Faculty Bibliography

Objective: To determine the incidence of euploidy and implantation and delivery of Blastocysts derived from 0PN and 1PN compared with 2PN embryos.
Design(s): Single center retrospective review of PGT-A cases over a 4 year period (2015-2018) where a biopsy and ploidy determination was performed on blastocysts (blasts) derived from zygotes where pronuclei (PNs) were either not evident (0 PN) or only 1 pronucleus (1 PN) was evident at the time of fertilization check.
Material(s) and Method(s): At our center fertilization checks are routinely conducted ~18 hours post insemination or ICSI. The number of PN in each egg is recorded and zygotes cultured individually. Cases where < 50% of the mature eggs exhibit 2PN are routinely rechecked later on Day 1 and omitted from this study if additional PNs seen. In cases for PGT-A, all viable inseminated eggs excluding those with > 3 PN remain in culture to Day 6/7. Good quality blastocysts with a distinct Inner cell mass and cohesive trophectoderm are considered for PGT-A regardless of whether they were 0PN, 1PN or 2PN at fertilization check. PGT-A results are shown in Table 1 along with PGT-A sex of blasts derived from each group.
Result(s): [Figure presented]
Conclusion(s): Prior to utilization of PGT-A and/or timelapse zygotes not exhibiting 2PN at fertilization check were routinely discarded. However, it is now obvious that a percentage of these, albeit small, are fertilized normally and are euploid. Though they account for only a small percentage these may be the only euploid blasts available. Implantation rates and LB rates following transfer of these blasts are similar to those for 2PN blastocysts. Of interest, ratios of XX:XY blasts derived from 1PN and 0PN zygotes were skewed towards female while those from 2PN zygotes were ~1:1. It should be noted that NGS cannot detect pure haploidy (23, X) or triploidy (69, XXX) thereby possibly misdiagnosing these as euploid although our IR and LB results indicate otherwise. Support: None References: None
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Objective: The use of PGT-A and vitrification to select euploid embryos for transfer has led to improved live birth success in IVF; however, some euploid embryos fail to progress following implantation. Our objective was to compare parameters from 1) the retrieval cycle (IVF) in which blastocysts were biopsied and vitrified, 2) the frozen embryo cycle (FETu) during which the uterus is prepared for transfer, 3) the embryo transfer (FETt), and 4) the embryology (Lab) records all consolidated to determine what best predicts pregnancy loss following establishment of pregnancy by euploid embryos.
Design(s): Multivariate analysis of 45 parameters from IVF, FETu, FETt and Lab and their association with loss of pregnancies after a positive pregnancy test (+hCG).
Material(s) and Method(s): Data were collected from our electronic records for patients with transfers of thawed single euploid embryos diagnosed as euploid by NGS during the IVF cycle. Parameters from IVF (17), FETu (5), FETt (4), and Lab (19) were considered. All cases of STEET using euploid embryos tested with Next Generation Sequencing (908) were considered for analysis. Transfers without +hCG (204) and clinical pregnancies without final outcomes (205) at the time of analysis were excluded. Those 499 remaining cases with a positive pregnancy test (hCG > 5 mIU/mL) and all the required fields. 144 cases failed to progress (75 biochemical pregnancies and 69 SAbs). Stepwise multiple logistic regression (152 combinations of parameters) was performed using the Akaike Information Criterion (AIC) to select parameters associated with loss of pregnancy precluding live birth following +hCG. +hCGs were considered implantations since 1) patients believe they are pregnant when they have a +hCG result and 2) no interfering hCG was administered to these patients.
Result(s): Parameters associated with increased pregnancy loss after positive hCG (in descending magnitude of standard partial regression coefficient) were: more expansion of the trophectoderm prior to biopsy (IVF); more serum estrogen on the day prior to progesterone administration (FETu) and more difficulty of the embryo transfer procedure (FETt ). Age at retrieval, embryo grades, as well as many other parameters were not associated with pregnancy loss.
