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Ectopic pregnancy refers to the implantation of a fertilized egg in a location outside of the uterinecavity, including the fallopian tubes (approximately 97.7%), cervix, ovary, cornual region of theuterus, and abdominal cavity. Of tubal pregnancies, the ampulla is the most common site ofimplantation (80%), followed by the isthmus (12%), fimbria (5%), cornua (2%), and interstitia (2-3%). (See the image below.)

Sites and frequencies of ectopic pregnancy. By Donna M. Peretin,RN. (A) Ampullary, 80%; (B) Isthmic, 12%; (C) Fimbrial, 5%; (D) Cornual/Interstitial, 2%; (E)Abdominal, 1.4%; (F) Ovarian, 0.2%; and (G) Cervical, 0.2%.

In ectopic pregnancy(the term ectopic is derived from the Greek word ektopos, meaning out ofplace), the gestation grows and draws its blood supply from the site of abnormal implantation. As

the gestation enlarges, it creates the potential for organ rupture, because only the uterine cavity isdesigned to expand and accommodate fetal development.Ectopic pregnancycan lead to massivehemorrhage, infertility, or death (see the images below). (See Etiology and Prognosis.)

A 12-week interstitial gestation, which eventually resulted in ahysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology atMedical College of Pennsylvania and Hahnemann University (MCPHU).

A 12-week interstitial gestation, which eventually resulted in ahysterectomy. Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology atMedical College of Pennsylvania and Hahnemann University (MCPHU).

In 1970, the Centers for Disease Control and Prevention (CDC) began to record statistics regardingectopic pregnancy, reporting 17,800 cases. By 1992, the number of ectopic pregnancies hadincreased to 108,800. Concurrently, however, the case-fatality rate decreased from 35.5 deaths per10,000 cases in 1970 to 2.6 per 10,000 cases in 1992. (See Epidemiology.)

The increased incidence of ectopic pregnancy has been partially attributed to improved ability inmaking an earlier diagnosis. Ectopic pregnancies that previously would have resulted in tubalabortion or complete, spontaneous reabsorption and remained clinically undiagnosed are now

detected. (See Presentation, DDx, and Workup.)In the 1980s and 1990s, medical therapy for ectopic pregnancy was implemented; it has now

replaced surgical therapy in many cases.[1, 2, 3] As the ability to diagnose ectopic pregnancy

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improves, physicians will be able to intervene sooner, preventing life-threatening sequelae andextensive tubal damage, as well as, it is hoped, preserving future fertility. (See Treatment andMedication.)

Implantation sites

The faulty implantation that occurs in ectopic pregnancy occurs because of a defect in the anatomyor normal function of either the fallopian tube (as can result from surgical or infectious scarring),the ovary (as can occur in women undergoing fertility treatments), or the uterus (as in cases of

bicornuate uterus or cesarean delivery scar). Reflecting this, most ectopic pregnancies are located inthe fallopian tube; the most common site is the ampullary portion of the tube, where over 80% ofectopic pregnancies occur. (See Etiology.)

Nontubal ectopic pregnancies are a rare occurrence, with abdominal pregnancies accounting for1.4% of ectopic pregnancies and ovarian and cervical sites accounting for 0.2% each. Some ectopic

pregnancies implant in the cervix (< 1%), in previous cesarean delivery scars, or in a rudimentaryuterine horn; although these may be technically in the uterus, they are not considered normal

intrauterine pregnancies.

[4]

About 80% of ectopic pregnancies are found on the same side as the corpus luteum (the old,

ruptured follicle), when present.[5] In the absence of modern prenatal care, abdominal pregnanciescan present at an advanced stage (>28 wk) and have the potential for catastrophic rupture and

bleeding.[6]

Etiology

An ectopic pregnancy requires the occurrence of 2 events: fertilization of the ovum and abnormalimplantation. Many risk factors affect both events; for example, a history of major tubal infection

decreases fertility and increases abnormal implantation.

