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Importance: The study summarises the selection prescreen criteria currently used in the UK for a uterus transplant and highlights the number of women who are suitable to proceed., Objectives: To assess the demographics, motivations, reasons and suitability among women with absolute uterine factor infertility (AUFI) to undergo uterine transplantation (UTx)., Design: A cross-sectional survey., Setting: An electronic questionnaire was sent via email to women with AUFI who had previously been referred to the UTx research team or approached the Womb Transplant UK Charity. The questions assessed suitability to undergo UTx based on demographic information, perceptions to adoption and surrogacy and reasons why UTx was preferable. Responses were assessed against the study selection criteria., Participants: Women with AUFI., Results: 210 women completed the questionnaire. The most common aetiology of AUFI in our cohort was Mayer-Rokitansky-Küster-Hauser (68%; n=143) whereas 29% (n=62) had previously undergone hysterectomy. 63% (n=132) of the cohort had previously considered adoption, 5% (n=11) had attempted it and 2 (1%) had successfully adopted. The most common reason cited to undergo UTx over adoption was to experience gestation (n=63; 53%), while 37% (n=44) wanted a biologically related child. 76% (n=160) of participants had previously considered surrogacy, 22 (10%) had attempted it and 2 (1%) had successfully become mothers using a surrogate. The most common reason to undergo UTx over surrogacy was to experience gestation (n=77; 54%). 15% (n=21) were concerned about the legal implications, 14% (n=20) identified the financial cost as a barrier and 8% (n=12) could not consider it due to religious reasons. On adhering to the selection criteria, 65 (31%) women were suitable to proceed with the trial., Conclusion: The study demonstrates that implementing commonly used selection criteria for a UTx led to an attrition rate of more than two-thirds of women who requested to initially undergo the process. As more studies present outcomes following UTx, critical assessment of the selection criteria currently used is warranted to ensure potential recipients are not being unnecessarily excluded., Trial Registration Number: NCT02388802., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Recognition of phenotypic variability in pediatric asthma allows for a more personalized therapeutic approach. Knowledge of the underlying pathophysiological and molecular mechanisms (endotypes) of corresponding biomarkers and new treatments enables this strategy to progress. Biologic therapies for children with severe asthma are becoming more relevant in this sense. The T2 phenotype is the most prevalent in childhood and adolescence, and non-T2 phenotypes are usually rare. This document aims to review the mechanism of action, efficacy, and potential predictive and monitoring biomarkers of biological drugs, focusing on the pediatric population. The drugs currently available are omalizumab, mepolizumab, benralizumab, dupilumab, and 1ezepelumab, with some differences in administrative approval prescription criteria between the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Previously, we described the characteristics of severe asthma in children and its diagnostic and therapeutic management.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO 2 /FiO 2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April-30 July 2020 and 21 January-19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0-1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40-60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Age-related fertility decline (ARFD) is a prevalent concern amongst western cultures due to the increasing age of first-time motherhood. Elective oocyte and embryo cryopreservation remain the most established methods of fertility preservation, providing women the opportunity of reproductive autonomy to preserve their fertility and extend their childbearing years to prevent involuntary childlessness. Whilst ovarian cortex cryopreservation has been used to preserve reproductive potential in women for medical reasons, such as in pre- or peripubertal girls undergoing gonadotoxic chemotherapy, it has not yet been considered in the context of ARFD. As artificial reproductive technology (ART) and surgical methods of fertility preservation continue to evolve, it is a judicious time to review current evidence and consider alternative options for women wishing to delay their fertility. This article critically appraises elective oocyte cryopreservation as an option for women who use it to mitigate the risk of ARFD and introduces the prospect of elective ovarian cortex cryopreservation as an alternative., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Uterine transplantation has evolved rapidly over the last decade. As the number of cases performed increases exponentially worldwide, emerging evidence continues to improve collective knowledge and understanding of the procedure, with the aim of improving both surgical and reproductive outcomes. Although currently restricted to women with absolute uterine factor infertility, increasing awareness as a method of fertility restoration has resulted in a demand for the procedure to be undertaken in transgender women. This manuscript summarizes the recent advances in uterine transplantation, and elaborates further upon the key novel avenues research within the field will focus on over the coming years., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Time-lapse systems have quickly become a common feature of in vitro fertilization laboratories all over the world. Since being introduced over a decade ago, the alleged benefits of time-lapse technology have continued to grow, from undisturbed culture conditions and round the clock, noninvasive observations to more recent computer-assisted selection of embryos through the development of algorithms. Despite the global uptake of time-lapse technology, its real impact on clinical outcomes is still controversial. This review aims to explore the different features offered by time-lapse technology, discussing incubation, algorithms, artificial intelligence and the regulation of nonessential treatment interventions, while assessing evidence on whether any benefit is offered over conventional technology., Competing Interests: None declared., (Thieme. All rights reserved.)

