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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
 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 require-
ments, 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 subse-
quent 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 non-
surgical management of ectopic pregnancy.

Key words: assisted conception/diagnosis/ectopic/management

TABLE OF CONTENTS                                                              ectopic pregnancies implant in the ampullary region of the
                                                                               Fallopian tube, followed by the isthmus, the fimbriae, and the
Introduction                                                          80
                                                                               cornual portion; these constitute >95% of all ectopic preg-
Incidence                                                             81
Risk factors                                                          81
                                                                                 Abulcasis (AD 936) was the first to report an ectopic preg-
Aetiology of ectopic pregnancy                                        82       nancy, while Duverney in 1708 was the first to describe an
Pathology of ectopic pregnancy                                        82       heterotopic pregnancy, the combination of intrauterine and
Clinical features of ectopic pregnancy                                82       extrauterine pregnancy. There is no doubt that the diagnosis
Diagnostic tests                                                      82       and management of ectopic pregnancies underwent another
Treatment                                                             84       revolution a century later, when Lawson Tait successfully
Conclusions                                                           88       performed a laparotomy to ligate the broad ligament and
References                                                            89       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
Ectopic pregnancy refers to the implantation of the blastocyst                 have been numerous reports of both ectopic and heterotopic
in any tissue outside the uterine cavity. The majority of                      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:
                                                      Extra-uterine pregnancy following assisted conception treatment          81

resulted in an increased likelihood of ectopic pregnancy          Risk factors
being unruptured at the time of diagnosis, thus making less-
                                                                  Risk factors are present in 25–50% of patients with an ectopic
invasive treatment options possible (Ling and Stovall, 1994).     pregnancy (Ling and Stovall, 1994). They include a history of
   Although the maternal mortality from ectopic pregnancies       pelvic inflammatory disease (PID), tubal surgery, previous
declined five-fold in the UK between 1975 and 1993 (Depart-       ectopic pregnancies, a progesterone intrauterine device and
ment of Health, 1996), ectopic pregnancy is still the leading     exposure to diethylstilboestrol in utero (Ling and Stovall,
cause of maternal deaths in the first trimester, accounting for   1994; Speroff et al., 1994; Ankum et al., 1996a). The most
12 out of the 134 direct maternal deaths (8.9%) in the last       convincing evidence that PID is the major cause of ectopic
triennial report (Department of Health, 1998). In contrast,       pregnancies comes from reports documenting a seven-fold
there were only eight deaths directly attributed to ectopic       increase in the ectopic pregnancies rate in women with lapar-
pregnancy out of the 323 maternal deaths reported in the          oscopically-proven salpingitis (Westrom, 1975; Westrom et
previous triennium (2.4%). This last report re-emphasized the     al., 1981).
importance of early diagnosis and the need for increased             Data on risk factors associated with ectopic pregnancies
                                                                  after IVF/embryo transfer are conflicting. Yovich et al.
awareness of the possibility of an extra-uterine pregnancy in
                                                                  (1985) reported a higher incidence of ectopic pregnancy
any woman of reproductive age.
                                                                  when the embryos were replaced higher than mid-cavity.
                                                                  Martinez and Trounson (1986) could not identify any risk
Incidence                                                         factor, while Cohen et al. (1986) identified two factors: the
                                                                  therapeutic use of clomiphene citrate (CC) and the number of
The true incidence of ectopic pregnancy is difficult to deter-    patent Fallopian tubes at the time of embryo transfer. Other
mine, but is in the range 0.25–1.0% of all pregnancies            authors (Dubuisson et al., 1991; Karande et al., 1991)
(Stabile and Grudzinskas, 1994). In addition, ectopic preg-       demonstrated that a previous history of an ectopic pregnancy
nancies are reported to complicate 2–11% of all pregnancies       and/or pre-existing tubal pathology was associated with a
resulting from IVF treatment (Smith et al., 1982; Lopata,         subsequent increased risk of an ectopic implantation.
1983; Cohen et al., 1986; Martinez and Trounson, 1986;            Verhulst et al. (1993) identified tubal damage and the use of
Correy et al., 1988; Karade et al., 1991; Dubuisson et al.,       CC combined with human menopausal gonadotrophins
1991; Ory, 1992; Verhulst et al., 1993). Likewise, the            (HMG) as risk factors. Marcus and Brinsden (1995) found
reported incidence of ectopic pregnancy after ovulation           that a history of PID was the main risk factor, with no statis-
induction with human chorionic gonadotrophin (HCG) in             tical evidence of an association between ectopic pregnancy
                                                                  and a past history of abortion, termination of pregnancy, still-
anovulatory women with apparently normal Fallopian tubes
                                                                  birth, neonatal death, or tubal surgery. They also found no
varied between 2.7% (Gemzell et al., 1982) and 3.1%
                                                                  association between the type of ovarian stimulation protocol
(McBain et al., 1980) of all conceptions. On the other hand,
                                                                  or the oestradiol, luteinizing hormone (LH) and progesterone
the incidence of heterotopic pregnancy in spontaneous             concentrations at the time of ovulation induction and ectopic
conception pregnancies, which was once considered very            pregnancies. The role of CC in the incidence of ectopic preg-
rare (1 in 30 000 pregnancies), now complicates 1 in 4000 to      nancies is controversial. With some authors suggesting an
1 in 7000 pregnancies (Ben-Rafael et al., 1985). This             increased rate of ectopic (Marchbanks et al., 1985) and heter-
increase is due primarily to the use of exogenous pituitary       otopic (Bello et al., 1986) conceptions subsequent to CC,
gonadotrophins (Dietz et al., 1993) and the increasing use of     while others (Dickey and Holtkamp, 1996) found no associ-
IVF (Chang et al., 1991; Rizk et al., 1991). The incidence of     ated risk between CC and ectopic pregnancy.
