European Journal of Obstetrics & Gynecology and Reproductive Biology 179 (2014) 175180

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European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb

Cut-off value of initial serum b-hCG level predicting a successful MTX

therapy in tubal ectopic pregnancy: a retrospective cohort study
S. Helmy a , Y. Bader b , E. Pablik c , D. Tiringer d , S. Pils e , T. Laml f , H. Klbl g , M. Koch h, *
a

Department of Gynaecology and Obstetrics, Medical University of Vienna, Vienna 1090, Austria
Department of Gynaecology and Obstetrics, Medical University of Vienna, Vienna 1090, Austria
c
Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna 1090, Austria
d
Department of Gynaecology and Obstetrics, Medical University of Vienna, Vienna 1090, Austria
e
Department of Gynaecology and Obstetrics, Medical University of Vienna, Vienna 1090, Austria
f
Department of Gynaecology and Obstetrics, Medical University of Vienna, Vienna 1090, Austria
g
Department of Gynaecology and Obstetrics, Medical University of Vienna, Vienna 1090, Austria
h
Department of Gynaecology and Obstetrics, Clinical Division of General Gynaecology and Gynaecological Oncology, Medical University of Vienna,
Waehringerguertel 18-20, Vienna 1090, Austria

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A B S T R A C T

Article history:
Received 14 February 2014
Received in revised form 20 May 2014
Accepted 22 May 2014

Objective: To determine the optimal serum b-hCG cut-off level to predict MTX treatment success in tubal
ectopic pregnancy (EP).
Study design: Data of 240 women, who presented between 2003 and 2011 at the Department of
Gynecology and Obstetrics, Medical University of Vienna, with tubal EP and who received MTX as
primary treatment, were retrieved from the hospital information system (KIS). 198 patients could be
included for nal evaluation. Statistical analysis included area under the ROC curve, maximal Euclidean
and Youden index, chi-squared and a ve-fold cross validation.
Results: The serum b-hCG level cut-off value was calculated at 2121 mlU/ml with a specicity of 76.54%
and sensitivity of 80.56% (AUC 0.789; p < 0.001). Patients with an initial serum b-hCG level below
2121 mlU/ml (n = 131) experienced MTX treatment failure in 5.3% (n = 7), compared to 43.3% (n = 29) of
patients with an initial serum b-hCG level equal to or above 2121 mlU/ml (n = 67). There was no
statistically signicant correlation between clinical symptoms and the MTX therapy outcome (p = 0.580;
likelihood quotient p = 0.716).
Conclusion: The correct decision of therapy in patients with tubal ectopic pregnancy still represents a
challenge. In this study we can conclude that, according to our results there is no endpoint of initial serum
b-hCG levels, which can be clearly used as cut-off value for the optimal management of tubal EP.
However, an initial serum b-hCG level of less than 2121 mlU/ml seems to be a good value to expect a
successful MTX treatment. Limitations are the retrospective study design and the inability of classifying
clinical symptoms like pain as an objective parameter. Wider implications of the ndings may include
more detailed patient information and more accurate selection of suitable patients for MTX therapy.
2014 Elsevier Ireland Ltd. All rights reserved.

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Keywords:
Initial serum b-hCG
Cut- off
MTX
Tubal ectopic pregnancy
b-hCG clearance
Clinical symptoms

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A R T I C L E I N F O

Introduction
Ectopic pregnancy (EP) is dened as a pregnancy, in which the
blastocyst does not implant in the decidual area of the corpus uteri
[1]. The most frequent localization is in the fallopian tubes (95% of
all ectopic pregnancies) [2]. Maternal mortality due to EP has

* Corresponding author. Tel.: +43 1 40 400 29620; fax: +43 1 40 400 29110.
E-mail address: marianne.koch@meduniwien.ac.at (M. Koch).

steadily decreased with the improvement of diagnostic resources

[3,4]. However, the incidence of EP consistently ranges between
1.5% and 2% of all pregnancies and therefore represents a highly
relevant gynaecological condition [3,5,6].
Established treatment options comprise expectant management, methotrexate (MTX) and surgery. However, the decision for
treatment of EP still represents a challenge and it occurs that MTX
treatment fails and subsequent surgery needs to be performed.
Previous studies have shown comparable results of MTX success
rates from 70% to 87%, which was also conrmed in our study (82%)

http://dx.doi.org/10.1016/j.ejogrb.2014.05.033
0301-2115/ 2014 Elsevier Ireland Ltd. All rights reserved.

