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Ruptured ectopic pregnancy after medical management: Current conservative management strategies
Ruptured Ectopic Pregnancy After Medical Management: Current Conservative Management Strategies JEAN ABBOTT,
MD, RICK ABBOTT,
MD
A case of hypotension caused by hemorrhage in a patient receiving systemic melhotrexate to treat a known ectopic pregnancy is presented. A primary goal of gynecologic practice in the 1990s is to conserve tubal patency and fertility. Consequently, ectopic pregnancy is more frequently being managed by conservative strategies. The emergency physician must be familiar with conservative methods for the management of ectopic pregnancy and the complications that may cause emergency presentations in these patients. (Am J Emerg Med 1993;11:480-482. Copyright 0 1993 by W.8. Saunders Company) The incidence of ectopic pregnancy has increased more than fivefold in the past 20 years.’ The increase is attributable to several factors such as higher rates of pelvic inflam-
matory disease, more frequent tubal-sparing surgical procedures, and ovulation induction to manage infertility.* In the patient with a ruptured ectopic pregnancy accompanied by extensive tubal damage, traditional salpingectomy remains the treatment of choice. Current management options for the stable and relatively asymptomatic patient include laparoscopy or laparotomy with ectopic pregnancy removal and tubal repair, sonographic or laparoscopic injection of chemotherapy into the gestation, systemic chemotherapy to ablate the pregnancy, or expectant management (observation alone). We present the case of a patient who presented to the emergency department (ED) with hypotension and signs of diffuse peritonitis caused by a ruptured ectopic pregnancy after outpatient parenteral methotrexate treatment. The emergency physician must be aware of these new management strategies, which carry the potential for both prolonged treatment of ectopic pregnancy and the occasional failure of obliterative procedures. In addition, we review the new concept of persistent ectopic pregnancy, which is being reported with increasing frequency as these new early and conservative strategies are more often used, and which represents the persistence of trophoblastic activity (ie, human chorionic gonadotropin [HCG] levels that do not drop as predicted) after surgical or nonsurgical management.3*4 CASE REPORT A 34-year-old G2 PO woman was under treatment by a reproductive endocrinologist for infertility with clomiphene citrate and was From the Division of Emergency Medicine, Department of Surgery, University of Colorado School of Medicine, Denver; and the Department of Emergency Medicine, Boulder Community Hospital, Boulder, CO. Manuscript received November 16, 1992; revision accepted March 8, 1993. Address reprint requests to Dr Abbott, MD, B-215 University Hospital, 4200 E 9th Ave, Denver, CO 80226. Key Words: Ectopic pregnancy, methotrexate. Copyright 0 1993 by W.B. Saunders Company 07356757/93/1105-0012$5.00/O
480
artificially inseminated at the time of ovulation. Two weeks later, her pregnancy test was positive, with a P-HCG level of 103 mIU/mL (international reference preparation [IRP]). Two days later, the P-HCG was 224 mIU/mL. The patient developed spotting at 6 weeks’ gestation (40 days after her last menstrual period) and some left lower back pain. Her P-HCG was 3.080 mIU/mL at this time, and she was observed closely by her gynecologist with ectopic precautions. An ultrasound performed at 6.5 weeks (46 days) after the LMP (HCG level, 12.000 mIU/mL) demonstrated no pregnancy in the uterus. She was presumed to have an ectopic pregnancy. and at 49 days and 57 days was treated with methotrexate 80 mg intramuscularly. At both ofice visits, her abdomen was soft, without peritoneal signs or tenderness. The patient presented to the ED at 8 weeks’ gestation (59 days), 2 days after her second dose of methotrexate. She stated that she had been lightheaded 3 days earlier and had progressive left lower quadrant (LLQ) pain on the day of admission. On physical examination, the patient was pale but alert; her vital signs were blood pressure, 60/40 mm Hg; pulse. 80 beatsimin; respirations, 20 breathsimin. No temperature was recorded. Her abdomen was distended, tender, especially in the LLQ, without bowel sounds, and with generalized peritoneal signs. On pelvic examination, she had spotting from the cervix, no cervical motion tenderness. no definite palpable mass, but extreme tenderness in the LLQ. Initial hematocrit was 41.8%, and the patient was Rh positive. The patient was resuscitated with a total of 4 L of normal saline and with oxygen by nasal cannula. Ultrasound showed a large amount of fluid in the cul-de-sac and free in the peritoneum, and no intrauterine pregnancy; no definite ectopic or adnexal mass was observed. She was taken to the operating room, where a culdocentesis was positive for 7 mL of nonclotted blood. At laparotomy, a 3-cm left ampullary rupturing ectopic pregnancy was managed by manual expression of the products of conception through the rupture site and tubal repair. A total of 350 mL of free blood was removed from the peritoneal cavity (although by clinical criteria, decrease in hematocrit, and ultrasonographic criteria, the actual blood loss was substantially more). The postoperative hematocrit was 25%. The patient had an uneventful postoperative course.
