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.

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.

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).

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.

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.

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.

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.

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.

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.

Hormone replacement in premenopausal women treated with bilateral oophorectomy for ovarian cancer - a nationwide population-based study.

OBJECTIVE: To study the extent of hormone replacement therapy (HRT) dispensing in premenopausal women after being treated with bilateral salpingo-oophorectomy (BSOE) for ovarian cancer (OC). METHODS: Nationwide population- and register-based cohort study including women 18-50 years old, registered in The Swedish Quality Register for Gynecological Cancer (SQRGC), where BSOE was performed due to epithelial (EOC) and non-epithelial ovarian cancers (NEOC) or borderline ovarian tumor (BOT) between 2008 and 2014. Data on HRT dispensing was obtained from the National Prescribed Drug Register analyzed at semi-annual intervals from surgery until end of follow-up December 2015, including a logistic regression analysis. RESULTS: A cohort of 664 women were identified with OC, whereas 396 women had an EOC, 61 a NEOC and 207 a BOT. At surgery 49% of the women were ≤44 years. HRT dispensed to the total cohort varied between 32% and 41% the first five years after surgery. During follow-up at first 0.5-1 year 51% of the women <40 years were dispensed HRT compared to 25% of women ≥40 years. Of women with EOC, 21% dispensed HRT at first 0.5-1 year. In the multivariable regression analysis; age <40 (OR6.17, p < 0.001) and age 40-44 (OR2.95, p < 0.001) as well as BOT histology (OR3.84, p < 0.001) were found significant variables for dispensing of HRT. CONCLUSION: A majority of premenopausal women undergoing BSOE for OC did not use HRT postoperatively. Our study shows that there is a need to address HRT use after OC treatment in young women to prevent from morbidity and a poorer quality of life.

Live birth, cumulative live birth and perinatal outcome following assisted reproductive treatments using donor sperm in single women vs. women in lesbian couples: a prospective controlled cohort study.

PURPOSE: Assisted reproductive technology (ART) treatments with donor sperm have been allowed for women in lesbian relationships (WLR) since 2005 in Sweden, but for single women (SW), these became approved only recently in 2016. This study was conducted to compare the outcomes of ART treatments in SW vs. WLR. METHODS: This is a prospective controlled cohort study of 251 women undergoing intrauterine insemination (D-IUI) or in vitro fertilization (D-IVF) using donor sperm between 2017 and 2019 at the department of Reproductive Medicine, Karolinska University Hospital. The cohort comprised 139 SW and 112 WLR. The main outcomes included differences in live birth rate (LBR) and cumulative live birth rate (cLBR) between the groups. The SW underwent 66 D-IUI and 193 D-IVF treatments and WLR underwent 255 D-IUI and 69 D-IVF treatments. Data on clinical characteristics, treatment protocols and clinical outcomes were extracted from the clinic's electronic database. The outcomes of D-IUI and D-IVF were separately assessed. RESULTS: The cohort of SW was significantly older than WLR (37.6 vs. 32.4 years, P < 0.001), and more commonly underwent IVF at first treatment (83% vs. 29%, P < 0.000). Conversely, WLR underwent more frequently D-IUI as a first treatment (71% vs. 17% of SW, P < 0.001) and more often in the natural cycle (89.9% vs. 70.8%, P = 0.019), respectively. There was no statistically significant difference in the main outcome LBR between the two groups, or between the two different types of treatment, when adjusted for age. Perinatal outcomes and cLBR were also similar among the groups. CONCLUSIONS: SW were, on average, older than WLR undergoing treatment with donor sperm. No significant differences were seen in the LBR and cLBR when adjusted for age between the two groups and between the two types of treatment (D-IVF vs. D-IUI). TRIAL REGISTRATION: ClinicalTrials.gov NTC04602962.

Profiling the Influence of Gene Variants Related to Folate-Mediated One-Carbon Metabolism on the Outcome of In Vitro Fertilization (IVF) with Donor Oocytes in Recipients Receiving Folic Acid Fortification.

