Publications by authors named "Richard T Scott"

171 Publications

Cumulus cells of euploid versus whole chromosome 21 aneuploid embryos reveals differentially expressed genes.

Reprod Biomed Online 2021 Jun 26. Epub 2021 Jun 26.

IVIRMA New Jersey, Basking Ridge NJ 07920, USA; Department of Reproductive Endocrinology and Infertility, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA 19107, USA.

Research Question: Can cumulus cells be used as a non-invasive target for the study of determinants of preimplantation embryo quality?

Design: Cumulus cells were collected from monosomy 21, trisomy 21 and euploid embryos and subjected to RNA sequencing analysis and real-time polymerase chain reaction assays. The differential gene expression was analysed for different comparisons.

Results: A total of 3122 genes in monosomy 21 cumulus cells and 19 genes in trisomy 21 cumulus cells were differentially expressed compared with euploid cumulus cells. Thirteen of these genes were differentially expressed in both monosomy and trisomy 21, compared with euploid, including disheveled segment polarity protein 2 (DVL2), cellular communication network factor 1 (CCN1/CYR61) and serum response factor (SRF), which have been previously implicated in embryo developmental competence. In addition, ingenuity pathway analysis revealed cell-cell contact function to be affected in both monosomy and trisomy 21 cumulus cells.

Conclusions: These findings support the use of cumulus cell gene expression analysis for the development of biomarkers evaluating oocyte quality for patients undergoing fertility preservation of oocytes.
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http://dx.doi.org/10.1016/j.rbmo.2021.06.015DOI Listing
June 2021

Consistency in rates of diagnosis of embryonic mosaicism, segmental abnormalities, and "no call" results among experienced embryologists performing preimplantation genetic testing for aneuploidy.

F S Rep 2020 Sep 28;1(2):119-124. Epub 2020 Sep 28.

IVI/RMA New Jersey, Basking Ridge, New Jersey.

Objective: To determine whether differences exist in rates of subchromosomal abnormalities, mosaicism, and "no call" results among embryologists performing and loading trophectoderm biopsies for preimplantation genetic testing for aneuploidy (PGT-A).

Design: Retrospective cohort.

Setting: Large infertility center.

Patients: All patients undergoing in vitro fertilization with PGT-A.

Interventions: The NexCCS next generation sequencing platform was used for PGT-A. The χ testing assessed differences in rates of primary outcomes between embryologists. Intraclass correlation coefficients evaluated inter-embryologist reliability in rates of abnormal and no call results. Median absolute performance difference (MAPD) scores, which quantify the impact of technical variation on analytical performance, were averaged for individual embryologists. Analysis of variance assessed differences in mean MAPD scores.

Main Outcome Measures: Interoperator variability in rates of mosaic, segmental, and no call results.

Results: Four embryologists performed 30,899 biopsies and 6 embryologists loaded specimens into designated tubes. Among individuals performing trophectoderm sampling, rates of mosaicism were 4.3% to 6.1%, segmental errors were 9.0% to 10.7%, and inconclusive results were 1.1% to 2.9%. For those loading, the incidence of mosaicism was 4.2% to 5.9%, subchromosomal abnormalities was 9.7% to 10.4%, and no call results was 1.2% to 2.2%. The intraclass correlation coefficient was 0.978 for embryologists performing biopsies and 0.981 for those loading. Differences in mean MAPD scores were within 0.6% and 0.2% of each other for doing biopsies and loading embryologists, respectively.

Conclusions: Rates of mosaicism, segmental, and no call PGT-A results are consistent among experienced embryologists. Due to the large sample size included, differences within 1% of the mean were deemed clinically irrelevant despite statistical significance.
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http://dx.doi.org/10.1016/j.xfre.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244265PMC
September 2020

Impact of paternal age on embryology and pregnancy outcomes in the setting of a euploid single-embryo transfer with ejaculated sperm: retrospective cohort study.

F S Rep 2020 Sep 2;1(2):99-105. Epub 2020 Sep 2.

Department of Reproductive Endocrinology & Infertility, IVI-Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey.

Objective: To evaluate the impact of paternal age on embryology and pregnancy outcomes in the setting of a euploid single-embryo transfer.

Design: Retrospective cohort study.

Setting: Not applicable.

Patients: Couples undergoing a first in vitro fertilization cycle with fresh ejaculated sperm who used intracytoplasmic sperm injection for fertilization followed by preimplantation genetic testing for aneuploidy and single-embryo transfer of a euploid embryo between January 2012 and December 2018.

Interventions: Not applicable.

Main Outcome Measures: Embryology outcomes assessed were fertilization rate, blastulation rate, and euploid rate. Pregnancy outcomes assessed included positive human chorionic gonadotropin rate, delivery rate, biochemical loss rate, and clinical loss rate.

Results: A total of 4,058 patients were assessed. After adjusting for female age, increased paternal age in the setting of fresh ejaculated sperm use was associated with decreased blastulation and decreased euploid rate using 40 years as an age cutoff.

Conclusions: In this study, advancing paternal age appears to have a detrimental impact on rates of blastocyst formation and euploid status. However, if a euploid embryo is achieved, older paternal age does not appear to affect negatively pregnancy outcomes.
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http://dx.doi.org/10.1016/j.xfre.2020.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244285PMC
September 2020

Mosaic embryos: hiding in plain sight.

Authors:
Richard T Scott

Fertil Steril 2021 07;116(1):77

Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey.

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http://dx.doi.org/10.1016/j.fertnstert.2021.04.039DOI Listing
July 2021

Individual culture leads to decreased blastocyst formation but does not affect pregnancy outcomes in the setting of a single, vitrified-warmed euploid blastocyst transfer.

J Assist Reprod Genet 2021 Aug 4;38(8):2157-2164. Epub 2021 Jun 4.

IVI-Reproductive Medicine Associates of New Jersey, Basking Ridge, NJ, USA.

Purpose: To evaluate embryology and pregnancy outcomes following individual and group embryo culture in the setting of contemporary laboratory practices and freeze-all cycles.

Methods: Patients underwent ovarian stimulation followed by intracytoplasmic sperm injection (ICSI). Embryos proceeded through individual culture and then underwent preimplantation genetic testing for aneuploidy (PGT-A) via trophectoderm biopsy. In a subsequent cycle, participants underwent single embryo transfer of a vitrified-warmed, euploid embryo. Outcomes were compared to controls undergoing group culture during the same time frame. The Mann-Whitney U test and logistic regression models were utilized.

