Risk of Osteoarthritis in an Incident Cohort of People With Psoriatic Arthritis: A Population-based Cohort Study.

OBJECTIVE: To determine the risk of a diagnosis of osteoarthritis (OA) in patients with psoriatic arthritis (PsA) compared to patients with psoriasis and a general population cohort. METHODS: Incident PsA patients aged 18-89 years at diagnosis were identified from the United Kingdom Clinical Practice Research Datalink between 1998 and 2014. All patients with PsA were matched to 2 cohorts of patients, both at a 1:4 ratio. The first cohort included patients with psoriasis (and no PsA) and the second was a general population cohort (with no psoriasis or PsA). The baseline prevalence of OA was calculated for each study cohort. The incidence of OA was calculated, and adjusted relative risks (RRadj) were calculated using conditional Poisson regression. RESULTS: We identified 6783 incident PsA patients. The baseline prevalence of OA ranged from 22.1% (95% CI 21.1-23.1) in the PsA cohort to 12.6% (95% CI 12.2-13.0) and 11.0% (95% CI 10.6-11.3) in the psoriasis and general population cohorts, respectively. The incidence of OA was significantly higher in the PsA cohort compared to the psoriasis and general population cohorts after adjusting for BMI (RRadj 1.68, 95% CI 1.46-1.93, and RRadj 1.86, 95% CI 1.62-2.14, respectively). CONCLUSION: An increased risk of OA was observed in patients with PsA compared to patients with psoriasis alone and those in the general population. Further work is needed to determine whether this reflects a true increase in OA risk or misdiagnosed PsA, and the extent to which it can be explained by differences in the opportunity for OA diagnosis between cohorts.

Statins during pregnancy: a cohort study using the General Practice Research Database to investigate pregnancy loss.

PURPOSE: The aim of this study was to determine if there are any differences between the types of pregnancy loss experienced by women who have been prescribed a statin just before or early in pregnancy compared with those who have not. METHODS: A retrospective cohort study using the General Practice Research Database was carried out. Women aged 10-49 years at pregnancy start who received a prescription for a statin in the 3 months before and/or during the first trimester of pregnancy were matched to up to 10 pregnancies on age at start date, diabetes and hypertension status before pregnancy. Pregnancies occurring between 1/1/1992 and 31/3/2009 were included. Pregnancy losses were identified and categorised as spontaneous (including miscarriage), induced for medical, other or unknown reasons. Freetext was used to determine the type of loss where this was not clear from the coded medical records. RESULTS: Two hundred eighty-one pregnancies potentially exposed to statins were identified and matched to 2643 unexposed pregnancies. About 54.45% of pregnancies potentially exposed to a statin resulted in a delivery compared with 62.81% of those not exposed. 25.27% of all pregnancies potentially exposed to a statin resulted in a spontaneous loss compared with 20.81% in those not exposed. Using a time to event analysis with exposure as a time-dependent covariate gave an adjusted hazards ratio of 1.64 (95%CI 1.10 to 2.46) of spontaneous pregnancy loss in the statin exposed group. CONCLUSIONS: This study is the first to report the differences in types of pregnancy loss following the potential exposure to a statin just before or early in pregnancy. Copyright © 2017 John Wiley & Sons, Ltd.

Prescribing of Antidiabetic Medicines before, during and after Pregnancy: A Study in Seven European Regions.