heterotopic pregnancy subsequent to IVF treatment ranges             An ectopic rate of 4.0% of all pregnancies or 1.5% of trans-
from 1 to 3% of all clinical pregnancies (Yovich et al., 1985;    fers has been quoted by the Society for Assisted Reproduc-
Berman et al., 1986; Dor et al., 1991; Dimitry and Reid,          tive Technology and the American Society for Reproductive
1993; Marcus et al., 1995; Tal et al., 1996).                     Medicine in their analysis of 1472 clinical pregnancies subse-
                                                                  quent to 4202 gamete intra-Fallopian transfer (GIFT)
  Despite the increased incidence of ectopic pregnancy in the
                                                                  retrieval cycles initiated in the USA in 1993 (Society for
last decade (Ory, 1992), ovarian pregnancy remains a rare
                                                                  Assisted Reproductive Technology/American Society for
phenomenon, accounting for <3% of all ectopic pregnancies         Reproductive Medicine, 1995). A similar rate of ectopic
(Seinera et al., 1997). Cervical pregnancy is less common,        pregnancies following GIFT has been repeated in the subse-
accounting for only 0.15% of all ectopic gestations (Parente      quent report (Society for Assisted Reproductive Technology/
et al., 1983). The rarest form of extrauterine pregnancy is       American Society for Reproductive Medicine, 1998) and this
interstitial or intramural pregnancy, with only 16 cases          is comparable with that reported previously (Formigli et al.,
reported thus far (Tucker, 1996).                                 1990).
82    N.Abusheikha, O.Salha and P.Brinsden

Aetiology of ectopic pregnancy                                   and not in the tube. As a result of trophoblastic activity, the
                                                                 human blastocyst can implant at any site at the appropriate
The aetiology of ectopic pregnancy subsequent to assisted
                                                                 stage of development. The role of the maternal decidua in this
conception treatment is multi-factorial, with destruction of
                                                                 process is a passive one.
the anatomy of the tube as the main factor. It has been
                                                                   Three mechanisms have been proposed to explain ovarian
proposed that a damaged tube may be unable to propel an
                                                                 implantation (Marcus and Brinsden, 1993): (i) one theory
embryo that has migrated into the tube back into the uterine
                                                                 suggests that fertilization occurs normally and implantation
cavity, whereas a normal functioning tube may be able to do
                                                                 on the ovary follows reflux of the conceptus from the tube
so (Berman et al., 1986). Reverse migration of the embryos
                                                                 (Crimes et al., 1983); (ii) the second theory suggests that
may also be associated with a high concentration of oestra-
                                                                 various disturbances in ovum release are responsible for
diol or an altered oestrogen/progesterone ratio (James, 1996).
                                                                 ovarian implantation (Tan and Yeo, 1968); and finally (iii)
Other factors include the ovarian stimulation protocol
                                                                 the application of intrauterine insemination could push some
(Benger and Taymor, 1972) and the number of embryos
                                                                 spermatozoa all the way to the ovarian surface and lead to
transferred (Dicken et al., 1989). The technique of embryo
                                                                 ovarian implantation (Bontis et al., 1997).
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          Clinical features of ectopic pregnancy
medium or use of excessive force during the embryo transfer
(Berman et al., 1986; Dor et al., 1991). Placing the transfer    Ectopic pregnancy is a great masquerader, since only half of
catheter beyond the mid-cavity or into the tube itself (Yovich   patients with ectopic pregnancies are correctly diagnosed on
et al., 1985), or to retrograde migration of the embryos into    clinical features alone (Tuomivaara et al., 1986). The clinical
the tube (Job-Spira et al., 1996) have also been blamed for      signs and symptoms of ectopic pregnancy overlap with those
the increased incidence of ectopic pregnancy subsequent to       of other surgical and gynaecological conditions, such as
IVF treatment. Nonetheless, Dor et al. (1991) evaluated the      threatened or incomplete miscarriage, pelvic inflammatory
use of ultrasound in embryo transfer and concluded that ultra-   disease, ruptured or haemorrhagic corpus luteal cyst, salpin-
sound-guided embryo transfer does not prevent ectopic preg-      gitis, adnexal torsion, degenerating fibroid, dysfunctional
nancy after IVF. Job-Spira et al. (1996) argued that             uterine bleeding, endometriosis and appendicitis.
chromosomal anomalies in the fertilized oocyte might play a        The first clinical symptom of ectopic pregnancy is usually
role in the aetiology of ectopic implantation. It is also        pain. This is present in 95% of cases, while 80% have amen-
possible that an ectopic pregnancy could result from sponta-     orrhoea and 50% experience abnormal vaginal bleeding. The
neously fertilized unrecovered oocytes if coitus occurred near   presentation may be acute, subacute or silent. In acute cases
the time of oocyte recovery. This possibility cannot be          associated with tubal rupture there may be massive i.p. haem-
excluded, particularly if the number of oocytes retrieved is     orrhage, causing acute abdominal pain, circulatory collapse
less than the number of follicles aspirated.                     with hypotension and tachycardia. In such patients, imme-
                                                                 diate laparotomy is necessary with salpingectomy being
                                                                 mandatory to arrest the bleeding.
