The impact of different strategies for modeling associations between medications at low doses and health outcomes: a simulation study and practical application to postpartum opioid use.

Pharmacoepidemiological studies commonly examine the association between drug dose and adverse health outcomes. In situations where no safe dose exists, the choice of modeling strategy can lead to identification of an apparent safe low dose range in the presence of a non-linear relationship or due to the modeling strategy forcing a linear relationship through a dose of 0. We conducted a simulation study to assess the performance of several regression approaches to model the drug dose-response curve at low doses in a setting where no safe range exists, including the use of a (1) linear dose term, (2) categorical dose term, and (3) natural cubic spline terms. Additionally, we introduce and apply an expansion of prior work related to modeling dose-response curves at low and infrequently used doses in the setting of no safe dose ("spike-at-zero" and "slab-and-spline"). Furthermore, we demonstrate and empirically assess the use of these regression strategies in a practical scenario examining the association between the dose of the initial postpartum opioid prescribed after vaginal delivery and the subsequent total dose of opioids prescribed in the entire postpartum period among a cohort of opioid-naïve women with a vaginal delivery enrolled in a State Medicaid program (2007-2014).

Risk of Acute Myocardial Infarction Among Patients With Laboratory-Confirmed Invasive Pneumococcal Disease: A Self-Controlled Case Series Study.

BACKGROUND: Acute myocardial infarction (AMI) events have been reported among patients with certain viral and bacterial infections. Whether invasive pneumococcal disease (IPD) increases the risk of AMI remains unclear. We examined whether laboratory-confirmed IPD was associated with the risk of AMI. METHODS: We conducted a self-controlled case series analysis among adult Tennessee residents with evidence of an AMI hospitalization (2003-2019). Patient follow-up started 1 year before the earliest AMI and continued through the date of death, 1 year after AMI, or study end (December 2019). Periods for AMI assessment included the 7 to 1 days before IPD specimen collection (pre-IPD detection), day 0 through day 7 after IPD specimen collection (current IPD), day 8 to 28 after IPD specimen collection (post-IPD), and a control period (all other follow-up). We used conditional Poisson regression to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for each risk period compared with control periods using within-person comparisons. RESULTS: We studied 324 patients hospitalized for AMI with laboratory-confirmed IPD within 1 year before or after the AMI hospitalization. The incidence of AMI was significantly higher during the pre-IPD detection (IRR, 10.29; 95% CI: 6.33-16.73) and the current IPD (IRR, 92.95; 95% CI: 72.17-119.71) periods but nonsignificantly elevated in the post-IPD risk period (IRR, 1.83; 95% CI: .86-3.91) compared with control periods. The AMI incidence was higher in the post-IPD control period (29 to 365 days after IPD; IRR, 2.95; 95% CI: 2.01-4.32). CONCLUSIONS: Hospitalizations with AMI were strongly associated with laboratory-confirmed IPD.

Respiratory syncytial virus immunoprophylaxis in high-risk infants and development of childhood asthma.

BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory tract infection is implicated in asthma development. RSV immunoprophylaxis during infancy is efficacious in preventing RSV-related hospitalizations and has been associated with decreased wheezing in the first years of life. OBJECTIVE: We investigated whether greater adherence to immunoprophylaxis in infants at high risk for severe RSV would be associated with decreased childhood asthma. METHODS: We conducted a retrospective cohort investigation including children born from 1996-2003 who were enrolled in Kaiser Permanente Northern California or Tennessee Medicaid and eligible to receive RSV immunoprophylaxis. Asthma was defined at 4.5 to 6 years of age by using asthma-specific health care visits and medication fills. We classified children into immunoprophylaxis eligibility groups and calculated adherence (percentage receipt of recommended doses). We used a set of statistical strategies (multivariable logistic regression and propensity score [PS]-adjusted and PS-matched analyses) to overcome confounding by medical complexity because infants with higher adherence (≥70%) have higher prevalence of chronic lung disease, lower birth weight, and longer nursery stays. RESULTS: By using multivariable logistic regression and PS-adjusted models in the combined group, higher adherence to RSV immunoprophylaxis was not associated with decreased asthma. However, in PS-matched analysis, treated children with 70% or greater adherence had decreased odds of asthma compared with those with 20% or less adherence (odds ratio, 0.62; 95% CI, 0.50-0.78). CONCLUSIONS: This investigation of RSV immunoprophylaxis in high-risk children primarily found nonsignificant associations on prevention of asthma in specific preterm groups. Our findings highlight the need for larger studies and prospective cohorts and provide estimates of potential preventive effect sizes in high-risk children.

The effect of regulatory advisories on maternal antidepressant prescribing, 1995-2007: an interrupted time series study of 228,876 pregnancies.

