The effectiveness of prolonged downregulation with gonadotrophin-releasing hormone analogue (GnRHa) treatment in women with adenomyosis undergoing IVF/ICSI: A systematic review and meta-analysis.

IMPORTANCE: Adenomyosis can reduce the chance of clinical pregnancy in women undergoing assisted conception. Treatment with prolonged gonadotrophin-releasing hormone analogue (GnRHa) downregulation prior to IVF/ICSI has been postulated to improve pregnancy outcomes. OBJECTIVE: We aimed to evaluate the effectiveness and safety of prolonged GnRHa treatment (minimum one month) versus no pre-treatment in women with adenomyosis undergoing IVF/ICSI using a systematic review and meta-analysis. DATA SOURCES: We searched electronic databases: Embase (OVID), MEDLINE® (OVID), APA PsycInfo (OVID), Maternity & Infant Care Database (MIDIRS (OVID), HMIC Health Management Information Consortium (OVID) and ClinicalTrials.gov from inception until 27th of March 2023. STUDY SELECTION AND SYNTHESIS: We included studies that reported on women with adenomyosis receiving GnRHa to down-regulate the hypothalamic-pituitary-ovarian axis for one to six months before IVF/ICSI. We pooled data using the Haensel-Mantel method and reported using Odds Ratio (OR) with 95 % confidence intervals (CI). We assessed the quality of included studies using the Newcastle-Ottowa Scale and confidence in evidence using the GRADE criteria. Bias analysis was conducted via the Cochrane recommended tool (RevMan Web, Academic License). MAIN OUTCOMES AND RESULTS: We screened 365 citations and eight retrospective studies were included in the meta-analysis (n = 2422 women). The median age was 34 years [IQR 31.95-35.05], median BMI 21.30 kg/m2 [IQR 21.05-23.55] and median duration of GnRHa downregulation was 2.5 months [Range 1-4; IQR 1.37-3]. Women with adenomyosis receiving prolonged GnRHa treatment had a higher implantation rate 1/OR 1.69 [95 % CI 1.09, 2.56], I2 = 81 %, (P = 0.02) and clinical pregnancy rate 1/OR 1.42 [95 % CI 1.03, 2.0], I2 70 %, P = 0.03. There was no overall difference in live birth rate 1/OR 1.12 [95 % CI 0.70, 1.79], I2 = 78 %, p = 0.63), miscarriage rate 1/OR 0.92 [95 % CI 0.63, 1.28, P = 0.61, I2 0 % or mean number of oocytes retrieved (10 oocytes [IQR 8.95; 11.15] vs. 9.28 [IQR 8; 10.20], p = 0.22) between groups. CONCLUSIONS AND RELEVANCE: The benefit of prolonged GnRHa treatment in women with adenomyosis undergoing assisted conception treatment is uncertain based on existing retrospective studies. Implantation and clinical pregnancy rates were higher following prolonged downregulation in this population, though there was no statistically significant difference in live birth and miscarriage rates. Given the limited, low-quality existing data, there is a need for a well-designed, prospective randomised controlled trial to precisely evaluate the effectiveness of prolonged GnRHa treatment in this population.

Comparing the treatment of endometriosis-related pain by excision of endometriosis or hysterectomy: A multicentre prospective cohort study.

