Intra-patient analysis of individual weight gain or loss between IVF cycles: cycle now and transfer later.

STUDY QUESTION: What is the impact of clinically significant weight change on outcomes related to IVF cycle performance? SUMMARY ANSWER: While individual weight loss did not significantly impact ovarian response to stimulation or other cycle outcome parameters in our study, some positive associations were found for individual weight gain. WHAT IS KNOWN ALREADY: The role of weight-change in patients undergoing IVF has been largely studied by comparing weight loss in different cohorts of patients stratified by a static BMI. Specifically, obesity has been extensively studied in relation to its negative effects on assisted or unassisted conception outcomes and ovulatory function. Previous research has shown conflicting results, while BMI, which is commonly used as a marker of obesity, may not accurately reflect the underlying factors affecting fertility in obese patients. STUDY DESIGN, SIZE, DURATION: This study utilized a retrospective within-patient repeated measurement analysis design to assess the impact of weight change on IVF outcomes in cycles where all embryos were cryopreserved at the blastocyst stage for transfer at a later date. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at an academically affiliated fertility center. The data included 961 women who underwent at least two IVF cycles between December 2014 and June 2020, with documented short-term weight gain (n = 607) or weight loss (n = 354) within 1 year from their initial IVF cycle. Multivariable generalized estimating equations (GEE) and generalized linear mixed models (GLMM) were employed to assess associations between weight change and outcomes across cycles. MAIN RESULTS AND THE ROLE OF CHANCE: The multivariable models indicated that weight loss did not show any significant associations with the numbers of oocytes retrieved, or mature oocytes, the fertilization rate or the blastulation rate. However, weight gain demonstrated a minor positive association with the number of oocytes retrieved in both GEE models (coefficient: 0.01, 95% CI: 0.00-0.01) and GLMM models (0.01, 95% CI: 0.01-0.00). There was also a potential increase in the fertilization rate with weight gain, as indicated by a positive coefficient in both GEE models (coefficient: 0.01, 95% CI: 0.00-0.02) and GLMM models (coefficient: 0.01, 95% CI: 0.00-0.01). However, the association between weight gain and the embryo blastulation rate was not statistically significant in any model. LIMITATIONS, REASONS FOR CAUTION: This study focused on cycle performance parameters instead of reproductive outcomes, which restricted our ability to evaluate the impact of weight change on cumulative live birth rates. Additionally, the study did not account for variables such as stimulation protocols, potentially introducing confounding factors and limiting the generalizability of the results. WIDER IMPLICATIONS OF THE FINDINGS: Although obesity is associated with adverse obstetrical risks, there is less evidence of adverse reproductive outcomes in IVF cycles. We therefore recommend that an IVF cycle should not be delayed due to weight, so that the patient is not adversely affected by increasing age. The IVF cycle should aim to freeze all embryos, so that embryo transfer can then occur after weight loss, so as to limit the recognized obstetrical risks. STUDY FUNDING/COMPETING INTEREST(S): The study was not funded and there were no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Day after rescue ICSI: eliminating total fertilization failure after conventional IVF with high live birth rates following cryopreserved blastocyst transfer.

STUDY QUESTION: What is the impact of day after rescue ICSI (r-ICSI) on success of fresh and frozen embryo transfers? SUMMARY ANSWER: The use of r-ICSI can virtually allay fears of total fertilization failure (TFF) after conventional IVF (C-IVF) and achieve high live birth rates after frozen blastocyst transfer. WHAT IS KNOWN ALREADY: More infertility clinics have resorted to the use of ICSI in place of C-IVF in IVF treatment owing to fear of TFF or a low fertilization rate. r-ICSI has been attempted either on the day of IVF or the day after. Day after r-ICSI has proved unsuccessful in the past. STUDY DESIGN, SIZE, DURATION: A retrospective data analysis was performed of 16 608 qualifying cases between April 2010 and July 2021 conducted at a single private academically affiliated fertility clinic. PARTICIPANTS/MATERIALS, SETTING, METHODS: r-ICSI was performed principally on patients with >4 metaphase II oocytes, showing no signs of fertilization 18 h after C-IVF. C-IVF was performed on patients who had >4 million total motile sperm after preparation. r-ICSI was then performed 18-24 h after insemination, using the sperm sample from the previous day. r-ICSI fertilization rates, cryopreservation of cleavage and blastocysts embryos, and pregnancy rates after fresh or frozen transfer were then assessed. MAIN RESULTS AND THE ROLE OF CHANCE: r-ICSI was performed on 377 patients (2.3% of eligible retrieval cycles) who had a mean (±SD) female and male age of 35.9 ± 4.5 and 38.1 ± 9.1 years, respectively. A total of 5459 oocytes were initially retrieved. Of the oocytes undergoing r-ICSI, 2389 (49.5%) fertilized normally, and 205 (54.4%) patients underwent a fresh embryo transfer. The live birth rates were 23/186 (12.3%) for fresh cleavage and 5/19 (26.3%) for fresh blastocyst stage transfers. In 145 cycles a blastocyst was frozen, and 137 transfers were performed with a 64/137 (46.7%) live birth rate. Of the 377 cycles receiving r-ICSI only, 25 of the qualifying cases failed to have any fertilization, reducing TFF to 25/16 608 (0.15%). LIMITATIONS, REASONS FOR CAUTION: This was a single-center retrospective study on a specific subset of patients, which may limit its generalizability to other clinics. WIDER IMPLICATIONS OF THE FINDINGS: r-ICSI allows a second opportunity to fertilize oocytes despite poor initial outcomes. Patients who had a frozen blastocyst transfer achieved high live birth rates, indicating that a resynchronization of the embryo with the endometrium can optimize r-ICSI cases. r-ICSI allays fears of TFF when using C-IVF, providing evidence that the overuse of ICSI in patients without male factor may not be warranted. STUDY FUNDING/COMPETING INTEREST(S): The study was internally funded by Boston IVF. The authors declare that they have no conflict of interest in relation to the data published in the article. TRIAL REGISTRATION NUMBER: N/A.