DISCUSSION Advances in the early diagnosis of pregnancy itself, and of abnormal pregnancy, combined with an increased awareness of the possibility of ectopic gestation by gynecologists and emergency physicians has changed the spectrum of ectopic pregnancy remarkably during the past 10 years. The increased risk of ectopic pregnancy is fueled not only by the epidemic of pelvic inflammatory disease, but also by the increased use of new reproductive procedures, such as embryo transfer and in vitro fertilization.5 After in vitro fertilization, heterotopic (ectopic combined with intrauterine pregnancy) pregnancy rates as high as 1 in 40 pregnancies have been reported.6 These infertility patients are monitored closely, and ectopic pregnancy is diagnosed or suspected early, frequently before symptoms become manifest. In
ABBOTT
AND ABBOTT
W MEDICAL
MANAGEMENT
OF ECTOPIC
many cases, the patient’s and physician’s motivation is understandably strong to salvage fertility by avoiding both rupture and invasive surgical procedures, as well as to protect any concomitant intrauterine gestation. Several conservative management strategies are commonly used for the patient with an early unruptured ectopic pregnancy. Although even conservative management has not been shown definitively to preserve greater subsequent fertility, it currently is recommended in the hope that such an outcome will occur in those women desiring further successful pregnancies.5v7 Techniques vary with region and patient, and no management algorithm is in wide usage to decide between alternatives. Conservative strategies that may be encountered by the emergency physician follow. Expectant Management It is well known that spontaneous resolution of ectopic pregnancy is not uncommon, either because of spontaneous regression of the pregnancy in situ or tubal abortion with subsequent resorption.’ This is probably an increasingly common likelihood because patients are being diagnosed with ectopic pregnancy at an early and relatively asymptomatic stage. Nonoperative management with serial HCG level monitoring is most commonly used for pregnancies of small diameter, those located in the ampullary portion of the fallopian tube, and in asymptomatic patients. Although expectant management was originally performed only after laparoscopic diagnosis of the pregnancy, it is now practiced in some centers for all patients without significant symptoms or with intraperitoneal bleeding of less than 500 mL, with an HCG level less than 2,000 mIU/mL (IRP), with gestational masses less than 2 to 3.5 cm in diameter, and with persistently decreasing HCG levels over time.5,7 Systemic Methotrexate and Other Medical Interventions Several compounds can be given to stop trophoblastic development. The most commonly used is methotrexate. Several intravenous or intramuscular protocols for methotrexate administration have been published. Again, patients must wish to preserve fertility (but not have a coexistent intrauterine pregnancy) and have no evidence of tubal rupture. Methotrexate is used in patients with less advanced gestations (HCG levels <5,000 mIU/mL IRP, no fetal heart activity, gestational mass ~3.5 cm, and no evidence of rupture).8 Although protocols requiring multiple doses have been used more recently (as in the case presented), a successful protocol requiring only a single intramuscular dose of methotrexate in an outpatient setting has also been reported.’ Several other compounds have been used to medically ablate an ectopic pregnancy. Systemically, mifepristone (RU 486) has been tried without great success as a means of nonsurgical treatment. More successfully, termination of ectopic pregnancies by local injection (under transvaginal sonographic guidance) of methotrexate, potassium chloride, and prostaglandins has reported; these techniques avoid the systemic side effects of parenteral methotrexate.‘* Laparoscopy With lntratubal Chemotherapy Instillation Under sonographic or laparoscopic guidance, methotrexate, potassium chloride, or prostaglandins can be injected
PREGNANCY
481
