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Ectopic Pregnancy

Practice Essentials
Ectopic pregnancy is the result of a flaw in human reproductive physiology that allows the conceptus to 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 an adnexal mass in the absence of an intrauterine pregnancy on transvaginal sonography had a positive likelihood ratio (LR+) of 111 for ectopic pregnancy, while the lack of adnexal abnormalities on transvaginal sonography decreases the likelihood of ectopic pregnancy. All components of the history had 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 ectopic pregnancy.[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 pregnancy See Clinical Presentation for more detail.

Diagnosis
Serum -HCG levels In a normal pregnancy, the -HCG level doubles every 48-72 hours until it reaches 10,00020,000mIU/mL. In ectopic pregnancies, -HCG levels usually increase less. Mean serum -HCG levels are lower in ectopic pregnancies than in healthy pregnancies.

No single serum -HCG level is diagnostic of an ectopic pregnancy. Serial serum -HCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated. The discriminatory zone of -HCG (ie, the level above which an imaging scan should reliably visualize a 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 multiple gestates[4] 6000-6500 mIU/mL with abdominal ultrasonography Absence of an intrauterine pregnancy on a scan when the -HCG level is above the discriminatory zone 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 exclude ectopic pregnancy.[5] Transvaginal ultrasonography, or endovaginal ultrasonography, can be used to visualize an intrauterine pregnancy by 24 days postovulation or 38 days after the last menstrual period (about 1 week earlier than transabdominal ultrasonography). An empty uterus on endovaginal ultrasonographic images in patients with a serum -HCG level greater than the discriminatory cut-off value is an ectopic pregnancy until proved otherwise. Color-flow Doppler ultrasonography improves the diagnostic sensitivity and specificity of transvaginal ultrasonography, 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 patients suspected 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. See Workup for 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 of rupture 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 occur despite low and declining serum levels of -HCG. Methotrexate Methotrexate is the standard medical treatment for unruptured ectopic pregnancy. A single-dose IM injection 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

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 usually reserved for patients who are hemodynamically unstable or for patients with cornual ectopic pregnancies; it also is a preferred method for surgeons inexperienced in laparoscopy and in patients in whom a laparoscopic approach is difficult. See Treatment and Medication for more detail.

Image library

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

Background
Ectopic pregnancy refers to the implantation of a fertilized egg in a location outside of the uterine cavity, 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 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 of place), 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 is designed to expand and accommodate fetal development. Ectopic pregnancy can lead to massive hemorrhage, infertility, or death (see the images below). (See Etiology and Prognosis.)

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, 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).

In 1970, the Centers for Disease Control and Prevention (CDC) began to record statistics regarding ectopic pregnancy, reporting 17,800 cases. By 1992, the number of ectopic pregnancies had increased to 108,800. Concurrently, however, the case-fatality rate decreased from 35.5 deaths per 10,000 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 in making an earlier diagnosis. Ectopic pregnancies that previously would have resulted in tubal abortion 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.[6, 7, 8] As the ability to diagnose ectopic pregnancy improves, physicians will be able to intervene sooner, preventing life-threatening sequelae and extensive tubal damage, 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 or 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 in the fallopian tube; the most common site is the ampullary portion of the tube, where over 80% of ectopic pregnancies 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 ectopic pregnancies implant in the cervix (< 1%), in previous cesarean delivery scars, or in a rudimentary uterine horn; although these may be technically in the uterus, they are not considered normal intrauterine pregnancies.[9] About 80% of ectopic pregnancies are found on the same side as the corpus luteum (the old, ruptured follicle), when present.[10] In the absence of modern prenatal care, abdominal pregnancies can present at 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 abnormal implantation. 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 that hampers 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 ectopic pregnancy: Tubal damage - Which can be the result of infections such as pelvic inflammatory disease (PID) or salpingitis (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 assisted reproduction seem to have a doubled risk of ectopic pregnancy (to 4%), although this is mostly due to 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 risk factor.[14] A 2009 literature review found 56 reported cases of ectopic pregnancy (by definition), dating back to 1937, after hysterectomy.[15]

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 asymptomatic cervicitis to salpingitis and florid PID. More than 50% of women who have been infected 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 of tubal damage increases after successive episodes of PID (ie, 13% after 1 episode, 35% after 2 episodes, 75% after 3 episodes). Effective vaccination against Chlamydia trachomatis is under investigation. Once clinically available, it should have a dramatic impact on the frequency of ectopic pregnancy, as well as on the overall 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 another ectopic pregnancy. Overall, a patient with a previous ectopic pregnancy has a 50-80% chance of having 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 include salpingostomy, 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 ectopic pregnancy; 35-50% of patients who conceive after a tubal ligation are reported to experience an ectopic pregnancy. Failure after bipolar tubal cautery is more likely to result in ectopic pregnancy than is occlusion using suture, rings, or clips. This failure is attributed to fistula formation that allows 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. [16]

