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.

Metabolic imaging of human embryos is predictive of ploidy status but is not associated with clinical pregnancy outcomes: a pilot trial.

STUDY QUESTION: Does fluorescence lifetime imaging microscopy (FLIM)-based metabolic imaging assessment of human blastocysts prior to frozen transfer correlate with pregnancy outcomes? SUMMARY ANSWER: FLIM failed to distinguish consistent patterns in mitochondrial metabolism between blastocysts leading to pregnancy compared to those that did not. WHAT IS KNOWN ALREADY: FLIM measurements provide quantitative information on NAD(P)H and flavin adenine dinucleotide (FAD+) concentrations. The metabolism of embryos has long been linked to their viability, suggesting the potential utility of metabolic measurements to aid in selection. STUDY DESIGN, SIZE, DURATION: This was a pilot trial enrolling 121 IVF couples who consented to have their frozen blastocyst measured using non-invasive metabolic imaging. After being warmed, 105 couples' good-quality blastocysts underwent a 6-min scan in a controlled temperature and gas environment. FLIM-assessed blastocysts were then transferred without any intervention in management. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eight metabolic parameters were obtained from each blastocyst (4 for NAD(P)H and 4 for FAD): short and long fluorescence lifetime, fluorescence intensity, and fraction of the molecule engaged with enzyme. The redox ratio (intensity of NAD(P)H)/(intensity of FAD) was also calculated. FLIM data were combined with known metadata and analyzed to quantify the ability of metabolic imaging to differentiate embryos that resulted in pregnancy from embryos that did not. De-identified discarded aneuploid human embryos (n = 158) were also measured to quantify correlations with ploidy status and other factors. Statistical comparisons were performed using logistic regression and receiver operating characteristic (ROC) curves with 5-fold cross-validation averaged over 100 repeats with random sampling. AUC values were used to quantify the ability to distinguish between classes. MAIN RESULTS AND THE ROLE OF CHANCE: No metabolic imaging parameters showed significant differences between good-quality blastocysts resulting in pregnancy versus those that did not. A logistic regression using metabolic data and metadata produced an ROC AUC of 0.58. In contrast, robust AUCs were obtained when classifying other factors such as comparison of Day 5 (n = 64) versus Day 6 (n = 41) blastocysts (AUC = 0.78), inner cell mass versus trophectoderm (n = 105: AUC = 0.88) and aneuploid (n = 158) versus euploid and positive pregnancy embryos (n = 108) (AUC = 0.82). LIMITATIONS, REASONS FOR CAUTION: The study protocol did not select which embryo to transfer and the cohort of 105 included blastocysts were all high quality. The study was also limited in number of participants and study sites. Increased power and performing the trial in more sites may have provided a stronger conclusion regarding the merits of the use of FLIM clinically. WIDER IMPLICATIONS OF THE FINDINGS: FLIM failed to distinguish consistent patterns in mitochondrial metabolism between good-quality blastocysts leading to pregnancy compared to those that did not. Blastocyst ploidy status was, however, highly distinguishable. In addition, embryo regions and embryo day were consistently revealed by FLIM. While metabolic imaging detects mitochondrial metabolic features in human blastocysts, this pilot trial indicates it does not have the potential to serve as an effective embryo viability detection tool. This may be because mitochondrial metabolism plays an alternative role post-implantation. STUDY FUNDING/COMPETING INTEREST(S): This study was sponsored by Optiva Fertility, Inc. Boston IVF contributed to the clinical site and services. Becker Hickl, GmbH, provided the FLIM system on loan. T.S. was the founder and held stock in Optiva Fertility, Inc., and D.S. and E.S. had options with Optiva Fertility, Inc., during this study. TRIAL REGISTRATION NUMBER: The study was approved by WCG Connexus IRB (Study Number 1298156).

Iatrogenic and demographic determinants of the national plural birth increase.

