Showing papers in "Reproductive Biomedicine Online in 2018"

Sperm cryopreservation: A review on current molecular cryobiology and advanced approaches.

Abstract: The cryopreservation of spermatozoa was introduced in the 1960s as a route to fertility preservation. Despite the extensive progress that has been made in this field, the biological and biochemical mechanisms involved in cryopreservation have not been thoroughly elucidated to date. Various factors during the freezing process, including sudden temperature changes, ice formation and osmotic stress, have been proposed as reasons for poor sperm quality post-thaw. Little is known regarding the new aspects of sperm cryobiology, such as epigenetic and proteomic modulation of sperm and trans-generational effects of sperm freezing. This article reviews recent reports on molecular and cellular modifications of spermatozoa during cryopreservation in order to collate the existing understanding in this field. The aim is to discuss current freezing techniques and novel strategies that have been developed for sperm protection against cryo-damage, as well as evaluating the probable effects of sperm freezing on offspring health.

A search for molecular mechanisms underlying male idiopathic infertility

Abstract: Infertility affects approximately 15% of the couples wanting to conceive. In 30 - 40% of the cases the aetiology of male infertility remains unknown and is called idiopathic male infertility. When assisted reproductive technologies are used to obtain pregnancy, an adequate (epi)genetic diagnosis of male infertility is of major importance to evaluate if a genetic abnormality will be transmitted to the offspring. In addition, there is need for better diagnostic seminal biomarkers to assess the success rates of these assisted reproductive technologies. This review investigated the possible causes and molecular mechanisms underlying male idiopathic infertility by extensive literature searches of: (i) causal gene mutations; (ii) proteome studies of spermatozoa from idiopathic infertile men;(iii) the role of epigenetics; (iv) post-translational modifications; and (v) sperm DNA fragmentation in infertile men. In conclusion, male infertility is a complex, multi-factorial disorder and the underlying causes often remain unknown. Further research on the (epi)genetic and molecular defects in spermatogenesis and sperm function is necessary to improve the diagnosis and to develop more personalized treatments of men with idiopathic infertility.

Sperm DNA fragmentation index as a promising predictive tool for male infertility diagnosis and treatment management – meta-analyses

Abstract: Conventional semen analyses have limitations in male infertility diagnosis and prognosis Assessment of sperm DNA fragmentation (sDF) has been proposed to discriminate fertile from infertile men and predict FSH treatment response in infertile men, although a comprehensive evaluation of this is not available The aims of these meta-analyses were to assess the power of sDF in male infertility diagnosis and its role in predicting FSH therapy response in infertile men Two literature searches were conducted in MEDLINE (PubMed), Embase, the Cochrane Library, Scopus and UpToDate First, interventional/observational clinical trials comparing fertile to infertile/subfertile men were included Second, interventional/observational clinical trials evaluating FSH-treated infertile men were assessed sDF levels were significantly higher in infertile men considering 28 studies (P

An evidence-based scoring system for prioritizing mosaic aneuploid embryos following preimplantation genetic screening

Abstract: The aim of this study was to devise an evidence-based scoring system for prioritizing mosaic aneuploid embryos for transfer A retrospective analysis was performed of all sequential cytogenetic and molecular results on chorionic villi samples (n = 72,472) and products of conception (n = 3806) analysed at a single centre The likelihood that a mosaic aneuploidy detected in chorionic villi samples will involve the fetus, the incidence of clinically significant fetal uniparental disomy in the presence of a mosaic in chorionic villi and the chance of the mosaicism culminating in miscarriage were used to generate a scoring system for prioritizing mosaic aneuploid embryos detected by preimplantation genetic screening A composite score was obtained for each individual mosaic aneuploidy after assignment of an individual risk score based on the incidence/likelihood of each adverse outcome A final additional score was assigned to viable full or mosaic aneuploidies with a well-defined phenotype The higher the composite score the lower the priority for embryo transfer In conclusion, due to the paucity of prospective studies on the actual transfer of mosaic aneuploid embryos, we suggest using this evidence-based scoring system to provide a useful tool for clinicians, embryologists and patients

Progesterone levels on pregnancy test day after hormone replacement therapy-cryopreserved embryo transfer cycles and related reproductive outcomes

