Fluoroquinolones and the risk of severe hypoglycaemia among sulphonylurea users: Population-based cohort study.

AIM: Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. MATERIALS AND METHODS: Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. RESULTS: Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. CONCLUSIONS: In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible.

Variable Selection When Estimating Effects in External Target Populations.

External validity is an important part of epidemiologic research. To validly estimate effects in specific external target populations using a chosen effect measure (i.e., "transport"), some methods require that one account for all effect measure modifiers [EMMs]. However, little is known about how including other variables that are not EMMs (i.e., non-EMMs) in adjustment sets impacts estimates. Using simulations, we evaluated how inclusion of non-EMMs affected estimation of the transported risk difference (RD) by assessing impacts of covariates that A) differ (or not) between the trial and the target, B) are associated with the outcome (or not), and C) modify the RD (or not). We assessed variation and bias when covariates with each possible combination of these factors were used to transport RDs using outcome modeling or inverse odds weighting. Including variables that differed in distribution between the populations but were non-EMMs reduced precision, regardless of whether they were associated with the outcome. However, non-EMMs associated with selection did not amplify bias resulting from omitting necessary EMMs. Including all variables associated with the outcome may result in unnecessarily imprecise estimates when estimating treatment effects in external target populations.

What is the ideal time to begin tapering opioid agonist treatment? A protocol for a retrospective population-based comparative effectiveness study in British Columbia, Canada.

INTRODUCTION: Opioid agonist treatment (OAT) tapering involves a gradual reduction in daily medication dose to ultimately reach a state of opioid abstinence. Due to the high risk of relapse and overdose after tapering, this practice is not recommended by clinical guidelines, however, clients may still request to taper off medication. The ideal time to initiate an OAT taper is not known. However, ethically, taper plans should acknowledge clients' preferences and autonomy but apply principles of shared informed decision-making regarding safety and efficacy. Linked population-level data capturing real-world tapering practices provide a valuable opportunity to improve existing evidence on when to contemplate starting an OAT taper. Our objective is to determine the comparative effectiveness of alternative times from OAT initiation at which a taper can be initiated, with a primary outcome of taper completion, as observed in clinical practice in British Columbia (BC), Canada. METHODS AND ANALYSIS: We propose a population-level retrospective observational study with a linkage of eight provincial health administrative databases in BC, Canada (01 January 2010 to 17 March 2020). Our primary outcomes include taper completion and all-cause mortality during treatment. We propose a 'per-protocol' target trial to compare different durations to taper initiation on the likelihood of taper completion. A range of sensitivity analyses will be used to assess the heterogeneity and robustness of the results including assessment of effectiveness and safety. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

Severe Maternal Morbidity and Mental Health Hospitalizations or Emergency Department Visits.

Importance: Severe maternal morbidity (SMM) can have long-term health consequences for the affected mother. The association between SMM and future maternal mental health conditions has not been well studied. Objective: To assess the association between SMM in the first recorded birth and the risk of hospitalization or emergency department (ED) visits for a mental health condition over a 13-year period. Design, Setting, and Participants: This population-based retrospective cohort study used data from postpartum individuals aged 18 to 55 years with a first hospital delivery between 2008 and 2021 in 11 provinces and territories in Canada, except Québec. Data were analyzed from January to June 2023. Exposure: SMM, defined as a composite of conditions, such as septic shock, severe preeclampsia or eclampsia, severe hemorrhage with intervention, or other complications, occurring after 20 weeks' gestation and up to 42 days after a first delivery. Main Outcomes and Measures: The main outcome was a hospitalization or ED visit for a mental health condition, including mood and anxiety disorders, substance use, schizophrenia, and other psychotic disorder, or suicidality or self-harm event, arising at least 43 days after the first birth hospitalization. Cox regression models generated hazard ratios with 95% CIs, adjusted for baseline maternal comorbidities, maternal age at delivery, income quintile, type of residence, hospital type, and delivery year. Results: Of 2 026 594 individuals with a first hospital delivery, 1 579 392 individuals (mean [SD] age, 30.0 [5.4] years) had complete ED and hospital records and were included in analyses; among these, 35 825 individuals (2.3%) had SMM. Compared with individuals without SMM, those with SMM were older (mean [SD] age, 29.9 [5.4] years vs 30.7 [6.0] years), were more likely to deliver in a teaching tertiary care hospital (40.8% vs 51.1%), and to have preexisting conditions (eg, ≥2 conditions: 1.2% vs 5.3%), gestational diabetes (8.2% vs 11.7%), stillbirth (0.5% vs 1.6%), preterm birth (7.7% vs 25.0%), or cesarean delivery (31.0% vs 54.3%). After a median (IQR) duration of 2.6 (1.3-6.4) years, 1287 (96.1 per 10 000) individuals with SMM had a mental health hospitalization or ED visit, compared with 41 779 (73.2 per 10 000) individuals without SMM (adjusted hazard ratio, 1.26 [95% CI, 1.19-1.34]). Conclusions and Relevance: In this cohort study of postpartum individuals with and without SMM in pregnancy and delivery, there was an increased risk of mental health hospitalizations or ED visits up to 13 years after a delivery complicated by SMM. Enhanced surveillance and provision of postpartum mental health resources may be especially important after SMM.