Uterine transplantation (UTx) is a fertility restoring treatment for women with absolute uterine factor infertility. At a time when there is no question of the procedure's feasibility, and as the number of livebirths begins to increase exponentially, various important reproductive, fetal, and maternal medicine implications have emerged. Detailed outcomes from 17 livebirths following UTx are now available, which are reviewed herein, along with contextualized extrapolation from pregnancy outcomes in other solid organ transplants. Differences in recipient demographics and reproductive aspirations between UTx and other transplant recipients make extrapolating management strategies and outcomes in other solid organ transplants inappropriate. Whereas preterm delivery remains prominent, small for gestational age or hypertensive disorders do not appear to be as prevalent following UTx when compared to other solid organ transplants. Given the primary objective of undertaking UTx is to achieve a livebirth, publication of reproductive outcomes is essential at this early stage, to reflect on and optimize the management of future cases., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The feasibility of freezing and thawing ovarian tissue is nowadays widely documented. However, ovarian tissue transplantation (OTT) is happening at a much slower pace, and clinical experience is somewhat limited. In this review, five European centers present their collective experience of transplanting ovarian tissue in 285 women. The focus is on surgical techniques and OTT outcomes, reproductive outcomes, the impact of chemotherapy before ovarian tissue cryopreservation (OTC), the risk of relapse, and endocrine resumption and longevity of transplanted tissue. The risk of relapse due to reimplantation of ovarian tissue appears to be very low according to current data. Recovery of endocrine function is seen in almost all women undergoing transplantation of ovarian tissue, and about one in four gives birth to a healthy child. The efficacy of in vitro fertilization in these patients is not very high, however, and needs to be substantially improved. Radiation to the pelvis, especially with relatively high doses, appears to considerably decrease the likelihood of a successful pregnancy and may be contraindicated. Our results demonstrate that chemotherapy before OTC does not impair the chances of success, depending, of course, on the total dose and type of chemotherapy administered. At this early stage of development of OTT for restoration of fertility, the results are encouraging and demonstrate clear potential. However, the method is far from being fully developed and requires continued research efforts to optimize our approach., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

A uterine transplantation is a nonvital, quality-of-life-enhancing solid organ transplant. Given improvements in donor risk profile and the anticipated shortage of suitable deceased donors, nondirected donation could facilitate sustainability as uterine transplantation moves from research into the clinical realm. The aim of this article is to determine perceptions and identify motivations of potential nondirected living uterus donors and assess acceptability and suitability., Methods: A cross-sectional survey using an electronic questionnaire among women who have inquired about donating their uterus for uterine transplantation., Results: The majority of respondents "strongly agreed" or "agreed" that the most prevalent motivations to donate their uterus include helping someone carry and give birth to their own baby (n = 150; 99%), helping others (n = 147; 97%), and because they no longer need their womb (n = 147; 97%). After considering risks of uterus donation, the majority were still keen to donate their uterus (n = 144; 95%), but following a process of exclusion using donor selection criteria, less than a third (n = 42; 29%) were found to be suitable to proceed., Conclusions: This study demonstrates novel insight into the motivations of women who wish to donate their uterus and displays high levels of acceptability after consideration of the risks involved. Despite the physical risk and transient impact upon ability to undertake activities of daily living, women who donate their uterus expect to gain psychological and emotional benefits from enabling another woman to gestate and give birth to their own future children. However, currently used selection criteria reduce the number of potential donors