Treatment of Uterine Fibroid Symptoms with Relugolix Combination Therapy.

BACKGROUND: Uterine fibroids are a common cause of heavy menstrual bleeding and pain. Treatment with the combination of relugolix (an oral gonadotropin-releasing hormone-receptor antagonist), estradiol, and norethindrone acetate, administered once daily, may have efficacy in women with uterine fibroids and heavy bleeding while avoiding hypoestrogenic effects. METHODS: We conducted two replicate international, double-blind, 24-week, phase 3 trials involving women with fibroid-associated heavy menstrual bleeding. Participants were randomly assigned in a 1:1:1 ratio to receive once-daily placebo, relugolix combination therapy (40 mg of relugolix, 1 mg of estradiol, and 0.5 mg of norethindrone acetate), or delayed relugolix combination therapy (40 mg of relugolix monotherapy, followed by relugolix combination therapy, each for 12 weeks). The primary efficacy end point in each trial was the percentage of participants with a response (volume of menstrual blood loss <80 ml and a ≥50% reduction in volume from baseline) in the relugolix combination therapy group, as compared with the placebo group. Key secondary end points were amenorrhea, volume of menstrual blood loss, distress from bleeding and pelvic discomfort, anemia, pain, fibroid volume, and uterine volume. Safety and bone mineral density were assessed. RESULTS: A total of 388 women in trial L1 and 382 in trial L2 underwent randomization. A total of 73% of the participants in the relugolix combination therapy group in trial L1 and 71% of those in trial L2 had a response (primary end point), as compared with 19% and 15%, respectively, of those in the placebo groups (P<0.001 for both comparisons). Both relugolix combination therapy groups had significant improvements, as compared with the placebo groups, in six of seven key secondary end points, including measures of menstrual blood loss (including amenorrhea), pain, distress from bleeding and pelvic discomfort, anemia, and uterine volume, but not fibroid volume. The incidence of adverse events was similar with relugolix combination therapy and placebo. Bone mineral density was similar with relugolix combination therapy and placebo but decreased with relugolix monotherapy. CONCLUSIONS: Once-daily relugolix combination therapy resulted in a significant reduction in menstrual bleeding, as compared with placebo, and preserved bone mineral density in women with uterine fibroids. (Funded by Myovant Sciences; LIBERTY 1 [L1] and LIBERTY 2 [L2] ClinicalTrials.gov numbers, NCT03049735 and NCT03103087, respectively.).

Female fertility preservation for family planning: a position statement of the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR).

PURPOSE: This position statement by the Italian Society of Fertility and Sterility and Reproductive Medicine (SIFES-MR) aims to establish an optimal framework for fertility preservation outside the standard before oncological therapies. Key topics include the role of fertility units in comprehensive fertility assessment, factors impacting ovarian potential, available preservation methods, and appropriate criteria for offering such interventions. METHODS: The SIFES-MR writing group comprises Italian reproductive physicians, embryologists, and scientists. The consensus emerged after a six-month period of meetings, including extensive literature review, dialogue among authors and input from society members. Final approval was granted by the SIFES-MR governing council. RESULTS: Fertility counselling transitions from urgent to long-term care, emphasizing family planning. Age, along with ovarian reserve markers, is the primary predictor of female fertility. Various factors, including gynecological conditions, autoimmune disorders, and prior gonadotoxic therapies, may impact ovarian reserve. Oocyte cryopreservation should be the preferred method. Women 30-34 years old and 35-39 years old, without known pathologies impacting the ovarian reserve, should cryopreserve at least 12-13 and 15-20 oocytes to achieve the same chance of a spontaneous live birth they would have if they tried to conceive at the age of cryopreservation (63% and 52%, respectively in the two age groups). CONCLUSIONS: Optimal fertility counselling necessitates a long-term approach, that nurtures an understanding of fertility, facilitates timely evaluation of factors that may affect fertility, and explores fertility preservation choices at opportune intervals.

Efficacy of a Triticum vulgare Extract as a Treatment of Cervical Ectropion: A Prospective Observational Cohort Study.

OBJECTIVES: To assess the effectiveness of a topical treatment for cervical ectropion with vaginal ovules containing aqueous extract of Triticum vulgare . METHODS: Prospective observational cohort study conducted between November 2020 and November 2022 at the colposcopy clinics of 2 different hospitals. Sexually active patients with a colposcopic diagnosis of cervical ectropion, awaiting ablative procedure, were included in the study and prescribed medical therapy with vaginal T. vulgare ovules (group 1) or wait-and-see therapy (group 2). At both enrollment and 2-month follow-up, a symptomatologic evaluation recording the intensity of postcoital bleeding, leucorrhea, and dyspareunia was performed with a Visual Analog Scale (VAS) questionnaire, and a colposcopic examination was performed, calculating the size of the ectropion area. RESULTS: A total of 116 patients (58 in group 1 and 58 in group 2) were included. Topical treatment with vaginal ovules containing aqueous extract of T. vulgare for 2 months resulted in significant decrease of symptoms related to cervical ectropion and significant reduction of the size of the ectropion area. CONCLUSIONS: Our results support the efficacy of topical treatment with vaginal ovules containing aqueous extract of T. vulgare for symptomatic cervical ectropion; our study also suggests that expectant management, despite being widely practiced, seems to lead to a worsening of the natural history of ectropion.