Abstract: Research question Do serum progesterone levels determine ongoing pregnancy rates (OPR) in hormone replacement therapy frozen–thawed embryo transfer (HRT–FET) cycles? Design A cohort study of 244 HRT–FET cycles from a Danish public fertility centre. Data from patients undergoing HRT–FET from January 2016 to December 2017 were extracted from a clinical database. All patients had transfer in HRT cycles of autologous embryos frozen on day 5 or 6. Endometrial preparation was performed using 6 mg oestradiol valerate daily from the second day of the cycle followed by vaginal micronized progesterone (90 mg/8 h). All patients had serum progesterone measurement during the artificial luteal phase. Results The optimal cut-off for ongoing pregnancy was 35 nmol/l based on sensitivity analysis of different progesterone levels as a factor variable and its association with ongoing pregnancy. No significant differences regarding number of embryos transferred, embryo quality, age, body mass index (BMI) or smoking were found in the two groups of progesterone Conclusions Serum progesterone levels

Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest

Abstract: Successful human reproduction initiates from normal gamete formation, fertilization and early embryonic development. Abnormalities in any of these steps will lead to infertility. Many infertile patients undergo several failures of IVF and intracytoplasmic sperm injection (ICSI) cycles, and embryonic developmental arrest is a common phenotype in cases of recurrent failure of IVF/ICSI attempts. However, the genetic basis for this phenotype is poorly understood. The subcortical maternal complex (SCMC) genes play important roles during embryonic development, and using whole-exome sequencing novel biallelic mutations in the SCMC genes TLE6, PADI6 and KHDC3L were identified in four patients with embryonic developmental arrest. A mutation in TLE6 was found in a patient with cleaved embryos that arrested on day 3 and failed to form blastocysts. Two patients with embryos that arrested at the cleavage stage had mutations in PADI6, and a mutation in KHDC3L was found in a patient with embryos arrested at the morula stage. No mutations were identified in these genes in an additional 80 patients. These findings provide further evidence for the important roles of TLE6, PADI6 and KHDC3L in embryonic development. This work lays the foundation for the genetic diagnosis of patients with recurrent IVF/ICSI failure.

The role of mitochondrial activity in female fertility and assisted reproductive technologies: overview and current insights.

Abstract: Mitochondria have been implicated as key factors regulating female reproductive processes. Notable progress has been made in determining the role of mitochondria with respect to oocyte maturation, fertilization and early embryo development. In addition, mitochondrial function and dysfunction has been the subject of various studies in ovarian ageing and metabolic stress models. However, the overall mitochondrial impact on female fertility is yet to be uncovered. The mitochondrial DNA content of granulosa, cumulus and trophectoderm cells is being explored as a biomarker of oocyte quality and embryo viability. As growing evidence suggests that embryo potential could be related to the ability of oocyte mitochondria to generate energy, efforts have been made to investigate the possibility of improving mitochondrial capacity in women with poor outcomes after treatment with assistedreproductive technologies. Thus far, therapeutic attempts have focused mainly on using nutrients to restore mitochondrial function and transferring mitochondria from autologous germline precursor cells. Moreover, new perspectives on optimizing infertility treatments have arisen with modern mitochondrial replacement therapies, which are being applied in women with mitochondrial disease-causing mutations. This review explores aspects of the distinctive contribution of mitochondria to reproductive processes and discusses current and emerging clinical implications.

Prevalence and confounders of chronic endometritis in premenopausal women with abnormal bleeding or reproductive failure

Abstract: In this retrospective cohort study, a consecutive series of 1551 premenopausal women underwent hysteroscopy and endometrial biopsy. Chronic endometritis was diagnosed when plasma cell in endometrial tissue was detected by immunohistochemistry using CD138 epitope. The overall prevalence of chronic endometritis in the population studied was 24.4% The prevalence was significantly increased in the following conditions: recurrent implantation failure (40.8%; P < 0.001), abnormal uterine bleeding (40.7 %; P < 0.001), endometrial hyperplasia (50.0%, P < 0.05) and submucosal fibroid (59.1%; P < 0.001) than those without the respective conditions. The prevalence in specimens obtained from the proliferative phase (26.0%) was significantly higher (P < 0.05) than those from the luteal phase (17.5%). Logistic regression analysis showed three significant factors affecting the prevalence, in descending order of importance: clinical presentation, endometrial hyperplasia and stage of the cycle from which the specimen was obtained. The confounding variables identified in this study may account for the wide range of published prevalence of the condition, and should be considered in the analysis of prevalence data relating to chronic endometritis.

