Corrigendum. ART in Europe, 2015: results generated from European registries by ESHRE.

[This corrects the article DOI: 10.1093/hropen/hoz038.].

ART in Europe, 2015: results generated from European registries by ESHRE.

STUDY QUESTION: What are the European trends and developments in ART and IUI in 2015 as compared to previous years? SUMMARY ANSWER: The 19th ESHRE report on ART shows a continuing expansion of treatment numbers in Europe, and this increase, the variability in treatment modalities and the rising contribution to the birth rates in most participating countries all point towards the increasing impact of ART on European society. WHAT IS KNOWN ALREADY: Since 1997, the ART data generated by national registries have been collected, analysed and reported in 18 manuscripts published in Human Reproduction. STUDY DESIGN SIZE DURATION: Collection of European data by the European IVF-Monitoring Consortium (EIM) for ESHRE. The data for treatments performed between 1 January and 31 December 2015 in 38 European countries were provided by national registries or on a voluntary basis by clinics or professional societies. PARTICIPANTS/MATERIALS SETTINGS METHODS: From 1343 institutions in 38 countries offering ART services a total of 849 811 treatment cycles, involving 155 960 with IVF, 385676 with ICSI, 218098 with frozen embryo replacement (FER), 21 041 with preimplantation genetic testing (PGT), 64 477 with egg donation (ED), 265 with IVM and 4294 with FOR were recorded. European data on IUI using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1352 institutions offering IUI in 25 countries and 21 countries, respectively. A total of 139 050 treatments with IUI-H and 49 001 treatments with IUI-D were included. MAIN RESULTS AND THE ROLE OF CHANCE: In 18 countries (14 in 2014) with a population of approximately 286 million inhabitants, in which all institutions contributed to their respective national registers, a total of 409 771 treatment cycles were performed, corresponding to 1432 cycles per million inhabitants (range: 727-3068 per million). After IVF the clinical pregnancy rates (PRs) per aspiration and per transfer were slightly lower in 2015 as compared to 2014, at 28.5 and 34.6% versus 29.9 and 35.8%, respectively. After ICSI, the corresponding PR achieved per aspiration and per transfer in 2015 were also slightly lower than those achieved in 2014 (26.2 and 33.2% versus 28.4 and 35.0%, respectively). On the other hand, after FER with own embryos the PR per thawing continued to rise from 27.6% in 2014 to 29.2% in 2015. After ED a slightly lower PR per embryo transfer was achieved: 49.6% per fresh transfer (50.3% in 2014) and 43.4% for FOR (48.7% in 2014). The delivery rates (DRs) after IUI remained stable at 7.8% after IUI-H (8.5% in 2014) and at 12.0% after IUI-D (11.6% in 2014). In IVF and ICSI together, 1, 2, 3 and ≥4 embryos were transferred in 37.7, 53.9, 7.9 and in 0.5% of all treatments, respectively (corresponding to 34.9, 54.5, 9.9 and in 0.7% in 2014). This evolution towards the transfer of fewer embryos in both IVF and ICSI resulted in a proportion of singleton, twin and triplet DR of 83.1, 16.5 and 0.4%, respectively (compared to 82.5, 17.0 and 0.5%, respectively, in 2014). Treatments with FER in 2015 resulted in twin and triplet DR of 12.3 and 0.3%, respectively (versus 12.4 and 0.3% in 2014). Twin and triplet delivery rates after IUI-H were 8.9 and 0.5%, respectively (in 2014: 9.5 and 0.3%), and 7.3 and 0.6% after IUI-D (in 2014: 7.7 and 0.3%). LIMITATIONS REASONS FOR CAUTION: The methods of data collection and reporting vary 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. WIDER IMPLICATIONS OF THE FINDINGS: The 19th EIM 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 worldwide, detailed information about ongoing developments in the field is provided. STUDY FUNDING/COMPETING INTERESTS: The study has no external funding and all costs are covered by ESHRE. There are no competing interests.

Survey on ART and IUI: legislation, regulation, funding and registries in European countries: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (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 INTERESTS: 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.

Correction to: Contribution of cryopreservation to the cumulative live birth rate: a large multicentric cycle-based data analysis from the Italian National Registry.

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

Contribution of cryopreservation to the cumulative live birth rate: a large multicentric cycle-based data analysis from the Italian National Registry.

