Josta de Jong

Antibiotic drug use of children in the Netherlands from 1999 till 2005.

OBJECTIVE Antibiotics are the most commonly prescribed drugs used by children. Excessive and irrational use of antibiotic drugs is a world-wide concern. We performed a drug utilization study describing the patterns of antibiotic use in children aged 0-19 years between 1999 and 2005 in the Netherlands. METHODS We used IADB.nl, a database with pharmacy drug dispensing data covering a population of 500,000 people and investigated all prescriptions of oral antibiotic drugs (ATC J01) for children <or=19 years between 1999 and 2005. RESULTS The total number of antibiotic prescriptions per 1000 children per year ranged from 282 in 2004 to 307 in 2001 and did not change between years during the study period in a clinically relevant way. The prevalence of receiving at least one prescription varied between 17.8% in 2004 and 19.3% in 2001. Amoxicillin was the most frequently prescribed drug (46.4% of all antibiotic prescriptions in 1999 and 43.2% in 2005). Between 1999 and 2005 there was a shift from the small-spectrum phenethicillin, a penicillin preparation [ratio 2005/1999 0.76; 95% confidence interval (CI) 0.72-0.81], to amoxicillin/clavulanic acid (ratio 2005/1999 1.70; 95% CI 1.61-1.79) and from the old macrolide erythromycin (ratio 2005/1999 0.35; 95% CI 0.32-0.39) to the new macrolide antibiotic azithromycin (ratio 2005/1999 1.78; 95% CI 1.65-1.92). CONCLUSION The use of antibiotic drugs in treating children in the Netherlands is comparable to that in other northern European countries. Broad-spectrum antibiotics were prescribed more frequently than recommended by the guidelines and increased during our study period. Initiatives to improve guideline-directed antibiotic prescribing are strongly recommended.

Antibiotic drug use of children in the Netherlands from 1999 till 2005

OBJECTIVE Antibiotics are the most commonly prescribed drugs used by children. Excessive and irrational use of antibiotic drugs is a world-wide concern. We performed a drug utilization study describing the patterns of antibiotic use in children aged 0-19 years between 1999 and 2005 in the Netherlands. METHODS We used IADB.nl, a database with pharmacy drug dispensing data covering a population of 500,000 people and investigated all prescriptions of oral antibiotic drugs (ATC J01) for children <or=19 years between 1999 and 2005. RESULTS The total number of antibiotic prescriptions per 1000 children per year ranged from 282 in 2004 to 307 in 2001 and did not change between years during the study period in a clinically relevant way. The prevalence of receiving at least one prescription varied between 17.8% in 2004 and 19.3% in 2001. Amoxicillin was the most frequently prescribed drug (46.4% of all antibiotic prescriptions in 1999 and 43.2% in 2005). Between 1999 and 2005 there was a shift from the small-spectrum phenethicillin, a penicillin preparation [ratio 2005/1999 0.76; 95% confidence interval (CI) 0.72-0.81], to amoxicillin/clavulanic acid (ratio 2005/1999 1.70; 95% CI 1.61-1.79) and from the old macrolide erythromycin (ratio 2005/1999 0.35; 95% CI 0.32-0.39) to the new macrolide antibiotic azithromycin (ratio 2005/1999 1.78; 95% CI 1.65-1.92). CONCLUSION The use of antibiotic drugs in treating children in the Netherlands is comparable to that in other northern European countries. Broad-spectrum antibiotics were prescribed more frequently than recommended by the guidelines and increased during our study period. Initiatives to improve guideline-directed antibiotic prescribing are strongly recommended.

Antibiotic usage, dosage and course length in children between 0 and 4 years.

Aim:  Antibiotic drugs are most frequently used by 0‐ to 4‐year‐old children. We performed a cross‐sectional study in the Netherlands using a pharmacy prescription database to investigate the use, dose and course length of antibiotic drugs in 0‐ to 4‐year‐olds.