Results: Outcomes were assessed for 144 patients whose embryos underwent individual culture and 449 controls whose embryos underwent group culture. There were no significant differences in fertilization rates between groups (81.7% for individual culture vs. 84.1% for group culture, p = 0.22). However, individual culture was associated with a decreased rate of blastocyst formation compared to group culture (43.5% vs. 48.5%, p < 0.01). Following single, vitrified-warmed euploid blastocyst transfer, there were no significant differences between individual culture and group culture, respectively, in rates of positive βhCG (81.9% vs. 81.5%, p = 0.91), sustained implantation (63.9% vs. 65.0%, p = 0.80), biochemical miscarriage (16.7% vs. 12.3%, p = 0.18), or clinical miscarriage (1.4% vs. 4.2%, p = 0.13).

Conclusion: While individual culture appears to negatively impact the rate of usable blastocyst formation compared to group culture, there were no significant differences in pregnancy outcomes following transfer of a single, vitrified-warmed euploid blastocyst.
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http://dx.doi.org/10.1007/s10815-021-02252-8DOI Listing
August 2021

Evaluation of genome-wide DNA methylation profile of human embryos with different developmental competences.

Hum Reprod 2021 05;36(6):1682-1690

IVIRMA, New Jersey, Basking Ridge, NJ, USA.

Study Question: Do embryos with different developmental competence exhibit different DNA methylation profiles at the blastocyst stage?

Summary Answer: We established genome-wide DNA methylome analysis for embryo trophectoderm (TE) biopsy samples and our findings demonstrated correlation of methylation profile of trophectoderm with euploidy status and with maternal age, indicating that genome-wide methylation level might be negatively correlated with embryo quality.

What Is Known Already: DNA methylation is a fundamental epigenetic regulatory mechanism that affects differentiation of cells into their future lineages during pre-implantation embryo development. Currently there is no established approach available to assess the epigenetic status of the human preimplantation embryo during routine IVF treatment.

Study Design, Size, Duration: In total, we collected trophectoderm biopsy samples from 30 randomly selected human blastocysts and conducted whole-genome bisulfite sequencing (WGBS) to evaluate their DNA methylation profile. Nested linear models were used to assess association between DNA methylation level and ploidy status (aneuploidy [n = 20] vs. euploidy [n = 10]), maternal age (29.4-42.5 years old), and time of blastulation (day 5 [n = 16] vs. day 6 [n = 14]), using embryo identity as a covariate.

Participants/materials, Setting, Methods: TE biopsy samples were obtained and submitted to bisulfite conversion. For WGBS, whole-genome sequencing libraries were then generated from the converted genome. An average of 75 million reads were obtained for each sample, and about 63% of the reads aligned to human reference. An average of 40 million reads used for the final analysis after the unconverted reads were filtered out.

Main Results And The Role Of Chance: We revealed an increase of genome-wide DNA methylation level in aneuploid embryo TE biopsies compared to euploid embryos (25.4% ± 3.2% vs. 24.7% ± 3.2%, P < 0.005). We also found genome-wide DNA methylation level to be increased with the maternal age (P < 0.005). On a chromosomal scale, we found monosomic embryos have lower methylation levels on the involved chromosome while no drastic change was observed for the involved chromosome in trisomies. Additionally, we revealed that WGBS data precisely revealed the chromosome copy number variance.

Limitations, Reasons For Caution: Though our results demonstrated a negative correlation of genome-wide methylation level and embryo quality, further WGBS analysis on a greater number of embryos and specific investigation of its correlation with implantation and live birth are needed before any practical use of this approach for evaluation of embryo competence.

Wider Implications Of The Findings: This study revealed a change in genome-wide DNA methylation profile among embryos with different developmental potentials, reinforcing the critical role of DNA methylation in early development.

Study Funding/competing Interest(s): No external funding was received for this study. Intramural funding was provided by the Foundation for Embryonic Competence (FEC). E.S. is a consultant for and receives research funding from the Foundation for Embryonic Competence; he is also co-founder and a shareholder of ACIS LLC and coholds patent US2019/055906 issued for utilizing electrical resistance measurement for assessing cell viability and cell membrane piercing.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deab074DOI Listing
May 2021

Endometrial receptivity screening in the general assisted reproductive technology population.

Authors:
Richard T Scott

Fertil Steril 2021 04;115(4):895-896

Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey.

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http://dx.doi.org/10.1016/j.fertnstert.2021.02.018DOI Listing
April 2021

PROGNOSTIC VALUE OF BLASTOCYST GRADE AFTER FROZEN EUPLOID EMBRYO TRANSFER IN PATIENTS WITH RECURRENT PREGNANCY LOSS.

F S Rep 2020 Sep 9;1(2):113-118. Epub 2020 Jul 9.

Division of Reproductive Endocrinology & Infertility, Department of Obstetrics & Gynecology, Stanford University.

Objective: To determine if trophectoderm (TE) grade or inner cell mass (ICM) grade have predictive value after euploid frozen embryo transfer (euFET) among RPL patients.

Design: Retrospective cohort study.

Setting: Single fertility center, 2012-2018.

Patients: Patients with ≥ 2 prior pregnancy losses performing PGT-A with ≥1 euploid embryo for transfer.

Interventions: All patients underwent ICSI, trophectoderm biopsy, blastocyst grading and vitrification, and single euFET. Outcome of the first transfer was recorded.

Main Outcome Measures: Live birth (LB) and clinical miscarriage (CM) rates.

Results: 660 euFET were included. In a binomial logistic regression analysis accounting for age, BMI, AMH and day of blastocyst biopsy, ICM grade C was not significantly associated with odds of live birth (aOR 0.50, 95% CI 0.24-1.02 p=0.057), miscarriage (aOR 1.67, 95% CI 0.56-5.00, p=0.36) or biochemical pregnancy loss (aOR 1.58, 95% CI 0.53-4.75, p=0.42). TE grade C was significantly associated with odds of live birth (aOR 0.49, 95% CI 0.28-0.86, p=0.01) and was not associated with odds of miscarriage (aOR 2.00, 95% CI 0.89-4.47, p=0.09) or biochemical pregnancy loss (aOR 1.85, 95% CI 0.77-4.44, p=0.17). Blastocyst grade CC had significantly lower LB rate compared to all other blastocyst grades (p<0.05, chi-square analysis).