into the ectopic gestation, leading to involution of the gestational nidus without surgical invasion of the tube.” Laparoscopy or Laparotomy With Salpingostomy or Other Tubal- Sparing Surgery When surgery is undertaken and tubal destruction is not severe, several alternatives to salpingectomy exist. The ectopic gestation can be manually expressed out the fimbrial ends without loss of the tubal integrity. A linear salpingostomy and pregnancy removal can also be performed. Surgery in the early stages of ectopic pregnancy balances the advantages of lesser tubal damage against the risk of incomplete removal of the gestation, which is reported with increasing frequency, particularly when surgery is performed before the pregnancy nidus is clearly demarcated.4s5 Persistent Ectopic Pregnancy All of the previously mentioned conservative management forms carry a risk of failure to eradicate the ectopic gestation. Patients with decreasing or even absent levels of The term “persistent ectopic pregS-HCG can rupture.“-” nancy” has been coined to denote patients who continue to show evidence of trophoblastic activity (with failure of HCG levels to decrease appropriately) after conservative surgical or medical therapy. The exact incidence of persistent ectopic pregnancy is not known, but it is thought to be approximately 5% with conservative surgical procedures.14 With nonsurgical management, the rate is higher: a 10% to 20% failure rate can be expected with medical or expectant management. “’ Failure of medical treatment is more likely, as in the case we report, when patients with large or rupturing pregnancies are selected for nonsurgical management. Generally, all of the nonsurgical treatments are most appropriate when the pregnancy is less than 3 cm in diameter, when there is an unruptured tube and no evidence of active bleeding, with lower HCG levels (cl.500 to 3,000 mIU/mL depending on the researcher), when no fetal heart activity is detectable by sonography, and when ~100 mL of fluid can be observed in the cul-de-sac.‘.” Failure of surgical treatment to completely remove trophoblastic tissue is also managed frequently with systemic methotrexate to avoid repeated invasive procedures.s CONCLUSION Conservative management of ectopic pregnancy is being used increasingly in women who would like to maintain fertility. We reviewed a case in which rupture of an ectopic pregnancy associated with hypovolemic shock occurred after treatment with systemic methotrexate. Conservative techniques for treating ectopic pregnancy may have up to a 10% or 20% failure rate. The emergency physician must anticipate that complications, including frank tubal rupture, may occur in patients receiving medical management or early conservative surgery for ectopic pregnancy. WEFERENCES 1. Nederlof KP, Lawson HW, Saftlas AF, et al: Ectopic pregnancy surveillance, United States, 1970-87. MMWR 1990;39:9-17 2. Doyle MB, DeCherney AH, Diamond MP: Epidemiology and etiology of ectopic pregnancy. Obstet Gynecol Clin N Am 1991;18(1):1-17
482
AMERICAN
JOURNAL
OF EMERGENCY
3. Lundorff P, Hahlin M, Sjoblom P, et al: Persistent trophoblast after conservative treatment of tubal pregnancy: Prediction and detection. Obstet Gynecol 1991;77:129-133 4. Stock RJ: Persistent tubal pregnancy. Obstet Gynecol 1991;77:267-270 5. Ory SJ: New options for diagnosis and treatment of ectopic pregnancy. JAMA 1992;267:534-537 6. Dmitry ES, Margara R, Suback-Sharpe R, et al: Nine cases of heterotopic pregnancies in 4 years of in vitro fertilization. Fertil Steril 1990;53:107-110 7. Stovall TG, Ling FW: Expectant management of ectopic pregnancy. Obstet Gynecol Clin N Am 1991;18(1):13>144 8. Stovall TG, Ling FW, Gray LA, et al: Methotrexate treatment of unruptured ectopic pregnancy: A report of 100 cases. Obstet Gynecol 1991;77:749-753 9. Stovall TG, Ling FW, Gray LA: Single-dose methotrexate
MEDICINE
n Volume
11, Number
5 n September
1993
for treatment of ectopic pregnancy. Obstet Gynecol 1991;77: 754-757 10. Pansky M, Golan A, Bukovsky I, et al: Nonsurgical management of tubal pregnancy. Am J Obstet Gynecol 1991;164: 888-895 11. Dumesic DA, Hafez GR: Delayed hemorrhage of a persistent ectopic pregnancy following laparoscopic salpingostomy and methotrexate therapy. Obstet Gynecol 1991;78:980-981 12. Gretz E, Quagliarello J: Declining serum concentrations of the beta-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987;156:940-941 13. Lonsky NM, Sauer MV: Ectopic pregnancy with shock and undetectable beta-human chorionic gonadotropin: A case report. J Reprod Med 1987;32(2):559-560 12. DiMarchi JM, Kosasa TS, Kobara TY, et al: Persistent ectopic pregnancy. Obstet Gynecol 1987;70:555-556
MD, RICK ABBOTT,
MD
A case of hypotension caused by hemorrhage in a patient receiving systemic melhotrexate to treat a known ectopic pregnancy is presented. A primary goal of gynecologic practice in the 1990s is to conserve tubal patency and fertility. Consequently, ectopic pregnancy is more frequently being managed by conservative strategies. The emergency physician must be familiar with conservative methods for the management of ectopic pregnancy and the complications that may cause emergency presentations in these patients. (Am J Emerg Med 1993;11:480-482. Copyright 0 1993 by W.8. Saunders Company) The incidence of ectopic pregnancy has increased more than fivefold in the past 20 years.’ The increase is attributable to several factors such as higher rates of pelvic inflam-
