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Importance: To date, recurrent implantation failure (RIF) has no clear definition and no clearly identified impaired function. Hence, the term RIF is currently used somewhat haphazardly, on the basis of clinicians' judgment., Objective: International experts in reproductive medicine met on July 1, 2022, in Lugano, Switzerland, to review the different facets of RIF and define the diagnosis and its appropriate management., Evidence Review: A systematic review without meta-analysis of studies published in English from January 2015 to May 2022., Findings: Data indicated that RIF has been largely overevaluated, overdiagnosed, and overtreated without sufficient critical assessment of its true nature. Our analyses show that true RIF is extremely uncommon-occurring in <5% of couples with infertility-and that reassurance and continued conventional therapies are warranted in most cases of assisted reproductive technology (ART) failure. Although the true biologic determinants of RIF may exist in a small subset of people with infertility, they elude the currently available tools for assessment. Without identification of the true underlying etiology(ies), it is reasonable not to assign this diagnosis to a patient until she has failed at least 3 euploid blastocyst transfers (or the equivalent number of unscreened embryo transfers, adjusted to the patient's age and corresponding euploidy rate). In addition, other factors should be ruled out that may contribute to her reduced odds of sustained implantation. In such cases, implantation failure should not be the only issue considered in case of ART failure because this may result from multiple other factors that are not necessarily repetitive or persistent. In reality, RIF impacting the probability of further ART success is a very rare occurrence., Conclusion: True RIF is extremely uncommon, occurring in <5% of couples with infertility. Reassurance and continued conventional therapies are warranted in most cases. It would seem reasonable not to assign this diagnosis to a patient until she has failed at least 3 euploid embryo transfers (or the equivalent number of unscreened embryos, adjusted to her age)., Relevance: Given the number of internationally recognized experts in the field present at the Lugano meeting 2022, our publication constitutes a consensus statement., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Infertility is a major reproductive health issue that affects about 12% of women of reproductive age in the United States. Aneuploidy in eggs accounts for a significant proportion of early miscarriage and in vitro fertilization failure. Recent studies have shown that genetic variants in several genes affect chromosome segregation fidelity and predispose women to a higher incidence of egg aneuploidy. However, the exact genetic causes of aneuploid egg production remain unclear, making it difficult to diagnose infertility based on individual genetic variants in mother's genome. In this study, we evaluated machine learning-based classifiers for predicting the embryonic aneuploidy risk in female IVF patients using whole-exome sequencing data. Using two exome datasets, we obtained an area under the receiver operating curve of 0.77 and 0.68, respectively. High precision could be traded off for high specificity in classifying patients by selecting different prediction score cutoffs. For example, a strict prediction score cutoff of 0.7 identified 29% of patients as high-risk with 94% precision. In addition, we identified MCM5, FGGY, and DDX60L as potential aneuploidy risk genes that contribute the most to the predictive power of the model. These candidate genes and their molecular interaction partners are enriched for meiotic-related gene ontology categories and pathways, such as microtubule organizing center and DNA recombination. In summary, we demonstrate that sequencing data can be mined to predict patients' aneuploidy risk thus improving clinical diagnosis. The candidate genes and pathways we identified are promising targets for future aneuploidy studies., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To determine whether increased endometrial B-cell lymphoma 6 (BCL6) expression is associated with live birth in a normal responder in vitro fertilization (IVF) population., Design: Case-control study., Setting: University-affiliated infertility center., Patient(s): Two groups of women undergoing IVF with preimplantation genetic testing for aneuploidy followed by warmed, single, euploid embryo transfer. Group 1 consisted of women who failed to achieve live birth, and group 2 consisted of women who achieved live birth., Intervention(s): None., Main Outcome Measure(s): Endometrial BCL6 expression measured by immunohistochemistry in endometrial tissue samples. Overexpression was defined by mean HSCORE with a cutoff of positivity of >1.4, as previously described in the literature., Result(s): Twenty-seven patients who achieved live birth and 23 patients who failed to achieve live birth were included. B-cell lymphoma 6 expression/HSCORE and live birth rate were not associated (Odds ratio [OR], 0.78 [0.24-2.55]). Using a cutoff of >1.4 for positivity, 8 of 23 samples were positive for BCL6 in the no