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Study question What are the characteristics of the psychological care and the emotional needs of couples undergoing ART treatment in Italy? Summary answer The presence of psychological support services in ART centers is poorly communicated to patients, with less than half being advised to take a pathway. What is known already Couples who decide to undergo ART treatment show significantly higher depression and shame scores, lower acceptance and self-compassion scores, greater reliance and avoidant coping strategies. Couples experience the procedure as source of stress, anxiety and pain, fluctuating between hope and despair, and all of this seem to negatively impact on treatment continuation and outcomes. A review of 25 studies using different psychological interventions (counseling, focused educational interventions and integrated educational programs) found positive effects on anxiety (61.5%), depression (38.4%) and infertility-related stress (100%) reduction. Several studies showed the effectiveness of psychological intervention in promoting pregnancy rates. Study design, size, duration The ART Italian National Register (National Health Institute) with the Department of Dynamic and Clinical Psychology and Health Studies (Sapienza University) proposed a national survey to 195 Italian ART centres and patient associations. Patient associations and the Medical Director of each centre were invited by e-mail to participate and to encourage all patients to fill a questionnaire made available on an on-line platform. Data collection was between March to October 2021. Participants/materials, setting, methods 324 ART patients completed an online questionnaire consisting of 19 closed-ended and 8 open-ended questions. In this abstract we focus on the closed-ended questions. The questionnaire was created ad hoc for the survey starting from a previous study on the characteristics of the services offered in Italian ART centres. Main results and the role of chance In 90% of cases women responded to the questionnaire, only 10% of responses were from men. On average, participants are 38 years old, married (60%), and have a bachelor's degree or post-graduate degree (59%). In half of the cases respondents are employed. In 68% of cases, participants performed ART treatment in centers with public service. Most of the respondents are facing their first or second ART cycle. They share their infertility condition with family and friends, and in 60% of cases they have been informed of the presence of the psychological service, mainly from gynecologists and through informed consent. Only in 31% of cases patients were invited to undertake psychological counseling, strongly recommended to only 8% of them. In fact, 65% of respondents never had a meeting with the psychologist during ART treatment. Those who resorted to counseling had mainly couple (45%) and individual (31.3%) meetings. Participants did not know the cost of counseling, would prefer it to be included in the cost of ART treatment, and would like it to be available throughout treatment The main emotions felt during ART treatment are sadness, fear and anger, those attributed to the partner are the same but joy also appears. Limitations, reasons for caution Firstly the limited sample size, mainly related to the ability of ART center staff to spread the initiative among patients. The low response from male partners, that could be related to their rare presence in ART centers, as the medical treatment is mainly targeted to women. Wider implications of the findings In conclusion, the results show that psychological services in Italian ART centers are not yet fully operational and integrated in the ART procedure. All this highlights the importance of further investigations with the aim of sharing information to establish common protocols for psychological interventions in ART centres. Trial registration number Not applicable

Study question Could factors inherent to individual centers, related to local clinical or laboratory variables, play a role in the increased incidence of monozygotic twins in IVF? Summary answer The rate of MZT did not significantly vary among IVF centers What is known already The risk of monozygotic twins (MZT) is increased in couples undergoing in vitro fertilization (IVF). Several systematic reviews have investigated the possible determinants linked to IVF, but results obtained have been inconclusive. Associations have been identified with the prolonged culture at blastocyst stage and young female age. Conventional IVF compared to ICSI, and assisted hatching emerged as possible additional risk factors, but evidence is controversial. Meta-analyses, however, cannot provide robust evidence because of the difficulty in performing multivariate analyses. Moreover, available investigations were retrospective and involved relatively small sample sizes hampering the quality of the collected data. Study design, size, duration This is a multicenter retrospective cohort study using the Italian ART National Registry database and involving the Centers reporting data from individual IVF cycles from 2015 to 2019. Eighteen IVF centers were included with a total of 87,076 IVF cycles reported during the study period. The primary aim of the study was to investigate whether the incidence of MZT differed among centers. Participants/materials, setting, methods Only single embryo transfer cycles were considered. Women who had sex-discordant twin deliveries were excluded. MZT rate was calculated as the number of multiple pregnancies out of the total number of clinical pregnancies. A binomial distribution model was used to determine the 95% CI of the frequency of MZT. The rates among centers were deemed heterogeneous if the 95% CI in at least one center did not include the mean MZT rate. Main results and the role of chance Ten centers reported data from 2015 to 2019, eight from 2017 to 2019. An analysis of the main characteristics of the centers revealed considerable variability. The total number of clinical pregnancies fulfilling our inclusion criteria were 10,440. Of these, 7 were found to be twin pregnancies with discordant gender and were excluded, leaving 10,433 for data analyses. The number of cases included per center varied between 11 and 2,823. Overall, 162 pregnancies were found to be multiple: 48 ended in a miscarriage, 28 spontaneously reduced to singletons and 86 women delivered two or more newborns. The vast majority were twins (n = 160), one was triplet, and one was quadruplet. Considering the denominator of 10,433 pregnancies, the rate of MZT was thus 1.5% (95%CI: 1.3 - 1.8%). The MZT rate among centers varied between 0% (95%CI: 0.0 - 25.9%) and 3.2% (95%CI: 1.3 - 8.1%). All the 95%CIs of the rates of MZT include the 1.5% common rate, thus rejecting the hypothesis that this incidence significantly differed among centers. Spearman correlations between the rate of MZT and variables associated with individual center policies could not identify any significant association. Even when restricting the analyses only to the largest centers, no association emerged. Limitations, reasons for caution Our study was limited by its retrospective nature. Furthermore, some centers provided less than 100 cases for data analysis and were therefore poorly informative. External confirmation from larger registries is therefore required. Wider implications of the findings This study provides evidences that the rate of MZT did not differ among IVF centers. Furthermore, no clinical and laboratory variables inherent to individual centers were identified in the determinism of IVF-associated MZT. Further studies are needed to identify the causes of increased risk of MZT in IVF practice. Trial registration number not applicable

