Clinical Expert Series

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Suspected Ectopic Pregnancy
Beata E. Seeber, MD, and Kurt T. Barnhart, MD, MSCE
Abstract: Women who present with pain and bleeding in the first trimester are at risk for ectopic
pregnancy, a life-threatening condition. Conditions that predispose a woman to ectopic
pregnancy are damaged fallopian tubes from prior tubal surgery or previous pelvic infection,
smoking, and conception using assisted reproduction. Many women without risk factors can
develop an ectopic pregnancy. A diagnostic algorithm that includes the use of transvaginal
ultrasonography, human chorionic gonadotropin (hCG) concentrations, and, sometimes, uterine
curettage can definitively diagnose women at risk in a timely manner. The absence of an
intrauterine pregnancy above an established cut point of hCG is consistent with an abnormal
pregnancy but does not distinguish a miscarriage from an ectopic pregnancy. When the initial
hCG value is low, serial hCG values can be used to determine whether a gestation is potentially
viable or spontaneously resolving. The minimal rise in hCG for a viable pregnancy is 53% in 2
days. The minimal decline of a spontaneous abortion is 2135% in 2 days, depending on the
initial level. A rise or fall in serial hCG values that is slower than this is suggestive of an ectopic
pregnancy. Women diagnosed with an unruptured ectopic pregnancy are potential candidates
for medical management with methotrexate. Intramuscular injection with methotrexate can be
used to safely treat an ectopic pregnancy with success rates, tubal patency rates, and future
fertility that are similar to those obtained with conservative surgery. Success rates using
methotrexate are inversely rated to baseline hCG values and are higher using multidose
compared with single-dose regimens. Surgical treatment may be conservative or definitive and
should be attempted in most cases via laparoscopy.
(Obstet Gynecol 2006;107:399413)
E
ctopic pregnancy, the implantation of a fertilized
ovum outside the endometrial cavity, continues to
be a major cause of morbidity and mortality in
reproductive-age women. It is estimated that about
2% of pregnancies in the United States are ectopic. If
undiagnosed and/or untreated, ectopic pregnancy
may result in rupture of the fallopian tube and
massive intraperitoneal hemorrhage, accounting for
about 9% of maternal pregnancy-related deaths in this
country.
1
Incidence
Between 1970 and 1992, a 6-fold increase was seen in
the number of ectopic pregnancies diagnosed in the
United States.
24
The cost of treatment for the 58,000
women needing hospitalization for ectopic pregnancy
in just one year, 1992, based on U.S. health care
statistics, was $1.1 billion.
5
Considering that many
more women are now treated with noninvasive sur-
gery and/or on an outpatient basis, it is difficult to
estimate the current number of annual ectopic preg-
nancies in the United States, as well as the cost of
treating the condition.
The prevalence of ectopic pregnancy appears to
be rising, in part because of earlier, more accurate
diagnosis of pregnancies. Further, an increased inci-
From the Department of Obstetrics and Gynecology, Penn Fertility Care,
Philadelphia, Pennsylvania; and the Center for Clinical Epidemiology, Univer-
sity of Pennsylvania, Philadelphia, Pennsylvania.
Corresponding author: Kurt T. Barnhart, MD, MSCE, PENN Fertility Care,
3701 Market Street, Suite 800, Philadelphia, PA 19003; e-mail:
KBarnhart@obgyn.upenn.edu.
2006 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/06
VOL. 107, NO. 2, PART 1, FEBRUARY 2006 OBSTETRICS & GYNECOLOGY 399
dence of sexually transmitted infections, earlier diag-
nosis of pelvic inflammatory disease resulting in tubal
damage but not complete blockage, and the rise in the
number of ectopic pregnancies resulting from assisted
reproductive technologies (ART) may account for the
overall increase. The advent of radioimmunoassay
(RIA) and specific antiserum to the -subunit of human
chorionic gonadotropin (hCG) has allowed for the ac-
curate quantification of -hCG and the ability to closely
follow trends in hormonal rise and fall.
6
Currently, hCG
is almost exclusively assayed by using chemolumines-
cence and third International Reference Preparation.
This standard is very similar to the original 1st Interna-
tional Reference Preparation.
Likewise, high resolution, transvaginal ultra-
sonography with Doppler flow imaging has improved
visualization of adnexal masses, including ectopic
pregnancies, at earlier gestational ages. As discussed
by Maymon and Shulman,
7
the incidence of tubal
pregnancy after oocyte retrieval/embryo transfer may
be as high as 4.5%, although this may be due to
already existing tubal pathology in these patients and
not solely to the ART intervention.
The incidence of heterotopic pregnancy is now
believed to be about 1:4,000 in the general population
and 1:100 in in vitro fertilization (IVF) pregnancies
much higher than the originally described prevalence
of 1:30,000 in the late 1940s.
7
This phenomenon may
be due to the increasing use of ovulation induction
agents that increase the chance of twinning and may
cause hormonal fluctuations affecting tubal motility,
and also due to the invasive nature of ART. Although
in the past the diagnosis of an intrauterine pregnancy
effectively ruled out an ectopic, it is important for
clinicians to be aware of the chances of a dual pregnancy
and thoroughly evaluate symptomatic patients.
Risk Factors
The risk factors for ectopic pregnancy were summa-
rized by Ankum et al
8
in a meta-analysis that included
36 prior studies. There is a strong association between
ectopic pregnancy and conditions that are thought to
impede the migration of the fertilized ovum to the
uterus. These include damage to the fallopian tube
from prior pelvic inflammatory disease, history of
ectopic pregnancy, and previous tubal surgery, in-
cluding previous tubal ligation. This same pathophys-
iologic mechanism of altered tubal integrity may be
the cause of an increased number of ectopic pregnan-
cies seen in patients with infertility or previous pelvic
surgery. Cigarette smoking (thought to affect tubal
motility), increasing age, and having more than one
lifetime sexual partner have also been weakly linked
to an increased risk of ectopic pregnancy. No clear
association has been documented between ectopic
pregnancy and oral contraceptive use, previous elec-
tive pregnancy termination, spontaneous miscarriage,
or cesarean delivery.
