Congenital clubfoot in Europe: A population-based study.

We aimed to assess prevalence, birth outcome, associated anomalies and prenatal diagnosis of congenital clubfoot in Europe using data from the EUROCAT network, and to validate the recording of congenital clubfoot as a major congenital anomaly by EUROCAT registries. Cases of congenital clubfoot were included from 18 EUROCAT registries covering more than 4.8 million births in 1995-2011. Cases without chromosomal anomalies born during 2005-2009, were randomly selected for validation using a questionnaire on diagnostic details and treatment. There was 5,458 congenital clubfoot cases of which 5,056 (93%) were liveborn infants. Total prevalence of congenital clubfoot was 1.13 per 1,000 births (95% CI 1.10-1.16). Prevalence of congenital clubfoot without chromosomal anomaly was 1.08 per 1,000 births (95% CI 1.05-1.11) and prevalence of isolated congenital clubfoot was 0.92 per 1,000 births (95% CI 0.90-0.95), both with decreasing trends over time and large variations in prevalence by registry. The majority of cases were isolated congenital clubfoot (82%) and 11% had associated major congenital anomalies. Prenatal detection rate of isolated congenital clubfoot was 22% and increased over time. Among 301 validated congenital clubfoot cases, diagnosis was confirmed for 286 (95%). In conclusion, this large population-based study found a decreasing trend of congenital clubfoot in Europe after 1999-2002, an increasing prenatal detection rate, and a high standard of coding of congenital clubfoot in EUROCAT.

Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study.

OBJECTIVES: To evaluate the risk of major congenital anomaly associated with first-trimester exposure to insulin analogues compared with human insulin in offspring of women with pregestational diabetes. DESIGN AND SETTING: A population-based cohort of women with pregestational diabetes (n=1661) who delivered between 1996 and 2012 was established retrospectively from seven European regions covered bythe European Surveillance of Congenital Anomalies (EUROCAT) congenital anomaly registries. PRIMARY OUTCOME MEASURES: The risk of non-chromosomal major congenital anomaly in live births, fetal deaths and terminations for a fetal anomaly exposed to insulin analogues in the first trimester of pregnancy was compared with the risk in those exposed to human insulin only. RESULTS: During the first trimester, 870 fetuses (52.4%) were exposed to human insulin only, 397 fetuses (23.9%) to insulin analogues only and 394 fetuses (23.7%) to both human insulin and insulin analogues. The risk of major congenital anomaly in fetuses exposed to insulin analogues only was lower than those exposed to human insulin only; the relative risk adjusted for glycaemic control and region was 0.56 (95% CI 0.29 to 1.06). The significantly lower risk related to exposure of insulin analogues only was observed in congenital heart defects: adjusted relative risk 0.14 (95% CI 0.03 to 0.62). CONCLUSIONS: In this retrospective population-based cohort study across Europe, first-trimester exposure to insulin analogues did not increase the risk of major congenital anomaly compared with exposure to human insulin. A possible lower risk of congenital heart defects among fetuses exposed to insulin analogues only deserves further investigation.

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

BACKGROUND: More 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. OBJECTIVES: We 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. METHODS: We 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. RESULTS: Topiramate 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. CONCLUSION: In 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.

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.

Lamotrigine use in pregnancy and risk of orofacial cleft and other congenital anomalies.

OBJECTIVE: To test previous signals of a risk of orofacial cleft (OC) and clubfoot with exposure to the antiepileptic lamotrigine, and to investigate risk of other congenital anomalies (CA). METHODS: This was a population-based case-malformed control study based on 21 EUROCAT CA registries covering 10.1 million births (1995-2011), including births to 2005 in which the clubfoot signal was generated and a subsequent independent study population of 6.3 million births. A total of 226,806 babies with CA included livebirths, stillbirths, and terminations of pregnancy following prenatal diagnosis. First-trimester lamotrigine monotherapy exposure in OC cases and clubfoot cases was compared to other nonchromosomal CA (controls). Odds ratios (OR) were adjusted for registry. An exploratory analysis compared the proportion of each standard EUROCAT CA subgroup among all babies with nonchromosomal CA exposed to lamotrigine monotherapy with non-AED exposed pregnancies. RESULTS: There were 147 lamotrigine monotherapy-exposed babies with nonchromosomal CA. For all OC, ORadj was 1.31 (95% confidence interval [CI] 0.73-2.33), isolated OC 1.45 (95% CI 0.80-2.63), isolated cleft palate 1.69 (95% CI 0.69-4.15). Overall ORadj for clubfoot was 1.83 (95% CI 1.01-3.31) and 1.43 (95% CI 0.66-3.08) in the independent study population. No other specific CA were significantly associated with lamotrigine monotherapy. CONCLUSIONS: The risk of OC was not significantly raised and we estimate the excess risk of OC to be less than 1 in every 550 exposed babies. We have not found strong independent evidence of a risk of clubfoot subsequent to our original signal. Our study cannot assess the general malformation risk among lamotrigine-exposed pregnancies.