Study question Evaluate the impact of restrictive measures, implemented to contain the spread SARS-CoV-2, on ART activity in Italy during 2020. Summary answer Due to periods of suspension of certain medical procedures in 2020, ART activity has undergone a substantial reduction. What is known already Since the end of February 2020, the spread of SARS-CoV-2 has taken a dramatic toll, especially in Northern Italy. In order to ensure that the majority of National Health System resources were employed to control the epidemic, non-urgent medical procedures such as ART treatments, were suspended or postponed by a Government Decree issued on March 9, 2020. Only fertility preservation in cancer patients continued as these procedures could not be deferred. The first suspension of activity lasted about two months. Then, throughout 2020 many ART centers were forced to suspend their activity again because of flairs in SARS-CoV-2 infection rates. Study design, size, duration The Italian Assisted Reproductive Technology Register (IARTR) retrospectively analyzed ART cycles applied in Italy in 2020 (67,928 ART cycles performed on 57,423 patients). The 2020 ART cycles were compared to those applied in 2019 (82,476 ART cycles performed on 67,633 patients). Data collection was organized yearly in two different time frames: the first regards the activity conducted during the year until pregnancy and the second regards pregnancy outcomes. Participants/materials, setting, methods A total of 205 ART clinics have sent data to the IARTR in 2019 and/or 2020. Among those clinics 54.1% were private, 37.1% were public and 8.9% were private covered by NHS. Records were securely kept in the IARTR archive. The analysis has been performed utilizing SPSS 27.0 Main results and the role of chance In 2020, the number of total ART cycles reported was 67,928 including 38,728 homologous fresh cycles (Fresh), 1,099 frozen/thawed oocytes (FO), 19,314 frozen embryo (FER) and 8,787 ART donation cycles. In 2019, 82,476 cycles were reported, including 50,324 Fresh, 1,361 FO, 21,796 FER and 8,995 gametes donation. In 2020, there have been 14,548 less ART cycles than in 2019, equivalent to a 17.6% of reduction in overall activity. However, the reduction was not homogeneous for all ART techniques, in particular there was a reduction of -23% in fresh cycles, of -11.4% in FER, of -19.3% in FO and of -2.3% for gametes donation. This overall reduction led to 3,325 fewer pregnancies. The reduction of treatment cycles observed in 2020 brings to 2,119 fewer deliveries (-18.0%) and to 2,539 fewer live born babies (-19.8%) compared to 2019. The percentage reduction of births is not homogeneous for the different ART techniques, ranging from -0.3% in donation cycles to -36.9% in fresh cycles. Lastly, during 2020 a reduction in multiple births (-2.1%) has been observed. Limitations, reasons for caution Since the national ART Register collect only summary data more deep analysis could not be performed. For some ART techniques the reduction may have been greater (i.e. donation cycles) if considering the growing trends of previous years. Wider implications of the findings Covid-19 pandemic has had a strong impact on Italian Health System. ART procedures suffered a reduction of availability. Since Italy has the lowest birth rate in Europe and ART plays an important role answering to the need of infertile couples, Government should support access to these treatments with dedicated actions. Trial registration number not applicable

Study question What is the point of view of physicians, psychologists and patients on the characteristics of the psychological assistance offered by Italian ART centres? Summary answer Physicians, psychologists and patients alike affirm the importance of specialised psychological support during ART treatment What is known already The European Society of Human Reproduction and Embryology (ESHRE) has produced specific recommendations, establishing that all staff members should share the responsibility related to patients’ psychological wellbeing through their treatments. Moreover, when patients show increased risk of negative consequences some specialized services, as psychological counseling or psychotherapy, should be provided. In Italy, the Law 40/2004 regulates ART treatment and also provides the “Guidelines for the application of Assisted Reproductive Technology” (2008, 2015). According to this law, psychological support for women and couples undergoing ART procedures at any step of medical treatment (before, during, after the treatment) should be routinely included. Study design, size, duration To explore opinions on the characteristics of the psychological support service in ART centres: An online questionnaire was sent to the physicians in charge of 341 ART centres. 5 focus groups with psychologists working in ART centres were carried out. An online questionnaire for patients was sent to 195 centres and 8 patient associations. The surveys were conducted over a period from January 2020 to October 2021. Participants/materials, setting, methods Physicians from 113 centres (37%) responded to questionnaires composed of 20 closed-ended and 6 open-ended questions; 28 psychologists working in ART centres in 3 italian regions participated in focus groups with 3 open-ended questions; and 324 patients responded to questionnaires composed of 19 closed-ended and 8 open-ended questions. The questionnaires were created ad hoc for the surveys starting from the characteristics of the services offered in Italian ART centers. Main results and the role of chance Physicians affirm the importance of the psychologist in the ART centre to support their work: managing couples’ emotional difficulties; improving couples’ mood; and reducing couples’ stress (9% of answers). They also ask for an effective psychological intervention protocol to adopt. Concerning the characteristics of psychological services, physicians do not identify priority areas of intervention, but they admit the usefulness of psychological intervention throughout the treatment. Most physicians admit the utility of psychological counseling as defined by the 2015 Guidelines. Psychologists would like more recognition of their function and they affirm the positive contribution of networking among ART psychologists, believing that specific training is needed to work in the field. The psychologists find that multidisciplinary work in the team is functional and improves the quality of service offered in this field. Patients say that ongoing psychological support throughout the treatment could be helpful for them. They believe that psychologists should have specific training in ART and they would like the cost of psychological support to be included in ART treatment. They argue that psychological support should help their relationship with physicians. Despite this, the psychologist is a stable professional figure in only half of the responding ART Centres (47%). Limitations, reasons for caution Physicians’ opinions are based on a 37% response rate from ART centres and cannot be considered conclusive. The 5 focus groups were conducted with psychologists working in ART centres located in only three Italian regions. There were few responses from male patients. Wider implications of the findings In conclusion, despite the scarce presence of psychological support in ART centres, physicians, psychologists and patients believe that it would be mportant throughout ART treatment. This highlights the importance of further investigation with the aim of sharing information to establish common protocols for psychological interventions in italian ART centres. Trial registration number not applicable