Multiple factors contribute to the relative risk of ectopic pregnancy. In theory, anything thathampers or delays the migration of the fertilized ovum (blastocyst) to the endometrial cavity can

predispose a woman to ectopic gestation. The following risk factors have been linked to ectopicpregnancy:

Tubal damage - Which can be the result of infections such aspelvic inflammatory disease(PID) or salpingitis (whether documented or not) or can result from abdominal surgery ortubal ligation or from maternal in utero diethylstilbestrol (DES) exposure

History of previous ectopic pregnancy

Smoking - A risk factor in about one third of ectopic pregnancies; smoking may contributeto decreased tubal motility by damage to the ciliated cells in the fallopian tubes

Altered tubal motility - As mentioned, this can result from smoking, but it can also occur asthe result of hormonal contraception; progesterone-only contraception and progesteroneintrauterine devices (IUDs) have been associated with an increased risk of ectopic pregnancy

History of 2 or more years of infertility (whether treated or not)[7] - Women using assistedreproduction seem to have a doubled risk of ectopic pregnancy (to 4%), although this is

mostly due to the underlying infertility[8]

History of multiple sexual partners[7]

Maternal age - Although this is not an independent risk factor[7]

The most logical explanation for the increasing frequency of ectopic pregnancy is previous pelvicinfection; however, most patients presenting with an ectopic pregnancy have no identifiable risk

factor.[9]

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A 2009 literature review found 56 reported cases of ectopic pregnancy (by definition), dating back

to 1937, after hysterectomy.[10]

Pelvic inflammatory disease

The most common cause of PID is an antecedent infection caused by Chlamydia trachomatis.

Patients with chlamydial infection have a range of clinical presentations, from asymptomaticcervicitis to salpingitis and florid PID. More than 50% of women who have been infected areunaware of the exposure.

Other organisms that cause PID, such asNeisseria gonorrhoeae, also increase the risk of ectopicpregnancy, and a history of salpingitis increases the risk of ectopic pregnancy 4-fold. The incidenceof tubal damage increases after successive episodes of PID (ie, 13% after 1 episode, 35% after 2episodes, 75% after 3 episodes).

Effective vaccination against Chlamydia trachomatis is under investigation. Once clinicallyavailable, it should have a dramatic impact on the frequency of ectopic pregnancy, as well as on theoverall health of the female reproductive system.

History of previous ectopic pregnancy

After 1 ectopic pregnancy, a patient incurs a 7- to 13-fold increase in the likelihood of anotherectopic pregnancy. Overall, a patient with a previous ectopic pregnancy has a 50-80% chance ofhaving a subsequent intrauterine gestation and a 10-25% chance of a future tubal pregnancy.

History of tubal surgery and conception after tubal ligation

Previous tubal surgery has been demonstrated to increase the risk of developing ectopic pregnancy.The increase depends on the degree of damage and the extent of anatomic alteration. Surgeries

carrying higher risk of subsequent ectopic pregnancy includesalpingostomy, neosalpingostomy,fimbrioplasty, tubal reanastomosis, and lysis of peritubal or periovarian adhesions.

Conception after previous tubal ligation also increases a women's risk of having an ectopicpregnancy; 35-50% of patients who conceive after a tubal ligation are reported to experience anectopic pregnancy. Failure after bipolar tubal cautery is more likely to result in ectopic pregnancythan is occlusion using suture, rings, or clips. This failure is attributed to fistula formation thatallows sperm passage. In one study, 33% of pregnancies occurring after tubal ligation were ectopic;

those who underwent electrocautery and women younger than 35 years were at higher risk. [11]

Ectopic pregnancies following tubal sterilizations usually occur 2 or more years after sterilizationrather than immediately after. In the first year, only about 6% of sterilization failures result inectopic pregnancy.

Smoking

Cigarette smoking has been shown to be a risk factor for ectopic pregnancy development. Studieshave demonstrated an elevated risk ranging from 1.6 to 3.5 times that of nonsmokers. A dose-response effect has also been suggested.

Based on laboratory studies in humans and animals, researchers have postulated severalmechanisms by which cigarette smoking might play a role in ectopic pregnancies. Thesemechanisms include one or more of the following: delayed ovulation, altered tubal and uterine

motility, and altered immunity. To date, however, no study has supported a specific mechanism bywhich cigarette smoking affects the occurrence of ectopic pregnancy.

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Use of oral contraceptives or an intrauterine device

All contraceptive methods lead to an overall lower risk of pregnancy and therefore to an overalllower risk of ectopic pregnancy. However, among cases of contraceptive failure, women atincreased risk of ectopic pregnancy compared with pregnant controls included those using

progestin-only oral contraceptives, progestin-only implants, or IUDs and those with a history of

tubal ligation.

