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R E V I E W A R T I C L E Open Access
The diagnosis and management of
interstitial ectopic pregnancies: a review
Maximilian Brincat
*
, Alison Bryant-Smith and T. K. Holland
Abstract
The objective of this article is to review the published literature on the diagnosis and management of interstitial
pregnancies (IPs). IPs account for 2–6% of all ectopic pregnancies and have the potential to cause life-threatening
haemorrhage resulting in a 2–5% mortality rate. There is little consensus on the best practice for diagnosing and
managing interstitial pregnancies. By reviewing the published data, we set out to determine what the best evidence-
based practice for the management of interstitial ectopic pregnancies is, what protocols can be used and whether this
improves post-operative outcomes and future fertility rates.
Keywords: Interstitial ectopic pregnancy, Methotrexate, Cornuostomy, Wedge resection, Fertility
Introduction
The diagnosis and management of interstitial pregnan-
cies (IPs) remains challenging, largely due to the rarity
of this diagnosis. Most units are likely to manage only
one or two cases per year. Appropriate first line manage-
ment is based on many factors, including the patient’s
symptoms, timely diagnosis, size of the pregnancy, depth
of surrounding myometrium, haemodynamic stability,
and desires for future fertility.
There is limited evidence on interstitial pregnancies
and their management with current evidence consisting
of small case series with no randomised controlled trials
(RCTs). This review will perform a comprehensive and
systematic review of the current evidence regarding the
diagnosis and management of interstitial pregnancies, to
help work toward a consensus on the appropriate man-
agement of such cases.
Definition, incidence, and pathophysiology
An interstitial pregnancy (IP) occurs when the blasto-
cyst implants in the most proximal section of the fallo-
pian tube (called the interstitial portion), which is
within the myometrium [1]. This interstitial section of
the fallopian tube is approximately 0.7-mm wide and
1–2-cm long [2].
IPs may be incorrectly referred to as ‘cornual’or ‘angu-
lar’pregnancies. It is important to correctly differentiate
between these terms, as the resultant maternal morbidity
and mortality vary greatly. An ‘angular pregnancy’occurs
when an embryo is implanted medial to the utero-tubal
junction, in the lateral angle of the uterine cavity, and as
such is neither an ectopic pregnancy nor dangerous
(Fig. 1). Cornual implantation describes those in the
upper and lateral uterine cavity, whereas interstitial de-
notes those blastocysts implanted within the proximal
intramural portion of the tube [1]. Therefore a ‘cornual
pregnancy’is any pregnancy which is implanted in the
horn of a uterus, which may be one horn of a bicornuate
uterus, which is not an ectopic pregnancy [3]ora
non-communicating, functional rudimentary cornua of a
unicornuate uterus, which is an ectopic pregnancy (Mav-
relos et al. 2007). Because the term ‘cornual’can be ap-
plied to many different types of pregnancy, it should be
avoided when discussing interstitial ectopic pregnancies.
The incidence of ectopic pregnancies is generally in-
creasing; there also appears to be a concurrent increase
in the proportion of ectopic pregnancies that are IPs.
The increase in incidence of IPs may be due to various
factors, including better diagnosis, more prevalent pelvic
inflammatory disease, pelvic surgery, and assisted repro-
ductive techniques [3,4]. IPs account for 2–6.8% of all
ectopic pregnancies [5–7].
* Correspondence: maxbrincat@gmail.com
Department of Women’s Health, Guy’s and St Thomas’NHS Trust, St Thomas’
Hospital, Westminster Bridge Road, Lambeth, London SE1 7EH, UK
G
y
necolo
g
ical Sur
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© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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Historically IPs were diagnosed at laparotomy after
rupture at the end of the first trimester or early in the
second trimester, and hysterectomy rates were as high as
40% [8]. However, the outcome from this diagnosis has
improved more recent case series that have estimated a
mortality rate of 2–2.5%, which is seven times the aver-
age for all ectopic pregnancies [7]. The increased mor-
bidity and mortality is due to catastrophic bleeding
secondary to rupture, due to the close proximity of the
gestational sac (GS) to the intramyometrial arcuate vas-
culature [3]. It is also likely that IPs are larger when they
rupture than tubal ectopic pregnancies as the layer of
overlying myometrium is able to accommodate larger
pregnancies, before rupture, than the uterine tube.
Methodology
A literature search was carried out in March 2018 using
key words ‘interstitial pregnancy’,‘cornual pregnancy’and
‘angular pregnancy’. Articles that were published from
January 2000 until March 2018 were obtained from
MEDLINE, EMBASE and PUBMED. This systematic
search initially identified 1666 articles. After reviewing
all abstracts, 86 articles were identified as being signifi-
cantly related to the diagnosis and management of inter-
stitial pregnancies.
Diagnosis
Timely diagnosis is key to the successful management of
patients with IPs. Diagnosing such cases may be difficult,
due to the wide spectrum of presenting symptoms and
signs and difficulties distinguishing an IP from an
intra-uterine or isthmic tubal ectopic pregnancy. Also,
some patients may present with rupture and haemo-
dynamic instability requiring immediate surgery before a
non-invasive diagnosis may be made. Patients may
present with abdominal pain and/or vaginal bleeding,
may be asymptomatic or have their IP diagnosed on rou-
tine early pregnancy scan.