LIBERTY randomized withdrawal study: relugolix combination therapy for heavy menstrual bleeding associated with uterine fibroids.

BACKGROUND: In the pivotal LIBERTY 1 and 2 trials and long-term extension study, once-daily relugolix combination therapy (40 mg relugolix, 1 mg estradiol, 0.5 mg norethindrone acetate) reduced menstrual blood loss volume and pain among women with uterine fibroids. Relugolix combination therapy was well tolerated with preservation of bone mineral density through 52 weeks. OBJECTIVE: This study aimed to report the 2-year relugolix combination therapy efficacy and safety results of the phase 3 LIBERTY randomized withdrawal study. STUDY DESIGN: Women with uterine fibroid-associated heavy menstrual bleeding who completed the 24-week LIBERTY 1 or 2 trials, followed by the 28-week long-term extension study (up to 52 weeks total treatment), and who met the responder criteria (menstrual blood loss volume <80 mL and ≥50% reduction from pivotal study baseline at week 48 [week 24 of long-term extension]) were randomized in a 1:1 ratio to either blinded treatment with relugolix combination therapy or placebo for 52 weeks (total treatment period, 104 weeks). For women who had a relapse of heavy menstrual bleeding during the study (menstrual blood loss volume ≥80 mL), open-label relugolix combination therapy was offered. The primary endpoint was the proportion of women who maintained menstrual blood loss volume <80 mL through week 76 (week 24 of randomized withdrawal study). Secondary endpoints included time to menstrual blood loss volume ≥80 mL, proportion of women who maintained a menstrual blood loss volume of <80 mL through week 104 (over the 52-week randomized treatment period), the proportion of women who achieved or maintained amenorrhea at week 76 at the end of treatment, and the change in Uterine Fibroid Symptom-Quality of Life Bleeding and Pelvic Discomfort Scale and symptom severity scores. Analyses were performed for the modified intent-to-treat population, including all randomized women who received ≥1 dose of the study drug. RESULTS: Of the 229 randomized women (relugolix combination therapy, n=115; placebo, n=114), 228 received the study drug and 175 (76.7%) completed the randomized withdrawal study. Through week 76, 78.4% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 15.1% in the placebo group (difference, 63.4%; 95% confidence interval, 52.9%-73.9%; P<.0001). At week 104, 69.8% of women on relugolix combination therapy maintained menstrual blood loss volume <80 mL vs 11.8% in the placebo group (difference, 58.0%; 95% confidence interval, 47.0%-69.1%; P<.0001). Through week 104, 88.3% of women on placebo relapsed with heavy menstrual bleeding (median time to relapse, 5.9 weeks). Among the 89 women in the placebo group who relapsed and received open-label rescue treatment, 87 women responded to relugolix combination therapy with a menstrual blood loss volume <80 mL. The proportion of women who achieved or maintained amenorrhea were 57.4% vs 13.3% at week 76 (difference, 44.1%; 95% confidence interval, 33.10%-55.1%; P<.0001) and 58.3% vs 10.6% at week 104 (difference, 47.6%; 95% confidence interval, 37.0%-58.3%; nominal P<.0001) for relugolix combination therapy and the placebo group, respectively. Relugolix combination therapy was generally well tolerated; no new safety signals were identified, and the adverse event profile over the second year was consistent with that reported through the first year of treatment. Bone mineral density remained stable in women who received relugolix combination therapy from week 52 to week 104. In women continuously treated with relugolix combination therapy up to 2 years, bone mineral density was generally preserved. CONCLUSION: After 2 years of treatment with relugolix combination therapy, there was evidence of durability of the effect in maintaining low menstrual blood loss volume in women with symptomatic uterine fibroids. Most women had return of heavy menstrual bleeding and associated symptoms after treatment cessation, which improved upon retreatment with relugolix combination therapy. Relugolix combination therapy was well tolerated, the adverse event profile remained consistent, and the mean bone mineral density was generally preserved through 2 years of treatment.

Quality of life with relugolix combination therapy for uterine fibroids: LIBERTY randomized trials.