Conclusion(s): Parameters from 3 categories were associated with loss of pregnancy as biochemical pregnancies or spontaneous abortions. Of these, some are under our control: serum estradiol levels on the day prior to progesterone administration and possibly the difficulty of the transfer and the expansion of the blastocyst prior to biopsy. However, it is possible that these parameters may be aliases for other features such as rate of blastocyst development, patient weight, and/or uterine contractions or presence of blood in the cervix or uterus. No Lab parameters were associated with pregnancy loss. Also notable was the lack of association between embryo grades and pregnancy loss.
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Objective: Treatment of chronic endometritis (CE) improves implantation rates in patients undergoing assisted reproductive technology (ART), but causative organisms are difficult to identify and the most effective treatment regimen remains undefined¹. Our objective was to identify the optimal duration and choice of antimicrobial agent(s) on clearance of CE.
Design(s): Retrospective cohort study of patients between 1/2017 and 12/2018 at a single academic center with an endometrial biopsy (EMB) showing CE.
Material(s) and Method(s): All patients diagnosed with CE (defined as >1 plasma cell/HPF, stained for CD138) on EMB followed by test of cure biopsy (TOC) were included. Antimicrobial agents prescribed and length of course were recorded. Regimens were classified as 14 days or less versus 15 days or more (up to 21 days), and by spectra of coverage: Gram positive, Gram negative, Anaerobe, Atypical and Anti-fungal. Primary outcome was presence or absence of CE on TOC. If a patient remained positive on TOC, subsequent treatment(s) were included as separate course(s) for analysis. Statistical analysis included chi square test of independence and a stepwise multiple logistic regression, with p < 0.05 significant.
Result(s): 144 women with an initial EMB positive for CE received a total of 225 treatment courses. 11 TOC results were unavailable, leaving 214 courses of treatment with known TOC outcomes. The most common indication for EMB was failed frozen embryo transfer(s) (FET) (mean 0.98+/-1.00, range 0-7), euploid pregnancy loss or recurrent pregnancy loss. The mean age of women in the cohort was 36.90+/-3.93 years (range 27-47). Mean number of courses required for clearance was 1.55+/-0.88 (range 0-6). All courses included antimicrobials providing gram positive and negative coverage. 62.6% (134/214) included anaerobic coverage and 66.3% (142/214) included atypical agent(s). 2 courses included anti-fungals. Including anaerobic coverage did not affect outcome (58.2% with vs 61.3% without, p = 0.67), nor did use of an atypical agent (59.2% with vs 59.67% without, p=1.00). Antibiotic regimens lasting 14 days or less (n=155) had lower rates of CE clearance when compared to those lasting 15 days or more (54.8% vs 71.2%, p < 0.03). Stepwise multiple logistic regression showed that only length of antimicrobial course retained a significant impact on TOC (B -0.762, p < 0.027, Omnibus test for variance p <0.024, Hosmer-Lemeshow test for fit p = 0.99).
Conclusion(s): CE is a treatable but poorly defined inflammatory process, which may affect ART success. Ideally, CE is cleared with the first course of antibiotics. Our results show that longer courses (15-21 days) are more effective, regardless of antimicrobial choice. This suggests that patients do not need to take less tolerable agents to achieve high clearance rates, and highlights the need for further, prospective analyses. References: ¹: Cicinelli E, et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Human Reproduction 2015;30(2):323-330.
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Objective: Clinical guidelines on the optimal duration of controlled ovarian stimulation and ideal follicle size were developed for fresh embryo transfer cycles. Whether these apply to freeze all cycles remain unclear. We evaluated the impact of lead follicle size and duration of stimulation on the probability of euploid embryos in women undergoing IVF/PGT-A Design: Cross-sectional study
Material(s) and Method(s): Data from 721 patients undergoing at least two cycles of COS for IVF with preimplantation genetic testing for aneuploidy (PGT-A) via Next Generation Sequencing (NGS) (1859 cycles). Mixed-effect logistic regression, which can account for correlations among repeated outcomes within sample patients, was used to evaluate the association between independent variables and probability of achieving euploid embryos. We first conducted a mixed-effect logistic regression in a univariate manner. All variables then were evaluated in a multivariate model to control for confounding effects. Significant variables to p<0.05 were retained in the final model. p-values <0.05 were considered significant. Statistical analyses were performed using "nlme" and "lme4" package from R project. Results are reported as odds ratios (OR) with 95% confidence intervals (CI).