The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs: A Literature Review

BackgroundMore information is needed about possible associations between the newer anti-epileptic drugs (AEDs) in the first trimester of pregnancy and specific congenital anomalies of the fetus.ObjectivesWe performed a literature review to find signals for potential associations between newer AEDs (lamotrigine, topiramate, levetiracetam, gabapentin, oxcarbazepine, eslicarbazepine, felbamate, lacosamide, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, vigabatrin, and zonisamide) and specific congenital anomalies.MethodsWe searched PubMed and EMBASE to find observational studies with pregnancies exposed to newer AEDs and detailed information on congenital anomalies. The congenital anomalies in the studies were classified according to the congenital anomaly subgroups of European Surveillance of Congenital Anomalies (EUROCAT). We compared the prevalence of specific congenital anomalies in fetuses exposed to individual AEDs in the combined studies with that of the general population in a reference database. A significantly higher prevalence based on three or more fetuses with anomalies was considered a signal.ResultsTopiramate showed a higher rate of congenital anomalies than the other newer AEDs. Four signals were found. The signals for associations between topiramate and cleft lip with/without cleft palate and hypospadias were considered strong. Associations between lamotrigine and anencephaly and transposition of great vessels were found within one study and were not supported by other studies. No signals were found for the other newer AEDs, or the information was too limited to provide such a signal.ConclusionIn terms of associations between monotherapy with a newer AED in the first trimester of pregnancy and a specific congenital anomaly, the signals for topiramate and cleft lip with/without cleft palate and hypospadias should be investigated further.

Insulin analogues in pregnancy and specific congenital anomalies: a literature review.

Insulin analogues are commonly used in pregnant women with diabetes. It is not known if the use of insulin analogues in pregnancy is associated with any higher risk of congenital anomalies in the offspring compared with use of human insulin. We performed a literature search for studies of pregnant women with pregestational diabetes using insulin analogues in the first trimester and information on congenital anomalies. The studies were analysed to compare the congenital anomaly rate among foetuses of mothers using insulin analogues with foetuses of mothers using human insulin. Of 29 studies, we included 1286 foetuses of mothers using short‐acting insulin analogues with 1089 references of mothers using human insulin and 768 foetuses of mothers using long‐acting insulin analogues with 685 references of mothers using long‐acting human insulin (Neutral Protamine Hagedorn). The congenital anomaly rate was 4.84% and 4.29% among the foetuses of mothers using lispro and aspart. For glargine and detemir, the congenital anomaly rate was 2.86% and 3.47%, respectively. No studies on the use of insulin glulisine and degludec in pregnancy were found. There was no statistically significant difference in the congenital anomaly rate among foetuses exposed to insulin analogues (lispro, aspart, glargine or detemir) compared with those exposed to human insulin or Neutral Protamine Hagedorn insulin. The total prevalence of congenital anomalies was not increased for foetuses exposed to insulin analogues. The small samples in the included studies provided insufficient statistical power to identify a moderate increased risk of specific congenital anomalies. Copyright

