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PURPOSE: Ovarian hyperstimulation syndrome (OHSS) represents a rare but dangerous condition associated with controlled ovarian stimulation (COS) in IVF/ICSI. Over the last decades, many strategies have been introduced into clinical practice with the objective of preventing this potentially life-threatening condition. Among these, the freeze-all policy has gained great popularity, thanks to improvements in vitrification. Nevertheless, not all clinics have adequate skills in vitrification procedures and patients may be dissatisfied with a longer time to pregnancy. METHODS: This study is a systematic review and network meta-analysis of randomized controlled trials comparing different strategies of ovarian stimulation in IVF/ICSI cycles (freeze-all policy, algorithm-based individualization of the starting dose, experience-based individualization of the starting dose, standard dose) in terms of reduction of OHSS, in normal responders. RESULTS: The results indicate that only the algorithm-based individualization of the starting gonadotropin dose reduces OHSS similarly to the freeze-all strategy. CONCLUSION: Albeit in the era of the freeze-all policy, the personalization of the starting gonadotropin dose obtained by the use of algorithms should be pursued as a valid and safe option for IVF. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-022-02503-2.

Purpose: The use of antioxidants is common practice in the management of infertile patients. However, there are no estab-lished guidelines by professional societies on antioxidant use for male infertility. Materials and Materials and Methods:Methods: Using an online survey, this study aimed to evaluate the practice pattern of reproductive specialists to determine the clinical utility of oxidative stress (OS) testing and antioxidant prescriptions to treat male infertility. Results:Results: Responses from 1,327 participants representing 6 continents, showed the largest participant representation being from Asia (46.8%). The majority of participants were attending physicians (59.6%), with 61.3% having more than 10 years of experience in the field of male infertility. Approximately two-thirds of clinicians (65.7%) participated in this survey did not order any diagnostic tests for OS. Sperm DNA fragmentation was the most common infertility test beyond a semen analysis that was prescribed to study oxidative stress-related dysfunctions (53.4%). OS was mainly tested in the presence of lifestyle risk factors (24.6%) or sperm abnormalities (16.3%). Interestingly, antioxidants were prescribed by 85.6% of clinicians, for a duration of 3 (43.7%) or 3?? months (38.6%). A large variety of antioxidants and dietary supplements were prescribed, and scientific evidence were mostly considered to be modest to support their clinical use. Results were not influenced by the physician?셲 age, geographic origin, experience or training in male infertility. Conclusions:Conclusions: This study is the largest online survey performed to date on this topic and demonstrates 1) a worldwide under-standing of the importance of this therapeutic option, and 2) a widely prevalent use of antioxidants to treat male infertility. Finally, the necessity of evidence-based clinical practice guidelines from professional societies is highlighted.

Define how and when fixed starting gonadotropin doses can be used in current clinical ART practices in Italy.A Delphi conference consisting of three rounds was performed in order to define the ideal clinical conditions in which fixed-gonadotropin-dose during COS should be applied. During the conference, 19 statements about the current ART practice were provided to a panel of twenty-nine national experts. Median score was 5 (IQ:4-6) in all Delphi rounds.Eleven statements (57.9%) were classified as shareable with high-degree of convergence, 2 (10.5%) as shareable with low convergence and 6 (31.6%) as un-shareable with high convergence. The panel reached high consensus regarding some statements: (i) fixed FSH-dose in normoresponders and poor-responder, (ii) importance of predicting ovarian response before COS, considering multiple markers to select the right stimulation protocol for each patient, (iii) importance of therapy simplification and standardization to improve efficiency during COS. Moreover, a low-convergence was reached about use of GnRH antagonist as first treatment line and drug storage at room temperature. However from these findings, the debate remains open regarding some other statements: (a) usefulness of Bologna-criteria to define poor-responders; (b) efficacy to change always stimulation protocol after a failure IVF; (c) utility of AMH-dosed with standardized automatic mode to define normo-responder patients; (d) usefulness to modify the dosage of 12.5 IU/die during COS to improve stimulation effectiveness.Controlled ovarian stimulation remains a challenging clinical step in Assisted Reproductive Technique, especially in some specific patient groups for which no clinical consensus is available. This study is the first attempt to describe the shared clinical opinion regarding the fixed versus variable gonadotropin dose in the real IVF practice.