STUDY QUESTION Are there any changes in the treatments involving ART and IUI initiated in Europe during 2013 compared with previous years? SUMMARY ANSWER An increase in the overall number of ART cycles resulting from a higher number of countries reporting data was evident, the pregnancy rates (PRs) in 2013 remained stable compared with those reported in 2012, the number of transfers with multiple embryos (3+) was lower than ever before yet the multiple delivery rates (DRs) remained unchanged, and IUI activity and success rates were similar to those of last years. WHAT IS KNOWN ALREADY Since 1997, ART data in Europe have been collected and reported in 16 manuscripts, published in Human Reproduction. STUDY DESIGN, SIZE, DURATION Retrospective data collection of European ART data by the European IVF-monitoring Consortium for ESHRE. Data for cycles between 1 January and 31 December 2013 were collected from National Registers, when existing, or on a voluntary basis by personal information. PARTICIPANTS/MATERIALS, SETTINGS, METHODS From 38 countries (+4 compared with 2012), 1169 clinics reported 686 271 treatment cycles including 144 299 of IVF, 330 367 of ICSI, 154 712 of frozen embryo replacement (FER), 40 244 of egg donation (ED), 247 of IVM, 9791 of PGD/PGS and 6611 of frozen oocyte replacements. European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1095 IUI labs in 22 countries. A total of 175 467 IUI-H and 43 785 IUI-D cycles were included. MAIN RESULTS AND THE ROLE OF CHANCE In 17 countries where all clinics reported to their ART register, a total of 374 177 ART cycles were performed in a population of around 310 million inhabitants, corresponding to 1175 cycles per million inhabitants (range, 235-2703 cycles per million inhabitants). For all IVF cycles, the clinical PRs per aspiration and per transfer were stable with 29.6% (29.4% in 2012) and 34.5% (33.8% in 2012), respectively. For ICSI, the corresponding rates also were stable with 27.8% (27.8% in 2012) and 32.9% (32.3% in 2012). In FER-cycles, the PR per thawing/warming increased to 27.0% (23.1% in 2012). In ED cycles, the PR per fresh transfer increased to 49.8% (48.4% in 2012), to 38.5% (35.9% in 2012) per thawed transfer, and to 46.4% for transfers after FOR (45.1% in 2012). The DRs after IUI remained stable at 8.6% (8.5% in 2012) after IUI-H and was slightly lower after IUI-D (11.1% versus 12.0% in 2012). In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 31.4, 56.3, 11.5, and 1.0% of the cycles, respectively (corresponding numbers were 30.2, 55.4, 13.3 and 1.1% in 2012). The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 82., 17.5 and 0.5%, respectively, resulting in a total multiple DR of 18.0% compared to 17.9% in 2012. In FER-cycles, the multiple DR was 12.8% (12.5% twins and 0.3% triplets), nearly the same as in 2012 (12.5, 12.2 and 0.3% respectively). Twin and triplet DRs associated with IUI cycles were 9.5%/0.6% and 7.5%/0.3%, following treatment with husband/donor semen, respectively. LIMITATIONS, REASONS FOR CAUTION The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, the results should be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS The 17th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 685 000 cycles reported in 2013 and an increasing contribution to birth rate in many countries. However, the need to improve and standardize the national registries, and to establish validation methodologies, remains manifest. STUDY FUNDING/COMPETING INTEREST(S) The study has no external funding; all costs are covered by ESHRE. There are no competing interests.

STUDY QUESTION How are ART and IUI regulated, funded and registered in European countries? SUMMARY ANSWER Of the 43 countries performing ART and IUI in Europe, and participating in the survey, specific legislation exists in only 39 countries, public funding (also available in the 39 countries) varies across and sometimes within countries and national registries are in place in 31 countries. WHAT IS KNOWN ALREADY Some information devoted to particular aspects of accessibility to ART and IUI is available, but most is fragmentary or out-dated. Annual reports from the European IVF-Monitoring (EIM) Consortium for ESHRE clearly mirror different approaches in European countries regarding accessibility to and efficacy of those techniques. STUDY DESIGN, SIZE, DURATION A survey was designed using the online SurveyMonkey tool consisting of 55 questions concerning three domains—legal, funding and registry. Answers refer to the countries’ situation on 31 December 2018. PARTICIPANTS/MATERIALS, SETTINGS, METHODS All members of EIM plus representatives of countries not yet members of the Consortium were invited to participate. Answers received were checked, and initial responders were asked to address unclear answers and to provide any additional information they considered important. Tables of individual countries resulting from the consolidated data were then sent to members of the Committee of National Representatives of ESHRE, asking for a second check. Conflicting information was clarified by direct contact. MAIN RESULTS AND THE ROLE OF CHANCE Information was received from 43 out of the 44 European countries where ART and IUI are performed. Thirty-nine countries reported specific legislation on ART, and artificial insemination was considered an ART technique in 35 of them. Accessibility is limited to infertile couples in 11 of the 43 countries. A total of 30 countries offer treatments to single women and 18 to female couples. In five countries ART and IUI are permitted for treatment of all patient groups, being infertile couples, single women and same sex couples, male and female. Use of donated sperm is allowed in 41 countries, egg donation in 38, the simultaneous donation of sperm and egg in 32 and embryo donation in 29. Preimplantation genetic testing (PGT) for monogenic disorders or structural rearrangements is not allowed in two countries, and PGT for aneuploidy is not allowed in 11; surrogacy is accepted in 16 countries. With the exception of marital/sexual situation, female age is the most frequently reported limiting criteria for legal access to ART—minimal age is usually set at 18 years and maximum ranging from 45 to 51 years with some countries not using numeric definition. Male maximum age is set in very few countries. Where permitted, age is frequently a limiting criterion for third-party donors (male maximum age 35 to 55 years; female maximum age 34 to 38 years). Other legal constraints in third-party donation are the number of children born from the same donor (in some countries, number of families with children from the same donor) and, in 10 countries, a maximum number of egg donations. How countries deal with the anonymity is diverse—strict anonymity, anonymity just for the recipients (not for children when reaching legal adulthood age), mixed system (anonymous and non-anonymous donations) and strict non-anonymity. Public funding systems are extremely variable. Four countries provide no financial assistance to patients. Limits to the provision of funding are defined in all the others i.e. age (female maximum age is the most used), existence of previous children, maximum number of treatments publicly supported and techniques not entitled for funding. In a few countries, reimbursement is linked to a clinical policy. The definition of the type of expenses covered within an IVF/ICSI cycle, up to what limit and the proportion of out-of-pocket costs for patients is also extremely dissimilar. National registries of ART and IUI are in place in 31 out of the 43 countries contributing to the survey, and a registry of donors exists in 18 of them. LIMITATIONS, REASONS FOR CAUTION The responses were provided by well-informed and committed individuals and submitted to double checking. Since no formal validation was in place, possible inaccuracies cannot be excluded. Also, results are a cross section in time and ART and IUI legislations within European countries undergo continuous evolution. Finally, several domains of ART activity were deliberately left out of the scope of this ESHRE survey. WIDER IMPLICATIONS OF THE FINDINGS Results of this survey offer a detailed view of the ART and IUI situation in European countries. It provides updated and extensive answers to many relevant questions related to ART usage at national level and could be used by institutions and policymakers in planning services at both national and European levels. Study funding/competing interest(s) The study has no external funding, and all costs were covered by ESHRE. There were no competing interests. ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

