Human Reproduction Update, Vol.20, No.2 pp.

250–261, 2014
Advanced Access publication on October 6, 2013 doi:10.1093/humupd/dmt047

Diagnosing ectopic pregnancy and

current concepts in the management
of pregnancy of unknown location
E. Kirk 1,2,*, C. Bottomley3, and T. Bourne 2,4
1
North Middlesex University Hospital, Sterling Way, London N18 1QX, UK 2Queen Charlotte’s & Chelsea Hospital, Imperial College, Du Cane
Road, London W12 0HS, UK 3Chelsea and Westminster Hospital, Fulham Road, London SW10 9NH, UK 4Department of Development and
Regeneration, University Hospitals Leuven, Campus Gasthuisberg, KU Leuven, B-3000 Leuven, Belgium

*Correspondence address. E-mail: ejkirk@hotmail.co.uk

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Submitted on April 10, 2013; resubmitted on July 31, 2013; accepted on August 15, 2013

table of contents
...........................................................................................................................
† Introduction
† Methods
† Tubal ectopic pregnancy
History and presentation
Ultrasound diagnosis
Surgical diagnosis
† Non-tubal ectopic pregnancy
Heterotopic pregnancy
† Pregnancy of unknown location
Diagnosis
Clinical outcomes
Clinical management
† Future work
† Conclusion

background: A diagnosis of ectopic pregnancy (EP) is primarily achieved using transvaginal ultrasonography (TVS). Pregnancy of unknown
location (PUL) is the term used to categorize a pregnancy in a woman with a positive pregnancy test when no pregnancy has been visualized using
TVS. This review appraises current tools for the diagnosis of EP, describes the diagnostic criteria for non-tubal EP and reviews the literature on the
clinical management of PUL.
methods: We performed a targeted search using the PubMed database. All articles published in the English language from January 1984 to
March 2013 were screened for eligibility.
results: Using TVS to diagnose EP is highly sensitive (87 –99%) and specific (94 –99.9%). Variations exist in the criteria used for ultrasound
diagnosis. Studies report that between 5 and 42% of women seen for ultrasound assessment with a positive pregnancy test have a PUL. For PUL,
measurements of serum human chorionic gonadotrophin (hCG) and progesterone are used to predict pregnancy viability and therefore give an
indication of the risk of an EP. Only 6– 20% of PUL are subsequently diagnosed with EP. Non-tubal EPs are relatively uncommon, difficult to diag-
nose and result in disproportionate morbidity and mortality.
conclusions: Access to expertise and equipment for high-quality TVS means the majority of women with EP in developed countries can be
diagnosed rapidly and accurately. Identifying PUL, which are low risk and therefore requiring less follow-up, finding better serum markers for EP
and safely identifying women who do not require intervention for EP are the current diagnostic challenges.
Key words: ectopic pregnancy / pregnancy of unknown location / transvaginal ultrasonography / prediction models / expectant management

