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Ectopic pregnancy
1111J Gw~c*c~~l Ohstet. international
1’992,37: 213-2I9
Federation
of Gynecology
213 and Obstetrics
Ectopic pregnancy ACOG Technical Bulletin Number (Replaces No. 126, March 1989)
150 -
The contemporary management of ectopic pregnancy has been greatly influenced by the availability of rapid and sensitive radioimmunoassays to detect the beta subunit of human chorionic gonadotropin (B-hCG) in serum and by technical advances in ultrasound. As a result, the earlier diagnosis of ectopic pregnancy has led to a decreased frequency of tubal rupture (~20% of cases in many centers) and an extensive use of conservative surgical procedures increasingly performed by operative laparoscopy. Despite these advances, however, ectopic pregnancy remains a leading cause of maternal morbidity. The new conservative approach to tubal pregnancy has been paralleled by a steady increase in its overall incidence: approximately 2% of pregnancies are ectopic (1). Reasons given for the increase are a greater prevalence of sexually transmitted diseases, more frequent recourse to sterilization procedures and reconstructive tubal surgery, and more successful clinical detection. Seventy-five percent of pregnancies occurring after failure of tubal sterilization procedures are likely to be ectopic (2). Contraceptive failures in women wearing intrauterine devices (IUDs) are also more likely to be tubal pregnancies, because the IUD acts preferentially to impair intrauterine implantation (3). Other conditions that predispose to ectopic implantal tion are in utero exposure to diethylstilbestrol (DES); accessory tubal ostia; and possibly abnormal peristalsis or ciliary function of the oviduct. Also implicated is the use of ovulation induction agents such as human menopausal gonadotropins (hMG) (4). Transmigrationof the ovum is also a factor, since in about one in every four tubal pregnancies, the corpus luteum is on the opposite ovary (5). The highest age-specific incidence rates per 100,000 women are observed in women 25-34 years of age (6). Implantation of the embryo in the oviduct is a
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condition unique to humans. An experimental model for tubal pregnancy in domestic or laboratory animals is lacking (5). Therefore, much of our knowledge about etiologic mechanisms and pathophysiology is based on circumstantial evidence. Although it appears that most ectopic pregnancies develop from a delay in ovum transport secondary to a diseased fallopian tube, extrauterine implantation may be influenced by abnormalities of the’ fertilized egg or its particular hormonal environment. Fetuses are found in almost half of tubal pregnancies (7), and the incidence of chromosomal derangements is lower in ectopic pregnancies than in spontaneous abortion material (8). The ampulla is the most common site of implantation, accounting for 78% of ectopic pregnancies; 12% are located in the isthmus, 5% in the fimbria, and 2% are comual or interstitial (9). The remainder are abdominal, cervical, or ovarian.
Evaluation and Diagnosis Over 90% of symptomatic patients with tubal pregnancies have abdominal or pelvic pain as well as vaginal bleeding, and many have palpable adnexal masses ( 10). These findings, however, are often present in women with other diagnoses. Patients with ectopic pregnancy can be encountered in two different clinical settings. Patients with mild, moderate, or severe abdominal pain and various degrees of hemodynamic alterations are often seen in an emergency room, usually at a more advanced gestational age. Another group of patients present earlier in the natural course of their disease and often are asymptomatic infertility patients at risk for ectopic pregnancy. This latter group provides the greatest opportunity for early diagnosis, expectant management, and conservative intervention by various surgical and medical modalities. Int J Gynecol Obstet 37
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ACOG Technical Bullerin
Testing The quantitation of hCG has been complicated by the existence of two reference standards for hCG immunoassay: the Second International Standard (Second IS) and the International Reference Preparation (IRP). The Second IS, actually the first reference standard available, was developed for use in hCG bioassays and was later utilized in radioimmunoassays. It is not well suited for use in hCG radioimmunoassays, since it is relatively heterogeneous, containing only 20% intact hCG. The IRP, a highly purified preparation, was developed to overcome these deficiencies and is ideal for use in radioimmunoassays. It is important to know which hCG reference standard is used when correlating hCG levels with ultrasound findings. A single quantitative serum hCG determination has limited value in determining the location or viability of an early pregnancy, because the date of conception is uncertain in most patients and serum hCG concentrations rise in an exponential fashion for the first 38 days after ovulation. Thereafter they begin to plateau at concentrations in excess of 30,000 mIU/ml (IRP). Serial quantitative hCG determinations are a more reliable indicator of gestational viability. The addition of ultrasonography allows the clinician to exclude intrauterine pregnancies when an ectopic gestation is suspected. A positive sonographic diagnosis can be made by identifying an extrauterine fetus, but this is an uncommon finding. In practice, ultrasound is more frequently used to exclude ectopic pregnancy by demonstrating an intrauterine gestational sac or fetus, because the coexistence of intrauterine and ectopic pregnancy is so rare (l/30,000). The incidence of heterotopic pregnancy, however, is increased at least lo-fold in patients who undergo ovulation induction therapy and have multiple ovulations (9). The concept of the discriminatory hCG zone was first defined as a range of serum hCG concentrations (6,000-6,500 mIU/ml [IRP]) above which a normal intrauterine gestation could be visualized by transabdominal ultrasonography 94% of the time and below which an intrauterine sac usually was not visible (11). The absence of an intrauterine gestational sac when the hCG concentration exceeds the discriminatory zone is diagnostic of ectopic pregnancy in 86% of cases (12). Patients with multiple pregnancies will exhibit higher levels of hCG relative to gestational sac findings. Less Int J Gynecol Obstet 37
