Impact of assisted reproduction techniques on the neuro-psycho-motor outcome of newborns: a critical appraisal.

Subfertility and infertility are common problems among couples of reproductive age, and they increasingly require the use of assisted reproductive techniques (ART). Understandably, doubts about the safety of such methods are increasing among future parents. The purpose of this review is to analyse the real impact of ART, such as in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), on the health of the unborn baby; in particular, this work is focussed on the problems related to the neuro-psycho-motor area. Twenty-four studies were reviewed and outcomes investigated were: risk of the onset of neurodevelopmental diseases, worsening of school cognitive performance and risk of developing infantile cerebral palsy (CP) or neurological sequelae. For the first two outcomes, we did not find a correlation with ART; nevertheless, the results of the included studies about risk of CP are discordant and influenced by various confounding factors, such as pre-term birth and multiple pregnancies.IMPACT STATEMENTWhat is already known on this subject? Assisted reproductive techniques (ART) are the main answer for achieving pregnancy in infertile couples. However, a wide number of studies have tried to focus on possible different outcomes in terms of maternal and foetal/new-born health. Regarding this scenario, a peculiar importance is given to diseases affecting the neuro-psycho-motor area of the new-born. Since this group of detrimental pathologies could heavily affect the new-born's quality of life and require costly social facilities, different studies have tried to focus on possible outcomes after ART.What do the results of this study add? This manuscript provides a review of the literature regarding ART procedures and neuro-psycho-motor implication. A review is strongly required due to the importance of collecting evidence from studies with different methodologies.What are the implications of these findings for clinical practice and/or further research? This manuscript provides evidence about the need for wider and more congruent studies regarding neurodevelopment disorders in new-borns after ART procedures. Data are prone to suggest a slight correlation, but several confounding factors can heavily hamper the possibility to draw a firm conclusion about the topic.

Neonatal Outcomes and Long-Term Follow-Up of Children Born from Frozen Embryo, a Narrative Review of Latest Research Findings.

In recent years, the growing use of ART (assisted reproductive techniques) has led to a progressive improvement of protocols; embryo freezing is certainly one of the most important innovations. This technique is selectively offered as a tailored approach to reduce the incidence of multiple pregnancies and, most importantly, to lower the risk of developing ovarian hyperstimulation syndrome when used in conjunction with an ovulation-triggering GnRH antagonist. The increase in transfer cycles with frozen embryos made it possible to study the effects of the technique in children thus conceived. Particularly noteworthy is the increase in macrosomal and LGA (large for gestational age) newborns, in addition to a decrease in SGA (small for gestational age) and LBW (low birth weight) newborns. The authors aimed to outline a broad-ranging narrative review by summarizing and elaborating on the most important evidence regarding the neonatal outcome of children born from frozen embryos and provide information on the medium and long-term follow- up of these children. However, given the relatively recent large-scale implementation of such techniques, further studies are needed to provide more conclusive evidence on outcomes and implications.

Psychological variables in medically assisted reproduction: a systematic review.

Introduction: The paths of medically assisted reproduction represent the most important scientific progress to cope with the inability to achieve spontaneous conception (SC) and to reach desired parenthood. Couples undergoing assisted reproductive technology (ART) and couples not facing ovulation induction and artificial fertilization show sufficient levels of well-being and psychological adjustment. However, in some cases couples undergoing ART show lower perceived quality of life than couples with SC.Our aim is to investigate the main psychological variables involved in the special risk condition of medically assisted reproduction and how they could direct specific guidelines to enhance mental wellbeing in dealing with infertility. Material and methods: In this regard, we performed a systematic review following the PRISMA guidelines. From all the studies included, the considered outcome measures were psychological, social, and relational variables and are presented in a systematic approach. Results: A total of 14 studies were included in this article, according to our strict inclusion criteria. Conclusions: Conflicting results have been proven by this systematic review. Even though all underlined the importance of taking charge of the psychological variables in infertility, few studies monitored and evaluated the effectiveness of these interventions. Moreover, none of the selected studies monitored the evolutionary implications of parental competence on the development of children born from ART.

Fertility-Sparing Approach in Women Affected by Stage I and Low-Grade Endometrial Carcinoma: An Updated Overview.