Concomitant Use of Selective Serotonin Reuptake Inhibitors With Oral Anticoagulants and Risk of Major Bleeding.

Importance: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed antidepressants associated with a small increased risk of major bleeding. However, the risk of bleeding associated with the concomitant use of SSRIs and oral anticoagulants (OACs) has not been well characterized. Objectives: To assess whether concomitant use of SSRIs with OACs is associated with an increased risk of major bleeding compared with OAC use alone, describe how the risk varies with duration of use, and identify key clinical characteristics modifying this risk. Design, Setting, and Participants: A population-based, nested case-control study was conducted among patients with atrial fibrillation initiating OACs between January 2, 1998, and March 29, 2021. Patients were from approximately 2000 general practices in the UK contributing to the Clinical Practice Research Datalink. With the use of risk-set sampling, for each case of major bleeding during follow-up, up to 30 controls were selected from risk sets defined by the case and matched on age, sex, cohort entry date, and follow-up duration. Exposures: Concomitant use of SSRIs and OACs (direct OACs and vitamin K antagonists [VKAs]) compared with OAC use alone. Main Outcomes and Measures: The main outcome was incidence rate ratios (IRRs) of hospitalization for bleeding or death due to bleeding. Results: There were 42 190 patients with major bleeding (mean [SD] age, 74.2 [9.3] years; 59.8% men) matched to 1 156 641 controls (mean [SD] age, 74.2 [9.3] years; 59.8% men). Concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OACs alone (IRR, 1.33; 95% CI, 1.24-1.42). The risk peaked during the initial months of treatment (first 30 days of use: IRR, 1.74; 95% CI, 1.37-2.22) and persisted for up to 6 months. The risk did not vary with age, sex, history of bleeding, chronic kidney disease, and potency of SSRIs. An association was present both with concomitant use of SSRIs and direct OACs compared with direct OAC use alone (IRR, 1.25; 95% CI, 1.12-1.40) and concomitant use of SSRIs and VKAs compared with VKA use alone (IRR, 1.36; 95% CI, 1.25-1.47). Conclusions and Relevance: This study suggests that among patients with atrial fibrillation, concomitant use of SSRIs and OACs was associated with an increased risk of major bleeding compared with OAC use alone, requiring close monitoring and management of risk factors for bleeding, particularly in the first few months of use.

Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study.