Study question What is the clinical efficacy of an oocyte donation program based on the transportation of vitrified oocytes between two countries? Summary answer The transnational oocyte donation program is efficient, safe and comparable to other strategies (transport of frozen sperm and embryos). What is known already Egg donation represents a valid treatment strategy for women who have exhausted their ovarian function and it has considerably increased in the last years. In Italy, egg donation is allowed after the judgment of the Constitutional Court n. 162 in 2014 but no reimbursement for the donors is provided. For this reason, the number of voluntary donors is irrelevant. Therefore, the great majority of egg donation cycles is carried out by using imported cryopreserved oocytes from foreign countries. However, recent evidence has questioned the overall efficacy of this strategy in comparison with the shipment of frozen sperm and vitrified embryos. Study design, size, duration A retrospective cohort study was conducted between July 2015-December 2020 at two private IVF clinics. 264 couples were treated (mean maternal age: 43.1± 4.6 years, range: 26–51; mean donor age: 24 ±3 years, range: 20–33) with vitrified oocytes shipped from a single Spanish egg bank (IMER, Valencia) to the receiving reproductive clinic in Italy (ANDROS Clinic, Palermo). All the oocytes for each batch were thawed. Participants/materials, setting, methods The primary outcome of this study was the cumulative clinical pregnancy rate (CPR) among the completed cycles for each batch of oocytes. Those cycles in which a clinical pregnancy was obtained, or all embryos derived by a single batch of oocytes had been transferred or no embryo was produced were defined as completed. In addition to main analyses, sensitivity analysis was performed to examine how the number of inseminated oocytes may affect CPR. Main results and the role of chance 2,367 oocytes in 355 batches were sent from Spain to Italy. 2,209 oocytes in 334 batches for 264 patients were thawed with a survival rate of 82.4% (1,821/2,209). The mean number of oocytes received per patient was 6.6 ± 1.0. The fertilization rate was 72.1% (1,312/1,821). 499 embryos were transferred (38.0%), 335 at the cleavage stage (67.1%) and 164 at the blastocyst stage (32.9%); 197 supernumerary embryos were vitrified (15.0%), 18 at the cleavage stage (9.1%) and 179 at the blastocyst stage (90.9%). 616 embryos were not viable (47.0%). No more than two embryos were transferred for each embryo transfer (ET). The completed cycles were 307 out of 334 (91.9%). The CPR per completed cycles was 46.6% (143/307) and 54.2% per patient (143/264). Clinical pregnancy rate per fresh ET in completed cycles with supernumerary cryopreserved embryos was significantly higher compared with that of the completed cycles without surplus embryos (56/101 versus 68/193, p = 0.001). Logistic regression revealed that the number of inseminated oocytes was positively associated with CPR in a significant manner (B = 0.220, p = 0.007; OR = 1.25, 95%CI=1.06–1.47). The multiple pregnancy rate was 15.4% (1 triplet and 21 twin pregnancies). The miscarriage rate was 22.4% (32/143). Limitations, reasons for caution The retrospective design of the study needs to be confirmed in larger and multicenter prospective studies comparing the strategy of vitrified donated oocytes and fresh ET with the policy of fresh donated oocyte and frozen/thawed ET. Wider implications of the findings: The transnational oocyte donation program with vitrified oocytes is associated with good success rates. The number of inseminated oocytes represents a crucial factor for increasing the CPR, improving the embryo selection for fresh ET and giving more chances of pregnancy with the transfer of surplus vitrified embryos. Trial registration number Not applicable

Study question Is the incidence of miscarriage rates increased in frozen embryo transfer (ET) compared with fresh ET? Summary answer The frozen ET is not associated with an increased risk of miscarriage in comparison with fresh ET. What is known already Nowadays, the freeze-all policy has gained great popularity because it minimizes OHSS and it seems to improve the reproductive outcomes. This increase was possible thanks to progress in vitrification procedures. Nevertheless, some recent evidence suggests more caution on the wide use of elective frozen ET in a general IVF population for its possible effect on some pregnancy-related complications. Endometrial preparation schemes for frozen ET include natural cycles or, more frequently, artificial cycles in which the endometrium is prepared with exogenous steroids. In this last case, the corpus luteum is absent, but its demise could be correlated with some pregnancy-related complications. Study design, size, duration A meta-analysis, based on PubMed, Cochrane CENTRAL, EMBASE, was conducted to estimate and compare the miscarriage rate (MR) in frozen versus fresh ET. Following PICOS, inclusion criteria were: Population, patients undergoing IVF/ICSI; Intervention, frozen ET; Comparison, fresh ET; Outcome, MR (primary one); clinical pregnancy rate (CPR), ongoing pregnancy rate (OPR) and live birth rates (LBR) (secondary ones). Study design: RCT. Participants/materials, setting, methods Electronic and manual search, conducted from 1990 to 2020, yielded 269 studies. Two researchers reviewed the studies independently, excluding 247 and 14 studies after the first and second screening. The outcome data from the 8 included studies were combined using a Mantel–Haenszel model and applying the random effects models. The dichotomous data results of each study were expressed as risk ratio (RR) with 95% confidence intervals (CI). Heterogeneity was evaluated using the I2 statistic. Main results and the role of chance The eight studies comprise 6,934 participants, 3,450 undergoing frozen ET and 3,484 fresh ET (Ferraretti et al., 1999; Shapiro et al., 2011a; Shapiro et al.; 2011b; Chen et al., 2016; Shi et al., 2018; Le et al., 2018; Wei et al., 2019; Stormlund et al., 2020). Preliminary analyses excluded interaction between covariates. RR of miscarriage ranged from 0.29 (Chen et al., 2016) to 3.24 (Ferraretti et al., 1999). The level of heterogeneity (I2) was 48% and it was considered as moderate. MR resulted not significantly different in frozen [279/1,601 pregnancies] compared with fresh ET [308/1,458 pregnancies] (RR = 0.727, 95%CI=0.43–1.25, p = 0.25). By analysing the 5 trials in which the endometrium was prepared with steroids (Ferraretti et al., 1999; Shapiro et al., 2011a; Shapiro et al., 2011b; Chen et al., 2016; Le et al., 2018), MR resulted not significantly different in frozen [126/720] versus fresh ET [160/682] (RR = 0.605, 95%CI 0.22–1.66; p = 0.33; I2=43%). For the secondary outcomes, CPR (RR = 1.14; 95%CI=0.97–1.35; 0.56 vs 0.52 for frozen and fresh ET, respectively), OPR (RR = 1.12; 95%CI=0.95–1.33; 0.49 vs 0.46 for frozen and fresh ET, respectively) and LBR (RR = 0.93; 95%CI=0.60–1.44; 0.49 vs 0.47 for frozen and fresh ET, respectively) were not significantly different between the two groups. Limitations, reasons for caution The MR was not the primary outcome of the included RCTs. This could have determined a sample size not calibrated for the analysis of the primary outcome of the present meta-analysis. Wider implications of the findings: This meta-analysis indicates that MR was similar between frozen and fresh ET. The endometrial preparation, in artificial cycles without corpus luteum, does not seem to influence the good course of pregnancy. Based on these results, the choice of a fresh ET should not derive by the presumed reduction of MR. Trial registration number Not applicable

