Boston IVF

The relationship between stress and infertility has been debated for years. Women with infertility report elevated levels of anxiety and depression, so it is clear that infertility causes stress. What is less clear, however, is whether or not stress causes infertility. The impact of distress on treatment outcome is difficult to investigate for a number of factors, including inaccurate self-report measures and feelings of increased optimism at treatment onset. However, the most recent research has documented the efficacy of psychological interventions in lowering psychological distress as well as being associated with significant increases in pregnancy rates. A cognitive-behavioral group approach may be the most efficient way to achieve both goals. Given the distress levels reported by many infertile women, it is vital to expand the availability of these programs.

BACKGROUND: Outcomes of in vitro fertilization (IVF) treatment are traditionally reported as pregnancies per IVF cycle. However, a couple's primary concern is the chance of a live birth over an entire treatment course. METHODS: We estimated cumulative live-birth rates among patients undergoing their first fresh-embryo, nondonor IVF cycle between 2000 and 2005 at one large center. Couples were followed until either discontinuation of treatment or delivery of a live-born infant. Analyses were stratified according to maternal age and performed with the use of both optimistic and conservative methods. Optimistic methods assumed that patients who did not return for subsequent IVF cycles would have the same chance of a pregnancy resulting in a live birth as patients who continued treatment; conservative methods assumed no live births among patients who did not return. RESULTS: Among 6164 patients undergoing 14,248 cycles, the cumulative live-birth rate after 6 cycles was 72% (95% confidence interval [CI], 70 to 74) with the optimistic analysis and 51% (95% CI, 49 to 52) with the conservative analysis. Among patients who were younger than 35 years of age, the corresponding rates after six cycles were 86% (95% CI, 83 to 88) and 65% (95% CI, 64 to 67). Among patients who were 40 years of age or older, the corresponding rates were 42% (95% CI, 37 to 47) and 23% (95% CI, 21 to 25). The cumulative live-birth rate decreased with increasing age, and the age-stratified curves (< 35 vs. > or = 40 years) were significantly different from one another (P<0.001). CONCLUSIONS: Our results indicate that IVF may largely overcome infertility in younger women, but it does not reverse the age-dependent decline in fertility.

a number of pathways, including interference with capacitation and possible damage to sperm membrane and DNA, which may impair the sperm's potential to fertilize an egg and develop into a healthy embryo. Adequate evaluation of male reproductive potential should therefore include an assessment of sperm OS. We propose the term Male Oxidative Stress Infertility, or MOSI, as a novel descriptor for infertile men with abnormal semen characteristics and OS, including many patients who were previously classified as having idiopathic male infertility. Oxidation-reduction potential (ORP) can be a useful clinical biomarker for the classification of MOSI, as it takes into account the levels of both oxidants and reductants (antioxidants). Current treatment protocols for OS, including the use of antioxidants, are not evidence-based and have the potential for complications and increased healthcare-related expenditures. Utilizing an easy, reproducible, and cost-effective test to measure ORP may provide a more targeted, reliable approach for administering antioxidant therapy while minimizing the risk of antioxidant overdose. With the increasing awareness and understanding of MOSI as a distinct male infertility diagnosis, future research endeavors can facilitate the development of evidence-based treatments that target its underlying cause.

BACKGROUND: Preimplantation genetic screening (PGS) has been used in an attempt to determine embryonic aneuploidy. Techniques that use new molecular methods to determine the karyotype of an embryo are expanding the scope of PGS. METHODS: We introduce a new method for PGS, termed 'parental support', which leverages microarray measurements from parental DNA to 'clean' single-cell microarray measurements on embryonic cells and explicitly computes confidence in each copy number call. The method distinguishes mitotic and meiotic copy errors and determines parental source of aneuploidy. RESULTS: Validation with 459 single cells of known karyotype indicated that per-cell false-positive and false-negative rates are roughly equivalent to the 'gold standard' metaphase karyotype. The majority of the cells were run in parallel with a clinical commercial PGS service. Computed confidences were conservative and roughly concordant with accuracy. To examine ploidy in human embryos, the method was then applied to 26 disaggregated, cryopreserved, cleavage-stage embryos for a total of 134 single blastomeres. Only 23.1% of the embryos were euploid, though 46.2% of embryos were mosaic euploid. Mosaicism affected 57.7% of the embryos. Counts of mitotic and meiotic errors were roughly equivalent. Maternal meiotic trisomy predominated over paternal trisomy, and maternal meiotic trisomies were negatively predictive of mosaic euploid embryos. CONCLUSIONS: We have performed a major preclinical validation of a new method for PGS and found that the technology performs approximately as well as a metaphase karyotype. We also directly measured the mechanism of aneuploidy in cleavage-stage human embryos and found high rates and distinct patterns of mitotic and meiotic aneuploidy.