Pathology of ectopic pregnancy                                     The most common situation is of a subacute presentation
Any difference between implantation in the uterus and that in    with amenorrhoea, abdominal pain and sometimes irregular
the tube can be easily explained by the anatomy of the two       vaginal bleeding. If rupture or tubal abortion occurs gradu-
organs. As the trophoblast invades the muscle layer of the       ally, the symptoms are less dramatic, and the diagnosis may
Fallopian tube, the connective tissue cells of the tubal wall    be missed. Similarly, the development of ovarian hyperstim-
become swollen and resemble decidual cells, but this             ulation syndrome (OHSS) subsequent to assisted conception
provides no resistance to the invading trophoblast. Some of      treatment may mask the symptoms of an ectopic pregnancy
the vessels that the trophoblast meets are large, and when       (Thakur and El-Menabawey, 1996; Paulson and Lobo, 1998).
these are invaded, the pressure of the blood stream is often
sufficient to destroy the embryonic cell mass.
                                                                 Diagnostic tests
   Early placental development in the tube is very similar to
that seen at normal sites, although it is often immature and     The morbidity and mortality associated with ectopic preg-
many villi demonstrate loss of vascularity with central hyali-   nancy are directly influenced by the time interval between the
nization, characteristic of collapse of the fetal circulation.   onset of symptoms and the start of treatment (Department of
Subsequently, there is failure of the tubal trophoblast to       Health, 1998). Thus the prospect of early treatment is
differentiate into chorion laeve and chorion frondosum. The      dependent on maintaining a high index of suspicion and the
degree of decidual reaction around the tubal implantation site   deployment of a few additional diagnostic tests, dictated by
is usually minimal. The decidua usually forms in the uterus      local availability and costs.
                                                      Extra-uterine pregnancy following assisted conception treatment         83

Biochemical tests                                                   Mol et al. (1997) evaluated the discriminative capacity of
                                                                  transvaginal sonography in combination with HCG measure-
                                                                  ment in the diagnosis of ectopic pregnancy after IVF/embryo
Human chorionic gonadotrophin (HCG)
                                                                  transfer, and found that whenever the serum β-HCG concen-
HCG may be detected in the urine as early as 14 days post-        tration on day 9 after embryo transfer was >18 IU/l, the preg-
conception by sensitive enzyme-linked immunosorbent               nancy was always intrauterine and viable. Therefore, they
assays (detection limits 25–50 IU/l; sensitivity 98–100%)         concluded that transvaginal sonography can be postponed
(Armstrong et al., 1984; Kingdom et al., 1991; Speroff et al.,    until 5 weeks after embryo transfer, except for patients with
1994). It can be detected in the serum 6–7 days post-concep-      abdominal pain and/or vaginal bleeding, or in patients with a
tion by immunometric radioassays (detection limits <5 IU/l;       serum β-HCG concentration of <18 IU/l.
sensitivity 100%) (Lenton et al., 1982; Speroff et al., 1994).
Early normal intrauterine pregnancies are associated with a       Serum progesterone
doubling of serum HCG concentrations every 1.4–2.1 days
(Kadar et al., 1981; Pittaway et al., 1981). An ectopic preg-     Serum progesterone concentrations are lower in ectopic than
nancy produces less HCG than a normal intrauterine preg-          in normal intrauterine pregnancies (Johansson, 1969;
nancy, which has the effect of prolonging the HCG doubling        Radwanska et al., 1978; Milwidsky et al., 1984; Mathews et
time (Check et al., 1992; Heiner et al., 1992). However, 15%      al., 1986). Whether ectopic implantation causes the shut-
of normal pregnancies will have an abnormal doubling time         down of progesterone by the corpus luteum or whether low
and 13% of ectopic pregnancies will have a normal doubling        progesterone concentrations actually lead to ectopic implan-
time (Ling and Stovall, 1994). Therefore, in order to increase    tation is still uncertain, although the electrophysiological
the sensitivity of quantitative HCG, a discriminatory zone has    studies of Pulkkinen and Jaakkola (1989) suggest the latter
been described, whereby an HCG titre of 1000–1500 IU/l            may be the case.
will be associated with the presence of an intrauterine sac on       To investigate the diagnostic accuracy of serum proges-
                                                                  terone in the diagnosis of ectopic pregnancy, Yeko et al.