STUDY QUESTION How are ART and IUI regulated, funded and registered in European countries? SUMMARY ANSWER Of the 43 countries performing ART and IUI in Europe, and participating in the survey, specific legislation exists in only 39 countries, public funding (also available in the 39 countries) varies across and sometimes within countries and national registries are in place in 31 countries. WHAT IS KNOWN ALREADY Some information devoted to particular aspects of accessibility to ART and IUI is available, but most is fragmentary or out-dated. Annual reports from the European IVF-Monitoring (EIM) Consortium for ESHRE clearly mirror different approaches in European countries regarding accessibility to and efficacy of those techniques. STUDY DESIGN, SIZE, DURATION A survey was designed using the online SurveyMonkey tool consisting of 55 questions concerning three domains—legal, funding and registry. Answers refer to the countries’ situation on 31 December 2018. PARTICIPANTS/MATERIALS, SETTINGS, METHODS All members of EIM plus representatives of countries not yet members of the Consortium were invited to participate. Answers received were checked, and initial responders were asked to address unclear answers and to provide any additional information they considered important. Tables of individual countries resulting from the consolidated data were then sent to members of the Committee of National Representatives of ESHRE, asking for a second check. Conflicting information was clarified by direct contact. MAIN RESULTS AND THE ROLE OF CHANCE Information was received from 43 out of the 44 European countries where ART and IUI are performed. Thirty-nine countries reported specific legislation on ART, and artificial insemination was considered an ART technique in 35 of them. Accessibility is limited to infertile couples in 11 of the 43 countries. A total of 30 countries offer treatments to single women and 18 to female couples. In five countries ART and IUI are permitted for treatment of all patient groups, being infertile couples, single women and same sex couples, male and female. Use of donated sperm is allowed in 41 countries, egg donation in 38, the simultaneous donation of sperm and egg in 32 and embryo donation in 29. Preimplantation genetic testing (PGT) for monogenic disorders or structural rearrangements is not allowed in two countries, and PGT for aneuploidy is not allowed in 11; surrogacy is accepted in 16 countries. With the exception of marital/sexual situation, female age is the most frequently reported limiting criteria for legal access to ART—minimal age is usually set at 18 years and maximum ranging from 45 to 51 years with some countries not using numeric definition. Male maximum age is set in very few countries. Where permitted, age is frequently a limiting criterion for third-party donors (male maximum age 35 to 55 years; female maximum age 34 to 38 years). Other legal constraints in third-party donation are the number of children born from the same donor (in some countries, number of families with children from the same donor) and, in 10 countries, a maximum number of egg donations. How countries deal with the anonymity is diverse—strict anonymity, anonymity just for the recipients (not for children when reaching legal adulthood age), mixed system (anonymous and non-anonymous donations) and strict non-anonymity. Public funding systems are extremely variable. Four countries provide no financial assistance to patients. Limits to the provision of funding are defined in all the others i.e. age (female maximum age is the most used), existence of previous children, maximum number of treatments publicly supported and techniques not entitled for funding. In a few countries, reimbursement is linked to a clinical policy. The definition of the type of expenses covered within an IVF/ICSI cycle, up to what limit and the proportion of out-of-pocket costs for patients is also extremely dissimilar. National registries of ART and IUI are in place in 31 out of the 43 countries contributing to the survey, and a registry of donors exists in 18 of them. LIMITATIONS, REASONS FOR CAUTION The responses were provided by well-informed and committed individuals and submitted to double checking. Since no formal validation was in place, possible inaccuracies cannot be excluded. Also, results are a cross section in time and ART and IUI legislations within European countries undergo continuous evolution. Finally, several domains of ART activity were deliberately left out of the scope of this ESHRE survey. WIDER IMPLICATIONS OF THE FINDINGS Results of this survey offer a detailed view of the ART and IUI situation in European countries. It provides updated and extensive answers to many relevant questions related to ART usage at national level and could be used by institutions and policymakers in planning services at both national and European levels. Study funding/competing interest(s) The study has no external funding, and all costs were covered by ESHRE. There were no competing interests. ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