& The Author 2013. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Current concepts in ectopic pregnancy and PUL
Introduction
Any pregnancy implanted outside the endometrial cavity is defined as an
ectopic pregnancy (EP). Most are located within the Fallopian tube. The
incidence of EP varies from 11 to 20 per 1000 live births in developed
countries (Centres for Disease Control, 1995; Boufous et al., 2001;
Bakken and Skjeldestad, 2003; Lewis 2007), though it is as high as 4%
in assisted conception populations (Fernandez and Gervaise, 2004).
The case fatality rate in developed countries has declined over recent
years, suggesting that earlier diagnosis and better treatment have made
an impact (O’Herlihy, 2011).
Diagnosis based on clinical signs of tubal rupture (hypovolaemic
shock) is now uncommon and transvaginal ultrasonography (TVS) is
the primary diagnostic tool for clinically stable women with a suspected
EP (Jurkovic and Wilkinson, 2011). Data from a specialist early pregnancy
unit show that up to 73.9% of women with an EP may be diagnosed on an
initial TVS assessment (Kirk et al., 2008) and 94% are diagnosed prior to
surgical intervention (Condous et al., 2005a).
Non-tubal EPs although relatively uncommon are associated with
higher morbidity and mortality. Pregnancy of unknown location (PUL)
is the term used to classify a pregnancy in women with a positive
urinary pregnancy test when an initial TVS detects neither an intrauterine
nor extrauterine pregnancy. A small proportion of women classified with
a PUL have an underlying EP.
The aim of this review is first to detail the diagnostic criteria for both
tubal and non-tubal EP. The secondary aim is to define the use of the
term ‘PUL’ and describe how to use biochemical markers to triage
women to appropriate follow-up when they have a PUL.
Methods
We performed a targeted search using the PubMed database employing
combinations of the following search terms: EP, tubal/cornual/interstitial/
Caesarean scar/intramural/ cervical/ abdominal EP, PUL. All articles
published in the English language from January 1984 to March 2013 were
selected. The restriction to articles after 1984 was due to this being when
TVS became commonly used in clinical practice.
All potential papers were screened for eligibility by review of the title and
abstract, to assess relevance in terms of focus on either diagnosis of any type
of EP or an original or review paper on any aspect of PUL. The full text ver-
sions of all papers selected in the screening process were read and assessed
for relevance. Reference lists of all primary and review articles were examined
for any relevant citations (from any year), which may have been missed in the
original key word search.
One main author performed the search for each specific section [tubal EP
diagnosis (CB), non-tubal EP diagnosis (EK), PUL (EK)] with all three authors
subsequently rechecking the included articles for relevance.
Tubal Ectopic Pregnancy
Most (93– 98%) EPs are located within the Fallopian tube. Of these, 13%
are isthmic, 75% ampullary and 12% fimbrial (Bouyer et al., 2002; Walker,
2007; Varma and Gupta, 2009). The aetiology remains poorly defined
but is likely to be a combination of impaired embryo –tubal transport
and alterations in the tubal environment allowing early implantation
(Shaw et al., 2010a, b).
251
History and presentation
Risk factors for tubal EP are well described, with highest risk associated
with tubal damage following surgery or infection (especially Chlamydia
trachomatis), smoking and IVF (Ankum et al., 1996; Tay et al., 2000;
Bouyer et al., 2003; Shaw et al., 2010a, b; Shaw et al., 2011). However
although the attributable risk of these factors is 0.76 (Bouyer et al.,
2003), many women with EP have no identifiable risk factors and most
women with a risk factor do not have an EP.
The triad of pain, vaginal bleeding and amenorrhoea was historically
used to suspect a diagnosis of EP (Weckstein et al., 1985). These symp-
toms, with or without syncope, shoulder tip pain and shock, generally led
to surgical intervention. Now, history and physical examination alone
rarely leads to the diagnosis or exclusion of an EP, with most diagnosed
earlier in the course of the disease. One-third of women with an EP have
no clinical signs and up to 10% have no symptoms (Kaplan et al., 1996; Tay
et al., 2000). The symptoms of EP are often non-specific and difficult to
differentiate from those of other gynaecological, gastrointestinal and uro-
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logical disorders, including appendicitis, salpingitis, corpus luteum cyst
rupture, miscarriage, adnexal torsion or urinary tract infection.
The amount of bleeding associated with EP varies, although classically
the patient will complain of ‘spotting’. Heavy bleeding, in the absence of
further TVS and hCG assessment, may lead to a clinical misdiagnosis of
miscarriage. Abdominal pain is often absent or a late finding, probably
due to earlier recognition of pregnancy from the use of highly sensitive
commercially available urinary pregnancy tests and to easy access to
TVS. The majority of women with abdominal pain in early pregnancy
do not have an EP (Bottomley et al., 2009).
Less common features of EP include nausea, vomiting and diarrhoea.
In ruptured EP, there may be abdominal distension and tenderness, peri-
tonism and haemorrhagic shock. A diagnosis of EP should be considered
in all women of reproductive age with a sudden onset of abdominal pain
or gastrointestinal symptoms (Lewis, 2007).
Ultrasound diagnosis
The use of ultrasonography to diagnose EP was first described over
40 years ago (Kobayashi et al., 1969). However until the 1980s, the ultra-
sound ‘diagnosis’ was based on an inability to visualize an intrauterine
pregnancy (IUP) rather than definitive identification of an extrauterine
pregnancy. This was considered an indication for laparoscopy, with an in-
evitable high rate of ‘negative laparoscopy’ (Brown and Doubilet, 1994).
The use of TVS has changed the diagnostic approach to one based on
visualizing the ectopic mass (Condous et al., 2005a). TVS has been
demonstrated to be superior to transabdominal ultrasound (TAS),
with sensitivities for the diagnosis of EP in early studies of 77– 80% for
TAS and 88 –90% for TVS (Cacciatore et al., 1989; Valenzano et al.,
1991). As expertise and equipment has improved, the sensitivity of
TVS for the diagnosis of EP has increased further (Condous et al.,
2005a; Kirk et al., 2007a).
The accuracy of a diagnosis of tubal EP using ultrasonography
It is important to appreciate that not all EP will be seen using TVS and cer-
tainly not on one visit. A prospective study on over 5000 consecutive
women including 120 tubal EPs found that 73.9% were visualized on
TVS when the patient first attended the clinic (Kirk et al., 2007a). The
remaining cases were not seen and were initially classified as PUL.
Most EPs were then visualized on subsequent follow-up scans (prior to
252 Kirk et al.

surgery) making the overall sensitivity of TVS 98.3%. A number of other

studies have also assessed the accuracy of TVS for diagnosing tubal EP.
They too report high sensitivities of 87.0 –99.0% and specificities of
94.0 –99.9% (Braffman et al., 1994; Shalev et al., 1998; Atri et al., 2003;
Condous et al., 2005a; Kirk et al., 2008). A meta-analysis of 2216
women with an EP concluded that visualizing an adnexal mass separate
from the ovary using TVS had a sensitivity of 84.4% and specificity of
98.9% (Brown and Doubilet, 1994).
A study comparing the features of women with an EP who had a diag-
nosis made on the initial scan compared with those first classified as a
PUL found that EPs in the PUL group were too small and probably too
early in their natural history to be visualized, rather than being ‘missed’
(Kirk et al., 2008). Suboptimal quality ultrasound equipment, operator in-
experience, increased maternal body mass index, uterine fibroids or
ovarian pathology may also make visualization of an EP difficult.

Criteria for the ultrasound diagnosis of tubal EP

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Endometrium. There is no specific endometrial appearance or thickness
that reliably supports a diagnosis of EP (Mehta et al., 1999). In up to 20%
cases a collection of fluid may be seen within the endometrial cavity, clas-
sically referred to as a ‘pseudosac’ (Marks et al., 1979; Frates and Laing,
1995; Benson et al., 2013). However, an hypoechoic area in the endo-
metrial cavity is far more likely to be an early IUP (Doubilet and
Benson, 2010), and so a presumptive diagnosis of EP should not be
made solely on the basis of this finding.

