Venous thromboembolism associated with medically assisted reproduction (MAR): British fertility society policy and practice guidance for assessment and prevention.

The association between Medically Assisted Reproduction (MAR) and thromboembolic complications has been reported widely in multiple published studies. Although venous thromboembolism (VTE) is not thought to be a common complication of MAR, it is associated with high morbidity and is often preventable. Since VTE usually occurs after completion of MAR treatment and is often managed outside of the treating fertility unit, these complications are likely to be underreported and there may be limited awareness of the risks among clinicians. As we continue to see a rise in the total number of MAR treatment cycles, particularly in women over 40 years of age, along with a steady increase in the number of fertility preservation cycles for both medical and social indications, it is likely that we will see an increase in absolute numbers of VTE complications. Currently, there is a lack of management guidance and reporting of VTE events associated with assisted conception treatment. The aim of this guidance is to provide clinicians with information on VTE risk factors, guidance on assessing VTE risk and the best practice recommendations on risk reducing strategies for individuals at risk of VTE undergoing ovarian stimulation and embryo transfer cycles.

Fertility and pregnancy outcomes in women with Turner syndrome: A single centre experience.

OBJECTIVE: Many women with Turner syndrome (TS) will consider fertility options and pregnancy. We wished to examine the fertility and pregnancy outcomes in women with TS undergoing oocyte donation (OD) treatment or spontaneous pregnancy in a large single-centre cohort. General population reference data or data from those with idiopathic premature ovarian insufficiency were used as comparators. DESIGN: A retrospective single-centre cross-sectional study. PATIENTS AND MEASUREMENTS: Seventy-four women with TS underwent OD treatment with a total of 105 pregnancies, and 31 women with TS had 71 spontaneous conceptions. Fertility outcomes included clinical pregnancy and live birth rate. Pregnancy outcomes included miscarriage rate, prevalence of hypertension, gestational diabetes, lower segment caesarean section (LSCS), small for gestational age (SGA), prematurity and vertical transmission of TS. RESULTS: In those with TS, OD pregnancies were associated with increased rates of LSCS and SGA compared to spontaneous pregnancies; LSCS (OR: 4.19, 95% CI: 1.6-10.8, p = .003) and SGA (OR: 2.92, 95% CI: 1.02-8.38, p = .04). There were no recorded cardiac events but 5 (17.2%) cases of vertical transmissions of TS in daughters were identified. OD in those with TS was associated with a lower live birth rate per cycle started (OR: 0.53, 95% CI: 0.34-0.84, p = .008) and a higher rate of miscarriage compared to women with POI (40% vs. 26.2%, p = .04). CONCLUSIONS: We show that pregnancy in women with TS, whether OD or spontaneously conceived, carries obstetric risks, and therefore, women with TS, considering pregnancy, should receive comprehensive pre-pregnancy counselling and optimal obstetric care.

Evidence based management of patients with endometriosis undergoing assisted conception: British fertility society policy and practice recommendations.

Endometriosis is a chronic inflammatory condition in women of reproductive age, which can lead to infertility and pelvic pain. Endometriosis associated infertility is multifactorial in nature adversely affecting each step of the natural reproductive physiology and thereby processes and outcomes of Assisted Reproductive Technology (ART) cycles. These outcomes are further complicated by the subtype of endometriosis, being peritoneal, deep infiltrating and ovarian, which bear negative effects on ovarian reserve, response to stimulation, accessibility for oocyte retrieval, intraoperative safety and endometrial receptivity. There is still a lack of clear guidance about the role of surgery for ovarian endometriosis/endometriomas. This guideline evaluates the evidence of the impact of pelvic endometriosis and endometriomas on the outcome of ART and provides recommendations for management options before and during ART including intra-uterine insemination. Recommendations are made based on the current evidence for the management of patients with endometriosis across each step of ART with the primary aim of improving ART outcomes.

Fertility preservation and realignment in transgender women.

Medical care for transgender people is multi-faceted and attention to individual reproductive aspirations and planning are an essential, yet often overlooked aspect of care. Given the impact of hormonal therapy and other gender affirmation procedures on reproductive function, extensive counselling and consideration of fertility preservation is recommended prior to their commencement. This review article explores the reproductive aspirations of transgender women and considers the current disparity between stated desires regarding utilisation of fertility preservation services. Current fertility preservation options and prospective treatments currently showing promise in the research arena are explored.

