1. family and parenting
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Human Reproduction Update 2000, Vol. 6 No. 1 pp. 80–92
© European Society of Human Reproduction and Embryology
Extra-uterine pregnancy following assisted
conception treatment
N.Abusheikha1, O.Salha2,* and P.Brinsden1
1
Bourn Hall Clinic, Bourn, Cambridge, and 2Assisted Conception Unit, St James’s University Hospital, Leeds, UK
Received on February 15, 1999; accepted on November 22, 1999
Ectopic pregnancy may be the only life-threatening disease in which prevalence has increased as mortality has
declined. The most prominent theory to explain this phenomenon involves increased sensitivity of serum β-human
chorionic gonadotrophin (HCG) immunoassay and improved quality of transvaginal ultrasound, combined with a
heightened awareness and increased suspicion of the condition among clinicians which has allowed early detection of
ectopic pregnancy. Laparotomy, once the standard treatment of ectopic pregnancy, has been replaced almost entirely
by operative laparoscopy. This is associated with a shorter hospital stay, fewer post-operative analgesic requirements, reduced costs and lower risk of adhesion formation. Laparotomy, however, remains necessary in cases with
haemodynamic instability and with exceptional locations, e.g. cervical, abdominal and interstitial implantation. In
selected cases, non-surgical management has also obtained high success rates. Among medical therapies, the most
common is systemic or local administration of methotrexate. The other option is expectant management involving
follow-up using serial serum HCG measurements and ultrasound scans. Thus, life-threatening ectopic pregnancy is
now evolving into a medical disease, with the possibility of lower-cost treatment, faster recovery and higher subsequent fertility. In this review we assess the risk of extra-uterine implantation after assisted conception treatment, the
accuracy of various diagnostic tools and focus on the efficacy, safety and the fertility outcomes of surgical and nonsurgical management of ectopic pregnancy.
Key words: assisted conception/diagnosis/ectopic/management
TABLE OF CONTENTS
Introduction
Incidence
Risk factors
Aetiology of ectopic pregnancy
Pathology of ectopic pregnancy
Clinical features of ectopic pregnancy
Diagnostic tests
Treatment
Conclusions
References
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Introduction
Ectopic pregnancy refers to the implantation of the blastocyst
in any tissue outside the uterine cavity. The majority of
ectopic pregnancies implant in the ampullary region of the
Fallopian tube, followed by the isthmus, the fimbriae, and the
cornual portion; these constitute >95% of all ectopic pregnancies.
Abulcasis (AD 936) was the first to report an ectopic pregnancy, while Duverney in 1708 was the first to describe an
heterotopic pregnancy, the combination of intrauterine and
extrauterine pregnancy. There is no doubt that the diagnosis
and management of ectopic pregnancies underwent another
revolution a century later, when Lawson Tait successfully
performed a laparotomy to ligate the broad ligament and
remove a ruptured Fallopian tube in 1883 (Tait, 1884;
Mascarerhas et al., 1997). The first pregnancy reported after
in-vitro fertilization (IVF) and embryo transfer was in fact
ectopic (Steptoe and Edwards, 1976), and ever since there
have been numerous reports of both ectopic and heterotopic
pregnancies occurring after IVF. Improved technology has
* To whom correspondence should be addressed at: Assisted Conception Unit, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK.
Tel: +44 113 243 3144; Fax: +44 113 242 6496; e-mail: [email protected]
Extra-uterine pregnancy following assisted conception treatment
resulted in an increased likelihood of ectopic pregnancy
being unruptured at the time of diagnosis, thus making lessinvasive treatment options possible (Ling and Stovall, 1994).
Although the maternal mortality from ectopic pregnancies
declined five-fold in the UK between 1975 and 1993 (Department of Health, 1996), ectopic pregnancy is still the leading
cause of maternal deaths in the first trimester, accounting for
12 out of the 134 direct maternal deaths (8.9%) in the last
triennial report (Department of Health, 1998). In contrast,
there were only eight deaths directly attributed to ectopic
pregnancy out of the 323 maternal deaths reported in the
previous triennium (2.4%). This last report re-emphasized the
importance of early diagnosis and the need for increased
awareness of the possibility of an extra-uterine pregnancy in
any woman of reproductive age.
Incidence
The true incidence of ectopic pregnancy is difficult to determine, but is in the range 0.25–1.0% of all pregnancies
(Stabile and Grudzinskas, 1994). In addition, ectopic pregnancies are reported to complicate 2–11% of all pregnancies
resulting from IVF treatment (Smith et al., 1982; Lopata,
1983; Cohen et al., 1986; Martinez and Trounson, 1986;
Correy et al., 1988; Karade et al., 1991; Dubuisson et al.,
1991; Ory, 1992; Verhulst et al., 1993). Likewise, the
reported incidence of ectopic pregnancy after ovulation
induction with human chorionic gonadotrophin (HCG) in
anovulatory women with apparently normal Fallopian tubes
varied between 2.7% (Gemzell et al., 1982) and 3.1%
(McBain et al., 1980) of all conceptions. On the other hand,
the incidence of heterotopic pregnancy in spontaneous
conception pregnancies, which was once considered very
rare (1 in 30 000 pregnancies), now complicates 1 in 4000 to
1 in 7000 pregnancies (Ben-Rafael et al., 1985). This
increase is due primarily to the use of exogenous pituitary
gonadotrophins (Dietz et al., 1993) and the increasing use of
IVF (Chang et al., 1991; Rizk et al., 1991). The incidence of
heterotopic pregnancy subsequent to IVF treatment ranges
from 1 to 3% of all clinical pregnancies (Yovich et al., 1985;
Berman et al., 1986; Dor et al., 1991; Dimitry and Reid,
1993; Marcus et al., 1995; Tal et al., 1996).
