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Ectopic pregnancy: A review

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Ectopic pregnancy: a review

Poonam Rana, Imran Kazmi, Rajbala

Singh, Muhammad Afzal, Fahad A. Al-
Abbasi, Ali Aseeri, Rajbir Singh,
Ruqaiyah Khan & Firoz Anwar
Archives of Gynecology and
Obstetrics

ISSN 0932-0067
Volume 288
Number 4

Arch Gynecol Obstet (2013)

288:747-757
DOI 10.1007/s00404-013-2929-2

1 23
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 Author's personal copy
Arch Gynecol Obstet (2013) 288:747–757
DOI 10.1007/s00404-013-2929-2

REPRODUCTIVE MEDICINE

Ectopic pregnancy: a review

Poonam Rana • Imran Kazmi • Rajbala Singh •
Muhammad Afzal • Fahad A. Al-Abbasi • Ali Aseeri •

Rajbir Singh • Ruqaiyah Khan • Firoz Anwar

Received: 24 December 2012 / Accepted: 22 May 2013 / Published online: 21 June 2013
Ó Springer-Verlag Berlin Heidelberg 2013

Abstract laparotomy or laparoscopy, medical treatment is usually

Purpose Ectopic pregnancy (EP) presents a major health systemic or through local route, or by expectant treatment.
problem for women of child-bearing age. EP refers to the Results It was concluded that review data reflect a
pregnancy occurring outside the uterine cavity that con- decrease in surgical treatment and not an actual decline in
stitutes 1.2–1.4 % of all reported pregnancies. All identi- EP occurrence so that further new avenues are needed to
fied risk factors are maternal: pelvic inflammatory disease, explore early detection of the EP.
Chlamydia trachomatis infection, smoking, tubal surgery,
induced conception cycle, and endometriosis. These Keywords b-hCG
TVS
Methotrexate
Laparotomy
developments have provided the atmosphere for trials
using methotrexate as a non-surgical treatment for EP. The Abbreviations
diagnosis measure of EP is serum human chorionic gona- EP Ectopic pregnancy
dotropin, urinary hCGRP/i-hCG, progesterone measure- CEP Cervical ectopic pregnancy
ment, transvaginal ultrasound scan, computed tomography, OEP Ovarian ectopic pregnancy
vascular endothelial growth factor, CK, disintegrin and CSEP Cesarean scar ectopic pregnancy
metalloprotease-12 and hysterosalpingography. The treat- IP Interstitial pregnancy
ment option of EP involves surgical treatment by PID Pelvic inflammatory disease
PROKR Prokineticin receptor
IVF In vitro fertilization
P. Rana
I. Kazmi
R. Singh (&)
M. Afzal (&)
R. Khan
ART Assisted reproductive technology
F. Anwar (&) b-hCG Serum human chorionic gonadotropin
Siddhartha Institute of Pharmacy, Dehradun 248001,
TVS Transvaginal ultrasound scan
Uttarakhand, India
e-mail: singhrajbala44@gmail.com CT Computed tomography
VEGF Vascular endothelial growth factor
M. Afzal
e-mail: afzalgufran@gmail.com ADAM-12 Disintegrin and metalloprotease-12
Hsg Hysterosalpingography
F. Anwar
e-mail: firoz_anwar2000@yahoo.com MTX Methotrexate
PPV Positive predictive value
F. A. Al-Abbasi
Department of Biochemistry, Faculty of Science,
King Abdulaziz University, Jeddah, Saudi Arabia

A. Aseeri Introduction
Lab Director, Jeddah Eye Hospital, Ministry of Health,
Jeddah, Saudi Arabia
Ectopic pregnancy (EP) or extra uterine pregnancy,
R. Singh accepted from the Greek word ‘‘ektopos’’ meaning out of
Alchemist Hospital, Panchkula, Haryana, India place [1], refers to the blastocyst implantation outside the

