Single versus Multiple-doses of Methotrexate: A Retrospective Cohort Study to Compare the Efficacy and Observed Side Effects in Management of Ectopic Pregnancies

  • Zeinab Nazari
  • Hamed Jafarpour
  • Mohammad Tabarestani
  • Sara Sadr
  • Ahmadreza Shafizadeh
  • Fatemeh Shafizadeh
Keywords: Ectopic pregnancy, methotrexate, single-dose protocol, multiple-dose protocol


Aim: In this study we aimed to compare the efficacy and observed side effects of the two used Methotrexate administration protocols in treatment of ectopic pregnancies. Methods: In this retrospective cohort study, 83 patients that met the inclusion criteria and were previously assigned to either the single-dose methotrexate regimen protocol (a single 50 mg/m2 intramuscular MTX injection) or the multiple-dose methotrexate protocol (1 mg/kg on the 1st, 3rd, 5th and 7th day of the treatment). Side effects and alterations in the human chorionic gonadotropin (β-HCG) levels on the 1st, 4th and 7th day after initiation of treatment were obtaines from patient case files. Results: Eighty three out of 98 patients that were treated with MTX met all the inclusion criteria. The average age of patients was 30.17 years, the mean gravida was 1.9 and the mean EP diameter was 36.63 mm. The hospitalization duration was shorter in the multiple-dose regimen group (3.85 days compared to 4.53 days). The endometrial thickness was higher in patients undergoing multiple-dose treatment (11.75 mm compared to 8.75). The prevalence of anemia, thrombocytopenia, leukopenia, raised liver enzymes and pain were not significantly different between the two groups (p>0.05). The treatment success rates were 78% and 85% for the single-dose regimen and the multiple-dose regimen, respectively (p>0.05). There was one reported case of fallopian tube rupture in the single-dose regimen group and two in the multiple-dose regimen group (p>0.05). Conclusion: Treatment success rates, the prevalence of side effects (Gastroenteritis, leukopenia, anemia, thrombocytopenia, bone marrow suppression) and alterations in β-HCG levels were not significantly different between the two treatment groups. We concluded that with fewer adverse effects and the same therapeutic benefits, a single-dose methotrexate regimen is preferable in a case of an unruptured EP with stable hemodynamics.


Kim HH, Fox JH. The fallopian tube and ectopic pregnancy. Kistner’s gynecology and women's health New York: Mosby Inc. 1999:143-65.

Kadar N, Caldwell BV, Romero R. A method of screening for ectopic pregnancy and its indications. Obstetrics and gynecology. 1981;58(2):162-6.

Nazac A, Gervaise A, Bouyer J, De Tayrac R, Capella‐Allouc S, Fernandez H. Predictors of success in methotrexate treatment of women with unruptured tubal pregnancies. Ultrasound in obstetrics & gynecology. 2003;21(2):181-5.

Bai SW, Lee JS, Park JH, Kim JY, Jung KA, Kim SK, et al. Failed methotrexate treatment of cervical pregnancy: predictive factors. Obstetrical & gynecological survey. 2002;57(10):669-70.

Barnhart KT, Gosman G, Ashby R, Sammel M. The medical management of ectopic pregnancy: a meta-analysis comparing “single dose” and “multidose” regimens. Obstetrics & Gynecology. 2003;101(4):778-84.

Tanaka T, Hayashi H, Kutsuzawa T, Fujimoto S, Ichinoe K. Treatment of interstitial ectopic pregnancy with methotrexate: report of a successful case. Fertility and sterility. 1982;37(6):851-2.

Elkilani O, Sayyed T, Metwalli A. Multiple doses versus single-dose methotrexate protocols for the management of some cases of ectopic pregnancy. Menoufia Medical Journal. 2015;28(1):250-3.

Sudha V, Thangaraj DR. A retrospective study on ectopic pregnancy: a two year study. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2016;5(12):4365-8.

Hamed HO, Ahmed SR, Alghasham AA. Comparison of double‐and single‐dose methotrexate protocols for treatment of ectopic pregnancy. International Journal of Gynecology & Obstetrics. 2012;116(1):67-71.

Song T, Kim MK, Kim M-L, Jung YW, Yun BS, Seong SJ. Single-dose versus two-dose administration of methotrexate for the treatment of ectopic pregnancy: a randomized controlled trial. Human Reproduction. 2015:dev312.

Saadati N, Najafian M, Masihi S, Safiary S, Abedi P. Comparison of Two Different Protocols of Methotrexate Therapy in Medical Management of Ectopic Pregnancy. Iranian Red Crescent Medical Journal. 2015;17(12).

Guvendag Guven ES, Dilbaz S, Dilbaz B, Aykan Yildirim B, Akdag D, Haberal A. Comparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study. Acta obstetricia et gynecologica Scandinavica. 2010;89(7):889-95.

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. Fertility and sterility. 2006;85(6):1661-6.

Bafghi AT, Zaretezerjani F, Sekhavat L, Firouzabadi RD, Ramazankhani Z. Fertility Outcome after Treatment of Unruptured Ectopic Pregnancy with Two Different Methotrexate Protocols. International journal of fertility & sterility. 2012;6(3):189.

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. Obstetrics & Gynecology. 1998;92(6):989-94.

