Ectopic pregnancy presents a major health problem for women of childbearing age.

It is the result of a flaw in human reproductive physiology that allows the conceptus to implant and mature outside the endometrial cavity, which ultimately ends in death of the fetus. Without timely diagnosis and treatment, ectopic pregnancy can become a lifethreatening situation. Ectopic pregnancy currently is the leading cause of pregnancy-related death during the first trimester in the United States, accounting for 9% of all pregnancy-related deaths. In addition to the immediate morbidity caused by ectopic pregnancy, the woman's future ability to reproduce may be adversely affected as well.

Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum. [ CLOSE WINDOW ]

Ectopic pregnancy. Laparoscopic picture of an unruptured right ampullary tubal pregnancy with bleeding out of the fimbriated end resulting in hemoperitoneum.

History of the Procedure

Ectopic pregnancy was first described in the 11th century, and, until the middle of the 18th century, it was usually fatal. John Bard reported the first successful surgical intervention to treat an ectopic pregnancy in New York City in 1759. The survival rate in the early 19th century was dismal. One report demonstrated only 5 patients of 30 surviving the abdominal operation. Interestingly, the survival rate in patients who were left untreated was 1 of 3. In the beginning of the 20th century, great improvements in anesthesia, antibiotics, and blood transfusion contributed to the decrease in the maternal mortality rate. In the early half of the 20th century, 200-400 deaths per 10,000 cases were attributed to ectopic pregnancy. In 1970, the Centers for Disease Control and Prevention (CDC) began to record the statistics regarding ectopic pregnancy, reporting 17,800 cases. By 1992, the number of ectopic pregnancies had increased to 108,800. Concurrently, however, the case-fatality rate decreased from 35.5 deaths per 10,000 cases in 1970 to 2.6 per 10,000 cases in 1992.

Ectopic pregnancy is derived from the Greek word ektopos, meaning out of place, and it refers to the implantation of a fertilized egg in a location outside of the uterine cavity, including the fallopian tubes, cervix, ovary, cornual region of the uterus, and the abdominal cavity. This abnormally implanted gestation grows and draws its blood supply from the site of abnormal implantation. As the gestation enlarges, it creates the potential for organ rupture because only the uterine cavity is designed to expand and accommodate fetal development. Ectopic pregnancy can lead to massive hemorrhage, infertility, or death.

Since 1970, the frequency of ectopic pregnancy has increased 6-fold, and it now occurs in 2% of all pregnancies. An estimated 108,800 ectopic pregnancies in 1992 resulted in 58,200 hospitalizations with an estimated cost of $1.1 billion.

Multiple factors contribute to the relative risk of ectopic pregnancy. In theory, anything that hampers the migration of the embryo to the endometrial cavity could predispose women to ectopic gestation. The most logical explanation for the increasing frequency of ectopic pregnancy is previous pelvic infection; however, most patients presenting with an ectopic pregnancy have no identifiable risk factor. The following risk factors have been linked with ectopic pregnancy: Pelvic inflammatory disease

The most common cause is antecedent infection caused by Chlamydia trachomatis. Patients with chlamydial infection have a range of clinical presentations, from asymptomatic cervicitis to salpingitis and florid pelvic inflammatory disease (PID). More than 50% of women who have been infected are unaware of the exposure. Other organisms causing PID, such as Neisseria gonorrhoeae, increase the risk of ectopic pregnancy. A history of salpingitis increases the risk of ectopic pregnancy 4-fold. The incidence of tubal damage increases after successive episodes of PID (ie, 13% after 1 episode, 35% after 2 episodes, 75% after 3 episodes). History of prior ectopic pregnancy After one ectopic pregnancy, a patient incurs a 7- to 13-fold increase in the likelihood of another ectopic pregnancy. Overall, a patient with prior ectopic pregnancy has a 50-80% chance of having a subsequent intrauterine gestation, and a 10-25% chance of a future tubal pregnancy. History of tubal surgery and conception after tubal ligation Prior tubal surgery has been demonstrated to increase the risk of developing ectopic pregnancy. The increase depends on the degree of damage and the extent of anatomic alteration. Surgeries carrying higher risk of subsequent ectopic pregnancy include salpingostomy, neosalpingostomy, fimbrioplasty, tubal reanastomosis, and lysis of peritubal or periovarian adhesions. Conception after previous tubal ligation increases a women's risk of developing ectopic pregnancies. Thirty-five to 50% of patients who conceive after a tubal ligation are reported to experience an ectopic pregnancy. Failure after bipolar tubal cautery is more likely to result in ectopic pregnancy than occlusion using suture, rings, or clips. Failure is attributed to fistula formation that allows sperm passage. Ectopic pregnancies following tubal sterilizations usually occur 2 or more years after sterilization, rather than immediately after. In the first year, only about 6% of sterilization failures result in ectopic pregnancy. Use of fertility drugs or assisted reproductive technology Ovulation induction with clomiphene citrate or injectable gonadotropin therapy has been linked with a 4-fold increase in the risk of ectopic pregnancy in a case-control study. This finding suggests that multiple eggs and high hormone levels may be significant factors. One study has demonstrated that infertility patients with luteal phase defects have a statistically higher ectopic pregnancy rate than patients whose infertility is caused by anovulation. The risk of ectopic pregnancy and heterotopic pregnancy (ie, pregnancies occurring simultaneously in different body sites) dramatically increases when a patient has used assisted reproductive techniques to conceive, such as in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT). In a study of 3000 clinical pregnancies achieved through in vitro fertilization, the ectopic pregnancy rate was 4.5%, which is more than

double the background incidence. Furthermore, studies have demonstrated that up to 1% of pregnancies achieved through IVF or GIFT can result in a heterotopic gestation, compared to an incidence of 1 in 30,000 pregnancies for spontaneous conceptions. Use of an intrauterine device The presence of an inert copper-containing or progesterone intrauterine device (IUD) traditionally has been thought to be a risk factor for ectopic pregnancy. However, only the progesterone IUD has a rate of ectopic pregnancy higher than that for women not using any form of contraception. The modern copper IUD does not increase the risk of ectopic pregnancy. Nevertheless, if a woman ultimately conceives with an IUD in place, it is more likely to be an ectopic pregnancy. The actual incidence of ectopic pregnancies with IUD use is 3-4%. Increasing age The highest rate of ectopic pregnancy occurs in women aged 35-44 years. A 3- to 4-fold increase in the risk for developing an ectopic pregnancy exists compared to women aged 15-24 years. One proposed explanation involves the myoelectrical activity in the fallopian tube, which is responsible for tubal motility. Aging may result in a progressive loss of myoelectrical activity along the fallopian tube. Smoking Cigarette smoking has been shown to be a risk factor for developing an ectopic pregnancy. Studies have demonstrated elevated risk ranging from 1.6-3.5 times that of nonsmokers. A dose-response effect also has been suggested. Based on laboratory studies in humans and animals, researchers have postulated several mechanisms by which cigarette smoking might play a role in ectopic pregnancies. These mechanisms include one or more of the following: delayed ovulation, altered tubal and uterine motility, or altered immunity. To date, no study has supported a specific mechanism by which cigarette smoking affects the occurrence of ectopic pregnancy. Salpingitis isthmica nodosum Salpingitis isthmica nodosum is defined as the microscopic presence of tubal epithelium in the myosalpinx or beneath the tubal serosa. These pockets of epithelium protrude through the tube, similar to small diverticula. Studies of serial histopathological sections of the fallopian tube have revealed that approximately 50% of patients treated with salpingectomy for ectopic pregnancy have evidence of salpingitis isthmica nodosum. The etiology of salpingitis isthmica nodosum is unclear, but proposed mechanisms include postinflammatory and congenital as well as acquired tubal changes such as observed with endometriosis. Other

Other risk factors associated with increased incidence of ectopic pregnancy include previous diethylstilbestrol (DES) exposure, a T-shaped uterus, prior abdominal surgery, failure with progestin-only contraception, and ruptured appendix.

