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Treatment of ectopic pregnancies

in 2014: new answers to some


old questions
 Fernandez, M.D., Ph.D.a,b,c
Perrine Capmas, M.D.,a,b,c Jean Bouyer, Ph.D.,b and Herve
a
 cologie Obste
trique, Ho
^ pital Bice
^tre, GHU Sud (AP-HP), b Inserm, Centre of Research in Epidemiology and
Service de Gyne
^ tre, France
Population Health (CESP), and c Faculty of Medicine, University of Paris Sud, Le Kremlin Bice

Over the past 20 years, a substantial body of research has accumulated about ectopic pregnancy, especially about its epidemiology, risk
factors, and diagnosis. Nonetheless, the care of women with these pregnancies remains a topic of debate, and no consensus or guidelines
exist to clarify the optimal treatment choices. This review revisits the four primary treatments for ectopic pregnancy and denes and
details the concept of activity, which guides the indications for each treatment. Recent ndings of no difference in fertility during the
2 years after an ectopic pregnancy have answered some old questions and raised new ones for
determining the optimal management of ectopic pregnancies. Most especially, they allow the
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he past 20 years have seen the


accumulation of a substantial
body of information about ectopic
pregnancies, especially about their
epidemiology (17), risk factors (818),
and diagnosis (1923). Nonetheless, the
care of women with these pregnancies
remains a topic of debate, and no
consensus or guidelines exist to clarify
the choice between different treatments
(1). Moreover, medical treatment is
subject to substantial variation,
including differing protocols and
varying routes of administration. In developing countries, ectopic pregnancy is a
potentially life-threatening condition,
and in developed countries, it is still a
leading cause of maternal mortality.
However, earlier diagnosis and better access to care have shifted concern to the is-

sues of preserving subsequent fertility,


the woman's own preferences, and cost
considerations. In particular, the recent
reports about subsequent fertility (24,
25) must be integrated into any
guidelines for the management of
ectopic pregnancy.
This review rst denes and details
the concept of activity, which guides the
indication for each treatment. We then
describe the four primary treatments,
and discuss the factors that aid in
choosing which treatment is appropriate.

ACTIVITY OF AN ECTOPIC
PREGNANCY
An ectopic pregnancy's level of activity is
the major factor in deciding the most
appropriate treatment. This concept is

Received November 26, 2013; revised and accepted January 16, 2014.
P.C. has nothing to disclose. J.B. has nothing to disclose. H.F. has nothing to disclose.
cologie Obste
trique, Ho
^ pital Bice
^tre, 78
Reprint requests: Perrine Capmas, M.D., Service de Gyne
 ne
ral Leclerc, 94275 Le Kremlin Bice
^tre, France (E-mail: perrine.capmas@bct.
avenue du Ge
aphp.fr).
Fertility and Sterility Vol. 101, No. 3, March 2014 0015-0282/$36.00
Copyright 2014 American Society for Reproductive Medicine, Published by Elsevier Inc.
http://dx.doi.org/10.1016/j.fertnstert.2014.01.029
VOL. 101 NO. 3 / MARCH 2014

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well recognized and generally applied as


a guideline for determining which ectopic
pregnancies may benet from medical
treatment. Nonetheless, the denition of
activity remains a subject of debate.
The most active ectopic pregnancies have a high risk of tubal rupture
or have already ruptured. In such cases,
medical treatment cannot be attempted
because of the high risk of failure. These
ectopic pregnancies include those with
hemodynamic failure, with abundant
hemoperitoneum, with symptoms of
rupture (such as pain and syncope), or
with a high human chorionic gonadotropin (hCG) level (for which the
threshold level is the subject of further
debate). The consensus about the management of these ectopic pregnancies is
that they require a surgical approach.
For other situations, the criteria for
dening active and less active ectopic
pregnancies and the cut-off line between
them are controversial. Some studies
have used scores, such as those of Fernandez et al. (25), who measured
including pain, time of amenorrhea,
hCG and progesterone level, size of
hematosalpinx, and importance of
615

