Clinical manifestations, diagnosis, and management of ectopic pregnancy Last literature review version 19.

2: mayo 2011 | This topic last updated: junio 14, 2011 INTRODUCTION The diagnosis of ectopic pregnancy is based on a combination of quantitative assay for human chorionic gonadotropin (hCG) and findings on high resolution transvaginal ultrasonography (TVUS). These tests enable early diagnosis of the ectopic pregnancy, before tubal rupture. The clinical manifestations and diagnosis of ectopic pregnancy will be reviewed here. The epidemiology, risk factors, pathology, and treatment of this disorder are discussed separately. (See "Incidence, risk factors, and pathology of ectopic pregnancy" and "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility" and "Methotrexate treatment of tubal and interstitial ectopic pregnancy".) CLINICAL MANIFESTATIONS Clinical manifestations typically appear six to eight weeks after the last normal menstrual period, but can occur later, especially if the pregnancy is not in the fallopian tube. Normal pregnancy discomforts (eg, breast tenderness, frequent urination, nausea) are often present in addition to the symptoms described below. History The classic symptoms of ectopic pregnancy are [1]: Abdominal pain Amenorrhea Vaginal bleeding These symptoms can occur in both ruptured and unruptured cases. In one representative series of 147 patients with ectopic pregnancy (78 percent were ruptured), abdominal pain was a presenting symptom in 99 percent, amenorrhea in 74 percent, and vaginal bleeding in 56 percent [2]. Ectopic pregnancy should be suspected in any women of reproductive age with these symptoms, especially those who have risk factors for an extrauterine pregnancy (table 1) [3]. However, these symptoms are not diagnostic of ectopic pregnancy; they are the same as those associated with threatened abortion, which is far more common (see 'Differential diagnosis' below). In addition, blood leaking out of the fallopian tube may irritate the diaphragm and cause shoulder pain, whereas blood pooling in the posterior cul-de-sac (pouch of Douglas) may cause an urge to defecate. Lightheadedness or shock suggests tubal rupture has occurred, resulting in severe intraabdominal hemorrhage. Failure to diagnose ectopic pregnancy before tubal rupture limits the treatment options and increases maternal morbidity and mortality. A population-based French study identified four factors that increased the risk of rupture when an ectopic pregnancy was suspected: (1) never having used contraception, (2) history of tubal damage and infertility, (3) induction of ovulation, and (4) high level of human chorionic gonadotropin (at least 10,000 IU/L) [4]. The overall rate of tubal rupture in this series was 18 percent. Physical examination Vital signs may reveal orthostatic changes and, occasionally, low grade fever. Findings on physical examination may include adnexal, cervical motion, and/or abdominal tenderness, an adnexal mass, and mild uterine enlargement. However, the physical examination is often unremarkable in a woman with a small, unruptured ectopic pregnancy. DIAGNOSIS No constellation of historical and physical findings can confirm or exclude the diagnosis of ectopic pregnancy with a high degree of reliability [5,6]. The diagnosis is usually made clinically, based upon results of the imaging studies (ultrasound) and laboratory tests (hCG) described below (see 'Diagnostic evaluation' below). The diagnosis can also be made by observation of the ectopic gestation at surgery or histopathologic examination, but surgery is not required in most cases. However, in the absence of definitive surgical, histopathologic, or sonographic findings, it is sometimes impossible to differentiate between an ectopic pregnancy and an early failed intrauterine gestation. Differential diagnosis The differential diagnosis of lower abdominal pain in women includes urinary tract infection, kidney stones, diverticulitis, appendicitis, ovarian neoplasms, endometriosis, endometritis, leiomyomas, pelvic inflammatory disease, and pregnancy-related conditions. Vaginal bleeding also has several pregnancy-related and nonpregnancy-related etiologies. Thus, a pregnancy test is important in premenopausal women who present with abdominal pain or vaginal bleeding in order to guide the direction of further evaluation. (See "Diagnostic approach to abdominal pain in adults" and "Overview of causes of genital tract bleeding in women".) Amenorrhea and abdominal pain, with or without vaginal bleeding, are common symptoms of complications of early pregnancy other than an ectopic pregnancy, such as threatened abortion, ruptured or torsed corpus luteum cyst, and degenerating uterine leiomyoma. Other common etiologies of pelvic pain or pressure in early pregnancy include constipation or ongoing uterine enlargement. (See "Diagnosis and clinical manifestations of early pregnancy" and "Overview of the etiology and evaluation of vaginal bleeding in pregnant women".) Recommended diagnostic tests TVUS is the most useful test for determining the location of a pregnancy. If the imaging study is nondiagnostic, it may be because the gestation is too early to be visualized on ultrasound. If so, serial measurements of the serum human chorionic gonadotropin (hCG) concentration should be taken until the hCG discriminatory zone is reached (see 'Discriminatory zone' below).

This combination of TVUS and hCG will permit a definitive diagnosis in almost all cases at a very early stage of pregnancy, thereby permitting treatment options less invasive than surgical excision [7-10]. Other diagnostic tests (eg, serum progesterone level, curettage, laparoscopy, culdocentesis) do not provide additional clinically useful information. Transvaginal ultrasound Ultrasound is used to detect the presence (or absence) of a pregnancy within or outside of the uterus. Ultrasound evaluation for ectopic pregnancy is discussed in detail separately. (See "Ultrasonography of pregnancy of unknown location".) Human chorionic gonadotropin hCG can be detected in serum and urine as early as eight days after the LH surge, if pregnancy has occurred. The hCG concentration in a normal intrauterine pregnancy rises in a curvilinear fashion until about 41 days of gestation, after which it rises more slowly until approximately 10 weeks, and then declines until reaching a plateau in the second and third trimesters [11,12]. There is a wide range in the normal hCG level across individuals at each week of pregnancy [13]. (See "Diagnosis and clinical manifestations of early pregnancy", section on 'Serum pregnancy test'.) Studies in viable intrauterine pregnancies have reported the following changes in serum hCG [12,14-16]: The mean doubling time for the hormone ranges from 1.4 to 2.1 days in early pregnancy. In 85 percent of viable intrauterine pregnancies, the hCG concentration rises by at least 66 percent every 48 hours during the first 40 days of pregnancy; only 15 percent of viable pregnancies have a rate of rise less than this threshold. The slowest recorded rise over 48 hours associated with a viable intrauterine pregnancy was 53 percent. The hCG concentration rises at a much slower rate in most, but not all, ectopic and nonviable intrauterine pregnancies [16,17]. In one series, as an example, only 21 percent of ectopic pregnancies were associated with hCG levels that followed the minimum doubling time of a viable intrauterine pregnancy (defined in this series as 53 percent increase over two days) [16]. There is a 10 to 15 percent interassay variability in hCG measurements as well as variability among laboratories. Thus, interpretation of serial hCG concentrations is more reliable when the assays are performed in the same laboratory. In addition, the possibility of falsely positive hCG test results should be considered [18-20]. (See "Gestational trophoblastic disease: Management of hydatidiform mole", section on 'Human chorionic gonadotropin'.) A falling hCG concentration is most consistent with a failed pregnancy (eg, arrested pregnancy, anembryonic pregnancy, tubal abortion, spontaneously resolving ectopic pregnancy, complete or incomplete abortion). Discriminatory zone The discriminatory zone is based upon the correlation between visibility of the gestational sac and the hCG concentration, and is of major diagnostic importance (see 'Diagnostic evaluation' below). It is defined as the serum hCG level above which a gestational sac should be visualized by ultrasound examination if an intrauterine pregnancy is present [17]. In most institutions, this serum hCG level is 1500 or 2000 IU/L with TVS (the level is higher [6500 IU/L] with transabdominal ultrasound). The level of the discriminatory zone was based upon observations that an intrauterine gestational sac could be detected by TVS in patients with serum hCG concentrations as low as 800 IU/L and was usually identified by expert ultrasonographers at concentrations above 1500 to 2000 IU/L [21]. In one representative study, 185 of 188 (98 percent) intrauterine pregnancies in women with hCG above 1500 IU/L were visualized [22]. Setting a threshold of 2000 IU/L instead of 1500 IU/L for the discriminatory zone minimizes the risk of interfering with a viable intrauterine pregnancy, if present, but increases the risk of delaying diagnosis of an ectopic pregnancy. The absence of an intrauterine gestational sac at hCG concentrations above the discriminatory zone strongly suggests an ectopic or nonviable intrauterine pregnancy, but is nondiagnostic with hCG values below the discriminatory zone. A negative ultrasound examination at hCG levels below the discriminatory zone is consistent with an early viable intrauterine pregnancy or an ectopic pregnancy or nonviable intrauterine pregnancy. Such cases are termed "pregnancy of unknown location" and 8 to 40 percent are ultimately diagnosed as ectopic pregnancies [23]. The discriminatory zone is dependent upon the skill of the ultrasonographer, the quality of the ultrasound equipment, the presence of physical factors (eg, fibroids, multiple gestation), and the laboratory characteristics of the hCG assay used. Diagnostic evaluation The evaluation of a pregnant woman with suspected ectopic gestation begins with TVS and quantitative hCG level (figure 1 and table 2). TVS alone is diagnostic if a yolk sac, embryo, or embryonic cardiac activity is demonstrable. HCG above the discriminatory zone An hCG concentration above the discriminatory zone is sensitive for detecting an intrauterine pregnancy. Visualization of an intrauterine pregnancy almost always excludes the presence of an ectopic pregnancy; exceptions include heterotopic pregnancies (see 'Heterotopic pregnancy' below) and misdiagnoses (eg, pregnancy in a rudimentary uterine horn or cornua). If TVS does not reveal an intrauterine pregnancy and shows a complex adnexal mass, an extrauterine pregnancy is almost certain. Embryonic cardiac activity or a gestational sac with a definite yolk sac or embryo at an extrauterine location is certain evidence of an ectopic gestation. Treatment of ectopic pregnancy should be instituted.

The diagnosis of ectopic pregnancy is less certain if no complex adnexal mass can be visualized, since there is variability in the level of expertise among ultrasonographers. Furthermore, a serum hCG greater than 1500 IU/L without visualization of intrauterine or extrauterine pathology may represent a multiple gestation, since there is no proven discriminatory level for multiple gestations. For these reasons, our next step in this setting is to repeat the TVS examination and hCG concentration two days later. If an intrauterine pregnancy is still not observed on TVS, then the pregnancy is abnormal. An ectopic pregnancy can be diagnosed if the serum hCG concentration is increasing or plateaued. Treatment can be instituted. A falling hCG concentration is most consistent with a failed pregnancy (eg, arrested pregnancy, blighted ovum, tubal abortion, spontaneously resolving ectopic pregnancy). The rate of fall is slower with an ectopic pregnancy than with a complete abortion. Weekly hCG concentrations should be monitored until the result is negative for pregnancy. HCG below the discriminatory zone TVS is not sensitive for determining the location of the pregnancy when the hCG level is below the discriminatory zone. A serum hCG concentration less than 1500 IU/L should be followed by repetition of hCG in three days to follow the rate of rise. HCG concentrations usually double every 1.4 to two days until six to seven weeks of gestation in viable intrauterine pregnancies (and in some ectopic gestations) (see 'Human chorionic gonadotropin' above). We find that measurement every 72 hours is more practical than every 48 hours, and allowing 72 hours for doubling helps to avoid misclassifying those viable pregnancies with slower than average doubling times. A normally rising hCG concentration should be evaluated with TVS when the hCG reaches the discriminatory zone. At that time, an intrauterine pregnancy or an ectopic pregnancy can be diagnosed. If the hCG concentration does not double over 72 hours (as discussed above, the minimum rise [99th percentile] over 48 hours for a potentially viable intrauterine pregnancy is 53 percent), then the pregnancy is abnormal (an ectopic gestation or intrauterine pregnancy that is destined to abort). The clinician can be reasonably certain that a normal intrauterine pregnancy is not present. If an adnexal mass is visualized on TVS, then medical or surgical treatment is administered for a presumed ectopic pregnancy. If an adnexal mass is not visualized, some clinicians administer methotrexate and others perform curettage to determine the type of nonviable pregnancy and thereby avoid medical therapy of nonviable intrauterine pregnancies [24]. (See 'Curettage' below.) Treatment of ectopic pregnancy is discussed separately. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy" and "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility".) A falling hCG concentration is most consistent with a failed pregnancy (eg, arrested pregnancy, blighted ovum, tubal abortion, spontaneously resolving ectopic pregnancy). The rate of fall is slower with an ectopic pregnancy than with a completed abortion. Weekly hCG concentrations should be monitored until the result is negative for pregnancy. Ancillary diagnostic tests Progesterone Serum progesterone concentrations are higher in viable intrauterine pregnancies than in ectopic pregnancies and intrauterine pregnancies that are destined to abort [25,26]. A meta-analysis of 26 studies on the performance of a single serum progesterone measurement in the diagnosis of ectopic pregnancy found that a level less than 5 ng/mL (15.9 nmol/L) was highly unlikely to be associated with a viable pregnancy: only 5 of 1615 patients (0.3 percent) with a viable intrauterine pregnancy had a serum progesterone below this value [25]. However, it was not possible to distinguish ectopic pregnancies from failed intrauterine pregnancies. On the other hand, a progesterone level greater than 20 ng/mL (63.6 mmol/L) reasonably excluded an ectopic pregnancy: only 29 of 1107 patients (2.6 percent) with ectopic pregnancies had a progesterone level above this value. The predictive value of a low serum progesterone for identifying nonviable pregnancies varies with the patient population. The sensitivity and specificity of a low serum progesterone concentration for predicting a nonviable pregnancy in spontaneously pregnant patients are different from those in infertile patients who have undergone controlled ovarian hyperstimulation for IVF or intrauterine insemination [27]. In our experience, progesterone measurements merely confirm diagnostic impressions already obtained by hCG measurements and transvaginal sonography. Therefore, we do not monitor progesterone concentration. Curettage The intrauterine location of a pregnancy is diagnosed with certainty if trophoblastic tissue is obtained by uterine curettage. Obviously, the use of curettage as a diagnostic tool is limited by the potential for disruption of a viable pregnancy [7]. Moreover, false negatives can occur: chorionic villi are not detected by histopathology in 20 percent of curettage specimens from elective termination of pregnancy [28]. Pipelle endometrial biopsy is even less sensitive than curettage for detection of villi; sensitivities reported in two small series were 30 and 60 percent [29,30]. If curettage is performed, serum hCG levels can be followed post curettage if histopathology does not confirm the clinical impression. When an intrauterine pregnancy has been evacuated, hCG levels should drop by at least 15 percent the day after evacuation [24]. Some authors have recommended performing curettage only on women with both a hCG concentration below the discriminatory zone and a low doubling rate (see 'HCG below the discriminatory zone' above) [31,32]. Approximately 30 percent of these