Most ectopic pregnancies are located in the fallopian tube (see Media file 1).

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

Sites and frequencies of ectopic pregnancy. By Donna M. Peretin, RN. (A) Ampullary, 80%; (B) Isthmic, 12%; (C) Fimbrial, 5%; (D) Cornual/Interstitial, 2%; (E) Abdominal, 1.4%; (F) Ovarian, 0.2%; (G) Cervical, 0.2%. The most common site is the ampullary portion of the tube, where over 80% occur. The next most common sites are the isthmic segment of the tube (12%), the fimbria (5%), and the cornual and interstitial region of the tube (2%). Nontubal sites of ectopic pregnancy are a rare occurrence, with abdominal pregnancies accounting for 1.4% of ectopic pregnancies and ovarian and cervical sites accounting for 0.2% each.

The classic clinical triad of ectopic pregnancy is pain, amenorrhea, and vaginal bleeding. Unfortunately, only 50% of patients present typically. Patients may present with other symptoms common to early pregnancy, including nausea, breast fullness, fatigue, low abdominal pain, heavy cramping, shoulder pain, and recent dyspareunia. Astute clinicians should have a high index of suspicion for ectopic pregnancy in any woman who presents with these symptoms and who presents with physical findings of pelvic tenderness, enlarged uterus, adnexal mass, or tenderness. Remember, however, that only 40-50% of patients with an ectopic pregnancy present with vaginal bleeding, 50% have a palpable adnexal mass, and 75% may have abdominal tenderness. Approximately 20% of patients with ectopic pregnancies are hemodynamically compromised at initial presentation, which is highly suggestive of rupture. Fortunately, using modern diagnostic techniques, most ectopic pregnancies may be diagnosed prior to rupturing. Numerous conditions may have a presentation similar to an extrauterine pregnancy. The most common of these are appendicitis, salpingitis, ruptured corpus luteum cyst or ovarian follicle, spontaneous abortion or threatened abortion, ovarian torsion, and urinary tract disease. Intrauterine pregnancies with other abdominal or pelvic problems such as degenerating fibroids must also be included in the differential diagnosis.

Medical therapy Medical therapy involving methotrexate may be indicated in certain patients. A number of factors must be considered. The patient must be hemodynamically stable, with no signs or symptoms of active bleeding or hemoperitoneum. Furthermore, she must be reliable, compliant, and able to return for follow-up. Another factor is size of the gestation, which should not exceed 3.5 cm at its greatest dimension on ultrasound (US) measurement. She should not have any contraindications to the use of methotrexate. Surgical therapy Within the last 2 decades, a more conservative surgical approach to unruptured ectopic pregnancy using minimally invasive surgery has been advocated to preserve tubal function (see Surgical Therapy). Laparoscopy has become the recommended approach in most cases. Laparotomy is usually reserved for patients who are hemodynamically unstable or patients with cornual ectopic pregnancies. It also is a preferred method for surgeons inexperienced in laparoscopy and in patients where laparoscopic approach is difficult (eg, secondary to the presence of multiple dense adhesions, obesity or massive hemoperitoneum). In a patient who has completed childbearing and no longer desires fertility, in a patient with a history of an ectopic pregnancy in the same tube, or in a patient with severely damaged tubes, total salpingectomy is the procedure of choice.

Expectant management Candidates for successful expectant management are asymptomatic and have no evidence of rupture or hemodynamic instability. Furthermore, they should portray objective evidence of resolution, such as declining bhCG levels. They must be fully compliant and must be willing to accept the potential risks of tubal rupture.

Relevant Anatomy
See Pathophysiology.

Medical therapy A bhCG level of greater than 15,000 IU/L, fetal cardiac activity, and free fluid in the culde-sac on US (presumably representing tubal rupture) are contraindications to medical therapy with methotrexate. Other contraindications to the use of methotrexate include documented hypersensitivity to methotrexate; breastfeeding; immunodeficiency; alcoholism; alcoholic liver disease or any liver disease; blood dyscrasias; leukopenia; thrombocytopenia; anemia; active pulmonary disease; peptic ulcer disease; and renal, hepatic, or hematologic dysfunction. Surgical therapy Surgical treatment in cases in which the pregnancy is located on the cervix, ovary, or in the interstitial or the cornual portion of the tube is often associated with increased risk of hemorrhage, often resulting in hysterectomy or oophorectomy. In these cases, treatment with methotrexate is an especially attractive option. In cases involving uncontrolled bleeding and hemodynamic instability, conservative treatment methods are avoided in favor of radical surgery.

What Is An Ectopic (Tubal) Pregnancy? An ectopic (tubal) pregnancy is one that is not normal. In a normal pregnancy, the fertilized egg is implanted in the uterus. In an ectopic pregnancy, the fertilized egg is implanted in places other than in the uterus. Some examples of this include the Fallopian tubes, cervix, abdomen, and ovaries. At first glance, this may not seem like that big of a deal. However, once you consider that the role of the uterus is to house a fertilized egg and it is designed to grow and expand, you can begin to understand the problems and complications that can arise. Other parts of the body such as the abdomen are not designed to grow and expand as the fetus grows. Causes And Pathophysiology Of Ectopic Pregnancy Actually, there are no known causes of ectopic pregnancy. It is unclear why the egg would implant itself someplace other than the uterus. The pathophysiology of ectopic pregnancy is such that the normal process of egg implantation is somehow disturbed. However, there are some factors that can put a woman at increased risk of ectopic pregnancy such as their age, problems with the fallopian tubes such as prior surgery or inflammation, if the woman already experienced an ectopic pregnancy, and invitrofertilization can all put someone at risk for it. Symptoms Of Ectopic (Tubular) Pregnancy The symptoms of ectopic (tubular) pregnancy can take a while to develop or the woman may not experience any at all. However, as the fetus starts to grow and expand, problems can arise. The uterus is designed for this concept. However, other parts are not. As a result, symptoms such as pain in the area where the egg implanted itself and mild vaginal bleeding can be early warning signs. A major problem, or symptom, of ectopic (tubal) pregnancy is internal bleeding that is usually related to a hemorrhaging of the area where the fetus is developing. This can prove serious and fatal if not treated. Diagnosing An Ectopic Pregnancy If any of those symptoms are present, it is wise to see a doctor so they can properly diagnose whether or not an ectopic pregnancy condition is present. There are a few ways that it can be determined. The doctor may diagnose an ectopic pregnancy via ultrasound. Another way to tell is because the hCg level will be elevated in the woman who has an ectopic pregnancy. To determine if the ectopic pregnancy is in the fallopian tube or pelvis, a laparoscopy or a laparotomy can be done so the doctor can see if the fetus is developing there. Treatment For Ectopic Pregnancy There are a few treatment options for ectopic pregnancy and the path taken will largely depend on whether or not the woman wants to have anymore children. A drug called methotrexate can be taken to cause a miscarriage. In some cases, it is not a good idea to

