Incidence, Diagnosis and Management of Tubal and Nontubal Ectopic Pregnancies: A Review

Panelli et al.
Fertility Research and Practice (2015) 1:15

DOI 10.1186/s40738-015-0008-z
REVIEW Open Access
Incidence, diagnosis and management of tubal

and nontubal ectopic pregnancies: a review
Danielle M. Panelli1*, Catherine H. Phillips2 and Paula C. Brady1
Abstract
Background: Ectopic pregnancy is a potentially life-threatening condition occurring in 1-2 % of all pregnancies. The
most common ectopic implantation site is the fallopian tube, though 10 % of ectopic pregnancies implant in the
cervix, ovary, myometrium, interstitial portion of the fallopian tube, abdominal cavity or within a cesarean section scar.
Findings: Diagnosis involves a combination of clinical symptoms, serology, and ultrasound. Medical management is a
safe and effective option in most clinically stable patients. Patients who have failed medical management, are
ineligible, or present with ruptured ectopic pregnancy or heterotopic pregnancy are most often managed with
excision by laparoscopy or, less commonly, laparotomy. Management of nontubal ectopic pregnancies may involve
medical or surgical treatment, or a combination, as dictated by ectopic pregnancy location and the patient's clinical
stability. Following tubal ectopic pregnancy, the rate of subsequent intrauterine pregnancy is high and independent
of treatment modality.
Conclusion: This review describes the incidence, risk factors, diagnosis, and management of tubal and non-tubal
ectopic and heterotopic pregnancies, and reviews the existing data regarding recurrence and future fertility.
Keywords: Ectopic pregnancy, Nontubal ectopic pregnancy, Heterotopic pregnancy
Findings uniformly require intervention and will not be included in

