Section 2 General gynecology

Chapter
Ectopic pregnancy

17 Nichole M. Barker and Thomas G. Stovall

Table 17.1 Ectopic pregnancy locations

Key points
Type of ectopic Location
 An ectopic gestation can implant on any surface pregnancy
outside the normal endometrium; however, over 90%
of ectopic pregnancies occur within the fallopian tube. Tubal pregnancy A pregnancy occurring in the fallopian
tube: ampullary, isthmic, or fimbrial regions
 While the incidence of ectopic pregnancy in the USA
of the tube
has plateaued over the last several years, disparity
Most commonly found in the ampullary region
between age and race still exists.
 The most common risk factors associated with the Interstitial A pregnancy that implants in the interstitial
development of an ectopic gestation are previous pregnancy portion of the fallopian tube
ectopic pregnancy, previous tubal surgery, including Abdominal Primary: the first and only implantation
tubal sterilization, and a history of pelvic pregnancy occurs on a peritoneal surface
inflammatory disease. Secondary: the first implantation begins in the
 The patient with an unruptured ectopic pregnancy tubal lumen; the pregnancy is later aborted
may be asymptomatic or may appear almost identical and then reimplants on a peritoneal surface
to the patient with a threatened abortion. Cervical The developing ovum implants within the
 Serial quantitative human chorionic gonadotropin pregnancy cervical canal
measurements combined with transvaginal Ligamentous A pregnancy that occurs when a primary
ultrasound are the primary modes for excluding a pregnancy ectopic pregnancy erodes into the broad
viable intrauterine pregnancy and thus making the ligament and secondarily implants and
diagnosis of ectopic pregnancy. develops between the leaves of the broad
 Treatment of most ectopic pregnancies is non-surgical ligament
if discovered and treated expeditiously. Surgical Heterotopic Concurrent intrauterine and ectopic
treatment, if indicated, is mostly performed via pregnancy pregnancies
laparoscopy.
Ovarian A pregnancy that develops within the
 Following resolution, the patient continues to have an pregnancy ovarian cortex
increased likelihood of a subsequent ectopic
pregnancy and an overall decreased risk of a
subsequently viable pregnancy. be associated with ectopic pregnancy; consequently early
detection is imperative. The advancement of diagnostic
Introduction methods has allowed ectopic management to be more conser-
A pregnancy can occur in either an intrauterine or an extra- vative than in the past. This chapter discusses the epidemi-
uterine location. While intrauterine pregnancies can be abnor- ology, pathogenesis, clinical presentations, diagnostic testing,
mal (incomplete or missed abortion), an extrauterine (ectopic) and treatments for ectopic pregnancy.
pregnancy is always abnormal. An ectopic pregnancy occurs
when a fertilized ovum implants in a location other than on Epidemiology
the normal endometrial lining in the endometrial cavity. The The incidence of ectopic pregnancy in the USA is roughly 2%.1
most common site for an ectopic pregnancy is the ampullary The increase of medical and outpatient treatment for ectopic
segment of the fallopian tube; however, it may occur in other pregnancy has made it difficult to determine the true inci-
locations (Table 17.1). Significant morbidity and mortality can dence, as patients may be more difficult to capture for tracking

Clinical Gynecology, Second edition, ed. Eric J. Bieber, Joseph S. Sanfilippo, Ira R. Horowitz and Mahmood I. Shafi. Published by Cambridge
University Press. © Cambridge University Press 2015.

Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
253
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
 Section 2: General gynecology
purposes. To address this issue, the Center for Disease Con-
trol’s National Hospital Discharge Survey and National Hos-
pital Ambulatory Medical Care Survey combined data to
report the incidence of ectopic pregnancy as 19.7/1000 preg-
nancies in 1992.1 Furthermore, the associated complication of
hemorrhage is the leading cause of maternal death in the first
trimester.2
Several studies have been conducted in order to identify
mortality trends associated with ectopic pregnancy. The most
recent report found that from 1980 to 2007 the ectopic preg-
nancy mortality rate declined to a 5-year national average of
0.5 per 100 000 live births, and with approximately 21 ectopic
pregnancy deaths annually in this period.3 This is an annual
decline in ectopic pregnancy mortality ratio of 3% in all
women from 1980 to 2007. An even more pronounced decline
of 28% overall in ectopic pregnancy mortality ratio is projected
to occur in 2013–2017 than in 2003–2007. Although this study
reported an overall decline in mortality, a discrepancy between
race and age was still seen. African-Americans were 6.5 times
more likely than white women to die from ectopic pregnancy
complications, while women older than 35 years of age had a
3.5 times greater risk of death resulting from ectopic preg-
nancy compared with women younger than 25 years.3
Once a woman has had one ectopic pregnancy, she has a 7- to
13-fold increased risk for a subsequent ectopic pregnancy. After
an ectopic pregnancy, the following pregnancy has a 60–80%
chance of being intrauterine and a 8–22% chance of again being
ectopic, while about 15% of patients will have infertility.4–7
Etiology and risk factors
It is felt that the majority of ectopic pregnancies develop from
an underlying tubal factor. The fallopian tubes can be damaged
by prior infection, inflammation, or surgery. A meta-analysis
in 1996 reported strong risk factors associated with ectopic
pregnancy, including previous history of ectopic pregnancy,
tubal disease from pelvic inflammatory disease (PID), tubal
surgery, and in utero exposure to diethylstilbestrol.8 There was
a small increase in risk with increase in age, more than one
lifetime sexual partner, and cigarette smoking. Use of intra-
uterine devices (IUDs), either copper or levonorgestrel, has not
been shown to increase the absolute risk of ectopic pregnancy,
likely because pregnancy prevention overall is high.9–11
Pelvic inflammatory disease
One of the major risk factors associated with development of
an ectopic pregnancy is a history of a PID.8 Episodes of PID
may increase the inflammatory response within the pelvis and
subsequently cause damage to the fallopian tube and/or adnexa
and pelvis. The two most common pathogens for PID are
Chlamydia trachomatis and Neisseria gonorrhoeae. Chlamydial
infections are the leading cause of permanent tubal damage
worldwide, mostly because patients may be asymptomatic or
manifest only mild symptoms with this disease.
254
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
Delaying treatment of PID longer than 9 days was shown to
increase the risk of infertility and ectopic pregnancy by three
times in a cohort study, with the strongest association seen in
patients with chlamydial infection.12 A large multicenter ran-
domized control trial (the Pelvic Inflammatory Disease Evalu-
ation and Clinical Health [PEACH] trial) published in
2002 compared outpatient and inpatient treatment for PID
and the reproductive outcomes. After a 35-month follow-up,
it was concluded that there were no significant differences in
pregnancy rates, time to pregnancy, PID recurrence, incidence
of chronic pelvic pain, or ectopic pregnancy between the two
treatment regimens.13
Fallopian tube surgery
Tubal sterilization is the most popular form of birth control
worldwide. Since the overall risk of pregnancy with tubal
sterilization is low, the absolute risk of ectopic pregnancy is
also low. However, if a patient achieves a pregnancy after a
tubal sterilization procedure, she is at a higher risk for ectopic
pregnancy. The proportion of ectopic pregnancy after tubal
sterilization varies by method and time from sterilization
procedure. The use of bipolar electrocautery is associated with
a higher incidence of tubal pregnancies (65%), whereas the
lowest incidence was reported in the spring clip procedure
(15%). Also, the risk of ectopic pregnancy is increased three-
fold in years 4–10 after the procedure compared with the first 3
years.14
There is also an increase in regret associated with tubal
sterilization, particularly in women younger than 30 years of
age within 14 years of the procedure.15 As a result, some
women who have had tubal sterilization are now opting to
undergo reversal of the sterilization procedure. Not only do
these women have an increase in the risk of developing an
ectopic pregnancy secondary to their prior sterilization pro-
cedure but they also have a risk associated with the subsequent
reanastomosis. The risks vary according to the method of
sterilization used, the site of the prior tubal occlusion, the
residual tube length after reanastomosis, coexisting disease,
and surgical technique. The ectopic pregnancy risks associated
with a tube that was cauterized are significantly higher than for
a tube that was occluded using the Pomeroy or tubal banding
techniques.16
Surgical sterilization is not the only tubal surgery that can
increase a woman’s risk for ectopic pregnancy. Tubal surgery
can be performed to relieve an obstruction, lyse adhesions, or
treat an existing ectopic pregnancy. Surgery on the tube is felt to
place a woman at increased risk for an ectopic pregnancy, but it
is unclear whether the increased risk is due to the surgery itself or
from the underlying problem that existed prior to the surgery.
Infertility treatment
An increasing number of women are undergoing treatment for
infertility, and the risk associated with ectopic pregnancy has
been studied in this population. An overall rate of 2.1% of