let this kind of pregnancy continue. Surgery can also be done to remove the developing fetus. In general, it is very difficult and very dangerous to let this condition continue. If an ectopic pregnancy does occur, it can affect the future ability to have children so swift treatment is necessary. Ectopic Pregnancy – What To Do As soon as a woman becomes pregnant, it is important to report any symptoms that occur to a doctor. They will be able to help determine if these symptoms are normal or if they determine an ectopic pregnancy. There are some treatment options and it is important to contact the doctor to figure out what to do. MORTALITY Despite the increased frequency of ectopic pregnancy, the case mortality rate has declined from 3.5 deaths per 1000 ectopic pregnancies in 1970 to 0.4 deaths per 1000 ectopic pregnancies in 1985. Although ectopic pregnancies accounted for only 1.5% of the total gestations in 1984 and 1985, they accounted for 14% of maternal deaths in 1984 and 11% in 1985.20 Ectopic pregnancy confers a greater risk of maternal mortality than either childbirth or legal abortion. An extrauterine gestation is 50 times more likely to result in a maternal death than a first-trimester abortion and 10 times more likely than delivery in the third trimester.21 A study of the clinical aspects of ectopic pregnancy mortality in the United States has shown that the most frequent direct causes of death are hemorrhage, infection, and anesthetic complications. Of women dying from hemorrhage, 70% did not undergo surgery. In 50% of women, the condition was misdiagnosed or confused with other pathology such as gastrointestinal disorders, intrauterine pregnancies, spontaneous abortions, PID, sequelae of induced abortion, and psychiatric disorders. In 70% of cases, patients had either called or visited a physician within 1 week of development of symptoms. Diagnostic delay could be ascribed to physician delay in 53% of cases and to combined patient and physician delay in 8% of cases. In 5% of cases, the physician made the diagnosis but did not act promptly enough to prevent maternal death. The site of implantation was also important, as interstitial and nontubal ectopic pregnancies account for only 5–10% of all ectopic pregnancies, but for 20% of all fatalities.22 PATHOPHYSIOLOGY The mechanisms responsible for ectopic implantation are unknown. The four main possibilities are an anatomic obstruction to the passage of the zygote, an abnormal conceptus, abnormalities in the mechanisms responsible for tubal motility, and transperitoneal migration of the zygote.

Anatomic distortion and obstruction of the fallopian tube are widely believed to be responsible for most ectopic implantations. Obstruction could result from PID, salpingitis isthmica nodosa,5 tubal endometriosis, or postsurgical fibrosis.23 Scarring of the endosalpinx could lead to diverticuli formation, in which the zygote could be trapped, or to simple obstruction of the tubal passage. Support for the contribution of an anatomic cause is the demonstration of histologic and gross evidence of past infection in 30–50% of cases of ectopic gestation.3, 24 Other researchers studying the isthmic portion of the fallopian tube, however, have failed to demonstrate significant pathology (e.g., fibrosis, chronic inflammation of endometriosis) associated with ectopic pregnancy.25 This observation suggests the contribution of nonanatomic factors to the etiology of ectopic pregnancy. Functional causes could include a defective conceptus, abnormalities in the motility of the fallopian tube, or transperitoneal migration. An abnormal conceptus could theoretically result in defective migration of premature implantation in an ectopic site. This possibility has been investigated by examining the chromosomal constitution of ectopic gestations. Elias and co-workers26 found that the incidence of chromosomal abnormalities in ectopic pregnancies is no different from that in intrauterine pregnancies. The bias with this type of study, however, is that a significant proportion of ectopic pregnancies cannot be adequately karyotyped because of the nonviability of their cells in culture. Similarly, Fedele and colleagues,27 in a case-control study, reported the risk of ectopic pregnancy (after adjustment for maternal age and parity) to be fourfold greater in women with a history of recurrent spontaneous abortion. Tubal motility seems to be influenced by the hormonal milieu. The suspicion that some cases of ectopic pregnancy may be due to endocrine abnormalities stems from clinical observations that have suggested an association in patients using a progesterone-only pill, an IUD,13, 15, 16 or human menopausal gonadotropins for ovulation induction.28, 29 It has been suggested that high estrogen levels noted in cases of hyperstimulation with human menopausal gonadotropins interfere with tubal transport. An alternative explanation is that an increased number of eggs are released (superovulation) in hyperstimulated patients, resulting in an increased risk of ectopic implantation. In contrast, subnormal estrogen levels subsequent to vigorous exercise and dietary fads have been hypothesized to contribute to increased ectopic rates in today's more health-conscious society.30 Korenga and Kadota31 have demonstrated the importance of luteal-phase progesterone in circular muscular activity of the fallopian tube. Abnormal progesterone levels in the luteal phase of the cycle could theoretically lead to impaired motility. Laufer and associates32 have shown differences in the secretions of the cumulus cell mass surrounding the ovum in cleaved versus noncleaved eggs (Fig. 1). Fig. 1. Steroid secretion in culture of intermediate and mature oocyte–corona–cumulus complexes that yielded cleaved and noncleaved oocytes. (Laufer N, Tarlatzis BC, DeCherney AH et al: Steroid secretion by human oocyte–corona–cumulus complexes associated with conceptions following in vitro

fertilization. J In Vitro Fert Embryo Transfer 2:159, 1985) Recent SART data from 2001 show that ectopic pregnancy occurs in 1.8% of recipients of embryo transfer during in vitro fertilization and up to 4.3% in patients undergoing zygote intrafallopian transfer (ZIFT).33 Indeed, the first pregnancy reported in humans with this technique was an ectopic pregnancy.34 Postulated mechanisms include the inadvertent injection of embryos into the fallopian tube, uterine irritability stimulating the contractile portion of the tube secondary to cervical and uterine manipulation, and a gravitational effect. It has been suggested that this inadvertent injection or migration of embryos into the fallopian tubes occurs more often than realized. A diseased tube is less likely than a normal tube to propel the embryo back into the uterus.35 In addition, infertile women undergoing gamete and zygote intrafallopian transfer should be counseled regarding at least a theoretic increased risk of tubal gestation.36