The M2a macrophage subset may be critically involved in the fibrogenesis of endometriosis in mice

Abstract: Research question Recent research has shown that endometriotic lesions are essentially wounds that undergo repeated tissue injury and repair, which results in epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation, smooth muscle metaplasia and ultimately fibrosis. Macrophages are a key regulator of tissue repair and fibrogenesis. But do macrophages also play a role in fibrogenesis of endometriosis, and, if yes, which subset of macrophages? Design To elucidate the role of macrophages in fibrogenesis of endometriosis, we conducted three experiments in mice. In experiment 1, endometriotic tissue samples from female Balb/C mice with induced endometriosis were serially harvested to evaluate the role of macrophages in fibrogenesis. In experiments 2 and 3, female transgenic mice (C57BL/6J background) expressing the human diphtheria toxin receptor under the control of the CD11b promoter had macrophage depletion by diphtheria toxin injection after induction of endometriosis. Additionally, in experiment 3, adoptive transfer of different subsets of macrophage was carried out after macrophage depletion. Results Lesional infiltration of M2 macrophages increased progressively as lesions progressed undisturbed, concomitant with progressive epithelial–mesenchymal transition, fibroblast-to-myofibroblast transdifferentiation and fibrosis. Macrophage depletion after induction of endometriosis significantly reduced lesional infiltration of total macrophages, significantly reduced lesional infiltration of M2 macrophages and significantly reduced lesional fibrotic content and lesion weight (P Conclusions The identification of a particular macrophage subset in fibrogenesis of endometriosis should further help to shed new light on the pathophysiology of endometriosis.

A demographic projection of the contribution of assisted reproductive technologies to world population growth.

Abstract: Enormous unmet needs for infertility treatment exist because access to assisted reproductive technologies is demographically skewed. Since the first IVF baby in 1978, the number of people conceived by reproductive technology has grown much faster than expected, reaching several million today and rapidly approaching 0.1% of the total world population. As more patients build families, and their children in turn become parents, the number owing their existence to assisted reproductive technologies, either directly or indirectly, will expand tremendously in future decades, but no attempts have been made hitherto to project the magnitude. We have projected growth to the year 2100, along with the fractional contribution to world population. The chief variable driving growth is access to fertility services. If it stagnates at current levels of about 400,000 babies per year, an estimated 157 million people alive at the end of the century will owe their lives to assisted reproductive technologies (1.4% of global population), but at an arbitrary upper limit of 30,000 extra births annually there will be 394 million additional people alive (3.5%). As the conquest of infertility continues, individuals who owe their lives to assisted reproductive technologies will quietly make a significant contribution to demographic growth as well as social progress.

Ultrasound-guided embryo transfer: summary of the evidence and new perspectives. A systematic review and meta-analysis.

Abstract: Despite the purported advantages of ultrasound guidance during embryo transfer, and the large number of clinical trials published on this topic, recommendations for the use of this technique in daily clinical practice are still under debate. We designed a meta-analysis based exclusively on evidence from published randomized controlled trials, with the aim of analysing the effect of trans-abdominal ultrasound guidance during embryo transfer versus clinical touch and of transvaginal ultrasound guidance (TV-US) versus the trans-abdominal approach on IVF outcomes. On the basis of 14 randomized trials, we found a moderate quality of evidence supporting the beneficial effects of transabdominal guidance during embryo transfer compared with conventional clinical touch in clinical pregnancy and ongoing or live birth rates. No significant differences were found in miscarriage and ectopic pregnancy rate, with low or very low quality of evidence, respectively. On the basis of three randomized trials, we found the quality of evidence supporting the equivalence of transvaginal versus transabdominal approach in clinical pregnancy and ongoing or live birth rates to be low. Finally, larger randomized controlled trials are necessary to explore the possible benefits of TV-US, three-dimensional ultrasound imaging modality, and uterine length measurement before transfer.

Effect of male body mass index on assisted reproduction treatment outcome: an updated systematic review and meta-analysis.

Abstract: Men with a body mass index (BMI) of 30 or over are more likely to have reduced fertility and fecundity rates. This systematic review and meta-analysis evaluated the effect of male BMI on IVF and intracytoplasmic sperm injection (ICSI) outcome. An electronic search for published literature was conducted in MEDLINE and EMBASE between 1966 and November 2016. Outcome measures were clinical pregnancy rates (CPR) and live birth rates (LBR) per IVF or ICSI cycle. Eleven studies were identified, including 14,372 cycles; nine reported CPR and seven reported LBR. Pooling of data from those studies revealed that raised male BMI was associated with a significant reduction in CPR (OR 0.78, 95% CI 0.63 to 0.98, P = 0.03) and LBR (OR 0.88, 95% CI 0.82 to 0.95, P = 0.001) per IVF-ICSI treatment cycle. Male BMI could be an important factor influencing IVF-ICSI outcome. More robust studies are needed to confirm this conclusion using standardized methods for measuring male BMI, adhering to the World Health Organization definitions of BMI categories, accounting for female BMI, IVF and ICSI cycle characteristics, including the number of embryos transferred and embryo quality, and use the live birth rate per cycle as primary outcome.