Despite the increased incidence of ectopic pregnancy in the
last decade (Ory, 1992), ovarian pregnancy remains a rare
phenomenon, accounting for <3% of all ectopic pregnancies
(Seinera et al., 1997). Cervical pregnancy is less common,
accounting for only 0.15% of all ectopic gestations (Parente
et al., 1983). The rarest form of extrauterine pregnancy is
interstitial or intramural pregnancy, with only 16 cases
reported thus far (Tucker, 1996).
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Risk factors
Risk factors are present in 25–50% of patients with an ectopic
pregnancy (Ling and Stovall, 1994). They include a history of
pelvic inflammatory disease (PID), tubal surgery, previous
ectopic pregnancies, a progesterone intrauterine device and
exposure to diethylstilboestrol in utero (Ling and Stovall,
1994; Speroff et al., 1994; Ankum et al., 1996a). The most
convincing evidence that PID is the major cause of ectopic
pregnancies comes from reports documenting a seven-fold
increase in the ectopic pregnancies rate in women with laparoscopically-proven salpingitis (Westrom, 1975; Westrom et
al., 1981).
Data on risk factors associated with ectopic pregnancies
after IVF/embryo transfer are conflicting. Yovich et al.
(1985) reported a higher incidence of ectopic pregnancy
when the embryos were replaced higher than mid-cavity.
Martinez and Trounson (1986) could not identify any risk
factor, while Cohen et al. (1986) identified two factors: the
therapeutic use of clomiphene citrate (CC) and the number of
patent Fallopian tubes at the time of embryo transfer. Other
authors (Dubuisson et al., 1991; Karande et al., 1991)
demonstrated that a previous history of an ectopic pregnancy
and/or pre-existing tubal pathology was associated with a
subsequent increased risk of an ectopic implantation.
Verhulst et al. (1993) identified tubal damage and the use of
CC combined with human menopausal gonadotrophins
(HMG) as risk factors. Marcus and Brinsden (1995) found
that a history of PID was the main risk factor, with no statistical evidence of an association between ectopic pregnancy
and a past history of abortion, termination of pregnancy, stillbirth, neonatal death, or tubal surgery. They also found no
association between the type of ovarian stimulation protocol
or the oestradiol, luteinizing hormone (LH) and progesterone
concentrations at the time of ovulation induction and ectopic
pregnancies. The role of CC in the incidence of ectopic pregnancies is controversial. With some authors suggesting an
increased rate of ectopic (Marchbanks et al., 1985) and heterotopic (Bello et al., 1986) conceptions subsequent to CC,
while others (Dickey and Holtkamp, 1996) found no associated risk between CC and ectopic pregnancy.
An ectopic rate of 4.0% of all pregnancies or 1.5% of transfers has been quoted by the Society for Assisted Reproductive Technology and the American Society for Reproductive
Medicine in their analysis of 1472 clinical pregnancies subsequent to 4202 gamete intra-Fallopian transfer (GIFT)
retrieval cycles initiated in the USA in 1993 (Society for
Assisted Reproductive Technology/American Society for
Reproductive Medicine, 1995). A similar rate of ectopic
pregnancies following GIFT has been repeated in the subsequent report (Society for Assisted Reproductive Technology/
American Society for Reproductive Medicine, 1998) and this
is comparable with that reported previously (Formigli et al.,
1990).
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Aetiology of ectopic pregnancy
The aetiology of ectopic pregnancy subsequent to assisted
conception treatment is multi-factorial, with destruction of
the anatomy of the tube as the main factor. It has been
proposed that a damaged tube may be unable to propel an
embryo that has migrated into the tube back into the uterine
cavity, whereas a normal functioning tube may be able to do
so (Berman et al., 1986). Reverse migration of the embryos
may also be associated with a high concentration of oestradiol or an altered oestrogen/progesterone ratio (James, 1996).
Other factors include the ovarian stimulation protocol
(Benger and Taymor, 1972) and the number of embryos
transferred (Dicken et al., 1989). The technique of embryo
transfer may be to blame for extrauterine implantation by
forcing the embryos through the tubal ostia by hydrostatic
pressure. This may be due to a large volume of transfer
medium or use of excessive force during the embryo transfer
(Berman et al., 1986; Dor et al., 1991). Placing the transfer
catheter beyond the mid-cavity or into the tube itself (Yovich
et al., 1985), or to retrograde migration of the embryos into
the tube (Job-Spira et al., 1996) have also been blamed for
the increased incidence of ectopic pregnancy subsequent to
IVF treatment. Nonetheless, Dor et al. (1991) evaluated the
use of ultrasound in embryo transfer and concluded that ultrasound-guided embryo transfer does not prevent ectopic pregnancy after IVF. Job-Spira et al. (1996) argued that
chromosomal anomalies in the fertilized oocyte might play a
role in the aetiology of ectopic implantation. It is also
possible that an ectopic pregnancy could result from spontaneously fertilized unrecovered oocytes if coitus occurred near
the time of oocyte recovery. This possibility cannot be
excluded, particularly if the number of oocytes retrieved is
less than the number of follicles aspirated.