Acceptance of genetic editing and of whole genome sequencing of human embryos by patients with infertility before and after the onset of the COVID-19 pandemic.

RESEARCH QUESTION: Has acceptance of heritable genome editing (HGE) and whole genome sequencing for preimplantation genetic testing (PGT-WGS) of human embryos changed after the onset of COVID-19 among infertility patients? DESIGN: A written survey conducted between April and June 2018 and July and December 2021 among patients at a university-affiliated infertility practice. The questionnaire ascertained the acceptance of HGE for specific therapeutic or genetic 'enhancement' indications and of PGT-WGS to prevent adult disease. RESULTS: In 2021 and 2018, 172 patients and 469 patients (response rates: 90% and 91%, respectively) completed the questionnaire. In 2021, significantly more participants reported a positive attitude towards HGE, for therapeutic and enhancement indications. In 2021 compared with 2018, respondents were more likely to use HGE to have healthy children with their own gametes (85% versus 77%), to reduce disease risk for adult-onset polygenic disorders (78% versus 67%), to increase life expectancy (55% versus 40%), intelligence (34% versus 26%) and creativity (33% versus 24%). Fifteen per cent of the 2021 group reported a more positive attitude towards HGE because of COVID-19 and less than 1% a more negative attitude. In contrast, support for PGT-WGS was similar in 2021 and 2018. CONCLUSIONS: A significantly increased acceptance of HGE was observed, but not of PGT-WGS, after the onset of COVID-19. Although the pandemic may have contributed to this change, the exact reasons remain unknown and warrant further investigation. Whether increased acceptability of HGE may indicate an increase in acceptability of emerging biomedical technologies in general needs further investigation.

ART outcomes in lean compared to obese phenotypes of polycystic ovarian syndrome.

RESEARCH QUESTION: To investigate differences in reproductive outcomes among IVF patients with lean compared to obese polycystic ovarian syndrome (PCOS) phenotypes. DESIGN: A retrospective cohort study of patients with PCOS who underwent IVF in a single, academically affiliated infertility center in the USA between December 2014 and July 2020. The diagnosis of PCOS was assigned based on Rotterdam criteria. Patients were designated as lean (< 25) or overweight/obese (≥ 25) PCOS phenotype based on BMI (kg/m2) at cycle start. Baseline clinical and endocrinologic laboratory panel, cycle characteristics, and reproductive outcomes were analyzed. The cumulative live birth rate included up to 6 consecutives cycles. A Cox proportional hazards model and Kaplan-Meier curve for estimating live birth rates were used to compare the two phenotypes. RESULTS: A total of 1395 patients who underwent 2348 IVF cycles were included. The mean (SD) BMI was 22.7 (2.4) in the lean and 33.8 (6.0) in the obese group (p < 0.001). A number of endocrinological parameters were similar between lean and obese phenotypes: total testosterone 30.8 ng/dl (19.5) vs 34.1 (21.9), p > 0.02 and pre-cycle hemoglobin A1C 5.33% (0.38) vs 5.51% (0.51) p > 0.001, respectively. The CLBR was higher in those with a lean PCOS phenotype: 61.7% (373/604) vs 54.0% (764/1414) respectively. Miscarriage rates were significantly higher for O-PCOS patients (19.7% (214/1084) vs 14.5% (82/563) p < 0.001) and the rate of aneuploids was similar (43.5%, 43.8%, p = 0.8). A Kaplan-Meier curve estimating the proportion of patients with a live birth was higher in the lean group (log-rank test p = 0.013). After adjusting for potential confounders, the lean phenotype was associated with an increased hazard ratio for live birth: HR = 1.38 p < 0.001. CONCLUSIONS: Lean PCOS phenotype is associated with a significantly higher CLBR compared to their obese counterparts. Miscarriage rates were significantly higher among obese patients, despite comparable pre-cycle HBA1C and similar aneuploidy rates in patients who underwent PGT-A.

