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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 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 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.

ObjectiveEvaluate the impact of the COVID-19 pandemic on access to contraception and pregnancy intentions.DesignNationwide prospective cohort study.SettingUnited Kingdom.ParticipantsWomen in the UK who were pregnant between 24 May and 31 December 2020.Main outcome measuresAccess 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.ResultsA 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%, pConclusionsAccess to contraception in the UK has become harder during the COVID-19 pandemic and the proportion of unplanned pregnancies has almost doubled.

Age at first date and sexual intercourse have been observed to be delayed in women with Turner syndrome (TS), with delayed puberty being the main factor. We sought to assess relationship and sexual experiences comparing women with TS and premature ovarian insufficiency (POI).Cross-sectional observational study.302 women with TS and 53 women with karyotypically normal POI (median age 33.0 [15.0-78.4] and 26.3 [17.8-52.3], respectively).A self-reporting questionnaire was used to collect data on relationship and sexual experiences.Women with TS were older than women with POI (P = .002). Compared to women with POI, a smaller proportion of women with TS had ever had vaginal sexual intercourse (VSI) (40 [78.4%] vs 169 [58.1%], respectively, P = .006) and women with TS exhibited a delay in the median age at first relationship and VSI (POI 19.3 ± 0.4 vs TS 22.2 ± 1.1, P = .001). Start of oestrogen replacement therapy at ≤ 14 years of age compared with 14 years did not result in earlier relationship and sexual debut. After adjusting for age and diagnosis, induction of puberty, as opposed to spontaneous puberty, was associated with a delay in the median age at first relationship and VSI and a reduced probability of having VSI (Hazard ratio = 0.44 [95% confidence interval: 0.32-0.60], P = .001).Turner syndrome and induction of puberty are associated with a reduced likelihood and a delay in relationship and sexual experiences. Women needing puberty induction and women with TS more than POI have a delayed mean age at first VSI compared to the general population.

Study question Is there a difference in treatment outcome between gonadotrophin releasing hormone (GnRH) pump or hMG for women with Type 1 anovulation undergoing ovulation induction? Summary answer Treatment with GnRH was more efficient compared to hMG, with fewer number of cycles to pregnancy, fewer days of stimulation and fewer cycle cancellations. What is known already Whilst there is a lot of information on ovulation induction in WHO type II anovulation (PCOS), type 1 anovulation is under-represented in research. WHO type 1 anovulation is characterised by low pituitary gonadotrophins and oestradiol. Treatment options used to include induction of ovulation using gonadotrophins (hMG) or the Gonadotrophin hormone releasing hormone (GnRH) pump delivering pulsatile GnRH. Since the withdrawal of GnRH pump, options have become limited. One study reveals that monofollicular cycles are lower and cycle cancellation higher in women with Type 1 anovulation women treated with gonadotrophins. Study design, size, duration: This is a single centre retrospective cohort study. All women with a diagnosis of WHO type 1 anovulation attending the Reproductive Medicine Unit at the University College London Hospital who received ovulation induction treatment using either hMG or GnRH pump between 1993 and 2020 were included in the study Participants/materials, setting, methods 147 women with WHO type 1 anovulation were included in the study. Diagnosis was based on the presence of primary or secondary amenorrhoea in combination with low gonadotrophins and oestradiol. Demographic and clinical data were obtained by reviewing medical records stored within an electronic database. A total of 599 treatment cycles were identified. Statistical analysis between the groups was performed using the independent T test and chi squared test. Main results and the role of chance 147 women with WHO type 1 anovulation underwent ovulation induction. hMG was used in 500 cycles (83.5%) and the GnRH pump in 99 cycles (16.5%). Per cycle started the pregnancy rate in the hMG cycles was 107/500 (21.4%) and in the GnRH pump cycles was 19/99 (19.2%) p = 0.36. Cycle cancellation was significantly greater in hMG than GnRH pump cycles (hMG 137/ 500 27.4% vs GnRH pump 17/99 17.2% p = 0.02). Over response was more common in hMG cycles than GnRH pump cycles (66/130 50.8% vs 3/16 18.8% p = 0.01). A total of 363/500 (72.5%) cycles in the hMG and 82/99 (82.8%) cycles in the GnRH pump group reached ovulation. There was no difference in the pregnancy rate after ovulation (hMG 107/363 29.5% vs GnRH pump 19/82 23.2% p = 0.15). The mean number of treatment cycles to achieve pregnancy was significantly fewer with the GnRH pump compared to hMG (1.8 (min 1 – max 3) vs 2.4 ( min 1 – max 8) p = 0.03).The mean days of stimulation required to reach ovulation was also significantly less with the GnRH pump compared to hMG (16.7 (min 8 – max 34) vs 23.4 (min 7 – max 72) p = Limitations, reasons for caution This is a retrospective cohort study and is reliant on the quality and quantity of the data entry at the time of clinical treatment. Wider implications of the findings: Ovulation induction for women with type 1 anovulation is now restricted to a single treatment, namely hMG. hMG is not as effective or optimal as GnRH. Reinstating GnRH in routine clinical practice should be promoted to allow more individualised treatment options and prevent the premature need for in vitro fertilisation.. Trial registration number NA

