Skip to main content

Advertisement

SpringerLink
Log in

Methotrexate for ectopic pregnancy: when and how

  • Review
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

Ectopic pregnancy is the leading cause of maternal death in the first trimester of pregnancy. The dosage of beta fraction of human chorionic gonadotropin (beta-hCG) and improvement of the transvaginal ultrasound allowed an earlier diagnosis and a conservative management. Currently, the use of systemic methotrexate (MTX) proved to be a great alternative with similar success rates and completely non-invasive.

Methods

We searched for the most relevant articles on the use of MTX in ectopic pregnancy published between 2003 and 2013 in high-impact journals. We performed a strategic search at the Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), National Institute for Health Research (NHS), International Prospective Register of Systematic Reviews (PROSPERO), The Cochrane Database of Systematic Reviews (CDSR) and Medical Literature Analysis and Retrieval System Online (MEDLINE) according to the descriptors “pregnancy, ectopic” and “methotrexate”, alone or combined.

Results

Thus, we based this review on 32 studies that were classified following the grades of recommendation and levels of evidence proposed by the Oxford Centre for Evidence-Based Medicine. Additionally, selected papers were used. Scientific evidence points to a growing trend in the choice of conservative treatment for ectopic pregnancies, whereas expectant management still lacks studies for definitive conclusions. Indeed, the well-established protocols which exhibit a greater number of studies are still based on the single-dose treatment.

Conclusion

Considering MTX, it proved to be more effective in cases of low titers of beta-hCG and masses with a small diameter, although there is still no uniformity of these parameters. The choice largely depends on the experience of the medical team and ultimately, on the woman’s reproductive desire.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

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

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Alleyassin A, Khademi A, Aghahosseini M, Safdarian L, Badenoosh B, Hamed EA (2006) 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 85:1661–1666

    Article  CAS  PubMed  Google Scholar 

  5. Cobellis G, Pierno G, Pecori E, Scaffa C, Stradella L, Messalli EM et al (2003) Methotrexate treatment for tubal pregnancy. Criteria for medical approach. Minerva Ginecol 55:531–535

    CAS  PubMed  Google Scholar 

  6. Mol F, Mol BW, Ankum WM, van der Veen F, Hajenius PJ (2008) 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 14:309–319

    Article  CAS  PubMed  Google Scholar 

  7. Van Mello NM, Mol F, Adriaanse AH, Boss EA, Dijkman AB, Doornbos JP et al (2008) The METEX study: methotrexate versus expectant management in women with ectopic pregnancy: a randomised controlled trial. BMC Womens Health 8:10

    Article  PubMed Central  PubMed  Google Scholar 

  8. Hajenius PJ, Mol F, Mol BWJ, Bossuyt PM, Ankum WM, van der Veen F (2009) Interventions for tubal ectopic pregnancy. Cochrane Database Syst Rev (1):CD000324.

  9. Guvendag Guven ES, Dilbaz S, Dilbaz B, Aykan Yildirim B, Akdag D, Haberal A (2010) Comparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study. Acta Obstet Gynecol Scand 89:889–895

    Article  PubMed  Google Scholar 

  10. Seror V, Gelfucci F, Gerbaud L, Pouly J-L, Fernandez H, Job-Spira N et al (2007) Care pathways for ectopic pregnancy: a population-based cost-effectiveness analysis. Fertil Steril 87:737–748

    Article  PubMed  Google Scholar 

  11. American College of Obstetricians and Gynecologists (2008) ACOG Practice Bulletin No. 94: Medical management of ectopic pregnancy. Obstet Gynecol 111:1479–1485 (can not apply oxford classification)

  12. Barnhart KT (2009) Ectopic Pregnancy. N Engl J Med 361:379–387 (can not apply oxford classification)

  13. Gervaise A, Masson L, de Tayrac R, Frydman R, Fernandez H (2004) Reproductive outcome after methotrexate treatment of tubal pregnancies. Fertil Steril 82:304–308

    Article  PubMed  Google Scholar 

  14. Fernandez H, Yves Vincent SC, Pauthier S, Audibert F, Frydman R (1998) Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility. Hum Reprod 13:3239–3243

    Article  CAS  PubMed  Google Scholar 

  15. Stovall TG, Ling FW (1993) Single-dose methotrexate: an expanded clinical trial. Am J Obstet Gynecol 168:1759–1762

    Article  CAS  PubMed  Google Scholar 

  16. Lermann J, Segl P, Jud SM, Beckmann MW, Oppelt P, Thiel FC, Renner SP, Müller A (2014) Low-dose methotrexate treatment in ectopic pregnancy: a retrospective analysis of 164 ectopic pregnancies treated between 2000 and 2008. Arch Gynecol Obstet 289:329–335

