Subclinical hypothyroidism in Wales from 2000 to 2021: A descriptive cohort study based on electronic health records.

BACKGROUND: Subclinical hypothyroidism (SCH) is a biochemical thyroid disorder characterised by elevated levels of Thyroid Stimulating Hormone (TSH) together with normal levels of thyroid hormones. Evidence on the benefits of treatment is limited, resulting in persistent controversies relating to its clinical management. AIM: This study describes the demographic and clinical characteristics of patients identified as having subclinical hypothyroidism in Wales between 2000 and 2021, the annual cumulative incidence during this period and the testing and treatment patterns associated with this disorder. METHODS: We used linked electronic health records from SAIL Databank. Eligible patients were identified using a combination of diagnostic codes and Thyroid Function Test results. Descriptive analyses were then performed. RESULTS: 199,520 individuals (63.8% female) were identified as having SCH, 23.6% (n = 47,104) of whom received levothyroxine for treatment over the study period. The median study follow-up time was 5.75 person-years (IQR 2.65-9.65). Annual cumulative incidence was highest in 2012 at 502 cases per 100,000 people. 92.5% (n = 184,484) of the study population had TSH levels between the upper limit of normal and 10mIU/L on their first test. 61.9% (n = 5,071) of patients identified using Read v2 codes were in the treated group. 41.9% (n = 19,716) of treated patients had a history of a single abnormal test result before their first prescription. CONCLUSION: In Wales, the number of incident cases of SCH has risen unevenly between 2000 and 2021. Most of the study population had mild SCH on their index test, but more than a third of the identified patients received levothyroxine after a single abnormal test result. Patients with clinically recorded diagnoses were more likely to be treated. Given the expectation of steadily increasing patient numbers, more evidence is required to support the clinical management of subclinical hypothyroidism.

Clustering long-term health conditions among 67728 people with multimorbidity using electronic health records in Scotland.

There is still limited understanding of how chronic conditions co-occur in patients with multimorbidity and what are the consequences for patients and the health care system. Most reported clusters of conditions have not considered the demographic characteristics of these patients during the clustering process. The study used data for all registered patients that were resident in Fife or Tayside, Scotland and aged 25 years or more on 1st January 2000 and who were followed up until 31st December 2018. We used linked demographic information, and secondary care electronic health records from 1st January 2000. Individuals with at least two of the 31 Elixhauser Comorbidity Index conditions were identified as having multimorbidity. Market basket analysis was used to cluster the conditions for the whole population and then repeatedly stratified by age, sex and deprivation. 318,235 individuals were included in the analysis, with 67,728 (21·3%) having multimorbidity. We identified five distinct clusters of conditions in the population with multimorbidity: alcohol misuse, cancer, obesity, renal failure, and heart failure. Clusters of long-term conditions differed by age, sex and socioeconomic deprivation, with some clusters not present for specific strata and others including additional conditions. These findings highlight the importance of considering demographic factors during both clustering analysis and intervention planning for individuals with multiple long-term conditions. By taking these factors into account, the healthcare system may be better equipped to develop tailored interventions that address the needs of complex patients.

Detection and evaluation of signals associated with exposure to individual and combination of medications in pregnancy: a signal detection study protocol.

INTRODUCTION: Considering the high prevalence of polypharmacy in pregnant women and the knowledge gap in the risk-benefit safety profile of their often-complex treatment plan, more research is needed to optimise prescribing. In this study, we aim to detect adverse and protective effect signals of exposure to individual and pairwise combinations of medications during pregnancy. METHODS AND ANALYSIS: Using a range of real-world data sources from the UK, we aim to conduct a pharmacovigilance study to assess the safety of medications prescribed during the preconception period (3 months prior to conception) and first trimester of pregnancy. Women aged between 15 and 49 years with a record of pregnancy within the Clinical Practice Research Datalink (CPRD) Pregnancy Register, the Welsh Secure Anonymised Information Linkage (SAIL), the Scottish Morbidity Record (SMR) data sets and the Northern Ireland Maternity System (NIMATS) will be included. A series of case control studies will be conducted to estimate measures of disproportionality, detecting signals of association between a range of pregnancy outcomes and exposure to individual and combinations of medications. A multidisciplinary expert team will be invited to a signal detection workshop. By employing a structured framework, signals will be transparently assessed by each member of the team using a questionnaire appraising the signals on aspects of temporality, selection, time and measurement-related biases and confounding by underlying disease or comedications. Through group discussion, the expert team will reach consensus on each of the medication exposure-outcome signal, thereby excluding spurious signals, leaving signals suggestive of causal associations for further evaluation. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Independent Scientific Advisory Committee, SAIL Information Governance Review Panel, University of St. Andrews Teaching and Research Ethics Committee and Office for Research Ethics Committees Northern Ireland (ORECNI) for access and use of CPRD, SAIL, SMR and NIMATS data, respectively.