2,3
Women with an intrauterine
device in place and those who have undergone tubal
ligation are more likely to have an ectopic pregnancy
than an intrauterine one if conception occurs, but
their baseline risk of pregnancy is far lower than that
of women not using family planning.
9
Studies have not supported the theory that certain
embryo factors, for example ones found in abnormal
gestations, may lead to erroneous implantation at an
ectopic site. Karyotype analysis of excised tubal preg-
nancies has shown a rate of chromosomal abnormal-
ities comparable to that expected for the maternal and
gestational age of the cases.
10,11
More recent studies
have focused on molecular level factors, based on the
theory that alterations in the molecular dialog be-
tween the implanting blastocyst and the site of im-
plantation may make ectopic pregnancy more likely.
Some plausible candidates responsible for this cell-
cell and cell-extracellular matrix interaction include
lectin, integrin, matrix-degrading cumulus and their
inhibitors, prostaglandins, as well as a host of growth
factors, cytokines, and their receptors and modulator
proteins.
12,13
DIAGNOSTIC APPROACH
The symptoms of abdominal or pelvic pain and
vaginal bleeding in the first trimester of pregnancy are
the most common complaints suggestive of ectopic
pregnancy. The multiple potential sites of ectopic
pregnancies add to the complexity of the diagnosis
(Fig. 1). These symptoms may be erratic and variable,
and, in some cases, absent. Likewise, such symptoms
are nonspecific and also have been associated with
spontaneous miscarriage, cervical irritation or
trauma, and infection. Therefore, patients may delay
reporting these symptoms to their physicians.
2,14
On
physical examination, hypotension and tachycardia
with rebound tenderness and guarding alert the clini-
cian to likely tubal rupture with immediate need for
surgical intervention. However, the majority of pa-
tients present with less severe symptoms and more
subtle signs on examination. For these patients, early
diagnosis is imperative. In fact, for those with a high
risk of ectopic pregnancy, some clinicians advocated
screening as soon as these women report a positive
pregnancy test.
15
However, because of the high false-
positive rate of screening,
16
there is little medical
economic benefit to screening asymptomatic women,
and we do not do so in our practice.
400 Seeber and Barnhart Suspected Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
Steps to Diagnosis
The diagnostic work-up for ectopic pregnancy re-
quires the exclusion of a normal intrauterine preg-
nancy, bearing in mind the incidence of heterotopic
pregnancy of about 1 in 4,000 (Fig. 2). For gestations
greater than 5
1
2 weeks, a transvaginal ultrasound
examination should identify an intrauterine preg-
nancy with near 100% accuracy.
17
Because of the
inaccuracies of pregnancy dating, -hCG is often used
as a surrogate for gestational age. Sequentially, struc-
tures become visible by transvaginal ultrasonography,
including a gestational sac (double decidual sign at
4
1
25 weeks after the last menstrual period), yolk sac
(at 5 weeks), and fetal pole with later cardiac motion
(at 5
1
26 weeks). A pseudosac is a collection of fluid
within the endometrial cavity that occurs due to
bleeding from the decidualized endometrium when
an extrauterine gestation is present. Although it may
sometimes be mistaken for a gestational sac, it can be
distinguished from one by its central location, filling
the endometrial cavity itself. However, the identifica-
tion of a presumed pseudosac on ultrasonography
should not be interpreted as diagnostic of ectopic
pregnancy because it has been shown to have a high
false-positive rate for ectopic pregnancy diagnosis.
18
Discriminatory Cutoff
Critical to the diagnosis and management of sus-
pected ectopic pregnancy is the concept of the dis-
criminatory cutoff of -hCG. This cutoff is defined as
that level of -hCG at which a normal intrauterine
pregnancy can be visualized by ultrasonography with
sensitivity approaching 100%.
19
Although the concept
was originally established using abdominal ultra-
sonography, it is now widely accepted that, above the
discriminatory cutoff of 1,5002,500 IU/L, using
transvaginal ultrasonography, a normal intrauterine
pregnancy should always be visualized. The absence
of such implies an abnormal gestation.
24
The discriminatory cutoff should be set by each
institution based on that hospitals success in correctly
identifying ectopic pregnancies, based mostly on
equipment used and expertise of the sonographers.
Varying the discriminatory cutoff will affect the sen-
sitivity (positively identifying an ectopic gestation)
and specificity (correctly excluding an ectopic when
none exists) for diagnosis. Some clinicians may
choose a low discriminatory cutoff, for example a
-hCG of 1,500 IU/L. Such a cutoff would have high
sensitivity for ectopic but at the cost of low specificity.
This increases the possibility of misclassifying a de-
veloping intrauterine pregnancy as an abnormal ges-
tation. Conversely, some clinicians may choose a high
discriminatory cutoff, for example a -hCG of 3,000
IU/L. In this situation a clinician would be provided
with extra reassurance that lack of visualization of
an intrauterine pregnancy did not miss an early viable
gestation. Using this approach, however, may delay
the diagnosis of ectopic pregnancy, decreasing the
initial sensitivity and resulting in the possibility of
Fig. 1. Possible anatomic sites
in ectopic pregnancies. Illustra-
tion: John Yanson.
Seeber. Suspected Ectopic
Pregnancy. Obstet Gynecol 2006.
VOL. 107, NO. 2, PART 1, FEBRUARY 2006 Seeber and Barnhart Suspected Ectopic Pregnancy 401
rupture. In our view, it is better to set the discrimina-
tory cutoff high, especially in a population of stable
patients who maintain close medical follow-up. Such
a principle would minimize the risk of interrupting a
viable pregnancy, a very costly error, at the expense
of initially delaying the diagnosis of a woman with an
ectopic pregnancy by a few days.
