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Implantation is a critical step in human reproduction. The success of this step is dependent on a competent blastocyst, receptive endometrium, and successful cross talk between the embryonic and maternal interfaces. Recurrent implantation failure is the lack of implantation after the transfer of several embryo transfers. As the success of in vitro fertilization has increased and failures have become more unacceptable for patients and providers, the literature on recurrent implantation failure has increased. While this clinical phenomenon is often encountered, there is not a universally agreed-on definition-something addressed in an earlier portion of this Views and Reviews. Implantation failure can result from several different factors. In this review, we discuss factors including the maternal immune system, genetics of the embryo and parents, anatomic factors, hematologic factors, reproductive tract microbiome, and endocrine milieu, which factors into embryo and endometrial synchrony. These potential causes are at various stages of research and not all have clear implications or immediately apparent treatment., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The male contribution to infertility has traditionally been overlooked, or at best oversimplified. In recent years efforts have been made to optimize diagnostic and therapeutic techniques to maximize fertility outcomes. A renewed focus on the male partner has resulted in an increased understanding of both genetic and epigenetic changes within the male germline. Furthermore, single-nucleotide polymorphisms, copy-number variants, DNA damage, sperm cryopreservation, obesity, and paternal age have recently been recognized as important factors that play a role in male fertility. Developing a deeper knowledge of these issues could potentially lead to improved success with assisted reproductive technology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The rate of embryonic aneuploidy increases with increasing female age and is the primary cause of lower pregnancy and live birth rates (LBR) in older reproductive age women. This retrospective cohort study evaluates single euploid embryo transfers to determine whether an age-related decline in reproductive efficiency persists., Methods: A total of 8175 non-donor single embryo transfers (SET) after pre-implantation testing for aneuploidy (PGT-A) and cryopreservation were included. These were divided into five groups by patient age: < 35 years old (n = 3789 embryos transferred), 35-37 (n = 2200), 38-40 (n = 1624), 41-42 (n = 319), and > 42 (n = 243). Implantation rate (IR), clinical pregnancy rate (CPR), and LBR were calculated for each group as a percentage of embryos transferred and compared. CPR was also analyzed as a percentage of implanted pregnancies, and LBR as a percentage of clinical pregnancies, to determine when age has the greatest impact. These results were then adjusted for confounding variables via a multivariate logistic regression model., Results: Implantation rates negatively correlated with age. After adjusting for confounders, women 38 years or older had a significantly lower IR than those under 35 (OR 0.85, 95%CI 0.73-0.99 for 38-40 years old; 0.69, 0.53-0.91 for 41-42, and 0.69, 0.51-0.94 for > 42). These differences are also apparent in CPR and LBR. The rates of progression to clinical pregnancy and live birth did not differ significantly by age group. Other factors observed to affect IR independently were anti-Müllerian hormone (AMH), day of embryo transfer, and embryo morphology., Conclusion: While selection of euploid embryos may be effective in overcoming a significant proportion of the age-related decline in reproductive efficiency, a decrease in IR, CPR, and LBR persists even when analyzing only euploid embryo transfers. The observed impact of aging is, therefore, independent of ploidy, as well as of other variables that affect reproductive efficiency. These results indicate that factors other than aneuploidy contribute to reproductive senescence.

Objective: To investigate whether telomere length (TL) in granulosa cells (GC) or cumulus cells (CC) correlates with TL in leukocytes (L)., Design: Prospective noninterventional study., Setting: Private assisted reproductive technology center., Patient(s): Thirty-five egg donors were included in the study., Interventions(s): None., Main Outcome Measure(s): Average relative leukocyte telomere length (LTL), cumulus cell telomere length (CCTL), and granulosa cell telomere length (GCTL) measurements from each study subject., Result(s): Participants had a mean age of 25.43 ± 4.57 years, antimüllerian hormone level of 1.90 ± 0.92 ng/mL, antral follicle count of 23.29 ± 5.11, and the mean number of mature oocytes retrieved was 23.29 ± 9.13. No significant association between these variables and GCTL, CCTL, or LTL was found. In addition, no correlation was observed between TL measurements of L vs. CC, L vs. GC, or CC vs. GC. Interestingly, CCTL was significantly higher than LTL (1.54-fold), although no significant differences were found between GCTL vs. CCTL or GCTL vs. LTL., Conclusion(s): CC from mature follicles have significantly longer telomeres than L, suggesting that the follicular environment could possess different mechanisms to cope against telomere shortening compared with other somatic tissues. Furthermore, these data do not support the utility of telomere DNA measurement in L as an estimate of TL in follicular cells., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