BACKGROUND: In natural conception only a few sperm cells reach the ampulla or the site of fertilization. This population is a selected group of cells since only motile cells can pass through cervical mucus and gain initial entry into the female reproductive tract. In animals, some studies indicate that the sperm selected by the reproductive tract and recovered from the uterus and the oviducts have higher fertilization rates but this is not a universal finding. Some species show less discrimination in sperm selection and abnormal sperm do arrive at the oviduct. In contrast, assisted reproductive technologies (ART) utilize a more random sperm population. In this review we contrast the journey of the spermatozoon in vivo and in vitro and discuss this in the context of developing new sperm preparation and selection techniques for ART. METHODS: A review of the literature examining characteristics of the spermatozoa selected in vivo is compared with recent developments in in vitro selection and preparation methods. Contrasts and similarities are presented. RESULTS AND CONCLUSIONS: New technologies are being developed to aid in the diagnosis, preparation and selection of spermatozoa in ART. To date progress has been frustrating and these methods have provided variable benefits in improving outcomes after ART. It is more likely that examining the mechanisms enforced by nature will provide valuable information in regard to sperm selection and preparation techniques in vitro. Identifying the properties of those spermatozoa which do reach the oviduct will also be important for the development of more effective tests of semen quality. In this review we examine the value of sperm selection to see how much guidance for ART can be gleaned from the natural selection processes in vivo.

