European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 105–109

Contents lists available at ScienceDirect

European Journal of Obstetrics & Gynecology and

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

Review

Overview and guidelines of off-label use of methotrexate in ectopic

pregnancy: report by CNGOF
Henri Marreta,b,j,* , Arnaud Fauconnierc,d,j, Gil Dubernarde,j , Hélène Mismee,j,
Laurence Lagarcef,j , Magali Lesavreg,j, Hervé Fernandezg,j , Camille Mimounc,d,j,
Claire Touretteh,j, Sandra Curinieri,j, Benoit Rabishongi,j, Aubert Agostinih,j
a
Centre Hospitalo-Universitaire de Tours, Hôpital Bretonneau Faculté de Médecine de Tours, François Rabelais, Boulevard Tonnellé, 37044 Tours Cedex 1,
France
b
UMR Inserm U 930, université François-Rabelais, 2, Boulevard Tonnellé, 37044 Tours Cedex 9, France
c
Université Versailles St-Quentin, unité de recherche EA 7285, 2 avenue de la source de la Bièvre, 78180 Montigny-le-Bretonneux, France
d
Service de gynécologie et obstétrique, Centre Hospitalier Intercommunal de Poissy-Saint-Germain-en-Laye, 10 rue du Champ Gaillard, BP 3082, 78303 Poissy
Cedex, France
e
Service de gynécologie-obstétrique, Hôpital de la Croix-Rousse – Hospices civils de Lyon, Université Claude Bernard Lyon 1, 103 Grande Rue de la Croix-
Rousse, 69004 Lyon, France
f
Centre régional de pharmacovigilance, CHU Angers, 4 rue Larrey, 49933 Angers Cedex 9, France
g
Service de gynécologie – obstétrique, CHU du Kremlin-Bicêtre, 78 avenue du général Leclerc, 94276 Le Kremlin-Bicêtre, France
h
Centre Hospitalo-Universitaire de Marseille, Hôpital de la Conception Pôle de Gynécologie Obstétrique, 147 Boulevard Baille, 13005 Marseille, France
i
Service Gynécologie Obstétrique et Médecine de le Reproduction, CHU Estaing, 1 Place Lucie Aubrac, 63003 Clermont-Ferrand Cedex, France
j
CNGOF, 91 Boulevarde de Sébastopol, 75002 Paris, France

A R T I C L E I N F O A B S T R A C T

Article history:
Received 23 July 2015 Our objective is to describe off-label use of methotrexate in ectopic pregnancy treatment using evidence
Received in revised form 1 July 2016 based medicine. The patient group includes all women with a pregnancy outside the usual endometrium,
Accepted 25 July 2016 or of unknown location.
Available online xxx Method used was a Medline search on ectopic pregnancy managed using methotrexate treatment;
evidence synthesis was done based on this current literature analysis.
Keywords: Level of evidence (LE) were given according to the centre for evidence base medicine rules. Grade was
Methotrexate proposed for guidelines but no recommendation was possible as misoprostol is off label use for all the
Ectopic pregnancy
indications studied.
Interstitial pregnancy
In the absence of any contraindication, the protocol recommended for medical treatment of ectopic
hCG
Cervical pregnancy pregnancy is a single intramuscular injection of methotrexate (MTX) at a dosage of 1 mg/kg or 50 mg/m2
Guideline (Grade A). It can be repeated once at the same dose should the hCG concentration not fall sufficiently.
Pretreatment laboratory results must include a complete blood count and kidney and liver function tests
(in accordance with its marketing authorization).
MTX is an alternative to conservative treatment such as laparoscopic salpingotomy for uncomplicated
tubal pregnancy (Grade A) with pretreatment hCG levels  5000 IU/l (Grade B). Expectant management is
preferred for hCG levels < 1000 IU/l or in the process of spontaneous decreasing (Grade B).
Intramuscular MTX is also recommended after the failure of surgical salpingotomy (Grade C) or
immediately after surgery, if monitoring is not possible. Except in special circumstances, a local insitu
ultrasound-guided MTX injection is not recommended for unruptured tubal pregnancies (Grade B).
In situ MTX is an option for treating cervical, interstitial, or cesarean-scar pregnancies (Grade C).
In pregnancies of unknown location persisting more than 10 days in an asymptomatic woman who has
an hCG level > 2000 IU/l, routine MTX treatment is an option.
MTX is not indicated for combination with treatments such as mifepristone or potassium.
ã 2016 Published by Elsevier Ireland Ltd.

