Fertility and reproductive concerns related to the new generation of cancer drugs and the clinical implication for young individuals undergoing treatments for solid tumors.

The treatment landscape of solid tumors has changed markedly in the last years. Molecularly targeted treatments and immunotherapies have been implemented and have, in many cancers, lowered the risk of relapse and prolonged survival. Patients with tumors harboring specific targetable molecular alterations or mutations are often of a younger age, and hence future fertility and family building can be important concerns in this group. However, there are great uncertainties regarding the effect of the new drugs on reproductive functions, including fertility, pregnancy and lactation and how young patients with cancers, both women and men should be advised. The goal with this review is to gather the current knowledge regarding oncofertility and the different novel therapies, including immune checkpoint inhibitors, antibody-drug conjugates, small molecules and monoclonal antibody targeted therapies. The specific circumstances and reproductive concerns in different patient groups where novel treatments have been broadly introduced are also discussed, including those with melanoma, lung, breast, colorectal and gynecological cancers. It is clear, that more awareness is needed regarding potential drug toxicity on reproductive tissues, and it is of essence that individuals are informed based on current expertise and on available fertility preservation methods.

Appropriate glycemic management protects the germline but not the uterine environment in hyperglycemia.

Emerging evidence indicates that parental diseases can impact the health of subsequent generations through epigenetic inheritance. Recently, it was shown that maternal diabetes alters the metaphase II oocyte transcriptome, causing metabolic dysfunction in offspring. However, type 1 diabetes (T1D) mouse models frequently utilized in previous studies may be subject to several confounding factors due to severe hyperglycemia. This limits clinical translatability given improvements in glycemic control for T1D subjects. Here, we optimize a T1D mouse model to investigate the effects of appropriately managed maternal glycemic levels on oocytes and intrauterine development. We show that diabetic mice with appropriate glycemic control exhibit better long-term health, including maintenance of the oocyte transcriptome and chromatin accessibility. We further show that human oocytes undergoing in vitro maturation challenged with mildly increased levels of glucose, reflecting appropriate glycemic management, also retain their transcriptome. However, fetal growth and placental function are affected in mice despite appropriate glycemic control, suggesting the uterine environment rather than the germline as a pathological factor in developmental programming in appropriately managed diabetes.

ESHRE guideline: number of embryos to transfer during IVF/ICSI†.