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Methods
Institutional review board approval was obtained at the Ethical
Commission of the Medical University of Vienna (EK Nr. 534/2009).
A total number of 240 patients with tubal ectopic pregnancy
(EP), who were primarily treated with MTX at the Department of
Gynaecology and Obstetrics of the Medical University of Vienna in
the period 20032011, were included in this study.
Patient data was extracted from the hospital information
system (KIS) in form of outpatient protocols, progress notes,
ultrasound ndings, laboratory-analyzed ndings and, if applicable, surgery protocols.
In all included patients, the denitive diagnosis of EP was made
on ultrasound scan. These patients had a positive pregnancy test
without a visible intrauterine pregnancy. Furthermore, a welldened adnexal mass was seen separate from the uterus and the
ovary containing the corpus luteum, which had typical morphologic characteristics of a tubal EP. Morphological features of EPs
were classied in 3 groups: gestational sac containing a life
embryo, an empty gestational sac with or without a yolk sac and a
solid hyperechoic swelling [24,25].
Women with non-diagnostic scans were offered surgery only if
they presented with severe, unexplained pain, cardiovascular
instability, or if there was clinical and ultrasound evidence of
intraperitoneal bleeding.
Women with inconclusive scans were not included in this data
analysis, as patients with positive pregnancy test and a non-visible
pregnancy on ultrasound are dened as pregnancy of unknown
location (PUL), which resolve in 69% without intervention, or
develop to viable pregnancies in 22% [26].
Among the women with conclusive scans, primary surgery was
only offered if serum b-hCG levels were 5000 mlU/ml, if an EP
with cardiac activity was seen on US, if the patient presented with
hemoperitoneum on US, or clinical instability, or on patients'
desire. A hemoperitoneum was dened as free echoic uid in the
pouch of Douglas. MTX was offered to patients in cases of serum
b-hCG levels 5000 mlU/ml, evidence of EP in US (as summarized
above), clinical stability and on patients' desire. Expectant
management was routinely offered to patients with serum
b-hCG levels 1500 mlU/ml without clinical symptoms and
decreasing serum b-hCG levels after 48 h. In our routine clinical
practice, we recommend allocation to therapy according to the
protocol as described above [5]. However, the patients' autonomy
is determinant to the nal treatment decision. Therefore, patients

with serum b-hCG levels higher than 5000 mlU/ml may have
received MTX treatment instead of primary surgery, if desired by
the patient despite detailed information on risks.
A database was created with the following patient data: clinical
symptoms (none, pain, bleeding, or both), initial serum b-hCG
level, therapy protocol (single dose MTX, multiple dose MTX and/
or surgery), date of the rst MTX injection, serum b-hCG and
progesteron level follow-up after rst and second MTX injection
(day 1, 4 and 7 each), time until serum b-hCG clearance (dened as
serum b-hCG 20 mlU/ml), date of the second MTX injection and
MTX treatment outcome (successful, unsuccessful, lost to followup).
For data protection purpose, the excel le was encoded and
anonymized by applying a number to each individual patient for
further data processing to prevent subsequent patient identication.
Before statistical analysis, criteria for successful and unsuccessful MTX treatment had to be standardized. Both single-dose, as
well as multiple-dose intramuscular MTX injection protocols
(50 mg/m2 per injection) were permissible [27]. Successful MTX
treatment was dened as a decrease of serum b-hCG of at least 15%
between day 4 and 7 after MTX application, followed by a weekly
decrease of at least 15% until the serum b-hCG level threshold of
20 mlU/ml was reached. If the serum b-hCG level decrease
between day 4 and 7 was insufcient, a second MTX application
(50 mg/m2) was performed [2729].
If patients did not show up for the serum b-hCG measurement
follow-up, they were contacted by the consultant of the outpatient
clinic and stressed to visit the hospital for another follow-up blood
test. If there was no success in contacting the patient, or patients
were incompliant, they were documented as lost to follow-up in
the hospital information system. In our study, a total number of 42
patients were marked as lost to follow-up and excluded from the
statistical analysis, as there was no documented serum b-hCG level
of 20 mlU/ml and no documentation of a subsequent surgery.
Reasons for lost to follow-up were non-appearance to the followup appointments at our hospital or further follow-up visits at the
practitioner or patients moving abroad. Secondary surgery in the
course of the MTX treatment was declared as unsuccessful MTX
treatment. Indications for secondary surgery were rising or
stagnating serum b-hCG levels and suspected tubal rupture.
Among the patients with secondary surgery after MTX treatment, 9
patients had received a second MTX dose according to the protocol
[27]. If the second MTX dose failed, indication for secondary
surgery was given. In 27 patients, a secondary emergency surgery
after rst MTX injection had to be done due to suspected tubal
rupture and/or severe pain.
The statistical analysis was conducted using the IBM SPSS
Statistics Version 21 (Licensed MaterialsProperty of IBM Corp.
Copyright IBM Corporation and other(s) 1989, 2012) and R
software (R Core Team (2013); R: a language and environment
for statistical computing; R Foundation for Statistical Computing,
Vienna, Austria, URL http://www.R-project.org/).