Study question Is there evidence that infertile patients have been more likely to experience distress during the COVID-19 outbreak with the consequent interruption of treatment plans? Summary answer High levels of psychological distress among infertile patients have been found during the COVID-19 pandemic, greater than that reported in the general population. What is known already Preliminary research on the negative consequences of the COVID-19 outbreak on mental health evidenced heightened levels of anxiety, depression and post-traumatic stress in some clinical populations as well as in community samples. However, little is known about the impact of COVID-19 on psychological distress of infertile patients who have been forced to suspend infertility treatment and postpone parenthood goals during the pandemic. The aim of this meta-analytic review is to summarize extant literature on the prevalence of psychological distress symptoms in infertile patients during the COVID-19 pandemic. Study design, size, duration A systematic review and meta-analysis were conducted following the PRISMA guidelines on PsycInfo, PubMed, Embase, Web of Science, MedRxiv from March 2020 to mid-December 2020. Study inclusion criteria were specified according to the PICOS guideline. All naturalistic or RCT studies published in 2020 that examined infertility as the primary diagnosis and had a quantitative measurement of distress, were eligible. The primary outcomes were symptoms of psychological distress and secondary outcomes were indicators of psychological health. Participants/materials, setting, methods The database search identified 144 papers. Two reviewers independently screened potential studies by title and abstracts based on the inclusion criteria. The full texts were then screened for eligibility. The Newcastle-Ottawa Scale was used to judge the methodological quality of the studies. In order to estimate the pooled prevalence of distress, Odds Ratios with 95% Confidence Interval were calculated as the effect size by using a random-effects model. Heterogeneity was tested using I2 statistics. Main results and the role of chance Fourteen studies met the inclusion criteria and were summarized for the systematic review (N = 6473). Only six studies did not include males although, in the surveys, females made up 92% of the total sample. Ten studies adopted a cross-sectional study design. 100% gathered data through an online survey. Nine studies showed a high risk of bias, and five had a moderate risk. Review results showed that 56,4% of patients wished to resume treatment; participants were mostly worried about the delay in treatment because of their age (>35 years) or diminished ovarian reserve, or money constraints and low education level. Only five studies examined the role of protective factors such as social support, coping, optimism trait and intolerance of uncertainty. Nine studies were included for meta-analysis. The prevalence of psychological distress was 0.58 (95% CI 0.32÷0.84). The pooled point estimates of prevalence for anxiety (N = 6) were 0.56 (95% CI 0.24÷0.88), whereas the prevalence for depression (N = 5) was 0.46 (95% CI 0.15÷0.77). There was significant heterogeneity among studies to estimate the prevalence (I² ranging from 99% to 100%). Limitations, reasons for caution Results are preliminary, given the small number of studies and their cross-sectional data. The risk of bias was high or moderate across studies. Wider implications of the findings Infertile couples reported high levels of distress due to cancellation of their diagnostic procedures or treatment; they would benefit from information, appropriate support and advice from healthcare professionals, with an important role in maintaining the wishes of infertile couples to continue their parenthood goals. Trial registration number not applicable

Study question Is the incidence of ectopic pregnancy (EP) increased in fresh compared with frozen embryo transfer (ET)? Summary answer The fresh ET is not associated with an increase of the incidence of EP in comparison with frozen ET. What is known already EP represents the first cause of mortality in the first trimester of pregnancy. Assisted reproductive technologies (ART) are associated with an increased EP risk. The reasons of this effect are inadequately explained and may be associated with variables patients-related as tubal diseases and ART-related as the number of embryos transferred, the depth of insertion of the catheter tip during ET and the supraphysiological estradiol levels during ovarian stimulation affecting endometrial receptivity and tubal function. The role of this last factor seems to be corroborated by higher incidence of EP in fresh versus frozen ET, as highlighted by some retrospective studies. Study design, size, duration A meta-analysis, based on PubMed, Cochrane CENTRAL, EMBASE, was conducted to estimate and compare the EP rate in fresh versus frozen-thawed ET. Following PICOS, inclusion criteria were: Population, patients undergoing IVF/ICSI; Intervention, fresh ET; Comparison, frozen/thawed ET; Outcome, EP (primary one), clinical/ongoing pregnancy and live birth rates (secondary ones). Study design: RCT. Participants/materials, setting, methods Electronic and manual search, conducted from 1990 to 2020, yielded 269 studies. Two researchers reviewed the studies independently, excluding 247 and 16 studies after the first and second screening. The outcome data from the 6 included studies were combined using a Mantel–Haenszel model and applying the random effects models. The dichotomous data results of each study were expressed as risk ratio (RR) with 95% confidence intervals (CI). Heterogeneity was evaluated using the I2 statistic. Main results and the role of chance The six studies included in the present review comprise in total 6,675 participants, 3,320 undergoing frozen ET and 3,355 fresh ET (Ferraretti et al., 1999; Chen et al., 2016; Le et al., 2018; Shi et al., 2018; Wei et al., 2019; Stormlund et al., 2020). Preliminary analyses excluded interaction between covariates, defining intervention/control groups and outcome. In particular, the incidence of tubal infertility was comparable between the two groups. Risk ratio of EP ranged from 0.03 (Ferraretti et al., 1999) to 2.77 (Shi et al., 2018). The level of heterogeneity (I2) between studies was 42% and it was considered as moderate. EP incidence resulted not significantly different in fresh ET [56/1,703 pregnancies] compared with frozen ET [44/1,799 pregnancies] (RR = 0.450, 95% CI 0.13–1.81, p = 0.29; I2=42%). Analysis of the secondary outcomes was conducted on 5 studies; results showed that clinical pregnancy rate was not significantly different between fresh (0.52) and frozen ET (0.56) (RR = 1.11; 95% CI = 0.93–1.34); at the same manner, the ongoing pregnancy rate (RR = 1.11; 95%CI=0.91–1.37; 0.46 vs 0.49 for fresh and frozen, respectively) and the live birth rate (RR = 0.93; 95%CI=0.60–1.44; 0.47 vs 0.49 for fresh and frozen, respectively) resulted not significantly different between the two groups. Limitations, reasons for caution The EP incidence was not the primary outcome of the included RCTs. This could have determined a sample size not calibrated for the analysis of the primary outcome of the present meta-analysis. Wider implications of the findings: This meta-analysis indicates that EP incidence is similar between fresh and frozen ET. The possible role on EP risk of the supraphysiological estradiol levels during ovarian stimulation should be reconsidered. Based on these results, the choice of a frozen ET should not derive by the presumed reduction of EP risk. Trial registration number Not applicable