Prevalence and demographic variation of cardiovascular, renal, metabolic, and mental health conditions in 12 million english primary care records.

BACKGROUND: Primary care electronic health records (EHR) are widely used to study long-term conditions in epidemiological and health services research. Therefore, it is important to understand how well the recorded prevalence of these conditions in EHRs, compares to other reliable sources overall, and varies by socio-demographic characteristics. We aimed to describe the prevalence and socio-demographic variation of cardiovascular, renal, and metabolic (CRM) and mental health (MH) conditions in a large, nationally representative, English primary care database and compare with prevalence estimates from other population-based studies. METHODS: This was a cross-sectional study using the Clinical Practice Research Datalink (CPRD) Aurum primary care database. We calculated prevalence of 18 conditions and used logistic regression to assess how this varied by age, sex, ethnicity, and socio-economic status. We searched the literature for population prevalence estimates from other sources for comparison with the prevalences in CPRD Aurum. RESULTS: Depression (16.0%, 95%CI 16.0-16.0%) and hypertension (15.3%, 95%CI 15.2-15.3%) were the most prevalent conditions among 12.4 million patients. Prevalence of most conditions increased with socio-economic deprivation and age. CRM conditions, schizophrenia and substance misuse were higher in men, whilst anxiety, depression, bipolar and eating disorders were more common in women. Cardiovascular risk factors (hypertension and diabetes) were more prevalent in black and Asian patients compared with white, but the trends in prevalence of cardiovascular diseases by ethnicity were more variable. The recorded prevalences of mental health conditions were typically twice as high in white patients compared with other ethnic groups. However, PTSD and schizophrenia were more prevalent in black patients. The prevalence of most conditions was similar or higher in the primary care database than diagnosed disease prevalence reported in national health surveys. However, screening studies typically reported higher prevalence estimates than primary care data, especially for PTSD, bipolar disorder and eating disorders. CONCLUSIONS: The prevalence of many clinically diagnosed conditions in primary care records closely matched that of other sources. However, we found important variations by sex and ethnicity, which may reflect true variation in prevalence or systematic differences in clinical presentation and practice. Primary care data may underrepresent the prevalence of undiagnosed conditions, particularly in mental health.

COVID-19 vaccination in pregnancy: the impact of multimorbidity and smoking status on vaccine hesitancy, a cohort study of 25,111 women in Wales, UK.