* Corresponding author at: Service de gynécologie, Hôpital Bretonneau 2, Boulevard Tonnellé 37044 Tours Cedex, France. Fax: +33 2 47 479273.
E-mail address: marret@med.univ-tours.fr (H. Marret).

http://dx.doi.org/10.1016/j.ejogrb.2016.07.489
0301-2115/ã 2016 Published by Elsevier Ireland Ltd.
106 H. Marret et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 105–109

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Dosage for off-label use in ectopic pregnancies [4–9] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Use of MTX in women with tubal pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Surgical treatment vs. MTX [10–14] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Comparison to expectant management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Use of MTX as an adjuvant to conservative surgery [15–17] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Ultrasound-guided transvaginal local MTX injection in tubal pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Selection criteria for treating ectopic pregnancy by MTX [18–27] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
According to symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
According to the b-hCG level . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
According to the ultrasound results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
According to a pretreatment score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
According to the patient’s history . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Ectopic pregnancy other than tubal [28–35] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Interstitial or cervical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Cesarean scar [32–34] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Ovarian [35] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
MTX and Pregnancies of Undetermined Location (PUL) [36–40] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
MTX associated with other treatments [41] . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Financial support for this work . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105

Introduction being easier to determine in everyday practice. The meta-analysis

In the context of vigilance increased towards the off label
prescription, it was useful and urgent that the CNGOF (French
college of gynaecology and obstetrics) produces a synthesis of the
scientific data on methotrexate (MTX) use in ectopic pregnancy
treatment. This text is the summary of large reviews on each
subject published in the French journal of gynaecology and
obstetrics [1]; full references could be found in the original texts,
only a main selection was presented in this paper. Level of evidence
(LE) were given according to the centre for evidence base medicine
rules [2]. No recommendation was possible as MTX is off label use
for all the indications studied. In red are proposed the CNGOF
conclusions.
Before any recommendations about the prescription of MTX for
the medical treatment of ectopic pregnancy, we note three
essential rules that must be complied with before any treatment:
 The diagnosis of ectopic pregnancy must be confirmed by
specific algorithms that are not considered in these guidelines.
The use of selection criteria is recommended (Grade B) [3].
 Gynecological contraindications must be ascertained by the
application of clinical and ultrasound criteria to eliminate/
minimize complications.
 The doctor must inform the woman of the diagnosis, its potential
consequences and the different treatments available. To the
extent possible, the treatment should be chosen in a shared
decision-making process.
by Barnhart et al. compared single- and multi-dose protocols: The
use of single dose was associated with a significantly greater
chance of failed medical management than the use of the
multidose in both crude (odds ratio [OR] 1.71; 1.04, 2.82) and
adjusted analyses (OR 4.74; 1.77, 12.62) and showed that the single-
dose version was associated with fewer adverse effects (LE1, odds
ratio 0.44 [0.31–0.63]). In such a single-dose protocol, folic acid
supplementation is not currently recommended but it should be
envisioned if a second dose turns out to be needed several days
later. So there are no validated pharmacological findings that could
currently justify a conclusion about the best protocol or whether
one or repeated injections should be used in ectopic pregnancy.
MTX is teratogenic and known to carry a risk of fetal
malformations. Malformations and miscarriages have been
reported after administration of MTX for suspected ectopic
pregnancy. A three-month waiting period before conception is
advisable after a MTX injection.
At this day, and in the absence of any contraindication, a single
IM injection of MTX at a dosage of 1 mg/kg or 50 mg/m2 is the
protocol with the best risk to benefit ratio for the medical
treatment of ectopic pregnancy. It can be repeated several days
later at the same dose. Pretreatment laboratory results must
include a complete blood count and kidney and liver function tests
(in accordance with its marketing authorization). This testing must
be performed before any MTX injection.
Use of MTX in women with tubal pregnancies

