The Journal of Emergency Medicine, Vol. 53, No. 6, pp.

819–828, 2017
Ó 2017 Elsevier Inc. All rights reserved.
0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2017.08.074

Clinical
Reviews in Emergency Medicine

EMERGENCY MEDICINE MYTHS: ECTOPIC PREGNANCY

EVALUATION, RISK FACTORS, AND PRESENTATION

Jennifer J. Robertson, MD, MSED,* Brit Long, MD,† and Alex Koyfman, MD‡
*Emory University School of Medicine, Atlanta, Georgia, †San Antonio Military Medical Center, Fort Sam Houston, Texas, and ‡University of
Texas-Southwestern, Parkland Hospital, Dallas, Texas
Reprint Address: Jennifer J. Robertson, MD, MSED, 3645 Habersham Road NE, Apartment T19, Atlanta, GA 30305

, Abstract—Background: Ectopic pregnancy (EP) is an INTRODUCTION

important cause of morbidity and mortality in females of
reproductive age. Proper diagnosis and treatment are
critical, as complications such as rupture, hemorrhagic
shock, and even death can occur. Objective: EP is a condition
emergency physicians are trained to detect, yet there are
multiple myths concerning its evaluation and diagnosis.
This article reviews several of these myths in order to improve
emergency department (ED) evaluation and diagnosis.
Discussion: EP is a difficult diagnosis and may be missed on
initial ED visit. While the diagnosis is often delayed simply
due to very early presentations, it can also be missed because
patients may not have all the same risk factors or demonstrate
the same symptoms. They may also not demonstrate the same
serum B-human chorionic gonadotropin levels and trends or
have the same ultrasound findings at equivalent gestational
ages. Some patients with early EP may have positive ultra-
sound findings with serum b-hCG levels under a defined
discriminatory zone (DZ). On the other hand, some patients
with an early viable intrauterine pregnancy may have no
visible findings on initial ultrasound, but have serum b-hCG
(quantitative) levels well above the DZ. Although rare, EP
has even been demonstrated in women with negative urine
b-hCG tests or low serum b-hCG levels. Conclusions: While
EP may be a challenging diagnosis, understanding the myths
surrounding EP may help emergency physicians consider it,
even when patient risk factors, symptoms, or ED laboratory
or imaging studies do not initially or easily define the diag-
nosis. Ó 2017 Elsevier Inc. All rights reserved.
, Keywords—ectopic; pregnancy; serum b-hCG; discrim-
inatory zone; ultrasound
An ectopic pregnancy (EP) is a condition in which a
fertilized ovum implants outside the endometrium (1).
The largest percentage of EPs occur in the fallopian
tubes, but they can also occur in the ovary, abdomen,
and cervix (2). Although the incidence of EP approxi-
mates 2% of all pregnancies, it remains an important
cause of morbidity and mortality (1,2). From 2003 to
2007, EP accounted for 0.26 maternal deaths per
100,000 live births in Caucasian women and 1.75
deaths per 100,000 live births in African-American
women. Undiagnosed or untreated EP can also lead to
complications, such as excessive hemorrhage, shock, or
renal failure (1).
Although it is important to diagnose and treat EP early,
the diagnosis can be challenging. Clinicians commonly
misdiagnose EP on an initial medical encounter (3,4).
Several recommendations attempt to simplify decision
making and facilitate the diagnosis with obtaining
accurate history, specific laboratory tests, and imaging
studies (5,6). However, not every patient with EP will
present similarly and, unfortunately, not every patient
will demonstrate similar findings on these laboratory or
imaging tests. The current article discusses EP and
some of these discrepancies in the diagnosis of EP in
the emergency department (ED). Of note, in this
particular article, all serum b-human chorionic
gonadotropin (b-hCG) levels refer to the quantitative test.

