume of blood. Rupture should be suspected in women with a sudden
onset of severe and persistent abdominal pain, rapid uterine bleeding, symptoms of faintness, or vital
signs suggestive of hemodynamic compromise. If rupture is suspected, the patient should be transferred
to an acute care facility where resuscitation and surgical treatment may be provided. (See "Initial
management of trauma in adults", section on 'Circulation'.)
Physical examination Vital signs should be measured and hemodynamic stability assessed. In
young, healthy patients with blood loss, assessing the vital signs should include an evaluation for
postural change. However, vital signs, including postural changes, may be normal early in the course of
significant bleeding due to compensatory mechanisms [11].
The abdominal examination is often unremarkable or may reveal lower abdominal tenderness. If
rupture with significant bleeding has occurred, the abdomen may be distended and diffuse, or localized
tenderness to palpation and/or rebound tenderness may be found on examination.
A complete pelvic examination should be performed. The speculum examination is used to confirm
that the uterus is the source of bleeding (rather than a cervical or vaginal lesion) and to assess the
volume of bleeding by noting the quantity of blood in the vagina and presence or absence of active
bleeding from the cervix.
A bimanual pelvic examination is performed; the examination is often unremarkable in a woman with a
small, unruptured ectopic pregnancy. Palpation of the adnexa should be performed with only a small
degree of pressure, since excessive pressure may rupture an ectopic pregnancy. Findings on
examination may include cervical motion, adnexal, and/or abdominal tenderness. An extraovarian
adnexal mass is noted in some women.
The uterus may be somewhat enlarged, but will likely be smaller than appropriate for gestational age.
Uterine enlargement in women with ectopic pregnancy may be due to endocrine changes of pregnancy,
rare cases of heterotopic pregnancy, or incidental uterine pathology (most commonly, uterine fibroids).
FAST ultrasound If the patient is not hemodynamically stable, she may be evaluated with abdominal
ultrasound to assess quickly for intraperitoneal hemorrhage. Ultrasound evaluation performed as part of
the initial examination and resuscitation of the trauma patient is known as the Focused Assessment
with Sonography for Trauma (FAST) [12-14]. Identification of intraperitoneal bleeding in a woman of
reproductive age should be considered a potential ruptured ectopic pregnancy until proven otherwise.
An unstable patient with this finding should undergo urgent surgical consultation and exploration. (See
"Emergency ultrasound in adults with abdominal and thoracic trauma", section on 'Focused Assessment
with Sonography for Trauma'.)
This approach should be reserved for hemodynamically unstable patient. Other women with suspected
ectopic pregnancy should be evaluated with transvaginal ultrasound. (See 'Transvaginal ultrasound'
below.)
Complete blood count Women with suspected ectopic pregnancy should be evaluated for anemia
with a hemoglobin and/or hematocrit.
In severe cases, if heavy bleeding is suspected, measurement of platelets or coagulation tests may also
be indicated. (See "Massive blood transfusion", section on 'Alterations in hemostasis'.)
If ectopic pregnancy is diagnosed and treatment with methotrexate is considered, a complete blood
count is also part of the pretreatment laboratory evaluation.
Additional laboratory tests Additional laboratory tests drawn at time of presentation include:
Blood type and screen An Rh(D) typing and antibody screen should be drawn if not previously
performed during the current pregnancy. Women with bleeding in pregnancy who are Rh(D)-negative
should be given anti-D immune globulin. (See "Prevention of Rhesus (D) alloimmunization in
pregnancy".)
If significant bleeding is suspected, a sample should be sent to the blood bank for crossmatching for
potential transfusion.
Pretreatment laboratory tests Women with a suspected ectopic pregnancy may require treatment
with methotrexate. Although treatment decisions will be made later in the course, methotrexate
pretreatment blood tests are typically ordered with the initial test. These include a complete blood count
and renal and liver function tests. (See "Ectopic pregnancy: Choosing a treatment and methotrexate
therapy", section on 'Pretreatment testing'.)
Step three: Assess pregnancy location The tests used to diagnose an ectopic pregnancy are a
combination of serum quantitative hCG level and transvaginal ultrasound (TVUS) (algorithm 1 and
table 2).
Transvaginal ultrasound TVUS is the most useful imaging test for determining the location of a
pregnancy. TVUS should be performed at time of presentation with a suspected ectopic pregnancy and
may need to be repeated, depending upon the hCG level or a suspicion of rupture. The ultrasound
should be performed by a clinician with expertise in gynecologic ultrasound and with the evaluation of
ectopic pregnancy, whenever possible.
