Reassessing the impact of letrozole co-administration in controlled ovarian hyperstimulation: findings from a single-center repeated measures study.

PURPOSE: To explore whether letrozole improved outcomes in subsequent controlled ovarian hyperstimulation (COH) cycles. METHODS: This was a retrospective repeated measures cohort study examining COH cycles. Patients were included if they underwent two cycles for unexplained infertility, male factor infertility, or planned oocyte/embryo cryopreservation. The first cycles for all patients implemented a non-letrozole, conventional gonadotropin protocol. Second cycles for the study group included letrozole (2.5-7.5 mg for 5 days) with no medication change to second cycles amongst controls. Our primary objective was to compare oocyte yield. Cohorts were then subdivided by pursuit of oocyte (OC) or embryo (IVF) cryopreservation. Secondary outcome amongst the OC subgroup was oocyte maturation index (metaphase II (MII)/total oocytes). Secondary outcomes amongst the IVF subgroup were normal fertilization rate (2-pronuclear zygotes (2PN)/oocytes exposed to sperm), blastocyst formation rate (blastocysts/2PNs), and embryo ploidy (%euploid and aneuploid). RESULTS: Fifty-four cycles (n = 27) were included in letrozole and 108 cycles (n = 54) were included in control. Oocyte yield was higher in second cycles (p < 0.008) in the letrozole group but similar in second cycles (p = 0.26) amongst controls. Addition of letrozole did not impact MII index (p = 0.90); however, MII index improved in second cycles amongst controls (p < 0.001). Both groups had similar rates of normal fertilization (letrozole: p = 0.52; control: p = 0.61), blast formation (letrozole: p = 0.61; control: p = 0.84), euploid (letrozole: p = 0.29; control: p = 0.47), and aneuploid embryos (letrozole: p = 0.17; control: p = 0.78) between cycles. CONCLUSIONS: Despite improved oocyte yield, letrozole did not yield any difference in oocyte maturation or embryo outcomes.

Coronavirus Disease 2019 (COVID-19) Vaccination and Assisted Reproduction Outcomes: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess the association between coronavirus disease 2019 (COVID-19) vaccination and female assisted reproduction outcomes through a systematic review and meta-analysis. DATA SOURCES: We searched Medline (OVID), EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov on January 11, 2023, for original articles on assisted reproduction outcomes after COVID-19 vaccination. The primary outcome was rates of clinical pregnancy; secondary outcomes included number of oocytes retrieved, number of mature oocytes retrieved, fertilization rate, implantation rate, ongoing pregnancy rate, and live-birth rate. METHODS OF STUDY SELECTION: Two reviewers independently screened citations for relevance, extracted pertinent data, and rated study quality. Only peer-reviewed published studies were included. TABULATION, INTEGRATION, AND RESULTS: Our query retrieved 216 citations, of which 25 were studies with original, relevant data. Nineteen studies reported embryo transfer outcomes, with a total of 4,899 vaccinated and 13,491 unvaccinated patients. Eighteen studies reported data on ovarian stimulation outcomes, with a total of 1,878 vaccinated and 3,174 unvaccinated patients. There were no statistically significant results among our pooled data for any of the primary or secondary outcomes: clinical pregnancy rate (odds ratio [OR] 0.94, 95% CI 0.88-1.01, P =.10), number of oocytes retrieved (mean difference -0.26, 95% CI -0.68 to 0.15, P =.21), number of mature oocytes retrieved (mean difference 0.31, 95% CI -0.14 to 0.75, P =.18), fertilization rate (OR 0.99, 95% CI 0.87-1.11, P =.83), implantation rate (OR 0.92, 95% CI 0.84-1.00, P =.06), ongoing pregnancy rate (OR 0.95, 95% CI 0.86-1.06, P =.40), or live-birth rate (OR 0.95, 95% CI 0.78-1.17, P =.63). A subanalysis based on country of origin and vaccine type was also performed for the primary and secondary outcomes and did not change the study results. CONCLUSION: Vaccination against COVID-19 is not associated with different fertility outcomes in patients undergoing assisted reproductive technologies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023400023.

Planned oocyte cryopreservation: the state of the ART.