RECEIVED: 4 March 2017; FINAL SUBMISSION RECEIVED: 31 July 2017;

ACCEPTED: 16 August 2017

819
820
DISCUSSION
Myth 1: If a Pregnant Patient Has a Serum hCG Above
the Discriminatory Zone and No Visualized Intrauterine
Pregnancy on Ultrasound, Then an Ectopic Pregnancy
Must Be Present
The discriminatory zone (DZ) describes the lowest serum
b-hCG level where ultrasound (US) should detect visible
signs of early pregnancy, such as yolk sac or fetal pole (7).
With improving US technology, over time the DZ has
fallen from a level of 6500 mIU/mL in the early 1980s
to 1000–2000 mIU/mL in the present day (8–10).
Women without evidence of a visible intrauterine
pregnancy (IUP) on transvaginal US are considered to
have pregnancy of unknown location (PUL), but it is
often presumed that a patient with a PUL and a serum
b-hCG level above the DZ has an EP, which may not be
a correct assumption (11).
Recent research has questioned that a single hCG
measurement can distinguish IUP from EP, even when
the measurement is above the DZ (12,13). From the
emergency practitioner’s standpoint, the initial goal is to
address a life-threatening condition. If any patient is
unstable with concerning signs and symptoms, resuscita-
tion and urgent obstetrics consultation is paramount. In
stable patients, a more thorough evaluation can occur.
The primary goal is to determine whether a viable IUP is
present (12). If no IUP is seen on US, then PUL is present,
and potential outcomes for this pregnancy may include
early viable IUP, early non-viable IUP, or EP (12).
If a patient has an hCG level below the DZ, it is often
thought an US is unnecessary because nothing can be
visualized. However, as will be mentioned in Myth 2,
this may not be the case. In situations where the hCG is
above the DZ and no IUP is seen, then it is often
presumed the pregnancy is not viable or an EP is present.
However, the hCG DZ is a surrogate marker for gesta-
tional age. A normal gestational sac should be visualized
around 5 weeks and 5 days from the last normal menstrual
period, regardless if it is a singleton or multiple gestation
(14). The b-hCG should be used in conjunction with
suspected gestational age, and a single level should not
be used alone in clinical decision making (15). Serum
progesterone level is another laboratory test that has
been used in conjunction with serum b-hCG level. It is
thought that low serum progesterone levels (< 5 ng/mL)
are associated with non-viable pregnancies (4,16–18).
However, single progesterone levels are inadequate for
determining EP vs. a non-viable IUP (18,19). Just as
with US, the combination of the serum b-hCG level
with a serum progesterone level may be useful in the
diagnosis of EP in those patients who have PUL (20).
This review will not discuss this further, but it is some-
J. J. Robertson et al.
thing for the emergency physician to note for reference
purposes.
Indeed, there have been cases where patients with an
initial PUL and serum b-hCG levels above the DZ have
gone on to have viable pregnancies (13,21,22). In 2014,
Ko et al. reviewed 113 patients with initial PUL and
hCG levels > 1000 mIU/mL. They followed these
patients for a specified time period to determine
outcomes, including eventual viable IUPs (21). The au-
thors evaluated only hemodynamically stable patients
without significant vaginal bleeding who had serum
b-hCG levels > 1000 mIU/mL taken within 12 h of US.
Transvaginal US was repeated when the hCG level
showed a rise > 53%. Laparoscopy occurred when there
was suboptimal rise in hCG, a visualized EP on repeat
US, or development of hemodynamic instability or hemo-
peritoneum. Overall, in those patients with eventual visu-
alized IUPs (n = 42), 23 were viable. Of these 23 patients,
the highest hCG level was 9083 mIU/mL, which occurred
in a patient with a triplet pregnancy conceived through
in vitro fertilization. Of the total 113 patients studied,
22 had EP diagnosed on laparoscopy, with initial serum
b-hCG level range of 1155–21,770 mIU/mL. The other
49 patients without confirmed EP or IUP were grouped
into ‘‘other,’’ which included resolved PUL (n = 45),
treated PUL (n = 2), and molar pregnancy (n = 2) (21).
The authors suspect several factors contributed to the
non-visualization of pregnancy on initial US, including
maternal obesity, adenomyosis, and uterine fibroids.
They conclude a single initial serum b-hCG level and
inconclusive initial transvaginal US findings are not pre-
dictive of eventual IUP or EP (21).
Similarly, other studies have documented cases in
which an embryo was not seen on initial US in patients
with serum b-hCG levels above the DZ but was later
seen on subsequent US scans (7,13,22). In 2013,
Connolly et al. reviewed the records of 651 patients
with known pregnancy outcomes who initially
presented with symptoms of EP or miscarriage (7).
They were evaluated with a serum b-hCG level and a
transvaginal US within 6 h of each other. In this popula-
tion, the highest observed hCG where no structure could
be visualized was 2317 mIU/mL. Using a logistic regres-
sion model, the authors calculated the predicted probabil-
ity of visualizing a gestational sac as a function of the
serum hCG values. They found that in their population
of patients with a DZ of 1500 mIU/mL, the predicted
probability of visualizing a gestational sac in a viable
pregnancy was 80.4% (7). The authors conclude that
even with improving US technology, initial structural
signs of pregnancy may not be seen on US in some
patients who have initial serum b-hCG levels above the
classically defined DZ of 1000–1500 mIU/mL (7).
Ectopic Pregnancy
