Maximizing the Yield of Assisted Reproductive Technologies at Every Step

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1 WHITE PAPER Maximizing the Yield of Assisted Reproductive Technologies at Every Step Author: Dr Filippo Maria Ubaldi, GENERA Centers for Reproductive Medicine, Italy Dr Ubaldi holds academic degrees in obstetrics and gynecology and Master of Science degrees in andrology and reproductive medicine. He has co-authored more than 110 peer-reviewed scientific papers (H-index 32), eight books, and more than 200 congress abstracts in the field of reproductive medicine. He has been invited to speak at more than 300 national and international meetings. Between 2005 and 2009, Dr Ubaldi was a member of the executive committee for the European Society of Human Reproduction and Embryology (ESHRE), and he chaired the 26 th ESHRE annual meeting held in Rome, in June Filippo Maria Ubaldi, MD, MSc; Medical Doctor and Clinical Director at the GENERA Centers for Reproductive Medicine, Italy Acknowledgements The scientific content and opinions presented in this paper are solely the views of Dr Filippo Maria Ubaldi. The author thanks Ileana Stoica, PhD and Antonio Alvau, PhD from Green Park Content for their assistance in writing the manuscript. Financial support to Green Park Content was provided by Merck KGaA, Darmstadt, Germany. DISCLOSURE Honoraria for lectures and unrestricted research grants from Merck and MSD. In my opinion, the methodological developments that can improve the efficiency of ART in the near future are in the IVF lab... and with these techniques we will be able to select the most competent embryo with non-invasive methods such as time lapse monitoring [...] or with minimally invasive methods such as preimplantation genetic testing. Infertility: a global problem Infertility is defined by the World Health Organization as the inability of a couple to achieve pregnancy after 12 months or more of trying to conceive naturally [1]. Affecting around 9% of women of reproductive age worldwide [2], infertility is recognized as a clinical and psychosocial problem that has detrimental effects on couples physical and emotional well-being and the quality of their relationships [3]. While the past two decades have seen major progress in both the diagnosis and treatment of infertility [4], couples undergoing assisted reproduction are still experiencing considerable levels of anxiety, depression and psychosocial distress, which persist over the duration of the intervention and beyond [3, 5]. 1

2 ART in perspective The pharmacological management of infertility consists of ovulation induction using fertility drugs, followed by either natural intercourse or Assisted Reproductive Technologies (ARTs). The latter include intrauterine insemination (IUI), in vitro fertilization (IVF), Intracytoplasmic Sperm Injection (ICSI), and third-party ART (egg and sperm donation) [1]. Non-pharmacological approaches to infertility include surgical management and other strategies such as adoption or surrogacy. ART has made great strides since the birth of Louise Brown in An estimated 6.5 million IVF babies have been born worldwide [6]. Moreover, the 15 th report on ART from the European Society of Human Reproduction and Embryology (ESHRE) showed a steady rise in the number of treatment cycles in Europe over recent years, with a concomitant decrease in the rate of multiple deliveries [7]. ART: progress to date and limiting factors The development of ART has offered options previously unavailable to infertile couples [8]. Recent decades have seen the attainment of key IVF milestones, including the development of technologies for fertility preservation; preimplantation testing for aneuploidy; mitochondrial DNA assessment; uterine transplantation; and mitochondrial replacement techniques for the prevention of inherited diseases [8, 9]. Despite these advances, assisted reproduction remains an area of high clinical need. The average ART cycle has a success rate of only 30% [10] and many couples undergo several rounds of treatment before achieving the desired outcome. Methodological developments are underway to address the current limitations of ART and ensure further access to high-quality infertility interventions worldwide. In Standards of Care for Women s Health in Europe, the European Board and College of Obstetrics and Gynecology (EBCOG) states: Each infertility treatment should result in the highest possible success rate and all appropriate measures for the patient s safety should be in place. The treatment protocols should minimize the risk of complications, such as ovarian hyperstimulation syndrome (OHSS) [4]. ARTs are complex procedures involving several different steps: controlled ovarian stimulation (COS); gamete collection; in vitro fertilization/ Intracytoplasmic Sperm Injection (IVF/ICSI); embryo culture, preservation, selection, transfer and implantation; and maintenance of pregnancy until the birth of a healthy child. All of these steps are equally important to ensure a successful outcome. Each stage of ART has unique challenges and limitations; for example, COS is a time-consuming step and has been linked to a higher risk of OHSS [11]. In addition to clinical challenges, the social aspects of assisted reproduction need to be addressed, especially those related to patients aims and expectations from treatment [8]. Defining the goals of fertility treatment While the ultimate aim of ART is to deliver a healthy baby, achieving this is by no means straightforward in everyday clinical practice, and for many couples the experience of assisted reproduction is a convoluted, anxious journey. The concept of patient-centered care is at the forefront nowadays, yet studies on ART improvement have typically focused on clinical effectiveness rather than patients experience and needs. Infertility statistics have shown that, although they have somewhat different priorities, when it comes to quality of care both men and women value reduced waiting times, good information, and staff who demonstrate commitment and empathy [12, 13]. 2