Use of antihypertensive drugs during pregnancy in the Netherlands

Background: Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor for liver, pancreatic, and colorectal cancer. T2DM patients show higher incidences of these cancers compared to the non-diabetic (non-DM) population. Current evidence, however, is inconsistent with respect to the incidences of other gastrointestinal (GI) malignancies. Objectives: To determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. Methods: A retrospective cohort study was conducted using the UK Clinical Practice Research Datalink (CPRD) during 1988-2012. A T2DM cohort of antidiabetic drug users was matched to a non-DM reference cohort, by age, sex, and practice. Crude incidence rates (IRs) per 100,000 person-years (105 py) and 95% confidence intervals (CI) were calculated, stratified by age, sex, and calendar period. IRs were compared using the normal theory test. Results: 333,438 T2DM subjects and 333,438 non- DM subjects were analyzed, with a total duration of follow-up of >3.6 million py and 10,977 observed GI cancer cases. Overall, IRs of any GI cancer (IR 330 vs. 276 per 105 py), liver cancer (IR 26 vs. 8.9 per 105 py), pancreatic cancer (IR 65 vs. 31 per 105 py), and colon cancer (IR 119 vs. 109 per 105 py) were significantly higher in the T2DM cohort compared to the non-DM cohort, whereas the IR of esophageal cancer was significantly lower (IR 41 vs. 47 per 105 py, pBackground: Progressive multifocal leukencephalopathy (PML) is a rare, often fatal viral disease, which affects the white matter of the brain. It is caused by John Cunningham (JC) polyomavirus, whi ...The article investigates the special features of state control over international transfer of special-purpose and dual-use goods. It was established what international organizations was created in the international community to determine the principles of control over international transfer of special-purpose and dual-use goods, as well as the question of Ukraines joining the circle of member-states of such organizations. The structure of the system of export control bodies in Ukraine was defined, as well as the main powers of the State Service of Export Control of Ukraine in the sphere of control over international transfer of goods. The essence and the concept of goods over which international transfer state export control is carried out in accordance with the Ukrainian legislation were revealed, as well as special aspects of the procedure of state control over their international transfer.Background: Different antiplatelet regimens are used for secondary prevention after ischemic stroke (IS)/transient ischemic attack (TIA), but studies on the relative effectiveness and safety of each regimen in daily practice are lacking. Objectives: To assess the relative effectiveness and safety of several antiplatelet regimens as secondary prevention in patients after an IS/TIA in clinical practice. Methods: A cohort study was conducted using the Clinical Practice Research Datalink. Patients aged ≥ 18 years with a first diagnosis of IS/TIA in 1998- 2013 were identified. Antiplatelet exposure was categorized into aspirin-dipyridamole, aspirin-only, clopidogrel-only, aspirin-clopidogrel, other regimens, and no-antiplatelet exposure. The primary effectiveness outcome was a composite endpoint of nonfatal IS, nonfatal myocardial infarction (MI), or cardiovascular (CV) death; and the safety outcome was major bleeding. Time-dependent Cox regression analysis was used to assess the association between antiplatelet regimens and CV effectiveness and major bleeding outcomes. Results: We followed 20,552 IS/TIA patients for a median duration of 2.3 years. There were 5,714 composite events during follow-up. All regimens were effective in reducing the primary effectiveness outcome compared to no-antiplatelet exposure. Aspirin-only, clopidogrel-only, aspirin-clopidogrel and other regimens were significantly (p <0.05) less effective compared to aspirin-dipyridamole (HR: 1.35, 1.12, 1.40, and 1.27, respectively), adjusted for age, sex, lifestyle factors, disease history and CV comedications. All other regimens were also significantly (p <0.05) associated with a higher relative risk of major bleeding compared to aspirin-dipyridamole (HR: 1.21, 1.32, 1.78, and 1.37, respectively), adjusted for age, sex, alcohol use, liver and renal disease, major bleeding history and comedications. Conclusions: Compared to aspirin-dipyridamole, all other antiplatelet regimens are less effective in reducing the risk of nonfatal IS, nonfatal MI or CV death, and associated with a higher risk of major bleeding in patients with IS/TIA.Characteristics of Patients at Initiation of Treatment for Primary Chronic Immune ThrombocytopeniaBackground: Guidelines for cardiovascular secondary prevention are based on evidence from relatively old clinical trials and need to be evaluated in daily clinical practice. Objectives: To evaluate effectiveness of the recommended drug classes after an acute coronary syndrome (ACS) for secondary prevention of cardiovascular diseases and all-cause mortality. Methods: This cohort study used data from a representative sample of the French national healthcare insurance system database (EGB). Patients hospitalised for an incident ACS between 2006 and 2011, and aged ≥ 20 years at time of ACS were included in the study. Patients non-exposed to any of the four recommended drug classes (beta-blockers, antiplatelet agents, statins, and angiotensin-converting-enzyme inhibitors, ACEI, or angiotensin II receptor blockers, ARB) in the first 3 months following ACS or who died during this period were not included in the cohort. Exposure status was determined daily during follow-up. Effectiveness of the four therapeutic classes in preventing the composite