TVUS alone (without measurement of hCG) can exclude or diagnose an ectopic pregnancy only if one
of the following findings is present:
Findings diagnostic of an IUP (ie, gestational sac with a yolk sac or embryo). However, in women
who conceived with ovulation induction or in vitro fertilization, a heterotopic pregnancy may rarely
occur.
Findings diagnostic of a pregnancy at an ectopic site (gestational sac with a yolk sac or embryo).
In either case, a gestational sac alone is not sufficient for diagnosis. In some ectopic gestations, a
pseudosac is formed, that is merely fluid/blood in the endometrial cavity that may appear to be a
gestational sac (see "Ultrasonography of pregnancy of unknown location", section on 'Pseudosac').
In the great majority of cases, either two findings above excludes or diagnoses an ectopic gestation.
The rare exceptions are heterotopic pregnancies and misdiagnoses of an IUP (ie, interstitial pregnancy
or rudimentary horn pregnancy). In a review of 568 cases of rudimentary uterine horn pregnancies from
1900 to 1999, a rupture rate of 50 percent was found with 80 percent occurring before the third
trimester [15]. (See 'Heterotopic pregnancy' below and 'Interstitial pregnancy' below.)
TVUS can also detect findings that are suggestive, but not diagnostic, of ectopic pregnancy. An
extraovarian adnexal mass is the most common ultrasound finding in ectopic pregnancy and is present
in 89 percent or more of cases [16-18].
If TVUS is nondiagnostic, it may be because the gestation is too early to be visualized on ultrasound. If
so, serial measurements of the serum hCG concentration should be taken until the hCG discriminatory
zone is reached [19]. (See 'Clinical protocol' below.)
The ultrasound examination is also used to evaluate whether rupture of the tube or other structure has
occurred. A finding of echogenic fluid (consistent with blood) in the pelvic cul-de-sac and/or abdomen
is consistent with rupture. However, a small amount of fluid is present in many women and a small
amount of blood may be present in other conditions (eg, spontaneous abortion). A ruptured ovarian cyst
is another condition that is common in pregnant women and may result in a small or large amount of
blood. Rupture is indicated by ultrasound findings of free fluid (blood) in the abdominal cavity.
Ultrasound evaluation for ectopic pregnancy versus IUP is discussed in detail separately. (See
"Ultrasonography of pregnancy of unknown location".)
Either ultrasound or other abdominal imaging modalities are used for evaluation in the rare cases of
abdominal pregnancy. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic
pregnancy", section on 'Diagnostic evaluation'.)
hCG discriminatory zone The discriminatory zone is the serum hCG level above which a gestational
sac should be visualized by TVUS if an IUP is present. In most institutions, the discriminatory zone is a
serum hCG level of 2000 international units/L; however, some data suggest that an IUP may not be
visible until a higher level is reached (3510 international units/L) [20].
Setting the discriminatory zone at 3510 international units/L minimizes the risk of interfering with a
viable IUP, if present, but increases the risk of delaying diagnosis of an ectopic pregnancy. However,
even in women with an hCG >3510 international units/L, if she is clinically stable, it is often prudent to
get a follow-up ultrasound to exclude a viable IUP rather than treat for ectopic pregnancy. Management
of women with ectopic pregnancy depends upon several factors and it is important to emphasize that a
patient should not be treated for an ectopic pregnancy based upon a single assessment with ultrasound
and hCG. If an IUP has not been confirmed, the hCG is between 2000 and 3510 international units/L,
the patient is stable, and the pregnancy is desired, the patient may be followed with close surveillance
until the hCG is at least 3510 international units/L. However, if an ectopic pregnancy seems likely and
the pregnancy is not desired, treatment may be given if the hCG is >2000 international units/L, the
serial hCG results are consistent with an abnormal pregnancy, and the ultrasound shows no IUP.
Importantly, if there are concerns about rupture of a fallopian tube or other structure by an ectopic
gestation, urgent treatment is required.
The discriminatory zone is higher for transabdominal ultrasound (approximately 6500 international
units/L), but TVUS is the standard modality used to evaluate ectopic pregnancy.
The reported sensitivity and specificity of TVUS for the detection of an IUP at a serum hCG of >1500
international units/L are 15.2 and 93.4 percent, respectively, and for an hCG level of >2000
international units/L, sensitivity and specificity are 10.9 and 95.2 percent, respectively [21]. However,
in order not administer methotrexate inadvertently, a decision to treat for ectopic pregnancy should not
be based solely on a single hCG value.