To evaluate the effectiveness of delay start protocol in improving the success of in vitro fertilization (IVF) in poor responders according to Bologna's criteria. Only randomized controlled trial (RCT) of infertile women undergoing a single IVF/ICSI cycle with ovarian stimulation protocol based on daily injections with delay start protocol or a conventional antagonist protocol were included in this systematic review and meta-analysis. The review protocol was registered in PROSPERO before starting the data extraction (CRD42019128284). Primary outcome was clinical pregnancy rate. Ongoing pregnancy rate, miscarriage rate, number of oocytes, number of MII oocytes, stimulation length, gonadotropin amount and cancellation rate were considered as secondary outcomes. Four randomized controlled trials were included with a total number of 380 participants. 189 patients were included in the delayed start protocol and 191 were allocated to the comparison group. The results showed a significant higher clinical pregnancy rate (CPR) in patients allocated to the intervention. Data from all studies failed to detect a statistical difference between groups in terms of ongoing pregnancy rate (OPR), miscarriage rate (MR), Total-Oocyte, MII-Oocyte and Total-Embryos. Gonadotropin amount (GA) was significantly lower in the intervention group in comparison to controls, with no difference in stimulation length (SL) and cancelled cycle (CC). Delayed start GnRH-antagonist protocol may reduce GA and improve CPR in poor ovarian responder according to Bologna criteria., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Owing to the fact that there are more microbial than human cells in our body and that humans contain more microbial than human genes, the microbiome has huge potential to influence human physiology, both in health and in disease. The use of next-generation sequencing technologies has helped to elucidate functional, quantitative and mechanistic aspects of the complex microorganism-host interactions that underlie human physiology and pathophysiology. The microbiome of semen is a field of increasing scientific interest, although this microbial niche is currently understudied compared with other areas of microbiome research. However, emerging evidence is beginning to indicate that the seminal microbiome has important implications for the reproductive health of men, the health of the couple and even the health of offspring, owing to transfer of microorganisms to the partner and offspring. As this field expands, further carefully designed and well-powered studies are required to unravel the true nature and role of the seminal microbiome.

Purpose: To explore clinical benefit of performing two intrauterine inseminations (IUI) 24 h apart-a double IUI vs. a single IUI among lesbian and single women., Methods: Retrospective cohort study using electronic medical record review during a 17-year period (11/1999-3/2017). A total of 11,396 patients at a single academic-affiliated private practice were included in this study. All cycles with a single or double IUI were included. A sub-analysis of first cycles only (n = 10,413) was also performed. Canceled IVF cycles converted to IUI were excluded. T tests and Wilcoxon rank-sum tests were used for continuous data, and chi-square for categorical data. Multivariable logistic regression controlled for patient age, day 3 follicle-stimulating hormone (D3 FSH), body mass index (BMI), peak estradiol (E2), and post-wash total motile sperm counts to model the association between IUI number and ongoing pregnancy rate (OPR) according to sperm source (autologous vs. donor). Generalized estimating equations and mixed effect models accounted for multiple cycles from the same woman. Adjusted odds ratio (AOR) with 95% CI was determined. Sub-analyses of sexual orientation and partner status were performed to compare heterosexual couples with proven infertility to women with lesbian and single women., Results: During the study period, 22,452 cycles met inclusion criteria (single IUI 1283 vs. double IUI 21,169). Mean patient age and BMI were similar between groups. For couples using autologous sperm, OPR was significantly higher with double IUI (12.0% vs. 14.1%; p = 0.0380). A similar increase was observed for donor sperm OPR among heterosexual couples (14.4% vs. 16.2%), though this did not reach statistical significance (p = 0.395). A sub-analysis restricted to donor sperm demonstrates a clinical benefit of second IUI in heterosexual couples, 8.5% vs. 17.6% OPR (AOR 2.94; CI 1.00-10.99; p = 0.0496). When lesbian and single patients were evaluated, there was no difference (17.2% vs. 15.2%; AOR 0.99; CI 0.59-1.70; p = 0.0958)., Conclusions: Double IUI is associated with a significantly higher OPR for heterosexual couples using an autologous or donor sperm source. The benefit of a second IUI is less clear in patients with undocumented fertility status using donor sperm, such as single and lesbian women.

