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Ectopic Pregnancy: Current Evaluation and Treatment

      The United States has witnessed an epidemic of ectopic pregnancies since 1970. Between 1970 and 1985, the incidence of ectopic pregnancies increased in excess of fourfold, from 17,800 to more than 78,400.
      • Centers for Disease Control
      Ectopic pregnancy—United States, 1984 and 1985.
      During the same 15-year interval, the relative and absolute mortality rates declined. In 1985,33 women died of ruptured ectopic pregnancies in the United States, a mortality rate of 0.042%.
      Several factors have been cited as contributing to the increased incidence, including the epidemic of sexually transmitted diseases, which began in the 1960s; the more frequent use of tubal surgical reconstruction, intrauterine devices, and ovulation-inducing drugs; and an increased frequency of occurrence of endometriosis.
      • Weckstein LN
      Current perspective on ectopic pregnancy.
      • Gilstrap III, LC
      • Harris RE
      Ectopic pregnancy: a review of 122 cases.
      • Tancer ML
      • Delke I
      • Veridiano NP
      A fifteen year experience with ectopic pregnancy.
      In comparison with the past, current evidence also indicates that the diagnosis is being made earlier and with greater certainty. The availability of a highly specific radioimmunoassay for human chorionic gonadotropin (hCG-RIA), the development of high-resolution ultrasonography, and the aggressive use of laparoscopy have permanently altered diagnostic practices. The extensive use of laparoscopy has led to earlier diagnosis; thus, some medical centers encounter tubal rupture in fewer than 10% of cases. These technologic advances have also probably contributed to the increase in the total number of ectopic pregnancies reported. A substantial number of tubal pregnancies terminate as spontaneous tubal abortions without clinical sequelae. Because of the enhanced diagnostic capabilities, fewer ectopic pregnancies now escape clinical detection.
      Despite these advances in the diagnosis of ectopic pregnancy, the overall fertility of affected women remains poor. Approximately 30% of women treated with salpingectomy subsequently experience term pregnancy. With conservative surgical treatment, future fertility is preserved in 50 to 60% of women with ectopic pregnancies.
      • Novy MJ
      Surgical alternatives for ectopics: is conservative treatment best?.
      Infertility may precede an ectopic pregnancy, and tubal pregnancies do not consistently result in infertility. In any event, even with advanced reproductive therapy such as in vitro fertilization, an estimated 30,000 of the 78,000 women with ectopic pregnancies are subsequently sterile.

      Diagnosis.