BACKGROUND: Symptomatic uterine fibroids are burdensome to live with; they are associated with symptom-related distress, affect daily activities, and reduce health-related quality of life. The LIBERTY randomized clinical trials showed that oral relugolix combination therapy (40 mg relugolix, 1 mg estradiol, and 0.5 mg norethindrone acetate once daily) markedly improved fibroid-associated symptoms and conditions, including heavy menstrual bleeding, pain, and anemia, and was well-tolerated. OBJECTIVE: This study aimed to evaluate the effect of relugolix combination therapy on the symptom burden and health-related quality of life among women with uterine fibroids. STUDY DESIGN: Two replicate, multinational, double-blind, 24-week, randomized, placebo-controlled, phase 3 studies, LIBERTY 1 and LIBERTY 2, were conducted in premenopausal women with uterine fibroid-associated heavy menstrual bleeding (≥80 mL per cycle for 2 cycles or ≥160 mL during 1 cycle). The symptom burden and health-related quality of life were secondary endpoints and were assessed using the validated Uterine Fibroid Symptom and Quality of Life questionnaire, which the participants completed at baseline and at week 12 and 24 of treatment. For this secondary analysis, the pooled LIBERTY 1 and LIBERTY 2 data set was used. The Uterine Fibroid Symptom and Quality of Life questionnaire is made up of a Symptom Severity scale and a Health-Related Quality of Life scale, the latter of which includes 6 subscales focusing on the following aspects of daily life: concern, activities, energy or mood, control, self-consciousness, and sexual function. The Revised Activities subscale of the Health-Related Quality of Life scale addresses the impact of uterine fibroids on physical and social activities. Symptom burden was also assessed via the Bleeding and Pelvic Discomfort subscale, a patient-reported outcome measure derived from the Uterine Fibroid Symptom Severity scale that focuses on distress from key uterine fibroid symptoms, which was a key secondary endpoint. Least squares mean changes from baseline to week 24 in the Symptom Severity scale, Bleeding and Pelvic Discomfort subscale, overall Health-Related Quality of Life scale, and the respective subscales were compared between the relugolix combination therapy and placebo groups. Responder analyses of the proportion of women who experienced a clinically meaningful change from baseline to week 24 were conducted for the Bleeding and Pelvic Discomfort and the activity subscales. A stratified Cochran-Mantel-Haenszel test, adjusted for stratification factors (region [North America vs rest of world] and baseline menstrual blood loss volume), was used for treatment comparisons. RESULTS: Across both trials, 509 women were randomized to the relugolix combination therapy or placebo groups (April 2017-December 2018). Participants on relugolix combination therapy showed a statistically significant reduction in symptom severity (-33.5 vs -12.1; nominal P<.0001) and the Bleeding and Pelvic Discomfort subscale from baseline to week 24 when compared with those on placebo treatment (-48.4 vs -17.4; nominal P<.0001). Overall, the total Health-Related Quality of Life scores improved significantly from baseline to week 24 in the relugolix combination therapy group when compared with the placebo (+37.6 vs +13.1; nominal P<.0001). Responder analyses demonstrated that more women treated with relugolix combination therapy reported a clinically meaningful reduction in the Bleeding and Pelvic Discomfort subscale and an improvement in physical and social activities when compared with those treated with the placebo (nominal P<.0001). CONCLUSION: After 24 weeks of treatment with relugolix combination therapy, women with symptomatic uterine fibroids experienced substantial improvements in health-related quality of life with all subscales showing improvement, including emotional well-being, physical and social activities, and sexual function. In addition, women reported substantial reductions in the overall symptom burden and distress caused by key fibroid-associated symptoms.

Relugolix combination therapy in European women with symptomatic uterine fibroids: a subgroup analysis from the randomized phase 3 LIBERTY pivotal trials.

OBJECTIVE: In the 24-week, phase 3 LIBERTY 1 (L1) and LIBERTY 2 (L2) trials, relugolix combination therapy (relugolix-CT (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0.5 mg)) reduced uterine fibroid (UF)-associated symptoms. This post hoc analysis assessed safety and efficacy of relugolix-CT in European women from L1/L2. METHODS: Premenopausal women (aged 18-50 years) with UF-associated heavy menstrual bleeding (HMB) were randomized 1:1:1 in L1 (N = 388) and L2 (N = 382) to relugolix-CT or placebo for 24 weeks, or delayed relugolix-CT (relugolix 40 mg then relugolix-CT; 12 weeks each). Primary endpoint: proportion of responders (menstrual blood loss (MBL) <80 mL and reduction of ≥50% from baseline MBL volume) over the last 35 days of treatment. Secondary endpoints: MBL volume, amenorrhea, UF-associated pain, symptom severity, distress related to bleeding and pelvic discomfort, health-related quality of life (HRQoL). Safety endpoints included adverse event (AE) reporting and bone mineral density (BMD) assessment. RESULTS: In European women from L1/L2 (N = 124, 16%), a significantly greater proportion of treatment responders was observed with relugolix-CT vs. placebo (85.4% vs. 19.1%, respectively; nominal p < .0001). There were statistically significant improvements with relugolix-CT vs. placebo for several secondary endpoints: reduction in MBL volume, amenorrhea rate, proportion achieving mild-to-no pain, reduction in symptom severity and distress from bleeding and pelvic discomfort, and improvement in HRQoL. Incidence of AEs and percentage changes in BMD from baseline to week 24 were similar for relugolix-CT and placebo. CONCLUSIONS: In European women with UF and HMB, once-daily relugolix-CT vs. placebo improved UF-associated symptoms and preserved BMD.

[The EASY-NET research programme: background, structure, and methodology]. / Il programma di rete EASY-NET: razionale, struttura e metodologie.