Risk factors for IP include previous ectopic preg-
nancy, tubal surgery, in vitro fertilisation (IVF), ovula-
tion induction, or history of sexually transmitted disease
[7,9,10](Table1). Hiersch et al. noted that 46% of the
women with IPs treated in their hospital had conceived
following assisted reproductive techniques [11]. With the
incidence of IVF increasing, one expects a resultant
increase in IPs. There does not appear to be a single
risk factor that clearly differentiates patients with an
IP from those with an ampullary or isthmic ectopic
pregnancy [12].
Since the introduction of high-resolution transvaginal
ultrasonography (TVUS) and highly sensitive β-hCG as-
says, timely and accurate diagnosis has become possible.
There is no evidence of particular serum β-hCG trends
that are sensitive in differentiating IPs from either nor-
mal intrauterine pregnancies or other types of ectopic
pregnancies.
Ultrasound diagnosis
Ever-improving ultrasound technology has resulted in
wider utilisation of ultrasound to diagnose gynaeco-
logical conditions. TVUS has been reported to have a
sensitivity of 56% at 8.2 weeks’gestation [10], and 71.4%
of patients at 6.9 weeks’gestation [7]. MacRae et al.’s
study reported 80% of IPs being correctly diagnosed on
2D-TVUS scanning [13]. There is no evidence that
3D-US is more accurate for diagnosing IPs than 2D-US;
however, it is easier to demonstrate the interstitial nature
of the pregnancy on 3D than 2D.
The diagnosis of IP by ultrasound is based on the fol-
lowing criteria: the GS is located outside the uterine cav-
ity; the interstitial part of Fallopian tube is seen
adjoining the lateral aspect of the uterine cavity and GS;
and the myometrial mantle extends laterally to encircle
the GS (Fig. 2)[14].
Fig. 1 US image of angular pregnancy
Table 1 Risk factors for interstitial pregnancies
Risk factors Percentage of women with
an IP who have this risk factor
Previous ectopic pregnancy 22.9–54%
Previous ipsilateral or bilateral
salpingectomy
22.9–54%
Conception after in vitro fertilisation 17.1–34.4%
History of sexually transmitted disease 12.5–25.0%
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The fallopian tube’s interstitial section is best evaluated
in the transverse plane at the level of the uterine fundus
and appears as a thin echogenic line extending from the
lateral aspect of the endometrium toward the uterine
serosa [15].
Magnetic resonance imaging (MRI) and surgical diagnosis
MRI may be used in clinically stable patients whose
diagnosis remains uncertain despite having a TVUS.
However, referral to a tertiary centre with sufficient
expertise in diagnosing and managing IPs may be
preferable [16]. Despite the above advances in the
radiological diagnosis of IP, a small cohort of patients
will only be diagnosed with an IP at laparoscopy or
laparotomy due to either the lack of sufficient ultra-
sound expertise or haemodynamic instability (Fig. 3).
Management
Historically, management of IPs included wedge resec-
tion by laparoscopic/open surgery or hysterectomy [3].
Less invasive and/or aggressive techniques may reduce
the risk of intra-operative complications, whilst improv-
ing long-term fertility and obstetric outcomes. Table 2il-
lustrates the various management options and their
associated benefits (in lighter grey) and drawbacks (in
darker grey); we will discuss these options in detail
below.
Conservative management (expectant and medical
management)
The establishment of early pregnancy assessment units,
use of high resolution TVUS and access to rapid quanti-
tative β-hCG testing facilitate early detection of ectopic
pregnancies, prior to tubal rupture [14]. Conservative
management (encompassing expectant and medical
management) should only be offered to patients with a
radiologically diagnosed IP who are haemodynamically
stable and have no obvious risks of immediate rupture,
such as large GS or rapidly increasing β-hCG levels.
Fastidious follow-up allows expectant or medical
management to be offered as first line management
in appropriate patients.
Expectant management
Spontaneous miscarriage is a common pregnancy out-
come, whether the pregnancy is intra-uterine or ectopic
[12]. Expectant management is an appropriate first line
approach for women with an IP and declining serum
β-hCG levels (irrespective of ectopic mass size and initial
serum β-hCG levels) [17,18]. Expectant management
should be abandoned if there is evidence of clinical
deterioration.
Retrospective case series carried out by Cassik et al.
and Poon et al. at King’s College Hospital (London) re-
ported a total of 26 cases which were initially offered ex-
pectant management (Table 3). Cassik et al. noted that
there were no significant differences in success rates be-
tween expectant or medical management options (P>
0.05) [14]. However, success rates for patients given local
methotrexate (21/23, 91%) may have been higher than
for expectant 5/7, 71% (95%CI 29–96) due to larger
numbers of patients. The authors did not find any sig-
nificant differences in either the initial β-hCG levels or
β-hCG resolution times between the three subgroups.
They did note that the initial serum β-hCG was signifi-
cantly lower in cases of successful conservative treat-
ment, with no failures occurring when the initial β-hCG
was less than 9000 IU/L. Poon et al. noted that the
length of follow-up for those patients managed expect-
antly ranged from 7 to 141 days, with a median duration
of 50.6 days [18]. Several other studies analysed expect-
ant management, but the number of patients was too
low to be able to detect significant differences in out-
come [16,19,20].