The purpose of this study was to assess whether antidepressant prescribing during pregnancy decreased following release of U.S. and Canadian public health advisory warnings about the risk of perinatal complications with antidepressants. We analyzed data from 228,876 singleton pregnancies among women (aged 15-44 years) continuously enrolled in Tennessee Medicaid with full pharmacy benefits (1995-2007). Antidepressant prescribing was determined through outpatient pharmacy dispensing files. Information on sociodemographic and clinical factors was obtained from enrollment files and linked birth certificates. An interrupted time series design with segmented regression analysis was used to quantify the impact of the advisory warnings (2002-2005). Antidepressant prescribing rates increased steadily from 1995 to 2001, followed by sharper increases from 2002 to late 2004. Overall antidepressant prescribing prevalence was 34.51 prescriptions [95 % confidence interval (CI) 33.37-35.65] per 1,000 women in January 2002, and increased at a rate of 0.46 (95 % CI 0.41-0.52) prescriptions per 1,000 women per month until the end of the pre-warning period (May 2004). During the post-warning period (October 2004-June 2005), antidepressant prescribing decreased by 1.48 (95 % CI 1.62-1.35) prescriptions per 1,000 women per month. These trends were observed for both selective serotonin reuptake inhibitors (SSRI) and non-SSRI antidepressants, although SSRI prescribing decreased at a greater rate. We conclude that antidepressant prescribing to pregnant women in Tennessee Medicaid increased from 1995 to late 2004. U.S. and Canadian public health advisories about antidepressant-associated perinatal complications were associated with steady decreases in antidepressant prescribing from late 2004 until the end of the study period, suggesting that the advisory warnings were impactful on antidepressant prescribing in pregnancy.

Maternal antidepressant use and adverse outcomes: a cohort study of 228,876 pregnancies.

OBJECTIVE: The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes. STUDY DESIGN: We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995-2007. RESULTS: Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2-2.3), 3.7 (95% CI, 2.8-4.6), and 4.9 (95% CI, 3.9-5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7-2.8); 2.8 (95% CI, 1.9-5.5); and 4.9 (95% CI, 2.6-9.5) for filling 1, 2, and ≥3 prescriptions, respectively. CONCLUSION: Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.

Accuracy of pharmacy and coded-diagnosis information in identifying tuberculosis in patients with rheumatoid arthritis.

PURPOSE: Previous studies suggest that disease-modifying anti-rheumatic drugs (DMARDs) increase tuberculosis (TB) risk. The accuracy of pharmacy and coded-diagnosis information to identify persons with TB is unclear. METHODS: Within a cohort of rheumatoid arthritis (RA) patients (2000-2005) enrolled in Tennessee Medicaid, we identified those with potential TB using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9-CM) diagnosis codes and/or pharmacy claims. Using the Tennessee TB registry as the gold standard for identification of TB, we estimated the sensitivity, specificity, predictive values, and the respective 95% confidence intervals for each TB case-ascertainment strategy. RESULTS: Ten of 18,094 RA patients had confirmed TB during 61,461 person-years of follow-up (16.3 per 100,000 person-years). The sensitivity and positive predictive value (PPV) and respective 95% confidence intervals were low for confirmed TB based on ICD9-CM codes alone (60.0% (26.2-87.8) and 1.3% (0.5-2.9)), pharmacy data alone (20% (2.5-55.6) and 4.1% (0.5-14.3)), and both (20% (2.5-55.6) and 25.0% (3.2-65.1)). CONCLUSIONS: Algorithms that use administrative data alone to identify TB have a poor PPV that results in a high false positive rate of TB detection.

Development and Testing of an Emergency Department Quality Measure for Pediatric Suicidal Ideation and Self-Harm.

OBJECTIVE: To develop and test a new quality measure assessing timeliness of follow-up mental health care for youth presenting to the emergency department (ED) with suicidal ideation or self-harm. METHODS: Based on a conceptual framework, evidence review, and a modified Delphi process, we developed a quality measure assessing whether youth 5 to 17 years old evaluated for suicidal ideation or self-harm in the ED and discharged to home had a follow-up mental health care visit within 7 days. The measure was tested in 4 geographically dispersed states (California, Pennsylvania, South Carolina, Tennessee) using Medicaid administrative data. We examined measure feasibility of implementation, variation, reliability, and validity. To test validity, adjusted regression models examined associations between quality measure scores and subsequent all-cause and same-cause hospital readmissions/ED return visits. RESULTS: Overall, there were 16,486 eligible ED visits between September 1, 2014 and July 31, 2016; 53.5% of eligible ED visits had an associated mental health care follow-up visit within 7 days. Measure scores varied by state, ranging from 26.3% to 66.5%, and by youth characteristics: visits by youth who were non-White, male, and living in an urban area were significantly less likely to be associated with a follow-up visit within 7 days. Better quality measure performance was not associated with decreased reutilization. CONCLUSIONS: This new ED quality measure may be useful for monitoring and improving the quality of care for this vulnerable population; however, future work is needed to establish the measure's predictive validity using more prevalent outcomes such as recurrence of suicidal ideation or deliberate self-harm.

Study design for a comprehensive assessment of biologic safety using multiple healthcare data systems.