The objective of this review is to provide an update on planned oocyte cryopreservation. This fertility preservation method increases reproductive autonomy by allowing women to postpone childbearing whilst maintaining the option of having a biological child. Oocyte cryopreservation is no longer considered experimental, and its use has increased dramatically in recent years as more women delay childbearing for personal, professional and financial reasons. Despite increased usage, most patients who have undergone oocyte cryopreservation have not yet warmed their oocytes. Most women who cryopreserve oocytes wait years to use them, and many never use them. Studies have demonstrated that oocyte cryopreservation results in live birth rates comparable with IVF treatment using fresh oocytes, and does not pose additional safety risks to offspring. Based on current evidence, cryopreserving ≥20 mature oocytes at <38 years of age provides a 70% chance of one live birth. However, larger studies from a variety of geographic locations and centre types are needed to confirm these findings. Additional research is also needed to determine the recommended age for oocyte cryopreservation, recommended number of oocytes to cryopreserve, return and discard/non-use rates, cost-effectiveness, and how best to distribute accurate and up-to-date information to potential patients.

Primary ovarian insufficiency: a glimpse into the racial and socioeconomic disparities found within third-party reproduction.

Objective: To describe a unique case of primary ovarian insufficiency and review the systemic barriers in place that hinder reproductive autonomy for Black women who require third-party reproduction. Design: Case report and review of the literature. Setting: Safety-net hospital in an urban community. Patients: A 36-year-old Black woman, gravida 0, with primary ovarian insufficiency who desires future fertility but is restricted by systemic barriers. Interventions: Chromosome analysis. Main Outcome Measures: Not applicable. Results: Balanced reciprocal translocation between chromosomes 1 and 13: 46,XX,t(1;13)(q25;q14.1). Conclusions: The field of assisted reproductive technology has evolved at an exponential rate, yet it unfortunately benefits some and not all. It is imperative that when we advocate for full spectrum infertility care, that this encompasses everyone. As we continue to further study and develop assisted reproductive technology, we must not forget to consider the factors leading to racial and socioeconomic disparities in reproductive care access, utilization, and outcomes.

Planned Oocyte Cryopreservation and the Black Obstetrician Gynecologist: Utilization and Perspectives.

The objective of this study was to describe the opinions and attitudes toward planned oocyte cryopreservation (POC) among Black Obstetrician Gynecologists (BOG) and their experiences in counseling patients of color. A web-based, cross-sectional survey was distributed to BOGs. The survey consisted of questions pertaining to personal family building goals, fertility preservation, education and patient counseling experiences regarding POC. Of the 136 potential participants, the response rate was 50% (n = 68). Sixty-six percent of respondents felt the need to postpone childbearing due to medical training and 19% had already undergone POC or planned to in the future. A majority (70%) felt that all women planning to undergo medical training should consider POC, and a subgroup analysis showed this was more likely to be reported within BOG trainees (p < 0.01). Fifty-seven percent received education on POC and 25% felt "very comfortable" counseling patients on POC. Those age < 35 years were more likely to feel the need to postpone family building due to their medical training (p < 0.01). Generalist attendings who had not undergone POC were significantly more likely to report regret, compared to subspecialists (p < 0.03). Medical careers may have an unfavorable impact on family building, and our results highlight this effect in Black women. A better understanding of the mitigating factors is needed to develop culturally appropriate counseling and educational interventions for Black women and other women of color.

Investigation of Global Gene Expression of Human Blastocysts Diagnosed as Mosaic using Next-generation Sequencing.

Embryos are diagnosed as mosaic if their chromosomal copy number falls between euploid and aneuploid. The purpose of this study was to investigate the impact of mosaicism on global gene expression. This study included 42 blastocysts that underwent preimplantation genetic testing for aneuploidy (PGT-A) and were donated for IRB approved research. Fourteen blastocysts were diagnosed as mosaic with Next-generation Sequencing (NGS). Three NGS diagnosed euploid embryos, and 25 aneuploid embryos (9 NGS, 14 array Comparative Genomic Hybridization, 2 Single Nucleotide Polymorphism array) were used as comparisons. RNA-sequencing was performed on all of the blastocysts. Differentially expressed genes (DEGs) were calculated using DESeq2/3.5 (R Bioconductor Package) with p < 0.05 considered significantly differentially expressed. Pathway analysis was performed on mosaic embryos using EnrichR with p < 0.05 considered significant. With euploid embryo gene expression used as a control, 12 of 14 mosaic embryos had fewer DEGs compared to aneuploid embryos involving the same chromosome. On principal component analysis (PCA), mosaic embryos mapped separately from aneuploid embryos. Pathways involving cell proliferation, differentiation, and apoptosis were the most disrupted within mosaic embryos. Mosaic embryos have decreased disruption of global gene expression compared to aneuploid embryos. This study was limited by the small sample size, lack of replicate samples for each mosaic abnormality, and use of multiple different PGT-A platforms for the diagnosis of aneuploid embryos.

