Estradiol to progesterone ratio is not a predictor of oocyte maturity at time of ovulation trigger.

PURPOSE: To evaluate the relationship between progesterone and oocyte maturity rate via estradiol to progesterone ratio (E/P) at the time of ovulatory trigger. METHODS: This is a retrospective cohort study of first autologous IVF cycles from January to December 2018 from a private practice fertility center. Serum estradiol and progesterone levels were measured on the day of ovulatory trigger. E/P was calculated to control for degree of response. Embryos were cultured to the blastocyst stage for trophectoderm biopsy. Preimplantation genetic testing for aneuploidy (PGT-A) was performed using next-generation sequencing (NGS). Oocyte retrieval rate (oocytes retrieved/follicles ≥ 13 mm), maturity rate (MII/oocytes retrieved), and euploid rate (euploid/total biopsied embryos) were calculated. Clinical pregnancy, ongoing pregnancy (> 10 weeks), and live births following frozen embryo transfer (FET) were examined in relation to E/P. Regression analyses were performed to analyze E/P as a categorical value (defined by quartile) on oocyte maturity. RESULTS: Two hundred eleven women underwent controlled ovarian hyperstimulation and had steroid levels at trigger available. Mean E at trigger was 3449 ± 2040 pg/mL while mean P was 1.13 ± 0.58 ng/mL, with mean E/P of 3.36 + 2.04. There were no differences between quartiles of E/P with respect to retrieval, maturity rate, or euploid rate. Two hundred eleven IVF cycles resulted in 138 euploid frozen embryo transfers. There were no differences between quartiles of E/P with respect to clinical pregnancy, ongoing pregnancy, or live birth rate. CONCLUSION: E/P ratio at the time of trigger does not impact oocyte retrieval rate, maturity rate, or euploid rate. Pregnancy and live birth outcomes were also not impacted.

Euploid rates among oocyte donors: is there an optimal age for donation?

PURPOSE: To examine cycle blastocyst euploid rates among age subgroups of oocyte donors. METHODS: Retrospective cohort analysis of ova donation in vitro fertilization cycles (OD-IVF) for which trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) by array comparative genomic hybridization (aCGH) or next generation gene sequencing (NGS) was employed between January 2015 and December 2018 in a single high-volume fertility center. RESULTS: Compared to oocyte donors age 26-30, oocyte donors age ≤ 25 had similar cycle blastocyst euploid rates (80 [66.7, 87.5]%, vs. 75 [62.5, 87.5]%, median [IQR], p = 0.07), blastocyst formation rates (66.7 [50, 75]%, vs. 62.5 [52, 75]%, p = 0.55), and number of retrieved oocytes (29 [23, 37] vs. 27 [20, 35], p = 0.18). Age of oocyte donor from 18 to 34 was not correlated with cycle blastocyst euploid rate. CONCLUSION: Oocyte donors age ≤ 25 had similar cycle blastocyst euploid rates, blastocyst formation rates, and number of retrieved oocytes compared to donors age 26-30. There was no correlation between cycle blastocyst euploid rates and age of the oocyte donor from 18 to 34 years. Given the lack of significant age-related change in cycle blastocyst euploid rates, our data support existing practices which do not favor a specific age subgroup of young oocyte donors.

Follicle-stimulating hormone receptor autoantibody associated primary ovarian insufficiency successfully treated with corticosteroids: a case report.

OBJECTIVE: To report a case of successful controlled ovarian stimulation (COH) for oocyte cryopreservation in a patient with autoimmune primary ovarian insufficiency (POI) and polyglandular autoimmune syndrome (PGAS) type 2. DESIGN: Case report. SETTING: Private in vitro fertilization clinic. PATIENTS: 25-Year-old woman, G0, with autoimmune POI and PGAS type 2. INTERVENTIONS: Diagnosis of autoimmune interference with FSH signaling, with subsequent high-dose corticosteroid immune suppression and successful oocyte cryopreservation. MAIN OUTCOMES MEASURES: Successful stimulation with exogenous gonadotropins, oocyte retrieval, and cryopreservation. RESULTS: Retrieval and cryopreservation of 36 metaphase-II (MII) oocytes. CONCLUSIONS: Scrutiny of POI cases will facilitate identification of a subset of patients in whom immune suppression with short-term, high-dose corticosteroids may enable successful COH.