Surgical treatment vs. MTX [10–14]

Dosage for off-label use in ectopic pregnancies [4–9]
The multidose protocol currently used, especially in the United
States, involves 4 doses of MTX (1 mg/kg, IM) on D1, D3, D5 and D7,
with 0.1 mg/kg of folinic acid IM on D2, D4, D6 and D8. The single-
dose protocol is used more often in France, but no validated
pharmacological data currently justify a conclusion about the
dosage (1 mg/kg or 50 mg/m2) to be preferred for treatment of
ectopic pregnancy. The dosage of 1 mg/kg has the advantage of
A meta-analysis shows that MTX at a single dose of 1 mg/kg is
less effective than laparoscopic salpingotomy in the treatment of
ectopic pregnancy to normalize the hCG level: OR = 0.38 [0.20–
0.71]. Initial use of a multidose regimen does not change the result
(LE1). The interpretation of this result nonetheless must be
qualified according to the principal endpoint chosen: failure of a
dose, or indication for surgery; that is, the meta-analysis found that
only 22.5% of the medical treatments resulted in a normalized HCG
level after a single dose, but only 5.8% ultimately required surgery;
 H. Marret et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 105–109
the others were successful after additional doses (total 2–4). This
protocol with a repeat dose when necessary produces results
similar to those of surgery (LE1).
Monitoring hCG levels after MTX injection is essential (LE2) and
should continue until hCG becomes undetectable (Grade B). An
assay on D7 is the minimum necessary to be able to evaluate MTX
management. Assays can also be performed on both D4 and D7.
In randomized trials, the repeat dose is offered as a single dose
when required by the rate of hCG decrease, generally on D7 (Grade
B).
On the other hand, MTX, especially with the multidose protocol,
is accompanied by more side effects than surgery.
The effects on quality of life by MTX and conservative surgery
have not yet been compared.
Three studies have assessed the cost of single-dose MTX,
compared with conservative surgery. All showed that MTX was
superior (LE2).
There is no long-term difference in fertility between these two
treatments, either for recurrence of ectopic pregnancy or occur-
rence of intrauterine pregnancy. Medical treatment with MTX thus
has no harmful effect on subsequent spontaneous fertility (LE2).
Patients must receive appropriate information.
Single-dose MTX is an alternative to conservative surgical
treatment such as laparoscopic salpingotomy for uncomplicated
tubal pregnancy (Grade A).
A second dose can be proposed at least once, according to the
rate of hCG decrease.
Comparison to expectant management
The success rate of the MTX treatment (hCG negativity) varies
from 65 to 95%, with a mean of 82% (LE1).
Several studies have compared MTX to expectant management.
None showed a significant difference in favor of MTX, although
their success rates were better. On the other hand, the success rate
differs significantly according to the initial hCG level. The threshold
is difficult to determine because studies have tested different
cutoffs. With expectant management, results worsen poorer when
hCG is greater than 2000 IU/l, even though patients are often
included only at levels below 1500 IU/l. Note that all the studies
used MTX as the standard or reference treatment arm.
Expectant management is an alternative treatment for ectopic
pregnancies with hCG < 1000 IU/l (LE3).
In documented tubal pregnancies with low or decreasing hCG
concentrations, MTX is not recommended as a first-line treatment
over expectant management (Grade B).
Use of MTX as an adjuvant to conservative surgery [15–17]
The risk of persistent trophoblastic tissue after salpingotomy
ranges from 11 to 22%, according to the study (LE1). This