patients have a nonviable intrauterine gestation and the remainder have an ectopic pregnancy [32,33]. Knowing the results of curettage avoids unnecessary methotrexate treatment of the 30 percent of patients without ectopic pregnancy. A decision analysis comparing the cost/complication rates in patients who undergo diagnostic curettage before administration of methotrexate to those who do not have a curettage concluded there was no significant benefit of one approach over the other [33]. However, the authors' preference was to perform curettage in these patients to be more certain of the diagnosis, and felt this information was useful prognostically (eg, risk of recurrence) and for future decision making. In contrast, we and others believe it is more practical and less invasive to continue observation or administer one dose of methotrexate than to perform curettage [34,35]. The side effects of one dose of methotrexate are negligible. (See"Methotrexate treatment of tubal and interstitial ectopic pregnancy".) Doppler Blood flow in the arteries of the fallopian tube containing an ectopic pregnancy is 20 to 45 percent higher than in the opposite tube and the Doppler waveform shows low impedance [11,36]. Color Doppler may demonstrate a ring of blood flow. These findings on Doppler support the diagnosis of ectopic pregnancy, especially if a complex adnexal mass is also visualized. Doppler examination can be performed when an adnexal mass is seen. In one study, the resistive index of ectopic pregnancies was higher than that of corpus luteum cyst [37]. A resistive index of less than 0.39 had a specificity of 100 percent and a positive predictive value of 100 percent for diagnosing ectopic pregnancy, but was present in only 15 percent of ectopic pregnancies. A resistive index of greater than 0.7 had a specificity of 100 percent and a positive predictive value of 100 percent for diagnosing ectopic pregnancy and was present in 31 percent of ectopic pregnancies. However, the use of TVS and hCG measurements is usually sufficient in establishing the diagnosis in routine clinical practice. Laparoscopy Laparoscopy is rarely required for diagnostic purposes only; transvaginal ultrasound examination and -hCG measurements are usually sufficient for diagnosis. However, an ectopic pregnancy detected at laparoscopy should be treated immediately by surgery. In this situation, a medical approach confers additional risk and has no proven benefit. Culdocentesis Culdocentesis is employed to detect blood in the posterior cul-de-sac; however, this finding can be easily demonstrated by transvaginal ultrasound (see 'Transvaginal ultrasound' above). Blood in the posterior cul-de-sac may be from bleeding from an unruptured or ruptured tubal pregnancy, but it may also be the result of a ruptured ovarian cyst. Therefore, a culdocentesis positive for blood is nondiagnostic. (See "Culdocentesis".) Magnetic resonance imaging Magnetic resonance imaging can be used to diagnose ectopic pregnancy, but is not a cost effective approach [38]. SCREENING ASYMPTOMATIC WOMEN As discussed above, over 50 percent of women are asymptomatic before tubal rupture and do not have an identifiable risk factor for ectopic pregnancy [39]. Identifying these women at a very early stage of pregnancy could reduce their risk of adverse outcome and permit treatment options less invasive than surgical excision. A decision analysis model showed that screening asymptomatic pregnant women for ectopic pregnancy reduced the frequency of rupture, but approximately three false positive diagnoses would occur per tubal rupture prevented if the prevalence of ectopic pregnancy was 2 percent [40]. Screening only appeared to be cost-effective in populations with a high prevalence (at least 8 percent) of ectopic pregnancy. We monitor women at high risk of ectopic pregnancy, such as those with a previous ectopic pregnancy, with laboratory and imaging studies as soon as their first missed menses. The diagnosis can then be established early, possibly before the occurrence of any symptoms. (See "Incidence, risk factors, and pathology of ectopic pregnancy", section on 'In vitro fertilization'.) UNCOMMON TYPES OF ECTOPIC PREGNANCY The possibility that an ectopic pregnancy may occur in a nontubal location, in conjunction with an intrauterine pregnancy, or even bilaterally [41], should be considered. These types of pregnancies are uncommon, and include heterotopic, hysterotomy scar, cervical, ovarian, rudimentary uterine horn, and abdominal pregnancy. Regardless of the location, the endometrium often responds to ovarian and placental production of pregnancy related hormones, so vaginal bleeding is a common symptom. Cervical pregnancy is estimated to occur in 1/2500 to 1/18,000 pregnancies and accounts for 1 percent of ectopic pregnancies [42-44]. Ovarian pregnancy occurs in 1/2100 to 1/60,000 pregnancies and accounts for 1 to 3 percent of ectopic pregnancies [45]. Interstitial pregnancy accounts for up to 1 to 3 percent of ectopic pregnancies [46,47]. Abdominal pregnancy accounts for up to 1.4 percent of ectopic pregnancies [48-50]. These pregnancies can go undetected until an advanced age and often result in severed hemorrhage [51]. Rates of maternal mortality have been reported as high as 20 percent [52,53]. Intramural pregnancy refers to pregnancy implanted within the myometrium of the uterus. This type of pregnancy is extremely rare with less than 50 reported cases in the literature [54]. Heterotopic pregnancy The investigation for ectopic pregnancy can be terminated, under most circumstances, if a transvaginal sonogram reveals an intrauterine pregnancy. Combined intrauterine and extrauterine pregnancy (heterotopic

pregnancy) is rare, except among women conceiving through IVF. The extrauterine pregnancy is usually in the fallopian tube, but can be at another location, such as the cervix. (See"Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) Early diagnosis of heterotopic pregnancy is difficult because of lack of symptoms. Thus, a high index of suspicion for this diagnosis is important, especially in patients who have undergone IVF and who experience pelvic pain. Serial hCG concentrations are not interpretable in the presence of both a viable intrauterine and ectopic pregnancy. On ultrasound examination, the diagnosis is suggested by visualization of both an ectopic and intrauterine pregnancy or the presence of echogenic fluid in the posterior cul de sac in the presence of an intrauterine pregnancy. Heterotopic tubal pregnancies have been reported as late as 16 weeks of gestation, while abdominal or rudimentary horn pregnancies can continue to develop late in gestation [52,55]. The ultrasonographer should carefully examine not only the uterus, but also the adnexae of women who conceive following IVF. We suggest that women with a confirmed intrauterine pregnancy who are experiencing abdominal or pelvic pain undergo serial TVS examinations every week until the possibility of a concomitant tubal ectopic pregnancy can be eliminated. Surgery (salpingectomy) is the standard treatment of heterotopic pregnancy with a tubal component, since the intrauterine pregnancy is a contraindication to medical therapy. If the ectopic pregnancy has not ruptured, then local injection of 5 mEq potassium chloride into the sac is another option [56-60]. Injection of potassium chloride can be guided sonographically, thus avoiding a surgical procedure. Methotrexate is absolutely contraindicated. Cervical pregnancy The most common symptom of cervical pregnancy is vaginal bleeding, which is often profuse and painless. Lower abdominal pain or cramps occur in fewer than one-third of patients; pain without bleeding is rare. Diagnosis and management of cervical pregnancy are discussed in detail separately. (See "Cervical pregnancy".) Hysterotomy scar pregnancy Symptoms are similar to tubal ectopic pregnancy, and include vaginal bleeding and abdominal pain. The diagnosis is made by sonographically visualizing an enlarged hysterotomy scar with an embedded mass [61]. Features which should be present include presence of trophoblast between the bladder and the anterior uterine wall, no fetal parts in the uterine cavity, absence of myometrium between the gestational sac and the bladder, and Doppler evidence of perfusion of the peritrophoblastic vasculature [61-63]. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) If the pregnancy has not ruptured, then local injection of potassium chloride into the sac under sonographic guidance is an effective treatment. Rupture can result in significant bleeding [64]. Ovarian pregnancy Sonographic diagnosis of an ovarian pregnancy is difficult. Ultrasound evaluation for ovarian pregnancy is discussed in detail separately. (See "Ultrasonography of pregnancy of unknown location".) The diagnosis of ovarian pregnancy is typically made at the time of surgery, but differentiation from a hemorrhagic ovarian cyst or pregnancy in the distal fallopian tube can be difficult. Ultrasound may suggest the diagnosis preoperatively [45]. Strict histopathological criteria are used to distinguish ovarian pregnancies from those originating in the fallopian tube. The exact diagnosis is not clinically important as these pregnancies are usually treated by surgical excision of the involved organs. Methotrexate treatment has been successful in case reports [65-67]. (See "Incidence, risk factors, and pathology of ectopic pregnancy", section on 'Ovarian pregnancy'.) Abdominal pregnancy Because of the variable location in the abdomen, abdominal pregnancy is associated with a wide range of signs and symptoms. These include abdominal pain, vaginal bleeding, vomiting, painful fetal movement, oligohydramnios, persistent unusual fetal lie, failure to deliver an intrauterine fetal demise, and labor abnormalities. In one report, hemothorax developed from implantation on the diaphragm [68]. Abdominal pregnancies rarely result in the birth of a viable infant. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) Interstitial pregnancy The interstitial portion of the fallopian tube is the proximal segment that is embedded within the muscular wall of the uterus. A pregnancy implanted at this site is called an interstitial pregnancy (figure 2); the term cornual pregnancy is also widely used to describe a pregnancy at this location. Originally, the term cornual pregnancy referred only to pregnancies implanted in either the horn of a bicornuate uterus, a rudimentary horn of a unicornuate uterus, or in the lateral half of a septated or partially septated uterus [47,69]. An interstitial pregnancy can be difficult to distinguish on ultrasound from an intrauterine pregnancy that is eccentrically positioned. Ultrasound evaluation for interstitial pregnancy is discussed in detail separately. (See "Ultrasonography of pregnancy of unknown location".) Grossly, an interstitial pregnancy appears as a gestational swelling lateral to the insertion of the round ligament (figure 2) [47]. The unique anatomic location of an interstitial pregnancy often leads to a delay in diagnosis, although an average delay of only four days in comparison with tubal pregnancies was reported in a large series [70]. Interstitial pregnancy presents with rupture in approximately 20 to 50 percent of cases [71-73]. A series of cases of interstitial pregnancy reported to a surgical registry included 14 patients with tubal rupture, all of which were before 12 weeks [71]. This is in