Objective Women with early-onset oestrogen deficiency are at risk of reduced bone mineral density (BMD). We sought to assess fracture history and BMD in women with Turner syndrome (TS) and premature ovarian insufficiency (POI). Design A cross-sectional observational study. Patients Two hundred and sixty seven women with TS (median age 34.3 years) and 67 women with POI (median age 28.1 years). Measurements A questionnaire was used to collect data on fracture history, co-morbidities and drug history including age at first oestrogen exposure. Clinical data included height, weight, serum vitamin D and hip and spine T-scores, which were adjusted for height and age. Fractures were subdivided into major osteoporotic fractures (MOF) and 'other' fracture types. Results Overall fracture rate was similar in women with TS and POI (82 [30.5%] vs 22 [32.8%] respectively, P = .74). Compared to women with POI, those with TS had more fractures at MOF sites (30.2% vs 52.7%, P = .012) and fewer phalangeal fractures (27.9% vs 9.8%, P = .005). There was no difference in BMD between women who sustained a fracture compared to those who did not. Women with TS who fractured were more likely to suffer from hearing impairment compared to those with no fracture (62.2% vs 48.1%, P = .045). Conclusions TS is not associated with an overall excess risk of bone fracture. The higher rate of fractures at MOF sites in women with TS may be secondary to hearing impairment, thin cortical bone and abnormal bone remodelling.

Objective: The dual diagnosis of hypoplastic uterus in association with ovarian dysgenesis is regularly reported but the pathogenesis of the association is unclear. The uterus, however, may be invisible to all imaging modalities without at least six months of exogenous oestrogen exposure in complete ovarian failure. We assessed all available case reports in this category to estimate whether the apparent association between primary ovarian insufficiency or Turner syndrome and Mullerian agenesis can be largely accounted for by oestrogen deficiency. Design: A literature review of all cases in which an association between ovarian insufficiency or Turner syndrome and hypoplastic uterus has been reported. Patients: PubMed was searched for all case reports associated with relevant key terms. In total, 22 publications with a total of 25 patients were identified and reviewed; 14 subjects had the normal female karyotype (46,XX), and 11 subjects had Turner Syndrome. Measurements: Proportion of subjects who had been exposed to adequate oestrogen prior to the absent uterine diagnosis. Results: A diagnosis of absent uterus was made prior to exposure to exogenous oestrogen in 22/25 (88%) of subjects with primary hypogonadism including 14/14 females with normal karyotype and 8/11 females with Turner syndrome. Conclusions: Oestrogen deficiency is a possible explanation for most subjects being reported as having Mullerian agenesis in association with Turner syndrome or primary ovarian insufficiency. In the presence of oestrogen deficiency, no conclusion can be made about the status of the uterus until adequate exposure to exogenous oestrogen has been completed and we suggest reassessment of the uterus when full adult dose has been reached towards the end of induction of puberty.

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.

Improvements in survival rates and the rise in the incidence of cancer, particularly in young people, has shifted the focus of treatment towards less gonadotoxic therapies, such that a larger number of survivors will remain fertile after treatment. Unfortunately, for the vast majority of cancer therapies, there is incomplete data on the extent of injury to the reproductive organs. This review uses case series and cohort studies on conception rates and menstrual cyclicity after gonadotoxic cancer therapies, and relevant studies on ovarian reserve assessment. It will aid clinicians wishing to provide evidence-based counselling on patients' reproductive potential after cancer treatment.

Introduction Turner Syndrome is associated with a variety of morbidities affecting nearly every body system, some of which increase in prevalence in adult life. The severity of clinical features in TS is roughly in parallel with the magnitude of the deficit of X chromosome material. The aim of this study was to extend the established karyotype phenotype relationships using data from a large adult cohort. Materials & Methods Karyotypes were available in 656 (78.1%), 611 of whom could be classified into five major groups within the cohort: 45,X; 45,X mosaicism (45,X/46,XX); isochromosome X (isochromosome Xq); mosaicism 45,X/46,XY and ring X. Continuous variables such as blood pressure and biochemical markers from clinic data were binarised allocating those in the upper quartile to represent at- risk individuals. With the exception of bone mineral density T- score for which the lower quartile was allocated as at risk. For co-morbidities, initiation of formal treatment was recorded. Results 45,X/46,XX had considerably lower incidences of co-morbidities compared to 45,X. The isochromosome group experienced similar outcomes to 45,X. Novel associations were found between the XY mosaic karyotype group and a decreased prevalence of thyroid disease and severe hearing loss. A previously unreported increased incidence of metabolic syndrome was noted within the ring chromosome subgroup. Conclusions Karyotype may play an important factor against stratifying risk of co-morbidity in TS and should be taken into consideration when managing adults with TS. Further investigations of the isochromosome (Xq) and ring groups are necessary to further clarify their associations with co-morbidities. This article is protected by copyright. All rights reserved.