EUROmediCAT signal detection: an evaluation of selected congenital anomaly-medication associations.

AIMS: To evaluate congenital anomaly (CA)-medication exposure associations produced by the new EUROmediCAT signal detection system and determine which require further investigation. METHODS: Data from 15 EUROCAT registries (1995-2011) with medication exposures at the chemical substance (5th level of Anatomic Therapeutic Chemical classification) and chemical subgroup (4th level) were analysed using a 50% false detection rate. After excluding antiepileptics, antidiabetics, antiasthmatics and SSRIs/psycholeptics already under investigation, 27 associations were evaluated. If evidence for a signal persisted after data validation, a literature review was conducted for prior evidence of human teratogenicity. RESULTS: Thirteen out of 27 CA-medication exposure signals, based on 389 exposed cases, passed data validation. There was some prior evidence in the literature to support six signals (gastroschisis and levonorgestrel/ethinylestradiol (OR 4.10, 95% CI 1.70-8.53; congenital heart disease/pulmonary valve stenosis and nucleoside/tide reverse transcriptase inhibitors (OR 5.01, 95% CI 1.99-14.20/OR 28.20, 95% CI 4.63-122.24); complete absence of a limb and pregnen (4) derivatives (OR 6.60, 95% CI 1.70-22.93); hypospadias and pregnadien derivatives (OR 1.40, 95% CI 1.10-1.76); hypospadias and synthetic ovulation stimulants (OR 1.89, 95% CI 1.28-2.70). Antipropulsives produced a signal for syndactyly while the literature revealed a signal for hypospadias. There was no prior evidence to support the remaining six signals involving the ordinary salt combinations, propulsives, bulk-forming laxatives, hydrazinophthalazine derivatives, gonadotropin releasing hormone analogues and selective serotonin agonists. CONCLUSION: Signals which strengthened prior evidence should be prioritized for further investigation, and independent evidence sought to confirm the remaining signals. Some chance associations are expected and confounding by indication is possible.

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.

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.

Actual Use of Medications Prescribed During Pregnancy: A Cross-Sectional Study Using Data from a Population-Based Congenital Anomaly Registry.

INTRODUCTION AND AIM: Data from prescription databases are increasingly being used to study associations between maternal medications used in pregnancy and congenital anomalies. We therefore investigated the extent to which prescriptions reflect the actual use of medication during pregnancy, and whether medicines used during pregnancy are taken according to the prescribed dosage and duration. METHODS: We performed a cross-sectional study in a population-based congenital anomaly register (EUROCAT Northern Netherlands). We included 202 women who had at least one prescription during their pregnancy and who gave birth between 2009 and 2011. Compliance with the prescribed medication was verified by telephone interview. We calculated the compliance rates for several medication groups by dividing the number of mothers who confirmed they had taken the medication by the total number to whom it had been prescribed. Compliance was positive if the mother confirmed she took the medication, even if she only took one of several prescriptions from the same medication group. For each prescription taken, we also determined whether her use conformed to the prescribed dosage and duration. RESULTS: During the first trimester, the compliance rates ranged from 0.84 (for chronic diseases) to 0.92 (for pregnancy-related symptoms). Most of the medications actually taken were used at the prescribed dosage or lower. More than half of the medications actually taken were used for the duration prescribed or shorter. CONCLUSION: Prescription records are generally a relatively reliable source of data for research into associations between medication use in pregnancy and congenital anomalies compared with other data sources. Pharmacy records of medication use in pregnancy might represent an overestimation, which should be taken into account. However, our results show that, except for 'corticosteroids, dermatological preparations'; 'ear, eye, nose and throat preparations'; and 'anxiolytics, hypnotics and sedatives', this overestimation generally seems minimal.