persistence is defined by a decrease <20% between 2 hCG assays
performed every 3 days.
Two approaches are possible:
1. An IM MTX injection as routine prophylaxis the day of the
salpingotomy is effective for reducing hCG levels: fewer than 2%
of women then require a second surgical treatment (LE2).
Nonetheless, this rate is identical to that of the control group for
the rate of repeat surgery if MTX is injected secondarily instead.
Its utility for women in terms of a reduction in secondary
surgical treatment has therefore not been established, especial-
ly as this hypothetical benefit must be balanced against the
potential side effects of MTX. An analytic study showed that
MTX prophylaxis would result in fewer cases of secondary tubal
rupture (0.4% vs. 3.7%) and fewer surgical reinterventions (1.9%
vs. 4.7%). This must be balanced against the complication rate
associated with MTX (5.5% vs. 0.8%).
107
2. IM MTX is performed only after salpingotomy failure, that is,
persistence of hCG 4–7 days after surgery. The MTX injection is
effective and produces the same results in terms of secondary
surgery as early routine injection, but no randomized study has
compared it with abstention.
Routine treatment by an IM MTX injection as a first-line
treatment immediately after salpingotomy, to replace monitoring
the hCG decrease, is not indicated (Grade B). Routine use of IM MTX
as an adjuvant is recommended, however, when conditions for
surgery or follow-up are not optimal.
Moreover, in cases where surgical salpingotomy fails, IM MTX is
recommended (Grade C) to avoid reintervention or when
monitoring is not possible.
Ultrasound-guided transvaginal local MTX injection in tubal
pregnancies
MTX (1 mg/kg) injected transvaginally under ultrasound
guidance is significantly less effective than laparoscopic salpin-
gotomy (LE1) when cardiac activity is present; the combination of
MTX by IM and local injection in the gestational sac is more
effective than IM MTX alone (LE3).
MTX (1 mg/kg) injected transvaginally under ultrasound
guidance is significantly more effective than when injected
laparoscopically (LE2).
Except in special circumstances (need to terminate the
pregnancy), ultrasound-guided injection of MTX locally into the
gestational sac is not indicated for unruptured tubal pregnancies
(Grade B).
Selection criteria for treating ectopic pregnancy by MTX [18–27]
According to symptoms
No study allows us to define validated clinical criteria that can
serve as either indications or contraindications to medical
treatment. Nonetheless, the clinical presentation of the ectopic
pregnancy is the major criterion for deciding whether a woman
with a tubal pregnancy should be treated by MTX in the reference
studies (LE1). Only women with few or no symptoms should
receive this treatment. MTX is not recommended for women with
symptoms suggesting a hemorrhagic complication of an ectopic
pregnancy, that is, severe pelvic or abdominal pain, faintness, or
hemodynamic instability, which should be handled by emergency
surgery (expert opinion).
According to the b-hCG level
Randomized trials and reference observational studies have
limited MTX use to hCG levels not exceeding 10,000 IU/l and most
often below 5000 IU/l. The initial hCG level is a major prognostic
factor for successful MTX treatment, but there is no validated
threshold value above which this treatment is known not to be
effective. Results showing that hCG normalization occurred in
fewer than half the women with an initial hCG level greater than
5000 IU/l (LE2) indicate that MTX can appropriately be offered to
women with pretreatment hCG levels  5000 IU/l (Grade B).
Moreover, recent results indicate that women should be informed
