Economic Burden of Medically Attended Respiratory Syncytial Virus Infections Among Privately Insured Children Under 5 Years of Age in the USA.

BACKGROUND: The cost of medically attended RSV LRI (lower respiratory infection) is critical in determining the economic value of new RSV immunoprophylaxes. However, most studies have focused on intermittent RSV encounters, not the episode of care that captures the entirety of RSV illness. METHODS: We created age- and condition-specific cohorts of children under 5 years of age using MarketScan® data (2015-2019). We contrasted aggregating healthcare costs over RSV-LRTI episodes to ascertaining costs based on RSV-specific encounters only. Economic burden was estimated by multiplying costs per encounter or per episode by their respective incidence rates. RESULTS: Average cost was higher per episode than per encounter regardless of settings (inpatient: $28,586 vs. $18,056 and outpatient/ED: $2099 vs. $407 for infants). Across ages, the economic burden was highest for infants and RSV-LRTI requiring inpatient care, but the burden in outpatient/ED settings was disproportionately higher than costs due to higher incidence rates (for inpatient vs. outpatient episodes: $226,403 vs. $101,269; for inpatient vs. outpatient encounters: $151,878 vs. $38,819 per 1000 infant-years). For high-risk children, cost and burden were up to 3-10 times higher, respectively. CONCLUSIONS: With a comprehensive stratification by settings and risk condition, the encounter- versus episode-based estimates provide a robust range for policymakers' economic appraisal of new RSV immunoprophylaxes.

Cannabis use and acute postoperative pain outcomes in older adults: a propensity matched retrospective cohort study.

INTRODUCTION: Cannabis use is increasing among older adults, but its impact on postoperative pain outcomes remains unclear in this population. We examined the association between cannabis use and postoperative pain levels and opioid doses within 24 hours of surgery. METHODS: We conducted a propensity score-matched retrospective cohort study using electronic health records data of 22 476 older surgical patients with at least 24-hour hospital stays at University of Florida Health between 2018 and 2020. Of the original cohort, 2577 patients were eligible for propensity-score matching (1:3 cannabis user: non-user). Cannabis use status was determined via natural language processing of clinical notes within 60 days of surgery and structured data. The primary outcomes were average Defense and Veterans Pain Rating Scale (DVPRS) score and total oral morphine equivalents (OME) within 24 hours of surgery. RESULTS: 504 patients were included (126 cannabis users and 378 non-users). The median (IQR) age was 69 (65-72) years; 295 (58.53%) were male, and 442 (87.70%) were non-Hispanic white. Baseline characteristics were well balanced. Cannabis users had significantly higher average DVPRS scores (median (IQR): 4.68 (2.71-5.96) vs 3.88 (2.33, 5.17); difference=0.80; 95% confidence limit (CL), 0.19 to 1.36; p=0.01) and total OME (median (IQR): 42.50 (15.00-60.00) mg vs 30.00 (7.50-60.00) mg; difference=12.5 mg; 95% CL, 3.80 mg to 21.20 mg; p=0.02) than non-users within 24 hours of surgery. DISCUSSION: This study showed that cannabis use in older adults was associated with increased postoperative pain levels and opioid doses.

Antihypertensive utilization patterns among pregnant persons with pre-existing hypertension in the US: A population-based study.

