Best practice recommendations for medically assisted reproduction in patients with known cardiovascular disease or at high risk of cardiovascular disease.

Increasing numbers of people are seeking assisted conception. In people with known cardiac disease or risk factors for cardiac disease, assisted conception may carry increased risks during treatment and any subsequent pregnancy. These risks should be assessed, considered and minimized prior to treatment.

Transfer of thawed frozen embryo versus fresh embryo to improve the healthy baby rate in women undergoing IVF: the E-Freeze RCT.

BACKGROUND: Freezing all embryos, followed by thawing and transferring them into the uterine cavity at a later stage (freeze-all), instead of fresh-embryo transfer may lead to improved pregnancy rates and fewer complications during in vitro fertilisation and pregnancies resulting from it. OBJECTIVE: We aimed to evaluate if a policy of freeze-all results in a higher healthy baby rate than the current policy of transferring fresh embryos. DESIGN: This was a pragmatic, multicentre, two-arm, parallel-group, non-blinded, randomised controlled trial. SETTING: Eighteen in vitro fertilisation clinics across the UK participated from February 2016 to April 2019. PARTICIPANTS: Couples undergoing their first, second or third cycle of in vitro fertilisation treatment in which the female partner was aged < 42 years. INTERVENTIONS: If at least three good-quality embryos were present on day 3 of embryo development, couples were randomly allocated to either freeze-all (intervention) or fresh-embryo transfer (control). OUTCOMES: The primary outcome was a healthy baby, defined as a live, singleton baby born at term, with an appropriate weight for their gestation. Secondary outcomes included ovarian hyperstimulation, live birth and clinical pregnancy rates, complications of pregnancy and childbirth, health economic outcome, and State-Trait Anxiety Inventory scores. RESULTS: A total of 1578 couples were consented and 619 couples were randomised. Most non-randomisations were because of the non-availability of at least three good-quality embryos (n = 476). Of the couples randomised, 117 (19%) did not adhere to the allocated intervention. The rate of non-adherence was higher in the freeze-all arm, with the leading reason being patient choice. The intention-to-treat analysis showed a healthy baby rate of 20.3% in the freeze-all arm and 24.4% in the fresh-embryo transfer arm (risk ratio 0.84, 95% confidence interval 0.62 to 1.15). Similar results were obtained using complier-average causal effect analysis (risk ratio 0.77, 95% confidence interval 0.44 to 1.10), per-protocol analysis (risk ratio 0.87, 95% confidence interval 0.59 to 1.26) and as-treated analysis (risk ratio 0.91, 95% confidence interval 0.64 to 1.29). The risk of ovarian hyperstimulation was 3.6% in the freeze-all arm and 8.1% in the fresh-embryo transfer arm (risk ratio 0.44, 99% confidence interval 0.15 to 1.30). There were no statistically significant differences between the freeze-all and the fresh-embryo transfer arms in the live birth rates (28.3% vs. 34.3%; risk ratio 0.83, 99% confidence interval 0.65 to 1.06) and clinical pregnancy rates (33.9% vs. 40.1%; risk ratio 0.85, 99% confidence interval 0.65 to 1.11). There was no statistically significant difference in anxiety scores for male participants (mean difference 0.1, 99% confidence interval -2.4 to 2.6) and female participants (mean difference 0.0, 99% confidence interval -2.2 to 2.2) between the arms. The economic analysis showed that freeze-all had a low probability of being cost-effective in terms of the incremental cost per healthy baby and incremental cost per live birth. LIMITATIONS: We were unable to reach the original planned sample size of 1086 and the rate of non-adherence to the allocated intervention was much higher than expected. CONCLUSION: When efficacy, safety and costs are considered, freeze-all is not better than fresh-embryo transfer. TRIAL REGISTRATION: This trial is registered as ISRCTN61225414. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 25. See the NIHR Journals Library website for further project information.

During in vitro fertilisation, eggs and sperm are mixed in a laboratory to create embryos. An embryo is placed in the womb 2­5 days later (fresh-embryo transfer) and the remaining embryos are frozen for future use. Initial research suggested that freezing all embryos followed by thawing and replacing them a few weeks later could improve treatment safety and success. Although these data were promising, the data came from small studies and were not enough to change practice and policy. We conducted a large, multicentre, clinical trial to evaluate the two strategies: fresh-embryo transfer compared with later transfer of frozen embryos. We also compared the costs of both strategies during in vitro fertilisation treatment, pregnancy and delivery. This study was conducted across 18 clinics in the UK from 2016 to 2019, and 619 couples participated. Couples were allocated to one of two strategies: immediate fresh-embryo transfer or freezing of all embryos followed later by transfer of frozen embryo. The study's aim was to find out which type of embryo transfer gave participants a higher chance of having a healthy baby. We found that freezing all embryos followed by frozen-embryo transfer did not lead to a higher chance of having a healthy baby. There were no differences between strategies in the number of live births, the miscarriage rate or the number of pregnancy complications. Fresh-embryo transfer was less costly from both a health-care and a patient perspective. A routine strategy of freezing all embryos is not justified given that there was no increase in success rates but there were extra costs and delays to embryo transfer.