Human Chorionic Gonadotropin Above
Discriminatory Cutoff
If no intrauterine pregnancy is visualized above the
discriminatory cutoff, we strongly advocate evacuat-
ing the contents of the uterus to differentiate an
abnormal intrauterine gestation (spontaneous abor-
tion) from an ectopic pregnancy. This management is
based on findings that the presumption that an ec-
topic pregnancy exists when there is no evidence of
an intrauterine pregnancy by ultrasonography and
the -hCG is above the discriminatory cutoff is incor-
rect in up to 54% of cases.
20
Similarly, diagnosing an
ectopic pregnancy based solely on serial -hCG levels
that are declining abnormally below the discrimina-
tory zone is inaccurate in up to 31% of cases.
20
Following the evacuation of the uterus, if intra-
uterine chorionic villi are not confirmed by patho-
logic examination, then treatment for ectopic preg-
nancy needs to be instituted. Alternatively, if
pathological examination is not available at the time
of tissue procurement, then the patients -hCG may
be checked approximately 1224 hours later. If the
level does not drop significantly on the day after
uterine evacuation, then an extrauterine gestation is
diagnosed. We use a drop of 15% as the minimal
needed but normally see a much steeper drop if the
pregnancy tissue has been successfully removed.
A technique to identify villi, such as floating tissue
in saline solution, is not as accurate as microscopic
examination, with data showing that the surgeon was
Fig. 2. Diagnostic algorithm for ectopic pregnancy.
Seeber. Suspected Ectopic Pregnancy. Obstet Gynecol 2006.
402 Seeber and Barnhart Suspected Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
only able to identify villi in this manner in about 50%
of cases.
21
To definitively confirm resolution of the
pregnancy in the absence of tissue diagnosis, -hCG
values should be followed at least weekly until unde-
tectable, a process that may take up to several weeks.
Currently we perform a dilation and curettage (D&C)
or a manual vacuum extraction because these are the
only reliable methods of determining the presence of
intrauterine products of conception. Office endome-
trial biopsy has been demonstrated not to be helpful
in the discrimination of a miscarriage from an ectopic
pregnancy.
22
Human Chorionic Gonadotropin Below
Discriminatory Cutoff
If the initial -hCG is below the discriminatory zone,
then serial -hCG measurements are needed to docu-
ment a growing (potentially viable) or a nonviable
pregnancy. The minimum rise for a potentially viable
pregnancy that presents with pain and/or vaginal bleed-
ing is 53%, based on the 99th percentile confidence
interval (CI) around the mean of the curve of -hCGrise
over time.
23
This curve was derived from data from 287
subjects with vaginal bleeding or pain complicating an
early pregnancy. These women were followed with
serial -hCG levels until an intrauterine pregnancy was
confirmed. Intervention for a -hCG rise of less than
66% over 2 days, a practice supported by previous data,
would potentially result in the interruption of many
viable pregnancies.
2426
Ultrasonography should be
used to document the presence, or absence, of an
intrauterine pregnancy when the -hCG levels have
risen above the discriminatory zone.
If the -hCG does not rise appropriately, or
declines, a nonviable pregnancy has been diagnosed.
A rapid decline in -hCG value is consistent with a
miscarriage that may resolve spontaneously. If the
-hCG does not fall 2135% in 2 days (depending on
the initial value), the presence of an ectopic preg-
nancy should be suspected.
27
These figures were
derived from standard curves for expected -hCG
decline for gestations subsequently confirmed to have
resulted in completed spontaneous abortion. These
were based on data from over 700 women whose
-hCG was falling and who were subsequently diag-
nosed with a miscarriage. The 90% CIs around the
mean for the curves were used to define the minimal
decline.
Definitive Diagnosis
In the absence of definitive ultrasound diagnosis of an
ectopic pregnancy, we strongly feel that the new
guidelines for minimal rise and fall of -hCG as
described above should be used in the diagnostic
work-up of ectopic pregnancy. These guidelines are
based on recent data from large numbers of women
and use conservative confidence intervals to minimize
the error of misdiagnosing an intrauterine pregnancy
as abnormal. More than 70% of women who have an
ectopic pregnancy will have a rise in hCG that is
slower than the minimal rise for a viable pregnancy or
a decline that is slower than the minimal rate of fall in
a spontaneous abortion (Fig. 3). However, there are
cases when the rise, or fall, in serial hCG values can
mimic that of a viable gestation or completed miscar-
Fig. 3. Hypothetical illustration of
the rise, or fall, of serial hCG values
in women with an ectopic preg-
nancy. A total of 71% of women
with an ectopic pregnancy (EP) will
have a rise in hCGslower than the 1
percentile of women with a viable
intrauterine pregnancy (IUP) and
slower than the 90% for women
with a spontaneous completed mis-
carriage (SAB). However, 21% of
ectopic pregnancies have an hCG
rise that mimics an intrauterine
pregnancy; 8% have a fall in hCG
similar to a spontaneous completed
miscarriage.
Seeber. Suspected Ectopic Pregnancy.
Obstet Gynecol 2006.
VOL. 107, NO. 2, PART 1, FEBRUARY 2006 Seeber and Barnhart Suspected Ectopic Pregnancy 403
riage. In these cases, the use of ultrasonography and the
serial evaluation of patients symptoms are paramount.
A rise (or fall) in -hCG of less than the value
described above strongly suggests an abnormal preg-
nancy but does not distinguish a miscarriage from an
ectopic pregnancy. A D&C or manual vacuum extrac-
tion should be used to obtain tissue diagnosis of
products of conception, differentiating an abnormal
intrauterine pregnancy from an ectopic pregnancy
before subsequent management.
20
Erroneous Use of Methotrexate
Unless a definitive diagnosis of an ectopic pregnancy is
made, the use of methotrexate as medical therapy
should not be undertaken. The use of methotrexate in
circumstances where the patient actually has a miscar-
riage may unnecessarily expose the woman or the
embryo to a chemotherapeutic agent. Moreover, the
presumptive treatment of a woman with an abnormal
pregnancy of unknown location with methotrexate in-
stead of first performing a D&C to obtain tissue diagno-
sis does not reduce the complications or cost of treat-
ment.
28
Such management is in concordance with the con-
clusion of a decision analysis by Gracia and Barnhart.