than 25% of ectopic pregnancies, however, have hCG concentrations greater than or equal to 6,000 mIU/ml at the initial evaluation (13). Transvaginal ultrasonography, with its higher resolution, may allow earlier determination of intrauterine pregnancies-as early as 35 days from the last menstrual period. An intrauterine sac can be visualized when the hCG level reaches approximately 1,500 mIU/ ml (IRP) or 900 mIU/ml (Second IS) (Table 1). Until the fetal pole or yolk sac is identified by ultrasound, however, an ectopic pregnancy cannot be excluded. The use of transvaginal imaging effectively lowers the discriminatory zone to allow earlier identification of abnormal gestations. Discriminatory zones of 2,0003,000 mIU/ml (IRP) may be more realistic with transvaginal probes. Earlier surgical intervention may lead to lack of identification of the site of implantation. Because there is variability among hCG assays and the resolution of different imaging systems, each laboratory and clinical service must establish its own discriminatory zones for transabdominal and transvaginal ultrasonography. In the future, adnexal findings will become increasingly helpful in the diagnosis of tubal pregnancy when the echogenic patterns, blood flow, and metabolic characteristics of the corpus luteum and the ectopic pregnancy can be differentiated. The infrequent finding of a complex echogenic mass by transabdominal ultrasonography in the adnexa has a positive predictive value for ectopic pregnancy of 94% (14). Transvaginal sonography provides improved resolution in the imaging of the uterine cavity, adnexa, and cul-de-sac fluid. False-positive gestational sacs are less common than with transabdominal scanning. Gestational sacs detected early in gestation (less than 5 mm in diameter), however, frequently exhibit a partial or absent echogenic rim. A point of differentiation between false and genuine sacs is the presence of a yolk sac. Transvaginal scanning is sensitive and specific in detecting cul-de-sac blood when the volume is greater than 100 ml. Early sac recognition may be hampered by the presence of uterine myomata. Transvaginal sonography has provided new information on normal early intrauterine development (15). The altered endocrine behavior of ectopic gestations (eg, abnormal patterns of change in hCG levels and lowered progesterone secretion) has been studied to aid in the diagnosis of ectopic gestation in its early
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TABLE1. RELATIONSHIPOFGESTATIONALAGE, hCG LEVELS,ANDTRANSVAGlNALULTRASOUNDFINDINGS* /3-hCG(mlU/ml)
Ultrasound Findings Sac Fetal pole Fetal heart motion
Days from Last Menstrual Period 34.8 f 2.2
40.3 f 3.4t 46.9 k 6.0t
International Reference Preparation 1.398 f 155
5,113 + 298’ 17,208 f 3,772’
‘Fossum GT, Davajan V, Kletzky OA. Early detection of pregnancy with transvaginal +P .Z 0.05 when compared with sac.
stages of development. The exponential rate of rise of hCG levels in pregnancy is not constant but gradually decreases with advancing gestational age and increasing hCG concentration. The hCG doubling time ranges from 1.5 days in very early pregnancy to 3.5 days at 7 weeks of gestation (16,17). From a practical standpoint, however, pregnancies near 6 weeks of gestation that demonstrate less than a 66% increase in hCG levels within a 48-hour interval are likely to represent either ectopic pregnancies or intrauterine pregnancies that are likely to abort (18). Progesterone production is decreased in ectopic gestation compared with an intrauterine pregnancy of the same gestational age (19). After a rise during the luteal phase, serum progesterone levels remain stable during the first 8 weeks of pregnancy. Therefore, a single determination may be adequate to judge the normalcy of pregnancy, and precise knowledge of gestational age is not required (19). Low levels of serum progesterone or its urinary metabolite, pregnanediol 3a-glucuronide, can be used to alert the physician to problem pregnancies even when the B-hCG levels are below the discriminatory zone of ultrasound examination (20,2 1). A single serum progesterone determination is highly predictive of an abnormal gestation, but it does not distinguish abnormal intrauterine from ectopic pregnancies. It will be less than 15 @ml in 81% of tubal pregnancies and in 93% of abnormal intrauterine pregnancies but in only 11% of normal intrauterine pregnancies (20). Conversely, fewer than 2% of ectopic pregnancies and not more than 4%of abnormal intrauterine pregnancies will have a serum progesterone level of greater than 25 ng/ml. Thus, a single serum progesterone of 25 ng/ml or greater is strongly indicative of a normal intrauterine pregnancy, whereas a value below 15 ng/ml strongly suggests an abnormal preg-
Second International Standard 914 f 106 3,783 + 683 13,178 f 2,898f
ultrasound.
Fertil Steril 1988;49(5):788-791
nancy. Progesterone measurements, however, may not be useful in the diagnosis of ectopic pregnancy during clomiphene- or menotropin-stimulated cycles, due to multiple corpora lutea (22).
Surgical Management In deciding upon the best management for a given patient, the patient’s age, reproductive history, and wishes for fertility must be taken into account. Other considerations are location and cause of the ectopic pregnancy, extent to which normal tubal ovarian relationships have been disrupted, and the amount of peritoneal blood loss. Culdocentesis with an 18-gauge spinal needle is an inexpensive and rapid means of patient evaluation. The predictive value of culdocentesis varies according to the probability of tubal rupture, which increases with advancing gestational age. Culdocentesis is most useful in diagnosing hemoperitoneum in patients who are symptomatic or clinically unstable and often provides the impetus for earlier surgical intervention. For most patients, the goal of treatment is to remove the ectopic pregnancy while preserving reproductive function. However, in the face of tubal rupture, significant anatomic distortion, or overt hemorrhage, or if future pregnancies are not desired, salpingectomy may be advisable. Ipsilateral salpingo-oophorectomy is not recommended unless the ovary is compromised or is otherwise grossly abnormal. The practice of comual wedge excision salpingectomy is unnecessary and is probably associated with a higher incidence of homolateral interstitial pregnancies (23,24). The patient who has had a tubal sterilization and now has a proximal fistula and an ectopic pregnancy in the distal fimbriated segment should have the fistula and the ectopic gestaInt J Gynecol Obstet 37
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tion excised. If no reversal of sterilization is contemplated, the fimbriated tubal segment on the opposite side should also be removed to prevent a future ectopic gestation at that site. A conservative operation on the tube is most appropriate when an infertile woman has an unruptured ectopic pregnancy and wishes to preserve her reproductive potential. Even some ruptured comual or isthmic pregnancies can be treated conservatively if the patient’s condition is stable and the remainder of the tube can be salvaged. Ampullary salpingotomy is the most common conservative tubal operation and is increasingly performed by operative laparoscopy. For the procedure, a linear incision is made with electrocautery, laser, or sharp dissection over the antimesenteric portion of the tube, and the products of conception and blood clot are removed with forceps or by gentle evacuation. Trophoblastic growth takes place within the tubal lumen in approximately two-thirds of ampullary pregnancies; in the remaining one-third, the trophoblastic expansion occurs extraluminally, or a mixed pattern is observed (7, 25). In most, the mucosa is disrupted only at the implantation site and the muscularis is preserved. Careful evacuation of blood clots and products of conception allows the tube to return to a nearly normal anatomic state. Bleeding is controlled by cauterization of serosal vessels. The injection of dilute vasopressin in the mesosalpinx below the conceptus or in the tubal wall is recommended by many surgeons, but its use is not free of complications. The intravascular injection of vasopressin may induce a pronounced increase in blood pressure. The incision is allowed to close by secondary intention. When the operation is complete, the tube is irrigated with an isotonic solution and observed for bleeding points, since reactive hyperemia may occur. Small bleeding vessels can be controlled by point cautery or compression with nontraumatic forceps. If necessary, the vessels in the mesosalpinx that supply the ectopic pregnancy are coagulated or ligated. Vigorous cauterization of the tubal lumen causes extensive damage and should be avoided. On occasion, the salpingotomy incision is closed in two layers with 6-O interrupted nonreactive sutures by microsurgical techniques. There is no evidence that either approach is superior to the other. In isthmic ectopic pregnancies, the implantation is usually extraluminal or mixed; the mucosa is generally not preserved, and the muscularis is destroyed in most Int J Gynecol Obstet 37