Objective: To determine if natural selection and follicular stimulation produces a lower risk for embryonic aneuploidy than that attained following superovulation with exogenous gonadotropins., Design: Prospective observational with historical control group., Setting: Large academically affiliated private practice., Patient(s): All patients presenting for their evaluation for infertility were offered participation in the study., Intervention(s): All participants in the natural cycle group underwent an unstimulated in vitro fertilization (IVF) cycle. A subsequent frozen embryo transfer was performed if a euploid blastocyst was attained., Main Outcome Measure(s): Rates of embryonic aneuploidy attained in unstimulated IVF cycles were compared to those observed in age-controlled historical cohort undergoing conventional stimulated IVF cycles with exogenous gonadotropins., Result(s): Aneuploidy rates were equivalent in unstimulated and stimulated IVF cycles. The prevalence of aneuploidy in natural cycles increased with the age of the female partner in a manner identical to that seen in stimulated IVF cycles. Finally, sustained implantation rates of euploid blastocysts were equivalent in natural and stimulated IVF cycles., Conclusion(s): Rates of embryonic aneuploidy are not impacted by follicular stimulation with exogenous gonadotropins. Prior concerns of inducing a higher risk of embryonic aneuploidy are not supported by this data., Clinical Trial Registration Number: NCT01866618., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the systematic review is to describe the obstetrical complications associated with pregnancies in the context of a thin endometrial lining., Methods: Systematic review of the literature., Results: Patients who conceive in the setting of a thin endometrium have a significantly increased risk of early pregnancy loss, namely miscarriage and ectopic pregnancy. These patients also have a twofold increase in low birth weight and preterm delivery, as well as a significantly higher risk of intrauterine growth restriction and composite adverse perinatal outcomes., Conclusions: In addition to the lower probability of conception, a thin endometrium in assisted reproductive technologies appears to be associated with both early and late pregnancy complications. These pregnancies thus warrant special attention and close follow-up from obstetricians.

Purpose of Review: Vitamin D deficiency has been associated with a wide range of human disease states and the global epidemic, particularly in reproductive aged women, has led to a focus on this complex hormones role in human reproduction. Indeed vitamin D receptors are found throughout the reproductive tract in the ovary, endometrium, and the placenta. It has roles both in calcium-dependent and independent pathways. However, agreement upon the most appropriate way to assess vitamin D status and ultimately its activity at various sites has proven challenging., Recent Findings: Investigators have studied vitamin D's role in assisted reproduction and found successful outcomes are correlated with vitamin D replete status. However, subsequent studies have found mixed results when parsing its role in folliculogenesis and oogenesis versus its impact on embryonic implantation in the endometrium. Correlation was shown in a donor oocyte model which suggests endometrial involvement; however, in a euploid blastocyst transfer model with attention to embryo and endometrial synchrony this was not seen. It may be that the major impact is proximal to blastocyst formation at the site of folliculogenesis as has been shown in a primate model. Taken together, these studies suggest that vitamin D's role may be more sophisticated when it comes to reproductive success. Further, it has become clear that the nonstandard method of determining vitamin D status in the clinical and research settings requires clarification to ensure more comparable data in future studies., Summary: Vitamin D has clear roles in human health and disease, and its impact on human reproduction seems promising but requires clarification. With new techniques for assessing its status in patients and its impact at end organs as well as evolving theories regarding its potential to influence folliculogenesis, endometrial receptivity, and ovarian aging, we will soon gain additional clarity and hope to be able to impact reproductive success in a positive way.

Purpose of Review: There have been great improvements in assisted reproduction in the recent decade; however, there are still a significant number of chromosomally normal blastocysts that fail to produce live births. The human microbiome is the totality of the microbes and their genomes that exist in and on the host. The understanding of its impact on health and human disease, particularly in human reproduction, is evolving., Recent Findings: New technologies have empowered metagenomic sample analysis that allows for more fully characterizing the reproductive tract microbiome. With these technologies, we have determined not only that sites previously thought to be sterile in fact have robust microbiomes, but also have better characterized the normal and abnormal vaginal and endometrial microbiome., Summary: The understanding of the microbiome in health and human disease, in particular in relation to human reproduction, is in its infancy. As the reproductive tract dysbiosis are better characterized and understood, we may be better equipped to manipulate it more expertly.