Pathology of ectopic pregnancy
Any difference between implantation in the uterus and that in
the tube can be easily explained by the anatomy of the two
organs. As the trophoblast invades the muscle layer of the
Fallopian tube, the connective tissue cells of the tubal wall
become swollen and resemble decidual cells, but this
provides no resistance to the invading trophoblast. Some of
the vessels that the trophoblast meets are large, and when
these are invaded, the pressure of the blood stream is often
sufficient to destroy the embryonic cell mass.
Early placental development in the tube is very similar to
that seen at normal sites, although it is often immature and
many villi demonstrate loss of vascularity with central hyalinization, characteristic of collapse of the fetal circulation.
Subsequently, there is failure of the tubal trophoblast to
differentiate into chorion laeve and chorion frondosum. The
degree of decidual reaction around the tubal implantation site
is usually minimal. The decidua usually forms in the uterus
and not in the tube. As a result of trophoblastic activity, the
human blastocyst can implant at any site at the appropriate
stage of development. The role of the maternal decidua in this
process is a passive one.
Three mechanisms have been proposed to explain ovarian
implantation (Marcus and Brinsden, 1993): (i) one theory
suggests that fertilization occurs normally and implantation
on the ovary follows reflux of the conceptus from the tube
(Crimes et al., 1983); (ii) the second theory suggests that
various disturbances in ovum release are responsible for
ovarian implantation (Tan and Yeo, 1968); and finally (iii)
the application of intrauterine insemination could push some
spermatozoa all the way to the ovarian surface and lead to
ovarian implantation (Bontis et al., 1997).
Clinical features of ectopic pregnancy
Ectopic pregnancy is a great masquerader, since only half of
patients with ectopic pregnancies are correctly diagnosed on
clinical features alone (Tuomivaara et al., 1986). The clinical
signs and symptoms of ectopic pregnancy overlap with those
of other surgical and gynaecological conditions, such as
threatened or incomplete miscarriage, pelvic inflammatory
disease, ruptured or haemorrhagic corpus luteal cyst, salpingitis, adnexal torsion, degenerating fibroid, dysfunctional
uterine bleeding, endometriosis and appendicitis.
The first clinical symptom of ectopic pregnancy is usually
pain. This is present in 95% of cases, while 80% have amenorrhoea and 50% experience abnormal vaginal bleeding. The
presentation may be acute, subacute or silent. In acute cases
associated with tubal rupture there may be massive i.p. haemorrhage, causing acute abdominal pain, circulatory collapse
with hypotension and tachycardia. In such patients, immediate laparotomy is necessary with salpingectomy being
mandatory to arrest the bleeding.
The most common situation is of a subacute presentation
with amenorrhoea, abdominal pain and sometimes irregular
vaginal bleeding. If rupture or tubal abortion occurs gradually, the symptoms are less dramatic, and the diagnosis may
be missed. Similarly, the development of ovarian hyperstimulation syndrome (OHSS) subsequent to assisted conception
treatment may mask the symptoms of an ectopic pregnancy
(Thakur and El-Menabawey, 1996; Paulson and Lobo, 1998).
Diagnostic tests
The morbidity and mortality associated with ectopic pregnancy are directly influenced by the time interval between the
onset of symptoms and the start of treatment (Department of
Health, 1998). Thus the prospect of early treatment is
dependent on maintaining a high index of suspicion and the
deployment of a few additional diagnostic tests, dictated by
local availability and costs.
Extra-uterine pregnancy following assisted conception treatment
Biochemical tests
Human chorionic gonadotrophin (HCG)
HCG may be detected in the urine as early as 14 days postconception by sensitive enzyme-linked immunosorbent
assays (detection limits 25–50 IU/l; sensitivity 98–100%)
(Armstrong et al., 1984; Kingdom et al., 1991; Speroff et al.,
1994). It can be detected in the serum 6–7 days post-conception by immunometric radioassays (detection limits <5 IU/l;
sensitivity 100%) (Lenton et al., 1982; Speroff et al., 1994).
Early normal intrauterine pregnancies are associated with a
doubling of serum HCG concentrations every 1.4–2.1 days
(Kadar et al., 1981; Pittaway et al., 1981). An ectopic pregnancy produces less HCG than a normal intrauterine pregnancy, which has the effect of prolonging the HCG doubling
time (Check et al., 1992; Heiner et al., 1992). However, 15%
of normal pregnancies will have an abnormal doubling time
and 13% of ectopic pregnancies will have a normal doubling
time (Ling and Stovall, 1994). Therefore, in order to increase
the sensitivity of quantitative HCG, a discriminatory zone has
been described, whereby an HCG titre of 1000–1500 IU/l
will be associated with the presence of an intrauterine sac on
transvaginal ultrasound (6000–6500 IU/l for transabdominal
ultrasound) (Kadar et al., 1981; Keith et al., 1993). Several
prospective studies employing diagnostic algorithms,
including clinical symptoms, quantitative serum HCG and
transvaginal ultrasound, have shown a diagnostic sensitivity
of this discriminatory zone for ectopic pregnancies of 95–
99% and a specificity of 95–100% (Fernandez et al., 1991a;
Ankrum et al., 1996b).
