Stem Cells and Infertility: A Review of Clinical Applications and Legal Frameworks.

Infertility is a condition defined by the failure to establish a clinical pregnancy after 12 months of regular, unprotected sexual intercourse or due to an impairment of a person's capacity to reproduce either as an individual or with their partner. The authors have set out to succinctly investigate, explore, and assess infertility treatments, harnessing the potential of stem cells to effectively and safely treat infertility; in addition, this paper will present the legal and regulatory complexities at the heart of stem cell research, with an overview of the legislative state of affairs in six major European countries. For couples who cannot benefit from assisted reproductive technologies (ART) to treat their infertility, stem-cells-based approaches have been shown to be a highly promising approach. Nonetheless, lingering ethical and immunological uncertainties require more conclusive findings and data before such treatment avenues can become mainstream and be applied on a large scale. The isolation of human embryonic stem cells (ESCs) is ethically controversial, since their collection involves the destruction of human embryonic tissue. Overall, stem cell research has resulted in important new breakthroughs in the treatment of infertility. The effort to untangle the complex web of ethical and legal issues associated with such therapeutic approaches will have to rely on evidence-based, broadly shared standards, guidelines, and best practices to make sure that the procreative rights of patients can be effectively reconciled with the core values at the heart of medical ethics.

Human Papillomavirus and Male Infertility: What Do We Know?

In recent years, increasing attention has been paid to understanding the causes of infertility, which is being recognized as a growing health problem affecting large numbers of couples worldwide. Male infertility is a contributing factor in approximately 30-40% of cases, and one of its etiological causes is sexually transmitted infections (STIs). Among sexually transmitted pathogens, human papillomavirus (HPV) can contribute in various ways to the failure of spontaneous and assisted reproduction, acting in the different phases of conception, especially in the early ones. In particular, HPV infection can affect sperm DNA integrity, sperm motility, count, viability, and morphology and can induce the production of anti-sperm antibodies (ASAs). In this narrative review, we aimed to provide an overview of existing research on the potential adverse effects of HPV infection on male reproductive health. Furthermore, we analyzed how limiting the spread of the infection, particularly with gender-neutral vaccination, could be a possible therapeutic tool to counteract male and female fertility problems.

Assisted Reproductive Techniques and Risk of Congenital Heart Diseases in Children: a Systematic Review and Meta-analysis.

Infertility is a growing phenomenon and leads to an increased use of assisted reproductive techniques (ARTs). In recent years, concerns about the safety of these procedures emerged and ARTs were hypothesized to be a risk factor for developing congenital heart diseases (CHDs) in offspring. Our aim is to investigate the association between ART and CHD, specifying results according to various subtypes of defects. We performed a systematic review and random-effects meta-analysis following the PRISMA guidelines. MEDLINE and Google Scholar were searched from January 2011 to May 2022. Data about incidence of CHD in ART were tabulated and extracted from all the studies included. Twenty-four studies were included. Pooled incidence of CHDs after IVF pregnancies was 3% (95% CI 0.3-0.4; I2 = 99%), decreasing to 1% (95% CI 0.00-0.01; I2 = 93%) for major CHDs only. An increased risk of CHDs, especially minor (i.e., not requiring surgical correction), seems to occur in ART compared with non-ART pregnancies [RR 1.71 (95% CI 1.25-2.34; I2 = 99%)]. For major CHDs, not enough evidence is available to assess the real risk. Moreover, some confounding factors (i.e., maternal age and male infertility) seem to play a critical role to determine an increased risk of CHDs. Conflicting results emerged among the studies, setting the need for further research to validate the actual evidence and state the real risk of CHD following ART pregnancies.

The Future Is Coming: Artificial Intelligence in the Treatment of Infertility Could Improve Assisted Reproduction Outcomes-The Value of Regulatory Frameworks.