3 Time to pregnancy/birth (TTP/B) has been suggested as one of the key considerations affecting treatment choices from both a patient and physician perspective. This outcome measure is particularly relevant as, increasingly, childbearing is being delayed until a later age. Given the decline in fertility in women over 35, individualized treatment approaches are needed to target women of advanced reproductive age [14]. Taken together, these observations create a compelling argument to establish TTP/B as a measure of ART success, and reduced TTP/B as a goal of treatment. In my clinic, we also use as a measure of success the time to live birth; I believe it is important to reduce the time to live birth as much as possible. Toward improved ART outcomes in the clinic Scientific advances over recent decades have broadened the accessibility of ART and raised its success rate [9], thus reducing TTP/B. On the other hand, new knowledge gaps have emerged in the field. For example, the relationship between chromosomal euploidy and successful pregnancy highlighted the need for safe and reliable tools to investigate chromosomal / genetic abnormalities in early embryos. Preimplantation genetic testing (PGT) Initially developed as a prenatal diagnostic tool for couples at increased reproductive risk, PGT has become increasingly focused on aneuploidy analysis (PGT-A) in embryos at the blastocyst stage [15]. The approach relies on Comprehensive Chromosome Screening (CCS) techniques such as Comparative Genomic Hybridization (acgh), array-single Nucleotide Polymorphisms (asnp), quantitative Polymerase Chain Reaction (qpcr) and Next-Generation Sequencing (NGS) to help identify and select euploid embryos with the highest potential for development [16]. An accurate and reliable selection of the embryo with the highest chance of implantation and live birth should be considered as a key step toward improving ART success rates while reducing IVF timelines. The application of PGT techniques has some limitations. There is a risk of false positives and false negatives, due to the paucity of sample material. Biopsy can also have a negative effect on the embryo s development potential, which raises ethical concerns. Current efforts are focused on the development of strategies with higher sensitivity and minimal impact on reproductive potential and embryo viability [15]. A comprehensive PGT approach should also include genetic counseling to guide couples toward informed yet autonomous decisions by providing a thorough explanation of the technical details, possible outcomes and risks associated with the technique [15, 17]. Elective single embryo transfer The benefit provided by PGT-based embryo selection could be further enhanced by selectively transferring to the uterus only the embryo with the highest developmental potential, an approach defined as elective Single Embryo Transfer (eset). The eset method (either after PGT or not) should be strongly recommended today because it significantly reduces one of the most important complications of IVF: multiple pregnancies. While current clinical guidelines recommend eset only for patients with a good prognosis, this strategy can also be beneficial for special patient groups, such as women of advanced maternal age [18]. Optimizing ovarian stimulation through treatment personalization A cornerstone of fertility treatments, pharmacologically-induced ovarian stimulation is designed to produce a cohort of metaphase II (MII) 3