Sociodemographic differences in utilization of fertility services among reproductive age women diagnosed with cancer in the USA.

PURPOSE: To determine whether sociodemographic differences exist among female patients accessing fertility services post-cancer diagnosis in a representative sample of the United States population. METHODS: All women ages 15-45 with a history of cancer who responded to the National Survey for Family Growth (NSFG) from 2011 to 2017 were included. The population was then stratified into 2 groups, defined as those who did and did not seek infertility services. The demographic characteristics of age, legal marital status, education, race, religion, insurance status, access to healthcare, and self-perceived health were compared between the two groups. The primary outcome measure was the utilization of fertility services. The complex sample analysis using the provided sample weights required by the NSFG survey design was used. RESULTS: Five hundred forty-five women reported a history of cancer and were included in this study. Forty-three (7.89%) pursued fertility services after their cancer diagnosis. Using the NSFG sample weights, this equates to a population of 161,500.7 female cancer survivors in the USA who did utilize fertility services and 1,811,955.3 women who did not. Using multivariable analysis, household income, marital status, and race were significantly associated with women utilizing fertility services following a cancer diagnosis. CONCLUSIONS: In this nationally representative cohort of reproductive age women diagnosed with cancer, there are marital, socioeconomic, and racial differences between those who utilized fertility services and those who did not. This difference did not appear to be due to insurance coverage, access to healthcare, or perceived health status.

Evaluating the unevaluated: a secondary analysis of the National Survey for Family Growth (NSFG) examining infertile women who did not access care.

PURPOSE: To characterize the demographic differences between infertile/sub-fertile women who utilized infertility services vs. those that do not. METHODS: A retrospective analysis of cross-sectional data obtained during the 2011-2013, 2013-2015, and 2015-2017 cycles of National Survey for Family Growth from interviews administered in home for randomly selected participants by a National Center of Health Statistics (NCHS) surveyor was used to analyze married, divorced, or women with long-term partners who reported difficulty having biological children (sub-fertile/infertile women). Demographic differences such as formal marital status, education, race, and religion were compared between women who presented for infertility care vs. those that did not. The primary outcome measure was presenting for infertility evaluation and subsequently utilizing infertility services. Healthcare utilization trends such as having a usual place of care and insurance status were also included as exposures of interest in the analysis. RESULTS: Of the 12,456 women included in the analysis 1770 (15.3%) had used infertility services and 1011 (8.3%) said it would be difficult for them to have a child but had not accessed infertility services. On univariate analysis, compared to women who used infertility services, untreated women had lower average household incomes (295.3 vs. 229.8% of the federal poverty line respectively). Untreated women also had lower levels of education and were more likely to be divorced or never have married. In terms of health status, unevaluated women were less likely to have a usual place for healthcare (87.3%) as compared to women presenting for fertility care (91.9%) (p = 0.004). When examining insurance status, 23.3% of unevaluated women were uninsured as compared to 8.3% of evaluated women. On multivariate analysis, infertile women without insurance were at 0.37 odds of utilizing infertility care compared to women with insurance. CONCLUSIONS: Demographic factors are associated with the utilization of infertility care. Insurance status is a significant predictor of whether or not infertile women will access treatment. Data from the three most recent NSFG surveys along with prior analyses demonstrate the need for expanded insurance coverage in order to address the socioeconomic disparities between infertile women who are accessing services vs. those that are not.

Self-reported quality of life scales in women undergoing oocyte freezing versus in vitro fertilization.

PURPOSE: The objective of this study was to investigate stress levels among women undergoing elective oocyte cryopreservation by comparing their self-reported quality of life measures with women undergoing in vitro fertilization during the fertility treatment cycle. METHODS: Patients undergoing oocyte retrieval at a single institution were offered a voluntary, anonymous, and written questionnaire. The survey was adapted and validated from the Fertility Quality of Life tool to assess self-reported fertility treatment-related problems and was tested for construct validity and reliability. Based on exploratory factor analyses, three subscales were created as follows: fertility treatment-related stress, tolerability, and environment. Relationships between patient characteristics and fertility treatment-related measures were examined with Fisher's exact test, ANOVA, and multivariate regression with significance p < 0.05. RESULTS: A total of 461 patients (331 IVF, 130 egg freeze) were included in the analysis. Medically indicated egg freezing patients were excluded. Overall, both IVF and egg freeze patients reported stress during the current fertility cycle and there were no significant differences between IVF and egg freeze patients for any subscale scores. Three sets of generalized linear models were run and found age to be associated with fertility treatment-related stress and tolerability scores, with younger patients experiencing greater difficulties. Additionally, patients who underwent repeat cycles reported more fertility treatment-related stress. CONCLUSIONS: Patients undergoing egg freezing have similar responses to quality of life questions as patients undergoing IVF. Repeat cycles and younger age contribute to perceptions of stress. This information supports developing stress reduction strategies for all women undergoing egg freezing.

