Kenneth K.C. Man

Exposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: a systematic review and meta-analysis of observational studies.

This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case-control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case-control studies were 2.13 (95% CI 1.66-2.73) and 1.81 (95% CI 1.47-2.24) respectively. Low heterogeneity was observed between studies. The two population-based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed.

ReviewExposure to selective serotonin reuptake inhibitors during pregnancy and risk of autism spectrum disorder in children: A systematic review and meta-analysis of observational studies

This study is a critical analysis of the association between selective serotonin reuptake inhibitors (SSRIs) exposure during pregnancy and autism spectrum disorder (ASD) risk in children. Electronic databases were searched for observational studies published from January 1946 to June 2014 related to the association between SSRI exposure during pregnancy and ASD in children. Studies relevant to the association between SSRI exposure during pregnancy and ASD in children were extracted and compiled for meta-analysis evaluation. Ninety-five citations were identified and seven observational studies were included. Four case-control studies were eligible for the meta-analysis and two cohort studies were narratively reviewed. The pooled crude and adjusted odds ratios of the case-control studies were 2.13 (95% CI 1.66-2.73) and 1.81 (95% CI 1.47-2.24) respectively. Low heterogeneity was observed between studies. The two population-based cohort studies, utilizing the same Denmark data set, have conflicting results. The findings of this meta-analysis and narrative review support an increased risk of ASD in children of mothers exposed to SSRIs during pregnancy; however, the causality remains to be confirmed.

Methylphenidate and the Risk of Trauma

BACKGROUND AND OBJECTIVE: Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) are prone to sustaining trauma that requires emergency department (ED) admission. Methylphenidate (MPH) can reduce ADHD symptoms and may thus theoretically reduce the risk of trauma-related ED admission, but previous studies do not make this association clear. This study examines this association. METHODS: A total of 17 381 patients aged 6 to 19 years who received MPH prescriptions were identified by using the Clinical Data Analysis & Reporting System (2001–2013). Using a self-controlled case series study design, the relative incidence of trauma-related ED admissions was compared with periods of patient exposure and nonexposure to MPH. RESULTS: Among 17 381 patients prescribed MPH, 4934 had at least 1 trauma-related ED admission. The rate of trauma-related ED admission was lower during exposed periods compared with nonexposed periods (incidence rate ratio [IRR]: 0.91 [95% confidence interval (CI): 0.86–0.97]). The findings were similar only when the incident trauma episode was assessed (IRR: 0.89 [95% CI: 0.82–0.96]). A similar protective association was found in both genders. In validation analysis using nontrauma-related ED admissions as a negative control outcome, no statistically significant association was found (IRR: 0.99 [95% CI: 0.95–1.02]). All sensitivity analyses demonstrated consistent results. CONCLUSIONS: This study supports the hypothesis that MPH is associated with a reduced risk of trauma-related ED admission in children and adolescents. A similar protective association was found in both male and female patients. This protective association should be considered in clinical practice.

An investigation of the potential association between retinal detachment and oral fluoroquinolones: a self-controlled case series study

OBJECTIVES A study reported a significant association between oral fluoroquinolones and the development of retinal detachment among current users of oral fluoroquinolones (Etminan M, Forooghian F, Brophy JM et al. JAMA 2012; 307: 1414-9). However, other published studies have discordant results. This study aimed to investigate this association and to estimate the absolute risk of developing retinal detachment in patients exposed to oral fluoroquinolones. METHODS A self-controlled case series study was conducted with data retrieved from the Hong Kong Clinical Data Analysis and Reporting System database and the Taiwan National Health Insurance Research Database. Hong Kong and Taiwanese patients who had prescriptions for oral fluoroquinolones and a procedure for retinal detachment between 2001 and 2012 and between 2000 and 2010, respectively, were defined as cases and included in the analysis. RESULTS A total of 9 events were found during the fluoroquinolone-exposed period and 1407 events were found during the non-exposed period. The adjusted incidence rate ratio in the combined model was 1.26 (0.65-2.47). The crude absolute risk of experiencing retinal detachment whilst on oral fluoroquinolones was ∼1.3 per 200 000 prescriptions. CONCLUSIONS Our study does not support the association between the use of fluoroquinolones and the development of retinal detachment and our findings are strikingly similar to that of the study conducted in Denmark. Doubt is cast on the association between the use of fluoroquinolones and the development of retinal detachment. Therefore, the use of fluoroquinolones should not be precluded based on the current evidence on the risk of retinal detachment. The impact of different ethnicities on the response to fluoroquinolones should also be investigated.

Effect of suboptimal anticoagulation treatment with antiplatelet therapy and warfarin on clinical outcomes in patients with nonvalvular atrial fibrillation: A population-wide cohort study

