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Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

Reproductive Biology
journal homepage: www.elsevier.com/locate/ejogrb
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Correlation of the volume of ectopic pregnancy and MTX therapy

outcome: a retrospective cohort study

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Q1 S.

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Helmy a, M. Koch a, H. Kolbl a, B. Grohmann-Izay b, E. Solomayer c, Y. Bader c,*

Department of Obstetrics and Gynecology, Medical University Vienna, Vienna, Austria

Medical University Vienna, Vienna, Austria
c
Department of Gynecology, Obstetrics and Reproductive Medicine, University Clinics of Saarland, Homburg/Saar, Germany
b

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 5 April 2014
Received in revised form 25 September 2014
Accepted 29 September 2014

Objective: To investigate a possible correlation between the volume of the tubal ectopic pregnancy (EP)
measured by vaginal-ultrasound (VUS) and methotrexate (MTX) therapy outcome.
Study design: Data of EP volume measured by one expert-sonographer, viability, clinical symptoms,
previous IVF/insemination, follow-up of b-hCG and progesterone levels, and treatment of EP was
collected of 100 patients with sonographically diagnosed EP, who attended the Department of Obstetrics
and Gynecology of the Medical University Vienna between March 2008 and September 2011.
Results: The mean volume of EP (mVol.) in the group with successful MTX therapy (n = 38) was 5.11 ml,
95%CI [2.4; 7.8] with a median 3.2 ml, IQR [5.0], in the group with unsuccessful MTX treatment (n = 11) it
was 15.24 ml, 95%CI [ 2.6; 33.1], with a median 4.4 ml, IQR [11.4]. We could observe a trend towards a
lower mVol. in the successful MTX group (5.11 ml vs. 15.24 ml). We could not show a signicant
correlation (u-test p = 0.208).
Conclusion: A clear tendency was observed towards a lower mVol. in the successful MTX therapy group,
but we could not verify a statistically signicant correlation of volume of EP and MTX therapy outcome
most likely due to the small sample size. This was the rst study investigating the correlation of volume
of EP and MTX therapy outcome as principal question.
2014 Elsevier Ireland Ltd. All rights reserved.

Keywords:
Ectopic pregnancy
Methotrexate
Ectopic pregnancy volume
Beta hCG
Progesterone

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Introduction
Q2

Ectopic pregnancy (EP) has an incidence of 1.52.0% of all

pregnancies [13] and is the leading cause of maternal deaths in
the rst trimester [4].
Risk factors are previous tubal surgeries, salpingitis [2], use of
intrauterine device, in vitro-fertilization (IVF) [5], and tubal
pathologies [6,7]. A combination of VUS and serum beta-human
chorionic gonadotropin (b-hCG) measurement [8] are the gold
standard to diagnose EP.
VUS can identify non-cystic adnexal masses with a specicity of
98.9% and a sensitivity of 84.4% [9]. Criteria for the sonographic
diagnosis of EP are, besides others, the detection of an extrauterine
chorionic cavity or trophoblastic-tissue, a separate corpus luteumcyst, mostly free hyper-echogenic liquid in the Douglas cavity [10].

* Corresponding author at: Department of Gynecology, Obstetrics and Reproductive Medicine, University Clinics of Saarland, Kirrbergerstr. 100, 66421 Homburg/Saar, Germany. Tel.: +49 68411628000; fax: +49 68411628110.
E-mail addresses: bader.yvonne@gmail.com, Yvonne.Bader@meduniwien.ac.at
(Y. Bader).

Evidenced based decision whether to treat an EP via MTX,

laparoscopy or expectant management still represents a challenge.
Existing study results mostly suggest that MTX should only be
applied in hemodynamically stable patients with a proven absence
of fetal cardiac activity, and a b-hCG level below 3000 IU/l [11,12],
leading to a success rate ranging between 70 and 87% [1317].
MTX therapy is equal to laparoscopy concerning the effectiveness [1821] and high serum b-hCG levels are the most important
risk factors associated with failure of treatment with a single dose
MTX therapy [5,9,22,23].
As we know that b-hCG levels do correlate with the MTX
therapy outcome, the aim of our study was to investigate a
potential relation of the volume of EP measured by VUS and the
MTX therapy outcome, in order to facilitate the prediction of the
therapy success and to identify a correlation of b-hCG and
progesterone levels with EP volume.

