Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice

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Purpose This study aims to make an account of the children born following transplantation of frozen-thawed ovarian tissue worldwide with specific focus on the perinatal outcome of the children. Furthermore, perinatal outcome of seven deliveries (nine children) from Denmark is reported. Methods PubMed was searched for papers of deliveries resulting from ovarian tissue cryopreservation (OTC). Seven women underwent OTC prior to chemotherapy. Four of these women still had low ovarian function and had tried to conceive. They therefore had tissue autotransplanted to augment their fertility. The other three women had developed premature ovarian insufficiency (POI) after the end of treatment.Results Worldwide, approximately 95 children have been born or will be born in the near future from OTC, including these 9 new children. Information on the perinatal outcome was found on 40 children. The mean gestational age was 39 weeks and the mean birth weight was 3168 g of the singleton pregnancies, which is within internationally recognized normal standards. Furthermore, half the singletons resulted from natural conception and all twins resulted from in vitro fertilization treatment. All seven Danish women became pregnant within 1-3 years after transplantation. They gave birth to nine healthy children. Conclusion The data is reassuring and further suggests that cryopreservation of ovarian tissue is becoming an established fertility preservation method. The seven Danish women reported in this study were all in their early thirties when OTC was performed. Most other reported cases were in the women's twenties. This suggests that the follicular pool in the thirties is large enough and sufficient to sustain fertility.Keywords Fertility preservation . Cryopreservation . Ovarian tissue transplantation . Deliveries IntroductionOvarian tissue cryopreservation (OTC) and transplantation is a relatively new procedure within the area of assisted reproduction technologies (ART). OTC differs from other ART procedures like freezing oocytes or embryos by cryopreserving intact tissue containing small non-growing follicles [1,2]. Although the cryoprotectant media used to freeze ovarian tissue resemble those media used for oocytes and embryos, there are often subtle differences [3,4]. Furthermore, extensive investigations on the effects of cryoprotectants on both human and animal ovarian tissue have not revealed any potential side effects. However, studies in women who had frozen-thawed ovarian tissue transplanted have The original version of this article was revised: There were errors in the Discussion section and the last paragraph should be removed.Capsule The data is reassuring and further suggests that cryopreservation of ovarian tissue is becoming an established fertility preservation method.

Section: Introductionmentioning

confidence: 99%

86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children

Jensen

Macklon²,

Fedder

et al. 2016

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160

“…Fertility preservation methods in young female cancer patients facing a potential gonadotoxic treatment have over the last decade proved valuable in securing fertility and continuous steroid production. Currently, almost 60 healthy children have been born worldwide as a result of transplanting frozen/thawed ovarian tissue [1]. These methods are currently entering clinical practice in many countries.…”

Section: Introductionmentioning

confidence: 99%

Vitrification of in vitro matured oocytes collected from surplus ovarian medulla tissue resulting from fertility preservation of ovarian cortex tissue

Yin

Jiang

Kristensen

et al. 2016

Purpose The aim of the study was to investigate the maturation rate of immature oocytes collected from ovarian medulla tissue normally discarded during preparation of ovarian cortical tissue for fertility preservation. Further we evaluated survival of derived MII oocytes following vitrification and warming. Methods 36 patients aged from 8 to 41 years who had one ovary excised for fertility preservation were included. Oocytes were collected from the medulla tissue and matured in vitro 44-48 h followed by vitrification. Number of oocytes collected, the rates of maturation and post-warming survival were assessed. Results On average, 11 immature oocytes were collected per patient. The overall maturation rate was 29 % irrespective of whether the ovary was transported 4-5 h on ice or obtained immediately after oophorectomy. The maturation rate in patients below 20 years of age (55 %) was significantly higher than that of patients aged 20-30 years (29 %) and above 30 years (26 %). The post-warming survival rate was 64 %. No significant relationship was observed between the number of collected oocytes and the age of patients.Conclusions Approximately three MII oocytes were obtained per patient following in vitro maturation (IVM) of immature oocytes collected from medulla tissue, of which two survived vitrification and warming. This approach represents an add-on method to potentially augment the fertility opportunity for cancer patients, especially in young women with cancer where transplantation of cortical tissue may pose a risk of relapse, but the IVM approach is currently too inefficient to be the only method used for fertility preservation.

“…Standard operating procedures (SOPs) for formulating Vitrification and Warming and Recovery medias that have been made for research purposes must be converted to fulfill the manufacturing and release guidelines put forth by the FDA with the goal of submitting the IND and performing clinical trials for establishing this procedure in clinical practice. Clinical use of this vitrified and recovered tissue could include autotransplant of the tissue back into the patient or isolation of specific cell types within the vitrified tissue for cytotherapy for restoring fertility and hormone production as previously reported [3]. An easy-to-follow kit would ensure standardized procedures for quality tissue preservation and recovery across 117 sites around the globe [oncofertility.northwestern.edu].…”

Section: Purposementioning

confidence: 99%

Good manufacturing practice requirements for the production of tissue vitrification and warming and recovery kits for clinical research

Laronda

McKinnon

Ting

et al. 2016

Products that are manufactured for use in a clinical trial, with the intent of gaining US Food and Drug Administration (FDA) approval for clinical use, must be produced under an FDA approved investigational new drug (IND) application. We describe work done toward generating reliable methodology and materials for preserving ovarian cortical tissue through a vitrification kit and reviving this tissue through a warming and recovery kit. We have described the critical steps, procedures, and environments for manufacturing products with the intent of submitting an IND. The main objective was to establish an easy-to-use kit that would ensure standardized procedures for quality tissue preservation and recovery across the 117 Oncofertility Consortium sites around the globe. These kits were developed by breaking down the components and steps of a research protocol and recombining them in a way that considers component stability and use in a clinical setting. The kits were manufactured utilizing current good manufacturing practice (cGMP) requirements and environment, along with current good laboratory practices (cGLP) techniques. Components of the kit were tested for sterility and endotoxicity, and morphological endpoint release criteria were established. We worked with the intended down-stream users of these kits for development of the kit instructions. Our intention is to test these initial kits, developed and manufactured here, for submission of an IND and to begin clinical testing for preserving the ovarian tissue that may be used for future restoration of fertility and/or hormone function in women who have gonadal dysgenesis from gonadotoxic treatment regimens or disease.Keywords Good manufacturing practice . Vitrification . Ovary . Oncofertility Purpose Current Good Manufacturing Practice (cGMP) regulations are enforced by the US Food and Drug Administration in order to ensure the quality of manufactured drug products. These guidelines are listed in the 21 Code of Federal Regulations (CFR) part 211 [1]. cGMPs include a set of guidelines for facility standards, proper documentation, and implementation of procedures. Additionally, equipment within facilities used for drug manufacturing must be monitored and calibrated under cGMP guidelines and personnel must be properly trained and proficient in the facility procedures in order to be compliant. Current good laboratory practices (cGLPs) are additional guidelines that ensure that the data generated by testing the Capsule The main objective of this study was to establish an easy-to-use kit for standardized ovarian tissue vitrification and recovery. We have described the critical steps, procedures, and environments for manufacturing media kits intended for an Investigational New Drug (IND) application for future clinical trials.Electronic supplementary material The online version of this article