live birth group, whereas 7 of 27 were positive in the live birth group. There was no significant association between BCL6 positivity and live birth (OR, 0.66 [0.19-2.21])., Conclusion(s): The proportion of patients with BCL6 positivity did not significantly differ between those who achieved live birth and those who did not. In the population of patients at our center, who compromise of women who respond normally to IVF stimulation, BCL6 overexpression was not associated with IVF success. Physicians implementing BCL6 testing as a diagnostic tool for clinical decision making should counsel patients that results may have limited utility in predicting IVF outcomes in this population., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To validate a commercially available noninvasive preimplantation genetic testing for aneuploidy (niPGT-A) assay by investigating the following: prevalence of deoxyribonucleic acid (DNA) amplification failure with niPGT-A; factors affecting amplification failure with niPGT-A; and frequency of discordant results between niPGT-A and traditional preimplantation genetic testing for aneuploidy., Design: Prospective cohort study SETTING: Academic-affiliated private practice PATIENT(S): One hundred sixty-six blastocysts and their surrounding culture media from couples undergoing in vitro fertilization between July 2019 and May 2020 were analyzed., Intervention(s): Blastocyst-stage spent culture media samples underwent niPGT-A using a commercially available kit that used whole-genome amplification with a modified multiple annealing and looping-based amplification cycle protocol followed by next-generation sequencing. Preimplantation genetic testing for aneuploidy of trophectoderm (TE) biopsies was performed using targeted next-generation sequencing., Main Outcome Measure(s): The primary outcome was failure to achieve an interpretable result with niPGT-A. Factors affecting DNA amplification were also assessed. Discrepancies between niPGT-A and TE biopsy results were analyzed, and clinical outcomes were evaluated., Result(s): Deoxyribonucleic acid amplification failures with niPGT-A were observed in 37.3% (62/166) of the samples. With TE biopsy, no embryos exhibited DNA amplification failure. Embryos with a shorter duration of exposure to the culture media and no evidence of whole-chromosome aneuploidy on the TE biopsy displayed high rates of DNA amplification failure with niPGT-A. Of 104 embryos with both niPGT-A and TE biopsy results available, whole-chromosome discordance was noted in 42 cases (40.4%). Three embryos classified as aneuploid based on the niPGT-A result progressed to successful delivery., Conclusion(s): The rates of DNA amplification failure were high among the niPGT-A samples, virtually precluding the clinical applicability of niPGT-A in its current form., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Assisted reproductive technology (ART) has been so widely deployed across the world that over 1% of all births are now ART babies, with even higher percentages in the Nordic countries. As pregnancy rates are limited by technical, population, and inherent limitations of human reproduction, key performance indicators should be defined for all the different facets of ART to measure the efficacy of the procedure., (Copyright © 2020 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

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 compare the transcriptome of cumulus cells associated with a euploid embryo that resulted in live birth with that of a sibling euploid embryo without sustained implantation., Design: Paired analysis., Setting: Academic institution., Patient(s): Couples undergoing in vitro fertilization (IVF)/intracytoplasmic sperm injection with preimplantation genetic screening with female age ≤42 years and normal ovarian reserve., Intervention(s): Transcriptome profiling of cumulus cells from sibling oocytes for correlation with live birth after euploid blastocyst transfer. Embryos were individually cultured to facilitate association with clinical outcomes. The cumulus cell transcriptome from the embryo resulting in live birth was compared with that of its sibling embryo without sustained implantation to investigate potential biomarkers that may aid in embryo selection., Main Outcome Measure(s): Differential gene expression in cumulus cells associated with a euploid embryo resulting in live birth and its sibling euploid embryo without sustained implantation using next-generation RNA sequencing (RNAseq)., Result(s): Cumulus cell RNAseq of 34 samples (from 17 patients) generated an average of 10.4 ± 4 × 10 6 reads per sample. A total of 132 differentially expressed genes between sibling embryos that resulted in a live birth and those that did not were identified (P<.05). However, after correcting for multiple testing none of the genes remained significantly differentially expressed (false discovery rate <.05)., Conclusion(s): The RNAseq profiles were similar between cumulus cells associated with a euploid embryo resulting in live birth and its sibling embryo that did not sustain implantation. The cumulus cell transcriptome is not predictive of live birth within an individual patient's cohort of euploid embryos., (Published by Elsevier Inc.)