Endometrial compaction does not predict live birth in single euploid frozen embryo transfers: a prospective study.

STUDY QUESTION: Is there a relationship between endometrial compaction and live birth in euploid frozen embryo transfer (FET) cycles? SUMMARY ANSWER: Live birth rates (LBRs) were similar in both patients that demonstrated endometrial compaction or no compaction in single euploid FETs. WHAT IS KNOWN ALREADY: There has been increasing interest in the correlation between endometrial compaction and clinical outcomes but there has been conflicting evidence from prior investigations. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study from 1 September 2020 to 9 April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed at a single, academically affiliated fertility center in which patients who had an autologous single euploid FET using a programmed or modified natural cycle protocol were included. All embryos had trophectoderm biopsy for preimplantation genetic testing for aneuploidy followed by vitrification at the blastocyst stage. Two ultrasound measurements of endometrial thickness (EMT) were obtained. The first measurement (T1) was measured transvaginally within 1 day of initiation of progesterone or ovulation trigger injection, and a second EMT (T2) was measured transabdominally at the time of embryo transfer (ET). The primary outcome (LBR) was based on the presence and proportion of compaction (percentage difference in EMT between T1 and T2). MAIN RESULTS AND THE ROLE OF CHANCE: Of the 186 participants included, 54%, 45%, 35%, 28% and 21% of women exhibited >0%, ≥5%, ≥10%, ≥15% and ≥20% endometrial compaction, respectively. Endometrial compaction was not predictive of live birth at any of the defined cutoffs. A sub-analysis stratified by FET protocol type (n = 89 programmed; n = 97 modified natural) showed similar results. LIMITATIONS, REASONS FOR CAUTION: There was the potential for measurement error in the recorded EMTs. The T2 measurement was performed transabdominally, which may cause potential measurement error, as it is generally accepted that transvaginal measurements of EMT are more accurate, though, any bias is expected to be non-differential. The sub-analysis performed looking at FET protocol type was underpowered and should be interpreted with caution. Our study, however, represents a pragmatic approach, as it allowed patients to avoid having to come in for an extra transvaginal ultrasound the day before or on the day of ET. WIDER IMPLICATIONS OF THE FINDINGS: Assessing endometrial compaction may lead to unnecessary cycle cancellation. However, further studies are needed to determine if routine screening for endometrial compaction would improve clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S): No authors report conflicts of interest or disclosures. There was no study funding. TRIAL REGISTRATION NUMBER: NCT04330066.

Impact of empathic physician contact on patient anxiety and distress during the waiting period after embryo transfer: a randomized controlled trial.

RESEARCH QUESTION: Can an empathic physician phone call in the interval between embryo transfer and first serum human chorionic gonadotrophin measurement decrease anxiety and distress amongst patients undergoing IVF? DESIGN: This was a randomized controlled trial at a single academically-affiliated fertility centre including patients aged 18-43 undergoing their first embryo transfer with autologous fresh or euploid cryopreserved embryos following preimplantation genetic testing for aneuploidies (frozen embryo transfer, FET/PGT-A). After embryo transfer, participants were randomized to a 5-minute scripted phone call (intervention) from a single physician 3-4 days after embryo transfer or to routine care. The primary and secondary outcomes included were change in State-Trait Anxiety Inventory (STAI) and Hospital Anxiety and Depression Scale (HADS) scores from the start of IVF stimulation to 8-9 days after embryo transfer, respectively. RESULTS: A total of 231 participants (164 fresh, 67 FET/PGT-A) were randomized to intervention (n = 116) or routine care (n = 115). While mean STAI and HADS scores increased in both groups, the intervention group experienced lower mean increases than the routine care group for both the STAI (3.3 [0.97] versus 7.8 [1.10], respectively; P = 0.002) and the HADS (0.3 [0.44] versus 2.4 [0.53], respectively; P = 0.003). Most participants in the intervention group found the call helpful (91.4%) and reported that it decreased distress and anxiety (81%). CONCLUSIONS: A brief empathic phone call from a physician during the waiting period resulted in significantly lower self-reported levels of patient anxiety and distress. As the intervention in this study averaged 5 min, implementing this in clinical practice would not be onerous and may ease the distress associated with the waiting period.