Elective freezing of embryos versus fresh embryo transfer in IVF: a multicentre randomized controlled trial in the UK (E-Freeze).

STUDY QUESTION: Does a policy of elective freezing of embryos, followed by frozen embryo transfer result in a higher healthy baby rate, after first embryo transfer, when compared with the current policy of transferring fresh embryos? SUMMARY ANSWER: This study, although limited by sample size, provides no evidence to support the adoption of a routine policy of elective freeze in preference to fresh embryo transfer in order to improve IVF effectiveness in obtaining a healthy baby. WHAT IS KNOWN ALREADY: The policy of freezing all embryos followed by frozen embryo transfer is associated with a higher live birth rate for high responders but a similar/lower live birth after first embryo transfer and cumulative live birth rate for normal responders. Frozen embryo transfer is associated with a lower risk of ovarian hyperstimulation syndrome (OHSS), preterm delivery and low birthweight babies but a higher risk of large babies and pre-eclampsia. There is also uncertainty about long-term outcomes, hence shifting to a policy of elective freezing for all remains controversial given the delay in treatment and extra costs involved in freezing all embryos. STUDY DESIGN, SIZE, DURATION: A pragmatic two-arm parallel randomized controlled trial (E-Freeze) was conducted across 18 clinics in the UK from 2016 to 2019. A total of 619 couples were randomized (309 to elective freeze/310 to fresh). The primary outcome was a healthy baby after first embryo transfer (term, singleton live birth with appropriate weight for gestation); secondary outcomes included OHSS, live birth, clinical pregnancy, pregnancy complications and cost-effectiveness. PARTICIPANTS/MATERIALS, SETTING, METHODS: Couples undergoing their first, second or third cycle of IVF/ICSI treatment, with at least three good quality embryos on Day 3 where the female partner was ≥18 and <42 years of age were eligible. Those using donor gametes, undergoing preimplantation genetic testing or planning to freeze all their embryos were excluded. IVF/ICSI treatment was carried out according to local protocols. Women were followed up for pregnancy outcome after first embryo transfer following randomization. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 619 couples randomized, 307 and 309 couples in the elective freeze and fresh transfer arms, respectively, were included in the primary analysis. There was no evidence of a statistically significant difference in outcomes in the elective freeze group compared to the fresh embryo transfer group: healthy baby rate {20.3% (62/307) versus 24.4% (75/309); risk ratio (RR), 95% CI: 0.84, 0.62 to 1.15}; OHSS (3.6% versus 8.1%; RR, 99% CI: 0.44, 0.15 to 1.30); live birth rate (28.3% versus 34.3%; RR, 99% CI 0.83, 0.65 to 1.06); and miscarriage (14.3% versus 12.9%; RR, 99% CI: 1.09, 0.72 to 1.66). Adherence to allocation was poor in the elective freeze group. The elective freeze approach was more costly and was unlikely to be cost-effective in a UK National Health Service context. LIMITATIONS, REASONS FOR CAUTION: We have only reported on first embryo transfer after randomization; data on the cumulative live birth rate requires further follow-up. Planned target sample size was not obtained and the non-adherence to allocation rate was high among couples in the elective freeze arm owing to patient preference for fresh embryo transfer, but an analysis which took non-adherence into account showed similar results. WIDER IMPLICATIONS OF THE FINDINGS: Results from the E-Freeze trial do not lend support to the policy of electively freezing all for everyone, taking both efficacy, safety and costs considerations into account. This method should only be adopted if there is a definite clinical indication. STUDY FUNDING/COMPETING INTEREST(S): NIHR Health Technology Assessment programme (13/115/82). This research was funded by the National Institute for Health Research (NIHR) (NIHR unique award identifier) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care. J.L.B., C.C., E.J., P.H., J.J.K., L.L. and G.S. report receipt of funding from NIHR, during the conduct of the study. J.L.B., E.J., P.H., K.S. and L.L. report receipt of funding from NIHR, during the conduct of the study and outside the submitted work. A.M. reports grants from NIHR personal fees from Merck Serono, personal fees for lectures from Merck Serono, Ferring and Cooks outside the submitted work; travel/meeting support from Ferring and Pharmasure and participation in a Ferring advisory board. S.B. reports receipt of royalties and licenses from Cambridge University Press, a board membership role for NHS Grampian and other financial or non-financial interests related to his roles as Editor-in-Chief of Human Reproduction Open and Editor and Contributing Author of Reproductive Medicine for the MRCOG, Cambridge University Press. D.B. reports grants from NIHR, during the conduct of the study; grants from European Commission, grants from Diabetes UK, grants from NIHR, grants from ESHRE, grants from MRC, outside the submitted work. Y.C. reports speaker fees from Merck Serono, and advisory board role for Merck Serono and shares in Complete Fertility. P.H. reports membership of the HTA Commissioning Committee. E.J. reports membership of the NHS England and NIHR Partnership Programme, membership of five Data Monitoring Committees (Chair of two), membership of six Trial Steering Committees (Chair of four), membership of the Northern Ireland Clinical Trials Unit Advisory Group and Chair of the board of Oxford Brain Health Clinical Trials Unit. R.M. reports consulting fees from Gedeon Richter, honorarium from Merck, support fees for attendance at educational events and conferences for Merck, Ferring, Bessins and Gedeon Richter, payments for participation on a Merck Safety or Advisory Board, Chair of the British Fertility Society and payments for an advisory role to the Human Fertilisation and Embryology Authority. G.S. reports travel and accommodation fees for attendance at a health economic advisory board from Merck KGaA, Darmstadt, Germany. N.R.-F. reports shares in Nurture Fertility. Other authors' competing interests: none declared. TRIAL REGISTRATION NUMBER: ISRCTN: 61225414. TRIAL REGISTRATION DATE: 29 December 2015. DATE OF FIRST PATIENT'S ENROLMENT: 16 February 2016.