PURPOSE: To estimate the contribution of cryopreservation to the cumulative live birth rate (CLBR) after law modification in Italy in the era of vitrification and freeze-all. METHODS: The Italian National Registry performed a cycle-based data collection. Nine Italian IVF clinics were involved incorporating a total of 10,260 fresh cycles performed between January 2015 and April 2016 resulting in 9273 oocyte retrievals and 3266 subsequent warming cycles from the same oocyte retrievals performed up to December 2016. Mean female age was 37 ± 4.3 years. Primary outcome measure was CLBR per oocyte retrieval. Confounding factors were tested in multivariate regression analysis, and the relative impact of cryopreservation to the CLBR in different patient categories was calculated. RESULTS: CLBR per oocyte retrieval was 32.6%, 26.5%, 18.7%, 13.0%, and 5.5% for women younger than 36, aged 36-39, 40-41, and older than 41 years, respectively. The total relative contribution of oocyte/embryo cryopreservation was 40.6% (95% CI 38.41-42.75). An association between maternal age, number of oocytes retrieved, fertilization rate, cryopreservation, and cumulative live birth was shown. When adjusted for confounders, a 2.3-fold increase was observed in the chance of live birth when cryopreservation was performed (OR 2.3; 95% CI 1.99-2.56). In high responder patients (> 15 oocytes retrieved) where freeze-all was applied in 67.6% of cycles to avoid the risk of hyper stimulation syndrome, the relative contribution of vitrification to the CLBR was 80.6%. CONCLUSIONS: Cryopreservation is essential in IVF and should always be available to patients to optimize success rates. Multicentric, cycle-based data analyses are crucial to provide infertile couples, clinicians, and regulatory bodies with accurate information on IVF effectiveness including fresh and cryopreserved cycles.

ART in Europe, 2014: results generated from European registries by ESHRE: The European IVF-monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE).

STUDY QUESTION: What are the European trends and developments in ART and IUI in 2014 as compared to previous years? SUMMARY ANSWER: 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. WHAT IS KNOWN ALREADY: 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. STUDY DESIGN, SIZE, DURATION: 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. PARTICIPANTS/MATERIALS, SETTING, METHODS: 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. MAIN RESULTS AND THE ROLE OF CHANCE: 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%). LIMITATION, REASONS FOR CAUTION: 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. WIDER IMPLICATIONS OF THE FINDINGS: 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. STUDY FUNDING/COMPETING INTEREST(S): The study has no external funding and all costs are covered by ESHRE. There are no competing interests.

Assisted reproductive technology in Europe, 2013: results generated from European registers by ESHRE.

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.

Oocyte and ovarian tissue cryopreservation in European countries: statutory background, practice, storage and use.