contrast to previous reports that rupture of interstitial pregnancy occurred late in pregnancy. Other clinical manifestations are the same as for all ectopic gestations (pelvic or abdominal pain, vaginal bleeding) [70]. Although the maternal mortality rate associated with tubal pregnancy is decreasing, the rate for interstitial pregnancies remains at 2 to 2.5 percent because of misdiagnosis of these gestations as intrauterine pregnancies. NATURAL HISTORY If left untreated, an ectopic pregnancy in the fallopian tube can progress to a tubal abortion or tubal rupture, or it may regress spontaneously. Rupture Tubal rupture is usually associated with profound hemorrhage, which can be fatal if surgery is not performed expeditiously to remove the ectopic gestation. Salpingectomy is the most common surgical approach when the tube has ruptured. Ruptured ectopic pregnancy is the major cause of pregnancy-related maternal mortality in the first trimester [74]. Most of these deaths occur prior to hospitalization or proximate to the woman's arrival in the emergency department. Abortion Tubal abortion refers to expulsion of the products of conception through the fimbria. This can be followed by resorption of the tissue or by reimplantation of the trophoblasts in the abdominal cavity (ie, abdominal pregnancy) or on the ovary (ie, ovarian pregnancy). Tubal abortion may be accompanied by severe intraabdominal bleeding, necessitating surgical intervention, or by minimal bleeding, not requiring further treatment. Spontaneous resolution The incidence of spontaneous resolution of an ectopic pregnancy is unknown. In one older (1955) series of 119 hospitalized patients with typical ectopic pregnancy symptoms, 57 were safely managed expectantly, without surgical or medical intervention (except opiates) [75]. It is difficult to predict which patients will experience uncomplicated spontaneous resolution. Potential candidates are hemodynamically stable women with an initial hCG concentration less than 2000 IU/L that is declining [76-78]. Gestational products left in the fallopian tube may resorb completely or, less commonly, may cause tubal obstruction [79]. Alternatively, a tubal abortion may occur. MANAGEMENT Virtually all women diagnosed with an ectopic gestation undergo medical or surgical treatment because the frequency and potential morbidity/mortality of rupture are high. Specific indications for surgical therapy include: Hemodynamic instability Impending or ongoing ectopic mass rupture Not able or willing to comply with medical therapy posttreatment follow-up Lack of timely access to a medical institution for management of tubal rupture Failed medical therapy In the absence of these criteria, medical therapy is an option. (See "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility" and "Methotrexate treatment of tubal and interstitial ectopic pregnancy", section on 'Medical versus surgical treatment'.) Expectant management is considered rarely in women with low and declining hCG levels. (See "Expectant management of ectopic pregnancy".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Ectopic pregnancy (The Basics)") Beyond the Basics topics (see "Patient information: Ectopic (tubal) pregnancy") SUMMARY AND RECOMMENDATIONS Abdominal pain, amenorrhea, and vaginal bleeding are the classic symptoms of ectopic pregnancy. Ectopic pregnancy should be suspected in any women of reproductive age with these symptoms, especially those who have risk factors for an extrauterine pregnancy (table 1). However, over 50 percent of women are asymptomatic before tubal rupture and do not have an identifiable risk factor for ectopic pregnancy. (See'Clinical manifestations' above.) The diagnosis is usually made clinically based upon results from ultrasound examination and human chorionic gonadotropin hormone (hCG) testing. Confirmation of the diagnosis by visualization at surgery or histopathological

examination of tissue is not necessary. However, in the absence of definitive surgical, sonographic, or histopathological findings, it may not be possible to differentiate between a failed intrauterine pregnancy and an ectopic pregnancy. (See 'Diagnosis' above.) The evaluation of a woman with suspected ectopic gestation begins with a transvaginal ultrasound examination and quantitative human chorionic gonadotropin (hCG) level. Transvaginal ultrasound is diagnostic if a true gestational sac, yolk sac, embryo, or embryonic cardiac activity is demonstrable inside or outside of the uterus. (See 'Diagnostic evaluation' above.) An extrauterine pregnancy is almost certain when the hCG concentration is greater than 1500 IU/L (discriminatory zone threshold) and transvaginal ultrasound examination reveals a complex adnexal mass and no intrauterine pregnancy. (See 'HCG above the discriminatory zone' above.) A serum hCG concentration less than 1500 IU/L with a negative transvaginal ultrasound examination should be followed by repetition of both of these tests in three days to follow the rate of rise of the hCG. A normally rising hCG concentration should be evaluated with ultrasound examination when the hCG reaches the discriminatory zone. At that time, an intrauterine pregnancy or an ectopic pregnancy can be diagnosed. If the hCG concentration rises but does not double over 72 hours, then the pregnancy is abnormal (an ectopic gestation or intrauterine pregnancy that is destined to abort). A falling hCG concentration is most consistent with a failed pregnancy. (See 'HCG below the discriminatory zone' above.) Uncommon types of ectopic pregnancy include heterotopic, cervical, hysterotomy scar, ovarian, interstitial, and abdominal pregnancy. (See'Uncommon types of ectopic pregnancy' above.) Risk factors for ectopic pregnancy Degree of risk High Risk factors Previous ectopic pregnancy Previous tubal surgery Tubal ligation Tubal pathology In utero DES exposure Current IUD use Moderate Infertility Previous cervicitis (gonorrhea, chlamydia) History of pelvic inflammatory disease Multiple sexual partners Smoking Low Previous pelvic/abdominal surgery Vaginal douching Early age of intercourse (<18 years) Odds ratio 9.3 - 47 6.0 - 11.5 3.0 - 139 3.5 - 25 2.4 - 13 1.1 - 45 1.1 - 28 2.8 - 3.7 2.1 - 3.0 1.4 - 4.8 2.3 - 3.9 0.93 - 3.8 1.1 - 3.1 1.1 - 2.5

Adapted from data in Ankum, WM, Mol, BWJ, Van Der Veen, F, Bossuyt, PMM. Fertil Steril 1996; 65:1093 and Murray, H, Baakdah, H, Bardell, T, Tulandi, T. CMAJ 2005; 173:905 and Bouyer, J, Coste, J, Shojaei, T, et al. Am J Epidemiol 2003; 157: 185.

Tests for suspected ectopic pregnancy

EP: ectopic pregnancy; IUP: intrauterine pregnancy;TVS: transvaginal ultrasound; hCG:

Significance of features associated with ectopic pregnancy Features Clinical features Estimated gestational age <70 days Vaginal bleeding Abdominal pain Abdominal tenderness Peritoneal signs Cervical motion tenderness Adnexal tenderness Adnexal mass Transvaginal ultrasound No intrauterine gestational sac Adnexal mass Separate from ovary Cardiac activity Yolk sac or embryo Tubal ring/yolk sac or embryo Fluid in pouch of Douglas Any Echogenic Color-flow Doppler -hCG combined with transvaginal ultrasound Empty uterus 1000 mIU/mL 1500 mIU/mL 2000 mIU/mL Adnexal mass* 1000 mIU/mL 1500 mIU/mL 73 46-64 85 92-96 43-96 40-99 38-48 86-100 84-96 80-98 63 56 95 69 96 98 93 20 37 65 99 100 100 99 100 89 95 69 97 85 23 33 69 5 27 26 15 50 95 91 62 96 SN (percent) SP (percent)

2000 mIU/mL

55

96

Sn: sensitivity; Sp: specificity; -hCG: beta human chorionic gonadotropin. * Mass or fluid in cul de sac for -hCG 1500 mIU/mL and 2000 mIU/mL. Data from: Ramakrishnan, K, Scheid, DC. Ectopic pregnancy: Forget the "classic presentation" if you want to catch it sooner: A new algorithm to improve detection. Journal of Family Practice 2006; 55:388. Incidence, risk factors, and pathology of ectopic pregnancy Last literature review version 19.2: mayo 2011 | This topic last updated: junio 14, 2011 INTRODUCTION Ectopic pregnancy occurs when the developing blastocyst becomes implanted at a site other than the endometrium of the uterine cavity. The most common extra-uterine location is the fallopian tube, which accounts for 98 percent of all ectopic gestations (picture 1A-B). Management of these pregnancies has changed dramatically over the years [1]. The guiding principle has become a conservative approach that attempts to save the tube, rather than salpingectomy. However, it is important to remember that hemorrhage from ectopic pregnancy is still the leading cause of pregnancy related maternal death in the first trimester and accounts for 4 to 10 percent of all pregnancy related deaths, despite improved diagnostic methods leading to earlier detection and treatment [2,3]. The incidence, risk factors, and pathology of ectopic pregnancy will be reviewed here. The clinical presentation, diagnosis, and treatment (medical and surgical) of this disorder are discussed separately. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy" and"Methotrexate treatment of tubal and interstitial ectopic pregnancy" and "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility".) INCIDENCE AND EPIDEMIOLOGY The prevalence of ectopic pregnancy among women who go to an emergency department with first trimester bleeding, pain, or both ranges from six to 16 percent [4]. The overall incidence of ectopic pregnancy increased during the mid twentieth century, plateauing at approximately almost 20 per 1000 pregnancies in the early 1990s, the last time national data were reported by the Centers for Disease Control [2]. This rising incidence is strongly associated with an increased incidence of pelvic inflammatory disease [5]. The current incidence of ectopic pregnancy is difficult to estimate from available data (hospitalizations, insurance billing records) because inpatient hospital treatment of ectopic pregnancy has decreased and multiple health care visits for a single ectopic pregnancy have increased [6]. Furthermore, since the incidence is expressed as the number of ectopic pregnancies/1000 pregnancies, the denominator is difficult to determine accurately since early pregnancy failures that do not result in delivery or hospitalization are often not counted. Ectopic pregnancy occurs with some seasonal variation and is most common in June and December [7]. The reason is unclear; the authors postulated that reproduction is seasonal, depends on photoperiod and temperature, and varies with different latitudes. Therefore, depending on the location of the investigation, ectopic pregnancy may show different seasonal rhythmicities. An altered maturation of the follicle and oocyte may negatively influence reproductive outcome in the transition between two reproductive steady states of high and low overall fecundity. In the United States between 1980 and 2007, 876 deaths were attributed to ectopic pregnancy. The ectopic pregnancy maternal mortality ratio declined by 57 percent between the periods of 1980 to 1984 and 2003 to 2007, from 1.15 to 0.50 deaths per 100,000 live births [8]. The mortality ratio was 6.8 times higher for African Americans than whites and 3.5 times higher for women older than 35 years than those younger than 25 years during 2003 to 2007. Of the 76 deaths among women hospitalized with ectopic pregnancy between 1998 and 2007, 71 percent of the gestations were located in the fallopian tubes rather than other sites. RISK FACTORS Risk factors for ectopic pregnancy can be divided into those that confer high, moderate, or low risk (table 1) [4,9,10]. However, the characteristics that place a woman at risk for ectopic pregnancy are not completely independent of one another. High risk factors Previous ectopic pregnancy Women who have had conservative treatment for ectopic pregnancy are at high risk (15 percent overall) for recurrence. This risk is related to both the underlying tubal disorder that led to the initial ectopic pregnancy and to the choice of treatment procedure. As an example, a study of surgical and medical therapy of ectopic pregnancy reported the rates of recurrent ectopic pregnancy after single dose methotrexate, salpingectomy, and linear salpingostomy were 8, 9.8, and 15.4 percent, respectively, among patients who attempted to conceive [1]. Tubal pathology and surgery The major cause of ectopic pregnancy is disruption of normal tubal anatomy from factors such as infection, surgery, congenital anomalies, or tumors. Anatomic distortion can be accompanied by functional impairment due to damaged ciliary activity.