17
Using a hypothetical cohort of 10,000 women and
previously published probabilities for pregnancy out-
come, these authors compared 6 diagnostic strategies
commonly employed in the evaluation of patients with
suspected ectopic pregnancy. The strategies included
the use of different combinations of serial physical
examination, -hCG, ultrasonography, and progester-
one level.
19,2932
They found that the best strategy was
transvaginal ultrasound examination performed on all
women presenting with symptomatic pregnancy. If the
ultrasound examination was nondiagnostic, then -hCG
should be measured. With this algorithm, no ectopic
pregnancies were missed, few potential intrauterine
pregnancies were interrupted, and a timely diagnosis
was achieved.
Progesterone
The use of serum progesterone levels to diagnose
ectopic pregnancy is still debated. Although it has
been shown that progesterone levels are higher in
intrauterine pregnancies than in ectopics, there is no
well-established upper cutoff to use to discriminate
between the two.
33
A recent meta-analysis of 26
studies examined the accuracy of single serum pro-
gesterone measurement and concluded that, although
serum progesterone measurement can identify pa-
tients at risk for ectopic pregnancy, this test alone is
insufficient to diagnose ectopic pregnancy with cer-
tainty.
33
Algorithms using progesterone can be prob-
lematic because they are associated with some missed
ectopic pregnancies, especially among high-risk wom-
en.
20
A study evaluating the diagnostic accuracy of 5
gynecologists to correctly identify ectopic pregnancies
out of a cohort of pregnancies of unknown location
using -hCG and progesterone (48 hours apart) re-
sulted in misdiagnoses of 35% of ectopic pregnan-
cies.
34
A low progesterone level of less than 5 ng/mL
can rule out a normal pregnancy with almost com-
plete certainty (99.8% accuracy) but does not discrim-
inate between an abnormal intrauterine gestation and
an ectopic pregnancy.
32
For these reasons, we do not
use progesterone levels in our diagnostic algorithm.
Novel Diagnostic Methods
The search for novel methods for the diagnosis of
ectopic pregnancy with the most precision continues.
The goal of such research is to develop a serum-based
test that relies on placental or pregnancy-specific
markers. Elevated levels of vascular endothelial
growth factor (VEGF) have been described in ectopic
gestations and have been noted 11 days after embryo
transfer during IVF cycles in ectopic gestations, but
with rather low predictive values.
35,36
Other putative
markers have included pregnancy-associated plasma
protein A (PAPP-A), pregnancy-specific B1-glycopro-
tein, human placental lactogen, and hCG, as well as
the nonplacental markers, glycodelin, VEGF, and
progesterone.
37
One study found that a combination
of VEGF, PAPP-A, and progesterone was able to
discriminate ectopic pregnancy from intrauterine
pregnancy with 97.7% sensitivity and 92.4% specific-
ity, although this discriminative power was lower for
early gestations. Gerton et al
38
set out to identify
serum markers of ectopic pregnancy with a proteomic
approach. In a publication of some preliminary find-
ings, they were able to identify several proteins that
may potentially discriminate between an ectopic
pregnancy and an intrauterine pregnancy. The next
step requires the characterization of these proteins.
Such promising results now require validation in a
prospective population. Other markers that have
been considered, but do not appear useful in the
clinical setting at this point, include creatinine kinase,
fetal fibronectin, leukemia inhibitory factor, smooth
muscle heavy-chain myosin, and CA 125.
3945
Modeling Risk
As an alternative approach, investigators have at-
tempted to optimize the diagnosis of women at risk
for ectopic pregnancy by using decision rules and
mathematical models.
46
Condous et al,
47
using logistic
404 Seeber and Barnhart Suspected Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
regression models to predict outcome of pregnancies
of unknown location, found that a model based on the
-hCG ratio at 0 and 48 hours was best at predicting
subsequent outcomes of a pregnancy with an initial
unknown location. However, with a minimum rise of
66% over 48 hours needed to classify a pregnancy as
an intrauterine pregnancy, those women whose
-hCG level rose more slowly would have been
misclassified with an abnormal gestation. Conversely,
there are cases of ectopic pregnancy whose -hCG
curve mimics that of an intrauterine pregnancy, with
a rapid initial rise giving erroneous reassurance that
an ectopic pregnancy is absent.
THERAPEUTIC APPROACH
The primary goal of accurate and early diagnosis of
ectopic pregnancy is to limit morbidity and eliminate
mortality resulting from this condition. If diagnosed
early, at a clinically stable state, the patient with an
ectopic pregnancy is a likely candidate for either
minimally invasive surgery or medical therapy. These
treatment modalities have been shown to have suc-
cess rates comparable to the gold-standard treatment
of laparotomy with salpingectomy, but with the poten-
tial benefit of fallopian tube conservation. Laparotomy is
still the mainstay of therapy for hemodynamically un-
stable patients with high suspicion of tubal rupture.
48
Methotrexate
Medical treatment with methotrexate (MTX) has be-
come a safe and effective means of treating ectopic
pregnancy without the risks associated with surgery. It
was first introduced as a novel therapy for ectopic
pregnancy in 1982. In many centers and among many
clinicians, it has become the primary treatment. The
goal of medical management with MTX is to selec-
tively kill the cytotrophoblasts, the rapidly dividing
cells at the fallopian tube implantation site. The body
will then spontaneously resorb the remaining prod-
ucts of conception and blood clot that constitute the
ectopic pregnancy. It is important for clinicians who
use this chemotherapeutic agent to be well versed
with its mechanism of action, dosing regimens, and
adverse effects.
Methotrexate belongs to the class of drugs called
folic acid antagonists.
49
Initially used for treating
leukemia, it gained wide use in gynecology for the
treatment and cure of choriocarcinoma.
50
Methotrex-
ate acts by inactivating the enzyme dihydrofolate
reductase (DHFR), leading to depletion of the cofac-
tors required for DNA and RNA synthesis. Leucov-
orin, a folinic acid, has been used as a rescue
medication that allows for higher MTX dose adminis-
tration by preventing some of the otherwise prohibitive
adverse effects.