It is important to note that there is a variation in the level of hCG across pregnancies for each
gestational age and the discriminatory levels are not always reliable. In one study, 185 of 188 (98
percent) IUPs in women with hCG above 1500 international units/L were visualized [22]. However, in
a study of 651 women with first trimester bleeding or pain, among viable IUPs, a gestational sac was
seen at differing hCG levels in the following proportion of pregnancies: 1500 milli-international
units/mL (80 percent of had a gestational sac visualized), 2000 milli-international units/mL (91
percent), and 3510 milli-international units/mL (99 percent) [20].
Other causes for variation of the discriminatory zone are that it is dependent upon the skill of the
ultrasonographer, the quality of the ultrasound equipment, the presence of physical factors (eg, fibroids,
multiple gestation, obesity), and the laboratory characteristics of the hCG assay used.
Step four: Follow with hCG and ultrasound to confirm or exclude ectopic pregnancy
Serial hCG Measurement of serum quantitative hCG is performed initially to diagnose pregnancy
and then followed to assess for ectopic pregnancy. For follow-up, hCG is measured serially (every 48
to 72 hours) to determine whether the increase is consistent with an abnormal pregnancy. A single hCG
measurement alone cannot confirm the diagnosis of ectopic or normal pregnancy.
Normal pattern of hCG in pregnancy Studies in viable IUPs have reported the following changes in
serum hCG [23,24]:
In a study of 20 patients in the first 40 days of pregnancy, the hCG concentration rose by at least 66
percent every 48 hours in 85 percent of viable IUPs; only 15 percent of viable pregnancies had a rate of
rise less than this threshold [25].
Two studies that included more than 1000 women with symptomatic early pregnancies found that
pregnancies with an hCG rise of 35 percent in two days should be considered potential IUPs. In one
study, 99.9 percent of IUPs had an hCG rise of 35 percent every two days [26]. The other study found
that diagnosis of intrauterine pregnancy by use of the criterion of an hCG rise of 35 percent every two
days had a sensitivity of 92 percent and specificity of 94 percent [27].
A serum hCG that does not rise appropriately is consistent with an abnormal pregnancy. The hCG
concentration rises at a much slower rate in most, but not all, ectopic and nonviable IUPs [24,28].
A decreasing hCG concentration is most consistent with a failed pregnancy (eg, arrested pregnancy,
tubal abortion, spontaneously resolving ectopic pregnancy, complete or incomplete abortion).
The hCG result varies across different assays and laboratories. The intra-assay and interassay
variabilities depend on the type of assay. In one study, the intra-assay and interassay coefficient of
variation were 4.87 and 6.25 percent, respectively [29]. Thus, interpretation of serial hCG
concentrations is more reliable when the assays are performed in the same laboratory. In addition, the
possibility of falsely positive or negative hCG test results should be considered [30,31]. (See "Human
chorionic gonadotropin: Testing in pregnancy and gestational trophoblastic disease and causes of low
persistent levels", section on 'False negative test (hook effect)' and "Human chorionic gonadotropin:
Testing in pregnancy and gestational trophoblastic disease and causes of low persistent levels", section
on 'False positive test or "phantom hCG"'.)
Clinical protocol The clinical protocol for the evaluation for an ectopic pregnancy includes
assessment with serum hCG and TVUS:
hCG below the discriminatory zone A serum hCG concentration <3500 international units/L (or
another value, the discriminatory zone for the institution should be used) should be followed by
repeated measurement of quantitative hCG to follow the rate of rise. As noted above, the slowest
recorded rise over 48 hours associated with a viable IUP was 35 percent. Also, the same laboratory
should be used for serial measurements. (See 'Serial hCG' above.)
The most common protocol is to measure the hCG every two days. In our practice, we find that
measurement every 72 hours is more practical than every 48 hours, and allowing 72 hours for doubling
helps to avoid misclassifying those viable pregnancies with slower than average doubling times. Yet, in
practice, management is usually based on clinical findings and by TVUS, with little emphasis on hCG
doubling time.
Thus, the protocol is as follows:
hCG is rising normally (increasing by 35 percent in 48 hours OR doubling in 72 hours) The
patient should be evaluated with TVUS when the hCG reaches 3500 international units/L. At that time,
an IUP or ectopic pregnancy can be diagnosed by TVUS.
hCG is rising, but NOT normally The lack of a normal rise in hCG across three measurements (the
initial serum quantitative hCG and two additional serial measurements) is consistent with an abnormal
pregnancy (an ectopic gestation or IUP that will ultimately abort). The hCG level may be rising slowly
or may plateau at or very close to the previous level. The clinician can be reasonably certain that a
normal IUP is not present. The number of serial measurements to use to make the diagnosis has not
been well studied. Some data suggest that use of three serial measurements is more effective than two
measurements [32].