Conclusion: Embryo grade CC and TE grade C are associated with decrease in odds of LB after euFET in RPL patients. Embryo grade is not associated with odds of CM in this cohort of RPL patients, suggesting that additional embryonic or uterine factors may influence risk of pregnancy loss.
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http://dx.doi.org/10.1016/j.xfre.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016183PMC
September 2020

Noninvasive prenatal testing in women undergoing in vitro fertilization with preimplantation genetic testing.

Curr Opin Obstet Gynecol 2021 06;33(3):184-187

IVI RMA, Basking Ridge, New Jersey.

Purpose Of Review: To discuss the utilization, performance, and interpretation of noninvasive prenatal testing (NIPT) results in women achieving pregnancy through in vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A).

Recent Findings: Although PGT-A is a highly accurate method for the selection of euploid embryos the possibility for error still exists. Many women pursue NIPT after conception via IVF with or without PGT-A, whereas some forgo prenatal screening all together. Recent evidence suggests that the prevalence of a positive NIPT following PGT-A is low, and the positive predictive value is altered in this population.

Summary: NIPT is a valuable prenatal screening tool that should be offered to pregnant women regardless of prior PGT. In women who conceive following IVF and PGT-A through the transfer of euploid embryos, positive test results should be interpreted with caution.
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http://dx.doi.org/10.1097/GCO.0000000000000707DOI Listing
June 2021

Noninvasive preimplantation genetic testing for aneuploidy exhibits high rates of deoxyribonucleic acid amplification failure and poor correlation with results obtained using trophectoderm biopsy.

Fertil Steril 2021 06 19;115(6):1461-1470. Epub 2021 Mar 19.

Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey; Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.

Objective: To validate a commercially available noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) assay by investigating the following: prevalence of deoxyribonucleic acid (DNA) amplification failure with niPGT-A; factors affecting amplification failure with niPGT-A; and frequency of discordant results between niPGT-A and traditional preimplantation genetic testing for aneuploidy.

Design: Prospective cohort study SETTING: Academic-affiliated private practice PATIENT(S): One hundred sixty-six blastocysts and their surrounding culture media from couples undergoing in vitro fertilization between July 2019 and May 2020 were analyzed.

Intervention(s): Blastocyst-stage spent culture media samples underwent niPGT-A using a commercially available kit that used whole-genome amplification with a modified multiple annealing and looping-based amplification cycle protocol followed by next-generation sequencing. Preimplantation genetic testing for aneuploidy of trophectoderm (TE) biopsies was performed using targeted next-generation sequencing.

Main Outcome Measure(s): The primary outcome was failure to achieve an interpretable result with niPGT-A. Factors affecting DNA amplification were also assessed. Discrepancies between niPGT-A and TE biopsy results were analyzed, and clinical outcomes were evaluated.

Result(s): Deoxyribonucleic acid amplification failures with niPGT-A were observed in 37.3% (62/166) of the samples. With TE biopsy, no embryos exhibited DNA amplification failure. Embryos with a shorter duration of exposure to the culture media and no evidence of whole-chromosome aneuploidy on the TE biopsy displayed high rates of DNA amplification failure with niPGT-A. Of 104 embryos with both niPGT-A and TE biopsy results available, whole-chromosome discordance was noted in 42 cases (40.4%). Three embryos classified as aneuploid based on the niPGT-A result progressed to successful delivery.

Conclusion(s): The rates of DNA amplification failure were high among the niPGT-A samples, virtually precluding the clinical applicability of niPGT-A in its current form.
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http://dx.doi.org/10.1016/j.fertnstert.2021.01.028DOI Listing
June 2021

Noninvasive preimplantation genetic testing for aneuploidy in spent culture medium as a substitute for trophectoderm biopsy.

Fertil Steril 2021 04 17;115(4):841-849. Epub 2021 Mar 17.

Department of Obstetrics and Gynecology, Valencia University and INCLIVA, Valencia, Spain; Department of Obstetrics and Gynecology, BIDMC Harvard University, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.fertnstert.2021.02.045DOI Listing
April 2021

Reproductive Endocrinology and Infertility fellowship programs: Does one size fit all?

Fertil Steril 2021 03;115(3):569-575

Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York, New York. Electronic address:

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http://dx.doi.org/10.1016/j.fertnstert.2021.01.036DOI Listing
March 2021

Role of the sperm, oocyte, and embryo in recurrent pregnancy loss.

Fertil Steril 2021 03;115(3):533-537

Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey; Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

Disorders affecting the sperm, oocyte, or embryo may cause a significant fraction of spontaneous miscarriages and cases of recurrent pregnancy loss (RPL). Altered chromosomal integrity of sperm and oocytes, which is highly dependent of the age of the mother, represents a major cause of miscarriage and in turn RPL. Avoiding transfers of abnormal embryos is possible with preimplantation genetic testing for aneuploidies. Chromosomal anomalies may also be caused by structural rearrangements of one or several chromosomes in either parents, a finding encountered in 12% of couples with RPL, including in those who have had one or several healthy babies. More than 40% of these chromosomal rearrangements are identifiable on regular karyotypes. When abnormal findings are made, preimplantation genetic testing for monogenic disorders allows selection of disease-free embryos. Finally, asymmetric inactivation of the X chromosome has been found more commonly in women with RPL, but no specific treatment is currently available.
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http://dx.doi.org/10.1016/j.fertnstert.2020.12.005DOI Listing
March 2021

Round spermatid injection into human oocytes: a systematic review and meta-analysis.

Asian J Androl 2021 Jul-Aug;23(4):363-369

Department of Reproductive Endocrinology and Infertility, IVI-Reproductive Medicine Associates of New Jersey, Basking Ridge, NJ 07920, USA.