Current status of spent embryo media research for preimplantation genetic testing.

In recent years, a growing body of literature has emerged investigating the clinical utility of spent embryo media (SEM) for preimplantation genetic testing for aneuploidy (PGT-A) (Hammond et al. in Fertil Steril. 107(1):220-8, 2017; Xu et al. in Proc Natl Acad Sci USA. 113(42):11907-12, 2016; Shamonki et al. in Fertil Steril. 106(6):1312-8, 2016; Feichtinger et al. in Reprod BioMed Online. 34(6):583-9, 2017; Vera-Rodriguez et al. in Hum Reprod. 33(4):745-56, 2018; Kuznyetsov et al. in PLoS One. 13(5):e0197262, 2018; Ho et al. in Fertil Steril. 110(3):467-75, 2018; Capalbo et al. in Fertil Steril. 110(5):870-9, 2018). Most of these studies have reported moderate success rates, suggesting the need for improvements in sensitivity and specificity. The concordance between spent media and embryo biopsy or whole embryo was reported to be between 30.4 and 90%, with 50-70% correlation being the most representative (Xu et al. in Proc Natl Acad Sci USA. 113(42):11907-12, 2016; Shamonki et al. in Fertil Steril. 106(6):1312-8, 2016; Feichtinger et al. in Reprod BioMed Online. 34(6):583-9, 2017; Vera-Rodriguez et al. in Hum Reprod. 33(4):745-56, 2018; Kuznyetsov et al. in PLoS One. 13(5):e0197262, 2018; Ho et al. in Fertil Steril. 110(3):467-75, 2018). Here, we will analyze all spent media testing strategies including SEM collection methods, whole genome amplification (WGA) strategies, chromosome copy number detection, and bioinformatics analysis tools. We will propose improvements to further increase the accuracy and sensitivity of the assay before bringing PGT-A with SEM into the clinical sphere.

Transfer of embryos with segmental mosaicism is associated with a significant reduction in live-birth rate.

OBJECTIVE: To evaluate the impact of segmental mosaicism on pregnancy outcomes from the transfer of embryos previously designated as euploid. DESIGN: Retrospective cohort analysis. SETTING: Single, private, high-volume fertility center. PATIENT(S): Three hundred and twenty-seven women who underwent 377 frozen single euploid embryo transfers. INTERVENTION(S): Trophectoderm biopsy of embryos cultured to the blastocyst stage, where all transferred embryos were designated euploid by high-density oligonucleotide array comparative genomic hybridization (aCGH); after ascertaining all outcomes, revaluation of aCGH results for evidence of segmental mosaicism (defined as mosaicism on a portion of a chromosome). MAIN OUTCOME MEASURE(S): Live-birth rate and spontaneous abortion rate. RESULT(S): Of the 377 embryos transferred, 357 were euploid with no mosaicism, and 20 embryos had segmental mosaicism. Segmental mosaics had a statistically significantly lower live-birth rate compared with euploid controls (30.0% vs. 53.8%). When controlling for age and day of Trophectoderm biopsy, the odds for live birth after transfer of segmental mosaics were reduced by 66% compared with euploid controls (0.34; 95% confidence interval, 0.13-0.92). The spontaneous abortion rate was statistically significantly higher after transfer of segmental mosaics compared with euploid controls (40.0% vs. 18.2%). CONCLUSION(S): Blastocysts with segmental mosaicism have reduced reproductive potential but retain the ability to result in live birth. These results support reporting segmental mosaicism to optimize selection of a single embryo for transfer that will maximize the chance of life birth.

Earlier day of blastocyst development is predictive of embryonic euploidy across all ages: essential data for physician decision-making and counseling patients.