OBJECTIVE: To study the contribution of ovulation induction and ovarian stimulation, in vitro fertilization (IVF), and unassisted conception to the increase in national plural births in the United States, a significant contributor to adverse maternal and infant health outcomes. DESIGN: National and IVF-assisted plural birth data were derived from the Centers for Disease Control and Prevention's National Vital Statistics System (1967-2021, after introduction of Clomiphene Citrate in the United States) and the National Assisted Reproductive Technology Surveillance System (1997-2021), respectively. SETTING: Not applicable. PATIENT(S): Not applicable. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): In addition to IVF-assisted plural births, the contributions of unassisted conception to plural births among women aged <35 and ≥35 years were estimated using plural birth rates from 1949-1966 and a Bayesian logistic model with race and age as independent variables. The contribution of ovulation induction and ovarian stimulation was estimated as the difference between national plural births and IVF-assisted and unassisted counterparts. RESULT(S): From 1967-2021, the national twin birth rate increased 1.7-fold to a 2014 high (33.9/1,000 live births), then declined to 31.2/1,000 live births; the triplet and higher order birth rate increased 6.7-fold to a 1998 high (1.9/1,000 live births), then declined to 0.8/1,000 live births. In 2021, the contribution of unassisted conception among women aged <35 years to the national plural births was 56.1%, followed by ovulation induction and ovarian stimulation (19.5%), unassisted conception among women aged ≥35 years (16.8%), and IVF (7.6%). During 2009-2021, the contribution of ovulation induction and ovarian stimulation has remained stable, the contribution of unassisted conception among women aged <35 and ≥35 years has increased, and the contribution of IVF has decreased. CONCLUSION(S): Ovulation induction and ovarian stimulation are leading iatrogenic contributors to plural births. They are, therefore, targets for intervention to reduce the adverse maternal and infant health outcomes associated with plural births. Maternal age of ≥35 years is a significant contributor to the national plural birth increase.

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.

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.

The role of growth hormone in assisted reproduction.

In contemporary ART, the use of "add-ons" during ovarian stimulation has increased, especially in poor responders. Growth Hormone (GH) is an adjunctive therapy that has been studied extensively in the translational and clinical setting, with an ongoing scientific debate over its effectiveness and optimal use. In this review, we aim to provide an overview of the physiologic basis for the use of GH in ART, and to summarize the latest evidence regarding its clinical use, primarily as an adjunct to ovarian stimulation, but also in the IVF lab and with regards to its effects on the endometrium.

The Massachusetts Infertility Insurance Mandate: not nearly enough.

Objective: To assess the impact of statutory federal and state exceptions to the state law mandating insurance coverage for the diagnosis and treatment of infertility. Design: Population-based cross-sectional study comprised of reproductive-age women (defined herein as 20-44 years of age) who resided in Massachusetts during the 2016-2019 interval. Statutory exemptions to the benefits afforded by the Massachusetts Infertility Insurance Mandate were identified in the Massachusetts General Laws as well as in the United States Code. Setting: Not applicable. Patients: Publicly available, deidentified, population-level data pertaining to state-based reproductive-age women (aged 20-44 years) were procured for the 2016-2019 interval. Data sources included the Massachusetts Census Bureau, Massachusetts Center for Health Information and Analysis, US Department of Defense, and US Office of Personnel Management. Interventions: None. Main Outcome Measures: The proportion of state-based reproductive-age women who constitute beneficiaries of the Massachusetts Infertility Insurance Mandate after accounting for the applicable state and federal statutory exemptions that limit its impact. Results: Public health plans (Medicare, MassHealth [state Medicaid], TRICARE, and the Federal Employees Health Benefits Program) are exempted from the Massachusetts Infertility Insurance Mandate by dint of federal or state statute. Self-insured employer-sponsored health plans are exempted from the Massachusetts Infertility Insurance Mandate by dint of the federal Employee Retirement Income Security Act. It follows that only 26.2%-36.0% of state-based reproductive-age women comprised eligible beneficiaries of the Massachusetts Infertility Insurance Mandate over the 2016-2019 interval. Conclusions: Contrary to commonly held views, multiple statutory exemptions to the Massachusetts Infertility Insurance Mandate render a significant proportion of state-based reproductive-age women ineligible for its cognate benefits. We propose herein that the Essential Health Benefit categories of the Affordable Care Act be expanded by the US Congress to include infertility care services.

The effect of interpregnancy interval on preterm birth and low birth weight in singleton pregnancies conceived without assistance or by infertility treatments.