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

Objective This longitudinal study aims to evaluate the effect of psychological counselling on quality of life, marital satisfaction and need for parenthood in couples undergoing fertility treatments (ART). Background Recent guidelines on the ART suggest that psychological counselling should target both members of the infertile couple in order to improve their conjoint management of the infertility-related stress. However, studies on the dyadic outcome of couples are scarce. Methods 262 patients were originally considered in the study and completed questionnaires on quality of life, need for parenthood and marital satisfaction, before treatment (T1) and at the day of intrauterine insemination/embryo transfer (T2). For the purposes of this study, 34 counselled couples were then matched to 34 non-counselled couples by propensity scores. The Common Fate Model (CFM) was used to examine dyadic changes. Results Couples receiving counselling had higher dyadic quality of life and lower dyadic stress due to the need for parenthood at T2 compared to non-counselled couples. No differences were found on marital satisfaction. Conclusion The findings provide support for the effectiveness of counselling on interpersonal outcome. The CFM allows researchers to examine how the dyad as a whole responds to counselling, highlighting the change in the couple's relational dynamics.

The number of oocytes retrieved is a relevant intermediate outcome in women undergoing IVF/intracytoplasmic sperm injection (ICSI). This trial compared the efficiency of the selection of the FSH starting dose according to a nomogram based on multiple biomarkers (age, day 3 FSH, anti-Mullerian hormone) versus an age-based strategy. The primary outcome measure was the proportion of women with an optimal number of retrieved oocytes defined as 8-14. At their first IVF/ICSI cycle, 191 patients underwent a long gonadotrophin-releasing hormone agonist protocol and were randomized to receive a starting dose of recombinant (human) FSH, based on their age (150 IU if ≤35 years, 225 IU if >35 years) or based on the nomogram. Optimal response was observed in 58/92 patients (63%) in the nomogram group and in 42/99 (42%) in the control group (+21%, 95% CI = 0.07 to 0.35, P = 0.0037). No significant differences were found in the clinical pregnancy rate or the number of embryos cryopreserved per patient. The study showed that the FSH starting dose selected according to ovarian reserve is associated with an increase in the proportion of patients with an optimal response: large trials are recommended to investigate any possible effect on the live-birth rate.

Objective The main problem to wide acceptability of celocentesis as earlier prenatal diagnosis is contamination of the sample by maternal cells. The objective of this study was to investigate the cellular composition of celomic fluid for morphological discrimination between maternal and embryo-fetal cells. Method Celomic fluids were aspired by ultrasound-guided transcervical celocentesis at 7-9 weeks’ gestation from singleton pregnancies before surgical termination for psychological reasons. DNA was extracted from celomic fluid cells showed the same morphology and quantitative fluorescentPCR assay was performed to evaluate their fetal or maternal origin. Results Six different types of non-hematological maternal and four different types of embryo-fetal cells were detected. The most common maternal cells were of epithelial origin. The majority of embryo-fetal cells were roundish with a nucleus located in an eccentric position near the wall. These cells were considered to be erythroblasts, probably derived from the yolk sac that serves as the initial site of erythropoiesis. Conclusions The combined use of morphology and DNA analysis make it possible to select and isolate embryo-fetal cells, even when maternal contamination is high. This development provides the opportunity for the use of celocentesis for early prenatal diagnosis of genetic diseases and application of array-CGH. This article is protected by copyright. All rights reserved.

There exists a lack of dyadic research examining how the attachment characteristics of infertile individuals influence their experience of infertility-related distress. The actor partner interdependence model was used to test a theoretical model by examining whether both infertile wives and husbands, who display high levels of attachment avoidance and/or attachment anxiety, will experience infertility-related distress. Seven hundred and seventy individuals (385 couples) completed the experience in close relationships, the fertility problem inventory, and the state-trait anxiety inventory prior to infertility treatment. Wives' distress was predicted by their own and by their husbands' attachment avoidance. Husbands' distress was predicted by wives' attachment anxiety. Moreover, interaction effects between two partners were observed when predicting husbands' distress. The results of the current study support the reciprocal nature of couple's attachment relationships.

Objective: The aim of this study is to prevent false positive results in non-invasive foetal sex determination from pregnant women’s plasma following strict anti-contamination criteria.Methods: cffDNA from 200 pregnant women (mean gestational age of 8.3 ± 0.2 weeks) was analyzed based on genetic forensic anti-contamination procedures and classical non-invasive foetal sex determination techniques.Results: No false positive or false negative was reported. The sensitivity and the specificity reached both a 100% value.Conclusions: Prevention of contamination following our anti-contamination criteria is a good practice for certain non-invasive sex determination, using cffDNA.