The role of adjuvant systemic steroids in the management of periorbital cellulitis secondary to sinusitis: a systematic review and meta-analysis.

PURPOSE: The role of adjuvant systemic corticosteroids in the management of periorbital cellulitis and subperiosteal/orbital abscesses secondary to sinonasal infections is not well understood. Our objective was to systematically review the current evidence on the efficacy and side effects of systemic steroids when used in the management of periorbital cellulitis. METHODOLOGY: A systematic review of literature was conducted in accordance with PRISMA guidance. A systematic search of MEDLINE, Embase and Cochrane databases, MetaRegister and ISI conference proceedings was conducted. The outcomes of interest were duration of inpatient stay, requirement for surgical intervention, adverse effects and recurrent/residual symptoms. RESULTS: Four studies were identified involving 118 patients. Of these, 78 underwent treatment with systemic corticosteroids and 40 were controls. Meta-analysis demonstrated that the mean duration of inpatient stay was significantly shorter in the steroid group (WMD - 2.90 days; 95% CI - 3.07, - 2.73; p < 0.00001). There were no significant differences in requirement for surgical intervention (RR 0.93; 95% CI 0.50, 1.75; p = 0.83). Side effects were reported in 6/78 patients (7.7%), with 5 patients showing signs of hyperactivity and 1 patient with insomnia. These were mild except in one case, which required early cessation of corticosteroids. There was one case of recurrence of symptoms in each cohort (steroid vs. non-steroid) following discharge. CONCLUSIONS: The evidence suggests that systemic corticosteroids may offer some benefit in the management of periorbital cellulitis secondary to sinonasal infections. However, there is significant heterogeneity and risk of bias. A well-designed randomised controlled trial may provide a better insight into the efficacy of systemic steroids for this condition.

Risk of foetal harm with letrozole use in fertility treatment: a systematic review and meta-analysis.

