Diagnosis and management of infertility: NICE-adapted guidelines from the Italian Society of Human Reproduction.

In Italy the fertility rate is very low, and an increasing number of patients are infertile and require treatments. The Italian Law concerning the safety of patient care, and the professional liability of health professionals, indicates that health professionals must comply with the recommendations set out in the guidelines developed by public and private bodies and institutions, as well as scientific societies and technical-scientific associations of the health professions, except for specific cases. Unfortunately, no guideline for the diagnosis and the management of infertility is currently available in Italy. In 2019, the Italian Society of Human Reproduction pointed out the need to produce Italian guidelines and subsequently approved the establishment of a multidisciplinary and multiprofessional working group (MMWG) to develop such a guideline. The MMWG was representative of 5 scientific societies, one national federation of professional orders, 3 citizens' and patients' associations, 5 professions (including lawyer, biologist, doctor, midwife, and psychologist), and 3 medical specialties (including medical genetics, obstetrics and gynecology, and urology). The MMWG chose to adapt a high-quality guideline to the Italian context instead of developing one from scratch. Using the Italian version of the Appraisal of Guidelines for Research and Evaluation II scoring system, the National Institute of Clinical Excellence guidelines were selected and adapted to the Italian context. The document was improved upon by incorporating comments and suggestions where needed. This study presents the process of adaptation and discusses the pros and cons of the often-neglected choice of adapting rather than developing new guidelines.

Rational design of an integrated directional coupler for wideband operation.

We consider a design procedure for directional couplers for which the coupling length is approximately wavelength-independent over a wide bandwidth. We show analytically that two coupled planar waveguides exhibit a maximum in the coupling strength, which ensures both wideband transmission and minimal device footprint. This acts as a starting point for mapping out the relevant part of phase space. This analysis is then generalized to the fully three-dimensional geometry of rib waveguides using an effective medium approximation. This forms an excellent starting point for fully numerical calculations and leads to designs with unprecedented bandwidths and compactness.

Interventions to prevent or reduce the incidence and severity of ovarian hyperstimulation syndrome: a systematic umbrella review of the best clinical evidence.

Ovarian hyperstimulation syndrome (OHSS) is a potentially life-threating iatrogenic complication of the early luteal phase and/or early pregnancy after in vitro fertilization (IVF) treatment. The aim of the current study was to identify the most effective methods for preventing of and reducing the incidence and severity of OHSS in IVF patients. A systematic review of systematic reviews of randomized controlled trials (RCTs) with meta-analysis was used to assess each potential intervention (PROSPERO website, CRD 268626) and only studies with the highest quality were included in the qualitative analysis. Primary outcomes included prevention and reduction of OHSS incidence and severity. Secondary outcomes were maternal death, incidence of hospital admission, days of hospitalization, and reproductive outcomes, such as incidence of live-births, clinical pregnancies, pregnancy rate, ongoing pregnancy, miscarriages, and oocytes retrieved. A total of specific interventions related to OHSS were analyzed in 28 systematic reviews of RCTs with meta-analyses. The quality assessment of the included studies was high, moderate, and low for 23, 2, and 3 studies, respectively. The certainty of evidence (CoE) for interventions was reported for 37 specific situations/populations and resulted high, moderate, and low-to-very low for one, 5, and 26 cases, respectively, while it was not reported in 5 cases. Considering the effective interventions without deleterious reproductive effects, GnRH-ant co-treatment (36 RCTs; OR 0.61, 95% C 0.51 to 0.72, n = 7,944; I2 = 31%) and GnRH agonist triggering (8 RCTs; OR 0.15, 95% CI 0.05 to 0.47, n = 989; I2 = 42%) emerged as the most effective interventions for preventing OHSS with a moderate CoE, even though elective embryo cryopreservation exhibited a low CoE. Furthermore, the use of mild ovarian stimulation (9 RCTs; RR 0.26, CI 0.14 to 0.49, n = 1,925; I2 = 0%), and dopaminergic agonists (10 RCTs; OR 0.32, 95% CI 0.23 to 0.44, n = 1,202; I2 = 13%) coadministration proved effective and safe with a moderate CoE. In conclusion, the current study demonstrates that only a few interventions currently can be considered effective to reduce the incidence of OHSS and its severity with high/moderate CoE despite the numerous published studies on the topic. Further well-designed RCTs are needed, particularly for GnRH-a down-regulated IVF cycles.