VIEWS AND REVIEWS


hemoperitoneum; and Elito et al. (26), who measured the hCG
level and the size of the mass, and emphasized the sonographic
aspects (live embryo, tubal ring, or hematosalpinx) and the
importance of color Doppler. Others have reported on sonographic ndings: the size of the hematosalpinx, or the presence
of a yolk sac, an embryo, or cardiac activity (2835). Most
studies have recommended measuring the pretreatment serum
hCG level (36). The cut-off for dening a less activethat is,
medically treatablepregnancy varies from 1,500 to 5,000 IU/
L (29, 3235), although the latter (higher) threshold appears to
be the more frequently used by recent studies.
The progesterone level is also included in the scoring of
Fernandez et al. (27). However, no studies have reported their
results using this concentration as a marker of the activity of
ectopic pregnancies, and no cut-off value has been demonstrated. A threshold of 10 ng/mL is the most commonly
used (27, 37, 38). Because progesterone levels are still not
sufciently evaluated or used to dene activity, the use of a
single parameter such as hCG level is probably easier for
current practice and for comparing studies.
In conclusion, we propose to dene a less active ectopic
pregnancy, that is, one that can be treated medically, with a
pretreatment serum hCG level <5,000 IU/L, with no cardiac
activity in the embryo, in a woman with no symptoms who
is hemodynamically stable. It might also be useful to dene
a very inactive ectopic pregnancy or pregnancies of unknown
location (PUL) as those with low (<1,500 IU/L) and plateauing
serum hCG concentrations.

THE FOUR TREATMENTS FOR ECTOPIC


PREGNANCY
Expectant Management
Monitoring until recovery is a good option for some ectopic
pregnancies as for PUL. Like intrauterine pregnancies, ectopic
pregnancies can resolve spontaneously. Expectant management consists of monitoring the woman until recovery (i.e.,
until the hCG level drops below 2 IU/L). The follow-up evaluation must be intensive: every other day at the beginning and
then weekly until the hCG level returns to normal.

Medical Treatment with Methotrexate


Tanaka et al. (39) reported the rst use of methotrexate as
medical treatment for ectopic pregnancy in 1982. Methotrexate is an antimetabolite that acts on actively proliferating
cells, including trophoblastic tissue. The dose of methotrexate
used in ectopic pregnancy is 1 mg/kg or 50 mg/m2. There are
different protocols for methotrexate injections.
Intramuscular injections. The single-dose methotrexate
regimen allows for reinjection at the same dose if needed
that is, should the hCG level not decrease sufciently (day 7
hCG > initial hCG rate, or subsequent decreases <15% each
week) (40). For the two-dose methotrexate regimen, the rst
injection is administered on day 0, and a second injection
of the same dose is administered on day 4 (41). The xed multidose methotrexate regimen consists of four injections of the
same dose on days 1, 3, 5, and 7, with administration of folinic
acid (0.1 mg/kg) on days 2, 4, 6, and 8.
616

In situ injection. In situ injection of methotrexate with sonographic guidance is often used for extratubal ectopic pregnancies (4245) but may also be used for tubal pregnancies.
The addition of folinic acid to methotrexate therapy has not
been found to provide any advantages: the half-life of methotrexate is very short, and even with the four-injection protocol the methotrexate dose is very low compared with the
levels used in rheumatology or oncology (46).
Hyperosmolar glucose has also been injected into the fallopian tube under sonographic guidance to resolve ectopic
pregnancies. Although it has been replaced by methotrexate
as a general rule, it is often still used in heterotopic pregnancies when the use of methotrexate is contraindicated (4750).

Conservative Surgery (Salpingotomy)


Currently, salpingotomy is performed by laparoscopy whenever
possible. The procedure calls for the introduction of a 10-mm (or
less) laparoscope through the umbilicus, and the insertion of two
5-mm (or less) ports in the left and right hypochondriac regions.
A 10-mm (but not less) suprapubic trocar is then inserted, and a
monopolar linear incision is made over the bulging antimesenteric portion of the tube. A 10-mm irrigation probe for hydrodissection is then used to remove the ectopic mass. The irrigation
probe must be 10 mm to be able to remove completely the
ectopic pregnancy; the only reported cohort with a <7% failure
rate with conservative surgery used a 10-mm irrigation probe
(51). Hemostasis must be obtained without extended coagulation to preserve a functional tube. The tubal incision is left
open to allow secondary healing, and the pelvis is irrigated (51).
Methotrexate as an adjuvant to salpingotomy. The major
disadvantage of conservative surgery is the risk of persistent
trophoblast cells. One well-designed randomized trial suggested that routine prophylactic postoperative injection of
methotrexate reduces this risk (52).