transvaginal ultrasound (6000–6500 IU/l for transabdominal
                                                                  (1978) identified a cut-off value of 15 ng/ml to differentiate
ultrasound) (Kadar et al., 1981; Keith et al., 1993). Several
                                                                  between viable and non-viable pregnancies. On the same
prospective studies employing diagnostic algorithms,
                                                                  notion, McCord et al. (1996) advised that when the serum
including clinical symptoms, quantitative serum HCG and
                                                                  progesterone is >17.5 ng/ml, patients thought to be at risk of
transvaginal ultrasound, have shown a diagnostic sensitivity
                                                                  ectopic pregnancies could reasonably be followed without
of this discriminatory zone for ectopic pregnancies of 95–
                                                                  ultrasound or further invasive diagnostic studies. The sensi-
99% and a specificity of 95–100% (Fernandez et al., 1991a;
                                                                  tivity of serum progesterone values <15 ng/ml to distinguish
Ankrum et al., 1996b).
                                                                  between normal pregnancies and ectopic gestation is ~80%
   Kadar and Romero (1988) were among the first to address        (Buck et al., 1988), with false-positive rates of ~10% (Stovall
the problem of distinguishing ectopic pregnancy from spon-        et al., 1989).
taneous abortion on the basis of falling HCG concentrations          In patients clinically suspected of having an ectopic preg-
over a 48 h period. In their study, if the half-life of HCG was   nancy, a progesterone concentration of <20 ng/ml suggests
<1.4 days, then a complete abortion was likely and the patient    early pregnancy failure, whatever the gestational age (Sauer
was best managed expectantly. If the half-life was >7 days,       et al., 1989). In their study of 135 patients who suffered
then an ectopic was likely. Thus, contrary to popular belief,     ectopic pregnancies following IVF/embryo transfer, Marcus
falling HCG concentrations are not synonymous with sponta-        et al. (1995) found that the mean plasma progesterone
neous abortion, and can be used to distinguish spontaneous        concentration was significantly lower than that of patients
abortion form ectopic pregnancies, provided the half-life of      with normal singleton pregnancies. On the other hand, other
HCG is calculated.                                                investigators, (Ling and Stovall, 1994; Speroff et al., 1994)
   In IVF patients, since more than one embryo is usually         found serum progesterone concentrations did not appear to
transferred, and more trophoblastic tissue may be present to      increase the diagnostic sensitivity.
produce HCG, an extra 2 or 3 days are required for a sac to          Other hormones, such as pregnancy-associated plasma
become visible. Okamato et al. (1987) were the first to report    protein A (PAPP-A), have been evaluated as possible ancil-
on the accuracy of serum β-HCG measurement in the diag-           lary diagnostic tests in suspected ectopic pregnancies
nosis of ectopic pregnancies after IVF/embryo transfer. They      (Tornehave et al., 1987). The two major proteins synthesized
reported a 100% sensitivity and a 68% specificity when            by the human endometrium; progesterone-dependent
comparing 88 viable intrauterine pregnancies with nine            endometrial protein (pectopic pregnancies ) and insulin-like
ectopic pregnancies. A serum HCG concentration of >295            growth factor binding protein (IGF-bp) have also emerged as
IU/l on day 16 post-embryo transfer was reported to give a        candidates as biochemical markers of ectopic implantation
90% chance of intrauterine implantation (Smith et al., 1982).     (Ruge et al., 1991; Pedersen et al., 1991).
84    N.Abusheikha, O.Salha and P.Brinsden

Ultrasound                                                           Colour and pulsed Doppler techniques may complement
                                                                   endovaginal sonographic findings, but they should be
The role of utrasonography in suspected ectopic gestation is       performed only after a thorough real-time evaluation of the
to diagnose and localize the pregnancy. The image resolution       adnexal region (Atri et al., 1996). Whilst Speroff et al. (1994)
and patient acceptance of transvaginal ultrasonography are         indicated that the use of colour Doppler imaging should only
considerably better than that of transabdominal ultrasound         be confined to research trials to increase the sensitivity of
(Bateman et al., 1990). In order of appearance, a normal           transvaginal ultrasonography, others (Chew et al., 1996;
intrauterine sac should contain a yolk sac and embryonic           Abramove et al., 1997) found that it failed to improve on the
echoes with visible heart activity at days 33, 38 and 43 from      results of transvaginal B-mode sonography in the detection of
the last menstrual period respectively (Cacciatore et al.,         ectopic pregnancy.
   There are three sonographic features of tubal pregnancy as
seen by a vaginal transducer. First, the demonstration of a        Other methods
live embryo within a gestational sac in the adnexa. This           Culdocentesis (Ling and Stovall, 1994; Speroff et al., 1994)
remains the gold standard for the sonographic diagnosis of         and uterine curettage (Speroff et al., 1994; Ramirez et al.,
ectopic pregnancy. It typically appears as an intact, well-        1996) have limited use in the diagnosis of ectopic pregnancy.