What are the European trends and developments in ART and IUI in 2014 as compared to previous years?The 18th ESHRE report on ART shows a continuing expansion of both treatment numbers in Europe and more variability in treatment modalities resulting in a rising contribution to the birth rates in most participating countries.Since 1997, ART data generated by national registries have been collected, analysed by the European IVF-monitoring (EIM) Consortium and reported in 17 manuscripts published in Human Reproduction.Continuous collection of European data by the EIM for ESHRE. The data for treatments performed in 2014 between 1 January and 31 December in 39 European countries were provided by national registries or on a voluntary basis by clinics or professional societies.From 39 countries and 1279 institutions offering ART services, a total of 776 556 treatment cycles, involving 146 148 with IVF, 362 285 with ICSI, 192 027 with frozen embryo replacement (FER), 15 894 with PGT, 56 516 with egg donation (ED), 292 with IVM and 3404 with frozen oocyte replacement (FOR) were reported. European data on IUI using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1364 institutions offering IUI in 26 countries and 21 countries, respectively. A total of 120 789 treatments with IUI-H and 49 163 treatments with IUI-D were included.In 14 countries (17 in 2013), where all institutions contributed to their respective national registers, a total of 291 235 treatment cycles were performed in a population of ~208 million inhabitants, corresponding to 1925 cycles per million inhabitants (range: 423-2978 per million inhabitants). After treatment with IVF the clinical pregnancy rates (PR) per aspiration and per transfer were marginally higher in 2014 than in 2013, at 29.9 and 35.8% versus 29.6 and 34.5%, respectively. After treatment with ICSI the PR per aspiration and per transfer were also higher than those achieved in 2013 (28.4 and 35.0% versus 27.8 and 32.9%, respectively). After FER with own embryos the PR continued to rise, from 27.0% in 2013 to 27.6% in 2014. After ED a similar trend was observed with PR reaching 50.3% per fresh transfer (49.8% in 2013) and 48.7% for FOR (46.4% in 2013). The delivery rates (DR) after IUI remained stable at 8.5% after IUI-H (8.6% in 2013) and at 11.6% after IUI-D (11.1% in 2013). In IVF and ICSI together, 1, 2, 3 and ≥4 embryos were transferred in 34.9, 54.5, 9.9 and in 0.7% of all treatments, respectively (corresponding to 31.4%, 56.3, 11.5% and 1% in 2013). This evolution in embryo transfer strategy in both IVF and ICSI resulted in a singleton, twin and triplet DR of 82.5, 17.0 and 0.5%, respectively (compared to 82.0, 17.5 and 0.5%, respectively, in 2013). Treatments with FER in 2014 resulted in a twin and triplet DR of 12.4 and 0.3%, respectively (versus 12.5 and 0.3% in 2013). Twin and triplet DR after IUI were 9.5 and 0.3%, respectively, after IUI-H (in 2013:9.5 and 0.6%) and 7.7 and 0.3% after IUI-D (in 2013: 7.5 and 0.3%).The method of data collection and reporting varies among European countries. The EIM receives aggregated data from various countries with variable levels of completeness. Registries from a number of countries have failed to provide adequate data about the number of initiated cycles and deliveries. As long as incomplete data are provided, the results should be interpreted with caution.The 18th ESHRE report on ART shows a continuing expansion of treatment numbers in Europe. The number of treatments reported, the variability in treatment modalities and the rising contribution to the birth rates in most participating countries point towards the increasing impact of ART on reproduction in Europe. Being the largest data collection on ART, the report gives detailed information about ongoing developments in the field.The study has no external funding and all costs are covered by ESHRE. There are no competing interests.

Study Question The 16th European IVF-monitoring (EIM) report presents the data of the treatments involving assisted reproductive technology (ART) and intrauterine insemination (IUI) initiated in Europe during 2012: are there any changes compared with previous years? Summary Answer Despite some fluctuations in the number of countries reporting data, the overall number of ART cycles has continued to increase year by year, the pregnancy rates (PRs) in 2012 remained stable compared with those reported in 2011, and the number of transfers with multiple embryos (3+) and the multiple delivery rates were lower than ever before. What is Known Already Since 1997, ART data in Europe have been collected and re-ported in 15 manuscripts, published in Human Reproduction. Study Design, Size, Duration Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE). Data for cycles between 1 January and 31 December 2012 were collected from National Registers, when existing, or on a voluntary basis by personal information. Participants/Materials, Setting, Methods From 34 countries (+1 compared with 2011), 1111 clinics reported 640 144 treatment cycles including 139 978 of IVF, 312 600 of ICSI, 139 558 of frozen embryo replacement (FER), 33 605 of egg donation (ED), 421 of in vitro maturation, 8433 of preimplantation genetic diagnosis/preimplantation genetic screening and 5549 of frozen oocyte replacements (FOR). European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1126 IUI labs in 24 countries. A total of 175 028 IUI-H and 43 497 IUI-D cycles were included. Main Results and the Role of Chance In 18 countries where all clinics reported to their ART register, a total of 369 081 ART cycles were performed in a population of around 295 million inhabitants, corresponding to 1252 cycles per million inhabitants (range 325-2732 cycles per million inhabitants). For all IVF cycles, the clinical PRs per aspiration and per transfer were stable with 29.4 (29.1% in 2011) and 33.8% (33.2% in 2011), respectively. For ICSI, the corresponding rates also were stable with 27.8 (27.9% in 2011) and 32.3% (31.8% in 2011). In FER cycles, the PR per thawing/warming increased to 23.1% (21.3% in 2011). In ED cycles, the PR per fresh transfer increased to 48.4% (45.8% in 2011) and to 35.9% (33.6% in 2011) per thawed transfer, while it was 45.1% for transfers after FOR. The delivery rate after IUI remained stable, at 8.5% (8.3% in 2011) after IUI-H and 12.0% (12.2% in 2011) after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 30.2, 55.4, 13.3 and 1.1% of the cycles, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 82.1, 17.3 and 0.6%, respectively, resulting in a total multiple delivery rate of 17.9% compared with 19.2% in 2011 and 20.6% in 2010. In FER cycles, the multiple delivery rate was 12.5% (12.2% twins and 0.3% triplets). Twin and triplet delivery rates associated with IUI cycles were 9.0%/0.4% and 7.2%/0.5%, following treatment with husband and donor semen, respectively. LIMITATIONS, REASONS FOR CAUTION The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution. Wider Implications of the Findings The 16th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 640 000 cycles reported in 2012 with an increasing contribution to birthrate in many countries. However, the need to improve and standardize the national registries, and to establish validation methodologies remains manifest. STUDY FUNDING/COMPETING INTERESTS The study has no external funding; all costs are covered by ESHRE. There are no competing interests.