Of all ectopic pregnancies, 97% occur in the fallopian tube (tubal), 2.5% in the uterine cornu, and the remaining 2% in various other locations including the cervix, abdomen, and ovary (Fig. 2). The majority of tubal pregnancies are located in the ampullary portion of the tube. Coexistence of an intrauterine and a tubal pregnancy (heterotopic) was initially reported to occur in 1:30,000 ectopic pregnancies, and the occurrence of bilateral ectopic pregnancy in the same cycle is even rarer.37, 38, 39 With the increased use of ovulation induction, the reported incidence of heterotopic pregnancy has increased to reports of 0.3%.40 Fig. 2. Sites and incidence of ectopic pregnancy. (Maheux R: Ectopic pregnancy. In DeCherney AH, Polan ML (eds): Reproductive Surgery. Chicago, Year Book Medical Publishers, 1986) Cervical pregnancy is a rare cause of mortality today.41 Causes include an endometrial lining that may be unreceptive to implantation (as with infection), uterine fibroids, an atrophic endometrium, a septate uterus, current IUD use, endometrial scarring, and use of oral contraceptives. Cesarean scar pregnancies are also relatively rare occuring at a rate of 1/1800 to 1/2216, but can be a significant cause of morbidity and mortality due to uterine rupture and intractable bleeding.42, 43 These pregnancies are becoming more common due to a rise in the rate of cesarean section. Ovarian pregnancies make up 0.5% of all extrauterine gestations.44, 45, 46 There is a higher proportion of these ectopic pregnancies in patients who use IUDs.46 To be classified as an ovarian pregnancy, a pregnancy must fulfill Spiegelberg's criteria: The tube on the affected side must be intact. The fetal sac must occupy a position in the ovary. The ovary must be connected to the uterus by the ovarian ligament Decidual ovarian tissue must be found in the sac wall.47

Anatomically, tubal pregnancies can be divided into two distinct types based on the anatomy of the tube in the specific location in which the pregnancy occurs. The first to be considered is an ectopic pregnancy occurring in the ampullary portion. The ampullary portion of the fallopian tube is made up of lining epithelium, loose connective tissue, and an ill-defined muscularis and serosa. This reflects the function of this portion of the tube. It is the incubator where fertilization and early cleavage occur. Therefore, ectopic pregnancies in this area rapidly erode through the tubal epithelium into this loose adventitious area surrounding the lumen; propagation then occurs in the space between the serosa and the tubal lumen, rendering the lining of the tube only partially damaged. This phenomenon was first described by Budowick and co-workers.48 The zygote also usually spends a very brief time in the isthmic portion of the tube. This portion has a very well-defined and functional muscularis, and its primary function is to squeeze the zygote into the waiting endometrial cavity. This compact muscularis causes the embryo to grow within the lumen of the tube, because this is the path of least resistance. The growth of the ectopic pregnancy in this portion of the tube destroys the surrounding luminal epithelium. These differences in the location and growth characteristics of ectopic pregnancies dictate the surgical technique used to correct these specific lesions.

Schermers49 reviewed the symptoms in 3970 ectopic pregnancies reported in the literature and found pain to be the most common presenting symptom, occurring in 96.3% of the patients; irregular bleeding was second, occurring in 74.1% of the patients. Other symptoms included shoulder pain, gastrointestinal symptoms, and syncope. Also reported as the second most common sign was adnexal tenderness, occurring in 85–95% of patients. The irregular vaginal bleeding might not be a result only of a breakdown of the endometrium, but of blood flowing from the fallopian tube into the uterine cavity and out the cervical os as well. Other findings also include the Arias–Stella phenomenon and decidual casts (Fig. 3). These are rare occurrences and are more a curiosity than a helpful adjunct in diagnosing an ectopic pregnancy. Physical findings, although helpful, are inconsistent other than in the case of hemorrhagic shock, and a pelvic mass is palpable in only approximately 50% of cases.50 This leads to a need for more objective criteria. Fig. 3. Arias–Stella phenomenon.

Patients clinically suspected of having ectopic pregnancy fall into two major categories: those who have an acute abdomen and in whom immediate surgery is indicated, and those who are clinically stable and in whom adjunctive diagnostic procedures can be performed. Patients with a surgical abdomen are evaluated in the emergency room with a rapid pregnancy test and potentially a culdocentesis. A positive culdocentesis in a patient with a

positive pregnancy test result has been reported to correspond with ectopic pregnancy in 99.2% of cases.51 Patients who will benefit most from a culdocentesis are those in whom a clinical suspicion of ectopic pregnancy exists, and who present at a time when expeditious diagnosis is desired and when sophisticated diagnostic modalities, such as ultrasonography and sensitive human chorionic gonadotropin (hCG) assays, cannot be obtained without significant delay. Under these circumstances, culdocentesis is an inexpensive, rapid, and easily performed means of patient evaluation that often provides the impetus for immediate intervention. The results of a culdocentesis can be classified as negative, positive, or nondiagnostic. A negative culdocentesis is indicated by the presence of clear fluid. A positive result refers to the free flow of nonclotting blood. If no fluid is obtained, the test is considered nondiagnostic. When bloody fluid is obtained, a hematocrit of the aspirate is helpful. Ectopic pregnancies are generally associated with hematocrits of more than 15%. Lower hematocrits frequently indicate the presence of cystic fluid. In our series, 86% of all positive culdocenteses performed in the emergency room were associated with an ectopic pregnancy.51 Other causes of positive culdocentesis included ruptured ovarian cysts, retrograde menstruation, endometriosis, torsion of the fallopian tube, and bleeding of unknown etiology. It should be emphasized that a nondiagnostic culdocentesis should not lower the suspicion of an ectopic pregnancy. In our series, 16% of ectopic pregnancies had nondiagnostic culdocentesis, and one-quarter of these were ruptured at the time of operation.51 In clinically stable patients, the approach to the evaluation is based on the combined use of sensitive pregnancy testing, ultrasound examination, and/or laparoscopy. hCG testing is used to screen for pregnancy, and ultrasonography is employed to locate it.52 Evaluation of the patient begins with a sensitive and rapid pregnancy test. Blood and urine pregnancy tests have been used to screen for ectopic pregnancy. Advances in technologies of enzyme-linked immunoassay and monoclonal antibodies to the β subunit have promoted the evolution of rapid, inexpensive, and similar qualitative urinary pregnancy tests. However, we prefer to use the sensitive blood pregnancy testing in the form of a radioimmunoassay against β-hCG. We recommend an assay with a sensitivity of 2.5 mIU/mL because with this system the false-negative rate is 0.5%. The radioreceptor assay, with a sensitivity of 200 mIU/mL, is not suitable for screening because its false-negative rate ranges between 6% and 12%, which is unacceptably high for a life-threatening condition.53, 54 A negative blood pregnancy test virtually rules out pregnancy and thus an ectopic gestation. A positive qualitative hCG result requires further investigation, mainly a determination of the hCG titer and an ultrasonographic examination (either abdominal or vaginal) of the pelvis.