Many azoospermic men do not possess mature spermatozoa at the time of surgical sperm extraction. This study is a systematic review and meta-analysis evaluating outcomes following round spermatid injection (ROSI), a technique which utilizes immature precursors of spermatozoa for fertilization. An electronic search was performed to identify relevant articles published through October 2018. Human cohort studies in English involving male patients who had round spermatids identified and used for fertilization with human oocytes were included. Fertilization rate, pregnancy rate, and resultant delivery rate were assessed following ROSI. Meta-analysis outcomes were analyzed using a random-effects model. Data were extracted from 22 studies involving 1099 couples and 4218 embryo transfers. The fertilization rate after ROSI was 38.7% (95% confidence interval [CI]: 31.5%-46.3%), while the pregnancy rate was 3.7% (95% CI: 3.2%-4.4%). The resultant delivery rate was low, with 4.3% of embryo transfers resulting in a delivery (95% CI: 2.3%-7.7%). The pregnancy rate per couple was 13.4% (95% CI: 6.8%-19.1%) and the resultant delivery rate per couple was 8.1% (95% CI: 6.1%-14.4%). ROSI has resulted in clinical pregnancies and live births, but success rates are considerably lower than those achieved with mature spermatozoa. While this technique may be a feasible alternative for men with azoospermia who decline other options, couples should be aware that the odds of a successful delivery are greatly diminished and the prognosis is relatively poor.
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http://dx.doi.org/10.4103/aja.aja_85_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269823PMC
February 2021

Interpretation of noninvasive prenatal testing results following in vitro fertilization and preimplantation genetic testing for aneuploidy.

Am J Obstet Gynecol MFM 2020 11 22;2(4):100232. Epub 2020 Sep 22.

IVI RMA New Jersey, Basking Ridge, NJ.

Background: The positive predictive value of noninvasive prenatal testing is approximately 69% in the general population. However, positive predictive value is dependent on the prevalence of the disease in the population being tested. Patients who undergo in vitro fertilization with preimplantation genetic testing for aneuploidy and transfer a euploid embryo are presumably a lower risk population than the general population.

Objective: In this study, we explored the positive predictive value of noninvasive prenatal testing in women undergoing in vitro fertilization with preimplantation genetic testing for aneuploidy and subsequent transfer of a euploid embryo.

Study Design: This study was a retrospective cohort study. All patients who underwent in vitro fertilization with preimplantation genetic testing for aneuploidy followed by transfer of a single euploid embryo between 2014 and 2019 at a university-affiliated fertility center were contacted. Noninvasive prenatal testing results were reviewed and those with positive noninvasive prenatal testing were identified. Results of any subsequent prenatal or postnatal diagnostic testing were used to classify each positive noninvasive prenatal testing as a true positive or a false positive. The prevalence and positive predictive value of positive noninvasive prenatal testing was calculated.

Results: A total of 1139 patients that underwent noninvasive prenatal testing after transfer of a euploid embryo were identified, 8 of which had positive noninvasive prenatal testing screens. Although 6 of these patients had subsequent definitive prenatal diagnostic testing that revealed a euploid karyotype concordant with their preimplantation genetic testing for aneuploidy results, 1 patient opted out of diagnostic testing and later delivered a normal baby. Of note, 1 patient who had noninvasive prenatal testing positive for Turner syndrome underwent amniocentesis, which confirmed Turner mosaicism (45,X karyotype in 80% of cells). Therefore, the positive predictive value of noninvasive prenatal testing in this patient cohort was 12.5%.

Conclusion: Clinicians and patients should recognize that patients undergoing transfer of a euploid embryo are at a relatively lower risk for fetal aneuploidy than the general population, and the positive predictive value of noninvasive prenatal testing is lower in this setting.
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http://dx.doi.org/10.1016/j.ajogmf.2020.100232DOI Listing
November 2020

Shorter telomere length of white blood cells is associated with higher rates of aneuploidy among infertile women undergoing in vitro fertilization.

Fertil Steril 2021 04 30;115(4):957-965. Epub 2020 Nov 30.

IVI-Reproductive Medicine Associates of New Jersey, Basking Ridge, New Jersey; Foundation for Embryonic Competence, Basking Ridge, New Jersey; Yale University School of Medicine, New Haven, Connecticut.

Objective: To evaluate whether the telomere length of white blood cells (WBC) and cumulus cells (CC) in an infertile population is associated with ovarian and embryonic performance.

Design: Prospective cohort study.

Setting: Academic-affiliated private practice.

Patients: A total of 175 infertile women undergoing in vitro fertilization (IVF) at a single center between July 2017 and December 2018.

Interventions: On the day of oocyte retrieval, genomic DNA was isolated from WBC and CC samples. Telomere length assessment was performed for both tissue types using quantitative real-time polymerase chain reaction. Telomere lengths were normalized using an AluYa5 sequence as an endogenous control, and linear regressions were applied.

Main Outcome Measures: This study assessed the relationship between relative telomere length of WBC and CC samples and measures of ovarian and embryonic performance. Specifically, patient age, antimüllerian hormone (AMH) level, peak estradiol (E) level, number of oocytes retrieved, number of mature (MII) oocytes retrieved, blastulation rate, and aneuploidy rate were assessed.

Results: There was a statistically significant relationship between WBC relative telomere length and patient age as well as rates of embryonic aneuploidy, with shorter WBC relative telomere length associated with increasing patient age (P<.01) and higher rates of aneuploidy (P=.01). No statistically significant relationships were observed between WBC relative telomere length and the other outcome measures. No significant associations were noted between CC relative telomere length and any outcomes assessed in this study.

Conclusion: The relationship between WBC relative telomere length and aneuploidy warrants further investigation, particularly because significant overlap exists between increasing maternal age and rates of embryonic aneuploidy.
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http://dx.doi.org/10.1016/j.fertnstert.2020.09.164DOI Listing
April 2021

Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.

Fertil Steril 2021 01 16;115(1):45-53. Epub 2020 Oct 16.

IVIRMA New Jersey, Basking Ridge, New Jersey.

Objective: To study the true prevalence of recurrent implantation failure.

Design: Retrospective cohort study.

Setting: A private assisted reproductive technology center.

Patient(s): Women (n = 4,429) with anatomically normal uterus who underwent up to three consecutive frozen euploid single embryo transfers (FE-SETs) were included in the study. Cycles with donor eggs or gestational carriers were excluded.

Intervention(s): None.

Main Outcome Measure(s): Cumulative outcomes from these cycles were analyzed. A logistic regression model was used to assess the differences of outcomes between first, second, and third FE-SET and a Kaplan-Meier curve as used to analyze cumulative implantation rate.