50
Leucovorin enters cells via a carrier-
mediated system and does not require reduction by
DHFR for conversion to active folate cofactors, prevent-
ing some of the adverse effects of methotrexate.
49
Methotrexate may be administered orally, intra-
muscularly, intrathecally, or by continuous infusion.
For the treatment of ectopic pregnancy, the intramus-
cular injection is preferred, although there have been
reports of success with the oral route.
51
It may be used
as primary treatment, treatment of persistent ectopic
pregnancy after salpingostomy, prophylaxis for sus-
pected persistent products of conception after conser-
vative surgery, and in cases of unusually located
ectopic pregnancies. If large MTX doses are used, as
in a multidose regimen to be discussed below,
leucovorin rescue should be used to salvage normal
cells and prevent cell toxicity. The 2 most common
regimens employed for the treatment of ectopic preg-
nancy are the multidose protocol and the single-
dose administration.
Methotrexate Dosing Regimens
The multidose regimen administers MTX as the
sodium salt (1 mg/kg per day intramuscularly) on
days 1, 3, 5, and 7; leucovorin as a calcium salt (0.1
mg/kg intramuscularly) is given on days 2, 4, 6, and 8.
Patients are given up to 4 doses (1 MTX, 1 leucov-
orin) until the -hCG decreases by at least 15% on 2
consecutive days
52
(Table 1). A second course after
one week may be given if there is an increase or
plateau in 2 consecutive -hCG values (Table 1).
A single-dose regimen was introduced to enhance
patient compliance and simplify administration. The
single-dose regimen uses 50 mg/m
2
given by intra-
muscular injection after calculating the patients body
surface are, and does not use leucovorin rescue.
Although called single-dose, under this protocol, a
second dose may be administered after 1 week if
-hCG values do not decline by at least 15% between
days 4 and 7 after treatment (Table 2). Using the
single-dose protocol, approximately 20% of women
require more than one treatment cycle.
54
It is difficult
to predict which patients may need more than a single
MTX dose.
Regardless of the MTX regimen used, patients
need to be followed weekly with surveillance -hCG
after their treatment until -hCG is undetectable in
serum. This is the only way to confirm complete
resolution of the ectopic pregnancy. It is important to
be aware that ectopic pregnancies may cause tubal
rupture even when the -hCG levels are on their way
down.
56,57
This may also be the case in situations
VOL. 107, NO. 2, PART 1, FEBRUARY 2006 Seeber and Barnhart Suspected Ectopic Pregnancy 405
where MTX has already been administered for treat-
ment. Specifically, in situations where the -hCG
increased at least 66% over 48 hours before MTX
administration and in cases where the -hCG contin-
ues to rise after MTX administration, the tubal rup-
ture risk may be as high as 20%.
58
Effectiveness of Methotrexate
The overall effectiveness of MTX was reviewed by
Pisarska et al.
4
Based on 12 studies with at least 20
patients each, the authors concluded that MTX treat-
ment has been shown to be successful in 7896% of
selected patients, that posttreatment hysterosalpingo-
gram-documented tubal patency approached 78%,
and that 65% of patients who attempted a subsequent
pregnancy succeeded, with a 13% incidence of recur-
rent ectopic pregnancy. Hajenius et al
59
confirmed the
comparable effectiveness of MTX therapy and lapa-
roscopic salpingostomy in the only randomized, pro-
spective trial published on the subject.
Single Dose Versus Multidose
Single-dose MTX therapy has been advocated by
some authors as preferable to the multidose proto-
col.
6062
However, these 2 regimes have never been
directly compared. Although there have been no
randomized trials directly comparing the 2 treatment
protocols, they were compared in a recent meta-
analysis by our group. Barnhart et al
63
included data
from 26 articles that met their search criteria, review-
ing 1,327 cases of women diagnosed with ectopic
pregnancy who were treated with MTX. They found
that the overall success rate for the use of methotrex-
ate was 89%. Considering each regimen separately,
the success rate of multidose therapy was 92.7%,
with a 95% CI of 8996%; for single-dose, 88.1 %,
Table 1. Multidose Methotrexate Protocol
Treatment
Day Lab Test Intervention
Pretreatment -hCG, CBC with differential,LFTs,
creatinine, type, and screen
Rule-out SAB
RhoGAM if Rh negative
1 -hCG MTX 1.0 mg/kg
2 LEU 0.1 mg/kg
3 -hCG MTX 1.0 mg/kg if 15% decline day 1 to day 3. If -hCG 15%,
stop treatment and start surveillance.*
4 LEU 0.1 mg/kg
5
-hCG MTX 1.0 mg/kg if 15% decline day 3 to day 5. If -hCG 15%,
stop treatment and start surveillance.*
6 LEU 0.1 mg/kg
7 -hCG MTX 1.0 mg/kg if 15% decline day 5 to day 7. If -hCG 15%,
stop treatment and start surveillance.*
8 LEU 0.1 mg/kg
CBC, complete blood cell count; LFTs, liver function tests; SAB, spontaneous completed miscarriage; MTX, methotrexate; LEU,
leucovorin.
* Surveillance: -hCG should be checked every 7 days until -hCG 5.
Data from Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993;168:175965.
53
Table 2. Single-Dose Methotrexate Protocol
Treatment
Day Lab Test Intervention
Pretreatment -hCG, CBC with differential,LFTs,
creatinine, type, and screen
Rule out SABRhoGAM if Rh negative
0 -hCG MTX 50 mg/m
2
IM*
4 -hCG
7 -hCG MTX 50 mg/m
2
IM

If -hCG 15%, decrease day 4 to day 7.

If 15%, stop treatment and start surveillance.

CBC, complete blood cell count; LFTs, liver function tests; SAB, spontaneous completed miscarriage; MTX, methotrexate; IM,
intramuscularly.
* Dose calculated by body surface area using nomogram.

Surveillance: -hCG should be checked every 7 days until -hCG 5.

Data from Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51:4358
52
; and
from Stovall TG, Ling FW, Gray LA. Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol
1991;77:74953.