BACKGROUND: The aromatase inhibitor letrozole is increasingly recommended for ovulation induction, as it is more effective with fewer side-effects than other agents. But many clinicians are reluctant to use the drug for fertility treatment due to a strong-label warning against its use, which warns about congenital malformation risk to the foetus in women seeking pregnancy. OBJECTIVE AND RATIONALE: The aim of this study was to determine the risks of congenital malformations and pregnancy loss with letrozole compared with clomiphene primarily, and with other fertility drugs and natural conception. SEARCH METHODS: A systematic review and meta-analysis using PRISMA harms guidelines. We searched MEDLINE, EMBASE and other sources from inception until January 2020, with the MeSH words for 'letrozole' and pregnancy OR foetal/neonatal outcome. We included studies reported on congenital malformations in foetuses born to mothers conceived after fertility treatment, with letrozole versus clomiphene, placebo, gonadotrophins, metformin, natural conception or other agents, from randomised trials, comparative cohort studies and non-comparative observational cohorts. Quality of the studies was assessed using Cochrane risk of bias tool and Newcastle Ottawa Scale. The McMaster tool was used to assess the quality of reported harm for foetal congenital malformations in the studies. We compared the absolute risk of events using risk difference measures and pooled the findings using a fixed-effect model. We evaluated the statistical heterogeneity using forest plots and the I2 statistic and funnel plot to assess publication bias. We assessed the strength of evidence for congenital malformation and pregnancy loss as per the GRADE recommendations and with the Fragility index. OUTCOMES: We included 46 studies (18 randomised trials; 21 comparative cohorts; 7 non-comparative cohorts). Overall 2.15% (101/4697; 95% CI 1.7 to 2.5) of babies conceived on letrozole for fertility treatment had congenital foetal malformations. We did not observe a significant increase in congenital malformations with letrozole versus clomiphene in the randomised trials (risk difference (RD) 0.01, 95% CI -0.02, 0.03; I2 = 0%; 14 studies) and found a significant reduction in the cohort studies (RD -0.02, 95% CI -0.04, -0.01; I2 = 0%, 11 studies). The fragility index was 44% (7/16) (either an increase in the intervention arm or a decrease in control arm was needed to alter the results). The risks of pregnancy loss were not increased with letrozole versus clomiphene in the 14 randomised trials (RD -0.01, 95% CI -0.06, 0.04; I2 = 0%), and the risks were reduced in the six cohort studies (RD -0.09, 95% CI -0.17, -0.00; I2 = 68%). The GRADE quality of evidence was low to moderate for congenital malformations and pregnancy loss. We did not find any increased congenital malformation risk with letrozole versus gonadotrophins, natural conception or natural cycle ART, but the number of studies was small. WIDER IMPLICATIONS: There is no evidence that letrozole increases the risk of congenital foetal malformation or pregnancy loss compared with clomiphene, natural conception or other fertility agents, to warrant warning against its use. Given its therapeutic benefits and lack of evidence of harm to the foetus, clinicians should consider letrozole as first-line agent for ovulation induction.

Peri-operative morbidity and fertility outcome after repeat abdominal myomectomy for large fibroid uterus.

This was a retrospective cohort study evaluating peri-operative morbidity of 66 women who underwent repeat abdominal myomectomy compared with 200 women who had primary myomectomy in the same period, matched for age and uterine size. We report the reproductive outcome of women seeking fertility after repeat myomectomy. More pre-operative GnRH analogues were used and midline abdominal skin incision performed in the repeat myomectomy group. The likelihood of major complication was three times higher in the repeat abdominal myomectomy group (OR 3.0, 95% CI 1.67-5.5, p < .001). There was a significantly longer mean hospital stay (p < .01), higher incidence of bleeding (p < .01) and urinary or wound infection (p < .01) in the repeat abdominal myomectomy group. Of the 47 women who had repeat myomectomy for fertility reasons, six women conceived and two live birth at term (4%). Our study highlights the significant peri-operative morbidity and poor subsequent live birth rate associated with repeat abdominal myomectomy.Impact statementWhat is already known on this subject? Repeat abdominal myomectomy is a major surgical procedure with significant morbidity. However, abdominal myomectomy for large fibroid uterus remains the preferred treatment method for women who wish to preserve fertility. Sufficient evidence related to the peri-operative morbidity and fertility outcome after repeat abdominal myomectomy is lacking.What do the results of this study add? This is the largest study reporting peri-operative morbidity and pregnancy outcome following repeat abdominal myomectomy. Our results highlight the three times increased risk of major complications associated with repeat abdominal myomectomy compared to primary myomectomy with the poor subsequent live birth rate.What are the implications of these findings for clinical practice and/or further research? Our study complements the sparse existing data on the outcome of repeat abdominal myomectomy and underscore the potentially significant peri-operative morbidity and poor subsequent live birth rate associated with the procedure. This information should be used in counselling women with fibroid recurrence after primary myomectomy before they embark on repeat surgery.

Medical and Surgical Treatment of Reproductive Outcomes in Polycystic Ovary Syndrome: An Overview of Systematic Reviews.

