Diagnosis and Management of Ectopic Pregnancy: Europe PMC Funders Group

Europe PMC Funders Group
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J Fam Plann Reprod Health Care. Author manuscript; available in PMC 2012 January 01.
Published in final edited form as:
J Fam Plann Reprod Health Care. 2011 October ; 37(4): 231240. doi:10.1136/jfprhc-2011-0073.
Europe PMC Funders Author Manuscripts
Diagnosis and management of ectopic pregnancy

Vanitha N Sivalingam1, W Colin Duncan2, Emma Kirk3, Lucy A Shephard2, and Andrew W
Horne2
1Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, 51 Little France
Crescent, Edinburgh EH16 4SA
2MRC
Centre for Reproductive Health, University of Edinburgh, Queens Medical Research

Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
3North
Middlesex University Hospital, Sterling Way, London, N18 1QX
Keywords
ectopic pregnancy; beta-human chorionic gonadotrophin; transvaginal ultrasound; methotrexate;
salpingectomy; salpingostomy
Overview
An ectopic pregnancy occurs when a fertilised ovum implants outside the normal uterine
cavity.1-3 It is a common cause of morbidity and occasionally of mortality in women of
reproductive age. The aetiology of ectopic pregnancy remains uncertain although a number
of risk factors have been identified.4 Its diagnosis can be difficult. In current practice, in
developed countries, diagnosis relies on a combination of ultrasound scanning and serial
serum beta-human chorionic gonadotrophin (-hCG) measurements.5 Ectopic pregnancy is
one of the few medical conditions that can be managed expectantly, medically or
surgically.136
Incidence
In the developed world, between 1% and 2% of all reported pregnancies are ectopic
pregnancies (comparable to the incidence of spontaneous twin pregnancy).7 The incidence is
thought to be higher in developing countries, but specific numbers are unknown. Although
the incidence in the developed world has remained relatively static in recent years, between
1972 and 1992 there was an estimated six-fold rise in the incidence of ectopic pregnancy.8
This increase was attributed to three factors: an increase in risk factors such as pelvic
inflammatory disease and smoking in women of reproductive age, the increased use of
assisted reproductive technology (ART) and increased awareness of the condition, facilitated
by the development of specialised early pregnancy units (EPUs).
CORRESPONDING AUTHOR: Dr Andrew Horne, MRC Centre for Reproductive Health, University of Edinburgh, Queens
Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK, [email protected] Tel +44 131 242 6609, Fax
+44 131 242 6441.
COMPETING INTEREST:
Andrew Horne holds a UK patent for a diagnostic biomarker for ectopic pregnancy (# 0712801.0).
Sivalingam et al.
Page 2
Morbidity and mortality
In the UK, ectopic pregnancy remains the leading cause of pregnancy-related first trimester
death (0.35/1000 ectopic pregnancies).369 However, in the developing world it has been
estimated that 10% of women admitted to hospital with a diagnosis of ectopic pregnancy
ultimately die from the condition.10 Ectopic pregnancy is a considerable cause of maternal
morbidity, causing acute symptoms such as pelvic pain and vaginal bleeding and long-term
problems such as infertility.3 Short- and long-term consequences of ectopic pregnancy on
health-related quality of life and on bereavement issues are likely to be significant but have
not been formally quantified.
Risk factors
Although women with ectopic pregnancy frequently have no identifiable risk factors, a
prospective case-controlled study has shown that increased awareness of ectopic pregnancy
and a knowledge of the associated risk factors helps identify women at higher risk in order
to facilitate early and more accurate diagnosis.11 Most risk factors are associated with risks
of prior damage to the Fallopian tube (Box 1). These factors include any previous pelvic or
abdominal surgery, and pelvic infection.11 Chlamydia trachomatis has been linked to
30-50% of all ectopic pregnancies.12 The exact mechanism of this association is not known
but it has been proposed that in addition to distortion of tubal architecture, it may to be due
to an effect on the tubal microenvironment.13
Ectopic pregnancy is more common in women attending infertility clinics14 even in the
absence of tubal disease. In addition, the use of ART increases the rate of ectopic
pregnancies. In vitro fertilisation (IVF) is associated with an ectopic pregnancy risk of 2-5%
and it may be higher than this where there is tubal disease. Indeed the first IVF pregnancy,
before the first IVF live birth, was a tubal ectopic pregnancy.15
Some types of contraception, such as progestogen-only contraception and the intrauterine

