Ectopic Pregnancy - Medscape

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Ectopic Pregnancy

Practice Essentials

Ectopic pregnancy is the result of a flaw in human reproductive physiology that allows the conceptusto implant and mature outside the endometrial cavity, which ultimately ends in the death of the fetus.Without timely diagnosis and treatment, ectopic pregnancy can become a life-threatening situation.[1]

Essential update: Best modality for diagnosing ectopic pregnancy

In a systematic review of 14 studies with 12,101 patients, researchers found that the presence of anadnexal mass in the absence of an intrauterine pregnancy on transvaginal sonography had a positivelikelihood ratio (LR+) of 111 for ectopic pregnancy, while the lack of adnexal abnormalities ontransvaginal sonography decreases the likelihood of ectopic pregnancy. All components of the historyhad an LR+ of less than 1.5. Physical examination findings of cervical motion tenderness (LR+ 4.9),an adnexal mass (LR+ 2.8), and adnexal tenderness (LR+ 1.9) all increased the likelihood of ectopicpregnancy.[2, 3]

Signs and symptoms

The classic clinical triad of ectopic pregnancy is as follows:

Abdominal pain Amenorrhea Vaginal bleeding

Unfortunately, only about 50% of patients present with all 3 symptoms.

Patients may present with other symptoms common to early pregnancy (eg, nausea, breast fullness).The following symptoms have also been reported:

Painful fetal movements (in the case of advanced abdominal pregnancy) Dizziness or weakness Fever

Flulike symptoms Vomiting Syncope Cardiac arrest

The presence of the following signs suggests a surgical emergency:

Abdominal rigidity Involuntary guarding Severe tenderness Evidence of hypovolemic shock (eg, orthostatic blood pressure changes, tachycardia)

Findings on pelvic examination may include the following:

The uterus may be slightly enlarged and soft Uterine or cervical motion tenderness may suggest peritoneal inflammation An adnexal mass may be palpated but is usually difficult to differentiate from the ipsilateral ovary Uterine contents may be present in the vagina, due to shedding of endometrial lining stimulated by

an ectopic pregnancySeeClinical Presentationfor more detail.

Diagnosis

Serum -HCG levels

In a normal pregnancy, the -HCG level doubles every 48-72 hours until it reaches 10,000-20,000mIU/mL. In ectopic pregnancies, -HCG levels usually increase less. Mean serum -HCGlevels are lower in ectopic pregnancies than in healthy pregnancies.
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No single serum -HCG level is diagnostic of an ectopic pregnancy. Serial serum -HCG levels arenecessary to differentiate between normal and abnormal pregnancies and to monitor resolution ofectopic pregnancy once therapy has been initiated.

The discriminatory zone of -HCG (ie, the level above which an imaging scan should reliably visualizea gestational sac within the uterus in a normal intrauterine pregnancy) is as follows:

1500-1800 mIU/mL with transvaginal ultrasonography, but up to 2300 mIU/mL with multiplegestates[4]

6000-6500 mIU/mL with abdominal ultrasonographyAbsence of an intrauterine pregnancy on a scan when the -HCG level is above the discriminatoryzone represents an ectopic pregnancy or a recent abortion.

Ultrasonography

Ultrasonography is probably the most important tool for diagnosing an extrauterine pregnancy.

Visualization of an intrauterine sac, with or without fetal cardiac activity, is often adequate to excludeectopic pregnancy.[5]

Transvaginal ultrasonography, or endovaginal ultrasonography, can be used to visualize anintrauterine pregnancy by 24 days postovulation or 38 days after the last menstrual period (about 1week earlier than transabdominal ultrasonography). An empty uterus on endovaginal ultrasonographicimages in patients with a serum -HCG level greater than the discriminatory cut-off value is an ectopicpregnancy until proved otherwise.

Color-flow Doppler ultrasonography improves the diagnostic sensitivity and specificity of transvaginalultrasonography, especially in cases in which a gestational sac is questionable or absent.

Laparoscopy

Laparoscopy remains the criterion standard for diagnosis; however, its routine use on all patientssuspected of ectopic pregnancy may lead to unnecessary risks, morbidity, and costs. Moreover,laparoscopy can miss up to 4% of early ectopic pregnancies.

Laparoscopy is indicated for patients who are in pain or hemodynamically unstable.

SeeWorkupfor more detail.

Management

Therapeutic options in ectopic pregnancy are as follows:

Expectant management Methotrexate Surgery

Expectant management

Candidates for successful expectant management should be asymptomatic and have no evidence ofrupture or hemodynamic instability. Candidates should demonstrate objective evidence of resolution(eg, declining -HCG levels).

Close follow-up and patient compliance are of paramount importance, as tubal rupture may occurdespite low and declining serum levels of -HCG.

Methotrexate

Methotrexate is the standard medical treatment for unruptured ectopic pregnancy. A single-dose IMinjection is the more popular regimen. The ideal candidate should have the following:

Hemodynamic stability No severe or persisting abdominal pain The ability to follow up multiple times Normal baseline liver and renal function test results
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Absolute contraindications to methotrexate therapy include the following:

Existence of an intrauterine pregnancy Immunodeficiency Moderate to severe anemia, leukopenia, or thrombocytopenia Sensitivity to methotrexate

Active pulmonary or peptic ulcer disease Clinically important hepatic or renal dysfunction Breastfeeding Evidence of tubal rupture

Surgical treatment

Laparoscopy has become the recommended surgical approach in most cases. Laparotomy is usuallyreserved for patients who are hemodynamically unstable or for patients with cornual ectopicpregnancies; it also is a preferred method for surgeons inexperienced in laparoscopy and in patientsin whom a laparoscopic approach is difficult.

SeeTreatmentandMedicationfor more detail.

Image library

An endovaginal sonogram demonstrates an early ectopic pregnancy. Anechogenic ring (tubal ring) found outside of the uterus can be seen in this view.

BackgroundEctopic 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 the uterus,and abdominal cavity. Of tubal pregnancies, the ampulla is the most common site of implantation(80%), followed by the isthmus (12%), fimbria (5%), cornua (2%), and interstitia (2-3%). (See theimage 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%.Inectopic 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 thegestation 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.)
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A 12-week interstitial gestation, which eventually resulted in a hysterectomy.Courtesy of Deidra Gundy, MD, Department of Obstetrics and Gynecology at Medical College of Pennsylvania and

Hahnemann University (MCPHU). A 12-week interstitial gestation, whicheventually resulted in a hysterectomy. 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 tubal abortionor complete, spontaneous reabsorption and remained clinically undiagnosed are now detected. (SeePresentation, DDx, and Workup.)

In the 1980s and 1990s, medical therapy for ectopic pregnancy was implemented; it has nowreplaced surgical therapy in many cases.[6, 7, 8]As the ability to diagnose ectopic pregnancy improves,physicians will be able to intervene sooner, preventing life-threatening sequelae and extensive tubaldamage, as well as, it is hoped, preserving future fertility. (See Treatment and Medication.)

Implantation sites

The faulty implantation that occurs in ectopic pregnancy occurs because of a defect in the anatomy ornormal function of either the fallopian tube (as can result from surgical or infectious scarring), theovary (as can occur in women undergoing fertility treatments), or the uterus (as in cases of bicornuateuterus or cesarean delivery scar). Reflecting this, most ectopic pregnancies are located in thefallopian tube; the most common site is the ampullary portion of the tube, where over 80% of ectopicpregnancies occur. (See Etiology.)