BACKGROUND The actual consequence of suboptimal anticoagulation management in patients with nonvalvular atrial fibrillation (NVAF) is unclear in the real-life practice. OBJECTIVE The purpose of this study was to identify the prevalence of suboptimally anticoagulated patients with NVAF and compare the effectiveness and safety of antiplatelet drugs with warfarin. METHODS We performed a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF during 2010-2013 were included in the analysis. A Cox proportional hazards regression model with 1:1 propensity score matching was used to compare the risk of ischemic stroke, intracranial hemorrhage, gastrointestinal bleeding, and all-cause mortality between patients receiving antiplatelet drugs and those receiving warfarin stratified by level of international normalized ratio (INR) control. RESULTS Of the 35,551 patients with NVAF, 30,294 (85.2%) had a CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes mellitus, age 65-74 years, prior stroke/transient ischemic attack [doubled], vascular disease, and sex category [female]) score of ≥2 (target group for anticoagulation). Of these, 7029 (23.2%) received oral anticoagulants and 18,508 (61.1%) received antiplatelet drugs alone. There were 1541 (67.7%) of warfarin users who had poor INR control (time in therapeutic range [2.0-3.0] <60%). Patients receiving warfarin had comparable risks of intracranial hemorrhage (hazard ratio [HR] 1.24; 95% confidence interval [CI] 0.65-2.34) and gastrointestinal bleeding (HR 1.23; 95% CI 0.84-1.81) and lower risk of ischemic stroke (HR 0.40; 95% CI 0.28-0.57) and all-cause mortality (HR 0.45; 95% CI 0.36-0.57) than did patients receiving antiplatelet drugs alone. Good INR control was associated with a reduced risk of ischemic stroke (HR 0.48; 95% CI 0.27-0.86) as compared with poor INR control. Modeling analyses suggested that ~40,000 stroke cases could be potentially prevented per year in the Chinese population if patients were optimally treated. CONCLUSION More than three-quarters of high-risk patients among this Chinese population with NVAF were not anticoagulated or had poor INR control. There is an urgent need to improve the optimization of anticoagulation for stroke prevention in patients with atrial fibrillation.

ADHD Drug Prescribing Trend Is Increasing Among Children and Adolescents in Hong Kong

Objective:To investigate the prevalence of ADHD medication prescribing of school-aged children in Hong Kong (HK) from 2001 to 2013 and to compare with other countries. Method: Using the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System, we investigated the epidemiology and prevalence of ADHD medication prescribing. Results: The prevalence of children on ADHD medication increased 14 times throughout the study period—0.072% in 2001 (95% confidence interval [CI] = [0.068%, 0.077%]) to 1.027% (95% CI = [1.008%, 1.047%]) in 2013. Prevalence in females increased at a faster rate than in males. The prescribing trend in kindergarten children (3- to 5-year-old) was relatively steady from 2001 to 2008—0.025% (95% CI = [0.019%, 0.033%]) in 2001—until a marked increase from 2009 to 2013—0.121% (95% CI = [0.105%, 0.139%]) in 2013. Conclusion: The prevalence of ADHD medication prescribing in Hong Kong is increasing but remains lower than most Western countries. However, the prevalence of ADHD medication prescribing for kindergarten children should be monitored to ensure appropriate use.

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation

Importance The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. Objective To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Design, Setting, and Participants Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Exposures Dabigatran or warfarin use during the study period. Main Outcomes and Measures Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Results Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, −0.68 [95% CI, −0.38 to −0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, −3.15 [95% CI, −2.40 to −3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, −0.04 [95% CI, 0.67 to −0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Conclusions and Relevance Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.

Proton pump inhibitors and risk of Clostridium difficile infection: a multi-country study using sequence symmetry analysis

ABSTRACT Objective: To determine the association between incident proton pump inhibitor (PPI) use and Clostridium difficile infections across multiple countries Method: National data covering the total population in Australia and Korea, the Canadian population over 65 years and a 3 million person random sample data set from Taiwan were assessed, as were data from a worker insurance population and a hospital inpatient/outpatient population in Japan. Sequence symmetry analysis was used to assess the association with oral vancomycin dispensing as the outcome of interest. Results: 54,957 patients were included. Positive associations were observed in Australia; adjusted sequence ratio (ASR) 2.48 (95% CI 1.90, 3.12), Korea ASR 2.15 (95%CI 2.11, 2.19), Canada ASR 1.45 (95% CI 1.16, 1.79), Japan hospital dataset ASR 3.21 (95%CI 2.12, 4.55) and Japan worker insurance dataset ASR 5.40 (95% CI 2.73, 8.75). The pooled result was ASR 2.40 (95%CI 1.88, 3.05) and 3.16 (95%CI 1.95, 5.10) when limited to Japan, Korean and Taiwan. Results did not vary by individual PPI. The temporal analysis showed effects within the first two weeks of PPI initiation. Conclusion: Our study confirms the association between PPI initiation and C. difficile infections across countries in the Asia-Pacific region.

Prescription sequence symmetry analysis: assessing risk, temporality, and consistency for adverse drug reactions across datasets in five countries

Prescription sequence symmetry analysis (PSSA) is a signal detection method for adverse drug events. Its capacity to consistently detect adverse drug events across different settings has not been tested. We aimed to determine the consistency of PSSA results for detecting positive and negative control adverse drug events across different settings.

Databases in the Asia-pacific region: The potential for a distributed network approach

Background: This study describes the availability and characteristics of databases in Asian-Pacific countries and assesses the feasibility of a distributed network approach in the region. Methods: A web-based survey was conducted among investigators using healthcare databases in the Asia-Pacific countries. Potential survey participants were identified through the Asian Pharmacoepidemiology Network. Results: Investigators from a total of 11 databases participated in the survey. Database sources included four nationwide claims databases from Japan, South Korea, and Taiwan; two nationwide electronic health records from Hong Kong and Singapore; a regional electronic health record from western China; two electronic health records from Thailand; and cancer and stroke registries from Taiwan. Conclusions: We identified 11 databases with capabilities for distributed network approaches. Many country-specific coding systems and terminologies have been already converted to international coding systems. The harmonization of health expenditure data is a major obstacle for future investigations attempting to evaluate issues related to medical costs.