Autoimmune diseases and adverse pregnancy outcomes: an umbrella review.

BACKGROUND: The prevalence of autoimmune conditions is two-fold higher in women than in men, especially during the reproductive years. Autoimmune conditions have been associated with a greater risk of adverse pregnancy outcomes, and some conditions have been studied more than others with inconsistent findings. The objective of this umbrella review was to identify, appraise, synthesise, and consolidate findings from published systematic reviews of autoimmune conditions and adverse pregnancy outcomes. METHODS: In this umbrella review, we searched Medline, Embase, and Cochrane databases for systematic reviews from inception to Sept 30, 2022, without language restrictions. We used the Medical Subject Headings and free text search for autoimmune conditions and pregnancy outcomes. Screening, data extraction, and quality appraisal (AMSTAR 2) were done by two independent reviewers. Data was extracted using a standardised form, which was piloted before use. Data were synthesised narratively and quantitatively. Odds ratios (ORs) with 95% CIs were reported. The protocol has been registered to PROSPERO (CRD42022334992). FINDINGS: We selected 33 reviews, which included 709 primary studies. Pregnant women with autoimmune conditions were at high risk of both adverse maternal and fetal outcomes. The risk of miscarriage was increased in pregnant women with Sjögren's syndrome (relative risk [RR] 8·85, 95% CI 3·10-25·26), systemic lupus erythematosus (SLE; OR 4·90, 95% CI 3·10-7·69), thyroid autoimmunity (OR 2·77, 2·10-3·65), systemic sclerosis (OR 1·60, 1·29-2·22), and coeliac disease (OR 1·38, 1·12-1·69). The risk of pre-eclampsia was increased in pregnant women with type 1 diabetes (T1DM; OR 4·19, 3·08-5·71) and SLE (OR 3·20, 2·54 - 4·20). The risk of gestational diabetes was increased in pregnant women with inflammatory bowel disease (IBD; OR 2·96, 1·47-5·98) and thyroid autoimmunity (OR 1·49, 1·07-2·07). The risk of intrauterine growth restriction (IUGR) was increased in pregnant women with systemic sclerosis (OR 3·20, 2·21-4·53) and coeliac disease (OR 1·71, 1·36-2·14). The risk of delivering a small-for-gestational age baby was increased in pregnant women with SLE (OR 2·49, 1·88-3·31) and rheumatoid arthritis (OR 1·49, 1·22-1·82). The risks of other fetal outcomes such as stillbirth, preterm birth, and low birthweight were also increased in pregnant women with autoimmune disorders. T1DM in women was associated with lower odds of small-for-gestational-age outcome (OR 0·68, 0·56-0·83). INTERPRETATION: Pregnant women with autoimmune conditions are at greater risk of developing adverse pregnancy outcomes. Further research is required to develop better preconception to post-natal care for women with autoimmune conditions. FUNDING: Medical Research Council (MRC) and the National Institute for Health and Care Research (NIHR).

Autoimmune diseases and adverse pregnancy outcomes: an umbrella review.

BACKGROUND: There is a high prevalence of autoimmune conditions in women specially in the reproductive years; thus, the association with adverse pregnancy outcomes has been widely studied. However, few autoimmune conditions/adverse outcomes have been studied more than others, and this umbrella review aims to consolidate existing knowledge in this area with the aim to provide new knowledge and also identify gaps in this research area. METHODS: Medline, Embase, and Cochrane databases were searched from inception to December 2023. Screening, data extraction, and quality appraisal (AMSTAR 2) were done by two independent reviewers. Data were synthesised narratively and quantitatively. Relative risks (RR)/odds ratio (OR) with 95% confidence intervals were reported. RESULTS: Thirty-two reviews were included consisting of 709 primary studies. The review reported the association between 12 autoimmune conditions and 16 adverse pregnancy outcomes. Higher risk of miscarriage is reported in women with Sjögren's syndrome RR 8.85 (95% CI 3.10-25.26) and systemic lupus erythematosus (SLE) OR 4.90 (3.10-7.69). Pre-eclampsia was reported higher in women with type 1 diabetes mellitus (T1DM) OR 4.19 (3.08-5.71) and SLE OR 3.20 (2.54-4.20). Women reported higher risk of diabetes during pregnancy with inflammatory bowel disease (IBD) OR 2.96 (1.47-5.98). There was an increased risk of intrauterine growth restriction in women with systemic sclerosis OR 3.20 (2.21-4.53) and coeliac disease OR 1.71 (1.36-2.14). Preterm birth was associated with T1DM OR 4.36 (3.72-5.12) and SLE OR 2.79 (2.07-3.77). Low birth weight babies were reported in women with women with SLE or systemic sclerosis OR 5.95 (4.54-7.80) and OR 3.80 (2.16-6.56), respectively. There was a higher risk of stillbirth in women with T1DM OR 3.97 (3.44-4.58), IBD OR 1.57 (1.03-2.38), and coeliac disease OR 1.57 (1.17-2.10). T1DM in women was associated with 32% lower odds of small for gestational age baby OR 0.68 (0.56-0.83). CONCLUSIONS: Pregnant women with autoimmune conditions are at a greater risk of developing adverse pregnancy outcomes. Further research is required to develop better preconception to postnatal care for women with autoimmune conditions.