OBJECTIVE: To compare the effectiveness of endometriosis excision alone to excision plus hysterectomy, with and without bilateral oophorectomy, for endometriosis-related symptoms. DESIGN: Multicentre prospective cohort. SETTING: Eighty-six specialist endometriosis centres. POPULATION: Women undergoing rectovaginal endometriosis surgery between 2009 and 2021. METHODS: We performed multivariable regression with random effects for patient and centre, controlling for age, BMI, smoking, laparoscopic versus open approach and type of bowel surgery performed, with sensitivity analysis for loss to follow-up. MAIN OUTCOME MEASURES: Pain scores, bowel symptoms and quality-of-life measures. RESULTS: Compared to endometriosis excision alone, women undergoing hysterectomy with conservation of ovaries had greater improvement in non-cyclical pain (MD: 1.41/10, 95% CI: 1.03-1.78, p < 0.001), dyspareunia (MD: 1.12/10, 95% CI: 0.71-1.53, p < 0.001), back pain (MD: 1.29/10, 95% CI: 0.92-1.67, p < 0.001) and quality-of-life scores (MD: 8.77/100, 95% CI: 5.79-11.75, p < 0.001) at 24 months post-operatively. Women undergoing hysterectomy with bilateral oophorectomy also had greater improvement in non-cyclical pelvic pain (MD: 2.22/10, 95% CI: 1.80-2.63, p < 0.001), dyspareunia (MD: 1.05/10, 95% CI: 0.59-1.52, p < 0.001), back pain (MD: 1.18/10, 95% CI: 0.77-1.59, p < 0.001) and quality of life (MD: 12.41/100, 95% CI: 9.07-15.74, p < 0.001) at 24 months compared to endometriosis excision alone. Compared to hysterectomy with ovarian conservation, hysterectomy with bilateral oophorectomy was associated with greater improvement in non-cyclical pelvic pain (MD: 0.81/10, 95% CI: 0.32-1.30, p = 0.001) at 24 months and quality of life (MD: 3.74/100, 95% CI: 0.56-6.92, p = 0.021) at 12 months, although this result was sensitive to loss to follow-up. CONCLUSIONS: Patients who undergo endometriosis excision plus hysterectomy experience greater improvement in pain and quality of life compared to those who have endometriosis excision alone. There are additional benefits of bilateral oophorectomy with hysterectomy, although its value is less clear due to loss of follow-up.

Healthcare and research priorities for women with polycystic ovary syndrome in the UK National Health Service: A modified Delphi method.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is a chronic lifelong condition affecting up to 20% of women worldwide. There is limited input from affected women to guide the provision of healthcare services and future research needs. Our objective was to scope the healthcare and research priorities of women with PCOS in the United Kingdom. DESIGN: A three-staged modified Delphi method, consisting of two questionnaires and a consensus meeting involving lay representatives and healthcare professionals. PATIENTS AND MEASUREMENTS: Lay patient representatives of women with PCOS. Participants were asked to identify and rank healthcare and research priorities for their importance. RESULTS: Six hundred and twenty-four lay participants took part in our Delphi method. Over 98% were diagnosed with PCOS (614/624, 98.4%). More than half experienced difficulties to receive a PCOS diagnosis (375/624, 60%), and the majority found it difficult to access specialised PCOS health services in the NHS (594/624, 95%). The top two healthcare priorities included better education for health professionals on the diagnosis and management of PCOS (238/273, 87.1%) and the need to set up specialist PCOS services (234/273, 85.7%). The top two research priorities focused on identifying better treatments for irregular periods (233/273, 85.3%) followed by better tests for early PCOS diagnosis (230/273, 84.2%). CONCLUSIONS: We identified 13 healthcare and 14 research priorities that reflect the current health needs of women with PCOS in the United Kingdom. Adopting these priorities in future healthcare and research planning will help to optimise the health of women with PCOS and increase patient satisfaction.

Long term pregnancy outcomes of women with cancer following fertility preservation: A systematic review and meta-analysis.