Objectives: To carry out an epidemiological analysis of the emerging epidemic in an Eastern European country and to compare the approach to prevention of mother-to-child transmission (MTCT) with that in Western Europe. Design: Prospective cohort study established in 1985 in Western Europe and extended to Ukraine in 2000. Methods: Data on 5967 HIV-infected pregnant women and their infants (1251 from Ukraine and 4716 from Western/Central Europe) was analysed. Factors associated with transmission were identified with logistic regression. Results: HIV-infection among pregnant women enrolled in Western European centres has shifted from being largely injecting drug use (IDU)-related to heterosexually-acquired; in Ukraine IDU also gradually declined with women increasingly identified without specific risk factors. In Ukraine in 2000-2004 most (80%) women received single dose nevirapine (sdNVP) and/or short-course zidovudine prophylaxis [MTCT rate 4.2%; 95% confidence interval (CI), 1.8-8.0 for sdNVP with short-course zidovudinel; 2% (n = 27) received antenatal HAART and 33% (n = 418) delivered by elective caesarean section (CS); in Western European centres 72% of women received HAART (MTCT rate 1.0%; 95% Cl, 0.4-1.9) and 66% delivered by elective CS during the same period. Conclusions: Our findings indicate distinct differences in the epidemics in pregnant women across Europe. The evolution of the MTCT epidemic in Ukraine does not appear to be following the same pattern as that in Western Europe in the 1980s and 1990s. Although uptake of preventive MTCT prophylaxis has been rapid in both Western Europe and Ukraine, substantial challenges remain in the more resource-constrained setting in Eastern Europe. (c) 2006 Lippincott Williams & Wilkins

The aim of the study was to describe the recent trends in antiretroviral treatment in late pregnancy and the sociodemographic changes among pregnant women with HIV over the last 6 years. Data from the National Program on Surveillance on Antiretroviral Treatment in Pregnancy in Italy were grouped per calendar year, and changes in antiretroviral treatment, population characteristics, maternal immunovirologic status and newborn clinical parameters were analyzed. A total of 981 HIV-infected mothers who delivered between 2002 and 2008 were evaluated. The proportion of women receiving at least three antiretroviral drugs at delivery increased significantly from 63.0% in 2002 to 95.5% in 2007-2008, paralleled by a similar upward trend in the proportion of women who achieved complete viral suppression at third trimester (from 37.3 in 2002 to 80.9 in 2007-2008; p < 0.001). The co-formulation of zidovudine plus lamivudine remained the most common nucleoside backbone in pregnancy, even if a significant increase in the use of tenofovir plus emtricitabine was observed in more recent years. Starting from 2003, nevirapine prescription declined, paralleled by a significant rise in the use of protease inhibitors (PI), which were present in more than 60% of regimens administered in 2007-2008. Nelfinavir was progressively replaced by ritonavir-boosted PIs, mainly lopinavir. No significant changes in preterm delivery, Apgar score, birth weight, and birth defects were observed during the study period, and the rate of HIV transmission remained below 2%. These data demonstrate a significant evolution in the treatment of HIV in pregnancy. Constant improvements in the rates of HIV suppression were observed, probably driven by the adoption of stronger and more effective regimens and by the increasing options available for combination treatment

Aims: To identify possible work related sources of psychosocial stress in order to develop pertinent questionnaire items for a cross-sectional health survey of 3000 Italian women flight attendants, and to solicit suggestions on improving survey participation. Methods: Qualitative study in which 26 current and former women flight attendants participated: three focus groups of 6-7 participants each and six in-depth individual interviews. The session themes included positive and negative aspects of the job; relationships with colleagues, superiors, and passengers; perception of occupational risk for serious diseases; compatibility of work and family; and experiences of work related sources of stress and their effect on health. A transcript based analysis of the focus groups and interviews was used to identify emerging themes related to risk factors for mental health problems. Results: The participants indicated that mental health was a major concern. Several work related risk factors possibly related to adverse outcomes, such as depression and anxiety, were highlighted. These included isolation and solitude, fears of being inadequate partners and mothers due to job demands, passenger relationships, and lack of protection by employers with respect to workplace exposures and violent passengers. The information gained was used to develop a mental health module for inclusion in the health survey questionnaire which included questions on history of severe depression or anxiety, suicidal ideation or attempt, substance abuse, workplace sexual harassment, social support, leisure time activities, relationship with a partner, and role as mother. Conclusions: Employing qualitative methods to identify work related sources of psychosocial stress enabled development of pertinent questionnaire items for a cross-sectional epidemiological study of women flight attendants. Follow up qualitative research may be necessary in order to put the cross-sectional study findings into context and to explore actions or strategies for preventing work related health problems evidenced from the survey.