cases (25). Resection of the involved segment of tube is most applicable when the pregnancy is in the proximal isthmus or at the uterine comu. Salpingotomy predisposes to scarring of the narrow lumen in this portion of the tube (26). Excision has the advantage of removing a presumably abnormal region of the tube while preserving the proximal and distal segments for anastomosis. Although end-to-end anastomosis at the time of the tubal pregnancy has been successfully accomplished and has resulted in normal pregnancies (9), the repair is usually postponed. The disadvantage of requiring a second operation is lessened if segmental resection is performed by laparoscopy; it is offset by allowing the microsurgeon to operate at a more opportune time and by avoiding the problems associated with inflammation and edema. Ectopic pregnancy may develop in the distal ligated segment if the contralateral tube is patent. This infrequent occurrence can be prevented, however, by using contraceptive measures prior to anastomosis. Some unruptured isthmic pregnancies can be managed by linear salpingotomy, especially when surgical intervention takes place early in the development of the ectopic pregnancy, when trophoblastic growth is intraluminal and the implantation site is at or near the isthmic-ampullary junction. Favorable postoperative tubal patency rates and reproductive outcome have been reported under these circumstances (27). Forcible expression of the products of conception can be damaging to the tube, but a favorable outcome has been reported in ftmbrial pregnancies that are loosely adherent or in the process of being extruded from the infundibulum (20 Operative laparoscopy has benefited from the development of new instrumentation that permits more complex surgical maneuvers and the removal of larger volumes of tissue by a process of morcellation. In the hands of the properly trained and equipped surgeon, translaparoscopic salpingotomy or even salpingectomy has been demonstrated to be safe and efficient and may be used in most patients with small (4-cm) ectopic pregnancies (29.30). Additional therapy may include the intraperitoneal instillation of 100 ml of dextran 70 (Hyskon), but its effectiveness in preventing adhesions in this setting is not proven, and rare allergic reactions can occur. Most authorities advise against incidental appendectomy, and ancillary surgical procedures are best limited to simple lysis of adhesions.
ACOG
Persistent Ectopic Pregnancy Persistence of viable trophoblastic tissue in the tube occurs in 5% of patients after conservative surgical treatment (29). Secondary implantation of displaced trophoblast is a potential but infrequent complication. Postoperatively, patients should undergo weekly serum hCG testing until nonpregnant levels are achieved. The clearance of hCG occurs in two phases: an initial phase with a half-life of 5-9 hours and a second, longer phase with a half-life of 22-32 hours (3 1). When removal of trophoblastic tissue is fairly complete, serum hCG concentrations will be 20% or less of intraoperative levels within 72 hours after surgery (32). If hCG levels continue to fall (albeit slowly), expectant management with serial monitoring of hCG levels is sufficient. If hCG levels reach a plateau or increase, treatment options, which include salpingectomy, partial salpingectomy, and medical therapy, should be considered.
Medical Treatment Expectant management with serial endocrine monitoring is an option for patients with small, unruptured (l3 cm in diameter) ectopic gestations with hCG values that continue to decline from an initial value below 1,000 mIU/ml (IRP) (9). With rare exceptions, such patients have a low risk of tubal rupture and hemorrhage (33). A review of preliminary data suggests that subsequent fertility in this select group of patients is comparable to other methods of treatment (9). The potential disadvantages of expectant management include prolonged outpatient follow-up and inflammation at the site of the ectopic gestation as one waits for spontaneous resorption. When trophoblastic proliferation continues, as manifested by stable or increasing hCG levels, it is possible to hasten dissolution of the ectopic trophoblast with chemotherapy. Methotrexate, a folic acid antagonist, has been used to inhibit the growth of trophoblastic cells in situations where surgical intervention might be hazardous. There are also numerous reports demonstrating favorable results with methotrexate and leucovorin calcium (citrovorum factor) as primary therapy for smaller ectopic gestations (9, 34). Screening of patients should include l3-hCG assays, ultrasound, laparoscopy, hepatic enzymes, and complete blood count with differential and platelet
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count. Recommended selection criteria for medical therapy include the following: H Ectopic size 3 cm or less n Desire for future fertility n Stable or rising hCG levels with peak values below 15,000 mIU/ml (IRP) n Tubal serosa intact n No active bleeding n Ectopic pregnancy fully visualized at laparoscopy n Selected cases of cervical and comual pregnancy Contraindications to chemotherapy include the following: n Poor patient compliance n History of active hepatic or renal disease n Presence of fetal cardiac activity n Abnormal serum creatinine or serum glutamic oxalacetic transaminase (SGOT) n Active peptic ulcer disease n Blood leukocyte count of <3,000 or a platelet count of <100,000 Presently, chemotherapy in conjunction with laparoscopic diagnosis offers no clear advantage over laparoscopic surgery for the routine management of ectopic pregnancy. Chemotherapy is the treatment of choice when surgery is contraindicated or in the management of postoperative persistent trophoblast. It is anticipated that more accurate ultrasonographic and endocrine diagnosis, in conjunction with dilation and curettage, may eventually supplant the need for laparoscopic diagnosis in some patients and thus extend the application of medical management (20). The merits of direct injection of methotrexate or other pharmacologic agents (eg, potassium chloride, hypertonic solutions, prostaglandins) into the gestational sac under sonographic or laparoscopic guidance are still uncertain. There is concern that many of these agents will incite an intense tissue reaction within the tube. The progesterone antagonist RU 486 has not been successful in the treatment of ectopic pregnancy (35).