This is the first contribution of a series of interventions describing the EASY-NET research program (Bando Ricerca Finalizzata 2016, funds 2014-2015; NET-2016-02364191). Here, the objective is to illustrate the background and the research question, the structure and organization, the methodologies and the expected results of the programme. The main theme is audit&feedback (A&F), a proven and widespread technique for improving the quality of health care. EASY-NET, funded by the Italian Ministry of Health and by the governments of the participating Italian Regions, starts its research activities in 2019 with the aim of evaluating the effectiveness of A&F in improving care for different clinical conditions in various organizational and legislative contexts. The research network involves seven Italian Regions, each conducting specific research activities described by as many work packages (WP): Lazio (the leading Region, coordinator of the research activities), Friuli Venezia Giulia, Piedmont, Lombardy, Emilia-Romagna, Calabria, and Sicily. The involved clinical areas include the management of chronic diseases, emergency care for acute conditions, surgery in the oncological area, the treatment of heart disease, obstetrics, and the use of caesarean section and post-acute rehabilitation. The involved settings concern the community, the hospital, the emergency room, and the rehabilitation facilities. Different experimental or quasi-experimental study designs are applied in each WP to achieve specific objectives of the specific clinical and organizational context. In all WPs, the process and outcome indicators are calculated on the basis of the Health Information Systems (HIS) and, in some cases, they are integrated with measures obtained from ad hoc data collections. The programme aims to contribute to the scientific evidence on A&F also exploring the obstacles and favourable factors for its effectiveness and to promote its implementation in the health service, with the ultimate aim of improving the access to healthcare and the health outcomes for citizens.

[How to optimize Audit&Feedback: experience from the EASY-NET programme]. / Come rendere più efficace l'Audit&Feedback: riflessioni dal programma di rete EASY-NET.

This is the second of a series of papers dedicated to the EASY-NET research programme (NET-2016-02364191). The rationale, structure and methodologies are described in the previous contribution. Scientific literature demonstrated that Audit & Feedback (A&F) is an effective strategy for continuous quality improvement and its effectiveness varies considerably according to factors that are currently little known. Some recent publication pointed out, with the contribution of an international group of experts, 15 suggestions to optimize A&F and developed a tool to evaluate their application. This tool, called REFLECT-52, includes 52 items related to the 15 suggestions and organized into four categories relating to the "Nature of the desired action", to the "Nature of the data available for feedback", to the "Feedback Display" and to the "Intervention delivery". Then, the aim of this work was to evaluate the level of adherence of A&F interventions tested in EASY-NET to suggestions from the literature by using a slightly adapted version of the REFLECT-52 tool, in its original language. In EASY-NET, 14 A&F interventions with different characteristics and in different clinical and organizational contexts were tested in seven Italian regions, each of these was evaluated by the respective research groups. Overall, the level of adherence was high in three of the four categories analysed, with some difficulties reported regarding the nature of the data available for feedback. In fact, contrary to what the literature suggests, it was not possible to send repeated feedback for some interventions and, in some cases, the data available for feedback presented a delay longer than one year. In summary, this analysis has confirmed a high level of compliance of the interventions tested with the suggestions from the literature, but it has also allowed researchers to identify critical aspects that need to be addressed for the future development of these strategies.

Perinatal and obstetric outcomes in singleton pregnancies following fresh versus cryopreserved blastocyst transfer: a meta-analysis.

The transfer of cryopreserved blastocysts is increasing in IVF centres. However, little is known about the perinatal and obstetric outcomes of this procedure. In an attempt to further elucidate these issues, a systematic review and meta-analysis was conducted to compare cryopreserved transfer with fresh blastocyst embryo transfer. The results show that the risk of both preterm (odds ratio [OR] 0.89, 95% confidence interval [CI] 0.80-0.99, P = 0.04) and low birthweight births (OR 0.82, 95% CI 0.68-0.99, P = 0.04) was significantly lower after cryopreserved blastocyst transfer than after fresh blastocyst transfer. The rate of large for gestational age births was significantly higher (OR 1.68, 95% CI 1.55-1.82, P < 0.00001) and the rate of small for gestational age births significantly lower (OR 0.59, 95% CI 0.54-0.65, P < 0.00001) after cryopreserved blastocyst transfer. The transfer of cryopreserved blastocysts was associated with a significantly lower risk of placental abruption (OR 0.58, 95% CI 0.40-0.83, P = 0.003) but a significantly higher risk of Caesarean section (OR 1.21, 95% CI 1.01-1.43, P = 0.03). In conclusion, the perinatal and obstetric outcomes associated with the transfer of cryopreserved blastocysts differ from those associated with fresh blastocyst transfer.

Awareness of gestational diabetes mellitus foetal-maternal risks: an Italian cohort study on pregnant women.

BACKGROUND: Gestational diabetes mellitus (GDM) incidence is increasing worldwide. It represents a major risk factor for adverse foetal-maternal outcomes. Awareness among women in regard to GDM-related risks (in particular foetus ones) has been proven to have an impact on compliance with recommendations. Therefore we aimed to evaluate the efficacy of our post-diagnosis counselling, that informs affected women of the GDM related risks for complications, in determining an adequate level of understanding. METHOD: This is a cohort study involving 400 women undergoing the 24-28 weeks 75 g oral glucose tolerance test. Two hundred women diagnosed with GDM received the post-diagnosis counselling (treatment group) and two hundred women diagnosed without did not receive any counselling (control group). Both populations were surveyed with a 5 question questionnaire regarding their awareness about GDM foetal-maternal related risks. Their level of education about GDM foetal-maternal related risks, estimated according to the number of correct answers, was scored as: primary (score 0-1), secondary (score 2-3) or tertiary (score 4-5). RESULTS: Most of the women in the treatment group after receiving the post-diagnosis counselling have demonstrated a secondary level of education 132/200 (66%). Their mean level of awareness was higher in comparison to the control group 2.6 ± 1.8 (SD) versus 2.14 ± 1.8 (SD) p value = 0.012. In particular, they've demonstrated to be more aware of the risks for the foetus to become macrosomic (p = 0.004) or to die in utero (p = 0.0001). A high level of education and to have had previous pregnancies positively affected correct answers. CONCLUSIONS: Our post-diagnosis counselling has played a role in improving women awareness about GDM foetal-maternal related risks. Future study will explore the impact of women's level of awareness on glycaemic control.