that the risk of failure is reasonably substantial and subsequent
surgery potentially necessary, when the hCG level is greater than
2000 IU/l (Grade B).
According to the ultrasound results
Hemoperitoneum extending beyond the pelvis is a contraindi-
cation to MTX treatment (Grade B) because of the risk of persistent
active bleeding (LE3). Limited pelvic hemoperitoneum reduces the
probability that medical treatment will be successful but does not
contraindicate it (Grade B).
108 H. Marret et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 105–109
The existence of a fetal heartbeat or a visible gestational sac and
therefore of an advanced term or a progressing pregnancy are risk
factors for the failure of MTX treatment by IM injection (LE3).
MTX is not indicated as a first-line treatment for a tubal
pregnancy with cardiac activity (Grade C) in view of the substantial
risk of both failure and complications (LE3). When it is used as a
second-line treatment, the patient should be informed of the
substantial risk of failure if either cardiac activity or a gestational
sac are visible on ultrasound and thus of the possible need for
secondary surgical management (Grade B).
According to a pretreatment score
Fernandez’s and Elito’s scores [21,22], both based on prognostic
criteria for ectopic pregnancy, have been assessed and found to
lack substantial external validation. Nonetheless, the success rate
is less than 50% for women with high scores (LE3). Use of the
progesterone assay is a limitation for the Fernandez score because
this assay can rarely be performed, especially on an emergency
basis. Serum progesterone was nevertheless tested in the
Aphrodite trial; in the subgroup with a progesterone level  10
ng/ml, the use of mifepristone as an adjuvant led to a significant
reduction of the risk of medical treatment failure (LE3). The value
of serum progesterone levels in this management thus requires
further assessment.
Scores are useful but are not recommended for assessing
whether MTX is indicated in tubal pregnancy (Grade C).
According to the patient’s history
An history of ectopic pregnancy, whether treated medically or
surgically, is a risk factor for the failure of MTX treatment (LE2). IM
MTX as a first-line treatment is not recommended for women with
a history of treatment for ectopic pregnancy, regardless of its type
(Grade C). When MTX is used as a second-line treatment, women
should be informed of the substantial risk of failure (and thus the
potential need for secondary surgery) if they have previously been
treated for ectopic pregnancy (Grade B).
Management after MTX requires clinical and laboratory follow-
up until hCG becomes undetectable (Grade A). Poor patient
compliance or difficulty of outpatient follow-up are contra-
indications to MTX treatment (Professional consensus).
Ectopic pregnancy other than tubal [28–35]
Interstitial or cervical
The published data (LE4) show that MTX as a first-line
treatment by either IM injection or in situ is an acceptable
treatment option for uncomplicated interstitial or cervical
pregnancies [30,31], in view of the considerable risks of hemor-
rhage in surgery (Grade C).
Women should be informed of the obstetric risks of resection of
the uterine horn for interstitial pregnancies and of the risk of
secondary hemorrhage that may require uterine artery embolization
or emergency hysterectomy for cervical pregnancies (Grade C).
Cesarean scar [32–34]
Review of the published data shows that no standard of
treatment currently exists. Use of MTX is conceivable (LE4). An in
situ injection is preferable to the systemic pathway, especially in
the case of cardiac activity (for termination of pregnancy) because
the complication rate is lower for a local MTX injection (LE4). Its
