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Tubal ectopic pregnancy: Diagnosis and management

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Arch Gynecol Obstet (2009) 279:443–453
DOI 10.1007/s00404-008-0731-3
REVIEW ARTICLE
Tubal ectopic pregnancy: diagnosis and management
Vivek Nama · Isaac Manyonda
Received: 24 June 2008 / Accepted: 8 July 2008 / Published online: 30 July 2008
© Springer-Verlag 2008
Abstract Ectopic pregnancy is the gynaecological emer-
gency par excellence and remains the leading cause of preg-
nancy-related Wrst trimester deaths in the UK. Its prevalence
continues to rise because of increases in the incidence of the
risk factors predisposing to ectopic pregnancy. Classically,
the diagnosis is based on a history of pelvic pain associated
with amenorrhoea, a positive pregnancy test with or without
slight vaginal bleeding. While the immediate diVerential
diagnosis includes threatened or inevitable miscarriage, the
likelihood of ectopic pregnancy is increased if transvaginal
sonography (TVS) reveals an empty uterine cavity, and is
conWrmed if an adnexal mass with or without an embryo is
seen. However, the diagnosis is often not that simple, espe-
cially when the patient presents early, has minimal pain, is
haemodynamically stable, and TVS shows an empty uterus
but no obvious adnexal mass. This could then be an early
intrauterine pregnancy, or could indeed be an ectopic—a
diagnosis of pregnancy of unknown location is made while
additional investigations are made. The latter usually
include serial measurements of serum beta human chorionic
gonadotrophin (beta-hCG) and repeat TVS. Changes in
beta-hCG levels in normal, failing and ectopic pregnancy
are now reasonably well characterised, and at early stages
of presentation where the risk of rupture of an ectopic are
minimal, the patient can often be managed as an outpatient
while the diagnosis is pursued. In the patient who presents
with pain and haemodynamic instability, the diagnosis is
often obvious, and the management is immediate laparotomy.
V. Nama (&) · I. Manyonda
Department of Obstetrics and Gynaecology,
St George’s University of London, Cranmer Terrace,
Tooting, London SW17 0RE, UK
e-mail: vnama@sgul.ac.uk
However, in modern gynaecological practice in the devel-
oped world the vast majority of ectopic pregnancies present
early, and the general consensus is that laparoscopic man-
agement oVers both economic and aesthetic advantages, and
should be used whenever possible. Salpingectomy (excision
of the fallopian tube containing the ectopic) is performed if
the contra-lateral tube is healthy, while salpingotomy (lin-
ear incision made in the fallopian tube with removal of
ectopic pregnancy and conservation of tube) is performed if
the contra-lateral tube is unhealthy. Medical therapy using
methotrexate given systemically or injected directly into the
ectopic pregnancy is an option occasionally used with good
results. There appear to be no major diVerences in subse-
quent fertility outcomes, or risk of recurrence of ectopic
pregnancy, between the surgical or medical treatments.
Although the rates of ectopic pregnancy are not falling in
the developed world, mortality and morbidity are falling
mainly due to early and improving diagnostic and treatment
modalities. Mass screening and treatment of Chlamydia in
the young, sexually active populations, and education
regarding risk factors, may in future result in a reduction in
the rates. Lack of resource mean that the picture may
remain dismal for some time to come in the developing
world, but the development of basic protocols, improved
training and the infusion of basic resources may go a long
way to improving the situation.
Keywords Ectopic · Pregnancy · TVS · Salpingectomy ·
Salpingotomy · Beta-hCG · Methotrexate · Tubal pregnancy
Introduction
In the medical literature, ectopic pregnancy is Wrst men-
tioned in the writings of famed Arab physician, Albucasis,
123
444
who in the eleventh century described fetal bones being
extruded from a suppurating sinus at the umbilicus [1].
Today, most ectopic pregnancies are diagnosed early, long
before they develop to the fetal stage with bone formation.
Having said that, there are from time to time reports of
extra-uterine pregnancies that have gone to term! Over the
past 20 years the incidence of ectopic pregnancy in the
developed world has increased, largely because of an
increase or persistence in the risk factors, mainly chla-
mydia infection [2]. However, both the morbidity and
mortality associated with ectopic pregnancy have declined
over the same period, largely because of early presentation
leading to early diagnosis and improved treatment modali-
ties. Although the case fatality rate has decreased to
0.08%, it still represents 3.8% of maternal mortality in the