Prenatal tests for chromosomal abnormalities detection (PTCAD): pregnant women's knowledge in an Italian Population.

BACKGROUND: Nowadays several Prenatal Tests for Chromosomal Abnormalities Detection (PTCAD) are available. In those cases in which there is not an Institutional protocol to advise women about the available PTCAD, the choice of which one to undergo is up to the woman and largely depends on her knowledge about them. Therefore, we decided to evaluate, as a primary outcome, knowledge about PTCAD among pregnant women attending our Term Clinic. As a secondary outcome we evaluated the relationship between the patient's knowledge and the subsequently chosen PTCAD. METHODS: From August 2017 to August 2018 an anonymous questionnaire with multiple-choice answers was administered to all pregnant women attending our Term antenatal Clinic, a tertiary obstetric unit in Catanzaro (Italy). RESULTS: Three hundred and twenty-five pregnant women were enrolled in the study. We observed that 28.8% of the pregnant women that chose one of the PTCAD, avoided the first trimester combined screening test; among these, 11.4% were in favour of the cell-free foetal DNA test. The latter was erroneously considered diagnostic by 34.3% of the women that had chosen it. CONCLUSIONS: This study demonstrated that women's knowledge about PTCAD is poor and that there is a potentially dangerous confusion between the words 'screening' and 'diagnostic'. Informative campaigns about PTCAD and the application of dedicated antenatal counselling appointments should be a health-care priority to avoid unnecessary risks and costs for pregnant women and possible legal issues.

In-bag manual versus uncontained power morcellation for laparoscopic myomectomy.

BACKGROUND: Uterine leiomyomas, also referred to as myomas or fibroids, are benign tumours arising from the smooth muscle cells of the myometrium. They are the most common pelvic tumour in women. The estimated rate of leiomyosarcoma, found during surgery for presumed benign leiomyomas, is about 0.51 per 1000 procedures, or approximately 1 in 2000. Treatment options for symptomatic uterine leiomyomas include medical, surgical, and radiologically-guided interventions. Laparoscopic myomectomy is the gold standard surgical approach for women who want offspring, or otherwise wish to retain their uterus. A limitation of laparoscopy is the inability to remove large specimens from the abdominal cavity through the laparoscope. To overcome this challenge, the morcellation approach was developed, during which larger specimens are broken into smaller pieces in order to remove them from the abdominal cavity via the port site. However, intracorporeal power morcellation may lead to scattering of benign tissues, with the risk of spreading leiomyoma or endometriosis. In cases of unsuspected malignancy, power morcellation can cause unintentional dissemination of malignant cells, and lead to a poorer prognosis by upstaging the occult cancer. A strategy to optimise women's safety is to morcellate the specimens inside a bag. In-bag morcellation may avoid the dissemination of tissue fragments. OBJECTIVES: To evaluate the effectiveness and safety of protected in-bag extracorporeal manual morcellation during laparoscopic myomectomy compared to intra-abdominal uncontained power morcellation. SEARCH METHODS: On 1 July 2019, we searched; the Cochrane Gynaecology and Fertility Group Specialized Register of Controlled Trials, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, PubMed, Google Scholar, and two trials registers. We reviewed the reference lists of all retrieved full-text articles, and contacted experts in the field for additional and ongoing trials. SELECTION CRITERIA: We included all randomised controlled trials comparing in-bag extracorporeal manual morcellation versus intracorporeal uncontained power morcellation during laparoscopic myomectomy in premenopausal women. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. Two review authors independently reviewed the eligibility of trials, extracted data, and evaluated the risk of bias. Data were checked for accuracy. The summary measures were reported as risk ratios (RR) or mean differences (MD) with 95% confidence interval (CI). The outcomes of interest were a composite of intraoperative and postoperative complications, operative times, ease of morcellation, length of hospital stay, postoperative pain, conversion to laparotomy, and postoperative diagnosis of leiomyosarcoma. Results for the five main outcomes follow. MAIN RESULTS: We included two trials, enrolling 176 premenopausal women with fibroids, who underwent laparoscopic myomectomy. The experimental group received in-bag manual morcellation, during which each enucleated myoma was placed into a specimen retrieval bag, and manually morcellated with scalpel or scissors. In the control group, intracorporeal uncontained power morcellation was used to reduce the size of the myomas. No intraoperative complications, including accidental morcellation of the liver, conversion to laparotomy, endoscopic bag disruption, bowel injury, bleeding, accidental injury to any viscus or vessel, were reported in either group in either trial. We found very low-quality evidence of inconclusive results for total operative time (MD 9.93 minutes, 95% CI -1.35 to 21.20; 2 studies, 176 participants; I² = 35%), and ease of morcellation (MD -0.73 points, 95% CI -1.64 to 0.18; 1 study, 104 participants). The morcellation operative time was a little longer for the in-bag manual morcellation group, however the quality of the evidence was very low (MD 2.59 minutes, 95% CI 0.45 to 4.72; 2 studies, 176 participants; I² = 0%). There were no postoperative diagnoses of leiomyosarcoma made in either group in either trial. We are very uncertain of any of these results. We downgraded the quality of the evidence due to indirectness and imprecision, because of limited sites in high-income settings and countries, small sample sizes, wide confidence intervals, and few events. AUTHORS' CONCLUSIONS: There are limited data on the effectiveness and safety of in-bag morcellation at the time of laparoscopic myomectomy compared to uncontained power morcellation. We were unable to determine the effects of in-bag morcellation on intraoperative complications as no events were reported in either group. We are uncertain if in-bag morcellation improves total operative time or ease of morcellation compared to control. Regarding morcellation operative time, the quality of the evidence was also very low and we cannot be certain of the effect of in-bag morcellation compared to uncontained morcellation. No cases of postoperative diagnosis of leiomyosarcoma occurred in either group. We found only two trials comparing in-bag extracorporeal manual morcellation to intracorporeal uncontained power morcellation at the time of laparoscopic myomectomy. Both trials had morcellation operative time as primary outcome and were not powered for uncommon outcomes such as intraoperative complications, and postoperative diagnosis of leiomyosarcoma. Large, well-planned and executed trials are needed.

