Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

Impact of COVID-19 Pandemic on Dispensing of Cardiovascular Drugs in Norway: An Interrupted Time Series Study.

INTRODUCTION: The COVID-19 pandemic resulted in changes in prescription patterns and fillings for certain medications, but little is known about its impact on the dispensing of cardiovascular drugs. METHODS: Trends in dispensing of cardiovascular drugs before and during the pandemic were examined using a population-based cohort in Norway. Using interrupted time series analyses and considering March 1, 2020 as the interruption point, the impact of the pandemic on defined daily dose dispensing of prescribed cardiovascular drugs was estimated in a population of adults with and without pre-existing cardiovascular disease from January 2018 to December 2021. All data were analyzed in 2023. RESULTS: In a total of 4,053,957 adults, 690,910 (17.0%) had pre-existing cardiovascular disease. Prior to the pandemic, there was a significant monthly increase in any cardiovascular drug dispensing among those with pre-existing cardiovascular disease (0.30 defined daily dose per month per adult), including prescription of diuretics, calcium channel blockers, and lipid-modifying agents. After controlling for preinterruption trends, there was a slight decrease in level change immediately after the start of the pandemic (2.5 defined daily dose per month per adult) but an increase in the postinterruption trend (0.06 defined daily dose per month per adult) for dispensing of cardiovascular prescriptions, although these changes were not significant. CONCLUSIONS: Although the COVID-19 pandemic did not appear to result in significant changes in patterns of cardiovascular drug dispensing in Norway, continued access to cardiovascular drugs remains important to prevent further related morbidity.

The Families First Program to Prevent Child Abuse: Results of a Cluster Randomized Controlled Trial in West Java, Indonesia.

The Families First parenting program is a 10-week paraprofessional-administered adaptation of the Positive Discipline in Everyday Parenting program for West Java, Indonesia. It has not been tested in a randomized controlled trial. The objective was to evaluate the effects of Families First on physical and emotional punishment. We conducted a cluster randomized controlled trial and randomly assigned 20 rural and urban villages in West Java, Indonesia, to intervention or waitlist. Caregivers of children aged 0-7 years in intervention villages received Families First. Between 2017 and 2018, measurements were taken before randomization, immediately post-intervention, and 6 months post-intervention. Primary outcome was presence versus absence of caregiver-reported physical or emotional punishment immediately post-intervention. Intention-to-treat regression models accounted for clustering within villages and were run to compare between groups. Participants and study personnel could not be blinded. There were 374 caregivers in the 10 intervention villages and 362 in the 10 waitlist villages included in the trial and in outcome analyses. The intervention did not result in a lower proportion of intervention families using punishment immediately post-intervention (odds ratio [OR] for physical or emotional punishment immediately post intervention = 1.20 (95% CI 0.79-1.82). There were no significant differences for positive and involved parenting, setting limits, and opinion on discipline, but caregivers in the intervention group had significantly lower odds of using positive discipline (OR = 0.65 (95% CI 0.53-0.80). Families First did not prevent punishment in a setting with low levels of reported punishment but should be tested in a setting with higher levels or among people selected for risk or presence.

The Use of the Target Trial Approach in Perinatal Pharmacoepidemiology: A Scoping Review Protocol.

Background: Pregnant and postpartum women have been historically excluded from clinical trials, with data on the safety of drugs relying on observational research. Methodological concerns regarding the timing and dosing of medications, data sources, study designs, and methods used for estimating associations are still problematic in observational studies. Answering causal questions is even more complex. Despite the increased interest in emulating target trials using observational data, little is known about this approach in perinatal pharmacoepidemiology. Objective: This scoping review protocol aims to describe the methodology for assessing the available literature concerning emulating target trials for studying outcomes in women exposed to medications in the preconception, perinatal, or postpartum periods. Methods and Analysis: We will follow the methods detailed in the Joanna Briggs Institute reviewer's manual. We will adopt the six-stage framework recommended by Arksey and O'Malley and Levac and others. Web scraping techniques will be used for identifying relevant studies. Two authors will select articles based on the title and abstract, with discrepancies resolved by consensus, by a third reviewer. Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews flow diagram will be presented to reflect the search process. We will use existing statements to identify quality gaps in the current literature. Variables related to the content for perinatal pharmacoepidemiologic research will be included. The Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) will guide the assessment of the target trial emulation (i.e., treatment strategies compared, assignment procedures, follow-up period, outcome, and causal contrasts). Discussion: Data regarding the safety of drugs taken, prior to and during pregnancy and while lactating are lacking and it is necessary to understand how we can answer these questions using rigorous methods in observational research. Through this scoping review, we intend to understand to what extent the target trial approach is being used in perinatal pharmacoepidemiology and provide recommendations to improve its use in this field. Ethics and Dissemination: Secondary data from published scientific articles will be used, not requiring approval by the Research Ethics Committee with human beings. Findings will be submitted to a peer-reviewed journal.

Characteristics and outcomes of pregnant women with SARS-CoV-2 infection and other severe acute respiratory infections (SARI) in Brazil from January to November 2020.