BACKGROUND: Multimorbidity, smoking status, and pregnancy are identified as three risk factors associated with more severe outcomes following a SARS-CoV-2 infection, thus vaccination uptake is crucial for pregnant women living with multimorbidity and a history of smoking. This study aimed to examine the impact of multimorbidity, smoking status, and demographics (age, ethnic group, area of deprivation) on vaccine hesitancy among pregnant women in Wales using electronic health records (EHR) linkage. METHODS: This cohort study utilised routinely collected, individual-level, anonymised population-scale linked data within the Secure Anonymised Information Linkage (SAIL) Databank. Pregnant women were identified from 13th April 2021 to 31st December 2021. Survival analysis was employed to examine and compare the length of time to vaccination uptake in pregnancy by considering multimorbidity, smoking status, as well as depression, diabetes, asthma, and cardiovascular conditions independently. The study also assessed the variation in uptake by multimorbidity, smoking status, and demographics, both jointly and separately for the independent conditions, using hazard ratios (HR) derived from the Cox regression model. RESULTS: Within the population cohort, 8,203 (32.7%) received at least one dose of the COVID-19 vaccine during pregnancy, with 8,572 (34.1%) remaining unvaccinated throughout the follow-up period, and 8,336 (33.2%) receiving the vaccine postpartum. Women aged 30 years or older were more likely to have the vaccine in pregnancy. Those who had depression were slightly but significantly more likely to have the vaccine compared to those without depression (HR = 1.08, 95% CI 1.03 to 1.14, p = 0.002). Women living with multimorbidity were 1.12 times more likely to have the vaccine compared to those living without multimorbidity (HR = 1.12, 95% CI 1.04 to 1.19, p = 0.001). Vaccine uptakes were significantly lower among both current smokers and former smokers compared to never smokers (HR = 0.87, 95% CI 0.81 to 0.94, p < 0.001 and HR = 0.92, 95% CI 0.85 to 0.98, p = 0.015 respectively). Uptake was also lower among those living in the most deprived areas compared to those living in the most affluent areas (HR = 0.89, 95% CI 0.83 to 0.96, p = 0.002). CONCLUSION: Younger women, living without multimorbidity, current and former smokers, and those living in the more deprived areas are less likely to have the vaccine, thus, a targeted approach to vaccinations may be required for these groups. Pregnant individuals living with multimorbidity exhibit a slight but statistically significant reduction in vaccine hesitancy towards COVID-19 during pregnancy.

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.

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.

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.

Trajectories in chronic disease accrual and mortality across the lifespan in Wales, UK (2005-2019), by area deprivation profile: linked electronic health records cohort study on 965,905 individuals.

Background: Understanding and quantifying the differences in disease development in different socioeconomic groups of people across the lifespan is important for planning healthcare and preventive services. The study aimed to measure chronic disease accrual, and examine the differences in time to individual morbidities, multimorbidity, and mortality between socioeconomic groups in Wales, UK. Methods: Population-wide electronic linked cohort study, following Welsh residents for up to 20 years (2000-2019). Chronic disease diagnoses were obtained from general practice and hospitalisation records using the CALIBER disease phenotype register. Multi-state models were used to examine trajectories of accrual of 132 diseases and mortality, adjusted for sex, age and area-level deprivation. Restricted mean survival time was calculated to measure time spent free of chronic disease(s) or mortality between socioeconomic groups. Findings: In total, 965,905 individuals aged 5-104 were included, from a possible 2.9 m individuals following a 5-year clearance period, with an average follow-up of 13.2 years (12.7 million person-years). Some 673,189 (69.7%) individuals developed at least one chronic disease or died within the study period. From ages 10 years upwards, the individuals living in the most deprived areas consistently experienced reduced time between health states, demonstrating accelerated transitions to first and subsequent morbidities and death compared to their demographic equivalent living in the least deprived areas. The largest difference were observed in 10 and 20 year old males developing multimorbidity (-0.45 years (99% CI: -0.45, -0.44)) and in 70 year old males dying after developing multimorbidity (-1.98 years (99% CI: -2.01, -1.95)). Interpretation: This study adds to the existing literature on health inequalities by demonstrating that individuals living in more deprived areas consistently experience accelerated time to diagnosis of chronic disease and death across all ages, accounting for competing risks. Funding: UK Medical Research Council, Health Data Research UK, and Administrative Data Research Wales.

Effect on life expectancy of temporal sequence in a multimorbidity cluster of psychosis, diabetes, and congestive heart failure among 1·7 million individuals in Wales with 20-year follow-up: a retrospective cohort study using linked data.