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748
uterine cavity endometrium with over 95.5 % implanting in
the fallopian tube [2–6]; where fetus or embryo is often
absent or stops growing. The other most common
implantation sites are ovarian (3.2 %) and abdominal
(1.3 %) sites [7]. This is a major track and significant cause
of morbidity and mortality with associated risks of tubal
rupture and intra abdominal hemorrhage in women and can
lead to substantial future reproductive morbidity, including
subsequent ectopic pregnancy and infertility [8–12].
Hence, it is a medical emergency that requires immediate
treatment [13].
The annual incidence of EP has increased over the past
30 years [14]. In the western world 4–10 % of pregnancy-
related deaths have been observed [15, 16], from this issue
and now it is a growing problem in developing countries
also [17]. Although advances in diagnostic methods have
allowed for earlier diagnosis, it still remains a life threat-
ening condition. Approximately, 75 % of deaths in the first
trimester and 9 % of all pregnancy-related deaths are due
to EP [12].
Around 10,000 EP are diagnosed annually in the UK.
The incidence of EP in the UK (11.1/1,000 pregnancies) is
similar to that in other countries, such as Norway (14.9/
1,000) and Australia (16.2/1,000) [18–20] from 1994, the
overall rate of EP and resulting mortality (0.35/1,000 EP in
2003–2005) has been static in the UK [20]. A French
population study undertaken from 1992 to 2002 found that,
over the duration of the study, the rate of reproductive
failure EP increased by 17 %. Haifa et al. studied that there
is an increasing trend in terms of EP in the eastern coun-
tries like Saudi Arabia [21]. Calderon et al. [22] reported an
EP rate in California of 11.2 per 1,000 pregnancies during
1991–2000; Sewell and Cundiff [23] noted a rate in
Maryland of 5.2 per 10,000 women aged 15–44 years
between 1994 and 1999 (Fig. 1).
Types of ectopic pregnancy
The fallopian tube is the dominant site [24] in the majority
of cases of tubal ectopic pregnancy. 75–80 % of EPs occur
in the ampullary portion, 10–15 % of EPs occur in the
isthmic portion and about 5 % of EP is in the fimbrial end
of the fallopian tube [25]. The tubal EP can be detected by
TVS, and implies an intact fallopian tube with a pregnancy
that is likely to be growing and visualized of an inhomo-
geneous mass that might well be a collapsed sac, which is
less likely to contain active trophoblastic tissue [26].
Cervical ectopic pregnancy (CEP) is rare and represents
only 0.15 % of all EP [27]. A cervical pregnancy before
1979 was almost always associated with hysterectomy for
uncontrollable vaginal bleeding, and this made women
sterile [28, 29]. It can be diagnosed by ultra sonography
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Arch Gynecol Obstet (2013) 288:747–757
according to the criteria described by Hofmann and Timor-
Tritsch. In true CEP, Doppler studies show characteristic
patterns of trophoblast with high flow velocity and low
impedance [30, 31].
Ovarian ectopic pregnancy (OEP) is one of the rarest
variants, and incidence is estimated to be 0.15–3 % of all
diagnosed OEP [32, 33]. Early diagnosis is necessary to
avoid more serious complications and emergency invasive
procedures [34]; moreover, Panda et al. [35] said that its
preoperative diagnosis remains a challenge, and it cannot
be early diagnosed. Medical therapy with MTX was not a
possible option due to the occurrence of massive bleeding.
In general, in case of hemoperitoneum most surgeons
prefer to perform laparotomy. Few cases of laparoscopic
treatment in women with hemoperitoneum have been
reported by various researchers [36].
Cesarean scar ectopic pregnancy (CSEP) is another
rarest form of EP with an incidence of 1:1,800 pregnancies
[37] due to increased number of cesarean deliveries over
the last 30 years [38]. It is widely spreading in society.
Here, the gestational sac is implanted in the myometrium at
the site of a previous cesarean section. Various complica-
tions, such as uterine rupture and massive hemorrhage,
may be life threatening and impact negatively on future
fertility in case of CSEP [38]. The etiology of cesarean scar
pregnancy is unclear although previous cesarean section,
myomectomy, adenomyosis, IVF, previous dilatation and
curettage, along with manual removal of placenta have
been linked as risk factors for such type of EP [39–41].
Interstitial pregnancy (IP) constitutes 2.5 % of all EP [2].
Correct diagnosis of IP can be quite difficult and it requires
accurate ultrasound interpretation. The diagnosis relies
heavily on ultrasound and potentially on laparoscopic
evaluation [42]. It is performed by visualization of the
interstitial line adjoining the gestational sac and the lateral
aspect of the uterine cavity followed by continuation of the
myometrial mantle around the ectopic sac [30]. A true
cornual ectopic pregnancy is one in the rudimentary horn of
a unicornuate uterus. It is one of the insolites, form of EP at
0.27 % of imports [43]. This term is often used in the
medical literature with interstitial EP [44, 45]. The tradi-
tional treatment of interstitial pregnancy has been cornual
resection or hysterectomy in cases of severely damaged
uterus [42]. However, there are successful case reports of
laparoscopic resection of cornual pregnancies [46]. Lapa-
roscopic excision is safe but attention needs to be paid to the
possibility of urinary tract anomalies which may be asso-
ciated with unicornuate uteri [47]. Advanced cases in the
second and third trimester, where the risk of rupture is high,
requires an open approach to excision at laparotomy [48].
Abdominal ectopic pregnancy with 1.3 % of cases [2] is
diagnosed at a rate of 1:10,000 births and is an extremely
rare and serious form of extrauterine gestation [49]. It is
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Arch Gynecol Obstet (2013) 288:747–757 749