Result(s): Increasing sum (1.034 [1.022 1.046]/p<0.001) and mean diameter (1.129 [1.046 1.219] p=0.002) of the 5 largest follicles increased the probability of forming euploid embryos. Increasing days of stimulation showed a non-significant trend toward lower chance of forming euploid embryos (0.976 [0.923 1.031]/p=0.382) (Table 1).
Conclusion(s): Allowing the lead follicles to exceed 18mm increases the total number of euploid embryos formed per cycle, presumably by enabling retrieval of additional mature oocytes. Evidence of a detrimental effect of excessive follicle size was not evident in our study, though the number of cycles with follicles exceeding 24 mm was limited. The non-significant trend toward decreased euploid embryos following prolonged stimulation may reflect the effects of poor responders. [Figure presented]
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Objective: PGT-A on TE biopsies (TE Bx/NGS) provides a method of selecting blastocysts with excellent prognosis for establishing clinical pregnancies, minimizing miscarriages and improving live birth rates per ART procedure. However some practitioners distrust the reliability of TE Bx/NGS because mosaicism is seen in normal placentae (derived from the TE) and small numbers of TE cells biopsied may not represent the fetus (derived from the inner cell mass). We examined rebiopsy specimens from the TE and the ICM to determine the reliability of the clinical biopsy to characterize the blastocyst. In particular, we determined concordance between the clinical biopsies and rebiopsy specimens, focusing on 1) chromosomal concordance for disomic results, aneuploid results or mosaic results in the clinical biopsy and 2) clinical concordance (whether biopsy of the ICM was concordant with the initial biopsy's result of "Euploid" vs "NOT euploid") Design: Rebiopsy of blastocysts with known results of clinical PGT-A
Material(s) and Method(s): Results of initial, clinical TE biopsies were obtained from Cooper Genomics. Vitrified blastocysts from patients consenting to research were selected for groups that had no aneuploidy (N = 10), aneuploidy with 1 or 2 aneuploid chromosomes (N = 4) or 1 aneuploid chromosome and 1 mosaic result (N =18). Blastocysts were rewarmed and cells from the TE and ICM were biopsied separately, obtaining as many rebiopsy specimens as possible. Biopsy specimens were subjected to WGA and NGS in our university's core laboratory. NGS results for rebiopsies were compared with results of the clinical biopsy. Rebiopsy chromosomes were considered concordant when the same chromosomal diagnosis was observed Results: Chromosomal concordances were 97.0%, 74.3%, and 13.7% per chromosome, respectively, for disomic (Di), aneuploid (An) and mosaic (Mo) chromosomes in the clinical biopsy. Discordant chromosome results were predominantly mosaic results (2.6%) for Di, mosaic or complementary results (21.6%) for An, or were not seen or non-mosaic aneuploid results (74.5%) for Mo observed for the same chromosome that was seen in the clinical biopsy. These minor discordances can be considered concordant since they mainly confirm the initial results. Counting them as concordant leads to concordances 99.6% for Di, 95.9% for An, and 88.2% for Mo per chromosome. Rebiopsies of inner cell mass were clinically concordant for 100% of the blastocysts (biopsy result of ICM agreed with the clinical result of "euploid" or "not euploid").
Conclusion(s): Despite small number of biopsied cells (required to avoid damage to the blastocyst) and mosaicism (demonstrated by rebiopsy specimens) the excellent chromosomal concordance for rebiopsy specimens (99.6% and 95.9%) and clinical concordance for ICM biopsies (100%) indicate that TE biopsy/NGS provides excellent accuracy in its assessment of ploidy. Within this non-randomly selected subset of blastocysts, mosaics detected in the clinical biopsy outnumbered mosaics detected only by rebiopsy 2.25:1 (18:8).
