ART in Europe, 2018: results generated from European registries by ESHRE.

STUDY QUESTION: What are the data and trends on ART and IUI cycle numbers and their outcomes, and on fertility preservation (FP) interventions, reported in 2018 as compared to previous years? SUMMARY ANSWER: The 22nd ESHRE report shows a continued increase in reported numbers of ART treatment cycles and children born in Europe, a decrease in transfers with more than one embryo with a further reduction of twin delivery rates (DRs) as compared to 2017, higher DRs per transfer after fresh IVF or ICSI cycles (without considering freeze-all cycles) than after frozen embryo transfer (FET) with higher pregnancy rates (PRs) after FET and the number of reported IUI cycles decreased while their PR and DR remained stable. WHAT IS KNOWN ALREADY: ART aggregated data generated by national registries, clinics or professional societies have been gathered and analysed by the European IVF-monitoring Consortium (EIM) since 1997 and reported in 21 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN SIZE DURATION: Data on medically assisted reproduction (MAR) from European countries are collected by EIM for ESHRE on a yearly basis. The data on treatment cycles performed between 1 January and 31 December 2018 were provided by either national registries or registries based on initiatives of medical associations and scientific organizations or committed persons of 39 countries. PARTICIPANTS/MATERIALS SETTING METHODS: Overall, 1422 clinics offering ART services in 39 countries reported a total of more than 1 million (1 007 598) treatment cycles for the first time, including 162 837 with IVF, 400 375 with ICSI, 309 475 with FET, 48 294 with preimplantation genetic testing, 80 641 with egg donation (ED), 532 with IVM of oocytes and 5444 cycles with frozen oocyte replacement (FOR). A total of 1271 institutions reported data on IUI cycles using either husband/partner's semen (IUI-H; n = 148 143) or donor semen (IUI-D; n = 50 609) in 31 countries and 25 countries, respectively. Sixteen countries reported 20 994 interventions in pre- and post-pubertal patients for FP including oocyte, ovarian tissue, semen and testicular tissue banking. MAIN RESULTS AND THE ROLE OF CHANCE: In 21 countries (21 in 2017) in which all ART clinics reported to the registry, 410 190 treatment cycles were registered for a total population of ∼ 300 million inhabitants, allowing a best estimate of a mean of 1433 cycles performed per million inhabitants (range: 641-3549). Among the 39 reporting countries, for IVF, the clinical PR per aspiration slightly decreased while the PR per transfer remained similar compared to 2017 (25.5% and 34.1% in 2018 versus 26.8% and 34.3% in 2017). In ICSI, the corresponding rates showed similar evolutions in 2018 compared to 2017 (22.5% and 32.1% in 2018 versus 24.0% and 33.5% in 2017). When freeze-all cycles were not considered for the calculations, the clinical PRs per aspiration were 28.8% (29.4% in 2017) and 27.3% (27.3% in 2017) for IVF and ICSI, respectively. After FET with embryos originating from own eggs, the PR per thawing was 33.4% (versus 30.2% in 2017), and with embryos originating from donated eggs 41.8% (41.1% in 2017). After ED, the PR per fresh embryo transfer was 49.6% (49.2% in 2017) and per FOR 44.9% (43.3% in 2017). In IVF and ICSI together, the trend towards the transfer of fewer embryos continues with the transfer of 1, 2, 3 and ≥4 embryos in 50.7%, 45.1%, 3.9% and 0.3% of all treatments, respectively (corresponding to 46.0%, 49.2%. 4.5% and 0.3% in 2017). This resulted in a reduced proportion of twin DRs of 12.4% (14.2% in 2017) and similar triplet DR of 0.2%. Treatments with FET in 2018 resulted in twin and triplet DRs of 9.4% and 0.1%, respectively (versus 11.2% and 0.2%, respectively in 2017). After IUI, the DRs remained similar at 8.8% after IUI-H (8.7% in 2017) and at 12.6% after IUI-D (12.4% in 2017). Twin and triplet DRs after IUI-H were 8.4% and 0.3%, respectively (in 2017: 8.1% and 0.3%), and 6.4% and 0.2% after IUI-D (in 2017: 6.9% and 0.2%). Among 20 994 FP interventions in 16 countries (18 888 in 13 countries in 2017), cryopreservation of ejaculated sperm (n = 10 503, versus 11 112 in 2017) and of oocytes (n = 9123 versus 6588 in 2017) were the most frequently reported. LIMITATIONS REASONS FOR CAUTION: The results should be interpreted with caution as data collection systems and completeness of reporting vary among European countries. Some countries were unable to deliver data about the number of initiated cycles and/or deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 22nd ESHRE data collection on ART, IUI and FP interventions shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Although it is the largest data collection on MAR in Europe, further efforts towards optimization of both the collection and reporting, with the aim of improving surveillance and vigilance in the field of reproductive medicine, are awaited. STUDY FUNDING/COMPETING INTERESTS: The study has received no external funding and all costs are covered by ESHRE. There are no competing interests.