Fig. 1 Summary of ectopic

pregnancy (EP)
Tubal EP (90-95%) Expectant treatment
PREGNANCY
Cervical EP (0.15%) Medical treatment (systemic or local
(EP)
Ovarian EP (0.15%-3%) route)

Caesarean scar EP (6%) Surgical treatment (laparotomy or

Interstitial EP (2.5%) laparoscopy)

Abdominal EP (1.3%)

Heterotopic EP (1-3%) Serum β-human chorionic gonadotropin (b-

hCG) test

Urinary hCGRP/i-hCG ratio

Light vaginal bleeding
Progesterone measurement
Pelvic inflammatory disease Nausea and Vomiting
(PID) Transvaginal ultrasonography (TVS)

Computed Tomography (CT) or MRI Lower abdominal pain

Age

Cigarette smoking Vascular Endothelial Growth Factor Sharp abdominal cramps

History of ART and IVF
Previous history of EP
Contraception pills
(VEGF)
Pain on one side of the body
Creatine kinase (CK)
Dizziness or weakness
Disintegrin and Metalloprotease-12
(ADAM-12)
Pain in the shoulder, neck, rectum
Hysterosalpingography (Hsg)

described as primary or secondary abdominal ectopic

pregnancy and usually results from an implantation fol-
lowing tubal rupture or abortion through the fimbricated
end of the fallopian tube. The fetus continues to grow
following attachment to an abdominal structure, using its
blood source, which may be extensive. It usually attaches
to the surface of the uterus, broad ligaments, or ovaries, but
may also attach to the liver, spleen, or intestines [24, 50].
The traditional management involves a laparotomy with
removal of the fetus with or without placental tissue [51].
One of the problems associated with the removal of
abdominal pregnancies after the first trimester is that the
risk of uncontrolled bleeding from the placental bed [52].
A heterotopic ectopic pregnancy is diagnosed when
women have any of the above said EP in conjunction with
an intra uterine pregnancy. It occurs with a rate \1:30,000
naturally occurring pregnancies, and 1:100 couples who
conceive through assisted reproduction [53]. It is also more
common (1–3 %) in in vitro fertilization and fertility
treatments involve superovulatory drugs [54, 55]. A high-
resolution transvaginal ultrasound with color Doppler will
be helpful to locate the trophoblastic tissue in the adnexa in
a case of heterotopic EP [56]. Different sites for ectopic
pregnancy are depicted in Fig. 2.
Fig. 2 Different site for ectopic pregnancy
Risk factor
women who have been infected are unaware of the expo-
EP is further common in women who have suffered with sure of PID [57]. Moreover, it is due to difficulties in
pelvic inflammatory disease (PID) and more than 50 % of determining the effect of female genital chlamydial