STUDY QUESTION Do children born after donor ART have an increased risk of developing childhood cancer in comparison to the general population? SUMMARY ANSWER This study showed no overall increased risk of childhood cancer in individuals born after donor ART. WHAT IS KNOWN ALREADY Most large population-based studies have shown no increase in overall childhood cancer incidence after non-donor ART; however, other studies have suggested small increased risks in specific cancer types, including haematological cancers. Cancer risk specifically in children born after donor ART has not been investigated to date. STUDY DESIGN, SIZE, DURATION This retrospective cohort study utilized record linkage to determine the outcome status of all children born in Great Britain (1992–2008) after donor ART. The cohort included 12 137 members who contributed 95 389 person-years of follow-up (average follow-up 7.86 years). PARTICIPANTS/MATERIALS, SETTING, METHODS Records of all children born in Great Britain (England, Wales, Scotland) after all forms of donor ART (1992–2008) were linked to the UK National Registry of Childhood Tumours (NRCT) to determine the number who subsequently developed cancer by 15 years of age, by the end of 2008. Rates of overall and type specific cancer (selected a priori) were compared with age, sex and calendar year standardized population-based rates, stratifying for potential mediating/moderating factors including sex, age at diagnosis, birth weight, multiple births, maternal previous live births, assisted conception type and fresh/ cryopreserved cycles. MAIN RESULTS AND THE ROLE OF CHANCE In our cohort of 12 137 children born after donor ART (52% male, 55% singleton births), no overall increased risk of cancer was identified. There were 12 cancers detected compared to 14.4 expected (standardized incidence ratio (SIR) 0.83; 95% CI 0.43–1.45; P = 0.50). A small, significant increased risk of hepatoblastoma was found, but the numbers and absolute risks were small ( LIMITATIONS REASONS FOR CAUTION Although this study includes a large number of children born after donor ART, the rarity of specific diagnostic subgroups of childhood cancer results in few cases and therefore wide CIs for such outcomes. As this is an observational study, it is not possible to adjust for all potential confounders; we have instead used stratification to explore potential moderating and mediating factors, where data were available. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to investigate cancer risk in children born after donor ART. Although based on small numbers, results are reassuring for families and clinicians. The small but significant increased risk of hepatoblastoma detected was associated with low birthweight, a known risk factor for this tumour type. It should be emphasized that the absolute risks are very small. However, on-going investigation with a longer follow-up is needed. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by Cancer Research UK (C36038/A12535) and the National Institute for Health Research (405526) and supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. The work of the Childhood Cancer Research Group (CCRG) was supported by the charity CHILDREN with CANCER UK, the National Cancer Intelligence Network, the Scottish Government and the Department of Health for England and Wales. There are no competing interests. TRIAL REGISTRATION NUMBER N/A.

Adequate uterine growth is an essential component of pubertal induction with exogenous oestradiol in those with hypogonadism. Poor uterine development will render the individual vulnerable in the context of fertility. We assessed uterine size using ultrasound in those who had undergone pubertal induction treatment compared with a reference group who had experienced spontaneous puberty.This is a single-centre, retrospective, cross-sectional study of women who underwent pubertal induction compared with a reference group.Ninety-five women with hypogonadism who had previously undergone pubertal induction and were receiving maintenance oestrogen replacement as adults were recruited: 48 women with Turner syndrome, 32 with premature ovarian insufficiency and 15 with gonadotrophin deficiency. The reference group consisted of 35 nulliparous women attending with male factor subfertility with a normal pelvis on ultrasonography.Pelvic ultrasound was performed by a single observer. Uterine dimensions (total length, anterior-posterior (AP), transverse, uterine volume and fundal cervical AP ratio (FCR) measurements) were recorded. Clinical details were also recorded.Those with hypogonadism had significantly reduced uterine dimensions compared with the reference group (uterine length 64 mm vs 71 mm P = .05, uterine volume 28.9 mL vs 43.9 mL P = .05). All women in the reference group attained a mature uterine configuration with a FCR1, compared with 84% of those with hypogonadism (P = .01). A total of 24% and 48% of the diagnostic group had total uterine length and uterine volume measurements less than the 5th percentile of the reference group, respectively. In a subgroup of 22 women in whom serum oestradiol concentrations could be analysed, there was a positive correlation between this parameter and uterine volume.Despite standard oestrogen therapy, uterine growth is often compromised in those with hypogonadism. Uterine health has historically been overlooked in pubertal induction protocols; however, with increasing options for fertility treatment, adequate uterine development is crucial. Given the variation in uterine size witnessed, a more tailored approach to treatment with regular monitoring of uterine dimensions should be advocated.

Introduction Since the first live birth from oocyte cryopreservation three decades ago, oocyte cryopreservation has become an important component of ART. Cryopreservation techniques have evolved, leading to higher success rates and the introduction of oocyte cryopreservation into IVF clinics worldwide. Concurrently, there has been an increase in patient demand, especially for so-called 'social egg freezing' that allows women to preserve their fertility in anticipation of age-related fertility decline. This review addresses a need to evaluate the current status of oocyte cryopreservation. It explores current techniques and success rates, clinical applications, the rise of elective oocyte cryopreservation, and future implications. Methods A search was performed using Web of Science and PubMed databases for publications between January 1980 and December 2015. Keywords used included 'egg freezing', 'oocyte freezing', 'oocyte cryopreservation', 'oocyte vitrification', and 'fertility preservation'. Results The success rate of oocyte cryopreservation has risen, and the increasing use of vitrification offers has improved outcomes, with IVF pregnancy rates now similar to those achieved with fresh oocytes. There are conflicting opinions about the comparative success rates of open and closed vitrification. Patients are accessing and receiving oocyte cryopreservation for a wide range of indications, and there has been a marked increase in patient numbers and oocyte cryopreservation cycles. Oocyte cryopreservation for circumventing age-related infertility is becoming more widely accepted. Conclusion Oocyte cryopreservation is an established component of ART, with vitrification now being the cryopreservation technique of choice. Increasing numbers of women undergo oocyte cryopreservation for both medical and social reasons. It is important to continue auditing outcomes and reporting long-term follow-up of children born from frozen-thawed oocytes.