Objective: To evaluate the association between relative DNA content of the trophectoderm biopsy and pregnancy outcomes., Design: Retrospective cohort study., Setting: Academic-affiliated private practice., Patient(s): This study included patients undergoing their first single embryo transfer after trophectoderm biopsy and comprehensive chromosome screening (CCS) at a single center between January 2010 and February 2014., Intervention(s): In phase 1 of the study, a standard curve was developed to estimate the relative DNA content of trophectoderm biopsies. Phase 2 of the study examined reproductive outcomes in patients undergoing single embryo transfer after trophectoderm biopsy and CCS. Samples were divided into quartiles according to their relative DNA content, and clinical outcomes were compared., Main Outcome Measure(s): Chemical pregnancy rate, clinical implantation rate, ongoing pregnancy rate, live birth rate., Result(s): The quartile of highest relative DNA content had a significantly lower live birth rate when compared with the other three quartiles (relative risk 0.84, 95% confidence interval 0.75-0.95). There was no difference between the quartiles regarding age, body mass index, ovarian response, or endometrial thickness. Among those patients who had a live birth, there was no difference in hCG levels, gestational age at delivery, or birth weight with respect to biopsy DNA content., Conclusion(s): Trophectoderm biopsies with the highest relative DNA content are associated with lower live birth rates after single embryo transfer. Possible explanations for this phenomenon include diminished accuracy of the euploid diagnosis vs. a mechanical impact of the biopsy. Regardless of the cause, the outcomes emphasize the importance of obtaining appropriately sized trophectoderm biopsies for CCS., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare maternal uterine natural killer cell immunoglobulin receptor (KIR) genotype and haplotype frequencies between patients whose euploid single-embryo transfer resulted in pregnancy loss and those that resulted in delivery and to determine if the risk of pregnancy loss was affected by the HLA-C genotype content in the embryo., Design: Retrospective cohort., Setting: Academic research center., Patient(s): Autologous fresh IVF cycles resulting in positive serum β-hCG during 2009-2014., Intervention(s): None., Main Outcome Measure(s): 1) Relative risk of pregnancy loss according to maternal KIR genotypes and haplotypes. 2) Comparison of pregnancy loss rates within each KIR haplotype according to HLA-C ligand present in trophectoderm biopsy samples., Result(s): A total of 668 euploid single-embryo transfers with stored maternal DNA and available preamplification DNA from prior trophectoderm biopsy samples were studied. KIR2DS1, KIR3DS1, and KIR2DS5 were more common in patients who experienced pregnancy loss. Carriers of KIR A haplotype exhibited a decreased risk of pregnancy loss compared with KIR B haplotype carriers. However, among KIR A haplotype carriers, the risk of loss was significantly influenced by whether the transferred embryo carried a C1 allele versus no C1 alleles., Conclusion(s): KIR A haplotype carriers experienced fewer pregnancy losses than KIR B haplotype carriers after euploid single-embryo transfer. However, this risk was modified by HLA-C alleles present in the embryo. High-risk combinations (KIR A/homozygous C2 and KIR B/homozygous C1) resulted in a 51% increased risk of loss over all other combinations., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: Options for preconception genetic screening have grown dramatically. Expanded carrier screening (ECS) now allows for determining carrier status for hundreds of genetic mutations by using a single sample, and some recommend ECS prior to in vitro fertilization. This study seeks to evaluate how often ECS alters clinical management when patients present for infertility care., Methods: All patients tested with ECS at a single infertility care center from 2011 to 2014 were evaluated. The overall rate of positive ECS results and the number of couples who were carriers of the same genetic disorder were evaluated., Results: A total of 6,643 individuals were tested, representing 3,738 couples; 1,666 (25.1%) of the individuals had a positive test result for at least one disorder. In 8 of the 3,738 couples, both members of the couple were positive for the same genetic disorder or had a test result that placed them at risk of having an affected child. Three of eight cases were cystic fibrosis. In this cohort, ECS affected clinical care eight times after 6,643 tests (0.12%, confidence interval: 0.05-0.24%) in 3,738 couples (0.21%, confidence interval: 0.09-0.42%)., Conclusions: ECS is becoming more widespread. In a large case series, ECS affected clinical decision making for patients presenting for infertility care in 0.21% of cases. This information must be weighed when utilizing these tests and may be a helpful part of patient counseling.Genet Med 18 11, 1097-1101.