Reconstructive surgery The association between tubal reconstructive surgery and subsequent ectopic pregnancy depends upon the condition of the tube, the type of surgery, and the surgeon's expertise. The tubal surgery itself is not the main cause of ectopic pregnancy; rather, the underlying tubal damage resulting from prior pelvic inflammatory disease or a prior ectopic pregnancy is the major culprit. Although tubal surgery is a high risk factor for ectopic pregnancy, most women with tubal damage are unlikely to conceive with either an intrauterine or ectopic pregnancy in the absence of tubal reconstructive surgery. Sterilization The estimated failure rate during the first year after tubal sterilization ranges from 0.1 to 0.8 percent; approximately one-third of these pregnancies are ectopic (table 2). The risk of sterilization failure was illustrated by a long-term, multicenter, prospective cohort study that followed 10,685 women after tubal sterilization [11]. These women had 47 ectopic pregnancies with a 10 year cumulative rate of 7.3 per 1000 procedures. The major additional findings from this analysis were: The risk of ectopic pregnancy was higher in women sterilized before the age of 30 Bipolar coagulation was more likely to result in ectopic pregnancy than postpartum partial salpingectomy (31.9 versus 1.2 ectopic pregnancies per 1000 procedures) The annual rate of ectopic pregnancy for all methods combined was similar in the first three years and in the fourth through tenth years after sterilization The high risk of ectopic pregnancy after bipolar coagulation may be due to formation of a tuboperitoneal fistula at the coagulated segment of the tube that allows spermatozoa to escape and reach the oocyte. In-utero DES exposure Women with a history of in-utero diethylstilbestrol (DES) exposure have a ninefold-increased risk of ectopic pregnancy due to abnormal tubal morphology and, possibly, impaired fimbrial function [12]. (See "Outcome of diethylstilbestrol (DES) exposed individuals".) Intrauterine contraception Intrauterine contraceptive devices (IUD), like most contraceptive methods, lower the overall risk of both ectopic and intrauterine pregnancy by preventing ovulation, fertilization, or implantation [13]. The rate of ectopic pregnancy in women using an IUD is one-tenth of the rate in women who are not using any type of contraceptive [14,15]. However, if a woman with an IUD becomes pregnant, she is at a higher risk of ectopic pregnancy than other pregnant women (table 2) [13,16]. Moderate risk factors Previous genital infections Pelvic infection (eg, nonspecific salpingitis, chlamydia, gonorrhea), especially recurrent infection, is a major cause of tubal pathology and, therefore, the increasing incidence of ectopic pregnancy [9]. As an example, a retrospective cohort study evaluated the risk of hospitalization for ectopic pregnancy in 11,000 Wisconsin women who had one or more chlamydial infections between 1985 and 1992 [17]. The odds ratios for ectopic pregnancy after two and after three or more episodes of chlamydial infection were 2.1 and 4.5, respectively [17]. (See "Pathogenesis of and risk factors for pelvic inflammatory disease".) Pelvic infection may alter tubal function, in addition to causing tubal obstruction and pelvic adhesive disease. Some data suggest that a history of chlamydial infection results in the production of a protein (PROKR2) that makes a pregnancy more likely to implant in the tubes [18]. Infertility The incidence of ectopic pregnancy is higher in the infertility population, although this could reflect the increased incidence of tubal abnormality in this group of women. Several reports have also suggested an association between fertility drugs and ectopic pregnancy, which may be related to altered tubal function secondary to hormonal fluctuation. As an example, one large multicenter study found that women taking clomiphene citrate doubled their risk of ectopic pregnancy from 3 to 6 percent [19]. The incidence of ectopic pregnancy after treatment with gonadotropin appears to be slightly higher as well [20,21]. Multiple sexual partners A lifetime number of sexual partners exceeding one is associated with a moderate risk of ectopic pregnancy. This is related to the increased risk of pelvic inflammatory disease in woman with a history of multiple sexual partners. (See "Pathogenesis of and risk factors for pelvic inflammatory disease".) Smoking Cigarette smoking in the periconceptional period increases the risk of ectopic pregnancy in a dose-dependent manner, thus it can be either a low or moderate risk factor depending on the patient's habits [10,22]. This may be the result of impaired immunity in smokers, thus predisposing them to pelvic inflammatory disease, or to impairment in tubal motility. Low risk factors In vitro fertilization In vitro fertilization (IVF) has been associated with an increased risk of both ectopic and heterotopic pregnancy (see'Heterotopic pregnancy' below) [23,24]. However, US registry data from 2002 showed an overall rate of ectopic pregnancy of 2.1 percent [25]. This rate is comparable to the ectopic pregnancy rate of 19 per 1000 pregnancies reported for the United States [2]. Cervical and interstitial pregnancies are other forms of ectopic pregnancy that are encountered more often following IVF (see 'Cervical pregnancy' below and 'Interstitial or cornual pregnancy' below). (See "In vitro fertilization".)

Vaginal douching Regular vaginal douching is associated with an increased risk of both pelvic inflammatory disease and ectopic pregnancy [26]. Age A young age (ie, less than age 18) at the first sexual encounter slightly increases the risk of ectopic pregnancy [27]. There is also an increasing proportion of ectopic pregnancies among women in the older age groups [28,29]. A Norwegian study reported the overall rate of ectopic pregnancy in the population was 1.8 percent; however, women over the age of 35 years had a rate of 4.1 percent, which was eight times higher than that seen in younger age groups [29]. This high incidence in older women may be a reflection of cumulative risk factors over time. Protective factors Women using hormonal contraception or an IUD are at very low risk of conceiving either an intrauterine or ectopic pregnancy. However, if they conceive, the probability of an ectopic pregnancy is generally higher than in women not using contraception. The number of ectopic pregnancies as a proportion of all pregnancies occurring in contraceptive users is shown in the table (table 2). PATHOLOGY Almost all ectopic pregnancies occur in the fallopian tube (98 percent). In one series of 1800 surgically treated cases, the distribution of sites was ampullary (70 percent), isthmic (12 percent), fimbrial (11.1 percent), ovarian (3.2 percent), interstitial (2.4 percent), and abdominal (1.3 percent) [30]. Regardless of the location, the endometrium often responds to ovarian and placental production of pregnancy related hormones. The most common types of endometrium associated with ectopic pregnancy are decidual reaction (42 percent), secretory endometrium (22 percent), and proliferative endometrium (12 percent) [31]. Tubal pregnancy As discussed above, 70 percent of tubal pregnancies occur in the ampullary portion of the fallopian tube, with the remainder about equally divided between the fimbrial and isthmus ends [30,32]. A very small proportion occur in the interstitial portion (see 'Interstitial or cornual pregnancy' below). Several factors may be involved in the pathogenesis of tubal pregnancies, but they are generally believed to be the result of (1) conditions that delay or prevent passage of the fertilized oocyte into the uterine cavity or (2) factors inherent in the embryo that result in premature implantation. Tubal conditions that can impair tubal transport include: Chronic salpingitis Tubal pathology, particularly chronic salpingitis, is observed in up to 90 percent of ectopic pregnancies. Chronic salpingitis is six times more common in tubes containing an ectopic pregnancy than in normal tubes [33]. The histologic features of chronic salpingitis are attenuation and blunting of the plicae and infiltration of the tubal wall by plasma cells and lymphocytes. Salpingitis isthmica nodosa Salpingitis isthmica nodosa (SIN) is noted in approximately 10 percent of women with a tubal pregnancy. The gross appearance of SIN is bilateral nodularities in the isthmic portion of the tube. Histologically, the tubal mucosa penetrates into the myosalpinx, leading to hypertrophy of the surrounding muscular layers. The etiology of salpingitis isthmica nodosa is not known. A number of factors (eg, lectin, integrin, matrix-degrading cumulus, prostaglandins, growth factors, cytokines, and modular proteins [34]) may cause premature implantation in the tube. The depth of implantation of the gestational sac varies according to the location of the ectopic pregnancy within the fallopian tube. A histopathologic study of 84 tubal pregnancies found that the gestational sac was inside the tubal lumen in one-half of ampullary pregnancies [32]. The muscularis of the tube was preserved in most of these cases. By comparison, the gestational sac was usually detected extraluminally or both inside and outside the lumen in isthmic pregnancies and the disruption of the tubal wall was more extensive. This suggests that the trophoblast penetrates the tubal wall relatively early in isthmic pregnancy. Embryos with cardiac activity have been identified by transvaginal ultrasound in approximately one-quarter of tubal pregnancies [35]. Fetal chromosomal and anatomic abnormalities have been found as well. However, chromosomal abnormality is probably not an important etiology of ectopic pregnancy [36,37]. As an example, in one study in which chorionic villi were karyotyped from 30 viable surgically excised ectopic gestations, the rate of karyotypic abnormality was not different from that of controls with intrauterine pregnancies [37]. Cervical pregnancy A cervical pregnancy is a rare form of ectopic pregnancy in which the trophoblast implants in the cervical tissue of the endocervical canal. (See "Cervical pregnancy".) Ovarian pregnancy Ovarian pregnancy occurs in 1:7000 pregnancies and is becoming more common or approximately 0.5 to 3 percent of ectopic pregnancies [38,39]. In contrast to tubal pregnancy, a history of pelvic inflammatory disease or the use of an intrauterine contraceptive device does not increase the risk of ovarian pregnancy. Ovarian pregnancy appears to be a random event that is not associated with a history of infertility or recurrent extra-uterine pregnancy. Strict histopathological criteria are used to distinguish ovarian pregnancies from those originating in the fallopian tube [40]. Interstitial or cornual pregnancy The interstitial portion of the fallopian tube is the proximal segment that is embedded within the muscular wall of the uterus. A pregnancy implanted at this site is called an interstitial pregnancy (figure 1); the term cornual pregnancy is also widely used to describe a pregnancy at this location. Originally, the term cornual pregnancy referred only to

pregnancies implanted in either the horn of a bicornuate uterus, a rudimentary horn of a unicornuate uterus, or in the lateral half of a septated or partially septated uterus [41,42]. Interstitial pregnancies may be misdiagnosed as intrauterine because they are partially implanted in the endometrium. A clue to correct diagnosis is its eccentric location and thin (less than 5 mm) myometrial mantle. Contrary to previous belief, rupture of interstitial pregnancy occurs relatively early in pregnancy [43]. (See "Ultrasonography of pregnancy of unknown location", section on 'Interstitial pregnancy'.) These pregnancies are uncommon, comprising about 2 to 3 percent percent of all ectopic pregnancies [44]. The risk factors are similar to those for other tubal pregnancies, except for ipsilateral salpingectomy which is a risk factor that is specific to interstitial pregnancy. Rudimentary uterine horn pregnancy A rudimentary horn pregnancy is not an ectopic pregnancy, but an intrauterine pregnancy that is located in the rudimentary uterine horn of a unicornuate uterus. The term cornual pregnancy was originally used to refer exclusive to either this location of a gestation or one located in the horn of a bicornuate uterus, as noted above. However, such pregnancies have a high risk of uterine rupture. This topic is discussed in detail separately. (See "Clinical manifestations and diagnosis of congenital anomalies of the uterus", section on 'Obstetrical complications'.) Angular pregnancy Angular pregnancy is an intrauterine pregnancy with a clinical course distinct from interstitial pregnancy [41,42]. The pregnancy is implanted medial to the uterotubal junction in the lateral angle of the uterine cavity, close to the proximal ostium of the fallopian tube. In contrast with an interstitial pregnancy, an angular pregnancy is located medial to the round ligament [41,42]. When viewed from the exterior of the uterus during laparoscopy or laparotomy, the uterine enlargement caused by an angular pregnancy displaces the round ligament superiorly and laterally, while remaining medial to the ligament itself. On the other hand, an interstitial pregnancy causes an enlargement of the uterus that is lateral to the round ligament. Angular pregnancy appears to be rare and there are few current reports regarding its diagnosis or management. In a classic review of a series of 39 angular pregnancies, the rate of spontaneous abortion was 39 percent [42]. Uterine rupture has rarely been reported with this type of pregnancy [42,45]. Hysterotomy scar pregnancy Ectopic pregnancy in a previous hysterotomy (cesarean) scar occurs in about 1 in 2000 pregnancies and 6 percent of ectopic pregnancies among women with a prior cesarean delivery [46]. It does not appear to be related to the number of cesarean deliveries. The pregnancy is located in the scar outside of the uterine cavity and surrounded by myometrium and connective tissue. Implantation in this location is believed to occur because the embryo migrates through a defect within the scar [47]. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) Heterotopic pregnancy Heterotopic pregnancy refers to the combination of an intrauterine pregnancy and a concurrent pregnancy at an ectopic location. The estimated incidence of heterotopic pregnancy is dependent upon the rates of ectopic pregnancy and dizygotic twinning. The incidence has been rising, mainly due to the increasing number of pregnancies derived from assisted reproductive technology (ART). (See"Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) The ectopic pregnancy is found in the fallopian tube in 90 percent of cases; other sites include the cornua (4 percent), ovary, cervix, and abdomen. A few cases have been diagnosed as late as 16 weeks of gestation [48]. Abdominal pregnancy An abdominal pregnancy may be primary, from direct implantation of the blastocyst on the peritoneal surface or abdominal viscera, or secondary, resulting from extrusion of an embryo from the tube [49]. In a review of deliveries over a 20 year period at one institution, the incidence of abdominal pregnancy was approximately 1:5000 deliveries with nine early and six advanced abdominal gestations [50]. (See "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (see "Patient information: Ectopic pregnancy (The Basics)") Beyond the Basics topics (see "Patient information: Ectopic (tubal) pregnancy") SUMMARY AND RECOMMENDATIONS

