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.

EUROmediCAT signal detection: a systematic method for identifying potential teratogenic medication.

AIMS: Information about medication safety in pregnancy is inadequate. We aimed to develop a signal detection methodology to routinely identify unusual associations between medications and congenital anomalies using data collected by 15 European congenital anomaly registries. METHODS: EUROmediCAT database data for 14 950 malformed foetuses/babies with first trimester medication exposures in 1995-2011 were analyzed. The odds of a specific medication exposure (coded according to chemical substance or subgroup) for a specific anomaly were compared with the odds of that exposure for all other anomalies for 40 385 medication anomaly combinations in the data. Simes multiple testing procedure with a 50% false discovery rate (FDR) identified associations least likely to be due to chance and those associations with more than two cases with the exposure and the anomaly were selected for further investigation. The methodology was evaluated by considering the detection of well-known teratogens. RESULTS: The most common exposures were genitourinary system medications and sex hormones (35.2%), nervous system medications (28.0%) and anti-infectives for systemic use (25.7%). Fifty-two specific medication anomaly associations were identified. After discarding 10 overlapping and three protective associations, 39 associations were selected for further investigation. These associations included 16 which concerned well established teratogens, valproic acid (2) and maternal diabetes represented by use of insulin (14). CONCLUSIONS: Medication exposure data in the EUROmediCAT central database can be analyzed systematically to determine a manageable set of associations for validation and then testing in independent datasets. Detection of teratogens depends on frequency of exposure, level of risk and teratogenic specificity.

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.

An International Study of the Ability and Cost-Effectiveness of Advertising Methods to Facilitate Study Participant Self-Enrolment Into a Pilot Pharmacovigilance Study During Early Pregnancy.

BACKGROUND: Knowledge of the fetal effects of maternal medication use in pregnancy is often inadequate and current pregnancy pharmacovigilance (PV) surveillance methods have important limitations. Patient self-reporting may be able to mitigate some of these limitations, providing an adequately sized study sample can be recruited. OBJECTIVE: To compare the ability and cost-effectiveness of several direct-to-participant advertising methods for the recruitment of pregnant participants into a study of self-reported gestational exposures and pregnancy outcomes. METHODS: The Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) pregnancy study is a non-interventional, prospective pilot study of self-reported medication use and obstetric outcomes provided by a cohort of pregnant women that was conducted in Denmark, the Netherlands, Poland, and the United Kingdom. Direct-to-participant advertisements were provided via websites, emails, leaflets, television, and social media platforms. RESULTS: Over a 70-week recruitment period direct-to-participant advertisements engaged 43,234 individuals with the study website or telephone system; 4.78% (2065/43,234) of which were successfully enrolled and provided study data. Of these 90.4% (1867/2065) were recruited via paid advertising methods, 23.0% (475/2065) of whom were in the first trimester of pregnancy. The overall costs per active recruited participant were lowest for email (€23.24) and website (€24.41) advertisements and highest for leaflet (€83.14) and television (€100.89). Website adverts were substantially superior in their ability to recruit participants during their first trimester of pregnancy (317/668, 47.5%) in comparison with other advertising methods (P<.001). However, we identified international variations in both the cost-effectiveness of the various advertisement methods used and in their ability to recruit participants in early pregnancy. CONCLUSIONS: Recruitment of a pregnant cohort using direct-to-participant advertisement methods is feasible, but the total costs incurred are not insubstantial. Future research is needed to identify advertising strategies capable of recruiting large numbers of demographically representative pregnant women, preferentially in early pregnancy.

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.

The association of albuminuria and high-sensitivity C-reactive protein with the efficacy of HMG-coenzyme A reductase inhibitors for cardiovascular event prevention.