The objective of this study was the elucidation of the possible role of the single-nucleotide polymorphisms (SNP) at position -29 and 2039 of the FSH receptor gene (FSHR) as independent predictive markers of ovarian response. Indeed, the tailoring of reproductive treatments is crucial for both maximizing the success of IVF patients and obtaining a reduction in hypo- or hyper-response rates. This prospective, observational study analyzed the association of -29 and 2039 FSHR polymorphisms with the number of retrieved oocytes in 140 patients attending an IVF/ICSI cycle for severe male factors (≤5,000,000 spermatozoa/mL) or tubal factors at the ANDROS Day Surgery Clinic, Palermo, Italy. The results of this study demonstrate that the genetic combination of A/G for polymorphism c.2039 A>G with G/G for polymorphism c.-29 G>A is significantly associated with the highest number of collected oocytes (p = 0.03). This association was significant even after controlling for the effect of other clinical variables. The A/G-G/G allelic variant, identified as an independent variable, if confirmed in a larger number of patients, could be considered as a new genetic biomarker, which could increase the efficacy of prediction models for ovarian stimulation.

The main problem to wide acceptability of celocentesis as earlier prenatal diagnosis is contamination of the sample by maternal cells. The objective of this study was to investigate the cellular composition of celomic fluid for morphological discrimination between maternal and embryo-fetal cells.Celomic fluids were aspired by ultrasound-guided transcervical celocentesis at 7-9 weeks' gestation from singleton pregnancies before surgical termination for psychological reasons. DNA extracted from celomic fluid cells showed the same morphology, and quantitative fluorescent polymerase chain reaction (PCR) assay was performed to evaluate their fetal or maternal origin.Six different types of non-hematological maternal and four different types of embryo-fetal cells were detected. The most common maternal cells were of epithelial origin. The majority of embryo-fetal cells were roundish with a nucleus located in an eccentric position near the wall. These cells were considered to be erythroblasts, probably derived from the yolk sac that serves as the initial site of erythropoiesis.The combined use of morphology and DNA analysis makes it possible to select and isolate embryo-fetal cells, even when maternal contamination is high. This development provides the opportunity for the use of celocentesis for early prenatal diagnosis of genetic diseases and application of array comparative genomic hybridization. © 2016 John WileySons, Ltd.

Study question Is the Fertility Quality of Life Questionnaire (FertiQoL)-Relational Scale a valid measure to assess the relational domain regarding quality of life in women and men undergoing infertility treatment? Summary answer The FertiQoL-Relational scale (FertiQoL-REL) showed good psychometric properties and captured core aspects of couple relationships. What is known already FertiQoL has become a gold standard for the assessment of infertility-related quality of life in patients undergoing assisted reproduction treatment (ART). Despite its growing importance, no previous studies have examined the convergent validity of the FertiQoL-REL and its discriminant validity across gender. Study design, size, duration Baseline cross-sectional data as part of a longitudinal study of infertile couples undergoing an ART between February 2013 and January 2015. Participants/materials, setting, methods Five hundred and eighty-nine patients (301 females and 288 males), prior to starting an ART in a private clinic, filled in the Fertility Quality of Life Questionnaire (FertiQoL) and several measures of the marital relationship (Dyadic Adjustment Scale, Marital Commitment Inventory and ENRICH Marital Satisfaction Scale) and infertility-related distress (Fertility Problem Inventory). Main results and the role of chance Confirmatory factor analysis showed that the FertiQoL four-factor solution provided a good fit for the observed data. Reliability of the FertiQoL-REL was higher for women than men. Significant correlations between the FertiQoL-REL scores and all the other measures of marital relationship were found for both women and men. FertiQoL-REL scores did not differ significantly in women and men. The FertiQoL-REL was able to differentiate subjects as regards the Dyadic Adjustment Scale and ENRICH Marital Satisfaction Scale threshold. Limitations, reasons for caution Findings are limited because the data were obtained from only one Italian private clinic. Wider implications of the findings FertiQoL-REL threshold scores are useful for identifying those patients undergoing ART who are more likely to report poor or good relationship quality. Clinicians should tailor their counselling strategies to the positive qualities in a couple's relationship, so as to reinforce the overall quality of life, especially among women, and to support patients in tackling the psychological burden, so that they can either continue treatment or choose discontinuation. Study funding/competing interests This research was supported by funds provided by Centro Andros S.r.l., Palermo, Italy. The authors declare no financial or commercial conflicts of interest in this study. Trial registration number Not necessary.

background: To understand which genes are really involved in the implantation process, we planned to study the gene basal expression profile during the window of implantation (WOI) of patients who became pregnant in a subsequent ICSI cycle. methods: Women attending their first ICSI cycle at ANDROS Day Surgery for severe male factor infertility were included in the study. An endometrial biopsy was performed during the WOI, in one of the last two cycles before the ICSI cycle. Forty-seven selected gene profiles were analyzed using Low Density Array technology. Only biopsies from women who subsequently became pregnant were evaluated, to exclude any bias regarding embryo viability and embryo transfer difficulties. results: Fifteen patients were included in the analysis as they became pregnant after ICSI procedure. Four of 47 selected genes were excluded from the analysis. Of the 43 genes analyzed, only 6 genes (VEGFA, PLA2G2A, ALPL, LIF, NNMT and STC1) showed a statistically uniform expression among patients who subsequently became pregnant. For all the other genes analyzed there were considerable differences in their expression levels amongst women who subsequently became pregnant. conclusions: Our data suggest that very few genes, which change their expression level during the WOI, show a quantitative homogeneous expression in endometrially-receptive patients. In conclusion, in this study only six genes showed a homogeneous expression, and are probably involved in embryo implantation mechanisms.

