The nonsurgical management of ectopic pregnancy

Emma Kirk and Tom Bourne

Purpose of review
This review discusses the diagnosis and nonsurgical
management of ectopic pregnancy.
Recent findings
In the majority of cases the diagnosis of ectopic pregnancy
should be made on transvaginal ultrasonography. Those for
which the diagnosis is not made on the first scan may
initially be classified as pregnancies of unknown location.
There are now a number of strategies and mathematical
models to predict ectopic pregnancy in this pregnancy of
unknown location population. Reported success rates for
expectant and medical management of ectopic pregnancy
vary due to different inclusion criteria. A number of
predictors of success have been studied: maternal age,
previous obstetric history, gestational age, ultrasound
features, human chorionic gonadotrophin levels,
progesterone levels and the change in human chorionic
gonadotrophin over time. At present the initial human
chorionic gonadotrophin level probably remains the single
most important predictor of success. Nonsurgical
management is also particularly important for nontubal
ectopic pregnancies: interstitial, cervical and caesarean
section scar pregnancies.
Summary
The majority of ectopic pregnancies can be visualized by
ultrasound and so can be considered for conservative
treatment. Nonsurgical management can be safe and
effective. Appropriate selection criteria remain an issue,
however, and a consensus needs to be reached on the
predictors of success and failure to optimize management.

Introduction
Over 10 000 ectopic pregnancies are diagnosed in the UK
annually, with the condition affecting 11 in 1000 pregnancies [1]. Fortunately, although the incidence of ectopic pregnancy has increased over the last 25 years, there
has been a decrease in the associated mortality [2]. This is
most probably due to improved diagnostic techniques
allowing ectopic pregnancies to be identified before the
occurrence of life threatening events. Home pregnancy
tests now enable a pregnancy to be diagnosed even before
a menstrual period is missed meaning that women often
present at earlier gestations. The wide availability of
transvaginal ultrasound and the rapid immunoassay of
serum human chorionic gonadotrophin (hCG) in early
pregnancy units also means that early ectopic pregnancies
are being diagnosed in asymptomatic women. Surgical
management in these women is not always necessary or
appropriate. Nonsurgical management is also important
for nontubal ectopic pregnancies, in which surgery can
often be hazardous due to the anatomical location of the
pregnancies. The aim of this review is to discuss the
recent literature relating to the nonsurgical management
of ectopic pregnancy.

Diagnosis
Historically ectopic pregnancies were diagnosed at the
time of surgery. This can no longer be the considered the
gold standard if nonsurgical approaches to the condition
are to be considered.
Ultrasound

Keywords
ectopic pregnancy, expectant management, methotrexate,
pregnancies of unknown location, transvaginal ultrasound
Curr Opin Obstet Gynecol 18:587593. 2006 Lippincott Williams & Wilkins.
Early Pregnancy Unit, St Georges Hospital, University of London, London, UK
Correspondence to Emma Kirk, Early Pregnancy Unit, St Georges Hospital,
University of London, Cranmer Terrace, London, SW17 0RE, UK
Tel: +44 20 8725 0050; fax: +44 20 8725 0094; e-mail: ejkirk@hotmail.co.uk
Current Opinion in Obstetrics and Gynecology 2006, 18:587593
Abbreviations
hCG
PUL

human chorionic gonadotrophin

pregnancy of unknown location

2006 Lippincott Williams & Wilkins

1040-872X

Transvaginal ultrasonography has become the imaging

modality of choice in haemodynamically stable women.
Diagnosis should be based on the positive visualization of
an adnexal mass or extra-uterine gestational sac rather
than the absence of an intra-uterine gestational sac. In a
prospective study of the transvaginal ultrasound findings
of 152 women with suspected ectopic pregnancy who
subsequently underwent surgery, over 90% of ectopic
pregnancies were visualized prior to surgery [3