Nutritional status and gene polymorphisms of one-carbon metabolism confer a well-known interaction that in pregnant women may affect embryo viability and the health of the newborn. Folate metabolism directly impacts nucleotide synthesis and methylation, which is of increasing interest in the reproductive medicine field. Studies assessing the genetic influence of folate metabolism on IVF treatments have currently been performed in women using their own oocytes. Most of these patients seeking to have a child or undergoing IVF treatments are advised to preventively intake folate supplies that restore known metabolic imbalances, but the treatments could lead to the promotion of specific enzymes in specific women, depending on their genetic variance. In the present study, we assess the influence of candidate gene variants related to folate metabolism, such as Serine Hydroxymethyltransferase 1 SHMT1 (rs1979276 and rs1979277), Betaine-Homocysteine S-Methyltransferase BHMT (rs3733890), Methionine synthase reductase MTRR (rs1801394), Methylenetetrahydrofolate reductase MTHFR (rs1801131 and rs1801133), methionine synthase MTR (rs12749581), ATP Binding Cassette Subfamily B Member 1 ABCB1 (rs1045642) and folate receptor alpha FOLR1 (rs2071010) on the success of IVF treatment performed in women being recipients of donated oocytes. The implication of such gene variants seems to have no direct impact on pregnancy consecution after IVF; however, several gene variants could influence pregnancy loss events or pregnancy maintenance, as consequence of folic acid fortification.

Genetic variants in the p53 pathway influence implantation and pregnancy maintenance in IVF treatments using donor oocytes.

PURPOSE: Single-nucleotide polymorphisms (SNPs) in the p53 pathways have shown to play a role in endometrial receptivity and implantation in infertile women undergoing in vitro fertilization (IVF). The present study aimed to assess the influence of these gene variants over pregnancy success through a receptivity model in recipients of egg donation treatments, when factors such as age and quality of the oocytes are standardized. METHODS: A nested case-control study was performed on 234 female patients undergoing their first fresh IVF treatment as recipients of donor oocytes. Genotyping of TP53 Arg72Pro (rs1042522), LIF (rs929271), MDM4 (rs1563828), and USP7 (rs1529916) SNPs in the recipients allowed comparison of allele and genotype frequencies and their association with the IVF treatment outcome. RESULTS: Grouped by genotypes, patients showed differences in IVF outcomes after the embryo transfer. Arg72Pro (rs1042522) gene variant was associated to changes in implantation and clinical pregnancy rates. The polymorphisms USP7 (rs1529916) and MDM4 (rs1563828) were associated to differential ongoing pregnancy rates and variable miscarriage events, respectively. CONCLUSIONS: This study highlights the association between gene polymorphisms related to P53 function and their influence over IVF reproductive outcomes. Arg72Pro variant may influence early events, as lower implantation rates were found in homozygous for Pro72 allele. By contrast, MDM4 (rs1563828) and USP7 (rs1529916) gene variants were associated with the later maintenance of pregnancy.

Efficacy and safety of controlled ovarian stimulation using GnRH antagonist protocols for emergency fertility preservation in young women with breast cancer-a prospective nationwide Swedish multicenter study.