AIM: To explore antidiabetic medicine prescribing to women before, during and after pregnancy in different regions of Europe. METHODS: A common protocol was implemented across seven databases in Denmark, Norway, The Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the rest of the UK. Women with a pregnancy starting and ending between 2004 and 2010, (Denmark, 2004-2009; Norway, 2005-2010; Emilia Romagna, 2008-2010), which ended in a live or stillbirth, were identified. Prescriptions for antidiabetic medicines issued (UK) or dispensed (non-UK) during pregnancy and/or the year before or year after pregnancy were identified. Prescribing patterns were compared across databases and over calendar time. RESULTS: 1,082,673 live/stillbirths were identified. Pregestational insulin prescribing during the year before pregnancy ranged from 0.27% (CI95 0.25-0.30) in Tuscany to 0.45% (CI95 0.43-0.47) in Norway, and increased between 2004 and 2009 in all countries. During pregnancy, insulin prescribing peaked during the third trimester and increased over time; third trimester prescribing was highest in Tuscany (2.2%) and lowest in Denmark (0.5%). Of those prescribed an insulin during pregnancy, between 50.5% in Denmark and 88.8% in the Netherlands received an insulin analogue alone or in combination with human insulin, this proportion increasing over time. Oral products were mainly metformin and prescribing was highest in the 3 months before pregnancy. Metformin use during pregnancy increased in some countries. CONCLUSION: Pregestational diabetes is increasing in many areas of Europe. There is considerable variation between and within countries in the choice of medication for treating pregestational diabetes in pregnancy, including choice of insulin analogues and oral antidiabetics, and very large variation in the treatment of gestational diabetes despite international guidelines.

Asthma medication prescribing before, during and after pregnancy: a study in seven European regions.

OBJECTIVES: To explore utilisation patterns of asthma medication before, during and after pregnancy as recorded in seven European population-based databases. DESIGN: A descriptive drug utilisation study. SETTING: 7 electronic healthcare databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna and Tuscany), Wales, and the Clinical Practice Research Datalink representing the rest of the UK. PARTICIPANTS: All women with a pregnancy ending in a delivery that started and ended between 2004 and 2010, who had been present in the database for the year before, throughout and the year following pregnancy. MAIN OUTCOME MEASURES: The percentage of deliveries where the woman received an asthma medicine prescription, based on prescriptions issued (UK) or dispensed (non-UK), during the year before, throughout or during the year following pregnancy. Asthma medicine prescribing patterns were described for 3-month time periods and the choice of asthma medicine and changes in prescribing over the study period were evaluated in each database. RESULTS: In total, 1,165,435 deliveries were identified. The prevalence of asthma medication prescribing during pregnancy was highest in the UK and Wales databases (9.4% (CI95 9.3% to 9.6%) and 9.4% (CI95 9.1% to 9.6%), respectively) and lowest in the Norwegian database (3.7% (CI95 3.7% to 3.8%)). In the year before pregnancy, the prevalence of asthma medication prescribing remained constant in all regions. Prescribing levels peaked during the second trimester of pregnancy and were at their lowest during the 3-month period following delivery. A decline was observed, in all regions except the UK, in the prescribing of long-acting ß-2-agonists during pregnancy. During the 7-year study period, there were only small changes in prescribing patterns. CONCLUSIONS: Differences were found in the prevalence of prescribing of asthma medications during and surrounding pregnancy in Europe. Inhaled ß-2 agonists and inhaled corticosteroids were, however, the most popular therapeutic regimens in all databases.

The incidence of childhood and adolescent seizures in the UK from 1999 to 2011: A retrospective cohort study using the Clinical Practice Research Datalink.

BACKGROUND: In postmarketing vaccine surveillance, adverse events observed in a vaccinated population are compared to the number expected based on a background incidence rate. The background rate should be accurate and obtained from a population comparable to the one vaccinated. Such rates are often not available. METHODS: The incidence rate of generalised convulsive, febrile and afebrile seizures was estimated in individuals born after 01-January-1998 and aged between 2 months and 15 years of age using the UK Clinical Practice Research Datalink (1999-2011). RESULTS: The study population consisted of 1532,992 individuals (4917,369 person years (PY) of follow up). A total of 28,917 generalised convulsive seizure events were identified during follow-up, the overall incidence rate was 5.88 per 1000PY. Age specific rates increased sharply from 4/1000PY at 2 months of age, peaked at 19/1000PY at 16 months and decreased until approximately 6 years of age at which point they became relatively stable at 2/1000PY. 67% of GCSs were categorised as febrile: 56% using Read codes, 11% using free text. Febrile seizures accounted for the age trend in GCS, with rates peaking at 16.1/1000PY at 16 months of age while afebrile seizure rates remained relatively stable across all ages (24 seizures per 1000PY). Analysis by first occurrence of febrile seizure showed a similar pattern, comparable to published studies on the incidence of seizures in childhood. DISCUSSION: The rates reported in this study could be used in the postmarketing surveillance of infant vaccines. However, given the variation across strata, and the potential underascertainment of seizure events presenting to A&E, care must be taken when interpreting and using these rates.