BACKGROUND: Hypertension among persons with childbearing potential is on the rise. Maintaining proper blood pressure during pregnancy is vital to prevent maternal and neonatal complications. Yet, limited evidence on the risk-benefit of various antihypertensives presents challenges for informed decision-making during this critical period. This study aimed to examine the utilization patterns of different classes of antihypertensives among persons with pre-existing hypertension before, during, and after pregnancy. METHODS: We used MarketScan® Commercial Database 2011-2020 to analyze antihypertensive utilization among pregnant persons aged 12 to 55 identified via a validated algorithm. Pre-existing hypertension was defined as ≥1 inpatient or ≥2 outpatient encounters for hypertension within the 180 days preceding the LMP. Antihypertensive utilization was described during target periods: 0-3 months (0-3M) before pregnancy, 1st/2nd/3rd trimester (T1/2/3), 0-3M, and 4-6M after pregnancy. RESULTS: We identified 1,950,292 pregnancies, of which 20,576 (12,978 live and 7,598 non-live) had pre-existing hypertension. Both groups had similar antihypertensive use (80.1% and 81.0%, respectively) during the 6 months before pregnancy (baseline). For live-birth pregnancies, 13.9% of baseline users discontinued treatment during pregnancy, while 28.9% of non-users initiated antihypertensives during pregnancy, and 17.2% started postpartum. Before pregnancy, the predominant antihypertensives included thiazide diuretics (21.9%), combined α- and ß-blockers (18.4%), and dihydropyridines (16.2%). During pregnancy, thiazide diuretics, cardioselective ß-blockers, and ACE inhibitors declined (T3: 3.0%, 4.2%, and 0.8%). Dihydropyridine use was steady during pregnancy, but preference shifted from amlodipine to nifedipine in T3 (2.2.% vs.10.8%). Central α2-agonists increased during pregnancy (up to 15.2% in T3) compared to both pre- (9.8%) and post-pregnancy (5.7%). ARBs mirrored ACE inhibitors, with less than 1% utilization in later trimesters. Combination agents dropped from 10.8% pre-pregnancy to 0.8% in T3, then rebounded to 7.3% post-pregnancy. CONCLUSION: Research is warranted to evaluate the choice of antihypertensives and optimal timing to switch to safer alternatives, considering maternal and fetal outcomes.

Triple challenges - Small sample size in both exposure and control groups to scan rare maternal outcomes in a signal identification approach: A simulation study.

There is a dearth of safety data on maternal outcomes after perinatal medication exposure. Data-mining for unexpected adverse event occurrence in existing datasets is a potentially useful approach. One method, the Poisson tree-based scan statistic (TBSS), assumes that the expected outcome counts, based on incidence of outcomes in the control group, are estimated without error. This assumption may be difficult to satisfy with a small control group. Our simulation study evaluated the effect of imprecise incidence proportions from the control group on TBSS' ability to identify maternal outcomes in pregnancy research. We simulated base case analyses with "true" expected incidence proportions and compared these to imprecise incidence proportions derived from sparse control samples. We varied parameters impacting Type I error and statistical power (exposure group size, outcome's incidence proportion, and effect size). We found that imprecise incidence proportions generated by a small control group resulted in inaccurate alerting, inflation of Type I error, and removal of very rare outcomes for TBSS analysis due to "zero" background counts. Ideally, the control size should be at least several times larger than the exposure size to limit the number of false positive alerts and retain statistical power for true alerts.

Antibiotic treatment to prevent pediatric acute otitis media infectious complications: A meta-analysis.

BACKGROUND: Most US children with acute otitis media [AOM] receive prompt antibiotic treatment, though guidelines encourage watchful waiting. Previous systematic reviews of antibiotics versus watchful waiting have focused on symptom resolution and RCTs, limiting the assessment of serious, rare complications. We sought to evaluate these complications by including observational studies. METHODS: RCTs and observational studies that compared antibiotics to placebo or watchful waiting for pediatric clinician diagnosed AOM were identified [PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, Central Register of Controlled Trials, and Web of Science] and reviewed for meta-analysis. Two reviewers independently extracted study characteristics, patient characteristics, and outcomes. We assessed publication bias, study bias with ROBINS-1 and RoB-2 and used random-effects models to assess treatment effects. RESULTS: 24 studies were included. Antibiotics decreased the risk of acute mastoiditis [incidence 0.02%, RR 0.48, 95% CI 0.40-0.59; NNT 5,368]. This protective effect may be underestimated because of misclassification of non-suppurative conditions as AOM. Intracranial complications remained too rare to assess. Antibiotics markedly increased the risk of adverse effects [incidence 10.5%, RR 1.49, 1.27-1.73; NNH 23]. Studies used non-specific criteria for acute mastoiditis, potentially underestimating treatment effects. CONCLUSIONS: Prompt antibiotic therapy reduces the risk for some AOM complications. The NNT to prevent serious, rare complications is high, while the NNH is relatively low. Large-scale population-based observational studies using real-world datasets with validated measures of severe complications are needed to improve understanding of risk factors for serious AOM complications, facilitate more selective antibiotic therapy, and optimize individual outcomes and public health.

Model correction of diagnostic coding-based RSV incidence for children 0-4 years in the US.