Optimal endometrial thickness to maximize live births and minimize pregnancy losses: Analysis of 25,767 fresh embryo transfers

Abstract: Research question What is the association of endometrial thickness with pregnancy losses and live births in IVF treatment and the optimal threshold that optimizes the IVF outcome? Design Data were analysed from 25,767 IVF cycles from centres of the CARE Fertility Group in the UK between 2007 and 2016. Transvaginal ultrasound was conducted to measure the maximum endometrial thickness during gonadotrophin stimulation. Live birth rates were per embryo transfer. Pregnancy loss rates included the combination of biochemical and clinical pregnancy losses. Results The live birth rate was 15.6% with 5 mm or less endometrial thickness and gradually increased to 33.1% with an endometrial thickness of 10 mm. On the other hand, the pregnancy loss rate was 41.7% with 5 mm or less endometrial thickness and gradually decreased to 26.5% with an endometrial thickness of 10 mm. Statistical modelling for optimal endometrial thickness threshold found 10 mm or more maximized live births and minimized pregnancy losses. This association was independent after adjusting for confounders such as age, oocyte number, number of transferred embryos, ovarian stimulation protocol and embryo quality for live births (crude RR 1.27; 95% CI 1.21 to 1.33; Adjusted RR 1.18; 95% CI 1.12 to 1.23) and pregnancy losses (crude RR 0.83; 95% CI 0.77 to 0.89; adjusted RR 0.86; 95% CI 0.8 to 0.92). Conclusions Endometrial thickness is strongly associated with pregnancy losses and live births in IVF, and the optimal endometrial thickness threshold of 10 mm or more maximized live births and minimized pregnancy losses.

Can time-lapse parameters predict embryo ploidy? A systematic review

Abstract: Embryo morphology assessment performs relatively poorly in predicting implantation Embryo aneuploidy screening (PGS) has recently improved, but its clinical value is still debated, and the development of a cheap non-invasive method for the assessment of embryo ploidy status is a highly desirable goal The growing implementation of time-lapse devices led some teams to test the effectiveness of morphokinetic parameters as predictors of embryo ploidy, with conflicting results The aim of this study was to conduct a comprehensive review of the literature on the predictive value of morphokinetic parameters for embryo ploidy status A systematic search on PubMed was conducted using the following key words: time-lapse, morphokinetic, aneuploidy, IVF, preimplantation genetic screening, PGS, chromosomal status A total of 13 studies were included in the analysis They were heterogeneous in design, patients, day of embryo biopsy, statistical approach and outcome measures No single or combined morphokinetic parameter was consistently identified as predictive of embryo ploidy status In conclusion, the available studies are too heterogeneous for firm conclusions to be drawn on the predictive value of time-lapse analysis for embryo aneuploidy screening Hence, morphokinetic parameters should not be used yet as a surrogate for PGS to determine embryo ploidy in vitro

Status of preimplantation genetic testing and embryo selection.

Abstract: At the recent 2018 PGDIS congress, a review of randomized controlled trials of preimplantation genetic testing for aneuploidies (PGT-A) showed improved ongoing pregnancy rates per transfer in experienced centres and in women aged 35 years and older. Young women produce 40% abnormal embryos (20-60% range), but not all centres see a selection advantage; this indicates the need for more emphasis in improving biopsy and case management. Some chromosome abnormalities are iatrogenic; PGT-A could, therefore, be used as assisted reproductive technology (ART) quality control. Great improvements in non-invasive PGT by testing spent media have been reported, ranging from 80-95% concordance with trophectoderm biopsy, probably precluding the need for biopsy soon. Mosaicism was widely discussed, with PGDIS agreeing to update their guidelines, but continuing to recommend prioritizing euploid, followed by mosaic embryos. Techniques to allow simultaneous single sample analysis of aneuploidy and inherited mutations are improving, but this does not extend to de-novo mutations. Convincing data were presented on the efficacy of using endometrial receptivity tests to improve ART outcomes adjuvant or independently of PGT-A. Imprinting, CRISPR and cloning were also discussed, with a concluding presentation on the first extensive data (aneuploidy and morphology) on in-vivo conceived embryos.