Result(s): The mean age of the patients included in the study was of 35.4 years. The sustained implantation rates of the first, second, and third FE-SET were 69.9%, 59.8%, and 60.3% per transfer, respectively. The cumulative sustained implantation rate after up to three consecutive FE-SET was 95.2%. The live birth rates after the first, second, and third FE-SET were 64.8%, 54.4%, and 54.1% per transfer, respectively. The cumulative live birth rate after up to three consecutive FE-SET was 92.6%. The miscarriage rate after observing a positive heartbeat was not different between the first (7.2%), second (8.8%), and third (12.7%) FE-SET.

Conclusion(s): Our findings suggest that true recurrent implantation failure is rare. For those patients with the ability to make euploid blastocysts, <5% would fail to achieve a clinical pregnancy with three embryos transferred. It remains to be further investigated whether this threshold identifies a truly recalcitrant group or simply a statistical certainty based on random variation.
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http://dx.doi.org/10.1016/j.fertnstert.2020.07.002DOI Listing
January 2021

Analysis of DNA variants in miRNAs and miRNA 3'UTR binding sites in female infertility patients.

Lab Invest 2021 04 17;101(4):503-512. Epub 2020 Oct 17.

Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.

Early human embryogenesis relies on maternal gene products accumulated during oocyte growth and maturation, until around day-3 post-fertilization when human zygotic genome activation occurs. The maternal-to-zygotic transition (MZT) is a tightly coordinated process of selective maternal transcript clearance and new zygotic transcript production. If MZT is disrupted, it will lead to developmental arrest and pregnancy loss. It is well established that microRNA (miRNA) mutations disrupt regulation of their target transcripts. We hypothesize that some cases of embryonic arrest and pregnancy loss could be explained by the mutations in the maternal genome that affect miRNA-target transcript pairs. To this end, we examined mutations within miRNAs or miRNA binding sites in the 3' untranslated regions (3'UTR) of target transcripts. Using whole-exome sequencing data from 178 women undergoing in vitro fertilization (IVF) procedures, we identified 1197 variants in miRNA genes, including 93 single nucleotide variants (SNVs) and 19 small insertions/deletions (INDELs) within the seed region of 100 miRNAs. Eight miRNA seed-region variants were significantly enriched among our patients when compared to a normal population. Within predicted 3'UTR miRNA binding sites, we identified 7393 SNVs and 1488 INDELs. Between our patients and a normal population, 52 SNVs and 30 INDELs showed significant association in the single-variant testing, whereas 51 genes showed significant association in the gene-burden analysis for genes that are expressed in preimplantation embryos. Interestingly, we found that many genes with disrupted 3'UTR miRNA binding sites follow gene expression patterns resembling MZT. In addition, some of these variants showed dramatic allele frequency difference between the patient and the normal group, offering potential utility as biomarkers for screening patients prior to IVF procedures.
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http://dx.doi.org/10.1038/s41374-020-00498-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987713PMC
April 2021

Young women with poor ovarian response exhibit epigenetic age acceleration based on evaluation of white blood cells using a DNA methylation-derived age prediction model.

Hum Reprod 2020 11;35(11):2579-2588

IVI-Reproductive Medicine Associates of New Jersey, Basking Ridge, NJ, USA.

Study Question: Is poor ovarian response associated with a change in predicted age based on a DNA methylation-derived age prediction model (the Horvath algorithm) in white blood cells (WBCs) or cumulus cells (CCs)?

Summary Answer: In young women, poor ovarian response is associated with epigenetic age acceleration within WBC samples but is not associated with age-related changes in CC.

What Is Known Already: The majority of human tissues follow predictable patterns of methylation which can be assessed throughout a person's lifetime. DNA methylation patterns may serve as informative biomarkers of aging within various tissues. Horvath's 'epigenetic clock', which is a DNA methylation-derived age prediction model, accurately predicts a subject's true chronologic age when applied to WBC but not to CC.

Study Design, Size, Duration: A prospective cohort study was carried out involving 175 women undergoing ovarian stimulation between February 2017 and December 2018. Women were grouped according to a poor (≤5 oocytes retrieved) or good (>5 oocytes) response to ovarian stimulation. Those with polycystic ovary syndrome (PCOS) (n = 35) were placed in the good responder group.

Participants/materials, Setting, Methods: DNA methylation patterns from WBC and CC were assessed for infertile patients undergoing ovarian stimulation at a university-affiliated private practice. DNA was isolated from peripheral blood samples and CC. Bisulfite conversion was then performed and a DNA methylation array was utilized to measure DNA methylation levels throughout the genome. Likelihood ratio tests were utilized to assess the relationship between predicted age, chronologic age and ovarian response.

Main Results And The Role Of Chance: The Horvath-predicted age for WBC samples was consistent with patients' chronologic age. However, predicted age from analysis of CC was younger than chronologic age. In subgroup analysis of women less than 38 years of age, poor ovarian response was associated with an accelerated predicted age in WBC (P = 0.017). Poor ovarian response did not affect the Horvath-predicted age based on CC samples (P = 0.502). No alternative methylation-based calculation was identified to be predictive of age for CC.

Limitations, Reasons For Caution: To date, analyses of CC have failed to identify epigenetic changes that are predictive of the aging process within the ovary. Despite the poor predictive nature of both the Horvath model and the novel methylation-based age prediction model described here, it is possible that our efforts failed to identify appropriate sites which would result in a successful age-prediction model derived from the CC epigenome. Additionally, lower DNA input for CC samples compared to WBC samples was a methodological limitation. We acknowledge that a universally accepted definition of poor ovarian response is lacking. Furthermore, women with PCOS were included and therefore the group of good responders in the current study may not represent a population with entirely normal methylation profiles.

Wider Implications Of The Findings: The process of ovarian and CC aging continues to be poorly understood. Women who demonstrate poor ovarian response to stimulation represent a common clinical challenge, so clarifying the exact biological changes that occur within the ovary over time is a worthwhile endeavor. The data from CC support a view that hormonally responsive tissues may possess distinct epigenetic aging patterns when compared with other tissue types. Future studies may be able to determine whether alternative DNA methylation sites can accurately predict chronologic age or ovarian response to stimulation from CC samples. Going forward, associations between epigenetic age acceleration and reproductive and general health consequences must also be clearly defined.