As the COVID-19 pandemic spreads around the world, we are starting to see the first waves of epidemiological data1Ng OT Marimuthu K Chia PY et al.SARS-CoV-2 Infection among Travelers Returning from Wuhan, China.N Engl J Med. 2020; (e-published ahead of print) March 12Crossref PubMed Scopus (95) Google Scholar,2Livingston E Bucher K Coronavirus Disease 2019 (COVID-19) in Italy.JAMA. 2020; (e-published ahead of print) March 17Crossref Scopus (770) Google Scholar and know that it disproportionately impacts older adults.3Applegate WB Ouslander JG COVID-19 Presents High Risk to Older Persons.J Am Geriatr Soc. 2020; (e-published ahead of print) March 10Crossref Scopus (125) Google Scholar However, with this still being a new and rapidly evolving global crisis, there is currently very little known about its broader impact on mental health. Clinicians are gaining early experiences around a range of issues that are highly relevant to the mental health care of older adults4Lloyd-Sherlock P Ebrahim S Geffen L et al.Bearing the brunt of covid-19: older people in low and middle income countries.BMJ. 2020 Mar 13; : 368Google Scholar in the context of COVID-19. Retrospective studies of the 2003 SARS epidemic found that rates of suicide among older adults spiked during the period of the epidemic.5Yip PS Cheung YT Chau PH et al.The impact of epidemic outbreak: the case of severe acute respiratory syndrome (SARS) and suicide among older adults in Hong Kong.Crisis. 2010; 31: 86-92Crossref PubMed Scopus (277) Google Scholar This finding highlights the urgency for studying the mental health impact of COVID-19 in real time, so that its adverse impact can be anticipated and minimized. Because of the need for rapidly generated evidence to guide the care, the American Journal of Geriatric Psychiatry proposes to serve as a forum for early clinical evidence and frontline research relevant to COVID-19 and geriatric mental health. We anticipate a need for timely and valid scientific information on a range of topics. These may include the distinct mental health impact related to the fatality risks from the coronavirus, stress around behaviors that may lead to contact/infection (including contact with caregivers), consequences from social distancing and isolation measures instituted by governments around the world6Freedman A Nicolle J Social isolation and loneliness: the new geriatric giants: approach for primary care.Can Fam Physician. 2020 Mar; 66: 176-182PubMed Google Scholar and the neurobiological consequences of the resulting stress and inflammation that may increase vulnerability to mental health issues. In a population where loneliness and isolation have already been described as an epidemic,7Jeste DV Lee EE Cacioppo S Battling the Modern Behavioral Epidemic of Loneliness: Suggestions for Research and Interventions.JAMA Psychiatry. 2020; (e-published ahead of print) March 4Crossref PubMed Scopus (222) Google Scholar the impact of even short-term social distancing measures merits careful study. Simultaneously we will need to pay attention to how social distancing impacts the dynamics between older adults, their caregivers and their treaters. Lessons learned from this acute crisis may inform our understanding of loneliness and isolation and the most effective management approaches.8National Academies of Sciences, Engineering, and MedicineSocial isolation and loneliness in older adults: Opportunities for the Health Care System. The National Academies Press, Washington, DC2019Google Scholar We need research that focuses not only on how old age is a risk factor for the COVID-19 infection, but also why many older people would not acquire the infection, or even when infected, would recover fully, without long-term pathology. The biological and psychosocial resilience manifested by these older adults should be studied as a protective and preventive factor. The nature and severity of specific symptomatology observed in the context of COVID-19 also needs to be chronicled to facilitate future work. In addition, there is an urgent need for documentation of measures taken by institutions and individuals to manage the mental health impact of COVID-19 on older adults in the absence of clear best practices, as well as strategies for prevention. We believe that a range of measures may have been implemented across various care settings worldwide, including inpatient and outpatient care and large tertiary care centers, community-based hospitals, primary care settings, nursing homes as well as residential environments such as assisted living facilities. It will be important for the field to assess the range and efficacy of these measures - these may include implementing telepsychiatry for direct care and psychotherapy,9Hollander JE Carr BG Virtually Perfect? Telemedicine for Covid-19.N Engl J Med. 2020; (e-published ahead of print) March 11Crossref PubMed Scopus (2086) Google Scholar using a range of technologies for social engagement and measures to facilitate physical activity and nutrition. It is equally important that we recognize how the impact on older adults will vary around the world and the factors impacting older adults in low- and middle-income countries may differ from developed countries.4Lloyd-Sherlock P Ebrahim S Geffen L et al.Bearing the brunt of covid-19: older people in low and middle income countries.BMJ. 2020 Mar 13; : 368Google Scholar We also anticipate that there will be a range of long-term mental health consequences to this pandemic. In this respect, the field of geriatric psychiatry is in an uncharted territory, given that this confluence of a global viral pandemic and increased life expectancy is a new phenomenon and hence, little literature exists in this area. The scope and drawn-out nature of this pandemic may also mean that lessons learned from managing natural disasters may not be fully applicable here.10Sakauye KM Streim JE Kennedy GJ et al.AAGP position statement: disaster preparedness for older Americans: critical issues for the preservation of mental health.Am J Geriatr Psychiatry. 2009 Nov; 17: 916-924Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar Moreover, even as we assess impact on aging individuals, we also account for their important contributions in disaster preparedness and response. Research has documented the important social capital, perspective and wisdom provided by these individuals in the form of their experience and pre-existing social networks.7Jeste DV Lee EE Cacioppo S Battling the Modern Behavioral Epidemic of Loneliness: Suggestions for Research and Interventions.JAMA Psychiatry. 2020; (e-published ahead of print) March 4Crossref PubMed Scopus (222) Google Scholar,11Howard A Blakemore T Bevis M Older people as assets in disaster preparedness, response and recovery: lessons from regional Australia.Aging & Society. 2017; 37: 517-536Crossref Scopus (37) Google Scholar Thus, older adults may have important lessons to teach COVID-19 sufferers, as well as healthcare professionals from all age groups. Simply put, a new body of knowledge needs to be generated to capture the wide impact of the pandemic on mental health and wellness. To serve the needs of our readership and the clinical and scientific communities at large, the journal invites a broad range of submissions related to COVID- 19 and geriatric mental health. This may include case reports, case series, commentary articles, and narrative reviews. Subsequently as more data are gathered, we anticipate publishing observational studies, and eventually longer-term epidemiological studies. As per editorial policy, all submissions will be subject to peer review, but we will expedite publication and all accepted papers related to COVID-19 will be published open access free of charge in the interest of public knowledge. We believe that in taking a proactive leadership role in this crisis, the journal and the American Association for Geriatric Psychiatry will empower the scientific and global health community to effectively plan for the care of older adults4Lloyd-Sherlock P Ebrahim S Geffen L et al.Bearing the brunt of covid-19: older people in low and middle income countries.BMJ. 2020 Mar 13; : 368Google Scholar, avoid the risk that this population is marginalized in policy discussions around COVID-1912Jones DS History in a Crisis - Lessons for Covid-19.N Engl J Med. 2020; (e-published ahead of print) March 12Crossref Scopus (235) Google Scholar and generate the highest possible level of valid evidence-based data to guide the most effective care at this critical time.