Outcome Conservative surgery for small unruptured ectopic pregnancies produces encouraging results. Tubal paInt J Gynecol Obsret 37
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ACOG
Technical Bulletin
In small, uncontrolled studies, a 4MO% intrauterine pregnancy rate with a lO-20% risk of recurrent ectopic gestation after linear salpingotomy has been reported (9,36). It is noteworthy that a recurrent ectopic pregnancy occurs in the contralateral tube as often as in the operated oviduct (24). Women with a history of infertility have a lower pregnancy rate (41%) than do women with normal reproductive histories (85%) (29). Pregnancy outcome after conservative surgery is also specifically correlated with the macroscopic condition of the contralateral adnexa. While the ratio of intrauterine to ectopic pregnancies is generally about 6: 1, it rises to about 10: 1 in patients with a normal contralateral tube
tency
is restored in more than 80% of patients.
(37). When the results of conservative surgery and salpingectomy are compared, patients with otherwise normal reproductive histories and normal pelvic findings have similar subsequent fertility and ectopic recurrence, suggesting that conservative surgery does little to predispose a woman to ectopic pregnancy (38). Fertility is substantially improved when conservative surgery is utilized instead of salpingectomy (subsequent intrauterine pregnancy rates of 76% and 44%, respectively) in patients who have adhesive disease in the contralatera1 adnexa and a history of infertility (38). The results of salpingotomy in patients with a tubal pregnancy in a sole patent oviduct (approximately 20% ectopic recurrence) suggest that a conserved tube is at similar risk for a repeat ectopic pregnancy as a diseased contralateral tube that was not operated on (23, 36). The risk of recurrence increases in patients who have had two or more ectopic pregnancies. Only one out of three will conceive again, and 20-57% of these pregnancies will be ectopic (39). It is reasonable to conclude that salpingotomy and evacuation of the tubal contents is a safe procedure that is unlikely to further impair tubal function and likely to maintainreproductivepotential. Laparoscopicretrieval of ectopic gestations may not be practical for all physicians, but in experienced hands, the procedure is less costly, requires shorter hospitalization, and allows a quickerrecovery than conventional laparotomy (32). A review of available evidence suggests that medical therapy, when applied to properly selected patients, results in tubal patency rates by hysterosalpingogram that are comparable to those achieved after conservative surgical procedures (9). Although subsequent normal Int J Gynecol Obstet 37
intrauterine pregnancies have been reported, long-term follow-up is needed to determine whether medical management promotes tubal healing and provides similar or possibly enhanced fertility in comparison to current surgical treatment.
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Kjer JJ, Knudsen LB. Ectopic pregnancy subsequent to laparoscopic sterilization. Am J Obstet Gynecol 1989; 160:1202-1204
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Ory HW. Ectopic pregnancy and intrauterine contraceptive devices: new perspectives. Obstet Gyencol 1981; 57:137
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McBain JC, Evans JH, Pepperell RJ, Robinson HP, Smith MA, Brown JB. An unexpectedly high rate of ectopic pregnancy following the induction of ovulation with human pituitary and chorionic gonadotropin. Br J Obstet Gynaecol 1980;87:5
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Insunza A, de Pablo F, Croxatto HD, Letelier LM, Morante M, Croxatto HB. On the rate of tubal pregnancy contralateral to the corpus luteum. Acta Obstet Gynecol Stand 1988;67(5):433436
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Makinen JI. Increase of ectopic pregnancy in Finlandcombination of time and cohort effects. Obstet Gynecol 1989;73:21-24
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Pauerstein CJ, Croxatto HB, Eddy CA, Ramzy I, Walters MD. Anatomy and pathology of tubal pregnancy. Obstet Gynecol 1986;67(3):301-308
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Busch DH, Benirschke K. Cytogenetic studies of ectopic pregnancies. Virchows Arch [B] 1974;16(4):319-330
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Leach RE, Ory SJ. Modem management of ectopic pregnancy. J Reprod Med 1989;34(5):324-338
10. Wekstein LN. Current perspective on ectopic pregnancy. Obstet Gynecol Surv 1985;40:259-272 11. Kadar N, DeVore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation for ectopic pregnancy. Obstet Gynecol 1981;58(2):156-161 12. Romero R, Kadar N, Jeanty P, Cope1 JA, Chervenak FA, DeChemey A, et al. Diagnosis of ectopic pregnancy: value of the discriminatory human chorionic gonadotropin zone. Obstet Gynecol 1985; 66(3):357-360 13. Daus K, Mundy D, Graves W, Slade BA. Ectopic pregnancy. What to do during the 20-day window. J Reprod Med 1989;34(2):162-166
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segmental resection as the treatment of choice. Steril 1985;44(3):307-312
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Romero R, Kadar N, Castro D, Jeanty P, Hobbins JC, DeChemey AH. The value of adnexal sonographic findings in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol 198&1X$(1):52-55
15. Bateman BG, Nunley WC, Kolp LA, Kitchin JD, Felder R. Vaginal sonography findings and hCG dynamics of early intrauterine and tubal pregnancies. Obstet Gynecol 1990;75:421-427 16. Pittaway DE, Wentz AC. Evaluation of early pregnancy by serial chorionic gonadotropin determinations: a comparison of methods by receiver operating characteristic curve analysis. Fertil Steril1985;43(4):529-533 17. Fritz MA, Guo SM. Doubling time of human chorionic gonadotropin (hCG) in early normal pregnancy: relationship to hCG concentration and gestational age. Fertil Steril 1987;47(4):584-589 18. Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstet Gynecol 1981;58(2):162-166 19. Hubinont CJ, Thomas C, Schwers JF. Luteal function in ectopic pregnancy. Am J Obstet Gynecol 1987; 156(3): 669-674 20.
