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Methotrexate does not affect ovarian reserve or subsequent assisted reproductive technology outcomes

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Abstract

Purpose

The purpose of this research was to study whether methotrexate (MTX) as treatment for ectopic pregnancy (EP) impacts the future fertility of women undergoing assisted reproductive technology (ART)

Methods

In a systematic review and multi-center retrospective cohort from four academic and private fertility centers, 214 women underwent an ART cycle before and after receiving MTX as treatment for an EP. Measures of ovarian reserve and responsiveness and rates of clinical pregnancy (CP) and live birth (LB) were compared in the ART cycles prior and subsequent to MTX.

Results

Seven studies were identified in the systematic review, and primary data from four institutions was included in the final analysis. Women were significantly older in post-MTX cycles (35.3 vs 34.7 years). There were no differences in follicle stimulating hormone, antral follicle count, duration of stimulation, oocytes retrieved, or fertilization rate between pre- and post-MTX cycles. However, post-MTX cycles received a significantly higher total dose of gonadotropins (4206 vs 3961 IU). Overall, 42 % of women achieved a CP and 35 % achieved a LB in the post-MTX ART cycle, which is similar to national statistics. Although no factors were identified that were predictive of LB in young women, the number of oocytes retrieved in the previous ART cycle and current AFC were predictive of LB (AUC 0.76, 0.75) for the older women.

Conclusions

MTX does not influence ovarian reserve, response to gonadotropin stimulation, and CP or LB rate after ART. MTX remains a safe and effective treatment option for women with asymptomatic EPs.

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References

  1. Zane SB, Kieke BA, 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;6:227–36.

    Article  PubMed  Google Scholar 

  2. Society of Assisted Reproductive Technology and the American Society for Reproductive Medicine. Assisted reproductive technology in the United States: 2000 results generated from the American Society for Reproductive Medicine/Society for Assisted Reproductive Technology Registry. Fertil Steri. 2004;81:1207–20.

    Article  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. Carson SA, Buster JE. Ectopic pregnancy. N Engl J Med. 1993;329:1174–81.

    Article  CAS  PubMed  Google Scholar 

  5. 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;341:1974–8.

    Article  CAS  PubMed  Google Scholar 

  6. Stovall TG, Ling FW, Gray LA. Single-dose methotrexate for treatment of ectopic pregnancy. Obstet Gynecol. 1991;77:754–7.

    CAS  PubMed  Google Scholar 

  7. Benian A, Guralp O, Uzun DD, Okyar A, Sahmay S. The effect of repeated administration of methotrexate (MTX) on rat ovary: measurement of serum antimullerian hormone (AMH) levels. Gynecol Endocrinol. 2013;29:226–9.

    Article  CAS  PubMed  Google Scholar 

  8. Blumenfeld Z. How to preserve fertility in young women exposed to chemotherapy? The role of GnRH agonist cotreatment in addition to cryopreservation of embrya, oocytes, or ovaries. Oncologist. 2007;12:1044–54.

    Article  PubMed  Google Scholar 

  9. Stovall TG, Ling FW, Buster JE. Reproductive performance after methotrexate treatment of ectopic pregnancy. Am J Obstet Gynecol. 1990;162:1620–3.

    Article  CAS  PubMed  Google Scholar 

  10. Keefe KA, Wald JS, Goldstein DP, Bernstein M, Berkowitz RS. Reproductive outcome after methotrexate treatment of tubal pregnancies. J Reprod Med. 1998;43:28–32.

    CAS  PubMed  Google Scholar 

  11. Buster JE, Krotz S. Reproductive performance after ectopic pregnancy. Sem Rep Med. 2007;25:131–3.

    Article  Google Scholar 

  12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264–9.

    Article  PubMed  Google Scholar 

  13. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011

  14. Singer T, Kofinas J, Huang JY, Elias R, Schattman GL, Rosenwaks Z. Anti-Mullerian hormone serum levels and reproductive outcome are not affected by methotrexate or laparoscopic salpingectomy for the treatment of ectopic pregnancy in IVF patients. Fertil Steril. 2011;96:S197.