Clinical outcomes and utilization from over a decade of planned oocyte cryopreservation.

RESEARCH QUESTION: What is the clinical experience of patients who have undergone planned oocyte cryopreservation and oocyte thawing and warming? DESIGN: Retrospective observational cohort study. All women who completed planned oocyte cryopreservation at a single large university-affiliated fertility centre between June 2006 and October 2020 were identified, including the subset who returned to use their oocytes. Patients who underwent oocyte cryopreservation for medical reasons were excluded. Baseline demographics, oocyte cryopreservation and thawing-warming cycle parameters, and clinical outcomes, were extracted from the electronic medical record. The primary outcome was cumulative live birth rate (LBR), and secondary outcomes were cumulative clinical pregnancy rate (CPR), and CPR and LBR per transfer. Results were stratified by age at time of cryopreservation (<38 and ≥38 years). RESULTS: Of 921 patients who underwent planned oocyte cryopreservation, 68 (7.4%) returned to use their oocytes. Forty-six patients (67.6%) completed at least one embryo transfer. The CPR per transfer was 47.5% and LBR was 39.3%. The cumulative LBR per patient who initiated thawing-warming was 32.4%. Cycle outcomes were not significantly different in patients aged younger than 38 years and those aged 38 years or over. No patient aged 40 years or older (n = 6) was successful with their cryopreserved oocytes. Ten patients (14.7%) who were unsuccessful with their cryopreserved oocytes achieved a live birth using donor oocytes, with most (7/10) of these patients aged 38 years and older. CONCLUSION: Only a small percentage of patients returned to use their oocytes, and 32% of those were able to achieve a live birth.

Multiple cryopreservation-warming cycles, coupled with blastocyst biopsy, negatively affect IVF outcomes.

RESEARCH QUESTION: Do multiple cryopreservation-warming cycles, coupled with blastocyst biopsy, negatively affect IVF outcomes? DESIGN: Patients undergoing IVF with homologous single embryo transfer, and who underwent trophectoderm biopsy for preimplantation genetic testing for aneuploidy (PGT-A) between 2013 and 2017, were divided into three groups based on degree of embryonic micromanipulation: once-biopsied, once-cryopreserved (group BC, n = 2603), once-biopsied, twice-cryopreserved (group CBC, n = 95) and twice-biopsied, twice-cryopreserved (group BCBC, n = 15). The primary outcome was live birth; secondary outcomes included positive serum pregnancy test, clinical pregnancy and miscarriage. RESULTS: Group CBC had a significantly lower chance of live birth (adjusted RR 0.57, 95% CI 0.41 to 0.79) and clinical pregnancy (adjusted RR 0.67, 95% CI 0.53 to 0.85) compared with group BC. Miscarriage rates were similar between groups BC and CBC (adjusted RR 1.3, 95% CI 0.64 to 2.7). CONCLUSIONS: Multiple cryopreservation-warming cycles, coupled with blastocyst biopsy, negatively affect IVF outcomes. Although PGT-A is thought to improve reproductive outcomes on a per transfer basis, caution must be exercised in counselling patients on the possibility of diminishing returns owing to further embryonic micromanipulation after an embryo has been cryopreserved.

Infertility remains a top stressor despite the COVID-19 pandemic.

RESEARCH QUESTION: What is the psychological impact of the COVID-19 pandemic on infertility patients? DESIGN: An anonymous cross-sectional online survey was sent to patients who attended a large university-affiliated infertility practice in the USA between 1 January 2019 and 1 April 2020. At three different time-points respondents were asked to note their top three stressors, from a list of 10 commonly reported life stressors. RESULTS: The questionnaire was sent to 10,481 patients, with 3604 responses (response rate 34%) received. A total of 2202 non-pregnant female respondents were included in the final analysis. One-third of respondents had a prior diagnosis of an anxiety disorder, and 11% reported taking anxiolytic medications; over one-quarter had a prior diagnosis of a depressive disorder and 11% reported taking antidepressant medications. At all three time-points, infertility was noted to be the most frequent top stressor. Coronavirus was noted to be the third most common stressor among the respondents in early March but, at the time of writing, is similar to that of infertility (63% and 66%, respectively). A total of 6% of patients stated that infertility treatment, including IVF, should not be offered during the COVID-19 pandemic. CONCLUSION: Despite the unprecedented global pandemic of COVID-19, causing economic and societal uncertainty, the stress of infertility remains significant and is comparable a stressor to the pandemic itself.

Blasts from the past: is morphology useful in PGT-A tested and untested frozen embryo transfers?