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6±9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; p<0.001), birthweight (OR: 1.17, 95% CI 1.09-1.12.7 per 100 g decrease; p=0.012) and maternal ventilatory support, including either need for oxygen or CPAP (OR: 4.12, 95% CI 2.3-7.9; p=0.001) were independently associated with composite adverse fetal outcome. Conclusions Early gestational age at infection, maternal ventilatory supports and low birthweight are the main determinants of adverse perinatal outcomes in fetuses with maternal COVID-19 infection. Conversely, the risk of vertical transmission seems negligible.

Similar miRNomic signatures characterize the follicular fluids collected after follicular and luteal phase stimulations in the same ovarian cycle.

PURPOSE: To detect putative differences in the miRNomic profile of follicular fluids collected after follicular-phase-stimulation (FPS-FFs) and paired luteal-phase-stimulation (LPS-FFs) in the same ovarian cycles (DuoStim). METHODS: Exploratory study at a private IVF center and University involving FPS-FFs and paired-LPS-FFs collected from 15 reduced ovarian reserve and advanced maternal age women undergoing DuoStim (n = 30 paired samples). The samples were combined in 6 paired pools (5 samples each) and balanced according to maternal age and number of cumulus-oocyte-complexes. Micro-RNAs were isolated and sequenced. Four miRNAs were then selected for further validation on 6 single pairs of FPS-FFs and LPS-FFs by qPCR. RESULTS: Forty-three miRNAs were detected in both FPS-FFs and paired-LPS-FFs after sequencing and no statistically significant differences were reported. Thirty-three KEGG pathways were identified as regulated from the detected miRNAs. Four miRNAs (miR-146b, miR-191, miR-320a, and miR-483) were selected for qPCR validation since consistently expressed in our samples and possibly involved in the regulation/establishment of a healthy follicular environment. Again, no significant differences were reported between FPS-FFs and paired-LPS-FFs, also when the analysis was corrected for maternal age and number of cumulus-oocyte-complexes in generalized linear models. CONCLUSIONS: These data complement the embryological, chromosomal, and clinical evidence of equivalence between FPS and LPS published to date.

State of the art and emerging drug therapies for female infertility.

At present, infertility is a key-issue. When applicable, in vitro fertilization (IVF) has become the standard approach to treat this condition but a thorough investigation and, whenever possible, the individual diagnosis of the underlying causes of infertility are required. For many female causes, indeed, efficient medical therapies are available to achieve a fast solution of the problem. This review is based on the relevant literature indexed in PubMed and SCOPUS and is focused on the most recent clinical literature on the treatment of women (and couples) affected from infertility. The reduction in IVF treatment burden and risks are now considered pivotal to set 'patient-friendly' therapies and represent crucial issues for both patients and physicians. To this end, the researchers are now focusing their attention on old drugs with new indications and new compounds with more appropriate functions, to improve the compliance of the women and reduce the burden of infertility, a condition that is becoming an important issue in the modern world, also for the Public Health System.

Subcutaneous Progesterone for Endometrial Polyps in Premenopausal Women: A Preliminary Retrospective Analysis.

