Prescription Patterns and Predisposing Factors of Benzodiazepine and Z-Hypnotic Use During Pregnancy: A Nationwide Cohort Study.

PURPOSE: The use of benzodiazepines and Z-hypnotics during pregnancy has raised significant concerns in recent years. However, there are limited data that capture the prescription patterns and predisposing factors in use of these drugs, particularly among women who have been long-term users of benzodiazepines and Z-hypnotics before pregnancy. METHODS: This population-based cohort study comprised 2 930 988 pregnancies between 2004 and 2018 in Taiwan. Women who were dispensed benzodiazepines or Z-hypnotics during pregnancy were identified and further stratified into groups based on their status before pregnancy: long-term users (with a supply of more than 180 days within a year), short-term users (with a supply of less than 180 days within a year), and nonusers. Trends in the use of benzodiazepines or Z-hypnotics and concomitant use with antidepressants or opioids were assessed. Logistic regression models were utilized to identify factors associated with use of these drugs during pregnancy, and interrupted time series analyses (ITSA) were employed to evaluate utilization patterns of these drugs across different pregnancy-related periods. RESULTS: The overall prevalence of benzodiazepine and Z-hypnotic use was 3.5% during pregnancy. Among prepregnancy long-term users, an upward trend was observed. The concomitant use of antidepressants or opioids among exposed women increased threefold (from 8.6% to 23.1%) and sixfold (from 0.3% to 1.7%) from 2004 to 2018, respectively. Women with unhealthy lifestyle behaviors, such as alcohol abuse (OR 2.48; 95% CI, 2.02-3.03), drug abuse (OR 10.34; 95% CI, 8.46-12.64), and tobacco use (OR 2.19; 95% CI, 1.96-2.45), as well as those with psychiatric disorders like anxiety (OR 6.99; 95% CI, 6.77-7.22), insomnia (OR 15.99; 95% CI, 15.55-16.45), depression (OR 9.43; 95% CI, 9.07-9.80), and schizophrenia (OR 21.08; 95% CI, 18.76-23.69), and higher healthcare utilization, were more likely to use benzodiazepines or Z-hypnotics during pregnancy. ITSA revealed a sudden decrease in use of benzodiazepines and Z-hypnotics after recognition of pregnancy (level change -0.55 percentage point; 95% CI, -0.59 to -0.51). In contrast, exposures to benzodiazepines and Z-hypnotics increased significantly after delivery (level change 0.12 percentage point; 95% CI, 0.09 to 0.16). CONCLUSIONS: In this cohort study, an increased trend of benzodiazepine and Z-hypnotic use during pregnancy among prepregnancy long-term users, as well as concomitant use with antidepressants or opioids were found. The findings have highlighted the existence of various risk factors associated with the use of these drugs during pregnancy. Utilization patterns varied across different stages of pregnancy, highlighting the need for prescription guidelines and educational services for women using these drugs during pregnancy.

Tyrosine Kinase Inhibitors and Vascular Adverse Events in Patients with Chronic Myeloid Leukemia: A Population-Based, Propensity Score-Matched Cohort Study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in patients with chronic myeloid leukemia (CML). Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese patients with CML treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors. MATERIALS AND METHODS: We conducted a retrospective cohort study using the Taiwan Cancer Registry Database and National Health Insurance Research Database. Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups. RESULTS: In total, 1,111 patients with CML were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with an HR of 3.13 (95% confidence interval (CI), 1.30-7.51), whereas dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI, 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age, and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs. CONCLUSION: These findings can support clinicians in making treatment decisions and monitoring VAEs in patients with CML in Taiwan. IMPLICATIONS FOR PRACTICE: This study found that patients with chronic myeloid leukemia (CML) treated with nilotinib and dasatinib may be exposed to a higher risk of developing vascular adverse events (VAEs) compared with those treated with imatinib. Thus, this study suggests that patients with CML who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of tyrosine kinase inhibitors.

Using real-world evidence for pharmacovigilance and drug safety-related decision making by a resource-limited health authority: 10 years of experience in Taiwan.