STUDY QUESTION: What is known in Europe about the practice of oocyte cryopreservation (OoC), in terms of current statutory background, funding conditions, indications (medical and 'non-medical') and specific number of cycles? SUMMARY ANSWER: Laws and conditions for OoC vary in Europe, with just over half the responding countries providing this for medical reasons with state funding, and none providing funding for 'non-medical' OoC. WHAT IS ALREADY KNOWN: The practice of OoC is a well-established and increasing practice in some European countries, but data gathering on storage is not homogeneous, and still sparse for use. Ovarian tissue cryopreservation (OtC) is only practiced and registered in a few countries. STUDY DESIGN SIZE AND DURATION: A transversal collaborative survey on OoC and OtC, was designed, based on a country questionnaire containing information on statutory or professional background and practice, as well as available data on ovarian cell and tissue collection, storage and use. It was performed between January and September 2015. PARTICIPANTS/MATERIALS SETTING AND METHODS: All ESHRE European IVF Monitoring (EIM) consortium national coordinators were contacted, as well as members of the ESHRE committee of national representatives, and sent a questionnaire. The form included national policy and practice details, whether through current existing law or code of practice, criteria for freezing (age, health status), availability of funding and the presence of a specific register. The questionnaire also included data on both the number of OoC cycles and cryopreserved oocytes per year between 2010 and 2014, specifically for egg donation, fertility preservation for medical disease, 'other medical' reasons as part of an ART cycle, as well as for 'non-medical reasons' or age-related fertility decline. Another question concerning data on freezing and use of ovarian tissue over 5 years was added and sent after receiving the initial questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: Out of 34 EIM members, we received answers regarding OoC regulations and funding conditions from 27, whilst 17 countries had recorded data for OoC, and 12 for OtC. The specific statutory framework for OoC and OtC varies from absent to a strict frame. A total of 34 705 OoC cycles were reported during the 5-year-period, with a continuous increase. However, the accurate description of numbers was concentrated on the year 2013 because it was the most complete. In 2013, a total of 9126 aspirations involving OoC were reported from 16 countries. Among the 8885 oocyte aspirations with fully available data, the majority or 5323 cycles (59.9%) was performed for egg donation, resulting in the highest yield per cycle, with an average of 10.4 oocytes frozen per cycle. OoC indication was 'serious disease' such as cancer in 10.9% of cycles, other medical indications as 'part of an ART cycle' in 16.1%, and a non-medical reason in 13.1%. With regard to the use of OoC, the number of specifically recorded frozen oocyte replacement (FOR) cycles performed in 2013 for all medical reasons was 14 times higher than the FOR for non-medical reasons, using, respectively, 8.0 and 8.4 oocytes per cycle. Finally, 12 countries recorded storage following OtC and only 7 recorded the number of grafted frozen/thawed tissues. LIMITATIONS REASONS FOR CAUTION: Not all countries have data regarding OoC collection, and some data came from voluntary collaborating centres, rather than a national authority or register. Furthermore, the data related to use of OoC were not included for two major players in the field, Italy and Spain, where numbers were conflated for medical and non-medical reasons. Finally, the number of cycles started with no retrieval is not available. Data are even sparser for OtC. WIDER IMPLICATIONS OF THE FINDINGS: There is a need for ART authorities and professional bodies to record precise data for practice and use of OoC (and OtC), according to indications and usage, in order to reliably inform all stakeholders including women about the efficiency of both methods. Furthermore, professional societies should establish professional standards for access to and use of OoC and OtC, and give appropriate guidance to all involved. STUDY FUNDING/COMPETING INTERESTS: The study was supported by ESHRE. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE.

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.

ACP1 genetic polymorphism and spermatic parameters in men with varicocele.

Platelet-derived growth factor (PDGF) and its receptors (PDGFRs) play a key role in the regulation of the embryonic and postnatal development of male gonads. PDGF deficiency is associated with severe spermatogenic impairment. ACP1 is a phosphoprotein tyrosine phosphatase that is able to dephosphorylate PDGFR, decreasing its activity as growth factor. The enzyme is polymorphic and shows strong differences in enzymatic activity among genotypes. At the Outpatient Department for Infertility, University of Rome La Sapienza, we investigated the effect of high-activity ACP1 genotype on spermatic parameters in 105 subjects referred to for varicocele. ACP1 genotype was determined by DNA analysis. In ACP1 *B/*C genotype, which shows the highest enzymatic activity, spermatic concentration is significantly lower and atypical spermatozoa are significantly more frequent as compared to other ACP1 genotypes. It is concluded that subjects carrying *B/*C genotype who represent about 10% of the population have a severe impairment of spermatic parameters in the presence of varicocele.

Assisted reproductive technologies in Italy, 2005-2007: results from the Italian Assisted Reproductive Technologies Register.

AIM: The aim of this study was to assess the quantitative and qualitative outcomes of assisted reproductive technologies in Italy, from 2005 to 2007, collected by the Italian Assisted Reproductive Technologies Register (IARTR). METHODS: We analyzed, retrospectively, 121,708 ART treatments performed by Italian assisted reproductive technologies (ART) centres from 2005 to 2007. RESULTS: In the study period ART Italian centers were reporting data to the IARTR. Number of total cycles (all homologous) reported was 121,708 including 110,074 fresh (FRESH), 8682 frozen/thawed oocytes (FO) and 2952 frozen embryo (FER). Pregnancy rates per cycle with respect to FRESH, FO and FER treatments were 19.1%, 10.2% and 15%, respectively. Delivery rate per cycle with at least one live birth was 10.8%, 5.8% and 8.4%, respectively, per type of procedure. Twin and "triplet or more" birth rate per delivery was 21% and 2.8%; 12% and 0.4%; 14.9% and 0.8%, respectively. During the study period 15923 ART infants were born (0.95% of all newborn in Italy). CONCLUSION: From 2005 to 2007 we registered a strong increase in ART procedures concomitantly with a qualitative improvement leading to increased pregnancy and live birth rates per cycles. Remarkably, pregnancy loss to follow-up decreased drastically during the three years study-period.