BACKGROUND AND AIMS: The effects of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) and liver disease remain poorly understood. Our multinational cohort study assessed the effectiveness and safety of DOACs in this high-risk population. METHODS: We assembled two population-based cohorts in United Kingdom and in Québec of NVAF patients with liver disease initiating DOACs or vitamin K antagonists (VKAs) between 2011 and 2020. Using an as-treated exposure definition, we compared DOACs to VKAs and apixaban to rivaroxaban. After inverse probability of treatment weighting, Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95 % confidence intervals (CIs) of ischemic stroke and major bleeding. Site-specific estimates were pooled using random-effects models. Analyses were repeated among NVAF patients with cirrhosis. RESULTS: There were 11,881 NVAF patients with liver disease (2683 with cirrhosis). Among those, 8815 initiated DOACs (4414 apixaban, 2497 rivaroxaban) and 3696 VKAs. The HRs (95 % CIs) for DOACs compared to VKAs were 1.01 (0.76-1.34) for ischemic stroke and 0.87 (0.77-0.99) for major bleeding. Results were consistent among patients with cirrhosis. The HRs (95 % CIs) for apixaban compared to rivaroxaban were 0.85 (0.60-1.20) for ischemic stroke and 0.80 (0.68-0.95) for major bleeding. This decreased bleeding risk was not observed among patients with cirrhosis (HR, 1.01; 95 % CI 0.72-1.43). CONCLUSIONS: Among NVAF patients with liver disease, DOACs were as effective and slightly safer than VKAs, and apixaban was as effective but safer than rivaroxaban. The safety benefit with apixaban was not present among patients with cirrhosis.

Prescribing trends of proton pump inhibitors and histamine blockers among children in the United Kingdom (1998-2019): A population-based assessment.

PURPOSE: To describe the prescribing trends of proton pump inhibitors (PPIs) and H2 receptor antagonists (H2 RAs) among children with gastroesophageal reflux in the United Kingdom between 1998 and 2019. METHODS: We conducted a population-based retrospective cohort study using data from the Clinical Practice Research Datalink that included all children aged ≤18 years with a first ever diagnosis of gastroesophageal reflux between 1998 and 2019. Using negative binomial regression, we estimated crude and adjusted annual prescription rates per 1000 person-years and corresponding 95% confidence intervals (CIs) for PPIs and H2 RAs. We also assessed rate ratios of PPIs and H2 RAs prescription rates to examine changes in prescribing over time. RESULTS: Our cohort included 177 477 children with a first ever diagnosis of gastroesophageal reflux during the study period. The median age was 13 years (IQR: 1, 17) among children prescribed PPIs and 0.2 years (IQR: 0.1, 0.6) among those prescribed H2 RAs. The total prescription rate of all GERD drugs was 1468 prescriptions per 1000 person-years (PYs) (95% CI 1463-1472). Overall, PPIs had a higher prescription rate (815 per 1000 PYs, 95% CI 812-818) than H2 RAs (653 per 1000 PYs 95% CI 650-655). Sex- and age-adjusted rate ratios of 2019 versus 1998 demonstrated a 10% increase and a 76% decrease in the prescription rates of PPIs and H2 RAs, respectively. CONCLUSIONS: Prescription rates for PPIs increased, especially during the first half of the study period, while prescription rates for H2 RA decreased over time.

Standardizing to Specific Target Populations in Distributed Networks and Multi-Site Pharmacoepidemiologic Studies.

Distributed networks and other multi-site studies assess drug safety and effectiveness in diverse populations by pooling information. Targeting groups of clinical or policy interest (including specific sites or site combinations) and applying weights based on effect measure modifiers (EMMs) prior to pooling estimates within multi-site studies may increase interpretability and improve precision. We simulated a four-site study, standardized each site using inverse odds weights (IOW) to resemble the three smallest sites or the smallest site, estimated IOW-weighted RDs, and combined estimates with inverse variance weights (IVW). We also created an artificial distributed network in the Clinical Practice Research Datalink (CPRD) Aurum consisting of one site for each geographic region. We compared metformin and sulfonylurea initiators with respect to mortality, targeting the smallest region. In the simulation, IOW reduced differences between estimates and increased precision when targeting the three smallest sites or the smallest site. In the CPRD study, the IOW + IVW estimate was also more precise (smallest region RD and 95% CI: 5.41%, 1.03%-9.79%), IOW+IVW RD and 95% CI: 3.25%, 3.07%-3.43%). When performing pharmacoepidemiologic research in distributed networks or multi-site studies in the presence of EMMs, designating target populations has the potential to improve estimate precision and interpretability.

The International Working Group on New Developments in Pharmacovigilance: Advancing Methods and Communication in Pharmacovigilance.