significantly., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Importance: Uterus transplant has been demonstrated to be a viable fertility-restoring treatment for women categorized as female at birth with absolute uterine factor infertility. Recent advancements, as well as considerations of fairness and equality in reproductive care, have now led to the possibility of uterus transplant being undertaken in transgender women., Objective: To investigate the reproductive aspirations of transgender women and their perceptions of uterus transplant., Design, Setting, and Participants: This cross-sectional survey study used a 27-item electronic questionnaire to investigate the reproductive aspirations of 182 transgender women older than 16 years, including their perceptions of and motivations for uterus transplant, between May 1 and November 1, 2019., Main Outcomes and Measures: Perceptions of and motivations for uterus transplant, including perceived significance of the ability to gestate, menstruate, and have a physiologically functioning vagina., Results: A total of 182 transgender women completed the questionnaire; most women (109 [60%]) were aged 20 to 29 years. Most did not have children prior to transitioning (167 [92%]) and expressed a desire to have children in the future (171 [94%]). In addition, most respondents agreed or strongly agreed that the ability to gestate and give birth to children (171 [94%]) and menstruate (161 [88%]) would enhance perceptions of their femininity. Similarly, high proportions strongly agreed or agreed that having a transplanted, functioning vagina would improve their sexual experience (163 [90%]), improve their quality of life (163 [90%]), and help them to feel like more of a woman (168 [92%]). Nearly all respondents (180 [99%]) believed that uterus transplant would lead to greater happiness in transgender women. More than three-quarters of the respondents (140 [77%]) strongly agreed or agreed that they would be more inclined to cryopreserve sperm if uterus transplant became a realistic option., Conclusions and Relevance: This study provides insights into the reproductive aspirations of transgender women and reports on their multifaceted motivation to undergo uterus transplant. The survey responses suggest that transgender women would choose to have female physiologic experiences, such as menstruation and gestation, as well as potentially having a physiologically functioning transplanted vagina. If proven feasible and safe in this setting, uterus transplant may facilitate the achievement of reproductive aspirations, improve quality of life, and further alleviate dysphoric symptoms in transgender women.

Purpose: Oncofertility focuses on providing fertility and endocrine-sparing options to patients who undergo life-preserving but gonadotoxic cancer treatment. The resources needed to meet patient demand often are fragmented along disciplinary lines. We quantify assets and gaps in oncofertility care on a global scale., Methods: Survey-based questionnaires were provided to 191 members of the Oncofertility Consortium Global Partners Network, a National Institutes of Health-funded organization. Responses were analyzed to measure trends and regional subtleties about patient oncofertility experiences and to analyze barriers to care at sites that provide oncofertility services., Results: Sixty-three responses were received (response rate, 25%), and 40 were analyzed from oncofertility centers in 28 countries. Thirty of 40 survey results (75%) showed that formal referral processes and psychological care are provided to patients at the majority of sites. Fourteen of 23 respondents (61%) stated that some fertility preservation services are not offered because of cultural and legal barriers. The growth of oncofertility and its capacity to improve the lives of cancer survivors around the globe relies on concentrated efforts to increase awareness, promote collaboration, share best practices, and advocate for research funding., Conclusion: This survey reveals global and regional successes and challenges and provides insight into what is needed to advance the field and make the discussion of fertility preservation and endocrine health a standard component of the cancer treatment plan. As the field of oncofertility continues to develop around the globe, regular assessment of both international and regional barriers to quality care must continue to guide process improvements., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Alexandra