Purpose of Review: Aneuploidy is a leading cause of pregnancy failure. Although initial attempts to perform preimplantation genetic screening did not improve outcomes, validated techniques were developed to safely and effectively increase pregnancy rates. Still, many embryos designated as euploid do not implant. Current approaches are being refined to provide additional biologic insight into why this is the case. At present, the diagnosis and clinical relevance of segmental aneuploidy and mosaicism are amongst the more heavily investigated., Recent Findings: Class I data have proven the safety of trophectoderm biopsy and validation studies have shown single nucleotide polymorphism array and quantitative PCR can accurately detect whole chromosome aneuploidy. Similar studies to validate next generation sequencing are underway. Although randomized control trials have demonstrated the clinical utility of preimplantation genetic screening, recent data on the impact of mosaicism and segmental aneuploidy require clarification., Summary: Several well powered randomized control trials have shown preimplantation genetic screening improves implantation rate. Plausible explanations for euploid failures include undetected mosaicism and segmental aneuploidy. However, the true incidence and dispersion of mosaicism within the embryo is unknown. Likewise, the resolution of detection and clinical significance of segmental aneuploidy is unclear. Further research to validate proposed detection algorithms and class I data to determine if detection impacts outcomes is needed.

Purpose: Dehydroepiandrosterone (DHEA) is often prescribed for poor responders in IVF in an effort to improve response to ovarian stimulation. The effect of DHEA supplementation and resultant supraphysiologic DHEA-S serum levels on sex steroid assays has not been evaluated in this population. This study seeks to determine the relationship between DHEA supplementation and progesterone measurements to characterize the degree of interference with particular immunoassays., Methods: Characterization was accomplished in two phases. First, DHEA-S standard control reagents with no progesterone present were assayed for both DHEA-S and progesterone levels. Second, serum pools from 60 unique IVF patients' serum were used to create six pooled serum samples: three from patients on DHEA supplementation and three from patients not on DHEA supplementation. The three pools were composed of patients whose serum fell into low, medium, and high progesterone ranges. Baseline DHEA-S and progesterone were measured, and the mean level of DHEA-S in the mid-range progesterone pool was used as the mid-point for addition of DHEA-S standard to the serum pools from patients without DHEA supplementation. Progesterone from these pools was then measured on three commercially available immunoassay systems., Results: The first experiment revealed a linear increase in progesterone when analyzing the DHEA-S standard ranging from 0.5 μg/dL [corrected] in the blank control (no DHEA-S) to up to 2.0 μg/dL [corrected] in the high control (DHEA-S >700 μg/dL), [corrected] indicating that the DHEA-S cross-reacts with the progesterone assays. In the second experiment, patients' serum DHEA-S and progesterone were measured from pooled serum samples of those taking DHEA and those not taking DHEA. Adding DHEA-S to the pooled serum of those not taking DHEA resulted in a linear increase in progesterone levels on two of three commercially available immunoassays (p < 0.05)., Conclusions: DHEA-S can interfere with standard progesterone immunoassays used in clinical ART programs, and thus serum progesterone levels in IVF patients on DHEA supplementation may not reflect truly bioactive progesterone.

C-X-C ligand 13 (CXCL13), a regulator of mucosal immunity, is secreted by human endometrial epithelium and may be involved in embryo implantation. However, cyclic expression of human endometrial CXCL13 in health and disease is not well studied. This study examines cycle stage-specific endometrial CXCL13 expression in normal humans when compared to those with biopsy-confirmed, stage 1 to 4 endometriosis using real-time reverse transcriptase, real-time polymerase chain reaction and immunohistochemistry. Eutopic endometrial CXCL13 expression was also compared between normal, control Rhesus macaques, and macaques with advanced endometriosis. In healthy women, CXLC13 messenger RNA expression was minimal in the proliferative phase and maximal in the secretory phase. However, in the presence of endometriosis, proliferative-phase endometrial expression markedly increased in both humans and rhesus subjects (P < .05). The cross-species and cross-stage concordance suggests a pathophysiologic role for CXCL13 in endometriosis and its use as a biomarker for disease., (© The Author(s) 2014.)