Medical management of tubal ectopic pregnancy
High dose intravenous/intramuscular methotrexate (MTX)
with oral folic acid rescue was first proposed as a safe
alternative for the management of IP in 1982 [21]
(Table 4). The dose of one-off systemic MTX is cal-
culated according to the Stovall et al. protocol: 50
mg/m
2
body surface area [22].
Fig. 2 US image of interstitial pregnancy
Brincat et al. Gynecological Surgery (2019) 16:2 Page 3 of 15
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Systemic MTX is now widely used as the first-line
management for patients with tubal ectopic pregnancy
who fulfil all the inclusion criteria [23]. An RCT compar-
ing methotrexate with laparoscopic salpingostomy sur-
gery for tubal ectopics showed that methotrexate is
equally successful to salpingostomy in terms of require-
ment for further treatment [24]. However, current guid-
ance is that for women with a normal contralateral tube
salpingectomy is recommended due to the risk of on-
going trophoblast, increased bleeding and no proven dif-
ferent in future intra-uterine pregnancy rates [25].
Another RCT comparing single methotrexate with lap-
aroscopic salpingostomy surgery concluded that single
dose methotrexate was less effective than salpingostomy
(65% vs. 93% respectively) [26]. However, RCTs compar-
ing expectant management versus management with
Fig. 3 Laparoscopic view of interstitial pregnancy
Table 2 Benefits and drawbacks of modes of management used in IPs
Benefits & Drawbacks of Modes of Management used in IPs
Expectant
management
Systemic
methotrexate
(MTX)
Local
methotrexate
(MTX)
US-guided D&C /
transcervical
forceps extraction
Laparoscopic
wedge
resection
Laparoscopic
Cornuostomy
Open surgical
management
Need to satisfy strict inclusion criteria Option for advanced cases not suited
for conservative management
Requires technical expertise
Avoids side-
effects from
medical
management;
eliminates
surgical risks
Risk of side
effects from MTX
Reduced
risk of
side
effects
from
MTX
Risk of intra-operative and post-operative
complications
Requires 24-hour availability of anaesthetists,
plus clinicians with adequate surgical expertise
Requirement of specialist facilities
Outpatient care May be performed as a day case Requires hospital
admission
Requires prolonged follow-up / hospitalisation Reduced length of follow-up
Unpredictable course Definitive management
Non-invasive Minimally invasive Invasive
Avoidance of uterine scar Necessitates a
uterine scar
Table illustrates the various management options and their associated benefits (in lighter grey) and drawbacks (in darker grey): we will discuss these options in
detail below
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MTX did not find any significant benefit for pregnancies
with β-hCG levels less than 1500 IU [27,28].
Medical management for interstitial ectopic pregnancy
For IP, in addition to intravenous or intramuscular ad-
ministration, MTX may also be injected locally either
into, or close to, the GS (under TVUS or laparoscopic
guidance). Doses for the local injection of MTX in the
studies below ranged from 25 to 50 mg.
Cassik et al. [14] published a case series of conserva-
tively managed IP. They found success rates for local
methotrexate, systemic methotrexate and expectant
management was 91%, 80% and 71% respectively al-
though the numbers were too small to show a statisti-
cally significant difference [14]. However, the 5/35
(14.3%) of the patients managed conservatively required
surgical treatment, all of whom had β-hCG levels greater
than 9000 IU/L [14].
Some authors advocate local injection of MTX or po-
tassium chloride into the GS when foetal cardiac activity
is present [14,29]: our review did not find any evidence
that this is beneficial in the management of IPs. Even
though Cassik et al. had a higher success rate in the local
MTX group than the systemic MTX group, this was not
found to be significant (P> 0.05) [14]. Of note, local
MTX administration is more invasive than systemic ad-
ministration and requires special facilities and trained
personnel; this makes it more operator-dependent, less
widely available and more costly than systemic MTX ad-
ministration. Local treatment can be administered under
ultrasound guidance into the gestational sac/chorionic
tissue, via transvaginal route using a fine spinal needle.
Table 3 Studies on expectant management on IPs
Article Location No. of
cases
Patient age
(years)
Gestation
(weeks)
Diameter of
GS (mm)
Foetal cardiac
activity present
β-hCG Comments
Cassik et al.
2005 [14]
King’s College
Hospital (London, UK)
[December 1996 to March 2003]
7 N/A 7 (4–13) N/A 0 1799
(438–11,460)
71% success rate ((95%CI 29–96)
No significant differences in success
rates between the three different
management options (P>0.05)
Poon et al.
2014 [18]
King’s College Hospital
(London, UK)
[January 2004 to April 2013]
19 31.26
(18–42)
10.1 19.0 (9–49) 0 3468.0
(157–89,968)
Overall success rate 89.5% (n= 17)
Two failed cases were subsequently
treated with MTX. No cases of uterine
rupture.