Endometrial cancer (EC) is a deleterious condition which strongly affects a woman's quality of life. Although aggressive interventions should be considered to treat high-grade EC, a conservative approach should be taken into consideration for women wishing to conceive. In this scenario, we present an overview about the EC fertility-sparing approach state of art. Type I EC at low stage is the only histological type which can be addressed with a fertility-sparing approach. Moreover, no myometrium and/or adnexal invasion should be seen, and lymph-vascular space should not be involved. Regarding the pharmaceutical target, progestins, in particular medroxyprogesterone acetate (MPA) or megestrol acetate (MA), are the most employed agent in conservative treatment of early-stage EC. The metformin usage and hysteroscopic assessment is still under debate, despite promising results. Particularly strict and imperious attention should be given to the follow-up and psychological wellbeing of women, especially because of the double detrimental impairment: both EC and EC-related infertility consequences.

Gonadotrophin-releasing hormone analogue or dienogest plus estradiol valerate to prevent pain recurrence after laparoscopic surgery for endometriosis: a multi-center randomized trial.

OBJECTIVES: To evaluate the efficacy of dienogest + estradiol valerate (E2V) and gonadotrophin-releasing hormone analogue (GnRH-a) in reducing recurrence of pain in patients with chronic pelvic pain due to laparoscopically diagnosed and treated endometriosis. DESIGN: Multi-center, prospective, randomized study. SETTING: Three university departments of obstetrics and gynecology in Italy. POPULATION: Seventy-eight women who underwent laparoscopic surgery for endometriosis combined with chronic pelvic pain. METHODS: Post-operative administration of dienogest + E2V for 9 months (group 1) or GnRH-a monthly for 6 months (group 2). MAIN OUTCOME MEASURES: A visual analogue scale was used to test intensity of pain before laparoscopic surgery at 3, 6 and 9 months of follow up. A questionnaire to investigate quality of life was administered before surgery and at 9 months of follow up. RESULTS: The visual analogue scale score did not show any significant differences between the two groups (p = 0.417). The questionnaire showed an increase of scores for all women compared with pre-surgery values, demonstrating a marked improvement in quality of life and health-related satisfaction with both treatments. No significant differences were found between the groups. The rate of apparent endometriosis recurrence was 10.8% in group 1 and 13.7% in group 2 (p = 0.962). CONCLUSION: Both therapies seemed equally efficacious in preventing endometriosis-related chronic pelvic pain recurrence in the first 9 months of follow-up.

Long and fluctuating bone fragments in uterine isthmus: a curious feature of true osseous metaplasia.

Osseous metaplasia in the uterine cavity is a rare phenomenon arising from an unusual transformation of non-osseous connective tissue into mature bone. It is unclear how this alteration occurs and it has no single clinical manifestation. We report a case of asymptomatic endometrial osseous metaplasia of the isthmus with a singular picture: numerous long, floating bone-like structures in the cavity. The lesion was treated by operative hysteroscopy. Histological findings described a rare picture of true osseous metaplasia with the extraordinary presence of cells referable to areas of hematopoietic tissue in the cavities of trabecular bone. Physicians should be more informed and alert regarding this rare disorder in all its strange shapes and localizations, so as to be able to follow suitable therapy.

Adenomyotic cyst in a 25-year-old woman: case report.

Adenomyotic cysts are uncommon findings, usually in the context of diffuse adenomyosis and <5 mm in diameter. Herein we report a 4.5-cm adenomyotic cyst in a 25-year-old nulliparous woman with severe dysmenorrhea and pelvic pain. Transvaginal ultrasonography and magnetic resonance imaging revealed a well-circumscribed hypoechogenic mass in the posterior uterine wall, well separated from the uterine cavity. Pathologic analysis demonstrated that the cyst was lined with endometrial epithelium and stroma and was surrounded by smooth muscle hyperplasia. In the literature, we found 30 reports of cysts with similar characteristics. Because this cyst has not been clearly defined, it has been called by various names including adenomyotic cyst, cystic adenomyosis, and cystic adenomyoma. We believe this lesion should not be called an adenomyoma, but is more correctly called an adenomyotic cyst or, depending on age at onset, a juvenile adenomyotic cyst.

Oral contraceptives in the prevention of endometrioma recurrence: does the different progestins used make a difference?