USA [3] and 3.4% in UK [4]. In the developing world, the
situation remains dismal, with women frequently present-
ing moribund, following rupture of a tubal ectopic. For
many the available meagre resources mean that interven-
tion is often too late, with case fatality rates being as high
as 27% [5, 6].
In the developed world, evidence-based medical practice
is the mantra of the day. Developments in technology such
as high resolution ultrasound equipment, minimal access
surgical instruments and acquisition of expertise in their
use, as well as reWnements in laboratory testing, have all
contributed to the evolution of the current management of
ectopic pregnancy where it has become possible to develop
guidelines and protocols to optimise practices. Ultrasound
is the key diagnostic tool when an ectopic pregnancy is sus-
pected from the history and examination. While historically
the ultrasound Wnding of an empty uterine cavity in associa-
tion with a positive pregnancy test was considered diagnos-
tic, in current practice the consensus is that the diagnosis of
an ectopic pregnancy should be based on the positive iden-
tiWcation of an adnexal mass, while a “diagnosis” of “preg-
nancy of unknown location” (PUL) is made if the uterine
cavity is empty and an adnexal mass is not seen. The vast
majority of ectopic pregnancies present un-ruptured and
can be treated with either laparoscopy or methotrexate
(MTX). Laparoscopy has economic advantages for the
health service providers and for patients, with short hospital
stay and early resumption of normal activities including
work [7]. The avoidance of a laparotomy scar also has aes-
thetic advantages for the woman.
Optimal care requires that each Unit that provides care
for women presenting with ectopic pregnancy has clear,
evidence-based guidelines and protocols. In this review we
discuss the modern approaches to early diagnosis and opti-
mal therapy, provide the evidence on which practices are
based, and present some Xow charts (Figs. 1, 2, 3) which
present the same information in a readily accessible and
concise format.
123
Arch Gynecol Obstet (2009) 279:443–453
The diagnosis of tubal ectopic pregnancy
For quick reference, we have prepared three Xow charts that
illustrate the diagnosis of treatment of ectopic pregnancy
(please see Figs. 1–3). The text below should therefore be
read in conjunction with these Wgures.
History
An ectopic pregnancy should be considered in the diVeren-
tial diagnosis in any woman presenting with abdominal
pain and a positive pregnancy test with or without vaginal
bleeding, but the classic triad of amenorrhoea, bleeding and
abdominal pain occurs in less than 50% of patients. In a
prospective consecutive case series 50% of cases of ectopic
pregnancy were missed at initial presentation based on his-
tory and physical examination only [8]. If ectopic preg-
nancy is to be picked up early, a high index of suspicion is
necessary. An adequate history should include the duration
and severity of the lower abdominal pain, presence and
duration of amenorrhoea, and duration and severity of vagi-
nal bleeding, if any. A change in the pattern of menstrua-
tion, be it the cycle or quantity of menstrual loss, may be
part of the clinical picture. Risk factors for ectopic preg-
nancy should be sought and these include previous ectopic
pregnancy, previous sexually transmitted diseases and pel-
vic inXammatory disease (PID), smoking, the presence of
an intrauterine device (IUD) and the use of progestin-only
birth control pills and implanted progestin contraception
methods. Two prospective studies have reported the pres-
ence of identiWable risk factors in 65% of patients with
ectopic pregnancy [9, 10], while a prospective case-control
study has shown that increased awareness of the risk factors
facilitate an early and accurate diagnosis [11]. In both
observational and clinical trial data of contraceptive meth-
ods submitted to the FDA for market approval, 50% of
pregnancies occurring with a progestin-containing IUD in-
situ, 14% occurring with Norplant in place and 5% occur-
ring with progestin-only oral contraceptive pills, were
ectopic in location [12, 13]. Although a meta-analysis has
shown that current IUD use does not increase the risk of the
ectopic pregnancy nevertheless a pregnancy with an IUD
in-situ is more often an ectopic than one with no IUD [14].
Examination
Not infrequently the physical signs of a ruptured ectopic
pregnancy may be obvious, and these may include shock,
tachycardia and orthostatic hypotension. Guarding, rigidity
or rebound tenderness on abdominal examination may also
indicate a ruptured ectopic pregnancy. The presence of
blood in the peritoneal cavity from a ruptured ectopic
pregnancy will produce pain and tenderness. Speculum
Arch Gynecol Obstet (2009) 279:443–453 445