Context Turner syndrome (TS) is often associated with delayed puberty. To induce puberty, estrogen is administered in incremental doses at an age determined by age of presentation. After puberty, various types of maintenance estrogen replacement therapy (ERT) are used. Objective We sought associations between age of induction of puberty and type of ERT on adult health outcomes. Design Health surveillance data included blood profiles, bone density, and blood pressure. We assessed interactions between these data and age at first estrogen exposure in women with primary amenorrhea. We also assessed these data according to ERT subgroups [combined oral contraceptive pill (OCP), oral estrogen (OE), and transdermal estradiol (TE)] using data from each of 6679 clinic visits, controlling for age, body mass index, and height. Setting Adult TS clinic at University College London Hospital. Patients Of 799 women with TS, 624 had primary amenorrhea and 599 had accurate maintenance ERT data. Main outcome measures Parameters of health surveillance derived from clinical guidelines. Results Estrogen start age was negatively correlated with adult bone density (spine: r = -0.20 and hip: r = -0.022; P ≤ 0.001). OCP users had higher blood pressure and an adverse lipid profile compared with other ERT subgroups. TE was associated with elevated liver enzymes and hemoglobin A1c compared with OE (P ≤ 0.01). Conclusions An earlier age of induction of puberty may be beneficial for adult bone density. Given the high prevalence of hypertension in TS, the use of OCP for ERT should be limited. OE may be a benefit for steatohepatitis.

Objective To investigate the risks of ovarian, breast, and corpus uteri cancer in women who have had assisted reproduction. Design Large, population based, data linkage cohort study. Setting and participants All women who had assisted reproduction in Great Britain, 1991-2010, as recorded by the Human Fertilisation and Embryology Authority (HFEA). Interventions HFEA fertility records for cohort members were linked to national cancer registrations. Main outcome measures Observed first diagnosis of ovarian, breast, and corpus uteri cancer in cohort members were compared with age, sex, and period specific expectation. Standardised incidence ratios (SIRs) were calculated by use of age, sex, and period specific national incidence rates. Results 255 786 women contributed 2 257 789 person years’ follow-up. No significant increased risk of corpus uteri cancer (164 cancers observed v 146.9 cancers expected; SIR 1.12, 95% confidence interval 0.95 to 1.30) was found during an average of 8.8 years’ follow-up. This study found no significantly increased risks of breast cancer overall (2578 v 2641.2; SIR 0.98, 0.94 to 1.01) or invasive breast cancer (2272 v 2371.4; SIR 0.96, 0.92 to 1.00). An increased risk of in situ breast cancer (291 v 253.5; SIR 1.15, 1.02 to 1.29; absolute excess risk (AER) 1.7 cases per 100 000 person years, 95% confidence interval 0.2 to 3.2) was detected, associated with an increasing number of treatment cycles (P=0.03). There was an increased risk of ovarian cancer (405 v 291.82; SIR 1.39, 1.26 to 1.53; AER 5.0 cases per 100 000 person years, 3.3 to 6.9), both invasive (264 v 188.1; SIR 1.40, 1.24 to 1.58; AER 3.4 cases per 100 000 person years, 2.0 to 4.9) and borderline (141 v 103.7; SIR 1.36, 1.15 to 1.60; AER 1.7 cases per 100 000 person years, 0.7 to 2.8). Increased risks of ovarian tumours were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumour in women treated because of only male factor or unexplained infertility. Conclusions No increased risk of corpus uteri or invasive breast cancer was detected in women who had had assisted reproduction, but increased risks of in situ breast cancer and invasive and borderline ovarian tumours were found in this study. Our results suggest that ovarian tumour risks could be due to patient characteristics, rather than assisted reproduction itself, although both surveillance bias and the effect of treatment are also possibilities. Ongoing monitoring of this population is essential.

Objective To study the safety and efficacy of ovarian stimulation and oocyte cryopreservation as a method of fertility preservation in women with Turner syndrome (TS). Design Retrospective cohort study. Setting Reproductive medicine clinic. Patient(s) Seven women with TS who attended the clinic between 2011 and 2017. Intervention(s) Ovarian stimulation and oocyte cryopreservation. Main Outcomes Measure(s) Number of oocytes cryopreserved, ovarian hyperstimulation syndrome. Result(s) The oocyte retrieval rates (mean ± SD, 9 ± 3.16) in women with TS were comparable to the published data from healthy women. The oocyte yield was higher than expected based on the low antimullerian hormone levels. There was no correlation between baseline antimullerian hormone or antral follicle count levels and the number of oocytes retrieved. Conclusion(s) Oocyte cryopreservation after ovarian stimulation appears to be safe and successful in women with mosaic TS who wish to consider fertility preservation.

