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Ectopic pregnancy: Choosing a treatment and methotrexate therapy

Togas Tulandi, MD, MHCM
Section Editor
Robert L Barbieri, MD
Deputy Editor
Sandy J Falk, MD, FACOG


An ectopic pregnancy is a pregnancy outside of the uterine cavity. Almost all ectopic pregnancies occur in the fallopian tube (98 percent) [1], but other possible sites include cervical, interstitial (also referred to as cornual; a pregnancy located in the proximal segment of the fallopian tube that is embedded within the muscular wall of the uterus), hysterotomy scar, intramural, ovarian, or abdominal. In addition, in rare cases, a multiple gestation may be heterotopic (include both a uterine and extrauterine pregnancy).

Ectopic pregnancy is a potentially life-threatening condition. While surgical approaches are the mainstay of treatment, advances in early diagnosis facilitated the introduction of medical therapy with methotrexate (MTX) in the 1980s [2]. Due to the routine use of early ultrasound among infertile patients who conceive, diagnosis of ectopic pregnancy can be established early and medical treatment can be administered in many cases. The overall success rate of medical treatment in properly selected women is nearly 90 percent [3-5].

Medical treatment of ectopic pregnancy will be reviewed here. The surgical treatment of ectopic pregnancy is reviewed elsewhere (see "Ectopic pregnancy: Surgical treatment"). Related topics regarding ectopic pregnancy are discussed in detail separately, including:

Epidemiology, risk factors, and pathology (see "Ectopic pregnancy: Incidence, risk factors, and pathology")

Clinical manifestations and diagnosis (see "Ectopic pregnancy: Clinical manifestations and diagnosis")


