Ectopic pregnancy is the leading cause of pregnancy-related death during the first trimester and the incidence of ectopic pregnancies has increased dramatically in the last 30 years. Yet, a timely diagnosis can be challenging. In this article, the authors review in great detail the risk factors and clinical considerations in a patient with possible ectopic pregnancy and clearly illustrate the sonographic findings that can confirm, or eliminate, the diagnosis.
are with the Department of Radiology, SUNY Upstate Medical
University, Syracuse, NY.
Ectopic pregnancy is the leading cause of pregnancy-related
death during the first trimester. A woman who has had one ectopic
pregnancy is at increased risk for another, as well as for future
infertility. Among women with prior ectopic pregnancies the
subsequent overall conception rate is approximately 60%. Of those
who conceive, only 80% are intrauterine while 20% are repeat
The number of hospitalizations for ectopic pregnancy has
declined since 1990.
This may reflect a shift toward treating early, unruptured ectopic
pregnancies in an outpatient setting. Outpatient management may
include laparoscopic salpingectomy, salpingostomy, or methotrexate
therapy. When reviewing the combined data for hospitalization and
outpatient diagnosis and treatment, however, the incidence of
ectopic pregnancy has increased steadily from approximately 18,000
cases in 1970 to more than 108,000 reported cases in 1992.
This is a rate of approximately 20 ectopics per 1000 reported
Fortunately, during this same period, the fatality rate
associated with this condition has decreased, despite the
increasing incidence. Estimates of the death rate from ectopic
pregnancy range from 0.5 to 1 death per 1000 ectopic pregnancies,
representing a decrease of more than 86% since 1970.
This is due to a combination of increased clinical awareness, the
development of more sensitive and specific pregnancy tests, and
improved ultrasound technology, particularly endovaginal scanning.
While maternal mortality from complications of ectopic pregnancy
has decreased in the last two decades, it still accounts for about
15% of all maternal deaths.
Risk factors for ectopic pregnancy
Most ectopic pregnancies occur in the fallopian tube, most
commonly the ampullary portion of the tube, followed by the
isthmus. Accordingly, the most common predisposing factor in
patients with ectopic pregnancy is tubal scarring, usually
associated with pelvic inflammatory disease. Up to 30% to 50% of
women with ectopic pregnancies have a history of prior salpingitis.
Salpingitis isthmica nodosa, nodular thickening of the isthmic
portion of the fallopian tubes with multiple diverticula, is seen
in more than 50% of surgically excised tubal ectopics.
The sites of diverticula correlate well with the locations of the
Other risk factors for the development of ectopic pregnancy
include abnormalities of the zygote, endocrine dysfunction that may
affect ovum transport, and the presence of an intrauterine
contraceptive device (IUD).
Some investigators believe that an IUD is far more effective in
preventing implantation in the uterus than at preventing ectopic
implantation. Others feel that the presence of an IUD may increase
the incidence of ectopic pregnancy by affecting tubal motility and
ovum transport, or by causing tubal infection. Infertile women who
undergo in vitro fertilization are also at increased risk due to
the high prevalence of tubal damage in these patients, the use of
superovulation, and multiple embryo transfer. Ovulation induction
also places a patient at increased risk due to the association with
multiple pregnancies, including heterotopic implantation
(coexistent intra- and extrauterine gestations).
The "classic" clinical triad for ectopic pregnancy consists of
pain, abnormal vaginal bleeding, and an adnexal mass. However, this
presentation is nonspecific and is present in fewer than 50% of
patients with ectopic pregnancy.
Many patients with this presentation are not even pregnant.
As a result of the nonspecific clinical presentation and the
varied physical findings, it is important for clinicians to have a
high index of suspicion and recognize that any woman in her
reproductive years is at risk for developing an ectopic
The development of the radio-immunoassay (RIA) for the serum
beta subunit of hCG has advanced the diagnosis and management of
ectopic pregnancy. These pregnancy tests offer several advantages
over the urine immunologic tests done previously. RIAs are specific
for hCG and will not cross-react with other substances. They are
also approximately 1000 times more sensitive than immunologic tests
and can detect as little as 1 or 2 mIU/mL of hCG.
Therefore, if the RIA is negative, the patient is not pregnant, and
an ectopic pregnancy can be excluded. If the RIA is positive,
serial quantitative levels of hCG can be measured to help determine
whether or not a pregnancy is progressing normally.
When interpreting quantitative levels of hCG, it is important to
be aware of the reporting standard being used. The Second
International Standard (2IS) was described in the 1960s. Later, a
purer standard was introduced as the International Reference
Preparation (IRP). HCG levels measured against the 2IS are
approximately half those measured against the IRP.