Median follow-up 50.6 days
Table 4 Combined data from current studies on medical management of interstitial ectopic pregnancy
Study Number of
patients in total
Number of patients
successfully managed
(local and systemic
MTX)
Number of
patients managed
with systemic
MTX
Number of patients
successfully managed
(systemic MTX)
Number of
patients managed
with local MTX
Number of patients
successfully managed
(local MTX)
Hafner et al.
1999 [16]
10 9 5 4 5 5
Jermy et al.
2004 [20]
18 14 18 14 N/A N/A
Tulandi et al
2004 [44]
8 5 N/A N/A N/A N/A
Cassik et al.
2005 [8]
28 24 5 4 23 21
Tang et al.
2006 [42]
11 10 11 10 N/A N/A
Surbone et al.
2013 [38]
98 32 66
Hiesch et al.
2014 [17]
17 12 17 12 N/A N/A
Framarino et al.
2014 [15]
14 14 N/A N/A 14 14
Tanaka et al.
2015 [40]
33 31 33 31 N/A N/A
Total 148 127 92 77 48 46
Success rate
(95%CI)
85.81% (84.17–87.45) 79.98% (72.68–87.29) 97.83% (93.56–100)
N/A implies that the particular study did not consider patients managed with that treatment
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This needle may be advanced through the anterior for-
nix, through the anterior uterine wall and into the tar-
geted area where the MTX may be delivered straight
into the gestational sac and surrounding area [14].
One proposed benefit of administering MTX locally (ra-
ther than systemically) is to reduce the incidence of
side-effects, such as transitory peripheral neuropathy, se-
vere constipation, and deterioration in liver function [30].
Significant side effects were documented in 2/5 (40%) of
women receiving systemic MTX in [14] study. Cassik and
Hafner et al. noted that patients who received MTX
injected locally into the GS did not experience any of
these side effects; however, numbers were too low to show
significance [14,30].
The safety of MTX management of IP relies upon
diligent follow-up and the capacity to perform expedi-
ent surgery if required. Close follow-up (such as that
outlined above) is crucial, as 10–20% of patients will
require either a second dose of MTX or surgery. Suc-
cess rates in the studies included in this review were
85.81% (95%CI 84.17–87.45). Of note, different MTX
regimens were used in these studies, including both
systemic and local MTX injection: the average success
rate for systemic MTX was 79.9% (95%CI 72.68–
87.29), whilst for local MTX injection, it was 97.83%
(95%CI 93.59–100). None of the studies reported any
significant difference in the success rate between sys-
temic and local MTX.
Our literature search did not identify the following
factors as significantly affecting the efficacy of MTX
management: initial β-hCG levels, GS size, gestation,
maternal age, or foetal cardiac activity (Table 5).
Hiersch et al. identified a higher rate of unsuccessful
first-line treatment in women with two previous ec-
topic pregnancies (4/5 cases, 80% versus 1/12 cases;
8.3%; P= 0.01) [11].
In Jermy et al.’s study, all patients with an initial
serum β-hCG < 5000 were managed successfully with
asingledoseofsystemicMTX[6](Table6). The key
indicators of failed MTX management were insuffi-
cient reduction in β-hCG levels, abdominal pain, or
rupture. 2.4% of the 167 cases experienced a ruptured
ectopic pregnancy, requiring emergency surgery. The
mean time taken for β-hCG levels to normalise was
47.93 days. The duration of hospital stay varied con-
siderably, with some patients being managed as out-
patients and others as inpatients: one patient was
admitted for 40 days.
Patients with continuously rising β-hCG levels warrant
closer surveillance, such as sonographic evaluation for
signs of pregnancy progression (e.g. the development of
foetal cardiac activity) or uterine/tubal rupture. Repeated
MTX dosing should be considered until one is satisfied
that the IP has been resolved.
Surgical management
Surgical management of IPs remains an important op-
tion, as it offers definitive treatment (Table 7). Historic-
ally, wedge resection or hysterectomy by laparotomy was
the mainstays of surgical management; however, the
morbidity associated with such invasive operations has
led to newer, less invasive techniques being preferred.
Women with IPs who are haemodynamically unstable
and/or have an ultrasound suggestive of pregnancy rup-
ture should undergo immediate surgical management.
Patients who present with heterotopic pregnancies (one
of which is both viable and wanted) should be offered
surgical rather than expectant management as accurate
monitoring with β-hCG levels is not possible in this
situation.
Advances in laparoscopic surgery allow for less inva-
sive and less traumatic surgical options for patients with
IPs than those practised historically (i.e. laparoscopic
cornual resection, rather than abdominal hysterectomy).
While cornual (‘wedge’) resection preserves patients’fu-
ture fertility, it may carry the risk of uterine rupture due
to the loss of myometrium and extensive uterine scar-
ring ([31],). Liao et al. reported an incidence of subse-
quent uterine rupture and dehiscence after wedge
resection of 30% [32]. This is considerably higher than
the uterine rupture rates post myomectomies, which
typically range from 0.49 to 0.70% in subsequent preg-
nancies [32] However, an alternate study has not shown
increased risk of uterine rupture in subsequent preg-
nancy although, in this cohort, the caesarean rate was
60% versus 30% of patients without a history of ectopic
pregnancy (P= 0.137) [33].