RESEARCH QUESTION: Day of cryopreservation, inner cell mass (ICM) grade, trophectoderm grade and blastocyst expansion grade have been associated with differences in live birth rate in frozen embryo transfer (FET) cycles. This study sought to examine the likelihood of live birth and whether the morphological grade of the blastocyst is more or equally useful in FET cycles among preimplantation genetic testing for aneuploidies (PGT-A) tested and untested blastocysts. DESIGN: This was a retrospective cohort study of 6271 vitrified-warmed, autologous, single-embryo transfer cycles among patients undergoing IVF from July 2013 to December 2017 at a single, university-affiliated infertility practice. The primary outcome was live birth, calculated by generalized estimating equations. RESULTS: Among PGT-A tested embryos, inferior ICM grade was associated with a lower chance of live birth (ICM grade B versus A: adjusted risk ratio [aRR] 0.91, 95% confidence interval [CI] 0.84-0.99). Among untested blastocysts there was a lower live birth rate in blastocysts cryopreserved on day 6 versus day 5 (aRR 0.87, 95% CI 0.78-0.96), and those with inferior pre-vitrification trophectoderm grade (trophectoderm grade B versus A: aRR 0.86, 95% CI 0.79-0.94). Blastocysts with a higher pre-vitrification expansion grade (pre-vitrification expansion grade 5 versus 4: aRR 1.1, 95% CI 1.01-1.2) were associated, but ICM grade was not associated (ICM grade B versus A: aRR 0.93, 95% CI 0.86-1.02), with chance of live birth. CONCLUSIONS: Among PGT-A untested blastocysts, assessing embryo quality by day of cryopreservation, trophectoderm grade and expansion grade may help to identify embryos with the highest likelihood of live birth. Identifying euploid embryos by PGT-A appears to homogenize the cohort, making blastocyst morphological grade and day of cryopreservation less important.

Non-inferiority of cleavage-stage versus blastocyst-stage embryo transfer in poor prognosis IVF patients (PRECiSE trial): study protocol for a randomized controlled trial.

BACKGROUND: With improvements in in vitro culture techniques there has been a steady shift in practice to transfer embryos at the blastocyst stage (post fertilization day (p.f.d.) 5-7), when embryos reach the endometrial cavity during natural conception. For patients with > 5 zygotes on day 1 of embryo development, fresh blastocyst embryo transfer (ET) increases live birth rates when compared to cleavage stage (p.f.d. 3) transfer. In poorer prognosis patients (≤ 5 zygotes) cleavage stage ET is commonly performed to reduce the risk of cycle cancellation if no embryo survives to the blastocyst stage. However, there is a dearth of randomized controlled trial (RCT) data demonstrating improved live birth rates per cycle for cleavage vs blastocyst stage ET in this subgroup of patients. The hypothesis of the PRECiSE (PooR Embryo Yield Cleavage Stage Versus blaStocyst Embryo Transfer) trial is that blastocyst ET is not inferior to cleavage stage ET with regard to live birth rates per retrieval in poorer prognosis patients. The adoption of routine blastocyst culture for all patients would result in higher rates of single embryo transfers (SET), reduced incidence of multiple pregnancies and simplified laboratory protocols, thereby reducing costs. METHODS/DESIGN: Multicenter, non-inferiority randomized controlled trial (RCT) comparing blastocyst to cleavage stage embryo transfer in poorer prognosis patients with ≤5 zygotes on day 1 after fertilization. The primary outcome is live birth per retrieval. Secondary outcomes include: time to pregnancy, clinical pregnancy, ongoing pregnancy, miscarriage and multiple pregnancy rate (per retrieval). This trial will enroll 658 women with ≤5 zygotes on day 1 at 6 IVF centers over the course of 22 months. DISCUSSION: If the hypothesis is proven true, the data from this trial may facilitate the adoption of uniform blastocyst culture in all IVF patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03764865. Registered 5 December 2019, Protocol issue date: 4 December 2018, Original.

Sperm selection methods in the 21st century.

Natural sperm selection in humans is a rigorous process resulting in the highest quality sperm reaching, and having an opportunity to fertilize, the oocyte. Relative to other mammalian species, the human ejaculate consists of a heterogeneous pool of sperm, varying in characteristics such as shape, size, and motility. Semen preparation in assisted reproductive technologies (ART) has long been performed using either a simple swim-up method or density gradients. Both methodologies provide highly motile sperm populations; however neither replicates the complex selection processes seen in nature. A number of methods have now been developed to mimic some of the natural selection processes that exist in the female reproductive tract. These methods attempt to select a better individual, or population of, spermatozoa when compared to classical methods of preparation. Of the approaches already tested, platforms based upon sperm membrane markers, such as hyaluronan or annexin V, have been used to either select or deselect sperm with varied success. One technology that utilizes the size, motility, and other characteristics of sperm to improve both semen analysis and sperm selection is microfluidics. Here, we sought to review the efficacy of both available and emerging techniques that aim to improve the quality of the sperm pool available for use in ART.