Lecuru F, Robin F, Bernard JP, Maizan de Malartic C, Mac‐Cordick C, Boucaya V, et al. Single‐dose methotrexate for unruptured ectopic pregnancy. International Journal of Gynecology & Obstetrics. 1998;61(3):253-9.

Kim J, Jung YM, Lee DY, Jee BC. Pretreatment serum human chorionic gonadotropin cutoff value for medical treatment success with single-dose and multi-dose regimen of methotrexate in tubal ectopic pregnancy. Obstet Gynecol Sci. 2017;60(1):79-86.

Aflatoonian A, Hojat H, Tabibnejad N. Epidemiological Study of Ectopic Pregnancy among Pregnant Women in Yazd, 1999. Journal of Ardabil University of Medical Sciences. 2004;4(4):20-4.

Morlock RJ, Lafata JE, Eisenstein D. Cost‐effectiveness of single‐dose methotrexate compared with laparoscopic treatment of ectopic pregnancy. Obstetrics & Gynecology. 2000;95(3):407-12.

Barnhart K, Hummel AC, Sammel MD, Menon S, Jain J, Chakhtoura N. Use of "2-dose" regimen of methotrexate to treat ectopic pregnancy. Fertility and sterility. 2007;87(2):250-6.

Zargar M RT, Barati M. Comparision of Single and Multidose of Methotrexate in Medical Treatment of Ectopic pregnancy. Pak J Med Sci. 2008;24:586-9.

Roussos D, Panidis D, Matalliotakis I, Mavromatidis G, Neonaki M, Mamopoulos M, et al. Factors that may predispose to rupture of tubal ectopic pregnancy. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2000;89(1):15-7.

Lipscomb GH, McCord ML, Stovall TG, Huff G, Portera SG, Ling FW. Predictors of success of methotrexate treatment in women with tubal ectopic pregnancies. New England Journal of Medicine. 1999;341(26):1974-8.

Gamzu R, Almog B, Levin Y, Pauzner D, Lessing JB, Jaffa A, et al. The ultrasonographic appearance of tubal pregnancy in patients treated with methotrexate. Human reproduction (Oxford, England). 2002;17(10):2585-7.

Lipscomb GH, Bran D, McCord ML, Portera JC, Ling FW. Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate. American journal of obstetrics and gynecology. 1998;178(6):1354-8.

Mirbolouk F, Yousefnezhad A, Ghanbari A. Predicting factors of medical treatment success with single dose methotrexate in tubal ectopic pregnancy: a retrospective study. Iranian journal of reproductive medicine. 2015;13(6):351.

Choi H-J, Im K-S, Jung H-J, Lim K-T, Mok J-E, Kwon Y-S. Clinical analysis of ovarian pregnancy: a report of 49 cases. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2011;158(1):87-9.

Mol F, Mol B, Ankum W, van der Veen F, Hajenius P. Current evidence on surgery, systemic methotrexate and expectant management in the treatment of tubal ectopic pregnancy: a systematic review and meta-analysis. Human reproduction update. 2008;14(4):309-19.

Gabbur N, Sherer DM, Hellmann M, Abdelmalek E, Phillip P, Abulafia O. Do serum beta-human chorionic gonadotropin levels on day 4 following methotrexate treatment of patients with ectopic pregnancy predict successful single-dose therapy? American journal of perinatology. 2006;23(03):193-6.

Erdem M, Erdem A, Arslan M, Öç A, Biberoğlu K, Gürsoy R. Single-dose methotrexate for the treatment of unruptured ectopic pregnancy. Archives of gynecology and obstetrics. 2004;270(4):201-4.

Menon S, Colins J, Barnhart KT. Establishing a human chorionic gonadotropin cutoff to guide methotrexate treatment of ectopic pregnancy: a systematic review. Fertility and sterility. 2007;87(3):481-4.

Nowak-Markwitz E, Michalak M, Olejnik M, Spaczynski M. Cutoff value of human chorionic gonadotropin in relation to the number of methotrexate cycles in the successful treatment of ectopic pregnancy. Fertility and sterility. 2009;92(4):1203-7.

Gamzu R, Almog B, Levin Y, Avni A, Jaffa A, Lessing JB, et al. Efficacy of methotrexate treatment in extrauterine pregnancies defined by stable or increasing human chorionic gonadotropin concentrations. Fertility and sterility. 2002;77(4):761-5.

Nguyen Q, Kapitz M, Downes K, Silva C. Are early human chorionic gonadotropin levels after methotrexate therapy a predictor of response in ectopic pregnancy? American journal of obstetrics and gynecology. 2010;202(6):630. e1-. e5.

Skubisz M, Lee J, Wallace E, Tong S. Decline in βhCG levels between days 0 and 4 after a single dose of methotrexate for ectopic pregnancy predicts treatment success: a retrospective cohort study. BJOG: An International Journal of Obstetrics & Gynaecology. 2011;118(13):1665-8.

Skubisz M, Dutton P, Duncan WC, Horne AW, Tong S. Using a decline in serum hCG between days 0–4 to predict ectopic pregnancy treatment success after single-dose methotrexate: a retrospective cohort study. BMC pregnancy and childbirth. 2013;13(1):30.

Original Research