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Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a \"freeze-all\" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and deserves further research.

PurposeTo evaluate obstetric outcome in women with endometriosis who conceive naturally and receive standard obstetric care in Italy.MethodsCases were consecutive women with endometriosis managed in eleven Italian referral centers. Controls were women in whom endometriosis was excluded. All women filled in a questionnaire addressing previous natural pregnancies. Marginal logistic regression models were fitted to evaluate the impact of endometriosis on obstetric outcome. A post hoc analysis was performed within the endometriosis group comparing women with severe adenomyosis versus women with absent or mild adenomyosis.ResultsThree hundred and fifty-five pregnancies in endometriosis group and 741 pregnancies in control group were included. Women with endometriosis had a higher risk of preterm delivery < 34 weeks (6.4% vs 2.8%, OR 2.42, 95% CI 1.22–4.82), preterm delivery < 37 weeks (17.8% vs 9.7%, OR 1.98, 95% CI 1.23–3.19), and neonatal admission to Intensive Care Unit (14.1% vs 7.0%, OR 2.04, 95% CI 1.23–3.36). At post hoc analysis, women with endometriosis and severe adenomyosis had an increased risk of placenta previa (23.1% vs 1.8%, OR 16.68, 95% CI 3.49–79.71), cesarean delivery (84.6% vs 38.9%, OR 8.03, 95% CI 1.69–38.25) and preterm delivery < 34 weeks (23.1% vs 5.7%, OR 5.52, 95% CI 1.38–22.09).ConclusionWomen with endometriosis who conceive naturally have increased risk of preterm delivery and neonatal admission to intensive care unit. When severe adenomyosis is coexistent with endometriosis, women may be at increased risk of placenta previa and cesarean delivery.Trial registrationClinical trial registration number: NCT03354793.

Abstract A network of endometriosis experts from 16 Italian academic departments and teaching hospitals distributed all over the country made a critical appraisal of the available evidence and definition of 10 suggestions regarding measures to be de-implemented. Strong suggestions were made only when high-quality evidence was available. The aim was to select 10 low-value medical interventions, characterized by an unfavorable balance between potential benefits, potential harms, and costs, which should be discouraged in women with endometriosis. The following suggestions were agreed by all experts: do not suggest laparoscopy to detect and treat superficial peritoneal endometriosis in infertile women without pelvic pain symptoms; do not recommend controlled ovarian stimulation and IUI in infertile women with endometriosis at any stage; do not remove small ovarian endometriomas (diameter <4 cm) with the sole objective of improving the likelihood of conception in infertile patients scheduled for IVF; do not remove uncomplicated deep endometriotic lesions in asymptomatic women, and also in symptomatic women not seeking conception when medical treatment is effective and well tolerated; do not systematically request second-level diagnostic investigations in women with known or suspected non-subocclusive colorectal endometriosis or with symptoms responding to medical treatment; do not recommend repeated follow-up serum CA-125 (or other currently available biomarkers) measurements in women successfully using medical treatments for uncomplicated endometriosis in the absence of suspicious ovarian cysts; do not leave women undergoing surgery for ovarian endometriomas and not seeking immediate conception without post-operative long-term treatment with estrogen–progestins or progestins; do not perform laparoscopy in adolescent women (<20 years) with moderate–severe dysmenorrhea and clinically suspected early endometriosis without prior attempting to relieve symptoms with estrogen–progestins or progestins; do not prescribe drugs that cannot be used for prolonged periods of time because of safety or cost issues as first-line medical treatment, unless estrogen–progestins or progestins have been proven ineffective, not tolerated, or contraindicated; do not use robotic-assisted laparoscopic surgery for endometriosis outside research settings. Our proposal is to better address medical and surgical approaches to endometriosis de-implementing low-value interventions, with the aim to prevent unnecessary morbidity, limit psychological distress, and reduce the burden of treatment avoiding medical overuse and allowing a more equitable distribution of healthcare resources.

Background An increased incidence of imprint-associated disorders has been reported in babies born from assisted reproductive technology (ART). However, previous studies supporting an association between ART and an altered DNA methylation status of the conceived babies have been often conducted on a limited number of methylation sites and without correction for critical potential confounders. Moreover, all the previous studies focused on the identification of methylation changes shared among subjects while an evaluation of stochastic differences has never been conducted. This study aims to evaluate the effect of ART and other common behavioral or environmental factors associated with pregnancy on stochastic epigenetic variability using a multivariate approach. Results DNA methylation levels of cord blood from 23 in vitro and 41 naturally conceived children were analyzed using the Infinium HumanMethylation450 BeadChips. After multiple testing correction, no statistically significant difference emerged in the number of cord blood stochastic epigenetic variations or in the methylation levels between in vitro- and in vivo-conceived babies. Conversely, four multiple factor analysis dimensions summarizing common phenotypic, behavioral, or environmental factors (cord blood cell composition, pre or post conception supplementation of folates, birth percentiles, gestational age, cesarean section, pre-gestational mother’s weight, parents’ BMI and obesity status, presence of adverse pregnancy outcomes, mother’s smoking status, and season of birth) were significantly associated with stochastic epigenetic variability. The stochastic epigenetic variation analysis allowed the identification of a rare imprinting defect in the locus GNAS in one of the babies belonging to the control population, which would not have emerged using a classical case-control association analysis. Conclusions We confirmed the effect of several common behavioral or environmental factors on the epigenome of newborns and described for the first time an epigenetic effect related to season of birth. Children born after ART did not appear to have an increased risk of genome-wide changes in DNA methylation either at specific loci or randomly scattered throughout the genome. The inability to identify differences between cases and controls suggests that the number of stochastic epigenetic variations potentially induced by ART was not greater than that naturally produced in response to maternal behavior or other common environmental factors.

