Endocrine and metabolic interactions in healthy pregnancies and hyperinsulinemic pregnancies affected by polycystic ovary syndrome, diabetes and obesity

During pregnancy, the fetoplacental unit is key in the pronounced physiological endocrine changes which support pregnancy, fetal development and survival, birth and lactation. In healthy women, pregnancy is characterized by changes in insulin sensitivity and increased maternal androgen levels. These are accompanied by a suite of mechanisms that support fetal growth, maintain glucose homeostasis and protect both mother and fetus from adverse effects of pregnancy induced insulin and androgen excess. In pregnancies affected by endocrine, metabolic disorders such as polycystic ovary syndrome (PCOS), diabetes and obesity, there is an imbalance of beneficial and adverse impacts of pregnancy induced endocrine changes. These inter-related conditions are characterized by an interplay of hyperinsulinemia and hyperandrogenism which influence fetoplacental function and are associated with adverse pregnancy outcomes including hypertensive disorders of pregnancy, macrosomia, preterm delivery and caesarean section. However, the exact underlying mechanisms and relationships of the endocrine and metabolic milieu in these disorders and the impact they have on the prenatal endocrine environment and developing fetus remain poorly understood. Here we aim to review the complex endocrine and metabolic interactions in healthy women during normal pregnancies and those in pregnancies complicated by hyperinsulinemic disorders (PCOS, diabetes and obesity). We also explore the relationships between these endocrine and metabolic differences and the fetoplacental unit, pregnancy outcomes and the developing fetus

Continuous quality improvement and metabolic screening during pregnancy at primary health centres attended by Aboriginal and Torres Strait Islander women

Objective: To investigate associations between the provision of routine metabolic screening and follow-up in pregnancy and participation by primary health care centres in a large-scale continuous quality improvement (CQI) initiative.Design: Longitudinal analysis of 2592 audited maternal health records.Setting and participants: Seventy-six community-controlled or government-operated primary health care centres serving predominantly Aboriginal and Torres Strait Islander communities, in urban, regional or remote locations in five Australian states and territories.Intervention: Up to four CQI cycles supported by the Audit and Best Practice for Chronic Disease Research Partnership.Main outcomes measures:Screening and follow-up for body mass index (BMI), blood pressure and diabetes in pregnancy.Results: Overall, 87.9% of women attending the participating health centres were Aboriginal or Torres Strait Islander. Women attending a health centre after it had conducted one or more CQI cycles were more likely to receive BMI, blood pressure and diabetes screening. For example, the proportion of women receiving diabetes screening at baseline (before the first CQI cycle) was 56.1%; after cycle 1 it was 63.7% (odds ratio [OR], 1.3; 95% CI, 1.0–1.6), after cycle 2, 61.6% (OR, 1.2; 95% CI, 0.9–1.7), after cycle 3, 63.7% (OR, 1.7; 95% CI, 1.1–2.6), and after cycle 4, 75.5% (OR, 3.4; 95% CI, 1.9–5.9). Diabetes screening was associated with higher self-ratings of overall organisational systems (P = 0.03), self-management support (P = 0.04) and organisational influence and integration (P = 0.01).Conclusion: These findings support the value of CQI approaches that focus on systems-level issues in primary care to improve the provision of recommended pregnancy care at primary health care centres in predominantly Aboriginal and Torres Strait Islander communities

Vaccine intention and hesitancy among Australian women who are currently pregnant or have recently given birth : the Birth in the Time of COVID-19 (BITTOC) national online survey