More recent studies favour cornuostomy over cornual
resection. Cornuostomy excises the IP, while preserving
uterine architecture and maintaining fertility ([34]). Cor-
nuostomy is considered to cause less tubal damage than
cornual resection and may have better pregnancy out-
comes in future (including fewer cases of uterine rup-
ture) [32]. The risk of persistent ectopic pregnancy (i.e.
failed initial management) after laparoscopic salpingos-
tomy in tubal pregnancies has been reported to be 5–
20% [35]); however, our review found a 99.16% (95%CI
97.51–100) success rate in patients with IPs who under-
went cornuostomy. Risk factors for recurrent IP follow-
ing salpingostomy/cornuostomy include an IP < 2 cm
and rapidly rising pre-operative β-hCG [36]. The smaller
the gestational sac, the harder it is to ensure that the en-
tire interstitial pregnancy has been excised, thereby in-
creasing the risk of persistent interstitial pregnancy [37].
A larger ectopic pregnancy does not appear to be an in-
dication for cornual resection (rather than cornuost-
omy): MacRae et al. and Watanabe et al. performed
cornuostomies for larger interstitial GSs [13,38]. How-
ever, this conflicts with the advice given by Cucinella
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Table 5 Studies on medical management of IPs
Paper Location MTX route of
administration
No. of cases Patient age
(years)
Gestation
(weeks)
Diameter of
GS (mm)
Foetal cardiac
activity (FCA)
present
β-hCG (mIU/mL) Comments
Hafner et al.
1999 [30]
King’s College Hospital
(London, UK)
Prospective
interventional study
2 cases of systemic MTX
(2 doses 1 mg/kg IM, 48
h apart, with rescue
folinic acid)
5 cases of local MTX
(single 25 mg dose of
MTX, TVUS-guided,
injected into the GS)
3 cases: 2–4 mEq of KCL
+ MTX if FHR present
10 34.18 6.5 (6–9) 24.8 (9–51) 3 9574 (102–41,150) 90% success rate in total
100% success rate with
local MTX therapy
80% for systemic MTX
No rupture
No difference between
local and systemic MTX
Rx in time taken for
resolution of β-hCG
Mean 18.8 days for β-
hCG to resolve (max 32
days)
All 3 FCA treated
successfully
Jermy et al.
2004 [6]
St George’s University
Hospital (London, UK)
[1998–2002]
Prospective
observational study
Single dose MTX IM 18 32.7 5.4 30.39 (12–54) 4 6452 (32–31,381) 50% treated successfully
with 1 dose of MTX
80% treated successfully
with second dose of MTX
All 4 FCA cases treated
successfully
No ruptures
All patients with β-hCG
< 5000 IU were treated
successfully with single
dose MTX
Hospital stay (days) 7
(0–40)
No side effects secondary
to MTX
Tulandi et al.
2004 [7]
Multi-centre
(Europe, North America,
Chile)
[1999–2002]
Retrospective case series
4 cases: local MTX
4 cases: systemic MTX
8 32.6 7.9 +/−0.9 15 +/−9–4683 +/−2056 62.5% success rate
37.5% required second
intervention (surgical
treatment)
No ruptures
FCA not a factor in
treatment success
Mean interval between
MTX administration and
β-hCG resolution was
52.7 +/−36.0 days
Cassik et al.
2005 [14]
King’s College Hospital
(London, UK)
[1996–2003]
Retrospective case series
23 cases: local MTX
injection
5 cases: systemic MTX
28 –7(4–13) –5 Local MTX: 6006
(102–69,820)
Systemic MTX: 5576
(793–41,150)
85.7% success rate
overall
Local MTX: 91% success
rate
Systemic MTX: 80%
success rate
No significant
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Table 5 Studies on medical management of IPs (Continued)
Paper Location MTX route of
administration
No. of cases Patient age
(years)
Gestation
(weeks)
Diameter of
GS (mm)
Foetal cardiac
activity (FCA)
present
β-hCG (mIU/mL) Comments
differences in success
rates between the three
different management
options (P> 0.05)
None of the women
receiving local MTX
experienced significant
side-effects
1 failed case had a
ruptured ectopic
Tang et al.
2006 [46]
Royal Brisbane and
Women’s Hospital
(Australia)
[2000–2005]
Retrospective case series
Medium-dose IV MTX
(100 mg/5 min, followed
by 200 mg/12 h), with
oral folinic acid rescue
(15 mg) on day 0
11 31 6.45 (5–8) 20.72 (10–60) 4 25,473 (1600–106,634) 91% success rate
1 case required second
dose of MTX on day 17
(due to plateauing
β-hCG), followed by
emergency laparotomy
on day 31 for rupture
Surbone et al.
2013 [47]
University Hospital of
Lausanne (Switzerland)
[2001–2011]
Retrospective case series
3 cases: single dose IM
MTX
6 cases: local MTX,
injected into the cornual
region
9 33 (25–39) 6 (5–9) –– 5838 (2974–15,022) 88.9% success rate
1 case who received IM
MTX required a second
dose of IM MTX, followed
by laparoscopic cornual
resection
Hiesch et al
2014 [11]
The Helen Schneider
Hospital for Women
(Israel)
[2003–2013]
Retrospective case series
14 case: multi dose MTX
regimen
3 cases: single dose MTX
17 32 +/−5.8 6.5 +/−1.3 36.0 +/−24.1 3 15,763 +/−25,147 70.5% success rate
All 3 patients treated
with single-dose MTX
were successful
5 unsuccessful cases of
multi-dose MTX required
selective uterine artery
MTX injection
Poon et al.