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infection on reproductive outcome arise from flaws in
specific study design and the lack of a reliable method for
measuring a history of pelvic infection [58]. Current
assumptions on the risks of subsequent pregnancy prob-
lems, following pelvic infection, are based on retrospective
case control studies, the incidence of tubal damage
increases after successive episodes of PID (i.e., 13 % after
1 episode, 35 % after 2, and 75 % after 3 episodes) [57,
59–62]. It has been proposed that an antibody response to
the chlamydial heat shock protein (hsp-60) may cause a
tubal inflammatory response leading to tubal blockage or a
predisposition to tubal implantation [63]. Repeated infec-
tions with C. trachomatis are thought to increase tubal
damage [64].
Age is the risk of EP increases with advancing maternal
age, with age over 35 years being a significant risk factor
[12]. Hypotheses for this association include the higher
probability of exposure to most other risk factors with
advancing age, increase in chromosomal abnormalities in
trophoblastic tissue and age-related changes in tubal
function delaying ovum transport, resulting in tubal
implantation [65]. The incidence of EP showed a steady
increase with the increase in maternal age at conception
from 1.4 % of all pregnancies at the age of 21 years to
6.9 % of pregnancies in women aged 44 years or more
[66, 67].
Cigarette smoking is the major cause of one-third of all
cases of EP [68]. Most studies investigating the effect of
smoke on the fallopian tube have been performed in
rodents and relate to cigarette smoke’s effect on ciliary
beat frequency and smooth muscle contraction [69–71].
Furthermore, the reason why smoking cause tubal ectopic
pregnancy is not understood [71]. Tubal EP is thought to be
a consequence of embryo retention within the fallopian
tube due to impaired smooth muscle contractility and
alterations in the tubal microenvironment. The cigarette
smoking increases transcription of prokineticin receptor 1
(PROKR1), a G-protein-coupled receptor [65]. The PRO-
KRs are receptors for PROK1, a molecule known for its
angiogenic properties, control of smooth muscle contrac-
tility, and regulation of genes important for intrauterine
implantation [72, 73]. Both PROKR1 and PROKR2
expression are altered in fallopian tube from women with
EP, where implantation has already occurred [65].
EP is more common in women attending infertility
clinics even in the absence of tubal disease. In addition, the
use of assisted reproductive technology (ART) increases
the rate of EP [74]. The rate of tubal EP following in vitro
fertilization (IVF) still remains higher (approximately
2–5 %) than the rate of tubal EP with spontaneous preg-
nancy (1–2 %) [12, 75]. The reason for the increased
incidence of tubal EP by IVF is unclear. The technique of
embryo transfer is a potential cause but there is little
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Arch Gynecol Obstet (2013) 288:747–757
evidence to support this. The risk of tubal EP has also been
reported to increase with the number of embryos that are
transferred during IVF treatment [76].
Women with a previous history of EP also have an
increased risk, which increases further in proportion to the
number of previous EP. In Shaw et al.’s [5] study, the OR
for having an EP was 12.5 % after one previous EP and
76.6 % after two. Prior tubal surgery (salpingostomy,
neosalpingostomy, fimbrioplasty, tubal reanastomosis, and
lysis of peritubal or periovarian adhesions) has an
increased risk for developing EP. This in turn depends on
the degree of damage and the extent of anatomic
alteration [57].
Some types of contraception, such as progestogen only
contraception and the intrauterine contraceptive device are
associated with an increased incidence of EP when there is
contraceptive failure, without necessarily increasing the
absolute risk of EP [77]. According to Patil et al. [57], case
control examination of the risk of the EP has been linked
with the fourfold elevation after OI with clomiphene citrate
or injectable gonadotrophins therapy.
Diagnosis
Previously EP was diagnosed on clinical symptoms such as
vaginal bleeding and lower abdominal pain but it imposed
severe constraints on early detection [78]. Initial diagnosis
of first-trimester hemorrhage presents an important chal-
lenge [79]. Recently, detection of EP is determined through