BACKGROUND: Although biologic treatments have excellent efficacy for many autoimmune diseases, safety concerns persist. Understanding the absolute and comparative risks of adverse events in patient and disease subpopulations is critical for optimal prescribing of biologics. PURPOSE: The Safety Assessment of Biologic Therapy collaborative was federally funded to provide robust estimates of rates and relative risks of adverse events among biologics users using data from national Medicaid and Medicare plus Medicaid dual-eligible programs, Tennessee Medicaid, Kaiser Permanente, and state pharmaceutical assistance programs supplementing New Jersey and Pennsylvania Medicare programs. This report describes the organizational structure of the collaborative and the study population and methods. METHODS: This retrospective cohort study (1998-2007) examined risks of seven classes of adverse events in relation to biologic treatments prescribed for seven autoimmune diseases. Propensity scores were used to control for confounding and enabled pooling of individual-level data across data systems while concealing personal health information. Cox proportional hazard modeling was used to analyze study hypotheses. RESULTS: The cohort was composed of 159,000 subjects with rheumatic diseases, 33,000 with psoriasis, and 46,000 with inflammatory bowel disease. This report summarizes demographic characteristics and drug exposures. Separate reports will provide outcome definitions and estimated hazard ratios for adverse events. CONCLUSION: This comprehensive research will improve understanding of the safety of these treatments. The methods described may be useful to others planning similar evaluations.

Building a Data Linkage Foundation for Mother-Child Pharmacoepidemiology Research.

BACKGROUND: Expanding our understanding of the effects of maternal medication exposure through research is a public health priority and will help inform both clinical and policy decision making, ultimately improving outcomes for pregnant women and their children. OBJECTIVE: Our objective was to describe a linked-data research platform that facilitates studies of pregnancy medication exposures and policy changes on maternal and child health outcomes. METHODS: Mothers receiving Medicaid benefits were probabilistically linked with newborns in the Tennessee Medicaid program (TennCare) through three distinct linkage processes. Medicaid claims data and state birth and fetal death certificate records (vital records) were used to identify and link potential mothers, deliveries, and newborn children. The linkage process started with the creation of a merged pool of potential mothers and eligible deliveries, which was linked to vital records and to children's records. In the last step, linked records from the preceding steps were combined into the final Mother-child linked records. For each data linkage step, rubrics and scoring systems for exact and partial matches and mismatches among key linkage fields were applied and used to examine the strength of the probabilistic linkages. Summary linkage yields for year 2013 are reported for illustration purposes. RESULTS: Among the 84,253 potential deliveries, 1,761,557 eligible potential mothers, and 51,400 eligible children identified in Tennessee Medicaid records in 2013, a total of 60,265 of these records were uniquely linked to vital records, including 46,172 (77%) with linked mother-child-vital records. Among the 51,400 eligible children records identified in Tennessee Medicaid for that year, 97% (50,053) had at least one link to vital records or a mother-delivery record. In linked records, the median maternal age was 24 years, and the median gestational age was 39 weeks. About 33% of pregnant women underwent cesarean birth, and 1% of births were classified as complicated deliveries. CONCLUSIONS: Supplementing existing Medicaid claims data with birth certificate records complements administrative claims information and allows for detailed assessments of pregnancy exposures and policy changes on mother and child outcomes.

Sickle cell trait, hemoglobin C trait, and invasive pneumococcal disease.

BACKGROUND: The cause of historically higher rates of invasive pneumococcal disease among blacks than whites has remained unknown. We tested the hypothesis that sickle cell trait or hemoglobin C trait is an independent risk factor for invasive pneumococcal disease. METHOD: Eligible children were born in Tennessee (1996-2003), had a newborn screen, enrolled in TennCare aged <1 year, and resided in a Tennessee county with laboratory-confirmed, pneumococcal surveillance. Race/ethnicity was ascertained from birth certificates. Children were followed through 2005 until loss of enrollment, pneumococcal disease episode, fifth birthday, or death. We calculated incidence rates by race/ethnicity and hemoglobin type before and after pneumococcal conjugate vaccine (PCV7) introduction. Poisson regression analyses compared invasive pneumococcal disease rates among blacks with sickle cell trait or hemoglobin C trait with whites and blacks with normal hemoglobin, controlling for age, gender, time (pre-PCV7, transition year, or post-PCV7) and high-risk conditions (eg, heart disease). RESULTS: Over 10 years, 415 invasive pneumococcal disease episodes occurred during 451,594 observed child-years. Before PCV7 introduction, disease rates/100,000 child-years were 2941 for blacks with sickle cell disease, 258 for blacks with sickle cell trait or hemoglobin C trait and 188, 172, and 125 for blacks, whites, and Hispanics with normal hemoglobin. Post-PCV7, rates declined for all groups. Blacks with sickle cell trait or hemoglobin C trait had 77% (95% CI = 22-155) and 42% (95% CI = 1-100) higher rates than whites and blacks with normal hemoglobin. CONCLUSION: Black children with sickle cell trait or hemoglobin C trait have an increased risk of invasive pneumococcal disease.