An ectopic pregnancy (EP) refers to the implantation of this review [2–4].
an embryo outside of the uterus. Due to advances in la- This review will describe the incidence, risk factors,
boratory testing, transvaginal ultrasound, chemotherapy diagnosis and management of women with tubal and
and laparoscopy, the evaluation, diagnosis and manage- nontubal EPs, as well as review the existing literature
ment of EP has rapidly evolved. In parallel, maternal regarding their future fertility.
mortality has declined, from 3.5 of 10,000 pregnancies in
1970 to 2.6 of 10,000 in 1992 [1]. Review
The most common EP location is in the fallopian tube, Incidence
predominantly the ampullary region of the fallopian tube. The overall rate of EP is 1–2 % in the general population,
Implantation outside the fallopian tube—in the cervix, and 2–5 % among patients who have utilized assisted
ovary, myometrium, abdominal cavity, interstitial (i.e., reproductive technology (ART) [5, 6]. Although the over-
intramuscular/proximal) portion of the fallopian tube or all mortality has decreased over time, ruptured EPs still
coincidentally with an intrauterine pregnancy—occurs in account for up to 6 % of all maternal deaths; a review of
less than 10 % of EPs. Heterotopic pregnancy (HP) refers mortality in ART-associated EPs similarly reported a mor-
to the coexistence of an intrauterine pregnancy with an EP tality rate of 31.9 deaths per 100,000 pregnancies [5, 7].
in any of these locations. ‘Cornual’ pregnancies are those Nontubal EPs are pregnancies that implant at sites other
implanted in a horn of an anomalous uterus (i.e., unicornu- than the fallopian tube. These pregnancies account for less
ate, bicornuate, didelphys or septate uteri); these do not than 10 % of all EPs, though their overall incidence has
been increasing in recent years [5]. Furthermore, nontubal
* Correspondence: dpanelli@partners.org EPs contribute disproportionately to maternal morbidity
1
Department of Obstcpetrics and Gynecology, Brigham and Women’s
Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA and mortality in comparison to tubal EPs. Cervical EPs are
Full list of author information is available at the end of the article estimated to occur in 1:2000 to 1:18,000 pregnancies [8].
© 2015 Panelli et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Panelli et al. Fertility Research and Practice (2015) 1:15 Page 2 of 20
The estimated incidence of cesarean scar EPs is 1:1800 to tubal function and ectopic pregnancy, though more re-
1:2216 pregnancies, or 6 % of all EPs in women with at search is needed to clarify these pathways [28–30].
least one cesarean delivery [9, 10]. Interstitial EPs account Inflammation in the fallopian tubes is also implicated in
for 4 % of EPs, though the associated morbidity is much the establishment of EP, by inducing tubal dysfunction or
higher, with mortality rates of 2.5 % or 7 times the mortal- damage that may lead to retention of an oocyte or
ity rate associated with other EP locations, largely due to embryo, and by promoting embryo implantation in the
hemorrhage [11, 12]. Pregnancies embedded within the fallopian tube via inflammatory cytokines [31]. Following
myometrium (intramural EPs) account for an estimated tubal damage by smoking or infection, upregulation of
1 % of EPs [13]. Abdominal pregnancies account for 1.3 % pro-inflammatory cytokines has been noted, promoting
of EPs [14]. These have been classified as primary or sec- embryo receptivity, invasion and angiogenesis in the tube.
ondary; secondary abdominal EPs are theorized to result For instance, interleukin 1 (IL-1), produced by tubal
from extrusion from the fallopian tube and subsequent epithelial cells following Chlamydia trachomatis infection,
intraabdominal reimplantation [15]. Most common im- is a vital signal for embryo implantation in the endomet-
plantation sites are in the pouches posterior and anterior rium; IL-1 also recruits neutrophils downstream, leading
to the uterus and on the serosa of the uterus and adnexa; to further tubal damage [32]. Macrophages and intrae-
retroperitoneal, omental, bowel, hepatic and splenic im- pithelial lymphocytes are also increased in women with
plantations have also been reported [16]. EP, potentially affecting tubal function and predisposing to
Estimates of the incidence of heterotopic pregnancy tubal EP [33–35].
(HP) vary by article and decade; the risk has been reported
from 1:4000 to 1:30,000 women in the general population Clinical risk factors
[5, 17]. The risk of HP following in vitro fertilization (IVF) Up to 50 % of women diagnosed with EPs have no iden-
has been estimated as high as 1:100 women [5, 17, 18]. tifiable risk factors; however, a number of risk factors
HPs can include an EP in any of the previously described have been associated with EP [5]. These include age,
locations; a triplet HP that included tubal and cervical EPs smoking, history of EP, tubal surgery or tubal damage,
has even been described [19]. The majority are tubal HPs; prior pelvic infection, DES exposure, IUD use and preg-
in a review of 80 cases of HP in the literature, 66 (72.5 %) nancy conceived by assisted reproduction.
were in the ampullary or interstitial portion of the fallo- Age has been shown to be a risk factor for EP, with the
pian tube, while 7 were cervical and 3 were implanted in highest incidence over the age of 35 in both spontaneous
the cesarean scar [17]. pregnancies and those conceived after assisted reproduct-
ive technologies [7, 36]. The explanation for this observa-
Etiology of tubal ectopic pregnancy tion is unknown, however age is theorized to affect tubal
The fallopian tube is a carefully controlled environment to function, including delay of oocyte transport [36, 37].
facilitate oocyte transport, fertilization, and migration of Prior EP is a strong risk factor for recurrent EP, with a
the early embryo to the uterus for implantation [20] Most recurrence rate of 5–25 %, or up to 10 times the risk in
data suggest tubal EP stems from both abnormal embryo the general population [38–40]. Prior treatment for EP,
transport and an alteration in the tubal environment, whether medical or surgical, may result in pathologic
which enables abnormal implantation to occur [21]. changes in tubal motility, ciliary function and uterine
The transport of an oocyte and embryo through the tube contractions [41]. (For fertility outcomes after prior EP,
relies on both smooth muscle contraction and ciliary beat- please see “Recurrence and future fertility”).
ing, which are affected by several local factors—toxic, infec- Smoking is thought to increase the risk of EP by caus-
tious, immunologic and hormonal. Smoking and infection ing tubal dysfunction, including deciliation [22]. To-
have been shown to decrease cilia density, while ciliary beat bacco may cause dysregulation of the paracrine signals
frequency has been shown to be responsive to the changing needed for coordinated embryo transport and develop-
hormonal milieu of the menstrual cycle [22–24]. Samples ment [21]. In a retrospective review of 481 IVF cycles,
of fallopian tube epithelium incubated in estradiol (E2) and the likelihood of a tubal EP was three times higher
nitric oxide (NO) have been found to demonstrate in- among smokers [41]. A dose-dependent relationship be-
creased ciliary motility, which may cause aberrant tubal tween smoking and EP has also been confirmed in spon-
transport [25, 26]. NO also affects smooth muscle contract- taneous pregnancies [36].
ility in the fallopian tube; expression of NO has been found A history of pelvic infection or pelvic inflammatory
to vary during the menstrual cycle, with possible implica- disease is associated with increased risk for subsequent
tions for normal and ectopic implantations [27]. Finally, EP. Chlamydia trachomatis in particular has been impli-
E2-mediated effects via estrogen receptors on gene regula- cated as a risk factor for EP, with the risk increasing with
tion and expression—including pathways implicated in im- each successive infection; ascending infection and result-
plantation and apoptosis—may be involved in aberrant ant salpingitis is thought to lead to tubal dysfunction
and aberrant implantation [5, 21, 42, 43]. Other infec- following IVF, the rate of EP following fresh cycles rose
tions potentially associated with pelvic inflammatory significantly from 1.7 % following single embryo transfer
disease and tubal damage include Neisseria gonorrhoeae, to 2.5 % following the transfer of 4 embryos [7]. Depth of
Mycoplasma and schistosomiasis [44, 45]. transfer may also have an effect; a randomized prospective
Prior tubal surgeries, including but not limited to tubal study of deep versus mid-fundal transfer reported an EP
reanastamosis, salpingostomy, tuboplasty and lysis of ad- rate of 1.5 versus 0.4 % [57]. Day of embryo transfer has
hesions, are risk factors for EP. Similarly, any causes of inconsistently been associated with risk of EP in prior
pelvic adhesions, including endometriosis, appendicitis, studies. A series of 13,654 fresh cycles reported an EP rate
or other pelvic surgeries, may distort the anatomy of the of 2.1 % following day 3 embryo transfers, as compared to
fallopian tube [46, 47]. The risk of EP after tubal reanas- a rate of 1.6 % following day 5 embryo transfers, which did
tamosis, specifically, is estimated at 2–13 %, and is simi- not reach statistical significance [58]. Conversely, a review
lar between abdominal and robotic approaches [6, 48]. of 1994 fresh transfers reported a significant difference in
After surgical sterilization, the failure rate across all ectopic pregnancy rates between day 3 and day 5 transfers,
sterilization methods is estimated at 18.5 per 1000, at 2.4 and 1.7 %, respectively [59].
approximately one-third of which are EPs [49]. Women The transfer of fresh embryos is associated with a higher
sterilized before 30 years of age are twice as likely to EP risk as compared to the transfer of thawed embryos;
have subsequent EPs as those sterilized after age following 15,042 fresh cycles, the EP rate was 1.97 %,
30 years. Rates of EP vary by sterilization technique: which was significantly higher than the 1.01 % EP rate
After bipolar coagulation, 65 % of pregnancies are EP, following 12,752 cryopreservation cycles [55]. It is theo-
while after unipolar or clip sterilization, approximately rized that the controlled ovarian hyperstimulation and
15 % of pregnancies are EP [50]. The proportion of EP hyperestrogenic environment preceding a fresh embryo
has been shown to be three times higher between 4 and transfer negatively effects endometrial receptivity [60].
10 years after sterilization, as compared to the first
3 years [49]. Risk factors for nontubal EP
Current IUD use dose not predispose to EP, though a Overall, the risk factors for ovarian EPs, interstitial EPs,
higher proportion of pregnancies conceived with an IUD and tubal HPs are similar to those for tubal pregnancy.
in place are ectopic as compared to the general popula- These include a history of a prior EP, pelvic infections and
tion [43, 51]. Among pregnancies conceived with IUDs use of in vitro fertilization [61]. The transfer of four or
in place, half are ectopic with a levonogestrel device in more embryos during IVF is an additional risk factor for
place, compared to 1:16 with a copper IUD in place [52]. HP [18, 62]. IUD use may be a risk factor for nontubal EP,
Overall, any contraceptive use decreases the risk of both particularly for ovarian EP [63]. An additional risk factor
intrauterine and ectopic pregnancy. for interstitial implantation includes prior ipsilateral sal-
Assisted reproductive technologies constitute a risk fac- pingectomy, with interstitial ectopic pregnancies occur-
tor for EP, as 2–5 % of pregnancies from assisted repro- ring up to 13 years after salpingectomy [4]. Risk factors
ductive technologies are ectopic [7]. The three main for other specific types of nontubal EPs are outlined in the
factors contributing to this increased risk are the specific following subsections.
type of procedure, the reproductive health characteristics
of the woman, and the estimated embryo implantation po-
tential [21, 53]. A history of infertility, even in the absence Intramural EP
of known tubal disease, is associated with EP, with the EP Risk factors for these rare EPs are theorized to include