It is important for the emergency physician to under-
stand the limitations of the serum b-hCG. If a patient’s
initial serum b-hCG level is higher than the DZ, but no
signs of pregnancy are seen on initial US, EP is not the
only diagnosis and only suggests the pregnancy is non-
viable (15). However, any outcome is possible. As long
as patients are hemodynamically stable, reflexively these
pregnancies as EPs would result in termination of an
otherwise desired pregnancy, as well as exposure to treat-
ment side effects (21). Stable patients may be discharged,
but should receive appropriate obstetrics follow-up (5). In
cases where patients return to the ED instead of their
obstetrics physician, repeat hCG may be used along
with US as a potentially helpful diagnostic tool. Accord-
ing to the most recent American College of Obstetricians
and Gynecologists guidelines, an increase in repeat serum
b-hCG < 53% in 48 h is suggestive of abnormal preg-
nancy (23). Using this, the combination of US with repeat
serum b-hCG level is helpful when evaluating patients
who return to the ED (13,15,21,22,24).
Myth 2: If the Serum b-hCG Level Is Less Than DZ, Then
US Is of Little Utility
The entire premise behind the DZ is that it helps deter-
mine whether signs of early pregnancy can be visualized
on US (9). It has been suggested that obtaining imaging in
patients with hCG levels below the DZ is of limited value
in locating the pregnancy. However, studies have demon-
strated that this is not the case, and some EPs can rupture
in patients with b-hCG levels below the DZ (7,25–31).
A 2007 study of 74 patients with US findings concern-
ing for EP evaluated hCG levels. Of these patients, 47
were eventually diagnosed with EP (25). In these patients
with a final diagnosis of EP, b-hCG levels ranged from 41
to 59,846 mIU/mL. In addition, 17 of these patients had
b-hCG levels < 1000 mIU/mL (25). Similarly, in the
study by Connolly et al. mentioned previously, a visible
pregnancy was noted in a patient with an hCG value of
390 mIU/mL (7). Most recently, Simsek et al. retrospec-
tively studied initial ED evaluations of 35 women with
known final diagnoses of EP (27). Overall, the mean
initial serum b-hCG value was 3560 mIU/mL; however,
there were values much lower than this, including a min-
imum value of 17 mIU/mL (27). They also found that any
single level of b-hCG did not predict EP rupture (27).
Case studies have also demonstrated that a single initial
b-hCG value under the DZ is not protective against EP
rupture (26,28–30). A 2012 paper discussed the case
with a serum b-hCG level of 364 mIU/mL and a
ruptured ectopic ovarian pregnancy and hemoperitoneum
(30). The patient was unstable, and emergency laparos-
copy and resection of a left ovarian EP were performed.
The patient recovered and had an otherwise uneventful
821
hospital course (30). Similarly, Fu et al. reported the cases
of 2 patients who had serum b-hCG levels < 10 mIU/mL
with EP rupture and hemoperitoneum (26). Other studies
have shown rupture of EP with low or even negative serum
b-hCG levels (28,29).
The most recent American College of Emergency
Physicians clinical guidelines provides a level B recom-
mendation on obtaining transvaginal US in patients
who have b-hCG levels below the DZ and concerning
signs and symptoms (5). Given the studies and guidelines
mentioned, it is prudent to consider imaging with US in
patients with concerning signs and symptoms for EP,
despite low or negative serum hCG levels (32). In addi-
tion, rupture can occur at any hCG level, and patients
should be counseled concerning the risks and symptoms
of rupture. It is recommended that serum b-hCG levels
be followed to zero (26).
Myth 3: Ectopic Pregnancies Demonstrate Reliable
Trends in Serum b-hCG Levels
In conjunction with clinical history and transvaginal US,
trending serial serum b-hCG levels are frequently utilized
to determine the ultimate outcome of a PUL, whether it is
a viable IUP, non-viable IUP, or EP (23). In the United
States, standard practice is to follow serial b-hCG levels
for a period of at least 48 h (6). Any deviation from a
‘‘normal’’ rise or fall in serum hCG seems to suggest a
diagnosis other than a viable IUP (6). This idea stemmed
from a small study showing that for viable IUPs, the
serum b-hCG should rise at least 66% in 48 h (9). Since
then, a slower rate of rise has been proposed in abnormal
pregnancies and, as mentioned previously, American
College of Obstetricians and Gynecologists guidelines
state an increase in serum b-hCG < 53% in 48 h is sugges-
tive of abnormal pregnancy (23).
Most patients with similar types of pregnancies tend to
follow similar b-hCG patterns. However, there are excep-
tions, as up to one-third of normal pregnancies will not
demonstrate these typical trends (33). Table 1 provides a
summary of the myths mentioned in this article that may
make the diagnosis difficult. While emergency physicians
are not necessarily the primary providers who trend b-
hCG levels in patients with PUL, it is important to under-
stand there is overlap in b-hCG trends among viable IUP,
non-viable IUP, and EP (34–37). This can be seen in
cases of both decreasing and increasing b-hCG levels.
First, an appropriate increase in the b-hCG level is not
automatically diagnostic of an IUP (38). In a 2006 cohort
study of 200 women with ultimate diagnoses of EP, 60%
had an initial rise in b-hCG over 48 h. Importantly, 20.8%
of these patients had hCG levels that rose $ 53%, similar
to a developing IUP (35). A study by Horne et al. found
that in patients with PUL, 16% with eventual EP had
822 J. J. Robertson et al.