Discontinuation is a problem in fertility clinics. Many couples discontinue assisted reproductive technologies (ART) without achieving a live birth for reasons other than poor prognosis or the cost of treatment. Discontinuation has been attributed to the burden of treatment. The causes of burden can be broadly classified according to whether they originate in the patient, clinic or treatment. Interventions to alleviate these burdens include provision of comprehensive educational material, screening to identify highly distressed patients, provision of tailored coping tools and improvements in the clinic environment and medical interventions. Practical interventions to reduce the different causes of burden in ART exist, but further development and evaluation of the efficacy of these interventions requires more precise definition of terms and theory. In this paper, we propose a general integrated approach to cover different perspectives in dealing with burden in ART clinics. We firstly describe the integrated approach and present common sources of burden. We then describe interventions that could help reduce the burden in ART. Our paper is aimed at fertility clinic staff because of their day-to-day involvement with patients. However, this discussion should also be relevant to companies that develop treatments and to psychosocial experts. Reducing the burden of treatment should lead to improved outcomes, namely better quality of life during treatment and lower discontinuation rates.

The CRISPR-Cas9 system has the potential to revolutionize genome editing in human pluripotent stem cells (hPSCs), but its advantages and pitfalls are still poorly understood. We systematically tested the ability of CRISPR-Cas9 to mediate reporter gene knockin at 16 distinct genomic sites in hPSCs. We observed efficient gene targeting but found that targeted clones carried an unexpectedly high frequency of insertion and deletion (indel) mutations at both alleles of the targeted gene. These indels were induced by Cas9 nuclease, as well as Cas9-D10A single or dual nickases, and often disrupted gene function. To overcome this problem, we designed strategies to physically destroy or separate CRISPR target sites at the targeted allele and developed a bioinformatic pipeline to identify and eliminate clones harboring deleterious indels at the other allele. This two-pronged approach enables the reliable generation of knockin hPSC reporter cell lines free of unwanted mutations at the targeted locus.

BACKGROUND: The study goal was to develop and test the effectiveness of a brief online education and support program for female infertility patients. METHODS: A randomized-controlled trial was conducted. Using a Solomon-four group design, 190 female patients were recruited from three US fertility centers and were randomized into two experimental and two no-treatment control groups. The psychological outcomes assessed included infertility distress, infertility self-efficacy, decisional conflict, marital cohesion and coping style. Program dosage and satisfaction were also assessed at four weeks follow-up. RESULTS: Women exposed to the online program significantly improved in the area of social concerns (P = 0.038) related to infertility distress, and felt more informed about a medical decision with which they were contending (P = 0.037). Trends were observed for decreased global stress(P = 0.10), sexual concerns (P = 0.059), distress related to child-free living (P = 0.063), increased infertility self-efficacy (P = 0.067) and decision making clarity (P = 0.079). A dosage response was observed in the experimental groups for women who spent >60 min online for decreased global stress (P = 0.028) and increased self efficacy (P = 0.024). CONCLUSIONS: This evidence-based eHealth program for women experiencing infertility suggests that a web-based patient education intervention can have beneficial effects in several psychological domains and may be a cost effective resource for fertility practices.

Microsurgical epididymal sperm aspiration was a great advance in the therapy of patients with non-reconstructable, obstructive azoospermia, most notably congenital bilateral absence of the vas deferens. Using conventional in-vitro fertilization, pregnancies were rarely achieved because the rate of oocyte fertilization was extremely poor. However, the use of retrieved spermatozoa in conjunction with intracytoplasmic sperm injection (ICSI) has dramatically increased the likelihood of embryo formation. Typically, sperm and oocyte harvesting are performed simultaneously. We have investigated whether frozen-thawed spermatozoa work as well as fresh spermatozoa. When we had concluded from our own population of patients (groups I and II) that they did, we adopted a policy of aspirating spermatozoa, primarily cryopreserving them and using them for ICSI at a later date. We found the fertilization rates of this latter cohort of patients (group III) to be excellent (37% per oocyte), and the ongoing pregnancy rate is quite satisfactory (40% per couple, 29% per cycle). We offer this approach as an alternative to the traditional scheme because it markedly eases the burden of partner scheduling on both the couple and the clinicians involved. In addition, assurance of the availability of male partner spermatozoa can be attained prior to beginning ovulation induction.