    Article  Google Scholar 

  15. Uyar I, Yucel OU, Gezer C, Gulhan I, Karis B, Hanhan HM, et al. Effect of single-dose methotrexate on ovarian reserve in women with ectopic pregnancy. Fertil Steril. 2013;100:1310–3.

    Article  CAS  PubMed  Google Scholar 

  16. Boots CE, Gustofson RL, Feinberg EC. Does methotrexate administration for ectopic pregnancy after in vitro fertilization impact ovarian reserve or ovarian responsiveness? Fertil Steril. 2013;100:1590–3.

    Article  CAS  PubMed  Google Scholar 

  17. Hill MJ, Cooper JC, Levy G, Alford C, Richter KS, DeCherney AH, et al. Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location. Fertil Steril. 2014;101:413–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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;92:515–9.

    Article  CAS  PubMed  Google Scholar 

  19. Oriol B, Barrio A, Pacheco A, Serna J, Zuzuarregui JL, Garcia-Velasco JA. Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve. Fertil Steril. 2008;90:1579–82.

    Article  CAS  PubMed  Google Scholar 

  20. Orvieto R, Kruchkovich J, Zohav E, Rabinson J, Anteby EY, Meltcer S. Does methotrexate treatment for ectopic pregnancy influence the patient’s performance during a subsequent in vitro fertilization/embryo transfer cycle? Fertil Steril. 2007;88:1685–6.

    Article  PubMed  Google Scholar 

  21. Provansal M, Agostini A, Lacroix O, Gerbeau S, Grillo JM, Gamerre M. Ultrasound monitoring in patients undergoing in-vitro fertilization after methotrexate treatment for ectopic pregnancy. Ultrasound Obstet Gynecol. 2009;34:715–9.

    Article  CAS  PubMed  Google Scholar 

  22. Wiser A, Gilbert A, Nahum R, Orvieto R, Haas J, Hourvitz A, et al. Effects of treatment of ectopic pregnancy with methotrexate or salpingectomy in the subsequent IVF cycle. Reprod Biomed Online. 2013;26:449–53.

    Article  CAS  PubMed  Google Scholar 

  23. Luke B, Brown MB, Stern JE, Missmer SA, Fujimoto VY, Leach R, et al. Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates. Hum Reprod. 2011;26:245–52.

    Article  PubMed  Google Scholar 

  24. Practice Committee of American Society for Reproductive Medicine. Medical treatment of ectopic pregnancy: a committee opinion. Fertil Steril. 2013;100:638–44.

    Article  Google Scholar 

  25. Svirsky R, Rozovski U, Vaknin Z, Pansky M, Schneider D, Halperin R. The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy. Reprod Toxicol. 2009;27:85–7.

    Article  CAS  PubMed  Google Scholar 

  26. Charache S, Condit PT, Humphreys SR. Studies on the folic acid vitamins, and the persistence of amethopterin in mammalian tissues. Cancer. 1960;13:236–40.

    Article  CAS  PubMed  Google Scholar 

  27. Ohannessian A, Loundou A, Courbière B, Cravello L, Agostini A. Ovarian responsiveness in women receiving fertility treatment after methotrexate for ectopic pregnancy: a systematic review and meta-analysis. Hum Reprod. 2014;29:1949–56.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

C.E.B. received support from the National Research Training Program in Reproductive Medicine sponsored by the National Institute of Health (T32 HD040135-13) and the Scientific Advisory Board of Vivere Health. E.S.J. received support from the Women’s Reproductive Health Research Program sponsored by the National Institute of Health (K12 HD063086), the Institute of Clinical and Translational Sciences at Washington University (UL1 TR000448), the Barnes Jewish Hospital Foundation, and the March of Dimes. This work was supported, in part, by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Christina E. Boots.