].
Women were diagnosed with an ectopic pregnancy if
any of the following were noted in the adnexal region: an
inhomogeneous mass adjacent to the ovary and moving
separately to the ovary; a mass with a hyper-echoic ring
around the gestational sac (bagel sign) or a gestational sac
with a fetal pole with or without cardiac activity (Fig. 1).
The sensitivity and specificity of transvaginal ultrasonography to detect ectopic pregnancy were 90.9% and
99.9% respectively, with positive and negative predictive
values of 93.5% and 99.8% respectively. Another recent
587

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588 Womens health

Figure 1 Transvaginal ultrasound images of tubal ectopic pregnancies

(a) An inhomogeneous mass adjacent to the ovary. (b) A mass with a hyper-echoic ring around the gestational sac (bagel sign). (c) A gestational sac
with a fetal pole. Reproduced with permission [12

].

publication assessed the endometrial trilaminar pattern

and thickness as ultrasonographic predictors for the ectopic pregnancy in 403 women [4]. The trilaminar pattern
was found to have a specificity of 94% and a sensitivity of
38% for the detection of ectopic pregnancy. The endometrial thickness was also found to be thinner in women
with an ectopic pregnancy.
Pregnancies of unknown location

The last 2 years have seen a number of publications on

the prediction and diagnosis of ectopic pregnancy in
women classified as pregnancies of unknown location
(PULs). In these women there is no evidence of either
an intra-uterine or extra-uterine pregnancy on the initial
ultrasound scan. Depending on the quality of ultrasonography in a given unit, 831% will be termed a PUL
[5

,6]. Whilst the majority of these are either failing
PULs or developing intra-uterine pregnancies that are
too early to visualize on transvaginal scan, a significant
proportion are ectopic pregnancies. The prevalence of
ectopic pregnancies in the PUL population is dependent
on the quality of ultrasound within a given unit. In
specialized ultrasound based units, ectopic rates of
8.714% can be expected in the PUL population
[7,8

]. Various strategies have been used to predict
ectopic pregnancy in these PULs. Commonly used diagnostic algorithms involve a combination of serum hCG
and progesterone measurements and uterine curettage.
A study on 1003 PULs, however, showed that established
criteria for the use of uterine curettage in the management of PULs, including those advocated by the
American Society for Reproductive Medicine (ASRM),
could theoretically result in inadvertent termination of an
ongoing intra-uterine pregnancy [5

]. Uterine curettage
should therefore not have a place in the management of
PULs and the diagnosis of ectopic pregnancy. Recently,
other studies have been published on the use of the
discriminatory zone, logistic regression models and

Bayesian networks to predict ectopic pregnancy

(Table 1) [8

,9,10
,11
]. The use of the discriminatory
zone, a level of hCG above which it is thought an intrauterine pregnancy should be seen on ultrasound is
unhelpful in diagnosing ectopic pregnancy in specialized
scanning units [8

]. Mathematical models using logistic
regression and Bayesian networks, however, would
appear to be successful in predicting ectopic pregnancy
and now need to be tested prospectively in other patient
populations [9,10
,11
]. These have the potential to
deskill the interpretation of serum hCG levels and lead
to more standardized management protocols.

Expectant management
Expectant management has been shown to be safe and
effective for appropriately selected women with both
tubal and nontubal ectopic pregnancies.
Tubal ectopic pregnancies

A review of previous studies on the expectant management of tubal ectopic pregnancies published in 2006
shows that success rates vary from 48100% [12

].
Success rates vary due to different inclusion criteria based
on size of ectopic mass, initial hCG level and pattern of
hCG change. Some studies also include PULs rather than
laparoscopically or sonographically visualized ectopic
pregnancies. The most recent study on expectant management was published in 2004 [13]. This was a prospective study on 107 women with tubal ectopic
pregnancies, identified on transvaginal ultrasound scan,
who were all managed expectantly. The aim was to
establish a combination of parameters that could be used
to identify ectopic pregnancies that could successfully
undergo expectant management. The optimal algorithm
led to a success rate for expectant management of 70%
(75/107). Maternal age, serum hCG and progesterone
levels were found to be significantly lower in women
with successful expectant management than in those