Cairo consensus on the IVF laboratory environment and air quality: report of an expert meeting

Abstract: This proceedings report presents the outcomes from an international Expert Meeting to establish a consensus on the recommended technical and operational requirements for air quality within modern assisted reproduction technology (ART) laboratories. Topics considered included design and construction of the facility, as well as its heating, ventilation and air conditioning system; control of particulates, micro-organisms (bacteria, fungi and viruses) and volatile organic compounds (VOCs) within critical areas; safe cleaning practices; operational practices to optimize air quality while minimizing physicochemical risks to gametes and embryos (temperature control versus air flow); and appropriate infection-control practices that minimize exposure to VOC. More than 50 consensus points were established under the general headings of assessing site suitability, basic design criteria for new construction, and laboratory commissioning and ongoing VOC management. These consensus points should be considered as aspirational benchmarks for existing ART laboratories, and as guidelines for the construction of new ART laboratories.

Should we continue to measure endometrial thickness in modern-day medicine? The effect on live birth rates and birth weight.

Abstract: The evaluation of endometrial thickness (EMT) is still part of standard cycle monitoring during IVF, despite the lack of robust evidence of any value of this measurement to predict little revalidation in contemporary medical practice; other tools, however, such as endocrine profile monitoring, have become increasingly popular. The aim of this study was to reassess whether EMT affects the outcome of a fresh embryo transfer in modern-day medicine, using a retrospective, single-centre cohort of 3350 IVF cycles (2827 women) carried out between 2010 and 2014. In the multivariate regression analysis, EMT was non-linearly associated with live birth, with live birth rates being the lowest with an EMT less than 7.0 mm (21.6%; P P = 0.008). An EMT less than 7.0 mm was also associated with a decrease in neonatal birthweight z-scores (−0.40; 95% CI −0.69 to −0.12). In conclusion, these results reaffirm the use of EMT as a potential prognostic tool for live birth rates and neonatal birthweight in contemporary IVF, namely when considered together with other ovarian stimulation monitoring methods, such as the late-follicular endocrine profile.

Depression and state anxiety scores during assisted reproductive treatment are associated with outcome: a meta-analysis

Abstract: This meta-analysis investigated whether state anxiety and depression scores during assisted reproductive technology (ART) treatment and changes in state anxiety and depression scores between baseline and during ART treatment are associated with treatment outcome. PubMed, PsycInfo, Embase, ScienceDirect, Web of Science and Scopus were searched and meta-analytic data analysed using random effects models to estimate standardized mean differences. Eleven studies (2202 patients) were included. Women who achieved pregnancy had significantly lower depression scores during treatment than women who did not become pregnant (-0.302; 95% CI: -0.551 to -0.054, z = -2.387, P = 0.017; I2 = 77.142%, P = 0.001). State anxiety scores were also lower in women who became pregnant (-0.335; 95% CI: -0.582 to -0.087, z = -2.649, P = 0.008; I2 = 81.339%, P = 0.001). However, changes in state anxiety (d = -0.056; 95% CI: -0.195 to 0.082, z = -0.794; I2 = 0.00%) and depression scores (d = -0.106; 95% CI: -0.296 to 0.085, z = -1.088; I2 = 0.00%) from baseline to treatment were not associated with ART outcome. Clinics should aim to promote better psychosocial care to help patients manage the psychological and physical demands of ART treatment, giving realistic expectations.

Repeated implantation failure at the crossroad between statistics, clinics and over-diagnosis

Abstract: The most common definition of repeated implantation failure (RIF) is the failure to obtain a clinical pregnancy after three completed IVF cycles. This definition, however, may lead to misuse of the diagnosis. To disentangle this, we set up a mathematical model based on the following main assumptions: rate of success of IVF constant and set at 30%; and RIF postulated to be a dichotomous condition (yes or no) with a prevalence of 10%. On this basis, the expected cumulative chance of pregnancy after three and six cycles was 59% and 79%, respectively. Consequently, the false-positive rate of a diagnosis of RIF is 75% and 51%, respectively. Increasing the rate of success of IVF or the prevalence of RIF lowers but does not make unremarkable the rate of false-positive diagnoses. Overall, this model shows that the commonly used definition of RIF based on three failed attempts in a standard population with good prognosis leads to over-diagnosis and, potentially, to over-treatments.

Sexual function in women with polycystic ovary syndrome: a systematic review and meta-analysis.