OBJECTIVE: To estimate whether exercise before the first cycle of in vitro fertilization (IVF) affects cycle outcomes. METHODS: A total of 2,232 patients were prospectively enrolled before undergoing their first cycle of IVF for the treatment of infertility from 1994-2003 at three IVF clinics in the greater Boston area. The primary IVF outcomes of interest included successful live birth and four points of cycle failure: cycle cancellation, failed fertilization, implantation failure, and pregnancy loss. Unconditional logistic regression adjusting for observed confounders was used to quantify the relation between self-reported exercise and cycle outcome. RESULTS: In general, women who reported regular exercise were no more likely to have a live birth compared with those women who did not report exercise (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.7-1.0; P = .07). Women who reported exercising 4 hours or more per week for 1-9 years were 40% less likely to have a live birth (OR 0.6, CI 0.4-0.8) and were almost three times more likely to experience cycle cancellation (OR 2.8, CI 1.5-5.3) and twice as likely to have an implantation failure (OR 2.0, CI 1.4-3.1) or pregnancy loss (OR 2.0, CI 1.2-3.4) than women who did not report exercise. In general, women who participated in cardiovascular exercise had a 30% lower chance of successful live birth (OR 0.7, CI 0.6-0.9) than women who reported no exercise. CONCLUSION: Regular exercise before in vitro fertilization may negatively affect outcomes, especially in women who exercised 4 or more hours per week for 1-9 years and those who participated in cardiovascular exercise. LEVEL OF EVIDENCE: II-2.

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

BACKGROUND: Infertility can significantly impact women's lives and personal relationships. Despite the negative impact of infertility, a significant number of women who are struggling to conceive do not consult a physician. This cross-sectional survey was conducted to determine the emotional impact of infertility on women to identify which aspects of fertility treatment contribute to the psychological stress experienced by so many patients and to identify barriers to seeking treatment. METHODS: Women (n = 445; 18-44 years) who had received fertility treatment within the past 2 years or were having trouble conceiving but had not received treatment, completed a 15-min survey online. RESULTS: Participants were from France (n = 108), Germany (n = 111), Italy (n = 112) and Spain (n = 114). Responses indicated that infertility causes a range of emotions and can strain relationships. Women who had received treatment were more likely to feel hopeful (26 versus 21%) and closer to their partner than women not in treatment (33 versus 19%, P < 0.05). Most women delayed starting treatment because of a desire to conceive naturally, and on the advice of physicians. Women aged ≥35 years took longer to seek help with their fertility issues. Injection-related anxiety was the second greatest barrier to treatment. CONCLUSIONS: This study has provided insight into the physical and psychological challenges of infertility treatments and permitted a better understanding of the factors that impact patient lives. A treatment protocol with minimal injections and provision of additional information may lessen the emotional impact and challenges of infertility and contribute to patient satisfaction with fertility treatment protocols.

The oxidation of phospholipid-bound docosahexaenoic acid (DHA) has been shown to be one of the major factors that limit the motile life span of sperm in vitro. Sperm samples show high cell-to-cell variability in life span and, consequently, in susceptibility toward lipid peroxidation. Therefore, we postulated that there is also cell-to-cell variability in DHA concentration in human spermatozoa. In this study, the concentration of DHA in subsets of human spermatozoa isolated by a discontinuous Percoll density gradient was determined by gas chromatography. Four subsets of human spermatozoa were isolated using a discontinuous Percoll gradient: fraction 1 was enriched in immature germ cells and immature sperm, fractions 2 and 3 contained, mostly, immature sperm with cytoplasmic droplets, and fraction 4 contained, for the most part, morphologically normal sperm, as determined by histochemical analysis. The results indicated that there were significant differences in DHA content in sperm from all 4 fractions. DHA content in sperm from fraction 1 was 2.5-fold higher than that found in fraction 4. DHA content in mouse sperm obtained from the seminiferous tubules was 3-fold higher than that found in mouse sperm obtained from the epididymis, consistent with the findings observed in ejaculated human sperm. The results of this study indicate (i) there is cell-to-cell variability in the concentration of DHA in human sperm and (ii) that there is a net decrease in DHA content in sperm during the process of sperm maturation.