Purpose: To characterize each chromosome's risk for being involved in embryonic aneuploidy., Methods: This is a retrospective cohort study conducted at a single, academic center. The cohort consisted of 15,169 consecutive trophectoderm biopsies which then underwent comprehensive chromosome screening utilizing validated real-time polymerase chain reaction (RT-PCR) or single nucleotide polymosphism (SNP) array platforms. Analysis was done to determine probability of aneuploidy by chromosome, changes in that risk with increasing maternal age, and in relationship of aneuploidy to chromosomal structure as classified by prior cytogenetic literature., Results: The highest prevalence of imbalances leading to aneuploidy was seen for chromosomes 13, 15, 16, 18, 19, 21, and 22. While elevated in all age groups, there was a disproportionate rise in aneuploidy rates for these chromosomes with increasing maternal age. When classic cytogenetic karyotype groups were compared, the overall smaller groups D, E, and G were associated with the highest rates. Similarly, when grouped based upon structure, acrocentric chromosomes exhibited the highest rates of aneuploidy, followed by the metacentric chromosomes, with the lowest prevalence of error in those with submetacentric structures., Conclusions: The highest rates of chromosomal aneuploidy were found in chromosomes known to be involved in clinically detectable, abnormal pregnancies, not just simply implantation failure. The rate of aneuploidy in these chromosomes rises disproportionately with age when compared to the other chromosomes which may provide information about chromosomal susceptibility to aging. The biological structure groupings did show varied aneuploidy rates which may provide insight into the biology of aneuploidy.

Since its inception, in vitro fertilization (IVF) has pursued molecular technology to improve patient outcomes, leading to enhanced methods of embryo selection. Comprehensive chromosomal screening (CCS) is a powerful tool that decreases maternal and neonatal morbidity due to multiple gestations by allowing the transfer of fewer embryos while maintaining success rates. To optimize this genetic test, physiological principles limiting the timing and type of cells to be removed had to be realized. Molecular barriers involved in genome amplification and ensuring the accuracy and validity of the CCS platform required a multistep approach to ensure that this technology was not used prematurely. Only after ensuring that the potential for harm was minimized and benefit maximized could clinicians use this technology to improve patient care., (Copyright © 2014. Published by Elsevier Ltd.)

Study Objective: To evaluate surgeon strain using validated ergonomic assessment tools., Design: Observational study (Canadian Task Force classification III)., Setting: Academic medical center., Participants: Robotic surgeons performing gynecologic oncology surgical procedures., Interventions: Videotape footage of surgeons performing robotic gynecologic oncology procedures was obtained. A human factors engineer experienced with health care ergonomics analyzed the video recordings and performed ergonomic evaluations of the surgeons., Measurements and Main Results: An initial evaluation was conducted using the Rapid Upper Limb Assessment (RULA) survey, an ergonomic assessment and prioritization method for determining posture, force, and frequency concerns with focus on the upper limbs. A more detailed analysis followed using the Strain Index (SI) method, which uses multiplicative interactions to identify jobs that are potentially hazardous. Seventeen hours of video recordings were analyzed, and descriptive data based on RULA/SI analysis were collected. Ergonomic evaluation of surgeon activity resulted in a mean RULA score of 6.46 (maximum possible RULA score, 7), indicating a need for further investigation. The mean SI grand score was 24.34. SI scores >10 suggest a potential for hazard to the operator. Thus, the current use of the surgical robot is potentially dangerous with regards to ergonomic positioning and should be modified., Conclusion: At a high-volume robotics center, there are ergonomics deficits that are hazardous to gynecologic surgeons and suggest the need for modification and intervention. A training strategy must be developed to address these ergonomic issues and knowledge deficiencies., (Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.)

Objectives: There is limited data regarding physical strain and minimally invasive gynecologic surgery (MIS). We sought to evaluate ergonomic strain among gynecologic oncologists., Methods: An online survey was sent to all physician members of the Society of Gynecologic Oncology in North America in 2010. The survey contained 42 questions and data was analyzed using univariate and bivariate analyses with summary statistics, t-tests, and chi-squared test., Results: There were 260 respondents (31.2%) to the survey. Case mix was 26% benign and 64% oncologic surgery. Over 52% of respondents had been in practice for greater than 11 years and 52% practice in an academic setting. Physical discomfort related to MIS was reported in 88% (216/244) of surgeons with 52% reporting persistent pain. Increased pain symptoms were associated with surgeon's height, glove size, age and female gender. Patient body mass index (BMI) was associated with pain symptoms in surgeons performing conventional laparoscopic surgery, but not robotic surgery. To decrease pain, surgeons changed positions (78%), limited the number of cases per day (14%), spread cases throughout the week (6%), or limited the total number of cases (3%). Only 29% had received treatment at any time for pain symptoms. Treatment included physical therapy (59%), medical management (28%), surgery (13%), and time off (1%). Only 16% of those with pain symptoms had received formal ergonomic training., Conclusion: Physical strain rates of 88% are far greater than previously reported. Such prevalent occupational strain presents a growing problem in the face of increasing demand for MIS., (Copyright © 2012 Elsevier Inc. All rights reserved.)