contraceptive device, are associated with an increased incidence of ectopic pregnancy when
there is contraceptive failure, without necessarily increasing the absolute risk of ectopic
pregnancy.16
One third of all cases of ectopic pregnancy are thought to be associated with smoking.17
There is a doseeffect relationship, with the highest adjusted odds ratio (OR) (3.9) when
more than 20 cigarettes are smoked a day.18 Several mechanisms for this association have
been suggested, including one or more of the following: delayed ovulation, altered tubal and
uterine motility and microenvironment, or altered immunity.1920
The risk of ectopic pregnancy increases with advancing maternal age, with age over 35 years
being a significant risk factor.6 Hypotheses for this association include the higher
probability of exposure to most other risk factors with advancing age, increase in
chromosomal abnormalities in trophoblastic tissue and age-related changes in tubal function
delaying ovum transport, resulting in tubal implantation.18
Women with a previous history of ectopic pregnancy also have an increased risk, which
increases further in proportion to the number of previous ectopic pregnancies. In one study
the OR for having an ectopic pregnancy was 12.5 after one previous ectopic pregnancy and
76.6 after two.18
Sivalingam et al.
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Aetiology
The exact aetiology of ectopic pregnancy is unknown. It is notable that it is unique to

humans, and perhaps the higher apes, so that there are no good animal models that could be
used to further our understanding.21 However, it is thought that tubal implantation occurs as
a result of a combination of arrest of the embryo in the Fallopian tube and changes in the
tubal microenvironment that allow early implantation to occur.4 Inflammation within the
tube, resulting from infection or smoking, may affect embryo-tubal transport by disrupting
smooth muscle contractility and ciliary beat activity and may also provide pro-implantation
signals. Molecular research generally involves studying Fallopian tube biopsies taken from
women with ectopic pregnancies. Interpretation is limited as comparable Fallopian tube
samples are not available from women with an intrauterine pregnancy (IUP) or in advance
of an ectopic pregnancy occurring. Thus, it is difficult to ascertain whether any molecular
changes observed are a cause or a consequence of ectopic implantation. Novel studies
focusing on the functional consequences of smoking and infection on Fallopian tube
physiology and pathobiology are required.
Clinical presentation
Patients with an ectopic pregnancy commonly present with pain and vaginal bleeding
between 6 and 10 weeks gestation.1 However, these are common symptoms in early
pregnancy, with one third of women experiencing some pain and/or bleeding.22-24 The pain
can be persistent and severe and is often unilateral. However unilateral pain is not always
indicative of ectopic pregnancy as, in early pregnancy, a prominent painful ovarian corpus
luteum cyst is common. Shoulder tip pain, syncope and shock occur in up to 20% of women
and abdominal tenderness in more than 75%. Bimanual examination, if performed at all,
should be done cautiously and gently. Cervical motion tenderness has been reported in up to
67% of cases, and a palpable adnexal mass in about 50%.23-25 More recently, it has been
reported that one third of women with ectopic pregnancy have no clinical signs and 9% have
no symptoms.2627
A ruptured ectopic pregnancy should be strongly suspected if a woman has a positive