STUDY OBJECTIVE: To investigate the effects of 3 cycles of subcutaneous progesterone administered during the luteal phase on the regression rate of symptomatic and asymptomatic endometrial polyps in premenopausal woman. DESIGN: A retrospective study (Canadian Task Force classification II-2). SETTING: A department of obstetrics and gynecology in a university hospital. PATIENTS: One hundred twenty-seven reproductive-aged women presented with endometrial polyps from January to December 2016. INTERVENTIONS: A retrospective comparison of patients treated with subcutaneous progesterone and those managed by the "wait and see" approach. MEASUREMENTS AND MAIN RESULTS: Patients were divided into 2 groups: the group treated with subcutaneous progesterone (cases) and the wait and see group (controls). Women in the treatment group were administered 25 mg subcutaneous progesterone during the luteal phase for 7 days for 3 months. The wait and see group included patients refusing progesterone therapy who were reevaluated 3 menstrual cycles after the transvaginal sonographic diagnosis. Both the treatment group (n = 61) and the wait and see group (n = 32) were evaluated with a follow-up ultrasound examination after 3 months. The regression rate of endometrial polyps in women treated with subcutaneous progesterone was compared with the wait and see patients. The regression in the number and/or dimensions of the polyps was greater in the treatment group than the control group. The regression rate was 47.5% and 12.5%, respectively (p < .001). CONCLUSION: Progesterone appears to be a valid therapeutic alternative for the management of endometrial polyps. A prospective, randomized study is ongoing at our institution to further validate these findings.

Metabolomic Signature of Endometrial Cancer.

Endometrial cancer (EC) is the most common cancer of the female reproductive tract in developed countries. At the moment, no effective screening system is available. Here, we evaluate the diagnostic performance of a serum metabolomic signature. Two enrollments were carried out, one consisting of 168 subjects: 88 with EC and 80 healthy women, was used for building the classification models. The second (used to establish the performance of the classification algorithm) was consisted of 120 subjects: 30 with EC, 30 with ovarian cancer, 10 with benign endometrial disease, and 50 healthy controls. Two ensemble models were built, one with all EC versus controls (Model I) and one in which EC patients were aggregated according to their histotype (Model II). Serum metabolomic analysis was conducted via gas chromatography-mass spectrometry, while classification was done by an ensemble learning machine. Accuracy ranged from 62% to 99% for the Model I and from 67% to 100% for the Model II. Ensemble model showed an accuracy of 100% both for Model I and II. The most important metabolites in class separation were lactic acid, progesterone, homocysteine, 3-hydroxybutyrate, linoleic acid, stearic acid, myristic acid, threonine, and valine. The serum metabolomics signature of endometrial cancer patients is peculiar because it differs from that of healthy controls and from that of benign endometrial disease and from other gynecological cancers (such as ovarian cancer).

Luteal phase anovulatory follicles result in the production of competent oocytes: intra-patient paired case-control study comparing follicular versus luteal phase stimulations in the same ovarian cycle.

STUDY QUESTION: Are the mean numbers of blastocysts obtained from sibling cohorts of oocytes recruited after follicular phase and luteal phase stimulations (FPS and LPS) in the same ovarian cycle similar? SUMMARY ANSWER: The cohorts of oocytes obtained after LPS are larger than their paired-FPS-derived cohorts and show a comparable competence, thus resulting in a larger mean number of blastocysts. WHAT IS KNOWN ALREADY: Three theories of follicle recruitment have been postulated to date: (i) the 'continuous recruitment' theory, (ii) the 'single recruitment episode' theory and (iii) the 'wave' theory. Yet, a clear characterization of this crucial biological process for human reproduction is missing. Recent advances implemented in in vitro fertilization (IVF), such as blastocyst culture, aneuploidy testing and vitrification, have encouraged clinicians to maximize the exploitation of the ovarian reserve through tailored stimulation protocols, which is crucial especially for poor prognosis patients aiming to conceive after IVF. LPS has been already successfully adopted to treat poor prognosis or oncological patients through Duostim, LPS-only or random-start ovarian stimulation approaches. Nevertheless, little, and mainly retrospective, evidence has been produced to support the safety of LPS in general. Feasibility of the LPS approach would severely question the classic 'single recruitment episode' theory of follicular development. STUDY DESIGN, SIZE, DURATION: This case-control study was conducted with paired follicular phase- and luteal phase-derived cohorts of oocytes collected after stimulations in the same ovarian cycle (DuoStim) at two private IVF clinics between October 2015 and December 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 188 poor prognosis patients undergoing DuoStim with preimplantation genetic testing for aneuploidies (PGT-A). FPS and LPS were performed with the same daily dose of recombinant-gonadotrophins in an antagonist protocol. Blastocyst culture, trophectoderm biopsy, vitrification and frozen-warmed euploid single blastocyst transfers were performed. The primary outcome was the mean number of blastocysts obtained per oocyte retrieval from paired-FPS- and LPS-derived cohorts (required sample size = 165 patients; power = 90%). Mean blastulation and euploidy rates were monitored, along with the number of oocytes, euploid blastocysts and clinical outcomes. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly fewer blastocysts were obtained after FPS than LPS (1.2 ± 1.1 vs. 1.6 ± 1.6, P < 0.01), due to fewer oocytes collected (3.6 ± 2.1 vs. 4.3 ± 2.8, P < 0.01) and a similar mean blastocyst rates per retrieval (33.1% ± 30.3% vs. 37.4% ± 30.8%, P = NS). The number of oocytes collected were correlated (R = 0.5, P < 0.01), while the blastocyst rates were uncorrelated among paired-FPS- and LPS-derived cohorts. Overall, a significantly lower chance of producing blastocyst(s) was reported after FPS than after LPS: 67.6% (n = 127/188, 95%CI: 60.3-74.1) vs. 77.1% (n = 145/188, 95%CI: 70.3-82.8; P = 0.05). The mean euploidy rates per retrieval were similar between FPS- and LPS-derived cohorts of oocytes (13.6% ± 22.8% vs. 16.3% ± 23.4%, P = NS). Therefore, on average fewer euploid blastocysts (0.5 ± 0.8 vs. 0.7 ± 1.0, P = 0.02) resulted from FPS. Similar ongoing-pregnancy/delivery rates were reported, to date, after FPS- and LPS-derived euploid single blastocyst transfers: 42.4% (n = 28/66, 95%CI: 30.5-55.2) vs. 53.8% (n = 35/65, 95%CI: 41.1-66.1; P = NS). LIMITATIONS, REASONS FOR CAUTION: More studies need to be conducted in the future to confirm the safety of LPS, especially in terms of ovarian and follicular environment, as well as the clinical, peri-natal and post-natal outcomes. Here, we showed preliminary data suggesting a similar ongoing implantation/delivery rate (>22 weeks) between FPS- and LPS-derived euploid blastocysts, that need to be extended in the future, to populations other than poor prognosis patients and using approaches other than DuoStim together with a constant monitoring of the related peri-natal and post-natal outcomes. WIDER IMPLICATIONS OF THE FINDINGS: These data, from a paired study design, highlight that LPS-derived oocytes are as competent as FPS-derived oocytes, thereby adding some evidence to support the use of LPS for poor prognosis and oncological patients and to question the 'single recruitment episode' theory of follicle recruitment. These findings also encourage additional studies of the basics of folliculogenesis, with direct clinical implications for the management of ovarian stimulation in IVF. TRIAL REGISTRATION: None. STUDY FUNDING/COMPETING INTEREST(S): No external funds were used for this study and there are no conflicts of interest.