Plasma metabolomic and lipidomic profiles accurately classify mothers of children with congenital heart disease: an observational study.

INTRODUCTION: Congenital heart disease (CHD) is the most common congenital anomaly, representing a significant global disease burden. Limitations exist in our understanding of aetiology, diagnostic methodology and screening, with metabolomics offering promise in addressing these. OBJECTIVE: To evaluate maternal metabolomics and lipidomics in prediction and risk factor identification for childhood CHD. METHODS: We performed an observational study in mothers of children with CHD following pregnancy, using untargeted plasma metabolomics and lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). 190 cases (157 mothers of children with structural CHD (sCHD); 33 mothers of children with genetic CHD (gCHD)) from the children OMACp cohort and 162 controls from the ALSPAC cohort were analysed. CHD diagnoses were stratified by severity and clinical classifications. Univariate, exploratory and supervised chemometric methods were used to identify metabolites and lipids distinguishing cases and controls, alongside predictive modelling. RESULTS: 499 metabolites and lipids were annotated and used to build PLS-DA and SO-CovSel-LDA predictive models to accurately distinguish sCHD and control groups. The best performing model had an sCHD test set mean accuracy of 94.74% (sCHD test group sensitivity 93.33%; specificity 96.00%) utilising only 11 analytes. Similar test performances were seen for gCHD. Across best performing models, 37 analytes contributed to performance including amino acids, lipids, and nucleotides. CONCLUSIONS: Here, maternal metabolomic and lipidomic analysis has facilitated the development of sensitive risk prediction models classifying mothers of children with CHD. Metabolites and lipids identified offer promise for maternal risk factor profiling, and understanding of CHD pathogenesis in the future.

Predictive and protective factors for failing first pass intubation in prehospital rapid sequence intubation: an aetiology and risk systematic review with meta-analysis.

BACKGROUND: Prehospital rapid sequence intubation first pass success rates vary between 59% and 98%. Patient morbidity is associated with repeat intubation attempts. Understanding what influences first pass success can guide improvements in practice. We performed an aetiology and risk systematic review to answer the research question 'what factors are associated with success or failure at first attempt laryngoscopy in prehospital rapid sequence intubation?'. METHODS: MEDLINE, EMBASE, CINAHL, and Cochrane Library were searched on March 3, 2023 for studies examining first pass success rates for rapid sequence intubation of prehospital live patients. Screening was performed via Covidence, and data synthesised by meta-analysis. The review was registered with PROSPERO and performed and reported as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Reasonable evidence was discovered for predictive and protective factors for failure of first pass intubation. Predictive factors included age younger than 1 yr, the presence of blood or fluid in the airway, restricted jaw or neck movement, trauma patients, nighttime procedures, chronic or acute distortions of normal face/upper airway anatomy, and equipment issues. Protective factors included an experienced intubator, adequate training, use of certain videolaryngoscopes, elevating the patient on a stretcher in an inclined position, use of a bougie, and laryngeal manoeuvres. CONCLUSIONS: Managing bloody airways, positioning well, using videolaryngoscopes with bougies, and appropriate training should be further explored as opportunities for prehospital services to increase first pass success. Heterogeneity of studies limits stronger conclusions. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42022353609).

Characteristics and Outcomes of Patients Referred to a General Practitioner by Victorian Paramedics.