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Materials and methods

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Ethical approval was obtained at the Ethical Commission of the

Medical University of Vienna on March 13th, 2012 (EK Nr: 1042/

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http://dx.doi.org/10.1016/j.ejogrb.2014.09.038
0301-2115/ 2014 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Helmy S, et al. Correlation of the volume of ectopic pregnancy and MTX therapy outcome: a
retrospective cohort study. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.09.038

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2012). All ultrasound investigations were performed on a GE

Voluson E8 Expert. The statistical program used was SPSS software
(Statistical Package for the Social Sciences), the signicance level
was dened as p < 0.05.
We included patients aged 18 or above with tubal EP diagnosed
by VUS within the period of March 2008 to September 2011 at the
Department of Obstetrics and Gynecology of the Medical
University Vienna. To maximally reduce inter-investigator variation we only included patients, whose EP was diagnosed by one
expert sonographer (head of the ultrasound department).
All scans were performed according to a standardized protocol.
An EP was only diagnosed when a gestational sac or products of
conception were visualised outside the uterine cavity and separate
from a corpus luteum. EP was dened as a mass in the adnexa,
usually just above and medial to the ovary. The sliding sign was
used to distinguish a bulging corpus luteum from an EP. Colour
Doppler was used to both aid identication, and to conrm the
presence of trophoblastic ow within an adnexal mass.
The EPs appearance may be a homogeneous or a solid mass, an
empty gestational sac or a gestational sac with a yolk sac or embryo
without cardiac activity or lastly an extra-uterine sac with a viable
embryo [24].
In order to gain the volume of EP (ml3), the adnexal mass was
measured three-dimensionally rst, then the volume was calculated by the formula for ellipsoid volume (a  b  c  0.523).
All EPs were measured in three perpendicular planes. Each
diameter was measured by placing the callipers on the outer
borders of the trophoblastic tissue. If visible, a surrounding
haematoma was excluded from the measurements. All measurements were transferred into the routinely used programm PIA (GE
Healthcare, View Point, Version 5.6.5.319) and the volume of the
EP could be calculated as mentioned above.
Moreover we collected data of patients obstetric history
(uterine anomalies, uterus myomatosus, hydrosalpinx, haematometra, heterotopic pregnancy, previous EP, previous operations
and miscarriages) and clinical symptoms (pain and bleeding).
We separated all patients into 3 groups depending on the
individual therapy protocol namely (1) MTX (successful or
unsuccessful), (2) laparoscopy (as rst therapy-choice), and (3)
expectant management.
If MTX was necessary a single dose of 50 mg MTX/m2 body
surface area (BSA) was administered. A decrease of beta hCG levels
of less than 15% from day 4 to day 7 after MTX application was
considered a treatment failure and required either an additional
MTX injection or surgical intervention.
For the (1) MTX-group we extracted all documented b-hCG
and progesterone levels, the date of diagnosis of the EP, the date/s
of MTX injection/s, and the duration in days until b-hCG clearance,
which was dened as a serum b-hCG level under the threshold of
25 mIU/ml or a negative urine pregnancy test.
For the (2) laparoscopy- and (3) expectant management-group
the date of diagnosis of the EP, the date of laparoscopy (for group
2), all b-hCG and progesterone levels from the initial measurement
to the b-hCG clearance and the amount of days in between the
b-hCG and progesterone-measurements were collected.

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Results

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We could include 100 patients, whose mean age was

31.4 years  0.525 (SD). 54 of these patients received MTX as primary
therapy, 28 were treated via laparoscopic intervention, and 18 were
observed via expectant management.
Of the 54 patients who received MTX as primary therapy,
11 patients experienced a failure of the MTX therapy and therefore
had to undergo laparoscopic surgery. Among the 43 patients with
successful MTX therapy, 5 had to be marked as lost because the