S. RashediEmployment: Cigna (I) Stock or Other Ownership: Cigna (I)Antoinette AnazodoResearch Funding: Merck SeronoCassio SartorioEmployment: Vida Centro de Fertilidade Leadership: Vida Centro de Fertilidade Stock or Other Ownership: Vida Centro de FertilidadeCatharina C.M. BeerendonkTravel, Accommodations, Expenses: GoodlifeEllen M. GreenblattConsulting or Advisory Role: Ferring Pharmaceuticals, EMD Serono Travel, Accommodations, Expenses: EMD SeronoFernando M. ReisHonoraria: Politec Saúde (I) Consulting or Advisory Role: Politec Saúde (I) Speakers’ Bureau: UCB (I) Travel, Accommodations, Expenses: Abbott Laboratories (I)Johan SmitzSpeakers’ Bureau: Ferring Pharmaceuticals Travel, Accommodations, Expenses: Ferring PharmaceuticalsMaria T. BourlonLeadership: Medivation, Astellas Pharma Honoraria: Medivation, Astellas Pharma Speakers’ Bureau: Asofarma Research Funding: Bristol-Myers Squibb Travel, Accommodations, Expenses: Janssen PharmaceuticalsMichel De VosHonoraria: Cook Medical Research Funding: Cook MedicalRichard A. AndersonConsulting or Advisory Role: Roche, HRA Pharma, NeRe Pharmaceuticals Speakers’ Bureau: Roche, Beckman Coulter, IBSA Institut Biochimque Research Funding: Ferring Pharmaceuticals Travel, Accommodations, Expenses: IBSA Institut BiochimqueRoberto de A. AntunesConsulting or Advisory Role: Merck Serono Speakers’ Bureau: Merck Serono Travel, Accommodations, Expenses: Merck Serono, MSDTeresa Almeida-SantosConsulting or Advisory Role: Merck, MSD Research Funding: MerckTeresa K. WoodruffResearch Funding: Ferring Pharmaceuticals (Inst) No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Purpose: In the accompanying article, "Survey of Fertility Preservation Options Available to Patients With Cancer Around the Globe," we showed that specific fertility preservation services may not be offered at various sites around the world because of cultural and legal barriers. We assessed global and regional experiences as well as the legal status of third-party reproduction and adoption to serve as a comprehensive international data set and resource for groups that wish to begin oncofertility interventions., Methods: We provide data on the legalities of third-party assisted reproductive technologies and other family-building options in the 28 oncofertility-practicing countries surveyed., Results: We found regional and country differences that will be important in the development of tailored resources for physicians and for patient brochures that are sensitive to these local restrictions and cultural norms., Conclusion: Because many patients first consult Web-based materials, the formal assessment of the availability of these options provides members of the global oncofertility community with data to which they might otherwise not have ready access to better serve their patients., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Alexandra S. RashediEmployment: Cigna (I) Stock or Other Ownership: Cigna (I)Antoinette AnazodoResearch Funding: Merck SeronoCassio SartorioEmployment: Vida Centro de Fertilidade Leadership: Vida Centro de Fertilidade Stock or Other Ownership: Vida Centro de FertilidadeCatharina C.M. BeerendonkTravel, Accommodations, Expenses: GoodlifeEllen M. GreenblattConsulting or Advisory Role: Ferring Pharmaceuticals, EMD Serono Travel, Accommodations, Expenses: EMD SeronoFernando M. ReisHonoraria: Politec Saúde (I) Consulting or Advisory Role: Politec Saúde (I) Speakers’ Bureau: UCB (I) Travel, Accommodations, Expenses: Abbott Laboratories (I)Flor SánchezPatents, Royalties, Other Intellectual Property: patent pendingJohan SmitzSpeakers’ Bureau: Ferring Pharmaceuticals Travel, Accommodations, Expenses: Ferring PharmaceuticalsMaria T. BourlonLeadership: Medivation, Astellas Pharma Honoraria: Medivation, Astellas PharmaRichard A. AndersonConsulting or Advisory Role: Roche, HRA Pharma, NeRe Pharmaceuticals Speakers’ Bureau: Roche, Beckman Coulter, IBSA Institut Biochimque Research Funding: Ferring Pharmaceuticals Travel, Accommodations, Expenses: IBSA Institut BiochimqueRoberto de A. AntunesConsulting or Advisory Role: Merck Serono Travel, Accommodations, Expenses: Merck Serono, MSDSergio RomeroPatents, Royalties, Other Intellectual Property: patent pendingTeresa Almeida-SantosConsulting or Advisory Role: Merck, MSD Research Funding: Merck SeronoTeresa K. WoodruffResearch Funding: Ferring Pharmaceuticals (Inst) No other potential conflicts of interest were reported., (© 2020 by American Society of Clinical Oncology.)