Free pelvic fluid. A small amount of anechoic free fluid in the Pouch of
Douglas is commonly found with both intrauterine and ectopic gesta-
tions (Nyberg et al., 1991). The presence of echogenic fluid has been
reported in 28 –56% of women with an EP (Fleischer et al., 1990;
Nyberg et al., 1991). This correlates well with the surgical findings of hae-
moperitoneum (Sickler et al., 1998), but does not confirm tubal rupture,
as blood commonly leaks from the fimbrial tube. The amount of echo-
genic fluid visualized in the pelvis correlates closely with findings at
surgery. As a rule of thumb, if fluid reaches the fundus of the uterus or
is present in the utero-vesical pouch, it is significant. A further marker
of serious intra-abdominal bleeding is the presence of fluid in Morrison’s
pouch between the liver and the kidney. This simple examination forms
the basis of the focused assessment by sonography for trauma (FAST
scan) used in emergency departments (Scalea et al., 1999).
Tubal EP. Tubal EPs are usually positively diagnosed using ultrasound by
visualizing an adnexal mass that moves separate to the ovary. The most
common finding, in around 60% of cases, is an inhomogeneous or a non-
cystic adnexal mass sometimes known as the ‘blob’ sign (Braffman et al.,
1994; Shalev et al., 1998; Atri et al., 2003; Condous et al., 2005a; Kirk
et al., 2008) (Fig. 1). A meta-analysis of 10 studies found that this was
the most effective criterion on which to base the diagnosis of a tubal EP
(Brown and Doubilet, 1994), with a specificity, positive predictive value,
sensitivity and negative predictive value of 98.9%, 96.3%, 84.4% and
94.8%, respectively. The mass is generally spherical, but a more tubular ap-
pearance may be seen if bleeding creates a haematosalpinx.
In around 20% of cases it may be possible to visualize an empty extra-
uterine gestational sac or ‘bagel sign’ (Condous et al., 2005a; Kirk et al.,
2008). In another 20%, this sac may contain a yolk sac and/or an embry-
onic pole that may or may not have cardiac activity (see Fig. 1). The term
‘viable ectopic’ is applied when embryonic cardiac activity is visualized.
Figure 1 Transvaginal scan images of tubal ectopic pregnancies:
(a) an inhomogeneous mass and (b) a yolk sac and fetal pole in an extra-
uterine sac.
Some authors consider that a definitive diagnosis of tubal EP can only
be made when an extra-uterine gestation sac containing a yolk sac or em-
bryonic pole is visualized (Barnhart et al., 2011). A recent consensus on
nomenclature proposed that the term ‘definite EP’ be used if a yolk sac
and/or embryo (with or without cardiac activity) is seen (Barnhart
et al., 2011). The term ‘probable EP’ is suggested if an inhomogeneous
mass or an extrauterine sac-like structure is visualized. Using this classi-
fication, the specificity of ultrasound to detect EP is very high, but the sen-
sitivity is lower as the inhomogeneous and empty sac masses are not
counted as definitive EPs.
The rationale for reserving the term ‘definite EP’ to those with embry-
onic structures is that false-positive diagnoses of EP, though rare, are
found even when the criteria for diagnosis are very strict (Krag Moeller
et al., 2009), likely due to other pathology such as the presence of ped-
unculated or broad ligament fibroids, pelvic inflammation or highly exo-
phytic ovarian cysts. This more conservative approach is linked to the
need for a very high level of diagnostic certainty in the event that
medical treatment is being considered. If methotrexate is used, a false-
positive diagnosis of EP may lead to the inadvertent termination of an un-
detected IUP (Nurmohamed et al., 2011), or severe abnormality in any
surviving pregnancy. The American College of Obstetricians and Gyne-
cologists (ACOG) recommend that methotrexate only be administered
Current concepts in ectopic pregnancy and PUL 253

to women with a ‘probable ectopic pregnancy‘ (as opposed to ‘defini-
tive’) in cases where the hCG has been serially monitored to confirm
the change is incompatible with an IUP. The difficult issue is how to
define ‘incompatible’. The ACOG defines this as a ,53% rise in hCG
over 48 h (Agency for Healthcare Research and Quality, 2008).
However, Condous et al. showed that a viable IUP may have an hCG
rise of significantly ,50%, so giving methotrexate with an hCG rise of
53% could possibly lead to termination of a wanted pregnancy.
An hCG rise of ,35% is now considered a safer definition of non-viability
in women with probable EP when methotrexate is being considered
(Seeber et al., 2006).
The lower threshold of an initial ultrasound finding of an inhomogen-
eous mass or empty sac structure is reasonable for the majority of
women, when surgical or expectant management is proposed, as the
management options do not jeopardize any possible intrauterine gesta-
tion. The criteria for ultrasound diagnosis of a tubal EP are summarized in
Table I.
in the authors’ opinions, this guidance will inevitably lead to cases where a
viable intauterine pregnancy is terminated in error (Newbatt et al., 2012;
Bourne et al., 2013).
Pulsed Doppler ultrasound has been examined as a tool for diagnosing
EP. However, the range of values for vascular indices associated with an
EP means that there is significant overlap with those associated with
angiogenesis within a corpus luteum (Bourne et al., 1991; Jurkovic
et al., 1992; Pellerito et al., 1995). Currently Doppler is not considered
to significantly contribute to the diagnosis of EP.
Surgical diagnosis
Most surgery for EP is now carried out as a therapeutic procedure after an
EP has been diagnosed with TVS (Jurkovic and Wilkinson, 2011). Diag-
nostic surgery is generally reserved for women presenting with signs of
an acute abdomen and hypovolaemic shock. A surgical diagnosis may
also be made in women with a PUL who become symptomatic. Although

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Against this background the recent guidelines in the UK published by
the National Institute for Clinical Excellence are a major concern. This
guidance recommends the use of methotrexate as the first-line treat-
ment for EP; however, no consideration is given to definitively excluding
the possibility of a viable IUP. The presumption therefore is that a false-
positive diagnosis of EP is not possible, which is clearly wrong. If followed,
laparoscopy is still considered by some to be the ‘gold standard’ for diag-
nosing EP, this position is now untenable given the high predictive value of
ultrasound (Condous et al., 2005a), the widespread use of conservative
management strategies and the clinical reality that false-positive and
-negative diagnoses of EP occur even at surgery (Li et al., 1991; Atri
et al., 1996). If an EP cannot be visualized with TVS performed by an

Table I Sonographic criteria for the diagnosis or ectopic pregnancies.