2014 [18]
King’s College Hospital
(London, UK)
[? years]
Retrospective case series
16 cases: local MTX
3 cases: systemic MTX
19 –7.8 (6–12.6) 13.0 (10–48) 4 7131 (562–8464) No comments
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Table 5 Studies on medical management of IPs (Continued)
Paper Location MTX route of
administration
No. of cases Patient age
(years)
Gestation
(weeks)
Diameter of
GS (mm)
Foetal cardiac
activity (FCA)
present
β-hCG (mIU/mL) Comments
Framarino et al.
2014 [48]
Umberto I Hospital,
Sapienza University
(Rome, Italy)
[2007–2012]
Retrospective
observational study
Local MTX (TVUS-
guided)
14 31 +/−3 6.5 +/−1.0 –2 2146 +/−807 100% success rate, so no
second line Rx needed,
and no patients required
hospitalisation
No reported side-effects
from MTX
β-hCG levels had
normalised within 2
months, but (on US) the GS
disappeared more slowly
(taking about 4 months)
Tanaka et al.
2015 [49]
Royal Brisbane and
Women’s Hospital
(Australia)
[2000–2012]
Retrospective
observational study
Double dose of IV MTX 33 31.8 (21–43) 6.45 24.1 7 20,546 (230–106,634) 93.9% success rate
2 cases (6.1%)
complicated by rupture
β-hCG resolution took
an average of 55.6 (19
to 137) days
3 patients had side-
effects from MTX
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who notes that cornual resection was preferred in cases
of advanced gestational age and/or when ectopic size
was > 4 cm in diameter [34]. Our experience is that with
intra-myometrial vasopressin use for haemostasis, large
and small IP can be treated laparoscopically.
Wedge resection disrupts the uterine architecture and
should only be performed in cases of ruptured IP with
troublesome bleeding or for patients not desiring future fer-
tility. Similar operations (such as myomectomy) carry a risk
of uterine rupture in subsequent pregnancies of 0.49–0.70%
[39]: cornual resection is an accepted risk factor for uterine
rupture in subsequent pregnancies [40] Cucinella et al.’s
systematic review compared 156 cases of cornuostomy with
198 cases of cornual resection: the pregnancy rates in a
small sample of these cases were 72% vs. 62% respectively,
of which the live birth rates 48% vs. 62% in the cornuost-
omy and cornual resection groups, respectively. Any differ-
ences in the fertility outcomes or live birth rates between
the two groups were not statistically significant [34].
Key steps in laparoscopic cornuostomy include cornual
incision, removal of the products of conception, cornual
repair and confirming haemostasis [41]. Prior to cornual
incision, various methods to reduce intra-operative blood
loss can be employed: vasopressin injection into
peri-cornual area, electric cauterisation of incision area,
endo-loop application to create a para-cornual tourniquet
and an encircling suture around the cornu. There are con-
cerns that electrocoagulation may damage the underlying
myometrium and interfere with the revascularisation
process, therefore weakening the area and theoretically in-
creasing the risk of uterine rupture in future [37]; electro-
cauterisation also increases the risk of damage to
surrounding organs, leading to injuries such as bowel per-
foration. Moon et al. concluded that the endo-loop and en-
circling suture methods are simple, safe, effective and
nearly bloodless in achieving haemostatic control during
treatment of IPs [37].
Ifpossible,oneshouldmanageIPsusingaminimallyinva-
sive approach, rather than open surgery. Tulandi et al. found
that the mean volume of intra-abdominal haemorrhage en-
countered for the laparotomy group was 1385.7+/−978.8
ml, compared to 460.0+/−70.7 ml for the laparoscopy group
(Pvalue—is this significant) [7]; this difference probably re-
flects surgeons’pre-operative decision-making (taking into
account patients’differing pre-operative blood loss or
haemodynamic stability), rather than blood loss caused by
the operative technique itself. Hwang et al. assessed 88 cases
of cornual resection, performed by either laparoscopy or
laparotomy: the only significant difference found between
the two groups was the duration of post-operative recovery
[42]. The post-operative pain, length of hospital stay, return
to normal function, return to work and cosmetic advantages
of a laparoscopic approach should also be considered.
Nirgianakis et al. noted similar rates of surgical complica-
tions (P= 0.413) and the need for subsequent MTX treat-
ment (P= 0.513) in patients with an IP treatment with
laparoscopic cornual resection, compared to women with
tubal ectopic pregnancies treated with laparoscopic salpin-
gectomy/salpingostomy [43].
Other management options
Ultrasound-guided transcervical forceps extraction (UTCE)
As described by Ahn et al 2013, UTCE utilises a natural
orifice to remove any products of conception [44]. The
Table 6 Combined data from current studies on surgical management of interstitial ectopic pregnancy
Study Number of
patients in total
Success rate of combined
(cornuostomy/cornual
resection)
Number of patients
treated by cornuostomy
Success rate of
cornuostomies
Number of patients
treated by cornual
resection
Success rate of
cornual resection
Moon et al.