In patients with an abnormal rise in hCG, the TVUS should be repeated. If there are findings that
confirm an IUP, an ectopic pregnancy is excluded and the patient should be managed as a failed
pregnancy. If an extraovarian adnexal mass consistent with an ectopic pregnancy is visualized, then
medical or surgical treatment is administered for a presumed ectopic pregnancy. If an extraovarian
adnexal mass is not visualized, some clinicians administer methotrexate and others perform curettage to
exclude an IUP and thereby avoid medical therapy of nonviable IUP [33]. (See 'Curettage' below.)
hCG is decreasing A decreasing hCG is most consistent with a failed pregnancy (eg, spontaneous
abortion, tubal abortion, spontaneously resolving ectopic pregnancy). To follow up with these patients,
weekly hCG concentrations should be measured until the result is undetectable.
Patients who are being followed for suspected ectopic pregnancy should be counseled about the risk of
rupture and should be advised to call if symptoms associated with rupture occur. These include the new
onset of or a significant worsening of abdominal pain, vaginal hemorrhage, or feeling faint. In addition,
women with a suspected ectopic pregnancy should be counseled about possible outcomes of the
evaluation, including viable IUP or the end of a pregnancy with treatment for ectopic pregnancy.
hCG above the discriminatory zone For women with a quantitative serum hCG above the
discriminatory zone, the results of TVUS guide management. If TVUS does not reveal an IUP and
shows a complex extraovarian adnexal mass, an extrauterine pregnancy is almost certain. Treatment of
ectopic pregnancy should be instituted. If the serum hCG level is 3500 milli-international units/mL
and no intrauterine pregnancy is visible on TVUS, it is almost certain that the pregnancy is
extrauterine.
The diagnosis of ectopic pregnancy is less certain if no complex extraovarian adnexal mass can be
visualized, since there is variability in the level of expertise among ultrasonographers. Furthermore, a
serum hCG >2000 international units/L without visualization of intrauterine or extrauterine pathology
may represent a multiple gestation, since there is no proven discriminatory level for multiple gestations.
For these reasons, our next step in this clinical scenario is to repeat the TVUS examination and hCG
concentration two days later. If an IUP is still not observed on TVUS, then the pregnancy is abnormal.
Ancillary diagnostic tests Additional diagnostic tests have been used in women with suspected
ectopic pregnancy. Except in selected cases, such tests do not provide additional clinically useful
information.
Progesterone Serum progesterone concentrations are higher in viable IUPs than in ectopic
pregnancies and IUPs that are destined to abort [34]. A meta-analysis of 26 cohort studies including
9436 women in the first trimester of pregnancy evaluated use of a single measurement of serum
progesterone for the diagnosis of a nonviable pregnancy [35]. For women with bleeding or pain and an
inconclusive pelvic ultrasound, a progesterone <3.2 to 6 ng/mL (10.2 to 19.1 nmol/L) had a sensitivity
of 75 percent and a specificity of 98 percent. For women with bleeding or pain alone, a progesterone
<10 ng/mL (31.8 nmol/L) had a sensitivity of 67 percent and a specificity of 96 percent.
The predictive value of a low serum progesterone for identifying nonviable pregnancies varies with the
patient population. The sensitivity and specificity of a low serum progesterone concentration for
predicting a nonviable pregnancy in spontaneously pregnant patients are different from those in
infertile patients who have undergone controlled ovarian hyperstimulation for IVF or intrauterine
insemination [36].
In our experience, progesterone measurements merely confirm diagnostic impressions already obtained
by hCG measurements and transvaginal sonography. We do not routinely measure serum progesterone.
However, measurement of serum progesterone may be useful in a patient with abdominal pain and
bleeding and who has a serum hCG level below that expected for her gestational age. It should be
noted, however, that the definition of a low progesterone is unclear.
Curettage The intrauterine location of a pregnancy is diagnosed with certainty if trophoblastic tissue
is obtained by uterine curettage. Obviously, the use of curettage as a diagnostic tool is limited by the
potential for disruption of a viable pregnancy. Moreover, false negatives can occur: chorionic villi are
not detected by histopathology in 20 percent of curettage specimens from elective termination of
pregnancy [37]. Pipelle endometrial biopsy is even less sensitive than curettage for detection of villi;
sensitivities reported in two small series were 30 and 60 percent [38,39]. If curettage is performed,
serum hCG levels can be followed post-curettage if histopathology does not confirm the clinical
impression. When an IUP has been evacuated, hCG levels should drop by at least 15 percent the day
after evacuation [33].