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Literature review current through: Jul 2017. | This topic last updated: Apr 10, 2017.
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  1. Bouyer J, Coste J, Fernandez H, et al. Sites of ectopic pregnancy: a 10 year population-based study of 1800 cases. Hum Reprod 2002; 17:3224.
  2. Lipscomb GH. Medical therapy for ectopic pregnancy. Semin Reprod Med 2007; 25:93.
  3. 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; 101:778.
  4. Farquhar CM. Ectopic pregnancy. Lancet 2005; 366:583.
  5. Morlock RJ, Lafata JE, Eisenstein D. Cost-effectiveness of single-dose methotrexate compared with laparoscopic treatment of ectopic pregnancy. Obstet Gynecol 2000; 95:407.
  6. Van Den Eeden SK, Shan J, Bruce C, Glasser M. Ectopic pregnancy rate and treatment utilization in a large managed care organization. Obstet Gynecol 2005; 105:1052.
  7. Practice Committee of the American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy. Fertil Steril 2006; 86:S96.
  8. Medical management of ectopic pregnancy. ACOG Practice Bulletin #94. American College of Obstetricians and Gynecologists, 2008.
  9. Kelly H, Harvey D, Moll S. A cautionary tale: fatal outcome of methotrexate therapy given for management of ectopic pregnancy. Obstet Gynecol 2006; 107:439.
  10. Teal SB. A cautionary tale: fatal outcome of methotrexate therapy given for management of ectopic pregnancy. Obstet Gynecol 2006; 107:1420.
  11. Willner N, Storch S, Tadmor T, Schiff E. Almost a tragedy: severe methotrexate toxicity in a hemodialysis patient treated for ectopic pregnancy. Eur J Clin Pharmacol 2014; 70:261.
  12. 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; 87:481.
  13. Lipscomb GH, McCord ML, Stovall TG, et al. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. N Engl J Med 1999; 341:1974.
  14. Lipscomb GH, Bran D, McCord ML, et al. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. Am J Obstet Gynecol 1998; 178:1354.
  15. Shalev E, Peleg D, Bustan M, et al. Limited role for intratubal methotrexate treatment of ectopic pregnancy. Fertil Steril 1995; 63:20.
  16. Nazac A, Gervaise A, Bouyer J, et al. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies. Ultrasound Obstet Gynecol 2003; 21:181.
  17. Tzafettas JM, Stephanatos A, Loufopoulos A, et al. Single high dose of local methotrexate for the management of relatively advanced ectopic pregnancies. Fertil Steril 1999; 71:1010.
  18. Gamzu R, Almog B, Levin Y, et al. The ultrasonographic appearance of tubal pregnancy in patients treated with methotrexate. Hum Reprod 2002; 17:2585.
  19. Romero R, Copel JA, Kadar N, et al. Value of culdocentesis in the diagnosis of ectopic pregnancy. Obstet Gynecol 1985; 65:519.
  20. Vermesh M, Graczykowski JW, Sauer MV. Reevaluation of the role of culdocentesis in the management of ectopic pregnancy. Am J Obstet Gynecol 1990; 162:411.
  21. Cartwright PS, Vaughn B, Tuttle D. Culdocentesis and ectopic pregnancy. J Reprod Med 1984; 29:88.
  22. Lipscomb GH, Puckett KJ, Bran D, Ling FW. Management of separation pain after single-dose methotrexate therapy for ectopic pregnancy. Obstet Gynecol 1999; 93:590.
  23. Bixby S, Tello R, Kuligowska E. Presence of a yolk sac on transvaginal sonography is the most reliable predictor of single-dose methotrexate treatment failure in ectopic pregnancy. J Ultrasound Med 2005; 24:591.
  24. Potter MB, Lepine LA, Jamieson DJ. Predictors of success with methotrexate treatment of tubal ectopic pregnancy at Grady Memorial Hospital. Am J Obstet Gynecol 2003; 188:1192.
  25. Dudley PS, Heard MJ, Sangi-Haghpeykar H, et al. Characterizing ectopic pregnancies that rupture despite treatment with methotrexate. Fertil Steril 2004; 82:1374.
  26. Takacs P, Rodriguez L. High folic acid levels and failure of single-dose methotrexate treatment in ectopic pregnancy. Int J Gynaecol Obstet 2005; 89:301.
  27. da Costa Soares R, Elito J Jr, Camano L. Increment in beta-hCG in the 48-h period prior to treatment: a new variable predictive of therapeutic success in the treatment of ectopic pregnancy with methotrexate. Arch Gynecol Obstet 2008; 278:319.
  28. Hajenius PJ, Mol F, Mol BW, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2007; :CD000324.
  29. Mol F, Mol BW, Ankum WM, et al. 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; 14:309.
  30. Mol F, Strandell A, Jurkovic D, et al. The ESEP study: salpingostomy versus salpingectomy for tubal ectopic pregnancy; the impact on future fertility: a randomised controlled trial. BMC Womens Health 2008; 8:11.
  31. Wiser A, Gilbert A, Nahum R, et al. Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy in the subsequent IVF cycle. Reprod Biomed Online 2013; 26:449.
  32. Nieuwkerk PT, Hajenius PJ, Ankum WM, et al. Systemic methotrexate therapy versus laparoscopic salpingostomy in patients with tubal pregnancy. Part I. Impact on patients' health-related quality of life. Fertil Steril 1998; 70:511.
  33. Oriol B, Barrio A, Pacheco A, et al. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril 2008; 90:1579.
  34. Gervaise A, Masson L, de Tayrac R, et al. Reproductive outcome after methotrexate treatment of tubal pregnancies. Fertil Steril 2004; 82:304.
  35. Juan YC, Wang PH, Chen CH, et al. Successful treatment of ovarian pregnancy with laparoscopy-assisted local injection of etoposide. Fertil Steril 2008; 90:1200.e1.
  36. Chen CH, Wang PH, Liu WM. Successful treatment of cesarean scar pregnancy using laparoscopically assisted local injection of etoposide with transvaginal ultrasound guidance. Fertil Steril 2009; 92:1747.e9.
  37. Fujioka S, Yamashita Y, Kawabe S, et al. A case of a methotrexate-resistant ectopic pregnancy in which dactinomycin was effective as a second-line chemotherapy. Fertil Steril 2009; 91:929.e13.