BACKGROUND: Knowledge about COVID-19 in pregnancy is limited, and evidence on the impact of the infection during pregnancy and postpartum is still emerging. AIM: To analyze maternal morbidity and mortality due to severe acute respiratory infections (SARI), including COVID-19, in Brazil. METHODS: National surveillance data from the SIVEP-Gripe (Sistema de Informação de Vigilância Epidemiológica da Gripe) was used to describe currently and recently pregnant women aged 10-49 years hospitalized for SARI from January through November, 2020. SARI cases were grouped into: COVID-19; influenza or other detected agent SARI; and SARI of unknown etiology. Characteristics, symptoms and outcomes were presented by SARI type and region. Binomial proportion and 95% confidence intervals (95% CI) for outcomes were obtained using the Clopper-Pearson method. RESULTS: Of 945,460 SARI cases in the SIVEP-Gripe, we selected 11,074 women aged 10-49 who were pregnant (7964) or recently pregnant (3110). COVID-19 was confirmed in 49.4% cases; 1.7% had influenza or another etiological agent; and 48.9% had SARI of unknown etiology. The pardo race/ethnic group accounted for 50% of SARI cases. Hypertension/Other cardiovascular diseases, chronic respiratory diseases, diabetes, and obesity were the most common comorbidities. A total of 362 women with COVID-19 (6.6%; 95%CI 6.0-7.3) died. Mortality was 4.7% (2.2-8.8) among influenza patients, and 3.3% (2.9-3.8) among those with SARI of unknown etiology. The South-East, Northeast and North regions recorded the highest frequencies of mortality among COVID-19 patients. CONCLUSION: Mortality among pregnant and recently pregnant women with SARIs was elevated among those with COVID-19, particularly in regions where maternal mortality is already high.

Characteristics and outcomes of pregnant women with SARS-CoV-2 infection and other severe acute respiratory infections (SARI) in Brazil from January to November 2020

ABSTRACT Background: Knowledge about COVID-19 in pregnancy is limited, and evidence on the impact of the infection during pregnancy and postpartum is still emerging. Aim: To analyze maternal morbidity and mortality due to severe acute respiratory infections (SARI), including COVID-19, in Brazil. Methods: National surveillance data from the SIVEP-Gripe (Sistema de Informação de Vigilância Epidemiológica da Gripe) was used to describe currently and recently pregnant women aged 10-49 years hospitalized for SARI from January through November, 2020. SARI cases were grouped into: COVID-19; influenza or other detected agent SARI; and SARI of unknown etiology. Characteristics, symptoms and outcomes were presented by SARI type and region. Binomial proportion and 95% confidence intervals (95% CI) for outcomes were obtained using the Clopper-Pearson method. Results: Of 945,460 SARI cases in the SIVEP-Gripe, we selected 11,074 women aged 10-49 who were pregnant (7964) or recently pregnant (3110). COVID-19 was confirmed in 49.4% cases; 1.7% had influenza or another etiological agent; and 48.9% had SARI of unknown etiology. The pardo race/ethnic group accounted for 50% of SARI cases. Hypertension/Other cardiovascular diseases, chronic respiratory diseases, diabetes, and obesity were the most common comorbidities. A total of 362 women with COVID-19 (6.6%; 95%CI 6.0-7.3) died. Mortality was 4.7% (2.2-8.8) among influenza patients, and 3.3% (2.9-3.8) among those with SARI of unknown etiology. The South-East, Northeast and North regions recorded the highest frequencies of mortality among COVID-19 patients. Conclusion: Mortality among pregnant and recently pregnant women with SARIs was elevated among those with COVID-19, particularly in regions where maternal mortality is already high.

Hypertensive Disorders of Pregnancy and Medication Use in the 2015 Pelotas (Brazil) Birth Cohort Study.

Hypertensive disorders of pregnancy account for approximately 22% of all maternal deaths in Latin America and the Caribbean. Pharmacotherapies play an important role in preventing and reducing the occurrence of adverse outcomes. However, the patterns of medications used for treating women with hypertensive disorders of pregnancy (HDP) living in this country is unclear. A population-based birth cohort study including 4262 women was conducted to describe the pattern of use of cardiovascular agents and acetylsalicylic acid between women with and without HDP in the 2015 Pelotas (Brazil) Birth Cohort. The prevalence of maternal and perinatal outcomes in this population was also assessed. HDP were classified according to Ministry of Health recommendations. Medications were defined using the Anatomical Therapeutic Chemical Classification System and the substance name. In this cohort, 1336 (31.3%) of women had HDP. Gestational hypertension was present in 636 (47.6%) women, 409 (30.6%) had chronic hypertension, 191 (14.3%) pre-eclampsia, and 89 (6.7%) pre-eclampsia superimposed on chronic hypertension. Approximately 70% of women with HDP reported not using any cardiovascular medications. Methyldopa in monotherapy was the most frequent treatment (16%), regardless of the type of HDP. Omega-3 was the medication most frequently reported by women without HDP. Preterm delivery, caesarean section, low birth weight, and neonatal intensive care admissions were more prevalent in women with HDP. Patterns of use of methyldopa were in-line with the Brazilian guidelines as the first-line therapy for HDP. However, the large number of women with HDP not using medications to manage HDP requires further investigation.

