Andrea Vidali

Successful treatment of unresponsive thin endometrium

OBJECTIVE To assess whether inadequate, thin endometrium (<7 mm), after failure to expand with standard treatment options, will be responsive to cytokine treatment. DESIGN Prospective cohort study of four patients. SETTING Two independent IVF centers in New York City. PATIENT(S) Four consecutive women undergoing IVF who, after standard endometrial preparation, still demonstrated highly inadequate endometrium. INTERVENTION(S) Transvaginal endometrial perfusion with granulocyte colony-stimulating factor (G-CSF). MAIN OUTCOME MEASURE(S) Endometrial thickness on day of ET, with pregnancy as secondary endpoint. RESULT(S) We report successful endometrial expansion to at least minimal thickness of 7 mm after uterine perfusion with G-CSF in four patients previously resistant to treatment with estrogen and vasodilators. All four patients therefore reached ET, and all four also conceived, although one pregnancy required termination because of intramural, corneal ectopic location. Endometrial expansion to minimal thickness occurred within approximately 48 hours from infusion. CONCLUSION(S) Uterine perfusion with G-CSF represents a promising new tool for the currently mostly intractable problem of inadequate, thin endometrium. This treatment also deserves further investigation for its potential to improve implantation chances in association with IVF and, therefore, pregnancy rates.

The status of public reporting of clinical outcomes in assisted reproductive technology

OBJECTIVE To assess the transparency of assisted reproductive technology (ART) surveillance reports published by the Centers for Disease Control and Prevention (CDC) and by the Society for Assisted Reproductive Technologies (SART). DESIGN Retrospective analysis. SETTING Private clinical ART and research center. PATIENT(S) We analyzed ART data for the years 2005-2010, which were reported under federal mandate to the CDC (818,927 completed cycles) and voluntarily to SART (812,400 initiated cycles). INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Initiated cycles excluded from final outcome reporting were used to evaluate transparency. RESULT(S) Only SART, but not CDC, reported initiated cycles, allowing analysis of excluded cycles. Excluded cycles increased significantly from 3.3% to 7.4% between 2005 and 2010. By 2010, 13/341 (3.8%) ART centers accounted for 50% of excluded cycles, representing an average of 37.3% of their cycles. These 13 clinics reported significantly better pregnancy and cancellations rates than national averages and collectively increased by 19.9% their share of U.S. ART cycles. CONCLUSION(S) Our data indicate decreasing transparency in public ART reporting in the United States, likely due to changes in practice and reporting patterns. A few clinics accounted for the majority of excluded cycles, leading to improved reported clinical outcomes and increasing market share. CDC and SART should ensure that all ART clinics publicly report the outcomes of all initiated cycles including embryo-banking cycles. ART surveillance and quality of care may be improved by prospectively tracking the total reproductive potential of each initiated cycle.

The utility of serum progesterone and inhibin A for monitoring natural-cycle IVF-ET

Purpose:Our purpose was to assess the value of monitoring serum P and inhibin A to determine how values might improve the clinical monitoring of natural cycle in vitro fertilization (IVF)-embryo transfer (ET) patients.Methods:All patients (n = 26) who underwent natural-cycle IVF-ET (n = 35) were analyzed. Groups were evaluated according to patients who had a spontaneous luteinizing hormone (LH) surge (group I) and women receiving human chorionic gonadotropin (hCG) who underwent subsequent oocyte aspiration (group II). Group II was further evaluated according to women who did (n = 10) and did not (n = 7) have an ET. All cycles were evaluated with serial transvaginal ultrasonography and serum estradiol, progesterone, and inhibin A. When follicle maturity was achieved, hCG, 10,000 IU, was administered intramuscularly if a LH surge was not detected. Transvaginal ultrasound-guided aspiration was performed 34–36 hr after hCG administration followed by a 48-hr transcervical ET.Results:No differences were seen in cycles the day prior to (d-1) and the day of a spontaneous LH surge, (n = 18) or hCG (d-0)(n = 17) in group I or group II with respect to lead follicular diameter (d-1,15.3 ± 0.6 vs. 14.2 ± 0.9 mm; d-0, 17.4 ± 0.8 vs. 17.8 ± 0.6 mm) and serum estradiol (d-l, 148 ± 15 vs. 150 ± 15 pg/ml; d-0, 218 ± 15 vs. 199 ± 16 pg/ml), respectively. However, serum progesterone was significantly elevated in group I compared with group II on d-l (0.82 ± 0.6 vs. 0.48 ± 0.04 ng/ml; P < 0.05) and d-0 (1.1 ± 0.12 vs. 0.63 ± 0.08 ng/ml; P < 0.05). Inhibin A was significantly greater on d-l in group I (24 ± 2.5 vs. 15 ± 2.2 pg/ml; P < 0.05). In group II, cycles that resulted in an ET (n = 10) compared with group II cycles that did not (n = 7) revealed a significant difference in serum progesterone (0.51 ± 0.05 vs. 0.7 ± 0.07 ng/ml; P < 0.05) and inhibin A (15 ± 2.5 vs. 37.3±5 pg/ml; P < 0.05) the day of hCG.Conclusions:The possible application of serum progesterone and inhibin A in managing natural-cycle IVF-ET is suggested. These assays may predict women who should be set up for egg retrieval, while canceling others in spite of the absence of an LH surge.