pregnancy test and presents with syncope and signs of shock including tachycardia, pallor
and collapse. There may be abdominal distension and marked tenderness. While a bimanual
examination may reveal tenderness, cervical excitation and an adnexal mass, great caution is
required as this may exacerbate bleeding. As ectopic pregnancy affects young, fit women
they are often able to mount remarkable haemodynamic compensation. Tachycardia is a
particularly important sign, but decompensation with shock is a sign of significant
intraperitoneal bleeding. In an emergency, where the patient has collapsed and there is high
clinical suspicion of tubal rupture, extensive clinical examination is inappropriate and
immediate surgical intervention is indicated.
Unfortunately, atypical presentation is also relatively common. Ectopic pregnancy may
mimic other gynaecological disorders and gastrointestinal or urinary tract disease, including
appendicitis, salpingitis, ruptured corpus luteum or follicular cysts, threatened or inevitable
spontaneous abortion, ovarian torsion and urinary tract infection. The 1997-1999 and
2003-2005 Confidential Enquiries into Maternal Deaths reports highlighted that most of the
women who died from ectopic pregnancy were misdiagnosed in the primary care or accident
and emergency settings.2829 It was therefore recommended that all clinicians should be
made aware of the atypical clinical presentations of ectopic pregnancy. While there has been
a welcome decline in the case death rate in women with ectopic pregnancies, a key lesson
emphasised in these reports does not appear to have been learnt. In the 2006-2008 Centre for
Maternal and Child Enquiries (CMACE) report, four of the six women who died from early
Sivalingam et al.
Page 4
ectopic pregnancy complained of diarrhoea, dizziness or vomiting as early symptoms,

without triggering any consideration of extrauterine pregnancy by their medical
attendants.30
However, it remains difficult to diagnose an ectopic pregnancy from risk factors, history and
examination alone. Clinicians should be suspicious of pregnancy in any such woman who
presents with abdominal or pelvic symptoms and should always bear in mind the possibility
of ectopic pregnancy in any woman of reproductive age who presents with any of the
symptoms mentioned above.
Diagnosis
Diagnosis of ectopic pregnancy has improved significantly due to advances in ultrasound
technology, rapid and sensitive serum hormone assays, the development of EPUs and an
increased awareness and understanding of the associated risk factors. Despite this, around
half of the women with an eventual diagnosis of ectopic pregnancy are not diagnosed at their
first presentation.3132 Early diagnosis reduces the risk of tubal rupture and allows more
conservative medical treatments to be employed.133
Currently, diagnosis in unruptured ectopic pregnancy is achieved using a combination of
transvaginal ultrasonography and measurement of serum -hCG concentrations. One of the
key elements in the diagnosis is the exclusion of a viable or non-viable IUP. Diagnosis can
be straightforward when a transvaginal ultrasound scan (TVS) positively identifies an IUP
or ectopic pregnancy34 (Figure 1). However, TVS fails to identify the location of a
pregnancy in a significant number of women and such women are currently diagnosed as
having a pregnancy of unknown location (PUL).3536
The 20062008 CMACE report drew attention to a maternal death secondary to ruptured
ectopic pregnancy where a diagnosis of PUL had been made.30 Although most patients with
a PUL will subsequently be diagnosed with either a failed IUP (a spontaneous abortion) or
viable IUP, the report highlights that 7-20% will be diagnosed with an ectopic pregnancy. It
is therefore very important that a diagnosis of PUL should trigger further diagnostic
pathways and follow-up until the final outcome of the pregnancy is known.
The concept of a discriminatory -hCG level was introduced in 1985 to highlight the
serum concentration of -hCG when a pregnancy should be visible on an ultrasound scan.
Using transabdominal ultrasound examination, it was reported then that the absence of an
intrauterine gestational sac at a -hCG concentration over 6500 IU/l had a sensitivity of
100%, specificity of 96%, positive predictive value of 87% and negative predictive value of
100% for the prediction of ectopic pregnancy. In the context of a 19.4% prevalence of
ectopic pregnancies in the study group, this diagnostic paradigm was 98% efficient.37 With
the introduction of high-resolution TVS, the discriminatory -hCG level of 6500 IU/l is now
less helpful.3538 An ectopic pregnancy can be detected at -hCG concentrations well below
this level and an ultrasound scan should not be delayed because of low -hCG
concentrations.
Transvaginal ultrasonography
High-definition ultrasonography, particularly using the transvaginal route, has
revolutionised the assessment of patients with early pregnancy problems, allowing for
clearer visualisation of both normal and abnormal gestations.39 In a healthy IUP, a TVS
should identify the intrauterine gestation sac with almost 100% accuracy at a gestational age
of 5.5 weeks.4041 Even so, it is recognised radiographic practice that an IUP is only
definitively diagnosed by ultrasound visualisation of a yolk sac or embryo in addition to a
Sivalingam et al.
Page 5
gestation sac.42-44 This is because an ectopic pregnancy can be accompanied by a