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[711]. MTX failure does not only cause inconveniences for the
patient in an already stressed situation, but also implies a greater
risk for complications, such as tubal rupture (up to 7% of cases) [5].
It is therefore highly relevant that the decision for treatment of
each individual patient is based on evidence. Previous studies have
investigated risk factors for MTX treatment failure, such as clinical
symptoms, cardiac activity, gestational sac size, serum b-hCG and
progesterone levels. Except for obvious factors, such as suspicion of
tubal rupture and/or haemodynamic instability, conclusions are
still controversial [5,10,1215].
Initial serum b-hCG levels represent so far the most reliable
indicator to whether MTX is applicable, but there is still no
consensus on a specic cut-off level, above which the treatment is
more likely to fail than to succeed. Previous studies describe serum
b-hCG cutoff levels in a range of 20005000 mlU/ml [7,8,1623].
Therefore, the aim of our study was to identify a statistically
signicant cut-off value for serum b-hCG, which can be used as
predictor for the success or failure of MTX treatment in our study
population. Furthermore we aimed to investigate a potential
correlation of clinical symptoms (pain, bleeding or both) and the
MTX treatment outcome.

Results
A total number of 198 patients could be included for statistical
analysis. All of these patients with tubal EP were primarily treated
with MTX. In total, 162 patients (81.8%) were successfully treated
with MTX compared to 36 patients (18.2%), who had unsuccessful
treatment and needed subsequent surgery.
The mean age of the patients was 30.57 years (standard
deviation 5.472 years; min 19; max 42). 51 patients (25.8%) were in
need of a second MTX injection compared to 147 patients (74.7%)
with a single injection. Among the patients with a second MTX
injection, 9 patients failed in treatment and underwent subsequent

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Fig. 1. Comparison of number of patients and b-hCG levels in successful and

unsuccessful MTX therapy outcome.
x. b-hCG (mlU/ml).
y. Frequency (number of patients).

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calculated the serum b-hCG level cut-off value at 2121 mlU/ml