Ectopic pregnancy is the leading cause of pregnancy related death in the first trimester of pregnancy. The most common site is the fallopian tube, but ectopic pregnancies also occur in cervical, interstitial, and cesarean scar locations as well as in combination with intrauterine pregnancy (heterotopic pregnancy). Early diagnosis of ectopic pregnancy allows detection before tubal rupture, thus decreasing maternal morbidity and mortality. A high index of suspicion, identification of risk factors, and the use of transvaginal ultrasound improve the likelihood of early diagnosis. Risk factors include a history of tubal disease, previous ectopic pregnancy, tubal surgery, previous genital infection, and pregnancy derived from in-vitro fertilization. Risk factors for ectopic pregnancy Degree of risk High Risk factors Previous ectopic pregnancy Previous tubal surgery Tubal ligation Tubal pathology In utero DES exposure Current IUD use Moderate Infertility Previous cervicitis (gonorrhea, chlamydia) History of pelvic inflammatory disease Multiple sexual partners Smoking Low Previous pelvic/abdominal surgery Vaginal douching Early age of intercourse (<18 years) Odds ratio 9.3 - 47 6.0 - 11.5 3.0 - 139 3.5 - 25 2.4 - 13 1.1 - 45 1.1 - 28 2.8 - 3.7 2.1 - 3.0 1.4 - 4.8 2.3 - 3.9 0.93 - 3.8 1.1 - 3.1 1.1 - 2.5

Adapted from data in Ankum, WM, Mol, BWJ, Van Der Veen, F, Bossuyt, PMM. Fertil Steril 1996; 65:1093 and Murray, H, Baakdah, H, Bardell, T, Tulandi, T. CMAJ 2005; 173:905 and Bouyer, J, Coste, J, Shojaei, T, et al. Am J Epidemiol 2003; 157: 185. Ectopic pregnancies as a proportion of all pregnancies by contraceptive method Contraceptive method Levonorgestrel intrauterine device Tubal sterilization Copper intrauterine device 1:2 1:3 1:16 Ectopic pregnancy/All pregnancies

Norethindrone-only pill Norgestrel-only pill Combination pills All women

1:20 1:21 0 1:50

Adapted from United Stated Food and Drug Administration reviews of data submitted by drug manufacturers to support marketing approval. Furlong, LA. J Reprod Med 2002; 47:881. Methotrexate treatment of tubal and interstitial ectopic pregnancy Author Togas Tulandi, MD, MHCM Section Editor Robert L Barbieri, MD Deputy Editor Sandy J Falk, MD Disclosures Last literature review version 19.2: mayo 2011 | This topic last updated: abril 22, 2011 INTRODUCTION Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the mainstay of treatment, advances in early diagnosis facilitated the introduction of medical therapy with methotrexate (MTX) in the 1980s [1]. In one report, approximately 35 percent of women with ectopic pregnancy are eligible for medical treatment [2]. Due to the routine use of early ultrasound among infertile patients who conceive, diagnosis of ectopic pregnancy can be established early and medical treatment can be administered in most cases. The overall success rate of medical treatment in properly selected women is nearly 90 percent [3-5]. Medical treatment of ectopic pregnancy will be reviewed here. Ectopic pregnancy diagnosis, surgical treatment and expectant management are discussed separately. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy" and "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility" and "Expectant management of ectopic pregnancy".) PHARMACOLOGY MTX is a folic acid antagonist widely used for treatment of neoplasia, severe psoriasis, and rheumatoid arthritis. It inhibits DNA synthesis and cell reproduction, primarily in actively proliferating cells such as malignant cells, trophoblasts, and fetal cells. MTX is rapidly cleared from the body by the kidneys, with 90 percent of an intravenous (IV) dose excreted unchanged within 24 hours of administration [6]. The dose of MTX used to treat ectopic pregnancy (50 mg/m2 or 1 mg/kg) is relatively low. High dose MTX (500 mg/m2) is used to treat some malignancies. In some protocols, reduced folates (leucovorin, also called folinic acid, N5-formyl-tetrahydrofolate, citrovorum factor) are given to bypass the metabolic block induced by MTX, and thus rescue normal cells from toxicity. (See "Therapeutic use of high-dose methotrexate", section on 'Clinical pharmacology'.) CANDIDATES FOR MEDICAL TREATMENT Optimal candidates The optimal candidates for MTX treatment of ectopic pregnancy are hemodynamically stable, willing and able to comply with posttreatment follow-up, have a human chorionic gonadotropin beta-subunit (hCG) concentration 5000 mIU/mL, and no fetal cardiac activity. Ectopic mass size less than 3 to 4 cm is also commonly used as a patient selection criterion; however, this has not been confirmed as a predictor of successful treatment (see 'Relative contraindications' below). Contraindications Some women are not appropriate candidates for medical therapy and should be managed surgically, including women with the following characteristics [7,8]: Hemodynamically unstable Signs of impending or ongoing ectopic mass rupture (ie, severe or persistent abdominal pain or >300 mL of free peritoneal fluid outside the pelvic cavity) Clinically important abnormalities in baseline hematologic, renal or hepatic laboratory values Immunodeficiency, active pulmonary disease, peptic ulcer disease Hypersensitivity to MTX Coexistent viable intrauterine pregnancy

Breastfeeding Unwilling or unable to be compliant with post-therapeutic monitoring Do not have timely access to a medical institution MTX is renally cleared, and in women with renal insufficiency, a single dose of MTX can lead to death or severe complications, including bone marrow suppression, acute respiratory distress syndrome and bowel ischemia. Dialysis does not provide normal renal clearance [9,10]. Relative contraindications High hCG concentration A high serum hCG concentration is the most important factor associated with treatment failure (table 1). Women with a high baseline hCG concentration (greater than 5000 mIU/mL) are more likely to require multiple courses of medical therapy or experience treatment failure [11,12].

A systematic review of observational studies involved 503 women in which the outcome of single dose MTX therapy was stratified according to initial hCG concentration [11]. There was a statistically significant increase in failure rates in patients with initial hCG levels of greater than 5000 mIU/mL compared with those who had initial levels of less than 5000 mIU/mL (OR 5.5, 95% CI 3.0-9.8). The failure rate for women who had an initial concentration between 5000 and 9999 mIU/mL was significantly higher than for those who had initial levels between 2000 and 4999 mIU/mL (OR 3.8, 95% CI 1.2-12.3). Multiple dose regimens were not evaluated. The authors calculated that for every 10 treatments, there would be one more failure if the hCG level is 5000 to 9999 mIU/mL than there would be if it is 2000 to 4999 mIU/mL. Fetal cardiac activity The presence of fetal cardiac activity is another relative contraindication to medical treatment [3,12]. In a metaanalysis, sonographic evidence of cardiac activity was significantly associated with treatment failure (OR 9.1, 95% CI 3.8-22.0) [3]. Large ectopic size Although large size of the ectopic pregnancy (3.5 cm) is often used as criterion for exclusion in medical treatment regimens, this restriction is based on small studies with inconsistent protocols and results [12-15]. Studies have generally restricted use of MTX to women with an ectopic mass less than 3 to 4 cm [12,13], thus there are few studies of larger masses [16]. As an example, one observational study found that the success rate for systematic MTX treatment was higher for women with ectopic masses smaller than 3.5 cm compared to masses between 3.5 and 4 cm (93 versus 90 percent) [13]. In addition, there are variations within and among studies regarding whether the size used is the actual gestational mass or the mass and surrounding hematoma [12-14]. Further, ectopic mass size does not appear to correlate with hCG level [17]. Peritoneal fluid The sonographic finding of free peritoneal fluid is another commonly used exclusion criterion for MTX treatment of ectopic pregnancy. Peritoneal fluid may be blood, however, this is not diagnostic of tubal rupture; peritoneal blood may also be the result of tubal abortion. Historically, culdocenteses detected blood in the peritoneal cavity of 70 to 83 percent of women with ectopic pregnancies, but only 50 to 62 percent of them had a ruptured fallopian tube [18-20].

In a large case series, free fluid confined to the pelvic cavity was not associated with medical treatment failure [12]. While surgical treatment of patients with free fluid in the paracolic gutters or upper abdomen may be prudent, the amount of allowable free fluid confined to the posterior cul-de-sac (pouch of Douglas) is controversial [7,21]. Other Preliminary reports have cited a variety of other factors which may be associated with treatment failure. These include: sonographic evidence of a yolk sac [12,22,23], isthmic location of ectopic mass (rather than ampullary) [12,24], high pretreatment folic acid level [25], and rate of hCG rise or fall prior to and within several days following treatment [24,26]. Further study is needed to validate these findings. In addition, women who are planning sterilization may desire concomitant surgical treatment for ectopic pregnancy and tubal ligation. DRUG ADMINISTRATION MTX can be given systemically (intravenously, intramuscularly, or orally) or by direct local injection into the ectopic pregnancy sac transvaginally or laparoscopically. Intramuscular (IM) administration is most common. Intramuscular therapy Intramuscular MTX administration is the predominant route for treatment of tubal pregnancy [1]. Local injection Local injection of MTX for ectopic pregnancy is rarely used. Local treatment is highly operator dependent and not practical when performed laparoscopically. Women bearing the costs and risks of laparoscopic surgery should have definitive treatment (ie, removal of the ectopic gestation) at the time of the procedure.

A systematic review found that treatment success with local injection of MTX may be higher than with systemic treatment; however, the difference did not reach statistical significance [27]. In addition, local and systemic MTX administration had similar rates of subsequent intrauterine pregnancies or repeat ectopic pregnancies. Efficacy of single versus multidose therapy The two most commonly used protocols for MTX administration are single dose and multiple dose (four MTX doses which alternate with oral leucovorin). Fourteen percent of patients on single dose regimens ultimately receive two or more doses and 10 percent of patients on multi-dose regimens receive a single dose [3] (see 'Single dose protocol' below and 'Multiple dose protocol' below). We prefer an initial approach with single dose therapy for tubal ectopic pregnancy for the following reasons. The overall rate of resolution of ectopic pregnancy reported in the literature is about 90 percent for both single and multiple dose protocols [3,27,28]. Multiple dose protocols appear to cause more adverse effects [3]. The single dose approach is less expensive, requires less intensive monitoring, and does not require folinic acid rescue. The following are systematic reviews of the two regimens: A systematic review of two randomized trials compared single dose with fixed multiple dose regimens [27]. There was no significant difference between treatment success rates, which ranged from 89 to 91 percent for single dose and 86 to 93 percent for multidose therapy [29,30]. There were no consistent findings regarding rates of complications between the two dose regimens. Another systematic review included 26 observational studies of 1300 women with ectopic pregnancy [3]. Overall success rates for single versus multiple dose regimens were 88 and 93 percent, a significant difference. This difference was even larger after adjustment for factors such as hCG concentration and presence of embryonic cardiac activity (OR 4.74, 95 percent CI 1.77-12.62). However, significantly fewer side effects were noted after single dose versus multidose treatment (31 versus 41 percent). A hybrid of the two protocols, a two-dose MTX regimen (50 mg/m 2 IM on days 0 and 4) has been proposed. A single report on this regimen found an 87 percent treatment success rate [31], infrequent complications and adverse effects, and high patient satisfaction. Further study to evaluate this protocol is needed before it can be recommended. On the other hand, we use multidose MTX therapy for interstitial pregnancies (see 'Interstitial pregnancy' below). Combination therapy with mifepristone Treatment of ectopic pregnancy using a combination of mifepristone and MTX has also been investigated [27]. A systematic review of randomized trials of single dose intramuscular MTX (50 mg/m2) in combination with oral mifepristone (600 mg) versus MTX alone found that combination therapy may increase treatment efficacy. Success rates for MTX or MTX/mifepristone therapy were 81 and 74 percent; the difference approached statistical significance. No differences were found in tubal preservation or tubal patency. No data are available on future fertility. More studies are needed to fully evaluate whether the addition of mifepristone to MTX regimens is beneficial. We do not recommend the use of this regimen. In addition, mifepristone is not approved for treatment of ectopic pregnancy in the United States. (See "Mifepristone for the medical termination of pregnancy".) Pretreatment testing HCG, blood type, complete blood count, renal and liver function tests are drawn prior to starting therapy. A transvaginal ultrasound is performed. (See 'Contraindications' above and "Clinical manifestations, diagnosis, and management of ectopic pregnancy".) Rh(D) immune globulin should be administered if the woman is Rh(D)-negative. (See "Prevention of Rh(D) alloimmunization".) We do not perform endometrial sampling in the management of ectopic pregnancy. Treatment with methotrexate is a less invasive option. Precautions during therapy Patients and clinicians should adhere to the following precautions during MTX treatment [7]: Avoid vaginal intercourse and new conception until hCG is undetectable Avoid pelvic exams during surveillance of MTX therapy due to theoretical risk of tubal rupture Avoid sun exposure to limit risk of MTX dermatitis Avoid foods and vitamins containing folic acid Avoid nonsteroidal antiinflammatory drugs, as the interaction with MTX may cause bone marrow suppression, aplastic anemia, or gastrointestinal toxicity Single dose protocol The most efficient approach to therapy is administration of a single IM dose of MTX (50 mg per square meter of body surface area) [32]. Body surface area (BSA) may be calculated based upon height and weight on the day of treatment using the formula BSA = square root ((cm X kg)/3600) or a BSA calculator (calculator 1). Approximately 15 to 20 percent of women will require a second dose of MTX and should be made aware of this [3,13]. Fewer than 1 percent of patients need more than two doses [3] (see 'Side effects and complications' below). Our single dose MTX protocol and another commonly reported protocol are described below and in the table (table 2). Protocols vary slightly; choice of protocol depends on provider preference.