55
406 Seeber and Barnhart Suspected Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
with a 95% CI of 8690%, a statistically significant
difference. Importantly, when the frequency of failure
was compared, controlling for initial hCG value and
the presence of embryonic cardiac activity, the failure
rate with single-dose therapy was almost 5 times
greater (odds ratio [OR] 4.75, 95% CI 1.7712.62).
Success and failure were calculated for each protocol
on an intention-to-treat basis, regardless of whether
one dose was used in the multidose protocol or
multiple doses were given as part of the single-dose
protocol. The frequency of actual dosing with the 3
protocols was also recorded, with 15% of patients
under a single-dose protocol actually receiving more
than one dose of methotrexate. Conversely, under the
multidose protocol, 54% of patients actually re-
ceived 4 or more doses, while 10% received only 1,
23% received 2, and 14% received 3.
The above findings are consistent with other
review papers that have examined the success of
single-dose MTX administration and found a range
of success between 64% and 89%. However, not all
the studies included in these reviews accounted for
how many subjects required more than one MTX
dose, making the exact success rate imprecise.
64,65
These findings about actual dosing support the idea
that the ideal dosing regimen may lie somewhere in
between these 2 protocols. A new protocol giving 2
doses of MTX (on day 1 and day 4) without leucov-
orin rescue and using the follow-up of the single-dose
protocol may more optimally balance convenience
and efficacy. Ultimately, the success of any medical
management regime should be compared with the
conservative surgical approach of laparoscopic salpin-
gostomy, whose failure rate ranges from 3% to 20%.
6
Medical management with MTX is reserved for
compliant patients who agree to return for follow-up.
They should be hemodynamically stable, with no
evidence of active bleeding, especially hemoperitone-
um.
2
Relative contraindications, as outlined by the
American College of Obstetricians and Gynecologists
(ACOG), are a gestational sac 3.5 cm or greater and
embryonic cardiac motion.
66
Absolute contraindica-
tions are listed in the box
6
, Absolute Contraindica-
tions to Medical Therapy With Methotrexate. Before
receiving her first MTX dose, a woman should be
screened with a complete blood count, liver function
tests, and electrolyte panel, especially serum creati-
nine. If she has a history of pulmonary disease, she
should have a chest X-ray because of the risk of
interstitial pneumonitis reported in patients with un-
derlying lung disease. When using the multidose
protocol, the above laboratory studies should be
repeated 1 week after the last dose of MTX. The
patient should discontinue folic acid supplements and
prenatal vitamins.
Predictors of Success
The most commonly identified predictors of success-
ful MTX treatment of ectopic pregnancy include
initial serum -hCG level, progesterone level, size
and volume of the gestational mass, presence or
absence of cardiac activity, and presence or absence
of free peritoneal blood.
64
Of these, -hCG levels are
most predictive. Tawfiq et al
67
found that treatment
failure occurred in 65% of cases when the -hCG
level was greater than 4,000 IU/L, compared with
7.5% when the level was less than 4,000 IU/L. Potter
et al
68
found that the median pretreatment serum
-hCG level was lower in women in whom treatment
was successful compared with women with treatment
failures (793 versus 3,802 mIU/mL). Elito et al
69
found greater success with lower -hCG level (espe-
cially 1,500 mIU/mL). A recent review of 350
women treated with single-dose MTX for ectopic
pregnancy found that the only factor that contributed
significantly to the failure rate was serum-hCG level
before treatment.
70
Above 5,000 mIU/mL, the failure
rate rose to about 13%. However, there is no absolute
level at which medical management is contraindi-
cated. We currently use the multidose protocol or the
new 2-dose protocol to treat women with a hCG
above 1,000 mIU/mL.
Post-Methotrexate Follow-up
It is important that both patients and physicians are
aware of the course of the ectopic pregnancy after
MTX treatment. Thirty-three to almost 60% of pa-
Absolute Contraindications to Medical
Therapy With Methotrexate
Breastfeeding
Overt or laboratory evidence of
immunodeficiency
Alcoholism, alcoholic liver disease, or other
chronic liver disease
Preexisting blood dyscrasias, such as bone
marrow hypoplasia, leukopenia,
thrombocytopenia, or significant anemia
Known sensitivity to methotrexate
Active pulmonary disease
Peptic ulcer disease
Hepatic, renal, or hematologic dysfunction
Adapted from American College of Obstetricians and Gynecologists.
Medical Management of Tubal Pregnancy. ACOG Practice Bulletin 3.
Washington, DC: ACOG; 1998.
VOL. 107, NO. 2, PART 1, FEBRUARY 2006 Seeber and Barnhart Suspected Ectopic Pregnancy 407
tients may experience an increase in abdominal pain
67 days after receiving the medication.
6,64,70
This
pain is often referred to as separation pain because it
is believed to result from tubal abortion or hematoma
formation with distention of the fallopian tube.
71
The
majority of these patients can be treated conserva-
tively with pain medications and close follow-up and
do not require surgical intervention. Surgery should
be undertaken if there is evidence of tubal rupture
with bleeding, as evidenced by declining hemoglobin
levels or ultrasound visualization. As previously dis-
cussed, the -hCG level may plateau, or even rise,
before it begins to fall. This phenomenon may be
explained by the fact that, although MTX arrests
mitosis in the cytotrophoblasts, the syncytiotropho-
blast continues to increase and produces hormone.
72
Similarly, ultrasound examination may show an in-
crease in the ectopic size and possibly an increase in
vascularity before resolution. According to Atri et al,
73
increases in ectopic size were not associated with
failure of treatment. Therefore, it is not necessary to
follow patients with serial ultrasound examinations
once they have received MTX treatment because
ultrasound findings would not alter management un-
less a new tubal rupture is seen. Signs of treatment
failure risking possible tubal rupture are summarized
in the box, Signs of Treatment Failure and/or Tubal
Rupture.
Methotrexate for Extratubal Ectopics
Methotrexate has also been used for ectopic pregnan-
cies located outside the fallopian tube, for example
cervical, interstitial, ovarian, or abdominal gestations.