OBJECTIVE: The primary aim of the study was to analyze the endometrioma recurrence rate in patients who underwent laparoscopic excision followed by postoperative long-term regimen of oral contraceptives (OCs). MATERIALS AND METHODS: 168 patients who underwent a conservative laparoscopic surgery for endometrioma, during the period between September 2009 and August 2010 in three university hospitals were studied. A long-term OCs therapy was offered to all women following surgery. Patients were randomly divided into three groups according to different progestins used (desogestrel, gestodene, dienogest). Women who refused a postoperative hormonal therapy served as control. Follow-up visits and transvaginal scan were planned at 1, 3, 6, 12, and 24 months after surgery. All patients who showed an ultrasound persistence of the endometrioma at 1 month follow-up were excluded from clinical analysis. RESULTS: Of the 168 patients, 131 completed the 24 months follow-up. Endometrioma recurrence was found in 21 (12.5 %) of all patients, it was unilateral in 17 cases while bilateral in 4 cases. The rate of recurrent endometrioma was statistically significant in non-users compared to the long-term OCs treated patients. CONCLUSION: The current data suggest the usefulness of long-term OCs regimen after conservative surgery for the prevention of ovarian endometrioma recurrence. As a statistical significant difference could not be observed between OCs groups, further study on the individual molecules is required in order to really understand the effect of each of them.

Colposcopy Accuracy and Diagnostic Performance: A Quality Control and Quality Assurance Survey in Italian Tertiary-Level Teaching and Academic Institutions-The Italian Society of Colposcopy and Cervico-Vaginal Pathology (SICPCV).

Quality Control (QC) and Quality Assurance (QA) principles are essential for effective cervical cancer prevention. Being a crucial diagnostic step, colposcopy's sensitivity and specificity improvements are strongly advocated worldwide since inter- and intra-observer differences are the main limiting factors. The objective of the present study was the evaluation of colposcopy accuracy through the results of a QC/QA assessment from a survey in Italian tertiary-level academic and teaching hospitals. A web-based, user-friendly platform based on 100 colposcopic digital images was forwarded to colposcopists with different levels of experience. Seventy-three participants were asked to identify colposcopic patterns, provide personal impressions, and indicate the correct clinical practice. The data were correlated with a panel of experts' evaluation and with the clinical/pathological data of the cases. Overall sensitivity and specificity with the threshold of CIN2+ accounted for 73.7% and 87.7%, respectively, with minor differences between senior and junior candidates. Identification and interpretation of colposcopic patterns showed full agreement with the experts' panel, ranging from 50% to 82%, in some instances with better results from junior colposcopists. Colposcopic impressions correlated with a 20% underestimation of CIN2+ lesions, with no differences linked to level of experience. Our results demonstrate the good diagnostic performance of colposcopy and the need for improving accuracy through QC assessments and adhesion to standard requirements and recommendations.

Attitudes of mothers of pre-adolescent girls on HPV vaccine in Italy. Do we need a turning point?

BACKGROUND: To investigate the knowledge, awareness and attitude of mothers of preadolescent girls regarding the HPV vaccination and cervical cancer, and to understand how to improve the efficacy of the Italian vaccination campaign through the gathered data. METHODS: A questionnaire-based survey was conducted in mothers of unvaccinated 9 to 12-year-old (yo) girls in Italy from November 2018 to July 2019, to evaluate their awareness and the attitude toward HPV, its vaccination and the information sources of the vaccination campaign. The selection of the distribution sites of the questionnaire was performed with randomization of 50 major places of aggregation located throughout the Italian territory. RESULTS: Three hundred mothers of unvaccinated girls were included in the study and divided into two groups (191 subjects <45yo, 109 subjects >45yo). Results showed that 79.6% of <45yo knew what HPV is, compared to 60.6% of >45yo (p-value <0.001); only 60.2% (<45yo) and 54.1% (>45yo) showed awareness about the HPV vaccine (p-value 0.03). The percentage of parents against vaccination in pre-adolescent was higher in the >45yo (29.4%); however, most of them appeared favorable to the information campaigns regarding the vaccine (p-value <0.001). CONCLUSIONS: Our study showed that mothers of unvaccinated pre-adolescent girls have suboptimal knowledge on the topic. Moreover, the implementation of communication strategies dedicated to the population segment appears as a central aspect. As HPV vaccination keeps being a public health concern, it is fundamental to understand which trigger should be managed by healthcare decision makers in order to boost the vaccination campaigns.

Vitamin D and Male Reproduction: Updated Evidence Based on Literature Review.

