Ectopic Pregnancy

Mary E. Rausch, Andrew M. Kaunitz, and Kurt Barnhart

The term “ectopic pregnancy” (EP) refers to any pregnancy resulting from the implantation of a fertilized ovum outside of the uterine cavity, most commonly in the fallopian tube.

Pregnancy-related deaths associated with an EP are on the decline, likely because of earlier detection and treatment (3). One half of deaths could have been prevented by more prompt diagnosis and treatment of EP by health profes­sionals, and one third of deaths could have been prevented by more prompt noti­fication of a physician by the patient (4). Although the average age of women with an EP is 28 years, the mortality rate is highest for teenagers (4). Misdiagnosis of a gastrointestinal disorder, intrauterine pregnancy (IUP), or pelvic inflammatory disease (PID) is common in this setting.

ETIOLOGY

Of the 96% of EPs found in the fallopian tube, 70% are ampullary, 12% isthmic, 11% fimbrial, and 2% interstitial, with extratubal sites being rare (5) (Fig. 3.1). The tube serves a complex function in the process of fertilization and transport of the oocyte from the ovary to the uterus, where the blastocyst implants. At ovulation, the fim­briated end of the fallopian tube picks up the expelled oocyte with its cumulus mass of follicular cells. Conduction of the egg toward the uterus is thought to be effected primarily by the negative tubal intraluminal pressure generated by muscu­lar contractions, with a secondary contribution from ciliary beating.

Although any form of contraception decreases the overall risk of pregnancy including EP, when contraceptive failure occurs in women using an intrauterine device (IUD) or following tubal sterilization, the risk of EP is elevated (7,9). With the copper T, approximately 6% of failures represent ectopic implantations (10). With the levonorgestrel IUD, this percentage is approximately 50 (11). Other fac­tors in the history which may be associated with risk of EP include a history of salpingitis, tubal infertility, and DES exposure (6,7).

Among patients presenting to the emergency room with an early symptom­atic pregnancy, the incidence of EP was lower for adolescents than adults (9.7% versus 21.7%) (12) and younger women (of the gestation, the site of implantation, and the existence of rupture and a hemoperitoneum. A his­tory of amenorrhea or abnormal vaginal bleeding may be difficult to elicit in some patients. It is imperative that the timing and character of the last two or three menstrual periods be investigated through direct questioning. Finally, attention must be paid to the obstetric and gynecologic history, particularly with regard to known risk factors for EP.

Physical Examination

The physical examination of the patient with an EP varies, depending on the ges­tational age and the presence of rupture with a resulting hemoperitoneum. The physical exam should include vital signs, with attention to orthostatic changes in pulse and blood pressure, as well as abdominal and pelvic examinations.

On abdominal exam, tenderness is the most common physical finding. The tenderness is classically unilateral and in the lower quadrant, but it can be bilat­eral. Rebound tenderness, guarding, and rigidity are not usually present except in cases with significant hemoperitoneum. Peritoneal signs are not commonly found in patients with EP but, when present, are predictive of EP (7,16).

A speculum exam of the vagina should be performed, looking closely at the source of any bleeding, the amount of blood present, and the presence of tissue at the cervical os. A bimanual pelvic exam will allow estimation of uterine size, determination of cervical dilation, and evaluation of the presence and tender­ness of adnexal masses. A pelvic mass is found in the minority of patients with EP and is not predictive of EP—in fact, most of the patients with a palpable mass have an IUP, with the mass likely representing a corpus luteum cyst (7). Given the potential risk for tubal rupture and subsequent hemoperitoneum with a digital vaginal exam, some authors have suggested that the limited additional diagnos­tic information obtained may not warrant the hazards of performing the exam in patients with suspected EPs, especially in light of the diagnostic capability of ultrasound and serum hCG levels (17).

A minority of EPs result from implantation in the interstitial portion of the oviduct or in the uterine cornu. These cases characteristically present at a more advanced gestational age. On examination, the uterus is enlarged to a degree consistent with an uncomplicated IUP, and fetal heart motion may be detected.