Study question The 13th European in vitro fertilization (IVF)-monitoring (EIM) report presents the results of treatments involving assisted reproductive technology (ART) initiated in Europe during 2009: are there any changes in the trends compared with previous years? Summary answer Despite some fluctuations in the number of countries reporting data, the overall number of ART cycles has continued to increase year by year and, while pregnancy rates in 2009 remained similar to those reported in 2008, the number of transfers with multiple embryos (3+) and the multiple delivery rates declined. What is known already Since 1997, ART data in Europe have been collected and reported in 12 manuscripts, published in Human Reproduction. Study design, size, duration Retrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE); cycles started between 1st January and 31st December are collected on a yearly basis; the data are collected by the National Registers, when existing, or on a voluntary basis. Participants/materials setting, methods From 34 countries (-2 compared with 2008), 1005 clinics reported 537 463 treatment cycles including: IVF (135 621), intracytoplasmic sperm injection (ICSI, 266 084), frozen embryo replacement (FER, 104 153), egg donation (ED, 21 604), in vitro maturation (IVM, 1334), preimplantation genetic diagnosis/screening (PGD/PGS, 4389) and frozen oocyte replacements (FOR, 4278). European data on intrauterine insemination using husband/partner's semen (IUI-H) and donor (IUI-D) semen were reported from 21 and 18 countries, respectively. A total of 162 843 IUI-H (+12.7%) and 29 235 IUI-D (+17.3%) cycles were included. Data available from each country are presented in the tables; total values (as numbers and percentages) refer to those countries where all data have been reported. Main results and the role of chance In 21 countries where all clinics reported to the ART register, a total of 399 020 ART cycles were performed in a population of 373.8 million, corresponding to 1067 cycles per million inhabitants. For IVF, the clinical pregnancy rates per aspiration and per transfer were 28.9 and 32.9%, respectively and for ICSI, the corresponding rates were 28.7 and 32.0%. In FER cycles, the pregnancy rate per thawing was 20.9%; in ED cycles, the pregnancy rate per transfer was 42.3%. The delivery rate after IUI-H was 8.3 and 13.4% after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 24.2, 57.7, 16.9 and 1.2%, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (combined) were 79.8, 19.4 and 0.8%, respectively, resulting in a total multiple delivery rate of 20.2%, compared with 21.7% in 2008, 22.3% in 2007, 20.8% in 2006 and 21.8% in 2005. In FER cycles, the multiple delivery rate was 13.0% (12.7% twins and 0.3% triplets). Twin and triplet delivery rates associated with IUI cycles were 10.4/0.7% and 10.3/0.5%, following treatment with husband and donor semen, respectively. Limitations, reasons for caution The method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution. Wider implications of the findings The 13th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than half a million of cycles reported in 2009. The use of ICSI has reached a plateau. Pregnancy and delivery rates after IVF and ICSI remained relatively stable compared with 2008 and 2007. The number of multiple embryo transfers (3+ embryos) and the multiple delivery rate have shown a clear decline.

The application of the European Tissues and Cells Directive requires that a high standard of quality and safety be applied to all tissue establishments, including that of assisted reproductive centres. In the countries where the Directive has been implemented, changes in the ART clinic and laboratory procedures have been made. However, many requirements stipulated in the Directive are already in place in some European countries and are mandatory by the country specific laws, while some other requirements have been recently implemented. In this article the benefits and the potential risks of the Directive implementation on the efficacy, safety and cost of all the different assisted reproductive technologies performed, including cryopreservation techniques and storage policies have been widely analysed. The feasibility of the implementation of some of the specific requirements when considering the delicate issues of reproductive cells in contrast to other cells or tissues covered by the Directive has been evaluated.

Over the last few years, there has been renewed interest and scientific debate concerning human oocyte cryopreservation. The aim of this study was to analyse the clinical data coming from our long experience of slow-freezing oocytes. Between 2001 and 2007, 1280 thawing cycles were carried out using oocytes previously frozen by means of a slow 1,2 propaniedol+sucrose protocol. A total of 7585 oocytes were thawed, of which 4409 survived and 3622 were microinjected; 144 clinical pregnancies were obtained. The number of thawing cycles increased from 19 in 2001 to 268 in 2007, and the number of thawed oocytes from 197 to 1652. Although the survival rate was significantly lower in the period 2002-2005 than in the period 2006-2007, pregnancy and implantation rates steadily improved from respectively 6.7% and 2.4% in 2001 to 15% and 8.2% in 2007. Our data demonstrate a clinically important improvement in oocyte crypreservation over the years in a Centres with proved experience, and can be offered as a standard of care not only before cancer treatment but also for couples refusing embryo crypreservation or in countries with very restrictive limitations on embryo or zygote freezing.

Vaginal isolates of Candida albicans from human immunodeficiency virus-positive (HIV + ) and HIV − women with or without candidal vaginitis were examined for secretory aspartyl proteinase (Sap) production in vitro and in vivo and for the possible correlation of Sap production with pathology and antimycotic susceptibility in vitro. HIV + women with candidal vaginitis were infected by strains of C. albicans showing significantly higher levels of Sap, a virulence enzyme, than strains isolated from HIV + , C. albicans carrier subjects and HIV − subjects with vaginitis. The greater production of Sap in vitro was paralleled by greater amounts of Sap in the vaginal fluids of infected subjects. In an estrogen-dependent, rat vaginitis model, a strain of C. albicans producing a high level of Sap that was isolated from an HIV + woman with vaginitis was more pathogenic than a strain of C. albicans that was isolated primarily from an HIV − , Candida carrier. In the same model, pepstatin A, a strong Sap inhibitor, exerted a strong curative effect on experimental vaginitis. No correlation was found between Sap production and antimycotic susceptibility, as most of the isolates were fully susceptible to fluconazole, itraconazole, and other antimycotics, regardless of their source (subjects infected with strains producing high or low levels of Sap, subjects with vaginitis or carrier subjects, or subjects with or without HIV). Thus, high Sap production is associated with virulence of C. albicans but not with fungal resistance to fluconazole in HIV-infected subjects, and Sap is a potentially new therapeutic target in candidal vaginitis.