OBJECTIVE: Many patients who are attended by paramedics do not require conveyance to an emergency department (ED). Our study focuses on comparing the characteristics and outcomes of patients who were advised to follow up with a general practitioner (GP) by an attending paramedic with those of patients who were discharged at scene or transported to hospital. METHODS: This was a retrospective data linkage cohort study of ambulance, ED, hospital admission, and death records for all adults attended by paramedics in Victoria, Australia between the 1st of January 2015 and 30th of June 2019. Patients were excluded if they presented in cardiac arrest, resided in a residential aged care facility, or were receiving palliative care services. Outcomes of interest included reattendance by ambulance, ED presentation; and, a high acuity outcome which we defined as a patient who (1) presented to ED and received an Australasian Triage Scale of category 1 (Resuscitation) or 2 (Emergency) AND was admitted to a ward OR (2) was admitted to an Intensive Care Unit, Coronary Care Unit or Catheter laboratory (regardless of triage category) OR (3) died. Outcomes of interest were considered within 48-h of initial EMS attendance. RESULTS: A total of 1,777,950 cases were included in the study of which 3.1% were referred to a GP, 9.0% were discharged at scene without a follow-up recommendation, and 87.9% were transported to hospital. Patients referred to a GP were more likely than those discharged at scene to subsequently present to an ED within 48 h of their attendance (5.3% vs 3.8%). However, GP referral was not associated with any change to high acuity outcome (0.3% vs 0.2%) or ambulance reattendance (6.0% vs 6.0%) compared to discharge at scene. The only factors that were associated with ambulance reattendance, ED presentation, and a high acuity outcome were male gender and elevated temperature. CONCLUSIONS: Despite increasing low and medium-acuity casework in this EMS system, paramedic referral to a GP is not common practice. Referring a patient to a GP did not reduce the likelihood of patients experiencing a high acuity outcome or recalling an ambulance within 48 h, suggesting opportunity exists to refine paramedic to GP referral practices.

Preconception health and care policies, strategies and guidelines in the UK and Ireland: a scoping review.

BACKGROUND: Preconception health has the potential to improve parental, pregnancy and infant outcomes. This scoping review aims to (1) provide an overview of the strategies, policies, guidelines, frameworks, and recommendations available in the UK and Ireland that address preconception health and care, identifying common approaches and health-influencing factors that are targeted; and (2) conduct an audit to explore the awareness and use of resources found in the scoping review amongst healthcare professionals, to validate and contextualise findings relevant to Northern Ireland. METHODS: Grey literature resources were identified through Google Advanced Search, NICE, OpenAire, ProQuest and relevant public health and government websites. Resources were included if published, reviewed, or updated between January 2011 and May 2022. Data were extracted into Excel and coded using NVivo. The review design included the involvement of the "Healthy Reproductive Years" Patient and Public Involvement and Engagement advisory panel. RESULTS: The searches identified 273 resources, and a subsequent audit with healthcare professionals in Northern Ireland revealed five additional preconception health-related resources. A wide range of resource types were identified, and preconception health was often not the only focus of the resources reviewed. Resources proposed approaches to improve preconception health and care, such as the need for improved awareness and access to care, preconceptual counselling, multidisciplinary collaborations, and the adoption of a life-course approach. Many behavioural (e.g., folic acid intake, smoking), biomedical (e.g., mental and physical health conditions), and environmental and social (e.g., deprivation) factors were identified and addressed in the resources reviewed. In particular, pre-existing physical health conditions were frequently mentioned, with fewer resources addressing psychological factors and mental health. Overall, there was a greater focus on women's, rather than men's, behaviours. CONCLUSIONS: This scoping review synthesised existing resources available in the UK and Ireland to identify a wide range of common approaches and factors that influence preconception health and care. Efforts are needed to implement the identified resources (e.g., strategies, guidelines) to support people of childbearing age to access preconception care and optimise their preconception health.

Parental hesitancy toward children vaccination: a multi-country psychometric and predictive study.

AIM: Understanding vaccine hesitancy, as a critical concern for public health, cannot occur without the use of validated measures applicable and relevant to the samples they are assessing. The current study aimed to validate the Vaccine Hesitancy Scale (VHS) and to investigate the predictors of children's vaccine hesitancy among parents from Australia, China, Iran, and Turkey. To ensure the high quality of the present observational study the STROBE checklist was utilized. DESIGN: A cross-sectional study. METHOD: In total, 6,073 parent participants completed the web-based survey between 8 August 2021 and 1 October 2021. The content and construct validity of the Vaccine Hesitancy Scale was assessed. Cronbach's alpha and McDonald's omega were used to assess the scale's internal consistency, composite reliability (C.R.) and maximal reliability (MaxR) were used to assess the construct reliability. Multiple linear regression was used to predict parental vaccine hesitancy from gender, social media activity, and perceived financial well-being. RESULTS: The results found that the VHS had a two-factor structure (i.e., lack of confidence and risk) and a total of 9 items. The measure showed metric invariance across four very different countries/cultures, showed evidence of good reliability, and showed evidence of validity. As expected, analyses indicated that parental vaccine hesitancy was higher in people who identify as female, more affluent, and more active on social media. CONCLUSIONS: The present research marks one of the first studies to evaluate vaccine hesitancy in multiple countries that demonstrated VHS validity and reliability. Findings from this study have implications for future research examining vaccine hesitancy and vaccine-preventable diseases and community health nurses.

