Guidelines for Reproductive Medicine in Japan

Abstract

Assisted reproductive technology (ART) is a relatively new field compared with other medical treatments; so far, the evidence that forms the basis of medical treatment and treatment guidelines has yet to be sufficiently established. In addition, there has been a tendency in the past for new techniques to be introduced into on-the-job medical care without evidence being established. As we entered the 21st century, evidence gradually increased, and the need for accurate evaluations of medical technologies has increased worldwide, resulting in the creation of multiple guidelines in Western countries in the last 10 years or so. Based on the "Law concerning special provisions of the Civil Code concerning the provision of assisted reproductive technology and the parent–child relationship of children born as a result" promulgated on December 11, 2020, in Japan, ART has been covered by insurance from April 2022 as a concrete measure (Act No. 76 of 2020). As a reference when considering insurance coverage, the government has requested the Japan Society for Obstetrics and Gynecology, which deals with obstetrics and gynecology in general, and the Japan Society for Reproductive Medicine, which deals with ART, including male infertility, to create medical treatment and treatment guidelines. Within this context, it was decided that medical care and treatment guidelines be created based on the actual medical conditions and evidence in Japan. The authors of the Guidelines Development Committee have contributed significantly to the drafting of the guidelines. A draft was published on the website of the Japan Society for Reproductive Medicine, and opinions were solicited from members, resulting in repeated amendments. Following deliberation by the evaluation committee, the content of the amendments was discussed, and on May 26, 2021, the original draft first proof composition policy was confirmed. In November 2021, the first edition of "Assisted Reproductive Technology Guidelines 2021," consisting of 40 Clinical Questions (CQ), and answers was published. Since this guideline is written in Japanese, there were some inconveniences for those who are not native speakers of the Japanese language. An English version was created to overcome this problem. This book includes "commentary," "actual conditions," "usage of drugs," "reference list," and "charts," but these parts have been omitted owing to space limitations. Furthermore, the description of the general infertility area has been excluded from this document to avoid duplication with the Obstetrics and Gynecology Practice Guidelines Gynecology Outpatient Edition 2020, which was edited and supervised by the Japan Society of Obstetrics and Gynecology and the Japan Association of Obstetricians and Gynecologists. As the Japan Society for Reproductive Medicine participated in the editing of these guidelines, we would like to add that we take great responsibility as an organization of medical researchers/medical professionals in helping patients suffering from infertility and hope that we can contribute to the healthy birth and growth of children who will usher our country into the future. Recommendation levels (strength) "A," "B," and "C" are shown in each CQ and answer. These recommendation levels were created by comprehensively considering the clinical usefulness, evidence, penetrance, and medical economic viewpoint of the recommended testing and treatment methods. Therefore, the answers are not necessarily based on "evidence." When evidence is lacking, a decision is reached by considering the balance between benefit and harm, values and preferences, penetrance, costs, and resource utilization. The recommendation levels are interpreted as follows: A: Highly recommended (for implementation, etc.), B: Recommended (for implementation, etc.), C: Considered (for implementation, etc.). Factors that determine the recommendation level include the quality of evidence, balance between benefits and harm, values and preferences, penetrance, cost, and resource utilization. The recommendation level is likely to be higher as the overall evidence increases in strength, if the desired effects outweigh the undesired effects and the gap between the two increases, and when the costs resources correspond to the net benefits. Ovulation induction is defined as pharmacological treatment with the intention of inducing normal ovulatory cycles of women with anovulation or oligo-ovulation for timed intercourse or intrauterine insemination (non-ART). Ovarian stimulation is defined as pharmacological treatment with the intention of inducing the development of ovarian follicles for IVF/ICSI (ART). Chapter A. Desirable equipment and personnel for Assisted Reproductive Technology (ART) (CQ001, CQ002). Chapter B. Indications for ART (CQ003–CQ005). Chapter C. Ovarian stimulation in ART (CQ006–CQ014). Chapter D. Prevention and treatment of ovarian hyperstimulation syndrome (OHSS) (CQ015). Chapter E. Embryo culture and manipulation (CQ016–CQ023). Chapter F. Fresh embryo transfer and frozen embryo transfer (CQ024–CQ028). Chapter G. Add-on medical treatment (CQ029–CQ035). Chapter H. Psychological support and counseling (CQ036). Chapter I. Male infertility (CQ037–040). CQ001: What are the conditions inside the egg collection/culture room? CQ002: What are the qualifications of the attending physician? What are the staffing requirements for non-physician personnel? CQ003: Is in vitro fertilization (IVF)/intracytoplasmic sperm injection effective for achieving pregnancy? What are the optimal number of trials and eligibility criteria for IVF/intracytoplasmic sperm injection? CQ004: In what cases would it be allowed for one to directly proceed to IVF/intracytoplasmic sperm injection? What tests and treatments are needed in each case? CQ005: What are the indications for testicular sperm extraction (TESE)? Is TESE with intracytoplasmic sperm injection effective? CQ006: Is the evaluation of the ovarian reserve effective in selecting the gonadotropin dose for ovarian stimulation? CQ007: Is hormone pretreatment effective for ART? CQ008: Are gonadotropin-releasing hormone (GnRH) antagonists more effective than GnRH agonists in ovarian stimulation for high responders? CQ009: Is adding a blood test to the ultrasound tomography effective in monitoring follicle development during the IVF cycle? CQ010: What are the precautions for ovarian stimulation by (ovarian stimulation protocol/LH surge suppression method/test) IVF? Is follicle-stimulating hormone (FSH) more effective for ovarian stimulation than human menopausal gonadotropin (hMG)? CQ011: Is natural cycle/mild ovarian stimulation effective for ovarian stimulation? CQ012: Is letrozole (LTZ) effective for ovarian stimulation in PCOS? Is metformin (Met) effective for ovarian stimulation in PCOS? Is LTZ effective for ovarian stimulation in unexplained infertility? Is gonadotropin therapy with LTZ more effective for ovarian stimulation than gonadotropin therapy with clomiphene citrate (CC)? CQ013: Is progestin-primed ovarian stimulation (PPOS) effective for ovarian stimulation in patients with unexplained infertility? CQ014: Are GnRH agonists more effective than human chorionic gonadotropin (hCG) for egg maturation and OHSS avoidance? CQ015: Is interventional treatment effective in preventing the onset and aggravation of OHSS associated with ART? CQ016: Is embryo culture effective to establish pregnancy? CQ017: What are the indications and effects of in vitro maturation (IVM)? CQ018: Is a time-lapse incubator effective in assessing embryonic development? Is time-lapse incubation effective in improving IVF performance? CQ019: What is the indication and effectiveness of preimplantation genetic testing for aneuploidy (PGT-A)? CQ020: Is elective single embryo transfer (SET) useful for reducing the risk of multiple pregnancies? CQ021: Is assisted hatching effective for ART? CQ022: Is sperm selection (e.g., intracytoplasmic morphologically selected sperm injection (IMSI) and physiological intracytoplasmic sperm injection (PICSI)) effective for ART with a high-magnification microscope? CQ023: Is artificial oocyte activation (AOA) effective for ART? CQ024: Is luteal support in fresh embryo transfer effective in improving ART performance? CQ025: How safe is fresh embryo transfer? CQ026: What is the effectiveness and safety of frozen/thawed embryo transfer? Is frozen embryo transfer more effective than fresh embryo transfer? CQ027: Is the hormone therapy cycle in frozen/thawed embryo transfer superior to the natural cycle? CQ028: What are the requirements and precautions for facilities that cryopreserve gametes, embryos, and ovaries? CQ029: Is the endometrial embryo receptivity test effective for repeated implantation failure? CQ030: Is the endometrial microbiome test effective in improving ART performance? CQ031: Is the stimulation of endometrium embryo transfer (SEET) method effective for repeated implantation failure? CQ032: Is type 1 T helper (Th1)/type 2 T helper (Th1) measurement recommended for repeated implantation failure? CQ033: Is a transfer medium containing high concentration of hyaluronic acid effective for repeated implantation failure? CQ034: Is endometrial scratching effective for improving ART outcome? CQ035: Is immunotherapy such as tacrolimus/low dose aspirin effective for repeated implantation failure? CQ036: What information and mental support do patients undergoing fertility treatment need? Are psychological and educational interventions effective in psychosocial assessment and support of infertile patients? CQ037: Is the Y-chromosome microdeletion test recommended before performing testicular sperm extraction (TESE)? CQ038: Are phosphodiesterase 5 (PDE5) inhibitors effective against male infertility with erectile dysfunction? CQ039: Is clomiphene citrate (CC) effective against male infertility? CQ040: Is amoxapine, a tricyclic antidepressant, effective in treating retrograde ejaculation? We would like to thank the editorial committee and academic committee of the Japan Society for Reproductive Medicine for proofreading the manuscript. None declared.

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