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STUDY QUESTIONCan risks associated with novelties in assisted reproduction technologies (ARTs) be assessed in a systematic and structured way?SUMMARY ANSWERAn ART-specific risk assessment tool has been developed to assess the risks associated with the development of novelties in ART (EuroGTP II-ART).WHAT IS KNOWN ALREADYHow to implement new technologies in ART is well-described in the literature. The successive steps should include testing in animal models, executing pre-clinical studies using supernumerary gametes or embryos, prospective clinical trials and finally, short- and long-term follow-up studies on the health of the offspring. A framework categorizing treatments from experimental through innovative to established according to the extent of the studies conducted has been devised. However, a systematic and standardized methodology to facilitate risk evaluation before innovations are performed in a clinical setting is lacking.STUDY DESIGN, SIZE, DURATIONThe EuroGTP II-ART risk assessment tool was developed on the basis of a generic risk assessment algorithm developed for tissue and cell therapies and products (TCTPs) in the context of the project ‘Good Practices for demonstrating safety and quality through recipient follow-up European Good Tissue and cells Practices II (EuroGTP II)’. For this purpose, a series of four meetings was held in which eight ART experts participated. In addition, several tests and simulations were undertaken to fine-tune the final tool.PARTICIPANTS/MATERIALS, SETTING, METHODSThe three steps comprising the EuroGTP II methodology were evaluated against its usefulness and applicability in ART. Ways to improve and adapt the methodology into ART risk assessment were agreed and implemented.MAIN RESULTS AND THE ROLE OF CHANCEAssessment of the novelty (Step 1), consisting of seven questions, is the same as for other TCTPs. Practical examples were included for better understanding. Identification of potential risks and consequences (Step 2), consisting of a series of risks and risk consequences to consider during risk assessment, was adapted from the generic methodology, adding more potential risks for processes involving gonadic tissues. The algorithm to score risks was also adapted, giving a specific range of highest possible risk scores. A list of strategies for risk reduction and definition of extended studies required to ensure effectiveness and safety (Step 3) was also produced by the ART experts, based on generic EuroGTP II methodology. Several explanations and examples were provided for each of the steps for better understanding within this field.LIMITATIONS, REASONS FOR CAUTIONA multidisciplinary team is needed to perform risk assessment, to interpret results and to determine risk mitigation strategies and/or next steps required to ensure the safety in the clinical use of novelties.WIDER IMPLICATIONS OF THE FINDINGSThis is a dynamic tool whose value goes beyond assessment of risk before implementing a novel ART in clinical practice, to re-evaluate risks based on information collected during the process.STUDY FUNDING / COMPETING INTEREST(S)This study was called EUROGTP II and was funded by the European Commission (Grant agreement number 709567). The authors declare no competing interests concerning the results of this study.

Pierre Zitoun,1 Jaya Parikh,2 Martine Nijs,3 Wenjie Zhang,4 Rachel Levy-Toledano,5 Boxiong Tang6 1American Hospital of Paris, Neuilly-sur-Seine, France; 2Lister Fertility Clinic, London, UK; 3Nij Geertgen, Elsendorp, the Netherlands; 4WG Group, New York, NY, USA; 5Theramex HQ UK Limited, London, UK; 6Teva Pharmaceuticals, Frazer, PA, USA Purpose: The purpose of this study was to assess product-specific features for a variety of self-administered injection devices and identify key factors that patients and nurses in select European markets find most important when selecting injection devices for self-administration of recombinant human follicle-stimulating hormone and urinary human follicle-stimulating hormone for fertility/reproductive therapy.Patients and methods: Patients (N=402) in France, Italy, Spain, Germany, the UK, the Netherlands, and Belgium, as well as reproductive/fertility nurses (N=40) in Germany, Italy, France, Spain, and the Czech Republic were surveyed. All patients were previously prescribed a follicle-stimulating hormone (FSH) treatment for either in vitro fertilization or ovulation induction. Patient and nurse preferences for attributes across all injection devices in the market were obtained via an online questionnaire and evaluated using the maximum differential scaling (MaxDiff) and conjoint analyses, which captured the relative importance of the selected FSH injection device attributes to determine specific qualities in overall product preference.Results: Both the MaxDiff and conjoint analyses indicated that, for patients and nurses, the ideal FSH injection device would be a highly accurate, multi-use reusable pen injector with a dial-back function that would be easy for both use and education/instruction. Patients and nurses each selected attributes pertinent to their own experiences with the FSH injection device. Categorically, patients valued factors that resulted in minimal impact on daily life, including reduced injection volume to minimize injection-site pain, as well as a reusable device that would be easy to use; nurses placed greater value on a device that would be easy to teach in order to instruct the greatest number of patients while minimizing risk.Conclusion: Patient and nurse preferences were aligned on certain selected attributes of the FSH products. Although this study was an unbranded examination of attributes across all injection devices currently in the market, results demonstrated that the preferred product attributes were all characteristics of the Ovaleap® Pen. Keywords: infertility, prefilled pen device, recombinant human follicle-stimulating hormone, urinary follicle-stimulating hormone, preference