Safety of Fluticasone Propionate Prescribed for Asthma During Pregnancy: A UK Population-Based Cohort Study.

BACKGROUND: Asthma is commonly treated during pregnancy, yet data on the safety of asthma medicines used during pregnancy are sparse. OBJECTIVE: The objective of this study was to evaluate the safety of the inhaled corticosteroid (ICS) fluticasone propionate (FP), alone and in fixed-dose combination with salmeterol (FSC) in terms of the risk of all major congenital malformations (MCMs), compared with all other non-FP ICS. METHODS: Women with asthma who had a pregnancy between January 1, 2000, and December 31, 2010, were identified in the United Kingdom's Clinical Practice Research Datalink. Exposure to asthma medicines during the first trimester of pregnancy was based on issued prescriptions. The mothers' and infants' medical records were linked where possible, and pregnancy outcomes with an MCM diagnosed by age 1 year were identified based on medical codes in the mother's and infant's medical records, including those MCMs prenatally diagnosed that ended in an induced pregnancy termination. The absolute and relative risks of an MCM after different ICS exposures, stratified by the asthma treatment intensity level, were calculated. RESULTS: A total of 14,654 mother-infant pairs were identified, of which 6,174 received an ICS prescription during the first trimester, in addition to 13 first trimester ICS exposed pregnancies that ended in an induced termination after a prenatal MCM diagnosis. In total, 5,362 pregnancies were eligible for the primary analysis at age 1 year. The absolute risk of an MCM after any first trimester FP exposure was 2.4% (CI95 0.8-4.1) and 2.7% (CI95 1.8-3.6) for the "moderate" and "considerable/severe" asthma treatment intensity levels, respectively. The adjusted odds ratios when compared with non-FP ICS were 1.1 (CI95 0.5-2.3) and 1.2 (CI95 0.7-2.0) for the "moderate" and "considerable/severe" intensity levels; risks for any FP and for FSC did not differ substantially. CONCLUSION: No increase in the overall risk of MCMs was identified after first trimester FP exposure compared with non-FP ICS.

Beginning and duration of pregnancy in automated health care databases: review of estimation methods and validation results.

PURPOSE: To describe methods reported in the literature to estimate the beginning or duration of pregnancy in automated health care data, and to present results of validation exercises where available. METHODS: Papers reporting methods for determining the beginning or duration of pregnancy were identified based on Pubmed searches, by consulting investigators with expertise in the field and by reviewing conference abstracts and reference lists of relevant papers. From each paper or abstract, we extracted information to characterize the study population, data sources, and estimation algorithm. We then grouped these studies into categories reflecting their general methodological approach. RESULTS: Methods were classified into 5 categories: (i) methods that assign a uniform duration for all pregnancies, (ii) methods that assign pregnancy duration based on preterm-delivery or health care related codes, or codes for other pregnancy outcomes, (iii) methods based on the timing of prenatal care, (iv) methods based on birth weight, and (v) methods that combine elements from 2 and 3. Validation studies evaluating these methods used varied approaches, with results generally reporting on the mistiming of the start of pregnancy, incorrect estimation of the duration of pregnancy, or misclassification of drug exposure during pregnancy or early pregnancy. CONCLUSIONS: In the absence of accurate information on the beginning or duration of pregnancy, several methods of varying complexity are available to estimate them. Validation studies have been performed for many of them and can serve as a guide for method selection for a particular study.