A Comparison of Pregnancy Outcomes in Patients Undergoing Donor Egg Single Embryo Transfers With and Without Preimplantation Genetic Testing.

Two of the many milestone developments in the field of assisted reproduction have been oocyte donation and preimplantation genetic testing for aneuploidy (PGT-A). Because it has been demonstrated that even young women produce a meaningful proportion of aneuploid embryos, screening out such abnormalities could potentially increase the efficacy of donor egg (DE) cycles. In this retrospective cohort study, we investigated the effect of PGT-A on DE cycle outcomes, including implantation rate (IR), spontaneous abortion rate (SABR), and ongoing pregnancy/live birth rate. We used fresh and frozen donor cycles not using PGT-A as comparison groups; all cases involved single embryo transfer. Data analysis revealed that PGT-A did not improve pregnancy outcome metrics in DE cycles, although there was a trend toward decreasing the SABR. There was a significant increase in IR with fresh cycles outperforming all frozen cycles. Overall, these results suggest that the benefits of performing PGT-A on embryos derived from young DEs may be limited and that there is an effect of the freezing process on pregnancy outcomes. These findings may provide useful insights into the science and practice of PGT-A across all of its applications.

Human blastocysts of normal and abnormal karyotypes display distinct transcriptome profiles.

Unveiling the transcriptome of human blastocysts can provide a wealth of important information regarding early embryonic ontology. Comparing the mRNA production of embryos with normal and abnormal karyotypes allows for a deeper understanding of the protein pathways leading to viability and aberrant fetal development. In addition, identifying transcripts specific for normal or abnormal chromosome copy number could aid in the search for secreted substances that could be used to non-invasively identify embryos best suited for IVF embryo transfer. Using RNA-seq, we characterized the transcriptome of 71 normally developing human blastocysts that were karyotypically normal vs. trisomic or monosomic. Every monosomy and trisomy of the autosomal and sex chromosomes were evaluated, mostly in duplicate. We first mapped the transcriptome of three normal embryos and found that a common core of more than 3,000 genes is expressed in all embryos. These genes represent pathways related to actively dividing cells, such as ribosome biogenesis and function, spliceosome, oxidative phosphorylation, cell cycle and metabolic pathways. We then compared transcriptome profiles of aneuploid embryos to those of normal embryos. We observed that non-viable embryos had a large number of dysregulated genes, some showing a hundred-fold difference in expression. On the contrary, sex chromosome abnormalities, XO and XXX displayed transcriptomes more closely mimicking those embryos with 23 normal chromosome pairs. Intriguingly, we identified a set of commonly deregulated genes in the majority of both trisomies and monosomies. This is the first paper demonstrating a comprehensive transcriptome delineation of karyotypic abnormalities found in the human pre-implantation embryo. We believe that this information will contribute to the development of new pre-implantation genetic screening methods as well as a better understanding of the underlying developmental abnormalities of abnormal embryos, fetuses and children.

Paternal Age Is Not Associated With Pregnancy Outcomes After Single Thawed Euploid Blastocyst Transfer.

Although controversial, increasing paternal age has been shown to negatively affect assisted reproductive technology (ART) outcomes and success rates. Most studies investigating the effect of paternal age on ART outcomes use a donor oocyte model to minimize maternal aneuploidy contribution. This study sought to determine whether increasing paternal age is associated with adverse in vitro fertilization (IVF) outcomes when aneuploidy is minimized using preimplantation genetic screening. There were 573 single thawed euploid embryo transfers from 473 patients undergoing oocyte donor and autologous IVF cycles. Cycles were categorized according to paternal age at oocyte retrieval, and an age adjustment was performed for maternal age in order to evaluate for an isolated paternal age effect. Fertilization rate was found to decrease significantly with increasing paternal age ( P = .04). After controlling for oocyte age, there was no significant difference in pregnancy outcomes across all paternal age categories after euploid embryo transfer, including implantation rate ( P = .23), clinical pregnancy rate ( P = .51), and spontaneous abortion rate ( P = .55). Therefore, if a couple is able to produce and transfer a single thawed euploid embryo, no difference in IVF pregnancy outcomes is identified with increasing paternal age.