OBJECTIVE: As cancer survivorship increases, there is higher uptake of fertility preservation treatments among affected women. However, there is limited evidence on the subsequent use of preserved material and pregnancy outcomes in women who underwent fertility preservation (FP) before cancer treatments. We aimed to systematically review the long-term reproductive and pregnancy outcomes in this cohort of women. PATIENTS: Women who underwent any type of the following FP treatments: embryo cryopreservation (EC), oocyte cryopreservation (OC) and ovarian tissue cryopreservation (OTC)) before any planned cancer treatment. EVIDENCE REVIEW: We searched electronic databases (MEDLINE, Embase, Cochrane CENTRAL, and HTA) from inception until May 2021 for all observational studies that met our inclusion criteria. We extracted data on reproductive and pregnancy outcomes in duplicate and assessed the risk of bias in included studies using the ROBINS-I tool. We pooled data using a random-effects model and reported using odds ratios (OR) with 95% confidence intervals (CI). MAIN OUTCOME MEASURES: Our primary outcome was live birth rate and other important reproductive and pregnancy outcomes. RESULTS: Of 5405 citations, we screened 103 and included 26 observational studies (n = 7061 women). Hematologic malignancy was the commonest cause for seeking FP treatments, followed by breast and gynecology cancers. Twelve studies reported on OTC (12/26, 46 %), eight included EC (8/26, 30 %), and twelve reported on OC (12/26, 46 %). The cumulative live birth rate following any FP treatment was 0.046 (95 %CI 0.029-0.066). Only 8 % of women returned to use their frozen reproductive material (558/7037, 8.0 %), resulting in 210 live births in total, including assisted conceptions following EC/OC/OTC and natural conceptions following OTC. The odds for live birth was OR 0.38 (95 %CI 0.29-0.48 I2 83.7 %). The odds for live birth was the highest among women who had EC (OR 0.45, 95 %CI 0.14-0.76, I2 95.1 %), followed by the OTC group (OR 0.37, 95 %CI 0.22-0.53, I2 88.7 %) and OC group (OR 0.31, 95 %CI 0.15-0.47, I2 78.2 %). CONCLUSIONS: Fertility preservation treatments offered good long-term reproductive outcomes for women with cancer with a high chance to achieve a live birth. Further research is needed to evaluate the long-term pregnancy and offspring outcomes in this cohort.

Bone and heart health in menopause.

Age at menopause has been shown to have an impact on bone and heart health, with younger menopause age consistently associated with a higher risk of cardiovascular disease, osteoporosis, and fracture. These risks are particularly high increased among women who encountering menopause at an early age, including women with premature ovarian insufficiency (POI) and early menopause, due to a prolonged period of oestrogen deprivation. Several interventions are suggested to optimise the bone and cardiovascular health of women with menopause including lifestyle modification, dietary supplements, hormonal, and non-hormonal therapies. Hormone therapy (HT) is indicated for women with POI. For women with early menopause, there is a paucity of evidence for the management of bone and cardiovascular health. For women beyond the average age of menopause, HT is not indicated solely for bone protection and cardiovascular health. In this group, screening for bone and heart disease, as well as primary and secondary prevention, should be undertaken in line with national and international guidelines.

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

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

Harmonizing research outcomes for polycystic ovary syndrome (HARP), a marathon not a sprint: current challenges and future research need.

Investing in clinical research and evidence-based medicine has helped to improve the care for women with polycystic ovary syndrome (PCOS). However, several important questions remain unanswered on the optimal prevention and management strategies for PCOS. Addressing this uncertainty is often hindered by suboptimal research conduct leading to inefficient evidence synthesis and research wastage. PCOS research is often practised by varied specialized teams in silo leading to disharmonious and fragmented efforts neglecting the lifelong impact of PCOS on women's wellbeing. Poor engagement among key stakeholders and lay consumers continues to limit the impact and benefits of research to society. Selective reporting on surrogate outcomes with a 'significant' P-value is a common malpractice in PCOS outputs. Effective adoption of the harmonizing research outcomes for PCOS (HARP) core outcome set is needed to minimize heterogeneity in reporting and promote research excellence. Small single-centre studies offer limited value to assess the varied PCOS phenotypes. Efficient large scale data-sharing is needed to address complex research questions and glean the benefits of big data research. We propose a roadmap to address these challenges and remedy future research need by promoting patient and public involvement in PCOS research to guide research efforts and address real patients' needs; engaging all key stakeholder groups to promote a multi-disciplinary lifelong approach to new research; continuously refining research needs and priorities to revise the knowledge gap and allocate resources judiciously; standardizing outcomes definitions and measurement tools to harmonize reporting and promote excellence in research; and by investing in large data-sharing infrastructure to facilitate big data research and govern ethical data sharing.

