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).

Association between pregnancy-related complications and development of type 2 diabetes and hypertension in women: an umbrella review.

BACKGROUND: Despite many systematic reviews and meta-analyses examining the associations of pregnancy complications with risk of type 2 diabetes mellitus (T2DM) and hypertension, previous umbrella reviews have only examined a single pregnancy complication. Here we have synthesised evidence from systematic reviews and meta-analyses on the associations of a wide range of pregnancy-related complications with risk of developing T2DM and hypertension. METHODS: Medline, Embase and Cochrane Database of Systematic Reviews were searched from inception until 26 September 2022 for systematic reviews and meta-analysis examining the association between pregnancy complications and risk of T2DM and hypertension. Screening of articles, data extraction and quality appraisal (AMSTAR2) were conducted independently by two reviewers using Covidence software. Data were extracted for studies that examined the risk of T2DM and hypertension in pregnant women with the pregnancy complication compared to pregnant women without the pregnancy complication. Summary estimates of each review were presented using tables, forest plots and narrative synthesis and reported following Preferred Reporting Items for Overviews of Reviews (PRIOR) guidelines. RESULTS: Ten systematic reviews were included. Two pregnancy complications were identified. Gestational diabetes mellitus (GDM): One review showed GDM was associated with a 10-fold higher risk of T2DM at least 1 year after pregnancy (relative risk (RR) 9.51 (95% confidence interval (CI) 7.14 to 12.67) and although the association differed by ethnicity (white: RR 16.28 (95% CI 15.01 to 17.66), non-white: RR 10.38 (95% CI 4.61 to 23.39), mixed: RR 8.31 (95% CI 5.44 to 12.69)), the between subgroups difference were not statistically significant at 5% significance level. Another review showed GDM was associated with higher mean blood pressure at least 3 months postpartum (mean difference in systolic blood pressure: 2.57 (95% CI 1.74 to 3.40) mmHg and mean difference in diastolic blood pressure: 1.89 (95% CI 1.32 to 2.46) mmHg). Hypertensive disorders of pregnancy (HDP): Three reviews showed women with a history of HDP were 3 to 6 times more likely to develop hypertension at least 6 weeks after pregnancy compared to women without HDP (meta-analysis with largest number of studies: odds ratio (OR) 4.33 (3.51 to 5.33)) and one review reported a higher rate of T2DM after HDP (hazard ratio (HR) 2.24 (1.95 to 2.58)) at least a year after pregnancy. One of the three reviews and five other reviews reported women with a history of preeclampsia were 3 to 7 times more likely to develop hypertension at least 6 weeks postpartum (meta-analysis with the largest number of studies: OR 3.90 (3.16 to 4.82) with one of these reviews reporting the association was greatest in women from Asia (Asia: OR 7.54 (95% CI 2.49 to 22.81), Europe: OR 2.19 (95% CI 0.30 to 16.02), North and South America: OR 3.32 (95% CI 1.26 to 8.74)). CONCLUSIONS: GDM and HDP are associated with a greater risk of developing T2DM and hypertension. Common confounders adjusted for across the included studies in the reviews were maternal age, body mass index (BMI), socioeconomic status, smoking status, pre-pregnancy and current BMI, parity, family history of T2DM or cardiovascular disease, ethnicity, and time of delivery. Further research is needed to evaluate the value of embedding these pregnancy complications as part of assessment for future risk of T2DM and chronic hypertension.

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.

Prodromal symptoms of rheumatoid arthritis in a primary care database: variation by ethnicity and socioeconomic status.