The purpose of this study was to clarify the vitamin D (VD) effect on male infertility. Our research was conducted using the following electronic databases: MEDLINE, Embase, Web of Science, Scopus, ClinicalTrials.gov, and Cochrane Library. Selection criteria included all published randomized controlled trials and non-randomized studies, focusing on vitamin D and male reproductive function. The results showed that the effects of VD on male reproduction has been investigated in three different topics: the molecular mechanism underlying VD effects on semen quality (SQ), the relationship between VD levels and SQ, and the effect of VD supplementation on SQ. Results supported the hypothesis of a relevant interrelation between concentrations of male VD and semen parameters, with particular reference to sperm motility; on the contrary, evidence on the effect of VD on male sex steroid hormone levels was inconclusive. The results of this review hold up the thesis that VD plays a role in male reproduction. Most of the data highlighted a positive effect on semen quality, particularly in sperm motility, both in fertile and infertile men. Additional dedicated studies are required to elucidate the still controversial aspects of this topic.

Potential impact of a nonavalent anti HPV vaccine in Italian men with and without clinical manifestations.

Human papilloma virus infection (HPV) is the most common sexually transmitted disease. Little is known about male infection. Nonavalent vaccine against types 6/11/16/18/31/33/45/52/58 was approved and neutral gender immunization programs have been proposed. This study evaluates the potential impact of nonavalent vaccine compared to quadrivalent in male living in Sicily (Italy). 58.7% of samples were HPV positive and forty-four types of HPV were identified. A significant higher estimated coverage of nonavalent vaccine than quadrivalent was observed (64.3% vs. 45.8%), with absolute and relative additional impact of 20.1% and 47.2%, respectively. Low impact of the vaccine were calculated as the empirical probability of HPV genotypes 6/11/16/18/31/33/45/52/58 alone or in combination; the high impact as empirical probability of HPV6/11/16/18/31/33/45/52/58 genotypes alone or in association with other genotypes. The potential impact of the nonavalent vaccine vs quadrivalent was significant for low and high impact (29.7% > 18:8%; 34:6% > 26.6%, respectively). Particularly, in men with lesions and risky sexual contact was significant only for low impact (35.5% > 29.7%; 31.4% > 19.7%, respectively). In partners with positive females was significant for low impact (26.3% > 15.1%) and high impact (33.7% > 23.2%). Nonavalent vaccine offers broader protection in men with HPV positive partners, who would have a potential role in the transmission of the infection.

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27-45 years of age compared to women 16-26 years of age: An open-label phase 3 study.

BACKGROUND: Efficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16-26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27-45 versus 16-26 years of age. METHODS: This international, open-label study (NCT03158220) was conducted in women 16-45 years of age. Participants (16-26 years, n = 570 and 27-45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study. RESULTS: At month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27-45 years were compared to those in women 16-26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27-45 years to 16-26 years) was 0.60-0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27-45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16-26 years, and 85.2% and 24.1% of women 27-45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study. CONCLUSIONS: The 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27-45 years compared with women 16-26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16-26 years to women 27-45 years of age. Clinical trial registration NCT03158220.

Endometriosis and strategies of fertility preservation: a systematic review of the literature.

Endometriosis is a common chronic inflammatory disorder, often causing both pain and infertility. It is estimated that 25-50 % of patients undergoing fertility treatments have had endometriosis as it involves an impairment of the ovarian reserve. For these reasons, endometriosis has been highlighted as a condition that may require a fertility preservation procedure, while being benign in nature. The aim of this review is to summarize the current evidence on fertility preservation techniques for patients affected by endometriosis, focusing on the main characteristics of the different approaches. A systematic review of literature was performed by searching in the main electronic databases (MEDLINE, EMBASE, Web of Science, Scopus, ClinicalTrial.gov, OVID and Cochrane Library), from their inception to February 2020 for studies testing fertility preservation (FP) techniques. Only scientific publications in English were included. Risk of Bias Assessment was performed. Eight articles were included in the study: 3 case reports (one paper reporting 2 cases), 1 prospective longitudinal analysis with only 1 reported case with criteria for inclusion in the review, 2 retrospective observational studies and 2 retrospective cohort studies. The results of our analysis showed embryo (1 article), oocyte (4 articles) and ovarian tissue cryopreservation (3 articles) as preservation methods proposed in international literature for patients with endometriosis. Only few authors reported details on successive outcomes. After ovarian tissue transplantation, 1 pregnancy with IVF and 1 case of endocrine function/ovulation recovery were described; six of 16 endometriotic patients, who underwent embryo cryopreservation, experienced livebirths after successive embryo-transfer; in a large series of 485 patients performing oocyte cryopreservation, an overall cumulative live-birth rate/patient of 46.4 % (225 babies) was reported. Based on the risk of premature ovarian failure related to endometriosis, the offer of FP techniques to these patients has significantly increased, as well as the reported experiences in recent medical literature. However, further studies concerning risks, benefits, effectiveness and cost-effectiveness are needed.