PURPOSE: Real-world evidence has become increasingly relevant in regulatory decision making. Compared to large regulatory bodies, the national pharmacovigilance system in Taiwan is still under development, and the aim of this study is to demonstrate how a resource-limited health authority utilizes real-world evidence in decision making. METHODS: We described different sources of real-world data available in Taiwan and illustrated the structural framework that integrates real-world evidence into Taiwan's national pharmacovigilance system. Additionally, we reviewed real-world studies conducted in the past 10 years and provided examples to show how these studies influenced drug safety-related decision making in Taiwan. RESULTS: During the past 10 years, real-world evidence used when making drug safety-related regulatory decisions in Taiwan was mainly generated from nationwide claims databases, but other sources of real-world data, such as national registries and large electronic hospital databases, also became available recently. Different types of real-world evidence, including drug utilization studies, risk evaluation studies, and risk minimization measure evaluation studies, have been used to support regulatory decisions in Taiwan. CONCLUSIONS: Through collaborations between the government and academics, Taiwan has started to integrate real-world evidence into the national pharmacovigilance system. However, future efforts, including linkages between different sources of real-world data and improvements in procedural and methodological practices, are needed to generate more regulatory-quality real-world evidence.

Risk of cutaneous adverse reactions associated with allopurinol or febuxostat in real-world patients: A nationwide study.

AIMS: Allopurinol carries a well-known risk of cutaneous adverse reactions (CARs). Although febuxostat, a xanthine-oxidase inhibitor with different chemical structure, has been considered an alternative to allopurinol, post-marketing case reports of life-threatening febuxostat-related CARs have been reported. We aimed to compare the risk of CARs between allopurinol and febuxostat in real-world settings and to assess the impact of the market entry of febuxostat on allopurinol use and associated CARs. METHODS: A nationwide study was conducted using Taiwan's National Health Insurance Research Database. In the new-user cohort study, patients who received their first prescriptions of allopurinol or febuxostat were included, and Poisson regression was used to estimate the incidence rate ratios (IRRs) of CARs. In the interrupted time series analysis, time series data on new users and incidence rate of CARs were divided into three periods based on the reimbursement scheme of febuxostat in Taiwan, and segmented regression models were used to estimate changes in both the level and trend in each period. RESULTS: We identified 526 cases of CARs with 487 among new users of allopurinol and 39 among new users of febuxostat (incidence rate: 15.37 vs 3.48 per 1000 person-years). Allopurinol was associated with higher risk of CARs (adjusted IRR 5.55, 95% CI [3.97-7.76]), mild CARs (1.86, [1.24-2.81]), severe CARs (16.75, [8.87-31.62]) and fatal CARs (16.18, [5.05-51.83]) than febuxostat. The overall incidence rates of xanthine-oxidase inhibitor-related CARs decreased from 15.28 to 14.28 per 1000 person-years after the initial reimbursement of febuxostat and further decreased to 9.46 after the reimbursement coverage of febuxostat expanded; however, the changes were not statistically significant. CONCLUSION: Febuxostat can be considered an alternative for patients carrying risk factors for allopurinol-related CARs. However, since there were fatal cases of febuxostat-related CARs, the closely monitoring of symptoms of CARs during the initiation of febuxostat is still warranted.

Temporal trends and patterns in carbamazepine use, related severe cutaneous adverse reactions, and HLA-B*15:02 screening: A nationwide study.