risk increasing with a longer duration of infertility [18, 43]. myometrial injury following uterine curettage, and prior
Tubal factor infertility specifically is associated with a two- myomectomy or cesarean section [13]. Assisted repro-
fold risk of EP following IVF [52, 54, 55]. ductive technologies have been used in approximately
Several IVF cycle parameters may be associated with 20 % of case reports, and another 19 % of patients car-
an increased risk of EP. Patients undergoing cycles trig- ried a diagnosis of adenomyosis.
gered with gonadotropin releasing hormone (GnRH)
agonists instead of recombinant hCG may be at higher Cesarean section EP
risk of EP; in a review of 466 IVF cycles, GnRH agonist Risk for cesarean scar implantation is not clearly corre-
triggers were associated with a significantly higher EP lated to the number of prior cesarean sections [64]. Risk
rate (5.3 % versus 1.4 % following hCG triggers). This for cesarean section scar implantation has not been cor-
finding is theorized to be due to poor endometrial recep- related to single versus double layer closure of the hys-
tivity following GnRH agonist administration [56]. terotomy at the time of cesarean section. Cesarean scar
The number of embryos transferred may be correlated implantation may be more common following cesarean
to the EP risk; in a review of 9480 ectopic pregnancies sections for elective indications, which is theorized to be
due to impaired healing of an unlabored lower uterine hCG levels. Obtaining a third β-hCG and early ultra-
segment [65]. sound decreased the misclassification of IUP to 2.7 % [73].
The expected rates of β-hCG rise and decline are the same
Cervical EP for multiple pregnancies, following assisted reproduction,
A history of dilation and curettage (D&C) in a previous and in obese patients [74]. The absolute β-hCG values,
pregnancy has been associated with subsequent cervical however, may be higher in multiple pregnancies or lower
EP; this risk factor is present in nearly 70 % of cases in patients with elevated body mass index.
[66, 67] In-vitro fertilization has been proposed as a
risk factor, but often coincides with D&C and other Serum progesterone
possible risk factors, so is difficult to isolate as an inde- Serum progesterone has been explored as a possible serum
pendent contributor to risk [68]. marker for nonviable pregnancies, including EPs, as pro-
gesterone levels have been shown to be lower in ectopic
Abdominal pregnancy and failing pregnancies than IUPs [75]. Several studies sug-
Risk factors for abdominal pregnancy are similar to those gest a progesterone cut-off of 10 nanograms per milliliter
for tubal EPs, including pelvic inflammatory disease, use (ng/mL) for the most accurate identification spontaneous
of assisted reproductive technologies and endometriosis EPs. In a meta-analysis including 4689 patients under
[69]. Most abdominal pregnancies have been published in 14 weeks gestational age with pain and/or bleeding, a
case reports; one details the occurrence of a twin preg- serum progesterone level of less than 10 ng/mL predicted
nancy implanted in the broad ligament after IVF. Uterine a non-viable pregnancy with a sensitivity of 66.5 % and spe-
perforation was suggested as a possible cause as the em- cificity of 96.3 % [76]. The optimal cut-off may be higher in
bryo transfer was performed using a stylet, which is more patients who received fertility treatments, as these patients
rigid than standard transfer catheters [70]. often have multiple corpora lutea secreting progesterone
and often receive exogenous progesterone. A cut-off of
Diagnosis 30 ng/mL, 28–49 days after the last menstrual period, may
Serum beta-human chorionic gonadotropin (β-hCG) be more appropriate in patients who received clomiphene
The diagnosis of EP often begins with the preliminary citrate, while an optimal cut-off has yet to be identified in
diagnosis of pregnancy of unknown location (PUL). PUL patients after IVF and is likely highly dependent on the
is defined as a positive serum beta-human chorionic number of days since embryo transfer [77, 78].
gonadotropin (β-hCG) in the absence of ultrasound find- Serum progesterone levels, however, have been shown
ings indicative of intrauterine or extrauterine pregnancy. to misclassify more normal pregnancies than serial β-hCG
Approximately 30 % of patients with PUL will develop measurements [79]. Serum progesterone also cannot fur-
an ongoing intrauterine pregnancy (IUP), while the ther distinguish between miscarriages and EPs. While pro-
majority (50–70 %) will be diagnosed with failing preg- gesterone may highlight patients at greater risk for EP, it is
nancies, either miscarriages or EPs [71]. insufficient in itself to discriminate between IUPs, miscar-
In the stable patient, measurement of β-hCG is crucial riages and EPs [80].
to clarify pregnancy location and prognosis. Produced pri-
marily by the syncytiotrophoblast in the placenta, β-hCG Other serum markers
is detectable in the blood by the second week of preg- Several studies have explored alternative serum markers
nancy until a peak at 10–12 weeks [72]. A single measure of EP, focusing on proteins associated with placental,
of β-hCG is insufficient to clarify pregnancy prognosis, endometrial and/or corpus luteal functions, angiogen-
and serial β-hCG levels are commonly used to monitor esis and inflammation [75]. These potential proteins
early pregnancies. The most recent recommendations for include, but are not limited to: Inhibin A, which is
β-hCG trends in early pregnancy, derived from a retro- produced by the corpus luteum; activin A, pregnancy-
spective review of 1005 patients with PUL, suggest the associated plasma protein-A (PAPP-A) and A Disinte-
minimum β-hCG rise of an IUP is 35 % in 2 days [73]. A grin and Metalloprotease-12 (ADAM-12) which are
β-hCG rise less than 35 % in 2 days has a positive predict- generated by the placenta; and vascular endothelial growth
ive value of 96.2 %, a negative predictive value of 69.7 %, factor (VEGF), which, produced by a variety of cell types,
and an overall accuracy of 80.2 % in predicting EP. is crucial for angiogenesis and may be upregulated in EP
Conversely, in this study, in patients eventually diag- [75]. Various messenger and micro-RNA—regulators of
nosed with miscarriages, the minimum expected β- downstream gene expression—may also be differentially
hCG decline in 2 days is 36–47 % (depending on the expressed by an EP [81, 82].
starting β-hCG level). Β-hCG cut-offs, however, are not Studies have also attempted to combine multiple mea-
ironclad; using these cut-offs, 16.8 % of EPs and 7.7 % sures; one such study incorporated VEGF, PAPP-A, and
of IUPs would be misclassified solely using serial β- progesterone, and reported sensitivity of 97.7 % and
specificity of 92.4 % in diagnosing EP, though this model shown a significant difference in endometrial stripe thick-
has not been validated in further studies [83]. For many ness between miscarriages and EPs [89]. Endometrial
of these markers, studies are inconclusive, and for all stripe thickness may indicate patients at higher risk for
markers, more research is needed before any of these abnormal pregnancies but cannot reliably be used in isola-
supplants β-hCG as the primary serologic method of tion to diagnose EP [90].
differentiating intra- and extrauterine pregnancies [81]. A small amount of anechoic free fluid in the posterior
cul de sac is normal in both intra- and extrauterine preg-
nancies [91]. Larger amounts of complex free fluid, par-
Imaging
ticularly in Morrison’s pouch by the liver, may indicate
Discriminatory zone
rupture of an EP, and correlates well to hemoperitoneum
Visualization of a gestational sac by transvaginal ultra-
observed intraoperatively [91, 92]. Hemoperitoneum can
sound (TVUS), confirming an intrauterine pregnancy
be assessed in the emergency setting using a Focused
(IUP), is expected at serum β-hCG levels above the “dis-
Assessment with Sonography for Trauma (FAST) scan,
criminatory zone.” The discriminatory zone was initially
which is a bedside ultrasound assessing for free fluid in the
proposed as 6500 milli-international units (mIU)/mL in
perihepatic, perisplenic and pelvic space; the full trauma
1981, using transabdominal ultrasound [84]. With ad-
assessment, not applicable to patients with suspected EP,
vances in ultrasound imaging, particularly with the use
also includes the pericardial space [93]. The determination
of transvaginal sonography, the discriminatory zone has
of extent of hemoperitoneum and need for intervention
been lowered to 1000 to 2000 mIU/mL [85].
depends on clinician assessment and the patient's
Studies report that normal IUPs may still develop in
hemodynamic stability. Of note, if an ultrasound shows an
patients with PULs and serum β-hCGs above the dis-
IUP, the risk of EP is much reduced, though not zero.
criminatory zone. In a review of patients with PUL,
Though rare, the patient may still be at risk of heterotopic
nine women with β-hCGs above 2000 mIU/mL at the
pregnancy, particularly following IVF [94].
time of their TVUS developed intrauterine pregnancies;
the highest β-hCG in this group was 4336 mIU/mL
Ultrasound diagnosis of tubal EP
[86]. In patients with multiple pregnancies, the serum
In women presenting with bleeding or pain, pregnancy
β-hCG at which an intrauterine gestational sac is seen can
location is often not definitively visualized on the initial
be higher than the discriminatory zone identified for
ultrasound at presentation; however, diagnosis of EP by
singleton IUPs. One review reported a serum β-hCG of
ultrasound is possible when following careful guidelines.
9083 mIU/mL without definitive ultrasound findings in a
Identification of a gestational sac and fetal pole, with or
patient later diagnosed with a triplet pregnancy [87].
without cardiac activity, or a hyperechoic ring—called
Other factors such as obesity or uterine fibroids may also
the ‘bagel’ or ‘tubal’ sign (Fig. 1)—with circumferential
be associated with nonvisualization of an intrauterine
Doppler flow (Fig. 2) is highly suggestive of an ectopic
gestational sac above the β-hCG discriminatory zone.
pregnancy [95, 96]. If a suspicious mass moves separ-
Serum β-hCG in the absence of definitive ultrasound
ately from the ovary—called the ‘blob’ sign - the positive
findings should not be the sole factor in diagnosing
predictive value is above 90 % in a symptomatic woman
pregnancy location or viability or dictating management,
with a positive serum b-hCG and no IUP on transvaginal
and that gestational age must be taken into account. A
ultrasound [97, 98].
positive pregnancy test at any level in the absence of an
intrauterine pregnancy should be approached as an EP
Ultrasound findings specific to nontubal EPs
until proven otherwise.
Ectopic pregnancies occurring in less common anatomic
areas can also be identified by ultrasound according to
Accessory ultrasound findings specific criteria. Diagnostic criteria of each type of nontu-
In the absence of definitive visualization of an EP, additional bal ectopic pregnancy are discussed below. All of these
markers on ultrasound can increase a clinician’s suspicion diagnostic criteria assume the absence of a visualized IUP.
for EP, and may be useful in conjunction with other clinical Ultrasound criteria for diagnosis of an interstitial ec-
data. These include a thin endometrial stripe thickness and topic pregnancy include a gestational sac at least 1 cm
the presence of intraabdominal free fluid. lateral to the edge of the uterine cavity, with a thin
In a review of 591 patients with vaginal bleeding and (5 mm or less) layer of overlying myometrium surround-
PUL, IUPs had a significantly higher mean endometrial ing it (Figs. 3 and 4) [99, 100]. An ‘interstitial line’ may
stripe thickness than miscarriages or EPs (17 mm versus also be seen (Fig. 5) [101].
12 mm, respectively); no intrauterine pregnancies oc- A cervical EP is identified on ultrasound by a distended
curred in patients with endometrial stripes below 8 mm in cervical canal containing a gestational sac with peripheral
thickness [88]. However, studies have not consistently Doppler flow (Fig. 6), below a closed internal cervical os
Fig. 3 Interstitial ectopic pregnancy by transvaginal ultrasound. The