pseudosac, a collection of fluid within the endometrial cavity that may be the result of
localised breakdown of the decidualised endometrium. However, its central location within
the endometrial cavity distinguishes it from the very early gestation sac that is typically
eccentrically placed.45 In addition, pseudosacs are transient rather than consistent and they
do not have a hyperechoic decidual reaction around them. Additional embryonic features
including the yolk sac and cardiac activity should be clearly visible after 6 weeks gestation.
A sonographer with experience in early pregnancy scanning should generally be able to tell
the difference between a pseudosac and an empty early intrauterine sac.
The identification of an IUP can rule out ectopic pregnancy in most settings unless a
heterotopic pregnancy is suspected, where an ectopic pregnancy coexists with an IUP.46
They are rare (1 in 40 000), although more common after assisted conception, and difficult
to diagnose.
In the absence of an intrauterine gestation sac, an ectopic pregnancy can be diagnosed by the
presence of an adnexal mass, often visible within the Fallopian tube. The positive
identification of a non-cystic adnexal mass with an empty uterus has a sensitivity of 84-90%
and a specificity of 94-99% for the diagnosis of an ectopic gestation.47 In one large
prospective study of 6621 patients, ectopic pregnancy was correctly diagnosed by TVS with
a sensitivity of 90.9% and specificity of 99.9%.24 False positives can, however, occur if
other structures such as the corpus luteum, bowel, a paratubal cyst, a hydrosalpinx or an
endometrioma are mistaken for an ectopic pregnancy. False negatives can occur if the
ectopic is small or if it is concealed by bowel or uterine anomalies such as fibroids. It is
therefore possible for an ectopic pregnancy to go unnoticed on an ultrasound scan,
especially if the patient is asymptomatic.
Around 80% of ectopic pregnancies will be on the same side as the ovarian corpus luteum,
the identification of which can help in the search for an adnexal mass. The mass may appear
as an inhomogenous echogenic area adjacent to the ovary that moves separately from it on
gentle pressure; a gestation sac enclosed by a hyperechoic ring (the so-called bagel
appearance); or a gestation sac with a fetal pole, with or without cardiac activity.
Suspicion of an ectopic pregnancy increases if free fluid (representing blood) is visualised,
either surrounding the uterus or in the Pouch of Douglas,48 although a small amount of free
fluid in the Pouch of Douglas, a transudate due to increased vascular permeability, is
common in early pregnancy.
Box 2 summarises ultrasonographic findings that are useful in diagnosing an ectopic
pregnancy.
Serum -hCG concentrations

The changes in serum -hCG concentrations over time have been used to predict the
outcome of PULs.49 Kadar and Romero50 were the first to describe these serial changes on
the basis of a small sample of 20 women using an 85% confidence interval (CI). They
showed that in a normal ongoing pregnancy, the minimal rate of increase in -hCG is 66%
in 2 days. In a recent study of 287 patients with pain or bleeding, the minimum rise in hCG for a viable IUP was 24% at 24 hours and 53% at 48 hours.51 In addition, Seeber et
al.52 produced data with a 99% CI that suggested a more conservative minimum rise of 35%
over 2 days. In current practice most units use a minimum value of between 50% and 66%
for the acceptable 48-hour increase in -hCG in a normal pregnancy.53 Some non-viable
IUPs will also demonstrate an exponential increase in serum -hCG, so normal -hCG
Sivalingam et al.
Page 6
changes do not necessarily confirm viability. However, absence of this expected rise
suggests early pregnancy failure.
A rapid decline in -hCG concentrations over 2 days, commonly by 21-35% or more, is

indicative of a spontaneous abortion52 or a resolving ectopic pregnancy. In an ectopic
pregnancy, -hCG concentrations are just as likely to fall as to rise, with no single pattern
able to characterise the condition.54 However, 71% have serial serum -hCG values that
increase more slowly than would be expected with a viable IUP and decrease more slowly
than would be expected with a spontaneous abortion.9
If the history is not compatible with a spontaneous abortion, or the -hCG concentrations
continue to rise and the scan location of the pregnancy is still unknown, an ectopic
pregnancy is likely and a clear management strategy should be put in place.
Serum progesterone
Although there are no definitive values that demarcate an ectopic pregnancy from an IUP,
the measurement of serum progesterone levels is a potentially useful adjunct in the
assessment of PULs.55 Serum progesterone concentrations in a viable IUP are >50 ng/ml.
Although progesterone assessment cannot easily discriminate between an ectopic pregnancy
and a failing IUP56 some EPUs use a low progesterone (<5 ng/ml) to differentiate between
low-risk patients, when a PUL may be suitable for conservative management, and at-risk
patients who require definitive treatment.57
Other serum biomarkers

