The effect of methotrexate injection for treatment of an ectopic pregnancy on ovarian reserve

7 01 2014

To the Editor:

We read with great interest the paper “Does methotrexate administration for ectopic pregnancy after in vitro fertilization (IVF) impact ovarian reserve or ovarian responsiveness?” by Boots et al. (1). In the article, the authors evaluated the effects of methotrexate (MTX) on the future fertility of women undergoing IVF by comparing markers of ovarian reserve (day 3 FSH, antral follicle count), measures of ovarian responsiveness (duration of stimulation, peak E2 level, total dose of gonadotropins, number of oocytes retrieved, fertilization rate), and time from MTX administration to subsequent IVF cycle, in the IVF cycle before and after an ectopic pregnancy (EP) treated with MTX. They concluded that MTX treatment of an EP does not compromise ovarian reserve or ovarian responsiveness in subsequent cycles. However, other studies have demonstrated that when gonadotropin stimulation dose remains unchanged, fewer oocytes may be collected after MTX is taken as management of an ectopic pregnancy, suggesting a decrease in ovarian reserve (2). Read the rest of this entry »


Regarding “Medical treatment of ectopic pregnancy: a committee opinion”

6 12 2013

To the Editor:

We welcome the recently published article by the Practice Committee of the American Society for Reproductive Medicine on the medical treatment of ectopic pregnancy (EP) (1). In selected patients, Methotrexate (MTX) is an effective treatment for unruptured EP and helps to avoid surgical intervention.

We are however concerned about some aspects of the committee’s opinion. The document advocates the use of single measurements of serum human chorionic gonadotropin (hCG) as a discriminatory zone to separate abnormal from normal gestations at the first presentation, if a transvaginal ultrasound scan (TVS) fails to identify the location of a pregnancy. This approach is not without risk. For example, it does not take into account the possibility of a multiple pregnancy where for a given gestational age serum hCG levels are higher than in a singleton. Consequently, hCG levels in multiple pregnancies are usually much higher before the pregnancy reaches a size that may be visualized on TVS (2). This could result in the administration of MTX to a woman with a pregnancy of unknown location (PUL) who has a developing twin pregnancy rather than an underlying EP. Such an outcome would in all likelihood lead to major congenital abnormalities in the developing fetuses. We recommend that the diagnosis of EP be based on the positive identification of an EP mass if inappropriate use of MTX is to be avoided. In the event of a PUL, waiting 48 hours to determine the hCG ratio has been shown to be a safe management approach, which offers further reassurance if the ratio is incompatible with a viable IUP (3). Read the rest of this entry »

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

Gestational Sac Aspiration and Instillation for Treatment of Early Ectopic Pregnancy

14 09 2011

To the Editor:

We thank Cepni et al. for sharing their recent case series, “An alternative treatment option in tubal ectopic pregnancies with fetal heartbeat: aspiration of the embryo followed by single-dose methotrexate administration” (1). This was of great interest to us, as we have used a similar aspiration and instillation technique using hyperosmolar glucose to treat a heterotopic pregnancy created after in vitro fertilization (IVF). Read the rest of this entry »