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Objective: To compare the efficacy of oocyte vitrification (OV) with that of ovarian cortex cryopreservation and transplantation (OCT) in women undergoing gonadotoxic treatments., Design: Prospective observational cohort study., Setting: Not applicable., Patient(s): Candidates for chemo-/radiotherapy who joined our fertility preservation (FP) program were included in this study between 2005 and 2015. One cohort included 1,024 patients undergoing OV; the other cohort included 800 patients undergoing OCT., Intervention(s): OV using the cryotop device and OCT using a slow freezing protocol., Main Outcome Measure(s): Live-birth rate (LBR) and clinical pregnancy rate (CPR)., Result(s): Basal antimüllerian hormone levels of the patients revealed no differences in ovarian reserve before FP (OV, 11.6 pM [5.4-24.7]; OCT, 11.8 pM [6.4-21.9]). In the OV cohort, 49 patients used the vitrified oocytes after a mean storage time of 3.9 years. In the OCT cohort, 44 sought pregnancy after a mean storage time of 5.5 years. A trend toward higher CPR and LBR (per patient) was observed in the OV group (risk ratio [RR CPR ], 1.31 [95% confidence interval, 0.90-1.92]; RR LBR 1.39 [95% confidence interval, 0.95-2.03]), although differences were not statistically significant. In the OCT group, 46.7% of pregnancies occurred spontaneously and no pregnancy was achieved when the tissue was harvested beyond the age of 36 years. All patients except three undergoing OCT resumed or improved endocrine ovarian function., Conclusion(s): Although we observed a trend toward higher LBR after OV, OCT is a very effective method to preserve fertility, allows for natural pregnancy, and restores ovarian function. In clinical scenarios where OV is not feasible, OCT remains the FP technique of choice and should no longer be considered experimental., (Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child., Design: Part of an observational study., Setting: University teaching hospital., Patient(s): Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother., Intervention(s): In vitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12 months after UTx, pregnancy controls, delivery, and hysterectomy., Main Outcome Measure(s): Results of IVF-ET, parameters of pregnancy/birth, and surgical data of transplantation/cesarean section/hysterectomy., Result(s): Two IVF cycles before UTx resulted in 10 cryopreserved embryos. Donor surgery included hysterectomy with vascular pedicles of uterine vessels and proximal vessels up to and including parts of internal iliacs. Recipient surgery was by bilateral vascular connections to external iliacs, vaginal-vaginal anastomosis, and uterine fixation. Pregnancy occurred at the first single ET, and the pregnancy proceeded uneventfully until gestational week 34, when the patient developed cholestasis with intense pruritus. Cesarean section was performed at 34+6, with delivery of a healthy boy (weight 2,335 g). Hysterectomy was performed 3.5 months after delivery. The weight of the healthy child at 12 months was 9.3 kg. Grandmother (uterus donor) and mother are in good health 3 years after UTx., Conclusion(s): This is the first report of a live birth after mother-to-daughter UTx, and it also represents the second birth ever after human UTx., Clinical Trial Registration: NCT01844362., (Copyright © 2016. Published by Elsevier Inc.)

Introduction: Uterus transplantation (UTx) is introduced as the first treatment for absolute uterine factor infertility (AUFI), affecting 1:500 fertile aged women. This review presents potential patients, research and human UTx cases., Sources of Data: Published articles and our research experience., Areas of Agreement: The first UTx live births in 2014 established UTx as a possible treatment for AUFI. This was proceeded by 15 years of systematic research., Areas of Controversy: Is a deceased donor UTx as effective as the proven successful live donor UTx?., Growing Points: Human UTx trials will accumulate data on risks, effectiveness and long-term consequences for donors, recipients and children. These should also include aspects of quality of life, psychological well-being and cognitive/neuropsychiatric development of children., Areas Timely for Developing Research: All new activities in human UTx within the coming years should be conducted as prospective observational studies, and data should also be collected within an international registry., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: A low response to controlled ovarian hyperstimulation implies a reduced number of embryos and impaired pregnancy rate. Follicular priming with steroids before controlled ovarian hyperstimulation has been suggested to improve the subsequent ovarian response., Objective: The purpose of this study was to determine the best follicular priming protocol in low responders and to investigate the intrafollicular mechanisms triggered by steroid hormone priming., Design: This was a single-center, randomized, parallel, open-label, controlled trial, in two phases., Setting: The setting was a university-based in vitro fertilization unit., Patients: Potential low responders (n = 99) underwent a first intracytoplasmic sperm injection cycle. Confirmed low responders (n = 66) were randomized to different priming protocols before a new intracytoplasmic sperm injection., Interventions: Randomized patients underwent one of the following priming strategies: transdermal testosterone (20 μg/kg/d), transdermal estradiol (200 μg/d), or combined estrogens and oral contraceptive pills (30 μg of ethinyl estradiol plus 150 μg of desogestrel administered during the luteal phase of two consecutive cycles) and 4 mg/d of estradiol valerate during the follicular phase between them., Main Outcomes Measures: Metaphase II (MII) oocytes were retrieved. Gene expression levels in the granulosa cells of steroidogenesis enzymes and FSH, LH, and androgen receptors were measured., Results: The number of retrieved MII oocytes did not differ between the interventional groups (testosterone, 2.2 ± 2.0; estrogen, 2.7 ± 1.7; and combined estrogens and oral contraceptive pills, 2.0 ± 1.3; not significant). Compared with those in nonprimed cycles, estradiol pretreatment yielded more MII oocytes (primed, 2.7 ± 1.7; nonprimed, 1.6 ± 1.2; P = .029) although the clinical pregnancy rate was higher in patients treated with testosterone (P = .003). Testosterone pretreatment increased androgen receptor expression (P = .028) compared with that for the previous cycle without priming., Conclusions: The results of the present trial do not support the superiority of one priming strategy over the others.