Reproductive outcomes after surgical sperm retrieval in couples with male factor subfertility: a 10-year retrospective national cohort.

OBJECTIVE: To determine any significant differences in the reproductive outcome from intracytoplasmic sperm injection (ICSI) with surgical sperm retrieval (SSR) between cycles using fresh and cryopreserved sperm and between cycles using epididymal and testicular sperm. DESIGN: A retrospective national cohort study using data from the UK Human Fertilisation and Embryology Authority, including all ICSI cycles performed in the United Kingdom over a 10-year period. SETTING: Hospital. PATIENT(S): All nondonor ICSI cycles from 2008 to 2017 categorized by sperm source and cryopreservation status. INTERVENTION(S): Intracytoplasmic sperm injection with SSR using fresh or cryopreserved sperm and using ejaculated, testicular, and epididymal sperm. MAIN OUTCOME MEASURE(S): Live birth rate, pregnancy rate, and implantation rate. RESULT(S): We analyzed data from 214,649 ICSI cycles, including 199,818 cycles of ejaculated sperm, 5,646 cycles of epididymal sperm, and 9,185 cycles of testicular sperm. Live births rates per ICSI cycle were 28.5%, 30.6%, and 28.7% for ejaculated, epididymal, and testicular sperm cycles, respectively. Epididymal sperm cycles had a higher live birth rate than that of testicular sperm cycles (odds ratio [OR], 1.067; 95% confidence interval [CI], 1.014-1.123). This was despite a higher mean male age (42.5 vs. 40.6 years; 95% CI of difference, 1.81-1.85 years) and female age (34.3 vs. 34.0 years; 95% CI of difference, 0.32-0.34 years) in epididymal cycles than in testicular cycles. Implantation (61.2% vs. 58.0%; OR, 1.086; 95% CI, 1.041-1.133) and clinical pregnancy rates (34.3% vs. 31.3%; OR, 1.085; 95% CI, 1.039-1.132) were also higher in epididymal cycles than in testicular cycles. There were no statistically significant differences in outcomes between cycles using fresh sperm and those using cryopreserved sperm for SSR-ICSI. CONCLUSION(S): Our study indicates that reproductive outcomes of SSR-ICSI are at least comparable with those of ICSI using ejaculated sperm and does not support the preferential use of fresh sperm over cryopreserved sperm in SSR-ICSI. Births per SSR-ICSI cycle were higher for cycles using epididymal sperm than for cycles using testicular sperm; however, the differences were small, which may provide reassurance to patients undergoing these procedures. The results must be interpreted with caution because multivariable analysis was not possible because of aggregation of data.

Fertility preservation provision in the NHS: a national assessment of care policies.

Fertility preservation has gained momentum in recent years. As cancer survival rates improve, late effects of loss of gonadal function have increased the need to consider fertility preservation. NICE recommends offering cryopreservation of gametes or embryos to patients undergoing gonadotoxic therapy, highlighting that this should be extrapolated to those with non-malignant conditions that pose a risk to fertility. We investigated whether variation in fertility preservation provision exists across the United Kingdom, with a view to identifying equitable models of provision. In England, cryopreservation of gametes and embryos is funded for all patients undergoing treatment for cancer, but eligibility criteria and duration of storage funding vary widely. In Scotland, a national policy is applied, with health boards equitably providing funding for cryopreservation of gametes, embryos, and ovarian and testicular tissue for those undergoing treatment for benign and malignant conditions which impair fertility, including gender incongruence. In Wales and Northern Ireland, cryopreservation of gametes and embryos is funded for those undergoing treatment likely to make them infertile, but ovarian tissue cryopreservation is not funded. Funding criteria for fertility preservation in England, Wales, and Northern Ireland deviates from NICE guidance. Standardization of fertility preservation policies is needed to provide equity of access for patients.

Urological and Gynaecological Considerations for the Use of Gonadotropin-releasing Hormone Analogues in Transgender and Nonbinary Adolescents: A Narrative Review.