Some experts have recommended performing curettage only on women with both an hCG
concentration below the discriminatory zone and a low doubling rate [40,41]. Approximately 30
percent of these patients have a nonviable intrauterine gestation, and the remainder have an ectopic
pregnancy [41,42]. Knowing the results of curettage avoids unnecessary methotrexate treatment of the
30 percent of patients without ectopic pregnancy.
A decision analysis comparing the cost/complication rates in patients who undergo diagnostic curettage
before administration of methotrexate with those who do not have a curettage concluded there was no
significant benefit of one approach over the other [42]. However, the authors' preference was to
perform curettage in these patients to be more certain of the diagnosis, and felt this information was
useful prognostically (eg, risk of recurrence) and for future decision-making.
In contrast, we and others believe it is more practical and less invasive to continue observation or
administer one dose of methotrexate than to perform curettage [43,44]. The side effects of one dose of
methotrexate are negligible. In addition, curettage carries a risk of intrauterine adhesion formation. (See
"Ectopic pregnancy: Choosing a treatment and methotrexate therapy" and "Intrauterine adhesions".)
Other tests Rarely, laparoscopy is used to confirm the diagnosis if hCG and ultrasound results are
ambiguous. An ectopic pregnancy detected at laparoscopy should be treated immediately by surgery. In
this situation, a medical approach confers additional risk and has no proven benefit.
Historically, culdocentesis was used to detect blood in the posterior cul-de-sac; however, this finding
can be easily demonstrated with transvaginal ultrasound. Blood in the posterior cul-de-sac may be from
bleeding from an unruptured or ruptured tubal pregnancy, but it may also be the result of a ruptured
ovarian cyst. Therefore, a culdocentesis positive for blood is nondiagnostic. (See "Culdocentesis".)
DIAGNOSIS The diagnosis of ectopic pregnancy is a clinical diagnosis made based upon serial
serum quantitative human chorionic gonadotropin (hCG) testing and transvaginal ultrasound (TVUS).
(See 'Transvaginal ultrasound' above and 'Serial hCG' above.)
In selected cases, uterine curettage is performed to confirm the absence of an intrauterine pregnancy
(IUP) prior to methotrexate therapy. If an ectopic pregnancy is treated surgically, histologic
confirmation is obtained following treatment.
Diagnostic criteria The diagnostic criteria depend upon the relationship to the hCG discriminatory
zone (serum hCG level above which a gestational sac should be visualized by TVUS if an IUP is
present). The hCG level of the discriminatory zone varies, but in most institutions it is 2000
international units/L; however, some data suggest that an IUP may not be visible until a higher level is
reached (3510 international units/L) (see 'hCG discriminatory zone' above and 'Clinical protocol'
above):
Below the discriminatory zone
If the serial hCG level does not rise appropriately across at least three measurements 48 to 72 hours
apart and there is no evidence on TVUS that confirms an IUP, the pregnancy is considered abnormal. A
presumptive diagnosis of ectopic pregnancy can be made and the patient may be treated. In selected
cases, uterine curettage is performed to confirm the absence of an IUP (see 'Curettage' above).
If the serial serum hCG level is rising appropriately, the patient is followed until the hCG is above the
discriminatory zone.
Above the discriminatory zone The diagnosis is made based upon the absence of TVUS findings
that diagnose an IUP OR findings at an extrauterine site that confirm an ectopic pregnancy. The
presence of a gestational sac with a yolk sac or embryo is diagnostic of a pregnancy. The gestational
sac is an early finding and is suggestive of, but does not fully confirm, an IUP (see 'Transvaginal
ultrasound' above).
Ultrasound findings suggestive of an ectopic pregnancy in the fallopian tube, ovary, or other sites
further support the diagnosis, but are not diagnostic on their own. (See 'Transvaginal ultrasound'
above.)
In the absence of a definitive sonogram confirming an IUP or histopathologic findings, it is sometimes
impossible to differentiate between an ectopic pregnancy and an early failed intrauterine gestation. This
is referred to as a pregnancy of unknown location, and 8 to 40 percent are ultimately diagnosed as
ectopic pregnancies [21].