Immunosuppressive drugs may influence spermatogenesis, but little is known about outcome of pregnancies fathered by transplanted males. We estimated risk of adverse outcomes in pregnancies (with data after the first trimester) fathered by males that had undergone organ transplantation and were treated with immunosuppression. A population-based study, linking data from the Norwegian transplant registry and the Medical Birth Registry of Norway during 1967-2009 was designed. All Norwegian men undergoing solid organ transplantation were included. Odds ratios for major malformations, preeclampsia, preterm delivery (<37 weeks) and small-for-gestational-age were obtained using logistic regression. A total of 2463 transplanted males, fathering babies of 4614 deliveries before and 474 deliveries after transplantation were identified. The risk of preeclampsia was increased (AOR: 7.4, 95% CI: 1.1-51.4,) after transplantation compared to prior to transplantation. No increased risk was found for congenital malformations or other outcomes when compared with pregnancies before transplantation or with the general population (2 511 506 births). Our results indicate an increased risk of preeclampsia mediated through the transplanted and immunosuppressed father. Importantly, no increased risk was found for other adverse obstetric outcomes or malformations, which may reassure male transplant recipients planning to father children., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To report the 12-month outcome of seven patients with viable uteri after uterus transplantation (UTx)., Design: Prospective observational study., Setting: University hospital., Patient(s): Seven patients with absolute uterine infertility and viable uteri for 12 months after live-donor UTx., Intervention(s): Predetermined immunosuppression was with tacrolimus and mychophenolate mofetil (MMF) during 6 months, whereupon MMF should be withdrawn. Frequent ultrasound examinations were performed to assess uterine appearance and uterine artery blood flow. Cervical biopsies (for histological detection of rejection) were obtained at preset time points, with temporary adjustments of immunosuppression if there were signs of rejection. Menstruations were systematically recorded., Main Outcome Measure(s): Menstruation, uterine artery blood flow, histology of cervical biopsies, and blood levels of tacrolimus., Result(s): All patients showed regular menses after 1-2 months. Uterine artery blood flow was unchanged, with a median pulsatility index of 1.9 (range, 0.5-5.4). Blood levels of tacrolimus were approximately 10, 9, and 8 (μg/L) during months 2, 9, and 12, respectively. Four recipients showed mild inflammation in biopsies after MMF withdrawal and were treated with corticosteroids and azathioprine during the remainder of the 12 months. Subclinical rejection episodes were detected on ectocervical biopsies in five recipients. Histology showed apoptotic bodies and occasional spongiosis in the squamous epithelium. Moderate infiltration of lymphocytes and neutrophils was seen in the epithelial/stromal interface. All rejection episodes were successfully treated for 2 weeks with corticosteroids or dose increments of tacrolimus., Conclusion(s): We demonstrate long-term uterine viability after UTx, with continued menstruation and unaltered uterine artery blood flow. Subclinical rejection episodes were effectively reversed by temporary increase of immunosuppression., Clinical Trial Registration Number: NCT01844362., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To report the 6-month results of the first clinical uterus transplantation (UTx) trial. This type of transplantation may become a treatment of absolute uterine-factor infertility (AUFI)., Design: Prospective observational study., Setting: University hospital., Patient(s): Nine AUFI women and their live uterine donors, the majority being mothers., Intervention(s): Live-donor UTx and low-dose induction immunosuppression., Main Outcome Measure(s): Data from preoperative investigations, surgery and follow-up for 6 months., Result(s): Durations of donor and recipient surgery ranged from 10 to 13 hours and from 4 to 6 hours, respectively. No immediate perioperative complications occurred in any of the recipients. After 6 months, seven uteri remained viable with regular menses. Mild rejection episodes occurred in four of these patients. These rejection episodes were effectively reversed by corticosteroid boluses. The two graft losses were because of acute bilateral thrombotic uterine artery occlusions and persistent intrauterine infection., Conclusion(s): The results demonstrate the feasibility of live-donor UTx with a low-dose immunosuppressive protocol., Clinical Trial Registration Number: NCT01844362., (Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Aggressive chemotherapy/radiotherapy and bone marrow transplantation can cure >90% of girls and young women affected by disorders requiring such treatment. However, the ovaries are very sensitive to cytotoxic drugs, especially