Pregnancy Tests

Given that the differential diagnosis for abnormal vaginal bleeding with or with­out pain in a woman of reproductive age is dependent on knowing her pregnancy status, a screening urine pregnancy test should be done as part of the initial evaluation. This will facilitate more timely diagnosis and minimize the risk of misdiagnosis. Using currently available urine pregnancy tests, 54% of tests are positive 11 days from the LH surge, and 98% are positive 14 days from the LH surge (18). However, these data are from normal pregnancies and may vary for abnormal pregnancies. Some women with EPs will have hCG titers below that detectable by even the sensitive urine screening tests. To exclude this remote possibility, a serum hCG should be obtained in a woman with a presentation consistent with EP despite a negative urine pregnancy test.

Ultrasonography

Once a symptomatic patient is known to be pregnant, vaginal ultrasound plays a key role in differentiating first trimester pregnancy pathology. Hardware for per­forming vaginal ultrasound is becoming more accessible in emergency depart­ments and physician’s offices, and the finding of an IUP on ultrasound virtually eliminates the possibility of an EP as heterotopic pregnancies are rare. Caution should be exercised in patients whose pregnancies are the result of ART, how­ever, as the rate of heterotopics in these patients may be as high as 1% (19), although more recent data estimate the heterotopic pregnancy rate in the United States to be 0.15% for patients undergoing ART (20).

Accurate gestational age is the best determinant of when an IUP should be seen within the uterus, and a gestational sac or sacs should be visible by approx­imately 5 weeks on transvaginal ultrasound (21). In the absence of proper gesta­tional dating, a discriminatory zone, or level above which a normal IUP should be visible, can guide management.

Although an IUP should be identified when the hCG level is above the dis­criminatory zone, ultrasound may provide useful information in symptomatic women whose hCG levels are below this level. In two studies of women ultimately found to have EPs, 39% with hCG < 1,000 mIU/mL (24) and 42% with hCG 5 mm indicates an embryonic demise (21).

After evaluating the uterine cavity, the clinician should examine the adn­exa bilaterally, evaluating for the presence of masses. Any suspicious masses should be measured for use in determining management pathways. A corpus luteum may be confused with an ovarian pregnancy. Ultrasound is diagnostic for EP if a gestational sac, possibly with a yolk sac or fetal pole, can be identified and localized outside the uterus. Other findings on transvaginal ultrasound can also be predictive of EP. These include a thick-walled cyst or complex mass separate from the ovary and/or a large amount of free fluid in the posterior cul-de-sac.

Both the cul-de-sac of Douglas and the abdominal cavity should be evalu­ated by ultrasound to assess for masses and free fluid. Although the presence of blood in the cul-de-sac in the appropriate clinical setting suggests EP, hemoperi­toneum may also be encountered in women with a ruptured corpus luteum, spleen/liver, or hepatic adenoma.

Special ultrasound studies have been researched in patients at increased risk for EP. The thickness of the endometrial stripe on transvaginal imaging is one example. A stripe of >8mm has been associated with the increased likeli­hood of an intrauterine IUP, while a stripe of 12%; (ii) negative—clear (serous) cul-de-sac fluid or blood-tinged fluid with a hematocrit of 2,000 mIU∕mL and no evidence of an intrauterine gestation on ultrasound, 54% will ultimately have a failed IUP (mis­carriage) (34). In the situation where serial hCG assessment has detected an abnormal pattern (below 2,000 mIU∕mL), 31% will actually have a miscarriage and not an EP (34). Presumptive treatment with medical management would therefore incorrectly treat a large number of patients if a definitive diagnosis is not made (34). Although dilation and curettage may yield a more accurate diagnosis, one must weigh the risks of a surgical procedure (rare, but potentially serious) against the risks of incorrectly treating some women with nonviable IUPs with methotrexate (MTX) (whose side effects are more common, but typically mild and resolve quickly). A cost-effectiveness study of presumptive MTX treat­ment versus dilation and curettage prior to MTX found no difference in side effects or treatment success, with a minimal cost difference of $200 between the two strategies (35). Clinicians, however, should keep in mind that a definitive diagnosis is necessary to provide a prognosis regarding a woman’s future repro­ductive potential and the need for a workup of recurrent miscarriage or tubal factor infertility.