Objective There is uncertainty whether treatment with dehydroepiandrosterone (DHEA) decreases menopausal symptoms for women in the peri- or postmenopausal phase. A previous systematic review considering this subject suggested that DHEA may slightly improve sexual function compared with placebo (CS. Scheffers, S. Armstrong, AEP. Cantineau, C. Farquhar, V. Jordan Dehydroepiandrosterone for women in the peri- or postmenopausal phase. Cochrane Database of Systematic Reviews 2015, Issue 1. Art. No.: CD011066. DOI: https://doi.org/10.1002/14651858.CD011066.pub2 ). The purpose of this article is to review recent research investigating whether the use of DHEA, and in particular intravaginal DHEA (Prasterone®), improves sexual function. Methods We conducted an online search using Medline OVID for recent articles related to DHEA and menopause. We found 48 relevant publications, out of which 14 papers were original research, all related to the development and licensing of intravaginal DHEA. We critically analysed these 14 articles in relation to sexual function. Results All the randomised controlled trials assessed the efficacy of vaginal DHEA in women with vulvovaginal atrophy and showed that sexual dysfunction improved with treatment regardless of the level of dyspareunia at baseline. Treatment with DHEA was found to be superior to placebo and at least as efficacious as vaginal oestrogens in improving symptoms. Conclusion Intravaginal DHEA appears to be a safe and effective treatment for menopausal vulvovaginal atrophy and dyspareunia in most women. Further studies are required before it can be recommended for women with a history of thrombosis, cardiovascular disease or hormone-sensitive neoplasms.

Fertility preservation in the female poses several challenges due to the invasive nature of the techniques available to achieve it. The guideline aims to bring together the evidence available for the measures for fertility preservation and their outcome. The guideline addresses fertility preservation for medical reasons and includes both oncological and non-oncological causes. The techniques that the guideline considers are: (i) embryo and oocyte cryopreservation; (ii) ovarian tissue cryopreservation; (iii) GnRH agonist suppression and (iv) ovarian transposition. Although ovarian tissue cryopreservation is still considered experimental, the availability of this technique is gaining momentum as more live births from auto-transplanted tissue are reported. The guideline also highlights use of current treatment modalities for benign and malignant conditions that have a better fertility sparing profile. The guideline recommends a multidisciplinary approach in counselling women and girls about the risk to their fertility and available techniques. The role of psychological support in assisting women and girls with decision-making is highlighted. The guideline also highlights the risks associated with these techniques. Women need to be medically fit to undergo invasive procedures. Fertility preservation techniques are appropriate when treatment has curative intent. Fertility preservation is a subject of on-going research on outcomes of different techniques and at the time of publication, studies are still likely to emerge adding to the available literature.

In recent years significant progress in cancer therapy has led to vastly improved survival rates in the adolescent and young adult diagnosed with cancer. Many patients receive treatment that results in the loss or compromise of future fertility. This has led to a greater focus on reproduction as an important aspect of survivorship. The simultaneous advances in assisted reproductive technology has meant that young people have a better opportunity for future fertility. Though national and international guidance recommend discussion and provision of fertility preservation where practicable there is considerable variation in clinical practice. Oncofertility centres set up in association with larger cancer centres has enabled a rapid access to specialist fertility services, and long term care of gonadal dysfunction in young cancer patients. It is hoped that development of oncofertility networks in the future will enable these resources to be accessed by all cancer centres and many more young people to avail of these services. In this chapter we provide a comprehensive understanding of the effect of cancer therapy on fertility and options of fertility preservation.

Objective To investigate the risks of ovarian, breast, and corpus uteri cancer in women who have had assisted reproduction. Design Large, population based, data linkage cohort study. Setting and Participants All women who had assisted reproduction in Great Britain, 1991-2010, as recorded by the Human Fertilisation and Embryology Authority (HFEA). Interventions HFEA fertility records for cohort members were linked to national cancer registrations. Main Outcome Measures Observed first diagnosis of ovarian, breast, and corpus uteri cancer in cohort members were compared with age, sex, and period specific expectation. Standardised incidence ratios (SIRs) were calculated by use of age, sex, and period specific national incidence rates. Results 255 786 women contributed 2 257 789 person years’ follow-up. No significant increased risk of corpus uteri cancer (164 cancers observed v 146.9 cancers expected; SIR 1.12, 95% confidence interval 0.95 to 1.30) was found during an average of 8.8 years’ follow-up. This study found no significantly increased risks of breast cancer overall (2578 v 2641.2; SIR 0.98, 0.94 to 1.01) or invasive breast cancer (2272 v 2371.4; SIR 0.96, 0.92 to 1.00). An increased risk of in situ breast cancer (291 v 253.5; SIR 1.15, 1.02 to 1.29; absolute excess risk (AER) 1.7 cases per 100 000 person years, 95% confidence interval 0.2 to 3.2) was detected, associated with an increasing number of treatment cycles (P=0.03). There was an increased risk of ovarian cancer (405 v 291.82; SIR 1.39, 1.26 to 1.53; AER 5.0 cases per 100 000 person years, 3.3 to 6.9), both invasive (264 v 188.1; SIR 1.40, 1.24 to 1.58; AER 3.4 cases per 100 000 person years, 2.0 to 4.9) and borderline (141 v 103.7; SIR 1.36, 1.15 to 1.60; AER 1.7 cases per 100 000 person years, 0.7 to 2.8). Increased risks of ovarian tumours were limited to women with endometriosis, low parity, or both. This study found no increased risk of any ovarian tumour in women treated because of only male factor or unexplained infertility. Conclusions No increased risk of corpus uteri or invasive breast cancer was detected in women who had had assisted reproduction, but increased risks of in situ breast cancer and invasive and borderline ovarian tumours were found in this study. Our results suggest that ovarian tumour risks could be due to patient characteristics, rather than assisted reproduction itself, although both surveillance bias and the effect of treatment are also possibilities. Ongoing monitoring of this population is essential.