Infertility is a global health issue affecting women and men of reproductive age with increasing incidence worldwide, in part due to greater awareness and better diagnosis. Assisted reproduction technologies (ART) are considered the ultimate step in the treatment of infertility. Recently, artificial intelligence (AI) has been progressively used in the many fields of medicine, integrating knowledge and computer science through machine learning algorithms. AI has the potential to improve infertility diagnosis and ART outcomes estimated as pregnancy and/or live birth rate, especially with recurrent ART failure. A broad-ranging review has been conducted, focusing on clinical AI applications up until September 2022, which could be estimated in terms of possible applications, such as ultrasound monitoring of folliculogenesis, endometrial receptivity, embryo selection based on quality and viability, and prediction of post implantation embryo development, in order to eliminate potential contributing risk factors. Oocyte morphology assessment is highly relevant in terms of successful fertilization rate, as well as during oocyte freezing for fertility preservation, and substantially valuable in oocyte donation cycles. AI has great implications in the assessment of male infertility, with computerised semen analysis systems already in use and a broad spectrum of possible AI-based applications in environmental and lifestyle evaluation to predict semen quality. In addition, considerable progress has been made in terms of harnessing AI in cases of idiopathic infertility, to improve the stratification of infertile/fertile couples based on their biological and clinical signatures. With AI as a very powerful tool of the future, our review is meant to summarise current AI applications and investigations in contemporary reproduction medicine, mainly focusing on the nonsurgical aspects of it; in addition, the authors have briefly explored the frames of reference and guiding principles for the definition and implementation of legal, regulatory, and ethical standards for AI in healthcare.

The Gender Gap in the Diagnostic-Therapeutic Journey of the Infertile Couple.

Medical procreation impairs both the biological and psychological lives of couples. However, male and female attitudes to infertility are different and require a different approach during the IVF journey. Thus, the gender impact assessment (GIA) method was used to analyse original studies present in the literature. We found some gender-related differences and, subsequently, possible outcomes of intervention to improve healthy reproduction management and prevent infertility. In particular, it became apparent that there was the need for an in-depth male infertility assessment and a gender-specific follow-up.

HPV Vaccination: The Position Paper of the Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV).

Human papillomavirus (HPV) related cervical cancer represents an issue of public health priority. The World Health Organization recommended the introduction of HPV vaccination in all national public programs. In Europe, vaccines against HPV have been available since 2006. In Italy, vaccination is recommended and has been freely offered to all young girls aged 11 years since 2008. Three prophylactic HPV vaccines are available against high- and low-risk genotypes. The quadrivalent vaccine contains protein antigens for HPV 6, 11, 16, and 18. The bivalent vaccine includes antigens for HPV 16 and 18. The nonavalent vaccine was introduced in 2014, and it targets HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Clinical trials demonstrated the effectiveness of the three vaccines in healthy young women. Likewise, all vaccines showed an excellent safety profile. The bivalent vaccine provides two doses in subjects aged between 9 and 14 years and three doses in subjects over 14 years of age. The quadrivalent vaccine provides two doses in individuals from 9 to 13 years and three doses in individuals aged 14 years and over. The nonavalent vaccine schedule provides two doses in individuals from 9 to 14 years of age and three doses in individuals aged 15 years and over at the time of the first administration. Preliminary results suggest that the HPV vaccine is effective in the prevention of cervical squamous intraepithelial lesions even after local treatment. Given these outcomes, in general, it is imperative to expand the vaccinated target population. Some interventions to improve the HPV vaccine's uptake include patient reminders, physicians-focused interventions, school-based vaccinations programs, and social marketing strategies. The Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV) is committed to supporting vaccination programs for children and adolescents with a catch-up program for young adults. The SICPCV also helps clinical and information initiatives in developing countries to decrease the incidence of cervico-vaginal and vulvar pathology.

Closed vs. Open Oocyte Vitrification Methods Are Equally Effective for Blastocyst Embryo Transfers: Prospective Study from a Sibling Oocyte Donation Program.