      The classic clinical manifestations of pelvic pain, atypical vaginal bleeding, and the presence of a palpable pelvic mass are typically encountered in more advanced cases of ectopic pregnancy. Currently, the condition is often diagnosed before the occurrence of major clinical symptoms in patients who are known to be at risk for tubal pregnancy. Such women include those with a history of pelvic inflammatory disease, a tubal surgical procedure, infertility, or ectopic pregnancies. The quantitative serum hCG-RIA is the most useful diagnostic test. In contrast to the urinary qualitative pregnancy tests, which are positive in 50% of patients with ectopic pregnancies, the quantitative serum hCG-RIA accurately detects pregnancy in more than 99% of cases.
      • Schwartz RO
      • Di Pietro DL
      β-hCG as a diagnostic aid for suspected ectopic pregnancy.
      The recently developed specific two-site immunoradiometric assay is capable of detecting hCG concentrations as low as 0.01 ng/ml, and pregnancy can be confirmed 7 to 8 days after ovulation or 1 week before the time of anticipated menses.
      Quantitation of hCG has been clinically useful in the evaluation of the viability of a pregnancy. Both ectopic pregnancies and spontaneous abortions are associated with impaired production of hCG in comparison with normal intrauterine gestations. Serum hCG levels double every 48 hours in patients with normal intrauterine pregnancies. These values increase by less than 66% in patients with ectopic pregnancies and in 87% of those destined to have a spontaneous abortion.
      • Kadar N
      • Caldwell BV
      • Romero R
      A method of screening for ectopic pregnancy and its indications.
      Serial hCG determinations have been helpful in the diagnosis of ectopic pregnancy but do necessitate at least a 48-hour delay to establish the diagnosis.
      Investigators have also recently noted that abnormal pregnancies are frequently associated with decreased production of progesterone. A single serum progesterone determination of less than 15 ng/ml is highly predictive of an ectopic pregnancy or an impending abortion but is not helpful in distinguishing between the two.
      • Hubinont CJ
      • Thomas C
      • Schwers JF
      Luteal function in ectopic pregnancy.
      The low production of progesterone does not seem to be a consequence of inadequate hCG levels.
      Until recently, ultrasonography was used principally to exclude the presence of an intrauterine pregnancy. Kadar and associates
      • Kadar N
      • DeVore G
      • Romero R
      Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy.
      described the presence of a “discriminatory zone,” an hCG level of 6,000 to 6,500 mIU/ml (international reference preparation), above which a gestational sac could be visualized with transabdominal ultrasonography in 94% of cases and below which an intrauterine sac could not be consistently visualized. The availability of higher resolution ultrasonography and, in particular, the advent of the vaginal transducer have enhanced the diagnostic imaging and necessitated the revision of the discriminatory zone to a lower range. Currently, each medical center should establish its own discriminatory zone based on the sensitivity of the hCG assay being used, the reference standard for hCG being applied, and the imaging capabilities available. At the Mayo Clinic, we are able to identify an intrauterine gestational sac when hCG levels are more than 1,500 mIU/ml (second international standard) by using a 5.0-MHz vaginal transducer. The presence of an ectopic gestation has been established by using vaginal ultrasonography without laparoscopy on several occasions. With use of these criteria, the diagnosis maybe established within 1 week of the time of expected menses, well before tubal rupture is a significant risk.
      Transvaginal ultrasonography is also more sensitive than other techniques in detecting the presence of an adnexal mass and free fluid in the cul-de-sac, findings that are also highly correlated with the presence of an ectopic pregnancy. Recently, a new generation of 6.0- to 9.0-MHz vaginal transducers has been introduced. In the future, these instruments may enable us to establish the diagnosis of ectopic pregnancy reliably without laparoscopy.
      It is implicitly assumed that the identification of an intrauterine gestational sac excludes the presence of an ectopic pregnancy and vice versa. Combined ectopic and intrauterine pregnancy is a rare event reported to occur at a rate of 1 in 30,000 pregnancies.
      • Reeves CP
      • Savarese MFR
      Simultaneous intra- and extrauterine pregnancies: report of a case.
      Since those data were compiled, the incidence of ectopic pregnancy has increased severalfold, and the number of multiple pregnancies has also increased as a consequence of ovulation-induction therapy. Currently, the estimated incidence of combined ectopic and intrauterine pregnancy ranges from 1 in 3,899 to 1 in 15,000.
      • Bello GV
      • Schonholz D
      • Moshirpur J
      • Jeng D-Y
      • Berkowitz RL
      Combined pregnancy: the Mount Sinai experience.

      Treatment.