Is qualitative social research in global health fulfilling its potential?: a systematic evidence mapping of research on point-of-care testing in low- and middle-income contexts.

BACKGROUND: Qualitative social research has made valuable contributions to understanding technology-based interventions in global health. However, we have little evidence of who is carrying out this research, where, how, for what purpose, or the overall scope of this body of work. To address these questions, we undertook a systematic evidence mapping of one area of technology-focused research in global health, related to the development, deployment and use of point-of-care tests (POCTs) for low-and middle-income countries (LMICs). METHODS: We conducted an exhaustive search to identify papers reporting on primary qualitative studies that explore the development, deployment, and use of POCTs in LMICs and screened results to identify studies meeting the inclusion criteria. Data were extracted from included studies and descriptive analyses were conducted. RESULTS: One hundred thirty-eight studies met our inclusion criteria, with numbers increasing year by year. Funding of studies was primarily credited to high income country (HIC)-based institutions (95%) and 64% of first authors were affiliated with HIC-based institutions. Study sites, in contrast, were concentrated in a small number of LMICs. Relatively few studies examined social phenomena related to POCTs that take place in HICs. Seventy-one percent of papers reported on studies conducted within the context of a trial or intervention. Eighty percent reported on studies considering POCTs for HIV and/or malaria. Studies overwhelmingly reported on POCT use (91%) within primary-level health facilities (60%) or in hospitals (30%) and explored the perspectives of the health workforce (70%). CONCLUSIONS: A reflexive approach to the role, status, and contribution of qualitative and social science research is crucial to identifying the contributions it can make to the production of global health knowledge and understanding the roles technology can play in achieving global health goals. The body of qualitative social research on POCTs for LMICs is highly concentrated in scope, overwhelmingly focuses on testing in the context of a narrow number of donor-supported initiatives and is driven by HIC resources and expertise. To optimise the full potential of qualitative social research requires the promotion of open and just research ecosystems that broaden the scope of inquiry beyond established public health paradigms and build social science capacity in LMICs.

Risk factors associated with severe COVID-19 outcomes in Jamaica: a cross-sectional study of national surveillance data.

Objectives: To describe the characteristics and outcomes of COVID-19 cases in Jamaica and to explore the risk factors associated with severe COVID-19 from 9 March to 31 December 2020. Methods: A cross-sectional analysis of national surveillance data was conducted using confirmed COVID-19 cases in Jamaica. Definitions of a confirmed case, disease severity, and death were based on World Health Organization guidelines. Chi-square and Fisher exact tests were used to determine association with outcomes. Logistic regression models were used to determine predictors of severe COVID-19. Results: This analysis included 12 169 cases of COVID-19 (median age, 36 years; 6 744 females [ 55.4%]) of which 512 cases (4.2%) presented with severe disease, and of those, 318 patients (62.1%) died (median age at death, 71.5 years). Severe disease was associated with being male (OR 1.4; 95% CI, 1.2-1.7) and 40 years or older (OR, 6.5; 95% CI, 5.1-8.2). COVID-19 death was also associated with being male (OR, 1.4; 95% CI, 1.1-1.7), age 40 years or older (OR, 17.9; 95% CI, 11.6-27.7), and in the Western versus South East Health Region (OR 1.7; 95% CI, 1.2-2.3). Conclusions: The findings of this cross-sectional analysis indicate that confirmed cases of COVID-19 in Jamaica were more likely to be female and younger individuals, whereas COVID-19 deaths occurred more frequently in males and older individuals. There is increased risk of poor COVID-19 outcomes beginning at age 40, with males disproportionately affected. COVID-19 death also varied by geographic region. This evidence could be useful to other countries with similar settings and to policymakers charged with managing outbreaks and health.

A pandemic of metrics.

The COVID-19 pandemic prompted critical attention to the performative power of metrics. We suggest that the existential capacities of metrics as a means of pandemic living warrant further consideration. We describe how the COVID-19 pandemic that came into existence as a public health and political event could only have occurred because of the anticipatory metrical practices that were used to transform SARS-COV-2 into a matter of global health concern. By exploring the affective potencies of COVID-19 metrics we show their abilities to engage the public in ways that cannot be contained; in detailing the narrative arcs created through metrics we show their opportunities, misdirections, and erasures. A pandemic way of life persists: a pandemic of metrics.