4 oocytes for the subsequent selection and transfer of the highest-quality embryo/embryos [19]. Cryopreservation and vitrification techniques have improved the efficiency and reliability of oocyte retrieval [20-22], allowing any surplus oocytes to be stored and preserved for later use. This approach has also introduced a new measure of ART success: the Cumulative Live Birth Rate (CLBR), defined as the number of live births obtained using all the embryos developed from a single-cycle stimulation. This innovative measure of success was shown to be suitable with various pharmacological options for ovarian stimulation [23]. Technical advances notwithstanding, there is controversy among clinicians around the optimal number of oocytes to be retrieved from one IVF cycle, though initiatives are in place for the development of expert guidance on the matter. While retrieving a high number of oocytes per cycle can maximize treatment effectiveness and reduce duration and costs, this approach may not be risk-free. A common concern is the link between ovarian stimulation and OHSS, which can have serious consequences [24]. In addition, it has been suggested that a high (>15) MII oocyte yield may jeopardize both oocyte and endometrial quality [19]. According to the literature, the optimal number of oocytes to optimize the live birth rate is between 10 and 15 [ ] but this is only true in the fresh embryo transfer cycles. If we consider the fresh and frozen-thawed cycles, the cumulative live birth rate will continue to increase with the number of oocytes retrieved. Vitrified vs. Slow-Frozen: Meta-Analysis Results A recent systematic review and meta-analysis of available randomized and cohort trials comparing outcomes for vitrification vs. slow-freezing of human oocytes and embryos was reported Significant improvement in embryo cryosurvival rate (RR=1.59, P<0.001) 2.28 Higher live birth rate per cycle from one RCT with embryos (RR=2.28; P=0.016) 2.81 Higher ongoing clinical pregnancy rate per cycle from one RCT with oocytes* (RR=2.81; P=0.039) *RR=1.89; P=0.051 for CPR per cycle using embryo vitrification vs slow-freezing. CPR=clinical pregnancy rate RCT=randomized controlled trial RR=risk ratio 1. Rienzi L, et al. Hum Reprod Update 2016:

5 Strategies for optimizing COS: single-cycle stimulation Recent studies have focused on understanding the relationship between oocyte vitrification and delivery rate [25]. In this context, a retrospective cohort study of 2,226 women undergoing IVF in a university clinic demonstrated the feasibility of the one and done concept: a single COS with high oocyte yield (>15 oocytes) can be used for different cycles [26]. The study investigators found that the group with 15 to 25 retrieved oocytes achieved the highest clinical pregnancy rate (42.8%), as well as the highest 1 live birth rate at Cycle 1 (37.1%) and the highest cumulative rate across all cycles (53.9%) [26]. An open-label RCT of 1,050 women, randomized 1:1 to either a GnRH-antagonist or GnRH-agonist, found similar CLBR values of 34.1% and 31.2%, respectively. As in the one and done study, women with 10 to 15 and >15 retrieved oocytes had an increased chance of live birth [23]. However, it is ultimately the patient s individual response to treatment that will determine the success of strategies such as one and done. This observation underscores the importance of developing personalized COS protocols that maximize the oocyte yield while keeping risks low [27]. Closing remarks The overall ART outcome depends on achieving success at every stage of the treatment cycle; therefore, each step should be optimized in order to reduce TTP/B. This depends not only on the stepwise implementation of ART, but also on the interplay between different steps. For example, cryopreservation/vitrification alone does not impact TTP/B; however, in synergy with an optimized COS regimen, it has the potential to maximize the delivery rate for each cycle, ultimately reducing TTP/B. According to my clinical experience, I believe we should aim to reduce the time to live birth. To better reach this goal, we should optimize the number of oocytes to be retrieved with individualized ovarian stimulation to maximize CLBR. We should try to select the single embryo, possibly at blastocyst stage, with the highest chance to implant and give a live birth. 5

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