PURPOSE: In 2019, the International Working Group (IWG), focusing on New Developments in Pharmacovigilance, was established. This group is coordinated by the Drug Safety Research Unit in the United Kingdom, and the mission of the IWG is to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines, thereby further protecting patients. Novel therapeutics are continuously being developed to alleviate medical conditions, but with advancing technologies, innovative pharmacovigilance methodologies need to be developed to effectively monitor the use and safety of these products. With reduced timelines proposed for premarketing clinical trials and increased application of real-world evidence supporting regulatory approvals, products may be used in real-world clinical practice in shorter timeframes than before. Therefore, the need for effective methods of monitoring medicines and collecting safety data in real-time is of paramount importance to public health. METHODS: The IWG aims to advance existing methodologies used in the detection, monitoring, and analysis of safety data in pharmacovigilance and to communicate best practice proposals to support decision making in health care. The IWG will identify areas requiring review of current processes or methodologic research and will communicate the output of the IWG through peer-reviewed publications, reports, and presentation of findings at relevant conferences and scientific meetings. FINDINGS: The IWG is currently reviewing two areas in pharmacovigilance; case-level causality assessment and the strengths and limitations of data sources. The IWG is advancing these areas by producing two scoping reviews which will be easily accessible to regulatory agencies, industry, academia, and interested persons or organizations. IMPLICATIONS: The scoping reviews comply with the IWGs mission to progress pharmacovigilance methodologies and promote the safe and effective use of medicines and vaccines. The present article shares details of the objectives of the IWG and provides an overview on the status of IWG activities.

Evaluating hybrid controls methodology in early-phase oncology trials: A simulation study based on the MORPHEUS-UC trial.

Phase Ib/II oncology trials, despite their small sample sizes, aim to provide information for optimal internal company decision-making concerning novel drug development. Hybrid controls (a combination of the current control arm and controls from one or more sources of historical trial data [HTD]) can be used to increase statistical precision. Here we assess combining two sources of Roche HTD to construct a hybrid control in targeted therapy for decision-making via an extensive simulation study. Our simulations are based on the real data of one of the experimental arms and the control arm of the MORPHEUS-UC Phase Ib/II study and two Roche HTD for atezolizumab monotherapy. We consider potential complications such as model misspecification, unmeasured confounding, different sample sizes of current treatment groups, and heterogeneity among the three trials. We evaluate two frequentist methods (with both Cox and Weibull accelerated failure time [AFT] models) and three different commensurate priors in Bayesian dynamic borrowing (with a Weibull AFT model), and modifications within each of those, when estimating the effect of treatment on survival outcomes and measures of effect such as marginal hazard ratios. We assess the performance of these methods in different settings and the potential of generalizations to supplement decisions in early-phase oncology trials. The results show that the proposed joint frequentist methods and noninformative priors within Bayesian dynamic borrowing with no adjustment on covariates are preferred, especially when treatment effects across the three trials are heterogeneous. For generalization of hybrid control methods in such settings, we recommend more simulation studies.

Glucagon like peptide-1 receptor agonists and the risk of skin cancer among patients with type 2 diabetes: Population-based cohort study.

AIMS: The objective of this study was to determine whether the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with an increased risk of melanoma and nonmelanoma skin cancer, separately, compared with the use of sulfonylureas among patients with type 2 diabetes. METHODS: Using the United Kingdom Clinical Practice Research Datalink (2007-2019), we assembled two new-user active comparator cohorts. In the first cohort assessing melanoma as the outcome, 11,786 new users of GLP-1 RAs were compared with 208,519 new users of sulfonylureas. In the second cohort assessing nonmelanoma skin cancer as the outcome, 11,774 new users of GLP-1 RAs were compared with 207,788 new users of sulfonylureas. Cox proportional hazards models weighted using propensity score fine stratification were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of melanoma and nonmelanoma skin cancer, respectively. RESULTS: Compared with sulfonylureas, GLP-1 RAs were not associated with an increased risk of either melanoma (42.6 vs. 43.9 per 100,000 person-years, respectively; HR 0.96, 95% CI 0.53-1.75) or nonmelanoma skin cancer (243.9 vs. 229.9 per 100,000 person-years, respectively; HR 1.03, 95% CI 0.80-1.33). There was no evidence of an association between cumulative duration of use with either melanoma or nonmelanoma skin cancer. Consistent results were observed in secondary and sensitivity analyses. CONCLUSIONS: In this population-based cohort study, GLP-1 RAs were not associated with an increased risk of melanoma or nonmelanoma skin cancer, compared with sulfonylureas.