Nontubal ectopic pregnancies are a rare occurrence, with abdominal pregnancies accounting for 1.4%of ectopic pregnancies and ovarian and cervical sites accounting for 0.2% each. Some ectopicpregnancies 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 normalintrauterine pregnancies.[9]

About 80% of ectopic pregnancies are found on the same side as the corpus luteum (the old, rupturedfollicle), when present.[10] In the absence of modern prenatal care, abdominal pregnancies can presentat an advanced stage (>28 wk) and have the potential for catastrophic rupture and bleeding.[11]

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.
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Multiple factors contribute to the relative risk of ectopic pregnancy. In theory, anything that hampers ordelays the migration of the fertilized ovum (blastocyst) to the endometrial cavity can predispose awoman to ectopic gestation. The following risk factors have been linked to ectopic pregnancy:

Tubal damage - Which can be the result of infections such aspelvic inflammatory disease(PID) orsalpingitis (whether documented or not) or can result from abdominal surgery or tubal 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 contribute to

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 as the result

of hormonal contraception; progesterone-only contraception and progesterone intrauterine devices(IUDs) have been associated with an increased risk of ectopic pregnancy

History of 2 or more years of infertility (whether treated or not)[12] - Women using assistedreproduction seem to have a doubled risk of ectopic pregnancy (to 4%), although this is mostly dueto the underlying infertility[13]

History of multiple sexual partners[12] Maternal age - Although this is not an independent risk factor[12]

The most logical explanation for the increasing frequency of ectopic pregnancy is previous pelvic

infection; however, most patients presenting with an ectopic pregnancy have no identifiable riskfactor.[14]

A 2009 literature review found 56 reported cases of ectopic pregnancy (by definition), dating back to1937, after hysterectomy.[15]

Pelvic inflammatory disease

The most common cause of PID is an antecedent infection caused by Chlamydiatrachomatis. Patients with chlamydial infection have a range of clinical presentations, fromasymptomaticcervicitisto salpingitis and florid PID. More than 50% of women who have beeninfected are unaware of the exposure.

Other organisms that cause PID, such as Neisseria gonorrhoeae, also increase the risk of ectopic

pregnancy, and a history of salpingitis increases the risk of ectopic pregnancy 4-fold. The incidence oftubal 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 clinically available, itshould have a dramatic impact on the frequency of ectopic pregnancy, as well as on the overall healthof 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 another ectopicpregnancy. Overall, a patient with a previous ectopic pregnancy has a 50-80% chance of having asubsequent 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. Surgeriescarrying higher risk of subsequent ectopic pregnancy includesalpingostomy, neosalpingostomy,fimbrioplasty, tubal reanastomosis, and lysis of peritubal or periovarian adhesions.

Conception after previoustubal ligationalso 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 pregnancy thanis occlusion using suture, rings, or clips. This failure is attributed to fistula formation that allows spermpassage. In one study, 33% of pregnancies occurring after tubal ligation were ectopic; those whounderwent electrocautery and women younger than 35 years were at higher risk.[16]
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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 in ectopicpregnancy.

Smoking

Cigarette smoking has been shown to be a risk factor for ectopic pregnancy development. Studies

have 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. These mechanismsinclude one or more of the following: delayed ovulation, altered tubal and uterine motility, and alteredimmunity. To date, however, no study has supported a specific mechanism by which cigarettesmoking affects the occurrence of ectopic pregnancy.

Use of oral contraceptives or an intrauterine device

All contraceptive methods lead to an overall lower risk of pregnancy and therefore to an overall lowerrisk of ectopic pregnancy. However, among cases of contraceptive failure, women at increased risk ofectopic pregnancy compared with pregnant controls included those using progestin-only oralcontraceptives, progestin-only implants, or IUDs and those with a history of tubal ligation.[17]

The presence of an inert, copper-containing or progesterone IUD traditionally has been thought to bea 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 copper IUDdoes not increase the risk of ectopic pregnancy. Nevertheless, if a woman ultimately conceives withan IUD in place, it is more likely to be an ectopic pregnancy. The actual incidence of ectopicpregnancies with IUD use is 3-4%.[18]

Emergency contraception (levonorgestrel, or Plan B) does not appear to lead to a higher-than-expected rate of ectopic pregnancy.[19]

Use of fertility drugs or assisted reproductive technology

Ovulation induction with clomiphene citrate or injectable gonadotropin therapy has been linked to a 4-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 thatinfertilitypatients with luteal phase defects have a statistically higherectopic pregnancy rate than do patients whose infertility is caused by anovulation. In addition, the riskof ectopic pregnancy and heterotopic pregnancy (ie, pregnancies occurring simultaneously in differentbody sites) dramatically increases when a patient has used assisted reproductive techniquessuchas such as in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT)to conceive.[20]

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 a heterotopic

gestation, compared with an incidence of 1 in 30,000 pregnancies for spontaneous conceptions.[21]

Increasing age

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

revealed 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
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proposed mechanisms include postinflammatory and congenital changes, as well as acquired tubalchanges, such as those observed with endometriosis.[22]

DES exposure

Before 1971, several million women were exposed in utero to DES, which was given to their mothersto prevent pregnancy complications. In utero exposure of women to DES is associated with a high

lifetime risk of a broad spectrum of adverse health outcomes, including infertility, spontaneousabortion, and ectopic pregnancy.[23]

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.[14]

Epidemiology

Occurrence in the United States

The incidence of ectopic pregnancy is reported most commonly as the number of ectopic pregnancies

per 1000 conceptions. Since 1970, when the reported rate in the United States was 4.5 cases per1000 pregnancies, the frequency of ectopic pregnancy has increased 6-fold, with ectopic pregnanciesnow accounting for approximately 1-2% of all pregnancies. Consequently, the prevalence is estimatedat 1 in 40 pregnancies, or approximately 25 cases per 1000 pregnancies. These statistics are basedon data from the US Centers for Disease Control and Prevention (CDC), which used hospitalizationsfor 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[24] but fell to 30,000 in 1998. An estimated 108,800 ectopic pregnanciesin 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 monitorincidence (and therefore mortality rates).[25]A review of hospital discharges in California found a rate of15 cases per 1,000 in 1991, declining to a rate of 9.3 cases per 1,000 in 2000,[26] but a review ofelectronic medical records (inpatient and outpatient) from a large health maintenance organization(HMO) in northern California found a stable rate of 20.7 cases per 1,000 reported pregnancies from1997-2000.[27] This suggests that the incidence of ectopic pregnancy in the United States remainedsteady 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 evenbeing addressed with medical therapy, without admission. Some authors believe the latter is true, buttruly accurate statistics are lacking.

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

International occurrenceThe 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%.[28]

The United Kingdom estimated the incidence of ectopic pregnancy at about 11.1 per 1,000 reportedpregnancies from 1997 to 2005, compared with 9.6 per 1,000 from 1991 to 1993.[29]

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.[30]

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 havean adjusted odds ratio of 2.9 for ectopic pregnancy.[14]


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Prognosis

Ectopic pregnancy presents a major health problem for women of childbearing age. It is the result of aflaw in human reproductive physiology that allows the conceptus to implant and mature outside theendometrial cavity, which ultimately ends in the death of the fetus. Without timely diagnosis andtreatment, ectopic pregnancy can become a life-threatening situation.[1]

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 trials comparingtreatment 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, comparing

the 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 aliterature review that laparoscopic salpingostomy had a reproductive performance that was equal to orslightly better than salpingectomy; however, slightly higher recurrent ectopic pregnancy rates werenoted in the salpingostomy group.[31]

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 of

persistent ectopic pregnancy, is possible and can result in a comparable fertility rate to tubalconservation surgery.[32] Future fertility rates were no different with either surgical approach when thecontralateral 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 animprovement in surgical technique.[33]

In an earlier study, Maymon et al, after reviewing 20 years of ectopic pregnancy treatment, concludedthat conservative tubal surgery provided no greater risk of recurrent ectopic pregnancy than the moreradical salpingectomy.[34]

The modern pelvic surgeon has been led to believe that the treatment of choice for unruptured ectopicpregnancy is salpingostomy, sparing the affected fallopian tube and thereby improving futurereproductive 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 fallopian tubebehind after removing the ectopic pregnancy but requiring extensive cautery to control bleeding doesnot 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 subsequentfertility rate is independent of the type of surgery.[35] Similarly, a prospective study of 88 patients by


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Ory et al indicated that the surgical method had no effect on subsequent fertility in women with anintact contralateral tube.[36]

Several other studies reported that the status of the contralateral tube, the presence of adhesions,and the presence of other risk factors, such as endometriosis, have a more significant impact onfuture fertility 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 theadditional costs and morbidity associated with persistent ectopic pregnancy and recurrent ectopicpregnancy in the already damaged tube.[37]

Future fertility rates have been found to be similar in patients who are treated surgically bylaparoscopy or laparotomy. Salpingectomy by laparotomy carries a subsequent intrauterinepregnancy rate of 25-70%, compared with laparoscopic salpingectomy rates of 50-60%. Very similarrates exist for laparoscopic salpingostomy versus laparotomy. The rate of persistent ectopicpregnancy 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%). This

surprising finding is believed to be secondary to increased adhesion formation in the group treated bylaparotomy.