Fig. 1 Diagnosis and manage-

ment of suspected ectopic SUSPECTED ECTOPIC
PREGNANCY
pregnancy
Lower abdo / pelvic pain,
Amenorrhoea / Bleeding,
Positive pregnancy test

Initial assessment of
vitals

Unstable vital signs: pallor, Vital Signs stable: no signs of

tachycardia, hypotension with shock; no signs of intra-
abdominal distension, guarding abdominal bleed; cervical
and rigidity suggestive of motion tenderness
haemoperitoneum; cervical
motion tenderness

Transvaginal
Sonography
Immediate transfer to theatre
Resuscitative measures
concurrent with laparotomy

Ectopic pregnancy Pregnancy of Intrauterine

diagnosed on TVS unknown location Pregnancy

See Figure2 See Figure 3 Further

management
based on viability

examination may show blood in the vagina, but the amount
of bleeding is usually minimal compared to that seen with
spontaneous miscarriage. Bimanual examination to check
for an adnexal mass may be performed with great caution
as this manoeuvre may cause rupture of the ectopic preg-
nancy. In reality it is often diYcult to make a diagnosis of
ectopic pregnancy from a bimanual examination, which
identiWes an adnexal mass. More informative is the elicita-
tion of cervical motion tenderness: prospective and retro-
spective case cohort studies have shown cervical motion
tenderness as the most frequent sign present in ectopic
pregnancy [9, 10]. Stretching of the peritoneum during
movement of the cervix is what elicits tenderness in the
presence of ectopic pregnancy.
In an emergency, with a collapsed patient and a high
index of suspicion, a physical examination may be quite
inappropriate: such a patient requires concurrent resuscita-
tion and admission to theatre for a laparotomy.
Investigations
Transvaginal sonography (TVS) is the pivotal investigative
tool for tubal pregnancy, but biochemical/hormonal testing
has allowed a reWnement of the approaches to investigation
and diagnosis.
Transvaginal ultrasound (TVS)
A systematic review of ten studies found that TVS can
identify any non-cystic adnexal mass with a sensitivity of
84.4% and a speciWcity of 98.9%, and has positive and neg-
ative predictive values of 96.3 and 94.8%, respectively
[15]. The authors concluded that TVS should be the Wrst
diagnostic test to be used when ectopic pregnancy is
suspected. A gestational sac, either intra-uterine or extra-
uterine, is typically visible if the beta human chorionic
gonadotrophin (beta-hCG) is more than 1,500 IU: this is

123
446
Fig. 2 Management of ectopic
pregnancy after diagnosis on
transvaginal sonography
Serum hCG < 3000 IU/L
No embryonic structures
Serum hCG level after 48 hrs
hCG ratio < 0.8* hCG ratio > 0.8
Expectant
management
*hCG ratio = Day 2 hCG/Day 0 hCG
deWned as the discriminatory zone. However, that is not to
say that an ectopic gestational sac cannot be seen when
beta-hCG levels are below 1,500 IU. Ultrasound diagnosis
of ectopic pregnancy should be based upon the positive
visualization of an adnexal mass (Fig. 4) rather than the
absence of an intrauterine gestational sac (Fig. 5). Analysis
of multiple diagnostic strategies in haemodynamically sta-
ble women with ectopic pregnancy showed that ultrasound,
followed by serum hCG for non-diagnostic scans, yielded
the most accurate diagnosis [16].
Serum beta-hCG levels
A large retrospective study of viable pregnancies showed
that the median slope for the rise of serum beta-hCG was
2.24 after 2 days (or a 124% rise) [17]. Thus two serum
beta-hCG levels measured 48 h apart can aid in the diagno-
sis of ectopic pregnancy. A 66% rise in beta-hCG level
was highly suggestive of a viable intrauterine pregnancy,
although 15% of such cases still turned out to be ectopic
pregnancies. A rise in the beta-hCG concentration of
<66% made the presence of an ectopic pregnancy more
likely (likelihood ratio of 25) [18, 19]. A fall in the beta-
hCG by less than 50% was almost always associated with
an abnormal pregnancy, while a fall of more than 50% was
highly suggestive of a spontaneous miscarriage [19]. Case
cohort studies showing a decline in the beta-hCG concen-
tration of >50% ruled out the possibility of an ectopic
123
Arch Gynecol Obstet (2009) 279:443–453
Ectopic pregnancy
diagnosed on TVS
Serum hCG 3000-5000 iu/l Serum hCG > 5000 IU/l or
and no visible heart beat fetal heart beat visible or
persistent symptoms
LAPAROSCOPY
Contralateral tube is
normal
Contralateral tube
is abnormal
Medical
management
Salpingectomy
Salpingostomy
with hCG follow up
pregnancy and a viable intrauterine pregnancy (likelihood
ratio 0) [19].
Serum progesterone levels
Values of progesterone in normal pregnancy are >50 ng/ml,
while those in failing intrauterine pregnancy are <10 ng/ml.
Progesterone values in between 10 and 50 can fall into
either category. When using a progesterone concentration
of less than 10.75 ng/ml as a cut-oV for the diagnosis of EP,
sensitivity, speciWcity, positive and negative predictive val-
ues were 85% [20]. A meta analysis has shown that serum
progesterone measurement can aid in the identiWcation of
patients at risk for ectopic pregnancy, who need further
evaluation, but its discriminative capacity is insuYcient to
diagnose ectopic pregnancy with certainty [21]. Thus serum
progesterone levels at deWned times can be used to predict
the immediate viability of a pregnancy of unknown loca-
tion, but cannot be used reliably to predict its location [22].
In conclusion serum progesterone can identify a sub group
of patients who are at risk of ectopic pregnancy, who will
need further evaluation, but its discriminative capacity is
insuYcient to diagnose ectopic pregnancy with certainty.
Endometrial sampling
Endometrial curettage is rarely, if ever, performed for diag-
nostic purposes (of ectopic pregnancy) in clinical practice.
Arch Gynecol Obstet (2009) 279:443–453 447