STUDY QUESTION: How efficacious and safe are the current approaches to controlled ovarian stimulation (COS) aimed at fertility preservation (FP) in women with breast cancer (BC)? SUMMARY ANSWER: In women with BC undergoing COS aiming at egg/embryo cryopreservation, letrozole-based protocols and those randomly started were equally effective compared with conventional COS, and the overall survival was similar between the women that proceeded to FP and those who did not. WHAT IS KNOWN ALREADY: Cryopreservation of oocytes and embryos is an established method for FP in women with BC. Recent improvements to COS protocols include concomitant use of letrozole, random-cycle start day of stimulation and the use of GnRHa for the egg maturation trigger. To date, limited sample size of the available studies has not allowed investigation of differences in the efficacy of the different approaches to COS for FP in this patient population. STUDY DESIGN, SIZE, DURATION: A prospective multicenter study with national coverage including 610 women with BC counseled between 1 January 1995 and 30 June 2017 at six Swedish FP regional programs. PARTICIPANTS/MATERIALS, SETTING, METHODS: After counseling, 401 women elected to undergo COS. Treatments differed in the use or not of concomitant letrozole, a conventional or random-cycle day COS initiation and the use of hCG versus GnRHa trigger for oocyte maturation. Numbers of cryopreserved oocytes and embryos were defined as primary outcome. Pregnancy attempts, reproductive outcomes and long-term survival, investigated by the linking of individuals of the cohort to the total population register of the Swedish Tax Agency (up to 25 November 2018), were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: Using letrozole or not resulted in similar numbers of oocytes and embryos cryopreserved (meanoocytes = 9.7 versus 10 and meanembryos 4.0 versus 5.3, respectively), similar to COS with random versus conventional start (meanoocytes 9.0 versus 10.6 and meanembryos 4.8 versus 4.8). In COS with letrozole, a GnRHa trigger was associated with a higher number of oocytes retrieved (P < 0.05) and embryos cryopreserved (P < 0.005), compared with conventional hCG trigger. Of 99 women who returned to fertility clinics after cancer treatment, 32 proceeded to thawing of oocytes or embryos and 10 of them had live births. The all-cause survival between the women that underwent COS and those who did not was similar and did not differ between the two groups. LIMITATIONS, REASONS FOR CAUTION: Data on tumor characteristics and estrogen receptor (ER) status were not known for all women at the time of FP counseling and planning of COS, thus protocols with letrozole have been used for both estrogen-sensitive and non-estrogen-sensitive BC. For the same reason, subsequent adjustment for ERs in the BC or tumor characteristics as potential confounders were not performed as these parameters were not available and did not influence the provision of FP through COS. WIDER IMPLICATIONS OF THE FINDINGS: The results of our study support the premise that recently introduced potential improvements to COS protocols for FP in women with BC are efficacious and safe. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by research grants from the Swedish Cancer Society, the Stockholm County Council, the Percy Falk Stiftelsen, Radiumhemmets Forskningsfonder, The Swedish Breast Cancer Association and Karolinska Institutet to K.A.R.W. J.B. reports grants from Amgen, AstraZeneca, Pfizer, Roche, Sanofi-Aventis and Merck, outside the submitted work, and payment from UpToDate to Asklepios Medicine HB for a chapter on BC prediction and prognostication. All the other authors have no competing interests to report.

A Swedish Nationwide prospective study of oncological and reproductive outcome following fertility-sparing surgery for treatment of early stage epithelial ovarian cancer in young women.

BACKGROUND: Epithelial ovarian cancer (EOC) is rare in women of reproductive age and fertility-sparing surgery (FSS) may be applied in early stages. The purpose of this study was to investigate the safety and efficacy of FSS for treatment of EOC. METHODS: The Swedish nationwide population-based Quality Register for Gynecological Cancer was used to identify all women 18-40 years of age diagnosed with stage I EOC between 2008 and 2015. Detailed data on surgery, staging, histopathology, and follow-up were extracted and reviewed. Cross-linking of individuals to population-based registries allowed retrieval of data on obstetrical and reproductive outcomes after FSS. Disease-free survival (DFS) and overall survival (OS) rates were compared (Kaplan-Meier method) between women who underwent FSS vs. radical surgery (RS). RESULTS: In total 83 women were identified; 36 who had FSS performed and 47 RS. The 5-year OS rate was 92% and no statistical differences between DFS or OS were found between women treated by FSS or RS. The recurrence rate after RS was 13% compared to 6% after FSS. Recurrences were more frequently found in women with stage IC tumor or with histologic subtypes with more aggressive behavior. In the FSS cohort, nine women gave birth to 12 healthy children, all delivered at fullterm. Only one women had received assisted reproductive technology treatment. CONCLUSION: In this nationwide population-based cohort study natural fertility was maintained after FSS. Specific histologic subtypes showed greater prognostic impact on the oncological outcome than the use of FSS. Recurrences occurred after FSS, but none in the uterus, which questions the need of hysterectomy in young women with EOC. TRIAL REGISTRATION: This article reports the results of a healthcare intervention using the data prospectively registered in the Swedish population-based registries including the Quality Register for Gynecological Cancer, the National Death Register, the Swedish Medical Birth Register, and the National Quality Register for Assisted Reproduction.