Although other potential serum biomarkers have been proposed,58 none of these are used in
common clinical practice. New biomarkers with clinical utility would be helpful in
improving the diagnosis of ectopic pregnancy, with the potential benefits of greater safety
and reduced diagnostic costs.532
Diagnostic laparoscopy
In cases where an ectopic pregnancy is suspected and ultrasound is inconclusive, a
diagnostic laparoscopy may be required. This is believed by many to be the gold standard
investigation in ectopic pregnancy. Indeed reluctance or delay in performing a diagnostic
laparoscopy has been highlighted as a factor in fatal cases.30 However, some small ectopic
pregnancies may be missed at the time of laparoscopy or laparotomy. In one study, 2 of 44
(4.5%) women reported to have no evidence of an ectopic pregnancy at the time of
laparoscopy were subsequently diagnosed with one.55 An alternative to diagnostic
laparoscopy may involve a repeat ultrasound examination, particularly when -hCG
concentrations are close to 1500 IU/l. Other strategies include alternative diagnostic tests,
such as serum progesterone or an endometrial biopsy, or empirical medical treatment as the
patient may well have an ectopic pregnancy. If -hCG concentrations are falling but an
ectopic has not been excluded, consideration should be given to performing serial -hCG
measurements until levels become undetectable, as rupture can still occur.40
Endometrial biopsy
In selected cases of PUL, an endometrial biopsy may be taken and analysed for the presence
or absence of chorionic villi. Their absence in the presence of a static -hCG is suggestive of
an ectopic pregnancy. A dilatation and curettage may be useful when performed in
association with a negative diagnostic laparoscopy for a suspected ectopic pregnancy. The
Sivalingam et al.
Page 7
clinician should be certain that the pregnancy, if intrauterine, is non-viable and appropriate
consent obtained, as this procedure could potentially interrupt a continuing pregnancy.
Management
Ectopic pregnancy may be managed surgically, medically or expectantly. In these days of

increasing outpatient diagnosis and management it is important to remember the risks of
ruptured ectopic pregnancy. Clear documentation of diagnostic and management strategies
with clinical, sonographic and biochemical assessment of the patient is therefore
important. Which management is most appropriate depends on ongoing assessment and on
numerous clinical factors. Management is tailored to individual patients, based on their
presentation and on the severity of their condition, suitability of treatment options and
patient preference. Figure 2 demonstrates a suggested diagnosis and management pathway.
Surgery
Surgical management is imperative in the clinical scenario of a ruptured ectopic pregnancy.
A laparoscopic approach is preferable to an open approach in a patient who is
haemodynamically stable. Laparoscopic procedures are associated with shorter operative
times, less intraoperative blood loss, shorter hospital stays and lower analgesia
requirements.59-61 Laparotomy should be reserved for patients who present with rupture and
are in a state of hypovolaemic shock and compromise. If the contralateral tube is healthy, the
preferred option is salpingectomy, where the entire Fallopian tube, or the affected segment
containing the ectopic gestation, is removed (Figure 3). A salpingostomy is the removal of
the ectopic pregnancy, by dissecting it out of the tube, leaving the Fallopian tube in situ in
an attempt to preserve fertility on that side.
A number of systematic reviews have examined reproductive outcomes following the two
procedures in patients with a healthy contralateral tube. Studies in this area can be criticised
with regard to patient selection, surgical techniques and follow-up times62-64 and some
studies report conflicting results.6566 However, it is generally accepted that the chance of
subsequent IUP is not increased after salpingostomy compared with salpingectomy. In
addition, the use of conservative surgical techniques exposes women to a small risk of tubal
bleeding in the immediate postoperative period and the potential need for further treatment
of persistent trophoblast.9 This supports current guidelines stating that the operation of
choice, where there is a healthy contralateral tube, is laparoscopic salpingectomy.67
In the presence of contralateral tubal disease, a laparoscopic salpingostomy should be
considered if future fertility is desired. Persistent trophoblast is the main concern after a
salpingostomy. This is usually detected by a failure of serum -hCG levels to fall and is
more common following active tubal bleeding, where the ectopic pregnancy size was >2 cm
or if serum -hCG concentrations are >3000 IU/l or rising prior to surgery.68 Women should
be followed up with serial -hCG measurements and systemic methotrexate treatment may
be required if the levels fail to fall as expected. While the short-term costs of postoperative
follow-up and treatment of persistent trophoblast are greater following a salpingostomy,69
the potential avoidance of the subsequent need for assisted conception will make it more
cost effective compared with salpingectomy.66
Medical treatment with methotrexate