OBJECTIVE: After discovering the association between the HLA-B*15:02 allele and carbamazepine-related severe cutaneous adverse reactions (SCARs), particularly in Southeastern Asian populations, clinical strategies to prevent carbamazepine-related SCARs have changed. We aimed to investigate 10-year trends in carbamazepine use and carbamazepine-related SCARs and to examine the patterns and determinants of HLA-B*15:02 screening in Taiwan. METHODS: A nationwide study was performed using Taiwan's National Health Insurance Research Database. In the first part of the study, new users of carbamazepine were included, and those who experienced SCAR-related admissions were further identified. In the second part of the study, recipients of HLA-B*15:02 screening (reimbursed by Taiwan's National Health Insurance since June 2010) were included and multivariate logistic regression was used to explore factors associated with the use of screening. RESULTS: The numbers of new users of carbamazepine and SCAR cases decreased remarkably during the 10-year period (-82.6% and -87.1%, respectively), and the incidence rates of SCARs showed a downward trend after 2011. The screening rate of the HLA-B*15:02 allele increased to 24.9% in 2014. Neurologists (odds ratio 12.33, 95% confidence interval 9.30-16.35), psychiatrists (9.97, 7.31-13.61), and neurosurgeons (3.23, 2.42-4.32) were more likely to perform screening tests than other specialties were. Physicians practicing in medical centers (6.00, 5.51-6.54) were more likely to perform screening tests than those practicing in other hospitals, whereas the screening rates in clinics remained at 0.0% throughout the study period. SIGNIFICANCE: In recent years, the number of carbamazepine-related SCAR cases has decreased substantially in Taiwan. However, only one-fourth of new users of carbamazepine received HLA-B*15:02 screening, and there were considerable disparities in the screening rates across different physician groups. Policymakers should consider solutions to barriers to implementing screening tests in clinical practice and should not neglect the value of other safety communications and regulations to complement the limitations of pharmacogenomic testing.

Epidemiology and long-term disease burden of herpes zoster and postherpetic neuralgia in Taiwan: a population-based, propensity score-matched cohort study.

BACKGROUND: The objectives of this study were to characterize the burden of herpes zoster, as well as the longitudinal and incremental changes of healthcare service utilization among individuals with herpes zoster and postherpetic neuralgia (PHN) compared to those without. METHODS: Using the National Health Insurance Research Database (NHIRD), we established a herpes zoster cohort of people diagnosed with herpes zoster between 2004 and 2008 as study cases. Another subset of the NHIRD, which was randomly selected from all elderly beneficiaries between 2004 and 2008 served as a non-herpes-zoster elderly control pool. Each case was then assigned one matched control according to age, gender, index date and propensity score. PHN cases were defined as those with persisting pain for more than 90 days after the onset of herpes zoster. RESULTS: Between 2004 and 2008, about 0.6 million patients were newly diagnosed with herpes zoster. The incidence increased with age, and most cases were identified during the summer period. Herpes zoster cases were found to have higher consumption of all types of healthcare services in the first year after the index date. Such increases were particularly obvious for patients with PHN, who showed incremental increases on average of 16.3 outpatient visits, 0.4 emergency room visits and 0.24 inpatient admissions per year. CONCLUSIONS: The incidence of herpes zoster increased with age and changed according to the seasons. Patients with herpes zoster were associated with higher healthcare utilization and this increase in healthcare utilization was most obvious for herpes zoster patients with PHN.

Benzodiazepine Use During Pregnancy and Risk of Miscarriage.

Importance: Benzodiazepine use during pregnancy has raised significant concerns due to the potential harmful effects of this drug class on neonates. Studies on the association between benzodiazepine use and the risk of miscarriage are limited. Objective: To quantify the risk of miscarriage associated with benzodiazepine use during pregnancy after controlling for unmeasured confounders and exposure time trends. Design, Setting, and Participants: This was a nationwide, population-based case-time-control study using Taiwan's National Birth Certificate Application database and the National Health Insurance database. Pregnancies resulting in miscarriage between 2004 and 2018 were included in the case group and were 1:1 matched with exposure time-trend control individuals using disease risk score, considering demographic characteristics and prepregnancy comorbidities. Data were analyzed from August 2022 to March 2023. Exposures: Discordant exposures to benzodiazepines during risk period (1-28 days before miscarriage) and 2 reference periods (31-58 days and 181-208 days before the last menstrual period) were compared for each pregnancy. Main Outcomes and Measures: Miscarriage was defined as any pregnancy loss occurring between the first prenatal care visit (usually 8 weeks) and the 19th completed week of pregnancy. Results: This study comprised a total of 3 067 122 pregnancies among 1 957 601 women, 136 134 of which (4.4%) resulted in miscarriage. The mean (SD) age of the study population was 30.61 (5.91) years. The use of benzodiazepines during pregnancy was associated with an increased risk of miscarriage (odds ratio [OR], 1.69; 95% CI, 1.52-1.87), and consistent findings were observed across multiple sensitivity analyses considering different time windows and accounting for misclassification. In subgroup analyses, an increased risk of miscarriage was associated with each commonly used individual benzodiazepine, ranging from case-time-control ORs of 1.39 (95% CI, 1.17-1.66) for alprazolam to 2.52 (95% CI, 1.89-3.36) for fludiazepam. Conclusions and Relevance: This nationwide case-time-control study revealed an increased risk of miscarriage associated with benzodiazepine use during pregnancy after accounting for measurable confounders, and results were unlikely to be due to unmeasured confounding. These findings underscore the necessity for health care professionals to meticulously balance the risk-benefit ratio when considering the use of benzodiazepines to treat psychiatric and sleep disorders during pregnancy.