In patients with an uncertain diagnosis, curettage can be performed in an ambulatory setting under local anesthesia. In many institutions, however, this may only be accomplished in an operating room with anesthesia, and not in the office or emergency room. Although it may be preferable in terms of cost and con­venience to detect the presence of chorionic villi with an endometrial biopsy, multiple studies have shown the 3-mm plastic piston-type endometrial biopsy devices (e.g., Pipelle) to be inferior to curettage for this purpose, with sensitivities of 30% to 63% (36,37), and as low as 13.3% for frozen endometrial biopsies (38).

Since the pathology results of the curettage are typically not available until at least the following day, frozen section has been proposed as a way to gain more rapid information to guide management. The sensitivity of frozen section is reported as 62% to 88% with a specificity of 98% to 100% (37,39-41). Although frozen section can guide initial management, given that false-negative results can occur on frozen section, following hCG levels for dropping levels the next morning and final pathology can help ensure the correct diagnosis is made.

Serum Markers

Serum progesterone levels have been proposed to help distinguish normal from abnormal pregnancies. Proposed algorithms use a progesterone level over the cutoff of 25ng∕mL to exclude EP, a number of other serum markers reported in the literature (interleukin-6, interleukin-8, vascular endothelial growth factor, tumor necrosis factor-a, activin A, creatine kinase, and cancer antigen-125, among others). However, at present, the results are not conclusive and none can be recom­mended for clinical use without further study.

Management

The presentation of patients with EP ranges from minimal symptoms to irreversible shock preceding death. If the patient appears to have a surgical abdomen, a complete blood count and blood type and cross-match should be obtained, and intravenous access should be ensured with two large-bore cannulas. If needed, fluid resuscitation should be commenced, followed by appropriate blood-component therapy. Although hemodynamic stability is desirable before subjecting a patient to surgical anesthesia, it must be remembered that often the surgical intervention itself will be required to achieve stability through control of active hemorrhage. Transfer to another facility is appropriate in the clinically stable patient if it will facilitate performance of diagnostic studies not available in the referring ambulatory setting. It may also be necessary for patients with a ruptured EP and∕or hemoperitoneum if immediate surgery cannot be performed at the referring site. In this case, the most expeditious mode of transportation is indicated, with appropri­ate intravenous infusions, advanced cardiac life support, and even consideration of the use of military antishock trousers. For the patient presenting in shock, an emer­gency consultation should be obtained from any readily available physician with the surgical expertise to perform a laparotomy.

More frequently, however, the patient suspected of having an EP will be hemodynamically stable. The earlier the diagnosis of EP is made, the more likely it is that fallopian tube conserving measures can be employed. This is of particular importance for the younger patient. Regardless of the treatment for EP, Rh immunoglobulin (Rhogam) should be given to all unsensitized Rh-negative women (44).

Surgical Management

Surgical management is required in patients with an EP who are hemodynamically unstable as well as those that fail medical therapy. Primary surgical therapy is also indicated for patients without tubal rupture who decline or are poor candidates for medical therapy. (See “Medical Management” below.)