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Ectopic pregnancy: nonsurgical management Kirk and Bourne 589

Table 1 Summary of recently published studies on the prediction of ectopic pregnancy in women with pregnancies of unknown
location

Year

First author

Method

2004

Condous [9]

Logistic regression
model

2005

Condous [8

]

Discriminatory zone
>1000 IU/l
>1500 IU/l
>2000 IU/l

2006

Kirk [10
]

Logistic regression
model

2006

Gevaert [11
]

Bayesian networks

Sensitivity
for detection
of ectopic
pregnancy

Specificity
for detection
of ectopic
pregnancy

Area under the

receiver operating
characteristic
curve (AUC)

91.7%

84.2%

0.885

21.7%
15.2%
10.9%

87.3%
93.4%
95.2%

82.8%

80.2%

0.88

Comments
Three multicategorical logistic
regression models were developed
and tested. M1 was based on the
hCG ratio (hCG 48 h/hCG 0 h),
M2 was based on the average
progesterone level (the mean of the
progesterone level at 0 and 48 h)
and M3 was based on the patients
age. M1 outperformed M2 and M3
when tested prospectively. A logistic
regression model had therefore
been developed based on two hCG
levels only (hCG 0 and 48 h) to
successfully predict the outcome
of PULs.
A prospective observational study
on 569 women with PUL who
were followed up until the final
diagnosis was known. There were
46 ectopic pregnancies (8.7%).
Three different discriminatory zones
were applied to the PUL population
(1000, 1500 and 2000 IU/l).
Varying the discriminatory zone
did not significantly improve the
detection of ectopic pregnancy in
the PUL population.
A previously developed logistic
model based on the hCG ratio
was used prospectively in the
clinical setting to predict the
outcome of 357 PULs. The
predicted outcome according
to the model was compared
to that of the subjective
assessment of an expert
operator and the true outcome
after follow-up. The model
compared favourably with
subjective assessment by
experienced operators. Those
with limited knowledge or
understanding of the
behaviour of serum biochemistry
in the first trimester can use
the model.
Bayesian networks allow for
arbitrary relations between all the
variables and were developed in
order to predict ectopic pregnancy
in PULs. Variables examined were
vaginal bleeding, lower abdominal
pain, ultrasound findings, serum
hCG and progesterone levels.
The Bayesian network using
gestational age, the hCG ratio and
the progesterone level at 48 h had
an AUC of 0.88 for the prediction
of ectopic pregnancy. Such models
can therefore be used to predict
ectopic pregnancy.

PUL, pregnancy of unknown location.

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590 Womens health

with failed expectant management. Women with an

initial serum hCG level of under 175 IU/l had the highest
success rate [96% (32/33)]. The success rate was only 21%
(3/14) if the initial hCG level was over 1500 IU/l. These
findings are in keeping with previously published studies,
which include the largest study to date on 118 women
managed expectantly [14]. In this study the success rate
for spontaneous resolution was 88% when the initial hCG
was <200 IU/l and only 25% if it was >2000 IU/l. Other
studies have shown that a decreasing trend in hCG levels,
the absence of an ectopic gestational sac and a longer
time from the last menstrual period are also predictors of
success [15,16]. At present it remains that the initial hCG
level is probably the best predictor of success for expectant management. Recent work suggests, however, that
the trend in hCG levels as assessed by the hCG ratio
(hCG 48 h/hCG 0 h) is superior to the absolute hCG level
in predicting the likely success from expectant management (Kirk et al., unpublished data).
An obvious advantage of expectant management is the
avoidance of any of the risks associated with a surgical
procedure. We must also consider whether there are any
other benefits particularly with regard to future fertility
Subsequent ipsilateral tubal patency rates on hysterosalpingogram of up to 93% have been reported after expectant management of tubal ectopic pregnancy and intrauterine pregnancy rates as high as 89% [17,18]. This
compares favourably with an intra-uterine pregnancy rate
of 88% after salpingotomy [19]. A study has also shown
similar pregnancy rates after expectant and surgical management (63% and 51% respectively) and interestingly
women undergoing delayed surgery owing to failure of
expectant management had similar subsequent pregnancy rates to those who underwent surgery as the initial
treatment option [20].
Nontubal ectopic pregnancies