Methotrexate is often considered a first-line treatment
in these complicated pregnancies because of the
difficulty and risk of surgical resection. Although
experience with MTX use for cervical ectopic is
limited, one review included 36 women treated with
systemic MTX, local injection of MTX or potassium
chloride (KCl), or a combination of these therapies
and found an 8090% success rate.
74
The estimated
success rate for medical treatment of interstitial preg-
nancy is 83%.
75
Medical treatment of the rare ovarian
ectopic has also been undertaken with success.
76
Multiple studies have suggested that systemic MTX
administration considerably reduces costs when com-
pared with surgical treatment.
5,7781
Complications of Methotrexate
Methotrexate, like most medications, has adverse
effects. As a folic acid analogue, MTX affects rapidly
dividing cells, especially those of the gastrointestinal
tract and the bone marrow. Consequently, the major
adverse effects include impaired liver function, stoma-
titis, gastritis-enteritis, and bone marrow suppres-
sion.
2,6
Hemorrhagic enteritis of the intestinal tract
leads to nausea, vomiting, stomatitis, elevated liver
enzymes, weight loss, and bloody diarrhea.
2
Destruc-
tion of bone marrow blood precursors puts patients at
risk of developing thrombocytopenia, reticulocytope-
nia, lymphopenia, and granulocytopenia. Thrombo-
cytopenia predisposes patients to life-threatening
hemorrhage and lymphopenia and granulocytopenia
that predispose patients to systemic infections. There
is also the potential for nephrotoxicity, interstitial
pneumonitis, alopecia dermatitis, and an anaphylactic
reaction.
49,82,83
Fortunately, the adverse effects reported with
MTX use for ectopic pregnancy have mostly been
minor and the medication has been well tolerated.
Stovall et al
55
reported on the adverse effects of 100
patients treated with the multidose regimen; 2 pa-
tients had stomatitis and 3 had elevated liver
transaminases, all of which spontaneously resolved.
In a follow-up study of 120 patients receiving a
single-dose regimen, one patient was reported to have
nausea and vomiting.
53
In their meta-analysis, Barn-
hart et al
63
reported the prevalence of adverse effects
of about 3040% using the single-dose and mul-
tidose regimens, finding no difference between the
two once they adjusted for -hCG values (Table 3). A
summary of adverse effects and treatment effects of
methotrexate administration are listed in the box,
Adverse Effects Associated With Methotrexate
Treatment.
Surgical Resection
Historically, laparotomy with tubal excision (salpin-
gectomy) was not only the treatment for ectopic
pregnancy but often the diagnostic procedure as well.
Today, with the advent of ultrasonography for diag-
nosis and laparoscopy for treatment, the minimally
Signs of Treatment Failure and/or Tubal
Rupture
Significantly worsening abdominal pain,
regardless of change in -hCG levels
Hemodynamic instability
Levels of -hCG that do not decline by at least
15% between day 4 and day 7 postinjection
Increasing or plateauing -hCG levels after the
first week of treatment
Adapted from American College of Obstetricians and Gynecologists.
Medical Management of Tubal Pregnancy. ACOG Practice Bulletin 3.
Washington, DC: ACOG; 1998.
408 Seeber and Barnhart Suspected Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
invasive approach has become the preferred surgical
approach. Laparotomy is reserved for cases of exten-
sive intraperitoneal bleeding with intravascular com-
promise due to active bleeding, where hypovolemic
shock must be prevented. In such cases, laparotomy
via a Pfannenstiel incision allows prompt access to the
pelvic structures and identification of the ectopic
pregnancy. Other situations in which the open surgi-
cal approach may be preferable include extensive
pelvic adhesions where adequate visualization of the
ectopic is impossible or extra-tubal, intra-abdominal
ectopic gestations where risk of injury to other pelvic
structures is high.
Compared with open surgery, the laparoscopic
approach has been associated with a decreased surgi-
cal blood loss, a decrease in the amount of analgesic
used, and shorter postoperative hospital stay.
8486
Not
only has the laparoscopic approach been shown to be
safe and effective, it is also less costly.
87
Salpingostomy Versus Salpingectomy
Removal of the ectopic pregnancy can be accomplished
by resection of the involved fallopian tube with the
implanted trophoblastic tissue (salpingectomy) or by
dissection and removal of only the ectopic pregnancy
with tubal conservation (salpingostomy). Segmental re-
section of the involved tube with subsequent reanasto-
mosis and tubal reconstruction has fallen out of favor
because of the success of bypassing the fallopian tube
altogether by using in vitro fertilization. If conservation
of the fallopian tube resulted in improved future repro-
ductive success with an equal success rate of treatment of
the ectopic pregnancy, then we would recommend
salpingostomy for all patients. However, the data to
support this contention are not clear-cut. Yao and
Tulandi
6
reviewed the data from 9 studies to examine
the reproductive outcomes after salpingostomy and sal-
pingectomy. The follow-up period in these studies
ranged from3 months to 15 years. Although the approx-
imately 50%subsequent intrauterine pregnancy rate was
similar in patients who had been treated with salpingos-
tomy and those treated with salpingectomy, the rate of a
subsequent ectopic appeared higher in the salpingos-
tomy group (15% versus 10%). Other studies have
suggested a higher intrauterine pregnancy rate in
women after salpingostomy (almost double that of sal-
pingectomy), but at the cost of a 2-fold risk of recurrent
ectopic after 3 years of follow-up.
33
Another recent study
found a high rate of successful pregnancy after salpin-
gostomy (88%) compared with salpingectomy (66%),
with an equal recurrent ectopic rate of about 16%after at
least 18 months of follow-up and, in some cases, up to 8
years posttreatment.
88
The concern with conservative treatment via
salpingostomy is that of the persistence of tropho-
blast tissue due to incomplete removal from the
fallopian tube. This problem has been reported as
complicating about 520% of cases treated with
tubal conservation.
8991
It has been reported as
being higher in those patients treated with laparos-
copy than with laparotomy.