Table 1. Summary

1. Pregnant patients with serum b-hCG levels greater than the DZ and no visualized IUP on US may or may not have an EP.
2. If the serum b-hCG level is less than DZ, US may definitely be helpful in diagnosing EP.
3. Patients with EP do not demonstrate reliable trends in serum b-hCG levels.
4. While rare, patients with EP have been found to have initial negative urine point-of-care b-hCG tests.
5. Patients with EP may or may not present with pain or adnexal tenderness.
6. Patients with a ruptured EP can have low negative serum or even negative urine b-hCG tests.
7. Overall, contraceptives protect against EP because they prevent pregnancy.
8. Many patients with EP do not have even one classic predisposing risk factor.

b-hCG = b–human chorionic gonadotropin; DZ = discriminatory zone; EP = ectopic pregnancy; IUP = intrauterine pregnancy;
US = ultrasound.

normally rising b-hCG levels (defined as $ 66%) in the
first 48 h (39). In a retrospective cohort study of 179
women with initial PUL and eventual EP diagnoses,
60% showed an increase in b-hCG (median 32% in-
crease) over the first two measurements (37). While the
authors do not discuss the actual number of patients
with trends similar to IUPs, 27% demonstrated b-hCG
trends resembling that of a growing IUP or miscarriage
(37). Declining b-hCG levels do not necessarily mean a
miscarriage is present, just as appropriately increasing
b-hCG levels do not indicate an IUP (37,38).
Secondly, while any progressive decline in serum
b-hCG likely indicates a non-viable pregnancy, EP is still
possible (38). In the same 2006 cohort study by Silva
et al., 8% of women with eventual EP had b-hCG levels
similar to those with completed spontaneous abortions
(35). A 2012 cohort study by Morse et al. also found
that of 179 patients with eventual EP diagnoses, 30
were initially misclassified with miscarriage or IUP
(34). Of these 30 women, 20% had declining b-hCG
levels similar to those with miscarriages (34). Another
cohort study also found similar inconsistencies with
b-hCG trends among EP, IUP, and miscarriages (33).
Overall, there is no one way for serum b-hCG patterns
to accurately diagnose EP (35). While the rise or fall of
the serum b-hCG can guide clinical management, this
technique does have limitations. Every patient will be
different, and patients with concerning signs and symp-
toms of EP should be closely monitored and considered
to have PUL until a final diagnosis is made (38).
Myth 4: If a Patient Has Concerning Signs and Symptoms
of EP but a Urine Point of Care b-hCG Test Is Negative,
Then EP Is Not Possible
While rare, it is possible for a urine b-hCG point-of-care
(POC) test to be falsely negative (40–44). False negative,
including serum, tests can be due to insufficient or diluted
urine, incorrect reading times, an EP with deficient
production of hCG, or chronic EP with inactive
trophoblasts (40,45). Of note, a chronic EP is an EP
that undergoes repeated small ruptures instead of one
single episode of rupture and bleeding. It typically
develops into a hematocele that contains old blood clots
and gestational tissue (46). The sonographic appearance
of a chronic EP is an adnexal mass with surrounding or
adjacent low-resistance arterial vessels and no IUP seen
(47).
Most recently, studies have suggested that false-
negative qualitative urine hCG tests may also be due to
‘‘hook like’’ or ‘‘hook-like variant’’ effects that occur
from abnormal antigen-antibody binding in the assays
(43). During pregnancy, various subunits of the hCG
hormone can be seen in the serum and urine. The concen-
tration of each subunit depends on gestational age and
whether another pathologic condition, such as gestational
trophoblastic disease, is present (48). The major hCG
subunit detected in the urine is the hCG b core fragment
(hCGbcf), especially as pregnancy progresses (48).
Some urine POC tests utilize one-step sandwich assays
in which antibodies recognize and bind hCGbcf to form
a ‘‘sandwich,’’ ultimately leading to a positive test. If this
hCGbcf concentration is in excess, it can saturate all of