Nontubal ectopic pregnancies are rarely managed expectantly. There are recent reports, however, on successful
resolution of interstitial, cervical ectopic pregnancies and
pregnancies implanted in previous caesarean section
scars [21,22,23
,24].

Medical management
Methotrexate is the most widely used drug for the
medical management of ectopic pregnancy and can be
given either systemically or locally.
Tubal ectopic pregnancies

In the UK, for tubal ectopic pregnancies methotrexate is

most commonly given as a single intramuscular injection
at a dose of 50 mg/m2 according to Stovalls original
protocol (Table 2) [25]. Absolute contraindications to
its use include severe pain, haemodynamic instability,
signs of an acute haemoperitoneum and liver, kidney

Table 2 Single-dose protocol for the medical management of

ectopic pregnancy with methotrexate
Day

Management

0
1

Blood tests: serum hCG, FBC, U&Es, LFTs, G&S

Blood test: serum hCG
Intramuscular methotrexate 50 mg/m2
Blood test: serum hCG
Blood tests: serum hCG, FBC, LFT
Second dose of methotrexate if hCG decrease
<15% day 47
If hCG decrease >15% repeat hCG weekly until <12 U/l

4
7

hCG, human chorionic gonadotrophin; FBC, full blood count; LFT, liver
function test; U&E, urea and electrolytes; G&S, sample for group and
save.

or bone marrow impairment. Relative contraindications

include an hCG level above 5000 IU/l and positive fetal
cardiac activity.
A review of cases treated with single dose methotrexate
from 19932004 has shown success rates ranging from
65 to 95% with 327% of women requiring an additional
dose [12

]. The largest single study to date has been on
495 women, with a success rate of 90.5% [26]. As for
expectant management, success rates vary owing to
different inclusion criteria. Some studies include PULs
and presumed but not sonographically visualized ectopic
pregnancies. Other studies also include cases with
already decreasing hCG levels that would have certainly
resolved without any intervention.
In the last couple of years, most of the studies on tubal
ectopic pregnancies treated with single-dose methotrexate have concentrated on identifying factors to predict
likely success or failure, a summary of these is shown in
Table 3. Factors studied include maternal age, previous
obstetric history, ultrasound findings, folic acid levels,
hCG levels and the trend in hCG levels before and after
methotrexate administration [2631]. As with expectant
management we recently showed that the pretreatment
hCG ratio has been shown to be a significant predictor of
success for medical management (Kirk et al., unpublished
data). In the published literature the initial serum hCG is
probably the single most important factor in predicting
the likely success of methotrexate, with significantly
higher failure rates when the hCG level is above
1000 IU/l [32].
Systemic methotrexate can also be given according to a
multiple-dose regimen. This involves giving 1 mg/kg on
days 1, 3 and 5 with folinic acid rescue on days 2, 4 and 6
(Table 4). A study in 2005 on 643 women treated with
either single-dose or multiple-dose methotrexate showed
comparable success rates: 90% and 95% respectively [33].
Serum hCG levels, progesterone levels, previous history
of ectopic pregnancy, gestational age, ectopic mass size
and volume were similar in both the groups. A more
recent randomized trial of 108 women has also shown that

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Ectopic pregnancy: nonsurgical management Kirk and Bourne 591