The surgical options for a tubal pregnancy include salpingostomy and salpingectomy. Salpingostomy preserves the tube but bears the risk for persis­tent trophoblast and repeat ipsilateral EP. Salpingectomy avoids this risk but leaves a reproductive-age woman with one less potentially functional tube. Pooled data from nonrandomized studies have reported comparable preg­nancy rates after either salpingectomy or salpingostomy, but with an increased 15% subsequent ectopic rate following salpingostomy compared with 10% subsequent to salpingectomy (45,46). More recent studies have suggested improved fertility rates with conservative surgery (47-49), though definitive studies are lacking. Concern has also been raised about ovarian function fol­lowing salpingectomy for EP. In a comparison of the ovaries in the same patient postsalpingectomy, the operated side had lower antral follicle counts and 3D power Doppler indices than the nonsurgical side (50). In a study directly com­paring postsalpingectomy versus postsalpingostomy patients undergoing IVF, fewer follicles developed and fewer oocytes were retrieved from the operated side in women who had undergone salpingectomy, but this had no effect on the overall number of follicles, oocytes, cycle characteristics, or pregnancy rates when these cycles were compared with those from postsalpingostomy patients (51). Of note, similar concerns about ovarian function have also been raised following MTX therapy, although decreased oocyte production with ovarian stimulation appears to be temporary (52). Overall, definitive data regarding long-term fertility outcomes comparing the various treatments are lacking.

As laparoscopic techniques and experience continue to improve, even EPs with a large degree of hemoperitoneum may be treated without laparotomy in some settings. Two recent meta-analyses examined the differences between laparoscopic and open salpingostomies. They found that laparoscopic salpingostomy is superior to laparotomy in terms of decreased cost, shorter operating time, shorter hospital stay, less blood loss, and shorter convalescence time (53,54). In stable patients with small, unruptured EPs, the open approach was more successful in eliminating the pregnancy, with a higher persistent trophoblast rate in the laparoscopic group (53,54), although it is of note that these pooled studies were from the 1980s and 1990s, when laparoscopy was a newer technique. Long-term follow-up of treated patients demonstrates no evidence of difference in subsequent IUPs, but a nonsig­nificant trend toward lower repeat EP in the laparoscopy versus the laparotomy groups (53,54). The addition of a single prophylactic dose of MTX within 24 hours of salpingostomy significantly decreases the risk of persistent trophoblast (53,54) and can be considered for patients undergoing conservative surgery.

Medical Management

MTX, a folic acid antagonist originally used as a chemotherapeutic agent, inhibits dihydrofolic acid reductase. MTX affects proliferating cells by interfering with DNA synthesis and repair and with cellular replication. All replicating cells are affected, including intestinal and buccal mucosa, respiratory epithelium, bone marrow, bladder, and fetal cells. Patients considered for this medical management must be hemodynamically stable, be reliable and able to comply with follow-up, and have no medical contraindications to the use of MTX (see Table 3.4). Given its toxicity to rapidly dividing tissues, it should not be given to women with blood dyscrasias, active gastrointestinal (peptic ulcer) disease, or respiratory disease. As it is renally excreted and may have a toxic effect on hepatocytes, renal and liver diseases (includ­ing alcoholism and alcoholic liver disease) are also contraindications. For these rea­sons, normal serum creatinine, liver transaminases, and complete blood count to check for leukopenia, thrombocytopenia, and anemia should be checked prior to administration, and these are rechecked 1 week after administration prior to further doses to ensure that the results of these tests remain normal. Other absolute con­traindications include IUP, breastfeeding, and known sensitivity to MTX (23,55).

Success with MTX depends on both the baseline characteristics of the patient’s pregnancy as well as the protocol utilized. Studies have reported increased failure with elevated hCG levels as well as fetal cardiac activity (56-58). A systematic review demonstrated a 3.7% failure rate with hCG levels 5,000 mIU/mL when a single-dose MTX regimen was used (59). Relative contraindications endorsed by both the American College of Obstetricians and Gynecologists (ACOG) as well as the American Society for Reproductive Medicine (ASRM) include embryonic cardiac motion and an ectopic mass size cutoff of 3.5 cm (ACOG) or 4 cm (ASRM) (23,55). ASRM also includes high initial hCG concentration (>5,000 mIU/mL) and refusal to accept blood transfusion as relative contraindications to MTX use (23).