      Until recently, all patients with an ectopic pregnancy underwent extirpative therapy including salpingectomy, salpingectomy with oophorectomy, or hysterectomy. After Parry's report in 1876
      • Parry JS
      of a 69% mortality rate in a large series of women with advanced ectopic pregnancies, Tait
      • Tait L
      Five cases of extra-uterine pregnancy operated upon at the time of rupture.
      discovered that salpingectomy was lifesaving. Removal of the affected organ became the treatment of choice. No improvement in subsequent fertility was demonstrated in a small number of patients treated with conservative surgical procedures in the 1950s and 1960s. In the late 1960s, however, with the advent of microsurgical techniques using magnification, atraumatic instruments, nonreactive suture, and adjuvants to retard subsequent formation of adhesions, the term pregnancy rate in patients who had had a prior ectopic pregnancy increased from 30% to approximately 60%.
      In the 1970s, various surgical procedures including linear salpingostomy, segmental excision, fimbrial expression, and cornual resection were developed for treatment of tubal pregnancies. Linear salpingostomy with removal of the conceptus is the procedure of choice for ampullary ectopic pregnancies. Segmental excision with intraoperative or delayed microsurgical reanastomosis is best suited for isthmic ectopic pregnancies. Manual fimbrial expression of the conceptus from the end of the tube should be avoided because this procedure seems to be associated with additional tissue trauma and a higher frequency of retained trophoblastic tissue. A conservative surgical procedure is currently used if a patient desires subsequent fertility, is hemodynamically stable, and has not had irreparable damage to the tubes.
      Several of these procedures are now performed through the laparoscope. A linear salpingostomy can be performed by using cautery, scissors, or a laser to incise the tube; the trophoblastic tissue can be removed with a grasping forceps. The fallopian tube is then allowed to close by secondary intention. Subsequent pregnancy rates that exceed 60% have been reported in patients who have undergone this procedure, and associated advantages are shorter hospitalization and lower costs.
      • DeCherney AH
      • Diamond MP
      Laparoscopic salpingostomy for ectopic pregnancy.
      A characteristic complication of all conservative procedures is the persistence of trophoblastic tissue after incomplete removal. The trophoblastic mass frequently dissects through the endosalpinx in ectopic pregnancy and thus prevents adequate visualization of all the tissue. Usually, the remaining trophoblastic tissue regresses without clinical sequelae. In several reported instances, however, the tissue has continued to proliferate and the patient has had a recurrence of signs and symptoms of an ectopic pregnancy within 2 weeks after the initial surgical procedure. The recurrence has been treated with an additional operation or chemotherapy. All patients undergoing conservative surgical treatment of ectopic pregnancy should be apprised of this risk and scheduled for weekly follow-up hCG determinations postoperatively to ensure that hCG levels are declining. hCG levels may be detected for 6 weeks or longer after surgical treatment.
      Many patients with tubal pregnancies experience spontaneous tubal abortion if clinically unattended. This outcome seems to be most common in early tubal pregnancies. When serial hCG levels are declining, abortion is inevitable. Often, this event does not result in an adverse clinical outcome; tubal disruption and impairment of fertility may be minimized. Occasionally, more advanced tubal pregnancies may progress to chronic ectopic pregnancy with tubal distortion. Recently, some investigators identified a group of patients who had declining hCG levels, used laparoscopy to confirm that they had tubal pregnancies, and maintained follow-up of these patients without surgical intervention.
      • Garcia AJ
      • Aubert JM
      • Sama J
      • Josimovich JB
      Expectant management of presumed ectopic pregnancies.
      Of the 13 patients, 12 had resolution of the condition after an uneventful course. One patient ultimately required surgical intervention. In the single failure, laparoscopic biopsy of the ectopic pregnancy through the tube was attempted, and the resultant bleeding seemed to be a consequence of the attempted biopsy rather than the natural course of the tubal pregnancy. Several viable intrauterine pregnancies have been reported after expectant therapy, but accurate assessment of the potential for fertility is still forthcoming. Observation may be warranted in patients who are clinically asymptomatic with low, declining hCG levels.
      Recently, interest has surfaced in the use of pharmacologic agents to induce dissolution of a proliferating ectopic pregnancy rather than intervening surgically or awaiting spontaneous tubal resorption. In some instances, the diagnosis has been established with hCG-RIA and ultrasonography, and surgical treatment has been avoided entirely. Usually, however, laparoscopy is performed to confirm the diagnosis. Potential advantages of this approach include less cost if the treatment is completed in an outpatient setting, improved healing of the tube, and enhanced potential for fertility. Only the first benefit has been substantiated to date.
      The folinic acid antagonist methotrexate is ideal for this purpose. Methotrexate is the treatment of choice for gestational trophoblastic disease and is associated with minimal morbidity in the moderate doses used for treating ectopic pregnancy. A group of Japanese investigators reported the first application of methotrexate therapy for ectopic pregnancy in 1982.
      • Tanaka T
      • Hayashi H
      • Kutsuzawa T
      • Fujimoto S
      • Ichinoe K
      Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case.
      To date, 76 patients reportedly have been treated with methotrexate, 93% of whom have had successful resolution of the ectopic pregnancy without clinical sequelae.
      • Leach RE
      • Ory SJ
      Modern management of ectopic pregnancy.
      • Ory SJ
      • Villanueva AL
      • Sand PK
      • Tamura RK
      Conservative treatment of ectopic pregnancy with methotrexate.
      Five patients with advanced pregnancies (hCG levels in excess of 10,000 mIU/ml) required surgical intervention. Associated morbidity has been slight and has primarily consisted of mild stomatitis and gastritis and transient elevations of transaminases. Methotrexate therapy is best suited for patients with early ectopic pregnancies and quantitative hCG levels of less than 3,000 mIU/ml without evidence of impending tubal rupture or significant hemoperitoneum. Four doses are usually administered intramuscularly (1 mg/kg) every other day, followed by leucovorin rescue on alternating days. Patients are monitored with quantitative hCG-RIA and sonograms to gauge the clinical response. Several reports have described successful term pregnancies after treatment, but currently available data are too scant and the follow-up intervals are too short for adequate assessment of subsequent fertility. Other pharmacologic agents including the antiproges-terone compound RU 486 (Hoechst-Roussel) and prostaglandin E2 have been used, but the results have been less successful.