To test or not to test? A framework for counselling patients on preimplantation genetic testing for aneuploidy (PGT-A).

STUDY QUESTION: What is the treatment path and cumulative live birth (CLB) rate from a single oocyte retrieval of patients who intend to pursue PGT-A at the start of an IVF cycle compared to matched controls? SUMMARY ANSWER: The choice of PGT-A at the start of the first IVF cycle decreases the CLB per oocyte retrieval for patients <38 years of age, however patients ≥38 years of age benefit significantly per embryo transfer (ET) when live birth (LB) is evaluated. WHAT IS KNOWN ALREADY: PGT-A has been shown to reduce the practice of transferring multiple embryos and to confer a higher live birth rate per transfer. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study from December 2014 to September 2016, involving 600 patients: those intending PGT-A for their first IVF cycle (N = 300) and their matched controls. Post-hoc power calculations (alpha of 0.05, power of 0.80) indicated that our study was powered adequately to demonstrate significant differences in CLB per retrieval and LB per transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was performed at a large academically affiliated infertility practice where approximately 80% of patients have insurance coverage for fertility care. Patients were identified through electronic medical records, and those who intended to pursue PGT-A at the start of stimulation were assessed. Patients were matched by age, time of oocyte retrieval and oocyte yield to the same number of controls. CLB outcomes per single retrieval, including the fresh and frozen transfers arising from the initial stimulation cycle, were calculated. MAIN RESULTS AND THE ROLE OF CHANCE: PGT-A was not beneficial when CLB rate was assessed per retrieval, however its benefits were significant when LB rate was assessed per transfer. First cycle, <38 year-old patients who intended to have PGT-A had a significantly (P < 0.001) lower CLB rate per oocyte retrieval compared to controls (49.4% vs. 69.1%). Conversely, patients ≥ 38 years in the PGT-A group had similar CLB rates compared to controls per oocyte retrieval, while LB rates per transfer were doubled compared to controls (62.1% vs. 31.7%; P < 0.001). Of the first-cycle PGT-A and control patients, 25.3% and 2.3% failed to achieve a transfer, respectively. LIMITATIONS, REASONS FOR CAUTION: This is not a true intention-to-treat study, due to its retrospective nature. Additionally, the number of patients with two or more previous miscarriages was significantly greater in the PGT-A group as compared to controls, however a sub-analysis showed that this failed to impact outcomes. WIDER IMPLICATIONS OF THE FINDINGS: The findings indicate that PGT-A may be detrimental for those <38 years old undergoing their first IVF cycle. PGT-A has the greatest clinical impact when a transfer is achieved in the ≥38 years old population. This study evaluates the typical treatment path following a patient's choice to pursue PGT-A at the cycle start, and can be used as a guide for counselling patients in relation to age and cycle number. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Mitotically Active Leiomyoma in a Woman with Mayer-Rokitansky-Küster-Hauser Syndrome: A Case Report.

BACKGROUND: Cases of women with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome developing leiomyomata are rare. A case with mitotically active leiomyomata has not previously been described to our knowledge. CASE: A 43-year-old woman with MRKH syndrome found to have an incidental pelvic mass on imaging studies underwent a diagnostic laparoscopy, followed by resection of leiomyomata and uterine remnant via mini laparotomy. Histopathology revealed focal infarction associated with a mitotically active area in one of the leiomyomata but with no evidence of marked cytologic atypia or hypercellularity. Focal adenomyosis was also noted. CONCLUSION: Studies have shown that mitotically active smooth cell tumors of the uterus having 5-9 mitoses/10 hpf and no cellular atypia have a metastatic rate too low to be regarded as sarcomas. Although the pathology findings in this case are benign with no need for continued surveillance by gynecologic oncology, regular follow-up with a gynecologist annually may be indicated for early diagnosis of recurrence secondary to the uncommon characteristics of this benign tumor, especially in this rare category of patients with Müllerian agenesis. Mitotically active leiomyomata can occur in patients with Müllerian agenesis, but the likelihood that a pelvic mass in a patient with MRKH syndrome is a sarcoma is extremely low.

Clustering of monozygotic twinning in IVF.