Benefit and risk of application of European tissue management regulation in ART.

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.

Italian Constitutional Court modifications of a restrictive assisted reproduction technology law significantly improve pregnancy rate.

BACKGROUND: In May 2009, the Italian Constitutional Court banned most of the limitations of a restrictive law regulating assisted reproduction technology on the grounds that it limited a couple's right to have access to the best possible medical treatment and reduce any possible higher risk of complications. The aim of the study was to compare our results in fresh cycles before and after this change. MATERIALS AND METHODS: We analysed retrospectively 3274 IVF cycles: 2248 before and 1026 after the law was modified. RESULTS: There was no significant difference between the two groups in terms of age, basal FSH levels, years of infertility, the number of previous cycles or the number of oocytes retrieved but the number of oocytes used (2.7 ± 0.6 versus 4.6 ± 1.8; P = <0.001), the number of embryos obtained (2.0 ± 0.9 versus 3.3 ± 1.8; P = <0.001) and transferred (2.2 ± 0.7 versus 2.3 ± 0.7; P = <0.001) were all higher after the removal of the previous restrictions, as was the pregnancy rate per started cycle (23.49% versus 20.42%; P = 0.047). Before modification of the law, the pregnancies were single in 74.11% of the cases (versus 71.43% afterwards), twins in 23.44% (versus 26.89%; P = 0.318) and triplets in 2.46% (versus 1.68%; P = 0.594). CONCLUSIONS: Our preliminary results after the removal of the previous legal restrictions show a higher pregnancy rate per started cycle (3.7% represents a 15% difference) and a positive (albeit non-significant) trend towards a reduction in the number of multiple pregnancies.

Analysis of oocyte cryopreservation in assisted reproduction: the Italian National Register data from 2005 to 2007.

This paper reports on oocyte cryopreservation efficacy in Italy with respect to successful IVF from 2005 to 2007, presenting data from 193 centres collected by the Italian National Register. Post-thawing survival rates, number of transferred embryos, implantation rates and clinical pregnancy rates per transfer with respect to frozen/vitrified oocytes (FVO) were analysed. These numbers were compared with those obtained using frozen embryos or fresh oocytes. A total of 121,708 cycles were initiated, of which, 7.1% (8682) were FVO cycles and 2.4% (2952) were frozen embryo cycles. Of the 81,786 FVO, 52.5% (42,917) were thawed and 26.9% (22,005) inseminated. Of those inseminated, 68.0% (14,966) yielded good embryos. These numbers were significantly lower than those using fresh oocytes in which 77.9% (197,242; fresh oocytes versus FVO P<0.001) of inseminated oocytes generated good embryos. Implantation rate using FVO was 6.9%, which was significantly lower than that using fresh oocytes (13.5%; P<0.001) and frozen embryos (8.8%; P<0.001). Pregnancy rate per transfer using FVO was 12.5% and significantly lower than that using fresh oocytes (24.9%; P<0.001) or frozen embryos (16.4%; P<0.001). There were 505 deliveries after IVF with FVO and 582 babies.

Exposure to psychoactive substances in women who request voluntary termination of pregnancy assessed by serum and hair testing.

Drug abuse is a worldwide phenomenon with significant health and socioeconomic impact and it is of particular concern in women of reproductive age and in pregnant women. We aimed to investigate the prevalence of drug use by serum and hair testing in a cohort of pregnant women at 12th week gestation who decided voluntarily to interrupt their pregnancy and to investigate the relationship between drug exposure and induced abortions (IA), repeated IA and contraception. The study was conducted in an obstetrics clinic authorised to perform IA in Murcia, Spain during an 18 months period (2007-2009). Apart from serum and/or hair testing, the 142 women enrolled in the study completed a detailed questionnaire regarding drug, alcohol and tobacco use in the previous 3 months. Serum and hair samples were analyzed by gas chromatography mass spectrometry assays. Hair and serum samples showed a 30% overall positivity to drugs of abuse. Of these samples, 20.4, 14.1, 4.2 and 1.4% were positive for cannabinoids, cocaine, opiates, and MDMA, respectively, with polydrug use in 5.6% cases. In this cohort, a positive association was found between drug use and repeated IA. The results highlight the need for promoting pregnancy planning for young women in general, especially when consuming psychoactive substances as well as promote safe and accessible contraception in women of reproductive age. In women requesting IA, specific drug abuse counselling should be implemented.