Response to comment on: Gleicher N et al., 2016. Reprod biol endocrinol Sep 5;14(1):54

We appreciate the interest of Tiegs et al. in our manuscript [1] but find the criticism surprising. When we wrote our paper, their abstract had been published in 2015 in Fertility&Sterility [2]. It, therefore, was appropriately referenced, while their full length manuscript, in contrast, had not yet been published and, therefore, was at the time unknown to us. The manuscript appeared only at the end of July [3]. Had we known of the manuscript we, of course, would have quoted the full length manuscript, rather than the abstract, though both in the end offered the same data set, out of a total of 525 embryo transfers, reporting on only 5 alleged clinical misdiagnoses that were reanalyzed. It is important to note that, therefore, only these 5 cases (and not 525 cases) underwent a second preimplantation genetic screening (PGS) testing round, thereby offering the opportunity to reevaluate only these cases for the possible presence of mosaicism. It is also noteworthy that this repeat testing was done with the same testing platform as before, array genomic hybridization (aCGH), which since has been declared “inadequate” for PGS testing by the PGD International Society (PGDIS) since aCGH cannot reliably detect mosaicism [4]. We will further discuss this fact below in more detail. Based on the repeat testing round, Tiegs et al. concluded that 2/5 embryos (40%) were mosaic because repeat testing gave different results. The remaining 520 embryos were, however, not reexamined. To, therefore, suggest that the mosaicism rate was 2/525 rather than 2/5 is incorrect. The authors, of course, have no way of knowing to what degree results of a second testing round of these 520 embryos would have differed from the first round. As the results of our study demonstrated, even within the same PGS laboratory multiple embryo biopsies from same embryos diverged in approximately 50 percent of embryos [1]. Others reported similar outcomes from multiple biopsies [5], and even the PGDIS has acknowledged this fact [4]. We, of course, do acknowledge that five embryos represent a small sample size but, until publication of our study [1], the literature really offered almost no data on embryos undergoing repeat and/or multiple biopsies. Even our study only reported on 11 embryos that underwent repeat biopsies. Tiegs et al., however, factually misrepresented our manuscript in their letter to the editors when claiming that we failed to point out that their study included only five cases. Very much to the contrary, this is exactly what we did when writing: “The small number of evaluated embryos (referring to our study) does not allow ultimate conclusions about what likely mosaicism rates in human embryos may be. Here presented data do, however, suggest that they are significantly higher than the 4.8% rate recently detected by Greco et al. [reference] and more in line with the 2/5 (40%) recently reported by Tiegs et al. [Reference].” We, thus, very clearly pointed out the small number of cases in their report. Because the basic concept of PGS is being questioned on theoretical, experimental and clinical grounds, our specialty is currently in the midst of an at times unfortunately vitriolic dispute about the clinical value of PGS. The work of our, an Italian [6] and an Israeli group [5] basically forced the PGDIS in July of this year to radically redefine how PGS results should be reported out [4]. In revised guidelines the PGDIS fully acknowledges that mosaicism at blastocyst stage is apparently much more * Correspondence: ngleicher@thechr.com The Center for Reproduction, 21 E 69th St, New York, NY 10021, USA The Foundation for Reproductive Medicine, New York, USA Full list of author information is available at the end of the article

Letter to the editorReply of the Authors

REPLY OF THE AUTHORS: We appreciate the interest of Kissin et al. (1) from the National ART Surveillance System (NASS) group at the Centers for Disease Control and Prevention (CDC) in our recent article. Our article also apparently prompted a communication from the president of the Society for Assisted Reproductive Technology (SART) to member clinics, acknowledging the issues we raised with public ART surveillance and promising to find a solution to improve transparency of future reports. Both of these communications confirm that a rapidly growing number of initiated in vitro fertilization (IVF) cycles with no reported outcomes are being categorized as embryo banking. The NASS team, furthermore, highlights the evergrowing number of indications for embryo banking. One cannot help but wonder whether the ‘‘observer effect,’’ and resulting competition among ART clinics to achieve superior pregnancy outcomes, may actually incentivize diversion into embryo banking of the patients with a less favorable prognosis. Our findings suggest that selective embryo banking for older patients (that is, unfavorable cycles) improved the reported pregnancy rates and increased the market share of the clinics that disproportionately practice embryo banking. The NASS letter suggests that we may incorrectly assume that clinics consciously choose to exclude cycles. Our study, however, suggests the opposite: we demonstrate that an overwhelming majority of clinics, based on a statistical distribution curve, report data accurately and within the intended framework allowed by the SART and the CDC. A small minority, however, clearly fall outside the norm and report excluded cycles that disproportionately involve older patients. Whether this happens with or without intent matters little because the consequence of such misleading reporting is the same: clinical pregnancy rates are artificially inflated, and the public is misled. The outdated reporting algorithms of SART and CDC undoubtedly contribute to the current situation, as the NASS letter and the call to action by SART appear to acknowledge. This, however, does not absolve centers from responsible reporting. It does not take extraordinary statistical expertise to recognize that a programs pregnancy outcomes will be artificially inflated if the worst prognosis patients are routinely excluded from consideration.

An unusual case of rebound ovulation during conservative management of an ectopic pregnancy following ovum donation

SummaryConservative medical management of ectopic gestations may be difficult in patients with elevated levels of β-hCG and cardiac activity. This case highlights the difficulty of managing such patients. Doppler flow studies and serum P, if available, should be used and can help determine those patients requiring repeated dosing of methotrexate. Patients using donor gametes and hormonal supplementation who subsequently develop an ectopic gestation may experience “re-bound” ovulation, which further clouds the clinical picture. Careful follow-up using serial blood testing and ultrasound study is essential in the correct interpretation of a potentially confusing clinical picture.