The aim of this study was to investigate the most suitable sperm preparation technique to apply in order to obtain a spermatozoon population with minimal DNA damage during in vitro fertilization procedures. We compared four preparation techniques: direct swim-up (DSU), pellet swim-up (PSU), density gradient (DG), and density gradient followed by swim-up (DG-SU), evaluating the effects of each technique on the DNA damage rate, evaluated by DNA fragmentation index of the spermatozoa obtained. In this observational study, 98 semen samples from couples undergoing IVF/ICSI cycles were included. Data were collected between April and November 2014 at the ANDROS Day Surgery Clinic, Palermo, Italy. The percentages of DNA fragmentation were 18.30 ± 10.8 in raw samples, 6.6 ± 5.7 after DSU, 4.2 ± 3.8 after PSU, 12.9 ± 9.9 after DG, and 3.7 ± 4.0 after DG-SU respectively. Compared to the raw evaluation, all the preparation techniques significantly decreased the total rate of the DNA fragmentation (DSU Z = −8.60, P

The factor structure of the Fertility Problem Inventory (FPI) and its invariance across gender were examined in Italian couples undergoing infertility treatment. About 1000 subjects (both partners of 500 couples) completed two questionnaires prior to commencing infertility treatment at a private Clinic in Palermo, Italy. Confirmatory Factor Analysis demonstrated that the original factor structure of the FPI was partially confirmed. Two correlated factors (Infertility Life Domains and Importance of Parenthood) were obtained via a post hoc Exploratory Factor Analysis. Finally, the invariance of this factor structure across gender was confirmed. The study supported the relevance of two interrelated factors specific to infertility stress which could help clinicians to focus on the core infertility-related stress domains of infertile couples.

BACKGROUND Our prospective randomized controlled trial was designed to assess whether the use of GnRH antagonists can improve the success rate of controlled ovarian stimulation (COS)/intrauterine insemination (IUI) treatments, via inhibition of the premature LH rise. METHODS A total of 104 patients were randomly divided, using a randomization list, into two groups: in group A (n = 52), recombinant FSH (rFSH) was given with GnRH antagonist Cetrorelix, and in group B (n = 52), the patients received rFSH alone in a manner similar to that of group A. The primary outcome measure was clinical pregnancy rate per couple. RESULTS The pregnancy rate per patient was 53.8% in group A and 30.8% in group B (P = 0.017). The rate of premature LH surge was 7% in group A and 35% in group B (P < 0.0001). A premature luteinization was observed in two cycles of 144 in group A (1.4%) and in 16 cycles of 154 in group B (10.4%) (P = 0.001). The mean values of LH and progesterone were significantly lower in patients receiving GnRH antagonist than in those who did not (3.3 +/- 3.3 mIU/ml in group A versus 9.9 +/- 7.9 mIU/ml in group B, P < 0.0001, for LH; 1.3 +/- 1.1 ng/ml versus 2.1 +/- 1.9 ng/ml for group A and B, respectively, P < 0.0001, for progesterone). CONCLUSION The use of GnRH antagonist in COS/IUI cycles improves pregnancy rate, preventing the premature LH rise and luteinization.

Prenatal diagnosis of hemoglobinopathies involves the study of fetal material from blood, amniocytes, trophoblast coelomatic cells and fetal DNA in maternal circulation. Its first application dates back to the 70s and it involves globin chain synthesis analysis on fetal blood. In the 1980s molecular analysis was introduced as well as amniocentesis and chorionic villi sampling under high-resolution ultrasound imaging. The application of direct sequencing and polymerase chain reactionbased methodologies improved the DNA analysis procedures and reduced the sampling age for invasive prenatal diagnosis from 18 to 16–11 weeks allowing fetal genotyping within the first trimester of pregnancy. In the last years, fetal material obtained at 7–8 weeks of gestation by coelocentesis and isolation of fetal cells has provided new platforms on which to develop diagnostic capabilities while non-invasive technologies using fetal DNA in maternal circulation are starting to develop.

PURPOSE: The objective of this experimental study was to compare the global gene expression profile of CC of mature oocytes in 18 patients with severe endometriosis and CC in 18 control patients affected by a severe male factor. METHODS: For each group, the CC were pooled, RNA was extracted and a microarray performed. For validating the microarray, a quantitative real-time PCR was performed in the CC of an independent set of patients with endometriosis (n = 5) and controls (n = 7). RESULTS: 595 differentially expressed genes (320 down-regulated, 275 up-regulated, p

Objective To demonstrate that reduction of the cumulative dropout rate (CDR) improves the accuracy of the estimate of the cumulative pregnancy rate (CPR) in a set of four intrauterine insemination (IUI) cycles (“four-cycle program”) and increases the total number of pregnancies obtained. Study design Single-centre retrospective observational cohort study of couples who underwent IUI cycles at the Andros Day Surgery Clinic, Palermo, from 1997 to 2011. The main outcome measure was the calculation of the CPR, with life table analysis, firstly by giving the same probability of pregnancy to the dropouts as the patients who continued the treatment (usual method) and secondly by considering this probability null (conservative method). The difference between these two methods was used to verify the accuracy of the estimate. Result(s) In the 15 years, 924 couples underwent 2956 cycles carried out consecutively in a set of four cycles. The CDR was 16%. The CPR was 31.4% with the usual method and 29.1% with the conservative method. The difference between the two estimates was not significant, indicating a high reliability of the results and a good accuracy of the calculation. Furthermore, maintenance of a low CDR permits improvement of the CPR, as was demonstrated by considering scenarios with worse dropout rates. Conclusion(s) The “four-cycle program” results in a reduction in the CDR, allowing a better estimation of the CPR, and increases the number of actual pregnancies in IUI. The CPR should become the focus for reporting outcome rates in IUI cycles. Reduction of the dropout rate allows us to give the patient a more reliable and accurate estimate of the pregnancy rate.