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PURPOSE/OBJECTIVE:To assess the experiences of two large fertility clinics in which embryos with positive results following preimplantation genetic testing for monogenic disorders (PGT-M) were transferred upon patient request, in order to explore the nature of the conditions for which these requests have been made and review ethical considerations. METHODS:Retrospective review of previous embryo transfers at the NYU Langone Fertility Center and ORM Fertility was performed. Embryo transfers prior to May 2019 in which embryo biopsy and PGT-M occurred were reviewed, and transferred embryos that were positive for a monogenic disorder (excluding autosomal recessive carriers) were identified. RESULTS:Seventeen patients were identified who elected to transfer 23 embryos that tested positive for nine different monogenic disorders. Most of the embryos transferred were positive for disorders that are autosomal dominant (15/23), are adult-onset (14/23), are associated with reduced penetrance (16/23), and have available management to lessen symptom severity (22/23). Transfer of positive embryos most commonly occurred for hereditary cancer susceptibility syndromes (9/23 embryos), particularly hereditary breast and ovarian cancer syndrome. CONCLUSIONS:When unaffected embryos are not produced following in vitro fertilization with PGT-M, some patients request to transfer embryos with positive test results. The majority of transfers were for embryos positive for adult-onset, reduced penetrance diseases. As these requests will likely increase over time, it is essential to consider the practical and ethical implications.

Objective: To determine the incidence of euploidy in Blastocysts derived from 0PN and 1PN compared with 2PN embryos.
Design(s): Single center retrospective review of PGT-A cases over a 4 year period (2015-2018) where a biopsy and ploidy determination was performed on blastocysts (blasts) derived from zygotes where pronuclei (PNs) were either not evident (0 PN) or only 1 pronucleus (1 PN) was evident at the time of fertilization check.
Material(s) and Method(s): At NYULMC fertilization checks are conducted ~18 hours post insemination or ICSI. The number of PN in each egg is recorded and zygotes are cultured individually. Cases where <=50% of the mature eggs exhibit 2PN are routinely rechecked later on Day 1. In cases for PGT-A, all viable inseminated eggs excluding those with >=3 PN remain in culture to Day 6/7. Good quality blastocysts with a distinct Inner cell mass and cohesive trophectoderm are considered for PGT-A regardless of whether they were 0PN, 1PN or 2PN at fertilization check. PGT-A results are shown in Table 1 along with PGT-A sex of blasts derived from each group.
Result(s): [Figure presented]
Conclusion(s): Prior to utilization of PGT-A and/or timelapse zygotes not exhibiting 2PN at fertilization check were routinely discarded. However, it is now obvious that a percentage of these, albeit small, are fertilized normally and are euploid. Though they account for only a small percentage these may be the only euploid blasts available. Implantation rates and LB rates following transfer of these blasts are similar to those for 2PN blastocysts. Of interest, ratios of XX:XY blasts derived from 1PN and 0PN zygotes were ~2:1 while those from 2PN zygotes were ~1:1. It should be noted that NGS cannot detect pure haploidy (23, XO) or triploidy (69, XXX thereby possibly misdiagnosing these as euploid although our IR and LB results indicate otherwise.
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Objective: 79.9% of patients surveyed in a fertility clinic felt social media (SM), the use of electronic communication to share information, benefited the patient experience.¹ Up to 40% of Americans doubt professional opinion when it conflicts with web-based findings.² We examined fertility-related SM accounts and factors that contribute to influencer status (credibility to a large SM audience).
Design(s): Cross-sectional analysis.
Material(s) and Method(s): The search function of Twitter (TW) and Instagram (IG) was used on 3/26/19 to generate a list of accounts with the terms: fertility, infertility, ttc, egg freezing, ivf, endometriosis and reproductive. Accounts not in English, private, no posts in > 1 year, or content unrelated to search terms were excluded. Between 3/31/19 - 4/7/19, accounts were assessed for: author type; REI board certification (REI-BC); influencer (INF) status (>10K followers on IG; verified check mark on TW); age of account (mo); number (n) of followers; n of posts; hashtags and content in last 5 posts. Statistical analysis included unpaired t-tests and a classification and regression tree (CART) using n of posts per month (ppm) and most frequent content to determine factors associated with INF status.