OBJECTIVE: To determine the association of interpregnancy interval on perinatal outcomes and whether this was influenced by mode of conception. DESIGN: Retrospective cohort. SETTING: Centers for Disease Control and Prevention's natality national database. PATIENT(S): Patients who had an index singleton live birth with a preceding live birth. Index pregnancies from 2016 to 2019 were conceived with in vitro fertilization (IVF) (n = 32,829) or ovulation induction/intrauterine insemination (OI/IUI) (n = 23,016) or without assistance (n = 7,564,042). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcomes evaluated were preterm birth (<37 weeks) and low birth weight (<2,500 g). Multivariable logistic regression was performed to evaluate the association of interpregnancy intervals with perinatal outcomes stratified by mode of conception. Adjusted odds ratios and 95% confidence intervals (CIs) were presented. RESULT(S): Compared with the interpregnancy interval reference group of 12 to <18 months, a <12 month interpregnancy interval was associated with an increase in preterm birth (<37 weeks) for pregnancies conceived with OI/IUI or without assistance (aOR, 1.42; 95% CI, 1.16-1.74, and aOR, 1.14; 95% CI, 1.13-1.15, respectively), whereas IVF was not associated with an increase (aOR, 0.90; 95% CI, 0.77-1.04). A <12 month interpregnancy interval was associated with an increase in low birth weight for pregnancies conceived with IVF or OI/IUI or without assistance (aOR, 1.34; 95% CI, 1.09-1.64; aOR, 1.33; 95% CI, 1.01-1.76; and aOR, 1.26; 95% CI, 1.24-1.27, respectively). CONCLUSION(S): An interpregnancy interval of at least 12 months reduces adverse perinatal outcomes for pregnancies conceived with and without infertility treatment.

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.

Coronavirus disease 2019, reproductive health, and public policy: lessons learned after two years of the ongoing pandemic-the American Society for Reproductive Medicine's Center for Policy and Leadership.

OBJECTIVE: To describe the experience of the ASRM COVID-19 Task Force over the past 2 years and to discuss lessons learned during the pandemic that can be applied to future public health crises. DESIGN: Descriptive narrative. SUBJECTS: None. INTERVENTION: Creation of the ASRM COVID-19 Task Force in March 2020. MAIN OUTCOME MEASURES: None. RESULTS: Effective pandemic management requires a joint effort on the part of physicians, scientists, government agencies, subject area experts and funders. CONCLUSION: Reproduction is a fundamental human right that should be protected at all times. Advanced preparation for future pandemics should include appointment of a standing group of experts so that a response is both informed and immediate when a public health crisis arises. This approach will help ensure that the ultimate objective - preserving the safety and well-being of patients and health care workers - is fulfilled. The recommendations put forth in this paper from the ASRM's Center for Policy and Leadership can be used as a template to prepare for future public health threats.

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.

Fluorescence lifetime imaging microscopy (FLIM) detects differences in metabolic signatures between euploid and aneuploid human blastocysts.

STUDY QUESTION: Can non-invasive imaging with fluorescence lifetime imaging microscopy (FLIM) detect metabolic differences in euploid versus aneuploid human blastocysts? SUMMARY ANSWER: FLIM has identified significant metabolic differences between euploid and aneuploid blastocysts. WHAT IS KNOWN ALREADY: Prior studies have demonstrated that FLIM can detect metabolic differences in mouse oocytes and embryos and in discarded human blastocysts. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study from August 2019 to February 2020. Embryo metabolic state was assessed using FLIM to measure the autofluorescence metabolic factors nicotinamide adenine dinucleotide dehydrogenase together with nicotinamide adenine phosphate dinucleotide dehydrogenase (NAD(P)H) and flavin adenine dinucleotide (FAD). Eight metabolic FLIM parameters were obtained from each blastocyst (four for NAD(P)H and four for FAD): short (T1) and long (T2) fluorescence lifetime, fluorescence intensity (I) and fraction of the molecules engaged with enzymes (F). The redox ratio (NAD(P)H-I)/(FAD-I) was also calculated for each image. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study was performed at a single academically affiliated centre where there were 156 discarded frozen blastocysts (n = 17 euploids; 139 aneuploids) included. Ploidy status was determined by pre-implantation genetic testing for aneuploidy (PGT-A). Discarded human blastocysts were compared using single FLIM parameters. Additionally, inner cell mass (ICM) and trophectoderm (TE) were also evaluated. Multilevel models were used for analysis. A post-hoc correction used Benjamini-Hochberg's false discovery rate, at a q-value of 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Comparing euploid (n = 17) versus aneuploid (n = 139) embryos, a significant difference was seen in NAD(P)H-F (P < 0.04), FAD-I (P < 0.04) and redox ratio (P < 0.05). Euploid ICM (n = 15) versus aneuploid ICM (n = 119) also demonstrated significantly different signatures in NAD(P)H-F (P < 0.009), FAD-I (P < 0.03) and redox ratio (P < 0.03). Similarly, euploid TE (n = 15) versus aneuploid TE (n = 119) had significant differences in NAD(P)H-F (P < 0.0001) and FAD-I (P < 0.04). LIMITATIONS, REASONS FOR CAUTION: This study utilized discarded human blastocysts, and these embryos may differ metabolically from non-discarded human embryos. The blastocysts analysed were vitrified after PGT-A biopsy and it is unclear how the vitrification process may affect the metabolic profile of blastocysts. Our study was also limited by the small number of rare donated euploid embryos available for analysis. Euploid embryos are very rarely discarded due to their value to patients trying to conceive, which limits their use for research purposes. However, we controlled for the imbalance with the bootstrap resampling analysis. WIDER IMPLICATIONS OF THE FINDINGS: These findings provide preliminary evidence that FLIM may be a useful non-invasive clinical tool to assist in identifying the ploidy status of embryos. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the Blavatnik Biomedical Accelerator Grant at Harvard University. Becker and Hickl GmbH and Boston Electronics sponsored research with the loaning of equipment for FLIM. D.J.N. is an inventor on patent US20170039415A1. There are no other conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