serum human chorionic gonadotropin (b-hCG) levels and
vaginal ultrasonography techniques [79–82].
Urinary hCGRP/i-hCG ratio measurement may be
effective in the diagnosis of EP [83] as a single serum
measurement of the b-hCG concentration may not show
the location of the gestational sac [84, 85]. Demonstration
of normal doubling of serum levels over 48 h supports a
diagnosis of fetal viability but does not rule out EP. Failing
levels on raising the level of b-hCG concentration to reach
50 % confirm non-viability suggesting EP [86, 87].
Progesterone measurement of the serum concentration
of progesterone has been deciphered as a potential useful
adjunct to serum b-hCG measurement. In contrast with
b-hCG concentrations, serum progesterone levels are stable
for first 8–10 weeks of gestation [5, 88]. Mol et al. [89]
investigated that sensitivity ranged of progesterone from 44
to 100 %, depending on the threshold. Both high ([22
ng/ml) and low (B5 ng/ml) cutoff points have been
assessed for their ability to correctly identify non-viable
and ectopic pregnancies; serum progesterone levels
B5 ng/ml could apparently be used to predict EP with
70–90 % sensitivity and 30–99 % specificity [90, 91].
Elson et al. [92] reported that if patients have serum pro-
gesterone measurements below 10 ng/ml (31.8 nmol/L)
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Arch Gynecol Obstet (2013) 288:747–757
and b-hCG levels below 1,500 mIU/L are more likely to
demonstrate spontaneous resolution of EP.
Transvaginal ultrasound scan (TVS) is very popular
from 1980, and by the mid 1990 sensitivity and specificity
were calculated at 84.4 and 98.9 %, respectively. It
remains the gold standard for diagnosis of EP [30, 93]. A
b-hCG level that has elevated above the detestable
threshold in the absence of sonographic signs of early
pregnancy is considered concomitant conformation of an
EP. With the evolution in ultrasound technology, the
detestable threshold has dropped from 6,500 IU/L with a
transabdominal approach to between 1,000 and 2,000 IU/L
with transvaginal imaging [94]. The spectrum of sono-
graphic findings in EP is broad. Identification of an extra-
uterine gestational sac containing a yolk sac (with or
without an embryo) confirms the diagnosis for EP [95].
Pregnant women generally do not undergo computed
tomography (CT) and MRI examination, due to radiation
but should be ruled out in all young women complaining of
the abdominal pain. CT findings of the ruptured EP are
sporadic and extremely rare. In emergency situations, the
role of CT imaging of the abdominal and pelvic cavity has
been evaluated: it remains the first-line treatment in such
situations, [96–98]. Usually, CT diagnosis is reported in the
context of suspected cases when the patient is extremely
unstable. The CT scans clearly identified the site of
bleeding and helped to differentiate and characterize other
various causes of acute abdominal pain [98, 99]. Some-
times, an MRI can be helpful as well; moreover, this is not
a first-line examination. It is rather used for a better pre-
operative planning, or as a problem-solving tool in preg-
nant patients, or for imaging of fetal anatomy and
pathology [100, 101].
Vascular endothelial growth factor (VEGF) is a potent
angiogenic factor that acts as a modulator of vascular
growth, remodeling, and permeability in the endometrium,
decidua, and trophoblast, as well as during vascular
development in the embryo, all of which are crucial pro-
cesses related to normal implantation and placentation
[102]. Serum values of VEGF were significantly increased
in EP. Daponte et al. [79] described higher serum VEGF
concentrations in women with EP (median 227.2 pg/ml)
than with abnormal intrauterine pregnancy (median
107.2 pg/ml) (p \ 0.001) and it concluded that VEGF
serum concentrations might be a useful marker for EP, and
suggested 174 pg/ml as the cut-off value for EP diagnosis.
On the other hand, some groups have found conflicting
results on whether serum measurement of VEGF could be
used for differentiation of EP [81, 103].
Existing evidence suggests elevated creatine kinase
(CK) as a tool for diagnosis of EP. The trophoblast usually
invades the muscle layer and maternal blood vessels are
eroded, allowing muscle cell products such as CK to enter
751
the circulation [104]; therefore, increased serum CK levels
are normal during EP [104, 105]. Saha et al. [105] per-
formed a study comprising 40 women; total serum CK