the antibodies and prevent this sandwich formation. This
is called the ‘‘hook effect’’ and is not typically seen unless
hCG concentrations reach 1,000,000 mIU/mL (40,43). For
the most part, modern manufacturers have developed tests
that can bind very high concentrations of hCG, and this
effect is rarely seen except in those who have
abnormally high hCG concentrations (43). However, a
recent 2014 study by Nerenz et al. found several assays
still demonstrated results similar to the hook effect, result-
ing in false-negative urine pregnancy tests (43).
The variant hook effect can also occur where a partic-
ular test’s antibodies are unable to detect certain hCG
variants also present later in the first trimester
(6–12 weeks) (40,41,43,49). If the concentration of one
particular hCG fragment is in surplus, it can bind one
antibody well and not another, which results in a false-
negative test (40,41,49). Overall, appropriate dilution is
the key to obtaining an accurate test (43). The variant
hook effect may occur in modern assays because of fluc-
tuating hCG fragments present in various concentrations
during the stages of pregnancy (40,41).
Ectopic Pregnancy
The inability of various urine pregnancy tests to prop-
erly detect hCG fragments in very early pregnancy is
also seen in both POC and over the counter (OTC) tests
(40,50,51). A 2009 study by Cervinsky et al. found some
OTC tests to have better analytical sensitivity than POC
tests in early pregnancy (within 10 days of expected
menses) (50). Another 2013 study evaluated two urine
POC tests and their sensitivities in detecting pregnancy
at 2–5 weeks (52). The authors measured patients’ serum
hCG levels and evaluated the ability of these patients’
urine POC tests to be appropriately positive. The ability
of one device to detect a positive result in urine in patients
with serum hCG levels > 20 mIU/mL was 80%. The ability
of the other device to detect a positive urine result in
patients with serum hCG concentrations > 20 mIU/mL
was 90% (52). Overall, the authors concluded that the sen-
sitivities of these two commonly used urine POC assays
were insufficient for detecting early pregnancy (mean
4 weeks) (52). Other studies have found similar results
that many urine pregnancy tests do not possess 100%
sensitivity in detecting early pregnancy (41,51,53).
Regardless of the mechanism, it is important to under-
stand false-negative urine test results can be seen in the
early and later stages of pregnancy. This has been seen
in several case reports and case series (40–42,44,54). In
patients with a negative urine pregnancy test but
concerning signs and symptoms of EP, a serum hCG
level and close monitoring are prudent.
Myth 5: Patients with EP Always Present with Pain or
Adnexal Tenderness on Examination
The classic symptoms and signs of EP are abdominal or
pelvic pain, vaginal bleeding, and amenorrhea (55).
While abdominal pain and vaginal bleeding in the first
trimester are common symptoms of EP, it should be
kept in mind that these symptoms are not sensitive or spe-
cific. Many women with normal IUPs also have these
symptoms, and this should be kept in mind when evalu-
ating any pregnant patient with pelvic pain or vaginal
bleeding (3,4).
Patients with EP can also have varied presentations
and may arrive with minimal or no symptoms (56). In
one prospective study of 481 women who presented to
an ED with first-trimester pain or vaginal bleeding, 56
were ultimately diagnosed with EP. Of these 56 patients,
9% had no pain and had vaginal bleeding as their only
presenting complaint. In addition, 36% of patients with
an ultimate diagnosis of EP had no adnexal tenderness
on examination (57).
In 2005, another prospective observational study eval-
uated 527 women with PUL, and of these, 46 had eventual
diagnoses of EP (13). Of these EP patients, 62%
presented with no lower abdominal pain (13). A limita-
823
tion of this study is that the studied population included
women who presented to an early pregnancy clinic and
not an ED.
Other studies have emphasized that the presentation of
EP can be non-specific, and women may have varied