Medical treatment is useful for patients with an unruptured tubal ectopic pregnancy who are
haemodynamically stable and have minimal symptoms and a low volume of free
intraperitoneal fluid on ultrasound scan.70 Intramuscular methotrexate is the most widely
used and successful medical therapy for ectopic pregnancy and is generally administered in
Sivalingam et al.
Page 8
a single-dose protocol.3469 Methotrexate is a folic acid antagonist that targets rapidly

dividing cells and arrests mitosis.971 In ectopic pregnancy, the drug prevents the
proliferation of cytotrophoblast cells, reducing cell viability and -hCG secretion and thus
progesterone support for the pregnancy. This facilitates the resolution of the ectopic
pregnancy and tissue remodelling.
After assessing patient suitability for medical management (Box 3), body surface area is
calculated using height and weight measurements. In addition, a baseline full blood count
and renal and liver function tests are obtained. In general, apart from some abdominal
discomfort 1-3 days after treatment and abdominal bloating, side effects are not common
and return to normal activities is quicker than after surgery. Potential serious side effects
such as significant hepatotoxicity, bone marrow toxicity or alopecia are extremely rare with
ectopic pregnancy treatment regimens. Patients require careful monitoring to ensure
complete resolution of the ectopic gestation using serial assessment of -hCG levels every
4-7 days (protocols vary between units) until the -hCG level is <5 IU/l.72
The commonly used single-dose methotrexate treatment regimen involves a deep
intramuscular injection at a dose of 50 mg/m2 of the calculated body surface area.
Approximately 14-20% of patients receiving single-dose treatment will require a repeat
dose,7374 usually decided on following a fall of the -hCG concentration of less than 15%
from Day 4 to 7 after treatment. This timescale is used as methotrexate can cause a transient
rise in serum -hCG after initial treatment. Approximately 10% of women will require
surgical intervention,75 although most of these are for slowly falling -hCG levels rather
than for acute tubal rupture. However, rupture still remains a possibility during treatment.
Close treatment surveillance, and staff and patient awareness of potential treatment failure,
are vital.
Two much less common uses of methotrexate for the treatment of ectopic gestation are the
multi-dose protocol and direct injection of methotrexate into the ectopic pregnancy. The
multi-dose regimen consists of methotrexate treatment on Days 1, 3, 5 and 7 to a maximum
of four doses and leucovorine rescue-therapy at a dose of 0.1 mg/kg on alternate Days 2, 4,
6 and 8. This treatment may be more appropriate for patients who present with a larger
adnexal masses and greater initial -hCG levels (>5000 IU/l). Direct injection of
methotrexate into the ectopic sac, either laparoscopically or with ultrasound guidance, limits
systemic toxicity and maintains a higher therapeutic level. However, local injection has no
significant advantage in most patients and is accompanied by a risk of provoking tubal
rupture.
Methotrexate treatment is very successful for small stable ectopic pregnancies. A metaanalysis of non-randomised studies showed success rates of 93% (95% CI 89-96%) for
multi-dose protocols and 88% (95% CI 86-90%) for single dose therapy.76 Failure of singledose medical management is associated with initial serum -hCG concentrations >5000 IU/
l, a moderate or large amount of free fluid on ultrasound, the presence of fetal cardiac
activity and a pretreatment increase in serum -hCG of >50% over a 48-hour period. It is not
known whether methotrexate treatment has better fertility outcomes than surgery but this is
likely to be the case when the ectopic gestation occurs in the only functioning tube.
Expectant management
Some ectopic pregnancies resolve spontaneously through either regression or tubal abortion,
without causing harm to the patient. Expectant management is a conservative strategy
consisting of observation and assessment of whether the ectopic pregnancy is continuing to
resolve spontaneously and successfully without intervention.34 A suitable candidate for
expectant management must have an ectopic pregnancy with no evidence of rupture, be
Sivalingam et al.
Page 9
clinically stable and asymptomatic, and have consistently declining -hCG concentrations.
A low serum progesterone is also a possible marker of suitability for the expectant approach.
Follow-up should be between one and three times weekly with -hCG measurement and
ultrasonography as required. Expectant management is reported to be most useful when the
initial -hCG is <1000 IU/l.58 A rapidly declining -hCG level also appears to predict a
favourable outcome.77 Success rates between 47% and 82% are reported, depending on the
patients initial status.78
The importance of compliance with follow-up and ease of access to the hospital should be
emphasised. If -hCG levels remain static or decline suboptimally, consideration should be
given to reverting to surgical or medical management.
Unusual sites of implantation