CONTEXT: Gonadotropin-releasing hormone analogues (GnRHAs) delay the progression of puberty in transgender and nonbinary (TGNB) adolescents and reduce the impact of dysphoria due to ongoing physical development. The intervention remains contentious despite growing evidence to support this practice. OBJECTIVE: To stimulate discussion on this topical issue in the urological and gynaecological community given potential ramifications for future fertility, physical development, and options for gender affirmation surgery (GAS). EVIDENCE ACQUISITION: We conducted searches of the MEDLINE (from 1946) and Embase (from 1974) databases for the benefits and potential challenges of hormone blockade in TGNB adolescents on February 1, 2022. Evidence with a primary focus on clinical issues of interest to urologists and gynaecologists was objectively synthesised and reported. EVIDENCE SYNTHESIS: The onset of puberty represents a period of distress for TGNB adolescents as secondary sexual characteristics develop. GnRHAs are prescribed to inhibit sex hormone production, but the decision to treat should be balanced against the known (and unknown) adverse effects. Fertility preservation is more likely to be successful if GnRHA treatment is delayed for as long as possible. Some adolescents may decide to stop GnRHA use to harvest spermatozoa or oocytes before starting gender-affirming hormone treatment. Transfeminine individuals should consider that options for genital GAS may become more limited, as vaginoplasty with penile skin inversion requires an adequate stretched penile length. Transmasculine individuals may no longer require chest reconstruction for breast development. CONCLUSIONS: Offers of GnRHA treatment to TGNB adolescents should be balanced by careful preparation and counselling. Urologists and gynaecologists can complement the expertise of specialist psychosocial and adolescent endocrinology teams, and should be involved early in and throughout the treatment pathway to maximise future functional and surgical outcomes. PATIENT SUMMARY: Puberty blockers for transgender and nonbinary adolescents have benefits, but timing is important to preserve fertility and surgical options.

Challenges in developing a quantitative method of measuring breast development using 3D imaging: An example of a novel method for use in induced breast development with exogenous oestrogen.

OBJECTIVE: Optimal breast development is an essential part of exogenous oestrogen treatment in females undergoing pubertal induction. We set out to develop a novel technique using three-dimensional (3D) imaging to determine change in breast volume that is applicable when no pre-existing breast contours are present. DESIGN: A prospective observational study. PATIENTS: The imaging methodology was developed using a single male subject to assess reproducibility and validity. The technique was then applied to 29 participants undergoing pubertal induction with exogenous oestradiol who were recruited from Paediatric Gynaecology and Reproductive Endocrinology clinics at University College London Hospital. MEASUREMENTS: Breast images were taken using a 3D photographic system. Two images, taken at different times, were manually superimposed to produce a differential breast volume. The initial step of method development set out to show that volume change was not secondary to positioning artefact or image manipulation. This was established by using images of a male participant taken on different occasions. The technique was then used to assess reproducibility in participants undergoing pubertal induction treatment. RESULTS: Good intraobserver reproducibility (intraclass correlation (ICC) 0.77) was demonstrated with static image manipulation. Validity of the imaging technique was established as there was no significant difference between the known reference volume produced by computer generated warping and that calculated by manual image manipulation. There was excellent intraobserver reproducibility for breast volume calculation in participants undergoing induced breast development (ICC 0.99). CONCLUSIONS: 3D imaging is a promising novel tool to provide quantitative breast volume assessment in individuals undergoing breast induction with exogenous oestradiol treatment.

An online survey of perimenopausal women to determine their attitudes and knowledge of the menopause.

INTRODUCTION: Women are not usually taught about the menopause formally, and many general practitioners have relatively little training. The aim of this study was to explore perimenopausal women's attitudes and knowledge of the menopause. METHOD: An online survey was designed to evaluate attitudes and knowledge of the menopause in women older than 40 years. The survey was generated with Qualtrics XM® and promoted via social media. In all, 3150 women started the survey. In this study, data from 947 perimenopausal women were analysed. RESULTS: Regarding women's attitudes to the menopause, 38.8% were accepting of it but more than 30% were dreading it. The women had experienced a number of menopause symptoms including mood swings (68.9%), brain fog (68.3%), and fatigue (66.8%). More than 90% of women had never been taught about the menopause at school, and more than 60% did not feel informed at all about the menopause. School was thought to be the best place for menopause education to start (83.6%). In all, 68.2% of women had only looked for information about the menopause as their symptoms started and they had talked to friends and used a variety of websites to look for information. When asked for their free-text views on the menopause, thematic analysis produced four themes: the overarching knowledge gap, the onset and impact of symptoms, perimenopause: the hidden phenomenon, and managing symptoms: differing schools of thought. CONCLUSION: Lack of education for women and their general practitioners is causing perimenopausal women to go through this important stage in their lives with a lack of knowledge and appropriate medical care. It is essential that women are taught about the menopause, from school onwards and that we offer health professionals appropriate training starting from the medical school curriculum.

