Ectopic pregnancy: a review

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Archives of Gynecology andObstetrics ISSN 0932-0067Volume 288Number 4 Arch Gynecol Obstet (2013)288:747-757DOI 10.1007/s00404-013-2929-2

Ectopic pregnancy: a review

Poonam Rana, Imran Kazmi, RajbalaSingh, Muhammad Afzal, Fahad A. Al-Abbasi, Ali Aseeri, Rajbir Singh,Ruqaiyah Khan & Firoz Anwar

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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

� Springer-Verlag Berlin Heidelberg 2013

Abstract

Purpose Ectopic pregnancy (EP) presents a major health

problem for women of child-bearing age. EP refers to the

pregnancy occurring outside the uterine cavity that con-

stitutes 1.2–1.4 % of all reported pregnancies. All identi-

fied risk factors are maternal: pelvic inflammatory disease,

Chlamydia trachomatis infection, smoking, tubal surgery,

induced conception cycle, and endometriosis. These

developments have provided the atmosphere for trials

using methotrexate as a non-surgical treatment for EP. The

diagnosis measure of EP is serum human chorionic gona-

dotropin, urinary hCGRP/i-hCG, progesterone measure-

ment, transvaginal ultrasound scan, computed tomography,

vascular endothelial growth factor, CK, disintegrin and

metalloprotease-12 and hysterosalpingography. The treat-

ment option of EP involves surgical treatment by

laparotomy or laparoscopy, medical treatment is usually

systemic or through local route, or by expectant treatment.

Results It was concluded that review data reflect a

decrease in surgical treatment and not an actual decline in

EP occurrence so that further new avenues are needed to

explore early detection of the EP.

Keywords b-hCG � TVS � Methotrexate � Laparotomy

Abbreviations

EP Ectopic pregnancy

CEP Cervical ectopic pregnancy

OEP Ovarian ectopic pregnancy

CSEP Cesarean scar ectopic pregnancy

IP Interstitial pregnancy

PID Pelvic inflammatory disease

PROKR Prokineticin receptor

IVF In vitro fertilization

ART Assisted reproductive technology

b-hCG Serum human chorionic gonadotropin

TVS Transvaginal ultrasound scan

CT Computed tomography

VEGF Vascular endothelial growth factor

ADAM-12 Disintegrin and metalloprotease-12

Hsg Hysterosalpingography

MTX Methotrexate

PPV Positive predictive value

Introduction

Ectopic pregnancy (EP) or extra uterine pregnancy,

accepted from the Greek word ‘‘ektopos’’ meaning out of

place [1], refers to the blastocyst implantation outside the

P. Rana � I. Kazmi � R. Singh (&) � M. Afzal (&) � R. Khan �F. Anwar (&)

Siddhartha Institute of Pharmacy, Dehradun 248001,

Uttarakhand, India

e-mail: [email protected]

M. Afzal


F. Anwar


F. A. Al-Abbasi

Department of Biochemistry, Faculty of Science,

King Abdulaziz University, Jeddah, Saudi Arabia

A. Aseeri

Lab Director, Jeddah Eye Hospital, Ministry of Health,

Jeddah, Saudi Arabia

R. Singh

Alchemist Hospital, Panchkula, Haryana, India

123

Arch Gynecol Obstet (2013) 288:747–757

DOI 10.1007/s00404-013-2929-2

Author's personal copy

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

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

748 Arch Gynecol Obstet (2013) 288:747–757

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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.

Risk factor

EP is further common in women who have suffered with

pelvic inflammatory disease (PID) and more than 50 % of

women who have been infected are unaware of the expo-

sure of PID [57]. Moreover, it is due to difficulties in

determining the effect of female genital chlamydial

Tubal EP (90-95%)

Cervical EP (0.15%)

Ovarian EP (0.15%-3%)

Caesarean scar EP (6%)

Interstitial EP (2.5%)

Abdominal EP (1.3%)

Heterotopic EP (1-3%)

Pelvic inflammatory disease (PID)

Age

Cigarette smoking

History of ART and IVF

Previous history of EP

Contraception pills

Light vaginal bleeding

Nausea and Vomiting

Lower abdominal pain

Sharp abdominal cramps

Pain on one side of the body

Dizziness or weakness

Pain in the shoulder, neck, rectum

PREGNANCY (EP)

Serum β-human chorionic gonadotropin (b-hCG) test

Urinary hCGRP/i-hCG ratio

Progesterone measurement

Transvaginal ultrasonography (TVS)

Computed Tomography (CT) or MRI

Vascular Endothelial Growth Factor (VEGF)

Creatine kinase (CK)

Disintegrin and Metalloprotease-12 (ADAM-12)

Hysterosalpingography (Hsg)

Expectant treatment

Medical treatment (systemic or local

route)

Surgical treatment (laparotomy or

laparoscopy)

Fig. 1 Summary of ectopic

pregnancy (EP)

Fig. 2 Different site for ectopic pregnancy

Arch Gynecol Obstet (2013) 288:747–757 749

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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

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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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

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].

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


123


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

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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Ectopic pregnancy: a review

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