STUDY QUESTION: What are the cohort trends of women undergoing oocyte cryopreservation (OC)? SUMMARY ANSWER: There has been a dramatic increase in OC cycles undertaken each year since 2010, and the demographics of women accessing OC has shifted to a younger age group, but so far very few women have returned to use their cryopreserved oocytes in treatments. WHAT IS KNOWN ALREADY: Although OC, as a method of fertility preservation, is offered around the world, global data are lacking on who is accessing OC, who is returning to thaw oocytes and whether these trends are changing. STUDY DESIGN, SIZE, DURATION: A trinational retrospective cohort study was performed of 31 191 OC cycles and 972 oocyte thaw (OT) cycles undertaken in the USA (2010-2016) and 3673 OC and 517 OT cycles undertaken in Australia/New Zealand (Aus/NZ; 2010-2015). PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were obtained from the USA Society for Assisted Reproductive Technology (SART) national registry and the Australian and New Zealand Assisted Reproduction Database (ANZARD). De-identified data were requested on all autologous oocyte freeze-all cycles and all cycles where autologous oocytes were thawed to be used in a treatment cycle for the time periods of interest. MAIN RESULTS AND THE ROLE OF CHANCE: In both the USA and Aus/NZ, there has been a dramatic rise in the number of OC cycles performed each year (+880% in the USA from 2010 to 2016 and +311% in Aus/NZ from 2010 to 2015). Across both regions, most women undergoing OC were aged in their late 30s, but the average age decreased over time (USA: 36.7 years vs 34.7 years in 2010 and 2016, respectively). The number of women returning for thaw cycles was low (USA: 413 in 2016, Aus/NZ: 141 in 2015) and most thaw cycles (47%) across both regions involved oocytes that were frozen for <6 months. In the USA, a higher proportion of cycles resulted in a live birth when only thawed oocytes were used, compared to cycles that combined thawed oocytes with fresh oocytes (25% vs 11%, respectively; P < 0.001). Age at retrieval influenced live birth rate in the USA; 38% of thaw cycles started in women who stored oocytes when aged ≤35 years resulted in a live birth, whereas only 16% resulted in a live birth for women who stored oocytes when aged ≥36 years. Similar data were unobtainable from Aus/NZ. LIMITATIONS, REASONS FOR CAUTION: There were limitations associated with both the SART and ANZARD data outputs received. The format in which the ANZARD data were provided, and the inconsistencies seen amongst cycle reporting in the SART dataset, restricted data interpretation. For example, both datasets did not provide a clear indication as to why women were undergoing OC and it was not possible to accurately calculate duration of storage for thaw cycles in the USA. We also did not obtain details on embryo quality from either database and acknowledge that embryo quality and subsequent outcome (embryo freezing or discard) would be of interest, especially when considering the efficacy of OC. WIDER IMPLICATIONS OF THE FINDINGS: The data show that there is widespread demand for OC, and it is increasingly undertaken by younger women; however, the limitations encountered in the dataset support the need for a shift to a more uniform approach to data collection and presentation by large databases, worldwide. STUDY FUNDING/COMPETING INTEREST(S): This study received funding from the Fertility Society of Australia to support the ANZARD data extraction. M.J. is supported by an Australian Government Research Training Program Scholarship stipend. The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

