Ovarian reserve and subsequent assisted reproduction outcomes after methotrexate therapy for ectopic pregnancy or pregnancy of unknown location

Administration of methotrexate for confirmed or suspected ectopic gestation after assisted reproduction and ovarian stimulation does not result in decreased markers of ovarian reserve or altered assisted reproduction outcomes.

Micah J. Hill, D.O., Janelle C. Cooper, M.D., Gary Levy, M.D., Connie Alford, M.D., Kevin S. Richter, Ph.D., Alan H. DeCherney, M.D., Charles Katz, M.D., Eric D. Levens, M.D., Erin F. Wolff, M.D.

Volume 101, Issue 2, Pages 413-419.e4, February 2014


To assess ovarian reserve after methotrexate treatment for ectopic pregnancy or pregnancy of unknown location after assisted reproductive technology (ART).

Retrospective cohort study.

Large ART practice.

Women receiving methotrexate or surgery after ART.


Main Outcome Measure(s):
Follicle-stimulating hormone (FSH), antral follicle count (AFC), and oocyte yield compared between women treated with methotrexate or surgery, with secondary outcomes of clinical pregnancy and live birth.

There were 153 patients in the methotrexate group and 36 patients in the surgery group. Neither group demonstrated differences in ovarian reserve or oocyte yield in a comparison of the before and after treatment values. The change in ovarian reserve and oocyte yield after treatment were similar between the two groups. The number of doses of methotrexate was not correlated with changes in ovarian reserve, indicating no dose-dependent effect. Time between treatment and repeat ART was not correlated with outcomes. Live birth in subsequent cycles was similar in the two groups.

Ovarian reserve and subsequent ART cycle outcomes were reassuring after methotrexate or surgical management of ectopic pregnancy. No adverse impact of methotrexate was detected in this large fertility cohort as has been previously described elsewhere.

  • Amanda N. Kallen

    Micah, this will be very helpful in couselling patients for ectopic pregnancy treatment. I am curious as to whether the surgical treatment group included patients receiving both salpingectomy and salpingostomy? If the “surgical” patients received salpingostomy only, it would be interesting in the future to see whether salpingectomy is also comparable to MTX in terms of ovarian reserve.

    • Micah Hill

      Thanks Amanda for the question! We didn’t have definitive enough data on the surgical management to breakdown salpingectomy versus salpingostomy. The DEMETER trial last year in HR didn’t see any difference in spontaneous pregnancy following MTX or conservative surgery or “radical surgery”. Although this is data from spontaneously pregnant patients, it is at least reassuring. Certainly the ART patients may be at more risk and logically salpingectomy would have more potential disruption in ovarian blood flow than salpingostomy. I think your question is a great one, but I don’t have the answer for it!

      • Amanda N. Kallen

        Thanks, Micah. The info about the DEMETER trial is also reassuring and I would think, based on that info, that your results would be generalizable to both radical and conservative surgery as well. Great paper!

  • Lauren Johnson

    Congratulations Micah on publication of your manuscript. This article appears to have generated quite a bit of discussion in F&S already!

    I do have a question about the paper. Your primary outcomes were change in FSH, AFC and oocyte yield after treatment for ectopic pregnancy. However, changes in FSH and AFC can only be calculated for those who returned for fertility treatment, and oocyte yield would only be calculated for those who underwent another fresh IVF cycle and made it to oocyte retrieval. My concern is that patients with DOR, which is the group most likely to be susceptible to the effects of a chemotherapeutic agent, may be less likely to undergo another cycle and would be at higher risk of cancellation if they did undergo another cycle. Thus, the group at the highest risk would also be most likely to be excluded from the analysis. Do you have any information about patients who were lost to follow-up or did not undergo oocyte retrieval after ectopic pregnancy?

    • Micah Hill

      That’s a really great point Lauren! What you say is true, that we potentially lose data on those who had DOR. The number of patients who did not follow up with another cycle was relatively low a (<10% of the overall cohort of ectopics during the time perdiod) but I don't have any data on post treatment ovarian reserve for patients that did no do a repeat cycle. We only had 5 patients with DOR in our cohort, and they had no negative effect of MTX in their follow-up cycle, but that number is obviously very small and limited. With only 5 DOR ectopics with follow-up testing out of 23,000 fresh autologous cycles during our study time frame, it would take huge (probably nation level) data to answer your question!

      • Lauren Johnson

        Thanks for your response, Micah. It’s great to hear that more than 90% of the cohort returned for another cycle. That suggests to me that the likelihood of selection bias due to loss of follow-up is low. Congratulations again on your paper!

  • Micah Hill

    We appreciate the opportunity to discuss our article on methotrexate and salpingectomy after IVF ectopic pregnancies. The data collected over 7 years at our practice demonstrated no adverse effect on ovarian reserve or subsequent IVF cycle outcomes from either methotrexate of salpingectomy. While we await RCT data on this topic, the bulk of current literature seems reassuring that current clinical management options are not detrimental to future reproductive capacity. I look forward to any question or comments on this topic.

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