Variability of response to early puberty induction demonstrated by transverse uterine diameter measurement and a novel method of 3D breast imaging.

OBJECTIVE: Induction of puberty with exogenous oestrogen results in considerable variability in final uterine and breast volumes. We set out to quantify the variability of these two outcome measures with a view to establishing monitoring methods that could be used to individualise treatment protocols. DESIGN: A prospective observational study. PARTICIPANTS: Sixteen participants with pubertal delay and primary amenorrhoea, due to hypogonadism were recruited from paediatric gynaecology and endocrinology clinics at University College London Hospital. A standardised protocol of transdermal 17ß oestradiol (17ßE) was used (Evorel™), with a starting dose of 12.5 mcg increasing to 25 mcg (patch changed twice weekly) after 4 months. Follow up was every 2 months for a total of 8 months. MEASUREMENTS: Uterine dimensions using ultrasound, oestradiol concentrations and breast development assessed by both Tanner staging and 3D photographic imaging. RESULTS: After 8 months of treatment, the changes in oestradiol concentrations (0-174 pmol), uterine volume growth (4.4-16.4 ml) and breast volume (1.76-140.1 ml) varied greatly between individuals. Of uterine parameters, transverse uterine diameter was most closely associated with serum oestradiol levels at 8 months (beta standardised coefficient = 0.80, p = .001). Change in breast volume was associated with age of treatment initiation (beta standardised coefficient 0.55 p = .04). CONCLUSIONS: We demonstrate variation in response to exogenous oestrogen, emphasising the necessity for individualised dose titration. In the absence of sensitive oestradiol assays, uterine transverse measurements may be used as a surrogate marker of oestrogen sensitivity to guide early dose adjustment. 3D breast imaging may provide a quantitative assessment of breast development to complement Tanner breast staging.

SARS-CoV-2 infection in the first trimester and the risk of early miscarriage: a UK population-based prospective cohort study of 3041 pregnancies conceived during the pandemic.