Fig. 3 Figure shows manage-

ment and follow-up of patients
with pregnancy of unknown Pregnancy of
location
Unknown

Serial beta-
hCG

Beta-hCG doubling
Beta-hCG < 10,000 48 hour value
every 48 hrs with
with abnormal rise Beta-hCG > 50
progesterone > 50 –
over 48 hours – Likely % fall from day 0
Likely intrauterine
ectopic pregnancy
pregnancy

Spontaneous
miscarriage
Transvaginal scan in
one week if
asymptomatic

Ectopic Nothing seen on Intrauterine

pregnancy scan Pregnancy

Continue follow
up with serial
Beta-hCG, Day 7

What often happens in practice is that an incomplete mis-
carriage is diagnosed, and endometrial curettage is per-
formed, especially where there is signiWcant vaginal
bleeding. Histology then shows the classical Aria-Stella
changes, which are considered diagnostic of an ectopic
pregnancy. However, if the beta-hCG has fallen by more
than 50%, and the patient is stable, often nothing further
beyond careful observation is required, since any ectopic
pregnancy that might have been would also be a failing
pregnancy. When TVS yields a non-diagnostic result with
no direct evidence of a normal intrauterine or ectopic preg-
nancy histology of endometrial curetting showing chorionic
villi excludes an ectopic pregnancy. However, absence of
chorionic villi does not always conWrm an ectopic
pregnancy, since chorionic villi will also be absent in
patients with complete spontaneous loss of an intrauterine
pregnancy. If curettage is being performed at the time of
laparoscopy during evaluation of a patient with a suspected
ectopic pregnancy, the patient should be thoroughly coun-
selled regarding the small possibility of losing a very early
viable pregnancy [23].
Treatment of tubal ectopic pregnancy
The options for the treatment of ectopic pregnancy include
surgical, medical and expectant, and to some extent depend
on the presentation. The woman who presents with an acute