Objective: To evaluate the relationship between genetic ethnicity using ancestry informative markers (AIMs) and ovarian reserve and response parameters as evidenced by FSH, antimüllerian hormone (AMH), basal antral follicle count (BAFC), and total oocyte yield in IVF., Design: Retrospective., Setting: Academic medical center., Patients(s): A total of 2,508 infertile patients undergoing IVF at a single center., Intervention(s): Patients were genotyped for 32 AIMs and analyzed for differences in allele frequencies. A validated Bayesian clustering algorithm was then used to assign individuals into one of four ethnic populations: European, African, Central/South Asian, or East Asian., Main Outcome Measure(s): FSH, AMH, BAFC, and oocyte yield variation., Result(s): After controlling for age and body mass index, genetic ethnicity had no impact on AMH, BAFC, and oocyte yield. FSH was found to be lower in patients of Central/South Asian ancestry (6.46 ng/mL vs. 6.97 ng/mL); however, the absolute difference is of little clinical significance. Subgroup analyses of 1,327 patients restricted to those with limited genetic admixture as determined by AIMs indicated that FSH, AMH, BAFC, and oocyte yield were equivalent., Conclusion(s): When determining ethnicity using AIMs, ethnic background does not have an impact on markers of ovarian reserve or ovarian response. Specifically, no differences were found in AMH, BAFC, or oocyte yield relative to genotypic ethnicity. Using AIMs rather than self-reported ethnicity allows for elimination of reporting biases and nonreporting of ethnicity, which can confound data. Based upon these data, specific recommendations for ovarian reserve testing should thus be made based on other factors besides ethnic background., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether sequential or monophasic media is the more optimal formulation for blastocyst development and sustained implantation rates (SIR) in IVF., Design: Paired randomized controlled trials., Setting: Academic., Patient(s): Infertile couples (N = 192) with female partner ≤42 years old and normal ovarian reserve., Intervention(s): Fertilized zygotes from each patient were randomly divided into two groups: [1] cultured in sequential media and [2] cultured in monophasic medium. Sequential media consisted of Quinn's Advantage Cleavage Medium (SAGE) followed by Blast Assist (Origio). The monophasic medium used was Continuous Single Culture (Irvine Scientific). Paired ETs were accomplished by transferring the best euploid blastocyst from each media group. DNA fingerprinting was used to link outcomes., Main Outcome Measure(s): The primary outcome measure was the proportion of blastocysts suitable for clinical use. Secondary outcome measures included timing of blastulation, aneuploidy rates, and SIR. Sustained implantation rate is defined as the number fetal heart beats at 8-9 weeks of gestation, divided by the number of embryos transferred., Result(s): A total of 192 patients had their 2PN embryos (N = 2,257) randomized to each culture system. Sequential media had higher blastulation rate than monophasic medium (55.2% vs. 46.9%). No differences were found in the day of blastulation or aneuploidy rate. Of the 168 patients who had euploid blastocysts suitable for transfer, 126 completed a paired ET. Among the double ETs, there was no difference in implantation between groups., Conclusion(s): This is the first randomized controlled trial to examine paired euploid transfers of sibling zygotes cultured in sequential versus monophasic media. This study demonstrates that the usable blastocyst rate is greatest after culture in the sequential media tested in comparison with the monophasic formulation selected for study. However, no difference exists in timing of blastulation, aneuploidy, or SIR. Whether these observations are generalizable to other media systems remains to be determined., Clinical Trial Registration Number: NCT01917240., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To develop a novel and robust protocol for multifactorial preimplantation genetic testing of trophectoderm biopsies using quantitative polymerase