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. It is characterized by a combination of hyperandrogenism (either clinical or biochemical), chronic oligo/anovulation, and polycystic ovaries. It is frequently associated with insulin resistance and obesity. PCOS receives considerable attention because of its high prevalence and possible reproductive, metabolic, and cardiovascular consequences. It is the most common cause of anovulatory infertility. Ovulation induction with clomifene citrate is the first line medical treatment. The aim of ovulation induction is monofollicular growth to avoid multiple pregnancy. The second line treatments include gonadotrophins and laparoscopic ovarian drilling. The role and benefit of metformin in ovulation induction is controversial. Woman with PCOS undergoing IVF are at significant risk of ovarian hyperstimulation syndrome. Women with PCOS are also at an increased risk of developing gestational diabetes, pregnancy induced hypertension, and pre-eclampsia.

The Royal College of Obstetricians and Gynaecologists defines ovarian hyperstimulation syndrome (OHSS) as a "systemic disease resulting from vasoactive products released by hyperstimulated ovaries". It is usually the result of gonadotrophin stimulation for in vitro fertilisation (IVF), with moderate and severe cases affecting about 3–8% of cycles. At the heart of OHSS is an increase in vascular permeability causing the movement of fluid out of the intravascular space, with resultant accumulation of fluid in the third space and intravascular depletion. The diagnosis is made according to recognised signs, symptoms and investigations on a background of ovarian stimulation. Prevention is better than cure in this iatrogenic disorder, but the aim of management is effective monitoring to confirm safe spontaneous improvement or alert the requirement for intervention in the event of deterioration; the crux of which concerns careful fluid management. This article reviews the pathogenesis, diagnosis, classification and management of OHSS.

Aims Cancer incidence has been investigated in children born after non-donor assisted conception, but incidence in children born after donor assisted conception remain uncertain. This study aimed to determine overall and site specific cancer incidence in a British cohort of children born after assisted conception using donor gametes. Methods This retrospective cohort study utilised records of all 12 186 children born in Britain (England, Wales and Scotland) after all forms of donor assisted conception between 1992 and 2008. Records were linked to the United Kingdom National Registry of Childhood Tumours to determine the number who developed cancer at under 15 years of age by the end of 2008. Overall and site specific cancer rates within the cohort were compared with population based rates in Great Britain over the same time period, stratifying for potential mediating and moderating factors including sex, age at diagnosis, birth weight, multiple births, parity, parental age, assisted conception type and parental infertility cause. Results No overall increased risk of cancer was identified in this population. 12 cancers were detected compared with 14.4 expected (Standardised incidence ratio (SIR) 0.83; 95% confidence interval (CI) 0.43, 1.45). A small but significant increased risk of hepatoblastoma was detected, but numbers were small ( Conclusion There was no overall increased risk of cancer in children born in Great Britain after donor assisted conception over this 16 year study period. A small increased risk of hepatoblastoma was detected, but numbers were small and absolute risks low. Our results mirror those found in a similar cohort of 1 06 000 children born after non-donor assisted conception over the same period in Britain.

Background Premature ovarian insufficiency (POI), often and misleadingly referred to as 'premature menopause', is defined as a loss of ovarian activity before the age of 40 years and is characterized by irregular or absent periods and reduced fertility. Symptoms include those associated with the natural menopause (night sweats and vaginal dryness), and with the long-term adverse effects of estrogen deficiency (osteoporosis and cardiovascular disease): the latter is believed to explain the shorter life expectancy associated with POI. Objective and rationale The objective of the current review was to collect all relevant studies supporting recommendations on the indications, treatment options, and risks of hormone replacement therapy (HRT) (estrogen, progestogens and androgens) for women with POI. Search methods The current review was written based on the best available evidence on the topic collected for the recently published ESHRE guideline on the management of women with POI. PUBMED/MEDLINE and the Cochrane library were searched in a stepwise approach. Relevant references were summarized in evidence tables, with assessment of the quality. Outcomes HRT is strongly recommended for women with POI, mainly for vasomotor and genito-urinary symptom relief. In addition, HRT has been shown to have a role in bone protection and probably also in primary prevention of cardiovascular disease. There is little evidence on the optimal type, regimen and dose of HRT; patient preference for route and method of administration of each component of HRT must be considered when prescribing, as should contraceptive needs. In women with POI, physiological replacement of estrogen (and progesterone) is essential for their health, and the controversies that surround the use of HRT in postmenopausal women do not apply. Limitations reasons for caution N/A. Wider implications New areas of study on HRT for women with POI should focus on life expectancy, quality of life and neurological function. Furthermore, randomized controlled trials comparing transdermal estradiol with oral estrogens with regard to efficacy, patient satisfaction and side effects are urgently needed. Study funding/competing interests The authors received no funding for the review. The costs for the development of the ESHRE guideline were covered by ESHRE. The authors have no conflicts of interest to disclose.