Comparison of medical and surgical treatment of small, intact extrauterine pregnancies also revealedsimilar success and subsequent spontaneous pregnancy rates in a prospective, randomized trial.[38]

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. Onestudy of 77 patients desiring subsequent pregnancy showed intrauterine pregnancies in 64% of thesepatients and recurrent ectopic pregnancy in 11% of them. Other studies have demonstrated similarresults, with intrauterine pregnancy rates ranging from 20-80%.

The average success rates for the single-dosage methotrexate regimen are reported to be from 88-94%. In a study by Stovall and Ling, 113 patients (94%) were treated successfully, 4 (3.3%) of whomneeded a second dose.[38] No adverse effects were encountered. Furthermore, 87.2% of thesepatients achieved a subsequent intrauterine pregnancy, whereas 12.8% experienced a subsequentectopic pregnancy.[38] Other studies have reported similar results, with some mild adverse effects andlower reproductive outcomes.

A meta-analysis that included data from 26 trials demonstrated a success rate of 88.1% with thesingle-dose methotrexate regimen and a success rate of 92.7% with the multiple-dose regimen.[39]Asmall, randomized clinical trial also demonstrated the single-dose regimen to have a slightly higherfailure rate.[40]A hybrid protocol, involving 2 equal doses of methotrexate (50 mg/m2) given on days 1and 4 without the use of leucovorin, has been shown to be an effective and convenient alternative to

the existing regimens.[41]

Complications

Complications of ectopic pregnancy can be secondary to misdiagnosis, late diagnosis, or treatmentapproach. Failure to make the prompt and correct diagnosis of ectopic pregnancy can result in tubalor uterine rupture (depending on the location of the pregnancy), which in turn can lead to massivehemorrhage, shock, disseminated intravascular coagulopathy (DIC), and death. Ectopic pregnancy isthe leading cause of maternal death in the first trimester, accounting for 9-13% of all pregnancy-related deaths. In the United States, an estimated 30-40 women die each year from ectopicpregnancy.

Any time a surgical approach is chosen as the treatment of choice, consider the complicationsattributable to the surgery, whether it is laparotomy or laparoscopy. These include bleeding, infection,

and damage to surrounding organs, such as the bowel, bladder, and ureters, and to the major vesselsnearby. Infertility may also result secondary to loss of reproductive organs after surgery. Also consider


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the risks and complications secondary to anesthesia. Make the patient aware of these complications,and obtain the appropriate written consents.

Mortality

In the United States, ectopic pregnancy is estimated to occur in 1-2% of all pregnancies and accountsfor 3-4% of all pregnancy-related deaths.[42] It is the leading cause of pregnancy-related mortality

during the first trimester in the United States. In a review of deaths from ectopic pregnancy inMichigan, 44% of the women who died were either found dead at home or were dead on arrival at theemergency department.[43]

Virtually all ectopic pregnancies are considered nonviable and are at risk of eventual rupture andresulting hemorrhage. In addition to the immediate morbidity caused by ectopic pregnancy, thewoman's future ability to reproduce may be adversely affected as well. However, patients who arediagnosed with ectopic pregnancy before rupture have a low mortality rate and also have a chance atpreserved fertility.

From 1970 to 1989, the US mortality rate for ectopic pregnancies dropped from 35.5 deaths to 3.8deaths per 10,000 ectopic pregnancies.[24] If the overall incidence of ectopic pregnancy remainedstable in the 1990s, then the mortality rate dropped to 3.19 deaths per 10,000 ectopic pregnancies by

1999.[44]

Surveillance data for pregnancy-related deaths in the United States from 1991-1999 showed thatectopic pregnancy was the cause of 5.6% of 4200 maternal deaths. Of these deaths, 93% occurredvia hemorrhage.[30]

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 with thetotal number of deaths (14) identified in national statistics for 2007. There was a high prevalence ofillicit drug use among the women who died in Florida.[42]

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.[28]

Using data from 1997 to 2002, the World Health Organization (WHO) estimated that ectopicpregnancy was the cause of 4.9% of pregnancy-related deaths in the industrialized world.[45] Ectopicpregnancy caused 26% of maternal deaths in early pregnancy in the United Kingdom from 2003-2005, second only to venous thromboembolism, despite a relatively low mortality rate of 0.035 per10,000 estimated ectopic pregnancies.[29]

Patient Education

Advise patients receiving methotrexate therapy to avoid alcoholic beverages, vitamins containing folicacid, nonsteroidal anti-inflammatory drugs (NSAIDs), and sexual intercourse, until advised otherwise.

A signed written consent demonstrating the patient's comprehension of the course of treatment must

be obtained.Provide an information pamphlet to all patients receiving methotrexate; the pamphlet should include alist of adverse effects, a schedule of follow-up visits, and a method of contacting the physician or thehospital in case of emergency, as well as the need to return to the emergency department forconcerning symptoms.

Patients with risk factors for ectopic pregnancy should be educated regarding their risk of having anectopic pregnancy. Women who are being discharged with a pregnancy of unknown location shouldbe educated regarding the possibility of ectopic pregnancy and their need for urgent follow-up.

Patients undergoingassisted reproduction technologyshould be educated regarding their risk ofheterotopic pregnancy.

For patient education information, see thePregnancy Centerand theWomen's Health Center, as wellasEctopic Pregnancy,Bleeding During Pregnancy,Vaginal Bleeding,Birth Control Overview,andBirth Control Methods.
http://emedicine.medscape.com/article/263907-overviewhttp://emedicine.medscape.com/article/263907-overviewhttp://emedicine.medscape.com/article/263907-overviewhttp://www.emedicinehealth.com/pregnancy/center.htmhttp://www.emedicinehealth.com/pregnancy/center.htmhttp://www.emedicinehealth.com/pregnancy/center.htmhttp://www.emedicinehealth.com/womens-health/center.htmhttp://www.emedicinehealth.com/womens-health/center.htmhttp://www.emedicinehealth.com/womens-health/center.htmhttp://www.emedicinehealth.com/ectopic_pregnancy/article_em.htmhttp://www.emedicinehealth.com/ectopic_pregnancy/article_em.htmhttp://www.emedicinehealth.com/ectopic_pregnancy/article_em.htmhttp://www.emedicinehealth.com/pregnancy_bleeding/article_em.htmhttp://www.emedicinehealth.com/pregnancy_bleeding/article_em.htmhttp://www.emedicinehealth.com/pregnancy_bleeding/article_em.htmhttp://www.emedicinehealth.com/vaginal_bleeding/article_em.htmhttp://www.emedicinehealth.com/vaginal_bleeding/article_em.htmhttp://www.emedicinehealth.com/vaginal_bleeding/article_em.htmhttp://www.emedicinehealth.com/birth_control_overview/article_em.htmhttp://www.emedicinehealth.com/birth_control_overview/article_em.htmhttp://www.emedicinehealth.com/birth_control_overview/article_em.htmhttp://www.emedicinehealth.com/birth_control_faqs/article_em.htmhttp://www.emedicinehealth.com/birth_control_faqs/article_em.htmhttp://www.emedicinehealth.com/birth_control_faqs/article_em.htmhttp://www.emedicinehealth.com/birth_control_faqs/article_em.htmhttp://www.emedicinehealth.com/birth_control_overview/article_em.htmhttp://www.emedicinehealth.com/vaginal_bleeding/article_em.htmhttp://www.emedicinehealth.com/pregnancy_bleeding/article_em.htmhttp://www.emedicinehealth.com/ectopic_pregnancy/article_em.htmhttp://www.emedicinehealth.com/womens-health/center.htmhttp://www.emedicinehealth.com/pregnancy/center.htmhttp://emedicine.medscape.com/article/263907-overview


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History

The classic clinical triad of ectopic pregnancy is pain, amenorrhea, and vaginal bleeding;unfortunately, only about 50% of patients present with all 3 symptoms. About 40-50% of patients withan ectopic pregnancy present with vaginal bleeding, 50% have a palpable adnexal mass, and 75%may have abdominal tenderness. In one case series of ectopic pregnancies, abdominal painpresented in 98.6% of patients, amenorrhea in 74.1% of them, and irregular vaginal bleeding in 56.4%of patients.[46]

These symptoms overlap with those of spontaneous abortion; a prospective, consecutive case seriesfound no statistically significant differences in the presenting symptoms of patients with unrupturedectopic pregnancies versus those with intrauterine pregnancies.[47]

In first-trimester symptomatic patients, pain as the presenting symptom is associated with an oddsratio of 1.42, and moderate to severe vaginal bleeding at presentation is associated with an odds ratioof 1.42 for ectopic pregnancy.[48] In one study, 9% of patients with ectopic pregnancy presented withpainless vaginal bleeding.[49]As a result, almost 50% of cases of ectopic pregnancy are not diagnosedat the first prenatal visit.