123
448
Fig. 4 Figure shows an adnexal mass with a gestational sac seen lying
adjacent to the left ovary on transvaginal ultrasound
Fig. 5 Figure shown a patient with a positive pregnancy test and an
empty uterus with thick endometrium on transvaginal ultrasound
abdomen and in cardiovascular shock warrants concurrent
resuscitation and laparotomy to stem the acute bleeding
from the ruptured ectopic. Here the fallopian tube with the
ectopic pregnancy is excised, haemostasis secured and
blood washed out of the abdomen/pelvis. Fortunately the
vast majority of ectopic pregnancies, at least in the devel-
oped world, present early and the woman are often haemo-
dynamically stable. Modern practice dictates that as many
ectopic pregnancies as possible be treated laparoscopically,
as this approach has signiWcant cost savings to the health
provider with short hospital stay, economic advantages to
the woman who recovers quicker than from a laparotomy
and is able to resume work early, and aesthetic advantages
by the avoidance of a large laparotomy scar. In expert
hands the presence of a haemoperitoneum does not exclude
laparoscopic intervention, provided the patient is haemody-
namically stable. Both at laparotomy and laparoscopy, the
options are salpingectomy or salpingotomy (see below).
Medical and expectant management options are appropriate
in carefully selected cases where the diagnosis of ectopic
pregnancy is made before the rupture.
123
Arch Gynecol Obstet (2009) 279:443–453
Surgical treatment
Salpingectomy (partial or complete excision of the fallo-
pian tube containing the ectopic pregnancy) is usually pre-
ferred when the contra-lateral tube is normal, or in patients
who are at high risk of complications. Other indication for
salpingectomy include severely damaged fallopian tube,
recurrent ectopic pregnancy in the same tube, uncontrolled
bleeding after salpingostomy, large tubal pregnancy (>5 cm),
heterotropic pregnancy or completed family.
Salpingostomy, when a linear incision is made in the fal-
lopian tube above the ectopic pregnancy, and the latter is
Xushed out and haemostasis secured is usually performed
when the contra-lateral tube is abnormal. Using a 22 gauge
needle, a solution of vasopressin is injected into the tube at
the area of maximum distension. This will decrease bleed-
ing from the tube during the procedure and facilitates visi-
bility. A 10–15 mm longitudinal incision is made on the
most distended part of the ante mesosalpinx wall of the tube
with a unipolar needle. The products of conception are
Xushed out of the tube with a high-pressure irrigating solu-
tion. Hydro-dissection more eYciently removes tropho-
blasts compared to attempts at piece meal removal using a
grasping forceps.
Concerns regarding salpingostomy revolve around the
possibility of retained trophoblastic tissue following the
procedure. Two randomised controlled trials have shown
that the risk of persistent trophoblastic tissue is higher with
laparoscopy than laparotomy [24, 25]. However, the risk of
persistence of trophoblastic tissue following laparoscopy
should be balanced against the reduced costs and a trend
towards lower risks of repeat ectopic pregnancy [26, 27]
when compared to laparotomy. In addition, the use of pro-
phylactic MTX decreases the risk of persistence tropho-
blastic tissue, although the number need to treat suggests
that monitoring serum hCG concentrations postoperatively
is a more appropriate approach [28].
One RCT comparing conventional laparotomy to mini
laparotomy showed signiWcantly lower postoperative com-
plications, costs and length of hospital stay in patients who
underwent mini laparotomy [29]. Thus the mini-laparotomy
approach is to be preferred over conventional laparotomy
when laparoscopy is not feasible.
Expectant management of tubal ectopic pregnancy
Although the exact proportion is not known, it is neverthe-
less well known that some tubal ectopic pregnancies
resolve spontaneously, often without any signiWcant symp-
toms. It therefore stands to reason that expectant manage-
ment of ectopic pregnancy is a viable option in selected
cases, such as clinically stable, asymptomatic women with
an ultrasound diagnosis of ectopic pregnancy and a falling
Arch Gynecol Obstet (2009) 279:443–453
serum beta-hCG, with initial levels less than 1,000 mIU/l.
An observational study of 478 women reported a successful
outcome from expectant management in 67% of cases. Low
initial serum beta-hCG levels, rapidly falling beta-hCG lev-
els and lack of an identiWable extra-uterine gestational sac
were predictors of good outcome [30–35]. Women man-
aged expectantly should be followed up with twice weekly
serial beta-hCG and weekly transvaginal scans. A reduction
in the size of the adnexal mass, if one had been seen and a
beta-hCG drop of at least 50% should be observed within
7 days. The beta-hCG should be monitored until levels are
less than 20 mIU/l. Intensive counselling regarding the
importance of compliance with follow-up is mandatory and
the patient should have easy access to the hospital.