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

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 doseresponse effect has also been suggested. Based on laboratory studies in humans and animals, researchers have postulated several mechanisms by which cigarette smoking might play a role in ectopic pregnancies. These mechanisms 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 by which cigarette smoking 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 lower risk of ectopic pregnancy. However, among cases of contraceptive failure, women at increased 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. [17] The presence of an inert, copper-containing or progesterone IUD traditionally has been thought to be a risk factor for ectopic pregnancy. However, only the progesterone IUD has a rate of ectopic pregnancy higher than that for women not using any form of contraception. The modern copper IUD does not increase the risk of ectopic pregnancy. Nevertheless, if a woman ultimately conceives with 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%.[18] Emergency contraception (levonorgestrel, or Plan B) does not appear to lead to a higher-thanexpected 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 4fold increase in the risk of ectopic pregnancy in a case-control study. This finding suggests that multiple eggs and high hormone levels may be significant factors. One study demonstrated that infertility patients with luteal phase defects have a statistically higher ectopic pregnancy rate than do patients whose infertility is caused by anovulation. In addition, the risk of ectopic pregnancy and heterotopic pregnancy (ie, pregnancies occurring simultaneously in different 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.[20] In a study of 3000 clinical pregnancies achieved through in vitro fertilization, the ectopic pregnancy rate was 4.5%, which is more than double the background incidence. Furthermore, studies have demonstrated 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 in the risk of developing an ectopic pregnancy exists compared with women aged 15-24 years. One proposed explanation suggests that aging may result in a progressive loss of myoelectrical activity in 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 the myosalpinx 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 have evidence of salpingitis isthmica nodosum. The etiology of salpingitis isthmica nodosum is unclear, but

proposed mechanisms include postinflammatory and congenital changes, as well as acquired tubal changes, 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 mothers to 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, spontaneous abortion, and ectopic pregnancy.[23]

Other
Other risk factors associated with increased incidence of ectopic pregnancy include anatomic abnormalities 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 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, the prevalence 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. This number rose to 88,000 in 1989[24] 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).[25] 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,[26] but a review of electronic 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 from 1997-2000.[27] This suggests that the incidence of ectopic pregnancy in the United 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 or whether 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%.[28] 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.[29]

Racial- and age-related demographics


In the United States from 1991 to 1999, ectopic pregnancy was the cause of 8% of all pregnancyrelated deaths among black women, compared with 4% among white women.[30] Any woman with functioning ovaries can potentially have an ectopic pregnancy, which includes women 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.[14]

Prognosis
Ectopic pregnancy presents a major health problem for women of childbearing age. It is the result of a flaw in human reproductive physiology that allows the conceptus to 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] The evidence in the literature reporting on the treatment of ectopic pregnancy with subsequent reproductive outcome is limited mostly to observational data and a few randomized trials comparing treatment options. Assessment of successful treatment and future reproductive outcome with various treatment options is often skewed by selection bias. For example, comparing a patient who was managed expectantly with a patient who received methotrexate or with a patient who had a laparoscopic salpingectomy is difficult. 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 with hemodynamic instability, an acute abdomen, and high initial -HCG levels must be managed surgically. 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 either salpingostomy or salpingectomy with regard to improving future reproductive outcome. However, despite the risk of persistent ectopic pregnancy, some studies have shown salpingostomy to improve reproductive outcome in patients with contralateral tubal damage. Yao and Tulandi concluded from a literature review that laparoscopic salpingostomy had a reproductive performance that was equal to or slightly better than salpingectomy; however, slightly higher recurrent ectopic pregnancy rates were noted in the salpingostomy group.[31] In reporting on 10 years of surgical experience in Paris, Dubuisson et al concluded that, for selected patients 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 tubal conservation surgery.[32] Future fertility rates were no different with either surgical approach when the contralateral tube was either normal or scarred but patent. Clausen reviewed literature from the previous 40 years and concluded that only a small number of investigators have suggested, indirectly, that conservative tubal surgery increases the rate of subsequent intrauterine pregnancy. He also concluded that the more recent studies may reflect an improvement in surgical technique.[33] 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.[34] The modern pelvic surgeon has been led to believe that the treatment of choice for unruptured ectopic pregnancy is salpingostomy, sparing the affected fallopian tube and thereby improving future reproductive outcome. However, if the treating surgeon has neither the laparoscopic skill nor the instrumentation necessary to atraumatically remove the trophoblastic tissue via linear salpingostomy, then salpingectomy by laparoscopy or laparotomy is not the wrong surgical choice. Leaving a scarred, charred fallopian tube 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 postsurgical fertility. Parker and Bistis concluded that when the contralateral fallopian tube is normal, the subsequent fertility rate is independent of the type of surgery.[35] Similarly, a prospective study of 88 patients by

Ory et al indicated that the surgical method had no effect on subsequent fertility in women with an intact 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 on future fertility than does the choice of surgical procedure. According to Rulin, salpingectomy should be the treatment of choice in women with intact contralateral tubes, because conservative treatment provides no additional benefit and incurs the additional costs and morbidity associated with persistent ectopic pregnancy and recurrent ectopic pregnancy in the already damaged tube.[37] Future fertility rates have been found to be similar in patients who are treated surgically by laparoscopy or laparotomy. Salpingectomy by laparotomy carries a subsequent intrauterine pregnancy rate of 25-70%, compared with laparoscopic salpingectomy rates of 50-60%. Very similar 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%). This surprising 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 also revealed similar 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, assuming that the previously mentioned selection criteria are observed. The average success rates using the multiple-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% of these patients and recurrent ectopic pregnancy in 11% of them. Other studies have demonstrated similar results, with intrauterine pregnancy rates ranging from 20-80%. The average success rates for the single-dosage methotrexate regimen are reported to be from 8894%. In a study by Stovall and Ling, 113 patients (94%) were treated successfully, 4 (3.3%) of whom needed a second dose.[38] No adverse effects were encountered. Furthermore, 87.2% of these patients achieved a subsequent intrauterine pregnancy, whereas 12.8% experienced a subsequent ectopic pregnancy.[38] Other studies have reported similar results, with some mild adverse effects and lower reproductive outcomes. A meta-analysis that included data from 26 trials demonstrated a success rate of 88.1% with the single-dose methotrexate regimen and a success rate of 92.7% with the multiple-dose regimen.[39] A small, randomized clinical trial also demonstrated the single-dose regimen to have a slightly higher failure rate.[40] A hybrid protocol, involving 2 equal doses of methotrexate (50 mg/m 2) given on days 1 and 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 treatment approach. Failure to make the prompt and correct diagnosis of ectopic pregnancy can result in tubal or uterine rupture (depending on the location of the pregnancy), which in turn can lead to massive hemorrhage, shock, disseminated intravascular coagulopathy (DIC), and death. Ectopic pregnancy is the leading cause of maternal death in the first trimester, accounting for 9-13% of all pregnancyrelated deaths. In the United States, an estimated 30-40 women die each year from ectopic pregnancy. Any time a surgical approach is chosen as the treatment of choice, consider the complications attributable 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 vessels nearby. Infertility may also result secondary to loss of reproductive organs after surgery. Also consider