Use of antibiotics in rural and urban regions in The Netherlands: an observational drug utilization study.

BACKGROUND: Large livestock farms might increase the infection risk for the nearby human population because of an increased risk for disease outbreaks and because antibiotic-resistant bacteria are more likely to be present. We hypothesized that populations residing in rural areas have more contact with cattle compared with populations in urban areas, and will use more antibiotics or more frequently require a new course of antibiotics. METHODS: Using data from the prescription database IADB.nl, we compared antibiotic use by patients living in rural areas to the use by patients living in urban areas. We also followed cohorts of antibiotic users and determined the patients who required a second antibiotic within 14 days after beginning the first antibiotic. RESULTS: The yearly prevalence of antibiotic use was greater in rural areas compared with urban areas (2009: 23.6% versus 20.2% (p < 0.001), especially in the younger age groups. More adult patients residing in rural areas required a second course of antibiotic treatment within 14 days after starting the first treatment. CONCLUSION: Individuals use more antibiotics, and adults more frequently require a second antibiotic prescription within 14 days, in rural areas compared with urban areas. Although the differences were small and the risks for the general rural population were not high, this difference should be investigated further.

Maternal high-dose folic acid during pregnancy and asthma medication in the offspring.

PURPOSE: Low-dose folic acid supplementation (0.5 mg) taken during pregnancy has been associated with an increased risk for childhood asthma. The effect of high-dose folic acid (5 mg) advised to women at risk for having a child with neural tube defect has not been assessed so far. Our aim was to investigate the effect of dispensed high-dose folic acid during pregnancy and asthma medication in the offspring. METHODS: We used data from the pregnancy database IADB.nl, which contains pharmacy-dispensing data of mothers and children from community pharmacies in the Netherlands from 1994 until 2011. The dispension of asthma medication in children exposed in utero to high-dose folic acid was compared with children who were not exposed to this high dose. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated. RESULTS: In 2.9% (N = 913) of the 39,602 pregnancies in the database, the mother was dispensed high-dose folic acid. Maternal high-dose folic acid was associated with an increased rate of asthma medication among children: recurrent asthma medication IRR = 1.14 (95%CI: 1.04-1.30) and recurrent inhaled corticosteroids IRR = 1.26 (95%CI: 1.07-1.47). Associations were clustered on the mother and adjusted for maternal age, maternal asthma medication, and dispension of benzodiazepines during pregnancy. CONCLUSION: Almost 3% of the children were prenatally exposed to high-dose folic acid. This study suggests that supplementation of high-dose folic acid during pregnancy might increase the risk of childhood asthma.

Teratogenic mechanisms associated with prenatal medication exposure.

Birth defects may originate through multiple mechanisms and may be caused by a variety of possible exposures, including medications in early pregnancy. In this review, we describe six principal teratogenic mechanisms suspected to be associated with medication use: folate antagonism, neural crest cell disruption, endocrine disruption, oxidative stress, vascular disruption, and specific receptor- or enzyme-mediated teratogenesis. Knowledge about these mechanisms, for some of which evidence is mainly derived from animal models, may not only be relevant for etiologic and post-marketing research, but may also have implications for prescribing behavior for women of reproductive age. Since combinations of seemingly unrelated medications may have effects through similar teratogenic mechanisms, the risk of birth defects may be strongly increased in multi-therapy.

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.

Drugs associated with teratogenic mechanisms. Part II: a literature review of the evidence on human risks.