BACKGROUND: Although administrative claims data have a high degree of completeness, not all medically attended Respiratory Syncytial Virus-associated lower respiratory tract infections (RSV-LRTIs) are tested or coded for their causative agent. We sought to determine the attribution of RSV to LRTI in claims data via modeling of temporal changes in LRTI rates against surveillance data. METHODS: We estimated the weekly incidence of LRTI (inpatient, outpatient, and total) for children 0-4 years using 2011-2019 commercial insurance claims, stratified by HHS region, matched to the corresponding weekly NREVSS RSV and influenza positivity data for each region, and modelled against RSV, influenza positivity rates, and harmonic functions of time assuming negative binomial distribution. LRTI events attributable to RSV were estimated as predicted events from the full model minus predicted events with RSV positivity rate set to 0. RESULTS: Approximately 42% of predicted RSV cases were coded in claims data. Across all regions, the percentage of LRTI attributable to RSV were 15-43%, 10-31%, and 10-31% of inpatient, outpatient, and combined settings, respectively. However, when compared to coded inpatient RSV-LRTI, 9 of 10 regions had improbable corrected inpatient LRTI estimates (predicted RSV/coded RSV ratio < 1). Sensitivity analysis based on separate models for PCR and antigen-based positivity showed similar results. CONCLUSIONS: Underestimation based on coding in claims data may be addressed by NREVSS-based adjustment of claims-based RSV incidence. However, where setting-specific positivity rates is unavailable, we recommend modeling across settings to mirror NREVSS's positivity rates which are similarly aggregated, to avoid inaccurate adjustments.

CYP2C19 Genotype Is Associated With Adverse Cardiovascular Outcomes in Black Patients Treated With Clopidogrel Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. METHODS AND RESULTS: Adults among 5 institutions who self-identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P<0.10. The population included 567 Black patients treated with clopidogrel (median age, 62 years; 46% women; 70% with an acute coronary syndrome indication for PCI). Major atherothrombotic events rates were significantly higher among clopidogrel-treated intermediate and poor metabolizers (24 of 125 [19.2%]) versus patients treated with clopidogrel without a no function allele (43 of 442 [9.7%]; 35.1 versus 15.9 events per 100 person-years; adjusted hazard ratio, 2.00 [95% CI, 1.20-3.33], P=0.008). Bleeding event rates were low overall (23 of 567 [4.1%]) and did not differ among the metabolizer groups. CONCLUSIONS: Black patients with CYP2C19 intermediate and poor metabolizer phenotypes who are treated with clopidogrel exhibit increased risk of adverse cardiovascular outcomes after PCI in a real-world clinical setting. Bleeding outcomes should be interpreted cautiously. Prospective studies are needed to determine whether genotype-guided use of prasugrel or ticagrelor in intermediate and poor metabolizers improves outcomes in Black patients undergoing PCI.

Prenatal Exposure to Valproic Acid Across Various Indications for Use.

Importance: Teratogenic outcomes associated with valproic acid use represent a substantial concern for persons of childbearing age. Regulatory agencies worldwide have enhanced warnings or implemented risk minimization programs to reduce exposure during pregnancy. Objectives: To determine pregnancy rates during valproic acid use and concomitant contraception use across indications. Design, Setting, and Participants: This retrospective cohort study used data from the Merative MarketScan commercial claims databases from January 1, 2005, to December 31, 2020, to identify female patients aged 12 to 44 years who initiated valproic acid treatment and had continuous insurance enrollment 6 months before initiation and 9 months after treatment end. A treatment episode included consecutive prescription fills that occurred within 7 days from the end of the days' supply of the previous dispensing. Data were analyzed from March 1 to September 10, 2023. Main Outcomes and Measures: Treatment episodes were categorized by inferred indication using diagnoses preceding treatment initiation, including epilepsy, migraine or headache, mood disorders, and unknown or off-label uses. Pregnancy incidence rate ratios (IRRs) were calculated and were adjusted for age and calendar year. Contraceptive use (prescription contraceptives, intrauterine devices, and implants) during treatment was examined. Results: The cohort included 165 772 valproic acid treatment episodes among 69 390 women (mean [SD] age, 29.8 [10.0] years). Mood disorders (42.5%) were the most common indication, followed by migraine or headache (20.1%), with epilepsy playing a minor role (14.9%). Pregnancy incidence rates during valproic acid use remained unchanged, with a rate of 1.74 (95% CI, 1.14-2.53) per 100 person-years in 2005 and a rate of 1.90 (95% CI, 1.16-3.12) per 100 person-years in 2019. Compared with epilepsy, pregnancy rates were more than double for mood disorder (IRR, 2.16 [95% CI, 1.93-2.42]) and migraine or headache (IRR, 2.01 [95% CI, 1.92-2.09]). Few treatment episodes coincided with contraceptive use (37 012 [22.3%]), and oral dosage forms were the most common (27 069 [73.1%]). Conclusions and Relevance: In this cohort study of patients of childbearing age who used valproic acid, pregnancy rates during valproic acid use did not decrease despite enhanced US Food and Drug Administration safety communications, and contraception use remained low. Patients with migraine and mood disorders accounted for the largest proportion of valproic acid use and had the highest pregnancy rates, while patients with epilepsy had the lowest. These findings suggest a need to enhance efforts to mitigate prenatal exposure to valproic acid, especially for indications where the risk of use during pregnancy outweighs the benefit.