Objectives To compare multipotent mesenchymal stem cells (MSCs) obtained from chorionic villi (CV), amniotic fluid (AF) and placenta, with regard to their phenotype and gene expression, in order to understand if MSCs derived from different extra-embryonic tissues, at different stages of human ontological development, present distinct stemness characteristics. Study design MSCs obtained from 30 samples of CV, 30 of AF and 10 placentas (obtained from elective caesarean sections) were compared. MSCs at second confluence cultures were characterized by immunophenotypic analysis with flow cytometry using FACS CANTO II. The expression of the genes Oct-4 (Octamer-binding transcription factor 4, also known as POU5F1), Sox-2 (SRY box-containing factor 2), Nanog, Rex-1 (Zfp-42) and Pax-6 (Paired Box Protein-6), was analyzed. Real-time quantitative PCR was performed by ABI Prism 7700, after RNA isolation and retro-transcription in cDNA. Statistical analysis was performed using non-parametric test Kruskal–Wallis (XLSTAT 2011) and confirmed by REST software, to estimate fold changes between samples. Each gene was defined differentially expressed if p -value was Results Cells from all samples were negative for haematopoietic antigens CD45, CD34, CD117 and CD33 and positive for the typical MSCs antigens CD13, CD73 and CD90. Nevertheless, MSCs from AF and placentas showed different fluorescence intensity, reflecting the heterogeneity of these tissues. The gene expression of OCT-4, SOX-2, NANOG was not significantly different among the three groups. In AF, REX-1 and PAX-6 showed a higher expression in comparison to CV. Conclusions MSCs of different extra-embryonic tissues showed no differences in immunophenotype when collected from second confluence cultures. The expression of OCT-4, NANOG and SOX-2 was not significantly different, demonstrating that all fetal sources are suitable for obtaining MSCs. These results open new possibilities for the clinical use of MSCs derived from easily accessible sources, in order to develop new protocols for clinical and experimental research.

Background. The possibility of obtaining mesenchymal stem cells (MSCs) from fetal tissue such as amniotic fluid, chorionic villi and placenta is well-known and a comparison between MSCs originating in different sources such as fetal tissue and those from bone marrow in terms of yield and function is a topical issue. The mesenchymal stem cells isolated from bone marrow are well-characterized. Unfortunately the low quantitative yield during isolation is a major problem. For this reason, other tissue sources for MSCs are of paramount importance. Conclusion. In this review, starting from a description of the molecular and cellular biology of MSCs, we describe alternative sources of isolation other than bone marrow. Finally, we describe the potential therapeutic application of these cells.

Not available (case report)

The objective of this study was to identify the endometrial gene expression profile in receptive phase, which could represent a useful prognostic tool for selecting IVF patients. Endometrial expression of 47 selected genes biopsied during the window of implantation in natural cycles was compared between patients who achieved a successful pregnancy spontaneously or after subsequent intracytoplasmic sperm injection (ICSI) cycles and patients who did not achieve a pregnancy after at least two failed ICSI cycles. The comparative analysis showed significantly different levels of expression in 19 genes, five implicated in apoptosis (CASP8, FADD, CASP10, APAF1, ANXA4), three in immunity (LIF, SPP1, C4BPA), five in transcriptional activity (MSX1, HOXA10, MSX2, HOXA11, GATA2), two in lipid metabolism (LEPR, APOD) and four in oxidative metabolism (AOX1, ALDH1A3, GPX3, NNMT). The evidence for these genes being differently expressed could represent the starting point of identifying the ideal receptive endometrial gene expression profile, which could be used in the future as a prognostic tool for IVF patients. Gene expression analysis technology has opened new important perspectives on the study of the physiological processes of different tissues and organs. Specifically for the endometrium, it would be really interesting to find out an endometrial gene expression profile of receptive phase, which could be used in future as a useful prognostic tool for selecting IVF patients. To achieve this aim, the objective of the present paper was the comparison of endometrial expression in natural cycles of 47 selected genes between the biopsies of patients who achieved a successful pregnancy, either spontaneously or after subsequent ICSI cycles, and those of patients who did not achieve a pregnancy after at least two failed ICSI cycles. The comparative analysis showed a significant different expression in 19 genes: five implicated in programmed cell death, known as apoptosis (CASP8, FADD, CASP10, APAF1, ANXA4), three in immunity (LIF, SPP1, C4BPA), five in transcriptional activity (MSX1, HOXA10, MSX2, HOXA11, GATA2), two in lipid metabolism (LEPR, APOD) and four in oxidative metabolism (AOX1, ALDH1A3, GPX3, NNMT). The evidence of these genes being differently expressed could represent the starting point of identifying the ideal receptive endometrial gene expression profile which could be used in the future as a prognostic tool for IVF patients.