Ruptured versus nonruptured ectopic pregnancy Diagnosis of rupture of the structure within which
the ectopic gestation is implanted (usually the fallopian tube) is a clinical diagnosis. The typical
findings of rupture are abdominal pain, shoulder pain due to diaphragmatic irritation by blood in the
peritoneal cavity, and, eventually, hypotension and shock. Abdominal examination findings include
tenderness and possible peritoneal signs. The typical finding on TVUS is free blood in the peritoneal
cavity. However, the presence or absence of peritoneal free fluid is not a reliable indicator of whether
an ectopic pregnancy has ruptured. (See "Ultrasonography of pregnancy of unknown location", section
on 'Peritoneal free fluid'.)
For women who undergo surgery, the diagnosis of rupture can be made by direct visualization.
DIFFERENTIAL DIAGNOSIS The classic symptoms of ectopic pregnancy are vaginal bleeding
and abdominal pain.
The differential diagnosis of bleeding or pain early in pregnancy also includes [45]:
Physiologic (ie, believed to be related to implantation)
Spontaneous abortion
Gestational trophoblastic disease
Cervical, vaginal, or uterine pathology
Subchorionic hematoma
Non-uterine sources of bleeding can be identified by physical examination. Screening for cervical
cancer should also be performed, as appropriate (table 3). (See "Differential diagnosis of genital tract
bleeding in women" and "Screening for cervical cancer".)
Even if another source of bleeding is identified, all women with first trimester bleeding should be
evaluated by transvaginal ultrasonography. When the human chorionic gonadotropin concentration is
unusually high for the gestational age, gestational trophoblastic disease should be suspected. The
evaluation of first-trimester vaginal bleeding is discussed separately. (See "Overview of the etiology
and evaluation of vaginal bleeding in pregnant women" and "Spontaneous abortion: Risk factors,
etiology, clinical manifestations, and diagnostic evaluation" and "Hydatidiform mole: Epidemiology,
clinical features, and diagnosis".)
The differential diagnosis of lower abdominal pain in women includes urinary tract infection, kidney
stones, diverticulitis, appendicitis, ovarian neoplasms, ovarian cyst rupture, ovarian torsion,
endometriosis, endometritis, leiomyomas, pelvic inflammatory disease, and pregnancy-related
conditions. (See "Evaluation of the adult with abdominal pain".)
SPECIAL ISSUES
Multiple gestation In women with an intrauterine multiple pregnancy, the serum human chorionic
gonadotropin (hCG) level could be higher than 1500 milli-international units/mL and yet ultrasound
examination will not reveal an intrauterine pregnancy (IUP) [19]. Levels of over 9000 international
units/L have been described for intrauterine triplet pregnancies unobserved by transvaginal ultrasound
(TVUS) [46].
Heterotopic pregnancy The investigation for ectopic pregnancy can be terminated, under most
circumstances, if a transvaginal sonogram reveals an IUP. Heterotopic pregnancy (combined
intrauterine and extrauterine pregnancy) is rare, except among women conceiving through in vitro
fertilization (IVF). The extrauterine pregnancy is usually in the fallopian tube, but can be at another
location, such as the cervix. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic
pregnancy".)
Early diagnosis of heterotopic pregnancy is difficult because of lack of symptoms. Thus, a high index
of suspicion for this diagnosis is important, especially in patients who have undergone IVF and who
experience abdominal pain or vaginal bleeding.
Serial hCG concentrations are not interpretable in the presence of both a viable intrauterine and ectopic
pregnancy. On ultrasound examination, the diagnosis is suggested by visualization of both an ectopic
pregnancy and IUP or the presence of echogenic fluid in the posterior cul-de-sac in the presence of an
IUP. Heterotopic tubal pregnancies have been reported as late as 16 weeks of gestation, while
abdominal or rudimentary horn pregnancies can continue to develop late in gestation [47,48].
The ultrasonographer should carefully examine not only the uterus but also the adnexa of women who
conceive following IVF. We suggest that women with a confirmed IUP who are experiencing
abdominal pain or vaginal bleeding undergo serial TVUS examinations every week until the possibility
of a concomitant tubal ectopic pregnancy can be eliminated.
The diagnosis and management of heterotopic pregnancy are discussed separately. (See "Abdominal
pregnancy, cesarean scar pregnancy, and heterotopic pregnancy", section on 'Heterotopic pregnancy'.)
Uncommon sites of ectopic pregnancy The possibility that an ectopic pregnancy may occur in a
non-tubal location, or even bilaterally [49], should be considered. These ectopic pregnancy sites are
uncommon, and include cervical, hysterotomy scar, rudimentary uterine horn, interstitial, ovarian, and
abdominal pregnancy. Regardless of the location, the endometrium often responds to ovarian and
placental production of pregnancy-related hormones, so vaginal bleeding is a common symptom.