Both standards are currently in use, along with a third
international standard that is numerically equivalent to the
Role of quantitative hCG determinations
In a patient who is clinically stable, it is useful to obtain a
baseline hCG level at presentation. Failure to detect a gestational
sac when the hCG value exceeds a discriminatory level places the
patient at higher risk for an ectopic pregnancy. Using the 2IS,
above 1800 mIU/mL an intrauterine gestational sac should be seen on
Transvaginal scanning has lowered the discriminatory level to 1000
If the hCG is below the discriminatory level and an intrauterine
pregnancy (IUP) is not visible, the differential diagnosis includes
an early normal or abnormal IUP, recent spontaneous abortion, or an
ectopic pregnancy. Depending on the clinical status of the patient,
serial quantitative hCG determinations may be obtained, or
laparoscopy may be considered. Trophoblastic tissue produces B-hCG
8 days after conception, with a normal doubling time of
approximately 48 hours.
If the hCG levels do not progress normally, demonstrating a 48-hour
doubling, an abnormal IUP or ectopic pregnancy will be present. In
the setting of a declining hCG level, a recent abortion or
nonviable ectopic pregnancy are likely considerations.
Ultrasonography of ectopic pregnancy
In the stable patient with a positive pregnancy test, an
ultrasound study should be performed for further evaluation. The
initial sonographic examination should be performed
transabdominally; if an intrauterine gestation is identified, the
diagnosis of ectopic pregnancy is virtually excluded (see below).
If transabdominal imaging does not confidently identify an
intrauterine gestational sac, a transvaginal scan should be done.
Transvaginal sonography can detect a normal intrauterine
gestational sac by a menstrual age of 4 to 5 weeks, approximately 1
week sooner than is possible with the transabdominal probe. For
patients with an IUP, transvaginal sonography often can identify
the source of symptoms, such as a large and/or hemorrhagic corpus
luteum cyst. Transabdominal ultrasound may detect an ectopic
pregnancy that is located too high to be visualized with the
transvaginal probe (figure 1).
The frequency of a coexistent ectopic pregnancy and an IUP
(heterotopic pregnancy) in a patient without risk factors is
approximately 1 in 7000.
However, the number of heterotopic pregnancies has been increasing
worldwide, in part because a larger number of women are being
treated for infertility. Women undergoing assisted reproduction may
have a risk as high as 1 in 100.
Ultrasound diagnosis of an early intrauterine
Stimulation of the uterine lining with hormones produced by an
ectopic pregnancy can result in endometrial changes (decidual
reaction) similar in appearance to those seen with an early IUP
(figure 2). Intrauterine fluid surrounded by decidual reaction in a
patient with an ectopic pregnancy can simulate a gestational sac at
transabdominal sonography ("pseudosac").
The presence of the "double sac sign" is useful to confirm the
diagnosis of an IUP; it discriminates a true gestational sac from a
pseudogestational sac of ectopic pregnancy before a fetal pole or
yolk sac can be recognized. The double sac appearance is caused by
two concentric echogenic borders; the echogenic border of the
endometrial cavity and the echogenic villi that surround the
gestational sac (figure 3). With the advent of endovaginal
sonography, reliance on the double sac sign has decreased.
When the mean sac diameter of the gestational sac reaches
approximately 8 to 10 mm, the yolk sac becomes visible consistently
by endovaginal scanning. At a sac diameter of 16 mm, an embryo
should be seen. The fetal heartbeat is usually visible when the
embryo reaches a crown-rump length of 5 mm.
Color and spectral Doppler imaging have also been used to
evaluate early pregnancies. A normally developing IUP will
demonstrate low impedance peritrophoblastic arterial signal with
minimal or absent venous flow. An abnormal IUP also demonstrates
peri-trophoblastic arterial flow, but may also demonstrate
increased venous flow. Generally, pseudogestational sacs are not
associated with either arterial or venous flow.
The most specific adnexal finding for diagnosing an ectopic
pregnancy is visualization of a living extrauterine embryo (figure
4). In a patient without a demonstrable IUP, characterization of
the adnexa improves the ability of sonography to predict the
presence of an ectopic gestation. The ovary should be identified
and used as an anatomic landmark in evaluating for ectopic
pregnancy. In most patients, the ovary is located near the
ampullary portion of the fallopian tube, which is the most frequent
site of ectopic implantation. Despite the low likelihood of finding
a heterotopic pregnancy, the adnexa should be carefully examined
for masses even in the presence of a documented intrauterine
gestation. Although most ectopics are located between the ovary and
the uterus, they may implant anywhere in the pelvis (figure 5).
Therefore, careful examination of the regions adjacent to the
uterine fundus, the cul-de-sac, and the lateral margins of the
pelvis is also necessary.