Type of EP Sonographic criteria

.............................................................................................................................................................................................
Tubal (1) Empty uterine cavity
(2) An inhomogeneous adnexal mass or, an empty extra-uterine gestation sac or a yolk sac or fetal pole + cardiac activity
in an extra-uterine sac
Interstitial (1) Empty uterine cavity
(2) Products of conception/gestation sac located in the interstitial (intramyometrial) portion of the tube
surrounded by a continuous rim of myometrium
(3) Interstitial line sign (thin echogenic line extending from a central uterine cavity echo to the periphery of the interstitial sac)
Cornual (1) A single interstitial portion of the Fallopian tube in the main uterine body
(2) Products of conception/gestation sac mobile and separate from the uterus surrounded by the myometrium
(3) Vascular pedicle joining the gestational sac to the unicornuate uterus
Cervical (1) Empty uterine cavity
(2) Barrel shaped cervix
(3) Products of conception/gestation sac below the level of the internal cervical os
(4) Negative sliding organ sign
Caesarean section scar (1) Empty uterine cavity
(2) Products of conception/gestation sac located anteriorly at the level of the internal os covering the presumed site of the previous
lower segment Caesarean section scar
(3) Negative sliding organ sign
(4) Evidence of peritrophoblastic flow on color Doppler examination
Ovarian (1) Empty uterine cavity
(2) Cystic structure with a wide echogenic ring on or within the ovary, generally seen surrounded by ovarian
cortex and separate from the corpus luteum
Intramural (1) Empty uterine cavity
(2) Products of conception/gestation sac completely surrounded by myometrium and separate from the endometrial cavity
Abdominal (1) Empty uterine cavity
(2) No evidence of a dilated Fallopian tube or complex adnexal mass
(3) Gestation sac surrounded by loops of bowel and separated by peritoneum
(4) Wide mobility similar to fluctuation of the sac