    Article  CAS  PubMed  Google Scholar 

  17. Rana P, Kazmi I, Singh R, Afzal M, Al-Abbasi FA, Aseeri A, Singh R, Khan R, Anwar F (2013) Ectopic pregnancy: a review. Arch Gynecol Obstet 288:747–757

    Article  PubMed  Google Scholar 

  18. Chetty M, Elson J (2009) Treating non-tubal ectopic pregnancy. Best Pract Res Clin Obstet Gynaecol 23:529–538

    Article  PubMed  Google Scholar 

  19. Balci O, Ozdemir S, Mahmoud AS, Acar A, Colakoglu MC (2010) The efficacy of multiple-dose methotrexate treatment for unruptured tubal ectopic pregnancy and conversion rate to surgery: a study on 294 cases. Fertil Steril 93:2415–2417

    Article  CAS  PubMed  Google Scholar 

  20. Da Costa Soares R, Elito J, Han KK, Camano L (2004) Endometrial thickness as an orienting factor for the medical treatment of unruptured tubal pregnancy. Acta Obstet Gynecol Scand 83:289–292

    Article  Google Scholar 

  21. Kirk E, Van Calster B, Condous G, Papageorghiou AT, Gevaert O, Van Huffel S et al (2011) Ectopic pregnancy: using the hCG ratio to select women for expectant or medical management. Acta Obstet Gynecol Scand 90:264–272

    PubMed  Google Scholar 

  22. Krag Moeller LB, Moeller C, Thomsen SG, Andersen LF, Lundvall L, Lidegaard Ø et al (2009) Success and spontaneous pregnancy rates following systemic methotrexate versus laparoscopic surgery for tubal pregnancies: a randomized trial. Acta Obstet Gynecol Scand 88:1331–1337

    Article  CAS  PubMed  Google Scholar 

  23. Gnisci A, Rua S, Courbiere B, Cravello L, Gamerre M, Agostini A (2011) Plasma creatine phosphokinase level may predict successful treatment after a single injection of methotrexate for ectopic pregnancy. Fertil Steril 95:2131–2133

    Article  CAS  PubMed  Google Scholar 

  24. Rozenberg P (2003) Medical treatment of ectopic pregnancies: a randomized clinical trial comparing methotrexate-mifepristone and methotrexate-placebo. Hum Reprod 18:1802–1808

    Article  CAS  PubMed  Google Scholar 

  25. Hamed HO, Ahmed SR, Alghasham AA (2012) Comparison of double- and single-dose methotrexate protocols for treatment of ectopic pregnancy. Int J Gynaecol Obstet 116:67–71

    Article  CAS  PubMed  Google Scholar 

  26. Li C, Li C, Feng D, Jia C, Liu B, Zhan X (2011) Transcatheter arterial chemoembolization versus systemic methotrexate for the management of cesarean scar pregnancy. Int J Gynaecol Obstet 113:178–182

    Article  PubMed  Google Scholar 

  27. Zhuang Y, Huang L (2009) Uterine artery embolization compared with methotrexate for the management of pregnancy implanted within a cesarean scar. Am J Obstet Gynecol 201(152):e1–e3

    PubMed  Google Scholar 

  28. Hirakawa M, Tajima T, Yoshimitsu K, Irie H, Ishigami K, Yahata H et al (2009) Uterine artery embolization along with the administration of methotrexate for cervical ectopic pregnancy: technical and clinical outcomes. AJR Am J Roentgenol 192:1601–1607

    Article  PubMed  Google Scholar 

  29. Li N, Zhu F, Fu S, Shi X (2012) Transvaginal ultrasound-guided embryo aspiration plus local administration of low-dose methotrexate for caesarean scar pregnancy. Ultrasound Med Biol 38:209–213

    Article  PubMed  Google Scholar 

  30. Wang JH, Xu KH, Lin J, Xu JY, Wu RJ (2009) Methotrexate therapy for cesarean section scar pregnancy with and without suction curettage. Fertil Steril 92:1208–1213

    Article  CAS  PubMed  Google Scholar 

  31. Xiaolin Z, Ling L, Chengxin Y, Yiqing T, Jun W, Yan C et al (2010) Transcatheter intraarterial methotrexate infusion combined with selective uterine artery embolization as a treatment option for cervical pregnancy. J Vasc Interv Radiol 21:836–841

    Article  PubMed  Google Scholar 

  32. Rotas MA, Haberman S, Levgur M (2006) Cesarean scar ectopic pregnancies: etiology, diagnosis, and management. Obstet Gynecol 107:1373–1381

    Article  PubMed  Google Scholar 

  33. Jeng CJ, Ko ML, Shen J (2007) Transvaginal ultrasound-guided treatment of cervical pregnancy. Obstet Gynecol 109:1076–1082

