Reply to commentary “Methotrexate treatment of ectopic pregnancies does not affect ovarian reserve in IVF patients”

26 11 2013

To the Editor:

We read with interest the editorial commentary by Dr. Moragianni (1) on our recent publication, evaluating the effect of methotrexate on ovarian reserve and subsequent assisted reproductive technology (ART) treatment outcomes (2). The potential adverse effects of methotrexate, specifically when used in infertile patients following ovarian hyperstimulation for ART, remain an important issue. As Dr. Moragianni summarizes, the majority of the literature does not demonstrate an adverse effect of methotrexate. However, these data are limited by the fact that all of the current studies are retrospective. An adequately powered randomized controlled trial would be the most appropriate way to answer this question definitively. However, the low rate of ectopic pregnancy occurring after ART has made addressing this issue in a prospective manner a challenge. Our study required a 7-year time span at a busy ART program to accrue 189 patients.

The DEMETER trial published earlier this year serves as a good study model to address this question (3). The DEMETER trial took place in 17 centers in France over a 5-year time frame, randomizing spontaneously occurring ectopic pregnancies in fertile women to methotrexate or conservative surgery. Two-hundred subjects were necessary to have a power of 80% to detect a 20% difference in subsequent cumulative fertility rates. Two years after treatment, the cumulative pregnancy rates were 67% in the methotrexate arm and 71% in the surgical arm, demonstrating no significant adverse effect of methotrexate on fertility in a spontaneously fertile population. We agree with Dr. Moragianni that a large randomized controlled trial is needed to definitively address this question in infertile patients who may be more vulnerable to treatment effects due to diminished ovarian reserve and ovarian hyperstimulation. Based on the large expected sample size, it is clear that a multicenter collaborative effort similar to the DEMETER trial would be needed to recruit a sufficient number of patients to be appropriately powered. Nevertheless, the current collective literature on methotrexate use in ART and naturally occurring ectopic pregnancies appears to be reassuring with respect to effects on ovarian reserve parameters and subsequent pregnancy.

Micah J. Hill, D.O.a
Eric D. Levens, M.D.b
Erin F. Wolff, M.D.a
aProgram in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
bShady Grove Fertility Reproductive Science Center, Rockville, MD


1. Moragianni VA. Methotrexate treatment of ectopic pregnancies does not affect ovarian reserve in IVF patients. Fertil Steril, in press.

2. Hill MJ, Cooper JC, Levy G, Alford C, Richter KS, DeCherney AH, et al. Ovarian reserve and subsequent ART outcomes following methotrexate therapy for ectopic pregnancy and pregnancy of unknown location. Fertil Steril, in press.

3. Fernandez H, Capmas P, Lucot JP, Resch B, Panel P, Bouyer J. Fertility after ectopic pregnancy: the DEMETER randomized trial. Hum Reprod 2013;28:1247-53.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2013.11.124