follow up could not be proceeded until the beta HCG level

clearance. Consequently, we could oppose 38 patients with
successful MTX therapy to 11 patients with unsuccessful MTX
therapy.
In our patient collective 8.2% had a diagnosed uterus anomaly
(uterus bicornis, uterus arcuatus) and 9% had uterine leiomyoma,
13.1% have had a previous EP, 3% have had one ore more previous
miscarriages, 1% had a heterotopic pregnancy and 4% had a known
pathology of hydrosalpinx. There was a signicantly higher
percentage of patients without a second diagnosis (Chi-square
test p > 0.001). Nine percent of patients had previous IVF
treatment and 3% a previous insemination.
In order to investigate a possible correlation of the initial
b-hCG- or progesterone-levels and the volume of EP, a nonparametric Spearman correlation rank coefcient was calculated.
The correlation between volume of EP and initial b-hCG levels was
statistically signicant (r = 0.323; p = 0.001) but it was not
clinically relevant. We could not verify a correlation between
volume of EP and initial progesterone levels (r = 0.031; p = 0.759).
Within the patient group that was treated with MTX, the mean
b-hCG level at the initial measurement was 2178.40 mIU/ml
(95%CI [1009.74; 3347.05]).
On the day of the rst MTX injection, the mean b-hCG level was
2667.63 mIU/ml (95%CI [1454.77; 3880.55]) and increased to a
mean level of 3035.74 mIU/ml (95%CI [1827.71; 4243.78]) on day
4. Between 4 days and 7 days after the MTX injection, b-hCG levels
were again decreasing to a mean level of 2483.51 mIU/ml (95%CI
[1505.04; 3461.99]) on day 7 post-injection.
The mean level of progesterone on the day of initial measurement was 11.40 ng/ml (95%CI [7.74; 15.04]). It continuously
decreased to a mean of 9.83 ng/ml (95%CI [5.37; 14.29]) on the rst
day of the MTX application, to a mean of 8.4 ng/ml (95%CI [4.88;
12]) on the fourth day, and to a mean of 6.08 ng/ml (95%CI [3.49;
8.68]) on the seventh day after MTX injection.
Among the patient group with successful MTX treatment, the
mean of days between the rst MTX application and the day of
measured b-hCG clearance was 36.5 days (95%CI [30.0; 43.1]. The
median was 35.4 days with an interquartile range (IQR) of [30]
(min. 9d; max. 91d).
In the patient group with successful MTX therapy, outcome the
mean volume of the EP (mVol.) was 5.11 ml (95%CI [2.4; 7.8]) and
the median was 3.2 ml (IQR [5.0]).
In the patient group with unsuccessful MTX therapy outcome
and subsequent laparoscopic therapy, the mVol. was 15.24 ml,
(95%CI [ 2.6; 33.1]) and the median was 4.4 ml (IQR [11.4]).
The mVol. of the group with unsuccessful MTX therapy was
considerably higher, but the difference to the group with
successful MTX therapy was not statistically signicant (u-test
p = 0.208) (Table 1).
Q3
When comparing mean volumes of EP in regards of different
therapy outcomes, patients with unsuccessful MTX therapy
outcome and primary laparoscopy showed a higher mean EP
volume than patients with successful MTX therapy or expectant
management (Table 2).
Table 1
Mean and median volume of ectopic pregnancy measured by VUS depending on the Q7
MTX therapy outcomes.
MTX therapy
outcome

Volume of ectopic pregnancy (volume in ml)

Mean value; 95%CI

Median value, IQR

Unsuccessful (n = 11)a
Successful (n = 38)b

15.24 [ 2.6; 33.1]

5.11 [2.4; 7.8]

4.4 [11.4]
3.2 [5.0]

a
Unsuccessful: EP-therapy included MTX-application followed by laparoscopy
due to MTX-therapy failure.
b
Successful: EP-therapy included MTX-application until b-hCG clearance only.

Please cite this article in press as: Helmy S, et al. Correlation of the volume of ectopic pregnancy and MTX therapy outcome: a
retrospective cohort study. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.09.038

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Table 2
Mean volume of ectopic pregnancy in the different therapy options (MTX, laparoscopic management, expectant management).
Therapy option

MTX n = 43
Laparoscopy n = 39
Expectant management n = 18
a
b

Volume of ectopic pregnancy (ml)

Total

Successful MTX-therapy
outcomea n = 38

Unsuccessful MTX-therapy
outcomeb n = 11

6.6 [3.6; 9.5]

12.4 [5.1; 19.7]
5.9 [2.6; 9.2]

5.1 [2.4; 7.8]

15.2 [ 2.6; 33.1]

Successful MTX-therapy outcome: EP-therapy included MTX-application until b-hCG clearance.

Unsuccessful MTX therapy: EP-therapy included MTX-application followed by laparoscopy due to MTX-therapy failure.