PURPOSE: To assess whether open and closed vitrification protocols are equally effective for sibling-oocyte cycles when performing blastocyst embryo transfers. MATERIALS AND METHODS: A prospective study was set up comparing the open and the closed vitrification techniques in oocyte recipients sharing sibling oocytes between 2014 and 2016. Sibling oocytes were randomly and equally assigned into the closed group (oocytes vitrified in a closed system) or the open group (oocytes vitrified in an open system). Intracytoplasmic sperm injection was performed on all cases. Embryo transfers were performed on day 5. Power analysis calculation showed that 94 cycles would be needed for each group in the study in order to achieve statistical significance at a 5% level with power 80%. RESULTS: The final number of donors included was 95. A total of 190 recipients matched with their donors were included in the study. There was no difference in the mean number of oocytes vitrified with the closed or the open system (8.26 ± 2.54 vs. 8.31 ± 2.57). No significant difference was observed between the 2 groups regarding survival rate, fertilization rate, cleavage rate, top-quality embryos on day 3, blastocyst rate, and top-quality blastocyst rate. Moreover, no statistically significant difference in the b-human chorionic gonadotropin-positive rate, clinical pregnancy rate per cycle, implantation rate, ongoing pregnancy rate, and live birth rate between closed and open groups. CONCLUSION: Οpen and closed vitrification protocols are equally effective for sibling-oocyte cycles.

[HPV vaccination: not only female adolescents and not only prophylactic. Review and position paper of the Italian HPV Study Group (IHSG)].

HPV vaccination has been introduced in clinical practice in recent years and represents the most effective strategy of primary prevention of cervical carcinoma and of female genital preneoplastic conditions. One of the major issues of the subject is represented by vaccination coverage of the target population. Since its introduction, HPV vaccine efficacy has been progressively demonstrated also towards extragenital HPV-correlated conditions and in males too. Moreover, even subjects of older age groups or subjects who already had HPV infections have been demonstrated to received benefits from vaccination, due to improvements of their immunological response. Recently, vaccine efficacy has also been investigated in terms of adjuvant administration after treatments of preneoplastic or benign conditions of the female lower genital tract caused by HPVs; preliminary results indicate an interesting and promising field of application. On this basis, in this article an analysis of the state of the art has been performed, with specific regard to the Italian scenario and with the focus of future perspectives of implementation of the HPV vaccination policy. From the available evidences, the Italian HPV Study Group recommends the extension of systematic HPV vaccination to males too, to adult subjects and also after conservative treatment of genital HPV correlated conditions.

Observational prospective study on Lactobacillus plantarum P 17630 in the prevention of vaginal infections, during and after systemic antibiotic therapy or in women with recurrent vaginal or genitourinary infections.

We performed a prospective cohort parallel observational study on the use of Lactobacillus plantarum P 17630 in the prevention of vaginal infections. Eligible were women with a diagnosis of bacterial vaginosis (<15 days) and documented history of recurrent vaginal infections; and/or cystitis (<15 days); and/or treatment with antibiotics for bacterial respiratory tract infections during the week before the study entry. Study subjects were prescribed Lactobacillus plantarum P 17630 > 100.000.000 UFC one vaginal capsule per day for 6 days, then a capsule per week for 16 weeks. Eligible subjects were enrolled in two parallel cohorts: 85 women using (group A) and 39 not using (group B) Lactobacillus plantarum P 17630. The risk of recurrent infection within 4 months from the study entry, was higher among untreated women: multivariate OR 2.6 (95%CI 0.7-9.4). The modification of presence/intensity or symptoms was significant in both the study groups (p < .001). Impact statement What is already known on this subject? The Lactobacillus plantarum P 17630 has been shown to be active in the treatment of bacterial vaginosis and vaginal candidiasis. No data are available on its efficacy in the prevention of recurrent vaginal or urological infection or as a prevention strategy during systemic treatment with antibiotics. What do the results of this study add? This observational study suggests that Lactobacillus plantarum given for 4 months may lower the risk of recurrent infection in women with recurrent vaginal or genitourinary infection or after antibiotic systemic treatment for bacterial respiratory tract infection. The finding, however, is not statistically significant, possibly due to the lower than expected rate of infection observed in our population and consequently the limited power of the study. What are the implications of these findings for clinical practice and/or further research? New studies are needed in order to evaluate in different populations the role of Lactobacillus plantarum in lowering the risk of recurrent infection in a high-risk populations.

Vulvar involvement in pediatric Crohn's disease: a systematic review.