BACKGROUND: To inform targeted public health strategies, it is crucial to understand how coexisting diseases develop over time and their associated impacts on patient outcomes and health-care resources. This study aimed to examine how psychosis, diabetes, and congestive heart failure, in a cluster of physical-mental health multimorbidity, develop and coexist over time, and to assess the associated effects of different temporal sequences of these diseases on life expectancy in Wales. METHODS: In this retrospective cohort study, we used population-scale, individual-level, anonymised, linked, demographic, administrative, and electronic health record data from the Wales Multimorbidity e-Cohort. We included data on all individuals aged 25 years and older who were living in Wales on Jan 1, 2000 (the start of follow-up), with follow-up continuing until Dec 31, 2019, first break in Welsh residency, or death. Multistate models were applied to these data to model trajectories of disease in multimorbidity and their associated effect on all-cause mortality, accounting for competing risks. Life expectancy was calculated as the restricted mean survival time (bound by the maximum follow-up of 20 years) for each of the transitions from the health states to death. Cox regression models were used to estimate baseline hazards for transitions between health states, adjusted for sex, age, and area-level deprivation (Welsh Index of Multiple Deprivation [WIMD] quintile). FINDINGS: Our analyses included data for 1 675 585 individuals (811 393 [48·4%] men and 864 192 [51·6%] women) with a median age of 51·0 years (IQR 37·0-65·0) at cohort entry. The order of disease acquisition in cases of multimorbidity had an important and complex association with patient life expectancy. Individuals who developed diabetes, psychosis, and congestive heart failure, in that order (DPC), had reduced life expectancy compared with people who developed the same three conditions in a different order: for a 50-year-old man in the third quintile of the WIMD (on which we based our main analyses to allow comparability), DPC was associated with a loss in life expectancy of 13·23 years (SD 0·80) compared with the general otherwise healthy or otherwise diseased population. Congestive heart failure as a single condition was associated with mean a loss in life expectancy of 12·38 years (0·00), and with a loss of 12·95 years (0·06) when preceded by psychosis and 13·45 years (0·13) when followed by psychosis. Findings were robust in people of older ages, more deprived populations, and women, except that the trajectory of psychosis, congestive heart failure, and diabetes was associated with higher mortality in women than men. Within 5 years of an initial diagnosis of diabetes, the risk of developing psychosis or congestive heart failure, or both, was increased. INTERPRETATION: The order in which individuals develop psychosis, diabetes, and congestive heart failure as combinations of conditions can substantially affect life expectancy. Multistate models offer a flexible framework to assess temporal sequences of diseases and allow identification of periods of increased risk of developing subsequent conditions and death. FUNDING: Health Data Research UK.

Prevalence of polypharmacy in pregnancy: a systematic review.

OBJECTIVES: The use of medications among pregnant women has been rising over the past few decades but the reporting of polypharmacy has been sporadic. The objective of this review is to identify literature reporting the prevalence of polypharmacy among pregnant women, the prevalence of multimorbidity in women taking multiple medications in pregnancy and associated effects on maternal and offspring outcomes. DESIGN: MEDLINE and Embase were searched from their inception to 14 September 2021 for interventional trials, observational studies and systematic reviews reporting on the prevalence of polypharmacy or the use of multiple medications in pregnancy were included.Data on prevalence of polypharmacy, prevalence of multimorbidity, combinations of medications and pregnancy and offspring outcomes were extracted. A descriptive analysis was performed. RESULTS: Fourteen studies met the review criteria. The prevalence of women being prescribed two or more medications during pregnancy ranged from 4.9% (4.3%-5.5%) to 62.4% (61.3%-63.5%), with a median of 22.5%. For the first trimester, prevalence ranged from 4.9% (4.7%-5.14%) to 33.7% (32.2%-35.1%). No study reported on the prevalence of multimorbidity, or associated pregnancy outcomes in women exposed to polypharmacy. CONCLUSION: There is a significant burden of polypharmacy among pregnant women. There is a need for evidence on the combinations of medications prescribed in pregnancy, how this specifically affects women with multiple long-term conditions and the associated benefits and harms. TWEETABLE ABSTRACT: Our systematic review shows significant burden of polypharmacy in pregnancy but outcomes for women and offspring are unknown. PROSPERO REGISTRATION NUMBER: CRD42021223966.

Maternal and child outcomes for pregnant women with pre-existing multiple long-term conditions: protocol for an observational study in the UK.