  38. Fishman DA, Padilla LA, Joob A, Lurain JR. Ectopic pregnancy causing hemothorax managed by thoracoscopy and actinomycin D. Obstet Gynecol 1998; 91:837.
  39. Bleyer WA. The clinical pharmacology of methotrexate: new applications of an old drug. Cancer 1978; 41:36.
  40. Hajenius PJ, Mol BW, Bossuyt PM, et al. Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev 2000; :CD000324.
  41. Nilsson UW, Johns TG, Wilmann T, et al. Effects of gefitinib, an epidermal growth factor receptor inhibitor, on human placental cell growth. Obstet Gynecol 2013; 122:737.
  42. Skubisz MM, Horne AW, Johns TG, et al. Combination gefitinib and methotrexate compared with methotrexate alone to treat ectopic pregnancy. Obstet Gynecol 2013; 122:745.
  43. Doubilet PM, Benson CB, Bourne T, et al. Diagnostic criteria for nonviable pregnancy early in the first trimester. N Engl J Med 2013; 369:1443.
  44. Lipscomb GH, Givens VM, Meyer NL, Bran D. Comparison of multidose and single-dose methotrexate protocols for the treatment of ectopic pregnancy. Am J Obstet Gynecol 2005; 192:1844.
  45. Alleyassin A, Khademi A, Aghahosseini M, et al. 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; 85:1661.
  46. Klauser CK, May WL, Johnson VK, et al. Methotrexate for ectopic pregnancy: a randomized single dose compared with multiple dose. Obstet Gynecol 2005; 105:64S.
  47. Barnhart K, Hummel AC, Sammel MD, et al. Use of "2-dose" regimen of methotrexate to treat ectopic pregnancy. Fertil Steril 2007; 87:250.
  48. Stovall TG, Ling FW, Gray LA, et al. Methotrexate treatment of unruptured ectopic pregnancy: a report of 100 cases. Obstet Gynecol 1991; 77:749.
  49. Stovall TG, Ling FW. Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 1993; 168:1759.
  50. Kirk E, Condous G, Van Calster B, et al. A validation of the most commonly used protocol to predict the success of single-dose methotrexate in the treatment of ectopic pregnancy. Hum Reprod 2007; 22:858.
  51. Natale A, Candiani M, Barbieri M, et al. Pre- and post-treatment patterns of human chorionic gonadotropin for early detection of persistence after a single dose of methotrexate for ectopic pregnancy. Eur J Obstet Gynecol Reprod Biol 2004; 117:87.
  52. Saraj AJ, Wilcox JG, Najmabadi S, et al. Resolution of hormonal markers of ectopic gestation: a randomized trial comparing single-dose intramuscular methotrexate with salpingostomy. Obstet Gynecol 1998; 92:989.
  53. Stovall TG, Ling FW, Buster JE. Outpatient chemotherapy of unruptured ectopic pregnancy. Fertil Steril 1989; 51:435.
  54. Fauconnier A, Mabrouk A, Salomon LJ, et al. Ultrasound assessment of haemoperitoneum in ectopic pregnancy: derivation of a prediction model. World J Emerg Surg 2007; 2:23.
  55. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet Gynecol 1990; 162:1620.
  56. McLaren JF, Burney RO, Milki AA, et al. Effect of methotrexate exposure on subsequent fertility in women undergoing controlled ovarian stimulation. Fertil Steril 2009; 92:515.
  57. Gougeon A. Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1986; 1:81.
  58. Strauss, JF, Williams, CJ. The ovarian life cycle. In: Yen and Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 5th ed, Strauss, JF, Barbieri, RL (Eds), Elsevier Saunders, Philadelphia 2004. p.213.
  59. Svirsky R, Rozovski U, Vaknin Z, et al. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol 2009; 27:85.
  60. Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril 2013; 100:638.
  61. Pektasides D, Rustin GJ, Newlands ES, et al. Fertility after chemotherapy for ovarian germ cell tumours. Br J Obstet Gynaecol 1987; 94:477.
  62. Ayhan A, Ergeneli MH, Yüce K, et al. Pregnancy after chemotherapy for gestational trophoblastic disease. J Reprod Med 1990; 35:522.
  63. Keefe KA, Wald JS, Goldstein DP, et al. Reproductive outcome after methotrexate treatment of tubal pregnancies. J Reprod Med 1998; 43:28.
  64. Kung FT, Chang SY, Tsai YC, et al. Subsequent reproduction and obstetric outcome after methotrexate treatment of cervical pregnancy: a review of original literature and international collaborative follow-up. Hum Reprod 1997; 12:591.
  65. Tulandi T, Al-Jaroudi D. Interstitial pregnancy: results generated from the Society of Reproductive Surgeons Registry. Obstet Gynecol 2004; 103:47.
  66. Lau S, Tulandi T. Conservative medical and surgical management of interstitial ectopic pregnancy. Fertil Steril 1999; 72:207.
  67. Jermy K, Thomas J, Doo A, Bourne T. The conservative management of interstitial pregnancy. BJOG 2004; 111:1283.
  68. Moawad NS, Mahajan ST, Moniz MH, et al. Current diagnosis and treatment of interstitial pregnancy. Am J Obstet Gynecol 2010; 202:15.
  69. Verity L, Ludlow J, Dickinson JE. Interstitial ectopic pregnancy: a contemporary case series. Aust N Z J Obstet Gynaecol 2003; 43:232.
  70. Tang A, Baartz D, Khoo SK. A medical management of interstitial ectopic pregnancy: a 5-year clinical study. Aust N Z J Obstet Gynaecol 2006; 46:107.
  71. Downey GP, Tuck SM. Spontaneous uterine rupture during subsequent pregnancy following non-excision of an interstitial ectopic gestation. Br J Obstet Gynaecol 1994; 101:162.
  72. Timor-Tritsch IE, Monteagudo A, Lerner JP. A 'potentially safer' route for puncture and injection of cornual ectopic pregnancies. Ultrasound Obstet Gynecol 1996; 7:353.
  73. Monteagudo A, Minior VK, Stephenson C, et al. Non-surgical management of live ectopic pregnancy with ultrasound-guided local injection: a case series. Ultrasound Obstet Gynecol 2005; 25:282.
  74. Deruelle P, Lucot JP, Lions C, Robert Y. Management of interstitial pregnancy using selective uterine artery embolization. Obstet Gynecol 2005; 106:1165.
  75. Ophir E, Singer-Jordan J, Oettinger M, et al. Uterine artery embolization for management of interstitial twin ectopic pregnancy: case report. Hum Reprod 2004; 19:1774.