Abstract: We present the first systematic review and meta-analysis of sexual function in women with polycystic ovary syndrome (PCOS) compared with women without PCOS. Data on this topic are limited and often contradicting. Sexual function is influenced by endocrine, mental and social factors, which are often compromised in women with PCOS. The main outcome measures were validated sexual function questionnaires and visual analogue scales (VAS). We identified and assessed 1925 original articles; 18 articles were included. Significant small effect sizes were found on sexual function subscales (total score: P = 0.006; arousal: P = 0.019; lubrication: P = 0.023; satisfaction: P = 0.015; orgasm: P = 0.028), indicating impaired sexual function in women with PCOS. Large effect sizes for the effect of body hair on sex were shown on VAS (P = 0.006); social effect of appearance (P = 0.007); sexual attractiveness (P < 0.001). Satisfaction with sex life was impaired (P < 0.001), but sexual satisfaction was rated equally important in women with PCOS and controls. We conclude that a satisfying sex life is important for women with PCOS; however, sexual function and feelings of sexual attractiveness are impaired. The findings imply that sexual function, sexual satisfaction and psychosocial functioning need to be part of every clinical assessment of women with PCOS.

Progress in the diagnosis and management of adolescent endometriosis: an opinion.

Abstract: Increasing evidence indicates that early onset endometriosis (EOE), starting around menarche or early adolescence, may have an origin different from the adult variant, originating from neonatal uterine bleeding (NUB). This implies seeding of naive endometrial progenitor cells into the pelvic cavity with NUB; these can then activate around thelarche. It has its own pathophysiology, symptomatology and risk factors, warranting critical management re-evaluation. It can also be progressive, endangering future reproductive capacity. This variant seems to be characterized by the presence of ovarian endometrioma. Today, the diagnosis of endometriosis in young patients is often delayed for years; if rapidly progressive, it can severely affect pelvic organs, even in the absence of serious symptoms. Given the predicament, great attention must be paid to symptomatology that is often non-specific, justifying a search for new, simple, non-invasive markers of increased risk. Better use of modern imaging techniques will aid considerably in screening for the presence of EOE. Traditional laparoscopy should be limited to cases in which imaging gives rise to suspicion of severity and a stepwise, minimally invasive approach should be used, followed by medical treatment to prevent recurrence. In conclusion, EOE represents a condition necessitating early diagnosis and stepwise management, including medical treatment.

Cumulative live birth rates after IVF in patients with polycystic ovaries: phenotype matters

Abstract: Research question Do cumulative live birth rates (CLBR) vary among women with different polycystic ovary syndrome (PCOS) phenotypes who undergo IVF/intracytoplasmic sperm injection (ICSI) treatment? Design In this retrospective cohort study, data from 567 patients undergoing an assisted reproductive technology (ART) cycle between January 2010 and December 2015 were collected. Demographical traits, cycle characteristics and clinical and laboratory data were analysed. Results After conventional ovarian stimulation using a gonadotrophin-releasing hormone antagonist protocol, the median number of oocytes retrieved ranged between 11 and 13.5 and did not differ significantly among the studied groups. Live birth rate (LBR) after fresh embryo transfer and CLBR after transfer of all fresh and vitrified embryos were significantly lower in women with hyperandrogenic PCOS phenotypes A (LBR 16.7%, CLBR 25.8%) and C (LBR 18.5%, CLBR 27.8%) compared with women with normoandrogenic PCOS phenotype D (LBR 33.7%, CLBR 48%) ( P -value for LBR 0.01 and 0.03, respectively; P -value for CLBR 0.002 and 0.01, respectively) and controls with a polycystic ovarian morphology (LBR 37.1%, CLBR 53.3%) ( P -value for LBR 0.002 and 0.01, respectively; P -value for CLBR Conclusions Hyperandrogenic PCOS phenotypes confer significantly lower CLBR compared with their normoandrogenic counterparts. These findings may imply the need for adapted counselling and tailored approaches when treating PCOS patients with hyperandrogenism who require ART.

New strategies of ovarian stimulation based on the concept of ovarian follicular waves: From conventional to random and double stimulation.

Abstract: The theory of a multicyclic development of follicles during the menstrual cycle prompted new approaches to ovarian stimulation, such as starting gonadotrophins for ovarian stimulation at any time during the menstrual cycle or using double stimulation during it, with stimulation in both the follicular and luteal phases. Because of the asynchrony between endometrial receptivity and embryo development with a 'non-conventional start' stimulation, all the oocytes/embryos are generally cryopreserved and transferred subsequently. This deferred transfer policy is currently possible given the advances in vitrification techniques, with success rates comparable to those following transfer with 'fresh' embryos. New stimulation approaches, together with advanced cryopreservation techniques, allow for a total 'disarticulation' between the time of the menstrual cycle, ovarian stimulation start and embryo transfer. This new approach to ovarian stimulation is particularly useful for women seeking fertility preservation, especially where a shortened time to starting cancer treatment is desirable. Also, poor responders could benefit from the new stimulation protocols by continuing ovarian stimulation after the first oocyte retrieval, thereby obtaining more oocytes or embryos compared with the conventional approach.