ectopic pregnancy for assisted-reproductive techniques was
found in the USA in 2006.17 An increase in ectopic pregnancy
was seen only in zygote intrafallopian transfer (3.6%) and there
was also a two-fold increase in women with a tubal factor
infertility diagnosis. A decrease in ectopic rate was seen in
donor oocyte in vitro fertilization and gestational carriers, at
1.4% and 0.9%, respectively.17
Contraception
Various contraceptive methods have been studied to determine
if any have an increased risk of ectopic pregnancy. Oral
contraceptive pills and emergency contraception with mife-
prestone or levonorgestrel have not been found to have an
increased risk of ectopic pregnancy compared with the general
population.18 The absolute risk of an ectopic pregnancy in a
woman with an IUD in place is low because overall pregnancy
risk is low. Furthermore, there is no increased risk for ectopic
pregnancy in a woman with an IUD and a history of ectopic
pregnancy.19 However, if a pregnancy is achieved with an IUD
in place, the proportion of ectopic pregnancy is higher than
that of the general population.11
Ectopic pregnancy after placement of Essure tubal occlu-
sion (Conceptus, Mt. View, CA, USA) has been described in
case reports, but incidence of ectopic pregnancy for this
method of contraception or for the single-rod implant with
etonogestrel (Implanon) cannot be be determined because of
the small number of pregnancies overall.20 Although levonor-
gestrel (Norplant) implant is no longer marketed in the USA, it
is still used in the developing world. It is effective at preventing
pregnancy and is not associated with an increase in ectopic
pregnancy in the first 5 years of use.21
Other risk factors
Other potential risk factors assessed have been shown to have
little to no risk for associated ectopic pregnancy. Smoking,
early age of coitarche, and vaginal douching have been shown
to have a slight increased risk of ectopic pregnancy, and all are
modifiable risk factors.8 Spontaneous and elective abortions,
cesarean sections, or previous abdominal surgery are not
believed to play a significant role in the development of future
ectopic pregnancies, as long as complications from the proced-
ure do not occur.22–24 Endometriosis and leiomyomas are two
common conditions affecting women of reproductive age.
Both conditions can result in obstruction of the fallopian
tubes. However, neither is commonly associated with the
development of an ectopic pregnancy.
Pathogenesis
An ectopic pregnancy is the attempted implantation and devel-
opment of the fertilized ovum in an extrauterine location. The
presence of chorionic villi is pathognomonic for an ectopic
pregnancy. The chorionic villi are usually located within the
lumen of the fallopian tube; however, they can be found
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
Chapter 17: Ectopic pregnancy
Fig. 17.1 Right tubal ectopic pregnancy, visualized by laparoscopy.
elsewhere in the abdomen. When the ectopic pregnancy is
located within the fallopian tube, the tube characteristically
exhibits an irregular dilatation and bluish discoloration sec-
ondary to the surrounding hematosalpinx (Fig. 17.1).
In ectopic pregnancies, bleeding is usually extraluminal;
however, it can remain confined to the fallopian tube, forming
a hematosalpinx. The presence of hemoperitoneum can cause a
varying degree of peritoneal irritation and subsequent pain.
Ectopic pregnancies can progress to the point of expulsion of
the pregnancy out of the fimbriated end of the fallopian tube,
to rupture of the tube, or to natural involution of the preg-
nancy. The most common time for rupture of the ectopic
pregnancy is around the sixth to eighth week of gestation,
but it is variable.
Histologically, the fallopian tubes may exhibit evidence of
chronic salpingitis. The associated inflammation can result in
the development of adhesive disease associated with the tubes.
Women who have ectopic pregnancies have been found to
demonstrate evidence of prior salpingitis.25
Histological findings in the endometrium include the
Arias–Stella reaction, which is characterized by localized
hyperplasia of endometrial glands, which are hypersecretory.
The cells have enlarged nuclei that are hyperchromatic and
irregular. Of note, the Arias–Stella reaction is a non-specific
finding that can also be seen in patients with intrauterine
pregnancies and has little practical significance for diagnostic
purposes in ectopic pregnancy.26
Clinical features and diagnosis
Ectopic pregnancies are associated with a significant degree of
morbidity and mortality; therefore, clinicians should have a
high degree of suspicion for an ectopic pregnancy. Patients’
presentations may range from asymptomatic to experiencing
an acute abdomen with hemodynamic instability. The majority
of patients with an unruptured ectopic gestation demonstrate
vaginal spotting, bleeding, and/or lower abdominal pain. The
symptoms and physical examination findings in a patient with
255
 Section 2: General gynecology
an ectopic pregnancy are sometimes indistinguishable from
the patient with an early viable intrauterine pregnancy or
threatened abortion. Therefore, the degree of suspicion must
be high in these patients since ectopic pregnancy complica-
tions not only affect future fertility but can be life threatening.
Because the goal is to make the diagnosis prior to rupture
of the ectopic pregnancy, diagnostic modalities other than the
physical examination may be utilized. If the diagnosis is made
prior to rupture, morbidity can be reduced and future fertility
maximized. Once rupture of the pregnancy has occurred, the
goal shifts to stabilizing the patient and achieving hemostasis.
History
The patient’s history is an important component in raising the
clinician’s awareness of the possibility of an ectopic pregnancy.
Many patients will not exhibit clinical symptoms; however,
when they do occur they usually involve one or all three of a
classic triad: amenorrhea, irregular vaginal bleeding/spotting,
and abdominal pain.
Abdominal pain is the most common symptom at presen-
tation in the patient with a ruptured ectopic pregnancy and
may occur after the development of a hemoperitoneum. The
severity of the pain can vary widely among patients, and no
particular type of abdominal pain is pathognomonic. The pain
can occur on only one side or be bilateral. It may be located in
the upper or lower abdomen and characterized by being dull,
sharp, or crampy in nature. The pain may be constant or
intermittent. It can remain localized but more commonly
radiates to the shoulders if a hemoperitoneum exists. Patients
may also present with syncope or shock.
In addition to the preceding symptoms, patients should be
questioned regarding a history of abnormal menses, prior
pregnancy outcomes, history of infertility, and current contra-
ceptive use, specifically an IUD.
Physical examination
The physical examination, like the history, is an important
component in recognizing and diagnosing an ectopic preg-
nancy. The clinician should be mindful of the patient’s vital
signs to evaluate for hemodynamic instability and examine the
abdomen and pelvis to evaluate for rupture of the ectopic
pregnancy.
Prior to rupture of the ectopic pregnancy, the patient often
exhibits non-specific symptoms. The vital signs are most often
normal, and the abdomen may be non-tender or only mildly
tender to palpation. The abdominal examination is usually
non-specific, and cervical motion tenderness may or may not
exist on bimanual examination. An adnexal mass may be
present; however, this could represent a functional corpus
luteum cyst.
As the ectopic pregnancy ruptures and the patient subse-
quently develops intra-abdominal bleeding, the physical exam-
ination findings change as well. The first change usually is the
development of tachycardia, with increasing hemodynamic
256
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
instability and hypotension. The abdomen becomes distended,
and peritoneal signs with tenderness and rebound become
evident.
Because the patient’s history and physical examination
generally do not provide the complete diagnosis, clinicians
must be prepared to initiate the appropriate workup to diag-
nose the ectopic pregnancy. A combination of diagnostic
modalities generally is required including measurement of
human β-chorionic gonadotropin (β-hCG) levels, transvaginal
ultrasound, and possibly endometrial curettage and laparos-
copy in specific cases.
Diagnostic testing
While the history and physical examination are important
components of diagnosis of an ectopic pregnancy, serum
quantitative β-hCG and transvaginal ultrasound are key tests
that can expedite the diagnosis.
Serial quantitative measurements of human
β-gonadotropin-releasing hormone
There is a wide range of variability of β-hCG levels for both
intrauterine and ectopic pregnancies, and the location of the
pregnancy for a given patient cannot be determined using a
single measurement. The single β-hCG is only useful if the test
is negative, which essentially excludes the diagnosis of preg-
nancy. The doubling time associated with serum β-hCG is an
important parameter for following an early pregnancy and
differentiating a normal from an abnormal pregnancy.
A patient’s β-hCG level correlates closely with gestational age
early in pregnancy. Within the first 6 weeks of pregnancy, the
patient’s β-hCG level increases exponentially. In early gesta-
tions, β-hCG doubles approximately every 1.98 days (95%
confidence limit).27 These β-hCG values are useful for diag-
nosing pregnancy, identifying an abnormal pregnancy at risk
for an early abortion or ectopic gestation, and following the
resolution of a treated ectopic pregnancy. When serial β-hCG
measurements are followed, the clinical pattern of a plateauing
β-hCG is the most predictive for an ectopic pregnancy.28
A single measurement of the β-hCG level is not helpful in
and of itself, particularly when the value is below what is called
the “discriminatory zone” for ultrasound visualization. The
discriminatory zone is the β-hCG level above which the ultra-
sonographer should be able to visualize normal intrauterine
pregnancies, which is typically 1500–2000 mIU/mL for trans-
vaginal ultrasound. (The discriminatory zone will be discussed
in more detail below.) If the physician is initially suspicious
that a patient has an ectopic pregnancy, an initial ultrasound is
obtained. If the ultrasound evaluation is indeterminate for
either an intrauterine or an ectopic pregnancy, serial β-hCG
levels are obtained. As long as the β-hCG levels continue to rise
appropriately (>50% over 48 hours), and the patient is rela-
tively asymptomatic, the physician could follow the patient
until the β-hCG level reaches the upper limit of 2000 mIU/
mL for transvaginal discrimination. At this point, a repeat