use does not prevent a secondary hemorrhage, even a very remote
one. No treatment has been shown to be superior to any other.
Uterine artery embolization should be considered to reduce the
risk of secondary hemorrhage (LE2).
MTX injected in situ to treat cesarean-scar pregnancies is
preferable to other options (Grade C). It should be accompanied by
a procedure to prevent secondary hemorrhage, such as uterine
artery embolization (Grade B).
Ovarian [35]
Treatment of ovarian pregnancies has been studied only in short
series; only case reports describe the use of medical treatment in
this situation.
MTX must not be a first-line treatment for ovarian pregnancies;
it has not been assessed for this indication. Laparoscopic surgery,
if possible conservative, remains the treatment of reference
(Grade C).
MTX and Pregnancies of Undetermined Location (PUL) [36–40]
For pregnancies of undetermined location (PUL), expectant
management with monitoring of hCG levels is recommended, in
view of the low incidence of ectopic pregnancies among those
labelled as PUL during a first consultation (7–20%).
The interval for monitoring before medical intervention should
range from 48 h to 10 days and should be assessed on a case-by-
case basis (LE3).
Treatment of persistent PUL by MTX has not been specifically
studied. One randomized study included an arm for persistent PUL
with an hCG plateau < 2000 IU/l. This study of a small number of
individuals found no significant difference between abstention
and IM MTX: there were somewhat fewer secondary surgical
procedures in the MTX group, but several doses were sometimes
needed (LE2).
MTX is not recommended as a first-line treatment in
asymptomatic women with a persistent PUL and a hCG level
< 2000 IU/l (Grade B).
Systematic treatment by MTX is an option for PUL persisting
more than 10 days in an asymptomatic woman with a hCG
level > 2000 IU/l.
Another approach, more interventionist, is to offer systematic
MTX as a treatment option for probably ectopic PUL after ruling out
an intrauterine pregnancy by intrauterine curettage or diagnostic
hysteroscopy.
MTX associated with other treatments [41]
1. Although the marketing authorization for mifepristone
specifically states that it is contraindicated in ectopic
pregnancy, some studies on this topic have nonetheless been
published: Its routine use with MTX mifepristone is not
recommended for the management of tubal pregnancy (Grade
B); the success rate of the two treatments was similar in the
two groups in the randomized trial (79% in the group with
mifepristone vs. 74% with placebo (LE2)). In the subgroup with a
serum progesterone level  10 ng/l, the addition of mifepristone
led to a significant reduction in the risk of medical treatment
failure (LE3).
2. The use of MTX with potassium chloride is not recommended in
tubal pregnancies (Grade C).
Conclusion
Temporary recommendation of MTX use (authorisation for
gynaecologist to prescribe MTX in ectopic pregnancy under
specific conditions) is in construction from CNGOF and ANSM
(national agency for drug security) and will start for 3 years in
2016.
Four major points for future research could be pointed:
 H. Marret et al. / European Journal of Obstetrics & Gynecology and Reproductive Biology 205 (2016) 105–109
– More randomized study to compare multidose vs. single dose or
two doses protocols.
– More study to precise HCG threshold for expectative and medical
treatment.
– More study to precise adjuvant therapy after surgery.
– Fernandez score validation.
Conflicts of interest
None for MTX.
Financial support for this work
By CNGOF French College of Gynecology and Obstetrics, 91 blvd
de Sébastopol 75002 Paris France only.
Acknowledgement
Mrs. Jo Ann Cahn for the English version of this manuscript.