with a specicity of 76.54% and sensitivity of 80.56% (Fig. 2).
In the group of patients with an initial serum b-hCG level below
2121 mlU/ml, 94.7% had a successful MTX therapy outcome
compared to 5.3% who had an unsuccessful MTX therapy outcome.
In the group of patients with an initial serum b-hCG level equal to
or above 2121 mlU/ml, 56.7% had a successful MTX therapy
outcome compared to 43.3% who had an unsuccessful outcome
(Table 2).
In a ve-fold cross validation, the cut-off-value maximizing the
Youden index was re-estimated using data from each combination
of four out of ve randomly selected and equally sized subsets of
the original data. Sensitivity and specicity of the cut-off-level
were calculated for these estimation data sets and for predictions
made on the complementary validation data sets. Three out of the
ve re-estimations resulted in the same cut-off level (2121 mlU/
ml) and two chose a higher level (2460 mlU/ml, 2475 mlU/ml). The
mean sensitivity in the estimation sets was 0.791 and the mean
specicity was 0.785 and therefore slightly higher than the mean
sensitivity (0.723) and specicity (0.780) in the validation data
sets, indicating a stable estimate for specicity, but a slightly
overestimated sensitivity.
As the number of lost to follow-up cases was n = 42, a
secondary analysis was done, hypothetically including these cases
in either the successful MTX therapy group or the unsuccessful
group. If all lost to follow-up cases were counted as successful
cases, the best serum b-hCG cut-off level (Youden index) was
2460 mlU/ml with a sensitivity of 0.75 and specicity of 0.8088. If
all lost to follow-up cases were counted as failures, the best
serum b-hCG cut-off level (Youden index) was 2121 mlU/ml with a
sensitivity of 0.5385 and a specicity of 0.7654 (Fig. 3).
This analysis shows, that the best serum b-hCG level cut-off
would be slightly higher if all lost to follow-up cases would be
included in the successful group, compared to the original analysis.
If all lost to follow-up cases would be added to the failure
group, the original best serum b-hCG level cut-off would remain at
exactly 2121 mlU/ml. In this case, however, the sensitivity (true
prediction of failures) would drastically drop to 54% (from 81% in
original analysis), as almost all lost to follow-up cases had a low
initial serum b-hCG. Nevertheless, the best serum b-hCG cut-off
level remains at 2121 mlU/ml, as the true successful cases below
this threshold overweigh the articially assumed failure cases.
In order to determine, whether the presence of clinical
symptoms (pain, bleeding or both) prior to the start of MTX
treatment has an effect on the MTX therapy outcome, a chisquared analysis was performed. In this patient collective, 74
patients (37.4%) did not experience clinical symptoms like lower
abdominal pain and vaginal bleeding except secondary amenorrhoea, 55 patients (27.8%) reported pain, 31 patients (15.7%)
reported bleeding, and 38 patients (19.2%) reported both pain and
bleeding.
Overall, 24 patients (66.66%) in the unsuccessful MTX therapy
outcome group and 100 patients (61.73%) in the successful MTX
therapy outcome group had documented clinical symptoms prior

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surgery and 42 patients had a successful MTX treatment outcome

after second dose.
The median serum b-hCG level at the initial measurement in
the group with successful MTX therapy outcome was 1058.50 mlU/
ml (IQR (1617)), whereas in the group of unsuccessful MTX therapy
outcome, the median was 3422.50 mlU/ml (IQR (2097)) (p
< 0.0001) (Fig. 1).
24 patients received MTX as primary therapy- and were
therefore included in this statistical analysis- despite their initial
serum b-hCG level 5000 mlU/ml. Reason for this treatment
decision was individual patient wish in all 24 cases.
In the group of patients that were labeled as lost to follow-up
(n = 42), the median serum b-hCG level at the initial measurement
was 815.50 mlU/ml (IQR (1945)). Of these 42 patients, 29 had an
initial serum b-hCG level <2121 mlU/ml, compared to 13 patients
with an initial serum b-hCG level 2121 mlU/ml.
In order to determine a cut-off value of serum b-hCG level,
which can be used as predictor for a successful MTX therapy, a
receiver operating characteristic (ROC) curve was used and the
area under the curve was calculated to evaluate the overall
prognostic performance of the serum b-hCG level. On the ROC
curve each point represents the sensitivity and specicity
corresponding to a particular cut-off value, and different algorithms to nd the best cut-off are described. We dened sensitivity
as the fraction of failures, and specicity as the fraction of
successful MTX-therapy cases, which could be correctly identied
by the method. The point of the maximal Youden index
(maximizing the sum of sensitivity and specicity) and the point
of the minimal Euclidian distance to the top left edge of the graph
(which would be reached if a cut-off point existed, that completely
separates the outcome groups) were calculated (Table 1).
This analysis showed a statistically signicant area under the
curve of 0.789 with a standard error of 0.040 and p < 0.001 (95% CI
(0.709; 0.868)). The subsequent application of the methods
minimal Euclidean distance and maximal Youden index both

Table 1
Area under the ROC curve.
Area under the curve
Test result variable(s): b-hCG serum level mlU/ml
Area

Std. errora

Asymptotic sig.b

Asymptotic 95% condence interval

Lower bound

Upper bound

.789

.040

.000

.709

.868

a
b

Under the nonparametric assumption.