Type of infertility and prevalence of congenital malformations.

BACKGROUND: Children conceived with assisted reproductive technologies (ART) or after a long waiting time have a higher prevalence of congenital malformations, but few studies have examined the contribution of type of infertility. OBJECTIVES: To quantify the association between causes of infertility and prevalence of malformations. METHODS: We compared the prevalence at birth of all and severe malformations diagnosed up to age 2 between 6656 children born in 1996-2017 to parents who had previously been assessed for infertility a an academic fertility clinic ("exposed") and 10,382 children born in the same period to parents with no recent medical history of infertility ("reference"). We estimated prevalence ratios (PR) and prevalence differences (PD), by infertility status, type of treatment (non-ART, ART), and infertility diagnosis, in all children and among singletons. RESULTS: Compared with children of parents with no infertility, children of parents with infertility had a higher prevalence of malformations (both definitions), particularly following ART conceptions. After accounting for treatment, ovulatory disorders were associated with a higher prevalence of both all (PR 1.49, 95% confidence interval (CI) 1.15, 1.93; PD 3.8, 95% CI 1.0, 6.6) and severe (PR 1.53, 95% CI 1.02, 2.29; PD 1.8, 95% CI -0.2, 3.7) malformations (the estimates refer to exposed children conceived without treatment). Unexplained and male factor infertility were associated with all and severe malformations, respectively. Estimates among singletons were similar. A diagnosis of ovulatory disorders was associated with all malformations also in analyses restricted to exposed children, regardless of treatment (we did not examine severe malformations, due to limited power). CONCLUSIONS: In this study, ovulatory disorders were consistently associated with a higher prevalence of congenital malformations (including severe malformations) among live births, regardless of mode of conception.

Dipeptidyl peptidase-4 inhibitors and the risk of skin cancer among patients with type 2 diabetes: a UK population-based cohort study.

INTRODUCTION: The dipeptidyl peptidase-4 (DPP-4) enzyme significantly influences carcinogenic pathways in the skin. The objective of this study was to determine whether DPP-4 inhibitors are associated with the incidence of melanoma and nonmelanoma skin cancer, compared with sulfonylureas. RESEARCH DESIGN AND METHODS: Using the United Kingdom Clinical Practice Research Datalink, we assembled two new-user active comparator cohorts for each skin cancer outcome from 2007 to 2019. For melanoma, the cohort included 96 739 DPP-4 inhibitor users and 209 341 sulfonylurea users, and 96 411 DPP-4 inhibitor users and 208 626 sulfonylurea users for non-melanoma skin cancer. Propensity score fine stratification weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs of melanoma and non-melanoma skin cancer, separately. RESULTS: Overall, DPP-4 inhibitors were associated with a 23% decreased risk of melanoma compared with sulfonylureas (49.7 vs 65.3 per 100 000 person-years, respectively; HR 0.77, 95% CI 0.61 to 0.96). The HR progressively reduced with increasing cumulative duration of use (0-2 years HR 1.14, 95% CI 0.84 to 1.54; 2.1-5 years HR 0.44, 95% CI 0.29 to 0.66; >5 years HR 0.33, 95% CI 0.14 to 0.74). In contrast, these drugs were not associated with the incidence of non-melanoma skin cancer, compared with sulfonylureas (448.1 vs 426.1 per 100 000 person-years, respectively; HR 1.06, 95% CI 0.98 to 1.15). CONCLUSIONS: In this large, population-based cohort study, DPP-4 inhibitors were associated with a reduced risk of melanoma but not non-melanoma skin cancer, compared with sulfonylureas.

Levothyroxine initiation and the risk of pregnancy loss among pregnant women with subclinical hypothyroidism: An observational study emulating a target trial.