A positive diagnosis of ectopic pregnancy can be made if fetal motion is demonstrated outside the uterus. Unfortunately, this is a rare and late finding, and awaiting its appearance would delay the diagnosis and conceivably increase the risk of tubal rupture. In practice, ultrasonography is used to identify an intrauterine pregnancy, which would render the simultaneous presence of an ectopic pregnancy extremely unlikely (1:30,000). Confirmation of the presence of an intrauterine pregnancy can be made by identifying either a gestational sac or a fetal pole within the endometrial cavity. Ultrasonographically, ectopic pregnancies can show a single-ring sac due to the presence of blood within the endometrial cavity in association with a significant decidual reaction. This appearance has been shown to occur in 10–20% of all cases (Fig. 4).55, 56, 57, 58, 59, 60, 61,
62, 63

Fig. 4. A. Segmental scan of the pelvis in an ectopic pregnancy. A fetus is visualized in the cul-de-sac. B. Gestational sac of two normal pregnancies. There is a double ring given by the separation of the decidual capsularis and the decidual parietalis. C. Pseudogestational sac in an ectopic pregnancy. There is a single ring. Nyberg and colleagues64 and Bradley and associates65 have proposed morphologic criteria to distinguish the pseudogestational sac of ectopic pregnancy from the gestational sac of a normal intrauterine pregnancy. They have described the normal intrauterine gestational sac as having a double contour produced by the decidua capsularis and the decidua parietalis. The pseudogestational sac of an ectopic pregnancy has only a single ring. The researchers have reported that 98.3% of all patients with a double-ring sac had an intrauterine pregnancy and 64 of 68 patients with a single-ring sac had ectopic pregnancies. The traditional abdominal ultrasonographic criterion used for the diagnosis of ectopic pregnancy is failure to visualize a gestational sac in the uterus of patients with more than 6 weeks of amenorrhea. The problem with this criterion is that one third of patients with ectopic pregnancy do not know the date of their last menstrual period, and in others irregular bleeding makes interpretation of the menstrual history difficult. It has been established that the sac of a normal intrauterine pregnancy becomes visible with abdominal ultrasonography when the hCG titer is greater than 6500 mIU/mL. When levels are higher than this, the absence of a sac is associated with an ectopic pregnancy in 86% of cases. This criterion has a sensitivity of 100%, a specificity of 96%, and a negative predictive value of 100%.51 The absence of a sac at levels less than 6000 mIU/mL is a nondiagnostic finding and should not lower or raise the suspicion of ectopic pregnancy.66, 67 Management of these patients depends on the clinical situation, however,

if transvaginal ultrasonography is available, it should be employed. If a patient remains clinically stable, serial hCG determinations are useful. Additionally, management can be based upon ultrasonographic findings of the adnexa and clinical suspicion. Romero and colleagues68 prospectively evaluated 220 patients who were suspected of having ectopic pregnancy and who had hCG titers less than 6000 mIU/mL and abdominal ultrasonographic adnexal findings. The demonstration of a noncystic mass, alone or associated with cul-de-sac fluid, was an indication for diagnostic laparoscopy. The value of transvaginal ultrasonography in the detection of ectopic pregnancy, especially in cases of hCG titers less than 6000 mIU/mL, is now recognized. Proximity of the ultrasound transducer to both the adnexa and the cul-de-sac allows increased resolution and image quality with the detection of an intrauterine pregnancy up to 7 days earlier than with the classic transabdominal approach (Fig. 5). Fig. 5. The increased sensitivity of transvaginal (right) versus transabdominal (left) ultrasonography in detecting an ectopic pregnancy. A. Proximity to the cul-de-sac allowed detection of this ectopic gestation (hCG titer 880 mIU/mL) by means of transvaginal ultrasonography in this patient. B. Transvaginal ultrasound permitted verification of a left infundibular pregnancy missed on abdominal scanning in another woman (hCG titer 4146 mIU/mL) Vaginal scanning has proved to be more accurate than abdominal scanning in detecting ectopic pregnancies (90% vs 80%) and cul-de-sac fluid (77% vs 46%) and in discerning whether the tubal pregnancy has ruptured (76% vs 50%).69 In the transvaginal ultrasonographic evaluation of pregnancy, Bernaschek and associates,70 using a 5-MHz transducer, proposed a “discriminatory zone” of an hCG titer of 750 mIU/mL (second International Standard) for the detection of an intrauterine gestational sac. Unfortunately, using this proposed criterion and similar ultrasonographic equipment, Fossum and associates71 may have inadvertently surgically investigated several pregnancies that proved to be normal intrauterine gestations (Fig. 6). If an hCG titer exceeds 2000 mIU/mL, we now expect to detect an intrauterine gestational sac using transvaginal ultrasonography. Fig. 6. Relationship between transvaginal ultrasonographic findings and serum hCG levels (range and mean ± SEM) using two World Health Organization standards: the IRP and the second International Standard. (Fossum GT, Davajan V, Kletzky OA: Early detection of pregnancy with transvaginal ultrasound. Fertil Steril 49:788, 1988. Reprinted with permission of the publisher, The American Fertility Society)

If ultrasonography is indeterminant, the value of serial hCG determinations cannot be overemphasized. Traditionally, quantitative hCG values were expected to rise by 66% over 2 days. However, this data was based upon a study of 20 patients in 1980 using an 85% confidence interval.72 More recent data indicate the potential for a slower rate of rise in viable intrauterine gestations. Barnhart and colleagues based their data on 281 patients who presented with pain or bleeding in early pregnancy and found that a 53% increase in 2 days represents the minimal rise for a viable pregnancy (confidence interval 99%).73 Another recent study focused on a cohort of patients eventually diagnosed with ectopic pregnancy and found that the hcg profile mimicked a normal viable pregnancy 29% of the time.74 Declining hCG levels may be indicative of a nonviable, nondetectable intrauterine gestation or could still be representative of an ectopic pregnancy. Up to 40% of patients eventually diagnosed with ectopic pregnancy may have initially declining serum hCG values.74 Serum progesterone values may prove a useful adjunct to hCG titers in distinguishing a viable intrauterine pregnancy from that of an ectopic or missed abortion. Accordingly, in two separate reports on 99 women, a progesterone value less than 15 ng/mL was always predictive either of an ectopic pregnancy or a nonviable intrauterine gestation.75, 76 We recommend laparoscopy or dilation and curettage (D&C) for patients with subnormal quantitative increases of hCG. Curettage productive of trophoblastic tissue confirms an abnormal intrauterine pregnancy and completion of therapy. Approximately 30% of patients with abnormally rising quantitative hCG values will have an abnormal intrauterine pregnancy. The remainder will be ectopics. Unfortunately, this test is limited by a false-negative rate of up to 20%.77 Endometrial biopsy with pipelle is even less sensitive than D&C for detection of chorionic villi with a sensitivity somewhere between 30 and 60%.78, 79 Normal increments in hCG are monitored until hCG titers exceed either 2000 or 6500 mIU/mL, at which time either transvaginal or transabdominal ultrasonography, respectively, may be performed. The presence or absence of a gestational sac above these hCG levels should be supportive either of an ectopic or an intrauterine gestation. A good algorithm for the management of ectopic pregnancy is shown below (see Fig. 7). Fig. 7. An algorithm for the management of an ectopic pregnancy.