Radical Surgery (Salpingectomy)


Salpingectomy is generally performed by laparoscopy. The
standard protocol calls for a 10-mm (or less) laparoscope to
be introduced through the umbilicus and three 5-mm (or
less) ports inserted in the left and the right hypochondriac
and suprapubic regions. Salpingectomy involves the removal
of the fallopian tube with the products of pregnancy inside it,
either from the horn to the mbrial portion (anterograde) or
from the mbrial portion to the horn (retrograde). It is performed by stepwise dissection of the mesosalpinx and fallopian tube with bipolar electrocautery forceps and scissors.
The salpinx is then removed from the abdominal cavity in a
specimen bag to avoid dissemination of trophoblasts.

INDICATIONS AND EFFECTIVENESS OF


TREATMENTS
Very Less Active Ectopic Pregnancies
Methotrexate should not be used as the rst-line therapy for
very inactive ectopic pregnancies (or PULs); expectant management should be preferred. The earliest data about expectant management come from a retrospective study
VOL. 101 NO. 3 / MARCH 2014

Fertility and Sterility


published in 1955, but many studies have been conducted
since then (5355). A favorable outcome can be anticipated
with expectant management in 20% of ectopic pregnancies,
regardless of their activity level.
A recent randomized trial (the METEX trial) compared
methotrexate with expectant management in women with an
ectopic pregnancy or PUL who had low and plateauing serum
hCG concentrations. This multicenter trial, which included 73
women over a 5-year period (41 with single-dose methotrexate,
and 32 with expectant management), found no difference in
the uneventful decline of serum hCG to undetectable levels:
76% after methotrexate treatment, and 59% after expectant
management, relative risk 1.3 (95% condence interval [CI],
0.91.8) (56). A nonsignicant trend was found, which could
have been improved by more power. The METEX trial results
showed that methotrexate should be used only as a secondline therapy in very less active ectopic pregnancies. Although
measurement of progesterone levels may contribute to conrming a very less active ectopic pregnancy, it cannot be recommended because the METEX study did not measure
progesterone levels, and there are no published data for progesterone in very less active ectopic pregnancies.

Less Active Ectopic Pregnancy

(6063), has a failure rate that ranges from 6.6% (51) to 17.5%
(64). The surgeon's skill and experience may play a major role,
but there are no published data to conrm this. The choice
between medical management versus conservative surgical
treatment depends on the woman's preference and her
commitment to follow-up observation until recoverya longer
period after medical management than after surgical treatment
(65). It also depends on her desire to preserve her subsequent
fertility and on the failure rates of each type of treatment. The
failure rate of conservative surgery also differs according to
whether a postoperative dose of methotrexate is injected.
Whether to routinely use a methotrexate injection is still
debated. The risk of side effects after a methotrexate injection
led the authors of the Cochrane review (63) to recommend
against its systematic use; the adverse effects reported for
methotrexate treatment of ectopic pregnancies are mainly
asymptomatic elevation of liver enzymes, with rare cases of
drug-induced hepatitis (1%). Both a randomized trial and a
prospective study found that the cost effectiveness of methotrexate treatment for women of was quite substantial (52, 64).
The randomized trial in 129 women showed a statistically
signicant decrease in persistent trophoblasts: 14.5% in the
group with no injection versus 1.9% in the group with a
postoperative intramuscular methotrexate injection (P>.05)
(52). The prospective study, which used in situ methotrexate
injections in 81 women, also observed a statistically
signicant decrease in persistent trophoblasts: 17.5% versus
0 (P>.05) (64). The DEMETER multicenter trial conrmed
the low failure rate with postoperative systematic injection
of methotrexate: 0.6% in 198 women (25).
The question of whether a systematic postoperative methotrexate injection is safe and cost effective needs a denitive
answer, especially given that the injection could simplify the
monitoring required. In view of its very low failure rate, only
one blood sample for hCG at 1 month would be required rather
than weekly monitoring.