Healthcare databases in Europe for studying medicine use and safety during pregnancy.

PURPOSE: The aim of this study was to describe a number of electronic healthcare databases in Europe in terms of the population covered, the source of the data captured and the availability of data on key variables required for evaluating medicine use and medicine safety during pregnancy. METHODS: A sample of electronic healthcare databases that captured pregnancies and prescription data was selected on the basis of contacts within the EUROCAT network. For each participating database, a database inventory was completed. RESULTS: Eight databases were included, and the total population covered was 25 million. All databases recorded live births, seven captured stillbirths and five had full data available on spontaneous pregnancy losses and induced terminations. In six databases, data were usually available to determine the date of the woman's last menstrual period, whereas in the remainder, algorithms were needed to establish a best estimate for at least some pregnancies. In seven databases, it was possible to use data recorded in the databases to identify pregnancies where the offspring had a congenital anomaly. Information on confounding variables was more commonly available in databases capturing data recorded by primary-care practitioners. All databases captured maternal co-prescribing and a measure of socioeconomic status. CONCLUSION: This study suggests that within Europe, electronic healthcare databases may be valuable sources of data for evaluating medicine use and safety during pregnancy. The suitability of a particular database, however, will depend on the research question, the type of medicine to be evaluated, the prevalence of its use and any adverse outcomes of interest. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

Colorectal cancer risk reduction following macrogol exposure: a cohort and nested case control study in the UK.

BACKGROUND AND AIMS: Animal studies have demonstrated macrogol laxatives may reduce colorectal cancer (CRC) risk. This study aimed to investigate the association between macrogol prescribing and CRC risk. METHODS: A case-control study nested within a cohort of laxative users was conducted using data from the UK General Practice Research Database. Six controls per case were identified and to account for the lead time of CRC, additional control sets were selected on the index date backdated by 1 to 5 years. Exposure to macrogols and covariate status before each of the backdated index dates was established. Conditional logistic regression was used to calculate the risk of CRC following macrogol prescribing adjusted for potential confounders. RESULTS: 4734 incident CRC cases were identified; 2722, 2195, 1789, 1481 and 1214 had received a laxative prescription before the index dates backdated by 1 to 5 years. A suggestion of a non-significant reduction in CRC risk associated with 'macrogol after other laxative' prescribing was observed when the index date was backdated by 1 and 2 years, ORadj = 0.87 (CI950.74-1.03) and ORadj = 0.80 (CI950.65-1.00) compared to non-macrogol laxative exposure. The odds ratios reduced further and were significant when backdated by 3, 4 and 5 years, ORadj = 0.68 (CI950.50-0.92), ORadj = 0.60 (CI950.40-0.90) and ORadj = 0.30 (CI950.14-0.64) respectively. This reduction in risk was not observed, however, for 'macrogol only' and 'macrogol before other laxative' exposure categories. CONCLUSIONS: In this study we observed a reduced CRC risk associated with macrogol prescribing after accounting for the lead time for CRC. Further studies are required to determine whether the association is causal and whether it can partly be explained by selective prescribing.

Asthma management in pregnancy.