Quantifying CD138+ cells in the endometrium to assess chronic endometritis in women at risk of recurrent pregnancy loss: A prospective cohort study and rapid review.

OBJECTIVE: To determine the value of uterine CD138+ cells, as a marker of chronic endometritis, in predicting subsequent reproductive outcome in women with history of recurrent pregnancy loss. DESIGN: A prospective longitudinal study. SETTING: Tertiary specialized clinic. PATIENTS: Women with history of recurrent pregnancy loss or implantation failure over a 12-months follow-up period. INTERVENTION: We quantified the CD138+ cells/high powered field (hpf) using immunohistochemistry and image analysis of endometrial biopsies obtained during the secretory stage post ovulation. MAIN OUTCOME MEASURES: Live birth and subsequent pregnancy loss. We calculated the receiver operator curve for predicting subsequent pregnancy loss and reported using relative risk (RR) and 95% confidence intervals (CI). RESULTS: We enrolled 344 women of whom 88 became pregnant (88/344, 25.5%). Half of them had a subsequent live birth (47/88, 53%) and the rest lost their pregnancy (41/88, 46%). The median CD138+ score was significantly lower in the live birth group (P < 0.005) and women with a CD138+ score ≥ 16/hpf had a higher risk of subsequent miscarriage (RR 10.0, 95% CI 2.78-36.02). CD138+ cells count showed a good prediction for subsequent pregnancy loss in high-risk women with an area under the curve of 0.75 (95% CI 0.59-0.82, P = 0.01). A cut-off value of 4-6 cells/hpf offered the best predictive accuracy with higher scores predicting worse reproductive outcome. Our findings are limited by the small event rate and the sample size of our cohort. CONCLUSION: Quantifying CD138+ cells by immunohistochemistry in women with a history of recurrent pregnancy loss is helpful to diagnose chronic endometritis and predict subsequent reproductive outcome.

Diminished ovarian reserve in recurrent pregnancy loss: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the association between diminished ovarian reserve (DOR) in women at risk of recurrent pregnancy loss (RPL) using ovarian reserve tests. DESIGN: Systematic review and meta-analysis. SETTING: University medical schools. PATIENT(S): Women with a history of RPL. INTERVENTION(S): Systematic reviews of major electronic databases (MEDLINE, EMBASE, Web of Science, and Scopus) for studies that evaluated the incidence of DOR in women with RPL. MAIN OUTCOME MEASURE(S): Association between RPL and DOR. RESULT(S): In studies up to May 2019 we assessed quality using the Newcastle-Ottawa Scale and meta-analyzed data using a random-effect model. We included 15 studies (n = 3,082 women) reporting on six ovarian reserve tests: antimüllerian hormone [AMH], antral follicle count, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and FSH:LH ratio. More women with RPL seemed to have DOR compared with women who did not have RPL as measured by low AMH levels (odds ratio [OR] 2.77; 95% confidence interval [CI], 1.41-5.46) and AFC (OR 2.45; 95% CI, 1.16-5.19). Women with unexplained RPL also seemed to have a higher association with DOR compared with women whose RPL had a known etiology, as measured by low AMH levels (OR 3.23; 95% CI, 1.81-5.76). No statistically significant differences were found in the levels of any of the remaining ovarian reserve tests between those groups of women. CONCLUSION(S): There is an apparent association between DOR and RPL. Low AMH and AFC levels could predict higher odds for pregnancy loss, but more studies are needed to evaluate their prognostic value in the management of women with RPL. SYSTEMATIC REVIEW REGISTRATION NUMBER: Prospero CRD42018114673.

Harmonising research outcomes for polycystic ovary syndrome: an international multi-stakeholder core outcome set.