BACKGROUND: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. OBJECTIVE: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. METHODS: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). CONCLUSIONS: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy.

Pregnancy, fetal, and neonatal outcomes after a first booster dose of covid-19 vaccine during pregnancy in Ontario, Canada: population based, retrospective cohort study.

Objective: To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy. Design: Population based, retrospective cohort study. Setting: Ontario, Canada, from 20 December 2021 to 31 August 2022. Participants: Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy. Main outcome measures: Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score <7, and small-for-gestational age infant (<10th percentile). We estimated hazard ratios and 95% confidence intervals for study outcomes, treating dose three as a time varying exposure and adjusting for confounding using inverse probability weighting. Results: Among 32 689 births, 18 491 (56.6%) were born to individuals who received a third covid-19 dose during pregnancy. Compared with eligible individuals who did not receive a third dose during pregnancy, no increased risks were associated with receiving a third covid-19 vaccine dose during pregnancy for placental abruption (adjusted hazard ratio 0.84 (95% confidence interval 0.70 to 1.02)), chorioamnionitis (0.67 (0.49 to 0.90)), postpartum haemorrhage (1.01 (0.89 to 1.16)), caesarean delivery (0.90 (0.87 to 0.94)), stillbirth (0.56 (0.39 to 0.81)), preterm birth (0.91 (0.84 to 0.99)), neonatal intensive care unit admission (0.96 (0.90 to 1.03)), 5 min Apgar score<7 (0.96 (0.82 to 1.14)), or small-for-gestational age infant (0.86 (0.79 to 0.93)). Conclusion: Receipt of a third covid-19 vaccine dose during pregnancy was not associated with an increased risk of adverse pregnancy, fetal, or neonatal outcomes. These findings can help to inform evidence based decision making about the risks and benefits of covid-19 booster doses during pregnancy.

First-line opioid agonist treatment as prevention against assisting others in initiating injection drug use: A longitudinal cohort study of people who inject drugs in Vancouver, Canada.

Background: Among people who inject drugs, frequent injecting and experiencing withdrawal are associated with facilitating others' first injections. As these factors may reflect an underlying substance use disorder, we investigated whether first-line oral opioid agonist treatment (OAT; methadone or buprenorphine/naloxone) reduces the likelihood that people who inject drugs help others initiate injecting. Methods: We used questionnaire data from semi-annual visits between December 2014-May 2018 on 334 people who inject drugs with frequent non-medical opioid use in Vancouver, Canada. We estimated the effect of current first-line OAT on subsequent injection initiation assistance provision (i.e., helped someone initiate injecting in the following six months) using inverse-probability-weighted estimation of repeated measures marginal structural models to reduce confounding and informative censoring by time-fixed and time-varying covariates. Results: By follow-up visit, 54-64% of participants reported current first-line OAT whereas 3.4-6.9% provided subsequent injection initiation assistance. Per the primary weighted estimate (n = 1114 person-visits), participants currently on first-line OAT (versus no OAT) were 50% less likely, on average, to subsequently help someone initiate injecting (relative risk [RR]=0.50, 95% CI=0.23-1.11). First-line OAT was associated with reduced risk of subsequent injection initiation assistance provision in participants who, at baseline, injected opioids less than daily (RR=0.15, 95% CI=0.05-0.44) but not in those who injected opioids daily (RR=0.86, 95% CI=0.35-2.11). Conclusions: First-line OAT seemingly reduces the short-term likelihood that people who inject drugs facilitate first injections. However, the extent of this potential effect remains uncertain due to imprecise estimation and observed heterogeneity by baseline opioid injecting frequency.

The Cardiovascular Safety of Five-Alpha-Reductase Inhibitors Among Men with Benign Prostatic Hyperplasia: A Population-Based Cohort Study.