vaginal ultrasound should be obtained. If the levels do not rise
appropriately, either an ectopic or non-viable intrauterine
pregnancy is present. The clinician may consider additional
issues such as patient compliance and geographic limitations
in considering optimal patient management.
If the hCG level is below the discriminatory zone and no
intrauterine or ectopic pregnancy is seen on ultrasound, the
physician can follow serial β-hCGs with appropriate counsel-
ing of the patient. In these settings, an intrauterine pregnancy
or ectopic cannot be excluded. If the β-hCG level is greater
than the discriminatory zone and no intrauterine or ectopic
pregnancy is seen, the physician would still need to follow
serial β-hCG measurements to differentiate between an ectopic
pregnancy and a completed abortion. Therefore, in almost all
instances, serial β-hCG measurements are required and serial
ultrasound evaluation may be helpful.
Ultrasonography
Ultrasound evaluation and serial serum β-hCGs have allowed
physicians to more accurately diagnose ectopic pregnancies.
Transvaginal ultrasound is superior to transabdominal ultra-
sound in visualization of pelvic structures, and an intrauterine
gestational sac can be visualized as much as 1 week earlier with
transvaginal imaging. Figure 17.2 demonstrates a right tubal
ectopic pregnancy as visualized on ultrasound.
The ultrasound results obtained should be correlated with
the patient’s β-hCG level, which, as described above, is the
discriminatory zone. With abdominal ultrasound, viable intra-
uterine pregnancies should be seen above β-hCG levels of
6500 mIU/mL, as opposed to 1500–2000 mIU/mL transvagin-
ally. If the β-hCG is 6500 mIU/mL for an abdominal ultra-
sound and 2000 mIU/mL for a vaginal ultrasound and a
pregnancy is not visualized, it is either a failed intrauterine
pregnancy or an ectopic pregnancy.
The difficulty with utilizing the discriminatory zone for
analysis is that an ectopic pregnancy can exist with either a
high or a low β-hCG value. In the stable patient, β-hCG
measurement and ultrasound should be repeated prior to
Fig. 17.2 Right tubal ectopic pregnancy, visualized by ultrasound.
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
Chapter 17: Ectopic pregnancy
instituting treatment. In other words, unless cardiac activity
is seen in the ectopic pregnancy or the clinical situation dic-
tates more immediate management, the ultrasound and β-hCG
findings are confirmed by repeat testing.
With ultrasound, early findings indicative of an intrauter-
ine pregnancy are the presence of a small, fluid-filled space and
the gestational sac with a surrounding echogenic ring. The
gestational sac typically has an eccentric uterine location. The
gestational sac can be visualized at 4 weeks after conception
vaginally versus 5 weeks abdominally. In an intrauterine preg-
nancy, the sac grows followed by the presence of a yolk sac and
subsequently an embryo with cardiac activity.
A normal gestational sac can be confused with a pseudosac.
The pseudosac is probably caused by bleeding from the
decidua into the endometrial cavity. Investigators have
wondered whether the presence of pseudosac is indicative of
an ectopic pregnancy; a study of 77 patients indicated that the
presence of the pseudosac could not be used reliably.29 The
presence of the pseudosac was not indicative of an ectopic
pregnancy because an intrauterine pregnancy failure could
not be differentiated from an ectopic pregnancy using
ultrasound.29
It has long been believed that the presence of a double
decidual sac sign is the best method to determine if a sac
present is a true gestational sac or a pseudosac. The double
decidual sac sign is thought to indicate a layer of decidua
surrounding the chorionic sac. Its presence is felt to be indica-
tive of an intrauterine pregnancy, and the clinician’s confi-
dence can increase when the yolk sac has been seen on
ultrasound. The yolk sac is usually visible with abdominal
ultrasound when the gestational sac reaches a size of 2.0 cm
and when it reaches 0.6–0.8 mm for transvaginal ultrasound.
When cardiac activity is seen within the uterine cavity, defini-
tive evidence of an intrauterine pregnancy exists. When a
gestational sac with fetal pole and cardiac activity is present
within the adnexa, the clinician can be relatively confident that
an ectopic pregnancy exists.
An ectopic pregnancy may exhibit a ring of blood flow
with color Doppler ultrasound (Fig. 17.2). This may help
to confirm the diagnosis when suspicions are high for an
ectopic pregnancy. In a study of 394 patients, the arterial
blood flow of the fallopian tube with an ectopic pregnancy
was shown to be as much as 45% higher than that of the
opposite tube.30 This finding can aid in the diagnosis, although
it should not be used exclusively and it must be correlated with
the clinical presentation, serial β-hCG, and other ultrasound
findings.
If, after ultrasonography is used to aid in diagnosis, the
uterus is found to be empty and the β-hCG level is below the
discriminatory zone, the clinician must consider the differen-
tial diagnosis of an early normal intrauterine pregnancy, an
abnormal intrauterine gestation, miscarriage, ectopic preg-
nancy, and even the non-pregnant state. In this situation,
further diagnostic tests such as follow-up laboratory studies
and repeat ultrasounds can be useful.
257
 Section 2: General gynecology
Although three-dimensional ultrasound and MRI have been
reported in diagnosing ectopic pregnancy, two-dimensional
ultrasound still remains the most common and cost-effective
modality at this time.
Serum progesterone measurement
Serum progesterone was previously used to distinguish a viable
from non-viable gestation. If the initial progesterone level was
25 ng/mL or greater, the diagnosis of ectopic pregnancy could
virtually be excluded with approximately 98% certainty.31 If
the progesterone level was <3.5 ng/mL, the diagnosis of a non-
viable pregnancy, either intrauterine or ectopic, could be guar-
anteed with almost 100% sensitivity. A systematic review of
26 articles indicated that a single serum progesterone level
could predict those women at risk for ectopic pregnancy, but
not the diagnosis of ectopic pregnancy with certainty.32 For
this reason, serum progesterone is not included in the diag-
nostic algorithm presented in Fig. 17.3. Interpreting serum
progesterone when a patient’s values are between 5 and
25 ng/mL is difficult and, in this case, the clinician must
continue to use β-hCG, ultrasound, and clinical history for
diagnosis.
Other markers
Other maternal serum markers, such as estradiol, creatine
kinase, pregnancy-associated plasma protein C, relaxin, CA125,
material serum a-fetoprotein, and C-reactive protein have all
been analyzed with regard to ectopic pregnancy. Their clinical
reliability has been mixed, and they are not currently used
clinically in the management of ectopic pregnancies. A case–
control study using a multiple marker test for women at risk for
ectopic pregnancy, consisting of serum progesterone, inhibin A,
and vascular endothelial growth factor, had 97% accuracy,
approaching 100% if the patient’s β-hCG was low.33 This and
other multiple markers appear promising in diagnosing ectopic
pregnancy, but larger studies are necessary for validation.
Dilatation and curettage
Dilatation and curettage (D&C) should be performed once the
pregnancy has been determined to be non-viable or its exact
location cannot be verified ultrasonographically. However,
care must be taken to not perform D&C in the presence of a
viable intrauterine pregnancy; therefore, D&C should be per-
formed when the ultrasound is inconclusive above the level of
the discriminatory zone and β-hCG levels have plateaued or
are rising suboptimally. The physician can immediately exam-
ine the specimen removed at the time of the endometrial
curettage. The specimen can be placed in normal saline and
examined. Chorionic villi exhibit a lacy, frond-like appearance,
and float on the saline. However, this technique, when used by
gynecologists, only diagnosed 50% of 272 patients with ectopic
pregnancy.34 Therefore, the specimen also should be examined
by a pathologist for the presence of chorionic villi and a serum
β-hCG level obtained.
258
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
If the follow-up β-hCG levels decrease by 15% or more in
the initial 12-hour period after the D&C, a completed abortion
is suspected. However, if the follow-up β-hCG levels plateau or
rise, the diagnosis of an ectopic pregnancy has been made.31
Culdocentesis
The practice of culdocentesis has declined in popularity for the
diagnosis of ectopic pregnancies with the advent of transvagi-
nal ultrasonography and serial β-hCG measurements. In cul-
docentesis, the posterior fornix of the vagina is visualized by
means of a speculum. The posterior cul-de-sac is then entered
with a spinal needle and the contents are aspirated with a
syringe. With a positive test (the presence of non-clotting
blood) a ruptured ectopic pregnancy may exist. If serous fluid
is aspirated, the test is thought to be negative. Culdocentesis is
considered non-diagnostic if clotted blood or no fluid is aspir-
ated. Historically, if the culdocentesis results were positive,
surgery was performed for a presumed diagnosis of ruptured
tubal pregnancy. However, the results of culdocentesis do not
always correlate with the status of the pregnancy. Although
approximately 70–90% of patients with an ectopic pregnancy
have a hemoperitoneum demonstrated by culdocentesis, less
than 50% of patients have a ruptured tube.35 Consequently, the
use of culdocentesis for diagnostic purposes in ectopic preg-
nancy has fallen out of favor.
Laparoscopy
The gold standard for diagnosing an ectopic pregnancy has
long been laparoscopy. Laparoscopy allows for visualization of
the pelvis, fallopian tubes, and ovaries while usually obtaining
a pathological diagnosis. A distinct advantage of laparoscopy is
that diagnosis and treatment can occur in the same setting.
Disadvantages of laparoscopy are that the patient has to
undergo a surgical procedure with its inherent risks, including
anesthesia, and small ectopic pregnancies may be missed. If
surgery can be avoided and fallopian tube spared, the patient’s
future fertility may be increased.
Diagnostic algorithm: a combination
of assessment techniques
The diagnostic algorithm in Fig. 17.3 was found to be 100%
accurate in a randomized clinical trial.31,36 Transvaginal ultra-
sound is an important diagnostic tool in the algorithm. If the
patient is found to have an intrauterine sac or pregnancy,
ectopic pregnancy can be excluded with a reasonable degree
of certainty. If the patient’s β-hCG is greater than the discrim-
inatory level and no intrauterine gestational sac is visualized,
the patient is considered to have an ectopic pregnancy. If
cardiac activity is found in an extrauterine location, most
specifically the adnexa, the diagnosis of ectopic pregnancy is
confirmed. With the sensitivity of ultrasound, masses >1 cm
can be identified. When the size of the ectopic pregnancy
reaches 3.5–4.0 cm, depending on the presence of fetal cardiac
 Chapter 17: Ectopic pregnancy