INTRODUCTION: One in five pregnant women has multiple pre-existing long-term conditions in the UK. Studies have shown that maternal multiple long-term conditions are associated with adverse outcomes. This observational study aims to compare maternal and child outcomes for pregnant women with multiple long-term conditions to those without multiple long-term conditions (0 or 1 long-term conditions). METHODS AND ANALYSIS: Pregnant women aged 15-49 years old with a conception date between 2000 and 2019 in the UK will be included with follow-up till 2019. The data source will be routine health records from all four UK nations (Clinical Practice Research Datalink (England), Secure Anonymised Information Linkage (Wales), Scotland routine health records and Northern Ireland Maternity System) and the Born in Bradford birth cohort. The exposure of two or more pre-existing, long-term physical or mental health conditions will be defined from a list of health conditions predetermined by women and clinicians. The association of maternal multiple long-term conditions with (a) antenatal, (b) peripartum, (c) postnatal and long-term and (d) mental health outcomes, for both women and their children will be examined. Outcomes of interest will be guided by a core outcome set. Comparisons will be made between pregnant women with and without multiple long-term conditions using modified Poisson and Cox regression. Generalised estimating equation will account for the clustering effect of women who had more than one pregnancy episode. Where appropriate, multiple imputation with chained equation will be used for missing data. Federated analysis will be conducted for each dataset and results will be pooled using random-effects meta-analyses. ETHICS AND DISSEMINATION: Approval has been obtained from the respective data sources in each UK nation. Study findings will be submitted for publications in peer-reviewed journals and presented at key conferences.

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.

Severe COVID-19 outcomes after full vaccination of primary schedule and initial boosters: pooled analysis of national prospective cohort studies of 30 million individuals in England, Northern Ireland, Scotland, and Wales.

BACKGROUND: Current UK vaccination policy is to offer future COVID-19 booster doses to individuals at high risk of serious illness from COVID-19, but it is still uncertain which groups of the population could benefit most. In response to an urgent request from the UK Joint Committee on Vaccination and Immunisation, we aimed to identify risk factors for severe COVID-19 outcomes (ie, COVID-19-related hospitalisation or death) in individuals who had completed their primary COVID-19 vaccination schedule and had received the first booster vaccine. METHODS: We constructed prospective cohorts across all four UK nations through linkages of primary care, RT-PCR testing, vaccination, hospitalisation, and mortality data on 30 million people. We included individuals who received primary vaccine doses of BNT162b2 (tozinameran; Pfizer-BioNTech) or ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our initial analyses. We then restricted analyses to those given a BNT162b2 or mRNA-1273 (elasomeran; Moderna) booster and had a severe COVID-19 outcome between Dec 20, 2021, and Feb 28, 2022 (when the omicron (B.1.1.529) variant was dominant). We fitted time-dependent Poisson regression models and calculated adjusted rate ratios (aRRs) and 95% CIs for the associations between risk factors and COVID-19-related hospitalisation or death. We adjusted for a range of potential covariates, including age, sex, comorbidities, and previous SARS-CoV-2 infection. Stratified analyses were conducted by vaccine type. We then did pooled analyses across UK nations using fixed-effect meta-analyses. FINDINGS: Between Dec 8, 2020, and Feb 28, 2022, 16 208 600 individuals completed their primary vaccine schedule and 13 836 390 individuals received a booster dose. Between Dec 20, 2021, and Feb 28, 2022, 59 510 (0·4%) of the primary vaccine group and 26 100 (0·2%) of those who received their booster had severe COVID-19 outcomes. The risk of severe COVID-19 outcomes reduced after receiving the booster (rate change: 8·8 events per 1000 person-years to 7·6 events per 1000 person-years). Older adults (≥80 years vs 18-49 years; aRR 3·60 [95% CI 3·45-3·75]), those with comorbidities (≥5 comorbidities vs none; 9·51 [9·07-9·97]), being male (male vs female; 1·23 [1·20-1·26]), and those with certain underlying health conditions-in particular, individuals receiving immunosuppressants (yes vs no; 5·80 [5·53-6·09])-and those with chronic kidney disease (stage 5 vs no; 3·71 [2·90-4·74]) remained at high risk despite the initial booster. Individuals with a history of COVID-19 infection were at reduced risk (infected ≥9 months before booster dose vs no previous infection; aRR 0·41 [95% CI 0·29-0·58]). INTERPRETATION: Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalisation and death after the initial vaccine booster and should, therefore, be prioritised for additional boosters, including novel optimised versions, and the increasing array of COVID-19 therapeutics. FUNDING: National Core Studies-Immunity, UK Research and Innovation (Medical Research Council), Health Data Research UK, the Scottish Government, and the University of Edinburgh.