Delayed intracytoplasmic sperm injection (ICSI) with trophectoderm biopsy and preimplantation genetic screening (PGS) show increased aneuploidy rates but can lead to live births with single thawed euploid embryo transfer (STEET).

PURPOSE: The aim of this study was to report the results of IVF with trophectoderm biopsy and preimplantation genetic screening (PGS) following delayed intracytoplasmic sperm injection (ICSI). METHODS: Patients undergoing IVF with PGS and delayed ICSI were included in the study. Indications for delayed ICSI included absent or poor fertilization via standard insemination or more than 50 % immature oocytes, noted post-cumulus stripping for standard ICSI procedure. Delayed ICSI was performed the day after retrieval due to absent or poor fertilization. The immature oocytes were kept in extended culture, and if demonstrated maturity, ICSI was performed. Primary outcome included fertilization rate and blastocyst stage formation, defined by the number of blastocysts for biopsy. Secondary outcome included aneuploidy rate and pregnancy outcomes following single thawed euploid embryo transfers (STEET). RESULTS: Sixteen patients with delayed ICSI were included in the study. Twelve were due to poor fertilization and four secondary to immature oocytes. A total of 219 oocytes were retrieved; ten were frozen upon patient request, 168 had standard insemination, and 13 had routine ICSI on the day of retrieval. A total of 129 oocytes underwent delayed ICSI. Sixty-three (49 %) fertilized, 19 (14.7 %) reached blastocysts for biopsy; fivw of which were chromosomally normal (26.3 %). Three patients underwent STEET of a delayed ICSI embryo; all three resulted in live births, including one embryo biopsied on day 8 of development. CONCLUSION: Fertilization failure or an excessive proportion of immature oocytes in an IVF cycle, necessitating delayed ICSI, showed equivalent fertilization and blast formation rates. With the implementation of trophectoderm biopsy and PGS, these embryos can lead to healthy live born babies.

Birth weight is associated with inner cell mass grade of blastocysts.

OBJECTIVE: To determine the relationship between blastocyst growth parameters and birth weight. DESIGN: Cohort study. SETTING: University-affiliated fertility center. PATIENT(S): In vitro patients who delivered a singleton after a single-blastocyst transfer. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Birth weight adjusted for gestational age at delivery and gender, with adjusted birth weight examined for association with blastocyst scores and grades. RESULT(S): After standard in vitro fertilization (IVF) and thawed embryo transfers, greater birth weight was associated with a higher inner cell mass grade. The grade of the trophectoderm and stage of the blastocyst did not relate to weight. CONCLUSION(S): Embryonic growth as early as day 5 can predict the progress of fetal development as measured by birth weight.

Using the oocyte donation model to identify early trophoblast pregnenolone production.

PURPOSE: To investigate production of progesterone's precursor, pregnenolone, in the early oocyte donation pregnancy. METHODS: Pregnenolone and progesterone were measured on luteal days 21, 28, 35, 60 and 80. Progesterone was measured via the Immulite system, pregnenolone by liquid chromatography separation with tandem mass spectrometric detection. RESULTS: Progesterone rose significantly from days 35 today 60. Pregnenolone likewise rose significantly from days 35-60, but at a much higher rate, with an increase of 57% by day 60, 75% to day 80. The increase in pregnenolone was statistically more significant than the increase in progesterone (p < .05). CONCLUSIONS: This is the first report describing that progesterone's precursor, pregnenolone, increases with time in the very early pregnancy. Because no corpus luteum is present in oocyte recipients, the main source of pregnenolone is the early placenta. Measurements of pregnenolone may provide information concerning early trophoblast function and may represent a method of assessing placental competency.

Symptomatic isolated pleural effusion as an atypical presentation of ovarian hyperstimulation syndrome.

Ovarian hyperstimulation syndrome (OHSS) presents in ~33% of ovarian stimulation cycles with clinical manifestations varying from mild to severe. Its pathogenesis is unknown. Pleural effusion is reported in ~10% of severe OHSS cases and is usually associated with marked ascites. The isolated finding of pleural effusions without ascites, as the main presenting symptom of OHSS is not frequently reported and its pathogenesis is also unknown. We describe two unusual cases of OHSS where dyspnea secondary to unilateral pleural effusion was the only presenting symptom. By reporting our experience, we would like to heighten physicians' awareness in detecting these cases early, as it is our belief that the incidence of pleural effusion in the absence of most commonly recognized risk factors for OHSS may be underestimated and may significantly compromise the health of the patient if treatment is not initiated in a reasonable amount of time.