    Article  PubMed  Google Scholar 

  34. Elito Júnior J, Araujo Júnior E, Martins Santana EF, Szejnfeld D, Helfer TM, Nardozza LM et al (2013) Uterine artery embolization with methotrexate infusion as treatment for cesarean scar pregnancy. Case report. Med Ultrason 2013(15):240–243

    Article  Google Scholar 

  35. OCEBM Levels of Evidence Working Group: “The Oxford 2011 Levels of Evidence”. http://www.cebm.net/index.aspx?o=5653. Accessed 16 Sept 2013

  36. van Mello NM, Mol F, Verhoeve HR, van Wely M, Adriaanse AH, Boss EA et al (2013) Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison. Hum Reprod 28:60–67

    Article  PubMed  Google Scholar 

  37. Jurkovic D (2012) Randomised double blind controlled trial of single dose methotrexate versus expectant management in women with tubal ectopic pregnancy. http://www.controlled-trials.com/ISRCTN95698259. Accessed 16 Sept 2013

  38. Casikar I, Lu C, Reid S, Bignard T, Mongelli M, Morris A, Wild R, Condous G (2012) Methotrexate vs placebo in early tubal ectopic pregnancy: a multi-centre double-blind randomised trial. Rev Recent Clin Trials 7:238–243

    Article  CAS  PubMed  Google Scholar 

  39. American Society for Reproductive Medicine (2013) Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril 100:638–644. (can not apply oxford classification)

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

    Article  CAS  PubMed  Google Scholar 

  41. Sagiv R, Debby A, Feit H, Cohen-Sacher B, Keidar R, Golan A (2012) The optimal cutoff serum level of human chorionic gonadotropin for efficacy of methotrexate treatment in women with extrauterine pregnancy. Int J Gynaecol Obstet 116:101–104

    Article  CAS  PubMed  Google Scholar 

  42. Da Costa Soares R, Elito J, Camano L (2008) 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 278:319–324

    Article  PubMed  Google Scholar 

  43. Takacs P, Chakhtoura N, De Santis T, Verma U (2005) Evaluation of the relationship between endometrial thickness and failure of single-dose methotrexate in ectopic pregnancy. Arch Gynecol Obstet 272:269–272

    Article  CAS  PubMed  Google Scholar 

  44. Soliman KB, Saleh NM, Omran AA (2006) Safety and efficacy of systemic methotrexate in the treatment of unruptured tubal pregnancy. Saudi Med J 27:1005–1010

    PubMed  Google Scholar 

  45. Júnior EJ, Musiello RB, Júnior EA, Souza E, Fava JL, Guerzet EA, Camano L (2013) Conservative management of cervical pregnancy with embryonic heart activity by ultrasound-guided local injection: an eight case series. J Matern Fetal Neonatal Med. doi:10.3109/14767058.2013.856413

  46. Seow KM, Wang PH, Huang LW, Hwang JL (2013) Transvaginal sono-guided aspiration of gestational sac concurrent with a local methotrexate injection for the treatment of unruptured cesarean scar pregnancy. Arch Gynecol Obstet 288:361–366

    Article  CAS  PubMed  Google Scholar 

  47. Cho GJ, Lee SH, Shin JW, Lee NW, Kim T, Kim HJ et al (2006) Predictors of success of repeated injections of single-dose methotrexate regimen for tubal ectopic pregnancy. J Korean Med Sci 21:86–89

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Elito J, Han KK, Camano L (2005) Values of beta-human chorionic gonadotropin as a risk factor for tubal obstruction after tubal pregnancy. Acta Obstet Gynecol Scand 84:864–867

    PubMed  Google Scholar 

  49. Elito J, Han KK, Camano L (2005) Tubal patency after clinical treatment of unruptured ectopic pregnancy. Int J Gynaecol Obstet 88:309–313

    Article  PubMed  Google Scholar 

  50. Oriol B, Barrio A, Pacheco A, Serna J, Zuzuarregui JL, Garcia-Velasco JA (2008) Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril 90:1579–1582

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Obstetrics, Federal University of São Paulo (UNIFESP), Rua Carlos Weber, 956, Apto. 113 Visage, Alto da Lapa, São Paulo, SP, CEP 05303-000, Brazil

    Gustavo Nardini Cecchino, Edward Araujo Júnior & Julio Elito Júnior

Authors
  1. Gustavo Nardini Cecchino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward Araujo Júnior
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Julio Elito Júnior
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward Araujo Júnior.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cecchino, G.N., Araujo Júnior, E. & Elito Júnior, J. Methotrexate for ectopic pregnancy: when and how. Arch Gynecol Obstet 290, 417–423 (2014). https://doi.org/10.1007/s00404-014-3266-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-014-3266-9

Keywords

Search

Navigation