STUDY QUESTION: What is the current state of knowledge on the human risks of drugs suspected to be associated with teratogenic mechanisms? SUMMARY ANSWER: Evidence for the presence or absence of human risks of birth defects is scarce or non-existent for the majority of drugs associated with teratogenic mechanisms. WHAT IS KNOWN ALREADY: Medical drugs suspected to be associated with teratogenic mechanisms are dispensed to a significant proportion of women in the first trimester of pregnancy. However, an overview of the current state of knowledge on the human teratogenic effects of these drugs is lacking. STUDY DESIGN, SIZE, DURATION: We performed an extensive literature review of studies in the English language which examined the associations between selected drugs and specific birth defects. The literature was identified from MEDLINE and EMBASE from database inception (January 1946 and January 1974, respectively) through December 2012 using 287 terms for the drugs of interest. We only included studies if they specified birth defect subtypes and, specifically for cohort studies, involved live born infants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of 14 406 potentially relevant articles, 556 full-text articles were assessed for eligibility and 250 met the inclusion criteria. The studies included were divided into four categories according to their design to increase the validity of our study. MAIN RESULTS AND THE ROLE OF CHANCE: Epidemiologic studies assessing teratogenic risks were identified for less than half of the drugs included in the review. A substantial variation in study design and data collection methods was observed. When the data collection method is of questionable validity, study quality may be affected considerably. For only 15 drugs of interest, birth defects were assessed in at least 1000 infants in cohort studies, and 13 of these were associated with one or more specific birth defects. The majority of associations observed in case-control studies are as yet unconfirmed. For most drugs and drug groups, however, the numbers of exposed infants studied were too small to draw any conclusions regarding their human teratogenic risks. LIMITATIONS, REASONS FOR CAUTION: The validity of our review is limited by the validity and reporting of the studies from which the data were extracted. Some relevant studies might have been missed owing to the exclusion of articles not in the English language and publication bias. WIDER IMPLICATIONS OF THE FINDINGS: It is a cause of concern that the drugs most often dispensed in the first trimester of pregnancy are not necessarily the drugs for which teratogenic risks have been studied. Future studies should focus on those drugs that are most commonly used during pregnancy and for which the teratogenic risks are unknown, such as iron preparations, serotonin receptor agonists or antagonists, drugs used in fertility treatment, dihydrofolate reductase inhibitors. STUDY FUNDING/COMPETING INTEREST(S): Marleen van Gelder was supported by the Netherlands Organisation for Scientific Research/NWO (grant no. 021.001.008). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Drugs associated with teratogenic mechanisms. Part I: dispensing rates among pregnant women in the Netherlands, 1998-2009.

STUDY QUESTION: What are the dispensing rates of drugs suspected to be associated with teratogenic mechanisms among pregnant Dutch women? SUMMARY ANSWER: In a substantial proportion of pregnancies in our study population at least one drug associated with a teratogenic mechanism was dispensed in the first trimester of pregnancy. WHAT IS KNOWN ALREADY: The main teratogenic mechanisms of medical drugs that may affect fetal development in the first trimester of pregnancy have been described previously. However, information on the dispensing rate of such drugs among women at all stages of pregnancy is lacking. STUDY DESIGN, SIZE, DURATION: To determine how often medications suspected to be associated with a teratogenic mechanism are used by pregnant women, we studied 32 016 pregnancies included in the IADB.nl database between 1998 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: We estimated dispensing rates of medical drugs suspected to be associated with teratogenic mechanisms in our study population. The IADB.nl database includes all pharmacy dispensings for an estimated population of 220 000 in 1994-1998 and c.500 000 since 1999. In addition, trends in first trimester dispensing rates over time and patterns of receiving multiple drugs associated with teratogenic mechanisms were evaluated. In addition, we determined the number of pregnancies in which multiple prescription drugs from one or more teratogenic categories were dispensed in the first trimester, and we evaluated the numbers of different medications dispensed that could be grouped within a specific teratogenic mechanism. MAIN RESULTS AND THE ROLE OF CHANCE: In 175 per 1000 pregnancies [95% confidence interval (CI), 171-179] at least one drug associated with a teratogenic mechanism was dispensed in the first trimester. The total dispensing rate was 236 per 1000 pregnancies (95% CI 232-241) in the 3 months before pregnancy and an increasing trend was seen in the second [214 per 1000 (95% CI 209-218)] and third [327 per 1000 (95% CI 322-332)] trimesters. The first trimester dispensing rates increased between 1998 and 2009 for selective serotonin-reuptake inhibitors (P < 0.001) and serotonin receptor agonists/antagonists (P < 0.001). In 71.8% of pregnancies in which drugs associated with teratogenic mechanisms were dispensed in the first trimester, women received drugs related to only one mechanism. Of the pregnancies in which drugs from multiple teratogenic categories were dispensed in the first trimester, 1148 (72.6%) women received drugs from 2 categories, 317 (20.0%) from three categories, 88 (5.6%) from 4 categories, 28 (1.8%) from 5 categories and 1 from 6 categories. Several women received multiple prescription medications grouped within a single teratogenic mechanism in the first trimester, ranging between 13.3% for cyclo-oxygenase inhibitors and 41.8% for serotonin receptor agonists/antagonists. LIMITATIONS, REASONS FOR CAUTION: We used a dispensing database, therefore actual use of the medication prescribed is unknown and non-compliance could have led to overestimation of exposure prevalences. WIDER IMPLICATIONS OF THE FINDINGS: Owing to the uncertainties concerning the safety of medication use during pregnancy, the results of this study stress the need for cautious prescription of medication associated with teratogenic mechanisms to women of reproductive age. This is further supported by our finding that women received multiple prescription medications grouped within a single teratogenic mechanism in the first trimester, which would theoretically increase strongly the risk of birth defects. STUDY FUNDING/COMPETING INTEREST(S): Marleen van Gelder was supported by the Netherlands Organisation for Scientific Research/NWO (grant no. 021.001.008). No competing interests are declared. TRIAL REGISTRATION NUMBER: N/A.