Concomitant use of antidepressants and benzodiazepines during pregnancy and associated risk of congenital malformations: a population-based cohort study in Taiwan.

BACKGROUND: Despite the frequent co-administration of antidepressants and benzodiazepines, the association between such concomitant use during pregnancy and the risk of congenital malformations remains inadequately explored. This study aims to examine the association between concomitant use of antidepressants and benzodiazepines during the first trimester and organ-specific congenital malformations. METHODS: We conducted a population-based cohort study using Taiwan's National Birth Certificate Application database, the Maternal and Child Health database, and Taiwan's National Health Insurance database. Pregnant people aged 15-50 years with singleton births between Jan 1, 2004, and Dec 31, 2018, were included. Use of antidepressants and benzodiazepines was defined as at least one prescription during the first trimester, and concomitant use was defined as the overlapping prescription of both drugs with an overlapping prescription period. The primary outcomes were overall congenital malformations and eight organ-specific malformations, consisting of the nervous system, heart, respiratory system, oral cleft, digestive system, urinary system, genital system, and limb malformations. Logistic regression models with propensity score fine stratification weighting approach were used to control for measured confounders. Analyses controlling for confounding by indication and sibling comparison analyses were done to address unmeasured confounders. No individuals with lived experience participated in the research or writing process. FINDINGS: The cohort included 2 634 021 singleton pregnancies, and 8599 (0·3%) individuals were concomitant users of antidepressants and benzodiazepines during the first trimester (mean age at delivery was 31·8 years [SD 5·2] for pregnancies with exposure to antidepressants and benzodiazepines vs 30·7 years [SD 4·9] for pregnancies without exposure). All study participants were female, and information about ethnicity was not available. Absolute risk of overall malformations was 3·81 per 100 pregnancies with exposure, compared with 2·87 per 100 pregnancies without exposure. The propensity score-weighted odds ratios (weighted ORs) did not suggest an increased risk for overall malformations (weighted OR 1·10, 95% CI 0·94-1·28), heart defects (1·01, 0·83-1·23), or any of the other organ-specific malformations, except for digestive system malformations, for which the weighted OR remained statistically significant after adjustment (1·63, 1·06-2·51). The absence of an increased risk for overall congenital malformations associated with concomitant use of antidepressants and benzodiazepines was supported by the analyses controlling for confounding by indication and sibling-matched comparisons. INTERPRETATION: The findings of this study suggest that the concomitant use of antidepressants and benzodiazepines during the first trimester is not associated with a substantial increase in risk for most malformation subtypes. However, considering other potential adverse effects of using both medications concomitantly, a thorough assessment of the risks and benefits is crucial for clinical decision making. FUNDING: National Science and Technology Council.

Risks of maternal cardiopulmonary events associated with ritodrine for tocolysis: A national database linkage study in 1 831 564 pregnant women.