Fertility specialists' views, behavior, and attitudes towards the use of endometrial scratching in Italy.

BACKGROUND: Endometrial scratching (ES) or injury is intentional damage to the endometrium performed to improve reproductive outcomes for infertile women desiring pregnancy. Moreover, recent systematic reviews with meta-analyses and randomized controlled trials demonstrated that ES is not effective, data on the safety are limited, and it should not be recommended in clinical practice. The aim of the current study was to assess the view and behavior towards ES among fertility specialists throughout infertility centers in Italy, and the relationship between these views and the attitudes towards the use of ES as an add-on in their commercial setting. METHODS: Online survey among infertility centers, affiliated to Italian Society of Human Reproduction (SIRU), was performed using a detailed questionnaire including 45 questions with the possibility to give "closed" multi-choice answers for 41 items and "open" answers for 4 items. Online data from the websites of the infertility centers resulting in affiliation with the specialists were also recorded and analyzed. The quality of information about ES given on infertility centers websites was assessed using a scoring matrix including 10 specific questions (scored from 0 to 2 points), and the possible scores ranged from 0 to 13 points ('excellent' if the score was 9 points or more, 'moderate' if the score was between 5 and 8, and 'poor' if it was 4 points or less). RESULTS: The response rate was of 60.6% (43 questionnaires / 71 infertility SIRU-affiliated centers). All included questionnaires were completed in their entirety. Most physicians (~ 70%) reported to offer ES to less than 10% of their patients. The procedure is mainly performed in the secretory phase (69.2%) using pipelle (61.5%), and usually in medical ambulatory (56.4%) before IVF cycles to improve implantation (71.8%) without drugs administration (e.g., pain drugs, antibiotics, anti-hemorrhagics, or others) before (76.8%) or after (64.1%) the procedure. Only a little proportion of infertility centers included in the analysis proposes formally the ES as an add-on procedure (9.3%), even if, when proposed, the full description of the indications, efficacy, safety, and costs is never addressed. However, the overall information quality of the websites was generally "poor" ranging from 3 to 8 and having a low total score (4.7 ± 1.6; mean ± standard deviation). CONCLUSIONS: In Italy, ES is a procedure still performed among fertility specialists for improving the implantation rate in IVF patients. Moreover, they have a poor attitude in proposing ES as an add-on in the commercial setting.

Beyond the Umbrella: A Systematic Review of the Interventions for the Prevention of and Reduction in the Incidence and Severity of Ovarian Hyperstimulation Syndrome in Patients Who Undergo In Vitro Fertilization Treatments.

Ovarian hyperstimulation syndrome (OHSS) is the main severe complication of ovarian stimulation for in vitro fertilization (IVF) cycles. The aim of the current study was to identify the interventions for the prevention of and reduction in the incidence and severity of OHSS in patients who undergo IVF not included in systematic reviews with meta-analyses of randomized controlled trials (RCTs) and assess and grade their efficacy and evidence base. The best available evidence for each specific intervention was identified, analyzed in terms of safety/efficacy ratio and risk of bias, and graded using the Oxford Centre for Evidence-Based Medicine (CEBM) hierarchy of evidence. A total of 15 interventions to prevent OHSS were included in the final analysis. In the IVF population not at a high risk for OHSS, follitropin delta for ovarian stimulation may reduce the incidence of early OHSS and/or preventive interventions for early OHSS. In high-risk patients, inositol pretreatment, ovulation triggering with low doses of urinary hCG, and the luteal phase administration of a GnRH antagonist may reduce OHSS risk. In conclusion, even if not supported by systematic reviews with homogeneity of the RCTs, several treatments/strategies to reduce the incidence and severity of OHSS have been shown to be promising.

Understanding the limits of parametrial resection in radical hysterectomy: a randomized controlled trial.