The psychological impact of the coronavirus disease 2019 pandemic on women who become pregnant after receiving treatment for infertility: a longitudinal study.

OBJECTIVE: To compare the impact of the coronavirus disease 2019 (COVID-19) pandemic on the psychological health of patients with infertility who have become pregnant with that of women who have not. DESIGN: Prospective cohort study conducted from April 2020 to June 2020. The participants completed three questionnaires over this period. SETTING: A single large, university-affiliated infertility practice. PATIENTS: A total of 443 pregnant women and 1,476 women still experiencing infertility who completed all three questionnaires. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Patient-reported primary stressor over three months of the first major COVID-19 surge; further data on self-reported sadness, anxiety, loneliness, and the use of personal coping strategies. RESULTS: Pregnant participants were significantly less likely to report taking an antidepressant or anxiolytic medication, were less likely to have a prior diagnosis of depression, were more likely to cite COVID-19 as a top stressor, and overall were less likely to practice stress-relieving activities during the first surge. CONCLUSIONS: Women who became pregnant after receiving treatment for infertility cited the pandemic as their top stressor and were more distressed about the pandemic than their nonpregnant counterparts but were less likely to be engaging in stress-relieving activities. Given the ongoing impact of the pandemic, patients with infertility who become pregnant after receiving treatment should be counseled and encouraged to practice specific stress-reduction strategies.

Single cell analysis of DNA in more than 10,000 individual sperm from men with abnormal reproductive outcomes.

PURPOSE: This pilot study sought to (1) validate the use of a novel technology for single-sperm-cell genome sequencing (Sperm-seq) in infertile men who may not have optimal quantity or quality of sperm for genomic analysis and (2) compare these results to fertile donors. METHODS: Infertile men undergoing IVF with female partners with a previous history of failed fertilization with ICSI (FF) or poor blastulation of embryos (PB) were recruited from a large IVF center. Sperm-seq was used to analyze thousands of individual sperm and was carried out at an affiliated university research institute. Global aneuploidy rate, crossover locations, and crossover frequencies were assessed in the infertile population, and compared with a control group of 20 fertile donors, which were analyzed previously at the same laboratory. RESULTS: Eight patients were initially included, but 3 samples did not yield high-quality genomic data for analysis. A total of 10,042 sperm were analyzed from 5 patients, 2 in the FF group, and 3 in the PB group. The global aneuploidy rate among the samples was 2-4%, similar to the control group. Likewise, crossover locations and frequencies were similar. CONCLUSION: Sperm-seq provides a robust analysis but may not be applicable to all male infertility cases due to technical limitations. This group of male infertility patients did not have higher rates of aneuploidy or abnormal crossover patterns compared to a fertile donor population. Our data may suggest that FF and PB phenotypes may not be related to sperm aneuploidy or meiotic errors but rather to other intrinsic nuclear anomalies.

Routine ketorolac at oocyte retrieval decreases postoperative narcotic use by more than 50.