Ultrastructural markers of quality in human mature oocytes vitrified using cryoleaf and cryoloop.

This study describes and compares the possible effects of vitrification on the ultrastructural morphology of 20 human mature oocytes vitrified using two different supports, cryoleaf (n = 10) and cryoloop (n = 10). Fresh human mature oocytes (n = 15) were used as controls. Fresh and vitrified-warmed oocytes appeared rounded, with a homogeneous cytoplasm, an intact oolemma and a continuous zona pellucida. Sparse microvacuolization was only occasionally detected in fresh and vitrified-warmed oocytes, to the same extent. About 50% of the vitrified oocytes contained atypical, small and slender mitochondria-smooth endoplasmic reticulum aggregates, whereas a non-homogeneous microvillar pattern was observable in only 30% of the oocytes subjected to vitrification, regardless of the support utilized. Cortical granule content appeared generally reduced after vitrification, but cryoleaf-supported oocytes contained more cortical granules than cryoloop-supported oocytes (P < 0.05). Thus good overall preservation and virtual absence of cytoplasmic vacuolization seem to be the most relevant markers of quality in vitrified-warmed oocytes, using either support. In addition, cryoleaf-supported oocytes retained a higher number of cortical granules than cryoloop-supported oocytes. The variety of ultrastructural alterations recorded emphasizes the need for further studies aimed at assessing the actual tolerance of human oocytes to vitrification.

Vitrification may increase the rate of chromosome misalignment in the metaphase II spindle of human mature oocytes.

The metaphase II (MII) spindle of the human oocyte may be damaged by cryopreservation. High performance confocal microscopy was used to assess meiotic spindle and chromosome organization in oocytes after vitrification by the cryoleaf system. Three hours after retrieval, donor mature oocytes were fixed or vitrified. Vitrification was performed by equilibration in 7.5% ethylene glycol (EG) and 7.5% dimethylsulphoxide (DMSO), transfer to 15% EG, 15% DMSO and 0.5 mol/l sucrose, and loading onto cryoleaf strips. Tubulin staining was found in all survived vitrified-warmed oocytes, the majority (62.8%) of which displayed a bipolar spindle. A normal bipolar spindle configuration and equatorial chromosome alignment was observed only in a part of vitrified-warmed oocytes (32.6%). This frequency was significantly lower in comparison to fresh oocytes (59.1%). In another fraction of vitrified-warmed oocytes (30.2%), spindle bipolarity was associated to one or more non-aligned scattered chromosomes that often appeared tenuously associated with the lateral microtubules of the spindle. Furthermore, in cryopreserved oocytes with a bipolar spindle, a significantly increased pole-to-pole distance (14.9 +/- 2.3 microm) was found in comparison to the fresh control (12.4 +/- 2.6 microm) (P = 0.001). Therefore, under the conditions tested, vitrified-warmed oocytes maintain a MII spindle with a bipolar organization. However, chromosome alignment appears to be partly compromised.

[Prenatal exposure to drugs of abuse using meconium analysis in a low socioeconomic population in Barcelona]. / Exposición prenatal a drogas de abuso a través del análisis de meconio en una población de bajo nivel socioeconómico en Barcelona.

INTRODUCTION: For the first time in Europe, the <> aimed to estimate the prevalence of drug use by pregnant women and the subsequent foetal exposure to illicit drugs. PATIENTS AND METHOD: Between October 2002 and February 2004, 1209 mother-infant dyads from the Hospital del Mar, Barcelona, Spain met eligibility criteria and agreed to participate in the study. Data on socio-economic and demographic characteristics and on drug habits during pregnancy were collected using a structured questionnaire. Neonatal meconium was collected within 24h after birth and analyzed by standardized chromatographic techniques for the presence of opiates, cocaine, cannabinoids and amphetamines. RESULTS: Meconium analysis showed an overall 10.9% positivity for drugs of abuse, with a specific prevalence of heroin, cocaine and cannabis with foetal exposure of 4.7, 2.6 and 5.3%, respectively. Structured interviews also revealed that 0.3, 1.2 and 1.5% of mothers used heroin, cocaine and cannabis, respectively, while only one mother declared ecstasy consumption, confirmed by meconium analysis. Parental ethnicity and working class was not associated with drug use. Drug consuming mothers were shown to have a higher number of previous abortions when compared to non-consumer mothers, which was probably due to a lack of family planning. Significantly lower birth weight and length was found in newborns from mothers exposed to cocaine alone or in combination with other drugs. CONCLUSIONS: This study, although developed in a low socio-economic-status cohort, may serve as an eye opener for any hidden non-negligible drug consumption during pregnancy. In this sense, meconium analysis can be important to identify neonates with a high suspicion of exposure to drugs of abuse in utero, and provides the basis for appropriate treatment and adequate medical and social follow-up.