Medical therapy. Medical treatment by methotrexate should


be used only in less active pregnancies; otherwise, the risk of
failure is high. In the absence of contraindications, which
include abnormal baseline liver and renal function test results, medical management can be chosen after the woman
has been informed about the method of treatment, the risk
of failure, and the necessity of follow-up observation. All
three previously described injection protocols can be used.
The reported success rates of methotrexate therapy range
from 63% to 96.7%. The heterogeneity of these results is due
to variations in patient characteristics, in study inclusion
criteria, in pretreatment hCG levels (see the denition of
less active ectopic pregnancy), and in methotrexate treatment
protocols (see the denition of treatment) as well as the
different denitions of treatment failure. Some studies, for
example, considered treatment failures to be only cases that
nally required surgery (25, 57, 58); other studies dened
failure as the need for a supplementary methotrexate
injection (59). In the DEMETER multicentre trial, 207
women were included in the arm comparing medical
management with conservative surgery, and the reported
success rate for methotrexate in 110 women was 75% (25).
Very few studies have reported on the use of in situ injection of methotrexate for tubal ectopic pregnancies, although
it is often used for nontubal ectopic pregnancies (such as
interstitial, cervical, or cesarean scar) (4245). A
retrospective study by Nazac et al. (31) reported a success
rate of 90% with tubal ectopic pregnancies, which is
signicantly better than the results with intramuscular
injections. This route of administration should be explored
further in a randomized trial.

Recovery time. Time until recovery after an ectopic pregnancy is dened as the time until the hCG level drops below
2 IU/L. After conservative management, the hCG level must
be monitored to be able to diagnose a persistent trophoblast,
especially if no postoperative injection of methotrexate was
performed. The recovery time varies from 20 to 31 days. After
medical treatment, this time is reported to be around 30 days
(range: 27 to 33 days) (65, 66). Two randomized studies have
reached different conclusions about the comparative time to
recovery for surgery and medical treatment: Saraj et al. (65)
reported that this period is shorter after surgery (20.2 versus
27.2 days, in a study of 38 women), while Colacurci et al.
(66) found no signicant difference (33.6 days after surgery
versus 31.5 after methotrexate, 30 women). In the DEMETER
trial, the recovery time after conservative surgery with a
postoperative injection of methotrexate was statistically
signicantly shorter than after methotrexate alone: 16
versus 30 days (P< .01) (25). The time until a woman
recovers from the effects of surgery can also vary, but
recovery times from laparoscopic surgery are typically short.

Conservative surgery. Conservative surgery, generally considered the standard treatment in less active ectopic pregnancies

Cost. A comparison between conservative surgery and medical therapy found a signicant reduction in direct costs with

VOL. 101 NO. 3 / MARCH 2014

617

VIEWS AND REVIEWS


a single-dose systemic methotrexate injection. The indirect
costs were reduced only in the subgroup of women who had
a pretreatment hCG level below 1,500 IU/L (59). The results
from the Auvergne ectopic pregnancy registry also found
that a protocol with a single dose of methotrexate was more
cost effective than laparoscopic surgery (67).
Women's preferences. Few published articles have examined
women's preferences among the available treatments for
ectopic pregnancy. One study comparing preference for methotrexate versus conservative surgery found that most women
preferred the methotrexate treatment, at least initially (68).
Opinions changed among some women when the hypothetical tubal patency rate decreased. In contrast, one group of
women never preferred systemic methotrexate, even when
they were told that tubal patency after methotrexate was
100%: those who disliked taking medications or found the
idea of a prolonged treatment duration to be distressing
(68). Women's preferences also depend the way the alternative treatment options are presented by the physician, a factor
that is difcult to take into account but cannot be ignored.

Active Ectopic Pregnancy


An active ectopic pregnancy requires surgical treatment. The
choice between conservative or radical surgery in these cases
depends on the woman's history (a homolateral recurrence
indicates the need for radical surgery), the appearance and
condition of the contralateral tube, and bleeding. Tubal
rupture does not systematically necessitate radical treatment,
except when hemostasis proves difcult to achieve. Salpingectomy might well be a better choice than leaving an
unhealthy tube in place.
The choice between radical and conservative surgery is
often made during the procedure. Radical surgery has a
100% efcacy rate. The failure rate for conservative surgery,
on the other hand, ranges from 6.6% to 17.5%, and with the
addition of a postoperative methotrexate injection, the failure
rate ranges from 0 to 2%.
Van Mello et al. (69) studied women's preferences for
radical or conservative surgery and found that most women
preferred avoiding a repeat ectopic pregnancythus,
choosing radical treatmentto having a higher chance of a
future spontaneous intrauterine pregnancy. However, Van
Mello et al. (69) showed that the risk of additional treatment
by methotrexate in cases of conservative surgery for persistent trophoblasts was acceptable if compensated for by a
small rise in the intrauterine pregnancy rate. Finally, women
preferred radical to conservative surgery after the risks of
recurrence and persistent trophoblasts were explained along
with information about the spontaneous intrauterine pregnancy rate. This preference was not related to the risk of
persistent trophoblasts or the potential need for a methotrexate injection; women were primarily concerned about
the risk of recurrence.