Polycystic ovary syndrome (PCOS) is a common, complex condition that affects up to 18% of reproductiveaged women, causing reproductive, metabolic and psychological dysfunctions. We performed an overview and appraisal of methodological quality of systematic reviews that assessed medical and surgical treatments for reproductive outcomes in women with PCOS. Databases (MEDLINE, EMBASE, CINAHL PLUS and PROSPERO) were searched on the 15th of September 2017. We included any systematic review that assessed the effect of medical or surgical management of PCOS on reproductive, pregnancy and neonatal outcomes. Eligibility assessment, data extraction and quality assessment by the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) tool were performed in duplicate. We identified 53 reviews comprising 44 reviews included in this overview; the majority were moderate to high quality. In unselected women with PCOS, letrozole was associated with a higher live birth rate than clomiphene citrate (CC), while CC was better than metformin or placebo. In women with CC-resistant PCOS, gonadotrophins were associated with a higher live birth rate than CC plus metformin, which was better than laparoscopic ovarian drilling (LOD). LOD was associated with lower multiple pregnancy rates than other medical treatments. In women with PCOS undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), the addition of metformin to gonadotrophins resulted in less ovarian hyperstimulation syndrome (OHSS), and higher pregnancy and live birth rates than gonadotrophins alone. Gonadotrophin releasing hormone (GnRH) antagonist was associated with less OHSS, gonadotrophin units and shorter stimulation length than GnRH agonist. Letrozole appears to be a good first line treatment and gonadotrophins, as a second line treatment, for anovulatory women with PCOS. LOD results in lower multiple pregnancy rates. However, due to the heterogeneous nature of the included populations of women with PCOS, further larger scale trials are needed with more precise assessment of treatments according to heterogeneous variants of PCOS.

The effect of myo-inositol/di-chiro-inositol on markers of ovarian reserve in women with PCOS undergoing IVF/ICSI: A systematic review and meta-analysis.

INTRODUCTION: High levels of anti-Mullerian hormone and a high antral follicle count in women with polycystic ovary syndrome, reflecting increased ovarian antral follicles, predisposes them to have a high number of retrieved oocytes with in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) and an increased risk of ovarian hyperstimulation syndrome. Inositols, which act as insulin sensitizers, have the potential to alter folliculogenesis and the functional ovarian reserve, with subsequent benefits to reproductive outcomes following IVF/ICSI treatment. Published literature is, however, unable to provide definitive evidence of its efficacy. The objective of our review was to evaluate the effect of inositols on anti-Mullerian hormone, antral follicle count and reproductive outcomes in women with polycystic ovary syndrome undergoing IVF/ICSI. MATERIAL AND METHODS: We performed a literature search using standard methodology recommended by Cochrane. Randomized controlled trials and non-randomized studies comparing inositols with no treatment, placebo or other treatment were included in the review. Using standard methodology recommended by Cochrane we pooled results using the random effects model; our findings were reported as relative risk or mean differences. PROSPERO registration: CRD42017082275. RESULTS: We included 18 trials. The primary outcome was a change in anti-Mullerian hormone and antral follicle count before and after treatment, for which data were unsuitable for meta-analysis. A narrative review showed no consistent direction or size of effect. A meta-analysis for the secondary outcomes showed no evidence of a significant difference between inositol and control groups for any outcome: number of oocytes (mean difference -0.39, 95% confidence interval [CI] -1.11 to 0.33), number of metaphase II oocytes (mean difference 0.29, 95% CI -0.83 to 1.40), number of top grade embryos (risk ratio [RR] 1.02, 95% CI 0.93-1.12), clinical pregnancy rate (RR 1.16, 95% CI 0.87-1.53), and risk of ovarian hyperstimulation syndrome (RR 0.73, 95% CI 0.39-1.37). The quality of evidence was assessed as very low. CONCLUSIONS: There is insufficient evidence for an effect of inositols on ovarian reserve markers and to support their use as pretreatment before IVF/ICSI in women with polycystic ovary syndrome.

Biomarkers of ovarian reserve in childhood and adolescence: A systematic review.

INTRODUCTION: Certain medical disorders as well as their management may affect gonadal function. Recent advances in the management of these conditions accompanied by the availability and success of methods of fertility preservation has highlighted the need for assessment of ovarian reserve in childhood and adolescence. Serum anti-Mullerian hormone (AMH) and antral follicle count are well established markers of ovarian reserve and serum inhibin has also been used. However, literature on reference ranges for ovarian reserve markers in this age-group is relatively scarce. Thus, our aim was to evaluate published data to estimate reference values of ovarian reserve makers in childhood and adolescence. MATERIAL AND METHODS: We performed a systematic review of the literature reporting ovarian reserve markers in childhood and adolescence. We included only those studies examining markers of ovarian reserve in the normal healthy population between the ages of 0 and 19 years. PROSPERO registration: CRD42018119064. RESULTS: Serum AMH emerged as the most common biomarker assessed. Serum AMH was detectable at birth and, after a transient increase in infancy, increased steadily in childhood. Following a slight decrease at puberty, levels were constant throughout adolescence with a peak in adolescence or early adulthood. The mean serum AMH values during infancy, childhood and adolescence were 10.55, 22.32 and 31.84 pmol/L, respectively. The corresponding median values were 9.85, 24.49 and 26.32 pmol/L. It was not possible to construct age-specific reference intervals because of methodological heterogeneity, variations in the assay used to measure AMH and differing interval width for age used in included studies. Serum inhibin showed an increase from childhood to adolescence, with median serum inhibin values of 53.86 pg/mL in adolescence. Antral follicle count showed a significant positive correlation with serum AMH and a median value of 30.52 in adolescence. CONCLUSIONS: We summarize the trends and levels of biomarkers of ovarian reserve from birth until young adulthood. Peak levels of serum AMH are reported in adolescence or early adulthood. We have reported median/mean values for serum AMH in different age-groups based on data pooled from several studies, which may be used as a reference when evaluating ovarian reserve in childhood and adolescence especially when considering fertility preservation.