Objective To examine the prevalence of COVID-19 vaccination, and factors associated with vaccination intention and hesitancy in pregnant and postnatal women in Australia. Design and setting A national online survey was conducted over 6 months between 31 August 2021 and 1 March 2022 and responses to vaccination status were categorised as: 'vaccinated', 'vaccine intended' and 'vaccine hesitant'. The data were weighted to reflect the proportion of women of reproductive age. Potential confounding variables were examined using multinomial logistic regression analyses, and all comparisons were made against vaccinated pregnant and postnatal women. Participants 2140 women responded to the survey (838 pregnant; 1302 recently post partum). Results Amongst pregnant women, 586 (69.9%) were vaccinated, 166 (19.8%) indicated intention and 86 (10.3%) were hesitant. In postnatal women, this was 1060 (81.4%), 143 (11.0%) and 99 (7.6%), respectively. Only 52 (6.2%) of pregnant women stated never wanting a COVID-19 vaccine. Vaccine hesitancy increased over time, and for pregnant women was associated with: living in a state other than New South Wales (NSW) (Adjusted Relative Risk (ARR) 2.77, 95%CI: 1.68-4.56 for vaccine intention and ARR=3.31, 95%CI: 1.52-7.20 for vaccine hesitancy), younger age <30 years, not having a university education, income <80K AUD, gestation <28 weeks, having no pregnancy risk factors, and being less satisfied with life (ARR=2.20, 95%CI: 1.04-4.65 for vaccine intention and ARR=2.53, 95%CI: 1.02-6.25 for vaccine hesitancy). For postnatal women: living in a state other than NSW or Victoria, income <80K AUD and having private obstetric care (ARR=2.06, 95%CI: 1.23-3.46) were significantly associated with vaccine hesitancy. Conclusions Around 1 in 10 pregnant women and just over 1 in 13 postnatal women reported vaccine hesitancy in this Australian survey, and hesitancy was higher in the latter 3-month period. Tailored messages to younger mothers and those from lower-middle socioeconomic groups, alongside advice from midwives and obstetricians, could help to reduce hesitancy among pregnant and postnatal women. Financial incentives may help to facilitate COVID-19 vaccine uptake. A real-time surveillance system and additional pregnancy fields added to the Australian immunisation register would support the safety monitoring of multiple vaccines in pregnancy and may build confidence

Experiences of organizational practices that advance women in health care leadership

Importance: Women are underrepresented in health care leadership positions. Organizational practices and culture play a key role in mitigating this disparity. Objective: To explore the experiences of women in leadership roles and inform how health care organizations can support the advancement of women into leadership. Design, Setting, and Participants: This qualitative study used a constructivist grounded theory approach applied over a 1-year period (May 1, 2021, to May 31, 2022) in a large private health care network in Australia. Women were eligible if they had been in leadership positions for more than 5 years. Purposive and theoretical sampling guided recruitment of 28 women, representing medical, nursing, and allied health specialties. Interviews lasted 1 hour, producing 500 pages of transcripts for analysis. Main Outcomes and Measures The primary outcome was a model of organizational practices and conditions that advance women in health care leadership, extrapolated from the collective experiences of women in leadership. Key elements pertained to organizational patterns of interaction and group norms and behaviors that contributed toward women’s experiences of career advancement. Results: Overall, 28 women (23 [82%] White; 3 [11%] Southeast Asian) participated in the study, 10 (36%) of whom were in nursing, 9 (32%) of whom were in allied health, and 9 (32%) of whom were in medical disciplines. Organizational practices that advance women in health care leadership were highly dependent on conducive organizational culture enhancing women’s credibility and capability as leaders. Four interrelated elements were identified that create the necessary conditions for an organizational culture to advance women in health care leadership, including (1) identifying and actively addressing systemic barriers, (2) challenging gendered assumptions and expectations of leadership behaviors, (3) providing mentorship to shape career opportunities, and (4) determining how these conditions all contribute toward raising women’s credibility to enable internalizing a leadership identity. For women, advancing to leadership involved organizations moving away from ad hoc, inconsistent applications of gender equity practices and generating supportive practices that reinforced a workforce culture of credibility, collaboration, and continuous improvement to support women. Conclusions and Relevance: In light of persisting inequity in health care leadership, women’s experiences were captured in this qualitative study to identify organizational practices that support their advancement. Insights into factors that influence efficacy of these practices, including building a supportive culture and mentoring, are discussed. This research informs a National Health and Medical Research Council initiative with international collaborators to support organizations in advancing women in health care leadership

Abdominal obesity and other risk factors largely explain the high CRP in Indigenous Australians relative to the general population, but not gender differences: a cross-sectional study

Background: Previous studies reported high C-reactive protein (CRP) levels in Indigenous Australians, which may contribute to their high risk of cardiovascular disease. We compared CRP levels in Indigenous Australians and the general population, accounting for obesity and other risk factors.Methods: Cross-sectional study of CRP and risk factors (weight, height, waist and hip circumferences, blood pressure, lipids, blood glucose, and smoking status) in population-based samples from the Diabetes and Related conditions in Urban Indigenous people in the Darwin region (DRUID) study, and the Australian Diabetes, Obesity and Lifestyle study (AusDiab) follow-up.Results: CRP concentrations were higher in women than men and in DRUID than AusDiab. After multivariate adjustment, including waist circumference, the odds of high CRP (&gt;3.0 mg/L) in DRUID relative to AusDiab were no longer statistically significant, but elevated CRP was still more likely in women than men. After adjusting for BMI (instead of waist circumference) the odds for elevated CRP in DRUID participants were still higher relative to AusDiab participants among women, but not men. Lower HDL cholesterol, impaired glucose tolerance (IGT), and higher diastolic blood pressure were associated with having a high CRP in both men and women, while current smoking was associated with high CRP in men but not women.Conclusions: High concentrations of CRP in Indigenous participants were largely explained by other risk factors, in particular abdominal obesity. Irrespective of its independence as a risk factor, or its aetiological association with coronary heart disease (CHD), the high CRP levels in urban Indigenous women are likely to reflect increased vascular and metabolic risk. The significance of elevated CRP in Indigenous Australians should be investigated in future longitudinal studies