OBJECTIVE: Real-world data on cardiopulmonary events among pregnant women receiving ß-agonist therapy are scarce. In the present study, we aimed to examine the absolute and relative risks of maternal cardiopulmonary events associated with the use of ß-agonist ritodrine during pregnancy. METHODS: By linking Taiwan's National Birth Certificate Application Database with National Health Insurance data, 1 831 564 pregnancies at ≥20 weeks' gestation were identified. Age-standardized incidence rates of cardiopulmonary events among pregnant women exposed to ritodrine were estimated. Nested case-control analyses were conducted to evaluate the relative risk of pulmonary edema, heart failure, and arrhythmia associated with prior ritodrine use. Cases and controls were matched using risk set sampling, and adjusted odds ratios were estimated using conditional logistic regression models. RESULTS: A total of 189 cases of pulmonary edema, 126 cases of heart failure, and 162 cases of arrhythmia were identified (corresponding age-standardized incidence rates: 20.90, 8.35, and 16.63 per 100 000 among pregnant women only exposed to oral ritodrine; 91.28, 36.01, and 14.61 per 100 000 among those ever exposed to intravenous ritodrine). Exposure to oral ritodrine was associated with a lower increased risk of pulmonary edema (aOR 1.76; 95% CI: 1.12-2.76) and arrhythmia (2.21; 1.47-3.32) whereas exposure to ritodrine injection was associated with a significantly higher risk of pulmonary edema (10.56; 6.39-17.45), arrhythmia (4.15; 1.99-8.64), and heart failure (5.58; 2.27-13.74). CONCLUSIONS: Pregnant women receiving intravenous ritodrine therapy had higher cardiopulmonary risks and should be intensively monitored. While the relative risk associated with oral ritodrine is not pronounced, it should be used judiciously among pregnant women as well.

Association between maternal benzodiazepine or Z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan.

BACKGROUND: Benzodiazepines and Z-hypnotics are commonly prescribed for anxiety and insomnia during pregnancy, but the evidence regarding potential adverse neonatal outcomes is insufficient because of poor control for confounding factors in previous studies. We therefore aimed to evaluate the association between the use of benzodiazepines or Z-hypnotics during early pregnancy and adverse neonatal outcomes (stillbirth, preterm birth, and small for gestational age). METHODS: We did a nationwide, population-based cohort study in Taiwan using three data sources: Taiwan's National Birth Certificate Application database, the National Health Insurance database, and the Maternal and Child Health Database. The study cohort included all singleton pregnancies of females aged 15-50 years who gave birth between Jan 1, 2004, and Dec 31, 2018. Pregnancies without valid information were excluded. Benzodiazepine and Z-hypnotic use was defined as at least one benzodiazepine or Z-hypnotic prescription during early pregnancy (the first 20 weeks of pregnancy). The primary outcomes were stillbirth (fetal death at or after 20 weeks' gestation), preterm birth (<37 weeks' gestation), and small for gestational age (birthweight below the 10th percentile for gestational age by sex). Logistic regression models with propensity score fine stratification weighting were used to control for potential confounders and examine the association between benzodiazepines or Z-hypnotics use during early pregnancy and the risk of adverse neonatal outcomes. Odds ratios (ORs) and 95% CIs were reported. We used confounding by indication control analyses, a sibling control study, and a paternal negative control design to account for unmeasured confounders. The risk associated with exposure during late pregnancy was also assessed. FINDINGS: Between Oct 7, 2021, and June 10, 2022, we analysed the study data. The cohort included 2 882 292 singleton pregnancies; of which, 75 655 (2·6%) of the mothers were dispensed one or more benzodiazepines or Z-hypnotics during early pregnancy. Women exposed during pregnancy were older (mean age at delivery was 31·0 years [SD 5·3] for exposed women vs 30·6 years [4·9] for unexposed women), had a higher prevalence of psychiatric disorders, and were more likely to have unhealthy lifestyle behaviours than unexposed women. Information about ethnicity was not available. Early pregnancy exposure was associated with adverse neonatal outcomes compared with non-exposure. The propensity score-weighted OR was 1·19 (95% CI 1·10-1·28) for stillbirth, 1·19 (1·16-1·23) for preterm birth, and 1·16 (1·13-1·19) for small for gestational age. After controlling for confounding by indication, there was no significant association between drug exposure and stillbirth risk; however, this attenuation was not observed for preterm birth and small for gestational age. In models with sibling controls that accounted for familial confounding and genetic factors, early exposure to benzodiazepines or Z-hypnotics was not associated with an increased risk of stillbirth and preterm birth, but it remained significantly associated with small for gestational age. The paternal negative control analyses with point estimates close to the null indicated no strong evidence of unmeasured confounding shared by the mother and the father. Substantially increased risks of stillbirth and preterm birth were observed for late pregnancy exposure. INTERPRETATION: Benzodiazepine or Z-hypnotic use in early pregnancy is not associated with a substantial increase in the risk of stillbirth and preterm birth after accounting for unmeasured confounding factors. Clinicians should be aware of the increased risk of small for gestational age and caution should be taken when prescribing these medications during late pregnancy. FUNDING: National Science and Technology Council, Taiwan. TRANSLATION: For the Taiwanese translation of the abstract see Supplementary Materials section.