symptoms and examination findings (36,58–60). A
recent observational cohort study of 72 patients with EP
diagnoses found that the presence of pelvic pain does
increase the risk that a patient will have an EP. However,
the study also found that 16 of 72 (22.2%) patients with
EP presented without pain (58). Another prospective
observational study demonstrated the large ranges of signs
and symptoms patients with EP can experience, including
pain severity and abdominal or pelvic tenderness (60).
Overall, authors concluded that there was no particular
pattern of historical or examination findings that could reli-
ably predict or exclude the diagnosis of EP (60).
While there have been no proven medical or economic
benefits to screening asymptomatic women for EP, it is
likely that women who present to the ED will likely
have some particular symptom resulting in their presenta-
tion to the ED (61). Some patients may present atypically,
and not all patients will present with pelvic or abdominal
pain. Pain may not be present, and vaginal bleeding may
be the only symptom. A painless EP occurs rarely, but
even without pain, emergency providers should consider
EP in the differential diagnosis in women of childbearing
age who present with other symptoms of EP, such as
vaginal bleeding or diarrhea.
Myth 6: A Ruptured EP Cannot Be Possible if a Patient
Has a Low or Even Negative Serum or Urine b-hCG Test
A ruptured EP is an important diagnosis, as it can lead to
serious consequences, including hemorrhagic shock and
death (29,31). While higher b-hCG levels (> 5–10,000
mIU/mL) are more commonly seen in cases of ruptured
EP, a low or even negative b-hCG in the concerning
patient does not rule out potential rupture (62). Reports
have demonstrated cases of patients with ruptured EPs
with negative urine b-hCG tests or low or negative serum
b-hCG levels (29–31,45,63). Trends in hCG from patient
to patient will vary. One level is not predictive of ruptured
or non-ruptured EP (64). In addition, the false negatives
mentioned in Myth 4 may also contribute to the false-
negative findings seen in ruptured EPs (45).
A retrospective chart review of 693 pregnancies found
234 of these were EPs. Of these 234 EPs, 37.6% (n = 88)
ruptured and 62.4% (n = 146) were unruptured (63). Of
the ruptured EPs, 11.4% had serum b-hCG levels < 100
mIU/mL. Another 38.6% of the patients with ruptured
EPs had serum b-hCG levels of 100–999 mIU/mL (63).
There were wide ranges of b-hCG levels for unruptured
and ruptured groups, and the authors concluded that there
824
seemed to be no correlation between serum b-hCG levels
and tubal rupture. Rupture can occur even in cases with
low serum b-hCG levels (63).
In 2006, another study evaluated 183 surgically treated
tubal EPs, 75 of which were ruptured (64). Each patient
had her serum hCG level drawn before surgery. Overall,
no significant differences were found between groups.
As in the study mentioned, there was no specific pattern
to the hCG levels with broad ranges. In the ruptured group,
the b-hCG levels ranged from a high of 75,071 mIU/mL to
a low of 8 mIU/mL. The unruptured group was similar,
showing a high of 89,504 mIU/mL and a low of 15 mIU/
mL. Consequently, the authors conclude that there is no
lower limit in serum b-hCG levels for ruptured EP (64).
A ruptured EP can be a serious and deadly diagnosis.
However, it can also be a difficult diagnosis, as patients
may present with low or even negative b-hCG tests. In
a case report by Lee et al., a 25-year-old patient with
persistent negative serum b-hCG tests presented in
hemodynamic shock from an EP after having presented
previously to six various hospitals (31). Her diagnosis
was made via laparoscopy, demonstrating an EP in a uter-
ine tube (31). Other authors have reported similar cases of
patients with negative b-hCG tests presenting with hemo-
dynamic instability secondary to a ruptured EP (29,45).
Given the potential morbidity and mortality of a
ruptured EP, emergency providers should keep in mind
the rare but possible situation of ruptured EP with negative