defined 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          Laparoscopy
ectopic embryo/fetus is reported to be seen in 12–20% of cases
                                                                   Laparoscopy as a method of diagnosing ectopic gestation has
with vaginal ultrasound (DeCrespigny, 1988; Stabile et al.,
                                                                   been used since 1937, when Hope reported the first 10 cases
1988). The second transvaginal sonographic appearance of
                                                                   (Hope, 1937). When laparoscopy became a routine procedure
tubal pregnancy is that of a poorly defined tubal ring,
                                                                   it facilitated the early diagnosis of ectopic pregnancy and in
possibly containing echogenic structures (Dodson, 1991; Atri
                                                                   up to 40% of cases laparotomies were avoided. The develop-
et al., 1996). Typically, the pouch of Douglas also contains
                                                                   ment of a very sensitive radioimmunoassay for β-HCG,
fluid and/or blood. These features are consistent with a tubal
                                                                   together with the use of ultrasound, has again changed our
pregnancy that is aborting. The third typical sonographic
                                                                   ability to diagnose ectopic pregnancies. Under these circum-
picture is the presence of varying amounts of fluid in the
                                                                   stances, the role of laparoscopy nowadays has moved from
pouch of Douglas, representing rupture of the tubal preg-
                                                                   being a diagnostic tool (false negatives 3–4%; false positives
nancy (Nyberg et al., 1991).
                                                                   5%) (Ling and Stovall, 1994) to become a treatment modality
   Arguments persist as to whether or not a pseudogestational      only (Barnhart et al., 1994; Ankum et al., 1996b).
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       Treatment
that it may be difficult, even with transvaginal sonography, to
                                                                   Early diagnosis of unruptured ectopic pregnancy (Figure 1)
evaluate an intrauterine sac <4 mm in diameter. However, in
                                                                   allows for conservative medical or invasive surgical therapy.
the absence of an eccentric placement of a gestational sac
                                                                   The recurrent ectopic pregnancy rates after radical and
within the endometrial cavity (which is the hallmark of a
                                                                   conservative management are similar (10–22%), while the
normal intrauterine pregnancy), a pseudogestational sac
                                                                   intrauterine pregnancy rate in subsequent pregnancies is 60%
should be suspected (Cacciatore et al., 1990).
                                                                   after conservative tubal surgery, 87% after medical treatment
   Despite recent advances in sonographic techniques and           and 40% after salpingectomy (Vermesh et al., 1989; Rulin,
better patient acceptability of the transvaginal method of         1995). Therefore, a conservative therapeutic approach should
scanning, considerable expertise is still needed for image         be attempted in patients with an ectopic pregnancy who
interpretation. Of particular difficulty is the diagnosis of       desire future fertility and are haemodynamically stable at
heterotopic pregnancy, which is fraught with potential pitfalls    presentation.
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, estab-       Surgical treatment
lishing the existence of an intrauterine pregnancy by ultra-
sonography, although reassuring, does not rule out a co-           Laparoscopy versus laparotomy
existing ectopic pregnancy (Hayes and Haley, 1984;
Goldman et al., 1992). Correct pre-operative diagnosis of          Laparoscopic salpingostomy (Figure 2) is rapidly replacing
ovarian pregnancies is equally difficult, being confused with      laparotomy for most cases of tubal ectopic pregnancy. In
corpus luteal cysts (Tan and Yeo, 1968; Raziel et al., 1990).      modern practice, the prevalent opinion is that laparotomy
                                                              Extra-uterine pregnancy following assisted conception treatment             85

                                                                            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 concen-
                                                                            trations 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 laparos-
                                                                            copy 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
Figure 1. Transvaginal ultrasound depicting an intact, well-defined tubal
                                                                            the number of women who desire pregnancy after the proce-
ring in the adnexa surrounding a completely sonolucent sac containing an
ectopic pregnancy with cardiac activity.                                    dure as the denominator, ~35% of women will have a subse-
                                                                            quent intrauterine pregnancy and 15% will have a repeat
                                                                            ectopic gestation (Lavy et al., 1987). Women undergoing
should be performed only in cases in which the laparoscopic                 IVF must, therefore, be informed of the risk of ectopic preg-
approach is difficult or the patient is haemodynamically                    nancy (Agrawal et al., 1996; Chen et al., 1998), even if they
unstable (Baumann et al., 1991; Lundorrff et al., 1991;                     have had bilateral salpingectomy, since cornual implantation
Murphy et al., 1992). The advantages of the laparoscopic                    can still occur (Manhes et al., 1983).
approach have been well-documented in terms of shorter
hospital stay (Kouam et al., 1996), fewer post-operative anal-
                                                                            Hysteroscopic resection
gesic requirements (Lundorrff et al., 1991), reduced cost
(Gray et al., 1995; Garry, 1996) and a lower risk of adhesion               Diagnostic hysteroscopy has been used in the management of
formation (Tuomivaara and Kaupilla, 1988). Recently,                        cervical pregnancy. Roussis et al. (1992) used the hystero-
ovarian ectopic pregnancies have also been reported to be                   scope to visualize a cervical pregnancy 40 days after failed
managed laparoscopically with variable success (Hage et al.,                systemic methotrexate treatment. As hysteroscopy confirmed
1994; Seinera et al., 1997).                                                minimal vascularity in the endocervical canal, they
                                                                            proceeded with suction aspiration of the trophoblastic tissue.