Protocol for a cluster randomised controlled trial evaluating a parenting with home visitation programme to prevent physical and emotional abuse of children in Indonesia: the Families First Programme.

INTRODUCTION: Every year, up to 1 billion children are victims of violence worldwide. Most child abuse takes place in the context of punishment. The Families First Programme, an adaptation of the Positive Discipline in Everyday Parenting Programme to the West Java context, is a parenting support programme anchored on children's rights that gives parents guidance on child development, parenting and positive discipline practices. This trial will evaluate the effectiveness of the Families First Programme compared with a waitlist control group. METHODS AND ANALYSIS: This is a pragmatic, parallel-group, stratified, cluster-randomised controlled trial. Twenty rural and urban villages in the Cianjur District, Indonesia, involving 720 caregivers of children up to 7 years of age, will be randomised. Villages will receive either a parenting programme consisting of 10 group sessions and four home visits over 3 months and standard community health and social services or just the latter. After completion of the trial period, the programme will be offered to those in the delayed group. Outcome data will be collected before randomisation (baseline), immediately postintervention (3 months postrandomisation) and 6 months later (9 months postrandomisation). The primary outcome will be frequency of physical and emotional punishment as measured by a weighted sum from three self-report items. Primary outcome analysis will use Poisson regression with generalised estimating equations and assess the interaction between intervention and time over baseline and 3 and 9 months postrandomisation assessments. Concurrent process evaluation will be conducted to assess programme satisfaction and facilitators and barriers to the implementation of the programme generalisable to other settings. ETHICS AND DISSEMINATION: Ethics approval was obtained from McGill University and Universitas Katolik Indonesia Atma Jaya. Results will be published in peer-reviewed journals and presented at scientific conferences and events for decision-makers, including in the participating communities. TRIAL REGISTRATION NUMBER: NCT03374761.

An ultrasound-based fetal weight reference for twins.

OBJECTIVE: The objective of the study was to construct an ultrasound-based estimated fetal weight-for-gestational-age reference for twin fetuses, stratified by chorionicity. STUDY DESIGN: We performed a retrospective cohort study of live-born nonanomalous twins delivered longer than 34 weeks at the Royal Victoria Hospital (Montreal, Canada). Fetal weight was estimated using ultrasound biometric measurements combined using Hadlock's formula. Multilevel linear regression models were used to adjust for clustering by twin pregnancy and to account for the serial ultrasound measurements taken on each fetus. Based on this model, smoothed estimates of fetal weight were made for the third, 10th, 50th, 90th, and 97th percentiles of the fetal weight distribution. Fetal weight references were stratified by fetal chorionicity. RESULTS: A total of 642 twin fetuses with a total of 3078 ultrasound observations were included. Sixteen percent of the cohort was monochorionic. Fetal growth accelerated in the second trimester and continued in a linear pattern in the third trimester until term. As expected, the median weight for monochorionic twins was lighter than the median weight for dichorionic twins throughout pregnancy. CONCLUSION: The reference values created in this study address serious methodological limitations of existing reference charts and thus provide an improved tool for assessing fetal growth in twin pregnancies. Importantly, dichorionic twins deviated from singleton reference charts at approximately 32 weeks, whereas monochorionic twins deviated at 28 weeks.

The positivity assumption and marginal structural models: the example of warfarin use and risk of bleeding.

Estimates of the average causal effect (ACE) of warfarin on the risk of bleeding may be confounded by indication as patients at high risk of bleeding are unlikely to be prescribed warfarin. One approach to estimating the ACE is inverse probability of treatment weighting (IPTW). This study was designed to examine the use of IPTW in this setting, and to demonstrate problems with the violation of the positivity assumption. We analyzed a case-control study on 4,028 cases of gastro-intestinal bleeding and 79,239 controls set in the United Kingdom's General Practice Research Database. Warfarin exposure was defined as a prescription issued in the 90 days before the index date. Secondary analyses were conducted restricted to patients more likely to receive warfarin and with a truncated weight distribution, to exclude subjects highly unlikely to be treated. The estimated association between warfarin use and bleeding was stronger with IPTW [odds ratio (OR): 17.2; 95% confidence interval (CI): 6.5-37.7] than with a standard logistic regression model (OR: 2.1; 95% CI: 1.7-2.5). The presence of large weights (five subjects with stabilized weight >500) indicated a potential violation of the positivity assumption. In the restricted analysis, both IPTW (OR: 2.0; 95% CI: 0.4-9.6) and standard regression (OR: 1.6; 95% CI: 1.3-2.0) were compatible with a meta-analysis of randomized trials inverse probability of treatment weighting is sensitive to the positivity assumption; however, such sensitivity may assist in diagnosing off-support inference.