Overview of systematic reviews of non-pharmacological interventions in women with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a major contributor to subfertility, diabetes and cardiovascular disease in women. The role of non-pharmacological interventions to prevent these outcomes has been reported in many systematic reviews, but robust conclusions have not been made due to variations in the scope, quality and findings of these reviews. OBJECTIVE AND RATIONALE: Our aim was to provide an overview of existing evidence on the effects of non-pharmacological interventions in women with PCOS on fertility and non-fertility outcomes by a review of existing systematic reviews. SEARCH METHODS: We reviewed systematic reviews of randomized trials that have evaluated the effects of non-pharmacological interventions, such as lifestyle interventions, nutritional supplements or alternative medicine therapies in women with PCOS on fertility, endocrine, glycaemic and weight-related outcomes. We assessed the quality of systematic reviews with the AMSTAR tool, and reported the outcomes with regard to: fertility (live birth, clinical pregnancy, ovulation and menstrual cycle regularization); endocrine outcomes (Ferriman-Gallwey score, free androgen index, free testosterone and total testosterone levels); and glycaemic (fasting blood insulin, fasting blood glucose, homoeostatic model assessment) and weight-related (BMI) outcomes. We assessed the strength of evidence for significant outcomes as per the grading of recommendations assessment, development and evaluation (GRADE) system. OUTCOMES: We found twelve eligible systematic reviews which included between three (143 women) and 27 randomized trials (2093 women). Four reviews assessed the effects of lifestyle interventions (diet, physical activity and/or behavioural interventions); four evaluated nutritional supplements (one each on n-acetylcysteine, omega-3 fatty acids, inositol and vitamin D); and four studied alternative medical therapies (Chinese herbal medicine and acupuncture). All of the included reviews were of high quality and scored between 8 and 11 with the AMSTAR tool (with a maximum score of 11).Randomized evidence is lacking for live birth rate. N-acetylcysteine, inositol and the addition of alternative medicine to ovulation induction agents show preliminary potential to improve fertility (odds ratios (OR) for clinical pregnancy rate range from 1.99 to 4.83). Lifestyle interventions show benefits in improving hirsutism (mean difference (MD): -1.01 to -1.19). Lifestyle interventions (MD: -1.10 to -2.02), inositol (MD: -2.1) and acupuncture (MD: -1.90 to -3.43) all show some evidence of improvement in glycaemic outcomes and there is some evidence of reduced BMI with lifestyle interventions (MD: -0.15 to -1.12). All of these outcomes scored either low or very low quality of evidence on the GRADE score. WIDER IMPLICATIONS: Lifestyle interventions in women with PCOS appear to improve glycaemic results, androgenic symptoms and anthropometric outcomes. The role of inositol and N-acetylcysteine in women with PCOS needs further evaluation. Large primary trials on all interventions are needed for an agreed set of core outcomes.

Pharmacological and surgical treatment of nonreproductive outcomes in polycystic ovary syndrome: An overview of systematic reviews.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects up to 13% women and is associated with significant complications. The quality of evidence supporting the recommendations on treatment of nonreproductive outcomes in PCOS is unknown. OBJECTIVE: To summarize and appraise the methodological quality of systematic reviews and meta-analyses evaluating pharmacological and surgical treatments for nonreproductive outcomes in PCOS. METHODS: A literature search from MEDLINE, EMBASE, CINAHL PLUS and PROSPERO was performed from inception until 15th of September 2017. Article selection, data extraction and quality appraisal of included reviews were performed in duplicate. A narrative synthesis of the findings was conducted. RESULTS: This overview included 31 reviews. The quality was low for 7 (23%), moderate for sixteen (52%) and high for 8 reviews (26%). Two reviews assessed psychological outcomes. Metformin improved anthropometric (7 of 10 reviews), metabolic (4 of 14 reviews) and endocrine outcomes (3 of twelve reviews). Thiazolidinediones improved metabolic (2 of 5 reviews) and endocrine outcomes (one of 5 reviews) but worsened weight gain (5 of 5 reviews). Combined oral contraceptive pill (COCP) improved clinical hyperandrogenism (2 of 2 reviews). Statins improved lipid profile (3 of 3 reviews) and testosterone level (2 of 3 reviews). There was no conclusive evidence from included systematic reviews regarding the use of other interventions. CONCLUSIONS: There is reliable evidence regarding the use of metformin for anthropometric outcomes and COCPs for hyperandrogenism in women with PCOS but not for other interventions. There is significant gap in knowledge regarding the management of psychological outcomes in women with PCOS which needs further evaluation.