Developing a consensus-based definition of out-of-hospital clinical deterioration: A Delphi study.

BACKGROUND: Clinical deterioration is a time-critical medical emergency requiring rapid recognition and intervention. Deteriorating patients are seen across various healthcare settings, including the out-of-hospital (OOH) environment. OOH care is an evolving area of medicine where decisions are made regarding priority and timing of clinical interventions, ongoing management, and transport to appropriate care. To date, the literature lacks a standardised definition of OOH clinical deterioration. OBJECTIVE: The objective of this study was to create a consensus-based definition of OOH clinical deterioration informed by emergency medicine health professionals. METHODS: A Delphi study consisting three rounds was conducted electronically between June 2020 and January 2021. The expert panel consisted of 30 clinicians, including emergency physicians and paramedics. RESULTS: A consensus-based definition of OOH clinical deterioration was identified as changes from a patient's baseline physiological status resulting in their condition worsening. These changes primarily take the form of measurable vital signs and assessable symptoms but should be evaluated in conjunction with the history of events and pertinent risk factors. Clinicians should be suspicious that a patient could deteriorate when changes occur in one or more of the following vital signs: respiratory rate, heart rate, blood pressure, Glasgow Coma Scale, oxygen saturation, electrocardiogram, and skin colour. Almost all participants (92%) indicated an early warning system would be helpful to assist timely recognition of deteriorating patients. CONCLUSION: The creation of a consensus-based definition of OOH clinical deterioration can serve as a starting point for the development and validation of OOH-specific early warning systems. Moreover, a standardised definition allows meaningful comparisons to be made across health services and ensures consistency in future research. This study has shown recognition of OOH clinical deterioration to be a complex issue requiring further research. Improving our understanding of key factors contributing to deterioration can assist timely recognition and intervention, potentially reducing unnecessary morbidity and mortality.

Maternal multimorbidity and preterm birth in Scotland: an observational record-linkage study.

BACKGROUND: Multimorbidity is common in women across the life course. Preterm birth is the single biggest cause of neonatal mortality and morbidity. We aim to estimate the prevalence of multimorbidity in pregnant women and to examine the association between maternal multimorbidity and PTB. METHODS: This is a retrospective cohort study using electronic health records from the Scottish Morbidity Records. All pregnancies among women aged 15 to 49 with a conception date between 1 January 2014 and 31 December 2018 were included. Multimorbidity was defined as the presence of two or more pre-existing long-term physical or mental health conditions, and complex multimorbidity as the presence of four or more. It was calculated at the time of conception using a predefined list of 79 conditions published by the MuM-PreDiCT consortium. PTB was defined as babies born alive between 24 and less than 37 completed weeks of gestation. We used Generalised Estimating Equations adjusted for maternal age, socioeconomic status, number of previous pregnancies, BMI, and smoking history to estimate the effect of maternal pre-existing multimorbidity. Absolut rates are reported in the results and tables, whilst Odds Ratios (ORs) are adjusted (aOR). RESULTS: Thirty thousand five hundred fifty-seven singleton births from 27,711 pregnant women were included in the analysis. The prevalence of pre-existing multimorbidity and complex multimorbidity was 16.8% (95% CI: 16.4-17.2) and 3.6% (95% CI: 3.3-3.8), respectively. The prevalence of multimorbidity in the youngest age group was 10.2%(95% CI: 8.8-11.6), while in those 40 to 44, it was 21.4% (95% CI: 18.4-24.4), and in the 45 to 49 age group, it was 20% (95% CI: 8.9-31.1). In women without multimorbidity, the prevalence of PTB was 6.7%; it was 11.6% in women with multimorbidity and 15.6% in women with complex multimorbidity. After adjusting for maternal age, socioeconomic status, number of previous pregnancies, Body Mass Index (BMI), and smoking, multimorbidity was associated with higher odds of PTB (aOR = 1.64, 95% CI: 1.48-1.82). CONCLUSIONS: Multimorbidity at the time of conception was present in one in six women and was associated with an increased risk of preterm birth. Multimorbidity presents a significant health burden to women and their offspring. Routine and comprehensive evaluation of women with multimorbidity before and during pregnancy is urgently needed.

Polypharmacy during pregnancy and associated risk factors: a retrospective analysis of 577 medication exposures among 1.5 million pregnancies in the UK, 2000-2019.