matory disease, more frequent tubal-sparing surgical procedures, and ovulation induction to manage infertility.* In the patient with a ruptured ectopic pregnancy accompanied by extensive tubal damage, traditional salpingectomy remains the treatment of choice. Current management options for the stable and relatively asymptomatic patient include laparoscopy or laparotomy with ectopic pregnancy removal and tubal repair, sonographic or laparoscopic injection of chemotherapy into the gestation, systemic chemotherapy to ablate the pregnancy, or expectant management (observation alone). We present the case of a patient who presented to the emergency department (ED) with hypotension and signs of diffuse peritonitis caused by a ruptured ectopic pregnancy after outpatient parenteral methotrexate treatment. The emergency physician must be aware of these new management strategies, which carry the potential for both prolonged treatment of ectopic pregnancy and the occasional failure of obliterative procedures. In addition, we review the new concept of persistent ectopic pregnancy, which is being reported with increasing frequency as these new early and conservative strategies are more often used, and which represents the persistence of trophoblastic activity (ie, human chorionic gonadotropin [HCG] levels that do not drop as predicted) after surgical or nonsurgical management.3*4 CASE REPORT A 34-year-old G2 PO woman was under treatment by a reproductive endocrinologist for infertility with clomiphene citrate and was From the Division of Emergency Medicine, Department of Surgery, University of Colorado School of Medicine, Denver; and the Department of Emergency Medicine, Boulder Community Hospital, Boulder, CO. Manuscript received November 16, 1992; revision accepted March 8, 1993. Address reprint requests to Dr Abbott, MD, B-215 University Hospital, 4200 E 9th Ave, Denver, CO 80226. Key Words: Ectopic pregnancy, methotrexate. Copyright 0 1993 by W.B. Saunders Company 07356757/93/1105-0012$5.00/O
480
artificially inseminated at the time of ovulation. Two weeks later, her pregnancy test was positive, with a P-HCG level of 103 mIU/mL (international reference preparation [IRP]). Two days later, the P-HCG was 224 mIU/mL. The patient developed spotting at 6 weeks’ gestation (40 days after her last menstrual period) and some left lower back pain. Her P-HCG was 3.080 mIU/mL at this time, and she was observed closely by her gynecologist with ectopic precautions. An ultrasound performed at 6.5 weeks (46 days) after the LMP (HCG level, 12.000 mIU/mL) demonstrated no pregnancy in the uterus. She was presumed to have an ectopic pregnancy. and at 49 days and 57 days was treated with methotrexate 80 mg intramuscularly. At both ofice visits, her abdomen was soft, without peritoneal signs or tenderness. The patient presented to the ED at 8 weeks’ gestation (59 days), 2 days after her second dose of methotrexate. She stated that she had been lightheaded 3 days earlier and had progressive left lower quadrant (LLQ) pain on the day of admission. On physical examination, the patient was pale but alert; her vital signs were blood pressure, 60/40 mm Hg; pulse. 80 beatsimin; respirations, 20 breathsimin. No temperature was recorded. Her abdomen was distended, tender, especially in the LLQ, without bowel sounds, and with generalized peritoneal signs. On pelvic examination, she had spotting from the cervix, no cervical motion tenderness. no definite palpable mass, but extreme tenderness in the LLQ. Initial hematocrit was 41.8%, and the patient was Rh positive. The patient was resuscitated with a total of 4 L of normal saline and with oxygen by nasal cannula. Ultrasound showed a large amount of fluid in the cul-de-sac and free in the peritoneum, and no intrauterine pregnancy; no definite ectopic or adnexal mass was observed. She was taken to the operating room, where a culdocentesis was positive for 7 mL of nonclotted blood. At laparotomy, a 3-cm left ampullary rupturing ectopic pregnancy was managed by manual expression of the products of conception through the rupture site and tubal repair. A total of 350 mL of free blood was removed from the peritoneal cavity (although by clinical criteria, decrease in hematocrit, and ultrasonographic criteria, the actual blood loss was substantially more). The postoperative hematocrit was 25%. The patient had an uneventful postoperative course.