STUDY QUESTION: What is the relationship between sperm DNA fragmentation and oxidative stress (OS) with increasing male age? SUMMARY ANSWER: Sperm DNA fragmentation increases with age and is likely related to both defective spermatogenesis and increasing OS levels. WHAT IS KNOWN ALREADY: Sperm quality declines with age. The presence of DNA damage in a high fraction of spermatozoa from a raw semen sample is associated with lower male fertility in natural conception and intrauterine insemination. STUDY DESIGN, SIZE, DURATION: A retrospective cohort study of 16 945 semen samples analysed at a single reference laboratory between January 2010 and December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: All males were undergoing an infertility evaluation. The cohort was divided into seven age categories: <30, 30-34, 35-39, 40-44, 45-49, 50 to <54 and ≥55 years. The mean age was 37.6 years (SD 6.8). Sperm DNA fragmentation index (DFI) and high DNA stainability (HDS) were calculated using flow cytometry. OS levels were measured using the oxidative stress adducts (OSA) test, by spectrophotometry. ANOVA with weighted polynomial contrast analysis was used to evaluate trends for DFI, OSA and HDS values across age categories. MAIN RESULTS AND THE ROLE OF CHANCE: Mean DFI significantly increased across all age groups (Ptrend < 0.001). OSA was lowest in patients <30 years old (mean 3.6, SD 1.0) and also increased as age increased (Ptrend < 0.001). There was a statistically significant difference between age groups for each of the three parameters (P < 0.001). There was a significant linear trend for DFI, OSA and HDS across the seven age categories (P < 0.001). Among patients with high DFI, there was a decreasing age-dependent trend in the patients observed with high OSA (P < 0.001). LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study. All males included in the study were undergoing a work-up for infertility and may not be representative of a fertile population. Additional patient demographics and clinical data were not available. WIDER IMPLICATIONS OF THE FINDINGS: DNA and/or oxidative damage in sperm may be just as important to understand as the chromosomal aberrations that are carried in the oocyte. Further studies are needed to evaluate the effect of advancing paternal age on the male genome and, ultimately, on the health of the offspring. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained for this study. V.D. is an employee of Reprosource/Quest Diagnostics. D.S. reports he was a Scientific Advisor to Cooper Surgical. TRIAL REGISTRATION NUMBER: N/A.

PURPOSE OF REVIEW: Despite the promising success rates of IVF, many couples have to undergo several cycles before achieving live birth. In counseling patients faced with subfertility, it is important to provide cumulative live-birth rates. This review evaluates the current knowledge on cumulative rates, summarizing recently published evidence. RECENT FINDINGS: Existing data have been mostly presented in the form of live-birth rates per IVF cycle as a function of maternal age or reason for subfertility. Recent publications have been reporting IVF success rates in terms of cumulative live-birth rate (CLBR) per woman, thus providing a more realistic estimate that becomes applicable to individual couples. In general, CLBR following IVF has been reported between 45 and 55%. Maternal age has been shown to significantly reduce these rates, as has preimplantation genetic diagnosis. On the contrary, techniques mostly used to decrease the chance of multiple births, such as elective single embryo transfer and natural cycle IVF, do not affect CLBR while achieving a significant reduction in the rates of multiples. SUMMARY: Couples should be counseled that CLBR following IVF lies mostly around 50% and that maternal age as well as genetics of transferred embryos remain factors that influence success.

Background: The early repair of acute proximal hamstring ruptures provides better clinical results than delayed repair. However, it is unclear how nonoperative treatment compares with the operative treatment of these injuries. Purpose: To compare the clinical results of the nonoperative and operative treatment of acute proximal hamstring ruptures. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 25 patients with complete, retracted proximal hamstring ruptures presenting to 1 institution were retrospectively reviewed. All patients were given the option of proximal hamstring repair at the time of the initial evaluation. Patients with at least 12 months of follow-up from the time of surgery or injury were included in the evaluation. Both nonoperative and operative treatment groups were evaluated using the same outcome measures. The primary outcome measure was the Lower Extremity Functional Scale (LEFS). Secondary outcome measures included the Short Form–12 (SF-12) physical and mental component summaries, strength testing, a single-leg hop test, the patient’s perception of strength, and the ability to return to activity. Results: There were 11 patients treated nonoperatively, with a mean follow-up of 2.48 ± 3.66 years, and 14 patients treated operatively, with a mean follow-up of 3.56 ± 2.11 years. The mean LEFS scores for the nonoperative and operative groups were 68.50 ± 7.92 and 74.71 ± 5.38, respectively ( P = .07). No statistical differences were found between the groups regarding SF-12 scores and mean single-leg hop distance compared with the uninjured leg. Isometric testing of the injured hamstring in the nonoperative group demonstrated significant clinical weakness compared with the uninjured side at both 45° and 90° of flexion (57.54% ± 7.8% and 67.73% ± 18.8%, respectively). Isokinetic testing of the injured leg in the operative group demonstrated 90.87% ± 16.3% strength of the uninjured leg. All patients in the operative group were able to return to preinjury activities, whereas 3 patients in the nonoperative group were unable to return (chi-square = 4.33, P = .07). Conclusion: Patients with acute proximal hamstring ruptures treated surgically regained approximately 90% strength of the uninjured extremity and tended to have a greater likelihood of returning to preinjury activities than patients treated nonoperatively.