Patients may present with other symptoms common to early pregnancy, including nausea, breast

fullness, fatigue, low abdominal pain, heavy cramping, shoulder pain, and recent dyspareunia. Painfulfetal movements (in the case of advanced abdominal pregnancy), dizziness or weakness, fever,flulike symptoms, vomiting, syncope, or cardiac arrest have also been reported. Shoulder pain may bereflective of peritoneal irritation.

Astute clinicians should have a high index of suspicion for ectopic pregnancy in any woman whopresents with these symptoms and who presents with physical findings of pelvic tenderness, enlargeduterus, adnexal mass, or tenderness.

Approximately 20% of patients with ectopic pregnancies are hemodynamically compromised at initialpresentation, which is highly suggestive of rupture. Fortunately, using modern diagnostic techniques,most ectopic pregnancies may be diagnosed before rupture.

Physical ExaminationThe physical examination of patients with ectopic pregnancy is highly variable and often unhelpful.Patients frequently present with benign examination findings, and adnexal masses are rarely found.Patients in hemorrhagic shock from ruptured ectopic may not be tachycardic.[50]

Some physical findings that have been found to be predictive (although not diagnostic) for ectopicpregnancy include the following:

Presence of peritoneal signs Cervical motion tenderness Unilateral or bilateral abdominal or pelvic tenderness - Usually much worse on the affected side

Abdominal rigidity, involuntary guarding, and severe tenderness, as well as evidence of hypovolemicshock, such as orthostatic blood pressure changes and tachycardia, should alert the clinician to a

surgical emergency; this may occur in up to 20% of cases. However, midline abdominal tenderness ora uterine size of greater than 8 weeks on pelvic examination decreases the risk of ectopicpregnancy.[51]

On pelvic examination, the uterus may be slightly enlarged and soft, and uterine or cervical motiontenderness may suggest peritoneal inflammation. An adnexal mass may be palpated but is usuallydifficult to differentiate from the ipsilateral ovary.

The presence of uterine contents in the vagina, which can be caused by shedding of endometriallining stimulated by an ectopic pregnancy, may lead to a misdiagnosis of an incomplete or completeabortion and therefore a delayed or missed diagnosis of ectopic pregnancy.

Diagnostic Considerations


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Only 50% of patients with an ectopic pregnancy present with the classic triad of pain, amenorrhea,and vaginal bleeding. Numerous conditions may have a presentation similar to an extrauterinepregnancy. The most common of these include the following:

Appendicitis Salpingitis

Ruptured corpus luteum cyst or ovarian follicle Spontaneous abortion or threatened abortion Ovarian torsion Urinary tract disease

Intrauterine pregnancies with other abdominal or pelvic problems, such as degenerating fibroids, mustalso be included in the differential diagnosis.

A study by Huchon et al found that the following 4 symptoms independently contributed to thediagnosis of tubal rupture:

Vomiting during pain Diffuse abdominal pain Acute pain for longer than 30 minutes

Flashing painThe sensitivity was 93% in the presence of 1 or more of these items, and the specificity was 44%,with a negative likelihood ratio for ruling out tubal rupture of 0.16.[52]

The following conditions should also be considered in the differential diagnosis of ectopic pregnancy:

Postabortion bleeding Retained products of abortion Molar pregnancy Cornual myoma or abscess Ovarian tumor Endometrioma Cervical phase of uterine abortion

Differential Diagnoses Abortion Complications Appendicitis Cervical Cancer Dysmenorrhea Early Pregnancy Loss Hemorrhagic Shock Hypovolemic Shock Placenta Previa

Approach Considerations

Patients with early, normal intrauterine pregnancies often present with signs and symptoms similar tothose encountered in patients with ectopic pregnancies and other gynecologic or gastrointestinalconditions. The availability of various biochemical, ultrasonographic, and surgical modalities can aidthe healthcare provider today in establishing a definitive diagnosis and differentiating among variousconditions.

In order to reduce the morbidity and mortality associated with ectopic pregnancy, a high index ofsuspicion is necessary to make a prompt and early diagnosis. As mentioned earlier, neither riskfactors nor signs and symptoms of ectopic pregnancy are sensitive or specific enough to establish adefinitive diagnosis. Hence, screen any female patient in her reproductive years who presents withabdominal pain, cramping, or vaginal bleeding for pregnancy.

Serum and urine assays for the beta subunit of human chorionic gonadotropin (bhCG) have been

developed to detect a pregnancy before the first missed period. While some commercial urine test kitsare able to detect bhCG in early gestation, they are associated with varying false-negative rates. In
http://emedicine.medscape.com/article/795001-overviewhttp://emedicine.medscape.com/article/795001-overviewhttp://emedicine.medscape.com/article/773895-overviewhttp://emedicine.medscape.com/article/773895-overviewhttp://emedicine.medscape.com/article/253513-overviewhttp://emedicine.medscape.com/article/253513-overviewhttp://emedicine.medscape.com/article/253812-overviewhttp://emedicine.medscape.com/article/253812-overviewhttp://emedicine.medscape.com/article/266317-overviewhttp://emedicine.medscape.com/article/266317-overviewhttp://emedicine.medscape.com/article/432650-overviewhttp://emedicine.medscape.com/article/432650-overviewhttp://emedicine.medscape.com/article/760145-overviewhttp://emedicine.medscape.com/article/760145-overviewhttp://emedicine.medscape.com/article/262063-overviewhttp://emedicine.medscape.com/article/262063-overviewhttp://emedicine.medscape.com/article/262063-overviewhttp://emedicine.medscape.com/article/760145-overviewhttp://emedicine.medscape.com/article/432650-overviewhttp://emedicine.medscape.com/article/266317-overviewhttp://emedicine.medscape.com/article/253812-overviewhttp://emedicine.medscape.com/article/253513-overviewhttp://emedicine.medscape.com/article/773895-overviewhttp://emedicine.medscape.com/article/795001-overview


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addition, the need for a quantitative value makes serum bhCG the criterion standard for biochemicaltesting.

Evidence-based guidelines have been established for the diagnostic and therapeutic management ofectopic pregnancy.[53] The highest adherence is the inclusion of vaginal ultrasonography in the workup(98%), whereas the lowest adherence (21%) is performing salpingostomy when the other tube is

abnormal.Blood type, Rh type, and antibody screen should be done in all pregnant patients with bleeding toidentify patients in need of RhoGAM and to ensure availability of blood products in case of excessiveblood loss.

BetaHuman Chorionic Gonadotropin Levels

Serum and urine assays for the beta subunit of human chorionic gonadotropin (-HCG) have beendeveloped to detect a pregnancy before the first missed period. Although some commercial urine testkits are able to detect -HCG in early gestation, they are associated with varying false-negative rates.In addition, the need for a quantitative value makes serum -HCG the criterion standard forbiochemical testing.

Rate of increaseSerum -HCG levels correlate with the size and gestational age in normal embryonic growth. In anormal pregnancy, the -HCG level doubles every 48-72 hours until it reaches 10,000-20,000mIU/mL.In ectopic pregnancies, -HCG levels usually increase less.

In early, healthy intrauterine pregnancies, serum levels of -HCG double approximately every 2 days(1.4-2.1 d). Kadar et al established that the lower limit of the reference range to which serum -HCGshould increase during a 2-day period is 66%.[4] For example, a pregnant patient with a serum -HCGlevel of 100 mIU/mL should have a serum -HCG level of at least 166 mIU/mL 2 days later.