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Stovall TG, Ling FW, Cope BJ, Buster JE. Preventing ruptured ectopic pregnancy with a single serum progesterone. Am J Obstet Gynecol 1989; 160: 1425-143 1 Sauer MV. Vermesh M, Anderson RE, Vijod AG, Stanczyk FZ, Lobo RA. Rapid measurement of urinary pregnanediolglucuronide todiagnoseectopicpregnancy. Am J Obstet Gynecol 1988;159(6):1531-1535 Gelder MS, Boots LR, Younger JB. Use of a single random serum progesterone value as a diagnostic aid for ectopic pregnancy. Abstract P-100, American Fertility Society Program andAbstracts. Birmingham, Alabama: AFS, 1989:SlOl-S102
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Smith HO, Toledo AA, Thompson JD. Conservative surgical management of isthmic ectopic pregnancies. Am J Obstet Gynecol 1987; 157(3):604-610
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Sherman D, Langer R, Herman A, Bukovsky I, Caspi E. Reproductive outcome after fimbrial evacuation of tubal pregnancy. Fertil Steril 1987;47(3):420-424
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Pouly JL, Mahnes H, Mage G, Canis M, Bruhat MA. Conservative laparoscopic treatment of 321 ctopic pregnancies. Fertil Steril 1986;46(6): 1093-10 %7
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Henderson SR. Ectopic tubal pregnancy treated by operative laparoscopy. Am J Obstet Gynecol 1989; 160(6):1462-1469
3 1. Midgley AR Jr, Jaffe RB. Regulation of human gonadotropins. II. Disappearance of human chorionic gonadotropin following delivery. J Clin Endocrinol Metab 1968;28(12):1712-1718 32.
Vermesh M, Silva PD. Rosen GF, Stein AL, Fossum GT, Sauer MV. Management of unruptured ectopic gestation by linear salpingotomy: a prospective, randomized clinical trial of laparoscopy versus laparotomy. Obstet Gynecol 1989;73(3 pt 1):400-404
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Gretz E, Quagliarello J. Declining serum concentrations of the R-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987; 156(4):94&941
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Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989;51(3):435438
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Kenigsberg D, Porte J, Hull M, Spitz IM. Medical treatment of residual ectopic pregnancy: RU 486 and methotrexate. Fertil Steril 1987;47(4):702-703
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Novy MJ. Surgical alternatives for ectopics: is conservative treatment best? Contemp Ob/Gyn 1983;2 l(1): 91-120
Vermesh M. Conservative management of ectopic gestation. Fertil Steril 1989;5 1(4):559-567
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Hallatt JG. Tubal conservation in ectopic pregnancy: a study of 200 cases, Am J Obstet Gynecol 1986; 154(6): 1216-1221
LangerR, Bukovsky I, Herman A, Sherman D, Sadovsky G, Caspi E. Conservative surgery for tubal pregnancy. Fertil Steril 1982;38(4):427-430
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Senterman M, Jibodh R, Tulandi T. Hitopathologic study of ampullary and isthmic tubal ectopic pregnancy. Am J Obstet Gynecol 1988; 159(4):939-94 1
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DeChemey AH, Silidker JS, Mezer HC, Tarlatzis BC. Rep&u&ive outcome following two ectopic pregnancies. Fertil Steril 1985;43(1):82-85
DeChemey AH, Boyers SP. Isthmic ectopic pregnancy:
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1’992,37: 213-2I9
Federation
of Gynecology
213 and Obstetrics
Ectopic pregnancy ACOG Technical Bulletin Number (Replaces No. 126, March 1989)
150 -
The contemporary management of ectopic pregnancy has been greatly influenced by the availability of rapid and sensitive radioimmunoassays to detect the beta subunit of human chorionic gonadotropin (B-hCG) in serum and by technical advances in ultrasound. As a result, the earlier diagnosis of ectopic pregnancy has led to a decreased frequency of tubal rupture (~20% of cases in many centers) and an extensive use of conservative surgical procedures increasingly performed by operative laparoscopy. Despite these advances, however, ectopic pregnancy remains a leading cause of maternal morbidity. The new conservative approach to tubal pregnancy has been paralleled by a steady increase in its overall incidence: approximately 2% of pregnancies are ectopic (1). Reasons given for the increase are a greater prevalence of sexually transmitted diseases, more frequent recourse to sterilization procedures and reconstructive tubal surgery, and more successful clinical detection. Seventy-five percent of pregnancies occurring after failure of tubal sterilization procedures are likely to be ectopic (2). Contraceptive failures in women wearing intrauterine devices (IUDs) are also more likely to be tubal pregnancies, because the IUD acts preferentially to impair intrauterine implantation (3). Other conditions that predispose to ectopic implantal tion are in utero exposure to diethylstilbestrol (DES); accessory tubal ostia; and possibly abnormal peristalsis or ciliary function of the oviduct. Also implicated is the use of ovulation induction agents such as human menopausal gonadotropins (hMG) (4). Transmigrationof the ovum is also a factor, since in about one in every four tubal pregnancies, the corpus luteum is on the opposite ovary (5). The highest age-specific incidence rates per 100,000 women are observed in women 25-34 years of age (6). Implantation of the embryo in the oviduct is a
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condition unique to humans. An experimental model for tubal pregnancy in domestic or laboratory animals is lacking (5). Therefore, much of our knowledge about etiologic mechanisms and pathophysiology is based on circumstantial evidence. Although it appears that most ectopic pregnancies develop from a delay in ovum transport secondary to a diseased fallopian tube, extrauterine implantation may be influenced by abnormalities of the’ fertilized egg or its particular hormonal environment. Fetuses are found in almost half of tubal pregnancies (7), and the incidence of chromosomal derangements is lower in ectopic pregnancies than in spontaneous abortion material (8). The ampulla is the most common site of implantation, accounting for 78% of ectopic pregnancies; 12% are located in the isthmus, 5% in the fimbria, and 2% are comual or interstitial (9). The remainder are abdominal, cervical, or ovarian.