In our single dose protocol, Day 1 is the day of MTX treatment [33]. We prefer to draw the second hCG level on Day 7, thereby saving the patient a visit on Day 4. Data from a study of hCG values on Days 1, 4, and 7 suggest that Day 4 serum hCG levels is not an accurate test to predict treatment success [34]. We administer a SECOND dose of MTX if the serum hCG concentration on Day 7 has not declined by at least 25 percent from the Day 1 level, and the protocol is repeated. In another commonly used protocol, Day 1 is the day of MTX treatment [1,35]. On Days 4 and 7, a serum hCG concentration is drawn [7,8,36]. If the decrease in hCG between Days 4 and 7 is less than 15 percent, a second dose of MTX 50 mg/m2 IM is administered. Posttreatment laboratory monitoring It is common to observe an increase in hCG levels in the first several days following therapy (ie, until Day 4) [37]. This is due to continued hCG production by syncytiotrophoblast despite cessation of production by cytotrophoblast. After Day 7 in both single dose protocols, hCG testing is repeated weekly. If any measurement shows a <25 percent decrease from the level on day 1 OR <15 percent decrease from the level on Day 4, an additional dose of MTX 50 mg/m2 IM is administered [1]. If an additional dose of MTX is indicated, we do not repeat pretreatment laboratory testing (complete blood count, renal and liver function tests); there are no data suggesting that one dose of MTX changes the results of these tests. Weekly measurements are continued until the hCG is undetectable (this level varies by laboratory). The hCG concentration usually declines to less than 15 mIU/mL by 35 days post-injection, but may take as long as 109 days [13,38]. We give a maximum of three doses of MTX. If the hCG falls <15 percent between weekly measurements after a third dose, we perform a laparoscopic salpingostomy or salpingectomy. (See "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility".) Folinic acid rescue is not required for women treated with the single dose protocol, even if multiple doses are ultimately given. Multiple dose protocol The most common multiple dose regimen administers MTX (1 mg/kg per day IM or IV) on Days 1, 3, 5, and 7, and oral leucovorin (0.1 mg/kg) on Days 2, 4, 6, and 8 [39]. HCG levels are drawn on Days 1, 3, 5, and 7. If the serum hCG declines MORE than 15 percent from the previous measurement, treatment is stopped and a surveillance phase begins. The surveillance phase consists of weekly hCG measurements. If the hCG declines LESS than 15 percent from the previous level, the patient is given an additional dose of MTX 1 mg/kg IM followed the next day with a dose of oral leucovorin 0.1 mg/kg. The hCG is followed until the level is undetectable. A systematic review of patients treated with multiple dose regimens found a 93 percent success rate [3]. Forty percent of women reported side effects, but these effects were relatively minor and transient [3]. Posttreatment management Ultrasound follow-up There appears to be no clinical benefit from routine serial ultrasound examinations [17]. After treatment, the ectopic pregnancy is often noted to increase in size and may persist for weeks on serial ultrasound examinations. This probably represents hematoma, rather than persistent trophoblastic tissue, and is not predictive of treatment failure. However, ultrasound evaluation for peritoneal fluid is indicated for women with severe abdominal pain. Side effects and complications Adverse reactions to MTX are usually mild and self-limited. The most common are stomatitis and conjunctivitis. Rare side effects include gastritis, enteritis, dermatitis, pneumonitis, alopecia, elevated liver enzymes, and bone marrow suppression. Approximately 30 percent of patients in the single dose protocol will have side effects; this rate is lower than with multidose regimens (40 percent) [3]. (See "Major side effects of low-dose methotrexate".) Pain after treatment Mild abdominal pain of short duration (one to two days) six to seven days after receiving the medication is also common. The pain may be due to tubal abortion or tubal distention from hematoma formation and can usually be controlled with acetaminophen. Nonsteroidal antiinflammatory drugs should be avoided because a clinically significant drug interaction with MTX occurs in some patients taking both drugs. Occasionally pain may be severe, but women with severe pain who are hemodynamically stable often do not need surgical intervention. As an example, a review of 56 women with abdominal pain severe enough to be evaluated in the clinic or emergency department, or requiring hospitalization, found that only eight patients subsequently required surgery [21]. A patient with severe pain may be further evaluated with transvaginal ultrasonography. Findings suggestive of hemoperitoneum raise clinical suspicion of tubal rupture. In one study, three parameters predicted hemoperitoneum 300 mL in women with ectopic pregnancy: moderate to severe pelvic pain, fluid above the uterine fundus or around the ovary, and serum hemoglobin concentration <10 g/dL [40]. A woman with none of these three criteria had a probability of 5.3 percent of hemoperitoneum 300 ml. When two or more criteria were present, the probability for hemoperitoneum 300 ml reached 92.6 percent. Women with severe pain should be closely observed for hemodynamic changes which may accompany a tubal rupture. Falling hCG levels do not preclude the possibility of tubal rupture. If tubal rupture is suspected, immediate surgery is required. SUBSEQUENT REPRODUCTIVE PERFORMANCE

Interval to conception There has been no study addressing when is the earliest and best time to conceive after MTX treatment of ectopic pregnancy. One study reported that patients with ectopic pregnancies treated with MTX had a timely return of menses and superior rates of conception compared with those treated with conservative surgical management [41]. However, a retrospective study of controlled ovarian hyperstimulation after methotrexate treatment of ectopic pregnancy reported decreased number of oocytes in the cycle within 180 days after methotrexate compared to that in later days [42]. Toxicology literature recommends a four to six month washout period [43,44]. A retrospective study of women who conceive after MTX treatment for ectopic pregnancy found no difference in fetal malformation and adverse outcome rates in those who conceived within less than six months (mean 3.61.7 months) compared with six or more months (mean 23.614.7 months) [45]. Thus, since, there is no apparent deleterious effect of previous methotrexate treatment on the offspring, it is reasonable to allow the patients to conceive. Women in this population should take the folate daily, according to routine preconceptual recommendations. (See "Folic acid for prevention of neural tube defects", section on 'Folic acid supplementation'.) Effect on fertility There is no evidence of adverse effects of MTX treatment of ectopic pregnancy on future pregnancies [4649]. In addition, treatment with MTX does not appear to compromise ovarian reserve [50]. Attempts to conceive may be resumed after the hCG level is undetectable. Extrauterine pregnancy is usually due to altered tubal function secondary to clinical or subclinical salpingitis; the functional disorder is bilateral and irreversible. Therefore, it is not surprising that ectopic pregnancy can be followed by infertility and recurrent ectopic pregnancy. The incidence of recurrent ectopic pregnancy is approximately 15 percent and rises to 30 percent following two ectopic pregnancies [51]. The risk of recurrence appears to be the same for both medical and surgical therapies [52]. (See 'Medical versus surgical treatment' below.) The initial level of hCG >5000 mIU/mL may be associated with increased risk of subsequent tubal obstruction, regardless of treatment approach [53]. MEDICAL VERSUS SURGICAL TREATMENT Approximately 35 percent of women with ectopic pregnancy are eligible for medical treatment [2]. In these women, systemic treatment with MTX is as effective as laparoscopic salpingostomy, and results in similar success rates for tubal patency and future intrauterine pregnancy [54]. Although adverse effects are increased with MTX over surgery, depending on the MTX regimen (fixed multiple dose versus single/variable dose), patient recovery may be improved with medical treatment. Medical treatment costs approximately $3000 less than surgery per resolved ectopic pregnancy [5]. In patients who are eligible for either medical or surgical treatment, the choice of therapy should be guided by the patient's preference after a detailed discussion of risks, benefits, outcome, and monitoring requirements of both medical and surgical approaches. Informed consent is obtained before administration of MTX, as well as before surgery. A systemic review of randomized trials compared methotrexate therapy with laparoscopic salpingostomy; major findings are listed below [54]: Intramuscular MTX therapy (single or multiple dose) and salpingostomy yielded similar treatment success rates, ranging from 82 to 95 percent for MTX therapy versus 80 to 92 percent for salpingostomy. Transvaginal injection of MTX was significantly less effective than salpingostomy. Adverse effects and complications were more common in women treated with systemic MTX than with surgery (60 versus 12 percent in one study). However, the studies were likely underpowered to detect a difference in rare perioperative complications. Physical and psychological functioning after treatment was improved for patients treated with single dose MTX compared to laparoscopic salpingostomy; however, women treated with multidose regimens showed greater functional impairment than their surgical counterparts. The time required for hCG concentrations to reach undetectable levels is faster after laparoscopic surgery, thus reducing the period of posttreatment monitoring, based on the only randomized trial to report this outcome. Posttreatment tubal patency and intrauterine pregnancy rates were similar. Risk of recurrent ectopic pregnancy did not differ by treatment approach. MEDICAL TREATMENT VERSUS EXPECTANT MANAGEMENT Expectant management should only be considered by women with unknown location of their pregnancy or suspected ectopic pregnancy, and low and declining serum hCG levels. (See "Expectant management of ectopic pregnancy".) INTERSTITIAL PREGNANCY We initially treat interstitial pregnancy (located at the junction of the fallopian tube and uterine cavity) with multidose medical therapy (figure 1) [39,55-58], resorting to surgical therapy if there is any deterioration in clinical status. There are no high quality data comparing single versus multidose MTX therapy for interstitial pregnancy. The most common multiple dose regimen administers MTX (1 mg/kg per day IM or IV) on Days 1, 3, 5, and 7 with leucovorin (0.1 mg/kg orally) on Days 2, 4, 6, and 8; a second course of MTX/leucovorin may be given seven days after the last dose [39].

