ART in Europe, 2019: 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 2019 as compared to previous years? SUMMARY ANSWER: The 23rd ESHRE report highlights the rising ART treatment cycles and children born, alongside a decline in twin deliveries owing to decreasing multiple embryo transfers; fresh IVF or ICSI cycles exhibited higher delivery rates, whereas frozen embryo transfers (FET) showed higher pregnancy rates (PRs), and reported IUI cycles decreased while maintaining stable outcomes. WHAT IS KNOWN ALREADY: ART aggregated data generated by national registries, clinics, or professional societies have been gathered and analyzed by the European IVF-Monitoring (EIM) Consortium since 1997 and reported in a total of 22 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 each year. The data on treatment cycles performed between 1 January and 31 December 2019 were provided by either national registries or registries based on initiatives of medical associations and scientific organizations or committed persons in one of the 44 countries that are members of the EIM Consortium. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 1487 clinics offering ART services in 40 countries reported, for the second time, a total of more than 1 million (1 077 813) treatment cycles, including 160 782 with IVF, 427 980 with ICSI, 335 744 with FET, 64 089 with preimplantation genetic testing (PGT), 82 373 with egg donation (ED), 546 with IVM of oocytes, and 6299 cycles with frozen oocyte replacement (FOR). A total of 1169 institutions reported data on IUI cycles using either husband/partner's semen (IUI-H; n = 147 711) or donor semen (IUI-D; n = 51 651) in 33 and 24 countries, respectively. Eighteen countries reported 24 139 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 2018) in which all ART clinics reported to the registry 476 760 treatment cycles were registered for a total population of approximately 300 million inhabitants, allowing the best estimate of a mean of 1581 cycles performed per million inhabitants (range: 437-3621). Among the reporting countries, for IVF the clinical PRs per aspiration slightly decreased while they remained similar per transfer compared to 2018 (21.8% and 34.6% versus 25.5% and 34.1%, respectively). In ICSI, the corresponding PRs showed similar trends compared to 2018 (20.2% and 33.5%, versus 22.5% and 32.1%) When freeze-all cycles were not considered for the calculations, the clinical PRs per aspiration were 28.5% (28.8% in 2018) and 26.2% (27.3% in 2018) for IVF and ICSI, respectively. After FET with embryos originating from own eggs, the PR per thawing was at 35.1% (versus 33.4% in 2018), and with embryos originating from donated eggs at 43.0% (41.8% in 2018). After ED, the PR per fresh embryo transfer was 50.5% (49.6% in 2018) and per FOR 44.8% (44.9% in 2018). In IVF and ICSI together, the trend toward the transfer of fewer embryos continues with the transfer of 1, 2, 3, and ≥4 embryos in 55.4%, 39.9%, 2.6%, and 0.2% of all treatments, respectively (corresponding to 50.7%, 45.1%, 3.9%, and 0.3% in 2018). This resulted in a reduced proportion of twin delivery rates (DRs) of 11.9% (12.4% in 2018) and a similar triplet DR of 0.3%. Treatments with FET in 2019 resulted in twin and triplet DR of 8.9% and 0.1%, respectively (versus 9.4% and 0.1% in 2018). After IUI, the DRs remained similar at 8.7% after IUI-H (8.8% in 2018) and at 12.1% after IUI-D (12.6% in 2018). Twin and triplet DRs after IUI-H were 8.7% and 0.4% (in 2018: 8.4% and 0.3%) and 6.2% and 0.2% after IUI-D (in 2018: 6.4% and 0.2%), respectively. Eighteen countries (16 in 2018) provided data on FP in a total number of 24 139 interventions (20 994 in 2018). Cryopreservation of ejaculated sperm (n = 11 592 versus n = 10 503 in 2018) and cryopreservation of oocytes (n = 10 784 versus n = 9123 in 2018) were most frequently reported. LIMITATIONS, REASONS FOR CAUTION: Caution with the interpretation of results should remain 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 23rd 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 toward optimization of both the collection and the reporting, from the perspective of improving surveillance and vigilance in the field of reproductive medicine, are awaited. STUDY FUNDING/COMPETING INTEREST(S): The study has received no external funding and all costs are covered by ESHRE. There are no competing interests.

Mechanism of spindle pole organization and instability in human oocytes.