Effect of male body mass index on assisted reproduction treatment outcome: an updated systematic review and meta-analysis.

Men with a body mass index (BMI) of 30 or over are more likely to have reduced fertility and fecundity rates. This systematic review and meta-analysis evaluated the effect of male BMI on IVF and intracytoplasmic sperm injection (ICSI) outcome. An electronic search for published literature was conducted in MEDLINE and EMBASE between 1966 and November 2016. Outcome measures were clinical pregnancy rates (CPR) and live birth rates (LBR) per IVF or ICSI cycle. Eleven studies were identified, including 14,372 cycles; nine reported CPR and seven reported LBR. Pooling of data from those studies revealed that raised male BMI was associated with a significant reduction in CPR (OR 0.78, 95% CI 0.63 to 0.98, P = 0.03) and LBR (OR 0.88, 95% CI 0.82 to 0.95, P = 0.001) per IVF-ICSI treatment cycle. Male BMI could be an important factor influencing IVF-ICSI outcome. More robust studies are needed to confirm this conclusion using standardized methods for measuring male BMI, adhering to the World Health Organization definitions of BMI categories, accounting for female BMI, IVF and ICSI cycle characteristics, including the number of embryos transferred and embryo quality, and use the live birth rate per cycle as primary outcome.

Routine serum thyroid-stimulating hormone testing-optimizing pre-conception health or generating toxic knowledge?

Monitoring subclinical hypothyroidism (SCH) in women is believed to be important in terms of preventing overt hypothyroidism and optimizing the health and cognitive development of their children. Current systematic reviews have suggested an association between maternal SCH and adverse obstetric and neonatal outcomes. However, initiating the administration of thyroxine during pregnancy has failed to demonstrate appreciable health benefits. Hence there are calls by professional endocrine societies for optimizing serum thyroid-stimulating hormone (TSH) levels pre-conception. The strategy of ensuring that serum TSH levels are below 2.5 mIU/l during the pre-conception period has generated considerable uncertainty partly because the recommended level of <2.5 mIU/l is lower than those previously used to define the condition and partly due to uncertainty about the best screening programme clinicians can use in this context. Recalibrating the expected normal peri-conceptional range of serum TSH (<2.5 mIU/l), will have a significant impact on clinical services due to an inevitable increase in numbers of women diagnosed with SCH who will need to be investigated, treated and monitored. Serum TSH fulfils the criteria for a screening test and oral thyroxine is an inexpensive drug. Therefore, there is no reason to believe that screening cannot be undertaken in all women planning to conceive. Yet this approach will miss women whose pregnancies are unplanned and generate anxiety, further tests and many more prescriptions for thyroxine, coupled with the need for lifelong monitoring in affected women. A number of existing and ongoing randomized trials have evaluated the use of thyroxine in women with infertility or miscarriage with detectable thyroid auto-antibodies. These are unlikely to answer the question whether routine pre-conception testing for SCH in asymptomatic women is beneficial. Routine screening of women at risk of pregnancy and optimization of their thyroid status could result in significant health benefits for their offspring. Alternatively this approach could prove to be an expensive way of generating toxic knowledge resulting in anxiety, increased drug use and potential harm. Only large, appropriately designed studies can reveal the answer.

Impact of the outcome of fresh blastocyst transfer on the subsequent frozen-thawed blastocyst transfer cycle.

The objective of this observational study was to assess the influence of the outcome of fresh blastocyst transfer on the success rate of the subsequent sibling frozen-thawed blastocyst transfer (FBT) cycle. In total, 1639 FBT cycles were divided into two groups: Group A (n = 698) cycles in which a positive pregnancy test result was achieved and Group B (n = 941) cycles in which no pregnancy was achieved in the preceding fresh IVF cycle. Mean age at cryopreservation, basal FSH level, number of oocytes retrieved, number of embryos transferred in the fresh cycle and survival rate of the thawed blastocysts in the FBT cycle were comparable between the two groups. Although significantly more thawed blastocysts were transferred in the FBT cycles in Group B compared with Group A, the live birth rate in Group A was significantly higher compared with Group B. After adjusting for potentially confounding variables, the likelihood of a live birth after FBT was significantly higher when a pregnancy was achieved in the preceding fresh IVF cycle. Achieving a pregnancy after fresh blastocyst transfer is an independent factor influencing the outcome of the subsequent sibling FBT.