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 accounts for 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 in Michigan, 44% of the women who died were either found dead at home or were dead on arrival at the emergency department.[43] Virtually all ectopic pregnancies are considered nonviable and are at risk of eventual rupture and resulting hemorrhage. In addition to the immediate morbidity caused by ectopic pregnancy, the woman's future ability to reproduce may be adversely affected as well. However, patients who are diagnosed with ectopic pregnancy before rupture have a low mortality rate and also have a chance at preserved fertility. From 1970 to 1989, the US mortality rate for ectopic pregnancies dropped from 35.5 deaths to 3.8 deaths per 10,000 ectopic pregnancies.[24] If the overall incidence of ectopic pregnancy remained stable 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 that ectopic pregnancy was the cause of 5.6% of 4200 maternal deaths. Of these deaths, 93% occurred via hemorrhage.[30] During 19992008, the ectopic pregnancy mortality rate in the United States was 0.6 deaths per 100,000 live births. The CDC reported a higher rate in Florida, 2.5 deaths per 100,000 live births during 2009-2010. The 11 ectopic pregnancy deaths in Florida during 2009-2010 contrasted with the 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.[42] The mortality rate reported in African hospital-based studies varied from 50-860 deaths per 10,000 ectopic 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 ectopic pregnancy was the cause of 4.9% of pregnancy-related deaths in the industrialized world.[45] Ectopic pregnancy caused 26% of maternal deaths in early pregnancy in the United Kingdom from 20032005, second only to venous thromboembolism, despite a relatively low mortality rate of 0.035 per 10,000 estimated ectopic pregnancies.[29]

Patient Education
Advise patients receiving methotrexate therapy to avoid alcoholic beverages, vitamins containing folic acid, 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 a list of adverse effects, a schedule of follow-up visits, and a method of contacting the physician or the hospital in case of emergency, as well as the need to return to the emergency department for concerning symptoms. Patients with risk factors for ectopic pregnancy should be educated regarding their risk of having an ectopic pregnancy. Women who are being discharged with a pregnancy of unknown location should be educated regarding the possibility of ectopic pregnancy and their need for urgent follow-up. Patients undergoing assisted reproduction technology should be educated regarding their risk of heterotopic pregnancy. For patient education information, see the Pregnancy Center and the Women's Health Center, as well as Ectopic Pregnancy, Bleeding During Pregnancy, Vaginal Bleeding, Birth Control Overview, and Birth Control Methods.

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 with an 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 pain presented 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 series found no statistically significant differences in the presenting symptoms of patients with unruptured ectopic pregnancies versus those with intrauterine pregnancies.[47] In first-trimester symptomatic patients, pain as the presenting symptom is associated with an odds ratio of 1.42, and moderate to severe vaginal bleeding at presentation is associated with an odds ratio of 1.42 for ectopic pregnancy.[48] In one study, 9% of patients with ectopic pregnancy presented with painless vaginal bleeding.[49] As a result, almost 50% of cases of ectopic pregnancy are not diagnosed at 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. Painful fetal 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 be reflective of peritoneal irritation. Astute clinicians should have a high index of suspicion for ectopic pregnancy in any woman who presents with these symptoms and who presents with physical findings of pelvic tenderness, enlarged uterus, adnexal mass, or tenderness. Approximately 20% of patients with ectopic pregnancies are hemodynamically compromised at initial presentation, which is highly suggestive of rupture. Fortunately, using modern diagnostic techniques, most ectopic pregnancies may be diagnosed before rupture.

Physical Examination
The 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 ectopic pregnancy 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 hypovolemic shock, 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 or a uterine size of greater than 8 weeks on pelvic examination decreases the risk of ectopic pregnancy.[51] On pelvic examination, the uterus may be slightly enlarged and soft, and 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. The presence of uterine contents in the vagina, which can be caused by shedding of endometrial lining stimulated by an ectopic pregnancy, may lead to a misdiagnosis of an incomplete or complete abortion and therefore a delayed or missed diagnosis of ectopic pregnancy.

Diagnostic Considerations

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 extrauterine pregnancy. 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, must also be included in the differential diagnosis. A study by Huchon et al found that the following 4 symptoms independently contributed to the diagnosis of tubal rupture: Vomiting during pain Diffuse abdominal pain Acute pain for longer than 30 minutes Flashing pain The 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 to those encountered in patients with ectopic pregnancies and other gynecologic or gastrointestinal conditions. The availability of various biochemical, ultrasonographic, and surgical modalities can aid the healthcare provider today in establishing a definitive diagnosis and differentiating among various conditions. In order to reduce the morbidity and mortality associated with ectopic pregnancy, a high index of suspicion is necessary to make a prompt and early diagnosis. As mentioned earlier, neither risk factors nor signs and symptoms of ectopic pregnancy are sensitive or specific enough to establish a definitive diagnosis. Hence, screen any female patient in her reproductive years who presents with abdominal 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 kits are able to detect bhCG in early gestation, they are associated with varying false-negative rates. In

addition, the need for a quantitative value makes serum bhCG the criterion standard for biochemical testing. Evidence-based guidelines have been established for the diagnostic and therapeutic management of ectopic 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 to identify patients in need of RhoGAM and to ensure availability of blood products in case of excessive blood loss.