Biochemical pregnancy loss after frozen embryo transfer seems independent of embryo developmental stage and chromosomal status.

RESEARCH QUESTION: Biochemical pregnancy loss (BPL), defined as serum beta-human chorionic gonadotropin levels ≥50 IU/l in at least two pregnancy tests, not associated with any ultrasonographical evidence of pregnancy, is often attributed to chromosomal abnormalities; however, no hard evidence exists to support this hypothesis. Are any IVF cycle parameters associated with the occurrence of a BPL? DESIGN: Retrospective study aimed at evaluating the effect of embryo developmental stage at transfer and chromosomal assessment on the BPL rate in IVF after frozen embryo transfer (FET). Specifically, 641 FET of 1179 cleavage stage untested embryos (Group A), 1021 FET of 1259 untested blastocyst stage embryos (Group B), and 789 blastocyst stage FET of 803 euploid embryos (Group C) were performed in a 6-year period. Only FET were evaluated to avoid a potential effect of ovarian stimulation on endometrial receptivity. RESULTS: The BPL rates were similar (n = 30/217, 13.8% in Group A; n = 37/412, 9.0% in Group B; n = 42/433, 9.7% in Group C). Neither embryo developmental stage at FET nor chromosomal assessment showed a correlation with BPL. Furthermore, logistic regression analyses did not show any association between BPL and patient, cycle and/or transfer characteristics. CONCLUSIONS: BPL seems independent of the embryo's developmental stage, the use of trophectoderm biopsy and the chromosomal constitution at FET. Similar BPL rates after transferring euploid blastocysts compared with both untested cleavage and blastocyst stage embryos suggest investigating the role of endometrial and other embryonic factors putatively involved in the process of implantation.

Progesterone for preparation of the endometrium for frozen-thawed blastocyst transfer in vitro fertilization cycles: a prospective study on patients' opinions on a new subcutaneous formulation.

We aimed to evaluate patients' perspectives on a progesterone subcutaneous formulation for endometrial preparation for frozen-thawed blastocyst transfer. In this prospective study, women with at least one experience with vaginal progesterone, undergone endometrial preparation with oral estradiol valerate and daily subcutaneous progesterone administered from the fifth day before the transfer until the day of the beta-hCG test. Patients completed three questionnaires, at enrollment (Q1), for gathering information on the experience with vaginal treatment and expectations about the subcutaneous route and then at the time of the transfer (Q2) and eight days later (Q3). Main outcome measures were patients' opinions on comfort, ease of use, convenience, overall satisfaction, level of anxiety and pain associated with the administration of subcutaneous progesterone in comparison with their previous experience. Sixty-nine women completed the questionnaires. All vaginal versus subcutaneous comparisons were significantly in favor of the subcutaneous route. When comparing patients' expectations at Q1 with patients' opinions at Q2 and Q3, all evaluations, except for one, demonstrated that the patient's positive expectation was confirmed after 5 and 13 days of treatment. In conclusion, in women with previous experience with vaginal progesterone, the subcutaneous route was associated with significantly increased acceptance.