Ackerman et al. (1993); Timor-Tritsch et al. (1994); Jurkovic et al. (1996); Jurkovic et al. (2003); Gerli et al. (2004); Jermy et al. (2004); Comstock et al. (2005); Condous et al. (2005a);
Laing(2007); Jurkovic and Marvelos (2007).
254
experienced operator, there is a low chance of finding a visible EP at
laparoscopy. In one study 4.5% (2/44) of women were subsequently
diagnosed with an EP following a negative laparoscopy (Li et al., 1991).
Another study reported a 3 –4% false-negative rate and 5% false-positive
rate associated with laparoscopy (Atri et al., 1996).
Non-tubal Ectopic Pregnancy
Up to 7% of EP are located outside the Fallopian tube (Bouyer et al.,
2002). Although relatively rare, these pregnancies are responsible for sig-
nificant morbidity and mortality (Lewis, 2007). The diagnostic criteria for
non-tubal EP are shown in Table I. Although these criteria exist, there are
a paucity of data relating to their diagnostic performance, and care must
be taken to avoid misdiagnosis. A common example is of a normal IUP
implanted laterally in an arcuate uterus being misdiagnosed as an intersti-
tial pregnancy. Furthermore, new developments in ultrasonography have
rendered some of these criteria redundant. Using 3D ultrasound, a
coronal view of the uterus can be obtained. This view means that invari-
ably a connection can be seen between the endometrial cavity and inter-
stitial portion of the Fallopian tube (Fig. 2). In the future it seems highly
Figure 2 Interstitial ectopic pregnancy: (a) 2D grey-scale image and
(b) 3D image.
Kirk et al.
likely that the use of 3D ultrasound in this context will be an integral
part of diagnostic guidance (Lawrence and Jurkovic, 1999).
The classification of a Caesarean section scar pregnancy may also be
difficult as it is not unusual for a gestation sac to implant over a scar,
without extending into the scar (Naji et al., 2013). Given these uncertain-
ties, there is an argument that all such pregnancies over or in a scar should
be referred to specialist centres both to confirm the diagnosis and for
treatment.
Heterotopic pregnancy
A heterotopic pregnancy occurs when any form of EP is found simultan-
eously with an IUP (Fig. 3). The incidence of heterotopic pregnancy in
natural conceptions was originally estimated to be 1 in 30 000 pregnan-
cies (DeVoe and Pratt, 1948). Clinically they are associated with assisted
reproductive techniques, where the incidence is thought to be 1 –3 in
100 pregnancies (Molloy et al., 1990; Fernandez and Gervaise, 2004).
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The risk increases in proportion to the number of embryos transferred
with IVF. If more than 4 embryos are transferred the risk has been
quoted as 1 in 45 (Dor et al., 1991). In clinical practice, it is important
to remember that visualizing an IUP does not exclude the presence of
a further pregnancy elsewhere in the pelvis, especially if the pregnancy
is the result of IVF.
Figure 3 Heterotopic pregnancy: (a) 2D grey-scale image and (b) 3D
image. The two images are not of the same case.
Current concepts in ectopic pregnancy and PUL
Pregnancy of unknown location
‘Pregnancy of unknown location’ (PUL) is a descriptive term used to clas-
sify a pregnancy when a TVS has shown no signs of either an intrauterine
or extrauterine pregnancy or retained products of conception. Studies
report that 5–42% of women attending for an ultrasound assessment
in early pregnancy will be classified as having a PUL (Hahlin et al., 1995;
Cacciatore et al., 1998; Banerjee et al., 1999, 2001; Condous et al.,
2004a). Reports from specialized early pregnancy units describe lower
PUL rates of 8 –10% (Kirk et al., 2007b; Cordina et al., 2011). A consen-
sus statement produced by the International Society of Ultrasound in
Obstetrics and Gynecology stated that modern units should try to main-
tain a PUL rate of ,15% (Condous et al., 2006a). The PUL rate may be
influenced by a number of factors but in particular the quality of the ultra-
sonography performed within a unit is important. Accordingly, it has
been proposed as a benchmark for judging the performance of any facility
offering early pregnancy ultrasound.
Diagnosis
PUL is not a diagnosis. It is a term used to classify a pregnancy until the
final clinical outcome is known. Any woman classified as having a PUL
needs follow-up to determine the final clinical outcome, which may be
an ongoing viable IUP, a failed pregnancy, an EP or rarely a persisting
PUL. The need for appropriate clinical supervision and follow-up when
caring for women with a PUL was highlighted in the 2006–2008
Centre for Maternal and Child Enquiries report where a maternal
death secondary to a ruptured EP occurred in a woman where a preg-
nancy described as a PUL was subsequently inappropriately managed
(O’Herlihy, 2011). Current thinking has moved away from establishing
pregnancy location towards triaging PUL according to the risk of harm
to the patient. Accordingly probable EPs are designated as high risk
and probable IUP are classified as low risk alongside PUL that are des-
tined to fail. In this way appropriate follow-up arrangements can be
made that reflect the chance of a complication occurring.
Before a pregnancy can be classified as a PUL, it follows that there need
to be clear criteria for definitively diagnosing IUP and EP. Unfortunately,
these criteria vary worldwide which partly explains why PUL rates and
subsequent outcomes differ both between units and in the literature.
In a recent review, there was such clinical heterogeneity in the definition
of PUL outcome, that only data for the outcome EP could be analyzed
(Van Mello et al., 2012). A consensus paper with authors from the
USA, UK, Belgium, the Netherlands and Australia also highlighted this
problem (Barnhart et al., 2011). The issue relates to when it is considered
safe to make a definitive diagnosis of a pregnancy in the uterus or tube.
These areas of uncertainty are outlined below.
PUL or early IUP?
When a small empty intrauterine gestational sac-like structure is visua-
lized on TVS, the concern is that it may not be a true gestation sac but
a collection of fluid in the endometrial cavity (‘pseudosac’). In the
absence of any visible embryonic structures, some operators will classify
such a finding as a PUL. To overcome this, Barnhart et al in their consen-
sus paper suggested the following new categorization system for initial
ultrasound findings:
(i) Definite EP: extrauterine gestational sac with yolk sac and/or
embryo (with or without cardiac activity).
255
(ii) PUL-probable EP: inhomogeneous adnexal mass or extrauterine
sac-like structure.
(iii) ‘True’ PUL: no signs of either an intrauterine or extrauterine preg-
nancy on TVS.
(iv) PUL-probable IUP: intrauterine gestational sac-like structure.
(v) Definite IUP: intrauterine gestational sac with yolk sac and/or
embryo (with or without cardiac activity).
Generally in the USA and some units in the UK where the broader def-
inition of PUL is used encompassing points 2, 3, and 4 above, a small intra-
uterine gestational sac without obvious embryonic structures would be
classified as a PUL. In other units, the same findings would be regarded as
confirmation of an intrauterine gestational sac.
PUL or miscarriage?
When a woman presents with a PUL and a history of heavy bleeding it is
tempting to make a diagnosis of complete miscarriage. However, the evi-
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dence shows that such cases should be classified as PUL and evaluated
further unless a prior ultrasound has confirmed an IUP. In a study of
152 women with such a history, 5.9% were subsequently found to
have an underlying EP (Condous et al., 2005b).
Difficulty also arises in women found to have a slightly thickened or ir-
regular endometrium with a possible small amount of retained products
of conception. We know that measurements of endometrial thickness or
volume on TVS are not good tests for predicting the finding of chorionic
villi at curettage, and so are unreliable for diagnosing an incomplete mis-
carriage (Sawyer et al., 2007), although the use of power Doppler has
been reported as being useful for confirming the presence of significant
retained products in the cavity (Casikar et al., 2012). There is currently
no consensus on the correct management of these cases. Where no de-
finitive retained products of conception are seen, it would seem appro-
priate to adopt the safer approach and manage these cases as PUL, thus
also avoiding the possibility of curettage in the presence of a potentially
viable early IUP. It follows that some units with very high PUL rates may
be managing a larger proportion of incomplete miscarriages as PUL
because of this diagnostic uncertainty.
PUL or EP?
In some protocols, the criteria to definitively diagnose an EP require an
extra-uterine gestational sac with a yolk sac or embryo to be visualized
(Barnhart et al., 2011). Therefore when an inhomogeneous adnexal
mass is seen, an initial classification of PUL will be made. This will lead
to more EP being classified as PUL. If a sonographer feels unable to cat-
egorically make a diagnosis of EP, it is now recommended that a diagnosis
of ‘probable EP’ be made (Barnhart et al., 2011).
These different approaches to the classification of PUL reflect the clin-
ical environment of a given unit. If the quality of ultrasound is inconsistent,
patient compliance low, and risk of litigation high, then criteria used to
make a definitive diagnosis of an IUP or EP will be more exacting. The
result will be that more women will be classified as having a PUL and
undergo some sort of supervised follow-up. When ultrasound findings
can be relied upon and patients can be expected to return to the clinic
in the event of problems, the balance of risk changes and diagnostic cri-
teria may be looser. The stricter criteria for making a definitive diagnosis
of EP become particularly relevant when treatment with methotrexate is
being considered.
256 Kirk et al.