Kadar and Romero (1988) were among the first to address
the problem of distinguishing ectopic pregnancy from spontaneous abortion on the basis of falling HCG concentrations
over a 48 h period. In their study, if the half-life of HCG was
<1.4 days, then a complete abortion was likely and the patient
was best managed expectantly. If the half-life was >7 days,
then an ectopic was likely. Thus, contrary to popular belief,
falling HCG concentrations are not synonymous with spontaneous abortion, and can be used to distinguish spontaneous
abortion form ectopic pregnancies, provided the half-life of
HCG is calculated.
In IVF patients, since more than one embryo is usually
transferred, and more trophoblastic tissue may be present to
produce HCG, an extra 2 or 3 days are required for a sac to
become visible. Okamato et al. (1987) were the first to report
on the accuracy of serum β-HCG measurement in the diagnosis of ectopic pregnancies after IVF/embryo transfer. They
reported a 100% sensitivity and a 68% specificity when
comparing 88 viable intrauterine pregnancies with nine
ectopic pregnancies. A serum HCG concentration of >295
IU/l on day 16 post-embryo transfer was reported to give a
90% chance of intrauterine implantation (Smith et al., 1982).
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Mol et al. (1997) evaluated the discriminative capacity of
transvaginal sonography in combination with HCG measurement in the diagnosis of ectopic pregnancy after IVF/embryo
transfer, and found that whenever the serum β-HCG concentration on day 9 after embryo transfer was >18 IU/l, the pregnancy was always intrauterine and viable. Therefore, they
concluded that transvaginal sonography can be postponed
until 5 weeks after embryo transfer, except for patients with
abdominal pain and/or vaginal bleeding, or in patients with a
serum β-HCG concentration of <18 IU/l.
Serum progesterone
Serum progesterone concentrations are lower in ectopic than
in normal intrauterine pregnancies (Johansson, 1969;
Radwanska et al., 1978; Milwidsky et al., 1984; Mathews et
al., 1986). Whether ectopic implantation causes the shutdown of progesterone by the corpus luteum or whether low
progesterone concentrations actually lead to ectopic implantation is still uncertain, although the electrophysiological
studies of Pulkkinen and Jaakkola (1989) suggest the latter
may be the case.
To investigate the diagnostic accuracy of serum progesterone in the diagnosis of ectopic pregnancy, Yeko et al.
(1978) identified a cut-off value of 15 ng/ml to differentiate
between viable and non-viable pregnancies. On the same
notion, McCord et al. (1996) advised that when the serum
progesterone is >17.5 ng/ml, patients thought to be at risk of
ectopic pregnancies could reasonably be followed without
ultrasound or further invasive diagnostic studies. The sensitivity of serum progesterone values <15 ng/ml to distinguish
between normal pregnancies and ectopic gestation is ~80%
(Buck et al., 1988), with false-positive rates of ~10% (Stovall
et al., 1989).
In patients clinically suspected of having an ectopic pregnancy, a progesterone concentration of <20 ng/ml suggests
early pregnancy failure, whatever the gestational age (Sauer
et al., 1989). In their study of 135 patients who suffered
ectopic pregnancies following IVF/embryo transfer, Marcus
et al. (1995) found that the mean plasma progesterone
concentration was significantly lower than that of patients
with normal singleton pregnancies. On the other hand, other
investigators, (Ling and Stovall, 1994; Speroff et al., 1994)
found serum progesterone concentrations did not appear to
increase the diagnostic sensitivity.
Other hormones, such as pregnancy-associated plasma
protein A (PAPP-A), have been evaluated as possible ancillary diagnostic tests in suspected ectopic pregnancies
(Tornehave et al., 1987). The two major proteins synthesized
by the human endometrium; progesterone-dependent
endometrial protein (pectopic pregnancies ) and insulin-like
growth factor binding protein (IGF-bp) have also emerged as
candidates as biochemical markers of ectopic implantation
(Ruge et al., 1991; Pedersen et al., 1991).
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N.Abusheikha, O.Salha and P.Brinsden
Ultrasound
The role of utrasonography in suspected ectopic gestation is
to diagnose and localize the pregnancy. The image resolution
and patient acceptance of transvaginal ultrasonography are
considerably better than that of transabdominal ultrasound
(Bateman et al., 1990). In order of appearance, a normal
intrauterine sac should contain a yolk sac and embryonic
echoes with visible heart activity at days 33, 38 and 43 from
the last menstrual period respectively (Cacciatore et al.,
1990).
There are three sonographic features of tubal pregnancy as
seen by a vaginal transducer. First, the demonstration of a
live embryo within a gestational sac in the adnexa. This
remains the gold standard for the sonographic diagnosis of
ectopic pregnancy. It typically appears as an intact, welldefined tubal ring (the ‘doughnut’ or ‘bagel’ sign) in which the
yolk sac and/or the embryonic pole, with or without cardiac
activity, are seen within a completely sonolucent sac. An
ectopic embryo/fetus is reported to be seen in 12–20% of cases
with vaginal ultrasound (DeCrespigny, 1988; Stabile et al.,
1988). The second transvaginal sonographic appearance of
tubal pregnancy is that of a poorly defined tubal ring,
possibly containing echogenic structures (Dodson, 1991; Atri
et al., 1996). Typically, the pouch of Douglas also contains
fluid and/or blood. These features are consistent with a tubal
pregnancy that is aborting. The third typical sonographic
picture is the presence of varying amounts of fluid in the
pouch of Douglas, representing rupture of the tubal pregnancy (Nyberg et al., 1991).