STUDY QUESTION: Does maternal infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the first trimester affect the risk of miscarriage before 13 week's gestation? SUMMARY ANSWER: Pregnant women with self-reported diagnosis of SARS-CoV-2 in the first trimester had a higher risk of early miscarriage. WHAT IS KNOWN ALREADY: Viral infections during pregnancy have a broad spectrum of placental and neonatal pathology. Data on the effects of the SARS-CoV-2 infection in pregnancy are still emerging. Two systematic reviews and meta-analyses reported an increased risk of preterm birth, caesarean delivery, maternal morbidity and stillbirth. Data on the impact of first trimester infection on early pregnancy outcomes are scarce. This is the first study, to our knowledge, to investigate the rates of early pregnancy loss during the SARS-CoV-2 outbreak among women with self-reported infection. STUDY DESIGN, SIZE, DURATION: This was a nationwide prospective cohort study of pregnant women in the community recruited using social media between 21 May and 31 December 2020. We recruited 3545 women who conceived during the SARS-CoV-2 pandemic who were <13 week's gestation at the time of recruitment. PARTICIPANTS/MATERIALS, SETTING, METHODS: The COVID-19 Contraception and Pregnancy Study (CAP-COVID) was an on-line survey study collecting longitudinal data from pregnant women in the UK aged 18 years or older. Women who were pregnant during the pandemic were asked to complete on-line surveys at the end of each trimester. We collected data on current and past pregnancy complications, their medical history and whether they or anyone in their household had symptoms or been diagnosed with SARS-CoV-2 infection during each trimester of their pregnancy. RT-PCR-based SARS-CoV-2 RNA detection from respiratory samples (e.g. nasopharynx) is the standard practice for diagnosis of SARS-CoV-2 in the UK. We compared rate of self-reported miscarriage in three groups: 'presumed infected', i.e. those who reported a diagnosis with SARS-CoV-2 infection in the first trimester; 'uncertain', i.e. those who did not report a diagnosis but had symptoms/household contacts with symptoms/diagnosis; and 'presumed uninfected', i.e. those who did not report any symptoms/diagnosis and had no household contacts with symptoms/diagnosis of SARS-CoV-2. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 3545 women registered for the CAP-COVID study at <13 weeks gestation and were eligible for this analysis. Data for the primary outcome were available from 3041 women (86%). In the overall sample, the rate of self-reported miscarriage was 7.8% (238/3041 [95% CI, 7-9]). The median gestational age (GA) at miscarriage was 9 weeks (interquartile range 8-11). Seventy-seven women were in the 'presumed infected' group (77/3041, 2.5% [95% CI 2-3]), 295/3041 were in the uncertain group (9.7% [95% CI 9-11]) and the rest in the 'presumed uninfected' (87.8%, 2669/3041 [95% CI 87-89]). The rate of early miscarriage was 14% in the 'presumed infected' group, 5% in the 'uncertain' and 8% in the 'presumed uninfected' (11/77 [95% CI 6-22] versus 15/295 [95% CI 3-8] versus 212/2669 [95% CI 7-9], P = 0.02). After adjusting for age, BMI, ethnicity, smoking status, GA at registration and the number of previous miscarriages, the risk of early miscarriage appears to be higher in the 'presumed infected' group (relative rate 1.7, 95% CI 1.0-3.0, P = 0.06). LIMITATIONS, REASONS FOR CAUTION: We relied on self-reported data on early pregnancy loss and SARS-CoV-2 infection without any means of checking validity. Some women in the 'presumed uninfected' and 'uncertain' groups may have had asymptomatic infections. The number of 'presumed infected' in our study was low and therefore the study was relatively underpowered. WIDER IMPLICATIONS OF THE FINDINGS: This was a national study from the UK, where infection rates were one of the highest in the world. Based on the evidence presented here, women who are infected with SARS-CoV-2 in their first trimester may be at an increased risk of a miscarriage. However, the overall rate of miscarriage in our study population was 8%. This is reassuring and suggests that if there is an effect of SARS-CoV-2 on the risk of miscarriage, this may be limited to those with symptoms substantial enough to lead to a diagnostic test. Further studies are warranted to evaluate a causal association between SARS-CoV-2 infection in early pregnancy and miscarriage risk. Although we did not see an overall increase in the risk of miscarriage, the observed comparative increase in the presumed infected group reinforces the message that pregnant women should continue to exercise social distancing measures and good hygiene throughout their pregnancy to limit their risk of infection. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by a grant from the Elizabeth Garrett Anderson Hospital Charity (G13-559194). The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. J.A.H. is supported by an NIHR Advanced Fellowship. A.L.D. is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support to J.A.H. and A.L.D. as above; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Interventions to optimize embryo transfer in women undergoing assisted conception: a comprehensive systematic review and meta-analyses.