BACKGROUND: It is not clear which hypercholesterolemic patients benefit most from ß-hydroxy-ß-methylglutaryl coenzyme A reductase inhibitors with respect to the prevention of cardiovascular events. Early signs of atherosclerotic vascular damage may identify high-risk patients. DESIGN: We studied whether subjects with hypercholesterolemia will benefit more from starting statin treatment in the case of high albuminuria and/or high-sensitivity C-reactive protein (hsCRP). METHODS: Included were subjects who had hypercholesterolemia at baseline, a negative cardiovascular disease history and who were not treated with statins. In total, 2011 subjects were analysed, of whom 695 started with a statin during a follow-up of 7.0 ± 1.7 years. Adjusted hazard ratios (HRs) for cardiovascular events were calculated in subjects who started versus those who did not start a statin stratified for albuminuria less than or ≥ 15 mg/day and/or hsCRP less than or ≥ 3 mg/L. RESULTS: The start of a statin was associated with a beneficial effect on cardiovascular risk in subjects with high albuminuria (HR 0.38 (0.23-0.60)), while the effect of starting a statin was non-significant in subjects with low albuminuria (HR 0.74 (0.44-1.24), P for interaction < 0.05). The effect of starting a statin was similar in subgroups with high and low hsCRP (P for interaction 0.34). When combining albuminuria and hsCRP subgroups, the start of statin treatment was associated with a lower risk of cardiovascular events dependent on albuminuria and not on the hsCRP level. CONCLUSIONS: The start of statin treatment is associated with a significantly lower absolute as well as relative risk of cardiovascular events in subjects with hypercholesterolemia and elevated albuminuria, whereas these drugs had less effect in subjects with normal albuminuria.

The Association of H1N1 Pandemic Influenza with Congenital Anomaly Prevalence in Europe: An Ecological Time Series Study.

BACKGROUND: In the context of the European Surveillance of Congenital Anomalies (EUROCAT) surveillance response to the 2009 influenza pandemic, we sought to establish whether there was a detectable increase of congenital anomaly prevalence among pregnancies exposed to influenza seasons in general, and whether any increase was greater during the 2009 pandemic than during other seasons. METHODS: We performed an ecologic time series analysis based on 26,967 pregnancies with nonchromosomal congenital anomaly conceived from January 2007 to March 2011, reported by 15 EUROCAT registries. Analysis was performed for EUROCAT-defined anomaly subgroups, divided by whether there was a prior hypothesis of association with influenza. Influenza season exposure was based on World Health Organization data. Prevalence rate ratios were calculated comparing pregnancies exposed to influenza season during the congenital anomaly-specific critical period for embryo-fetal development to nonexposed pregnancies. RESULTS: There was no evidence for an increased overall prevalence of congenital anomalies among pregnancies exposed to influenza season. We detected an increased prevalence of ventricular septal defect and tricuspid atresia and stenosis during pandemic influenza season 2009, but not during 2007-2011 influenza seasons. For congenital anomalies, where there was no prior hypothesis, the prevalence of tetralogy of Fallot was strongly reduced during influenza seasons. CONCLUSIONS: Our data do not suggest an overall association of pandemic or seasonal influenza with congenital anomaly prevalence. One interpretation is that apparent influenza effects found in previous individual-based studies were confounded by or interacting with other risk factors. The associations of heart anomalies with pandemic influenza could be strain specific.

Antiepileptic drug prescribing before, during and after pregnancy: a study in seven European regions.