Arguments persist as to whether or not a pseudogestational
sac is seen using transvaginal ultrasound. In the experience of
some (Timor-Tritsch et al., 1988), a pseudogestational sac is
not visible when a tubal gestation is detected. Others admit
that it may be difficult, even with transvaginal sonography, to
evaluate an intrauterine sac <4 mm in diameter. However, in
the absence of an eccentric placement of a gestational sac
within the endometrial cavity (which is the hallmark of a
normal intrauterine pregnancy), a pseudogestational sac
should be suspected (Cacciatore et al., 1990).
Despite recent advances in sonographic techniques and
better patient acceptability of the transvaginal method of
scanning, considerable expertise is still needed for image
interpretation. Of particular difficulty is the diagnosis of
heterotopic pregnancy, which is fraught with potential pitfalls
and is often delayed (Bello et al., 1986). To be conclusive,
the diagnosis requires the demonstration of a foetus or a
gestational sac both in and outside the uterus. Thus, establishing the existence of an intrauterine pregnancy by ultrasonography, although reassuring, does not rule out a coexisting ectopic pregnancy (Hayes and Haley, 1984;
Goldman et al., 1992). Correct pre-operative diagnosis of
ovarian pregnancies is equally difficult, being confused with
corpus luteal cysts (Tan and Yeo, 1968; Raziel et al., 1990).
Colour and pulsed Doppler techniques may complement
endovaginal sonographic findings, but they should be
performed only after a thorough real-time evaluation of the
adnexal region (Atri et al., 1996). Whilst Speroff et al. (1994)
indicated that the use of colour Doppler imaging should only
be confined to research trials to increase the sensitivity of
transvaginal ultrasonography, others (Chew et al., 1996;
Abramove et al., 1997) found that it failed to improve on the
results of transvaginal B-mode sonography in the detection of
ectopic pregnancy.
Other methods
Culdocentesis (Ling and Stovall, 1994; Speroff et al., 1994)
and uterine curettage (Speroff et al., 1994; Ramirez et al.,
1996) have limited use in the diagnosis of ectopic pregnancy.
Laparoscopy
Laparoscopy as a method of diagnosing ectopic gestation has
been used since 1937, when Hope reported the first 10 cases
(Hope, 1937). When laparoscopy became a routine procedure
it facilitated the early diagnosis of ectopic pregnancy and in
up to 40% of cases laparotomies were avoided. The development of a very sensitive radioimmunoassay for β-HCG,
together with the use of ultrasound, has again changed our
ability to diagnose ectopic pregnancies. Under these circumstances, the role of laparoscopy nowadays has moved from
being a diagnostic tool (false negatives 3–4%; false positives
5%) (Ling and Stovall, 1994) to become a treatment modality
only (Barnhart et al., 1994; Ankum et al., 1996b).
Treatment
Early diagnosis of unruptured ectopic pregnancy (Figure 1)
allows for conservative medical or invasive surgical therapy.
The recurrent ectopic pregnancy rates after radical and
conservative management are similar (10–22%), while the
intrauterine pregnancy rate in subsequent pregnancies is 60%
after conservative tubal surgery, 87% after medical treatment
and 40% after salpingectomy (Vermesh et al., 1989; Rulin,
1995). Therefore, a conservative therapeutic approach should
be attempted in patients with an ectopic pregnancy who
desire future fertility and are haemodynamically stable at
presentation.
Surgical treatment
Laparoscopy versus laparotomy
Laparoscopic salpingostomy (Figure 2) is rapidly replacing
laparotomy for most cases of tubal ectopic pregnancy. In
modern practice, the prevalent opinion is that laparotomy
Extra-uterine pregnancy following assisted conception treatment
Figure 1. Transvaginal ultrasound depicting an intact, well-defined tubal
ring in the adnexa surrounding a completely sonolucent sac containing an
ectopic pregnancy with cardiac activity.
should be performed only in cases in which the laparoscopic
approach is difficult or the patient is haemodynamically
unstable (Baumann et al., 1991; Lundorrff et al., 1991;
Murphy et al., 1992). The advantages of the laparoscopic
approach have been well-documented in terms of shorter
hospital stay (Kouam et al., 1996), fewer post-operative analgesic requirements (Lundorrff et al., 1991), reduced cost
(Gray et al., 1995; Garry, 1996) and a lower risk of adhesion
formation (Tuomivaara and Kaupilla, 1988). Recently,
ovarian ectopic pregnancies have also been reported to be
managed laparoscopically with variable success (Hage et al.,
1994; Seinera et al., 1997).
Laparoscopic salpingostomy versus laparoscopic
salpingectomy
In a patient with a diseased tube or a damaged contralateral
tube, the question arises as to whether laparoscopic treatment
should be by salpingectomy or salpingostomy. In patients
where the contralateral tube is diseased, but nevertheless
patent (Tuomivaara and Kaupilla, 1988; Silva et al., 1993;
Bronson, 1997) the post-operative chances of conception are
not significantly different whether treatment is by salpingectomy or salpingostomy. This finding is important since laparoscopic salpingectomy posses a number of advantages
compared with salpingotomy. It is more simple, requiring no
specific equipment (Dubuisson et al., 1996) and does not
carry the risk of leaving intra-tubal residual trophoblastic
tissue. Subsequent persistent trophoblast has been reported to
occur in 15–20% of cases following laparoscopic salpingostomy (Vermesh et al., 1989; Murphy et al., 1992; Buster and
Carson, 1995; Kouam et al., 1996). Since persistent trophob-
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last tends to be found in the proximal portion of the tube, it is
recommended that suction irrigation should be used to flush
the gestational products out of the tube. In addition, it is
advisable to perform weekly β-HCG measurements as a
follow up after surgery. The average time for β-HCG concentrations to become undetectable is 4 weeks (Ling and Stovall,
1994). It is encouraging that the pregnancy rate does not seem
to be decreased after persistent ectopic pregnancy (Seifer
et al., 1994).