Perinatal outcomes after stimulated versus natural cycle IVF: a systematic review and meta-analysis

Abstract: Pregnancies resulting from assisted reproductive techniques are at higher risk of adverse perinatal outcomes compared with spontaneous conceptions. Underlying infertility and IVF procedures have been linked to adverse perinatal outcomes. It is important to know if ovarian stimulation influences perinatal outcomes after IVF. A systematic search for relevant studies was conducted up to November 2016 on the following databases: PubMed, EMBASE, DARE and Cochrane Central Register of Controlled Trials. Perinatal outcomes included preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA), large for gestational age (LGA) and congenital anomalies. Data from four studies, which included a total of 96,996 and 704 singleton live births after stimulated IVF and natural or modified natural cycle IVF, were included in the meta-analysis. The risk of PTB (RR 1.27, 95% CI 1.03 to 1.58) and LBW (RR 1.95, 95% CI 1.03 to 3.67) were significantly higher after stimulated compared with natural or modified natural cycle IVF. Data from one study were available for SGA, LGA, congenital anomalies and no significant differences were reported between the groups. This study suggests a higher risk of PTB and LBW after stimulated IVF compared with natural or modified natural IVF, although the absolute increase in risk may be low.

Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review.

Abstract: Recurrent pregnancy loss (RPL) is a common, yet elusive, complication of pregnancy. Among couples at high risk of RPL, such as those carrying a structural chromosomal rearrangement, preimplantation genetic diagnosis (PGD) has been proposed as a tool to improve live birth rates and reduce the incidence of miscarriage; however, no clear consensus has been reached on its benefits in this population. This systematic review summarizes existing published research on the effect of PGD on pregnancy outcomes among carriers of chromosomal abnormalities with RPL. A comprehensive search of common databases was conducted, which yielded 20 studies. Meta-analysis was precluded owing to significant heterogeneity between studies. The primary outcome of interest was live birth rate (LBR), and a pooled total of 847 couples who conceived naturally had a LBR ranging from 25–71% compared with 26.7–87% among 562 couples who underwent IVF and PGD. Limitations of the study include lack of large comparative or randomized control studies. Patients experiencing RPL with structural chromosomal rearrangement should be counselled that good reproductive outcomes can be achieved through natural conception, and that IVF–PGD should not be offered first-line, given the unproven benefits, additional cost and potential complications associated with assisted reproductive technology.

Time-lapse imaging algorithms rank human preimplantation embryos according to the probability of live birth.

Abstract: Research question Can blastocysts leading to live births be ranked according to morphokinetic-based algorithms? Design Retrospective analysis of 781 single blastocyst embryo transfers, including all patient clinical factors that might be potential confounders for the primary outcome measure of live birth, was weighed using separate multi-variable logistic regression models. Results There was strong evidence of effect of embryo rank on odds of live birth. Embryos were classified A, B, C or D according to calculated variables; time to start (tSB) and duration (dB{tB – tSB}) of blastulation. Embryos of rank D were less likely to result in live birth than embryos of rank A (odds ratio [OR] 0.3046; 95% confidence interval [CI] 0.129, 0.660; P Conclusions Time-lapse imaging morphokinetic-based algorithms for blastocysts can provide objective hierarchical ranking of embryos for predicting live birth and may have greater discriminating power than conventional blastocyst morphology assessment.

Endometrial thickness of less than 7.5 mm is associated with obstetric complications in fresh IVF cycles: a retrospective cohort study