According to Kadar et als study, an increase in -HCG of less than 66% would be associated with anabnormal intrauterine pregnancy or an extrauterine pregnancy. However, remember that 15% ofhealthy intrauterine pregnancies do not increase by 66% and that 13% of all ectopic pregnancies

have normally rising -HCG levels of at least 66% in 2 days.

Shepherd et al demonstrated that 64% of very early ectopic pregnancies initially may have normaldoubling serum -HCG levels.[54] Later, Barnhart et al more reported that the minimum rise in serum -HCG for a potentially viable pregnancy in women who present with vaginal bleeding or pain is 53%per 2 days (up to 5000 IU/L).[55] Hence, intervention when the serum -HCG level rises less than 66%but more than 53% should be undertaken according to other clinical and biochemical criteria.

Furthermore, even though ectopic pregnancies have been established to have lower mean serum -HCG levels than healthy pregnancies, no single serum -HCG level is diagnostic of an ectopicpregnancy. In short, serial serum -HCG levels are necessary to differentiate between normal andabnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has beeninitiated.

Discriminatory zone

The discriminatory zone of -HCG is the level above which a normal intrauterine pregnancy is reliablyvisualized. Once -HCG has reached a level of 700-1000 mIU/mL, a gestational sac should be seenwithin the uterus on transvaginal ultrasonographic images. Once it has reached 6000 mIU/mL, agestational sac should be visualized within the uterus on abdominal scan images.

The lack of an intrauterine pregnancy when the -HCG level is above the discriminatory zonerepresents an ectopic pregnancy or a recent abortion.

Drawbacks to -HCG testing

The major disadvantage in relying on serial -HCG titers to distinguish between normal and abnormalpregnancies is the potential for delay in reaching the diagnosis. Furthermore, although serial -HCG

titers may be used to differentiate between a normal and an abnormal gestation, the test does little to


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indicate the location of the pregnancy. Hence, additional diagnostic modalities, includingultrasonography and other biochemical markers, are needed.

Another disadvantage is in cases of multiple gestations; if a multiple gestation is suspected, as inpregnancies resulting from assisted reproduction, the -HCG discriminatory zone must be usedcautiously. Patients with normal multiple gestates were found to have levels of -HCG above the

discriminatory zone before any ultrasonographic evidence of the gestation was apparent,

[4]

and theyshowed multiple gestations with -HCG levels of up to 2300 mIU/mL before transvaginalultrasonographic recognition.

Also remember that a discriminatory zone is operator and institution dependent; the clinician must beaware of the zone used by a particular institution before interpreting results there.

Progesterone Levels

A single serum progesterone level is another tool that is useful in differentiating abnormal gestationsfrom healthy intrauterine pregnancies. Serum progesterone levels have the following characteristics:

They are not gestational agedependent They remain relatively constant during the first trimester of normal and abnormal pregnancies

They do not return to the reference range if initially abnormal They do not correlate with betahuman chorionic gonadotropin (-HCG) levels

However, no consensus on a single progesterone value that differentiates between a normal and anabnormal pregnancy currently exists.

Several authors have proposed different cutoffs with varying sensitivity and specificity. In one largestudy, a progesterone value of greater than 25 ng/mL excluded ectopic pregnancy with 97.4%certainty. Furthermore, levels of 5 ng/mL or less indicated a nonviable pregnancy, ectopic orintrauterine, and excluded normal pregnancy with 100% sensitivity.

Although inexpensive, the usefulness of serum progesterone is limited by the fact that a significantnumber of results fall in the equivocal range of 5-25 ng/mL. Also, this test is unreliable indifferentiating between normal and abnormal pregnancies in patients who conceive after in vitro

fertilization (IVF), because of excessive progesterone production from multiple corpora lutea, as wellas the practice of pharmacologic progesterone supplementation.

Other Markers

Several other serum and urine markers are under investigation to help distinguish normal andabnormal pregnancies. These include serum estradiol, inhibin, pregnancy-associated plasma protein

A, pregnanediol glucuronide, placental proteins, creatinine kinase, and a quadruple screen of serumprogesterone, betahuman chorionic gonadotropin (-HCG), estriol, and alfa-fetoprotein (AFP). Thesemarkers are usually either early pregnancy proteins or signs of inflammation and damage in smoothmuscles and have not been sufficiently sensitive to be useful in clinical medicine.

Ultrasonography

Ultrasonography is probably the most important tool for diagnosing an extrauterine pregnancy,although it is more frequently used to confirm an intrauterine pregnancy.

Visualization of an intrauterine sac, with or without fetal cardiac activity, is often adequate to excludeectopic pregnancy.[5] The exception to this is in cases of heterotropic pregnancies, which occur inbetween 1 in 4000 and 1 in 30,000 spontaneous pregnancies.

In patients undergoing ovarian stimulation and assisted reproduction, screening the adnexa byultrasonography is mandatory even when an intrauterine pregnancy has been visualized, becausethese patients have a 10-fold increased risk of heterotropic pregnancy. Heterotopic pregnancy is acombined intrauterine and ectopic pregnancy, and it may occur in approximately 1 in 30,000.

The value of ultrasonography is highlighted further by its ability to demonstrate free fluid in the cul-de-sac. However, although free fluid can represent hemoperitoneum, it is not specific for ruptured ectopic

pregnancy. Free fluid on ultrasonographic images can represent physiologic peritoneal fluid or bloodfrom retrograde menstruation and unruptured ectopic pregnancies.


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Ultrasonography can also be used to detect the presence of other pathologic conditions that maydisplay the signs and symptoms of ectopic pregnancy.

Transvaginal/endovaginal ultrasonography

Transvaginal ultrasonography, or endovaginal ultrasonography, with its greater resolution, can beused to visualize an intrauterine pregnancy by 24 days postovulation or 38 days after the last

menstrual period (which is about 1 week earlier than transabdominal ultrasonography can be used forthis). This imaging technique can be performed in the outpatient clinic or emergency department andhas been reported to have a sensitivity of 90% and a specificity of 99.8%, with positive and negativepredictive values of 93% and 99.8% respectively.[56]

Gestational sac

The gestational sac, which is an ultrasonographic term and not an anatomic term, is the first structurethat is recognizable on transvaginal ultrasonographic images. It has a thick, echogenic rimsurrounding a sonolucent center corresponding to the trophoblastic decidual reaction surrounding thechorionic sac. Structures that represent a developing embryo cannot be recognized until a later time.

A pseudosac is a collection of fluid within the endometrial cavity created by bleeding from the

decidualized endometrium and is often associated with an extrauterine pregnancy (see the imagebelow); this should not be mistaken for a normal, early intrauterine pregnancy. The true gestationalsac is located eccentrically within the uterus beneath the endometrial surface, whereas thepseudosac fills the endometrial cavity.

A pseudogestational sac of ectopic pregnancy can be confused with embryonicdemise. This sac is produced when an ectopic pregnancy stimulates the endometrium, with degeneration of the centraldecidual reaction.The yolk sac is the first visible structure within the gestational sac. It resembles a distinct circularstructure with a bright, echogenic rim and a sonolucent center. It can first be recognized at 3 weekspostconception, about 5 weeks after the last menstrual period. The embryo is recognized first as athickening along the edge of the yolk sac; embryonic cardiac motion can be observed at 3.5-4 weekspostconception, about 5.5-6 weeks after the last menstrual period.

Definite intrauterine pregnancy

In a definite intrauterine pregnancy, a gestational sac with a sonolucent center (>5mm in diameter) issurrounded by a thick, concentric, echogenic ring located within the endometrium and contains a fetalpole, a yolk sac, or both. (See the image below.)

An endovaginal sonogram reveals an intrauterine pregnancy at approximately 6weeks. A yolk sac (ys), gestational sac (gs), and fetal pole (fp) are depicted.Probable abnormal intrauterine pregnancy

In a probable abnormal intrauterine pregnancy, the gestational sac is larger than 10mm in diameter,

without a fetal pole or with a definite fetal pole but without cardiac activity. This frequently has anirregular or crenelated border.


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Presumed ectopic pregnancy

An empty uterus on endovaginal ultrasonographic images in patients with a serum betahumanchorionic gonadotropin (-HCG) level greater than the discriminatory cut-off value is an ectopicpregnancy until proven otherwise. An empty uterus may also represent a recent abortion.