Antibiotics prescribed before, during and after pregnancy in the Netherlands: a drug utilization study.

PURPOSE: To describe the prescription of antibiotics before, during and after pregnancy, and the trends over a 16-year period in the Netherlands, and to determine whether they were prescribed according to national guidelines. METHODS: The IADB (http://iadb.nl) contains prescriptions dispensed by community pharmacies in the Netherlands. We extracted information on 18,873 pregnancies for 14,969 women between 1994 and 2009, focusing on antibiotics dispensed in the four trimesters before conception to two trimesters after birth (nine trimesters in total). We calculated trends in prescription rates during pregnancy and over time, and also compared the prescription of antibiotics in the Netherlands with safety category based on the Australian Drug Evaluation Committee. RESULTS: During pregnancy 20.8% of the women were prescribed at least one antibiotic. The 'beta-lactam antibacterials/penicillins' group and the specific antibiotic amoxicillin were most commonly prescribed in the nine trimesters covered. The prescription rate of the 'other antibacterials' group during pregnancy increased over the years, in contrast to that of the 'sulphonamides/trimethoprim' group, which decreased. In total, 2.0% of pregnancies were exposed to a 'potentially harmful' antibiotic and 0.8% to a 'harmful' antibiotic. Compared with the period before conception, 'safe' antibiotics were prescribed more often during pregnancy than the other groups. CONCLUSIONS: One in five women was prescribed at least one antibiotic during pregnancy in the Netherlands, which is comparable with rates in other European countries. Our results suggest that antibiotics appear to be prescribed to pregnant women generally in accordance with national recommendations.

Identifying associations between maternal medication use and birth defects using a case-population approach: an exploratory study on signal detection.

BACKGROUND: The effects of many drugs on the unborn child are unknown. In a case-population design, drug exposure of cases is compared with that of a source population; this kind of study can be useful for generating signals. OBJECTIVE: To see whether a comparison of drug use rates from the birth defect registry EUROCAT NNL (cases) with prescription rates from a population-based prescription database, the IADB (population), could be used to detect signals of teratogenic risk of drugs. METHODS: We defined 3,212 cases from the EUROCAT NNL database, a population-based birth defect registry in the Northern Netherlands and 29,223 population controls from the IADB, a prescription database with data from community pharmacies in the same geographical area, born between 1998 and 2008. We classified the malformations of the 3,212 cases into several malformation groups according to organ system (based on the International Classification of Diseases codes and the EUROCAT guidelines). If a child had multiple malformations in several organ systems (n = 253, 7.9 %), he/she was counted in all the categories represented. For several groups of malformations we calculated rate ratios (RR) and 95 % confidence intervals for drugs acting on the central nervous system and for drugs considered to be safe for use in pregnancy. The RRs were based on first-trimester drug use rates from the cases in the EUROCAT NNL database and prescription rates from the population controls in the IADB. RESULTS: For drugs acting on the central nervous system we found significantly increased RRs for the anti-epileptic drug valproic acid and for some selective serotonin reuptake inhibitors. For drugs considered to be safe only the anti-hypertensive methyldopa showed significantly increased RRs. CONCLUSION: We show that a case-population study is a suitable method for detecting signals of possible teratogenicity, provided that the teratogenic effects and the drugs under study are as specific as possible and the drugs are widely used.