ART in Europe, 2017: results generated from European registries by ESHRE.

STUDY QUESTION: What are the data on ART and IUI cycles, and fertility preservation (FP) interventions reported in 2017 as compared to previous years, as well as the main trends over the years? SUMMARY ANSWER: The 21st ESHRE report on ART and IUI shows the continual increase in reported treatment cycle numbers in Europe, with a decrease in the proportion of transfers with more than one embryo causing an additional slight reduction of multiple delivery rates (DR) as well as higher pregnancy rates (PR) and DR after frozen embryo replacement (FER) compared to fresh IVF and ICSI cycles, while the number of IUI cycles increased and their outcomes remained stable. WHAT IS KNOWN ALREADY: Since 1997, ART aggregated data generated by national registries, clinics or professional societies have been gathered and analyzed by the European IVF-monitoring Consortium (EIM) and communicated in a total of 20 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN SIZE DURATION: Data on European medically assisted reproduction (MAR) are collected by EIM for ESHRE on a yearly basis. The data on treatments performed between 1 January and 31 December 2017 in 39 European countries were provided by either National Registries or registries based on personal initiatives of medical associations and scientific organizations. PARTICIPANTS/MATERIALS SETTING METHODS: Overall, 1382 clinics offering ART services in 39 countries reported a total of 940 503 treatment cycles, including 165 379 with IVF, 391 379 with ICSI, 271 476 with FER, 37 303 with preimplantation genetic testing (PGT), 69 378 with egg donation (ED), 378 with IVM of oocytes, and 5210 cycles with frozen oocyte replacement (FOR). A total of 1273 institutions reported data on 207 196 IUI cycles using either husband/partner's semen (IUI-H; n = 155 794) or donor semen (IUI-D; n = 51 402) in 30 countries and 25 countries, respectively. Thirteen countries reported 18 888 interventions for FP, including oocyte, ovarian tissue, semen and testicular tissue banking in pre- and postpubertal patients. MAIN RESULTS AND THE ROLE OF CHANCE: In 21 countries (20 in 2016) in which all ART clinics reported to the registry, 473 733 treatment cycles were registered for a total population of approximately 330 million inhabitants, allowing a best-estimate of a mean of 1435 cycles performed per million inhabitants (range: 723-3286).Amongst the 39 reporting countries, the clinical PR per aspiration and per transfer in 2017 were similar to those observed in 2016 (26.8% and 34.6% vs 28.0% and 34.8%, respectively). After ICSI the corresponding rates were also similar to those achieved in 2016 (24% and 33.5% vs 25% and 33.2% in 2016). When freeze all cycles were removed, the clinical PRs per aspiration were 30.8% and 27.5% for IVF and ICSI, respectively.After FER with embryos originating from own eggs the PR per thawing was 30.2%, which is comparable to 30.9% in 2016, and with embryos originating from donated eggs it was 41.1% (41% in 2016). After ED the PR per fresh embryo transfer was 49.2% (49.4% in 2016) and per FOR 43.3% (43.6% in 2016).In IVF and ICSI together, the trend towards the transfer of fewer embryos continues with the transfer of 1, 2, 3 and ≥4 embryos in 46.0%, 49.2%, 4.5% and in 0.3% of all treatments, respectively (corresponding to 41.5%, 51.9%. 6.2% and 0.4% in 2016). This resulted in a reduced proportion of twin DRs of 14.2% (14.9% in 2016) and stable triplet DR of 0.3%. Treatments with FER in 2017 resulted in a twin and triplet DR of 11.2% and 0.2%, respectively (vs 11.9% and 0.2% in 2016).After IUI, the DRs remained similar at 8.7% after IUI-H (8.9% in 2016) and at 12.4% after IUI-D (12.4.0% in 2016). Twin and triplet DRs after IUI-H were 8.1% and 0.3%, respectively (in 2016: 8.8% and 0.3%) and 6.9% and 0.2% after IUI-D (in 2016: 7.7% and 0.4%). Amongst 18 888 FP interventions in 13 countries, cryopreservation of ejaculated sperm (n = 11 112 vs 7877 from 11 countries in 2016) and of oocytes (n = 6588 vs 4907 from eight countries in 2016) were the most frequently reported. LIMITATIONS REASONS FOR CAUTION: As the methods of data collection and levels of reporting vary amongst European countries, interpretation of results should remain cautious. Some countries were unable to deliver data about the number of initiated cycles and deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 21st ESHRE report on ART, IUI and FP interventions shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Being already the largest data collection on MAR in Europe, efforts should continue to optimize data collection and reporting with the perspective of improved quality control, transparency and vigilance in the field of reproductive medicine. STUDY FUNDING/COMPETING INTERESTS: The study has received no external funding and all costs are covered by ESHRE. There are no competing interests.