Nonsteroidal Anti-Inflammatory Drugs and Risk of First Hospitalization for Heart Failure in Patients with No History of Heart Failure: A Population-Based Case-Crossover Study.

INTRODUCTION: Traditional nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause salt and fluid retention and should thus be used cautiously in patients with documented heart failure. Recent studies have found that some NSAIDs, including cyclooxygenase (COX)-2 inhibitors, are associated with an increased risk of incident heart failure regardless of the related medical history of the patient. OBJECTIVE: This study aimed to investigate the potential link between NSAIDs (both COX-2 inhibitors and traditional nonselective NSAIDs) and heart failure in patients without a history of heart failure. METHODS: We conducted a case-crossover study using the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 5615 subjects with a first hospitalization for heart failure between 2005 and 2013 were identified from the NHIRD. Exposure to individual NSAIDs between the case period (1-30 days before the index date) and control period (121-150 days before the index date) were retrieved. Multivariable conditional logistic regression models were used to estimate the adjusted odds ratios (aORs) of the incident heart failure associated with NSAID use after adjustments for potential confounders. Multiple sensitivity analyses, including the case-time-control analysis, were performed to test the robustness of the study results. RESULTS: Overall, NSAID use was associated with a 1.58-fold risk [aOR 1.58; 95% confidence interval (CI) 1.40-1.79] of heart failure leading to hospitalization in the main analysis, and similar results were obtained in the case-time-control analysis [aOR 1.40 (95% CI 1.18-1.67)]. The increased risks of heart failure were comparable between traditional NSAIDs [aOR 1.53 (95% CI 1.35-1.74)] and COX-2 inhibitors [aOR 1.74 (95% CI 1.25-2.44)]. Among all NSAIDs, ketorolac was associated with the highest risk of heart failure [aOR 1.98 (95% CI 1.37-2.86)]. CONCLUSION: Both traditional NSAIDs and COX-2 inhibitors were associated with an increased risk of heart failure leading to hospitalization in patients without a related history of heart failure.

Association between the risk of lung cancer and influenza: A population-based nested case-control study.

BACKGROUND: Previous animal studies have shown that certain respiratory oncoviruses can lead to tumorigenesis, especially influenza virus. However, no clinical studies other than animal studies have been conducted to test this hypothesis. OBJECTIVE: To investigate the association between influenza and the risk of lung cancer using the Taiwan Cancer Registry Database (TCRD) and Taiwan's National Health Insurance Research Database (NHIRD). METHODS: We identified a study cohort consisting of patients aged 40 years or above who were enrolled in the NHIRD between 1 January 2012 and 31 December 2014. Among them, we identified patients with lung cancer (cases) and their matched controls (matched by age, sex, and disease risk score (DRS) at a ratio of 1:10). Multivariate conditional logistic regression models were used to evaluate the association between exposure to influenza (timing and cumulative number) and risk of lung cancer. RESULTS: We identified 32,063 cases and 320,627 matched controls. Influenza was associated with a 1.09-fold increased risk of lung cancer (aOR 1.09, 95% CI 1.04-1.14, p<0.0001). The risk of lung cancer increased slightly with cumulative exposure to influenza (1-2 exposures: aOR 1.05, 95% CI 1.00-1.11; 3-4 exposures: aOR 1.12, 95% CI 1.00-1.25; 5+ exposures: aOR 1.25, 95% CI 1.13-1.39). CONCLUSION: Exposure to influenza was associated with an increased risk of lung cancer and the risk increased with cumulative exposure to influenza. However, the lack of valid information on smoking could lead to confounding, and future studies collecting patients' smoking histories are warranted to validate the association between influenza and lung cancer.