Ethics declarations

Authors from each institution obtained ethical approval from their Institutional Review Board. In addition, IRB approval was obtained from Washington University prior to the chart review and data extraction.

Conflict of interest

There are no conflicts of interest to declare.

Additional information

Capsule As treatment for an ectopic pregnancy, methotrexate does not affect ovarian reserve, response to gonadotropin stimulation, clinical pregnancy, or live birth rates in subsequent assisted reproductive tenchology cycles.

Appendix

Appendix

Embase

8/27/2013, Limits: English, 546 Results

‘methotrexate’/exp OR ‘methotrexate’ OR ‘mtx’ OR ‘4 amino 10 methylfolic acid’ OR ‘4 amino 10 methylpteroylglutamic acid’ OR ‘4 amino n10 methylpteroylglutamic acid’ OR ‘a methopterine’ OR ‘abitrexate’ OR ‘amethopterin’ OR ‘amethopterine’ OR ‘ametopterine’ OR ‘antifolan’ OR ‘biotrexate’ OR ‘canceren’ OR ‘cl 14377’ OR ‘cl14377’ OR ‘emtexate’ OR ‘emthexat’ OR ‘emthexate’ OR ‘emtrexate’ OR ‘enthexate’ OR ‘farmitrexat’ OR ‘farmitrexate’ OR ‘farmotrex’ OR ‘folex’ OR ‘ifamet’ OR ‘imeth’ OR ‘lantarel’ OR ‘ledertrexate’ OR ‘maxtrex’ OR ‘metex’ OR ‘methoblastin’ OR ‘methohexate’ OR ‘methotrate’ OR ‘methotrexat’ OR ‘methotrexato’ OR ‘methoxtrexate’ OR ‘methrotrexate’ OR ‘methylaminopterin’ OR ‘methylaminopterine’ OR ‘meticil’ OR ‘metoject’ OR ‘metothrexate’ OR ‘metotrexat’ OR ‘metotrexate’ OR ‘metotrexin’ OR ‘metrex’ OR ‘mexate’ OR ‘mpi 5004’ OR ‘mpi5004’ OR ‘neotrexate’ OR ‘novatrex’ OR ‘nsc 740’ OR ‘nsc740’ OR ‘reumatrex’ OR ‘rheumatrex’ OR ‘texate’ OR ‘texorate’ OR ‘trexall’ OR ‘xaken’ OR ‘zexate’ AND (‘ovarian reserve’/exp OR ‘oocyte development’/exp OR ‘ovary function’/de OR ‘ovary follicle’/exp OR ‘ovary cycle’/exp OR ‘follitropin’/exp OR ‘muellerian inhibiting factor’/exp OR ‘oocyte reserve’ OR ‘ovarian reserve’ OR ‘ovarian responsiveness’ OR ‘ovarian stimulation’ OR ‘ovarian cycle’ OR ‘ovulation cycle’ OR ‘reproductive cycle’ OR ‘ovarian activity’ OR ‘ovarian function’ OR ‘ovarium function’ OR ‘egg development’ OR ‘oocyte growth’ OR ‘oocytogenesis’ OR ‘oogenesis’ OR ‘ovogenesis’ OR ‘ovum development’ OR ‘oocyte maturation’ OR ‘egg maturation’ OR ‘follicle maturation’ OR ‘fertiline’ OR ‘fertinom p’ OR ‘follicle stimulating hormone’ OR ‘follicotropin’ OR ‘folliculostimulating hormone’ OR ‘follitrophin’ OR ‘follitropine’ OR ‘folltropin’ OR ‘fsh’ OR ‘ovagen’ OR ‘super ov’ OR ‘ovarian follicles’ OR ‘ovarian follicle’ OR ‘graafian follicle’ OR ‘graafian follicles’ OR ‘atretic follicle’ OR ‘atretic follicles’ OR ‘hfsh’ OR ‘anthrogon’ OR ‘antral follicle count’ OR ‘afc’ OR ‘anti-mullerian hormone’ OR ‘amh’ OR ‘anti mullerian hormone’ OR ‘antimuellerian hormone’ OR ‘antimullerian hormone’ OR ‘muellerian inhibiting substance’ OR ‘muellerian inhibitor’ OR ‘mullerian inhibiting factor’ OR ‘mullerian inhibiting substance’ OR ‘mullerian inhibitor’ OR ‘mullerian inhibiting hormone’ OR ‘mullerian-inhibitory substance’ OR ‘mullerian inhibitory substance’ OR ‘mullerian-inhibiting factor’ OR ‘mullerian-inhibiting hormone’ OR ‘anti-mullerian factor’ OR ‘anti mullerian factor’ OR ‘mullerian regression factor’) NOT ([animals]/lim NOT [humans]/lim) AND [english]/lim