Cervical pregnancy is estimated to occur in 1/2500 to 1/18,000 pregnancies and accounts for 1
percent of ectopic pregnancies [50].
Interstitial pregnancy accounts for up to 1 to 3 percent of ectopic pregnancies [51,52].
Ovarian pregnancy occurs in 1/2100 to 1/60,000 pregnancies and accounts for 1 to 3 percent of
ectopic pregnancies [53].
Abdominal pregnancy accounts for up to 1.4 percent of ectopic pregnancies [54]. These pregnancies
can go undetected until an advanced age and often result in severe hemorrhage [55]. Rates of maternal
mortality have been reported as high as 20 percent [47,56].
Intramural pregnancy refers to pregnancy implanted within the myometrium of the uterus. This type
of pregnancy is extremely rare with less than 50 reported cases in the literature [57].
Ovarian pregnancy Sonographic diagnosis of an ovarian pregnancy is difficult. Ultrasound
evaluation for ovarian pregnancy is discussed in detail separately. (See "Ultrasonography of pregnancy
of unknown location".)
The diagnosis of ovarian pregnancy is typically made at the time of surgery, but differentiation from a
hemorrhagic ovarian cyst or pregnancy in the distal fallopian tube can be difficult. Ultrasound may
suggest the diagnosis preoperatively [53]. Strict histopathological criteria are used to distinguish
ovarian pregnancies from those originating in the fallopian tube. The exact diagnosis is not clinically
important, as these pregnancies are usually treated by surgical excision of the involved organs.
Methotrexate treatment has been successful in case reports [58]. (See "Ectopic pregnancy: Incidence,
risk factors, and pathology", section on 'Ovarian pregnancy'.)
Interstitial pregnancy The interstitial portion of the fallopian tube is the proximal segment that is
embedded within the muscular wall of the uterus. A pregnancy implanted at this site is called an
interstitial pregnancy (figure 1); the term cornual pregnancy is also widely used to describe a
pregnancy at this location. Originally, the term cornual pregnancy referred only to pregnancies
implanted in either the horn of a bicornuate uterus, a rudimentary horn of a unicornuate uterus, or in
one side of a septated or partially septated uterus [52].
An interstitial pregnancy can be difficult to distinguish on ultrasound from an IUP that is eccentrically
positioned. Ultrasound evaluation for interstitial pregnancy is discussed in detail separately. (See
"Ultrasonography of pregnancy of unknown location".)
Grossly, an interstitial pregnancy appears as a gestational swelling lateral to the insertion of the round
ligament (figure 1) [52]. The unique anatomic location of an interstitial pregnancy often leads to a
delay in diagnosis, although an average delay of only four days in comparison with tubal pregnancies
was reported in a large series [59].
Interstitial pregnancy presents with rupture in approximately 20 to 50 percent of cases [60-62]. A series
of cases of interstitial pregnancy reported to a surgical registry included 14 patients with tubal rupture,
all of which were before 12 weeks [60]. This is in contrast to previous reports that rupture of interstitial
pregnancy occurred late in pregnancy. Other clinical manifestations are the same as for all ectopic
gestations (pelvic or abdominal pain, vaginal bleeding) [59].
Although the maternal mortality rate associated with tubal pregnancy is decreasing, the rate for
interstitial pregnancies remains at 2 to 2.5 percent because of misdiagnosis of these gestations as IUPs.
Other sites Diagnosis and management of cesarean scar and abdominal pregnancy are discussed in
detail separately. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".)
Screening asymptomatic women Routine prenatal care does not include serial measurement of
serum hCG. The exceptions to this are women at high risk of an ectopic pregnancy, including those
with an IVF pregnancy, pregnancy after reconstructive surgery of the fallopian tube, or prior history of
ectopic pregnancy. For women who are monitored in this way, an ectopic pregnancy may present with
an abnormal rise in hCG. The normal pattern of the rise in serum hCG in early pregnancy is discussed
below. (See 'Serial hCG' above.)
In our practice, we monitor women at high risk of ectopic pregnancy (table 1) with laboratory and
imaging studies. We use the same protocol as for the diagnosis of ectopic pregnancy, and start with the
first missed menses or after embryo transfer for IVF. The goal is to establish the diagnosis early to
avoid rupture. (See "Ectopic pregnancy: Incidence, risk factors, and pathology", section on 'Risk
factors' and "In vitro fertilization", section on 'Monitoring for pregnancy'.)