References
[1] Marret H, Fauconnier A, Dubernard G, et al. Evidence-based evaluation and
expertise of methotrexate off label use in gynaecology and obstetrics: work of
the CNGOF. J Gynecol Obstet Biol Reprod 2015;44:230–6.
[2] Burns P, Rohrich R, Chung K. The levels of evidence and their role in evidence-
based medicine. Plast Reconstr Surg 2011;128:305–10.
[3] Collège National des Gynécologues et Obstétriciens Français. [Ectopic
pregnancy management. Guidelines]. J Gynecol Obstet Biol Reprod (Paris)
2003;32(November (7 Suppl.)):S109–12.
[4] Stika CS. Methotrexate the pharmacology behind medical treatment for
ectopic pregnancy. Clin Obstet Gynecol 2012;55:433–9.
[5] Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of
ectopic pregnancy: a meta-analysis comparing single dose and multidose
regimens. Obstet Gynecol 2003;101:778–84.
[6] Darbhamulla A, Bhal K, Lal S. Is routine monitoring of hepatic and renal
function beneficial following single-dose methotrexate treatment for ectopic
pregnancy? A 4-year review of experience from a teaching hospital. J Obstet
Gynaecol 2008;28:434–5.
[7] Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of
ectopic pregnancy. Obstet Gynecol 1991;77:754–7.
[8] Stovall TG, Ling FW, Gray LA, Carson SA, Buster JE. Methotrexate treatment of
unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol
1991;77:749–53.
[9] Hyoun SC, Obican SG, Scialli AR. Teratogen update: methotrexate. Birth Defects
Res A Clin Mol Teratol 2012;94:187–207.
[10] Hajenius PJ, Mol F, Mol BWJ, Bossuyt PMM, Ankum WM, van der Veen F.
Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007
(1), doi:http://dx.doi.org/10.1002/14651858.CD000324.pub2 Art. No.:
CD000324.
[11] Korhonen J, Stenman UH, Ylöstalo P. Low-dose oral methotrexate with
expectant management of ectopic pregnancy. Obstet Gynecol 1996;88:775–8.
[12] Bouyer J, Fernandez H, Coste J, Pouly J-L, Job-Spira N. Fertility after ectopic
pregnancy: 10-year results in the Auvergne registry. J Gynécol Obstét Biol
Reprod 2003;32:431–8.
[13] Fernandez H, Capmas P, Lucot JP, et al. Fertility after ectopic pregnancy: the
DEMETER randomized trial. Hum Reprod Oxf Engl 2013;28:1247–53.
[14] Mol F, Mol BW, Ankum WM, van der Veen F, Hajenius PJ. Current evidence on
surgery, systemic methotrexate and expectant management in the treatment
of tubal ectopic pregnancy: a systematic review and meta-analysis. Hum
Reprod Update 2008;14:309–19.
[15] Graczykowski JW, Mishell DR. Methotrexate prophylaxis for persistent ectopic
pregnancy after conservative treatment by salpingostomy. Obstet Gynecol
1997;89:118–22.
[16] Gracia CR, Brown HA, Barnhart KT. Prophylactic methotrexate after linear
salpingostomy: a decision analysis. Fertil Steril 2001;76:1191–5.
109
[17] Lund CO, Nilas L, Bangsgaard N, Ottesen B. Persistent ectopic pregnancy after
linear salpingotomy: a non-predictable complication to conservative surgery
for tubal gestation. Acta Obstet Gynecol Scand 2002;81:1053–9.
[18] Fernandez H, Pauthier S, Doumerc S, et al. Ultrasound-guided injection of
methotrexate versus laparoscopic salpingotomy in ectopic pregnancy. Fertil
Steril 1995;3:25–9.
[19] Lipscomb GH, Givens VA, Meyer NL, Bran D. Previous ectopic pregnancy as a
predictor of failure of systemic methotrexate therapy. Fertil Steril
2004;81:1221–4.
[20] Gnisci A, Stefani L, Bottin P, Ohannessian A, Gamerre M, Agostini A. Predictive
value of hemoperitoneum for outcome of methotrexate treatment in ectopic
pregnancy: an observational comparative study. Ultrasound Obstet Gynecol
2014;43:698–701.
[21] Elito Jr. J, Reichmann AP, Uchiyama MN, Camano L. Predictive score for the
systemic treatment of unruptured ectopic pregnancy with a single dose of
methotrexate. Int J Gynaecol Obstet 1999;67:75–9.