Positive urine Transvaginal

pregnancy test ultrasound No IUP

IUP Signs and Immediate

symptoms of surgical
ruptured ectopic treatment

Assess risk factors for

ectopic pregnancy

Quantitative
hCG

Rising or Vaginal ultrasound

and hCG within 15% decline
plateaued
24–48 hours in hCG
hCG

No IUP No IUP No IUP Ultrasound Ultrasound

IUP
Mass > 4.0 cm* No mass or Mass >4.0 cm* continent with continent with
suspicious for mass < 4.0 cm* suspecious for completed incomplete
ectopic hCG 2000 ectopic abortion abortion
hCG hCG 2000

hCG/USG in Non-laparoscopic Repeat hCG

Laparoscopy
48 hours methotrexate in 48–72 hours

D&C

No IUP 50% No IUP plateaued

IUP Falling
rise in hCG hCG or rise 50%

Completed Plateau of
Repeat hCG/USG abortion rising hCG
when hCG is expected D&C
to be 2000

No IUP
Ultrasound
consistent with
unruptured
ectopic
No IUP IUP No IUP Uterine curettings
No mass or Mass > 4.0 cm floated in oaline
mass < 4.0 cm

Repeat hCG
in 48 – 72 hours
Non-laparoscopic
methotrexate
Villi present Villi absent

Repeat hCG in 12 – 24 hours

Await final
Transvaginal ultrasound
histology

hCG Increasing hCG Increasing Decreasing

mass > 4.0 cm mass 4.0 cm hCG
Villi present Villi absent

Ectopic Increasing Follow-up hCG

Incomplete Laparoscopic pregnancy hCG in 48 hours
absorption
Routine
follow-up
Completed AB
Decreasing Ectopic
Non-laparoscopic
hCG spontaneous
methotrexate
resolution
£ 3.5cm if cardiac activity present

Fig. 17.3 Non-laparoscopic algorithm for diagnosis of ectopic pregnancy. AB, abortion; D&C, dilatation and curettage; hCG, human chorionic gonadotropin
(2000 is 2000 mIU/mL); IUP, intrauterine pregnancy; USG, ultrasound.

Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
259
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
 Section 2: General gynecology
activity, surgical treatment becomes the preferred method of
treatment.
Treatment
Medical and surgical options exist for the treatment of ectopic
pregnancy. Both methods are effective, and the individual
patient’s clinical scenario, including the β-hCG level, and loca-
tion and size of the ectopic pregnancy, should determine
treatment.
Medical treatment
The most popular current medical treatment for ectopic preg-
nancy is methotrexate. The routes of treatment vary from
systemic administration (intravenous, intramuscular, and oral)
to local administration: laparoscopically guided direct injec-
tions, transvaginal ultrasound-directed injections, and retro-
grade fallopian tube treatments.
Methotrexate
Methotrexate is the most popular form of medical treatment
for women with unruptured ectopic pregnancies. Methotrexate
is a folic acid analog and functions by inhibiting dihydrofolate
reductase. With the synthesis of folate disrupted, the synthesis
of DNA is prevented. Methotrexate is also used for the treat-
ment of gestational trophoblastic disease. The most common
side-effects are leukopenia, thrombocytopenia, bone marrow
aplasia, ulcerative stomatitis, diarrhea, and hemorrhagic
enteritis. Other less common side-effects include alopecia,
dermatitis, elevated liver function tests, and pneumonitis.
These side-effects are more common at the higher therapeutic
doses associated with chemotherapy and are not associated
with the lower dosing regimens necessary to treat ectopic
pregnancies. A patient who requires multiple doses for treat-
ment of ectopic pregnancy is more prone to develop the minor
side-effects. The incidence of these side-effects can be reduced
with the administration of citrovorum factor (folinic acid).37
Stovall et al. were the first to publish the use of multidose
intramuscular methotrexate (1 mg/kg daily) followed by citro-
vorum factor (0.1 mg/kg daily) for ectopic pregnancy; 100
patients receiving injections on alternate days showed a success
rate of 96%.37,38 This treatment regimen was continued until
the β-hCG level began to decline by at least 15% between two
consecutive β-hCG levels. Citrovorum factor was given on the
day following the methotrexate injection even if the patient
required no further methotrexate injections. Once the treat-
ment was discontinued, the patient’s β-hCG levels were meas-
ured until they became negative. A second treatment course of
methotrexate was given only if the patient’s β-hCG levels
plateaued or began to rise (Table 17.2). In this study, 17 women
received one methotrexate/citrovorum injection while
19 received four doses among the 100 patients ultimately
required surgical management secondary to rupture. Each of
these four patients differed with respect to ectopic pregnancy
size, β-hCG level, and time of rupture.37 This study provided
260
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
Table 17.2 Multidose methotrexate–citrovorum (folinic acid) protocol for
unruptured ectopic pregnancya
Day Therapy
1 CBC, SGOT, BUN, creatinine, β-hCG, blood type and Rh,
MTX
2 CF, β-hCG
3 MTX, β-hCG
4 CF, β-hCG
5 MTX, β-hCG
6 CF, β-hCG
7 MTX, β-hCG
8 CF, β-hCG, CBC, SGOT, BUN, creatinine
>8 Weekly β-hCG until <10 mIU/mL
BUN, blood urea nitrogen; CBC, complete blood count with differential and
platelet count; CF, intramuscular citrovorum factor 0.1 mg/kg; hCG, human
chorionic gonadotropin; MTX, intramuscular methotrexate 1.0 mg/kg; SGOT,
serum glutamic–oxaloacetic transaminase.
a
Methotrexate/citrovorum is given until there is a 15% decline in two
consecutive hCG titers; any time methotrexate is given, citrovorum is given
on the following day; patients with a hematocrit <35% are given oral iron
therapy; patients are told to refrain from alcohol, folic acid-containing
vitamins, and sexual intercourse during the treatment period; oral or barrier
contraceptives are used until the hysterosalpingogram is completed;
hysterosalpingogram may be performed on days 6–9 after the second
menstrual cycle to evaluate tubal patency.
the efficacy and safety profile of methotrexate for ectopic
pregnancy on which further research was built.
In an effort to reduce the side-effects associated with meth-
otrexate and eliminate the need for citrovorum, a single-dose
protocol was devised. Initially, 31 patients were treated with a
single dose of methotrexate (50 mg/m2). Approximately 97%
of the treated patients (29/30) were treated successfully.37
A major advantage of this treatment was that the incidence
of side-effects was less than 1% when the single-dose regimen
was utilized, while the failure rate was similar to that of
conservative forms of laparoscopic surgery.37 In addition, the
single-dose treatment protocol is less expensive than the multi-
dose protocol, has increased patient acceptance/compliance
secondary to decreased patient monitoring during therapy,
with similar treatment results and prospects for future fertility.
Table 17.3 outlines the single-dose protocol.
A meta-analysis of 26 studies found the single-dose regi-
men to have more therapy failures than the multidose regimen.
The rate of methotrexate failures increased with higher β-hCG
and the presence of embryonic cardiac activity.39 However, no
randomized controlled trials have compared the two regimens.
A series of 101 patients receiving a “two-dose” methotrex-
ate regimen sought to find a balance between convenience and
efficacy for the patient receiving methotrexate.40 The regimen
consisted of 50 mg/m2 intramuscular methotrexate on day
0 followed by the same dose on day 4. If a 15% fall in β-hCG
did not occur from days 4–7, additional doses were given on