ART in Europe, 2016: results generated from European registries by ESHRE.

STUDY QUESTION: What are the reported data on cycles in ART, IUI and fertility preservation (FP) interventions in 2016 as compared to previous years, as well as the main trends over the years? SUMMARY ANSWER: The 20th ESHRE report on ART and IUI shows a progressive increase in reported treatment cycle numbers in Europe, with a decrease in the number of transfers with more than one embryo causing a reduction of multiple delivery rates (DR), as well as higher pregnancy rates and DR after frozen embryo replacement (FER) compared to fresh IVF and ICSI cycles, while the outcomes for IUI cycles remained stable. WHAT IS KNOWN ALREADY: Since 1997, ART aggregated data generated by national registries, clinics or professional societies have been collected, analysed by the European IVF-monitoring Consortium (EIM) and reported in 19 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN SIZE DURATION: Yearly collection of European medically assisted reproduction (MAR) data by EIM for ESHRE. The data on treatments performed between 1 January and 31 December 2016 in 40 European countries were provided by either National Registries or registries based on personal initiatives of medical associations and scientific organizations. PARTICIPANTS/MATERIALS SETTING METHODS: In all, 1347 clinics offering ART services in 40 countries reported a total of 918 159 treatment cycles, involving 156 002 with IVF, 407 222 with ICSI, 248 407 with FER, 27 069 with preimplantation genetic testing, 73 927 with egg donation (ED), 654 with IVM of oocytes and 4878 cycles with frozen oocyte replacement (FOR). European data on IUI using husband/partner's semen (IUI-H) and donor semen (IUI-D) were reported from 1197 institutions offering IUI in 29 and 24 countries, respectively. A total of 162 948 treatments with IUI-H and 50 467 treatments with IUI-D were included. A total of 13 689 FP interventions from 11 countries including oocyte, ovarian tissue, semen and testicular tissue banking in pre-and postpubertal patients were reported. MAIN RESULTS AND THE ROLE OF CHANCE: In 20 countries (18 in 2015) with a total population of approximately 325 million inhabitants, in which all ART clinics reported to the registry, a total of 461 401 treatment cycles were performed, corresponding to a mean of 1410 cycles per million inhabitants (range 82-3088 per million inhabitants). In the 40 reporting countries, after IVF the clinical pregnancy rates (PR) per aspiration and per transfer in 2016 were similar to those observed in 2015 (28.0% and 34.8% vs 28.5% and 34.6%, respectively). After ICSI, the corresponding rates were also similar to those achieved in 2015 (25% and 33.2% vs 26.2% and 33.2%). After FER with own embryos, the PR per thawing is still on the rise, from 29.2% in 2015 to 30.9% in 2016. After ED, the PR per fresh embryo transfer was 49.4% (49.6% in 2015) and per FOR 43.6% (43.4% in 2015). In IVF and ICSI together, the trend towards the transfer of fewer embryos continues with the transfer of 1, 2, 3 and ≥4 embryos in 41.5%, 51.9%, 6.2% and 0.4% of all treatments, respectively (corresponding to 37.7%, 53.9%, 7.9% and 0.5% in 2015). This resulted in a proportion of singleton, twin and triplet DRs of 84.8%, 14.9% and 0.3%, respectively (compared to 83.1%, 16.5% and 0.4%, respectively in 2015). Treatments with FER in 2016 resulted in twin and triplet DR of 11.9% and 0.2%, respectively (vs 12.3% and 0.3% in 2015). After IUI, the DRs remained similar at 8.9% after IUI-H (7.8% in 2015) and at 12.4% after IUI-D (12.0% in 2015). Twin and triplet DRs after IUI-H were 8.8% and 0.3%, respectively (in 2015: 8.9% and 0.5%) and 7.7% and 0.4% after IUI-D (in 2015: 7.3% and 0.6%). The majority of FP interventions included the cryopreservation of ejaculated sperm (n = 7877 from 11 countries) and of oocytes (n = 4907 from eight countries). LIMITATIONS REASONS FOR CAUTION: As the methods of data collection and levels of completeness of reported data vary among European countries, the results should be interpreted with caution. A number of countries failed to provide adequate data about the number of initiated cycles and deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 20th ESHRE report on ART and IUI shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Being already the largest data collection on MAR in Europe, continuous efforts to stimulate data collection and reporting strive for future quality control of the data, transparency and vigilance in the field of reproductive medicine. STUDY FUNDING/COMPETING INTERESTS: The study has no external funding and all costs were covered by ESHRE. There are no competing interests.