BACKGROUND: Several interventions and techniques are suggested to improve the outcome of embryo transfer (ET) in assisted conception. However, there remains no consensus on the optimal practice, with high variations among fertility specialists. OBJECTIVE AND RATIONALE: We conducted a comprehensive systematic review and meta-analyses of randomized controlled trials (RCTs) aiming to identify effective interventions that could be introduced around the time of ET to improve reproductive outcomes. SEARCH METHODS: We searched the electronic databases (MEDLINE, EMBASE and Cochrane CENTRAL) from inception until March 2021 using a multi-stage search strategy of MeSH terms and keywords, and included all RCTs that evaluated an intervention in the 24-h period before/after ET in women undergoing IVF/ICSI. Our primary outcome was clinical pregnancy rate post-ET confirmed as viable pregnancy on ultrasound scan. We assessed the risk of bias in included trials and extracted data in duplicate. We pooled data using a random-effect meta-analysis and reported using risk ratio (RR) with 95% CI. We explored publication bias and effect modifiers using subgroup analyses. OUTCOMES: Our search yielded 3685 citations of which we included 188 RCTs (38 interventions, 59 530 participants) with a median sample size of 200 (range 26-1761). The quality of included RCTs was moderate with most showing a low risk of bias for randomization (118/188, 62.8%) and attrition (105/188, 55.8%) but there was a significant risk of publication bias (Egger's test P = 0.001). Performing ET with ultrasound guidance versus clinical touch (n = 24, RR 1.265, 95% CI 1.151-1.391, I2 = 38.53%), hyaluronic acid versus routine care (n = 9, RR 1.457, 95% CI 1.197-1.261, I2 = 46.48%) and the use of a soft versus hard catheter (n = 27, RR 1.122, 95% CI 1.028-1.224, I2 = 57.66%) led to higher clinical pregnancy rates. Other pharmacological add-ons also showed a beneficial effect including granulocyte colony-stimulating factor (G-CSF: n = 4, RR 1.774, 95% CI 1.252-2.512, I2 = 0), Atosiban (n = 7, RR 1.493, 95% CI 1.184-1.882, I2 = 68.27%) and hCG (n = 17, RR 1.232, 95% CI 1.099-1.382, I2 = 57.76%). Bed rest following ET was associated with a reduction in clinical pregnancy (n = 6, RR 0.857, 95% CI 0.741-0.991, I2 = 0.01%). Other commonly used interventions, such as non-steroidal anti-inflammatory drugs, prophylactic antibiotics, acupuncture and cervical mucus removal, did not show a significant benefit on reproductive outcomes. Our effect estimates for other important outcomes, including miscarriage and live birth, were limited by the varied reporting across included RCTs. WIDER IMPLICATIONS: Using ultrasound guidance, soft catheters and hyaluronic acid at the time of ET appears to increase clinical pregnancy rates. The use of Atosiban, G-CSF and hCG showed a trend towards increased clinical pregnancy rate, but larger trials are required before adopting these interventions in clinical practice. Bed rest post-ET was associated with a reduction in clinical pregnancy and should not be recommended.

Oocyte yield in social, medical and donor oocyte cryopreservation cycles.

To determine if oocyte yield in women undergoing cryopreservation for social (SOC), medical (MOC) and oocyte donation (OD) cycles is comparable when matched for age. 315 oocyte retrievals were performed for SOC, 116 for MOC and 392 for OD. Non-parametric Kruskal-Wallis tests and Poisson regression were used to assess the impact of age stratification. The median ages of women undergoing SOC, MOC, and OD were 38, 31 and 26 years respectively. The median (IQR) number of oocytes in the three categories was 7, 10, and 12. The oocyte yield was significantly higher in women aged 30-34 years undergoing SOC, compared to the MOC group. For the SOC group, age in years, oestradiol levels per 1000 pmol/and follicle count >12mm on the day of trigger were significant predictors of oocyte yield. Women embarking on SOC are significantly older than those undergoing MOC and OD, and thus oocyte yield is reduced when stratified for age. This study highlights the significant predictors of oocyte yield amongst women undergoing oocyte cryopreservation for specific indications. The findings can be used to optimise the yield and overall chance of successful livebirth.

Management of recurrent implantation failure: British Fertility Society policy and practice guideline.

Recurrent implantation failure (RIF) is defined as the absence of a positive pregnancy test after three consecutive transfers of good quality embryos. There remains significant variation in clinical practice in the management of RIF. This British Fertility Society (BFS) Policy and Practice guideline analyses the evidence for investigations and therapies that are employed in RIF and provides recommendations for clinical practice and for further research. Evidence for investigations of sperm and egg quality, uterine and adnexal factors, immunological factors and thrombophilia, endocrine conditions and genetic factors and for associated therapies have been evaluated. This guideline has been devised to assist reproductive medicine specialists and patients in making shared decisions concerning management of RIF. Finally, suggestions for research towards improving understanding and management of RIF have also been provided.

Current approaches to management of bone sarcoma in adolescent and young adult patients.

Bone tumors are a group of histologically diverse diseases that occur across all ages. Two of the commonest, osteosarcoma (OS) and Ewing sarcoma (ES), are regarded as characteristic adolescent and young adult (AYA) cancers with an incidence peak in AYAs. They are curable for some but associated with unacceptably high rates of treatment failure and morbidity. The introduction of effective new therapeutics for bone sarcomas is slow, and to date, complex biology has been insufficiently characterized to allow more rapid therapeutic exploitation. This review focuses on current standards of care, recent advances that have or may soon change that standard of care and challenges to the expert clinical research community that we suggest must be met.