STUDY QUESTION: What are the key core outcomes to be reported in studies on polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: We identified 3 generic and 30 specific core outcomes in 6 specialist domains: metabolic (8), reproductive (7), pregnancy (10), oncological (1), psychological (1) and long-term outcomes (1). WHAT IS KNOWN ALREADY: Research reporting PCOS is heterogeneous with high variation in outcome selection, definition and quality. STUDY DESIGN, SIZE, DURATION: Evidence synthesis and a modified Delphi method with e-surveys were used as well as a consultation meeting. PARTICIPANTS/MATERIALS, SETTING, METHODS: Overall, 71 health professionals and 123 lay consumers (women with lived experience of PCOS and members of advocacy and peer support groups) from 17 high-, middle- and low-income countries were involved in this analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The final core outcome set included 3 generic outcomes (BMI, quality of life, treatment satisfaction) that are applicable to all studies on women with PCOS and 30 specific outcomes that were categorised into six specialist domains: 8 metabolic outcomes (waist circumference, type 2 diabetes, insulin resistance, impaired glucose tolerance, hypertension, coronary heart disease, lipid profile, venous thromboembolic disease); 7 reproductive outcomes [viable pregnancy (confirmed by ultrasound including singleton, twins and higher multiples), clinical and biochemical hyperandrogenism, menstrual regularity, reproductive hormonal profile, chronic anovulation, ovulation stimulation success including the number of stimulated follicles ≥ 12 mm, incidence and severity of ovarian hyperstimulation syndrome]; 10 pregnancy outcomes (live birth, miscarriage, stillbirth, neonatal mortality, gestational weight gain, gestational diabetes, preterm birth, hypertensive disease in pregnancy, baby birth weight, major congenital abnormalities); 3 psychological outcomes (depression, anxiety, eating disorders); 1 oncological (abnormal endometrial proliferation including atypical endometrial hyperplasia and endometrial cancer); and 1 outcome in the long-term domain (long-term offspring metabolic and developmental outcomes). LIMITATIONS, REASONS FOR CAUTION: We involved lay consumers in all stages of study through e-surveys but not through focus groups, thereby limiting our understanding of their choices. We did not address the variations in the definitions and measurement tools for some of the core outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Implementing this core outcome set in future studies on women with PCOS will improve the quality of reporting and aid evidence synthesis. STUDY FUNDING/COMPETING INTEREST(S): Evidence synthesis was funded through the Australian government, National Health and Medical Research Council (NHMRC) Centre for Research Excellence in PCOS, and H.T. is funded through an NHMRC fellowship. B.H.A. is funded through an NIHR lectureship. All authors have no competing interest to declare.

Placenta chorioangioma: a rare case and systematic review of literature.

OBJECTIVES: Placental chorioangioma is a relatively rare condition that often results in serious prenatal complications and adverse pregnancy outcome. We report a case of a large chorioangioma that was prenatally diagnosed at 23 weeks with polyhydramnios and fetal anemia. With prenatal monitoring, transplacental therapy with a COX-2 inhibitor and intrauterine transfusion, the pregnancy resulted in the live birth at 30 weeks. Due to the paucity of evidence relating to the management protocols in cases of placental chorioangiomas, we have conducted a systematic review of the literature. METHODS: All reported cases in the English language were captured using the electronic databases. Bibliographies of relevant articles were manually searched. RESULTS: Sixty-four articles were included reporting 112 cases of placental chorioangioma. In 79, there was no prenatal treatment and in 33 there was in-utero treatment. A systematic comparison of antenatal complications and pregnancy outcomes was performed. No strong conclusion could be made due to the low number and quality of the reported cases. CONCLUSION: Placenta chorioangioma represents a challenge with its potentially serious complications adversely affecting pregnancy outcome. An international registry of pregnancies with this rare complication and documentation of pregnancy outcomes will improve the evidence base for prospective management.