BACKGROUND: The number of medications prescribed during pregnancy has increased over the past few decades. Few studies have described the prevalence of multiple medication use among pregnant women. This study aims to describe the overall prevalence over the last two decades among all pregnant women and those with multimorbidity and to identify risk factors for polypharmacy in pregnancy. METHODS: A retrospective cohort study was conducted between 2000 and 2019 using the Clinical Practice Research Datalink (CPRD) pregnancy register. Prescription records for 577 medication categories were obtained. Prevalence estimates for polypharmacy (ranging from 2+ to 11+ medications) were presented along with the medications commonly prescribed individually and in pairs during the first trimester and the entire pregnancy period. Logistic regression models were performed to identify risk factors for polypharmacy. RESULTS: During the first trimester (812,354 pregnancies), the prevalence of polypharmacy ranged from 24.6% (2+ medications) to 0.1% (11+ medications). During the entire pregnancy period (774,247 pregnancies), the prevalence ranged from 58.7 to 1.4%. Broad-spectrum penicillin (6.6%), compound analgesics (4.5%) and treatment of candidiasis (4.3%) were commonly prescribed. Pairs of medication prescribed to manage different long-term conditions commonly included selective beta 2 agonists or selective serotonin re-uptake inhibitors (SSRIs). Risk factors for being prescribed 2+ medications during the first trimester of pregnancy include being overweight or obese [aOR: 1.16 (1.14-1.18) and 1.55 (1.53-1.57)], belonging to an ethnic minority group [aOR: 2.40 (2.33-2.47), 1.71 (1.65-1.76), 1.41 (1.35-1.47) and 1.39 (1.30-1.49) among women from South Asian, Black, other and mixed ethnicities compared to white women] and smoking or previously smoking [aOR: 1.19 (1.18-1.20) and 1.05 (1.03-1.06)]. Higher and lower age, higher gravidity, increasing number of comorbidities and increasing level of deprivation were also associated with increased odds of polypharmacy. CONCLUSIONS: The prevalence of polypharmacy during pregnancy has increased over the past two decades and is particularly high in younger and older women; women with high BMI, smokers and ex-smokers; and women with multimorbidity, higher gravidity and higher levels of deprivation. Well-conducted pharmaco-epidemiological research is needed to understand the effects of multiple medication use on the developing foetus.

The development of a core outcome set for studies of pregnant women with multimorbidity.

BACKGROUND: Heterogeneity in reported outcomes can limit the synthesis of research evidence. A core outcome set informs what outcomes are important and should be measured as a minimum in all future studies. We report the development of a core outcome set applicable to observational and interventional studies of pregnant women with multimorbidity. METHODS: We developed the core outcome set in four stages: (i) a systematic literature search, (ii) three focus groups with UK stakeholders, (iii) two rounds of Delphi surveys with international stakeholders and (iv) two international virtual consensus meetings. Stakeholders included women with multimorbidity and experience of pregnancy in the last 5 years, or are planning a pregnancy, their partners, health or social care professionals and researchers. Study adverts were shared through stakeholder charities and organisations. RESULTS: Twenty-six studies were included in the systematic literature search (2017 to 2021) reporting 185 outcomes. Thematic analysis of the focus groups added a further 28 outcomes. Two hundred and nine stakeholders completed the first Delphi survey. One hundred and sixteen stakeholders completed the second Delphi survey where 45 outcomes reached Consensus In (≥70% of all participants rating an outcome as Critically Important). Thirteen stakeholders reviewed 15 Borderline outcomes in the first consensus meeting and included seven additional outcomes. Seventeen stakeholders reviewed these 52 outcomes in a second consensus meeting, the threshold was ≥80% of all participants voting for inclusion. The final core outcome set included 11 outcomes. The five maternal outcomes were as follows: maternal death, severe maternal morbidity, change in existing long-term conditions (physical and mental), quality and experience of care and development of new mental health conditions. The six child outcomes were as follows: survival of baby, gestational age at birth, neurodevelopmental conditions/impairment, quality of life, birth weight and separation of baby from mother for health care needs. CONCLUSIONS: Multimorbidity in pregnancy is a new and complex clinical research area. Following a rigorous process, this complexity was meaningfully reduced to a core outcome set that balances the views of a diverse stakeholder group.

Impact of Fkbp5 × early life adversity × sex in humanised mice on multidimensional stress responses and circadian rhythmicity.