STUDY QUESTION: Which clinical and embryological factors should be considered to apply double embryo transfer (DET) instead of elective single embryo transfer (eSET)? SUMMARY ANSWER: No clinical or embryological factor per se justifies a recommendation of DET instead of eSET in IVF/ICSI. WHAT IS KNOWN ALREADY: DET is correlated with a higher rate of multiple pregnancy, leading to a subsequent increase in complications for both mother and babies. These complications include preterm birth, low birthweight, and other perinatal adverse outcomes. To mitigate the risks associated with multiple pregnancy, eSET is recommended by international and national professional organizations as the preferred approach in ART. STUDY DESIGN, SIZE, DURATION: The guideline was developed according to the structured methodology for development and update of ESHRE guidelines. Literature searches were performed in PUBMED/MEDLINE and Cochrane databases, and relevant papers published up to May 2023, written in English, were included. Live birth rate, cumulative live birth rate, and multiple pregnancy rate were considered as critical outcomes. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the collected evidence, recommendations were discussed until a consensus was reached within the Guideline Development Group (GDG). A stakeholder review was organized after the guideline draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 35 recommendations on the medical and non-medical risks associated with multiple pregnancies and on the clinical and embryological factors to be considered when deciding on the number of embryos to transfer. These recommendations include 25 evidence-based recommendations, of which 24 were formulated as strong recommendations and one as conditional, and 10 good practice points. Of the evidence-based recommendations, seven (28%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (three recommendations; 12%), or very low-quality evidence (15 recommendations; 60%). Owing to the lack of evidence-based research, the guideline also clearly mentions recommendations for future studies. LIMITATIONS, REASONS FOR CAUTION: The guideline assessed different factors one by one based on existing evidence. However, in real life, clinicians' decisions are based on several prognostic factors related to each patient's case. Furthermore, the evidence from randomized controlled trials is too scarce to formulate high-quality evidence-based recommendations. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides health professionals with clear advice on best practice in the decision-making process during IVF/ICSI, based on the best evidence currently available, and recommendations on relevant information that should be communicated to patients. In addition, a list of research recommendations is provided to stimulate further studies in the field. STUDY FUNDING/COMPETING INTEREST(S): The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, the literature searches, and the dissemination of the guideline. The guideline group members did not receive payment. DPB declared receiving honoraria for lectures from Merck, Ferring, and Gedeon Richter. She is a member of ESHRE EXCO, and the Mediterranean Society for reproductive medicine and the president of the Croatian Society for Gynaecological Endocrinology and Reproductive Medicine. CDG is the past Chair of the ESHRE EIM Consortium and a paid deputy member of the Editorial board of Human Reproduction. IR declared receiving reimbursement from ESHRE and EDCD for attending meetings. She holds an unpaid leadership role in OBBCSSR, ECDC Sohonet, and AER. KAR-W declared receiving grants for clinical researchers and funding provision to the institution from the Swedish Cancer Society (200170F), the Senior Clinical Investigator Award, Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council FoU (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963), NovoNordisk, Merck and Ferring Pharmaceuticals. She received consulting fees from the Swedish Ministry of Health and Welfare. She received honoraria from Roche, Pfizer, and Organon for chairmanship and lectures. She received support from Organon for attending meetings. She participated in advisory boards for Merck, Nordic countries, and Ferring. She declared receiving time-lapse equipment and grants with payment to institution for pre-clinical research from Merck pharmaceuticals and from Ferring. SS-R received research funding from Roche Diagnostics, Organon/MSD, Theramex, and Gedeo-Richter. He received consulting fees from Organon/MSD, Ferring Pharmaceuticals, and Merck Serono. He declared receiving honoraria for lectures from Ferring Pharmaceuticals, Besins, Organon/MSD, Theramex, and Gedeon Richter. He received support for attending Gedeon Richter meetings and participated in the Data Safety Monitoring Board of the T-TRANSPORT trial. He is the Deputy of ESHRE SQART special interest group. He holds stock options in IVI Lisboa and received equipment and other services from Roche Diagnostics and Ferring Pharmaceuticals. KT declared receiving payment for honoraria for giving lectures from Merck Serono and Organon. She is member of the safety advisory board of EDQM. She holds a leadership role in the ICCBBA board of directors. ZV received reimbursement from ESHRE for attending meetings. She also received research grants from ESHRE and Juhani Aaltonen Foundation. She is the coordinator of EHSRE SQART special interest group. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose (full disclaimer available at https://www.eshre.eu/Guidelines-and-Legal).

Gonadotropin Releasing Hormone agonist (GnRHa) during chemotherapy and post-cancer childbirths - a Nationwide population-based cohort study of 24,922 women diagnosed with cancer in Sweden.