Success rates of 66 to 100 percent have been reported [57]. In one study, the mean duration to achieve an undetectable serum hCG concentration was 43 64 days [56]. A residual interstitial mass or heterogeneous area with persistent vascularity on ultrasound has been reported despite complete hCG resolution [59,60]. Close follow-up in patients treated medically is advised. In those with increasing abdominal pain, early surgical intervention should be considered. After medical treatment of an interstitial pregnancy, there is an unknown risk of uterine rupture in a future pregnancy [61]. There are also case reports of management of interstitial pregnancy using selective arterial embolization alone or with MTX [62,63]. Surgical treatment of interstitial pregnancy is discussed separately. (See "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility", section on 'Cornuostomy or cornual resection of interstitial pregnancy'.) NONTUBAL ECTOPIC PREGNANCIES Medical and surgical management of heterotopic, cervical, cesarean scar, or abdominal pregnancy are discussed separately. (See "Cervical pregnancy" and "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) Success of single dose methotrexate according to hCG concentration hCG concentration (IU/L) <1000 1000 to 1999 2000 to 4999 5000 to 9999 10,000 to 150,000 Number of women successfully treated (percent) 133 (99) 51 (94) 106 (96) 42 (86) 18 (82) 2 (1) 3 (6) 4 (4) 7 (14) 4 (18) Number of women failing treatment (percent)

Adapted from: Menon, S, et al. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril 2007; 87:481. Methotrexate treatment protocol for tubal or interstitial ectopic pregnancy Pretreatment testing and instructions hCG concentration Transvaginal ultrasound Blood group and Rh(D) typing; give anti Rh(D) immune globulin 300 mcg IM, if indicated Complete blood count Liver and renal function tests Discontinue folic acid supplements Counsel patient to avoid nonsteroidal antiinflammatory medications, recommend acetaminophen if an analgesic is needed Advise patient to refrain from sexual intercourse and strenuous exercise

Tto day 1

Single dose protocol hCG concentration MTX 50 mg/m2 body surface area IM hCG concentration MTX 1mg/kg bodyweight IM LEU 0.1 mg/kg PO hCG

Multiple dose protocol

2 3

If <15 percent hCG decline from day 1 to 3, give MTX 1 mg/kg IM If 15 percent decline from day 1 to 3, begin weekly hCG 4 5 hCG (protocols vary, see day 7) LEU 0.1 mg/kg PO* hCG If <15 percent decline from day 3 to 5 MTX, give MTX 1 mg/kg IM If 15 percent decline from day 3 to 5, begin weekly hCG 6 7 hCG If <15 percent hCG decline from day 4 to 7 (OR <25 percent decline from day 1 to 7), give additional dose of MTX 50 mg/m2 IM If 15 percent hCG decline from day 4 to 7 (OR 25 percent decline from day 1 to 7), draw hCG concentration weekly until hCG is undetectable 8 14 hCG If <15 percent hCG decline from day 7 to 14, give additional dose of MTX 50 mg/m2 IM If 15 percent hCG LEU 0.1 mg/kg PO* hCG If <15 percent decline from day 5 to 7 MTX, give MTX 1 mg/kg IM

If 15 percent decline from day 5 to 7, begin weekly hCG

LEU 0.1 mg/kg PO* hCG If <15 percent hCG decline from day 7 to 14, give additional dose of MTX 1 mg/kg IM (give LEU 0.1 mg/kg PO on day 15)

If 15 percent hCG decline from day 7 to 14, check hCG weekly

decline from day 7 to 14, check hCG weekly until undetectable 21 and 28 If 3 doses have been given and there is a <15 percent hCG decline from day 21 to 28, proceed with laparocopic surgery

until undetectable

If 5 doses have been given and there is a <15 percent hCG decline from day 14 to 21, proceed with laparoscopic surgery

Laparoscopy If severe abdominal pain or an acute abdomen suggestive of tubal rupture occurs If ultrasonography reveals greater than 300 mL pelvic or other intraperitoneal fluid hCG: human chorionic gonadotropin beta-subunit; MTX: methotrexate; IM: intramuscular; LEU: leucovorin; PO: oral route. * Leucovorin is given only if methotrexate was given on the previous day. Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility Last literature review version 19.2: mayo 2011 | This topic last updated: junio 9, 2011 INTRODUCTION Management of ectopic pregnancy has dramatically moved away from a primarily surgical approach [1]. Currently, most women with unruptured ectopic pregnancies are treated with methotrexate. However, some women undergo surgical therapy by choice or by necessity, if they are not good candidates for medical therapy. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy".) The surgical treatment of ectopic pregnancy and prognosis for subsequent fertility will be reviewed here. Risk factors, clinical manifestations, diagnosis, and pathology of ectopic pregnancy are discussed separately. (See "Incidence, risk factors, and pathology of ectopic pregnancy" and"Clinical manifestations, diagnosis, and management of ectopic pregnancy".) INDICATIONS FOR SURGICAL TREATMENT Indications for surgical rather than medical therapy include: Hemodynamic instability Impending or ongoing rupture of ectopic mass Contraindications to methotrexate Coexisting intrauterine pregnancy Not able or willing to comply with medical therapy post-treatment follow-up Lack of timely access to a medical institution for management of tubal rupture Desire for permanent contraception Known tubal disease with planned in vitro fertilization for future pregnancy (only in patients who are otherwise good candidates for surgical therapy) Failed medical therapy In addition, women with a serum beta human chorionic gonadotropin (hCG) concentration greater than 5000 mIU/mL before treatment or fetal cardiac activity on ultrasonographic examination are more likely to experience treatment failure with methotrexate. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy".) In hemodynamically stable women, surgical intervention should only be considered if a transvaginal ultrasound examination (TVUS) clearly shows a tubal ectopic pregnancy or an adnexal mass suggestive of ectopic pregnancy. If no abnormality is imaged sonographically, there is a high probability that a tubal pregnancy will not be visualized or palpated at surgery. Therefore, these women should be managed conservatively with either medical therapy or expectant management. A repeat ultrasound examination after a few days may visualize an abnormality, thus enabling a surgical procedure, if this option is desired. We do not perform dilation and curettage to rule out a failed intrauterine pregnancy. ALTERNATIVES TO SURGICAL THERAPY The advantages of surgical treatment are less time for resolution of the ectopic pregnancy and avoidance of the need for prolonged monitoring. Medical treatment, primarily with methotrexate, is the preferred alternative to surgical therapy of ectopic pregnancy, but requires laboratory monitoring after drug administration. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy".) In almost all settings, expectant management is not consistent with the local standard of care. It is safe in only rare circumstances. (See"Expectant management of ectopic pregnancy".) SURGICAL PROCEDURE

Salpingostomy versus salpingectomy The choice of salpingostomy or salpingectomy for treatment of ectopic pregnancy is controversial; randomized trials comparing these two procedures have not been reported (but are ongoing). Operative morbidity is similar for both procedures. The disadvantage of salpingostomy is the potential risk of persistent or recurrent ectopic pregnancy. Thus, leaving the affected tube in situ is best justified if it results in a higher rate of future intrauterine pregnancy than salpingectomy. A review of cohort studies comparing fertility outcome after salpingostomy and salpingectomy for tubal ectopic pregnancy did not find an overall beneficial effect of salpingostomy [2]. The rate of future intrauterine pregnancy was not consistently higher after salpingostomy than after salpingectomy [1-9], whereas the risk of repeat ectopic pregnancy was slightly increased [2]. Discordancies in reproductive outcome among these studies likely reflect tubal status at surgery, rather than the choice of surgical procedure. Salpingectomy does not appear to compromise the rate of subsequent intrauterine pregnancy in women whose contralateral fallopian tube appears to be normal and avoids the complication of persistent or recurrent ectopic pregnancy in the same tube [10]. We perform salpingostomy in women who are hemodynamically stable and appear to have a reasonable probability of future normal tubal function in the affected tube. We perform salpingectomy, instead of salpingostomy in the following situations: Uncontrolled bleeding from the implantation site Recurrent ectopic pregnancy in the same tube Severely damaged tube Large tubal pregnancy (ie, greater than 5 cm) Women who have completed childbearing (with or without a tubal sterilization procedure), or who will be treated with in vitro fertilization In these situations, there is a low probability of future normal tubal function and the risk of persistent or recurrent tubal problems is high. Laparoscopy versus laparotomy Laparoscopic surgery is the standard surgical approach for ectopic pregnancy. Most ectopic pregnancies, even in the presence of hemoperitoneum, heterotopic pregnancy, and interstitial pregnancy, can be treated by a laparoscopic procedure. However, the surgical approach depends upon the experience and judgment of the surgeon and the anesthetist, and the clinical status of the patient. The benefits of laparoscopy were illustrated in a systematic review of randomized trials that compared laparoscopic salpingostomy with the open surgical approach [2]. Laparoscopic salpingostomy resulted in significantly shorter operation time (73 versus 88 minutes), less perioperative blood loss (79 versus 195 ml), shorter duration of hospital stay (1 to 2 versus 3 to 5 days), shorter convalescence time (11 versus 24 days), and, therefore, lower costs. Laparoscopic salpingostomy also resulted in a higher rate of persistent trophoblast than salpingostomy via laparotomy (OR 3.5, 95% CI 1.1- 11; actual risk 9/78 [11.5 percent] versus 3/87 [3.4 percent]) [2]. However, there were no significant differences in the rate of subsequent intrauterine pregnancy or repeat ectopic pregnancy. The higher rate of persistent ectopic pregnancy following laparoscopic salpingostomy may reflect the experience of the laparoscopic surgeon. Removing the products of conception piecemeal with forceps may lead to retained trophoblastic tissue, particularly in the area of the tube proximal to the ectopic gestation. We suggest flushing the gestational products out of the tube using suction irrigation under pressure. (See 'Persistent ectopic pregnancy' below.) Procedure for laparoscopic salpingostomy Linear salpingostomy is the standard approach for management of ectopic pregnancy in women who wish to preserve their fertility. The ectopic pregnancy is identified and the tube is immobilized with laparoscopic forceps [11]. A 22-gauge needle is inserted through a 5 mm portal and used to inject a solution of vasopressin (0.2 IU/mL of physiologic saline) into the wall of the tube at the area of maximal distention; this helps to minimize bleeding at the salpingostomy site. Using laser, unipolar needle electrocautery, ultrasonic cutting and coagulation device (eg, Harmonic Scalpel), or scissors, a 10 to 15 mm longitudinal incision is then made along the antimesenteric border overlying the ectopic (figure 1). The products of conception are released from the tube using a combination of hydrodissection with irrigating solution under high pressure and gentle blunt dissection with a suction irrigator. The specimen can then be grasped with 10 mm claw forceps to remove it from the abdominal cavity; a laparoscopic pouch is useful for removal of large fragments of placental tissue. The tube is carefully irrigated and inspected under water for hemostasis. Bleeding points can be controlled by pressure or coagulated with light application of bipolar coagulation. In order to avoid excessive coagulation to the tube, we use a microbipolar forceps. If bleeding persists, vessels in the mesosalpinx can be ligated with 6-0 polyglactin suture (figure 2). The placental bed inside the tube should not be coagulated because this will seriously damage the tube. The incision is left open to heal by secondary intention; the subsequent rates of fertility and adhesion formation are similar after secondary intention or primary closure [12,13].

Procedure for laparoscopic salpingectomy There are several methods for total laparoscopic salpingectomy. One approach is to bring the fallopian tube through a pre-tied surgical loop using a grasping forceps and two to three laparoscopy ports (figure 3). The knot is tightened and a second loop is similarly placed. The tube can then be resected and removed. Alternatively, electrosurgery can be used to fulgurate vessels in the mesosalpinx followed by resection of the specimen with scissors (figure 4). The cornual portion of the tube is desiccated close to the uterus. It is important to elevate the tube when applying electrocautery to avoid inadvertently damaging the ovarian vessels. A partial or segmental salpingectomy can also be done. Procedure for open salpingectomy Laparotomy is rarely performed due to the widespread acceptability of laparoscopy. Total salpingectomy is accomplished by placing a clamp across the mesosalpinx and then placing a second clamp across the proximal portion of the fallopian tube as close as possible to the cornua (figure 5). The tips of the clamps should touch to completely occlude the vessels in the mesosalpinx. The tube is then excised and the pedicles ligated using a 2-0 or 3-0 synthetic absorbable suture. If the tubal damage is confined to the tubal segment containing the ectopic gestation, a partial salpingectomy can be performed. The clamps are placed proximal and distal to the ectopic gestation. The decision for partial versus total salpingectomy depends on the patient's age and desire to conceive. In general, we perform partial salpingectomy to allow the option for tubal anastomosis at a future date. However, in women who will undergo IVF treatment, we prefer total salpingectomy to decrease the possibility of tubal stump pregnancy and the development of hydrosalpinx of the proximal portion of the tube. The presence of a hydrosalpinx decreases the in vitro fertilization pregnancy rate. Cornuostomy or cornual resection of interstitial pregnancy Historically, cornual resection and hysterectomy were the most common procedures for treatment of interstitial pregnancy, probably as a result of delayed diagnosis [14-17]. More recently, widespread use and availability of transvaginal ultrasound and sensitive beta-hCG assays has allowed diagnosis of these pregnancies at an earlier gestational age and prior to rupture, thus providing an opportunity for conservative medical or surgical treatment [18]. We initially treat these patients medically [14,18-20], resorting to surgical therapy if there is any deterioration in clinical status. (See"Methotrexate treatment of tubal and interstitial ectopic pregnancy".) Our preference is laparoscopic removal of the gestation via cornuostomy, with resection of the interstitial portion of the tube (cornual resection) if necessary (figure 6) [21]. Dilute intramyometrial vasopressin is injected into the cornual myometrium at the commencement of the operation to minimize blood loss and improve visibility. Alternatively, hemostasis can be achieved by ligating the ascending branches of the uterine vessels. If a cornuostomy is planned, the products of conception can be removed with hydrodissection, grasping forceps, aspiration, or gentle curettage. We prefer hydrodissection to flush out the gestational products, as it helps to ascertain complete removal of trophoblast. Successful hysteroscopic removal of interstitial ectopic pregnancy has been described [22,23]. The efficacy and long-term results of this technique are unknown. The possibility of uterine rupture during a subsequent pregnancy should be discussed with women undergoing treatment for interstitial pregnancy. Unfortunately, the risk of uterine rupture after medical treatment of an interstitial pregnancy is unknown and the integrity of the uterus following conservative surgical treatment is unclear, although cases of uterine rupture have been reported [23-25]. Multilayered suturing of the myometrium and serosa of the uterine cornua following conservative surgical treatment may prevent this complication. Close antenatal monitoring of women with a history of interstitial pregnancy is mandatory. We suggest scheduling a cesarean delivery at term to avoid the risk of uterine rupture during labor. OUTCOME AND PROGNOSIS Persistent ectopic pregnancy The incidence of persistent ectopic pregnancy reported in case series ranges from 4 to 15 percent, and, as noted above, is generally higher after laparoscopic salpingostomy than after open procedures [26]. The clearance rate of serum beta-hCG following salpingostomy is similar to that after salpingectomy. One study found that the serum beta-hCG concentration on the first postoperative day generally declined by more than 50 percent of the preoperative value [27]. In this series of 147 women treated conservatively for ectopic pregnancy, there were no cases of persistent ectopic pregnancy when the postoperative beta-hCG on day 1 fell by more than 76 percent [27]. Some experts suggest weekly measurement of serum beta-hCG concentration after laparoscopic salpingostomy to look for women with persistent disease. Since the incidence of persistent ectopic pregnancy in our hands is extremely low, we perform a single serum beta-hCG measurement one week after surgery. A level that is less than 5 percent of the preoperative value is consistent with complete resolution of the ectopic pregnancy; a higher value calls for repeat measurement one week later. If the level is still more than 5 percent of the preoperative value, we administer a single dose of methotrexate (50 mg/m2 intramuscularly). (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy".)