In this preliminary prospective randomized study of 420 patients undergoing ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI), 17 patients (4%) developed moderate to severe ovarian hyperstimulation syndrome (OHSS). Re-evaluation for OHSS on day 4 and 6 after oocyte retrieval identified one patient with continuous risk for severe OHSS, resulting in cancellation of the transfer (1/17, 5.8%). Prospectively, two of three patients had the zona pellucida of the blastocyst removed by pronase exposure prior to transfer. Significantly more patients became pregnant when a zona-free blastocyst was transferred in comparison to transfer of a single zona-intact embryo (9/11 or 82% versus 1/5 or 20%; P < 0.01). Higher ongoing singleton pregnancy rates were obtained when the zona pellucida was removed prior to the transfer (6/11 and 1/5 respectively). This preliminary prospective randomized study indicates that by prolonging the evaluation time for patients at risk of developing OHSS for up to 6 days after the oocyte retrieval, those patients at risk for developing severe OHSS can be identified. Transferring a single zona-free day 5 embryo (blastocyst) and freezing of the supernumerary embryos offers the patient with moderate OHSS an optimal chance for a singleton pregnancy, while avoiding the serious maternal complications of ovarian hyperstimulation syndrome.

Since the first reports of successful pregnancies in humans after treatment with intracytoplasmic sperm injection (ICSI), intensive investigations have focused on several important aspects of this form of assisted reproductive technology. In addition to the technical development of ICSI and increasing understanding of the biochemical and biophysical processes involved during fertilization after injection of an immobilized sperm, studies have aimed to define the indications for patients for a first-line ICSI treatment. One of the major concerns is of course the safety of the technique in terms of the health and reproductive life of the babies born after ICSI. The rhesus monkey is an excellent model to investigate all aspects of this micromanipulation technique. This article provides an evaluation of ICSI.

This is the first report of an intrauterine pregnancy following timed coitus, resulting from transperitoneal sperm and/or oocyte migration as the oocyte originated from an ectopic (undescended) ovary. The patient was treated in the infertility clinic after a history of primary infertility for 2 years. Diagnosis of a moderate teratozoospermia and the presence of a unicornuate uterus with one right-sided normal ovary was made. During the first intrauterine insemination (IUI) treatment cycle with clomiphene citrate stimulation, a discrepancy between oestradiol concentrations and follicular growth was observed. Magnetic resonance imaging (MRI) was carried out because the presence of an ectopic ovary was suspected. The diagnosis of a left-sided undescended ovary was made, containing several follicles, the largest measuring 16 mm in diameter. Because of a spontaneous LH surge 2 days later without substantial follicular growth in the normal right-sided ovary, IUI was cancelled and timed intercourse was planned. Surprisingly, and although the largest follicle in the normally located ovary reached a maximum diameter of only 12 mm on repetitive ultrasound monitoring, this patient became pregnant and gave birth to a healthy baby boy.

Background: Low (or poor) responder patients are women who require large doses of stimulation medications and produce less than an optimal number of oocytes during IVF cycles. Low responder patients produce few oocytes and embryos, which significantly reduces their chances for success in a preimplantation genetic diagnosis (PGD) cycle. Accumulation of vitrified oocytes or embryos before the actual PGD cycle is a possible strategy that might increase patient’s chances for a healthy pregnancy.Aim of the study: This retrospective study evaluates the efficacy of a PGD program in low responder patients after repeated ovarian stimulation cycles with cumulative vitrification of oocytes and embryos.Methods: Over a period of 30 months, 13 patients entering the PGD program were identified as poor responders after their first ovarian stimulation. These patients started a PGD cycle for one of the following indications: history of recurrent implantation failure (n=1), cystic fibrosis (n=1), X-linked microtubular myopathy (n=1), recurrent miscarriages (n=5), Duchene muscular dystrophy (n=1), chromosomal translocation (n=1) and high sperm aneuploidy (n=1). After multiple ovarian hormonal stimulations patients had either all mature oocytes (Group A; 3 patients) or all of their day 2 embryos vitrified (group B; 10 patients). Mean total number of oocyte collections per patient was 2.3 (range: 2 - 5 cycles).Results: In the actual PGD cycle, all vitrified oocytes from group A patients were warmed and underwent intra cytoplasmic sperm injection (ICSI) followed by culture up to day 3. For group B patients all vitrified day 2 embryos were warmed and cultured overnight. On day 3 of culture, all embryos from Group A and B had blastomere biopsy followed by genetic analysis. In group A, 20 embryos were found suitable for biopsy and genetic analysis; at least one healthy embryo was available for transfer for each patient. For group B, 72 embryos in total were available for biopsy and PGD. All patients, except one, had at least one healthy day 5 embryo for transfer (mean number of 2.1 embryos per transfer). Nine patients had a clinical pregnancy; 7 patients delivered a healthy baby.Conclusion: Low responder patients entering a PGD program might increase their chances for a healthy pregnancy by repeat ovarian stimulation in combination with cumulative oocyte or embryo vitrification.