Interestingly, a randomized prospective study has shown
that the reproductive outcome after conservative treatment by
salpingostomy is comparable, whether carried out by laparoscopy or laparotomy (Vermesh and Presser, 1992). The
reported subsequent intrauterine pregnancy rates vary from
23 to 70% and the incidence of recurrent ectopic pregnancies
ranges from 10 to 30%. These wide variations are largely due
to differences in reporting characteristics. However, by using
the number of women who desire pregnancy after the procedure as the denominator, ~35% of women will have a subsequent intrauterine pregnancy and 15% will have a repeat
ectopic gestation (Lavy et al., 1987). Women undergoing
IVF must, therefore, be informed of the risk of ectopic pregnancy (Agrawal et al., 1996; Chen et al., 1998), even if they
have had bilateral salpingectomy, since cornual implantation
can still occur (Manhes et al., 1983).
Hysteroscopic resection
Diagnostic hysteroscopy has been used in the management of
cervical pregnancy. Roussis et al. (1992) used the hysteroscope to visualize a cervical pregnancy 40 days after failed
systemic methotrexate treatment. As hysteroscopy confirmed
minimal vascularity in the endocervical canal, they
proceeded with suction aspiration of the trophoblastic tissue.
Ash and Farrell (1996) also described hysteroscopic resection
of a cervical pregnancy and concluded that operative hysteroscopy permits complete resection of a cervical pregnancy.
When it is successful, this treatment should result in prompt
resolution of the ectopic pregnancy, thus avoiding the need
for a prolonged follow up or hysterectomy. Hysteroscopy has
also been used successfully to diagnose and treat interstitial
ectopic pregnancy (Laury, 1995; Alexander et al., 1996).
Medical treatment
Although operative laparoscopy has substantially fewer complications than laparotomy (Lundorrff et al., 1991; Murphy et al.,
1992) there remains an irreducible minimal degree of morbidity
intrinsic to surgery and anaesthesia. Though they are not yet
standard therapy in many centres, medical treatments can greatly
reduce this morbidity, and consequently there is increasing
interest in using them. To supplant surgery, however, medical
therapies must match the success rates, low complication rates,
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N.Abusheikha, O.Salha and P.Brinsden
Figure 2. Transvaginal ultrasound depicting poorly-defined tubal ring in
the adnexa, containing an ectopic pregnancy. The empty uterine cavity with
a thickened endometrium is illustrated adjacent to the ectopic pregnancy.
eter by ultrasound, are eligible for treatment with methotrexate (Stovall et al., 1990, 1991b; Darai et al., 1995a).
Patients with ectopic pregnancies with larger masses, cardiac
activity within the adnexal mass, or evidence of acute intraabdominal bleeding are ineligible for methotrexate therapy
(Stovall et al., 1990, 1991a,b; Kooi and Kock, 1992).
Tanaka et al. (1982) first reported the treatment of ectopic
pregnancy using methotrexate in 1982. Since then, methotrexate has been used widely for unruptured ectopic pregnancies (Pansky et al., 1989; Alexander et al., 1996; Stika et al.,
1996). It can be given systemically (orally, i.v. or i.m.)
(Pansky et al., 1989; Balasch et al., 1992; Stovall and Ling,
1993), or by local injection under laparoscopic control (Lindblom et al., 1987; Stovall et al., 1989; Zakut et al., 1989;
Kojima et al., 1990), or under ultrasound guidance (Feichtinger and Kemeter, 1987; Aboulghar et al., 1990; Menard
et al., 1990; Tulandi et al., 1992; Fernandez et al., 1993,
1994; Pérez et al., 1993; Darai et al., 1995b).
Systemic methotrexate
and subsequent reproductive potential achieved with laparoscopic operations. This appears to have been achieved (Stovall,
1995; Alexander et al., 1996).
The first case report describing the use of medical therapy
for tubal pregnancy appeared in 1982 (Tanaka et al., 1982).
Observational studies in the mid-1980s used, with varying
success, methotrexate (Leach and Ory, 1989), prostaglandins
(Husslein et al., 1988; Lindblom et al., 1990), actinomycin
(Altaras et al., 1988), hyperosmolar glucose (Lang et al.,
1990), and anti-HCG antibodies (Frydman et al., 1989).
Potassium chloride (Robertson et al., 1987; Aboulghar et al.,
1990) is particularly useful in the treatment of heterotopic
pregnancy, as it has no effect on the intrauterine fetus(s).
Mifepristone (RU486) (Kenigsberg et al., 1987), an oral
progesterone antagonist abortifacient with low toxicity, was
ineffective except in combination with methotrexate
(Gazvani et al., 1998). Although treatments given systemically have proved most practical, several of these agents have
been injected into the ectopic gestational sac under laparoscopic or ultrasound guidance or by hysteroscopic intratubal
cannulation.
Methotrexate
A folic acid antagonist, methotrexate inhibits the spontaneous synthesis of purines and pyrimidines, thus interfering
with DNA synthesis and the multiplication of cells (Chu et
al., 1990). Actively proliferating trophoblast was shown to be
vulnerable to methotrexate treatment of gestational trophoblastic disease (Sand et al., 1986; Leach and Ory, 1989).