Impact of the SARS-CoV-2 pandemic on access to contraception and pregnancy intentions: a national prospective cohort study of the UK population.

OBJECTIVE: Evaluate the impact of the COVID-19 pandemic on access to contraception and pregnancy intentions. DESIGN: Nationwide prospective cohort study. SETTING: United Kingdom. PARTICIPANTS: Women in the UK who were pregnant between 24 May and 31 December 2020. MAIN OUTCOME MEASURES: Access to contraception and level of pregnancy intentions, using the London Measure of Unplanned Pregnancy (LMUP) in women whose last menstrual period was before or after 1 April 2020. While the official date of the first UK lockdown was 23 March, we used 1 April to ensure that those in the post-lockdown group would have faced restrictions in the month that they conceived. RESULTS: A total of 9784 women enrolled in the cohort: 4114 (42.0%) conceived pre-lockdown and 5670 (58.0%) conceived post-lockdown. The proportion of women reporting difficulties accessing contraception was higher in those who conceived after lockdown (n=366, 6.5% vs n=25, 0.6%, p<0.001) and continued to rise from March to September 2020. After adjusting for confounders, women were nine times more likely to report difficulty accessing contraception after lockdown (adjusted odds ratio (aOR) 8.96, 95% CI 5.89 to 13.63, p<0.001). There is a significant difference in the levels of pregnancy planning, with higher proportions of unplanned (n=119, 2.1% vs n=55, 1.3%) and ambivalent pregnancies (n=1163, 20.5% vs n=663, 16.1%) and lower proportions of planned pregnancies (n=4388, 77.4% vs n=3396, 82.5%) in the post-lockdown group (p<0.001). After adjusting for confounders, women who conceived after lockdown were still significantly less likely to have a planned pregnancy (aOR 0.88, 95% CI 0.79 to 0.98, p=0.025). CONCLUSIONS: Access to contraception in the UK has become harder during the COVID-19 pandemic and the proportion of unplanned pregnancies has almost doubled.

Effectiveness of modified downregulation for women with moderate and severe adenomyosis of the uterus prior to frozen thawed embryo transfer (MODA) study protocol: a pragmatic randomised-controlled trial.

INTRODUCTION: Adenomyosis can adversely reduce chances of pregnancy in couples undergoing assisted conception. We aim to evaluate the effect of two different downregulation protocols on the reproductive outcomes in women with moderate and severe adenomyosis undergoing frozen-thawed embryo transfer (FTET). METHODS AND ANALYSIS: We will conduct a two-armed pragmatic randomised clinical trial comparing modified downregulation with gonadotrophin-releasing hormone (GnRH) analogue for 6 weeks to standard downregulation with GnRH analogue for 1 week prior to FTET. Our primary outcome is clinical pregnancy, defined as a viable intrauterine pregnancy confirmed by ultrasound at greater than 6 weeks gestation, with other secondary reproductive, neonatal and safety outcomes. We aim to randomise 162 patients over 3 years to achieve 80% power for detecting a 20% difference in the primary outcome at 5% significance. ETHICS AND DISSEMINATION: To date there is no consensus on the optimal protocol for management of subfertile women with adenomyosis. Modified downregulation could improve the clinical pregnancy rate by reducing the endometrial inflammatory reaction and/or myometrial contractility and their impact on uterine receptivity in women with moderate and severe adenomyosis of the uterus undergoing FTET. The MODA trial is designed to offer pragmatic, real-life evaluation of the optimal protocol for downregulation for this population during assisted conception treatments. Our findings will be published in peer-reviewed journals and presented at national and international scientific meetings and congresses. Ethical approval was granted by the NHS Research Ethics Committees (19/LO/1567). TRIAL REGISTRATION NUMBER: NCT03946722.

Paternal age over 50 years decreases assisted reproductive technology (ART) success: A single UK center retrospective analysis.