Table 17.3 Single-dose methotrexate protocol for ectopic pregnancya
Day Therapy
0 Dilatation and curettage, hCG measurement
1 CBC, SGOT, BUN, creatinine, blood type and Rhesus factor;
methotrexate 50 mg/m2 intramuscular
4 hCG measurement
7 hCG measurement
BUN, blood urea nitrogen; CBC, complete blood count; hCG, human
β-chorionic gonadotropin; SGOT, serum glutamic-oxaloacetic transaminase.
a
Treatment is never begun based on a single hCG titer unless cardiac activity
is visualized on transvaginal scan in the ectopic pregnancy; if <15%
decline in hCG level between days 4 and 7, a second dose of methotrexate
50 mg/m2 is given on day 7; if >15% decline in hCG level between days
4 and 7, it is followed weekly until hCG<10 mIU/mL; in patients not
requiring dilatation and curettage (hCG >2000 mIU/mL and no gestational
sac on transvaginal ultrasonography), days 0 and 1 are combined.
days 7 and 11. If a 15% decrease in β-hCG was not seen from
days 7–11, the patient was treated surgically. Success rate was
87%, with high patient satisfaction.40 This regimen has not
been compared with the single or multidose regimens in ran-
domized studies.
Treatment initiation
Before methotrexate therapy can be initiated, the physician
must confirm that the patient is a good candidate for therapy.
Good candidates for therapy are patients (1) who have an hCG
level that is present and plateaued or rising after salpingostomy
or salpingectomy; (2) who have a rising or plateaued β-hCG
level at least 12 to 24 hours following a diagnostic D&C; and
(3) who are without an intrauterine gestational sac or fluid
collection by transvaginal ultrasound, have an abnormally
rising hCG level above 1500–2000 mIU/mL, have an ectopic
mass measuring <4.0 cm without cardiac activity, <3.5 cm
with or without fetal cardiac activity, or <4.0 cm without fetal
cardiac activity.
Absolute contraindications to methotrexate have been out-
lined by the American Congress of Obstetricians and Gyne-
cologists as hepatic, renal, or hematological dysfunction; peptic
ulcer disease; breastfeeding; laboratory evidence of immuno-
deficiency; alcoholism, alcoholic or chronic liver disease; pre-
existing blood dyscrasias; active pulmonary disease; or known
sensitivity to methotrexate. Relative contraindications are
gestational sac measuring >3.5 cm or embryonic cardiac
motion.41
The patient must be instructed to refrain from alcohol,
multivitamins containing folic acid, and unprotected sexual
intercourse until hCG level is negative. The patient must also
be aware that lower abdomen and pelvic pain can be normal
during the first 10–14 days of treatment, but severe pain,
lightheadedness, and/or heavy vaginal bleeding should prompt
immediate evaluation by her physician. This is essential to
maximize the safety and efficacy of the methotrexate therapy.
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
Chapter 17: Ectopic pregnancy
Follow-up
Once methotrexate has been administered, the patient is sent
home for follow-up as an outpatient. Serial hCG measure-
ments, usually weekly, are obtained until negative. Following
the initial treatment, patients are instructed to monitor their
pain and to call in if there is any increase in pain. If the pain is
prolonged or severe, the hematocrit is evaluated and a trans-
vaginal ultrasound should be obtained. The ultrasound may be
helpful if an increase in abdominal free fluid is noted; however,
a small amount of physiological fluid may be present within
the pelvis.
Surgical treatment
Historically, the gold standard treatment was laparotomy,
which is now mainly reserved for hemodynamically unstable
patients with active intraperitoneal bleeding.42 More recently,
ectopic pregnancies requiring surgical treatment are now per-
formed using minimally invasive laparoscopy. Patients who
are unable to be routinely evaluated after medical therapy, do
not have access to a medical facility in case of emergency, or
have a contraindication to methotrexate are also candidates for
surgical therapy.
Surgical approach
Most ectopic pregnancies that need surgery can be treated via
laparoscopy. Rupture of the ectopic pregnancy does not neces-
sitate laparotomy. Laparotomy is typically chosen if the patient
is hemodynamically unstable or if the patient has extensive
pelvic adhesions or abdominal pregnancy possibly comprom-
ising adequate visualization.42
Studies have shown that laparoscopy and laparotomy are
both safe and effective treatment measures. However, laparos-
copy is more economical secondary to reduced costs and
shorter hospitalizations.32,43 Patients treated laparoscopically
also have a shorter time for recovery and convalescence and
reduced postoperative pain requirements. It has also been
concluded that laparoscopy results in the formation of fewer
adhesions postoperatively and less blood loss.43,44 For these
reasons, many physicians consider laparoscopy the preferred
method of surgical treatment for ectopic pregnancies. Future
pregnancy rates are similar in patients treated by both laparot-
omy and laparoscopy.44
Surgical technique
The most common techniques to surgically treat an ectopic
pregnancy are salpingostomy and salpingectomy. A widely
accepted method for surgical treatment in a patient who has
not experienced rupture of the ectopic pregnancy and who
desires future fertility is salpingostomy. In this procedure,
the fallopian tube is opened along the antimesenteric border,
and the products of conception are removed. A fine incision
should be utilized and carried out with the needle tip cautery,
scalpel, scissors, or laser. Salpingectomy involves removal of
the affected fallopian tube with the ectopic pregnancy in situ.
261
 Section 2: General gynecology
Either technique can be executed through laparotomy or
laparoscopy.
Several factors need to be considered when making a
decision to perform one or the other method, including risk
of persistent trophoblastic tissue, risk of recurrent ectopic
pregnancy, severity of tubal damage, and desired fertility. Risk
of persistent trophoblastic tissue in a salpingostomy has been
reported to be as high as 15.5% and is higher in those patients
treated via laparoscopy compared with laparotomy.45,46 The
literature is conflicting in regards to risk of recurrent ectopic
pregnancy. It appears the risk is increased for salpingostomy
compared with salpingectomy, while maintaining similar
intrauterine pregnancy rates.46 If the affected tube has rup-
tured or is actively bleeding, or the patient does not wish
to preserve her fertility, a salpingectomy is the preferred
treatment. Also, no difference was found in future fertility
rates in patients with a normal-appearing contralateral fallo-
pian tube.47
Other modalities
The primary alternative treatment modality – salpingocent-
esis – includes the injection of various substances into the
ectopic pregnancy transvaginally utilizing ultrasound
guidance, transcervically via tubal cannulization, or laparosco-
pically. Agents such as potassium chloride, methotrexate, pros-
taglandins, and hyperosmolar glucose are used.48 The
advantages of this treatment are that it is a one-time, localized
treatment that can avoid most of the systemic side-effects
associated with methotrexate.
Spontaneous resolution
Not all ectopic pregnancies require medical or surgical man-
agement. Some resolve by resorption or by a tubal abortion.
Some investigators feel that expectant management may be
appropriate for the management of early ectopic pregnancies.
Following serum β-hCG levels until resorption or tubal abor-
tion occurs has been advocated. Some authors feel that expect-
ant management is the best way to preserve future fertility;
however, this is controversial. Falling β-hCG levels are the
most reliable indicator of success, but the physician should
be mindful that rupture can occur even with a falling or low
β-hCG level. One report found 88% of patients with initial
β-hCG <200 mIU/mL can have spontaneous resolution.49
Expectant management should be attempted only in extremely
compliant patients.
Ectopic pregnancy types
Non-tubal ectopic pregnancies
Cervical pregnancy
The rates associated with a cervical pregnancy have been
reported to range from 1 in 2400 to 1 in 50 000 in the
USA. The differential diagnosis initially must include
262
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
cervical cancer, presence of a cervical fibroid, trophoblastic
tumor, and abnormalities of placental location such as
a placenta previa or low-lying placenta. Patients are at
risk of developing a cervical pregnancy if they have under-
gone a prior elective abortion, developed Asherman syn-
drome, had a prior cesarean delivery, been exposed to
diethylstilbestrol, developed leiomyomas, or undergone in
vitro fertilization.50
Clinical criteria that should alert the physician to the pos-
sibility of a cervical pregnancy include smaller size of the
surrounding uterus than of the distended cervix, the presence
of a closed internal os, no chorionic tissue found on curettage
of the endometrial cavity, and dilation of the external os
sooner than would be expected in the presence of a spontan-
eous miscarriage.
Ultrasound is very useful in diagnosis of a cervical preg-
nancy (Fig. 17.4). Ultrasound diagnostic criteria of a cervical
pregnancy consist of the presence of an echo-free uterine
cavity, decidual transformation of the endometrium, a diffuse
uterine wall structure in an hourglass shape, enlargement and
ballooning of the cervical canal, and a closed internal cervical
os with a gestational sac and placental tissue within the cervical
canal.
When a cervical pregnancy is diagnosed, the patient can be
treated medically with methotrexate or surgically. If surgical
treatment is to be performed, the patient should give consent
for a D&C with the possibility of blood transfusion and even
hysterectomy. Typed and cross-matched blood should be avail-
able prior to initiation of the procedure. If bleeding does occur
at the time of diagnosis or treatment, it may range from light
to heavy. Attempts to control the bleeding can be accom-
plished through various techniques such as uterine packing,
lateral cervical suture placement in an attempt to ligate the
lateral cervical vessels, placement of a cerclage, or insertion of a
30 mL Foley catheter into the cervix for tamponade. If these
measures are unsuccessful, embolization of the bleeding vessels
can be attempted. If the patient requires laparotomy, the
Fig. 17.4. Cervical pregnancy, visualized by ultrasound.

uterine arteries can be ligated. If all these methods are unsuc-
cessful, the patient requires hysterectomy.
Ovarian pregnancy
The most common site for a non-tubal ectopic pregnancy is
the ovary. Ovarian pregnancy represents 1–3% of all ectopic
pregnancies.51 The primary difference between a tubal ectopic
pregnancy and an ovarian pregnancy is that an ovarian preg-
nancy is not associated with PID or infertility. The primary
risk factor associated with the development of an ovarian
pregnancy is concurrent use of an IUD. Patients with an
ovarian ectopic pregnancy have similar symptoms to those of
other ectopic pregnancies.
Ovarian pregnancy may be misdiagnosed as a ruptured
corpus luteum cyst, and ultrasonography may aid in the diag-
nosis. Spiegelberg’s primary criteria for diagnosis of an ovarian
pregnancy52 are:
 the fallopian tube on the affected side must be intact
 the fetal sac must occupy the position of the ovary
 the ovary must be connected to the uterus by the ovarian
ligament
 ovarian tissue must be located in the sac wall.
Historically, the treatment for an ovarian pregnancy was
oophorectomy; however, the current trend is to perform an
ovarian cystectomy. If medical treatment is an option, metho-
trexate therapy could also be attempted.
Abdominal pregnancy
Abdominal pregnancies occur with a frequency of approxi-
mately 1 in 372 to 1 in 9714 live births in the USA.53 Abdom-
inal pregnancies are classified as either primary or secondary,
with secondary being the most common. A primary abdom-
inal pregnancy occurs in the presence of normal fallopian
tubes and ovaries without evidence of a prior pregnancy. With
a primary pregnancy, there is also no evidence of a uteropla-
cental fistula. A primary pregnancy must be related exclusively
to the peritoneal surface. Secondary abdominal pregnancies
usually develop as a result of a tubal abortion, tubal rupture,
or uterine rupture with intra-abdominal implantation
(Fig. 17.5).
Abdominal pregnancies carry a significant risk of maternal
morbidity and mortality. The risk of mortality associated with
an abdominal pregnancy is approximately eight times higher
than for ectopic pregnancy and 90 times higher than for
intrauterine gestation. Few abdominal pregnancies are carried
to term. If they are, these pregnancies are associated with
significant perinatal morbidity, mortality, and congenital
anomalies.
Once an abdominal pregnancy is suspected, the patient
should be treated with surgery. The placenta should be
removed only if its vascular supply can be identified and
ligated. Many patients require abdominal packing, which is
left in place and removed after 24 to 48 hours. If the vascular
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
Chapter 17: Ectopic pregnancy
Fig. 17.5 Abdominal pregnancy, visualized by ultrasound.
supply to the placenta is not identifiable, it should be left in
place and the umbilical cord ligated at the base. The involution
of the placenta can be followed with serial ultrasound images
and serial β-hCG levels. Patients should be monitored for the
development of a bowel obstruction, fistula formation, and
sepsis as the placental tissue degenerates. In this situation,
methotrexate is contraindicated since it leads to rapid tissue
necrosis, subsequently causing a high rate of complications
such as sepsis and death.54
Interstitial pregnancy
Interstitial pregnancies (also known as cornual) present later
than typical ectopic pregnancies and represent 1% of all
ectopic pregnancies. An interstitial pregnancy can occur when
a pregnancy implants within the musculature of the uterus
where the proximal portion of the fallopian tube inserts. Due
to its location, diagnosis of an interstitial pregnancy from an
intrauterine pregnancy can be difficult to determine by ultra-
sound (Fig. 17.5). The potential of delayed diagnosis of these
pregnancies may lend to an increase rate of uterine rupture
and higher associated rate of maternal mortality than are
typical ectopic pregnancies. The treatment is to attempt to
achieve hemostasis and perform a cornual resection either
through laparoscopy or laparotomy.
Interligamentous pregnancy
The development of an interligamentous pregnancy is a rare
occurrence in the development of ectopic gestations, but there
have been reported cases of live births from an interligamen-
tous pregnancy. It is believed that an interligamentous preg-
nancy develops as the trophoblastic tissue penetrates the tubal
serosa into the mesosalpinx, with further implantation
between the leaves of the broad ligament. It can also occur if
a fistula is present between the uterine cavity and the retro-
peritoneal space of the broad ligament. Complications arise as
the placenta can be firmly adherent to the adjacent pelvic
263
 Section 2: General gynecology