Abstract: Research question Does endometrial thickness affect the occurrence of obstetric complications in fresh IVF cycles? Design We conducted a retrospective cohort study that included all singleton deliveries resulting from fresh embryo transfers in a single centre between 2008 and 2014. Obstetric complications, i.e. preeclampsia, placental abruption, placenta previa, small for gestational age and preterm delivery, in singleton live births were compared among patients with an endometrial thickness of less than 7.5 mm and 7.5 mm or over on day of HCG triggering. We adjusted for confounders, including maternal age, body mass index, smoking, peak oestradiol, parity, chronic hypertension, pre-gestational diabetes, gestational diabetes, vanishing twin, inherited or acquired thrombophilia, and past pregnancy complications. Results A total of 5546 fresh embryo transfer cycles were carried out during the study period, of which 864 singleton deliveries met inclusion criteria. After adjusting for potential confounders, an endometrial thickness of less than 7.5 mm was found to be associated with increased risk for adverse obstetric outcome (adjusted OR 1.53; 95% CI 1.03 to 2.42; P = 0.04) even after excluding patients with prior pregnancy complications (adjusted OR 2.2; 95% CI 1.05 to 4.59; P = 0.035). Conclusions Our results demonstrated that a thin endometrial lining was associated with obstetric complications that might be related to poor placentation. These findings should be validated in large prospective cohort studies.

hsa-miRNA-154-5p expression in plasma of endometriosis patients is a potential diagnostic marker for the disease

Abstract: Research question As microRNA (miRNA) are stable in circulation, this study tested whether they could serve as putative non-invasive biomarkers for endometriosis, and their expression differences between endometriosis patients and controls. It also addressed whether the combination of differently expressed miRNA together with clinical parameters in a statistical model could distinguish between endometriosis patients and controls. Design This prospective cohort study explored the possibility of using changes in extracellular miRNA spectra in plasma of 51 patients with endometriosis compared with 41 controls combined with clinical data as non-invasive biomarkers for the disease. The project was divided into three different phases for biomarker screening, discovery and validation. The differences in expression levels of plasma miRNA obtained from women with and without endometriosis were analysed with quantitative PCR-based microarrays. The diagnostic performance of the selected individual and/or combined differentially expressed miRNA candidates and clinical parameters was assessed using in silico bioinformatics modelling and receiver operating characteristic curve analysis. Results Data showed that a specific plasma miRNA signature is associated with endometriosis and that hsa-miR-154-5p, which alone or in combination with hsa-miR-196b-5p, hsa-miR-378a-3p, and hsa-miR-33a-5p and the clinical parameters of body mass index and age, are potentially applicable for non-invasive diagnosis of the disease. Changes in the levels of expression of certain circulating plasma miRNA also occurred within the phases of the menstrual cycle. Conclusions miRNA seem to be promising candidates for the non-invasive diagnosis of endometriosis. Further, other clinical parameters may help in distinguishing women suffering from endometriosis from healthy individuals.

In-vitro regulation of primordial follicle activation: challenges for fertility preservation strategies.

Abstract: Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. While the only available option to restore fertility is autologous transplantation, this treatment is not appropriate for all patients due to the risk of reintroducing cancer cells and causing disease recurrence. Harnessing the full reproductive potential of this tissue to restore fertility requires the development of culture systems that support oocyte development from the primordial follicle stage. While this has been achieved in the mouse, the goal of obtaining oocytes of sufficient quality to support embryo development has not been reached in higher mammals despite decades of effort. In vivo , primordial follicles gradually exit the resting pool, whereas when primordial follicles are placed into culture, global activation of these follicles occurs. Therefore, the addition of a factor(s) that can regulate primordial follicle activation in vitro may be beneficial to the development of culture systems for ovarian tissue from cancer patients. Several factors have been observed to inhibit follicle activation, including anti-Mullerian hormone, stromal-derived factor 1 and members of the c-Jun-N-terminal kinase pathway. This review summarizes the findings from studies of these factors and discusses their potential integration into ovarian tissue culture strategies for fertility preservation.

Oocyte retrieval difficulties in women with ovarian endometriomas.

Abstract: Research question What are the frequency, characteristics and consequences of technical diffiiculties encountered by physicians when carrying out oocyte retrieval in women with ovarian endometriomas? Design We prospectively recruited women undergoing IVF and compared technical difficulties between women with ( n = 56) and without ( n = 227) endometriomas. Results In exposed women, the cyst had to be transfixed in eight cases (14%, 95% CI 7 to 25%) and accidental contamination of the follicular fluid with the endometrioma content was recorded in nine women (16%, 95% CI 8 to 27%). Moreover, follicular aspiration was more frequently incomplete (OR 3.6, 95% CI 1.4 to 9.6). In contrast, the retrievals were not deemed to be more technically difficult by the physicians and the rate of oocytes retrieved per developed follicle did not differ. No pelvic infections or cyst ruptures were recorded (0%, 95% CI 0 to 5%). Conclusions Oocyte retrieval in women with ovarian endometriomas is more problematic but the magnitude of these increased difficulties is modest.