Result(s): 710 accounts (347 TW, 363 IG) were identified, of which 537 (278 TW, 259 IG) were included. There were 4 academic/professional societies (4 TW/1 INF, 0 IG/0 INF), 90 REI clinics (42 TW/1 INF, 48 IG/0 INF, 24 REI physicians (15 TW/1 INF, 9 IG/0 INF), 28 allied health professionals (18 TW/1 INF, 10 IG/2 INF), 8 organizations with an MD advisor (5 TW/1 INF, 3 IG/1 INF), 162 patients (67 TW/4 INF, 95 IG/7 INF), 123 support groups (75 TW/23 INF, 48 IG/7 INF), 23 wellness accounts (9 TW/0 INF, 14 IG/4 INF), and 75 classified as others (43 TW/7 INF, 32 IG/6 INF). Mean n of TW posts was 9,329 (10 - 251,000) with mean 16,947 for INFs. Mean n of IG posts was 284 (1 - 2,784) with mean 915 INF. Mean n of TW followers was 9,728 (77 - 561,000) with mean 15,915 INF. Mean n of IG followers was 3,706 (6 - 55,900) with mean 20,514 INF. INFs were more likely to be awareness and support accounts (59.8% TW, 25.0% IG), patients (12.8% TW, 25% IG), or other (17.9% TW, 21.0%IG). Only 7.7% TW and 7.1% IG INFs were REI-BC. Mean age of INFs was older than non-INFs (TW 102.3 +/- 26.5 vs 84.2 +/- 34.5, p < 0.0017; IG 39.1 +/- vs 21.0 +/- 17.2, p < 0.0001). IG content (1290 posts reviewed) was primarily personal stories (31.7%) or inspiration/support (23.7%). TW content (1390 posts reviewed) was mostly promotion (28.2%) and research/education (20.2%). Top hashtags included #infertility (128) and #ttc (54), with #infertile (2) and #tryingtoconceive (5) less common. CART analysis showed that the best predictor for classification as an INF was high activity (>50ppm TW, >10ppm IG). Inclusion of the most frequent content by platform did not accurately classify INFs.
Conclusion(s): As patients increasingly utilize SM to obtain and engage with health information, it is critical for REI physicians and clinics to understand the fertility-related SM landscape in order to successfully enhance relationships with patients and ensure dissemination of accurate and evidence-based information. References: 1. Broughton D, Schelble A, Cipolla K, Cho M, Franasiak J, Omurtag KR. Social media in the REI clinic: what do patients want? J Assist Reprod Genet. 2018 Jul;35(7): 1259-1263. 2. Kane G et al. Community Relations 2.0. Harv Bus Rev. 2009 Nov;87 (11): 45-50, 132.
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Introduction: Clinical pregnancy represents success outcome in a PGT-a in cycle. It can be defined as the presence of sacs with fetal heart beats at 7-8 weeks. Main purpose of PGT-a study is to identify euploid embryos in order to be replaced to patient endometrium. Nevertheless, PGT-a cycles differs in relation with attributes related to patients as well cycle information. The main goal of the present study is to design an predictive model capable to give a probability of clinical pregnancy before embryo transfer takes place.
Material(s) and Method(s): Dataset used included 1190 cycles that belong at New York University Fertility Center between 2012 and 2015. Patient id was encrypted with an alphanumeric code. The classifier implement was a Multilayer Perceptron. Feature engineering and standardization was carried out in the original variables. Algorithm was implemented using Python programing language.Model parameters was searched using grid search methodology. Classification performance was evaluated via 5-fold cross validation and area under the curve (AUC) Results: Variables used as a predictor were: maternal age, biopsy specimen method, reason for referral and quantity of euploid and aneuploid embryos generated in the cycle. In order to evaluate normality distribution among the dependent variables selected D'Agostino's K2 test was performed as a goodness-of-fit measure. Results variables showed a non gaussian distribution (p>0.05). Lack of normality was due to presence of outliers. To mitigate it effects we employed a technique called feature engineering applying mathematical function to the original variables. In order to include categorical variables, it were coded using numerical encoding. Model implemented achieves an Area Under the Curve (AUC) of 80%. In other words, the sensitivity-specificity tradeoff in the classifier was of 80%. It is important to note that threshold selected was 0.5. It means that cases with an output after classification with values higher than the cut-off were classified as Pregnant. On the other hand cases with output lower than 0.5 were assigned as non pregnant. Furthermore, Sensitivity (True Positive / True Positive + False Negative) and Specificity (True Negative / True Negative + False Positive) were 82% and 69% respectively.