levels were found to be significantly higher in the EP group
as compared to the controls (p \ 0.001), suggesting that
this test might be used as a indicator for EP. Similarly,
Katsikis et al. [106] studied 40 women with EP; and con-
cluded that women with EP had significantly higher CK
concentrations compared to women with intrauterine
abortive pregnancies and controls, suggesting that CK
concentrations could be used to predict EP.
Disintegrin and metalloprotease-12 (ADAM-12), a
proteomics evaluation of serum from women with EP, is
diagnosed with the presence of latter has both novel
marker disintegrin and metalloprotease-12. It has both an
adhesion and protease domain, plays a role in myoblast
fusion [107] as well as giant cell macrophage and osteo-
clast formation in bone [108]. In humans, ADAM-12 is
expressed in placenta, and potently provokes myogenesis.
In first-trimester placentas, it is localized to the cyto-
trophoblasts as well as the apical side of the synctio-
trophoblasts and to play a role in syncytial fusion in the
trophoblast [109]. If ADAM-12 is involved in the normal
implantation of pregnancy, and decreased levels are a
harbinger of an abnormal pregnancy or the abnormal
implantation of pregnancy, then decreased levels in ecto-
pic pregnancy may be biologically plausible; the ADAM-
12 test would be more sensitive in the group of EP with
lower b-hCG levels [110–112].
Hysterosalpingography (Hsg) is the radiographic eval-
uation of the uterine cavity and fallopian tubes after the
administration of a radio opaque medium through the
cervical canal. The Hsg was first practiced in 1910 and was
considered to be the special radiologic procedure. A
properly performed Hsg can decipher the contour of the
uterine cavity and the width of the cervical canal. Further
contrast medium injection will outline the cornua isthmic
and ampullary portions of the tubes and will show the
degree of spillage [113, 114]. There is a high probability
that tubal obstruction really exist because of high speci-
ficity of Hsg, while the observation of tubal permeability
shown after the examination does not exclude tubal
pathology, since it does not assess its function. In addition,
Hsg is a safe and inexpensive procedure [115, 116]; being
the most cost effective method in the study of the fallopian
tubes EP [117].
Medical management
The treatment option of EP involves surgical treatment by
laparotomy or laparoscopy, and medical treatment is usu-
ally systemic or through local route, or by expectant
treatment [118, 119].
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Expectant treatment
Expectant treatment can be applied in a selected subset of
patients with self-limiting ectopic pregnancy; the propor-
tion over treated must be accepted until a marker that
identifies this subgroup of patients is found [120, 121].
Studies evaluating expectant management of ectopic
pregnancy are primarily based on this concept of tropho-
blast in regression, and therefore exposed to the uncer-
tainties of definite primary EP which are diagnosis [122].
According to the most recent guideline, published by the
American College of Obstetricians and Gynecologists,
there may be a role for expectant management when the
b-hCG level is \200 mIU/ml and which is further in
decline phase. It should only be offered when TVS remains
non-diagnostic and b-hCG levels continue to decline.
Tubal rupture has occurred with low or declining b-hCG
levels. However, almost all EPs resolve spontaneously
when the b-hCG level reaches 15 mIU/ml [123, 124].
Another multivariate analysis has shown that the favorable
prognostic signs for successful expectant management of
ectopic pregnancy are the following—absent or minimal
clinical symptoms with no evidence of haemodynamic
compromise: evidence of ectopic resolution by declining
b-hCG levels preceding expectant treatment can be used
for such dilation; low initial serum b-hCG: successful
expectant management occurs in 98 % of cases for hCG
\200 IU/L, in 73 % for b-hCG\500 IU/L and in 25 % for
b-hCG \2,000 IU/L. Overall, if initial serum b-hCG
\1,000 IU/L then successful expectant management might
occur in most patients (88 %) with an ectopic pregnancy
size of \4 cm, without a fetal heart beat on transvaginal
sonography; followed by haemoperitoneum \50 ml. Evi-
dence of ectopic resolution on scan is another way to
diagnosis. A decrease in ectopic pregnancy size on day 7