Background: Worldwide, an increasing number of women with cancer are receiving Gonadotropin Releasing Hormone agonist (GnRHa) co-treatment during chemotherapy aiming at ovarian protection. There is divergence among guidelines, and some have recommended GnRHa co-treatment for women with breast cancer, however, the effect of GnRHa on future fertility is uncertain. Methods: In this population-based cohort study we included all women diagnosed with cancer at ages 15-45 between July 2005 and March 2017 in Sweden, identified in the Swedish Cancer Register. Exposure to GnRHa co-treatment was captured using the Prescribed Drug Register. Post-cancer childbirth, extracted from the Medical Birth Register, was the main outcome. Secondary outcomes included childbirths achieved through natural conception (NC), infertility diagnosis and cancer mortality. For each outcome, adjusted hazard ratios (aHR) and 95% confidence intervals (CI) were estimated using delayed-entry Cox models, stratified by age and cancer site. Findings: Among 24,922 women diagnosed with cancer, 1.5% had GnRHa co-treatment. Breast cancer diagnoses were found in 80.2% of GnRHa exposed women and the GnRHa exposure was not associated with higher rates of childbirth (aHR 1.23, 95% CI 0.80-1.89), or NC childbirth (aHR 1.02, 95% CI 0.62-1.67), whereas the rate of infertility was significantly higher (aHR 2.42, 95% CI 1.44-4.08). In women with lymphoma and other cancers, GnRHa exposure was not associated with higher rates of childbirth, NC childbirth or infertility. GnRHa exposure was not associated with higher cancer mortality for any cancer type. Interpretation: We did not find evidence of improved or maintained fertility, estimated as childbirth rates post-cancer, in women who received GnRHa during cancer treatment. Funding: This study was financed by research grants from The Swedish Cancer Society (CAN 2017/704; 190249Pj, 200170F), The Swedish Research Council (Dnr 2019-00446), the Nordic Cancer Union NCU (Grant 2017), The Swedish Childhood Cancer Fund (KP2016-0031), Radiumhemmets Forskningsfonder (Dnr: 201313), Stockholm County Council (FoUI-953912) and Karolinska Institutet (Dnr 2020-01963).

Outcomes of SARS-CoV-2 infection in early pregnancy-A systematic review and meta-analysis.

INTRODUCTION: Available data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and pregnancy outcomes mostly refer to women contracting the infection during advanced pregnancy or close to delivery. There is limited information on the association between SARS-CoV-2 infection in early pregnancy and outcomes thereof. MATERIAL AND METHODS: We aimed to systematically review the maternal, fetal and neonatal outcomes following SARS-CoV-2 infection in early pregnancy, defined as <20 weeks of gestation (PROSPERO Registration 2020 CRD42020177673). Searches were carried out in PubMed, Medline, EMBASE, and Scopus databases from January 2020 until April 2023 and the WHO database of publications on coronavirus disease 2019 (COVID-19) from December 2019 to April 2023. Cohort and case-control studies on COVID-19 occurring in early pregnancy that reported data on maternal, fetal, and neonatal outcomes were included. Case reports and studies reporting only exposure to SARS-CoV-2 or not stratifying outcomes based on gestational age were excluded. Data were extracted in duplicate. Meta-analyses were conducted when appropriate, using R meta (R version 4.0.5). RESULTS: A total of 18 studies, 12 retrospective and six prospective, were included in this review, reporting on 10 147 SARS-CoV-2-positive women infected in early pregnancy, 9533 neonates, and 180 882 SARS-CoV-2 negative women. The studies had low to moderate risk of bias according to the Newcastle-Ottawa quality assessment Scale. The studies showed significant clinical and methodological heterogeneity. A meta-analysis could be performed only on the outcome miscarriage rate, with a pooled random effect odds ratio of 1.44 (95% confidence interval 0.96-2.18), showing no statistical difference in miscarriage in SARS-CoV-2-infected women. Individual studies reported increased incidences of stillbirth, low birthweight and preterm birth among neonates born to mothers affected by COVID-19 in early pregnancy; however, these results were not consistent among all studies. CONCLUSIONS: In this comprehensive systematic review of available evidence, we identified no statistically significant adverse association between SARS-CoV-2 infection in early pregnancy (before 20 weeks of gestation) and fetal, neonatal, or maternal outcomes. However, a 44% increase in miscarriage rate is concerning and further studies of larger sample size are needed to confirm or refute our findings.

The male pachynema-specific protein MAPS drives phase separation in vitro and regulates sex body formation and chromatin behaviors in vivo.