                                                                            Ash and Farrell (1996) also described hysteroscopic resection
Laparoscopic salpingostomy versus laparoscopic
                                                                            of a cervical pregnancy and concluded that operative hyster-
                                                                            oscopy permits complete resection of a cervical pregnancy.
In a patient with a diseased tube or a damaged contralateral                When it is successful, this treatment should result in prompt
tube, the question arises as to whether laparoscopic treatment              resolution of the ectopic pregnancy, thus avoiding the need
should be by salpingectomy or salpingostomy. In patients                    for a prolonged follow up or hysterectomy. Hysteroscopy has
where the contralateral tube is diseased, but nevertheless                  also been used successfully to diagnose and treat interstitial
patent (Tuomivaara and Kaupilla, 1988; Silva et al., 1993;                  ectopic pregnancy (Laury, 1995; Alexander et al., 1996).
Bronson, 1997) the post-operative chances of conception are
not significantly different whether treatment is by salpingec-
                                                                            Medical treatment
tomy or salpingostomy. This finding is important since lapar-
oscopic salpingectomy posses a number of advantages                         Although operative laparoscopy has substantially fewer compli-
compared with salpingotomy. It is more simple, requiring no                 cations than laparotomy (Lundorrff et al., 1991; Murphy et al.,
specific equipment (Dubuisson et al., 1996) and does not                    1992) there remains an irreducible minimal degree of morbidity
carry the risk of leaving intra-tubal residual trophoblastic                intrinsic to surgery and anaesthesia. Though they are not yet
tissue. Subsequent persistent trophoblast has been reported to              standard therapy in many centres, medical treatments can greatly
occur in 15–20% of cases following laparoscopic salpingos-                  reduce this morbidity, and consequently there is increasing
tomy (Vermesh et al., 1989; Murphy et al., 1992; Buster and                 interest in using them. To supplant surgery, however, medical
Carson, 1995; Kouam et al., 1996). Since persistent trophob-                therapies must match the success rates, low complication rates,
86     N.Abusheikha, O.Salha and P.Brinsden

                                                                             eter by ultrasound, are eligible for treatment with meth-
                                                                             otrexate (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 intra-
                                                                             abdominal 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, meth-
                                                                             otrexate has been used widely for unruptured ectopic pregnan-
                                                                             cies (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 (Lind-
                                                                             blom et al., 1987; Stovall et al., 1989; Zakut et al., 1989;
                                                                             Kojima et al., 1990), or under ultrasound guidance (Feicht-
                                                                             inger and Kemeter, 1987; Aboulghar et al., 1990; Menard
                                                                             et al., 1990; Tulandi et al., 1992; Fernandez et al., 1993,
Figure 2. Transvaginal ultrasound depicting poorly-defined tubal ring in
                                                                             1994; Pérez et al., 1993; Darai et al., 1995b).
the adnexa, containing an ectopic pregnancy. The empty uterine cavity with
a thickened endometrium is illustrated adjacent to the ectopic pregnancy.
                                                                             Systemic methotrexate
and subsequent reproductive potential achieved with laparo-                  Oral methotrexate cannot generally be recommended and is
scopic operations. This appears to have been achieved (Stovall,              rarely used for the treatment of ectopic pregnancy. More
1995; Alexander et al., 1996).                                               commonly, methotrexate has been used in multiple i.m. doses
  The first case report describing the use of medical therapy                or in single doses, in a schedule of 0.5–1.0 mg/kg every other
for tubal pregnancy appeared in 1982 (Tanaka et al., 1982).                  day for 5–7 days (Farabow et al., 1983; Fernandez et al.,
Observational studies in the mid-1980s used, with varying                    1994), or 50 mg/m2 of body surface area (Stovall et al.,
success, methotrexate (Leach and Ory, 1989), prostaglandins                  1991a).
(Husslein et al., 1988; Lindblom et al., 1990), actinomycin                     Transient pelvic pain frequently occurs 3–7 days after the
(Altaras et al., 1988), hyperosmolar glucose (Lang et al.,                   start of methotrexate therapy. This pain is presumably due to
1990), and anti-HCG antibodies (Frydman et al., 1989).                       tubal abortion and normally lasts 4–12 h (Stovall et al., 1990,
Potassium chloride (Robertson et al., 1987; Aboulghar et al.,                1991b). Perhaps the most difficult aspect of methotrexate
1990) is particularly useful in the treatment of heterotopic                 therapy is learning to differentiate between the transient
pregnancy, as it has no effect on the intrauterine fetus(s).                 abdominal pain of successful therapy from that of a rupturing
Mifepristone (RU486) (Kenigsberg et al., 1987), an oral                      ectopic pregnancy (Figure 3). Objectively, surgical interven-
progesterone antagonist abortifacient with low toxicity, was                 tion is necessary when the pain is associated with tachy-
ineffective except in combination with methotrexate                          cardia, hypotension or a falling haematocrit.