study question: Are attachment anxiety and avoidance dimensions in female and male partners in couples seeking infertility treat- ment associated with her and his infertility-related stress? summary answer: Attachment dimensions are significantly associated with several aspects of infertility stress in couples undergoing IVF treatment. what is known and what this paper adds: Attachment dimensions of anxiety and avoidance (where highly anxious individuals fear rejection and are preoccupied with maintaining proximity to their partner and highly avoidant individuals are uncomfortable with intimacy and prefer to maintain distance from their partner) may influence the well being of individuals undergoing IVF/ICSI treatment. This study showed that one partner’s attachment dimensions had a direct effect on the infertility-related stress of the other partner. design: Cross-sectional study of consecutive couples before starting their first IVF/ICSI treatment in 2009–2011 at the ANDROS clinic in Palermo, Italy. participants and setting: Three hundred and fifty-nine couples undergoing fertility treatments were invited to participate in the research. The final sample comprised 316 females and 316 males who filled out the psychological questionnaires (Experiences in Close Rela- tionships; Fertility Problem Inventory; State scale of State-Trait Anxiety Inventory). The participants included patients who had a primary infertility diagnosis and were about to undergo their first IVF or ICSI treatment. data analysis method: Paired t-tests were used to examine gender differences on the study variables (attachment anxiety, attach- ment avoidance, infertility stress, state anxiety, etc.). Associations between infertility-related stress and the study variables were explored using hierarchical stepwise multivariate linear regression analyses. main results and the role of chance: Attachment anxiety and attachment avoidance were significantly associated with global infertility stress in both women (b 1⁄4 0.24, P , 0.01 and b 1⁄4 0.27, P , 0.01) and men (b 1⁄4 0.23, P , 0.01 and b 1⁄4 0.37, P , 0.01). Regarding the cross-partner effects, men’s infertility stress and relationship concerns were associated with their partners’ attachment avoidance (b 1⁄4 0.10 P , 0.05 and b 1⁄4 0.12, P , 0.05); and the infertility stress of women and the scores for need of parenthood were associated with their partners’ attachment anxiety (b 1⁄4 0.14 P , 0.05 and b 1⁄4 0.16, P , 0.05). bias, confounding and other reasons for caution: The study data are cross sectional, and specifically focus on associations between adult attachment style and infertility stress. Treating the data from couples as independent observations may be a limi- tation of the analysis. Potential moderators of such relationships (e.g. coping strategies, stress appraisal) are not included in this study.

Objective To describe the occurrence and management of conjoined twins (CTs) in a trichorionic quadruplet pregnancy after the transfer of three embryos obtained by intracytoplasmic sperm injection (ICSI) that had undergone assisted zona hatching (AZH) using a noncontact laser. Design Case report. Setting Private and public IVF centers. Patient(s) A 38-year-old nulliparous woman. Intervention(s) IVF, diagnosis by two-dimensional, three-dimensional, and four-dimensional ultrasound, selective termination at 12 weeks gestation. Main Outcome Measure(s) Clinical follow-up and delivery. Result(s) After diagnosis, counselling, and selective termination, the subsequent prenatal course was uneventful, and two healthy boys were delivered by elective cesarean section at 38 weeks gestation. Conclusion(s) Monozygotic twinning (MZT) and CTs could complicate multifetal pregnancies obtained by assisted reproduction techniques. The relationship between CTs, IVF, and AZH should be better studied to fully understand the mechanisms that lead to MZT (with the possible role of AZH) and CTs in MZT, in particular. Three-dimensional and four-dimensional ultrasound improve prenatal assessment of the condition. Selective embryo reduction is a safe procedure for the management of these pregnancies.

Objective To evaluate the predictive value for implantation and pregnancy rates of the number of embryos that reach the eight-cell stage with less than 20% fragmentation (good quality embryos) on day 3. Design Prospective observational study. Setting Private IVF center. Patient(s) One hundred eighty-nine women undergoing IVF, or intracytoplasmic sperm injection with at least four zygotes, who have had three embryos transferred on day 3. Intervention(s) None. Main outcome measure(s) Pregnancy rate and implantation rate. Result(s) All patients (n = 189) had 3 embryos transferred. The patients were divided in five groups according to the number of good quality embryos on day 3 (0, 1, 2, 3, >3; respectively). For the five groups, the pregnancy rates were 2.9%, 33.3%, 45.5%, 39.4%, and 64.3%; the implantation rates were 2.0%, 17.0%, 20.5%, 19.3%, and 35.7%. No statistically significant differences in pregnancy rate or implantation rate were found for groups 1, 2, and 3 (when 1, 2, or 3 good quality embryos were present). The data were also analyzed after pooling these three groups. A statistically significant difference in pregnancy rate and implantation rate was found for group 0 (no good quality embryos), groups 1, 2, and 3 (1, 2, or 3 good quality embryos), and group >3 (>3 good quality embryos). Conclusion(s) The number of good quality embryos available on day 3 is a strong predictive value for both pregnancy rate and implantation rate. When good quality embryos are present on day 3, only two embryos should be transferred to minimize multiple pregnancies.

The aim of this prospective, longitudinal study was to examine the association between couples' pre-treatment psychological characteristics (state anxiety and infertility-related stress levels of both partners) and ovarian response during assisted reproductive technology treatment in a well-controlled sample. A total of 217 heterosexual couples (434 patients), suffering from primary infertility and undergoing their first assisted reproductive technology treatment at the Reproductive Medicine Unit of ANDROS Day Surgery Clinic in Palermo (Italy), were recruited. Psychological variables were assessed using the State Scale of State-Trait Anxiety Inventory (STAI-S) and the Fertility Problem Inventory (FPI). The number of follicles ≥16 mm in diameter, evaluated by transvaginal ultrasound scan on the eleventh day of the workup, was chosen as the outcome measure. No association between women's level of anxiety and infertility-related stress, and the number of follicles ≥16 mm in diameter was found. Moreover, the male partner's infertility stress and anxiety did not influence the relationship between the woman's infertility-related stress, anxiety level and ovarian response. Fertility staff should reassure couples that the woman's biological response to ovarian stimulation is not influenced by either partner's level of psychological distress.