Dynamic chromosome remodeling and nuclear compartmentalization take place during mammalian meiotic prophase I. We report here that the crucial roles of male pachynema-specific protein (MAPS) in pachynema progression might be mediated by its liquid-liquid phase separation in vitro and in cellulo. MAPS forms distinguishable liquid phases, and deletion or mutations of its N-terminal amino acids (aa) 2-9 disrupt its secondary structure and charge properties, impeding phase separation. Maps-/- pachytene spermatocytes exhibit defects in nucleus compartmentalization, including defects in forming sex bodies, altered nucleosome composition, and disordered chromatin accessibility. MapsΔ2-9/Δ2-9 male mice expressing MAPS protein lacking aa 2-9 phenocopy Maps-/- mice. Moreover, a frameshift mutation in C3orf62, the human counterpart of Maps, is correlated with nonobstructive azoospermia in a patient exhibiting pachynema arrest in spermatocyte development. Hence, the phase separation property of MAPS seems essential for pachynema progression in mouse and human spermatocytes.

Pregnancy After Breast Cancer in Young BRCA Carriers: An International Hospital-Based Cohort Study.

Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.

Transcriptomics and Spatial Proteomics for Discovery and Validation of Missing Proteins in the Human Ovary.

Efforts to understand the complexities of human biology encompass multidimensional aspects, with proteins emerging as crucial components. However, studying the human ovary introduces unique challenges due to its complex dynamics and changes over a lifetime, varied cellular composition, and limited sample access. Here, four new RNA-seq samples of ovarian cortex spanning ages of 7 to 32 were sequenced and added to the existing data in the Human Protein Atlas (HPA) database www.proteinatlas.org, opening the doors to unique possibilities for exploration of oocyte-specific proteins. Based on transcriptomics analysis of the four new tissue samples representing both prepubertal girls and women of fertile age, we selected 20 protein candidates that lacked previous evidence at the protein level, so-called "missing proteins" (MPs). The proteins were validated using high-resolution antibody-based profiling and single-cell transcriptomics. Fourteen proteins exhibited consistent single-cell expression patterns in oocytes and granulosa cells, confirming their presence in the ovary and suggesting that these proteins play important roles in ovarian function, thus proposing that these 14 proteins should no longer be classified as MPs. This research significantly advances the understanding of MPs, unearthing fresh avenues for prospective exploration. By integrating innovative methodologies and leveraging the wealth of data in the HPA database, these insights contribute to refining our understanding of protein roles within the human ovary and opening the doors for further investigations into missing proteins and human reproduction.

First 15 Years of Assisted Reproductive Technology Using Washed Sperm in HIV-Positive Individuals Under Antiretroviral Therapy: Sweden's Nationwide Outcomes.

Antiretroviral therapy has made HIV a chronic infectious disease. In Sweden, assisted reproductive technologies using sperm washing were implemented in 2004 for treatment of all HIV-positive males in serodiscordant couples at Karolinska Hospital in Stockholm. This study aimed to assess efficacy and safety of this approach and to investigate the effect of antiretroviral regimens on sperm quality of men treated for HIV. The study included all HIV-positive men (n = 53) adherent to antiretroviral treatment, including nucleoside/nucleotide analog reverse-transcriptase inhibitors (NRTIs) combined with non-nucleoside reverse-transcriptase inhibitors (NNRTIs) in 22 cases, or with other medication in 31 cases wishing fertility treatment. Sperm was washed using gradient centrifugation with a double tube system, frozen and thawed. Thereafter, single spermatozoa were injected in oocytes by intracytoplasmic sperm injection (ICSI). Treatment outcomes were compared to those of hepatitis B virus (HBV)-seropositive men in serodiscordant couples (n = 56), undergoing similar sperm washing protocols and ICSI at the center. In total, 82 fresh and 39 frozen/thawed embryo transfer (FET) cycles were performed in discordant HIV couples and 92 fresh and 36 FET cycles in HBV. Fertilization rates (69.2% vs. 64.6%, p = 0.310), clinical pregnancy rates (39.2% vs. 32.6%, p = 0.378), and live birth rates (35.8% vs. 31.5%, p = 0.565) were similar between the groups and the cumulative results yielded similar outcomes with a live birth rate of 52.8% and 51.8% (p = 0.913), respectively. No post-wash sperm sample was found positive for HIV viral particles. No partner seroconversion or offspring infection was reported. NNRTI-treated men had significantly lower motile sperm concentration than non-NNRTI-treated patients (54.48% vs. 36.41%, p < 0001). This study showed that in vitro fertilization/ICSI treatment with sperm washing was safe in individuals compliant to antiretroviral treatment and the reproductive outcome was similar to that of HBV-positive men. The observed moderate negative impact on sperm motility of NNRTI regimens may be overcome by using ICSI.