BetaHuman Chorionic Gonadotropin Levels


Serum and urine assays for the beta subunit of human chorionic gonadotropin ( -HCG) have been developed to detect a pregnancy before the first missed period. Although some commercial urine test kits 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 for biochemical testing.

Rate of increase
Serum -HCG levels correlate with the size and gestational age in normal embryonic growth. 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. 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 -HCG should increase during a 2-day period is 66%.[4] For example, a pregnant patient with a serum -HCG level 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 an abnormal intrauterine pregnancy or an extrauterine pregnancy. However, remember that 15% of healthy 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 normal doubling 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 ectopic pregnancy. In short, serial serum -HCG levels are necessary to differentiate between normal and abnormal pregnancies and to monitor resolution of ectopic pregnancy once therapy has been initiated.

Discriminatory zone
The discriminatory zone of -HCG is the level above which a normal intrauterine pregnancy is reliably visualized. Once -HCG has reached a level of 700-1000 mIU/mL, a gestational sac should be seen within the uterus on transvaginal ultrasonographic images. Once it has reached 6000 mIU/mL, a gestational 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 zone represents 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 abnormal pregnancies 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

indicate the location of the pregnancy. Hence, additional diagnostic modalities, including ultrasonography and other biochemical markers, are needed. Another disadvantage is in cases of multiple gestations; if a multiple gestation is suspected, as in pregnancies resulting from assisted reproduction, the -HCG discriminatory zone must be used cautiously. 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 they showed multiple gestations with -HCG levels of up to 2300 mIU/mL before transvaginal ultrasonographic recognition. Also remember that a discriminatory zone is operator and institution dependent; the clinician must be aware 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 gestations from 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 an abnormal pregnancy currently exists. Several authors have proposed different cutoffs with varying sensitivity and specificity. In one large study, 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 or intrauterine, and excluded normal pregnancy with 100% sensitivity. Although inexpensive, the usefulness of serum progesterone is limited by the fact that a significant number of results fall in the equivocal range of 5-25 ng/mL. Also, this test is unreliable in differentiating between normal and abnormal pregnancies in patients who conceive after in vitro fertilization (IVF), because of excessive progesterone production from multiple corpora lutea, as well as the practice of pharmacologic progesterone supplementation.

Other Markers
Several other serum and urine markers are under investigation to help distinguish normal and abnormal pregnancies. These include serum estradiol, inhibin, pregnancy-associated plasma protein A, pregnanediol glucuronide, placental proteins, creatinine kinase, and a quadruple screen of serum progesterone, betahuman chorionic gonadotropin (-HCG), estriol, and alfa-fetoprotein (AFP). These markers are usually either early pregnancy proteins or signs of inflammation and damage in smooth muscles 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 exclude ectopic pregnancy.[5] The exception to this is in cases of heterotropic pregnancies, which occur in between 1 in 4000 and 1 in 30,000 spontaneous pregnancies. In patients undergoing ovarian stimulation and assisted reproduction, screening the adnexa by ultrasonography is mandatory even when an intrauterine pregnancy has been visualized, because these patients have a 10-fold increased risk of heterotropic pregnancy. Heterotopic pregnancy is a combined 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-desac. 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 blood from retrograde menstruation and unruptured ectopic pregnancies.

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

Transvaginal/endovaginal ultrasonography
Transvaginal ultrasonography, or endovaginal ultrasonography, with its greater resolution, can be used 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 for this). This imaging technique can be performed in the outpatient clinic or emergency department and has been reported to have a sensitivity of 90% and a specificity of 99.8%, with positive and negative predictive 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 structure that is recognizable on transvaginal ultrasonographic images. It has a thick, echogenic rim surrounding a sonolucent center corresponding to the trophoblastic decidual reaction surrounding the chorionic 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 image below); this should not be mistaken for a normal, early intrauterine pregnancy. The true gestational sac is located eccentrically within the uterus beneath the endometrial surface, whereas the pseudosac fills the endometrial cavity.

A pseudogestational sac of ectopic pregnancy can be confused with embryonic demise. This sac is produced when an ectopic pregnancy stimulates the endometrium, with degeneration of the central decidual reaction.

The yolk sac is the first visible structure within the gestational sac. It resembles a distinct circular structure with a bright, echogenic rim and a sonolucent center. It can first be recognized at 3 weeks postconception, about 5 weeks after the last menstrual period. The embryo is recognized first as a thickening along the edge of the yolk sac; embryonic cardiac motion can be observed at 3.5-4 weeks postconception, 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) is surrounded by a thick, concentric, echogenic ring located within the endometrium and contains a fetal pole, a yolk sac, or both. (See the image below.)

An endovaginal sonogram reveals an intrauterine pregnancy at approximately 6 weeks. 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 an irregular or crenelated border.

Presumed ectopic pregnancy An empty uterus on endovaginal ultrasonographic images in patients with a serum beta human chorionic gonadotropin (-HCG) level greater than the discriminatory cut-off value is an ectopic pregnancy 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 is located 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, with a small yolk sac present within. The mass is more echogenic relative to the uterus above and represents an ectopic pregnancy.