Risk of thrombocytopenic, haemorrhagic and thromboembolic disorders following COVID-19 vaccination and positive test: a self-controlled case series analysis in Wales.

There is a need for better understanding of the risk of thrombocytopenic, haemorrhagic, thromboembolic disorders following first, second and booster vaccination doses and testing positive for SARS-CoV-2. Self-controlled cases series analysis of 2.1 million linked patient records in Wales between 7th December 2020 and 31st December 2021. Outcomes were the first diagnosis of thrombocytopenic, haemorrhagic and thromboembolic events in primary or secondary care datasets, exposure was defined as 0-28 days post-vaccination or a positive reverse transcription polymerase chain reaction test for SARS-CoV-2. 36,136 individuals experienced either a thrombocytopenic, haemorrhagic or thromboembolic event during the study period. Relative to baseline, our observations show greater risk of outcomes in the periods post-first dose of BNT162b2 for haemorrhagic (IRR 1.47, 95%CI: 1.04-2.08) and idiopathic thrombocytopenic purpura (IRR 2.80, 95%CI: 1.21-6.49) events; post-second dose of ChAdOx1 for arterial thrombosis (IRR 1.14, 95%CI: 1.01-1.29); post-booster greater risk of venous thromboembolic (VTE) (IRR-Moderna 3.62, 95%CI: 0.99-13.17) (IRR-BNT162b2 1.39, 95%CI: 1.04-1.87) and arterial thrombosis (IRR-Moderna 3.14, 95%CI: 1.14-8.64) (IRR-BNT162b2 1.34, 95%CI: 1.15-1.58). Similarly, post SARS-CoV-2 infection the risk was increased for haemorrhagic (IRR 1.49, 95%CI: 1.15-1.92), VTE (IRR 5.63, 95%CI: 4.91, 6.4), arterial thrombosis (IRR 2.46, 95%CI: 2.22-2.71). We found that there was a measurable risk of thrombocytopenic, haemorrhagic, thromboembolic events after COVID-19 vaccination and infection.

The impact of the management strategies for patients with subclinical hypothyroidism on long-term clinical outcomes: An umbrella review.

AIM: This umbrella review summarises and compares synthesised evidence on the impact of subclinical hypothyroidism and its management on long-term clinical outcomes. METHODS: We conducted comprehensive searches on MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews, JBI Evidence Synthesis, the PROSPERO register, Epistemonikos Database and PDQ Evidence from inception to February and July 2021 using keywords on subclinical hypothyroidism, treatment with levothyroxine, monitoring and primary outcomes (all-cause mortality, cardiovascular events, stroke, frailty fractures and quality of life). Only systematic reviews and meta-analyses on adult patient populations were considered. Study selection, data extraction and quality appraisal using AMSTAR-2 were done independently by two reviewers and discrepancies were resolved through discussion. Overlap across the selected reviews was also assessed, followed by a narrative synthesis of findings. RESULTS: A total of 763 studies were identified from literature searches; 20 reviews met inclusion criteria. Methodological quality ratings were high (n = 8), moderate (n = 7), and low (n = 5), but no reviews were excluded on this basis. Though there was slight overlap across all reviews, some pairwise comparisons had high corrected covered area scores. Compared to euthyroidism, untreated subclinical hypothyroidism was associated with a higher risk of cardiovascular events or death if Thyroid Stimulating Hormone was above 10mIU/L at baseline. Treatment was associated with a lower risk of death from all causes for patients younger than 70 years and possibly better cognitive and quality of life scores than untreated individuals. Evidence on the risk of strokes and fractures was inconclusive. CONCLUSION: In the long term, treatment of subclinical hypothyroidism may be beneficial for some patient groups. However, the findings of this review are negatively impacted by the relative sparseness and poor quality of available evidence. Additional large and adequately powered studies are needed to investigate this topic further. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42021235172).