[12]

The presence of an inert, copper-containing or progesterone IUD traditionally has been thought tobe a risk factor for ectopic pregnancy. However, only the progesterone IUD has a rate of ectopicpregnancy higher than that for women not using any form of contraception. The modern copperIUD does not increase the risk of ectopic pregnancy. Nevertheless, if a woman ultimately conceiveswith an IUD in place, it is more likely to be an ectopic pregnancy. The actual incidence of ectopic

pregnancies with IUD use is 3-4%.[13]

Emergency contraception (levonorgestrel, or Plan B) does not appear to lead to a higher-than-

expected rate of ectopic pregnancy.[14]

Use of fertility drugs or assisted reproductive technology

Ovulation induction with clomiphene citrate or injectable gonadotropin therapy has been linked to a4-fold increase in the risk of ectopic pregnancy in a case-control study. This finding suggests thatmultiple eggs and high hormone levels may be significant factors.

One study demonstrated that infertility patients with luteal phase defects have a statistically higherectopic pregnancy rate than do patients whose infertility is caused by anovulation. In addition, therisk of ectopic pregnancy and heterotopic pregnancy (ie, pregnancies occurring simultaneously indifferent body sites) dramatically increases when a patient has used assisted reproductive techniques

such as such as in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT)to conceive.[15]

In a study of 3000 clinical pregnancies achieved through in vitro fertilization, the ectopic pregnancyrate was 4.5%, which is more than double the background incidence. Furthermore, studies havedemonstrated that up to 1% of pregnancies achieved through IVF or GIFT can result in aheterotopic gestation, compared with an incidence of 1 in 30,000 pregnancies for spontaneous

conceptions.[16]

Increasing age

The highest rate of ectopic pregnancy occurs in women aged 35-44 years. A 3- to 4-fold increase in

the risk of developing an ectopic pregnancy exists compared with women aged 15-24 years. Oneproposed explanation suggests that aging may result in a progressive loss of myoelectrical activityin the fallopian tube; myoelectrical activity is responsible for tubal motility.

Salpingitis isthmica nodosum

Salpingitis isthmica nodosum is defined as the microscopic presence of tubal epithelium in themyosalpinx or beneath the tubal serosa. These pockets of epithelium protrude through the tube,similar to small diverticula. Studies of serial histopathologic sections of the fallopian tube haverevealed that approximately 50% of patients treated with salpingectomy for ectopic pregnancy haveevidence of salpingitis isthmica nodosum. The etiology of salpingitis isthmica nodosum is unclear,

but proposed mechanisms include postinflammatory and congenital changes, as well as acquiredtubal changes, such as those observed with endometriosis.[17]

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DES exposure

Before 1971, several million women were exposed in utero to DES, which was given to theirmothers to prevent pregnancy complications. In utero exposure of women to DES is associated witha high lifetime risk of a broad spectrum of adverse health outcomes, including infertility,

spontaneous abortion, and ectopic pregnancy.[18]

Other

Other risk factors associated with increased incidence of ectopic pregnancy include anatomicabnormalities of the uterus such as a T-shaped or bicornuate uterus, fibroids or other uterine tumors,

previous abdominal surgery, failure with progestin-only contraception, and ruptured appendix.[9]

Epidemiology

Occurrence in the United States

The incidence of ectopic pregnancy is reported most commonly as the number of ectopicpregnancies per 1000 conceptions. Since 1970, when the reported rate in the United States was 4.5cases per 1000 pregnancies, the frequency of ectopic pregnancy has increased 6-fold, with ectopic

pregnancies now accounting for approximately 1-2% of all pregnancies. Consequently, theprevalence is estimated at 1 in 40 pregnancies, or approximately 25 cases per 1000 pregnancies.These statistics are based on data from the US Centers for Disease Control and Prevention (CDC),which used hospitalizations for ectopic pregnancy to determine the total number of ectopic

pregnancies.

Looking at raw data, 17,800 hospitalizations for ectopic pregnancies were reported in 1970. Thisnumber rose to 88,000 in 1989[19]but fell to 30,000 in 1998. An estimated 108,800 ectopic

pregnancies in 1992 resulted in 58,200 hospitalizations, with an estimated cost of $1.1 billion.