Definite ectopic pregnancy

In the presence of a definite ectopic pregnancy, a thick, brightly echogenic, ringlike structure islocated outside the uterus, with a gestational sac containing an obvious fetal pole, a yolk sac, or both.This is an unusual finding. (See the image below.)

An endovaginal sonogram revealing a complex mass outside of the uterus, witha small yolk sac present within. The mass is more echogenic relative to the uterus above and represents an ectopicpregnancy.Other ultrasonographic findings in ectopic pregnancy

Findings such as an adnexal mass (usually a corpus luteum, occasionally hematoma), free cul-de-sacfluid, and/or severe adnexal tenderness with probe palpation may be present. Patients with no definiteintrauterine pregnancy and the above-mentioned findings may be at high risk for an ectopicpregnancy.

An appreciation for the spectrum of ultrasonographic findings in ectopic pregnancy, discussed below,may allow physicians to recognize an early ectopic pregnancy.

Tubal ringA tubal ring is an echogenic, ringlike structure found outside of the uterus that represents an earlyectopic pregnancy. (See the image below.)

An endovaginal sonogram demonstrates an early ectopic pregnancy. Anechogenic ring (tubal ring) found outside of the uterus can be seen in this view.Extrauterine mass

The presence of a tender adnexal mass on ultrasonographic images suggests an ectopic pregnancy.One study suggested that the presence of any adnexal mass other than a simple cyst was the mostsignificant ultrasonographic finding for the diagnosis of ectopic pregnancy.

Interstitial ectopic pregnancy

An interstitial ectopic pregnancy implants at the highly vascular region of the uterus near the insertionof the fallopian tube. These types can grow larger than those within the fallopian tube, because theendometrial tissue is more expandable. Owing to the increased size and partial endometrial

implantation, these advanced ectopic pregnancies can be misdiagnosed as intrauterine pregnancies.


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An aid in the diagnosis of an interstitial ectopic pregnancy is the eccentric location of the gestationalsac. Evaluating the amount of uterine myometrium surrounding the gestational sac and echogenicdecidual layer is important. This is termed the myometrial mantle. At least 5mm of myometrium shouldbe present. The presence of less than 5mm suggests the diagnosis. Another ultrasonographic findingis the interstitial line sign.

Hemosalpinx and ruptured ectopic pregnancyA hemosalpinx is a condition in which the fallopian tubes may fill with blood or free fluid. Findings of aruptured ectopic pregnancy on ultrasonographic images include free fluid or clotted blood in the cul-de-sac or in the intraperitoneal gutters, such as the Morrison pouch.

Ultrasonography and discriminatory zone of -HCG

In the absence of reliable menstrual and ovulatory history, a discriminatory zone of -HCG levelsvalidates the ultrasonographic findings. The discriminatory zone is the level of -HCG (using the ThirdInternational Standard for quantitative -HCG) at which all intrauterine pregnancies should be visibleon ultrasonography. With abdominal ultrasonography, that level is 6000-6500 mIU/mL, but high-resolution transvaginal ultrasonography has reduced this level to 1500-1800 mIU/mL. If transvaginalultrasonography does not reveal an intrauterine pregnancy when the discriminatory -HCG levels are

reached, the pregnancy generally can be considered extrauterine.

An exception to this is multiple gestations. Kadar et al reported that patients with normal multiplegestates not only had levels of -HCG above the discriminatory zone before any ultrasonographicevidence of the gestation was apparent, they also showed that multiple gestations with -HCG levelsof up to 2300 mIU/mL could be present before transvaginal ultrasonographic recognition.[4] Therefore,if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the -HCGdiscriminatory zone must be used cautiously.

Nonetheless, the effectiveness of using ultrasonography with a discriminatory zone of -HCG levelshas been well established in the literature.

In one large study of more than 1200 patients, Barnhart et al reported that 78.8% of patients werediagnosed definitively at the initial visit using an algorithm that included the use of ultrasonography,along with serum -HCG levels above the discriminatory zone.[57] In this study, if the patient's serum -HCG level was above the established discriminatory zone at initial presentation and an intrauterinesac was not identified, an operative approach involving curettage and possible operative laparoscopywas used to diagnose ectopic pregnancy.[57]

If the patient's serum -HCG levels were below the discriminatory zone, serial -HCG titers wereperformed every 2 days. Once a patient's levels reached the discriminatory zone, ultrasonographywas performed.[57] If, however, the patient's -HCG levels failed to rise appropriately (ie, at least 66%in 2 d), operative intervention was undertaken with dilatation and curettage or with laparoscopy, toexclude the diagnosis of ectopic pregnancy. With this protocol, Barnhart et al reported a sensitivity of100% and a specificity of 99.9%.[57]

A discriminatory zone is operator and institution dependent, and the clinician must be aware of the

zone used by a particular institution before interpreting results.

Doppler ultrasonography

Color-flow Doppler ultrasonography has been demonstrated to improve the diagnostic sensitivity andspecificity of transvaginal ultrasonography, especially in cases in which a gestational sac isquestionable or absent. A study of 304 patients at high risk for ectopic pregnancy found that the useof color-flow Doppler ultrasonography, compared with transvaginal ultrasonography alone, increasedthe diagnostic sensitivity from 71% to 87% for ectopic pregnancy, from 24% to 59% for failedintrauterine pregnancy, and from 90% to 99% for viable intrauterine pregnancy.

The addition of color-flow Doppler ultrasonography may expedite earlier diagnosis and eliminatedelays caused by using levels of -HCG for diagnosis. Furthermore, color-flow Dopplerultrasonography can potentially be used to identify involuting ectopic pregnancies that may be

candidates for expectant management.


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Dilatation and Curettage

A simple way to rule out an ectopic pregnancy is to establish the presence of an intrauterinepregnancy. Once the presence of an abnormal pregnancy has been established by assessing betahuman chorionic gonadotropin (-HCG) or progesterone levels, dilatation and curettage can provide arapid, cost-effect method to help differentiate between an intrauterine and an ectopic pregnancy.

If the tissue obtained is positive for villi by floating in saline or by histologic diagnosis on frozen orpermanent section, then a nonviable intrauterine pregnancy has occurred. In the absence of villi, thediagnosis of ectopic pregnancy is made. Laparoscopy can be performed at that time, or the case maybe followed using serial serum -HCG levels and be treated medically or surgically at a later time,depending on the clinical setting.

This method of diagnostic dilatation and curettage may be used, of course, only in cases in whichcontinuation of a pregnancy is not desired even if it were an intrauterine gestation.

In a patient undergoing a dilatation and curettage for the diagnosis of ectopic pregnancy, obtainingconsent for a diagnostic, and possibly operative, laparoscopy is also necessary in case the diagnosisof ectopic pregnancy is made; this spares the patient exposure to an additional operative procedure.

Although dilatation and curettage is easy and effective, it can provide false reassurance in cases ofheterotropic pregnancies, in which multiple gestations are present, with at least 1 being intrauterineand 1 being extrauterine.

Culdocentesis

Culdocentesis is another rapid and inexpensive method of evaluation for ruptured ectopic pregnancy.It is performed by inserting a needle through the posterior fornix of the vagina into the cul-de-sac andattempting to aspirate blood. When nonclotting blood is found in conjunction with a suspected ectopicpregnancy, operative intervention is indicated, because the likelihood of a ruptured ectopic pregnancyis high.

Although culdocentesis is of historic interest, its use today is rare. This procedure is associated with ahigh false-negative rate (10-14%), usually reflecting blood from an unruptured ectopic pregnancy, a

ruptured corpus luteum, an incomplete abortion, or retrograde menstruation. Furthermore, theimproved technology with ultrasonographic and hormonal assays is far superior in sensitivity andspecificity in reaching the correct diagnosis.

Laparoscopy

Patients in pain and/or those who are hemodynamically unstable should proceed to laparoscopy.Laparoscopy allows assessment of the pelvic structures, the size and exact location of the ectopicpregnancy, the presence of hemoperitoneum (see the image below), and the presence of otherconditions, such as ovarian cysts and endometriosis, which, when present with an intrauterinepregnancy, can mimic an ectopic pregnancy. Furthermore, laparoscopy provides the option to treatonce the diagnosis is established.