MTX can be administered as a single-dose, a two-dose, or a multidose regimen. These regimens are outlined below according to the ACOG guidelines (55). Prior to administration, a normal complete blood count, liver, and renal tests should be documented as detailed above. Screening for blood type and Rh status should also be completed to assess the need for rhogam.

Single-dose regimen: MTX (50mg∕m²) is administered intramuscularly on day 1. hCG levels are checked on post treatment days 4 and 7, with an expected 15% drop. If the drop is as expected, hCG levels are measured

Medical Contraindications to MTX Use

Hemodynamically unstable patient

Alcoholism

Liver disease

Immunodeficiency

Blood dyscrasias

Breastfeeding

Unreliable patient

Peptic ulcer disease

Renal dysfunction

Hematologic dysfunction

Active pulmonary disease weekly until they are negative, and an additional dose of MTX (50 mg/m²) may be considered for a plateau or increase in hCG during this time. If the drop is rupture occurs. In stable patients, medical management with MTX offers a successful nonoperative treatment strategy for a substantial portion of women presenting with an EP.

References

1. Zane SB, Kieke BA Jr, Kendrick JS, Bruce C. Surveillance in a time of changing health care practices: estimating ectopic pregnancy incidence in the United States. Matern Child Health J. 2002 Dec;6(4):227-236.

2. Goldner TE, Lawson HW, Xia Z, Atrash HK. Surveillance for ectopic pregnancy— United States, 1970-1989. MMWR CDC SurveillSumm. 1993 Dec;42(6):73-85.

3. Berg CJ, Chang J, Callaghan WM, Whitehead SJ. Pregnancy-related mortality in the United States, 1991-1997. Obstet Gynecol. 2003 Feb;101(2):289-296.

4. Dorfman SF, Grimes DA, Cates W Jr, Binkin NJ, Kafrissen ME, O’Reilly KR. Ectopic pregnancy mortality, United States, 1979 to 1980: clinical aspects. Obstet Gynecol. 1984 Sep;64(3):386-390.

5. Bouyer J, Coste J, Fernandez H, Pouly JL,Job-Spira N. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod. 2002 Dec;17(12):3224-3230.

6. Ankum WM, Mol BW, Van der Veen F, Bossuyt PM. Risk factors for ectopic preg­nancy: a meta-analysis. Fertil Steril. 1996 Jun;65(6):1093-1099.

7. Dart RG, Kaplan B, Varaklis K. Predictive value of history and physical examination in patients with suspected ectopic pregnancy. Ann Emerg Med. 1999 Mar;33(3):283-290.

8. Barnhart KT, Sammel MD, Gracia CR, Chittams J, Hummel AC, Shaunik A. Risk fac­tors for ectopic pregnancy in women with symptomatic first-trimester pregnancies. Fertil Steril. 2006 Jul;86(1):36-43.

9. Mol BW, Ankum WM, Bossuyt PM, Van der Veen F. Contraception and the risk of ectopic pregnancy: a meta-analysis. Contraception. 1995 Dec;52(6):337-341.

10. Mishell DR Jr. Intrauterine devices: mechanisms of action, safety, and efficacy. Contraception. 1998 Sep;58(3 Suppl.):45S-53S; quiz 70S.

11. Backman T, Rauramo I, Huhtala S, Koskenvuo M. Pregnancy during the use of levonorgestrel intrauterine system. Am JObstet Gynecol. 2004Jan;190(1):50-54.

12. Menon S, Sammel MD, Vichnin M, Barnhart KT. Risk factors for ectopic pregnancy: a comparison between adults and adolescent women. J Pediatr Adolesc Gynecol. 2007 Jun;20(3):181-185.

13. Assisted reproductive technology in the United States: 2001 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology registry. Fertil Steril. 2007 Jun;87(6):1253-1266.