Other ultrasonographic findings in ectopic pregnancy


Findings such as an adnexal mass (usually a corpus luteum, occasionally hematoma), free cul-de-sac fluid, and/or severe adnexal tenderness with probe palpation may be present. Patients with no definite intrauterine pregnancy and the above-mentioned findings may be at high risk for an ectopic pregnancy. An appreciation for the spectrum of ultrasonographic findings in ectopic pregnancy, discussed below, may allow physicians to recognize an early ectopic pregnancy. Tubal ring A tubal ring is an echogenic, ringlike structure found outside of the uterus that represents an early ectopic pregnancy. (See the image below.)

An endovaginal sonogram demonstrates an early ectopic pregnancy. An echogenic 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 most significant 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 insertion of the fallopian tube. These types can grow larger than those within the fallopian tube, because the endometrial tissue is more expandable. Owing to the increased size and partial endometrial implantation, these advanced ectopic pregnancies can be misdiagnosed as intrauterine pregnancies.

An aid in the diagnosis of an interstitial ectopic pregnancy is the eccentric location of the gestational sac. Evaluating the amount of uterine myometrium surrounding the gestational sac and echogenic decidual layer is important. This is termed the myometrial mantle. At least 5mm of myometrium should be present. The presence of less than 5mm suggests the diagnosis. Another ultrasonographic finding is the interstitial line sign. Hemosalpinx and ruptured ectopic pregnancy A hemosalpinx is a condition in which the fallopian tubes may fill with blood or free fluid. Findings of a ruptured ectopic pregnancy on ultrasonographic images include free fluid or clotted blood in the culde-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 levels validates the ultrasonographic findings. The discriminatory zone is the level of -HCG (using the Third International Standard for quantitative -HCG) at which all intrauterine pregnancies should be visible on ultrasonography. With abdominal ultrasonography, that level is 6000-6500 mIU/mL, but highresolution transvaginal ultrasonography has reduced this level to 1500-1800 mIU/mL. If transvaginal ultrasonography 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 multiple gestates not only had levels of -HCG above the discriminatory zone before any ultrasonographic evidence of the gestation was apparent, they also showed that multiple gestations with -HCG levels of 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 -HCG discriminatory zone must be used cautiously. Nonetheless, the effectiveness of using ultrasonography with a discriminatory zone of -HCG levels has been well established in the literature. In one large study of more than 1200 patients, Barnhart et al reported that 78.8% of patients were diagnosed 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 intrauterine sac was not identified, an operative approach involving curettage and possible operative laparoscopy was used to diagnose ectopic pregnancy.[57] If the patient's serum -HCG levels were below the discriminatory zone, serial -HCG titers were performed every 2 days. Once a patient's levels reached the discriminatory zone, ultrasonography was 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, to exclude the diagnosis of ectopic pregnancy. With this protocol, Barnhart et al reported a sensitivity of 100% 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 and specificity of transvaginal ultrasonography, especially in cases in which a gestational sac is questionable or absent. A study of 304 patients at high risk for ectopic pregnancy found that the use of color-flow Doppler ultrasonography, compared with transvaginal ultrasonography alone, increased the diagnostic sensitivity from 71% to 87% for ectopic pregnancy, from 24% to 59% for failed intrauterine pregnancy, and from 90% to 99% for viable intrauterine pregnancy. The addition of color-flow Doppler ultrasonography may expedite earlier diagnosis and eliminate delays caused by using levels of -HCG for diagnosis. Furthermore, color-flow Doppler ultrasonography can potentially be used to identify involuting ectopic pregnancies that may be candidates for expectant management.

Dilatation and Curettage


A simple way to rule out an ectopic pregnancy is to establish the presence of an intrauterine pregnancy. Once the presence of an abnormal pregnancy has been established by assessing beta human chorionic gonadotropin (-HCG) or progesterone levels, dilatation and curettage can provide a rapid, 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 or permanent section, then a nonviable intrauterine pregnancy has occurred. In the absence of villi, the diagnosis of ectopic pregnancy is made. Laparoscopy can be performed at that time, or the case may be 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 which continuation 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, obtaining consent for a diagnostic, and possibly operative, laparoscopy is also necessary in case the diagnosis of 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 of heterotropic pregnancies, in which multiple gestations are present, with at least 1 being intrauterine and 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 and attempting to aspirate blood. When nonclotting blood is found in conjunction with a suspected ectopic pregnancy, operative intervention is indicated, because the likelihood of a ruptured ectopic pregnancy is high. Although culdocentesis is of historic interest, its use today is rare. This procedure is associated with a high false-negative rate (10-14%), usually reflecting blood from an unruptured ectopic pregnancy, a ruptured corpus luteum, an incomplete abortion, or retrograde menstruation. Furthermore, the improved technology with ultrasonographic and hormonal assays is far superior in sensitivity and specificity 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 ectopic pregnancy, the presence of hemoperitoneum (see the image below), and the presence of other conditions, such as ovarian cysts and endometriosis, which, when present with an intrauterine pregnancy, can mimic an ectopic pregnancy. Furthermore, laparoscopy provides the option to treat once 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 patients suspected 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 expected to rise.

Approach Considerations
Among the greatest advances in the management of ectopic pregnancy has been the development of medical management, which became available in the mid-1980s. Initial protocols for medical therapy required long-term hospitalization and multiple doses of methotrexate and were associated with significant side effects. Modification and refinement of these protocols, however, have led to singledose outpatient therapy.