Updated core competencies in pharmacoepidemiology to inform contemporary curricula and training for academia, government, and industry.

PURPOSE: The first paper to specify the core content of pharmacoepidemiology as a profession was published by an ISPE (International Society for Pharmacoepidemiology) workgroup in 2012 (Jones JK et al. PDS 2012; 21[7]:677-689). Due to the broader and evolving scope of pharmacoepidemiology, ISPE considers it important to proactively identify, update and expand the list of core competencies to inform curricula of education programs; thus, better positioning pharmacoepidemiologists across academic, government (including regulatory), and industry positions. The aim of this project was to update the list of core competencies in pharmacoepidemiology. METHODS: To ensure applicability of findings to multiple areas, a working group was established consisting of ISPE members with positions in academia, industry, government, and other settings. All competencies outlined by Jones et al. were extracted from the initial manuscript and presented to the working group for review. Expert-based judgments were collated and used to identify consensus. It was noted that some competencies could contribute to multiple groups and could be directly or indirectly related to a group. RESULTS: Five core domains were proposed: (1) Epidemiology, (2) Clinical Pharmacology, (3) Regulatory Science, (4) Statistics and data science, and (5) Communication and other professional skills. In total, 55 individual competencies were proposed, of which 25 were new competencies. No competencies from the original work were dropped but aggregation or amendments were made where considered necessary. CONCLUSIONS: While many core competencies in pharmacoepidemiology have remained the same over the past 10 years, there have also been several updates to reflect new and emerging concepts in the field.

Advancing the utilization of real-world data and real-world evidence in clinical pharmacology and translational research-Proceedings from the ASCPT 2023 preconference workshop.

Real-world data (RWD) and real-world evidence (RWE) are now being routinely used in epidemiology, clinical practice, and post-approval regulatory decisions. Despite the increasing utility of the methodology and new regulatory guidelines in recent years, there remains a lack of awareness of how this approach can be applied in clinical pharmacology and translational research settings. Therefore, the American Society of Clinical Pharmacology & Therapeutics (ASCPT) held a workshop on March 21st, 2023 entitled "Advancing the Utilization of Real-World Data (RWD) and Real-World Evidence (RWE) in Clinical Pharmacology and Translational Research." The work described herein is a summary of the workshop proceedings.

Effectiveness of Clopidogrel vs Alternative P2Y12 Inhibitors Based on the ABCD-GENE Score.

BACKGROUND: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. OBJECTIVES: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). METHODS: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. RESULTS: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). CONCLUSIONS: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.

Short- and long-term safety of discontinuing chronic opioid therapy among older adults with Alzheimer's disease and related dementia.

BACKGROUND: Limited evidence exists on the short- and long-term safety of discontinuing versus continuing chronic opioid therapy (COT) among patients with Alzheimer's disease and related dementias (ADRD). METHODS: This cohort study was conducted among 162,677 older residents with ADRD and receipt of COT using a 100% Medicare nursing home sample. Discontinuation of COT was defined as no opioid refills for ≥90 days. Primary outcomes were rates of pain-related hospitalisation, pain-related emergency department visit, injury, opioid use disorder (OUD) and opioid overdose (OD) measured by diagnosis codes at quarterly intervals during 1- and 2-year follow-ups. Poisson regression models were fit using generalised estimating equations with inverse probability of treatment weights to model quarterly outcome rates between residents who discontinued versus continued COT. RESULTS: The study sample consisted of 218,040 resident episodes with COT; of these episodes, 180,916 residents (83%) continued COT, whereas 37,124 residents (17%) subsequently discontinued COT. Discontinuing (vs. continuing) COT was associated with higher rates of all outcomes in the first quarter, but these associations attenuated over time. The adjusted rates of injury, OUD and OD were 0, 69 and 60% lower at the 1-year follow-up and 11, 81 and 79% lower at the 2-year follow-up, respectively, for residents who discontinued versus continued COT, with no difference in the adjusted rates of pain-related hospitalisations or emergency department visits. CONCLUSIONS: The rates of adverse outcomes were higher in the first quarter but lower or non-differential at 1-year and 2-year follow-ups between COT discontinuers versus continuers among older residents with ADRD.