Study Funding/competing Interest(s): No external funding was obtained for the study and there are no conflicts of interest.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa206DOI Listing
November 2020

A multicenter, prospective, blinded, nonselection study evaluating the predictive value of an aneuploid diagnosis using a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy assay and impact of biopsy.

Fertil Steril 2021 03 28;115(3):627-637. Epub 2020 Aug 28.

IVI RMA New Jersey, Basking Ridge, New Jersey; Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.

Objective: To determine the predictive value of an aneuploid diagnosis with a targeted next-generation sequencing-based preimplantation genetic testing for aneuploidy (PGT-A) assay in prognosticating the failure of a successful delivery.

Design: Prospective, blinded, multicenter, nonselection study. All usable blastocysts were biopsied, and the single best morphologic blastocyst was transferred before genetic analysis. Preimplantation genetic testing for aneuploidy was performed after clinical outcome was determined. Clinical outcomes were compared to PGT-A results to calculate the predictive value of a PGT-A aneuploid diagnosis.

Setting: Fertility centers.

Patient(s): Couples undergoing their first in vitro fertilization cycle without recurrent pregnancy loss, antral follicle count < 8, or body mass index ≥ 35 kg/m.

Intervention(s): None.

Main Outcome Measure(s): The primary outcome was the ability of the analytical result of aneuploid to predict failure to deliver (clinical result). A secondary outcome was the impact of the trophectoderm biopsy on sustained implantation.

Result(s): Four hundred two patients underwent 484 single, frozen, blastocyst transfers. The PGT-A aneuploid diagnosis clinical error rate was 0%. There was no difference in sustained implantation between the study group and an age-matched control group, where biopsy was not performed (47.9% vs. 45.8).

Conclusion(s): The PGT-A assay evaluated was highly prognostic of failure to deliver when an aneuploid result was obtained. Additionally, the trophectoderm biopsy had no detectable adverse impact on sustained implantation.

Clinical Trial Registration Numbers: NCT02032264 and NCT03604107.
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http://dx.doi.org/10.1016/j.fertnstert.2020.07.052DOI Listing
March 2021

Developmental potential of aneuploid human embryos cultured beyond implantation.

Nat Commun 2020 08 10;11(1):3987. Epub 2020 Aug 10.

Mammalian Embryo and Stem Cell Group, University of Cambridge, Department of Physiology, Development and Neuroscience, Downing Street, Cambridge, CB2 3DY, UK.

Aneuploidy, the presence of an abnormal number of chromosomes, is a major cause of early pregnancy loss in humans. Yet, the developmental consequences of specific aneuploidies remain unexplored. Here, we determine the extent of post-implantation development of human embryos bearing common aneuploidies using a recently established culture platform. We show that while trisomy 15 and trisomy 21 embryos develop similarly to euploid embryos, monosomy 21 embryos exhibit high rates of developmental arrest, and trisomy 16 embryos display a hypo-proliferation of the trophoblast, the tissue that forms the placenta. Using human trophoblast stem cells, we show that this phenotype can be mechanistically ascribed to increased levels of the cell adhesion protein E-CADHERIN, which lead to premature differentiation and cell cycle arrest. We identify three cases of mosaicism in embryos diagnosed as full aneuploid by pre-implantation genetic testing. Our results present the first detailed analysis of post-implantation development of aneuploid human embryos.
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http://dx.doi.org/10.1038/s41467-020-17764-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418029PMC
August 2020

Exome sequencing links CEP120 mutation to maternally derived aneuploid conception risk.

Hum Reprod 2020 09;35(9):2134-2148

Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.

Study Question: What are the genetic factors that increase the risk of aneuploid egg production?

Summary Answer: A non-synonymous variant rs2303720 within centrosomal protein 120 (CEP120) disrupts female meiosis in vitro in mouse.

What Is Known Already: The production of aneuploid eggs, with an advanced maternal age as an established contributing factor, is the major cause of IVF failure, early miscarriage and developmental anomalies. The identity of maternal genetic variants contributing to egg aneuploidy irrespective of age is missing.

Study Design, Size, Duration: Patients undergoing fertility treatment (n = 166) were deidentified and selected for whole-exome sequencing.

Participants/materials, Setting, Methods: Patients self-identified their ethnic groups and their ages ranged from 22 to 49 years old. The study was performed using genomes from White, non-Hispanic patients divided into controls (97) and cases (69) according to the number of aneuploid blastocysts derived during each IVF procedure. Following a gene prioritization strategy, a mouse oocyte system was used to validate the functional significance of the discovered associated genetic variants.

Main Results And The Role Of Chance: Patients producing a high proportion of aneuploid blastocysts (considered aneuploid if they missed any of the 40 chromatids or had extra copies) were found to carry a higher mutational burden in genes functioning in cytoskeleton and microtubule pathways. Validation of the functional significance of a non-synonymous variant rs2303720 within Cep120 on mouse oocyte meiotic maturation revealed that ectopic expression of CEP120:p.Arg947His caused decreased spindle microtubule nucleation efficiency and increased incidence of aneuploidy.

Limitations, Reasons For Caution: Functional validation was performed using the mouse oocyte system. Because spindle building pathways differ between mouse and human oocytes, the defects we observed upon ectopic expression of the Cep120 variant may alter mouse oocyte meiosis differently than human oocyte meiosis. Further studies using knock-in 'humanized' mouse models and in human oocytes will be needed to translate our findings to human system. Possible functional differences of the variant between ethnic groups also need to be investigated.

Wider Implications Of The Findings: Variants in centrosomal genes appear to be important contributors to the risk of maternal aneuploidy. Functional validation of these variants will eventually allow prescreening to select patients that have better chances to benefit from preimplantation genetic testing.

Study Funding/competing Interest(s): This study was funded through R01-HD091331 to K.S. and J.X. and EMD Serono Grant for Fertility Innovation to N.R.T. N.R.T. is a shareholder and an employee of Genomic Prediction.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828473PMC
September 2020

Analysis of accessible chromatin landscape in the inner cell mass and trophectoderm of human blastocysts.

Mol Hum Reprod 2020 09;26(9):702-711

IVI-RMA, New Jersey, Basking Ridge, NJ, USA.