PURPOSE: The aim of the study is to report a systematic review (from 2000 to 2017) of all pediatric cases of vulvar Crohn's disease (VCD) and to highlight the key-points for a correct diagnosis and management of this rare condition. METHODS: An electronic search using the Pubmed/Medline, Scopus, EMBASE, Cochrane database and Google Scholar database was performed according to PRISMA guidelines. RESULTS: Twenty pediatric studies and 22 cases of VCD were included for analysis. All the articles reported a single case, except two articles where two cases, respectively, are described. Clinical vulvar examination showed the following main manifestations: vulvar erythema (9/22 cases, 40.9%), vulvar swelling (8/22 cases, 36.4%), vulvar edema (8/22 cases, 36.4%), vulvar ulcers (4/22 cases, 18.2%). Perianal and/or anal involvement (fissures, vegetations, skin tags, erythema, papules, nodules) were recorded in ten cases (45.4%). Steroids per os and/or topical administration were the most prescribed treatment, achieving clinical remission in 11 cases (50%), used alone or in combination with metronidazole or 5-aminosalicylic acid, azathioprine or sulphasalazine/mesalazine. CONCLUSIONS: This review shows that pediatric VCD is an uncommon disease, difficult to be diagnosed as either symptoms or clinical lesions are not specific. A multidisciplinary approach is advised to reach a correct diagnosis and plan clinical treatment.

The Patient and Observer Scar Assessment Scale to Evaluate the Cosmetic Outcomes of the Robotic Single-Site Hysterectomy in Endometrial Cancer.

OBJECTIVE: The objective of this study was to evaluate the cosmetic outcome of robotic single-site hysterectomy (RSSH) in early-stage endometrial cancer. METHODS: We prospectively collected patient demographics, operative times, complications, pathologic results, and length of stay on all patients who underwent RSSH for early-stage endometrial cancer. The Patient and Observer Scar Assessment Scale (POSAS) was used for the evaluation of the cosmetic outcome. RESULTS: Forty-five patients were included in our study from January 2012 to October 2015. The median age of patients was 63 years (range, 35-84 years), and the median body mass index was 26.5 kg/m (range, 18-39 kg/m). No laparoscopic/laparotomic conversion was registered. The median docking time, console time, and total operative time were 7 minutes (range, 4-14 minutes), 46 minutes (range, 20-100 minutes), and 90 minutes (range, 45-150 minutes), respectively. The median blood loss was 50 mL (range, 10-150 mL). Nine patients underwent pelvic lymphadenectomy, and the median number of pelvic lymph nodes was 13 (range, 10-32). The median time to discharge was 3 days (range, 2-6 days). No intraoperative complications occurred, whereas we did observe 1 early postoperative complication. The oncological outcome was directly comparable to the literature. Patients reported low pain scores and high satisfaction in terms of postoperative scarring. The POSAS scores confirmed excellent cosmetic outcome of RSSH. CONCLUSION: Robotic single-site hysterectomy provided an efficient option for gynecologic oncologic surgery. The POSAS revealed high objective and patient-evaluated outcome, and patients were highly satisfied with the overall outcome of the appearance of their scars.

Potential impact of a nonavalent HPV vaccine on HPV related low-and high-grade cervical intraepithelial lesions: A referral hospital-based study in Sicily.

While bivalent and quadrivalent HPV vaccines have been used for about 10 years, a nonavalent vaccine against HPV types 6/11/16/18/31/33/45/52 and 58 has been recently approved by FDA and EMA and is now commercially available. The objective of our study was to evaluate the potential impact of the nonavalent vaccine on HPV infection and related low- and high-grade squamous intraepithelial lesions (LSIL, HSIL), compared to the impact of the quadrivalent vaccine, in a female population living in Sicily (Italy). Low estimates of HPV vaccine impact were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes, alone or in association, but excluding presence of other HPV types; high estimates were calculated as prevalence of HPV 6/11/16/18/31/33/45/52 and 58 genotypes alone or in association, in the presence of other HPV types. The nonavalent HPV vaccine showed increased impact, compared to the quadrivalent vaccine. Estimates of potential impact varied from 30.9% (low estimate) to 53.3% (high estimate) for LSIL, and from 56.9% to 81,0% for HSIL. The proportion of additional cases potentially prevented by the nonavalent vaccine was 14.4%-23.8% for LSIL, and 19.0%-32.8% for HSIL. The benefit of the nonavalent vaccine compared to the quadrivalent vaccine was more than 80% for both low and high impact estimates for LSIL and more than 50% for both low and high impact estimates for HSIL. The present study confirms that the switch from a first generation HPV vaccines to a nonavalent vaccine would increase the prevention of cervical HSIL in up to 90% of cases.