Medical versus surgical therapy


Historically, the treatment of ectopic pregnancy was limited to surgery. With evolving experience with methotrexate, the treatment of selected ectopic pregnancies has been revolutionized. Medical therapy of ectopic pregnancy is appealing over surgical options for a number of reasons, including eliminating morbidity from surgery and general anesthesia, potentially less tubal damage, and less cost and need for hospitalization. Measures of current trends in the management of ectopic pregnancy in the United States from 2002 to 2007 indicated that the percentage of patients treated with methotrexate increased from 11.1% to 35.1%, whereas surgical management decreased from approximately 90% to 65%.[6] In this study, the authors reported that more than 60% of surgical cases were done laparoscopically and that about 5% of surgical cases required medical therapy. In the medical treatment group, 15% of cases were categorized as failures and required surgery.[6]

Consultations
An obstetrics specialist should be consulted as needed for ectopic pregnancies and for follow-up care of patients with failing/failed intrauterine pregnancies or pregnancies of unknown location. Any patient who is clinically unstable should have the consultation in the emergency department. Furthermore, an obstetrics specialist or a radiologist should be consulted for transvaginal ultrasonography as needed, according to institutional policy.

Expectant Management
The increased incidence of ectopic pregnancy is partially attributed to improved ability in making earlier diagnosis. Ectopic pregnancies that previously would have resulted in tubal abortion or complete, spontaneous reabsorption and remained clinically undiagnosed are now detected. Some investigators have questioned the need for unnecessary surgical or medical intervention in very early cases and have advocated expectant management in select cases. However, distinguishing patients who are experiencing spontaneous resolution of their ectopic pregnancies from patients who have proliferative ectopic pregnancies could pose a clinical dilemma. Candidates for successful expectant management should be asymptomatic and have no evidence of rupture or hemodynamic instability. Furthermore, they should demonstrate objective evidence of resolution, such as declining betahuman chorionic gonadotropin (-HCG) levels. They must also be fully compliant and be willing to accept the potential risks of tubal rupture. Approximately one fourth of women presenting with ectopic pregnancies have declining -HCG levels, and 70% of this group experience successful outcomes with close observation, as long as the gestation is 4cm or less in its greatest dimension. An initial low -HCG titer also correlates with successful spontaneous resolution. Although data are limited on this matter, initial -HCG titers below 1000 mIU/mL have been demonstrated to predict a successful outcome in 88% of cases managed expectantly. Note that no cutoff value below which expectant management is uniformly safe has been established. Furthermore, rupture despite low and declining serum levels of -HCG has been reported, making close follow-up and patient compliance of paramount importance.

Methotrexate Therapy
Methotrexate is an antimetabolite chemotherapeutic agent that binds to the enzyme dihydrofolate reductase, which is involved in the synthesis of purine nucleotides. This interferes with deoxyribonucleic acid (DNA) synthesis and disrupts cell multiplication.

Methotrexate has long been known to be effective in the treatment of leukemias, lymphomas, and carcinomas of the head, neck, breast, ovary, and bladder. It has also been used as an immunosuppressive agent in the prevention of graft versus host disease and in the treatment of severe psoriasis and rheumatoid arthritis. The effectiveness of methotrexate on trophoblastic tissue has been well established and is derived from experience gained in using this agent in the treatment of hydatiform moles and choriocarcinomas. As used in the treatment of ectopic pregnancy, methotrexate is administered in a single or in multiple intramuscular (IM) injections. Treatment with methotrexate is an especially attractive option when the pregnancy is located on the cervix or ovary or in the interstitial or the cornual portion of the tube. Surgical treatment in these cases is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy. In a study by Verma et al, only 1 of 64 cervical, cornual, or cesarean delivery scar pregnancies treated with systemic methotrexate alone or combined with intracardiac injection required surgery.[58] Successful medical treatment using methotrexate has been reported in the literature with good subsequent reproductive outcomes. By avoiding surgery, the risk of tubal injury is reduced.[59]

Indications
Medical therapy for ectopic pregnancy involving methotrexate may be indicated in certain patients. To determine acceptable candidates for methotrexate therapy, first establish the diagnosis by one of the following criteria: Abnormal doubling rate of the betahuman chorionic gonadotropin (-HCG) level and ultrasonographic identification of a gestational sac outside of the uterus Abnormal doubling rate of the -HCG level, an empty uterus, and menstrual aspiration with no chorionic villi A number of other factors must also be considered once the diagnosis is established, as follows: The patient must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum (must be met by every patient) The patient must be reliable, compliant, and able to return for follow-up care (must be met by every patient) The size of the gestation should not exceed 4cm at its greatest dimension (or exceed 3.5 cm with cardiac activity) on ultrasonographic measurement - Exceeding this size is a relative, but not absolute, contraindication to medical therapy Absence of fetal cardiac activity on ultrasonographic findings - The presence of fetal cardiac activity is a relative contraindication No evidence of tubal rupture - Evidence of tubal rupture is an absolute contraindication -HCG level less than 5000 mIU/mL - Higher levels are a relative contraindication

Contraindications
A -HCG level of greater than 5,000 IU/L, fetal cardiac activity, and free fluid in the cul-de-sac on ultrasonographic images (presumably representing tubal rupture) are contraindications to medical therapy with methotrexate. Although patients with -HCG levels above 5,000 IU/L and fetal cardiac activity have been treated successfully with methotrexate, these patients require much greater surveillance and carry a higher risk of subsequent operative intervention. There is an inverse association between -HCG levels and successful medical management of an ectopic pregnancy. A systematic review by Menon et al confirmed that there is a substantial increase in failure of medical management of ectopic pregnancy with single-dose methotrexate when the initial -HCG is above 5,000 IU/L.[60] Other contraindications to the use of methotrexate include the following : Documented hypersensitivity to methotrexate Breastfeeding Immunodeficiency