PubMed

8/27/2013, Limits: English, 89 Results

(“Methotrexate”[Mesh] OR “methotrexate” OR “MTX” OR “4 amino 10 methylfolic acid” OR “4 amino n10 methylpteroylglutamic acid” OR “a methopterine” OR “amethopterin” OR “amethopterine” OR “ametopterine” OR “emthexat” OR “emtrexate” OR “folex” OR “ledertrexate” OR “metex” OR “methotrexat” OR “methoxtrexate” OR “methrotrexate” OR “methylaminopterin” OR “metoject” OR “metothrexate” OR “metotrexat” OR “metotrexate” OR “metrex” OR “mexate” OR “neotrexate” OR “nsc 740” OR “rheumatrex” OR “texate”) AND (“Ovarian Follicle”[Mesh] OR “Follicle Stimulating Hormone”[Mesh] OR “Anti-Mullerian Hormone”[Mesh] OR “ovarian reserve” OR “oocyte development” OR “ovary function” OR “ovary follicle” OR “ovary cycle” OR “follitropin” OR “Mullerian inhibiting factor” OR “oocyte reserve” OR “ovarian reserve” OR “ovarian responsiveness” OR “ovarian stimulation” OR “ovarian cycle” OR “ovulation cycle” OR “reproductive cycle” OR “ovarian activity” OR “ovarian function” OR “egg development” OR “oocyte growth” OR “oocytogenesis” OR “oogenesis” OR “ovogenesis” OR “ovum development” OR “oocyte maturation” OR “egg maturation” OR “follicle maturation” OR “fertiline” OR “follicle stimulating hormone” OR “follicotropin” OR “folliculostimulating hormone” OR “follitrophin” OR “follitropine” OR “folltropin” OR “FSH” OR “ovagen” OR “super ov” OR “Ovarian Follicles” OR “Ovarian Follicle” OR “Graafian Follicle” OR “Graafian Follicles” OR “Atretic Follicle” OR “Atretic Follicles” OR “hFSH” OR “Anthrogon” OR “Antral follicle count” OR “AFC” OR “Anti-Mullerian Hormone” OR “AMH” OR “anti mullerian hormone” OR “antimullerian hormone” OR “muellerian inhibiting substance” OR “mullerian inhibiting substance” OR “mullerian inhibitor” OR “Mullerian Inhibiting Hormone” OR “Mullerian-Inhibitory Substance” OR “Mullerian Inhibitory Substance” OR “Mullerian-Inhibiting Factor” OR “Mullerian-Inhibiting Hormone” OR “Anti-Mullerian Factor” OR “Anti Mullerian Factor” OR “Mullerian Regression Factor”) NOT ((“Animals”[Mesh]) NOT (“Animals”[Mesh] AND “Humans”[Mesh]))

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Boots, C.E., Hill, M.J., Feinberg, E.C. et al. Methotrexate does not affect ovarian reserve or subsequent assisted reproductive technology outcomes. J Assist Reprod Genet 33, 647–656 (2016). https://doi.org/10.1007/s10815-016-0683-7

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  • DOI: https://doi.org/10.1007/s10815-016-0683-7

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