Early embryonic development is characterized by drastic changes in chromatin structure that affects the accessibility of the chromatin. In human, the chromosome reorganization and its involvement in the first linage segregation are poorly characterized due to the difficulties in obtaining human embryonic material and limitation on low input technologies. In this study, we aimed to explore the chromatin remodeling pattern in human preimplantation embryos and gain insight into the epigenetic regulation of inner cell mass (ICM) and trophectoderm (TE) differentiation. We optimized ATAC-seq (an assay for transposase-accessible chromatin using sequencing) to analyze the chromatin accessibility landscape for low DNA input. Sixteen preimplantation human blastocysts frozen on Day 6 were used. Our data showed that ATAC peak distributions of the promoter regions (<1 kb) and distal regions versus other regions were significantly different between ICM versus TE samples (P < 0.01). We detected that a higher percentage of accessible binding loci were located within 1 kb of the transcription start site in ICM compared to TE (P < 0.01). However, a higher percentage of accessible regions was detected in the distal region of TE compared to ICM (P < 0.01). In addition, eight differential peaks with a false discovery rate <0.05 between ICM and TE were detected. This is the first study to compare the landscape of the accessible chromatin between ICM and TE of human preimplantation embryos, which unveiled chromatin-level epigenetic regulation of cell lineage specification in early embryo development.
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http://dx.doi.org/10.1093/molehr/gaaa048DOI Listing
September 2020

Mitochondrial DNA content is not predictive of reproductive competence in euploid blastocysts.

Reprod Biomed Online 2020 Aug 14;41(2):183-190. Epub 2020 May 14.

Department of Obstetrics, Gynecology and Reproductive Sciences, Yale School of Medicine, 310 Cedar street, LSOG 304B, New Haven CT, 06525, USA; IVIRMA New Jersey, 140 Allen Road, Basking Ridge NJ, 07920, USA. Electronic address:

Research Question: Does mitochondrial DNA (mtDNA) copy number predict the reproductive potential of euploid human blastocysts?

Design: To investigate whether the amount of mtDNA in trophectoderm biopsies correlates with IVF outcome, euploid human blastocysts (n = 615) used in single embryo transfer were analysed. Furthermore, to determine whether mtDNA content is predictive of reproductive outcome within a given cohort, paired sibling embryos (n = 78) transferred in two consecutive cycles carried out in the same patient (in which one cycle failed to result in implantation and the other cycle resulted in sustained implantation) were studied. Targeted amplification followed by quantitative real-time polymerase chain reaction for two mitochondrial loci (16S and MajArc) relative to a multicopy nuclear genome locus (AluYb8) were carried out to determine relative mtDNA copy number.

Results: Sustained implantation was not associated with relative mtDNA copy number (P = 0.78), and there was no threshold value above or below which ongoing implantation was more or less likely. No correlation was observed between maternal age and relative mtDNA copy number (P = 0.39). In addition, no association was found between relative mtDNA levels of sibling embryos and ensuing implantation and delivery rates in women who underwent a successful single embryo transfer before or after a failed transfer using embryos derived from the same cohort of oocytes (P = 0.70).

Conclusions: In trophectoderm samples, mitochondrial DNA copy number analysis was not found to be predictive of euploid human embryo reproductive competence. These data do not support the use of mitochondrial DNA copy number in clinical decision making when selecting which embryo to transfer.
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http://dx.doi.org/10.1016/j.rbmo.2020.04.011DOI Listing
August 2020

Introduction: Key performance indicators in assisted reproductive technologies.

Fertil Steril 2020 07 9;114(1):4-5. Epub 2020 Jun 9.

Department of Obstetrics and Gynecology, Hôpital Foch, Université de Paris Ouest (UVSQ), Paris, France. Electronic address:

Assisted reproductive technology (ART) has been so widely deployed across the world that over 1% of all births are now ART babies, with even higher percentages in the Nordic countries. As pregnancy rates are limited by technical, population, and inherent limitations of human reproduction, key performance indicators should be defined for all the different facets of ART to measure the efficacy of the procedure.
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http://dx.doi.org/10.1016/j.fertnstert.2020.04.057DOI Listing
July 2020

Three simple metrics to define in vitro fertilization success rates.

Fertil Steril 2020 07 9;114(1):6-8. Epub 2020 Jun 9.

RMA of New Jersey, Basking Ridge, New Jersey; IVIRMA Global, Basking Ridge, New Jersey. Electronic address:

Describing clinical outcomes from assisted reproduction technology (ART) treatment cycles has been an evolving challenge throughout the world. Three simple metrics provide a transparent and highly accurate summary of ART outcomes. The first metric is the probability of having no embryos available to transfer. This metric incorporates all causes of failure from initiation of the treatment cycle up to the point immediately before actual embryo transfer. Patients will know what the risk is of failing, whether it is due to poor follicular stimulation, failed fertilization, poor embryo development, or abnormal preimplantation genetic testing for aneuploidy (PGT-A) results. The second and most important metric is sustained implantation rate: the probability that any transferred embryo will implant and progress to delivery. In the event of a single-embryo transfer, the metric is identical to delivery rate per transfer. By calculating per embryo, it provides a summary of the quality of outcomes within the program without the obscuring effect of multiple-embryo transfer. The final metric is the number of supernumerary embryos cryopreserved during the cycle. This speaks to the efficiency of the process by providing an estimate of potential benefits which may come from an additional transfer should the first one be unsuccessful or even to allow the couple to pursue an additional child without another full ART cycle. These metrics are easy to calculate and provide a detailed picture of the outcomes attained by the program.
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http://dx.doi.org/10.1016/j.fertnstert.2020.04.056DOI Listing
July 2020

Effects of intraovarian injection of autologous platelet rich plasma on ovarian reserve and IVF outcome parameters in women with primary ovarian insufficiency.

Aging (Albany NY) 2020 06 5;12(11):10211-10222. Epub 2020 Jun 5.

IVI RMA New Jersey, Basking Ridge, NJ 07920, USA.