The Reporting Recommendations Intended for Pharmaceutical Risk Minimization Evaluation Studies: Standards for Reporting of Implementation Studies Extension (RIMES-SE).

INTRODUCTION: The Reporting recommendations Intended for pharmaceutical risk Minimization Evaluation Studies (RIMES) was developed to improve the quality of reporting of risk minimization program evaluations. In light of continued inadequacies in study reporting, and high-profile program implementation failures, we updated the RIMES Checklist to incorporate additional concepts from the Standards for Reporting of Implementation studies (StaRI). METHODS: The development of the updated checklist, the RIMES-StaRI Extension (RIMES-SE), entailed developing a study protocol and drafting an initial pool of items based on a mapping of the RIMES against the StaRI checklist. A modified e-Delphi exercise was then conducted to determine the importance and understandability of items for checklist inclusion. An expert workshop and an online commentary period for additional feedback followed. RESULTS: The RIMES-SE contains 27 items. It includes two signature features of the StaRI Checklist: 1) a dual strand of items (represented in two columns) describing the risk minimization program (the 'intervention') and the corresponding implementation strategy; and 2) applicable to an array of different research methodologies. CONCLUSIONS: The RIMES-SE Statement and Checklist extends the reporting guidelines set forth in the original RIMES Checklist via inclusion of key implementation science concepts. It is intended to improve the quality and transparency of reporting of risk minimization evaluation studies so as to advance drug safety science.

Comparing pregnancy and pregnancy outcome rates between adolescents with and without pre-existing mental disorders.

BACKGROUND: There are limited population-based data on the role of mental disorders in adolescent pregnancy, despite the presence of mental disorders that may affect adolescents' desires and decisions to become pregnant. OBJECTIVE: This study aimed to examine the relationship between specific types of mental disorders and pregnancy rates and outcome types among adolescents aged 13-19 years, using single-year age groups. METHODS: We conducted a retrospective cohort study using data from the Merative™ MarketScan Research Databases. The study population consisted of females aged 13-19 years with continuous insurance enrollment for three consecutive calendar years between 2005 and 2015. Pregnancy incidence rates were calculated both overall and within the different categories of mental disorders. The presence of mental disorders, identified through diagnosis codes, was classified into 15 categories. Pregnancy and pregnancy outcome types were determined using diagnosis and procedure codes indicating the pregnancy status or outcome. To address potential over- or underestimations of mental disorder-specific pregnancy rates resulting from variations in age distribution across different mental disorder types, we applied age standardization using 2010 U.S. Census data. Finally, multivariable logistic regression models were used to examine the relationships between 15 specific types of mental disorders and pregnancy incidence rates, stratified by age. RESULTS: The age-standardized pregnancy rate among adolescents diagnosed with at least one mental disorder was 15.4 per 1,000 person-years, compared to 8.5 per 1,000 person-years among adolescents without a mental disorder diagnosis. Compared to pregnant adolescents without a mental disorder diagnosis, those with a mental disorder diagnosis had a slightly but significantly higher abortion rate (26.7% vs 23.8%, P-value < 0.001). Multivariable logistic regression models showed that substance use-related disorders had the highest odds ratios (ORs) for pregnancy incidence, ranging from 2.4 [95% confidence interval (CI): 2.1-2.7] to 4.5 [95% CI:2.1-9.5] across different age groups. Overall, bipolar disorders (OR range: 1.6 [95% CI:1.4-1.9]- 1.8 [95% CI: 1.7-2.0]), depressive disorders (OR range: 1.4 [95% CI: 1.3-1.5]- 2.7 [95% CI: 2.3-3.1]), alcohol-related disorders (OR range: 1.2 [95% CI: 1.1-1.4]- 14.5 [95% CI: 1.2-178.6]), and attention-deficit/conduct/disruptive behavior disorders (OR range: 1.1 [95% CI: 1.0-1.1]- 1.8 [95% CI: 1.1-3.0]) were also significantly associated with adolescent pregnancy, compared to adolescents without diagnosed mental disorders of the same age. CONCLUSION: This study emphasizes the elevated rates of pregnancy and pregnancy ending in abortion among adolescents diagnosed with mental disorders, and identifies the particular mental disorders associated with higher pregnancy rates.