OBJECTIVES: To assess whether prodromal symptoms of rheumatoid arthritis (RA), as recorded in the Clinical Practice Research Datalink Aurum (CPRD) database of English primary care records, differ by ethnicity and socioeconomic status. METHODS: A cross-sectional study to determine the coding of common symptoms (≥0.1% in the sample) in the 24 months preceding RA diagnosis in CPRD Aurum, recorded between January 1st 2004 to May 1st 2022. Eligible cases were adults with a code for RA diagnosis. For each symptom, a logistic regression was performed with the symptom as dependent variable, and ethnicity and socioeconomic status as independent variables. Results were adjusted for sex, age, BMI, and smoking status. White ethnicity and the highest socioeconomic quintile were comparators. RESULTS: In total, 70115 cases were eligible for inclusion, of which 66.4% female. Twenty-one symptoms were coded in > 0.1% of cases so were included in the analysis. Patients of South Asian ethnicity had higher frequency of codes for several symptoms, with the largest difference by odds ratio being muscle cramps (OR 1.71, 1.44-2.57) and shoulder pain (1.44, 1.25-1.66). Patients of Black ethnicity had higher prevalence of several codes including unintended weight loss (2.02, 1.25-3.28) and ankle pain (1.51, 1.02-2.23). Low socioeconomic status was associated with morning stiffness (1.74, 1.08-2.80) and falls (1.37, 2.03-1.82). CONCLUSION: There are significant differences in coded symptoms between demographic groups, which must be considered in clinical practice in diverse populations and to avoid algorithmic bias in prediction tools derived from routinely collected healthcare data.

Trends in the prevalence and pharmacological management of migraine during pregnancy in the UK, 2000-2018.

BACKGROUND: Migraine is common in women of reproductive age. This study aimed to (1) describe the prevalence of migraine in pregnant women in the UK, (2) identify drugs commonly prescribed for migraine during pregnancy and (3) identify characteristics associated with being prescribed medication for migraine during pregnancy. METHODS: The Clinical Practice Research Datalink pregnancy register, a database of pregnancy episodes identified in anonymised primary care health records, was used.Crude and age-standardised prevalence of migraine during pregnancy and the proportion of women with migraine prescribed drugs used for migraine management were calculated for each year between 2000 and 2018.Logistic regression was used to describe the relationship between patient characteristics and being prescribed migraine medication during pregnancy. RESULTS: 1 377 053 pregnancies were included, of which 187 328 were in women with a history of migraine. The age-adjusted prevalence increased from 11.4% in 2000 to 17.2% in 2018. There was an increase in the rates of prescription for numerous medications for the management of migraine.Older women (adjusted OR (aOR) 1.41 (1.20 to 1.66)), women of black (aOR 1.40 (1.32 to 1.48)) and South Asian ethnicity (aOR 1.48 (1.38 to 1.59)), those living in the most deprived areas (aOR 1.60 (1.54 to 1.66)), women who were obese (aOR 1.39 (1.35 to 1.43)), smokers (aOR 1.15 (1.12 to 1.18)) and those with comorbid conditions were more likely to receive a prescription during pregnancy. CONCLUSIONS: Rates of recorded migraine have increased over the past two decades as well as rates of prescribing in women with migraine. Higher prescribing rates are seen in certain groups, which has the potential to exacerbate health inequalities.

Inequalities in the management of diabetic kidney disease in UK primary care: A cross-sectional analysis of a large primary care database.

AIMS: To determine differences in the management of diabetic kidney disease (DKD) relevant to patient sex, ethnicity and socio-economic group in UK primary care. METHODS: A cross-sectional analysis as of January 1, 2019 was undertaken using the IQVIA Medical Research Data dataset, to determine the proportion of people with DKD managed in accordance with national guidelines, stratified by demographics. Robust Poisson regression models were used to calculate adjusted risk ratios (aRR) adjusting for age, sex, ethnicity and social deprivation. RESULTS: Of the 2.3 million participants, 161,278 had type 1 or 2 diabetes, of which 32,905 had DKD. Of people with DKD, 60% had albumin creatinine ratio (ACR) measured, 64% achieved blood pressure (BP, <140/90 mmHg) target, 58% achieved glycosylated haemoglobin (HbA1c, <58 mmol/mol) target, 68% prescribed renin-angiotensin-aldosterone system (RAAS) inhibitor in the previous year. Compared to men, women were less likely to have creatinine: aRR 0.99 (95% CI 0.98-0.99), ACR: aRR 0.94 (0.92-0.96), BP: aRR 0.98 (0.97-0.99), HbA1c : aRR 0.99 (0.98-0.99) and serum cholesterol: aRR 0.97 (0.96-0.98) measured; achieve BP: aRR 0.95 (0.94-0.98) or total cholesterol (<5 mmol/L) targets: aRR 0.86 (0.84-0.87); or be prescribed RAAS inhibitors: aRR 0.92 (0.90-0.94) or statins: aRR 0.94 (0.92-0.95). Compared to the least deprived areas, people from the most deprived areas were less likely to have BP measurements: aRR 0.98 (0.96-0.99); achieve BP: aRR 0.91 (0.8-0.95) or HbA1c : aRR 0.88 (0.85-0.92) targets, or be prescribed RAAS inhibitors: aRR 0.91 (0.87-0.95). Compared to people of white ethnicity; those of black ethnicity were less likely to be prescribed statins aRR 0.91 (0.85-0.97). CONCLUSIONS: There are unmet needs and inequalities in the management of DKD in the UK. Addressing these could reduce the increasing human and societal cost of managing DKD.