outcome ACS, transient ischemic attack, ischemic stroke, or all-cause-death was estimated using a time-dependent Cox proportional hazards model, which was adjusted for time-fixed confounders measured at baseline (general characteristics and characteristics of the initial ACS) and time-dependent confounders during follow-up (co-morbidities and co-medications). Results: Of the 2874 patients included in the study, 33.9% were women and the median age was 67 years (interquartile range, IQR: 56-77). The median time of follow-up was 3.6 years (IQR: 2.2-5.3). The risk of the composite outcome decreased with use of antiplatelet agents (adjusted hazard ratio (aHR) 0.76, 95% confidence interval (CI) 0.63; 0.91), use of statins (aHR 0.71, 95%CI 0.57; 0.87), and use of ACEI/ARB (aHR 0.67, 95%CI 0.57; 0.80). Use of beta-blockers was not associated with a lower risk of the composite outcome (aHR, 0.90, 95%CI 0.74; 1.09]). Conclusions: Use of antiplatelet agents, statins, and ACEI/ARB after an ACS, but not beta-blockers, was associated with a lower risk of cardiovascular morbidity and all-cause mortality.Abstracts of the 32nd International Conference on Pharmacoepidemiology & Therapeutic Risk Management, The Convention Centre Dublin, Dublin, Ireland August 25–28, 2016Background: Cough and angioedema are adverse events associated with especially angiotensinconverting enzyme (ACE) inhibitors but also reported with angiotensin receptor blockers (ARBs) and aliskiren, a direct renin inhibitor (DRI). Susceptibility of developing cough/angioedema with ACE inhibitors depends on ethnicity, which is not documented in spontaneous reporting systems of drug safety. Objectives: To assess the impact of ethnicity on the occurrence of cough/angioedema with renin angiotensin system (RAS) inhibitors using information reported to the the World Health Organization database (VigiBase). Methods: A case/non-case study was performed in VigiBase. Cases were defined as reports of cough/angioedema and non-cases were all reports of other adverse events. The reporting countries were divided into three categories: black African countries, East Asian countries and other countries. Logistic regression analysis was used to assess the association between reporting of cough/angioedema with each class of RAS inhibitors stratified by country group and to control for confounding. Results: The reporting of cough with ACE inhibitors was significantly higher in East Asian countries than black African countries and other countries (adjusted reporting odds ratios (RORs): 256, 95%CI (236-278), 48.9, 95%CI (42.7-56.1) and 35.4, 95%CI (34.8- 35.9), respectively. The reporting of angioedema with ACE inhibitors was significantly higher in black African countries than East Asian countries and other countries (adjusted RORs: 55.3, 95%CI (45.5-67.2), 5.29, 95%CI(3.89-7.21) and 16.5, 95%CI (16.1- 16.8), respectively. There was no difference in reporting of cough/angioedema with ARBs and DRI between black African countries, East Asian countries and other countries. Conclusions: Our results by grouping countries according to ethnicity in VigiBase are consistent with previous results in the literature suggesting that the occurrence of cough with ACE inhibitors is higher in East Asian patients and the occurrence of angioedema with ACE inhibitors is higher in black patients. These findings indicate that ethnicity should be included as scientific parameter in pharmacovigilance.An Automatized Model for Sequential Monitoring of Effectiveness of New Drugs using Dronedarone as ExampleGeneral Pharmacological Treatments Preceding A Primary Chronic Immune Thrombocytopenia DiagnosisBackground: Several studies showed a bidirectional association between type 2 diabetes and psychiatric disorders in adults. There is limited information available about the association of type 1 diabetes (T1D) and psychiatric disorders in children and adolescents. Objectives: To assess the extent of psychiatric medication use before and after the onset of T1D in children and adolescents compared with a reference cohort without T1D. Methods: A population-based cohort study was conducted in the Dutch PHARMO Record Linkage System. All children and adolescents <19 years) with at least two insulin dispensings between 1999 and 2009 were identified as a T1D cohort (N=925) and matched with an up to four times larger diabetes-free reference cohort (N=3591) by age and sex. The period prevalences of psychiatric medication use (psycholeptics (ATC N05) and psychoanaleptics (ATC N06)) were calculated by dividing the number of patients with at least one dispensing by the number of patients available in the cohort during that time. Prevalences were calculated from 5 years before until 5 years after the onset of T1D (the index date in both cohorts) and stratified by age, sex, medication subgroup, and before/after the onset of T1D. Results: The mean age of the study participants was 10.1 years and 51% were boys. The 5-year prevalence of psychiatric medication use before the index date was significantly higher in the T1D cohort than in the reference cohort (7.2 vs. 4.7%, respectively, p=0.002). The same pattern was observed for the period after developing T1D (10.4 vs. 7.9% in the T1D and reference cohort respectively, p=0.015). In both cohorts adolescents (15-19 years) and boys had higher prevalences of psychiatric medication use. This increased prevalence of psychiatric medication use both before and after the index date in T1D cohort was mainly driven by an increased use of psycholeptics (mainly anxiolytics). Conclusions: Children with T1D were more likely to use psychiatric medication in the years before and after the onset of type 1 diabetes. This increased use was mainly driven by psycholeptics both before and after onset of T1D.