Human oocytes are prone to assembling meiotic spindles with unstable poles, which can favor aneuploidy in human eggs. The underlying causes of spindle instability are unknown. We found that NUMA (nuclear mitotic apparatus protein)-mediated clustering of microtubule minus ends focused the spindle poles in human, bovine, and porcine oocytes and in mouse oocytes depleted of acentriolar microtubule-organizing centers (aMTOCs). However, unlike human oocytes, bovine, porcine, and aMTOC-free mouse oocytes have stable spindles. We identified the molecular motor KIFC1 (kinesin superfamily protein C1) as a spindle-stabilizing protein that is deficient in human oocytes. Depletion of KIFC1 recapitulated spindle instability in bovine and aMTOC-free mouse oocytes, and the introduction of exogenous KIFC1 rescued spindle instability in human oocytes. Thus, the deficiency of KIFC1 contributes to spindle instability in human oocytes.

Psychosomatically Oriented Diagnostics and Therapy for Fertility Disorders. Guideline of the DGPFG (S2k-Level, AWMF Registry Number 016/003, December 2019).

Aim The purpose of this official guideline published and coordinated by the German Society for Psychosomatic Gynecology and Obstetrics [Deutsche Gesellschaft für Psychosomatische Frauenheilkunde und Geburtshilfe (DGPFG)] is to provide a consensus-based overview of psychosomatically oriented diagnostic procedures and treatments for fertility disorders by evaluating the relevant literature. Method This S2k guideline was developed using a structured consensus process which included representative members of various professions; the guideline was commissioned by the DGPFG and is based on the 2014 version of the guideline. Recommendations The guideline provides recommendations on psychosomatically oriented diagnostic procedures and treatments for fertility disorders.

Fully human glyco-optimized recombinant FSH (follitropin epsilon) - a randomized, comparator-controlled phase II clinical trial.

RESEARCH QUESTION: The study aimed to determine the standard treatment dose of follitropin epsilon for ovarian stimulation in the context of IVF treatment. DESIGN: A total of 247 women aged 18-37 years were treated with either 52.5, 75, 112.5 or 150 IU follitropin epsilon daily, or 150 IU every other day, or 150 IU follitropin alfa daily in a long gonadotrophin-releasing hormone agonist protocol. The study was performed as a randomized, assessor-blinded, comparator-controlled, six-armed phase II trial in eight fertility clinics in two European countries. RESULTS: The primary results were as follow. First, none of the doses of follitropin epsilon showed superiority for the main outcome measure, i.e. number of follicles ≥12 mm in size. Follitropin epsilon 75 IU produced results most similar to those of follitropin alfa 150 IU. In terms of secondary results, stronger effects of follitropin epsilon 112.5 IU compared with follitropin alfa 150 IU were seen for secondary outcome measures such as hormone concentrations (oestradiol, inhibin B and progesterone) and oocyte number. CONCLUSIONS: Follitropin epsilon 75 IU daily results in a similar ovarian response to a standard dose of 150 IU follitropin alfa. This dose could be tested in a phase III trial.

Possible Reasons for Discontinuation of Therapy: an Analysis of 571 071 Treatment Cycles From the German IVF Registry.

Introduction Numerous couples discontinue fertility treatment before achieving the objective, the birth of a child. The aim of this retrospective data analysis is to identify the reasons for early discontinuation of therapy (drop-out). Materials and Methods Retrospective data analysis. With the aid of the German IVF Registry (D·I·R ® ), a total of 122 560 "last cycles" in Germany in the period 2012 - 2015 were identified and the courses were analysed. Results From the named cohort of "last cycles", 37.3% of the female patients (45 699) gave birth to a child and ended the therapy. The remaining 76 861 discontinued the treatment before having a child. The fertility treatment was conducted due to a purely male indication in 46.27% of cases and in 17.96% the cause lay exclusively with the woman. 4.53% of the drop-outs suffered a miscarriage in the last cycle. 73.56% of the drop-out patients ended the therapy after the lack of a positive pregnancy test. After the third therapy cycle, 67% of the couples ended their treatment. Conclusion The results make it possible to provide couples with individual counselling. They offer an option for preparing for the emotional and physical hurdles.

Multicenter, noninterventional, post-marketing surveillance study to evaluate dosing of recombinant human follicle-stimulating hormone using the redesigned follitropin alfa pen in women undergoing ovulation induction.