Table 3 Published studies on predictors of success and failure for management with single-dose methotrexate
Year

First author

Predictor of success/failure

Comments

2004

Lipscomb [26]

Serum hCG level

Serum progesterone
Ectopic cardiac activity
Previous ectopic pregnancy

2004

Dudley [32]

Serum hCG
Serum hCG incremental rate

2005

Takacs [27]

Folic acid levels

2005

Takacs [28]

Endometrial thickness

2005

Bixby [29]

Presence of a yolk sac

2006

Dilbaz [30]

Subchorionic tubal haematoma

Presence of an embryo
Serum hCG

2006

Gabbur [31]

Day 7 serum hCG levels

n 495. Univariant analysis showed that serum hCG and progesterone levels
and ectopic cardiac activity were significantly different between successful and
failed therapy. Logistic regression analysis for these four variables showed that
only hCG and history of previous methotrexate remained significant risk factors
for failure of methotrexate therapy. The likelihood of failure in patients with a
previous ectopic was not influenced by previous treatment with salpingostomy,
salpingectomy, or medical treatment.
n 81. Failure rate was significantly higher when the serum hCG was >1000 IU/l.
The hCG incremental rate before and after methotrexate administration was
positively associated with tubal rupture. Serum hCG values prior to ectopic
diagnosis that increased >66% over 48 h and rising hCG values after treatment
with methotrexate were independent predictors of tubal rupture.
A serum folate level >50 nmol/l (22 ng/ml) was found to be associated with failure
of methotrexate treatment.
n 73. An endometrial thickness of >12 mm was found to increase the risk for
treatment failure with single-dose methotrexate. The failure rate was 53% in those
with an endometrial thickness >12 mm compared to 5% in those with an
endometrial thickness <12 mm (P < 0.01).
n 62. The presence of a yolk sac (n 15; 88% of failures) was always associated
with treatment failure. Maternal age, size of the ectopic mass, presence of a
pseudogestational sac and amount of free fluid did not correlate with the outcome.
n 58. The presence of a subchorionic tubal haematoma in the ectopic gestation
(OR 22.9, CI 2.7194.7, P 0.004), the presence of an embryo (OR 24,
CI 2.1269, P 0.01) and day 1 serum hCG level 3 000 IU/l (OR 27.1,
CI 2.1342.5, P 0.01) were the main predictors of treatment failure. Follow-up
serum b-hCG levels 3 500 IU/l (OR 42.9, CI 4.3421) on day 3 were
significant predictors of treatment failure.
n 83. The aim of the study was to assess whether serum hCG levels on day 4
could be used to predict likely success or failure. Receiver operator characteristic
curves had areas under the curves of 0.449, 0.592 and 0.754 for serum hCG
levels on days 1,4 and 7 respectively. Only day 7 serum hCG levels were
associated with successful single-dose methotrexate therapy.

hCG, human chorionic gonadotrophin.

single-dose treatment is as successful as multiple-dose

treatment with success rates of 88.9% and 92.6% respectively, P 0.7 [34
]. The incidence of complications did
not differ between the two groups. It would therefore
appear that single-dose therapy should be the first line of
treatment in selected patients.
Methotrexate can also be given locally either under
ultrasound guidance or at the time of laparoscopy.
One study showed methotrexate given under ultrasound guidance to have a success rate of 83% [35].
There have been no recent publications comparing
local to systemic administration for tubal ectopic
Table 4 Multiple-dose protocol for the medical management of
ectopic pregnancy with methotrexate
Days

Management

0
1,3,5

Blood tests: serum hCG, FBC, U&Es, LFTs, G&S

Blood test: serum hCG
Intramuscular methotrexate 1 mg/kg
Blood test: serum hCG
Intramuscular folinic acid 0.1 mg/kg
Monitoring
Continue until hCG decreased >15% in 48 h or 4 doses of
methotrexate given