chain reaction (qPCR)., Design: Prospective and blinded., Setting: Not applicable., Patient(s): Couples indicated for preimplantation genetic diagnosis (PGD)., Intervention(s): None., Main Outcome Measure(s): Allele dropout (ADO) and failed amplification rate, genotyping consistency, chromosome screening success rate, and clinical outcomes of qPCR-based screening., Result(s): The ADO frequency on a single cell from a fibroblast cell line was 1.64% (18/1,096). When two or more cells were tested, the ADO frequency dropped to 0.02% (1/4,426). The rate of amplification failure was 1.38% (55/4,000) overall, with 2.5% (20/800) for single cells and 1.09% (35/3,200) for samples that had two or more cells. Among 152 embryos tested in 17 cases by qPCR-based PGD and CCS, 100% were successfully given a diagnosis, with 0% ADO or amplification failure. Genotyping consistency with reference laboratory results was >99%. Another 304 embryos from 43 cases were included in the clinical application of qPCR-based PGD and CCS, for which 99.7% (303/304) of the embryos were given a definitive diagnosis, with only 0.3% (1/304) having an inconclusive result owing to recombination. In patients receiving a transfer with follow-up, the pregnancy rate was 82% (27/33)., Conclusion(s): This study demonstrates that the use of qPCR for PGD testing delivers consistent and more reliable results than existing methods and that single gene disorder PGD can be run concurrently with CCS without the need for additional embryo biopsy or whole genome amplification., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of the study is to determine if thrombophilic single nucleotide polymorphisms (SNPs) affect outcomes in fresh in vitro fertilization (IVF) cycles in a large general infertility population., Methods: A prospective cohort analysis was performed at a university-affiliated private IVF center of female patients undergoing fresh non-donor IVF cycles. The effect of the following thrombophilic SNPs on IVF outcomes were explored: factor V (Leiden and H1299R), prothrombin (G20210A), factor XIII (V34L), β-fibrinogen (-455G → A), plasminogen activator inhibitor-1 (4G/5G), human platelet antigen-1 (a/b9L33P), and methylenetetrahydrofolate reductase (C677T and A1298C). The main outcome measures included positive pregnancy test, clinical pregnancy, embryo implantation, live birth, and pregnancy loss., Results: Patients (1717) were enrolled in the study, and a total of 4169 embryos were transferred. There were no statistically significant differences in positive pregnancy test, clinical pregnancy, embryo implantation, live birth, or pregnancy loss in the analysis of 1717 patients attempting their first cycle of IVF. Receiver operator characteristics and logistic regression analyses showed that outcomes cannot be predicted by the cumulative number of thrombophilic mutations present in the patient., Conclusions: Individual and cumulative thrombophilic SNPs do not affect IVF outcomes. Therefore, initial screening for these SNPs is not indicated.

The human microbiome has been termed the "second human genome" and data that has come about of late certainly makes it appear every bit as complex. The human body contains 10-fold more microbial cells than the human cells and accounts for 1%-3% of our total body mass. As we learn more about this symbiotic relationship, it appears this complex interaction occurs in nearly every part of the body, even those areas at one time considered to be sterile. Indeed, the microbiome in human reproduction has been investigated in terms of both the lower and upper reproductive tract and includes interactions even at the point of gametogenesis. What is all the more fascinating is that we have known about the importance of microbes for over 150 years, even before they existed in name. And now, with the assistance of an exciting technologic revolution which has pushed forward our understanding of the microbiome, we appear to stand on the precipice of a higher level of understanding of microbes, the biofilms they create, and their impact of health and disease in human reproduction., (Copyright © 2015. Published by Elsevier Inc.)