BACKGROUND: Asthma is common during pregnancy, however research is limited regarding the extent and timing of changes in asthma management associated with pregnancy. OBJECTIVE: To determine the prevalence of asthma during pregnancy and identify changes in treatment and asthma exacerbation rates associated with pregnancy, while controlling for seasonal influences. METHODS: Pregnant women with asthma were identified from the UK General Practice Research Database between 2000 and 2008. For each woman asthma medication prescribed during the study period was identified; for each product combination the British Thoracic Society medication-defined asthma treatment step was identified. Asthma exacerbations were identified during pregnancy and in the corresponding 12 months prior. Analyses of changes in asthma treatment and exacerbation rates during pregnancy relative to the corresponding period 12 months prior, to control for seasonality, were stratified by trimester and asthma treatment intensity level. RESULTS: The prevalence of treated asthma in pregnancies resulting in a delivery was 8.3%. From 14,141 pregnancies, in 12,828 women with asthma, 68.4% received prescriptions for a short-acting ß2-agonist and 41.2% for inhaled corticosteroids; 76.5% were managed with asthma treatment Step 1 or 2. Poor persistence to inhaled corticosteroids, defined as a gap of up to 60 days between prescriptions, was common. In 45.0% of pregnancies, an increase in average treatment step was observed whereas in 25.6% the treatment step decreased. Treatment intensity remained the same in 29.5% of pregnancies. Exacerbations occurred in 4.8% of pregnancies compared to 5.9% in the same season the year before (p<0.001). CONCLUSION: Exacerbation rates during pregnancy were slightly lower than in the year before. However, treatment patterns and exacerbation rates in this study suggest asthma control during pregnancy is variable, and women may require close monitoring especially in those with evidence of poor control before pregnancy.

Comparing the General Practice Research Database and the UK Epilepsy and Pregnancy Register as tools for postmarketing teratogen surveillance: anticonvulsants and the risk of major congenital malformations.

BACKGROUND: Use of pregnancy registries is a common method of postmarketing surveillance of pregnancy outcomes to identify potential teratogens. However, with the increase in electronic capture of healthcare data for administrative, audit and research purposes, data generated during routine clinical practice might be used to address questions similar to those explored using pregnancy registries. OBJECTIVES: To establish how data from the UK General Practice Research Database (GPRD) compares with data from the UK Epilepsy and Pregnancy Register and to assess how it can contribute to postmarketing surveillance of pregnancy outcomes. METHODS: Pregnancy outcomes were identified from the GPRD for women aged 14-49 years with a diagnosis of epilepsy and supporting evidence. Outcomes with a major congenital malformation (MCM) were identified and the relative risks (RRs) of an MCM following a range of first-trimester antiepileptic drug (AED) exposures were calculated and compared with those reported by the UK Epilepsy and Pregnancy Register. In addition, we also evaluated whether the known association between valproate and spina bifida could be identified using data from the GPRD. The study period ran from 1 January 1990 until 31 December 2006. RESULTS: A total of 1766 live mother-baby pairs were identified, as well as 551 pregnancy terminations, 13 stillbirths and 1 neonatal death. Including those that resulted in a termination, there were 62 unique pregnancy outcomes with an MCM. An increased risk of spina bifida was identified using the GPRD following first-trimester monotherapy exposure to valproate when compared with those with no AED exposure (RR 8.02; 95% CI 1.5, 43.5). More generally, comparing the GPRD with the UK register, the GPRD ascertained a lower number of first-trimester AED exposures: monotherapy 711 versus 2468; polytherapy 156 versus 718. We reproduced the UK register results of an increased MCM risk following first-trimester polytherapy AED exposure compared with no AED exposure (RR 2.89; 95% CI 1.43, 5.84). Using the GPRD, we identified similar point estimates to the UK register following monotherapy and polytherapy exposures (4.1% vs 3.7% and 7.1% vs 6.0%, respectively) but we were unable to reproduce the level of statistical significance. For individual AEDs, the MCM rate following valproate exposure was 4.9% (11/225) in the GPRD compared with 6.2% (44/715) in the UK register. CONCLUSIONS: The GPRD has potential for the identification of malformations and of a teratogenic association. For epilepsy, the GPRD does, however, identify fewer exposed pregnancies than a pregnancy registry. Therefore, in many circumstances pregnancy registries are likely to remain preferable as a method of surveillance. The GPRD may be better suited to monitoring medicines used in the treatment of more prevalent conditions, such as depression, or for monitoring medicines that have been on the market for a long time and for which no registry has been set up.

Identifying major congenital malformations in the UK General Practice Research Database (GPRD): a study reporting on the sensitivity and added value of photocopied medical records and free text in the GPRD.