PURPOSE OF REVIEW: The goal of this review was to summarize the recent research on the relationship between stress and assisted reproductive technology treatment. RECENT FINDINGS: Women and men with infertility report high levels of distress that can impact their quality of life. There are numerous psychosocial interventions, including cognitive behavior therapy and/or self-help ones, which may decrease distress, increase patient retention and improve pregnancy rates. SUMMARY: Patient distress is an important factor to consider. Decreasing burden of care may lead to significant improvements in assisted reproductive technology outcome.

STUDY QUESTION: Is the combined use of fluorescence lifetime imaging microscopy (FLIM)-based metabolic imaging and second harmonic generation (SHG) spindle imaging a feasible and safe approach for noninvasive embryo assessment? SUMMARY ANSWER: Metabolic imaging can sensitively detect meaningful metabolic changes in embryos, SHG produces high-quality images of spindles and the methods do not significantly impair embryo viability. WHAT IS KNOWN ALREADY: Proper metabolism is essential for embryo viability. Metabolic imaging is a well-tested method for measuring metabolism of cells and tissues, but it is unclear if it is sensitive enough and safe enough for use in embryo assessment. STUDY DESIGN, SIZE, DURATION: This study consisted of time-course experiments and control versus treatment experiments. We monitored the metabolism of 25 mouse oocytes with a noninvasive metabolic imaging system while exposing them to oxamate (cytoplasmic lactate dehydrogenase inhibitor) and rotenone (mitochondrial oxidative phosphorylation inhibitor) in series. Mouse embryos (n = 39) were measured every 2 h from the one-cell stage to blastocyst in order to characterize metabolic changes occurring during pre-implantation development. To assess the safety of FLIM illumination, n = 144 illuminated embryos were implanted into n = 12 mice, and n = 108 nonilluminated embryos were implanted into n = 9 mice. PARTICIPANTS/MATERIALS, SETTING, METHODS: Experiments were performed in mouse embryos and oocytes. Samples were monitored with noninvasive, FLIM-based metabolic imaging of nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD) autofluorescence. Between NADH cytoplasm, NADH mitochondria and FAD mitochondria, a single metabolic measurement produces up to 12 quantitative parameters for characterizing the metabolic state of an embryo. For safety experiments, live birth rates and pup weights (mean ± SEM) were used as endpoints. For all test conditions, the level of significance was set at P < 0.05. MAIN RESULTS AND THE ROLE OF CHANCE: Measured FLIM parameters were highly sensitive to metabolic changes due to both metabolic perturbations and embryo development. For oocytes, metabolic parameter values were compared before and after exposure to oxamate and rotenone. The metabolic measurements provided a basis for complete separation of the data sets. For embryos, metabolic parameter values were compared between the first division and morula stages, morula and blastocyst and first division and blastocyst. The metabolic measurements again completely separated the data sets. Exposure of embryos to excessive illumination dosages (24 measurements) had no significant effect on live birth rate (5.1 ± 0.94 pups/mouse for illuminated group; 5.7 ± 1.74 pups/mouse for control group) or pup weights (1.88 ± 0.10 g for illuminated group; 1.89 ± 0.11 g for control group). LIMITATIONS, REASONS FOR CAUTION: The study was performed using a mouse model, so conclusions concerning sensitivity and safety may not generalize to human embryos. A limitation of the live birth data is also that although cages were routinely monitored, we could not preclude that some runt pups may have been eaten. WIDER IMPLICATIONS OF THE FINDINGS: Promising proof-of-concept results demonstrate that FLIM with SHG provide detailed biological information that may be valuable for the assessment of embryo and oocyte quality. Live birth experiments support the method's safety, arguing for further studies of the clinical utility of these techniques. STUDY FUNDING/COMPETING INTEREST(S): Supported by the Blavatnik Biomedical Accelerator Grant at Harvard University and by the Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Institutes of Health Award UL1 TR001102), by NSF grants DMR-0820484 and PFI-TT-1827309 and by NIH grant R01HD092550-01. T.S. was supported by a National Science Foundation Postdoctoral Research Fellowship in Biology grant (1308878). S.F. and S.A. were supported by NSF MRSEC DMR-1420382. Becker and Hickl GmbH sponsored the research with the loaning of equipment for FLIM. T.S. and D.N. are cofounders and shareholders of LuminOva, Inc., and co-hold patents (US20150346100A1 and US20170039415A1) for metabolic imaging methods. D.S. is on the scientific advisory board for Cooper Surgical and has stock options with LuminOva, Inc.