(Gazvani et al., 1998). Although treatments given systemi-                      The reported outcome of systemic methotrexate treatment
cally have proved most practical, several of these agents have               of ectopic pregnancy compares favourably with that of lapar-
been injected into the ectopic gestational sac under laparo-                 oscopic salpingostomy (Tanaka et al., 1982; Miyazaki, 1983;
scopic or ultrasound guidance or by hysteroscopic intratubal                 Ory et al., 1986; Haans et al., 1987; Ichinoe et al., 1987;
cannulation.                                                                 Sauer et al., 1987; Bryrjalsen, 1991; Stovall et al., 1991b;
                                                                             Prevost et al., 1992; Isaacs et al., 1996; Maymon and
Methotrexate                                                                 Shulman, 1996). A success rate (i.e. patients who did not
                                                                             need subsequent therapy) of 90–95% has been achieved, with
A folic acid antagonist, methotrexate inhibits the sponta-                   a non-response rate and/or tubal rupture rate of 3–4%
neous synthesis of purines and pyrimidines, thus interfering                 (Lipscomb et al., 1998). Of the women followed, 71% subse-
with DNA synthesis and the multiplication of cells (Chu et                   quently became pregnant, with 11% of those pregnancies
al., 1990). Actively proliferating trophoblast was shown to be               being ectopic (Slaughter and Grimes, 1995). More recently,
vulnerable to methotrexate treatment of gestational trophob-                 Fernandez et al. (1998) compared methotrexate treatment
lastic disease (Sand et al., 1986; Leach and Ory, 1989).                     with laparoscopic salpingotomy in a prospective randomized
  Haemodynamically stable patients with ectopic pregnancy,                   study. They found that medical treatment was associated with
in which the mass is unruptured and measures ≤4 cm in diam-                  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   Figure 4. Transvaginal ultrasound depicting a pseudogestational sac within
fluid in the pouch of Douglas (see dark area adjacent to the uterus).      the uterus.

returned to normal concentrations more rapidly after laparo-               diluent may range from 0.8 to 10 ml. On the other hand,
scopic treatment. Spontaneous reproductive performance                     direct injection under ultrasound control is preferable, as it
was similar in both groups, but overall rates of intrauterine              enables treatment on an outpatient basis, with neither general
pregnancy were higher and repeat ectopic pregnancies lower                 anaesthesia nor laparoscopy being required (Goldenberg
after methotrexate treatment. They concluded that in selected              et al., 1993). But this may also be offset by the risk of acci-
cases of ectopic pregnancy, methotrexate treatment appeared                dental damage to other pelvic organs and the requirement for
as safe and efficient as conservative treatment by laparoscopy             specialized invasive training.
and was associated with improved subsequent fertility.                       Systemic and intratubal methotrexate were shown to have
   In the search for a more potent alternative to a single i.m.            similar efficacy and resulted in comparable subsequent preg-
injection of methotrexate for unruptured ectopic pregnancy,                nancy rates (Kooi and Kock, 1990; Fernandez et al., 1993).
combination therapy was suggested. Gazavani et al. (1998)                  Nevertheless, the success rate of local injection of meth-
randomized 50 patients with unruptured ectopic pregnancies                 otrexate is highly dependent on the proper selection of
to receive a single i.m. injection of 50 mg/m2 body surface                patients (Goldenberg et al., 1993). The success rate for direct
methotrexate alone or in combination with 600 mg of oral                   methotrexate injection under ultrasound guidance ranges
mifepristone. The success rates for treatment arms were                    from 70 to 95% (Feichtinger and Kemeter, 1987; Menard
similar, however, median administration to resolution times                et al., 1990; Fernandez et al., 1991b; Tulandi et al., 1992;
was shorter and a second injection or laparotomy was less                  Darai et al., 1995b) and between 43 and 100% under laparo-
likely to be needed in the combination group.                              scopic 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)
Local methotrexate
                                                                           prepared a suspension of methotrexate dissolved in lipidol
In 1987 Feichtinger and Kemeter reported the direct injection              with phosphatidylcholine added as a dispersing stabilizer to
of methotrexate under transvaginal ultrasound guidance.                    maintain the high tissue concentration and to prolong the
They instilled 1 ml (10 mg) of methotrexate into the ectopic               effect. Their results showed that this suspension seems to be
gestational sac and resolution occurred within 2 weeks.                    more effective than methotrexate solution alone.