Haemodynamically stable patients with ectopic pregnancy,
in which the mass is unruptured and measures ≤4 cm in diam-
Oral methotrexate cannot generally be recommended and is
rarely used for the treatment of ectopic pregnancy. More
commonly, methotrexate has been used in multiple i.m. doses
or in single doses, in a schedule of 0.5–1.0 mg/kg every other
day for 5–7 days (Farabow et al., 1983; Fernandez et al.,
1994), or 50 mg/m2 of body surface area (Stovall et al.,
1991a).
Transient pelvic pain frequently occurs 3–7 days after the
start of methotrexate therapy. This pain is presumably due to
tubal abortion and normally lasts 4–12 h (Stovall et al., 1990,
1991b). Perhaps the most difficult aspect of methotrexate
therapy is learning to differentiate between the transient
abdominal pain of successful therapy from that of a rupturing
ectopic pregnancy (Figure 3). Objectively, surgical intervention is necessary when the pain is associated with tachycardia, hypotension or a falling haematocrit.
The reported outcome of systemic methotrexate treatment
of ectopic pregnancy compares favourably with that of laparoscopic salpingostomy (Tanaka et al., 1982; Miyazaki, 1983;
Ory et al., 1986; Haans et al., 1987; Ichinoe et al., 1987;
Sauer et al., 1987; Bryrjalsen, 1991; Stovall et al., 1991b;
Prevost et al., 1992; Isaacs et al., 1996; Maymon and
Shulman, 1996). A success rate (i.e. patients who did not
need subsequent therapy) of 90–95% has been achieved, with
a non-response rate and/or tubal rupture rate of 3–4%
(Lipscomb et al., 1998). Of the women followed, 71% subsequently became pregnant, with 11% of those pregnancies
being ectopic (Slaughter and Grimes, 1995). More recently,
Fernandez et al. (1998) compared methotrexate treatment
with laparoscopic salpingotomy in a prospective randomized
study. They found that medical treatment was associated with
a significantly shorter post-operative stay, but HCG values
Extra-uterine pregnancy following assisted conception treatment
87
Figure 3. Transvaginal ultrasound depicting a heterotopic pregnancy with
fluid in the pouch of Douglas (see dark area adjacent to the uterus).
Figure 4. Transvaginal ultrasound depicting a pseudogestational sac within
the uterus.
returned to normal concentrations more rapidly after laparoscopic treatment. Spontaneous reproductive performance
was similar in both groups, but overall rates of intrauterine
pregnancy were higher and repeat ectopic pregnancies lower
after methotrexate treatment. They concluded that in selected
cases of ectopic pregnancy, methotrexate treatment appeared
as safe and efficient as conservative treatment by laparoscopy
and was associated with improved subsequent fertility.
In the search for a more potent alternative to a single i.m.
injection of methotrexate for unruptured ectopic pregnancy,
combination therapy was suggested. Gazavani et al. (1998)
randomized 50 patients with unruptured ectopic pregnancies
to receive a single i.m. injection of 50 mg/m2 body surface
methotrexate alone or in combination with 600 mg of oral
mifepristone. The success rates for treatment arms were
similar, however, median administration to resolution times
was shorter and a second injection or laparotomy was less
likely to be needed in the combination group.
diluent may range from 0.8 to 10 ml. On the other hand,
direct injection under ultrasound control is preferable, as it
enables treatment on an outpatient basis, with neither general
anaesthesia nor laparoscopy being required (Goldenberg
et al., 1993). But this may also be offset by the risk of accidental damage to other pelvic organs and the requirement for
specialized invasive training.
Systemic and intratubal methotrexate were shown to have
similar efficacy and resulted in comparable subsequent pregnancy rates (Kooi and Kock, 1990; Fernandez et al., 1993).
Nevertheless, the success rate of local injection of methotrexate is highly dependent on the proper selection of
patients (Goldenberg et al., 1993). The success rate for direct
methotrexate injection under ultrasound guidance ranges
from 70 to 95% (Feichtinger and Kemeter, 1987; Menard
et al., 1990; Fernandez et al., 1991b; Tulandi et al., 1992;
Darai et al., 1995b) and between 43 and 100% under laparoscopic control (Kojima et al., 1990).
In an effort to find a more effective and safe method for the
local injection of methotrexate, Fujishita et al. (1995)
prepared a suspension of methotrexate dissolved in lipidol
with phosphatidylcholine added as a dispersing stabilizer to
maintain the high tissue concentration and to prolong the
effect. Their results showed that this suspension seems to be
more effective than methotrexate solution alone.
The side-effects of local methotrexate therapy include:
gastrointestinal disorders, liver dysfunction, bone marrow
suppression, opportunistic infections, blood dyscrasias,
reversible alopecia, persistent haematosalpinx and methotrexate-induced lung disease. These side-effects are infrequent and in the shorter treatment schedules used in ectopic
pregnancies and can be attenuated by the administration of
leucovorin (macrophage colony stimulating factor) (Leach
Local methotrexate
In 1987 Feichtinger and Kemeter reported the direct injection
of methotrexate under transvaginal ultrasound guidance.
They instilled 1 ml (10 mg) of methotrexate into the ectopic
gestational sac and resolution occurred within 2 weeks.