Changes in the management of ectopic pregnancy, however, have made it difficult to reliably

monitor incidence (and therefore mortality rates).[20] A review of hospital discharges in California

found a rate of 15 cases per 1,000 in 1991, declining to a rate of 9.3 cases per 1,000 in 2000,[21]buta review of electronic medical records (inpatient and outpatient) from a large health maintenanceorganization (HMO) in northern California found a stable rate of 20.7 cases per 1,000 reported

pregnancies from 1997-2000.[22] This suggests that the incidence of ectopic pregnancy in theUnited States remained steady at about 2% in the 1990s, despite the shift to outpatient treatment.

The above data raise the question of whether the number of ectopic pregnancies is declining orwhether many ectopic pregnancies are now being treated in ambulatory surgical centers or are even

being addressed with medical therapy, without admission. Some authors believe the latter is true,but truly accurate statistics are lacking.

Approximately 85-90% of ectopic pregnancies occur in multigravid women. In the United States,rates are nearly twice as high for women of other races compared with white women.

International occurrence

The increase in incidence of ectopic pregnancy in the 1970s in the United States was also mirrored

in Africa, although data there tend to be hospital based rather than derived from nationwide surveys,

with estimates in the range of 1.1-4.6%.[23]

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The United Kingdom estimated the incidence of ectopic pregnancy at about 11.1 per 1,000 reported

pregnancies from 1997 to 2005, compared with 9.6 per 1,000 from 1991 to 1993.[24]

Racial- and age-related demographics

In the United States from 1991 to 1999, ectopic pregnancy was the cause of 8% of all pregnancy-

related deaths among black women, compared with 4% among white women.[25]

Any woman with functioning ovaries can potentially have an ectopic pregnancy, which includeswomen from the age of menarche until menopause. Women older than 40 years were found to have

an adjusted odds ratio of 2.9 for ectopic pregnancy.[9]

Prognosis

Ectopic pregnancy presents a major health problem for women of childbearing age. It is the resultof a flaw in human reproductive physiology that allows the conceptus to implant and mature outsidethe endometrial cavity, which ultimately ends in the death of the fetus. Without timely diagnosis and

treatment, ectopic pregnancy can become a life-threatening situation.[26]

The evidence in the literature reporting on the treatment of ectopic pregnancy with subsequentreproductive outcome is limited mostly to observational data and a few randomized trialscomparing treatment options.

Assessment of successful treatment and future reproductive outcome with various treatment optionsis often skewed by selection bias. For example, comparing a patient who was managed expectantlywith a patient who received methotrexate or with a patient who had a laparoscopic salpingectomy isdifficult.

A patient with spotting, no abdominal pain, and a low initial betahuman chorionic gonadotropin

(-HCG) level that is falling may be managed expectantly, whereas a patient who presents withhemodynamic instability, an acute abdomen, and high initial -HCG levels must be managedsurgically. These 2 patients probably represent different degrees of tubal damage; thus, comparingthe future reproductive outcomes of the 2 cases would be flawed.

Salpingostomy, salpingectomy, and tubal surgery

Data in the literature have failed to demonstrate substantial and consistent benefit from eithersalpingostomy or salpingectomy with regard to improving future reproductive outcome. However,despite the risk of persistent ectopic pregnancy, some studies have shown salpingostomy to improvereproductive outcome in patients with contralateral tubal damage. Yao and Tulandi concluded from

a literature review that laparoscopic salpingostomy had a reproductive performance that was equalto or slightly better than salpingectomy; however, slightly higher recurrent ectopic pregnancy rates

were noted in the salpingostomy group.[27]

In reporting on 10 years of surgical experience in Paris, Dubuisson et al concluded that, for selectedpatients who desire future fertility, using salpingectomy, which is simpler and avoids the risk ofpersistent ectopic pregnancy, is possible and can result in a comparable fertility rate to tubal

conservation surgery.[28] Future fertility rates were no different with either surgical approach whenthe contralateral tube was either normal or scarred but patent.