[In vitro fertilization and intracytoplasmic sperm injection: current medical aspects]. / In-vitro-Fertilisation und intrazytoplasmatische Spermieninjektion : Aktuelle medizinische Aspekte.

Since the delivery of the first baby conceived via in vitro fertilization (IVF) in 1978, IVF has become a standard procedure in sterility treatment. In Germany, 78,000 IVF/intracytoplasmic sperm injection (ICSI) cycles are performed annually with a delivery rate per embryo transfer of about 20 %. The cumulative delivery rate after three trials is more than 50 %. The main medical problems are the high rates of multiple pregnancies of more than 20 %, which carry an increased risk for mothers (preeclampsia) and children (preterm delivery, lung immaturity, brain problems). Also singleton babies after IVF are more often too small (small for gestational age, SGA) and delivered preterm. As a result, proper counselling is necessary. New laboratory methods have increased the success rate. Cryopreservation techniques such as vitrification are standard for freezing oocytes, pronuclear-stage oocytes and embryos if they are not needed during the current treatment cycle. Continuous observation of embryos by time-lapse imaging helps to identify the best embryos for transfer. The current legislation in the German embryo protection act (Embryonenschutzgesetz) is the main problem. It is unclear how many fertilized oocytes can be cultured to achieve a transfer of one to three embryos. The prohibition of oocyte donation and surrogacy are not comprehensible from a medical, psychological, and ethical point of view. Reimbursement of publicly insured patients is restricted in comparison with other European countries. Married couples receive half of the payment for three IVF/ICSI cycles; non-married couples receive no payment at all.

[The physician's role in various clinical contexts. Physician counseling on in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD)]. / Die Arztrolle in unterschiedlichen klinischen Kontexten. Ärztliche Beratung bei In-vitro-Fertilisation (IVF) und Präimplantationsdiagnostik (PID).

The role of the physician in the context of in vitro fertilization and preimplantation genetic diagnosis has certain distinct characteristics. Involuntary childlessness by definition of the WHO is a disease with good treatment options. As it is not considered a medical emergency, the focus lies more on intensive information giving, education, and counseling. Because the diagnosis and treatment can be a medical and psychological strain for the couple, counseling should address both medical and psychological aspects. The physician needs to have detailed medical knowledge as well as good communication skills to be able to meet the specific needs of the couple. Moreover, the physician should point out the realistic success rates of treatment and should refer to alternatives, such as remaining childless, adoption, and sperm or egg donation. The concurrent inclusion of biological, psychological, social, and ethical aspects in terms of psychosomatic basic care (Psychosomatische Grundversorgung) seems to be useful. There is potential for conflicts, for example, due to the economic interests of the physician. On the other hand, the treatment can be a financial burden for the couple. Of importance are the physician's and the patient's moral concepts, especially concerning some aspects of therapy (sperm and egg donation, surrogacy). The expected welfare of the intended child should also be respected (e.g., higher risk of preterm birth in multiple pregnancies). Further possible conflicts in reproductive medicine arise because of the crossing of moral boundaries (oocyte donation for postmenopausal women, surrogacy, cloning of human beings). The framework of counseling is based on the guidelines of the German Medical Association (Bundesärztekammer) for assisted reproduction (2006). Preimplantation genetic diagnosis has special requirements from a medical and psychosocial point of view.

Cryoconservation of Oocytes in a Patient with Breast Cancer and Intrauterine Early Pregnancy.