Introduction: The aim was to evaluate whether adding specific educational medical illustrations may help gynecologists to better understand the limits of parametrial resection in radical hysterectomy from type A to type C2. Study Design: randomized controlled trial. Material and methods: Institute of Obstetric and Gynecologic Pathology, University of Catania, Italy. Materials and methods: 30 senior Obstetrics and Gynecology (Ob/Gyn) residents and 30 general Ob/Gyn consultants were enrolled in the study, and randomized to two groups of 15 people (group A and group B). Both groups had a copy of the article on the Querleu-Morrow Classification of Radical Hysterectomy (2017) for reading comprehension. Group B also had 10 unpublished medical illustrations, prepared for this paper. After one month the level of self-perceived understanding related to parametrectomy limits in radical hysterectomy was evaluated in both groups using a numeric visual analog scale, where each participant evaluated his degree of comprehension. The data were statistically analyzed using the U Mann-Whitney test. Results: Group A participants (only article) had a lower level of comprehension of parametrectomy limits compared to group B participants (article plus drawings). The difference between the mean scale score, reported by group A, equal to 5.9 ±1.4, and that reported by group B, equal to 7.2 ±1.5, was statistically significant (p < 0.01). Conclusions: The results of this study suggest that educational materials, such as the proposed drawings, may help both Ob/Gyn consultants and residents to better understand the relationship between the extent of parametrial resection and cervical disease severity, and the related postoperative complications.

Is fertility reduced in ovulatory women with polycystic ovary syndrome? An opinion paper.

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility; however, whether women with PCOS and spontaneous or drug-induced ovulatory cycles have the same reproductive potential as non-PCOS controls is a matter of debate. In the present opinion paper, the author takes the opportunity to summarize the collective evidence supporting the hypothesis of reduced fertility potential in women with PCOS, regardless of ovulatory status, and speculate that reduced reproductive potential may be caused by altered oocytes, embryo and endometrial competence, and infertility-related co-morbidities as well as an increased risk of pregnancy complications.

Changes in visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment: a systematic review.

As all the structures of the human eye are characterized by sex hormone receptors, this study tested the hypothesis that assisted reproductive technology (ART) treatment influences visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment. A systematic literature search of all original articles published up to August 2018 was performed using the PubMed database, including all original studies available in the literature. Review articles, studies in which participants underwent mixed interventions (i.e. other than ART treatment), studies reporting data on ocular malformations in ART offspring, and studies written in languages other than English were excluded. All selected articles were analysed to assess the level of evidence according to the Oxford Centre for Evidence-Based Medicine 2011 guidelines, and the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation system. Although sparse data suggest that ART treatment can influence visual function and ocular morphology in women who have undergone ART treatment and children born as a result of ART treatment, the available evidence is inconclusive given its low level and quality. More high-quality research is needed to assess the potential interaction between ART treatment and the eye.

Lifestyle and fertility: the influence of stress and quality of life on female fertility.

There is growing evidence that lifestyle choices account for the overall quality of health and life (QoL) reflecting many potential lifestyle risks widely associated with alterations of the reproductive function up to the infertility. This review aims to summarize in a critical fashion the current knowledge about the potential effects of stress and QoL on female reproductive function. A specific literature search up to August 2017 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science and Google Scholar. Current review highlights a close relationship in women between stress, QoL and reproductive function, that this association is more likely reported in infertile rather than fertile women, and that a vicious circle makes them to have supported each other. However, a precise cause-effect relationship is still difficult to demonstrate due to conflicting results and the lack of objective measures/instruments of evaluation.

Radiations and female fertility.

Hundreds of thousands of young women are diagnosed with cancer each year, and due to recent advances in screening programs, diagnostic methods and treatment options, survival rates have significantly improved. Radiation therapy plays an important role in cancer treatment and in some cases it constitutes the first therapy proposed to the patient. However, ionizing radiations have a gonadotoxic action with long-term effects that include ovarian insufficiency, pubertal arrest and subsequent infertility. Cranial irradiation may lead to disruption of the hypothalamic-pituitary-gonadal axis, with consequent dysregulation of the normal hormonal secretion. The uterus might be damaged by radiotherapy, as well. In fact, exposure to radiation during childhood leads to altered uterine vascularization, decreased uterine volume and elasticity, myometrial fibrosis and necrosis, endometrial atrophy and insufficiency. As radiations have a relevant impact on reproductive potential, fertility preservation procedures should be carried out before and/or during anticancer treatments. Fertility preservation strategies have been employed for some years now and have recently been diversified thanks to advances in reproductive biology. Aim of this paper is to give an overview of the various effects of radiotherapy on female reproductive function and to describe the current fertility preservation options.