Over 98% of ectopic pregnancies implant in the Fallopian tube, in its ampullary region
(70%), isthmus (12%) or fimbria (11.1%). Interstitial or cornual ectopics, where the
pregnancy implants in the intramyometrial portion of the Fallopian tube, are less common
(2.4%) but have a mortality twice that of any other type of Fallopian tube ectopic
pregnancy.77 Rarely, an ectopic pregnancy implants at an extratubal location, such as the
cervix, ovary, abdomen, liver, spleen or Caesarean section scar.1 This produces a diagnostic
challenge and colour Doppler visualisation aids in the identification of the ectopic
pregnancy by creating awareness of vasculature supplying the implanted gestation.77
Surgical treatment is difficult and systemic methotrexate is considered first-line treatment,
with an early recourse to more than one dose, for the majority of extratubal ectopic
pregnancies.78 A more detailed description of the management of these unusual cases is
beyond the scope of this review.
Subsequent pregnancies
Studies suggest that around 60% of women affected by an ectopic pregnancy go on to have a
viable IUP.79 This figure includes those who do not plan to have another pregnancy and so
the proportion will be higher if further pregnancy is planned. There is thought to be a 5-20%
risk of a recurrence of ectopic pregnancy with one previous ectopic pregnancy and a risk of
32% or more following more than one previous ectopic.79 However, the risk is reduced after
each subsequent IUP.80 Even when there has been a bilateral salpingectomy there is still a
risk of ectopic pregnancy in the interstitial tube or in tubal remnants following IVF. Women
should receive an early scan in their next pregnancy to exclude a recurrent ectopic
pregnancy.
The future
There have been major advances in the diagnosis and management of ectopic pregnancies
during the last 20 years. However, even now a significant proportion of ectopic pregnancies
are not diagnosed at presentation and there are wide variations in management strategies
between different units. Current screening methods have a high false-positive rate, and are
not cost effective. Consequently, there are a number of ongoing studies developing
biomarkers that allow definitive diagnosis.5358 81 In addition, there is a lack of randomised
trials investigating the optimal management of ectopic pregnancy, particularly focusing on
recurrence rates and impact on future fertility. Results are awaited from a large randomised
trial comparing laparoscopic salpingectomy with salpingostomy.82
Acknowledgments
The authors thank Ronnie Grant for graphics support and Dr Graeme Walker for images.
Sivalingam et al.
Page 10
FINANCIAL SUPPORT:
AWH receives grant support from UK Medical Research Council (2009-13) (G0802808), IKTF (2009-2011) and an
Albert McKern Bequest (2010-11). WCD holds a Scottish Senior Clinical Fellowship and has grant support from
The Cunningham Trust.
Funding
Andrew Horne receives grant support from the UK Medical Research Council (2009-2013), IKTF (2009-2011) and
an Albert McKern Bequest (2010-2011). Colin Duncan holds a Scottish Senior Clinical Fellowship and has grant
support from The Cunningham Trust.
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Sivalingam et al.
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Key message points
Clinicians should be suspicious of ectopic pregnancy in any woman of