arrow indicates thin (<5 mm) myometrium overlying the ectopic
pregnancy. This finding by ultrasound, in combination with the
lateral location of the gestation, has a reported specificity of 88-93 %
but a sensitivity of just 40 % [101].
absent between the gestational sac and the bladder (Fig. 8).
A negative ‘sliding organ’ and the presence of peripheral
Doppler flow are expected [9].
Fig. 1 Tubal ectopic pregnancy by transvaginal ultrasound. The arrow
indicates the ectopic gestation with a surrounding hyperechoic ring,
On ultrasound or MRI, intramural EPs should be com-
called the ‘bagel’ or ‘tubal’ sign pletely surrounded by myometrium circumferentially, with
no communication with the intrauterine cavity [69, 105].
Intramural EPs are notoriously challenging to diagnose on
[102, 103]. The ‘sliding organ’ sign, or movement when ultrasound and have been mistaken for fibroids or intra-
pressure is applied with the transvaginal probe, is associ- uterine pregnancies [106].
ated with spontaneous abortions in progress and should Ovarian EPs may be suspected by ultrasound when
be absent in a cervical ectopic pregnancy. a hypoechogenic area is seen surrounded by a wide
Diagnostic criteria for a cesarean scar EP by ultrasound
include visualization of the gestational sac at the site of the
prior hysterotomy (Fig. 7), outside the endometrial cavity
[104]. The myometrium should be very thin (1–3 mm) or
Fig. 4 Interstitial ectopic pregnancy by magnetic resonance imaging,