The human microbiome has gained much attention recently for its role in health and disease. This interest has come as we have begun to scratch the surface of the complexity of what has been deemed to be our "second genome" through initiatives such as the Human Microbiome Project. Microbes have been hypothesized to be involved in the physiology and pathophysiology of assisted reproduction since before the first success in IVF. Although the data supporting or refuting this hypothesis remain somewhat sparse, thanks to sequencing data from the 16S rRNA subunit, we have begun to characterize the microbiome in the male and female reproductive tracts and understand how this may play a role in reproductive competence. In this review, we discuss what is known about the microbiome of the reproductive tract as it pertains to assisted reproductive technologies., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare monozygotic twinning (MZT) rates in patients undergoing blastocyst or cleavage-stage ET., Design: Retrospective cohort., Setting: Academic research center., Patient(s): Autologous, fresh IVF cycles resulting in a clinical pregnancy from 1999 to 2014., Intervention(s): None., Main Outcome Measure(s): Monozygotic twin pregnancy in blastocyst-stage transfer vs. cleavage-stage transfer when controlling for patient prognosis and embryo cohort quality factors., Result(s): There were a total of 9,969 fresh transfer cycles resulting in a pregnancy during the study period. Of these pregnancies, 234 monozygotic twin pregnancies were identified (2.4%). Of all transfers, 5,191 were cleavage-stage and 4,778 were blastocyst-stage transfers. There were a total of 99 MZT identified in the cleavage-stage group (1.9%) and 135 MZT in the blastocyst ET group (2.4%), which was significant. Multivariable logistic regression revealed that increasing age was associated with a significant reduction in MZT, regardless of transfer order. Embryo cohort quality factors, including the number and proportion of six- to eight-cell embryos and availability of supernumerary embryos, were also significant. When controlling for patient age, time period during which the cycle took place, the number and proportion of six- to eight-cell embryos, and availability of supernumerary embryos, there was no longer a difference in MZT rate between blastocyst and cleavage transfer., Conclusion(s): Patient prognosis and embryo cohort quality seem to be major factors in MZT rate in women undergoing blastocyst transfer. Although technology-based effects cannot be excluded, patient and embryo characteristics play an important role., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether endometrial hCG infusion at the time of human blastocyst transfer impacts implantation rates., Design: Randomized double-blinded placebo-controlled trial., Setting: Academic., Patient(s): Infertile couples with the female partner less than 43 years old (n = 300) undergoing fresh or frozen ET of one or two blastocysts., Intervention(s): Patients undergoing ET were randomized into either a treatment or a control group. The treatment group received an infusion of 500 IU of hCG diluted in ET media. The control group received a sham infusion of ET media. Infusions were done using a separate catheter less than 3 minutes before actual ET., Main Outcome Measure(s): Sustained implantation rate: ongoing viable gestation (primary outcome) and ongoing pregnancy rate (secondary outcome)., Result(s): A total of 473 blastocysts were transferred into 300 patients. There were no differences between the two groups in sustained implantation rate (48.1% in the hCG group, 44.2% in the control group) or ongoing pregnancy rate (58.8% in the hCG group, 52.0% in the control group)., Conclusion(s): Endometrial infusion of hCG at the time of blastocyst ET does not improve sustained implantation rates., Clinical Trial Registration Number: NCT01643993., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

Medicine and aviation have a striking number of similarities. Both are led by highly-trained individuals performing complex tasks that are critical to outcomes. They also integrate the efforts of other professionals to assure that the flight, procedures, or processes are completed successfully. Also in common, is the potential for errors to have catastrophic and even life-threatening consequences. Both aviation and medicine have responded to this complex operating environment by building safety programs. Unfortunately, those in medicine have not been optimal in reducing significant adverse outcomes, including deaths. It has been suggested that given the parallels, that aviation safety programs might be adapted to clinical medicine. One such measure would the formation of a Clinical Safety Board (CSB) modeled after the National Transportation Safety Board (NTSB). Such a board would collect data across the nation and determine root causes of errors. They may then provide recommendations to professional societies and regulatory agencies for consideration for implementation. Such programs would be dependent on accurate and thorough reporting. Indemnification, similar to that enacted by the federal government for aviation, would be critical. In the end, a CSB should empower better patient care with reduced liability to the providers and programs., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine both the negative and positive predictive values of comprehensive chromosome screening (CCS) results for clinical outcome., Design: Data obtained from two prospective, double-blinded, nonselection studies., Setting: Academic center for reproductive medicine., Patient(s): One hundred forty-six couples with a mean maternal age of 34.0 ± 4.4 years and a mean paternal age of 37.3 ± 5.8 years., Intervention(s): Embryo biopsy for DNA fingerprinting