The population-based prescription database IADB.nl: its development, usefulness in outcomes research and challenges.

Research databases with large numbers of prescriptions in observational settings can provide valuable information in addition to the initial randomized controlled trials. This paper reports on the development of prescription database IADB, formerly known as InterAction Database. IADB contains prescriptions from 54 community pharmacies in The Netherlands and covers a population of 500,000 people. Both the age distribution and the prevalence of drugs used are comparable to a large extent with the Dutch population. The representativeness of the population covered is examined by comparing population composition and drug use with data of the whole Dutch population. Enriching IADB with, among others, clinical parameters by linking to other databases is explored. A strong and unique aspect of IADB is the possibility to track patients over time, even when they receive their medication from different pharmacies. The authors conclude IADB is a useful tool for pharmacoepidemiological and pharmacoeconomic outcomes research.

Assessing the effect of a guideline change on drug use prevalence by including the birth cohort dimension: the case of benzodiazepines.

PURPOSE: The aim of this study was to investigate whether including the birth cohort dimension in time series analysis leads to a more accurate estimation of the (long-term) effect of a guideline change on the trend of benzodiazepine use. METHODS: We calculated age-specific (20-84 years) and sex-specific prevalence of benzodiazepine use per 1000 population per quarter year (1998 to 2008) using a prescription database set in the Netherlands. We studied the prevalence over time by age group and within birth cohorts through interrupted time series analyses to estimate the effect of the guideline change in 2001. RESULTS: From 1998 to 2008, the overall age-standardized prevalence of benzodiazepine use per 1000 population declined from ~54 for men and ~107 for women to ~45 for men and ~85 for women. The relative change increased significantly after 2001 for both sexes and for the majority of age groups. Within birth cohorts, the prevalence increased with age until the year 2001 and leveled thereafter. The age-period approach overall had worse model fit indicators than the within-cohort approach and predicted larger long-term effects than the within-cohort approach. The age-period projection estimated 36% decline in benzodiazepine use relative to 2008, whereas the birth-cohort projection estimated 8% decline. CONCLUSION: Explicitly following birth cohort trajectories led to models with better fit; the conventional approach estimated a stronger long-term guideline effect. This has important implications for professional practice.

Inhaled corticosteroids and the occurrence of oral candidiasis: a prescription sequence symmetry analysis.

OBJECTIVES: The primary aim of the study was to gain insight into the relative risk of clinically relevant oral candidiasis following inhaled corticosteroid (ICS) initiation over time. A secondary aim was to analyse the influence of patient characteristics and co-medication on the occurrence of this adverse effect. METHODS: Drug prescription data from 1994 to 2011 were retrieved from the IADB.nl database. To study the influence of ICS use on occurrence of oral candidiasis, a prescription symmetry analysis was used, including patients using medication for oral candidiasis up to 1 year before or after ICS initiation. The relative risk was calculated by dividing the number of patients receiving medication for oral candidiasis after ICS initiation by the number of patients receiving the same medication before ICS initiation. Sub-analyses were conducted to compare the relative risks at several time points after ICS initiation and to account for therapy persistence by only including chronic users of ICS. A multivariate logistic regression model was used to identify predictive factors. RESULTS: A total of 52,279 incident users of ICS therapy were identified, of which 1,081 received medication for oral candidiasis up to 1 year before or after ICS initiation. A total of 701 patients received medication for oral candidiasis after ICS initiation, while 361 received these medications in the reversed sequence, resulting in a sequence ratio (SR) of 1.94 (95 % CI 1.71-2.21). In the first 3 months after ICS initiation, the SR was 2.72 (95 % CI 2.19-3.38) and then decreased to 1.47 (95 % CI 1.11-1.95) 9-12 months after ICS initiation. Predictive factors were higher daily dose of ICS and concomitant use of oral corticosteroids. CONCLUSIONS: This study found a significant and clinically relevant increased number of patients receiving medication for oral candidiasis in the first year after therapy initiation with ICS. Relative risk is highest in the first 3 months, but remains increased up to at least 1 year after ICS initiation. This study stresses the need for patient education and inhalation instruction.