6
It is, therefore, very
Adverse Effects Associated with
Methotrexate Treatment
Drug Adverse Effects
Nausea
Vomiting
Stomatitis
Gastric Distress
Dizziness
Severe neutropenia (rare)
Reversible alopecia (rare)
Pneumonitis
Treatment Effects
Increase in abdominal pain
Increase in hCG levels during first 13
days of treatment
Vaginal bleeding or spotting
Adapted from American College of Obstetricians and Gynecologists.
Medical Management of Tubal Pregnancy. ACOG Practice Bulletin 3.
Washington, DC: ACOG; 1998.
Table 3. Prevalence of Adverse Effects From Use of Single-Dose and Multidose Regimens
Single Dose
[% (95% CI)]
Multidose
[% (95% CI)] Crude OR Adjusted OR*
Adverse effect 31.3 (27.335.6) 41.2 (34.847.8) 0.44 (0.310.63) 0.79 (0.213.01)
Abdominal pain 21.5 (18.025.4) 25.6 (19.232.8) 0.80 (0.531.19) 1.11 (0.831.47)
Hospital admissions 12.4 (10.214.8) 11.0 (7.215.9) 1.11 (0.831.47) 1.02 (0.651.58)
OR, odds ratio; CI, confidence interval.
* Adjusted for actual hCG value given in original articles.
Adapted from 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;101:77884.
63
VOL. 107, NO. 2, PART 1, FEBRUARY 2006 Seeber and Barnhart Suspected Ectopic Pregnancy 409
important to document a complete resolution of the
ectopic pregnancy by monitoring the -hCG values
until they return to zero. Levels that fail to drop, or
ones that plateau, indicate a likely persistent ec-
topic pregnancy that should be treated. This can be
accomplished successfully in almost all cases where
tubal rupture is not present by the administration of
MTX, with a single dose usually being sufficient.
Some clinicians elect to give the MTX immediately
after salpingostomy as a prophylactic measure
against persistent tissue, especially in cases where
incomplete resection is more probable.
92,93
Very
early gestations, ectopic pregnancies less than 2 cm
in size, and those with high starting -hCG levels
are at increased risk of persistence.
93
The decision to perform a salpingostomy as
opposed to a salpingectomy is often made intraop-
eratively. In cases of tubal rupture or obvious
severe damage, tubal conservation is not indicated.
Likewise, if tubal bleeding is encountered that
requires extensive coagulation to achieve hemosta-
sis, then future tubal function would likely be
compromised, and salpingectomy may be the ap-
propriate intervention. Recurrent ectopic preg-
nancy in a previously incised tube should also be
treated with salpingectomy.
Complications of Surgery
Complications of surgical treatment of ectopic preg-
nancy include the usual operative risk factors as well
as those associated with anesthesia. Postoperative
adhesion formation is more likely after laparotomy
than laparoscopy.
94
Postoperative adhesion formation
may be reduced by minimizing desiccation and ma-
nipulation of pelvic and abdominal structures during
surgery, as well as by using barrier agents such as
oxidized regenerated cellulose (Interceed; Johnson
and Johnson Medical, New Brunswick, NJ).
95
FOLLOW-UP
Reproductive Outcome
Because ectopic pregnancy occurs mostly as a result
of fallopian tube pathology, there is a substantial risk
of recurrence, both at a previously operated tubal site
and in the contralateral tube. Thus, women who have
undergone salpingectomy still have an increased risk
of developing an ectopic pregnancy in the remaining
tube.
The risk of recurrent ectopic pregnancy after
MTX treatment is similar to that after salpingostomy,
about 10%.
96,97
Butts et al
98
found that the risk of a
recurrent ectopic pregnancy increased with a history
of surgery, history of live birth, and history of spon-
taneous miscarriage, and not with history of gonor-
rhea, chlamydia, pelvic inflammatory disease, cesar-
ean delivery, or pregnancy termination. They also
found that patients with a recurrent ectopic pregnancy
were less likely to bleed on initial presentation, had
similar complaints of pain, and like primary ectopic
patients, the majority had nondiagnostic initial ultra-
sound evaluations.
Tubal patency after MTX treatment is best as-
sessed with hysterosalpingography (HSG), and this
has been compared with patency after conservative
surgery. Stovall
97
summarized the results of his
groups studies. Although we do not know the pre-
treatment tubal patency rates, 58 women of 100 study
participants who had received multidose MTX for an
ectopic pregnancy underwent HSG, and of these,
84.5% had tubal patency and 89.7% had at least one
patent tube. After single-dose MTX therapy, 62 pa-
tients underwent HSG, with 82.3% showing ipsilateral
tubal patency. Hajenius et al
59
found that ipsilateral
tubal patency was equal in the groups of patients
treated with MTX and salpingostomy. However, they
found much lower overall patency rates, 62% in the
MTX group and 66% in the salpingostomy group,
compared with previous reports.
One group from Sweden followed 89 women
who had been treated for ectopic pregnancy with
expectant management, MTX, or salpingostomy and
found that an equal number in each group had an
intrauterine pregnancy within 2
1
2 years. Of those who
had been treated with MTX, 64% attained a pregnan-
cy.
99
Dias Pereira et al
100
found that the cumulative
spontaneous intrauterine pregnancy rate at 18 months
posttreatment for ectopic was 36% in the MTX group
and 43% in the laparoscopic salpingostomy group, a
difference that was not statistically significant.
Reproductive outcome after a previously treated
ectopic pregnancy appears to be similar, whether the
treatment method had been MTX or conservative
surgery. Intrauterine pregnancy rates seem to be
comparable in both of these groups, with a possible
slightly lower risk of recurrent ectopic seen in the
medically treated group.
101
Women who have had a previous ectopic preg-
nancy should be followed closely during their subse-
quent pregnancy to ensure its proper site of implan-
tation. However, even among a population of women
at increased risk for ectopic, screening them with
transvaginal ultrasonography and performing -hCG
testing when they are asymptomatic does not appear
to have much benefit in decreasing morbidity.
16
410 Seeber and Barnhart Suspected Ectopic Pregnancy OBSTETRICS & GYNECOLOGY
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