Perinatal depression in Australian women during the COVID-19 pandemic : the birth in the time of COVID-19 (BITTOC) study

The COVID-19 pandemic has impacted perinatal mental health globally. We determined the maternal factors and pandemic-related experiences associated with clinically significant perinatal (pregnant and post-partum) depressive symptoms in Australian women. Participants (n = 2638; pregnant n = 1219, postnatal n = 1419) completed an online survey (August 2020 through February 2021) and self-reported on depression, social support, and COVID-19 related experiences. We found elevated depressive symptoms amongst 26.5% (pregnant) and 19% (postnatal) women. Multiple logistic regression analyses showed higher likelihood of elevated depression associated with residence in Victoria, lower education, past/current mental health problems, greater non-pandemic prenatal stress, age ≥ 35 years (pregnant women) and existing physical health issues or disability in self or others (postnatal women). Greater family stress/discord and lower social support (friends) was associated with higher odds of elevated perinatal depression, while lower social support (family) was significantly associated with elevated depressive symptoms in pregnant women. Greater depression was associated with social distancing, pandemic-related news exposure and changes to prenatal care (pregnant women). Single postnatal women showed lower odds of elevated depression than partnered women. Our findings underscore the importance of universal screening for depression and targeted support during a pandemic for perinatal women displaying vulnerability factors

Development, validation and clinical utility of a risk prediction model for adverse pregnancy outcomes in women with gestational diabetes:The PeRSonal GDM model

BACKGROUND: The ability to calculate the absolute risk of adverse pregnancy outcomes for an individual woman with gestational diabetes mellitus (GDM) would allow preventative and therapeutic interventions to be delivered to women at high-risk, sparing women at low-risk from unnecessary care. We aimed to develop, validate and evaluate the clinical utility of a prediction model for adverse pregnancy outcomes in women with GDM. METHODS: A prediction model development and validation study was conducted on data from a observational cohort. Participants included all women with GDM from three metropolitan tertiary teaching hospitals in Melbourne, Australia. The development cohort comprised those who delivered between 1 July 2017 to 30 June 2018 and the validation cohort those who delivered between 1 July 2018 to 31 December 2018. The main outcome was a composite of critically important maternal and perinatal complications (hypertensive disorders of pregnancy, large-for-gestational age neonate, neonatal hypoglycaemia requiring intravenous therapy, shoulder dystocia, perinatal death, neonatal bone fracture and nerve palsy). Model performance was measured in terms of discrimination and calibration and clinical utility evaluated using decision curve analysis. FINDINGS: The final PeRSonal (Prediction for Risk Stratified care for women with GDM) model included body mass index, maternal age, fasting and 1-hour glucose values (75-g oral glucose tolerance test), gestational age at GDM diagnosis, Southern and Central Asian ethnicity, East Asian ethnicity, nulliparity, past delivery of an large-for-gestational age neonate, past pre-eclampsia, GWG until GDM diagnosis, and family history of diabetes. The composite adverse pregnancy outcome occurred in 27% (476/1747) of women in the development (1747 women) and in 26% (244/955) in the validation (955 women) cohorts. The model showed excellent calibration with slope of 0.99 (95% CI 0.75 to 1.23) and acceptable discrimination (c-statistic 0.68; 95% CI 0.64 to 0.72) when temporally validated. Decision curve analysis demonstrated that the model was useful across a range of predicted probability thresholds between 0.15 and 0.85 for adverse pregnancy outcomes compared to the alternatives of managing all women with GDM as if they will or will not have an adverse pregnancy outcome. INTERPRETATION: The PeRSonal GDM model comprising of routinely available clinical data shows compelling performance, is transportable across time, and has clinical utility across a range of predicted probabilities. Further external validation of the model to a more disparate population is now needed to assess the generalisability to different centres, community based care and low resource settings, other healthcare systems and to different GDM diagnostic criteria. FUNDING: This work is supported by the Mothers and Gestational Diabetes in Australia 2 NHMRC funded project #1170847