ProFertil study protocol for the investigation of gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy aiming at fertility protection of young women and teenagers with cancer in Sweden-a phase III randomised double-blinded placebo-controlled study.

BACKGROUND: Gonadotropin-releasing hormone agonists (GnRHa) cotreatment used to transiently suppress ovarian function during chemotherapy to prevent ovarian damage and preserve female fertility is used globally but efficacy is debated. Most clinical studies investigating a beneficial effect of GnRHa cotreatment on ovarian function have been small, retrospective and uncontrolled. Unblinded randomised studies on women with breast cancer have suggested a beneficial effect, but results are mixed with lack of evidence of improvement in markers of ovarian reserve. Unblinded randomised studies of women with lymphoma have not shown any benefit regarding fertility markers after long-term follow-up and no placebo-controlled study has been conducted so far. The aim of this study is to investigate if administration of GnRHa during cancer treatment can preserve fertility in young female cancer patients in a double-blind, placebo-controlled clinical trial. METHODS AND ANALYSIS: A prospective, randomised, double-blinded, placebo-controlled, phase III study including 300 subjects with breast cancer. In addition, 200 subjects with lymphoma, acute leukemias and sarcomas will be recruited. Women aged 14-42 will be randomised 1:1 to treatment with GnRHa (triptorelin) or placebo for the duration of their gonadotoxic chemotherapy. Follow-up until 5 years from end of treatment (EoT). The primary endpoint will be change in anti-Müllerian hormone (AMH) recovery at follow-up 12 months after EoT, relative to AMH levels at EoT, comparing the GnRHa group and the placebo group in women with breast cancer. ETHICS AND DISSEMINATION: This study is designed in accordance with the principles of Good Clinical Practice (ICH-GCP E6 (R2)), local regulations (ie, European Directive 2001/20/EC) and the ethical principles of the Declaration of Helsinki. Within 6 months of study completion, the results will be analysed and the study results shall be reported in the EudraCT database. STUDY REGISTRATION: The National Institutional review board in Sweden dnr:2021-03379, approval date 12 October 2021 (approved amendments 12 June 2022, dnr:2022-02924-02 and 13 December 2022, dnr:2022-05565-02). The Swedish Medical Product Agency 19 January 2022, Dnr:5.1-2021-98927 (approved amendment 4 February 2022). Manufacturing authorisation for authorised medicinal products approved 6 December 2021, Dnr:6.2.1-2020-079580. Stockholm Medical Biobank approved 22 June 2022, RBC dnr:202 253. TRIAL REGISTRATION NUMBER: NCT05328258; EudraCT number:2020-004780-71.

Prevalence and predictors for fertility-related distress among 1010 young adults 1.5 years following cancer diagnosis - results from the population-based Fex-Can Cohort study.

BACKGROUND: Cancer treatment during reproductive ages may negatively impact fertility and there is a need of firm knowledge about the prevalence and predictors of fertility-related distress. The aim was to examine fertility-related distress in a population-based sample of young women and men recently treated for cancer and to identify predictors for this outcome. MATERIAL AND METHODS: This nationwide cohort study included 1010 individuals (694 women and 316 men), mean age 34.5 ± 4.9 and 32.1 ± 5.5, respectively, diagnosed with breast, cervical, ovarian, testicular cancers, brain tumors or lymphoma at ages 18-39 in Sweden. Participants completed a survey 1.5-year post-diagnosis to assess fertility-related distress (RCAC), emotional distress (HADS) and self-efficacy, as well as sociodemographic and clinical factors and fertility preservation. Logistic regression was used to examine associations between explanatory factors and high fertility-related distress (RCAC subscale mean >4). RESULTS: Many participants (69% of women and 47% of men) had previous children and about half reported a wish for future children. High fertility-related distress was more prevalent among women (54%) than men (27%), and women were more likely than men to report distress concerning all but one RCAC dimension after adjustment for sociodemographic factors. Use of fertility preservation was unevenly distributed (15% of women and 71% of men) and was not associated with decreased fertility-related distress. In multivariable logistic regression models, a wish for future children, being single, not having previous children, symptoms of anxiety and low self-efficacy regarding one's ability to handle threats of infertility were associated with high fertility-related distress. CONCLUSION: This nationwide study found a high prevalence of fertility-related distress in young women and men recently treated for cancer and identified sociodemographic and psychological predictors. Fertility preservation was not found to act as a buffer against fertility-related distress, indicating the continuous need to identify strategies to alleviate fertility distress following cancer.