reproductive age presenting with abdominal or pelvic symptoms.
The diagnosis of ectopic pregnancy can be difficult and protracted.
A diagnosis of pregnancy of unknown location should trigger further

diagnostic pathways and follow-up until the final outcome of the pregnancy
is known.
Medical management with methotrexate is successful for small, stable

ectopic pregnancies.

Sivalingam et al.
Page 15
Box 1
Risk factors for ectopic pregnancy
Fallopian tube damage
Previous tubal surgery (including female sterilisation) and pelvic surgery

including Caesarean section and ovarian cystectomy
Previous abdominal surgery including appendicectomy and bowel surgery
Confirmed genital infection and pelvic inflammatory disease, commonly
caused by chlamydial infection
Infertility
Documented tubal disease
Assisted reproductive technology
Endometriosis
Unexplained infertility
Contraceptive failure
Progestogen-only contraception
Intrauterine contraceptive device
Cigarette smoking including past exposure.
Age >35 years
Previous ectopic pregnancy
Previous spontaneous abortion or induced abortion

Sivalingam et al.
Page 16
Box 2
Useful ultrasonographic findings in the diagnosis of ectopic pregnancy
Absence of intrauterine pregnancy (IUP)
Positive identification of an ectopic pregnancy mass: inhomogenous mass,

empty adnexal gestation sac or adnexal sac containing yolk sac or fetal pole
Free fluid (i.e. blood): suggestive of ectopic pregnancy in the absence of IUP,
but not diagnostic (small amount may be physiological)

Sivalingam et al.
Page 17
Box 3
Inclusion criteria for medical management of ectopic pregnancy with
methotrexate
Patient characteristics
Would prefer medical option

Willing to attend follow-up for up to 6 weeks
Willing to abstain from alcohol for 7 days following the treatment
Not breastfeeding or willing to stop
Clinical features
Haemodynamically stable
Minimal abdominal pain
Ultrasound scan findings

No fetal heart activity or clear yolk sac in adnexal mass
Small amount of free fluid
Unlikely to be early intrauterine pregnancy failure
Serum beta-human chorionic gonadotrophin (-hCG) concentrations

Usually <3000 IU/l (Although limits of <5000 IU/l are used in some units
and earlier studies, treatment success rates are higher when this more
commonly used lower limit applies.)
Medical history
No active peptic ulcer disease
No severe medical conditions including renal disease, hepatic disease, severe

anaemia, leucopenia or thrombocytopenia
Should not be on concurrent medication

Non-steroidal anti-inflammatory agents (NSAIDs), aspirin, penicillins,
sulphonamides, trimethoprim, tetracyclines, diuretics, phenytoin,
antimalarials, ciclosporin, retinoids, probenecid, folic acid, hypoglycaemics,
live vaccines, nephrotoxic or hepatotoxic drugs
Sivalingam et al.
Page 18
Figure 1.
Transvaginal ultrasound images of an intrauterine pregnancy (IUP) and ectopic pregnancy.

(A) An IUP at 6 weeks. The central dark area is the intrauterine gestational sac and within
the sac is a circular ringed structure that is the yolk sac. The small oval structure below the
yolk sac is the fetus. (B) An ectopic pregnancy. To the right of the image is the normal
uterus and to the left of the uterus is the doughnut-shaped ectopic pregnancy.

Sivalingam et al.
Page 19

Figure 2.
Recommended diagnostic and management approach for suspected ectopic pregnancy. It is

important to highlight that the figure of 66% is used as a practical guide only and that all
cases of pregnancy of unknown location should be considered as a potential ectopic
pregnancy until assessment proves otherwise or management is complete. -hCG, betahuman chorionic gonadotrophin.
Sivalingam et al.
Page 20
Figure 3.
(A) Left tubal ectopic pregnancy at laparoscopy. (B) Tubal ectopic pregnancy has been
removed by salpingectomy.


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