and aneuploidy assessment., Main Outcome Measure(s): Failure rate of embryos predicted aneuploid by CCS (negative predictive value) and success rate of embryos predicted euploid by CCS (positive predictive value)., Result(s): A total of 255 IVF-derived human embryos were cultured and selected for transfer without influence from CCS analysis. Embryos were biopsied before transfer, including 113 blastomeres at the cleavage stage and 142 trophectoderm biopsies at the blastocyst stage. Comprehensive chromosome screening was highly predictive of clinical outcome, with 96% of aneuploid predicted embryos failing to sustain implantation and 41% sustained implantation from embryos predicted to be euploid., Conclusion(s): These nonselection data provide the first prospective, blinded, clinical study directly measuring the predictive value of aneuploidy screening for clinical outcome. The clinical error rate of an aneuploidy designation is very low (4%), whereas implantation and delivery rates of euploid embryos are increased relative to the entire cohort of transferred embryos., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

The combination of trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based technology for comprehensive chromosome screening results in high implantation and live birth rates that could contribute to the practical application of single embryo transfer for infertility patients., (Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the predictive value and define threshold levels for basal antral follicle number and mean ovarian diameter in patients undergoing ART cycles., Design: Retrospective., Setting: Tertiary care center., Patients: Two hundred seventy-eight patients who had ovarian measurements performed on cycle day 3 before beginning treatment with gonadotropins., Intervention: Pretreatment ovarian ultrasound measurements., Main Outcome Measure: Number of oocytes retrieved, hormone levels, and cycle outcomes., Results: A direct linear correlation was observed between mean ovarian diameter and basal follicle number. Both measures demonstrated a positive linear correlation with recovered oocytes, basal E(2), and peak E(2). Both demonstrated a negative linear correlation with ampules of gonadotropins administered, days of stimulation, patient age, cycle day 3 FSH, and FSH:LH ratio. An antral follicle count of

Objective: To test the hypothesis that women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B levels before a rise in day 3 serum FSH levels., Design: Case-control study., Setting: Tertiary care fertility center., Patient(s): One hundred nine women with nonovarian infertility (tubal factor or male factor) and 47 women with declining ovarian reserve who underwent assisted reproductive techniques., Intervention(s): None., Main Outcome Measure(s): Serum inhibin B and FSH levels, number of ampules of gonadotropins administered, E2 levels on the day of hCG administration, number of oocytes retrieved, clinical pregnancy rate, and cycle cancellation rate., Result(s): Women who had declining ovarian reserve as demonstrated by an increased gonadotropin requirement, a decreased E2 response, fewer retrieved oocytes, a lower clinical pregnancy rate, and a higher cycle cancellation rate had lower day 3 serum inhibin B levels despite having nonelevated day 3 FSH levels similar to those of women with nonovarian infertility., Conclusion(s): Women with declining ovarian responsiveness and clinical outcomes consistent with declining ovarian reserve had decreased day 3 serum inhibin B levels despite having nonelevated day 3 serum FSH concentrations. Declining ovarian reserve may be demonstrated by a decrease in day 3 inhibin B levels before a rise in day 3 FSH levels.

To determine the distribution of results of an in-vitro cervical mucus penetration system employing both human and bovine mucus (Tru-Trax) in a general infertility population, 133 couples prospectively underwent in-vitro and post-coital testing of cervical mucus. The distribution of Tru-Trax results in couples with normal semen analyses and Insler scores showed significantly greater penetration in bovine (22.3 +/- 6.0 mm) than in human mucus (20.3 +/- 5.4 mm) (P < 0.001). However, the lower limit of the 95% confidence interval of the normal population with either type of mucus was approximately 10 mm. This limit was significantly lower than that described by the kit manufacturer. The predictive value for post-coital tests using human mucus in the Tru-Trax system was good (> 90%) in all groups. The overall penetration into either human or bovine mucus was significantly correlated with the percentage of motile spermatozoa in the semen sample (P < 0.001). In conclusion, in-vitro cervical mucus penetration tests with the Tru-Trax system are related to in-vivo post-coital tests, although the lower limit of the range of anticipated results in the normal population was significantly lower than that described by the manufacturer. The ultimate value of this type of testing will await clinical trials which evaluate clinical end-points such as pregnancy rates.

Approximately one in seven couples are infertile. Half of these couples fail to conceive following conventional therapies. Recently, technologies have evolved which provide hope to these couples and lead to cumulative pregnancy rates of 65%. An assisted reproduction (AR) program has recently been established at Wilford Hall Medical Center. The reproductive endocrinologists, on-service residents, and clinic support staff are responsible for all aspects of care including stimulation, retrieval, andrology, embryology, and transfer. To date, there have been 104 transfers with 28 pregnancies. In summary, AR is available in the Armed Forces and allows infertile couples to receive state-of-the-art health care.