Conclusion(s): We are aware about the presence of an intrinsic bias closely related to the Fertility Center where the PGT-a cycles was performed. In order to overcome that we are developing a new algorithm capable to solve current limitation being capable to be adapted for a specific center. A scoring tool based on artificial intelligence can be helpful in selecting those patients with high probability to achieve clinical pregnancy during PGT-a cycle. Artificial neural networks is a robust estimator that allowed us to overcome multicollinearity between the original variables. Overall performance of the model was high (80%) giving strong evidence that the cycles can be accurately classified.
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STUDY QUESTION/OBJECTIVE:What factors are associated with decision regret and anxiety following preimplantation genetic testing for aneuploidy (PGT-A)? SUMMARY ANSWER/UNASSIGNED:The majority of patients viewed PGT-A favourably regardless of their outcome; although patients with negative outcomes expressed greater decision regret and anxiety. WHAT IS KNOWN ALREADY/UNASSIGNED:PGT-A is increasingly utilized in in vitro fertilization (IVF) cycles to aid in embryo selection. Despite the increasing use of PGT-A technology, little is known about patients' experiences and the possible unintended consequences of decision regret and anxiety related to PGT-A outcome. STUDY DESIGN, SIZE, DURATION/UNASSIGNED:Anonymous surveys were distributed to 395 patients who underwent their first cycle of autologous PGT-A between January 2014 and March 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS/UNASSIGNED:There were 69 respondents who underwent PGT-A at a university-affiliated fertility centre, completed the survey and met inclusion criteria. Respondents completed three validated questionnaires including the Brehaut Decision Regret (DR) Scale, short-form State-Trait Anxiety Inventory (STAI-6) and a health literacy scale. The surveys also assessed demographics, fertility history, IVF and frozen embryo transfer cycle data. MAIN RESULTS AND THE ROLE OF CHANCE/UNASSIGNED:The majority of respondents were Caucasian, >35 years of age and educated beyond an undergraduate degree. The majority utilized PGT-A on their first IVF cycle, most commonly to 'maximize the efficiency of IVF' or reduce per-transfer miscarriage risk. The overall median DR score was low, but 39% of respondents expressed some degree of regret. Multiple regression confirmed a relationship between embryo ploidy and decision regret, with a lower number of euploid embryos associated with a greater degree of regret. Patients who conceived following euploid transfer reported less regret than those who miscarried or failed to conceive (P < 0.005). Decision regret was inversely associated with number of living children but not associated with age, education, race, insurance coverage, religion, marital status or indication for IVF/PGT-A. Anxiety was greater following a negative pregnancy test or miscarriage compared to successful conception (P < 0.0001). Anxiety was negatively associated with age, time since oocyte retrieval and number of living children, and a relationship was observed between anxiety and religious affiliation. Overall, decision regret was low, and 94% of all respondents reported satisfaction with their decision to pursue PGT-A; however, patients with a negative outcome were more likely to express decision regret and anxiety. LIMITATIONS, REASON FOR CAUTION/UNASSIGNED:This survey was performed at a single centre with a relatively homogenous population, and the findings may not be generalizable. Reasons for caution include the possibility of response bias and unmeasured differences among those who did and did not respond to the survey, as well as the possibility of recall bias given the retrospective nature of the survey. Few studies have examined patient perceptions of PGT-A, and our findings should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS/UNASSIGNED:Overall decision regret was low following PGT-A, and the vast majority deemed the information gained valuable for reproductive planning regardless of outcome. However, more than one-third of the respondents expressed some degree of regret. Respondents with no euploid embryos were more likely to express regret, and those with a negative outcome following euploid embryo transfer expressed both higher regret and anxiety. These data identify unanticipated consequences of PGT-A and suggest opportunities for additional counselling and support surrounding IVF with PGT-A. STUDY FUNDING/COMPETING INTEREST(S)/UNASSIGNED:No external funding was obtained for this study. D.H.M. reports personal fees, honorarium, and travel expenses from Ferring Pharmaceuticals, personal fees and travel expenses from Granata Bio, and personal fees from Biogenetics Corporation, The Sperm and Embryo Bank of New York, and ReproART: Georgian American Center for Reproductive Medicine. All conflicts are outside the submitted work.