Comparing expectant management with systemic MTX
(see below) showed similar success rates in stable women
with small tubal ectopic pregnancy without fetal cardiac
activity [36]. A case cohort study of 442 women showed
comparable fertility outcomes in women with ectopic preg-
nancy managed expectantly and with salpingectomy [37].
Medical management of ectopic pregnancy
Systemic methotrexate (MTX)
MXT is a folic acid analogue that competitively binds to
the enzyme dihydrofolic acid reductase, an enzyme that
converts dihydrofolate to tetrahydrofolate. This binding
prevents the reduction of folate to its active form, tetrahy-
drofolate. Without tetrahydrofolate, DNA synthesis, DNA
repair, and cellular replication are impaired. MTX is rap-
idly cleared from the body by the kidneys, with 90% of an
intravenous dose excreted unchanged within 24 h of injec-
tion.
In the treatment of ectopic pregnancy, MTX can be
administered with either a single-dose or multi-dose proto-
col to patients who are hemodynamically stable, without
signs of rupture of the ectopic pregnancy. Single dose MTX
is given at a dose of 50 mg/m2 of calculated body surface
area. Multi-dose regimen is given as 50 mg/kg of body
weight, alternating daily with 0.1 mg/kg of folinic acid and
a maximum of four doses per treatment cycle (MTX on day
1, 3, 5, 7 followed by 6 days without medication). Although
the single-dose protocol is more convenient for the patient,
with the potential for fewer side eVects, the multi-dose reg-
imen is more eVective in eliminating ectopic pregnancies
[7]. Blood tests prior to treatment testing should include
serum beta-hCG concentration, a full blood count, liver and
renal function tests. DiVerential count, creatinine and liver
enzymes should be monitored during therapy. MTX is con-
tra-indicated in women with hepatic, renal, GI or haemo-
poietic disease. Pre-treatment counselling should include
clear information (preferably written) about the possible
449
need for further treatment and adverse eVects following
treatment. Women should be able to return easily for
assessment at anytime during the follow-up. Further preg-
nancy should be avoided for 3 months after injection of
MTX.
Beta-hCG levels should be monitored serially to ensure
disappearance or resolution of ectopic trophoblastic tissue.
The expected response is a fall in beta-hCG of >15%
between days 4 and 7, in which case beta-hCG is measured
on a weekly basis until levels falls below 15 IU/ml. Resolu-
tion time is usually 35 days but may be delayed up to
109 days, and late rupture is a possibility.
Repeat methotrexate treatments are required
in the following circumstances
– After single dose therapy if the beta-hCG level does
not fall by at least 15% between days 4 and 7. If the
beta-hCG fall is >15% then weekly follow-up with
beta-hCG is instituted until levels falls below 15 IU/ml.
If on follow-up the beta-hCG level declines <15% in
any week, repeat MTX dosing is administered and the
protocol is again restarted at a new day 1. Around 20%
will need more than one treatment [38].
– After multiple dose regimen if the serum beta-hCG at day
14 is more than 40% above the initial value on Day 0.
MTX causes trophoblast cell lysis and can lead to some
intra-peritoneal bleeding at the site of ectopic implantation.
It is common for patients to experience an episode of
increased abdominal pain during medical treatment for an
ectopic pregnancy. Although the true cause of this pain is
unknown, it is likely that the pain results from either a tubal
abortion or tubal stretching from haematoma formation. The
pain is usually self limiting but if it is severe and the patient
is hemodynamically stable at admission, observation with
serial haematocrit may be appropriate. It has been reported
that 56% of ectopic masses will increase after MTX therapy,
and most of these patients remain asymptomatic [39]. These
masses frequently persist for some time and may even per-
sist after the disappearance of beta-hCG. Thus women
treated with MTX (and indeed any tube-sparing, conserva-
tive surgical therapy) should be educated regarding the need
for follow up of beta-hCG until they reach non-pregnant
levels to exclude persistent trophoblastic tissue. It should be
explained that ectopic pregnancy rupture and intra perito-
neal bleeding after MTX treatment can occur even with fall-
ing beta-hCG levels, and women should be encouraged to
report any side eVects or unusual symptoms, especially
fever, stomatitis, nausea and vomiting. They should also
avoid alcohol, folic acid supplements, NSAIDs, excessive
sun exposure, and also intercourse until conWrmation that
the ectopic pregnancy has resolved.
123
450
Predictors of successful outcome following MXT ther-
apy were a low initial hCG level [40, 41], low levels of ini-
tial progesterone, and the absence of ectopic cardiac
activity [42, 43]. Success was less likely if cardiac activity
was noticed in the ectopic mass or if the initial beta-hCG
levels were high. Ectopic size, hematoma volume and the