Prenatal Care Initiation and Exposure to Teratogenic Medications.

Importance: With new legal abortion restrictions, timing of prenatal care initiation is critical to allow for discussion of reproductive options among pregnancies exposed to teratogenic medications. Objective: To investigate the prevalence of prenatal exposure to teratogenic medications and prenatal care initiation across gestational weeks. Design, Setting, and Participants: This descriptive, population-based cross-sectional study used health encounter data from a national sample of individuals with employer-sponsored health insurance. A validated algorithm identified pregnancies among persons identifying as female that ended with a live or nonlive outcome between January 2017 and December 2019. Data were analyzed from December 2022 to December 2023. Exposures: Prenatal exposure to any of 137 teratogenic medications, measured via pharmacy and medical claims. Measurement of prenatal care initiation was adapted from the Children's Health Care Quality Measures. Main Outcomes and Measures: Prevalence of prenatal exposure to teratogens and prenatal care initiation by gestational week. Timing of prenatal teratogenic exposure was compared with timing of prenatal care initiation and legal abortion cutoffs. Results: Among 639 994 pregnancies, 472 472 (73.8%; 95% CI, 73.7%-73.9%) had a live delivery (mean [SD] age, 30.9 [5.4] years) and 167 522 (26.2%; 95% CI, 26.1%-26.3%) had a nonlive outcome (mean [SD] age, 31.6 [6.4] years). Of pregnancies with live deliveries, 5.8% (95% CI, 5.7%-5.8%) were exposed to teratogenic medications compared with 3.1% (95% CI, 3.0%-3.2%) with nonlive outcomes. Median time to prenatal care was 56 days (IQR, 44-70 days). By 6 weeks' gestation, 8186 pregnancies had been exposed to teratogenic medications (25.2% [95% CI, 24.7%-25.7%] of pregnancies exposed at any time during gestation; 1.3% [95% CI, 1.3%-1.3%] of all pregnancies); in 6877 (84.0%; 95% CI, 83.2%-84.8%), prenatal care was initiated after 6 weeks or not at all. By 15 weeks, teratogenic exposures had occurred for 48.9% (95% CI, 48.4%-49.5%) of all teratogen-exposed pregnancies (2.5% [2.4-2.5] of all pregnancies); prenatal care initiation occurred after 15 weeks for 1810 (16.8%; 95% CI, 16.1%-17.5%) with live deliveries and 2975 (58.3%; 95% CI, 56.9%-59.6%) with nonlive outcomes. Teratogenic medications most used within the first 15 gestational weeks among live deliveries included antiinfectives (eg, fluconazole), anticonvulsants (eg, valproate), antihypertensives (eg, lisinopril), and immunomodulators (eg, mycophenolate). For nonlive deliveries, most antihypertensives were replaced by vitamin A derivatives. Conclusions and Relevance: In this cross-sectional study, most exposures to teratogenic medications occurred in early pregnancy and before prenatal care initiation, precluding prenatal risk-benefit assessments. Prenatal care commonly occurred after strict legal abortion cutoffs, prohibiting consideration of pregnancy termination if concerns about teratogenic effects arose.

Sociodemographic Characteristics of Adverse Event Reporting in the USA: An Ecologic Study.