Awareness of and access to services remains poor in the UK Advances in the treatment of cancer in children and young adults have meant that more survivors are living with the long term consequences of treatment.1 Loss of fertility is a big concern,2 and infertility is common after high dose chemotherapy and pelvic irradiation.3 Fertility preservation has been available to men for many years; semen cryostorage before treatment yields viable sperm for later in vitro fertilisation (IVF). Women, however, require more complex and invasive procedures.4 This aspect of the holistic care of young people with cancer has been highlighted by the recent announcement of the first baby born in the UK to a woman who had regrafting of ovarian tissue that was cryopreserved 10 years earlier.5 The options for women facing loss of fertility from treatment for cancer or other therapies include cryopreservation of oocytes, embryos, or, more experimentally, ovarian tissue. Embryo freezing has been used successfully for three decades. Oocyte freezing is technically more …

We read with interest editorial on the National Institute for Health and Care Excellence (NICE) menopause guideline,1 and their comments on the presentation of evidence underpinning the guideline’s recommendations.2 We dispute their allegation that “methodological deficiencies undermine its conclusions.” The development of this guideline was based on a rigorous methodological approach involving a complex meta-analysis, known as a network meta-analysis. This method was used to assess the relative effectiveness of different treatments (pharmacological and non-pharmacological) to reduce the occurrence of vasomotor symptoms. This complex meta-analysis is methodologically superior to conventional meta-analyses because it allows the simultaneous comparison of different treatments to achieve an outcome for the population of interest (in this case, women in menopause). All the relevant peer reviewed publications …

Item does not contain fulltext STUDY QUESTION: What is the optimal management of women with premature ovarian insufficiency (POI) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group (GDG) formulated 99 recommendations answering 31 key questions on the diagnosis and treatment of women with POI. WHAT IS KNOWN ALREADY: NA. STUDY DESIGN, SIZE, DURATION: This guideline was produced by a multidisciplinary group of experts in the field using the methodology of the Manual for ESHRE Guideline Development, including a thorough systematic search of the literature, quality assessment of the included papers up to September 2014 and consensus within the guideline group on all recommendations. The GDG included a patient representative to ensure input from women with POI. After finalization of the draft, the European Society for Human Reproduction and Embryology (ESHRE) members and professional organizations were asked to review the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS: NA. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 17 recommendations on diagnosis and assessment of POI and 46 recommendations on the different sequelae of POI and their consequences for monitoring and treatment. Furthermore, 24 recommendations were formulated on hormone replacement therapy in women with POI, and two on alternative and complementary treatment. A chapter on puberty induction resulted in five recommendations. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the guideline is that, due to the lack of data, many of the recommendations are based on expert opinion or indirect evidence from studies on post-menopausal women or women with Turner Syndrome. WIDER IMPLICATIONS OF THE FINDINGS: Despite the limitations, the guideline group is confident that this document will be able to guide health care professionals in providing the best practice for managing women with POI given current evidence. Furthermore, the guideline group has formulated research recommendations on the gaps in knowledge identified in the literature searches, in an attempt to stimulate research on the key issues in POI. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the implementation of the guideline. The guideline group members did not receive payment. Dr Davies reports non-financial support from Novo Nordisk, outside the submitted work; the other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: NA.

Objective. Fertility preservation is an important survivorship issue for women treated for breast cancer. The aim of this work was to examine the referral practices of health care professionals who treat women with breast cancer in the United Kingdom, and to investigate their understanding and knowledge of the fertility preservation options available. Method. An invitation to participate in a confidential, online questionnaire was e-mailed to surgeons, oncologists, and clinical nurse specialists who manage patients with breast cancer in the United Kingdom. Results. n = 306 respondents. Factors which influenced whether fertility preservation options were discussed with a patient included the following: patient's age (78%), final tumor/nodes/metastasis status (37.9%); concern that fertility preservation would delay chemotherapy (37.3%); whether the patient had children (33.5%) or a partner (24.7%); estrogen receptor expression (22.6%), lack of knowledge regarding the available options (20.9%); and concern that fertility preservation would compromise the success of cancer treatment (19.8%). Twenty-seven percent did not know whether fertility preservation was available for their patients on the National Health Service. Nearly half (49.4%) of respondents said that gonadotropin-releasing hormone agonists were used for fertility preservation outside the setting of a clinical trial. Knowledge regarding the available options varied according to different members of the multidisciplinary team, with consultant oncologists better informed than consultant surgeons or clinical nurse specialists (p < .05). Conclusions. Many health care professionals have incomplete knowledge regarding the local arrangements for fertility preservation for patients with breast cancer. This may result in patients receiving inadequate or conflicting information regarding fertility preservation.