PURPOSE: The aim of this analysis was to study whether monozygotic twinning (MZT) events occur in clusters after IVF and, if so, to explore possible explanations for this clustering. METHODS: This is a retrospective cohort study carried out in a single, large university-affiliated reproductive medicine practice. Medical records of all patients who had undergone fresh IVF cycles, resulting in a viable clinical pregnancy, from Jan 2002 to Dec 2013 were reviewed. The incidence of MZT in 6-month intervals and the association with independent risk factors such as maternal age, extended embryo culture, PGD/intracytoplasmic sperm injection (ICSI)/assisted hatching performed were analyzed. RESULTS: Over the 12-year study period, 25,502 fresh IVF cycles were performed, resulting in 8598 clinical pregnancies. Ninety-five cycles (1.1 %) resulted in MZ twins. The percentage of MZT was >2 standard deviations (SD) higher than the overall percentage of MZT in 4 of the 24 6-month intervals. PGD, extended embryo culture (≥4 days), and more recent cycles (2005 or later) were independent risk factors for MZT. The use of multivariable logistic regression modeling to control for risk factors for MZT did not correct for this clustering effect, with both high-risk interval (clustering) and extended embryo culture remaining significant. CONCLUSION: This study supports our hypothesis that MZT occurs in clusters and that this clustering effect could not be explained by demographics and cycle characteristics alone. Although we are unable to explain the clustering phenomenon, this study is important as it highlights high-risk intervals for MZT and opens the door to performing a more detailed investigation, to identify the mechanisms responsible for the spikes of MZT incidence.

Serum estradiol:oocyte ratio as a predictor of reproductive outcome: an analysis of data from >9000 IVF cycles in the Republic of Ireland.

PURPOSE: The purpose of this study was to evaluate the serum estradiol (E2) per oocyte ratio (EOR) as a function of selected embryology events and reproductive outcomes with IVF. METHODS: This retrospective analysis included all IVF cycles where oocyte collection and fresh transfer occurred between January 2001 and November 2012 at a single institution. Patients were divided by three age groups (<35, 35-39, and ≥40 years) and further stratified into nine groups based on EOR (measured in pmol/L/oocyte). Terminal serum E2 (pmol/mL) was recorded on day of hCG trigger administration, and fertilization rate, cleavage rate, number of good quality embryos, and reproductive outcomes were recorded for each IVF cycle. RESULTS: During the study interval, 9109 oocyte retrievals were performed for 5499 IVF patients (mean = 1.7 cycles/patient). A total of 63.4 % of transfers were performed on day 3 (n = 4926), while 36.6 % were carried out on day 5 (n = 2843). Clinical pregnancy rates were highest in patients with EOR of 250-750 and declined as this ratio increased, independent of patient age. While the odds ratio (OR) for clinical pregnancy where EOR = 250-750 vs. EOR > 1500 was 3.4 (p < 0.001; 95 % CI 2.67-4.34), no statistically significant correlation was seen in fertilization, cleavage rates or number of good quality embryos as a function of EOR. CONCLUSIONS: Predicting reproductive outcomes with IVF has great utility both for patients and providers. The former have the opportunity to build realistic expectations, and the latter are better able to counsel according to measured clinical parameters. A better understanding of follicular dynamics and ovarian response to gonadotropin stimulation could optimize IVF treatments going forward.

Utilization of Cryopreserved Oocytes in Patients With Poor Ovarian Response After Planned Oocyte Cryopreservation.

Importance: Poor ovarian response (POR) to stimulation may impact patients' desire or need to utilize cryopreserved oocytes for family building in the future. These findings, captured by Society for Assisted Reproductive Technology (SART) national data, underscore the need for tailored counseling and further research into the decision-making processes influencing oocyte utilization. Objective: To examine the association of ovarian response to stimulation and the number of vitrified oocytes with the likelihood and timing of patients returning for oocyte utilization following planned oocyte cryopreservation (OC). Design, Setting, and Participants: This cohort study used data in the SART Clinical Outcome Reporting System for patients in US fertility clinics and data was used for eligible patients who underwent planned OC from January 2014 through December 2020. Data were analyzed from November 2022 to June 2023. Main outcomes and measures: The association between number of oocytes cryopreserved on return rate to utilize cryopreserved oocytes and the time from vitrification to warming. Results: A total of 67 893 autologous oocyte freezing cycles were performed in the US between 2014 and 2020, among 47 363 patients (mean [SD] age, 34.5 [4.7] years). Of these, 6421 (13.5%) were classified as patients with POR, with fewer than 5 oocytes vitrified across all ovarian stimulation cycles. A total of 1203 patients (2.5%) returned for oocyte warming and utilization. The rate of return was significantly higher in the POR group, with 260 (4.0%) returning compared with 943 (2.3%) in the normal responder group (P < .001). This trend was most notable in the age 30 to 34 years (warm cycle, 46 of 275 [16.7%] vs no warm cycle, 982 of 11 743 [8.4%]; P < .001) and age 35 to 39 years groups (warm cycle, 124 of 587 [21.1%] vs no warm cycle, 3433 of 23 012 [14.9%]; P < .001). The time elapsed from vitrification to warming was comparable between patients with POR (mean [SD], 716.1 [156.1] days) and normal responders (803.8 [160.7] days). A multivariate analysis adjusted for age, clinic region in the US, body mass index, and history of endometriosis was conducted to identify factors associated with the utilization of oocytes. The analysis revealed that having fewer than 5 oocytes vitrified was associated with higher odds of utilizing oocytes (OR, 1.52; 95% CI, 1.32-1.76). Conclusions and Relevance: This cohort study reveals a distinct pattern in the utilization of cryopreserved oocytes among patients undergoing planned OC in the US. Despite the increase in number of patients pursuing OC, there is a notably low rate of return to utilize previously vitrified oocytes; notably, patients with POR are more likely to return, although the time to return is similar to those with normal ovarian response.