Evaluation and Diagnosis Over 90% of symptomatic patients with tubal pregnancies have abdominal or pelvic pain as well as vaginal bleeding, and many have palpable adnexal masses ( 10). These findings, however, are often present in women with other diagnoses. Patients with ectopic pregnancy can be encountered in two different clinical settings. Patients with mild, moderate, or severe abdominal pain and various degrees of hemodynamic alterations are often seen in an emergency room, usually at a more advanced gestational age. Another group of patients present earlier in the natural course of their disease and often are asymptomatic infertility patients at risk for ectopic pregnancy. This latter group provides the greatest opportunity for early diagnosis, expectant management, and conservative intervention by various surgical and medical modalities. Int J Gynecol Obstet 37
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Testing The quantitation of hCG has been complicated by the existence of two reference standards for hCG immunoassay: the Second International Standard (Second IS) and the International Reference Preparation (IRP). The Second IS, actually the first reference standard available, was developed for use in hCG bioassays and was later utilized in radioimmunoassays. It is not well suited for use in hCG radioimmunoassays, since it is relatively heterogeneous, containing only 20% intact hCG. The IRP, a highly purified preparation, was developed to overcome these deficiencies and is ideal for use in radioimmunoassays. It is important to know which hCG reference standard is used when correlating hCG levels with ultrasound findings. A single quantitative serum hCG determination has limited value in determining the location or viability of an early pregnancy, because the date of conception is uncertain in most patients and serum hCG concentrations rise in an exponential fashion for the first 38 days after ovulation. Thereafter they begin to plateau at concentrations in excess of 30,000 mIU/ml (IRP). Serial quantitative hCG determinations are a more reliable indicator of gestational viability. The addition of ultrasonography allows the clinician to exclude intrauterine pregnancies when an ectopic gestation is suspected. A positive sonographic diagnosis can be made by identifying an extrauterine fetus, but this is an uncommon finding. In practice, ultrasound is more frequently used to exclude ectopic pregnancy by demonstrating an intrauterine gestational sac or fetus, because the coexistence of intrauterine and ectopic pregnancy is so rare (l/30,000). The incidence of heterotopic pregnancy, however, is increased at least lo-fold in patients who undergo ovulation induction therapy and have multiple ovulations (9). The concept of the discriminatory hCG zone was first defined as a range of serum hCG concentrations (6,000-6,500 mIU/ml [IRP]) above which a normal intrauterine gestation could be visualized by transabdominal ultrasonography 94% of the time and below which an intrauterine sac usually was not visible (11). The absence of an intrauterine gestational sac when the hCG concentration exceeds the discriminatory zone is diagnostic of ectopic pregnancy in 86% of cases (12). Patients with multiple pregnancies will exhibit higher levels of hCG relative to gestational sac findings. Less Int J Gynecol Obstet 37
than 25% of ectopic pregnancies, however, have hCG concentrations greater than or equal to 6,000 mIU/ml at the initial evaluation (13). Transvaginal ultrasonography, with its higher resolution, may allow earlier determination of intrauterine pregnancies-as early as 35 days from the last menstrual period. An intrauterine sac can be visualized when the hCG level reaches approximately 1,500 mIU/ ml (IRP) or 900 mIU/ml (Second IS) (Table 1). Until the fetal pole or yolk sac is identified by ultrasound, however, an ectopic pregnancy cannot be excluded. The use of transvaginal imaging effectively lowers the discriminatory zone to allow earlier identification of abnormal gestations. Discriminatory zones of 2,0003,000 mIU/ml (IRP) may be more realistic with transvaginal probes. Earlier surgical intervention may lead to lack of identification of the site of implantation. Because there is variability among hCG assays and the resolution of different imaging systems, each laboratory and clinical service must establish its own discriminatory zones for transabdominal and transvaginal ultrasonography. In the future, adnexal findings will become increasingly helpful in the diagnosis of tubal pregnancy when the echogenic patterns, blood flow, and metabolic characteristics of the corpus luteum and the ectopic pregnancy can be differentiated. The infrequent finding of a complex echogenic mass by transabdominal ultrasonography in the adnexa has a positive predictive value for ectopic pregnancy of 94% (14). Transvaginal sonography provides improved resolution in the imaging of the uterine cavity, adnexa, and cul-de-sac fluid. False-positive gestational sacs are less common than with transabdominal scanning. Gestational sacs detected early in gestation (less than 5 mm in diameter), however, frequently exhibit a partial or absent echogenic rim. A point of differentiation between false and genuine sacs is the presence of a yolk sac. Transvaginal scanning is sensitive and specific in detecting cul-de-sac blood when the volume is greater than 100 ml. Early sac recognition may be hampered by the presence of uterine myomata. Transvaginal sonography has provided new information on normal early intrauterine development (15). The altered endocrine behavior of ectopic gestations (eg, abnormal patterns of change in hCG levels and lowered progesterone secretion) has been studied to aid in the diagnosis of ectopic gestation in its early
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TABLE1. RELATIONSHIPOFGESTATIONALAGE, hCG LEVELS,ANDTRANSVAGlNALULTRASOUNDFINDINGS* /3-hCG(mlU/ml)
Ultrasound Findings Sac Fetal pole Fetal heart motion
Days from Last Menstrual Period 34.8 f 2.2
40.3 f 3.4t 46.9 k 6.0t
International Reference Preparation 1.398 f 155
5,113 + 298’ 17,208 f 3,772’
‘Fossum GT, Davajan V, Kletzky OA. Early detection of pregnancy with transvaginal +P .Z 0.05 when compared with sac.
stages of development. The exponential rate of rise of hCG levels in pregnancy is not constant but gradually decreases with advancing gestational age and increasing hCG concentration. The hCG doubling time ranges from 1.5 days in very early pregnancy to 3.5 days at 7 weeks of gestation (16,17). From a practical standpoint, however, pregnancies near 6 weeks of gestation that demonstrate less than a 66% increase in hCG levels within a 48-hour interval are likely to represent either ectopic pregnancies or intrauterine pregnancies that are likely to abort (18). Progesterone production is decreased in ectopic gestation compared with an intrauterine pregnancy of the same gestational age (19). After a rise during the luteal phase, serum progesterone levels remain stable during the first 8 weeks of pregnancy. Therefore, a single determination may be adequate to judge the normalcy of pregnancy, and precise knowledge of gestational age is not required (19). Low levels of serum progesterone or its urinary metabolite, pregnanediol 3a-glucuronide, can be used to alert the physician to problem pregnancies even when the B-hCG levels are below the discriminatory zone of ultrasound examination (20,2 1). A single serum progesterone determination is highly predictive of an abnormal gestation, but it does not distinguish abnormal intrauterine from ectopic pregnancies. It will be less than 15 @ml in 81% of tubal pregnancies and in 93% of abnormal intrauterine pregnancies but in only 11% of normal intrauterine pregnancies (20). Conversely, fewer than 2% of ectopic pregnancies and not more than 4%of abnormal intrauterine pregnancies will have a serum progesterone level of greater than 25 ng/ml. Thus, a single serum progesterone of 25 ng/ml or greater is strongly indicative of a normal intrauterine pregnancy, whereas a value below 15 ng/ml strongly suggests an abnormal preg-
Second International Standard 914 f 106 3,783 + 683 13,178 f 2,898f
ultrasound.