Exposición prenatal a drogas de abuso a través del análisis de meconio en una población de bajo nivel socioeconómico en Barcelona / Prenatal exposure to drugs of abuse using meconium analysis in a low socioeconomic population in Barcelona

Introducción: por primera vez en Europa, el «Proyecto Meconio» ha estimado la prevalencia del consumo de drogas ilegales por mujeres embarazadas y la consiguiente exposición fetal. Pacientes y método: entre octubre de 2002 y febrero de 2004, se incluyó en el estudio a 1.209 parejas madre-recién nacido del Hospital del Mar, Barcelona. Se recogieron datos sobre las características socioeconómicas y demográficas y los hábitos tóxicos durante el embarazo empleando un cuestionario. Se recogió el meconio neonatal antes de 24 horas después del nacimiento y se analizó empleando técnicas cromatográficas estandarizadas para detectar opiáceos, cocaína, cannabinoides y anfetaminas. Resultados: el análisis del meconio demostró una positividad para las drogas de abuso del 10,9% del total, con una prevalencia específica de exposición fetal a heroína, cocaína y cannabis del 4,7, el 2,6 y el 5,3%, respectivamente. El cuestionario estructurado detectó que el 0,3, el 1,2 y el 1,5% de las madres habían consumido heroína, cocaína y cannabis, y sólo una madre declaró el consumo de éxtasis, confirmado mediante el análisis del meconio. La etnia de los padres y la clase laboral no se asociaron con el consumo de drogas. Las madres consumidoras de drogas mostraron un número de abortos previos más elevado que las madres no consumidoras. Se encontró que el peso y la talla al nacimiento eran significativamente más bajos en los recién nacidos de las madres expuestas a cocaína sola o en combinación con otras drogas. Conclusiones: este estudio puede servir como aviso de un consumo de drogas durante el embarazo oculto y significativo. En este sentido, el análisis del meconio puede ser importante para identificar a recién nacidos en elevada sospecha de exposición intrauterina a drogas de abuso y proporciona la base para un tratamiento médico y un seguimiento social apropiados (AU)

Introduction: For the first time in Europe, the «Meconium Project» aimed to estimate the prevalence of drug use by pregnant women and the subsequent foetal exposure to illicit drugs. Patients and method: Between October 2002 and February 2004, 1209 mother–infant dyads from the Hospital del Mar, Barcelona, Spain met eligibility criteria and agreed to participate in the study. Data on socio-economic and demographic characteristics and on drug habits during pregnancy were collected using a structured questionnaire. Neonatal meconium was collected within 24h after birth and analyzed by standardized chromatographic techniques for the presence of opiates, cocaine, cannabinoids and amphetamines. Results: Meconium analysis showed an overall 10.9% positivity for drugs of abuse, with a specific prevalence of heroin, cocaine and cannabis with foetal exposure of 4.7, 2.6 and 5.3%, respectively. Structured interviews also revealed that 0.3, 1.2 and 1.5% of mothers used heroin, cocaine and cannabis, respectively, while only one mother declared ecstasy consumption, confirmed by meconium analysis. Parental ethnicity and working class was not associated with drug use. Drug consuming mothers were shown to have a higher number of previous abortions when compared to non-consumer mothers, which was probably due to a lack of family planning. Significantly lower birth weight and length was found in newborns from mothers exposed to cocaine alone or in combination with other drugs. Conclusions: This study, although developed in a low socio-economic-status cohort, may serve as an eye opener for any hidden non-negligible drug consumption during pregnancy. In this sense, meconium analysis can be important to identify neonates with a high suspicion of exposure to drugs of abuse in utero, and provides the basis for appropriate treatment and adequate medical and social follow-up (AU)

Oocyte cryopreservation.

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.