Fig. 2 Tubal ectopic pregnancy by transvaginal ultrasound. The arrow T1 weighted. The arrow indicates thin (<5 mm) myometrium overlying
indicates the ectopic gestation with circumferential Doppler flow, called the ectopic pregnancy. In a stable patient, MRI may be useful in the
the “Ring of Fire” confirmation of interstitial pregnancy location
Fig. 5 Interstitial ectopic pregnancy by transvaginal ultrasound. The Fig. 7 Cesarean scar ectopic pregnancy by transvaginal ultrasound.
arrow indicates the ‘interstitial line,’ extending from the endometrium The arrow shows the gestational sac implanted in the region of the
to the cornua, abutting the suspicious mass cesarean scar, clearly outside the endometrial canal
echogenic ring with peripheral Doppler flow. Some may be evidence of more common ectopic implantation sites,
completely surrounded by ovarian cortex. [106, 107] A fetal such as the fallopian tubes or cesarean section scar [110].
pole is seldom present [107]. When pressure is applied
with the transvaginal probe, an ovarian EP will move with Endometrial sampling
the ovary, and should be connected to the uterus by the At many medical centers, a patient with a PUL and an
ovarian ligament [107, 108]. These EP can be difficult to abnormal β-hCG trend as described above may receive
differentiate from ovarian cysts, which may have a similar methotrexate (MTX) without precise diagnosis [111]. Up
appearance and peripheral Doppler flow [108]. Given the to 40 % of these patients, however, may ultimately have
difficulty of making this diagnosis by imaging, laparoscopy failing IUPs, unnecessarily exposing these patients to
is often required for definitive diagnosis [107]. MTX [112]. While not universally employed, endomet-
Abdominal EP is rare, and ultrasound guidelines are rial sampling may allow these patients to avoid unneces-
few. Suggested guidelines include visualization of an extra- sary treatment with MTX [113].
uterine gestational sac, fetus and/or placenta, with no Identification of villi on endometrial sampling is diagnos-
myometrium seen between the fetus and urinary bladder tic of a failed IUP, and in such cases, no further treatment
[109]. This gestational sac or fetus will be in unusually is usually needed [5, 114, 115]. Serum β-hCG should also
close proximity to the anterior abdominal wall, and may be checked the day after endometrial sampling; a decline
be surrounded by loops of bowel. There should be no of 15–20 % after sampling indicates the disruption of a
Fig. 6 Cervical ectopic pregnancy by transvaginal ultrasound. Doppler

shows circumferential flow. The arrow indicates Doppler flow inside the
gestational sac, associated with the embryo. Such Doppler flow will not Fig. 8 Cesarean scar ectopic pregnancy by transvaginal ultrasound.
be found in a spontaneous abortion, which may slide down into a The arrow indicates the thin myometrium (3 mm) between the bladder
similar position at the cervix (indicated with the number 1) and the gestational sac
failing IUP, even if no villi are identified [5]. A postopera- dividing cells and, in an EP, disrupts primarily tropho-
tive plateau or increase in the β-hCG value strongly sug- blastic tissue [131]. Its use as treatment for EP was first
gests an EP. A patient with an adequate decrease in the β- reported in 1982 [132]. The most common side effects
hCG level after sampling can be monitored with serial β- associated with MTX treatment for EP include pelvic
hCG measurements until levels are undetectable, or until pain, nausea, headaches, abdominal pain, and dermatitis.
pathological evaluation of the curettage specimen shows Less common side effects include mucositis, diarrhea, and
chorionic villi [116]. alopecia [127, 133].
The standard endometrial sampling method for PUL Several studies have demonstrated the efficacy of
is D&C, though these are associated with greater cost intramuscular (IM) MTX for treatment of EP, though
and anesthesia requirement than outpatient procedures success rates are inversely correlated to β-hCG levels
[112, 117, 118]. Endometrial biopsy pipelles, while [134]. In a meta-analysis including 503 women with EPs
effective in screening for endometrial carcinoma, have treated with single dose MTX, successful treatment,
insufficient sensitivity and specificity to replace D&C in defined as avoidance of surgery, for initial β-hCG levels
the diagnosis of PUL [119, 120]. Karman cannulas, at- between 1000 and 1999 mIU/mL was 94.4 %, compared
tached to hand-held suction devices, are as efficacious with just 81.8 % in patients with starting β-hCG levels of
as D&C for diagnosing endometrial pathology and are 10,000 to 150,000 mIU/mL [134]. A β-hCG above 5000
frequently used for the evacuation of first trimester mIU/mL was proposed as a relative contraindication to
pregnancies in the outpatient setting [121–124]. In a re- treatment with MTX, with a success rate of just 85 %.
view of 45 patients with PUL and abnormal β-hCG
trends after IVF, over two-thirds of patients were diag- Pre-methotrexate assessment
nosed with failing IUP by final pathology and/or falling Before treatment with MTX, blood work should be ob-
β-hCG, and were spared MTX [116]. It is unknown tained to assess hematologic, hepatic and renal function;
whether this device performs similarly in spontaneous a chest x-ray should be considered in patients with active
pregnancies. pulmonary disease. The patient’s Rhesus (Rh) status must
also be obtained in order to determine the need for Rho(D)
Medical management immune globulin therapy, required in Rh negative patients.
The most common interventions for the treatment of EP A pelvic ultrasound should be obtained to characterize any
are medical management with systemic MTX and surgical ectopic mass and exclude a concomitant IUP. Several con-
removal of the pregnancy. Medical management of EP with traindications for treatment of EP with MTX exist (Table 1)
MTX has been demonstrated to be more cost-effective [135]. Patients with ectopic pregnancies and relative con-
than surgical management while maintaining similar treat- traindications to treatment with methotrexate may receive
ment success and future fertility [38, 125–127]. Injections the medication if deemed appropriate by the clinician;
of hyperosmolar glucose into tubal EPs have been studied, these patients should be hemodynamically stable and well
but have significantly higher failure rates than standard counseled and have capacity to make the decision [6].
medical or surgical management and are not recom- Patients should be advised to stop taking prenatal vita-
mended [128–130]. mins, as the folate supplementation will counteract the
MTX is a dihydrofolate reductase inhibitor, disrupting action of MTX. Patients should also avoid excessive sun-
DNA and RNA precursor synthesis; it targets rapidly light due to possible MTX-induced dermatitis; nonsteroidal
Table 1 Absolute and relative contraindications of treatment of EP with MTX