Fertil Steril 1988;49(5):788-791
nancy. Progesterone measurements, however, may not be useful in the diagnosis of ectopic pregnancy during clomiphene- or menotropin-stimulated cycles, due to multiple corpora lutea (22).
Surgical Management In deciding upon the best management for a given patient, the patient’s age, reproductive history, and wishes for fertility must be taken into account. Other considerations are location and cause of the ectopic pregnancy, extent to which normal tubal ovarian relationships have been disrupted, and the amount of peritoneal blood loss. Culdocentesis with an 18-gauge spinal needle is an inexpensive and rapid means of patient evaluation. The predictive value of culdocentesis varies according to the probability of tubal rupture, which increases with advancing gestational age. Culdocentesis is most useful in diagnosing hemoperitoneum in patients who are symptomatic or clinically unstable and often provides the impetus for earlier surgical intervention. For most patients, the goal of treatment is to remove the ectopic pregnancy while preserving reproductive function. However, in the face of tubal rupture, significant anatomic distortion, or overt hemorrhage, or if future pregnancies are not desired, salpingectomy may be advisable. Ipsilateral salpingo-oophorectomy is not recommended unless the ovary is compromised or is otherwise grossly abnormal. The practice of comual wedge excision salpingectomy is unnecessary and is probably associated with a higher incidence of homolateral interstitial pregnancies (23,24). The patient who has had a tubal sterilization and now has a proximal fistula and an ectopic pregnancy in the distal fimbriated segment should have the fistula and the ectopic gestaInt J Gynecol Obstet 37
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tion excised. If no reversal of sterilization is contemplated, the fimbriated tubal segment on the opposite side should also be removed to prevent a future ectopic gestation at that site. A conservative operation on the tube is most appropriate when an infertile woman has an unruptured ectopic pregnancy and wishes to preserve her reproductive potential. Even some ruptured comual or isthmic pregnancies can be treated conservatively if the patient’s condition is stable and the remainder of the tube can be salvaged. Ampullary salpingotomy is the most common conservative tubal operation and is increasingly performed by operative laparoscopy. For the procedure, a linear incision is made with electrocautery, laser, or sharp dissection over the antimesenteric portion of the tube, and the products of conception and blood clot are removed with forceps or by gentle evacuation. Trophoblastic growth takes place within the tubal lumen in approximately two-thirds of ampullary pregnancies; in the remaining one-third, the trophoblastic expansion occurs extraluminally, or a mixed pattern is observed (7, 25). In most, the mucosa is disrupted only at the implantation site and the muscularis is preserved. Careful evacuation of blood clots and products of conception allows the tube to return to a nearly normal anatomic state. Bleeding is controlled by cauterization of serosal vessels. The injection of dilute vasopressin in the mesosalpinx below the conceptus or in the tubal wall is recommended by many surgeons, but its use is not free of complications. The intravascular injection of vasopressin may induce a pronounced increase in blood pressure. The incision is allowed to close by secondary intention. When the operation is complete, the tube is irrigated with an isotonic solution and observed for bleeding points, since reactive hyperemia may occur. Small bleeding vessels can be controlled by point cautery or compression with nontraumatic forceps. If necessary, the vessels in the mesosalpinx that supply the ectopic pregnancy are coagulated or ligated. Vigorous cauterization of the tubal lumen causes extensive damage and should be avoided. On occasion, the salpingotomy incision is closed in two layers with 6-O interrupted nonreactive sutures by microsurgical techniques. There is no evidence that either approach is superior to the other. In isthmic ectopic pregnancies, the implantation is usually extraluminal or mixed; the mucosa is generally not preserved, and the muscularis is destroyed in most Int J Gynecol Obstet 37
cases (25). Resection of the involved segment of tube is most applicable when the pregnancy is in the proximal isthmus or at the uterine comu. Salpingotomy predisposes to scarring of the narrow lumen in this portion of the tube (26). Excision has the advantage of removing a presumably abnormal region of the tube while preserving the proximal and distal segments for anastomosis. Although end-to-end anastomosis at the time of the tubal pregnancy has been successfully accomplished and has resulted in normal pregnancies (9), the repair is usually postponed. The disadvantage of requiring a second operation is lessened if segmental resection is performed by laparoscopy; it is offset by allowing the microsurgeon to operate at a more opportune time and by avoiding the problems associated with inflammation and edema. Ectopic pregnancy may develop in the distal ligated segment if the contralateral tube is patent. This infrequent occurrence can be prevented, however, by using contraceptive measures prior to anastomosis. Some unruptured isthmic pregnancies can be managed by linear salpingotomy, especially when surgical intervention takes place early in the development of the ectopic pregnancy, when trophoblastic growth is intraluminal and the implantation site is at or near the isthmic-ampullary junction. Favorable postoperative tubal patency rates and reproductive outcome have been reported under these circumstances (27). Forcible expression of the products of conception can be damaging to the tube, but a favorable outcome has been reported in ftmbrial pregnancies that are loosely adherent or in the process of being extruded from the infundibulum (20 Operative laparoscopy has benefited from the development of new instrumentation that permits more complex surgical maneuvers and the removal of larger volumes of tissue by a process of morcellation. In the hands of the properly trained and equipped surgeon, translaparoscopic salpingotomy or even salpingectomy has been demonstrated to be safe and efficient and may be used in most patients with small (4-cm) ectopic pregnancies (29.30). Additional therapy may include the intraperitoneal instillation of 100 ml of dextran 70 (Hyskon), but its effectiveness in preventing adhesions in this setting is not proven, and rare allergic reactions can occur. Most authorities advise against incidental appendectomy, and ancillary surgical procedures are best limited to simple lysis of adhesions.