Direct injection delivers concentrations of methotrexate to                  The side-effects of local methotrexate therapy include:
the implantation site which are many times higher than those               gastrointestinal disorders, liver dysfunction, bone marrow
achieved with systemic administration. Thus there is less                  suppression, opportunistic infections, blood dyscrasias,
systemic distribution of the drug, a smaller therapeutic dose,             reversible alopecia, persistent haematosalpinx and meth-
and less toxicity.                                                         otrexate-induced lung disease. These side-effects are infre-
  Injection of methotrexate into the gestational site under                quent and in the shorter treatment schedules used in ectopic
laparoscopic guidance is performed with varying dosages,                   pregnancies and can be attenuated by the administration of
ranging from 5 to 100 mg, and the amount of normal saline                  leucovorin (macrophage colony stimulating factor) (Leach
88    N.Abusheikha, O.Salha and P.Brinsden

and Ory, 1989; Stovall et al., 1991a,b; Issacs et al., 1996).     assays, combined with the availability of high-resolution
Extensive experience with methotrexate in gestational             transvaginal sonography, expectant management of unrup-
trophoblastic disease has diminished concern about the risks      tured ectopic pregnancies has become safer. When the β-
of subsequent neoplasia, increased abortion rates and fetal       HCG concentration is <1000 IU/l and the plasma proges-
congenital anomalies (Ross, 1976). Nevertheless, it is true to    terone <5 ng/ml, spontaneous resolution occurs in 74% of
assume that most patients can expect a low risk of mild           cases of ectopic pregnancies with expectant management
complications. Although Stovall and Ling (1993) reported no       (Darai et al., 1995a). A review of 10 prospective studies of
significant side-effects in patients treated with local or        expectant management reported success rates of 46.7–100%
systemic methotrexate, Kooi and Kock (1992) observed that         (Yao and Tulandi, 1997). Generally speaking, there is a
2% of their patients treated with topical methotrexate devel-     decreased chance of successful expectant management the
oped some side-effects, compared with 21% treated systemi-        higher the initial serum β-HCG concentrations are (Adoni
cally. On the other hand, Glock et al. (1994) reported mild       et al., 1986). As there is no certain limit below which tubal
side-effects in 34% of their 35 patients, while Fernandez         rupture will not occur, we believe, as others do (Mascarerhas
et al. (1993) reported mild side-effects in three out of 100      et al., 1997; Lipscomb et al., 1998), that methotrexate treat-
patients. Suffice to say that, although generally safe and        ment may be a more appropriate alternative.
effective, methotrexate should be used with the utmost care
in the treatment of ectopic pregnancy.
   Methotrexate treatment, administered either systemically       Conclusions
or locally, has been reported to be less satisfactory as a        Although the mortality from ectopic pregnancy has
primary treatment of cervical pregnancy than of tubal preg-       decreased due to earlier diagnosis and more medical treat-
nancy. Some authors claimed that their cases failed initial       ment, ectopic pregnancy is still a common cause of maternal
methotrexate treatment and required additional interventions,     morbidity and mortality. Recent advances in the measure-
including suction curettage (Mantalenakis et al., 1995),          ment of quantitative serum β-HCG and progesterone,
salvage chemotherapy with the same agent (Kaplan et al.,          together with the development of high-resolution ultrasound
1990; Hung et al., 1996), feticide with intra-amniotic injec-     scanning, has improved the rate of early diagnosis of ectopic
tion of potassium chloride (Kung et al., 1995), angiographic
                                                                  pregnancy and had made it possible in most cases to diagnose
immobilization (Cosin et al., 1997), ligation of bilateral
                                                                  extra-uterine pregnancy without resort to laparoscopy.
uterine arteries (Wolcott et al., 1988) or even hysterectomy
                                                                    Several options exist today for the treatment of ectopic
(Dall et al., 1994). Hung et al. (1998) conducted a Medline
                                                                  pregnancy. The chosen treatment depends on the size and site
search to identify the clinical factors that might lead to an
                                                                  of the ectopic, the expertise and facilities available and the
unsatisfactory outcome of primary methotrexate treatment in
                                                                  general condition of the patient. Successful outcome after
cases of cervical pregnancy. They concluded that systemic
                                                                  medical treatment could be perfected by improved selection
administration of low dose methotrexate is ideal for patients
                                                                  of patients. Although methotrexate is generally safe and
who are clinically stable with cervical pregnancies of <9
weeks gestation and serum HCG concentration of <10 000            effective, it should be used with the utmost care in the treat-
IU/l. If embryonic cardiac activity is evident, concomitant       ment of ectopic pregnancy.
feticide must be performed to minimize the potential risk of       Surgical treatment is increasingly carried out by laparos-
methotrexate treatment failure.                                   copy, which is effective in decreasing morbidity and
                                                                  mortality, but of unproved benefit in subsequent reproductive
                                                                  outcome. Laparotomy remains necessary in emergency
Expectant management                                              cases, with haemodynamic instability and with exceptional
The concept of expectant management is not new. Lund              locations, such as abdominal, cervical or interstitial pregnan-
(1955) randomized patients to receive expectant management        cies. There is no definitive answer on whether laparoscopic
or surgical treatment. Among 114 patients randomized to be        surgery or methotrexate should be first line of treatment. This
treated expectantly, the success rate was 57%. However,           question can only be answered by carrying out a large multi-
most of the patients who failed expectant management              centre trial. Ultimately, breakthroughs in the understanding
returned with significant symptoms including haemoperito-         of the mechanism of implantation and in the natural history of
neum, or cardiovascular collapse. Criteria for expectant          the disease will provide advances in treatment options. Mean-
management are similar to those for medical treatment,            while, increased vigilance and application of technological
including falling β-HCG titres (Garcia et al., 1987; Speroff et   advances should ensure early diagnosis and less invasive
al., 1994; Yao and Tulandi, 1997). Nowadays, as a conse-          therapy achieving a continued reduction in the mortality and
quence of the improvement in diagnostic serial serum β-HCG        morbidity of ectopic pregnancy
                                                                    Extra-uterine pregnancy following assisted conception treatment                          89

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