[22] Fernandez H, Lelaidier C, Thouvenez V, Frydman R. The use of a pretherapeutic,
predictive score to determine inclusion criteria for the non-surgical treatment
of ectopic pregnancy. Hum Reprod 1991;6:995–8.
[23] Fernandez H, Bourget P, Ville Y, Lelaidier C, Frydman R. Treatment of
unruptured tubal pregnancy with methotrexate: pharmacokinetic analysis of
local versus intramuscular administration. Fertil Steril 1994;62:943–7.
[24] Krissi H, Peled Y, Eitan R, Bishara A, Goldchmit C, Ben-Haroush A. Single-dose
methotrexate injection for treatment of ectopic pregnancy in women with
relatively low levels of human chorionic gonadotropin. Int J Gynaecol Obstet
2013;121:141–3.
[25] Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of
success of methotrexate treatment in women with tubal ectopic pregnancies.
N Engl J Med 1999;23(341):1974–8.
[26] Rabischong B, Tran X, Sleiman AA, et al. Predictive factors of failure in
management of ectopic pregnancy with single-dose methotrexate: a general
population-based analysis from the Auvergne register, France. Fertil Steril
2011;95:401–4 404.e1.
[27] Wang M, Chen B, Wang J, Ma X, Wang Y. Nonsurgical management of live tubal
ectopic pregnancy by ultrasound-guided local injection and systemic
methotrexate. J Minim Invasive Gynecol 201423(January).
[28] Bouyer J, Coste J, Ferrnandez H, et al. Sites of ectopic pregnancy; a 10 year
population-based study of 1800 cases. Hum Reprod 2002;17:3224–30.
[29] Jermy K, Thomas J, Doo A, Bourne T. The conservative management of
interstitial pregnancy. BJOG 2004;111:1283–8.
[30] Jeng CJ, Ko ML, Shen J. Transvaginal ultrasoundguided treatment of cervical
pregnancy. Obstet Gynecol 2007;109:1076–82.
[31] Verma U, Goharkhay N. Conservative management of cervical ectopic
pregnancy. Fertil Steril 2009;91:671–4.
[32] Timor-Tritsch IE, Monteagudo A. Unforeseen consequences of the increasing
rate of cesarean deliveries: early placenta accreta and cesarean scar pregnancy.
A review. Am J Obstet Gynecol 2012;207:14–29.
[33] Timor-Tritsch IE, Monteagudo A, Santos R, Tsymbal T, Pineda G, Arslan AA. The
diagnosis, treatment, and follow-up of cesarean scar pregnancy. Am J Obstet
Gynecol 2012;207(44):e1–e13.
[34] Wu X, Zhang X, Zhu J, Di W. Caesarean scar pregnancy: comparative efficacy
and safety of treatment by uterine artery chemoembolization and systemic
methotrexate injection. Eur J Obstet Gynecol Reprod Biol 2012;161:75–9.
[35] Raziel A, Schachter M, Mordechai E, Friedler S, Panski M, Ron-El R. Ovarian
pregnancy a 12 year experience of 19 cases in one institution. Eur J Obstet
Gynecol Reprod Biol 2004;114(1):92–6.
[36] Barnhart K, van Mello NM, Bourne T, et al. Pregnancy of unknown location: a
consensus statement of nomenclature, definitions, and outcome. Fertil Steril
2011;95:857–66.
[37] Kirk E, Condous G, Van Calster B, Van Huffel S, Timmerman D, Bourne T.
Rationalizing the follow-up of pregnancies of unknown location. Hum Reprod
Oxf Engl 2007;22:1744–50.
[38] Condous G, Lu C, Van Huffel SV, Timmerman D, Bourne T. Human chorionic
gonadotrophin and progesterone levels in pregnancies of unknown location.
Int J Gynaecol Obstet 2004;86:351–7.
[39] Condous G, Van Calster B, Kirk E, et al. Prediction of ectopic pregnancy in
women with a pregnancy of unknown location. Ultrasound Obstet Gynecol
2007;29:680–7.
[40] Van Mello NM, Mol F, Verhoeve HR, et al. Methotrexate or expectant
management in women with an ectopic pregnancy or pregnancy of unknown
location and low serum hCG concentrations? A randomized comparison. Hum
Reprod Oxf Engl 2013;28:60–7.
[41] Rozenberg P, Chevret S, Camus E, et al. Medical treatment of ectopic
pregnancies: a randomized clinical trial comparing methotrexate-mifepris-
tone and methotrexate-placebo. Hum Reprod Oxf Engl 2003;18:1802–8.