Clinical outcomes misconception that a single level of serum hCG, for example
,1000 IU/l, means an EP is unlikely. This is a false assumption as the ma-
There are four possible clinical outcomes once a pregnancy has been
jority of EPs detected in modern practice have initial serum hCG values
classified as a PUL: an IUP or failed PUL (low risk of complications) or
below this level (Condous et al., 2005c). Similarly, a high hCG (for
an EP or persistent PUL (higher risk of complications). The concern for
example .2000 IU/l) does not necessarily exclude the presence of a
clinicians when a woman is classified with a PUL is that a diagnosis of
viable IUP, although it makes it less likely (because a miscarriage may
EP may have been missed. Hence, previously the clinical scenario we
be classified as a PUL before the hCG level has declined significantly).
now call a PUL would often be categorized as a ‘query ectopic’ or
In contrast serial measurement of serum hCG offers good test per-
‘ectopic until proved otherwise’. This is entirely inappropriate as the
formance for predicting viability and is certainly better at predicting loca-
terms are clearly not synonymous. Evidence shows that from 6% and
tion than measurements of serum progesterone. The use of the serial
at most 20% of women with a PUL have an EP (Hahlin et al., 1995;
hCG level was first described by Kadar and Romero in 1981 who sug-
Banerjee et al., 1999, 2001; Condous et al., 2007a, b; Kirk et al.,
gested that the minimal rate of increase in serum hCG with a viable
2007b). Between 30 and 47% of PUL are ultimately diagnosed with an
IUP was 66% in 48 h. A subsequent study showed the minimum rise in
ongoing IUP (Kirk et al., 2006, 2007b; Condous et al., 2007a; Bignardi
hCG for a viable IUP to be 24% at 24 h and 53% at 48 h (Barnhart
et al., 2010) with the majority (50 –70%) found to be failing pregnancies
et al., 2004a). More recently, a rise of 35% over 48 h was proposed as
where the location is never confirmed (Banerjee et al., 1999, 2001;
the minimal rise consistent with a viable IUP (Seeber et al., 2006). In clin-
Condous et al., 2006a, 2007a; Kirk et al., 2007b). It is therefore clear
ical practice many units use a minimum value of between 50 and 66% to
that most women with PUL are not at risk of significant complications.