or low hCG levels. While low or negative hCG tests are not
commonly seen in ruptured EP, it may be appropriate for
providers to consider the diagnosis in any female of child-
bearing age who is hemodynamically unstable and has
concerning history or symptoms. Just as in the myths
mentioned, hCG levels will vary in patients and are poor
predictors of EP. It is not recommended that one quantita-
tive hCG level be relied on to guide decision making,
including whether to obtain imaging (45,64).
Myth 7: Contraceptives, Including Tubal Ligation,
Intrauterine Devices, and Emergency Methods Are
Associated with More Ectopic Pregnancies Than Those in
the General Population
This statement is actually not a true myth but it is important
to mention that these methods, if taken properly, do not in-
crease a women’s risk of EP. Rather, the risk of EP is only
higher if the method fails (2,65). As compared to using no
contraception, female sterilization and intrauterine devices
(IUDs) actually reduce the risk of EP because they reduce
the risk of pregnancy overall. When used properly, the
same is true for emergency contraceptive methods
(2,65–67). It is important to remember IUDs and
sterilization decrease the overall risk of EP because they
reduce the absolute risk of pregnancy.
J. J. Robertson et al.
There has also been concern that emergency contracep-
tion, such as levonorgestrel, ulipristal acetate, and
mifepristone (not available in the United States), also
places women at risk for EP (68). While there have been
cases of EP in patients taking emergency contraception,
studies have shown low rates of EP after emergency
contraception, and it remains an effective method of pre-
venting pregnancy (66,68–72). A 2015 case-control study
found levonorgestrel to be an effective contraceptive,
while not increasing overall risk of EP. However, similar
to other contraceptive methods, the study demonstrated
that if pregnancy did occur, the risk of EP increased
(odds ratio 2.79; 95% confidence interval 2.27–3.43)
(68). A systematic review of 136 studies evaluated preg-
nancy rates after either mifepristone or levonorgestrel,
and it demonstrated low rates of EP (66). Of all cases of
failed contraception, the authors found a rate of 0.6% of
EP in the mifepristone group and 1% in the levonorgestrel
group. Compared to the general population, these rates do
not differ much from the average rate of EP (66). Finally,
of three clinical trials evaluating levonorgestrel emergency
contraception, one EP was found out of 67 women with
failed pregnancies (73–75).
The most recently approved emergency contraceptive
is ulipristal. According to clinical trials and post-
marketing data, no EPs were recorded after using ulipris-
tal acetate (69). In a later study evaluating ulipristal after
its debut in 2010, there were 376 pregnancies reported,
with 4 EPs (1.0%). The limitation to this is that all of
the data are self-reported. However, it does demonstrate
the small number of EPs reported in comparison to other
types of pregnancy outcomes (71).
Contraceptive tools are successful in preventing
pregnancy. When compared to not using contraception,
these methods may help prevent EP simply by preventing
pregnancy. Physicians should understand that failure of
these methods can lead to an increased risk of EP. Thus,
emergency providers should consider EP in patients
who are utilizing contraception and present with concern-
ing signs and symptoms.
Myth 8: The Majority of Patients with EP Have at Least
One Risk Factor That Predisposes to the Condition
The major risk factors for EP include disorders or proced-
ures that may result in fallopian tube damage (76,77).
Based on available literature, suspected risk factors for
EP include a history of tubal surgery or congenital tube
abnormalities, assisted reproductive technology, a history
of induced abortions, previous EP, older pregnancy age,
and pelvic inflammatory disease (PID) (63,78,79). While
women with risk factors are likely more prone to
developing EP, approximately 50% of EP cases are in
women without known risk factors (2,60,63).
Ectopic Pregnancy 825