A prospective study on the long-term outcome of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation prior to hematologic stem cell transplantation.

BACKGROUND: Few studies have reported the long-term outcomes of prepubertal and pubertal boys undergoing testicular biopsy for fertility preservation (FP). PROCEDURE: This prospective longitudinal study examined 21 boys (aged 1.5-14.5 years) who underwent testicular biopsy for FP prior to allogeneic (n = 20) or autologous (n = 1) hematological stem cell transplantation (HSCT) between 2003 and 2010. During counseling, pubertal boys were encouraged to produce a sperm sample by masturbation , while prepubertal boys were presented with surgical testicular tissue retrieval as an option for experimental FP. Clinical outcomes included postoperative complications, pubertal development, and sex-hormone levels. Survivors approaching adulthood were encouraged to provide semen samples. RESULTS: Twenty boys, including 14 in prepuberty and six in early puberty (Tanner stage 2-3), underwent open testicular biopsies. Two pubertal biopsies contained mature sperms, which were cryopreserved. Testicular tissue was vitrified in the remaining 18 cases. One pubertal boy (Tanner stage 4) underwent percutaneous testicular sperm aspiration and sperms obtained were cryopreserved. Postoperative complications (hematoma or infection) were rare. Overall, 14 boys survived >5 years (mean follow-up after HSCT, 7.2 years) and 11 showed advanced puberty. Semen samples were provided by five boys and obtained sperm were cryopreserved from two. Individuals at adulthood had normal testosterone levels but subnormal testicular size, high follicle stimulating hormone, and low inhibin B and anti-Müllerian hormone levels. CONCLUSION: No long-term risks were detected during continuous clinical follow-up. Experimental testicular biopsies for FP were well accepted by the patients and families, despite the absence of methods to use prepubertal tissue for fertility treatment.

GM-CSF does not rescue poor-quality embryos: secondary analysis of a randomized controlled trial.

PURPOSE: To evaluate implantation potential of cleavage-stage embryos cultured in medium containing 2 ng/ml granulocyte-macrophage colony-stimulating factor (GM-CSF) versus control medium, according to embryo morphological quality and then transferred on day 3. METHODS: Explorative secondary data analysis of a multicenter, randomized, placebo-controlled, double-blinded prospective study of 1149 couples with embryo transfer after IVF/ICSI. This analysis includes a subgroup of 422 subjects with either single-embryo transfer (SET, N = 286) or double-embryo transfer of two embryos with equivalent morphological quality (DET, N = 136). Implantation rate and live birth rate were assessed according to category of morphological embryo quality on day 3. RESULTS: Culture with GM-CSF did not increase the implantation rate for embryos classified as poor quality. A trend towards greater benefit of GM-CSF on implantation and survival until live birth for top-quality embryos (TQEs) compared with poor-quality embryos was observed, although not statistically significant. For TQEs, the percentage of transferred embryos resulting in a live born baby was: 40.9 ± 5.3% (GM-CSF) versus 30.5 ± 4.6% (control) (P = 0.24; odds ratio [OR] 1.43, 95% confidence interval [CI] 0.79-2.59), and for embryos with less than 6 cells at day 3 this same rate was: 7.4 ± 3.3% (GM-CSF) versus 12.0 ± 4.0% (control) (P = 0.26; OR 0.53, 95% CI 0.17-1.61). CONCLUSION: This exploratory analysis is consistent with GM-CSF protecting morphologically normal embryos from culture-induced stress and does not support an effect of GM-CSF in rescuing poor-quality embryos. ClinicalTrials.gov identifier: NCT00565747.