2000 [41]
24 23 24 23 N/A N/A
Tulandi et al.
2004 [7]
24 23 3 3 21 20
Choi et al.
2009 [50]
8 8 8 8 N/A N/A
Moon et al.
2010 [37]
20 20 20 20 N/A N/A
Watanabe et al.
2014 [38]
13 13 13 13 N/A N/A
Liao et al.
2016 [32]
29 29 N/A N/A 29 29
Nirgianakis et al.
2017 [43]
10 10 N/A N/A 10 10
Total 128 126 68 67 60 59
Success rate
(95%CI)
98.1% (95.48–100) 99.16% (97.51–100) 98.41% (95.30–100)
N/A implies that the particular study did not consider patients managed with that treatment
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Table 7 Studies on surgical management of IPs
Paper Location Mode of surgical
management (cases)
No. of
cases
Patient age
(years)
Gestation
(weeks)
Diameter of
GS (mm)
Foetal cardiac
activity (FCA)
present
β-hCG (IU/ml) Comments
Moon et al.
2000 [41]
Moon Hwa Hospital,
Pusan
(South Korea)
[1993–1998]
Retrospective case
series
Laparoscopic
cornuostomy (24)
Endo-loop vs.
vasopressin + electric
cauterization vs.
encircling suture
24 33.4 +/−5.8 7.6 35.29 7 2652.8 95.8% success rate
75% pregnancy rate in future
No ipsilateral ectopics
Tulandi et al.
2004 [7]
Multi-centre
(Europe, North
America, Chile)
[1999–2002]
Retrospective case
series
Laparoscopic: cornual
resection (8) vs.
cornuostomy (3)
11 32.6 +/−1.0 5.4 +/−1.0 11 +/−6–2086.9 +/−698.2 90.9% success rate
1 failed primary treatment
(9.1%)
Subsequent treatment: single
dose/multi-dose MTX (for
persistently elevated β-hCG)
Tulandi et al.
2004 [7]
Multi-centre
(Europe, North
America, Chile)
[1999–2002]
Retrospective case
series
Laparotomic cornual
resection
13 7.3 +/−0.4 14 +/−8 11,471 +/−6281 100% success rate
9 cases had tubal rupture
confirmed
Choi et al.
2009 [50]
EUN Hospital (South
Korea)
[? Years]
Retrospective case
series
Laparoscopic
cornuostomy (8)
8–7.6 +/−1.11 33 +/−6.7 5 3656 +/−2573 100% success rate
Operatingtime50+/−22 min
No major post-operative
complications
β-hCG normalised by 26.5
+/−7 days
Moon et al.
2010 [37]
Moon Hwa Hospital,
Pusan
(South Korea)
[2003–2006]
Retrospective case
series
Laparoscopic
cornuostomy (20)
20 33.5 +/−3.2 6.7 +/−1.2 –1095 (? range) 100% success rate
Time to resumption of
menstrual period: 38.6 days
Hwang et al.
2011 [42]
Korea University
Medical Center
(South Korea)
[1998–2009]
Case –control study
Open cornual
resection (49) vs.
laparoscopic cornual
resection (39)
88 32.5 (19–42) 7.86 +/−1.7 22 (22.5%) 12,741 +/−
103–81,351)
5 cases of laparoscopic
management needed
conversion to open
management.
No statistical differences in
operating time, estimated
blood loss, blood transfusion
requirements, or complications
Mean post-operative inpatients
admission was 5.89 +/−1.86
days (laparotomy) vs. 4.53 +/−
1.44 days (laparosocopy)
(P= 0.0001)
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Table 7 Studies on surgical management of IPs (Continued)
Paper Location Mode of surgical
management (cases)
No. of
cases
Patient age
(years)
Gestation
(weeks)
Diameter of
GS (mm)
Foetal cardiac
activity (FCA)
present
β-hCG (IU/ml) Comments
Poon et al.
2014 [18]
King’s College Hospital
(London, UK)
[2004–2013]
Retrospective case
series
9 8.21 (5.1–11) 31.5 (13–44) 3 (33%) 9,402 (2225–
75,530)
No comments
Hiersch et al.
2014 [11]
The Helen Schneider
Hospital for Women
(Israel)
[2003–2013]
Retrospective case
series
732+/−5.8 10.5 +/−5.5 –– 2094.8 +/−1721.3 No comments
Watanabe et al.
2014 [38]
NTT East Japan Tohoku
Hospital and Sendai
City Hospital (Japan)
[2000–2012]
Retrospective case
series
Laparoscopic
cornuostomy + MTX
administration to
local site (13)
13 7.6 +/−1.3
weeks (5–9)
34.6 +/−10.2 3 20,800 +/−18,100 100% success rate
Mean operative time 107
+/−23 min (61–160)
Mean haemoglobin drop
was from 12.4 +/−1.0 to 10.3
+/−1.7 g/dL
No major post-operative
complications
No persistent ectopic
pregnancies
10/13 patients followed up
8 conceived spontaneously
[average 13 months after the
procedure]:
1 pregnancy ended in early
miscarriage;
3 delivered by ventouse
delivery, the other? 2 by
elective caesarean section
Liao et al.