Case Report: A 38-year-old patient newly diagnosed with invasive ductal breast cancer wished to cryoconserve her unfertilised oocytes. Stimulation was started on the 26th day of her menstrual cycle with daily administration of 300 IE hMG s. c. and a GnRH antagonist (cetrorelix 0.25 mg s. c.). The patient additionally received an aromatase inhibitor during the first 5 days of stimulation (letrozole 5 mg p. o.). Induction of ovulation occurred on the 11th day of stimulation with hCG (10 000 IE s. c.) and a GnRH agonist (triptorelin 0.2 mg s. c.). Seventeen oocytes were retrieved during follicle puncture and 11 were cryopreserved. Despite the administration of cetrotide (a GnRH antagonist) no luteolysis occurred during stimulation. A pregnancy test was therefore done on the 11th day of stimulation and the result was positive (ß-HCG 3493 mIU/ml). Sonography showed an intrauterine pregnancy. The patient was in gestational week 5 + 0. The aspirated oocytes mostly showed a normal morphology (metaphase II) despite high progesterone levels during stimulation. The patient decided to terminate the pregnancy before starting adjuvant chemotherapy. Conclusion: We describe the case of a patient who underwent stimulation for cryopreservation of oocytes during a spontaneous pregnancy conceived in the same cycle just before starting stimulation. Stimulation was done over a short period using a combination of a GnRH antagonist and an aromatase inhibitor to ensure the lowest possible estradiol levels. The quality of the oocytes does not appear to have been negatively affected by the high progesterone levels of early pregnancy.

Premature chromosome condensation of the sperm nucleus after intracytoplasmic sperm injection.

A cytogenetic-cytological study was performed on unfertilized human oocytes (first polar body visible) after intracytoplasmic sperm injection (ICSI) with respect to the rate of prematurely condensed sperm chromosomes (G1-PCC). Out of 163 prepared oocytes derived from 41 ICSI cycles, 133 (approximately 82%) could be analysed successfully. a total of 60 oocytes (45.1%) showed metaphase II chromosomes in the haploid range along with an intact sperm head and 27 oocytes (20.3%) were missing the sperm head, but two of them showed an approximately diploid set of chromosomes; 38 oocytes (28.4%) exhibited the maternal metaphase II chromosomes as well as G1-PCC of the sperm nucleus showing a remarkable variation in the degree of condensation. Ten ICSI cycles (each followed by an embryo transfer) were characterized each by 2-3 oocytes demonstrating G1-PCC. It is concluded that the main cause of failed fertilization after ICSI is the failure of oocyte activation. When the sperm nucleus is able to act with the chromosome condensing factors and the oocyte does not become activated, this will lead to the induction of PCC. Absence of the sperm head might be due to injection or ejection of the spermatozoon in the perivitelline space except for two cases in which fertilization might have occurred. Finally, the observation of both a single chromatin region (n = 6) or two chromatin regions (n = 2) indicated oocyte activation which, however, was followed by developmental arrest.

[Male subfertility and conventional in vitro fertilization in Germany 1990 to 1993]. / Männliche Subfertilität und konventionelle In-vitro-Fertilisation in Deutschland 1990 bis 1993.

A retrospective study was carried out to compare the results of in vitro fertilisation (IVF) in 20936 patients with different sperm parameters who underwent IVF in Germany between 1990 and 1993. The study was designed to evaluate prognostic factors for IVF outcome, such as sperm parameters and pre-treatment diagnosis. The percentage of subfertile sperm parameters ( < 10 millions sperm per ml and/or < 30% progressive mobility and/or < 30% normal morphology) increased from 31.4% in 1990 to 51.1% in 1993. The fertilisation rate per puncture varied between 87.9% in patients with normozoospermia and 38.7% in patients with severe oligo-astheno-teratozoospermia (OAT). The fertilisation rate in patients with tubal indication was significantly higher than in patients with male indication and comparable spermatozoa. The pregnancy rate per embryo transfer was 23% in patients with normozoospermia and 13.8% in patients with "severe OAT syndrome" in the IVF semen parameters. On the other hand, patients with male sterility as pre-treatment diagnosis showed significantly higher chances of pregnancy than patients with a tubal factor (24% versus 20%, p < 0.05). Comparing percoll and swim-up preparation techniques, we found significantly higher fertilisation rates in normozoospermia and significantly higher pregnancy rates in subfertile patients after percoll sperm preparation. The results of the study demonstrated that patients with moderate subfertile sperm parameters have good chances of fertilisation and pregnancy following conventional IVE. It seems reasonable to set the boundary at a sperm count of 10 millions sperm/ml with 30% progressive motility and 30% normal morphology. Below these limits intracytoplasmic sperm injection shows better IVF outcome.