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GENERAL GYNECOLOGY
Methotrexate success rates in progressing ectopic

pregnancies: a reappraisal
Aviad Cohen, MD; Liat Zakar, MD; Yaron Gil, MD; Jonia Amer-Alshiek, MD; Guy Bibi, MD; Benny Almog, MD;
Ishai Levin, MD
OBJECTIVE: The purpose of this study was to determine the success
rates of methotrexate in progressing ectopic pregnancies and to correlate
them with betaehuman chorionic gonadotropin (b-hCG) levels.
STUDY DESIGN: This retrospective cohort study that was carried out in
a tertiary university-affiliated medical center included women who had
been diagnosed with ectopic pregnancies between January 2001 and
June 2013. Daily b-hCG follow-up examinations were performed to
determine the progression of the ectopic pregnancy. Women with
hemodynamically stable progressing ectopic pregnancies received
methotrexate (50 mg/m2 of body surface). We measured the success
and failure rates for methotrexate treatment in correlation to b-hCG
level.
RESULTS: One thousand eighty-three women were candidates for
watchful waiting (b-hCG follow up). Spontaneous resolution and
decline of b-hCG levels occurred in 674 patients (39.5%); 409
women (24.0%) had stable or increasing b-hCG levels and were

treated with methotrexate. In 356 women (87.0%), the treatment
was successful; 53 women (13.0%) required laparoscopic salpingectomy. Compared with prompt administration of methotrexate,
our protocol resulted in lower overall success rates for all levels of
b-hCG in women with progressing ectopic pregnancies: 75% in
women with b-hCG levels of 2500-3500 mIU/mL, and 65% in
women with b-hCG levels >4500 mIU/mL. A mathematic model was
found describing the failure rates for methotrexate in correlation with
b-hCG levels.
CONCLUSION: The success rates for methotrexate treatment in progressing ectopic pregnancies after daily follow-up evaluation of b-hCG
levels are lower than previously reported. This reflects redundant
administration of methotrexate in cases in which the ectopic pregnancy eventually will resolve spontaneously.
Cite this article as: Cohen A, Zakar L, Gil Y, et al. Methotrexate success rates in progressing ectopic pregnancies: a reappraisal. Am J Obstet Gynecol 2014;211:128.e1-5.
B ACKGROUND
AND
O BJECTIVE
Patients who are diagnosed with extrauterine pregnancy and who are hemodynamically stable are almost universally
treated with methotrexate. Recent years
of research have established the dominance of the levels of betaehuman
chorionic gonadotropin (b-hCG) as a
predictor of methotrexate success rates;
other parameters, such as the size of the
ectopic mass or gestational age, have
proved less important.
Recently, we have shown that sequential b-hCG level follow up can differentiate true progressing ectopic pregnancies
from spontaneously resolving ectopic
pregnancies. We previously demonstrated
that, in true progressing ectopic pregnancies, the success rates of methotrexate
From the Department of Gynecology, Tel Aviv

Sourasky Medical Center, Sackler School of
Medicine, Tel Aviv University, Tel Aviv, Israel.
The authors report no conict of interest.
0002-9378/free
2014 Mosby, Inc. All rights reserved.
http://dx.doi.org/10.1016/j.ajog.2014.03.043
are lower than those reported in the

literature. This is merely a reection of
the fact that the group of patients who
were treated promptly with methotrexate
was composed of patients with progressing and spontaneously resolving
ectopic pregnancies.
The objective of our study was to
bring forward the success rates of
methotrexate in ectopic pregnancies that
are not resolving spontaneously according to b-hCG levels.
M ATERIALS
AND
M ETHODS
We reviewed the medical records of all

patients who were admitted to our
department with hemodynamically stable ectopic pregnancies from January
2001 through June 2013. Both b-hCG
level measurements and transvaginal
ultrasonography imaging were used to
evaluate the condition of women with
suspected extrauterine pregnancy.
Patients who were hemodynamically
stable and demonstrated no contraindications for methotrexate therapy
were treated expectantly. Those who
demonstrated a spontaneous daily
128 American Journal of Obstetrics & Gynecology AUGUST 2014
decrease in b-hCG levels by >15% were