COVID-19-Induced Acute Respiratory Distress Syndrome Treated with Hyperbaric Oxygen: Interim Safety Report from a Randomized Clinical Trial (COVID-19-HBO).

BACKGROUND: A few prospective trials and case series have suggested that hyperbaric oxygen therapy (HBOT) may be efficacious for the treatment of severe COVID-19, but safety is a concern for critically ill patients. We present an interim analysis of the safety of HBOT via a randomized controlled trial (COVID-19-HBO). METHODS: A randomized controlled, open-label, clinical trial was conducted in compliance with good clinical practice to explore the safety and efficacy of HBOT for severe COVID-19 in critically ill patients with moderate acute respiratory distress syndrome (ARDS). Between 3 June 2020, and 17 May 2021, 31 patients with severe COVID-19 and moderate-to-severe ARDS, a ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) < 26.7 kPa (200 mmHg), and at least two defined risk factors for intensive care unit (ICU) admission and/or mortality were enrolled in the trial and randomized 1:1 to best practice, or HBOT in addition to best practice. The subjects allocated to HBOT received a maximum of five treatments at 2.4 atmospheres absolute (ATA) for 80 min over seven days. The subjects were followed up for 30 days. The safety endpoints were analyzed. RESULTS: Adverse events (AEs) were common. Hypoxia was the most common adverse event reported. There was no statistically significant difference between the groups. Numerically, serious adverse events (SAEs) and barotrauma were more frequent in the control group, and the differences between groups were in favor of the HBOT in PaO2/FiO2 (PFI) and the national early warning score (NEWS); statistically, however, the differences were not significant at day 7, and no difference was observed for the total oxygen burden and cumulative pulmonary oxygen toxicity dose (CPTD). CONCLUSION: HBOT appears to be safe as an intervention for critically ill patients with moderate-to-severe ARDS induced by COVID-19. CLINICAL TRIAL REGISTRATION: NCT04327505 (31 March 2020) and EudraCT 2020-001349-37 (24 April 2020).

Fertility assessment and treatment in adolescent and young adult cancer survivors.

In the survivorship setting, adolescent and young adult (AYA) cancer survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status, and may under- or overestimate their treatment-related risk for infertility. In female AYA survivors, ovarian function usually parallels fertility, and can be assessed with serum hormone levels and ultrasonography. Posttreatment fertility preservation may be appropriate for survivors at risk for primary ovarian insufficiency. In male AYA survivors, fertility and gonadal function are not always equally affected, and can be assessed with a semen analysis and serum hormones, respectively. As reproductive health issues are commonly cited as an important concern by survivors of AYA cancer, multidisciplinary care teams including oncology, endocrinology, psychology, and reproductive medicine are advocated, with the aim of optimal provision of fertility advice and care for AYA cancer survivors.

The Late Effects of Cancer Treatment on Female Fertility and the Current Status of Fertility Preservation-A Narrative Review.