How migraine and its associated treatment impact on pregnancy outcomes: Umbrella review with updated systematic review and meta-analysis.

BACKGROUND: Migraine is common in reproductive aged women. Understanding the impact of migraine and associated treatments on pregnancy outcomes remains very important. An umbrella review of systematic reviews, with or without meta-analyses, examined the link between migraine and pregnancy outcomes. METHODS: We systematically searched Medline, Embase and Cochrane to 27 October 2022. Quality appraisal was carried out using the AMSTAR2 tool. An established framework was used to determine whether included reviews were eligible for update. RESULTS: Four studies met review criteria. Migraine was reported to be associated with increased odds ratio (OR) of pre-eclampsia, low birth weight and peripartum mental illness (pooled OR = 3.54 (2.24-5.59)). Triptan-exposed women had increased odds of miscarriage compared to women without migraine (pooled OR = 3.54 (2.24-5.59)). In updated meta-analyses, migraine was associated with an increased odds of pre-eclampsia and preterm birth (pooled OR = 2.05 (1.47-2.84) and 1.26 (1.21-1.32) respectively). CONCLUSIONS: Migraine is associated with increased odds of pre-eclampsia, peripartum mental illness and preterm birth. Further investigation of the relationship between migraine and placental abruption, low birth weight and small for gestational age is warranted, as well as the relationship between migraine, triptans and miscarriage risk.Systematic Review Registration: Prospero CRD42022357630.

Automating incidence and prevalence analysis in open cohorts.

MOTIVATION: Data is increasingly used for improvement and research in public health, especially administrative data such as that collected in electronic health records. Patients enter and exit these typically open-cohort datasets non-uniformly; this can render simple questions about incidence and prevalence time-consuming and with unnecessary variation between analyses. We therefore developed methods to automate analysis of incidence and prevalence in open cohort datasets, to improve transparency, productivity and reproducibility of analyses. IMPLEMENTATION: We provide both a code-free set of rules for incidence and prevalence that can be applied to any open cohort, and a python Command Line Interface implementation of these rules requiring python 3.9 or later. GENERAL FEATURES: The Command Line Interface is used to calculate incidence and point prevalence time series from open cohort data. The ruleset can be used in developing other implementations or can be rearranged to form other analytical questions such as period prevalence. AVAILABILITY: The command line interface is freely available from https://github.com/THINKINGGroup/analogy_publication .

The association between menstrual cycle characteristics and cardiometabolic outcomes in later life: a retrospective matched cohort study of 704,743 women from the UK.