INTRODUCTION: To study whether paternal age exerts an effect, independent of maternal age, on the outcomes of fresh in vitro fertilization/ intracytoplasmic sperm injection (IVF/ICSI) cycles. Semen quality deteriorates with increasing paternal age; however, there is conflicting evidence for any impact paternal age may have on the outcome of IVF/ICSI. Several retrospective and prospective cohort studies have shown that paternal age increases the miscarriage rate and reduces the live birth rate. Some studies have shown no effect of paternal age on live birth rate or miscarriage rate. Studies involving donor oocytes have tended to show no independent effect of paternal age on assisted reproductive technology (ART) outcomes. The age at which paternal age may exert a significant deleterious effect on outcome is not known and there is no limit to paternal age in IVF/ICSI treatment. MATERIAL AND METHODS: A single-center retrospective cohort study was carried out at the Centre for Reproductive and Genetic Health, London, UK. Included in the analysis were all couples with primary or secondary infertility undergoing IVF/ICSI cycles in which the male partner produced a fresh semen sample and the cycle proceeded to fresh embryo transfer. All cycles of IVF/ICSI that used donor oocytes-donor sperm, frozen sperm, cycles leading to embryo storage and cycles including preimplantation genetic testing (PGT-A/PGT-M)-were excluded from analysis. The primary outcome was live birth rate and secondary outcomes were clinical pregnancy rate and miscarriage rate. Multivariate logistic regression analysis with live birth as a dependent variable and maternal and paternal age class as independent variables was performed. RESULTS: During the study period there were 4833 cycles, involving 4271 men, eligible for analysis; 1974/4833 (40.8%, 95% confiene intervals [CI] 39.5-42.2%) cycles resulted in a live birth. A significantly lower proportion of men over 51 years met World Health Organization semen analysis criteria (56/133, [42.1%, 95% CI 34.1-50.6]) compared with men under 51 years of age (2530/4138 [61.1%, 95% CI 60.0-62.6]) (p = 0.001). Both maternal and paternal age were retained in the multivariate model and for all maternal age subgroups the probability of live birth decreased with paternal age over 50 years (odds ratio [OR] 0.674, 95% CI 0.482-0.943) (p = 0.021). Paternal age over 50 years was not an independent predictor of miscarriage (OR 0.678, 95% CI 0.369-1.250) (p = 0.214). CONCLUSIONS: Paternal age over 50 significantly affects the chance of achieving a live birth following ART. Paternal age does not independently affect the risk of miscarriage following ART. There should be a public health message for men not to delay fatherhood.

Clinical Practice Guidelines on the Diagnosis and Management of Polycystic Ovary Syndrome: A Systematic Review and Quality Assessment Study.

CONTEXT: Clinical practice guidelines (CPGs) are key instruments to implement the practice of evidence-based medicine. We aimed to evaluate the methodological quality and variations in CPGs recommendations on the diagnosis and management of polycystic ovary syndrome (PCOS). EVIDENCE ACQUISITION: We searched MEDLINE, EMBASE, and CENTRAL until December 2020 for all evidence-based CPGs and consensus statements on PCOS. We extracted data in duplicate to map clinical recommendations across prespecified disease domains and assessed CPGs methodological quality of using the Appraisal of Guidelines, Research & Evaluation II tool. EVIDENCE SYNTHESIS: We included 13 PCOS CPGs published between 2007 and 2018. CPGs recommendations were mostly focused on screening for and managing metabolic disease (12/13, 92%), followed by cardiovascular risk assessment (10/13, 77%). Mental health (8/13, 62%) and diagnosis in adolescents (7/13, 54%) were the least reported domains. Most CPGs had a high quality for scope and purpose description (12/13, 92%) while stakeholder's involvement and applicability of recommendations to clinical practice were appropriate in only 2 CPGs (2/13, 15%). We identified inconsistency in recommendations on PCOS diagnosis in adolescents, optimal lifestyle interventions, hirsutism and acne treatments, interventions to reduce the risk of ovarian hyperstimulation syndrome, the frequency and screening criteria for metabolic and cardiovascular disease, and optimal screening tools for mental health illness in women with PCOS. CONCLUSION: Current CPGs on the diagnosis and management of PCOS vary in their scope and methodological quality, which may hinder evidence translation into clinical practice. We identified disease domains with existing evidence gap to guide future research and guideline updates.