PURPOSE: The aim of this study was to explore antiepileptic drug (AED) prescribing before, during and after pregnancy as recorded in seven population-based electronic healthcare databases. METHODS: Databases in Denmark, Norway, the Netherlands, Italy (Emilia Romagna/Tuscany), Wales and the Clinical Practice Research Datalink, representing the rest of the UK, were accessed for the study. Women with a pregnancy starting and ending between 2004 and 2010, which ended in a delivery, were identified. AED prescriptions issued (UK) or dispensed (non-UK) at any time during pregnancy and the 6 months before and after pregnancy were identified in each of the databases. AED prescribing patterns were analysed, and the choice of AEDs and co-prescribing of folic acid were evaluated. RESULTS: In total, 978 957 women with 1 248 713 deliveries were identified. In all regions, AED prescribing declined during pregnancy and was lowest during the third trimester, before returning to pre-pregnancy levels by 6 months following delivery. For all deliveries, the prevalence of AED prescribing during pregnancy was 51 per 10 000 pregnancies (CI95 49-52%) and was lowest in the Netherlands (43/10 000; CI95 33-54%) and highest in Wales (60/10 000; CI95 54-66%). In Denmark, Norway and the two UK databases lamotrigine was the most commonly prescribed AED; whereas in the Italian and Dutch databases, carbamazepine, valproate and phenobarbital were most frequently prescribed. Few women prescribed with AEDs in the 3 months before pregnancy were co-prescribed with high-dose folic acid: ranging from 1.0% (CI95 0.3-1.8%) in Emilia Romagna to 33.5% (CI95 28.7-38.4%) in Wales. CONCLUSION: The country's differences in prescribing patterns may suggest different use, knowledge or interpretation of the scientific evidence base. The low co-prescribing of folic acid indicates that more needs to be done to better inform clinicians and women of childbearing age taking AEDs about the need to offer and receive complete preconception care.

Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study.

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

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.

Direct-to-Patient Research: Piloting a New Approach to Understanding Drug Safety During Pregnancy.

BACKGROUND: Little is known about the effects of human fetal exposure when a new drug is authorized unless it was specifically developed for use in pregnancy. Since many factors may contribute to adverse fetal effects, having comprehensive information about in utero exposures will enhance our ability to make correct determinations about causality. OBJECTIVE: The objective of the study was to assess the extent to which women, recruited without the intervention of health care professionals (HCPs), will provide information, suitable for research purposes, via the Internet or by phone on some potential risk factors in pregnancy. METHODS: To pilot direct-to-patient research for pharmacovigilance, we conducted a prospective, noninterventional study of medication use and lifestyle factors as part of the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium (PROTECT) Consortium. Consenting women who self-identified as pregnant and residing in the United Kingdom (UK), Denmark (DK), The Netherlands, or Poland were recruited and could then choose to provide data every 2 or 4 weeks via the Internet or a telephonic interactive voice response system (IVRS). Self-reported drug use was compared with pharmacy register data in DK and with electronic health records in the UK. RESULTS: Recruited women were on average older and more highly educated than the general population. Most respondents chose a frequency of every 4 weeks (56.99%, 1177/2065). Only 29.83% (464/1555) of women with due dates occurring during the study provided information on pregnancy outcome. For those responding by Internet, over 90.00% (1915/2065) reported using >1 pregnancy-related medication, 83.34% (1721/2065) reported using >1 other medicine, and 23.53% (486/2065) reported only over-the-counter medications, not counting herbals and dietary supplements. Some respondents (7.16%, 148/2065) reported that they chose not to take a prescribed medication (mostly medicines for pain or inflammation, and for depression) and 1.30% (27/2065) reported using medicines that had been prescribed to a friend or family member (oxycodone, paracetamol, and medications for acid-related problems). Relatively few respondents reported using fish oil (4.60%, 95/2065), other dietary supplements (1.88%, 39/2065), herbal products (7.07%, 146/2065), or homeopathic products (1.16%, 24/2065). Most medications for chronic conditions that were listed in the Danish prescription registry were also self-reported (83.3%, 145/174 agreement), with larger discrepancies for medications indicated for short-term use (54.0%, 153/283 agreement) and pregnancy-related medications (66.1%, 78/118). CONCLUSIONS: Self-reported information on medication use as well as other potential teratogenic factors can be collected via the Internet, although recruitment costs are not insubstantial and maintaining follow-up is challenging. Direct data collection from consumers adds detail, but clinical input may be needed to fully understand patients' medical histories and capture birth outcomes.

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.