Transvaginal ultrasound examination of the pelvis and measurement of serum beta-hCG concentration are then performed weekly until the level is undetectable. Alternatively, prophylactic treatment with one dose of methotrexate can be given after all salpingostomies [28], limited to cases where the surgeon is not sure whether the entire products of conception have been removed. The reproductive outcome within three years of treatment of persistent ectopic pregnancy was illustrated in a review of 50 cases [1]. Approximately 60 percent of women who attempted to conceive achieved an intrauterine pregnancy and there were no recurrent ectopic pregnancies. The pregnancy rate was comparable to that in women who were successfully treated for their primary ectopic pregnancy [29]. Future pregnancy Ectopic implantation usually occurs because clinical or subclinical salpingitis has caused anatomic and functional changes in the fallopian tubes. These changes are typically bilateral and permanent; thus, it is not surprising that ectopic pregnancy often leads to recurrent ectopic pregnancy and infertility. Intrauterine pregnancy In women with a history of ectopic pregnancy, review of observational data from a variety of patient populations and with varying durations of follow-up shows that 38 to 89 percent will achieve a subsequent intrauterine gestation [26]. Recurrent ectopic pregnancy The incidence of recurrent ectopic pregnancy is approximately 15 percent (range 4 to 28 percent) [26]. The recurrence risk rises to 30 percent following two ectopic pregnancies [30]. As an example, a prospective study followed 328 women who were not using intrauterine contraception at the time of their ectopic pregnancy, and who subsequently tried to become pregnant [31]. Cumulative outcomes after 12 months were: pregnancy rate (66 percent), intrauterine pregnancy rate (56 percent), ectopic pregnancy rate (13 percent), and live birth rate (31 percent). Maternal age greater than 35 years, history of infertility, and tubal damage were associated with decreased reproductive performance. Many factors influence a woman's fertility after a tubal pregnancy. A history of prior infertility is the most important factor for predicting subsequent fertility [32]. The pregnancy rate following ectopic pregnancy in women with a history of infertility is one-fourth that of women without known infertility [33]. Prior tubal damage is associated with a decreased rate of future pregnancy compared to controls with normal appearing tubes (pregnancy rate 42 and 79 percent, respectively) [7]. Ipsilateral periadnexal adhesions reflect poor condition of the tube [34]. Women who have an intrauterine contraceptive device at the time of their ectopic pregnancy appear to have a better prognosis for future fertility. Among 23 intrauterine contraception users, there was no recurrence of ectopic pregnancy, while 28 percent of 305 nonusers had recurrences in the following two years [35]. Almost all (93 percent) spontaneous pregnancies after surgical treatment of ectopic pregnancy occur in the first 18 months following the procedure [36]. If the woman does not conceive in the first 12 to 18 months, or her contralateral tube is damaged or absent, referral for in vitro fertilization is appropriate. (See "In vitro fertilization".) Interval to conception There are not data to establish the optimal interval to conception following surgical treatment of an ectopic pregnancy. In our practice, we advise patients that they may try to conceive again following their next menstrual period. TREATMENT OF NONTUBAL ECTOPIC PREGNANCY Management of cervical, abdominal, and cesarean scar pregnancies is reviewed separately. (See "Cervical pregnancy" and "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy".) Linear salpingostomy (A) The tube is stabilized and injected with a dilute solution of vasopressin; (B) An incision is made on the antimesenteric border overlying the ectopic; (C) The products of conception are removed using atraumatic forceps; (D) The implantation site is irrigated and hemostasis obtained. Courtesy of William J Mann, Jr, MD. Expectant management of ectopic pregnancy Author Togas Tulandi, MD, MHCM Section Editor Robert L Barbieri, MD Deputy Editor Sandy J Falk, MD

Disclosures Last literature review version 19.2: mayo 2011 | This topic last updated: junio 16, 2009 INTRODUCTION Ectopic pregnancy is a gynecologic emergency, generally requiring expeditious surgical or medical treatment. However, in a small number of cases in which the risk of tubal rupture is minimal, expectant management is appropriate. Women who are candidates for expectant management of ectopic pregnancy require informed consent about the risks of this strategy and close observation until the pregnancy has resolved. In a historic study, expectant management versus surgery in women with ectopic pregnancy, regardless of risk factors for tubal rupture, resulted in a 57 percent success rate [1]. However, most of the patients who failed this approach had significant complications (ie, tubal rupture) or ultimately required surgery for ongoing pregnancy. The use of more stringent selection criteria results in an increase in the efficacy of expectant management to approximately 70 percent [2]. Success rates vary from 48 to 100 percent, depending in large part on differences in inclusion criteria [3]. Expectant management of ectopic pregnancy will be discussed here. Medical and surgical management of ectopic pregnancy are reviewed separately. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy" and "Surgical treatment of ectopic pregnancy and prognosis for subsequent fertility" and "Abdominal pregnancy, cesarean scar pregnancy, and heterotopic pregnancy" and "Cervical pregnancy".) CANDIDATES FOR EXPECTANT MANAGEMENT Selection criteria We employ expectant management in limited clinical situations: when we suspect ectopic pregnancy, but TVUS fails to reveal extrauterine findings suggestive of ectopic pregnancy and the beta-human chorionic gonadotropin (hCG) concentration is low (200 mIU/mL) and declining [4]. Arbitrarily, we define "not declining" as the equal hCG levels at the first and the third measurements. In addition, the patient must be aware of, and accept the risks of, expectant management and be willing and able to comply with follow-up. In such cases, imaging and laboratory assessment do not clearly distinguish between a failed intrauterine pregnancy and a resolving ectopic pregnancy. No studies have evaluated ultrasound criteria for successful use of expectant management in suspected ectopic pregnancy. Women with an extrauterine mass suspicious for an ectopic pregnancy on TVUS, but with low and declining hCG level could be treated expectantly. This could represent an involuting ectopic pregnancy or another type of adnexal mass. As with all patients managed expectantly, such women should be treated medically or surgically if hCG levels are increasing or if there are signs of tubal rupture. We do not perform endometrial sampling in the management of ectopic pregnancy. (See "Clinical manifestations, diagnosis, and management of ectopic pregnancy".) The upper limit of serum hCG level that allows for expectant management of ectopic pregnancy without unnecessary risk of tubal rupture is unknown. Several study protocols, including an upcoming randomized trial, use expectant management in women with hCG levels of 1000 mIU/mL or higher [4-6]. Use of an hCG cutoff of <1000 mIU/mL for expectant ectopic management was found to be successful in 88 percent of patients in a case control study of 67 women [5]. Similarly, in a decision analysis using data from a series of 107 women with presumed ectopic pregnancy, the spontaneous resolution rate was 96 percent in those with hCG <175 mIU/mL versus 21 percent in women with hCG >1500 mIU/mL [7]. Pregnancies that do not resolve spontaneously require medical or surgical treatment to avoid complications. Taking into account the potentially serious risks of tubal rupture and hemorrhage with ectopic pregnancy and the safety and efficacy of medical and surgical treatment, one can reasonably argue that the most stringent criteria should be used for expectant management. Thus, in the absence of high quality data regarding the safety of using a higher hCG limit, we restrict expectant management of ectopic pregnancy to women with a serum level hCG 200 mIU/mL. This is also the threshold cited by the American College of Obstetricians and Gynecologists [8]. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy".) Contraindications Expectant treatment should not be attempted or should be abandoned in women with known or suspected ectopic pregnancy with the following characteristics: Hemodynamically unstable Signs of impending or ongoing ectopic mass rupture (ie, severe or persistent abdominal pain or >300 mL of free peritoneal fluid outside the pelvic cavity) hCG that is greater than 200 mIU/mL, is increasing, or is not declining Unwilling or unable to comply with monitoring Does not have timely access to a medical institution OUTCOME Success rates for expectant management of ectopic pregnancy of 48 to 100 percent have been reported. The wide variation is due, in part, to differences in inclusion criteria [2-4,6,9]. Expectant management appears reasonable in selected patients based upon the following data:

In the only randomized trial to evaluate expectant management, 60 women with ectopic pregnancy were assigned to placebo or oralmethotrexate (2.5 mg for five days) [4]. Ectopic pregnancy was diagnosed based on a positive serum hCG and TVUS finding of an adnexal mass or gestational sac with no evidence of an intrauterine pregnancy. Exclusion criteria were: adnexal mass 4 cm, serum hCG rise 50 percent in two days, moderate or severe abdominal pain, and signs of intraabdominal bleeding. Mean hCG levels did not differ significantly between groups; in the placebo group, the mean hCG was 211 mIUm/L (range 30 to 1343). Ultrasound findings were not reported. In both groups, 77 percent of patients recovered without the need for laparoscopy. The time from start of treatment to reaching an undetectable hCG level was similar for both groups, 24 days in the placebo group and 27 days in the methotrexate group. One limitation of this trial is that there is no evidence to support the efficacy of low dose oral methotrexate in treatment of ectopic pregnancy; thus, it is not surprising that both groups had similar outcomes. In addition, success rates with standard therapies (eg, intramuscular methotrexate, laparoscopy) are higher than 77 percent. (See "Methotrexate treatment of tubal and interstitial ectopic pregnancy".) A review of 10 studies including 347 patients that prospectively evaluated expectant management in selected patients found an overall efficacy of approximately 70 percent [2]. The diagnosis of ectopic pregnancy was not always confirmed by TVUS or laparoscopy. All patients were hemodynamically stable and had decreasing serum hCG levels. However, other variables were not consistently specified, including size and location of the ectopic pregnancy, presence of fetal cardiac activity, the presence of symptoms, and the amount of free fluid in the pelvis, were not always specified. FOLLOW-UP Patients treated with expectant management should be monitored closely. Tubal rupture has been reported in women with low and declining hCG levels [10]. We suggest following the hCG level every 48 hours for three measurements to confirm that it continues to decline, and then weekly until it is undetectable, at which point tubal rupture is highly unlikely. Asymptomatic women who are managed expectantly and have hCG levels that are slowly declining or have plateaued can be offered continuation of expectant management or methotrexate injection. Expectant treatment should be abandoned if a patient experiences significant increase in abdominal pain, serum hCG starts to increase or fails to decrease, or a patient experiences increasing abdominal pain. SUBSEQUENT REPRODUCTIVE PERFORMANCE Subsequent hysterosalpingography has shown tubal patency of the affected tube in 93 percent of cases [11]. Intrauterine pregnancy rates of 63 to 88 percent have been reported after expectant management of presumed ectopic pregnancy [11-14].