The Playing Field is Changing . . .

7 01 2014

To the Editor:

The clinical practice of assisted reproductive technology (ART) has continued to evolve rapidly. The Practice Committee of the American Society for Reproductive Medicine (ASRM) in collaboration with the Society for Assisted Reproductive Technology (SART) in October 2012 e-published a guideline indicating that the cryopreservation of oocytes should no longer be experimental (1). As a direct result, the current system of data collection for SART and the Center for Disease Control and Prevention (CDC) requires revision. Additional data collection is required to comply with the Fertility Clinic Success Rate and Certification Act (FCSRCA) of 1992 (Wyden Law).

Moreover, other trends in ART practice have been identified. The freezing of embryos following blastocyst biopsy is often necessary to allow adequate time to obtain results of genetic testing prior to embryo transfer (2). Some clinics also freeze eggs or embryos from multiple stimulations/retrievals prior to transfer as a strategy to manage low responder patients (3). Critiques of our current reporting system together with suggested changes have recently been published by SART members (4, 5). SART has been well aware of these practice trends and the inability of our current reporting system to handle them. 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

Is universal application of blastocyst biopsy with comprehensive chromosome screening for embryo selection ready for prime time?

29 05 2013

To the Editor:

We read with great interest the article by Scott and colleagues, “Blastocyst biopsy with comprehensive chromosome screening and fresh embryo transfer significantly increases IVF implantation and delivery rates: a randomized controlled trial” (1). This is the highly anticipated third study of a planned three-phase initial strategy designed to validate the use of the authors’ rapid qPCR-based comprehensive chromosome screening (CCS) technology for embryo screening and selection.

In the first of the three studies, validation of the technology was confirmed using cell lines and discarded blastocysts of previously confirmed ploidy status (either aneuploid or euploid) (2). In the second study, the technology was shown to have a high negative predictive value (NPV, failure to deliver when aneuploid embryos were transferred) of 96% albeit the positive predictive value (PPV, delivery per euploid embryo transferred) was considerably lower at 41.4% (3). In this, the third, study comprising a randomized controlled trial (RCT) to assess clinical utility of CCS, results showed that use of CCS resulted in impressively high implantation and delivery rates (79.8% and 84.7%, respectively) which were, indeed, both significantly greater than those obtained from embryos transferred after morphological evaluation alone (63.2% and 67.5%).

We appreciate the forward-thinking approach of the investigators in their systematic approach to validate and then assess efficacy of the technology for embryo screening and selection. However, we would like to raise some queries regarding the results reported, as well as discuss several limitations of this study. Read the rest of this entry »

Whatever its variability, AMH remains the most stable hormonal predictor

8 04 2013

To the Editor:

Dr. Hadlow and colleagues argue that antimüllerian hormone (AMH) levels decrease in the luteal phase and that the hormone should be measured in the follicular phase, since this variability may lead to misprediction of ovarian response in IVF. This assumption was made on the basis of few, not frequent, blood samples performed on a very limited sample of women (1).

In the study, the intra-individual variability of AMH was found to be similar to that of FSH. This finding is really surprising and points out a critical revision of the results obtained. Both of the largest available studies to date (2, 3) reported that 89% of the variation in AMH was due to between-subjects variation, while only 11% was due to true individual fluctuations. AMH may exhibit some variability, but the important point is that the fluctuations are randomly distributed throughout the menstrual cycle (4), raising the possibility that a fixed day for its measurement, as proposed, would be useless. The suggested cyclic moifications of AMH in Dr. Hadlow’s study need to be confirmed in studies investigating hormonal variability through more frequent samples and across at least two menstrual cycles. A logical and agreeable hypothesis explaining why AMH should reduce in the luteal phase needed to be formulated by the authors. If AMH is produced by antral follicles, the number of which shows no significant reduction in the luteal phase, and since AMH seems to be only marginally influenced by gonadotropins, why should its concentration reduce in the second part of the cycle? Read the rest of this entry »

Response to commentary of Drs. Rosenwaks and Reichman: “But isn’t AMH still better than FSH?”

27 03 2013

To the Editor:

We sincerely appreciate Drs. Rosenwaks’ and Reichman’s commentary (1) on our opinion piece. We are especially grateful for their explicit reporting of their program’s IVF outcomes in cases of low AMH levels, which is the largest experience yet reported. (Perhaps our admittedly provocative title spurred their useful and pertinent report of these results.) Finding that 6.2 eggs were retrieved from 1,052 patients with an AMH below 0.5 ng/mL, resulting in a 25.7% clinical pregnancy rate per retrieval, is reassuring. Perhaps more surprising is the 19% clinical pregnancy rate per retrieval among the 224 patients with AMH levels below the limit of detection (<0.16 ng/mL), who on average produced 3.9 eggs. Pertinent to our case, however, is the high cancellation rate they report for these groups: 26.1% for those with an AMH <0.50 ng/mL, and 38.8% when the AMH was <0.16 ng/mL.

We agree with Drs. Rosenwaks and Reichman that patients “should not be dissuaded from pursuing IVF solely because of a low AMH value,” as one of us (JPT) previously cautioned regarding elevated FSH values (2). Nonetheless, we do believe we have an obligation to warn that low AMH levels predict low ovarian response, higher cancellation rates, and lower pregnancy rates. We also continue to believe that AMH is a more sensitive and specific marker of low response than FSH ever was, so we still prefer it to FSH for this purpose.

James P. Toner, M.D., Ph.D.
Atlanta Center for Reproductive Medicine, Atlanta, GA
David B. Seifer, M.D., Ph.D.
Genesis Fertility and Reproductive Medicine, Brooklyn, NY


(1) Rosenwaks Z, Reichman DE. Use of antimüllerian hormone: the risks of interpreting ovarian reserve markers in isolation. Fertil Steril 2013, in press.

(2) Toner JP. Modest FSH elevations in young women: warn but don’t disqualify. Fertil Steril 2004; 81: 1493-5.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2012.04.045

Is there a place for corifollitropin alfa in IVF/ICSI cycles? A systematic review and meta-analysis

29 02 2012

To the Editor:

As the sponsor of all four trials included in a recent systematic review and meta-analysis of corifollitropin alfa, we reviewed the manuscript authored by Youssef and co-workers (1) with great interest. This combined analysis includes two phase II dose-finding trials and two phase III randomized controlled trials.

Related to the OHSS incidence per woman randomized, the authors report on page 3 that the number needed to harm (NNH) is equal to 1. This is an obvious error. If the absolute risk increase is 1% as the authors state, the NNH should have been 100. However, the absolute risk increase is less than 1%. This can be demonstrated by combining the control OHSS rate of 2% (page 3) with the OHSS odds ratio of 1.29 (figure 2C). This gives an Elonva OHSS rate of 2.6%, an increase of 0.6% corresponding to an NNH of 177. In a recent pooled analysis by Tarlatzis (2), only the two phase III randomized controlled trials were included and the odds ratio for OHSS, adjusted for trial, was 1.18 (95%CI 0.81-1.71). Read the rest of this entry »

Defining Case Control Studies

6 04 2011

We read with great interest the article “Obstetric outcome of women with in vitro fertilization pregnancies hospitalized for ovarian hyperstimulation syndrome: a case-control study” by Courbiere et al. (1). It is our belief that, despite the title, the study did not adhere to the principles of a case-control study. Read the rest of this entry »