\"SO FAR AWAY\" * How Doctors Can Contribute to Making Endometriosis Hell on Earth [* by Knopfler M. In Dire Straits. Brothers in Arms. Vertigo Records, U.K., 1985]. The distance physicians may create within the relationship with their patients by not having a humanistic approach to their practice may strongly influence clinical outcomes. The purpose of this paper is to convey the well-known narrative of patient dissatisfaction into pro-action by discussing the aspects of dehumanization, which may occur in the relationship between physicians and women with endometriosis. Eight dimensions of dehumanization are examined and related to everyday scenarios occurring in endometriosis care settings and the possible downstream consequences on patients' clinical outcomes are described. Objectification, which may come across as minimization of pain, may not only increase patients' perception of pain but also lead to undertreatment of unrecognized forms of endometriosis, especially among adolescents. Passivity, that is not favoring shared decision-making nor self-management, may compromise adherence to treatment, reducing patients' trust in physicians and quality of life. The same consequences may result from homogenization, that is giving for granted that all patients have the same access to care. Both isolation, ie not practicing therapeutic empathy, and loss of meaning, ie not supporting patients in the re-definition of their life plans, may affect women's psychological wellbeing and further increase pain perception. Ignoring women's personal journey by not providing clear information on the consequences endometriosis may have on their lives may favor women's self-silencing. Not promoting an un-biased communication and not setting aside scientific polarization are the main features of dislocation, which may jeopardize patient empowerment. Lastly, having a reductionist approach to the body may contribute to chronicization of pain, thus compromising quality of life. This considered, taking time to listen to women with endometriosis and tailoring decisions on the basis of their individual needs should be fostered as a moral duty. Physicians should always keep in mind that they are not only deliverers of treatment; they are a form of treatment themselves.

Objectives The introduction of vaccination against hepatitis B initially reduced the number of HBV (hepatitis B virus) and HDV (hepatitis delta virus) infections, but the decreasing trend of HDV infection seems to have stopped. The aim of this study was to assess the prevalence of HDV infection in the general population living in the catchment area of Legnano Hospital in northern Italy. Methods Of the 22,758 subjects tested in 2007–2008, the 488 who were HBsAg (hepatitis B surface antigen)-positive [including 107 (21.9%) of non-Italian origin] were subsequently tested for anti-HDV antibodies. Results Of the 488 subjects who tested positive for HBsAg, 24 (4.9%) were anti-HDV positive, all aged between 30 and 60 years. The difference in prevalence between males (7.1%) and females (1.9%) was statistically significant ( p  < 0.05), but not that between Italian (5.0%) and non-Italian patients (4.7%). The differences in anti-HDV seropositivity between the patients with acute (0%) and chronic infections (6.3%), and between the incident (2.5%) and prevalent cases (7.4%), were not statistically significant, but there was a significant difference ( p  < 0.01) between those with asymptomatic (2.1%) and clinically symptomatic infections (10.3%). Intravenous drug abuse was the main source of infection. Conclusions In the catchment area of our hospital, the prevalence of HDV infection does not seem to be due to patients of non-Italian origin, but to Italian patients who are not vaccinated against HBV and who survived the HDV epidemic of the 1970s and 1980s. Nevertheless, the increase in the number of immigrants from non-EU countries in recent years is soon likely to lead to a change in the epidemiology of HDV.

The management of endometriosis-related infertility is still a challenging issue. Women can be managed with either surgery or in vitro fertilization (IVF). The decision is tailored to the patients considering pros and cons of both approaches. Surgery might increase the chances of natural conception and relieve symptoms. IVF may be more effective, but costs are higher and unoperated women face some peculiar additional risks during the procedure and pregnancy. The unavailability of randomized trials comparing the two strategies hampers the possibility to provide precise estimates. This Randomized Controlled Trial (RCT) aims at filling this gap. This is a multicenter, non-blinded, randomized controlled trial with parallel groups and allocation 1:1. Three Italian Academic Infertility Units will be involved. Main inclusion criteria are infertility for more than one year, age less than 40 years and a sonographic diagnosis of endometriosis (ovarian endometriomas or deep peritoneal lesions). Previous IVF and previous surgery for endometriosis are exclusion criteria. Women will be randomized to either surgery and then natural pregnancy seeking or a standard program of three IVF cycles. The primary aim is the comparison of live birth rate between the two groups (IVF versus surgery) within one year of randomization. The secondary aim is the evaluation of cost-effective profile of the two interventions. The present study can influence the clinical practice of infertility treatment in women with endometriosis. From a public health perspective, information on the more cost-effective clinical management strategy would consent a wiser allocation of resources. Trial registration: NCT04743167 , registered on 8 February 2021.