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indicate an increase in serum hCG compatible with viability (Horne et al.,
Recent management protocols have begun to reflect this, with the em-
2011), but this is not sufficiently conservative and may lead to inadvertent
phasis on triage according to risk rather than establishing pregnancy loca-
termination of a pregnancy should an intervention be carried out.
tion (Cordina et al., 2011; Van Calster et al., 2013).
It should also be remembered that some EP also demonstrate a
A very small proportion of women with a PUL may be given the de-
‘normal’ rise in hCG.
scriptive term of ‘persisting PUL’. In such cases the hCG level does not
The changes expected in serum hCG levels over 48 h for failing PULs
spontaneously decline and no intrauterine or EP is identified on follow-up
have also been examined. The rate of decline in hCG is dependent on the
TVS (Condous et al., 2004a). These are likely to be either a small EP that
initial serum hCG level, with a more rapid decline associated with higher
has not been visualized or retained trophoblast in the endometrial cavity.
starting concentrations (Barnhart et al., 2004b). In a study, the rate of
The final classification of a persisting PUL is dependent on the interven-
hCG decline ranged from 21 to 35% at 48 h to 60 to 84% at 7 days
tion or treatment given and includes: treated persistent PUL, resolved
(Barnhart et al., 2004b). The change in serum hCG over 48 h may be re-
persistent PUL and non-visualized EP. These are explained in more
ferred to as the hCG ratio (hCG at 48 h/hCG at 0 h). A decrease in hCG
detail in the 2011 consensus statement (Barnhart et al., 2011).
of .13% or an hCG ratio of ,0.87 has a sensitivity of 92.7% and speci-
A treated persistent PUL is defined as one managed medically with
ficity of 96.7% for predicting a failing PUL (Condous et al., 2006b).
methotrexate without confirmation of the location of the pregnancy
Unfortunately, there is no single method to characterize the pattern of
by ultrasound, laparoscopy or uterine evacuation. These cases are im-
serum hCG change over 48 h in women classified with a PUL who are
portant as treatment should only be considered when a potentially
subsequently diagnosed with an EP (Silva et al., 2006). Up to 15–20%
viable IUP has been definitively excluded (Agency for Healthcare Re-
will have serum hCG doubling times similar to that of an IUP whilst
search and Quality, 2008).
around 10% EP will have hCG pattern behaving like a failing PUL
A resolved persistent PUL is defined as resolution of serum hCG to a
(Goldstein, 2006; Silva et al., 2006). The majority though, will have
non-pregnant value after expectant management or after uterine evacu-
serial serum hCG levels that increase more slowly than would be
ation without evidence of chorionic villi on pathological examination. If
expected with an IUP (‘suboptimal rise’) or decrease more slowly than
the hCG level rises after a uterine evacuation which fails to identify chori-
would be expected with a failing PUL. The sensitivity of the serum
onic villi, a diagnosis of a ‘non-visualized EP’ can be made. In the rare event
hCG ratio to predict EP ranges from 74 to 100% and the specificity
of relatively low and unresolving levels of serum hCG, clinicians should
ranges from 28 to 97% (Van Mello et al., 2012).
also be alert to the possibility of an hCG-secreting tumour being
present (Condous et al., 2003; Einenkel et al., 2010; Cong et al., 2011).
Progesterone. The serum progesterone level is a good indicator of early
The optimal management of persisting PUL is not known and there is
pregnancy viability, but a poor predictor of location. Levels of
the need for a randomized trial between expectant management,
,20 nmol/l have a high positive predictive value for failing pregnancies
uterine curettage and methotrexate. There is no International Classifica-
(Banerjee et al., 2001), whilst levels .25 nmol/l are ‘likely to predict’
tion of Diseases (ICD-10) code for a final diagnosis of persistent or
and levels .60 nmol/l are ‘strongly associated with’ viable pregnancies
resolved PUL. A new code has been ascribed to such cases in
(RCOG, 2006). A meta-analysis of 26 studies was performed to assess
Denmark and the authors recommend such a classification is adopted
the accuracy of a single progesterone level for the diagnosis of EP (Mol
internationally.
et al., 1998). This study found that progesterone did not have sufficient
discriminative capacity to diagnose EP with certainty.
Serum biochemistry The utility of progesterone is in fact in selecting women with failing PUL
Human chorionic gonadotrophin. Single measurements of serum hCG are as being at low risk and so needing reduced follow-up. Whether these
not used to predict the outcome of PUL. A recent meta-analysis con- failing PUL are failing EP or failing IUP is not of clinical importance.
firmed that absolute single levels of hCG perform poorly as a predictor A recent systematic review and meta-analysis (5 studies with 1998 par-
of PUL outcome (Van Mello et al., 2012). There is a common ticipants and cut-off values from 3.2 to 6 ng/ml) has shown that a single
Current concepts in ectopic pregnancy and PUL
progesterone level predicts a non-viable pregnancy with a pooled sensi-
tivity of 74.6% (95% confidence interval 50.6 –89.4%), specificity of
98.4% (90.9–99.7%), positive likelihood ratio of 45 (7.1 –289) and nega-
tive likelihood ratio of 0.26 (0.12–0.57) (Verhaegen et al., 2012).
Other serum markers. Creatine kinase, cancer antigen 125, activin A,
inhibin A, inhibin pro-aC-related immunoreactivity and insulin-like
growth factor-binding protein have all been evaluated (Condous et al.,
2005c; Kirk et al., 2009; Chetty et al., 2011). Of these, inhibin A may
be useful for predicting spontaneous resolution of PUL, but is not as
good as progesterone (Kirk et al., 2009; Chetty et al., 2011).
Finding a novel marker to better discriminate EP from the rest of the
PUL population nevertheless remains an important area of research.
Recent attention has focused on metalloprotease 12 (ADAM 12)
(Rausch et al., 2011) and fibronectin (Brown et al., 2013) as potentially
promising candidate markers.
Mathematical prediction models
A number of mathematical models have been developed for the predic-
tion of PUL outcome. These include logistic regression models and
Bayesian networks, based on variables such as serum hCG and proges-
terone levels, endometrial thickness and the amount of vaginal bleeding
(Banerjee et al., 2001; Condous et al., 2004b, 2007a, b; Gevaert et al.,
2006). These models have been shown to have high sensitivities for
the prediction of PUL outcome and can be used to rationalize follow-up
(Kirk et al., 2007b). The most widely evaluated model developed is M4
(Condous et al., 2007a), which takes into account the fact that the
initial hCG level adds information regarding the likely outcome as well
as the hCG ratio.
Rationalizing follow-up
Initially mathematical models were optimized to identify EPs in the PUL
population. The main aim for their use now is to identify PUL that are ‘low
risk’ (failing PULs and IUPs) in order to safely reduce follow-up for these
pregnancies whilst focusing resources towards pregnancies at increased
risk of being an EP. In a multi-centre diagnostic accuracy study of 1962
patients using the model M4 to predict outcome, 62 –75% of PULs
were considered low risk of which 96–98% were confirmed to have
either a failed PUL or IUP (Van Calster et al., 2013). In contrast,
80 –92% of EPs were considered high risk. In the majority of EP, allocated
to the low-risk group, the hCG ratio was declining and so it is likely that
these EP would have resolved without the need for intervention.
It is interesting to contrast this approach with the PUL triage study
using single measurements of progesterone evaluated by Cordina et al.
(2011). In this study a serum progesterone of ,10 nmol/l was used to
define a failing pregnancy. Of 676 PUL, 252 were classified as failing
PUL with this approach and only 4 of these needed intervention.
These results, although not externally validated, are of interest, though
with 252 failing PUL in the study, and with 10% of these cases lost to
follow-up, it is hard to make a definitive comment on safety. These
results contrast with those of Condous et al. (2005e). He defined a
low-risk PUL as one with a single hCG of ,25 IU/l or progesterone
of ,10 nmol/l. It was found that when this approach was applied retro-
spectively, 84% of non-ectopic or failing pregnancies could have been dis-
charged from the system, but at a cost of 67% of EP in the study
population potentially having no further follow-up. This study suggests
257
a single visit strategy should be approached with caution pending external
validation of the approach.