The cumulative load of genetic predisposition, early life adversity (ELA) and lifestyle shapes the prevalence of psychiatric disorders. Single nucleotide polymorphisms (SNPs) in the human FKBP5 gene were shown to modulate disease risk. To enable investigation of disease-related SNPs in behaviourally relevant context, we generated humanised mouse lines carrying either the risk (AT) or the resiliency (CG) allele of the rs1360780 locus and exposed litters of these mice to maternal separation. Behavioural and physiological aspects of their adult stress responsiveness displayed interactions of genotype, early life condition, and sex. In humanised females carrying the CG- but not the AT-allele, ELA led to altered HPA axis functioning, exploratory behaviour, and sociability. These changes correlated with differential expression of genes in the hypothalamus, where synaptic transmission, metabolism, and circadian entrainment pathways were deregulated. Our data suggest an integrative role of FKBP5 in shaping the sex-specific outcome of ELA in adulthood.

The needs and opportunities for housing improvement for malaria control in southern Tanzania.

BACKGROUND: Malaria disproportionately affects low-income households in rural communities where poor housing is common. Despite evidence that well-constructed and mosquito-proofed houses can reduce malaria risk, housing improvement is rarely included in malaria control toolboxes. This study assessed the need, magnitude, and opportunities for housing improvement to control malaria in rural Tanzania. METHODS: A mixed-methods study was conducted in 19 villages across four district councils in southern Tanzania. A structured survey was administered to 1292 community members to assess need, perceptions, and opportunities for housing improvement for malaria control. Direct observations of 802 houses and surrounding environments were done to identify the actual needs and opportunities, and to validate the survey findings. A market survey was done to assess availability and cost of resources and services necessary for mosquito-proofing homes. Focus group discussions were conducted with key stakeholders to explore insights on the potential and challenges of housing improvement as a malaria intervention. RESULTS: Compared to other methods for malaria control, housing improvement was among the best understood and most preferred by community members. Of the 735 survey respondents who needed housing improvements, a majority needed window screening (91.1%), repairs of holes in walls (79.4%), door covers (41.6%), closing of eave spaces (31.2%) and better roofs (19.0%). Community members invested significant efforts to improve their own homes against malaria and other dangers, but these efforts were often slow and delayed due to high costs and limited household incomes. Study participants suggested several mechanisms of support to improve their homes, including government loans and subsidies. CONCLUSION: Addressing the need for housing improvement is a critical component of malaria control efforts in southern Tanzania. In this study, a majority of the community members surveyed needed modest modifications and had plans to work on those modifications. Without additional support, their efforts were however generally slow; households would take years to sufficiently mosquito-proof their houses. It is, therefore, crucial to bring together the key players across sectors to reduce barriers in malaria-proofing housing in endemic settings. These may include government subsidies or partnerships with businesses to make housing improvement more accessible and affordable to residents.

Associations of prenatal exposure to non-steroidal anti-inflammatory drugs with preterm birth and small for gestational age infants among women with autoimmune disorders.

PURPOSE: Estimate associations between prenatal non-steroidal anti-inflammatory (NSAID) exposure and preterm birth and small for gestational age among women with autoimmune conditions. METHODS: Participants were enrolled in the MotherToBaby cohort and had an autoimmune disorder and singleton live birth >20 weeks gestation (n = 2007). We characterized self-reported NSAID exposure over gestation for timing, duration, and average daily dose. Outcomes were preterm birth (i.e., <37 weeks' gestation) and small for gestational age infants (SGA; <10th percentile birthweight). We used Poisson regression to estimate associations between NSAID exposure and study outcomes adjusting for demographics, co-use of other medications (Model 1), and disease severity at baseline (Model 2). Secondarily, we considered the role of acetaminophen use by individually matching NSAID users to controls on cumulative dose of acetaminophen exposure. RESULTS: Overall, 15% of women reported NSAID use in pregnancy, with most use in the first trimester. No NSAID use exposure variables were associated with risk of preterm birth. Any NSAID use was associated with 1.7 (95% CI 1.2, 2.5) times greater risk of SGA and this estimate was attenuated to 1.5 (95% CI 1.0, 2.3) after adjustment for baseline disease severity. NSAID exposure in the first trimester was most strongly associated with SGA. After matching on acetaminophen exposure, associations between any NSAID use and preterm birth and SGA were 0.9 (95% CI 0.6, 1.4) and 1.8 (95% CI 1.1, 2.9). CONCLUSIONS: NSAID use in pregnancy is associated with SGA but not preterm birth. Future research should explore mechanisms that may explain these findings. Future research must also consider alternative explanations for these associations.

Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis.

Proapoptotic BCL-2 proteins converge upon the outer mitochondrial membrane (OMM) to promote mitochondrial outer membrane permeabilization (MOMP) and apoptosis. Here we investigated the mechanistic relationship between mitochondrial shape and MOMP and provide evidence that BAX requires a distinct mitochondrial size to induce MOMP. We utilized the terminal unfolded protein response pathway to systematically define proapoptotic BCL-2 protein composition after stress and then directly interrogated their requirement for a productive mitochondrial size. Complementary biochemical, cellular, in vivo, and ex vivo studies reveal that Mfn1, a GTPase involved in mitochondrial fusion, establishes a mitochondrial size that is permissive for proapoptotic BCL-2 family function. Cells with hyperfragmented mitochondria, along with size-restricted OMM model systems, fail to support BAX-dependent membrane association and permeabilization due to an inability to stabilize BAXα9·membrane interactions. This work identifies a mechanistic contribution of mitochondrial size in dictating BAX activation, MOMP, and apoptosis.

Maternal metabolomic profiling and congenital heart disease risk in offspring: A systematic review of observational studies.

Aetiological understanding and screening methods for congenital heart disease (CHD) are limited. Maternal metabolomic assessment offers the potential to identify risk factors and biomarkers. We performed a systematic review (PROSPERO CRD42022308452) investigating the association between fetal/childhood CHD and endogenous maternal metabolites. Ovid-MEDLINE, Ovid-EMBASE and Cochrane Library were searched between inception and 06/09/2022. Case control studies included analysing maternal blood or urine metabolites in pregnancy or postpartum where there was foetal/childhood CHD. Risk of bias assessment utilised the Scottish Intercollegiate Guidelines Network methodology checklist and narrative synthesis was performed. A total of 134 records were screened with eight eligible studies (n = 3242 pregnancies, n = 842 CHD-affected offspring). Five studies performed metabolomic analysis in pregnancy. Metabolites distinguishing case and control groups spanned lipid, glucose and amino-acid pathways, with the development of sensitive risk prediction models. No single metabolite consistently distinguished cases and controls across studies. Three studies performed targeted analysis postnatally with altered lipid and amino acid metabolites and raised homocysteine and markers of oxidative stress identified in cases. Included studies reported small sample sizes, analysing different biosamples at variable time points using differing techniques. At present, there is not enough evidence to confidently associate maternal metabolomic profiles with offspring CHD risk. However, several identified pathways warrant further investigation.

Key outcomes for reporting in studies of pregnant women with multiple long-term conditions: a qualitative study.

BACKGROUND: Maternal multiple long-term conditions are associated with adverse outcomes for mother and child. We conducted a qualitative study to inform a core outcome set for studies of pregnant women with multiple long-term conditions. METHODS: Women with two or more pre-existing long-term physical or mental health conditions, who had been pregnant in the last five years or planning a pregnancy, their partners and health care professionals were eligible. Recruitment was through social media, patients and health care professionals' organisations and personal contacts. Participants who contacted the study team were purposively sampled for maximum variation. Three virtual focus groups were conducted from December 2021 to March 2022 in the United Kingdom: (i) health care professionals (n = 8), (ii) women with multiple long-term conditions (n = 6), and (iii) women with multiple long-term conditions (n = 6) and partners (n = 2). There was representation from women with 20 different physical health conditions and four mental health conditions; health care professionals from obstetrics, obstetric/maternal medicine, midwifery, neonatology, perinatal psychiatry, and general practice. Participants were asked what outcomes should be reported in all studies of pregnant women with multiple long-term conditions. Inductive thematic analysis was conducted. Outcomes identified in the focus groups were mapped to those identified in a systematic literature search in the core outcome set development. RESULTS: The focus groups identified 63 outcomes, including maternal (n = 43), children's (n = 16) and health care utilisation (n = 4) outcomes. Twenty-eight outcomes were new when mapped to the systematic literature search. Outcomes considered important were generally similar across stakeholder groups. Women emphasised outcomes related to care processes, such as information sharing when transitioning between health care teams and stages of pregnancy (continuity of care). Both women and partners wanted to be involved in care decisions and to feel informed of the risks to the pregnancy and baby. Health care professionals additionally prioritised non-clinical outcomes, including quality of life and financial implications for the women; and longer-term outcomes, such as children's developmental outcomes. CONCLUSIONS: The findings will inform the design of a core outcome set. Participants' experiences provided useful insights of how maternity care for pregnant women with multiple long-term conditions can be improved.