had a sensitivity of 84 % and specificity of 100 % in pre-
dicting spontaneous resolution [122].
Medical treatment
Medical treatment of EP is quite less expensive than sur-
gery [125]. Many different agents have been used to treat
ectopic pregnancies including systemic and local metho-
trexate (MTX), local potassium chloride, hyperosmolar
glucose, prostaglandins, danazol, etoposide, and mifepri-
stone (RU486) [126–128]. Current therapies focus pri-
marily on MTX treatments. A better understanding of the
pathogenesis of the disease could avoid the risk in women
by providing better prediction and prevention [9, 65]. MTX
was first used in diagnosed EP in the 1960 to aide safe
surgical removal of the placenta from its abdominal
implantation sites in second and third trimester cases [129].
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Arch Gynecol Obstet (2013) 288:747–757
Patients treated with MTX should be monitored closely
because as mentioned earlier, it causes severe abdominal
pain and side effect too. The serum b-hCG concentration
should be measured weekly. If the serum b-hCG concen-
tration has not declined by at least 25 % in first week after
MTX administration, a second dose should be given which
is only required 15–20 % of patients [6]. Two common
regimens are available for MTX, multidose (MTX 1.0 mg/kg
i.m daily; days 0, 2, 4, and 6 alternated with folinic acid
0.1 mg/kg orally on days 1, 3, 5, 7) and single dose (MTX
0.4 to 1.0 mg/kg or 50 mg/m2 i.m. without folinic acid)
[129]. The multidose regimen alternates an every other day
dose of intramuscular MTX 1.0 mg/kg with an every other
day dose of intramuscular leucovorin calcium 0.1 mg/kg, a
folic acid antagonist antidote, up to four doses of each until
the b-hCG level decreases by 15 % on two consecutive
days. The single-dose regimen is an intramuscular injection
of MTX, 50 mg/m2, based on the patient’s body surface,
and does not include leucovorin rescue. If b-hCG levels do
not decline by 15 % on days 4 and 7 after treatment, a
second dose of MTX may be given after 1 week. About
20 % of women will need a second treatment cycle [130–
133]. Many side-effects associated with MTX treatment are
nausea and vomiting, stomatitis, diarrhea, abdominal dis-
comfort, pneumonitis, photosensitivity skin reaction,
impaired liver function, reversible, severe neutropenia
(rare), reversible alopecia (rare) [122].
Gabbur et al. reported that on its retrospective analysis
of stable women with small unruptured EP treated with
single-dose intramuscular MTX concluded that day 4 post
treatment b-hCG levels do not predict successful treatment
or need for surgery. Only day 7 b-hCG levels were asso-
ciated with successful single-dose MTX treatment [134].
Barnhart et al. [135] investigated in their meta-analysis
of both regimens (multi dose and single dose) and con-
cluded that the multi-dose regimen was more effective than
the single-dose regimen, with success rate reported as 93 %
for the multi-dose regimen and 88 % for the single-dose
regimen.
Kirk et al. evaluated that the TVS is a non-surgical
workup logarithm of patients with suspected EP. From
1993, a monitoring protocol has been developed based on
serial serum b-hCG taken evaluated on day 1, 4, 7, and
weekly until resolution. Efficacy of treatment is determined
when there is a C15 % fall in serum b-hCG between days 4
and 7. This definition of treatment success has a positive
predictive value (PPV) of 93 %, with a sensitivity of 93 %
and a specificity of 84.2 % [136].
Barnhart et al. was attempted by the challenge to
develop an optimum regimen that balances efficacy and
safety on the one hand and convenience on the other hand,
and he first described what is called the ‘‘double-dose
protocol’’. In a study that included 101 patients, two doses
 Author's personal copy
Arch Gynecol Obstet (2013) 288:747–757
of MTX were administered on days 0 and 4 without
measuring b-hCG between doses. The authors reported a
success rate of 76 % after two doses and 87 % after a
further two doses [137].
Hossam et al. found that the double-dose protocol was
an efficient and safe alternative to the single-dose regimen.
It has the advantage of a shorter follow-up duration that
improves patient compliance, treatment satisfaction, and
costs [138].
Surgical treatment
Surgical treatment is the preferred treatment for EP when
there is rupture, hypotension, anemia, diameter of the
gestational sac greater than 4 cm on ultrasonography, or