BACKGROUND: Five-alpha reductase inhibitors (5αRIs) are used to treat benign prostatic hyperplasia (BPH). However, the cardiovascular effects of 5αRIs remain poorly understood. The study objective was to compare the rate of hospitalization for heart failure among men with BPH prescribed 5αRIs to that of men with BPH not prescribed BPH medications. METHODS: Using the Clinical Practice Research Datalink linked with hospitalization and vital statistics data, we conducted a population-based cohort study among patients newly diagnosed with BPH. We defined exposure as the current use of 5αRIs, current use of alpha-blockers, and no current use of BPH medications in a time-varying approach. The primary endpoint was hospitalization for heart failure, and secondary endpoints were myocardial infarction, stroke, and cardiovascular death. We used time-dependent Cox-proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Our cohort included 94,440 men with incident BPH. A total of 3893 hospitalizations for heart failure occurred over 527,660 person-years of follow-up (incidence rate 7.38; 95% CI, 7.15-7.61, per 1000 person-years). Compared with no current use of BPH medications, current use of 5αRIs was not associated with an increased risk of hospitalization for heart failure (HR 0.94; 95% CI, 0.86-1.03), myocardial infarction (HR 0.92; 95% CI, 0.81-1.05), stroke (HR 0.94; 95% CI, 0.85-1.05), or cardiovascular death (HR 0.89; 95% CI, 0.80-0.99). CONCLUSIONS: The use of 5αRIs was not associated with an increased risk of hospitalization for heart failure, myocardial infarction, stroke, or cardiovascular death compared with non-use.

Risk of recurrent severe maternal morbidity: a population-based study.

BACKGROUND: Severe maternal morbidity is a composite indicator of maternal health and obstetrical care. Little is known about the risk of recurrent severe maternal morbidity in a subsequent delivery. OBJECTIVE: This study aimed to estimate the risk of recurrent severe maternal morbidity in the next delivery after a complicated first delivery. STUDY DESIGN: We analyzed a population-based cohort study of women with at least 2 singleton hospital deliveries between 1989 and 2021 in Quebec, Canada. The exposure was severe maternal morbidity in the first hospital-recorded delivery. The study outcome was severe maternal morbidity at the second delivery. Log-binomial regression models adjusted for maternal and pregnancy characteristics were used to generate relative risks and 95% confidence intervals comparing women with and without severe maternal morbidity at first delivery. RESULTS: Among 819,375 women, 43,501 (3.2%) experienced severe maternal morbidity in the first delivery. The rate of severe maternal morbidity recurrence at second delivery was 65.2 vs 20.3 per 1000 in women with and without previous severe maternal morbidity (adjusted relative risk, 3.11; 95% confidence interval, 2.96-3.27). The adjusted relative risk for recurrence of severe maternal morbidity was greatest among women who had ≥3 different types of severe maternal morbidity at their first delivery, relative to those with none (adjusted relative risk, 5.50; 95% confidence interval, 4.26-7.10). Women with cardiac complication at first delivery had the highest risk of severe maternal morbidity in the next delivery. CONCLUSION: Women who experience severe maternal morbidity have a relatively high risk of recurrent morbidity in the subsequent pregnancy. In women with severe maternal morbidity, these study findings have implications for prepregnancy counseling and maternity care in the next pregnancy.

Methods for comparative effectiveness based on time to confirmed disability progression with irregular observations in multiple sclerosis.

Real-world data sources offer opportunities to compare the effectiveness of treatments in practical clinical settings. However, relevant outcomes are often recorded selectively and collected at irregular measurement times. It is therefore common to convert the available visits to a standardized schedule with equally spaced visits. Although more advanced imputation methods exist, they are not designed to recover longitudinal outcome trajectories and typically assume that missingness is non-informative. We, therefore, propose an extension of multilevel multiple imputation methods to facilitate the analysis of real-world outcome data that is collected at irregular observation times. We illustrate multilevel multiple imputation in a case study evaluating two disease-modifying therapies for multiple sclerosis in terms of time to confirmed disability progression. This survival outcome is derived from repeated measurements of the Expanded Disability Status Scale, which is collected when patients come to the healthcare center for a clinical visit and for which longitudinal trajectories can be estimated. Subsequently, we perform a simulation study to compare the performance of multilevel multiple imputation to commonly used single imputation methods. Results indicate that multilevel multiple imputation leads to less biased treatment effect estimates and improves the coverage of confidence intervals, even when outcomes are missing not at random.