Obstetric and perinatal outcomes in subfertile patients who conceived following low technology interventions for fertility enhancement: a comprehensive review.

PURPOSE: Low technology interventions for fertility enhancement (LTIFE) are strategies that avoid retrieval, handling, and manipulation of female gametes. The definition of LTIFE is yet to be widely accepted and clarified, but they are commonly used in milder cases of infertility and subfertility. Based on these considerations, the aim of the present study was comprehensively to review and investigate the obstetric and perinatal outcomes in subfertile patients who underwent LTIFE. METHODS: A literature search up to May 2017 was performed in IBSS, SocINDEX, Institute for Scientific Information, PubMed, Web of Science, and Google Scholar. An evidence-based hierarchy was used according to The Oxford Centre for Evidence-Based Medicine to determine which articles to include and analyze, and to provide a level of evidence of each association between intervention and outcome. RESULTS: This analysis identified preliminary and low-grade evidence on the influence of LTIFE on obstetric and perinatal outcomes in subfertile women. CONCLUSIONS: LTIFE women should deserve major consideration from Clinicians/Researchers of Reproductive Medicine, because these treatments could be potentially responsible for mothers' and babies' complications. So far, the lack of well-designed and unbiased studies makes further conclusions difficult to be drawn.

Fano enhancement in hybrid plasmonic nanoresonator.

Combining the advantages of photonics (low loss) and plasmonics (high field confinement), while mitigating their respective drawbacks, can greatly enhance the light-matter interaction efficiency. Here we make use of a time-dependent coupled mode theory in order to theoretically model the excitation of a plasmonic nanoantenna via a photonic resonator. We show that including the light source-nanoantenna direct coupling substantially enhances the overall coupling efficiency, maintaining the same input power.

General analytic expression and numerical approach for the Kerr nonlinear coefficient of optical waveguides.

The Kerr nonlinear coefficient γ is a key parameter that quantifies the nonlinear strength of an optical waveguide. For lossy waveguides such as plasmonic waveguides, the literature is confusing because various expressions derived by different groups have generally not been validated, and the conditions when they apply are not explicitly specified. Here we derive a rigorous and full-vectorial model, leading to both a general analytic expression and a general numerical approach for finding γ, as well as to their underlying relationship. Our results, exemplified by lossless and lossy waveguides, are consistent not only with each other, but also with the results in literature under appropriate limiting conditions. This work provides a benchmarked framework to understand and engineer nonlinear nanophotonic devices.

Shedding new light on female fertility: The role of vitamin D.

In the last decades several studies suggested that vitamin D is involved in the modulation of the reproductive process in women due to the expression of VDR and 1α-hydroxylase in reproductive tissues such as ovary, uterus, placenta, pituitary and hypothalamus. Vitamin D has also a role in the regulation of sex hormone steroidogenesis. Increasing evidence suggests that vitamin D might have a regulatory role in polycystic ovary syndrome (PCOS)-associated symptoms, including ovulatory dysfunction, insulin resistance and hyperandrogenism. Vitamin D deficiency also has been reported to contribute to the pathogenesis of endometriosis due to its immunomodulatory and anti-inflammatory properties. Although most of the studies supported a role of vitamin D in the onset of these diseases, randomized controlled trials to assess the efficacy of vitamin D supplementation have never been performed. In this review we critically discuss the role of vitamin D in female fertility, starting from in vitro and in vivo studies, focusing our attention on the two most frequent causes of female infertility: PCOS and endometriosis.

The effect of a uterine manipulator on the recurrence and mortality of endometrial cancer: a multi-centric study by the Italian Society of Gynecological Endoscopy.