14. Peterson HB, Xia Z, Hughes JM, Wilcox LS, Tylor LR, Trussell J. The risk of ectopic pregnancy after tubal sterilization. U.S. Collaborative Review of Sterilization Working Group. NEngl JMed. 1997 Mar;336(11):762-767.

15. Hallatt JG, Steele CH Jr, Snyder M. Ruptured corpus luteum with hemoperitoneum: a study of 173 surgical cases. Am J Obstet Gynecol. 1984 May;149(1):5-9.

16. Buckley RG, King KJ, Disney JD, Gorman JD, Klausen JH. History and physical exam­ination to estimate the risk of ectopic pregnancy: validation of a clinical prediction model. Ann Emerg Med. 1999 Nov;34(5):589-594.

17. Mol BW, Hajenius PJ, Engelsbel S, et al. Should patients who are suspected of having an ectopic pregnancy undergo physical examination? Fertil Steril. 1999 Jan;71(1):155-157.

18. Johnson SR, Miro F, Barrett S, Ellis JE. Levels of urinary human chorionic gonadotro­phin (hCG) following conception and variability of menstrual cycle length in a cohort of women attempting to conceive. Curr Med Res Opin. 2009 Mar;25(3):741-748.

19. Svare J, Norup P, Grove Thomsen S, et al. Heterotopic pregnancies after in-vitro fertil­ization and embryo transfer—a Danish survey. Hum Reprod. 1993 Jan;8(1):116-118.

20. Clayton HB, Schieve LA, Peterson HB, Jamieson DJ, Reynolds MA, Wright VC. Ectopic pregnancy risk with assisted reproductive technology procedures. Obstet Gynecol. 2006 Mar;107(3):595-604.

21. Albayram F, Hamper UM. First-trimester obstetric emergencies: spectrum of sonographic findings. J Clin Ultrasound. 2002 Mar-Apr;30(3):161-177.

22. Cacciatore B, Stenman UH, Ylostalo P. Comparison of abdominal and vaginal sonography in suspected ectopic pregnancy. Obstet Gynecol. 1989 May;73(5, pt 1): 770-774.

23. Medical treatment of ectopic pregnancy. Fertil Steril. 2008 Nov;90(5 Suppl.): S206-S212.

24. Dart RG, Kaplan B, Cox C. Transvaginal ultrasound in patients with low beta-human chorionic gonadotropin values: how often is the study diagnostic? Ann Emerg Med. 1997 Aug;30(2):135-140.

25. Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol. 1999 Oct;94(4):583-587.

26. Spandorfer SD, Barnhart KT. Endometrial stripe thickness as a predictor of ectopic pregnancy. Fertil Steril. 1996 Sep;66(3):474-477.

27. Taylor KJ, Ramos IM, Feyock AL, et al. Ectopic pregnancy: duplex Doppler evalua­tion. Radiology. 1989 Oct;173(1):93-97.

28. Kirchler HC, Seebacher S, Alge AA, Muller-Holzner E, Fessler S, Kolle D. Early diag­nosis of tubal pregnancy: changes in tubal blood flow evaluated by endovaginal color Doppler sonography. Obstet Gynecol. 1993 Oct;82(4, pt 1):561-565.

29. Dillon EH, Feyock AL, Taylor KJ. Pseudogestational sacs: Doppler US differentiation from normal or abnormal intrauterine pregnancies. Radiology. 1990 Aug;176(2): 359-364.

30. Barnhart KT, Sammel MD, Rinaudo PF, Zhou L, Hummel AC, Guo W. Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined. Obstet Gynecol. 2004 Jul;104(1):50-55.

31. Barnhart K, Sammel MD, Chung K, Zhou L, Hummel AC, Guo W. Decline of serum human chorionic gonadotropin and spontaneous complete abortion: defining the normal curve. Obstet Gynecol. 2004 Nov;104(5, pt 1):975-981.

32. Chung K, Sammel M, Zhou L, Hummel A, Guo W, Barnhart K. Defining the curve when initial levels of human chorionic gonadotropin in patients with spontaneous abortions are low. Fertil Steril. 2006 Feb;85(2):508-510.