Although an adnexal mass is present in the majority of patients
with ectopic pregnancy, it is nonspecific and may have a wide
variety of sonographic appearances. An extraovarian adnexal or
tubal ring may be visible and is characterized by an anechoic
center and an echogenic periphery.
An adnexal ring, however, is not specific and can be simulated by
an ovarian cyst. In some patients, the ring may contain a fetal
pole or yolk sac allowing a confident diagnosis of ectopic
pregnancy (figure 4A). Hematosalpinx may appear as a heterogeneous
or homogeneous solid mass in the adnexal area (figure 6); a
gestational sac may not be visualized, particularly if the
fallopian tube has ruptured.
Complex intraovarian lesions are unlikely to represent an
ectopic pregnancy as the incidence of ovarian pregnancies is less
Similarly, simple ovarian cysts are of low suspicion; these usually
represent the corpus luteum.
Color and spectral Doppler evaluation of adnexal masses may aid
in the sonographic diagnosis of ectopic pregnancy. As with an
intrauterine pregnancy, ectopic tissue is characterized by
increased color flow that displays a low-resistance, high-velocity
peritrophoblastic flow pattern.
However, it is generally recognized that other pelvic pathology
including pelvic inflammatory disease, pedunculated fibroids, or
even an exophytic corpus luteum cyst may demonstrate a similar flow
pattern. Nonetheless, the use of color Doppler may attract one's
attention to a small mass which may otherwise have been
Despite meticulous scanning, no adnexal mass will be identified
in up to one third of patients with ectopic pregnancy.
In these patients, the presence of free intraperitoneal fluid may
suggest the diagnosis. Free fluid is the least specific finding
associated with ectopic pregnancy, however. Transvaginal sonography
is more sensitive than transabdominal scanning for detecting small
amounts of free fluid. Fluid in the cul-de-sac may result from
active bleeding from the fimbriated end of the fallopian tube,
tubal rupture, or tubal abortion.
While hemoperitoneum may appear completely anechoic, echogenic or
complex cul-de-sac fluid suggests that diagnosis (figure 7). An
amorphous solid mass in the cul-de-sac may represent clotted
Unusual forms of ectopic pregnancy
--Implantation of a pregnancy within the interstitial, or
intramural, portion of the fallopian tube is uncommon, accounting
for only 2% to 4% of ectopic pregnancies.
Since the myometrium surrounds only a portion of the expanding
gestational sac and a blood supply develops, the sac can enlarge
painlessly for a relatively long period of time until uterine
rupture results in massive hemorrhage. As a result, the morbidity
and mortality of interstitial pregnancies is higher than for tubal
An interstitial ectopic pregnancy may be suggested on ultrasound
examination if there is an eccentric location of the gestational
sac, thinning or absence of myometrium surrounding the sac, and
separation of the sac from the endometrial cavity (figure 8). In an
attempt to improve the diagnostic ability of endovaginal
sonography, the interstitial line sign has been proposed.
This sign describes a thin echogenic line that extends from the
central uterine cavity to the periphery of the interstitial
gestational sac. This line reportedly represents the interstitial
portion of the fallopian tube or the endometrial canal in patients
with large interstitial pregnancies. These signs in combination may
be useful in the early diagnosis of interstitial ectopic
--Cervical pregnancies are uncommon and account for less than 1% of
all ectopic pregnancies.
Predisposing conditions in the genesis of cervical ectopics include
in vitro fertilization, prior uterine curettage, fibroids, an
indwelling IUD, and previously treated Asherman's syndrome.
The diagnosis can be suggested when a well-formed gestational sac
that contains a yolk sac, embryo, or cardiac activity is identified
within the cervix. In the past, patients with cervical ectopic
pregnancies were managed with hysterectomy because of the risk of
uncontrollable hemorrhage. Now with the earlier diagnosis of
cervical pregnancy afforded by endovaginal sonography, treatment
with local potassium chloride injection, systemic methotrexate
treatment, or preoperative uterine artery embolization before
dilation and evacuation can be used to preserve future fertility.
Ectopic pregnancy can present a difficult diagnostic dilemma. It
is important for the referring clinician to maintain a high index
of suspicion in evaluating women of reproductive age. Sensitive
pregnancy tests that are specific for the beta subunit of hCG will
distinguish the subset of patients who may harbor an ectopic from
those that are not pregnant. The use of high-resolution endovaginal
sonography allows for the earlier detection of an intrauterine
gestation, which permits exclusion of ectopic pregnancy with a high
degree of certainty. In the absence of an IUP, identification of a
mass in the adnexa and/or complex fluid in the cul-de-sac increases
the probability that an ectopic pregnancy is present. Serial
quantitative hCG analysis and follow up sonography can assist the
clinician in managing the stable patient.
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