BACKGROUND: Postmarketing teratogen surveillance is essential and requires a data source that can reliably capture a wide range of congenital malformations. The UK General Practice Research Database (GPRD) may have the potential to be used for this kind of surveillance. OBJECTIVE: To assess the extent to which this database can be used to accurately identify major congenital malformations. METHODS: This study was carried out as part of a broader study to compare data on anticonvulsant use and safety in pregnancy between the GPRD and a pregnancy registry. The study period ran from 1 January 1990 until 31 December 2006. Mother-baby pairs where the mother had a record of epilepsy, seizure or convulsion were identified using the GPRD computerized medical records. Infants of mother-baby pairs who had a record of a major congenital malformation were identified. Full photocopied paper medical records were requested from the infant's general practitioner and where this was not possible any data entries consisting of uncoded comments, so-called 'free text', in the electronic GPRD record were requested from the database provider. This additional information was then reviewed in order to determine the extent to which the congenital malformation diagnoses identified via the computerized records could be confirmed or rejected and then classified as being major or minor. RESULTS: Within the study population of 3869 live mother-baby pairs, 188 potentially major congenital malformations were identified from the GPRD computerized record relating to 161 unique individuals. Using a combination of photocopied medical records and free text it was possible to verify 160 malformations (85.1%) as the malformation indicated by the computerized records; this ranged from 91.7% of those cases verified using photocopied medical records and 77.9% of cases verified using free text. Of the verified congenital malformations, using a combination of computerized data, photocopied medical records and free text, it was possible to classify 78.1% as being major and 15.0% as minor, and this percentage was found to be the same for those cases reviewed by photocopied records and those where free text was used. The proportions of malformations that could be verified and those that could be classified as major or minor were found to vary by malformation class. CONCLUSIONS: The GPRD can be used to ascertain a wide range of congenital malformations. In many cases, when a malformation is identified in the GPRD via the computerized medical records, the malformation is likely to exist. However, in this study a small proportion of identified cases had to be excluded because they had been coded incorrectly or diagnostically ruled out. Therefore, depending on the congenital malformation of interest, verification of such malformations using photocopied medical records or free text is generally recommended.

Data resources for investigating drug exposure during pregnancy and associated outcomes: the General Practice Research Database (GPRD) as an alternative to pregnancy registries.

Pregnancy registries are the most commonly used data resource for the post-marketing surveillance of drug teratogenicity. However, the limited sample size and potential selection bias in these registries has led us to investigate the potential of the UK General Practice Research Database (GPRD) as an alternative data source for monitoring drug safety during pregnancy. In addition, a literature review identified further observational data sources that monitor pregnancy outcomes for future evaluation. Initial feasibility studies focused on the ability of the GPRD to capture pregnancy outcomes for a range of drug class exposures, all of which are currently under investigation in pregnancy registries, during pregnancy. The comparator pregnancy registries were identified via a MEDLINE search, whilst eligible pregnancies, in which women received one or more prescriptions for the drug of interest during pregnancy, were identified in the GPRD using the mother-baby link. The number of pregnancy outcomes following exposure to medication for a range of conditions with varying prevalence, including depression, migraine, epilepsy, herpes simplex and HIV, captured by the two data sources were compared. For depression, a relatively prevalent condition, the GPRD recorded the same number of mean annual intrauterine exposures to fluoxetine as the pregnancy registry (118 exposures/year). Ascertainment of intrauterine exposure to drug treatments for less prevalent conditions was found to be higher for the pregnancy registries than the GPRD; for the older antiepileptic drugs (valproate and carbamazepine), the pregnancy registry recorded between four and five times as many mean annual exposures as the GPRD. Virtually no antiretroviral exposures (three) were identified during the time period of interest on the GPRD, compared with 3946 in the Antiretroviral Pregnancy Registry. Data from the GPRD meet established criteria for evaluating outcomes of pregnancy. For prevalent conditions, it has the potential to replace or work alongside standard pregnancy registries and the alternative data sources identified. Further studies are now needed to assess its ability to replicate known teratogenic associations.