BACKGROUND: Although widely adopted, the use of a uterine manipulator during laparoscopic treatment of endometrial cancer represents a debated issue, and some authors hypothesize that it potentially may cause an increased risk of relapse, particularly at specific sites. OBJECTIVE: Our aim was to evaluate the risk and site of disease recurrence, overall survival, and disease-specific survival in women who had laparoscopic surgery with and without the use of a uterine manipulator. STUDY DESIGN: Data were reviewed from consecutive patients who had laparoscopic surgery for endometrial cancer staging in 7 Italian centers. Subjects were stratified according to whether a uterine manipulator was used during surgery; if so, the type of manipulator was identified. Multivariable analysis to correct for possible confounders and propensity score that matched the minimize selection bias were utilized. The primary outcome was the risk of disease recurrence. Secondary outcomes were disease-specific and overall survival and the site of recurrence, according to the use or no use of the uterine manipulator and to the different types of manipulators used. RESULTS: We included 951 patients: 579 patients in the manipulator group and 372 patients in the no manipulator group. After a median follow-up period of 46 months (range,12-163 months), the rate of recurrence was 13.5% and 11.6% in the manipulator and no manipulator groups, respectively (P=.37). Positive lymph nodes and myometrial invasion of >50% were associated independently with the risk of recurrence after adjustment for possible confounders. The use of a uterine manipulator did not affect the risk of recurrence, both at univariate (odds ratio, 1.18; 95% confidence interval, 0.80-1.77) and multivariable analysis (odds ratio, 1.00; 95% confidence interval, 0.60-1.70). Disease-free, disease-specific, and overall survivals were similar between groups. Propensity-matched analysis confirmed these findings. The site of recurrence was comparable between groups. In addition, the type of uterine manipulator and the presence or not of a balloon at the tip of the device were not associated significantly with the risk of recurrence. CONCLUSION: The use of a uterine manipulator during laparoscopic surgery does not affect the risk of recurrence and has no impact on disease-specific or overall survival and on the site of recurrence in women affected by endometrial cancer.

Assisted reproductive technology treatments and quality of life: a longitudinal study among subfertile women and men.

PURPOSE: Quality of life (QoL) may represent a comprehensive indicator for the assessment of the psychological impact of complex clinical conditions, such as infertility. Infertile women have a worse QoL compared to both infertile men and non-infertile controls. However, the initial phases of infertility treatments have been frequently investigated using cross-sectional study designs. This prospective longitudinal study aimed at assessing the health-related QoL change across different phases of assisted reproductive technology (ART) treatments in subfertile women and men. METHODS: Eighty-five subfertile women and men undergoing ART cycles were assessed at the beginning of the ovarian stimulation, during oocyte retrieval before discharging, and around 14 days after the embryo transfer. QoL was assessed through the Short Form 36. RESULTS: Irrespective of the cause of infertility, work status, and age, QoL levels decreased from the first to the third assessment, and women scored significantly lower than men to each QoL indicator. Additionally, a higher number of previous ART failures had a negative impact on QoL, irrespective of gender and the phase of treatment. ART outcome marginally affected women's QoL across time. CONCLUSION: Infertile women have a worse QoL throughout all phases of ARTs compared to men, and this difference increases in infertile patients with more than one previous ART failure.

Nonlinear optical frequency mixing response of single and multilayer graphene.

It has been shown that graphene exhibits unique electronic, thermal, mechanical, and optical properties. In particular, due to its gapless band structure and linear dispersion relation around the Dirac points, graphene exhibits a strong nonlinear optical response, which has been theoretically predicted to depend on the number of graphene layers. In this Letter, we experimentally validate the theoretical predictions by probing multilayer graphene χ(3) nonlinearities. The intensity of the four-wave mixing signal is observed to grow monotonically as a function of the number of graphene layers, up to a maximum intensity corresponding to ∼32 layers, after which it decreases, well in agreement with theoretical predictions.

Degenerate four-wave mixing in silicon hybrid plasmonic waveguides.

Silicon-based plasmonic waveguides show high confinement well beyond the diffraction limit. Various devices have been demonstrated to outperform their dielectric counterparts at micrometer scales, such as linear modulators, capable of generating high field confinement and improving device efficiency by increasing access to nonlinear processes, limited by ohmic losses. By using hybridized plasmonic waveguide architectures and nonlinear materials, silicon-based plasmonic waveguides can generate strong nonlinear effects over just a few wavelengths. We have theoretically investigated the nonlinear optical performance of two hybrid plasmonic waveguides (HPWG) with three different nonlinear materials. Based on this analysis, the hybrid gap plasmon waveguide (HGPW), combined with the DDMEBT nonlinear polymer, shows a four-wave mixing (FWM) conversion efficiency of -16.4 dB over a 1 µm propagation length, demonstrating that plasmonic waveguides can be competitive with standard silicon photonics structures over distances three orders of magnitude shorter.