Fig. 17.6 A heterotopic pregnancy.

organs and sidewalls. As is the case with an abdominal preg-

nancy, the placenta should be removed if possible; however, if
the placenta cannot be removed with good hemostasis, it
should be left in place and allowed to resorb.

Heterotopic pregnancy
A heterotopic pregnancy is the presence of both an intrauter-
ine and an ectopic pregnancy (Fig. 17.6). The occurrence is
rare; however, patients having undergone ovulation induc-
tion with clomiphene citrate and gonadotropins, or in vitro
fertilization, are at a greater risk for a heterotopic
pregnancy.55
The ectopic pregnancy may be missed as the ultrasonogra-
pher focuses on the intrauterine gestation. Serial β-hCG levels
Fig. 17.7 Ectopic pregnancy in hysterotomy scar.
are usually not useful secondary to the normal intrauterine
gestation causing a normal doubling time.
The treatment for a heterotopic pregnancy is surgical man- Multiple ectopic pregnancies
agement of the ectopic pregnancy with expectant management
The majority of multiple ectopic pregnancies are twin tubal
of the intrauterine gestation. Heterotopic pregnancies have
pregnancies; however, there have been reports of ovarian,
been successfully treated with potassium chloride and hyper-
interstitial, and abdominal pregnancies. Management of mul-
osmolar glucose solutions injected directly into the ectopic
tiple ectopic pregnancies is similar to that of single ectopic
pregnancy either laparoscopically or transvaginally.48
pregnancies and depends on patient stability and location of
the pregnancies.
Ectopic pregnancy in hysterotomy scar
Finding of an ectopic pregnancy in a hysterotomy scar, usually Pregnancy after hysterectomy
from a cesarean section, can occur but is rare. Diagnosis is Hysterectomy is expected to eliminate the risk of an ectopic
usually made by ultrasound, where a mass can be located pregnancy; however, the situation has been reported.57
between the bladder and uterus without myometrium in A patient undergoing hysterectomy could have a luteal-phase
between; no gestational sac is visualized in the cavity, and pregnancy at the time of the initial surgery and subsequently
Doppler flow may be present (Fig. 17.7).56 These pregnancies have an ectopic pregnancy within the remaining fallopian tube.
can be life threatening if rupture ensues, so first trimester Additionally, in a patient with a vaginal wall defect or supra-
intervention is suggested. Management for these pregnancies cervical hysterectomy, sperm could gain intra-abdominal
consists of conservative single-dose methotrexate or local access to the peritoneal cavity and fertilize an egg, resulting
injection of methotrexate, potassium chloride, or hyperosmo- in an ectopic pregnancy. Treatment is similar to that of an
lar glucose with ultrasound guidance. abdominal pregnancy.