Compared with conventional insemination, intracytoplasmic sperm injection provides no benefit in cases of nonmale factor infertility as evidenced by comparable euploidy rate.

OBJECTIVE: To evaluate whether differences in euploidy rates exist between intracytoplasmic sperm injection (ICSI) and conventional insemination (CI) in nonmale factor infertility cases. DESIGN: Retrospective cohort study. SETTING: A single, academically affiliated infertility center in the United States. PATIENTS: A total of 3554 patients who underwent in vitro fertilization cycles from January 2014 to December 2021. All cycles that had preimplantation testing for aneuploidy (PGT-A) performed by trophectoderm biopsy and had a postpreparation sperm concentration >4 million total motile sperm per milliliter were included. MAIN OUTCOME MEASURES: The primary outcome was the embryo euploidy rate per embryo biopsied in the ICSI vs. CI group. Secondary outcomes included the fertilization rate and number of embryos biopsied. Generalized estimating equations with a Poisson distribution were used to estimate the euploid rate ratio (with total embryos biopsied as an offset), while accounting for multiple retrievals per patient. To adjust for confounding, a propensity score model was fit for ICSI using 14 baseline female and male characteristics. RESULTS: Oocytes retrieved and the number of embryos biopsied were similar in both groups, while the fertilization rate per oocyte retrieved was significantly lower with ICSI (0.64 vs. 0.66). The proportion of euploid embryos in the ICSI group was significantly lower when compared with CI (0.47 vs. 0.52), with a euploid rate ratio of 0.89. Interestingly, when accounting for the variation in PGT reference laboratories over the study time period, adjusting for the date of procedure did not change the relationship between ICSI and euploid rate (rate ratio = 0.89); however, after adjusting for the PGT reference laboratory, the relationship between ICSI and euploid rate was no longer significant (rate ratio = 0.97). CONCLUSIONS: In the setting of nonmale factor infertility, ICSI resulted in a lower fertilization rate and an 11% lower embryo euploid rate compared with CI. Although the data are not statistically significant when adjusted for the PGT reference laboratory, we still can conclude that ICSI does not provide any benefit. These data support the recommendation that CI should be the preferred methodology for fertilization in nonmale factor infertility cases.

Modified natural and optimized programmed frozen embryo transfers have equivalent live birth rates: an analysis of 6,682 cycles.

OBJECTIVE: To compare the live birth rates (LBRs) in modified natural and programmed single blastocyst frozen embryo transfer (FET) cycles. DESIGN: Retrospective cohort study. SETTING: University-affiliated fertility practice. PATIENT(S): Patients who underwent single blastocyst FETs between January 2014 and December 2019. A total of 15,034 FET cycles from 9,092 patients were reviewed; 1,186 modified natural and 5,496 programmed FET cycles from 4,532 patients met the inclusion criteria for analysis. INTERVENTION(S): No intervention. MAIN OUTCOME MEASURE(S): The primary outcome measure was the LBR. RESULT(S): There was no difference in live birth after programmed cycles using intramuscular (IM) progesterone or a combination of vaginal progesterone and IM progesterone compared with that after modified natural cycles (adjusted relative risks, 0.94 [95% confidence interval {CI}, 0.85-1.04] and 0.91 [95% CI, 0.82-1.02], respectively). The relative risk of live birth decreased in programmed cycles that used exclusively vaginal progesterone compared with that in modified natural cycles (adjusted relative risk, 0.77 [95% CI, 0.69-0.86]). CONCLUSION(S): The LBR decreased in programmed cycles that used only vaginal progesterone. However, no difference in the LBRs existed between modified natural and programmed cycles if programmed cycles used either IM progesterone or a combination of IM and vaginal progesterone protocols. This study demonstrates that modified natural FET cycles and optimized programmed FET cycles have equivalent LBRs.