The ultimate decision regarding surgical management depends on a patient's desire for future fertility. However, it is important to note that whatever procedure is performed, the pregnancy rate after an ectopic pregnancy may be decreased by 40–70%.47 If a patient is not interested in future fertility, the appropriate surgical procedure is salpingectomy. Additional indications for salpingectomy include recurrent ectopic pregnancy in the same tube, a severely damaged tube, prior unsuccessful conservative surgery, and uncontrolled

bleeding.80 If a patient does desire future fertility, however, much data from the past few years support performing conservative surgery in a majority of these cases. Conservative options vary from expression of a tubal abortion through the distal end of the tube to linear salpingostomy to segmental resection and secondary anastomosis of an isthmic ectopic pregnancy. A majority of ectopic pregnancies are associated with contralateral tubal disease, such as salpingitis. The fact that clinical assessment and evaluation of the contralateral tube during the initial surgery correlates poorly with postoperative hysterosalpingographic findings underscores the importance of intraoperative conservative management whenever feasible.81 It is not recommended that a test of tubal patency be done during the operation for an ectopic pregnancy in order to evaluate the status of the contralateral tube. The information provided can be erroneous because decidual reaction around the cornual portion might give a false impression of an occluded tube. The possibility of introducing infection into an already compromised pelvis is also an important consideration. Laparotomy versus Laparoscopy A number of early studies documented the appropriateness of laparoscopic treatment of ectopic pregnancies.82, 83, 84 Rates of conception of an intrauterine pregnancy after the procedure were as high as 70% in these cases. Pouly and associates85 reported on 321 women with ectopic pregnancies who underwent conservative laparoscopic treatment. Of the women who did not have a history of infertility or a previous ectopic pregnancy, 86% had a subsequent intrauterine pregnancy. The advantages of laparoscopic removal of an ectopic pregnancy are a shortened operating time, convalescence, and hospital stay. It is imperative, however, that proper case selection be exercised.86 If laparoscopic therapy is to be warranted, the first criterion is the expertise of the operator in performance of a laparoscopic surgical procedure. Patients must be stable without evidence of a significant hematoperitoneum. One of the complications of conservative surgery via laparoscopy, persistent ectopic pregnancy, appears to be higher with laparoscopy (5–20% vs. 2–11%). This is thought to be associated with the learning curve seen with laparoscopy. Optimally, the ectopic pregnancy should be confined to the ampullary portion of the tube and should at least 2 cm in size.87 The tube must be easily accessible. Salpingectomy versus Salpingo-oophorectomy In 1955, Jeffcoate88 suggested that in conjunction with a salpingectomy, which is still the most commonly employed surgical treatment for ectopic pregnancy, an oophorectomy on the ipsilateral side be done as well. The theory behind this is that all ovulations would be into the good tube; this discounts the importance of transmigration. There are no data that justify this conjecture. Several reports have shown that there is no advantage in performing a salpingo-oophorectomy compared with salpingectomy in terms of pregnancy rates and repeat ectopic pregnancies in those patients.89 Considering the

successful pregnancy rates with in vitro fertilization and embryo transfer, every effort must be maintained to conserve as much ovarian tissue as possible in any eventuality. Salpingectomy versus Salpingostomy (Conservative Surgery) In a stable patient who desires future childbearing, a salpingostomy is the treatment of choice. The incision for a salpingostomy is made on the antimesenteric border of the tube over the area of maximal bulge; as small an incision as possible is made, but a surgeon must make sure that the products of conception are removed entirely. There seems to be no quantitative difference between use of a laser, scalpel, or electrocautery to make the incision. The products of conception can be removed with duckbill forceps or hydrodissection (Fig. 12).84 It is also important not to debride the base or to treat the base too vigorously to achieve hemostasis. These incisions in the tube seem to heal well, as documented in follow-up surgery and hysterosalpingogram. Hemostasis is critical. Preincisional serosal surface injection of vasopressive agents often reduces incisional bleeding, but may distort the area of maximal tubal bulge. If bleeding continues, vessels in the broad ligament can be ligated with fine suture material (4-0), but remember that this ligation devascularizes the tube and may cause some ischemia in the tube that may lead to decreased reproductive function and adhesion formation.90 Fig. 12. Laparoscopic removal of an ectopic pregnancy. A. Initial salpingostomy incision was made with the argon laser. B. Expulsion of products of conception after the incision is made. The controversy surrounding salpingectomy versus salpingostomy was based on two assumptions. Those in support of salpingectomy feared (1) that patients undergoing salpingostomy would be more likely to have a repeat ectopic pregnancy, and (2) that salpingostomy is a tedious surgical procedure because tubal hemorrhage during surgery is difficult to control. Neither of these assumptions has proved correct, and in fact, intrauterine pregnancy rates have actually increased or remained stable with the use of conservative surgical techniques (Table 3),91 primarily as a result of the application of modern microsurgical techniques to acute tubal pathology. Early reports showed an increased repeat ectopic pregnancy rate (21% after conservative surgery vs. 12.5% after salpingectomy).92 Since then, results have been contradictory with some demonstrating a lower repeat ectopic pregnancy rate93, 94, 95 and others a higher repeat ectopic pregnancy rate with conservative surgery.96, 97 Table 3. Choice of surgical treatment and subsequent fertility among 151 fatients with ectopic pregnancy No. of subsequent pregnancies (% in parentheses)

Incidence of sterility

Surgical treatment Conservative Radical

No. of patients 47 104

Intrauterine Repeat ectopic 39 (83) 75 (72.1) 3 (6.4) 6 (5.8) 175 225

(Sherman D, Lunger R, Sadovsky G: Improved fertility following ectopic pregnancy. Fertil Steril 37:497, 1982. Reproduced with permission of the publisher, The American Fertility Society) There are no substantial data to support the role of cornual resection in conjunction with a salpingectomy. The theoretic rationale is to prevent interstitial implantation. A review of the literature by Kalchman and Meltzer98 demonstrated only 75 cases of interstitial pregnancy following a salpingectomy, leading to the conclusion that this is a rare occurrence and should not dictate surgical technique. Hallatt has suggested that the procedure has some inherent risks secondary to increased bleeding at the time of the original surgery and the possibility of a rupture in the course of a subsequent intrauterine pregnancy.89 Uterotubal fistula formation after this procedure is also a possibility. Therefore, for aesthetic reasons, only a small, shallow cornual resection should be performed. Salpingostomy versus Salpingotomy The primary difference between a salpingostomy and a salpingotomy is that, in the latter, the fallopian tube is closed by primary intention. Stromme99 was the first to describe salpingotomy. This procedure involves an antimesenteric incision over the ectopic pregnancy, excising the products of conception and closing the tube in either one or two layers with fine suture material after hemostasis is achieved. The sutures used should be interrupted. Other reports have modified this technique but still espouse primary closure of the tube.91, 94 Anecdotal reports of tuboperitoneal fistulas subsequent to salpingostomy, but not salpingotomy, support performance of the latter procedure.100 A salpingostomy can be performed based on the evidence describing the propagation of ampullary ectopic pregnancies outside of the lumen itself in the adventitious space between the serosa and the tubal epithelium. Salpingostomy may be associated also with an increased incidence (43%) of recurrent ectopic pregnancy, decreased chances of complete trophoblast removal, and delayed postoperative hemorrhage.101, 102, 103, 104 Salpingostomy seems to have no adverse effect on a tube's anatomic and physiologic future. This is a simpler procedure that can be used by all gynecologic surgeons. In 1951, Israel105 performed total linear salpingostomies in eight patients for PID. The procedures were done between 1935 and 1949. Seven of the eight were done for gonorrheal salpingitis and one for tuberculous salpingitis. Five of the eight patients went on to conceive. The procedure was then tried on six dogs. The dogs were operated on at 2-, 4-, and 8-week intervals. At 2 weeks, the raw edges were separated from each other and epithelialized. At 4 weeks, the gaping incision was beginning to be bridged by fibrous