NATURAL HISTORY If left untreated, an ectopic pregnancy in the fallopian tube can progress to a
tubal abortion or tubal rupture, or it may regress spontaneously.
Rupture Tubal rupture is usually associated with profound hemorrhage, which can be fatal if
surgery is not performed expeditiously to remove the ectopic gestation. Salpingectomy is the most
common surgical approach when the tube has ruptured. Ruptured ectopic pregnancy is the major cause
of pregnancy-related maternal mortality in the first trimester [63]. Most of these deaths occur prior to
hospitalization or proximate to the woman's arrival in the emergency department.
Abortion Tubal abortion refers to expulsion of the products of conception through the fimbria. This
can be followed by resorption of the tissue or by reimplantation of the trophoblasts in the abdominal
cavity (ie, abdominal pregnancy) or on the ovary (ie, ovarian pregnancy). Tubal abortion may be
accompanied by severe intra-abdominal bleeding, necessitating surgical intervention, or by minimal
bleeding, not requiring further treatment.
Spontaneous resolution The incidence of spontaneous resolution of an ectopic pregnancy is
unknown. In one older (1955) series of 119 hospitalized patients with typical ectopic pregnancy
symptoms, 57 were safely managed expectantly, without surgical or medical intervention (except
opiates) [64]. It is difficult to predict which patients will experience uncomplicated spontaneous
resolution. Potential candidates are hemodynamically stable women with an initial hCG concentration
less than 2000 international units/L that is declining [65].
Gestational products left in the fallopian tube may resorb completely or, less commonly, may cause
tubal obstruction [66]. Alternatively, a tubal abortion may occur.
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
An ectopic pregnancy is an extrauterine pregnancy. Almost all ectopic pregnancies occur in the
fallopian tube (98 percent), but other possible sites include cervical, interstitial, hysterotomy (cesarean)
scar, ovarian, or abdominal. In rare cases, a multiple gestation may be heterotopic (include both a
uterine and extrauterine pregnancy). (See 'Introduction' above and 'Uncommon sites of ectopic
pregnancy' above.)
Abdominal pain and vaginal bleeding are the most common symptoms of ectopic pregnancy. Ectopic
pregnancy should be suspected in any women of reproductive age with these symptoms, especially
those who have risk factors (table 1). However, over 50 percent of women are asymptomatic before
tubal rupture and do not have an identifiable risk factor for ectopic pregnancy. (See 'Clinical
presentation' above.)
The key components of the evaluation of a woman with suspected ectopic gestation are a transvaginal
ultrasound (TVUS) examination and quantitative human chorionic gonadotropin (hCG) level. The hCG
is measured serially every two to three days. (See 'Clinical protocol' above.)
Additional testing is performed to evaluate for anemia, for Rh(D) blood typing, and for pretreatment
evaluation for potential methotrexate therapy. (See 'Additional laboratory tests' above.)
The diagnosis of ectopic pregnancy is a clinical diagnosis made based upon serial hCG testing and
TVUS. A diagnosis of ectopic pregnancy cannot be made based upon a single hCG result. Histologic
confirmation of the diagnosis is not typically required. (See 'Transvaginal ultrasound' above and 'Serial
hCG' above and 'Diagnosis' above.)
The diagnostic criteria depend upon the relationship to the hCG discriminatory zone (serum hCG
level above which a gestational sac should be visualized by TVUS if an intrauterine pregnancy [IUP] is
present). The hCG level of the discriminatory zone varies, but in most institutions it is 2000
international units/L; however, some data suggest that an IUP may not be visible until a higher level is
reached (3510 international units/L). (See 'hCG discriminatory zone' above and 'Diagnostic criteria'
above.)
If the serial hCG is rising abnormally (does not increase by at least 35 percent in 48 hours OR
doubling in 72 hours) and is below the discriminatory zone, the diagnosis is made based upon the hCG
pattern.
If the hCG is above the discriminatory zone, the diagnosis is made based upon ultrasound findings
that confirm either an intrauterine or extrauterine pregnancy (gestational sac with a yolk sac or
embryo).
Diagnosis of rupture of the structure within which the ectopic gestation is implanted (usually the
fallopian tube) is a clinical diagnosis made primarily based upon a finding of echogenic fluid
(consistent with blood) in the pelvic cul-de-sac and/or abdomen combined with the presence of
abdominal pain and/or tenderness. (See 'Ruptured versus nonruptured ectopic pregnancy' above.)
Use of UpToDate is subject to the Subscription and License Agreement.

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