33. Silva C, Sammel MD, Zhou L, Gracia C, Hummel AC, Barnhart K. Human chorionic gonadotropin profile for women with ectopic pregnancy. Obstet Gynecol. 2006 Mar;107(3):605-610.

34. Barnhart KT, Katz I, Hummel A, Gracia CR. Presumed diagnosis of ectopic preg­nancy. Obstet Gynecol. 2002 Sep;100(3):505-510.

35. Ailawadi M, Lorch SA, Barnhart KT. Cost-effectiveness of presumptively medically treating women at risk for ectopic pregnancy compared with first performing a dila­tation and curettage. Fertil Steril. 2005 Feb;83(2):376-382.

36. Ries A, Singson P, Bidus M, Barnes JG. Use of the endometrial pipelle in the diagnosis of early abnormal gestations. Fertil Steril. 2000 Sep;74(3):593-595.

37. Barnhart KT, Gracia CR, Reindl B, Wheeler JE. Usefulness of pipelle endometrial biopsy in the diagnosis of women at risk for ectopic pregnancy. Am J Obstet Gynecol. 2003 Apr;188(4):906-909.

38. Al-Ramahi M, Nimri C, Bata M, Saleh S. The value of frozen section Pipelle endometrial biopsy as an outpatient procedure in the diagnosis of ectopic pregnancy. J Obstet Gynecol. 2006 Jan;26(1):63-65.

39. Spandorfer SD, Menzin AW, Barnhart KT, LiVolsi VA, Pfeifer SM. Efficacy of frozen- section evaluation of uterine curettings in the diagnosis of ectopic pregnancy. Am J Obstet Gynecol. 1996 Sep;175(3, pt 1):603-605.

40. Heller DS, Hessami S, Cracchiolo B, Skurnick JH. Reliability of frozen section of uterine curettings in evaluation of possible ectopic pregnancy. J Am Assoc Gynecol Laparosc. 2000 Nov;7(4):519-522.

41. Barak S, Oettinger M, Perri A, Cohen HI, Barenboym R, Ophir E. Frozen section examination of endometrial curettings in the diagnosis of ectopic pregnancy. Acta Obstet Gynecol Scand. 2005 Jan;84(1):43-47.

42. Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med. 1993 Oct;329(16):1174-1181.

43. Mol BW, Lijmer JG, Ankum WM, Van der Veen F, Bossuyt PM. The accuracy of single serum progesterone measurement in the diagnosis of ectopic pregnancy: a meta-analysis. Hum Reprod. 1998 Nov;13(11):3220-3227.

44. Jabara S, Barnhart KT. Is Rh immune globulin needed in early first-trimester abortion? A review. Am J Obstet Gynecol. 2003 Mar;188(3):623-627.

45. Yao M, Tulandi T. Current status of surgical and nonsurgical management of ectopic pregnancy. Fertil Steril. 1997 Mar;67(3):421-433.

46. Clausen I. Conservative versus radical surgery for tubal pregnancy. A review. Acta Obstet Gynecol Scand. 1996 Jan;75(1):8-12.

47. Mol BW, Matthijsse HC, Tinga DJ, et al. Fertility after conservative and radical surgery for tubal pregnancy. Hum Reprod. 1998 Jul;13(7):1804-1809.

48. Bouyer J, Job-Spira N, Pouly JL, Coste J, Germain E, Fernandez H. Fertility following radical, conservative-surgical or medical treatment for tubal pregnancy: a popula­tion-based study. BJOG. 2000 Jun;107(6):714-721.

49. Bangsgaard N, Lund CO, Ottesen B, Nilas L. Improved fertility following conserva­tive surgical treatment of ectopic pregnancy. BJOG. 2003 Aug;110(8):765-770.