BACKGROUND: Female reproductive factors are gaining prominence as factors that enhance cardiovascular disease (CVD) risk; nonetheless, menstrual cycle characteristics are under-recognized as a factor associated with CVD. Additionally, there is limited data from the UK pertaining to menstrual cycle characteristics and CVD risk. METHODS: A UK retrospective cohort study (1995-2021) using data from a nationwide database (The Health Improvement Network). Women aged 18-40 years at index date were included. 252,325 women with history of abnormal menstruation were matched with up to two controls. Two exposures were examined: regularity and frequency of menstrual cycles; participants were assigned accordingly to one of two separate cohorts. The primary outcome was composite cardiovascular disease (CVD). Secondary outcomes were ischemic heart disease (IHD), cerebrovascular disease, heart failure (HF), hypertension, and type 2 diabetes mellitus (T2DM). Cox proportional hazards regression models were used to derive adjusted hazard ratios (aHR) of cardiometabolic outcomes in women in the exposed groups compared matched controls. RESULTS: During 26 years of follow-up, 20,605 cardiometabolic events occurred in 704,743 patients. Compared to women with regular menstrual cycles, the aHRs (95% CI) for cardiometabolic outcomes in women with irregular menstrual cycles were as follows: composite CVD 1.08 (95% CI 1.00-1.19), IHD 1.18 (1.01-1.37), cerebrovascular disease 1.04 (0.92-1.17), HF 1.30 (1.02-1.65), hypertension 1.07 (1.03-1.11), T2DM 1.37 (1.29-1.45). The aHR comparing frequent or infrequent menstrual cycles to menstrual cycles of normal frequency were as follows: composite CVD 1.24 (1.02-1.52), IHD 1.13 (0.81-1.57), cerebrovascular disease 1.43 (1.10-1.87), HF 0.99 (0.57-1.75), hypertension 1.31 (1.21-1.43), T2DM 1.74 (1.52-1.98). CONCLUSIONS: History of either menstrual cycle irregularity or frequent or infrequent cycles were associated with an increased risk of cardiometabolic outcomes in later life. Menstrual history may be a useful tool in identifying women eligible for periodic assessment of their cardiometabolic health.

Incidence of immune-mediated inflammatory diseases following COVID-19: a matched cohort study in UK primary care.

BACKGROUND: Some patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) go on to experience post-COVID-19 condition or long COVID. Preliminary findings have given rise to the theory that long COVID may be due in part to a deranged immune response. In this study, we assess whether there is an association between SARS-CoV-2 infection and the incidence of immune-mediated inflammatory diseases (IMIDs). METHODS: Matched cohort study using primary care electronic health record data from the Clinical Practice Research Datalink Aurum database. The exposed cohort included 458,147 adults aged 18 years and older with a confirmed SARS-CoV-2 infection and no prior diagnosis of IMIDs. They were matched on age, sex, and general practice to 1,818,929 adults with no diagnosis of confirmed or suspected SARS-CoV-2 infection. The primary outcome was a composite of any of the following IMIDs: autoimmune thyroiditis, coeliac disease, inflammatory bowel disease (IBD), myasthenia gravis, pernicious anaemia, psoriasis, rheumatoid arthritis (RA), Sjogren's syndrome, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1DM), and vitiligo. The secondary outcomes were each of these conditions separately. Cox proportional hazard models were used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for the primary and secondary outcomes, adjusting for age, sex, ethnic group, smoking status, body mass index, relevant infections, and medications. RESULTS: Six hundred and nighty six (0.15%) and 2230 (0.12%) patients in the exposed and unexposed cohort developed an IMID during the follow-up period over 0.29 person-years, giving a crude incidence rate of 4.59 and 3.65 per 1000 person-years, respectively. Patients in the exposed cohort had a 22% increased risk of developing an IMID, compared to the unexposed cohort (aHR 1.22, 95% CI 1.12 to 1.33). The incidence of three IMIDs was significantly associated with SARS-CoV-2 infection. These were T1DM (aHR 1.56, 1.09 to 2.23), IBD (aHR 1.36, 1.18 to 1.56), and psoriasis (1.23, 1.05 to 1.42). CONCLUSIONS: SARS-CoV-2 was associated with an increased incidence of IMIDs including T1DM, IBD and psoriasis. However, these findings could be potentially due to ascertainment bias. Further research is needed to replicate these findings in other populations and to measure autoantibody profiles in cohorts of individuals with COVID-19.

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.

A matched cohort study investigating premature, accentuated, and accelerated aging in people living with HIV.