INTRODUCTION: The Food and Drug Administration Adverse Event Reporting System (FAERS) is a vital source of new drug safety information, but whether adverse event (AE) information collected from these systems adequately captures experiences of the overall United States (US) population is unknown. OBJECTIVE: To examine determinants of consumer AE reporting in the USA. METHODS: Five-year AE reporting rate per 100,000 residents per US county were calculated, mapped, and quartiled for AE reports received directly from consumers between 2011 and 2015. Associations between county-level sociodemographic factors obtained from County Health Rankings and AE reporting rates were evaluated using negative binomial regression. RESULTS: Reporting rates were variable across US counties with > 17.6 reports versus ≤ 5.5 reports/100,000 residents in the highest and lowest reporting quartile, respectively. Controlling for drug utilization, counties with higher reporting rates had higher proportions of individuals age ≥ 65 years (e.g., 2.4% reporting increase per 1% increase in individuals age > 65, incidence rate ratio (IRR): 1.024, 95% confidence interval (CI): 1.017-1.030), higher proportions of females (IRR: 1.027, 95% CI 1.012-1.043), uninsured (IRR: 1.009, 95% CI 1.005-1.013), higher median log household incomes (IRR: 1.897, 95% CI 1.644-2.189) and more mental health providers per 100,000 residents (IRR: 1.003, 95% CI 1.001-1.004). Lower reporting was observed in counties with higher proportions of individuals age ≤ 18 years (IRR: 0.966, 95% CI 0.959-0.974), American Indian or Alaska Native individuals (IRR: 0.991, 95% CI 0.986-0.996), individuals not proficient in English (IRR: 0.978, 95% CI 0.965-0.991), and individuals residing in rural areas within a county (IRR: 0.998, 95% CI 0.997-0.998). CONCLUSIONS: Observed variations in consumer AE reporting may be related to sociodemographic factors and healthcare access. Because these factors may also correspond to AE susceptibility, voluntary AE reporting systems may be suboptimal for capturing emerging drug safety concerns among more vulnerable populations.

Evaluating Provider and Pharmacy Discordance in Potential Calcium Channel Blocker-Loop Diuretic Prescribing Cascade.

BACKGROUND: Prescribing cascades occur when a drug-induced adverse event is treated with a new medication. Identifying clinical scenarios in which prescribing cascades are more likely to occur may help determine ways to prevent prescribing cascades. OBJECTIVE: To understand the extent to which discordant providers and discordant pharmacies contribute to the dihydropyridine calcium channel blocker (DH CCB)-loop diuretic prescribing cascade. STUDY POPULATION AND DESIGN: A retrospective cohort study using Medicare Fee-For-Service data (2011-2018) of adults aged ≥ 66 years. EXPOSURES: Patients who initiated DH CCB with subsequent initiation of loop diuretic (DH CCB-loop diuretic dyad) within 90 days or patients who initiated angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) with subsequent initiation of a loop diuretic (ACEI/ARB-loop diuretic dyad; control). MAIN OUTCOMES: The primary outcomes were provider and pharmacy discordance for prescribing cascades and control drug pairs. Baseline clinical and socio-demographic characteristics were balanced using inverse probability of treatment weighting with propensity scores. RESULTS:  Overall, we identified 1987 DH CCB-loop diuretic dyads and 3148 ACEI/ARB-loop diuretic dyads. Discordant providers occurred in 64% of DH CCB-loop diuretic dyads and 55% of ACEI/ARB-loop diuretic dyads, while discordant pharmacies occurred in 19% of DH CCB-loop diuretic dyads and 16% of ACEI/ARB-loop diuretic dyads. After adjustment, the risk of having discordant providers was 20% {Relative Risk (RR) 1.20 [95% confidence interval (CI), 1.14-1.26]} higher in the DH CCB-loop diuretic dyad compared with the ACEI/ARB-loop diuretic dyad. Moreover, pharmacy discordance was 17% (RR 1.17 [95% CI 1.02-1.33]) higher. CONCLUSION: Our findings suggest that discordant providers and discordant pharmacies were more commonly involved in the potential prescribing cascade when compared with a similar control dyad of medications. Opportunities for enhanced care coordination and medication reconciliation should be explored to prevent unnecessary polypharmacy.

Associations Between Postdischarge Care and Cognitive Impairment-Related Hospital Readmissions for Ketoacidosis and Severe Hypoglycemia in Adults With Diabetes.