DISCUSSION Advances in the early diagnosis of pregnancy itself, and of abnormal pregnancy, combined with an increased awareness of the possibility of ectopic gestation by gynecologists and emergency physicians has changed the spectrum of ectopic pregnancy remarkably during the past 10 years. The increased risk of ectopic pregnancy is fueled not only by the epidemic of pelvic inflammatory disease, but also by the increased use of new reproductive procedures, such as embryo transfer and in vitro fertilization.5 After in vitro fertilization, heterotopic (ectopic combined with intrauterine pregnancy) pregnancy rates as high as 1 in 40 pregnancies have been reported.6 These infertility patients are monitored closely, and ectopic pregnancy is diagnosed or suspected early, frequently before symptoms become manifest. In
ABBOTT
AND ABBOTT
W MEDICAL
MANAGEMENT
OF ECTOPIC
many cases, the patient’s and physician’s motivation is understandably strong to salvage fertility by avoiding both rupture and invasive surgical procedures, as well as to protect any concomitant intrauterine gestation. Several conservative management strategies are commonly used for the patient with an early unruptured ectopic pregnancy. Although even conservative management has not been shown definitively to preserve greater subsequent fertility, it currently is recommended in the hope that such an outcome will occur in those women desiring further successful pregnancies.5v7 Techniques vary with region and patient, and no management algorithm is in wide usage to decide between alternatives. Conservative strategies that may be encountered by the emergency physician follow. Expectant Management It is well known that spontaneous resolution of ectopic pregnancy is not uncommon, either because of spontaneous regression of the pregnancy in situ or tubal abortion with subsequent resorption.’ This is probably an increasingly common likelihood because patients are being diagnosed with ectopic pregnancy at an early and relatively asymptomatic stage. Nonoperative management with serial HCG level monitoring is most commonly used for pregnancies of small diameter, those located in the ampullary portion of the fallopian tube, and in asymptomatic patients. Although expectant management was originally performed only after laparoscopic diagnosis of the pregnancy, it is now practiced in some centers for all patients without significant symptoms or with intraperitoneal bleeding of less than 500 mL, with an HCG level less than 2,000 mIU/mL (IRP), with gestational masses less than 2 to 3.5 cm in diameter, and with persistently decreasing HCG levels over time.5,7 Systemic Methotrexate and Other Medical Interventions Several compounds can be given to stop trophoblastic development. The most commonly used is methotrexate. Several intravenous or intramuscular protocols for methotrexate administration have been published. Again, patients must wish to preserve fertility (but not have a coexistent intrauterine pregnancy) and have no evidence of tubal rupture. Methotrexate is used in patients with less advanced gestations (HCG levels <5,000 mIU/mL IRP, no fetal heart activity, gestational mass ~3.5 cm, and no evidence of rupture).8 Although protocols requiring multiple doses have been used more recently (as in the case presented), a successful protocol requiring only a single intramuscular dose of methotrexate in an outpatient setting has also been reported.’ Several other compounds have been used to medically ablate an ectopic pregnancy. Systemically, mifepristone (RU 486) has been tried without great success as a means of nonsurgical treatment. More successfully, termination of ectopic pregnancies by local injection (under transvaginal sonographic guidance) of methotrexate, potassium chloride, and prostaglandins has reported; these techniques avoid the systemic side effects of parenteral methotrexate.‘* Laparoscopy With lntratubal Chemotherapy Instillation Under sonographic or laparoscopic guidance, methotrexate, potassium chloride, or prostaglandins can be injected
PREGNANCY
481