264
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019

References
1. Centers for Disease Control and
Prevention. Ectopic Pregnancy: United
States, 1990–1992. MMWR 1995;44:
46–48.
2. Goldner TE, Lawson HW, Xia Z, Atrash
JK. Surveillance for ectopic pregnancy-
United States, 1970–1989. MMWR
Surveill Summ 1993;42:73–85.
3. Creanga AA, Shapiro-Mendoza CK,
et al. Trends in ectopic pregnancy
mortality in the United States. Obstet
Gynecol 2011;117:837–843.
4. Skejeldestad FE, Hadgu A, Eriksson N.
Epidemiology of repeat ectopic
pregnancy: a population-based
prospective cohort study. Obstet
Gynecol 1998;91:129–135.
5. Sherman D, Langer R, Sadovsky G,
Bukovsky I, Caspi E. Improved fertility
following ectopic pregnancy. Fertil
Steril 1982;37:497–502.
6. Pouly JL, Mahnes H, Mage G, Canis M,
Bruhat MA. Conservative laparoscopic
treatment of 321 ectopic pregnancies.
Fertil Steril 1986;46:1093–1097.
7. Maikinen JI, Salmi TA, Nikkanen VPJ.
Encouraging rates of fertility after
ectopic pregnancy. Int J Fertil
1989;34:46–51.
8. Ankum WM, Mol BW, van der Veen F,
Bossuyt RM. Risk of factors for ectopic
pregnancy: a meta-analysis. Fertil Steril
1996;65:1093–1099.
9. Sivin I. Dose- and age-dependent
ectopic pregnancy risks with
intrauterine contraception. Obstet
Gynecol 1991;78:291–298.
10. Sivin I, Stern J. Health during
prolonged use of levonorgestrel
20 micrograms/d and the copper TCu
380Ag intrauterine contraceptive
devices: a multicenter study.
International Committee for
Contraception Research (ICCR). Fertil
Steril 1994;61:70–77.
11. Xiong X, Buekens P, Wollast E. IUD use
and the risk of ectopic pregnancy: a
meta-analysis of case–control studies.
Contraception 1995;52:23–34.
12. Hillis SD, Joesoef R, Marchbanks PA,
et al. Delayed care of pelvic
inflammatory disease as a risk factor for
impaired fertility. Am J Obstet Gynecol
1993;168:1503–1509.
13. Ness RB, Soper DE, Holley RL, et al.
Effectiveness of inpatient and
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
outpatient treatment strategies for
women with pelvic inflammatory
disease: results for the Pelvic
Inflammatory Disease Evaluation and
Clinical Health (PEACH) Randomized
Trial. Am J Obstet Gynecol
2002;186:929–937.
14. Peterson HB, Xia Z, Hughes JM, et al.
The risk of ectopic pregnancy after
tubal sterilization. US Collaborative
Review of Sterilization Working
Group. N Engl J Med 1997;336:
762–767.
15. Hillis SD, Marchbanks PA, Tylor LR,
Peterson HB. Poststerilization regret:
findings from the United States
Collaborative Review of Sterilization.
Obstet Gynecol 1999;93:889–895.
16. Hulka JF, Halme J. Sterilization
reversal: results of 101 attempts.
Am J Obstet Gynecol 1988;159:
767–774.
17. Clayton HB, Schieve LA, Peterson HB,
et al. Ectopic pregnancy risk with
assisted reproductive technology
procedures. Obstet Gynecol
2006;107:595–604.
18. Cleland K, Raymond E, Trussell J,
Cheng L, Zhu H. Ectopic pregnancy
and emergency contraceptive pills: a
systematic review. Obstet Gynecol
2010;115:1263–1266.
19. Centers for Disease Control and
Prevention. US medical eligibility
criteria for contraceptive use, 2010.
MMWR 2010;59(RR-4):1–86.
20. Bjornnson HM, Graffeo CS, Davis SS.
Ruptured ectopic pregnancy after
previously confirmed tubal occlusion
by the Essure procedure. Ann Emerg
Med 2011;57:310–311.
21. Sivin I, Campodonico I, Kiriwat O,
et al. The performance of levonorgestrel
rod and Norplant contraceptive
implants: a 5 year randomized study.
Hum Reprod 1998;13:3371–3378.
22. Kendrick JS, Tierney EF, Lawson HW,
et al. Previous cesarean delivery and the
risk of ectopic pregnancy. Obstet
Gynecol 1996;87:297–301.
23. Atash HK, Strauss LT, Kendrick JS,
Skjeldestad FE, Ahn YW. The relation
between induced abortion and ectopic
pregnancy. Obstet Gynecol
1997;89:512–518.
24. Barnhart K, Esposito M, Coutifaris C.
An update on the medical treatment of
ectopic pregnancy. Obstet Gynecol Clin
North Am 2000;27:653–667.
Chapter 17: Ectopic pregnancy
25. Westrom L. Effect of acute pelvic
inflammatory disease on fertility. Am
J Obstet Gynecol 1975;121:707–713.
26. Arias-Stella J. The Arias–Stella reaction:
facts and fancies four decades after. Adv
Anat Pathol 2002;9:12–23.
27. Kadar N, Romero R. Further
observations on serial human chorionic
gonadotropin patterns in ectopic
pregnancies and spontaneous
abortions. Fertil Steril 1988;50:367–370.
28. Kadar N, Caldwell BY, Romero R.
A method of screening for ectopic
pregnancy and its indications. Obstet
Gynecol 1981;58:162–165.
29. Ahmed A, Tom BDM, Calabrese P.
Ectopic pregnancy diagnosis and the
pseudo-sac. Fertil Steril 2004;81:1225–
1228.
30. Kirchler HC, Seebacher S, Alge AA,
et al. Early diagnosis of tubal
pregnancy: changes in tubal blood flow
evaluated by endovaginal color Doppler
sonography. Obstet Gynecol
1993;82:561–565.
31. Stovall TG, Ling FW, Carson SA, et al.
Serum progesterone and uterine
curettage in differential diagnosis of
ectopic pregnancy. Fertil Steril
1992;57:456–458.
32. Mol BW, Lijmer JG, Ankum WM, van
der Veen F, Bossuyt PM. The accuracy
of single serum progesterone
measurement in the diagnosis of
ectopic pregnancy: a meta-analysis.
Hum Reprod 1998;13:3220–3227.
33. Rausch ME, Sammel MD, Takacs P,
et al. Development of a multiple marker
test for ectopic pregnancy. Obstet
Gynecol 2011;117:573–581.
34. Lindahl B, Ahlgren M. Identification of
chorion villi in abortion specimens.
Obstet Gynecol 1986;67:79–81.
35. Romero R, Copel JA, Kadar N, et al.
Value of culdocentesis in the diagnosis
of ectopic pregnancy. Obstet Gynecol
1985;65:519–522.
36. Stovall TG, Ling FW. Ectopic
pregnancy: diagnostic and therapeutic
algorithms minimizing surgical
intervention. J Reprod Med
1993;38:807–810.
37. Stovall TG, Ling FW, Gray LA. Single-
dose methotrexate for treatment of
ectopic pregnancy. Obstet Gynecol
1991;77:754–757.
38. Stovall TG, Ling FW, Buster JE.
Outpatient chemotherapy of
265
 Section 2: General gynecology
unruptured ectopic pregnancy. Fertil
Steril 1989;51:435–438.
39. Barnhart KT, Gosman G, Ashby R,
Sammel M. The medical management
of ectopic pregnancy: a meta-analysis
comparing “single dose” and
“multidose” regimens. Obstet Gynecol
2003;101:778–784.
40. Barnhart K, Hummel AC, Sammel MD,
et al. Use of “2-dose” regimen of
methotrexate to treat ectopic
pregnancy. Fertil Steril 2007;87:
250–256.
41. American Congress of Obstetricians
and Gynecologists. ACOG Practice
Bulletin No.94: medical management of
ectopic pregnancy. Obstet Gynecol
2008;111:1479–1485.
42. Seeber BE, Barnhart KT. Suspected
ectopic pregnancy. Obstet Gynecol
2006;107:399–413.
43. Gray DT, Thorburn J, Lundorff P,
Strandell A, Lindbloom B. A cost-
effectiveness study of a randomized trial
of laparoscopy versus laparotomy for
ectopic pregnancy. Lancet
1995;345:1139–1143.
44. Lundorff P, Thorburn J, Lindbloom B.
Fertility outcome after conservative
surgical treatment of ectopic pregnancy
266
Downloaded from https://www.cambridge.org/core. The University of British Columbia Library, on 27 Nov 2017 at 16:48:51, subject to the Cambridge Core terms of use, available at
https://www.cambridge.org/core/terms. https://doi.org/10.1017/CBO9781139628938.019
evaluated in randomized trial. Fertil
Steril 1992;57:998–1002.
45. Seifer DB, Gutmann JN, Grant WD,
Kamps CA, DeCherney AH.
Comparison of persistent ectopic
pregnancy after laparoscopic
salpingostomy versus salpingectomy at
laparotomy for ectopic pregnancy.
Obstet Gynecol 1993;81:378–382.
46. Yao M, Tulandi T. Current status of
surgical and nonsurgical management
of ectopic pregnancy. Fertil Steril
1997;67:421–433.
47. Ory SJ, Nnadi E, Herrmann R, et al.
Fertility after ectopic pregnancy. Fertil
Steril 1993;60:231–235.
48. Strohmer H, Obruca A, Lehner R, et al.
Successful treatment of a heterotopic
pregnancy by sonographically guided
instillation of hyperosmolar glucose.
Fertil Steril 1998;69:149–151.
49. Korhonen J, Stenman UH, Ylotalo P.
Serum human chorionic gonadotropin
dynamics during spontaneous
resolution of ectopic pregnancy. Fertil
Steril 1994;61:632–636.
50. Parente JT, Ou CS, Levy J, et al.
Cervical pregnancy analysis: a review
and report of five cases. Obstet Gynecol
1983;62:79–82.
51. Comstock C, Huston K, Lee W. The
ultrasonographic appearance of ovarian
ectopic pregnancies. Obstet Gynecol
2005;105:42–45.
52. Spiegelberg O. Zur Gosuistik de
Ovarialscwangerschalt. Arch Gynackol
1973;13:73–76.
53. Atrash HK, Friede A, Hogue CJR.
Abdominal pregnancy in the
United States: frequency and
maternal mortality. Obstet Gynecol
1987;69:333.
54. Martin JN Jr., Sessums JK, Martin RW,
et al. Abdominal pregnancy: current
concepts of management. Obstet
Gynecol 1988;71:549–557.
55. Clayton HB, Shieve LA, Peterson HB,
et al. A comparison of heterotopic
and intrauterine-only pregnancy
outcomes after assisted reproductive
technologies in the United States
1999–2002. Fertil Steril 2007;87:303.
56. Ash A, Smith A, Maxwell D. Cesarean
scar pregnancy. BJOG 2007;114:
253–263.
57. Jackson P, Barrowclough IW, France
JT, et al. A successful pregnancy
following total hysterectomy.
Br J Obstet Gynaecol 1980;87:
353–355.