Absolute Contraindications Relative Contraindications
Clinical instability or significant pain suggestive of ruptured EP Presence of fetal cardiac activity
Heterotopic pregnancy with viable and desired IUP β-hCG level over 5000 mIU/mL
Liver function tests more than 2 times the upper limit of normal An ectopic mass size greater than 4 cm in largest dimension
White blood cell count of <1500/uL Patient refusal of blood transfusion
Platelet count <100,000/uL Patient inability to follow up
Creatinine ≥1.5 mg/dL
Current breastfeeding
Active pulmonary disease
Active peptic ulcer disease
Moderate to severe anemia
Sensitivity to methotrexate
anti-inflammatory drugs, which may delay renal excretion (92.7 vs. 88.1 %, respectively) [137]. Side effects, including
of MTX; alcohol, which may lead to elevation of hepatic nausea, vomiting and alopecia, were less common in the
enzymes; and sexual activity, vigorous physical activity and single dose treatment group. Of note, both treatment regi-
pelvic exams, which could lead to rupture of the EP [136]. mens were more likely to be successful in patients report-
ing side effects of the MTX.
Systemic methotrexate Few comparisons have been published involving the two
Single dose methotrexate The single dose regimen dose regimen. A retrospective comparison of 87 women
consists of an IM injection of MTX (50 mg/m2 of body receiving either single or two dose MTX regimens reported
surface area), with administration of additional doses at comparable success rates of 87 and 90 % at mean starting
weekly intervals in patients with an inadequate response serum hCGs of 4801 and 4278 mIU/mL, respectively, and
(Table 2) [6]. Repeat injections are permitted every 7 days no difference in side effects [141]. In the literature, it is
for up to 4 doses; a second dose is needed in 20 % or unclear which of these (single, two or multiple dose) regi-
more of patients, while less than 1 % of patients require mens is used most commonly, though single and multiple
3 or more doses [137]. The single dose regimen is asso- dose regimens are discussed more often than the two dose
ciated with fewer side effects as compared to other regi- regimen; MTX dosing is likely dependent on the provider
mens [6, 138, 139]. and/or institution.
Regardless of which treatment regimen is chosen, if
Two dose methotrexate the β-hCG level does not decline adequately—after the
A two dose regimen has been proposed by Barnhart and multiple dose regimen, or 4 doses of MTX in single or
colleagues (Table 3) [133]. In their prospective study of 101 two dose regimens—surgical management should be
women with a mean serum β-hCG at treatment initiation considered. A continued rise in serum β-hCG through-
of 2013 mIU/mL, the success rate, defined as avoidance of out the multiple dose regimen or after 2 doses of single
surgery, was 87 %. Patients suffered just mild and transient dose MTX may indicate higher risk of rupture of a tubal
side effects, including nausea, headaches and abdominal EP [6, 142]. Finally, medical management should be
pain, despite the lack of leucovorin supplementation. abandoned in favor of surgical management if the
patient presents with hemodynamic instability or other
Multiple dose methotrexate clinical parameters concerning for ruptured EP, such as
The multiple dose regimen was derived from chemo- pain. If a patient’s serum β-hCG declines adequately
therapeutic regimens for gestational trophoblastic dis- and she requires no further intervention, the β-hCG
ease, involving administration of MTX and leucovorin level should be monitored weekly to an undetectable
(folinic acid) on alternating days for 8 days or until the level. On average, the β-hCG normalizes in 2 to 3 weeks,
β-hCG falls by 15 % from its peak value (Table 4) [6]. but can take up to 8 weeks in patients with higher start-
Up to 50 % of patients will not require the full 8 day ing β-hCG levels [6, 143].
regimen [6]. Leucovorin is administered to counteract
the mechanism of MTX to limit side effects. Surgical management
The reported success rates among the dosing regimens Surgical management is indicated in patients with con-
vary in the literature [127, 137, 138]. A recent randomized traindications to medical treatment as described in the
controlled trial of 120 women receiving single or multiple previous section, hemodynamic compromise or other
dose MTX reported no difference in success rates, though clinical signs of ruptured EP including pain or evidence
the time until β-hCG normalization was longer following of intra-abdominal bleeding, and according to patient
the single dose regimen (22.3 vs. 18.3 days, respectively) preference.
[140]. Conversely, a meta-analysis of 1327 EPs reported The standard surgical intervention was laparotomy until
that the rate of successful treatment with multiple dose the laparoscopic approach was introduced in 1973 by Sha-
MTX was significantly higher than with single dose MTX piro and Adler; it has since gained wide acceptance [144].
Table 2 Single dose methotrexate (MTX) for treatment of ectopic pregnancy

Day 1 Day 4 Day 7
Labs 1. β-hCG β-hCG 1. β-hCG
2. Safety labs (complete blood count, BUN, creatinine, AST, ALT) 2. Safety labs
3. Blood type and antibody screen
Action Give MTX (50 mg/m2 of body surface area IM) no action β-hCG decline <15 % from Day 4 to Day 7: MTX, return to day 1 of
protocol. Repeat MTX up to a total of 4 doses
β-hCG decline >15 %: Check β-hCG at 1 week intervals until zero.
Table 3 Two dose methotrexate (MTX) for treatment of ectopic pregnancy

Day 0 Day 4 Day 7 Day 11 Day 14
Labs 1. β-hCG β-hCG 1. β-hCG β-hCG 1. β-hCG
2. Safety labs (complete blood 2. Safety labs 2. Safety labs
count, BUN, creatinine, AST, ALT)
3. Blood type and antibody screen
Action Give MTX (50 mg/m2 of body Give MTX (50 mg/m2 β-hCG decline <15 % β-hCG decline <15 % β-hCG decline <15 %
surface area IM) of body surface area IM) from Day 4 to Day 7: from Day 7 to Day 11: from Day 11 to Day 14:
Give MTX Give MTX Refer for surgery
β-hCG decline >15 % β-hCG decline >15 % β-hCG decline >15 %
from Day 4 to Day 7: from Day 7 to Day 11: from Day 11 to Day 14:
Check β-hCG at 1 week Check β-hCG at 1 week Check β-hCG at 1 week
intervals until zero. intervals until zero. intervals until zero.
Three prospective randomized trials have demonstrated control trial of 446 women undergoing salpingostomy or
the superiority of a laparoscopic approach over laparot- salpingectomy reported similar recurrent EP and ongoing
omy in terms of lower blood loss, pain medication re- pregnancy rates between groups: 8 and 60.7 %, respectively,
quirement, length of hospital stay and cost [145–148]. after salpingostomy and 5 and 56.2 %, respectively, after
Reproductive outcomes, including rates of recurrent EP salpingectomy [39]. Persistent trophoblastic tissue, which
and subsequent IUP, are not significantly different be- usually requires treatment with MTX, was more common
tween laparoscopy and laparotomy [149]. after salpingostomy (7 %) than after salpingectomy (<1 %).
Regardless of the mode of abdominal entry, two methods Of note, 43 women (20 %) randomized to salpingostomy
of excision of a tubal EP have been extensively reported: underwent an intra-operative conversion to salpingectomy
Salpingectomy, or removal of the fallopian tube in part or during the initial surgery due to uncontrolled bleeding.
in full, and salpingostomy (also called salpingotomy), or Similarly, in a review of 1064 women with EPs attempting
removal of the EP through a tubal incision while leaving subsequent conception, the rates of intrauterine pregnan-
the tube in situ. Salpingectomy is recommended in cases cies within 2 years were not significantly different, at 67 %
of extensive tubal damage and/or rupture, uncontrolled after salpingectomy and 76 % after salpingostomy [38]. The
bleeding, prior tubal sterilization, or a large tubal EP (5 cm rate of EP recurrence was also similar between groups, or
or more in diameter) [143]. The surgical approach is also 18.5 % overall. Following salpingectomy, if final pathologic
determined by the status of the patient’s contralateral fallo- analysis of the fallopian tube demonstrates evidence of a
pian tube, the patient’s plans for future fertility, and sur- tubal gestation, no follow up β-hCG levels or any other as-
geon comfort or preference. sessment is needed.
Salpingectomy Salpingostomy
Despite being termed “radical” in the literature, salpingec- Intraoperatively, if salpingostomy is planned, dilute vaso-
tomy results in similar rates of subsequent IUP and ectopic pressin can be injected at the planned incision site for
recurrence as compared to salpingostomy. A randomized additional hemostasis [143]. After a 1–2 cm linear
Table 4 Multiple dose methotrexate (MTX) and leucovorin (LEU) for treatment of ectopic pregnancy
Day 1 Day 2 Day 3 Day Day 5 Day Day 7 Day
4 6 8
Labs 1. β-hCG β-hCG β-hCG β-hCG
2. Safety labs (complete
blood count, BUN,
creatinine, AST, ALT)
3. Blood type and
antibody screen
Action MTX (1 mg/kg, IM) LEU (0.1 mg/kg, IM) β-hCG decline <15 % LEU β-hCG decline <15 % LEU β-hCG decline <15 % LEU
Give MTX Give MTX Give MTX
β-hCG decline >15 % β-hCG decline >15 % β-hCG decline >15 %
Check β-hCG at one Check β-hCG at one Check β-hCG at
week intervals until zero. week intervals until zero. one week intervals
until zero.
incision is made with electrocautery, laser or scissors Management of nontubal EP