Direct injection delivers concentrations of methotrexate to
the implantation site which are many times higher than those
achieved with systemic administration. Thus there is less
systemic distribution of the drug, a smaller therapeutic dose,
and less toxicity.
Injection of methotrexate into the gestational site under
laparoscopic guidance is performed with varying dosages,
ranging from 5 to 100 mg, and the amount of normal saline
88
N.Abusheikha, O.Salha and P.Brinsden
and Ory, 1989; Stovall et al., 1991a,b; Issacs et al., 1996).
Extensive experience with methotrexate in gestational
trophoblastic disease has diminished concern about the risks
of subsequent neoplasia, increased abortion rates and fetal
congenital anomalies (Ross, 1976). Nevertheless, it is true to
assume that most patients can expect a low risk of mild
complications. Although Stovall and Ling (1993) reported no
significant side-effects in patients treated with local or
systemic methotrexate, Kooi and Kock (1992) observed that
2% of their patients treated with topical methotrexate developed some side-effects, compared with 21% treated systemically. On the other hand, Glock et al. (1994) reported mild
side-effects in 34% of their 35 patients, while Fernandez
et al. (1993) reported mild side-effects in three out of 100
patients. Suffice to say that, although generally safe and
effective, methotrexate should be used with the utmost care
in the treatment of ectopic pregnancy.
Methotrexate treatment, administered either systemically
or locally, has been reported to be less satisfactory as a
primary treatment of cervical pregnancy than of tubal pregnancy. Some authors claimed that their cases failed initial
methotrexate treatment and required additional interventions,
including suction curettage (Mantalenakis et al., 1995),
salvage chemotherapy with the same agent (Kaplan et al.,
1990; Hung et al., 1996), feticide with intra-amniotic injection of potassium chloride (Kung et al., 1995), angiographic
immobilization (Cosin et al., 1997), ligation of bilateral
uterine arteries (Wolcott et al., 1988) or even hysterectomy
(Dall et al., 1994). Hung et al. (1998) conducted a Medline
search to identify the clinical factors that might lead to an
unsatisfactory outcome of primary methotrexate treatment in
cases of cervical pregnancy. They concluded that systemic
administration of low dose methotrexate is ideal for patients
who are clinically stable with cervical pregnancies of <9
weeks gestation and serum HCG concentration of <10 000
IU/l. If embryonic cardiac activity is evident, concomitant
feticide must be performed to minimize the potential risk of
methotrexate treatment failure.
Expectant management
The concept of expectant management is not new. Lund
(1955) randomized patients to receive expectant management
or surgical treatment. Among 114 patients randomized to be
treated expectantly, the success rate was 57%. However,
most of the patients who failed expectant management
returned with significant symptoms including haemoperitoneum, or cardiovascular collapse. Criteria for expectant
management are similar to those for medical treatment,
including falling β-HCG titres (Garcia et al., 1987; Speroff et
al., 1994; Yao and Tulandi, 1997). Nowadays, as a consequence of the improvement in diagnostic serial serum β-HCG
assays, combined with the availability of high-resolution
transvaginal sonography, expectant management of unruptured ectopic pregnancies has become safer. When the βHCG concentration is <1000 IU/l and the plasma progesterone <5 ng/ml, spontaneous resolution occurs in 74% of
cases of ectopic pregnancies with expectant management
(Darai et al., 1995a). A review of 10 prospective studies of
expectant management reported success rates of 46.7–100%
(Yao and Tulandi, 1997). Generally speaking, there is a
decreased chance of successful expectant management the
higher the initial serum β-HCG concentrations are (Adoni
et al., 1986). As there is no certain limit below which tubal
rupture will not occur, we believe, as others do (Mascarerhas
et al., 1997; Lipscomb et al., 1998), that methotrexate treatment may be a more appropriate alternative.
Conclusions
Although the mortality from ectopic pregnancy has
decreased due to earlier diagnosis and more medical treatment, ectopic pregnancy is still a common cause of maternal
morbidity and mortality. Recent advances in the measurement of quantitative serum β-HCG and progesterone,
together with the development of high-resolution ultrasound
scanning, has improved the rate of early diagnosis of ectopic
pregnancy and had made it possible in most cases to diagnose
extra-uterine pregnancy without resort to laparoscopy.
Several options exist today for the treatment of ectopic
pregnancy. The chosen treatment depends on the size and site
of the ectopic, the expertise and facilities available and the
general condition of the patient. Successful outcome after
medical treatment could be perfected by improved selection
of patients. Although methotrexate is generally safe and
effective, it should be used with the utmost care in the treatment of ectopic pregnancy.
Surgical treatment is increasingly carried out by laparoscopy, which is effective in decreasing morbidity and
mortality, but of unproved benefit in subsequent reproductive
outcome. Laparotomy remains necessary in emergency
cases, with haemodynamic instability and with exceptional
locations, such as abdominal, cervical or interstitial pregnancies. There is no definitive answer on whether laparoscopic
surgery or methotrexate should be first line of treatment. This
question can only be answered by carrying out a large multicentre trial. Ultimately, breakthroughs in the understanding
of the mechanism of implantation and in the natural history of
the disease will provide advances in treatment options. Meanwhile, increased vigilance and application of technological
advances should ensure early diagnosis and less invasive
therapy achieving a continued reduction in the mortality and
morbidity of ectopic pregnancy
Extra-uterine pregnancy following assisted conception treatment
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Received on February 15, 1999; accepted on November 22, 1999