      Summary.

      During the past 20 years, the diagnosis and treatment of ectopic pregnancy have improved considerably. With the current diagnostic modalities, patients at risk for ectopic pregnancy can be followed expectantly, and the diagnosis can be made within a few days of the time of anticipated menses. An enhanced understanding of the varied clinical course of ectopic pregnancy has been gained in the process, and greater individualization of patient care has been possible. Patients with spontaneous tubal abortion are being identified, and they may be better served by observation. The precise role and limitations of pharmacologic agents and the new surgical procedures are still being determined, but the ultimate goal with use of these modalities is an improved potential for fertility.

      REFERENCES

        • Centers for Disease Control
        Ectopic pregnancy—United States, 1984 and 1985.
        MMWR. 1988; 37: 637-639
        • Weckstein LN
        Current perspective on ectopic pregnancy.
        Obstet Gynecol Surv. 1985; 40: 259-272
        • Gilstrap III, LC
        • Harris RE
        Ectopic pregnancy: a review of 122 cases.
        South Med J. 1976; 69: 604-606
        • Tancer ML
        • Delke I
        • Veridiano NP
        A fifteen year experience with ectopic pregnancy.
        Surg Gynecol Obstet. 1981; 152: 179-182
        • Novy MJ
        Surgical alternatives for ectopics: is conservative treatment best?.
        Contemp Obstet Gynecol. 1983; 21: 91-120
        • Schwartz RO
        • Di Pietro DL
        β-hCG as a diagnostic aid for suspected ectopic pregnancy.
        Obstet Gynecol. 1980; 56: 197-203
        • Kadar N
        • Caldwell BV
        • Romero R
        A method of screening for ectopic pregnancy and its indications.
        Obstet Gynecol. 1981; 58: 162-166
        • Hubinont CJ
        • Thomas C
        • Schwers JF
        Luteal function in ectopic pregnancy.
        Am J Obstet Gynecol. 1987; 156: 669-674
        • Kadar N
        • DeVore G
        • Romero R
        Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy.
        Obstet Gynecol. 1981; 58: 156-161
        • Reeves CP
        • Savarese MFR
        Simultaneous intra- and extrauterine pregnancies: report of a case.
        Obstet Gynecol. 1954; 4: 492-495
        • Bello GV
        • Schonholz D
        • Moshirpur J
        • Jeng D-Y
        • Berkowitz RL
        Combined pregnancy: the Mount Sinai experience.
        Obstet Gynecol Surv. 1986; 41: 603-613
        • Parry JS
        Extrauterine Pregnancies: Its Causes, Species, Pathologic Anatomy, Clinical History, Diagnosis, Prognosis and Treatment. Lea & Febiger, Philadelphia1876
        • Tait L
        Five cases of extra-uterine pregnancy operated upon at the time of rupture.
        Br Med J. 1884; 1: 1250-1251
        • DeCherney AH
        • Diamond MP
        Laparoscopic salpingostomy for ectopic pregnancy.
        Obstet Gynecol. 1987; 70: 948-950
        • Garcia AJ
        • Aubert JM
        • Sama J
        • Josimovich JB
        Expectant management of presumed ectopic pregnancies.
        Fertil Steril. 1987; 48: 395-400
        • Tanaka T
        • Hayashi H
        • Kutsuzawa T
        • Fujimoto S
        • Ichinoe K
        Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case.
        Fertil Steril. 1982; 37: 851-852
        • Leach RE
        • Ory SJ
        Modern management of ectopic pregnancy.
        J Reprod Med. 1989; 34: 324-338
        • Ory SJ
        • Villanueva AL
        • Sand PK
        • Tamura RK
        Conservative treatment of ectopic pregnancy with methotrexate.
        Am J Obstet Gynecol. 1986; 154: 1299-1303