PURPOSE: The purpose of this study is to evaluate whether day of blastocyst development is associated with embryo chromosomal status as determined by high-density oligonucleotide microarray comparative genomic hybridization (aCGH). METHODS: This is a retrospective cohort analysis, including women who underwent in vitro fertilization (IVF) with trophectoderm biopsy at a single private fertility center from January 2014 to December 2014. Repeat cycles were excluded. Cycles were assessed for percentage of blastocysts biopsied on days 5, 6, or 7 and rate of euploid embryos per cycle. Cycles were stratified by Society for Assisted Reproductive Technology (SART) age groups (< 35, 35-37, 38-40, 41-42, > 42) and by donor status. RESULTS: A total of 388 IVF cycles and 2132 biopsied blastocysts were evaluated. The percentages of blastocysts biopsied on days 5, 6, and 7 were 62.5, 35.8, and 1.7%, respectively. Blastocyst euploid rates on days 5, 6, and 7 were 49.5, 36.5, and 32.9%, respectively. Earlier blastocyst development was associated with a significantly increased euploid rate (p < 0.0001). Younger maternal age (p < 0.0001) and higher number of blastocysts biopsied per patient (p = 0.0063) were both independently associated with greater percentage of euploidy. CONCLUSIONS: Earlier blastocyst development is independently associated with a higher likelihood of embryonic euploidy in both autologous and donor embryos. In non-biopsied embryos, these data support selection of day 5 blastocysts for transfer over later-developing embryos. These results can assist with patient counseling regarding expectations and outcomes. To our knowledge, this is the first study to examine embryonic euploidy as stratified by both day of blastocyst development and SART age group.

Attributes That Fellowship Directors Value in the Selection of Reproductive Endocrinology and Infertility Fellows.

OBJECTIVE: To investigate which attributes of reproductive endocrinology and infertility (REI) fellowship applicants are most valued by fellowship program directors during the match process. STUDY DESIGN: An electronic survey was administered to determine characteristics most favored by program directors in the selection of REI fellows. A 5-point Likert scale was utilized to rank characteristics, with 1 being "most important" and 5 being" least important." The main outcome measures were factors desired by REI fellowship directors. RESULTS: The overall response rate was 61%. Objective factors that ranked highly were training at a competitive obstetrics and gynecology (OB/GYN) residency program, and clinical or basic science research experience. First authorship research ranked favorably regardless of whether it was in the form of a peer-reviewed paper, oral presentation, or poster abstract. Personal interview and perceived ability to work well with others were subjective factors considered favorably by REI fellowship directors. CONCLUSION: When selecting REI fellows for interviews, fellowship directors value candidates who have trained at competitive OB/GYN residency programs, who have clinical or basic science research experience, and who have contributed to scientific literature as first author. When subsequently ranking fellowship applicants, however, the most important factors are those found in the interview process, such as identification as a "team player".

Cost-Benefit Analysis of Hysteroscopic Polypectomy Before Controlled Ovarian Hyperstimulation and Intrauterine Insemination in Infertile Women.

Objective: To examine the cost benefit of performing hysteroscopic polypectomy (HP) in infertile women with endometrial polyp(s) before controlled ovarian hyperstimulation with intrauterine insemination (COH/IUI). Study Design: Decision analytic model comparing costs and clinical outcomes. Results: HP and COH/IUI costs ranged from $537­$12,530 and $800­$7,600, respectively. Performing an HP before COH/IUI lowered fertility cost by $7,652 per clinical pregnancy. When COH/IUI costs remained constant, HP was most cost beneficial when the cost of HP was below a threshold value of $9,452. When HP costs remained constant, the threshold value at which HP was no longer cost beneficial was at COH/IUI costs below $704. The cost benefit was greatest when an office-based HP is performed. Conclusion: HP before COH/IUI is more cost beneficial than fertility treatment alone, particularly when office-based hysteroscopy is performed.

Proof of concept: preimplantation genetic screening without embryo biopsy through analysis of cell-free DNA in spent embryo culture media.

OBJECTIVE: To assess whether preimplantation genetic screening (PGS) is possible by testing for free embryonic DNA in spent IVF media from embryos undergoing trophectoderm biopsy. DESIGN: Prospective cohort analysis. SETTING: Academic fertility center. PATIENT(S): Seven patients undergoing IVF and 57 embryos undergoing trophectoderm biopsy for PGS. INTERVENTION(S): On day 3 of development, each embryo was placed in a separate media droplet. All biopsied embryos received a PGS result by array comparative genomic hybridization. Preimplantation genetic screening was performed on amplified DNA extracted from media and results were compared with PGS results for the corresponding biopsy. MAIN OUTCOME MEASURE(S): [1] Presence of DNA in spent IVF culture media. [2] Correlation between genetic screening result from spent media and corresponding biopsy. RESULT(S): Fifty-five samples had detectable DNA ranging from 2-642 ng/µL after a 2-hour amplification. Six samples with the highest DNA levels underwent PGS, rendering one result with a derivative log ratio SD (DLRSD) of <0.85 (a quality control metric of oligonucleotide array comparative genomic hybridization). The fluid sample and trophectoderm results were identical demonstrating (45XY, -13). Three samples were reamplified 1 hour later and tested showing improving DLRSD. One of the three samples with a DLRSD of 0.85 demonstrated (46XY), consistent with the biopsy. Overnight DNA amplification showed DNA in all samples. CONCLUSION(S): We demonstrate two novel findings: the presence of free embryonic DNA in spent media and a result that is consistent with trophectoderm biopsy. Improvements in DNA collection, amplification, and testing may allow for PGS without biopsy in the future.