Laparoscopic picture of an unruptured right ampullary tubal pregnancy;bleeding out of the fimbriated end has resulted in hemoperitoneum.Laparoscopy remains the criterion standard for diagnosis; however, its routine use on all patientssuspected of ectopic pregnancy may lead to unnecessary risks, morbidity, and costs. Moreover,laparoscopy can miss up to 4% of early ectopic pregnancies; as more ectopic pregnancies are

diagnosed earlier in gestation, the rate of false-negative results with laparoscopy would be expectedto rise.
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Alcoholism Alcoholic liver disease Any other type of liver disease Blood dyscrasias Leukopenia Thrombocytopenia Anemia Active pulmonary disease Peptic ulcer disease Renal, hepatic, or hematologic dysfunction

Adverse effects and mandatory patient counseling

Adverse effects associated with the use of methotrexate can be divided into adverse drug effects andtreatment effects. Adverse drug effects include the following:

Nausea Vomiting Stomatitis Diarrhea Gastric distress Dizziness

Transient elevation in liver enzymes is also known to occur. Serious reactions such as bone marrowsuppression, dermatitis, pleuritis, pneumonitis, and reversible alopecia can occur with higher dosesbut are rare with doses used in the treatment of ectopic pregnancy.

Treatment effects of methotrexate include an increase in abdominal pain (occurring in up to two thirdsof patients), an increase in -HCG levels during the first 1-3 days of treatment, and vaginal bleedingor spotting.

The medical treatment of ectopic pregnancy requires compulsive compliance. The physician mustemphasize the importance of patient follow-up and have patient information on hand, including thepatient's home address, telephone numbers at home and work, and the means to reach a contact

person in case attempts to reach the patient directly are unsuccessful. Proper documentation ofattempts to reach the patient, including records of telephone calls and certified mail are importantmedical-legal considerations.

Before injection of methotrexate, the patient must be counseled extensively on the risks, benefits, andadverse effects of the treatment and on the possibility of failure of medical therapy, which would resultin tubal rupture and necessitate surgery. Patients should be aware of the signs and symptomsassociated with tubal rupture, and they should be advised to contact their physician with significantlyworsening abdominal pain or tenderness, heavy vaginal bleeding, dizziness, tachycardia, palpitations,or syncope.

Most patients experience at least 1 episode of increased abdominal pain, which usually occurs 2-3days after the injection. Increased abdominal pain is believed to be caused by the separation of the

pregnancy from the implanted site. It can be differentiated from tubal rupture in that it is milder, oflimited duration (lasting 24-48 h), and is not associated with signs of acute abdomen or hemodynamicinstability.

Advise patients to avoid alcoholic beverages, vitamins containing folic acid, nonsteroidal anti-inflammatory drugs (NSAIDs), and sexual intercourse, until advised otherwise. A signed writtenconsent demonstrating the patient's comprehension of the course of treatment must be obtained.Provide an information pamphlet to all patients receiving methotrexate; the pamphlet should include alist of adverse effects, a schedule of follow-up visits, and a method of contacting the physician or thehospital in case of emergency.

Methotrexate Treatment Protocols

A number of accepted protocols with injected methotrexate exist for the treatment of ectopic

pregnancy.


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Multiple-dose regimen

Initial experience used multiple doses of methotrexate with leucovorin to minimize adverse effects.Leucovorin is folinic acid that is the end product of the reaction catalyzed by dihydrofolate reductase,the same enzyme inhibited by methotrexate. Normal dividing cells preferentially absorb leucovorin;hence, it decreases the action of methotrexate, thereby decreasing methotrexates adverse systemiceffects.

This regimen involves administration of methotrexate as 1 mg/kg IM on days 0, 2, 4, and 6, followedby 4 doses of leucovorin as 0.1 mg/kg on days 1, 3, 5, and 7. Because of a higher incidence ofadverse effects and the increased need for patient motivation and compliance, the multiple dosageregimen has fallen out of favor in the United States.

Single-dose regimen

The more popular regimen today is the single-dose injection, which involves injection of methotrexateas 50 mg/m2 IM in a single injection or as a divided dose injected into each buttock. Studiescomparing the multiple methotrexate dosage regimen with the single dosage regimen havedemonstrated that the 2 methods have similar efficacy. With smaller dosing and fewer injections,fewer adverse effects are anticipated, and the use of leucovorin can be abandoned.

The protocol for single-dose methotrexate is detailed below. Using this protocol, Stovall et al achieveda 96% success rate with a single injection of methotrexate.[8]

Day 0

Obtain -HCG level, ultrasonography, and +/- dilatation and curettage.

Day 1

Obtain levels of the following:

-HCG Liver function - Eg, aspartate aminotransferase (AST or serum glutamic-oxaloacetic transaminase

[SGOT]), alanine aminotransferase (ALT or serum glutamic-pyruvic transaminase [SGPT]) Blood urea nitrogen (BUN) Creatinine

Evidence of hepatic or renal compromise is a contraindication to methotrexate therapy. Blood type,Rh status, and antibody screening are also performed, and all Rh-negative patients are given Rhimmunoglobulin.

Methotrexate (50 mg/m2) is administered by IM injection. Advise patients not to take vitamins with folicacid until complete resolution of the ectopic pregnancy. They should also refrain from alcoholconsumption and intercourse for the same period.

Day 4

The patient returns for measurement of her -HCG level. The level may be higher than the

pretreatment level. The day-4 hCG level is the baseline level against which subsequent levels aremeasured.

Day 7

Draw -HCG and AST levels and perform a complete blood count (CBC). If the -HCG level hasdropped 15% or more since day 4, obtain weekly -HCG levels until they have reached the negativelevel for the lab. If the weekly levels plateau or increase, a second course of methotrexate may beadministered.

If the -HCG level has not dropped at least 15% from the day-4 level, administer a second IM dose ofmethotrexate (50 mg/m2) on day 7, and observe the patient similarly. If no drop has occurred by day14, surgical therapy is indicated.

If the patient develops increasing abdominal pain after methotrexate therapy, repeat a transvaginalultrasonographic scan to evaluate for possible rupture.


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Treatment monitoring protocols

The best predictor of success of medical therapy is the initial -HCG level. Based on efficacy studiesdone by Lipscomb et al, success exceeded 90% for single-dose methotrexate when -HCG levelswere less than 5000 mIU/mL but dropped to about 80% when levels were 5-10,000 mIU/mL. Successwas less than 70% with an initial -HCG level of greater than 15,000 mIU/mL.[7]

Before initiating therapy, draw blood to determine baseline laboratory values for renal, hepatic, andbone marrow function, as well as a baseline -HCG level. Determine blood type, Rh factor, and thepresence of antibodies. Patients who are Rh negative should receive Rh immunoglobulin.

Obtain repeat -HCG levels 4 days and 7 days after the methotrexate injection. An initial increase in-HCG levels often occurs by the third day and is not a cause for alarm. A decline in -HCG levels ofat least 15% from days 4 to 7 postinjection indicates a successful medical response. Other effectivemonitoring protocols have also been reported.[61] The patient's -HCG levels should be measuredweekly, until they become undetectable.

Failure of medical treatment is defined when -HCG levels increase, plateau, or fail to decreaseadequately by 15% from days 4 to 7 postinjection. At this time, surgical intervention may bewarranted. A repeat single dose of methotrexate can also be a viable option after reevaluation of the

patients' indications and contraindications (including repeat ultrasonography) for medical therapy.

Investigational Medical Treatments

The use of oral methotrexate is under investigation; although preliminary reports show promisingresults, efficacy remains to be established. Direct local injection (salpingocentesis) of methotrexateinto the ectopic pregnancy under laparoscopic or ultrasonographic guidance has also been reportedin the literature; however, these studies have yielded inconsistent results, and the advantage of thistechnique over IM injection remains to be established.

Although methotrexate has remained the most effective and popular drug used in medical therapy foran ectopic pregnancy, other protocols have been used, such as potassium chloride, hyperosmolarglucose, mifepristone (RU 486), and prostaglandins, and these agents have been administered orally,systemically, and locally into the ectopic pregnancy directly. These therapies remain experimental at

present because the efficacy of such treatments, as well as their advantage over standardmethotrexate protocol, has not been established.