STAT5 activation promotes progression and chemotherapy-resistance in early T-cell precursor acute lymphoblastic leukemia

IL-7 supports the growth and chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL), particularly the early T-cell precursor subtype (ETP-ALL), which frequently has activating mutations of IL-7 signaling. STAT5 is an attractive therapeutic target because it is almost universally activated in ETP-ALL, even in the absence of mutations of upstream activators such as the IL-7R, JAK and FLT3. To examine the role of activated STAT5 in ETP-ALL, we have used a Lmo2-transgenic (Lmo2Tg) mouse model in which we can monitor chemoresistant pre-leukemia (pre-LSCs) and leukemia stem cells (LSCs) that drive T-ALL development and relapse following chemotherapy. Using IL-7R-deficient Lmo2Tg mice, we show that IL-7 signaling was not required for the formation of pre-LSCs but essential for their expansion and clonal evolution into LSCs to generate T-ALL. Activated STAT5B was sufficient for the development of T-ALL in IL-7R; Lmo2Tg mice, indicating that inhibition of STAT5 is required to block the supportive signals provided by IL-7. To further understand the role of activated STAT5 in LSCs of ETP-ALL, we developed a new transgenic mouse that enables T-cell specific and doxycycline-inducible expression of the constitutively activated STAT5B1∗6 mutant. Expression of STAT5B1∗6 in T-cells had no effect alone but promoted expansion and chemoresistance of LSCs in Lmo2Tg mice. Pharmacologic inhibition of STAT5 with Pimozide induced differentiation and loss of LSCs, whilst enhancing response to chemotherapy. Furthermore, Pimozide significantly reduced leukemia burden in vivo and overcame chemoresistance of patient-derived ETP-ALL xenografts. Overall, our results demonstrate that STAT5 is an attractive therapeutic target for eradicating LSCs in ETP-ALL

Systematic review and meta-analysis : the prevalence of mental illness in child and adolescent refugees and asylum seekers

Objective Over half of the world’s refugee population are under the age of 18 years. This systematic review aims to summarise the current body of evidence for the prevalence of mental illness in child and adolescent refugee populations. Method Eight electronic databases, grey literature, and Google Scholar were searched for articles from 1 January 2003 to 5 February 2018. Strict inclusion criteria regarding the diagnosis of mental illness were imposed. Study quality was assessed using a template according to study design, and study heterogeneity using I2 statistic. Random effects meta-analyses results were presented given heterogeneity among studies. The protocol for this systematic review was registered with PROSPERO (CRD42016046349). Results Eight studies were eligible, involving 779 child and adolescent refugees and asylum seekers, with studies conducted in five countries. The overall prevalence of post-traumatic stress disorder (PTSD) was 22.71% (95% CI 12.79-32.64), depression 13.81% (95% CI 5.96-21.67), and anxiety disorders 15.77% (95% CI 8.04-23.50). Attention-deficit/hyperactivity disorder (ADHD) was 8.6% (1.08-16.12) and oppositional defiant disorder (ODD) was 1.69% (95% CI -0.78 – 4.16). Due to high heterogeneity, further subgroup analyses were conducted. Conclusion Refugee and asylum seeker children have high rates of PTSD, depression, and anxiety. Without the serious commitment by health and resettlement services to provide early support to promote mental health, these findings suggest a high proportion of refugee children are at risk of educational disadvantage and poor social integration in host communities, potentially affecting their life course

Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome

STUDY QUESTION: What is the recommended assessment and management of those with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? SUMMARY ANSWER: International evidence-based guidelines address prioritized questions and outcomes and include 254 recommendations and practice points, to promote consistent, evidence-based care and improve the experience and health outcomes in PCOS. WHAT IS KNOWN ALREADY: The 2018 International PCOS Guideline was independently evaluated as high quality and integrated multidisciplinary and consumer perspectives from six continents; it is now used in 196 countries and is widely cited. It was based on best available, but generally very low to low quality, evidence. It applied robust methodological processes and addressed shared priorities. The guideline transitioned from consensus based to evidence-based diagnostic criteria and enhanced accuracy of diagnosis, whilst promoting consistency of care. However, diagnosis is still delayed, the needs of those with PCOS are not being adequately met, evidence quality was low and evidence-practice gaps persist. STUDY DESIGN, SIZE, DURATION: The 2023 International Evidence-based Guideline update reengaged the 2018 network across professional societies and consumer organizations, with multidisciplinary experts and women with PCOS directly involved at all stages. Extensive evidence synthesis was completed. Appraisal of Guidelines for Research and Evaluation-II (AGREEII)-compliant processes were followed. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength and diversity and inclusion were considered throughout. PARTICIPANTS/MATERIALS, SETTING, METHODS: This summary should be read in conjunction with the full Guideline for detailed participants and methods. Governance included a six-continent international advisory and management committee, five guideline development groups, and paediatric, consumer, and translation committees. Extensive consumer engagement and guideline experts informed the update scope and priorities. Engaged international society-nominated panels included paediatrics, endocrinology, gynaecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, obesity care, public health and other experts, alongside consumers, project management, evidence synthesis, statisticians and translation experts. Thirty-nine professional and consumer organizations covering 71 countries engaged in the process. Twenty meetings and five face-to-face forums over 12 months addressed 58 prioritized clinical questions involving 52 systematic and 3 narrative reviews. Evidence-based recommendations were developed and approved via consensus across five guideline panels, modified based on international feedback and peer review, independently reviewed for methodological rigour, and approved by the Australian Government National Health and Medical Research Council (NHMRC). MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS has generally improved in the past five years, but remains of low to moderate quality. The technical evidence report and analyses (∼6000 pages) underpins 77 evidence-based and 54 consensus recommendations, with 123 practice points. Key updates include: i) further refinement of individual diagnostic criteria, a simplified diagnostic algorithm and inclusion of anti-Müllerian hormone (AMH) levels as an alternative to ultrasound in adults only; ii) strengthening recognition of broader features of PCOS including metabolic risk factors, cardiovascular disease, sleep apnea, very high prevalence of psychological features, and high risk status for adverse outcomes during pregnancy; iii) emphasizing the poorly recognized, diverse burden of disease and the need for greater healthcare professional education, evidence-based patient information, improved models of care and shared decision making to improve patient experience, alongside greater research; iv) maintained emphasis on healthy lifestyle, emotional wellbeing and quality of life, with awareness and consideration of weight stigma; and v) emphasizing evidence-based medical therapy and cheaper and safer fertility management. LIMITATIONS, REASONS FOR CAUTION: Overall, recommendations are strengthened and evidence is improved, but remains generally low to moderate quality. Significantly greater research is now needed in this neglected, yet common condition. Regional health system variation was considered and acknowledged, with a further process for guideline and translation resource adaptation provided. WIDER IMPLICATIONS OF THE FINDINGS: The 2023 International Guideline for the Assessment and Management of PCOS provides clinicians and patients with clear advice on best practice, based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the Guideline with an integrated evaluation program. STUDY FUNDING/COMPETING INTEREST(S): This effort was primarily funded by the Australian Government via the National Health Medical Research Council (NHMRC) (APP1171592), supported by a partnership with American Society for Reproductive Medicine, Endocrine Society, European Society for Human Reproduction and Embryology, and European Society for Endocrinology. The Commonwealth Government of Australia also supported Guideline translation through the Medical Research Future Fund (MRFCRI000266). HJT and AM are funded by NHMRC fellowships. JT is funded by a Royal Australasian College of Physicians (RACP) fellowship. Guideline development group members were volunteers. Travel expenses were covered by the partnering organizations. Disclosures of interest were strictly managed according to NHMRC policy and are available with the full guideline, technical evidence report, peer review and responses (www.monash.edu/medicine/mchri/pcos). Of named authors HJT, CTT, AD, LM, LR, JBoyle, AM have no conflicts of interest to declare. JL declares grant from Ferring and Merck; consulting fees from Ferring and Titus Health Care; speaker's fees from Ferring; unpaid consultancy for Ferring, Roche Diagnostics and Ansh Labs; and sits on advisory boards for Ferring, Roche Diagnostics, Ansh Labs, and Gedeon Richter. TP declares a grant from Roche; consulting fees from Gedeon Richter and Organon; speaker's fees from Gedeon Richter and Exeltis; travel support from Gedeon Richter and Exeltis; unpaid consultancy for Roche Diagnostics; and sits on advisory boards for Roche Diagnostics. MC declares travels support from Merck; and sits on an advisory board for Merck. JBoivin declares grants from Merck Serono Ltd.; consulting fees from Ferring B.V; speaker's fees from Ferring Arzneimittell GmbH; travel support from Organon; and sits on an advisory board for the Office of Health Economics. RJN has received speaker's fees from Merck and sits on an advisory board for Ferring. AJoham has received speaker's fees from Novo Nordisk and Boehringer Ingelheim. The guideline was peer reviewed by special interest groups across our 39 partner and collaborating organizations, was independently methodologically assessed against AGREEII criteria and was approved by all members of the guideline development groups and by the NHMRC.</p