Logarithmic curves depicting initial level and rise of serum beta human chorionic gonadotropin and live delivery outcomes with in vitro fertilization: an analysis of 6021 pregnancies.

OBJECTIVE: To correlate the live delivery rate with the initial level and rise of serum beta-hCG. DESIGN: Retrospective cohort analysis. SETTING: Large private academic center for assisted reproductive technologies and infertility. PATIENT(S): Records of all patients from 1999 to 2005 undergoing IVF with detectable early serum beta-hCG after ET. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live delivery rate. RESULT(S): Data from 6021 pregnancies were analyzed. Initial beta-hCG was predictive for delivery rate for all patients and for each age group. After controlling for the first beta-hCG, there were higher loss rates as age increased. Percent rise in second beta-hCG drawn 2 days later added predictive value. A decline in beta-hCG almost always resulted in a failure to deliver. There was a progressive increase in delivery rate as the percent rise in beta-hCG went from 0 to 100%; however, there was no further enhancement in delivery rates beyond the 100% rise point. While a better rise in beta-hCG was a good prognostic factor in all age groups, the differences in outcomes for the different age groups remained, even after controlling for first beta-hCG and percent rise. CONCLUSION(S): Initial level and rise in beta-hCG predicts live delivery rate, with oocyte age providing additional predictive value. The established logarithmic curves should provide convenient reference tools for tracking outcomes and counseling patients.

Embryonic synergism may reduce pregnancy loss: a multivariate regression analysis.

OBJECTIVE: To evaluate clinical and assisted reproductive technology (ART) cycle variables related to spontaneous embryo reduction. DESIGN: Observational retrospective cohort study. SETTING: Private ART center. PATIENT(S): A total of 3,467 patients achieving a first-trimester pregnancy after IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rate of any spontaneous embryo reduction and rate of spontaneous single embryo reduction. RESULT(S): Adjusting for all analyzed variables, only initial gestational sac count, age, and body mass index were associated with the spontaneous embryo reduction rate. Twins had a lower chance of having a spontaneous embryo reduction than singletons (odds ratio 0.6, 95% confidence interval 0.50-0.79). When only spontaneous single embryo reduction was assessed, women with two or three initial gestational sacs were less prone to have a spontaneous single embryo reduction than women with one initial gestational sac. CONCLUSION(S): When spontaneous embryo reduction and spontaneous single embryo reduction were evaluated independently of other clinical and ART cycle variables, they were less frequent in twin pregnancies than in singleton pregnancies. This suggests a role for embryonic synergism in sustaining implantation.

Immunohistochemical expression of endometrial L-selectin ligand is higher in donor egg recipients with embryonic implantation.

OBJECTIVE: To correlate L-selectin ligand (LSL) expression in human endometrium with embryonic implantation. DESIGN: Retrospective cohort analysis. SETTING: University-based fertility center. PATIENT(S): Donor egg recipients (DERs) who underwent programmed hormonal replacement for ET with prior mock cycle luteal phase endometrial biopsy. INTERVENTION(S): Immunohistochemical expression of LSL using MECA-79 antibody was examined. Slides were scored with a new scoring system, the IHC-Level (range 0-4) as follows: strength of staining-absent (0), weak (1), or strong (2); plus distribution of staining-absent (0), <50% of tissue (1), and >50% (2). Cellular apex and cytoplasm were scored independently in both the endometrial glandular and surface epithelium. MAIN OUTCOME MEASURE(S): Endometrial LSL expression in pregnant versus nonpregnant patients. RESULT(S): MECA-79 IHC-Level of the apex of surface epithelium was significantly higher for pregnant versus nonpregnant DERs (3.8 vs. 3.4). When controlling for embryo morphology, there continues to be a significant difference in apex score on surface epithelium (3.8 vs. 3.3, respectively). The new scoring system results correlated with an established scoring system, the HSCORE. CONCLUSION(S): We demonstrate significantly higher expression of LSL at the apex of human endometrial surface epithelium obtained from DERs with embryonic implantation. Furthermore, we present the IHC-Level, a method of evaluating immunohistochemistry that may be applied to other markers of endometrial receptivity.