Null hypothesis: true area = 0.5.

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Most previous studies have calculated their results on the base

of rather small numbers of cases, which may also explain the wide
range of proposed serum b-hCG cut-off levels. The largest study on
this topic investigated 350 patients with EP, but did not describe a
specic serum b-hCG cut-off value [22]. In addition to the
calculation of this serum b-hCG cut off level, we furthermore
investigated whether the presence of clinical symptoms prior to
MTX treatment correlated with the MTX therapy outcome. Current
international guidelines recommend MTX therapy only in patients
with minimal clinical symptoms [5].
In our study we can draw the conclusion that patients with
tubal EP, who are presenting with serum b-hCG levels above
2121 mlU/ml, do have a signicantly higher chance of MTX therapy
failure. In our study population, 5.3% of the patients with initial
serum b-hCG levels below 2121 mlU/ml had an unsuccessful MTX
therapy outcome, compared to 43.3% of those who had serum
b-hCG levels equal to or above 2121 mlU/ml.
A documentation of clinical symptoms (pain, bleeding or both)
prior to MTX treatment was present in 67% of the patients in the
group with unsuccessful MTX therapy outcome, and 62% of the
patients in the successful group. The statistical analysis showed no
signicant correlation of clinical symptoms prior to treatment and
MTX therapy outcome.
We were able to include 198 patients in the statistical analysis,
which therefore would represent one of the bigger study
populations with focus on a specic serum b-hCG cut-off value.
However, we are aware of larger study populations described in
previous studies [22].
The primary results were re-evaluated by a ve-fold cross
validation, which conrmed the original results. Diagnosis and
MTX treatment of EP was conducted according to a uniform
protocol for all included patients as described in the methods. A
total number of 24 patients received MTX despite an initial serum
b-hCG 5000 mlU/ml due to individual patients' desire. However,
the limitation of this study is its retrospective design and the
inability of classifying clinical symptoms like pain as an objective
parameter. Our study may be criticized for a relatively high number
of patients, which were lost to follow-up after MTX application. We
serve mostly an inner city population with a high proportion of
recent immigrants to Austria. As a result the population is very
mobile, which is a likely explanation for our inability to follow up
these women. However, the patient collective who had to be
labeled as lost to follow-up did not differ from those patients that
were included in the statistical analysis in regards of initial serum
b-hCG levels. This shows that the number of lost to follow-up
patients is unlikely to introduce a bias in the analysis.

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to therapy. There was no statistically signicant correlation of the

presence of clinical symptoms prior to the start of MTX treatment
and the MTX therapy outcome (chi-squared test p = 0.580;
likelihood ratio = 0.577).

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Fig. 2. Best serum b-hCG cut-off value (mlU/ml); area under the ROC curve;
maximal Youden index.

Comment

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Conducting this study, we aimed to gain further evidence for

clinical decisions to prevent cases of tubal EP, in which MTX
treatment fails and subsequent surgical intervention becomes
necessary. MTX treatment failure occurs in 1330% of patients with
EP, who are primarily treated with MTX, and besides causing
inconveniences to the patients, it furthermore implies risk factors,
such as tubal rupture [5,711].
Previous studies have targeted this problem and have sought
factors that may identify a risk for MTX treatment failure. So far,
the most signicant indicator seems to be the serum b-hCG level
prior to treatment, and previously described cut-off levels, above
which MTX treatment failure is more likely than success, are
ranging between 2000 mlU/ml and 5000 mlU/ml [7,8,1621].
Table 2
MTX therapy outcome at serum b-hCG cut-off level 2121 mlU/ml.
Serum b-hCG level (mlU/ml)  MTX therapy outcome crosstabulation

MTX therapy outcome

Unsuccessful
Serum b-hCG level (mlU/ml)

b-hCG below 2121 mlU/ml

b-hCG above or equal 2121 mlU/ml

Total

Total

Successful

Count
% Within serum b-hCG level (mlU/ml)
% Within MTX therapy outcome
% of total
Count
% Within serum b-hCG level (mlU/ml)
% Within MTX therapy outcome
% of total