Fertility counseling should be offered to all individuals of young reproductive age early in the patient's trajectory following a cancer diagnosis. Systemic cancer treatment and radiotherapy often have an inherent gonadotoxic effect with the potential to induce permanent infertility and premature ovarian failure. For the best chances to preserve a patient's fertility potential and to improve future quality of life, fertility preservation methods should be applied before cancer treatment initiation, thus multidisciplinary team-work and timely referral to reproductive medicine centers specialized in fertility preservation is recommended. We aim to review the current clinical possibilities for fertility preservation and summarize how infertility, as a late effect of gonadotoxic treatment, affects the growing population of young female cancer survivors.

Trends and outcomes of fertility preservation for girls, adolescents and young adults with Turner syndrome: A prospective cohort study.

Background: In Scandinavian countries, programs for fertility preservation (FP) are offered free of charge at tertiary-care university hospitals to all patients facing infertility risks due to malignant diagnoses or benign conditions. In this prospective study we aimed to investigate trends and outcomes of FP indicated by a diagnosis of Turner syndrome. Methods: Prospective cohort study of patients with Turner karyotype receiving fertility preservation counselling at the Karolinska University Hospital between 1 January 1999 and 31 December 2021. Results: The cohort included 100 women and girls that received counselling, whereof 27% were prepubertal girls, 59% were adolescents and 14% of adult age. Before 2006 all patients were referred for fertility counselling at the time of Turner diagnosis. Based on updated guidelines, mainly patients who showed signs of puberty were referred after 2006. As a result, spontaneous menarche was more common in the later period. In total, 39% of the cohort had monosomal karyotype (45X), 20% had 45X/46XX or 45X/47XXX mosaicisms and 36% had an X-chromosomal structural anomaly. Ovarian tissue cryopreservation was planned for 73% of all patients, and oocyte cryopreservation following gonadotropin stimulation was planned for 10% of the patients. Follicles were present in 25% of all biopsies analyzed. Adolescents were more likely to have follicles present (30%) than prepubertal girls (16%) or adult women (17%). The ten patients that underwent gonadotropin stimulation for oocyte cryopreservation underwent a total of 15 cycles and eight patients successfully preserved oocytes. In total, 26% of the cohort has undergone fertility treatment or expressed further interest in fertility preservation. Six women have given birth using donated oocytes and three following spontaneous conception. Two women have undergone re-transplantation of cryopreserved ovarian tissue, without regaining ovarian function, and none of the women that have cryopreserved oocytes has returned to use them. Conclusion: Fertility counselling for girls with Turner syndrome should ideally be offered at onset of spontaneous puberty to improve the chances of fertility preservation. Since the girls and women in this cohort are still young, the return rate and utilization of the preserved tissue and oocytes is expected to increase with time. Clinical Trial Registration: ClinicalTrials.gov, identifier NTC04602962.

Risk of obstetric and perinatal complications in women presenting with breast cancer during pregnancy and the first year postpartum in Sweden 1973-2017: A population-based matched study.

INTRODUCTION: For women presenting with breast cancer during pregnancy, treatment guidelines were historically restricted to only surgical treatment. Over the past decades, chemotherapy administered during pregnancy has been gradually introduced. Although breast cancer treatments during ongoing pregnancy have been deemed safe, detailed information on potential obstetric risks is lacking. We aimed to assess the risk of adverse obstetric and perinatal outcomes of breast cancer in pregnancy and within 1 year postpartum and in relation to trimester at breast cancer diagnosis, tumor stage, and cancer treatment during pregnancy. MATERIAL AND METHODS: Population-based matched study. Women diagnosed with breast cancer during pregnancy in 1973-2017 were identified in the Swedish Cancer Register and the Medical Birth Register, with additional information from the National Quality Register for Breast Cancer. Each birth with maternal breast cancer (n = 208 pregnant, n = 672 postpartum) was matched by age, calendar year, and birth order to 10 unexposed births from cancer-free women in the population (n = 2080 and n = 6720). Adjusted conditional logistic and multinomial regression models were used to estimate odds ratios and relative risk ratios, commonly denoted relative risks (RR) with 95% confidence intervals (CI), of adverse obstetric and perinatal outcomes. RESULTS: Breast cancer during pregnancy was associated with higher risks of preterm birth, both planned (RR 67.1, 95% CI 33.2-135.6) and spontaneous preterm birth (RR 3.8, 95% CI 2.0-7.5), and low birthweight (<2500 g: RR 7.5, 95% CI 4.9-11.3). The associated risks were higher if the breast cancer was diagnosed in the second trimester, and of similar magnitude irrespective of stage and treatment groups. There was a higher risk of low birthweight for gestational age (<25th centile) if breast cancer was diagnosed in the first trimester (RR 2.8, 95% CI 1.1-7.3). Risks of other pregnancy complications were similar to those of unexposed women, as were risks of neonatal mortality and malformations. Postpartum breast cancer was only associated with bleeding during pregnancy (RR 1.6, 95% CI 1.0-2.8). CONCLUSIONS: Preterm birth and related adverse outcomes were more common in women diagnosed with breast cancer during pregnancy. Reassuringly, breast cancer was not associated with other maternal pregnancy complications or adverse outcomes in children.