Antibiotic use in children and the use of medicines by parents

Background: The effect of guideline changes on trends of prescription drug use are commonly studied by age and over time period. This masks the birth cohort dimension which affects the age-specific trends in each time period. Objectives: We investigated whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the effect of a guideline change on the trend of benzodiazepine use. Methods: Outpatient pharmacy data from a drug prescription database in the Netherlands (IADB.nl) were used to obtain the age- (18-85) and sex -specific number of users of benzodiazepine (ATC: N05BA and N05CD) per 1,000 population (prevalence) per quarter year from 1998 to 2008. We studied the prevalence over time by age groups and by birth cohorts. Interrupted time series analyses were performed to the de-seasonalized trend to estimate the effect of the guideline change in 2001. Results: From 1998 to 2008 the overall age-standardized prevalence of benzodiazepine use per 1,000 population declined from ∼55 for males and ∼105 for females to ∼42 for males and ∼78 for females, this decline strengthened in 2001 for both sexes (significant slope change of p <0.05). Similar patterns over time, including slope changes (p <0.05), can be found within the majority of age categories, providing no additional information. Within birth cohorts the prevalence first increased over time but after 2001 this increase stopped or weakened (p <0.05), indicating a reduction in starters or less chronic use of benzodiazepine. Conclusions: Studying trends within birth cohorts can be a useful addition to time series analyses because the same or similar individuals are followed over time, making analysis more intuitive. This is not the case for trends within age-categories, potentially leading to less informed conclusions about guideline effects.Background: Epidemiological research has been criticized as being unreliable. Scientific evidence is strengthened when the study procedures of important findings are transparent, open for review, and easily reproduced by different investigators and in various settings. Studies often have common scientific workflows. The development of generalized execution engines, reusing epidemiological software/script program code for specific clinical questions, can serve as a valuable tool for transparent and reproducible research. Objectives: Learn about standards for transparent, reproducible and reusable research and how it is being applied in pharmacoepidemiolgy. Description: The focus of the symposium will be transparent, reproducible and reusable research. Principles of reproducible research in the context of the Medication History Estimator will be discussed. In addition, an overview of the IMI-PROTECT WP2: Framework for pharmacoepidemiologic studies and the Observational Medical Outcomes Partnership will be given. Outline: 1. Principles of reliability (Helga Gardarsdottir): Introduction to basic principles of transparent reproducible and reusable research. 2. Standardization (Huifang Liang): Standardization of data for drug utilization studies. A discussion of steps involved to convert the raw data into the readily usable data, including how to impute certain fields with examples. 3. Demonstration of the Medication History Estimator (MHE) and a description of the VINCI EpiTools (Brian Sauer). The MHE will be presented to demonstrate concepts of transparency, reproducibility and reuse. 4. The IMI-PROTECT project (Olaf Klungel & Robert Reynolds). Experiences with developing, testing and disseminating methodological standards for the design, conduct and analysis of database studies will be discussed. 5. Lessons from the Observational Medical Outcomes Partnership (Patrick Ryan, PhD). Standardized analytics tools developed by the OMOP community to characterize, visualize, and explore the effects of medical products within a distributed network of observational databases will be presented. 6. Closing summary/discussion. Chairs: Helga Gardarsdottir & Brian Sauer.Background: The Netherlands Pharmacovigilance Centre Lareb received six reports of hearing impairment in association with oral terbinafine use. This study describes these cases and provides support for this association from the Lareb database of spontaneous ADR reporting and from Vigibase, the adverse drug reaction database of the WHO UppsalaMonitoring Centre. Objectives: The objective of the study is to identify whether the observed association between oral terbinafine use and hearing impairment, based on several cases received by Lareb, supports a safety signal. Methods: Cases of hearing impairment in oral terbinafine users are described. In a case/non-case analysis, the strength of the association in Vigibase and the Lareb database was determined by calculating the reporting odds ratios (ROR), adjusted for possible confounding