Salpingostomy and Salpingectomy

Within the last 2 decades, a more conservative surgical approach to unruptured ectopic pregnancyusing minimally invasive surgery has been advocated to preserve tubal function. The conservativeapproaches include linear salpingostomy and milking the pregnancy out of the distal ampulla. Themore radical approach includes resecting the segment of the fallopian tube that contains thegestation, with or without reanastomosis.

Laparoscopy has become the recommended approach in most cases. Laparotomy is usually reservedfor patients who are hemodynamically unstable or for patients with cornual ectopic pregnancies; italso is a preferred method for surgeons inexperienced in laparoscopy and in patients in whom alaparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions,obesity, or massive hemoperitoneum).

Multiple studies have demonstrated that laparoscopic treatment of ectopic pregnancy results in fewerpostoperative adhesions than laparotomy. Furthermore, laparoscopy is associated with significantlyless blood loss and a reduced need for analgesia. Finally, laparoscopy reduces cost, hospitalizationtime, and convalescence period.

Linear salpingostomy along the antimesenteric border to remove the products of conception is theprocedure of choice for unruptured ectopic pregnancies in the ampullary portion of the tube. Ectopicpregnancies in the ampulla are usually located between the lumen and the serosa and, thus, are idealcandidates for linear salpingostomy. Several studies have demonstrated no benefit of primary closure(salpingotomy) over healing by secondary intention (salpingostomy).


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Total salpingectomy is the procedure of choice in a patient who has completed childbearing and nolonger desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in apatient with severely damaged tubes.

In cases involving uncontrolled bleeding and hemodynamic instability, conservative treatmentmethods are avoided in favor of radical surgery.

Linear salpingostomy

In linear salpingostomy, the involved tube is identified and freed from surrounding structures. Tominimize bleeding, a dilute solution containing 20 U of vasopressin in 20 mL of isotonic sodiumchloride solution may be injected into the mesosalpinx just below the ectopic pregnancy. Make surethat the needle is not in a blood vessel by aspirating before injecting, because intravascular injectionof vasopressin may precipitate acute arterial hypertension and bradycardia.

Next, using a microelectrode, scissors, harmonic scalpel, or laser, a 1- to 2-cm linear incision is madealong the antimesenteric side of the tube along the thinnest segment of the gestation. (See the imagebelow.)

Linear incision being made at the antimesenteric side of the ampullary portion of thefallopian tube.

At this time, the pregnancy usually protrudes out of the incision and may slip out of the tube.Occasionally, it must be teased out using forceps or aqua-dissection, which uses pressurizedirrigation to help dislodge the pregnancy. (See the images below.)

Laparoscopic picture of an ampullary ectopic pregnancy protruding out after a

linear salpingostomy was performed. Schematic of a tubal gestation beingteased out after linear salpingostomy.

Coagulation of oozing areas may be necessary and can be accomplished using microbipolar forceps.Some ampullary pregnancies can be teased out and expressed through the fimbrial end (milking ofthe tube) by using digital expression, suction, or aqua-dissection. However, this approach carries with
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it a higher rate of bleeding, persistent trophoblastic tissue, tubal damage, and recurrent ectopicpregnancy (33%).

Segmental tubal resection and total salpingectomy

In some cases, resection of the tubal segment containing the gestation or a total salpingectomy ispreferred over salpingostomy. This is true for isthmic pregnancies, in which the endosalpinx is usually

damaged. These patients do poorly with linear salpingostomy, with a high rate of recurrent ectopicpregnancy occurring.

Segmental tubal resection is performed by grasping the tube at the proximal and distal borders of thesegment of the tube containing the gestation and coagulating thoroughly from the antimesentericborder to the mesosalpinx. This portion of the tube is then excised. The underlying mesosalpinx isalso coagulated and excised, with particular attention to minimize the damage to the surroundingvasculature.

Delayed microsurgical reanastomosis can be performed to reestablish tubal patency if enough healthyfallopian tube is present. Take care to minimize the thermal injury to the tube during excision, so thatan adequate portion of healthy tube remains for the reanastomosis.

Total salpingectomy can be achieved by progressively coagulating and cutting the mesosalpinx,starting from the fimbriated end and advancing toward the proximal isthmic portion of the tube. At thispoint, the tube is separated from the uterus by coagulating and excising with scissors or laser.

Preoperative details

The optimal surgical management for a patient with an ectopic pregnancy depends on several factors,including the following:

Patient's age, history, and desire for future fertility History of previous ectopic pregnancy or pelvic inflammatory disease (PID) Condition of the ipsilateral tube - Ie, ruptured or unruptured Condition of the contralateral tube - Eg, adhesions, tubal occlusion Location of the pregnancy - Ie, interstitium, ampulla, isthmus Size of the pregnancy Presence of confounding complications

In a patient who has completed childbearing and no longer desires fertility, in a patient with a historyof an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, totalsalpingectomy is the procedure of choice. The presence of uncontrolled bleeding and hemodynamicinstability warrants radical surgery over conservative methods. The preferred approach based on thelocation of the pregnancy varies, as previously discussed. In all instances, regardless of desiredfertility, fully inform the patient of the possibility of a laparotomy with bilateral salpingectomy.

Intraoperative details

Throughout the procedure, take care to minimize blood loss and reduce the potential for retainedtrophoblastic tissue, which can reimplant and persist. Remove large gestations in an endoscopic bag,

and perform copious irrigation and suctioning to remove any remaining fragments. Inspect theperitoneal cavity and remove any detected residual trophoblastic tissue.

Note the condition of the contralateral tube, the presence of adhesions, or other pathologic processesbecause this helps in the postoperative counseling of the patient with regard to future fertility potential.

Postoperative details

Proper pain control and hemodynamic stability are important postoperative considerations. Mostoften, patients treated with laparoscopy are discharged on the same day of surgery; however,overnight admission may be necessary for some patients in order to monitor postoperative bleedingand achieve adequate pain control. Patients treated by laparotomy are usually hospitalized for a fewdays.

Monitoring


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After surgical excision of an ectopic gestation, weekly monitoring of quantitative betahumanchorionic gonadotropin (-HCG) levels is necessary until the level is zero to ensure that treatment iscomplete. This is especially true following treatment with conservative surgery, ie, salpingostomy,which carries a 5-15% rate of persistent trophoblastic tissue. The average time for -HCG to clear thesystem is 2-3 weeks, but up to 6 weeks can be required.

After tubal-sparing surgical removal of an ectopic pregnancy, a fall in -HCG levels of less than 20%every 72 hours represents incomplete treatment. Although most of these cases are caused byincomplete removal of trophoblastic tissue, some actually may represent multiple ectopic pregnanciesin which only 1 gestation is initially recognized and treated.

The incidence of persistent trophoblastic tissue is greater with higher initial -HCG levels and isrelatively rare with titers of less than 3000 IU/L. The risk of persistent trophoblastic tissue is verysignificant when a hematosalpinx is greater than 6cm in diameter, a -HCG titer is more than 20,000IU/L, and a hemoperitoneum is greater than 2 L.

While resolution without any further intervention is the general rule, the persistence of trophoblastictissue has been associated with tubal rupture and hemorrhage even in the presence of declining -HCG levels. Further medical treatment with methotrexate or surgery in symptomatic patients may benecessary if -HCG levels do not decline or persist. Some authors have suggested administration of a

prophylactic dose of methotrexate after conservative surgery to reduce the risk of persistent ectopicpregnancy

Medication Summary

The standard medical treatment for unruptured ectopic pregnancy is methotrexate therapy.Methotrexate is an antineoplastic agent that inhibits cell proliferation by destroying rapidly dividingcells. It acts as a folate antagonist.[62] The decision to use this agent should be made in conjunctionwith, if not by, the consulting obstetric specialist.

The ideal candidate for medical treatment should have the following:

Hemodynamic stability No severe or persisting abdominal pain The ability to follow up multiple times Normal baseline liver and renal function test results.

Contraindications

Absolute contraindications to methotrexate therapy include the following:

Existence of an intrauterine pregnancy Immunodeficiency Moderate to severe anemia, leukopenia, or thrombocytopenia Sensitivity to methotrexate Act

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Ectopic Pregnancy - Medscape