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 and treatment 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 marrow suppression, dermatitis, pleuritis, pneumonitis, and reversible alopecia can occur with higher doses but 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 thirds of patients), an increase in -HCG levels during the first 1-3 days of treatment, and vaginal bleeding or spotting. The medical treatment of ectopic pregnancy requires compulsive compliance. The physician must emphasize the importance of patient follow-up and have patient information on hand, including the patient'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 of attempts to reach the patient, including records of telephone calls and certified mail are important medical-legal considerations. Before injection of methotrexate, the patient must be counseled extensively on the risks, benefits, and adverse effects of the treatment and on the possibility of failure of medical therapy, which would result in tubal rupture and necessitate surgery. Patients should be aware of the signs and symptoms associated with tubal rupture, and they should be advised to contact their physician with significantly worsening 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 2-3 days 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, of limited duration (lasting 24-48 h), and is not associated with signs of acute abdomen or hemodynamic instability. Advise patients to avoid alcoholic beverages, vitamins containing folic acid, nonsteroidal antiinflammatory 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 a list of adverse effects, a schedule of follow-up visits, and a method of contacting the physician or the hospital in case of emergency.

Methotrexate Treatment Protocols


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

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 systemic effects. This regimen involves administration of methotrexate as 1 mg/kg IM on days 0, 2, 4, and 6, followed by 4 doses of leucovorin as 0.1 mg/kg on days 1, 3, 5, and 7. Because of a higher incidence of adverse effects and the increased need for patient motivation and compliance, the multiple dosage regimen 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 methotrexate as 50 mg/m2 IM in a single injection or as a divided dose injected into each buttock. Studies comparing the multiple methotrexate dosage regimen with the single dosage regimen have demonstrated 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 achieved a 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 Rh immunoglobulin. Methotrexate (50 mg/m2) is administered by IM injection. Advise patients not to take vitamins with folic acid until complete resolution of the ectopic pregnancy. They should also refrain from alcohol consumption 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 are measured. Day 7 Draw -HCG and AST levels and perform a complete blood count (CBC). If the -HCG level has dropped 15% or more since da y 4, obtain weekly -HCG levels until they have reached the negative level for the lab. If the weekly levels plateau or increase, a second course of methotrexate may be administered. If the -HCG level has not dropped at least 15% from the day-4 level, administer a second IM dose of methotrexate (50 mg/m2) on day 7, and observe the patient similarly. If no drop has occurred by day 14, surgical therapy is indicated. If the patient develops increasing abdominal pain after methotrexate therapy, repeat a transvaginal ultrasonographic scan to evaluate for possible rupture.

Treatment monitoring protocols


The best predictor of success of medical therapy is the initial -HCG level. Based on efficacy studies done by Lipscomb et al, success exceeded 90% for single-dose methotrexate when -HCG levels were less than 5000 mIU/mL but dropped to about 80% when levels were 5-10,000 mIU/mL. Success was 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, and bone marrow function, as well as a baseline -HCG level. Determine blood type, Rh factor, and the presence 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 of at least 15% from days 4 to 7 postinjection indicates a successful medical response. Other effective monitoring protocols have also been reported.[61] The patient's -HCG levels should be measured weekly, until they become undetectable. Failure of medical treatment is defined when -HCG levels increase, plateau, or fail to decrease adequately by 15% from days 4 to 7 postinjection. At this time, surgical intervention may be warranted. 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 promising results, efficacy remains to be established. Direct local injection (salpingocentesis) of methotrexate into the ectopic pregnancy under laparoscopic or ultrasonographic guidance has also been reported in the literature; however, these studies have yielded inconsistent results, and the advantage of this technique over IM injection remains to be established. Although methotrexate has remained the most effective and popular drug used in medical therapy for an ectopic pregnancy, other protocols have been used, such as potassium chloride, hyperosmolar glucose, 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 standard methotrexate protocol, has not been established.

Salpingostomy and Salpingectomy


Within the last 2 decades, a more conservative surgical approach to unruptured ectopic pregnancy using minimally invasive surgery has been advocated to preserve tubal function. The conservative approaches include linear salpingostomy and milking the pregnancy out of the distal ampulla. The more radical approach includes resecting the segment of the fallopian tube that contains the gestation, with or without reanastomosis. Laparoscopy has become the recommended approach in most cases. Laparotomy is usually reserved for patients who are hemodynamically unstable or for patients with cornual ectopic pregnancies; it also is a preferred method for surgeons inexperienced in laparoscopy and in patients in whom a laparoscopic 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 fewer postoperative adhesions than laparotomy. Furthermore, laparoscopy is associated with significantly less blood loss and a reduced need for analgesia. Finally, laparoscopy reduces cost, hospitalization time, and convalescence period. Linear salpingostomy along the antimesenteric border to remove the products of conception is the procedure of choice for unruptured ectopic pregnancies in the ampullary portion of the tube. Ectopic pregnancies in the ampulla are usually located between the lumen and the serosa and, thus, are ideal candidates for linear salpingostomy. Several studies have demonstrated no benefit of primary closure (salpingotomy) over healing by secondary intention (salpingostomy).

Total salpingectomy is the procedure of choice in a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes. In cases involving uncontrolled bleeding and hemodynamic instability, conservative treatment methods are avoided in favor of radical surgery.

Linear salpingostomy
In linear salpingostomy, the involved tube is identified and freed from surrounding structures. To minimize bleeding, a dilute solution containing 20 U of vasopressin in 20 mL of isotonic sodium chloride solution may be injected into the mesosalpinx just below the ectopic pregnancy. Make sure that the needle is not in a blood vessel by aspirating before injecting, because intravascular injection of 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 made along the antimesenteric side of the tube along the thinnest segment of the gestation. (See the image below.)