'Secondary prevention' against female HPV infection: literature review of the role of carrageenan.

Introduction: Human papillomaviruses (HPVs) are common sexually transmitted pathogens, causally associated with cervical cancer and other anogenital cancers, as well as approximately 20% of head and neck cancers. The HPV vaccine is an exceptional primary prevention tool, but the question of adequate secondary-prevention strategies remains open. The aim of this review is to better clarify the role of carrageenan in HPV prevention-strategies. Areas covered: A comprehensive literature search was performed (PubMed/MEDLINE, Embase, Google Scholar, Cochrane Databases) to identify articles on the use of carrageenan against HPV infection. The studies were identified using combinations of the search terms 'carrageenan,' 'papillomavirus,' 'HPV,' including only English language papers. Expert opinion: Our review data confirmed the 'inhibitory role' of carrageenan against HPV- pseudoviruses infection on different cell types. The most accredited mechanism to explain this effect involves the direct binding of CG to the viral capsid creating a 'physical' obstacle. However, a different susceptibility to carrageenan for different HPV types has been highlighted, suggesting the possibility of other strategies to infect the host. There are also relevant emerging data regarding the possible role of carrageenan as an adjuvant for antigen-specific immune responses and antitumor effects.

The Role of Hysteroscopy in the Diagnosis and Treatment of Adenomyosis.

Uterine adenomyosis is a common gynecologic disorder in women of reproductive age, characterized by the presence of ectopic endometrial glands and stroma within the myometrium. Dysmenorrhea, abnormal uterine bleeding, chronic pelvic pain, and deep dyspareunia are common symptoms of this pathological condition. However, adenomyosis is often an incidental finding in specimens obtained from hysterectomy or uterine biopsies. The recent evolution of diagnostic imaging techniques, such as transvaginal sonography, hysterosalpingography, and magnetic resonance imaging, has contributed to improving accuracy in the identification of this pathology. Hysteroscopy offers the advantage of direct visualization of the uterine cavity while giving the option of collecting histological biopsy samples under visual control. Hysteroscopy is not a first-line treatment approach for adenomyosis and it represents a viable option only in selected cases of focal or diffuse "superficial" forms. During office hysteroscopy, it is possible to enucleate superficial focal adenomyomas or to evacuate cystic haemorrhagic lesions of less than 1.5 cm in diameter. Instead, resectoscopic treatment is indicated in cases of superficial adenomyotic nodules > 1.5 cm in size and for diffuse superficial adenomyosis. Finally, endometrial ablation may be performed with the additional removal of the underlying myometrium.

Outcomes of monopolar versus bipolar endometrial ablation on uterine bleeding and psychophysical wellbeing.

BACKGROUND: To compare outcomes of endometrial ablation with monopolar versus bipolar resection on uterine bleeding and psychophysical wellbeing. METHODS: In a prospective randomized study, 100 perimenopausal patients, without desire of pregnancy and with no response to pharmacological treatment, underwent endometrial ablation from 2012 to 2014. They were randomly divided in two groups: 50 patients treated with monopolar electrode resection loop (group A) and 50 patients treated with bipolar electrode resection loop (group B). Operative parameters were immediately assessed. Menstrual outcome parameters and psycho-physical well-being parameters were evaluated after 12 months. RESULTS: No significant difference in operating time was recorded between the two groups. No serious hysteroscopic complication occurred with a similar immediate cumulative complication rate but two cases of intravasation were recorded in group A. The late cumulative complication rate was higher in group A than group B (44% vs. 24%). Cycle was overall controlled in over the 80% of the cases in the two groups without significant difference. The analysis of Short Form-36 showed an improvement of all assessed items after the endometrial ablation without significant difference. CONCLUSIONS: Hysteroscopic endometrial ablation performed with bipolar loop electrode is as effective as resectoscopy with unipolar loop electrode regarding menstrual and psychophysical wellbeing outcomes. Endometrial ablation with bipolar electrode loop is safer but more expansive than monopolar electrode loop.