On February 19th 2004 in Italy was promulgate a law that regulates all assisted reproduction techniques (ART) ( * ). In this law is established the creation of the National ART Register (Registro Nazionale della Procreazione Medicalmente Assistita) at the National Institute of Health (Istituto Superiore di Sanita, ISS). The National Health Institute prepares an annual report to the Ministry of Health, with all the data from the ART clinics operating in Italy. Sending data to the Register is mandatory. The aims of the Register are: list all the authorized structures that apply ART techniques in Italy, collect and diffuse transparent information of these techniques and the results of their application. Diffuse the correct information to all citizens and infertile couples in particular on reproductive health, prevention of infertility and possible therapeutic interventions. The Register data collection is made on a specific web site ( www.iss.it/rpma ) create to allow ART clinics to complete and send out the annual summary data reports “on-line”. Each clinic has an username and a password that consent them the access to a private zone in this web site where they can communicate with the Italian National ART register. Actual law requires The Register to collect information also on children born after ART procedures. Actually all the ART clinics have big problems to recruit such kind of data, because not all the couples let them know if their treatments have been successfully. The data covering treatments and births starts during a specific year. The data are usually available two years after the end of the treatment period. The summaries of each clinic contain data regarding: number of ART procedures, pregnancies and deliveries by ART procedure including standard IVF, ICSI, FIVET, GIFT and FER; the number of cycles started, number of oocyte aspirations and of embryo transfers; abortions an ectopic pregnancies; the number of live born children; the number of IVF treatments, reported per ART procedure, the indications for treatment and women's age (in five year intervals); the number of embryo replaced per procedure. Data collection take place twice a year: the first data collection regards ART treatments results and the other one for data regarding surveillance of children born after ART procedures. The Italian Register cooperate with other 29 countries sending data to the eim European IVF Monitoring. The European data collection is made once a year from all the participating countries and the results are published after two years. In addition, the Italian ART Register is trying to build up a report system of individual cycle data. As a matter of fact it was created a specific software freely distribute among ART clinics to consent them the collection of individual cycle data and to administrate their own patients flow. Unfortunately the national privacy protection authorities (“Garante della Privacy”) until today has not gave the permission to collect this kind of data.

Infertility is a problem afflicting about 1/6 couples, and in 40% of cases this is primarily due to the male. Male infertility is a multifactorial pathology and it seems mainly related to sperm motility or sperm number. However, a diagnosis of infertility is frequently not followed by a precise explanation of its cause, reflecting our poor understanding of the spermatogenesis-related regulatory mechanisms and gene expression profiles. Therefore, this study was design to investigate the relative gene expression of a specific gene profile in ejaculate spermatozoa of men affected by infertility. This profile included 13 mitochondrial gene encoding subunits of respiratory chain and 7 nuclear sperm motility-related genes. We used values of progressive sperm motility (PR) to separate subjects affected by infertility into two groups, showing PR values higher (H group) or lower (L group) than the mean of the sample, and to classify fertile men (control group). We did not obtain a statistically significant difference in nuclear gene expression patterns in spermatozoa among these three groups. On the other hand, we observed an over-expression in 11/13 tested mitochondrial genes in the population of infertile males with altered sperm motility compared to the control group. This over-expression led us to speculate that there is an abnormal mRNA transcription of these 11 subunits, that impaired the normal energy supply ensuring sperm motility. Regarding the under-expression of 2/13 tested mitochondrial genes, we could assume that the spermatozoa mtDNA has accumulated mutations involving these two genes (CYB and ND4L). In conclusion, our results will provide useful information for the development of molecular diagnostic tools for clinical assessment of sperm health. However, further investigation into other sperm-related genes is needed to establish their roles in male fertility.

Objective To evaluate the efficacy of oocyte cryopreservation by a single slow-cooling protocol involving sucrose (0.2 mol/L) in the freezing solution. Design Observational comparison of the clinical outcome in fresh and frozen thawed cycles. Setting Public and private IVF centers. Patient(s) Infertile couples undergoing IVF treatment. Intervention(s) Use of a maximum three oocytes in fresh cycles, as established by local law, and cryopreservation and later use of surplus oocytes. Likewise fresh cycles, maximum three thawed oocytes were used per cycle. All thawed oocytes were microinjected. Main Outcome Measure(s) Embryologic and clinical parameters of fresh and thawed cycles. Result(s) Two thousand forty-six patients underwent 2,209 oocyte retrievals involving oocyte cryopreservation. Overall, the survival rate of thawed oocytes was 55.8%. In 940 thaw cycles, the mean numbers of inseminated oocytes and fertilization rates were significantly decreased vs. fresh cycles outcomes (2.6 ± 0.7 vs. 2.9 ± 0.2 and 72.5% vs. 78.3%, respectively), as were the rates of implantation (10.1% vs. 15.4%), pregnancy rates per transfer (17.0% vs. 27.9%), and pregnancy rates per cycle (13.7% vs. 26.2%). Differences in clinical outcome were found among centers. A pregnancy rate per thawing cycle above 14% was achieved by most clinics. Fifty-seven retrievals involving oocyte cryopreservation achieved a pregnancy after fresh embryo replacement. Implantation and pregnancy rates per embryo transfer and per thawing cycles were 17.5%, 28.6%, and 24.6%, respectively. Conclusion(s) Under the conditions tested, the clinical outcome of oocyte slow-cooling cryopreservation is reduced compared with fresh cycles. Nevertheless, in cases of inapplicability of embryo cryopreservation, oocyte cryopreservation should be offered to patients with surplus oocytes.

[This corrects the article DOI: 10.1093/hropen/hoz038.]., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

The original article unfortunately contained a mistake. The names of the collaborators were captured as authors of the article.