Overview of the benefits and potential issues of the nonavalent HPV vaccine.

HPV-related diseases affect anogenital and oropharyngeal regions, heavily affecting the psychosexual dimension of both male and female individuals. HPV vaccination programs based on a bivalent or quadrivalent vaccine have opened broad perspectives for primary prevention. A nonavalent HPV vaccine (9vHPV), covering nine genotypes (HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58), might provide further improvement in terms of direct protection. In the present report, efficacy and safety data from 9vHPV vaccine development programs are examined. Efficacy data come from a pivotal trial, which was conducted among women aged 16-26 years randomly assigned to receive either the 9vHPV or the quadrivalent HPV (4vHPV) vaccine. The 9vHPV vaccine was shown to have potential benefits as compared with 4vHPV, increasing the overall estimated rate of prevention to 90% for cervical cancer and up to 80% for precancerous cervical lesions. For all other HPV-related pre-invasive and invasive lesions, 9vHPV showed potentially greater disease reduction, depending on the anatomic region examined. Thus, the 9vHPV vaccine shows clinical potential for the prevention of HPV-related diseases in both sexes. Future adoption of 9vHPV will depend on factors including market price, cost-effectiveness data, use of a two-dose schedule, and safety and efficacy monitoring in real-life programs.

Prospective sonographic detection of spina bifida at 11-14 weeks and systematic literature review.

OBJECTIVE: To conduct a literature review to assess the effectiveness of first trimester ultrasonographic markers of spina bifida (SB) integrating data with our prospective experience. METHODS: The analysis of the SB cases that we prospectively detected in the first trimester, between January 2012 and February 2014, and a systematic review of all the papers evaluating the effectiveness of SB ultrasonographic markers at 11-14 weeks, namely brain stem diameter (BS), fourth ventricle/intracranial translucency (IT), cisterna magna (CM), brain stem/occipital bone distance (BSOB), the ratio between BS and BSOB. Some studies assess only the effectiveness of IT, others include more parameters, and few include them all. RESULTS: We prospectively detected four SB cases, three open (OSB) and one closed (CSB), in a low risk population undergoing first trimester screening. In the three OSB, CM (in 2/3 cases) and BSOB (3/3) distance were below the 5th percentile, BS and BS/BSOB ratio (3/3) were above the 95th percentile. In the CSB, all the measurements were within normal limits. CONCLUSION: The literature and our data agree that most fetuses with OSB demonstrate in the first trimester positive sonographic markers in the posterior fossa, but additional prospective studies are needed to establish the best protocol for OSB screening.

Cold loops applied to bipolar resectoscope: A safe "one-step" myomectomy for treatment of submucosal myomas with intramural development.

AIM: To assess the safety and efficacy of cold loop myomectomy applied to bipolar resectoscope to perform "one-step" myomectomy of submucosal myomas with intramural involvement. METHODS: Seventy-two patients with at least one symptomatic G1 or G2 myoma (Wamsteker's classification) underwent cold loop myomectomy from January 2011 to January 2013. All surgical procedures were performed using a 26Fr resectoscope and bipolar energy source. At one month after the procedure, all patients underwent an office hysteroscopy check-up. A subgroup of seven infertile patients underwent an office hysteroscopy every two-weeks to evaluate recovery time of the myometrial fovea. RESULTS: Resectoscopic myomectomies were successfully performed in one surgical step in 70 out of 72 patients without any significant complications. Overall, the mean diameter of resected myomas was 32.2 ± 9 mm. Median operative time was 34.2 ± 24.1 min. Median fluid deficit was 761.22 ± 480.34 ml. The fovea was almost completely restored (>80%) six weeks after surgery in six of the seven infertile patients who underwent repeated follow-up office hysteroscopies every two weeks. CONCLUSIONS: Data from the present study show that the use of cold loops applied to bipolar resectoscope represent an effective, safe technique for "one-step" myomectomy of G1-G2 myomas, allowing rapid recovery of the myometrial fovea.