tissue, and at 8 weeks the organs appeared totally healed, with “fusion of the tunica propria as well as a conjunction of the circular muscle layer. Its salient feature is the absence of a visible scar.”105 Blood testing demonstrates the disappearance of β-hCG levels over time (Fig. 8.)106 Fig. 8. Disappearance curve of hCG in patients treated by salpingectomy versus conservative surgical treatment for ectopic pregnancy. This similarity demonstrates the clearance of the hormone rather than the persistence of viable trophoblastic tissue. (Kamrava MM, Taymor ML, Berger MJ et al: Disappearance of human chorionic gonadotropin following removal of ectopic pregnancy. Obstet Gynecol 62:484, 1983)

Ectopic pregnancies that occur in the isthmic portion of the tube present a different entity entirely. A recent histopathologic comparison of ampullary and isthmic ectopic pregnancies noted preservation of the ampullary muscularis in 85% of the former cases and only a 43% preservation rate of the muscularis in isthmic pregnancies. The disruption of the tubal wall was also more extensive in isthmic pregnancies.107 This is why patients with isthmic ectopic pregnancies are believed to be the only ectopic pregnancy patients who develop a tuboperitoneal fistula after linear salpingostomy (Fig. 9). Therefore, segmental resection is most commonly recommended.108 Fig. 9. Total peritoneal fistula following salpingostomy for an isthmic ectopic pregnancy. The option then becomes to close the tube by primary intention, which has been done successfully by Stangel and colleagues,109 or to perform a second procedure and do an anastomosis at that time. The major advantage of doing an anastomosis at the time of resection of the ectopic pregnancy is that the wide lumen of the tube facilitates the anastomosis. However, edema and the presence of blood may increase the chance of infection. Normal intrauterine pregnancies are achieved regardless of the mode of anastomosis employed. It is recommended that patients waiting for a secondary anastomosis be placed on birth control pills so that they do not form an ectopic pregnancy in the blind distal portion of the tube that has been created (Fig. 10).110 In either event, the anastomosis is performed in two layers using the operating microscope. Four to six 8-0 polyglycolic acid or polydioxanone sutures are placed approximating the muscularis. The serosa is then loosely opposed with running 6-0 Vicryl or PDS sutures (Fig. 11).

Fig. 10. Transmigration of sperm to the contralateral horn of the tube, resulting in an ectopic pregnancy.(Cartwright PS, Entman SS: Repeat ipsilateral tubal pregnancy following partial salpingectomy: A case report. Fertil Steril 42:647, 1984. Reproduced with permission of the publisher, The American Fertility Society) Fig. 11. Isthmic anastomosis following segm for an ectopic pregnancy. With the move toward laparoscopic conservative surgery, it is of interest to note Smith and colleagues'111 similar postoperative tubal patency rates when microsurgical anastomosis was compared with linear salpingostomy in the treatment of isthmic ectopic gestation at the time of laparotomy. Pouly and associates85 accordingly treated 22 isthmic ectopic pregnancies by laparoscopic linear salpingostomy, yielding a 54.5% subsequent intrauterine pregnancy rate. DeCherney and Boyers,112 however, showed that treating isthmic pregnancy with linear salpingostomy by laparotomy resulted in subsequent occlusion of the tube in three of four patients. A rare form of ectopic pregnancy occurs in the infundibular portion of the tube between the fimbria and the ampulla. These are usually treated by “milking or squeezing” the pregnancy out through the distal end. Schermers49 reported a higher incidence of delayed hemorrhage after the milking-out procedure. This experience has been substantiated by Bruhat.82 Success rates are also lowest with this procedure; therefore, these patients also should have a linear salpingostomy rather than “milking out.” This entity is different from a tubal abortion, in which the products of conception are already partially or completely extruded from the fimbriated end of the fallopian tube. This process can be completed, if necessary, simply by removing the remaining products of conception.

Consideration should be given to the use of prophylactic antibiotics, such as doxycycline 100 mg twice a day. Additionally, Rh-negative patients should receive Rh0 (D) immune globulin (RhoGAM).113 Postoperatively, patients should be followed with a hysterosalpingogram 4 months after surgery and laparoscopy 1 year after surgery if pregnancy has not occurred.

Nonoperative management can be divided into observation/expectant care and medical therapy. As early as 1955, Lund114 reported on a series of 119 women with ectopic pregnancies treated with observation. In this series, 55% of the cases resolved without intervention; the remainder required laparotomy. More recently, several investigators have reported their experience with expectant management of unruptured ectopic

pregnancy. In Maymon's115 review of 8 series of patients (total of 81 patients) managed expectantly, 76% resolved spontaneously, 23% required laparotomy for rupture, and 79% demonstrated ipsilateral tubal patency on follow-up hysterosalpingogram. The subsequent pregnancy rate, however, was only 16%. In all these studies, patients were rigorously selected, with documented unruptured ectopic pregnancies at laparoscopy, with no active bleeding. The only advantage seen in these reports was the avoidance of surgery. Disadvantages included an increased risk of tubal rupture, a possible increase in pelvic adhesions, and a protracted course of illness. At this time, expectant management should be considered an option only for patients with extreme surgical risk, falling hCG titers, or in a research setting.