over the bulging ectopic gestation, the contents are re- Ovarian EP
moved using forceps or high pressure irrigation, also Management of ovarian EP is most commonly surgical,
called hydrodissection [143, 150–152]. The use of hydro- and little data is available on the medical management
dissection to flush out gestational products may be pref- of this condition [6]. Successful treatment of ovarian EPs
erable to piecemeal removal with forceps, as the latter with systemic MTX alone has been described, using
can lead to incomplete removal of trophoblastic tissue either the single or multiple dose regimens, up to a
[4]. The tubal incision can be left open to heal by sec- serum β-hCG of 5201 mIU/mL [158, 159]. Systemic
ondary intention or sutured closed; a Cochrane review MTX has also been described, following limited biopsy
reported an insignificant difference in rates of recurrent of a suspected ovarian EP, to address residual tropho-
EP and subsequent IUP between the two techniques blastic tissue [160, 161]. Successful management with
[148]. transvaginal or laparoscopic injections of 50 mg of MTX
After salpingostomy, weekly β-hCG measurements are directly into the ovarian EP, with β-hCG levels up to
necessary to rule out persistent trophoblastic tissue, 12,075 mIU/mL, has also been reported [162, 163].
which can occur in up to 20 % of cases [153]. Adminis- Often, laparoscopy is required for diagnosis, at which
tration of a single dose of intratubal MTX intraopera- point definitive surgical management is often completed
tively or IM MTX within 24 h postoperatively has been [107]. Management of ovarian EPs is primary surgical, and
shown to decrease the rate of persistent trophoblastic laparoscopic surgery has become the standard for manage-
tissue (from 14.5–17.5 to 0–1.9 %) [154, 155]. ment of hemodynamically stable patients with ovarian EPs
[164, 165]. Resection of the EP and retention of the ovary
Expectant management is a reasonable surgical objective, particularly in patients
A carefully selected subset of patients may be candidates desiring future fertility. This resection has most commonly
for expectant management of tubal EP. Studies suggest taken the form of an ovarian wedge resection, attempting
that well-counseled, stable women with EPs and serum to remove as little normal ovarian tissue as possible [165].
β-hCG of 175–200 mIU/mL and declining may be can- In reports of surgical management of ovarian ectopic,
didates for expectant management. hemostasis is obtained with electrocautery or ultrasonic
In an observational study of 107 patients diagnosed energy; the latter is less damaging to the surrounding ovar-
with tubal EP by transvaginal ultrasound (a mass separ- ian cortex [166, 167].
ate from the ovary), expectant management was offered
to asymptomatic patients without fetal cardiac activity Cervical EP
[156]. Expectant management was discontinued due to Management of cervical pregnancies may be medical or
severe pain or failure of the serum β-hCG to decline on surgical, with many centers utilizing a combination of
sequential measurements. Ninety-six percent of women approaches. The use of single or multiple dose systemic
with a β-hCG of 175 mIU/mL or less did not require MTX and/or local MTX has been described in case
other treatment, compared to 66 % of those with β-hCG reports and small series [168–170]. A series of 38 cer-
of 175–1500 mIU/mL and just 21 % of those with β- vical EPs treated with local MTX, with additional local
hCG above 1500 mIU/mL. Expectant management was potassium chloride (KCl) in the presence of fetal cardiac
more likely to be successful in patients with serum pro- activity, reported an overall success rate of 87 %; all fail-
gesterone below 10 nmol/L (3.1 ng/mL), gestational age ures had fetal cardiac activity [171]. In a review of 52
less than 6 weeks, and EP mass greater than 15 mm. cervical EPs, 61.5 % were successfully treated with
Similarly, a prospective observational study of 118 pa- upfront systemic or local MTX [172]. Gestational age
tients with EPs managed expectantly reported that 88 % greater than 9 weeks, β-hCG titer over 10,000 mIU/mL,
resolved with β-hCG levels below 200 mIU/mL, as presence of fetal cardiac activity or fetal crown-rump
opposed to just 25 % with β-hCG levels above 2000 length greater than 10 mm were associated with failure
mIU/mL [157]. of upfront MTX.
The American College of Obstetricians and Gyne- Dilation and curettage is seldom used in isolation as a
cologists recommends that patients with EPs and first line treatment, given the risk of hemorrhage; in a
serum β-hCG less than 200 mIU/mL and decreasing review of 15 cases with mean gestational age of 8.9 weeks,
(though this is not strictly defined) are potential can- the risk of hysterectomy was 40 % [103]. Methods for de-
didates for expectant management [136]. Patients creasing the risk of bleeding include injection of vasocon-
undergoing expectant management for EP must be stricting agents into the cervix, such as dilute vasopressin,
reliable for follow up, and willing and able to accept or placement of cervical stay sutures [173]. Placement of
the risks of EP rupture, hemorrhage and emergency intracervical catheter for tamponade, such as a 30 mL foley
surgery. catheter, has also been described [174]. In the presence of
fetal cardiac activity, preoperative injection of feticides may Transabdominal excision of these lesions has been de-
decrease the risk of hemorrhage [175]. scribed by laparotomy, and standard or robotic-assisted
Uterine artery embolization (UAE) may have a role in laparoscopy [191]. Resection also allows for revision of
preventing or controlling hemorrhage; case series have the lower uterine segment, which theoretically may re-
reported both prophylactic UAE prior to medical and/or duce risk for recurrence [193]. Laparotomy may be indi-
surgical management, or emergent use to control cated in patients with suspected uterine rupture and
hemorrhage [170, 176–178]. This therapy is not currently hemodynamic instability, and hysterectomy may be re-
recommended for women who wish to conceive in the quired for otherwise uncontrollable hemorrhage [194].
future, as its ramifications for fertility have not been Definitive management with total laparoscopic hyster-
conclusively described. ectomy has also been described, in a patient with a
starting β-hCG of 155,009 mIU/mL who failed treat-
Cesarean scar EP ment with local KCl and multiple dose MTX [195]. Of
Interruption of a cesarean scar EP upon diagnosis is rec- note, complications of medical or surgical management
ommended, given the risk of hemorrhage, hysterectomy include formation of arterio-venous malformations,
and maternal morbidity [179, 180]. Live births resulting which are prone to bleeding; in one series of 60 cesarean
from a cesarean scar ectopic implantation have been scar EPs, this occurred at a rate of 8.5 %, requiring UAE
described; however, these deliveries are frequently or hysterectomy (Fig. 9) [183].
associated with hemorrhage and emergent cesarean
hysterectomy [9, 181, 182]. In a series of 10 patients Interstitial EP
with cesarean scar EPs with fetal cardiac activity who In patients who are hemodynamically stable without
elected for expectant management, 4 patients (40 %) evidence of rupture of the interstitial EP, non-surgical
had live births, 3 of whom (75 %) required hysterecto- management may be appropriate. Both single dose and
mies; overall, 80 % required hysterectomies [183].
Medical management with single or multiple dose
systemic MTX regimens has been described. Patients with
serum β-hCG greater than 6000 mIU/mL may be at higher
risk of requiring additional therapies, including local MTX,
D&C or uterine artery embolization (UAE) [9, 64]. Local
injections of MTX or KCl have also been described, usually
in conjunction with systemic MTX or other surgical man-
agement (D&C or hysteroscopy) [184].
Several surgical approaches have also been reported,
with the benefit of leading to more rapid resolution of
β-hCG levels as compared to medical management [185].
Regardless of the chosen treatment modality, serum β-
hCG should be followed to zero, as persistent tropho-
blastic tissue may occur after any medical or surgical
treatments except hysterectomy [9, 186]. In patients
undergoing upfront surgical management, D&C alone is
often complicated by hemorrhage. In a meta-analysis of 21
cases, 76 % required further treatment, and 14 % required
hysterectomy [64]. Initial steps for managing hemorrhage
include tamponade with a transcervical catheter and
hemostatic cervical cerclage sutures [187]. UAE has been
used as both hemorrhage prophylaxis and salvage therapy
in the event of hemorrhage [188]. UAE is not currently
recommended for patients desiring future fertility.
Hysteroscopic resection of cesarean scar EPs has been
Fig. 9 Left uterine artery arterio-venous malformation (AVM) by pelvic
performed successfully and without complication using angiogram. This patient had undergone an uncomplicated
biopolar or ‘electric’ loops, in patients with serum β-hCG ultrasound-guided D&C for a 10 week size cesarean scar ectopic
up to 28,333 mIU/mL [186, 189, 190]. Hysteroscopic re- pregnancy 2 months prior to presentation with vaginal bleeding and
section is not recommended when the residual myome- diagnosis of a left uterine artery AVM (arrow). The AVM was embolized
with coils, but the patient required emergent hysterectomy for
trium is less than 3 mm, given the risk of anterior wall
hemorrhage
perforation and bladder injury [191, 192].
multiple dose MTX regimens have been used to treat intramural EPs diagnosed by imaging, medical manage-
interstitial EPs with comparable success, ranging from ment is an option. In case reports, intramural EPs have
66 to 100 % [196]. UAE has also been successfully used been treated with single or multiple dose systemic MTX,
as an adjunct to these therapies [197, 198]. Local MTX successful in patients with serum β-hCG up to 25,140
has also been used; a meta-analysis of 11 cases reported mIU/ml [207–209]. Successful management with local
a success rate of 86 %, up to a serum hCG of 35,000 MTX and KCl for an intramural EP with fetal cardiac
mIU/mL [4]. activity and a β-hCG of 74,872 mIU/mL has also been re-
Surgical intervention is indicated following failed ported, as well as UAE for an intramural EP with a β-hCG
medical management, according to patient preference, of 12,250 mIU/mL [210, 211].
or when the patient demonstrates hemodynamic in- Most cases of intramural EP reported in the literature
stability and/or findings concerning for rupture of an have been managed surgically via laparotomy, sometimes
interstitial EP, including pain or evidence of hemoperi- requiring hysterectomy, as many patients present with
toneum on imaging. Laparotomy and hysterectomy rupture of the EP and hemorrhage [13]. Given the increas-
were formerly first line treatment, likely due to late ing ability of noninvasive imaging to diagnose intramural
diagnosis of interstitial pregnancies and higher rates of EPs and the advancement of minimally invasive surgery,
rupture and hemorrhage. These methods may still be more recent case reports have described laparoscopic ex-
necessary in patients with hemodynamic instability and cision of intramural ectopic gestations [212, 213]. A surgi-
severe hemorrhage. cal approach should be determined by a patient’s clinical
Minimally invasive surgeries are increasingly pursued as stability, desire for future fertility, and location of the ec-
imaging modalities allow for earlier diagnosis. Small case topic gestation.
series have described ultrasound or laparoscopy-guided
dilation and curettage [199–201]. Several laparoscopic sur- Abdominal EP
gical approaches have been described, including cornuost- Intervention for resolution of an abdominal EP is
omy, salpingostomy, and cornual resection. recommended upon diagnosis, given the extremely high
Cornuostomy entails injection of dilute vasopressin at risk for maternal morbidity; the mortality risk associ-
the cornua followed by a linear incision, through which ated with abdominal EPs is nearly 8 times the rate with
the gestation is removed with blunt and/or sharp dissec- tubal EPs [16]. Rare reports detail expectant manage-
tion or hydrodissection, after which the incision is closed ment in order to attain a live birth. Expectant manage-
with absorbable suture [4]. Case series have also de- ment of abdominal EPs may potentially be considered
scribed successful surgical management with placement when the diagnosis is made after 20 weeks of gestation
of an Endoloop around the base of the cornua before or in a healthy patient who can be followed very closely
after excision for both hemostasis and closure [202]. through a tertiary care center. The fetus should have no
Less commonly, salpingostomy for interstitial ectopic congenital malformations, and the placenta should be
has been reported, which is most appropriate for inter- implanted away from the upper abdomen. Delivery is
stitial EP less than 3.5 cm, given the smaller incision recommended at 34 weeks, and the placenta is often left
with limited visualization [203, 204]. in place given the risk for hemorrhage [214, 215].
Cornual resection has been recommended for surgical Most abdominal EPs reported in the literature have
management of more advanced interstitial pregnancies been managed surgically; the operative approach must be
(greater than 3–4 cm) [12, 205]. This technique entails tailored to the patient’s clinical presentation and stability,
injection of dilute vasopressin followed by a circumfer- and the location of the EP. Abdominal EPs have been
ential incision using scissors or an energy source—elec- approached by laparoscopy or laparotomy, with or with-
trosurgical or ultrasonic—preferably 1–2 cm above the out prophylactic embolization of the placental bed; more
cornual pregnancy to allow for redundant serosa and recent cases in the literature have been managed laparo-
myometrium for closure [11, 12]. This incision should scopically in hemodynamically stable patients [216–218].
be closed in layers akin to a myomectomy closure. The Intraoperative blood transfusion is common; in a meta-
fallopian tube adjacent to this cornua should also be ex- analysis, the highest transfusion rate was associated with
cised. UAE has also been used as a prophylactic measure hepatic (46 %) and retroperitoneal (40 %) implantations,
before laparoscopic cornual resection [206]. while abdominal wall implantations had the lowest trans-
fusion rate (14 %) [16].
When abdominal EPs are removed surgically at any
Intramural EP gestational age—though more commonly after 20 weeks
As with other types and locations of EP, management of of gestation—the placenta can be left in place to avoid
intramural EPs is largely dictated by patients’ clinical sta- hemorrhage [16]. Embolization of the remaining placenta
bility at presentation. In clinically stable patients with and/or administration of systemic MTX or mifepristone
have been employed to hasten resolution of these retained HPs are similarly rare; live birth after local hyperosmolar
placentas [219, 220]. The most common complication of glucose injection has been reported, as well as after lap-
an intraabdominal retained placenta is infection [16]. aroscopic wedge resection; surgical intervention carries
As diagnostic modalities have advanced and these the theoretical risk of interrupting hormonal support of
pregnancies are diagnosed earlier, case reports of med- the coexisting IUP by the corpus luteum [233, 234].
ical management for abdominal EP have been pub-
lished. Medical management with systemic MTX and/ Recurrence and future fertility
or local injections of MTX or KCl has been reported, The risk of recurrence of tubal EP ranges from 5 to 25 %
though nearly half may require subsequent surgical [38–40, 235]. The risk of recurrent EP is not affected by
management [16, 221–223]. Despite logistic regression, treatment modality—medical or surgical—or surgical pro-
a meta-analysis failed to identify risk factors for failed cedure [38]. In a randomized controlled study of 446
medical management [16]. women undergoing surgical management for tubal EP, the
recurrence rate was similar after salpingostomy (8 %) and
Heterotopic pregnancies salpingectomy (5 %) [39].
Treatment of a HP is tailored to the specific EP location, A review of 53 cases of prior interstitial EP reported a re-
and the patient’s clinical presentation and stability [78]. currence rate of 9.4 % following either medical or surgical
Medical management of tubal HPs includes local injections management [236]. In patients with a prior interstitial EP,
of KCl or a hyperosmolar glucose solution, though over data is limited regarding the risk of uterine rupture in a
half of tubal HPs managed with local KCl may require sub- subsequent IUP, though uterine rupture has been reported
sequent salpingectomy [17, 224]. Treatment with systemic after both expectant management and cornual resection
or local MTX, a known teratogen, is contraindicated in the [237, 238]. Vaginal deliveries have been reported following
presence of a viable IUP [225]. Surgical management has cornuostomy or cornual resection; the optimal mode of
been described more frequently, as patients with tubal HPs delivery in this group remains to be determined [12].
present more often with rupture and hemodynamic com- The reported rate of recurrent cesarean scar EP is highly
promise than those with tubal EPs [226]. Salpingectomy is variable, as high as 25 % in small series [239, 240]. Risk
preferable to salpingostomy as persistent trophoblastic factors for recurrence are bulging of the prior cesarean
tissue cannot be monitored in the setting of ongoing IUP scar EP into the uterovesical fold, initial presentation with
[78]. Patients with HPs suffer spontaneous abortions at irregular vaginal bleeding or pain, early termination
higher rates than intrauterine-only pregnancies (up to (≤56 days) of the first cesarean scar EP, prior cesarean de-
30 %) [18]. livery at a rural community hospital and thin lower uterine
segment (5 mm or less at the time of diagnosis of recur-
Nontubal HP rent cesarean scar EP) [241].
For the management of interstitial HPs, expectant man- The risk of recurrent cervical EP appears to be low:
agement, aspiration or injection of hyperosmolar glucose One recurrence was noted in a series of 34 pregnant
of the interstitial HP, and cornual resections have been women with prior cervical EP treated with several differ-
reported, leading to live birth [227–229]. One patient ent modalities [67]. The data are insufficient to com-
attempting expectant management required a laparot- ment on subsequent IUP and recurrence rates in
omy for rupture of the interstitial EP [227]. patients with prior ovarian, intramural or abdominal
Cesarean HPs have been successfully managed using EPs. Rates of recurrence and IUP after HP have not been
local KCl and/or aspiration of the gestation, or excision extensively reported in the literature, and likely depend
by laparoscopy or hysteroscopy [230]. Hysteroscopy car- on the location of the HP and the treatment modality.
ries the theoretical risk of disrupting an IUP due to the Regardless of ectopic location, conception is not recom-
high pressure infusion of fluid. mended for 3 months after exposure to MTX, though data
Cervical HPs addressed with expectant management, for this recommendation is lacking [6]. Results of
local KCl or hyperosmolar glucose injections, extraction population-based studies of pregnancy outcomes after a
with forceps, suction curettage or hysteroscopic resec- prior tubal EP are encouraging, and independent of treat-
tion, with or without subsequent foley tamponade, have ment modality. The rates of IUP have been shown to be
resulted in live birth. Rare case reports also detail cerc- similar following salpingectomy and salpingostomy in sev-
lage placement following intervention. Following this eral large series [39, 40]. Additionally, among 1064 women
range of interventions, a review of 30 cases reported a with prior tubal EPs attempting conception, the rates of
live birth rate of 80 % [231]. IUP within 2 years were similar among salpingectomy
Abdominal HPs are rarely encountered, though live (67 %), salpingostomy (76 %), and medical management
birth after local injection of KCl into the abdominal (76 %) [38]. After two prior EPs, however, the rate of
pregnancy has been reported in 3 cases [232]. Ovarian subsequent IUP may be as low as 4 % [235].
Conclusions 6. Practice Committee of the American Society for Reproductive Medicine.