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Comment

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The aim of our study was to investigate the volume of the EP as a

potential additional predictive factor of the MTX therapy outcome
in order to allow a more accurate therapy management. This
predictive factor might facilitate a separation into those patients
who benet of MTX therapy, and those who benet of a primary
laparoscopy and might avoid cases, in which patients receive both
MTX treatment and ultimately laparoscopy.
Our study conrmed previous ndings that b-hCG levels do
correlate with the MTX therapy outcome [5,9,22,23]. But only a few
studies have additionally investigated a possible correlation of the
size of EP and MTX therapy outcome, but were not able to nd
signicant outcomes [22,25,26].
We could show that the mVol. of EP in the group with successful
MTX treatment outcome (no necessity for subsequent surgery
until b-hCG clearance) was 5.11 ml (median 3.2 ml), opposed to
15.24 ml (median 4.4 ml) in the group with unsuccessful MTX
treatment (need of subsequent laparoscopic surgery due to MTX
treatment failure). This was a clear tendency towards higher
volumes of EP in the group with unsuccessful MTX therapy
outcome, unfortunately these ndings were not statistically
signicant, which might be due to the small patient population.
The highest mVol. of EP could be detected in those patients, who
were primarily treated with MTX and had an unsuccessful therapy
outcome (15.2 ml), followed by the group of patients, which
received laparoscopy as primary therapy (11.3 ml). The volume of
EP was similar in the group with successful MTX treatment (5.1 ml)
and in the group with expectant management (5.9 ml). We could
therefore observe a tendency towards higher volumes of EP in the
group of laparoscopic management.
Unfortunately it was not possible to give prognosis on the MTX
therapy outcome solely based on the volume of EP.
Furthermore we wanted to oppose the initial serum b-hCG
levels to the volume of EP in order to gain a possibility of
connecting the volume of EP to the MTX therapy outcome. Our
results showed a statistically signicant correlation between
the initial b-hCG levels and the volume of EP, which would
therefore strenghten the hypothesis, that the volume of EP is a
predictive factor for the MTX therapy outcome. This would support
the assumption, that the non- signicancy of correlation of volume
of EP and MTX therapy outcome in this study resulted from the
small sample size, and that a true correlation might be conrmed
within a larger sample.
The RCOG (Royal College of Obstetricians and Gynaecologists)
state that women who are most suitable for MTX therapy are those
with a serum b-hCG below 3000 IU/l and minimal symptoms.
In our study 63% of the patients with MTX treatment and 33.33%
of the patients with expectant management had clinical symptoms, which did not show a statistically signicant correlation of
clinical symptoms and the therapy protocol (Likelihood Quotient
p = 0.065). However, the result has limitations, as the information
on clinical symptoms was not standardized evaluated and could
only be retrospectively extracted from the patients history.

Moreover, we did not compare the presence of clinical symptoms

to the level of b-hCG, the second determining factor for the
decision of therapy.
We furthermore investigated the duration of the b-hCG
clearance in days, starting with the day of rst MTX application,
resulting in 36.5 days (median 35.4 days).
As far as we know this is the rst study that focuses specically
on volume of EP gained by the formula for ellipsoid volumes and
the MTX therapy outcome as the principal question, whereas
previous investigations did either observe data of three dimensions of EP as secondary issue, or multiplied its two greatest
dimensions, and dened the size of the EP as its maximal diameter
[22,25,26].
Still we have to admit that our study was limited by this rather
small patient population of n = 100. Since the study was
retrospective we were dependent on the already documented
patient histories and were not able to standardize specic details.
However, further prospective studies with a larger patient
population might be able to receive statistically signicant results
and could be able to proof a relation of volume of EP and the MTX
therapy outcome.

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Conict of interest

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The authors have nothing to disclose.

Funding
Funding was not required for the conduction of this study.
Uncited references
[27,28].
Acknowledgements

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Q4249

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The authors of this manuscript acknowledge the support of the Q5252

Department of Gynaecology and Obstetrics of the Medical Q6253
University of Vienna, in specic O.Univ.-Prof. Dr.med.univ. Peter 254
Wolf Husslein (Head of Department).
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Please cite this article in press as: Helmy S, et al. Correlation of the volume of ectopic pregnancy and MTX therapy outcome: a
retrospective cohort study. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.09.038

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Please cite this article in press as: Helmy S, et al. Correlation of the volume of ectopic pregnancy and MTX therapy outcome: a
retrospective cohort study. Eur J Obstet Gynecol (2014), http://dx.doi.org/10.1016/j.ejogrb.2014.09.038

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