50. Chan CC, Ng EH, Li CF, et al. Impaired ovarian blood flow and reduced antral follicle count following laparoscopic salpingectomy for ectopic pregnancy. Hum Reprod. 2003 Oct;18(10):2175-2180.

51. Lass A, Ellenbogen A, Croucher C, et al. Effect of salpingectomy on ovarian response to superovulation in an in vitro fertilization-embryo transfer program. Fertil Steril. 1998 Dec;70(6):1035-1038.

52. McLaren JF, Burney RO, Milki AA, Westphal LM, Dahan MH, Lathi RB. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil Steril. 2009 Aug;92(2):512-519.

53. Mol F, Mol BW, Ankum WM, Van der Veen F, Hajenius PJ. Current evidence on sur­gery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod Update. 2008 Jul-Aug;14(4):309-319.

54. Hajenius PJ, Mol F, Mol BW, Bossuyt PM, Ankum WM, Van der Veen F. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev. 2007(1):CD000324.

55. ACOG Practice Bulletin No. 94: Medical management of ectopic pregnancy. Obstet Gynecol. 2008 Jun;111(6):1479-1485.

56. Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstet Gynecol. 2003 Apr;101(4):778-784.

57. Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med. 1999 Dec;341(26):1974-1978.

58. Elito J Jr, Reichmann AP, Uchiyama MN, Camano L. Predictive score for the systemic treatment of unruptured ectopic pregnancy with a single dose of methotrexate. Int J Gynaecol Obstet. 1999 Nov;67(2):75-79.

59. Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cut­off to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertil Steril. 2007 Mar;87(3):481-484.

60. Alleyassin A, Khademi A, Aghahosseini M, Safdarian L, Badenoosh B, Hamed EA. Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial. Fertil Steril. 2006 Jun;85(6):1661-1666.

61. Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of “2-dose” regimen of methotrexate to treat ectopic pregnancy. Fertil Steril. 2007 Feb;87(2): 250-256.

62. Saraj AJ, Wilcox JG, Najmabadi S, Stein SM, Johnson MB, Paulson RJ. Resolution of hormonal markers of ectopic gestation: a randomized trial comparing single-dose intramuscular methotrexate with salpingostomy. Obstet Gynecol. 1998 Dec;92(6): 989-994.

63. Hajenius PJ, Engelsbel S, Mol BW, et al. Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubal pregnancy. Lancet. 1997 Sep;350(9080): 774-779.

64. Tulandi T, Al-Jaroudi D. Interstitial pregnancy: results generated from the Society of Reproductive Surgeons Registry. Obstet Gynecol. 2004 Jan;103(1):47-50.

65. Kung FT, Chang SY. Efficacy of methotrexate treatment in viable and nonviable cer­vical pregnancies. Am J Obstet Gynecol. 1999 Dec;181(6):1438-1444.

66. Lund J. Early ectopic pregnancy; comments on conservative treatment. J Obstet Gynaecol Br Emp. 1955 Feb;62(1):70-76.

67. Carp HJ, Oelsner G, Serr DM, Mashiach S. Fertility after nonsurgical treatment of ectopic pregnancy. J ReprodMed. 1986 Feb;31(2):119-122.

68. Makinen JI, Kivijarvi AK, Irjala KM. Success of non-surgical management of ectopic pregnancy. Lancet. 1990 May;335(8697):1099.

69. Ylostalo P, Cacciatore B, Sjoberg J, Kaariainen M, Tenhunen A, Stenman UH. Expect­ant management of ectopic pregnancy. Obstet Gynecol. 1992 Sep;80(3, pt 1):345-348.

70. Trio D, Strobelt N, Picciolo C, Lapinski RH, Ghidini A. Prognostic factors for successful expectant management of ectopic pregnancy. Fertil Steril. 1995 Mar;63(3): 469-472.

71. Tulandi T, Hemmings R, Khalifa F. Rupture of ectopic pregnancy in women with low and declining serum beta-human chorionic gonadotropin concentrations. Fertil Steril. 1991 Oct;56(4):786-787.