pain persisting beyond 24 h [139]. In America, the first
abdominal surgery for EP was performed in 1759 by John
Bard, and became increasingly attempted in the nineteenth
century. Robert Lawson Tait, an eminent British surgeon,
described treatment of ruptured EP by ligating bleeding
vessels at laparotomy in 1884. This was a major
advancement in development of effective surgical man-
agement of this condition [140]. Surgical treatment of EP
should be reserved for those patients who have contrain-
dications to medical treatment or to whom medical treat-
ment has failed and those who are hemodynamically
unstable. Two techniques are described to remove the EP
from the fallopian tube—(1) salpingectomy: the pregnancy
is removed en bloc with the tube, (2) salpingostomy: an
incision is made on the fallopian tube over the swelling, the
EP carefully removed with forceps or irrigation and the
incision should be either closed or left to heal by secondary
intention [125, 140].
The preferred method of surgical treatment of EP today
is diagnostic laparoscopy with salpingostomy and tubal
conservation [130, 141]. Laparotomy is indicated in the
case of hemodynamic instability because it allows rapid
access to pelvic structures [130]. The success rate of sal-
pingostomy is 92 % and failure cases can be managed with
MTX [142]. Serial b-hCG measurements should be taken
until undetectable to be certain that there is no persistence
of trophoblastic tissue. Sometimes a prophylactic dose of
MTX is given with salpingosotomy [130].
Persistent EP occurs as a result of incomplete removal of
trophoblastic tissue [143], the most common complication
of laparoscopic salpingostomy, occurs at a frequency of
5–20 % [139, 144]. It is diagnosed during follow-up when
b-hCG concentrations measured once a week plateau
or rise. Factors increasing risk are small ectopic pregnan-
cies (\2 cm diameter), early therapy (\42 days from
last menstrual period), high concentrations of b-hCG
([3,000 IU/L) preoperatively, and implantation medial to
753
the salpingostomy site [145]. In high-risk cases, a single
dose of MTX (1 mg/kg) can be administered postopera-
tively for prophylaxis [144, 145]. In one randomized con-
trolled trial of laparoscopic surgery, prophylactic MTX
lowered the rate of persistent ectopic pregnancy from 14.5
to 1.9 %. The major benefit was in the shorter duration of
postoperative monitoring [144]. Since experience is lim-
ited, there is no single optimum treatment as on date. In the
largest series, all of 19 patients with persistent ectopic
pregnancies were successfully treated with single-dose
systemic MTX (50 mg/m2) [143].
Discussion and conclusion
Ectopic pregnancy in developing countries is a serious
threat, just because of poor medical facility so that a sig-
nificant morbidity rate and the potential for maternal death
generally are seen. Many patients have no documented risk
factors and no physical indications of EP, yet they suffer
from the complication. On the other hand, in developed
countries, it is now not so threatening as in past because
they have advanced technique of diagnosis and women are
much more aware of their health. Management is dictated
by the clinical presentation, serum b-hCG levels and TVS
findings. Expert consultation with radiologists and gyne-
cologists is recommended whenever ectopic pregnancy is
suspected. The use of MTX for treatment of early unrup-
tured EP reported to be safe and effective. Surgical treat-
ment is particularly appropriate for women who are
hemodynamically unstable or unlikely to be compliant with
post treatment monitoring and those who do not have
immediate access to medical care. The choice of treatment
should be guided by the patient’s preference, after a
detailed discussion about monitoring, outcome, risks, and
benefits of the approaches. The radiologists and gynecol-
ogists should have been firstly the identification of clinical
features or biomarkers predictive of MTX success and the
secondly is the use of additional medical treatments or
novel adjuncts that reduce treatment failures. The current
analysis of EP would suggest declining trends over time.
However, this reflects a decrease in surgical treatment and
not an actual decline in EP occurrence. Further, new ave-
nues are needed to explore early detection and less side
effect medication of the EP.
Conflict of interest None declared.
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