Background Although endometriosis may benefit from primary prevention measures, the epidemiological risk factors identified are equivocal. Two genome-wide association studies (GWAS) have been conducted for endometriosis in two different ethnic populations but results are still to be replicated consistently and across various ethnicities. To confirm the association of GWAS-derived susceptibility loci, we conducted a replication Italian case-control study and a meta-analysis. Methods An independent set of 305 laparoscopically-proven endometriosis patients and 2710 controls were recruited. Four SNPs—CDKN2BAS rs1333049, rs7521902 close to WNT4, rs12700667 in an inter-genic region on 7p15.2 and fibronectin 1 rs1250248—were selected for this association study. Results Rs1333049 risk allele G frequency resulted significantly higher in endometriosis patients compared with controls (OR 1.32, 95% CI 1.11 to 1.57), confirming the role of this locus also in the Caucasian population. The meta-analysis showed that rs7521902 was associated with endometriosis at a genome-wide significance (pmeta=2.23×10−9) while for rs1250248, a genome-wide significant pmeta value of 3.89×10−9 was detected only in association with severe forms. An epistatic interaction between rs7521902 and rs1250248 (OR 1.56, p=1.19×10−2) was found especially in presence of ovarian disease (OR=2.15, p=3.12×10−4). Conclusions We confirm WNT4, CDKN2BAS and FN1 as the first identified common loci for endometriosis.

Background Vitamin D plays an important role in human physiology and pathology. The receptor for vitamin D regulates 0.5–5% of the human genome. Accordingly, vitamin D insufficiency has been shown to increase the risk of several diseases. In recent years, based on growing evidence, on a role of vitamin D has been also postulated in reproductive health both in animals and humans, especially in female fertility female fertility. In vitro fertilization success was shown to be higher in women with appropriate reserves of vitamin D. However a causal relation has not been demonstrated and randomized controlled trials testing the effectiveness of vitamin D supplementation in IVF are warranted. Methods This is a multicenter randomized double blinded placebo controlled study aimed at determining the benefits of vitamin D [25(OH)D] supplementation in improving clinical pregnancy rate in women undergoing IVF. Eligible women with a serum level of 25-hydroxyvitamin D [25(OH)D] < 30 ng/ml will be randomized. Recruited women will be given the drug (either 600,000 IU of 25(OH) D or placebo in a single oral administration) at the time of randomization. Two centres will participate and the sample size (700 women) is foreseen to be equally distributed between the two. Patients will be treated according to standard IVF protocols. Discussion The primary aim of the study is the cumulative clinical pregnancy rate per oocyte retrieval. Clinical pregnancy is defined as the presence of at least one intrauterine gestational sac with viable foetus at first ultrasound assessment (3 weeks after a positive human chorionic gonadotropin [hCG] assessment). Secondary outcomes include: 1) clinical and embryological variables; 2) oocyte and endometrium quality at a molecular level. To investigate this latter aspect, samples of cumulus cells, follicular and endometrial fluids will be obtained from a subgroup of 50 age-matched good-prognosis cases and controls. Trial registration The protocol was included in EudraCT on 22nd September 2015 with the registration number assigned ‘ 2015-004233-27 ’; it was submitted through the database of the Italian “Osservatorio Nazionale della Sperimentazione Clinica (OsSC)” - (National Monitoring Centre of Clinical Trials) to the National Competent Authority on 8th March 2016 and approved on 23rd June 2016.

Endometriosis is a chronic inflammatory condition that is responsive to management with steroids. The establishment of a steady hormonal environment and inhibition of ovulation can temporarily suppress ectopic implants and reduce inflammation as well as associated pain symptoms. In terms of pharmacological management, the currently available agents are not curative, and treatment often needs to be continued for years or until pregnancy is desired. Similar efficacy has been observed from the various therapies that have been investigated for endometriosis. Accordingly, combined oral contraceptives and progestins, based on their favourable safety profile, tolerability and cost, should be considered as first-line options, as an alternative to surgery and for post-operative adjuvant use. In situations where progestins and oral contraceptives prove ineffective, are poorly tolerated or are contraindicated, gonadotrophin-releasing hormone analogues, danazol or gestrinone may be used. Future therapeutic options for managing endometriosis must compare favourably against existing agents before they can be considered for inclusion into current practice. Finally, as reproductive prognosis is not ameliorated by medical treatment, it is not indicated for women seeking conception.