INTRODUCTION: The impact of HIV infection on the aging process is disputed and largely unknown. We aimed to identify whether people living with HIV experience premature, accelerated, and/or accentuated aging by investigating the development of four age-related non-communicable diseases in people living with versus without HIV. METHODS: This population-based matched cohort study design used UK-based primary care electronic health records from the IQVIA Medical Research Database. Between January 2000 and January 2020, all people living with and without HIV aged ≥18 years were eligible. Outcomes included cardiovascular disease (CVD), hypertension, type 2 diabetes mellitus (T2DM), and chronic kidney disease (CKD), which were identified by Read codes. We used age at diagnosis to investigate premature aging and age at exit date to investigate accentuation and acceleration. For each outcome, people with and without HIV were excluded if they had the outcome of interest at baseline. Participants were matched based on propensity scores (1:1 ratio). Linear regression was used to report any difference in age at diagnosis between the two groups and to report the prevalence trends for age at exit date. RESULTS: In total, 8880 people living with HIV were matched with 8880 people without HIV and were found to have an earlier onset of CVD (54.5 vs. 56.8; p = 0.002). Similarly, people living with HIV had an earlier onset of hypertension (49.7 vs. 51.4; p = 0.002). No difference was found for T2DM or CKD (53.4 vs. 52.6; p = 0.368 and 57.6 vs. 58.1; p = 0.483, respectively). The burden of CKD increased over time, whereas no difference in the burden was found for the other conditions. CONCLUSION: The earlier development of CVD and hypertension in people living with HIV than in those without HIV indicates premature aging, whereas the increased burden of CKD indicates accelerated aging.

Empagliflozin is associated with lower cardiovascular risk compared with dipeptidyl peptidase-4 inhibitors in adults with and without cardiovascular disease: EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study results from Europe and Asia.

BACKGROUND: Studies that have reported lower risk for cardiovascular outcomes in users of Sodium-Glucose Cotransporter-2 Inhibitors (SGLT-2i) are limited by residual cofounding and lack of information on prior cardiovascular disease (CVD). This study compared risk of cardiovascular events in patients within routine care settings in Europe and Asia with type 2 diabetes (T2D) initiating empagliflozin compared to dipeptidyl peptidase-4 inhibitors (DPP-4i) stratified by pre-existing CVD and history of heart failure (HF). METHODS AND RESULTS: Adults initiating empagliflozin and DPP-4i in 2014-2018/19 from 11 countries in Europe and Asia were compared using propensity score matching and Cox proportional hazards regression to assess differences in rates of primary outcomes: hospitalisation for heart failure (HHF), myocardial infarction (MI), stroke; and secondary outcomes: cardiovascular mortality (CVM), coronary revascularisation procedure, composite outcome including HHF or CVM, and 3-point major adverse cardiovascular events (MACE: MI, stroke and CVM). Country-specific results were meta-analysed and pooled hazard ratios (HR) with 95% confidence intervals (CI) from random-effects models are presented. In total, 85,244 empagliflozin/DPP4i PS-matched patient pairs were included with overall mean follow-up of 0.7 years. Among those with pre-existing CVD, lower risk was observed for HHF (HR 0.74; 95% CI 0.64-0.86), CVM (HR 0.55; 95% CI 0.38-0.80), HHF or CVM (HR 0.57; 95% CI 0.48-0.67) and stroke (HR 0.79; 95% CI 0.67-0.94) in patients initiating empagliflozin vs DPP-4i. Similar patterns were observed among patients without pre-existing CVD and those with and without pre-existing HF. CONCLUSION: These results from diverse patient populations in routine care settings across Europe and Asia demonstrate that initiation of empagliflozin compared to DPP-4i results in favourable cardioprotective effects regardless of pre-existing CVD or HF status.

Associations between primary care recorded cannabis use and mental ill health in the UK: a population-based retrospective cohort study using UK primary care data.