into the ectopic gestation, leading to involution of the gestational nidus without surgical invasion of the tube.” Laparoscopy or Laparotomy With Salpingostomy or Other Tubal- Sparing Surgery When surgery is undertaken and tubal destruction is not severe, several alternatives to salpingectomy exist. The ectopic gestation can be manually expressed out the fimbrial ends without loss of the tubal integrity. A linear salpingostomy and pregnancy removal can also be performed. Surgery in the early stages of ectopic pregnancy balances the advantages of lesser tubal damage against the risk of incomplete removal of the gestation, which is reported with increasing frequency, particularly when surgery is performed before the pregnancy nidus is clearly demarcated.4s5 Persistent Ectopic Pregnancy All of the previously mentioned conservative management forms carry a risk of failure to eradicate the ectopic gestation. Patients with decreasing or even absent levels of The term “persistent ectopic pregS-HCG can rupture.“-” nancy” has been coined to denote patients who continue to show evidence of trophoblastic activity (with failure of HCG levels to decrease appropriately) after conservative surgical or medical therapy. The exact incidence of persistent ectopic pregnancy is not known, but it is thought to be approximately 5% with conservative surgical procedures.14 With nonsurgical management, the rate is higher: a 10% to 20% failure rate can be expected with medical or expectant management. “’ Failure of medical treatment is more likely, as in the case we report, when patients with large or rupturing pregnancies are selected for nonsurgical management. Generally, all of the nonsurgical treatments are most appropriate when the pregnancy is less than 3 cm in diameter, when there is an unruptured tube and no evidence of active bleeding, with lower HCG levels (cl.500 to 3,000 mIU/mL depending on the researcher), when no fetal heart activity is detectable by sonography, and when ~100 mL of fluid can be observed in the cul-de-sac.‘.” Failure of surgical treatment to completely remove trophoblastic tissue is also managed frequently with systemic methotrexate to avoid repeated invasive procedures.s CONCLUSION Conservative management of ectopic pregnancy is being used increasingly in women who would like to maintain fertility. We reviewed a case in which rupture of an ectopic pregnancy associated with hypovolemic shock occurred after treatment with systemic methotrexate. Conservative techniques for treating ectopic pregnancy may have up to a 10% or 20% failure rate. The emergency physician must anticipate that complications, including frank tubal rupture, may occur in patients receiving medical management or early conservative surgery for ectopic pregnancy. WEFERENCES 1. Nederlof KP, Lawson HW, Saftlas AF, et al: Ectopic pregnancy surveillance, United States, 1970-87. MMWR 1990;39:9-17 2. Doyle MB, DeCherney AH, Diamond MP: Epidemiology and etiology of ectopic pregnancy. Obstet Gynecol Clin N Am 1991;18(1):1-17
482
AMERICAN
JOURNAL
OF EMERGENCY
3. Lundorff P, Hahlin M, Sjoblom P, et al: Persistent trophoblast after conservative treatment of tubal pregnancy: Prediction and detection. Obstet Gynecol 1991;77:129-133 4. Stock RJ: Persistent tubal pregnancy. Obstet Gynecol 1991;77:267-270 5. Ory SJ: New options for diagnosis and treatment of ectopic pregnancy. JAMA 1992;267:534-537 6. Dmitry ES, Margara R, Suback-Sharpe R, et al: Nine cases of heterotopic pregnancies in 4 years of in vitro fertilization. Fertil Steril 1990;53:107-110 7. Stovall TG, Ling FW: Expectant management of ectopic pregnancy. Obstet Gynecol Clin N Am 1991;18(1):13>144 8. Stovall TG, Ling FW, Gray LA, et al: Methotrexate treatment of unruptured ectopic pregnancy: A report of 100 cases. Obstet Gynecol 1991;77:749-753 9. Stovall TG, Ling FW, Gray LA: Single-dose methotrexate
MEDICINE
n Volume
11, Number
5 n September
1993
for treatment of ectopic pregnancy. Obstet Gynecol 1991;77: 754-757 10. Pansky M, Golan A, Bukovsky I, et al: Nonsurgical management of tubal pregnancy. Am J Obstet Gynecol 1991;164: 888-895 11. Dumesic DA, Hafez GR: Delayed hemorrhage of a persistent ectopic pregnancy following laparoscopic salpingostomy and methotrexate therapy. Obstet Gynecol 1991;78:980-981 12. Gretz E, Quagliarello J: Declining serum concentrations of the beta-subunit of human chorionic gonadotropin and ruptured ectopic pregnancy. Am J Obstet Gynecol 1987;156:940-941 13. Lonsky NM, Sauer MV: Ectopic pregnancy with shock and undetectable beta-human chorionic gonadotropin: A case report. J Reprod Med 1987;32(2):559-560 12. DiMarchi JM, Kosasa TS, Kobara TY, et al: Persistent ectopic pregnancy. Obstet Gynecol 1987;70:555-556