by age, sex and possibly ototoxic concomitant medication. RORs are calculated for deafness, hypoacusis, and the combination of both, defined as hearing impairment. Results: In the Lareb database, six reports concerning individuals aged 31-82 years, who developed hearing impairment after starting oral terbinafine, are present. The use of oral terbinafine is disproportionally associated with hypoacusis in both the Lareb database (adjusted ROR = 3.9, 95% CI: 1.7-9.0), and in Vigibase (adjusted ROR = 1.7, 95% CI: 1.0-2.8). Deafness is not disproportionally present in either of the databases. The pharmacological action of terbinafine is based on the inhibition of squalene epoxidase, an enzyme present in both fungal and human cells. This inhibition might result in decreased cholesterol levels in, among others, the outer hair cells of the cochlea, possibly leading to impaired cochlear function and hearing impairment. Conclusions: To our knowledge, hearing impairment associated with oral terbinafine use has not been described before. A causal relationship between the use of oral terbinafine and hearing impairment is possible, based on statistical analysis of reported cases in different databases and a possible pathophysiological explanation.Background: In observational studies of time-varying exposure and confounders, the use of propensity score (PS) is limited to assigning weights as in marginal structural models (MSMs). Stratification and conditioning on time-varying cofounders which are also intermediates can induce collider-stratification bias and adjust-away the (indirect) effect of exposure. Similar bias could be expected when one conditions on time-dependent PS. Objectives: We explored collider-stratification and confounding bias due to conditioning or stratifying on timedependent PS in a clinical example on the effect of inhaled short and long-acting beta2-agonist use (SABA and LABA, respectively) on coronary heart disease (CHD). Methods: A cohort of patients with an indication for SABA and/or LABA use was extracted from the Netherlands University Medical Center Utrecht General Practitioner Research Network. Information from 1995 to 2005 was used. SABA and LABA use and potential confounders were ascertained on 3 month intervals. Follow-up began the first day of diagnosis of bronchitis, asthma, or COPD and ended at the occurrence of CHD, death, unregistration with the GP, or end of the study, whichever occurred first. HR were estimated using PS stratification as well as covariate adjustment and compared with those of MSMs in both SABA and LABA separately. In MSMs, censoring was accounted for by including inverse probability of censoring weights. Results: The crude HR of CHD was 0.90 [95% CI: 0.63, 1.28] and 1.55 [95% CI: 1.06, 2.62] in SABA and LABA users respectively. When PS stratification, adjustment using PS, and MSMs were used, the HRs were 1.09 [95%CI: 0.74, 1.61], 1.07 [95% CI: 0.72, 1.60], and 0.86 [95% CI: 0.55, 1.34] for SABA, and 1.09 [95%CI: 0.74, 1.62], 1.13 [95%CI: 0.76, 1.67], 0.77 [95% CI: 0.45, 1.33] for LABA, respectively. Conclusions: Results were similar for different PS methods, but systematically higher than those of MSMs. When treatment and confounders vary during follow-up, conditioning or stratification on time-dependent PS may induce substantial collider-stratification or confounding bias. Hence, the use of methods such as MSMs is recommended.Background: Compared to RCTs, observational (nonrandomized) studies often comprise larger sample sizes, which gives adequate power to study interaction. Observational studies, however, are prone to confounding. Objectives: To determine the validity of subgroup and interaction effects (differences between subgroups) for different study designs. Methods: We compared effects of medical interventions based on observational studies, RCTs, and Individual Patient Data Meta-Analysis of RCTs (IPDMAs; reference) on three different clinical topics: (1) mammography screening effects on breast cancer mortality; (2) CABG and all-cause mortality; (3) statins and the incidence of major coronary events. Main, subgroup, and interaction effects were compared. Results: Main and subgroup effects were comparable with respect to the direction of effects for IPDMAs, RCTs, and observational studies. Small differences in the magnitude of subgroup effects in observational studies yielded different interactions compared to IPDMA. In the mammography example the Ratio of Risk Ratios (RRR) (i.e., interaction effect) among observational studies was 1.46 (95% CI 1.09;1.96) compared to an IPDMA effect of 110 (95% CI 0.89;1.37). For the CABG studies the observational RRR was 1.03 (95% CI 0.84;1.26), whereas in the IPDMA this was 1.40 (95% CI 1.08;11.81). Finally, in the statin example the RRR was 1.35 (95% CI 113;1.61) for observational studies, in the IPDMA this was 0.90 (95% CI 0.84;0.97). Conclusions: Main and subgroup effects based on observational data are in line with main and subgroup effects in IPDMAs based on RCTs, yet interactions may differ substantially.Background: Both antidepressants (AD) and benzodiazepines (BZD) have been associated with an increased risk for hip fracture. However, the hazard function is not constant over exposure time and differs for these two medication classes. Hence, the timing of initiation of co-use will determine the overall hazard function. Objectives: The aim of this study was to describe timing of BZD co-medication use among AD users. Methods: The study population included patients from the Netherlands Information Network of General Practice who initiated ADs between 2002 and 2009. AD-treatment episodes were constructed for each patient assuming the start of a new episode when 90 days elapsed between the theoretical end-date of a prior AD prescription (Rx) and the start-date of the next AD Rx. Within the first AD episode, three groups of BZD co-use were defined: “simultaneous” (simultaneous start of AD and BZD, no BZD during 182 days prior to start), “before” and “during” starters. These groups were described according to intensity of BZD use (number of Rxs), mono/polytherapy of AD and duration of AD episode. Results: The study population consisted of 16,617 AD users. The mean age was 50 years (SD = 18) and 63.2% were female. The median duration of the AD episode was 80 days (IQR = 259). Of 28.5% of patients used both AD and BZD. Of these, 57.2% started BZD before the AD, 19.0% were “simultaneous” starters and 23.8% started BZD during their first AD episode. In general, “simultaneous” starters were younger (mean = 45.3 vs. 56.4 years) yet had less intensity of BZD use (mean = 4.3 vs. 7.5 Rxs) compared to “before” starters. “After” starters were slightly older (mean = 48.0 vs. 45.3 years), had more AD polytherapy (20.2% vs. 14.9%) however less intensive BZD use (mean = 3.7 vs. 4.3 Rxs) compared to “simultaneous” starters. Conclusions: Timing of initiating BZD use in AD users is important, as each BZD co-use group is expected to have a different overall hazard function for hip fracture as opposed to when co-medication is defined as constant over time. To calculate accurate hazard function, it is important to take into consideration the timing of initiation of co-medication use in pharmacoepidemiological studies.Background: Pregnancy outcomes in women with preexisting diabetes are known to be worse than in the healthy population: rates of congenital malformations have been reported to be 2 to 10-fold higher. This is due to poor glycaemic control. Objectives: To determine rates of congenital malformations in babies of mothers with type1 (DM1) and type2 (DM2) diabetes and compare with the healthy population. Methods: Patients with pre-existing DM1 or DM2 during pregnancy were identified on the General Practice Research Database using diagnoses, prescribing, use of testing equipment and referral records. Mothers were matched to babies using registration records with the same family number, within 2 months of delivery date. Major congenital malformations were identified in the baby’s record and malformations verified with at least two related medical records; free text entries were checked. Results: Between January 1992 and March 2007 1,057 DM1 patients had 1,329 pregnancies and 365 DM2 patients had 441 pregnancies that resulted in a live birth. Eighty-four major malformations were found in 78 babies of DM1 mothers: 41 were cardiac, 11 were urogenital and eight were limb defects. Twenty-six major malformations were identified in 22 babies of DM2 mothers (seven cardiac defects). Overall, 5.9% of babies of DM1 mothers and 5.0% of babies of DM2 mothers had a malformation compared to 2–3% in the healthy population. The malformation rate for babies of DM2 mothers was comparable with another study (5.8%) but was lower for DM1 (8.2%). The proportion of cardiac malformations in babies of DM1 mothers was three times higher than in the healthy population. Conclusions: Babies whose mothers had DM1 or DM2 during pregnancy had double the rate of malformations. Pregnancy loss due to malformation has not been included but previous work found a greater proportion of terminations for medical reasons (1% in DM1, 1.8% in DM2) compared to healthy pregnancies (0.8%). Limitations include potentially differential recording of malformations between babies of mothers with DM1 and DM2 and the lack of records of glycaemic control. Differences in rates of malformations between treatments including analogue and human insulin will be evaluated next.

Could adverse reactions of antibiotic drugs in children be detected in a prescription database

To explore the possibility to detect adverse drug reactions (ADRs) from a pharmacy prescription database by examining the use of proxy‐drugs during the treatment.