Variation in the estimated prevalence of multimorbidity: systematic review and meta-analysis of 193 international studies.

OBJECTIVE: (1) To estimate the pooled prevalence of multimorbidity in all age groups, globally. (2) To examine how measurement of multimorbidity impacted the estimated prevalence. METHODS: In this systematic review and meta-analysis, we conducted searches in nine bibliographic databases (PsycINFO, Embase, Global Health, Medline, Scopus, Web of Science, Cochrane Library, CINAHL and ProQuest Dissertations and Theses Global) for prevalence studies published between database inception and 21 January 2020. Studies reporting the prevalence of multimorbidity (in all age groups and in community, primary care, care home and hospital settings) were included. Studies with an index condition or those that did not include people with no long-term conditions in the denominator were excluded. Retrieved studies were independently reviewed by two reviewers, and relevant data were extracted using predesigned pro forma. We used meta-analysis to pool the estimated prevalence of multimorbidity across studies, and used random-effects meta-regression and subgroup analysis to examine the association of heterogeneous prevalence estimates with study and measure characteristics. RESULTS: 13 807 titles were screened, of which 193 met inclusion criteria for meta-analysis. The pooled prevalence of multimorbidity was 42.4% (95% CI 38.9% to 46.0%) with high heterogeneity (I2 >99%). In adjusted meta-regression models, participant mean age and the number of conditions included in a measure accounted for 47.8% of heterogeneity in effect sizes. The estimated prevalence of multimorbidity was significantly higher in studies with older adults and those that included larger numbers of conditions. There was no significant difference in estimated prevalence between low-income or middle-income countries (36.8%) and high-income countries (44.3%), or between self-report (40.0%) and administrative/clinical databases (52.7%). CONCLUSIONS: The pooled prevalence of multimorbidity was significantly higher in older populations and when studies included a larger number of baseline conditions. The findings suggest that, to improve study comparability and quality of reporting, future studies should use a common core conditions set for multimorbidity measurement and report multimorbidity prevalence stratified by sociodemographics.PROSPERO registration numberCRD42020172409.

Epidemiology of pre-existing multimorbidity in pregnant women in the UK in 2018: a population-based cross-sectional study.

BACKGROUND: Although maternal death is rare in the United Kingdom, 90% of these women had multiple health/social problems. This study aims to estimate the prevalence of pre-existing multimorbidity (two or more long-term physical or mental health conditions) in pregnant women in the United Kingdom (England, Northern Ireland, Wales and Scotland). STUDY DESIGN: Pregnant women aged 15-49 years with a conception date 1/1/2018 to 31/12/2018 were included in this population-based cross-sectional study, using routine healthcare datasets from primary care: Clinical Practice Research Datalink (CPRD, United Kingdom, n = 37,641) and Secure Anonymized Information Linkage databank (SAIL, Wales, n = 27,782), and secondary care: Scottish Morbidity Records with linked community prescribing data (SMR, Tayside and Fife, n = 6099). Pre-existing multimorbidity preconception was defined from 79 long-term health conditions prioritised through a workshop with patient representatives and clinicians. RESULTS: The prevalence of multimorbidity was 44.2% (95% CI 43.7-44.7%), 46.2% (45.6-46.8%) and 19.8% (18.8-20.8%) in CPRD, SAIL and SMR respectively. When limited to health conditions that were active in the year before pregnancy, the prevalence of multimorbidity was still high (24.2% [23.8-24.6%], 23.5% [23.0-24.0%] and 17.0% [16.0 to 17.9%] in the respective datasets). Mental health conditions were highly prevalent and involved 70% of multimorbidity CPRD: multimorbidity with ≥one mental health condition/s 31.3% [30.8-31.8%]). After adjusting for age, ethnicity, gravidity, index of multiple deprivation, body mass index and smoking, logistic regression showed that pregnant women with multimorbidity were more likely to be older (CPRD England, adjusted OR 1.81 [95% CI 1.04-3.17] 45-49 years vs 15-19 years), multigravid (1.68 [1.50-1.89] gravidity ≥ five vs one), have raised body mass index (1.59 [1.44-1.76], body mass index 30+ vs body mass index 18.5-24.9) and smoked preconception (1.61 [1.46-1.77) vs non-smoker). CONCLUSION: Multimorbidity is prevalent in pregnant women in the United Kingdom, they are more likely to be older, multigravid, have raised body mass index and smoked preconception. Secondary care and community prescribing dataset may only capture the severe spectrum of health conditions. Research is needed urgently to quantify the consequences of maternal multimorbidity for both mothers and children.