BACKGROUND: Cannabis use is a global public health issue associated with increased risks of developing mental health disorders, especially in young people. We aimed to investigate the relationships between cannabis exposure and risks of receiving mental illness diagnoses or treatment as outcomes. METHODS: A population based, retrospective, open cohort study using patients recorded in 'IQVIA medical research data', a UK primary care database. Read codes were used to confirm patients with recorded exposure to cannabis use who were matched up to two unexposed patients. We examined the risk of developing three categories of mental ill health: depression, anxiety or serious mental illness (SMI). RESULTS: At study entry, the exposed cohort had an increased likelihood of having experienced mental ill health [odds ratio (OR) 4.13; 95% confidence interval (CI) 3.99-4.27] and mental ill health-related prescription (OR 2.95; 95% CI 2.86-3.05) compared to the unexposed group. During the study period we found that exposure to cannabis was associated with an increased risk of developing any mental disorder [adjusted hazard ratio (aHR) 2.73; 95% CI 2.59-2.88], also noted when examining by subtype of disorder: anxiety (aHR 2.46; 95% CI 2.29-2.64), depression (aHR 2.34; 95% CI 2.20-2.49) and SMI (aHR 6.41; 95% CI 5.42-7.57). These results remained robust in sensitivity analyses. CONCLUSION: These findings point to the potential need for a public health approach to the management of people misusing cannabis. However, there is a gross under-recording of cannabis use in GP records, as seen by the prevalence of recorded cannabis exposure substantially lower than self-reported survey records.

Risk of progression from pre-diabetes to type 2 diabetes in a large UK adult cohort.

AIMS: People with pre-diabetes are at high risk of progressing to type 2 diabetes. This progression is not well characterised by ethnicity, deprivation and age, which we describe in a large cohort of individuals with pre-diabetes. METHODS: A retrospective cohort study with The Health Improvement Network (THIN) database was conducted. Patients aged 18 years and over and diagnosed with pre-diabetes [HbA1c 42 mmol/mol (6.0%) to 48 mmol/mol (6.5%) were included]. Cox proportional hazards regression was used to calculate adjusted hazard rate ratios (aHR) for the risk of progression from pre-diabetes to type 2 diabetes for each of the exposure categories [ethnicity, deprivation (Townsend), age and body mass index (BMI)] separately. RESULTS: Of the baseline population with pre-diabetes (n = 397,853), South Asian (aHR 1.31; 95% CI 1.26-1.37) or Mixed-Race individuals (aHR 1.22; 95% CI 1.11-1.33) had an increased risk of progression to type 2 diabetes compared with those of white European ethnicity. Likewise, deprivation (aHR 1.17; 95% CI 1.14-1.20; most vs. least deprived) was associated with an increased risk of progression. Both younger (aHR 0.63; 95% CI 0.58-0.69; 18 to <30 years) and older individuals (aHR 0.85; 95% CI 0.84-0.87; ≥65 years) had a slower risk of progression from pre-diabetes to type 2 diabetes, than middle-aged (40 to <65 years) individuals. CONCLUSIONS: South Asian or Mixed-Race individuals and people with social deprivation had an increased risk of progression from pre-diabetes to type 2 diabetes. Clinicians need to recognise the differing risk across their patient populations to implement appropriate prevention strategies.

Sodium-glucose cotransporter-2 inhibitors and the risk of gout in patients with type 2 diabetes mellitus: A propensity-score-matched, new-user design study with an active comparator using the IQVIA Medical Research Data UK database.

AIM: To conduct a pharmacoepidemiological study to explore the association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and gout in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A retrospective open cohort study using the IQVIA Medical Research Data UK database was performed between November 1, 2012 and December 31, 2018, estimating the risk of gout in patients with T2DM who were new users of SGLT2 inhibitors, compared to propensity-score-matched new users of dipeptidyl peptidase-4 (DPP-4) inhibitors. RESULTS: A total of 85 incident cases of gout were recorded over 30 389 person-years of observation in 13 617 new users of SGLT2 inhibitors and 29 426 new users of DPP-4 inhibitors. Crude incidence rates (IRs) per 1000 person-years were 2.90 and 2.47 for new users of SGLT2 inhibitors and DPP-4 inhibitors, respectively. The unadjusted hazard ratio (HR) was 1.18 (95% confidence interval [CI] 0.76-1.83). The adjusted HR was 1.20 (95% CI 0.77-1.86). In the at-treatment analysis, crude IRs per 1000 person-years were found to be 2.68 and 2.53 for SGLT2 inhibitor and DPP-4 inhibitor users, respectively. In the adjusted model, the adjusted HR was 1.3 (95% CI 0.90-2.29). Sensitivity analyses did not change the findings. CONCLUSIONS: In this nationwide study, no difference in the incidence of gout was documented in patients treated with SGLT2 inhibitors compared to DPP-4 inhibitor users. This neutral finding remained consistent in sensitivity analyses.