2016 [32]
Mennonite Christian
Hospital
(? country)
[1992–2013]
Retrospective case
series
Laparoscopic cornual
resection (29)
29 31 (18–43) 8 (5–12 + 1) Of the 10 pregnancies post-
cornual resection, there were
3 cases of subsequent uterine
rupture or dehiscence (30%)
71.4% of patients who were
trying to conceive achieved
subsequent pregnancy
No recurrent ectopic
pregnancies
Nirgianakis et
al. 2017 [43]
University of Bern
(Switzerland)
[2009–2015]
Retrospective case
series
Laparoscopic cornual
resection (10)
10 34.50 +/−6.21 53.25 +/−
16.79 days
27,634 +/−35,198 100% success rate
EBL 137.00 +/−178.64 mL
3 patients required blood
transfusions
Length of hospitalisation was
2.67 +/−1.00 days
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IP is approached through the vagina and cervical canal,
then the GS is removed using small forceps (presumably
through the tubal ostium), under transabdominal US
guidance [44]).
Ahn et al. conducted a retrospective review of all IPs
diagnosed between 1 March 2008 and 31 December
2011 at Ulsan University Hospital (South Korea). Six of
the 16 IPs were managed by UTCE; these women were
all haemodynamically stable at diagnosis. Five of these
patients were treated successfully; one required further
management. No patients had serious complications; the
average drop in haemoglobin was 1.7 g/dL (0.3–2.2 g/
dL). Three women went on to have successful pregnan-
cies. The small number of patients and low power of this
study means that statistically significant results cannot
be easily inferred. The authors state that a potential
benefit is that UTCE does not breach (and therefore
weaken) the myometrium, as no incision into the myo-
metrium is needed; however, we believe that manage-
ment of IPs by this procedure would be difficult to
achieve without damage to the myometrium.
Transcervical suction under laparoscopic and hysteroscopic
guidance
An alternative to UTCE is transcervical suction under
laparoscopic and hysteroscopic guidance. Cai et al. de-
scribed how seven IPs of > 2 mm size were removed
using a flexible 8F paediatric suction catheter introduced
transvaginally [45]. However, two of their seven suffered
from a uterine perforation and increased blood loss
(> 500 ml). These complications necessitated subse-
quent surgical management.
Conclusion
The diagnosis and management of interstitial pregnan-
cies remains challenging, in part due to the rarity of
these cases and the paucity of evidence to guide man-
agement. The high sensitivity of US, when sufficient ex-
pertise is available, makes it the best first line
investigation that one may use to diagnose IPs.
IPs should be managed in early pregnancy units that
have experience in managing such cases. Conservative
management (encompassing expectant and medical
management) should only be offered to patients with a
radiologically diagnosed IP, who are haemodynamically
stable and have no obvious risks of immediate rupture,
such as large gestational sac or rapidly increasing β-hCG
levels. Expectant management is an appropriate first line
approach for women with an IP and declining serum
β-hCG levels (irrespective of ectopic mass size and initial
serum β-hCG levels) [17,18]. Expectant management
should, however, be abandoned if there is any evidence
of clinical deterioration. MTX has been advocated widely
in the literature; however, much of the safety data is
from retrospective cohort studies which may be suscep-
tible to selection bias. The success rates for MTX man-
agement vary from 79.9% for systemic MTX to 97.83%
for local MTX injection; however, the numbers in these
studies were small. It needs to be remembered that fail-
ure of medical management resulting in rupture may
have catastrophic consequences. For this reason, surgical
management with a likely higher success rate (99.16%) is
becoming more popular in centres with sufficient experi-
ence. Laparoscopic cornuostomy is preferable to wedge
resection due to the decreased intra-operative blood
loss, reduced distortion of uterine anatomy and possible
reduction in the risk of uterine rupture in subsequent
pregnancies.
Further studies using prospective data from multiple
centres are required to assess the impact of the various
management options on the short term complications
and long term outcomes such as fertility and pregnancy/
labour complications.
Abbreviations
GS: Gestational sac; IP: Interstitial pregnancy; IVF: In vitro fertilisation;
MRI: Magnetic resonance imaging; MTX: Methotrexate; RCT: Randomised
control trial; TVUS: Transvaginal ultrasound scan; UTCE: Ultrasound-guided
transcervical forceps extraction; β-hCG: Beta human chorionic gonadotrophin
Funding
Not funded
Disclosure statement
The authors declare that they have no conflicts of interest and nothing to
disclose.
Authors’contributions
MB contributed to the study conception, performed the searches, reviewed
titles and abstracts, reviewed full text articles, extracted data, performed data
analysis and drafted the manuscripts. AB-S contributed to the study conception,
review of full-text articles and data analysis as well as reviewed the manuscript
for important intellectual content. TKH contributed to the study conception,
providing clinical expertise on interstitial pregnancies, and reviewed the
manuscript for important intellectual content. All authors read and approved
the final manuscript.
Ethics approval and consent to participate
Not required
Consent for publication
Not required
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Received: 28 September 2018 Accepted: 28 December 2018
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