Development of an algorithm to classify primary care electronic health records of alcohol consumption: experience using data linkage from UK Biobank and primary care electronic health data sources.

OBJECTIVES: Develop a novel algorithm to categorise alcohol consumption using primary care electronic health records (EHRs) and asses its reliability by comparing this classification with self-reported alcohol consumption data obtained from the UK Biobank (UKB) cohort. DESIGN: Cross-sectional study. SETTING: The UKB, a population-based cohort with participants aged between 40 and 69 years recruited across the UK between 2006 and 2010. PARTICIPANTS: UKB participants from Scotland with linked primary care data. PRIMARY AND SECONDARY OUTCOME MEASURES: Create a rule-based multiclass algorithm to classify alcohol consumption reported by Scottish UKB participants and compare it with their classification using data present in primary care EHRs based on Read Codes. We evaluated agreement metrics (simple agreement and kappa statistic). RESULTS: Among the Scottish UKB participants, 18 838 (69%) had at least one Read Code related to alcohol consumption and were used in the classification. The agreement of alcohol consumption categories between UKB and primary care data, including assessments within 5 years was 59.6%, and kappa was 0.23 (95% CI 0.21 to 0.24). Differences in classification between the two sources were statistically significant (p<0.001); More individuals were classified as 'sensible drinkers' and in lower alcohol consumption levels in primary care records compared with the UKB. Agreement improved slightly when using only numerical values (k=0.29; 95% CI 0.27 to 0.31) and decreased when using qualitative descriptors only (k=0.18;95% CI 0.16 to 0.20). CONCLUSION: Our algorithm classifies alcohol consumption recorded in Primary Care EHRs into discrete meaningful categories. These results suggest that alcohol consumption may be underestimated in primary care EHRs. Using numerical values (alcohol units) may improve classification when compared with qualitative descriptors.

Measuring multimorbidity in research: Delphi consensus study.

Objective: To develop international consensus on the definition and measurement of multimorbidity in research. Design: Delphi consensus study. Setting: International consensus; data collected in three online rounds from participants between 30 November 2020 and 18 May 2021. Participants: Professionals interested in multimorbidity and people with long term conditions were recruited to professional and public panels. Results: 150 professional and 25 public participants completed the first survey round. Response rates for rounds 2/3 were 83%/92% for professionals and 88%/93% in the public panel, respectively. Across both panels, the consensus was that multimorbidity should be defined as two or more long term conditions. Complex multimorbidity was perceived to be a useful concept, but the panels were unable to agree on how to define it. Both panels agreed that conditions should be included in a multimorbidity measure if they were one or more of the following: currently active; permanent in their effects; requiring current treatment, care, or therapy; requiring surveillance; or relapsing-remitting conditions requiring ongoing care. Consensus was reached for 24 conditions to always include in multimorbidity measures, and 35 conditions to usually include unless a good reason not to existed. Simple counts were preferred for estimating prevalence and examining clustering or trajectories, and weighted measures were preferred for risk adjustment and outcome prediction. Conclusions: Previous multimorbidity research is limited by inconsistent definitions and approaches to measuring multimorbidity. This Delphi study identifies professional and public panel consensus guidance to facilitate consistency of definition and measurement, and to improve study comparability and reproducibility.