to alkylating agents. Several options are currently available to preserve fertility in cancer patients. The present review reports the results of 60 orthotopic reimplantations of cryopreserved ovarian tissue performed by three teams, as well as 24 live births reported in the literature to date. Restoration of ovarian activity occurred in almost all cases in the three series. Among the 60 patients, eleven conceived and six of those had already delivered twelve healthy babies. In the future, we are looking to: 1) improve freezing techniques; and 2) enhance the "vascular bed" before reimplantation to increase pregnancy rates. On the other hand, cryopreservation of ovarian tissue may be combined with removal, via puncture, of small antral follicles, making it possible to freeze both ovarian tissue and isolated immature oocytes., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effects of the immunosuppressant tacrolimus on rejection of a transplanted uterus and on uterine expression of markers of inflammation and implantation., Design: Experimental study., Setting: University laboratory., Animal(s): Female rats., Intervention(s): Uteri from brown Norway rats were transplanted to Lewis rats, receiving either tacrolimus or no treatment. Sham groups underwent either hemihysterectomy or tacrolimus treatment., Main Outcome Measure(s): Gross morphology, histology, density of T-lymphocytes by immunohistochemistry, and mRNA levels of interleukin (IL)-1α, leukemia inhibitory factor (LIF), galectin-1, CD200, IL-15, interferon-inducible protein-10 (IP-10), and nuclear factor-κB (NF-κB) at 14 days' post-transplantation., Result(s): Nontreated uterine grafts showed rejection with necrosis. Sham groups and the tacrolimus-treated transplanted group exhibited normal uterine morphology with low numbers of T-lymphocytes in all uteri except in two out of seven uteri of the tacrolimus-treated transplant group. Uteri of the nontreated transplanted group showed elevated mRNA expression of IL-1α and IP-10 and reduced galectin-1, compared with the tacrolimus-treated transplanted group. There was no difference between any groups concerning uterine expression of LIF, NF-κB, IL-15, and CD200., Conclusion(s): Tacrolimus monotherapy suppresses rejection of an allotransplanted uterus and normalizes the expression of IL-1α and IP-10 and prevents T-lymphocyte infiltration., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Study Question: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection?, Summary Answer: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used., What Is Known Already: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks., Participants/materials, Setting and Methods: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated., Main Results and the Role of Chance: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity., Limitations and Reasons for Caution: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection., Wider Implications of the Findings: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed., Study Funding/competing Interest(s): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest.

Objective: To estimate uterine vessel lengths and diameters recovered at radical hysterectomy to assess prospects for direct vascular anastomosis bilaterally to the external iliacs in uterus transplantation, and thereby the feasibility of live uterus donation as a future treatment of absolute uterine factor infertility., Methods: Patients (n=19; study group) undergoing radical hysterectomy for gynecologic malignancy participated. Preoperative magnetic resonance imaging (MRI) was performed in four patients to evaluate the usefulness in estimation of vessel lengths. At hysterectomy, the uterine arteries and veins were dissected separately from the anterior divisions of the internal iliacs to their attachments to the uterine cervix. The lengths of the free vascular pedicles were measured bilaterally and the distal vessel diameters were recorded. The inter-external iliac artery distance, corresponding to distance between proposed bilateral anastomosis sites, was measured. Perioperative and postoperative outcomes were compared with 76 patients (control group) undergoing standard radical hysterectomy without particular uterine vessel dissection., Results: The MRI showed uterine artery lengths of 55-100 mm. The duration of surgery was slightly longer in the study group (median 297 minutes) compared with the control group (262 minutes), but with no differences in perioperative and postoperative morbidity. The lengths (median) of the free portions of the left uterine artery and vein were 68 mm and 55 mm, and the right uterine artery and vein were 65 mm and 50 mm, respectively. The inter-external iliac artery distance (median) was 90 mm., Conclusion: This study demonstrates that long vascular pedicles can be obtained after selective dissections of the uterine arteries and veins without compromising postoperative recovery in a live uterine donor situation., Level of Evidence: II.