presence of free peritoneal blood conWned to the pelvis did
not have any inXuence on the success or otherwise of treat-
ment. Despite lack of evidence showing the inXuence of the
size of the ectopic pregnancy on treatment outcome, never-
theless recommendations for the upper limit for the size of
the sac are 4 cm if cardiac activity is absent or 3.5 cm if
cardiac activity is present [44].
Single-dose MXT therapy has been compared to laparo-
scopic salpingostomy in four studies: MXT was signiW-
cantly less successful in the elimination of tubal ectopic
pregnancy. This was due to inadequately declining serum
hCG for which additional MTX injections were required
[45–47]. On the other hand, the multiple-dose intramuscu-
lar MXT regimen showed similar success rate and compli-
cation rates when compared to laparoscopic salpingostomy
[48]. No diVerences were found in rates of spontaneous
intrauterine pregnancy rate and repeat ectopic pregnancy
rate when compared to salpingostomy [49], tubal patency
rates and future fertility between MTX therapy and salpin-
gostomy [45–47].
Direct local injection of MXT
Injection of a chemo-therapeutic medication directly into
the ectopic pregnancy has theoretical advantages that
include limiting systemic toxicity, achieving higher and
more prolonged therapeutic levels at the site of the ectopic,
and being able to ascertain the immediate cessation of fetal
heart activity, if present. Added advantages would be the
rare situation of heterotopic pregnancy, where it is critical
to avoid systemic exposure to MTX. In women with contra-
indications to MXT, such as in immunocompromised
patients, women who are breast-feeding, or have blood dys-
crasia, active pulmonary disease and peptic ulcer, other
agents such as potassium chloride or hyperosomolar (50%)
glucose are better options that can be injected directly.
Depending on the size of the sac and embryo, aspiration
of Xuid may be performed and the injection introduced into
the sac or directly into the fetus. Aspiration of the sac Xuid
may help to disrupt the gestation as well as to minimize the
risk of distension and tubal rupture with the subsequent
instillation of the chemotherapeutic agent. If there appears
to be leakage of the chemotherapeutic agent into the perito-
neal cavity, warm Ringer’s Lactate solution can be instilled
to dilute the chemotherapeutic agent and minimize any per-
itoneal reaction, possible pain and/or adhesion formation.
Fluid may also be aspirated to assess for intra-abdominal
123
Arch Gynecol Obstet (2009) 279:443–453
bleeding. Patient follow-up is similar to systemic single
dose MTX treatment.
Injection of the agent locally by laparoscopy permits
direct visualization of the pelvis compared with ultrasound.
This allows deWnitive exclusion of rupture, correlation of
size and location with sonography Wndings and, infre-
quently, visualization of very early pregnancies that may
not be seen on ultrasound. An intra-operative decision can
be made based on the anatomy. A severely damaged tube
may be better treated via salpingectomy. If the decision is
made to spare the tube, local chemotherapeutic injection
may be technically easier than a salpingostomy. One major
drawback is the more invasive approach of laparoscopy,
with its associated risks and delayed recovery when com-
pared to ultrasound. The treatment success of 100 mg MTX
administered transvaginal under ultrasound guidance was
signiWcantly better than blind intra-tubal injection of
100 mg of MTX under laparoscopic guidance [50]. The
ability to aspirate sac Xuid and inject the medication accu-
rately into the sac may be limited compared with a TVS
approach, and the medication may be delivered inadver-
tently into the pregnancy-induced hematoma or otherwise
miss the ectopic. There are no signiWcant diVerences in pri-
mary treatment success, subsequent intrauterine pregnan-
cies and repeat ectopic pregnancies when MTX is given
systemically or transvaginal under sonography guidance
[51, 52].
Hysteroscopic injection may be feasible in cornual preg-
nancy and interstitial pregnancies. It may be diYcult in dis-
tal interstitial or isthmic pregnancies [53]. The visualization
might be limited by the presence of blood in the uterine
cavity and the pressure generated by the distension media
might lead to rupture of a cornual ectopic pregnancy.
Other medical agents in the management of ectopic
pregnancy
Other agents like dactinomycin, prostaglandins and RU 486
have been administered by oral, intramuscular or intrave-
nous routes, data on their safety and eYcacy is still limited.
They should therefore be restricted to experimental use.
Outcomes following treatment for ectopic pregnancy
Follow-up
Following treatment for ectopic pregnancy where an
aVected fallopian tube is conserved (usually because the
contra-lateral tube showed signs of damage, or following
treatment with MXT), especially if the woman wishes to
conceive, tubal patency testing by hysterosalpingography is
indicated. Early (5–7 weeks gestation) TVS in every future