SUBSEQUENT FERTILITY
As previously mentioned, in developed countries, preservation of future fertility is now an important objective in the
618

treatment of ectopic pregnancies. Until recently, the results


for fertility after treatment came only from observational
studies. For example, the results of the Auvergne ectopic
pregnancy registry suggested that fertility is better after conservative treatment, either medical or surgical (24). As will be
discussed, some trials have reported results, but until very
recently they lacked adequate statistical power for denitive
conclusions.

Comparison between Conservative Surgery and


Medical Treatment
The most recent and thorough results from the Auvergne registry conclude that there is no signicant difference in terms
of subsequent fertility between the two conservative treatments (24, 7072). Three randomized trials also concluded
that no signicant difference exists between them, but these
studies were not powerful enough to reach denitive
conclusions (57, 73, 74). Similarly, the Cochrane review
found insufcient data are available to reach a conclusion
about future fertility (63). Recently, however, the DEMETER
randomized trial conrmed with sufcient power that there
was no signicant difference in subsequent 2-year fertility
when comparing medical management and conservative surgery: 67% versus 71% intrauterine pregnancies, hazard ratio
0.85 (0.591.22; P .37) (25). It should be noted, moreover,
that when an ectopic pregnancy is treated with methotrexate
there is no need for a waiting period before attempting
another pregnancy; although methotrexate is a teratogenic
agent, its half-life is very short (46).

Comparison between Conservative and Radical


Surgery
Until the DEMETER trial, there were no prospective data for
comparing conservative and radical surgery. The DEMETER
trial showed no difference in subsequent 2-year fertility:
70% versus 64% for intrauterine pregnancy, respectively,
hazard ratio 1.06 (0.691.63; P .78) (25). Nevertheless, it is
important to mention that the rate of recurrence for ectopic
pregnancies ranges from 6% to 10%, regardless of the treatment option chosen.

NEW STRATEGIES
Using a selective progesterone receptor modulator (i.e., mifepristone) as an adjuvant for medical therapy has been suggested. A randomized trial showed no benet from the
systematic addition of mifepristone, except perhaps in women
with a progesterone level of 10 ng/L or more (37).
Use of epidermal growth factor receptor inhibitor should
be an interesting treatment to combine with methotrexate in
the medical therapy of ectopic pregnancy. Results in vitro on
placental cells show an inhibition in placental cell growth.
These results were conrmed in vivo in mouse models (two
cases), revealing doubled rates of fetal resorption when
combining the two drugs (75). In a phase I nonrandomized
open study, 12 women with ectopic pregnancy were treated
with methotrexate and oral getinib (epidermal growth factor
receptor blocker) compared with 71 controls treated with
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Fertility and Sterility


methotrexate alone. Both median serum hCG levels by day 7
and time to resolution were signicantly shorter after combination therapy, although the latter also was commonly associated with minor side effects such as transient diarrhea and
rash (76). These new therapeutics are promising but need to
be evaluated further. Superselective uterine artery embolization combined with intra-arterial injection of methotrexate
(leading to an in situ injection of methotrexate) also has suggested good results (77).

11.

12.

13.

14.

CONCLUSION
Recent ndings of no difference in fertility during the 2 years
after an ectopic pregnancy when comparing medical treatment versus conservative surgery and conservative surgery
versus radical surgery have answered some longstanding
questions and raised new ones for determining the optimal
management of ectopic pregnancies. These ndings in particular have allowed consideration and weighing of a wider
range of factors, including women's preferences, efcacy,
and the period of monitoring until recovery.
In choosing conservative or radical surgery, it is important to bear in mind that the newer randomized trial results
pertain only to 2-year subsequent spontaneous fertility rates;
thus, these results should not lead to a broad extension of
radical treatment. Radical treatment might have a harmful effect on long-term spontaneous fertility in cases of contralateral recurrence. The good results for expectant management
in very inactive ectopic pregnancies, another major nding,
should encourage a less interventionist approach to PUL.
Finally, the characteristics of the women most likely to
benet from medical treatment remain to be claried as do
the best protocols for medical treatment. A consensus about
the indications for medical treatment would make it easier
to compare future studies and thus to advance our knowledge
of these points.

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25.

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