Uterus transplantation research has been conducted toward its introduction in the human as a treatment of absolute uterine-factor infertility, which is considered to be the last frontier to conquer for infertility research. In this review we describe the patient populations that may benefit from uterus transplantation. The animal research on uterus transplantation conducted during the past two decades is summarized, and we describe our views regarding a future research-based human attempt., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate four different protocols for cryopreservation of the whole rat ovary with intact vasculature to evaluate whether differences exist in post-thawing viability of the ovary after either vitrification or slow freezing., Design: Experimental study., Setting: Obstetrics and gynecology department., Animal(s): Immature Sprague-Dawley female rats., Intervention(s): Ovaries were isolated with the vascular tree intact up to the bifurcation of the abdominal aorta and were subsequently cannulated. The ovaries were flushed with increasing concentrations of the cryoprotectant dimethyl sulfoxide (DMSO) to either 1.5 or 7 M. The ovaries underwent cryopreservation by vitrification or passive slow freezing., Main Outcome Measure(s): After thawing, the ovaries were subjected to neutral red viability staining to assess the density of viable small follicles and for long-term (48 hours) incubation evaluation of steroid secretion, histology, and apoptosis assay., Result(s): The follicular viability was decreased in both vitrification groups and in the slow-freezing group with the high concentration of DMSO, as compared with fresh controls. Estradiol levels in the incubation medium followed the same pattern. Light microscopy revealed well-preserved morphology in all groups after 48 hours' incubation. Apoptosis was increased in both vitrified and cryopreserved ovaries., Conclusion(s): We have developed a new method that can be used in basic studies to improve cryopreservation protocols. Our initial findings suggest that a moderate concentration of the cryoprotectant DMSO is superior to a high DMSO concentration for both vitrification and slow freezing., (Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Uterine transplantation (UTx) aims to treat unconditional uterine factor infertility by replacing a non-functioning or non-existing uterus. After one attempt of UTx in the human 10 years ago, intensive research has been performed. The results of these specific studies on surgical technique, ischaemia-reperfusion injury, immunosuppression and fertility are discussed., (© 2011 The Authors. Australian and New Zealand Journal of Obstetrics and Gynaecology © 2011 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Background: Uterus transplantation (UTx) research aims towards the introduction of UTx as a treatment for uterine factor infertility. The rat model is the principal rodent model used and this study aims to assess the potential for pregnancy and to assess effects on pregnancy outcome., Methods: Female Lewis rats underwent hysterectomy and received syngeneic uterine transplants (with one horn removed) by end-to-side anastomosis between the common iliac vessels of the recipient and the graft. The graft was placed in an orthotopic position with anastomosis to the upper part of the native uterine horn and vagina to allow for pregnancy by mating. Controls had only one uterine horn removed. Mating and pregnancy frequencies, successful deliveries and pup weight trajectory were compared., Results: Pregnancy was achieved in rats after UTx with the pregnancy rate, number of pups and growth trajectory of pups being similar to controls. However, numbers of resorbed pregnancies and arrested parturitions were more common in the UTx group., Conclusions: A model for orthotopic UTx was developed and pregnancies with live offspring were for the first time demonstrated in the rat model of UTx. The model will be useful in future studies of fertility after UTx.

Objectives: The aims of this study were (1) to assess the accuracy of estimated fetal weight (EFW) in twins and (2) to assess the accuracy of sonographic examination to predict birth weight discordance (BWD)., Methods: We retrospectively analyzed collected data on twin pregnancies between 2004 and 2007. All twin pregnancies with at least one ultrasound (US) examination within 15 days of delivery were included in this study. EFW was calculated according to Hadlock1, Hadlock2, Ong, Shepard and Warsof formulas. Mean and SD of the standardized errors and percentage of newborns with birth weight (BW) within 10% of EFW were calculated., Results: Two hundred eighty-three twin pregnancies were included. Mean and SD (%) of the standardized errors were 1.54 +/- 12.19, 0.19 +/- 11.87, 10.93 +/- 15.55, - 1.91 +/- 14.93 and 5.37 +/- 14.91 for Hadlock1, Hadlock2, Shepard, Ong and Warsof formulas, respectively. Hadlock2's formula allowed for the highest proportion of newborns with BW within 10% of EFW and it also performed best to predict discordance of more than 25% as assessed by area under the ROC curve., Conclusions: Sonographic prediction of inter-twin BWD within 15 days of delivery seems to be accurate enough for routine clinical use. Performance and predictive values depend on the threshold chosen to define EFW and BW discordance., (Copyright (c) 2010 John Wiley & Sons, Ltd.)