Laparoscopic Excision Versus Ablation for Endometriosis-associated Pain: An Updated Systematic Review and Meta-analysis.

The aim of this study was to update the evidence on the surgical management of endometriosis-associated pain. Does laparoscopic excision offer any benefits over laparoscopic ablation? This is a systematic review and meta-analysis in which we searched MEDLINE, Embase, Institute for Scientific Information conference proceedings, the International Standard Randomised Controlled Trial Number registry, the Register and Meta-register for randomized controlled trials, the World Health Organization trials search portal, the Cochrane Library, and the British Library of electronic theses. Three randomized controlled trials were included, which enrolled 335 participants with a sample size per study ranging from 24 to 178 participants. Of these 3 studies, data from 2 could be pooled for meta-analysis. The primary outcome measure was the reduction in the visual analog scale score for dysmenorrhea. The secondary outcome measures included the reduction in the visual analog scale score for dyspareunia, dyschezia, and chronic pelvic pain and the reduction in Endometriosis Health Profile-30 core pain scores. The meta-analysis showed that the excision group had a significantly greater reduction in symptoms of dysmenorrhea (mean difference [MD] = 0.99; 95% confidence interval [CI], -0.02 to 2.00; p = .05) and dyschezia (MD = 1.31; 95% CI, 0.33-2.29; p = .009) compared with ablation. The symptoms of dyspareunia showed a nonsignificant benefit with excision (MD = 0.96; 95% CI, -0.07 to 1.99; p = .07). Data from 1 study showed a significant reduction in chronic pelvic pain (MD = 2.57; 95% CI, 1.27-3.87; p = .0001) and Endometriosis Health Profile-30 core pain scores (MD = 13.20; 95% CI, 3.70-22.70; p = .006) with the excision group compared with the ablation group. The limited available evidence shows that at 12 months postsurgery, symptoms of dysmenorrhea, dyschezia, and chronic pelvic pain secondary to endometriosis showed a significantly greater improvement with laparoscopic excision compared with ablation.

Efficacy and safety of transdermal testosterone in postmenopausal women with hypoactive sexual desire disorder: a systematic review and meta-analysis.

OBJECTIVE: To systematically review and summarize the existing evidence related to the efficacy and safety of transdermal T in postmenopausal women for the treatment of hypoactive sexual desire disorder (HSDD). DESIGN: Systematic reviews and meta-analysis. SETTING: Not applicable. PATIENT(S): Seven randomized controlled trials enrolled 3,035 participants; 1,350 women were randomized to treatment with T patch, and 1,379 women were randomized to placebo. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcome: satisfying sexual episodes. SECONDARY OUTCOMES: sexual activity, orgasm, Profile of Female Sexual Function domains (desire), personal distress score, adverse events, acne, increased hair growth, facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction, total adverse events, serious adverse events, withdrawal from study, and follow-up rate. RESULT(S): The T group had significantly more satisfying sexual episodes, sexual activity, orgasms, desire, significant change in Personal Distress Scale score, androgenic adverse events, acne, and hair growth compared with the placebo group. There was no significant difference between the two groups in increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study. CONCLUSION(S): The short-term efficacy in terms of improvement of sexual function and safety of transdermal T in naturally and surgically menopausal women affected by HSDD either on or not on estrogen progestin hormone therapy is evident from this systematic review. The use of transdermal T is associated with increase in androgenic adverse events such as acne but is not associated with any serious adverse events.

Outcome of preimplantation genetic diagnosis using FISH analysis for recurrent miscarriage in low-risk reciprocal translocation carriers.

OBJECTIVE: To assess PGD outcome using FISH analysis in couples with a history of recurrent miscarriage associated with a parental carrier of reciprocal translocation. STUDY DESIGN: Couples in whom one partner was a carrier of a reciprocal translocation and had a history of two or more miscarriages and a low risk of a live born offspring with an unbalanced chromosomal rearrangement, underwent PGD treatment between 2000 and 2012. RESULTS: 91 couples started 171 fresh and 11 frozen PGD cycles. Of the fresh cycles, 162 (95%) reached oocyte retrieval and 107 (63%) had embryo transfer. In 14 cycles (8%), surplus embryos were cryopreserved. Pregnancy was achieved in 52 fresh PGD cycles, leading to 20 miscarriages and 32 live births. Eleven frozen embryo transfer cycles resulted in two miscarriages and three live births. The overall live birth rate was 19% per fresh and frozen PGD cycle started (35/182) and miscarriage rate was 39% per pregnancy (22/57). The cumulative live birth rate was 32% per couple (29/91). CONCLUSION: After PGD for recurrent miscarriage in low-risk reciprocal translocation carriers, the miscarriage risk remains high and chance of live birth is low. For those translocation carriers, natural conception may be a better option.