Fertility-sparing surgery for treatment of non-epithelial ovarian cancer: Oncological and reproductive outcomes in a prospective nationwide population-based cohort study.

OBJECTIVE: To compare the oncologic outcome of women who underwent fertility-sparing surgery (FSS) vs. radical surgery (RS) for treatment of NEOC in a prospective, nationwide, population-based study and report on the reproductive outcomes in women after FSS. METHODS: Using the Swedish Quality Register for Gynecological Cancer, we identified all women ages 18-40 treated with either FSS or RS for stage I NEOC between 2008 and 2015. Progression-free survival (PFS) and overall survival (OS) rates were compared using the Kaplan-Meier method. Data on use of assisted reproductive technology (ART) treatments and obstetrical outcomes after FSS were extracted from the National Quality Register for Assisted Reproduction (Q-IVF) and the Swedish Medical Birth Register. RESULTS: During the study period, 73 women ages 18-40 received a stage I NEOC diagnosis. The majority, 78% (n = 57), underwent FSS. The 5-year OS rate, regardless of surgical approach, was 98%. There were no statistical differences between OS and PFS rates in women treated with FSS, compared to RS. Recurrences were more common after RS than FSS: 12.5% (2/16) vs. 3.5% (2/57), respectively. Following FSS, 11 women gave birth to 13 healthy children (all conceived naturally). Additionally, 12% of the women in the cohort developed infertility and received ART treatment (n = 7). CONCLUSION: FSS is not associated with worse oncologic outcomes than RS in young women with early stage NEOC. The prognosis was excellent in both groups, with an OS of 98%. Natural fertility was maintained in women treated with FSS, only 12% required ART treatment.

A prospective study of women and girls undergoing fertility preservation due to oncologic and non-oncologic indications in Sweden-Trends in patients' choices and benefit of the chosen methods after long-term follow up.

INTRODUCTION: In Scandinavian countries, programs for fertility preservation are offered free of charge at tertiary-care university hospitals to all patients facing treatments with risk of subsequent sterility. In this prospective study we aimed to investigate trends in female patients' choices after counseling and fertility preservation outcomes during follow up in relation to benign vs malignant indications. MATERIAL AND METHODS: Data on 1254 females including 1076 adults and 178 girls who received fertility preservation counseling for either oncologic (n = 852) or benign indications (n = 402) at Karolinska University Hospital, Stockholm, between 1 October 1998 and 1 December 2018 were analyzed. As appropriate, t tests and chi-square tests were used to compare groups. Logistic regression was used to compare outcomes among groups depending on indications. RESULTS: Adult women generally elected to undergo oocyte retrieval after controlled ovarian stimulation for cryopreservation of embryos or oocytes (n = 538, 73%), whereas a minor proportion opted for cryopreservation of ovarian tissue retrieved through laparoscopy (n = 221, 27%). More than half of the women with a partner chose either not to fertilize their oocytes aiming at cryopreservation of oocytes or to share obtained oocytes attempting both cryopreservation of oocytes and cryopreservation of embryos. All pre-pubertal (n = 48) and 73% of post-pubertal girls (n = 66) elected cryopreservation of ovarian tissue. In recent years, an increasing number of teenagers have opted for controlled ovarian stimulation aiming at cryopreservation of oocytes, either before (n = 24, 17%) or after completion of cancer treatment (n = 15, 10%). During follow up, 27% of the women returned for a new reproductive counseling, additional fertility preservation or to attempt pregnancy. Utilization rates among individuals who were alive and of childbearing age by December 2018 indicated 29%, 8% and 5% for embryos, oocytes and ovarian tissue with live birth rates of 54%, 46% and 7%, respectively. Women with benign indications were significantly younger than women with previous malignant indications at the time of attempting pregnancy. Although the pregnancy rates were similar among both groups, the live birth rate was significantly higher in women with benign vs previous malignant indications (47% vs 21%, P = .002). CONCLUSIONS: Trends in fertility preservation choices have changed over time. Women with previous malignancy had lower live birth rates than women with benign fertility preservation indications.