2,4,6

hCG, human chorionic gonadotrophin; FBC, full blood count; LFT, liver
function test; U&E, urea and electrolytes; G&S, sample for group and
save.

pregnancies. This is probably because success rates

for local administration are similar to those for systemic
therapy and with systemic therapy there is no need
for specialist equipment and the same degree of skill
and training.
Future reproductive outcome has also been studied
in women receiving methotrexate for tubal ectopic
pregnancies. Posttreatment hysterosalpingograms have
shown ipsilateral tubal patency rates of up to 82% and
intra-uterine pregnancy rates up to 69% [25]. A study
in 2004 showed cumulative intra-uterine pregnancy
rates of 57.5% after 1 year and 66.9% after 2 years
[36]. The cumulative ectopic pregnancy rate was 15.4%
after 1 year and 23.7% after 2 years. This ectopic
pregnancy recurrence rate is similar to that found in
a study comparing salpingectomy and salpingotomy
which found rates of 17% and 16% respectively [19].
Nontubal ectopic pregnancies

Interstitial, cervical, and caesarean section scar pregnancies are commonly managed nonsurgically. Nonsurgical
treatment options include local or systemic methotrexate
and potassium chloride.
A prospective study on 17 women with interstitial
pregnancy described a success rate of 94% (16/17) for

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592 Womens health

single-dose methotrexate [22]. Another study of seven

women with cervical ectopic pregnancies showed successful nonsurgical management in all cases with expectant
management, systemic single-dose or multiple-dose methotrexate, intra-amniotic methotrexate or intra-amniotic
potassium chloride [23
]. Injection with potassium
chloride tends to be reserved for pregnancies with fetal
cardiac activity or with heterotopic pregnancies. A study
published in 2005 demonstrated the successful nonsurgical
treatment of 18 live ectopic pregnancies (10 cervical, four
cornual and four tubal), all with ultrasound guided injection of methotrexate or potassium chloride [37].

Conclusion
Nonsurgical management can be safe and effective for
some women with ectopic pregnancy. With a good
ultrasound service the majority of these ectopic pregnancies should be visualized on a transvaginal scan. The
remainder may be initially classified as PULs. There are
a number of strategies and mathematical models to accurately predict those PULs at high risk of ectopic pregnancy. These women can then be closely followed up until
the diagnosis can be confirmed on ultrasound.
The key to successful nonsurgical management is appropriate patient selection. Based on current criteria, a
significant proportion of women will apparently fail this
form of management. It is vital that women who choose
this form of treatment are well motivated and compliant
and have ready access to emergency care should they run
into difficulties. There are, however, problems. Using
current criteria only a relatively small proportion of
ectopic pregnancies can be managed in this way. Beyond
doubt there are ectopic pregnancies with high initial hCG
levels that will resolve without intervention. The question is how to recognize them. Looking at the initial
change in serum hCG over time may be one approach to
this. There are also no universally agreed definitions of
treatment failure: in some units patients will undergo
surgery if they have pain, in others they will be admitted
for observation on the assumption that they are having a
tubal miscarriage and not tubal rupture. Further work in
this area would be welcome.
In general as we diagnose smaller ectopic pregnancies at
an earlier stage there is a tendency to become complacent
about the risks associated with this condition. Some
ectopic pregnancies are dangerous; the challenge for
the clinician is to recognize them. Laparoscopy remains
a relatively safe and simple treatment for most tubal
ectopic pregnancies. It is hard to explain any adverse
outcome from expectant management set against the
knowledge that an alternative safe management option
does exist. Careful selection and meticulous follow-up
are therefore essential for anyone contemplating managing their patients in this way.

References and recommended reading

Papers of particular interest, published within the annual period of review, have
been highlighted as:


of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 670671).
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3

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Ectopic pregnancy: nonsurgical management Kirk and Bourne 593

17 Rantala M, Makinen J. Tubal patency and fertility outcome after expectant
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