LETTER TO THE EDITOR Methotrexate for assisted reproductive technology (ART) ectopic pregnancy 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 after 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, the 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 (Evaluation of Therapeutic Strategies for Treatment of Ectopic Pregnancies and Evaluation of Subsequent Fertility) 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
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in infertile patients who may be more vulnerable to treatment effects owing 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 regarding 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 a Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland; and b Shady Grove Fertility Reproductive Science Center, Rockville, Maryland November 26, 2013 http://dx.doi.org/10.1016/j.fertnstert.2013.11.124
REFERENCES 1. 2.
Moragianni VA. Methotrexate treatment of ectopic pregnancies does not affect ovarian reserve in IVF patients. Fertil Steril 2014;101:337–8. 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 2014; 101:413–9. 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.