OBJECTIVE: To study the impact of routine ketorolac administration during oocyte retrieval on the proportion of patients who require postoperative narcotics for analgesia. DESIGN: Retrospective cohort study. SETTING: Single, university-affiliated infertility clinic. PATIENTS: All women undergoing oocyte retrieval between July and November 2016 (non-ketorolac group [NKG]; n = 826) and April-August 2017 (ketorolac group, KG; n = 1780). INTERVENTIONS: A single 30 mg intravenous dose of ketorolac was administered after the oocyte retrieval procedure. MAIN OUTCOME MEASURES: The number of patients who required postoperative narcotic analgesia, postoperative complication rate, and fresh embryo transfer pregnancy outcomes were examined. RESULTS: In the KG, we found a significant decrease in the patients who required narcotics after oocyte retrieval compared with the NKG (12% KG vs. 25.5% NKG). We found no significant change in the clinical pregnancy rate (CPR) resulting from fresh embryo transfer after our intervention (NKG CPR 32.6%, KG CPR 32.4%). Furthermore, there was no increase in postoperative bleeding complications in the KG. CONCLUSIONS: Routine use of ketorolac at the time of oocyte retrieval may decrease the rate of postoperative opioid use without adversely impacting pregnancy and complication rates.

Perinatal outcomes in singleton pregnancies after in vitro fertilization cycles over 24 years.

OBJECTIVE: To determine how a shift in clinical practice along with laboratory changes has impacted singleton perinatal outcomes after autologous in vitro fertilization (IVF) cycles. DESIGN: Retrospective cohort. SETTING: Single academic fertility clinic. PATIENT(S): Singleton live births resulting from all IVF cycles (n = 14,424) from August 1, 1995 to October 31, 2019. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live birth weight, large for gestational age (GA), small for GA, and preterm birth. RESULT(S): The entire cohort consisted of 9,280 fresh and 5,144 frozen IVF cycles. Maternal age, parity, body mass index, neonatal sex, and GA at delivery were similar in both groups. There was a decrease in adjusted birth weight per year over the study period for the entire cohort of IVF cycles (-4.42g, 95% confidence interval [CI]: -6.63g to -2.22g). Rates of large for GA newborns decreased by 1.7% (95% CI: 2.9% to 0.6%) annually across the entire cohort of IVF cycles. Furthermore, there was a decrease in annual rates of preterm birth before 32 weeks by 3.2% (95% CI: 5.9% to 0.5%) across the entire cohort of IVF cycles. Trends were also seen in annual reduction of rates of preterm birth before 37 and 28 weeks. CONCLUSION(S): With the gradual evolution of clinical and IVF laboratory practices, there has been a decrease in birth weight over 24 years for the entire cohort of IVF cycles. Concurrently, noteworthy practice changes have resulted in an improvement in IVF outcomes with decreased rates of large for GA newborns and preterm birth before 32 weeks for the entire cohort of IVF cycles.

The use of propensity score matching to assess the benefit of the endometrial receptivity analysis in frozen embryo transfers.

OBJECTIVE: To study the impact of the endometrial receptivity analysis (ERA) on live birth rates in frozen embryo transfer (FET) cycles. DESIGN: Retrospective cohort study. SETTING: A single, large, university-affiliated infertility practice. PATIENT(S): Autologous FET cycles between January 1, 2014, and June 30, 2019, were reviewed. Multiple covariates that impact outcomes were used for propensity score matching; 133 ERA patients were matched to 353 non-ERA patients. Patients were assigned to the ERA group if they had an ERA during treatment and underwent at least one "personalized" FET based on the ERA recommendations. INTERVENTION(S): No interventions administered. MAIN OUTCOME MEASURE(S): Live birth rates per cycle in the FET cycle after ERA compared with that of matched non-ERA patients. RESULT(S): The live birth rates for the ERA group, 49.62%, and the matched non-ERA group, 54.96%, (odds ratio 0.8074; 95% confidence interval, 0.5424-1.2018) were not significantly different, nor was a difference seen in subanalyses based on prior number of FETs or receptivity status. CONCLUSION(S): The ERA identifies a patient's putative window of implantation with the goal of improving synchrony with the embryo, thereby achieving higher live birth rates. This study used propensity score matching to control for multiple covariates in a heterogenous group of patients to compare live birth rates. There was no difference in the live birth rate in patients who underwent the ERA compared with that of those who did not.

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.