Oocyte and ovarian tissue cryopreservation: indications, techniques, and applications.

With recent advances in cryobiology, cryopreservation of the oocyte and ovarian tissue is rapidly becoming an important service provided by medical centers throughout the world. The general indication for oocyte or ovarian tissue cryopreservation is to retain future fertility potential for women who face the possibility of premature or imminent ovarian failure resulting from treatments for various disease states including cancer. Considering limitations imposed by age, lack of a partner, or sufficient time to undergo embryo cryopreservation, these patients have few options if they desire preservation of their fertility. The objective of this manuscript is to review the basic aspects of oocyte and ovarian tissue cryopreservation, and to discuss the current and future applications of these technologies in fertility preservation.

Ultrasound-guided trial transfer may be beneficial in preparation for an IVF cycle.

BACKGROUND: The objective of this study is to determine if ultrasound-guided trial transfer (UTT) in the office in preparation for an IVF cycle can be utilized as an alternative and/or adjunct to ultrasound-guided embryo transfer (UGET). METHODS: Patients planning to undergo an IVF cycle at an academic centre were included. Each patient underwent an UTT in the office by the same practitioner. The difference in length (DL), if any, was measured from the perceived top of the uterine cavity (catheter tip) to the actual cavity apex as visualized by ultrasound. RESULTS: Of the 64 patients enrolled, 19 patients (29.7%) had a measurable DL, of which 14 (21.9%) had a DL exists 0.5 cm, and nine (14.1%) had a DL exists 1.0 cm. Significant differences were noted between patients when comparing DL to previous pregnancy status and the total cavity depth (sounding depth + DL) (P < 0.05). CONCLUSION: UTT in the office setting appears to be beneficial in preparation for an IVF cycle with embryo transfer.

Ovarian tissue cryopreservation: benefits and risks.

An increasing number of women have been subjected to cytotoxic chemoradiotherapy for various malignant and nonmalignant diseases. Women who face the possibility of premature or imminent ovarian failure caused by cytotoxic therapy may retain their fertility potential with ovarian tissue cryopreservation. Until recently, this technique could only be performed in a few highly specialized institutions. However, with the latest advances in cryobiology, ovarian tissue cryopreservation is rapidly becoming a more widely offered technique by many medical centers around the world. The indications now extend beyond cancer. Even though the risk of re-implanting pre-existing cancer cells is minimal or non-existent for most types of cancer, this risk needs to be ascertained according to the cancer type and disease stage. The objective of this manuscript is to review the indications, risks and benefits of ovarian tissue cryopreservation.

Ultrasound-guided embryo transfer and the accuracy of trial embryo transfer.

BACKGROUND: Studies have suggested that ultrasound-guided embryo transfer (UG-ET) may improve the outcome in IVF; however, several factors may account for the improvement in pregnancy rate. This study examines the use of ultrasound to determine the accuracy of trial transfer (TT) in preparation for ET. METHODS: Sixty-seven consecutive patients prospectively underwent UG-ET over a 2 month period. Total cavity length by US was compared with the length noted by TT. A difference of > or = 1 cm was considered significant. All embryos were placed within 1-2 cm of the fundus by US. RESULTS: Twenty patients (29.9%) had a difference of > or = 1 cm and 13 patients (19.4%) had a difference of < or = 1.5 cm. Patients with a difference of > or = 1 or > or = 1.5 cm had a significantly greater depth at transfer (P < 0.001) and uterine cavity length (P < 0.001) when compared with patients without a difference. Clinical pregnancy, implantation, delivery and overall miscarriage rates did not differ between patients with a difference of > or = 1 or > or = 1.5 cm versus no difference. There were no ectopic pregnancies. CONCLUSIONS: Nineteen percent of patients had a discrepancy of > or = 1.5 cm and approximately 30% had a difference of > or = 1 cm from TT at UG-ET, suggesting a benefit to UG-ET. A large prospective randomized trial comparing UG-ET with blind transfer is required to assess further if UG-ET should be used in all cases of ET.