Hysteroscopy and treatment of uterine polyps.

This article summarizes and analyzes the salient topics on the diagnosis and management of endometrial polyps, focusing on the role of the hysteroscopy. Noninvasive investigations such as transvaginal ultrasonography, with or without the use of three-dimensional ultrasonography (3D US) and contrast techniques, remain the mainstay of first-line investigation. Hysteroscopic resection represents the gold standard minimally invasive treatment for endometrial polyps. It is the most effective management and allows histologic assessment, whereas blind biopsy or curettage have low diagnostic accuracy and should not be performed.

Use of trans-labial ultrasound in the diagnosis of female urethral diverticula: A diagnostic option to be strongly considered.

AIM: To demonstrate effectiveness of trans-labial ultrasound (TL-US) in the evaluation of female urethral diverticula (UD). METHODS: In the study period, 20 UD were diagnosed and treated. All data on demographic characteristics, presenting symptoms, physical examination findings, diagnostic and operative procedures, were considered. Patients were referred to TL-US for diverticular evaluation, using a 2D 7.5-MHz endfire probe. For each UD, size, complexity, echogenicity content, and presence of diverticular neck were considered. Follow-up controls were carried out at 1, 6 and 12 months after surgery, to evaluate outcome and need for further intervention. RESULTS: Mean patient age was 46 years (range, 35-55 years) and mean parity was 1 (range, 0-3). The principal symptoms associated with the diverticular mass was dysuria (25%). In all evaluated cases, UD was single (simple in 15 cases and complex in 5). The mean size of the diverticula was 28 mm (range, 8-50 mm). Nineteen diverticula were diagnosed on TL-US, and urethrocystoscopy was carried out for confirmation. Treatment consisted of diverticulectomy. At 1-, 6- and 12-month follow up after surgery, TL-US showed no recurrence of UD in any of the patients. CONCLUSIONS: TL-US is a valid, mini-invasive and reproducible method to diagnose UD.

Interstitial pregnancy: a 'road map' of surgical treatment based on a systematic review of the literature.

An electronic search concerning the surgical approach in cases of interstitial pregnancy from January 2000 to May 2013 has been carried out. Fifty three studies have been retrieved and included for statistical analysis. Conservative and radical surgical treatments in 354 cases of interstitial pregnancy are extensively described. Hemostatic techniques have been reported as well as clinical criteria for the medical approach. Surgical outcome in conservative versus radical treatment were similar. When hemostatic techniques were used, lower blood losses and lower operative times were recorded. Conversion to laparotomy involved difficulties in hemostasis and the presence of persistent or multiple adhesions. Laparoscopic injection of vasopressin into the myometrium below the cornual mass was the preferred approach.

Simplified first-trimester fetal cardiac screening (four chamber view and ventricular outflow tracts) in a low-risk population.

OBJECTIVES: Our aim was to assess the accuracy of a simplified fetal cardiac study, inclusive of four-chamber view (4CV) and ventricular outflow tracts, performed during the 11-14 week screening by well-trained obstetricians to detect congenital heart diseases (CHDs). METHODS: A transabdominal ultrasound was performed on 4820 singleton pregnant women at 11-14 weeks to visualize the visceral site, the 4CV, and the outflow tracts. Neonatal outcomes were recorded 6 and 12 months after birth. RESULTS: Among the 4820 patients reviewed, 790 were excluded because of loss at prenatal or postnatal follow-up (649 cases), or inability to obtain adequate first-trimester sonographic cardiac evaluation (141 cases). Among the 4030 included cases, 32 CHD cases were detected (20 major and 12 minor); 18 of the major (90%) and five of the minor (42%) were detected or suspected in the first trimester, one major and six minor in the second trimester, and one major and one minor only after birth. CONCLUSIONS: A simplified protocol is an effective tool to screen for CHD at 11-14 weeks.