Potentially high-risk medication categories and unplanned hospitalizations: a case-time-control study.

Empirical data of medication-related hospitalization are very limited. We aimed to investigate the associations between 12 high risk medication categories (diabetic agents, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), anticoagulants, antiplatelets, antihypertensives, antiarrhythmics, anticonvulsants, antipsychotics, antidepressants, benzodiazepine (BZD)/Z-hypnotics, and narcotics) and unplanned hospitalizations. A population-based case-time-control study was performed using Taiwan's National Health Insurance Research Database. Patients who experienced an unplanned hospitalization (index visit) were identified as index subjects and matched to a randomly selected reference visit within users of a specific category of high-risk medication. An unplanned hospitalization was defined as a hospital admission immediately after an emergency department visit. Discordant exposures to the high-risk medication during the case period (1-14 days before the visit) and the control period (366-379 days before the visit) were examined in both index and reference visits. Antipsychotics was associated with the highest risk of unplanned hospitalizations (adjusted OR: 1.54, 95% CI [1.37-1.73]), followed by NSAIDs (1.50, [1.44-1.56]), anticonvulsants (1.34, [1.10-1.64]), diuretics (1.24, [1.15-1.33]), BZD/Z-hypnotics (1.23, [1.16-1.31]), antidepressants (1.17, [1.05-1.31]) and antiplatelets (1.16, [1.07-1.26]). NSAIDs and narcotics were associated with the highest risks of unplanned hospitalizations with a length of stay ≥10 days. These medication categories should be targeted for clinical and policy interventions.

Impact of Safety-Related Regulations on Codeine Use in Children: A Quasi-Experimental Study Using Taiwan's National Health Insurance Research Database.

INTRODUCTION: Safety concerns regarding potential life-threatening adverse events associated with codeine have resulted in policy decisions to restrict its use in pediatrics. However, whether these drug safety communications have had an immediate and strong impact on codeine use remains in question. OBJECTIVE: We aimed to investigate the impact of the two implemented safety-related regulations (label changes and reimbursement regulations) on the use of codeine for upper respiratory infection (URI) or cough. METHODS: A quasi-experimental study was performed using Taiwan's National Health Insurance Research Database. Quarterly data of codeine prescription rates for URI/cough visits were reported, and an interrupted time series design was used to assess the impact of the safety regulations on the uses of codeine among children with URI/cough visits. Multivariable logistic regression models were used to explore patient and provider characteristics associated with the use of codeine. RESULTS: The safety-related regulations were associated with a significant reduction in codeine prescription rates of -4.24% (95% confidence interval [CI] -4.78 to -3.70), and the relative reduction compared with predicted rates based on preregulation projections was 60.4, 56.6, and 53.2% in the first, second, and third year after the regulations began, respectively. In the postregulation period, physicians specializing in otolaryngology (odds ratio [OR] 1.47, 95% CI 1.45-1.49), practicing in district hospitals (OR 6.84, 95% CI 5.82-8.04) or clinics (OR 6.50, 95% CI 5.54-7.62), and practicing in the least urbanized areas (OR 1.60, 95% CI 1.55-1.64) were more likely to prescribe codeine to children than their counterparts. CONCLUSIONS: Our study provides a successful example of how to effectively reduce the codeine prescriptions in children in the 'real-world' settings, and highlights areas where future effort could be made to improve the safety use of codeine. Future research is warranted to explore whether there was a simultaneous decrease in the incidence rates of codeine-related adverse events following the safety-related regulations.