ACOG
Persistent Ectopic Pregnancy Persistence of viable trophoblastic tissue in the tube occurs in 5% of patients after conservative surgical treatment (29). Secondary implantation of displaced trophoblast is a potential but infrequent complication. Postoperatively, patients should undergo weekly serum hCG testing until nonpregnant levels are achieved. The clearance of hCG occurs in two phases: an initial phase with a half-life of 5-9 hours and a second, longer phase with a half-life of 22-32 hours (3 1). When removal of trophoblastic tissue is fairly complete, serum hCG concentrations will be 20% or less of intraoperative levels within 72 hours after surgery (32). If hCG levels continue to fall (albeit slowly), expectant management with serial monitoring of hCG levels is sufficient. If hCG levels reach a plateau or increase, treatment options, which include salpingectomy, partial salpingectomy, and medical therapy, should be considered.
Medical Treatment Expectant management with serial endocrine monitoring is an option for patients with small, unruptured (l3 cm in diameter) ectopic gestations with hCG values that continue to decline from an initial value below 1,000 mIU/ml (IRP) (9). With rare exceptions, such patients have a low risk of tubal rupture and hemorrhage (33). A review of preliminary data suggests that subsequent fertility in this select group of patients is comparable to other methods of treatment (9). The potential disadvantages of expectant management include prolonged outpatient follow-up and inflammation at the site of the ectopic gestation as one waits for spontaneous resorption. When trophoblastic proliferation continues, as manifested by stable or increasing hCG levels, it is possible to hasten dissolution of the ectopic trophoblast with chemotherapy. Methotrexate, a folic acid antagonist, has been used to inhibit the growth of trophoblastic cells in situations where surgical intervention might be hazardous. There are also numerous reports demonstrating favorable results with methotrexate and leucovorin calcium (citrovorum factor) as primary therapy for smaller ectopic gestations (9, 34). Screening of patients should include l3-hCG assays, ultrasound, laparoscopy, hepatic enzymes, and complete blood count with differential and platelet
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count. Recommended selection criteria for medical therapy include the following: H Ectopic size 3 cm or less n Desire for future fertility n Stable or rising hCG levels with peak values below 15,000 mIU/ml (IRP) n Tubal serosa intact n No active bleeding n Ectopic pregnancy fully visualized at laparoscopy n Selected cases of cervical and comual pregnancy Contraindications to chemotherapy include the following: n Poor patient compliance n History of active hepatic or renal disease n Presence of fetal cardiac activity n Abnormal serum creatinine or serum glutamic oxalacetic transaminase (SGOT) n Active peptic ulcer disease n Blood leukocyte count of <3,000 or a platelet count of <100,000 Presently, chemotherapy in conjunction with laparoscopic diagnosis offers no clear advantage over laparoscopic surgery for the routine management of ectopic pregnancy. Chemotherapy is the treatment of choice when surgery is contraindicated or in the management of postoperative persistent trophoblast. It is anticipated that more accurate ultrasonographic and endocrine diagnosis, in conjunction with dilation and curettage, may eventually supplant the need for laparoscopic diagnosis in some patients and thus extend the application of medical management (20). The merits of direct injection of methotrexate or other pharmacologic agents (eg, potassium chloride, hypertonic solutions, prostaglandins) into the gestational sac under sonographic or laparoscopic guidance are still uncertain. There is concern that many of these agents will incite an intense tissue reaction within the tube. The progesterone antagonist RU 486 has not been successful in the treatment of ectopic pregnancy (35).
Outcome Conservative surgery for small unruptured ectopic pregnancies produces encouraging results. Tubal paInt J Gynecol Obsret 37
2 IX
ACOG
Technical Bulletin
In small, uncontrolled studies, a 4MO% intrauterine pregnancy rate with a lO-20% risk of recurrent ectopic gestation after linear salpingotomy has been reported (9,36). It is noteworthy that a recurrent ectopic pregnancy occurs in the contralateral tube as often as in the operated oviduct (24). Women with a history of infertility have a lower pregnancy rate (41%) than do women with normal reproductive histories (85%) (29). Pregnancy outcome after conservative surgery is also specifically correlated with the macroscopic condition of the contralateral adnexa. While the ratio of intrauterine to ectopic pregnancies is generally about 6: 1, it rises to about 10: 1 in patients with a normal contralateral tube
tency
is restored in more than 80% of patients.
(37). When the results of conservative surgery and salpingectomy are compared, patients with otherwise normal reproductive histories and normal pelvic findings have similar subsequent fertility and ectopic recurrence, suggesting that conservative surgery does little to predispose a woman to ectopic pregnancy (38). Fertility is substantially improved when conservative surgery is utilized instead of salpingectomy (subsequent intrauterine pregnancy rates of 76% and 44%, respectively) in patients who have adhesive disease in the contralatera1 adnexa and a history of infertility (38). The results of salpingotomy in patients with a tubal pregnancy in a sole patent oviduct (approximately 20% ectopic recurrence) suggest that a conserved tube is at similar risk for a repeat ectopic pregnancy as a diseased contralateral tube that was not operated on (23, 36). The risk of recurrence increases in patients who have had two or more ectopic pregnancies. Only one out of three will conceive again, and 20-57% of these pregnancies will be ectopic (39). It is reasonable to conclude that salpingotomy and evacuation of the tubal contents is a safe procedure that is unlikely to further impair tubal function and likely to maintainreproductivepotential. Laparoscopicretrieval of ectopic gestations may not be practical for all physicians, but in experienced hands, the procedure is less costly, requires shorter hospitalization, and allows a quickerrecovery than conventional laparotomy (32). A review of available evidence suggests that medical therapy, when applied to properly selected patients, results in tubal patency rates by hysterosalpingogram that are comparable to those achieved after conservative surgical procedures (9). Although subsequent normal Int J Gynecol Obstet 37
intrauterine pregnancies have been reported, long-term follow-up is needed to determine whether medical management promotes tubal healing and provides similar or possibly enhanced fertility in comparison to current surgical treatment.
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