pregnancies should be advised. This will increase the
Arch Gynecol Obstet (2009) 279:443–453
chance of early diagnosis of an unruptured ectopic preg-
nancy, and therefore the treatment interventions described
in the preceding sections of this review.
Risk of recurrence of ectopic pregnancy
The recurrence rates of ectopic pregnancies are not known,
but it is reasonable to suppose that they are highly dependent
upon the risk factors for ectopic pregnancy. The rates have
been variably reported in the literature, some authors quoting
rates as high as 33% [54]. Follow-up studies have shown
cumulative ectopic pregnancy rate of 14–15% [55, 56] after
1 year and 23–30% after 2 years [55]. The impact of treat-
ment choice on recurrence risk is not known. Hence concern
for risk of recurrence should not be considered when selecting
between any treatment modality for ectopic pregnancy [57].
Reproductive performance after ectopic pregnancy
Women undergoing treatment for unruptured ectopic preg-
nancy are concerned about future child bearing. It would
therefore seem reasonable to consider reproductive perfor-
mance as an important variable in treatment selection.
However, a comparison of four treatments (laparoscopic
salpingostomy, multiple-dose MTX, single dose MTX and
expectant management) found that although expectant
management was associated with inferior rates of resolu-
tion of trophoblastic tissue compared to the other three
treatments, there was no diVerence in reproductive perfor-
mance among all the treatments.
Four cohort studies have examined reproductive outcomes
in women with contra-lateral disease and show a trend
toward a greater subsequent intrauterine pregnancy following
laparoscopic salpingostomy compared with laparoscopic
salpingectomy [58–61]. As a consequence salpingostomy
of ectopic pregnancy by laparotomy or laparoscopy in
the presence of contra-lateral fallopian tube pathology has
become the recommended treatment. In women with a
damaged or absent contra-lateral tube, in vitro fertilisation
is likely to be required if salpingectomy is performed. The
pregnancy rate of 3% would make salpingotomy a cost
eVective treatment compared to salpingectomy. It may not
always be possible to do a salpingostomy even when the
contra-lateral tube is abnormal. In cases of a badly ruptured
or a large ectopic pregnancy it may be safer to perform a
salpingectomy rather than a salpingostomy.
Contraception after ectopic pregnancy
The levonorgestrel IUS is highly eVective but if it fails in
situ, there is a risk of about 1 in 20 of these pregnancies
being ectopic. However, it should be remembered that this
risk is far lower in IUS users than in women using no
451
contraceptive method (when the incidence is 1.4 per 100
women). Overall, it is estimated that the incidence of
ectopic pregnancy in IUS users is about 1 in 1,000 over a
5-year period. Recent guidance has also supported the use
of the IUS in women who have previously suVered an
ectopic pregnancy, because using such a highly eVective
contraceptive will reduce their future absolute risk.
Prospects for reducing the rates of ectopic pregnancy
The risk of ectopic pregnancy can be decreased by prevent-
ing fallopian tube damage occurring due to pelvic infection
and surgical trauma. A signiWcantly high number of
patients with ectopic pregnancy are Chlamydia titre posi-
tive [62, 63] and an observational study of 2,233 patients
showed ectopic pregnancy rates mirroring Chlamydia
infection rates in a Swedish population [64]. A mathemati-
cal model evaluating the beneWt of Chlamydia screening
showed a reduction in the incidence of ectopic pregnancy
with screening for both men and women [65]. Chlamydia
infections are asymptomatic and if untreated lead to PID in
40% of women. Annual routine Chlamydia screening for all
women under the age of 25 and encouraging women to
avoid at risk behaviour, such as unprotected intercourse and
multiple sexual partners decreases the incidence of ectopic
pregnancy.
Tubal surgery, such as occlusion (sterilization) or previ-
ous ectopic pregnancy increases the risk of ectopic preg-
nancy, as does prior pelvic surgery [66]. Ten percent of all
ectopic pregnancies occur after tubal sterilization. It is
thought that these result from the development of a tubo-
peritoneal Wstula in the proximal stump, allowing sperm to
enter the peritoneal cavity and fertilize the ovum. Hence
placement of clips or such sterilizing devices should avoid
the very proximal portions of the fallopian tubes where
Wstula formation is common. The frequency of tubal
implantation when previous tubal sterilization fails varies
but an NIH sponsored collaborative review of over 10,000
sterilizations yielded an overall rate of 7.3 per 1,000 proce-
dures [67]. The risk varied with the technique used. The
highest risk of tubal pregnancy occurred following previous
tubal bipolar cautery before the age of 30 [68]. All this
informs potential approaches to minimising the risk of
ectopic pregnancy associated with sterilisation.
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