The use of drug therapy for ectopic pregnancy was first reported in 1982, in a patient with an interstitial pregnancy who refused surgery.116 Since then, many investigators have reported the successful treatment of selected patients using a variety of agents, including parenteral methotrexate, intratubal or intra-amniotic methotrexate, and intratubal osmotic agents.117, 118, 119, 120, 121 To date, there have not been a significant number of reports of successful treatment of ectopic pregnancy using mefipristone (RU-486). At this time, parenteral (intramuscular) methotrexate is the best studied and most accepted agent for the medical treatment of ectopic pregnancy. Methotrexate is a folic acid antagonist that interferes with the synthesis of DNA. It is most commonly administered intramuscularly, though reports of oral administration are available.122 Patients receiving medical therapy must be hemodynamically stable and desire future fertility. Contraindications include a ruptured ectopic, ectopic mass greater than 3.5 cm, fetal cardiac activity, high level hCG value (10,000 IU), breastfeeding, immunodeficiency, elevated creatinine or liver function tests, alcoholism, and active pulmonary or gastrointestinal disease. In 1993, Stovall117 reported a prospective study of 120 women treated with a single dose (50 mg/m2) of intramuscular methotrexate. In this series, the author reported a success rate of 94%, with subsequent tubal patency rates similar to those quoted for conservative surgical treatment. Pregnancy rates were nearly 80%, with approximately 88% of these being intrauterine. There were no adverse effects of methotrexate therapy reported in this series; however, there have been recent reports of tubal rupture and hematosalpinx after methotrexate therapy.123, 124 Overall, the outcome of medical treatment of ectopic pregnancy closely approximates results obtained surgically, and there is evidence to support a significant improvement in cost-effectiveness.125 Lipscomb et al. in 1998 reported on 315 patients treated with single-dose methotrexate and reported a success rate of 90.1%.126 There has been some controversy over the use of single-dose versus multiple-dose methotrexate. Direct comparisons of the two therapies have so far found no significant difference.87 A recent study described higher ipsilateral tubal obstruction (as noted by

hysterosalpingogram) in patients treated with multiple-dose versus single-dose regimens. This may be attributable to preexisting obstruction or the potential for tubal harm with a multiple dose of methotrexate.127 Additionally, there is some concern for the long-term effects of methotrexate on ovarian function, in that chemotherapy for gestational trophoblastic tumors may hasten menopause by 3 years.128 Although the harm with multiple-dose therapy has not been proven, there does not appear to be any additional benefit over single-dose therapy. Once a patient is treated with medical therapy for ectopic pregnancy, she must be followed closely to ensure resolution. Day 1 is considered the day of administration of methotrexate. Follow-up hCG levels should be obtained on days 4 and 7, with an expected 15% drop between the two latter values. Thereafter, hCG values should be followed weekly until negative. Treatment failure is indicated by a less than 15% drop in hCG values between days 4 and 7, worsening abdominal pain concerning for rupture, and increasing or plateauing hCG values after the first week of therapy. If the patient is hemodynamically stable, a second injection of methotrexate can be given with weekly follow-up. A second dose may be required in at least 11% of patients. Tubal rupture may occur in up to 8% of patients requiring subsequent surgery.129 Patients should be counseled regarding the side effects of medical therapy. These can include nausea and vomiting, abdominal pain, diarrhea, stomatitis, dizziness, and rarely neutropenia or reversible alopecia.130

Conservative surgical treatment can be carried out without lowering the chance of a subsequent intrauterine pregnancy or raising the incidence of an extrauterine pregnancy. A review of the literature summarizing 467 cases operated on for ectopic pregnancy is summarized in Table 4.131 Of these patients, 46% had a subsequent intrauterine pregnancy and 12% had a repeat ectopic pregnancy. These results do not differ greatly from older statistics based on the results after radical surgery. DeCherney and Oelsner131 reviewed 1630 cases treated radically and found a 41% intrauterine pregnancy rate and a 14% repeat extrauterine pregnancy rate. It is hoped that over time, with the use of modern microsurgical techniques, the intrauterine pregnancy rate will increase and the repeat ectopic pregnancy rate will decrease in these patients. Table 4. Results of radical and conservative surgery for extrauterine pregnancy

Women desiring pregnancy Radical sugery 1630

Women with intrauterine pregnancy 667 (41%)

Women with extrauterine pregnancy 231 (14%)

Conservative 467 215 (46%) 54 (12%) surgery (Adapted from DeCherney AH, Oelsner G: Ectopic pregnancy. In Garcia C-R, Mikuta JJ, Rosenblum NG (eds): Current Therapy in Surgical Gynecology. Toronto, BC Decker, 1986) Based on the similar findings in radically and conservatively treated patients, an important question is whether salpingostomy works at all. This begs the question that perhaps those patients who conceive are using the tube that was not operated on. This possibility has been reviewed, and the intrauterine pregnancy rate and the repeat ectopic pregnancy rate seem to be the same in patients who had salpingostomies performed on only one fallopian tube with an ectopic pregnancy for both the group receiving radical treatment and the group receiving conservative treatment.47 These statistics do not hold, however, for patients who have had two or more ectopic pregnancies. In these patients, the incidence of repeat ectopic pregnancy approximates that of a subsequent intrauterine gestation.132, 133 An unanswered question at this point remains: How many conservative procedures for an ectopic pregnancy can a patient undergo before her reproductive future is compromised to the point where in vitro fertilization is the only viable alternative (Table 5)?132, 133 Table 5. Reproductive Outcome of 47 Patients After Two Ectopic Pregnancies

Number of Patients (% in parentheses) Outcome Sterilized (unable to conceive) At least one tube present Using contraception Trying to conceive Intrauterine pregnancy Term Spontaneous abortion Third ectopic gestation (% of those trying to conceive) Not able to conceive DeCherney et al. N = 23 Tulandi N = 24 6 (26.1) 17 (73.9) 4 (23.5) 13 (76.5) 4 (30.8) 4 (30.8) 0 (0.0) 1 (20.0) (7.7) 8 (61.5) 4 (16.7) 20 (83.3) 4 (20) 16 (80) 8 (50.0) 5 (31.3) 3 (18.8) 3 (27.3) (18.8) 5 (31.3)

(Adapted from DeCherney AT, Silidker JS, Mezer HC et al: Reproductive outcome following two ectopic pregnancies. Fertil Steril 43:82, 1985; Tulandi T: Reproductive performance of women after two ectopic pregnancies. Fertil Steril 50:164, 1988, Reproduced with permission of the publisher, The American Fertility Society) With the advent of effective medical therapy for ectopic pregnancy, there exist a wide variety of available treatment choices. A recent review compared laparoscopic salpingostomy, multiple-dose methotrexate, single-dose methotrexate, and expectant management. The authors concluded that there was no significant clinical difference between the four groups with subsequent intrauterine pregnancy rates varying from 5261% and subsequent ectopic pregnancy rates ranging from 8–13%. However, successful resolution with expectant management appeared lower at 68% (compared with 87–93% for other therapies).134 Therefore it seems reasonable to conclude that treatment choice should be based upon physician comfort and patient characteristics. CONCLUSION During the past decade, the incidence of ectopic pregnancy has noticeably increased. Although 50% of ectopic pregnancies are attributable to infection, the remainder remain unexplained. Clinical findings such as adnexal tenderness, irregular bleeding, and abdominal pain still represent reliable but imperfect clues that a patient has an ectopic pregnancy. It is the advent of newer diagnostic techniques, including laparoscopy, serial β-hCG testing, and transvaginal ultrasonography, that has allowed for the earlier diagnosis of ectopic pregnancy. Previously, 85% of ectopic pregnancies were diagnosed as ruptured and 15% as unruptured.135 Today, this ratio is reversed. The diagnosis of many cases of small, unruptured ectopic pregnancies has led to a reversal from surgical management to medical management with methotrexate especially in patients desirous of future fertility. The hallmark of improved diagnostic management remains the β-hCG test, with failure to achieve a normal slope of increase during the early stages of gestation heralding an ectopic pregnancy or an inevitable abortion.136