BACKGROUND: Clomifene citrate (CC) is accepted as the first-line method for ovulation induction (OI) in patients with polycystic ovary syndrome (PCOS) associated with infertility owing to anovulation. Low-dose FSH has been reserved for women failing to conceive with CC. In this RCT, we tested the hypothesis that pregnancy rate (PR) and live birth rates (LBR) are higher after OI with low-dose FSH than with CC as first-line treatment. METHODS: Infertile women (, peer-reviewed

Within endocrinology, the long-term management of Turner syndrome (TS) in adults is fast becoming a specialist subject in its own right. The complications of TS can affect every system in the body, and the main reason why it falls to endocrinologists to coordinate health care is that many features are clearly within the endocrine remit: hypothyroidism, diabetes, hypertension, osteoporosis, hypogonadism. Endocrinologists as general physicians can often cover surveillance of problems in other areas such as congenital heart disease, inflammatory bowel disease and deafness, calling upon specialist input only if the need arises. In this way, a simple 'one stop shop' can offer a well-woman service for women with TS in a cost-effective manner. Such a service requires a multidisciplinary approach.

Human admixed embryos contain various combinations of animal and human material but are nevertheless predominantly human. A new Human Fertilisation and Embryology Bill is due to come into force in October 2009 that will make provisions for research using four categories of human admixed embryos: cytoplasmic hybrids, true hybrids, transgenic embryos and chimeric embryos. The science underpinning this research relates to nuclear reprogramming and embryonic stem cell technology amongst others. The information gathered holds great promise for providing in-depth understanding of the molecular basis of disease as well as opening the door for exciting new therapeutic options. However, the use of such embryos has ignited public debate and raises contentious ethical issues. Here we outline some of the fundamental aspects of embryonic stem cell technology and the contribution of human admixed embryos to this and allied scientific endeavours. We also discuss the current regulatory climate in the UK and explore some of the ethical concerns raised by research on human admixed embryos.

To assess long-term health effects of ovarian-stimulation drugs we followed-up for over 20 years a British cohort of 7355 women with ovulatory disorders, 43% of whom were prescribed ovarian-stimulation drugs, and identified a total of 274 deaths and 367 incident cancers. Relative to the general population, the cohort experienced lower mortality from most causes, including from all neoplasms combined, and lower incidence of cervical cancer, but higher incidence of cancers of the breast (relative risk: 1.13; 95% CI 0.97, 1.30) and corpus uteri (2.02; 1.37, 2.87). There were, however, no significant differences in the risk of cancers of the breast, corpus uteri, ovary, or of any other site, between women who had been prescribed ovarian-stimulation drugs and those who had not. Further analyses by type of drug and dose revealed a dose-response gradient in the risk of cancer of the corpus uteri (P for linear trend=0.03), with women given >or=2250 mg of clomiphene having a 2.6-fold (2.62; 0.94, 6.82) increase in risk relative to those who were not treated. These findings do not support strong associations between ovulation-stimulation drugs and cancer risks, but they indicate the need for continued monitoring to establish whether risks are elevated in certain subgroups of users.

What you need to know Preterm birth is the single biggest cause of neonatal mortality and morbidity in the UK, affecting over 52 000 babies (around 7.3% of live births) in England and Wales in 2012.1 About 75% of women delivering preterm do so after preterm labour,2 which is sometimes preceded by preterm prelabour membrane rupture.2 A “cause” for preterm labour is not always found, but it may be associated with infection. In other cases, preterm birth may result from elective delivery. Babies born preterm have high rates of mortality, with the risk of mortality being inversely proportional to gestational age at birth.3 Babies who survive have increased rates of disability.3 This article summarises the most recent recommendations on the prevention, diagnosis, and management of preterm labour from the National Institute for Health and Care Excellence (NICE).4 #### What’s new in this guidance

The improved long-term survival of adolescents and young women treated for cancer has resulted in an increased focus on the effects of chemotherapy on ovarian function and its preservation. These women may seek advice and treatment regarding their reproductive status, including ways of preserving their fertility and preventing a premature menopause--factors that can have a profound impact on their quality of life. This article comprehensively reviews ovarian reserve testing (ORT) in general. Special emphasis is placed on patients with cancer, including the pathophysiology of gonadal damage following chemotherapy, fertility preservation and the potential role of ORT. Baseline parameters of ovarian reserve [FSH LH, estradiol, inhibin B and anti-Mullerian hormone (AMH)] have not yet performed sufficiently well in predicting poor outcome in assisted reproduction, but biochemical markers of ovarian reserve appear to be better than chronological age. Inhibin B and AMH show potential for future use. Dynamic testing appears to show much promise, especially stimulated levels of inhibin B and estradiol. The most promising tests of ovarian reserve are the biophysical markers, where total antral follicle count was found to be most discriminatory followed by ovarian volume. Combination of biochemical, biophysical and clinical markers of ovarian reserve may also improve predictive capacity. However, there is a lack of data pertinent to ORT in cancer. As yet there is no single clinically useful test to predict ovarian reserve accurately. Patients with cancer represent a distinct cohort who have particular concerns about their future fertility and the possibility of a premature menopause, they can benefit greatly from knowledge of their functional ovarian reserve. Large, prospective, randomized, adequately controlled studies specific to different geographical areas are required in a control population of comparable reproductive age to determine the potential role of ORT in clinical practice.