We aimed to determine whether intraovarian injection of autologous platelet rich plasma (PRP) improves response to ovarian stimulation and in vitro fertilization (IVF) outcome in women with primary ovarian insufficiency (POI). Women (N=311; age 24-40) diagnosed with POI based on ESHRE criteria underwent intraovarian PRP injection. Markers of ovarian reserve, and IVF outcome parameters were followed. PRP treatment resulted in increased antral follicle count (AFC) and serum antimullerian hormone (AMH), while serum follicle stimulating hormone (FSH) did not change significantly. After PRP injection, 23 women (7.4%) conceived spontaneously, 201 (64.8%) developed antral follicle(s) and attempted IVF, and 87 (27.8%) had no antral follicles and therefore did not receive additional treatment. Among the 201 women who attempted IVF, 82 (26.4% of total) developed embryos; 25 of these women preferred to cryopreserve embryos for transfer at a later stage, while 57 underwent embryo transfer resulting in 13 pregnancies (22.8% per transfer, 4% of total). In total, of the 311 women treated with PRP, 25 (8.0%) achieved livebirth/sustained implantation (spontaneously or after IVF), while another 25 (8.0%) cryopreserved embryos. Our findings suggest that in women with POI, intraovarian injection of autologous PRP might be considered as an alternative experimental treatment option.
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http://dx.doi.org/10.18632/aging.103403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346073PMC
June 2020

Key metrics and processes for validating embryo diagnostics.

Fertil Steril 2020 07 4;114(1):16-23. Epub 2020 Jun 4.

IVIRMA Global, Basking Ridge, New Jersey. Electronic address:

Embryo diagnostics are somewhat controversial in clinical assisted reproduction technology (ART) practice and remain an active area of investigation. Application of embryo diagnostics holds great potential to raise the standard of clinical care by eliminating futile transfers, allowing highly effective single-embryo transfer, and reducing the probability of clinical loss and ongoing abnormal gestations. These advantages are accompanied by risks, principally the chance that a reproductively competent embryo will be mislabeled and discarded. This would lower the ultimate probability that one or more of the embryos might implant and lead to delivery of a healthy infant. Rigorous validation should be required for embryo diagnostics. Metrics for validation can be divided into three simple areas: analytical validation, determination of clinical predictive values for normal and abnormal test results, and a randomized clinical trial to demonstrate that the selection advantage gained through the diagnostic improves clinical outcomes.
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http://dx.doi.org/10.1016/j.fertnstert.2020.04.053DOI Listing
July 2020

Evaluation of fertilization, usable blastocyst development and sustained implantation rates according to intracytoplasmic sperm injection operator experience.

Reprod Biomed Online 2020 Jul 19;41(1):19-27. Epub 2020 Mar 19.

IVI-RMA, 140 Allen Road, Basking Ridge, Basking Ridge NJ 07920, USA; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia PA 19107, USA.

Research Question: Is intracytoplasmic sperm injection (ICSI) operator experience associated with fertilization, usable blastocyst development and sustained implantation rates (SIR) when at least two embryologists carry out ICSI for a single cohort of oocytes?

Design: A retrospective cohort study of all IVF/ICSI cycles at a single large infertility centre between 2008 and 2018. Cycles were included if a cohort of oocytes was split between two embryologists for ICSI. The embryologist's experience of ICSI was used to evaluate laboratory and clinical outcomes overall and by pairs of inseminating embryologists. Logistic regression, analysis of variance and Kruskal-Wallis testing were used where appropriate.

Results: Analysis of 14,362 ICSI procedures showed an association between least ICSI experience and lower mean fertilization rates (P < 0.0001), higher odds of failed fertilization (adjusted OR 4.3; P < 0.0001) and lower number of fertilization 'wins' per cohort (P < 0.0001). Usable blastocyst development rates (number of usable blastocysts/number of two pronuclear zygotes) were not associated with ICSI embryologist experience (P = 0.44), but the odds of obtaining no usable blastocysts were higher (adjusted OR 1.4; P < 0.0001) and the proportion of usable blastocyst 'wins' was lower (P = 0.0001) when embryologists with the least experience carried out ICSI. Increased ICSI experience was associated with higher mean SIR (P < 0.0001). Laboratory and clinical outcomes were similar among embryologists once 1000 ICSI cycles and above were carried out.

Conclusions: Increased ICSI operator experience is associated with higher fertilization rates, SIR and a lower likelihood of failed fertilization and usable blastocyst development. Splitting a single oocyte cohort between more than one embryologist for ICSI is a quality-control measure that can be implemented.
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http://dx.doi.org/10.1016/j.rbmo.2020.03.008DOI Listing
July 2020

The impact of age beyond ploidy: outcome data from 8175 euploid single embryo transfers.

J Assist Reprod Genet 2020 Mar 16;37(3):595-602. Epub 2020 Mar 16.

IVIRMA New Jersey, Basking Ridge, NJ, USA.

Purpose: The rate of embryonic aneuploidy increases with increasing female age and is the primary cause of lower pregnancy and live birth rates (LBR) in older reproductive age women. This retrospective cohort study evaluates single euploid embryo transfers to determine whether an age-related decline in reproductive efficiency persists.

Methods: A total of 8175 non-donor single embryo transfers (SET) after pre-implantation testing for aneuploidy (PGT-A) and cryopreservation were included. These were divided into five groups by patient age: < 35 years old (n = 3789 embryos transferred), 35-37 (n = 2200), 38-40 (n = 1624), 41-42 (n = 319), and > 42 (n = 243). Implantation rate (IR), clinical pregnancy rate (CPR), and LBR were calculated for each group as a percentage of embryos transferred and compared. CPR was also analyzed as a percentage of implanted pregnancies, and LBR as a percentage of clinical pregnancies, to determine when age has the greatest impact. These results were then adjusted for confounding variables via a multivariate logistic regression model.

Results: Implantation rates negatively correlated with age. After adjusting for confounders, women 38 years or older had a significantly lower IR than those under 35 (OR 0.85, 95%CI 0.73-0.99 for 38-40 years old; 0.69, 0.53-0.91 for 41-42, and 0.69, 0.51-0.94 for > 42). These differences are also apparent in CPR and LBR. The rates of progression to clinical pregnancy and live birth did not differ significantly by age group. Other factors observed to affect IR independently were anti-Müllerian hormone (AMH), day of embryo transfer, and embryo morphology.

Conclusion: While selection of euploid embryos may be effective in overcoming a significant proportion of the age-related decline in reproductive efficiency, a decrease in IR, CPR, and LBR persists even when analyzing only euploid embryo transfers. The observed impact of aging is, therefore, independent of ploidy, as well as of other variables that affect reproductive efficiency. These results indicate that factors other than aneuploidy contribute to reproductive senescence.
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http://dx.doi.org/10.1007/s10815-020-01739-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125286PMC
March 2020
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