Ectopic pregnancy is a relatively common clinical scenario Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril.
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ADAM-12: A Disintegrin and Metalloprotease-12; ART: Assisted reproductive
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FAST: Focused assessment with sonography for trauma;
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GnRH: Gonadotropin-releasing hormone; hCG: Human chorionic
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gonadotropin; HP: Heterotopic pregnancy; IM: Intramuscular; IUD: Intrauterine
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PAPPA: Pregnancy-associated plasma protein-A; PUL: Pregnancy of unknown 14. Khan KS, Wojdyla D, Say L, Gulmezoglu AM, Van Look PF. WHO analysis of
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VEGF: Vascular endothelial growth factor. 15. Rana P, Kazmi I, Singh R, Afzal M, Al-Abbasi FA, Aseeri A, et al. Ectopic
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Competing interests systematic review of the literature. Gynecol Obstet Invest. 2012;74:249–60.
The authors declare that they have no competing interests. 17. Barrenetxea G, Barinaga-Rementeria L, Lopez de Larruzea A, Agirregoikoa JA,
Mandiola M, Carbonero K. Heterotopic pregnancy: two cases and a
Authors’ contributions comparative review. Fertil Steril. 2007;82:9–15.
DP and PB participated in the planning and drafting of the manuscript. CP 18. Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds MA, Wright VC.
selected and edited the radiologic imaging. All authors read and approved Ectopic pregnancy risk with assisted reproductive technology procedures.
the final manuscript. Obset Gynecol. 2006;107:595–604.
19. Lin CK, Wen KC, Sung PL, Lin SC, Lai CR, Chao KC, et al. Heterotopic triplet
Authors’ information pregnancy with an intrauterine, a tubal, and a cervical gestation following
Danielle Panelli is a resident in the Brigham and Women’s Hospital/ in vitro fertilization and embryo transfer. Taiwan J Obstet Gynecol.
Massachusetts General Hospital Integrated Residency Program in Obstetrics 2013;52:287–9.
and Gynecology, an affiliate of the Harvard Medical School. 20. Talbot P, Riveles K. Smoking and reproduction: the oviduct as a target of
Catherine Phillips is the chief resident at the Brigham and Women’s Hospital cigarette smoke. Reprod Biol Endocrinol. 2005;3:52.
Diagnostic Radiology Residency Program, an affiliate of Harvard Medical School. 21. Shaw JL, Dey SK, Critchley HO, Horne AW. Current knowledge of the
Paula Brady is a resident in the Brigham and Women’s Hospital/Massachusetts aetiology of human tubal ectopic pregnancy. Hum Reprod Update.
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Author details hamsters. Reprod Toxicol. 1995;9:513–25.
1
Department of Obstcpetrics and Gynecology, Brigham and Women’s 23. Lyons RA, Saridogan E, Djahanbakhch O. The reproductive significance of
Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA. human Fallopian tube cilia. Hum Reprod Update. 2006;12:363–72.
2
Department of Radiology, Brigham and Women’s Hospital, Harvard Medical 24. Jansen RP. Endocrine response in the fallopian tube. Endocr Rev. 1984;5:525–51.
School, Boston, MA, USA. 25. Paltieli Y, Eibschitz I, Ziskind G, Ohel G, Silbermann M, Weichselbaum A.
High progesterone levels and ciliary dysfunction–a possible cause of
Received: 16 June 2015 Accepted: 29 September 2015 ectopic pregnancy. J Assist Reprod Genet. 2000;17:103–6.
26. Jain B, Rubinstein I, Robbins RA, Sisson JH. TNF-alpha and IL-1 beta
upregulate nitric oxide-dependent ciliary motility in bovine airway
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Incidence, Diagnosis and Management of Tubal and Nontubal Ectopic Pregnancies: A Review

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Panelli et al.

Fertility Research and Practice (2015) 1:15

REVIEW Open Access

Incidence, diagnosis and management of tubal

Findings uniformly require intervention and will not be included in

Fig. 3 Interstitial ectopic pregnancy by transvaginal ultrasound. The

Fig. 4 Interstitial ectopic pregnancy by magnetic resonance imaging,

Fig. 6 Cervical ectopic pregnancy by transvaginal ultrasound. Doppler

Table 1 Absolute and relative contraindications of treatment of EP with MTX

Table 2 Single dose methotrexate (MTX) for treatment of ectopic pregnancy

Table 3 Two dose methotrexate (MTX) for treatment of ectopic pregnancy

incision is made with electrocautery, laser or scissors Management of nontubal EP

Conclusions 6. Practice Committee of the American Society for Reproductive Medicine.

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