Linear incision being made at the antimesenteric side of the ampullary portion of the fallopian 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 pressurized irrigation to help dislodge the pregnancy. (See the images below.)

Laparoscopic picture of an ampullary ectopic pregnancy protruding out after a

linear salpingostomy was performed. teased out after linear salpingostomy.

Schematic of a tubal gestation being

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 of the tube) by using digital expression, suction, or aqua-dissection. However, this approach carries with

it a higher rate of bleeding, persistent trophoblastic tissue, tubal damage, and recurrent ectopic pregnancy (33%).

Segmental tubal resection and total salpingectomy


In some cases, resection of the tubal segment containing the gestation or a total salpingectomy is preferred 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 ectopic pregnancy occurring. Segmental tubal resection is performed by grasping the tube at the proximal and distal borders of the segment of the tube containing the gestation and coagulating thoroughly from the antimesenteric border to the mesosalpinx. This portion of the tube is then excised. The underlying mesosalpinx is also coagulated and excised, with particular attention to minimize the damage to the surrounding vasculature. Delayed microsurgical reanastomosis can be performed to reestablish tubal patency if enough healthy fallopian tube is present. Take care to minimize the thermal injury to the tube during excision, so that an 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 this point, 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 history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, total salpingectomy is the procedure of choice. The presence of uncontrolled bleeding and hemodynamic instability warrants radical surgery over conservative methods. The preferred approach based on the location of the pregnancy varies, as previously discussed. In all instances, regardless of desired fertility, 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 retained trophoblastic 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 the peritoneal cavity and remove any detected residual trophoblastic tissue. Note the condition of the contralateral tube, the presence of adhesions, or other pathologic processes because 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. Most often, 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 bleeding and achieve adequate pain control. Patients treated by laparotomy are usually hospitalized for a few days.

Monitoring

After surgical excision of an ectopic gestation, weekly monitoring of quantitative beta human chorionic gonadotropin (-HCG) levels is necessary until the level is zero to ensure that treatment is complete. 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 the system 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 by incomplete removal of trophoblastic tissue, some actually may represent multiple ectopic pregnancies in which only 1 gestation is initially recognized and treated. The incidence of persistent trophoblastic tissue is greater with higher initial -HCG levels and is relatively rare with titers of less than 3000 IU/L. The risk of persistent trophoblastic tissue is very significant when a hematosalpinx is greater than 6cm in diameter, a -HCG titer is more than 20,000 IU/L, and a hemoperitoneum is greater than 2 L. While resolution without any further intervention is the general rule, the persistence of trophoblastic tissue 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 be necessary 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 ectopic pregnancy

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 dividing cells. It acts as a folate antagonist.[62] The decision to use this agent should be made in conjunction with, 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 Active pulmonary or peptic ulcer disease Clinically important hepatic or renal dysfunction Breastfeeding Evidence of tubal rupture Relative contraindications that indicate likely failure of methotrexate therapy include the following: Sonogram findings of an ectopic gestational sac greater than 4cm in size (or 3.5cm, if the ectopic pregnancy has fetal heart motion) An initial betahuman chorionic gonadotropin (-HCG) concentration of greater than 5000 mIU/mL Significant free fluid Fetal cardiac activity

Regimen
The multiple-dose regimen for methotrexate consists of the administration of daily IM doses of 1 mg/kg, with leucovorin (folinic acid, which reduces side effects) given on alternating days, until there is a 15% decline in -HCG over 2 days.

The single-dose regimen consists of 1 dose of methotrexate 50 mg/m 2, followed by a repeat -HCG measurement at day 4, and another dose of methotrexate 50 mg/m 2 if the -HCG has declined less than 15% between days 4 and 7. Efficacy and adverse effects Both treatment regimens show an efficacy similar to that of surgical management for unruptured ectopic pregnancies in the ideal patient population. Common side effects include an increase in abdominal girth, vaginal bleeding or spotting, abdominal pain, gastrointestinal (GI) symptoms, stomatitis, and dizziness. Rare side effects include severe neutropenia, reversible alopecia, and pneumonitis.[62]

Antineoplastics, Antimetabolite
Class Summary
Antimetabolite agents are used to terminate pregnancy.
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Methotrexate (Trexall, Rheumatrex)


Methotrexate is used for the treatment of unruptured tubal pregnancy and for persistent disease after salpingostomy

Vitamins
Class Summary
Vitamins are used to correct folic acid deficiency resulting from use of folic acid antagonists.
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Leucovorin
Leucovorin is used with folic acid antagonists, such as methotrexate. It is a reduced form of folic acid that does not require enzymatic reduction reaction for activation. It allows for purine and pyrimidine synthesis, both of which are needed for normal erythropoiesis. It is an important cofactor for the enzymes used in production of red blood cells. Leucovorin (folinic acid, which reduces adverse effects) is given alternating with methotrexate days, until there is a 15% decline in -HCG over 2 days.

Vasopressors
Class Summary
Vasopressors are used for their alpha1 and beta1 properties and for stimulating vasoconstriction in peripheral circulation.
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Vasopressin (Pitressin)
Vasopressin has vasopressor and antidiuretic hormone (ADH) activity. In linear salpingostomy, the involved tube is identified and freed from surrounding structures. To minimize bleeding, a dilute solution containing 20 U of vasopressin in 20 mL of isotonic sodium chloride solution may be injected into the mesosalpinx just below the ectopic pregnancy. Make sure that the needle is not in a blood vessel by aspirating before injecting, because intravascular injection of vasopressin may precipitate acute arterial hypertension and bradycardia.

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