The problem with the use of serum progesterone is that it classifies
many viable IUP as high risk, which clearly limits the ability to function
as an effective triage tool. The M4 model, on the other hand, classifies
both failing pregnancies and viable IUP as low risk, which greatly enhances
its utility for triage. Looking forward, it seems likely that a system using
both progesterone and hCG as a two-step procedure will be the
optimal approach which will enable some failing PUL to be triaged at
the initial visit, and the residual pregnancies should be triaged at 48 h
after application of the M4 model. The M4-based protocol can be
accessed from the following link: http://homes.esat.kuleuven.be/~
biomed/M4PUL/M4triage.htm.
Surgical intervention
The combination of the absence of a visualized IUP using TVS and a serum
hCG level above a set discriminatory zone historically was considered an
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indication for diagnostic laparoscopy. This is no longer the case. Laparos-
copy is now rarely indicated unless a woman is symptomatic or haemo-
dynamically unstable. This is because many failing PUL and some IUP may
have initial hCG levels above, and some clinically significant EP will have
hCG levels below, given any discriminatory zone. Condous et al.
(2005d) evaluated the diagnostic accuracy of discriminatory zones for
hCG levels of .1000, 1500 and 2000 IU/l for the detection of EP in
women with a PUL. It was found that as the discriminatory zone
increases, the sensitivity to detect EP decreases, and most EP in the
population of women with PUL studied had serum hCG levels below
the often-quoted discriminatory zone of 1000 IU/l.
Uterine curettage is used by some clinicians to diagnose pregnancy lo-
cation with the aim of differentiating between an EP and a non-viable IUP.
Advocates of curettage report that a failure to definitively ascertain the
location of a pregnancy may have implications for counseling about
future risk of EP and lead to unnecessary exposure to methotrexate
(Chung et al., 2011). However, there is the risk that a potentially
ongoing IUP may be terminated if the preoperative criteria are not strin-
gent enough to exclude a viable IUP before the procedure. Recognized
indications for curettage include: (i) no visible IUP on TVS with a
serum hCG . 2000 IU/ml; (ii) an abnormal rise in hCG level, defined
as ,50% increase in 2 days and (iii) an abnormal fall in hCG level,
defined as ,20% decline in 2 days (Chung et al., 2011). In a study of
321 women who underwent uterine curettage with no visible IUP or
those with an abnormal hCG trend, 73.2% were ultimately diagnosed
with an EP whilst 26.8% were found to have a non-viable IUP (Chung
et al., 2011). These and other biochemical criteria that define non-
viability in the PUL population have been evaluated to establish if the
criteria used could result in inadvertent termination of a pregnancy if
curettage was performed (Condous et al., 2006c). Up to 12.3% of
women undergoing curettage were deemed at risk of having a viable
IUP interrupted (Condous et al., 2006c). Uterine curettage should there-
fore not be used routinely in the management of PUL but may have a role
in diagnosing the location of failing PULs, once the possibility of a poten-
tially viable IUP has been excluded.
Clinical management
The majority of women categorized with a PUL have minimal or absent
symptoms and are haemodynamically stable. Expectant outpatient
258
management of such cases is safe (Hahlin et al., 1995; Banerjee et al.,
1999, 2001; Kirk et al., 2007b). All compliant women with a PUL
should be counselled about the possible outcomes and be given
written information detailing the plan for further investigation and
when and how to seek urgent medical care during any follow-up period.
The majority of women classified with a PUL will be subsequently diag-
nosed with a failed pregnancy, resolving spontaneously without interven-
tion (Banerjee et al., 1999). There is no consensus on what is an
acceptable surgical intervention rate in women classified with a PUL
(Condous et al., 2006a), although studies report rates of between 0.5
and 11% (Banerjee et al., 2001; Condous et al. 2003; Kirk et al., 2007b;
Cordina et al., 2011). It is evident that the management of PUL needs
to concentrate resources and surveillance on women with the highest
risk of significant pathology, whilst minimizing intervention and follow-up
in women at low risk of complications.
Most women with a PUL are followed up with serum hCG measure-
ments and repeat TVS examination until a final diagnosis is confirmed.
Women with PUL should be triaged into low- and high-risk groups
that require different levels of intensity for follow-up. By using the M4
model or hCG ratio, PUL may be classified as being ‘low-risk failing’ or
‘low-risk intrauterine’. ‘Low-risk failing’ may be followed up with a
urinary pregnancy test after 2 weeks and telephone advice. A woman
with a ‘low-risk intrauterine’ may return for an ultrasound scan to
Figure 4 Possible PUL management algorithm. *Women must be given information and advice, be deemed compliant with follow-up and have no sig-
nificant language or other communication barrier. Women should be advised to return for review before the scheduled follow-up visit if they have any severe
pain or concerns. **If hCG . 1000 IU/l at 0 h and history not suggestive of complete miscarriage, then repeat TVS as soon as possible. Adapted from
Condous et al. (2006b); Kirk et al. (2007b). TVS, transvaginal ultrasound.
Kirk et al.
assess viability in 2 weeks. In the event of being classified as high risk,
further assessment is required either with a further ultrasound scan
within 48 h or a further hCG measurement. Figure 4 summarizes sug-
gested management algorithms for PUL.
Future work
The ideal diagnostic tool for an EP would be a single serum marker to
replace ultrasound and serial biochemistry (Shaw et al., 2010a). While
the major focus of work until now has been on diagnosing all EP, reliable
tools are needed to identify those women with EP or PUL who do not
require active intervention.
The common assumption is that earlier diagnosis of EP means more
effective management, because more conservative management
options may be employed (Hajenius et al., 2007), although this is not
borne out in studies thus far (Fernandez et al., 2013; Van Mello et al.,
Downloaded from http://humupd.oxfordjournals.org/ by guest on January 12, 2017
2013). Until robust evidence suggests that medical treatment leads to
lower subsequent EP rates or higher subsequent IUP rates, then the
overall benefit from earlier diagnosis is unproved providing the diagnosis
is made prior to tubal rupture. It is likely that women with suspected or
definite EP that would otherwise spontaneously resolve are currently
being over-treated.
Current concepts in ectopic pregnancy and PUL
Conclusion
The primary assessment approach for a woman with a possible EP is
ultrasonography. This should be carried out transvaginally and all
recent data on diagnosing EP, defining PUL, performance of discrimin-
atory zones and diagnosing miscarriage relate to this approach. Ultra-
sound is operator dependent and requires appropriate training and
significant experience for good results to be obtained. We have shown
that where there is easy access to expertise and equipment to provide
high-quality TVS, the vast majority of women with tubal EPs may be diag-
nosed rapidly and accurately. The diagnosis of non-tubal EP can also be
achieved through careful ultrasound assessment, although diagnosis is
more often delayed leading to increased morbidity.
The need for a single serum marker for EP and a method to differen-
tiate between women with PUL and EP who do and do not require inter-
vention are the current diagnostic challenges. The current trend in the
management of PUL is thus directed to detecting the women with
‘low-risk’ PUL who can undergo minimal follow-up whilst concentrating
resources on the women with ‘high-risk’ PUL in whom the majority of
harmful EPs will be found. In the meantime, algorithms such to manage
women with PUL safely, consistently and with minimal unnecessary inter-
vention should be adopted.
Authors’ roles
All three authors (E.K., C.B and T.B.) made substantial contributions to
the plan of the article, review and interpretation of the literature and
drafting and revision of the manuscript. All authors approved the final
version to be published.
Funding
T.B. is supported by the National Institute for Health Research (NIHR)
Biomedical Research Centre based at Imperial College Healthcare
NHS Trust and Imperial College London. The views expressed are
those of the authors and not necessarily reflect those of the NHS, the
NIHR or the Department of Health.
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