Concern for EP based on

history and examination?

- Resuscitate with IV blood products

Unstable - Obtain Serum hCG, CBC, T&S
Assess hemodynamic status - Perform US: FAST for free fluid, with
focus on pelvic window and uterus
-Emergent OB/GYN consultation
Stable

Evaluate for other

- Concern for EP still No etiology for symptoms,
Urine hCG present or concern for consider other imaging
reliability of Urine hCG? (Pelvic US, CT)
Yes
+

Serum hCG Perform Pelvic US IUP

EP – Ectopic Pregnancy
IV – Intravenous No IUP
CBC – Complete Blood Cell Count
T&S – Type and Screen
US – Ultrasound
FAST – Focused Assessment with
Sonography for Trauma
OB/GYN – Obstetrics/Gynecology Yes
Is there strong suspicion of Consult OB/GYN for
CT – Computed Tomography EP OR is serum suspected EP
hCG > 1000-2000 mIU/mL?

No

Discuss with OB/GYN and

obtain follow up for patient
at 48 hours for repeat hCG
and US

Fig. 1. Algorithm for diagnosis and management of ectopic pregnancy.

In one retrospective study by Saxon and colleagues,
risk factors such as previous EP, previous PID, previous
IUD use, a history of infertility, or previous tubal ligation
or tubal surgery were evaluated in 693 EPs (ruptured and
unruptured). Overall, the authors found 57% of these
women had none of these risk factors (63). In addition,
33% had one risk factor, while 9.4% had two risk factors,
2.2% had three, and 0.7% had four of these risk factors.
Other authors have demonstrated similar results
(78,80,81). A recent retrospective analysis of 109
patients with known EP showed 53.21% of patients had
no known risk factors. These risk factors included
previous EP, history of tuboplasty or tubal ligation, a
history of infertility, PID, a history of abortion, or
history of pelvic surgery (78). Another study of 38
women found risk factors such as infertility, previous
EP, previous tubal surgery, and history of IUD use were
not present in 39.5% of the patients studied (80).
While patients with risk factors such as PID and a his-
tory of EP are at greater risk for EP, the absence of risk
factors is also not protective. Many women with EPs do
not have concerning histories. In patients with concerning
signs and symptoms without known risk factors for EP,
EP is still a possibility.
CONCLUSIONS
EP can be a challenging diagnosis and is commonly missed
on initial evaluation. Not all patients possess the classic
serum hCG DZ levels or demonstrate reliable b-hCG
trends. Rupture can occur at low b-hCG levels, and patients
with EP may even have initial negative urine pregnancy
tests. Patients may not present with adnexal pain, and not
all patients with EP will have a known risk factor. Knowl-
edge of several myths concerning US, hCG, risks factors,
and history and examination can provide assistance in
826
the evaluation of EP. Clinicians should consider these
myths when evaluating all women of reproductive age
who present with concerning signs and symptoms of EP,
including abdominal or pelvic pain, vaginal bleeding, or
hemodynamic instability of unknown etiology. Figure 1
may be helpful toward making the diagnosis when a patient
presents with concerning signs and symptoms of EP.
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828 J. J. Robertson et al.

ARTICLE SUMMARY
1. Why is this topic important?
Ectopic pregnancy (EP) is an important cause of
morbidity and mortality in women of reproductive age.
Patients may present to the emergency department with
concerning signs and symptoms, but may not demonstrate
all of the classic findings of EP on initial evaluation and
workup.
2. What does this review attempt to show?
This review attempts to show patients with EP may not
always show the classic findings on history or evaluation,
including lack of risk factors, abnormal serum b–human
chorionic gonadotropin (b-hCG) levels or trends, and ul-
trasound (US) findings that do not correlate with the
classic discriminatory zone levels.
3. What are the key findings?
This article describes some key findings in that patients
may still require an US even if their serum b-hCG levels
are under the discriminatory zone (DZ). In addition, a
pregnancy of unknown location (PUL) may still be viable,
even if the serum b-hCG level is greater than the DZ.
Serum b-hCG levels do not rise and fall predictively,
and urine pregnancy tests can be negative in a rare number
of patients with EP. Not all patients will present with pain
or have any known risk factors. Finally, contraceptives do
not increase absolute risk of EP.
4. How is patient care impacted?
In patients without abdominal pain or risk factors, the
clinician may still consider EP in the differential diag-
nosis. In addition, he or she may also consider ordering
US in patients who have serum b-hCG levels under the
DZ because findings can still be visualized. Thus, an
earlier diagnosis of EP can be made. In addition, patients
who are stable with PUL and levels greater than the DZ
may simply require further monitoring as a viable preg-
nancy may still be possible. Finally, patients can also be
counseled that contraception does not increase the abso-
lute risk of EP.