Hyperbaric oxygen therapy for long COVID (HOT-LoCO), an interim safety report from a randomised controlled trial.

BACKGROUND: With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug. METHODS: The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. RESULTS: Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60-40.90) vs 83.5 (23.9) p < 0.001 in Rand-36 PF and mean 0.00 (0.00) in RP. Very low physical performance compared to norm data. 6MWT 442 (180) (95% CI 358-525) vs 662 (18) meters p < 0.001. 31 AEs occurred in 60% of subjects. In 20 AEs, there were at least a possible relationship with the study drug, most commonly cough and chest pain/discomfort. CONCLUSIONS: An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials. Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448 . EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE.

Obstetric and Perinatal Outcomes of Singleton Births Following Single- vs Double-Embryo Transfer in Sweden.

Importance: Pregnancies resulting from assisted reproductive technology are associated with an increased risk of adverse perinatal outcomes compared with those following natural conception. Previous studies have shown an association of pregnancies resulting from transfer of multiple embryos with these negative findings. Objective: To determine the risk for adverse outcomes in singletons conceived through assisted reproduction using double-embryo transfer (DET) vs single-embryo transfer (SET). Design, Setting, and Participants: This cohort study used data from women who achieved singleton deliveries after SET or DET in Sweden between 2007 and 2017 as recorded in the National Quality Registry for Assisted Reproduction. All embryo transfers, at cleavage or blastocyst stage, replaced in fresh or frozen treatment cycles were included. Data on obstetric and neonatal outcomes were retrieved by linkage to the National Medical Birth Register. Naturally conceived singletons were included as a reference group. Data were analyzed between September 2021 and August 2022. Exposures: Double-embryo transfer leading to singleton birth. Main Outcomes and Measures: Relative risk ratios or odds ratios (ORs) and absolute risk differences (ARDs) in percentage points with 95% CIs were calculated for obstetric and perinatal outcomes in singleton births conceived using DET vs SET. Results: Among 1 115 863 singleton births, 30 713 singletons were born after SET and 5123 after DET. A higher risk of neonatal death was found in singletons after DET vs SET (OR, 2.67 [95% CI, 1.28-5.55]; ARD, 0.2 percentage points [95% CI, 0.0-0.4 percentage points]). In frozen embryo transfers, DET was associated with a higher risk of low birth weight (OR, 1.64 [95% CI, 1.19-2.25]; ARD, 2.0 percentage points [95% CI, 0.5-3.5 percentage points]). Among blastocyst transfers, DET was associated with very preterm birth (relative risk ratio, 2.64 [95% CI, 1.50-4.63]; ARD, 1.8 percentage points [95% CI, 0.3-3.4 percentage points]) and low birth weight (OR, 1.83 [95% CI, 1.29-2.60]; ARD, 3.2 percentage points [95% CI, 0.9-5.5 percentage points]). Conclusions and Relevance: These results indicate a higher risk of adverse outcomes following DET, even when the result is a singleton birth, vs singletons born after SET. Adverse outcomes were mainly observed in singletons following DET using frozen embryos and blastocysts.