Depression and anxiety in women with idiopathic intracranial hypertension compared to migraine: A matched controlled cohort study.

OBJECTIVE: To evaluate mental health burden in women with idiopathic intracranial hypertension (IIH) compared to matched women with migraine and population controls. BACKGROUND: Depression and anxiety are recognized comorbid conditions in those with IIH and lead to worse predicted medical outcomes. The mental health burden in IIH has not been previously evaluated in a large, matched cohort study. METHODS: We performed a population-based matched, retrospective cohort study to explore mental health outcomes (depression and anxiety). We used data from IQVIA Medical Research Data, an anonymized, nationally representative primary care electronic medical records database in the United Kingdom, from January 1, 1995, to September 25, 2019. Women aged ≥16 years were eligible for inclusion. Women with IIH (exposure) were matched by age and body mass index with up to 10 control women without IIH but with migraine (migraine controls), and without IIH or migraine (population controls). RESULTS: A total of 3411 women with IIH, 30,879 migraine controls and 33,495 population controls were included. Of these, 237, 2372 and 1695 women with IIH, migraine controls and population controls, respectively, developed depression during follow-up, and 179, 1826 and 1197, respectively, developed anxiety. There was a greater hazard of depression and anxiety in IIH compared to population controls (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.20-1.58; and aHR 1.40, 95% CI 1.19-1.64, respectively), while hazards were similar to migraine controls (aHR 0.98, 95% CI 0.86-1.13; and aHR 0.98, 95% CI 0.83-1.14, respectively). CONCLUSION: Depression and anxiety burden in women with IIH is higher than in the general population, and comparable to that in matched women with migraine. This may indicate that presence of headache is a potential driver for comorbid depression and anxiety in IIH.

Safety and efficacy of tuberculosis vaccine candidates in low- and middle-income countries: a systematic review of randomised controlled clinical trials.

BACKGROUND: Tuberculosis (TB) remains a leading cause of death worldwide, with 98% of cases occurring in low- and middle-income countries (LMICs). The only vaccine licenced for the prevention of TB has limited protection for adolescents, adults and vulnerable populations. A safe and effective vaccine for all populations at risk is imperative to achieve global elimination of TB. We aimed to systematically review the efficacy and safety of TB vaccine candidates in late-phase clinical trials conducted in LMICs. METHODS: Medline, Embase, CENTRAL, PubMed, Clinicaltrials.gov and Greylit.org were searched in June 2021 to identify phase 2 or later clinical randomised controlled trials that report the efficacy or safety (adverse events) of TB vaccine candidates with participants of any age living in an LMIC. TB vaccine candidates listed in the 2020 WHO Global TB Report were eligible for inclusion aside from BCG revaccination. Trials were excluded if all participants had active TB at baseline. Two reviewers independently assessed papers for eligibility, and for bias and quality using the Risk of Bias 2 tool and GRADE guidelines, respectively. We report efficacy rates and frequencies of adverse events from each included trial where available and qualitatively synthesise the findings. RESULTS: Thirteen papers representing eleven trials met our inclusion criteria. Seven vaccine candidates were reviewed across seven countries: M72/AS01, RUTI, VPM1002, H56:IC31, MTBVAC, DAR-901 and ID93 + GLA-SE. Two trials reported on efficacy: an efficacy rate of 54% (95% CI 11.5, 76.2) was reported for M72/AS01 in adults with latent TB and 3% (95% CI -13.9, 17.7) for DAR-901 in healthy adolescents. However, the latter trial was underpowered. All vaccine candidates had comparable occurrences of adverse events between treatment arms and demonstrated acceptable safety profiles; though, RUTI resulted in one serious complication in a person living with HIV. M72/AS01 was the only vaccine considered safe across a diverse group of people including people living with HIV or latent TB and healthy infants and adolescents. CONCLUSION: Further efficacy trials for M72/AS01 are warranted to include additional populations at risk where safety has been demonstrated. Further safety trials are needed for the remaining vaccine candidates to confirm safety in vulnerable populations.