Clausen reviewed literature from the previous 40 years and concluded that only a small number ofinvestigators have suggested, indirectly, that conservative tubal surgery increases the rate ofsubsequent intrauterine pregnancy. He also concluded that the more recent studies may reflect an

improvement in surgical technique.[29]

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In an earlier study, Maymon et al, after reviewing 20 years of ectopic pregnancy treatment,concluded that conservative tubal surgery provided no greater risk of recurrent ectopic pregnancy

than the more radical salpingectomy.[30]

The modern pelvic surgeon has been led to believe that the treatment of choice for unrupturedectopic pregnancy is salpingostomy, sparing the affected fallopian tube and thereby improvingfuture reproductive outcome.

However, if the treating surgeon has neither the laparoscopic skill nor the instrumentation necessaryto atraumatically remove the trophoblastic tissue via linear salpingostomy, then salpingectomy bylaparoscopy or laparotomy is not the wrong surgical choice. Leaving a scarred, charred fallopiantube behind after removing the ectopic pregnancy but requiring extensive cautery to control

bleeding does not preserve reproductive outcome.

Fertility following surgery

Previous history of infertility has been found to be the most significant factor affecting postsurgicalfertility.

Parker and Bistis concluded that when the contralateral fallopian tube is normal, the subsequent

fertility rate is independent of the type of surgery.[31] Similarly, a prospective study of 88 patientsby Ory et al indicated that the surgical method had no effect on subsequent fertility in women with

an intact contralateral tube.[32]

Several other studies reported that the status of the contralateral tube, the presence of adhesions, andthe presence of other risk factors, such as endometriosis, have a more significant impact on futurefertility than does the choice of surgical procedure.

According to Rulin, salpingectomy should be the treatment of choice in women with intactcontralateral tubes, because conservative treatment provides no additional benefit and incurs the

additional costs and morbidity associated with persistent ectopic pregnancy and recurrent ectopicpregnancy in the already damaged tube.[33]

Future fertility rates have been found to be similar in patients who are treated surgically bylaparoscopy or laparotomy. Salpingectomy by laparotomy carries a subsequent intrauterine

pregnancy rate of 25-70%, compared with laparoscopic salpingectomy rates of 50-60%. Verysimilar rates exist for laparoscopic salpingostomy versus laparotomy. The rate of persistent ectopic

pregnancy between the 2 groups is also similar, ranging from 5-20%.

A slightly higher recurrent ectopic pregnancy rate exists in patients treated by laparotomy (7-28%),regardless of conservative or radical approach, when compared with laparoscopy (6-16%). Thissurprising finding is believed to be secondary to increased adhesion formation in the group treated

by laparotomy.

Comparison of medical and surgical treatment of small, intact extrauterine pregnancies alsorevealed similar success and subsequent spontaneous pregnancy rates in a prospective, randomized

trial.[34]

Methotrexate versus surgery

The success rates after methotrexate are comparable with laparoscopic salpingostomy, assumingthat the previously mentioned selection criteria are observed. The average success rates using themultiple-dosage regimen are in the range of 91-95%, as demonstrated by multiple investigators.

One study of 77 patients desiring subsequent pregnancy showed intrauterine pregnancies in 64% ofthese patients and recurrent ectopic pregnancy in 11% of them. Other studies have demonstratedsimilar results, with intrauterine pregnancy rates ranging from 20-80%.

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During 19992008, the ectopic pregnancy mortality rate in the United States was 0.6 deaths per100,000 live births. The CDC reported a higher rate in Florida, 2.5 deaths per 100,000 live birthsduring 2009-2010. The 11 ectopic pregnancy deaths in Florida during 2009-2010 contrasted withthe total number of deaths (14) identified in national statistics for 2007. There was a high

prevalence of illicit drug use among the women who died in Florida.[38]

The mortality rate reported in African hospital-based studies varied from 50-860 deaths per 10,000ectopic pregnancies; these were almost certainly underestimates resulting from underreporting of

maternal deaths and misclassification of ectopic pregnancies as induced abortions.[23]

Using data from 1997 to 2002, the World Health Organization (WHO) estimated that ectopic

pregnancy was the cause of 4.9% of pregnancy-related deaths in the industrialized world.[41]

Ectopic pregnancy caused 26% of maternal deaths in early pregnancy in the United Kingdom from2003-2005, second only to venous thromboembolism, despite a relatively low mortality rate of

0.035 per 10,000 estimated ectopic pregnancies.[24]