OBJECTIVE: Patients with severe hypoglycemia (SH) or diabetic ketoacidosis (DKA) experience high hospital readmission after being discharged. Cognitive impairment (CI) may further increase the risk, especially in those experiencing an interruption of medical care after discharge. This study examined the effect modification role of postdischarge care (PDC) on CI-associated readmission risk among U.S. adults with diabetes initially admitted for DKA or SH. RESEARCH DESIGN AND METHODS: We used the Nationwide Readmissions Database (NRD) (2016-2018) to identify individuals hospitalized with a diagnosis of DKA or SH. Multivariate Cox regression was used to compare the all-cause readmission risk at 30 days between those with and without CI identified during the initial hospitalization. We assessed the CI-associated readmission risk in the patients with and without PDC, an effect modifier with the CI status. RESULTS: We identified 23,775 SH patients (53.3% women, mean age 65.9 ± 15.3 years) and 140,490 DKA patients (45.8% women, mean age 40.3 ± 15.4 years), and 2,675 (11.2%) and 1,261 (0.9%), respectively, had a CI diagnosis during their index hospitalization. For SH and DKA patients discharged without PDC, CI was associated with a higher readmission risk of 23% (adjusted hazard ratio [aHR] 1.23, 95% confidence interval 1.08-1.40) and 35% (aHR 1.35, 95% confidence interval 1.08-1.70), respectively. However, when patients were discharged with PDC, we found PDC was an effect modifier to mitigate CI-associated readmission risk for both SH and DKA patients (P < 0.05 for all). CONCLUSIONS: Our results suggest that PDC can potentially mitigate the excessive readmission risk associated with CI, emphasizing the importance of postdischarge continuity of care for medically complex patients with comorbid diabetes and CI.

Common teratogenic medication exposures-a population-based study of pregnancies in the United States.

BACKGROUND: Risk mitigation for most teratogenic medications relies on risk communication via drug label, and prenatal exposures remain common. Information on the types of and risk factors for prenatal exposures to medications with teratogenic risk can guide strategies to reduce exposure. OBJECTIVE: This study aimed to identify medications with known or potential teratogenic risk commonly used during pregnancy among privately insured persons. STUDY DESIGN: We used the Merative™ MarketScan® Commercial Database to identify pregnancies with live or nonlive (ectopic pregnancies, spontaneous and elective abortions, stillbirths) outcomes among persons aged 12 to 55 years from 2011 to 2018. Start/end dates of medication exposure and pregnancy outcomes were identified via an adapted algorithm based on validation studies. We required continuous health plan enrollment from 90 days before conception until 30 days after the pregnancy end date. Medications with known or potential teratogenic risk were selected from TERIS (Teratogen Information System) and drug monographs based on the level of risk and quality of evidence (138 with known and 60 with potential risk). We defined prenatal exposure on the basis of ≥1 outpatient pharmacy claim or medical encounter for medication administration during target pregnancy periods considering medication risk profiles (eg, risk only in the first trimester or at a certain dose threshold). Sex hormones and hormone analogs, and abortion and postpartum/abortion hemorrhage treatments were not considered as teratogenic medications because of challenges in separating pregnancy-related indications, nor were opioids (because of complex risk-benefit considerations) or antiobesity medications if their only teratogenic mechanism was weight loss. RESULTS: Among all pregnancies, the 10 medications with known teratogenic risk and the highest prenatal exposures were sulfamethoxazole/trimethoprim (1988 per 100,000 pregnancy-years), high-dose fluconazole (1248), topiramate (351), lisinopril (144), warfarin (57), losartan (56), carbamazepine (50), valproate (49), vedolizumab (28 since 2015), and valsartan (25). Prevalence of exposure to sulfamethoxazole/trimethoprim decreased from 2346 to 1453 per 100,000 pregnancy-years from 2011 to 2018, but prevalence of exposure to vedolizumab increased 6-fold since its approval in 2015. Prenatal exposures in the first trimester were higher among nonlive pregnancies than among live-birth pregnancies, with the largest difference observed for warfarin (nonlive 370 vs live birth 78), followed by valproate (258 vs 86) and topiramate (1728 vs 674). Prenatal exposures to medications with potential teratogenic risk were most prevalent for low-dose fluconazole (6495), metoprolol (1325), and atenolol (448). The largest first-trimester exposure differences between nonlive and live-birth pregnancies were observed for lithium (242 vs 89), gabapentin (1639 vs 653), and duloxetine (1914 vs 860). Steady increases in hydralazine and gabapentin exposures were observed during the study years, whereas atenolol exposure decreased (561 to 280). CONCLUSION: Several medications with teratogenic risk for which there are potentially safer alternatives continue to be used during pregnancy. The fluctuating rates of prenatal exposure observed for select teratogenic medications suggest that regular reevaluation of risk mitigation strategies is needed. Future research focusing on understanding the clinical context of medication use is necessary to develop effective strategies for reducing exposures to medications with teratogenic risk during pregnancy.