This prospective, noninterventional, post-marketing surveillance study evaluated doses of recombinant human follicle-stimulating hormone (r-hFSH) using the redesigned follitropin alfa pen in women who were anovulatory or oligomenorrheic and undergoing ovulation induction (OI) alone or OI with intrauterine insemination. The primary endpoint was the proportion of patients who achieved monofollicular or bifollicular development (defined as one or two follicles ≥15 mm). Secondary endpoints included characteristics of ovulation stimulation treatment, such as mean total and mean daily r-hFSH doses. Data were analyzed for 3,193 patients from 30 German fertility centers. The proportion of patients with monofollicular or bifollicular development was 71.1% (n=2,270 of a total of 3,193 patients; intent-to-treat population). The mean±standard deviation total and daily doses of r-hFSH were 696.9±542.5 IU and 61.7±29.4 IU, respectively. The three doses prescribed most frequently were: 37.5 IU (n=703 from N=3,189; 22.0%), 50.0 IU (n=1,056 from N=3,189; 33.1%), and 75.0 IU (n=738 from N=3,189; 23.1%) on the first day of stimulation; and 37.5 IU (n=465 from N=3,189; 14.6%), 50.0 IU (n=922 from N=3,189; 28.9%), and 75.0 IU (n=895 from N=3,189; 28.1%) on the last day of stimulation. This noninterventional, post-marketing surveillance study found that monofollicular or bifollicular development was achieved in 71% of patients studied and the small dose increment (12.5 IU) of the redesigned follitropin alfa pen allowed individualized treatment of women undergoing OI.

Individualized recombinant human follicle-stimulating hormone dosing using the CONSORT calculator in assisted reproductive technology: a large, multicenter, observational study of routine clinical practice.

PURPOSE: This postmarketing surveillance survey was conducted to investigate the utility of the CONsistency in r-FSH Starting dOses for individualized tReatmenT (CONSORT) calculator for individualizing recombinant human follicle-stimulating hormone (r-hFSH) starting doses for controlled ovarian stimulation (COS) in routine clinical practice. METHODS: This was a 3-year, open-label, observational study evaluating data from women undergoing COS for assisted reproductive technology at 31 German fertility centers. Physicians stated their recommended r-hFSH starting dose, then generated a CONSORT-recommended r-hFSH starting dose. Physicians could prescribe any r-hFSH starting dose. The primary objective was to compare the r-hFSH starting dose recommended by the physician with the CONSORT-calculated dose and that prescribed. Statistical analyses were conducted post hoc. RESULTS: Data were collected from 2,579 patients; the mean (standard deviation [SD]) age was 30.5 (2.93) years (range: 19-40 years). The mean (SD) CONSORT-calculated r-hFSH starting dose was significantly lower than the physician-recommended dose (134.5 [38.0] IU versus 164.6 [47.1] IU; P<0.0001); the mean (SD) starting dose prescribed was 162.2 (48.4) IU. CONSORT-calculated doses were prescribed for 27.3% (number [n] =677) of patients, and non-CONSORT-calculated doses prescribed for 72.7% (n=1,800). The mean (SD) number of oocytes retrieved per patient was 10.6 (6.15) and 11.4 (6.66) in the CONSORT and non-CONSORT groups, respectively; the mean (SD) number of embryos transferred per patient was 1.98 (0.41) and 2.03 (0.45), respectively. Clinical pregnancy rates per COS cycle were 38.8% (CONSORT) and 34.8% (non-CONSORT) (P=0.142); clinical pregnancy rates per embryos transferred were 45.0% and 39.5%, respectively (P=0.049). Miscarriage occurred in 14.8% of all clinical pregnancies ( CONSORT: 12.5%; non- CONSORT: 15.3%). The rate of grade 3 ovarian hyperstimulation syndrome (OHSS) was 0.3% (n=2) in the CONSORT group and 0.6% (n=11) in the non-CONSORT group. OHSS led to hospitalization in 0.81% (n=21) of cases (CONSORT group: 0.74% [n=5]; non-CONSORT group: 0.83% [n=15]). CONCLUSION: Physician-recommended r-hFSH starting doses were generally higher than those calculated by CONSORT; most patients were prescribed a higher starting dose than that recommended by CONSORT.