7
5.3%
19.4%
3.5%
29
43.3%
80.6%
14.6%

124
94.7%
76.5%
62.6%
38
56.7%
23.5%
19.2%

131
100.0%
66.2%
66.2%
67
100.0%
33.8%
33.8%

Count
% Within serum b-hCG level (mlU/ml)
% Within MTX therapy outcome
% of total

36
18.2%
100.0%
18.2%

162
81.8%
100.0%
81.8%

198
100.0%
100.0%
100.0%

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179

Funding
Funding was not required for the conduction of this study.
Acknowledgement
The authors of this manuscript acknowledge the support of the
Department of Gynaecology and Obstetrics of the Medical
University of Vienna, in specic O.Univ.Prof. Dr.med.univ. Peter
Wolf Husslein (Head of Department).
References

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Fig. 3. Best serum b-hCG cut-off value (mlU/ml) including lost to follow-up
cases; area under the ROC curve; maximal Youden index. (For interpretation of the
references to colour in this gure legend, the reader is referred to the web version of
this article.)
Full line: area under the ROC curve as described in (Fig. 2). Best serum b-hCG cut-off
(Youden index): 2121 mlU/ml; sensitivity (80.56%), specicity (76.54%).
Dotted line: area under the ROC curve including all lost to follow-up patients
(n = 42) in successful group. Best serum b-hCG cut-off (Youden index): 2460 mlU/
ml; sensitivity (53.85%), specicity (76.54%).
Dashed line: area under the ROC curve including all lost to follow-up patients
(n = 42) in failure group. Best serum b-hCG cut-off (Youden index): 2121 mlU/ml;
sensitivity (53.85%), specicity (76.54%).

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Predictors of success of methotrexate treatment in women with tubal ectopic
pregnancies. N Engl J Med 1999;341(26):19748.
[23] Stika CS, Anderson L, Frederiksen MC. Single-dose methotrexate for the
treatment of ectopic pregnancy: Northwestern Memorial Hospital three-year
experience. Am J Obstet Gynecol 1996;174(6)18406 [discussion 1846-8].

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Despite this statistically signicant result, we are well aware

that the clinical management of patients with tubal EP does still
represent a complex challenge and clinical decisions denitely
cannot be solemnly based on serum b-hCG level values. If we
apply the serum b-hCG cut-off level of 2121 mlU/ml to our study
population and simulate that all patients with serum b-hCG
levels below 2121 mlU/ml would have been treated with MTX,
and all patients with levels above 2121 mlU/ml would have
received primary surgery, a total number of 45 patients (22.73%)
would have been misleadingly classied. 38 patients would have
been treated surgically, although MTX treatment was in truth
successful, and 7 patients would have experienced MTX
treatment failure although their serum b-hCG level was below
2121 mlU/ml. Although, by applying the serum b-hCG cut off level
of 2121 mlU/ml, we would be able to reduce the cases of MTX
treatment failure down to 5.3% of all patients who would have
received MTX (n = 131), we are only achieving this reduction at the
cost of 56.7% of patients who would have been treated surgically
(n = 67), but in whom MTX therapy would have actually been
successful.
As an overall summary of this study we can conclude that,
according to our results there is no endpoint of initial serum b-hCG
levels, which can be clearly used as cut-off value for the optimal
management of tubal EP. However, an initial serum b-hCG level of
less than 2121 mlU/ml seems to be a good value to expect a
successful MTX treatment. Above this level, there still seems to be a
high number of possible successful MTX treatment options, but we
need to be aware of the increasing necessity for secondary surgery.
This information could be elementary part of the informed consent
of tubal EP therapy options in addition to clinical symptoms, desire
for subsequent pregnancy and patient wish.
Disclosure of interests
The authors have nothing to disclose.

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pregnancy. N Engl J Med 2000;343(18):13259.
[28] Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of
ectopic pregnancy. Obstet Gynecol 1991;77(5):7547.
[29] Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J
Obstet Gynecol 1993;168(6 Pt 1)175962 [discussion 1762-5].

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[24] Elson J, Tailor A, Banerjee S, Salim R, Hillaby K, Jurkovic D. Expectant

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