considered to be spontaneously resolving
ectopic pregnancies and were discharged.
Patients who demonstrated a daily increase of 15% in b-hCG level were
treated with methotrexate. In all other
patients whose b-hCG levels were plateauing (daily change, <15%), in-hospital follow up and repeat b-hCG levels
were measured daily. Serial measurement
and decision-making were repeated each
day with a 5-day limit, when we administered methotrexate.
Methotrexate was given according to
the single dose protocol at a dose of
50 mg/m2 of body surface area. The injection day was considered day zero.
Repeated b-hCG measurements were
taken on days 4 and 7 in our outpatient
clinics with the use of the same hospital
laboratory. When b-hCG concentration
failed to decline by 15% between days
4 and 7, an additional injection of
methotrexate was administered. We
dened treatment failure when patient
returned with severe abdominal pain,
hemodynamic instability, or continuous
rise in b-hCG level, despite 2 sequential
General Gynecology
www.AJOG.org
injections of methotrexate. We calculated the success rates for methotrexate
and correlated them with the last b-hCG
level before treatment.
R ESULTS
From January 2001 through June 2013,
1703 women were admitted to our
department with the diagnosis of ectopic
pregnancy. Immediate surgery was carried out in 620 patients. According to
our protocol, 1083 patients were candidates for b-hCG follow up. No patients
were referred for surgery during this
watchful waiting period.
Spontaneous resolution and decreased
b-hCG levels occurred in 674 patients
(39.5%); 409 women (24.0%) were candidates for methotrexate treatment. In
all, 356 women (87.0%) were treated
successfully with methotrexate, and
53 women (13.0%) required surgical
intervention because of methotrexate
treatment failure. The Table demonstrates the success rates for methotrexate treatment in correlation with
b-hCG levels.
C OMMENT
Medical management of ectopic pregnancy with methotrexate has become the
treatment of choice for hemodynamically
stable ectopic pregnancies. A great deal of
research and effort has addressed the
criteria for patient selection to augment
success rates and prevent potentially lifethreatening failures.
Prompt administration of methotrexate will yield high rates of success,
because patients with both true progressing ectopic pregnancies and spontaneously resolving ectopic pregnancies
will be treated. Withholding methotrexate, especially in women with plateauing b-hCG levels, eventually will
single out patients with spontaneous
resolution and declining b-hCG levels
without intervention. A result will be
medical treatment of fewer patients at
the expense of lower success rates.
In our previous study, the watchful
waiting approach with daily repeated
b-hCG testing signicantly reduced the
number of women who were treated. Up
to 46.4% of candidates for methotrexate
Research
TABLE
Success rates for methotrexate treatment according to b-hCG level

b-hCG level, IU/mL
Cases, n
0-500
106
96.23
500-1000
82
93.90
1000-1500
54
90.74
1500-2000
43
88.37
2000-2500
37
75.68
2500-3500
36
75.00
3500-4500
22
72.73
>4500
29
10
65.52
409
53
87.04
Total
Failures, n
Success rate, %a
b-hCG, betaehuman chorionic gonadotropin level.

a
P < .0001.
Cohen. Methotrexate in progressing ectopic pregnancies. Am J Obstet Gynecol 2014.
treatment were discharged eventually

without the need for any treatment
because of spontaneous ectopic resolution. We signicantly reduced the number of patients who were treated at the
expense of reduced success rates of
73.8% for methotrexate (for progressing
ectopic pregnancies).
In our present study, we used a
watchful waiting approach to single out
patients with progressing ectopic pregnancies. To the best of our knowledge,
this represents the largest group of patients with true progressing ectopic
pregnancies to be studied. In accordance
with our past ndings, 39.5% of our
patients were discharged home after
spontaneous decline of b-hCG levels.
This protocol clearly results in lower
success rates for all levels of b-hCG with
an overall success rate of 87%, a 75%
success rate in patients with levels 25003500 mIU/mL, and a 65% success rate for
patients with levels >4500 mIU/mL. Our
single-dose methotrexate protocol proved
to be less successful with higher failure
rates than was reported previously. This is
a reection of the fact that we treated only
progressing, as opposed to spontaneously
resolving, ectopic pregnancies.
In addition, we were able to correlate
the failure rates of methotrexate treatment to the levels of b-hCG using a
mathematic model. This exponential

function of b-hCG gives an accurate
estimation of the failure rates for methotrexate in progressing ectopic pregnancies. The ability to estimate the
likelihood of failure or success can help
us and our patients create treatment
plans more wisely.
Our study provides success rates for
methotrexate treatment in progressing
ectopic pregnancy after careful b-hCG
follow up. The results provide data for
clinicians who are willing to follow a
watchful waiting protocol to reduce unnecessary treatment with methotrexate.
CLINICAL IMPLICATIONS
-
Sequential follow up of betaehuman

chorionic gonadotropin (b-hCG)
levels can differentiate true progressing ectopic pregnancy from spontaneously resolving ectopic pregnancy.
In true progressing ectopic pregnancy, the success rates of methotrexate are lower than reported in the
literature.
Withholding methotrexate, especially
in women with plateauing b-hCG
levels, will eventually single out patients with spontaneous resolution
and declining b-hCG levels without
need for intervention.
-
AUGUST 2014 American Journal of Obstetrics & Gynecology
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Research

Methotrexate success rates in progressing ectopic

women (24.0%) had stable or increasing b-hCG levels and were

From the Department of Gynecology, Tel Aviv

are lower than those reported in the

We reviewed the medical records of all

128 American Journal of Obstetrics & Gynecology AUGUST 2014

decrease in b-hCG levels by >15% were

Success rates for methotrexate treatment according to b-hCG level

b-hCG, betaehuman chorionic gonadotropin level.

Cohen. Methotrexate in progressing ectopic pregnancies. Am J Obstet Gynecol 2014.

treatment were discharged eventually

mathematic model. This exponential

Sequential follow up of betaehuman

AUGUST 2014 American Journal of Obstetrics & Gynecology

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